CN105218523B - Pyridine derivate PIM kinase inhibitor and preparation method thereof and the application in pharmacy - Google Patents

Pyridine derivate PIM kinase inhibitor and preparation method thereof and the application in pharmacy Download PDF

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CN105218523B
CN105218523B CN201510594164.6A CN201510594164A CN105218523B CN 105218523 B CN105218523 B CN 105218523B CN 201510594164 A CN201510594164 A CN 201510594164A CN 105218523 B CN105218523 B CN 105218523B
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pyridin
difluorophenyl
fluoro
amido
pyridine
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CN105218523A (en
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葛羽
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SHANGHAI JIKAI MEDICAL TECHNOLOGY Co Ltd
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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
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    • 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
    • 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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Abstract

The present invention provides a kind of PIM kinase inhibitor and its preparation method and application, structural formula is following general formula Compound I:

Description

Pyridine derivate PIM kinase inhibitor and preparation method thereof and the application in pharmacy
Technical field
The present invention relates to pharmaceutical chemistry, and in particular to PIM kinase inhibitor and preparation method thereof and the application in pharmacy.
Background technique
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 is by more and more for studying treatment tumour With the target of immunoregulation medicament.PIM-1 (Provirus 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, encodes the gene of PIM-2 (Provirus Integration of Maloney 2) Also 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 its protein sequence is consistent with PIM-1 height (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 odd gold lymphoma leukemia has 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, thus the existence to hematopoietic cell to the stimulation of growth factor and cell factor With diffusion generation effect.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 of 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 member BAD (FEBS Letters, 571,43-49,2004) 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 4EBP1 (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 diffusion.So inhibiting overexpression PIM kinases in tumour is the new for the treatment of cancer Effective ways.
Since PIM kinases is related with entity tumor in many liquid tumors, many PIM kinase inhibitors be used to develop newly The anti-tumor drug of a generation.It is shown in a series of cell and animal model experiment, PIM kinase inhibitor can inhibit significantly 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 inhibitor also has 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 bladder cancer (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 studies have shown that PIM kinases to two most important drug transporters (drug efflux transporters), MDR-1 and The expression of BCRP and activity are related (Drug Resistance Updates, 14,203-211,2011).Experiment shows that PIM swashs Enzyme inhibitor and chemotherapeutics share can significantly improve to the curative effect of drug resistance prostate cancer (Mol.Cancer Ther.8, 2882-2893,2009).Therefore, PIM inhibitor can be used for reversing the drug resistance to chemotherapy.
Experiment display, PIM kinase expression occur along with the activation of T- cell, and PIM-1/3 inhibitor can effectively treat CD4 Enteritis caused by+T- cell.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 T- such as inflammatory bowel disease cell-mediated 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 substituent 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 substituent is that H or F have little effect the PIM activity of these compounds, will not be changed The ability of compound inhibition PIM-1 enzymatic activity.
Summary of the invention
During studying a new generation's PIM kinase inhibitor, surprisingly, it was found that it is different with known knowledge, Meet in compounds of formula I at one group, 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, so that further increasing compound inhibits the active energy of PIM-1 Power, highest activity improve 8 times or more, averagely 4.4 times.Specific data are shown in the table 2 of embodiment 60.
Technical problem to be solved by the present invention lies in research PIM kinase inhibitor noval chemical compound, design preparation treatment cancers Disease, the drug of the T- such as polytropism drug resistance and inflammatory bowel disease cell-mediated inflammation.
The present invention provides PIM kinase inhibitor, structural formula is following general formula Compound I:
Formula Compound I is the PIM kinase inhibitor of pyridine compounds and their 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 ring 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 ring base, 5-10 member 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 has 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 member or the aromatic group of 5-12 member, or have 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 ring base, 5-10 member aryl and heterocyclic aryl； The cyclic hydrocarbon radical, the substituent group on aryl and heterocyclic aryl can be halogen (F, Cl, Br, I) ,-CN ,-NIH respectively2,-NHR7, C1-4Alkyl, 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 are selected from-F ,-Cl ,-Br ,-I ,-OH ,-NH2, C1-3Alkyl, C1-3Oxyl, halogenated C1-3Replaced the group of alkyl；Into The preferred R of one step6For phenyl, pyridyl group, 2-F-6-OCH3Phenyl, 2,6- difluorophenyls.
In another part embodiment of the invention, 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
In another part embodiment of the invention, 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
In another part embodiment of the invention, 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 It not can 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 without containing heteroatomic alkyl.Therefore, the term include straight chained alkyl such as Methyl, ethyl, propyl, butyl, amyl, hexyl, 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 there is at least one unsaturation, that is, two of them adjacent carbon atom Pass through doubly linked alkyl as defined above.
The term as used herein " alkynyl " is related to the alkyl that two of them adjacent carbon atom passes through 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、-CHF2、-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 that wherein R and R ' is each independently selected from the group-of hydrogen or low alkyl group NRR ', wherein R and R ' is not H simultaneously.
The term " arylamino " of this paper refers to that wherein R is aryl and R ' is the group-of hydrogen, low alkyl group or aryl 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 that wherein aralkyl is -0 one aralkyl of one alkylidene of group of loweraralkyl.
The term as used herein " amino carbonyl " refers to group-C (=O)-NH2；" substituted amino carbonyl " is herein Refer to that wherein R is low alkyl group and R ' is group C (O)-NRR ' of hydrogen or low alkyl group.In some embodiments, R and R ' can " heterocycloalkylcarbonyl " is formed together with the N atom 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 replaced " 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 that wherein R is ester-C (=O)-OR of alkyl." elementary alkoxy carbonyl " refers to that wherein R is the ester-C (=O)-of low alkyl group OR." cyclo alkoxy carbonyl " refers to that wherein R is C (=O)-OR of 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 unsaturated naphthenic base in part ", " naphthenic base of fractional saturation " and " cycloalkenyl " all refer to wherein have at least One unsaturation, that is, the naphthenic base that the adjacent annular atom of two of them 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 " replace heterocycle ", " heterocyclic group " or " heterocycle " refer to containing one selected from nitrogen, oxygen and Heteroatomic wantonly 3 or 4 Yuans rings of sulphur or the heteroatomic 5- or 6- person's ring that nitrogen, oxygen or sulphur are selected from containing one to three；Wherein institute 5- person's ring is stated with 0-2 double bond, 6- person's ring has 0-3 double bond；Wherein nitrogen and sulphur atom are optionally oxidized；And it wraps Include any bicyclic group that the above-mentioned heterocycle of any of them and phenyl ring or the other 5- or 6- element heterocycles independently defined above condense.This Term used in text " Heterocyclylalkyl " refers to the heteroatomic 5- or 6- person's ring that nitrogen, oxygen or sulphur are selected from 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 " is heteroatomic ring and fractional saturation and fully saturated ring including wherein nitrogen.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 azetidine 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 replace or Three replace, the substituent group independently selected from hydroxyl, halogen, oxo (C=O), (RN=, wherein R is lower alkyl 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 field of medicinal chemistry 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 including 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 " is in this article referred 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 Replacement；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 usually hydrogen, into Base or low alkyl group；When substituted substituent group includes straight chain group, which can be located in chain (for example, 2- hydroxyl third Base, 2- aminobutyl etc.) or chain end (for example, 2- hydroxyethyl, 3- aminopropyl etc.).Substituted substituent group can be covalently 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 Any pharmaceutical salt, ester, metabolin and pro-drug 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 pharmaceutical salt any in them, ester, Metabolin and pro-drug may include the carbon atom of Asymmetrical substitute.The carbon atom of such Asymmetrical substitute can produce 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 1974RECOMMENDATIONS FOR SECTION E, FUNDAMENTAL STEREOCHEMISTRY, Pure Defined in Appl.Chem.45:13-30 (1976).Term and ring position for cyclic compound.Reference plane-side is excellent The substituent group of choosing is located at that side of lower numbered positions.Positioned at those of reference plane opposite side substituent group with originally describing.It should infuse Meaning, this usage is different from for the usage of cyclic stereocenter (stereoparents), in the later case, " " meaning " be located at plane under " and indicate absolute configuration.The term as used herein and configuration such as CHEMICALABSTRACTS INDEX The 203rd section of GUIDE-APPENDIX IV (1987) is 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 reaction are to prepare.Typical salt includes but is 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- isethionate, lactate, Maleate, mesylate, nicotinate, 2- naphthalene sulfonate, 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 Group comprising 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 the suitable for example pharmaceutically acceptable metal cation of alkali Object, carbonate or bicarbonate or ammonia or the reaction of organic primary, secondary or tertiary amine are to prepare.Pharmaceutical salt includes but is 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 " refers to the ester hydrolyzed in vivo simultaneously, including in human body it is easily decomposes from And release those of parent compound or its salt ester.Suitable ester includes such as those white pharmaceutical aliphatic carboxylic acids of derivative, 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 in reasonable medical judgment, is suitable for and people and rudimentary The tissue contact of animal is simultaneously without excessive toxicity, irritation, allergic reaction etc., with reasonable 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 in vivo conversion rapidly, is for example converted by hydrolyzing in blood, thus on generating The compound of the parent compound of formula.Pro-drug (Pro- in T.Higuchi and v.Stella, 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 had 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, Nitrogen, oxygen, phosphorus, fluorine and chlorine isotope, such as2H、3H、11C、13C、14C、15N、18F、31P、32P、35S、36Cl、125I.Packet of the present invention The compound of this paper institute 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 research.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 replaces isotope-labeled reagent to be prepared.In addition, with heavier isotope, especially deuterium (that is,2H or D) it sets It changes and can provide certain treatment benefits, 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 The plain enrichment factor in position " refers to the ratio between the isotope abundance and natural abundance of specified isotope.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 less 5000 (75% deuterium is mixed into), be at least 5500 (82.5% deuterium is mixed into), is at least 6000 (90% deuterium is mixed into), extremely It is less 6333.3 (95% deuterium is mixed into), is at least 6466.7 (97% deuterium is mixed into), is at least 6600 (99% deuterium is mixed into) Or at least 6633.3 (99.5% deuterium is mixed into) isotope enrichment factor.
