CN106336413A - Compounds used as JAK inhibitor, and use of compounds - Google Patents

Compounds used as JAK inhibitor, and use of compounds Download PDF

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CN106336413A
CN106336413A CN201610536665.3A CN201610536665A CN106336413A CN 106336413 A CN106336413 A CN 106336413A CN 201610536665 A CN201610536665 A CN 201610536665A CN 106336413 A CN106336413 A CN 106336413A
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compound
formula
base
independently
methyl
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CN106336413B (en
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刘兵
黄九忠
郑常春
张英俊
欧阳罗
毛洪芬
聂飚
许娟
陈红分
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • 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
    • C07D487/12—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 three hetero rings
    • C07D487/14—Ortho-condensed systems

Abstract

The invention provides compounds used as a JAK inhibitor, and a use of the compounds, and concretely provides compounds (represented by formula (I)) with JAK inhibition activity or a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, and a medicinal composition including the compounds. The invention also discloses a use of the compounds or the medicinal composition thereof in the preparation of medicines used for treating autoimmune diseases or proliferative diseases.

Description

Compound as jak inhibitor and application thereof
Invention field
The invention belongs to pharmaceutical technology field, and in particular to a class has the compound of jak inhibitory activity, comprises the present invention The pharmaceutical composition of compound, and the compound of the present invention or pharmaceutically comprise the pharmaceutical composition of the compounds of this invention in medicine Application in thing.
Background of invention
Janus kinases (jak) belongs to family tyrosine kinase, and by jak1, jak2, jak3 and tyk2 form.Jak is in cell Play an important role in factor signal transduction.The stream substrates of jak family kinase include transcription signal sensing and activation (stat) albumen.The transmission implication in the mediation of a lot of abnormal immune responses of jak/stat signal, such as allergy, Asthma, autoimmune disease, such as transplant rejection, rheumatoid arthritiss, amyotrophic lateral sclerosiss and multiple sclerosiss, with And entity and hematologic malignancies, such as leukemia and lymphoma.Jak1, jak2 and tyk2 can suppress several genes to express, But jak3 only plays a role in granulocyte.The exemplary functions of cytokine receptor are that exist as heterodimer form, because This is frequently not that a kind of jak kinases is acted on cytokine receptor.
Genetic biology research show, jak1 by with ifnalpha, the cell factor receptor such as ifngamma, il-2, il-6 Body acts on and plays a role, and jak1 knock-out mice is dead because lif receptor signal lacks.Observe the feature of jak1 knock-out mice Tissue, finds that jak1 plays an important role in ifn, the cell pathway such as il-10, il-2/il-4 and il-6.
Jak2 also implication in myeloproliferative disorder, this includes polycythemia vera, essential thrombocytopenia Increase, Chronic Spontaneous myelofibrosises, the myeloid metaplasia with myelofibrosises, chronic lymphocytic leukemia, slow Property myelomonocytic leukemia, chronic eosinophilic leukemia, HES and systemic mast are thin Born of the same parents' disease.
Jak3 is specific to act on gamma cells factor acceptor chain, and it is in il-2, il-4, il-7, il-9, il-15, il- Exist in 21 grade cytokine receptor.Jak3, in lymphocyte growth, hypertrophy, plays an important role in mutation process, occurs different Serious immune deficiency often can be led to.Jak3 implication in the mediation of a lot of abnormal immune responses, such as allergy, roar Breathe heavily, autoimmune disease such as suppress transplant rejection, rheumatoid arthritiss, muscle contracting lateral sclerosis and multiple sclerosiss and Entity and hematologic malignancies such as leukemia, lymphoma.Jak3 inhibitor is as being useful for following immunosuppressant Therapeutic agent: organ transplantation, xenotransplantation, lupus, multiple sclerosiss, rheumatoid arthritiss, psoriasiss, i patients with type Ⅰ DM and come From the complication of diabetes, cancer, asthma, atopic dermatitiss, autoimmune thyroid disorder, ulcerative colitiss, Crow grace Disease, presenile dementia, leukemia and the suitable other symptoms of immunosuppressant.There was reported the non-hematopoietic expression of jak3, although This meaning functionally not clear (j.immunol., 2002,168:2475-2482).
Tyk2 acts on i type interferon, the cytokine receptor complex such as il-6, il-10, il-12, il-23.Phase therewith Consistent, it is derived from the primary cell of the people of tyk2 disappearance, in i type interferon, the letter of il-6, il-10, il-12, il-23 Number conduction in there is obstacle.
Bruton's tyrosine kinase (bruton ' s tyrosine kinase, btk), a kind of nonreceptor tyrosine kinase The member of tec family, is the pass of expression in all hematopoetic cell types in addition to t lymphocyte and natural killer cell Key signals enzyme.Btk lacks in btk- to the effect of allergic disorder and/or autoimmune disease and/or inflammatory diseasess It is confirmed in mouse model.For example, before the standard murine of Systemic Lupus Eryhamatosus (sle) clinical (preclinical) Model in, shown that btk disappearance can substantially change disease process.
EGF-R ELISA (epidermal growth factor receptor, egfr) is a kind of receptor type cheese Histidine kinase, is distributed widely in the multi-functional glycoprotein on each cell membranes in tissue of human body, is birds erythroblastic leukemia virus (avian erythroblastic leukemia viral, v-erb-b) oncogene autoploid.Egfr etc. is in epithelial origin Tumor, as multiple in squamous cell carcinoma of the head and neck, breast carcinoma, rectal cancer, ovarian cancer, carcinoma of prostate, nonsmall-cell lung cancer etc. swollen All overexpression in tumor, their expression is related to phenomenons such as cancer cell multiplication, transfers.
T790m mutation is one of aobvious factor point mutation outside egfr20, is current more one of resistance mechanism of accreditation. T790m is located at the entrance of egfr and atp binding pocket, and the size of its side chain directly affects the binding ability of egfr and atp.t790m Mutation spatially hinders the effect of egfr inhibitor and atp binding site, increases the affinity to atp for the egfr, so that carefully Born of the same parents produce drug resistance to egfr inhibitor.Initially, t790m is only found in nsclc patient's specimen of Endodontic failure, but subsequently Specimen without any treatment is also found, therefore it is now recognized that this mutation exists in the tumor tissues without tki treatment In, but it is detected in minority clone cell, because these clone cells are selected to the repellence of tki and after the treatment.
Therefore it provides the suppression protein kinase for the treatment of disease (such as autoimmune disease, inflammatory diseasess and cancer) Compound exist need.The compound of the present invention can effectively suppress the activity of protein kinase, such as jak1, jak2, jak3, Btk, egfr or egfr t790m.This kind of compound will be sent out in treatment autoimmune disease and/or inflammatory diseasess and/or cancer Wave potential effect.
Content of the invention
The compound for protein kinase activity of the present invention has inhibitory action.More satisfactory, the compound of the present invention There is multiple suppression function, jak1, jak2, jak3, btk, egfr or egfr t790m can be suppressed.Especially, the present invention relates to And compound and pharmaceutically acceptable pharmaceutical composition, jak1, jak2, jak3, btk, egfr can be effective as Or egfr t790m inhibitor.
On the one hand, the present invention relates to a kind of compound, it is the compound shown in compound or formula (i) as shown in formula (i) Stereoisomer, geometric isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite with And pharmaceutically acceptable salt or prodrug:
Wherein, a ring is further individually optionally by 1,2,3 or 4 r1Replace；
A ring, e ring, each r1、r2、r3、r5With m, there is implication as described in the present invention.
In some embodiments, the present invention relates to a kind of compound, it is the compound or formula (ia) institute as shown in formula (ia) Show the stereoisomer of compound, geometric isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, generation Thank product and pharmaceutically acceptable salt or prodrug:
Wherein, a ring is further individually optionally by 1,2,3 or 4 r1Replace；
A ring, e ring, each r1、r2、r3, each r4、r5With m, there is implication as described in the present invention.
In some embodiments, the present invention relates to a kind of compound, it is the compound or formula (ib) institute as shown in formula (ib) Show the stereoisomer of compound, geometric isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, generation Thank product and pharmaceutically acceptable salt or prodrug:
Wherein, a ring is further individually optionally by 1,2,3 or 4 r1Replace；
A ring, r5With each r1There is implication as described in the present invention.
In some embodiments, the present invention relates to a kind of compound, it is the compound or formula (ic) institute as shown in formula (ic) Show the stereoisomer of compound, geometric isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, Metabolite and pharmaceutically acceptable salt or prodrug:
Wherein, a ring is further individually optionally by 1,2,3 or 4 r1Replace；
A ring, r5With each r1There is implication as described in the present invention.
In some embodiments, the present invention relates to a kind of compound, it is as formula (i) (or formula (ia), formula (ib) or formula (ic) compound shown in) or the stereoisomer of compound shown in formula (i) (or formula (ia), formula (ib) or formula (ic)), geometry Isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable Salt or prodrug: wherein, a ring is c3-9Cycloalkyl, c5-9Cycloalkenyl group, c1-9Heterocyclic radical, c6-10Aryl, c1-9Heteroaryl, c6-12Condense double Ring group, c5-12Condense miscellaneous bicyclic group, c6-12Spiral shell bicyclic group or c5-12The miscellaneous bicyclic group of spiral shell；A ring is further individually optionally by 1,2,3 Or 4 r1Replace；Each r1There is implication as described in the present invention.
In some embodiments, the present invention relates to a kind of compound, it is as formula (i) (or formula (ia), formula (ib) or formula (ic)) Shown compound or the stereoisomer of compound shown in formula (i) (or formula (ia), formula (ib) or formula (ic)), geometrical isomerism Body, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable salt or Prodrug: wherein, a ring is A ring is further individually optionally by 1,2,3 or 4 r1Replace；
Wherein, x1And x2It is each independently-c (r14r14a)-,-n (r15)-,-o- ,-s (=o)p- or-c (=o)-；
x3, x4, x5And x6It is each independently cr14Or n；
Each r14And r14aIt independently is hydrogen, deuterium, c1-4Alkyl, c2-6Thiazolinyl, c2-6Alkynyl or c1-4Haloalkyl；
Each r15It independently is hydrogen, deuterium, c1-4Alkyl, c2-6Thiazolinyl, c2-6Alkynyl or c1-4Haloalkyl；
Each r1With p, there is implication as described in the present invention.
In some embodiments, the present invention relates to a kind of compound, it is as formula (i) (or formula (ia), formula (ib) or formula (ic)) institute The compound showing or the stereoisomer of compound shown in formula (i) (or formula (ia), formula (ib) or formula (ic)), geometric isomer, mutually make a variation Structure body, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable salt or prodrug: wherein, a ring For A ring is further individually optionally by 1,2,3 or 4 r1Replace；
Each r1There is implication as described in the present invention.
In some embodiments, the present invention relates to a kind of compound, it is as formula (i) (or formula (ia), formula (ib) Or formula (ic)) shown in compound or compound shown in formula (i) (or formula (ia), formula (ib) or formula (ic)) solid Isomer, geometric isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite with And pharmaceutically acceptable salt or prodrug: wherein, a ring is
In some embodiments, the present invention relates to a kind of compound, it is the compound or formula as shown in formula (i) (or formula (ia)) The stereoisomer of compound shown in (i) (or formula (ia)), geometric isomer, tautomer, raceme, nitrogen oxides, hydration Thing, solvate, metabolite and pharmaceutically acceptable salt or prodrug: wherein, the subformula that e ring is as follows: " * " represents and r5Connected one end；Wherein, when e ring isWhen, a ring is cyclopropyl；
Wherein, r5, each r4With m, there is implication as described in the present invention.
In some embodiments, the present invention relates to a kind of compound, it is as formula (i) (or formula (ia), formula (ib) or formula (ic) compound shown in) or the stereoisomer of compound shown in formula (i) (or formula (ia), formula (ib) or formula (ic)), geometry Isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable Salt or prodrug: wherein, each r1It independently is h, deuterium, f, cl, br, i, cn, alkyl, thiazolinyl, alkynyl, haloalkyl, r- (cr6r7)n- o-, r- (cr6r7)n1-, r8o-(cr6r7)n-, r8- c (=o)-n (r9)-, cn- (cr6r7)n-r0-(cr6r7)n-n (r9)-, r9a-n(r9)-c (=o)-, r or r-n (r9)-；
Wherein, each r, each r0, each r6, each r7, each r8, each r9, each r9a, each n and each n1 has and contains as described in the present invention Justice.
In some embodiments, the present invention relates to a kind of compound, it is as formula (i) (or formula (ia), formula (ib) or formula (ic) compound shown in) or the stereoisomer of compound shown in formula (i) (or formula (ia), formula (ib) or formula (ic)), geometry Isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable Salt or prodrug: wherein each r1It independently is h, deuterium, f, cl, br, i, cn, c1-4Alkyl, c2-6Thiazolinyl, c2-6Alkynyl, c1-4Alkyl halide Base, cn- (cr6r7)n-r0-(cr6r7)n-n(r9)-, r- (cr6r7)n- o-, r- (cr6r7)n1-, r8o-(cr6r7)n-, r8- c (= o)-n(r9)-, cn- (cr6r7)n- s (=o)p-r0-(cr6r7)n-n(r9)-, r9a-n(r9)-c (=o)-, r or r-n (r9)-；
Wherein, each r, each r0, each r6, each r7, each r8, each r9, each r9a, each n and each n1 has and contains as described in the present invention Justice.
In some embodiments, the present invention relates to a kind of compound, it is as formula (i) (or formula (ia), formula (ib) or formula (ic) compound shown in) or the stereoisomer of compound shown in formula (i) (or formula (ia), formula (ib) or formula (ic)), geometry Isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable Salt or prodrug: wherein each r1It independently is h, deuterium, f, cl, br, i, cn, methyl, ethyl, n-pro-pyl, isopropyl, trifluoromethyl, cn-(cr6r7)n-r0-(cr6r7)n-n(r9)-, r- (cr6r7)n- o-, r- (cr6r7)n1-, r8o-(cr6r7)n-, r8- c (=o)-n (r9)-, cn- (cr6r7)n- s (=o)p-r0-(cr6r7)n-n(r9)-, r9a-n(r9)-c (=o)-, r or r-n (r9)-；Wherein, respectively r0, each r, each r6, each r7, each r8, each r9, each r9a, each n and each n1 there is implication as described in the present invention.
In some embodiments, the present invention relates to a kind of compound, it is as formula (i) (or formula (ia), formula (ib) or formula (ic) compound shown in) or the stereoisomer of compound shown in formula (i) (or formula (ia), formula (ib) or formula (ic)), geometry Isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable Salt or prodrug: wherein each r0It independently is c3-9Cycloalkylidene, c5-9Sub- cycloalkenyl group, c1-9Sub- heterocyclic radical, c6-10Arlydene, c1-9Sub- Heteroaryl, c6-12Sub- condensed-bicyclic base, c5-12Asia condenses miscellaneous bicyclic group, c6-12Sub- spiral shell bicyclic group or c5-12The miscellaneous bicyclic group of sub- spiral shell；Respectively r0Individually optionally by 1,2,3 or 4 r6aReplace；
Each r independently is c3-9Cycloalkyl, c5-9Cycloalkenyl group, c1-9Heterocyclic radical, c6-10Aryl, c1-9Heteroaryl, c6-12Condense double Ring group, c5-12Condense miscellaneous bicyclic group, c6-12Spiral shell bicyclic group or c5-12The miscellaneous bicyclic group of spiral shell；Each r is individually optionally by 1,2,3 or 4 r6a Replace；Wherein, each r6aThere is implication as described in the present invention.
In some embodiments, the present invention relates to a kind of compound, it is as formula (i) (or formula (ia), formula (ib) or formula (ic)) Shown compound or the stereoisomer of compound shown in formula (i) (or formula (ia), formula (ib) or formula (ic)), geometrical isomerism Body, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable salt or Prodrug: wherein each r0It independently is Each r0Individually optionally by 1,2,3 or 4 r6aReplace；
Each r independently isEach r independently appoints Selection of land is by 1,2,3 or 4 r6aReplace；
Wherein, y1And y2It is each independently-c (r16r16a)-,-n (r17)-,-o- ,-s (=o)p- or-c (=o)-；
y3, y4And y5It is each independently cr16Or n；
Each r16And r16aIt independently is hydrogen, deuterium, c1-4Alkyl, c2-6Thiazolinyl, c2-6Alkynyl or c1-4Haloalkyl；
Each r17It independently is hydrogen, deuterium, c1-4Alkyl, c2-6Thiazolinyl, c2-6Alkynyl or c1-4Haloalkyl；
Wherein, each r6aThere is implication as described in the present invention.
In some embodiments, the present invention relates to a kind of compound, it is as formula (i) (or formula (ia), formula (ib) or formula (ic)) Shown compound or the stereoisomer of compound shown in formula (i) (or formula (ia), formula (ib) or formula (ic)), geometric isomer, Tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable salt or prodrug: Wherein each r0It independently is Each r0Individually optionally by 1,2,3 or 4 r6aReplace；
Each r independently is Each r is individually optionally by 1,2,3 or 4 r6aReplace；Wherein, each r6aThere is implication as described in the present invention.
In some embodiments, the present invention relates to a kind of compound, it is as formula (i) (or formula (ia), formula (ib) or formula (ic) compound shown in) or the stereoisomer of compound shown in formula (i) (or formula (ia), formula (ib) or formula (ic)), geometry Isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable Salt or prodrug: wherein each r6aIt independently is hydrogen, deuterium, c1-4Alkyl, c2-6Thiazolinyl, c2-6Alkynyl, f, cl, br, i, cn, r6b- (cr6r7)n- s (=o)p-, hydroxyl, nitro, amino, carboxyl or c1-4Alkoxyl；
Wherein, each r6, each r7、r6b, n and p there is implication as described in the present invention.
In some embodiments, the present invention relates to a kind of compound, it is as formula (i) (or formula (ia), formula (ib) or formula (ic) compound shown in) or the stereoisomer of compound shown in formula (i) (or formula (ia), formula (ib) or formula (ic)), geometry Isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable Salt or prodrug: wherein each r6bIt independently is hydrogen, deuterium, c1-4Alkyl, c2-6Thiazolinyl, c2-6Alkynyl, f, cl, br, i, cn, hydroxyl, nitre Base, c1-4Haloalkyl, amino, carboxyl or c1-4Alkoxyl.
In some embodiments, the present invention relates to a kind of compound, it is as formula (i) (or formula (ia), formula (ib) or formula (ic) compound shown in) or the stereoisomer of compound shown in formula (i) (or formula (ia), formula (ib) or formula (ic)), geometry Isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable Salt or prodrug: wherein each r6It independently is hydrogen, deuterium, c1-4Alkyl, c2-6Thiazolinyl, c2-6Alkynyl, f, cl, br, i, cn, hydroxyl, nitre Base, c1-4Haloalkyl, amino, carboxyl or c1-4Alkoxyl.
In some embodiments, the present invention relates to a kind of compound, it is as formula (i) (or formula (ia), formula (ib) or formula (ic) compound shown in) or the stereoisomer of compound shown in formula (i) (or formula (ia), formula (ib) or formula (ic)), geometry Isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable Salt or prodrug: wherein each r7It independently is hydrogen, deuterium, c1-4Alkyl, c2-6Thiazolinyl, c2-6Alkynyl, f, cl, br, i, cn, hydroxyl, nitre Base, c1-4Haloalkyl, amino, carboxyl or c1-4Alkoxyl.
In some embodiments, the present invention relates to a kind of compound, it is as formula (i) (or formula (ia), formula (ib) or formula (ic) compound shown in) or the stereoisomer of compound shown in formula (i) (or formula (ia), formula (ib) or formula (ic)), geometry Isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable Salt or prodrug: wherein each r8It independently is hydrogen, deuterium, c1-4Alkyl, c1-4Haloalkyl or ho- (cr6r7)n-；Wherein, each r6, each r7 With each n, there is implication as described in the present invention.
In some embodiments, the present invention relates to a kind of compound, it is as formula (i) (or formula (ia), formula (ib) or formula (ic) compound shown in) or the stereoisomer of compound shown in formula (i) (or formula (ia), formula (ib) or formula (ic)), geometry Isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable Salt or prodrug: wherein each r9It independently is hydrogen, deuterium, c1-4Alkyl, c1-4Haloalkyl or ho- (cr6r7)n-；Wherein, each r6, each r7 With each n, there is implication as described in the present invention.
In some embodiments, the present invention relates to a kind of compound, it is as formula (i) (or formula (ia), formula (ib) or formula (ic) compound shown in) or the stereoisomer of compound shown in formula (i) (or formula (ia), formula (ib) or formula (ic)), geometry Isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable Salt or prodrug: wherein each r9aIt independently is hydrogen, deuterium, c1-4Alkyl, c1-4Haloalkyl or ho- (cr6r7)n-；Wherein, each r6, each r7With each n, there is implication as described in the present invention.
In some embodiments, the present invention relates to a kind of compound, its be compound as shown in formula (i) (or formula (ia)) or The stereoisomer of compound shown in formula (i) (or formula (ia)), geometric isomer, tautomer, raceme, nitrogen oxides, Hydrate, solvate, metabolite and pharmaceutically acceptable salt or prodrug: wherein r2For h, deuterium, f, cl, br, i, cn, c1-4Alkyl, c2-6Thiazolinyl, c2-6Alkynyl, c1-4Haloalkyl, r8o-(cr6r7)n-, r8- c (=o)-n (r9)-, r9a-n(r9)-c (=o)-or r9a-n(r9)-；Wherein, each r6, each r7, each r8, each r9, each r9aWith each n, there is implication as described in the present invention.
In some embodiments, the present invention relates to a kind of compound, its be compound as shown in formula (i) (or formula (ia)) or The stereoisomer of compound shown in formula (i) (or formula (ia)), geometric isomer, tautomer, raceme, nitrogen oxides, Hydrate, solvate, metabolite and pharmaceutically acceptable salt or prodrug: wherein r3For h, deuterium, f, cl, br, i, cn, c1-4Alkyl, c2-6Thiazolinyl, c2-6Alkynyl, c1-4Haloalkyl, r8o-(cr6r7)n-, r8- c (=o)-n (r9)-, r9a-n(r9)-c (=o)-or r9a-n(r9)-；Wherein, each r6, each r7, each r8, each r9, each r9aWith each n, there is implication as described in the present invention.
In some embodiments, the present invention relates to a kind of compound, its be compound as shown in formula (i) (or formula (ia)) or The stereoisomer of compound shown in formula (i) (or formula (ia)), geometric isomer, tautomer, raceme, nitrogen oxides, Hydrate, solvate, metabolite and pharmaceutically acceptable salt or prodrug: wherein r4For h, deuterium, f, cl, br, i, cn, c1-4Alkyl, c2-6Thiazolinyl, c2-6Alkynyl, c1-4Haloalkyl, r8o-(cr6r7)n-, r8- c (=o)-n (r9)-, r9a-n(r9)-c (=o)-or r9a-n(r9)-；Wherein, each r6, each r7, each r8, each r9, each r9aWith each n, there is implication as described in the present invention.
In some embodiments, the present invention relates to a kind of compound, it is as formula (i) (or formula (ia), formula (ib) or formula (ic) compound shown in) or the stereoisomer of compound shown in formula (i) (or formula (ia), formula (ib) or formula (ic)), geometry Isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable Salt or prodrug: wherein r5For cn- (cr10r11)n1-n(r12)-, cn- (cr10r11)n1- c (=o)-n (r12)-, cn- (cr10r11)n- c3-9Cycloalkyl-n (r12)-, r13-o-(cr10r11)n1-n(r12)-, cn- (cr10r11)n1-c1-9Heterocyclic radical-c (=o)-n (r12)-, cn-(cr10r11)n- c (=o)-c1-9Heterocyclic radical-(cr10r11)n-n(r12)-, r13-(cr10r11)n1- s (=o)p-(cr10r11)n-n (r12)-, r13-(cr10r11)n- s (=o)p-(r12a)n-c3-9Cycloalkyl-n (r12)-, r13-(cr10r11)n-n(r12)-c (=o)- (cr10r11)n-(r12a) n-, cn- (cr10r11)n-n(r12)-c (=o)-(cr10r11)n-(r12a) n-, cn- (cr10r11)n-c1-9 Heterocyclic radical-(cr10r11)n-n(r12)-, cn- (cr10r11)n1- s (=o)p-(r12a) n-, cn- (cr10r11)n- c (=o)-c1-9Miscellaneous Ring group-(cr10r11)n-, cn- (cr10r11)n-c3-9Cycloalkyl-(cr10r11)n1-, ho- (cr10r11)n-c3-9Cycloalkyl- (cr10r11)n1-, cn- (cr10r11)n-c1-9Heterocyclic radical-(cr10r11)n1-, cn- (cr10r11)n1-n(r12)-c (=o)-, cn- (cr10r11)n1-, c6-10Aryl-(cr10r11)n1-, (r12a)n(r12)-c (=o)-(cr10r11)n1-, cn- (cr10r11)n-c1-9Miscellaneous Ring group-(cr10r11)n-n(r12)-s (=o)p-, cn- (cr10r11)n-c1-9Heterocyclic radical-(cr10r11)n- s (=o)p-, cn- (cr10r11)n- s (=o)p-, r13-(cr10r11)n-(r12a) n-s (=o)p-, r13-(cr10r11)n-n(r12)-c (=o)- (cr10r11)n-(r12a) n-s (=o)p- or cn- (cr10r11)n1-(r12a) n-s (=o)p-；Wherein said aryl, heterocyclic radical Individually optionally with cycloalkyl by 1,2,3 or 4 r6cReplace；Wherein, each r6c, each r10, each r11, each r12, each r12a, each r13, each N, each n1 and each p have implication as described in the present invention.
In some embodiments, the present invention relates to a kind of compound, it is as formula (i) (or formula (ia), formula (ib) or formula (ic) compound shown in) or the stereoisomer of compound shown in formula (i) (or formula (ia), formula (ib) or formula (ic)), geometry Isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable Salt or prodrug: wherein r5For cn- (cr10r11)n1-n(r12)-, cn- (cr10r11)n1- c (=o)-n (r12)-, cn- (cr10r11)n- c3-6Cycloalkyl-n (r12)-, r13-o-(cr10r11)n1-n(r12)-, cn- (cr10r11)n1-c3-6Heterocyclic radical-c (=o)-n (r12)-, cn-(cr10r11)n- c (=o)-c3-6Heterocyclic radical-(cr10r11)n-n(r12)-, r13-(cr10r11)n- s (=o)p-(r12a)n-c3-6 Cycloalkyl-n (r12)-, r13-(cr10r11)n-n(r12)-c (=o)-(cr10r11)n-(r12a) n-, cn- (cr10r11)n-n(r12)-c (=o)-(cr10r11)n-(r12a) n-, r13-(cr10r11)n1- s (=o)p-(cr10r11)n-n(r12)-, cn- (cr10r11)n-c3-6 Heterocyclic radical-(cr10r11)n-n(r12)-, cn- (cr10r11)n1- s (=o)p-(r12a) n-, cn- (cr10r11)n- c (=o)-c3-6Miscellaneous Ring group-(cr10r11)n-, cn- (cr10r11)n-c3-6Cycloalkyl-(cr10r11)n1-, ho- (cr10r11)n-c3-6Cycloalkyl- (cr10r11)n1-, cn- (cr10r11)n-c3-6Heterocyclic radical-(cr10r11)n1-, cn- (cr10r11)n1-, phenyl-(cr10r11)n1-, (r12a)n(r12)-c (=o)-(cr10r11)n1-, cn- (cr10r11)n1-n(r12)-c (=o)-, cn- (cr10r11)n-c3-6Heterocycle Base-(cr10r11)n- s (=o)p-, cn- (cr10r11)n- s (=o)p-, cn- (cr10r11)n-c3-6Heterocyclic radical-(cr10r11)n-n (r12)-s (=o)p-, r13-(cr10r11)n-(r12a) n-s (=o)p-, r13-(cr10r11)n-n(r12)-c (=o)- (cr10r11)n-(r12a) n-s (=o)p- or cn- (cr10r11)n1-(r12a) n-s (=o)p-；Wherein said phenyl, heterocyclic radical Individually optionally with cycloalkyl by 1,2,3 or 4 r6cReplace；Wherein, each r6c, each r10, each r11, each r12, each r12a, each r13, each N, each n1 and each p have implication as described in the present invention.
In some embodiments, the present invention relates to a kind of compound, it is as formula (i) (or formula (ia), formula (ib) or formula (ic)) shown in compound or compound shown in formula (i) (or formula (ia), formula (ib) or formula (ic)) vertical Body isomer, geometric isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolism is produced Thing and pharmaceutically acceptable salt or prodrug: wherein r5For
In some embodiments, the present invention relates to a kind of compound, it is as formula (i) (or formula (ia), formula (ib) or formula (ic) compound shown in) or the stereoisomer of compound shown in formula (i) (or formula (ia), formula (ib) or formula (ic)), geometry Isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable Salt or prodrug: wherein each r10It independently is hydrogen, deuterium, c1-4Alkyl, c2-6Thiazolinyl, c2-6Alkynyl or c1-4Haloalkyl.
In some embodiments, the present invention relates to a kind of compound, it is as formula (i) (or formula (ia), formula (ib) or formula (ic) compound shown in) or the stereoisomer of compound shown in formula (i) (or formula (ia), formula (ib) or formula (ic)), geometry Isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable Salt or prodrug: wherein each r10It independently is hydrogen, deuterium, methyl, ethyl, n-pro-pyl, isopropyl, 2,2,2- trifluoroethyls or fluoroform Base.
In some embodiments, the present invention relates to a kind of compound, it is as formula (i) (or formula (ia), formula (ib) or formula (ic) compound shown in) or the stereoisomer of compound shown in formula (i) (or formula (ia), formula (ib) or formula (ic)), geometry Isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable Salt or prodrug: wherein each r11It independently is hydrogen, deuterium, c1-4Alkyl, c2-6Thiazolinyl, c2-6Alkynyl or c1-4Haloalkyl.
In some embodiments, the present invention relates to a kind of compound, it is as formula (i) (or formula (ia), formula (ib) or formula (ic) compound shown in) or the stereoisomer of compound shown in formula (i) (or formula (ia), formula (ib) or formula (ic)), geometry Isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable Salt or prodrug: wherein each r11It independently is hydrogen, deuterium, methyl, ethyl, n-pro-pyl, isopropyl, 2,2,2- trifluoroethyls or fluoroform Base.
In some embodiments, the present invention relates to a kind of compound, it is as formula (i) (or formula (ia), formula (ib) or formula (ic) compound shown in) or the stereoisomer of compound shown in formula (i) (or formula (ia), formula (ib) or formula (ic)), geometry Isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable Salt or prodrug: wherein each r13It independently is hydrogen, deuterium, c1-4Alkyl, c2-6Thiazolinyl, c2-6Alkynyl or c1-4Haloalkyl.
In some embodiments, the present invention relates to a kind of compound, it is as formula (i) (or formula (ia), formula (ib) or formula (ic) compound shown in) or the stereoisomer of compound shown in formula (i) (or formula (ia), formula (ib) or formula (ic)), geometry Isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable Salt or prodrug: wherein each r13It independently is hydrogen, deuterium, methyl, ethyl, n-pro-pyl, isopropyl, 2,2,2- trifluoroethyls or fluoroform Base.
