CN105130959B - Pyrimidine derivatives PIM kinase inhibitors and preparation method thereof and the application in pharmacy - Google Patents
Pyrimidine derivatives PIM kinase inhibitors and preparation method thereof and the application in pharmacy Download PDFInfo
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- ACFVPYQFGCKHKH-UHFFFAOYSA-N C=NC1CCCC1 Chemical compound C=NC1CCCC1 ACFVPYQFGCKHKH-UHFFFAOYSA-N 0.000 description 1
- GNEJHSIOMNIEGE-UHFFFAOYSA-N CN(C1c(c(F)ccc2)c2F)C(C(Nc2cncnc2OC2CCNCCC2)=O)=CC=C1C(F)(F)F Chemical compound CN(C1c(c(F)ccc2)c2F)C(C(Nc2cncnc2OC2CCNCCC2)=O)=CC=C1C(F)(F)F GNEJHSIOMNIEGE-UHFFFAOYSA-N 0.000 description 1
- GWJLTCGRKGCBMZ-UHFFFAOYSA-N Cc(cc1)nc(-c(c(F)ccc2)c2F)c1F Chemical compound Cc(cc1)nc(-c(c(F)ccc2)c2F)c1F GWJLTCGRKGCBMZ-UHFFFAOYSA-N 0.000 description 1
- KKVUMKHUMBXLMH-UHFFFAOYSA-N Cc(cc1)nc(Br)c1F Chemical compound Cc(cc1)nc(Br)c1F KKVUMKHUMBXLMH-UHFFFAOYSA-N 0.000 description 1
- FNJFCAGLRSJBLT-UHFFFAOYSA-N NCC(CCl)Oc1ncncc1NC(c(cc1)nc(-c(c(F)ccc2)c2F)c1F)=O Chemical compound NCC(CCl)Oc1ncncc1NC(c(cc1)nc(-c(c(F)ccc2)c2F)c1F)=O FNJFCAGLRSJBLT-UHFFFAOYSA-N 0.000 description 1
- JPQCYZWPENCLJR-UHFFFAOYSA-N NCC(CO)COc(ncnc1)c1NC(c1nc(-c(c(F)ccc2)c2F)c(C(F)(F)F)cc1)=O Chemical compound NCC(CO)COc(ncnc1)c1NC(c1nc(-c(c(F)ccc2)c2F)c(C(F)(F)F)cc1)=O JPQCYZWPENCLJR-UHFFFAOYSA-N 0.000 description 1
- ZWQBZQZZCCIDSU-UHFFFAOYSA-N NCC(COc1ccncc1NC(c(c(N)c1)nc(-c(c(F)ccc2)c2F)c1F)=O)CCl Chemical compound NCC(COc1ccncc1NC(c(c(N)c1)nc(-c(c(F)ccc2)c2F)c1F)=O)CCl ZWQBZQZZCCIDSU-UHFFFAOYSA-N 0.000 description 1
- IIUSLSPBPCKXKS-UHFFFAOYSA-N NCCCCOc(ncnc1)c1NC(c(cc1)nc(-c(c(F)ccc2)c2F)c1F)=O Chemical compound NCCCCOc(ncnc1)c1NC(c(cc1)nc(-c(c(F)ccc2)c2F)c1F)=O IIUSLSPBPCKXKS-UHFFFAOYSA-N 0.000 description 1
- DRDZCNTVTXCLBP-UHFFFAOYSA-N O=C(c(cc1)nc(-c(c(F)ccc2)c2F)c1F)Nc(cncn1)c1OC1CNC1 Chemical compound O=C(c(cc1)nc(-c(c(F)ccc2)c2F)c1F)Nc(cncn1)c1OC1CNC1 DRDZCNTVTXCLBP-UHFFFAOYSA-N 0.000 description 1
- RPXDRIDLCIGQMF-UHFFFAOYSA-N O=C(c(cc1)nc(-c(c(F)ccc2)c2F)c1F)Nc1cncnc1OC1CCNCCC1 Chemical compound O=C(c(cc1)nc(-c(c(F)ccc2)c2F)c1F)Nc1cncnc1OC1CCNCCC1 RPXDRIDLCIGQMF-UHFFFAOYSA-N 0.000 description 1
- DBZAICSEFBVFHL-UHFFFAOYSA-N OB(c(c(F)ccc1)c1F)O Chemical compound OB(c(c(F)ccc1)c1F)O DBZAICSEFBVFHL-UHFFFAOYSA-N 0.000 description 1
- AOAAHFLYMMKXEW-UHFFFAOYSA-N OCCCOc(ncnc1)c1NC(c(cc1)nc(-c(c(F)ccc2)c2F)c1F)=O Chemical compound OCCCOc(ncnc1)c1NC(c(cc1)nc(-c(c(F)ccc2)c2F)c1F)=O AOAAHFLYMMKXEW-UHFFFAOYSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The present invention provides a kind of PIM kinase inhibitors and its preparation method and application, structural formula is following general formula Compound I:
Description
Technical field
The present invention relates to pharmaceutical chemistry, and in particular to PIM kinase inhibitors and preparation method thereof and the application in pharmacy.
Background technology
PIM kinases is three homology serine/threonine kinases, belongs to calmodulin dependent protein kinase (CAMK) one
Race.Research has shown that, PIM kinases have in hematopoietic tissue extensive expression (J.Biol.Chem., 280,14168-14176,
2005;Blood, 105,4477-4483,2005), and to cells survival and it is diffused with important role, and in human body cancer
Have in disease tumour and under inflammatory conditions overexpression (J.Exp.Med., 201,259-266,2005;
Biochem.Soc.Trans., 32,315-319,2004).Therefore, PIM kinases treats tumour by more and more for studying
With the target of immunoregulation medicament.PIM-1 (Provims Integration of Maloney 1) gene is that Moloney mouse is white
The position that provirus is frequently inserted into the t cell lymphoma of blood disease virus induction, PIM-1 kinases also therefore and gain the name (Cell,
37,141-150,1984).Hereafter it finds, the gene of coding PIM-2 (Provims Integration of Maloney 2)
There is same weakness (J.Clin.Invest., 115,2679-2688,2005).The initial entitled KID-1 (Kinase of PIM-3
Induced by Depolarization 1), afterwards because of its protein sequence and PIM-1 highly consistent (71% amino acid multiplicity)
And rename (Nature, 428,332-337,2005;Cell, 56,673-682,1989).PIM-1,2,3 in many neoplastic hematologic disorders
In have overexpression (PNAS USA, 86,8857-8861,1989).PIM-1 has during being found in prostate cancer development
More expression (J.Clin.Pathol., 59,285-288,2006), PIM-2 is in human body chronic lymphocytic leukemia and Fei Huo
Expression in strange gold lymphoma leukemia has an increase (Leuk.Lymph., 45,951-955,2004), and the exception table of PIM-3
Up to be then considered to fibroma of liver (Int.J.Cancer, 114,209-218,2005) and cancer of pancreas (Cancer Res., 66,
6741-6747,2006) development and diffusion has played important role.
PIM-1,2,3 usually generate reaction to the stimulation of growth factor and cell factor, thus to the existence of hematopoietic cell
It is acted with diffusion.PIM-1 is rejected, the mouse of 2,3 genes can normally survive, but height is smaller, and expand in hematopoietic cell
The reaction of growth factor is also weakened during dissipating.It is not apparent to mouse if only rejecting one kind in three kinds of PIM
It influences, it is seen that the function of three kinds of PIM is overlapped (Cell, 56,673-682,1989).The substrate specificity of PIM kinases includes adjusting
The Bcl-2 family members BAD (FEBS Letters, 571,4349,2004) of ganglion cell's apoptosis, adjusts the p21 of cell cycle
(Biochim.Biophys.Acta, 1593,45-55,2002), CDC25A, C-TA, (J.Biol.Chem., 279,48319-
48328,2004) and regulatory protein matter synthesis 4EBPl (Blood, 105,4477-4483,2005).PIM kinases these
Effect shows that it has the function of preventing Apoptosis and promote cell growth and diffusion.Therefore, PIM kinases is excessive in tumour
The existence that expression has encouraged cancer cell is lived and is spread.So it is the new for the treatment of cancer to inhibit overexpression PIM kinases in tumour
Effective ways.
Since PIM kinases is related with entity tumor in many liquid tumors, many PIM kinase inhibitors be used to develop new
The antitumor drug of a generation.It is shown in a series of cell and animal model experiment, PIM kinase inhibitors can significantly inhibit liquid
The diffusion of body tumour cell and the growth of tumour, these liquid tumors include acute lymphoblastic leukemia (ALL), acute myeloid
Leukaemia (AML), chronic myelocytic leukemia (CML), non-Hodgkin lymphoma (NHL) and Huppert's disease (MM)
(Clin.Cancer Res.20 (7), 1834-1845,2014;Blood 123 (6), 905-913,2014;Blood 122
(21), 4435,2013).Experimental result also shows that PIM kinase inhibitors also have the solid tumor that PIM kinases over-expresses good
Good effect, these tumours include cancer of pancreas (Cancer Biol.Ther.7 (9), 1352-9,2008Cancer Res.2006;
66(13):6741-7;Cancer Res.70 (24), 10288-10298,2010), prostate cancer (Prostate, 65 (3),
276-86,2005;Prostate, 73 (13), 1462-1469,2013), liver cancer (J.Surg.Res., 153 (1), 17-22,
2009;Int.J.Cancer, 114 (2), 209-18,2005), gastric cancer (J.Cancer Res.Clin.Oncol., 134 (4),
481-8,2008) and carcinoma of urinary bladder (J.Exp.Clin.Cancer Res., 29,161,2010).
The generation of anticancer drug drug resistance is always the major obstacle (Drug of chemotherapy and molecular targeted agents
Resistance Updat.12,114-126.2009), the drug resistance for solving anticancer drug is the important topic for the treatment of of cancer.Perhaps
More most important drug transporters of studies have shown that PIM kinases pair two (drug efflux transporters), MDR-1 and
The expression of BCRP and activity are related (DrugResistance Updates, 14,203-211,2011).Experiment shows PIM kinases
Inhibitor shares (Mol.Cancer Ther.8,2882- the effect of capable of significantly improving to drug resistance prostate cancer with chemotherapeutics
2893,2009).Therefore, PIM inhibitor can be used for reversing the drug resistance to chemotherapy.
Experiment display, PIM kinase expressions occur along with the activation of T- cells, and PIM-1/3 inhibitor can effectively treat CD4
Enteritis caused by+T- cells.Oral clinical test drug AR452530 can at least reduce rectum inflammation, body of gland loss, edema and
Mucosal hyperplasia 80% (Cellular Immunology, 272,200-213,2012).Therefore PIM inhibitor can also be used to treat
The disease cell-mediated T- such as inflammatory bowel disease.
According to the kinase inhibitor document (United States Patent (USP) US8592455B2) delivered:
General formula A and Formula B are all PIM inhibitor, when their substituent Ra, RbAnd RcWhen being just as, they are only
One difference is the 5- bit substituents on pyridine ring 1, and general formula A is hydrogen atom, and Formula B is fluorine atom.Document data show,
In all 29 pairs of compounds, 5- bit substituents are that H or F have little effect the PIM activity of these compounds, will not be changed
The compound inhibits the ability of PIM-1 enzymatic activitys.
Invention content
During studying a new generation's PIM kinase inhibitors, surprisingly, it was found that it is different with known knowledge,
In one group meets compounds of formula I, when other structures are just the same, due to R6For cyclic structure, by R3It is changed into from H
When his substituent group, since steric hindrance increases, R is hindered6Ring is freely rotated, to improve their activity.Work as R3It changes into
F or CF3When, due to improving the lipophilicity at this position of molecule, inhibit the active energy of PIM-1 to further increase compound
Power, highest activity improve nearly 6 times, averagely 4.19 times.Specific data are shown in the table 2 of embodiment 57.
Technical problem to be solved by the present invention lies in research PIM kinase inhibitor noval chemical compounds, design prepares treatment cancer
Disease, the drug of the inflammation cell-mediated T- such as polytropism drug resistance and inflammatory bowel disease.
The present invention provides PIM kinase inhibitors, structural formula is following general formula Compound I:
Formula Compound I is the PIM kinase inhibitors of pyrimidines structure.
The present invention also provides the stereoisomer of compound of formula I, tautomer and pharmaceutical salts.
In above-mentioned Formulas I
R1For-H ,-NHR4, halogen (F, Cl, Br, I) ,-OH ,-OC1-3Alkyl ,-SH ,-SC1-3Alkyl, C1-3Alkyl, it is halogenated
Methyl, halogenated ethyl ,-CN and-NO2;
R2For-H ,-NHR4, halogen (F, Cl, Br, I) ,-OH ,-SH ,-the OC of with or without substituent group1-3Alkyl ,-
SC1-3Alkyl, C1-3Alkyl and C3-7Cyclic hydrocarbon radical, halogenated methyl, halogenated ethyl ,-CN and-NO2;
R3For-NHR5, halogen (F, Cl, Br, I) ,-OH ,-SH ,-the OC of with or without substituent group1-3Alkyl ,-SC1-3
Alkyl, C1-3Alkyl and C3-7Cyclic hydrocarbon radical, halogenated methyl, halogenated ethyl ,-CN and-NO2;
R4For-H ,-C (=O)-R5, the C of with or without substituent group1-8Alkyl, C3-7Cyclic hydrocarbon radical, 4-7 circle heterocyclic rings base, 5-
10 yuan of aryl and heterocyclic aryl;
R5For the C of with or without substituent group1-8Alkyl, C1-8Oxyl, C3-7Cyclic hydrocarbon radical;
R6For the C of with or without substituent group3-7Cyclic hydrocarbon radical, 4-7 circle heterocyclic rings base, 5-10 members aryl and heterocyclic aryl;Institute
Cyclic hydrocarbon radical is stated, the substituent group on aryl and heterocyclic aryl can be halogen (F, Cl, Br, I) ,-CN ,-NH respectively2,-NHR7, C1-4
Alkyl, C1-4Halohydrocarbyl, C3-7Cyclic hydrocarbon radical ,-OR7,-NO2,-C (=O) OR7,-C (=O) R7,-C (=O) N (R7)2,-C (=O)
NH2,-C (=O) NHR7;
R7For-H or with or without substituent group C1-4Alkyl;
R22For the C of with or without substituent group1-8Alkyl or the group defined for following formula:
Wherein R23, R24And R25Respectively halogen (F, Cl, Br, I) ,-OR15,-NR16R17,-C (=O) NR18R19Or it carries
Or the C without substituent group1-8Alkyl;
R15、R16、R17、R18、R19The C of respectively-H or with or without substituent group1-8Alkyl
G1For CH2Or N;
G2For NR28、CHR29Or O;
B1 and B2 is 0,1,2 or 3;
B3 is 0,1,2;
B4 is 0,1;
R26And R27The C of respectively-H or with or without substituent group1-8Alkyl;
R28For-H, the C of with or without substituent group1-8Alkyl, C3-7Cyclic hydrocarbon radical, C3-7Heterocyclic hydrocarbyl ,-C (=O) R30,-
C (=O) OR30Or-C (=O) NHR30;
R29For-H ,-OH, the C of with or without substituent group1-8Alkyl, C3-7Cyclic hydrocarbon radical, C3-7Heterocyclic hydrocarbyl ,-NHR30、-
C (=O) OR30Or-C (=O) NHR30;
R30For-H or the C of with or without substituent group1-8Alkyl;
Heretofore described substituent group can be selected from hydroxyl, nitro, amino, imino group, cyano, halogen unless otherwise specified
Element, thio group, sulfonyl, thio acylamino (thioamido), amidino groups, imidino, oxo amidino groups (oxamidino), methoxy
Base amidino groups (methoxamidino), guanidine radicals, sulfonamido, carboxyl, formoxyl, low alkyl group, junior alkyl halides, lower alkyl
Base amino, junior alkyl halides amino, lower alkoxy, halogenated lower alkoxy, low-grade alkoxy alkyl, alkyl-carbonyl, ammonia
Base carbonyl, aryl carbonyl, aromatic alkyl carbonyl, heteroaryl.
It is described " rudimentary ", it is unless otherwise specified, different according to the substituent group of restriction, respectively refer to C1-8Linear chain or branched chain base
Group, the non-aromatic cyclic radical of 3-7 members or the aromatic group of 5-12 members, or carry C1-8Linear chain or branched chain substituent group 5-
12 yuan of aromatic group.