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 pro-drug any in them can be by human or animals Body is metabolized and is processed in vivo into the cell, to generate metabolin.The term as used herein " metabolin ", which refers to, to be applied With the derivative of any structural formula generated in vivo after parent compound in individual.These derivatives can be intracorporal by individual Various biochemical transformations are for example aoxidized, are restored, hydrolyzing or combining and being generated by parent compound, and including such as 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 it is any 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 ", which refers to, can obtain the Cancerous disease of advantageous treatment by inhibition PIM kinases, including Such as solid tumor, if cancer is (for example, lung cancer, cancer of pancreas, thyroid cancer, oophoroma, bladder cancer, breast cancer, prostate cancer or colon Cancer), melanoma, bone marrow disorder (for example, myelocytic leukemia, Huppert's disease and erythroleukemia), adenoma is (for example, suede Hairy colonic adenoma) and sarcoma (for example, osteosarcoma), liquid tumor, such as chronic lymphocytic leukemia, acute lymphoblastic it is white Blood disease, acute myeloid leukemia, chronic myelocytic leukemia, non-Hodgkin lymphoma and Huppert's disease.
PIM kinase inhibitor provided by the invention includes following compounds:
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (piperidin-4-yl methoxyl group) pyridin-3-yl) -2- pyridine carboxamide
N- (4- (azetidine -3- ylmethoxy) pyridin-3-yl) fluoro- 2- pyridine first of -6- (2,6- difluorophenyl) -5- Amide
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (piperidin-4-yl oxygroup) pyridin-3-yl) -2- pyridine carboxamide
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (pyrroles's -3- base oxygroup) pyridin-3-yl) -2- pyridine carboxamide
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (piperidines -3- base oxygroup) pyridin-3-yl) -2- pyridine carboxamide
N- (4- (azacyclo- hept- 4- base oxygroup) pyridin-3-yl) fluoro- 2- pyridine carboxamide of -6- (2,6- difluorophenyl) -5-
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (piperidines -3- ylmethoxy) pyridin-3-yl) -2- pyridine carboxamide
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (pyrroles -3- ylmethoxy) pyridin-3-yl) -2- pyridine carboxamide
N- (4- (azetidin -3- base oxygroup) pyridin-3-yl) fluoro- 2- pyridine carboxamide of -6- (2,6- difluorophenyl) -5-
N- (4- (((1r, 4r) -4- aminocyclohexyl) oxygroup) pyridin-3-yl) fluoro- 2- of -6- (2,6- difluorophenyl) -5- Pyridine carboxamide
N- (4- ((3- aminocyclohexyl) oxygroup) pyridin-3-yl) fluoro- 2- pyridinecarboxylic of -6- (2,6- difluorophenyl) -5- Amine
N- (4- (3- amine propoxyl group) pyridin-3-yl) fluoro- 2- pyridine carboxamide of -6- (2,6- difluorophenyl) -5-
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (3- (methylamino) propoxyl group) pyridin-3-yl) -2- pyridine carboxamide
6- (2,6- difluorophenyl)-N- (4- (3- (dimethyl amido) propoxyl group) pyridin-3-yl) fluoro- 2- pyridine first of -5- Amide
N- (4- (4- amido butoxy) pyridin-3-yl) fluoro- 2- pyridine carboxamide of -6- (2,6- difluorophenyl) -5-
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (4- (methylamino) butoxy) pyridin-3-yl) -2- pyridine carboxamide
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (3- hydroxy propyloxy group) pyridin-3-yl) -2- pyridine carboxamide
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (3- hydroxybutoxy) pyridin-3-yl) -2- pyridine carboxamide
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (4- hydroxy butoxy) pyridin-3-yl) -2- pyridine carboxamide
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- ((4- hydroxy-4-methyl amoxy) pyridin-3-yl) -2- pyridine first Amide
6- (2,6- difluorophenyl)-N- (4- (3,4- dihydroxy butoxy) pyridin-3-yl) fluoro- 2- pyridine carboxamide of -5-
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (oxinane -4- methoxyl group)-pyridin-3-yl) -2- pyridinecarboxylic Amine
The fluoro- N- of 3- amido -6- (2,6- difluorophenyl) -5- (4- (piperidin-4-yl methoxyl group) pyridin-3-yl) -2- pyridine Formamide
The fluoro- N- of 3- amido -6- (2,6- difluorophenyl) -5- (4- (pyrroles's -3- base oxygroup) pyridin-3-yl) -2- pyridine first Amide
The fluoro- N- of 3- amido -6- (2,6- difluorophenyl) -5- (4- (piperidin-4-yl oxygroup) pyridin-3-yl) -2- pyridine first Amide
3- amido-N- (4- (azacyclo- hept- 4- base oxygroup) pyridin-3-yl) fluoro- 2- pyrrole of -6- (2,6- difluorophenyl) -5- Pyridine formamide
3- amido-N- (4- (((1r, 4r) -4- aminocyclohexyl) oxygroup) pyridin-3-yl) -6- (2,6- difluorophenyl) - The fluoro- 2- pyridine carboxamide of 5-
The fluoro- N- of 3- amido -6- (2,6- difluorophenyl) -5- (4- (pyrroles -3- ylmethoxy) pyridin-3-yl) -2- pyridine Formamide
N- (4- ((1- amido -3- chloropropyl -2- base) oxygroup) pyridin-3-yl) fluoro- 2- of -6- (2,6- difluorophenyl) -5- Pyridine carboxamide
N- (4- (3- amido -2- (chloromethyl) propoxyl group) pyridin-3-yl) fluoro- 2- pyridine of -6- (2,6- difluorophenyl) -5- Formamide
3- amido-N- (4- (azetidin -3- base oxygroup) pyridin-3-yl) fluoro- 2- pyrrole of -6- (2,6- difluorophenyl) -5- Pyridine formamide
3- amido-N- (4- (azetidine -3- ylmethoxy) pyridin-3-yl) -6- (2,6- difluorophenyl) -5- is fluoro- 2- pyridine carboxamide
3- amido-N- (4- ((1- amido -3- chloropropyl -2- base) oxygroup) pyridin-3-yl) -6- (2,6- difluorophenyl) - The fluoro- 2- pyridine carboxamide of 5-
3- amido-N- (4- (3- amido -2- (chloromethyl) propoxyl group) pyridin-3-yl) -6- (2,6- difluorophenyl) -5- Fluoro- 2- pyridine carboxamide
The fluoro- N- of 3- amido -6- (2,6- difluorophenyl) -5- (4- (piperidines -3- ylmethoxy) pyridin-3-yl) -2- pyridine Formamide
3- amido-N- (4- (4- amido butoxy) pyridin-3-yl) fluoro- 2- pyridinecarboxylic of -6- (2,6- difluorophenyl) -5- Amine
3- amido-N- (4- ((3- aminocyclohexyl) oxygroup) pyridin-3-yl) fluoro- 2- pyrrole of -6- (2,6- difluorophenyl) -5- Pyridine formamide
The fluoro- 6- phenyl-N- of 3- amido -5- (4- (pyrrolidin-3-yl oxygroup) pyridin-3-yl) -2- pyridine carboxamide
The fluoro- N- of 3- (4- (piperidin-4-yl oxygroup) pyridin-3-yl)-(2,4 '-bipyridyl) -6- formamide
N- (4- (azacyclo- hept- 4- base oxygroup) pyridin-3-yl) fluoro- 2- pyridine carboxamide of -6- (2,6- difluorophenyl) -3-
N- (4- (azacyclo- hept- 4- base oxygroup) pyridin-3-yl) the fluoro- 6- of -5- (the fluoro- 6- methoxyphenyl of 2-) -2- pyridine Formamide
N- (4- (azacyclo- hept- 4- base oxygroup) pyridin-3-yl) -6- (2,6- difluorophenyl) -5- trifluoromethyl -2- pyridine Formamide
6- (2,6- difluorophenyl)-N- (4- (piperidin-4-yl methoxyl group) pyridin-3-yl) -5- trifluoromethyl -2- pyridine first Amide
N- (4- (azetidin -3- ylmethoxy) pyridin-3-yl) -6- (2,6- difluorophenyl) -5- trifluoromethyl -2- pyrrole Pyridine formamide
6- (2,6- difluorophenyl)-N- (4- (piperidin-4-yl oxygroup) pyridin-3-yl) -5- trifluoromethyl -2- pyridinecarboxylic Amine
N- (4- (((1r, 4r) -4- aminocyclohexyl) oxygroup) pyridin-3-yl) -6- (2,6- difluorophenyl) -5- fluoroform Base -2- pyridine carboxamide
6- (2,6- difluorophenyl)-N- [4- (tetrahydropyran -4-base) oxygroup) pyridin-3-yl) -5- trifluoromethyl -2- pyrrole Pyridine formamide
3- amido-N- (4- (azacyclo- hept- 4- base oxygroup) pyridin-3-yl) -6- (2,6- difluorophenyl) -5- fluoroform Base -2- pyridine carboxamide
3- amido -6- (2,6- difluorophenyl)-N- (4- (piperidin-4-yl methoxyl group) pyridin-3-yl) -5- trifluoromethyl - 2- pyridine carboxamide
3- amido-N- (4- (azetidin -3- ylmethoxy) pyridin-3-yl) -6- (2,6- difluorophenyl) -5- fluoroform Base -2- pyridine carboxamide
3- amido -6- (2,6- difluorophenyl)-N- (4- (piperidin-4-yl oxygroup) pyridin-3-yl) -5- trifluoromethyl -2- Pyridine carboxamide
3- amido-N- (4- (((1r, 4r) -4- aminocyclohexyl) oxygroup) pyridin-3-yl) -6- (2,6- difluorophenyl) - 5- trifluoromethyl -2- pyridine carboxamide
3- amido -6- phenyl-N- (4- (pyrrolidin-3-yl oxygroup) pyridin-3-yl) -5- trifluoromethyl -2- pyridinecarboxylic Amine
N- (4- (3- amido -2- (chloromethyl) propoxyl group) pyridin-3-yl) -6- (2,6- difluorophenyl) -5- trifluoromethyl - 2- pyridine carboxamide
3- amido-N- (4- (3- amido -2- (chloromethyl) propoxyl group) pyridin-3-yl) -6- (2,6- difluorophenyl) -5- three Methyl fluoride -2- pyridine carboxamide
N- (4- (3- amido -2- (methylol) propoxyl group) pyridin-3-yl) fluoro- 2- pyridine of -6- (2,6- difluorophenyl) -5- Formamide
3- amido-N- (4- (3- amido -2- (methylol) propoxyl group) pyridin-3-yl) -6- (2,6- difluorophenyl) -5- Fluoro- 2- pyridine carboxamide
N- (4- (3- amido -2- (methylol) propoxyl group) pyridin-3-yl) -6- (2,6- difluorophenyl) -5- trifluoromethyl - 2- pyridine carboxamide
3- amido-N- (4- (3- amido -2- (methylol) propoxyl group) pyridin-3-yl) -6- (2,6- difluorophenyl) -5- three Methyl fluoride -2- pyridine carboxamide
It is a further object of the present invention to provide the preparation methods of above-mentioned PIM kinase inhibitor.