In some embodiments, the present invention relates to a kind of compound, it is as formula (i) (or formula (ia), formula (ib) or formula (ic) compound shown in) or the stereoisomer of compound shown in formula (i) (or formula (ia), formula (ib) or formula (ic)), geometry Isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable Salt or prodrug: wherein each r12It independently is hydrogen, deuterium, c1-4Alkyl, c2-6Thiazolinyl, c2-6Alkynyl or c1-4Haloalkyl.
In some embodiments, the present invention relates to a kind of compound, it is as formula (i) (or formula (ia), formula (ib) or formula (ic) compound shown in) or the stereoisomer of compound shown in formula (i) (or formula (ia), formula (ib) or formula (ic)), geometry Isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable Salt or prodrug: wherein each r12It independently is hydrogen, deuterium, methyl, n-pro-pyl, ethyl or isopropyl；
In some embodiments, the present invention relates to a kind of compound, it is as formula (i) (or formula (ia), formula (ib) or formula (ic) compound shown in) or the stereoisomer of compound shown in formula (i) (or formula (ia), formula (ib) or formula (ic)), geometry Isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable Salt or prodrug: wherein each r12aIt independently is hydrogen, deuterium, c1-4Alkyl, c2-6Thiazolinyl, c2-6Alkynyl or c1-4Haloalkyl.
In some embodiments, the present invention relates to a kind of compound, it is as formula (i) (or formula (ia), formula (ib) or formula (ic) compound shown in) or the stereoisomer of compound shown in formula (i) (or formula (ia), formula (ib) or formula (ic)), geometry Isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable Salt or prodrug: wherein each r12aIt independently is hydrogen, deuterium, methyl, n-pro-pyl, ethyl or isopropyl；
In some embodiments, the present invention relates to a kind of compound, it is as formula (i) (or formula (ia), formula (ib) or formula (ic) compound shown in) or the stereoisomer of compound shown in formula (i) (or formula (ia), formula (ib) or formula (ic)), geometry Isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable Salt or prodrug: wherein each r6cIt independently is hydrogen, deuterium, c1-4Alkyl, f, cl, br, i, cn, hydroxyl, nitro, amino, carboxyl or c1-4 Alkoxyl.
In some embodiments, the present invention relates to a kind of compound, it is as formula (i) (or formula (ia), formula (ib) or formula (ic) compound shown in) or the stereoisomer of compound shown in formula (i) (or formula (ia), formula (ib) or formula (ic)), geometry Isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable Salt or prodrug: wherein each r6cIt independently is hydrogen, deuterium, methoxyl group, f, cl, br, i, cn, hydroxyl, nitro, amino, methyl, positive third Base, ethyl or isopropyl.
In some embodiments, the present invention relates to a kind of compound, it is as formula (i) (or formula (ia), formula (ib) or formula (ic) compound shown in) or the stereoisomer of compound shown in formula (i) (or formula (ia), formula (ib) or formula (ic)), geometry Isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable Salt or prodrug: wherein each n independently is 0,1,2 or 3.
In some embodiments, the present invention relates to a kind of compound, it is as formula (i) (or formula (ia), formula (ib) or formula (ic) compound shown in) or the stereoisomer of compound shown in formula (i) (or formula (ia), formula (ib) or formula (ic)), geometry Isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable Salt or prodrug: wherein each n1 independently is 1,2,3 or 4.
In some embodiments, the present invention relates to a kind of compound, its be compound as shown in formula (i) (or formula (ia)) or The stereoisomer of compound shown in formula (i) (or formula (ia)), geometric isomer, tautomer, raceme, nitrogen oxides, Hydrate, solvate, metabolite and pharmaceutically acceptable salt or prodrug: wherein m is 0,1,2,3 or 4.
In some embodiments, the present invention relates to a kind of compound, it is as formula (i) (or formula (ia), formula (ib) or formula (ic) compound shown in) or the stereoisomer of compound shown in formula (i) (or formula (ia), formula (ib) or formula (ic)), geometry Isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable Salt or prodrug: wherein each p independently is 0,1 or 2
On the one hand, the present invention relates to a kind of compound, it is the compound as shown in formula (ii) or chemical combination shown in formula (ii) The stereoisomer of thing, geometric isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite And pharmaceutically acceptable salt or prodrug:
Wherein, w ring optionally further by 1,2,3 or 4 independently selected from fluorine, chlorine, bromine, c1-4Haloalkyl, nitro, Cyano group, ho- (cr3r4)m-, h- (cr3r4)m- o-, r-n (r5)-c (=o)-, r-c (=o)-n (r5)-, r-n (r5)-, r-c (= O)-, r-c (=o) o-, r-oc (=o)-, r-s (=o)2-, r-s (=o)-, r-s-, r-n (r5)-s (=o)2-, r-s (=o )2-n(r5)-, r-n (r5)-c (=o)-n (r6)-or the substituent group of r replaced；
r、r3、r4、r5、r6, m, w ring, r0、r00、l、z1、z2With n, there is implication as described in the present invention.
In some embodiments, the present invention relates to a kind of compound, it is the compound or formula (iia) as shown in formula (iia) The stereoisomer of shown compound, geometric isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, Metabolite and pharmaceutically acceptable salt or prodrug:
Wherein,Optionally further by 1,2,3 or 4 independently selected from fluorine, chlorine, bromine, c1-4Halo Alkyl, nitro, cyano group, ho- (cr3r4)m-, h- (cr3r4)m- o-, r-n (r5)-c (=o)-, r-c (=o)-n (r5)-, r-n (r5)-, r-c (=o)-, r-c (=o) o-, r-oc (=o)-, r-s (=o)2-, r-s (=o)-, r-s-, r-n (r5)-s (= o)2-, r-s (=o)2-n(r5)-, r-n (r5)-c (=o)-n (r6)-or the substituent group of r replaced；Represent singly-bound or double bond；
r、r3、r4、r5、r6、m、x、y、r1、r0、r00、l、z1、z2With n, there is implication as described in the present invention.
In some embodiments, the present invention relates to a kind of compound, it is the compound as shown in formula (ii) (or formula (iia)) Or the stereoisomer of compound shown in formula (ii) (or formula (iia)), geometric isomer, tautomer, raceme, nitrogen oxidation Thing, hydrate, solvate, metabolite and pharmaceutically acceptable salt or prodrug: wherein, z1And z2It is each independently n Or ch.
In some embodiments, the present invention relates to a kind of compound, it is the compound or formula (ii) institute as shown in formula (ii) Show the stereoisomer of compound, geometric isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, Metabolite and pharmaceutically acceptable salt or prodrug: wherein, the ring that w ring is as follows:W ring is appointed Selection of land further by 1,2,3 or 4 independently selected from fluorine, chlorine, bromine, c1-4Haloalkyl, nitro, cyano group, ho- (cr3r4)m-, h- (cr3r4)m- o-, r-n (r5)-c (=o)-, r-c (=o)-n (r5)-, r-n (r5)-, r-c (=o)-, r-c (=o) o-, r-oc (=o)-, r-s (=o)2-, r-s (=o)-, r-s-, r-n (r5)-s (=o)2-, r-s (=o)2-n(r5)-, r-n (r5)-c (= o)-n(r6)-or the substituent group of r replaced；Represent singly-bound or double bond；
Wherein r, r3、r4、r5、r6、m、x、y、r1、r0、r00、z1、z2With n, there is implication as described in the present invention.
In some embodiments, the present invention relates to a kind of compound, it is the compound as shown in formula (ii) (or formula (iia)) Or the stereoisomer of compound shown in formula (ii) (or formula (iia)), geometric isomer, tautomer, raceme, nitrogen oxidation Thing, hydrate, solvate, metabolite and pharmaceutically acceptable salt or prodrug: wherein, x is n, nraOr crb；Y is crc；
ra、rbAnd rcIt is each independently hydrogen or c1-4Alkyl；raAnd rcForm five yuan together with the annular atom being connected with them Or hexa-atomic heteroaryl；Or rbAnd rcForm five yuan or hexa-atomic heteroaryl together with the annular atom being connected with them；Described heteroaryl Base can be individually optionally by r2Replace；
Wherein r2There is implication as described in the present invention.
In some embodiments, the present invention relates to a kind of compound, it is the compound or formula (ii) institute as shown in formula (ii) Show the stereoisomer of compound, geometric isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, generation Thank product and pharmaceutically acceptable salt or prodrug: wherein, the subformula that w ring is as follows:
W ring optionally further by 1,2,3 or 4 independently selected from fluorine, chlorine, bromine, trifluoromethyl, 2,2- bis- fluoro ethyls, 3,3,3- trifluoro propyls, nitro, cyano group, ho- (cr3r4)m-, h- (cr3r4)m- o-, r-n (r5)-c (=o)-, r-c (=o)-n (r5)-, r-n (r5)-, r-c (=o)-, r-c (=o) o-, r-oc (=o)-, r-s (=o)2-, r-s (=o)-, r-s-, r-n (r5)-s (=o)2-, r-s (=o)2-n(r5)-, r-n (r5)-c (=o)-n (r6)-or the substituent group of r replaced；
Wherein r, r3、r4、r5、r6、m、r1And r2There is implication as described in the present invention.
In some embodiments, the present invention relates to a kind of compound, it is the compound as shown in formula (ii) (or formula (iia)) Or the stereoisomer of compound shown in formula (ii) (or formula (iia)), geometric isomer, tautomer, raceme, nitrogen oxidation Thing, hydrate, solvate, metabolite and pharmaceutically acceptable salt or prodrug: wherein, r1For h, deuterium, c1-4Alkyl, c2-6Thiazolinyl, c2-6Alkynyl or hydroxyl.
In some embodiments, the present invention relates to a kind of compound, it is the compound as shown in formula (ii) (or formula (iia)) Or the stereoisomer of compound shown in formula (ii) (or formula (iia)), geometric isomer, tautomer, raceme, nitrogen oxidation Thing, hydrate, solvate, metabolite and pharmaceutically acceptable salt or prodrug: wherein, r1For h, deuterium, methyl, second Base, isopropyl or n-pro-pyl.
In some embodiments, the present invention relates to a kind of compound, it is the compound as shown in formula (ii) (or formula (iia)) Or the stereoisomer of compound shown in formula (ii) (or formula (iia)), geometric isomer, tautomer, raceme, nitrogen oxygen Compound, hydrate, solvate, metabolite and pharmaceutically acceptable salt or prodrug: wherein, r2For h, deuterium, c1-4Alkane Base, c2-6Thiazolinyl, c2-6Alkynyl or hydroxyl.
In some embodiments, the present invention relates to a kind of compound, it is the compound as shown in formula (ii) (or formula (iia)) Or the stereoisomer of compound shown in formula (ii) (or formula (iia)), geometric isomer, tautomer, raceme, nitrogen oxidation Thing, hydrate, solvate, metabolite and pharmaceutically acceptable salt or prodrug: wherein, r2For h, deuterium, methyl, second Base, isopropyl or n-pro-pyl.
In some embodiments, the present invention relates to a kind of compound, it is the compound as shown in formula (ii) (or formula (iia)) Or the stereoisomer of compound shown in formula (ii) (or formula (iia)), geometric isomer, tautomer, raceme, nitrogen oxidation Thing, hydrate, solvate, metabolite and pharmaceutically acceptable salt or prodrug: wherein, r0For fluorine, chlorine, bromine, c1-4Halogen Substituted alkyl, nitro, cyano group, ho- (cr3r4)m-, h- (cr3r4)m- o-, r-n (r5)-c (=o)-, r-c (=o)-n (r5)-, r-n (r5)-, r-c (=o)-, r-c (=o) o-, r-oc (=o)-, r-s (=o)2-, r-s (=o)-, r-s-, r-n (r5)-s (= o)2-, r-s (=o)2-n(r5)-, r-n (r5)-c (=o)-n (r6)-or r；
Wherein r, r3、r4、r5、r6With m, there is implication as described in the present invention.
In some embodiments, the present invention relates to a kind of compound, it is the compound as shown in formula (ii) (or formula (iia)) Or the stereoisomer of compound shown in formula (ii) (or formula (iia)), geometric isomer, tautomer, raceme, nitrogen oxidation Thing, hydrate, solvate, metabolite and pharmaceutically acceptable salt or prodrug: wherein, r0For fluorine, chlorine, bromine, trifluoro Methyl, 2,2- bis- fluoro ethyls, 3,3,3- trifluoro propyls, nitro, cyano group, ho- (cr3r4)m-, h- (cr3r4)m- o-, r-n (r5)-c (=o)-, r-c (=o)-n (r5)-, r-n (r5)-, r-c (=o)-, r-c (=o) o-, r-oc (=o)-, r-s (=o)2-, r-s (=o)-, r-s-, r-n (r5)-s (=o)2-, r-s (=o)2-n(r5)-, r-n (r5)-c (=o)-n (r6)-or r；
Wherein r, r3、r4、r5、r6With m, there is implication as described in the present invention.
In some embodiments, the present invention relates to a kind of compound, it is the compound as shown in formula (ii) (or formula (iia)) Or the stereoisomer of compound shown in formula (ii) (or formula (iia)), geometric isomer, tautomer, raceme, nitrogen oxidation Thing, hydrate, solvate, metabolite and pharmaceutically acceptable salt or prodrug: wherein, r00For fluorine, chlorine, bromine, nitro, Cyano group, ho-, h-s-, h2N-c (=o)-, h-c (=o)-nh-, nh2-, h-c (=o)-, h-c (=o) o-, h-oc (=o)-, h- S (=o)4-, h-s (=o)-, h2N-s (=o)2-, h-s (=o)2- nh-, h2N-c (=o)-nh-, ch3O-, phenyl, c1-4Alkane Base, c2-6Thiazolinyl, c1-4Haloalkyl or c2-6Alkynyl.
In some embodiments, the present invention relates to a kind of compound, it is the compound as shown in formula (ii) (or formula (iia)) Or the stereoisomer of compound shown in formula (ii) (or formula (iia)), geometric isomer, tautomer, raceme, nitrogen oxidation Thing, hydrate, solvate, metabolite and pharmaceutically acceptable salt or prodrug: wherein, l is-nh-s (=o)2- or- nh-.
In some embodiments, the present invention relates to a kind of compound, it is the compound as shown in formula (ii) (or formula (iia)) Or the stereoisomer of compound shown in formula (ii) (or formula (iia)), geometric isomer, tautomer, raceme, nitrogen oxidation Thing, hydrate, solvate, metabolite and pharmaceutically acceptable salt or prodrug: wherein, each r independently is h, deuterium, c1-4Alkyl, c2-6Thiazolinyl, c1-4Haloalkyl or c2-6Alkynyl.
In some embodiments, the present invention relates to a kind of compound, it is the compound as shown in formula (ii) (or formula (iia)) Or the stereoisomer of compound shown in formula (ii) (or formula (iia)), geometric isomer, tautomer, raceme, nitrogen oxidation Thing, hydrate, solvate, metabolite and pharmaceutically acceptable salt or prodrug: wherein, each r independently is h, deuterium, three Methyl fluoride, 2,2- bis- fluoro ethyls, 3,3,3- trifluoro propyls, methyl, ethyl, isopropyl or n-pro-pyl.
In some embodiments, the present invention relates to a kind of compound, it is the compound as shown in formula (ii) (or formula (iia)) Or the stereoisomer of compound shown in formula (ii) (or formula (iia)), geometric isomer, tautomer, raceme, nitrogen oxidation Thing, hydrate, solvate, metabolite and pharmaceutically acceptable salt or prodrug: wherein, each r3It independently is h, deuterium, c1-4Alkyl, c2-6Thiazolinyl, c1-4Haloalkyl or c2-6Alkynyl.
In some embodiments, the present invention relates to a kind of compound, it is the compound as shown in formula (ii) (or formula (iia)) Or the stereoisomer of compound shown in formula (ii) (or formula (iia)), geometric isomer, tautomer, raceme, nitrogen oxidation Thing, hydrate, solvate, metabolite and pharmaceutically acceptable salt or prodrug: wherein, each r3It independently is h, deuterium, Trifluoromethyl, 2,2- bis- fluoro ethyls, 3,3,3- trifluoro propyls, methyl, ethyl, isopropyl or n-pro-pyl.
In some embodiments, the present invention relates to a kind of compound, it is the compound as shown in formula (ii) (or formula (iia)) Or the stereoisomer of compound shown in formula (ii) (or formula (iia)), geometric isomer, tautomer, raceme, nitrogen oxidation Thing, hydrate, solvate, metabolite and pharmaceutically acceptable salt or prodrug: wherein, each r4It independently is h, deuterium, c1-4Alkyl, c2-6Thiazolinyl, c1-4Haloalkyl or c2-6Alkynyl.
In some embodiments, the present invention relates to a kind of compound, it is the compound as shown in formula (ii) (or formula (iia)) Or the stereoisomer of compound shown in formula (ii) (or formula (iia)), geometric isomer, tautomer, raceme, nitrogen oxidation Thing, hydrate, solvate, metabolite and pharmaceutically acceptable salt or prodrug: wherein, each r4It independently is h, deuterium, Trifluoromethyl, 2,2- bis- fluoro ethyls, 3,3,3- trifluoro propyls, methyl, ethyl, isopropyl or n-pro-pyl.
In some embodiments, the present invention relates to a kind of compound, it is the compound as shown in formula (ii) (or formula (iia)) Or the stereoisomer of compound shown in formula (ii) (or formula (iia)), geometric isomer, tautomer, raceme, nitrogen oxidation Thing, hydrate, solvate, metabolite and pharmaceutically acceptable salt or prodrug: wherein, each r5It independently is h, deuterium, c1-4Alkyl, c2-6Thiazolinyl, c1-4Haloalkyl or c2-6Alkynyl.
In some embodiments, the present invention relates to a kind of compound, it is the compound as shown in formula (ii) (or formula (iia)) Or the stereoisomer of compound shown in formula (ii) (or formula (iia)), geometric isomer, tautomer, raceme, nitrogen oxidation Thing, hydrate, solvate, metabolite and pharmaceutically acceptable salt or prodrug: wherein, each r5It independently is h, deuterium, Trifluoromethyl, 2,2- bis- fluoro ethyls, 3,3,3- trifluoro propyls, methyl, ethyl, isopropyl or n-pro-pyl.
In some embodiments, the present invention relates to a kind of compound, it is the compound as shown in formula (ii) (or formula (iia)) Or the stereoisomer of compound shown in formula (ii) (or formula (iia)), geometric isomer, tautomer, raceme, nitrogen oxidation Thing, hydrate, solvate, metabolite and pharmaceutically acceptable salt or prodrug: wherein, each r6It independently is h, deuterium, c1-4Alkyl, c2-6Thiazolinyl, c1-4Haloalkyl or c2-6Alkynyl.
In some embodiments, the present invention relates to a kind of compound, it is the compound as shown in formula (ii) (or formula (iia)) Or the stereoisomer of compound shown in formula (ii) (or formula (iia)), geometric isomer, tautomer, raceme, nitrogen oxidation Thing, hydrate, solvate, metabolite and pharmaceutically acceptable salt or prodrug: wherein, each r6It independently is h, deuterium, Trifluoromethyl, 2,2- bis- fluoro ethyls, 3,3,3- trifluoro propyls, methyl, ethyl, isopropyl or n-pro-pyl.
In some embodiments, the present invention relates to a kind of compound, it is the compound as shown in formula (ii) (or formula (iia)) Or the stereoisomer of compound shown in formula (ii) (or formula (iia)), geometric isomer, tautomer, raceme, nitrogen oxidation Thing, hydrate, solvate, metabolite and pharmaceutically acceptable salt or prodrug: wherein, each n independently be 1,2,3 or 4.
In some embodiments, the present invention relates to a kind of compound, it is the compound as shown in formula (ii) (or formula (iia)) Or the stereoisomer of compound shown in formula (ii) (or formula (iia)), geometric isomer, tautomer, raceme, nitrogen oxidation Thing, hydrate, solvate, metabolite and pharmaceutically acceptable salt or prodrug: wherein, m is 0,1,2,3 or 4.
On the one hand, the present invention relates to a kind of compound, it is the compound or formula (iii) shownization as shown in formula (iii) The stereoisomer of compound, geometric isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolism is produced Thing and pharmaceutically acceptable salt or prodrug:
V ring isWherein " * " expression is connected with-nh- One end；
Q is 1,2,3 or 4；
P is 1,2,3 or 4；
r8For ho- (cr10r11)p-, h- (cr10r11)p- o-, r9-n(r12)-, r9- c (=o) o- or r9；
r12For h, deuterium, c1-6Alkyl, c2-6Thiazolinyl, c2-6Alkynyl or c1-4Haloalkyl；
Each r9、r11And r10It independently is h, deuterium, c1-6Alkyl, c2-6Thiazolinyl, c2-6Alkynyl, c1-4Haloalkyl or c1-4Alcoxyl Base.
In some embodiments, the present invention relates to a kind of compound, it is the compound or formula (iii) as shown in formula (iii) The stereoisomer of shown compound, geometric isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, Metabolite and pharmaceutically acceptable salt or prodrug: wherein, r12For h, deuterium, trifluoromethyl, 2,2- bis- fluoro ethyls, 3,3,3- Trifluoro propyl, methyl, ethyl, isopropyl or n-pro-pyl；
Each r9、r11And r10It independently is h, deuterium, methyl, ethyl, n-pro-pyl, isopropyl, the tert-butyl group, 2- methyl-propyl, three Methyl fluoride, methoxy or ethoxy.
A kind of compound, it is to have the compound of one of following structure or the solid with one of following structural compounds Isomer, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable Salt or prodrug:
One aspect of the present invention is related to pharmaceutical composition, comprises the compound of the present invention, or their stereoisomer, geometry Isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite, metabolic precursor thereof, pharmaceutically may be used The salt accepting or their prodrug, or optional pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or Combinations thereof.
Some of them embodiment is that pharmaceutical composition of the present invention further comprises additional therapeutic agent, and it is selected from Chemotherapeutics or antiproliferative, anti-inflammatory agent, immunomodulator or immunosuppressant, neurotrophic factor, for treating cardiovascular disease The activating agent of disease, for treating the activating agent of diabetes and the activating agent for treating autoimmune disease.
Another aspect of the present invention is directed to use with a kind of compound of the present invention or comprises the medicine group of the compound of the present invention Compound is preparing for preventing, processing or treat autologous patient immunological diseases or proliferative disease, and mitigates its order of severity The purposes of medicine.
Some of them embodiment is that autoimmune disease of the present invention is lupus, multiple sclerosiss, muscle contracting side Rope hardens, rheumatoid arthritiss, psoriasises, i patients with type Ⅰ DM, the complication leading to because of organ transplantation, and foreign body is transplanted, glycosuria Disease, cancer, asthma, atopic dermatitiss, autoimmune thyroid disease, ulcerative colitiss, Crohn disease, Alzheimer Disease, leukemia or lymphoma.
Some of them embodiment is that 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) Disease, glioblastoma, myeloproliferative disease, atherosclerosiss or pulmonary fibrosiss.
On the other hand, the present invention relates to the compounds of this invention or the pharmaceutical composition that comprises the compounds of this invention are preparing use Purposes in suppression or the medicine of regulatory protein kinase activity.
Some of them embodiment is that protein kinase is jak1, jak2, jak3, btk, egfr or egfrt790m.
On the one hand, the present invention relates to formula (i), formula (ia), formula (ib), formula (ic), formula (ii), formula (iia) or formula (iii) intermediate of the compound being comprised.
Another aspect of the present invention is related to formula (i), formula (ia), formula (ib), formula (ic), formula (ii), formula (iia) or formula (iii) The method of the preparation of the compound being comprised, separation and purification.
The present invention also comprises the compound of the present invention and its application of pharmaceutically acceptable salt, for producing medical product Treatment autoimmune disease or proliferative disease, described in the invention including those.
The present invention comprises pharmaceutical composition, and this pharmaceutical composition includes formula (i), formula (ia), formula (ib), formula (ic), formula (ii), formula (iia) or the compound representated by formula (iii) and at least one pharmaceutically acceptable carrier, adjuvant or diluent The effectively treatment consumption needed for combination.
The present invention equally comprises to treat autologous patient immunological diseases or proliferative disease, or the method sensitive to this disease, The method comprises using formula (i), formula (ia), formula (ib), formula (ic), formula (ii), formula (iia) or compound representated by formula (iii) Therapeutically effective amount patient is treated.
Unless other aspects show, all of stereoisomer of compound of the present invention, geometric isomer, tautomerism Body, raceme, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt and prodrug broadly fall into this Bright scope.
The compound of present invention description can have one or more stereocenters, and each center there may be r Or s configuration.The compound that the present invention provides includes the form of all diastereomers, enantiomer and epimer, And its suitable mixture.If necessary, stereoisomer can be obtained by methods known in the art, for example, pass through chirality Chromatograph post separation stereoisomer.
The salt of the compound of the present invention, is also included for preparation or purification formula (i), formula (ia), formula (ib), formula (ic), formula (ii), formula (iia) or the intermediate of compound shown in formula (iii) or formula (i), formula (ia), formula (ib), formula (ic), formula (ii), formula (iia) or the detached enantiomer of compound shown in formula (iii) salt, but be not necessarily pharmaceutically acceptable salt.
In addition, compound disclosed by the invention, including their salt it is also possible to their hydrate forms or comprise it The form of solvent (such as ethanol, dmso, etc.) obtains, for their crystallization.Compound disclosed by the invention can be with medicine On, acceptable solvent (inclusion water) inherently or passes through design forming solvate；Therefore, it is contemplated that including solvent Form that change and unsolvated.
Any structural formula that the present invention is given be also intended to expression these compounds not by the form of isotope enrichment and with The form of position element enrichment.The compound of isotope enrichment has the structure of the formula description that the present invention provides, except one or many Individual atom is replaced by the atom with selected atomic weight or mass number.The exemplary same position in the compounds of this invention can be introduced into Element includes hydrogen, carbon, nitrogen, oxygen, phosphorus, the isotope of sulfur, fluorine and chlorine, such 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 defined in the present invention of isotope enrichment, for example, its In there is radiosiotope, such as3H,14C and18Those compounds of f, or wherein there is non radioactive isotope, such as2H and13c.The compound of such isotope enrichment can be used for metabolism research and (uses14C), Reaction kinetics research are (using for example2H or3H), detection or imaging technique, as positron emission tomography (pet) or inclusion medicine or substrate tissue measure of spread SPECT (single photon emission computed tomography) (spect), or can be used in the radiotherapy of patient.18The compound of f enrichment to pet or It is especially desirable for spect research.The formula (i) of isotope enrichment, formula (ia), formula (ib), formula (ic), formula (ii), formula Or compound shown in formula (iii) can be by the enforcement in routine techniquess familiar to the person skilled in the art or the present invention (iia) Substitute originally used unmarked reagent using suitable isotope labeling reagent described by example and preparation process to prepare.
Additionally, higher isotope particularly deuterium is (i.e.,2H or replacement d) can provide some treatment advantages, and these advantages are Brought by metabolic stability is higher.For example, Half-life in vivo increases or volume requirements reduce or therapeutic index obtains improving band Come.It should be appreciated that the deuterium in the present invention is counted as formula (i), formula (ia), formula (ib), formula (ic), formula (ii), formula (iia) or formula (iii) substituent group of compound shown in.The dense of such higher isotope particularly deuterium can be defined with isotope enrichment factor Degree.Term " isotope enrichment factor " used in the present invention refer to specified isotopic isotope abundance and natural abundance it Between ratio.If the substituent group of the compounds of this invention is designated as deuterium, this compound has for each D-atom specified At least 3500 (at each specified D-atoms 52.5% deuterium mix), at least 4000 (60% deuterium mixes), at least 4500 (67.5% Deuterium mix), at least 5000 (75% deuterium mix), at least 5500 (82.5% deuterium mixes), at least 6000 (90% deuterium is mixed Enter), at least 6333.3 (95% deuterium mix), at least 6466.7 (97% deuterium mixes), at least 6600 (99% deuterium mixes) Or the isotope enrichment factor of at least 6633.3 (99.5% deuterium mixes).The pharmaceutically useful solvate of the present invention includes wherein tying Brilliant solvent can be the such as d that isotope replaces2O, acetone-d6、dmso-d6Those solvates.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects and other aspect Content is made more specific complete description below.
Detailed description of the invention book
Definition and general terms
Describe certain embodiments of the present invention in detail now, the example is by the structural formula enclosed and chemical formula explanation.This Invention intention covers all of replacement, modification and equivalent technical solutions, and they are included in as the present invention of claim definition In the range of.Those skilled in the art will appreciate that many and of the present invention similar or equivalent methods and material can be used in Put into practice the present invention.The present invention is not limited to method of the present invention and material.In the document being combined, patent and similar material One or more different from the application or conflicting in the case of (including but not limited to defined term, term application, institute The technology of description, etc.), it is defined by the application.
It will further be appreciated that some features of the present invention, it is clearly visible, carry out in multiple independent embodiments Description is but it is also possible to provide in combination in single embodiment.Conversely, the various features of the present invention, for brevity, Single embodiment is described but it is also possible to 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's It is generally understood that identical implication.All patents according to the present invention and public publication are integrally incorporated this by reference Bright.
Unless otherwise indicated it should apply following definition used in the present invention.For purposes of the present invention, chemical element With periodic table of elements cas version, and " Handbook of Chemistry and Physics ", the 75th edition, 1994 is consistent.Additionally, organic chemistry General Principle can Reference " organic chemistry ", thomas sorrell, university science books, sausalito: 1999, and " march's advanced organic chemistry " by michael b.smith and jerry Description in march, john wiley＆sons, new york:2007, entire contents are incorporated by reference into the present invention.
There are unless otherwise stated or in context obvious conflict, article " " used herein, " one (kind) " " described " is intended to including " at least one " or " one or more ".Therefore, these articles used herein refer to one or The article of more than one (being at least one) object.For example, " component " refers to one or more components it is possible to have more than one Component be taken into account in the embodiment of described embodiment using or use.
Term "comprising" is open language, that is, include the content specified by the present invention, but be not precluded from otherwise Content.
" stereoisomer " refers to there is identical chemical constitution, but the spatially different change of arrangement mode of atom or group Compound.Stereoisomer includes enantiomer, diastereomer, conformer (rotamer), geometric isomer (cis/trans) isomer, atropisomer, etc..
" chiral " be have with its mirror image can not overlapping property molecule；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 stereoisomerism of two or more chiral centres and its molecule not mirror image each other Body.Diastereomer has different physical propertys, such as fusing point, boiling point, spectral quality and reactivity.Diastereomer mixes Compound can be by high resolution analysises operation as electrophoresis and chromatograph, and such as hplc is separating.
Stereochemical definitions used in the present invention and rule typically follow s.p.parker, ed., mcgraw-hill dictionary of chemical terms(1984)mcgraw-hill book company,new york；and eliel,e.and wilen,s.,“stereochemistry of organic compounds”,john wiley&sons, inc.,newyork,1994.
Many organic compound are existed with optical active forms, and that is, they have makes the plane of linearly polarized light rotate Ability.When describing optically active compound, represent molecule with regard to one or more handss using prefix d and l or r and s The absolute configuration at property center.Prefix d and l or (+) and (-) are the symbols for linearly polarized light rotation caused by appointed compound, Wherein (-) or l represent that compound is left-handed.Prefix be (+) or the compound of d be dextrorotation.A kind of specific stereoisomerism Body is enantiomer, and the mixture of this isomer is referred to as enantiomeric mixture.The 50:50 mixture of enantiomer Referred to as racemic mixture or racemic modification, when chemical reaction or during there is no stereo selectivity or stereospecificity when, May occur in which this situation.