In certain embodiments of the present invention, compound of Formula I and its stereoisomer, the medicine of tautomer and they
With salt, R1For-H ,-NHR4, halogen (F, Cl, Br, I) ,-OH ,-SH ,-the OC of with or without substituent group1-3Alkyl ,-SC1-3
Alkyl, C1-3Alkyl and C3-7Cyclic hydrocarbon radical ,-CN and-NO2;It is preferred that R1For-H ,-NH2, halogen (F, Cl, Br, I) ,-OH ,-CN and-
NO2;Further preferred R1For-H ,-NH2,-F.
In another part embodiment of the present invention, compound of Formula I and its stereoisomer, tautomer and they
Pharmaceutical salts, R2For-H ,-NHR4, halogen (F, Cl, Br, I) ,-OH ,-SH ,-the OC of with or without substituent group1-3Alkyl ,-
SC1-3Alkyl, C1-3Alkyl and C3-7Cyclic hydrocarbon radical ,-CN and-NO2;It is preferred that R2For-H, halogen (F, Cl, Br, I) ,-CN;It is further excellent
Select R2For-H, halogen (F, Cl, Br, I).
In another part embodiment of the present invention, compound of Formula I and its stereoisomer, tautomer and they
Pharmaceutical salts, R3For-NHR5, halogen (F, Cl, Br, I) ,-OH ,-SH ,-the OC of with or without substituent group1-3Alkyl ,-SC1-3
Alkyl, C1-3Alkyl and C3-7Cyclic hydrocarbon radical, halogenated methyl, halogenated ethyl ,-CN and-NO2;It is preferred that R3For halogen (F, Cl, Br, I), band
Have or without substituent group C1-3Alkyl and-OC1-3Alkyl, halogenated methyl ,-CN and-NO2;Further preferred R3For halogen (F,
Cl, Br, I) ,-CF3, and-CN;Still further preferably R3For halogen (F, Cl, Br, I) and-CF3。
In another part embodiment of the present invention, compound of Formula I and its stereoisomer, tautomer and they
Pharmaceutical salts, R6For the C of with or without substituent group3-7Cyclic hydrocarbon radical, 4-7 circle heterocyclic rings base, 5-10 members aryl and heterocyclic aryl;
The cyclic hydrocarbon radical, the substituent group on aryl and heterocyclic aryl can be halogen (F, Cl, Br, I) ,-CN ,-NH respectively2,-NHR7,
C14Alkyl, C1-4Halohydrocarbyl, C3-7Cyclic hydrocarbon radical ,-OR7,-NO2,-C (=O) OR7,-C (=O) R7,-C (=O) N (R7)2,-C (=
O)NH2,-C (=O) NHR7;It is preferred that R6For phenyl, piperazinyl and pyridyl group, the phenyl, piperazinyl and pyridyl group can be by 1-3
It is a to be selected from-F ,-Cl ,-Br ,-I ,-OH ,-NH2, C1-3Alkyl, C1-3Oxyl, halogenated C1-3The group of alkyl is replaced;Further
It is preferred that R6For phenyl, pyridyl group, 2-F-6-OCH3Phenyl, 2,6- difluorophenyls.
The present invention another part embodiment in, compound of Formula I and its stereoisomer, tautomer and it
Pharmaceutical salts in, preferably R22For with or without the cyclobutane base of substituent group, pentamethylene base, cyclohexyl, cycloheptyl alkyl, azepine
Cyclobutane base, pyrrolidinyl, piperidyl, nitrogen heterocyclic heptyl, epoxy butane base, tetrahydrofuran base, THP trtrahydropyranyl;Further
It is preferred that R22For cyclohexyl, pyrrolidinyl, piperidyl, nitrogen heterocyclic heptyl;On the group with substituent group, there can be 1-
4 substituent groups can be respectively selected from halogen (F, Cl, Br, I) ,-NH2,-OH, methylamino, ethylamino-, Propylamino, dimethylamino,
Diethylin, methyl, ethyl, propyl, methoxyl group, ethyoxyl, propoxyl group, monohaloalkyl methyl, polyhalo methyl, monohaloalkyl second
Base, polyhalo ethyl;Preferred substituents are halogen (F, Cl, Br, I) ,-NH2,-OH, methylamino, methyl and methoxyl group;Further
Preferred substituents are-NH2,-OH and methyl
The present invention another part embodiment in, compound of Formula I and its stereoisomer, tautomer and it
Pharmaceutical salts, R22For with or without the cyclobutane ylmethyl of substituent group, pentamethylene ylmethyl, cyclohexyl methyl, cycloheptyl
Ylmethyl, azetidine ylmethyl, pyrrolidinylmethyl, piperidino methyl, azepan ylmethyl, epoxy butane Ji Jia
Base, tetrahydrofuran ylmethyl, oxinane ylmethyl;Further preferred R22For cyclohexyl methyl, pyrrolidinylmethyl, piperidines
Ylmethyl, azepan ylmethyl;On the group with substituent group, there can be 1-4 substituent group, can be respectively selected from
Halogen (F, Cl, Br, I) ,-NH2,-OH, methylamino, ethylamino-, Propylamino, dimethylamino, diethylin, methyl, ethyl, third
Base, methoxyl group, ethyoxyl, propoxyl group, monohaloalkyl methyl, polyhalo methyl, monohaloalkyl ethyl, polyhalo ethyl;It is preferred that replacing
Base is halogen (F, Cl, Br, I) ,-NH2,-OH, methylamino, methyl and methoxyl group;Further preferred substituent group is-NH2,-OH and
Methyl
The present invention another part embodiment in, compound of Formula I and its stereoisomer, tautomer and it
Pharmaceutical salts, R22For with or without the C of substituent group2-5Alkyl can have up to 4 substituent groups on these alkyl, they point
Can not be halogen (F, Cl, Br, I), NH2, methylamino, ethylamino-, Propylamino, dimethylamino, diethylin, hydroxyl, methyl,
Ethyl, propyl ,-CH2OH ,-CH2(OH)CH3,-CH2CH2OH, monohaloalkyl methyl, polyhalo methyl, monohaloalkyl ethyl, polyhalo
Ethyl, C1-4Alkyl-O-, C1-4Alkyl-S-;
In certain embodiments of the present invention, compound of Formula I and its stereoisomer, the medicine of tautomer and they
With salt, preferred embodiment is listed in table 2.
The definition of the term as used herein:
The term as used herein " alkyl " refers to not containing heteroatomic alkyl.Therefore, the term include straight chained alkyl such as
Methyl, ethyl, propyl, butyl, amyl, base, heptyl, octyl, nonyl, decyl, undecyl, dodecyl etc..The term
Further include the branched isomer of straight chained alkyl, including but not limited to for example below group:-CH(CH3)2、CH(CH3)
(CH2CH3)、CH(CH2CH3)2、-C(CH3)3、-C(CH2CH3)3、-CH2CH(CH3)2、-CH2CH(CH3)(CH2CH3)、-CH2CH
(CH2CH3)2、-CH2C(CH3)3、-CH2C(CH2CH3)3、-CH(CH3)CH(CH3)(CH2CH3)、-CH2CH2CH(CH3)2、-
CH2CH2CH(CH3)(CH2CH3)、-CH2CH2CH(CH2CH3)2、-CH2CH2C(CH3)3、-CH2CH2C(CH2CH3)3、-CH(CH3)
CH2CH(CH3)2、-CH(CH3)CH(CH3)CH(CH3)2、CH(CH2CH3)CH(CH3)CH(CH3)(CH2CH3) etc..Therefore, term
Alkyl includes primary alkyl, secondary alkyl and tertiary alkyl.Preferred alkyl includes straight chain and branched alkane with 1 to 12 carbon atom
Base.A kind of preferred " alkyl ", which defines, is related to C1-4Straight chained alkyl such as methyl, ethyl, n-propyl and normal-butyl.Preferred alkyl is fixed
Justice further includes C3-5Branched alkyl, including-CH (CH3)2、-CH2CH(CH3)2、-CH(CH3)CH2CH3、-C(CH3)3、-CH(CH3)
CH2CH2CH3、-CH(CH3)CH(CH3)2、-CH2CH(CH3)CH2CH3、-CH2CH2CH(CH3)2With-CH (CH2CH3)2Deng.
The term as used herein " alkenyl " refers to wherein having at least one unsaturation, that is, two of which adjacent carbon atom
Pass through doubly linked alkyl as defined above.
The term as used herein " alkynyl " is related to alkyl of the two of which adjacent carbon atom by three key connections.
The term as used herein " alkoxy " refers to-OR, and wherein R is alkyl.
The term as used herein " alkyl " is the general designation of alkyl, alkenyl and alkynyl.
The term as used herein " halogen " or " halogenated " refer to fluorine, chlorine, bromine and iodine (F, Cl, Br, I) group." alkyl halide
Base " refers to the alkyl replaced by one or more halogen atoms.Therefore, term " halogenated alkyl " includes monohaloalkyl alkyl, dihalo-
Substituted alkyl, tri haloalkyl etc..Typical monohaloalkyl alkyl includes-CH2F、-CH2Cl、-CH2CH2F、-CH2CH2Cl、-CH(F)
CH3、-CH(Cl)CH3;Typical dihalo alkyl includes-CHCl2、-CHE2、-CCl2CH3、-CH(Cl)CH2Cl、-
CH2CHCl2、-CH2CHF2;Typical tri haloalkyl includes-CCl3、-CF3、-CCl2CH2Cl、-CF2CH2F、-CH(Cl)
CHCl2、-CH(F)CHF2;Typical whole haloalkyl includes-CCl3、-CF3、-CCl2CCl3、-CF2CF3。
" amino " used herein refers to group NH2。
The term " alkyl amino " of this paper refers to the group-that wherein R and R ' is each independently selected from hydrogen or low alkyl group
It is H when NRR ', wherein R and R ' are different.
The term " arylamino " of this paper refer to wherein R be aryl and R ' be hydrogen, low alkyl group or aryl group-
NRR′。
The term " aryl alkyl amino " of this paper refers to that wherein R is loweraralkyl and R ' is hydrogen, low alkyl group, aryl or low
Group-the NRR ' of grade aralkyl.
The term as used herein cyano refers to group-CN.
The term as used herein nitro refers to group-NO2。
The term as used herein " alkoxyalkyl " refers to that wherein alk1 is alkyl or alkenyl and alk2 is alkyl or alkene
Group-the alk1-0-alk2 of base.Term " low-grade alkoxy alkyl " refer to wherein alk1 be low alkyl group or low-grade alkenyl and
Alk2 is the alkoxyalkyl of low alkyl group or low-grade alkenyl.Term " aryloxy alkyl " refers to -0 one virtue of one alkyl of group
Base.Term " sweet-smelling alkoxy alkyl " refers to -0 one aralkyl of one alkylidene of group that wherein aralkyl is loweraralkyl.
The term as used herein " amino carbonyl " refers to group-C (=O)-NH2;" substituted amino carbonyl " is herein
Refer to wherein R be low alkyl group and R ' be hydrogen or low alkyl group group C (O)-NRR '.In some embodiments, R and R ' can
" heterocycloalkylcarbonyl " is formed together with the N atoms connected with them.Term " aromatic yl aminocarbonyl " in this article refers to it
Middle R is aryl and R ' is group-C (O)-NRR ' of hydrogen, low alkyl group or aryl." Aralkylaminocarbonyl " in this article refers to
Wherein R is loweraralkyl and R ' is group-C (O)-NRR ' of hydrogen, low alkyl group, aryl or loweraralkyl.
" amino-sulfonyl " used herein refers to group-S (O)2NH2" amino-sulfonyl of substitution " in this article refers to
Wherein R is low alkyl group and R ' is the group-S (O) of hydrogen or low alkyl group2NRR′.Term " aralkylaminosulfonlyaryl "
In this article refer to the group aryl-S (O) that wherein aralkyl is loweraralkyl2- NH aralkyl.
" carbonyl " used herein refers to bivalent group-C (O)-." carboxyl " refers to-C (=O)-OH." alkoxy carbonyl "
Refer to ester-C (=O)-OR that wherein R is alkyl." elementary alkoxy carbonyl " refers to the ester-C (=O)-that wherein R is low alkyl group
OR." cyclo alkoxy carbonyl " refers to C (=O)-OR that wherein R is naphthenic base.
" naphthenic base " used herein refers to the carbocyclic alkyl substituent of single or multiple ring.Carbocyclic ring alkyl is that wherein all rings are former
Son is all the naphthenic base of carbon.Typical naphthenic substituent has 3 to 8 skeleton (that is, ring) atoms, wherein each skeletal atom is
Carbon or hetero atom.Term " Heterocyclylalkyl " in this article refer in ring structure have 1 to 5, and more typically have 1 to
4 heteroatomic naphthenic substituents.Suitable hetero atom is nitrogen, oxygen and sulphur used in the compounds of this invention.It is representative
Heterocycloalkyl portion includes such as morpholino, piperazinyl, piperidyl.Carbocyclic ring alkyl is the rings that wherein all annular atoms are all carbon
Alkyl.When being used in combination with naphthenic substituent, term " polycyclic " in this article refer to condensed and non-condensed alkyl
Cyclic structure.Term " the undersaturated naphthenic base in part ", " naphthenic base of fractional saturation " and " cycloalkenyl group ", which all refer to wherein, to be had at least
One unsaturation, that is, the naphthenic base that the adjacent annular atom of two of which is connected by double or triple bonds.Illustrative example packet
Include hexamethylene alkynyl, ring pentynyl, cyclopropanyl, the fast base of ring fourth etc..
The term as used herein heterocycle of " substitution ", " heterocyclic group " or " heterocycle " refer to containing there are one selected from nitrogen, oxygen and
Heteroatomic wantonly 3 or 4 Yuans rings of sulphur or heteroatomic 5- or 6- person's ring selected from nitrogen, oxygen or sulphur containing one to three;Wherein institute
Stating 5- person's ring, there is 0-2 double bond, 6- person's ring to have 0-3 double bond;Wherein nitrogen and sulphur atom are optionally aoxidized;And it wraps
Include the above-mentioned heterocycle of any of which any bicyclic group condensed with phenyl ring or the other 5- or 6- element heterocycles independently defined above.This
Term " Heterocyclylalkyl " used in text refers to the heteroatomic 5- or 6- person's ring for being selected from nitrogen, oxygen or sulphur containing one to three, wherein
The ring does not have double bond.For example, term heterocycle-C5Alkyl refers to 6 Yuans rings containing 5 carbon atoms and a hetero atom such as N.Cause
This, term " heterocycle " includes that wherein nitrogen is heteroatomic ring and fractional saturation and fully saturated ring.Preferably heterocycle includes
Such as:Phenodiazine(diazapinyl), pyrrole radicals, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyrrole
Piperidinyl, piperidyl, pyridazinyl, piperazinyl, pyrazinyl, N methyl piperazine base, azetidinyl, N- methyl azetidines
Base, pyrimidine radicals, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl,
Isothiazolyl, isothiazole alkyl, indyl, quinolyl, isoquinolyl, benzene imidazole radicals, benzothiazolyl, isoxazolyl benzenesulfonamide base, furans
Base, thienyl, triazolyl and benzothienyl;Heterocyclic moiety can it is unsubstituted or by various substituent groups it is monosubstituted or two substitution or
Three substitution, the substituent group independently selected from hydroxyl, halogen, oxo (C=O), (RN=, wherein R are lower alkyls to alkyl imino
Base or lower alkoxy), amino, alkyl amino, dialkyl amido, acylaminoalkyl, alkoxy, thio alkoxy, more alkane
Oxygroup, low alkyl group, naphthenic base or halogenated alkyl.
In conjunction with disclosure herein, organic and medicinal chemistry art technical staff is it will be understood that heterocyclic group
It can be attached in various positions.Typical heterocycle includes such as imidazole radicals, pyridyl group, piperazinyl, piperidyl, azacyclo-
Butane group, thiazolyl, furyl, triazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl,
Thiazolinyl, quinoline room quinoline base, phthalazinyl, indyl, naphthyridines base, indazolyl and quinazinyl.
