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CN105254624A - Isothiazole derivative PIM kinase inhibitor and preparation method thereof, and application of inhibitor in pharmacy - Google Patents

Isothiazole derivative PIM kinase inhibitor and preparation method thereof, and application of inhibitor in pharmacy Download PDF

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CN105254624A
CN105254624A CN201510594165.0A CN201510594165A CN105254624A CN 105254624 A CN105254624 A CN 105254624A CN 201510594165 A CN201510594165 A CN 201510594165A CN 105254624 A CN105254624 A CN 105254624A
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base
isothiazole
difluorophenyl
amido
alkyl
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CN105254624B (en
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葛羽
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SHANGHAI JIKAI MEDICAL TECHNOLOGY Co Ltd
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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
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention provides a PIM kinase inhibitor and a preparation method and application thereof. The PIM kinase inhibitor is a compound with a structural formula as shown in a general formula I which is described in the specification. The invention further provides stereoisomer, tautomer and medicinal salt of the compound as shown in the general formula I. The compound exerts obvious inhibitory effect on the activity of PIM kinase, and the IC50 value of the compound is in a range of 0.1 to 50 nM. The PIM kinase inhibitor can be used for preparation of drugs used for treating or preventing cancers, autoimmune diseases, anaphylaxis diseases or the like or resisting organ transplant rejection. The PIM kinase inhibitor has a great clinical application value.

Description

Isothizole derivatives PIM kinase inhibitor and preparation method thereof and the application in pharmacy
Technical field
The present invention relates to pharmaceutical chemistry, be specifically related to PIM kinase inhibitor and preparation method thereof and the application in pharmacy.
Background technology
PIM kinases is three homology serine/threonine kinases, belongs to calmodulin dependent protein kinase (CAMK) gang together.Research proves, PIM kinases has in hemopoietic tissue expresses (J.Biol.Chem., 280,14168-14176,2005 widely; Blood, 105,4477-4483,2005), and have important effect to cells survival and diffusion, and in human carcinoma's tumour and under inflammatory conditions, have overexpression (J.Exp.Med., 201,259-266,2005; Biochem.Soc.Trans., 32,315-319,2004).Therefore, PIM kinases is by the increasing target for studying treatment tumour and immunoregulation druge.PIM-1 (ProvirusIntegrationofMaloney1) gene is the position that in the t cell lymphoma of Moloney murine leukemia virus induction, provirus frequently inserts, the PIM-1 kinases also therefore (Cell that gains the name, 37,141-150,1984).After this find, the gene of coding PIM-2 (ProvirusIntegrationofMaloney2) also has same weakness (J.Clin.Invest., 115,2679-2688,2005).PIM-3 is KID-1 (KinaseInducedbyDepolarization1) by name at first, rear because of its protein sequence and PIM-1 highly consistent (71% amino acid multiplicity) rename (Nature, 428,332-337,2005; Cell, 56,673-682,1989).PIM-1,2,3 have overexpression (PNASUSA, 86,8857-8861,1989) in a lot of neoplastic hematologic disorder.PIM-1 is found in prostate cancer development process and has more multilist and reach (J.Clin.Pathol., 59,285-288,2006), the expression of PIM-2 in human body chronic lymphocytic leukemia and non-Hodgkin lymphoma leukemia has increase (Leuk.Lymph., 45,951-955,2004), the unconventionality expression of PIM-3 is then considered to fibroma of liver (Int.J.Cancer, 114,209-218,2005) and carcinoma of the pancreas (CancerRes., 66,6741-6747,2006) development and diffusion play important effect.
PIM-1,2,3 produce reaction to the stimulation of somatomedin and cytokine usually, thus to existence and the diffusion generation effect of hematopoietic cell.Reject PIM-1, the mouse energy survive of 2,3 genes, but height is less, and in hematopoietic cell diffusion process, the reaction of somatomedin is also weakened to some extent.If only reject the one in three kinds of PIM, mouse is not significantly affected, the function overlapping to some extent (Cell, 56,673-682,1989) of visible three kinds of PIM.The kinase whose substrate specificity of PIM comprises adjustment apoptotic Bcl-2 race member BAD (FEBSLetters, 571,43-49,2004) p21 (Biochim.Biophys.Acta, 1593 of cell cycle, are regulated, 45-55,2002), CDC25A, C-TA, (J.Biol.Chem., 279,48319-48328,2004), and the 4EBP1 (Blood of Function protein matter synthesis, 105,4477-4483,2005).PIM these effects kinase whose show it the function preventing apoptosis and Promote cell's growth and diffusion.Therefore, the overexpression of PIM kinases in tumour has encouraged existence work and the diffusion of cancer cells.So overexpression PIM kinases is the new effective ways of Therapeutic cancer in Tumor suppression.
Because PIM kinases is relevant with noumenal tumour in many liquid tumors, many PIM kinase inhibitor are used to the antitumor drug of Development of New Generation.In a series of cell and animal model experiment display, PIM kinase inhibitor can suppress the diffusion of liquid tumors cell and the growth of tumour significantly, these liquid tumors comprise acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myelocytic leukemia (CML), non-Hodgkin lymphoma (NHL), with multiple myeloma (MM) (Clin.CancerRes.20 (7), 1834-1845,2014; Blood123 (6), 905-913,2014; Blood122 (21), 4435,2013).Experimental result also shows, and the solid tumor of PIM kinase inhibitor to the overexpression of PIM kinases also has good effect, and these tumours comprise carcinoma of the pancreas (CancerBiol.Ther.7 (9), 1352-9,2008CancerRes.2006; 66 (13): 6741-7; CancerRes.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), cancer of the stomach (J.CancerRes.Clin.Oncol., 134 (4), 481-8,2008) and bladder cancer (J.Exp.Clin.CancerRes., 29,161,2010).
The generation of cancer therapy drug resistance is the major obstacle (DrugResistanceUpdat.12,114-126.2009) of chemotherapy and molecular targeted agents always, and the resistance solving cancer therapy drug is the important topic of cancer therapy.Many research displays, PIM kinases is to two most important drug transporters (drugeffluxtransporters), and the expression of MDR-1 with BCRP is relevant with activity (DrugResistanceUpdates, 14,203-211,2011).Experiment shows, PIM kinase inhibitor and chemotherapeutics share the curative effect (Mol.CancerTher.8,2882-2893,2009) that can significantly improve resistance prostate cancer.Therefore, PIM inhibitor can also be used for reversing the resistance to chemotherapy.
Experiment display, PIM kinase expression occurs along with the activation of T-cell, and PIM-1/3 inhibitor effectively can treat the enteritis that CD4+T-cell causes.Oral clinical trial medicine AR452530 at least can reduce rectum inflammation, and body of gland loses, edema and mucosal hyperplasia 80% (CellularImmunology, 272,200-213,2012).Therefore PIM inhibitor also can be used for treating the cell-mediated disease of the T-such as inflammatory bowel.
Kinase inhibitor document (US Patent No. 8592455B2) according to having delivered:
General formula A and Formula B are all PIM inhibitor, when their substituent R a, R band R cwhen being all the same, their unique differences are the 5-bit substituents on pyridine ring 1, and general formula A is hydrogen atom, and Formula B is fluorine atom.Document data presentation, in all 29 pairs of compounds, 5-bit substituent is that the PIM activity of H or F on these compounds does not almost affect, and can not change the ability that this compound suppresses PIM-1 enzymic activity.
Summary of the invention
In research PIM kinase inhibitor process of new generation, we find unexpectedly, different with known knowledge, meet in the compound of general formula I at one group, when other structure is just the same, due to R 6for ring texture, by R 3when changing other substituting groups into from H, due to sterically hindered increase, hinder R 6freely rotating of ring, thus the activity that improve them.Work as R 3change F or CF into 3time, owing to improve the lipotropy at this position of molecule, thus improve the ability of compound suppression PIM-1 activity further, the highest activity raising reaches 9 times, average 5.1 times.Concrete data are shown in the table 2 of embodiment 60.
Technical problem to be solved by this invention is research PIM kinase inhibitor new compound, and design prepares Therapeutic cancer, the medicine of the inflammation that the T-such as polytropism resistance and inflammatory bowel are cell-mediated.
The invention provides PIM kinase inhibitor, structural formula is following compound of Formula I:
Formula I is the PIM kinase inhibitor of pyrimidines structure.
Present invention also offers the steric isomer of formula I, tautomer and pharmaceutical salts.
In above-mentioned formula I
R 1for-H ,-NHR 4, halogen (F, Cl, Br, I) ,-OH ,-OC 1-3alkyl ,-SH ,-SC 1-3alkyl, C 1-3alkyl, halogenated methyl, halogenated ethyl ,-CN and-NO 2;
R 2for-H ,-NHR 4, halogen (F, Cl, Br, I) ,-OH ,-SH, the substituent-OC of with or without 1-3alkyl ,-SC 1-3alkyl, C 1-3alkyl and C 3-7cyclic hydrocarbon radical, halogenated methyl, halogenated ethyl ,-CN and-NO 2;
R 3for-NHR 5, halogen (F, Cl, Br, I) ,-OH ,-SH, the substituent-OC of with or without 1-3alkyl ,-SC 1-3alkyl, C 1-3alkyl and C 3-7cyclic hydrocarbon radical, halogenated methyl, halogenated ethyl ,-CN and-NO 2;
R 4for-H ,-C (=O)-R 5, the substituent C of with or without 1-8alkyl, C 3-7cyclic hydrocarbon radical, 4-7 unit heterocyclic radical, 5-10 unit's aryl and heterocyclic aryl;
R 5for the substituent C of with or without 1-8alkyl, C 1-8-oxyl, C 3-7cyclic hydrocarbon radical;
R 6for the substituent C of with or without 3-7cyclic hydrocarbon radical, 4-7 unit heterocyclic radical, 5-10 unit's aryl and heterocyclic aryl; Described cyclic hydrocarbon radical, the substituting group on aryl and heterocyclic aryl can be halogen (F, Cl, Br, I) respectively ,-CN ,-NH 2,-NHR 7, C 1-4alkyl, C 1-4halo alkyl, C 3-7cyclic hydrocarbon radical ,-OR 7,-NO 2,-C (=O) OR 7,-C (=O) R 7,-C (=O) N (R 7) 2,-C (=O) NH 2,-C (=O) NHR 7;
R 7for-H or with or without substituting group C 1-4alkyl;
R 22for the substituent C of with or without 1-8alkyl or the group for following formula definition:
Wherein R 23, R 24and R 25be halogen (F, Cl, Br, I) ,-OR separately 15,-NR 16r 17,-C (=O) NR 18r 19or the substituent C of with or without 1-8alkyl;
R 15, R 16, R 17, R 18, R 19be-H or the substituent C of with or without separately 1-8alkyl
G 1for CH 2or N;
G 2for NR 28, CHR 29or O;
B1 and B2 is 0,1,2 or 3;
B3 is 0,1,2;
B4 is 0,1;
R 26and R 27be-H or the substituent C of with or without separately 1-8alkyl;
R 28for-H, the substituent C of with or without 1-8alkyl, C 3-7cyclic hydrocarbon radical, C 3-7heterocycle alkyl ,-C (=O) R 30,-C (=O) OR 30or-C (=O) NHR 30;
R 29for-H ,-OH, the substituent C of with or without 1-8alkyl, C 3-7cyclic hydrocarbon radical, C 3-7heterocycle alkyl ,-NHR 30,-C (=O) OR 30or-C (=O) NHR 30;
R 30for-H or the substituent C of with or without 1-8alkyl;
Substituting group described in the present invention, if no special instructions, hydroxyl can be selected from, nitro, amino, imino-, cyano group, halogen, thio group, alkylsulfonyl, thio acylamino (thioamido), amidino groups, imidino, oxo amidino groups (oxamidino), methoxamidino (methoxamidino), guanidine radicals, sulfonamido, carboxyl, formyl radical, low alkyl group, junior alkyl halides, low-grade alkyl amino, junior alkyl halides is amino, lower alkoxy, halogenated lower alkoxy, low-grade alkoxy alkyl, alkyl-carbonyl, aminocarboxyl, aryl carbonyl, aromatic alkyl carbonyl, heteroaryl.
Described " rudimentary ", if no special instructions, different according to the substituting group limited, refer to C respectively 1-8straight or branched group, the non-aromatic cyclic radical of 3-7 unit, or the aromatic group of 5-12 unit, or with C 1-8the aromatic group of 5-12 unit of straight or branched substituted radical.
In certain embodiments of the present invention, compound of Formula I and steric isomer thereof, tautomer and their pharmaceutical salts, R 1for-H ,-NHR 4, halogen (F, Cl, Br, I) ,-OH ,-SH, the substituent-OC of with or without 1-3alkyl ,-SC 1-3alkyl, C 1-3alkyl and C 3-7cyclic hydrocarbon radical ,-CN and-NO 2; Preferred R 1for-H ,-NH 2, halogen (F, Cl, Br, I) ,-OH ,-CN and-NO 2; Preferred R further 1for-H ,-NH 2,-F.
In another part embodiment of the present invention, compound of Formula I and steric isomer thereof, tautomer and their pharmaceutical salts, R 2for-H ,-NHR 4, halogen (F, Cl, Br, I) ,-OH ,-SH, the substituent-OC of with or without 1-3alkyl ,-SC 1-3alkyl, C 1-3alkyl and C 3-7cyclic hydrocarbon radical ,-CN and-NO 2; Preferred R 2for-H, halogen (F, Cl, Br, I) ,-CN; Preferred R further 2for-H, halogen (F, Cl, Br, I).
In another part embodiment of the present invention, compound of Formula I and steric isomer thereof, tautomer and their pharmaceutical salts, R 3for-NHR 5, halogen (F, Cl, Br, I) ,-OH ,-SH, the substituent-OC of with or without 1-3alkyl ,-SC 1-3alkyl, C 1-3alkyl and C 3-7cyclic hydrocarbon radical, halogenated methyl, halogenated ethyl ,-CN and-NO 2; Preferred R 3for halogen (F, Cl, Br, I), the substituent C of with or without 1-3alkyl and-OC 1-3alkyl, halogenated methyl ,-CN and-NO 2; Preferred R further 3for halogen (F, Cl, Br, I) ,-CF 3, and-CN; Further preferably R again 3for halogen (F, Cl, Br, I) and-CF 3.
