CN105732637A - Hetero-aromatic compounds and applications thereof in pharmacy - Google Patents

Hetero-aromatic compounds and applications thereof in pharmacy Download PDF

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Publication number
CN105732637A
CN105732637A CN201511020679.1A CN201511020679A CN105732637A CN 105732637 A CN105732637 A CN 105732637A CN 201511020679 A CN201511020679 A CN 201511020679A CN 105732637 A CN105732637 A CN 105732637A
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alkyl
alkoxyl
replace
cyano group
compound
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CN105732637B (en
Inventor
刘兵
黄九忠
任兴业
李志�
龙伯华
张英俊
郑常春
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Guangdong HEC Pharmaceutical
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Dongguan Het Pharm Research And Development Co Ltd
Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Abstract

The invention discloses hetero-aromatic compounds and applications thereof in pharmacy. Specifically, the invention provides hetero-aromatic compounds, and steric isomers, geometric isomers, tautomers, racemic bodies, nitrogen oxides, hydrates, solvates, metabolism products, and pharmaceutically acceptable salts or prodrug thereof. The compounds mentioned above can be used to treat autoimmune diseases or proliferative diseases. The invention also discloses a pharmaceutical composition comprising the compounds mentioned above, and an application of the compounds or the pharmaceutical composition in the preparation of drugs for treating autoimmune diseases or proliferative diseases.

Description

Assorted aromatic compound and the application in medicine thereof
Invention field
The invention belongs to pharmaceutical technology field, be specifically related to the assorted aromatic compound that a class has protein kinase inhibiting activity and the pharmaceutical composition comprising the compounds of this invention.The invention still further relates to the compound about the present invention or the pharmaceutical composition pharmaceutically comprising the compounds of this invention application in medicine.
Background of invention
Janus kinases (JAK) belongs to family tyrosine kinase, is made up of JAK1, JAK2, JAK3 and TYK2.JAK plays an important role in cytokine signaling conducts.JAK1, JAK2 and TYK2 can suppress several genes to express, but JAK3 only plays a role in granulocyte.The exemplary functions of cytokine receptor is to exist as heterodimer form, is therefore frequently not a kind of jak kinase and cytokine receptor effect.
The interior part of the kytoplasm of cytokine receptor every kind preferential and discrete for JAK associates (Annu.Rev.Immunol.1998,16, pp.293-322).JAK is activated after part combines, and is conducted by the commencing signal by cytokine receptor phosphorylation, and described cytokine receptor itself lacks inherent kinase activity.This phosphorylation produces the stop position being used for being called other molecules of stat protein (signal transducer and the activator transcribed) on receptor, and the JAK of phosphorylation is in conjunction with multiple stat protein.Stat protein, or STAT is the DBP activated by tyrosine residue phosphorylation, and simultaneously work as the effect of signal transduction molecule and transcription factor, and be eventually combined in the promoter of cytokine-response group exist specific DNA sequences on (J.AllergyClin.Immunol., Leonard, etal, 2000,105:877-888).
Genetic biology research shows, JAK1 by with the cytokine receptor effect such as IFNalpha, IFNgamma, IL-2, IL-6 and play a role, JAK1 knock-out mice is dead due to LIF receptor signal disappearance.Observe the feature organization of JAK1 knock-out mice, it has been found that JAK1 plays an important role in the cell pathways such as IFN, IL-10, IL-2/IL-4 and IL-6.
Genetic biology research shows, JAK2 and strand, there is contact between IL-3 and interferon gamma cytokine receptor family.Corresponding, JAK2 knock-out mice dies from anemia.Kinase mediated JAK2 variation is relevant to human bone marrow's proliferative disorder, including polycythemia vera, hemorrhagic thrombocythemia, chronic idiopathic myelofibrosis, with the myeloide metaplasia of myelofibrosis, chronic special myelomatosis, chronic myelomonocytic leukemia etc..
JAK3 is specific acts on gamma cells factor acceptor chain, and it exists in the cytokine receptor such as IL-2, IL-4, IL-7, IL-9, IL-15, IL-21.JAK3, in lymphocyte growth, hypertrophy, plays an important role in mutation process, occurs extremely to cause serious immune deficiency.Now verify that the gene defect of the γ chain that the JAK3 protein level suffering from XSCID colony seriously reduces or it is total, display immunosuppressive action are to have been transmitted by the signal in JAK3 path owing to having blocked.Zooscopy shows that the lymphocytic maturation of B and T is not only played pivotal role by JAK3, and is also required to JAK3 to maintain the function of T cell from constituting.Regulating lymphocytic effect based on it, the path of JAK3 and JAK3 mediation is used for regulating immunosuppressant indication.JAK3 implication in the mediation of a lot of abnormal immune responses, such as allergy, asthma, autoimmune disease is as suppressed transplant rejection, rheumatoid arthritis, muscle contracting lateral sclerosis and multiple sclerosis and entity and hematologic malignancies such as leukemia, lymphoma.
JAK3 inhibitor is as being useful therapeutic agent for following immunosuppressant: organ transplantation, xenotransplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type i diabetes and from suitable other symptoms of the complication of diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorder, ulcerative colitis, Crohn disease, presenile dementia, leukemia and immunosuppressant.
There was reported the non-hematopoietic of JAK3 to express, although this meaning functionally not clear (J.Immunol., 2002,168:2475-2482).Owing to being medicable (Blood, 2004,103:2009-2018) for the bone marrow transplantation of SCID, it appears that unlikely JAK3 has the non-redundant function of necessity in its hetero-organization or organ.Therefore, contrary with other targets of immunosuppressive drug, the restriction distribution of JAK3 is attracting.Act on the activating agent with the molecular target being limited to immune expression and may result in the drug effect of the best: toxicity ratio.Therefore, in theory, when needing it (namely to the cell being actively engaged in immunne response) is provided immunosuppressant by targeting JAK3, and is not resulted in any effect outside these cell colonys.Although at multiple STAT-/-Bacterial strain has been described with defective immunne response (J.Investig.Med., 1996,44:304-311；Curr.Opin.CellBiol., 1997,9:233-239), but the generally distribution of STAT and these molecules lack can by the enzymatic activity of micromolecular inhibitor targeting the fact facilitated them as immunosuppressant key target non-selective.
TYK2 acts on interferon type Ⅰ, IL-6, IL-10, IL-12, the cytokine receptor complex such as IL-23.Consistent with it, it is derived from the primary cell of the people of TYK2 disappearance, at interferon type Ⅰ, IL-6, IL-10, IL-12, the signal conduction of IL-23 exists obstacle.
Therefore, for suppressing protein kinase JAK, thus provide the compound of the treatment to disease (such as autoimmune disease, inflammatory diseases and cancer) to there are needs.
Summary of the invention
The compound for protein kinase activity of the present invention has inhibitory action.More satisfactory, the compound of the present invention has multiple suppression function, it is possible to suppress JAK1, JAK2, JAK3, BTK, EGFR or EGFRT790M.Especially, the compound that the present invention relates to and pharmaceutically acceptable pharmaceutical composition, JAK1, JAK2, JAK3, BTK, EGFR or EGFRT790M inhibitor can be effective as.
On the one hand, the present invention relates to a kind of compound, it is the compound shown in formula (I) or the stereoisomer of compound shown in formula (I), geometric isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable salt or prodrug:
Wherein:
X is CH or N；
R is R1,-C (=O)-R2,-C (=O)-(CRaRb)m-R3、-(CRaRb)m-C (=O)-R3、-(CRaRb)m-R4,-C (=O)-N (Rc)-(CRaRb)n-R5,-S (=O)2-R6,-S (=O)2-N(Rc)-(CRaRb)n-R7Or-C (=O)-OR7；
R1For C3-6Cycloalkyl, C4-6Heterocyclic radical, C3-6Cycloalkenyl group, C6-10Aryl or C1-5Heteroaryl；
R2For C6-8Cycloalkyl, C2-10Heterocyclic radical, C3-6Cycloalkenyl group or C6-10Aryl, condition is to work as R2During for pyrrolidinyl, at least by a R2xReplace；
Each R2xIndependently be deuterium, fluorine, chlorine, bromine, iodine, cyano group, nitro, amino, carboxyl ,-C (=O)-NH2,-S (=O)2-NH2、C1-6Alkyl, C1-6Alkoxyl, C1-6Alkylamino, halo C1-6Alkyl, halo C1-6The C that alkoxyl, hydroxyl replace1-6The C that alkyl, hydroxyl replace1-6The C that alkoxyl, cyano group replace1-6The C that alkyl, cyano group replace1-6The C that alkoxyl or cyano group replace1-6Alkylamino；
Each R3Independently be C6-8Cycloalkyl, C2-10Heterocyclic radical, C3-6Cycloalkenyl group, C6-10Aryl or C1-5Heteroaryl；
R4For C3-6Cycloalkyl, C2-10Heterocyclic radical, C3-6Cycloalkenyl group, C6-10Aryl or C1-5Heteroaryl, condition is to work as R4During for phenyl, at least by a R4xReplace；
Each R4xIndependently be deuterium, chlorine, bromine, iodine, cyano group, nitro, amino, carboxyl ,-C (=O)-NH2,-S (=O)2-NH2,-S (=O)2-C2-10Heterocyclic radical, C1-6Alkyl, C1-6Alkoxyl, C1-6Alkylamino, halo C1-6Alkyl, halo C1-6The C that alkoxyl, hydroxyl replace1-6The C that alkyl, hydroxyl replace1-6The C that alkoxyl, cyano group replace1-6The C that alkyl, cyano group replace1-6The C that alkoxyl or cyano group replace1-6Alkylamino；
R5For C3-6Cycloalkyl, C2-10Heterocyclic radical, C3-6Cycloalkenyl group, C6-10Aryl or C4-5Heteroaryl；
R6For C3-6Cycloalkyl, C2-10Heterocyclic radical, C3-6Cycloalkenyl group, C6-10Aryl or C1-5Heteroaryl, condition is R6It it is not 5-methyl-isoxazole-4-base；
Each R7Independently be C3-6Cycloalkyl, C2-10Heterocyclic radical, C3-6Cycloalkenyl group, C6-10Aryl or C1-5Heteroaryl；
Each RaAnd RbIndependently be H, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, amino, carboxyl or C1-3Alkyl；
Each RcIndependently be H, C1-3The C that alkyl or cyano group replace1-3Alkyl；
Each m independently be 1,2,3,4,5 or 6；
Each n independently be 0,1,2,3,4,5 or 6；
Each R1、R2、R3、R4、R5、R6And R7Individually optionally by one or more RxReplace；
Each RxIndependently be deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, oxo (=O) ,-C (=O)-NH2,-S (=O)2-NH2、C1-6Alkyl, C1-6Alkoxyl, C1-6Alkylamino, halo C1-6Alkyl, halo C1-6The C that alkoxyl, hydroxyl replace1-6The C that alkyl, hydroxyl replace1-6The C that alkoxyl, cyano group replace1-6The C that alkyl, cyano group replace1-6The C that alkoxyl, cyano group replace1-6Alkylamino, C2-10Heterocyclic radical or C2-10Heterocyclyloxy base, wherein said C2-10Heterocyclic radical and C2-10Heterocyclyloxy base is individually optionally by one or more RyReplace；With
Each RyIndependently be deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, oxo (=O) ,-C (=O)-NH2,-S (=O)2-NH2、C1-6Alkyl, C1-6Alkoxyl, C1-6Alkylamino, halo C1-6Alkyl, halo C1-6The C that alkoxyl, hydroxyl replace1-6The C that alkyl, hydroxyl replace1-6The C that alkoxyl, cyano group replace1-6The C that alkyl, cyano group replace1-6The C that alkoxyl or cyano group replace1-6Alkylamino.
Some of them embodiment is, each RcIndependently be the propyl group that H, methyl, ethyl, propyl group, isopropyl, cyanogen methyl, cyanoethyl or cyano group replace.
Some of them embodiment is, each RxIndependently be deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, oxo (=O) ,-C (=O)-NH2,-S (=O)2-NH2、C1-4Alkyl, C1-3Alkoxyl, C1-3Alkylamino, halo C1-3Alkyl, halo C1-3The C that alkoxyl, hydroxyl replace1-3The C that alkyl, hydroxyl replace1-3The C that alkoxyl, cyano group replace1-3The C that alkyl, cyano group replace1-4The C that alkoxyl, cyano group replace1-4Alkylamino, C2-6Heterocyclic radical or C2-6Heterocyclyloxy base, wherein said C2-6Heterocyclic radical and C2-6Heterocyclyloxy base is individually optionally by one or more RyReplace；Wherein RyThere is implication as described in the present invention.
Some of them embodiment is, each RyIndependently be deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, oxo (=O) ,-C (=O)-NH2,-S (=O)2-NH2、C1-4Alkyl, C1-3Alkoxyl, C1-3Alkylamino, halo C1-3Alkyl, halo C1-3The C that alkoxyl, hydroxyl replace1-3The C that alkyl, hydroxyl replace1-3The C that alkoxyl, cyano group replace1-3The C that alkyl, cyano group replace1-4The C that alkoxyl or cyano group replace1-4Alkylamino.
Some of them embodiment is, R is R1,-C (=O)-R2,-C (=O)-(CH2)m-R3、-(CH2)m-C (=O)-R3、-(CH2)m-R4,-C (=O)-N (Rc)-(CH2)n-R5,-S (=O)2-R6,-S (=O)2-N(Rc)-(CH2)n-R7Or-C (=O)-OR7；
Wherein each m, n, Rc、R1、R2、R3、R4、R5、R6And R7There is implication as described in the present invention.
Some of them embodiment is, R1For phenyl, cyclobutyl, cyclopropanyl, cyclobutane base, cyclopentenyl, cyclopentadienyl group, cyclohexenyl group or cyclohexadienyl；R1Optionally by one or more RxReplace；Wherein RxThere is implication as described in the present invention.
Some of them embodiment is, R2For phenyl；R2Optionally by one or more RxReplace；Wherein RxThere is implication as described in the present invention.
Some of them embodiment is, each R3Independently be phenyl；Each R3Individually optionally by one or more RxReplace；Wherein RxThere is implication as described in the present invention.
Some of them embodiment is, R4For by 1,2,3,4 or 5 R4xThe phenyl replaced；Further, R4Optionally by one or more RxReplace；Wherein RxAnd R4xThere is implication as described in the present invention.
Some of them embodiment is, R5For phenyl；R5Optionally by one or more RxReplace；Wherein RxThere is implication as described in the present invention.
Some of them embodiment is, R6For phenyl；R6Optionally by one or more RxReplace；Wherein RxThere is implication as described in the present invention.
Some of them embodiment is, each R7Independently be phenyl；Each R7Individually optionally by one or more RxReplace；Wherein RxThere is implication as described in the present invention.
Some of them embodiment is, R2For following subformula:
R2Optionally by one or more RxReplace；
Wherein Y, Z, t, r, s, p, RxAnd R2xThere is implication as described in the present invention.
Some of them embodiment is, each R3Independently be following subformula:
Each R3Individually optionally by one or more RxReplace；
Wherein Y, Z, t, r, s, p, RxAnd R2xThere is implication as described in the present invention.
Some of them embodiment is, R4For following subformula:
R4Optionally by one or more RxReplace；
Wherein Y, Z, t, r, s, p, RxAnd R2xThere is implication as described in the present invention.
Some of them embodiment is, R5For following subformula:
R5Optionally by one or more RxReplace；
Wherein Y, Z, t, r, s, p, RxAnd R2xThere is implication as described in the present invention.
Some of them embodiment is, R6For following subformula:
R6Optionally by one or more RxReplace；
Wherein Y, Z, t, r, s, p, RxAnd R2xThere is implication as described in the present invention.
Some of them embodiment is, each R7Independently be following subformula:
Each R7Individually optionally by one or more RxReplace；
Wherein Y, Z, t, r, s, p, RxAnd R2xThere is implication as described in the present invention.
Some of them embodiment is, each Y independently be-CH2-,-NH-,-O-,-S-,-S (=O)-or-S (=O)2-；
Each Z independently be-NH-,-O-,-S-,-S (=O)-or-S (=O)2-；
Each t independently be 0,1,2 or 3；
Each r independently be 0,1 or 2；
Each s independently be 1 or 2；
Each p independently be 1 or 2.
Some of them embodiment is, R2xFor deuterium, fluorine, chlorine, bromine, iodine, cyano group, nitro, amino, carboxyl ,-C (=O)-NH2,-S (=O)2-NH2、C1-3Alkyl, C1-3Alkoxyl, C1-3Alkylamino, halo C1-3Alkyl, halo C1-3The C that alkoxyl, hydroxyl replace1-3The C that alkyl, hydroxyl replace1-3The C that alkoxyl, cyano group replace1-3The C that alkyl, cyano group replace1-3The C that alkoxyl or cyano group replace1-3Alkylamino.
Some of them embodiment is, R4xFor deuterium, chlorine, bromine, iodine, cyano group, nitro, amino, carboxyl ,-C (=O)-NH2,-S (=O)2-NH2,-S (=O)2-C2-6Heterocyclic radical, C1-3Alkyl, C1-3Alkoxyl, C1-3Alkylamino, halo C1-3Alkyl, halo C1-3The C that alkoxyl, hydroxyl replace1-3The C that alkyl, hydroxyl replace1-3The C that alkoxyl, cyano group replace1-3The C that alkyl, cyano group replace1-3The C that alkoxyl or cyano group replace1-3Alkylamino.
Some of them embodiment is, each R1、R2、R3、R4、R5、R6And R7Individually optionally by one or more RxReplace；Wherein RxThere is implication as described in the present invention.
Some of them embodiment is, each RxIndependently be deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, oxo (=O) ,-C (=O)-NH2,-S (=O)2-NH2, methyl, ethyl, propyl group, isopropyl, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, methylamino, dimethylamino, ethylamino, the third amino, halo C1-3Alkyl, halo C1-3The C that alkoxyl, hydroxyl replace1-3The C that alkyl, hydroxyl replace1-3The C that alkoxyl, cyano group replace1-3The C that alkyl, cyano group replace1-4The C that alkoxyl, cyano group replace1-3Alkylamino, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, 1-oxo thio-morpholinyl, 1,1-dioxothiomorpholinyl, homopiperidinyl, homopiperazine base, high morpholinyl, tetrahydrofuran base oxygen base or THP trtrahydropyranyl oxygen base, wherein said piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, 1-oxo thio-morpholinyl, 1,1-dioxothiomorpholinyl, homopiperidinyl, homopiperazine base, high morpholinyl, tetrahydrofuran base oxygen base or THP trtrahydropyranyl oxygen base are individually optionally by one or more RyReplace；Wherein RyThere is implication as described in the present invention.