" aryl " used herein refers to 3 to 14 skeleton carbons or the heteroatomic monocycle optionally replaced and polycyclic virtue
Race's group, and include isocyclic aryl and heterocyclic aryl.Isocyclic aryl is that all annular atoms wherein in aromatic ring are all carbon
Aryl.Term " heteroaryl " in this article refers to have 1 to 4 hetero atom as annular atom and remaining ring in aromatic ring
Atom is the aryl of carbon atom.When being used in combination with aryl substituent, term " polyaromatic " in this article refers to wherein extremely
A few ring structure is condensed and non-condensed the cyclic structure of aromatics, such as (it has a kind of and benzene to benzo dioxolane
The condensed heterocycle structure of base, that is, naphthalene etc.).The example for being used as the aryl moiety of substituent group in the compounds of this invention includes benzene
Base, pyridyl group, pyrrole radicals, thiazolyl, indyl, imidazole radicals, oxadiazoles base, tetrazole radical, pyrazinyl, triazolyl, thienyl, furan
It mutters base, quinolyl, purine radicals, naphthalene, benzothiazolyl, benzo pyridyl group and benzimidazolyl etc..
" optionally replacing " used herein or " substitution " refers to one or more hydrogen atoms by unit price or bivalent group
It replaces;Suitable substituent group includes such as hydroxyl, nitro, amino, imino group, cyano, halogen, thio group, sulfonyl, sulphur
For acylamino- (thioamido), amidino groups, imidino, oxo amidino groups (oxamidino), methoxamidino
(methoxamidino), guanidine radicals, sulfonamido, carboxyl, formoxyl, low alkyl group, junior alkyl halides, low-grade alkyl amino,
Junior alkyl halides amino, lower alkoxy, halogenated lower alkoxy, low-grade alkoxy alkyl, alkyl-carbonyl, amino carbonyl,
Aryl carbonyl, aromatic alkyl carbonyl, Heteroarylcarbonyl, heteroaralkyl-carbonyl, alkylthio group, aminoalkyl, cyanoalkyl, aryl etc.;
Substituent group itself can be substituted;Substitute onto the group on substituent group can be carboxyl, halogen, nitro, amino, cyano, hydroxyl,
Low alkyl group, lower alkoxy, amino carbonyl, SR, thio acylamino, SO3H、SO2R or naphthenic base, wherein R be typically hydrogen, into
Base or low alkyl group;When substituted substituent group includes straight chain group, which can be located in chain (for example, 2- hydroxyls third
Base, 2- aminobutyls etc.) or chain end (for example, 2- hydroxyethyls, 3- aminopropyls etc.).Substituted substituent group can be covalent
In conjunction with carbon or heteroatomic straight chain, branch or annular arrangement.Definition above does not include the substitute mode (example not allowed
Such as, by methyl that five fluorin radicals replace or the halogen atom replaced by another halogen atom);Such substitution mould not allowed
Formula is well known to those skilled in the art.
To those skilled in the art it will also be apparent that the compounds of this invention or their stereoisomer and it
Pharmaceutical salt, ester, metabolin and the pro-drug of any type can be with tautomerization and therefore can be wherein to divide
The proton of one atom of son is displaced to the chemical bond between atoms of another atom and molecule therefore rearranges various mutual
Become isomeric form to exist.See, e.g., March, Advanced Organic Chemistry:Reaction, mechanism and structure (Advanced Organic
Chemistry:Reactions, Mechanisms and Structures), fourth edition, John Wiley&Sons, 69-74
Page (1992).The term as used herein " tautomer " refers to the compound generated by proton displacement, and should be clear
It is, as long as there may be all tautomeric forms are all included in the present invention for it.
The compound of the present invention or their tautomer and the pharmaceutical salt, ester of any type in them,
Metabolin and pro-drug may include the carbon atom of Asymmetrical substitute.The carbon atom of such Asymmetrical substitute can be generated with mapping
The compounds of this invention existing for isomers, diastereoisomer and other stereoisomeric forms in any ratio, these forms can be according to absolutely vertical
Body chemistry is defined, such as (R)-or (S)-form.Therefore, such all possible isomers of the compounds of this invention, its rotation
The single stereoisomer of the pure form of light, its mixture, racemic mixture (or " racemic modification "), diastereoisomer it is mixed
It closes object and single diastereoisomer is included in the present invention.The term as used herein " S " and " R " configuration such as IUPAC
1974 RECOMMENDATIONS FOR SECTION E, FUNDAMENTAL STEREOCHEMISTRY, Pure
Appl.Chem.45:Defined in 13-30 (1976).Term and ring position for cyclic compound.Reference plane-side is excellent
The substituent group of choosing is located at that side of relatively low numbered positions.Positioned at those of reference plane offside substituent group with originally describing.It should note
Meaning, this usage is different from for the usage of cyclic stereocenter (stereoparents), in the later case, " " meaning
It " being located under plane " and indicates absolute configuration.The term as used herein and configuration such as CHEMICALABSTRACTS INDEX
The 203rd section of GUIDE-APPENDIX IV (1987) are defined.
The term as used herein " pharmaceutical salts " refers to the nontoxic hydrochlorate or alkali salt of compound of formula I.These salt can
To be prepared on the spot during the last separation and purifying in compound of formula I, or can by respectively by alkali or acid functional group with
Suitable organic or inorganic acid or alkali react to prepare.Typically salt includes but not limited to following salt:Acetate, adipic acid
Salt, alginates, citrate, aspartate, benzoate, benzene sulfonate, disulfate, butyrate, camphor hydrochlorate, sulfonic acid
Salt, digluconate, cyclopentane propionate, lauryl sulfate, esilate, gluceptate, glycerophosphate, half
Sulfate, enanthate, caproate, fumarate, hydrochloride, hydrobromide, hydriodide, 2- isethionates, lactate,
Maleate, mesylate, nicotinate, 2- naphthalene sulfonates, oxalates, pamoate, fruit amino acid salt, persulfate, 3- phenyl third
Hydrochlorate, picrate, pivalate, propionate, succinate, sulfate, tartrate, rhodanate, p- toluene fulfonate
And undecanoate.Reagent such as elementary alkyl halide can also be used, such as methyl, ethyl, propyl and butyl chloride compound, bromide
And iodide;Dialkylsulfates such as dimethyl suflfate, diethylester, dibutyl ester and diamyl ester, long chain halide such as decyl, the moon
Gui Ji, nutmeg base and stearyl chlorides, bromide and iodide, aralkyl halide such as benzyl bromide and phenethyl bromide etc. will
Including the group of basic nitrogen is quaternized.Thus to obtain water or oily soluble or water or the dispersible product of oil.
The example that can be used to form the acid of pharmaceutically acceptable acid addition salts includes inorganic acid such as hydrochloric acid, sulfuric acid and phosphoric acid, Yi Jiyou
Machine acid such as oxalic acid, maleic acid, methanesulfonic acid, succinic acid and citric acid.Base addition salts can in the last separation of formula (I) compound and
It is prepared on the spot during purifying, or can be by making the hydroxide of carboxylic moiety and for example pharmaceutically acceptable metal cation of suitable alkali
Object, carbonate or bicarbonate or ammonia or organic primary, secondary or tertiary amine are reacted to prepare.Pharmaceutical salt includes but not limited to alkali
With cationic such as sodium, lithium, potassium, calcium, magnesium, aluminium salt and nontoxic ammonium, quaternary ammonium and the amine cation based on alkaline-earth metal,
The including but not limited to salt of ammonium, tetramethyl-ammonium, tetraethyl ammonium, methyl amine, dimethylamine, trimethylamine, triethylamine, ethamine etc..For
The other organic limbs of typical case for forming base addition salts include diethylamine, ethylenediamine, ethanol amine, diethanol amine, piperazine etc..
The term as used herein " pharmaceutical ester " refer to the ester that hydrolyzes in vivo simultaneously, including in human body it is easily decomposes from
And release those of parent compound or its salt ester.Suitable ester include for example those be derived from pharmaceutical aliphatic carboxylic acid,
Especially those of alkanoic acid, alkenoic acid, aphthenic acids and chain docosandioic acid ester, wherein each alkyl or said alkenyl moiety preferably have not
More than 6 carbon atoms.The example of certain esters includes formic acid esters, acetic acid esters, propionic ester, butyrate, acrylate and ethyl amber
Acid esters.
The term as used herein " pharmaceutical pro-drug " refers to being suitable for and people and rudimentary in rational medical judgment
The tissue contact of animal is simultaneously without excessive toxicity, irritation, allergic reaction etc., with rational benefit/risk ratio and right
Those of the effectively pro-drug of the compounds of this invention of application needed for it and may in situation the compounds of this invention both sexes from
Sub- form.Term " pro-drug " refers to converting rapidly, for example being converted by hydrolyzing in blood in vivo, on generating
The compound of the parent compound of formula.In T.Higuchi and v.Stella, the pro-drug (Pro- as novel transmission system
Drugs as Novel Delivery Systems), Vol.14, A.C.S.Symposium Series and Edward
B.Roche is edited, the bioreversible carrier (Bioreversible Carriers in Drug Design) in drug design
In provide and be discussed in detail, the two is all incorporated by reference herein.
Any structural formula given herein is also represented by the unmarked form and isotope labelled form of the compound.Together
The compound of position element label has structure described in structural formula illustrated herein, and only one or more atoms are by with selected
Atomic mass or mass number atom replace.The example for the isotope that can be incorporated into the compounds of this invention include hydrogen, carbon,
The isotope of nitrogen, oxygen, phosphorus, fluorine and chlorine, such as2H、3H、11C、13C、14C、15N、18F、31p、32p、35S、36Cl、125I.Packet of the present invention
The compound of this paper institutes work doctrine of various isotope labellings is included, such as wherein there is radioactive isotope such as3H and14Those of C
Compound.The compound of such isotope labelling can be used for being metabolized research and (use14C), Reaction kinetics research are (with for example2H or3H), detection or imaging technique, such as positron emission tomography (PET) or single photon emission computed tomography
(SPECT), including drug or substrate tissue distribution assays, or can be used in the radiation treatment of patient.Particularly,18F or mark
Remember that compound is particularly suitable for PET or SPECT researchs.The compounds of this invention of isotope labelling and its pro-drug are usual
It can be by the operation disclosed in implementing procedure or following embodiments and preparation example, by with the isotope labelling being easily obtained
Reagent is prepared instead of isotope-labeled reagent.In addition, with heavier isotope, especially deuterium (that is,2H or D) it sets
Certain treatment benefits can be provided by changing, these treatment benefits increase derived from metabolic stability, such as Half-life in vivo increase or required
Dosage reduces or improvment of therapeutic index.It should be understood that the deuterium in this background is considered as the substitution of formula (1) compound
Base.The concentration of such higher isotope, especially deuterium can be defined with isotope enrichment factor.The term as used herein is " same
Plain enrichment factor " the ratio between the isotope abundance and natural abundance of isotope specified by referring in position.If chemical combination of the present invention
Substituent group in object is designated as deuterium, then such compound for each specified D-atom, with being at least 3500, (build by each specify
52.5% deuterium is mixed on atom), be at least 4000 (60% deuterium is mixed into), be at least 4500 (67.5% deuterium is mixed into), extremely
It is 5000 (75% deuterium is mixed into) less, be at least 5500 (82.5% deuterium is mixed into), is at least 6000 (90% deuterium is mixed into), extremely
It is 6333.3 (95% deuterium is mixed into) less, is at least 6466.7 (97% deuterium is mixed into), is at least 6600 (99% deuterium is mixed into)
Or the isotope enrichment factor of at least 6633.3 (99.5% deuterium is mixed into).
Formula (I) compound of isotope labelling can usually be prepared with the known routine techniques of those skilled in the art or
Method similar to those described in the appended examples and preparations can be used, with the reagent generation of suitable isotope labelling
It is prepared for isotope-labeled reagent used before.
It will be apparent for a person skilled in the art that the compound of the present invention or their tautomer, precursor
Drug and stereoisomer and pharmaceutical salt, ester and the pro-drug of any type can be by human or animals in them
Body is metabolized and is processed in vivo into the cell, to generate metabolin.The term as used herein " metabolin " refers to applying
With the derivative of any structural formula generated in vivo in individual after parent compound.These derivatives can be by individual internal
Various biochemical transformations for example aoxidize, restore, hydrolyzing or combine generated by parent compound, and include for example oxide and
Demethyl derivative.The metabolin of known routine techniques identification the compounds of this invention in the prior art can be used.See, for example,
Bertolini, G. et al. ,] .Med.Chem.40:2011-2016(1997);Shan, D. et al., J.Pharm.Sci.86 (7):
765-767;Bagshawe K., Drug Dev.Res.34:220-230(1995);Bodor, N., Advances in Drug
Res.13:224-331(1984);Bundgaard, H., Design of Prodrugs (Elsevier Press 1985);With
Larsen, 1.K., Design and Application of Prodrugs, Drug Design and Development
(Krogsgaard-Larsen et al., Harwood Academic Publishers, 1991).It should be understood that being used as Formulas I
Compound or their tautomer, pro-drug and stereoisomer and in them any type it is pharmaceutical
The chemical compound of the metabolin of salt, ester and pro-drug is included in the present invention.
The term as used herein " cancer " refer to can by inhibit PIM kinases obtain the Cancerous disease of advantageous treatment, including
Such as including such as solid tumor, such as lung cancer, cancer of pancreas, thyroid cancer, oophoroma, carcinoma of urinary bladder, breast cancer, prostate cancer or colon
Cancer, melanoma, bone marrow disorder for example, myelocytic leukemia, Huppert's disease and erythroleukemia, adenoma for example, villiform
Colonic adenoma and sarcoma are for example, osteosarcoma;Liquid tumor such as chronic lymphocytic leukemia, acute lymphoblastic leukemia are acute
Marrow series leukemia, chronic myelocytic leukemia, non-Hodgkin lymphoma and Huppert's disease.