Any asymmetric atom (for example, carbon etc.) of the open compound of the present invention can be enriched with raceme or enantiomer Presented in, for example (r)-, (s)-or (r, s)-configuration exist.In certain embodiments, each asymmetric atom exists R ()-or (s)-configuration aspect has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake Amount, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomer Excessive.
According to the selection of starting material and method, the compounds of this invention can with one of possible isomer or they Mixture, the form of such as racemic modification and non-corresponding isomer mixture (this depends on the quantity of asymmetric carbon atom) deposits ?.Optically active (r)-or (s)-isomer using chiral synthon or chiral reagent preparation, or can be torn open using routine techniquess Point.If compound contains a double bond, substituent group may be e or z configuration；If containing dibasic cycloalkanes in compound Base, the substituent group of cycloalkyl may have cis or trans configuration；As the embodiment of the present invention 37 has taking advantage of a situation and instead of pyrrolidinyl Formula configuration.
Term " tautomer " or " tautomeric form " refer to that Tong Guo the mental retardation with different-energy builds (low Energy barrier) mutual inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can reach The chemical equilibrium of tautomer.For example, proton tautomer (proton tautomer) (also referred to as proton translocation change Isomer (prototropic tautomer)) include migrating, by proton, the mutual inversion of phases to carry out, such as keto-enol isomerization And imine-enamine isomerizations.Valence tautomerism body (valence tautomer) includes the restructuring by some bonding electronss Come the mutual inversion of phases to carry out.The instantiation of ketoenol tautomerization is pentane -2,4- diketone and 4- hydroxyl amyl- 3- alkene -2- ketone The change of tautomer.Another example tautomeric is phenol-keto tautomerism.One of phenol-keto tautomerism is concrete Example is pyridine -4- alcohol and the change of pyridine -4 (1h) -one tautomer.Unless otherwise noted, the institute of the compounds of this invention Tautomeric forms are had to be within the scope of the present invention.
As described in the invention, the compound of the present invention can optionally be replaced by one or more substituent groups, such as General formula compound above, or as special example inside embodiment, subclass, and the class compound that the present invention is comprised. Should be appreciated that " optionally substituted " this term and " substituted or non-substituted " this term can exchange use.In general, art Language is " substituted " to represent that one or more of given structure hydrogen atom is replaced by concrete substituent group.Unless other aspect tables Bright, an optional substituted radical can be replaced each commutable position in group.When in given structural formula not One or more substituent groups that only position can be selected from concrete group are replaced, then substituent group can identical or differently Replace in each position.Wherein said substituent group can be, but is not limited to, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitre Base, amino, carboxyl, alkyl, alkoxyl, aryloxy group, heteroaryl epoxide, heterocyclic radical epoxide, alkoxy aryl, heteroarylalkoxy Base, alkyl acyl, miscellaneous alkyl, cycloalkyl, cycloalkenyl group, cycloalkyl-alkyl, heterocyclic radical, cycloheteroalkylalkyl, heterocyclylacyl, virtue Base, aryl alkyl, fragrant amino, heteroaryl, heteroaryl alkyl, heteroaryl amino, amide groups, sulfonyl, amino-sulfonyl etc..
In addition, it is necessary to explanation, unless otherwise explicitly pointed out, the describing mode that adopted in the present invention " each ... independently be " and " ... be each independently " and " ... independently be " can be exchanged, and all should be interpreted broadly, it both may be used To refer in different groups, do not affect it is also possible to represent in phase mutually between expressed concrete option between same-sign In same group, do not affect mutually between expressed concrete option between same-sign.With r10As a example, structural formula " r13- (cr10r11)n1- s (=o)p-(cr10r11)n-n(r12)-" and structural formula " r13-(cr10r11)n-n(r12)-c (=o)- (cr10r11)n-(r12a) n- " r between the two10Concrete option unaffected from each other, meanwhile, in same chemical formula " r13- (cr10r11)n-n(r12)-c (=o)-(cr10r11)n-(r12a) n- " in, two r10Concrete option unaffected from each other.
In each several part of this specification, the substituent group of the open compound of the present invention is open according to radical species or scope.Special Do not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and scope.For example, term “c1-c6Alkyl " or " c1-6Alkyl " refers in particular to individually disclosed methyl, ethyl, c3Alkyl, c4Alkyl, c5Alkyl and c6Alkyl.
In each several part of the present invention, describe connect substituent.When this structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.For example, if this structure needs linking group and for this The Markush group definition of variable lists " alkyl " or " aryl ", then it should be understood that should " alkyl " or " aryl " represent respectively The alkylidene group connecting or arylene group.For example, " cn- (cr10r11)n1-c1-9Heterocyclic radical-c (=o)-n (r12)-", respectively By c1-9Heterocyclic radical is connected with the remainder of structural formula, when enumerating heterocyclic radical it is thus understood that " heterocyclic radical " represents connection Sub- heterocyclyl groups.Such as " cn- (cr again6r7)n-r0-(cr6r7)n-n(r9In)-", r0For cycloalkyl etc., cycloalkyl therein Etc. can be understood as cycloalkylene group etc..
Terminology used in the present invention " alkyl " or " alkyl group ", represent contain 1 to 10 carbon atom, the straight chain of saturation or Side chain univalent hydrocarbyl group, wherein, the substituent group institute that described alkyl group can optionally be described by one or more present invention Replace.Unless otherwise detailed instructions, alkyl group contains 1-6 carbon atom；In yet another embodiment, alkyl group contains 1- 4 carbon atoms；Also in one embodiment, alkyl group contains 1-3 carbon atom.The example of alkyl group comprises, but not It is limited to, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, 2- amyl group, 3- penta Base, 2- methyl -2- butyl, 3- methyl -2- butyl, 3- methyl isophthalic acid-butyl, n-hexyl, 2- hexyl, etc..
The example of term " thiazolinyl " group includes, but is not limited to, vinyl, pi-allyl, acrylic etc..
The example of term " alkynyl " group includes, but is not limited to, acetenyl (- c ≡ ch), propargyl (- ch2c≡ch)、 1- propinyl (- c ≡ c-ch3) etc..
Term " alkoxyl " represents that alkyl group is connected with molecule remainder by oxygen atom, and wherein alkyl group has Implication as described in the present invention.Unless otherwise detailed instructions, described alkoxy base contains 1-6 carbon atom；In another enforcement In scheme, 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 replaces.The example of alkoxy base Include, but is not limited to, methoxyl group, ethyoxyl, 1- propoxyl group, 2- propoxyl group, 1- butoxy, etc..
Term " haloalkyl ", represents that alkyl group is replaced by one or more halogen atoms, such example comprises, But it is not limited to ,-ch2F ,-chf2, trifluoromethyl ,-ch2Cl ,-chcl2,-ccl3,-ch2cf3,-ch2ch2cf3Deng.
Term " carbocylic radical " or " carbocyclic ring " represent containing 3-12 carbon atom, the saturation of unit price or multivalence or part insatiable hunger With monocyclic, bicyclic or three-ring system, wherein monocyclic, bicyclic or tricyclic in do not comprise aromatic rings.It is double that carbon bicyclic group includes spiral shell carbon Ring group and condense carbon bicyclic group, suitable carbocylic radical group includes, but is not limited to, cycloalkyl, cycloalkenyl group and cycloalkynyl radical.Carbocyclic ring The example of base group further includes, cyclopropyl, cyclobutyl, cyclopenta, 1- cyclopenta -1- thiazolinyl, 1- cyclopenta -2- thiazolinyl, 1- cyclopenta -3- thiazolinyl, cyclohexyl, 1- cyclohexyl -1- thiazolinyl, 1- cyclohexyl -2- thiazolinyl, 1- cyclohexyl -3- thiazolinyl, hexamethylene two Thiazolinyl, suberyl, cyclooctyl, cyclononyl, etc..
Term " cycloalkyl " represents that, containing 3-12 carbon atom, the saturation of unit price or multivalence is monocyclic, bicyclic or three ring bodies System, wherein monocyclic, bicyclic or tricyclic in do not comprise aromatic rings.In one embodiment, cycloalkyl comprises 3-9 carbon atom；? In another embodiment, cycloalkyl comprises 3-6 carbon atom.Described group of naphthene base can be independently unsubstituted or by one Or multiple substituent group described in the invention is replaced.Such example includes, but is not limited to, cyclopropyl, cyclobutyl, ring penta Base, cyclohexyl, suberyl, cyclooctyl, cyclononyl, cyclodecyl, ring undecyl, cyclo-dodecyl, etc..
The example of term " cycloalkenyl group " includes, but is not limited to, cyclobutane base, cyclopentenyl, cyclopentadienyl group, cyclohexene Base, cyclohexadienyl, cycloheptenyl, cyclo-octene base, cyclonoene base and cyclodecene base, etc..
Term " heterocyclic radical " and " heterocycle " are used interchangeably herein, all referring to the saturation comprising 3-12 annular atom or portion Point undersaturated monocyclic, bicyclic or tricyclic, wherein monocyclic, bicyclic or tricyclic in do not comprise aromatic rings, and at least one annular atom Selected from nitrogen, sulfur and oxygen atom.Unless otherwise indicated, heterocyclic radical can be carbon-based or nitrilo, and-ch2- group can be optionally By-c (=o)-replacement.The sulphur atom of ring can optionally be oxidized to s- oxide.The nitrogen-atoms of ring can be optionally by oxygen Chemical conversion n- oxygen compound.- ch in heterocyclic radical2- group is included, but not limited to 2- oxo pyrroles by the example of-c (=o)-replacement Alkyl, oxo -1,3-thiazoles alkyl, 2- piperidone base, 3,5- dioxy piperazine piperidinyls.The oxidized example of sulphur atom in heterocyclic radical Include, but not limited to sulfolane base, 1,1- dioxothiomorpholinyl.
In one embodiment, heterocyclic radical is 4-7 former molecular heterocyclic radical, refers to comprise the full of 4-7 annular atom And/or partly undersaturated monocyclic, wherein at least one annular atom is selected from nitrogen, sulfur and oxygen atom.Example includes, but are not limited to: nitrogen Heterocycle butyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, 2- pyrrolinyl, 3- pyrrolinyl, pyrazolidinyl, imidazoline Base, imidazolidinyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, 1,3- dioxy cyclopenta, two sulfur rings Amyl group, THP trtrahydropyranyl, dihydro pyranyl, 2h- pyranose, 4h- pyranose, tetrahydro thiapyran base, piperidyl, tetrahydro pyridyl, Morpholinyl, thio-morpholinyl, piperazinyl, dialkyl group, dithiane base, thiophene alkyl, homopiperazine base, homopiperidinyl, oxa- ring Heptane base, thia cycloheptyl alkyl.- ch in heterocyclic radical2- group is included, but not limited to 2- oxo by the example of-c (=o)-replacement Pyrrolidinyl, oxo -1,3-thiazoles alkyl, 2- piperidone base, 3,5- dioxy piperazine piperidinyls.In heterocyclic radical, sulphur atom is oxidized Example includes, but not limited to sulfolane base, 1,1- dioxothiomorpholinyl.4-7 described former molecular heterocyclic radical base Group can optionally be replaced by one or more substituent groups described in the invention.In another embodiment, heterocyclic radical is 4 Individual former molecular heterocyclic radical, example includes, but are not limited to: azelidinyl, oxetanylmethoxy, thietanyl.Another In embodiment, heterocyclic radical is 5 former molecular heterocyclic radicals, and example includes, but are not limited to: pyrrolidinyl, 2- pyrrolinyl, 3- pyrrolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro thiophene Fen base, 1,3- dioxy cyclopenta, two sulfur cyclopenta, 2- oxo-pyrrolidine base, oxo -1,3-thiazoles alkyl, sulfolane base.Another In one embodiment, heterocyclic radical is 6 former molecular heterocyclic radicals, and example includes, but are not limited to: THP trtrahydropyranyl, dihydro pyrrole Mutter base, 2h- pyranose, 4h- pyranose, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, dialkyl group, Dithiane base, thiophene alkyl, 2- piperidone base, 3,5- dioxy piperazine piperidinyls, 1,1- dioxothiomorpholinyl.Described 6 Former molecular heterocyclyl groups can optionally be replaced by one or more substituent groups described in the invention.
Term " condensed-bicyclic " and " condensed-bicyclic base " are used interchangeably herein, refer to saturation or the portion of unit price or multivalence Divide undersaturated bridged-ring system, described bridged-ring system refers to bicyclic system.Term " bridged ring " refers to that any two ring shares two The atom being joined directly together or not being joined directly together.Example includes, but is not limited to, hexahydro furyl simultaneously [3,2-b] furan, and 2,3,3a, 4,7,7a- hexahydro -1h- indenes, 7- azabicyclo [2.2.1] heptane, condensed-bicyclic [3.3.0] octane, condensed-bicyclic [3.1.0] is own Alkane, 1,2,3,4,4a, 5,8,8a- octahydro naphthalenes.
Term " condensing miscellaneous bicyclic " expression saturation or partly undersaturated fused ring system, and at least one member ring systems comprises one Individual or multiple hetero atoms, each of which member ring systems comprise 3-7 yuan of rings, that is, comprise 1-6 carbon atom and be selected from n, the 1- of o, p, s 3 hetero atoms, are optionally replaced by one or more oxygen atoms in this s or p and obtain as so, so2, po, po2Group, so Example include, but is not limited to hexahydro furyl simultaneously [3,2-b] furan, 7- azabicyclo [2.2.1] heptane, 3- azabicyclo [3.3.0] octane, 3,5,8- trioxa-l-phosphabicyclos [5,1,0] octane, 1- azepine -4,6- dioxy-bicyclo [3.3.0] octane etc., and It is described that to condense miscellaneous bicyclic group can be substituted or non-substituted.
Term " spiral shell bicyclic group " or " spiral shell is bicyclic " are used interchangeably herein, refer to the saturation of unit price or multivalence or part not Saturated ring system, one of ring originates from specific ring carbon atom on another ring.Each ring in spiral shell bicyclic group can It is carbocylic radical or heterocyclic radical, and each ring is optionally replaced by one or more substituent groups described in the invention.
Term " the miscellaneous bicyclic group of spiral shell " represents that a ring originates from particularly ring-shaped carbon on another ring, and at least one ring body System comprises one or more hetero atoms, and each of which member ring systems comprise 3-7 yuan of rings, that is, comprise 1-6 carbon atom and be selected from n, The 1-3 hetero atom of o, p, s, is optionally replaced by one or more oxygen atoms in this s or p and obtains such as so, so2, po, po2 Group, such example includes, but is not limited to 4- azaspiro [2.4] heptane -5- base, 4- oxaspiro [2.4] heptane -5- Base, 5- azaspiro [2.4] heptane -5- base, 7- hydroxyl -5- azaspiro [2.4] heptane -5- base etc..
Term " hetero atom " refers to o, s, n, p and si, including the form of any oxidation state of n, s and p；Primary, secondary, tertiary amine and season The form of ammonium salt；Or the form that the hydrogen on nitrogen-atoms in heterocycle is substituted, for example, n is (as in 3,4- dihydro -2h- pyrrole radicals N), nh (nh as in pyrrolidinyl) or nr (nr as in the pyrrolidinyl that n- replaces).
Term " halogen " refers to fluorine (f), chlorine (cl), bromine (br) or iodine (i).
Term " aryl " represents and contains 6-14 annular atom, or 6-12 annular atom, or 6-10 annular atom is monocyclic, double Ring and the carbocyclic ring system of three rings, wherein, at least one member ring systems is aromatic, and it is individual former that each of which member ring systems comprise 3-7 Molecular ring, and have one or more attachment points to be connected with the remainder of molecule.Term " aryl " can be with term " fragrance Ring " exchanges and uses.The example of aromatic yl group can include phenyl, indenyl, naphthyl and anthryl.
Term " heteroaryl " represent contain 5-12 annular atom, or 5-10 annular atom, or 5-6 annular atom monocyclic, Bicyclic and three-ring system, wherein at least one member ring systems are aromatic, and at least one member ring systems comprise one or more miscellaneous Atom, each of which member ring systems comprise 5-7 former molecular ring, and have one or more attachment points and molecule remainder It is connected.Term " heteroaryl " can be exchanged with term " hetero-aromatic ring " or " heteroaromaticss " and use.Described heteroaryl groups are appointed Selection of land is replaced by one or more substituent groups described in the invention.In one embodiment, 5-10 is individual former molecular miscellaneous Aryl comprises 1,2,3 or 4 and is independently selected from o, the hetero atom of s and n.The example of heteroaryl groups includes, but is not limited to, 2- furan Mutter base, 3- furyl, n- imidazole radicals, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyl, 4- isoxazolyl, 5- is different Oxazolyl, 2- oxazolyl, 4- oxazolyl, 5- oxazolyl, n- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals, 2- pyridine radicals, 3- pyridine Base, 4- pyridine radicals, 2- pyrimidine radicals, 4- pyrimidine radicals, 5- pyrimidine radicals, pyridazinyl (as 3- pyridazinyl), 2- thiazolyl, 4- thiazolyl, 5- thiazolyl, tetrazole radical (as 5- tetrazole radical), triazolyl (as 2- triazolyl and 5- triazolyl), 2- thienyl, 3- thienyl, pyrrole Oxazolyl (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-triazines Base, pyrimidine ketone group, pyriconyl；Also include following bicyclic, but it is bicyclic to be not limited to these: benzimidazolyl, benzofuran Base, benzo tetrahydrofuran base, benzothienyl, indyl (as 2- indyl), purine radicals, quinolyl (such as 2- quinolyl, 3- quinoline Quinoline base, 4- quinolyl), tetrahydric quinoline group (such as 1,2,3,4- tetrahydric quinoline groups), isoquinolyl is (as 1- isoquinolyl, 3- isoquinoline Quinoline base or 4- isoquinolyl), tetrahydro isoquinolyl (such as 1,2,3,4- tetrahydro isoquinolyls), imidazo [1,2-a] pyridine radicals, pyrrole Azoles simultaneously [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..
In one embodiment, heteroaryl groups are following subformula:
Etc..
No matter term " carboxyl ", be single use or be used in conjunction with other terms, such as " carboxyalkyl ", expression-co2h.
As described in the present invention, substituent group r is bonded, by one, the member ring systems formed on the ring at the center of being connected to and represents substituent group r Can any on ring may replace or any rational position is replaced.For example, formula a represents any possible quilt on d ring and b ring The position replacing all can be replaced by r, such as formula b, formula c, formula d, formula e, and formula f, shown in formula g and formula h.
As described in the present invention, substituent group (r)nBy one, the member ring systems formed are bonded on the ring at the center of being connected to and represent n Substituent group r can be replaced any commutable position on ring.For example, formula i represents and any on d ring and b ring may be taken The position in generation all can be replaced by n r.
As described in the invention, ring c there are two junction points can be connected with molecule remainder, for example, as formula j institute Show, represent both can be e " end can also be e ' end be connected with the remainder of molecule, that is, the connected mode at two ends can be exchanged.
As described in the present invention, attachment point can be connected with molecule remainder any attachable position on ring.Example As formula k represents any position that may be connected on ring all can be used as the point connecting.
As described in the present invention, attachment point can be connected with molecule remainder any attachable position on ring, with When the two ends that connect can exchange.For example, formula m represent any position that may be connected on ring all can as the point connecting, with When junction point two ends can exchange.
When term " blocking group " or " pg " refer to a substituent group and other reacted with functional groups, it is commonly used to hinder Feature disconnected or that protection is special.For example, " blocking group of amino " refers to that a substituent group is connected to block with amino group Or in protection compound amino feature, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (boc, boc), benzyloxycarbonyl group (cbz, cbz) and 9-fluorenylmethyloxycarbonyl (fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl Substituent group be used for blocking or protecting the feature of hydroxyl, suitable blocking group includes acetyl group and silicyl." carboxyl is protected Shield group " refers to the substituent group of carboxyl for blocking or protecting the feature of carboxyl, general carboxyl-protecting group includes- ch2ch2so2Ph, cyano ethyl, 2- (TMS) ethyl, 2- (TMS) ethoxyl methyl, 2- is (to toluene Sulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro-ethyl, etc..For protection The general description of group refers to document: t w.greene, protective groups in organic synthesis, john wiley&sons,new york,1991；and p.j.kocienski,protecting groups,thieme, stuttgart,2005.
Term " prodrug " used in the present invention, represents a compound and is converted into formula (i), formula (ia), formula in vivo (ib), formula (ic), formula (ii), formula (iia) or the compound shown in formula (iii).Such conversion is by prodrug in blood Hydrolysis or in blood or tissue through enzymatic conversion for precursor structure impact.Pro-drug compounds of the present invention can be ester, In existing invention, ester can be used as the phenyl ester class that have of prodrug, aliphatic (c1-24) esters, pivaloyloxymethyl esters, carbon Acid esters, carbamatess and amino acid esters.A such as compound in the present invention comprises hydroxyl, you can be acylated Obtain the compound of prodrug form.Other prodrug form include phosphate ester, and such as these phosphate compounds are Obtain through the di on parent.May be referred to documents below with regard to the complete discussion of prodrug: t.higuchi and v.stella,pro-drugs as novel delivery systems,vol.14of the a.c.s.symposium series,edward b.roche,ed.,bioreversible carriers in drug design,american pharmaceutical association and pergamon press,1987,j.rautio et al.,prodrugs: design and clinical applications,nature review drug discovery,2008,7,255-270, and s.j.hecker et al.,prodrugs of phosphates and phosphonates,journal of medicinal chemistry,2008,51,2328-2345.
" metabolite " refers to specific compound or its salt in vivo by the product obtained by metabolism.One change The metabolite of compound can be identified by technology known to art, and its activity can be retouched by such as the present invention Adopt as stating and experimentally characterized.Such product can be by being administered compound through peroxidating, reducing, water Solution, amidated, desamido- acts on, esterification, degreasing, and enzymatic lysises etc. method obtains.Correspondingly, the present invention includes compound Metabolite, be 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 the organic salt of compound and the inorganic salt of the present invention.Medicine On, acceptable salt is known to us in art, such as document: s.m.berge et al., describe pharmaceutically acceptable salts in detail in j.pharmaceutical sciences, 1977,66:1-19. it is described.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochlorate, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by described on books document Additive method such as ion exchange obtaining these salt.Other pharmaceutically acceptable salts include adipate, alginate, resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, Camphora hydrochlorate, Camphora sulphur Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonic acid Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2- naphthalene sulphur Hydrochlorate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, bitterness Hydrochlorate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through The salt that suitable alkali obtains includes alkali metal, alkaline-earth metal, ammonium and n+(c1-4Alkyl)4Salt.The present invention is also intended to contemplate any The quaternary ammonium salt that the compound of the group of comprised n is formed.Water solublity or oil-soluble or dispersion product can be turned into by quaternary ammonium With obtaining.Alkali metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further includes to fit When, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halogenide, hydroxide, carboxylate, sulphuric acid Compound, phosphoric acid compound, nitric acid compound, c1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention refers to the association that the compound of one or more solvent molecules and the present invention is formed Thing.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.
" inflammatory diseasess " used in the present invention refer to the excessive inflammation being led to by inflammatory responses excessive or out of control Property symptom, host tissue infringement or function of organization any disease of losing, disorderly or symptom." inflammatory diseasess " also refer to by leukocyte Inflow and/or the pathologic state of Neutrophil chemotaxis mediation.
" inflammation " used in the present invention refers to by tissue damaged or destroys the topical protective response causing, it is used for brokenly Bad, dilute or separate (isolation) be harmful to material and impaired tissue.Inflammation flows into leukocyte and/or neutrophil cell becomes The property changed has significant contact.Inflammation can result from pathogenic organism and viral infection and non-infectious mode, the such as heart Wound after muscle infarction or apoplexy or Reperfu- sion, the immunne response to exotic antigen and autoimmune response.Therefore, it can with this The inflammatory diseasess of disclosure of the invention compounds for treating include: react with specificity system of defense and non-specific defense system reacts Related disease.
" autoimmune disease " used in the present invention or " autoimmune disease " refers to and body fluid or cell-mediated The set of any disease of the tissue injury related to body itself component response.The example of autoimmune disease includes lupus, Multiple sclerosiss, muscle contracting lateral sclerosis, rheumatoid arthritiss, psoriasises, i patients with type Ⅰ DM, because organ transplantation leads to Complication, foreign body is transplanted, diabetes, cancer, asthma, atopic dermatitiss, autoimmune thyroid disease, ulcerative colitiss, Crohn disease, Alzheimer, leukemia and lymphoma.
" arthritis disease " refers to be attributable to various etiologic etiological arthritis and damage to be as used in the present invention Any disease of feature." dermatitis " refers to be characterized to be attributable to various etiologic etiological scytitiss as used in the present invention The extended familys of dermatosis in any one." transplant rejection " refers to transplanting or surrounding tissue as used in the present invention Function forfeiture, the antagonism transplanting tissue that is characterized of pain, swelling, leukocytosiss and thrombocytopenia, such as organ or cell Any immunoreation of (as bone marrow).The Therapeutic Method of the present invention is included for treating the disease related to inflammatory cell activation Method.
Term " cancer " and " cancer " are referred to or describe the physiology being generally characterized with cell growth out of control in patient Disease." tumor " comprises one or more cancerous cell.The example of cancer includes but is not limited to cancer (carcinoma), lymphoma, embryo Glucagonoma, sarcoma and leukemia, or malignant lymph proliferative disease (lymphoid malignancies).Such cancer is more Specific example includes squamous cell carcinoma (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 (hepatocellular cancer), gastric cancer (gastric Or stomach cancer) (inclusion human primary gastrointestinal cancers), cancer of pancreas, glioblastoma, cervical cancer, ovarian cancer, hepatocarcinoma (liver Cancer), bladder cancer, hepatoma (hepatoma), breast carcinoma, colon and rectum carcinoma, colorectal cancer, carcinoma of endometrium or Uterus carcinoma, salivary-gland carcinoma, renal carcinoma or renal cancer (kidney or renal cancer), carcinoma of prostate, carcinoma vulvae, thyroid Cancer, liver cancer (hepatic carcinoma), anus cancer, carcinoma of penis and head and neck cancer.
In addition, compound disclosed by the invention, including their salt it is also possible to their hydrate forms or comprise it The form of solvent (such as ethanol, dmso, etc.) obtains, for their crystallization.The open compound of the present invention can be with pharmacy Upper acceptable solvent (inclusion water) inherently or passes through design forming solvate；Therefore, it is contemplated that including solvation And unsolvated form.
Any structural formula that the present invention is given be also intended to expression these compounds not by the form of isotope enrichment and with The form of position element enrichment.The compound of isotope enrichment has the structure of the formula description that the present invention provides, except one or many Individual atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes in the compounds of this invention can be introduced into Including the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H,3H,11C,13C,14C,15N,17O,18O,18F,31P,32P,35S,36Cl and125i.
The pharmaceutical composition of the compounds of this invention, preparation and administration
The present invention provides a kind of pharmaceutical composition, and it comprises the open compound of the present invention and pharmaceutically acceptable figuration Agent, carrier, adjuvant, solvent or combinations thereof.In pharmaceutical composition disclosed by the invention, the amount of compound refers to effectively to examine Measure the amount of suppression biological specimen or protein kinase in the patient.
It will also be appreciated that some compounds of the present invention can exist for treating in a free form, or if suitably Can be presented in its pharmaceutically acceptable derivates.Some nonrestrictive enforcements of pharmaceutically acceptable derivant Scheme includes pharmaceutically acceptable prodrug, salt, ester, the salt of these esters, or when patient in need is administered can directly or Any other adduct of offer compound of the present invention or its metabolite or residue or derivant indirectly.
Drug pharmaceutical compositions disclosed by the invention can be prepared and be packaged as (bulk) in bulk form, wherein can extract safety The compound of the present invention of effective dose, then gives patient with powder or syrup form.Or, medicine group disclosed by the invention Unit dosage forms can be prepared and be packaged as to compound, and wherein each physically discrete unit contains the of the present invention of safe and effective amount Compound.When being prepared with unit dosage forms, pharmaceutical composition disclosed by the invention generally can contain, for example, 0.5mg to 1g or The compound disclosed by the invention of 1mg to 700mg or 5mg to 100mg.
The present invention " pharmaceutically acceptable excipient " used means related to form of administration or pharmaceutical composition concordance Pharmaceutically acceptable material, mixture or solvent.Every kind of excipient must be become with other of pharmaceutical composition in mixing Split-phase is held, can substantially reduce the present invention openly interaction of effect of compound and leading to not when avoiding patient be administered It is the interaction of pharmaceutically acceptable pharmaceutical composition.Additionally, every kind of excipient must be pharmaceutically acceptable, example As having sufficiently high purity.
Suitably 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, rectify Taste agent, odor mask, coloring agent, anticaking agent, wetting agent, chelating agen, plasticiser, viscosifier, antioxidant, preservative, stable Agent, surfactant and buffer agent.Technical staff can be appreciated that, some pharmaceutically acceptable excipient can provide more than one Function, and provide alternative function, this depends on existing in preparation has those other in how many this excipient and preparation Excipient.
Exemplary pharmaceutically acceptable carrier or its component are saccharides, such as Lactose, dextrose and saccharose；Starch, example As corn starch and potato starch；Cellulose and its derivates, such as sodium carboxymethyl cellulose, ethyl cellulose and Methyl cellulose Element；Powdered tragacanth；Fructus Hordei Germinatus；Gelatin；Talcum；Kollag, such as stearic acid and magnesium stearate；Calcium sulfate；Artificial oil；Plant Thing oil, such as Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, Oleum sesami, olive oil and Semen Maydis oil；Polyhydric alcohol, such as propylene glycol, glycerol, Sorbitol, manna Alcohol and Polyethylene Glycol；Alginic acid；Phosphate buffered solution；Emulsifying agent, such as Tweenses；Wetting agent, such as sodium lauryl sulphate； Coloring agent；Flavoring agent；Tablet agent；Stabilizer；Antioxidant；Preservative；Apirogen water；Isotonic saline solution；Molten with phosphate-buffered Liquid.
Compound disclosed in this invention can also be combined with the soluble polymer as target medicine carrier.Such Polymer includes Polyvinylpyrrolidone, pyran co-polymer, poly- hydroxypropyhnethacrylamide-phenol, poly-hydroxyethyl Radix Asparagi acyl Amine phenol or the oxide polylysine of palmitoyl residues replacement.Additionally, compound disclosed in this invention can with reality Used in the control release of existing medicine, a class Biodegradable polymeric combines, for example, polylactic acid, poly-epsilon-caprolactone, poly- Hydroxybutyric acid, poe, polyacetals, the crosslinking of poly- dihydropyran, polybutylcyanoacrylate and hydrogel or amphiphilic block are altogether Polymers.
The pharmaceutical composition that the present invention provides can be common with the other active component without compromising on expected therapeutical effect Prepare, or the material co-formulation with supplementary expected effect.
Suitably include, but are not limited to containing transporter: water, saline, normal saline or phosphate buffered saline (PBS) (pbs), Sodium chloride injection, ringers injection, isotonic Glucose Injection, Sterile Water Injection, glucose and Lactated Ringers injection.Non- transporter includes, but not limited to the fixed oil of plant origin, Oleum Ricini, Semen Maydis oil, Semen Gossypii The middle chain of oil, olive oil, Oleum Arachidis hypogaeae semen, Oleum menthae, safflower oil, Oleum sesami, Oleum Glycines, hydrogenated vegetable oil, hydrogenated soybean oil and Oleum Cocois Triglyceride and palm seed oil.Water miscibility carrier includes, but not limited to ethanol, 1,3 butylene glycol, the poly- second of liquid two Alcohol (such as Liquid Macrogol and PEG400), propylene glycol, glycerol, n- N-methyl-2-2-pyrrolidone N, n, n- dimethylacetamide Amine and dimethyl sulfoxide.