In another part embodiment of the present invention, compound of Formula I and steric isomer thereof, tautomer and their pharmaceutical salts, R 6for the substituent C of with or without 3-7cyclic hydrocarbon radical, 4-7 unit heterocyclic radical, 5-10 unit's aryl and heterocyclic aryl; Described cyclic hydrocarbon radical, the substituting group on aryl and heterocyclic aryl can be halogen (F, Cl, Br, I) respectively ,-CN ,-NH 2,-NHR 7, C 1-4alkyl, C 1-4halo alkyl, C 3-7cyclic hydrocarbon radical ,-OR 7,-NO 2,-C (=O) OR 7,-C (=O) R 7,-C (=O) N (R 7) 2,-C (=O) NH 2,-C (=O) NHR 7; Preferred R 6for phenyl, piperazinyl and pyridyl, described phenyl, piperazinyl and pyridyl can be selected from-F ,-Cl ,-Br ,-I ,-OH ,-NH by 1-3 2, C 1-3alkyl, C 1-3-oxyl, halo C 1-3the group of alkyl replaced; Preferred R further 6for phenyl, pyridyl, 2-F-6-OCH 3-phenyl, 2,6-difluorophenyl.
In another part embodiment of the present invention, compound of Formula I and steric isomer thereof, in tautomer and their pharmaceutical salts, preferred R 22for with or without substituent tetramethylene base, pentamethylene base, cyclohexyl, suberane base, azetidinyl, pyrrolidyl, piperidyl, azepan base, butylene oxide ring base, tetrahydrofuran base, THP trtrahydropyranyl; Preferred R further 22for cyclohexyl, pyrrolidyl, piperidyl, azepan base; On the substituent group of described band, 1-4 substituting group can be had, halogen (F, Cl, Br, I) can be selected from respectively ,-NH 2,-OH, methylamino, ethylamino-, Propylamino, dimethylin, diethylin, methyl, ethyl, propyl group, methoxyl group, oxyethyl group, propoxy-, single halogenated methyl, many halogenated methyls, single halogenated ethyl, many halogenated ethyls; Preferred substituents is halogen (F, Cl, Br, I) ,-NH 2,-OH, methylamino, methyl and methoxyl group; Further preferred substituents is-NH 2,-OH and methyl
In another part embodiment of the present invention, compound of Formula I and steric isomer thereof, tautomer and their pharmaceutical salts, its R 22for with or without substituent tetramethylene ylmethyl, pentamethylene ylmethyl, cyclohexyl methyl, CycloheptylmethyI, azetidine ylmethyl, pyrrolidinylmethyl, piperidino methyl, azepan ylmethyl, butylene oxide ring ylmethyl, tetrahydrofuran (THF) ylmethyl, tetrahydropyrans ylmethyl; Preferred R further 22for cyclohexyl methyl, pyrrolidinylmethyl, piperidino methyl, azepan ylmethyl; On the substituent group of described band, 1-4 substituting group can be had, halogen (F, Cl, Br, I) can be selected from respectively ,-NH 2,-OH, methylamino, ethylamino-, Propylamino, dimethylin, diethylin, methyl, ethyl, propyl group, methoxyl group, oxyethyl group, propoxy-, single halogenated methyl, many halogenated methyls, single halogenated ethyl, many halogenated ethyls; Preferred substituents is halogen (F, Cl, Br, I) ,-NH 2,-OH, methylamino, methyl and methoxyl group; Further preferred substituents is-NH 2,-OH and methyl
In another part embodiment of the present invention, compound of Formula I and steric isomer thereof, tautomer and their pharmaceutical salts, its R 22for with or without substituent C 2-5alkyl, these alkyl can have at most 4 substituting groups, and they can be halogen (F, Cl, Br, I) respectively, NH 2, methylamino, ethylamino-, Propylamino, dimethylin, diethylin, hydroxyl, methyl, ethyl, propyl group ,-CH 2oH ,-CH 2(OH) CH 3,-CH 2cH 2oH, single halogenated methyl, many halogenated methyls, single halogenated ethyl, many halogenated ethyls, C 1-4alkyl-O-, C 1-4alkyl-S-;
In certain embodiments of the present invention, compound of Formula I and steric isomer thereof, tautomer and their pharmaceutical salts, its preferred embodiment lists in table 2.
The definition of term used herein:
Term used herein " alkyl " refers to not containing heteroatomic alkyl.Therefore, this term comprises straight chained alkyl as methyl, ethyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl, undecyl, dodecyl etc.This term also comprises the branched chain isomer of straight chained alkyl, includes but not limited to the group such as :-CH (CH 3) 2, CH (CH 3) (CH 2cH 3), CH (CH 2cH 3) 2,-C (CH 3) 3,-C (CH 2cH 3) 3,-CH 2cH (CH 3) 2,-CH 2cH (CH 3) (CH 2cH 3) ,-CH 2cH (CH 2cH 3) 2,-CH 2c (CH 3) 3,-CH 2c (CH 2cH 3) 3,-CH (CH 3) CH (CH 3) (CH 2cH 3) ,-CH 2cH 2cH (CH 3) 2,-CH 2cH 2cH (CH 3) (CH 2cH 3) ,-CH 2cH 2cH (CH 2cH 3) 2,-CH 2cH 2c (CH 3) 3,-CH 2cH 2c (CH 2cH 3) 3,-CH (CH 3) CH 2cH (CH 3) 2,-CH (CH 3) CH (CH 3) CH (CH 3) 2, CH (CH 2cH 3) CH (CH 3) CH (CH 3) (CH 2cH 3) etc.Therefore, term alkyl comprises primary alkyl, secondary alkyl and tertiary alkyl.Preferred alkyl comprises the straight chain and branched-chain alkyl with 1 to 12 carbon atom.A kind of preferred " alkyl " definition relates to C 1-4straight chained alkyl is as methyl, ethyl, n-propyl and normal-butyl.Preferred alkyl definition also comprises C 3-5branched-chain alkyl, comprises-CH (CH 3) 2,-CH 2cH (CH 3) 2,-CH (CH 3) CH 2cH 3,-C (CH 3) 3,-CH (CH 3) CH 2cH 2cH 3,-CH (CH 3) CH (CH 3) 2,-CH 2cH (CH 3) CH 2cH 3,-CH 2cH 2cH (CH 3) 2with-CH (CH 2cH 3) 2deng.
Term used herein " thiazolinyl " refers to wherein at least one unsaturated point, that is, wherein two adjacent carbonss pass through doubly linked alkyl as defined above.
Term used herein " alkynyl " relates to the alkyl that wherein two adjacent carbonss are connected by triple bond.
Term used herein " alkoxyl group " refers to-OR, and wherein R is alkyl.
Term used herein " alkyl " is the general designation of alkyl, thiazolinyl and alkynyl.
Term used herein " halogen " or " halo " refer to fluorine, chlorine, bromine and iodine (F, Cl, Br, I) group." haloalkyl " refers to the alkyl replaced by one or more halogen atom.Therefore, term " haloalkyl " comprises single haloalkyl, dihalo alkyl, tri haloalkyl etc.Typical single haloalkyl comprises-CH 2f ,-CH 2cl ,-CH 2cH 2f ,-CH 2cH 2cl ,-CH (F) CH 3,-CH (Cl) CH 3; Typical dihalo alkyl comprises-CHCl 2,-CHF 2,-CCl 2cH 3,-CH (Cl) CH 2cl ,-CH 2cHCl 2,-CH 2cHF 2; Typical tri haloalkyl comprises-CCl 3,-CF 3,-CCl 2cH 2cl ,-CF 2cH 2f ,-CH (Cl) CHCl 2,-CH (F) CHF 2; Typical whole haloalkyl comprises-CCl 3,-CF 3,-CCl 2cCl 3,-CF 2cF 3.
" amino " used herein refers to group NH 2.
Term " alkylamino " herein refers to that wherein R and R ' is selected from the group-NRR ' of hydrogen or low alkyl group independently of one another, is H when wherein R and R ' is different.
Term " arylamino " herein refers to that wherein R is aryl and R ' is the group-NRR ' of hydrogen, low alkyl group or aryl.
Term " aryl alkyl amino " herein refers to that wherein R is loweraralkyl and R ' is the group-NRR ' of hydrogen, low alkyl group, aryl or loweraralkyl.
Term cyano group used herein refers to group-CN.
Term nitro used herein refers to group-NO 2.
Term used herein " alkoxyalkyl " refers to that wherein alk1 is alkyl or alkenyl and alk2 is the group-alk1-0-alk2 of alkyl or alkenyl.Term " low-grade alkoxy alkyl " refers to that wherein alk1 is 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 group one alkyl-0 one aryl.Term " sweet-smelling alkoxy alkyl " refers to that wherein aralkyl is group one alkylidene group-0 one aralkyl of loweraralkyl.
Term used herein " aminocarboxyl " refers to group-C (=O)-NH 2; " aminocarboxyl of replacement " in this article refers to wherein R and is low alkyl group and R ' is group C (the O)-NRR ' of hydrogen or low alkyl group.In some embodiments, the atom N that R with R ' can be connected with them is formed " heterocycloalkylcarbonyl " together.Term " aromatic yl aminocarbonyl " in this article refers to wherein R and is aryl and R ' is group-C (the O)-NRR ' of hydrogen, low alkyl group or aryl." Aralkylaminocarbonyl " in this article refers to wherein R and is loweraralkyl and R ' is group-C (the O)-NRR ' of hydrogen, low alkyl group, aryl or loweraralkyl.
" amino-sulfonyl " used herein refers to group-S (O) 2nH 2" replace amino-sulfonyl " in this article refers to wherein R and is low alkyl group and R ' is the group-S (O) of hydrogen or low alkyl group 2nRR '.Term " aralkylaminosulfonlyaryl " in this article refers to the group aryl-S (O) that wherein aralkyl is loweraralkyl 2-NH aralkyl.
" carbonyl " used herein refer to divalent group-C (O)-." carboxyl " refers to-C (=O)-OH." alkoxy carbonyl " refers to that wherein R is ester-C (=the O)-OR of alkyl." elementary alkoxy carbonyl " refers to that wherein R is ester-C (=the O)-OR of low alkyl group." cyclo alkoxy carbonyl " refers to that wherein R is C (=the O)-OR of cycloalkyl.
" cycloalkyl " used herein refers to the carbocyclic alkyl substituent of single or many rings.Carbocyclic ring alkyl is that wherein all annular atomses are all the cycloalkyl of carbon.Typical naphthenic substituent has 3 to 8 skeletons (that is, ring) atom, and wherein each skeletal atom is carbon or heteroatoms.Term " Heterocyclylalkyl " in this article refers to has 1 to 5 in ring structure, and more typically has 1 to 4 heteroatomic naphthenic substituent.Suitable heteroatoms used in the compounds of this invention is nitrogen, oxygen and sulphur.Representational heterocycloalkyl portion comprises such as morpholino, piperazinyl, piperidyl etc.Carbocyclic ring alkyl is that wherein all annular atomses are all the cycloalkyl of carbon.When with naphthenic substituent conbined usage, term " many rings " in this article refers to that condense with alkyl cyclic structures that is non-condensed.Term " the undersaturated cycloalkyl of part ", " cycloalkyl of fractional saturation " and " cycloalkenyl group " all refer to wherein there is at least one unsaturated point, that is, the wherein cycloalkyl that is connected by double bond or triple bond of two adjacent annular atomses.Illustrative example comprises hexamethylene alkynyl, ring pentynyl, cyclopropenyl radical, the fast base of ring fourth etc.
Term used herein " replace heterocycle ", " heterocyclic group " or " heterocycle " refer to and are selected from heteroatomic wantonly 3 or 4 Yuans rings of nitrogen, oxygen and sulphur containing one or are selected from heteroatomic 5-or 6-person's ring of nitrogen, oxygen or sulphur containing one to three; Wherein said 5-person's ring has 0-2 double bond, and 6-person's ring has 0-3 double bond; Wherein nitrogen and sulphur atom are optionally oxidized; And comprise wherein any above-mentioned heterocycle and phenyl ring or any bicyclic groups of condensing of independent other 5-or 6-element heterocycle defined above.Term used herein " Heterocyclylalkyl " refers to the heteroatomic 5-or the 6-person's ring that are selected from nitrogen, oxygen or sulphur containing one to two, and wherein this ring does not have double bond.Such as, term heterocycle-C 5alkyl refers to 6 Yuans rings containing 5 carbon atoms and a heteroatoms such as N.Therefore, term " heterocycle " comprises wherein nitrogen is heteroatomic ring and fractional saturation and completely saturated ring.Preferred heterocycle comprises such as: phenodiazine (diazapinyl), pyrryl, pyrrolinyl, pyrrolidyl, pyrazolyl, pyrazolinyl, pyrazolidyl, pyridyl, piperidyl, pyridazinyl, piperazinyl, pyrazinyl, N methyl piperazine base, azetidinyl, N-methyl azetidine base, pyrimidyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidyl, isothiazolyl, isothiazole alkyl, indyl, quinolyl, isoquinolyl, benzene imidazolyl, benzothiazolyl, isoxazolyl benzenesulfonamide base, furyl, thienyl, triazolyl and benzothienyl, heterocyclic moiety can not replace or monosubstituted or two replacement or three replacements by various substituting group, described substituting group is independently selected from hydroxyl, halogen, oxo (C=O), alkyl imino (RN=, wherein R is low alkyl group or lower alkoxy), amino, alkylamino, dialkyl amido, acylaminoalkyl, alkoxyl group, thio alkoxy, many alkoxyl groups, low alkyl group, cycloalkyl or haloalkyl.
In conjunction with content disclosed herein, organic and technician that is medicinal chemistry art is readily appreciated that, heterocyclic group can connect on various position.Typical heterocycle comprises such as imidazolyl, pyridyl, piperazinyl, piperidyl, azetidinyl, thiazolyl, furyl, triazolyl, benzimidazolyl-, benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl, thiazolinyl, quinoline room quinoline base, phthalazinyl, indyl, naphthyridinyl, indazolyl and quinolizinyl.
" aryl " used herein refers to the monocycle and polycyclic aromatic group with 3 to 14 skeleton carbon or heteroatomic optional replacement, and comprises isocyclic aryl and heterocyclic aryl.The aryl of isocyclic aryl to be all annular atomses wherein in aromatic ring be all carbon.Term " heteroaryl " in this article refers to has 1 to 4 heteroatoms as annular atoms and remaining annular atoms is the aryl of carbon atom in aromatic ring.When being combined with aryl substituent, term " polyaromatic " in this article refers to the ring texture with non-condensed that condenses that wherein at least one ring structure is aromatics, such as benzo dioxa penta ring (it has a kind of heterocycle structure condensed with phenyl, that is, naphthyl etc.).The example being used as substituent aryl moiety in the compounds of this invention comprises phenyl, pyridyl, pyrryl, thiazolyl, indyl, imidazolyl, oxadiazoles base, tetrazyl, pyrazinyl, triazolyl, thienyl, furyl, quinolyl, purine radicals, naphthyl, benzothiazolyl, benzo pyridyl and benzimidazolyl-etc.