PIM kinase inhibitors provided by the invention include following compounds:
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (piperidin-4-yl methoxyl group) pyrimidine -5- bases) -2- pyridine carboxamides
N- (4- (azetidin -3- ylmethoxies) pyrimidine -5- bases) fluoro- 2- pyridinecarboxylics of -6- (2,6- difluorophenyl) -5-
Amine
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (piperidin-4-yl oxygroup) pyrimidine -5- bases) -2- pyridine carboxamides
6- (2,6- difluorophenyl) -5- fluorine N- (4- (pyrrolidin-3-yl oxygroup) pyrimidine -5- bases) -2- pyridine carboxamides
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (piperidines -3- bases oxygroup) pyrimidine -5- bases) -2- pyridine carboxamides
N- (4- (azacyclo- hept- 4- bases oxygroup) pyrimidine -5- bases) fluoro- 2- pyridine carboxamides of -6- (2,6- difluorophenyl) -5-
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (piperidines -3- ylmethoxies) pyrimidine -5- bases) -2- pyridine carboxamides
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (pyrrolidin-3-yl methoxyl group) pyrimidine -5- bases) -2- pyridine carboxamides
N- (4- (azetidin -3- bases oxygroup) pyrimidine -5- bases) fluoro- 2- pyridine carboxamides of -6- (2,6- difluorophenyl) -5-
N- (4- (((1r, 4r) -4- aminocyclohexyls) oxygroup) pyrimidine -5- bases) fluoro- 2- of -6- (2,6- difluorophenyl) -5-
Pyridine carboxamide
N- (4- ((3- aminocyclohexyls) oxygroup) pyrimidine -5- bases) fluoro- 2- pyridinecarboxylics of -6- (2,6- difluorophenyl) -5-
Amine
N- (4- (3- amine propoxyl group) pyrimidine -5- bases) fluoro- 2- pyridine carboxamides of -6- (2,6- difluorophenyl) -5-
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (3- (methylamino) propoxyl group) pyrimidine -5- bases) -2- pyridine carboxamides
6- (2,6- difluorophenyl)-N- (4- (3- (dimethyl amido) propoxyl group) pyrimidine -5- bases) fluoro- 2- pyridines first of -5-
Amide
N- (4- (4- amidos butoxy) pyrimidine -5- bases) fluoro- 2- pyridine carboxamides of -6- (2,6- difluorophenyl) -5-
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (4- (methylamino) butoxy) pyrimidine -5- bases) -2- pyridine carboxamides
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (3- hydroxy propyloxy groups) pyrimidine -5- bases) -2- pyridine carboxamides
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (3- hydroxybutoxies) pyrimidine -5- bases) picolinamide
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (4- hydroxy butoxies) pyrimidine -5- bases) -2- pyridine carboxamides
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- ((4- hydroxy-4-methyls amoxy) pyrimidine -5- bases) -2- pyridine first
Amide
6- (2,6- difluorophenyl)-N- (4- (3,4- dihydroxy butoxy) pyrimidine -5- bases) fluoro- 2- pyridine carboxamides of -5-
The fluoro- N- of 6- (2,6- difluorophenyl) -5- [4- (oxinane -4- methoxyl groups) pyrimidine -5- bases) -2- pyridine carboxamides
The fluoro- N- of 3- amidos -6- (2,6- difluorophenyl) -5- (4- (piperidin-4-yl methoxyl group) pyrimidine -5- bases) picolinamide
The fluoro- N- of 3- amidos -6- (2,6- difluorophenyl) -5- (4- (pyrrolidin-3-yl oxygroup) pyrimidine -5- bases) -2- pyridines
Formamide
The fluoro- N- of 3- amidos -6- (2,6- difluorophenyl) -5- (4- (piperidin-4-yl oxygroup) pyrimidine -5- bases) -2- pyridine first
Amide
3- amidos-N- (4- (azacyclo- hept- 4- bases oxygroup) pyrimidine -5- bases) fluoro- 2- pyrroles of -6- (2,6- difluorophenyl) -5-
Pyridine formamide
3- amidos-N- (4- (((1r, 4r) -4- aminocyclohexyls) oxygroup) pyrimidine -5- bases) -6- (2,6- difluorophenyl) -
5- fluorine picolinamides
The fluoro- N- of 3- amidos -6- (2,6- difluorophenyl) -5- (4- (pyrrolidin-3-yl methoxyl group) pyrimidine -5- bases) -2- pyrroles
Pyridine formamide
N- (4- ((1- amido -3- chloropropyl -2- bases) oxygroup) pyrimidine -5- bases) fluoro- 2- of -6- (2,6- difluorophenyl) -5-
Pyridine carboxamide
N- (4- (3- amidos -2- (chloromethyl) propoxyl group) pyrimidine -5- bases) fluoro- 2- pyridines of -6- (2,6- difluorophenyl) -5-
Formamide
3- amidos-N- (4- (azetidin -3- bases oxygroup) pyrimidine -5- bases) fluoro- 2- pyrroles of -6- (2,6- difluorophenyl) -5-
Pyridine formamide
3- amidos-N- (4- (azetidin -3- ylmethoxies) pyrimidine -5- bases) fluoro- 2- of -6- (2,6- difluorophenyl) -5-
Pyridine carboxamide
3- amidos-N- (4- ((1- amido -3- chloropropyl -2- bases) oxygroup) pyrimidine -5- bases) -6- (2,6- difluorophenyl) -
The fluoro- 2- pyridine carboxamides of 5-
3- amidos-N- (4- (3- amidos -2- (chloromethyl) propoxyl group) pyrimidine -5- bases) -6- (2,6- difluorophenyl) -5-
Fluoro- 2- pyridine carboxamides
The fluoro- 6- phenyl-N- of 3- amidos -5- (4- (pyrrolidin-3-yl oxygroup) pyrimidine -5- bases) -2- pyridine carboxamides
The fluoro- N- of 3- (4- (piperidin-4-yl oxygroup) pyrimidine -5- bases)-(2,4 '-bipyridyl) -6- formamides
N- (4- (azacyclo- hept- 4- bases oxygroup) pyrimidine -5- bases) fluoro- 2- pyridine carboxamides of -6- (2,6- difluorophenyl) -3-
N- (4- (azacyclo- hept- 4- bases oxygroup) pyrimidine -5- bases) the fluoro- 6- of -5- (the fluoro- 6- methoxyphenyls of 2-) -2- pyridines
Formamide
N- (4- (azacyclo- hept- 4- bases oxygroup) pyrimidine -5- bases) -6- (2,6- difluorophenyl) -5- trifluoromethyl -2- pyridines
Formamide
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (piperidin-4-yl methoxyl group) pyrimidine -5- trifluoromethyl -2- pyridine first
Amide
N- (4- (azetidin -3- ylmethoxies) pyrimidine -5- bases) -6- (2,6- difluorophenyl) -5- trifluoromethyl -2- pyrroles
Pyridine formamide
6- (2,6- difluorophenyl)-N- (4- (piperidin-4-yl oxygroup) pyrimidine -5- bases) -5- trifluoromethyl -2- pyridinecarboxylics
Amine
N- (4- (((1r, 4r) -4- aminocyclohexyls) oxygroup) pyrimidine -5- bases) -6- (2,6- difluorophenyl) -5- fluoroforms
Base -2- pyridine carboxamides
6- (2,6- difluorophenyl)-N- [4- (tetrahydropyran -4-base) methoxyl group) pyrimidine -5- bases) -5- trifluoromethyls -2-
Pyridine carboxamide
3- amidos-N- (4- (azacyclo- hept- 4- bases oxygroup) pyrimidine -5- bases) -6- (2,6- difluorophenyl) -5- fluorine pyridine acyls
Amine
The fluoro- N- of 3- amidos -6- (2,6- difluorophenyl) -5- (4- (piperidin-4-yl methoxyl group) pyrimidine -5- trifluoromethyls -2-
Pyridine carboxamide
3- amidos-N- (4- (azetidin -3- ylmethoxies) pyrimidine -5- bases) -6- (2,6- difluorophenyl) -5- fluoroforms
Base -2- pyridine carboxamides
3- amidos -6- (2,6- difluorophenyl)-N- (4- (piperidin-4-yl oxygroup) pyrimidine -5- bases) -5- trifluoromethyls -2-
Pyridine carboxamide
3- amidos-N- (4- (((1r, 4r) -4- aminocyclohexyls) oxygroup) pyrimidine -5- bases) -6- (2,6- difluorophenyl) -
5- trifluoromethyl -2- pyridine carboxamides
3- amido -6- phenyl-N- (4- (pyrrolidin-3-yl oxygroup) pyrimidine -5- bases) -5- trifluoromethyl -2- pyridinecarboxylics
Amine
N- (4- (3- amidos -2- (chloromethyl) propoxyl group) pyrimidine -5- bases) -6- (2,6- difluorophenyl) -5- trifluoromethyls -
2- pyridine carboxamides
3- amidos-N- (4- (3- amidos -2- (chloromethyl) propoxyl group) pyrimidine -5- bases) -6- (2,6- difluorophenyl) -5- three
Methyl fluoride -2- pyridine carboxamides
N- (4- (3- amidos -2- (methylol) propoxyl group) pyrimidine -5- bases) fluoro- 2- pyridines of -6- (2,6- difluorophenyl) -5-
Formamide
3- amidos-N- (4- (3- amidos -2- (methylol) propoxyl group) pyrimidine -5- bases) -6- (2,6- difluorophenyl) -5-
Fluoro- 2- pyridine carboxamides
N- (4- (3- amidos -2- (methylol) propoxyl group) pyrimidine -5- bases) -6- (2,6- difluorophenyl) -5- trifluoromethyls -
2- pyridine carboxamides
3- amidos-N- (4- (3- amidos -2- (methylol) propoxyl group) pyrimidine -5- bases) -6- (2,6- difluorophenyl) -5- three
Methyl fluoride -2- pyridine carboxamides
It is a further object of the present invention to provide the preparation methods of above-mentioned PIM kinase inhibitors.
The compound of the present invention is prepared since commercially available starting material and reagent.The method following formula table of the present invention
Show:
Alcohol B (1.1 equivalent) elder generations of with or without blocking group and alkali, if NaH (1.1 equivalent) is in solvent, such as four
In hydrogen furans, react 1 hour under room temperature (25 DEG C), then again with 5- amino -4- chlorine pyrimidines A (1 equivalent) in a heated condition,
Aminopyrimidine ether C is obtained as reacted 1-10 hours at 100 DEG C.The aromatic carboxylic acids D (1 equivalent) of with or without blocking group exists
Coupling reagent, such as HATU (1.1 equivalent), alkali, in the presence of DIEA (3 equivalent), in solvent, as anti-with amine C (1 equivalent) in DMF
It answers, obtains ether compound E.If not having blocking group in E, E is the ether compound that E substituent groups are oxyl in Formulas I.
If carrying blocking group, such as BOC (tert-butoxy formic acid esters) or trimethyl silane, E then trifluoracetic acids with 10 to 100 equivalents again
And isometric dichloromethane or 2 centinormal 1 methanol hydrochloride solutions stirs 1-16 hours after the mixing of (25 DEG C) of room temperature, so
Vacuum distillation obtains the ether compound that the E substituent groups in Formulas I are oxyl after removing solvent under room temperature (25 DEG C) afterwards.
It is yet another object of the invention to provide application of the above-mentioned PIM kinase inhibitors in pharmacy.
Tested through PIM kinases biochemical activity methods of testing, the compound in all embodiments all to PIM-1, PIM-2 and
The activity of PIM-3 kinases has apparent inhibiting effect, and IC50 is in the range of 0.1-50nM.Therefore, PIM kinases of the invention
Inhibitor can be used for preparing drug.
The present invention provides above-mentioned PIM kinase inhibitors in preparing treatment or prevention autoimmune disease drug for this
Using.
The present invention provides above-mentioned PIM kinase inhibitors to prepare answering in treating or preventing allergic reaction disease medicament
With.
The present invention provides above-mentioned PIM kinase inhibitors answering in preparing the drug for treating or preventing atherosclerosis
With.
The present invention provides above-mentioned PIM kinase inhibitors in preparing the anti-organ transplant rejection drug for the treatment of or prevention
Application.
Invention provides above-mentioned PIM kinase inhibitors and is preparing the application in treating or preventing cancer drug.
The present invention provides above-mentioned PIM kinase inhibitors to prepare answering in treating or preventing polytropism drug resistance drug
With.
The present invention provides above-mentioned PIM kinase inhibitors in preparing the anti-inflammatory drugs for treating or preventing T cell mediation
Using.
The pharmaceutical composition that drug of the present invention is made of PIM kinase inhibitors as active constituent and pharmaceutical carrier.
The present invention provides the new applications of PIM kinase inhibitors, there is larger clinical value.
The compound of the present invention and pharmaceutical composition, can be used to treat or prevent cancer, reverse anticancer and other medicines
Drug resistance, inflammatory bowel disease, auto-immune disease, allergic reaction disease, atherosclerosis, anti-organ transplant rejection,
The inflammation that polytropism drug resistance, T cell mediate;" cancer " refers to can be by inhibiting PIM kinases to obtain the carcinous disease of advantageous treatment
Disease, including such as solid tumor, as lung cancer, cancer of pancreas, thyroid cancer, oophoroma, carcinoma of urinary bladder, breast cancer, prostate cancer or colon cancer,
Melanoma, bone marrow disorder for example, myelocytic leukemia, Huppert's disease and erythroleukemia, adenoma for example, villous colon
Adenoma and sarcoma are for example, osteosarcoma;Liquid tumor such as chronic lymphocytic leukemia, acute lymphoblastic leukemia, acute myeloid
Leukaemia, chronic myelocytic leukemia, non-Hodgkin lymphoma and Huppert's disease.
Invention also provides aforesaid compound and pharmaceutical compositions to treat or prevent cancer preparing, reverse anticancer and
The drug resistance of other medicines, inflammatory bowel disease, auto-immune disease, allergic reaction disease, atherosclerosis, anti-organ transplant
The inflammation that rejection, polytropism drug resistance, T cell mediate;" cancer " refers to can be by inhibiting PIM kinases to obtain advantageous treatment
Cancerous disease, including such as solid tumor, such as lung cancer, cancer of pancreas, thyroid cancer, oophoroma, carcinoma of urinary bladder, breast cancer, prostate cancer
Or colon cancer, melanoma, bone marrow disorder for example, myelocytic leukemia, Huppert's disease and erythroleukemia, adenoma for example,
Villous colon adenoma and sarcoma are for example, osteosarcoma;Liquid tumor such as chronic lymphocytic leukemia, the white blood of acute lymphoblastic
The application of the drug of disease, acute myeloid leukemia, chronic myelocytic leukemia, non-Hodgkin lymphoma and Huppert's disease.
Specific implementation mode
The purpose of following embodiment is that the present invention is described in more detail.The scope of the invention is not limited to these
Embodiment.
The synthesis of intermediate 2- pyridine carboxylic acids (D)
The synthesis of the fluoro- 2- pyridine carboxylic acids (D1) of 6- 1. (2,6- difluorophenyl) -5-
(i) synthesis of the fluoro- 6- picolines (c) of 2- (2,6- difluorophenyl) -3-
By the fluoro- 6- picolines (a) of the bromo- 3- of 2- (279mg, 1.77mmol), 2,6- difluorophenyl boronic acids (b) (167mg,
0.88mmol) and potassium fluoride (169mg, 2.91mmol) is dissolved in tetrahydrofuran/water mixed solvent (10: 1,8ml), deaerates 5 minutes,
Pd is added under nitrogen protection2(dba)3(25mg, 0.044mmol) and tri-tert-butylphosphine (18mg, 0.088mmol), is heated to
60oC reacts 1 hour, is cooled to room temperature, and ethyl acetate (10ml) is added, and uses water (10ml) and saturated salt solution (10ml) successively
Washing, be dried over anhydrous sodium sulfate, filter after remove solvent, gained crude product is dissolved in ethyl alcohol (10ml), addition NaBH4 (17mg,
1 hour plus 10ml water are stirred at room temperature after 0.44mmol), then extracts (3x10ml) with ether, combined organic layer is used full
Crude product is obtained with after saline solution (10ml) washing, anhydrous sodium sulfate drying, removing solvent.Crude product silica gel column chromatography column purification
Product c (162mg, 0.73mmol) is obtained after (5: 1 petroleum ethers: dichloromethane).
(ii) synthesis of the fluoro- 2- pyridine carboxylic acids (D1) of 6- (2,6- difluorophenyl) -5-
Reflux after compound c (300mg, 1.34mmol) and potassium permanganate (423mg, 2.68mmol) are dissolved in 45ml water
It 24 hours, is filtered with diatomite after cooling, filtrate obtains white solid, filtrate acetic acid second after being neutralized to pH=1 with 6N hydrochloric acid
Ester extracts (3x50ml), and extract liquor is concentrated into after 10ml and extracts (3x5ml) with 1N sodium hydroxide solutions, in extract liquor concentrated hydrochloric acid
With to obtaining solid after pH=1.Say twice solid merge after obtain product D1 (153mg, 0.603mmol)
2. the synthesis of the 3- amidos -6- fluoro- 2-Pyridinecarboxylic Acids of (2,6- difluorophenyl) -5- (D2)
(i) synthesis of the fluoro- 2- pyridine carboxylic acid methyl esters (f) of 3- amidos -5-
The addition bromo- 5- fluorine pyridines (500mg, 2.62mmol) of 3- amidos 2- in autoclave, triethylamine (0.59ml,
4.16mmol), Pd (BINAP) Cl2(32mg, 0.039mmol), absolute methanol (20ml), CO gas is filled with after degassing
(60psi) is heated to 100 DEG C, and 12 hours postcoolings of reaction are to room temperature, then add Pd (BINAP) Cl2(10mg, 0.012mmol),
Continuation reacts 12 hours postcoolings to room temperature, filtering at 60psi carbon monoxide, 100 DEG C.Ethyl acetate is added in filtrate
(30ml), then washed with water (20ml) and saturated salt solution (20ml), anhydrous sodium sulfate drying, filtering obtains yellow after concentration
Grease product (f) (155mg, 0.917mmol).
(ii) synthesis of the fluoro- 2- pyridine carboxylic acid methyl esters (g) of the bromo- 5- of 3- amidos -6-
The fluoro- 2- pyridine carboxylic acids methyl esters (100mg, 0.588mmol) of 3- amidos -5- are dissolved in second cyanogen (2ml), are added at room temperature
Enter NBS (105mg, 0.647mmol), after 2 minutes plus water (10ml) terminates reaction.Reaction solution is extracted with ethyl acetate
(2x10ml), saturated common salt water washing (10ml), anhydrous sodium sulfate drying, filtering.The crude product silicon obtained after filtrate concentration
Product (g) (59mg, 0.235mmol) is obtained after glue column chromatography (20-60% ethyl acetate/petroleum ethers)
(iii) synthesis of the fluoro- 2- pyridine carboxylic acid methyl esters (h) of 3- amidos -6- (2,6- difluorophenyl) -5-
The synthetic method of reference compound c is obtained with the fluoro- 2- pyridine carboxylic acid methyl esters (g) of the bromo- 5- of 3- amidos -6- for raw material
Product (h).
(iv) synthesis of the fluoro- 2- pyridine carboxylic acids (D2) of 3- amidos -6- (2,6- difluorophenyl) -5-
By the fluoro- 2- pyridine carboxylic acid methyl esters (g) of the bromo- 5- of 3- amidos -6- (56mg, 0.20mmol) be dissolved in 1: 1 tetrahydrofuran/
Methanol mixed solvent (1ml) is added 1M lithium hydroxide solutions (0.4ml, 0.40mmol), 1N is used after being stirred at room temperature 2 hours
Hydrochloric acid is extracted with ethyl acetate (3x5ml) after being neutralized to pH=7, and extract liquor is washed with water (5ml) and saturated salt solution (5ml),
Anhydrous sodium sulfate is dried, and filtering obtains product (D2) (48mg, 0.18mml) after concentration.
