CN103304552A - Substituted pyridine compound as well as application method and usage thereof - Google Patents
Substituted pyridine compound as well as application method and usage thereof Download PDFInfo
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- CN103304552A CN103304552A CN2013100775335A CN201310077533A CN103304552A CN 103304552 A CN103304552 A CN 103304552A CN 2013100775335 A CN2013100775335 A CN 2013100775335A CN 201310077533 A CN201310077533 A CN 201310077533A CN 103304552 A CN103304552 A CN 103304552A
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- alkylidene group
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- 0 CC(C)CC1C*CC1 Chemical compound CC(C)CC1C*CC1 0.000 description 10
- HEAMSNGDSHQYOW-VTSJMVTISA-N CC12OCCC1OC[C@@H]2O Chemical compound CC12OCCC1OC[C@@H]2O HEAMSNGDSHQYOW-VTSJMVTISA-N 0.000 description 1
- KEWTZVVXHPJANA-SCMQIHGUSA-N C[C@H](c(c(C)ccc1F)c1Cl)Oc1c(N)ncc(-c2c[n](C[C@H](C3)NCC3F)nc2)c1 Chemical compound C[C@H](c(c(C)ccc1F)c1Cl)Oc1c(N)ncc(-c2c[n](C[C@H](C3)NCC3F)nc2)c1 KEWTZVVXHPJANA-SCMQIHGUSA-N 0.000 description 1
- SCAOFDOJWMGIMB-VVAGSORKSA-N C[C@H](c(c(Cl)ccc1F)c1Cl)Oc1c(N)ncc(-c2c[n](C(CNCC3)[C@H]3O)nc2)c1 Chemical compound C[C@H](c(c(Cl)ccc1F)c1Cl)Oc1c(N)ncc(-c2c[n](C(CNCC3)[C@H]3O)nc2)c1 SCAOFDOJWMGIMB-VVAGSORKSA-N 0.000 description 1
- SCAOFDOJWMGIMB-SSKCKEOISA-N C[C@H](c(c(Cl)ccc1F)c1Cl)Oc1c(N)ncc(-c2c[n]([C@H](CNCC3)[C@@H]3O)nc2)c1 Chemical compound C[C@H](c(c(Cl)ccc1F)c1Cl)Oc1c(N)ncc(-c2c[n]([C@H](CNCC3)[C@@H]3O)nc2)c1 SCAOFDOJWMGIMB-SSKCKEOISA-N 0.000 description 1
- DWYHMABLMFCNRU-XSFKQQOJSA-N C[C@H](c1c(C)c(F)ccc1C)Oc1cc(-c2c[n](C3CN[C@H](CO)C3)nc2)cnc1N Chemical compound C[C@H](c1c(C)c(F)ccc1C)Oc1cc(-c2c[n](C3CN[C@H](CO)C3)nc2)cnc1N DWYHMABLMFCNRU-XSFKQQOJSA-N 0.000 description 1
Abstract
The invention provides a substituted pyridine compound with a structure as shown in a formula (I), as well as a pharmaceutically acceptable salt and a pharmaceutical preparation thereof. The substituted pyridine compound is used for regulating the activity of protein kinase and regulating signal response between cells or in the cells. The invention further relates to a pharmaceutical composition comprising the compound provided by the invention and a method of utilizing the pharmaceutical composition to treat mammal and especially human high hyperplastic diseases.
Description
The application requires to submit on 03 09th, 2012 that Patent Office of the People's Republic of China, application number are 201210061335.5, denomination of invention submits for the Chinese patent application of " pyridine compounds of replacement and using method thereof and purposes " with on 03 21st, 2012 that Patent Office of the People's Republic of China, application number are 201210076143.1 to, denomination of invention is the right of priority of the Chinese patent application of " the spiral shell dicyclo of replacement and fused bicyclic compound and using method and purposes ", and its full content is by reference in conjunction with in this application.
Technical field
The invention belongs to technical field of pharmaceuticals, relate in particular to a kind of pyridine compounds and using method and purposes of replacement.
Background technology
One of member that protein kinase as the important conditioning agent of cell function, is quantity maximum in the gene family, function is the widest.They regulate activity, position and the allomeric function of multiple protein by substrate protein is increased phosphate group, and participate in the many cell processes of layout.Kinases in the cooperation of signal conduction and sophisticated functions, as: the cell cycle, occupy the position of giving prominence to very much.In 518 kinds of human kinase proteins, have 478 kinds because the catalytic domain sequence is close, be included into a superfamily, according to the similarity and the biochemical activity that increase sequence, they can be divided into different groups, family or subfamily again.
Wherein said kinases is partly tabulated and is comprised 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 one type of abundant transmembrane protein, can be used as the acceptor of cytokine, somatomedin, hormone and other signaling molecules.Receptor tyrosine kinase is expressed in polytype cell, plays an important role in various cell processes, comprises cell growth, differentiation and vasculogenesis.Kinase whose activation starts from the extracellular region territory and is combined with part, causes conformational change to cause receptor dimerizationization mutual phosphorylation between the acceptor of dimerization, the outer tyrosine residues of autophosphorylation catalysis region subsequently then.This autophosphorylation can the stable activation acceptor conformation, set up phosphorylation in again can the albumen of signal conduction in cell and pile up point.
By the receptor activation sudden change, gene amplifies, approach such as growth factor activation, and receptor tyrosine kinase shows as high reactivity in many human entity knurls and malignant hematologic disease.The acceleration of PTKs activates has promoter action to various tumorigenesis factors, as hyperplasia, survival, intrusion, transfer and vasculogenesis, therefore, the activity that suppresses receptor tyrosine kinase is considered to effective scheme (Sharma PS, et al. (2009) " Receptor tyrosine kinase inhibitors as potent weapons in war against cancers. " the Curr Pharm Des.15 (7): 758-76.) of cancer therapy.
Receptor tyrosine kinase Nucleophosmin-anaplastic lymphoma kinase (ALK) belongs to the insulin receptor superfamily, and is relevant with the generation of multiple human tumor.In fact, confirm that tentatively ALK exists with the form that constitutively activate and oncogene merge, to be present in (NPM)-ALK-the most common (Morris, the S.W. in the primary cutaneous type (the lymphadenomatous a kind of independent type of Fei Huojinsen); Et al " Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. " Science1994,263:1281 – 4.).
In addition, people have also found the ALK fusion gene in struvite myofibroblastoma (IMTs), and in the subspecies of esophageal squamous cell carcinoma, have also found ALK fusion gene---TPM4-ALK.Studies show that, in familial form and the diversity neuroblastoma, all have the sudden change of multiple ALK gene.This sudden change that is present in the neuroblastoma cell can cause composing type ALK phosphorylation and hypofunction.Opposite, use sRNA and small molecules ALK inhibitor can suppress quick growth (Palmer, the R.H. of cell strain; 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 part echinoderms microtubule-associated protein sample 4(EML4) the multiple hypotype of the fusion gene of gene and ALK genomic constitution.The NSCLC patient of nearly 3-7% is detected EML4-ALK fusion gene transcript.Confirm that with external test EML4-ALK fusion gene albumen has the oncogenic transformation activity in the body, the mankind are suffered from NSCLC material impact (Soda, M; 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 tangible carinogenicity, and its unusual tyrosine kinase activity can be strengthened cell proliferation and survival, causes cytoskeleton to be reset, and cell shape is changed.In the carcinogenic ALK signal transduction process, ALK and downstream molecules interact, signal path in the activating cells then, the same with most of normal and carcinogenic Tyrosylprotein kinases, the ALK fusion gene can activate multiple different path, these paths closely link to each other, and overlap, and form the signal transduction network of a complexity at last.According to the literature, the most relevant, and research comparatively clearly path have three: the path Ras-ERK(extracellular signal-regulated kinase), JAK3(Janus kinases 3)-STAT3 path and PI3K(phosphatidyl-inositol 3-kinase)-the Akt path.Many sites in these three paths can mediate the activation of ALK.In a word, JAK3-STAT3 path and PI3K-Akt path play crucial effects (Nat Rev Cancer.2008,8:11 – 23 to cell survival and phenotypic alternation; Barreca, A.; Et al " Anaplastic lymphoma kinase (ALK) in human cancer. " JMolEndocrinol.2011,47:R11 – 23.).
It is related that complete, normal ALK acceptor and the generation of other malignancy diseases also exist, such as, glioblastoma multiforme, neuroblastoma, breast cancer, etc.In the collection investigation of a human cancer cell strain, people such as Dirks confirm, in nervous system cell strain and most of ectoderm entity cancer cell strain, there is the expression of ALK transcript, these cell strains comprise retinoblastoma, melanoma and breast cancer (Dirks, P.B., Nature Medicine2008,14,373 – 375.).
C-Met, i.e. hepatocyte growth factor receptor (HGFR), its significant feature point is at endotheliocyte, and has confirmed it at endotheliocyte, myogenous cells all has expression in hematopoietic cell and the motor neuron.The natural part of c-Met is pHGF (HGF), and it is a multi-functional somatomedin, i.e. dispersion factor (SF).In fetus and adult, activate the formation that c-Met can promote some form, for example, invasive growth will cause the quick growth of cell, intercellular division and cell move (" From Tpr-Met to Met, tumorigenesis and tubes. " Oncogene2007 on every side to it, 26,1276; " Met Receptor Tyrosine Kinase as a Therapeutic Anticancer Target. " Cancer Letter, 2009,280,1-14).
Extensively the human malignancies that exists exists lasting c-Met to stimulate, cross and express or variation, comprises mammary cancer, liver cancer, lung cancer, ovarian cancer, kidney, thyroid carcinoma, colorectal carcinoma, glioblastoma, prostate cancer etc.C-Met involves atherosclerosis and pulmonary fibrosis equally.By the interaction of mesenchyma stroma of tumors, comprise the HGF/c-Met approach, the invasive growth speed of these cancer cells has thoroughly been improved.Therefore, a large amount of evidences show that the c-Me signal response is relevant with certain cancers advancing of disease speed, and improved its with c-Met be role status (" Molecular cancer therapy:can our expectation be MET. " Euro.J.Cancer in the cancer drug exploitation of main target spot, 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 to be used for treating cancer.Ke Zhuo is the competitive ALK inhibitor of a kind of small molecules ATP for Buddhist nun (Crizotinib), simultaneously, also can act on the c-Met receptor tyrosine kinase.On August 26th, 2008, drugs approved by FDA gram tall and erect for the Buddhist nun (Pfizer ' s Xalkori, originally known as PF-02341066) is used for the treatment of local late period or metastatic, has the nonsmall-cell lung cancer of Nucleophosmin-anaplastic lymphoma kinase (ALK) gene rearrangement.ALK(EML4-ALK) rearrangement of gene causes cell mutation, has promoted the malignant phenotype of lung carcinoma cell.Therefore, the kinases ALK of mutation inhibiting is effective for the treatment cancer.
Summary of the invention
In view of this, the invention provides a kind of pyridine compounds of new replacement, this compound is inhibited to protein tyrosine kinase, can be for the preparation of the medicine for the treatment of cell proliferation disorders.
Compound of the present invention has restraining effect to protein tyrosine kinase activity, more satisfactory is, compound of the present invention can suppress to comprise the ALK fusion gene as ALK(, as: EML4-ALK, or c-Met acceptor (hepatocyte growth factor receptor) signal response NPM-ALK etc.).Correspondingly, the present invention also provides the inhibitor of some new protein tyrosine kinase receptor signal responses, as the response of ALK receptor signal, or the response of c-Met receptor signal.
Especially, compound involved in the present invention, and pharmaceutically acceptable composition can be effective as tyrosine kinase receptor, as the inhibitor of ALK or c-Met.
On the one hand, the present invention relates to a kind of suc as formula the compound shown in (I):
Or its steric isomer, geometrical isomer, tautomer, oxynitride, solvate, meta-bolites, pharmacy acceptable salt or its prodrug, wherein, R
1, R
2, R
3, R
4, R
5, R
6Has implication as described in the present invention with Z.
In some embodiments, each R
1, R
2, R
3, R
4, R
5And R
6Be H independently, D or F;
Z is
(1) (C
3-C
7) heterocyclic radical, and by 1,2,3,4 or 5 independently are selected from D, F, Cl, Br, I, N
3, (C
1-C
6) alkyl, (C
1-C
6) haloalkyl ,-CN ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
4) alkylidene group-CN ,-(C
1-C
4) alkylidene group-OH ,-(C
1-C
4) alkylidene group-OR
aOr-(C
1-C
4) alkylidene group-NR
bR
cSubstituting group replace;
When the ring members of heterocyclic radical comprise-N (H)-time ,-N (H)-in hydrogen atom can not be substituted;
Work as R
1, R
2, R
3, R
4, R
5And R
6Be H, when Z was mono-substituted piperidyl, the 4-position on the piperidine ring can not be replaced by D;
(2)-(C
1-C
4) alkylidene group-(C
3-C
7) heterocyclic radical, and by 1,2,3,4 or 5 independently are selected from D, F, Cl, Br, I, N
3, (C
1-C
6) haloalkyl ,-CN ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
4) alkylidene group-OH ,-(C
1-C
4) alkylidene group-OR
aOr-(C
1-C
4) alkylidene group-NR
bR
cSubstituting group replace;
-(C
1-C
4) alkylidene group-(C
3-C
7) in the heterocyclic radical heterocyclic radical can not by-OH is single to be replaced;
(3) (C
5-C
12) the condensed-bicyclic base, and randomly by 1,2,3,4 or 5 independently are selected from D, F, Cl, Br, I, N
3, (C
1-C
6) alkyl, (C
1-C
6) haloalkyl ,-CN ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
4) alkylidene group-CN ,-(C
1-C
4) alkylidene group-OH ,-(C
1-C
4) alkylidene group-OR
aOr-(C
1-C
4) alkylidene group-NR
bR
cSubstituting group replace, and the ring in the bicyclic system can be carbocyclic ring or heterocycle; Or
(4)-(C
1-C
4) alkylidene group-(C
5-C
12) the condensed-bicyclic base, and randomly by 1,2,3,4 or 5 independently are selected from D, F, Cl, Br, I, N
3, (C
1-C
6) alkyl, (C
1-C
6) haloalkyl ,-CN ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
4) alkylidene group-CN ,-(C
1-C
4) alkylidene group-OH ,-(C
1-C
4) alkylidene group-OR
aOr-(C
1-C
4) alkylidene group-NR
bR
cSubstituting group replace, and the ring in the bicyclic system can be carbocyclic ring or heterocycle;
Wherein, R
aBe (C
1-C
6) alkyl, (C
1-C
6) thiazolinyl, (C
1-C
6) alkynyl, (C
3-C
6) cycloalkyl, (C
3-C
6) heterocyclic radical, (C
6-C
10) aryl, (C
1-C
9) heteroaryl ,-(C
1-C
4) alkylidene group-(C
3-C
6) cycloalkyl ,-(C
1-C
4) alkylidene group-(C
3-C
6) heterocyclic radical ,-(C
1-C
4) alkylidene group-(C
6-C
10) aryl or-(C
1-C
4) alkylidene group-(C
1-C
9) heteroaryl, described each (C
1-C
6) alkyl, (C
1-C
6) thiazolinyl, (C
1-C
6) alkynyl, (C
3-C
6) cycloalkyl, (C
3-C
6) heterocyclic radical, (C
6-C
10) aryl, (C
1-C
9) heteroaryl ,-(C
1-C
4) alkylidene group-(C
3-C
6) cycloalkyl ,-(C
1-C
4) alkylidene group-(C
3-C
6) heterocyclic radical ,-(C
1-C
4) alkylidene group-(C
6-C
10) aryl and-(C
1-C
4) alkylidene group-(C
1-C
9) heteroaryl is randomly by 1,2,3 or 4 independently are selected from D, F, Cl, N
3,-CN ,-OH ,-NH
2, the substituting group of alkoxyl group or alkylamino replaces;
R
bAnd R
cBe H independently, (C
1-C
6) alkyl, (C
3-C
6) cycloalkyl, (C
3-C
6) heterocyclic radical, (C
6-C
10) aryl, (C
1-C
9) heteroaryl ,-(C
1-C
4) alkylidene group-(C
3-C
6) cycloalkyl ,-(C
1-C
4) alkylidene group-(C
3-C
6) heterocyclic radical ,-(C
1-C
4) alkylidene group-(C
6-C
10) aryl or-(C
1-C
4) alkylidene group-(C
1-C
9) heteroaryl; Described each (C
1-C
6) alkyl, (C
3-C
6) cycloalkyl, (C
3-C
6) heterocyclic radical, (C
6-C
10) aryl, (C
1-C
9) heteroaryl ,-(C
1-C
4) alkylidene group-(C
3-C
6) cycloalkyl ,-(C
1-C
4) alkylidene group-(C
3-C
6) heterocyclic radical ,-(C
1-C
4) alkylidene group-(C
6-C
10) aryl and-(C
1-C
4) alkylidene group-(C
1-C
9) heteroaryl is randomly by 1,2,3, or 4 independently are selected from D, F, Cl, N
3,-CN ,-OH ,-NH
2, the substituting group of alkoxyl group or alkylamino replaces; Work as R
bAnd R
cWhen linking to each other with same nitrogen-atoms, R
b, R
cWith the nitrogen-atoms that links to each other with them, can also randomly form (C
3-C
6) heterocyclic radical.
In the other embodiment, R
1, R
2, R
3, R
4, R
5And R
6Be H or D independently.
In the other embodiment, Z is:
(1) (C
3-C
7) heterocyclic radical, and by 1,2,3,4 or 5 independently are selected from D, F, N
3, (C
1-C
3) alkyl, (C
1-C
3) haloalkyl ,-CN ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
3) alkylidene group-CN ,-(C
1-C
3) alkylidene group-OH ,-(C
1-C
3) alkylidene group-OR
aOr-(C
1-C
3) alkylidene group-NR
bR
cSubstituting group replace;
(2)-(C
1-C
4) alkylidene group-(C
3-C
7) heterocyclic radical, and by 1,2,3,4 or 5 independently are selected from D, F, N
3, (C
1-C
3) haloalkyl ,-CN ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
3) alkylidene group-OH ,-(C
1-C
3) alkylidene group-OR
aOr-(C
1-C
3) alkylidene group-NR
bR
cSubstituting group replace;
(3) (C
5-C
12) the condensed-bicyclic base, and randomly by 1,2,3,4 or 5 independently are selected from D, F, Cl, Br, I, N
3, (C
1-C
3) alkyl, (C
1-C
3) haloalkyl ,-CN ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
3) alkylidene group-CN ,-(C
1-C
3) alkylidene group-OH ,-(C
1-C
3) alkylidene group-OR
aOr-(C
1-C
3) alkylidene group-NR
bR
cSubstituting group replace, and the ring in the bicyclic system can be carbocyclic ring or heterocycle; Or
(4)-(C
1-C
4) alkylidene group-(C
5-C
12) the condensed-bicyclic base, and randomly by 1,2,3,4 or 5 independently are selected from D, F, Cl, Br, I, N
3, (C
1-C
3) alkyl, (C
1-C
3) haloalkyl ,-CN ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
3) alkylidene group-CN ,-(C
1-C
3) alkylidene group-OH ,-(C
1-C
3) alkylidene group-OR
aOr-(C
1-C
3) alkylidene group-NR
bR
cSubstituting group replace, and the ring in the bicyclic system can be carbocyclic ring or heterocycle.
In the other embodiment, R
aBe (C
1-C
3) alkyl, (C
1-C
3) thiazolinyl, (C
1-C
6) alkynyl, (C
3-C
6) cycloalkyl or-(C
1-C
3) alkylidene group-(C
3-C
6) cycloalkyl, described each (C
1-C
3) alkyl, (C
1-C
3) thiazolinyl, (C
1-C
6) alkynyl, (C
3-C
6) cycloalkyl and-(C
1-C
3) alkylidene group-(C
3-C
6) cycloalkyl is randomly by 1,2,3 or 4 substituting groups that independently are selected from D or F replace.
In the other embodiment, R
bAnd R
cBe H independently, (C
1-C
3) alkyl, (C
3-C
6) cycloalkyl or-(C
1-C
4) alkylidene group-(C
3-C
6) alkyl; Described each (C
1-C
3) alkyl, (C
3-C
6) cycloalkyl and-(C
1-C
4) alkylidene group-(C
3-C
6) alkyl is randomly by 1,2,3 or 4 substituting groups that independently are selected from D or F replace; Work as R
bAnd R
cWhen linking to each other with same nitrogen-atoms, R
b, R
cWith the nitrogen-atoms that links to each other with them, can also randomly form (C
3-C
6) heterocyclic radical.
In the other embodiment, Z is selected from any one in the minor structure shown in the formula (a)～(k):
Or its steric isomer, wherein:
N is 0,1,2 or 3;
Each X and X' be-O-or-N (H)-;
Minor structure shown in the formula (a)～(k) or its steric isomer are independently by 1,2, and 3,4 or 5 independently are selected from D, F, (C
1-C
3) haloalkyl ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
3) alkylidene group-OH ,-(C
1-C
3) alkylidene group-OR
aOr-(C
1-C
3) alkylidene group-NR
bR
cSubstituting group replace;
When n is 1,2 or 3 o'clock, above-mentioned each minor structure or its steric isomer can not by-OH is single to be replaced;
When each X and X' be independently-N (H)-time ,-N (H)-in hydrogen atom can not be substituted;
Work as R
1, R
2, R
3, R
4, R
5And R
6Be H, when Z was mono-substituted piperidyl, the 4-position of piperidine ring can not be replaced by D.
In the other embodiment, Z is selected from any one in the minor structure shown in the formula (l)～(x):
Or its steric isomer, wherein:
N is 0,1,2 or 3;
Each W and W' be-O-,-N (H)-or-N (C
1-C
3) alkyl-;
Minor structure shown in the formula (l)～(x) or its steric isomer are randomly by 1,2, and 3,4 or 5 independently are selected from D, F, (C
1-C
3) alkyl, (C
1-C
3) haloalkyl ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
3) alkylidene group-OH ,-(C
1-C
3) alkylidene group-ORa or-(C
1-C
3) alkylidene group-NR
bR
cSubstituting group replace.
In the other embodiment, Z is selected from any one in the minor structure shown in formula (101)～(111):
Or its steric isomer, wherein:
Minor structure shown in formula (101)～(111) or its steric isomer are independently by 1,2, and 3,4 or 5 independently are selected from D, F, (C
1-C
3) haloalkyl ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
3) alkylidene group-OH ,-(C
1-C
3) alkylidene group-OR
aOr-(C
1-C
3) alkylidene group-NR
bR
cSubstituting group replace.
In the other embodiment, Z is selected from any one in the minor structure shown in formula (201)～(214):
Or its steric isomer, wherein:
Minor structure shown in formula (201)～(214) or its steric isomer are independently by 1,2, and 3,4 or 5 independently are selected from D, F, (C
1-C
3) haloalkyl ,-OR
a,-NR
bR
c,-(C
1-C
3) alkylidene group-OH ,-(C
1-C
3) alkylidene group-OR
aOr-(C
1-C
3) alkylidene group-NR
bR
cSubstituting group replace.
In the other embodiment, Z is selected from any one in the minor structure shown in formula (301)～(323):
Or its steric isomer, wherein:
Minor structure shown in formula (301)～(323) or its steric isomer are randomly by 1,2, and 3,4 or 5 independently are selected from D, F, (C
1-C
3) alkyl, (C
1-C
3) haloalkyl ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
3) alkylidene group-OH ,-(C
1-C
3) alkylidene group-OR
aOr-(C
1-C
3) alkylidene group-NR
bR
cSubstituting group replace.
In the other embodiment, R
aBe (C
1-C
2) alkyl, and randomly by 1,2,3 or 4 substituting groups that independently are selected from D or F replace.
In the other embodiment, R
bAnd R
cBe H or (C independently
1-C
2) alkyl; Described (C
1-C
2) alkyl and (C
3-C
6) heterocyclic radical is randomly by 1,2,3 or 4 substituting groups that independently are selected from D or F replace; Work as R
bAnd R
cWhen linking to each other with same nitrogen-atoms, R
b, R
cWith the nitrogen-atoms that links to each other with them, can also randomly form (C
3-C
6) 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, vehicle, thinner, assistant agent, vehicle or their combination.
In some embodiments, pharmaceutical composition of the present invention further comprises the additional treatment agent, these additional treatment agent are selected from chemotherapeutic agent, and antiproliferative is used for the treatment of atherosclerotic medicine, the medicine that is used for the treatment of pulmonary fibrosis, or their combination.
In the other embodiment, pharmaceutical composition of the present invention, wherein related additional treatment agent is Chlorambucil (chlorambucil), melphalan (melphalan), endoxan (cyclophosphamide), ifosfamide (ifosfamide), busulfan (busulfan), carmustine (carmustine), lomustine (lomustine), streptozotocin (streptozocin), cis-platinum (cisplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin), Dacarbazine (dacarbazine), Temozolomide (temozolomide), Procarbazine (procarbazine), methotrexate (methotrexate), Fluracil (fluorouracil), cytosine arabinoside (cytarabine), gemcitabine (gemcitabine), purinethol (mercaptopurine), fludarabine (fludarabine), vinealeucoblastine(VLB) (vinblastine), vincristine(VCR) (vincristine), vinorelbine (vinorelbine), taxol (paclitaxel), Docetaxel (docetaxel), topotecan (topotecan), irinotecan (irinotecan), Etoposide (etoposide), bent shellfish is for fixed (trabectedin), gengshengmeisu (dactinomycin), Dx (doxorubicin), epirubicin (epirubicin), daunomycin (daunorubicin), mitoxantrone (mitoxantrone), bleomycin (bleomycin), ametycin (mitomycin), ipsapirone (ixabepilone), tamoxifen (tamoxifen), flutamide (flutamide), gonadorelin analogue (gonadorelinanalogues), megestrol (megestrol), prednisone (prednidone), dexamethasone (dexamethasone), methylprednisolone (methylprednisolone), Thalidomide (thalidomide), interferon alpha (interferon alfa), Calciumlevofolinate (leucovorin), sirolimus (sirolimus), sirolimus resin (temsirolimus), everolimus (everolimus), Ah method is for Buddhist nun (afatinib), alisertib, amuvatinib, A Pa is for Buddhist nun (apatinib), and A Xi is for Buddhist nun (axitinib), Velcade (bortezomib), ripple relaxes for Buddhist nun (bosutinib), brivanib, cabozantinib, ground, west Buddhist nun's cloth (cediranib), crenolanib, Ke Zhuo is for Buddhist nun (crizotinib), dabrafenib, dacomitinib, danusertib, Dasatinib (dasatinib), dovitinib, Tarceva (erlotinib), foretinib, ganetespib, Gefitinib (gefitinib), ibrutinib, Ai Ke is for Buddhist nun (icotinib), imatinib (imatinib), iniparib, lapatinibditosylate (lapatinib), lenvatinib, linifanib, linsitinib, the Marseille is for Buddhist nun (masitinib), momelotinib, for husky Buddhist nun (motesanib), do not come that to replace Buddhist nun (neratinib), nilotinib (nilotinib), niraparib, oprozomib, olaparib, handkerchief azoles handkerchief Buddhist nun (pazopanib), pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, fork clip is for Buddhist nun (saracatinib), saridegib, Xarelto (sorafenib), Sutent (sunitinib), tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, ZD6474 (vandetanib), veliparib, Wei Luofeini (vemurafenib), vismodegib, volasertib, alemtuzumab (alemtuzumab), rhuMAb-VEGF (bevacizumab), brentuximab vedotin, block 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 (ofatumumab) difficult to understand, handkerchief Buddhist nun monoclonal antibody (panitumumab), Rituximab (rituximab), tositumomab (tositumomab), Herceptin (trastuzumab) or their combination.
On the other hand, can use The compounds of this invention or pharmaceutical composition to come for the preparation of the purposes of protecting, handle, treat or alleviate the medicine of patient's proliferative disease.
In some embodiments, proliferative disease of the present invention is metastatic carcinoma, colorectal carcinoma, adenocarcinoma of stomach, bladder cancer, mammary cancer, kidney, liver cancer, lung cancer, thyroid carcinoma, head and neck cancer, prostate cancer, carcinoma of the 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 come for the preparation of the purposes that suppresses or regulate the medicine of protein kinase activity in biological sample, described purposes comprises uses The compounds of this invention to contact with described biological sample.
Some embodiments therein, kinases of the present invention is receptor tyrosine kinase.
In the other embodiment, receptor tyrosine kinase of the present invention is ALK, c-Met, or their combination.
On the other hand, the invention provides some pharmaceutical compositions, it comprises the present invention as the compound of tyrosine kinase receptor inhibitor, or its steric isomer, geometrical isomer, tautomer, solvate, meta-bolites, or its pharmacy acceptable salt, pharmaceutically acceptable carrier, thinner, assistant agent, vehicle, or their combination.In some embodiments, pharmaceutical composition provided by the present invention comprises the compound that can be used as inhibition ALK receptor signal response or the response of c-Met receptor signal, or its steric isomer, geometrical isomer, tautomer, solvate, meta-bolites, or its pharmacy acceptable salt, or pharmaceutically acceptable carrier, thinner, assistant agent, vehicle, or their combination.In the other embodiment, pharmaceutical composition of the present invention further comprises the additional treatment agent.
On the other hand, the present invention relates to the method for arrestin tyrosine kinase activity, this method comprises The compounds of this invention or its pharmaceutical composition contacts with described kinases.In some embodiments, the present invention relates to suppress the response of ALK receptor signal, the method for c-Met receptor signal response, this method comprises The compounds of this invention or its pharmaceutical composition contacts with described acceptor.The other embodiment is that arrestin kinases receptors activity in cell or multicellular organisms particularly suppresses the activity that ALK or c-Met receptor signal respond.According to method of the present invention, this method comprises uses The compounds of this invention or its pharmaceutical composition that described multicellular organisms is carried out administration.In some embodiments, described multicellular organisms refers to Mammals.In the other embodiment, described multicellular organisms refers to the mankind.In some embodiments, the method for the invention further comprises the additional treatment agent and contacts with described kinases.
On the other hand, the present invention relates to a kind of method that suppresses cell-proliferation activity, described method comprises effective therapeutic dose and the cells contacting of using The compounds of this invention or its pharmaceutical composition can suppress propagation.In some embodiments, the method for the invention further comprises additional treatment agent and cells contacting.
On the other hand, the present invention relates to a kind of method of the patient's for the treatment of cell proliferation disorders, described method comprises uses effective therapeutic dose of The compounds of this invention or its pharmaceutical composition that the patient is carried out administration.In some embodiments, the method for the invention further comprises the administration of additional treatment agent.
On the other hand, the present invention relates to a kind of method that suppresses the patient tumors growth, described method comprises uses effective therapeutic dose of The compounds of this invention or its pharmaceutical composition that the patient is carried out administration.In some embodiments, the method for the invention further comprises the administration of additional treatment agent.
On the other hand, the present invention relates to the method for preparation, separation and the purifying of the compound that formula (I) comprises.
Experimental result shows that compound provided by the invention shows good transformation period and good pharmacokinetic property, and ALK and c-Met are had good inhibition effect, and the growth of tumour is also had good inhibition effect.
Content noted earlier has only been summarized some aspect of the present invention, but is not limited to these aspects.The content of these aspects and other aspect will be done concrete more complete description below.
Embodiment
Definition and general terms
The present invention will list the corresponding document of determining of specializing of content in detail, and embodiment is attended by the diagram of structural formula and chemical formula.The present invention has expectedly contains all choices, variant and coordinator, and these may be included in existing invention field as claim is defined.The those skilled in the art will identify many similar or be equal to method described herein and material, and these can be applied to go in the practice of the present invention.The present invention is limited to the description of method and material absolutely not.Have a lot of documents to distinguish mutually with the present patent application with similar material or conflict, comprising but never be limited to the definition of term, the usage of term, the technology of description, or the scope of controlling as the present patent application.
Unless other aspects show that the present invention will use to give a definition:
According to purpose of the present invention, chemical element is according to the periodic table of elements, CAS version and pharmaceutical chemicals handbook, and 75,
ThEd, 1994 define.In addition, the organic chemistry General Principle is seen " Organic Chemistry; " Thomas Sorrell, University Science Books, Sausalito:1999, and " March's Advanced Organic Chemistry, " by Michael B.Smith and Jerry March, John Wiley﹠amp; Sons, New York:2007, so all contents have all merged reference.
Picture is described in the invention, and compound of the present invention can randomly be replaced by one or more substituting group, as top general formula compound, perhaps as the special example in embodiment the inside, the compounds that subclass and the present invention comprise.Should be appreciated that " optional replacement " this term and " replacement or non-replacement " this term can exchange use." randomly " or " choosing wantonly " meaning refer to subsequently described event or situation can but may not take place, and this description comprises the situation that this event or situation wherein take place, and the situation that this event or situation wherein do not take place.For example: " heterocyclic radical randomly independently is selected from D by 1 or 2; the group of F replaces " meaning refer to this D, F can but may not exist, and this description comprises that wherein heterocyclic radical independently is selected from D by 1 or 2, the situation that the group of F replaces, and the unsubstituted situation of heterocyclic radical.
Generally speaking, term " replacement ", expression can be replaced for the one or more hydrogen atoms in the structure by concrete substituting group.Unless other aspects show that an optional substituted radical can have a substituting group to replace in each commutable position of group.Not only position one or more substituting group that can be selected from concrete group replaces in given structural formula, and substituting group can replace in each position identical or differently so.Wherein said substituting group can be, but be not limited to deuterium, fluorine, chlorine, bromine; iodine, cyano group, nitro, azido-, alkyl; haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl; aminoalkyl group, alkyl amino alkyl, cyano group alkyl, hydroxyl, alkoxyl group; sulfydryl, alkylthio, amino, alkylamino, aminoacyl; the alkylamino acyl group, aminoacyl oxygen base, alkylamino acyloxy, aryl, heteroaryl etc.
The part of employed term " undersaturated " expression in the present invention contains one or more degrees of unsaturation.
It is open language that term " comprises ", namely comprises the content that the present invention is specified, but does not get rid of otherwise content.
Single hydrogen atom represented in term " H ".Such atomic group can be connected with other groups, for example links to each other with Sauerstoffatom, forms oh group.
Term " D " or "
2H " represent single D atom.Such atomic group links to each other with a methyl, forms list-deuterium for methyl (CDH
2), two D atoms link to each other with a methyl, form two-deuterium for methyl (CD
2H), and three D atoms link to each other with a methyl, form three-deuterium for methyl (CD
3).
Term " N
3" nitrine structure of expression.This group can be connected with other groups, for example, is connected with methyl group, can form triazonmethane (triazo-methane, MeN
3); And be connected with phenyl group, then form aziminobenzene (PhN
3).
Term " halogen " refers to F, Cl, Br or I.
Term " alkyl " or " alkyl group " that the present invention uses, expression contains saturated straight chain or the side chain monovalence alkyl of 1-20 carbon atom.Unless otherwise indicated, alkyl group contains 1-20 carbon atom; Some of them embodiment is that alkyl group contains 1-10 carbon atom, among the other embodiment, alkyl group contains 1-6 carbon atom, and among the other embodiment, alkyl group contains 1-3 carbon atom, also have among some embodiment, alkyl group contains 1-2 carbon atom.