Some of them embodiment is, each RyIndependently be deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, oxo (=O) ,-C (=O)-NH2,-S (=O)2-NH2、C1-3Alkyl, C1-3Alkoxyl, C1-3Alkylamino, halo C1-3Alkyl, halo C1-3The C that alkoxyl, hydroxyl replace1-3The C that alkyl, hydroxyl replace1-3The C that alkoxyl, cyano group replace1-3The C that alkyl, cyano group replace1-3The C that alkoxyl or cyano group replace1-3Alkylamino.
Other embodiment is, R1For following subformula:
Other embodiment is, R2For following subformula:
Other embodiment is, each R3Independently be following subformula:
Other embodiment is, R4For following subformula:
Other embodiment is, each R2、R3、R4、R5、R6And R7Independently be following subformula:
On the other hand, the present invention relates to a kind of compound, it is the compound shown in formula (II) or the stereoisomer of compound shown in formula (II), geometric isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable salt or prodrug:
Wherein:
R11For deuterium, bromine, iodine, cyano group, hydroxyl, nitro, carboxyl ,-C (=O)-NR12R13,-S (=O)2-NR12R13、C1-3Alkyl, halo C1-3Alkyl, amino C1-3Alkyl, C1-4Alkyl amino C1-4Alkyl, (C1-4Alkyl)2N-C1-4Alkyl-, hydroxyl replace C1-3The C that alkyl, cyano group replace1-3Alkyl, C1-4Alkoxyl, C1-4Alkylamino, C3-6Cycloalkyl amino, C6-10Virtue amino, C1-5Heteroaryl amino ,-N (R14)-C (=O)-R15、-N(R14)-S (=O)2-R15、C3-6Cycloalkyl, C3-6Cycloalkenyl group, C2-8Heterocyclic radical, C6-10Aryl, C1-5Heteroaryl, C3-6Cycloalkyl C1-3Alkyl, C3-6Cycloalkyl C1-3Alkoxyl, C3-6Cycloalkenyl group C1-3Alkyl, C3-6Cycloalkenyl group C1-3Alkoxyl, C2-6Heterocyclic radical C1-3Alkyl, C2-6Heterocyclic radical C1-6Alkoxyl, C6-10Aryl C1-3Alkyl, C6-10Aryl C1-3Alkoxyl, C1-5Heteroaryl C1-3Alkyl or C1-5Heteroaryl C1-3Alkoxyl；
Each R12And R13Independently be H, deuterium or C1-3Alkyl；
Each R14Independently be H, deuterium or C1-3Alkyl；
Each R15Independently be H, deuterium or C1-4Alkyl；With
R11Optionally by one or more selected from deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, oxo ,-C (=O)-NH2,-S (=O)2-NH2、C1-6Alkyl, C1-6Alkoxyl, C1-6Alkylamino, halo C1-6Alkyl, halo C1-6The C that alkoxyl, hydroxyl replace1-6The C that alkyl, hydroxyl replace1-6The C that alkoxyl, cyano group replace1-6The C that alkyl, cyano group replace1-6The C that alkoxyl, cyano group replace1-6Alkylamino, C2-8Heterocyclic radical or C2-8The substituent group of heterocyclyloxy base is replaced.
Some of them embodiment is, R11Optionally by one or more selected from deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, oxo ,-C (=O)-NH2,-S (=O)2-NH2、C1-3Alkyl, C1-3Alkoxyl, C1-3Alkylamino, halo C1-3Alkyl, halo C1-3The C that alkoxyl, hydroxyl replace1-3The C that alkyl, hydroxyl replace1-3The C that alkoxyl, cyano group replace1-3The C that alkyl, cyano group replace1-3The C that alkoxyl, cyano group replace1-3Alkylamino, C2-6Heterocyclic radical or C2-6The substituent group of heterocyclyloxy base is replaced.
Some of them embodiment is, R11For deuterium, bromine, iodine, cyano group, hydroxyl, nitro, carboxyl ,-C (=O)-NH2,-S (=O)2NH2, methoxyl group, ethyoxyl, methylamino, ethylamino ,-NH-C (=O)-CH3,-NH-C (=O)-CH2CH3、(CH3)2N-CH2-、(CH3)2N-CH2-CH2-、(CH3CH2)2N-CH2-、(CH3CH2)2N-CH2-CH2-, morpholinyl methyl, morpholinyl ethyl, morpholinyl propyl, morpholinyl methoxyl group, morpholinyl ethyoxyl, morpholinopropoxy, phenylamino, (4-morpholino phenyl) amino, pyrazolyl amino, N-methylpyrazole base amino, imidazole radicals amino, pyridinylamino or pyrimidinyl-amino.
Another aspect, the present invention relates to a kind of compound, it is the compound shown in formula (III) or the stereoisomer of compound shown in formula (III), geometric isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable salt or prodrug:
Wherein:
Each E, G, M and J independently be N or CR16；
K is-O-,-S-or-N (R17)-；
Each R16Independently be hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl ,-C (=O)-NH2,-S (=O)2-NH2、C1-6Alkyl, C1-6Alkoxyl, C1-6Alkylamino, halo C1-6Alkyl, halo C1-6The C that alkoxyl, hydroxyl replace1-6The C that alkyl, hydroxyl replace1-6The C that alkoxyl, cyano group replace1-6The C that alkyl, cyano group replace1-6The C that alkoxyl or cyano group replace1-6Alkylamino；With
R17For hydrogen, deuterium or C1-6Alkyl.
On the other hand, the present invention comprises but is not limited to have the compound of one of following structure or has one of the following stereoisomer of structural compounds, geometric isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug:
One aspect of the present invention relates to a kind of pharmaceutical composition, comprises compound of the present invention.
Some of them embodiment is, pharmaceutical composition of the present invention comprises at least one of pharmaceutically acceptable carrier, excipient, diluent, adjuvant and vehicle further.
Some of them embodiment is, pharmaceutical composition of the present invention comprises additional treatment agent further, its selected from chemotherapeutics or antiproliferative, anti-inflammatory agent, immunomodulator or immunosuppressant, neurotrophic factor, for treating the activating agent of cardiovascular disease, for treating the activating agent of diabetes and for treating the activating agent of autoimmune disease.
The pharmaceutical composition of compound that another aspect of the present invention is directed to use with a kind of present invention or the compound that comprises the present invention is prepared for preventing, process or treat autologous patient immunological diseases or proliferative disease, and alleviates the purposes of the medicine of its order of severity.
Some of them embodiment is, autoimmune disease of the present invention is lupus, multiple sclerosis, muscle contracting lateral sclerosis, rheumatoid arthritis, psoriasis, type i diabetes, because of the complication that organ transplantation causes, foreign body is transplanted, diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn disease, Alzheimer, leukemia and lymphoma.
Some of them embodiment is, proliferative disease of the present invention is metastatic carcinoma, colon cancer, adenocarcinoma of stomach, bladder cancer, breast carcinoma, renal carcinoma, hepatocarcinoma, pulmonary carcinoma, thyroid carcinoma, head and neck cancer, carcinoma of prostate, cancer of pancreas, the cancer of CNS (central nervous system), glioblastoma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis.
On the other hand, the present invention relates to the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention prepares the purposes for suppression in biological sample or the medicine regulating protein kinase activity, described purposes comprises the pharmaceutical composition using the compounds of this invention or comprise the compounds of this invention and contacts with described biological sample.
Some of them embodiment is, protein kinase is JAK1, JAK2, JAK3, BTK, EGFR or EGFRT790M.
On the one hand, the present invention relates to the intermediate of the compound that preparation formula (I), (II) or (III) comprises.
Another aspect of the present invention relates to the method for the preparation of compound, separation and purification that formula (I), (II) or (III) comprises.
The present invention also comprises the compound of the present invention and the application of pharmaceutically acceptable salt thereof, is used for producing medical product treatment autoimmune disease or proliferative disease, described in the invention including those.The compound of the present invention is equally used for producing a kind of pharmaceuticals for alleviating, and stops, controls or treat the disease mediated by JAK1, JAK2, JAK3, BTK, EGFR or EGFRT790M.
The present invention comprises pharmaceutical composition, this pharmaceutical composition includes compound representated by formula (I), (II) or (III) and at least one pharmaceutically acceptable carrier, effectively treats consumption needed for the combination of adjuvant or diluent.
The present invention comprises treatment autologous patient immunological diseases or proliferative disease equally, or the method that this disease is sensitive, the method comprises the therapeutically effective amount of compound representated by use formula (I), (II) or (III) and patient is treated.
Unless other aspects show, all of stereoisomer of compound of the present invention, geometric isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite, metabolic precursor thereof, salt and pharmaceutically acceptable prodrug broadly fall into the scope of the present invention.
Specifically, salt is pharmaceutically acceptable salt.Term " pharmaceutically acceptable " includes material or compositions must be suitable for chemistry or toxicologically, relevant with other components of composition preparation and the mammal for treating.
The salt of the compound of the present invention, also include the salt of the enantiomer of shown in preparation or purification formula (I), (II) or (III) intermediate of compound or compound separation shown in formula (I), (II) or (III), but be not necessarily pharmaceutically acceptable salt.
nullPharmaceutically useful acid-addition salts can be formed with mineral acid and organic acid，Such as acetate、Hydroxyl acetate、Aspartate、Benzoate、Benzene sulfonate、Bromide/hydrobromate、Bicarbonate/carbonate、Disulfate/sulfate、Camsilate、Chloride/hydrochlorate、Chloro theophylline salt、Citrate、Ethanedisulphonate、Fumarate、Gluceptate、Gluconate、Glucuronate、Hippurate、Hydriodate/iodide、Isethionate、Lactate、Lactobionate、Lauryl sulfate、Malate、Maleate、Malonate、Mandelate、Mesylate、Esilate、Methylsulfate、Naphthoate、Naphthalene sulfonate、Nicotinate、Nitrate、Octadecanoate、Oleate、Oxalates、Palmitate、Pamoate、Phosphate/phosphor acid hydrogen salt/dihydric phosphate、Poly-galactose hydrochlorate、Propionate、Stearate、Succinate、Sulfosalicylate、Tartrate、Toluene fulfonate and trifluoroacetate.
Pharmaceutically acceptable base addition salts can be formed with inorganic base and organic base.
Can be included by its derivative inorganic base obtaining salt, for instance the metal of the I race of ammonium salt and periodic chart to XII race.In certain embodiments, this salt is derived from sodium, potassium, ammonium, calcium, magnesium, ferrum, silver, zinc and copper；Particularly suitable salt includes ammonium, potassium, sodium, calcium and magnesium salt.
Can being included primary amine, secondary amine and tertiary amine by its derivative organic base obtaining salt, the amine of replacement includes the amine of naturally occurring replacement, cyclic amine, deacidite etc..Some organic amine includes, for instance, 2-aminopropane., benzathine benzylpenicillin (benzathine), choline salt (cholinate), diethanolamine, diethylamine, lysine, meglumine (meglumine), piperazine and trometamol.
The officinal salt of the present invention can be synthesized by parent compound, alkalescence or acidic moiety with conventional chemical processes.Generally speaking, such salt can pass through to make the free acid form of these compounds react with the suitable alkali (such as the hydroxide of Na, Ca, Mg or K, carbonate, bicarbonate etc.) of stoichiometry, or by making the suitable acid reaction of the free alkali form of these compounds and stoichiometry be prepared.Such reaction generally carries out in water or organic solvent or the mixture of the two.Usually, when suitable, it is necessary to use non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile.At such as " Remington ' sPharmaceuticalSciences ", the 20th edition, MackPublishingCompany, Easton, Pa., (1985)；With " pharmaceutical salts handbook: character, selection and application (HandbookofPharmaceuticalSalts:Properties; Selection; andUse) ", StahlandWermuth (Wiley-VCH, Weinheim, Germany, 2002) list of the suitable salt of other can be found in.
It addition, compound disclosed by the invention, include their salt, it is also possible to obtain with their hydrate forms or the form that comprises its solvent (such as ethanol, DMSO, etc.), for their crystallization.Disclosure compound inherently or can pass through design forming solvate with pharmaceutically acceptable solvent (including water)；Therefore, it is contemplated that include solvation and non-solvation form.
Any structural formula that the present invention provides is also intended to represent that these compounds are not by the form of the form of isotope enrichment and isotope enrichment.The compound of isotope enrichment has the structure of the formula description that the present invention provides, except one or more atoms are replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes in the compounds of this invention can be introduced and include the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, as2H,3H,11C,13C,14C,15N,17O,18O,18F,31P,32P,35S,36Cl and125I。
On the other hand, compound of the present invention includes the compound that the present invention of isotope enrichment is defined, for instance, wherein there is radiosiotope, as3H,14C and18Those compounds of F, or wherein there is non radioactive isotope, as2H and13C.The compound of such isotope enrichment can be used for metabolism research and (uses14C), kinetics research (uses such as2H or3H), detection or imaging technique, such as positron emission tomography (PET) or the SPECT (single photon emission computed tomography) (SPECT) including medicine or substrate tissue measure of spread, or can be used in the radiotherapy of patient.18PET or SPECT research is especially desirable by the compound of F enrichment.Compound shown in the formula (I), (II) or (III) of isotope enrichment can by the embodiment in routine techniques that those skilled in the art are familiar with or the present invention with use suitable isotope labeling reagent to substitute original used unmarked reagent described by preparation process to prepare.
Additionally, higher isotope particularly deuterium is (that is,2H or D) replacement can provide some treatment advantage, these advantages are brought by metabolic stability is higher.Such as, Half-life in vivo increases or volume requirements reduces or therapeutic index improves and bringing.Should be appreciated that the deuterium in the present invention is counted as the substituent group of compound shown in formula (I), (II) or (III).The concentration of such higher isotope particularly deuterium can be defined by the isotope enrichment factor.Term used in the present invention " the isotope enrichment factor " refers to specified ratio between isotopic isotope abundance and natural abundance.If the substituent group of the compounds of this invention is designated as deuterium, each D-atom specified is had at least 3500 (each deuterium specifying D-atom place 52.5% mixes) by this compound, at least 4000 (deuterium of 60% mixes), at least 4500 (deuterium of 67.5% mixes), at least 5000 (deuterium of 75% mixes), at least 5500 (deuterium of 82.5% mixes), at least 6000 (deuterium of 90% mixes), at least 6333.3 (deuterium of 95% mixes), at least 6466.7 (deuterium of 97% mixes), the isotope enrichment factor of at least 6600 (deuterium of 99% mixes) or at least 6633.3 (deuterium of 99.5% mixes).It can be the such as D that isotope replaces that the pharmaceutically useful solvate of the present invention includes wherein recrystallisation solvent2O, acetone-d6、DMSO-d6Those solvates.
Content noted earlier only outlines certain aspects of the invention, but the content being not limited to these aspects and other aspect will do more specifically complete description below.
Detailed description of the invention book
Definition and general terms
Certain embodiments of the present invention be will now be described in more detail, and the example is by the structural formula enclosed and chemical formula explanation.The invention is intended to contain all of replacement, amendment and equivalent technical solutions, they are included in the scope of the invention such as claim definition.Those skilled in the art will appreciate that many and of the present invention similar or equivalent methods and material can be used in putting into practice the present invention.The present invention is not limited to method of the present invention and material.In one or more different from the application or conflicting situations of the document combined, patent and similar material (include but not limited to defined term, term application, described technology, etc.), it is as the criterion with the application.
It will further be appreciated that some feature of the present invention, for it will be clear that be described in multiple independent embodiments but it also may provide in combination in single embodiment.Otherwise, the various features of the present invention, for brevity, it is described in single embodiment but it also may individually or with the sub-portfolio being arbitrarily suitable for provide.
Unless otherwise indicated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention be generally understood that identical implication.The all patents that the present invention relates to and public publication are integrally incorporated the present invention by reference.
Unless otherwise indicated, it should apply following definition used in the present invention.For purposes of the present invention, chemical element and periodic table of elements CAS version, and " chemically and physically handbook ", the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle is referred to " OrganicChemistry ", ThomasSorrell, UniversityScienceBooks, Sausalito:1999, and " March'sAdvancedOrganicChemistry " byMichaelB.SmithandJerryMarch, john wiley & sons, description in NewYork:2007, its full content is incorporated by reference into the present invention.
Except as otherwise noted or in context, have obvious conflict, article used in the present invention " ", " one (kind) " and " described " are intended to include " at least one " or " one or more ".Therefore, these articles used in the present invention refer to the article of one or more than one (i.e. at least one) object.Such as, " component " refers to one or more component, it is possible to has more than one component to be taken into account in the embodiment of described embodiment and adopts or use.
Term used in the present invention " study subject " refers to animal.Typically described animal is mammal.Study subject, for instance also refer to primate (the such as mankind, sex), cattle, sheep, goat, horse, dog, cat, rabbit, rat, mice, fish, bird etc..In certain embodiments, described study subject is primate.In other embodiments, described study subject is people.
Term used in the present invention " patient " refers to people's (including adult and child) or other animals.In some embodiments, " patient " refers to people.
Term " comprises " for open language, namely includes the content specified by the present invention, but is not precluded from otherwise content.
" stereoisomer " refers to have identical chemical constitution, but the compound that atom or group spatially arrangement mode is different.Stereoisomer includes enantiomer, diastereomer, conformer (rotamer), geometric isomer (cis/trans) isomer, atropisomer, etc..
" chirality " is that have can not the molecule of overlapping character with its mirror image；And " achirality " refer to can be overlapping with its mirror image molecule.
" enantiomer " refer to two of a compound can not be overlapping but be mutually the isomer of mirror image relationship.
" diastereomer " refers to the stereoisomer of two or more chiral centres and its molecule not mirror image each other.Diastereomer has different physical propertys, such as fusing point, boiling point, spectral quality and reactivity.Non-enantiomer mixture can pass through high resolution analysis and operate such as electrophoresis and chromatograph, for instance HPLC separates.
Stereochemical definitions used in the present invention and rule generally follow S.P.Parker, Ed., McGraw-HillDictionaryofChemicalTerms (1984) McGraw-HillBookCompany, NewYork；andEliel,E.andWilen,S.,"StereochemistryofOrganicCompounds",JohnWiley&Sons,Inc.,NewYork,1994.
Many organic compound exist with optical active forms, and namely they have the ability making the plane of linearly polarized light rotate.When describing optically active compound, prefix D and L or R and S is used to represent the molecule absolute configuration about one or more chiral centre.Prefix d and l or (+) and (-) are the symbols that linearly polarized light caused by appointed compound rotates, wherein (-) or l represent that compound is left-handed.Prefix for (+) or the compound of d be dextrorotation.A kind of concrete stereoisomer is enantiomer, and the mixture of this isomer is called enantiomeric mixture.The 50:50 mixture of enantiomer is called racemic mixture or racemic modification, when not having stereo selectivity or stereospecificity in chemical reaction or process, may occur in which this situation.