3. the synthesis of the fluoro- 6- phenyl -2- pyridine carboxylic acids (D3) of 3- amidos -5-
With reference to the synthesis of D2,2,6- difluorophenyl boronic acids (b) therein are replaced that product (D3) is made with phenylboric acid (b1)
4. the synthesis of fluoro- (2,4 '-connect the pyridine) -6- carboxylic acids (D4) of 3-
With reference to the synthesis of D1,2,6- difluorophenyl boronic acids (b) therein are replaced that product is made with 4- pyridinylboronic acids (b2)
(D4)
The synthesis of the fluoro- 2- pyridine carboxylic acids (D5) of 6- 5. (2,6- difluorophenyl) -3-
With reference to the synthesis of D1, the fluoro- 6- picolines (a) of the bromo- 3- of 2- therein use the bromo- 3- of 6- fluoro- 2- picolines (k) generations
For obtained product (D5)
6. the synthesis of 6- (2,6- difluorophenyl) -5- trifluoromethyl -2- pyridine carboxylic acids (D6)
(i) 2- methoxycarbonyl -5- trifluoromethylpyridin -1- oxides (n)
5- trifluoromethyl -2- pyridine carboxylic acid methyl esters (m) (1.03g, 5.0mmol) and metachloroperbenzoic acid (1.2g,
It 7.0mmol) is dissolved in after dichloromethane (15ml) and being stirred 6 hours at 60 DEG C, purify to obtain with silica gel column chromatography after removing solvent
Product (n) (387mg, 1.8mmol).
(ii) synthesis (o) of the bromo- 3- trifluoromethyls -2- pyridine carboxylic acid methyl esters of 2-
POBr3 is added in 2- methoxycarbonyl -5- trifluoromethylpyridin -1- oxides (n) (221mg, 1.0mmol)
(2.5g, 8.Smmol) stirs 2 hours postcoolings to room temperature at 80oC, pours into 20ml water, mixture is extracted with ethyl acetate
It takes (3x10ml).Organic phase is washed (10ml) with saturation NaCl solution, is concentrated after anhydrous sodium sulfate drying, gained crude product silica gel
Product (o) (128mg, 0.45mmol) is obtained after column chromatography (5: 1 petrol ether/ethyl acetate).
(iii) synthesis of 6- (2,6- difluorophenyl) -5- trifluoromethyl -2- pyridine carboxylic acids (D6)
With reference to the synthesis of D3, the fluoro- 2- pyridine carboxylic acid methyl esters (g) of the bromo- 5- of 3- amidos -6- therein use the bromo- 3- fluoroforms of 2-
Base -2- pyridine carboxylic acid methyl esters (o) replaces being worth product (D6)
7. the synthesis of 3- amidos -6- (2,6- difluorophenyl) -5- trifluoromethyl -2- pyridine carboxylic acids (D7)
(i) synthesis (r) of the bromo- 3- nitros -5- trifluoromethyl pyridines of 2-
It is added in acetonitrile (25ml) solution of 3- nitro -5- trifluoromethyl pyridine -2- alcohol (q) (3.12g, 15mmol)
POBr3(8.6g, 30mmol).It is stirred at room temperature after being heated to reflux 4 hours 12 hours.Reaction solution pours into the carbonic acid quickly stirred
The aqueous solution (60ml) of hydrogen sodium (11g).Mixture extracts (3x20ml) with dichloromethane, organic phase water (20ml) and saturation chlorine
After changing sodium solution (10ml) washing, it is dried over anhydrous sodium sulfate, product (r) (2.44g, 9.0mmol) is obtained after concentration
(ii) synthesis (s) of 2- cyano -3- nitros -5- trifluoromethyl pyridines
It is added in toluene (50ml) solution of the bromo- 3- nitro -5- trifluoromethyl pyridines (r) of 2- (2.0g, 7.37mmol)
Tetrabutylammonium bromide (2.2g, 7.37mmol) and cuprous cyanide (CuCN) (1.98g, 22.2mmol), are heated to reflux 9 hours, cold
But to water (150ml) after room temperature, being added and ethyl acetate (150ml) mixes.Organic phase water (2x50ml) and saturated sodium-chloride
After solution (20ml) washing, it is dried over anhydrous sodium sulfate, product (s) (1.04g, 4.79mmol) is obtained after concentration
(iii) synthesis (t) of 3- amidos -2- cyano -5- trifluoromethyl pyridines
2- cyano -3- nitro -5- trifluoromethyl pyridines (s) (1.0g, 4.61mmol) are dissolved in ethyl acetate (20ml) and add afterwards
Enter 10% palladium/activated carbon (0.10g), it is straight after filtering, concentration to obtain crude product (t) after 1 atmospheric pressure stirring under hydrogen 18 hours
It connects for reacting in next step.
(iv) synthesis (u) of 3- amidos -5- trifluoromethyls -2- pyridine carboxylic acid formicesters
Above-mentioned 3- amido -2- cyano -5- trifluoromethyl pyridines (t) are dissolved in concentrated hydrochloric acid (5ml) and the mixing of methanol (5ml) is molten
Agent, reflux remove solvent after 48 hours, are produced after gained crude product silica gel column chromatography column purification (5: 1 petrol ether/ethyl acetate)
Product (u) (256mg, 1.16mmol)
(v) synthesis (v) of the bromo- 5- trifluoromethyls -2- pyridine carboxylic acid formicesters of 3- amidos -6-,
In 3- amido -5- trifluoromethyl -2- pyridine carboxylic acid formicesters (u) (1.0g, 4.55mmol) water (30ml), dense sulphur is added
The acetum (3ml) (10 minutes) of bromine (0.23ml, 4.55mmol) is added dropwise in sour (0.5ml, 9.1mmol) afterwards.Reactant is in room
The lower stirring of temperature is diluted after 24 hours with water (50ml), after being neutralized to pH=7 through sodium bicarbonate, is extracted with dichloromethane (3x30ml)
It taking, organic phase facilitates with saturated sodium bicarbonate solution (30ml), after water (30ml) and saturated nacl aqueous solution (20ml) washing, warp
Anhydrous sodium sulfate is dried, and product is obtained after gained crude product silica gel column chromatography column purification (5: 1 petrol ether/ethyl acetate) after concentration
(v) (843mg, 2.82mmol).
(vi) synthesis of 3- amidos -6- (2,6- difluorophenyl) -5- trifluoromethyl -2- pyridine carboxylic acids (D7)
With reference to the synthesis of D2, the fluoro- 2- pyridine carboxylic acids methyl esters 3- amine of 3- amidos -6- (2,6- difluorophenyl) -5- therein
The bromo- 5- trifluoromethyl -2- pyridine carboxylic acid formicesters (v) of base -6- replace that product (D7) is made.
Embodiment 1
Prepare 6- (2,6- difluorophenyl) -5- fluoro- N- (4- (piperidin-4-yl methoxyl group) pyrimidine -5- bases) -2- pyridinecarboxylics
Amine (1)
(1) preparation of 4- (((5- aminopyrimidine -4- bases) oxygroup) methyl) piperidines -1- t-butyl formates (C1)
Under the conditions of room temperature (25 DEG C), 4- methylols-piperidines -1- t-butyl formates are added in NaH (67mg, 2.8mmol)
(B1) then 4- chlorine pyrimidines -5- is added in THF (tetrahydrofuran) (10mL) solution & stir of (500mg, 2.32mmol) 1 hour
Amine (H) (346mg, 2.67mmol).Reactant is heated to 100 DEG C under nitrogen protection, in room temperature (20-30 after stirring 4 hours
DEG C) under vacuum rotating concentrate.Residue by silica gel chromatography column purification (eluent after concentration:10-30% ethyl acetate/petroleum ethers)
Obtain product 4- (((5- aminopyrimidine -4- bases) oxygroup) methyl) piperidines -1- t-butyl formates (Cl) (370mg, 1.2mmol).
(2) 4- (((5- (the fluoro- 2- pyridinecarboxylics amidos of 6- (2,6- difluorophenyl) -5-) pyrimidine-4-yl) oxygroup) methyl)
The preparation of piperidines -1- t-butyl formates (E1)
Compound (C1) (49mg, 0.16mmol), the fluoro- 2- pyridine carboxylic acids (D1) of compound 6- (2,6- difluorophenyl) -5-
(40mg, 0.17mmol), the mixture of HATU (77mg, 0.20mmol) and DIEA (888,0.50mmol) in DMF (5mL) exist
It is stirred 1 hour at 50 DEG C.It is diluted with ethyl acetate (50mL) after cooling, then with saturated common salt water washing.Organic phase is through Na2SO4It is dry
Vacuum rotating concentrates under room temperature (20-30 DEG C) after dry.(eluent after residue by silica gel chromatography column purification after concentration:10-
30% ethyl acetate/petroleum ether) obtain product 4- (((5- (6- (2,6- difluorophenyl) -5- fluorine picolinamides base) pyrimidine -4-
Base) oxygroup) methyl) piperidines -1- t-butyl formates (E1) 30mg, 0.0596mmol).
(3) the fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (piperidin-4-yl methoxyl group) pyrimidine -5- bases) -2- pyridinecarboxylics
The preparation (1) of amine
Under the conditions of room temperature (25 DEG C), by TFA (trifluoracetic acid) (0.5mL) be added compound (E1) (20mg,
CH 0.0394mmol)2Cl2(1mL) solution stirs 10 minutes, under room temperature (25 DEG C) after vacuum rotating concentration, by residue
It is dissolved in CH2Cl2(10mL), solution are washed with the sodium hydroxide (5mL) of 1 equivalent and saturated salt solution (5mL) respectively, organic phase warp
Na2SO4Product 6- (2,6- difluorophenyl) -5- fluorine N- (4- (piperidines is made in vacuum rotating concentration under room temperature (25 DEG C) after drying
4- ylmethoxies) pyrimidine -5- bases) picolinamide (1) (12mg, 0.025mmol).
Embodiment 2
Prepare N- (4- (azetidin -3- ylmethoxies) pyrimidine -5- bases) fluoro- 2- pyridines of -6- (2,6- difluorophenyl) -5-
Formamide (2)
Preparation method is with reference to embodiment 1.The wherein compound B-11 of step (1) 3- methylols-azetidine -1- formic acid
The tert-butyl ester (B2) replaces, and product 2 is made.
Embodiment 3
Prepare 6- (2,6- difluorophenyl) -5- fluorine N- (4- (piperidines 4- bases oxygroup) pyrimidine -5- bases) -2- pyridine carboxamides
(3)
Preparation method is with reference to embodiment 1.The wherein compound B-11 of step (1) 4- hydroxyls-piperidines -1- t-butyl formates (B3)
Instead of product 3 is made.
Embodiment 4
Prepare 6- (2,6- difluorophenyl) -5- fluorine N- (4- (pyrrolidin-3-yl oxygroup) pyrimidine -5- bases) -2- pyridinecarboxylics
Amine (4)
Preparation method is with reference to embodiment 1.The wherein compound B-11 of step (1) 3- hydroxy-pyrrolidine -1- t-butyl formates
(B4) it replaces, product 4 is made.
Embodiment 5
Prepare 6- (2,6- difluorophenyl) -5- fluoro- N- (4- (piperidines -3- bases oxygroup) pyrimidine -5- bases) -2- pyridine carboxamides
(5)
Preparation method is with reference to embodiment 1.The wherein compound B-11 of step (1) 3- hydroxy piperidine -1- t-butyl formates
(B5) it replaces, product 5 is made.
Embodiment 6
Prepare N- (4- (azacyclo- hept- 4- bases oxygroup) pyrimidine -5- bases) fluoro- 2- pyridines first of -6- (2,6- difluorophenyl) -5-
Amide (6)
Preparation method is with reference to embodiment 1.The wherein compound B-11 of step (1) is with 4- hydroxy-azepane -1- formic acid uncles
Butyl ester (B6) replaces, and product 6 is made.
Embodiment 7
Prepare 6- (2,6- difluorophenyl) -5- fluoro- N- (4- (piperidines -3- ylmethoxies) pyrimidine -5- bases) -2- pyridinecarboxylics
Amine (7)
Preparation method is with reference to embodiment 1.The wherein compound B-11 of step (1) 4- methylols-piperidines -1- t-butyl formates
(B7) it replaces, product 7 is made.
Embodiment 8
Prepare 6- (2,6- difluorophenyl) -5- fluoro- N- (4- (pyrrolidin-3-yl methoxyl group) pyrimidine -5- bases) -2- pyridine first
Amide (8)
Preparation method is with reference to embodiment 1.The wherein compound B-11 of step (1) 3- methylols-tertiary fourth of pyrrolidines -1- formic acid
Ester (B8) replaces, and product 8 is made.
Embodiment 9
Prepare N- (4- (azetidin -3- bases oxygroup) pyrimidine -5- bases) fluoro- 2- pyridines first of -6- (2,6- difluorophenyl) -5-
Amide (9)
Preparation method is with reference to embodiment 1.The wherein compound B-11 of step (1) is with 3- hydroxyl -1- azetidinecarboxylic acid uncles
Butyl ester (B9) replaces, and product 9 is made.
Embodiment 10
Prepare N- (4- (((1r, 4r) -4- aminocyclohexyls) oxygroup) pyrimidine -5- bases) -6- (2,6- difluorophenyl) -5-
Fluoro- 2- pyridine carboxamides (10)
Preparation method is with reference to embodiment 1.The wherein trans- 4- hydroxy-cyciohexyls-carbamic acid of the compound B-11 of step (1)
The tert-butyl ester (B10) replaces, and product 10 is made.
Embodiment 11
Prepare N- (4- ((3- aminocyclohexyls) oxygroup) pyrimidine -5- bases) fluoro- 2- pyridines of -6- (2,6- difluorophenyl) -5-
Formamide (11)
Preparation method is with reference to embodiment 1.The wherein compound B-11 of step (1) 3- hydroxy-cyciohexyls-tertiary fourth of carbamic acid
Ester (B11) replaces, and product 11 is made.
Embodiment 12
Prepare N- (4- (3- amine propoxyl group) pyrimidine -5- bases) fluoro- 2- pyridine carboxamides of -6- (2,6- difluorophenyl) -5-
(12)
Preparation method is with reference to embodiment 1.The wherein compound B-11 of step (1) 3- hydroxypropylamine -1- t-butyl formates
(B12) it replaces, product 12 is made.
Embodiment 13
Prepare 6- (2,6- difluorophenyl) -5- fluoro- N- (4- (3- (methylamino) propoxyl group) pyrimidine -5- bases) -2- pyridine first
Amide (13)
Preparation method is with reference to embodiment 1.The wherein compound B-11 of step (1) is with N- methyl -3- hydroxypropylamine -1- formic acid uncles
Butyl ester (B13) replaces, and product 13 is made.
Embodiment 14
Prepare 6- (2,6- difluorophenyl)-N- (4- (3- (dimethyl amido) propoxyl group) pyrimidine -5- bases) fluoro- 2- pyrroles of -5-
Pyridine formamide (14)
Preparation method is with reference to embodiment 1.Wherein compound B-11 N, the N- dimethyl -3- hydroxypropylamines (B14) of step (1)
Instead of step (3) deprotection is omitted, and product 14 is made.
Embodiment 15
Prepare N- (4- (4- amidos butoxy) pyrimidine -5- bases) fluoro- 2- pyridine carboxamides of -6- (2,6- difluorophenyl) -5-
(15)
Preparation method is with reference to embodiment 1.The wherein compound B-11 of step (1) 4- hydroxyl butylamine -1- t-butyl formates
(B15) it replaces, product 15 is made.
Embodiment 16
Prepare 6- (2,6- difluorophenyl) -5- fluoro- N- (4- (4- (methylamino) butoxy) pyrimidine -5- bases) -2- pyridine first
Amide (16)
Preparation method is with reference to embodiment 1.The wherein compound B-11 of step (1) is with N- methyl -4- hydroxyl butylamine -1- formic acid uncles
Butyl ester (B16) replaces, and product 16 is made.
Embodiment 17
Prepare 6- (2,6- difluorophenyl) -5- fluoro- N- (4- (3- hydroxy propyloxy groups) pyrimidine -5- bases) -2- pyridine carboxamides
(17)
Preparation method is with reference to embodiment 1.Wherein the compound B-11 of step (1) is replaced with 1,3-PD (B17), step
(3) deprotection is omitted, and product 17 is made.