The example of alkyl group comprises, but is not limited to, methyl (Me ,-CH
3), ethyl (Et ,-CH
2CH
3), n-propyl (n-Pr ,-CH
2CH
2CH
3), sec.-propyl (i-Pr, i-propyl ,-CH (CH
3)
2), normal-butyl (n-Bu, n-butyl ,-CH
2CH
2CH
2CH
3), isobutyl-(i-Bu, i-butyl ,-CH
2CH (CH
3)
2), sec-butyl (s-Bu, s-butyl ,-CH (CH
3) CH
2CH
3), the tertiary butyl (t-Bu, t-butyl ,-C (CH
3)
3), n-pentyl (n-pentyl ,-CH
2CH
2CH
2CH
2CH
3), 2-amyl group (CH (CH
3) CH
2CH
2CH
3), 3-amyl group (CH (CH
2CH
3)
2), 2-methyl-2-butyl (C (CH
3)
2CH
2CH
3), 3-methyl-2-butyl (CH (CH
3) CH (CH
3)
2), 3-methyl isophthalic acid-butyl (CH
2CH
2CH (CH
3)
2), 2-methyl-1-butene base (CH
2CH (CH
3) CH
2CH
3), n-hexyl (CH
2CH
2CH
2CH
2CH
2CH
3), 2-hexyl (CH (CH
3) CH
2CH
2CH
2CH
3), 3-hexyl (CH (CH
2CH
3) (CH
2CH
2CH
3)), 2-methyl-2-amyl group (C (CH
3)
2CH
2CH
2CH
3), 3-methyl-2-amyl group (CH (CH
3) CH (CH
3) CH
2CH
3), 4-methyl-2-amyl group (CH (CH
3) CH
2CH (CH
3)
2), 3-methyl-3-amyl group (C (CH
3) (CH
2CH
3)
2), 2-methyl-3-amyl group (CH (CH
2CH
3) CH (CH
3)
2), 2,3-dimethyl-2-butyl (C (CH
3)
2CH (CH
3)
2), 3,3-dimethyl-2-butyl (CH (CH
3) C (CH
3)
3), n-heptyl, n-octyl, etc.And alkyl can be to replace or non-replacement, and wherein substituting group can be, but is not limited to, deuterium, fluorine, chlorine, bromine, iodine, azido-, alkyl, haloalkyl, cyano group, hydroxyl, alkoxyl group, amino, alkylamino, the cyano group alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl group, 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.
The term " alkylidene group " that the present invention uses, the expression saturated bivalent hydrocarbon radical that two hydrogen atoms of cancellation obtain from the straight or branched saturated hydrocarbon.Unless otherwise detailed instructions, alkylidene group contains 1-10 carbon atom, and some of them embodiment is, alkylidene group contains 1-6 carbon atom, and other embodiment is that alkylidene group contains 1-4 carbon atom, also having some embodiment is that alkylidene group contains 1-3 carbon atom.The example of alkylidene group comprises, but is not limited to methylene radical (CH
2-), ethylidene (CH
2CH
2-), isopropylidene (CH (CH
3) CH
2-) etc.Alkylidene group can further be replaced, and substituting group can be, but be not limited to deuterium, fluorine, chlorine, bromine, iodine, azido-, alkyl, haloalkyl, cyano group, hydroxyl, alkoxyl group, amino, alkylamino, the cyano group alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl group, alkyl amino alkyl, etc.
2-12 carbon atom of term " thiazolinyl " expression, or 2-8 carbon atom, or 2-6 carbon atom, or the monovalence alkyl of the straight or branched of 2-4 carbon atom, wherein at least one position is undersaturated condition, namely a C-C is sp
2Two keys, alkenyl group can have the location of " suitable ", negation or " E ", " Z ", and concrete example comprises, but is not limited to vinyl (CH=CH
2), allyl group (CH
2CH=CH
2), etc.Thiazolinyl of the present invention can independently randomly further be replaced, and substituting group can be, but be not limited to deuterium, fluorine, chlorine, bromine, iodine, azido-, alkyl, haloalkyl, cyano group, hydroxyl, alkoxyl group, amino, alkylamino, the cyano group alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl group, alkyl amino alkyl, etc.
2-12 carbon atom of term " alkynyl " expression, or 2-8 carbon atom, or 2-6 carbon atom, or the monovalence alkyl of 2-4 carbon atom straight chain or side chain, wherein at least one position is undersaturated condition, namely a C-C is the sp triple bond, concrete example comprises, but be not limited to ethynyl (C ≡ CH), propargyl (CH
2C ≡ CH) etc.Wherein hydrocarbyl group can independently randomly further be replaced, and substituting group can be, but be not limited to deuterium, fluorine, chlorine, bromine, iodine, azido-, alkyl, haloalkyl, cyano group, hydroxyl, alkoxyl group, amino, alkylamino, the cyano group alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl group, alkyl amino alkyl, etc.
Employed term " alkoxyl group " or " alkoxy base " among the present invention refer to that alkyl is connected on the main carbochain by Sauerstoffatom, and 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 that alkoxy base contains 1-10 carbon atom; Among the other embodiment, alkoxy base contains 1-8 carbon atom; Among the other embodiment, alkoxy base contains 1-6 carbon atom; Also have among some embodiment, alkoxy base contains 1-4 carbon atom.
The specific examples of alkoxy base includes, but are not limited to: methoxyl group (MeO ,-OCH
3), oxyethyl group (EtO ,-OCH
2CH
3), 1-propoxy-(n-PrO, n-propoxy ,-OCH
2CH
2CH
3), 2-propoxy-(i-PrO, i-propoxy ,-OCH (CH
3)
2), 1-butoxy (n-BuO, n-butoxy ,-OCH
2CH
2CH
2CH
3), 2-methyl-l-propoxy-(i-BuO, i-butoxy ,-OCH
2CH (CH
3)
2), 2-butoxy (s-BuO, s-butoxy ,-OCH (CH
3) CH
2CH
3), 2-methyl-2-propoxy-(t-BuO, t-butoxy ,-OC (CH
3)
3), 1-pentyloxy (n-pentoxy ,-OCH
2CH
2CH
2CH
2CH
3), 2-pentyloxy (OCH (CH
3) CH
2CH
2CH
3), 3-pentyloxy (OCH (CH
2CH
3)
2), 2-methyl-2-butoxy (OC (CH
3)
2CH
2CH
3), 3-methyl-2-butoxy (OCH (CH
3) CH (CH
3)
2), 3-methyl-l-butoxy (OCH
2CH
2CH (CH
3)
2), 2-methyl-l-butoxy (OCH
2CH (CH
3) CH
2CH
3), etc.
" " the expression alkyl group is replaced by one or more alkoxy base alkoxyalkyl term, wherein alkyl group and alkoxy base have implication as described in the present invention, and such example comprises, but is not limited to methoxymethyl, ethoxyl methyl, ethoxyethyl group etc.
" hydroxyalkyl " comprises the C that is replaced by one or more hydroxyl to term
1-10The straight or branched alkyl group.Some of them embodiment is, hydroxyalkyl is by C that one or more oh group replaced
1-6" more rudimentary hydroxyalkyl ", such example comprise, but are not limited to methylol, hydroxyethyl, hydroxypropyl, hydroxyl butyl and hydroxyl hexyl.
Term " haloalkyl " and " halogenated alkoxy " expression alkyl or alkoxy base are replaced by one or more identical or different halogen atoms, wherein alkyl and alkoxyl group have implication as described in the present invention, such example comprises, but be not limited to, chloromethyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, etc.
Term " alkylamino " or " alkylamino " comprise " N-alkylamino " and " N, N-dialkyl amido ", and wherein amino group is replaced by one or two alkyl group respectively independently.Some of them embodiment is that alkylamino is one or two C
1-6Alkyl is connected to the more rudimentary alkylamino group on the nitrogen-atoms.Other embodiment is that alkylamino is C
1-3More rudimentary alkylamino group.Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example comprises, but is not limited to N-methylamino-, N-ethylamino, N, N-dimethylamino, N, N-diethylin etc.
Term " aminoalkyl group " comprises the C that is replaced by one or more amino
1-10The straight or branched alkyl group.Some of them embodiment is, aminoalkyl group is by C that one or more amino group replaced
1-6" more rudimentary aminoalkyl group ", such example comprise, but are not limited to aminomethyl, aminoethyl, aminopropyl, ammonia butyl and ammonia hexyl.
Term " cyano group alkyl " comprises the C that is replaced by one or more cyano group
1-10The straight or branched alkyl group.Some of them embodiment is, the cyano group alkyl is by C that one or more cyano group replaced
1-6" more rudimentary cyano group alkyl ", such example comprise, but are not limited to cyano methyl, cyano ethyl, cyano group propyl group, cyano group butyl and cyano group hexyl.
Term " alkyl amino alkyl " comprises the alkyl group that is replaced by alkylamino.Some of them embodiment is that alkyl amino alkyl is C
1-6More rudimentary alkyl amino alkyl.Other embodiment is that alkyl amino alkyl is C
1-3More rudimentary alkyl amino alkyl.Suitable alkyl amino alkyl group can be that monoalkyl or dialkyl group replace, and such embodiment comprises, but is not limited to N-methylamino methyl, N, N-dimethyl aminoethyl, N, N-diethylamino methyl etc.
Term " cycloalkyl " refers to the alkyl of monovalence or multivalence, is the monocycle system that contains 3-12 carbon atom.Some of them embodiment is, cycloalkyl comprises 3-8 carbon atom, and other embodiment is that cycloalkyl comprises 3-6 carbon atom.And cycloalkyl can further be replaced, and substituting group can be, but be not limited to deuterium, fluorine, chlorine, bromine, iodine, azido-, alkyl, haloalkyl, cyano group, hydroxyl, alkoxyl group, amino, alkylamino, the cyano group alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl group, alkyl amino alkyl, etc.
Term " cycloalkyl alkylidene group " expression alkyl group can be replaced by one or more group of naphthene base, and wherein alkyl and group of naphthene base have implication as described in the present invention.Some of them embodiment is, the cycloalkyl alkylidene group refers to " more rudimentary cycloalkyl alkylidene group " group, and namely group of naphthene base is connected to C
1-6Alkyl group on.Other embodiment is that group of naphthene base is connected to C
1-4Alkyl group on.Other embodiment is that group of naphthene base is connected to C
1-3Alkyl group on.Such example comprises, but is not limited to cyclopropyl ethyl, cyclopentyl-methyl, cyclohexyl methyl etc.The cycloalkyl alkylidene group can further be replaced, and this substituting group can be, but be not limited to deuterium, fluorine, chlorine, bromine, iodine, azido-, alkyl, haloalkyl, cyano group, hydroxyl, alkoxyl group, amino, alkylamino, the cyano group alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl group, alkyl amino alkyl, etc.
One or more O represented in term " heteroatoms ", S, and N, P and Si comprise N, the form of S and any oxidation state of P; The primary, the form of the second month in a season, tertiary amine and quaternary ammonium salt; The perhaps substituted form of the hydrogen on the nitrogen-atoms in the heterocycle, for example, N(is as the N in 3, the 4-dihydro-2 h-pyrrole base), NH(is as the NH in the pyrrolidyl) or the pyrrolidyl that replaces as N-of NR(in NR).
Term " heterocycle ", " heterocyclic radical " or " heterocycle " commutative use herein, all refer to the monocycle system, wherein the upward one or more atoms of ring are independent is randomly replaced by heteroatoms, ring can be saturated fully or comprise one or more degrees of unsaturation, but never be the fragrant same clan, have only a tie point to be connected to other molecules and get on.One or more ring hydrogen atoms are independent randomly to be replaced by one or more substituting groups described in the invention.Some of them embodiment is, " heterocycle ", " heterocyclic radical " or " heterocycle " group be 3-7 unit ring monocycle (2-6 carbon atom and be selected from N, O, P, the 1-3 of a S heteroatoms is randomly replaced by one or more Sauerstoffatom at this S or P and to obtain looking like SO, SO
2, PO, PO
2Group, when described ring is triatomic ring, wherein have only a heteroatoms).
Heterocyclic radical can be carbon back or heteroatoms base.The example of heterocycle comprises, but is not limited to pyrrolidyl, tetrahydrofuran base, the dihydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl thioxane base, piperazinyl, high piperazinyl, azelidinyl, the oxa-cyclobutyl, thia cyclobutyl, homopiperidinyl, epoxypropyl, the nitrogen heterocyclic heptyl, oxepane base, thia suberyl, oxygen azatropylidene base, the diazepine base, sulphur azatropylidene base, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxy amyl group, pyrazolinyl, the dithiane base, dithiode alkyl, dihydro-thiophene base, pyrazolidyl, imidazolinyl, imidazolidyl, the example of heterocyclic group also comprises, encircles two carbon atoms by the oxygen (=pyrimidine dione base and 1, the 1-dioxy thio-morpholinyl that O) replace.And described heterocyclic radical is independent randomly to be replaced by the one or more substituting groups among the present invention, and wherein substituting group can be, but is not limited to, deuterium, fluorine, chlorine, bromine, iodine, azido-, alkyl, haloalkyl, cyano group, hydroxyl, alkoxyl group, amino, alkylamino, the cyano group alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl group, alkyl amino alkyl, etc.
Term " heterocyclic radical alkylidene group " expression alkyl group can be replaced by one or more heterocyclic radical groups, and wherein alkyl and heterocyclic radical group have implication as described in the present invention.Some of them embodiment is, the heterocyclic radical alkylidene group refers to " more rudimentary heterocyclic radical alkylidene group " group, and namely the heterocyclic radical group is connected to C
1-6Alkyl group on.Other embodiment is that the heterocyclic radical group is connected to C
1-4Alkyl group on.Such example comprises, but is not limited to 2-tetramethyleneimine ethyl etc.The heterocyclic radical alkylidene group can further be replaced, and this substituting group can be, but be not limited to deuterium, fluorine, chlorine, bromine, iodine, azido-, alkyl, haloalkyl, cyano group, hydroxyl, alkoxyl group, amino, alkylamino, the cyano group alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl group, alkyl amino alkyl, etc.
Term " aryl " and " aromatic ring ", commutative use herein, expression contains the monocycle of 6-14 unit ring altogether, dicyclo, with the carbocyclic ring system of three rings, wherein, at least one member ring systems is aromatic, wherein each member ring systems comprises 3-7 unit ring, and has only an attachment point to link to each other with the rest part of molecule.Aromatic nucleus can comprise phenyl, naphthyl and anthracene.And described aryl can be to replace or non-replacement, and wherein substituting group can be, but is not limited to, deuterium, fluorine, chlorine, bromine, iodine, azido-, alkyl, haloalkyl, cyano group, hydroxyl, alkoxyl group, amino, alkylamino, the cyano group alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl group, alkyl amino alkyl, etc.
Term " aryl alkylene " expression alkyl group can be replaced by one or more aromatic yl group, wherein alkyl and aromatic yl group have implication as described in the present invention, some of them embodiment is, the aryl alkylene group refers to " more rudimentary aryl alkylene " group, and namely aromatic yl group is connected to C
1-6Alkyl group on.Other embodiment is that the aryl alkylene group refers to contain C
1-4" the benzene alkylene " of alkyl.Wherein specific examples comprises benzyl, diphenyl methyl, styroyl etc.Aryl alkylene can further be replaced, and this substituting group can be, but be not limited to deuterium, fluorine, chlorine, bromine, iodine, azido-, alkyl, haloalkyl, cyano group, hydroxyl, alkoxyl group, amino, alkylamino, the cyano group alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl group, alkyl amino alkyl, etc.
Term " heteroaryl ", " fragrant heterocycle " and " heteroaromatics ", commutative use in this article, expression contains the monocycle of 5-14 annular atoms, dicyclo, and three-ring system, wherein at least one member ring systems is aromatic, and has at least a member ring systems to comprise one or more heteroatomss, wherein each member ring systems comprises 5-7 unit ring, and has only an attachment point to link to each other with the molecule rest part.And described heteroaryl can be to replace or non-replacement, and wherein substituting group can be, but is not limited to, deuterium, fluorine, chlorine, bromine, iodine, azido-, alkyl, haloalkyl, cyano group, hydroxyl, alkoxyl group, amino, alkylamino, the cyano group alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl group, alkyl amino alkyl, etc.
Other embodiment is that heteroaryl comprises following monocycle, but is not limited to these monocycles: 2-furyl, 3-furyl, TMSIM N imidazole base, the 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, the 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, the N-pyrryl, 2-pyrryl, 3-pyrryl, 2-pyridyl, the 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, the 5-pyrimidyl, pyridazinyl (as the 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, the 5-thiazolyl, tetrazyl (as the 5-tetrazyl), triazolyl (as 2-triazolyl and 5-triazolyl), 2-thienyl, the 3-thienyl, pyrazolyl (as the 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazole base, 1,2,5-oxadiazole base, 1,2,4-oxadiazole base, the 1,2,3-triazoles base, 1,2,3-thio biphosphole base, 1,3,4-thio biphosphole base, 1,2,5-thio biphosphole base, pyrazinyl, the 1,3,5-triazines base; Also comprise following dicyclo, but never be limited to these dicyclos: benzimidazolyl-, benzofuryl, benzothienyl, indyl (as the 2-indyl), purine radicals, quinolyl (as the 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (as the 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl).
Term " heteroaryl alkylidene group " expression alkyl group can be replaced by one or more heteroaryl groups, wherein alkyl and heteroaryl groups have implication as described in the present invention, some of them embodiment is, the heteroaryl alkylidene group refers to " more rudimentary heteroaryl alkylidene group " group, and namely heteroaryl groups is connected to C
1-6Alkyl group on.Other embodiment is that heteroaryl groups is connected to C
1-4Alkyl group on.Wherein specific examples comprises the 2-picolyl, 3-furans ethyl etc.Can further be substituted on the heteroaryl alkylidene group, this substituting group can be, but be not limited to deuterium, fluorine, chlorine, bromine, iodine, azido-, alkyl, haloalkyl, cyano group, hydroxyl, alkoxyl group, amino, alkylamino, the cyano group alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl group, alkyl amino alkyl, etc.
Term " virtue is amino " expression amine groups is replaced by one or two aromatic yl group, and such example comprises, but is not limited to the N-phenylamino.Some of them embodiment is that the aromatic ring on the fragrant amino can further be substituted.
No matter term " carboxyl " is to use separately or be used in conjunction with other terms, as " carboxyalkyl ", expression-CO
2H; No matter term " carbonyl " is to use separately or be used in conjunction with other terms, as " aminocarboxyl " or " acyloxy ", and expression-(C=O)-.
Term " condensed-bicyclic ", " fused rings ", " condensed-bicyclic base " or " condensing cyclic group ", shown in a-c, represent between two five-rings that (, between two six-rings (formula b), and (formula c) shares the bridged-ring system of a C-C key between five-ring and the six-ring likes a).Unsaturated link(age) isolated or conjugation be can comprise in the system, but aromatic nucleus or hetero-aromatic ring (substituting group can be aromaticity) do not comprised in the core ring structure.Each ring in the condensed-bicyclic can be carbocyclic ring or heterocycle.
The example of condensed-bicyclic includes, but not limited to also [2,3-b] furans-3-base of hexahydro furyl, and hexahydro furyl is [3,2-b] furans-3-base also, and the octahydro pentamethylene is [c] pyrroles-5-base also, octahydro pentalene-2-base, and octahydro-1H-isoindole-5-base, etc.The condensed-bicyclic base can be to replace or non-replacement, and wherein substituting group can be, but is not limited to, deuterium, fluorine, chlorine, bromine, iodine, azido-, alkyl, haloalkyl, cyano group, hydroxyl, alkoxyl group, amino, alkylamino, the cyano group alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl group, alkyl amino alkyl, etc.
Term " condensed-bicyclic base alkylidene group " expression alkyl is replaced by one or more condensed-bicyclic base groups, wherein alkyl group and condensed-bicyclic base group have implication as described in the present invention, such example comprises, but be not limited to hexahydro furyl also [2,3-b] furans-3-ylmethyl, hexahydro furyl also [2,3-b] furans-3-base two deuteriums for methyl, etc.Condensed-bicyclic base alkylidene group can be to replace or non-replacement, and wherein substituting group can be, but is not limited to, deuterium, fluorine, chlorine, bromine, iodine, azido-, alkyl, haloalkyl, cyano group, hydroxyl, alkoxyl group, amino, alkylamino, the cyano group alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl group, alkyl amino alkyl, etc.
Picture is described in the invention, and substituting group is drawn a key and is connected to the member ring systems (being shown below) that forms on the ring at center and represent substituting group and can replace any commutable position on encircling.For example, formula d represents the substituted position of any possibility on the B ring, shown in e.
Unless other aspects show, structural formula described in the invention comprises that all isomeric forms are (as enantiomerism, diastereo-isomerism, and rotamerism (or conformational isomerism)): the R, the S configuration that for example contain asymmetric center, (Z) of two keys, (E) isomer and (Z), the conformer of (E).Therefore, the single three-dimensional chemical isomer of compound of the present invention or its enantiomer, diastereomer, or the mixture of geometrical isomer (or conformer) all belongs to scope of the present invention.
Term used in the present invention " tautomer " or " tautomeric form " expression have the structure isomeride of different-energy can cross low energy barrier, thereby transforms mutually.For example, proton tautomerism body (being prototropy) comprises by proton shifting and carries out change, as the change of keto-enol formula and imines-enamine isomerization.Valence tautomers comprises by some bonding electrons reorganization carries out change.
Unless other aspects show that all tautomeric forms of compound of the present invention are included within the scope of the present invention.In addition, unless other aspects show that the structural formula of compound described in the invention comprises the enriched isotope of one or more different atoms.
Term used in the present invention " prodrug " represents a compound and is converted into the compound shown in the formula (I) in vivo.Such conversion is subjected to prodrug hydrolysis or be the influence of precursor structure through enzymatic conversion in blood in blood or tissue.Prodrug compounds of the present invention can be ester, and what ester can be used as prodrug in existing invention has phenyl ester class, an aliphatics (C
1-24) the ester class, acyloxy methyl ester class, carbonic ether, amino formate and amino acid esters.For example a compound in the present invention comprises the OH group, namely its acidylate can be obtained the compound of prodrug form.Other prodrug form comprises phosphoric acid ester, is that hydroxyl phosphorylation on parent obtains as these phosphate compounds.Can be with reference to following document about the complete discussion of prodrug: 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 piece of document is contained in this by reference.
" meta-bolites " refers to that concrete compound or its salt is in vivo by the resulting product of metabolism.The meta-bolites of a compound can identify that its activity can characterize by the method that adopts test as described in the invention by affiliated field technique known.Such product can be by to the oxidation of drug compound process, reduces, and hydrolysis, amidated, the desamido-effect, esterification, fat abstraction, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes the meta-bolites of compound, comprise compound of the present invention is fully contacted the meta-bolites that for some time produces with Mammals.
The definition of neutral body chemistry of the present invention and the use of convention be reference following document: S.P.Parker usually, 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﹠amp; Sons, Inc., New York, 1994. compounds of the present invention can comprise asymmetric center or chiral centre, therefore have different steric isomers.The stereoisomeric forms in any ratio that compound of the present invention is all comprises but never is limited to, diastereomer, and enantiomer, atropisomer and their mixture as racemic mixture, have been formed a part of the present invention.A lot of organic compound all exist with the optical activity form, i.e. the plane of their capable Plane of rotation polarized light.When describing optically active compound, prefix D, L or R, S are used for representing the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) are used for naming the symbol of compound plane polarized light rotation, and (-) or l refer to that compound is left-handed, and prefix (+) or d refer to that compound is dextrorotation.The chemical structure of these steric isomers is identical, but their three-dimensional arrangement is different.Specific steric isomer can be enantiomorph, and mixture of isomers is commonly referred to enantiomeric mixture.The mixture of enantiomers of 50:50 is called as racemic mixture or racemic modification, and this may cause not having stereoselectivity or stereospecificity in the chemical reaction process.Term " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomers, lack optical activity.
" pharmacy acceptable salt " used in the present invention refers to organic salt and the inorganic salt of compound of the present invention.Pharmacy acceptable salt is for we are known in affiliated field, as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66:1-19,1977. put down in writing.The salt that pharmaceutically acceptable nontoxic acid forms comprises, but is not limited to, and the inorganic acid salt that forms with the amino group reaction has hydrochloride, hydrobromate, phosphoric acid salt, vitriol, perchlorate and organic acid salt such as acetate, oxalate, maleate, tartrate, Citrate trianion, succinate, malonate, or obtain these salt by additive method such as the ion exchange method of putting down in writing on the books document.Other pharmacy acceptable salts comprise adipate, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, bisulfate, borate, butyrates, camphorate, camsilate, cyclopentyl propionate, digluconate, dodecyl sulfate, esilate, formate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodate, 2-hydroxyl-esilate, lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, pivalate, propionic salt, stearate, thiocyanate-, tosilate, undecylate, valerate, etc.The salt that obtains by suitable alkali comprises basic metal, alkaline-earth metal, ammonium and N
+(C
1-4Alkyl)
4Salt.The present invention also intends having conceived any formed quaternary ammonium salt of compound that comprises the group of N.Water-soluble or oil soluble or disperse product to obtain by quaternization.Basic metal or alkaline earth salt comprise sodium, lithium, and potassium, calcium, magnesium, etc.Pharmacy acceptable salt further comprises suitable, nontoxic ammonium, the amine positively charged ion that quaternary ammonium salt and gegenions form, and as halogenide, oxyhydroxide, carboxylate, hydrosulfate, phosphorylation thing, nitrification thing, C
1-8Azochlorosulfonate acid compound and aromatic sulphonic acid thing.
" solvate " of the present invention refers to one or more solvent molecules and the formed associated complex of compound of the present invention.The solvent that forms solvate comprises, but is not limited to water, Virahol, ethanol, methyl alcohol, methyl-sulphoxide, ethyl acetate, acetic acid, monoethanolamine.Term " hydrate " refers to that solvent molecule is the formed associated complex of water.
When term " blocking group " or " PG " refer to a substituting group and other reacted with functional groups, be commonly used to block or protect special functional.For example; " amino blocking group " refers to that a substituting group links to each other to block or protect in the compound amino functional with amino group; suitable amido protecting group comprises ethanoyl; trifluoroacetyl group; tertbutyloxycarbonyl (BOC), carbobenzoxy-(Cbz) (CBZ) and 9-fluorenes methylene oxygen carbonyl (Fmoc).Similarly, " hydroxy-protective group " refers to that the substituting group of hydroxyl is used for blocking or protecting the functional of hydroxyl, and suitable blocking group comprises ethanoyl and silyl." carboxy protective group " refers to that the substituting group of carboxyl is used for blocking or protecting the functional of carboxyl, and general carboxyl-protecting group comprises-CH
2CH
2SO
2Ph, cyano ethyl, 2-(TMS) ethyl, 2-(TMS) ethoxyl methyl, 2-(p-toluenesulfonyl) ethyl, 2-(p-nitrophenyl alkylsulfonyl) ethyl, 2-(diphenylphosphino) ethyl, nitro-ethyl, etc.But for the general description reference of blocking group: T W.Greene, Protective Groups in Organic Synthesis, John Wiley﹠amp; Sons, New York, 1991; And P.J.Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
Compound
The heterogeneous ring compound that the present invention relates to, its pharmacy acceptable salt, and pharmaceutical preparation, to tyrosine kinase receptor, especially disease or the treatment of conditions of the adjusting of ALK and c-Met acceptor have potential purposes.Particularly, the present invention relates to a kind of suc as formula the compound shown in (I):
Or its steric isomer, geometrical isomer, tautomer, oxynitride, solvate, meta-bolites, pharmacy acceptable salt or its prodrug.
Wherein, R
1, R
2, R
3, R
4, R
5, R
6Have implication as described below with Z:
R
1, R
2, R
3, R
4, R
5And R
6Be H independently, D or F in the other embodiment, can be H or D independently.
Z can for:
(1) (C
3-C
7) heterocyclic radical, and by 1,2,3,4 or 5 independently are selected from D, F, Cl, Br, I, N
3, (C
1-C
6) alkyl, (C
1-C
6) haloalkyl ,-CN ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
4) alkylidene group-CN ,-(C
1-C
4) alkylidene group-OH ,-(C
1-C
4) alkylidene group-OR
aOr-(C
1-C
4) alkylidene group-NR
bR
cSubstituting group replace; Described (C
3-C
7) heterocyclic radical in the other embodiment, can be by 1,2,3,4 or 5 independently are selected from D, F, N
3, (C
1-C
3) alkyl, (C
1-C
3) haloalkyl ,-CN ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
3) alkylidene group-CN ,-(C
1-C
3) alkylidene group-OH ,-(C
1-C
3) alkylidene group-OR
aOr-(C
1-C
3) alkylidene group-NR
bR
cSubstituting group replace;
Z is (C
3-C
7) during heterocyclic radical, meet the following conditions simultaneously:
When the ring members of heterocyclic radical comprise-N (H)-time ,-N (H)-in hydrogen atom can not be substituted;
Work as R
1, R
2, R
3, R
4, R
5And R
6Be H, when Z is mono-substituted piperidyl, 4-position on the piperidine ring can not be replaced by D, namely working as formula (I) compound is that (1-(2 for (R)-3-, 6-two chloro-3-fluorophenyls) oxyethyl group)-during 5-(1-(piperidin-4-yl)-1H-pyrazoles-4-yl) pyridine-2-aminated compounds, the 4-position on the piperidine ring can not be replaced by D.
Z also can for:
(2)-(C
1-C
4) alkylidene group-(C
3-C
7) heterocyclic radical, and by 1,2,3,4 or 5 independently are selected from D, F, Cl, Br, I, N
3, (C
1-C
6) haloalkyl ,-CN ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
4) alkylidene group-OH ,-(C
1-C
4) alkylidene group-OR
aOr-(C
1-C
4) alkylidene group-NR
bR
cSubstituting group replace; Described-(C
1-C
4) alkylidene group-(C
3-C
7) heterocyclic radical in the other embodiment, can be by 1,2,3,4 or 5 independently are selected from D, F, N
3, (C
1-C
3) haloalkyl ,-CN ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
3) alkylidene group-OH ,-(C
1-C
3) alkylidene group-OR
aOr-(C
1-C
3) alkylidene group-NR
bR
cSubstituting group replace;
-(C
1-C
4) alkylidene group-(C
3-C
7) in the heterocyclic radical heterocyclic radical can not by-OH is single to be replaced.
Z can also for:
(3) (C
5-C
12) the condensed-bicyclic base, and randomly by 1,2,3,4 or 5 independently are selected from D, F, Cl, Br, I, N
3, (C
1-C
6) alkyl, (C
1-C
6) haloalkyl ,-CN ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
4) alkylidene group-CN ,-(C
1-C
4) alkylidene group-OH ,-(C
1-C
4) alkylidene group-OR
aOr-(C
1-C
4) alkylidene group-NR
bR
cSubstituting group replace, and the ring in the bicyclic system can be carbocyclic ring or heterocycle; Described (C
5-C
12) the condensed-bicyclic base in the other embodiment, can be randomly by 1,2,3,4 or 5 independently are selected from D, F, Cl, Br, I, N
3, (C
1-C
3) alkyl, (C
1-C
3) haloalkyl ,-CN ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
3) alkylidene group-CN ,-(C
1-C
3) alkylidene group-OH ,-(C
1-C
3) alkylidene group-OR
aOr-(C
1-C
3) alkylidene group-NR
bR
cSubstituting group replace, and the ring in the bicyclic system can be carbocyclic ring or heterocycle.
Z can also for:
(4)-(C
1-C
4) alkylidene group-(C
5-C
12) the condensed-bicyclic base, and randomly by 1,2,3,4 or 5 independently are selected from D, F, Cl, Br, I, N
3, (C
1-C
6) alkyl, (C
1-C
6) haloalkyl ,-CN ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
4) alkylidene group-CN ,-(C
1-C
4) alkylidene group-OH ,-(C
1-C
4) alkylidene group-OR
aOr-(C
1-C
4) alkylidene group-NR
bR
cSubstituting group replace, and the ring in the bicyclic system can be carbocyclic ring or heterocycle; Described-(C
1-C
4) alkylidene group-(C
5-C
12) the condensed-bicyclic base in the other embodiment, can be randomly by 1,2,3,4 or 5 independently are selected from D, F, Cl, Br, I, N
3, (C
1-C
3) alkyl, (C
1-C
3) haloalkyl ,-CN ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
3) alkylidene group-CN ,-(C
1-C
3) alkylidene group-OH ,-(C
1-C
3) alkylidene group-OR
aOr-(C
1-C
3) alkylidene group-NR
bR
cSubstituting group replace, and the ring in the bicyclic system can be carbocyclic ring or heterocycle.
Particularly, Z can be selected from any one in the minor structure shown in following (a)～(k) or its steric isomer:
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 steric isomer are independently by 1,2, and 3,4 or 5 independently are selected from D, F, (C
1-C
3) haloalkyl ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
3) alkylidene group-OH ,-(C
1-C
3) alkylidene group-OR
aOr-(C
1-C
3) alkylidene group-NR
bR
cSubstituting group replace;
When n is 1,2 or 3 o'clock, the minor structure shown in described (a)～(k) or its steric isomer can not by-OH is single to be replaced;
When each X and X' be independently-N (H)-time ,-N (H)-in hydrogen atom can not be substituted;
Work as R
1, R
2, R
3, R
4, R
5And R
6Be H, when Z was mono-substituted piperidyl, the 4-position of piperidine ring can not be replaced by D.
Z also can be selected from any one in the minor structure shown in (l)～(x) or its steric isomer:
In the minor structure shown in described (l)～(x):
N is 0,1,2 or 3;
W and W' be-O-,-N (H)-or-N (C
1-C
3) alkyl-;
Minor structure shown in described (l)～(x) or its steric isomer are randomly by 1,2, and 3,4 or 5 independently are selected from D, F, (C
1-C
3) alkyl, (C
1-C
3) haloalkyl ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
3) alkylidene group-OH ,-(C
1-C
3) alkylidene group-ORa or-(C
1-C
3) alkylidene group-NR
bR
cSubstituting group replace.
Z can also be selected from any one in the minor structure shown in (101)～(111) or its steric isomer:
Minor structure shown in described (101)～(111) or its steric isomer are independently by 1,2, and 3,4 or 5 independently are selected from D, F, (C
1-C
3) haloalkyl ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
3) alkylidene group-OH ,-(C
1-C
3) alkylidene group-OR
aOr-(C
1-C
3) alkylidene group-NR
bR
cSubstituting group replace.
Z can also be selected from any one in the minor structure shown in (201)～(214) or its steric isomer:
Minor structure shown in described (201)～(214) or its steric isomer are independently by 1,2, and 3,4 or 5 independently are selected from D, F, (C
1-C
3) haloalkyl ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
3) alkylidene group-OH ,-(C
1-C
3) alkylidene group-OR
aOr-(C
1-C
3) alkylidene group-NR
bR
cSubstituting group replace.
Z can also be selected from any one in the minor structure shown in (301)～(323) or its steric isomer:
Minor structure shown in described (301)～(323) or its steric isomer are randomly by 1,2, and 3,4 or 5 independently are selected from D, F, (C
1-C
3) alkyl, (C
1-C
3) haloalkyl ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
3) alkylidene group-OH ,-(C
1-C
3) alkylidene group-OR
aOr-(C
1-C
3) alkylidene group-NR
bR
cSubstituting group replace.