Any asymmetric atom (such as, carbon etc.) of disclosure compound can exist with the form that raceme or enantiomer are enriched with, for instance (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess in (R)-or (S)-configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
According to the selection of starting material and method, the compounds of this invention can with in possible isomer or their mixture, for instance the form of racemic modification and non-corresponding isomer mixture (this depends on the quantity of asymmetric carbon atom) exists.Optically active (R)-or (S)-isomer can use chiral synthon or chiral reagent to prepare, or use routine techniques to split.If compound contains a double bond, substituent group is likely E or Z configuration；If containing dibasic cycloalkyl in compound, the substituent group of cycloalkyl is likely to there is cis or trans configuration.
The mixture of any stereoisomer of gained can be separated into pure or substantially pure geometric isomer, enantiomer, diastereomer according to the difference in component physicochemical properties, for instance, by chromatography and/or Steppecd crystallization.
By known method, the method that the racemic modification of any gained end-product or intermediate is familiar with by those skilled in the art can be split into optical antipode, e.g., by its diastereoisomeric salt obtained is easily separated.Racemic product can also be separated by chiral chromatogram, e.g., uses the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, enantiomer can be prepared by asymmetric synthesis, for instance, it is referred to Jacques, etal., Enantiomers, RacematesandResolutions (WileyInterscience, NewYork, 1981)；PrinciplesofAsymmetricSynthesis(2ndEd.RobertE.Gawley,JeffreyAube,Elsevier,Oxford,UK,2012)；Eliel,E.L.StereochemistryofCarbonCompounds(McGraw-Hill,NY,1962)；Wilen,S.H.TablesofResolvingAgentsandOpticalResolutionsp.268(E.L.Eliel,Ed.,Univ.ofNotreDamePress,NotreDame,IN1972)；ChiralSeparationTechniques:APracticalApproach(Subramanian,G.Ed.,Wiley-VCHVerlagGmbH&Co.KGaA,Weinheim,Germany,2007).
Term " tautomer " or " tautomeric form " refer to the constitutional isomer converted mutually by low energy barrier (lowenergybarrier) with different-energy.If tautomerism is possible (as in the solution), then can reach the chemical equilibrium of tautomer.Unless otherwise noted, all tautomeric forms of the compounds of this invention are within the scope of the present invention.
As described in the invention, the compound of the present invention can be optionally replaced by one or more substituent groups, such as general formula compound above, or as example special inside embodiment, subclass, and the compounds that the present invention comprises.Should be appreciated that " optionally substituted " this term and " substituted or non-substituted " this term can exchange use.It is said that in general, term " replacement " represents that the one or more hydrogen atoms in given structure are replaced by concrete substituent group.Unless other aspects show, an optional substituted radical can replace in each commutable position of group.In given structural formula, to be selected from one or more substituent groups of concrete group replaced in more than one position, then substituent group can replace in each position identical or differently.nullWherein said substituent group can be，But it is not limited to，Deuterium，Fluorine，Chlorine，Bromine，Iodine，Cyano group，Hydroxyl，Nitro，Amino，Carboxyl，Alkyl，Alkoxyl，Alkoxyalkyl，Alkyloxy-alkoxy，Alkoxyl alkylamino，Aryloxy group，Heteroaryl oxygen base，Heterocyclyloxy base，Alkoxy aryl，Heteroarylalkoxy，Heterocyclylalkoxy，Cycloalkyl alkoxy，Alkylamino，Alkyl amino alkyl，Alkylamino alkylamino，Cycloalkyl amino，Amino-n-cycloalkyl，Alkylthio group，Haloalkyl，Halogenated alkoxy，The alkyl that hydroxyl replaces，The alkylamino that hydroxyl replaces，The alkyl that cyano group replaces，The alkoxyl that cyano group replaces，The alkylamino that cyano group replaces，The alkyl that amino replaces，Alkyl acyl，Assorted alkyl，Cycloalkyl，Cycloalkenyl group，Cycloalkyl-alkyl，Heterocyclic radical，Cycloheteroalkylalkyl，Heterocyclylacyl，Aryl，Aryl alkyl，Virtue amino，Heteroaryl，Heteroaryl alkyl，Heteroaryl amino，Amide groups，Sulfonyl，Amino-sulfonyl etc..
Additionally, it should be noted that, unless otherwise explicitly pointed out, the describing mode that adopts in the present invention " each ... to independently be " and " ... be each independently " and " ... independently be " can exchange, all should being interpreted broadly, it both may refer to, in different groups, not affect mutually between concrete option expressed between same-sign, can also represent in identical group, not affect mutually between concrete option expressed between same-sign.
At each several part of this specification, the substituent group of disclosure compound is open according to radical species or scope.Particularly pointing out, the present invention includes each independent sub-combinations thereof of each member of these radical species and scope.Such as, term " C1-C6Alkyl " or " C1-6Alkyl " refer in particular to individually disclosed methyl, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
At each several part of the present invention, describe connection substituent group.When this structure clearly needs linking group, the Ma Kushi variable cited by this group is interpreted as linking group.Such as, if this structure needs linking group and the Ma Kushi group definition for this variable to list " alkyl " or " aryl ", then it should be understood that be somebody's turn to do " alkyl " or " aryl " to represent alkylidene group or the arylene group of connection respectively.
The term " alkyl " of present invention use or " alkyl group ", represent that saturated straight or branched univalent hydrocarbyl group, wherein, the substituent group that described alkyl group can optionally be described by one or more present invention is replaced containing 1 to 20 carbon atom.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom.In one embodiment, alkyl group contains 1-12 carbon atom；In one embodiment, alkyl group contains 1-8 carbon atom；In another embodiment, alkyl group contains 1-6 carbon atom；In yet another embodiment, alkyl group contains 1-4 carbon atom；Also in one embodiment, alkyl group contains 1-3 carbon atom.
The example of alkyl group comprises, but is not limited to, methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-pro-pyl (n-Pr ,-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), isobutyl group (i-Bu ,-CH2CH(CH3)2), sec-butyl (s-Bu ,-CH (CH3)CH2CH3), the tert-butyl group (t-Bu ,-C (CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-amyl group (-CH (CH3)CH2CH2CH3), 3-amyl group (-CH (CH2CH3)2), 2-methyl-2-butyl (-C (CH3)2CH2CH3), 3-methyl-2-butyl (-CH (CH3)CH(CH3)2), 3-methyl isophthalic acid-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butene base (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH (CH3)CH2CH2CH2CH3), 3-hexyl (-CH (CH2CH3)(CH2CH2CH3)), 2-methyl-2-amyl group (-C (CH3)2CH2CH2CH3), 3-methyl-2-amyl group (-CH (CH3)CH(CH3)CH2CH3), 4-methyl-2-amyl group (-CH (CH3)CH2CH(CH3)2), 3-methyl-3-amyl group (-C (CH3)(CH2CH3)2), 2-methyl-3-amyl group (-CH (CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C (CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH (CH3)C(CH3)3), n-heptyl, n-octyl, etc..
Two obtained saturated bivalent hydrocarbon radical groups of hydrogen atom are removed in term " alkylidene " expression from saturated straight or branched alkyl.Unless otherwise detailed instructions, alkylidene group contains 1-12 carbon atom, 1-6 carbon atom, 1-4 carbon atom, 1-3 carbon atom or 1-2 carbon atom.Such example includes methylene (-CH2-), ethylidene (-CH2CH2-), isopropylidene (-CH (CH3)CH2-) etc..
Term " alkoxyl " represents that alkyl group passes through oxygen atom and is connected with molecule remainder, and wherein alkyl group has implication as described in the present invention.Unless otherwise detailed instructions, described alkoxy base contains 1-12 carbon atom.In one embodiment, alkoxy base contains 1-6 carbon atom；In another embodiment, alkoxy base contains 1-4 carbon atom；In yet another embodiment, alkoxy base contains 1-3 carbon atom.The substituent group that described alkoxy base can optionally be described by one or more present invention is replaced.
The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH3), ethyoxyl (EtO ,-OCH2CH3), 1-propoxyl group (n-PrO, n-propoxyl group ,-OCH2CH2CH3), 2-propoxyl group (i-PrO, i-propoxyl group ,-OCH (CH3)2), 1-butoxy (n-BuO, n-butoxy ,-OCH2CH2CH2CH3), 2-methyl-l-propoxyl group (i-BuO, i-butoxy ,-OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy ,-OCH (CH3)CH2CH3), 2-methyl-2-propoxyl group (t-BuO, t-butoxy ,-OC (CH3)3), 1-amoxy (n-amoxy ,-OCH2CH2CH2CH2CH3), 2-amoxy (-OCH (CH3)CH2CH2CH3), 3-amoxy (-OCH (CH2CH3)2), 2-methyl-2-butoxy (-OC (CH3)2CH2CH3), 3-methyl-2-butoxy (-OCH (CH3)CH(CH3)2), 3-methyl-l-butoxy (-OCH2CH2CH(CH3)2), 2-methyl-l-butoxy (-OCH2CH(CH3)CH2CH3), etc..
Term " alkoxyalkyl " represents that alkyl group is replaced by one or more alkoxy bases, wherein alkyl group and alkoxy base have implication as described in the present invention, and such example includes, but is not limited to methoxy, methoxy ethyl, ethoxyethyl group etc..
Term " alkyloxy-alkoxy " represents that alkoxy base is replaced by one or more alkoxy bases, and wherein alkoxy base has implication as described in the present invention.
Term " haloalkyl " or " halogenated alkoxy " represent that alkyl or alkoxy base are replaced by one or more halogen atoms, and such example comprises, but is not limited to, trifluoromethyl, trifluoromethoxy ,-CH2Cl ,-CH2CF3,-CH2CH2CF3Deng.
Term " alkyl that cyano group replaces " represents that alkyl group is replaced by one or more cyano group, and wherein alkyl group has implication as described in the present invention, and such example comprises, but is not limited to ,-CH2CN ,-CH2CH2CN ,-CH2CH2CH2CN etc..
Term " alkoxyl that cyano group replaces " represents that alkoxy base is replaced by one or more cyano group, and wherein alkoxy base has implication as described in the present invention, and such example comprises, but is not limited to ,-OCH2CN ,-OCH2CH2CN ,-OCH2CH2CH2CN ,-OCH (CN) CH3Deng.
It is replaced that term " alkyl that hydroxyl replaces " represents that alkyl group is optionally substituted with one or more hydroxyl, and wherein alkyl group has implication as described in the present invention, and such example comprises, but is not limited to ,-CH2OH ,-CH2CH2OH ,-CH2CH2CH2OH etc..
It is replaced that term " alkoxyl that hydroxyl replaces " represents that alkoxy base is optionally substituted with one or more hydroxyl, and wherein alkoxy base has implication as described in the present invention, and such example comprises, but is not limited to ,-OCH2OH ,-OCH2CH2OH ,-OCH2CH2CH2OH ,-OCH (OH) CH3Deng.
Term " cycloalkyl " represents containing 3-12 carbon atom, the saturated monocycle of unit price or multivalence, dicyclo or three-ring system.In one embodiment, cycloalkyl comprises 3-12 carbon atom；In another embodiment, cycloalkyl comprises 3-8 carbon atom；In yet another embodiment, cycloalkyl comprises 3-6 carbon atom.Described group of naphthene base can be unsubstituted independently or replaced by one or more substituent groups described in the invention.Such example includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, ring octyl group, ring nonyl, ring decyl, ring undecyl, cyclo-dodecyl, etc..
Term " cycloalkenyl group " represents containing 3-12 carbon atom, the unsaturated monocycle of part of unit price or multivalence, dicyclo or three-ring system, the unsaturated site of at least one of which, namely has a carbon-to-carbon sp2Double bond.In one embodiment, cycloalkenyl group comprises 3-12 carbon atom；In another embodiment, cycloalkenyl group comprises 3-8 carbon atom；In yet another embodiment, cycloalkenyl group comprises 3-6 carbon atom.Described cycloalkenyl groups can be unsubstituted independently or replaced by one or more substituent groups described in the invention.Such example includes, but is not limited to, cyclopropanyl, cyclobutane base, cyclopentenyl, cyclopentadienyl group, cyclohexenyl group, cyclohexadienyl, etc..
Term " cycloalkyl-alkyl " represents that alkyl group is replaced by one or more groups of naphthene base, wherein alkyl group and group of naphthene base have implication as described in the present invention, such example includes, but is not limited to Cvclopropvlmethvl, cyclopropylethyl, cyclobutylmethyl, CYCLOBUTYLETHYL, cyclopentyl-methyl, cyclopentyl ethyl, cyclohexyl methyl, cyclohexyl-ethyl etc..
Term " cycloalkyl alkoxy " represents that alkoxy base is replaced by one or more groups of naphthene base, wherein alkoxy base and group of naphthene base have implication as described in the present invention, such example includes, but is not limited to cyclo propyl methoxy, cyclopropylethoxy, cyclobutyl methoxyl group, cyclobutyl ethyoxyl, cyclopentylmethoxy, cyclopenta ethyoxyl, cyclohexyl methoxy, cyclohexylethoxy radical etc..
Term " cycloalkenyl alkyl " represents that alkyl group is replaced by one or more cycloalkenyl groups, wherein alkyl group and cycloalkenyl groups have implication as described in the present invention, such example includes, but it is not limited to cyclopropenylmethyl, cyclobutane ylmethyl, cyclopentenylethyl, cyclopentadienylpropyl, cyclobutane base isopropyl etc..
Term " cycloalkenyl group alkoxyl " represents that alkoxy base is replaced by one or more cycloalkenyl groups, wherein alkoxy base and cycloalkenyl groups have implication as described in the present invention, such example includes, but it is not limited to cyclopropanyl methoxyl group, cyclobutane ylmethoxy, cyclopentenyl ethyoxyl, cyclopentadienyl group propoxyl group etc..
Term " heterocyclic radical " and " heterocycle " are used interchangeably herein, all referring to comprising the saturated of 3-12 annular atoms or the undersaturated monocycle of part, dicyclo or three rings, monocycle, dicyclo or three rings wherein do not comprise aromatic rings, and at least one annular atoms is selected from nitrogen, sulfur and oxygen atom.Unless otherwise indicated, heterocyclic radical can be carbon back or nitrilo, and-CH2-group can optionally by-C (O)-replacement.The sulphur atom of ring can optionally be oxidized to S-oxide.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.The example of heterocyclic radical includes, but it is not limited to: Oxyranyle, azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, 1, 3-dioxy cyclopenta, two sulfur cyclopenta, THP trtrahydropyranyl, dihydro pyranyl, 2H-pyranose, 4H-pyranose, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, (1-oxo)-thio-morpholinyl, (1, 1-dioxo)-thio-morpholinyl, piperazinyl, dialkyl group, dithiane base, thiophene alkyl, homopiperazine base, homopiperidinyl, oxepane alkyl, thia cycloheptane base, 2-oxa--5-azabicyclo [2.2.1]-5-in heptan base.-CH in heterocyclic radical2-group is included, but not limited to 2-oxo-pyrrolidine base, oxo-1,3-thiazoles alkyl, 2-piperidone base, 3,5-dioxopiperidine bases by the example of-C (O)-replacement.The example that in heterocyclic radical, sulphur atom is oxidized includes, but not limited to sulfolane base, 1,1-dioxothiomorpholinyl.Described heterocyclyl groups can be optionally replaced by one or more substituent groups described in the invention.
In one embodiment, heterocyclic radical is 4-7 former molecular heterocyclic radical, refers to and comprises the saturated of 4-7 annular atoms or the undersaturated monocycle of part, and at least one of which annular atoms is selected from nitrogen, sulfur and oxygen atom.The example of 4-7 former molecular heterocyclic radical includes, but it is not limited to: azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, 1, 3-dioxy cyclopenta, two sulfur cyclopenta, THP trtrahydropyranyl, dihydro pyranyl, 2H-pyranose, 4H-pyranose, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, dialkyl group, dithiane base, thiophene alkyl, homopiperazine base, homopiperidinyl, oxepane alkyl, thia cycloheptane base.-CH in heterocyclic radical2-group is included, but not limited to 2-oxo-pyrrolidine base, oxo-1,3-thiazoles alkyl, 2-piperidone base, 3,5-dioxopiperidine bases by the example of-C (O)-replacement.The example that in heterocyclic radical, sulphur atom is oxidized includes, but not limited to sulfolane base, 1,1-dioxothiomorpholinyl.Described 4-7 former molecular heterocyclyl groups can be optionally replaced by one or more substituent groups described in the invention.
In another embodiment, heterocyclic radical is 4 former molecular heterocyclic radicals, refers to and comprises the saturated of 4 annular atomses or the undersaturated monocycle of part, and at least one of which annular atoms is selected from nitrogen, sulfur and oxygen atom.The example of 4 former molecular heterocyclic radicals includes, but are not limited to: azelidinyl, oxetanylmethoxy, thietanyl.4 described former molecular heterocyclyl groups can be optionally replaced by one or more substituent groups described in the invention.
In another embodiment, heterocyclic radical is 5 former molecular heterocyclic radicals, refers to and comprises the saturated of 5 annular atomses or the undersaturated monocycle of part, and at least one of which annular atoms is selected from nitrogen, sulfur and oxygen atom.The example of 5 former molecular heterocyclic radicals includes, but are not limited to: pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, 1,3-dioxy cyclopenta, two sulfur cyclopenta.-CH in heterocyclic radical2-group is included, but not limited to 2-oxo-pyrrolidine base, oxo-1,3-thiazoles alkyl by the example of-C (O)-replacement.The example that in heterocyclic radical, sulphur atom is oxidized includes, but not limited to sulfolane base.5 described former molecular heterocyclyl groups can be optionally replaced by one or more substituent groups described in the invention.
In another embodiment, heterocyclic radical is 6 former molecular heterocyclic radicals, refers to and comprises the saturated of 6 annular atomses or the undersaturated monocycle of part, and at least one of which annular atoms is selected from nitrogen, sulfur and oxygen atom.The example of 6 former molecular heterocyclic radicals includes, but are not limited to: THP trtrahydropyranyl, dihydro pyranyl, 2H-pyranose, 4H-pyranose, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, dialkyl group, dithiane base, thiophene alkyl.-CH in heterocyclic radical2-group is included, but not limited to 2-piperidone base by the example of-C (O)-replacement, 3,5-dioxopiperidine bases.The example that in heterocyclic radical, sulphur atom is oxidized includes, but not limited to 1,1-dioxothiomorpholinyl.6 described former molecular heterocyclyl groups can be optionally replaced by one or more substituent groups described in the invention.