Embodiment 18
Prepare 6- (2,6- difluorophenyl) -5- fluoro- N- (4- (3- hydroxybutoxies) pyrimidine -5- bases) -2- pyridine carboxamides
(18)
Preparation method is with reference to embodiment 1.Wherein the compound B-11 of step (1) is replaced with 1,3-BDO (B18), step
(3) deprotection is omitted, and product 18 is made.
Embodiment 19
Prepare 6- (2,6- difluorophenyl) -5- fluoro- N- (4- (4- hydroxy butoxies) pyrimidine -5- bases) -2- pyridine carboxamides
(19)
Preparation method is with reference to embodiment 1.Wherein the compound B-11 of step (1) is replaced with 1,4-butanediol (B19), step
(3) deprotection is omitted, and product 19 is made.
Embodiment 20
Prepare 6- (2,6- difluorophenyl) -5- fluoro- N- (4- ((4- hydroxy-4-methyls amoxy) pyrimidine -5- bases) -2- pyrroles
Pyridine formamide (20)
Preparation method is with reference to embodiment 1.The wherein compound B-11 4- methyl-1s of step (1), 4- pentanediols (B20) generation
It replaces, step (3) deprotection is omitted, and product 20 is made.
Embodiment 21
Prepare 6- (2,6- difluorophenyl)-N- (4- (3,4- dihydroxy butoxy) pyrimidine -5- bases) fluoro- 2- pyridines first of -5-
Amide (21)
(1) 6- (2,6- difluorophenyl)-N- (4- (2- (2,2- dimethyl -1,3-dioxolane -4-) ethyoxyl -) pyrimidines -
5- yls) the fluoro- 2- pyridine carboxamides (E21) of -5- preparation
Preparation method with reference to the method for step (1) and (2) in embodiment 1, wherein step (1) compound B-11 use (2,
2- dimethyl -1,3- dioxolanes -4- bases) ethyl alcohol (B21) replacement, product E21 is made.
(2) 6- (2,6- difluorophenyl)-N- (4- (3,4- dihydroxy butoxy) pyrimidine -5- bases) the fluoro- 2- pyridinecarboxylics of -5-
The preparation of amine (21)
Under the conditions of room temperature (25 DEG C), E21 (20mg, 0.042mmol) is dissolved in methanol (2mL), concentrated hydrochloric acid is added afterwards
(0.5mL), stirring use 10%Na after 4 hours2CO3Solution is neutralized to pH=7, adds water (20mL) by vacuum filter and 25 DEG C of skies
Product 21 (11mg, 0.025mmol) is obtained after gas drying.
Embodiment 22
The fluoro- N- of preparation 6- (2,6- difluorophenyl) -5- [4- (oxinane -4- methoxyl groups) pyrimidine -5- bases) -2- pyridine first
Amide (22)
Preparation method is with reference to embodiment 1.Wherein the compound B-11 of step (1) is replaced with oxinane -4- methanol (B22),
Step (3) deprotection is omitted, and product 22 is made.
Embodiment 23
Prepare 3- amidos -6- (2,6- difluorophenyl) -5- fluoro- N- (4- (piperidin-4-yl methoxyl group) pyrimidine -5- bases) -2-
Pyridine carboxamide (23)
Preparation method is with reference to embodiment 1.The wherein compound D1 of step (2) 3- amidos -6- (2,6- difluorophenyl) -
The fluoro- 2-Pyridinecarboxylic Acids of 5- (D2) replace, and product 23 is made.
Embodiment 24
Prepare 3- amidos -6- (2,6- difluorophenyl) -5- fluoro- N- (4- (pyrrolidin-3-yl oxygroup) pyrimidine -5- bases) -2-
Pyridine carboxamide (24)
Preparation method is with reference to embodiment 23.The compound B-11 of wherein step (1) is replaced with B4, and product 24 is made.
Embodiment 25
Prepare 3- amidos -6- (2,6- difluorophenyl) -5- fluoro- N- (4- (piperidin-4-yl oxygroup) pyrimidine -5- bases) -2- pyrroles
Pyridine formamide (25)
Preparation method is with reference to embodiment 23.The compound B-11 of wherein step (1) is replaced with B3, and product 25 is made.
Embodiment 26
It is fluoro- to prepare 3- amidos-N- (4- (azacyclo- hept- 4- bases oxygroup) pyrimidine -5- bases) -6- (2,6- difluorophenyl) -5-
2- pyridine carboxamides (26)
Preparation method is with reference to embodiment 23.The compound B-11 of wherein step (1) is replaced with B6, and product 26 is made.
Embodiment 27
Prepare 3- amidos-N- (4- (((1r, 4r) -4- aminocyclohexyls) oxygroup) pyrimidine -5- bases) -6- (2,6- difluorobenzenes
Base) the fluoro- 2- pyridine carboxamides (27) of -5-
Preparation method is with reference to embodiment 23.The compound B-11 of wherein step (1) is replaced with B10, and product 27 is made.
Embodiment 28
Prepare the fluoro- N- of 3- amidos -6- (2,6- difluorophenyl) -5- (4- (pyrrolidin-3-yl methoxyl group) pyrimidine -5- bases -2-
Pyridine carboxamide (28)
Preparation method is with reference to embodiment 23.The compound B-11 of wherein step (1) is replaced with B8, and product 28 is made.
Embodiment 29
Prepare N- (4- ((1- amido -3- chloropropyl -2- bases) oxygroup) pyrimidine -5- bases) -6- (2,6- difluorophenyl) -5-
Fluoro- 2- pyridine carboxamides (29)
Compound 9 (20mg, 0.050mmol) is dissolved in 4 moles of HCl methanol solutions (1ml) at room temperature, after stirring 4 hours
Solvent is removed, obtained solid is dried in vacuo after being washed with ether, obtains compound 29 (21mg, 0.044mmol)
Embodiment 30
Prepare N- (4- (3- amidos -2- (chloromethyl) propoxyl group) pyrimidine -5- bases) fluoro- 2- of -6- (2,6- difluorophenyl) -5-
Pyridine carboxamide (30)
Preparation method is with reference to embodiment 29.Compound 9 therein is replaced with 2, and product 30 is made.
Embodiment 31
It is fluoro- to prepare 3- amidos-N- (4- (azetidin -3- bases oxygroup) pyrimidine -5- bases) -6- (2,6- difluorophenyl) -5-
2- pyridine carboxamides (31)
Preparation method is with reference to embodiment 23.The compound B-11 of wherein step (1) is replaced with B9, and product 31 is made.
Embodiment 32
Prepare 3- amidos-N- (4- (azetidin -3- ylmethoxies) pyrimidine -5- bases) -6- (2,6- difluorophenyl) -5-
Fluoro- 2- pyridine carboxamides (32)
Preparation method is with reference to embodiment 23.The compound B-11 of wherein step (1) is replaced with B2, and product 32 is made.
Embodiment 33
Prepare 3- amidos-N- (4- ((1- amido -3- chloropropyl -2- bases) oxygroup) pyrimidine -5- bases) -6- (2,6- difluorobenzenes
Base) the fluoro- 2- pyridine carboxamides (29) of -5-
Preparation method is with reference to embodiment 29.Compound 9 therein is replaced with compound 31, and product 33 is made.
Embodiment 34
Prepare 3- amidos-N- (4- (3- amidos -2- (chloromethyl) propoxyl group) pyrimidine -5- bases) -6- (2,6- difluorophenyl) -
The fluoro- 2- pyridine carboxamides (34) of 5-
Preparation method is with reference to embodiment 29.Compound 9 therein is replaced with compound 32, and product 34 is made.
Embodiment 35
Prepare 3- amidos -5- fluoro- 6- phenyl-N- (4- (pyrrolidin-3-yl oxygroup) pyrimidine -5- bases) -2- pyridine carboxamides
(35)
Preparation method is with reference to embodiment 1.The compound B-11 of wherein step (1) is replaced with B4, and the compound D1 of step (2) is used
The fluoro- 6- phenyl of 3- amidos -5-) -2-Pyridinecarboxylic Acid (D3) replacement, product 35 is made.
Embodiment 36
Prepare the fluoro- N- of 3- (4- (piperidin-4-yl oxygroup) pyrimidine -5- bases)-(2,4 '-bipyridyl) -6- formamides (36)
Preparation method is with reference to embodiment 1.The compound B-11 of wherein step (1) is replaced with B3, and the compound D1 of step (2) is used
Fluoro- (2,4 '-connect the pyridine) -6- carboxylic acids (D4) of 3- replace, and product 36 is made.
Embodiment 37
Prepare N- (4- (azacyclo- hept- 4- bases oxygroup) pyrimidine -5- bases) fluoro- 2- pyridines first of -6- (2,6- difluorophenyl) -3-
Amide (37)
Preparation method is with reference to embodiment 1.The compound B-11 of wherein step (1) is replaced with B6, and the compound D1 of step (2) is used
6- (2,6- difluorophenyl) -3- fluorine picolinic acids (D5) replace, and product 37 is made.
Embodiment 38
Prepare N- (4- (azacyclo- hept- 4- bases oxygroup) pyrimidine -5- bases) the fluoro- 6- of -5- (the fluoro- 6- methoxyphenyls of 2-) -2-
Pyridine carboxamide (38)
Compound 6 (10mg, 0.023mmol) is dissolved in the methanol solution (1ml) of 0.1M sodium hydroxides, is stirred at 50 DEG C
2 hours.Obtained solid is washed with water after removing solvent, through being dried to obtain product 38 (8mg, 0.018mmol).
Embodiment 39
Prepare N- (4- (azacyclo- hept- 4- bases oxygroup) pyrimidine -5- bases) -6- (2,6- difluorophenyl) -5- trifluoromethyls -2-
Pyridine carboxamide (39)
Preparation method is with reference to embodiment 1.The wherein compound B-11 of step (1) is with 4- hydroxy-azepane -1- formic acid uncles
Butyl ester (B6) replaces, and the compound D1 of step (2) is with 6- (2,6- difluorophenyl) -5- trifluoromethyl -2- pyridine carboxylic acid (D6) generations
It replaces, product 39 is made.
Embodiment 40
Prepare 6- (2,6- difluorophenyl) -5- fluoro- N- (4- (piperidin-4-yl methoxyl group) pyrimidine -5- trifluoromethyl -2- pyrroles
Pyridine formamide (40)
Preparation method is with reference to embodiment 1.The wherein compound D1 of step (2) 6- (2,6- difluorophenyl) -5- fluoroforms
Base -2- pyridine carboxylic acids (D6) replace, and product 40 is made.
Embodiment 41
Prepare N- (4- (azetidin -3- ylmethoxies) pyrimidine -5- bases) -6- (2,6- difluorophenyl) -5- trifluoromethyls -
2- pyridine carboxamides (41)
Preparation method is with reference to embodiment 1.The wherein compound B-11 of step (1) 3- methylols-azetidine -1- formic acid
The tert-butyl ester (B2) replaces, compound D1 6- (2,6- the difluorophenyl) -5- trifluoromethyl -2- pyridine carboxylic acids (D6) of step (2)
Instead of product 41 is made.
Embodiment 42
Prepare 6- (2,6- difluorophenyl)-N- (4- (piperidin-4-yl oxygroup) pyrimidine -5- bases) -5- trifluoromethyl -2- pyridines
Formamide (42)
Preparation method is with reference to embodiment 1.The wherein compound B-11 of step (1) 4- hydroxyls-piperidines -1- t-butyl formates (B3)
Instead of the compound D1 of step (2) is replaced with 6- (2,6- difluorophenyl) -5- trifluoromethyl -2- pyridine carboxylic acids (D6), and production is made
Object 42.
Embodiment 43
Prepare N- (4- (((1r, 4r) 4- aminocyclohexyls) oxygroup) pyrimidine -5- bases) -6- (2,6- difluorophenyl) -5- three
Methyl fluoride -2- pyridine carboxamides (43)
Preparation method is with reference to embodiment 1.The wherein trans- 4- hydroxy-cyciohexyls-carbamic acid of the compound B-11 of step (1)
The tert-butyl ester (B10) replaces, compound D1 6- (2,6- the difluorophenyl) -5- trifluoromethyl -2- pyridine carboxylic acids (D6) of step (2)
Instead of product 43 is made.
Embodiment 44
Preparation 6- (2,6- difluorophenyl)-N- [4- (tetrahydropyran -4-base) methoxyl group) pyrimidine -5- bases) -5- fluoroforms
Base -2- pyridine carboxamides (44)
Preparation method is with reference to embodiment 1.Wherein the compound B-11 of step (1) is replaced with oxinane -4- methanol (B22),
The compound D1 of step (2) is replaced with 6- (2,6- difluorophenyl) -5- trifluoromethyl -2- pyridine carboxylic acids (D6), step (3) remove-insurance
Shield is omitted, and product 44 is made.
Embodiment 45
Prepare 3- amidos-N- (4- (azacyclo- hept- 4- bases oxygroup) pyrimidine -5- bases) -6- (2,6- difluorophenyl) -5- fluorine pyrroles
Pyridine amide (45)
Preparation method is with reference to embodiment 1.The wherein compound B-11 of step (1) is with 4- hydroxy-azepane -1- formic acid uncles
Butyl ester (B6) replaces, compound D1 3- amidos -6- (2,6- the difluorophenyl) -5- trifluoromethyl -2- pyridine carboxylic acids of step (2)
(D7) it replaces, product 45 is made.
Embodiment 46
Prepare 3- amidos -6- (2,6- difluorophenyl) -5- fluoro- N- (4- (piperidin-4-yl methoxyl group) pyrimidine -5- fluoroforms
Base -2- pyridine carboxamides (46)
Preparation method is with reference to embodiment 1.The wherein compound D1 of step (2) 3- amidos -6- (2,6- difluorophenyl) -5-
Trifluoromethyl -2- pyridine carboxylic acids (D7) replace, and product 46 is made.
Embodiment 47
Prepare 3- amidos-N- (4- (azetidin -3- ylmethoxies) pyrimidine -5- bases) -6- (2,6- difluorophenyl) -5- three
Methyl fluoride -2- pyridine carboxamides (47)
Preparation method is with reference to embodiment 1.The wherein compound B-11 of step (1) 3- methylols-azetidine -1- formic acid
The tert-butyl ester (B2) replaces, compound D1 3- amidos -6- (2,6- difluorophenyl) -5- trifluoromethyl -2- pyridine first of step (2)
Sour (D7) is replaced, and product 47 is made.
Embodiment 48
Prepare 3- amidos -6- (2,6- difluorophenyl)-N- (4- (piperidin-4-yl oxygroup) pyrimidine -5- bases) -5- fluoroforms
Base -2- pyridine carboxamides (48)
Preparation method is with reference to embodiment 1.The wherein compound B-11 of step (1) 4- hydroxyls-piperidines -1- t-butyl formates (B3)
Instead of the compound D1 of, step (2) with 3- amidos -6- (2,6- difluorophenyl) -5- trifluoromethyl -2- pyridine carboxylic acid (D7) generations
It replaces, product 48 is made.
Embodiment 49
Prepare 3- amidos-N- (4- (((1r, 4r) -4- aminocyclohexyls) oxygroup) pyrimidine -5- bases) -6- (2,6- difluorobenzenes
Base) -5- trifluoromethyl -2- pyridine carboxamides (49)
Preparation method is with reference to embodiment 1.The wherein trans- 4- hydroxy-cyciohexyls-carbamic acid of the compound B-11 of step (1)
The tert-butyl ester (B10) replaces, compound D1 3- amidos -6- (2,6- the difluorophenyl) -5- trifluoromethyl -2- pyridines of step (2)
Formic acid (D7) replaces, and product 49 is made.
Embodiment 50
Prepare 3- amido -6- phenyl-N- (4- (pyrrolidin-3-yl oxygroup) pyrimidine -5- bases) -5- trifluoromethyl -2- pyridines
Formamide (50)
Preparation method is with reference to embodiment 1.The wherein compound B-11 of step (1) 3- hydroxy-pyrrolidine -1- t-butyl formates
(B4) it replaces, compound D1 3- amidos -6- (2,6- the difluorophenyl) -5- trifluoromethyl -2- pyridine carboxylic acids (D7) of step (2)
Instead of product 50 is made.