The compound of the present invention is prepared since commercially available starting material and reagent.Method following formula table of the invention Show:
Alcohol B (1.1 equivalent) elder generation of with or without blocking group and alkali, if NaH (1-3 equivalent) is in solvent, such as four In hydrogen furans, reacted under room temperature (25 DEG C) 1 hour, it is then anti-at 25-50 DEG C with the chloro- 3- nitropyridine A of 4- (1 equivalent) again It answers and obtains within 1-10 hours nitro-pyrimidine ether C.C (1 equivalent) is in solvent appropriate such as 1: 1 methanol and ethyl acetate and catalysis appropriate Amido is obtained after restoring 4-12 hours under hydrogen (1-3 atmospheric pressure) environment under agent such as 10%Pd/C (0.1-0.5 equivalent) catalysis Pyridine D.The picolinic acid E (1 equivalent) of with or without blocking group is in coupling reagent appropriate, such as HATU (1.1 equivalent), Alkali, in the presence of DIEA (3 equivalent), in solvent appropriate, as reacted at 25-50 DEG C in DMF with amido pyridine D (1 equivalent) 1-10 hours, obtain product F.If not having blocking group in F, F is the final ether compound in Formulas I.If with protection Group, such as BOC (tert-butoxy formic acid esters) or trimethyl silane, F then again with the trifluoracetic acid of 10 to 100 equivalents and isometric Methylene chloride or 2 centinormal 1 methanol hydrochloride solutions stir 1-16 hours after (25 DEG C) of room temperature mixing, then in room temperature Vacuum distillation obtains the final ether compound in Formulas I after removing solvent under (25 DEG C).
It is yet another object of the invention to provide application of the above-mentioned PIM kinase inhibitor in pharmacy.
Tested through PIM kinases biochemical activity method 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 to treat or prevent the application in cancer drug in preparation.
The present invention provides above-mentioned PIM kinase inhibitors to treat or prevent answering in autoimmune disease drug in preparation With.
The present invention provides above-mentioned PIM kinase inhibitors to treat or prevent answering in allergic reaction disease medicament in preparation With.
The present invention provides above-mentioned PIM kinase inhibitor answering in the drug that preparation treats or prevents atherosclerosis With.
The present invention provides above-mentioned PIM kinase inhibitors to treat or prevent in anti-organ transplant rejection drug in preparation Application.
The present invention provides above-mentioned PIM kinase inhibitors to treat or prevent answering in polytropism drug resistance drug in preparation With.
The present invention provides above-mentioned PIM kinase inhibitors in the anti-inflammatory drugs that preparation treats or prevents that T cell mediates Using.
The pharmaceutical composition that drug of the present invention is made of PIM kinase inhibitor as active constituent and pharmaceutical carrier.
The present invention provides the new applications of PIM kinase inhibitor, there is biggish 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, bladder cancer, 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 in preparation, 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, bladder cancer, 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 embodiment
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 acid (E)
The synthesis of the fluoro- 2- pyridine carboxylic acid (E1) of 1.6- (2,6- difluorophenyl) -5-
(i) synthesis of the fluoro- 6- picoline (c) of 2- (2,6- difluorophenyl) -3-
By the fluoro- 6- picoline (a) of the bromo- 3- of 2- (279mg, 1.77mmol), 2,6- difluorophenyl boronic acids (b) (167mg, It 0.88mmol) is dissolved in tetrahydrofuran/water mixed solvent (10: 1,8ml), deaerates 5 minutes with potassium fluoride (169mg, 2.91mmol), Pd is added under nitrogen protection2(dba)3(25mg, 0.044mmol) and tri-tert-butylphosphine (18mg, 0.088mmol), is heated to 60 DEG C, it reacts 1 hour, is cooled to room temperature, be added ethyl acetate (10ml), successively washed with water (10ml) and saturated salt solution (10ml) Wash, be dried over anhydrous sodium sulfate, filter after remove solvent, gained crude product is dissolved in ethyl alcohol (10ml), be added 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: methylene chloride).
(ii) synthesis of the fluoro- 2- pyridine carboxylic acid (E1) 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 after cooling with diatomite, 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 solution, in extract liquor concentrated hydrochloric acid With to obtaining solid after pH=1.Say twice solid merge after obtain product E1 (153mg, 0.603mmol)
The synthesis of the 2.3- amido -6- fluoro- 2-Pyridinecarboxylic Acid of (2,6- difluorophenyl) -5- (E2)
(i) synthesis of the fluoro- 2- pyridine carboxylic acid methyl esters (f) of 3- amido -5-
The addition bromo- 5- fluorine pyridine (500mg, 2.62mmol) of 3- amido 2- in autoclave, triethylamine (0.59ml, 4.16mmol), Pd (BINAP) Cl2(32mg, 0.039mmol), anhydrous methanol (20ml), is filled with CO gas after degassing (60psi) is heated to 100 DEG C, and reaction was cooled to room temperature, then plus Pd (BINAP) Cl after 12 hours2(10mg, 0.012mmol), Continuation is cooled to room temperature after reacting 12 hours at 60psi carbon monoxide, 100 DEG C, filters.Ethyl acetate is added in filtrate (30ml), then washed with water (20ml) and saturated salt solution (20ml), anhydrous sodium sulfate dries, filters, and yellow is obtained 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- amido -6-
The fluoro- 2- pyridine carboxylic acid methyl esters (100mg, 0.588mmol) of 3- amido -5- is dissolved in second cyanogen (2ml), at room temperature plus 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 dries, filters.The crude product silicon obtained after filtrate concentration Product (g) (59mg, 0.235mmol) is obtained after glue column chromatography (20-60% ethyl acetate/petroleum ether)
(iii) synthesis of the fluoro- 2- pyridine carboxylic acid methyl esters (h) of 3- amido -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- amido -6- for raw material Product (h).
(iv) synthesis of the fluoro- 2- pyridine carboxylic acid (E2) of 3- amido -6- (2,6- difluorophenyl) -5-
By the fluoro- 2- pyridine carboxylic acid methyl esters (g) of the bromo- 5- of 3- amido -6- (56mg, 0.20mmol) be dissolved in 1: 1 tetrahydrofuran/ Methanol mixed solvent (1ml) is added 1M lithium hydroxide solution (0.4ml, 0.40mmol), uses 1N 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 dries, filters, and product (E2) (48mg, 0.18mml) is obtained after concentration.
The synthesis of the fluoro- 6- phenyl -2- pyridine carboxylic acid (E3) of 3.3- amido -5-
Referring to the synthesis of E2,2,6- difluorophenyl boronic acid (b) therein is replaced that product (E3) is made with phenylboric acid (b1)
The synthesis of fluoro- (2,4 '-connect the pyridine) -6- carboxylic acid (E4) of 4.3-
Referring to the synthesis of E1,2,6- difluorophenyl boronic acid (b) therein is replaced that product is made with 4- pyridinylboronic acid (b2) (E4)
The synthesis of the fluoro- 2- pyridine carboxylic acid (E5) of 5.6- (2,6- difluorophenyl) -3-
Referring to the synthesis of E1, the fluoro- 6- picoline (a) of the bromo- 3- of 2- therein uses the bromo- 3- of 6- fluoro- 2- picoline (k) generation For obtained product (E5)
The synthesis of 6.6- (2,6- difluorophenyl) -5- trifluoromethyl -2- pyridine carboxylic acid (E6)
(i) 2- methoxycarbonyl -5- trifluoromethylpyridin -1- oxide (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 methylene chloride (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- trifluoromethyl -2- pyridine carboxylic acid methyl esters of 2-
POBr3 is added in 2- methoxycarbonyl -5- trifluoromethylpyridin -1- oxide (n) (221mg, 1.0mmol) (2.5g, 8.5mmol) is cooled to room temperature after stirring 2 hours at 80 DEG C, pours into 20ml water, mixture is extracted with ethyl acetate Take (3x10ml).Organic phase is washed (10ml) with saturation NaCl solution, is concentrated after anhydrous sodium sulfate is dry, 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 acid (E6)
Referring to the synthesis of E3, the fluoro- 2- pyridine carboxylic acid methyl esters (g) of the bromo- 5- of 3- amido -6- therein uses the bromo- 3- fluoroform of 2- Base -2- pyridine carboxylic acid methyl esters (o) replaces being worth product (E6)
The synthesis of 7.3- amido -6- (2,6- difluorophenyl) -5- trifluoromethyl -2- pyridine carboxylic acid (E7)
(i) synthesis (r) of the bromo- 3- nitro -5- trifluoromethyl pyridine 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 is extracted with dichloromethane (3x20ml), 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- nitro -5- trifluoromethyl pyridine
It is added in toluene (50ml) solution of the bromo- 3- nitro -5- trifluoromethyl pyridine (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- amido -2- cyano -5- trifluoromethyl pyridine
2- cyano -3- nitro -5- trifluoromethyl pyridine (s) (1.0g, 4.61mmol) is dissolved in ethyl acetate (20ml) and adds afterwards Enter 10% palladium/active carbon (0.10g), is filtered after 1 atmospheric pressure stirring under hydrogen 18 hours, obtains crude product (t) after concentration directly It connects for reacting in next step.