" optional replacement " used herein or " replacement ", refer to that one or more hydrogen atom is replaced by unit price or divalent group, suitable substituted radical comprises such as hydroxyl, nitro, amino, imino-, cyano group, halogen, thio group, alkylsulfonyl, thio acylamino (thioamido), amidino groups, imidino, oxo amidino groups (oxamidino), methoxamidino (methoxamidino), guanidine radicals, sulfonamido, carboxyl, formyl radical, low alkyl group, junior alkyl halides, low-grade alkyl amino, junior alkyl halides is amino, lower alkoxy, halogenated lower alkoxy, low-grade alkoxy alkyl, alkyl-carbonyl, aminocarboxyl, aryl carbonyl, aromatic alkyl carbonyl, Heteroarylcarbonyl, heteroaralkyl-carbonyl, alkylthio, aminoalkyl group, cyanoalkyl, aryl etc., substituting group itself can be substituted, the group substituted onto on substituting group can be carboxyl, halogen, nitro, amino, cyano group, hydroxyl, low alkyl group, lower alkoxy, aminocarboxyl, SR, thio acylamino, SO 3h, SO 2r or cycloalkyl, wherein R normally hydrogen, enter base or low alkyl group, when the substituting group replaced comprises straight chain group, this substituting group can be positioned at chain (such as, 2-hydroxypropyl, 2-aminobutyl etc.) or chain end (such as, 2-hydroxyethyl, 3-aminopropyl etc.).The substituting group replaced can be covalently bound carbon or heteroatomic straight chain, side chain or circular permutation.Definition above does not comprise unallowed substitute mode (methyl such as, replaced by five fluorin radicals or the halogen atom replaced by another halogen atom); Such unallowed substitute mode well known to a person skilled in the art.
It is evident that equally those skilled in the art, the pharmaceutically useful salt of the compounds of this invention or their steric isomer and their any one, ester, metabolite and prodrug can tautomerizations and therefore can be displaced to another atom with the proton of of its a Middle molecule atom and the various tautomeric forms that therefore chemical bond between atoms of molecule rearranges exist.See, such as, March, Advanced Organic Chemistry: reaction, mechanism and structure (AdvancedOrganicChemistry:Reactions, MechanismsandStructures), 4th edition, JohnWiley & Sons, 69-74 page (1992).Term used herein " tautomer " refers to the compound produced by proton displacement, as long as and it should be understood that it may exist, all tautomeric forms are all included in the present invention.
Compound of the present invention or their tautomer and in them the pharmaceutically useful salt of any one, ester, metabolite and prodrug may comprise the carbon atom of Asymmetrical substitute.The carbon atom of such Asymmetrical substitute can produce the compounds of this invention existed with enantiomer, diastereomer and other stereoisomeric forms in any ratio, these forms can define according to absolute stereochemical, as (R)-or (S)-form.Therefore, the mixture of the single steric isomer of such possible isomer all of the compounds of this invention, the pure form of its optically-active, its mixture, racemic mixture (or " racemic modification "), diastereomer and single diastereomer all comprise in the present invention.Term used herein " S " and " R " configuration defined as in IUPAC1974RECOMMENDATIONSFORSECTIONE, FUNDAMENTALSTEREOCHEMISTRY, PureAppl.Chem.45:13-30 (1976).Term and the ring position for ring compound.Reference plane-side is that side that preferred substituting group is positioned at lower numbered positions.Be positioned at those substituting groups of reference plane offside with describing from the beginning.It should be noted that this usage is different from the usage for the three-dimensional parent (stereoparents) of ring-type, in the later case, " " means " under being positioned at plane " and represents absolute configuration.Term used herein and configuration as CHEMICALABSTRACTSINDEXGUIDE-APPENDIXIV (1987) the 203rd section define.
Term used herein " pharmaceutical salts " refers to nontoxic hydrochlorate or the alkaline earth salt of formula I.These salt can be prepared on the spot during the last abstraction and purification of formula I, or can by alkali or acid functional group being prepared with the acid of suitable organic or inorganic or alkali reaction respectively.Typical salt includes but not limited to salt below: acetate, adipate, alginate, Citrate trianion, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, camphorate, sulfonate, digluconate, cyclopentane propionate, dodecyl sulfate, esilate, gluceptate, glycerophosphate, Hemisulphate, enanthate, hexanoate, fumarate, hydrochloride, hydrobromide, hydriodide, 2-isethionate, lactic acid salt, maleate, mesylate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, fruit amino acid salt, persulphate, 3-phenylpropionic acid salt, picrate, pivalate, propionic salt, succinate, vitriol, tartrate, thiocyanate-, p-tosylate and undecane hydrochlorate.Also reagent can be used as elementary alkyl halide, as methyl, ethyl, propyl group and Butyryl Chloride compound, bromide and iodide; Dialkylsulfates such as methyl-sulfate, diethyl ester, dibutylester and diamyl ester, long chain halide are if decyl, lauryl, nutmeg base and stearyl chlorides, bromide and iodide, aralkyl halide are if bromotoluene and phenethyl bromide etc. are by quaternized for the group comprising basic nitrogen.Obtain water or the solvable or water of oil or oily dispersible product thus.
The example that can be used for the acid forming pharmaceutically acceptable acid additive salt comprises mineral acid example hydrochloric acid, sulfuric acid and phosphoric acid, and organic acid is as oxalic acid, toxilic acid, methylsulfonic acid, succsinic acid and citric acid.Base addition salt can be prepared on the spot during the abstraction and purification that formula (I) compound is last, or can react to prepare by making carboxylic moiety and suitable alkali such as the oxyhydroxide of pharmaceutically acceptable metallic cation, carbonate or supercarbonate or ammonia or organic primary, secondary or tertiary amine.Pharmaceutically useful salt includes but not limited to that positively charged ion based on alkali and alkaline-earth metal is as sodium, lithium, potassium, calcium, magnesium, aluminium salt etc., and nontoxic ammonium, quaternary ammonium and amine positively charged ion, include but not limited to the salt of ammonium, tetramethyl-ammonium, tetraethyl ammonium, methylamine, dimethylamine, Trimethylamine 99, triethylamine, ethamine etc.Other typical organic limb for the formation of base addition salt comprises diethylamine, quadrol, thanomin, diethanolamine, piperazine etc.
Term used herein " pharmaceutically useful ester " refers to that the ester that is hydrolyzed in vivo also, is included in human body and is easy to decompose thus discharges those esters of parent compound or its salt.Suitable ester comprises such as that those are derived from those esters of pharmaceutically useful aliphatic carboxylic acid, particularly paraffinic acid, alkenoic acid, naphthenic acid and chain docosandioic acid, and wherein each alkyl or said alkenyl moiety preferably have and be no more than 6 carbon atoms.The example of certain esters comprises manthanoate, acetic ester, propionic ester, butyric ester, acrylate and ethyl succinate.
Term used herein " pharmaceutically useful prodrug " refers in rational medical judgment, be suitable for there is no excessive toxicity, pungency, anaphylaxis etc. with the contact tissue of people and lower animal simultaneously, there is rational benefit/risk ratio and to apply needed for it those the compounds of this invention effective prodrug and may the zwitterionic form of the compounds of this invention in situation.Term " prodrug " referring in vivo conversion rapidly, such as transforming by being hydrolyzed in blood, thus produces the compound of the parent compound of above formula.At T.Higuchi and v.Stella, as the prodrug (Pro-drugsasNovelDeliverySystems) of novel transfer system, Vol.14, A.C.S.SymposiumSeries and EdwardB.Roche edits, provide in bioreversible carrier (BioreversibleCarriersinDrugDesign) in medicinal design and discuss in detail, the two is all introduced into herein as a reference.
Any structural formula provided herein also represents unmarked form and the isotope labelled form of described compound.Structure shown in isotope-labeled compound has herein described by structural formula, just one or more atom is replaced by the atom with selected atomic mass or total mass number.The isotopic example that can be incorporated in the compounds of this invention comprises the isotropic substance of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2h, 3h, 11c, 13c, 14c, 15n, 18f, 31p, 32p, 35s, 36cl, 125i.The present invention includes the compound of various isotope-labeled this paper institutes work doctrine, such as wherein exist radio isotope as 3h and 14those compounds of C.Such isotope-labeled compound can be used for metabolism research and (uses 14c), reaction kinetics research (is used such as 2h or 3h), detection or imaging technique, as positron emission tomography (PET) or single photon emission computed tomography (SPECT), comprise medicine or substrate tissue distribution assays, or can be used in the radiation treatment of patient.Especially, 18f or tagged compound study particularly suitable for PET or SPECT.Isotope-labeled the compounds of this invention and its prodrug usually by operation disclosed in implementing procedure or following embodiment and preparation example, by replacing nonisotopically labelled reagent to be prepared with the isotope-labeled reagent being easy to obtain.In addition, with heavier isotropic substance, particularly deuterium (that is, 2h or D) displacement can provide some treatment benefit, these treatment benefits derive from metabolic stability increase, such as Half-life in vivo increase or required dosage reduce or therapeutic index improve.It should be understood that the deuterium in this background is considered to the substituting group of formula (1) compound.The concentration of such higher isotope, particularly deuterium can define by the isotopic enrichment factor.Term used herein " the isotopic enrichment factor " refers to specified ratio between isotopic isotopic abundance and natural abundance.If the substituting group in the compounds of this invention is designated as deuterium, then this compounds has for each D atom of specifying and is at least 3500 (each deuterium building on atom 52.5% of specifying is mixed into), be at least 4000 (deuterium of 60% is mixed into), be at least 4500 (deuterium of 67.5% is mixed into), be at least 5000 (deuterium of 75% is mixed into), be at least 5500 (deuterium of 82.5% is mixed into), be at least 6000 (deuterium of 90% is mixed into), be at least 6333.3 (deuterium of 95% is mixed into), be at least 6466.7 (deuterium of 97% is mixed into), be at least 6600 (deuterium of 99% is mixed into) or be at least the isotopic enrichment factor of 6633.3 (deuterium of 99.5% is mixed into).
Isotope-labeled formula (I) compound can oneself knows with those skilled in the art routine techniques to be prepared or can by the method similar with those methods described in appended embodiment and preparation example usually, and before replacing with suitable isotope-labeled reagent, nonisotopically labelled reagent used is prepared.
It will be apparent for a person skilled in the art that, compound of the present invention or their tautomer, prodrug and steric isomer and in them the pharmaceutically useful salt of any one, ester and prodrug process in body by carrying out metabolism in human or animal body or cell, thus produce metabolite.Term used herein " metabolite " refers to the derivative of any structural formula produced in individual body after using parent compound.These derivatives such as can be oxidized, reduce, be hydrolyzed or be combined by the various biochemical conversions in individual body and be produced by parent compound, and comprise such as oxide compound and demethyl derivative.The metabolite of the compounds of this invention can be identified with the routine techniques that in prior art, oneself knows.See such as, the people such as Bertolini, G. ,] .Med.Chem.40:2011-2016 (1997); The people such as Shan, D., J.Pharm.Sci.86 (7): 765-767; BagshaweK., DrugDev.Res.34:220-230 (1995); Bodor, N., AdvancesinDrugRes.13:224-331 (1984); Bundgaard, H., DesignofProdrugs (ElsevierPress1985); And Larsen, 1.K., DesignandApplicationofProdrugs, DrugDesignandDevelopment (people such as Krogsgaard-Larsen, HarwoodAcademicPublishers, 1991).It should be understood that as formula I or their tautomer, prodrug and steric isomer and in them the chemical compound of the metabolite of the pharmaceutically useful salt of any one, ester and prodrug all comprise in the present invention.
Term used herein " cancer " refers to can by the Cancerous disease suppressing PIM kinases to obtain advantageous treatment, comprise such as solid tumor, as lung cancer, carcinoma of the pancreas, thyroid carcinoma, ovarian cancer, bladder cancer, breast cancer, prostate cancer or colorectal carcinoma, melanoma, bone marrow disorder such as, myelocytic leukemia, multiple myeloma and erythroleukemia, adenoma are such as, villous colon adenoma and sarcoma such as, osteosarcoma; Liquid tumor as chronic lymphocytic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelocytic leukemia, non-Hodgkin lymphoma, and multiple myeloma.