In above-mentioned each structure of Z, R
aBe (C
1-C
6) alkyl, (C
1-C
6) thiazolinyl, (C
1-C
6) alkynyl, (C
3-C
6) cycloalkyl, (C
3-C
6) heterocyclic radical, (C
6-C
10) aryl, (C
1-C
9) heteroaryl ,-(C
1-C
4) alkylidene group-(C
3-C
6) cycloalkyl ,-(C
1-C
4) alkylidene group-(C
3-C
6) heterocyclic radical ,-(C
1-C
4) alkylidene group-(C
6-C
10) aryl or-(C
1-C
4) alkylidene group-(C
1-C
9) heteroaryl, described each (C
1-C
6) alkyl, (C
1-C
6) thiazolinyl, (C
1-C
6) alkynyl, (C
3-C
6) cycloalkyl, (C
3-C
6) heterocyclic radical, (C
6-C
10) aryl, (C
1-C
9) heteroaryl ,-(C
1-C
4) alkylidene group-(C
3-C
6) cycloalkyl ,-(C
1-C
4) alkylidene group-(C
3-C
6) heterocyclic radical ,-(C
1-C
4) alkylidene group-(C
6-C
10) aryl and-(C
1-C
4) alkylidene group-(C
1-C
9) heteroaryl is randomly by 1,2,3 or 4 independently are selected from-D ,-F ,-Cl, N
3,-CN ,-OH ,-NH
2, the substituting group of alkoxyl group or alkylamino replaces; In the other embodiment, R
aCan be (C
1-C
3) alkyl, (C
1-C
3) thiazolinyl, (C
1-C
6) alkynyl, (C
3-C
6) cycloalkyl or-(C
1-C
3) alkylidene group-(C
3-C
6) cycloalkyl, described each (C
1-C
3) alkyl, (C
1-C
3) thiazolinyl, (C
1-C
6) alkynyl, (C
3-C
6) cycloalkyl and-(C
1-C
3) alkylidene group-(C
3-C
6) cycloalkyl is randomly by 1,2,3 or 4 substituting groups that independently are selected from D or F replace; , in the other embodiment, R
aCan also be (C
1-C
2) alkyl, and randomly by 1,2,3 or 4 substituting groups that independently are selected from D or F replace;
R
bAnd R
cBe H independently, (C
1-C
6) alkyl, (C
3-C
6) cycloalkyl, (C
3-C
6) heterocyclic radical, (C
6-C
10) aryl, (C
1-C
9) heteroaryl ,-(C
1-C
4) alkylidene group-(C
3-C
6) cycloalkyl ,-(C
1-C
4) alkylidene group-(C
3-C
6) heterocyclic radical ,-(C
1-C
4) alkylidene group-(C
6-C
10) aryl or-(C
1-C
4) alkylidene group-(C
1-C
9) heteroaryl; Described each (C
1-C
6) alkyl, (C
3-C
6) cycloalkyl, (C
3-C
6) heterocyclic radical, (C
6-C
10) aryl, (C
1-C
9) heteroaryl ,-(C
1-C
4) alkylidene group-(C
3-C
6) cycloalkyl ,-(C
1-C
4) alkylidene group-(C
3-C
6) heterocyclic radical ,-(C
1-C
4) alkylidene group-(C
6-C
10) aryl and-(C
1-C
4) alkylidene group-(C
1-C
9) heteroaryl is randomly by 1,2,3, or 4 independently are selected from D, F, Cl, N
3,-CN ,-OH ,-NH
2, the substituting group of alkoxyl group or alkylamino replaces; In some other embodiment, R
b, R
cCan also be H independently, (C
1-C
3) alkyl, (C
3-C
6) cycloalkyl or-(C
1-C
4) alkylidene group-(C
3-C
6) alkyl; Described each (C
1-C
3) alkyl, (C
3-C
6) cycloalkyl and-(C
1-C
4) alkylidene group-(C
3-C
6) alkyl is randomly by 1,2,3 or 4 substituting groups that independently are selected from D or F replace; In some other embodiment, R
b, R
cCan be H or (C independently also
1-C
2) alkyl; Described (C
1-C
2) alkyl and (C
3-C
6) heterocyclic radical is randomly by 1,2,3 or 4 substituting groups that independently are selected from D or F replace;
In the present invention, work as R
bAnd R
cWhen linking to each other with same nitrogen-atoms, R
b, R
cWith the nitrogen-atoms that links to each other with them, can also randomly form (C
3-C
6) heterocyclic radical, i.e. R
b, R
cWith the nitrogen-atoms that links to each other with them, can form (C
3-C
6) heterocyclic radical, also can not form heterocyclic radical, for other structures well known to those skilled in the art, as N-R
a-R
bOr R
a-N-R
bDeng.
The compound of formula of the present invention (I) structure includes but not limited to following particular compound or its oxynitride, hydrate, and solvate, meta-bolites, pharmacy acceptable salt or its prodrug:
Unless other aspects show, the steric isomer that compound of the present invention is all, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, salt and pharmaceutically acceptable prodrug all belong to scope of the present invention.
Specifically, salt is pharmacy acceptable salt.Term " pharmaceutically acceptable " comprises that material or composition must be to be fit to chemistry or toxicologically, and is relevant with other components of forming preparation and the Mammals that is used for the treatment of.
The salt of compound of the present invention also comprise for the preparation of or purifying formula (I) shown in the salt of enantiomer of compound separation shown in the intermediate of compound or the formula (I), but pharmacy acceptable salt not necessarily.
If compound of the present invention is alkaline, then conceivable salt can obtain by the prepared by any suitable process that provides on the document, for example, uses mineral acid, example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid etc.Perhaps use organic acid, as acetic acid, toxilic acid, succsinic acid, amygdalic acid, fumaric acid, propanedioic acid, pyruvic acid, oxalic acid, hydroxyethanoic acid and Whitfield's ointment; The pyrans saccharic acid is as glucuronic acid and galacturonic acid; Alpha-hydroxy acid is as citric acid and tartrate; Amino acid is as aspartic acid and L-glutamic acid; Aromatic acid is as phenylformic acid and styracin; Sulfonic acid, as tosic acid, ethyl sulfonic acid, etc.
If compound of the present invention is acid, then conceivable salt can prepare by suitable method, as, use mineral alkali or organic bases, as ammonia (uncle's ammonia, parahelium, uncle's ammonia), alkali metal hydroxide or alkaline earth metal hydroxides, etc.Suitable salt comprises, but is not limited to, and from the organic salt that amino acid obtains, as glycine and arginine, ammonia is as uncle's ammonia, parahelium and uncle's ammonia, with ring-type ammonia, as piperidines, morpholine and piperazine etc. and from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium obtain inorganic salt.
The present invention also comprises the application of compound of the present invention and pharmacy acceptable salt thereof, and the disease of mediation namely takes place for the production of pharmaceutical prod treatment acute and chronic blood vessel, comprises the application in producing cancer therapy drug that those are described in the invention.Compound of the present invention alleviates for the production of a kind of medical supplies equally, stops the disease that control or treatment are mediated by ALK or c-Met.The present invention comprises pharmaceutical composition, and this pharmaceutical composition comprises compound and at least one pharmaceutically acceptable carrier of formula (I) representative, assistant agent or thinner in conjunction with required effective treatment consumption.
The present invention comprises the disease that mediates for the treatment of patient vessel equally, or to the method for this illness sensitivity, this method comprises the treatment significant quantity of use formula (I) representative compound the patient is treated.
Composition
According on the other hand, the present invention also provides a kind of pharmaceutical composition, comprises the compound of formula (I), the compound that the present invention is listed, or the compound of embodiment 1-24 and pharmaceutically acceptable carrier, assistant agent, or vehicle.The amount of compound can effectively, detectablely suppress the protein kinase in biological sample or the patient's body in the composition of the present invention.
There is free form in compound of the present invention, or suitable, as pharmaceutically acceptable derivates.According to the present invention, pharmaceutically acceptable derivates comprises, but be not limited to, pharmaceutically acceptable prodrug, salt, ester, the salt of ester class, or can be directly or indirectly according to other any adducts or derivatives of patient's needs administration, other aspects of the present invention described compound, its meta-bolites or his residue.
Picture is described in the invention, and the pharmaceutically acceptable composition of the present invention further comprises pharmaceutically acceptable carrier, assistant agent, or vehicle, these are applied as the present invention, comprise any solvent, thinner, or other liquid excipients, dispersion agent or suspension agent, tensio-active agent, isotonic agent, thickening material, emulsifying agent, sanitas, solid binder or lubricant, etc., be suitable for distinctive target formulation.Described as following document: In Remington:The Science and Practice of Pharmacy, 21st edition, 2005, ed.D.B.Troy, Lippincott Williams﹠amp; Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988-1999, Marcel Dekker, New York, the comprehensive content of document herein shows that different carriers can be applicable to preparation and their known preparation methods of pharmaceutically acceptable composition.Carrier medium and the inconsistent scope of compound of the present invention except any routine, the any bad biological effect that for example produces or the interaction that produces in harmful mode with any other component of pharmaceutically acceptable composition, their purposes also is the scope that the present invention considers.
The material that can be used as pharmaceutically acceptable carrier comprises, but is not limited to ion-exchanger, aluminium, aluminum stearate, Yelkin TTS, serum protein, as the human serum protein, buffer substance such as phosphoric acid salt, glycine, Sorbic Acid, potassium sorbate, the partial glycerol ester mixture of saturated vegetable fatty acid, water, salt or ionogen, as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, colloid silicon, Magnesium Trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-blocking-up polymer, lanolin, sugar, as lactose, dextrose plus saccharose; Starch such as W-Gum and potato starch; Mierocrystalline cellulose and its derivative such as Xylo-Mucine, ethyl cellulose and rhodia; The natural gum powder; Fructus Hordei Germinatus; Gelatin; Talcum powder; Auxiliary material such as cocoa butter and suppository wax; Oily as peanut oil, oleum gossypii seminis, Thistle oil, sesame oil, sweet oil, Semen Maydis oil and soya-bean oil; The glycols compound is as propylene glycol and polyoxyethylene glycol; Ester class such as ethyl oleic acid ester and ethyl laurate; Agar; Buffer reagent such as magnesium hydroxide and aluminium hydroxide; Lalgine; Pyrogen-free water; Deng oozing salt; Lin Ge (family name) solution; Ethanol, phosphate buffer solution and other nontoxic examples of suitable lubricants such as Sulfuric acid,monododecyl ester, sodium salt and Magnesium Stearate, tinting material, releasing agent, dressing dress material, sweeting agent, seasonings and spices, sanitas and antioxidant.
Composition of the present invention can be oral administration, drug administration by injection, and the spraying inhalation, topical, the per rectum administration, nose administration contains the clothes administration, vagina administration or by the administration of the property implanted medicine box.Term as used herein " through what inject " comprises subcutaneous, vein, intramuscular, IA, in the synovial membrane (chamber), intrasternal, in the film, intraocular, in the liver, injection intralesional and encephalic or infusion techniques.Preferred compositions is oral administration, to intraperitoneal administration or intravenous injection.The injection system of composition sterile of the present invention can be suspension water or oleaginous.These suspension can adopt suitable dispersion agent, wetting agent and suspension agent to make by prescription according to known technology.Aseptic injection can be aseptic parenteral solution or suspension, is nontoxic acceptable diluent or solvent of injection, as 1,3 butylene glycol solution.These acceptable vehicle and solvent can be water, Ringer's solution and isotonic sodium chlorrde solution.Further, aseptic nonvolatile oil can be used as solvent or suspension medium by convention.
With this end in view, the nonvolatile oil of any gentleness can be list or the DG that synthesizes.Lipid acid can be used for the preparation of injectable as the glyceride derivative of oleic acid and it, as natural pharmaceutically acceptable grease, and as sweet oil or Viscotrol C, their polyoxyethylene deriv particularly.These oil solutions or suspension can comprise long-chain alcohol thinner or dispersion agent, and as carboxymethyl cellulose or similar dispersion agent, the pharmaceutical preparation that generally is used for pharmaceutically acceptable formulation comprises emulsion and suspension.The tensio-active agent that other are commonly used, as Tweens, the reinforcer of spans and other emulsifying agents or bioavailability generally is used for pharmaceutically acceptable solid, liquid, or other formulations, and can be applied to the preparation of drug target preparation.
The pharmaceutically acceptable composition of the present invention can be to carry out oral administration with any acceptable oral dosage form, comprising, but be not limited to capsule, tablet, water suspension processed or solution.Orally use about tablet, carrier generally comprises lactose and W-Gum.Lubricant as Magnesium Stearate, all typically is added.For the capsule oral administration, suitable diluent comprises lactose and the W-Gum of doing.When oral administration was water suspension processed, its effective constituent was made up of emulsifying agent and suspension agent.If expect these formulations, some sweeting agent, seasonings or tinting material also can be added.
In addition, the pharmaceutically acceptable composition of the present invention can be with the form rectal administration of suppository.These can form by reagent and suitable non-perfusion adjuvant are mixed with, and this adjuvant at room temperature is solid but is liquid in that the temperature of rectum is next, thus fusing and discharge medicine in rectum.Such material comprises cocoa butter, beeswax, and polyethylene glycols.The pharmaceutically acceptable composition of the present invention can be topical, and particularly during local application, the therapeutic goal that relates to zone or organ reaches easily, as the disease of eye, skin or lower intestinal tract.Suitable local application's preparation can prepare and be applied to these fields or organ.
Above-mentioned rectal suppository or suitable enema can be applied to the local application of lower intestine.The local skin spot is medication so also.For local application, pharmaceutically acceptable composition can be prepared into suitable ointment by formulation method, and this ointment comprises activeconstituents and is suspended in or is dissolved in one or more carriers.The carrier compound of topical of the present invention comprises, but is not limited to mineral oil, whiteruss, white vaseline, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.In addition, pharmaceutically acceptable composition can be prepared into suitable lotion or emulsion, and this lotion or emulsion comprise activeconstituents and is suspended in or is dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers comprises, but is not limited to mineral oil, Arlacel-60 (Arlacel-60), polysorbate60 (Polysorbate 60), cetyl esters wax, palmityl alcohol, 2-Standamul G, phenylcarbinol and water.
Can be prepared into preparation for composition eye usefulness, pharmaceutically acceptable; as the micronize suspension that grade is oozed, the Sterile Saline of pH regulator or other aqueous solution, preferably; the Sterile Saline of isotonic solution and pH regulator or other aqueous solution can add disinfection preservative such as benzalkonium chloride.In addition, for eye usefulness, pharmaceutically acceptable composition can be prepared into ointment such as vaseline oil by pharmaceutical formulation.The pharmaceutically acceptable composition of the present invention can carry out administration by gaseous solvents or the inhalation of nose.Such composition can prepare according to the known technology of pharmaceutical formulation, maybe can be prepared into salts solution, use phenylcarbinol or other suitable sanitass, absorption enhancer, fluorocarbon or other conventional solubilizing agent or dispersion agent to improve bioavailability.
The liquid dosage form of oral administration comprises, but is not limited to pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir.Except the active ingredient beyond the region of objective existence, liquid dosage form can comprise known general inert diluent, for example, and water or other solvents, solubilizing agent and emulsifying agent, as ethanol, Virahol, ethyl-carbonate, ethyl acetate, phenylcarbinol, peruscabin, propylene glycol, 1,3 butylene glycol, dimethyl formamide, grease (cottonseed particularly, Semen arachidis hypogaeae, corn, microorganism, olive, castor-oil plant and sesame oil), glycerine, Tetrahydrofurfuryl Alcohol, polyoxyethylene glycol, sorbitan alcohol fatty acid ester, and their mixture.Except the thinner of inertia, oral compositions also can comprise assistant agent such as wetting agent, emulsifying agent or suspension agent, sweeting agent, seasonings and perfume compound.
Injection can adopt suitable dispersion agent, wetting agent and suspension agent to prepare by pharmaceutical formulation according to known technology as aseptic parenteral solution or oleaginous suspension.Aseptic injection can be nontoxic aseptic parenteral solution, suspension or the emulsion of making through acceptable diluent or solvent parenterally, for example, and 1,3 butylene glycol solution.Acceptable vehicle and solvent can be water, Lin Ge (family name) solution, U.S.P. and isotonic sodium chlorrde solution.In addition, aseptic nonvolatile oil is by convention as solvent or suspension medium.With this end in view the nonvolatile oil of any gentleness can comprise synthetic list or DG.In addition, lipid acid such as oleic acid can be applied to injection.
Injection can be aseptic, filters as defending strainer by bacterium, or mixes disinfectant with the form of aseptic solid composite, and disinfectant can be dissolved in or be scattered in sterilized water or other aseptic injection media before use.In order to prolong the effect of compound of the present invention, need slow down the absorption of compound usually by subcutaneous injection or intramuscularly.Can realize utilizing liquid suspension to solve the problem of crystal or amorphous material poorly water-soluble like this.The specific absorption of compound depends on its dissolution rate, depends on grain size and crystal shape successively.In addition, can in the oils vehicle, dissolve or disperse to finish the delay absorption of compound injection administration by compound.
Injection storage form is by biodegradable polymkeric substance, finishes as the microcapsule matrix of many lactic acid-polyglycolide formation compound.The controlled release ratio of compound depends on the ratio of compound formation polymkeric substance and the character of particular polymer.Other biodegradable polymers comprise poly-(positive ester class) and gather (acid anhydrides).Injection storage form also can embed liposome or the microemulsion compatible with bodily tissue by compound and prepare.
Some of them embodiment is, the composition of rectum or vagina administration is suppository, suppository can be by mixing compound of the present invention to prepare with auxiliary material or the carrier of suitable non-perfusion, as cocoa butter, polyoxyethylene glycol, or the suppository wax, they are solid but next for liquid at body temperature in room temperature, therefore just melt release of active compounds in vagina or cavity of tunica vaginalis.
The solid dosage of oral administration comprises capsule, tablet, pill, pulvis and granula.In these formulations, active compound mixes with at least a pharmaceutically acceptable inert excipient or carrier, as Trisodium Citrate or calcium phosphate or filling agent or a) weighting agent such as starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid, b) tackiness agent such as carboxymethyl cellulose, alginate, gelatin, Povidone, sucrose and gum arabic, c) wetting Agent for Printing Inks such as glycerine, d) disintegrating agent such as agar, calcium carbonate, potato starch or tapioca (flour), Lalgine, some silicate and yellow soda ash, e) retarding agent solution such as paraffin, f) absorption enhancer such as quaternary ammonium compounds, g) wetting agent such as hexadecanol and glyceryl monostearate, h) absorption agent such as white bole and bentonite, i) lubricant such as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, Sulfuric acid,monododecyl ester, sodium salt, and their mixture.As for capsule, tablet and pill, these formulations can comprise buffer reagent.
The solids composition of similar type can be that weighting agent riddles soft or hard capsule, and employed auxiliary material has lactose and high molecular polyoxyethylene glycol etc.The agent of solid dosage photo, lozenge, capsule, pill and granula can be by dressings, add that known coating method prepares on shell such as enteric coating and the other drug preparation.They can randomly comprise opalizer, or preferably, in certain part of enteron aisle, at random, with the unique activeconstituents in the method release composition that postpones.Can comprise polymer material and wax as implant compositions.
Active compound can form microcapsule formulations with one or more vehicle described in the invention.The agent of solid dosage photo, lozenge, capsule, pill and granula can or add shell by dressing, as enteric coating, controlled release coat and other known drug formulation process.In these solid dosages, active compound can mix with at least a inert diluent, as sucrose, and lactose or starch.Such formulation also can comprise substance except inert diluent as general application, as compressing tablet lubricant and other compression aids such as Magnesium Stearate and Microcrystalline Cellulose.As for capsule, tablet and pill, these formulations can comprise buffer reagent.They can randomly comprise tranquilizer, or preferably, in certain part of enteron aisle, with the unique activeconstituents in the method release composition of any delay.Applicable implant compositions can comprise, but be not limited to polymer and wax.
Compound of the present invention by the part or comprise ointment, paste, emulsion, lotion, gelifying agent, pulvis, solution, sprays, inhalation, paster through the formulation of percutaneous drug delivery.Activeconstituents mixes mutually with pharmaceutically acceptable carrier and any essential sanitas or essential buffer reagent under aseptic condition.The pharmaceutical preparation of ophthalmology, ear drop and eye drops all are the scopes that the present invention considers.In addition, the present invention also considers the application of transdermal patch, and it has more advantage aspect the control compound is delivered in the body, and such formulation can prepare in suitable medium by dissolving or decentralized compound.Absorption enhancer can increase the flow that compound passes skin, through-rate control film or compound is scattered in polymer matrix or gelatin is controlled its speed.
Compound of the present invention preferably is prepared into the dose unit type to alleviate the homogeneity of dosage and dosage by pharmaceutical formulation.Term " dosage " unit's type " refer to that herein the patient is suitably treated the physics discrete units of required medicine.Yet, should be appreciated that compound of the present invention or composition total usage every day will be next definite according to reliable medical science scope judgement by the doctor in charge.Concrete effective dose level will depend on that for any one special patient or organism many factors comprise the illness of being treated and the seriousness of illness, the activity of particular compound, used concrete composition, patient's age, body weight, healthy state, sex and food habits, administration time, the discharge rate of route of administration and used particular compound, the time length for the treatment of, medicinal application in drug combination or with specific compound coupling, and the known factor of some other pharmaceutical field.
Can depend in conjunction with the change of consumption that carrier substance produces the compound of the present invention of single dosage form composition and cure mainly and special mode of administration.Some of them embodiment is that composition can be prepared into dosage at the inhibitor of 0.01-200mg/kg body weight/day by formulation method, accepts the amount of composition by the patient and carries out administration.
Compound of the present invention can come administration with only pharmaceutical agents or in conjunction with one or more other additional treatment (pharmacy) agent, wherein drug combination causes acceptable untoward reaction, and this has special meaning for high proliferative disease such as treatment for cancer.In this case, compound of the present invention can be in conjunction with known cytotoxic agent, single transduction inhibitor or other antitumor and anticancer agents, and their mixture and combination.Picture is used in the present invention, the disease that the normal drug treatment of additional treatment agent is special, known exactly " treating disease suitably "." additional treatment agent " used in the present invention comprises that chemotherapeutic agent or other antiproliferative medicines can be in conjunction with compounds for treating proliferative disease of the present invention or cancers.
Chemotherapeutic agent or other anti-proliferative drugs comprise histon deacetylase (HDAC) (HDAC) inhibitor, include, but are not limited to SAHA, MS-275; MGO103, and the described compound of those following patents: 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 reagent comprises, but is not limited to, 5-mix nitrogen-2 '-Deoxyribose cytidine (5-aza-dC); azacitidine (Vidaza); Decitabine (Decitabine) and the described compound of following document: 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 that chemotherapy agents or other anti-proliferative drugs can be in conjunction with compounds for treating proliferative disease of the present invention and cancers.Known chemotherapy agents comprises, but be not limited to, other therapies or the cancer therapy drug that can unite use with cancer therapy drug of the present invention, operation, radiotherapy (a little example such as gamma-radiation, the neutron beam radiotherapy, the electron beam radiotherapy, proton therapy, brachytherapy and system's isotope therapy), endocrinotherapy, taxanes (taxol (Taxol), Docetaxel (Taxotere) etc.), platinum derivatives (cis-platinum (Cisplatin), carboplatin (Carboplatin), oxaliplatin (oxaliplatin), husky platinum (satraplatin)), biological response modifier (Interferon, rabbit, interleukin), tumour necrosis factor (TNF, TRAIL receptor target thing), overheated and psychrotherapy, alleviate the reagent (as antiemetic) of any untoward reaction, with other approved chemotherapeutics, include, but are not limited to, alkanisation medicine (mustargen (mechlorethamine), Chlorambucil (chlorambucil), endoxan (cyclophosphamide), melphalan (melphalan), ifosfamide (Ifosfamide)), metabolic antagonist (methotrexate (Methotrexate), pemetrexed (Pemetrexed) etc.), purine antagonist and pyrimidine antagonist (6-mercaptopurine (6-Mercaptopurine), 5 FU 5 fluorouracil (5-Fluorouracil), cytosine arabinoside (Cytarabile), gemcitabine (Gemcitabine)), spindle poison (vinealeucoblastine(VLB) (Vinblastine), vincristine(VCR) (Vincristine), vinorelbine (Vinorelbine)), podophyllotoxin (Etoposide (Etoposide), irinotecan (Irinotecan), Hycamtin (Topotecan)), microbiotic (Zorubicin (Doxorubicin), bleomycin (Bleomycin), mitomycin (Mitomycin)), nitrosourea (carmustine (Carmustine), lomustine (Lomustine)), (KSP is by the mitotic kinesins inhibitor for the cell division cycle inhibitor, CENP-E and CDK inhibitor), enzyme (asparaginase (Asparaginase)), hormone (tamoxifen (Tamoxifen), Leuprolide (Leuprolide), flutamide (Flutamide), megestrol (Megestrol), dexamethasone (Dexamethasone) etc.).Angiogenesis inhibitor reagent (Avastin (Avastin) etc.).Monoclonal antibody (Baily monoclonal antibody (Belimumab), Brentuximab, Cetuximab (Cetuximab), WAY-CMA 676 (Gemtuzumab), her monoclonal antibody (Ipilimumab), Ofatumumab, handkerchief Buddhist nun monoclonal antibody (Panitumumab), thunder pearl monoclonal antibody (Ranibizumab), Rituximab (Rituximab), tositumomab (Tositumomab), Herceptin (Trastuzumab)).Kinase inhibitor (imatinib (Imatinib), Sutent (Sunitinib), Xarelto (Sorafenib), Tarceva (Erlotinib), Gefitinib (Gefitinib), Dasatinib (Dasatinib), Ni Luo is for Buddhist nun (Nilotinib), lapatinibditosylate (Lapatinib), gram is tall and erect for Buddhist nun (Crizotinib), Ruxolitinib, Vemurafenib, Vandetanib, Pazopanib, etc.).Medicine suppresses or activates approach such as the mTOR of cancer, HIF (hypoxia inducible factor) approach and other.Http:// www.nci.nih.gov/ is seen in cancer therapy forum more widely, the oncology list of medications of FAD approval is seen http://www.fda.gov/cder/cancer/druglist-rame.htm, with the Merck handbook, the 18 edition .2006, all contents all are to combine reference.
Other embodiment is that compound of the present invention can be in conjunction with the cytotoxin carcinostatic agent.Such carcinostatic agent can find in the 13 edition the Merck index (2001) lining.These carcinostatic agents comprise, but never are limited to asparaginase, bleomycin, carboplatin, carmustine, Chlorambucil, cis-platinum, altheine enzyme, endoxan, cytosine arabinoside, Dacarbazine, dactinomycin, daunorubicin, Zorubicin (Dx), epirubicin, Etoposide, 5-fluor-uracil, hexamethyl trimeric cyanamide, hydroxyurea, ifosfamide, irinotecan, folinic acid, lomustine, mustargen, Ismipur, mesna, methotrexate, ametycin, mitoxantrone, prednisolone, prednisone, Procarbazine, raloxifene, streptozocin, tamoxifen, Tioguanine, Hycamtin, vinealeucoblastine(VLB), vincristine(VCR), and vindesine.
Comprise with other suitable cytotoxic drugs of compound drug combination of the present invention, but be not limited to, these are applied to the compound of neoplastic disease treatment admittedly, described in following document: Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition, 1996, McGraw-Hill.); These carcinostatic agents comprise; but never be limited to; aminoglutethimide (Aminoglutethimide); the L-Asparaginase; azathioprine; 5-azacytidine, CldAdo (Cladribine), busulfan (Busulfan); stilboestrol; 2,2'-difluoro dCDP choline, Docetaxel; red hydroxyl nonyl VITAMIN B4 (Erythrohydroxynonyladenine); Ethinylestradiol, 5 FU 5 fluorouracil deoxynucleoside, floxuridine monophosphate; fludarabine phosphate (Fludarabine phosphate); Fluoxymesterone (Fluoxymesterone), flutamide (Flutamide), Hydroxyprogesterone caproate bp 98; idarubicin (Idarubicin); Interferon, rabbit, medroxyprogesterone acetate, Magace; melphalan (Melphalan); mitotane (Mitotane), taxol, pentostatin (Pentostatin); N-phosphoric acid ethanoyl-L-aspartic acid (PALA); Plicamycin (Plicamycin), Me-CCNU (Semustine), teniposide (Teniposide); Uniteston; plug is for sending (Thiotepa), trimethylammonium trimeric cyanamide, urine nucleosides and vinorelbine.
Other cytotoxin class carcinostatic agents suitable and compound combined utilization of the present invention comprise newfound cytotoxic substance, comprising, but be not limited to, oxaliplatin (Oxaliplatin), gemcitabine (Gemcitabine), capecitabine (Capecitabine), Macrolide antitumour drug and natural or synthetic derivative thereof, 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), with kinesin spindle body protein inhibitor Eg5 (Wood et al., Curr.Opin.Pharmacol.2001,1,370-377).
Other embodiment is that compound of the present invention can be in conjunction with other signal transduction inhibitors.What is interesting is signal transduction inhibitor 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) with their parts separately.Such reagent comprises, but never is limited to, antibody therapy such as Herceptin (Trastuzumab), Cetuximab (Cetuximab), her monoclonal antibody (Ipilimumab) and handkerchief trastuzumab (Pertuzumab).Such therapy also comprises, but never is limited to small molecules kinase inhibitor such as imatinib (Imatinib), Sutent (Sunitinib), Xarelto (Sorafenib), Tarceva (Erlotinib), Gefitinib (Gefitinib), Dasatinib (Dasatinib), the Buddhist nun Lip river is for Buddhist nun (Nilotinib), lapatinibditosylate (Lapatinib), gram is tall and erect for Buddhist nun (Crizotinib), Ruxolitinib, Vemurafenib, Vandetanib, Pazopanib, Ah method replaces Buddhist nun (Afatinib), amuvatinib, and A Xi is for Buddhist nun (axitinib), ripple relaxes for Buddhist nun (bosutinib), brivanib, canertinib, cabozantinib, ground, west Buddhist nun's cloth (cediranib), dabrafenib, dacomitinib,, danusertib, dovitinib, foretinib, ganetespib, ibrutinib, iniparib, lenvatinib, linifanib, linsitinib, the Marseille is for Buddhist nun (masitinib), momelotinib, for husky Buddhist nun (motesanib), do not come that to replace Buddhist nun (neratinib), niraparib, oprozomib, olaparib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, fork clip is for Buddhist nun (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 that compound of the present invention can the bonding histone deacetylase inhibitors.Such reagent comprises, but never is 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 that compound of the present invention can be in conjunction with other carcinostatic agents such as proteasome inhibitor and m-TOR inhibitor.These comprise, but never be limited to Velcade (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).Compound of the present invention can also be in conjunction with other carcinostatic agents such as topoisomerase enzyme inhibitor, comprises but never is limited to camptothecine.
Those additional treatment agent can with comprise compound compositions separate administration of the present invention, as the part of many dosage regimens.Perhaps, those therapeutical agents can be the parts of one-pack type, form single composition with compound of the present invention together.If administration is as the part of many dosage regimens, two promoting agents can transmit mutually simultaneously continuously or in for some time, thereby obtain the destination agent activity.
Can produce compound and the additional treatment agent of one-pack type in conjunction with carrier substance, the change of its consumption (those compositions that comprise an additional treatment agent are as described in the invention) is depended on and is cured mainly and special mode of administration.Normally, the amount of composition additional treatment of the present invention agent will be no more than composition and comprise therapeutical agent as the amount of the normal administration of unique promoting agent.On the other hand, the scope of the amount of existing disclosed composition additional treatment agent approximately is the 50%-100% of existing composition normal amount, and the reagent that comprises is as unique active therapeutic agent.Comprise in the composition of additional treatment agent at those, the additional treatment agent will play synergy with compound of the present invention.
The application of compound and composition
Above-claimed cpd provided by the invention and pharmaceutical composition can be used for for the preparation of the medicine that protects, handles, treats or alleviate proliferative disease, also can be for the preparation of the medicine that is used for suppressing or regulating protein kinase activity.
Particularly, the compound activity of arrestin kinases such as ALK or c-Met effectively detectablely in the composition of the present invention.The compounds of this invention can be used as ALK and c-Met signal response were treated or reduced to antitumor drug to the patient deleterious effect.
Compound of the present invention can be applied to, but never is limited to, and uses the significant quantity of compound of the present invention or composition patient's administration to be prevented or treats patient's proliferative disease.Such disease comprises cancer, metastatic carcinoma especially, atherosclerosis and pulmonary fibrosis etc.
Compound of the present invention and pharmaceutical composition can be applied to the treatment of knurl, comprise cancer and metastatic carcinoma, further include, but are not limited to, cancer such as bladder cancer, mammary cancer, colorectal carcinoma, kidney, liver cancer, lung cancer (comprising small cell lung cancer), esophagus cancer, carcinoma of gallbladder, ovarian cancer, carcinoma of the pancreas, cancer of the stomach, cervical cancer, thyroid carcinoma, prostate cancer, and skin carcinoma (comprising squamous cell carcinoma); Lymphsystem hematopoiesis tumour (comprises leukemia, acute lymphoblastic tumour leukemia, acute lymphoblastic leukemia, B cell lymphoma, t cell lymphoma, He Jiejin (family name) lymphoma, non-hodgkin's (family name) lymphoma, hairy cell leukemia and Burkitt lymphoma); Marrow system hematopoiesis tumour (comprising the acute and chronic myelocytic leukemia, myelodysplastic syndrome and promyelocyte leukemia); The tumour (comprising fibrosarcoma and rhabdosarcoma and other sarcomas, as soft tissue and cartilage) of mesenchymal cell origin; Maincenter peripheral nervous system knurl (comprising astrocytoma, neuroblastoma, neurospongioma, and schwannoma); With other tumours (comprising melanoma, spermocytoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicle knurl and Ka Bo Ji (family name) sarcoma).
Compound of the present invention and pharmaceutical composition also can be used for treating for example corneal graft rejection of eye disease, and the new vessel of eye forms, and retinal neovascularization forms and comprises that damage or metainfective new vessel form; Diabetic retinopathy; Terry's sign disease, and neovascular glaucoma; Retinal ischemia; Vitreous hemorrhage; Ulcer disease such as stomach ulcer; Pathological but non-pernicious situation such as vascular tumor comprise baby's hemangioendothelioma, the hemangiofibroma of nasopharynx and ANB; Female repro ductive system is disorderly as endometriosis.These compounds equally also are used for the treatment of oedema and the too high situation of vascular permeability.
Compound of the present invention and pharmaceutical composition can also be for the treatment of the situation relevant with diabetes such as diabetic retinopathy and microangiopathies.Compound of the present invention and pharmaceutical composition are used for the situation that cancer patients's volume of blood flow reduces equally.Compound of the present invention and pharmaceutical composition shift to reduce to patient tumors also beneficial effect.
Compound of the present invention and pharmaceutical composition also can be applicable to the animal of veterinary treatment pet, introduced variety and the animal on farm except useful to the human treatment, comprise Mammals, rodent etc.The example of other animal comprises horse, dog and cat.At this, compound of the present invention comprises its pharmaceutically acceptable derivates.
Plural form is being applied to compound, and under the situation of salt etc., it also means single compound, salt etc.
The present invention also provides the methods for the treatment of that comprises compound of the present invention or composition administration, further comprise the administration to patient's additional treatment agent (combination therapy), wherein the additional treatment agent is selected from: chemotherapy, antiproliferative or anti-inflammatory agent, wherein the additional treatment agent is applicable to the disease for the treatment of, and the additional treatment agent can with compound of the present invention or composition Combined Preparation, compound of the present invention or composition be as single formulation, or the compound that separates or composition are as the part of multi-form.The additional treatment agent can with compound of the present invention administration simultaneously or not administration simultaneously.The latter's situation, administration can stagger and carry out as 6 hours, 12 hours, 1 day, 2 days, 3 days, in 1 week, in 2 weeks, in 3 weeks, carry out in 1 month or 2 months.
The present invention comprises equally to expressing the cytostatic method of ALK or c-Met, and this method comprises compound of the present invention or composition and cells contacting, thus cell growth inhibiting.The cell that can be suppressed growth comprises: breast cancer cell, colorectal cancer cell, lung carcinoma cell, the papillary carcinoma cell, prostate cancer cell, lymphoma cell, colon cancer cell, pancreatic cancer cell, ovarian cancer cell, cervical cancer cell, central nervous system cancer cells, human osteosarcoma cell, kidney cancer cell, hepatocellular carcinoma cells, transitional cell bladder carcinoma cell line, stomach cancer cell, head or carcinoma of neck cell, melanoma cell and leukemia cell.