(iv) synthesis (u) of 3- amido -5- trifluoromethyl -2- pyridine carboxylic acid formicester
Above-mentioned 3- amido -2- cyano -5- trifluoromethyl pyridine (t) is dissolved in concentrated hydrochloric acid (5ml) and the mixing of methanol (5ml) is molten Agent, reflux removed solvent after 48 hours, and gained crude product after silica gel column chromatography column purification (5:1 petrol ether/ethyl acetate) with being produced Product (u) (256mg, 1.16mmol)
(v) synthesis (v) of the bromo- 5- trifluoromethyl -2- pyridine carboxylic acid formicester of 3- amido -6-,
In 3- amido -5- trifluoromethyl -2- pyridine carboxylic acid formicester (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 Temperature is diluted after lower stirring 24 hours with water (50ml), after sodium bicarbonate is neutralized to pH=7, is extracted with methylene chloride (3x30ml) It taking, organic phase facilitates with saturated sodium bicarbonate solution (30ml), after water (30ml) and saturated sodium chloride solution (20ml) washing, warp Anhydrous sodium sulfate is dry, and gained crude product is with obtaining product after silica gel column chromatography column purification (5: 1 petrol ether/ethyl acetate) after concentration (v) (843mg, 2.82mmol).
(vi) synthesis of 3- amido -6- (2,6- difluorophenyl) -5- trifluoromethyl -2- pyridine carboxylic acid (E7)
Referring to the synthesis of E2, the fluoro- 2- pyridine carboxylic acid methyl esters 3- amine of 3- amido -6- (2,6- difluorophenyl) -5- therein The bromo- 5- trifluoromethyl -2- pyridine carboxylic acid formicester (v) of base -6- replaces that product (E7) is made.
Embodiment 1
Prepare the fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (piperidin-4-yl methoxyl group) pyridin-3-yl) -2- pyridinecarboxylic Amine (1)
(1) 4- (3- nitropyridine -4- yloxymethyl) piperidines -1- t-butyl formate (C1) is prepared
Under the conditions of room temperature (25 DEG C), 4- methylol-piperidines -1- t-butyl formate is added in NaH (33mg, 1.16mmol) (B1) the chloro- 3- nitro of 4- is then added in solution & stir 1 hour the THF (tetrahydrofuran) (10mL) of (250mg, 1.16mmol) Pyridine (A) (184mg, 1.39mmol).Vacuum rotating is concentrated after reactant stirs 16 hours under room temperature (20-30 DEG C).Concentration Residue by silica gel chromatography column purification (eluent: 10-30% ethyl acetate/petroleum ether) obtains product 4- (3- nitropyridine-afterwards 4- yloxymethyl) piperidines -1- t-butyl formate (C1) (245mg, 0.754mmol).
(2) 4- (((3- aminopyridine -4- base) oxygroup) methyl) piperidines -1- t-butyl formate (D1) is prepared
C1 (200mg, 0.593mmol) is added in methanol (2ml) and acetic acid in 10%Pd/C (20mg) under room temperature (25 DEG C) In the mixed solution of ethyl ester (2ml).Reactant filters after stirring 10 hours under hydrogen (1 atmospheric pressure).After concentrating filter liquor To product D1 (167mg, 0.546mmol).
(3) 4- (((3- (6- (2,6- difluorophenyl) -5- fluorine picolinamide base) pyridin-4-yl) oxygroup) methyl) piperidines - The preparation of 1- t-butyl formate (Boc-F1)
Compound (D1) (49mg, 0.16mmol), compound 6- (2,6- difluorophenyl) -5- fluorine picolinic acid (E1) The mixture of (40mg, 0.16mmol), HATU (72mg, 0.19mmol) and DIEA (88 μ L, 0.51mmol) in DMF (5mL) It is stirred 1 hour at 50 DEG C.It is diluted after cooling with ethyl acetate (50mL), then with saturated common salt water washing.Organic phase is through Na2SO4 Vacuum rotating is concentrated under room temperature (20-30 DEG C) after drying.(eluent: 10- after residue by silica gel chromatography column purification after concentration 30% ethyl acetate/petroleum ether) obtain product Boc-F1 (33mg, 0.061mmol).
Prepare the fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (piperidin-4-yl methoxyl group) pyridin-3-yl) -2- pyridinecarboxylic Amine (1)
Under the conditions of room temperature (25 DEG C), by TFA (trifluoracetic acid) (0.5mL) be added compound (1A) (20mg, CH 0.037mmol)2Cl2(1mL) solution stirs 10 minutes, under room temperature (25 DEG C) after vacuum rotating concentration, residue is molten In CH2Cl2(10mL), solution are washed with the sodium hydroxide (5mL) of 1 equivalent and saturated salt solution (5mL) respectively, organic phase warp Na2SO4Vacuum rotating is concentrated and product 1 (14mg, 0.032mmol) is made under room temperature (25 DEG C) after drying.
Embodiment 2
Prepare N- (4- (azetidine -3- ylmethoxy) pyridin-3-yl) fluoro- 2- pyrrole of -6- (2,6- difluorophenyl) -5- Pyridine formamide (2)
Preparation method is referring to embodiment 1.The wherein compound B-11 of step (1) 3- methylol-azetidine -1- formic acid The tert-butyl ester (B2) replaces, and product 2 is made.
Embodiment 3
Prepare the fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (piperidin-4-yl oxygroup) pyridin-3-yl) -2- pyridine carboxamide (3)
Preparation method is referring to embodiment 1.The wherein compound B-11 of step (1) 4- hydroxyl-piperidines -1- t-butyl formate (B3) Instead of product 3 is made.
Embodiment 4
Prepare the fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (pyrroles's -3- base oxygroup) pyridin-3-yl) -2- pyridine carboxamide (4)
Preparation method is referring to embodiment 1.The wherein compound B-11 of step (1) 3- hydroxy-pyrrolidine -1- t-butyl formate (B4) it replaces, product 4 is made.
Embodiment 5
Prepare the fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (piperidines -3- base oxygroup) pyridin-3-yl) -2- pyridine carboxamide (5)
Preparation method is referring to embodiment 1.The wherein compound B-11 of step (1) 3- hydroxy piperidine -1- t-butyl formate (B5) it replaces, product 5 is made.
Embodiment 6
Prepare N- (4- (azacyclo- hept- 4- base oxygroup) pyridin-3-yl) fluoro- 2- pyridine first of -6- (2,6- difluorophenyl) -5- Amide (6)
Preparation method is referring to embodiment 1.Wherein the compound B-11 of step (1) is with 4- hydroxy-azepane -1- formic acid uncle Butyl ester (B6) replaces, and product 6 is made.
Embodiment 7
Prepare the fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (piperidines -3- ylmethoxy) pyridin-3-yl) -2- pyridinecarboxylic Amine (7)
Preparation method is referring to embodiment 1.The wherein compound B-11 of step (1) 4- methylol-piperidines -1- t-butyl formate (B7) it replaces, product 7 is made.
Embodiment 8
Prepare the fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (pyrroles -3- ylmethoxy) pyridin-3-yl) -2- pyridinecarboxylic Amine (8)
Preparation method is referring to embodiment 1.The wherein compound B-11 of step (1) 3- methylol-tertiary fourth of pyrrolidines -1- formic acid Ester (B8) replaces, and product 8 is made.
Embodiment 9
Prepare N- (4- (azetidin -3- base oxygroup) pyridin-3-yl) fluoro- 2- pyridine first of -6- (2,6- difluorophenyl) -5- Amide (9)
Preparation method is referring to embodiment 1.Wherein the compound B-11 of step (1) is with 3- hydroxyl -1- azetidinecarboxylic acid uncle Butyl ester (B9) replaces, and product 9 is made.
Embodiment 10
Prepare N- (4- (((1r, 4r) -4- aminocyclohexyl) oxygroup) pyridin-3-yl) -6- (2,6- difluorophenyl) -5- Fluoro- 2- pyridine carboxamide (10)
Preparation method is referring to embodiment 1.The wherein trans- 4- hydroxy-cyciohexyl-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- aminocyclohexyl) oxygroup) pyridin-3-yl) fluoro- 2- pyridine of -6- (2,6- difluorophenyl) -5- Formamide (11)
Preparation method is referring to embodiment 1.The wherein compound B-11 of step (1) 3- hydroxy-cyciohexyl-tertiary fourth of carbamic acid Ester (B11) replaces, and product 11 is made.
Embodiment 12
Prepare N- (4- (3- amine propoxyl group) pyridin-3-yl) fluoro- 2- pyridine carboxamide of -6- (2,6- difluorophenyl) -5- (12)
Preparation method is referring to embodiment 1.The wherein compound B-11 of step (1) 3- hydroxypropylamine -1- t-butyl formate (B12) it replaces, product 12 is made.
Embodiment 13
Prepare the fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (3- (methylamino) propoxyl group) pyridin-3-yl) -2- pyridine first Amide (13)
Preparation method is referring to embodiment 1.Wherein the compound B-11 of step (1) is with N- methyl -3- hydroxypropylamine -1- formic acid uncle Butyl ester (B13) replaces, and product 13 is made.