Also in one embodiment, heterocyclic radical is 7-12 former molecular heterocyclic radical, refers to and comprises the saturated of 7-12 annular atoms or the assorted dicyclo of the undersaturated spiral shell of part or condense assorted dicyclo, and at least one of which annular atoms is selected from nitrogen, sulfur and oxygen atom.The example of 7-12 former molecular heterocyclic radical includes, but are not limited to: 2-oxa--5-azabicyclo [2.2.1]-5-in heptan base.Described 7-12 former molecular heterocyclyl groups can be optionally replaced by one or more substituent groups described in the invention.
Also in one embodiment, heterocyclic radical refers to Heterocyclylalkyl.Term " Heterocyclylalkyl " refers to the unit price containing 3-12 annular atoms or the saturated monocycle of multivalence, dicyclo or three-ring system, and at least one of which annular atoms is selected from nitrogen, sulfur or oxygen atom.
Term " cycloheteroalkylalkyl " refers to the alkyl that heterocyclic radical replaces；Wherein heterocyclic radical and alkyl group have implication as described in the present invention.Such example includes, but is not limited to thiomorpholine-4-ylmethyl, oxolane-3-ylmethyl, oxetanes-3-ylmethyl, pyrrolidin-2-yl methyl, morpholine-4-ylmethyl etc..
Term " heterocyclylalkoxy " refers to the alkoxyl that heterocyclic radical replaces, and wherein oxygen atom is connected with the remainder of molecule；Wherein heterocyclic radical and alkoxy base have implication as described in the present invention.Such example includes, but is not limited to thiomorpholine-4-ylmethoxy, oxolane-3-ylmethoxy, oxetanes-3-ylmethoxy, pyrrolidin-2-yl methoxyl group, morpholine-4-ylmethoxy, morpholine-4-base oxethyl, morpholine-4-base propoxyl group etc..
Term " heterocyclyloxy base " includes optionally substituted heterocyclic radical, as defined herein, being connected on oxygen atom, and be connected with molecule remainder by oxygen atom, wherein heterocyclyl groups has implication as described in the present invention, such example includes, but it is not limited to morpholinyl oxygen base, piperidyl oxygen base, pyrrolidinyl oxygen base, tetrahydrofuran base oxygen base (oxolane-2-base oxygen base, oxolane-3-base oxygen base) etc..
Term " condensed-bicyclic ", " condensed ring ", " condensed-bicyclic base " and " condensed ring radical " are used interchangeably herein, and all referring to the undersaturated bridged-ring system of saturated or part of unit price or multivalence, described bridged-ring system refers to the bicyclic system of non-aromatic.Such system can comprise independent or conjugation unsaturated system, but its core texture does not comprise aromatic rings or heteroaromatic (but aromatic group can as substituent group thereon).
Term " volution base ", " volution ", " spiral shell bicyclic group " or " spiral shell dicyclo " is used interchangeably herein, refers to the unsaturated member ring systems of saturated or part of unit price or multivalence, and one of them ring originates from specific ring carbon atom on another ring.Such as, as under described by facial a, a saturated bridged-ring system (ring B and B ') is referred to as " condensed-bicyclic ", and ring A and ring B shares a carbon atom in two saturated member ring systems, is referred to as " volution " or " spiral shell dicyclo ".Each ring in condensed-bicyclic base and spiral shell bicyclic group can be carbocylic radical or heterocyclic radical, and each ring is optionally replaced by one or more substituent groups described in the invention.
Term " n former molecular ", wherein n is integer, typically describes the number of ring member nitrogen atoms in molecule, and in described molecule, the number of ring member nitrogen atoms is n.Such as, piperidyl is 6 former molecular Heterocyclylalkyls.
The term " undersaturated " used in the present invention represents in group containing one or more degrees of unsaturation.
Term " hetero atom " refers to O, S, N, P and Si, including the form of any oxidation state of N, S and P；The form of primary, secondary, tertiary amine and quaternary ammonium salt；Or the form that in heterocycle, the hydrogen on nitrogen-atoms is replaced, for instance, N (N as in 3,4-dihydro-2 h-pyrrole bases), NH (NH as in pyrrolidinyl) or NR (NR as in the N-pyrrolidinyl replaced).
Term " halogen " refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
Term " aryl " represents containing 6-14 annular atoms, or 6-12 annular atoms, or the carbocyclic ring system of the monocycle of 6-10 annular atoms, dicyclo and three rings, wherein, at least one ring is aromatic, each of which ring comprises 3-7 former molecular ring, and has one or more attachment point to be connected with the remainder of molecule.Term " aryl " can use with term " aromatic rings " exchange.The example of aromatic yl group can include phenyl, indenyl, naphthyl and anthryl.Described aromatic yl group can be individually optionally replaced by one or more substituent groups described in the invention.
Term " aryl alkyl " or " aralkyl " represent that alkyl is replaced by one or more aromatic yl groups, and wherein alkyl and aromatic yl group have implication as described in the present invention, and such example includes, but are not limited to benzyl, and phenethyl, to methylphenylethyl etc..
Term " alkoxy aryl " represents that alkoxyl is replaced by one or more aromatic yl groups, and wherein alkoxyl and aromatic yl group have implication as described in the present invention, and such example includes, but are not limited to Phenylmethoxy, phenyl ethoxy etc..
Term " aryloxy group " includes optionally substituted aryl, as defined herein, it is connected on oxygen atom, and it is connected with molecule remainder by oxygen atom, wherein aromatic yl group has implication as described in the present invention, and such example includes, but is not limited to phenoxy group, to toloxyl, to second phenoxy group etc..
Term " heteroaryl " represents containing 5-12 annular atoms, or 5-10 annular atoms, or the monocycle of 5-6 annular atoms, dicyclo and three-ring system, at least one of which ring is aromatic, and at least one ring comprises one or more hetero atom, each of which ring comprises 5-7 former molecular ring, and has one or more attachment point to be connected with molecule remainder.Term " heteroaryl " can exchange with term " hetero-aromatic ring " or " heteroaromatics " and use.Described heteroaryl groups is optionally replaced by one or more substituent groups described in the invention.In one embodiment, 5-10 former molecular heteroaryl comprises 1,2,3 or 4 hetero atom being independently selected from O, S and N.
nullThe example of heteroaryl groups includes，But it is not limited to，2-furyl，3-furyl，TMSIM N imidazole base，2-imidazole radicals，4-imidazole radicals，5-imidazole radicals，3-isoxazole base，4-isoxazole base，5-isoxazole base，2-azoles base，4-azoles base，5-azoles base，N-pyrrole radicals，2-pyrrole radicals，3-pyrrole radicals，2-pyridine radicals，3-pyridine radicals，4-pyridine radicals，2-pyrimidine radicals，4-pyrimidine radicals，5-pyrimidine radicals，Pyridazinyl (such as 3-pyridazinyl)，2-thiazolyl，4-thiazolyl，5-thiazolyl，Tetrazole radical (such as 5-tetrazole radical)，Triazolyl (such as 2-triazolyl and 5-triazolyl)，2-thienyl，3-thienyl，Pyrazolyl (such as 2-pyrazolyl)，Isothiazolyl，1,2,3-di azoly，1,2,5-di azoly，1,2,4-di azoly，1,2,3-triazolyl，1,2,3-thio biphosphole base，1,3,4-thio biphosphole base，1,2,5-thio biphosphole base，Pyrazinyl，1,3,5-triazine radical；Also following dicyclo is included, but it is not limited to these dicyclos: benzimidazolyl, benzofuranyl, benzothienyl, indyl (such as 2-indyl), purine radicals, quinolyl is (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl is (such as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl), imidazo [1, 2-a] pyridine radicals, pyrazolo [1, 5-a] pyridine radicals, pyrazolo [1, 5-a] pyrimidine radicals, imidazo [1, 2-b] pyridazinyl, [1, 2, 4] triazol [4, 3-b] pyridazinyl, [1, 2, 4] triazol [1, 5-a] pyrimidine radicals, [1, 2, 4] triazol [1, 5-a] pyridine radicals, etc..
Term " heteroaryl alkyl " represents that alkyl group is replaced by one or more heteroaryl groups, and wherein alkyl group and heteroaryl groups have implication as described in the present invention.Term " heteroarylalkoxy " represents that alkoxy base is replaced by one or more heteroaryl groups, and wherein alkoxy base and heteroaryl groups have implication as described in the present invention.
No matter term " carboxyl ", be single use or be used in conjunction with other terms, such as " carboxyalkyl ", expression-CO2H。
Term " alkyl amino " or " alkylamino " include " N-alkyl amino " and " N, N-dialkyl amido ", and wherein amino group is separately replaced by one or two alkyl group.Some of them embodiment is, alkyl amino is one or two C1-6The alkylamino group of the lower level that alkyl is connected on nitrogen-atoms.Other embodiment is, alkyl amino is C1-3The alkylamino group of lower level.Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example includes, but is not limited to, N-methylamino, N-ethylamino, N, N-dimethylamino, N, N-lignocaine etc..
Term " alkylamino that cyano group replaces " represents that alkylamino radicals is replaced by one or more cyano group, and such example comprises, but is not limited to ,-NHCH2CN ,-N (CH3)CH2CN ,-NHCH2CH2CN ,-NHCH2CH2CH2CN ,-N (CH3)CH(CN)CH3Deng.
Term " cycloalkyl amino " refers to that amino group is replaced by one or two group of naphthene base.
Term " alkyl amino alkyl " represents that alkyl group is replaced by one or more alkylamino radicals, wherein alkyl group and alkylamino radicals have implication as described in the present invention, such example includes, but it is not limited to N-Methyaminomethyl, N-Ethylaminomethyl, N, N-dimethylaminoethyl, N, N-diethyllaminoethyl etc..
Term " virtue amino " or " arylamino " represent that amino group is replaced by one or two aromatic yl group, and such example includes, but is not limited to N-phenylamino.Some of them embodiment is, the aromatic ring on virtue amino can be replaced further.
Term " heteroaryl amino " represents that amino group is replaced by one or two heteroaryl groups, hetero-aromatic ring on heteroaryl amino can be described by the present invention further substituent group replaced, such example includes, but it is not limited to pyrazolyl amino, N-methylpyrazole base amino, imidazole radicals amino, pyridinylamino or pyrimidinyl-amino.
Term " aminoalkyl " includes by the replaced C of one or more amino1-10Straight or branched alkyl group.Some of them embodiment is, aminoalkyl is by the replaced C of one or more amino groups1-6" aminoalkyl of lower level ", such example includes, but is not limited to, aminomethyl, aminoethyl, aminopropyl, ammonia butyl and ammonia hexyl.
The hydrogen that term " alkylaminoalkyl group " refers in aminoalkyl on amino is replaced by one or two alkyl.Such example includes, but is not limited to, Methylaminomethyl, dimethylaminomethyl, methylaminoethyl, dimethyl aminoethyl, ethylaminomethyl, diethylamino methyl, ethylaminoethyl, propylcarbamic methyl, butylamino methyl.
Time term " blocking group " or " PG " refer to a substituent group and other reacted with functional groups, it is commonly used to block or protect special functional.Such as; " blocking group of amino " refers to that a substituent group is connected with amino group and blocks or protect the functional of amino in compound; suitable amido protecting group includes acetyl group; trifluoroacetyl group; tertbutyloxycarbonyl (BOC; Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9-fluorenes Asia methoxycarbonyl group (Fmoc).Similarly, " hydroxy-protective group " refers to that the substituent group of hydroxyl is for blocking or protect the functional of hydroxyl, and suitable blocking group includes acetyl group and silicyl." carboxy protective group " refers to that the substituent group of carboxyl is for blocking or protect the functional of carboxyl, and general carboxyl-protecting group includes-CH2CH2SO2Ph; cyano ethyl; 2-(TMS) ethyl; 2-(TMS) ethoxyl methyl; 2-(p-toluenesulfonyl) ethyl, 2-(p-nitrophenyl sulfonyl) ethyl, 2-(diphenylphosphino) ethyl; nitro-ethyl, etc..The description general for blocking group is referred to document: TW.Greene, ProtectiveGroupsinOrganicSynthesis, john wiley & sons, NewYork, and 1991；andP.J.Kocienski,ProtectingGroups,Thieme,Stuttgart,2005.
Term used in the present invention " prodrug ", represents a compound and is converted into the compound shown in formula (I), (II) or (III) in vivo.Such conversion by prodrug be hydrolyzed in blood or blood or tissue in through enzymatic conversion be the impact of precursor structure.Prodrug compounds of the present invention can be ester, and in existing invention, ester can have phenyl ester class, aliphatic (C as prodrug1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as, a compound in the present invention comprises hydroxyl, and namely its acidylate can obtain the compound of prodrug form.Other prodrug form includes phosphate ester, if these phosphate compounds are that the di on parent obtains.nullThe discussion complete about prodrug is referred to documents below: T.HiguchiandV.Stella,Pro-drugsasNovelDeliverySystems,Vol.14oftheA.C.S.SymposiumSeries,EdwardB.Roche,ed.,BioreversibleCarriersinDrugDesign,AmericanPharmaceuticalAssociationandPergamonPress,1987,J.Rautioetal.,Prodrugs:DesignandClinicalApplications,NatureReviewDrugDiscovery,2008,7,255-270,andS.J.Heckeretal.,ProdrugsofPhosphatesandPhosphonates,JournalofMedicinalChemistry,2008,51,2328-2345.
" metabolite " refers to that concrete compound or its salt passes through the product that metabolism is obtained in vivo.The metabolite of one compound can be identified by the known technology of art, and its activity can pass through adopting like that and experimentally characterize as described in the present invention.Such product can be through to drug compound through oxidation, reduction, hydrolysis, amidated, desamido-effect, and esterification, degreasing, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes the metabolite of compound, is fully contacted metabolite produced by a period of time including by the compound of the present invention and mammal.
" pharmaceutically acceptable salt " used in the present invention refers to organic salt and the inorganic salt of the compound of the present invention.Pharmaceutically acceptable salt is known for us at art, such as document: S.M.Bergeetal., described in describepharmaceuticallyacceptablesaltsindetailinJ.Pharm aceuticalSciences, 1977,66:1-19..The salt obtained by suitable alkali includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.The present invention is also intended to contemplate the quaternary ammonium salt that the compound of the group of any comprised N is formed.Water solublity or oil-soluble or dispersion product can be obtained by quaternization.Alkali metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt farther includes the amine cation that suitable, nontoxic ammonium, quaternary ammonium salt and gegenions are formed, such as halogenide, hydroxide, carboxylate, hydrosulphate, phosphoric acid compound, nitric acid compound, C1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention refers to the associated complex that the compound of one or more solvent molecule and the present invention is formed.The solvent forming solvate includes, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid and ethylaminoethanol.Term " hydrate " refers to that solvent molecule is the associated complex that water is formed.
Term as used in the present invention " treatment " any disease or disease, some embodiment middle fingers improve disease or disease (namely slow down or stop or palliate a disease or the development of its at least one clinical symptoms) wherein.In other embodiments, " treatment " refers to relax or improve at least one body parameter, including being likely to the body parameter do not discovered for patient.In other embodiments, " treatment " refer to (such as to stablize perceptible symptom) from health or physiology upper (such as stablizing the parameter of health) or above-mentioned two aspects adjustment disease or diseases.In other embodiments, " treatment " refer to prevention or postpone disease or the outbreak of disease, generation or deterioration.
" inflammatory diseases " used in the present invention refers to any disease that the infringement of the excessive inflammatory symptoms owing to inflammatory responses excessive or out of control causes, host tissue or function of organization lose, disorderly or symptom." inflammatory diseases " also refers to be subject to the pathologic state that leukocyte flows into and/or Neutrophil chemotaxis mediates.
" inflammation " used in the present invention refers to the topical protective response caused by tissue damaged or destruction, and it is used for destroying, dilute or separate (isolation) harmful material and impaired tissue.Inflammation and leukocyte flow into and/or Neutrophil chemotaxis has and contacts significantly.Inflammation can result from the infection of pathogenic organism and virus and non-infectious mode, such as the wound after myocardial infarction or apoplexy or Reperfu-sion, immunne response and the autoimmune response to exotic antigen.Therefore, it can include by the inflammatory diseases of disclosure compounds for treating: react to specificity system of defense and non-specific defense system reacts relevant disease.
" autoimmune disease " used in the present invention or " autoimmune disease " refer to and the set of body fluid or any disease of the cell-mediated tissue injury that health self component response is relevant.The example of autoimmune disease includes lupus, multiple sclerosis, muscle contracting lateral sclerosis, rheumatoid arthritis, psoriasis, type i diabetes, because of the complication that organ transplantation causes, foreign body is transplanted, diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn disease, Alzheimer, leukemia and lymphoma.
" arthritis disease " refers to be attributable to any disease that the damage of various etiologic etiological arthritis is feature as used in the present invention." dermatitis " refers to any one in the extended familys to be attributable to the dermatosis that various etiologic etiological scytitis is feature as used in the present invention.Tissue is transplanted in the antagonism that " transplant rejection " refers to transplant or the afunction of surrounding tissue, pain, swelling, leukocytosis and thrombocytopenia are feature as used in the present invention, such as any immunoreation of organ or cell (such as bone marrow).The Therapeutic Method of the present invention includes the method for treating the disease relevant to inflammatory cell activation.
The physiological conditions that term " cancer " and " cancer " refer to or describe is generally feature with Growth of Cells out of control in patient." tumor " comprises one or more cancerous cell.The example of cancer includes but not limited to cancer (carcinoma), lymphoma, blastoma, sarcoma and leukemia or malignant lymph proliferative disease (lymphoidmalignancies).nullThe example more specifically of this type of cancer includes squamous cell carcinoma (such as epithelium squamous cell carcinoma)、Pulmonary carcinoma (includes small cell lung cancer、Nonsmall-cell lung cancer (NSCLC)、Adenocarcinoma of lung and lung squamous cell carcinoma)、Peritoneal cancer、Hepatocarcinoma (hepatocellularcancer)、Gastric cancer (gastricorstomachcancer) (including human primary gastrointestinal cancers)、Cancer of pancreas、Glioblastoma、Cervical cancer、Ovarian cancer、Hepatocarcinoma (livercancer)、Bladder cancer、Hepatoma (hepatoma)、Breast carcinoma、Colon cancer、Rectal cancer、Colorectal cancer、Carcinoma of endometrium or uterus carcinoma、Salivary-gland carcinoma、Renal carcinoma or renal cancer (kidneyorrenalcancer)、Carcinoma of prostate、Carcinoma vulvae、Thyroid carcinoma、Liver cancer (hepaticcarcinoma)、Anus cancer、Carcinoma of penis and head and neck cancer.
Term used in the present invention " biological sample " refers to the specimen of vitro, include, but not limited to, and cell is cultivated or cell extraction；From the biopsy material that mammal or its extract obtain；Blood, saliva, urine, feces, seminal fluid, tear, or other living tissue liquid substance and extracts thereof.Suppress or regulate kinase activity, particularly BLK, JAK1, JAK2, JAK3, BTK, BMX, TEC, ITK, TXK, HER2, HER4, EGFR or EGFRT790M kinase activity in biological sample, can be used for the known multiple use of one of ordinary skill in the art.Such purposes includes, but is not limited to, hematometachysis, organ transplantation, and biological sample is stored and bioassay.