PIM kinase inhibitor provided by the invention comprises following compounds:
The fluoro-N-of 6-(2,6-difluorophenyl)-5-(5-(piperidin-4-yl methoxyl group) isothiazole-4-base) picolinamide
N-(5-(azetidine-3-ylmethoxy) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-fluorine picolinamide
The fluoro-N-of 6-(2,6-difluorophenyl)-5-(5-(piperidin-4-yl oxygen base) isothiazole-4-base) picolinamide
The fluoro-N-of 6-(2,6-difluorophenyl)-5-(5-(pyrroles-3-base oxygen base) isothiazole-4-base) picolinamide
The fluoro-N-of 6-(2,6-difluorophenyl)-5-(5-(piperidines-3-base oxygen base) isothiazole-4-base) picolinamide
N-(5-(nitrogen heterocyclic-4-in heptan base oxygen base) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-fluorine picolinamide
The fluoro-N-of 6-(2,6-difluorophenyl)-5-(5-(piperidines-3-ylmethoxy) isothiazole-4-base) picolinamide
The fluoro-N-of 6-(2,6-difluorophenyl)-5-(5-(pyrroles-3-ylmethoxy) isothiazole-4-base) picolinamide
N-(5-(azetidin-3-base oxygen base) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-fluorine picolinamide
N-(5-(((1r, 4r)-4-aminocyclohexyl) oxygen base) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-fluorine picolinamide
N-(5-((3-aminocyclohexyl) oxygen base) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-fluorine picolinamide
N-(5-(3-amine propoxy-) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-fluorine picolinamide
The fluoro-N-of 6-(2,6-difluorophenyl)-5-(5-(3-(methylamino) propoxy-) isothiazole-4-base) picolinamide
6-(2,6-difluorophenyl)-N-(5-(3-(dimethyl amido) propoxy-) isothiazole-4-base)-5-fluorine picolinamide
N-(5-(4-amido butoxy) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-fluorine picolinamide
The fluoro-N-of 6-(2,6-difluorophenyl)-5-(5-(4-(methylamino) butoxy) isothiazole-4-base) picolinamide
The fluoro-N-of 6-(2,6-difluorophenyl)-5-(5-(3-hydroxy propyloxy group) isothiazole-4-base) picolinamide
The fluoro-N-of 6-(2,6-difluorophenyl)-5-(5-(3-hydroxybutoxy) isothiazole-4-base) picolinamide
The fluoro-N-of 6-(2,6-difluorophenyl)-5-(5-(4-hydroxy butoxy) isothiazole-4-base) picolinamide
The fluoro-N-of 6-(2,6-difluorophenyl)-5-(5-((4-hydroxy-4-methyl pentyloxy) isothiazole-4-base) picolinamide
6-(2,6-difluorophenyl)-N-(5-(3,4-dihydroxyl butoxy) isothiazole-4-base)-5-fluorine picolinamide
The fluoro-N-of 6-(2,6-difluorophenyl)-5-(5-(tetrahydropyrans-4-methoxyl group)-isothiazole-4-base) picolinamide
The fluoro-N-of 3-amido-6-(2,6-difluorophenyl)-5-(5-(piperidin-4-yl methoxyl group) isothiazole-4-base) picolinamide
The fluoro-N-of 3-amido-6-(2,6-difluorophenyl)-5-(5-(pyrroles-3-base oxygen base) isothiazole-4-base) picolinamide
The fluoro-N-of 3-amido-6-(2,6-difluorophenyl)-5-(5-(piperidin-4-yl oxygen base) isothiazole-4-base) picolinamide
3-amido-N-(5-(nitrogen heterocyclic-4-in heptan base oxygen base) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-fluorine picolinamide
3-amido-N-(5-(((1r, 4r)-4-aminocyclohexyl) oxygen base) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-fluorine picolinamide
The fluoro-N-of 3-amido-6-(2,6-difluorophenyl)-5-(5-(pyrroles-3-ylmethoxy) isothiazole-4-base)-2-pyridine carboxamide
N-(5-((1-amido-3-chloropropyl-2-base) oxygen base) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-fluorine picolinamide
N-(5-(3-amido-2-(chloromethyl) propoxy-) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-fluorine picolinamide
3-amido-N-(5-(azetidin-3-base oxygen base) isothiazole-4-base) the fluoro-2-pyridine carboxamide of-6-(2,6-difluorophenyl)-5-
3-amido-N-(5-(azetidine-3-ylmethoxy) isothiazole-4-Ji-Ji) the fluoro-2-pyridine carboxamide of-6-(2,6-difluorophenyl)-5-
3-amido-N-(5-((1-amido-3-chloropropyl-2-base) oxygen base) isothiazole-4-base) the fluoro-2-pyridine carboxamide of-6-(2,6-difluorophenyl)-5-
3-amido-N-(5-(3-amido-2-(chloromethyl) propoxy-) isothiazole-4-base) the fluoro-2-pyridine carboxamide of-6-(2,6-difluorophenyl)-5-
The fluoro-N-of 3-amido-6-(2,6-difluorophenyl)-5-(5-(piperidines-3-ylmethoxy) isothiazole-4-base)-2-pyridine carboxamide
3-amido-N-(5-(4-amido butoxy) isothiazole-4-base) the fluoro-2-pyridine carboxamide of-6-(2,6-difluorophenyl)-5-
3-amido-N-(5-((3-aminocyclohexyl) oxygen base isothiazole-4-base) the fluoro-2-pyridine carboxamide of-6-(2,6-difluorophenyl)-5-
The fluoro-6-phenyl of 3-amido-5--N-(5-(pyrrolidin-3-yl oxygen base) isothiazole-4-base)-2-pyridine carboxamide
The fluoro-N-of 3-(5-(piperidin-4-yl oxygen base) isothiazole-4-base)-(2,4 '-dipyridyl)-6-methane amide
N-(4-(nitrogen heterocyclic-4-in heptan base oxygen base) isothiazole-4-base) the fluoro-2-pyridine carboxamide of-6-(2,6-difluorophenyl)-3-
N-(4-(nitrogen heterocyclic-4-in heptan base oxygen base) isothiazole-4-base) the fluoro-6-of-5-(the fluoro-6-p-methoxy-phenyl of 2-)-2-pyridine carboxamide
N-(5-(nitrogen heterocyclic-4-in heptan base oxygen base) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxamide
6-(2,6-difluorophenyl)-N-(5-(piperidin-4-yl methoxyl group) isothiazole-4-base)-5-trifluoromethyl-2-pyridine carboxamide
N-(5-(azetidin-3-ylmethoxy) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxamide
6-(2,6-difluorophenyl)-(5-(piperidin-4-yl oxygen base) isothiazole-4-base)-5-trifluoromethyl-2-pyridine carboxamide
N-(5-(((1r, 4r)-4-aminocyclohexyl) oxygen base) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxamide
6-(2,6-difluorophenyl)-N-(5-(tetrahydropyran-4-base) methoxyl group) isothiazole-4-base)-5-trifluoromethyl-2-pyridine carboxamide
3-amido-N-(5-(nitrogen heterocyclic-4-in heptan base oxygen base) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxamide
3-amido-6-(2,6-difluorophenyl)-N-(5-(piperidin-4-yl methoxyl group) isothiazole-4-base)-5-trifluoromethyl-2-pyridine carboxamide
3-amido-N-(5-(azetidin-3-ylmethoxy) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxamide
3-amido-6-(2,6-difluorophenyl)-N-(5-(piperidin-4-yl oxygen base) isothiazole-4-base)-5-trifluoromethyl-2-) pyridine carboxamide
3-amido-N-(5-(((1r, 4r)-4-aminocyclohexyl) oxygen base) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxamide
3-amido-6-phenyl-N-(5-(pyrrolidin-3-yl oxygen base) isothiazole-4-base)-5-trifluoromethyl-2-pyridine carboxamide
N-(5-(3-amido-2-(chloromethyl) propoxy-) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxamide
N-(5-(3-amido-2-(chloromethyl) propoxy-) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxamide
N-(5-(3-amido-2-(methylol) propoxy-) isothiazole-4-base) the fluoro-2-pyridine carboxamide of-6-(2,6-difluorophenyl)-5-
3-amido-N-(4-(3-amido-2-(methylol) propoxy-) isothiazole-4-base) the fluoro-2-pyridine carboxamide of-6-(2,6-difluorophenyl)-5-
N-(5-(3-amido-2-(methylol) propoxy-) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxamide
3-amido-N-(5-(3-amido-2-(methylol) propoxy-) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxamide
Another object of the present invention there is provided the preparation method of above-mentioned PIM kinase inhibitor.
Compound of the present invention, prepares from commercially available starting raw material and reagent.Method of the present invention represents with following formula:
With or without blocking group alcohol B (1.1 equivalent) elder generation and alkali; if NaH (1-3 equivalent) is at solvent; as in tetrahydrofuran (THF); react 1 hour under room temperature (25 DEG C), and then react at 25-50 DEG C with 5-bromo-4-nitro isothiazole A (1 equivalent) and within 1-10 hour, obtain nitro isothiazole ether C.C (1 equivalent) suitable solvent as 1: 1 methyl alcohol and ethyl acetate and suitable catalyzer as 10%Pd/C (0.1-0.5 equivalent) catalysis under reduce under hydrogen (1-3 normal atmosphere) environment after 4-12 hour and obtain amido isothiazole D.The pyridine carboxylic acid E (1 equivalent) of with or without blocking group is at suitable coupling reagent; as HATU (1.1 equivalent); alkali; as under DIEA (3 equivalent) existence; at suitable solvent; as reacted 1-10 hour with amido pyridine D (1 equivalent) at 25-50 DEG C in DMF, obtain product F.If do not have blocking group in F, then F is the final ether compound in formula I.If with blocking group; as BOC (tert.-butoxy manthanoate) or trimethyl silane; F then again with trifluoracetic acid and isopyknic methylene dichloride of 10 to 100 equivalents; or 2 centinormal 1 methanol hydrochloride solution after room temperature (25 DEG C) mixing, stir 1-16 hour, then under room temperature (25 DEG C) underpressure distillation except the final ether compound obtained after desolventizing in formula I.
Another object of the present invention there is provided the application of above-mentioned PIM kinase inhibitor in pharmacy.
Through the test of PIM kinases chemical-biological activities method of testing, the compound in all embodiments all has obvious restraining effect to the kinase whose activity of PIM-1, PIM-2 and PIM-3, and its IC50 is in the scope of 0.1-50nM.Therefore, PIM kinase inhibitor of the present invention may be used for preparing medicine.
The invention provides the application of above-mentioned PIM kinase inhibitor in preparation treatment or preventing cancer medicine.
The invention provides the application of above-mentioned PIM kinase inhibitor in preparation treatment or prevention of autoimmune diseases medicine.
The invention provides the application of above-mentioned PIM kinase inhibitor in preparation treatment or Ammonium Glycyrrhizate reaction disease medicament.
The invention provides the application of above-mentioned PIM kinase inhibitor in the medicine that preparation is treated or prevention of arterial is atherosis.
The invention provides above-mentioned PIM kinase inhibitor treat in preparation or prevent the application in anti-organ transplant rejection medicine.
The invention provides the application of above-mentioned PIM kinase inhibitor in preparation treatment or prevention polytropism resistance medicine.
The invention provides the application of above-mentioned PIM kinase inhibitor in the anti-inflammatory drugs that preparation is treated or prevention T cell mediates.
The pharmaceutical composition that medicine of the present invention is made up of as activeconstituents and pharmaceutical carrier PIM kinase inhibitor.
The invention provides the novelty teabag of PIM kinase inhibitor, have larger clinical value.
Compound of the present invention and pharmaceutical composition, can be used for treatment or preventing cancer, reverse resistance that is anticancer and other medicines, inflammatory bowel, the inflammation of auto-immune disease, anaphylaxis disease, atherosclerosis, anti-organ transplant rejection, polytropism resistance, T cell mediation; " cancer " refers to can by the Cancerous disease suppressing PIM kinases to obtain advantageous treatment, comprise such as solid tumor, as lung cancer, carcinoma of the pancreas, thyroid carcinoma, ovarian cancer, bladder cancer, breast cancer, prostate cancer or colorectal carcinoma, melanoma, bone marrow disorder such as, myelocytic leukemia, multiple myeloma and erythroleukemia, adenoma are such as, villous colon adenoma and sarcoma such as, osteosarcoma; Liquid tumor as chronic lymphocytic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelocytic leukemia, non-Hodgkin lymphoma, and multiple myeloma.
Invention also provides aforesaid compound and pharmaceutical composition in preparation treatment or preventing cancer, reverse resistance that is anticancer and other medicines, inflammatory bowel, the inflammation of auto-immune disease, anaphylaxis disease, atherosclerosis, anti-organ transplant rejection, polytropism resistance, T cell mediation; " cancer " refers to can by the Cancerous disease suppressing PIM kinases to obtain advantageous treatment, comprise such as solid tumor, as lung cancer, carcinoma of the pancreas, thyroid carcinoma, ovarian cancer, bladder cancer, breast cancer, prostate cancer or colorectal carcinoma, melanoma, bone marrow disorder such as, myelocytic leukemia, multiple myeloma and erythroleukemia, adenoma are such as, villous colon adenoma and sarcoma such as, osteosarcoma; Liquid tumor as chronic lymphocytic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelocytic leukemia, non-Hodgkin lymphoma, and the application of the medicine of multiple myeloma.
Embodiment
The object of following examples is described in more detail the present invention.Scope of the present invention is not limited to these embodiments.
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-
The synthesis of fluoro-6-picoline (c) of (i) 2-(2,6-difluorophenyl)-3-
By fluoro-for bromo-for 2-3-6-picoline (a) (279mg, 1.77mmol), 2, 6-difluorophenyl boronic acid (b) (167mg, 0.88mmol) be dissolved in tetrahydrofuran (THF)/water mixed solvent (10: 1,8ml) with Potassium monofluoride (169mg, 2.91mmol), degassed 5 minutes, under nitrogen protection, add Pd 2(dba) 3(25mg, 0.044mmol) and tri-butyl phosphine (18mg, 0.088mmol), be heated to 60 DEG C, react 1 hour, cool to room temperature, add ethyl acetate (10ml), use water (10ml) and saturated aqueous common salt (10ml) washing successively, through anhydrous sodium sulfate drying, solvent is removed after filtration, the thick product of gained is dissolved in ethanol (10ml), add NaBH4 (17mg, at room temperature stir 0.44mmol) and add 10ml water in 1 hour, then extracted with diethyl ether (3x10ml) is used, the organic layer merged washs with saturated aqueous common salt (10ml), anhydrous sodium sulfate drying, except obtaining thick product after desolventizing.Product c (162mg, 0.73mmol) is obtained after thick product silica gel column chromatography column purification (5: 1 sherwood oils: methylene dichloride).
(ii) synthesis of the fluoro-2-pyridine carboxylic acid (E1) of 6-(2,6-difluorophenyl)-5-
By compound c (300mg, 1.34mmol) and potassium permanganate (423mg, 2.68mmol) be dissolved in after in 45ml water and reflux 24 hours, cool rear diatomite filtration, filtrate obtains white solid after being neutralized to pH=1 with 6N hydrochloric acid, filtrate is extracted with ethyl acetate (3x50ml), and extract (3x5ml) with 1N sodium hydroxide solution after extraction liquid is concentrated into 10ml, extraction liquid concentrated hydrochloric acid obtains solid after being neutralized to pH=1.Say for 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)
The synthesis of fluoro-2-pyridine carboxylic acid methyl esters (f) of (i) 3-amido-5-
3-amido 2-bromo-5-fluorine pyridine (500mg, 2.62mmol) is added, triethylamine (0.59ml, 4.16mmol), Pd (BINAP) Cl in autoclave 2(32mg, 0.039mmol), anhydrous methanol (20ml), is filled with CO (carbon monoxide converter) gas (60psi), is heated to 100 DEG C after degassed, react cool to room temperature after 12 hours, then add Pd (BINAP) Cl 2(10mg, 0.012mmol), continues at 60psi carbon monoxide, reacts cool to room temperature after 12 hours at 100 DEG C, filters.Ethyl acetate (30ml) is added in filtrate, use water (20ml) and saturated aqueous common salt (20ml) washing again, anhydrous sodium sulfate drying, filters, yellow oil product (f) (155mg, 0.917mmol) is obtained after concentrated.
(ii) synthesis of fluoro-2-pyridine carboxylic acid methyl esters (g) of the bromo-5-of 3-amido-6-
3-amido-5-fluoro-2-pyridine carboxylic acid methyl esters (100mg, 0.588mmol) is dissolved in second cyanogen (2ml), at room temperature adds NBS (105mg, 0.647mmol), added water after 2 minutes (10ml) termination reaction.Reaction solution is extracted with ethyl acetate (2x10ml), saturated common salt water washing (10ml), anhydrous sodium sulfate drying, filters.Product (g) (59mg, 0.235mmol) is obtained after the thick product silica gel column chromatography column purification (20-60% ethyl acetate/petroleum ether) obtained after filtrate concentrates
(iii) synthesis of fluoro-2-pyridine carboxylic acid methyl esters (h) of 3-amido-6-(2,6-difluorophenyl)-5-
The synthetic method of reference compound c, with fluoro-2-pyridine carboxylic acid methyl esters (g) of the bromo-5-of 3-amido-6-for raw material obtains product (h).