Suitable antimicrobial or preservative include, but not limited to phenol, cresol, mercurial, benzyl alcohol, chlorobutanol, Methyl parahydroxybenzoate and propyl p-hydroxybenzoate, thimerosal, benzalkonium chloride (such as benzethonium chloride), methyl hydroxybenzoate and Propylparaben and sorbic acid.Suitable isotonic agent includes, but not limited to sodium chloride, glycerol and glucose.Suitable buffer agent Include, but not limited to phosphate and citrate.Suitable antioxidant is as present invention description, including sulfurous acid Hydrogen salt and sodium metabisulfite.Suitable local anesthetic includes, but are not limited to procaine hydrochloride.Suitable suspending agent and point Powder is as present invention description, including sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidine Ketone.Suitable emulsifying agent includes those of present invention description, including polyoxyethylene sorbitan monolaurate.Polyoxyethylene Arlacel-80 80 and triethanolamine oleate ester.Suitable sequestering agent or chelating agen include, but are not limited to edta.Suitable ph regulator includes, but are not limited to sodium hydroxide, hydrochloric acid, citric acid and lactic acid.Suitable chelating agent includes, But it is not limited to cyclodextrin, including alpha-cyclodextrin, beta-schardinger dextrin-, HP-β-CD, Sulfobutylether-beta-schardinger dextrin-and sulphur Base butyl ether 7- beta-schardinger dextrin-(cydex,lenexa,ks).
The pharmaceutical composition that the present invention provides can be configured to single dose or multiple dose administration.Described single-dose preparations are wrapped It is contained in ampulla, bottle or syringe.Described multiple dose parenteral administration must comprise the anti-micro- of antibacterial or fungistatic concentrations Biological agent.All of parenteral administration must be all aseptic, as known in the art with practice.
Purposes
The present invention is provided and is swashed by jak using compound disclosed in this invention and medicine composite for curing, prevention or improvement Enzyme includes jak1, jak2, jak3 or tyk2 kinases behavior mediation or the disease otherwise affecting or disorder or is swashed by jak Enzyme includes jak1, jak2, jak3 or tyk2 kinases behavior mediation or one kind or many of the disease otherwise affecting or disorder The method planting symptom.
Jak kinases can be wild type and/or the mutation of jak1, jak2, jak3 or tyk2 kinases.
In one embodiment, the present invention provides class compound disclosed in this invention or comprises presently disclosedization The pharmaceutical composition of compound, for treating, preventing or improve by unsuitable jak1 kinases behavior mediation or otherwise shadow The disease rung or the disorderly or disease that affects by unsuitable jak1 kinases behavior mediation or otherwise or the one of disorder Plant or multiple symptom.
In another embodiment, one or more symptom of described disease, disorder or disease or disorder with inappropriate Jak2 kinases behavior related.
Also in one embodiment, one or more symptom of described disease, disorder or disease or disorder with inappropriate Jak3 kinases behavior related.
" unsuitable jak kinases behavior " refers to occur the jak deviateing normal jak kinases behavior with particular patient to swash Enzyme behavior.Unsuitable jak kinases behavior can show as the such as abnormal growth of activity or jak kinases time of the act point Form with the deviation in control.This unsuitable kinases behavior comes from, for example, the overexpression of protein kinase or mutation and The inappropriate or uncontrolled behavior leading to.Therefore, the present invention provides and treats these diseases and disorderly method.
Consistent with above description, such disease or disorder include but is not limited to: myeloproliferative diseases, for example very Property erythrocytosiss (pcv), essential thrombocythemia, idiopathic myelofibrosis (imf)；Leukemia, such as medullary system Leukemia includes chronic myelogenous leukemia (cml), the cml form of resistance to imatinib, acute myeloid leukemia (aml) and aml's Hypotype, acute megakaryoblastic leukemia (amkl)；Lymphoproliferative disease, such as myeloma；Cancer includes incidence cancer, front Row adenocarcinoma breast carcinoma, ovarian cancer, melanoma, pulmonary carcinoma, the cerebral tumor, cancer of pancreas and renal carcinoma；And with immunologic function disorder, immunodeficiency, The relevant diseases associated with inflammation of immunomodulating or disorder, autoimmune disease, tissue transplantation rejection, graft versus host disease, wound Mouth healing, nephropathy, multiple sclerosiss, thyroiditiss, i patients with type Ⅰ DM, sarcoidosises, psoriasises, allergic rhinitis, inflammatory bowel Close including Crohn disease and ulcerative colitiss (uc), systemic lupus erythematosus (sle) (sle), arthritis, osteoarthritis, rheumatoid Section inflammation, osteoporosis, asthma and chronic obstructive pulmonary disease (copd) and dry eye syndrome (or keratoconjunctivitis sicca (kcs)).
On the one hand, the present invention provides class compound disclosed in this invention or the medicine comprising presently disclosed compound Compositions, for preventing and/or treating the proliferative disease of mammal (include the mankind), autoimmune disease, anaphylaxis Disease, inflammatory diseasess or transplant rejection.
On the other hand, the present invention provides a kind for the treatment of to suffer from or the risky mammal suffering from disease disclosed herein Method, methods described includes giving effectively treatment disease amount or effective one or more medicine disclosed herein preventing disease amount Compositions or compound.On the other hand, provided herein is a kind for the treatment of is suffered from or risky suffered from proliferative disease, autologous exempts from Epidemic disease, the method for the mammal of anaphylactic disease, inflammatory diseasess or transplant rejection.
In a kind of method in terms for the treatment of, the present invention provides treatment and/or prevention to be susceptible or suffering from proliferative disease The method of mammal, methods described include giving effectively treatment amount or one or more of effective preventive dose disclosed herein Pharmaceutical composition or compound.In particular instances, proliferative disease is selected from cancer (for example, solid tumor such as uterine smooth muscle Sarcoma or carcinoma of prostate), polycythemia vera, primary thrombocytosiss, myelofibrosises, leukemia (for example, Aml, cml, all or cll) and multiple myeloma.
On the other hand, provided herein is class compound disclosed herein, for treating and/or preventing proliferative disease.? In specific embodiment, proliferative disease be selected from cancer (for example, solid tumor such as leiomyosarcoma of uterus or carcinoma of prostate), Polycythemia vera, primary thrombocytosiss, myelofibrosises, leukemia (for example, aml, cml, all or cll) And multiple myeloma.
On the other hand, provided herein is class compound disclosed herein, or comprise the drug regimen of compound is disclosed herein Thing, for the medicine of preparation treatment or prevention proliferative disease.In particular instances, (for example, in fact proliferative disease is selected from cancer Body tumor such as leiomyosarcoma of uterus or carcinoma of prostate), polycythemia vera, primary thrombocytosiss, bone marrow fine Dimensionization, leukemia (for example, aml, cml, all or cll) and multiple myeloma.
On the other hand, provided herein is treatment and/or prevention are susceptible or suffering from the side of the mammal of autoimmune disease Method, methods described includes giving one or more pharmaceutical composition disclosed herein or the change of effectively treatment amount or effective preventive dose Compound.In particular instances, autoimmune disease is selected from copd, asthma, systemic lupus erythematosus (sle), skin lupus erythematosuss, wolf Skin ulcer nephritis, dermatomyositiss, sjogren syndrome, psoriasises, i patients with type Ⅰ DM and inflammatory bowel.
On the other hand, provided herein is class compound disclosed herein, for treating and/or preventing autoimmune disease. In certain embodiments, autoimmune disease is selected from copd, asthma, systemic lupus erythematosus (sle), skin lupus erythematosuss, wolf Skin ulcer nephritis, dermatomyositiss, sjogren syndrome, psoriasises, i patients with type Ⅰ DM and inflammatory bowel.
On the other hand, provided herein is class compound disclosed herein, or comprise the drug regimen of compound is disclosed herein Thing, for the medicine of preparation treatment or prevention autoimmune disease.In certain embodiments, autoimmune disease is selected from Copd, asthma, systemic lupus erythematosus (sle), skin lupus erythematosuss, lupus nephritis, dermatomyositiss, sjogren syndrome, psoriasises, i Patients with type Ⅰ DM and inflammatory bowel.
On the other hand, provided herein is treating and/or preventing the method being susceptible or suffering from the mammal of anaphylactic disease, Methods described includes giving one or more pharmaceutical composition disclosed herein or the chemical combination of effectively treatment amount or effective preventive dose Thing.In certain embodiments, anaphylactic disease is selected from respiratory anaphylactic disease, sinusitis, eczema and measles, food mistake Quick and insect venom allergies.
On the other hand, provided herein is class compound disclosed herein, for treating and/or preventing anaphylactic disease.? In specific embodiment, anaphylactic disease be selected from respiratory anaphylactic disease, sinusitis, eczema and measles, food anaphylaxiss and Insect venom allergies.
On the other hand, provided herein is class compound disclosed herein, or comprise the drug regimen of compound is disclosed herein Thing, for the medicine of preparation treatment or prevention anaphylactic disease.In certain embodiments, anaphylactic disease is selected from respiratory tract Anaphylactic disease, sinusitis, eczema and measles, food anaphylaxiss and insect venom allergies.
On the other hand, provided herein is class compound disclosed herein, for treating and/or preventing inflammatory diseasess.In spy In fixed embodiment, inflammatory diseasess are selected from inflammatory bowel, Crohn disease, rheumatoid arthritiss, juvenile arthritises and silver Bits disease arthritis.
On the other hand, provided herein is class compound disclosed herein, or comprise the drug regimen of compound is disclosed herein Thing, for the medicine of preparation treatment or prevention inflammatory diseasess.In certain embodiments, inflammatory diseasess be selected from inflammatory bowel, Crohn disease, rheumatoid arthritiss, juvenile arthritises and psoriasis arthropathica.
On the other hand, provided herein is class compound disclosed herein, for treating and/or preventing transplant rejection.In spy In fixed embodiment, transplant rejection is organ-graft refection, tissue transplantation rejection and cell transplant rejection.
On the other hand, provided herein is class compound disclosed herein, or comprise the drug regimen of compound is disclosed herein Thing, for the medicine of preparation treatment or prevention transplant rejection.In particular instances, transplant rejection is organ-graft refection, tissue Transplant rejection and cell transplant rejection.
On the other hand, provided herein is a class is especially used as treating as medicine and/or prevents disease medicament noted earlier Compound disclosed herein.It is also provided with medicine compound manufacture treatment being disclosed herein and/or preventing disease noted earlier Thing.
One special projects of this method include giving the open chemical combination of the present invention of the study subject effective dose with inflammation For a period of time, the described time be enough to reduce the level of inflammation of study subject thing, and preferably terminates the process of described inflammation.Should The special embodiment of method includes the present invention giving to suffer from or be susceptible to suffer from tested patients' effective dose of bone rheumatoid arthritiss For a period of time, the described time be enough to reduce or prevent the arthritis of described patient respectively open compound, and preferably terminates The process of described inflammation.
Another special projects of this method include giving the present invention of the study subject effective dose with proliferative disease For a period of time, the described time be enough to reduce the hyperplasia level of study subject open compound, and preferably terminates described increasing The process of growing property disease.The special embodiment of the method includes giving being disclosed herein of the tested patients' effective dose with cancer For a period of time, the described time be enough to reduce or prevent the cancer symptom of described patient respectively compound, and preferably terminates described The process of cancer.
Compound disclosed in this invention and pharmaceutical composition are kinase inhibitors, comprise btk inhibitor.These inhibitor Can be used for treating the disease of one or more of mammal response kinase inhibition, thin including response btk suppression and/or b- The disease of born of the same parents' Proliferation Ability.It is not intended to be bound by any specific theoretical it is believed that the interaction of the compounds of this invention and btk is led Cause the suppression of btk activity, and therefore obtain the pharmaceutical applications of these compounds.Therefore, the present invention includes thering is sound for treatment Answer the suppression of btk activity and/or the mammal of the disease of suppression b- cell proliferation, the method for such as people, the method includes: to There are the chemical entities of the offer at least one herein of the mammal effective dosage of such disease.Can be in experiment On for example pass through measure compound haemoconcentration, or in theory pass through calculate bioavailability, determine valid density.Except It is also possible to affected other kinases includes but is not limited to outside btk, other tyrosine kinase and serine/threonine kinase Enzyme.
In the scope relevant with disease in btk, the mitigation of disease and disease symptomses, prophylaxiss and prophylactic treatment are all at this In the range of invention.
In some embodiments, the disease of response btk activity and/or b cell and/or myeloid cell activity suppression is cancer Disease, osteopathia, allergic disease and/or autoimmune and/or inflammatory diseasess and/or acute inflammatory reaction.
The present invention includes treatment with cancer, osteopathia, allergic disease and/or autoimmune and/or inflammatory diseasess And/or the method for the patient of acute inflammatory reaction, it is by the compounds of this invention of effective dosage and its pharmaceutically acceptable Salt, solvate and mixture.
In some embodiments, using the compounds of this invention, the disease that can affect and disease include but is not limited to:
Allergic disease, including but not limited to eczema, allergic rhinitis or rhinitis, pollinosiss, bronchial asthma, nettle Measles (urticaria) and food anaphylaxiss and other atopy disease；
Autoimmune and/or inflammatory diseasess, including but not limited to psoriasises, Crohn disease, irritable bowel syndrome, drying are comprehensive Simulator sickness, tissue transplantation rejection reaction and the hyperacute rejection of transplant organ, asthma, systemic lupus erythematosus (sle) are (and related Glomerulonephritiies), dermatomyositiss, multiple sclerosiss, scleroderma, vasculitises (anca related and other vasculitises), autoimmune Hemolytic disease and thrombocytopenic state, goodpasture syndrome (and the glomerulonephritiies of correlation and pneumorrhagia), dynamic Pulse atherosclerosis, rheumatoid arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura (itp), Addison disease, handkerchief The gloomy disease of gold, Alzheimer, diabetes (1 type), septic shock, myasthenia graviss, ulcerative colitiss, aplastic Anemia, coeliac disease, wegener granulomatosises and wherein cell and antibody are caused by individual autologous tissue and facedown The Other diseases of the autologous tissue of body；
Acute inflammatory reaction, including but not limited to skin sunburn, inflammatory pelvic disease, inflammatory bowel, urethritiss, Fructus Vitis viniferae Film inflammation, sinusitis, pneumonia, encephalitis, meningitiss, myocarditiss, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gum Inflammation, appendicitis, pancreatitiss and cholecystitis；
Cancer, including but not limited to malignant hematologic disease such as b cell lymphoma and acute lymphoblastic leukemia, urgency Property myelogenous leukemia, chronic myelogenous leukemia, chronic and acute lymphoblastic leukemia, hairy cell leukemia, Hodgkin, Non-Hodgkin lymphoma, multiple myeloma and other diseases of being characterized with blood or lymphoid cancer；With
Osteopathia, including but not limited to osteoporosises.
Btk is the apoptotic inhibitor of known lymphoma b.Defect apoptosis contributes to human leukemia and lymphadenomatous Disease and Drug resistance.Therefore, promotion or the apoptotic method of abduction delivering btk are also provided, it includes making described cell and this Invention compound and its pharmaceutically acceptable salt, solvate contact with mixture.
The open compound of the present invention can be administered simultaneously, or before it or afterwards with one or more other therapeutic agent. The compounds of this invention can be administered by identical or different route of administration respectively with other therapeutic agents, or therewith with medicine Composition forms are administered.
For the individuality of about 50-70kg, the open pharmaceutical composition of the present invention and combination can be containing about 1-1000mg, Or the unit dose of about 1-500mg or about 1-250mg or about 1-150mg or about 0.5-100mg or about 1-50mg active component Amount form.The therapeutically effective amount of compound, pharmaceutical composition or its combination be depending on individuality species, body weight, the age and Individual instances, treated disease (disorder) or disease (disease) or its order of severity.Possesses the doctor of conventional technical ability Teacher, clinicist or veterinary can easily determine prevention, treatment or suppression disease (disorder) or disease (disease) development During required each active component effective dose.
Dose Characteristics cited above using favourable mammal (such as mice, rat, Canis familiaris L., monkey) or its from Confirm in the external and in vivo test of body organ, tissue and specimen.The open compound of the present invention is with solution, such as aqueous solution form In vitro using it is also possible to such as suspension or aqueous solution form enteral in vivo, parenteral, especially intravenouss use.
In one embodiment, the treatment effective dose of the open compound of the present invention is daily about 0.1mg to about 2, 000mg.Its pharmaceutical composition should provide about 0.1mg to about 2,000mg this compound of dosage.In a particular In, the pharmaceutical dosage unit forms of preparation are provided that about 1mg to about 2,000mg, about 10mg to about 1,000mg, and about 20mg is to about 500mg, or the main active of about 25mg to about 250mg or the combination of each main component in every dosage unit form.One In particular, the pharmaceutical dosage unit forms of preparation are provided that about 10mg, 20mg, 25mg, 50mg, 100mg, 250mg, 500mg, 1000mg or 2000mg main active.
Additionally, compound disclosed by the invention can be administered with prodrug forms.In the present invention, the open compound of the present invention " prodrug " when being that patient is administered, finally can discharge the functional derivatives of the open compound of the present invention in vivo.In the past When medicine form gives compound disclosed by the invention, those skilled in the art can implement one of following manner and more than: (a) The internal onset time of change compound；B () changes the internal acting duration of compound；C () changes the internal of compound Conveying or distribution；D () changes the internal dissolubility of compound；And (e) overcomes the side effect that compound faced or other difficult points. For preparing the typical functional derivatives of prodrug, comprise in vivo chemically or enzyme the mode compound that cracks Variant.These variants comprising to prepare phosphate, amide, ester, monothioester, carbonate and carbaminate are to people in the art It is well-known for member.
General building-up process
Usually, the compound of the present invention can be prepared by method described in the invention, unless there are further Explanation, the wherein definition of substituent group such as formula (i), formula (ia), formula (ib), formula (ic), formula (ii), formula (iia) or formula (iii) institute Show.Following reaction scheme and embodiment 1-100 are used for present disclosure is further illustrated.
Those skilled in the art will realize that: chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds of many present invention, and other methods of the compound for preparing the present invention are considered as the model in the present invention Within enclosing.For example, according to the present invention, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art Completed by method of modifying, such as suitable protection disturbs group, by using reagent known to other except described in the invention , or modification reaction condition being made some routines.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is applied to the preparation of other compounds of the present invention.
The embodiments described below, unless other aspects show all of temperature and are set to degree Celsius.Reagent is bought in business Product supplier such as aldrich chemical company, arco chemical company and alfa chemical Company, not through being further purified, unless other aspects show during use.General reagent is from western Gansu Province, Shantou chemical industry Factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, dragon chemistry examination is risen in Qingdao Agent company limited and Haiyang Chemical Plant, Qingdao are commercially available.
Anhydrous tetrahydro furan, dioxane, toluene, ether is to be dried to obtain through metallic sodium backflow.Anhydrous methylene chloride It is to be dried to obtain through calcium hydride backflow with chloroform.Ethyl acetate, petroleum ether, normal hexane, n, n- dimethyl acetylamide and n, n- Dimethylformamide is to be dried in advance through anhydrous sodium sulfate to use.
Hereinafter reaction is usually to cover a drying tube under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects Show), reaction bulb all suitable rubber closures 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 mesh) is purchased from Haiyang Chemical Plant, Qingdao.The survey of proton nmr spectra Strip part is: under room temperature condition, the nuclear magnetic resonance spectrometer of Brooker (bruker) 400mhz or 600mhz, with cdc13, d6- dmso, cd3Od or d6- acetone is solvent (report is in units of ppm), with tms (0ppm) or chloroform (7.26ppm) as reference standard. When multiplet occurs, by using following abbreviation: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), q (quartet, quartet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, double doublet), (doublet of doublet of doublets, double two times double for ddd Peak), dt (doublet of triplets, double triplets).Coupling constant, is represented with hertz (hz).
The condition of Algorithm (ms) data determination is: agilent 6120quadrupole hplc-ms (pillar Model: zorbax sb-c18,2.1x30mm, 3.5 μm, 6min, flow velocity is 0.6ml/min, mobile phase: 5%-95% (contains The ch of 0.1% formic acid3Cn) in (h containing 0.1% formic acid2O) ratio in)), detected with uv in 210/254nm, with electron spray electricity From pattern (esi).
The characteristic manner of compound purity is: agilent 1260 preparative high performance liquid chromatography (pre-hplc) or Calesep pump 250 preparative high performance liquid chromatography (pre-hplc) (pillar model: novasep, 50/80mm, dac), 210nm/254nm is detected with uv.
The use of brief word below runs through the present invention:
h2O water；meoh,ch3Oh methanol；cd3Od deuterated methanol；Semcl 2- (trimethylsilyl) ethoxymethyl chlorine；
chcl3Chloroform, chloroform；cdcl3Deuterochloroform；Dmso dimethyl sulfoxide；dmso-d6Deuterated dimethyl sulfoxide；
Dmf n, n- dimethylformamide；Hobt I-hydroxybenzotriazole；na2so4Sodium sulfate；Pd/c palladium carbon；
Hatu 2- (7- azo BTA)-n, n, n', n'- tetramethylurea hexafluorophosphoric acid ester；Tscl tolysulfonyl Chlorine；
pd(dppf)cl2[double (diphenylphosphino) ferrocene of 1,1'-] palladium chloride；The double diphenyl of xantphos 4,5- Phosphine -9,9- dimethyl xanthene；
X-phos 2- dicyclohexyl phosphorus -2,4,6- tri isopropyl biphenyl；pd2(dba)3Three (dibenzalacetone) two palladium；
T-budavephos 2- (di-t-butyl phosphine) -2'- (n, n- dimethylamino) biphenyl；Dbu 1,8- diaza is double Ring [5.4.0] 11 carbon -7- alkene；
G gram；Mg milligram；Mol mole；Mmol mM；H hour；Min minute；L liter；Ml, ml milliliter；R.t, rt room temperature；
Rt retention time；Hepes hydroxyethyl piperazine second sulfacid；Brij-35 Brij-35；Dtt bis- sulfur Threitol；
Edta ethylenediaminetetraacetic acid；Egfr EGF-R ELISA；Btk bruton's tyrosine kinase；
Egfr t790m EGF-R ELISA t790m mutant；Peptide fam-p22 FAM-labeled peptide 22；
Atp adenosine triphosphate；96-well plate 96 orifice plate；384-well plate 384 orifice plate； Staurosporine staurosporine；
Coating reagent#3 #3 fruit glaze agent.
Intermediate synthetic schemes 1
Midbody compound(6)Can be prepared by intermediate synthetic schemes 1, wherein r19And r19aIndependently of one another For halogen；r20For ph3The blocking groups such as c-, sem-；r3There is the implication as described in formula (i).Compound(1)Pass through Transition metal-catalyzed with trimethylsilyl acetylene in polar solvent (such as: dimethyl sulfoxide, n, n- dimethylformamide, Isosorbide-5-Nitrae-dioxane Deng) in, reaction obtains compound(3)；Compound(3)Alkali (such as: sodium tert-butoxide, potassium tert-butoxide, Sodium ethylate etc.), or fluorination Compound is obtained in the presence of thing (such as: tetrabutyl ammonium fluoride)(4)；Compound(4)Make in halogenating agent (such as: nis, nbs etc.) With under obtain compound(5)；Compound(5)With r20Cl is (as ph3Ccl, semcl etc.) reacting generating compound(6).
Intermediate synthetic schemes 2
Midbody compound(10)Can be prepared by intermediate synthetic schemes 2, wherein r19And r19aIndependently of one another For halogen；r20For ph3The blocking groups such as c-, sem-；r3And r2There is the implication as described in formula (i).Compound(1) By transition metal-catalyzed with(such as: dimethyl sulfoxide, n, n- dimethylformamide, Isosorbide-5-Nitrae-dioxane etc.) In, reaction obtains compound(7)；Compound(7)Alkali (such as: sodium tert-butoxide, potassium tert-butoxide, Sodium ethylate etc.), or fluoride Compound is obtained in the presence of (such as: tetrabutyl ammonium fluoride)(8)；Compound(8)In halogenating agent (such as: nis, nbs etc.) effect Under obtain compound(9)；Compound(9)With r20Cl is (as ph3Ccl, semcl etc.) reacting generating compound(10).
Intermediate synthetic schemes 3
Midbody compound(12)Can be prepared by intermediate synthetic schemes 3, wherein r19And r19aIndependently of one another For halogen；r20For ph3The blocking groups such as c-, sem-；E ring, m, r4、r5、r3And r2There is containing as described in formula (i) Justice.Compound(10)And compound(11)Obtain compound in transition metal-catalyzed lower generation suzuki cross-coupling reaction(12).
Intermediate synthetic schemes 4
Midbody compound(12)Can be prepared by intermediate synthetic schemes 4, wherein r19And r19aIndependently of one another For halogen；r20For ph3The blocking groups such as c-, sem-；E ring, m, r4、r5、r3And r2There is containing as described in formula (i) Justice.Compound(10)And compound(16)Obtain compound in transition metal-catalyzed lower generation suzuki cross-coupling reaction(12).
Intermediate synthetic schemes 5
Midbody compound(18)Can be prepared by intermediate synthetic schemes 5, wherein r19And r19aIndependently of one another For halogen；r20For ph3The blocking groups such as c-, sem-；A ring, r3And r2There is the implication as described in formula (i).Compound(10)And compound(17)Obtain compound in transition metal-catalyzed lower generation suzuki cross-coupling reaction(18).
Intermediate synthetic schemes 6
Midbody compound(18)Can be prepared by intermediate synthetic schemes 6, wherein r19And r19aIndependently of one another For halogen；r20For ph3The blocking groups such as c-, sem-；A ring, r3And r2There is the implication as described in formula (i).Compound(10)And compound(13)Obtain compound in transition metal-catalyzed lower generation suzuki cross-coupling reaction(18).
Intermediate synthetic schemes 7
Midbody compound(14)Can be prepared by intermediate synthetic schemes 7, wherein r19For halogen；r20For ph3The blocking groups such as c-, sem-；A ring, e ring, m, r4、r5、r3And r2There is the implication as described in formula (i).Compound(12)And compound(13)Obtain compound in transition metal-catalyzed lower generation suzuki cross-coupling reaction(14).
Intermediate synthetic schemes 8
Midbody compound(14)Can be prepared by intermediate synthetic schemes 8, wherein r19For halogen；r20For ph3The blocking groups such as c-, sem-；A ring, e ring, m, r4、r5、r3And r2There is the implication as described in formula (i).Compound(12)And compound(17)Obtain compound in transition metal-catalyzed lower generation suzuki cross-coupling reaction(14).
Intermediate synthetic schemes 9
Midbody compound(14)Can be prepared by intermediate synthetic schemes 9, wherein r19aFor halogen；r20For ph3The blocking groups such as c-, sem-；A ring, e ring, m, r4、r5、r3And r2There is the implication as described in formula (i).Compound(18)And compound(16)Obtain compound in transition metal-catalyzed lower generation suzuki cross-coupling reaction(14).
Intermediate synthetic schemes 10
Midbody compound(14)Can be prepared by intermediate synthetic schemes 10, wherein r19aFor halogen；r20For ph3The blocking groups such as c-, sem-；A ring, e ring, m, r4、r5、r3And r2There is the implication as described in formula (i).Compound(18)And compound(11)Obtain compound in transition metal-catalyzed lower generation suzuki cross-coupling reaction(14).
Intermediate synthetic schemes 11
Midbody compound(12a)Can be prepared by intermediate synthetic schemes 11, wherein r18、r19And r19aEach It independently is halogen；r20For ph3The blocking groups such as c-, sem-；z1、z2、r0、r00, n and l have as described in formula (ii) Implication.Compound(10a)And compound(16a)Obtain chemical combination in transition metal-catalyzed lower generation suzuki cross-coupling reaction Thing(12a).
Intermediate synthetic schemes 12
Midbody compound(12a)Can be prepared by intermediate synthetic schemes 12, wherein r18、r19And r19aEach It independently is halogen；r20For ph3The blocking groups such as c-, sem-；z1、z2、r0、r00, n and l have as described in formula (ii) Implication.Compound(10a)And compound(11a)Obtain chemical combination in transition metal-catalyzed lower generation suzuki cross-coupling reaction Thing(12a).
Synthetic schemes 1
Compound(15)Can be prepared by synthetic schemes 1, r20For ph3The blocking groups such as c-, sem-；A ring, e ring, m、r4、r5、r3And r2There is the implication as described in formula (i).Compound(14)Obtain compound in deprotection reaction(15).
Synthetic schemes 2
Compound(15a)Can be prepared by synthetic schemes 2, wherein r18And r19It is each independently halogen；r20For ph3The blocking groups such as c-, sem-；z1、z2、r1、r0、r00, n and l there is the implication as described in formula (ii).Compound(12a)Deprotection reaction is occurred to obtain compound(15a).
Synthetic schemes 3
Compound(2a)Can be prepared by synthetic schemes 3, wherein r19aFor halogen；z1、z2, w ring, r0、r00, n and l There is the implication as described in formula (ii).Compound(1a)And compound(16a)In transition metal-catalyzed lower generation Suzuki cross-coupling reaction obtains compound(2a).
Synthetic schemes 4
Compound(2a)Can be prepared by synthetic schemes 4, wherein r19aFor halogen；z1、z2, w ring, r0、r00, n and l There is the implication as described in formula (ii).Compound(1a)And compound(11a)In transition metal-catalyzed lower generation Suzuki cross-coupling reaction obtains compound(2a).
INTERMEDIATES Example 1
The iodo- 5- of 2- bromo- 3- methyl -7- ((2- (TMS) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrrole Piperazine
Step 1: the synthesis of the bromo- 6- chloropyrazine -2- amine of compound 3,5- bis-
Under room temperature, chloroform (15ml) solution of bromine (5.89g, 36.54mmol, 1.90ml) was slowly dripped in 5 minutes It is added in chloroform (170ml) solution of 6- methylpyrazine -2- amine (2.00g, 18.33mmol).After completion of dropping, stir at room temperature Mix reaction 4.5h.Add water (100ml) reaction is quenched, organic layer is washed with water (100ml), and anhydrous magnesium sulfate is dried, and organic layer subtracts Pressure concentrates, and carries out post separation (petrol ether/ethyl acetate (v/v)=2/1) and obtains 4.20g buff white solid, yield: 86.0%.
1h nmr(400mhz,dmso-d6):δ(ppm)6.83(s,2h),2.34(s,3h)；
ms(esi,pos.ion)m/z:266.0[m+1]+.