The pharmaceutical composition of the compounds of this invention
The present invention provides a kind of pharmaceutical composition, and it comprises disclosure compound and pharmaceutically acceptable excipient, carrier, adjuvant, solvent or their combination.In pharmaceutical composition disclosed by the invention, the amount of compound refers to effectively to detect the amount suppressing biological specimen or protein kinase in the patient.
It will also be appreciated that some compound of the present invention can exist in a free form for treating, if or suitably can exist with the form of its pharmaceutically acceptable derivates.Some non-limiting embodiments of pharmaceutically acceptable derivant include pharmaceutically acceptable prodrug, salt, ester, the salt of these esters, or any other adduct or the derivant of compound of the present invention or its metabolite or residue can be directly or indirectly provided when patient in need is administered.
Drug pharmaceutical compositions disclosed by the invention can prepare and be packaged as (bulk) in bulk form, wherein can extract the compound shown in formula (I), (II) or (III) of safe and effective amount, then give patient with powder or syrup form.Or, pharmaceutical composition disclosed by the invention can be prepared and be packaged as unit dosage forms, and wherein each physically discrete unit contains the compound shown in formula (I), (II) or (III) of safe and effective amount.When preparing with unit dosage forms, pharmaceutical composition disclosed by the invention generally can be containing, for instance, the compound disclosed by the invention of 0.5mg to 1g or 1mg to 700mg or 5mg to 100mg.Described dosage form includes those dosage forms being suitable for following route of administration: (1) oral administration, for instance tablet, capsule, caplet agent, pill, containing tablet, powder, granule, syrup, elixir, suspensoid, solution, Emulsion, sachet agent and cachet；(2) parenteral, for instance sterile solution agent, suspensoid, Emulsion, micelle, liposome, microsphere, nanometer system and redissolution powder；(3) transdermal administration, for instance percutaneous plaster agent；(4) rectally, for instance suppository；(5) suck, for instance aerosol, solution and dry powder doses；(6) topical, for instance ointment, ointment, lotion, solution, paste, spray, foam and gel.
The present invention " pharmaceutically acceptable excipient " used means the pharmaceutically acceptable material relevant to form of administration or pharmaceutical composition concordance, mixture or solvent.Every kind of excipient must be compatible with other composition of pharmaceutical composition when mixing, can be substantially reduced the interaction of effect of disclosure compound and can cause it not being the interaction of pharmaceutically acceptable pharmaceutical composition during to avoid patient is administered.Additionally, every kind of excipient must be pharmaceutically acceptable, for instance, there is sufficiently high purity.
Suitable pharmaceutically acceptable excipient can be different according to selected concrete dosage form.Additionally, pharmaceutically acceptable excipient can be selected according to they specific functions in the composition.Suitable pharmaceutically acceptable excipient includes following kind of excipient: diluent, filler, binding agent, disintegrating agent, lubricant, fluidizer, granulating agent, coating materials, wetting agent, solvent, cosolvent, suspending agent, emulsifying agent, sweeting agent, correctives, odor mask, coloring agent, anticaking agent, wetting agent, chelating agen, plasticiser, viscosifier, antioxidant, preservative, stabilizer, surfactant and buffer agent.Technical staff it can be appreciated that, some pharmaceutically acceptable excipient can provide more than one function, and provides alternative function, and this depends on having in how many these excipient and preparation there are which other excipient in preparation.
Technical staff grasps the knowledge and skills of this area, so that they can select that the suitable pharmaceutically acceptable excipient of the appropriate amount for the present invention.Additionally, there are the obtainable resource of a large amount of technical staff, they describe pharmaceutically acceptable excipient, and for selecting suitable pharmaceutically acceptable excipient.
nullAt Remington:TheScienceandPracticeofPharmacy,21stedition,2005,ed.D.B.Troy,LippincottWilliams&Wilkins,Philadelphia,andEncyclopediaofPharmaceuticalTechnology,eds.J.SwarbrickandJ.C.Boylan,1988-1999,MarcelDekker,NewYork discloses the various carriers for configuring pharmaceutically acceptable compositions，With the known technology prepared for it，The respective content of these documents is incorporated by reference into the present invention.Except any such as because producing any less desirable biological agent, or outside any commonly employed carrier inconsistent with disclosure compound so that harmful way and other composition any in pharmaceutically acceptable compositions occur to interact, pay close attention to its application and belong to the scope of the present invention.
Pharmaceutical composition disclosed by the invention uses technology well known by persons skilled in the art and method to prepare.The description of some common methods of this area can referring to Remington'sPharmaceuticalSciences (MackPublishingCompany).
The purposes of the compounds of this invention and compositions
The present invention provides use compound disclosed in this invention and medicine composite for curing, prevention, or improves and included JAK1, JAK2, JAK3 or TYK2 kinases behavior mediation or the disease otherwise affected or disorderly or included the method for one or more symptoms of JAK1, JAK2, JAK3 or TYK2 kinases behavior mediation or the disease otherwise affected or disorder by jak kinase by jak kinase.
Jak kinase can be the kinase whose wild type of JAK1, JAK2, JAK3 or TYK2 and/or sudden change.
In one embodiment, the present invention provides a class compound disclosed in this invention or the pharmaceutical composition comprising presently disclosed compound, for treating, prevent or improve by unsuitable JAK1 kinases behavior mediation or the disease otherwise affected or one or more symptoms disorderly or by unsuitable JAK1 kinases behavior mediation or the disease otherwise affected or disorder.
In another embodiment, one or more symptoms of described disease, disorder or disease or disorder are relevant to unsuitable JAK2 kinases behavior or relevant with unsuitable JAK3 kinases behavior.
" unsuitable jak kinase behavior " refers to that generation is in the jak kinase behavior deviateing normal jak kinase behavior with particular patient.Unsuitable jak kinase behavior can show as the form of the deviation in such as active abnormal growth or jak kinase time of the act point and control.This unsuitable kinases behavior comes from, for instance, overexpression or the sudden change of protein kinase and the inappropriate or uncontrolled behavior that causes.Therefore, the present invention provides and treats these diseases and disorderly method.
Consistent with above description, such disease or disorder include but not limited to: myeloproliferative diseases, for instance polycythemia vera (PCV), essential thrombocythemia, idiopathic myelofibrosis (IMF)；Leukemia, for instance marrow series leukemia includes chronic myelogenous leukemia (CML), the CML form of resistance to imatinib, acute myeloid leukemia (AML) and the hypotype of AML, acute megakaryoblastic leukemia (AMKL)；Lymphoproliferative disease, for instance myeloma；Cancer includes incidence cancer, carcinoma of prostate breast carcinoma, ovarian cancer, melanoma, pulmonary carcinoma, the cerebral tumor, cancer of pancreas and renal carcinoma；And with immunologic function disorder, immunodeficiency, diseases associated with inflammation that immunomodulating is relevant or disorder, autoimmune disease, tissue transplantation rejection, graft versus host disease, wound healing, nephropathy, multiple sclerosis, thyroiditis, type i diabetes, sarcoidosis, psoriasis, allergic rhinitis, inflammatory bowel includes Crohn disease and ulcerative colitis (UC), systemic lupus erythematosus (sle) (SLE), arthritis, osteoarthritis, rheumatoid arthritis, osteoporosis, asthma and chronic obstructive pulmonary disease (COPD) and dry eye syndrome (or keratoconjunctivitis sicca (KCS)).
On the one hand, the present invention provides a class compound disclosed in this invention or the pharmaceutical composition comprising presently disclosed compound, is used for preventing and/or treat the proliferative disease of mammal (including the mankind), autoimmune disease, anaphylactic disease, inflammatory diseases or transplant rejection.
On the other hand, the present invention provides a kind for the treatment of to suffer from or the risky mammiferous method suffering from presently disclosed disease, and described method includes giving effectively treatment disease amount or effective one or more pharmaceutical composition disclosed by the invention or compounds preventing disease amount.On the other hand, the present invention provides a kind for the treatment of to suffer from or the risky mammiferous method suffering from proliferative disease, autoimmune disease, anaphylactic disease, inflammatory diseases or transplant rejection.
In a kind of method in treatment, the present invention provides treatment and/or prevention to be susceptible or suffering from the mammiferous method of proliferative disease, and described method includes one or more pharmaceutical composition disclosed by the invention or compounds of giving effective therapeutic dose or effective preventive dose.In particular instances, proliferative disease is selected from cancer (such as, solid tumor such as leiomyosarcoma of uterus or carcinoma of prostate), polycythemia vera, primary thrombocytosis, myelofibrosis, leukemia (such as, AML, CML, ALL or CLL) and multiple myeloma.
On the other hand, the present invention provides a class compound disclosed by the invention, is used for treating and/or preventing proliferative disease.In certain embodiments, proliferative disease is selected from cancer (such as, solid tumor such as leiomyosarcoma of uterus or carcinoma of prostate), polycythemia vera, primary thrombocytosis, myelofibrosis, leukemia (such as, AML, CML, ALL or CLL) and multiple myeloma.
On the other hand, the present invention provides a class compound disclosed by the invention, or comprises the pharmaceutical composition of disclosure compound, for preparing treatment or the medicine of prevention proliferative disease.In particular instances, proliferative disease is selected from cancer (such as, solid tumor such as leiomyosarcoma of uterus or carcinoma of prostate), polycythemia vera, primary thrombocytosis, myelofibrosis, leukemia (such as, AML, CML, ALL or CLL) and multiple myeloma.
On the other hand, the present invention provides treatment and/or prevention to be susceptible or suffering from the mammiferous method of autoimmune disease, and described method includes one or more pharmaceutical composition disclosed by the invention or compounds of giving effective therapeutic dose or effective preventive dose.In particular instances, autoimmune disease is selected from COPD, asthma, systemic lupus erythematosus (sle), skin lupus erythematosus, lupus nephritis, dermatomyositis, sjogren syndrome, psoriasis, type i diabetes and inflammatory bowel.
On the other hand, the present invention provides a class compound disclosed by the invention, is used for treating and/or preventing autoimmune disease.In certain embodiments, autoimmune disease is selected from COPD, asthma, systemic lupus erythematosus (sle), skin lupus erythematosus, lupus nephritis, dermatomyositis, sjogren syndrome, psoriasis, type i diabetes and inflammatory bowel.
On the other hand, the present invention provides a class compound disclosed by the invention, or comprises the pharmaceutical composition of disclosure compound, for preparing treatment or the medicine of prevention autoimmune disease.In certain embodiments, autoimmune disease is selected from COPD, asthma, systemic lupus erythematosus (sle), skin lupus erythematosus, lupus nephritis, dermatomyositis, sjogren syndrome, psoriasis, type i diabetes and inflammatory bowel.
On the other hand, the present invention provides treatment and/or prevention to be susceptible or suffering from the mammiferous method of anaphylactic disease, and described method includes one or more pharmaceutical composition disclosed by the invention or compounds of giving effective therapeutic dose or effective preventive dose.In certain embodiments, anaphylactic disease is selected from respiratory anaphylactic disease, sinusitis, eczema and measles, food anaphylaxis and insect venom allergies.
On the other hand, the present invention provides a class compound disclosed by the invention, for treatment and/or Polyglucan disease.In certain embodiments, anaphylactic disease is selected from respiratory anaphylactic disease, sinusitis, eczema and measles, food anaphylaxis and insect venom allergies.
On the other hand, the present invention provides a class compound disclosed by the invention, or comprises the pharmaceutical composition of disclosure compound, for preparing the medicine for the treatment of or Polyglucan disease.In certain embodiments, anaphylactic disease is selected from respiratory anaphylactic disease, sinusitis, eczema and measles, food anaphylaxis and insect venom allergies.
On the other hand, the present invention provides treatment and/or prevention to be susceptible or suffering from the mammiferous method of inflammatory diseases, and described method includes one or more pharmaceutical composition disclosed by the invention or compounds of giving effective therapeutic dose or effective preventive dose.In certain embodiments, inflammatory diseases is selected from inflammatory bowel, Crohn disease, rheumatoid arthritis, juvenile arthritis and psoriasis arthropathica.
On the other hand, the present invention provides a class compound disclosed by the invention, is used for treating and/or preventing inflammatory diseases.In certain embodiments, inflammatory diseases is selected from inflammatory bowel, Crohn disease, rheumatoid arthritis, juvenile arthritis and psoriasis arthropathica.
On the other hand, the present invention provides a class compound disclosed by the invention, or comprises the pharmaceutical composition of disclosure compound, for preparing treatment or the medicine of prevention inflammatory diseases.In certain embodiments, inflammatory diseases is selected from inflammatory bowel, Crohn disease, rheumatoid arthritis, juvenile arthritis and psoriasis arthropathica.
On the other hand, the present invention provides treatment and/or prevention to be susceptible or suffering from the mammiferous method of transplant rejection, and described method includes one or more pharmaceutical composition disclosed by the invention or compounds of giving effective therapeutic dose or effective preventive dose.In particular instances, transplant rejection is organ-graft refection, tissue transplantation rejection and cell transplant rejection.
On the other hand, the present invention provides a class compound disclosed by the invention, is used for treating and/or preventing transplant rejection.In certain embodiments, transplant rejection is organ-graft refection, tissue transplantation rejection and cell transplant rejection.
On the other hand, the present invention provides a class compound disclosed by the invention, or comprises the pharmaceutical composition of disclosure compound, for preparing treatment or the medicine of prevention transplant rejection.In particular instances, transplant rejection is organ-graft refection, tissue transplantation rejection and cell transplant rejection.
On the other hand, the present invention provides a class to be used as medicine and is especially used as treating and/or preventing the compound disclosed by the invention of disease medicament noted earlier.It is also provided with disclosure compound manufacture treatment and/or prevents the medicine of disease noted earlier.
One special projects of this method includes the disclosure compound a period of time suffering from the study subject effective dose of inflammation, and the described time is enough to reduce the level of inflammation of study subject, and preferably terminates the process of described inflammation.The special embodiment of the method includes the disclosure compound a period of time suffering from or being susceptible to suffer from tested patients's effective dose of bone rheumatoid arthritis, the described time is enough to reduce respectively or prevent the arthritis of described patient, and preferably terminates the process of described inflammation.
Another special projects of this method includes the disclosure compound a period of time suffering from the study subject effective dose of proliferative disease, and the described time is enough to reduce the hyperplasia level of study subject, and preferably terminates the process of described proliferative disease.The special embodiment of the method includes the disclosure compound a period of time suffering from tested patients's effective dose of cancer, and the described time is enough to reduce respectively or prevent the cancer symptom of described patient, and preferably terminates the process of described cancer.
Therapeutic alliance
The compounds of this invention as independent active agent administration, or can be administered with other therapeutic agent, including having same or similar therapeutic activity and being defined as other compound safe and efficient for this type of administering drug combinations.
On the one hand, the method that the present invention provides treatment, prevents or improve disease or disease, including the combination medicine comprising disclosure compound and one or more therapeutically active agents giving safe and effective amount.In one embodiment, combination medicine comprises one or both other treatment agent.Such as, disclosure compound and β are comprised2The associating of-adrenoceptor agonists, corticosteroid, nonsteroidal GR agonist, nonsteroidal anti-inflammatory drug (NSAID's), phosphodiesterase 4 (PDE4) inhibitor, anticholinergic, H1 antagonist, antihistaminic or its combination.
The example of other therapeutic agent includes including but not limited to: anticarcinogen, including chemotherapeutics and antiproliferative；Antiinflammatory；With immunity regulatin remedy agent or immunosuppressant.
On the other hand, the present invention provides and includes the compounds of this invention and the product of other therapeutic agent at least one, the combination can prepare in the treatment simultaneously, separately or sequentially used.In one embodiment, treatment is the treatment for the disease mediated by jak kinase activity or symptom.The product that combining preparation provides includes being present in the compositions comprising disclosure compound and other treatment agent in same pharmaceutical composition, or the disclosure compound existed in different forms and other treatment agent, for instance, medicine box.
On the other hand, the present invention provides a kind of pharmaceutical composition comprising disclosure compound and another or multiple therapeutic agent.In one embodiment, pharmaceutical composition can comprise pharmaceutically acceptable excipient as above, carrier, adjuvant or solvent.
On the other hand, the present invention provides the medicine box comprising two kinds or above drug alone compositions, and at least one of which pharmaceutical composition comprises disclosure compound.In one embodiment, medicine box includes the instrument that individually keeps described compositions, for instance container, bottle separately or paper tinsel box separately.The example of this kind of medicine box is blister package, is commonly used for package troche, capsule etc..
Present invention also offers the compounds of this invention purposes in the disease or symptom for the treatment of jak kinase activity mediation, wherein patient's previously (such as in 24 hours) has treated with other treatment agent.Present invention also offers other treatment agent purposes in the disease and symptom for the treatment of jak kinase activity mediation, wherein patient's previously (such as in 24 hours) has treated with the compounds of this invention.
Disclosure compound can also be advantageously utilised in the combination with other compounds, or with other treatment agent, especially in the combination of antiproliferative.Such antiproliferative includes, but not limited to aromatase inhibitor；Estrogen antagonist；Topoisomerase I inhibitor；Topoisomerase II inhibitors；Microtubule active agent；Alkylating agent；Antibiotic FR 901228；The compound of Cell differentiation inducing activity process；Cyclooxygenase-2 inhibitors；MMP inhibitor；MTOR inhibitors；Antitumor antimetabolite；Platinum compounds；The compound of targeting/reduction albumen or lipid kinase activity and the compound of other angiogenesis inhibitor；The compound of targeting, reduction or suppression albumen or lipid phosphate esterase active；Gonadorelin excitomotor；Androgen antagonist；Methionine aminopeptidase inhibitor；Diphosphonate；Biological response modifier；Antiproliferation antibodies；Heparanase inhibitors；The carcinogenic hypotype inhibitor of Ras；Telomerase inhibitor；Proteasome inhibitor；The medicament for the treatment of neoplastic hematologic disorder；The compound of targeting, reduction or suppression Flt-3 activity；Hsp90 inhibitor；TemozolomideAnd calcium folinate.
" associating " represents the fixing joint in single dosage unit form or the medicine box of the part for administering drug combinations, wherein compound disclosed by the invention and associating companion in same time individual application or can use respectively in certain time interval, can particularly make associating companion show cooperation, such as synergism.Term " co-administered " or " administering drug combinations " etc. are intended to include selected associating companion are applied to the single individuality (such as patient) needing it, and are intended to include wherein material without going through identical route of administration or the therapeutic scheme that is administered simultaneously.Term " medication combined " represents the mixing of more than one active component or combines obtained product, and the fixing joint both having included active component also includes on-fixed associating.Term " fixing joint " represents active component such as compound disclosed by the invention, and associating companion is applied to patient with the form of single entities or dosage simultaneously.Term " on-fixed associating " represents active component such as compound disclosed by the invention, with associating companion all as corpus separatum simultaneously, common or successively patient is administered without special time restriction ground, wherein this administering mode is providing the therapeutically effective level of two kinds of compounds in the patient.The latter applies also for HAART, for instance use three kinds or more kind active component.