The invention provides in biological sample the method that suppresses ALK or c-Met kinase activity, this method comprises compound of the present invention or composition is contacted with biological sample.Term used in the present invention " biological sample " refers to the sample of live body outside, comprises but never is limited to cell cultures or cell extraction; The examination of living tissue material that obtains from Mammals or its extract; Blood, saliva, urine, ight soil, seminal fluid, tears, or other living tissue liquid substance and extracts thereof.Suppress kinase activity, particularly ALK or c-Met kinase activity in the biological sample, can be used for the known multiple use of one of ordinary skill in the art.Such purposes comprises, but never is limited to hematometachysis, organ transplantation, biological sample storage and biological assay.
" significant quantity " of compound of the present invention or pharmaceutically acceptable composition or " effective dose " refer to handle or alleviate the significant quantity of the severity of illness that one or more the present invention mentions.The method according to this invention, compound and composition can be the severity that any dosage and any route of administration are come effectively for the treatment of or palliated a disease.Essential amount accurately will change according to patient's situation, and this depends on the race, the age, and patient's general condition, the severity of infection, special factor, administering mode, etc.Compound or composition can with one or more other treatment agent Combined Preparation, discuss as the present invention.
Compound of the present invention or its pharmaceutical composition can be applied to the dressing of implantable medical device, as prosthese, and artificial valve, artificial blood vessel, stem and catheter.For example, the vascular stem has been used to overcome restenosis (contraction again of damage back vessel wall).Yet the patient uses stem or other implantable devices will have the risk of clot formation or platelet activation.These disadvantageous effects can stop by the pharmaceutically acceptable composition precoating device that use comprises compound of the present invention or alleviate.
The general preparation method of suitable dressing and the dressing of implantable device is in document US 6,099,562; US5,886,026; And US5, to describe to some extent in 304,121, dressing is biocompatible polymer material such as hydrogel polymer typically, poly-methyl two silicon ethers, polycaprolactone, polyoxyethylene glycol, poly(lactic acid), ethane-acetic acid ethyenyl ester, and composition thereof.Dressing can randomly further be covered by suitable dressing, as the fluoro Simethicone, and polysaccharidase, polyoxyethylene glycol, phospholipid, or their combination, the feature of coming the control of performance group compound to discharge.Another aspect of the present invention comprises the implantable device that uses compound coating of the present invention.Compound of the present invention also can be coated on the interior medical instruments of implantable, as pearl, or " medicine storage institute " be provided with polymkeric substance or other molecular mixing, therefore with the pharmaceutical aqueous solution administering mode relatively, allow drug release that longer time limit is arranged.
The synthetic method of compound
Usually, compound of the present invention can prepare by method described in the invention, unless further instruction is arranged, wherein substituent definition is suc as formula shown in (I).Following reaction scheme and embodiment are used for further illustrating content of the present invention.
The professional in affiliated field will recognize: chemical reaction described in the invention can be used for preparing suitably many other compounds of the present invention, and all is contemplated within the scope of the present invention for the preparation of other method of compound of the present invention.For example; the synthetic of the compound of those non-illustrations can successfully be finished by modifying method by the those skilled in the art according to the present invention; disturb group as suitable protection, by utilizing other known reagent except described in the invention, or reaction conditions is made the modification of some routines.In addition, reaction disclosed in this invention or known reaction conditions also are applicable to the preparation of other compounds of the present invention admittedly.
The embodiments described below are decided to be degree centigrade unless other aspects show all temperature.Reagent is bought in goods providers such as Aldrich Chemical Company, and Arco Chemical Company and Alfa Chemical Company is unless other aspects show all do not have during use through being further purified.General reagent is from chemical plant, Gansu Province, west, Shantou, Guangdong brilliance chemistry chemical reagent work, Guangzhou Chemical Reagent Factory, the Tianjin space chemical company limited of residing well, Tianjin good fortune chemical reagent in morning factory, the prosperous China in Wuhan development in science and technology far away company limited, imperial chemical reagent company limited is risen in Qingdao and Haiyang Chemical Plant, Qingdao's purchase obtains.
Anhydrous tetrahydro furan, dioxane, toluene, ether are to obtain through sodium Metal 99.5 backflow drying.Anhydrous methylene chloride and chloroform are to obtain through hydrolith backflow drying.Ethyl acetate, sherwood oil, normal hexane, N,N-dimethylacetamide and N, dinethylformamide are through anhydrous sodium sulphate dry use in advance.
Below reaction generally is at nitrogen or argon gas direct draught or at anhydrous solvent cover one drying tube (unless showing aspect other), and reaction flask is suitable soft rubber ball beyond the Great Wall all, and substrate is squeezed into by syringe.Glassware all is dry the mistake.
Chromatographic column is to use silicagel column.Silica gel (300-400 order) is purchased in Haiyang Chemical Plant, Qingdao.NMR (Nuclear Magnetic Resonance) spectrum is with CDC1
3, d
6-DMSO, CD
3OD or d
6-acetone is solvent (report is unit with ppm), uses TMS (0ppm) or chloroform (7.25ppm) as reference standard.When multiplet occurring, following abbreviation will be used: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, quartet), dt (doublet of triplets, two triplets).Coupling constant is with hertz (Hz) expression.
The condition of low resolution mass spectrum (MS) data is: and Agilent1200 or Agilent6120Series LCMS (the pillar model: Zorbax SB-C18,2.1 * 30mm, 3.5 microns, 6min, flow velocity are 0.6mL/min.Moving phase: 5-95%(contains the CH of 0.1% formic acid
3CN) at (H that contains 0.1% formic acid
2O) ratio in detects with UV at 210/254nm, with low-response EFI pattern (ESI).
The characteristic manner of pure compound is: Agilent1100Series high speed liquid chromatography (HPLC), detect with UV at 210nm and 254nm.Pillar is operated under 40 ° of C usually.
BBr
3Boron tribromide
BINAP 2, the two diphenyl phosphines-1 of 2'-, 1'-dinaphthalene
BOC, the Boc tert-butoxycarbonyl
The BSA bovine serum albumin
CDC1
3Deuterochloroform
CHCl
3Chloroform
CH
2Cl
2, the DCM methylene dichloride
CH
3SO
2Cl, the MsCl Tosyl chloride
Cs
2CO
3Cesium carbonate
Cu copper
The CuI cuprous iodide
The DAST diethylaminosulfur trifluoride
DBU 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene
The DEAD diethyl azodiformate
The DIAD diisopropyl azodiformate
The DIBAL diisobutyl aluminium hydride
DIEA, the DIPEA diisopropyl ethyl amine
DMAP 4-Dimethylamino pyridine
DMF N, dinethylformamide
The DMSO dimethyl sulfoxide (DMSO)
The DPPA diphenyl phosphate azide
EDCI 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride
EtOAc, the EA ethyl acetate
Et
2The O ether
Et
3N, the TEA triethylamine
The FBS foetal calf serum
Fe iron
The g gram
H hour
HATU O-(7-pyridine and triazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester
The HBr Hydrogen bromide
HBTU O-benzotriazole-N, N, N', N'-tetramethyl-urea hexafluorophosphate
HCl hydrochloric acid
H
2Hydrogen
H
2O water
H
2O
2Hydrogen peroxide
HOAc, AcOH acetic acid
The HOBt I-hydroxybenzotriazole
K
2CO
3Salt of wormwood
KOH potassium hydroxide
LiHMDS hexamethyl two silica-based amido lithiums
The LDA lithium diisopropyl amido
The MCPBA metachloroperbenzoic acid
MeCN, CH
3The CN acetonitrile
The MeI methyl iodide
MeOH, CH
3OH methyl alcohol
2-MeTHF 2-methyltetrahydrofuran
MgSO
4Sal epsom
ML, the ml milliliter
N
2Nitrogen
NaBH
4Sodium borohydride
NaBH
3The CN sodium cyanoborohydride
NaCl sodium-chlor
NaClO
2Textone
The NaH sodium hydride
NaHCO
3Sodium bicarbonate
NaH
2PO
4SODIUM PHOSPHATE, MONOBASIC
The NaI sodium iodide
NaO (t-Bu) sodium tert-butoxide
NaOH sodium hydroxide
Na
2SO
4Sodium sulfate
NBS N-bromo-succinimide
NH
3Ammonia
NH
4The C1 ammonia chloride
NIS N-iodo succimide
The NMP N-Methyl pyrrolidone
The PBS phosphate buffered saline (PBS)
P (t-Bu)
3Three (tertiary butyl) phosphine
Pd/C palladium/carbon
Pd
2(dba)
3Two (dibenzyl subunit acetone) palladium
Pd (dppf) Cl
2Two (diphenylphosphino) ferrocene palladium chlorides of 1,1-
Pd (OAc)
2Palladium
Pd (OH)
2Palladium hydroxide
Pd (PPh
3)
4Tetrakis triphenylphosphine palladium
Pd (PPh
3)
2Cl
2Two (triphenylphosphine) palladium chloride
PE sherwood oil (60-90 ° of C)
POC1
3Phosphorus oxychloride
PyBop 1H-benzotriazole-1-base oxygen tripyrrole alkyl hexafluorophosphate
RT, rt, r.t. room temperature
The Rt retention time
The TBAB Tetrabutyl amonium bromide
TBAHSO
44-butyl ammonium hydrogen sulfate
TBTU O-(1H-benzotriazole-1-yl)-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid ester
The TFA trifluoroacetic acid
TEAC two (tetraethyl ammonium) carbonate
The THF tetrahydrofuran (THF)
μ L microlitre
Following synthetic schemes has been described the come into the open step of compound of preparation the present invention.Unless otherwise indicated, R
1, R
2, R
3, R
4, R
5, R
6Has definition as described in the present invention with Z.
Synthetic method 1
Compound shown in the formula (I) can prepare by following process:
Formula (
1) shown in (R)-aryl alcohol and formula (
2) shown in the fluorinated pyridine of replacement under the effect of sodium hydride, in aprotic solvent such as tetrahydrofuran (THF), react, obtain formula (
3) shown in coupled product.Formula (
3) shown in coupled product in nitro on the pyridine ring under the acidic reduction condition, use reductive agent such as iron powder change an accepted way of doing sth (
4) shown in aminocompound.Then under the NBS effect, by the regioselectivity bromination on the pyridine ring, obtain formula (
5) shown in compound.At last, formula (
5) shown in compound and formula (
6) shown in alkynes, as 2-methyl fourth-3-alkynes-2 alcohol, under suitable Pd catalyst action, the compound shown in the coupling production (I), reaction process is as follows:
Synthetic method 2
Compound shown in the formula (I) can prepare by following process:
According to the method in the synthetic method 1 or additive method prepare formula (
5) shown in compound, formula (
5) shown in compound and the Boc acid anhydrides in the presence of alkali such as yellow soda ash, sodium bicarbonate or triethylamine, production (
8) shown in the amido protecting compound.Formula (
8) shown in amido protecting compound and connection boric acid pinacol ester at the Pd catalyzer that is fit to, as Pd (dppf) Cl
2CH
2Cl
2And Pd (PPh
3)
2Cl
2Down coupling of effect, obtain formula (
9) shown in boronic acid compounds, this be reflected at non-protonic solvent (as, methyl-sulphoxide, N, dinethylformamide Huo diox) in carry out.Afterwards, at alkali and catalyzer such as Pd (dppf) Cl
2CH
2Cl
2Existence under, formula (
9) shown in boronic acid compounds and formula (
10) shown in nitrogen-containing heterocycle compound the Suzuki reaction takes place, production (
11) shown in compound.The alkali that is fit in the Suzuki reaction comprises sodium bicarbonate, saleratus, and yellow soda ash, salt of wormwood, cesium carbonate, and other.This reaction is preferably in mixed solvent, and as carrying out in glycol dimethyl ether/water ， diox/water, temperature is controlled between 70～100 ° of C.At last, under acidic conditions, as the dichloromethane solution of trifluoroacetic acid, the ethyl acetate solution of hydrogenchloride is sloughed Boc and other protecting groups, obtains the compound shown in the formula (I), and reaction process is as follows:
The present invention adopts following method that the compound shown in the formula (I) is carried out biological test:
1, bioanalytical method
Adopt the LC/MS/MS system to analyze, comprise Agilent1200 series vacuum degassing furnace, binary syringe pump, orifice plate automatic sampler, post thermostat container, three grades of level Four bars of Agilent G6430 mass spectrograph in charged spray ionization (ESI) source.Quantitative analysis is carried out under the MRM pattern, and the parameter of MRM conversion is shown in Table A:
The parameter of Table A MRM conversion
| Many reaction detection scannings | 490.2→383.1 |
| Cracked voltage | 230V |
| Capillary voltage | 55V |
| Dryer temperature | 350°C |
| Spraying gun | 40psi |
| The moisture eliminator flow velocity | 10L/min |
Analyze and use Agilent XDB-C18,2.1x30mm, 3.5 μ M posts inject 5 μ L samples.Analysis condition: moving phase is 0.1% aqueous formic acid (A) and 0.1% formic acid methanol solution (B).Flow velocity is 0.4mL/min.Eluent gradient is shown in table B:
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 |
In addition, the series of the Agilent6330 in addition LC/MS/MS spectrograph that is used for analyzing is equipped with G1312A binary syringe pump, G1367A automatic sampler and G1314C UV detector; The LC/MS/MS spectrograph adopts the ESI radioactive source.Each analyte is carried out suitable positively charged ion models treated to the use reference liquid and best analysis is carried out in the MRM conversion.Use Capcell MP-C18 post during analyzing, specification is: 100x4.6mm I.D., 5 μ M (Phenomenex, Torrance, California, USA).Moving phase is the 5mM ammonium acetate, 0.1% methanol aqueous solution (A): the 5mM ammonium acetate, 0.1% methanol acetonitrile solution (B) (70:30, v/v); Flow velocity is 0.6mL/min; Column temperature remains on room temperature; Inject 20 μ L samples.
2, the stability analysis of compound in people and rats'liver particulate
(1) places the polypropylene test tube to hatch people or rat liver microsomes, and guide it to copy.Typically hatch mixed solution and comprise people or rat liver microsomes (0.5mg protein/mL), compound to be analyzed (5 μ M) and cumulative volume are NADPH (1.0mM) potassium phosphate buffer (PBS of 200 μ L, 100mM, the pH value is 7.4), with compound dissolution to be analyzed in DMSO, and use PBS that it is diluted, the concentration that makes its final DMSO solution is 0.05%.And under 37 ° of C with in the water-bath that air communicates, hatch, preincubate added albumen and begins reaction in mixed solution after 3 minutes.In different time points (0,5,10,15,30 and 60min), add the cold acetonitrile termination reaction of consubstantiality accumulated ice.Sample is preserved under-80 ° of C up to carrying out LC/MS/MS and is analyzed.
The concentration of compound in people or rat liver microsomes mixtures incubated is to measure by the method for LC/MS/MS.The linearity range of concentration range is determined by each test-compound.
Parallel microsome of hatching test use sex change is hatched under 37 ° of C as negative control, is reflected at different time point (0,15 and 60 minute) and stops.
Dextromethorphane Hbr (70 μ Μ) is hatched under 37 ° of C as positive control, is reflected at different time point (0,5,10,15,30 and 60 minutes) and stops.All comprise positive and negative control sample in each measuring method, to guarantee the integrity of microsome hatching system.
(2) stability data of compound of the present invention in people or rat liver microsomes also can be obtained by following test: place the polypropylene test tube to hatch people or rat liver microsomes, and guide it to copy.Typical mixtures incubated comprise people or rat liver microsomes (ultimate density: 0.5mg albumen/mL), compound to be analyzed (ultimate density: 1.5 μ M) and cumulative volume be 30 μ L K-buffered soln (contain 1.0mM EDTA, 100mM, pH7.4).In DMSO, and with K-buffered soln dilution, the ultimate density that makes DMSO is 0.2% with compound dissolution to be analyzed.Behind the preincubate 10 minutes, (ultimate density: 2mM) carry out enzymatic reaction, whole test is carried out in the incubation tube of 37 ° of C to add 15 μ L NADPH.In different time points (0,15,30 and 60 minutes), add 135 μ L acetonitrile (containing IS) termination reactions.With 4000rpm centrifugal 10 minutes, except Deproteinization, collect supernatant liquid, analyze with LC-MS/MS.
In above-mentioned test, ketanserin (1 μ M) is selected as positive control, hatches under 37 ° of C, is reflected at different time point (0,15,30 and 60 minutes) and stops.All comprise positive control sample in each measuring method, to guarantee the integrity of microsome hatching system.
The present invention adopts following method to carry out data analysis, to obtain the stability analysis result:
For each reaction, with the per-cent mapping of the concentration (with per-cent represent) of compound in people or rat liver microsomes are hatched by the Relative Zero time point, infer CLint CL in the body with this
Int(ref.:Naritomi Y, Terashita S, Kimura S, Suzuki A, Kagayama A, Sugiyama Y.Prediction of human hepatic clearance from 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 pharmacokinetics evaluation in animal body
The present invention adopts following method that the pharmacokinetic of The compounds of this invention in mouse, rat, dog or monkey body assessed:
The compounds of this invention is with the aqueous solution of the aqueous solution or 2%HPMC+1% soil temperature-80, the salt brine solution of 5%DMSO+5%, and 4%MC or capsule form are carried out administration.For intravenous administration, animal gives 1 or the dosage of 2mg/kg.For oral dosage (p.o.), rat and mouse are 5 or 10mg/kg, and dog and monkey are 10mg/kg.Be 0.25,0.5,1.0,2.0 at time point, 3.0,4.0,6.0,8.0, got blood (0.3mL) in 12 and 24 hours, and 3,000 or 4,000rpm under centrifugal 10 minutes.Collect plasma solutions, and under-20 ° of C or-70 ° of C, preserve up to carrying out above-mentioned LC/MS/MS analysis.
4, kinase assay
Kinase assay by detection mix γ-
33The myelin basic protein of P-ATP (MBP) is finished.MBP (Sigma#M-1891) Tutofusin tris buffer salt solution (TBS for preparing 20 μ g/ml; 50mM Tris pH8.0,138mM NaCl, 2.7mM KCl), wrap by white 384 orifice plates (Greiner) of high associativity every hole 60 μ L.4 ° of C are hatched 24h.Wash plate 3 times with 100 μ L TBS afterwards.Kinase reaction is kinase buffer liquid (5mM Hepes pH7.6,15mM NaCl, 0.01% bovine serum albumin (Sigma#I-5506), the 10mM MgCl of 34 μ L at cumulative volume
2, 1mM DTT carries out in 0.02%TritonX-100).Compound dissolution in DMSO, is added in each hole, and the ultimate density of DMSO is 1%.Each data determination twice, the mensuration of each compound carry out twice test at least.Such as, the ultimate density of enzyme is 10nM or 20nM.Add the ATP (10 μ M) do not have mark and γ-
33The ATP of P mark (every hole 2x10
6Cpm 3000Ci/mmol) begins reaction.Reflection at room temperature concussion was carried out 1 hour.384 orifice plates clean with the PBS of 7x, add the scintillation solution of every hole 50 μ L then.With Wallac Trilux counter detected result.To those of ordinary skill in the art, this only is a kind of in numerous detection methods, and other method also can.
The IC that above-mentioned test method can be inhibited
50And/or inhibition constant K
iIC
50Be defined as under test conditions the compound concentration when suppressing 50% enzymic activity.Utilize the extension rate of 1/2log to make the curve that comprises 10 concentration point, estimation IC
50Value (for example, making a typical curve by following compound concentration: 10 μ M, 3 μ M, 1 μ M, 0.3 μ M, 0.1 μ M, 0.03 μ M, 0.01 μ M, 0.003 μ M, 0.001 μ M, 0 μ M).
Kinase assay among the present invention by Britain Millipore company finish (Millipore UK Ltd, Dundee Technology Park, Dundee DD21SW, UK).
4.1ALK (h) kinase assays
People ALK is 7.0 MOPS in 8mM pH value, 0.2mM EDTA, and 250 μ M KKKSPGEYVNIEFG are hatched under the condition of 10mM magnesium acetate and [γ-33P-ATP] (about 500cpm/pmol of specific activity, concentration is determined according to demand) existence.Begin reaction after adding the MgATP mixture.After hatching 40 minutes under the room temperature, come termination reaction to wherein adding 3% phosphoric acid solution.The reaction solution of 10 μ L is on the mottled P30 of the being distributed in strainer, and cleans 3 times in 5 minutes with 75mM phosphoric acid, and before dry and scintillation counting, put into methanol solution at once and preserve.
4.2c-Met (h) kinase assays
People c-Met is 7.0 MOPS in 8mM pH value, 0.2mM EDTA, 250 μ MKKKSPGEYVNIEFG, the 10mM magnesium acetate and [γ-
33P-ATP] hatch under (the about 500cpm/ pmol of specific activity, concentration according to demand determine) condition of existing.Begin reaction after adding the MgATP mixture.After hatching 40 minutes under the room temperature, come termination reaction to wherein adding 3% phosphoric acid solution.The reaction solution of 10 μ L is on the mottled P30 of the being distributed in strainer, and cleans 3 times in 5 minutes with 75mM phosphoric acid, and before dry and scintillation counting, put into methanol solution at once and preserve.
5, xenotransplantation tumor model
The drug effect of The compounds of this invention is to estimate by the standard muroid model of transplantation tumor, and method is as follows:
Human tumor cells (for example, the U87MG neuroblastoma cell) after cultivating, collecting, in back veutro subcutaneous vaccination (BALB/cA nu/nu, Shanghai SLAC Animal Lab.) (for group of solvents n=10, for each dosage group n=8) in the 6-7 female nude mouse body in age in week.When gross tumor volume reaches 100-250mm
3The time, animal is divided into solvent control group (aqueous solution of 2%HPMC+1% soil temperature-80) and compound group randomly.The following adopted compound carries out gastric infusion (3-50mpk/dose is dissolved in the aqueous solution of 2%HPMC+1% soil temperature-80) to animal, beginning Anywhere 0 to 15 day behind tumor cell inoculation, and carry out once every day in test usually.
5.1 suppressing (TGI), tumor growth analyzes
The evolution growth of tumour is estimated by gross tumor volume and time relation.The major axis of Subcutaneous tumor (L) and minor axis (W) measure twice weekly by calipers, and tumor size (TV) is by formula (L * W
2)/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 intermediate value, recently represents with the percentage of solvent control group gross tumor volume intermediate value, calculates by following formula:
Primary statistics is analyzed by repeating variance determination and analysis (RMANOVA) and is finished.Next carry out multiple comparisons by Scheffe psot hoc test method.Independent solvent (2%HPMC+1% soil temperature-80, etc.) negative contrast.
The result shows that compound provided by the invention shows good transformation period and good pharmacokinetic property, and ALK and c-Met are had good inhibition effect, and the growth of tumour is also had good inhibition effect.
Below in conjunction with embodiment compound provided by the invention, pharmaceutical composition and application thereof are further specified.
Embodiment 13-((R)-1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group)-5-(1-(4-fluorine tetrahydrofuran (THF)-3-yl)-1H-pyrazoles-4-yl) pyridine-2-amine
Step 1) (R)-3-(1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group)-2-nitropyridine
(10g 47.84mmol) is dissolved in the tetrahydrofuran (THF) (150mL), is cooled to 0 ℃, in 30 minutes, to wherein add sodium hydride (60% is suspended in the mineral oil for 2.3g, 57.41mmol) in batches with (R)-1-(2,6-, two chloro-3-fluorophenyls) ethanol.After the mixture stirring at room 2 hours, be cooled to 0 ℃ again, in 20 minutes, in system, drip 3-fluoro-2-nitropyridine (8.2g, tetrahydrofuran (THF) 57.41mmol) (80mL) solution.Reaction solution stirring at room 3 hours.Reaction is finished, with frozen water (10mL) cancellation, and concentrating under reduced pressure.Residue is dispersed in ethyl acetate (150mL) and the water (150mL), and the water of separation extracts with ethyl acetate (150mL * 2).The organic phase that merges uses saturated sodium bicarbonate solution (400mL), salt solution (400mL) to wash successively, anhydrous sodium sulfate drying, and concentrating under reduced pressure, the gained residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purifying, 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-, two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine
With (R)-3-(1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group)-2-nitropyridine (13.4g 40.47mmol) is dissolved in the ethanol (250mL), and to wherein add iron powder (11g, 197mmol).Mixture 90 ℃ stir 20 minutes after, in 15 minutes, add in two batches in the system hydrochloric acid (1M, 8mL).Reaction solution continues to stir 2 hours at 90 ℃.Reaction is finished, and is cooled to room temperature, uses diatomite filtration, and filter cake washs with ethanol (80mL * 3).The filtrate decompression that merges is concentrated, and obtaining title compound is light brown solid (12g, 98.5%).
LC-MS(ESI,pos.ion)m/z:301[M+H]
+；
1H?NMR(400MHz,DMSO-d
6)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) (R)-5-bromo-3-(1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine
With (R)-3-(1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine (12g 39.8mmol) is dissolved in the acetonitrile (250mL), is cooled to 0 ℃, in 20 minutes, to wherein add in batches NBS (9.2g, 51.7mmol).Reaction solution stirred 1 hour at 0 ℃.Reaction is finished, and concentrating under reduced pressure, gained residue are through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=3/1) purifying, and obtaining title compound is light brown solid (10g, 66%).
LC-MS(ESI,pos.ion)m/z:379[M+H]
+；
1H?NMR(400MHz,DMSO-d
6)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) (R)-5-bromo-N, two (tertbutyloxycarbonyl)-3-(1-(2,6-, the two chloro-3-fluorophenyls) oxyethyl group) pyridines-2-amine of N-
With (R)-5-bromo-3-(1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine (4.5g, 11.8mmol), DMAP (1.46g, 11.8mmol) (7.33g 35.4mmol) is dissolved in the tetrahydrofuran (THF) (100mL) with the Boc acid anhydrides, and to wherein add triethylamine (3.65g, 36mmol).Reaction solution spends the night 70 ℃ of stirrings.Reaction is finished, concentrating under reduced pressure.The gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=10/1) purifying, and obtaining title compound is viscous liquid (6g, 87.28%).
Step 5) (R)-N, two (the tertbutyloxycarbonyl)-3-(1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) of N--5-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl) pyridine-2-amine
With (R)-5-bromo-N, (1-(2 for two (the tertbutyloxycarbonyl)-3-of N-, 6-two chloro-3-fluorophenyls) pyridine-2-amine (6g oxyethyl group), 11.8mmol), connection boric acid frequently the sodium alcohol ester (3.6g, 14.6mmol) and potassium acetate (3.54g 35.4mmol) is suspended in the methyl-sulphoxide (150mL), after placing nitrogen atmosphere, in system, add Pd (dppf) Cl
2CH
2Cl
2(0.48g, 0.59mmol).Reaction solution after 5 hours, is cooled to room temperature 80 ° of C heating, adds water (300mL) dilution, and extracts with ethyl acetate (300mL * 3).The organic phase that merges is washed anhydrous sodium sulfate drying, and concentrating under reduced pressure with salt solution (200mL).The gained residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=6/1) purifying, and obtaining title compound is colorless oil (5.8g, 89.25%).
LC-MS(ESI,pos.ion)m/z:627[M+H]
+；
1H?NMR(400MHz,CDCl
3)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-two oxabicyclos [3.1.0] hexane
With 2,5-dihydrofuran (5.3mL 71.3mmol) is dissolved in the methylene dichloride (250mL), to wherein add m-CPBA (24.6g, 142.6mmol).Reaction solution stirring at room 48 hours.Reaction is finished, and uses diatomite filtration, and filter cake is washed with methylene dichloride (50mL).Filtrate is washed with salt solution (200mL), anhydrous sodium sulfate drying, and concentrating under reduced pressure, obtaining thick product is colorless oil (4.12g, 67%).
GC-MS?m/z:86(M)；
1H?NMR(400MHz,CDCl
3)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) tetrahydrofuran (THF)-3-alcohol
With 4-iodo-1H-pyrazoles (10.8g 57.6mmol) is dissolved in the dry tetrahydrofuran (THF) (60mL), is cooled to-78 ℃, to wherein add LDA (31.2mL, 62.4mmol).Solution after 1 hour, adds 3,6-, two oxabicyclos [3.1.0] hexane (4.12g, tetrahydrofuran (THF) 48mmol) (50mL) solution-40 ℃ of stirrings in system.Reaction solution stirring at room 1 hour is warming up to 80 ℃ then, continues to stir 36 hours.Reaction is finished, and solution is cooled to room temperature, adds water (50mL) dilution, and extracts with ethyl acetate (100mL * 3).The organic phase that merges is washed anhydrous sodium sulfate drying, and concentrating under reduced pressure with salt solution (100mL).The gained residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purifying, and obtaining title compound is white solid (5g, 37%).
LC-MS(ESI,pos.ion)m/z:281(M+1)；
1H?NMR(400MHz,CDCl
3)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 tetrahydrofuran (THF)-3-yl)-4-iodo-1H-pyrazoles
With 4-(4-iodo-1H-pyrazol-1-yl) tetrahydrofuran (THF)-3-alcohol (1.5g 5.4mmol) is dissolved in the methylene dichloride (15mL), be cooled to-78 ℃ after, to wherein slowly adding DAST (1.53mL, 10.8mmol, 95%).Reaction solution after 2 hours, returns to room temperature-78 ℃ of stirrings, continues to stir 40 hours.Reaction is finished, and mixed solution adds water (30mL) cancellation, and extracts with methylene dichloride (80mL * 3).The organic phase that merges is washed anhydrous sodium sulfate drying, and concentrating under reduced pressure with salt solution (100mL).The gained residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1), and obtaining title compound is yellow oil (1.1g, 72%).
LC-MS(ESI,pos.ion)m/z:283(M+1)；
1H?NMR(400MHz,CDCl
3)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) N, two (the tertbutyloxycarbonyl)-3-((R)-1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) of N--5-(1-(4-fluorine tetrahydrofuran (THF)-3-yl)-1H-pyrazoles-4-yl) pyridine-2-amine
With (R)-N, two (the tertbutyloxycarbonyl)-3-(1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) of N--5-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl) pyridine-2-amine (266mg, 0.43mmol), 1-(4-fluorine tetrahydrofuran (THF)-3-yl)-4-iodo-1H-pyrazoles (0.1g, 0.35mmol) and yellow soda ash (150mg, 1.42mmol) be dissolved in glycol dimethyl ether/water (3mL/0.7mL) mixed solution, place nitrogen atmosphere after, in system, add Pd (PPh
3)
2Cl
2(25mg, 0.035mmol).Reaction solution stirred 16 hours at 90 ° of C.Reaction is finished, and is cooled to room temperature, adds ethyl acetate (60mL) dilution, and uses diatomite filtration.Filtrate is washed through salt solution (20mL * 2), after the vacuum-drying, uses through purification by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), and obtaining title compound is yellow solid (136mg, 59%).
LC-MS(ESI,pos.ion)m/z:655(M+1)；
1H?NMR(400MHz,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group)-5-(1-(4-fluorine tetrahydrofuran (THF)-3-yl)-1H-pyrazoles-4-yl) pyridine-2-amine
With N, two (tertbutyloxycarbonyl)-3-((the R)-1-(2 of N-, 6-two chloro-3-fluorophenyls) oxyethyl group)-5-(1-(4-fluorine tetrahydrofuran (THF)-3-yl)-1H-pyrazoles-4-yl) pyridine-2-amine (136mg, 0.2mmol) be dissolved in the methylene dichloride (5mL), be cooled to 0 ° of C, to the ethyl acetate solution that wherein slowly adds hydrogenchloride (3M, 1.5mL).The reaction solution stirred overnight at room temperature.Reaction is finished, concentrating under reduced pressure.Residue is dissolved in the water (10mL), and regulating the pH value with saturated sodium carbonate solution is 10, and extracts with methylene dichloride (50mL * 3).The organic phase that merges is through anhydrous sodium sulfate drying, and behind the concentrating under reduced pressure, with silica gel column chromatography (PE/EtOAc (v/v)=1/1) purifying, obtaining title compound is white solid (90mg, 95%).
LC-MS(ESI,pos.ion)m/z:455(M+1)；
1H?NMR(400MHz,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group) pyridin-3-yl)-1H-pyrazol-1-yl) tetrahydrofuran (THF)-3-alcohol
Step 1) 4-iodo-1-(4-(tetrahydrochysene-2H-pyrans-2-base oxygen base) tetrahydrofuran (THF)-3-yl)-1H-pyrazoles
With 4-(4-iodo-1H-pyrazol-1-yl) tetrahydrofuran (THF)-3-alcohol (1g, 3.57mmol), PPTS (113mg 0.43mmol) is suspended in the methylene dichloride (46mL), to wherein add DHP (788mg, 9.4mmol).Reaction solution stirring at room 48 hours.Reaction is finished, concentrating under reduced pressure.The gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=4/1) purifying, and obtaining title compound is colorless oil (1.3g, 100%).
LC-MS(ESI,pos.ion)m/z:365(M+1)；
1H?NMR(400MHz,CDCl
3)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) N, two (the tertbutyloxycarbonyl)-3-((R)-1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) of N--5-(1-(4-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) tetrahydrofuran (THF)-3-yl)-1H-pyrazoles-4-yl) pyridine-2-amine
Title compound prepares by the described method of embodiment 1 step 9, is about to (R)-N, and (1-(2 for two (the tertbutyloxycarbonyl)-3-of N-, 6-two chloro-3-fluorophenyls) oxyethyl group)-5-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl) pyridine-2-amine (224mg, 0.357mmol), 4-iodo-1-(4-(tetrahydrochysene-2H-pyrans-2-base oxygen base) tetrahydrofuran (THF)-3-yl)-1H-pyrazoles (100mg, 0.275mmol), yellow soda ash (117mg, 1.1mmol) and Pd (PPh
3)
2Cl
2(21.6mg 0.031mmol) is suspended in the mixed solution of glycol dimethyl ether/water (2.5mL/0.6mL) and prepares, and thick product is through silica gel column chromatography (PE/EtOAc (v/v)=2/1) purifying, and obtaining title compound is white solid (87mg, 44%).
LC-MS(ESI,pos.ion)m/z:737(M+1)；
1H?NMR(400MHz,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group) pyridin-3-yl)-1H-pyrazol-1-yl) tetrahydrofuran (THF)-3-alcohol
Title compound prepares by the described method of embodiment 1 step 10, namely use N, two (tertbutyloxycarbonyl)-3-((the R)-1-(2 of N-, 6-two chloro-3-fluorophenyls) oxyethyl group)-5-(1-(4-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) tetrahydrofuran (THF)-3-yl)-1H-pyrazoles-4-yl) pyridine-2-amine (264mg, 0.36mmol) methylene dichloride (12mL) solution and hydrogenchloride ethyl acetate solution (3.5mL, 3M) preparation, thick product is through silica gel column chromatography (100% ethyl acetate) purifying, obtaining title compound is yellow solid (131mg, 80%).
LC-MS(ESI,pos.ion)m/z:453(M+1)；
1H?NMR(400MHz,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group)-5-(1-(4-fluoropyrrolidine-3-yl)-1H-pyrazoles-4-yl) pyridine-2-amine
The step 1) t-butyl carbamate
(10g 45.8mmol) is dissolved in the methyl alcohol (200mL), is cooled to 0 ° of C, feeds NH with tert-Butyl dicarbonate
3Reaction solution rises to room temperature after 0 ° of C stirs 2 hours, continue to stir 5 hours.Reaction is finished, and with the mixture concentrating under reduced pressure, residue dilutes with normal hexane, and is heated to 65 ° of C, is incubated 30 minutes.Be cooled to room temperature, filter, filter cake normal hexane drip washing, obtaining title compound is white solid (5g, 94%).