Step 2: the synthesis of compound 5- bromo- 6- methyl -3- ((TMS) acetenyl) pyrazine -2- amine
Under nitrogen protection, when 15 DEG C, trimethylsilyl acetylene (1.50g, 16.00mmol) is slowly added into 3,5- bis- Bromo- 6- methylpyrazine -2- amine (4.00g, 15.00mmol), Hydro-Giene (Water Science). (600mg, 3.15mmol), two (triphenylphosphine) dichloro Change palladium (pd (pph3)2cl2) (600mg, 0.85mmol) and triethylamine (2.40g, 24.00mmol, 3.30ml) oxolane (42ml), in mixture, after completion of dropping, after being naturally warmed to room temperature, continue reaction 16h.Kieselguhr filters, and is washed with ethyl acetate Wash, concentrating under reduced pressure, concentrated residue adds 100ml water, extract (100ml x 3) with dichloromethane, organic layer anhydrous sodium sulfate is done Dry, concentrating under reduced pressure, carry out post separation (petrol ether/ethyl acetate (v/v)=2/1) and obtain 3.50g buff white solid, yield: 82.0%.
1h nmr(400mhz,dmso-d6):δ(ppm)6.69(s,2h),2.39(s,3h),0.26(s,9h)；
ms(esi,pos.ion)m/z:284.1[m+1]+.
Step 3: the synthesis of compound 2- bromo- 3- methyl -5h- pyrrolo- [2,3-b] pyrazine
n2Under protection, by bromo- for 5- 6- methyl -3- ((TMS) acetenyl) pyrazine -2- amine at -30 DEG C The tetrahydrofuran solution (11ml) of (3.50g, 12.00mmol) is slowly dropped to the four of potassium tert-butoxide (1.80g, 16.00mmol) In hydrogen furan (18ml) solution.After completion of dropping, after reaction 1h at -30 DEG C, naturally it is warmed to room temperature stirring reaction overnight.Instead Liquid kieselguhr is answered to filter, ethyl acetate is washed, filtrate reduced in volume, concentrated residue adds water (150ml), is extracted with ethyl acetate (150ml x 3), organic layer anhydrous sodium sulfate drying, it is concentrated under reduced pressure to give 2.1g crocus solid, crude product is not further purified It is directly used in next step reaction, yield: 60.0%.
ms(esi,pos.ion)m/z:212.1[m+1]+.
Step 4: the synthesis of compound 2- bromo- 3- methyl -7- iodo- 5h- pyrrolo- [2,3-b] pyrazine
At 0 DEG C, n- N-iodosuccinimide (2.60g, 11.00mmol) is dividedly in some parts 2- bromo- 3- methyl -5h- pyrrole Cough up in acetone (30ml) solution of simultaneously [2,3-b] pyrazine (2.05g, 7.25mmol), reaction 3h is stirred at room temperature.It is removed under reduced pressure molten Agent, adds water (30ml) and dichloromethane (30ml) toward in residue, and solid filters, and washs solid with little water and dichloromethane, Brown solid again at 60 DEG C vacuum drying obtain 2.50g brown solid, crude product is not further purified and is directly used in next step reaction.
ms(esi,pos.ion)m/z:337.7[m+1]+.
Step 5: the iodo- 5- of compound 2- bromo- 3- methyl -7- ((2- (TMS) ethyoxyl) methyl) -5h- pyrroles And the synthesis of [2,3-b] pyrazine
At 0 DEG C, sodium hydride (450mg, 11.25mmol) is dividedly in some parts the iodo- 5h- pyrrolo- of 2- bromo- 3- methyl -7- The n of [2,3-b] pyrazine (2.50g, 7.4mmol), in n- dimethylformamide (30ml) mixed liquor.After stirring 2h under room temperature.0 It is slowly added dropwise trimethyl silicane base oxethyl methyl chloride (1.90g, 11.00mmol, 2.00ml), after completion of dropping, under room temperature at DEG C Stirring reaction is overnight.Add water (100ml) reaction be quenched, dichloromethane (100ml x 3) extracts, organic layer saturated aqueous common salt (100ml) wash, anhydrous sodium sulfate drying, concentrate and remove solvent, residue carries out column chromatography for separation (petrol ether/ethyl acetate (v/v) 1.20g pale yellow oil, two step gross production rates: 35.0%=10/1) are obtained.
ms(esi,pos.ion)m/z:467.9[m+1]+.
Using corresponding raw material, the synthetic method according to INTERMEDIATES Example 1 prepares intermediate as follows:
INTERMEDIATES Example 6
The chloro- 7- of 2- iodo- 5- trityl -5h- pyrrolo- [2,3-b] pyrazine
Step 1: the synthesis of compound 2- chloro- 5h- pyrrolo- [2,3-b] pyrazine
Add in 1,4- dioxane (20ml) solution of 2- bromo- 5h- pyrrolo- [2,3-b] pyrazine (3.1g, 16mmol) Enter phosphorus oxychloride (2.27ml, 24.1mmol) and triethylamine (220 μ l, 1.58mmol), 110 DEG C of back flow reaction 6 hours, slowly plus Enter in water (100ml) to be quenched, potassium hydroxide solution is adjusted to ph 7, ethyl acetate extracts (50mlx3), anhydrous sodium sulfate drying, After concentration, pull an oar (petrol ether/ethyl acetate (v/v)=2/1), filter, be dried to obtain 1.3g gray solid, yield: 54%.
ms(esi,pos.ion)m/z:154.1[m+1]+.
Step 2: the synthesis of the chloro- 7- of compound 2- iodo- 5h- pyrrolo- [2,3-b] pyrazine
N- iodo is added in acetone (15ml) solution of 2- chloro- 5h- pyrrolo- [2,3-b] pyrazine (1.3g, 8.5mmol) Butanimide (2.9g, 13mmol), is stirred at room temperature 12 hours, and add water (40ml) dilution, and dichloromethane extracts (55mlx3), no Aqueous sodium persulfate is dried, and concentrates column chromatography (petrol ether/ethyl acetate (v/v)=2/1) and obtains 2.2mg pale solid, yield: 93%.
ms(esi,pos.ion)m/z:280.0[m+1]+.
Step 3: the synthesis of the chloro- 7- of compound 2- iodo- 5- trityl -5h- pyrrolo- [2,3-b] pyrazine
To the n of the chloro- 7- of 2- iodo- 5h- pyrrolo- [2,3-b] pyrazine (300mg, 1.07mmol), n- dimethylformamide (8ml) sodium carbonate (230mg, 2.17mmol) and triphenylchloromethane (330mg, 1.18mmol), 45 DEG C of heating are added in solution Reaction 5 hours, add water (20ml) dilution, and dichloromethane extracts (25mlx3), and anhydrous sodium sulfate drying concentrates column chromatography (oil Ether/ethyl acetate (v/v)=8/1) obtain 320mg white solid, yield: 57.13%.
ms(esi,pos.ion)m/z:522.10[m+1]+；
1h nmr(400mhz,cdcl3)δ(ppm)7.92(s,1h),7.65(s,1h),7.31(m,9h),7.17(m,6h).
INTERMEDIATES Example 7
The bromo- 6- methyl -5- of 2,7- bis- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrazine
Step 1: the synthesis of the bromo- 3- of compound 5- (propine -1- base) pyrazine -2- amine
To in oxolane (8ml) solution of 3,5- bis- bromo-pyrazine -2- amine (200mg, 0.79mmol), sequentially add iodate Cuprous (15mg, 0.07mmol), two (triphenylphosphine) palladium chloride (56mg, 0.08mmol) and triethylamine (340 μ l, 2.44mmol), under nitrogen protection, under ice bath, slowly Deca adds 3% propine n-heptane solution (2.3ml, 1.2mmol), natural Stir 3 hours after being warmed to room temperature, diatom proposes filtration, concentrate, column chromatography (petrol ether/ethyl acetate (v/v)=8/1) obtains 150mg faint yellow solid, yield: 89.45%.
ms(esi,pos.ion)m/z:212.1,214.1[m+1]+.
Step 2: the synthesis of compound 2- bromo- 6- methyl -5h- pyrazolo [2,3-b] pyrazine
Under room temperature, under nitrogen protection, in oxolane (8ml) solution of potassium tert-butoxide (118mg, 1.05mmol), plus Enter the tetrahydrofuran solution (5ml) of the bromo- 3- of 5- (propine -1- base) pyrazine -2- amine (150mg, 0.70mmol), back flow reaction 1 is little When, kieselguhr filters, and removes solvent, it is faint yellow that residue column chromatography (petrol ether/ethyl acetate (v/v)=2/1) obtains 124mg Solid product, yield: 82.67%.
ms(esi,pos.ion)m/z:212.1,214.1[m+1]+；
1h nmr(400mhz,dmso-d6)δ(ppm)12.19(s,1h),8.21(s,1h),6.35(s,1h),2.49(s, 3h).
Step 3: the synthesis of bromo- 6- methyl -5h- pyrrolo- [2,3-b] pyrazine of compound 2,7- bis-
Under room temperature, to the n of 2- bromo- 6- methyl -5h- pyrazolo [2,3-b] pyrazine (500mg, 2.35mmol), n- dimethyl In Methanamide (12ml) solution, add n- bromo-succinimide (630mg, 3.54mmol), be stirred at room temperature 5 hours, add water (20ml) dilute, dichloromethane extracts (25mlx3), anhydrous sodium sulfate drying, concentrate column chromatography (petrol ether/ethyl acetate (v/ V)=2/1) obtain 450mg faint yellow solid, yield: 65.95%.
ms(esi,pos.ion)m/z:292.0[m+1]+.
Step 4: the bromo- 6- methyl -5- of compound 2,7- bis- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5h- pyrrolo- The synthesis of [2,3-b] pyrazine
At 0 DEG C, to the tetrahydrochysene furan of bromo- 6- methyl -5h- pyrrolo- [2,3-b] pyrazine (450mg, 1.54mmol) of 2,7- bis- Mutter and add sodium hydride (92mg, 2.30mmol) in (12ml) solution, after continuing reaction at this temperature 1 hour, be slowly added dropwise to Semcl (410 μ l, 2.32mmol), continues to be stirred at room temperature, and add water (20ml) dilution, and dichloromethane extracts (25mlx3), anhydrous sulfur Sour sodium is dried, and concentrates column chromatography (petrol ether/ethyl acetate (v/v)=2/1) and obtains 360mg brown oil, yield: 55.26%.
ms(esi,pos.ion)m/z:422.1[m+1]+.
INTERMEDIATES Example 8
The bromo- 2- of 7- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrazine
To the bromo- 5- of 2,7- bis- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrazine (1.0g, 1- methylpyrazole -4- borate (620mg, 2.98mmol), sodium carbonate is sequentially added in acetonitrile (6ml) solution 2.5mmol) (650mg, 6.13mmol), pd (pph3)2cl2(180mg, 0.26mmol) and water (6ml), 80 DEG C of heated and stirred 3 hours, add water (40ml) dilute, dichloromethane extracts (25mlx3), anhydrous sodium sulfate drying, concentrate column chromatography (petrol ether/ethyl acetate (v/ V)=2/1) obtain 1.0g yellow solid, yield: 99%.
ms(esi,pos.ion)m/z:408.10,410.10[m+1]+.
Using corresponding raw material, the synthetic method according to INTERMEDIATES Example 8 prepares intermediate as follows:
INTERMEDIATES Example 12
N- (2- (mesyl) ethyl) -4- (4,4,5,5- tetramethyl -1,3,2- dioxy boron pentane -2- base) amine
Step 1: the synthesis of the iodo- n- of compound 4- (2- (mesyl) ethyl) amine
Under nitrogen protection, dmso (15ml) is added to paradiiodobenzene (408mg, 1.24mmol), 2- (mesyl) second Amine hydrochlorate (220mg, 1.38mmol), Hydro-Giene (Water Science). (250mg, 1.31mmol), cesium carbonate (1.20g, 3.70mmol), diformazan In the mixture of base glycine (208mg, 1.21mmol), 80 DEG C of reaction 22h, reactant liquor is cooled to room temperature, is extracted with ethyl acetate Take (50mlx3), be spin-dried for organic faciess, column chromatography for separation (petrol ether/ethyl acetate (v/v)=1/1) obtains 78mg white solid, Yield: 19.4%.
ms(esi,pos.ion)m/z:326.1[m+1]+.
Step 2: compound n- (2- (mesyl) ethyl) -4- (4,4,5,5- tetramethyl -1,3,2- dioxy boron pentane - 2- yl) amine synthesis
Nitrogen protection under, by dmso (12ml) be added to the iodo- n- of 4- (2- (mesyl) ethyl) amine (78mg, 0.24mmol), connection pinacol borate (75mg, 0.30mmol), potassium acetate (75mg, 0.76mmol), pd (dppf) cl2 In (9mg, 0.01mmol) mixture, 105 DEG C of reaction 17h, reactant liquor is cooled to room temperature, is extracted with ethyl acetate (50mlx3), Concentrate organic faciess, column chromatography for separation (petrol ether/ethyl acetate (v/v)=1/2) obtains 58mg colorless oil, yield: 74.4%.
ms(esi,pos.ion)m/z:326.3[m+1]+.
Using corresponding raw material, the synthetic method according to INTERMEDIATES Example 12 prepares intermediate as follows:
INTERMEDIATES Example 32
4,4,5,5- tetramethyl -2- (1,4- dioxy spiral shell [4.5] certain herbaceous plants with big flowers alkane -7- alkene -8- base) -1,3,2- dioxy boron pentane
Step 1: the synthesis of compound 1,4- dioxy spiral shell [4.5] certain herbaceous plants with big flowers alkane -7- alkene -8- triflate
At -78 DEG C, in oxolane (15ml) solution of Isosorbide-5-Nitrae-dioxy spiral shell [4.5] certain herbaceous plants with big flowers alkane -8- ketone (2.0g, 13mmol) Add the tetrahydrofuran solution (26ml) of potassium hexamethyldisilazide (1m, 26ml, 26mmol), continue to stir at such a temperature Mix, add n, the tetrahydrofuran solution (15ml) of n- bis- (trifyl) aniline (5.46g, 15.3mmol), naturally rise to Be stirred overnight at room temperature, add water (30ml) be quenched, dichloromethane extract (30mlx3), anhydrous sodium sulfate drying, concentrate column chromatography (stone Oily ether/ethyl acetate (v/v)=5/1) obtain 4.5g pale yellow oil, yield: 80.23%.
ms(esi,pos.ion)m/z:289.0[m+1]+.
Step 2: compound 4,4,5,5- tetramethyl -2- (1,4- dioxy spiral shell [4.5] certain herbaceous plants with big flowers alkane -7- alkene -8- base) -1,3,2- two The synthesis of oxygen boron pentane
The 1,4- dioxane of 1,4- dioxy spiral shell [4.5] certain herbaceous plants with big flowers alkane -7- alkene -8- triflate (500mg, 1.73mmol) (8ml) potassium acetate (260mg, 2.64mmol), connection boric acid pinacol fat (530mg, 2.08mmol), pd are sequentially added in solution (dppf)cl2(130mg, 0.17mmol), nitrogen is protected, 110 DEG C of back flow reaction 10 hours, filters, and concentrates column chromatography (oil Ether/ethyl acetate (v/v)=2/1) obtain 540mg yellow oil, yield: 99%.
ms(esi,pos.ion)m/z:267.30[m+1]+.
Using corresponding raw material, the synthetic method according to INTERMEDIATES Example 32 prepares intermediate as follows:
INTERMEDIATES Example 34
(r) -2- methyl -2- ((3- (4,4,5,5- tetramethyl -1,3,2- dioxy boron pentane -2- base) phenyl) amino)-n- (2,2,2- trifluoroethyl) butyramide
Step 1: the synthesis of compound (r) -2- ((3- bromophenyl) amino) -2-Methyl Butyric Acid
Sequentially add in dmf (5ml) solution of a bromo-iodobenzene (500mg, 1.76mmol) Hydro-Giene (Water Science). (340mg, 1.78mmol), cesium carbonate (870mg, 2.67mmol), (r) -2- amino-2-methyl butanoic acid (550mg, 4.55mmol), 80 DEG C add Thermal response 8 hours, directly concentrates and mixes sample, column chromatography (petrol ether/ethyl acetate (v/v)=1/1) obtains 130mg brown solid, Yield: 27.02%.
ms(esi,pos.ion)m/z:271.9,273.9[m+1]+.
Step 2: compound (r) -2- ((3- bromophenyl) amino) -2- methyl-n- (2,2,2- trifluoroethyl) butyramide Synthesis
To in dmf (5ml) solution of (r) -2- ((3- bromophenyl) amino) -2-Methyl Butyric Acid (70mg, 0.25mmol) according to Secondary addition n- methyl morpholine (80mg, 0.79mmol), 2,2,2- trifluoroethylamine hydrochlorates (60mg, 0.44mmol) and hatu (146mg, 0.38mmol), is stirred at room temperature 2 hours, and add water (30ml) dilution, and dichloromethane extracts (30mlx3), anhydrous sodium sulfate It is dried, concentrate column chromatography (petrol ether/ethyl acetate (v/v)=1/1) and obtain 70mg yellow solid, yield: 77.05%.
ms(esi,pos.ion)m/z:353.2,355.1[m+1]+.
Step 3: compound (r) -2- methyl -2- ((3- (4,4,5,5- tetramethyl -1,3,2- dioxy boron pentane -2- base) benzene Base) amino)-n- (2,2,2- trifluoroethyl) butyramide synthesis
To (r) -2- ((3- bromophenyl) amino) -2- methyl-n- (2,2,2- trifluoroethyl) butyramide (350mg, Sequentially add potassium acetate (250mg, 2.54mmol) in dimethyl sulfoxide (8ml) solution 0.99mmol), join pinacol borate (380mg, 1.49mmol) and pd (dppf) cl2(70mg, 0.09mmol), under nitrogen atmosphere, 110 DEG C of reacting by heating 8 hours, Add water (30ml) dilution, and dichloromethane extracts (30ml x 3), and anhydrous sodium sulfate drying concentrates column chromatography (petroleum ether/acetic acid second Ester (v/v)=8/1) obtain 350mg pale yellow oil, yield: 60.52%.
ms(esi,pos.ion)m/z:401.0[m+1]+.
Using corresponding raw material, the synthetic method according to INTERMEDIATES Example 34 prepares intermediate as follows:
INTERMEDIATES Example 37
1- (2- cyanoethyl)-n- (3- (4,4,5,5- tetramethyl -1,3,2- dioxy boron pentane -2- base) phenyl) pyrrolidine - 3- Methanamide
Step 1: the synthesis of compound 1- t-butyl formate-pyrrolidine -3- carboxylic acid
Water (15ml) solution of sodium hydroxide (0.80g, 20.00mmol) is added to 1- t-butyl formate-pyrrolidine -3- Methanol (30ml) solution of methyl formate (2.30g, 10.00mmol), reactant liquor reacts 3 hours at room temperature, and concentrating under reduced pressure removes Remove methanol, with the glacial acetic acid of 2m, ph is adjusted to ph=4, dichloromethane (50ml x 3) extracts, anhydrous sodium sulfate drying subtracts Pressure is concentrated to give grease 1.80g, yield: 83.00%.
ms(esi,pos.ion)m/z:160.1[m-55]+.
Step 2: the synthesis of compound 3- ((3- bromophenyl) carbamoyl) pyrrolidine -1- t-butyl formate
3- bromaniline (1.40g, 8.40mmol, 0.91ml) is added to 1- t-butyl formate-pyrrolidine -3- carboxylic acid (1.80g, 8.40mmol), hatu (6.40g, 17.00mmol) and n, n- diisopropylethylamine (3.30g, 25.00mmol, In dichloromethane (20ml) solution 4.40ml), under room temperature, react 4h.Reaction, dichloromethane (50ml x are quenched with water (50ml) 3) extract, organic layer is washed with saturated aqueous common salt (50ml), anhydrous sodium sulfate drying, concentrating under reduced pressure, and concentrated solution carries out post separation (petrol ether/ethyl acetate (v/v)=2/1) obtains 2.40g pale tan oil, yield: 78.0%.
ms(esi,pos.ion)m/z:312.9[m-55]+.
Step 3: compound 3- ((3- (4- (4,4,5,5- tetramethyl -1,3,2- dioxy boron pentane -2- base) phenyl) amino Formoxyl) pyrrolidine -1- t-butyl formate synthesis
Under nitrogen protection, to 3- ((3- bromophenyl) carbamoyl) pyrrolidine -1- t-butyl formate (2.40g, 6.50mmol), connection pinacol borate (9.80mg, 2.50mmol), potassium acetate (1.30mg, 13.00mmol), pd (dppf) cl2Injection dimethyl sulfoxide (20ml) in the mixture of (240mg, 0.32mmol), reactant liquor reacts 12h at 100 DEG C.It is cooled to room Temperature, with water (150ml) and ethyl acetate (150ml) by reaction liquid layer, aqueous phase is extracted with ethyl acetate (150mlx3), organic Layer washed with saturated brine (100ml x 2), anhydrous sodium sulfate drying, concentrating under reduced pressure, concentrated solution carry out post separation (petroleum ether/ Ethyl acetate (v/v)=2/1) obtain 1.20g pale yellow oil, yield: 44.0%.
ms(esi,pos.ion)m/z:361.3[m+1]+.
Step 4: compound n- (3- (4,4,5,5- tetramethyl -1,3,2- dioxy boron pentane -2- base) phenyl) pyrrolidine -3- The synthesis of carboxamide hydrochloride
Under room temperature by the ethyl acetate solution (2m, 14.00mmol, 7.00ml) of hydrogen chloride be added to 3- ((3- (4- (4,4, 5,5- tetramethyl -1,3,2- dioxy boron pentane -2- base) phenyl) carbamoyl) pyrrolidine -1- t-butyl formate (1.20g, In ethyl acetate (15ml) solution 2.90mmol), react 2h.It is concentrated under reduced pressure to give 1.20g grease, yield: 120.0%.
ms(esi,pos.ion)m/z:317.1[m+1]+.
Step 5: compound 1- (2- cyanoethyl)-n- (3- (4,4,5,5- tetramethyl -1,3,2- dioxy boron pentane -2- base) Phenyl) pyrrolidine -3- Methanamide synthesis
Under room temperature, by 3- bromopropionitrile (1.00g, 7.00mmol) be added to n- (3- (and 4,4,5,5- tetramethyl -1,3,2- bis- Oxygen boron pentane -2- base) phenyl) pyrrolidine -3- carboxamide hydrochloride (1.20g, 3.4mmol) and cesium carbonate (5.50g, In acetonitrile (25ml) solvent 17.00mmol), reaction back flow reaction 4h at 90 DEG C.Kieselguhr filters, and is washed with ethyl acetate Filter cake, concentrating under reduced pressure, concentrated solution carries out post separation (methylene chloride/methanol (v/v)=15/1) and obtains the faint yellow oily of 550mg Thing, yield: 44.0%.
ms(esi,pos.ion)m/z:370.0[m+1]+.
INTERMEDIATES Example 38
(r) -2- methyl -2- ((3- (4,4,5,5- tetramethyl -1,3,2- dioxy boron pentane -2- base) phenyl) amino)-n- (2,2,2- trifluoroethyl) butyramide
Step 1: the synthesis of compound (r) -2- ((tertbutyloxycarbonyl) amino) -2-Methyl Butyric Acid
Nitrogen protection under, by (r) -2- amino-2-methyl butanoic acid (2.05g, 17.50mmol), triethylamine (7.01ml, 50.20mmol), di-tert-butyl dicarboxylate (5.70g, 26.00mmol) is added together, adds oxolane (20ml), heats up To 70 DEG C of reaction 3h, reactant liquor is cooled to room temperature, and ethyl acetate (50ml × 3) extracts, and uses anhydrous na2so4It is dried, remove solvent, Carry out post separation (methylene chloride/methanol (v/v)=10/1) and obtain 3.60g colorless oil, yield: 97.0%.
ms(esi,pos.ion)m/z:118.2[m-99]+.
Step 2: compound (r)-(2- methyl isophthalic acid-oxygen -1- ((2,2,2- trifluoroethyl) amino) butyl -2- base) amino first The synthesis of acid esters
Under nitrogen protection, by 2,2,2- trifluoroethyl amine hydrochlorates (2.85g, 21.01mmol), (r) -2- ((tertiary butyloxycarbonyl Base) amino) -2-Methyl Butyric Acid (3.71g, 17.01mmol), hatu (8.81g, 23.02mmol), n- methyl morpholine (5.21g, 51.01mmol) added together, add dmf (30ml), 5h be stirred at room temperature, ethyl acetate (100ml × 3) extracts, with anhydrous na2so4It is dried, removes solvent, carry out post separation (petrol ether/ethyl acetate (v/v)=2/1) and obtain 3.57g white solid, produce Rate: 70.1%.
ms(esi,pos.ion)m/z:199.1[m-99]+.
Step 3: compound (r) -2- ((3- bromophenyl) amino) -2- methyl-n- (2,2,2- trifluoroethyl) butyramide Synthesis
Under room temperature, (r)-(2- methyl isophthalic acid-oxygen -1- ((2,2,2- trifluoroethyl) amino) butyl -2- base) carbamate (3.57g, 12.01mmol) is dissolved in the ethyl acetate solution (15ml) of hydrogen chloride, and 5h is stirred at room temperature, and concentrating under reduced pressure reacts Liquid.Under nitrogen protection, add Hydro-Giene (Water Science). (1.60g, 8.40mmol), cesium carbonate (11.80g, 36.20mmol), l- proline (970mg, 8.43mmol), a bromo-iodobenzene (3.73g, 13.20mmol), dmf (40ml), are warming up to 70 DEG C of stirring 17h, acetic acid second Ester (100ml × 3) extracts, and uses anhydrous na2so4It is dried, remove solvent, carry out post separation (petrol ether/ethyl acetate (v/v)=2/ 1) 3.61g dark yellow oil thing, yield: 84.9% are obtained.
ms(esi,pos.ion)m/z:355.2[m+1]+.
Step 4: compound (r) -2- methyl -2- ((3- (4,4,5,5- tetramethyl -1,3,2- dioxy boron pentane -2- base) benzene Base) amino)-n- (2,2,2- trifluoroethyl) butyramide synthesis
Under nitrogen protection, by (r) -2- ((3- bromophenyl) amino) -2- methyl-n- (2,2,2- trifluoroethyl) butyramide (3.59g, 10.21mmol), connection pinacol borate (3.08g, 12.11mmol), potassium acetate (3.21g, 33.02mmol) and pd (dppf)cl2(450mg, 0.60mmol) is added together, adds dmso (45.00ml), 115 DEG C of reaction 17h, reactant liquor cools down To room temperature, it is extracted with ethyl acetate (100ml × 3), be spin-dried for organic faciess, column chromatography for separation (petrol ether/ethyl acetate (v/v)= 2/1) 2.86g dark oil thing, yield: 70.2% are obtained.
ms(esi,pos.ion)m/z:401.4[m+1]+.
Using corresponding raw material, the synthetic method according to INTERMEDIATES Example 38 prepares intermediate as follows:
INTERMEDIATES Example 40
1- (2- fluorophenyl) -4- (4,4,5,5- tetramethyl -1,3,2- dioxy boron pentane -2- base) -1h- pyrazoles
Under nitrogen protection, dmf (12ml) is added to adjacent fluorine bromobenzyl (706mg, 3.71mmol), 4- (4,4,5,5- tetramethyls Base -1,3,2- dioxy boron pentane -2- base) -1h- pyrazoles (480mg, 2.47mmol), cesium carbonate (2.10g, 6.19mmol) and iodine Change in potassium (150mg, 1.24mmol) mixture, room temperature reaction 12h, it is extracted with ethyl acetate (50mlx3), be spin-dried for organic faciess, post Chromatography (petrol ether/ethyl acetate (v/v)=10/1) obtains 400mg colorless oil, yield: 53.5%.
ms(esi,pos.ion)m/z:303.3[m+1]+.
Using corresponding raw material, the synthetic method according to INTERMEDIATES Example 40 prepares intermediate as follows:
INTERMEDIATES Example 46
2- (1- (acetonitrile sulfonyl) -3- (4- (4,4,5,5- tetramethyl -1,3,2- dioxy boron pentane -2- base) -1h- pyrrole Azoles -1- base) azetidine -3- base) acetonitrile
Step 1: compound 3- (cyano ethyl) -3- (4- (4,4,5,5- tetramethyl -1,3,2- dioxy boron pentane -2- base) - 1h- pyrazol-1-yl) azetidine -1- t-butyl formate synthesis
To 1h- pyrazoles boric acid fat (200mg, 1.03mmol), 3- (cyanomethylene) azetidine -1- t-butyl formate Dbu (80 μ l, 0.53mmol) is added in acetonitrile (8ml) solution of (220mg, 1.13mmol), 50 DEG C of reacting by heating 4 hours, directly Connect concentration, column chromatography (petrol ether/ethyl acetate (v/v)=2/1) obtains 340mg pale yellow oil, yield: 84.93%.
ms(esi,pos.ion)m/z:333.3[m-55]+.
Step 2: compound 2- (1- (acetonitrile sulfonyl) -3- (4- (4,4,5,5- tetramethyl -1,3,2- dioxy boron pentane - 2- yl) -1h- pyrazol-1-yl) azetidine -3- base) and acetonitrile synthesis
To 3- (cyano ethyl) -3- (4- (4,4,5,5- tetramethyl -1,3,2- dioxy boron pentane -2- base) -1h- pyrazoles -1- Base) azetidine -1- t-butyl formate (330mg, 0.85mmol) dichloromethane (8ml) solution in add trifluoroacetic acid (0.7ml, 9mmol), is stirred at room temperature 2 hours, concentrated solvent, adds dichloromethane (8ml) dissolving, adds et under ice bath3n(400 μ l, 2.8mmol), ethyl chloride (0.15ml, 1.6mmol), be stirred at room temperature 2 hours, add water (30ml) be quenched, dichloromethane Extraction (30ml x 3), anhydrous sodium sulfate drying, concentrate column chromatography (petrol ether/ethyl acetate (v/v)=1/1) and obtain 120mg Pale yellow oil, yield: 37.13%.
ms(esi,pos.ion)m/z:381.2[m+1]+.
INTERMEDIATES Example 47
1- t-butyl formate -4- ((4- (4,4,5,5- tetramethyl -1,3,2- dioxy boron pentane -2- base) -1h- pyrroles -1- Base)) piperidines
Step 1: the synthesis of compound 1- t-butyl formate -4- methanesulfonyloxy group piperidines
Under ice bath, methylsufonyl chloride (2.44g, 21.3mmol, 1.65ml) is slowly dropped to n- t-butyl formate -4- hydroxyl In the dichloromethane solution of phenylpiperidines (3.10g, 15.00mmol) and triethylamine (3.00g, 30mmol, 4.00ml) (40ml), drip Add after finishing, under room temperature, react 1.5h.The hydrochloric acid (1m, 40ml) adding to reactant liquor is quenched reaction, and organic layer saturation is eaten Saline (30ml) washs, anhydrous sodium sulfate drying, and concentrating under reduced pressure obtains 4.30g beige solid, yield: 100.0%.
ms(esi,pos.ion)m/z:224.2[m-55]+；
1h nmr(400mhz,cdcl3):δ(ppm)4.90(m,1h),3.72(m,2h),3.31(m,2h),3.05(s, 3h),1.97(m,2h),1.84(m,2h),1.47(s,9h).