(iv) synthesis of the fluoro-2-pyridine carboxylic acid (E2) of 3-amido-6-(2,6-difluorophenyl)-5-
By fluoro-2-pyridine carboxylic acid methyl esters (the g) (56mg of the bromo-5-of 3-amido-6-, 0.20mmol) be dissolved in the tetrahydrofuran (THF)/methanol mixed solvent (1ml) of 1: 1, add 1M lithium hydroxide solution (0.4ml, 0.40mmol), at room temperature stir after being neutralized to pH=7 with 1N hydrochloric acid after 2 hours and be extracted with ethyl acetate (3x5ml), extraction liquid use water (5ml) and saturated aqueous common salt (5ml) washing, anhydrous sodium sulfate drying, filter, product (E2) (48mg, 0.18mml) is obtained after concentrated.
The synthesis of the fluoro-6-phenyl of 3.3-amido-5--2-pyridine carboxylic acid (E3)
With reference to the synthesis of E2, the phenyl-boron dihydroxide (b1) of 2,6-difluorophenyl boronic acid (b) wherein replaces obtained product (E3)
The synthesis of 4.3-fluoro-(2,4 '-Lian pyridine)-6-carboxylic acid (E4)
With reference to the synthesis of E1,4-pyridinylboronic acid (b2) of 2,6-difluorophenyl boronic acid (b) wherein replaces obtained product (E4)
The synthesis of the fluoro-2-pyridine carboxylic acid (E5) of 5.6-(2,6-difluorophenyl)-3-
With reference to the synthesis of E1, fluoro-6-picoline (a) of the bromo-3-of 2-wherein replaces obtained product (E5) with fluoro-2-picoline (k) of the bromo-3-of 6-
The synthesis of 6.6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxylic acid (E6)
(i) 2-methoxycarbonyl-5-trifluoromethylpyridin-1-oxide compound (n)
5-trifluoromethyl-2-pyridine carboxylic acid methyl esters (m) (1.03g, 5.0mmol) with metachloroperbenzoic acid (1.2g, stir 6 hours at 60 DEG C after 7.0mmol) being dissolved in methylene dichloride (15ml), product (n) (387mg, 1.8mmol) is obtained with purification by silica gel column chromatography except after desolventizing.
(ii) synthesis (o) of the bromo-3-trifluoromethyl of 2--2-pyridine carboxylic acid methyl esters
By 2-methoxycarbonyl-5-trifluoromethylpyridin-1-oxide compound (n) (221mg, 1.0mmol) add POBr3 (2.5g, 8.5mmol), cool to room temperature after 2 hours is stirred at 80 DEG C, pour in 20ml water, mixture is extracted with ethyl acetate (3x10ml).The saturated NaCl solution of organic phase is washed (10ml), concentrated after anhydrous sodium sulfate drying, product (o) (128mg, 0.45mmol) is obtained after gained crude product silica gel column chromatography column purification (5: 1 petrol ether/ethyl acetate).
(iii) synthesis of 6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxylic acid (E6)
With reference to the synthesis of E3, fluoro-2-pyridine carboxylic acid methyl esters (g) of the bromo-5-of 3-amido-6-wherein replaces being worth product (E6) with bromo-3-trifluoromethyl-2-pyridine carboxylic acid methyl esters (o) of 2-
The synthesis of 7.3-amido-6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxylic acid (E7)
The synthesis (r) of the bromo-3-nitro of (i) 2--5-5-flumethiazine
POBr is added in acetonitrile (25ml) solution of 3-nitro-5-5-flumethiazine-2-alcohol (q) (3.12g, 15mmol) 3(8.6g, 30mmol).Reflux at room temperature stirred 12 hours after 4 hours.Reaction solution pours the aqueous solution (60ml) of the sodium bicarbonate (11g) of rapid stirring into.Mixture is with dichloromethane extraction (3x20ml), after organic phase washed with water (20ml) and saturated nacl aqueous solution (10ml) wash, through anhydrous sodium sulfate drying, after concentrated, obtain product (r) (2.44g, 9.0mmol)
(ii) synthesis (s) of 2-cyano group-3-nitro-5-5-flumethiazine
At bromo-3-nitro-5-5-flumethiazine (the r) (2.0g of 2-, Tetrabutyl amonium bromide (2.2g is added in toluene (50ml) solution 7.37mmol), 7.37mmol) with cuprous cyanide (CuCN) (1.98g, 22.2mmol), reflux 9 hours, after cool to room temperature, add water (150ml) and ethyl acetate (150ml) mixing.After organic phase washed with water (2x50ml) and saturated nacl aqueous solution (20ml) wash, through anhydrous sodium sulfate drying, after concentrated, obtain product (s) (1.04g, 4.79mmol).
(iii) synthesis (t) of 3-amido-2-cyano group-5-5-flumethiazine
2-cyano group-3-nitro-5-5-flumethiazine (s) (1.0g, add 10% palladium/gac (0.10g) after 4.61mmol) being dissolved in ethyl acetate (20ml), filter after 18 hours at 1 normal atmosphere stirring under hydrogen, concentrated after obtain crude product (t) and be directly used in next step reaction.
(iv) synthesis (u) of 3-amido-5-trifluoromethyl-2-pyridine carboxylic acid formicester
Above-mentioned 3-amido-2-cyano group-5-5-flumethiazine (t) is dissolved in the mixed solvent of concentrated hydrochloric acid (5ml) and methyl alcohol (5ml), reflux after 48 hours except desolventizing, product (u) (256mg, 1.16mmol) is obtained after gained crude product silica gel column chromatography column purification (5: 1 petrol ether/ethyl acetate).
The synthesis (v) of the bromo-5-trifluoromethyl of (v) 3-amido-6--2-pyridine carboxylic acid formicester,
3-amido-5-trifluoromethyl-2-pyridine carboxylic acid formicester (u) (1.0g, 4.55mmol) in water (30ml), add the vitriol oil (0.5ml, the acetum (3ml) (10 minutes) of bromine (0.23ml, 4.55mmol) is dripped 9.1mmol).Reactant at room temperature stirs after 24 hours with water (50ml) dilution, after being neutralized to pH=7 through sodium bicarbonate, extract with methylene dichloride (3x30ml), the convenient saturated sodium bicarbonate solution of organic phase (30ml), after water (30ml) and saturated nacl aqueous solution (20ml) wash, through anhydrous sodium sulfate drying, product (v) (843mg, 2.82mmol) is obtained after gained crude product silica gel column chromatography column purification (5: 1 petrol ether/ethyl acetate) after concentrated.
(vi) synthesis of 3-amido-6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxylic acid (E7)
With reference to the synthesis of E2, bromo-5-trifluoromethyl-2-pyridine carboxylic acid formicester (v) of 3-amido-6-(2,6-difluorophenyl)-5-fluoro-2-pyridine carboxylic acid methyl esters 3-amido-6-wherein replaces obtained product (E7).
Embodiment 1
Preparation 6-(2,6-difluorophenyl)-5-fluoro-N-(5-(piperidin-4-yl methoxyl group) isothiazole-4-base) picolinamide (1)
(1) 4-(4-nitro isothiazole-5-yloxymethyl) piperidines-1-t-butyl formate (C1) is prepared
Under room temperature (25 DEG C) condition, by NaH (33mg, 1.16mmol) add 4-methylol-piperidines-1-t-butyl formate (B1) (250mg, THF (tetrahydrofuran (THF)) (10mL) solution & stir 1.16mmol) 1 hour, then 5-bromo-4-nitro isothiazole (A) (242mg, 1.16mmol) is added.Reactant stirs 16 hours final vacuum spin concentration under room temperature (20-30 DEG C).After concentrated, residue obtains product C l (247mg, 0.719mmol) through silica gel column chromatography column purification (elutriant: 10-30% ethyl acetate/petroleum ether).
(2) 4-((4-amido isothiazole-5-base) oxygen methyl) piperidines-1-t-butyl formate (D1) is prepared
Under room temperature (25 DEG C), 10%Pd/C (20mg) is added C1 (200mg, 0.582mmol) in the mixing solutions of methyl alcohol (2ml) and ethyl acetate (2ml).Reactant stirs after 10 hours and filters under hydrogen (1 normal atmosphere).Product D 1 (167mg, 0.534mmol) is obtained after concentrating filter liquor.
(3) preparation of 4-((4-(6-(2,6-difluorophenyl)-5-fluorine picolinamide base) isothiazole-4-base) oxygen methyl) piperidines-1-t-butyl formate (Boc-F1)
Compound (D1) (50mg, 0.16mmol), compound 6-(2,6-difluorophenyl)-5-fluorine pyridine carboxylic acid (E1) (40mg, 0.16mmol), HATU (72mg, 0.19mmol) and DIEA (88 μ L, the 0.51mmol) mixture in DMF (5mL) stirs 1 hour at 50 DEG C.Cool rear ethyl acetate (50mL) dilution, then use saturated common salt water washing.Organic phase is through Na 2sO 4after drying, under room temperature (20-30 DEG C), vacuum rotating concentrates.After concentrated, residue (elutriant: 10-30% ethyl acetate/petroleum ether) after silica gel column chromatography column purification obtains product B oc-F1 (31mg, 0.056mmol).
(4) the fluoro-N-of 6-(2,6-difluorophenyl)-5-(4-(piperidin-4-yl methoxyl group) pyridin-3-yl)-2-pyridine carboxamide (1) is prepared
Under room temperature (25 DEG C) condition, TFA (trifluoracetic acid) (0.5mL) is added the CH of compound (1A) (20mg, 0.037mmol) 2cl 2(1mL) solution, stirs 10 minutes, after vacuum rotating concentrates under room temperature (25 DEG C), residue is dissolved in CH 2cl 2(10mL), solution uses sodium hydroxide (5mL) and saturated aqueous common salt (5mL) washing of 1 equivalent respectively, and organic phase is through Na 2sO 4after drying, under room temperature (25 DEG C), vacuum rotating is concentrated obtains product 1 (10mg, 0.022mmol).
Embodiment 2
Preparation N-(5-(azetidine-3-ylmethoxy) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-fluorine picolinamide (2)
Preparation method is with reference to embodiment 1.Wherein the compound B-11 3-methylol-azetidine-1-t-butyl formate (B2) of step (1) replaces, obtained product 2.
Embodiment 3
Preparation 6-(2,6-difluorophenyl)-5-fluoro-N-(5-(piperidin-4-yl oxygen base) isothiazole-4-base) picolinamide (3)
Preparation method is with reference to embodiment 1.Wherein the compound B-11 4-hydroxyl-piperidines-1-t-butyl formate (B3) of step (1) replaces, obtained product 3.
Embodiment 4
Preparation 6-(2,6-difluorophenyl)-5-fluoro-N-(5-(pyrroles-3-base oxygen base) isothiazole-4-base) picolinamide (4)
Preparation method is with reference to embodiment 1.Wherein the compound B-11 of step (1) replaces with 3-hydroxy-pyrrolidine-1-t-butyl formate (B4), obtained product 4.
Embodiment 5
Preparation 6-(2,6-difluorophenyl)-5-fluoro-N-(5-(piperidines-3-base oxygen base) isothiazole-4-base) picolinamide (5)
Preparation method is with reference to embodiment 1.Wherein the compound B-11 of step (1) replaces with 3-hydroxy piperidine-1-t-butyl formate (B5), obtained product 5.
Embodiment 6
Preparation N-(5-(nitrogen heterocyclic-4-in heptan base oxygen base) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-fluorine picolinamide (6)
Preparation method is with reference to embodiment 1.Wherein the compound B-11 of step (1) replaces with 4-hydroxy-azepane-1-t-butyl formate (B6), obtained product 6.
Embodiment 7
Preparation 6-(2,6-difluorophenyl)-5-fluoro-N-(5-(piperidines-3-ylmethoxy) isothiazole-4-base) picolinamide (7)
Preparation method is with reference to embodiment 1.Wherein the compound B-11 4-methylol-piperidines-1-t-butyl formate (B7) of step (1) replaces, obtained product 7.
Embodiment 8
Preparation 6-(2,6-difluorophenyl)-5-fluoro-N-(5-(pyrroles-3-ylmethoxy) isothiazole-4-base) picolinamide (8)
Preparation method is with reference to embodiment 1.Wherein the compound B-11 3-methylol-tetramethyleneimine-1-t-butyl formate (B8) of step (1) replaces, obtained product 8.
Embodiment 9
Preparation N-(5-(azetidin-3-base oxygen base) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-fluorine picolinamide (9)
Preparation method is with reference to embodiment 1.Wherein the compound B-11 of step (1) replaces with the 3-hydroxyl-1-azetidinecarboxylic acid tert-butyl ester (B9), obtained product 9.
Embodiment 10
Preparation N-(5-(((1r, 4r)-4-aminocyclohexyl) oxygen base) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-fluorine picolinamide (10)
Preparation method is with reference to embodiment 1.Wherein the compound B-11 of step (1) replaces with trans-4-hydroxy-cyciohexyl-t-butyl carbamate (B10), obtained product 10.
Embodiment 11
Preparation N-(5-((3-aminocyclohexyl) oxygen base) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-fluorine picolinamide (11)
Preparation method is with reference to embodiment 1.Wherein the compound B-11 of step (1) replaces with 3-hydroxy-cyciohexyl-t-butyl carbamate (B11), obtained product 11.
Embodiment 12
Preparation N-(5-(3-amine propoxy-) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-fluorine picolinamide (12)
Preparation method is with reference to embodiment 1.Wherein the compound B-11 of step (1) replaces with 3-hydroxypropylamine-1-t-butyl formate (B12), obtained product 12.
Embodiment 13
Preparation 6-(2,6-difluorophenyl)-5-fluoro-N-(5-(3-(methylamino) propoxy-) isothiazole-4-base) picolinamide (13)
Preparation method is with reference to embodiment 1.Wherein the compound B-11 of step (1) replaces with N-methyl-3-hydroxypropylamine-1-t-butyl formate (B13), obtained product 13.
Embodiment 14
Preparation 6-(2,6-difluorophenyl)-N-(5-(3-(dimethyl amido) propoxy-) isothiazole-4-base)-5-fluorine picolinamide (14)
Preparation method is with reference to embodiment 1.The wherein compound B-11 N of step (1), N-dimethyl-3-hydroxypropylamine (B14) replace, and step (3) deprotection omits, obtained product 14.
Embodiment 15
Preparation N-(5-(4-amido butoxy) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-fluorine picolinamide (15)
Preparation method is with reference to embodiment 1.Wherein the compound B-11 of step (1) replaces with 4-hydroxyl butylamine-1-t-butyl formate (B15), obtained product 15.
Embodiment 16
Preparation 6-(2,6-difluorophenyl)-5-fluoro-N-(5-(4-(methylamino) butoxy) isothiazole-4-base) picolinamide (16)
Preparation method is with reference to embodiment 1.Wherein the compound B-11 of step (1) replaces with N-methyl-4-hydroxyl butylamine-1-t-butyl formate (B16), obtained product 16.