1H?NMR(400MHz,CDCl
3)δ(ppm):4.48(brs,2H,),1.46(s,9H)。
Step 2) 1-(tertbutyloxycarbonyl)-2,5-dihydro-1H-pyrroles
With t-butyl carbamate (5g 42.5mmol) is dissolved in N, in the dinethylformamide (50 mL), is cooled to 0 ° of C, in 15 minutes, to wherein add in batches sodium hydride (3.1g, 106mmol).Mixture after 0 ° of C stirs 1 hour, continue in system, to drip suitable-1,4-two chloro-2-butylene (8mL).Reaction solution stirred 5 hours at 80 ° of C, was cooled to room temperature, added water (150mL) cancellation, and extracted with ethyl acetate (150mL * 3).The organic phase that merges is washed with salt solution (400mL), anhydrous sodium sulfate drying, and concentrating under reduced pressure, and obtaining thick product is yellow oil (6.5g), this product is not purified, is directly used in next step reaction.
Step 3) 4-bromo-1-(tertbutyloxycarbonyl) tetramethyleneimine-3-alcohol
With 1-(tertbutyloxycarbonyl)-2,5-dihydro-1H-pyrroles (6.4g 37.8mmol) is dissolved in the mixed solution of methyl-sulphoxide/water (30mL/3mL), is cooled to 0 ° of C, to wherein add in batches NBS (8g, 45.4mmol).Reaction solution stirring at room 2 hours.Reaction is finished, and adds water (100mL) cancellation, and extracts with ethyl acetate (100mL * 3).The organic phase that merges is washed with salt solution (300mL), anhydrous sodium sulfate drying, and concentrating under reduced pressure, residue through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=3/1) purifying, obtaining title compound is white solid (5g, 60%).
1H?NMR(400MHz,CDCl
3)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
(2.5g 9.4mmol) is dissolved in the mixed solution of 2M sodium hydroxide/tetrahydrofuran (THF) (20mL/10mL) with 4-bromo-1-(tertbutyloxycarbonyl) tetramethyleneimine-3-alcohol.Reaction solution stirring at room 2 hours.Reaction is finished, and adds water (40mL) dilution, and extracts with methylene dichloride (50mL * 3).The organic phase that merges is washed with salt solution (50mL), anhydrous sodium sulfate drying, and concentrating under reduced pressure, and obtaining title compound is yellow oil (1.6g, 98%).
1H?NMR(400MHz,CDCl
3)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) tetramethyleneimine-3-alcohol
Title compound prepares by the described method of embodiment 1 step 7, be about to 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) is dissolved in preparation in the tetrahydrofuran (THF) (20mL), thick product is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purifying, and obtaining target product is white solid (2g, 67%).
1H?NMR(400MHz,CDCl
3)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-yl)-4-iodo-1H-pyrazoles
(1g 2.5mmol) is dissolved in the methylene dichloride (20mL), is cooled to-78 ° of C, to the methylene dichloride that wherein drips DAST (1.5mL) (2mL) solution with 1-(tertbutyloxycarbonyl)-4-(4-iodo-1H-pyrazol-1-yl) tetramethyleneimine-3-alcohol.Mixed solution returns to room temperature after-78 ° of C stir 1 hour, stirring is spent the night.Reaction is finished, with the mixed solution concentrating under reduced pressure, residue dilutes with 1M sodium bicarbonate (30mL), and with ethyl acetate (30mL * 3) extraction, the organic phase of merging is washed anhydrous sodium sulfate drying with salt solution (70mL), and concentrating under reduced pressure, the gained residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=5/1) purifying, and obtaining title compound is yellow oil (0.5g, 50%).
1H?NMR(400MHz,CDCl
3)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-yl)-4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-1H-pyrazoles
Under the nitrogen protection, with 1-(1-(tertbutyloxycarbonyl)-4-fluoropyrrolidine-3-yl)-4-iodo-1H-pyrazoles (0.5g, 1.3mmol), connection boric acid pinacol ester (0.4g, 1.5mmol), Pd (dppf) Cl
2(60mg, 0.13mmol) and potassium acetate (0.38g, methyl-sulphoxide 3.9mmol) (10mL) suspension stirred 2 hours at 75 ° of C.Reaction is finished, and is cooled to room temperature, adds water (30mL) cancellation, and extracts with ethyl acetate (30mL * 3).The organic phase that merges is washed with salt solution (70mL), and anhydrous sodium sulfate drying, and concentrating under reduced pressure, gained residue are through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purifying, and obtaining title 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-yl)-1H-pyrazoles-4-yl)-3-((R)-1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine
Under the nitrogen protection; with (R)-5-bromo-3-(1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine (0.48g, 1.26mmol); 1-(1-(tertbutyloxycarbonyl)-4-fluoropyrrolidine-3-yl)-4-(4; 4,5,5-tetramethyl--1; 3; 2-dioxane pentaborane-2-yl)-and the 1H-pyrazoles (0.4g, 1.05mmol), Pd (OAc)
2(84mg, 0.37mmol), Cs
2CO
3(0.86g, 2.63mmol) and (t-Bu)
3Glycol dimethyl ether (20mL) suspension of P (0.925mmol, the toluene solution of 1M) stirred 36 hours at 87 ° of C.Reaction is finished, add water (50mL) cancellation, and extract with ethyl acetate (50mL * 3), the organic phase that merges is washed with salt solution (100mL), anhydrous sodium sulfate drying, and concentrating under reduced pressure, the gained residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=1/1) purifying, obtaining title compound is yellow solid (0.16g, 32%).
1H?NMR(400MHz,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group)-5-(1-(4-fluoropyrrolidine-3-yl)-1H-pyrazoles-4-yl) pyridine-2-amine
With 5-(1-(1-(tertbutyloxycarbonyl)-4-fluoropyrrolidine-3-yl)-1H-pyrazoles-4-yl)-3-((R)-1-(2,6-two chloro-3-fluorophenyls) pyridine-2-amine (0.16g oxyethyl group), 0.29mmol) be dissolved in the ethyl acetate (5mL), and to wherein adding HCl (5mL, the ethyl acetate solution of 1M).Reaction solution stirred 1 hour at 40 ° of C.Reaction is finished, and uses 2M sodium carbonate solution (5mL), water (20mL) to handle successively, and with ethyl acetate extraction (20mL * 3).The organic phase that merges is washed with saturated aqueous common salt (60mL), and anhydrous sodium sulfate drying, and concentrating under reduced pressure, gained residue are through silica gel column chromatography (methylene chloride (v/v)=10/1) purifying, and obtaining title compound is yellow solid (0.1g, 78%).
LC-MS(ESI,pos.ion)m/z:227.6[M+2]/2；
1H?NMR(400MHz,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group) pyridin-3-yl)-1H-pyrazol-1-yl) tetramethyleneimine-3-alcohol
Step 1) 1-(1-(tertbutyloxycarbonyl)-4-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) tetramethyleneimine-3-yl)-4-iodo-1H-pyrazoles
With 1-(tertbutyloxycarbonyl)-4-(4-iodo-1H-pyrazol-1-yl) tetramethyleneimine-3-alcohol (1g 2.6mmol) is dissolved in the methylene dichloride (20mL), to wherein add DHP (1mL) and PPTS (0.065g, 0.26mmol).Reaction solution stirring at room 12 hours.Reaction is finished, concentrating under reduced pressure.Residue is through silica gel column chromatography (PE/EtOAc (v/v)=4/1) purifying, and obtaining title compound is white solid (1.1g, 92%).
LC-MS(ESI,pos.ion)m/z:464(M+1)；
1H?NMR(400MHz,CDCl
3)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) N, two (the tertbutyloxycarbonyl)-5-(1-(1-(tertbutyloxycarbonyl)-4-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) tetramethyleneimine-3-yl)-1H-pyrazoles-4-yl) of N--3-((R)-1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine
With (R)-N, (1-(2 for two (the tertbutyloxycarbonyl)-3-of N-, 6-two chloro-3-fluorophenyls) oxyethyl group)-5-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl) pyridine-2-amine (0.6g, 1.1mmol), 1-(1-(tertbutyloxycarbonyl)-4-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) tetramethyleneimine-3-yl)-4-iodo-1H-pyrazoles (0.5g, 1.05mmol) and yellow soda ash (0.22g, 2.1mmol) be dissolved in the mixed solution of glycol dimethyl ether/water (30mL/2mL), solution places nitrogen atmosphere, adds Pd (dppf) Cl in system
2CH
2Cl
2(0.075g, 0.01mmol).Reaction solution stirred 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) purifying, and obtaining title compound is light yellow solid (250mg, 92%).
LC-MS(ESI,pos.ion)m/z:836(M+1)；
1H?NMR(400MHz,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group) pyridin-3-yl)-1H-pyrazol-1-yl) tetramethyleneimine-3-alcohol
With N, two (the tertbutyloxycarbonyl)-5-(1-(1-(tertbutyloxycarbonyl)-4-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) tetramethyleneimine-3-yl)-1H-pyrazoles-4-yl) of N--3-((R)-1-(2,6-two chloro-3-fluorophenyls) pyridine-2-amine (0.23g oxyethyl group), 0.275mmol) be dissolved in the ethyl acetate (10mL), to wherein adding HCl (10mL, the ethyl acetate solution of 1M).Reaction solution stirred 3 hours at 40 ° of C, and reaction is finished, and is cooled to room temperature, and added water (20mL) dilution.After the water that separates is washed with ethyl acetate (20mL * 2), add 2M sodium carbonate solution (10mL) and handle, the gained mixture extracts with ethyl acetate (20mL * 3).The organic phase that merges is washed with salt solution (60mL), anhydrous sodium sulfate drying, and concentrating under reduced pressure, obtaining title compound is white solid (70mg, 62%).
LC-MS(ESI,pos.ion)m/z:452(M+1);
1H?NMR(400MHz,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group) pyridin-3-yl)-1H-pyrazol-1-yl) tetramethyleneimine-2-yl) methyl alcohol
Step 1) (3R, 5S)-1-(tertbutyloxycarbonyl)-5-(methoxycarbonyl) tetramethyleneimine-3-base methanesulfonates
With (3R, 5S)-1-(tertbutyloxycarbonyl)-5-(methoxycarbonyl) tetramethyleneimine-3-alcohol (0.50g, 2.04mmol) be dissolved in the methylene dichloride (20mL), to wherein adding DMAP (3mg, 0.02mmol) and triethylamine (0.28mL, 2.04mmol), after mixed solution is cooled to 0 ° of C, continuation drip in the system methylsulfonyl chloride (0.16mL, 2.04mmol).Reaction solution stirred 1 hour at 0 ° of C, returned to room temperature, continued to stir 24 hours.Reaction is finished, and with the mixture concentrating under reduced pressure, obtaining thick product is yellow viscous liquid (0.64g, 100%), and this product is not 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) tetramethyleneimine-3-yl)-4-iodo-1H-pyrazoles
(0.35g 1.80mmol) is dissolved in dry N, in the dinethylformamide (6mL), is cooled to 0 ° of C, to wherein adding sodium hydride (60% is dispersed in the mineral oil for 0.15g, 3.75mmol) with 4-iodo-1H-pyrazoles.Mixture after 0 ° of C stirs 1 hour, add in the system (3R, 5S)-1-(tertbutyloxycarbonyl)-5-(methoxycarbonyl) tetramethyleneimine-3-base methanesulfonates (0.64g, dry N 1.98mmol), dinethylformamide (4mL) solution.Reaction solution stirred 12 hours at 100 ° of C, and reaction is finished, and is cooled to room temperature, adds water (40mL) cancellation, and extracts with methylene dichloride (30mL * 4).Use 5% lithium chloride solution (100mL * 2), salt solution (100mL) to wash anhydrous sodium sulfate drying, and concentrating under reduced pressure successively the organic phase that merges.The gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=4/1) purifying, and 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) tetramethyleneimine-2-yl) methyl alcohol
With 1-((5S)-1-(tertbutyloxycarbonyl)-5-(methoxycarbonyl) tetramethyleneimine-3-yl)-4-iodo-1H-pyrazoles (0.46g 1.09mol) is dissolved in the tetrahydrofuran (THF) (10mL), is cooled to 0 ° of C, to wherein add in batches lithium borohydride (0.12g, 5.46mmol).Mixture returns to room temperature after 0 ° of C stirs 30 minutes, stirring is spent the night.Reaction is finished, and adds water (10mL) cancellation, and extracts with ethyl acetate (30mL * 4).The organic phase that merges is washed anhydrous sodium sulfate drying, and concentrating under reduced pressure with salt solution (30mL).The gained residue is with silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purifying, and obtaining title compound is viscous liquid (0.21g, 28%).
LC-MS(ESI,pos.ion)m/z:338.0[M-56+H]；
1H?NMR(400MHz,CDCl
3)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-dioxane pentaborane-2-yl)-1H-pyrazol-1-yl) tetramethyleneimine-2-yl) methyl alcohol
With ((2S)-1-(tertbutyloxycarbonyl)-4-(4-iodo-1H-pyrazol-1-yl) tetramethyleneimine-2-yl) methyl alcohol (0.50g, 1.27mmol) be dissolved in the methyl-sulphoxide (12mL), to wherein adding connection boric acid sodium alcohol ester (0.48g frequently, 1.91mmol) after, place nitrogen atmosphere, continue to wherein adding Pd (dppf)
2Cl
2CH
2Cl
2(0.10g, 0.13mmol) and potassium acetate (0.50g, 5.09mmol).Reaction solution stirs at 90 ° of C and spends the night, and reaction is finished, and is cooled to room temperature, adds water (40mL) dilution, and extracts with ethyl acetate (50mL * 3).The organic phase that merges is washed anhydrous sodium sulfate drying, and concentrating under reduced pressure with salt solution (50mL).The gained residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purifying, 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,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group) pyridin-3-yl)-1H-pyrazol-1-yl)-1-(tertbutyloxycarbonyl) tetramethyleneimine-2-yl) methyl alcohol
(0.30g is 0.79mmol) with ((4-(4 for (2S)-1-(tertbutyloxycarbonyl)-4-with (R)-5-bromo-3-(1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine, 4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-and the 1H-pyrazol-1-yl) tetramethyleneimine-2-yl) methyl alcohol (0.46g, 1.18mmol) be dissolved in the glycol dimethyl ether (10mL), place nitrogen atmosphere after, to wherein adding cesium carbonate (0.77g, 2.37mmol), Pd (dppf) Cl
2CH
2Cl
2(64mg, 0.08mmol) and water (2mL).Reaction solution refluxes and spends the night.Reaction is finished, and is cooled to room temperature, adds water (30mL) dilution, and extracts with methylene dichloride (40mL * 3).The organic phase that merges is washed anhydrous sodium sulfate drying, and concentrating under reduced pressure with salt solution (50mL).The gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=2/1) purifying, and obtaining title compound is yellow solid (0.26g, 58%).
LC-MS(ESI,pos.ion)m/z:566.2[M+H]；
1H?NMR(400MHz,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group) pyridin-3-yl)-1H-pyrazol-1-yl) tetramethyleneimine-2-yl) methyl alcohol
With (((((R)-1-(2 for 6-amino-5-for 4-for (2S)-4-, 6-two chloro-3-fluorophenyls) pyridin-3-yl oxyethyl group))-the 1H-pyrazol-1-yl)-1-(tertbutyloxycarbonyl) tetramethyleneimine-2-yl) methyl alcohol (0.26g, 0.46mmol) be dissolved in the methylene dichloride (10mL), to wherein adding HCl (3mL, the ethyl acetate solution of 3M).The reaction solution stirred overnight at room temperature.Reaction is finished, concentrating under reduced pressure.Residue with saturated sodium carbonate solution (10mL) and ethyl acetate (10mL) dilution, is stirred after 10 minutes, and the water of separation extracts with the mixed solution (30mL * 3) of ethyl acetate/methanol (v/v, 10/1).Merge organic phase, (40mL) washes with salt solution, anhydrous sodium sulfate drying, and concentrating under reduced pressure.The gained residue is through silica gel column chromatography (DCM/MeOH (v/v)=8/1) purifying, and obtaining title compound is yellow solid (84mg, 39%).
LC-MS(ESI,pos.ion)m/z:466.2[M+H]；
1H?NMR(400MHz,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group)-5-(1-((S)-tetramethyleneimine-3-yl)-1H-pyrazoles-4-yl) pyridine-2-amine
Step 1) (R)-1-(tertbutyloxycarbonyl) tetramethyleneimine-3-base methanesulfonates
(1g, 5.3mmol), triethylamine (1.2mL) is dissolved in the methylene dichloride (15mL), is cooled to 0 ° of C, to wherein dripping methylsulfonyl chloride (0.62mL) with (R)-1-(tertbutyloxycarbonyl) tetramethyleneimine-3-alcohol.Reaction solution stirring at room 2 hours, reaction is finished, concentrating under reduced pressure.Residue water (35mL) dilutes, and extracts with ethyl acetate (25mL * 3).Merge organic phase, use 1M potassium hydrogen sulfate solution (20mL), water (20mL) to wash successively, through anhydrous sodium sulfate drying, and behind the concentrating under reduced pressure, obtaining thick product is yellow oil (1.4g), and this compound is not purified, is directly used in next step.
Step 2) (S)-1-(1-(tertbutyloxycarbonyl) tetramethyleneimine-3-yl)-4-iodo-1H-pyrazoles
(840mg 7.4mmol) is dissolved at N, in the dinethylformamide (15mL), is cooled to 0 ° of C, to wherein adding sodium hydride (90% is dispersed in the mineral oil for 320mg, 12mmol) with 4-iodo-1H-pyrazoles.Mixture adds the N of (R)-1-(tertbutyloxycarbonyl) tetramethyleneimine-3-base methanesulfonates (1.4g) in the system, dinethylformamide (5mL) solution after 0 ° of C stirs 1 hour.Reaction solution stirred 6 hours at 70 ° of C, was cooled to room temperature, added water (50mL) cancellation, and extracted with ethyl acetate (30mL * 3).The organic phase that merges is washed with salt solution (20mL), and anhydrous sodium sulfate drying, and concentrating under reduced pressure, gained residue are through silica gel column chromatography (PE/EtOAc (v/v)=5/1) purifying, and obtaining title compound is colorless oil (1.6g, 80%).
LC-MS(ESI,pos.ion)m/z:308[M+H-56]
+；
1H?NMR(400MHz,CDCl
3)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) tetramethyleneimine-3-yl)-4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-1H-pyrazoles
Under the nitrogen protection, with (S)-1-(1-(tertbutyloxycarbonyl) tetramethyleneimine-3-yl)-4-iodo-1H-pyrazoles (1g, 2.75mmol), connection boric acid frequently the sodium alcohol ester (0.8g, 3.32mmol), Pd (dppf) Cl
2CH
2Cl
2(0.22g, 0.275mmol) and potassium acetate (0.53g, methyl-sulphoxide 5.3mmol) (15mL) suspension stirred 2 hours at 80 ° of C.Reaction is finished, and is cooled to room temperature, adds water (30mL) dilution, and extracts with ethyl acetate (25mL * 3).The organic phase that merges is washed anhydrous sodium sulfate drying, and concentrating under reduced pressure with salt solution (75mL).The gained residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purifying, and obtaining target compound is white solid (800mg, 80%).
LC-MS(ESI,pos.ion)m/z:364[M+H]
+。
Step 4) 5-(1-((S)-1-(tertbutyloxycarbonyl) tetramethyleneimine-3-yl)-1H-pyrazoles-4-yl)-3-((R)-1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine
Under the nitrogen protection; with (R)-5-bromo-3-(1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine (500mg, 1.32mmol); (S)-1-(1-(tertbutyloxycarbonyl) tetramethyleneimine-3-yl)-4-(4; 4,5,5-tetramethyl--1; 3; 2-dioxane pentaborane-2-yl)-and the 1H-pyrazoles (500mg, 1.32mmol), Pd (PPh
3)
2Cl
2(108mg, 0.15mmol) and yellow soda ash (2.64mmol, glycol dimethyl ether/water 280mg) (15mL/1.5mL) suspension stirred 16 hours at 87 ° of C.Reaction is finished, and concentrating under reduced pressure, gained residue are through silica gel column chromatography (PE/EtOAc (v/v)=1/1) purifying, and obtaining target compound is brown solid (300mg, 42.4%).
LC-MS(ESI,pos.ion)m/z:536[M+H]
+；
1H?NMR(400MHz,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group)-5-(1-((S)-tetramethyleneimine-3-yl)-1H-pyrazoles-4-yl) pyridine-2-amine
With 5-(1-((S)-1-(tertbutyloxycarbonyl) tetramethyleneimine-3-yl)-1H-pyrazoles-4-yl)-3-((R)-1-(2,6-two chloro-3-fluorophenyls) pyridine-2-amine (280mg oxyethyl group), 0.523mmol) be dissolved in the ethyl acetate (5mL), to wherein adding HCl (5mL, the ethyl acetate solution of 1M).Reaction solution stirred 1 hour at 40 ° of C.Reaction is finished, and is cooled to room temperature, adds water (35mL) dilution, and washes with ethyl acetate (20mL).After mixed solution usefulness 2M sodium carbonate solution (3mL) processing, extract with ethyl acetate (containing 1% methyl alcohol, 15mL * 3).The organic phase that merges is washed through salt solution (40mL), anhydrous sodium sulfate drying, and concentrating under reduced pressure, and obtaining title compound is yellow solid (180mg, 80%).
LC-MS(ESI,pos.ion)m/z:436[M+H]
+；
1H?NMR(400MHz,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group)-5-(1-((4,4-dimethyl oxygen heterocycle fourth-2-yl) methyl)-1H-pyrazoles-4-yl) pyridine-2-amine
Step 1) 2-methylpent-4-alkene-2-alcohol
Under the argon shield, allyl group bromination magnesium (20mL, 0.02mol, the diethyl ether solution of 2M) is placed two-neck bottle, and is cooled to 0 ℃ with ice bath, in 10 minutes to wherein drip acetone (1.7mL, 0.02mol).Reaction solution refluxes and stirs after 2 hours the water while lowering the temperature (10mL) cancellation.Be cooled to 0 ℃, and dripping hydrochloric acid in the mixture (3mL, 6M) regulating pH value is 2, the water of separation extracts with ether (50mL * 2).. merge organic phase, (50mL) washes with salt solution, anhydrous magnesium sulfate drying, and concentrating under reduced pressure, and obtaining thick product is colorless oil (1g, 50%).
LC-MS(ESI,pos.ion)m/z:101[M+H]
+；
1H?NMR(400MHz,CDCl
3)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 trimethylene oxide
With 2-methylpent-4-alkene-2-alcohol (510mg, 5.1mmol), iodine (1.81g 7.14mmol) is suspended in the methylene dichloride (43mL), place nitrogen atmosphere after, to wherein add two (2) silver perchlorates (3.5g, 7.14mmol).Reaction solution stirring at room 24 hours.Reaction is finished, and uses diatomite filtration, and filter cake is washed with ethyl acetate (50mL).Filtrate successively after 10% Sulfothiorine (10mL * 2), 10% hydrochloric acid (50mL * 2) are washed, concentrating under reduced pressure.Gained residue silica gel column chromatography (sherwood oil/methylene dichloride (v/v)=1/2) purifying, obtaining title compound is colorless oil (629mg, 55%).
LC-MS(ESI,pos.ion)m/z:226[M+H]
+；
1H?NMR(400MHz,CDCl
3)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 fourth-2-yl) methyl)-4-iodo-1H-pyrazoles
(1.13g 5.85mmol) is dissolved in dry N, in the dinethylformamide (32mL), is cooled to 0 ° of C, to wherein add sodium hydride (296mg, 11.7mmol, 95%) in batches with 4-iodo-1H-pyrazoles.After the mixture stirring at room 1.5 hours, in system, add 4-(iodomethyl)-2, and 2-dimethyl trimethylene oxide (1.32g, 5.85mmol).Reaction solution stirred 19 hours at 90 ° of C.Reaction is finished, and is cooled to room temperature, adds saturated ammonium chloride solution (20mL) cancellation, and extracts with ethyl acetate (80mL * 2).The organic phase that merges is through anhydrous sodium sulfate drying, and behind the concentrating under reduced pressure, with silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purifying, obtaining title compound is colorless oil (890mg, 53%).
1H?NMR(400MHz,CDCl
3)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 fourth-2-yl) methyl)-4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-1H-pyrazoles
To join boric acid sodium alcohol ester (995mg frequently; 3.9mmol) be dissolved in the methyl-sulphoxide (22mL); to wherein adding 1-((4; 4-dimethyl oxygen heterocycle fourth-2-yl) methyl)-4-iodo-1H-pyrazoles (880mg; 3.0mmol) and potassium acetate (1.22g; 12mmol), after the nitrogen protection, continue in system, to add Pd (PPh
3)
2Cl
2(218mg, 0.3mmol).Reaction solution stirred 3 hours at 80 ° of C.Reaction is finished, and is cooled to room temperature, and uses diatomite filtration, and filter residue is washed with ethyl acetate (100mL).Filtrate is washed anhydrous sodium sulfate drying, and concentrating under reduced pressure with salt solution (50mL * 2).Residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purifying, and obtaining title compound is colorless oil (650mg, 74%).
LC-MS(ESI,pos.ion)m/z:293[M+H]
+；
1H?NMR(400MHz,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group)-5-(1-((4,4-dimethyl oxygen heterocycle fourth-2-yl) methyl)-1H-pyrazoles-4-yl) pyridine-2-amine
(1-(2 with (R)-5-bromo-3-, 6-two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine (1.27g, 3.3mmol), 1-((4,4-dimethyl oxygen heterocycle fourth-2-yl) methyl)-4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-and the 1H-pyrazoles (650mg, 2.2mmol), Pd (OAc)
2(50mg 0.22mmol) is suspended in the glycol dimethyl ether (20mL), and (707mg, water 6.7mmol) (3.25mL) solution after the nitrogen protection, continue to add (t-Bu) in system to wherein adding yellow soda ash
3P (0.7mL, the toluene solution of 1M).Reaction solution stirred 16 hours at 90 ° of C.Reaction is finished, and is cooled to room temperature, adds ethyl acetate (30mL) dilution, and uses diatomite filtration, and filter residue is washed with ethyl acetate (50mL).Filtrate is washed anhydrous sodium sulfate drying, and concentrating under reduced pressure with salt solution (20mL * 2).The gained residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=1/1) purifying, and obtaining title compound is yellow solid (370mg, 36%).
LC-MS(ESI,pos.ion)m/z:465[M+H]
+；
1H?NMR(400MHz,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group)-5-(1-((3-fluoropyrrolidine-3-yl) methyl)-1H-pyrazoles-4-yl) pyridine-2-amine
Step 1) 5-(tertbutyloxycarbonyl)-1-oxa--5-azaspiro [2.4] heptane
(2.57g 11.7mmol) is dissolved in the methyl-sulphoxide (8.8mL), is cooled to 10 ℃, to wherein adding sodium hydride (351mg, 80% is dispersed in the mineral oil) with Trimethylsulfoxonium Iodide.After the mixture stirring at room 2 hours, in system, add 1-(tertbutyloxycarbonyl) tetramethyleneimine-3-ketone (2.00g, methyl-sulphoxide 10.8mmol) (3.0mL) solution.Reaction solution continues to stir 3 hours.Reaction is finished, and successively with frozen water (50mL), salt solution (50mL) cancellation, and extracts with methylene dichloride (100mL * 3).The organic phase that merges is washed with salt solution (50mL), and anhydrous sodium sulfate drying, and concentrating under reduced pressure obtain viscous liquid, and this liquid is not purified, is directly used in next step reaction.
Step 2) 1-(tertbutyloxycarbonyl)-3-((4-iodo-1H-pyrazol-1-yl) methyl) tetramethyleneimine-3-alcohol
With 4-iodo-1H-pyrazoles (2.1g, 10.8mmol) be dissolved in N, in the dinethylformamide (20mL), be cooled to 0 ° of C, to wherein adding sodium hydride (390mg, 80% is dispersed in the mineral oil), mixture is after 0 ° of C stirs 1 hour, in system, add 5-(tertbutyloxycarbonyl)-1-oxa--5-azaspiro [2.4] heptane (2.1g, N 10.8mmol), dinethylformamide (10ml) solution.Reaction solution was 70 ° of C heated and stirred 36 hours.Reaction is finished, and is cooled to room temperature, adds water (10mL) cancellation, and concentrating under reduced pressure.Residue is dispersed in methylene dichloride (100mL) and the water (100mL), and the organic phase of separation is washed with salt solution (50mL), anhydrous sodium sulfate drying, and concentrating under reduced pressure.Residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=3/1) purifying, and obtaining 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-d
6)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-yl) methyl)-4-iodo-1H-pyrazoles
With DAST (0.5mL, 4mmol) be dissolved in the methylene dichloride (30mL), be cooled to-78 ° of C, to wherein dripping 1-(tertbutyloxycarbonyl)-3-((4-iodo-1H-pyrazol-1-yl) methyl) tetramethyleneimine-3-alcohol (786mg, methylene dichloride 2.0mmol) (10mL) solution.Reaction solution stirring at room 6 hours.Reaction is finished, the dilution (50mL) that adds methylene chloride, and water (20mL) and salt solution (20mL) are washed successively.With the solution anhydrous sodium sulfate drying, and concentrating under reduced pressure.The gained residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purifying, and obtaining title compound is colorless oil (600mg, 76%).
LC-MS(ESI,pos.ion)m/z:340[M+H-56]
+；
1H?NMR(400MHz,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group)-5-(1-((3-fluoropyrrolidine-3-yl) methyl)-1H-pyrazoles-4-yl) pyridine-2-amine
With 1-((1-(tertbutyloxycarbonyl)-3-fluoropyrrolidine-3-yl) methyl)-4-iodo-1H-pyrazoles (215mg; 0.54mmol) and (R)-N; (1-(2 for two (the tertbutyloxycarbonyl)-3-of N-; 6-two chloro-3-fluorophenyls) oxyethyl group)-5-(4; 4; 5; 5-tetramethyl--1; 3,2-dioxane pentaborane-2-yl) (284mg 0.45mmol) is dissolved in the glycol dimethyl ether (40mL) pyridine-2-amine; to wherein adding yellow soda ash (148mg successively; 1.4mmol) water (10mL) solution, after the nitrogen protection, continue in system, to add Pd (dppf) Cl
2CH
2Cl
2(35mg, 0.05mmol).Reaction solution was 88 ° of C heated and stirred 16 hours.Reaction is finished, and concentrating under reduced pressure is dispersed in residue in methylene dichloride (60mL) and the water (60mL), and the organic phase of separation is washed with salt solution (30mL), anhydrous sodium sulfate drying, and concentrating under reduced pressure.The gained residue obtains thick product through silica gel column chromatography (PE/EtOAc (v/v)=1/1) purifying.This product is dissolved in the methylene dichloride (40mL), be cooled to 0 ° of C after, to wherein adding HCl (8mL, the ethyl acetate solution of 1M).Reaction solution stirred 12 hours.Reaction is finished, concentrating under reduced pressure.Residue water (100mL) is dissolved again, and adding saturated sodium carbonate solution adjusting pH value is 10, and extracts with methylene chloride mixed solution (8/1,50mL * 3).The organic phase that merges is through anhydrous sodium sulfate drying, and behind the concentrating under reduced pressure, through silica gel column chromatography (DCM/MeOH (v/v)=7/1) purifying, obtaining title compound is yellow solid (75mg, 31%) with residue.
LC-MS(ESI,pos.ion)m/z:234.5(M+2)/2；
1H?NMR(400MHz,DMSO-d
6)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-, two chloro-3-fluorophenyls) oxyethyl group)-5-(1-((S)-tetramethyleneimine-2-ylmethyl)-1H-pyrazoles-4-yl) pyridine-2-amine
Step 1) (S)-(1-(tertbutyloxycarbonyl) tetramethyleneimine-2-yl) methylmethanesulfonate ester
Title compound prepares by the described method of embodiment 6 steps 1, be about to (S)-(1-(tertbutyloxycarbonyl) tetramethyleneimine-2-yl) methyl alcohol (1g, 4.9mmol), methylsulfonyl chloride (0.6mL) and triethylamine (1.1mL) are dissolved in preparation in the methylene dichloride (15mL), obtaining thick product is yellow oil (1.4g), this product is not purified, is directly used in next step.
Step 2) (S)-1-((1-(tertbutyloxycarbonyl) tetramethyleneimine-2-yl) methyl)-4-iodo-1H-pyrazoles
Title compound prepares by the described method of embodiment 6 steps 2, be about to 4-iodo-1H-pyrazoles (840mg, 7.4mmol), (S)-(1-(tertbutyloxycarbonyl) tetramethyleneimine-2-yl) methylmethanesulfonate ester (1.4g) and sodium hydride (90% is dispersed in the mineral oil for 320mg, 12mmol) be dissolved in N, preparation in the dinethylformamide (20mL), thick product is through silica gel column chromatography (PE/EtOAc (v/v)=5/1) purifying, and obtaining target product is colorless oil (1.6g, 89%).
LC-MS(ESI,pos.ion)m/z:378.1[M+H]
+；
1H?NMR(400MHz,CDCl
3)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) tetramethyleneimine-2-yl) methyl)-4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-1H-pyrazoles
Title compound prepares by the described method of embodiment 6 steps 3, (1g 2.65mmol), joins boric acid sodium alcohol ester (3.9mmol frequently to be about to (S)-1-((1-(tertbutyloxycarbonyl) tetramethyleneimine-2-yl) methyl)-4-iodo-1H-pyrazoles, 1g), Pd (dppf) Cl
2CH
2Cl
2(0.2g, 0.265mmol) and potassium acetate (0.53g 5.3mmol) is suspended in preparation in the methyl-sulphoxide (15mL), and thick product is through silica gel column chromatography (PE/EtOAc (v/v)=4/1) purifying, and obtaining target product is white solid (800mg, 80%).
LC-MS(ESI,pos.ion)m/z:378.1[M+H]
+；
1H?NMR(400MHz,CDCl
3)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) tetramethyleneimine-2-yl) methyl)-1H-pyrazoles-4-yl)-3-((R)-1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine
Title compound prepares by the described method of embodiment 6 steps 4, be about to (R)-5-bromo-3-(1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine (500mg, 1.32mmol), (S)-1-((1-(tertbutyloxycarbonyl) tetramethyleneimine-2-yl) methyl)-4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-and the 1H-pyrazoles (500mg, 1.32mmol), Pd (PPh
3)
2Cl
2(108mg, 15.3mmol) and yellow soda ash (2.64mmol 280mg) is suspended in preparation in glycol dimethyl ether/water (15mL/1.5mL), and thick product is through silica gel column chromatography (PE/EtOAc (v/v)=1/1) purifying, obtaining target compound is brown solid (200mg, 27%).