Step 2: compound 1- t-butyl formate -4- ((4- (4,4,5,5- tetramethyl -1,3,2- dioxy boron pentane -2- Base) -1h- pyrroles's -1- base)) synthesis of piperidines
1- t-butyl formate -4- methanesulfonyloxy group piperidines (2.00g, 7.16mmol) is added to 4- (4,4,5,5- tetra- Methyl isophthalic acid, 3,2- dioxy boron pentane -2- base) -1h- pyrazoles (1.50g, 7.70mmol) and cesium carbonate (3.50g, 11.00mmol) N, in the solution of n- dimethylformamide (15ml), 100 DEG C of reactant liquor reaction 24h, be cooled to room temperature, with water (100ml) and Ethyl acetate (100ml) extracts, and aqueous phase is extracted with ethyl acetate (100ml x 3), uses saturated aqueous common salt after merging organic faciess (100ml x 3) wash, anhydrous sodium sulfate drying, concentrating under reduced pressure, concentrated solution mix sample cross post (petrol ether/ethyl acetate (v/v)= 2/1) obtain 950mg colorless solid, yield: 35.2%.
ms(esi,pos.ion)m/z:378.4[m+1]+；
1h nmr(400mhz,cdcl3):δ(ppm)7.81(s,1h),7.74(s,1h),4.28(m,3h),2.90(m, 2h),2.14(m,2h),1.92(m,2h),1.49(s,9h),1.33(s,12h).
Using corresponding raw material, the synthetic method according to INTERMEDIATES Example 47 prepares intermediate as follows:
INTERMEDIATES Example 49
6- fluoro- 1- methyl -3- (tri-n-butyl tin base) -1h- indazole
Step 1: the synthesis of the fluoro- 3- of compound 6- iodo- 1h- indazole
Under room temperature, in dmf (5ml) solution of 6- fluoro- 1h- indazole (97mg, 0.71mmol), sequentially add potassium hydroxide (130mg, 2.32mmol) and elemental iodine (280mg, 1.10mmol), is stirred at room temperature 11h, saturated sodium thiosulfate Solutions Solution (10ml) it is quenched, ethyl acetate extracts (15mlx3), anhydrous sodium sulfate drying, concentrate column chromatography (petrol ether/ethyl acetate (v/ V)=6/1) obtain 150mg brown solid, yield: 80.34%.
ms(esi,pos.ion)m/z:263.0[m+1]+.
Step 2: the synthesis of the fluoro- 3- of compound 6- iodo- 1- methyl isophthalic acid h- indazole
Under room temperature, in dmso (5ml) solution of the iodo- 1h- indazole of the fluoro- 3- of 6- (97mg, 0.37mmol), sequentially add carbon Sour caesium (60mg, 0.18mmol) and iodomethane (70 μ l, 0.76mmol), are stirred at room temperature 1.5 hours, add water (10ml) be quenched, second Acetoacetic ester extracts (15mlx3), anhydrous sodium sulfate drying, concentrates column chromatography (petrol ether/ethyl acetate (v/v)=6/1) and obtains 100mg yellow solid, yield: 99%.
ms(esi,pos.ion)m/z:277.0[m+1]+.
Step 3: the synthesis of compound 6- fluoro- 1- methyl -3- (tri-n-butyl tin base) -1h- indazole
At -16 DEG C, to oxolane (30ml) solution of the fluoro- 3- of 6- iodo- 1- methyl isophthalic acid h- indazole (4.1g, 15mmol) In, sequentially add isopropylmagnesium chloride (2m, 9ml, 18mmol), stirring at this temperature added three n-butylmagnesium chloride after 20 minutes After stannum (4.8ml, 18mmol), after being naturally warmed to room temperature, continue stirring 5 hours, add saturated ammonium chloride solution (30ml) to be quenched, Ethyl acetate extracts (15mlx3), anhydrous sodium sulfate drying, concentrates column chromatography (petrol ether/ethyl acetate (v/v)=8/1) and obtains 6.1g pale yellow oil, yield: 94%.
ms(esi,pos.ion)m/z:440.2[m+1]+.
INTERMEDIATES Example 50
N- (3- (the bromo- 5- of 2- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrazine -7- base) Phenyl) -2- cyanoacetamide
To the iodo- 5- of the bromo- 7- of 2- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrazine (30mg, 0.07mmol), connection pinacol borate (25mg, 0.08mmol), sodium carbonate (20mg, 0.19mmol) and dichloro two (triphenyl Phosphine) palladium (6mg, 0.01mmol) mixture in sequentially add acetonitrile (4ml) and water (1ml), under nitrogen atmosphere, 65 DEG C of heating are anti- Answer 4.5 hours.Saturated ammonium chloride solution (10ml) is added to be quenched, ethyl acetate extracts (15mlx3), anhydrous sodium sulfate drying, Concentrate column chromatography (petrol ether/ethyl acetate (v/v)=2/1) and obtain 29mg yellow solid, yield: 90%.
ms(esi,pos.ion)m/z:487.4[m+1]+.
Using corresponding raw material, the synthetic method according to INTERMEDIATES Example 50 prepares intermediate as follows:
INTERMEDIATES Example 65
(r) -2- ((2- (2- chloro- 5- trityl -5h- pyrrolo- [2,3-b] pyrazine -7- base) pyrimidine-4-yl) amino) - 2- methyl-n- (2,2,2- trifluoroethyl) butyramide
Step 1: the synthesis of compound (r) -2- ((2- chloropyrimide -4- base) amino) -2-Methyl Butyric Acid
Sequentially add r- 2-amino-3-methylpentanoic acid in isopropanol (8ml) solution of 2,4- dichloro pyrimidine (600mg, 4.02mmol) (550mg, 4.55mmol), potassium carbonate (850mg, 6.15mmol), 90 DEG C of back flow reaction 5.5 hours, it is directly added into silica gel mixed sample, Column chromatography (petrol ether/ethyl acetate (v/v)=0/1) obtains 600mg white solid, yield: 93%.
ms(esi,pos.ion)m/z:230.0[m+1]+.
Step 2: compound (r) -2- ((2- chloropyrimide -4- base) amino) -2- methyl-n- (2,2,2- trifluoroethyl) butyryl The synthesis of amine
0 DEG C, to (r) -2- ((2- chloropyrimide -4- base) amino) -2-Methyl Butyric Acid (50mg, 0.21mmol), 2,2,2- tri- Fluorine ethylamine hydrochloride (44mg, 0.32mmol) and the n of diisopropyl ethyl amine (120 μ l, 0.68mmol), n- dimethylformamide (4ml) add 50% propylphosphonic anhydride ethyl acetate solution (510mg, 0.80mmol) in solution, be stirred at room temperature 12 hours, add water (15ml) dilute, dichloromethane extracts (20mlx3), anhydrous sodium sulfate drying, concentrate column chromatography (petrol ether/ethyl acetate (v/ V)=2/1) obtain 30mg faint yellow solid, yield: 44.35%.
ms(esi,pos.ion)m/z:311.1[m+1]+.
Step 3: the chloro- 7- of compound 2- (4,4,5,5- tetramethyl -1,3,2- dioxy boron pentane -2- base) -5- triphenyl first The synthesis of base -5h- pyrrolo- [2,3-b] pyrazine
- 20 DEG C, to the chloro- 7- of 2- iodo- 5- trityl -5h- pyrrolo- [2,3-b] pyrazine (380mg, 0.73mmol), different It is slowly added into the four of isopropylmagnesium chloride in oxolane (8ml) solution of propanol pinacol borate (200 μ l, 0.98mmol) Hydrogen tetrahydrofuran solution (2.0m, 850 μ l, 1.1mmol), continues reaction 1.5 hours at this temperature, adds ethyl acetate (20ml) dilute Release, add saturated ammonium chloride solution (20ml) to be quenched, ethyl acetate extracts (25mlx3), anhydrous sodium sulfate drying, evaporating column layer Analysis (petrol ether/ethyl acetate (v/v)=10/1) obtains 320mg faint yellow solid, yield: 84.21%.
ms(esi,pos.ion)m/z:521.8[m+1]+.
Step 4: ((2- (2- chloro- 5- trityl -5h- pyrrolo- [2,3-b] pyrazine -7- base) is phonetic for compound (r) -2- Pyridine -4- base) amino) -2- methyl-n- (2,2,2- trifluoroethyl) butyramide synthesis
To the chloro- 7- of 2- (4,4,5,5- tetramethyl -1,3,2- dioxy boron pentane -2- base) -5- trityl group -5h- pyrroles And ((2- chlorine is phonetic to sequentially add (r) -2- in 1,4- dioxane (4ml) solution of [2,3-b] pyrazine (30mg, 0.057mmol) Pyridine -4- base) amino) -2- methyl-n- (2,2,2- trifluoroethyl) butyramide (17mg, 0.05mmol), potassium carbonate (12mg, 0.08mmol), pd (dppf) cl2(5mg, 0.01mmol) and water (1ml), under nitrogen atmosphere, 110 DEG C of back flow reaction 4.5 hours, Add saturated ammonium chloride solution (20ml) to be quenched, dichloromethane extracts (25mlx3), anhydrous sodium sulfate drying, concentrate column chromatography (petrol ether/ethyl acetate (v/v)=2/1) obtains 220mg pale yellow oil, yield: 46.72%.
ms(esi,pos.ion)m/z:669.7[m+1]+.
Using corresponding raw material, the synthetic method according to INTERMEDIATES Example 65 prepares intermediate as follows:
INTERMEDIATES Example 67
N- isopropyl -5- (4,4,5,5- tetramethyl -1,3,2- dioxy boron pentane -2- base) -1- ((2- (trimethyl silicon substrate) Ethyoxyl) methyl) -1h- pyrazolo [2,3-b] pyridine-3-carboxamide
Step 1: the synthesis of compound 5- bromo- 1h- pyrrolo- [2,3-b] pyridine-3-carboxylic acid
5- bromo-7-azaindole (10.00g, 50.75mmol) is dissolved in dichloromethane (200ml), adds aluminum chloride (34.00g, 254.99mmol), is stirred at room temperature 10 minutes, adds trichloro-acetic chloride (8.6ml, 77mmol), continues to be stirred at room temperature Overnight, reactant liquor is poured in frozen water, be sufficiently stirred for, be filtrated to get white solid, filtrate is extracted with ethyl acetate (200ml x 3), concentrate and merge the white solid filtering out, add oxolane (250ml) and water (125ml) dissolving, add triethylamine (50ml), 24h is stirred at room temperature, solvent concentration is evaporated, adjust ph to 5-6 with 1.0m dilute hydrochloric acid, filter, 50 DEG C of vacuum drying, obtain It is 8.20g pale solid to product, yield: 67.0%.
ms(esi,pos.ion)m/z:241.2[m+1]+.
Step 2: the synthesis of compound 5- bromo- n- isopropyl -1h- pyrrolo- [2,3-b] pyridine-3-carboxamide
To the n of 5- bromo- 1h- pyrrolo- [2,3-b] pyridine-3-carboxylic acid (600mg, 2.49mmol), n- dimethylformamide (20ml) sequentially add 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (1.44g, 7.43mmol) in solution, 1- hydroxy benzo triazole (1.01g, 7.46mmol) and 2- 2-aminopropane. (1.27ml, 14.90mmol), are stirred overnight at room temperature.Plus Enter saturated aqueous common salt (20ml), dichloromethane (15mlx 3) extracts, with anhydrous sodium sulfate drying, remove solvent, concentrated solution is carried out It is 360mg brown solid that pillar layer separation (eluent: petrol ether/ethyl acetate (v/v)=5/1) obtains product, yield: 51.3%.
ms(esi,pos.ion)m/z:282.0[m+1]+.
Step 3: compound 5- bromo- n- isopropyl -1- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -1h- pyrrolo- [2, 3-b] pyridine-3-carboxamide synthesis
Bromo- for 5- n- isopropyl -1h- pyrrolo- [2,3-b] pyridine-3-carboxamide (360mg, 1.28mmol) is dissolved in n, n- In dimethylformamide (20ml), under ice bath, add 60% sodium hydride (102.1mg, 2.55mmol), add after 0.5h is stirred at room temperature Enter 2- (trimethyl silicon substrate) ethoxyl methyl chlorine (338.7 μ l, 1.82mmol), continue to be stirred overnight at room temperature, add saturated common salt Water (20ml), dichloromethane (15ml x 3) extracts, and with anhydrous sodium sulfate drying, removes solvent, concentrated solution carries out column chromatography and divides Obtaining product from (eluent: petrol ether/ethyl acetate (v/v)=6/1) is 500mg brown solid, yield: 99.0%.
ms(esi,pos.ion)m/z:412.1[m+1]+.
Step 4: compound n- isopropyl -5- (4,4,5,5- tetramethyl -1,3,2- dioxy boron pentane -2- base) -1- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -1h- pyrazolo [2,3-b] pyridine-3-carboxamide synthesis
By bromo- for 5- n- isopropyl -1- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -1h- pyrrolo- [2,3-b] pyridine - 3- Methanamide (600mg, 1.45mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (10ml), sequentially adds connection pinacol borate (443.7mg, 1.74mmol), potassium carbonate (357.3mg, 3.64mmol) and pd (dppf) cl2(106.4mg, 0.14mmol), nitrogen Gas shielded, 115 DEG C of back flow reaction 4 hours, it is cooled to room temperature, kieselguhr filters, concentrates filtrate, concentrated solution carries out pillar layer separation (eluent: petrol ether/ethyl acetate (v/v)=2/1) obtains product is 610mg yellow solid, yield: 91.25%.
ms(esi,pos.ion)m/z:460.30[m+1]+.
Embodiment 1
3- ((3- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5h- pyrrolo- [2,3-b] pyrazine -7- base) phenyl) amino) third Nitrile
Step 1: compound 3- ((3- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (trimethyl silicon substrate) ethyoxyl) Methyl) -5h- pyrrolo- [2,3-b] pyrazine -7- base) phenyl) amino) propionitrile synthesis
To the bromo- 2- of 7- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5h- pyrroles And sequentially add 3- ((3- (4,4,5,5- in 1,4- dioxane (4ml) solution of [2,3-b] pyrazine (30mg, 0.07mmol) Tetramethyl -1,3,2- dioxy boron pentane -2- bases) phenyl) amino) propionitrile (24mg, 0.08mmol), potassium carbonate (16mg, 0.12mmol), pd (dppf) cl2(10mg, 0.01mmol) and water (1ml), under nitrogen atmosphere, 110 DEG C of reacting by heating 7 hours, Add water (10ml) dilution, and dichloromethane extracts (15mlx3), and anhydrous sodium sulfate drying concentrates column chromatography (petrol ether/ethyl acetate (v/v)=2/1) obtain 26mg brown oil, yield: 74.74%.
ms(esi,pos.ion)m/z:474.3[m+1]+.
Step 2: compound 3- ((3- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5h- pyrrolo- [2,3-b] pyrazine -7- base) Phenyl) amino) propionitrile synthesis
To 3- ((3- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5h- pyrrole Cough up simultaneously [2,3-b] pyrazine -7- base) phenyl) amino) and propionitrile (260mg, 0.55mmol) dichloromethane (6ml) solution in, add Trifluoroacetic acid (2.5ml), is stirred at room temperature 2h, concentrated solvent, adds oxolane (6ml) dissolving, Deca sodium hydroxide solution (2n) to ph > 7,2h is stirred at room temperature, add water (20ml) dilution, dichloromethane extracts (15mlx3), anhydrous sodium sulfate drying concentrates Column chromatography (petrol ether/ethyl acetate (v/v)=0/1) obtains 50mg yellow solid, yield: 31.83%.
ms(esi,pos.ion)m/z:344.2[m+1]+；
1h nmr(600mhz,dmso-d6)δ(ppm)12.10(s,1h),8.62(m,1h),8.37(s,1h),8.26(s, 1h), 8.15 (s, 1h), 7.67 (m, 1h), 7.46 (d, j=7.7hz, 1h), 7.15 (m, 1h), 6.52 (dd, j=8.0, 1.7hz, 1h), 5.95 (t, j=6.2hz, 1h), 3.94 (s, 3h), 3.46 (dd, j=12.9,6.5hz, 2h), 2.80 (t, j= 6.6hz,2h)；
13c nmr(150mhz,dmso-d6)δ(ppm)148.3,141.8,140.9,137.3,136.3,135.0, 134.4,129.6,129.3,128.3,121.8,120.2,114.8,113.8,110.7,110.2,40.5,39.2,17.9.
Using corresponding raw material, the synthetic method according to embodiment 1 prepares compound as follows:
Embodiment 2
3- ((3- (2- cyclopropyl -5h- pyrrolo- [2,3-b] pyrazine -7- base) phenyl) amino) propionic acid amide.
Step 1: compound 3- ((3- (2- cyclopropyl -5- ((2- (TMS) ethyoxyl) methyl) -5h- pyrroles And [2,3-b] pyrazine -7- base) phenyl) amino) propionitrile synthesis
Under nitrogen protection, toluene (10ml) and water (1.2ml) are added to 7- bromo- 2- cyclopropyl -5- ((2- (trimethyl silicane Alkyl) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrazine (200mg, 0.42mmol), cyclopropylboronic acid (72mg, 0.85mmol), seven water potassium phosphates (440mg, 1.36mmol), palladium (6mg, 0.02mmol), thricyclohexyl phosphorus (15mg, 0.04mmol) in mixture, 110 DEG C of back flow reaction 19h, reactant liquor is cooled to room temperature, and kieselguhr filters, filtrate reduced in volume, Carry out post separation (petrol ether/ethyl acetate (v/v)=4/1) and obtain 160mg pale red solid, yield: 87.2%.
ms(esi,pos.ion)m/z:434.3[m+1]+.
Step 2: compound 3- ((3- (2- cyclopropyl -5h- pyrrolo- [2,3-b] pyrazine -7- base) phenyl) amino) propionyl The synthesis of amine
Under room temperature, 3- ((3- (2- cyclopropyl -5- ((2- (TMS) ethyoxyl) methyl) -5h- pyrrolo- [2, 3-b] pyrazine -7- base) phenyl) amino) propionitrile (158mg, 0.36mmol) is dissolved in dichloromethane (6ml), adds trifluoro second Sour (6ml), stirring reaction 12h under room temperature.Concentrating under reduced pressure reactant liquor, adds dichloromethane (6ml), ethylenediamine (1ml), under room temperature Stirring 2h, reactant liquor adds silica gel, is directly spin-dried for mixing sample, column chromatography for separation (methylene chloride/methanol (v/v)=50/1) obtains 86mg light yellow solid, yield: 77.8%.
ms(esi,pos.ion)m/z:304.1[m+1]+；
1h nmr(600mhz,dmso-d6):δ(ppm)11.99(s,1h),8.26(s,1h),8.21(s,1h),7.54(s, 1h), 7.36 (d, j=7.6hz, 1h), 7.13 (t, j=7.8hz, 1h), 6.50 (dd, j1=8.0hz, j2=1.9hz, 1h), 5.89 (t, j=6.2hz, 1h), 3.43 (q, j=6.6hz, 2h), 2.79 (t, j=6.6hz, 2h), 2.32 2.28 (m, 1h), 1.05–1.02(m,4h)；
13c nmr(150mhz,dmso-d6):δ(ppm)151.1,148.2,141.3,136.3,136.0,135.2, 129.5,127.9,120.1,114.7,113.5,111.3,109.5,39.6,18.0,14.8,10.3.
Using corresponding raw material, the synthetic method according to embodiment 2 prepares compound as follows:
Embodiment 3
3- ((3- (2- (6- fluoro- 1- methyl isophthalic acid h- indazole -3- base) -5h- pyrrolo- [2,3-b] pyrazine -7- base) phenyl) ammonia Base) propionitrile
Step 1: compound 3- ((3- (2- (6- fluoro- 1- methyl isophthalic acid h- indazole -3- base) -5- ((2- (TMS) Ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrazine -7- base) phenyl) amino) and propionitrile synthesis
Under nitrogen protection, by 3- ((3- (the bromo- 5- of 2- ((2- (TMS) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrazine -7- base) phenyl) amino) propionitrile (200mg, 0.42mmol), 6- fluoro- 1- methyl -3- (tributyl stannane) - 1h- indazole (380mg, 0.85mmol), Hydro-Giene (Water Science). (16mg, 0.08mmol), tetra-triphenylphosphine palladium (26mg, 0.02mmol) add To together, add dmf (15ml), be warming up to 90 DEG C of reaction 4.5h, reactant liquor is cooled to room temperature, ethyl acetate (50ml × 3) Extraction, uses anhydrous na2so4It is dried, remove solvent, carry out post separation (petrol ether/ethyl acetate (v/v)=4/1) and obtain 200mg Light yellow oil, yield: 84.7%.
ms(esi,pos.ion)m/z:542.3[m+1]+.
Step 2: compound 3- ((3- (2- (6- fluoro- 1- methyl isophthalic acid h- indazole -3- base) -5h- pyrrolo- [2,3-b] pyrazine - 7- yl) phenyl) amino) and propionitrile synthesis
3- ((3- (2- (6- fluoro- 1- methyl isophthalic acid h- indazole -3- base) -5- ((2- (TMS) ethyoxyl) methyl) - 5h- pyrrolo- [2,3-b] pyrazine -7- base) phenyl) amino) and propionitrile (240mg, 0.44mmol) according to embodiment 2 step 2 conjunction One-tenth method prepares 180mg light yellow solid, yield: 96.2%.
ms(esi,pos.ion)m/z:412.2[m+1]+；
1h nmr(600mhz,dmso-d6):δ(ppm)12.34(s,1h),9.05(s,1h),8.71(dd,j1=8.7hz, j2=5.5hz, 1h), 8.33 (s, 1h), 7.63 (dd, j1=9.6hz, j2=1.5hz, 1h), 7.53 (d, j=7.5hz, 1h), 7.49 (s, 1h), 7.30 7.19 (m, 2h), 6.60 (d, j=7.9hz, 1h), 5.92 (t, j=6.0hz, 1h), 4.14 (s, 3h),3.46(dd,j1=12.6hz, j2=6.3hz, 1h), 2.79 (t, j=6.5hz, 2h)；
13c nmr(150mhz,dmso-d6):δ(ppm)162.9,161.3,148.6,142.4,142.1,142.1, 141.8,141.4,135.9,135.2,134.8,129.8,128.8,125.1,125.0,120.2,119.0,115.4, 114.8,111.8,111.6,111.4,110.1,96.4,96.2,39.5,36.3,18.0.
Using corresponding raw material, the synthetic method according to embodiment 3 prepares compound as follows:
Embodiment 16
1- (cyanogen methyl) -3- (4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5h- pyrrolo- [2,3-b] pyrazine -7- base) benzene Base) urea
Step 1: compound 4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (TMS) ethyoxyl) first Base) -5h- pyrrolo- [2,3-b] pyrazine -7- base) aniline synthesis
4- (4,4,5,5- tetramethyl -1,3,2- dioxy boron pentane -2- base) aniline (120mg, 0.55mmol), the bromo- 2- of 7- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (TMS) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrazine (114mg, 0.28mmol), potassium carbonate (115mg, 0.82mmol) and pd (dppf) cl2(13mg, 0.02mmol) is according to embodiment The synthetic method of 1 step 1 prepares 104mg yellow solid, yield: 88.6%.
ms(esi,pos.ion)m/z:421.4[m+1]+.
Step 2: compound 4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5h- pyrrolo- [2,3-b] pyrazine -7- base) aniline Synthesis
4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (TMS) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrazine -7- base) aniline (300mg, 0.71mmol), trifluoroacetic acid (6ml) and ethylenediamine (1ml) be according to embodiment 2 step Rapid 2 synthetic method prepares 146mg yellow solid, yield: 71.2%.
ms(esi,pos.ion)m/z:291.4[m+1]+.
Step 3: compound 1- (cyanogen methyl) -3- (4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5h- pyrrolo- [2,3-b] Pyrazine -7- base) phenyl) urea synthesis
Toluene (5ml) is added to 4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5h- pyrrolo- [2,3-b] pyrazine -7- Base) aniline (36mg, 0.12mmol), in triphosgene (33mg, 0.11mmol), add two triethylamines, 110 DEG C of back flow reaction 5h, reactant liquor is cooled to room temperature, adds aminoacetonitrile HCl salt (28mg, 0.30mmol), triethylamine (100mg, 0.10mmol), 12h is stirred at room temperature, reaction adds silica gel, is directly spin-dried for mixing sample, carries out post separation (methylene chloride/methanol (v/v)=15/1) and obtain To 35mg white solid, yield: 75.8%.
ms(esi,neg.ion)m/z:371.2[m-1]-；
1h nmr(600mhz,dmso-d6):δ(ppm)9.32(s,1h),9.14(s,1h),8.78(s,1h),8.67(s, 1h), 8.54 (s, 1h), 8.28 (d, j=8.6hz, 2h), 8.24 (s, 1h), 7.57 (d, j=8.6hz, 2h), 6.83 (t, j= 5.7hz, 1h), 4.17 (d, j=5.6hz, 2h), 3.96 (s, 3h)；
13c nmr(150mhz,dmso-d6):δ(ppm)155.2,150.2,144.5,139.7,139.6,138.6, 137.7,134.1,130.4,127.6,125.7,125.5,120.6,119.0,118.7,118.0,117.0,39.3,29.6.
Using corresponding raw material, the synthetic method according to embodiment 16 prepares compound as follows:
Embodiment 20
3- ((4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5h- pyrrolo- [2,3-b] pyrazine -7- base) cyclohexyl) amino) Propionitrile
Step 1: compound 2- (1- methyl isophthalic acid h- pyrazoles -4- base) -7- (1,4- dioxy spiral shell [4.5] certain herbaceous plants with big flowers alkane -7- alkene -8- Base) -5- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrazine synthesis
The bromo- 2- of 7- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrazine (30mg, 0.07mmol), 4,4,5,5- tetramethyl -2- (Isosorbide-5-Nitrae-dioxy spiral shell [4.5] certain herbaceous plants with big flowers alkane -7- alkene -8- base) - 1,3,2- dioxy boron pentane (40mg, 0.15mmol), potassium carbonate (15mg, 0.10mmol), pd (dppf) cl2(6mg, 0.01mmol) with water (1ml), 21mg pale yellow oil is prepared according to the synthetic method of embodiment 1 step 1, yield: 61.14%.
ms(esi,pos.ion)m/z:468.3[m+1]+.
Step 2: compound 2- (1- methyl isophthalic acid h- pyrazoles -4- base) -7- (1,4- dioxy spiral shell [4.5] certain herbaceous plants with big flowers alkane -8- base) -5- The synthesis of ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrazine
To 2- (1- methyl isophthalic acid h- pyrazoles -4- base) -7- (1,4- dioxy spiral shell [4.5] certain herbaceous plants with big flowers alkane -7- alkene -8- base) -5- ((2- (three Methylsilyl) ethyoxyl) methyl) in -5h- pyrrolo- [2,3-b] pyrazine (320mg, 0.68mmol) and methanol (8ml) solution plus Enter pd/c (10%, 156mg, 0.14mmol), be stirred at room temperature under an atmosphere of hydrogen 3 hours, filter, concentrate, obtain 330mg yellow Grease crude product, directly carries out next step reaction, yield: 99%.
ms(esi,pos.ion)m/z:470.4[m+1]+.
Step 3: compound 4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (trimethyl silicon substrate) ethyoxyl) first Base) -5h- pyrrolo- [2,3-b] pyrazine -7- base) Ketohexamethylene synthesis
To 2- (1- methyl isophthalic acid h- pyrazoles -4- base) -7- (1,4- dioxy spiral shell [4.5] certain herbaceous plants with big flowers alkane -8- base) -5- ((2- (trimethyl Silicon substrate) ethyoxyl) methyl) and -5h- pyrrolo- [2,3-b] pyrazine (330mg, 0.70mmol) acetone (10ml) solution in, add P-methyl benzenesulfonic acid (363mg, 2.10mmol), is stirred at room temperature 8 hours, directly concentrates column chromatography (petrol ether/ethyl acetate (v/v) =2/1) obtain 180mg yellow solid, yield: 60.18%.
ms(esi,pos.ion)m/z:426.4[m+1]+.
Step 4: compound 3- ((4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (trimethyl silicon substrate) ethyoxyl) Methyl) -5h- pyrrolo- [2,3-b] pyrazine -7- base) cyclohexyl) amino) propionitrile synthesis
Under room temperature, to 4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) - 5h- pyrrolo- [2,3-b] pyrazine -7- base) Ketohexamethylene (15mg, 0.03mmol), the four of 3- aminopropionitrile (30 μ l, 0.41mmol) Add sodium triacetoxy borohydride (12mg, 0.05mmol) in hydrogen furan (4ml) solution, be stirred at room temperature 6 hours, add water (20ml) it is quenched, dichloromethane extracts (20mlx3), anhydrous sodium sulfate drying, concentrate column chromatography (methylene chloride/methanol (v/v) =10/1) obtain 12mg yellow oil, yield: 70.98%.
ms(esi,pos.ion)m/z:480.0[m+1]+.
Step 5: compound 3- ((4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5h- pyrrolo- [2,3-b] pyrazine -7- base) Cyclohexyl) amino) propionitrile synthesis
3- ((4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5h- pyrroles And [2,3-b] pyrazine -7- base) cyclohexyl) amino) propionitrile (130mg, 0.27mmol), trifluoroacetic acid (2ml) and ethylenediamine (1ml) 16mg faint yellow solid is prepared according to the synthetic method of embodiment 2 step 2, yield: 16.90%.
ms(esi,pos.ion)m/z:350.30[m+1]+；
1h nmr(600mhz,dmso-d6)δ(ppm)11.72(s,1h),9.27(s,1h),8.55(s,1h),8.29(s, 1h), 8.03 (s, 1h), 7.58 (d, j=103.8hz, 1h), 3.91 (s, 3h), 2.94 (m, 5h), 2.19 (d, j=7.4hz, 1h), 1.82 (m, 6h), 1.26 (d, j=28.4hz, 2h).
Embodiment 21
3- (methyl (4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5h- pyrrolo- [2,3-b] pyrazine -7- base) phenyl) ammonia Base) propionitrile
Step 1: compound 3- (methyl (4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (TMS) second Epoxide) methyl) -5h- pyrrolo- [2,3-b] pyrazine -7- base) phenyl) amino) and propionitrile synthesis
At 0 DEG C, by sodium hydride (60%, 55mg, 1.38mmol) be dividedly in some parts 3- ((4- (2- (1- methyl isophthalic acid h- pyrazoles- 4- yl) -5- ((2- (TMS) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrazine -7- base) phenyl) amino) third The n of nitrile (320mg, 0.54mmol), in n- dimethylformamide (15ml) mixed liquor.After stirring 1.5h under room temperature, then at 0 DEG C Under be slowly added dropwise iodomethane (200mg, 2.00mmol), after completion of dropping, stirring reaction 15h under room temperature.Add water (50ml) be quenched Reaction, ethyl acetate (50ml x 3) extracts, and organic layer is washed with saturated aqueous common salt (50ml), anhydrous sodium sulfate drying, concentrates Remove solvent, residue carries out column chromatography for separation (petrol ether/ethyl acetate (v/v)=1/1) and obtains 180mg faint yellow solid, Yield: 54.6%.
ms(esi,pos.ion)m/z:487.9[m+1]+.
Step 2: compound 3- (methyl (4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5h- pyrrolo- [2,3-b] pyrazine - 7- yl) phenyl) amino) and propionitrile synthesis
3- (methyl (4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (TMS) ethyoxyl) methyl) - 5h- pyrrolo- [2,3-b] pyrazine -7- base) phenyl) amino) propionitrile (180mg, 0.37mmol), trifluoroacetic acid (2ml) and second two Amine (1ml) prepares 40mg crocus solid, yield: 30.3% according to the synthetic method of embodiment 2 step 2.
ms(esi,pos.ion)m/z:376.1[m+1]+.