Embodiment 17
Preparation 6-(2,6-difluorophenyl)-5-fluoro-N-(5-(3-hydroxy propyloxy group) isothiazole-4-base) picolinamide (17)
Preparation method is with reference to embodiment 1.Wherein the compound B-11 of step (1) replaces with 1,3-PD (B17), and step (3) deprotection omits, obtained product 17.
Embodiment 18
Preparation 6-(2,6-difluorophenyl)-5-fluoro-N-(5-(3-hydroxybutoxy) isothiazole-4-base) picolinamide (18)
Preparation method is with reference to embodiment 1.Wherein the compound B-11 of step (1) replaces with 1,3 butylene glycol (B18), and step (3) deprotection omits, obtained product 18.
Embodiment 19
Preparation 6-(2,6-difluorophenyl)-5-fluoro-N-(5-(4-hydroxy butoxy) isothiazole-4-base) picolinamide (19)
Preparation method is with reference to embodiment 1.Wherein the compound B-11 of step (1) replaces with BDO (B19), and step (3) deprotection omits, obtained product 19.
Embodiment 20
The fluoro-N-of preparation 6-(2,6-difluorophenyl)-5-(5-((4-hydroxy-4-methyl pentyloxy) isothiazole-4-base) picolinamide (20)
Preparation method is with reference to embodiment 1.The wherein compound B-11 4-methyl isophthalic acid of step (1), 4-pentanediol (B20) replaces, and step (3) deprotection omits, obtained product 20.
Embodiment 21
Preparation 6-(2,6-difluorophenyl)-N-(5-(3,4-dihydroxyl butoxy) isothiazole-4-base)-5-fluorine picolinamide (21)
(1) 6-(2 is prepared, 6-difluorophenyl)-N-(5-(2-(2,2-dimethyl-DOX-4-base) oxyethyl group-) isothiazole-4 base) the fluoro-2-pyridine carboxamide (ProtectedF21) of-5-
Step (1) in preparation method's reference embodiment 1 and the method for (2), wherein the compound B-11 of step (1) is with (2,2-dimethyl-1,3-dioxolanes-4-base) ethanol (B21) replacement, obtained product P rotectedF21.
(2) 6-(2,6-difluorophenyl)-N-(5-(3,4-dihydroxyl butoxy) isothiazole-4-base) the fluoro-2-pyridine carboxamide (21) of-5-is prepared
Under room temperature (25 DEG C) condition, after ProtectedF21 (20mg, 0.042mmol) being dissolved in methyl alcohol (2mL), add concentrated hydrochloric acid (0.5mL), stir and use 10%Na after 4 hours 2cO 3solution is neutralized to pH=7, and add water (20mL) obtains product 21 (14mg, 0.032mmol) by after vacuum filtration and 25 DEG C of dry airs.
Embodiment 22
Preparation 6-(2,6-difluorophenyl)-5-fluoro-N-(5-(tetrahydropyrans-4-methoxyl group) isothiazole-4-base) picolinamide (22)
Preparation method is with reference to embodiment 1.Wherein the compound B-11 of step (1) replaces with tetrahydropyrans-4-methyl alcohol (B22), and step (3) deprotection omits, obtained product 22.
Embodiment 23
Preparation 3-amido-6-(2,6-difluorophenyl)-5-fluoro-N-(5-(piperidin-4-yl methoxyl group) isothiazole-4-base) picolinamide (23)
Preparation method is with reference to embodiment 1.Compd E 1 wherein in step (3) 3-amido-6-fluoro-2-Pyridinecarboxylic Acid of (2,6-difluorophenyl)-5-(E2) replaces, obtained product 23.
Embodiment 24
Preparation 3-amido-6-(2,6-difluorophenyl)-5-fluoro-N-(5-(pyrroles-3-base oxygen base) isothiazole-4-base) picolinamide (24)
Preparation method is with reference to embodiment 23.Wherein the compound B-11 B4 of step (1) replaces, obtained product 24.
Embodiment 25
Preparation 3-amido-6-(2,6-difluorophenyl)-5-fluoro-N-(5-(piperidin-4-yl oxygen base) isothiazole-4-base) picolinamide (25)
Preparation method is with reference to embodiment 23.Wherein the compound B-11 B3 of step (1) replaces, obtained product 25.
Embodiment 26
Preparation 3-amido-N-(5-(nitrogen heterocyclic-4-in heptan base oxygen base) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-fluorine picolinamide (26)
Preparation method is with reference to embodiment 23.Wherein the compound B-11 B6 of step (1) replaces, obtained product 26.
Embodiment 27
Preparation 3-amido-N-(5-(((1r, 4r)-4-aminocyclohexyl) oxygen base) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-fluorine picolinamide (27)
Preparation method is with reference to embodiment 23.Wherein the compound B-11 B10 of step (1) replaces, obtained product 27.
Embodiment 28
Preparation 3-amido-6-(2,6-difluorophenyl)-5-fluoro-N-(5-(pyrroles-3-ylmethoxy) isothiazole-4-base)-2-pyridine carboxamide (28)
Preparation method is with reference to embodiment 23.Wherein the compound B-11 B8 of step (1) replaces, obtained product 28.
Embodiment 29
Preparation N-(5-((1-amido-3-chloropropyl-2-base) oxygen base) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-fluorine picolinamide (29)
Compound 9 (20mg, 0.050mmol) is dissolved in 4 moles of HCl methanol solutions (1ml) under room temperature, stir except desolventizing after 4 hours, gained solid washed with ether final vacuum is dry, obtains compound 29 (21mg, 0.044mmol)
Embodiment 30
Preparation N-(5-(3-amido-2-(chloromethyl) propoxy-) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-fluorine picolinamide (30)
Preparation method is with reference to embodiment 29.Compound 9 wherein replaces with 2, obtained product 30.
Embodiment 31
Preparation 3-amido-N-(5-(azetidin-3-base oxygen base) isothiazole-4-base) the fluoro-2-pyridine carboxamide (31) of-6-(2,6-difluorophenyl)-5-
Preparation method is with reference to embodiment 23.Wherein the compound B-11 B9 of step (1) replaces, obtained product 31.
Embodiment 32
Preparation 3-amido-N-(5-(azetidine-3-ylmethoxy) isothiazole-4-Ji-Ji) the fluoro-2-pyridinecarboxylic (32) of-6-(2,6-difluorophenyl)-5-
Preparation method is with reference to embodiment 23.Wherein the compound B-11 B2 of step (1) replaces, obtained product 32.
Embodiment 33
Preparation 3-amido-N-(5-((1-amido-3-chloropropyl-2-base) oxygen base) isothiazole-4-base) the fluoro-2-pyridine carboxamide (33) of-6-(2,6-difluorophenyl)-5-
Preparation method is with reference to embodiment 29.Compound 9 wherein replaces with compound 31, obtained product 33.
Embodiment 34
Preparation 3-amido-N-(5-(3-amido-2-(chloromethyl) propoxy-) isothiazole-4-base) the fluoro-2-pyridine carboxamide (34) of-6-(2,6-difluorophenyl)-5-
Preparation method is with reference to embodiment 29.Compound 9 wherein replaces with 32, obtained product 34.
Embodiment 35
Preparation 3-amido-6-(2,6-difluorophenyl)-5-fluoro-N-(5-(piperidines-3-ylmethoxy) isothiazole-4-base)-2-pyridine carboxamide (35)
Preparation method is with reference to embodiment 23.Wherein the compound B-11 B7 of step (1) replaces, obtained product 35.
Embodiment 36
Preparation 3-amido-N-(5-(4-amido butoxy) isothiazole-4-base) the fluoro-2-pyridine carboxamide (36) of-6-(2,6-difluorophenyl)-5-
Preparation method is with reference to embodiment 23.Wherein the compound B-11 B15 of step (1) replaces, obtained product 36.
Embodiment 37
Preparation 3-amido-N-(5-((3-aminocyclohexyl) oxygen base) isothiazole-4-base) the fluoro-2-pyridine carboxamide (37) of-6-(2,6-difluorophenyl)-5-
Preparation method is with reference to embodiment 23.Wherein the compound B-11 B11 of step (1) replaces, obtained product 37.
Embodiment 38
The fluoro-6-phenyl of preparation 3-amido-5--N-(4-(pyrrolidin-3-yl oxygen base) pyridin-3-yl)-2-pyridine carboxamide (38)
Preparation method is with reference to embodiment 1.Wherein the compound B-11 B4 of step (1) replaces, the compd E 1 fluoro-6-phenyl of 3-amido-5-of step (2))-2-Pyridinecarboxylic Acid (E3) replacement, obtained product 38.
Embodiment 39
Preparation 3-fluoro-N-(4-(piperidin-4-yl oxygen base) pyridin-3-yl)-(2,4 '-dipyridyl)-6-methane amide (39)
Preparation method is with reference to embodiment 1.Wherein the compound B-11 B3 of step (1) replaces, and the compd E 1 of step (2) replaces with 3-fluoro-(2,4 '-Lian pyridine)-6-carboxylic acid (E4), obtained product 39.
Embodiment 40
Preparation N-(4-(nitrogen heterocyclic-4-in heptan base oxygen base) pyridin-3-yl) the fluoro-2-pyridine carboxamide (40) of-6-(2,6-difluorophenyl)-3-
Preparation method is with reference to embodiment 1.Wherein the compound B-11 B6 of step (1) replaces, and the compd E 1 of step (2) replaces with 6-(2,6-difluorophenyl)-3-fluorine pyridine carboxylic acid (E5), obtained product 40.
Embodiment 41
Preparation N-(4-(nitrogen heterocyclic-4-in heptan base oxygen base) pyridin-3-yl) the fluoro-6-of-5-(the fluoro-6-p-methoxy-phenyl of 2-)-2-pyridine carboxamide (41)
Compound 6 (10mg, 0.022mmol) is dissolved in the methanol solution (1ml) of 0.1M sodium hydroxide, stirs 2 hours at 50 DEG C.Except gained solids washed with water after desolventizing, drying obtains product 41 (8mg, 0.017mmol).
Embodiment 42
Preparation N-(4-(nitrogen heterocyclic-4-in heptan base oxygen base) pyridin-3-yl)-6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxamide (42)
Preparation method is with reference to embodiment 1.Wherein the compound B-11 of step (1) replaces with 4-hydroxy-azepane-1-t-butyl formate (B6), compd E 1 6-(2 of step (2), 6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxylic acid (E6) replacement, obtained product 42.
Embodiment 43
Preparation 6-(2,6-difluorophenyl)-N-(4-(piperidin-4-yl methoxyl group) pyridin-3-yl)-5-trifluoromethyl-2-pyridine carboxamide (43)
Preparation method is with reference to embodiment 1.Wherein the compd E 1 of step (2) replaces with 6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxylic acid (E6), obtained product 43.
Embodiment 44
Preparation N-(4-(azetidin-3-ylmethoxy) pyridin-3-yl)-6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxamide (44)
Preparation method is with reference to embodiment 1.Wherein the compound B-11 3-methylol-azetidine-1-t-butyl formate (B2) of step (1) replaces, compd E 1 6-(2 of step (2), 6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxylic acid (E6) replacement, obtained product 44.
Embodiment 45
Preparation 6-(2,6-difluorophenyl)-N-(4-(piperidin-4-yl oxygen base) pyridin-3-yl)-5-trifluoromethyl-2-pyridine carboxamide (45)
Preparation method is with reference to embodiment 1.Wherein the compound B-11 4-hydroxyl-piperidines-1-t-butyl formate (B3) of step (1) replaces, compd E 1 6-(2 of step (2), 6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxylic acid (E6) replacement, obtained product 45.
Embodiment 46
Preparation N-(4-(((1r, 4r)-4-aminocyclohexyl) oxygen base) pyridin-3-yl)-6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxamide (46)
Preparation method is with reference to embodiment 1.Wherein the compound B-11 of step (1) replaces with trans-4-hydroxy-cyciohexyl-t-butyl carbamate (B10), compd E 1 6-(2 of step (2), 6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxylic acid (E6) replacement, obtained product 46.
Embodiment 47
Preparation 6-(2,6-difluorophenyl)-N-[4-(tetrahydropyran-4-base) oxygen base) pyridin-3-yl)-5-trifluoromethyl-2-pyridine carboxamide (47)
Preparation method is with reference to embodiment 1.Wherein the compound B-11 of step (1) replaces with tetrahydropyrans-4-methyl alcohol (B22); compd E 1 6-(2 of step (2); 6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxylic acid (E6) replacement; step (3) deprotection omits, obtained product 47.
Embodiment 48
Preparation 3-amido-N-(4-(nitrogen heterocyclic-4-in heptan base oxygen base) pyridin-3-yl)-6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxamide (48)
Preparation method is with reference to embodiment 1.Wherein the compound B-11 of step (1) replaces with 4-hydroxy-azepane-1-t-butyl formate (B6), the compd E 1 3-amido-6-(2 of step (2), 6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxylic acid (E7) replacement, obtained product 48.
Embodiment 49
Preparation 3-amido-6-(2,6-difluorophenyl)-N-(4-(piperidin-4-yl methoxyl group) pyridin-3-yl)-5-trifluoromethyl-2-pyridine carboxamide (49)
Preparation method is with reference to embodiment 1.Wherein the compd E 1 of step (2) replaces with 3-amido-6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxylic acid (E7), obtained product 49.
Embodiment 50
Preparation 3-amido-N-(4-(azetidin-3-ylmethoxy) pyridin-3-yl)-6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxamide (50)
Preparation method is with reference to embodiment 1.Wherein the compound B-11 3-methylol-azetidine-1-t-butyl formate (B2) of step (1) replaces, the compd E 1 3-amido-6-(2 of step (2), 6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxylic acid (E7) replacement, obtained product 50.
Embodiment 51
Preparation 3-amido-6-(2,6-difluorophenyl)-N-(4-(piperidin-4-yl oxygen base) pyridin-3-yl)-5-trifluoromethyl-2-pyridine carboxamide (51)
Preparation method is with reference to embodiment 1.Wherein the compound B-11 4-hydroxyl-piperidines-1-t-butyl formate (B3) of step (1) replaces, the compd E 1 3-amido-6-(2 of step (2), 6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxylic acid (E7) replacement, obtained product 51.
Embodiment 52
Preparation 3-amido-N-(4-(((1r, 4r)-4-aminocyclohexyl) oxygen base) pyridin-3-yl)-6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxamide (52)
Preparation method is with reference to embodiment 1.Wherein the compound B-11 of step (1) replaces with trans-4-hydroxy-cyciohexyl-t-butyl carbamate (B10), the compd E 1 3-amido-6-(2 of step (2), 6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxylic acid (E7) replacement, obtained product 52.