LC-MS(ESI,pos.ion)m/z:550[M+H]
+。
Step 5) 3-((R)-1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group)-5-(1-((S)-tetramethyleneimine-2-ylmethyl)-1H-pyrazoles-4-yl) pyridine-2-amine
Title compound prepares by the described method of embodiment 6 steps 5, be about to 5-(1-(((S)-1-(tertbutyloxycarbonyl) tetramethyleneimine-2-yl) methyl)-1H-pyrazoles-4-yl)-3-((R)-1-(2,6-two chloro-3-fluorophenyls) pyridine-2-amine (160mg oxyethyl group), 0.29mmol) and HCl (5mL, the ethyl acetate solution of 1M) is dissolved in preparation in the 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,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group)-5-(1-(((2S)-4-fluoropyrrolidine-2-yl) methyl)-1H-pyrazoles-4-yl) pyridine-2-amine
Step 1) (2S)-1-(tertbutyloxycarbonyl)-4-fluoropyrrolidine-2-methyl-formiate
Title compound prepares by the described method of embodiment 1 step 8, be about to (2S)-1-(tertbutyloxycarbonyl)-4-hydroxyl pyrrolidine-2-methyl-formiate (1g, 4.1mmol) and DAST (1.1mL, 8.2mmol) be dissolved in preparation in the methylene dichloride (5mL), thick product is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=5/1) purifying, obtaining target product is yellow oil (0.93g, 93%).
LC-MS(ESI,pos.ion)m/z:248[M+H]
+。
Step 2) ((2S)-1-(tertbutyloxycarbonyl)-4-fluoropyrrolidine-2-yl) methyl alcohol
With (2S)-1-(tertbutyloxycarbonyl)-4-fluoropyrrolidine-2-methyl-formiate (0.95g 3.85mmol) in dissolving tetrahydrofuran (THF) (18mL), is cooled to 0 ° of C, to wherein slowly add lithium borohydride (0.13g, 5.78mmol).Reaction solution is risen to room temperature, and stirring is spent the night.Reaction is finished, and adds acetic acid,diluted (0.5mL is dissolved in 60mL water) cancellation, and extracts with ethyl acetate (20mL * 3).The organic phase that merges uses 1M sodium hydrogen carbonate solution (50mL), salt solution (50mL) to wash successively, anhydrous sodium sulfate drying, and concentrating under reduced pressure, the gained residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purifying, obtaining title compound is yellow oil (0.82g, 97%).
LC-MS(ESI,pos.ion)m/z:242[M+Na]
+。
Step 3) ((2S)-1-(tertbutyloxycarbonyl)-4-fluoropyrrolidine-2-yl) methylmethanesulfonate ester
With ((2S)-1-(tertbutyloxycarbonyl)-4-fluoropyrrolidine-2-yl) methyl alcohol (0.41g, 1.87mmol) and DMAP (22.8mg, 0.1mmol) be dissolved in the methylene dichloride (6mL), be cooled to 0 ° of C, successively to wherein adding triethylamine (0.52mL, 3.74mmol) and methylsulfonyl chloride (0.23mL, 2.81mmol).Reaction solution stirring at room 2.5 hours.Reaction is finished, and adds 1M sodium hydrogen carbonate solution (25mL) cancellation, and extracts with methylene dichloride (30mL * 3), and the organic phase of merging is washed with salt solution (25mL), anhydrous sodium sulfate drying, and concentrating under reduced pressure, and the gained residue is not purified, is directly used in next step reaction.
Step 4) 1-(((2S)-1-(tertbutyloxycarbonyl)-4-fluoropyrrolidine-2-yl) methyl)-4-iodo-1H-pyrazoles
With 4-iodo-1H-pyrazoles (0.51g, 2.64mmol) be dissolved in dry N, in the dinethylformamide (45mL), be cooled to 0 ° of C, to wherein add in batches sodium hydride (0.17g, 7.0mmol), mixture is after 0 ° of C stirs 8 hours, rise to room temperature, and to wherein adding ((2S)-1-(tertbutyloxycarbonyl)-4-fluoropyrrolidine-2-yl) methylmethanesulfonate ester.Reaction solution is heated to 100 ° of C, stirring reaction 8 hours.Reaction is finished, and adds NH
4The Cl aqueous solution (50mL), and extract with ethyl acetate (50mL * 3).The organic phase that merges is washed anhydrous Na with saturated aqueous common salt (25mL)
2SO
4Drying, and concentrating under reduced pressure, gained residue are through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=6/1) purifying, and obtaining title compound is colorless oil (700mg, 95%).
LC-MS(ESI,pos.ion)m/z:396[M+H]
+；
1H?NMR(400MHz,CDCl
3)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-yl) methyl)-4-(4,4,5,5-tetramethyl--1,3-dioxane pentaborane-2-yl)-1H-pyrazoles
Title compound prepares by the described method of embodiment 7 steps 4, be about to 1-(((2S)-1-(tertbutyloxycarbonyl)-4-fluoropyrrolidine-2-yl) 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 (PPh
3)
2Cl
2(62mg 0.09mmol) is suspended in preparation in the methyl-sulphoxide (10mL), and thick product is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purifying, and obtaining target product is yellow oil (0.66g, 94%).
LC-MS(ESI,pos.ion)m/z:398[M+H]
+；
1H?NMR(400MHz,CDCl
3)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-yl) methyl)-1H-pyrazoles-4-yl)-3-((R)-1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine
Title compound prepares by the described method of embodiment 7 steps 5, (1-(2 to be about to (R)-5-bromo-3-, 6-two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine (0.54g, 1.44mmol), 1-(((2S)-1-(tertbutyloxycarbonyl)-4-fluoropyrrolidine-2-yl) methyl)-4-(4,4,5,5-tetramethyl--1,3-dioxane pentaborane-2-yl)-1H-pyrazoles (0.38g, 0.96mmol), Pd (OAc)
2(22mg, 0.096mmol), Na
2CO
3(0.3g, 2.87mmol) and (t-Bu)
3(49mg 0.24mmol) is suspended in preparation in glycol dimethyl ether/water (6mL/1.5mL) to P, and thick product is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=1/2) purifying, and obtaining target product is yellow solid (0.5g, 55%).
LC-MS(ESI,pos.ion)m/z:569[M+H]
+；
1H?NMR(400MHz,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group)-5-(1-(((2S)-4-fluoropyrrolidine-2-base-) methyl)-1H-pyrazoles-4-yl) pyridine-2-amine
The method that title compound is described by embodiment 1 step 10 prepares, be about to 5-(1-(((2S)-1-(tertbutyloxycarbonyl)-4-fluoropyrrolidine-2-yl) methyl)-1H-pyrazoles-4-yl)-3-((R)-1-(2,6-two chloro-3-fluorophenyls) pyridine-2-amine (0.4g oxyethyl group), 0.52mmol) and HCl (5mL, the ethyl acetate solution of 3M) is dissolved in preparation in the methylene dichloride (15mL), thick product is through silica gel column chromatography (methylene chloride/triethylamine (v/v/v)=200/20/1) purifying, obtaining title compound is yellow solid (0.29g, 90%).
LC-MS(ESI,pos.ion)m/z:468[M+H]
+；
1H?NMR(400MHz,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group)-5-(1-(((S)-4,4-two fluoropyrrolidines-2-yl) methyl)-1H-pyrazoles-4-yl) pyridine-2-amine
Step 1) (2S)-1-(tertbutyloxycarbonyl)-4-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) tetramethyleneimine-2-methyl-formiate
With (2S)-1-(tertbutyloxycarbonyl)-4-hydroxyl pyrrolidine-2-methyl-formiate (2.0g 8.15mmol) is suspended in methylene dichloride (100mL), and to wherein add DHP (1.71g, 20.4mmol) and PPTS (246mg, 0.978mmol).Reaction solution was 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) purifying, obtaining title compound is colorless oil (2.65g, 99%).
1H?NMR(400MHz,CDCl
3)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-yl) oxygen base) tetramethyleneimine-2-yl) methyl alcohol
With (2S)-1-(tertbutyloxycarbonyl)-4-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) tetramethyleneimine-2-methyl-formiate (1.0g 3.0mmol) is dissolved in the tetrahydrofuran (THF) (15mL), with after the ice bath cooling, to wherein add lithium borohydride (94.5mg, 4.5mmol).Reaction solution stirs at 35 ° of C and spends the night.Reaction is finished, and with the ice bath cooling, slowly adds saturated ammonium chloride solution (20mL) cancellation, and extracts with ethyl acetate (60mL * 3).The organic phase that merges is used anhydrous sodium sulfate drying, and concentrating under reduced pressure.The gained residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purifying, and obtaining title compound is colorless oil (850mg, 94%).
LC-MS(ESI,pos.ion)m/z:324[M+Na]
+；
1H?NMR(400MHz,CDCl
3)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-yl) oxygen base) tetramethyleneimine-2-yl) methylmethanesulfonate ester
The method that title compound is described by embodiment 10 steps 3 prepares, be about to ((2S)-1-(tertbutyloxycarbonyl)-4-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) tetramethyleneimine-2-yl) methyl alcohol (1.0g, 3.3mmol), methylsulfonyl chloride (0.38mL, 4.95mmol), DMAP (40mg, 0.33mmol) and triethylamine (0.92mL 6.6mmol) is dissolved in and prepares thick product (1.25g, 100%) in the methylene dichloride (10mL), this product is not purified, is directly used in next step reaction.
Step 4) 1-(((2S)-1-(tertbutyloxycarbonyl)-4-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) tetramethyleneimine-2-yl) methyl)-4-iodo-1H-pyrazoles
With 4-iodo-1H-pyrazoles (704.2mg 3.63mmol) is dissolved in dry N, in the dinethylformamide (15mL), be cooled to 0 ℃ after, to wherein add sodium hydride (7.6mmol, 192mg, 95%) in batches.Suspension 0 ℃ stir 8 hours after, returned to stirring at room 1.5 hours, and continue in system, to add ((2S)-1-(tertbutyloxycarbonyl)-4-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) tetramethyleneimine-2-yl) methylmethanesulfonate ester (1.25g, 3.3mmol) N, dinethylformamide (3mL) solution.Reaction solution stirred 13 hours at 100 ℃.Reaction is finished, and is cooled to room temperature, adds saturated ammonium chloride solution (30mL) cancellation, and extracts with ethyl acetate (50mL * 2).The organic phase that merges is washed anhydrous sodium sulfate drying, and concentrating under reduced pressure with salt solution (25mL).The gained residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purifying, and obtaining title compound is white solid (1.3g, 83%).
LC-MS(ESI,pos.ion)m/z:478[M+H]
+；
1H?NMR(400MHz,CDCl
3)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) tetramethyleneimine-3-alcohol
With 1-(((2S)-1-(tertbutyloxycarbonyl)-4-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) tetramethyleneimine-2-yl) methyl)-4-iodo-1H-pyrazoles (200mg, 0.42mmol) be suspended in the mixed solution of tetrahydrofuran (THF)/water (5mL/5mL), to wherein add acetic acid (1mL, 16.8mmol).Reaction solution stirred 16 hours at 70 ℃.Reaction is finished, and is cooled to room temperature.It is 10 that mixture is regulated the pH value with saturated sodium carbonate solution, and extracts with ethyl acetate (50mL * 3).With the organic phase anhydrous sodium sulfate drying that merges, behind the concentrating under reduced pressure, with silica gel column chromatography (petrol ether/ethyl acetate (v/v)=1/1) purifying, obtaining title compound is colorless oil (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) tetramethyleneimine-3-ketone
With (5S)-1-(tertbutyloxycarbonyl)-5-((4-iodo-1H-pyrazol-1-yl) methyl) tetramethyleneimine-3-alcohol (1.39g 3.54mmol) is suspended in the methylene dichloride (44mL), to wherein add the Dess-Martin oxygenant (3g, 7.07mmol).Reaction solution stirring at room 16 hours is filtered.After filtrate decompression is concentrated, with silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purifying, obtaining title compound was white solid (1.2g, 87%).
1H?NMR(400MHz,CDCl
3)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-two fluoropyrrolidines-2-yl) methyl)-4-iodo-1H-pyrazoles
With (S)-1-(tertbutyloxycarbonyl)-5-((4-iodo-1H-pyrazol-1-yl) methyl) tetramethyleneimine-3-ketone (100mg 0.26mmol) is dissolved in the methylene dichloride (3mL), is cooled to-78 ℃, to wherein add DAST (95%, 0.15mL, 1.04mmol).Reaction solution returns to room temperature after-40 ° of C stir 2 hours, continue to stir 21 hours.Reaction is finished, and concentrating under reduced pressure dilutes residue water (30mL), and extracts with methylene dichloride (30mL * 3).The organic phase that merges is washed anhydrous sodium sulfate drying, and concentrating under reduced pressure with salt solution (30mL).The gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=4/1) purifying, and obtaining target product is yellow oil (100mg, 93%).
LC-MS(ESI,pos.ion)m/z:414[M+H]
+；
1H?NMR(400MHz,CDCl
3)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-two fluoropyrrolidines-2-yl) methyl)-4-(4,4,5,5-tetramethyl--1,3-dioxolanes-2-yl)-1H-pyrazoles
To join boric acid sodium alcohol ester (128mg frequently, 0.504mmol) be dissolved in the methyl-sulphoxide (3mL), to wherein adding (S)-1-((1-(tertbutyloxycarbonyl)-4,4-two fluoropyrrolidines-2-yl) methyl)-4-iodo-1H-pyrazoles (80mg, 0.194mmol) and potassium acetate (76mg, 0.776mol), system is placed nitrogen atmosphere, continue to wherein adding Pd (PPh
3)
2Cl
2(16.3mg, 0.023mmol).Reaction solution is cooled to room temperature after 80 ° of C stir 3 hours, add water (30mL) dilution, and extracts with ethyl acetate (30mL * 3).The organic phase that merges is through anhydrous sodium sulfate drying, and behind the concentrating under reduced pressure, with silica gel column chromatography (petrol ether/ethyl acetate (v/v)=5/1) purifying, 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-two fluoropyrrolidines-2-yl) methyl)-1H-pyrazoles-4-yl)-3-((R)-1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine
(1-(2 with (R)-5-bromo-3-, 6-two chloro-3-fluorophenyls) pyridine-2-amine (195mg oxyethyl group), 0.51mmol), (S)-1-((1-(tertbutyloxycarbonyl)-4,4-two fluoropyrrolidines-2-yl) methyl)-4-(4,4,5,5-tetramethyl--1,3-dioxolanes-2-yl)-and the 1H-pyrazoles (141mg, 0.34mmol) and Pd (OAc)
2(7.7mg 0.034mmol) is suspended in glycol dimethyl ether/water (3mL/0.5mL), and (145mg, water 1.37mmol) (0.5mL) solution after the nitrogen protection, continue to add (t-Bu) in system to wherein adding yellow soda ash
3P (0.15mL, the toluene solution of 1M).Reaction solution is down to room temperature after 90 ° of C stir 13 hours, add ethyl acetate (40mL) dilution, and use diatomite filtration, and filter residue is washed with ethyl acetate (40mL).Collect filtrate, wash through salt solution (30mL * 2), behind the concentrating under reduced pressure, with silica gel column chromatography (petrol ether/ethyl acetate (v/v)=1/2) purifying, obtaining target product is yellow solid (80mg, 44%).
LC-MS(ESI,pos.ion)m/z:586[M+H]
+。
Step 10) 3-((R)-1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group)-5-(1-(((S)-4,4-two fluoropyrrolidines-2-yl) methyl)-1H-pyrazoles-4-yl) pyridine-2-amine
Target compound prepares by the described method of embodiment 1 step 10, be about to 5-(1-(((S)-1-(tertbutyloxycarbonyl)-4,4-two fluoropyrrolidines-2-yl) methyl)-1H-pyrazoles-4-yl)-3-((R)-1-(2,6-two chloro-3-fluorophenyls) pyridine-2-amine (140mg oxyethyl group), 0.24mmol) and HCl (2mL, the ethyl acetate solution of 3M) is dissolved in preparation in the methylene dichloride (6mL), thick product is through silica gel column chromatography (ethyl acetate/methanol (v/v)=20/1) purifying, obtaining title compound is yellow solid (80mg, 69%).
LC-MS(ESI,pos.ion)m/z:243(M+1/2)；
1H?NMR(400MHz,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group) pyridin-3-yl)-1H-pyrazol-1-yl) methyl) tetramethyleneimine-3-alcohol
Step 1) 1-(((2S)-1-(tertbutyloxycarbonyl)-4-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) tetramethyleneimine-2-yl) methyl)-4-(4,4,5,5-tetramethyl--1,3-dioxane pentaborane-2-yl)-1H-pyrazoles
Title compound prepares by the described scheme of embodiment 11 steps 8, be about to 1-(((2S)-1-(tertbutyloxycarbonyl)-4-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) tetramethyleneimine-2-yl) methyl)-4-iodo-1H-pyrazoles (100mg, 0.21mmol), connection boric acid is sodium alcohol ester (140mg frequently, 0.54mmol), Pd (PPh
3)
2Cl
2(16mg, 0.23mmol) and potassium acetate (82mg 0.84mol) is suspended in preparation in the methyl-sulphoxide (3mL), and thick product is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=1/4) purifying, and obtaining target compound is white solid (80mg, 80%).
LC-MS(ESI,pos.ion)m/z:477[M+H]
+；
1H?NMR(400MHz,CDCl
3)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-yl) oxygen base) tetramethyleneimine-2-yl) methyl)-1H-pyrazoles-4-yl)-3-((R)-1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine
The scheme that title compound is described by embodiment 11 steps 9 prepares, (1-(2 to be about to (R)-5-bromo-3-, 6-two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine (96mg, 0.25mmol), 1-(((2S)-1-(tertbutyloxycarbonyl)-4-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) tetramethyleneimine-2-yl) methyl)-4-(4,4,5,5-tetramethyl--1,3-dioxane pentaborane-2-yl)-1H-pyrazoles (100mg, 0.21mmol), Pd (OAc)
2(4.7mg, 0.021mmol), yellow soda ash (89mg, 0.84mmol) and (t-Bu)
3P (0.06mL, the toluene solution of 1M) is suspended in the mixed solution of glycol dimethyl ether/water (3mL/0.5mL) and prepares, and thick product is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=1/1) purifying, and obtaining title compound is yellow solid (60mg, 44%).
LC-MS(ESI,pos.ion)m/z:650[M+H]
+；
1H?NMR(400MHz,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group) pyridin-3-yl)-1H-pyrazol-1-yl) methyl) tetramethyleneimine-3-alcohol
Target compound prepares by the described method of embodiment 1 step 10, be about to 5-(1-(((2S)-1-(tertbutyloxycarbonyl)-4-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) tetramethyleneimine-2-yl) methyl)-1H-pyrazoles-4-yl)-3-((R)-1-(2,6-two chloro-3-fluorophenyls) pyridine-2-amine (250mg oxyethyl group), 0.385mmol) and HCl (3.5mL, the ethyl acetate solution of 3M) is dissolved in preparation in the methylene dichloride (12mL), thick product is through silica gel column chromatography (ethyl acetate/methanol (v/v)=5/1) purifying, obtaining title compound is yellow solid (120mg, 67%).
LC-MS(ESI,pos.ion)m/z:233(M+1/2)；
1H?NMR(400MHz,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group) pyridin-3-yl)-1H-pyrazol-1-yl) tetrahydrochysene-2H-pyrans-3-alcohol (13a)
3-(4-(6-amino-5-((R)-1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridin-3-yl)-1H-pyrazol-1-yl) tetrahydrochysene-2H-pyrans-4-alcohol (13b)
Step 1) 3,6-dihydro-2H-pyrans
With tetrahydrochysene-2H-pyrans-4-alcohol (20.4g, 0.2mol) and triethylamine (36.2mL 0.26mol) is dissolved in the methylene dichloride (200mL), is cooled to 0 ° of C, to wherein add methylsulfonyl chloride (17mL, 0.22mol).After the reaction solution stirring at room 3 hours, pour in the water (100mL).The organic phase of separating is washed through salt solution (100mL * 2), anhydrous sodium sulfate drying, and concentrating under reduced pressure obtains orange.This oily matter is heated to 50 ° of C, then to wherein dripping DBU (40mL).Mixture stirred 2 hours at 100 ° of C.Residue is through underpressure distillation (92-93 ° of C) purifying, and obtaining title compound is colourless liquid (10.0g, 60%).
GC-MS?m/z:84(M)。
Step 2) 3,7-two oxa-dicyclo [4.1.0] heptane
With m-CPBA (25.6g 296mmol) is suspended in the methylene dichloride (200mL), is cooled to 0 ° of C, to wherein drip 3,6-dihydro-2H-pyrans (8.3g, 98.7mmol).The reaction solution stirred overnight at room temperature.Reaction is finished, concentrating under reduced pressure, and residue dilutes with methylene dichloride (30mL).Mixture is cooled to 0 ° of C, filters, it is colorless oil (7.5g, 76%) that filtrate obtains title compound through concentrating under reduced pressure.
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 (60% is dispersed in the mineral oil for 1.6g, 40.0mmol) is suspended in N, in the dinethylformamide (30mL), is cooled to 0 ° of C, to wherein add 4-iodo-1H-pyrazoles (5.8g, 30.0mmol).Mixture continues to wherein adding 3,7-, two oxa-dicyclo [4.1.0] heptane (2.0g, N 20.0mmol), dinethylformamide (5mL) solution after 0 ° of C stirs 2.5 hours.Reaction solution after 100 ° of C stir 18 hours, concentrating under reduced pressure.Residue is dispersed in ethyl acetate (300mL) and the water (150mL), water phase separated, and extract with ethyl acetate (300mL).The organic phase that merges is through anhydrous sodium sulfate drying, and behind the concentrating under reduced pressure, with silica gel column chromatography (petrol ether/ethyl acetate (v/v)=3/1) purifying, obtaining (13.3a) and mixture (13.3b) 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-, two chloro-3-fluorophenyls) oxyethyl group) pyridin-3-yl)-1H-pyrazol-1-yl) tetrahydrochysene-2H-pyrans-3-alcohol (13a)
3-(4-(6-amino-5-((R)-1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridin-3-yl)-1H-pyrazol-1-yl) tetrahydrochysene-2H-pyrans-4-alcohol (13b)
(530mg 1.8mmol) is dissolved in the glycol dimethyl ether (25mL), to wherein adding (R)-N with (13.3a) and mixture (13.3b); two (the tertbutyloxycarbonyl)-3-(1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) of N--5-(4,4; 5; 5-tetramethyl--1,3,2-dioxane pentaborane-2-yl) pyridine-2-amine (941mg; 1.5mmol) and cesium carbonate (1467mg; 4.5mmol) water (5mL) solution, after the nitrogen protection, continue in system, to add Pd (dppf) Cl
2CH
2Cl
2(122mg, 0.15mmol).Reaction solution stirred 18 hours at 90 ° of C.Reaction is finished, and pours in the salt solution (50mL), and extracts with ethyl acetate (100mL * 3).The organic phase that merges is through anhydrous sodium sulfate drying, and behind the concentrating under reduced pressure, with silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purifying, obtaining title compound is the off-white color solid.This solid is dissolved in the methylene dichloride (20mL), is cooled to 0 ° of C, to wherein adding HCl (3mL, the ethyl acetate solution of 3M).The reaction solution stirred overnight at room temperature, concentrating under reduced pressure.Residue water (15mL) dilution adds saturated sodium carbonate solution and regulates pH10, and extracts mixed solution with ethyl acetate (100mL * 3).The organic phase that merges is through anhydrous sodium sulfate drying, and behind the concentrating under reduced pressure, (5mL) washes with ether, and obtaining (13a) and mixture (13b) is brown solid (55mg, 7%).
LC-MS(ESI,pos.ion)m/z:467[M+H]
+。
Embodiment 143-((R)-1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group)-5-(1-(5-fluorine piperidines-3-yl)-1H-pyrazoles-4-yl) pyridine-2-amine
Step 1) 1-(tertbutyloxycarbonyl) piperidin-4-yl methanesulfonates
With 1-(tertbutyloxycarbonyl) piperidines-4-alcohol (10g, 49.3mmol) and triethylamine (10g 74mmol) is dissolved in the methylene dichloride (150mL), be cooled to 0 ℃ after, to wherein drip methylsulfonyl chloride (8.6g, 59mmol).Reaction solution was stirring at room 2 hours.Reaction is finished, and with methylene dichloride (100mL) dilution, uses saturated sodium carbonate solution (250mL), salt solution (250 mL) to wash successively mixed solution.Organic phase is through anhydrous sodium sulfate drying, and concentrating under reduced pressure, and obtaining thick product is yellow oil (14g, 97%), and this compound is not purified, is directly used in next step reaction.
Step 2) 1-(tertbutyloxycarbonyl)-1,2,3, the 6-tetrahydropyridine
(14g, DBU 48mmol) (80mL) solution is heated to 80 ℃, stirs 16 hours with 1-(tertbutyloxycarbonyl) piperidin-4-yl methanesulfonates.Reaction is finished, and is cooled to room temperature, adds water (200mL) dilution, and extracts with ethyl acetate (150mL x3), and the organic phase of merging uses 1M hydrochloric acid (450mL * 3), saturated sodium carbonate solution (450mL * 2) to wash successively.Gained solution is through anhydrous sodium sulfate drying, and concentrating under reduced pressure to obtain title compound be brown oil (8g, 100%), this compound is not purified, is directly used in next step.
LC-MS(ESI,pos.ion)m/z:128[M+H-56]
+；
1H?NMR(400MHz,CDCl
3)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
With m-CPBA (20g 87.4mmol) is dissolved in the methylene dichloride (150mL), is cooled to 0 ℃, to wherein dripping 1-(tertbutyloxycarbonyl)-1,2,3, the 6-tetrahydropyridine (8g, 43.7mmol).Reaction solution stirring at room 14 hours.Reaction is finished, and filters.Filter cake is washed with methylene dichloride (50mL * 2), and the filtrate of merging is washed with saturated sodium carbonate solution (300mL * 2).Gained solution is through anhydrous sodium sulfate drying, and behind the concentrating under reduced pressure, with silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purifying, obtaining title compound is colorless oil (8g, 93%).
1H?NMR(400MHz,CDCl
3)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 piperidines-3-alcohol
(100mg 0.5mmol) is dissolved in N, and dinethylformamide (5mL) is after the ice bath cooling, to ISiMe wherein with 3-(tertbutyloxycarbonyl)-7-oxa--3-azabicyclo [4.1.0] heptane
3(0.078mL, 0.55mmol).The reaction solution stirred overnight at room temperature.Reaction is finished, and adds ethyl acetate (50mL) dilution, uses 1M hydrochloric acid (25mL * 2), saturated sodium carbonate solution (20mL * 2) to wash successively.Mixed solution is through anhydrous sodium sulfate drying, and behind the concentrating under reduced pressure, with silica gel column chromatography (PE/EtOAc (v/v)=4/1) purifying, obtaining title compound is yellow oil (60mg, 37%).
LC-MS(ESI,pos.ion)m/z:350[M+Na]
+,254[M+H-56-18]
+；
1H?NMR(400MHz,CDCl
3)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) 1-(tertbutyloxycarbonyl)-4-iodo-3-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) piperidines
With 1-(tertbutyloxycarbonyl)-4-iodine piperidines-3-alcohol (1g, 3.1mmol), PPTS (77mg 0.31mmol) is suspended in the methylene dichloride (20mL), to wherein add DHP (0.56mL, 9.4mmol).The reaction solution stirred overnight at room temperature.Reaction is finished, concentrating under reduced pressure, and gained residue silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purifying, obtaining title compound is colorless oil (1.0g, 80%).
LC-MS(ESI,pos.ion)m/z:434[M+Na]
+；
1H?NMR(400MHz,CDCl
3)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-yl) oxygen base)-1,2,3, the 6-tetrahydropyridine
To 1-(tertbutyloxycarbonyl)-4-iodo-3-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) piperidines (7.7g, 18.7mmol) the middle DBU (50mL) that adds.Reaction solution stirred 27 hours at 80 ° of C.Reaction is finished, and is cooled to room temperature, adds ethyl acetate (50mL) dilution.Mixed solution uses 1M hydrochloric acid (50mL * 3), saturated sodium carbonate solution (50mL * 2) to wash anhydrous sodium sulfate drying, and concentrating under reduced pressure successively.The gained residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=15/1) purifying, and obtaining title compound is colorless oil (4.2g, 72%).
LC-MS(ESI,pos.ion)m/z:306[M+Na]
+；
1H?NMR(400MHz,CDCl
3)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
With 1-(tertbutyloxycarbonyl)-3-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base)-1,2,3, (500mg 1.64mmol) is dissolved in methylene chloride (25mL/5mL) mixed solution 6-tetrahydropyridine, is cooled to 0 ° of C, to wherein slowly adding HCl (11mL, the ethyl acetate solution of 3M).After the reaction solution stirred overnight at room temperature, concentrating under reduced pressure obtains thick product, and this product directly is dissolved in the mixed solution of tetrahydrofuran (THF)/water (76mL/60mL).Solution is regulated pH10 with saturated sodium carbonate solution, to wherein adding Boc acid anhydrides (1.5mL).The reaction solution stirred overnight at room temperature.Reaction is finished, and adds ethyl acetate/water (30mL/30mL) dilution, and the water of separation extracts with ethyl acetate (80mL * 2).The organic phase that merges is through anhydrous sodium sulfate drying, and behind the concentrating under reduced pressure, with silica gel column chromatography (PE/EtOAc (v/v)=2/1) purifying, 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)-ketone
With 1-(tertbutyloxycarbonyl)-1,2,3,6-tetrahydropyridine-3-alcohol (350mg 1.76mmol) is dissolved in the methylene dichloride (12mL), to wherein add the Dess-Martin oxygenant (1.5g, 3.52mmol).After the reaction solution stirring at room 2 hours, filter.Filtrate is washed with saturated sodium carbonate solution (50mL), and concentrating under reduced pressure, and the gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=2/1) purifying, and 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,CDCl
3)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
With 4-iodo-1H-pyrazoles (389.9mg 2.01mmol) is dissolved in the acetonitrile (6mL), to wherein adding 1-(tertbutyloxycarbonyl)-1,6-dihydropyridine-3 (2H)-ketone (260mg, 1.34mmol).Reaction solution stirs at 80 ° of C and spends the night.Reaction is finished, and is cooled to room temperature, adds water (20mL) dilution, and extracts with ethyl acetate (30mL * 2).The organic phase that merges is through anhydrous sodium sulfate drying, and behind the concentrating under reduced pressure, with silica gel column chromatography (PE/EtOAc (v/v)=2/1) purifying, 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,CDCl
3)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) piperidines-3-alcohol
With 1-(tertbutyloxycarbonyl)-5-(4-iodo-1H-pyrazol-1-yl) piperidines-3-ketone (3.45g 8.82mmol) is dissolved in the methyl alcohol (50mL), is cooled to 0 ℃, to wherein add sodium borohydride (670mg, 17.64mmol).Reaction solution stirring at room 1 hour.Reaction is finished, and adds saturated ammonium chloride solution (50mL) cancellation, and extracts with ethyl acetate (100mL * 2).The organic phase that merges is through anhydrous sodium sulfate drying, and behind the concentrating under reduced pressure, with silica gel column chromatography (PE/EtOAc (v/v)=4/1) purifying, obtaining title compound is white solid (2.1g, 60.7%).
LC-MS(ESI,pos.ion)m/z:394[M+H]
+。
Step 11) 1-(tertbutyloxycarbonyl)-3-fluoro-5-(4-iodo-1H-pyrazol-1-yl) piperidines
Title compound can prepare by the described method of embodiment 11 steps 7, be about to 1-(tertbutyloxycarbonyl)-5-(4-iodo-1H-pyrazol-1-yl) piperidines-3-alcohol (240mg, 0.61mmol), DAST (95%, 0.15mL, 1.04mmol) being dissolved in preparation in the methylene dichloride (5mL), thick product is through silica gel column chromatography (PE/EtOAc (v/v)=2/1) purifying, obtaining target product is yellow solid (900mg, 45%).
MS(ESI,pos.ion)m/z:340[M+H-56]
+。
Step 12) 1-(tertbutyloxycarbonyl)-3-fluoro-5-(4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-1H-pyrazol-1-yl) piperidines
Target compound prepares by the described step of embodiment 11 steps 8, be about to 1-(tertbutyloxycarbonyl)-3-fluoro-5-(4-iodo-1H-pyrazol-1-yl) piperidines (900mg, 2.07mmol), connection boric acid frequently the sodium alcohol ester (1.04g, 4.14mmol), Pd (PPh
3)
2Cl
2(174.6mg, 0.12mmol) and potassium acetate (608mg 6.21mol) is suspended in preparation in the methyl-sulphoxide (50mL), and thick product is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=5/1) purifying, 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 piperidines-3-yl)-1H-pyrazoles-4-yl)-3-((R)-1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine
Target compound prepares by the described step of embodiment 11 steps 9, be about to (R)-5-bromo-3-(1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine (195mg, 0.5139mmol), 1-(tertbutyloxycarbonyl)-(4-(4 for 3-fluoro-5-, 4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-the 1H-pyrazol-1-yl) piperidines (521.5mg, 1.32mmol), Pd (OAc)
2(35.5mg, mmol), yellow soda ash (560mg, 5.28mmol) and (t-Bu)
3P (0.15mL, the toluene solution of 1M) is suspended in preparation in glycol dimethyl ether/water (15mL/4mL), and thick product is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=1/1) purifying, and obtaining title compound is yellow solid (350mg, 47%).
MS(ESI,pos.ion)m/z:568[M+H]
+。
Step 14) 3-((R)-1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group)-5-(1-(5-fluorine piperidines-3-yl)-1H-pyrazoles-4-yl) pyridine-2-amine
Target compound prepares by the described method of embodiment 1 step 10, be about to 5-(1-(1-(tertbutyloxycarbonyl)-5-fluorine piperidines-3-yl)-1H-pyrazoles-4-yl)-3-((R)-1-(2,6-two chloro-3-fluorophenyls) pyridine-2-amine (350mg oxyethyl group), 0.62mmol) and HCl (4mL, the ethyl acetate solution of 3M) is dissolved in preparation in the methylene dichloride (6mL), thick product is through silica gel column chromatography (ethyl acetate/methanol (v/v)=6/1) purifying, obtaining title compound is yellow solid (235mg, 81%).
LC-MS(ESI,pos.ion)m/z:234.5(M+1/2)；
1H?NMR(400MHz,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group) pyridin-3-yl)-1H-pyrazol-1-yl) piperidines-3-alcohol
Step 1) 1-(tertbutyloxycarbonyl)-5-(4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-1H-pyrazol-1-yl) piperidines-3-alcohol
With 1-(tertbutyloxycarbonyl)-5-(4-iodo-1H-pyrazol-1-yl) piperidines-3-alcohol (1.5g; 3.81mmol) and connection boric acid frequency sodium alcohol ester (1.94g; 7.62mmol) be dissolved in the methyl-sulphoxide (20mL); to wherein adding potassium acetate (1.5g; 15.24mmol); under the nitrogen protection, continue in system, to add Pd (dppf) Cl
2CH
2Cl
2(310mg, 0.38mmol).Reaction solution is cooled to room temperature, and pours in water/ethyl acetate (100mL/300mL) mixed solution after 90 ° of C stir 12 hours.The organic phase of separating is washed anhydrous sodium sulfate drying, and concentrating under reduced pressure with salt solution (100mL).The gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=2/1) purifying, and 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-, two chloro-3-fluorophenyls) oxyethyl group) pyridin-3-yl)-1H-pyrazol-1-yl)-1-(tertbutyloxycarbonyl) piperidines-3-alcohol
With (R)-5-bromo-3-(1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine (515mg, 1.36mmol) and 1-(tertbutyloxycarbonyl)-5-(4-(4; 4; 5,5-tetramethyl--1,3; 2-dioxane pentaborane-2-yl)-and the 1H-pyrazol-1-yl) piperidines-3-alcohol (800mg; 2.03mmol) be dissolved in the glycol dimethyl ether (25mL), (1.33g is behind water 4.08mmol) (5mL) solution to wherein adding cesium carbonate; under nitrogen protection, continue in system, to add Pd (dppf) Cl
2CH
2Cl
2(114mg, 0.14mmol).Reaction solution stirred 12 hours at 90 ° of C, was cooled to room temperature, added water (20mL) dilution, and (3 * 50mL) extract with methylene dichloride.The organic phase that merges is washed anhydrous sodium sulfate drying, and concentrating under reduced pressure with salt solution (100mL).The gained residue is through silica gel column chromatography (methylene chloride (v/v)=60/1) purifying, and obtaining title compound is yellow oil (400mg, 52%).