Embodiment 14
Prepare 6- (2,6- difluorophenyl)-N- (4- (3- (dimethyl amido) propoxyl group) pyridin-3-yl) fluoro- 2- pyrrole of -5- Pyridine formamide (14)
Preparation method is referring to embodiment 1.Wherein compound B-11 N, the N- dimethyl -3- hydroxypropylamine (B14) of step (1) Instead of step (3) deprotection is omitted, and product 14 is made.
Embodiment 15
Prepare N- (4- (4- amido butoxy) pyridin-3-yl) fluoro- 2- pyridine carboxamide of -6- (2,6- difluorophenyl) -5- (15)
Preparation method is referring to embodiment 1.The wherein compound B-11 of step (1) 4- hydroxyl butylamine -1- t-butyl formate (B15) it replaces, product 15 is made.
Embodiment 16
Prepare the fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (4- (methylamino) butoxy) pyridin-3-yl) -2- pyridine first Amide (16)
Preparation method is referring to embodiment 1.Wherein the compound B-11 of step (1) is with N- methyl -4- hydroxyl butylamine -1- formic acid uncle Butyl ester (B16) replaces, and product 16 is made.
Embodiment 17
Prepare the fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (3- hydroxy propyloxy group) pyridin-3-yl) -2- pyridine carboxamide (17)
Preparation method is referring 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 the fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (3- hydroxybutoxy) pyridin-3-yl) -2- pyridine carboxamide (18)
Preparation method is referring 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 the fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (4- hydroxy butoxy) pyridin-3-yl) -2- pyridine carboxamide (19)
Preparation method is referring 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 the fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- ((4- hydroxy-4-methyl amoxy) pyridin-3-yl) -2- pyrrole Pyridine formamide (20)
Preparation method is referring to embodiment 1.The wherein compound B-11 4- methyl-1 of step (1), 4- pentanediol (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) pyridin-3-yl) fluoro- 2- pyridine first of -5- Amide (21)
(1) 6- (2,6- difluorophenyl)-N- (4- (2- (2,2- dimethyl -1,3-dioxolane -4-) ethyoxyl -) pyridine - 3- yl) the fluoro- 2- pyridine carboxamide of -5- (Protected F21) preparation
Preparation method referring 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- base) ethyl alcohol (B21) replacement, product E21 is made.
(2) 6- (2,6- difluorophenyl)-N- (4- (3,4- dihydroxy butoxy) pyridin-3-yl) the fluoro- 2- pyridinecarboxylic of -5- The preparation of amine (21)
Under the conditions of room temperature (25 DEG C), ProtectedF21 (20mg, 0.042mmol) is dissolved in methanol (2mL) and is added afterwards Concentrated hydrochloric acid (0.5mL), stirring used 10%Na after 4 hours2CO3Solution is neutralized to pH=7, add water (20mL) by vacuum filter and 25 DEG C be air-dried after obtain product 21 (11mg, 0.025mmol).
Embodiment 22
Prepare the fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (oxinane -4- methoxyl group)-pyridin-3-yl) -2- pyridine Formamide (22)
Preparation method is referring 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 the fluoro- N- of 3- amido -6- (2,6- difluorophenyl) -5- (4- (piperidin-4-yl methoxyl group) pyridin-3-yl) -2- Pyridine carboxamide (23)
Preparation method is referring to embodiment 1.The wherein 3- amido -6- (2,6- difluorophenyl)-of the compound E1 in step (3) The fluoro- 2-Pyridinecarboxylic Acid of 5- (E2) replaces, and product 23 is made.
Embodiment 24
Prepare the fluoro- N- of 3- amido -6- (2,6- difluorophenyl) -5- (4- (pyrroles's -3- base oxygroup) pyridin-3-yl) -2- pyrrole Pyridine formamide (24)
Preparation method is referring to embodiment 23.Wherein the compound B-11 of step (1) is replaced with B4, and product 24 is made.
Embodiment 25
Prepare the fluoro- N- of 3- amido -6- (2,6- difluorophenyl) -5- (4- (piperidin-4-yl oxygroup) pyridin-3-yl) -2- pyrrole Pyridine formamide (25)
Preparation method is referring to embodiment 23.Wherein the compound B-11 of step (1) is replaced with B3, and product 25 is made.
Embodiment 26
It is fluoro- to prepare 3- amido-N- (4- (azacyclo- hept- 4- base oxygroup) pyridin-3-yl) -6- (2,6- difluorophenyl) -5- 2- pyridine carboxamide (26)
Preparation method is referring to embodiment 23.Wherein the compound B-11 of step (1) is replaced with B6, and product 26 is made.
Embodiment 27
Prepare 3- amido-N- (4- (((1r, 4r) -4- aminocyclohexyl) oxygroup) pyridin-3-yl) -6- (2,6- difluorobenzenes Base) the fluoro- 2- pyridine carboxamide (27) of -5-
Preparation method is referring to embodiment 23.Wherein the compound B-11 of step (1) is replaced with B10, and product 27 is made.
Embodiment 28
Prepare the fluoro- N- of 3- amido -6- (2,6- difluorophenyl) -5- (4- (pyrroles -3- ylmethoxy) pyridin-3-yl) -2- Pyridine carboxamide (28)
Preparation method is referring to embodiment 23.Wherein the compound B-11 of step (1) is replaced with B8, and product 28 is made.
Embodiment 29
Prepare N- (4- ((1- amido -3- chloropropyl -2- base) oxygroup) pyridin-3-yl) -6- (2,6- difluorophenyl) -5- Fluoro- 2- pyridine carboxamide (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- amido -2- (chloromethyl) propoxyl group) pyridin-3-yl) fluoro- 2- of -6- (2,6- difluorophenyl) -5- Pyridine carboxamide (30)
Preparation method is referring to embodiment 29.Compound 9 therein is replaced with 2, and product 30 is made.
Embodiment 31
It is fluoro- to prepare 3- amido-N- (4- (azetidin -3- base oxygroup) pyridin-3-yl) -6- (2,6- difluorophenyl) -5- 2- pyridine carboxamide (31)
Preparation method is referring to embodiment 23.Wherein the compound B-11 of step (1) is replaced with B9, and product 31 is made.
Embodiment 32
Prepare 3- amido-N- (4- (azetidine -3- ylmethoxy) pyridin-3-yl) -6- (2,6- difluorophenyl) -5- Fluoro- 2- pyridine carboxamide (32)
Preparation method is referring to embodiment 23.Wherein the compound B-11 of step (1) is replaced with B2, and product 32 is made.
Embodiment 33
Prepare 3- amido-N- (4- ((1- amido -3- chloropropyl -2- base) oxygroup) pyridin-3-yl) -6- (2,6- difluorobenzenes Base) the fluoro- 2- pyridyl-methanamine (33) of -5-
Preparation method is referring to embodiment 29.Compound 9 therein is replaced with compound 31, and product 33 is made.
Embodiment 34
Prepare 3- amido-N- (4- (3- amido -2- (chloromethyl) propoxyl group) pyridin-3-yl) -6- (2,6- difluorophenyl) - The fluoro- 2- pyridine carboxamide (34) of 5-
Preparation method is referring to embodiment 29.Compound 9 therein is replaced with 32, and product 34 is made.
Embodiment 35
Prepare the fluoro- N- of 3- amido -6- (2,6- difluorophenyl) -5- (4- (piperidines -3- ylmethoxy) pyridin-3-yl) -2- Pyridine carboxamide (35)
Preparation method is referring to embodiment 23.Wherein the compound B-11 of step (1) is replaced with B7, and product 35 is made.
Embodiment 36
Prepare 3- amido-N- (4- (4- amido butoxy) pyridin-3-yl) fluoro- 2- pyridine of -6- (2,6- difluorophenyl) -5- Formamide (36)
Preparation method is referring to embodiment 23.Wherein the compound B-11 of step (1) is replaced with B15, and product 36 is made.
Embodiment 37
It is fluoro- to prepare 3- amido-N- (4- ((3- aminocyclohexyl) oxygroup) pyridin-3-yl) -6- (2,6- difluorophenyl) -5- 2- pyridine carboxamide (37)
Preparation method is referring to embodiment 23.Wherein the compound B-11 of step (1) is replaced with B11, and product 37 is made.
Embodiment 38
Prepare the fluoro- 6- phenyl-N- of 3- amido -5- (4- (pyrrolidin-3-yl oxygroup) pyridin-3-yl) -2- pyridine carboxamide (38)
Preparation method is referring to embodiment 1.Wherein the compound B-11 of step (1) is replaced with B4, and the compound E1 of step (2) is used The fluoro- 6- phenyl of 3- amido -5-) -2-Pyridinecarboxylic Acid (E3) replacement, product 38 is made.
Embodiment 39
Prepare the fluoro- N- of 3- (4- (piperidin-4-yl oxygroup) pyridin-3-yl)-(2,4 '-bipyridyl) -6- formamide (39)
Preparation method is referring to embodiment 1.Wherein the compound B-11 of step (1) is replaced with B3, and the compound E1 of step (2) is used Fluoro- (2,4 '-connect the pyridine) -6- carboxylic acid (E4) of 3- replaces, and product 39 is made.
Embodiment 40
Prepare N- (4- (azacyclo- hept- 4- base oxygroup) pyridin-3-yl) fluoro- 2- pyridine first of -6- (2,6- difluorophenyl) -3- Amide (40)
Preparation method is referring to embodiment 1.Wherein the compound B-11 of step (1) is replaced with B6, and the compound E1 of step (2) is used 6- (2,6- difluorophenyl) -3- fluorine picolinic acid (E5) replaces, and product 40 is made.
Embodiment 41
Prepare N- (4- (azacyclo- hept- 4- base oxygroup) pyridin-3-yl) the fluoro- 6- of -5- (the fluoro- 6- methoxyphenyl of 2-) -2- Pyridine carboxamide (41)
Compound 6 (10mg, 0.023mmol) is dissolved in the methanol solution (1ml) of 0.1M sodium hydroxide, is stirred at 50 DEG C 2 hours.Obtained solid is washed with water after removing solvent, is dried to obtain product 41 (8mg, 0.018mmol).