1h nmr(400mhz,dmso-d6): δ (ppm) 11.97 (d, j=2.3hz, 1h), 8.61 (s, 1h), 8.36 (s, 1h), 8.16 (m, 2h), 8.13 (s, 1h), 8.11 (s, 1h), 6.87 (d, j=8.9hz, 2h), 3.94 (s, 3h), 3.71 (t, j =6.7hz, 2h), 2.99 (s, 3h), 2.75 (t, j=6.7hz, 2h)；
13c nmr(100mhz,dmso-d6):δ(ppm)146.80,141.5,140.9,137.1,136.2,134.2, 129.3,127.2,126.4,123.1,121.9,120.1,113.7,113.1,48.4,38.4,32.0,15.2.
Embodiment 22
4- (4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5h- pyrrolo- [2,3-b] pyrazine -7- base) piperidin-1-yl) fourth Nitrile
Step 1: compound 4- (the bromo- 5- of 2- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrrole Piperazine -7- base) -5,6- dihydropyridine -1 (2h)-t-butyl formate synthesis
The iodo- 5- of the bromo- 7- of 2- ((2- (trimethylsilyl) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrazine (600mg, 1.32mmol), 4- (4,4,5,5- tetramethyl -1,3,2- dioxy boron pentane -2- base) -5,6- dihydropyridine -1 (2h)-formic acid uncle Butyl ester (425mg, 1.37mmol), sodium carbonate (356mg, 3.35mmol), pd (pph3)2cl2(100mg, 0.14mmol) and water (6ml) 540mg faint yellow solid is prepared according to the synthetic method of embodiment 1 step 1, yield: 80.23%.
ms(esi,pos.ion)m/z:509.2,511.2[m+1]+.
Step 2: compound 4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (trimethyl silicon substrate) ethyoxyl) first Base) -5h- pyrrolo- [2,3-b] pyrazine -7- base) -5,6- dihydropyridine -1 (2h)-t-butyl formate synthesis
4- (the bromo- 5- of 2- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrazine -7- base) -5, 6- dihydropyridine -1 (2h)-t-butyl formate (325mg, 0.63mmo), potassium carbonate (140mg, 1.01mmol), 1- methylpyrazole Borate (172mg, 0.82mmol) and pd (dppf) cl2(50mg, 0.06mmol) is according to the synthetic method of embodiment 2 step 1 Prepare 270mg yellow solid, yield: 82.88%.
ms(esi,pos.ion)m/z:511.4[m+1]+.
Step 3: compound 4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (trimethyl silicon substrate) ethyoxyl) first Base) -5h- pyrrolo- [2,3-b] pyrazine -7- base) piperidines -1- t-butyl formate synthesis
To 4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrazine -7- base) -5,6- dihydropyridine -1 (2h)-t-butyl formate (270mg, 0.52mmol) methanol (8ml) molten Add pd/c (10%, 30mg, 0.028mmol) in liquid, under an atmosphere of hydrogen, be stirred overnight at room temperature, filter, after concentration, post layer Analysis (petrol ether/ethyl acetate (v/v)=0/1) obtains 250mg yellow oil, yield: 92.23%.
ms(esi,pos.ion)m/z:513.4[m+1]+.
Step 4: compound 2- (1- methyl isophthalic acid h- pyrazoles -4- base) -7- (piperidin-4-yl) -5- ((2- (trimethyl silicon substrate) Ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrazine synthesis
Under ice bath, to 4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) - 5h- pyrrolo- [2,3-b] pyrazine -7- base) piperidines -1- t-butyl formate (250mg, 0.48mmol) methanol (8ml) solution in, Add chloroacetic chloride (70 μ l, 0.97mmol), be stirred overnight at room temperature, reaction finishes, directly concentrate, column chromatography (methylene chloride/methanol (v/v)=8/1) obtain 260mg yellow solid, yield: 99%.
ms(esi,pos.ion)m/z:413.4[m+1]+.
Step 5: compound 4- (4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (trimethylsilyl) ethyoxyl) first Base) -5h- pyrrolo- [2,3-b] pyrazine -7- base) piperidin-1-yl) and butyronitrile synthesis
To 2- (1- methyl isophthalic acid h- pyrazoles -4- base) -7- (piperidin-4-yl) -5- ((2- (trimethyl silicon substrate) ethyoxyl) first Base) -5h- pyrrolo- [2,3-b] pyrazine (130mg, 0.31mmol) acetonitrile (8ml) solution in sequentially add potassium carbonate (110mg, 0.79mmol), potassium iodide (10mg, 0.06mmol) and 4- chlorobutyronitrile (0.05ml, 0.5mmol), 50 DEG C of reacting by heating 24 hours, added water (20ml) dilution, and dichloromethane extracts (20ml x 3), and anhydrous sodium sulfate drying concentrates column chromatography (dichloromethane Alkane/methanol (v/v)=8/1) obtain 120mg yellow oil, yield: 79.40%.
ms(esi,pos.ion)m/z:480.0[m+1]+.
Step 6: compound 4- (4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5h- pyrrolo- [2,3-b] pyrazine -7- base) Piperidin-1-yl) butyronitrile synthesis
4- (4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (trimethylsilyl) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrazine -7- base) piperidin-1-yl) butyronitrile (120mg, 0.25mmol) and trifluoroacetic acid (2ml) be according to embodiment 2 step 2 synthetic method prepares 36mg faint yellow solid, yield: 41.19%.
ms(esi,pos.ion)m/z:351.00[m+1]+；
1h nmr(400mhz,dmso-d6)δ(ppm)11.69(s,1h),8.55(s,1h),8.32(s,1h),8.04(s, 1h), 7.58 (s, 1h), 3.91 (s, 3h), 3.01 (dd, j=126.5,49.0hz, 5h), 2.57 (s, 2h), 1.99 (m, 8h).
Embodiment 23
3- ((3- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5h- pyrrolo- [2,3-b] pyrazine -7- base) cyclohexyl) amino) Propionitrile
Step 1: compound 3- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (TMS) ethyoxyl) first Base) -5h- pyrrolo- [2,3-b] pyrazine -7- base) cyclonene synthesis
Nitrogen protection under, by Isosorbide-5-Nitrae-dioxane (16ml)/water (4ml) be added to the bromo- 2- of 7- (1- methyl isophthalic acid h- pyrazoles- 4- yl) -5- ((2- (TMS) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrazine (500mg, 1.22mmol), 3- (4- (4,4,5,5- tetramethyl -1,3,2- dioxy boron pentane -2- base) cyclonene (650mg, 2.34mmol), potassium carbonate (340mg, 0.2.46mmol) and pd (dppf) cl2In (45mg, 0.06mmol) mixture, 110 DEG C of back flow reaction 8h, reactant liquor It is cooled to room temperature, kieselguhr filters, filtrate reduced in volume carries out post separation (petrol ether/ethyl acetate (v/v)=0/1) and obtains 450mg yellow solid, yield: 69.4%.
ms(esi,pos.ion)m/z:424.0[m+1]+.
Step 2: compound 3- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (TMS) ethyoxyl) first Base) -5h- pyrrolo- [2,3-b] pyrazine -7- base) Hexalin synthesis
Pd/c (10%, 200mg) is added to 3- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (trimethyl silane Base) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrazine -7- base) cyclonene methanol solution in, under room temperature react 24h, Reactant liquor kieselguhr filters, and washs filter cake, filtrate reduced in volume with dichloromethane, carries out post separation (methylene chloride/methanol (v/ V)=15/1) obtain 350mg yellow oil, yield: 77.0%.
ms(esi,pos.ion)m/z:428.0[m+1]+.
Step 3: compound 3- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (TMS) ethyoxyl) first Base) -5h- pyrrolo- [2,3-b] pyrazine -7- base) Ketohexamethylene synthesis
Dess-martin reagent (360mg, 0.85mmol) is added to 3- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (TMS) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrazine -7- base) Hexalin (300mg, In dichloromethane (15ml) solution 0.70mmol), react 3 days under room temperature, quenched with the hypo solution (30ml) of saturation Go out reaction, aqueous phase is extracted with dichloromethane (20ml x 3), organic layer anhydrous sodium sulfate drying carries out post separation (petroleum ether/second Acetoacetic ester (v/v)=1/3) obtain 100mg yellow oil, yield: 33.5%.
ms(esi,pos.ion)m/z:426.0[m+1]+.
Step 4: compound 3- ((3- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (TMS) ethoxy Base) methyl) -5h- pyrrolo- [2,3-b] pyrazine -7- base) cyclohexyl) amino) and propionitrile synthesis
By sodium triacetoxy borohydride (70mg, 0.33mmol) be added to 3- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) - 5- ((2- (TMS) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrazine -7- base) Ketohexamethylene (80mg, 0.19mmol) and in the tetrahydrofuran solution (5ml) of 3- aminopropionitrile (20mg, 0.28mmol), under room temperature, react 2h.Add water (30ml) reaction is quenched, with dichloromethane (30ml x 3) extraction, organic layer anhydrous sodium sulfate drying, carries out post separation (dichloro Methane/methanol (v/v)=30/1) obtain 50mg yellow oil, yield: 55.4%.
ms(esi,pos.ion)m/z:480.4[m+1]+.
Step 5: compound 3- ((3- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5h- pyrrolo- [2,3-b] pyrazine -7- base) Hexamethylene) amino) propionitrile synthesis
3- ((3- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (TMS) ethyoxyl) methyl) -5h- pyrrole Cough up simultaneously [2,3-b] pyrazine -7- base) cyclohexyl) amino) propionitrile (110mg, 0.20mmol), trifluoroacetic acid (2ml) and ethylenediamine (1ml) prepare 25mg yellow solid according to the synthetic method of embodiment 2 step 2, yield: 76.3%.
ms(esi,pos.ion)m/z:350.0[m+1]+.
1h nmr(600mhz,dmso-d6): δ (ppm) 11.58 (d, j=1.8hz, 1h), 8.54 (s, 1h), 8.26 (s, 1h), 8.03 (s, 1h), 7.51 (d, j=2.3hz, 1h), 3.91 (s, 3h), 2.94 (s, 1h), 2.86 (m, 2h), 2.65 (td, j =6.7,1.7hz, 2h), 2.04 (dd, j=31.6,10.8hz, 2h), 1.80 (m, 2h), 1.64 (m, 2h), 1.51 (m, 2h)；
13c nmr(150mhz,dmso-d6):δ(ppm)140.7,140.6,137.3,136.9,134.0,129.0, 126.7,121.9,120.7,119.6,51.8,43.0,39.1,36.9,32.6,30.9,28.1,20.7,18.7.
Embodiment 24
1- ((4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5h- pyrrolo- [2,3-b] pyrazine -7- base) phenyl) sulfonyl) Azetidine -3- formonitrile HCN
Step 1: the synthesis of compound 1- ((4- bromophenyl) sulfonyl) azetidine -3- formonitrile HCN
Under nitrogen protection, dichloromethane (12ml) is added to 4- bromobenzene sulfonyl chloride (252mg, 0.99mmol), 3- acetonitrile In ring butylamine hydrochloride (90mg, 0.76mmol), triethylamine (230mg, 2.28mmol), room temperature reaction 12h, reactant liquor acetic acid Ethyl ester extracts (50mlx3), is spin-dried for organic faciess, it is white that column chromatography for separation (petrol ether/ethyl acetate (v/v)=3/1) obtains 179mg Color solid, yield: 78.3%.
1h nmr(400mhz,dmso-d6): δ (ppm) 7.94 (d, j=8.5hz, 2h), 7.78 (d, j=8.5hz, 2h), 4.00 (t, j=8.7hz, 2h), 3.87 (dd, j1=8.5hz, j2=5.9hz, 2h), 3.69 3.58 (m, 1h).
Step 2: compound 1- ((4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (TMS) ethoxy Base) methyl) -5h- pyrrolo- [2,3-b] pyrazine -7- base) phenyl) sulfonyl) and azetidine -3- formonitrile HCN synthesis
Nitrogen protection under, by Isosorbide-5-Nitrae-dioxane (12ml) be added to 1- ((4- bromophenyl) sulfonyl) azetidine- 3- formonitrile HCN (148mg, 0.49mmol), connection pinacol borate (138mg, 0.54mmol), potassium acetate (150mg, 1.53mmol), pd(dppf)cl2In (23mg, 0.03mmol) mixture, 110 DEG C of back flow reaction 11h, reactant liquor is cooled to room temperature, and nitrogen is protected Under, add water (2.5ml), potassium carbonate (130mg, 0.93mmol), the bromo- 2- of 7- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (TMS) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrazine (120mg, 0.29mmol), pd (dppf) cl2 (23mg, 0.03mmol), 110 DEG C of back flow reaction 10h, reactant liquor is cooled to room temperature, and kieselguhr filters, and filtrate reduced in volume enters Row post separation (petrol ether/ethyl acetate (v/v)=1/2) obtains 150mg yellow solid, yield: 55.5%.
ms(esi,pos.ion)m/z:549.8[m+1]+.
Step 3: compound 1- ((4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5h- pyrrolo- [2,3-b] pyrazine -7- base) Phenyl) sulfonyl) azetidine -3- formonitrile HCN synthesis
1- ((4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (TMS) ethyoxyl) methyl) -5h- pyrrole Cough up simultaneously [2,3-b] pyrazine -7- base) phenyl) sulfonyl) azetidine -3- formonitrile HCN (150mg, 0.27mmol), trifluoroacetic acid (6ml) with ethylenediamine (1ml), 91mg light yellow solid is prepared according to the synthetic method of embodiment 2 step 2, yield: 79.5%.
ms(esi,pos.ion)m/z:419.9[m+1]+；
1h nmr(600mhz,dmso-d6+d2O): δ (ppm) 8.72 (d, j=8.4hz, 2h), 8.72 (s, 1h), 8.65 (s, 1h), 8.49 (s, 1h), 8.21 (s, 1h), 7.90 (d, j=8.4hz, 2h), 4.02 (t, j=8.7hz, 2h), 3.95 (s, 3h),3.88(dd,j1=8.3hz, j2=6.2hz, 2h), 3.65 (m, 1h)；
13c nmr(150mhz,dmso-d6):δ(ppm)142.5,141.2,140.2,137.4,136.3,135.1, 130.6,129.8,129.3,129.2,126.3,121.5,120.3,111.3,53.8,40.5,39.3,17.2.
Embodiment 25
3- ((4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5h- pyrrolo- [2,3-b] pyrazine -7- base) phenyl) sulfonyl) Propionitrile
Step 1: compound 3- ((4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (TMS) ethoxy Base) methyl) -5h- pyrrolo- [2,3-b] pyrazine -7- base) phenyl) thio) synthesis of propionitrile
Potassium carbonate (76mg, 0.55mmol), the bromo- 2- of 7- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (trimethyl silane Base) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrazine (90mg, 0.22mmol), 3- ((4- (4,4,5,5- tetramethyl -1, 3,2- dioxy boron pentane -2- base) phenyl) thio) propionitrile (95mg, 0.33mmol) and pd (dppf) cl2(7mg,0.01mmol) 45mg yellow oil is prepared according to the synthetic method of embodiment 1 step 1, yield: 41.6%.
ms(esi,pos.ion)m/z:491.3[m+1]+.
Step 2: compound 3- ((4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5h- pyrrolo- [2,3-b] pyrazine -7- base) Phenyl) thio) synthesis of propionitrile
3- ((4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (TMS) ethyoxyl) methyl) -5h- pyrrole Cough up simultaneously [2,3-b] pyrazine -7- base) phenyl) thio) propionitrile (45mg, 0.09mmol), trifluoroacetic acid (6ml) and ethylenediamine (1ml) The shallow white solid of 27mg, yield: 81.7% are prepared according to the synthetic method of embodiment 2 step 2.
ms(esi,pos.ion)m/z:361.2[m+1]+.
Step 3: compound 3- ((4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5h- pyrrolo- [2,3-b] pyrazine -7- base) Phenyl) sulfonyl) propionitrile synthesis
Under room temperature, 3- ((4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5h- pyrrolo- [2,3-b] pyrazine -7- base) phenyl) Thio) propionitrile (36mg, 0.10mmol) is dissolved in dichloromethane (10ml), add metachloroperbenzoic acid (60mg, 0.30mmol), room temperature reaction 12h, reactant liquor adds silica gel, and room temperature is spin-dried for mixing sample, column chromatography for separation (methylene chloride/methanol (v/ V)=20/1) obtain 43mg light yellow solid, then obtain 6mg field gray solid, yield: 15.3% with preparing thin layer and purify.
ms(esi,pos.ion)m/z:393.2[m+1]+；
1h nmr(600mhz,dmso-d6): δ (ppm) 8.71 (s, 1h), 8.66 (d, j=8.4hz, 2h), 8.64 (s, 1h), 8.48 (s, 1h), 8.19 (s, 1h), 7.97 (d, j=8.4hz, 2h), 3.95 (s, 3h), 3.74 (t, j=6.8hz, 2h), 2.89 (t, j=6.8hz, 2h)；
13c nmr(150mhz,dmso-d6):δ(ppm)142.5,140.5,137.4,136.3,135.1,134.4, 130.7,130.1,129.8,129.0,126.2,121.5,118.3,111.3,50.3,39.3,12.1.
Using corresponding raw material, the synthetic method according to embodiment 24 prepares compound as follows:
Embodiment 38
2- ((4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5h- pyrrolo- [2,3-b] pyrazine -7- base) phenyl) amino) second Nitrile
Step 1: compound 4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (TMS) ethyoxyl) first Base) -5h- pyrrolo- [2,3-b] pyrazine -7- base) aniline synthesis
The bromo- 2- of 7- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (TMS) ethyoxyl) methyl) -5h- pyrroles And [2,3-b] pyrazine (200mg, 0.49mmol), 4- (4,4,5,5- tetramethyl -1,3,2- dioxy boron pentane -2- base) aniline The double Diphenyl phosphino ferrocene palladium chloride of (150mg, 0.68mmol), potassium carbonate (120mg, 0.87mmol) and 1,1'- (20mg, 0.03mmol) 180mg yellow oil is prepared according to the synthetic method of embodiment 1 step 1, yield: 72.3%.
ms(esi,pos.ion)m/z:421.0[m+1]+.
Step 2: compound 2- ((4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (TMS) ethoxy Base) methyl) -5h- pyrrolo- [2,3-b] pyrazine -7- base) phenyl) amino) and acetonitrile synthesis
2- bromoacetonitrile (70mg, 0.60mmol, 0.04ml) will be added to 4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (TMS) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrazine -7- base) aniline (180mg, 0.42mmol) In potassium carbonate (90mg, 0.65mmol), the solution of the acetonitrile (15ml) of potassium iodide (110mg, 0.66mmol), reactant liquor is 90 DEG C back flow reaction overnight, is cooled to room temperature, and kieselguhr filters, concentrating under reduced pressure, and concentrated solution carries out post separation (petroleum ether/acetic acid second Ester (v/v)=0/1) obtain 140mg khaki solid, yield: 71.2%.
ms(esi,pos.ion)m/z:460.4[m+1]+.
Step 3: compound 2- ((4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5h- pyrrolo- [2,3-b] pyrazine -7- base) Phenyl) amino) acetonitrile synthesis
2- ((4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (TMS) ethyoxyl) methyl) -5h- pyrrole Cough up simultaneously [2,3-b] pyrazine -7- base) phenyl) amino) acetonitrile (130mg, 0.28mmol), trifluoroacetic acid (2ml) and ethylenediamine (1ml) 50mg yellow solid is prepared according to the synthetic method of embodiment 2 step 2, yield: 53.7%.
ms(esi,pos.ion)m/z:329.9[m+1]+；
1h nmr(600mhz,dmso-d6):δ(ppm)11.99(s,1h),8.62(s,1h),8.38(s,1h),8.17(d, J=2.6hz, 1h), 8.13 (s, 1h), 8.12 (s, 2h), 6.83 (d, j=8.6hz, 2h), 6.24 (t, j=6.9hz, 1h), 4.30 (d, j=6.8hz, 2h), 3.94 (s, 3h)；
13c nmr(150mhz,dmso-d6):δ(ppm)145.1,141.5,140.8,137.1,136.1,134.3, 129.4,127.1,126.6,124.4,121.8,119.2,113.7,113.6,40.4,39.2.
Embodiment 40
2- methyl -2- ((2- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5h- pyrrolo- [2,3-b] pyrazine -7- base) pyrimidine - 4- yl) amino)-n- (2,2,2- trifluoroethyl) butyramide
Step 1: compound (r) -2- methyl -2- ((2- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- trityl -5h- Pyrrolo- [2,3-b] pyrazine -7- base) pyrimidine-4-yl) amino) and-n- (2,2,2- trifluoroethyl) butyramide synthesis
(r) -2- ((2- (2- chloro- 5- trityl -5h- pyrrolo- [2,3-b] pyrazine -7- base) pyrimidine-4-yl) amino) - 2- methyl-n- (2,2,2- trifluoroethyl) butyramide (240mg, 0.36mmol), potassium carbonate (75mg, 0.54mmol), 1- methyl- 4- pyrazoles borate (115mg, 0.55mmol) and pd (dppf) cl2(30mg, 0.04mmol) is according to the conjunction of embodiment 2 step 1 One-tenth method prepares 120mg pale solid, yield: 46.81%.
ms(esi,pos.ion)m/z:716.45[m+1]+.
Step 2: compound 2- methyl -2- ((2- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5h- pyrrolo- [2,3-b] pyrrole Piperazine -7- base) pyrimidine-4-yl) amino) and-n- (2,2,2- trifluoroethyl) butyramide synthesis
(r) -2- methyl -2- ((2- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- trityl -5h- pyrrolo- [2,3-b] Pyrazine -7- base) pyrimidine-4-yl) amino)-n- (2,2,2- trifluoroethyl) butyramide (110mg, 0.15mmol), trifluoroacetic acid (330 μ l, 4.443mmol) and triethyl silicane (670 μ l, 4.19mmol) are prepared into according to the synthetic method of embodiment 2 step 2 To 20mg yellow solid, yield: 27.49%.
ms(esi,pos.ion)m/z:474.30[m+1]+；
1h nmr(600mhz,cd3od)δ(ppm)8.70(s,1h),8.49(s,1h),8.45(s,1h),8.31(s,1h), 8.26 (m, 1h), 6.62 (s, 1h), 4.02 (s, 3h), 3.85 (m, 2h), 2.24 (dd, j=21.7,6.4hz, 1h), 2.03 (dd, j=19.9,10.2hz, 1h), 1.66 (s, 3h), 0.98 (t, j=9.4hz, 3h)；
13c nmr(150mhz,cd3od)δ(ppm)175.8,161.2,143.2,140.8,137.4,135.8,135.3, 129.9,129.4,128.4,125.5,125.3,123.5,121.2,103.8,60.8,48.1,40.1,37.7,20.5,6.7.
Embodiment 62
(r)-n- (2- nitrile ethyl) -3- (2- (1- (2- hydroxypropyl) -1h- pyrazoles -4- base) -5h- pyrrolo- [2,3-b] pyrrole Piperazine -7- base) benzsulfamide
Step 1: compound (r)-n- (2- cyanoethyl) -3- (2- (1- (2- hydroxypropyl) -1h- pyrazoles -4- base) -5- ((2- (TMS) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrazine -7- base) and benzsulfamide synthesis
Under room temperature, by cesium carbonate (840mg, 2.58mmol), 4- (4,4,5,5- tetramethyl -1,3,2- dioxy boron pentane -2- Base) -1h- pyrazoles (250mg, 1.29mmol) and (r)-expoxy propane (285mg, 4.91mmol) added together, add acetonitrile (15ml), tube sealing is warming up to 130 DEG C of reaction 22h, and reactant liquor is extracted with ethyl acetate (50ml × 3), is spin-dried for organic faciess.Nitrogen is protected Under shield, addition 3- (the bromo- 5- of 2- ((2- (TMS) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrazine -7- base) - N- (2- cyanoethyl) benzsulfamide (150mg, 0.28mmol), potassium carbonate (100mg, 0.72mmol), [double (diphenylphosphine of 1,1'- Base) ferrocene] palladium chloride (12mg, 0.02mmol), add dioxane (15ml), water (3ml), 110 DEG C are reacted 24h, Reactant liquor is cooled to room temperature, and kieselguhr filters, and filtrate reduced in volume carries out post separation (ethyl acetate) and obtains 150mg yellow oil Shape thing, yield: 92.2%.
ms(esi,pos.ion)m/z:582.3[m+1]+.
Step 2: compound (r)-n- (2- nitrile ethyl) -3- (2- (1- (2- hydroxypropyl) -1h- pyrazoles -4- base) -5h- pyrroles And [2,3-b] pyrazine -7- base) benzsulfamide synthesis
(r)-n- (2- cyanoethyl) -3- (2- (1- (2- hydroxypropyl) -1h- pyrazoles -4- base) -5- ((2- (trimethyl silane Base) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrazine -7- base) benzsulfamide (160mg, 0.28mmol), trifluoroacetic acid (6ml) with ethylenediamine (1ml), 56mg white solid is prepared according to the synthetic method of embodiment 2 step 2, yield: 45.1%.
ms(esi,pos.ion)m/z:452.4[m+1]+；
1h nmr(600mhz,dmso-d6):δ(ppm)8.98(s,1h),8.71(s,1h),8.52(s,1h),8.49(d,j =7.3hz, 1h), 8.39 (s, 1h), 8.19 (s, 1h), 7.72 7.63 (m, 2h), 5.00 (s, 2h), 4.16 3.99 (m, 3h), 3.09 (t, j=6.4hz, 2h), 2.68 (t, j=6.4hz, 2h), 1.10 (d, j=5.8hz, 3h)；
13c nmr(150mhz,dmso-d6):δ(ppm)142.3,141.0,140.9,137.4,136.0,135.5, 135.0,130.1,129.4,129.4,129.3,123.9,123.8,121.2,119.4,111.5,65.9,59.4,39.2, 21.4,19.1.
With corresponding raw material, the synthetic method according to embodiment 62 prepares compound as follows:
Embodiment 72
3- (4- (4- (2- cyclopropyl -5h- pyrrolo- [2,3-b] pyrazine -7- base) -1h- pyrazol-1-yl) piperidin-1-yl) - 3- oxygen propionitrile
Step 1: compound 1- t-butyl formate -4- ((4- (2- cyclopropyl -5- ((2- (TMS) ethyoxyl) Methyl) -5h- pyrrolo- [2,3-b] pyrazine -7- base) -1h- pyrazol-1-yl)) synthesis of piperidines
1,4- dioxane (16ml)/water (4ml), 1- t-butyl formate -4- ((4- (2- bromo- 5- ((2- (trimethyl silane Base) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrazine -7- base) -1h- pyrazol-1-yl)) piperidines (430mg, 0.74mmol), the double diphenylphosphine two of cyclopropylboronic acid (95mg, 1.11mmol), potassium carbonate (160mg, 1.16mmol) and 1,1'- It is yellow that the mixture of luxuriant ferrum palladium chloride (30mg, 0.04mmol) prepares 280mg according to the synthetic method of embodiment 2 step 1 Color grease, yield: 69.8%.
ms(esi,pos.ion)m/z:539.4[m+1]+.
Step 2: compound 2- cyclopropyl -7- (1- (piperidin-4-yl) -1h- pyrazoles -4- base) -5h- pyrrolo- [2,3-b] The synthesis of pyrazine
1- t-butyl formate -4- ((4- (2- cyclopropyl -5- ((2- (TMS) ethyoxyl) methyl) -5h- pyrroles And [2,3-b] pyrazine -7- base) -1h- pyrazol-1-yl)) piperidines (260mg, 0.48mmol), trifluoroacetic acid (2ml) and ethylenediamine (1ml) 110mg faint yellow solid is prepared according to the synthetic method of embodiment 2 step 2, yield: 73.9%.
ms(esi,pos.ion)m/z:309.3[m+1]+.
Step 3: compound 3- (4- (4- (2- cyclopropyl -5h- pyrrolo- [2,3-b] pyrazine -7- base) -1h- pyrazoles -1- Base) piperidin-1-yl) -3- oxygen propionitrile synthesis
By 2- cyclopropyl -7- (1- (piperidin-4-yl) -1h- pyrazoles -4- base) -5h- pyrrolo- [2,3-b] pyrazine (100mg, 0.32mmol) it is added to cyanoacetic acid (65mg, 0.76mmol), I-hydroxybenzotriazole (hobt) (110mg, 0.81mmol), 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (150mg, 0.78mmol) and triethylamine (0.08g, 0.1ml, 0.80mmol) n, in n- dimethylformamide (5ml) mixture, under room temperature react 6h, be quenched instead with water (50ml) Should, ethyl acetate extracts (50ml x 4), and organic layer is washed, anhydrous sodium sulfate drying with saturated aqueous common salt (50ml x 2), subtracts Pressure concentrates, and concentrated solution carries out post separation (methylene chloride/methanol (v/v)=12/1) and obtains 80mg faint yellow solid, yield: 65.7%.
ms(esi,pos.ion)m/z:375.9[m+1]+；
1h nmr(600mhz,dmso-d6): δ (ppm) 11.81 (s, 1h), 8.23 (d, j=6.8hz, 2h), 8.01 (s, 1h), 8.00 (d, j=2.6hz, 1h), 4.52 (m, 1h), 4.43 (d, j=13.2hz, 1h), 4.12 (q, j=18.9hz, 2h), 3.79 (d, j=13.7hz, 1h), 3.25 (m, 1h), 2.86 (t, j=11.8hz, 1h), 2.28 (m, 1h), 2.09 (m, 2h), 1.99(m,1h),1.82(m,1h),1.03(m,4h)；
13c nmr(150mhz,dmso-d6):δ(ppm)161.8,150.8,140.8,136.4,136.1,135.8, 125.9,124.7,116.6,114.2,106.5,57.9,44.8,41.1,32.7,32.1,25.3,14.8,10.2.
Prepare according to the synthetic method of embodiment 72 with corresponding raw material, prepare following compound:
Embodiment 90
5- ((3- propionamido- phenyl) amido) pyrazolo [1,5-a] pyrimidine -3- methyl formate
Step 1: the synthesis of compound 3- iodopyrazol theta [1,5-a] pyrimidine -5- hydroxyl
By pyrazoles [1,5-a] pyrimidine -5- hydroxyl (1g, 7.40mmol) and n- N-iodosuccinimide (1.83g, 8.14mmol) dissolve in n, n- dimethylformamide (20ml), reaction meeting slowly heat release at room temperature, in a few minutes, have a large amount of solids Generate, reaction is stirred at room temperature 1 hour.Cool down under ice bath, filter, collect white solid, with dichloromethane (20ml) filter wash Cake, is dried to obtain 1.7g white solid, yield: 88%.
1h nmr(600mhz,dmso-d6):δ(ppm)12.24(s,1h),8.48(s,1h),7.84(s,1h),6.00(s, 1h).
Step 2: the synthesis of compound 5- hydroxypyrazoles [1,5-a] pyrimidine -3- methyl formate
n2Under protection by methanol (10ml) injection 3- iodopyrazol theta simultaneously [1,5-a] pyrimidine -5- hydroxyl (0.2g, 0.76mmol), in the mixture of palladium (35mg, 0.15mmol) and triethylamine (0.32ml, 2.3mmol), it is passed through an oxidation Carbon, 5h is reacted in reaction at 55 DEG C.Kieselguhr filters, concentrating under reduced pressure, and washing residue (35ml) is extracted with dichloromethane (35mlx3), anhydrous sodium sulfate drying, concentrating under reduced pressure, carry out post separation (methylene chloride/methanol (v/v)=30/1) and obtain 45mg White solid, yield: 30.4%.