LC-MS(ESI,pos.ion)m/z:566.20[M+H]
+；
1H?NMR(400MHz,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group) pyridin-3-yl)-1H-pyrazol-1-yl) piperidines-3-alcohol
Target compound prepares by the described method of embodiment 1 step 10, be about to 5-(4-(6-amino-5-((R)-1-(2,6-two chloro-3-fluorophenyls) pyridin-3-yl oxyethyl group))-the 1H-pyrazol-1-yl)-1-(tertbutyloxycarbonyl) piperidines-3-alcohol (350mg, 0.62mmol) and HCl (4mL, the ethyl acetate solution of 3M) is dissolved in preparation in the methylene dichloride (5mL), thick product is through silica gel column chromatography (methylene chloride (v/v)=40/1) purifying, obtaining title compound is pale brown look solid (60mg, 21%).
LC-MS(ESI,pos.ion)m/z:466.20[M+H]
+；
1H?NMR(400MHz,DMSO-d
6)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-, two deuterium generation-4-yls)-1H-pyrazoles-4-yl)-3-((R)-1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine
Step 1) 4-hydroxy piperidine-2-ketone
With piperidines-2, the 4-diketone (1g 8.8mmol) is dissolved in the methyl alcohol (25mL), is cooled to 0 ℃, to wherein add sodium borohydride (1g, 26.55mmol).The reaction solution stirred overnight at room temperature.Reaction is finished, concentrating under reduced pressure.The gained residue is through silica gel column chromatography (methylene chloride (v/v)=5/1) purifying, and 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-yl) oxygen base) piperidines-2-ketone
With 4-hydroxy piperidine-2-ketone (1.4g, 12.18mmol), PPTS (367mg 1.462mmol) is suspended in the methylene dichloride (200mL), to wherein add DHP (4.1g, 48.72mmol).Reaction solution after 35 ° of C stir 48 hours, concentrating under reduced pressure.The gained residue is through silica gel column chromatography (methylene chloride (v/v)=10/1) purifying, and obtaining title compound is white solid (2.16g, 89%).
LC-MS(ESI,pos.ion)m/z:200[M+H]
+。
1H?NMR(400MHz,CDCl
3)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 deuteriums are for piperidines-4-alcohol
(1.17g 5.88mmol) is dissolved in the tetrahydrofuran (THF) (33.3mL), with ice bath cooling, and to wherein adding LiAlD with 4-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) piperidines-2-ketone
4(272mg, 6.47mmol).Reaction solution stirs at 70 ° of C and spends the night.Reaction is finished, and with the ice bath cooling, slowly adds saturated ammonium chloride solution (50mL) cancellation again.Mixture is extracted with ethyl acetate (50mL * 2), and the organic phase of merging is through anhydrous sodium sulfate drying, and concentrating under reduced pressure, obtains thick product, and this product is used immediately.
MS(ESI,pos.ion)m/z:188[M+H]
+。
2,2-, two deuterium generation-4-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) piperidines is dissolved in the methylene chloride (45mL/9mL), is cooled to 0 ° of C, to wherein adding HCl (26mL, the ethyl acetate solution of 3M).After the reaction solution stirred overnight at room temperature, concentrating under reduced pressure.
(16.80g 158.5mmol) is dissolved in the mixed solution of tetrahydrofuran (THF)/water (76mL/60mL), to wherein adding Boc acid anhydrides (5mL) with gained residue and yellow soda ash.The reaction solution stirred overnight at room temperature.Reaction is finished, and is dispersed in ethyl acetate (50mL) and the water (50mL), and the water of separation extracts with ethyl acetate (50mL * 2).The organic phase that merges is through anhydrous sodium sulfate drying, and behind the concentrating under reduced pressure, with silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purifying, obtaining title compound is white solid (0.52g, 17%).
LC-MS(ESI,pos.ion)m/z:149[M+H-56]
+；
1H?NMR(400MHz,CDCl
3)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) 1-(tertbutyloxycarbonyl)-2,2-two deuterium generation-4-(4-iodo-1H-pyrazol-1-yl) piperidines
With 1-(tertbutyloxycarbonyl)-2,2-two deuteriums are for piperidines-4-alcohol (490mg, 2.41mmol) and DMAP (29.4mg, 0.241mmol) be dissolved in the methylene dichloride (15mL), be cooled to 0 ℃, to wherein add triethylamine (0.67mL, 4.82mmol) after, continuation dropping methylsulfonyl chloride (0.223mL, 2.897mmol).Reaction solution stirring at room 5 hours.Reaction is finished, and adds 1M sodium hydrogen carbonate solution (25mL) cancellation, and extracts with methylene dichloride (50mL * 2).The organic phase that merges is washed through salt solution (25mL), and anhydrous sodium sulfate drying, and concentrating under reduced pressure obtain residue, and this residue is used immediately.
(467.5mg 2.41mmol) is dissolved in dry N, in the dinethylformamide (8mL), is cooled to 0 ℃, to wherein add sodium hydride (60% is dispersed in the mineral oil for 193mg, 4.82mmol) in batches with 4-iodo-1H-pyrazoles.After the mixture stirring at room 2 hours, continue in system, to add the N of above-mentioned residue, dinethylformamide (4mL) solution.Reaction solution stirred 12 hours at 100 ℃.Reaction is finished, and is cooled to room temperature, adds saturated ammonium chloride solution (50mL) cancellation, and extracts with ethyl acetate (50mL * 2).The organic phase that merges is washed anhydrous sodium sulfate drying, and concentrating under reduced pressure with salt solution (25mL).Residue is through silica gel column chromatography (PE/EtOAc (v/v)=4/1) purifying, and obtaining title compound is yellow solid (620mg, 68%).
LC-MS(ESI,pos.ion)m/z:324[M+H-56]
+；
1H?NMR(400MHz,CDCl
3)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) 1-(tertbutyloxycarbonyl)-2,2-two deuterium generation-4-(4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-1H-pyrazol-1-yl) piperidines
Title compound prepares by the described method of embodiment 11 steps 8, be about to 1-(tertbutyloxycarbonyl)-2,2-two deuterium generation-4-(4-iodo-1H-pyrazol-1-yl) piperidines (300mg, 0.792mmol), connection boric acid is sodium alcohol ester (281.6mg frequently, 1.11mmol), Potassium ethanoate (310.5mg, 3.17mol) and Pd (PPh
3)
2Cl
2(33.36mg 0.0475mmol) is suspended in preparation in the methyl-sulphoxide (6mL), and thick product is through silica gel column chromatography (PE/EtOAc (v/v)=2/1) purifying, and obtaining title compound is white solid (250mg, 83%).
LC-MS(ESI,pos.ion)m/z:380[M+H]
+。
Step 6) 5-(1-(1-(tertbutyloxycarbonyl)-2,2-two deuteriums are for piperidin-4-yl)-1H-pyrazoles-4-yl)-3-((R)-1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine
With (R)-5-bromo-3-(1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine (300.8mg, 0.792mmol); 1-(tertbutyloxycarbonyl)-2, (4-(4,4 for 2-two deuterium generation-4-; 5; 5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-the 1H-pyrazol-1-yl) piperidines (250mg; 0.66mmol) and yellow soda ash (245mg; 2.31mmol) be suspended in the mixed solution of glycol dimethyl ether/water (6mL/1mL), under the nitrogen protection, to wherein adding Pd (PPh
3)
2Cl
2(37mg, 0.053mmol).Reaction solution stirred 14 hours at 90 ° of C.Reaction is finished, and is cooled to room temperature, adds ethyl acetate (150mL) dilution, and uses diatomite filtration, and filter cake is washed with ethyl acetate (50mL).The filtrate that merges is washed through salt solution (50mL * 2), and behind the concentrating under reduced pressure, with silica gel column chromatography (PE/EtOAc (v/v)=1/1) purifying, obtaining title compound is yellow solid (180mg, 50%).
LC-MS(ESI,pos.ion)m/z:552[M+H]
+。
Step 7) 5-(1-(2,2-, two deuterium generation-4-yls)-1H-pyrazoles-4-yl)-3-((R)-1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine
Target compound prepares by the described method of embodiment 1 step 10, be about to 5-(1-(1-(tertbutyloxycarbonyl)-2,2-two deuteriums are for piperidin-4-yl)-1H-pyrazoles-4-yl)-3-((R)-1-(2,6-two chloro-3-fluorophenyls) pyridine-2-amine (440mg oxyethyl group), 0.80mmol) and HCl (5mL, the ethyl acetate solution of 3M) be dissolved in preparation in the methylene dichloride (20mL), thick product is through silica gel column chromatography (DCM/MeOH/Et
3N (v/v/v)=100/20/1) purifying, obtaining title compound is white solid (180mg, 50%).
LC-MS(ESI)m/z:226.6(M+2/2)；
1H?NMR(400MHz,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group)-5-(1-((3S, 4R)-3-fluorine piperidin-4-yl)-1H-pyrazoles-4-yl) pyridine-2-amine (17a)
3-((R)-1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group)-5-(1-((3R, 4S)-3-fluorine piperidin-4-yl)-1H-pyrazoles-4-yl) pyridine-2-amine (17b)
Step 1)
1-(tertbutyloxycarbonyl)-4-(4-iodo-1H-pyrazol-1-yl) piperidines-3-alcohol (17.1a)
1-(tertbutyloxycarbonyl)-3-(4-iodo-1H-pyrazol-1-yl) piperidines-4-alcohol (17.1b)
With 4-iodo-1H-pyrazoles (3g 16mmol) is dissolved in the tetrahydrofuran (THF) (20mL), is cooled to-78 ° of C, in 30 minutes to wherein dripping LDA (10mL, 2M in THF).Mixture stirred after 3 hours, in 20 minutes to wherein dripping 3-(tertbutyloxycarbonyl)-7-oxa--3-azabicyclo [4.1.0] heptane (3g, tetrahydrofuran (THF) 14mmol) (20mL) solution.Reaction solution stirring at room 1 hour is heated to 70 ° of C then, continues to stir 12 hours.Reaction is finished, and is cooled to room temperature, adds water (4mL) cancellation, behind the concentrating under reduced pressure, (PE/EtOAc (v/v)=4:1) purifying, obtaining (17.1a) (2.5g, 41%) and 1-(tertbutyloxycarbonyl)-3-(4-iodo-1H-pyrazol-1-yl) piperidines-4-alcohol (17.1b) is white solid through silica gel column chromatography.
(17.1a):
LC-MS(ESI,pos.ion)m/z:394[M+H]
+；
1H?NMR(400MHz,CDCl
3)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,CDCl
3)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-yl) oxygen base) piperidines
With 1-(tertbutyloxycarbonyl)-4-(4-iodo-1H-pyrazol-1-yl) piperidines-3-alcohol (0.5g, 1.27mmol) and PPTS (0.032g 0.127mmol) is dissolved in the methylene dichloride (20mL), to wherein adding DHP (0.5mL).After the reaction solution stirring at room 3 hours, concentrating under reduced pressure.Gained residue silica gel column chromatography (PE/EtOAc (v/v)=4/1) purifying, obtaining title compound is 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-yl) oxygen base)-4-(4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-1H-pyrazol-1-yl) piperidines
Under the nitrogen protection, with 1-(tertbutyloxycarbonyl)-4-(4-iodo-1H-pyrazol-1-yl)-3-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) piperidines (0.5g, 1mmol), connection boric acid frequently the sodium alcohol ester (0.8g, 3mmol), potassium acetate (0.2g, 2mmol) and Pd (dppf) Cl
2CH
2Cl
2(0.08g, methyl-sulphoxide 0.1mmol) (15mL) suspension stirred 4 hours at 50 ° of C.Reaction is finished, and is cooled to room temperature, adds water (40mL) dilution, and extracts with ethyl acetate (30mL * 3).The organic phase that merges is washed anhydrous sodium sulfate drying, and concentrating under reduced pressure with salt solution (80mL x2).Residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=3/1) purifying, and obtaining title chemical combination 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-yl) oxygen base) piperidin-4-yl)-1H-pyrazoles-4-yl)-3-((R)-1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine
((tetrahydrochysene-2H-pyrans-2-yl) oxygen base)-(4-(4 for 4-with 1-(tertbutyloxycarbonyl)-3-, 4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-and the 1H-pyrazol-1-yl) piperidines (0.45g, 0.94mmol), (R)-5-bromo-3-(1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine (0.4g, 1mmol), Pd (OAc)
2(22mg, 0.1mmol) and yellow soda ash (0.22g 2mmol) is suspended in the mixed solution of glycol dimethyl ether/water (20mL/1mL), under the nitrogen protection, to wherein adding (t-Bu)
3P (0.25mL, the toluene solution of 1M).Reaction solution after 100 ° of C stir 36 hours, concentrating under reduced pressure.The gained residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=1/2) purifying, and obtaining title compound is light brown solid (0.38g, 61%).
LC-MS(ESI,pos.ion)m/z:650[M+H]
+；
1H?NMR(400MHz,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group) pyridin-3-yl)-1H-pyrazol-1-yl)-1-(tertbutyloxycarbonyl) piperidines-3-alcohol (17.5a)
(3S, 4S)-4-(4-(6-amino-5-((R)-1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridin-3-yl)-1H-pyrazol-1-yl)-1-(tertbutyloxycarbonyl) piperidines-3-alcohol (17.5b)
With 5-(1-(1-(tertbutyloxycarbonyl)-3-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) piperidin-4-yl)-1H-pyrazoles-4-yl)-3-((R)-1-(2,6-two chloro-3-fluorophenyls) pyridine-2-amine (1g oxyethyl group), 1.54mmol) and PPTS (0.12g, methyl alcohol 0.46mmol) (30mL) solution stirred 30 hours at 75 ° of C.Reaction is finished, and concentrating under reduced pressure adds water (40mL) dilution, and extracts with methylene dichloride (30mL * 3).The organic phase water (90mL) that merges is washed anhydrous sodium sulfate drying, and concentrating under reduced pressure.The gained residue is through silica gel column chromatography (DCM/MeOH (v/v)=40/1) purifying, and obtaining (17.5a) and mixture (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 piperidin-4-yl)-1H-pyrazoles-4-yl)-3-((R)-1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine (17.6a)
5-(1-((3R, 4S)-1-(tertbutyloxycarbonyl)-3-fluorine piperidin-4-yl)-1H-pyrazoles-4-yl)-3-((R)-1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine (17.6b)
(0.6g 1mmol) is dissolved in the methylene dichloride (15mL), is cooled to-78 ° of C, to wherein dripping DAST (0.34g, methylene dichloride 2mmol) (5mL) solution with (17.5a) and mixture (17.5b).Reaction solution is stirred in-78 ° of C and stirs after 30 minutes, is warming up to-40 ° of C, continues to stir 4 hours.Reaction is finished, and adds 1M sodium hydrogen carbonate solution (30mL) cancellation, and extracts with methylene dichloride (30mL * 3).Water (90mL), salt solution (90mL) are washed anhydrous sodium sulfate drying, and concentrating under reduced pressure to the organic phase that merges successively.The gained residue is through silica gel column chromatography (methylene chloride (v/v)=40/1) purifying, and obtaining (17.6a) and mixture (17.6b) is brown solid (0.28g, 47%).
LC-MS(ESI,pos.ion)m/z:568[M+H]
+。
Step 7)
3-((R)-1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group)-5-(1-((3S, 4R)-3-fluorine piperidin-4-yl)-1H-pyrazoles-4-yl) pyridine-2-amine (17a)
3-((R)-1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group)-5-(1-((3R, 4S)-3-fluorine piperidin-4-yl)-1H-pyrazoles-4-yl) pyridine-2-amine (17b)
With HCl (10mL, the ethyl acetate solution of 1M) be added drop-wise to (17.6a) and mixture (17.6b) (0.28g, 0.49mmol) in.Reaction solution stirring at room 2 hours.Reaction is finished, concentrating under reduced pressure.After residue is handled with 2M sodium carbonate solution (20mL), with methylene dichloride (20mL x3) extraction.The organic phase that merges is washed anhydrous sodium sulfate drying, and concentrating under reduced pressure with salt solution (60mL).Residue is through silica gel column chromatography (DCM/MeOH/NH
4OH (v/v/v)=50/1/1) purifying, obtaining (17a) and mixture (17b) is light yellow solid (0.15g, 75%).
LC-MS(ESI,pos.ion)m/z:234.7(M+2)/2；
1H?NMR(400MHz,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group) pyridin-3-yl)-1H-pyrazol-1-yl) piperidines-3-alcohol (18a)
(3S, 4S)-4-(4-(6-amido-5-((R)-1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridin-3-yl)-1H-pyrazol-1-yl) piperidines-3-alcohol (18b)
With HCl (5mL, the ethyl acetate solution of 1M) is added drop-wise to 5-(1-(1-(tertbutyloxycarbonyl)-3-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) piperidin-4-yl)-1H-pyrazoles-4-yl)-3-((R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine (0.25g, 0.38mmol) in.Reaction solution stirring at room 2 hours.Reaction is finished, and adds water (20mL) dilution, and washes with ethyl acetate (20mL * 2).After mixed solution usefulness 2M sodium carbonate solution (10mL) processing, add ethyl acetate (20mL * 3) extraction.The organic phase that merges is washed through salt solution (60mL), anhydrous sodium sulfate drying, 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,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group) pyridin-3-yl)-1H-pyrazol-1-yl) piperidines-4-alcohol (19a)
(3S, 4S)-3-(4-(6-amino-5-((R)-1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) 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-yl) oxygen base) piperidines
The method that title compound is described by embodiment 17 steps 2 prepares, be about to 1-(tertbutyloxycarbonyl)-3-(4-iodo-1H-pyrazol-1-yl) piperidines-4-alcohol (1g, 2.6mmol), PPTS (0.064g, 0.26mmol) and DHP (1mL) is suspended in, and methylene dichloride (30mL) is middle to be prepared, thick product is through silica gel column chromatography (PE/EtOAc (v/v)=6/1) purifying, and obtaining title compound 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-yl) oxygen base)-3-(4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-1H-pyrazol-1-yl) piperidines
Title compound prepares by the described method of embodiment 17 steps 3, be about to 1-(tertbutyloxycarbonyl)-3-(4-iodo-1H-pyrazol-1-yl)-4-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) piperidines (0.6g, 1.25mmol), connection boric acid is sodium alcohol ester (0.9g frequently, 3.8mmol), potassium acetate (0.25g, 2.5mmol) and Pd (dppf) Cl
2CH
2Cl
2(0.1g 0.125mmol) is suspended in preparation in the methyl-sulphoxide (20mL).Thick product is through silica gel column chromatography (PE/EtOAc (v/v)=2/1) purifying, and obtaining 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-yl) oxygen base) piperidines-3-yl)-1H-pyrazoles-4-yl)-3-((R)-1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine
Title compound prepares by the described method of embodiment 17 steps 4, be about to (R)-5-bromo-3-(1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine (0.6g, 1.58mmol), ((tetrahydrochysene-2H-pyrans-2-yl) oxygen base)-(4-(4 for 3-for 1-(tertbutyloxycarbonyl)-4-, 4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-the 1H-pyrazol-1-yl) piperidines (0.58g, 1.2mmol), Pd (OAc)
2(34mg, 0.15mmol), yellow soda ash (0.26g, 2.5mmol) and (t-Bu)
3P (0.38mL, the toluene solution of 1M) is suspended in the suspension of glycol dimethyl ether/water (30mL/1mL) and prepares.Thick product is through silica gel column chromatography (PE/EtOAc (v/v)=1/1) purifying, and obtaining title compound is light brown solid (0.5g, 60%).
LC-MS(ESI,pos.ion)m/z:650[M+H]
+；
1H?NMR(400MHz,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group) pyridin-3-yl)-1H-pyrazol-1-yl) piperidines-4-alcohol (19a)
(3S, 4S)-3-(4-(6-amino-5-((R)-1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridin-3-yl)-1H-pyrazol-1-yl) piperidines-4-alcohol (19b)
Title compound prepares by embodiment 18 described methods, namely use HCl (5mL, the ethyl acetate solution of 1M) and 5-(1-(1-(tertbutyloxycarbonyl)-4-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) piperidines-3-yl)-1H-pyrazoles-4-yl)-3-((R)-1-(2,6-two chloro-3-fluorophenyls) pyridine-2-amine (0.25g oxyethyl group), 0.38mmol) prepare, the gained target product is white solid (0.09g, 50%).
LC-MS(ESI,pos.ion)m/z:233.7(M+2)/2；
1H?NMR(400MHz,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group)-5-(1-((hexahydro furyl is [2,3-b] furans-3-yl also) methyl)-1H-pyrazoles-4-yl) pyridine-2-amine
Step 1) (2R, 3S)-2-(allyloxy)-3-iodine tetrahydrofuran (THF)
With NIS (15.1g 66.6mmol) is suspended in the methylene dichloride (150mL), is cooled to 0 ° of C, in 30 minutes, to wherein add dihydrofuran (5.1mL, 66.6mmol) and vinyl carbinol (6.8mL, methylene dichloride 100mmol) (50mL) solution.Reaction solution stirred 3 hours under 0 ° of C.Reaction is finished, and returns to room temperature, and adds water (200mL) dilution.The gained mixture is after room temperature continues to stir 1 hour, with methylene dichloride (200mL) extraction.Organic phase is washed with salt solution (400mL), and anhydrous sodium sulfate drying, and concentrating under reduced pressure, gained residue are through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=9/1) purifying, and obtaining title compound is yellow oil (15.53g, 91.8%).
1H?NMR(400MHz,CDCl
3)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 [2,3-b] furans also
Will (2R, 3S)-(2g 7.87mmol) is suspended in the water (100mL) 2-(allyloxy)-3-iodine tetrahydrofuran (THF), under the nitrogen protection, to wherein adding triethyl-boron (0.7mL, the tetrahydrofuran solution of 1M).Reaction solution stirring at room 3 hours.Reaction is finished, with ethyl acetate (100mL * 3) extraction.The organic phase that merges is washed with salt solution (300mL), anhydrous sodium sulfate drying, and concentrating under reduced pressure, and obtaining title compound is yellow oil (1.6g, 80%), this product is not purified, is directly used in next step reaction.
MS(ESI,pos.ion)m/z254[M+H]
+；
1H?NMR(400MHz,CDCl
3)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 is [2,3-b] furans-3-yl also) methyl)-4-iodo-1H-pyrazoles
With 4-iodo-1H-pyrazoles (2g, 9.48mmol) be dissolved in anhydrous N, in the dinethylformamide (30mL), be cooled to 0 ° of C, to wherein add sodium hydride (0.7g in batches, 23.7mmol, 80% is dispersed in the mineral oil) after, continue to add also [2,3-b] furans (1.6g of 3-(iodomethyl) hexahydro furyl, 7.9mmol) N, dinethylformamide (10mL) solution.Reaction solution stirred 10 hours at 80 ° of C, and reaction is finished, and is cooled to room temperature, adds water (80mL) cancellation, and extracts with ethyl acetate (100mL * 3).The organic phase that merges is washed with salt solution (300mL), and anhydrous sodium sulfate drying, and concentrating under reduced pressure, gained residue are through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=3/1) purifying, and obtaining title compound is yellow oil (1.5g, 60%).
LC-MS(ESI,pos.ion)m/z:321[M+H]
+；
1H?NMR(400MHz,CDCl
3)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 is [2,3-b] furans-3-yl also) methyl)-4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-1H-pyrazoles
With 1-((hexahydro furyl also [2; 3-b] furans-3-yl) 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) be dissolved in the methyl-sulphoxide (25mL), under the nitrogen protection, to wherein adding Pd (dppf) Cl
2CH
2Cl
2(153mg, 0.19mmol).Reaction solution stirred 3 hours at 80 ° of C, and reaction is finished, and is cooled to room temperature, added water (60mL) dilution, and extracted with ethyl acetate (50mL * 3).The organic phase that merges is washed with salt solution (120mL), and anhydrous sodium sulfate drying, and concentrating under reduced pressure, gained residue are through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purifying, and obtaining title compound is yellow oil (0.6g, 50%).
1H?NMR(400MHz,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group)-5-(1-((hexahydro furyl is [2,3-b] furans-3-yl also) methyl)-1H-pyrazoles-4-yl) pyridine-2-amine
With (R)-5-bromo-3-(1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine (0.8g, 1.8mmol); 1-((hexahydro furyl is [2,3-b] furans-3-yl also) methyl)-4-(4,4; 5; 5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-1H-pyrazoles (0.8g; 2mmol) and yellow soda ash (0.4g; 3.6mmol) be dissolved in the mixed solution of glycol dimethyl ether/water (20mL/0.2mL), under the nitrogen protection, to wherein adding Pd (OAc) successively
2(40mg, 0.18mmol) and (t-Bu)
3P (0.6mL, the toluene solution of 1M).Reaction solution stirred 16 hours at 100 ° of C.Reaction is finished, and is cooled to room temperature, and concentrating under reduced pressure.The gained residue is through silica gel column chromatography (petrol ether/ethyl acetate/methyl alcohol (v/v/v)=10/10/1) purifying, and obtaining title compound is white solid (0.3g, 25%).
LC-MS(ESI,
pos.ion)m/z:493[M+H]
+；
1H?NMR(400MHz,CDCl
3)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)-and 6-(4-(6-amino-5-((R)-1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridin-3-yl) methyl)-1H-pyrazol-1-yl) hexahydro furyl [3,2-b] furan-3-ol also
Step 1)
(3R, 3aR, 6S, 6aS)-6-hydroxyl hexahydro furyl [3,2-b] furans-3-p-toluenesulfonic esters (21.1a) also
(3S, 3aR, 6R, 6aS)-6-hydroxyl hexahydro furyl [3,2-b] furans-3-p-toluenesulfonic esters (21.1b) also
(3R, 3aR, 6S, 6aR)-and hexahydro furyl [3,2-b] furans-3 also, 6-two (p-toluenesulfonic esters) is (21.1c)
(5g 34.2mmol) is dissolved in the water (20mL), is cooled to 0 ° of C, to wherein adding Tosyl chloride (7.34g, (25mL) solution of toluene 38.5mmol) and potassium hydroxide (2.5g, water 44.6mmol) (9mL) solution successively with Isosorbide.Reaction solution returns to room temperature after 5 ° of C stir 4 hours, continue to stir and spend the night.Reaction is finished, and mixture adds water (100mL) cancellation, and extracts with ethyl acetate (100mL * 3).The organic phase that merges is washed with salt solution (120mL), anhydrous sodium sulfate drying, and concentrating under reduced pressure, the gained residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purifying, 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-yl) oxygen base) hexahydro furyl [3,2-b] furans-3-p-toluenesulfonic esters also
DHP is dissolved in the methylene dichloride (20mL), and cryosel is bathed cooling, and (0.2g 0.9mmol), under the nitrogen protection, continues to add (21.1a) and (21.1b) (2.7g, methylene dichloride 9mmol) (20mL) solution in system to wherein adding PPTS.Reaction solution returns to room temperature after 0 ° of C stirs 30 minutes, continue to stir and spend the night.Reaction is finished, and with the mixture concentrating under reduced pressure, residue adds water (50mL) dilution, and extracts with ethyl acetate (50mL * 3).The organic phase that merges is washed with salt solution (150mL), and anhydrous sodium sulfate drying, and concentrating under reduced pressure, gained residue are through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=3/1) purifying, and obtaining title compound is colorless oil (3.1g, 88.5%).
LC-MS(ESI,pos.ion)m/z:407[M+H]
+；
1H?NMR(400MHz,CDCl
3)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) 4-iodo-1-((3aS, 6S, 6aR)-6-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) hexahydro furyl [3,2-b] furans-3-yl also)-the 1H-pyrazoles
(0.89g 4.5mmol) is dissolved in anhydrous N, in the dinethylformamide (15mL), is cooled to 0 ° of C, to wherein add sodium hydride (80% is dispersed in the mineral oil for 0.3g, 9mmol) in batches with 4-iodo-1H-pyrazoles.Mixture adds (3R, 3aR in system after 0 ° of C stirs 1 hour, 6S, 6aS)-6-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) hexahydro furyl [3,2-b] furans-3-p-toluenesulfonic esters (1.6g also, 5.2mmol) N, dinethylformamide (10mL) solution.Reaction solution stirred 30 minutes at 0 ° of C, was heated to 80 ° of C then, continued to stir 10 hours.Reaction is finished, and adds water (70mL) cancellation, and extracts with ethyl acetate (70mL * 3).The organic phase that merges is washed with salt solution (180mL), and anhydrous sodium sulfate drying, and concentrating under reduced pressure, gained residue are through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purifying, and 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-yl) oxygen base) hexahydro furyl [3,2-b] furans-3-yl also)-4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-1H-pyrazoles
With 4-iodo-1-((3aS; 6S; 6aR)-6-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) hexahydro furyl also [3; 2-b] furans-3-yl)-the 1H-pyrazoles (0.9g, 2.2mmol), connection boric acid pinacol ester (1.5g; 6.6mmol) and Potassium ethanoate (646mg; 6.6mmol) be dissolved in the methyl-sulphoxide (20mL), under the nitrogen protection, to wherein adding Pd (dppf) Cl
2(179mg, 0.22mmol).Reaction solution stirred 2 hours at 60 ° of C.Reaction is finished, and is cooled to room temperature, adds water (50mL) dilution, and extracts with ethyl acetate (40mL * 3).The organic phase that merges is washed with salt solution (100mL), and anhydrous sodium sulfate drying, and concentrating under reduced pressure, gained residue are through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=1/1) purifying, and obtaining title compound is yellow solid (0.6g, 67%).
LC-MS(ESI,pos.ion)m/z:407[M+H]
+；
1H?NMR(400MHz,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group)-5-(1-((3aS, 6S, 6aR)-6-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) hexahydro furyl [3,2-b] furans-3-yl also)-1H-pyrazoles-4-yl) pyridine-2-amine
With 1-((3aS; 6S; 6aR)-6-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) hexahydro furyl also [3; 2-b] furans-3-yl)-4-(4; 4; 5,5-tetramethyl--1,3; 2-dioxane pentaborane-2-yl)-1H-pyrazoles (857mg; 2.3mmol), (R)-5-bromo-3-(1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine (0.77g; 1.89mmol) and yellow soda ash (0.4g; 3.78mmol) be dissolved in the mixed solution of glycol dimethyl ether/water (25mL/2mL), under the nitrogen protection, add Pd (OAc) successively
2(43mg, 0.19mmol) and (t-Bu)
3P (0.57mL, the toluene solution of 2N).Mixture stirred 18 hours at 87 ° of C.Reaction is finished, and is cooled to room temperature, and concentrating under reduced pressure.The gained residue is through silica gel column chromatography (petrol ether/ethyl acetate/methyl alcohol (v/v/v)=10/10/1) purifying, and obtaining title compound is yellow solid (0.7g, 54%).
LC-MS(ESI,pos.ion)m/z:579[M+H]
+；
1H?NMR(400MHz,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group) pyridin-3-yl)-1H-pyrazol-1-yl) hexahydro furyl [3,2-b] furan-3-ol also
With 3-((R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group)-5-(1-((3aS, 6S, 6aR)-6-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) hexahydro furyl also [3,2-b] furans-3-yl)-1H-pyrazoles-4-yl) pyridine-2-amine (0.5g, 0.86mmol) be dissolved in the methyl alcohol (25mL), to wherein adding 2M hydrochloric acid (2mL).Reaction solution stirred 1 hour at 45 ° of C, and reaction is finished, concentrating under reduced pressure.With residue methylene dichloride (30mL), water (30mL) and 2M sodium carbonate solution (5mL) dilution, the gained mixture extracts with methylene dichloride (30mL * 2).The organic phase that merges is washed with salt solution (100mL), and anhydrous sodium sulfate drying, and concentrating under reduced pressure, residue are through silica gel column chromatography (petrol ether/ethyl acetate/methyl alcohol (v/v/v)=10/10/1) purifying, and obtaining title compound is yellow solid (0.3g, 70%).
LC-MS(ESI,pos.ion)m/z:495[M+H]
+；
1H?NMR(400MHz,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group)-5-(1-((3aS, 6R, 6aR)-6-fluorine hexahydro furyl [3,2-b] furans-3-yl also)-1H-pyrazoles-4-yl) pyridine-2-amine
With (3S, 3aS, 6aS)-6-(4-(6-amino-5-((R)-1-(2,6-two chloro-3-fluorophenyls) pyridin-3-yl oxyethyl group))-and the 1H-pyrazol-1-yl) hexahydro furyl also [3,2-b] (0.14g 0.28mmol) is dissolved in the methylene dichloride (4mL) furan-3-ol, is cooled to-78 ° of C, in system, drip DAST (70mg, methylene dichloride 0.43mmol) (1mL) solution.Reaction solution returns to room temperature after-78 ° of C stir 1 hour, and stirs and spend the night.Reaction is finished, concentrating under reduced pressure, and the gained residue is through silica gel column chromatography (petrol ether/ethyl acetate/methyl alcohol (v/v/v)=20/20/1) purifying, and obtaining title compound is yellow solid (40m
g, 28.5%).
LC-MS(ESI,pos.ion)m/z:497[M+H]
+；
1H?NMR(400MHz,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group)-5-(1-(the octahydro pentamethylene is [c] pyrroles 5-yl also)-1H-pyrazoles-4-yl) pyridine-2-amine
Step 1) 2-(tertbutyloxycarbonyl)-2,3,3a, 4,7,7a-, six hydrogen-1H-isoindole
With lithium aluminium hydride (3.04g 80mmol) is dissolved in the tetrahydrofuran (THF) (80mL), to wherein adding 3a in batches, 4,7,7a-tetrahydrochysene-1H-isoindole-1,3 (2H)-diketone (5.26g, 34.8mmol).Reaction solution stirred 21 hours at 60 ° of C.Reaction is finished, and is cooled to room temperature, after adding ethyl acetate (25mL) dilution, and water (3mL) and 15% potassium hydroxide solution (3mL) cancellation successively.The gained mixture continues at room temperature to stir 1 hour, uses diatomite filtration then, and filter cake is washed with methylene dichloride (40mL).Filtrate decompression is concentrated, obtain 2,3,3a, 4,7,7a-, six hydrogen-1H-isoindole is yellow oil.
With 2,3,3a, 4,7,7a-, six hydrogen-1H-isoindole (3.89g 31.3mmol) is dissolved in the methylene dichloride (40mL), is cooled to 0 ° of C, to wherein add the Boc acid anhydrides (10.3g, 47mmol).Reaction solution returns to room temperature after 0 ° of C stirs 0.5 hour, continue to stir 21 hours.Reaction is finished, and with the mixture concentrating under reduced pressure, residue dilutes with ethyl acetate (80mL).Gained solution uses 1M citric acid (17mL * 2), water (17mL * 2), saturated sodium bicarbonate solution (17mL * 2) and salt solution (17mL) to wash successively.Organic solution is through anhydrous sodium sulfate drying, and behind the concentrating under reduced pressure, with silica gel column chromatography (n-hexane/ethyl acetate (v/v)=85/15) purifying, obtaining title compound is orange red oily matter (4.7g, 54.5%).