Embodiment 42
Prepare N- (4- (azacyclo- hept- 4- base oxygroup) pyridin-3-yl) -6- (2,6- difluorophenyl) -5- trifluoromethyl -2- Pyridine carboxamide (42)
Preparation method is referring to embodiment 1.Wherein the compound B-11 of step (1) is with 4- hydroxy-azepane -1- formic acid uncle Butyl ester (B6) replaces, and the compound E1 of step (2) is with 6- (2,6- difluorophenyl) -5- trifluoromethyl -2- pyridine carboxylic acid (E6) generation It replaces, product 42 is made.
Embodiment 43
Prepare 6- (2,6- difluorophenyl)-N- (4- (piperidin-4-yl methoxyl group) pyridin-3-yl) -5- trifluoromethyl -2- pyrrole Pyridine formamide (43)
Preparation method is referring to embodiment 1.The wherein compound E1 of step (2) 6- (2,6- difluorophenyl) -5- fluoroform Base -2- pyridine carboxylic acid (E6) replaces, and product 43 is made.
Embodiment 44
Prepare N- (4- (azetidin -3- ylmethoxy) pyridin-3-yl) -6- (2,6- difluorophenyl) -5- trifluoromethyl - 2- pyridine carboxamide (44)
Preparation method is referring to embodiment 1.The wherein compound B-11 of step (1) 3- methylol-azetidine -1- formic acid The tert-butyl ester (B2) replaces, compound E1 6- (2,6- the difluorophenyl) -5- trifluoromethyl -2- pyridine carboxylic acid (E6) of step (2) Instead of product 44 is made.
Embodiment 45
Prepare 6- (2,6- difluorophenyl)-N- (4- (piperidin-4-yl oxygroup) pyridin-3-yl) -5- trifluoromethyl -2- pyridine Formamide (45)
Preparation method is referring to embodiment 1.The wherein compound B-11 of step (1) 4- hydroxyl-piperidines -1- t-butyl formate (B3) Instead of the compound E1 of step (2) is replaced with 6- (2,6- difluorophenyl) -5- trifluoromethyl -2- pyridine carboxylic acid (E6), is made and is produced Object 45.
Embodiment 46
Prepare N- (4- (((1r, 4r) -4- aminocyclohexyl) oxygroup) pyridin-3-yl) -6- (2,6- difluorophenyl) -5- three Methyl fluoride -2- pyridine carboxamide (46)
Preparation method is referring to embodiment 1.The wherein trans- 4- hydroxy-cyciohexyl-carbamic acid of the compound B-11 of step (1) The tert-butyl ester (B10) replaces, compound E1 6- (2,6- the difluorophenyl) -5- trifluoromethyl -2- pyridine carboxylic acid (E6) of step (2) Instead of product 46 is made.
Embodiment 47
Preparation 6- (2,6- difluorophenyl)-N- [4- (tetrahydropyran -4-base) oxygroup) pyridin-3-yl) -5- trifluoromethyl - 2- pyridine carboxamide (47)
Preparation method is referring to embodiment 1.Wherein the compound B-11 of step (1) is replaced with oxinane -4- methanol (B22), The compound E1 of step (2) is replaced with 6- (2,6- difluorophenyl) -5- trifluoromethyl -2- pyridine carboxylic acid (E6), step (3) remove-insurance Shield is omitted, and product 47 is made.
Embodiment 48
Prepare 3- amido-N- (4- (azacyclo- hept- 4- base oxygroup) pyridin-3-yl) -6- (2,6- difluorophenyl) -5- trifluoro Methyl -2- pyridine carboxamide (48)
Preparation method is referring to embodiment 1.Wherein the compound B-11 of step (1) is with 4- hydroxy-azepane -1- formic acid uncle Butyl ester (B6) replaces, compound E1 3- amido -6- (2,6- the difluorophenyl) -5- trifluoromethyl -2- pyridine carboxylic acid of step (2) (E7) it replaces, product 48 is made.
Embodiment 49
Prepare 3- amido -6- (2,6- difluorophenyl)-N- (4- (piperidin-4-yl methoxyl group) pyridin-3-yl) -5- fluoroform Base -2- pyridine carboxamide (49)
Preparation method is referring to embodiment 1.The wherein compound E1 of step (2) 3- amido -6- (2,6- difluorophenyl) -5- Trifluoromethyl -2- pyridine carboxylic acid (E7) replaces, and product 49 is made.
Embodiment 50
Prepare 3- amido-N- (4- (azetidin -3- ylmethoxy) pyridin-3-yl) -6- (2,6- difluorophenyl) -5- three Methyl fluoride -2- pyridine carboxamide (50)
Preparation method is referring to embodiment 1.The wherein compound B-11 of step (1) 3- methylol-azetidine -1- formic acid The tert-butyl ester (B2) replaces, compound E1 3- amido -6- (2,6- difluorophenyl) -5- trifluoromethyl -2- pyridine first of step (2) Sour (E7) is replaced, and product 50 is made.
Embodiment 51
Prepare 3- amido -6- (2,6- difluorophenyl)-N- (4- (piperidin-4-yl oxygroup) pyridin-3-yl) -5- fluoroform Base -2- pyridine carboxamide (51)
Preparation method is referring to embodiment 1.The wherein compound B-11 of step (1) 4- hydroxyl-piperidines -1- t-butyl formate (B3) Instead of the compound E1 of, step (2) with 3- amido -6- (2,6- difluorophenyl) -5- trifluoromethyl -2- pyridine carboxylic acid (E7) generation It replaces, product 51 is made.
Embodiment 52
Prepare 3- amido-N- (4- (((1r, 4r) -4- aminocyclohexyl) oxygroup) pyridin-3-yl) -6- (2,6- difluorobenzenes Base) -5- trifluoromethyl -2- pyridine carboxamide (52)
Preparation method is referring to embodiment 1.The wherein trans- 4- hydroxy-cyciohexyl-carbamic acid of the compound B-11 of step (1) The tert-butyl ester (B10) replaces, compound E1 3- amido -6- (2,6- the difluorophenyl) -5- trifluoromethyl -2- pyridine of step (2) Formic acid (E7) replaces, and product 52 is made.
Embodiment 53
Prepare 3- amido -6- phenyl-N- (4- (pyrrolidin-3-yl oxygroup) pyridin-3-yl) -5- trifluoromethyl -2- pyridine Formamide (53)
Preparation method is referring to embodiment 1.The wherein compound B-11 of step (1) 3- hydroxy-pyrrolidine -1- t-butyl formate (B4) it replaces, compound E1 3- amido -6- (2,6- the difluorophenyl) -5- trifluoromethyl -2- pyridine carboxylic acid (E7) of step (2) Instead of product 53 is made.
Embodiment 54
Prepare N- (4- (3- amido -2- (chloromethyl) propoxyl group) pyridin-3-yl) -6- (2,6- difluorophenyl) -5- trifluoro Methyl -2- pyridine carboxamide (54)
Preparation method is referring to embodiment 29.Compound 9 therein is replaced with compound 44, and product 54 is made.
Embodiment 55
Prepare 3- amido-N- (4- (3- amido -2- (chloromethyl) propoxyl group) pyridin-3-yl) -6- (2,6- difluorophenyl) - 5- trifluoromethyl -2- pyridine carboxamide (55)
Preparation method is referring to embodiment 29.Compound 9 therein is replaced with compound 50, and product 55 is made.
Embodiment 56
Prepare N- (4- (3- amido -2- (methylol) propoxyl group) pyridin-3-yl) fluoro- 2- of -6- (2,6- difluorophenyl) -5- Pyridine carboxamide (56)
Compound 2 (40mg, 0.096mmol) is dissolved in 1: 1 trifluoracetic acid and methanol solution (1ml), stirring 4 at room temperature It is neutralized after hour with saturated sodium carbonate solution, removes solvent, obtained solid silica gel column chromatography column purification (1: 1 ethyl acetate/petroleum Ether) after obtain compound 56 (10mg, 0.023mmol)
Embodiment 57
Prepare 3- amido-N- (4- (3- amido -2- (methylol) propoxyl group) pyridin-3-yl) -6- (2,6- difluorophenyl) - The fluoro- 2- pyridine carboxamide (57) of 5-
Preparation method is referring to embodiment 56.Compound 2 therein is replaced with compound 32, and product 57 is made.
Embodiment 58
Prepare N- (4- (3- amido -2- (methylol) propoxyl group) pyridin-3-yl) -6- (2,6- difluorophenyl) -5- trifluoro Methyl -2- pyridine carboxamide (58)
Preparation method is referring to embodiment 56.Compound 2 therein is replaced with compound 44, and product 58 is made.
Embodiment 59
Prepare 3- amido-N- (4- (3- amido -2- (methylol) propoxyl group) pyridin-3-yl) -6- (2,6- difluorophenyl) - 5- trifluoromethyl -2- pyridine carboxamide (59)
Preparation method is referring to embodiment 56.Compound 2 therein is replaced with compound 50, and product 59 is made.
The structural analysis data of prepared compound in 1. embodiment of the present invention of table
Embodiment 60
R3Substituent group inhibits the influence of PIM-1 kinase activity to the compounds of this invention
In order to verify R3Substituent group inhibits the influence of PIM-1 kinase activity to the compounds of this invention (general formula I), we design 6 groups have different structure, the compound with different functional groups, and have synthesized this 6 groups with the method that above-described embodiment describes 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 inhibition 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 3.1 times of 1b, therefore the activity of compound 1b is 3.1 times of compound 1a.In this 6 groups of compounds, It is 3.1 times (compound 1a/1b) that activity, which improves least, and improving most is 8.3 times (compound 3a/3c), average out to 4.4 Times.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 Substituent group (R3Respective compound for H) is significantly improved, this is different from existing knowledge.