General building-up process
Usually, the compound of the present invention can be prepared by method described in the invention, unless there are further instruction, wherein shown in the definition of substituent group such as formula (I), (II) or (III).Following reaction scheme and embodiment are used for being further illustrated by present disclosure.
Those skilled in the art will realize that: chemical reaction described in the invention can be used to prepare suitably other compounds of many present invention, and other method of the compound for preparing the present invention is considered as within the scope of the present invention.Such as; the synthesis of the compound according to those non-illustrations of the present invention can successfully be completed by method of modifying by those skilled in the art; such as suitable protection interference group, by utilizing reagent that other are known except described in the invention, or reaction condition is made the amendment of some routines.It addition, reaction disclosed in this invention or known reaction condition are also applicable to the preparation of other compounds of the present invention admittedly.
The embodiments described below, unless other aspects show all of temperature and are decided to be degree Celsius.Reagent is bought in goods providers such as AldrichChemicalCompany, ArcoChemicalCompanyandAlfaChemicalCompany, all without through being further purified during use, unless other aspects show.General reagent is from Xi Long chemical plant, Shantou, and Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Qingdao Teng Long chemical reagent company limited and Haiyang Chemical Plant, Qingdao are commercially available.
Anhydrous tetrahydro furan, dioxane, toluene, ether is to dry through metallic sodium backflow to obtain.Anhydrous methylene chloride and chloroform are to dry through calcium hydride backflow to obtain.Ethyl acetate, petroleum ether, normal hexane, N,N-dimethylacetamide and DMF are through anhydrous sodium sulfate dry use in advance.
Hereinafter reaction is usually under nitrogen or argon gas positive pressure or on anhydrous solvent and overlaps a drying tube (unless showing in other), and the rubber closure that reaction bulb is suitable all beyond the Great Wall, substrate is squeezed into by syringe.Glass drying oven is all dried.
Chromatographic column is to use silicagel column.Silica gel (300-400 order) is purchased from Haiyang Chemical Plant, Qingdao.The test condition of proton nmr spectra is: under room temperature condition, and the nuclear magnetic resonance spectrometer of Brooker (Bruker) 400MHz or 600MHz, with CDC13, d6-DMSO, CD3OD or d6-acetone is solvent (report in units of ppm), with TMS (0ppm) or chloroform (7.26ppm) as reference standard.When multiplet occurs time, following abbreviation will be used: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), q (quartet, quartet), m (multiplet, multiplet), br (broadened, broad peak), dd (doubletofdoublets, double doublet), dt (doubletoftriplets, double; two triplets).Coupling constant, represents with hertz (Hz).
The condition of Algorithm (MS) data determination is: Agilent6120QuadrupoleHPLC-MS (pillar model: ZorbaxSB-C18,2.1x30mm, 3.5 μm, 6min, flow velocity is 0.6mL/min, mobile phase: the 5%-95% (CH containing 0.1% formic acid3CN) at (H containing 0.1% formic acid2O) ratio in)), detect at 210/254nm UV, with electron spray ionisation pattern (ESI).
The characteristic manner of compound purity is: Agilent1260 preparative high performance liquid chromatography (Pre-HPLC) or CalesepPump250 preparative high performance liquid chromatography (Pre-HPLC) (pillar model: NOVASEP, 50/80mm, DAC), detect at 210nm/254nm UV.
The use of brief word below runs through the present invention:
HPLC high performance liquid chromatography；H2O water；MeOH,CH3OH methanol；CD3OD deuterated methanol；EtOH, ethanol ethanol；HCOOH formic acid；CH3CN, MeCN acetonitrile；DCM,CH2Cl2Dichloromethane；CHCl3Chloroform, chloroform；CDCl3Deuterochloroform；DMFN, dinethylformamide；EDCI1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride；HOBT1-hydroxybenzotriazole；SEMCl2-(TMS) ethoxymethyl chlorine；THF oxolane；PE petroleum ether；EtOAc ethyl acetate；Na2SO4Sodium sulfate；Pd/C palladium/carbon；POCl3Phosphorus oxychloride；NaIO4/RuCl3Sodium metaperiodate/ruthenium trichloride；NaH sodium hydride；NH3·H2O ammonia；CNCH2COOH cyanoacetic acid；H hour；Min minute.
Synthetic method one
Target compound 8 can pass through synthetic method one and prepare, wherein RxThere is implication as described in the present invention.Compound 1 and paratoluensulfonyl chloride are obtained by reacting compound 2；Compound 2 and compound 3 are obtained by reacting compound 4；Compound 4 deprotection obtains compound 5；Compound 5 deprotection obtains compound 6；Compound 6 and compound 7 are obtained by reacting target compound 8.
Synthetic method two
Target compound 10 can pass through synthetic method two and prepare, wherein Y, t and RxThere is implication as described in the present invention.Compound 6 and compound 9 are obtained by reacting target compound 10.
Synthetic method three
Target compound 12 can pass through synthetic method three and prepare, and wherein Rx has implication as described in the present invention.Compound 6 and compound 11 are obtained by reacting target compound 12.
Synthetic method four
Target compound 16 can pass through synthetic method four and prepare.Compound 13 obtains compound 14 through esterification；Compound 14 triethylamine exist under with NH2CH2CN is obtained by reacting compound 15；Compound 15 and compound 6 are obtained by reacting target compound 16.
Synthetic method five
Target compound 19 can pass through synthetic method five and prepare, wherein RLFor leaving groups such as halogens；Each m and R4There is implication as described in the present invention.Compound 6 and compound 17 are obtained by reacting target compound 19.
Target compound 20 can pass through synthetic method five and prepare, wherein RLFor leaving groups such as halogens；Each m and R3There is implication as described in the present invention.Compound 6 and compound 18 are obtained by reacting target compound 20.
Synthetic method six
Target compound 29 can pass through synthetic method six and prepare, and wherein E, G and M have implication as described in the present invention.Compound 21 and compound 22 are obtained by reacting compound 23；Compound 23 and POCl3It is obtained by reacting compound 24；Compound 24 and compound 3 are obtained by reacting compound 25；Compound 25 is at NaIO4/RuCl3Compound 26 it is obtained by reacting under existence；Compound 26 is at NH3·H2There is lower cyclization and obtain compound 27 in O；Compound 27 under Pd/C catalysis with H2It is obtained by reacting compound 28；Compound 28 and CNCH2COOH is obtained by reacting target compound 29.
Synthetic method seven
Target compound 36 can pass through synthetic method seven and prepare, and wherein E, G and M have implication as described in the present invention.Compound 21 and compound 30 are obtained by reacting compound 31；Compound 31 and POCl3It is obtained by reacting compound 32；Compound 32 and compound 3 are obtained by reacting compound 33；Compound 33 and hydrazine hydrate are obtained by reacting compound 34；Compound 34 under Pd/C catalysis with H2It is obtained by reacting compound 35；Compound 35 and CNCH2COOH is obtained by reacting target compound 36.
Embodiment
Embodiment 14-((3R, 4R)-4-methyl-3-(methyl (7H-pyrrolo-[2,3-d] pyrimidine-4-yl) amine) piperidines-1-carbonyl) cyanophenyl
Step 1: the synthesis of compound 4-chloro-7-p-toluenesulfonyl-7H-pyrrolo-[2,3-d] pyrimidine
By 4-chlorine pyrrolo-[2,3-d] pyrimidine (5.00g, 32.56mmol) and p-methyl benzenesulfonic acid chlorine (6.83g, 35.82mmol) be dissolved in acetone (50mL), at 0 DEG C, in reactant liquor, it is slowly added dropwise water (20mL) solution of sodium hydroxide (1.56g, 39.07mmol), after dropwising, reaction 8 hour is stirred at room temperature.Reacting complete, be filtered by reactant liquor, filter cake is dry after washing with the mixed solvent of acetone/water (10mL, v/v=1/1), obtains white solid 9.39g, productivity: 93.71%.
MS(ESI,pos.ion)m/z:308.2[M+1]+.
Step 2: the synthesis of compound N-((3R, 4R)-1-benzyl-4-methyl piperidine-3-base)-N-methyl-7-p-toluenesulfonyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine
By (3R; 4R)-1-benzyl-4-methyl-3-methylamino-piperidines (1g; 4.58mmol) with potassium carbonate (3.80g; 27.48mmol) put into 4-chloro-7-p-toluenesulfonyl-7H-pyrrolo-[2 successively; 3-d] pyrimidine (2.82g; in water (45mL) solution 9.16mmol), stirring reaction 18 hours at 105 DEG C.React complete, filter, through silica gel column chromatography (eluent: CH2Cl2/CH3OH (v/v)=20/1), purification obtains white solid 1.54g, productivity: 68.75%.
MS(ESI,pos.ion)m/z:490.1[M+1]+.
Step 3: the synthesis of compound N-((3R, 4R)-1-benzyl-4-methyl piperidine-3-base)-N-methyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine
By potassium tert-butoxide (1.77g; 15.75mmol) put into N-((3R; 4R)-1-benzyl-4-methyl piperidine-3-base)-N-methyl-7-p-toluenesulfonyl-7H-pyrrolo-[2; 3-d] pyrimidine-4-amine (1.54g; in oxolane (24mL) solution 3.15mmol), stirring reaction 2 hours under room temperature.Reacting complete, add water (50mL) cancellation reaction in reactant liquor, ethyl acetate (100mL) extracts, and merges organic facies, uses anhydrous Na2SO4Dry, filter, concentrating under reduced pressure, the residue obtained is through silica gel column chromatography (eluent: CH2Cl2/CH3OH (v/v)=20/1), purification obtains white solid 1.01g, productivity: 95.28%.
MS(ESI,pos.ion)m/z:336.2[M+1]+.
Step 4: the synthesis of compound N-methy-N-((3R, 4R)-4-methyl piperidine-3-base)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine
By palladium dydroxide (20%, 2.0g) with trifluoroacetic acid (1.36g, 11.92mmol) it is sequentially added into N-((3R, 4R)-1-benzyl-4-methyl piperidine-3-base)-N-methyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine (2.0g, in methanol (15mL) solution 5.96mmol), at H2Reaction 1.5 hour is stirred at room temperature in atmosphere.React complete, filter, filtrate reduced in volume, obtain white solid 867.7mg.
MS(ESI,pos.ion)m/z:246.3[M+1]+.
Step 5: the synthesis of compound 4-((3R, 4R)-4-methyl-3-(methyl (7H-pyrrolo-[3,4-d] pyrimidine-4-yl) amine) piperidines-1-carbonyl) cyanophenyl
By N-methyl-N-((3R, 4R)-4-methyl piperidine-3-base)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine (182.0mg, 0.74mmol), paracyanobenzoic acid (217.8mg, 1.48mmol) with 2-(7-azo BTA)-N, N, N', N'-tetramethylurea hexafluorophosphoric acid ester (562.7mg, 1.48mmol) are dissolved in DMF (10mL), it is subsequently adding N, N-diisopropylethylamine (382.6mg, 2.96mmol), mixed liquor is stirred at room temperature reaction 2 hours.Reacting complete, add water (20mL) cancellation reaction in reactant liquor, ethyl acetate (60mL) extracts, the organic facies anhydrous Na of merging2SO4Dry, filter, concentrating under reduced pressure, the residue obtained is through silica gel column chromatography (eluent: CH2Cl2/ MeOH (v/v)=15/1), purification obtains white solid 52.9mg, productivity: 19.69%.
MS(ESI,pos.ion)m/z:375.2[M+1]+；
1HNMR(400MHz,DMSO-d6): δ (ppm) 11.91 (s, 1H), 8.20 (s, 1H), 7.86-7.96 (m, 2H), 7.59-7.63 (m, 2H), 7.23 (s, 1H), 6.68 (s, 1H), 5.76 (s, 1H), 4.87-4.97 (m, 1H), 4.11-4.14 (m, 1H), 3.85-3.91 (m, 2H), 3.17-3.28 (m, 3H), 2.43-2.44 (m, 1H), 1.78 (s, 1H), 1.56 (s, 1H), 1.24 (s, 1H), 1.04 (d, J=6.8Hz, 3H).
Embodiment 23-((3R, 4R)-4-methyl-3-(methyl (7H-pyrrolo-[2,3-d] pyrimidine-4-yl) amine) piperidines-1-carbonyl) benzsulfamide
By N-methyl-N-((3R, 4R)-4-methyl piperidine-3-base)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine (114.0mg, 0.46mmol), between sulfonamide benzoic acid (185.1mg, 0.92mmol) with 2-(7-azo BTA)-N, N, N', N'-tetramethylurea hexafluorophosphoric acid ester (349.8mg, 0.92mmol) are dissolved in DMF (8mL), it is subsequently adding N, N-diisopropylethylamine (237.8mg, 1.84mmol), mixed liquor is stirred at room temperature reaction 2 hours.Reacting complete, add water (20mL) cancellation reaction in reactant liquor, ethyl acetate (60mL) extracts, the organic facies anhydrous Na of merging2SO4Dry, filter, concentrating under reduced pressure, the residue obtained is through silica gel column chromatography (eluent: CH2Cl2/ MeOH (v/v)=10/1), purification obtains white solid 46.0mg, productivity: 23.34%.
MS(ESI,pos.ion)m/z:429.1[M+1]+；
1HNMR(400MHz,MeOH-d4): δ (ppm) 7.99-8.14 (m, 3H), 7.70 (s, 2H), 7.14 (s, 1H), 6.62-6.70 (m, 1H), 3.94-4.23 (m, 2H), 3.60-3.65 (m, 1H), 3.49-3.54 (m, 3H), 3.37 (s, 1H), 2.53 (s, 1H), 1.92 (s, 1H), 1.68 (s, 1H), 1.30-1.34 (m, 1H), 1.13 (d, J=7.2Hz, 3H).
Embodiment 31-((3R, 4R)-4-methyl-3-(methyl (7H-pyrrolo-[2,3-d] pyrimidine-4-yl) amine) piperidines-1-carbonyl)-3-cyanide nitrogen azetidine
By 3-cyano group azetidine hydrochloride (162.4mg, 1.377mmol) and N, N-diisopropylethylamine (389.0mg, 3.01mmol) add triphosgene (69.6mg, in dichloromethane (12mL) solution 0.51mmol), stirring reaction 1h under room temperature, it is subsequently adding N-methyl-N-((3R, 4R)-4-methyl piperidine-3-base)-7H-pyrrolo-[2, 3-d] pyrimidine-4-amine (336mg, 1.37mmol), it is slowly added dropwise N again, N-diisopropylethylamine (195.2mg, dichloromethane (8mL) solution 1.51mmol), room temperature reaction 48h.Reacting complete, concentrating under reduced pressure, the residue obtained is through silica gel column chromatography (eluent: CH2Cl2/CH3OH (v/v)=14/1), purification obtains white solid 47.7mg, productivity: 9.85%.
MS(ESI,pos.ion)m/z:354.3[M+1]+；
1HNMR(400MHz,CDCl3): δ (ppm) 10.83 (s, 1H), 8.28 (s, 1H), 7.07 (d, J=3.6Hz, 1H), 6.55 (d, J=3.6Hz, 1H), 5.08 (s, 1H), 4.18-4.29 (m, 4H), 3.61-3.71 (m, 2H), 3.36-3.45 (m, 4H), 2.45-2.51 (m, 1H), 2.25 (s, 3H), 1.85-1.93 (m, 1H), 1.63-1.71 (m, 1H), 1.08 (d, J=7.1Hz, 3H).
Embodiment 41-((3R, 4R)-4-methyl-3-(methyl (7H-pyrrolo-[2,3-d] pyrimidine-4-yl) amine) piperidines-1-carbonyl)-3-cyano group aza-cyclopentane
By 3-cyanide nitrogen Polymorphs heptane hydrochloride salt (172.4mg, 1.3030mmol) and N, N-diisopropylethylamine (369.6mg, 2.86mmol) add triphosgene (142.4mg, in dichloromethane (15mL) solution 0.48mmol), stirring reaction 1h under room temperature, it is subsequently adding N-methyl-N-((3R, 4R)-4-methyl piperidine-3-base)-7H-pyrrolo-[2, 3-d] pyrimidine-4-amine (320mg, 1.30mmol), it is slowly added dropwise N again, N-diisopropylethylamine (184.8mg, dichloromethane (8mL) solution 1.43mmol), room temperature reaction 2 days.Reacting complete, concentrating under reduced pressure, the residue obtained is through silica gel column chromatography (eluent: CH2Cl2/CH3OH (v/v)=14/1), purification obtains white solid 90.1mg, productivity: 18.86%.MS(ESI,pos.ion)m/z:368.3[M+1]+；
1HNMR(400MHz,CDCl3): δ (ppm) 11.06 (s, 1H), 8.24 (s, 1H), 7.04 (d, J=3.6Hz, 1H), 6.52 (d, J=3.5Hz, 1H), 5.03 (s, 1H), 3.72-3.82 (m, 1H), 3.46-3.63 (m, 5H), 3.38 (d, J=2.3Hz, 3H), 3.00-3.08 (m, 1H), 2.49 (s, 3H), 2.10-2.24 (m, 2H), 2.03 (s, 1H), 1.86-1.93 (m, 1H), 1.62-1.66 (m, 1H), 1.05 (dd, J=7.1,1.5Hz, 3H).
Embodiment 52-(1,1-titanium dioxide thiomorpholine)-1-((3R, 4R)-4-methyl-3-(methyl (7H-pyrrolo-[2,3-d] pyrimidine-4-yl) amine) piperidin-1-yl) ethyl ketone
By N-methyl-N-((3R, 4R)-4-methyl piperidine-3-base)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine (236.0mg, 0.96mmol), 2-(1,1-titanium dioxide thiomorpholine) acetic acid (278.0mg, 1.44mmol), HOBT (260.0mg, 1.92mmol) with EDCI (368.0mg, 1.92mmol) it is dissolved in DMF (10mL), is subsequently adding DIPEA (373.0mg, 2.87mmol), mixed liquor is stirred at room temperature reaction overnight.Reacting complete, add water (30mL) cancellation reaction in reactant liquor, dichloromethane (150mL) extracts, the organic facies anhydrous Na of merging2SO4Dry, filter, concentrating under reduced pressure, the residue obtained is through silica gel column chromatography (eluent: CH2Cl2/ MeOH (v/v)=15/1), purification obtains white solid 91.0mg, productivity: 22.49%.