MS(ESI,pos.ion)m/z168.2[(M+H)
+-C
4H
8]；
1H?NMR(400MHz,CDCl
3)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) tetramethyleneimine-3,4-two bases) oxalic acid
With 2-(tertbutyloxycarbonyl)-2,3,3a, (4.7g 21mmol) is dissolved in CCl to 4,7,7a-, six hydrogen-1H-isoindole
4(50mL), in the mixed solution of MeCN (50mL) and water (75mL), and to wherein adding NaIO successively
4(18g, 84.2mmol) and RuO
2(0.16g, 1.2mmol).Reaction solution after 24 hours, with DCM (60mL) dilution, and is used diatomite filtration in stirring at room, and water extracts with DCM (50mL).The organic phase that merges is washed Na with salt solution (60mL)
2SO
4Drying, and concentrating under reduced pressure, residue are through silica gel column chromatography (100%DCM) purifying, and obtaining title compound is yellow oil (3g, 49.6%).
MS(ESI,pos.ion)m/z232.2[(M+H)
+-C
4H
8]；
1H?NMR(400MHz,CDCl
3)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) six hydrogen pentamethylene are [c] pyrroles-5 (1H)-ketone also
With 2,2'-(1-(tertbutyloxycarbonyl) tetramethyleneimine-3,4-two bases) oxalic acid (3g 10.4mmol) is dissolved in the diacetyl oxide (30mL), to wherein add sodium acetate (0.79g, 9.6mmol).Reaction solution after 120 ° of C stir 3 hours, cool to room temperature, and filtering.Filter cake is washed with ethyl acetate (20mLx2), and filtrate decompression concentrates.The gained residue is through silica gel column chromatography (n-hexane/ethyl acetate (v/v)=1/1) purifying, and obtaining title compound is orange-yellow oily thing (0.55g, 23.4%).
1H?NMR(400MHz,CDCl
3)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 is [c] pyrroles-5-alcohol also
With 2-(tertbutyloxycarbonyl) octahydro pentamethylene also [c] pyrroles-5-alcohol (0.9g 4mmol) is dissolved in the ethanol (20mL), to wherein add in batches sodium borohydride (0.82g, 21.7mmol).Reaction solution stirring at room 4.5 hours.Reaction is finished, concentrating under reduced pressure.Residue is diluted with ethyl acetate (50mL), and water (50mL), salt solution (50mL) are washed successively.Gained solution is through anhydrous sodium sulfate drying, concentrating under reduced pressure, and obtaining title compound is yellow oil (0.99g, 100%).This compound does not need purifying, is directly used in next step.
Step 5) 2-(tertbutyloxycarbonyl) octahydro pentamethylene is [c] pyrroles-5-base methanesulfonates also
With 2-(tertbutyloxycarbonyl) octahydro pentamethylene [c] pyrroles-5-alcohol (0.91g also, 3.56mmol) be dissolved in the methylene dichloride (8mL), be cooled to 0 ° of C, to wherein adding triethylamine (0.8mL successively, 5.74mmol), methylsulfonyl chloride (0.35mL, 4.52mmol) and DMAP (5mg, methylene dichloride 0.04mmol) (2mL) suspension.Reaction solution stirring at room 16 hours, reaction is finished, and water (15mL), salt solution (15mL) are washed successively.Gained solution is through anhydrous sodium sulfate drying, and concentrating under reduced pressure, and obtaining title compound is yellow oil (1.3g, 100%).This product is not purified, is directly used in next step.
Step 6) 2-(tertbutyloxycarbonyl)-5-(4-iodo-1H-pyrazol-1-yl) octahydro pentamethylene is [c] pyrroles also
(1.16g 6mmol) is dissolved in anhydrous N, in the dinethylformamide (10mL), is cooled to 0 ° of C, to wherein add sodium hydride (80% is dispersed in the mineral oil for 538mg, 17.9mmol) in batches with 4-iodo-1H-pyrazoles.Mixture adds also [c] pyrroles-5-base methanesulfonates (1.22g, N 4mmol), dinethylformamide (5mL) solution of 2-(tertbutyloxycarbonyl) octahydro pentamethylene in system after 0 ° of C stirs 1 hour.Reaction solution stirred 21 hours at 100 ° of C.Reaction is finished, and is cooled to room temperature, adds ethyl acetate (30mL) dilution.Mixture water (20mL * 3), salt solution (20mL) is successively washed, anhydrous sodium sulfate drying, and concentrating under reduced pressure, the gained residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=5/1) purifying, obtain title compound light yellow solid (1.37g, 85.1%).
MS(ESI,pos.ion)m/z348.0[(M+H)
+-C
4H
8]；
1H?NMR(400MHz,CDCl
3)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-dioxane pentaborane-2-yl)-1H-pyrazol-1-yl) octahydro pentamethylene is [c] pyrroles also
With 2-(tertbutyloxycarbonyl)-5-(4-iodo-1H-pyrazol-1-yl) octahydro pentamethylene [c] pyrroles (0.48g also; 1.2mmol) and connection boric acid pinacol ester (0.36g; 1.44mmol) be dissolved in the methyl-sulphoxide (8mL); to wherein adding Potassium ethanoate (0.35g; 3.6mmol); after the nitrogen protection, continue in system, to add Pd (dppf) Cl
2(98mg, 0.12mmol).Reaction solution stirred 1 hour at 80 ° of C.Reaction is finished, and adds water (10mL) cancellation, and extracts with ethyl acetate (20mL * 3).The organic phase that merges is washed anhydrous sodium sulfate drying, and concentrating under reduced pressure with salt solution (30mL).The gained residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purifying, and obtaining title compound is yellow oil (256mg, 53.3%).
MS(ESI,pos.ion)m/z404.3[M+H]
+；
1H?NMR(400MHz,CDCl
3)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 is [c] pyrroles-5-yl also)-1H-pyrazoles-4-yl)-4-((R)-1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine
(4-(4,4,5 with 2-(tertbutyloxycarbonyl)-5-; 5-tetramethyl--1; 3,2-dioxane pentaborane-2-yl)-the 1H-pyrazol-1-yl) the octahydro pentamethylene also [c] pyrroles (256mg, 0.64mmol) and (R)-(1-(2 for 5-bromo-3-; 6-two chloro-3-fluorophenyls) pyridine-2-amine (326mg oxyethyl group); 0.95mmol) be dissolved in the glycol dimethyl ether (8mL), to wherein add the 1.2M sodium carbonate solution (2mL, 1.91mmol); after the nitrogen protection, continue in system, to add Pd (dppf) Cl
2(104mg, 0.13mmol).Reaction solution stirred 8 hours at 100 ° of C, and reaction is finished, and is cooled to room temperature, added water (20mL) dilution, and extracted with ethyl acetate (20mL * 3).The organic phase that merges is washed with salt solution (30mL), and anhydrous sodium sulfate drying, and concentrating under reduced pressure, residue are through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=1/2) purifying, and obtaining title compound is yellow solid (157mg, 42.9%).
LC-MS(ESI,pos.ion)m/z:576.2[M+H]
+；
1H?NMR(400MHz,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group)-5-(1-(the octahydro pentamethylene is [c] pyrroles 5-yl also)-1H-pyrazoles-4-yl) pyridine-2-amine
With 5-(1-(2-(tertbutyloxycarbonyl) octahydro pentamethylene is [c] pyrroles-5-yl also)-1H-pyrazoles-4-yl)-4-((R)-1-(2,6-two chloro-3-fluorophenyls) pyridine-2-amine (157mg oxyethyl group), 0.27mmol) be dissolved in the methylene dichloride (10mL), to wherein slowly adding HCl (4mL, the ethyl acetate solution of 3M).After the reaction solution stirring at room 2 hours, concentrating under reduced pressure.With residue water (30mL) and methylene dichloride (50mL) dilution, regulate pH10 with saturated sodium carbonate solution then, and extract with methylene dichloride (50mL * 3).The organic phase that merges is washed with salt solution (80mL), and anhydrous sodium sulfate drying, and concentrating under reduced pressure, residue are through silica gel column chromatography (methylene chloride/triethylamine (v/v/v)=500/50/1) purifying, and obtaining title compound is yellow solid (0.1g, 76.9%).
LC-MS(ESI,pos.ion)m/z:476.1[M+H]；
1H?NMR(400MHz,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group)-5-(1-(octahydro-1H-isoindole-5-yl)-1H-pyrazoles-4-yl) pyridine-2-amine
Step 1) 2-(tertbutyloxycarbonyl) octahydro-1H-isoindole-5-alcohol
With 2-(tertbutyloxycarbonyl)-2,3,3a, (3.16g 14.2mmol) is dissolved in the anhydrous tetrahydro furan (35mL) 4,7,7a-, six hydrogen-1H-isoindole, after the nitrogen protection, is cooled to 0 ℃, to wherein dripping BH
3-DMS (1.5mL, 15.0mmol, the tetrahydrofuran solution of 10M).The reaction solution stirred overnight at room temperature, reaction is finished, and is cooled to 0 ℃.Reaction solution is used methyl alcohol (8mL), 3M sodium hydroxide (5mL) and the cancellation of 30% hydrogen peroxide (5mL) mixed solution successively.Gained suspension after 1.5 hours, is down to room temperature 60 ℃ of stirrings, and add diethyl ether/water (30mL/30mL) dilutes, and extracts with ethyl acetate (30mL * 3).The organic phase that merges is washed with salt solution (30mL * 3), and anhydrous sodium sulfate drying, and concentrating under reduced pressure obtain orange (2.46g, 71.7%), and this product is not purified, is directly used in next step.
LC-MS(ESI,pos.ion)m/z:186.2[M+H-56]
+；
1H?NMR(400MHz,CDCl
3)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-isoindole-5-base methanesulfonates
Title compound prepares by the described method of embodiment 23 steps 5, be about to 2-(tertbutyloxycarbonyl) octahydro-1H-isoindole-5-alcohol (4.51g, 18.69mmol), triethylamine (4mL, 28.70mmol), methylsulfonyl chloride (2.2mL, 28.41mmol) and DMAP (34.3mg 0.28mmol) is suspended in preparation in the methylene dichloride (50mL), obtaining thick product is brown oil (5.30g, 88.8%), this product is not 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-isoindole
Title compound prepares by the described method of embodiment 23 steps 6, be about to 2-(tertbutyloxycarbonyl) octahydro-1H-isoindole-5-base methanesulfonates (5.30g, 16.6mmol), 4-iodo-1H-pyrazoles (4.83g, 24.9mmol) and sodium hydride (2.26g, 56.4mmol, 60% is dispersed in the mineral oil) be suspended in anhydrous N, preparation in the dinethylformamide (60mL), thick product is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=6/1) purifying, 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,CDCl
3)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-dioxane pentaborane-2-yl)-1H-pyrazol-1-yl) octahydro-1H-isoindole
Title compound prepares by the described method of embodiment 23 steps 7, be about to 2-(tertbutyloxycarbonyl)-5-(4-iodo-1H-pyrazol-1-yl) octahydro-1H-isoindole (2.67g, 6.40mmol), connection boric acid pinacol ester (1.95g, 7.68mmol), potassium acetate (1.88g, 19.20mmol) and Pd (dppf) Cl
2(523mg 0.64mmol) is suspended in preparation in the methyl-sulphoxide (50mL), and thick product is through silica gel column chromatography (PE/EtOAc (v/v)=4/1) purifying, and obtaining title compound is orange (1.34g, 50.2%).
LC-MS(ESI,pos.ion)m/z:418.1[M+H]
+；
1H?NMR(400MHz,CDCl
3)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-isoindole-5-yl)-1H-pyrazoles-4-yl)-3-((R)-1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine
Title compound prepares by the described method of embodiment 23 steps 8, be about to (R)-5-bromo-3-(1-(2,6-, two chloro-3-fluorophenyls) oxyethyl group) pyridine-2-amine (1.83g, 4.82mmol), (4-(4 for 2-(tertbutyloxycarbonyl)-5-, 4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-the 1H-pyrazol-1-yl) octahydro-1H-isoindole (1.34g, 3.21mmol), Pd (dppf) Cl
2(524mg, 0.642mmol) and the 1.2M sodium carbonate solution (8mL 9.63mmol) is suspended in preparation in the glycol dimethyl ether (40mL), and thick product is through silica gel column chromatography (PE/EtOAc (v/v)=1/2) purifying, obtaining title compound is orange solids (230mg, 12.1%).
LC-MS(ESI,pos.ion)m/z:590.0[M+H]
+;
1H?NMR(400MHz,CDCl
3)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-, two chloro-3-fluorophenyls) oxyethyl group)-5-(1-(octahydro-1H-isoindole-5-yl)-1H-pyrazoles-4-yl) pyridine-2-amine
Title compound prepares by the described method of embodiment 23 steps 9, be about to 5-(1-(2-(tertbutyloxycarbonyl) octahydro-1H-isoindole-5-yl)-1H-pyrazoles-4-yl)-3-((R)-1-(2,6-two chloro-3-fluorophenyls) pyridine-2-amine (0.23g oxyethyl group), 0.39mmol) and HCl (4mL, the ethyl acetate solution of 3M) is dissolved in, and methylene dichloride (10mL) is middle to be prepared.Thick product is through silica gel column chromatography (methylene chloride/triethylamine (v/v/v)=250/50/1) purifying, and obtaining title compound is yellow solid (100mg, 52.4%).
LC-MS(ESI,pos.ion)m/z:489.9[M+H]
+；
1H?NMR(400MHz,CDCl
3)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)。
Biological test
Adopt method and apparatus mentioned above that the compound of embodiment of the invention preparation is carried out bioanalysis.
The stability of embodiment A in people and rat liver microsomes
Place the polypropylene test tube to hatch people or rat liver microsomes, and guide it to copy.Typically hatch mixed solution and comprise people or rat liver microsomes (0.5mg protein/mL), target compound (5 μ M) and cumulative volume are NADPH (1.0mM) potassium phosphate buffer (PBS of 200 μ L, 100mM, the pH value is 7.4), with compound dissolution in DMSO, and use PBS that it is diluted, the concentration that makes its final DMSO solution is 0.05%.And under 37 ° of C with in the water-bath that air communicates, hatch, preincubate added albumen and begins reaction in mixed solution after 3 minutes.In different time points (0,5,10,15,30 and 60min), add the cold acetonitrile termination reaction of consubstantiality accumulated ice.Sample is preserved under-80 ° of C up to carrying out LC/MS/MS and is analyzed.
The concentration of compound in people or rat liver microsomes mixtures incubated is to measure by the method for LC/MS/MS.The linearity range of concentration range is determined by each test-compound.
Parallel microsome of hatching test use sex change is hatched under 37 ° of C as negative control, is reflected at different time point (0,15 and 60 minute) and stops.
Dextromethorphane Hbr (70 μ Μ) is hatched under 37 ° of C as positive control, is reflected at different time point (0,5,10,15,30 and 60 minutes) and stops.All comprise positive and negative control sample in each measuring method, to guarantee the integrity of microsome hatching system.
For each reaction, with the per-cent mapping of the concentration (with per-cent represent) of compound in people or rat liver microsomes are hatched by the Relative Zero time point, infer CLint CL in the body with this
Int(ref.:Naritomi Y, Terashita S, Kimura S, Suzuki A, Kagayama A, Sugiyama Y.Prediction of human hepatic clearance from vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans.Drug Metabolism and Disposition2001,29:1316-1324.), the result is referring to table 1, the experimental result of compound stability in people and rats'liver particulate that table 1 provides for the embodiment of the invention.
The experimental result of the compound that table 1 embodiment of the invention provides stability in people and rats'liver particulate
As shown in Table 1, when being incubated in compound provided by the invention in people and the rat liver microsomes, compound of the present invention shows good transformation period (T
1/2).
The pharmacokinetics evaluation in animal body of Embodiment B The compounds of this invention
The present invention assesses the pharmacokinetic of The compounds of this invention in mouse, rat, dog or monkey body.
The compounds of this invention carries out administration with aqueous solution form.For oral dosage (p.o.), rat and mouse are 5 or 10mg/kg, and dog and monkey are 10mg/kg.Be 0.25,0.5,1.0,2.0 at time point, 3.0,4.0,6.0,8.0, got blood (0.3mL) in 12 and 24 hours, and 3,000 or 4,000rpm under centrifugal 10 minutes.Collect plasma solutions, and under-20 ° of C or-70 ° of C, preserve up to carrying out above-mentioned LC/MS/MS analysis.The result shows, during with compound oral administration provided by the invention, it shows good pharmacokinetic property, comprises desirable clearance rate (Cl), transformation period (T
1/2) oral administration biaavailability of becoming reconciled.
The compounds of this invention carries out administration with aqueous solution form.For intravenous administration, animal gives 1 or the dosage of 2mg/kg.Be 0.25,0.5,1.0,2.0 at time point, 3.0,4.0,6.0,8.0, got blood (0.3mL) in 12 and 24 hours, and 3,000 or 4,000rpm under centrifugal 10 minutes.Collect plasma solutions, and under-20 ° of C or-70 ° of C, preserve up to carrying out above-mentioned LC/MS/MS analysis.The result shows, during with the quiet notes administration of compound provided by the invention, it shows good pharmacokinetic property, comprises desirable clearance rate (Cl), transformation period (T
1/2) oral administration biaavailability of becoming reconciled.
The Embodiment C kinase assay
The compound that the embodiment of the invention is provided according to method mentioned above carries out ALK (h) kinase assays and c-Met (h) kinase assays, and the result is referring to table 2, the kinase assay result that table 2 provides for the embodiment of the invention.
The kinase assay result that table 2 embodiment of the invention provides
As shown in Table 2, compound of the present invention generally demonstrates very high activity in the test of ALK and c-Met (h).
Embodiment D xenotransplantation tumor model
Adopt method mentioned above to set up U87MG transplanted tumor model, and adopt method mentioned above to analyze.In U87MG transplanted tumor model, with embodiment compound every day (QD) oral administration (p.o.), and lasting 13-21 days, the result is referring to table 3, the transplanted tumor result of study that table 3 provides for the embodiment of the invention.
The transplanted tumor result of study that table 3 embodiment of the invention provides
As shown in Table 3, under 60mg/kg dosage, the embodiment compound all has the meaning on the statistics, can suppress the growth of nude mice Subcutaneous tumor.
At last, it should be noted that other modes are used for implementing the present invention in addition.Correspondingly, embodiments of the invention are to describe as illustration, but are not limited to content described in the invention, also may be the modification of doing within the scope of the present invention or the equivalents of adding in the claims.All publications that the present invention quotes or patent all will be as reference of the present invention.
Claims (21)
1. one kind suc as formula the compound shown in (I):
Or its steric isomer, geometrical isomer, tautomer, oxynitride, solvate, meta-bolites, pharmacy acceptable salt or its prodrug, wherein:
Each R
1, R
2, R
3, R
4, R
5And R
6Be H independently, D or F;
Z is
(1) (C
3-C
7) heterocyclic radical, and by 1,2,3,4 or 5 independently are selected from D, F, Cl, Br, I, N
3, (C
1-C
6) alkyl, (C
1-C
6) haloalkyl ,-CN ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
4) alkylidene group-CN ,-(C
1-C
4) alkylidene group-OH ,-(C
1-C
4) alkylidene group-OR
aOr-(C
1-C
4) alkylidene group-NR
bR
cSubstituting group replace;
When the ring members of heterocyclic radical comprise-N (H)-time ,-N (H)-in hydrogen atom can not be substituted;
Work as R
1, R
2, R
3, R
4, R
5And R
6Be H, when Z was mono-substituted piperidyl, the 4-position on the piperidine ring can not be replaced by D;
(2)-(C
1-C
4) alkylidene group-(C
3-C
7) heterocyclic radical, and by 1,2,3,4 or 5 independently are selected from D, F, Cl, Br, I, N
3, (C
1-C
6) haloalkyl ,-CN ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
4) alkylidene group-OH ,-(C
1-C
4) alkylidene group-OR
aOr-(C
1-C
4) alkylidene group-NR
bR
cSubstituting group replace;
-(C
1-C
4) alkylidene group-(C
3-C
7) in the heterocyclic radical heterocyclic radical can not by-OH is single to be replaced;
(3) (C
5-C
12) the condensed-bicyclic base, and randomly by 1,2,3,4 or 5 independently are selected from D, F, Cl, Br, I, N
3, (C
1-C
6) alkyl, (C
1-C
6) haloalkyl ,-CN ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
4) alkylidene group-CN ,-(C
1-C
4) alkylidene group-OH ,-(C
1-C
4) alkylidene group-OR
aOr-(C
1-C
4) alkylidene group-NR
bR
cSubstituting group replace, and the ring in the bicyclic system can be carbocyclic ring or heterocycle; Or
(4)-(C
1-C
4) alkylidene group-(C
5-C
12) the condensed-bicyclic base, and randomly by 1,2,3,4 or 5 independently are selected from D, F, Cl, Br, I, N
3, (C
1-C
6) alkyl, (C
1-C
6) haloalkyl ,-CN ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
4) alkylidene group-CN ,-(C
1-C
4) alkylidene group-OH ,-(C
1-C
4) alkylidene group-OR
aOr-(C
1-C
4) alkylidene group-NR
bR
cSubstituting group replace, and the ring in the bicyclic system can be carbocyclic ring or heterocycle;
Wherein, R
aBe (C
1-C
6) alkyl, (C
1-C
6) thiazolinyl, (C
1-C
6) alkynyl, (C
3-C
6) cycloalkyl, (C
3-C
6) heterocyclic radical, (C
6-C
10) aryl, (C
1-C
9) heteroaryl ,-(C
1-C
4) alkylidene group-(C
3-C
6) cycloalkyl ,-(C
1-C
4) alkylidene group-(C
3-C
6) heterocyclic radical ,-(C
1-C
4) alkylidene group-(C
6-C
10) aryl or-(C
1-C
4) alkylidene group-(C
1-C
9) heteroaryl, described each (C
1-C
6) alkyl, (C
1-C
6) thiazolinyl, (C
1-C
6) alkynyl, (C
3-C
6) cycloalkyl, (C
3-C
6) heterocyclic radical, (C
6-C
10) aryl, (C
1-C
9) heteroaryl ,-(C
1-C
4) alkylidene group-(C
3-C
6) cycloalkyl ,-(C
1-C
4) alkylidene group-(C
3-C
6) heterocyclic radical ,-(C
1-C
4) alkylidene group-(C
6-C
10) aryl and-(C
1-C
4) alkylidene group-(C
1-C
9) heteroaryl is randomly by 1,2,3 or 4 independently are selected from D, F, Cl, N
3,-CN ,-OH ,-NH
2, the substituting group of alkoxyl group or alkylamino replaces;
R
bAnd R
cBe H independently, (C
1-C
6) alkyl, (C
3-C
6) cycloalkyl, (C
3-C
6) heterocyclic radical, (C
6-C
10) aryl, (C
1-C
9) heteroaryl ,-(C
1-C
4) alkylidene group-(C
3-C
6) cycloalkyl ,-(C
1-C
4) alkylidene group-(C
3-C
6) heterocyclic radical ,-(C
1-C
4) alkylidene group-(C
6-C
10) aryl or-(C
1-C
4) alkylidene group-(C
1-C
9) heteroaryl; Described each (C
1-C
6) alkyl, (C
3-C
6) cycloalkyl, (C
3-C
6) heterocyclic radical, (C
6-C
10) aryl, (C
1-C
9) heteroaryl ,-(C
1-C
4) alkylidene group-(C
3-C
6) cycloalkyl ,-(C
1-C
4) alkylidene group-(C
3-C
6) heterocyclic radical ,-(C
1-C
4) alkylidene group-(C
6-C
10) aryl and-(C
1-C
4) alkylidene group-(C
1-C
9) heteroaryl is randomly by 1,2,3, or 4 independently are selected from D, F, Cl, N
3,-CN ,-OH ,-NH
2, the substituting group of alkoxyl group or alkylamino replaces; Work as R
bAnd R
cWhen linking to each other with same nitrogen-atoms, R
b, R
cWith the nitrogen-atoms that links to each other with them, can also randomly form (C
3-C
6) heterocyclic radical.
2. compound according to claim 1 is characterized in that, wherein, and R
1, R
2, R
3, R
4, R
5And R
6Be H or D independently.
3. compound according to claim 1 is characterized in that, wherein, Z is:
(1) (C
3-C
7) heterocyclic radical, and by 1,2,3,4 or 5 independently are selected from D, F, N
3, (C
1-C
3) alkyl, (C
1-C
3) haloalkyl ,-CN ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
3) alkylidene group-CN ,-(C
1-C
3) alkylidene group-OH ,-(C
1-C
3) alkylidene group-OR
aOr-(C
1-C
3) alkylidene group-NR
bR
cSubstituting group replace;
(2)-(C
1-C
4) alkylidene group-(C
3-C
7) heterocyclic radical, and by 1,2,3,4 or 5 independently are selected from D, F, N
3, (C
1-C
3) haloalkyl ,-CN ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
3) alkylidene group-OH ,-(C
1-C
3) alkylidene group-OR
aOr-(C
1-C
3) alkylidene group-NR
bR
cSubstituting group replace;
(3) (C
5-C
12) the condensed-bicyclic base, and randomly by 1,2,3,4 or 5 independently are selected from D, F, Cl, Br, I, N
3, (C
1-C
3) alkyl, (C
1-C
3) haloalkyl ,-CN ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
3) alkylidene group-CN ,-(C
1-C
3) alkylidene group-OH ,-(C
1-C
3) alkylidene group-OR
aOr-(C
1-C
3) alkylidene group-NR
bR
cSubstituting group replace, and the ring in the bicyclic system can be carbocyclic ring or heterocycle; Or
(4)-(C
1-C
4) alkylidene group-(C
5-C
12) the condensed-bicyclic base, and randomly by 1,2,3,4 or 5 independently are selected from D, F, Cl, Br, I, N
3, (C
1-C
3) alkyl, (C
1-C
3) haloalkyl ,-CN ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
3) alkylidene group-CN ,-(C
1-C
3) alkylidene group-OH ,-(C
1-C
3) alkylidene group-OR
aOr-(C
1-C
3) alkylidene group-NR
bR
cSubstituting group replace, and the ring in the bicyclic system can be carbocyclic ring or heterocycle.
4. compound according to claim 1, wherein, R
aBe (C
1-C
3) alkyl, (C
1-C
3) thiazolinyl, (C
1-C
6) alkynyl, (C
3-C
6) cycloalkyl or-(C
1-C
3) alkylidene group-(C
3-C
6) cycloalkyl, described each (C
1-C
3) alkyl, (C
1-C
3) thiazolinyl, (C
1-C
6) alkynyl, (C
3-C
6) cycloalkyl and-(C
1-C
3) alkylidene group-(C
3-C
6) cycloalkyl is randomly by 1,2,3 or 4 substituting groups that independently are selected from D or F replace.
5. compound according to claim 1 is characterized in that, wherein, and R
bAnd R
cBe H independently, (C
1-C
3) alkyl, (C
3-C
6) cycloalkyl or-(C
1-C
4) alkylidene group-(C
3-C
6) alkyl; Described each (C
1-C
3) alkyl, (C
3-C
6) cycloalkyl and-(C
1-C
4) alkylidene group-(C
3-C
6) alkyl is randomly by 1,2,3 or 4 substituting groups that independently are selected from D or F replace; Work as R
bAnd R
cWhen linking to each other with same nitrogen-atoms, R
b, R
cWith the nitrogen-atoms that links to each other with them, can also randomly form (C
3-C
6) heterocyclic radical.
6. compound according to claim 1 is characterized in that, wherein, Z is selected from any one in the minor structure shown in the formula (a)～(k):
Or its steric isomer, wherein:
N is 0,1,2 or 3;
Each X and X' be-O-or-N (H)-;
Minor structure shown in the formula (a)～(k) or its steric isomer are independently by 1,2, and 3,4 or 5 independently are selected from D, F, (C
1-C
3) haloalkyl ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
3) alkylidene group-OH ,-(C
1-C
3) alkylidene group-OR
aOr-(C
1-C
3) alkylidene group-NR
bR
cSubstituting group replace;
When n is 1,2 or 3 o'clock, above-mentioned each minor structure or its steric isomer can not by-OH is single to be replaced;
When each X and X' be independently-N (H)-time ,-N (H)-in hydrogen atom can not be substituted;
Work as R
1, R
2, R
3, R
4, R
5And R
6Be H, when Z was mono-substituted piperidyl, the 4-position of piperidine ring can not be replaced by D.
7. compound according to claim 1 is characterized in that, wherein, Z is selected from any one in the minor structure shown in the formula (l)～(x):
Or its steric isomer, wherein:
N is 0,1,2 or 3;
Each W and W' be-O-,-N (H)-or-N (C
1-C
3) alkyl-;
Minor structure shown in the formula (l)～(x) or its steric isomer are randomly by 1,2, and 3,4 or 5 independently are selected from D, F, (C
1-C
3) alkyl, (C
1-C
3) haloalkyl ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
3) alkylidene group-OH ,-(C
1-C
3) alkylidene group-ORa or-(C
1-C
3) alkylidene group-NR
bR
cSubstituting group replace.
8. compound according to claim 6 is characterized in that, wherein, Z is selected from any one in the minor structure shown in formula (101)～(111):
Or its steric isomer, wherein:
Minor structure shown in formula (101)～(111) or its steric isomer are independently by 1,2, and 3,4 or 5 independently are selected from D, F, (C
1-C
3) haloalkyl ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
3) alkylidene group-OH ,-(C
1-C
3) alkylidene group-OR
aOr-(C
1-C
3) alkylidene group-NR
bR
cSubstituting group replace.
9. compound according to claim 6 is characterized in that, wherein, Z is selected from any one in the minor structure shown in formula (201)～(214):
Or its steric isomer, wherein:
Minor structure shown in formula (201)～(214) or its steric isomer are independently by 1,2, and 3,4 or 5 independently are selected from D, F, (C
1-C
3) haloalkyl ,-OR
a,-NR
bR
c,-(C
1-C
3) alkylidene group-OH ,-(C
1-C
3) alkylidene group-OR
aOr-(C
1-C
3) alkylidene group-NR
bR
cSubstituting group replace.
10. compound according to claim 7 is characterized in that, wherein, Z is selected from any one in the minor structure shown in formula (301)～(323):
Or its steric isomer, wherein:
Minor structure shown in formula (301)～(323) or its steric isomer are randomly by 1,2, and 3,4 or 5 independently are selected from D, F, (C
1-C
3) alkyl, (C
1-C
3) haloalkyl ,-OH ,-OR
a,-NR
bR
c,-(C
1-C
3) alkylidene group-OH ,-(C
1-C
3) alkylidene group-OR
aOr-(C
1-C
3) alkylidene group-NR
bR
cSubstituting group replace.
11. compound according to claim 1 is characterized in that, wherein, and R
aBe (C
1-C
2) alkyl, and randomly by 1,2,3 or 4 substituting groups that independently are selected from D or F replace.
12. compound according to claim 1 is characterized in that, wherein, and R
bAnd R
cBe H or (C independently
1-C
2) alkyl; Described (C
1-C
2) alkyl and (C
3-C
6) heterocyclic radical is randomly by 1,2,3 or 4 substituting groups that independently are selected from D or F replace; Work as R
bAnd R
cWhen linking to each other with same nitrogen-atoms, R
b, R
cWith the nitrogen-atoms that links to each other with them, can also randomly form (C
3-C
6) heterocyclic radical.
13. compound according to claim 1 is characterized in that, has following one of them structure:
14. a pharmaceutical composition comprises any described compound of claim 1～13 or pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or their combination.
15. pharmaceutical composition according to claim 14 is characterized in that, also comprises the additional treatment agent, these additional treatment agent are selected from chemotherapeutic agent, antiproliferative is used for the treatment of atherosclerotic medicine, is used for the treatment of the medicine of pulmonary fibrosis or their combination.
16. pharmaceutical composition according to claim 15 is characterized in that, wherein said additional treatment agent is Chlorambucil, melphalan, endoxan, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, cis-platinum, carboplatin, oxaliplatin, Dacarbazine, Temozolomide, Procarbazine, methotrexate, Fluracil, cytosine arabinoside, gemcitabine, purinethol, fludarabine, vinealeucoblastine(VLB), vincristine(VCR), vinorelbine, taxol, Docetaxel, topotecan, irinotecan, Etoposide, bent shellfish is for deciding gengshengmeisu, Dx, epirubicin, daunomycin, mitoxantrone, bleomycin, ametycin, ipsapirone, tamoxifen, flutamide, gonadorelin analogue, megestrol, prednisone, dexamethasone, methylprednisolone, Thalidomide, interferon alpha, Calciumlevofolinate, sirolimus, sirolimus resin, everolimus, Ah method is for Buddhist nun, alisertib, amuvatinib, Ah handkerchief are for the Buddhist nun, and A Xi is for the Buddhist nun, Velcade, ripple relax for the Buddhist nun, brivanib, cabozantinib, ground, west Buddhist nun's cloth, crenolanib, Ke Zhuo is for Buddhist nun, dabrafenib, dacomitinib, danusertib, Dasatinib, dovitinib, Tarceva, foretinib, ganetespib, Gefitinib, ibrutinib, the dust gram is for the Buddhist nun, imatinib, iniparib, lapatinibditosylate, lenvatinib, linifanib, linsitinib, the Marseille is for the Buddhist nun, and momelotinib is not for husky Buddhist nun, come that to replace the Buddhist nun, nilotinib, niraparib, oprozomib, olaparib, handkerchief azoles handkerchief Buddhist nun, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, fork clip is for Buddhist nun, saridegib, Xarelto, Sutent, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, ZD6474, veliparib, Wei Luofeini, vismodegib, volasertib, alemtuzumab, rhuMAb-VEGF, brentuximab vedotin blocks appropriate rope monoclonal antibody, Cetuximab, ground promise monoclonal antibody, lucky trastuzumab, her monoclonal antibody, Buddhist nun's trastuzumab, method wood monoclonal antibody difficult to understand, handkerchief Buddhist nun monoclonal antibody, Rituximab, tositumomab, Herceptin or their combination.
17. a right to use requires 1～13 any described compound or any described pharmaceutical composition of claim 14～16 to come for the preparation of the purposes of protecting, handle, treat or alleviate the medicine of patient's proliferative disease.
18. the purposes according to the described compound of claim 17 or pharmaceutical composition is characterized in that wherein said proliferative disease is metastatic carcinoma, colorectal carcinoma, adenocarcinoma of stomach, bladder cancer, mammary cancer, kidney, liver cancer, lung cancer, thyroid carcinoma, head and neck cancer, prostate cancer, carcinoma of the pancreas, the cancer of central nervous system, glioblastoma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis.
19. a right to use requires 1～13 any described compound or any described pharmaceutical composition of claim 14～16 to come for the preparation of the purposes that suppresses or regulate the medicine of protein kinase activity in biological sample, described purposes comprises right to use and requires 1～13 any described compound or right to use to require 14～16 any described pharmaceutical compositions to contact with described biological sample.
20. purposes according to claim 19 is characterized in that, wherein said protein kinase is the receptor tyrosine kinase acceptor.
21. purposes according to claim 20 is characterized in that, wherein said receptor tyrosine kinase acceptor is ALK, c-Met or their combination.
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| CN2012100761431 | 2012-03-21 | ||
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| CN103664778A (en) * | 2013-11-27 | 2014-03-26 | 苏州摩尔医药有限公司 | Synthesis method of antineoplastic drug cabozant inib |
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| US11034669B2 (en) | 2018-11-30 | 2021-06-15 | Nuvation Bio Inc. | Pyrrole and pyrazole compounds and methods of use thereof |
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| CN110577974A (en) * | 2019-09-10 | 2019-12-17 | 杭州澳赛诺生物科技有限公司 | synthesis method of chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine |
| 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 |
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