Embodiment 61
The detection and result of the biological activity of the compounds of this invention.
The bioactivity of the compounds of this invention, which is entrusted, protects (Changping District, Beijing life section, 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 method
Kinases PIM active determination in vitro --- IMAP fluorescence polarization method
1. principle
PIM is serine/threonine protein kitase, the small peptide substrate phosphorylation that 5-FAM can be marked.It is unphosphorylated Substrate not can be incorporated on binding reagents (immobilization metal chelates pearl), and fluorescence polarization value is lower.And the small peptide of phosphorylation can be with It is integrated on binding reagents, so that fluorescence polarization value increases.The high low reaction of the small peptide substrate phosphorylation degree of 5-FAM label The size of PIM kinase activity.By testing the compounds of this invention under a certain concentration to the inhibiting effect of PIM kinase activity, These compounds can be determined to the rejection ability of PIM kinase activity.
2. instrument
EnVision, PerkinElmer
3. reagent and 384 orifice plates
PIM1 (Millipore catalog number (Cat.No.) 14-573) (Millipore Corporation company, the U.S. Gou Bai)
PIM2 (Millipore catalog number (Cat.No.) 14-607) (is purchased from U.S. Millipore Corporation company)
The small peptide (5-FAM-RSRHSSYPAGT, AnaSpec catalog number (Cat.No.) #63801) of 5-FAM label (is purchased from the U.S. AnaSpec Inc. company)
IMAP FP Screening Express kit (IMAP FP screening reagent box) (Molecular Devices mesh Record #R8127) (being purchased from U.S. Molecular Devices company)
IMAP Progressive binding reagent (IMAP bonding agent)
IMAP Progressive binding buffer A (5X) (IMAP combination buffer A)
IMAP Progressive binding buffer B (5X) (IMAP combination buffer B)
384-well black plate (Corning, catalog number (Cat.No.) #3573) (is purchased from U.S. Corning company)
4. surveying buffer living
Tris-HCl (trishydroxymethylaminomethane-hydrochloric acid) (pH 7.2): 10mM
MgCl2: 10mM
Triton X-100 (Triton X-100 X-100): 0.01%
DTT (dithiothreitol (DTT)): 2mM
5. step
The compounds of this invention used in this experiment is made by above-described embodiment.
A) the compounds of this invention liquid storage of 10mM is diluted to respective concentration with 100%DMSO (dimethyl sulfoxide), then changes It closes object and dilutes 10 times with buffer (dithiothreitol (DTT)) living is surveyed, make DMSO concentration 10%.
B) live body system 10ul:
1ul compound and 4ul enzyme (PIM-1 and the final concentration of 3nM of PIM-3 final concentration of 0.025nM, PIM-2) are in 23 DEG C It is incubated for 15 minutes, 2.5ul ATP is 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) originate 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 in the reaction system of minimum value control with survey slow Fliud flushing (dithiothreitol (DTT)) replaces enzyme.
C) be added 30ul IMAP bonding agent (containing 75%IMAP combination buffer 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, emits light 530nm.
6. data processing
Suppression percentage=(fluorescence polarization value mP- minimum value) × 100/ (maximum value-minimum value)
Tested through PIM kinases biochemical activity method 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 0.1-50nM.

Claims (14)

1. having compounds of formula I:
In above-mentioned Formulas I
R1For-H ,-NH2, F:
R2For-H；
R3For F or-CF3；R6Selected from phenyl, pyridyl group or 2,6- difluorophenyl；
R22For with or without the cyclohexyl of substituent group, suberyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, nitrogen Trioxepane base, cyclobutylmethyl, cyclopentyl-methyl, cyclohexyl methyl, CycloheptylmethyI, azetidine ylmethyl, pyrroles Alkyl methyl, piperidino methyl, piperizinylmethyl, azepan ylmethyl, epoxy butane ylmethyl, tetrahydrofuran ylmethyl Or oxinane ylmethyl；The R with substituent group22There are one or more substituent groups, the substituent group is respectively selected from- NH2,-OH, methyl, ethyl or methoxyl group；
Or R22For the C with substituent group2-C5Alkyl, can have up to 4 substituent groups on these alkyl, and the substituent group respectively can To be F, Cl, Br, I, NH2, methylamino, ethylamino-, Propylamino, dimethylamino, diethylin, hydroxyl, methyl, ethyl, propyl, Monohaloalkyl methyl, polyhalo methyl, monohaloalkyl ethyl, polyhalo ethyl.
2. a kind of compound, which is characterized in that the compound is following compounds:
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (piperidin-4-yl methoxyl group) pyridin-3-yl) -2- pyridine carboxamide
N- (4- (azetidine -3- ylmethoxy) pyridin-3-yl) fluoro- 2- pyridine carboxamide of -6- (2,6- difluorophenyl) -5-
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (piperidin-4-yl oxygroup) pyridin-3-yl) -2- pyridine carboxamide
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (pyrroles's -3- base oxygroup) pyridin-3-yl) -2- pyridine carboxamide
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (piperidines -3- base oxygroup) pyridin-3-yl) -2- pyridine carboxamide
N- (4- (azacyclo- hept- 4- base oxygroup) pyridin-3-yl) fluoro- 2- pyridine carboxamide of -6- (2,6- difluorophenyl) -5-
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (piperidines -3- ylmethoxy) pyridin-3-yl) -2- pyridine carboxamide
The fluoro- N| of 6- (2,6- difluorophenyl) -5- (4- (pyrroles -3- ylmethoxy) pyridin-3-yl) -2- pyridine carboxamide
N- (4- (azetidin -3- base oxygroup) pyridin-3-yl) fluoro- 2- pyridine carboxamide of -6- (2,6- difluorophenyl) -5-
N- (4- (((1r, 4r) -4- aminocyclohexyl) oxygroup) pyridin-3-yl) fluoro- 2- pyridine of -6- (2,6- difluorophenyl) -5- Formamide
N- (4- ((3- aminocyclohexyl) oxygroup) pyridin-3-yl) fluoro- 2- pyridine carboxamide of -6- (2,6- difluorophenyl) -5-
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (3- (methylamino) propoxyl group) pyridin-3-yl) -2- pyridine carboxamide
6- (2,6- difluorophenyl)-N- (4- (3- (dimethyl amido) propoxyl group) pyridin-3-yl) fluoro- 2- pyridine carboxamide of -5-
N- (4- (4- amido butoxy) pyridin-3-yl) fluoro- 2- pyridine carboxamide of -6- (2,6- difluorophenyl) -5-
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (4- (methylamino) butoxy) pyridin-3-yl) -2- pyridine carboxamide
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (3- hydroxy propyloxy group) pyridin-3-yl) -2- pyridine carboxamide
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (3- hydroxybutoxy) pyridin-3-yl) -2- pyridine carboxamide
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (4- hydroxy butoxy) pyridin-3-yl) -2- pyridine carboxamide
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- ((4- hydroxy-4-methyl amoxy) pyridin-3-yl) -2- pyridine carboxamide
6- (2,6- difluorophenyl)-N- (4- (3,4- dihydroxy butoxy) pyridin-3-yl) fluoro- 2- pyridine carboxamide of -5-
The fluoro- N- of 6- (2,6- difluorophenyl) -5- (4- (oxinane -4- methoxyl group)-pyridin-3-yl) -2- pyridine carboxamide
The fluoro- N- of 3- amido -6- (2,6- difluorophenyl) -5- (4- (piperidin-4-yl methoxyl group) pyridin-3-yl) -2- pyridinecarboxylic Amine
The fluoro- N- of 3- amido -6- (2,6- difluorophenyl) -5- (4- (pyrroles's -3- base oxygroup) pyridin-3-yl) -2- pyridine carboxamide
The fluoro- N- of 3- amido -6- (2,6- difluorophenyl) -5- (4- (piperidin-4-yl oxygroup) pyridin-3-yl) -2- pyridine carboxamide
3- amido-N- (4- (azacyclo- hept- 4- base oxygroup) pyridin-3-yl) fluoro- 2- pyridine first of -6- (2,6. difluorophenyl) -5- Amide
3- amido-N- (4- (((1r, 4r) -4- aminocyclohexyl) oxygroup) pyridin-3-yl) -6- (2,6- difluorophenyl) -5- is fluoro- 2- pyridine carboxamide
The fluoro- N- of 3- amido -6- (2,6- difluorophenyl) -5- (4- (pyrroles -3- ylmethoxy) pyridin-3-yl) -2- pyridinecarboxylic Amine
N- (4- ((1- amido -3- chloropropyl -2- base) oxygroup) pyridin-3-yl) fluoro- 2- pyridine of -6- (2,6- difluorophenyl) -5- Formamide
N- (4- (3- amido -2- (chloromethyl) propoxyl group) pyridin-3-yl) fluoro- 2- pyridinecarboxylic of -6- (2,6- difluorophenyl) -5- Amine
3- amido-N- (4- (azetidin -3- base oxygroup) pyridin-3-yl) fluoro- 2- pyridine first of -6- (2,6- difluorophenyl) -5- Amide
3- amido-N- (4- (azetidine -3- ylmethoxy) pyridin-3-yl) fluoro- 2- pyrrole of -6- (2,6- difluorophenyl) -5- Pyridine formamide
3- amido-N- (4- ((1- amido -3- chloropropyl -2- base) oxygroup) pyridin-3-yl) -6- (2,6- difluorophenyl) -5- is fluoro- 2- pyridine carboxamide
3- amido-N- (4- (3- amido -2- (chloromethyl) propoxyl group) pyridin-3-yl) fluoro- 2- of -6- (2,6- difluorophenyl) -5- Pyridine carboxamide
The fluoro- N- of 3- amido -6- (2,6- difluorophenyl) -5- (4- (piperidines -3- ylmethoxy) pyridin-3-yl) -2- pyridinecarboxylic Amine
3- amido-N- (4- (4- amido butoxy) pyridin-3-yl) fluoro- 2- pyridine carboxamide of -6- (2,6- difluorophenyl) -5-