Embodiment 51
Prepare N- (4- (3- amidos -2- (chloromethyl) propoxyl group) pyrimidine -5- bases) -6- (2,6- difluorophenyl) -5- trifluoros
Methyl -2- pyridine carboxamides (51)
Preparation method is with reference to embodiment 29.Compound 9 therein is replaced with compound 41, and product 51 is made.
Embodiment 52
Prepare 3- amidos-N- (4- (3- amidos -2- (chloromethyl) propoxyl group) pyrimidine -5- bases) -6- (2,6- difluorophenyl) -
5- trifluoromethyl -2- pyridine carboxamides (52)
Preparation method is with reference to embodiment 29.Compound 9 therein is replaced with compound 47, and product 52 is made.
Embodiment 53
Prepare N- (4- (3- amidos -2- (methylol) propoxyl group) pyrimidine -5- bases) fluoro- 2- of -6- (2,6- difluorophenyl) -5-
Pyridine carboxamide (53)
Compound 2 (40mg, 0.096mmol) is dissolved in 1: 1 trifluoracetic acid and methanol solution (1ml), stirring 4 at room temperature
It is neutralized with saturated sodium carbonate solution after hour, removes solvent, obtained solid silica gel column chromatography column purification (1: 1 ethyl acetate/oil
Ether) after obtain compound 53 (8mg, 0.018mmol)
Embodiment 54
Prepare 3- amidos-N- (4- (3- amidos -2- (methylol) propoxyl group) pyrimidine -5- bases) -6- (2,6- difluorophenyl) -
The fluoro- 2- pyridinecarboxylics amine amides (54) of 5-
Preparation method is with reference to embodiment 53.Compound 2 therein is replaced with compound 32, and product 54 is made.
Embodiment 55
Prepare N- (4- (3- amidos -2- (methylol) propoxyl group) pyrimidine -5- bases) -6- (2,6- difluorophenyl) -5- trifluoros
Methyl -2- pyridine carboxamides (55)
Preparation method is with reference to embodiment 53.Compound 2 therein is replaced with compound 41, and product 55 is made.
Embodiment 56
Prepare 3- amidos-N- (4- (3- amidos -2- (methylol) propoxyl group) pyrimidine -5- bases) -6- (2,6- difluorophenyl) -
5- trifluoromethyl -2- pyridine carboxamides (56)
Preparation method is with reference to embodiment 53.Compound 2 therein is replaced with compound 47, and product 56 is made.
The structural analysis data of prepared compound in 1. embodiment of the present invention of table
Embodiment 57
R3Substituent group inhibits the compounds of this invention the influence of PIM-1 kinase activities
In order to verify R3Substituent group inhibits the compounds of this invention (general formula I) influence of PIM-1 kinase activities, we design
6 groups have different structure, carry the compound of different functional groups, and the method that above-described embodiment describes is used in combination to synthesize this 6 groups
Compound.In this 6 groups of compounds, between the compound a and compound b, c in every group of compound, in addition to R3Substituent group is different outer,
The molecular structure of other parts is identical.The wherein R of compound a3=H, the R of compound b3=F, the R of compound c3=CF3。
The difference of their bioactivity has directly displayed R3Influence to compound activity.This 6 groups of compounds are to inhibiting PIM-1 kinases
IC50It is listed in table 2.
Table 2.R3Substituent group is on the active influence of the compounds of this invention
The data of table 2 show, the IC of the compound b and c of all 5- substitutions50It is all smaller than corresponding compound a, for example
The IC of compound 1a50It is 3.75 times of 1b, therefore the activity of compound 1b is 3.75 times of compound 1a.In this 6 groups of compounds
In, it is 2.7 times (compound 4a/4b) that activity, which improves at least, is improved most for 5.9 times (compound 5a/5b), average out to
4.2 again.This result shows that, as the R in the compounds of this invention3When substituent group is F or other substituent groups, active ratio does not have
Substituted base (R3For H) respective compound be significantly improved, this is different from existing knowledge.
Embodiment 58
The detection of the biological activity of the compounds of this invention and result.
The bioactivity of the compounds of this invention, which is entrusted, protects (Changping District, Beijing life section of scientific and technological (Beijing) Co., Ltd of promise
The Building E of study column road 29) it is responsible for test.Test method is kinases PIM active determination in vitro --- IMAP fluorescence polarization methods
Kinases PIM active determination in vitro --- IMAP fluorescence polarization methods
1. principle
PIM is serine/threonine protein kitase, the small peptide substrate phosphorylation that can mark 5-FAM.It is unphosphorylated
Substrate not can be incorporated on binding reagents (immobilization metal chelates pearl), and fluorescence polarization value is relatively low.And the small peptide of phosphorylation can be with
It is attached on binding reagents so that fluorescence polarization value increases.The high low reaction of the small peptide substrate phosphorylation degree of 5-FAM labels
The size of PIM kinase activities.By testing inhibiting effect of the compounds of this invention under a certain concentration to PIM kinase activities,
It can determine rejection ability of these compounds to PIM kinase activities.
2. instrument
EnVision, PerkinElmer
3. reagent and 384 orifice plates
PIM1 (Millipore catalog number (Cat.No.) 14-573) (is purchased from Millipore Corporation companies of the U.S.)
PIM2 (Millipore catalog number (Cat.No.) 14-607) (is purchased from Millipore Corporation companies of the U.S.)
The small peptide (5-FAM-RSRHSSYPAGT, AnaSpec catalog number (Cat.No.) #63801) of 5-FAM labels (is purchased from the U.S.
AnaSpec Inc. companies)
IMAP FP Screening Express kit (IMAP FP screening reagents box) (Molecular Devices mesh
Record #R8127) (being purchased from Molecular Devices companies of the U.S.)
IMAP Progressive binding reagent (IMAP bonding agents)
IMAP Progressive binding buffer A (5X) (IMAP combination buffer A)
IMAP Progressive binding buffer B (5X) (IMAP combination buffer B)
384-well black plate (Coming, catalog number (Cat.No.) #3573) (are purchased from Coming companies of the U.S.)
4. surveying buffer solution living
Tris-HCl (trishydroxymethylaminomethane-hydrochloric acid) (pH7.2):10mM
MgCl2:10mM
Triton X-100 (Triton X-100 X-100):0.01%
DTT (dithiothreitol (DTT)):2mM
5. step
The compounds of this invention is made by above-described embodiment used in this experiment.
A) the compounds of this invention liquid storage of 10mM is diluted to respective concentration with 100%DMSO (dimethyl sulfoxide (DMSO)), then changes
It closes object and dilutes 10 times with buffer solution (dithiothreitol (DTT)) living is surveyed, make DMSO a concentration of 10%.
B) live body system 10ul:
1ul compounds are with 4ul enzymes (PIM-1 and the final concentration of 3nM of PIM-3 final concentration of 0.025nM, PIM-2) in 23 DEG C
It is incubated 15 minutes, 2.5ul ATP are added, and (in the determination of activity of PIM-1, PIM-2 and PIM-3, the final concentration of ATP is respectively
30uM, 5uM and 30uM) and 2.5ul 5-FAM label small peptide (final concentration of 100nM) starting reaction.React on 23 DEG C of progress
60 minutes.Compound is replaced with DMSO in the reaction system of maximum value control, is lived with survey in the reaction system of minimum value control slow
Fliud flushing (dithiothreitol (DTT)) replaces enzyme.
C) be added 30ul IMAP bonding agents (containing 75%IMAP combination buffers A, 25%IMAP combination buffer B, 1/
600 immobilization metals chelate pearl), reaction is terminated, is incubated at room temperature 60 minutes.
D) read plate obtains fluorescence polarization value mP, exciting light 485nm, transmitting light 530nm.
6. data processing
Suppression percentage=(fluorescence polarization value mP- minimum values) × 100/ (maximum value-minimum value)
Tested through PIM kinases biochemical activity methods of testing, the compound in all embodiments all to PIM-1, PIM-2 and
The activity of PIM-3 kinases has apparent inhibiting effect, IC50In the range of 0.1-500nM.
Claims (36)
1. with compounds of formula I, its stereoisomer, tautomer and its pharmaceutical salts
In above-mentioned Formulas I
R1For-H ,-NH2, halogen ,-CN ,-NO2Or C1-8Oxyl;
R2For-H, halogen ,-NH2, C1-8Alkyl or C1-8Oxyl;
R3For halogen ,-OC1-3Alkyl, halogenated methyl ,-CN and-NO2;
R4For-H ,-C (=O)-R5, the C of with or without substituent group1-8Alkyl, C3-7Cyclic hydrocarbon radical, 4-7 circle heterocyclic rings base, 5-10 members
Aryl and heterocyclic aryl;
R5For the C of with or without substituent group1-8Alkyl, C1-8Oxyl, C3-7Cyclic hydrocarbon radical;
R6For with or without the 5 or 6 yuan of aryl or heteroaryl of substituent group;Aryl or heteroaryl can have one or more substitutions
Base, these substituent groups are respectively-CN ,-NO2, halogen ,-OH ,-NH2, C1-4Oxyl, C1-4Substituted amido, C1-4Alkyl or
C3-6Cyclic hydrocarbon radical;
R7For-H or with or without substituent group C1-4Alkyl;
R22For the C of with or without substituent group1-8Alkyl or the group defined for following formula:
Wherein R23, R24And R25Respectively halogen ,-OR15,-NR16R17,-C (=O) NR18R19Or with or without substituent group
C1-8Alkyl;
R15、R16、R17、R18、R19The C of respectively-H or with or without substituent group1-8Alkyl
G1For CH or N;
G2For NR28、CHR29Or O;
B1 and B2 is 0,1,2 or 3;
B3 is 0,1,2;
B4 is 0,1;
R26And R27The C of respectively-H or with or without substituent group1-8Alkyl;
R28For-H, the C of with or without substituent group1-8Alkyl, C3-7Cyclic hydrocarbon radical, C3-7Heterocyclic hydrocarbyl ,-C (=O) R30,-C (=
O)OR30Or-C (=O) NHR30;R29For-H ,-OH, the C of with or without substituent group1-8Alkyl, C3-7Cyclic hydrocarbon radical, C3-7Heterocycle
Alkyl ,-NHR30,-C (=O) OR30Or-C (=O) NHR30;R30For-H or the C of with or without substituent group1-8Alkyl;
The substituent group is selected from hydroxyl, nitro, amino, imino group, cyano, halogen, thio group, sulfonyl, thio acylamino
(thioamido), amidino groups, imidino, oxo amidino groups (oxamidino), methoxamidino (methoxamidino), guanidine radicals, sulphur
Acylamino-, carboxyl, formoxyl, C1-8Alkyl, halogenated C1-8Alkyl, C1-8Alkyl amino, halogenated C1-8Alkyl amino, C1-8Alkoxy,
Halogenated C1-8Alkoxy, C1-8Alkoxyalkyl, alkyl-carbonyl, amino carbonyl, aryl carbonyl, aromatic alkyl carbonyl, heteroaryl;
Halogen is F, Cl, Br or I;
" heterocycle " refers to containing there are one heteroatomic wantonly 3 or 4 Yuans rings selected from nitrogen, oxygen and sulphur or being selected from containing one to three
The heteroatomic 5- or 6- person's ring of nitrogen, oxygen or sulphur;There is wherein described 5- person's ring 0-2 double bond, 6- person's ring to have 0-3 pairs
Key;
" heteroaryl " refers to that have 1 to 4 hetero atom in aromatic ring as annular atom and remaining annular atom be carbon
The aryl of atom.
2. compound according to claim 1, which is characterized in that
R22For with or without the cyclopenta of substituent group, cyclohexyl, suberyl, azetidinyl, pyrrolidinyl, piperidyl, piperazine
Piperazine base, nitrogen heterocyclic heptyl, cyclobutylmethyl, cyclopentyl-methyl, cyclohexyl methyl, CycloheptylmethyI, azetidinyl first
Base, pyrrolidinylmethyl, piperidino methyl, piperizinylmethyl, azepan ylmethyl, epoxy butane ylmethyl, tetrahydrochysene furan
It mutters ylmethyl or oxinane ylmethyl;The R with substituent group22Can there are one or more substituent groups, each respectively can
To be-NH2,-OH, methyl, ethyl or methoxyl group.
3. compound according to claim 1, which is characterized in that
R22For the C with substituent group2-C5Alkyl, can have up to 4 substituent groups on these alkyl, and the substituent group is F, Cl, Br,
I, NH2, methylamino, ethylamino-, Propylamino, dimethylamino, diethylin, hydroxyl, methyl, ethyl, propyl ,-CH2OH,-CH2
(OH)CH3,-CH2CH2OH, monohaloalkyl methyl, polyhalo methyl, monohaloalkyl ethyl, polyhalo ethyl, C1-4Alkyl-O-, C1-4Hydrocarbon
Base-S-.
4. according to claim 1-3 any one of them compounds, which is characterized in that R3Selected from halogen, halogenated methyl ,-CN and-
NO2。
5. according to claim 1-4 any one of them compounds, it is characterised in that R3Selected from halogen and-CF3。
6. according to claim 1-5 any one of them compounds, which is characterized in that R6It, can be with selected from phenyl or pyridyl group
It is selected from-F ,-Cl ,-Br ,-I ,-OH ,-NH by 1-32, C1-3Alkyl, C1-3The group of oxyl is replaced.
7. according to claim 1-6 any one of them compounds, which is characterized in that R6For phenyl, pyridyl group, 2,6- difluorobenzenes
Base.