MS(ESI,pos.ion)m/z:421.2[M+1]+；
1HNMR(400MHz,DMSO-d6): δ (ppm) 1.01-1.08 (m, 3H), 1.24 (s, 1H), 1.56-1.79 (m, 2H), 2.37-2.40 (m, 1H), 2.86-2.91 (m, 3H), 3.04-3.17 (m, 5H), 3.27 (s, 2H), 3.40-3.59 (m, 3H), 3.66-3.96 (m, 2H), 6.57 (d, J=8.4Hz, 1H), 7.14 (d, J=2.5Hz, 1H), 8.10 (s, 1H), 11.64 (s, 1H).
Embodiment 64-(2-((3R, 4R)-4-methyl-3-(methyl (7H-pyrrolo-[2,3-d] pyrimidine-4-yl) amine) piperidin-1-yl)-2-acetyl group) morpholine-3-ketone
By N-methyl-N-((3R, 4R)-4-methyl piperidine-3-base)-7H-pyrazole, pyrrole also [2,3-d] pyrimidine-4-amine (330.0mg, 1.35mmol), 2-(3-oxo morpholine) acetic acid (321.0mg, 2.02mmol), HOBT (363.0mg, 2.69mmol) with EDCI (515.0mg, 2.69mmol) it is dissolved in DMF (25mL), it is subsequently adding N, N-diisopropylethylamine (521.0mg, 4.03mmol), mixed liquor is stirred at room temperature reaction overnight.Reacting complete, add water (30mL) cancellation reaction in reactant liquor, dichloromethane (150mL) extracts, the organic facies anhydrous Na of merging2SO4Dry, filter, concentrating under reduced pressure, the residue obtained is through silica gel column chromatography (eluent: CH2Cl2/ MeOH (v/v)=18/1), purification obtains white solid 248.1mg, productivity: 47.73%.
MS(ESI,pos.ion)m/z:387.3[M+1]+；
1HNMR(400MHz,DMSO-d6): δ (ppm) 11.66 (s, 1H), 8.12 (d, J=7.3Hz, 1H), 7.15 (s, 1H), 6.57 (s, 1H), 4.22-4.34 (m, 2H), 4.06 (s, 1H), 3.98-4.00 (m, 1H), 3.89-3.93 (m, 1H), 3.82-3.85 (m, 2H), 3.66-3.73 (m, 2H), 3.42-3.50 (m, 3H), 3.27 (s, 3H), 2.40 (s, 1H), 1.60-1.82 (m, 2H), 1.23-1.26 (m, 1H), 1.02 (d, J=7.1Hz, 3H).
Embodiment 7 (3R, 4R)-N-(cyanomethylene)-4-methyl-3-(methyl (7H-pyrrolo-[2,3-d] pyrimidine-4-yl) amine) piperidines-1-Methanamide
By aminoacetonitrile HCl salt (75.9mg, 0.82mmol) and N, N-diisopropylethylamine (232.63mg, dichloromethane (5mL) solution 1.80mmol) is slowly added dropwise into triphosgene (80.1mg, in dichloromethane (3mL) solution 0.27mmol), stirring reaction 1h under room temperature, it is subsequently adding N-methyl-N-((3R, 4R)-4-methyl piperidine-3-base)-7H-pyrrolo-[2, 3-d] pyrimidine-4-amine (200mg, 0.82mmol), it is slowly added dropwise N again, N-diisopropylethylamine (116.32mg, dichloromethane (5mL) solution 0.90mmol), room temperature reaction 19 hours.Reacting complete, concentrating under reduced pressure, the residue obtained is through silica gel column chromatography (eluent: CH2Cl2/CH3OH (v/v)=8/1), purification obtains white solid 52.1mg, productivity: 19.40%.
MS(ESI,pos.ion)m/z:328.2[M+1]+；
1HNMR(400MHz,DMSO-d6): δ (ppm) 8.12 (s, 1H), 7.11 (t, J=4.0Hz, 1H), 6.66 (t, J=3.2Hz, 1H), 4.10 (s, 2H), 3.73-3.88 (m, 2H), 3.48-3.63 (m, 2H), 3.43 (s, 3H), 3.24-3.25 (m, 1H), 2.43-2.47 (m, 1H), 1.86-1.91 (m, 1H), 1.69-1.74 (m, 1H), 1.10 (d, J=7.2Hz, 3H).
Embodiment 84-(2-((3R, 4R)-4-methyl-3-(methyl (7H-pyrrolo-[2,3-d] pyrimidine-4-yl) amine) piperidin-1-yl)-2-acetyl group) benzonitrile
By N-methyl-N-((3R, 4R)-4-methyl piperidine-3-base)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine (93.0mg, 0.38mmol), to cyano group phenylacetic acid (133.1mg, 0.76mmol) with 2-(7-azo BTA)-N, N, N', N'-tetramethylurea hexafluorophosphoric acid ester (289.0mg, 0.76mmol) are dissolved in DMF (6mL), it is subsequently adding N, N-diisopropylethylamine (196.4mg, 1.52mmol), mixed liquor is stirred at room temperature reaction 2 hours.Reacting complete, add water (10mL) cancellation reaction in reactant liquor, ethyl acetate (60mL) extracts, the organic facies anhydrous Na of merging2SO4Dry, filter, concentrating under reduced pressure, the residue obtained is through silica gel column chromatography (eluent: CH2Cl2/ MeOH (v/v)=10/1), purification obtains white solid 120.8mg, productivity: 81.84%.
MS(ESI,pos.ion)m/z:389.2[M+1]+；
1HNMR(400MHz,DMSO-d6null):δ(ppm)11.69(s,1H),8.09(s,1H),7.79(d,J=8.0Hz,1H),7.61(d,J=8.0Hz,1H),7.46(d,J=8.0Hz,1H),7.39(d,J=8.0Hz,1H),7.13(s,1H),6.48(d,J=25.0Hz,1H),3.77-4.06(m,4H),3.50-3.69(m,2H),3.23(s,3H),2.35-2.36(m,1H),1.99(s,1H),1.67-1.69(m,1H),1.52-1.56(m,1H),1.00(d,J=6.8Hz,3H).
Embodiment 94-(4-((3R, 4R)-4-methyl-3-(methyl (7H-pyrrolo-[2,3-d] pyrimidine-4-yl) amine) piperidin-1-yl)-4-bytyry) morpholine-3-ketone
Step 1: the synthesis of compound 4-(3-oxo morpholine) ethyl n-butyrate.
At 0 DEG C, by NaH (60%, 474mg, 11.86mmol) add 3-morpholone (600mg, 5.93mmol) with in dry DMF (15mL) solution of bromobutyrate (2.32g, 11.86mmol), room temperature reaction is overnight.Reacting complete, add water (30mL) cancellation reaction in reactant liquor, EtOAc (150mL) extracts, the organic facies anhydrous Na of merging2SO4Dry, filter, concentrating under reduced pressure, the residue obtained is through silica gel column chromatography (eluent: PE/EtOAc (v/v)=3/1), and purification obtains colourless liquid 309mg, productivity: 24.20%.
MS(ESI,pos.ion)m/z:216.3[M+1]+.
Step 2: the synthesis of compound 4-(3-oxo morpholine) butanoic acid
Being joined by water (2mL) solution of NaOH (287mg, 7.18mmol) in ethanol (10mL) solution of 4-(3-oxo morpholine) ethyl n-butyrate. (309mg, 1.44mmol), room temperature reaction is overnight.Reacting complete, concentrating under reduced pressure removes ethanol, regulates pH with concentrated hydrochloric acid and is about 6, filters, filtration cakes torrefaction, obtain white solid 250mg, be not further purified, direct plunge into next step.
MS(ESI,pos.ion)m/z:188.2[M+1]+.
Step 3: the synthesis of compound 4-(4-((3R, 4R)-4-methyl-3-(methyl (7H-pyrrolo-[2,3-d] pyrimidine-4-yl) amine) piperidin-1-yl)-4-bytyry) morpholine-3-ketone
By N-methyl-N-((3R, 4R)-4-methyl piperidine-3-base)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine (218mg, 0.89mmol), 4-(3-oxo morpholine) butanoic acid (249.0mg, 1.33mmol), HOBT (240.0mg, 1.78mmol) with EDCI (340.0mg, 1.78mmol) it is dissolved in DMF (25mL), add N, N-diisopropylethylamine (459.0mg, 3.56mmol), mixed liquor is stirred at room temperature reaction 12h.Reacting complete, add water (30mL) cancellation reaction in reactant liquor, dichloromethane (150mL) extracts, the organic facies anhydrous Na of merging2SO4Dry, filter, concentrating under reduced pressure, the residue obtained is through silica gel column chromatography (eluent: CH2Cl2/ MeOH (v/v)=15/1), purification obtains white solid 55mg, productivity: 14.90%.
MS(ESI,pos.ion)m/z:415.2[M+1]+；
1HNMR(400MHz,DMSO-d6): δ (ppm) 11.90 (s, 1H), 8.17 (s, 1H), 7.21 (s, 1H), 6.64 (s, 1H), 3.94-4.02 (m, 2H), 3.74-3.83 (m, 4H), 3.46-3.68 (m, 6H), 3.26-3.29 (m, 3H), 2.29-2.39 (m, 3H), 1.71-1.79 (m, 3H), 1.19-1.23 (m, 2H), 1.03 (d, J=7.0Hz, 3H).
Embodiment 10 (3R, 4R)-(R)-oxolane-3-base 4-methyl-3-(methyl (1H-pyrazolo [3,4-d] pyrimidine-4-yl) amine) piperidines-1-formic acid esters
Step 1: the synthesis of compound 4-chloro-1-((2-(trimethyl silicon based) ethyoxyl) methyl)-1H-pyrazolo [3,4-d] pyrimidine
By chloro-for 4-1H-pyrazolo [3,4-d] pyrimidine (1.00g, 6.47mmol) with 2-(TMS) ethoxymethyl chlorine (1.35g, 8.09mmol) it is dissolved in the mixed solvent of THF (15mL) and DMF (8mL), it is subsequently adding N, N-diisopropylethylamine (1.05g, 8.09mmol), mixed liquor is stirring reaction 1 hour at-20 DEG C.Reacting complete, add water (20mL) cancellation reaction in reactant liquor, dichloromethane (90mL) extracts, the organic facies anhydrous Na of merging2SO4Dry, filter, concentrating under reduced pressure, the residue obtained is through silica gel column chromatography (eluent: PE/EtOAc (v/v)=15/1), and purification obtains colourless liquid 935.1mg, productivity: 50.82%.
MS(ESI,pos.ion)m/z:285.1[M+1]+.
Step 2: compound N-((3R, 4R)-1-benzyl-4-methyl piperidine-3-base) synthesis of-N-methyl isophthalic acid-((2-(trimethyl silicon based) ethyoxyl) methyl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine
By chloro-for 4-1-((2-(trimethyl silicon based) ethyoxyl) methyl)-1H-pyrazolo [3,4-d] pyrimidine (830mg, 3.51mmol) with (3R, 4R)-1-benzyl-4-methyl-3-methylamino-piperidines (590mg, 2.70mmol) it is dissolved in DMF (10mL), is subsequently adding DIPEA (1.40g, 10.80mmol), stirring reaction 17h at mixed liquor 60 DEG C.Reacting complete, add water (20mL) cancellation reaction in reactant liquor, ethyl acetate (90mL) extracts, the organic facies anhydrous Na of merging2SO4Dry, filter, concentrating under reduced pressure, the residue obtained is through silica gel column chromatography (eluent: PE/EtOAc (v/v)=2/1), and purification obtains brown color liquid 1.21g, productivity: 96.03%.
MS(ESI,pos.ion)m/z:467.4[M+1]+.
Step 3: the synthesis of compound N-((3R, 4R)-1-benzyl-4-methyl piperidine-3-base)-N-methyl isophthalic acid H-pyrazolo [3,4-d] pyrimidine-4-amine
By the ethyl acetate solution (4.0M of hydrogen chloride, 16mL) at room temperature it is added dropwise to N-((3R, 4R)-1-benzyl-4-methyl piperidine-3-base)-N-methyl isophthalic acid-((2-(trimethyl silicon based) ethyoxyl) methyl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine (1.21g, in ethyl acetate (8mL) solution 2.59mmol), 40 DEG C of reacting by heating 2.5 hours.Reacting complete, by reaction mixture concentrating under reduced pressure, the residue obtained is through silica gel column chromatography (eluent: CH2Cl2/ MeOH (v/v)=15/1), purification obtains faint yellow solid 824.8mg, productivity: 94.65%.
MS(ESI,pos.ion)m/z:337.3[M+1]+.
Step 4: the synthesis of compound N-methy-N-((3R, 4R)-4-methyl piperidine-3-base)-1H-pyrazolo [3,4-d] pyrimidine-4-amine
By palladium dydroxide carbon (20%, 829mg) with trifluoroacetic acid (561mg, 4.92mmol) it is sequentially added into N-((3R, 4R)-1-benzyl-4-methyl piperidine-3-base)-N-methyl isophthalic acid H-pyrazolo [3,4-d] pyrimidine-4-amine (829mg, in MeOH (25mL) solution 2.46mmol), at H2In atmosphere, 50 DEG C of reacting by heating 17 hours.Reacting complete, filter, filtrate reduced in volume, the residue obtained is through silica gel column chromatography (eluent: CH2Cl2/ MeOH (v/v)=10/1), purification obtains weak yellow liquid 507.2mg, productivity: 83.71%.
MS(ESI,pos.ion)m/z:247.2[M+1]+.
Step 5: the synthesis of compound (3R, 4R)-(R)-oxolane-3-base 4-methyl-3-(methyl (1H-pyrazolo [3,4-d] pyrimidine-4-yl) amine) piperidines-1-formic acid esters
By (R)-(-)-3-hydroxyl tetrahydrofuran (156.0mg, 1.77mmol) add N, N'-carbonyl dimidazoles (249.7mg, in THF (10mL) solution 1.54mmol), reaction 0.5 hour is stirred at room temperature, it is subsequently adding triethylamine (3.35g, 33.11mmol), add N-methyl-N-((3R, 4R)-4-methyl piperidine-3-base)-1H-pyrazolo [3,4-d] THF (10mL) solution of pyrimidine-4-amine (190.0mg, 0.77mmol), reactant mixture is stirring reaction 48h at 60 DEG C.Reacting complete, by reactant liquor concentrating under reduced pressure, the residue obtained is through silica gel column chromatography (eluent: CH2Cl2/ MeOH (v/v)=10/1), purification obtains white solid 87.3mg, productivity: 31.46%.
MS(ESI,pos.ion)m/z:361.1[M+1]+；
1HNMR(400MHz,DMSO-d6): δ (ppm) 0.97 (d, J=6.8Hz, 3H), 1.23 (s, 1H), 1.54-1.59 (m, 1H), 1.71 (s, 1H), 1.89-1.91 (m, 1H), 2.08 (s, 1H), 2.32 (s, 1H), 3.32 (s, 3H), 3.47 (s, 2H), 3.58-3.75 (m, 6H), 5.14 (s, 1H), 8.17 (s, 2H), 8.23 (s, 1H), (13.50 s, 1H).
Embodiment 113-(3-((2-methoxyl group-7H-pyrrolo-[2,3-d] pyrimidine-4-yl) (methyl) amino)-4-methyl piperidine-1-base)-3-carbonyl propionitrile
Step 1: the synthesis of the chloro-7-of compound 2,4-bis-((2-(trimethyl silicon based) ethyoxyl) methyl)-7H-pyrrolo-[2,3-d] pyrimidine
At 0 DEG C, to 2,4-bis-chloro-7H-pyrrolo-es [2,3-d] and pyrimidine (500mg, 2.67mmol) and sodium hydride (60%, 126.16mg, mixture 3.20mmol) adds DMF (15mL), 0 DEG C of stirring 1h, it is slowly added into SEMCl (516.5 μ L, 2.95mmol), after room temperature reaction 1h, slowly drip water (20mL) cancellation, dichloromethane (25mL × 3) extracts, and uses anhydrous Na2SO4Dry, remove solvent, concentrated solution carries out column chromatography for separation (eluent: PE/EtOAc (v/v)=5/1), obtains colorless oil 680mg, productivity: 79.6%.MS(ESI,pos.ion)m/z:318.1[M+1]+.
Step 2: the synthesis of compound N-(1-benzyl-4-methyl piperidine-3-base)-2-chloro-n-methyl-7-((2-(trimethyl silicon based) ethyoxyl) methyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine
By 2, the chloro-7-of 4-bis-((2-(trimethyl silicon based) ethyoxyl) methyl)-7H-pyrrolo-[2,3-d] pyrimidine (100mg, 0.51mmol), 3-methylamino-4-methyl isophthalic acid-benzyl piepridine (68.55mg, 0.31mmol), potassium carbonate (256.68mg, 1.86mmol) it is placed in tube sealing with the mixture of oxolane/water (2mL/2mL), 110 DEG C of reaction 24h.Adding saturated aqueous common salt (10mL) cancellation, dichloromethane (15mL × 3) extracts, and uses anhydrous Na2SO4Dry, remove solvent, concentrated solution carries out column chromatography for separation (eluent: PE/EtOAc (v/v)=2/1), obtains colorless oil 86mg, productivity: 54.7%.
MS(ESI,pos.ion)m/z:500.3[M+1]+.
Step 3: the synthesis of compound N-(1-benzyl-4-methyl piperidine-3-base)-2-methoxy-. N-methyl-7-((2-(trimethyl silicon based) ethyoxyl) methyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine
At room temperature, by N-(1-benzyl-4-methyl piperidine-3-base)-2-chloro-n-methyl-7-((2-(trimethyl silicon based) ethyoxyl) methyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine (50mg, 0.1mmol) it is dissolved in methanol (7mL), add Feldalat NM (54.1mg, 1.0mmol), back flow reaction 12h, slowly add water (10mL) cancellation, dichloromethane (15mL × 3) extracts, and uses anhydrous Na2SO4Dry, remove solvent, concentrated solution carries out column chromatography for separation (eluent: PE/EtOAc (v/v)=1/1), obtains colorless oil 50mg, productivity: 99%.
MS(ESI,pos.ion)m/z:496.40[M+1]+.
Step 4: the synthesis of compound N-(1-benzyl-4-methyl piperidine-3-base)-2-methoxy-. N-methyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine
By N-(1-benzyl-4-methyl piperidine-3-base)-2-methoxy-. N-methyl-7-((2-(trimethyl silicon based) ethyoxyl) methyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine (100mg, 0.20mmol) it is dissolved in dichloromethane (3mL), add trifluoroacetic acid (0.25mL), 8h is stirred at room temperature, concentration, add oxolane (3mL) to dissolve, add sodium hydroxide solution (4M, 0.2mL), stirred overnight at room temperature, ethyl acetate (15mL × 3) extracts, and uses anhydrous Na2SO4Dry, remove solvent, concentrated solution carries out column chromatography for separation (eluent: CH2Cl2/ MeOH (v/v)=30/1), obtain pale yellow oil 68mg, productivity: 93.2%.