Embodiment 53
Preparation 3-amido-6-phenyl-N-(4-(pyrrolidin-3-yl oxygen base) pyridin-3-yl)-5-trifluoromethyl-2-pyridine carboxamide (53)
Preparation method is with reference to embodiment 1.Wherein the compound B-11 of step (1) replaces with 3-hydroxy-pyrrolidine-1-t-butyl formate (B4), the compd E 1 3-amido-6-(2 of step (2), 6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxylic acid (E7) replacement, obtained product 53.
Embodiment 54
Preparation N-(4-(3-amido-2-(chloromethyl) propoxy-) pyridin-3-yl)-6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxamide (54)
Preparation method is with reference to embodiment 29.Compound 9 wherein replaces with compound 44, obtained product 54.
Embodiment 55
Preparation 3-amido-N-(4-(3-amido-2-(chloromethyl) propoxy-) pyridin-3-yl)-6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxamide (55)
Preparation method is with reference to embodiment 29.Compound 9 wherein replaces with compound 50, obtained product 55.
Embodiment 56
Preparation N-(4-(3-amido-2-(methylol) propoxy-) pyridin-3-yl) the fluoro-2-pyridine carboxamide (56) of-6-(2,6-difluorophenyl)-5-
By compound 2 (40mg under room temperature, 0.095mmol) be dissolved in trifluoracetic acid and the methanol solution (1ml) of 1: 1, stir and neutralize with saturated sodium carbonate solution after 4 hours, except desolventizing, compound 56 (12mg, 0.027mmol) is obtained after gained solid silica gel column chromatography column purification (1: 1 ethyl acetate/petroleum ether)
Embodiment 57
Preparation 3-amido-N-(4-(3-amido-2-(methylol) propoxy-) pyridin-3-yl) the fluoro-2-pyridine carboxamide (57) of-6-(2,6-difluorophenyl)-5-
Preparation method is with reference to embodiment 56.Compound 2 wherein replaces with compound 32, obtained product 57.
Embodiment 58
Preparation N-(4-(3-amido-2-(methylol) propoxy-) pyridin-3-yl)-6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxamide (58)
Preparation method is with reference to embodiment 56.Compound 2 wherein replaces with compound 44, obtained product 58.
Embodiment 59
Preparation 3-amido-N-(4-(3-amido-2-(methylol) propoxy-) pyridin-3-yl)-6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxamide (59)
Preparation method is with reference to embodiment 56.Compound 2 wherein replaces with compound 50, obtained product 59.
The structural analysis data of compound prepared in table 1. embodiment of the present invention
Embodiment 60
R 3substituting group suppresses the impact of PIM-1 kinase activity to the compounds of this invention
In order to verify R 3substituting group suppresses the impact of PIM-1 kinase activity to the compounds of this invention (general formula I), and we devise 6 groups and have different structure, with the compound of different functional groups, and has synthesized this 6 groups of compounds by the method that above-described embodiment describes.In these 6 groups of compounds, often organize compound a in compound and between compound b, c, except R 3outside substituting group difference, the molecular structure of other parts is identical.The wherein R of compound a 3=H, the R of compound b 3=F, the R of compound c 3=CF 3.Their bioactive difference directly show R 3on the impact of compound activity.These 6 groups of compounds are to the kinase whose IC of suppression PIM-1 50list in table 2.
Table 2.R 3substituting group is on the impact of the compounds of this invention activity
The data presentation of table 2, the IC of compound b and c that all 5-positions replace 50all little than corresponding compound a, such as the IC of compound 1a 50be 2.8 times of 1b, therefore the activity of compound 1b is 2.8 times of compound 1a.In these 6 groups of compounds, active to improve minimum be 2.7 times (compound 4a/4b), and improving maximum is 9.2 times (compound 3a/3c), average out to 5.1 times.This result shows, as the R in the compounds of this invention 3substituting group be F or other substituent time, its specific activity does not have substituting group (R 3for H) respective compound be significantly improved, these are different from existing knowledge.
Embodiment 61
The detection of the biologic activity of the compounds of this invention and result.
The biological activity of the compounds of this invention is all entrusted and is protected the responsible test of promise science and technology (Beijing) company limited (Building E, No. 29, Living Science park Road, Changping District, BeiJing City).Testing 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 little peptide substrates phosphorylation that 5-FAM can be marked.Unphosphorylated substrate not can be incorporated on binding reagents (immobilization metal chelating pearl), and fluorescence polarization value is lower.And the little peptide of phosphorylation can be incorporated on binding reagents, fluorescence polarization value is raised.The high low reaction size of PIM kinase activity of the little peptide substrates phosphorylation degree of 5-FAM mark.By the compounds of this invention of test under finite concentration to the restraining effect of PIM kinase activity, the rejection ability of these compounds to PIM kinase activity can be determined.
2. instrument
EnVision，PerkinElmer
3. reagent and 384 orifice plates
PIM1 (Millipore catalog number (Cat.No.) 14-573) (purchased from American MilliporeCorporation company)
PIM2 (Millipore catalog number (Cat.No.) 14-607) (purchased from American MilliporeCorporation company)
Little peptide (5-FAM-RSRHSSYPAGT, AnaSpec catalog number (Cat.No.) #63801) (the purchased from American AnaSpecInc. company) of 5-FAM mark
IMAPFPScreeningExpresskit (IMAPFP screening reagent box) (MolecularDevices catalog number (Cat.No.) #R8127) (purchased from American MolecularDevices company)
IMAPProgressivebindingreagent (IMAP bonding agent)
IMAPProgressivebindingbufferA (5X) (IMAP binding buffer liquid A)
IMAPProgressivebindingbufferB (5X) (IMAP binding buffer liquid B)
384-wellblackplate (Corning, catalog number (Cat.No.) #3573) (purchased from American Corning company)
4. survey damping fluid of living
Tris-HCl (Tutofusin tris-hydrochloric acid) (pH7.2): 10mM
MgCl 2：10mM
TritonX-100 (Triton X-100 X-100): 0.01%
DTT (dithiothreitol (DTT)): 2mM
5. step
This is tested the compounds of this invention used and is obtained by above-described embodiment.
A) the compounds of this invention liquid storage 100%DMSO (dimethyl sulfoxide (DMSO)) of 10mM is diluted to respective concentration, and then compound survey damping fluid (dithiothreitol (DTT)) alive dilutes 10 times, makes DMSO concentration be 10%.
B) live body system 10ul is surveyed:
(PIM-1 and PIM-3 final concentration is 0.025nM for 1ul compound and 4ul enzyme, PIM-2 final concentration is 3nM) hatch 15 minutes in 23 DEG C, add 2.5ulATP (PIM-1, in the determination of activity of PIM-2 and PIM-3, the final concentration of ATP is 30uM, 5uM and 30uM respectively) and 2.5ul5-FAM mark little peptide (final concentration is 100nM) initial action.React on 23 DEG C and carry out 60 minutes.Replace compound with DMSO in the reaction system of maximum value contrast, in the reaction system of minimum value contrast, replace enzyme with survey damping fluid (dithiothreitol (DTT)) alive.
C) 30ulIMAP bonding agent (containing 75%IMAP binding buffer liquid A, 25%IMAP binding buffer liquid B, 1/600 immobilization metal chelating pearl) is added, termination reaction, incubated at room 60 minutes.
D) read plate and obtain fluorescence polarization value mP, exciting light 485nm, utilizing emitted light 530nm.
6. data processing
Suppress per-cent=(fluorescence polarization value mP-minimum value) × 100/ (maximum value-minimum value)
Through the test of PIM kinases chemical-biological activities method of testing, the compound in all embodiments all has obvious restraining effect to the kinase whose activity of PIM-1, PIM-2 and PIM-3, its IC 50in the scope of 0.1-50nM.

Claims (20)

1. there is the compound of general formula I:
In above-mentioned formula I
R 1for-H ,-NHR 4, halogen (F, Cl, Br, I) ,-OH ,-OC 1-3alkyl ,-SH ,-SC 1-3alkyl, C 1-3alkyl, halogenated methyl, halogenated ethyl ,-CN and-NO 2;
R 2for-H ,-NHR 4, halogen (F, Cl, Br, I) ,-OH ,-SH, the substituent-OC of with or without 1-3alkyl ,-SC 1-3alkyl, C 1-3alkyl and C 3-7cyclic hydrocarbon radical, halogenated methyl, halogenated ethyl ,-CN and-NO 2;
R3 is-NHR 5, halogen (F, Cl, Br, I) ,-OH ,-SH, the substituent-OC of with or without 1-3alkyl ,-SC 1-3alkyl, C 1-3alkyl and C 3-7cyclic hydrocarbon radical, halogenated methyl, halogenated ethyl ,-CN and-NO 2;
R 4for-H ,-C (=O)-R 5, the substituent C of with or without 1-8alkyl, C 3-7cyclic hydrocarbon radical, 4-7 unit heterocyclic radical, 5-10 unit's aryl and heterocyclic aryl;
R 5for the substituent C of with or without 1-8alkyl, C 1-8-oxyl, C 3-7cyclic hydrocarbon radical;
R 6for the substituent C of with or without 3-7cyclic hydrocarbon radical, 4-7 unit heterocyclic radical, 5-10 unit's aryl and heterocyclic aryl; Described cyclic hydrocarbon radical, the substituting group on aryl and heterocyclic aryl can be halogen (F, Cl, Br, I) respectively ,-CN ,-NH 2,-NHR 7, C 1-4alkyl, C 1-4halo alkyl, C 3-7cyclic hydrocarbon radical ,-OR 7,-NO 2,-C (=O) OR 7,-C (=O) R 7,-C (=O) N (R 7) 2,-C (=O) NH 2,-C (=O) NHR 7;
R 7for-H or with or without substituting group C 1-4alkyl;
R 22for the substituent C of with or without 1-8alkyl or the group for following formula definition:
Wherein R 23, R 24and R 25be halogen (F, Cl, Br, I) ,-OR separately 15,-NR 16r 17,-C (=O) NR 18r 19or the substituent C of with or without 1-8alkyl;
R 15, R 16, R 17, R 18, R 19be-H or the substituent C of with or without separately 1-8alkyl
G 1for CH 2or N;
G 2for NR 28, CHR 29or O;
B1 and B2 is 0,1,2 or 3;
B3 is 0,1,2;
B4 is 0,1;
R 26and R 27be-H or the substituent C of with or without separately 1-8alkyl;
R 28for-H, the substituent C of with or without 1-8alkyl, C 3-7cyclic hydrocarbon radical, C 3-7heterocycle alkyl ,-C (=O) R 30,-C (=O) OR 30or-C (=O) NHR 30;
R 29for-H ,-OH, the substituent C of with or without 1-8alkyl, C 3-7cyclic hydrocarbon radical, C 3-7heterocycle alkyl ,-NHR 30,-C (=O) OR 30or-C (=O) NHR 30;
R 30for-H or the substituent C of with or without 1-8alkyl;
Described substituting group, if no special instructions, hydroxyl can be selected from, nitro, amino, imino-, cyano group, halogen, thio group, alkylsulfonyl, thio acylamino (thioamido), amidino groups, imidino, oxo amidino groups (oxamidino), methoxamidino (methoxamidino), guanidine radicals, sulfonamido, carboxyl, formyl radical, low alkyl group, junior alkyl halides, low-grade alkyl amino, junior alkyl halides is amino, lower alkoxy, halogenated lower alkoxy, low-grade alkoxy alkyl, alkyl-carbonyl, aminocarboxyl, aryl carbonyl, aromatic alkyl carbonyl, heteroaryl.
2. compound according to claim 1, is characterized in that,
R 1for-H ,-NH 2, halogen (F, Cl, Br, I) ,-CN ,-NO 2or C 1-8-oxyl;
R 2for-H, halogen (F, Cl, Br, I) ,-NH 2, C 1-8alkyl or C 1-8-oxyl;
R 3for halogen (F, Cl, Br, I), the substituent C of with or without 1-3alkyl and-OC 1-3alkyl, halogenated methyl ,-CN and-NO 2
R 6for with or without substituent 5 or 6 yuan of aryl or heteroaryl; Aryl or heteroaryl can have one or more substituting groups, and these substituting groups are respectively-CN separately, NO 2, halogen (F, Cl, Br, I) ,-OH ,-NH 2, C 1-4-oxyl, C 1-4substituted amido, C 1-4alkyl or C 3-6cyclic hydrocarbon radical.
3. the compound according to any one of claim 1-2, is characterized in that,
R 22for with or without substituent cyclopentyl, cyclohexyl, suberyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, azepan base, cyclobutylmethyl, cyclopentyl-methyl, cyclohexyl methyl, CycloheptylmethyI, azetidine ylmethyl, pyrrolidinylmethyl, piperidino methyl, piperizinylmethyl, azepan ylmethyl, butylene oxide ring ylmethyl, tetrahydrofuran (THF) ylmethyl or tetrahydropyrans ylmethyl; The substituent R of described band 22can have one or more substituting groups, they can be-NH separately respectively 2,-OH, methyl, ethyl or methoxyl group.
4. the compound according to any one of claim 1-2, is characterized in that,
R 22for being with substituent C 2-C 5alkyl, these alkyl can have at most 4 substituting groups, and they can be halogen (F, Cl, Br, I) respectively, NH 2, methylamino, ethylamino-, Propylamino, dimethylin, diethylin, hydroxyl, methyl, ethyl, propyl group ,-CH 2oH ,-CH 2(OH) CH 3,-CH 2cH 2oH, single halogenated methyl, many halogenated methyls, single halogenated ethyl, many halogenated ethyls, C 1-4alkyl-O-, C 1-4alkyl-S-.
5. the compound according to any one of claim 1-4, is characterized in that, R 3be selected from halogen (F, Cl, Br, I), halogenated methyl ,-CN and-NO 2.
6. the compound according to any one of claim 1-5, is characterized in that R 3be selected from halogen (F, Cl, Br, I) and-CF 3.
7. the compound according to any one of claim 1-6, is characterized in that, R 6be selected from phenyl or pyridyl, it can be selected from-F ,-Cl ,-Br ,-I ,-OH ,-NH by 1-3 2, C 1-3alkyl, C 1-3-oxyl, halo C 1-3the group of alkyl replaced.
8. the compound according to any one of claim 1-7, is characterized in that, R 6for phenyl, pyridyl, 2-F-6-OCH 3-phenyl, 2,6-difluorophenyl.