8. compound according to claim 1, which is characterized in that the compound is following compounds:
The fluoro- N- of 6- (2,6- difluorophenyls) -5- (4- (piperidin-4-yl methoxyl group) pyrimidine -5- bases) -2- pyridine carboxamides
N- (4- (azetidin -3- ylmethoxies) pyrimidine -5- bases) fluoro- 2- pyridine carboxamides of -6- (2,6- difluorophenyls) -5-
The fluoro- N- of 6- (2,6- difluorophenyls) -5- (4- (piperidin-4-yl oxygroup) pyrimidine -5- bases) -2- pyridine carboxamides
The fluoro- N- of 6- (2,6- difluorophenyls) -5- (4- (pyrrolidin-3-yl oxygroup) pyrimidine -5- bases) -2- pyridine carboxamides
The fluoro- N- of 6- (2,6- difluorophenyls) -5- (4- (piperidines -3- bases oxygroup) pyrimidine -5- bases) -2- pyridine carboxamides
N- (4- (azacyclo- hept- 4- bases oxygroup) pyrimidine -5- bases) fluoro- 2- pyridine carboxamides of -6- (2,6- difluorophenyls) -5-
The fluoro- N- of 6- (2,6- difluorophenyls) -5- (4- (piperidines -3- ylmethoxies) pyrimidine -5- bases) -2- pyridine carboxamides
The fluoro- N- of 6- (2,6- difluorophenyls) -5- (4- (pyrrolidin-3-yl methoxyl group) pyrimidine -5- bases) -2- pyridine carboxamides
N- (4- (azetidin -3- bases oxygroup) pyrimidine -5- bases) fluoro- 2- pyridine carboxamides of -6- (2,6- difluorophenyls) -5-
N- (4- (((1r, 4r) -4- aminocyclohexyls) oxygroup) pyrimidine -5- bases) fluoro- 2- pyridines of -6- (2,6- difluorophenyls) -5-
Formamide
N- (4- ((3- aminocyclohexyls) oxygroup) pyrimidine -5- bases) fluoro- 2- pyridine carboxamides of -6- (2,6- difluorophenyls) -5-
N- (4- (3- amine propoxyl group) pyrimidine -5- bases) fluoro- 2- pyridine carboxamides of -6- (2,6- difluorophenyls) -5-
The fluoro- N- of 6- (2,6- difluorophenyls) -5- (4- (3- (methylamino) propoxyl group) pyrimidine -5- bases) -2- pyridine carboxamides
6- (2,6- difluorophenyls)-N- (4- (3- (dimethyl amido) propoxyl group) pyrimidine -5- bases) fluoro- 2- pyridine carboxamides of -5-
N- (4- (4- amidos butoxy) pyrimidine -5- bases) fluoro- 2- pyridine carboxamides of -6- (2,6- difluorophenyls) -5-
The fluoro- N- of 6- (2,6- difluorophenyls) -5- (4- (4- (methylamino) butoxy) pyrimidine -5- bases) -2- pyridine carboxamides
The fluoro- N- of 6- (2,6- difluorophenyls) -5- (4- (3- hydroxy propyloxy groups) pyrimidine -5- bases) -2- pyridine carboxamides
The fluoro- N- of 6- (2,6- difluorophenyls) -5- (4- (3- hydroxybutoxies) pyrimidine -5- bases) picolinamide
The fluoro- N- of 6- (2,6- difluorophenyls) -5- (4- (4- hydroxy butoxies) pyrimidine -5- bases) -2- pyridine carboxamides
The fluoro- N- of 6- (2,6- difluorophenyls) -5- (4- ((4- hydroxy-4-methyls amoxy) pyrimidine -5- bases) -2- pyridine carboxamides
6- (2,6- difluorophenyls)-N- (4- (3,4- dihydroxy butoxy) pyrimidine -5- bases) fluoro- 2- pyridine carboxamides of -5-
The fluoro- N- of 6- (2,6- difluorophenyls) -5- [4- (oxinane -4- methoxyl groups) pyrimidine -5- bases) -2- pyridine carboxamides
The fluoro- N- of 3- amidos -6- (2,6- difluorophenyls) -5- (4- (piperidin-4-yl methoxyl group) pyrimidine -5- bases) picolinamide
The fluoro- N- of 3- amidos -6- (2,6- difluorophenyls) -5- (4- (pyrrolidin-3-yl oxygroup) pyrimidine -5- bases) -2- pyridinecarboxylics
Amine
The fluoro- N- of 3- amidos -6- (2,6- difluorophenyls) -5- (4- (piperidin-4-yl oxygroup) pyrimidine -5- bases) -2- pyridine carboxamides
3- amidos-N- (4- (azacyclo- hept- 4- bases oxygroup) pyrimidine -5- bases) fluoro- 2- pyridines first of -6- (2,6- difluorophenyls) -5-
Amide
3- amidos-N- (4- (((1r, 4r) -4- aminocyclohexyls) oxygroup) pyrimidine -5- bases) -6- (2,6- difluorophenyls) -5- fluorine
Picolinamide
The fluoro- N- of 3- amidos -6- (2,6- difluorophenyls) -5- (4- (pyrrolidin-3-yl methoxyl group) pyrimidine -5- bases) -2- pyridine first
Amide
N- (4- ((1- amido -3- chloropropyl -2- bases) oxygroup) pyrimidine -5- bases) fluoro- 2- pyridines of -6- (2,6- difluorophenyls) -5-
Formamide
N- (4- (3- amidos -2- (chloromethyl) propoxyl group) pyrimidine -5- bases) fluoro- 2- pyridinecarboxylics of -6- (2,6- difluorophenyls) -5-
Amine
3- amidos-N- (4- (azetidin -3- bases oxygroup) pyrimidine -5- bases) fluoro- 2- pyridines first of -6- (2,6- difluorophenyls) -5-
Amide
3- amidos-N- (4- (azetidin -3- ylmethoxies) pyrimidine -5- bases) fluoro- 2- pyridines of -6- (2,6- difluorophenyls) -5-
Formamide
3- amidos-N- (4- ((1- amido -3- chloropropyl -2- bases) oxygroup) pyrimidine -5- bases) -6- (2,6- difluorophenyls) -5- is fluoro-
2- pyridine carboxamides
3- amidos-N- (4- (3- amidos -2- (chloromethyl) propoxyl group) pyrimidine -5- bases) fluoro- 2- of -6- (2,6- difluorophenyls) -5-
Pyridine carboxamide
The fluoro- 6- phenyl-N- of 3- amidos -5- (4- (pyrrolidin-3-yl oxygroup) pyrimidine -5- bases) -2- pyridine carboxamides
The fluoro- N- of 3- (4- (piperidin-4-yl oxygroup) pyrimidine -5- bases)-(2,4 '-bipyridyl) -6- formamides
N- (4- (azacyclo- hept- 4- bases oxygroup) pyrimidine -5- bases) fluoro- 2- pyridine carboxamides of -6- (2,6- difluorophenyls) -3-
N- (4- (azacyclo- hept- 4- bases oxygroup) pyrimidine -5- bases) the fluoro- 6- of -5- (the fluoro- 6- methoxyphenyls of 2-) -2- pyridinecarboxylics
Amine
N- (4- (azacyclo- hept- 4- bases oxygroup) pyrimidine -5- bases) -6- (2,6- difluorophenyls) -5- trifluoromethyl -2- pyridinecarboxylics
Amine
The fluoro- N- of 6- (2,6- difluorophenyls) -5- (4- (piperidin-4-yl methoxyl group) pyrimidine -5- trifluoromethyl -2- pyridine carboxamides
N- (4- (azetidin -3- ylmethoxies) pyrimidine -5- bases) -6- (2,6- difluorophenyls) -5- trifluoromethyl -2- pyridine first
Amide
6- (2,6- difluorophenyls)-N- (4- (piperidin-4-yl oxygroup) pyrimidine -5- bases) -5- trifluoromethyl -2- pyridine carboxamides
N- (4- (((1r, 4r) -4- aminocyclohexyls) oxygroup) pyrimidine -5- bases) -6- (2,6- difluorophenyls) -5- trifluoromethyls -
2- pyridine carboxamides
6- (2,6- difluorophenyls)-N- [4- (tetrahydropyran -4-base) methoxyl group) pyrimidine -5- bases) -5- trifluoromethyl -2- pyridines
Formamide
3- amidos-N- (4- (azacyclo- hept- 4- bases oxygroup) pyrimidine -5- bases) -6- (2,6- difluorophenyls) -5- fluorine picolinamides
The fluoro- N- of 3- amidos -6- (2,6- difluorophenyls) -5- (4- (piperidin-4-yl methoxyl group) pyrimidine -5- trifluoromethyl -2- pyridines
Formamide
3- amidos-N- (4- (azetidin -3- ylmethoxies) pyrimidine -5- bases) -6- (2,6- difluorophenyls) -5- trifluoromethyls -
2- pyridine carboxamides
3- amidos -6- (2,6- difluorophenyls)-N- (4- (piperidin-4-yl oxygroup) pyrimidine -5- bases) -5- trifluoromethyl -2- pyridines
Formamide
3- amidos-N- (4- (((1r, 4r) -4- aminocyclohexyls) oxygroup) pyrimidine -5- bases) -6- (2,6- difluorophenyls) -5- three
Methyl fluoride -2- pyridine carboxamides
3- amido -6- phenyl-N- (4- (pyrrolidin-3-yl oxygroup) pyrimidine -5- bases) -5- trifluoromethyl -2- pyridine carboxamides
N- (4- (3- amidos -2- (chloromethyl) propoxyl group) pyrimidine -5- bases) -6- (2,6- difluorophenyls) -5- trifluoromethyl -2- pyrroles
Pyridine formamide
3- amidos-N- (4- (3- amidos -2- (chloromethyl) propoxyl group) pyrimidine -5- bases) -6- (2,6- difluorophenyls) -5- fluoroforms
Base -2- pyridine carboxamides
N- (4- (3- amidos -2- (methylol) propoxyl group) pyrimidine -5- bases) fluoro- 2- pyridinecarboxylics of -6- (2,6- difluorophenyls) -5-
Amine
3- amidos-N- (4- (3- amidos -2- (methylol) propoxyl group) pyrimidine -5- bases) fluoro- 2- of -6- (2,6- difluorophenyls) -5-
Pyridine carboxamide
N- (4- (3- amidos -2- (methylol) propoxyl group) pyrimidine -5- bases) -6- (2,6- difluorophenyls) -5- trifluoromethyl -2- pyrroles
Pyridine formamide
3- amidos-N- (4- (3- amidos -2- (methylol) propoxyl group) pyrimidine -5- bases) -6- (2,6- difluorophenyls) -5- fluoroforms
Base -2- pyridine carboxamides.
9. a kind of preparation method of any compounds of claim 1-8, it is characterised in that include the following steps:
10. a kind of preparation method of any compounds of claim 1-8, it is characterised in that include the following steps:
The alcohol B of with or without blocking group first with alkali in a solvent, react 1 hour at room temperature, then again with 5- amino-
4- chlorine pyrimidines A reacts in a heated condition obtains aminopyrimidine ether C for 1-10 hours;The fragrant carboxylic of with or without blocking group
Sour D is reacted with amine C in a solvent in the presence of coupling reagent, alkali, obtains ether compound E;If there is no blocking group in E,
E is ether compound final in Formulas I;If carry blocking group, E again with trifluoracetic acid and dichloromethane or hydrochloric acid first
Alcoholic solution stirs 1-16 hours after mixed at room temperature, then at room temperature vacuum distillation remove obtain after solvent it is final in Formulas I
Ether compound.
11. a kind of preparation method of any compounds of claim 1-8, it is characterised in that include the following steps:
The alcohol B elder generations of 1.1 equivalents of with or without blocking group and alkali, in a solvent, at room temperature react 1 hour, so
It is reacted in a heated condition with 1 equivalent 5- amino -4- chlorine pyrimidines A again afterwards and obtains within 1-10 hours aminopyrimidine ether C;With or without
1 equivalent aromatic carboxylic acids D of blocking group reacts with 1 equivalent amine C in the presence of coupling reagent, alkali, obtains ethers in a solvent
Compound E;If not having blocking group in E, E is ether compound final in Formulas I;If carry blocking group, E again with
The trifluoracetic acid of 10 to 100 equivalents and isometric dichloromethane or 2 centinormal 1 methanol hydrochloride solutions are after mixed at room temperature
Stirring 1-16 hours, then vacuum distillation obtains ether compound final in Formulas I after removing solvent at room temperature.
12. a kind of method using any compounds of claim 1-8 includes appointing the claim 1-8 of effective dose
One compound is as the application for preparing PIM kinase inhibitor drugs.
13. a kind of purposes of any compounds of claim 1-8, it is characterised in that:As PIM kinase inhibitors in pharmacy
In application.
14. according to the purposes of compound described in claim 13, it is characterised in that:As PIM-1, the suppression of PIM-2 and PIM-3 kinases
Application of the preparation in pharmacy.
15. a kind of method using any compounds of claim 1-8 includes appointing the claim 1-8 of effective dose
Application of one compound as active ingredient in medicine preparation, it is characterised in that:
The drug reverses anticancer and the drug resistance of other medicines, inflammatory bowel disease, from immune disease for treating or preventing cancer
The inflammation that disease, allergic reaction disease, atherosclerosis, anti-organ transplant rejection, polytropism drug resistance, T cell mediate
Disease.
16. a kind of method using the compound of claim 1,7 or 8 includes by the claim 1,7 or 8 of effective dose
Application of the compound as active ingredient in medicine preparation, it is characterised in that:
The drug reverses anticancer and the drug resistance of other medicines, inflammatory bowel disease, from immune disease for treating or preventing cancer
The inflammation that disease, allergic reaction disease, atherosclerosis, anti-organ transplant rejection, polytropism drug resistance, T cell mediate
Disease.
17. a kind of pharmaceutical composition, it is characterised in that:Including any compounds of claim 1-8 as active constituent with it is medicinal
The pharmaceutical composition of carrier composition.
18. a kind of pharmaceutical composition, it is characterised in that:PIM kinase inhibitors including claim 1 or 7 or 8 compounds
Pharmaceutical composition as active constituent and pharmaceutical carrier composition.
19. a kind of application of 17 or 18 described pharmaceutical composition of claim, it is characterised in that:It is used to prepare treatment or prevention cancer
Disease reverses anticancer and the drug resistance of other medicines, inflammatory bowel disease, auto-immune disease, allergic reaction disease, Atherosclerosis
The drug for the inflammation that change, anti-organ transplant rejection, polytropism drug resistance, T cell mediate.
20. the preparation method of compound according to claim 10, it is characterised in that include the following steps:
The alcohol B of with or without blocking group reacts 1 hour at room temperature first with NaH in tetrahydrofuran, then again with 5-
Amino -4- chlorine pyrimidines A reacts in a heated condition obtains aminopyrimidine ether C for 1-10 hours;
If not having blocking group in E, E is ether compound final in Formulas I;If carrying protecting group BOC or trimethyl silicane
Base, E is then stirred 1-16 hours with trifluoracetic acid and dichloromethane or methanol hydrochloride solution after mixed at room temperature again, then in room
The lower vacuum distillation of temperature obtains ether compound final in Formulas I after removing solvent.
21. the preparation method of compound according to claim 11, it is characterised in that include the following steps:
Alcohol B elder generations and the 1.1 equivalent NaH of 1.1 equivalents of with or without blocking group, in solvents tetrahydrofurane, in room
The lower reaction of temperature 1 hour, then again with 1 equivalent 5- amino -4- chlorine pyrimidines A in a heated condition, as reacted 1-10 hours at 100 DEG C
Obtain aminopyrimidine ether C;In 1.1 equivalent HATU of coupling reagent, 3 work as 1 equivalent aromatic carboxylic acids D of with or without blocking group
In the presence of measuring DIEA, is reacted with 1 equivalent amine C in DMF, obtain ether compound E;If not having blocking group in E, E is
Final ether compound in Formulas I;If carry protecting group BOC or trimethyl silicon substrate, E again with the trifluoro vinegar of 10 to 100 equivalents
The sour and isometric centinormal 1 methanol hydrochloride solution of dichloromethane or 2 stirs 1-16 hours after mixed at room temperature, then exists
Vacuum distillation obtains ether compound final in Formulas I after removing solvent at room temperature.
22. the method according to claim 15 using any compounds of claim 1-8, it is characterised in that:
Cancer refers to can be by inhibiting PIM kinases to obtain the Cancerous disease of advantageous treatment.
23. the method according to claim 22 using any compounds of claim 1-8, it is characterised in that:
Cancer refers to solid tumor and liquid tumor.
24. the method for the method compound according to claim 22 using any compounds of claim 1-8,
It is characterized in that:
Cancer includes lung cancer, cancer of pancreas, thyroid cancer, oophoroma, carcinoma of urinary bladder, breast cancer, prostate cancer or colon cancer, melanoma, gland
Tumor, sarcoma;Bone marrow disorder.
25. the method according to claim 24 using any compounds of claim 1-8, it is characterised in that:Institute
It includes villous colon adenoma to state adenoma;The sarcoma includes osteosarcoma;The bone marrow disorder includes myelocytic leukemia, more
Hair property myeloma and erythroleukemia.
26. the method according to claim 22 using any compounds of claim 1-8, it is characterised in that:Cancer
Including chronic lymphocytic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelocytic leukemia, non-
Hodgkin lymphoma, and Huppert's disease.
27. the method according to claim 16 using the compound of claim 1,7 or 8, it is characterised in that:Cancer is
Referring to can be by inhibiting PIM kinases to obtain the Cancerous disease of advantageous treatment.
28. the method according to claim 27 using the compound of claim 1,7 or 8, it is characterised in that:Cancer is
Refer to solid tumor and liquid tumor.
29. the method according to claim 27 using the compound of claim 1,7 or 8, it is characterised in that:Cancer packet
Include lung cancer, cancer of pancreas, thyroid cancer, oophoroma, carcinoma of urinary bladder, breast cancer, prostate cancer or colon cancer, melanoma, adenoma and sarcoma;
Bone marrow disorder.
30. the method according to claim 29 using the compound of claim 1,7 or 8, it is characterised in that:It is described
Bone marrow disorder includes myelocytic leukemia, Huppert's disease and erythroleukemia;The adenoma includes villous colon adenoma;
The sarcoma includes osteosarcoma.
31. the method according to claim 27 using the compound of claim 1,7 or 8, it is characterised in that:Cancer packet
Include chronic lymphocytic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelocytic leukemia, it is non-suddenly
Strange gold lymthoma, and Huppert's disease.
32. the application of the pharmaceutical composition of compound according to claim 19, it is characterised in that:Cancer refers to that can pass through
PIM kinases is inhibited to obtain the Cancerous disease of advantageous treatment.
33. the application of the pharmaceutical composition of compound according to claim 32, it is characterised in that:Cancer refer to solid tumor and
Liquid tumor.
34. the application of the pharmaceutical composition of compound according to claim 32, it is characterised in that:Cancer includes lung cancer, pancreas
Gland cancer, thyroid cancer, oophoroma, carcinoma of urinary bladder, breast cancer, prostate cancer or colon cancer, melanoma, adenoma, sarcoma;Bone marrow disorder.
35. application according to claim 34, it is characterised in that:The adenoma includes villous colon adenoma;The meat
Tumor includes osteosarcoma;The bone marrow disorder includes myelocytic leukemia, Huppert's disease and erythroleukemia.
36. application according to claim 32, it is characterised in that:Cancer includes chronic lymphocytic leukemia, acute lymphoblastic
Chronic myeloid leukemia, acute myeloid leukemia, chronic myelocytic leukemia, non-Hodgkin lymphoma and Huppert's disease.
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