3- amido-N- (4- ((3- aminocyclohexyl) oxygroup) pyridin-3-yl) fluoro- 2- pyridine first of -6- (2,6- difluorophenyl) -5- Amide
The fluoro- 6- phenyl-N- of 3- amido -5- (4- (pyrrolidin-3-yl oxygroup) pyridin-3-yl) -2- pyridine carboxamide
The fluoro- N- of 3- (4- (piperidin-4-yl oxygroup) pyridin-3-yl)-(2,4 '-bipyridyl) -6- formamide
N- (4- (azacyclo- hept- 4- base oxygroup) pyridin-3-yl) fluoro- 2- pyridine carboxamide of -6- (2,6- difluorophenyl) -3-
N- (4- (azacyclo- hept- 4- base oxygroup) pyridin-3-yl) the fluoro- 6- of -5- (the fluoro- 6- methoxyphenyl of 2-) -2- pyridinecarboxylic Amine
N- (4- (azacyclo- hept- 4- base oxygroup) pyridin-3-yl) -6- (2,6- difluorophenyl) -5- trifluoromethyl -2- pyridinecarboxylic Amine
6- (2,6- difluorophenyl)-N- (4- (piperidin-4-yl methoxyl group) pyridin-3-yl) -5- trifluoromethyl -2- pyridine carboxamide
N- (4- (azetidin -3- ylmethoxy) pyridin-3-yl) -6- (2,6- difluorophenyl) -5- trifluoromethyl -2- pyridine first Amide
6- (2,6- difluorophenyl)-N- (4- (piperidin-4-yl oxygroup) pyridin-3-yl) -5- trifluoromethyl -2- pyridine carboxamide
N- (4- (((1r, 4r) -4- aminocyclohexyl) oxygroup) pyridin-3-yl) -6- (2,6- difluorophenyl) -5- trifluoromethyl - 2- pyridine carboxamide
6- (2,6- difluorophenyl)-N- [4- (tetrahydropyran -4-base) oxygroup) pyridin-3-yl) -5- trifluoromethyl -2- pyridine first Amide
3- amido-N- (4- (azacyclo- hept- 4- base oxygroup) pyridin-3-yl) -6- (2,6- difluorophenyl) -5- trifluoromethyl -2- Pyridine carboxamide
3- amido -6- (2,6- difluorophenyl)-N- (4- (piperidin-4-yl methoxyl group) pyridin-3-yl) -5- trifluoromethyl -2- pyrrole Pyridine formamide
3- amido-N- (4- (azetidin -3- ylmethoxy) pyridin-3-yl) -6- (2,6- difluorophenyl) -5- trifluoromethyl - 2- pyridine carboxamide
3- amido -6- (2,6- difluorophenyl)-N- (4- (piperidin-4-yl oxygroup) pyridin-3-yl) -5- trifluoromethyl -2- pyridine Formamide
3- amido-N- (4- (((1r, 4r) -4- aminocyclohexyl) oxygroup) pyridin-3-yl) -6- (2,6- difluorophenyl) -5- three Methyl fluoride -2- pyridine carboxamide
3- amido -6- phenyl-N- (4- (pyrrolidin-3-yl oxygroup) pyridin-3-yl) -5- trifluoromethyl -2- pyridine carboxamide
N- (4- (3- amido -2- (chloromethyl) propoxyl group) pyridin-3-yl) -6- (2,6- difluorophenyl) -5- trifluoromethyl -2- pyrrole Pyridine formamide
3- amido-N- (4- (3- amido -2- (chloromethyl) propoxyl group) pyridin-3-yl) -6- (2,6 one difluorophenyl) -5- trifluoro Methyl -2- pyridine carboxamide
N- (4- (3- amido -2- (methylol) propoxyl group) pyridin-3-yl) fluoro- 2- pyridinecarboxylic of -6- (2,6- difluorophenyl) -5- Amine
3- amido-N- (4- (3- amido -2- (methylol) propoxyl group) pyridin-3-yl) fluoro- 2- of -6- (2,6- difluorophenyl) -5- Pyridine carboxamide
N- (4- (3- amido -2- (methylol) propoxyl group) pyridin-3-yl) -6- (2,6- difluorophenyl) -5- trifluoromethyl -2- pyrrole Pyridine formamide
3- amido-N- (4- (3- amido -2- (methylol) propoxyl group) pyridin-3-yl) -6- (2,6- difluorophenyl) -5- fluoroform Base -2- pyridine carboxamide
3. a kind of preparation method of any compound of claim 1-2, it is characterised in that include the following steps:
4. a kind of preparation method of compound according to claim 3, it is characterised in that include the following steps:
The alcohol B of with or without blocking group is first reacted with alkali at room temperature, then again with the chloro- 3- nitropyridine A of 4- in 25- It is reacted 1-10 hours at 50 DEG C and obtains nitro-pyrimidine ether C；It is small that C restores 4-12 under solvent appropriate and catalyst environment appropriate When after obtain amido pyridine D；The picolinic acid E of with or without blocking group in the presence of coupling reagent appropriate, alkali, It is reacted at 25-50 DEG C 1-10 hours in solvent appropriate with amido pyridine D, obtains product F；If there is no blocking group in F, F is the final ether compound in Formulas I；If have blocking group tert-butoxy formic acid esters or trimethyl silane, F again with Trifluoracetic acid and methylene chloride or methanol hydrochloride solution stir 1-16 hours after mixed at room temperature, and then decompression is steamed at room temperature Distillation obtains the final ether compound in Formulas I after removing solvent.
5. a kind of preparation method of compound according to claim 4, it is characterised in that include the following steps:
1.1 equivalent alcohol B elder generations of with or without blocking group and alkali, 1-3 equivalent NaoH in solvent, tetrahydrofuran, It reacts 1 hour at room temperature, is then reacted at 25-50 DEG C 1-10 hours with the chloro- 3- nitropyridine A of 1 equivalent 4- again and obtain nitro Pyrimidine ether C；1 equivalent C is under solvent appropriate, 1: 1 methanol and ethyl acetate and catalyst 0.1-0.5 equivalent 10%Pd/C catalysis Amido pyridine D: 1 equivalent of with or without blocking group is obtained after restoring 4-12 hours under hydrogen 1-3 atmospheric pressure environment Picolinic acid E is in coupling reagent, 1.1 equivalent HATU, alkali, in the presence of 3 equivalent DIEA, in solvent DMF with 1 equivalent amido pyridine D reacts 1-10 hours at 25-50 DEG C, obtains product F；If not having blocking group in F, F is the final ethers in Formulas I Close object；If having the tert-butoxy formic acid esters or trimethyl silane of blocking group, the F trifluoracetic acid with 10 to 100 equivalents again And isometric methylene chloride or 2 centinormal 1 methanol hydrochloride solutions stirs 1-16 hours after mixed at room temperature, then in room The lower vacuum distillation of temperature obtains the final ether compound in Formulas I after removing solvent.
6. a kind of purposes of any compound of claim 1-2, it is characterised in that: as PIM kinase inhibitor in pharmacy In application.
7. wanting the purposes of 6 compounds according to right, it is characterised in that: as PIM-1, PIM-2 and PIM-3 kinase inhibitor Application in pharmacy.
8. the purposes of compound according to claim 7, which is characterized in that prepared drug is for treating or preventing cancer Disease reverses the drug resistance of anticancer and other medicines, inflammatory bowel disease, auto-immune disease, allergic reaction disease, Atherosclerosis The inflammation that change, anti-organ transplant rejection, polytropism drug resistance, T cell mediate；Cancer refers to can be by inhibiting PIM kinases Obtain the Cancerous disease of advantageous treatment.
9. the purposes of compound according to claim 8, the cancer is solid tumor, bone marrow disorder, liquid tumor.
10. the purposes of compound according to claim 9, the solid tumor be lung cancer, cancer of pancreas, thyroid cancer, oophoroma, Bladder cancer, breast cancer, prostate cancer or colon cancer, melanoma, villous colon adenoma, osteosarcoma；The bone marrow disorder is that marrow is thin Born of the same parents' property leukaemia and erythroleukemia；The liquid tumor is chronic lymphocytic leukemia, acute lymphoblastic leukemia, acute marrow It is leukaemia, chronic myelocytic leukemia, non-Hodgkin lymphoma.
11. a kind of pharmaceutical composition based on any compound of claim 1-2, it is characterised in that: wanted including right Ask any compound of 1-2 as the pharmaceutical composition of active constituent and pharmaceutical carrier composition.
12. a kind of pharmaceutical composition of the PIM kinase inhibitor based on any compound of claim 1-2, including power Benefit requires the PIM kinase inhibitor of any compound of 1-2 as the pharmaceutical composition of active constituent and pharmaceutical carrier composition.
13. a kind of application of the pharmaceutical composition based on any compound of claim 1-2, it is characterised in that: be used for Preparation treats or prevents cancer, reverses the drug resistance of anticancer and other medicines, inflammatory bowel disease, auto-immune disease, anaphylaxis are anti- The drug for the inflammation for answering disease, atherosclerosis, anti-organ transplant rejection, polytropism drug resistance, T cell to mediate；Cancer Solid tumor, bone marrow disorder, liquid tumor can be selected from by inhibiting PIM kinases to obtain the Cancerous disease of advantageous treatment by referring to.
14. the application of the pharmaceutical composition of compound according to claim 13, it is characterised in that: the solid tumor is lung Cancer, cancer of pancreas, thyroid cancer, oophoroma, bladder cancer, breast cancer, prostate cancer or colon cancer, melanoma, villous colon adenoma, Osteosarcoma；Institute's bone marrow disorder is myelocytic leukemia, Huppert's disease and erythroleukemia；The liquid tumor is chronic lymphatic Chronic myeloid leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelocytic leukemia, non-Hodgkin lymphoma.
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