9. compound according to claim 1, is characterized in that, described compound is following compounds:
The fluoro-N-of 6-(2,6-difluorophenyl)-5-(5-(piperidin-4-yl methoxyl group) isothiazole-4-base) picolinamide
N-(5-(azetidine-3-ylmethoxy) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-fluorine picolinamide
The fluoro-N-of 6-(2,6-difluorophenyl)-5-(5-(piperidin-4-yl oxygen base) isothiazole-4-base) picolinamide
The fluoro-N-of 6-(2,6-difluorophenyl)-5-(5-(pyrroles-3-base oxygen base) isothiazole-4-base) picolinamide
The fluoro-N-of 6-(2,6-difluorophenyl)-5-(5-(piperidines-3-base oxygen base) isothiazole-4-base) picolinamide
N-(5-(nitrogen heterocyclic 4-in heptan base oxygen base) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-fluorine picolinamide
The fluoro-N-of 6-(2,6-difluorophenyl)-5-(5-(piperidines-3-ylmethoxy) isothiazole-4-base) picolinamide
The fluoro-N-of 6-(2,6-difluorophenyl)-5-(5-(pyrroles-3-ylmethoxy) isothiazole-4-base) picolinamide
N-(5-(azetidin-3-base oxygen base) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-fluorine picolinamide
N-(5-(((1r, 4r)-4-aminocyclohexyl) oxygen base) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-fluorine picolinamide
N-(5-((3-aminocyclohexyl) oxygen base) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-fluorine picolinamide
N-(5-(3-amine propoxy-) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-fluorine picolinamide
The fluoro-N-of 6-(2,6-difluorophenyl)-5-(5-(3-(methylamino) propoxy-) isothiazole-4-base) picolinamide
6-(2,6-difluorophenyl)-N-(5-(3-(dimethyl amido) propoxy-) isothiazole-4-base)-5-fluorine picolinamide
N-(5-(4-amido butoxy) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-fluorine picolinamide
The fluoro-N-of 6-(2,6-difluorophenyl)-5-(5-(4-(methylamino) butoxy) isothiazole-4-base) picolinamide
The fluoro-N-of 6-(2,6-difluorophenyl)-5-(5-(3-hydroxy propyloxy group) isothiazole-4-base) picolinamide
The fluoro-N-of 6-(2,6-difluorophenyl)-5-(5-(3-hydroxybutoxy) isothiazole-4-base) picolinamide
The fluoro-N-of 6-(2,6-difluorophenyl)-5-(5-(4-hydroxy butoxy) isothiazole-4-base) picolinamide
The fluoro-N-of 6-(2,6-difluorophenyl)-5-(5-((4-hydroxy-4-methyl pentyloxy) isothiazole-4-base) picolinamide
6-(2,6-difluorophenyl)-N-(5-(3,4-dihydroxyl butoxy) isothiazole-4-base)-5-fluorine picolinamide
The fluoro-N-of 6-(2,6-difluorophenyl)-5-(5-(tetrahydropyrans-4-methoxyl group)-isothiazole-4-base) picolinamide
The fluoro-N-of 3-amido-6-(2,6-difluorophenyl)-5-(5-(piperidin-4-yl methoxyl group) isothiazole-4-base) picolinamide
The fluoro-N-of 3-amido-6-(2,6-difluorophenyl)-5-(5-(pyrroles-3-base oxygen base) isothiazole-4-base) picolinamide
The fluoro-N-of 3-amido-6-(2,6-difluorophenyl)-5-(5-(piperidin-4-yl oxygen base) isothiazole-4-base) picolinamide
3-amido-N-(5-(nitrogen heterocyclic-4-in heptan base oxygen base) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-fluorine picolinamide
3-amido-N-(5-(((1r, 4r)-4-aminocyclohexyl) oxygen base) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-fluorine picolinamide
The fluoro-N-of 3-amido-6-(2,6-difluorophenyl)-5-(5-(pyrroles-3-ylmethoxy) isothiazole-4-base)-2-pyridine carboxamide
N-(5-((1-amido-3-chloropropyl-2-base) oxygen base) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-fluorine picolinamide
N-(5-(3-amido-2-(chloromethyl) propoxy-) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-fluorine picolinamide
3-amido-N-(5-(azetidin-3-base oxygen base) isothiazole-4-base) the fluoro-2-pyridine carboxamide of-6-(2,6-difluorophenyl)-5-
3-amido-N-(5-(azetidine-3-ylmethoxy) isothiazole-4-Ji-Ji) the fluoro-2-pyridine carboxamide of-6-(2,6-difluorophenyl)-5-
3-amido-N-(5-((1-amido-3-chloropropyl-2-base) oxygen base) isothiazole-4-base) the fluoro-2-pyridine carboxamide of-6-(2,6-difluorophenyl)-5-
3-amido-N-(5-(3-amido-2-(chloromethyl) propoxy-) isothiazole-4-base) the fluoro-2-pyridine carboxamide of-6-(2,6-difluorophenyl)-5-
The fluoro-N-of 3-amido-6-(2,6-difluorophenyl)-5-(5-(piperidines-3-ylmethoxy) isothiazole-4-base)-2-pyridine carboxamide
3-amido-N-(5-(4-amido butoxy) isothiazole-4-base) the fluoro-2-pyridine carboxamide of-6-(2,6-difluorophenyl)-5-
3-amido-N-(5-((3-aminocyclohexyl) oxygen base isothiazole-4-base) the fluoro-2-pyridine carboxamide of-6-(2,6-difluorophenyl)-5-
The fluoro-6-phenyl of 3-amido-5--N-(5-(pyrrolidin-3-yl oxygen base) isothiazole-4-base)-2-pyridine carboxamide
The fluoro-N-of 3-(5-(piperidin-4-yl oxygen base) isothiazole-4-base)-(2,4 '-dipyridyl)-6-methane amide
N-(4-(nitrogen heterocyclic-4-in heptan base oxygen base) isothiazole-4-base) the fluoro-2-pyridine carboxamide of-6-(2,6-difluorophenyl)-3-
N-(4-(nitrogen heterocyclic-4-in heptan base oxygen base) isothiazole-4-base) the fluoro-6-of-5-(the fluoro-6-p-methoxy-phenyl of 2-)-2-pyridine carboxamide
N-(5-(nitrogen heterocyclic-4-in heptan base oxygen base) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxamide
6-(2,6-difluorophenyl)-N-(5-(piperidin-4-yl methoxyl group) isothiazole-4-base)-5-trifluoromethyl-2-pyridine carboxamide
N-(5-(azetidin-3-ylmethoxy) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxamide
6-(2,6-difluorophenyl)-(5-(piperidin-4-yl oxygen base) isothiazole-4-base)-5-trifluoromethyl-2-pyridine carboxamide
N-(5-(((1r, 4r)-4-aminocyclohexyl) oxygen base) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxamide
6-(2,6-difluorophenyl)-N-(5-(tetrahydropyran-4-base) methoxyl group) isothiazole-4-base)-5-trifluoromethyl-2-pyridine carboxamide
3-amido-N-(5-(nitrogen heterocyclic-4-in heptan base oxygen base) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxamide
3-amido-6-(2,6-difluorophenyl)-N-(5-(piperidin-4-yl methoxyl group) isothiazole-4-base)-5-trifluoromethyl-2-pyridine carboxamide
3-amido-N-(5-(azetidin-3-ylmethoxy) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxamide
3-amido-6-(2,6-difluorophenyl)-N-(5-(piperidin-4-yl oxygen base) isothiazole-4-base)-5-trifluoromethyl-2-) pyridine carboxamide
3-amido-N-(5-(((1r, 4r)-4-aminocyclohexyl) oxygen base) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxamide
3-amido-6-phenyl-N-(5-(pyrrolidin-3-yl oxygen base) isothiazole-4-base)-5-trifluoromethyl-2-pyridine carboxamide
N-(5-(3-amido-2-(chloromethyl) propoxy-) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxamide
N-(5-(3-amido-2-(chloromethyl) propoxy-) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxamide
N-(5-(3-amido-2-(methylol) propoxy-) isothiazole-4-base) the fluoro-2-pyridine carboxamide of-6-(2,6-difluorophenyl)-5-
3-amido-N-(4-(3-amido-2-(methylol) propoxy-) isothiazole-4-base) the fluoro-2-pyridine carboxamide of-6-(2,6-difluorophenyl)-5-
N-(5-(3-amido-2-(methylol) propoxy-) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxamide
3-amido-N-(5-(3-amido-2-(methylol) propoxy-) isothiazole-4-base)-6-(2,6-difluorophenyl)-5-trifluoromethyl-2-pyridine carboxamide.
10. a preparation method for the arbitrary described compound of claim 1-9, is characterized in that comprising the steps:
The preparation method of 11. 1 kinds of arbitrary described compounds of claim 1-9, is characterized in that comprising the steps:
With or without blocking group alcohol B first at room temperature react 1 hour with alkali, and then react at 25-50 DEG C with 5-bromo-4-nitro isothiazole A and within 1-10 hour, obtain nitro isothiazole ether C; C reduces after 4-12 hour and obtains amido isothiazole D under suitable solvent and suitable catalyzer environment; The pyridine carboxylic acid E of with or without blocking group, under suitable coupling reagent, alkali exist, in suitable solvent, reacts 1-10 hour, obtains product F at 25-50 DEG C; If do not have blocking group in F, then F is the final ether compound in formula I; If with blocking group F, then with trifluoracetic acid and methylene dichloride, or methanol hydrochloride solution stirs 1-16 hour after mixed at room temperature, and then at room temperature underpressure distillation is except the final ether compound obtained after desolventizing in formula I.
The preparation method of 12. 1 kinds of arbitrary described compounds of claim 1-9, is characterized in that comprising the steps:
With or without blocking group 1.1 equivalent alcohol B elder generation and alkali, if 1-3 equivalent NaH is at solvent, as in tetrahydrofuran (THF), at room temperature react 1 hour, and then react at 25-50 DEG C with 1 equivalent 5-bromo-4-nitro isothiazole A and within 1-10 hour, obtain nitro isothiazole ether C; 1 equivalent C suitable solvent as 1: 1 methyl alcohol and ethyl acetate and suitable catalyzer as 10%Pd/C (0.1-0.5 equivalent) catalysis under reduce under 1-3 normal atmosphere hydrogen environment after 4-12 hour and obtain amido isothiazole D; 1 equivalent pyridine carboxylic acid E of with or without blocking group, at suitable coupling reagent, as 1.1 equivalent HATU; alkali, as under 3 equivalent DIEA existence, at suitable solvent; as reacted 1-10 hour with 1 equivalent amido pyridine D at 25-50 DEG C in DMF, obtain product F.If do not have blocking group in F, then F is the final ether compound in formula I.If with blocking group; as tert.-butoxy manthanoate BOC or trimethyl silane; F then again with trifluoracetic acid and isopyknic methylene dichloride of 10 to 100 equivalents; or 2 centinormal 1 methanol hydrochloride solution after mixed at room temperature, stir 1-16 hour, then at room temperature underpressure distillation is except the final ether compound obtained after desolventizing in formula I.
13. 1 kinds of application rights require the method for the arbitrary described compound of 1-9, comprise the object arbitrary for the claim 1-9 of effective dose described compound being given needs treatment.
The purposes of 14. 1 kinds of arbitrary described compounds of claim 1-9, is characterized in that: as the application of PIM kinase inhibitor in pharmacy.
15., according to the purposes of compound described in claim 14, is characterized in that: as the application of PIM-1, PIM-2 and PIM-3 kinase inhibitor in pharmacy.
16. 1 kinds of application rights require the method for the arbitrary described compound of 1-9, comprise the object arbitrary for the claim 1-9 of effective dose described compound being given needs treatment, it is characterized in that:
Treatment or preventing cancer, reverse resistance that is anticancer and other medicines, inflammatory bowel, the inflammation of auto-immune disease, anaphylaxis disease, atherosclerosis, anti-organ transplant rejection, polytropism resistance, T cell mediation; " cancer " refers to can by the Cancerous disease suppressing PIM kinases to obtain advantageous treatment, comprise such as solid tumor, as lung cancer, carcinoma of the pancreas, thyroid carcinoma, ovarian cancer, bladder cancer, breast cancer, prostate cancer or colorectal carcinoma, melanoma, bone marrow disorder such as, myelocytic leukemia, multiple myeloma and erythroleukemia, adenoma are such as, villous colon adenoma and sarcoma such as, osteosarcoma; Liquid tumor as chronic lymphocytic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelocytic leukemia, non-Hodgkin lymphoma, and multiple myeloma.
17. 1 application rights require the method for PIM kinase inhibitor described in 1 or 8 or 9, comprise object PIM kinase inhibitor described in the claim 9 of effective dose being given needs treatment, it is characterized in that:
Treatment or preventing cancer, reverse resistance that is anticancer and other medicines, inflammatory bowel, the inflammation of auto-immune disease, anaphylaxis disease, atherosclerosis, anti-organ transplant rejection, polytropism resistance, T cell mediation; " cancer " refers to can by the Cancerous disease suppressing PIM kinases to obtain advantageous treatment, comprise such as solid tumor, as lung cancer, carcinoma of the pancreas, thyroid carcinoma, ovarian cancer, bladder cancer, breast cancer, prostate cancer or colorectal carcinoma, melanoma, bone marrow disorder such as, myelocytic leukemia, multiple myeloma and erythroleukemia, adenoma are such as, villous colon adenoma and sarcoma such as, osteosarcoma; Liquid tumor as chronic lymphocytic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelocytic leukemia, non-Hodgkin lymphoma, and multiple myeloma.
18. 1 kinds, based on the pharmaceutical composition of the arbitrary described compound of claim 1-9, is characterized in that: comprise the pharmaceutical composition that the arbitrary compound of claim 1-9 forms as activeconstituents and pharmaceutical carrier.
19. 1 pharmaceutical compositions based on the PIM kinase inhibitor of the compound of claim 9, the pharmaceutical composition that the PIM kinase inhibitor comprising compound described in claim 1 or 8 or 9 forms as activeconstituents and pharmaceutical carrier.
20. 1 kinds of application based on the pharmaceutical composition of the arbitrary described compound of claim 1-9, it is characterized in that: for the preparation for the treatment of or preventing cancer, reverse resistance that is anticancer and other medicines, inflammatory bowel, the inflammation of auto-immune disease, anaphylaxis disease, atherosclerosis, anti-organ transplant rejection, polytropism resistance, T cell mediation; " cancer " refers to can by the Cancerous disease suppressing PIM kinases to obtain advantageous treatment, comprise such as solid tumor, as lung cancer, carcinoma of the pancreas, thyroid carcinoma, ovarian cancer, bladder cancer, breast cancer, prostate cancer or colorectal carcinoma, melanoma, bone marrow disorder such as, myelocytic leukemia, multiple myeloma and erythroleukemia, adenoma are such as, villous colon adenoma and sarcoma such as, osteosarcoma; Liquid tumor as chronic lymphocytic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelocytic leukemia, non-Hodgkin lymphoma, and the application of the medicine of multiple myeloma.
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