MS(ESI,pos.ion)m/z:366.30[M+1]+.
Step 5: the synthesis of compound 3-(3-((2-methoxyl group-7H-pyrrolo-[2,3-d] pyrimidine-4-yl) (methyl) amino)-4-methyl piperidine-1-base)-3-carbonyl propionitrile
By N-(1-benzyl-4-methyl piperidine-3-base)-2-methoxy-. N-methyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine (68mg, 0.19mmol) it is dissolved in methanol (5mL), add palladium dydroxide (20%, 13mg), 50 DEG C of oil bath reaction 5h, filter, concentration；Add N, dinethylformamide (3mL) dissolves, it is sequentially added into triethylamine (77.4 μ L, 0.56mmol), EDCI (53.3mg, 0.28mmol), HOBT (37.7mg, 0.28mol) and cyanoacetic acid (23.7mg, 0.28mmol), stirred overnight at room temperature, concentration removes solvent, and concentrated solution carries out column chromatography for separation (eluent: CH2Cl2/ MeOH (v/v)=30/1), obtain colorless oil 11mg, productivity: 17.4%.
MS(ESI,pos.ion)m/z:343.3[M+1]+；
1HNMR(400MHz,CDCl3): δ (ppm) 6.90 (m, 1H), 6.55 (m, 1H), 5.05 (m, 1H), 3.99 (m, 2H), 3.92 (s, 3H), 3.87 (m, 1H), 3.62-3.74 (m, 2H), 3.48 (m, 1H), 3.40 (d, 3H), 2.53 (m, 1H), 1.94 (m, 1H), 1.79 (m, 1H), 1.12 (dd, J=7.2Hz, 3H).
By the similar synthetic method of the embodiment of the present invention, and the synthetic method described in the present invention, with suitable optional initiation material, prepare the compound shown in table 1:
Table 1 compound title and sign data
Biologic activity
Biological Examples 1
The required reagent of experiment and producer:
JAK3, Carna, article No. 08-046；LANCEDetectionBuffer, 10X, PerkinElmer, article No. CR97-100；TopSealTM-A, PerkinElmer, article No. 6005185.
The present invention adopts following methods that the compounds of this invention is carried out biologic test:
1. adopt LanceAssay detection compound to JAK1/2/3 enzyme inhibition；
2. preparation kinase buffer liquid: 50mMHEPESpH7.5,1mMEGTA, 10mMMgCl2, 2mMDTT and 0.01%Tween-20；
3. preparation reaction terminating liquid: 1 × DetectionBuffer dissolves 40mMEDTA；
4. preparation detection mixed liquor: adopting 1 × LANCEDetectionBuffer to dilute Eu-anti-phosphotyrosineantibody (PT66) is 8nM；
5. adopting white 384 orifice plates to detect, reaction system is as follows:
Table 2 compound is to JAK1/2/3 enzyme IC50Detection system
Setup Experiments test sample sample wells, Positive control wells, negative control hole, each sample utilizes the compound inhibitory action to JAK1/2/3 enzyme concentration under duplicate hole 8 concentration of detection, utilize JAK enzyme and without substrate reacting hole as positive control, without enzyme hole (kinase reaction liquid) as negative control.After each hole adds respective sample, buffer and enzyme by table 2 order, 25 DEG C of (RT) calorstats hatch 5min, then every hole adds the Eu-anti-phospho tyrosineAntibody (PT66) configured, and in 25 DEG C of constant-temperature incubation 60min, utilizesMultilabelReader FP320nM excite/665nM transmitted wave strong point detects, and reads data.
Measurement result measures the percentage ratio of activity with compound to be tested and control compound and represents and be (test compound activity/control compound activity) * 100, and obtains percentage ratio and the 100-(test compound activity/control compound activity) * 100 of compound to be tested and control compound inhibitory activity.Adopt Hill's equation curve the Fitting Calculation to go out the meansigma methods of measurement result, draw suppression/concentration-response curve, by the nonlinear regression analysis of suppression/concentration-response curve is calculated IC50Value, EC50Value and hill coefficient (nH).Hill's equation is:
Y = D + [ A - D 1 + ( C / C 50 ) n H ]
Wherein Y=given activity, the left asymptote of A=curve, the right asymptote of D=curve, C=compound concentration, C50=IC50Or EC50, nH=slope factor.Interpretation of result adopts Hill software, and by be applicable toBusiness software4.0 data generated are compared to checking, and experimental result is in Table 3.
The enzyme (JAK1/2/3) of table 3 compound suppresses data
Table 3 data show, JAK1, JAK2 or JAK3 kinases is had stronger inhibitory action by the compounds of this invention；Or JAK1, JAK2 and JAK3 kinases is respectively provided with stronger inhibitory action by the compounds of this invention；Embodiment in table 3 is the Typical Representative in the compounds of this invention, and this makes the activity being known by inference the similar compound of other structures by it be possibly realized.

Claims (10)

1. a compound, it is the compound shown in formula (I) or the stereoisomer of compound shown in formula (I), geometric isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable salt or prodrug:
Wherein:
X is CH or N；
R is R1,-C (=O)-R2,-C (=O)-(CRaRb)m-R3、-(CRaRb)m-C (=O)-R3、-(CRaRb)m-R4,-C (=O)-N (Rc)-(CRaRb)n-R5,-S (=O)2-R6,-S (=O)2-N(Rc)-(CRaRb)n-R7Or-C (=O)-OR7；
R1For C3-6Cycloalkyl, C4-6Heterocyclic radical, C3-6Cycloalkenyl group, C6-10Aryl or C1-5Heteroaryl；
R2For C6-8Cycloalkyl, C2-10Heterocyclic radical, C3-6Cycloalkenyl group or C6-10Aryl, condition is to work as R2During for pyrrolidinyl, at least by a R2xReplace；
Each R2xIndependently be deuterium, fluorine, chlorine, bromine, iodine, cyano group, nitro, amino, carboxyl ,-C (=O)-NH2,-S (=O)2-NH2、C1-6Alkyl, C1-6Alkoxyl, C1-6Alkylamino, halo C1-6Alkyl, halo C1-6The C that alkoxyl, hydroxyl replace1-6The C that alkyl, hydroxyl replace1-6The C that alkoxyl, cyano group replace1-6The C that alkyl, cyano group replace1-6The C that alkoxyl or cyano group replace1-6Alkylamino；
Each R3Independently be C6-8Cycloalkyl, C2-10Heterocyclic radical, C3-6Cycloalkenyl group, C6-10Aryl or C1-5Heteroaryl；
R4For C3-6Cycloalkyl, C2-10Heterocyclic radical, C3-6Cycloalkenyl group, C6-10Aryl or C1-5Heteroaryl, condition is to work as R4During for phenyl, at least by a R4xReplace；
Each R4xIndependently be deuterium, chlorine, bromine, iodine, cyano group, nitro, amino, carboxyl ,-C (=O)-NH2,-S (=O)2-NH2,-S (=O)2-C2-10Heterocyclic radical, C1-6Alkyl, C1-6Alkoxyl, C1-6Alkylamino, halo C1-6Alkyl, halo C1-6The C that alkoxyl, hydroxyl replace1-6The C that alkyl, hydroxyl replace1-6The C that alkoxyl, cyano group replace1-6The C that alkyl, cyano group replace1-6The C that alkoxyl or cyano group replace1-6Alkylamino；
R5For C3-6Cycloalkyl, C2-10Heterocyclic radical, C3-6Cycloalkenyl group, C6-10Aryl or C4-5Heteroaryl；
R6For C3-6Cycloalkyl, C2-10Heterocyclic radical, C3-6Cycloalkenyl group, C6-10Aryl or C1-5Heteroaryl, condition is R6It it is not 5-methyl-isoxazole-4-base；
Each R7Independently be C3-6Cycloalkyl, C2-10Heterocyclic radical, C3-6Cycloalkenyl group, C6-10Aryl or C1-5Heteroaryl；
Each RaAnd RbIndependently be H, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, amino, carboxyl or C1-3Alkyl；
Each RcIndependently be H, C1-3The C that alkyl or cyano group replace1-3Alkyl；
Each m independently be 1,2,3,4,5 or 6；
Each n independently be 0,1,2,3,4,5 or 6；
Each R1、R2、R3、R4、R5、R6And R7Individually optionally by one or more RxReplace；
Each RxIndependently be deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, oxo (=O) ,-C (=O)-NH2,-S (=O)2-NH2、C1-6Alkyl, C1-6Alkoxyl, C1-6Alkylamino, halo C1-6Alkyl, halo C1-6The C that alkoxyl, hydroxyl replace1-6The C that alkyl, hydroxyl replace1-6The C that alkoxyl, cyano group replace1-6The C that alkyl, cyano group replace1-6The C that alkoxyl, cyano group replace1-6Alkylamino, C2-10Heterocyclic radical or C2-10Heterocyclyloxy base, wherein said C2-10Heterocyclic radical and C2-10Heterocyclyloxy base is individually optionally further by one or more RyReplace；With
Each RyIndependently be deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, oxo (=O) ,-C (=O)-NH2,-S (=O)2-NH2、C1-6Alkyl, C1-6Alkoxyl, C1-6Alkylamino, halo C1-6Alkyl, halo C1-6The C that alkoxyl, hydroxyl replace1-6The C that alkyl, hydroxyl replace1-6The C that alkoxyl, cyano group replace1-6The C that alkyl, cyano group replace1-6The C that alkoxyl or cyano group replace1-6Alkylamino.
2. compound according to claim 1, wherein R1For phenyl, cyclobutyl, cyclopropanyl, cyclobutane base, cyclopentenyl, cyclopentadienyl group, cyclohexenyl group or cyclohexadienyl；
Each R2、R3、R5、R6And R7Independently be phenyl；
R4For by 1,2,3,4 or 5 R4xThe phenyl replaced；
Or each R2、R3、R4、R5、R6And R7Independently be following subformula:
Wherein:
Each Y independently be-CH2-,-NH-,-O-,-S-,-S (=O)-or-S (=O)2-；
Each Z independently be-NH-,-O-,-S-,-S (=O)-or-S (=O)2-；
Each t independently be 0,1,2 or 3；
Each r independently be 0,1 or 2；
Each s independently be 1 or 2；
Each p independently be 1 or 2；
R2xFor deuterium, fluorine, chlorine, bromine, iodine, cyano group, nitro, amino, carboxyl ,-C (=O)-NH2,-S (=O)2-NH2、C1-3Alkyl, C1-3Alkoxyl, C1-3Alkylamino, halo C1-3Alkyl, halo C1-3The C that alkoxyl, hydroxyl replace1-3The C that alkyl, hydroxyl replace1-3The C that alkoxyl, cyano group replace1-3The C that alkyl, cyano group replace1-3The C that alkoxyl or cyano group replace1-3Alkylamino；
R4xFor deuterium, chlorine, bromine, iodine, cyano group, nitro, amino, carboxyl ,-C (=O)-NH2,-S (=O)2-NH2,-S (=O)2-C2-6Heterocyclic radical, C1-3Alkyl, C1-3Alkoxyl, C1-3Alkylamino, halo C1-3Alkyl, halo C1-3The C that alkoxyl, hydroxyl replace1-3The C that alkyl, hydroxyl replace1-3The C that alkoxyl, cyano group replace1-3The C that alkyl, cyano group replace1-3The C that alkoxyl or cyano group replace1-3Alkylamino；
Each R1、R2、R3、R4、R5、R6And R7Individually optionally by one or more RxReplace；
Each RxIndependently be deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, oxo (=O) ,-C (=O)-NH2,-S (=O)2-NH2、C1-4Alkyl, C1-3Alkoxyl, C1-3Alkylamino, halo C1-3Alkyl, halo C1-3The C that alkoxyl, hydroxyl replace1-3The C that alkyl, hydroxyl replace1-3The C that alkoxyl, cyano group replace1-3The C that alkyl, cyano group replace1-4The C that alkoxyl, cyano group replace1-4Alkylamino, C2-6Heterocyclic radical or C2-6Heterocyclyloxy base, wherein said C2-6Heterocyclic radical and C2-6Heterocyclyloxy base is individually optionally further by one or more RyReplace；With
Each RyIndependently be deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, oxo (=O) ,-C (=O)-NH2,-S (=O)2-NH2、C1-4Alkyl, C1-3Alkoxyl, C1-3Alkylamino, halo C1-3Alkyl, halo C1-3The C that alkoxyl, hydroxyl replace1-3The C that alkyl, hydroxyl replace1-3The C that alkoxyl, cyano group replace1-3The C that alkyl, cyano group replace1-4The C that alkoxyl or cyano group replace1-4Alkylamino.
3. compound according to claim 2, wherein each R2、R3、R4、R5、R6And R7Independently be following subformula:
4. a compound, it is the compound shown in formula (II) or the stereoisomer of compound shown in formula (II), geometric isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable salt or prodrug:
Wherein:
R11For deuterium, bromine, iodine, cyano group, hydroxyl, nitro, carboxyl ,-C (=O)-NR12R13,-S (=O)2-NR12R13、C1-3Alkyl, halo C1-3Alkyl, amino C1-3Alkyl, C1-4Alkyl amino C1-4Alkyl, (C1-4Alkyl)2N-C1-4The C that alkyl, hydroxyl replace1-3The C that alkyl, cyano group replace1-3Alkyl, C1-4Alkoxyl, C1-4Alkylamino, C3-6Cycloalkyl amino, C6-10Virtue amino, C1-5Heteroaryl amino ,-N (R14)-C (=O)-R15、-N(R14)-S (=O)2-R15、C3-6Cycloalkyl, C3-6Cycloalkenyl group, C2-8Heterocyclic radical, C6-10Aryl, C1-5Heteroaryl, C3-6Cycloalkyl C1-3Alkyl, C3-6Cycloalkyl C1-3Alkoxyl, C3-6Cycloalkenyl group C1-3Alkyl, C3-6Cycloalkenyl group C1-3Alkoxyl, C2-6Heterocyclic radical C1-3Alkyl, C2-6Heterocyclic radical C1-6Alkoxyl, C6-10Aryl C1-3Alkyl, C6-10Aryl C1-3Alkoxyl, C1-5Heteroaryl C1-3Alkyl or C1-5Heteroaryl C1-3Alkoxyl；
Each R12And R13Independently be H, deuterium or C1-3Alkyl；
Each R14Independently be H, deuterium or C1-3Alkyl；
Each R15Independently be H, deuterium or C1-4Alkyl；With
R11Optionally by one or more selected from deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, oxo ,-C (=O)-NH2,-S (=O)2-NH2、C1-6Alkyl, C1-6Alkoxyl, C1-6Alkylamino, halo C1-6Alkyl, halo C1-6The C that alkoxyl, hydroxyl replace1-6The C that alkyl, hydroxyl replace1-6The C that alkoxyl, cyano group replace1-6The C that alkyl, cyano group replace1-6The C that alkoxyl, cyano group replace1-6Alkylamino, C2-8Heterocyclic radical or C2-8The substituent group of heterocyclyloxy base is replaced.
5. compound according to claim 4, wherein R11For deuterium, bromine, iodine, cyano group, hydroxyl, nitro, carboxyl ,-C (=O)-NH2,-S (=O)2NH2, methoxyl group, ethyoxyl, methylamino, ethylamino ,-NH-C (=O)-CH3,-NH-C (=O)-CH2CH3、(CH3)2N-CH2-、(CH3)2N-CH2-CH2-、(CH3CH2)2N-CH2-、(CH3CH2)2N-CH2-CH2-, morpholinyl methyl, morpholinyl ethyl, morpholinyl propyl, morpholinyl methoxyl group, morpholinyl ethyoxyl, morpholinopropoxy, phenylamino, (4-morpholino phenyl) amino, pyrazolyl amino, N-methylpyrazole base amino, imidazole radicals amino, pyridinylamino or pyrimidinyl-amino.
6. a compound, it is the compound shown in formula (III) or the stereoisomer of compound shown in formula (III), geometric isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable salt or prodrug:
Wherein:
Each E, G, M and J independently be N or CR16；
K is-O-,-S-or-N (R17)-；
Each R16Independently be hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl ,-C (=O)-NH2,-S (=O)2-NH2、C1-6Alkyl, C1-6Alkoxyl, C1-6Alkylamino, halo C1-6Alkyl, halo C1-6The C that alkoxyl, hydroxyl replace1-6The C that alkyl, hydroxyl replace1-6The C that alkoxyl, cyano group replace1-6The C that alkyl, cyano group replace1-6The C that alkoxyl or cyano group replace1-6Alkylamino；With
R17For hydrogen, deuterium or C1-6Alkyl.
7. a compound, it is have the compound of one of following structure or have one of the following stereoisomer of structural compounds, geometric isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug:
8. a pharmaceutical composition, it comprises the compound described in claim 1-7 any one, and described pharmaceutical composition comprises at least one of pharmaceutically acceptable carrier, excipient, diluent, adjuvant and vehicle further；Or/and
Described pharmaceutical composition comprises additional treatment agent further, described additional treatment agent selected from chemotherapeutics or antiproliferative, anti-inflammatory agent, immunomodulator or immunosuppressant, neurotrophic factor, for treating the activating agent of cardiovascular disease, for treating the activating agent of diabetes and for treating the activating agent of autoimmune disease.
9. the pharmaceutical composition described in the compound used described in claim 1-7 any one or claim 8 is prepared for preventing, process, treatment or alleviate the purposes of medicine of autologous patient immunological diseases or proliferative disease, wherein said autoimmune disease is lupus, multiple sclerosis, muscle contracting lateral sclerosis, rheumatoid arthritis, psoriasis, type i diabetes, because of the complication that organ transplantation causes, foreign body is transplanted, diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn disease, Alzheimer, leukemia or lymphoma；Described proliferative disease is metastatic carcinoma, colon cancer, adenocarcinoma of stomach, bladder cancer, breast carcinoma, renal carcinoma, hepatocarcinoma, pulmonary carcinoma, thyroid carcinoma, head and neck cancer, carcinoma of prostate, cancer of pancreas, the cancer of CNS (central nervous system), glioblastoma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis.
10. the pharmaceutical composition described in the compound used described in claim 1-7 any one or claim 8 prepares the purposes of medicine for suppressing or regulate protein kinase activity in biological sample, described purposes comprises use compound described in claim 1-7 any one or the pharmaceutical composition described in claim 8 contacts with described biological sample, and described protein kinase is JAK1, JAK2, JAK3, BTK, EGFR or EGFRT790M.
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