1h nmr(400mhz,dmso-d6): δ (ppm) 11.87 (s, 1h), 8.57 (d, j=7.9hz, 1h), 8.15 (s, 1h),6.16(s,1h),3.77(s,3h).
Step 3: the synthesis of compound 5- chlorine pyrazolo [1,5-a] pyrimidine -3- methyl formate
5- hydroxypyrazoles [1,5-a] pyrimidine -3- methyl formate (0.028g, 0.14mmol), phosphorus oxychloride (0.8ml, 8mmol) and n, n- diisopropylethylamine (0.01ml, 0.06mmol) back flow reaction 2h in toluene (2ml) solution.It is cooled to room Temperature, is removed under reduced pressure phosphorus oxychloride, and residue warm water (35ml) is quenched, and dichloromethane (35ml x 3) extracts, and anhydrous sodium sulfate is done Dry, concentrating under reduced pressure, carry out post separation (methylene chloride/methanol (v/v)=80/1) and obtain 19mg white solid, yield: 61.9%.
1h nmr(400mhz,dmso-d6): δ (ppm) 9.33 (d, j=7.2hz, 1h), 8.68 (s, 1h), 7.41 (d, j= 7.2hz,1h),3.83(s,3h).
Step 4: the synthesis of compound 5- ((3- propionamido- phenyl) amido) pyrazoles [1,5-a] pyrimidine -3- methyl formate
n2Under protection, Isosorbide-5-Nitrae-dioxane (8ml) is added to 5- chlorine pyrazoles [1,5-a] pyrimidine -3- methyl formate (0.08g, 0.37mmol), xantphos (0.011g, 0.02mmol), palladium (4mg, 0.02mmol), cesium carbonate (0.14g, 0.42mmol) and in the mixture of n- (3- amido benzene) propionic acid amide. (0.08g, 0.48mmol), 110 DEG C of back flow reaction 6h, filter, Filtrate water (30ml) is washed, and aqueous phase, with dichloromethane back extraction (30ml x 3), merges organic layer, anhydrous sodium sulfate drying, decompression Concentrate, carry out post separation (methylene chloride/methanol (v/v)=30/1) and obtain yellow-brown solid, recycle high efficiency chromatography method to separate Obtain 20mg buff white solid, yield: 15.59%.
ms(esi,pos.ion)m/z:340.1[m+1]+；
1h nmr(600mhz,dmso-d6): δ (ppm) 10.08 (s, 1h), 9.87 (s, 1h), 8.75 (d, j=7.6hz, 1h), 8.36 (d, j=6.7hz, 1h), 8.29 (s, 1h), 7.94 (s, 1h), 7.30 (t, j=8.1hz, 1h), 7.12 (d, j= 7.8hz, 1h), 6.70 (d, j=7.6hz, 1h), 3.81 (s, 3h), 2.34 (q, j=7.5hz, 2h), 1.11 (t, j=7.5hz, 3h)；
13c nmr(150mhz,dmso-d6):δ(ppm)172.0,162.6,154.7,147.2,146.0,140.0, 139.4,136.4,129.0,114.2,113.9,110.3,102.2,98.5,50.7,29.5,9.7.
Embodiment 91
N- (2- cyanoethyl) -3- (1,6- pyrrolin [2,3-b] [1,2,3] triazole [4,5-d] pyridine -8- base) benzene sulphur Amide
Step 1: the synthesis of compound 4-chloro -1- p-toluenesulfonyl -1h- pyrroles [2,3-b] pyridine
Under room temperature, by chloro- for 4- 1h- pyrroles [2,3-b] pyridine (1.50g, 9.80mmol), triethylamine (1.81g, 18.01mmol), dmap (205mg, 1.59mmol) is added together, sequentially adds dichloromethane (20ml), paratoluensulfonyl chloride (2.25g, 11.80mmol), room temperature reaction 36h, reactant liquor add water (50ml) be quenched, with dichloromethane extract (50ml × 3), rotation Dry organic faciess, column chromatography for separation (petrol ether/ethyl acetate (v/v)=10/1) obtains 1.46g white solid, yield 49.1%.
ms(esi,pos.ion)m/z:306.9[m+1]+.
Step 2: the synthesis of compound 4-chloro -5- nitro -1- p-toluenesulfonyl -1h- pyrroles [2,3-b] pyridine
At -5 DEG C, by chloro- for 4- 1- p-toluenesulfonyl -1h- pyrroles [2,3-b] pyridine (1.48g, 4.82mmol), four fourths Base ammonium nitrate (1.84g, 5.86mmol), dichloromethane (30ml) are added together, are then slowly added into trifluoroacetic anhydride (0.92ml, 6.50mmol), be warmed to room temperature after adding reaction 6h, add at -5 DEG C tetrabutyl ammonium nitrate (0.46g, 1.45mmol), trifluoroacetic anhydride (0.28ml, 2.01mmol), is warmed to room temperature reaction 18h after adding, reactant liquor adds water (70ml) It is quenched, extract (100ml × 3) with dichloromethane, be spin-dried for organic faciess, column chromatography for separation (petrol ether/ethyl acetate (v/v)=10/ 1) obtain 1.21g white solid, yield: 71.6%.
ms(esi,pos.ion)m/z:352.1[m+1]+.
Step 3: the synthesis of compound 5- nitro -1- p-toluenesulfonyl -1h- pyrroles [2,3-b] pyridine -4- amine
Under room temperature, by chloro- for 4- 5- nitro -1- p-toluenesulfonyl -1h- pyrroles [2,3-b] pyridine (300mg, 0.85mmol), strong aqua ammonia (2ml) is added together, sequentially adds dioxane (20ml), 80 DEG C of reaction 6h, reactant liquor cools down To room temperature, add water (50ml) dilution, extracts (50ml × 3) with dichloromethane, is spin-dried for organic faciess, column chromatography for separation (petroleum ether/second Acetoacetic ester (v/v)=4/1) obtain 130mg yellow solid, yield: 45.9%.
ms(esi,pos.ion)m/z:333.2[m+1]+.
Step 4: the synthesis of compound 1- p-toluenesulfonyl -1h- pyrroles [2,3-b] pyrazine -4,5- diamidogen
Under room temperature, by 5- nitro -1- p-toluenesulfonyl -1h- pyrroles [2,3-b] pyridine -4- amine (130mg, 0.39mmol), ammonium chloride (124mg, 2.34mmol), iron powder (90mg, 1.61mmol) are added together, add ethanol (10ml), water (3ml), 90 DEG C of reaction 4h, reactant liquor is cooled to room temperature, and add water after kieselguhr filtration (50ml) dilution, uses acetic acid Ethyl ester extracts (50ml × 3), is spin-dried for organic faciess, column chromatography for separation (methylene chloride/methanol (v/v)=20/1) obtains 80mg brown Grease, yield: 67.6%.
ms(esi,pos.ion)m/z:303.2[m+1]+.
Step 5: compound 6- p-toluenesulfonyl -1,6- pyrrolin [2,3-b] [1,2,3] triazole [4,5-d] pyrrole The synthesis of pyridine
By 1- p-toluenesulfonyl -1h- pyrroles [2,3-b] pyrazine -4,5- diamidogen (70mg, 0.23mmol), sodium nitrite (19mg, 0.28mmol) is added together, adds acetic acid (8ml), room temperature reaction 3h, and add water (50ml) dilution, uses ethyl acetate Extraction (50ml × 3), is spin-dried for organic faciess, it is light yellow that column chromatography for separation (petrol ether/ethyl acetate (v/v)=1/2) obtains 40mg Solid, yield: 55.2%.
ms(esi,pos.ion)m/z:314.3[m+1]+；
1h nmr(400mhz,dmso-d6): δ (ppm) 9.19 (s, 1h), 8.03 (t, j=5.5hz, 3h), 7.43 (d, j= 8.3hz, 2h), 7.07 (d, j=3.9hz, 1h), 2.34 (s, 3h).
Step 6: compound 8- bromo- 6- p-toluenesulfonyl -1,6- pyrrolin [2,3-b] [1,2,3] triazole [4,5- D] pyridine synthesis
Under room temperature, by 6- p-toluenesulfonyl -1,6- pyrrolin [2,3-b] [1,2,3] triazole [4,5-d] pyridine (150mg, 0.48mmol), nbs (128mg, 0.72mmol) are added together, add dmf (10ml), room temperature reaction 10h, add water (50ml) dilute, be extracted with ethyl acetate (50ml × 3), be spin-dried for organic faciess, column chromatography for separation (petrol ether/ethyl acetate (v/v) =1/2) obtain 160mg light yellow solid, send hplc to prepare 79mg light yellow solid, yield: 42.1%.
ms(esi,pos.ion)m/z:392.0[m+1]+；
1h nmr(400mhz,dmso-d6+d2O): δ (ppm) 9.23 (s, 1h), 8.26 (s, 1h), 8.04 (d, j= 8.4hz, 2h), 7.42 (d, j=8.2hz, 2h), 2.31 (s, 3h).
Step 7: compound n- (2- cyanoethyl) -3- (6- p-toluenesulfonyl -1,6- pyrrolin [2,3-b] [1,2,3] Triazole [4,5-d] pyridine -8- base) benzsulfamide synthesis
Under nitrogen protection, Isosorbide-5-Nitrae-dioxane (12ml)/water (3ml) is added to n- (2- cyanoethyl) -3- (4,4,5,5- Tetramethyl -1,3,2- dioxaborinate -2- base) benzsulfamide (132mg, 0.39mmol), 8- bromo- 6- p-toluenesulfonyl -1, 6- pyrrolin [2,3-b] [1,2,3] triazole [4,5-d] pyridine (79mg, 0.20mmol), potassium carbonate (73mg, 0.52mmol)、pd(dppf)cl2In (12mg, 0.02mmol) mixture, 110 DEG C of back flow reaction 7h, reactant liquor is cooled to room Temperature, kieselguhr filters, and filtrate reduced in volume carries out post separation (petrol ether/ethyl acetate (v/v)=1/3) and obtains 95mg brown Grease, yield: 90.5%.
ms(esi,pos.ion)m/z:522.2[m+1]+.
Step 8: compound n- (2- cyanoethyl) -3- (1,6- pyrrolin [2,3-b] [1,2,3] triazole [4,5-d] pyrrole Pyridine -8- base) benzsulfamide synthesis
Under room temperature, by n- (2- cyanoethyl) -3- (6- p-toluenesulfonyl -1,6- pyrrolin [2,3-b] [1,2,3] three Nitrogen azoles [4,5-d] pyridine -8- base) benzsulfamide (106mg, 0.20mmol), potassium tert-butoxide (100mg, 0.84mmol) be added to one Rise, add anhydrous tetrahydro furan (5ml), room temperature reaction 3h, reactant liquor adds silica gel room temperature to be spin-dried for mixing sample, column chromatography for separation (methylene chloride/methanol (v/v)=10/1) obtains 100mg red solid, then prepares 50mg white solid with hplc, produces Rate: 67.0%.
ms(esi,pos.ion)m/z:368.0[m+1]+；
1h nmr(600mhz,dmso-d6): δ (ppm) 11.77 (s, 1h), 9.16 (d, j=7.8hz, 1h), 8.94 (s, 1h), 8.75 (s, 1h), 7.80 (s, 1h), 7.65 (t, j=7.8hz, 1h), 7.57 (d, j=7.9hz, 1h), 5.33 (t, j= 4.6hz, 1h), 3.21 (t, j=6.3hz, 2h), 2.80 (t, j=6.3hz, 2h)；
13c nmr(150mhz,dmso-d6):δ(ppm)143.5,143.3,141.1,138.1,136.2,130.7, 130.1,129.7,123.9,122.5,119.7,119.4,114.8,105.1,35.6,19.2.
Embodiment 92
N- (2- cyanoethyl) -3- (1- methyl isophthalic acid, 6- pyrrolin [2,3-b] [1,2,3] triazole [4,5-d] pyridine -8- Base) benzsulfamide
Step 1: compound n- methyl-5-nitro -1- p-toluenesulfonyl -1h- pyrrolo- [2,3-b] pyridine -4- amine Synthesis
By chloro- for 4- 5- nitro -1- p-toluenesulfonyl -1h- pyrrolo- [2,3-b] pyridine (300mg, 0.85mmol), first It is solid that amine ethanol solution (6.38m, 15ml, 95.7mmol) prepares 184mg yellow according to the synthetic method of embodiment 15 step 3 Body, yield: 62.3%.
ms(esi,pos.ion)m/z:333.2[m+1]+.
Step 2: the synthesis of compound n- methyl isophthalic acid-p-toluenesulfonyl -1h- pyrrolo- [2,3-b] pyridine -4,5- diamidogen
By n- methyl-5-nitro -1- p-toluenesulfonyl -1h- pyrrolo- [2,3-b] pyridine -4- amine (40mg, 0.12mmol), ammonium chloride (37mg, 0.70mmol), iron powder (26mg, 0.47mmol) ethanol (10ml), water (3ml) are according to enforcement The synthetic method of example 15 step 4 prepares 20mg red solid, yield: 54.7%.
ms(esi,pos.ion)m/z:317.2[m+1]+.
Step 3: compound 1- methyl -6- p-toluenesulfonyl -1,6- pyrrolin [2,3-b] [1,2,3] triazole [4, 5-d] pyridine synthesis
By n- methyl isophthalic acid-p-toluenesulfonyl -1h- pyrroles [2,3-b] pyridine -4,5- diamidogen (215mg, 0.68mmol), It is shallow that sodium nitrite (56mg, 0.81mmol) and acetic acid (8ml) prepare 150mg according to the synthetic method of embodiment 15 step 5 Yellow solid, yield: 67.2%.
ms(esi,pos.ion)m/z:328.2[m+1]+.
Step 4: compound 1- methyl -8- bromo- 6- p-toluenesulfonyl -1,6- pyrrolin [2,3-b] [1,2,3] three nitrogen The synthesis of azoles [4,5-d] pyridine
By 1- methyl -6- p-toluenesulfonyl -1,6- pyrrolin [2,3-b] [1,2,3] triazole [4,5-d] pyridine (156mg, 0.48mmol), nbs (128mg, 0.72mmol), dmf (10ml) are prepared according to the synthetic method of embodiment 15 step 6 Obtain 160mg light yellow solid, send hplc to prepare 53mg light yellow solid, yield: 27.3%.
ms(esi,pos.ion)m/z:406.1[m+1]+；
1h nmr(400mhz,dmso-d6): δ (ppm) 9.26 (s, 1h), 8.34 (s, 1h), 8.07 (d, j=8.4hz, 2h), 7.44 (d, j=8.2hz, 2h), 4.69 (s, 3h), 2.34 (s, 3h).
Step 5: compound n- (2- cyanoethyl) -3- (1- methyl -6- p-toluenesulfonyl -1,6- pyrrolin [2,3-b] [1,2,3] triazole [4,5-d] pyridine -8- base) benzsulfamide synthesis
1,4- dioxane (12ml)/water (3ml), n- (2- cyanoethyl) -3- (4,4,5,5- tetramethyl -1,3,2- dioxy Miscellaneous borine -2- base) benzsulfamide (82mg, 0.24mmol), 1- methyl -8- bromo- 6- p-toluenesulfonyl -1,6- pyrrolin [2,3-b] [1,2,3] triazole [4,5-d] pyridine (53mg, 0.14mmol), potassium carbonate (50mg, 0.36mmol), pd (dppf) cl2The mixture of (7mg, 0.01mmol) prepares 60mg light yellow solid according to the synthetic method of embodiment 15 step 7, produces Rate: 85.8%.
ms(esi,pos.ion)m/z:536.2[m+1]+.
Step 6: compound n- (2- cyanoethyl) -3- (1- methyl isophthalic acid, 6- pyrrolin [2,3-b] [1,2,3] triazole [4,5-d] pyridine -8- base) benzsulfamide synthesis
N- (2- cyanoethyl) -3- (6- p-toluenesulfonyl -1,6- pyrrolin [2,3-b] [1,2,3] triazole [4,5- D] pyridine -8- base) benzsulfamide (76mg, 0.14mmol), potassium tert-butoxide (50mg, 0.42mmol) is according to embodiment 15 step 8 Synthetic method prepare 60mg light yellow oil, then obtain 30mg soil with the making beating of the mixed liquor of methylene chloride/methanol Gray solid, yield: 55.4%.
ms(esi,pos.ion)m/z:382.2[m+1]+；
1h nmr(600mhz,dmso-d6):δ(ppm)12.67(s,1h),9.08(s,1h),8.15(s,1h),7.98(s, 1h), 7.92 (d, j=7.5hz, 1h), 7.87 (d, j=7.8hz, 1h), 7.73 (t, j=7.7hz, 1h), 7.69 (s, 1h), 3.82 (s, 3h), 3.05 (t, j=6.3hz, 2h), 2.65 (t, j=6.3hz, 2h)；
13c nmr(150mhz,dmso-d6):δ(ppm)145.5,140.5,140.2,137.6,137.5,134.8, 132.9,130.0,128.3,125.9,124.1,119.4,114.9,101.5,39.0,38.2,19.2.
Embodiment 93
N- (2- cyano ethyl) -3- (3h- imidazo [1,2-a] pyrrolo- [2,3-e] pyrazine -1- base) benzsulfamide
Step 1: compound (the bromo- 5- of 7- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrrole Piperazine -2- base) t-butyl carbamate synthesis
To the bromo- 5- of 2,7- bis- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrazine (100mg, Xantphos (30mg, 0.05mmol), potassium carbonate is sequentially added in Isosorbide-5-Nitrae-dioxane (4ml) solution 0.24mmol) (50mg, 0.36mmol), palladium (6mg, 0.03mmol) and t-butyl carbamate (45mg, 0.38mmol), nitrogen atmosphere Under, 115 DEG C of back flow reaction 6 hours, kieselguhr filters, and concentrates, and column chromatography (petrol ether/ethyl acetate (v/v)=8/1) obtains 100mg brown oil, yield: 91.83%.
ms(esi,pos.ion)m/z:443.2,445.3[m+1]+.
Step 2: the bromo- 5- of compound 7- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrazine - The synthesis of 2- amino
To (the bromo- 5- of 7- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrazine -2- base) amino In dichloromethane (2ml) solution of t-butyl formate (100mg, 0.22mmol), add isopropanol solution of hydrogen chloride (7n, 4ml), Be stirred at room temperature 6 hours, remove solvent, add saturated sodium bicarbonate to be adjusted to ph 7, dichloromethane extracts (25ml x 3), and drying is dense Contracting, residue column chromatography (petrol ether/ethyl acetate (v/v)=0/1) obtains 58mg faint yellow solid product, yield: 74.91%.
ms(esi,pos.ion)m/z:343.2,345.1[m+1]+.
Step 3: the bromo- 3- of compound 1- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -3h- imidazo [1,2-a] pyrroles And the synthesis of [2,3-e] pyrazine
To the bromo- 5- of 7- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrazine -2- amino 40% aqueous chloroacetaldehyde solution (70 μ l, 0.42mmol) is sequentially added in ethanol (6ml) solution of (58mg, 0.17mmol), 85 DEG C Back flow reaction 6 hours, directly plus silica gel mixed sample, column chromatography obtains 60mg faint yellow solid, yield: 96.69%.
ms(esi,pos.ion)m/z:368.6[m+1]+.
Step 4: compound n- (2- cyano ethyl) -3- (3- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -3h- imidazoles And [1,2-a] pyrrolo- [2,3-e] pyrazine -1- base) benzsulfamide synthesis
The bromo- 3- of 1- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -3h- imidazo [1,2-a] pyrrolo- [2,3-e] pyrazine Isosorbide-5-Nitrae-dioxane (5ml) solution of (20mg, 0.05mmol), potassium carbonate (12mg, 0.08mmol), n- (2- cyano ethyl)- 3- (4,4,5,5- tetramethyl -1,3,2- dioxy boron pentane -2- base) benzsulfamide (30mg, 0.09mmol), pd (dppf) cl2 (6mg, 0.008mmol) and water (1ml) prepare 7mg yellow solid according to the synthetic method of embodiment 15 step 7, yield: 25.88%.
ms(esi,pos.ion)m/z:497.4[m+1]+.
Step 5: compound n- (2- cyano ethyl) -3- (3h- imidazo [1,2-a] pyrrolo- [2,3-e] pyrazine -1- base) The synthesis of benzsulfamide
To n- (2- cyano ethyl) -3- (3- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -3h- imidazo [1,2-a] pyrrole Cough up simultaneously [2,3-e] pyrazine -1- base) add trifluoro second in dichloromethane (6ml) solution of benzsulfamide (100mg, 0.20mmol) Sour (2ml, 26.93mmol), is stirred at room temperature 3 hours, concentrated solvent, adds oxolane (6ml) dissolving, adds ethylenediamine to be adjusted to Ph > 7, continues to be stirred at room temperature, and add water (20ml) dilution, and dichloromethane extracts (20ml x 3), anhydrous sodium sulfate drying, evaporating column Chromatography (petrol ether/ethyl acetate (v/v)=0/1) obtains 37mg yellow solid, yield: 50.16%.
ms(esi,pos.ion)m/z:367.25[m+1]+；
1h nmr(600mhz,dmso-d6):δ(ppm)12.62(s,1h),8.74(s,1h),7.99(s,1h),7.89(d, J=7.6hz, 1h), 7.85 (d, j=7.9hz, 1h), 7.78 (d, j=7.8hz, 1h), 7.77 (s, 1h), 7.74 (s, 1h), 7.69 (s, 1h), 3.09 (t, j=6.3hz, 2h), 2.66 (t, j=6.3hz, 2h)；
13c nmr(150mhz,dmso-d6):δ(ppm)141.1,140.0,135.3,134.7,134.6,134.4, 133.4,130.4,127.0,125.3,122.0,119.3,112.9,112.2,110.3,39.1,19.1.
Embodiment 94
N- (2- cyanoethyl) -3- (3h- imidazo [1,2-a] pyrrolo- [2,3-e] pyrazine -8- base) benzsulfamide
Step 1: the synthesis of compound 2- bromo- 5- p-toluenesulfonyl -5h- pyrrolo- [2,3-b] pyrazine
- 15 DEG C, to oxolane (150ml) solution of 2- bromo- 5h- pyrrolo- [2,3-b] pyrazine (10g, 50.5mmol) After middle addition sodium hydride (60%, 3.1g, 78mmol), be stirred at room temperature 1 hour, add under ice bath paratoluensulfonyl chloride (12.6g, 65.4mmol), continue to be stirred at room temperature, add water (100ml) dilution, dichloromethane extracts (100ml x 3), and anhydrous sodium sulfate is done Dry, concentrate column chromatography (petrol ether/ethyl acetate (v/v)=8/1) and obtain the faint yellow fluffy solid of 14.1g, yield: 79.3%.
ms(esi,pos.ion)m/z:352.1,354.1[m+1]+.
Step 2: compound (5- p-toluenesulfonyl -5h- pyrrolo- [2,3-b] pyrazine -2- base) t-butyl carbamate Synthesis
The 1,4- dioxy six of 2- bromo- 5- p-toluenesulfonyl -5h- pyrrolo- [2,3-b] pyrazine (100mg, 0.28mmol) Ring (6ml) solution, xantphos (34mg, 0.06mmol), potassium carbonate (60mg, 0.43mmol), palladium (7mg, 0.03mmol) prepared according to the synthetic method of embodiment 17 step 1 with t-butyl carbamate (50mg, 0.43mmol) 87mg red brown solid product, yield: 78.89%.
ms(esi,pos.ion)m/z:389.3[m+1]+；
1h nmr(400mhz,dmso-d6): δ (ppm) 10.11 (s, 1h), 8.77 (s, 1h), 8.18 (d, j=4.0hz, 1h), 7.97 (d, j=8.2hz, 2h), 7.43 (d, j=8.2hz, 2h), 6.85 (d, j=4.0hz, 1h), 2.34 (s, 3h), 1.37(s,10h).
Step 3: the synthesis of compound 2- amino -5- p-toluenesulfonyl -5h- pyrrolo- [2,3-b] pyrazine
(5- p-toluenesulfonyl -5h- pyrrolo- [2,3-b] pyrazine -2- base) t-butyl carbamate (900mg, Dichloromethane (3ml) solution 2.32mmol) and hydrogen chloride-aqueous isopropanol (6n, 7ml, 42mmol) are according to embodiment 17 step Rapid 2 synthetic method prepares the faint yellow drying solid of 440mg, yield: 65.86%
ms(esi,pos.ion)m/z:289.0[m+1]+.
Step 4: the synthesis of compound 3- p-toluenesulfonyl-imidazo [1,2-a] pyrrolo- [2,3-e] pyrazine
The ethanol of 2- amino -5- p-toluenesulfonyl -5h- pyrrolo- [2,3-b] pyrazine (170mg, 0.5897mmol) (6ml) solution and 40%2- 2-Chloro-1-ethanal (150 μ l, 0.9mmol) prepare according to the synthetic method of embodiment 17 step 3 170mg yellow green, yield: 92.29%.
ms(esi,pos.ion)m/z:313.2[m+1]+；
1h nmr(400mhz,dmso-d6): δ (ppm) 8.90 (s, 1h), 8.58 (s, 1h), 8.04 (dd, j=13.5, 6.1hz, 4h), 7.45 (d, j=8.2hz, 2h), 7.35 (d, j=3.8hz, 1h), 2.35 (s, 3h).
Step 5: the conjunction of compound 8- iodo- 3- p-toluenesulfonyl -3h- imidazo [1,2-a] pyrrolo- [2,3-e] pyrazine Become
Dmf to 3- p-toluenesulfonyl-imidazo [1,2-a] pyrrolo- [2,3-e] pyrazine (420mg, 1.34mmol) (8ml) add n- Iodosuccinimide (450mg, 2.0mmol) in solution, be stirred at room temperature 3 hours, add sodium thiosulfate molten Liquid (20ml) is quenched, and dichloromethane extracts (25mlx3), anhydrous sodium sulfate drying, concentrates column chromatography (petrol ether/ethyl acetate (v/v)=1/1) obtain 599mg faint yellow solid, yield: 100%.
ms(esi,pos.ion)m/z:439.10[m+1]+；
1h nmr(400mhz,dmso-d6): δ (ppm) 8.78 (d, j=6.7hz, 1h), 8.00 (m, 3h), 7.92 (s, 1h), 7.72 (d, j=4.1hz, 1h), 7.45 (d, j=8.3hz, 2h), 2.35 (s, 3h).
Step 6: compound n- (2- cyano ethyl) -3- (3- para toluene sulfonamide -3h- imidazo [1,2-a] pyrrolo- [2,3-e] pyrazine -8- base) benzsulfamide synthesis
8- iodo- 3- p-toluenesulfonyl -3h- imidazo [1,2-a] pyrrolo- [2,3-e] pyrazine (300mg, 0.68mmol) 1,4- dioxane (8ml), n- (2- cyano ethyl) -3- (4,4,5,5- tetramethyl -1,3,2- dioxy boron pentane -2- base) Benzsulfamide (210mg, 0.62mmol), potassium carbonate (150mg, 1.08mmol), pd (dppf) cl2(50mg, 0.07mmol) and Water (2ml) obtains 200mg faint yellow solid according to the synthetic method of embodiment 15 step 7, yield: 56.11%.
ms(esi,pos.ion)m/z:521.20[m+1]+.
Step 7: compound n- (2- cyanoethyl) -3- (3h- imidazo [1,2-a] pyrrolo- [2,3-e] pyrazine -8- base) benzene The synthesis of sulfonamide
Under room temperature, to n- (2- cyano ethyl) -3- (3- para toluene sulfonamide -3h- imidazo [1,2-a] pyrrolo- [2,3- E] pyrazine -8- base) benzsulfamide (180mg, 0.35mmol) oxolane (8ml) solution in add potassium tert-butoxide (124mg, 1.10mmol), it is stirred at room temperature 2 hours, be directly added into silica gel mixed sample, column chromatography (petrol ether/ethyl acetate (v/v)=0/1) To 98mg faint yellow solid, yield: 77.36%, purity: 96.08% (hplc).
ms(esi,pos.ion)m/z:367.25[m+1]+；
1h nmr(600mhz,dmso-d6): δ (ppm) 12.38 (s, 1h), 8.72 (s, 1h), 8.22 (t, j=5.8hz, 1h), 8.09 (d, j=15.1hz, 1h), 7.96 (m, 2h), 7.92 (s, 1h), 7.84 (t, j=7.8hz, 1h), 7.37 (t, j= 3.1hz, 1h), 6.06 (dd, j=3.0,2.0hz, 1h), 3.09 (q, j=6.2hz, 2h), 2.66 (t, j=6.4hz, 2h)；
13c nmr(150mhz,dmso-d6): δ (ppm) 141.1,140.3,134.8,134.8,134.6,133.7, 130.5,130.4,127.3,126.9,125.2,122.2,119.3,114.8,95.2,39.1,19.1.
Embodiment 95
N- cyclobutyl -2- (3- propionamido- phenyl) -5h- pyrroles [2,3-b] pyrazine -7- Methanamide
Step 1: compound n- cyclobutyl -2- (3- propionamido- phenyl) -5- ((2- (trimethyl silicon substrate) ethyoxyl) first Base) -5h- pyrroles [2,3-b] pyrazine -7- Methanamide synthesis
Isosorbide-5-Nitrae dioxane (8ml)/water (2ml), 2- bromo- n- cyclobutyl -5- (2- (TMS) ethyoxyl) first Base) -5h- pyrroles [2,3-b] pyrazine -7- Methanamide (0.22g, 0.51mmol), n- (3- phenylboric acid pinacol ester phenyl) propionyl Amine (0.21g, 0.76mmol), potassium carbonate (0.2g, 1.44mmol) and pd (dppf) cl2(18mg, 0.02mmol) is according to enforcement The synthetic method of example 1 step 1 prepares 220mg beige solid, yield: 86.17%.
ms(esi,pos.ion)m/z:493.3[m+1]+.
Step 2: compound n- cyclobutyl -2- (3- propionamido- phenyl) -5h- pyrroles [2,3-b] pyrazine -7- Methanamide Synthesis
Under room temperature, by n- cyclobutyl -2- (3- propionamido- phenyl) -5- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) - (0.22g, the 0.44mmol) of 5h- pyrroles [2,3-b] pyrazine -7- Methanamide is dissolved in dichloromethane (20ml), adds trifluoro Acetic acid (8ml), after stirring 6h under room temperature.Concentrating under reduced pressure, residue dissolves in oxolane (15ml), is adjusted with saturated sodium bicarbonate solution To alkalescence, react overnight under room temperature.Dilute (30ml), dichloromethane extracts (30ml x 3), organic layer anhydrous slufuric acid Sodium is dried, and decompressed concentrate (methylene chloride/methanol (v/v)=30/1) carries out post separation and obtains yellow solid 150mg, yield: 92.63%.
ms(esi,pos.ion)m/z:364.2[m+1]+；
1h nmr(600mhz,dmso-d6):δ(ppm)12.79(s,1h),10.05(s,1h),8.96(s,1h),8.84 (s, 1h), 8.59 (d, j=8.2hz, 1h), 8.41 (s, 1h), 7.85 (d, j=7.5hz, 1h), 7.52 7.43 (m, 2h), 4.56 (dd, j=16.5,8.2hz, 1h), 2.38 (q, j=7.5hz, 2h), 2.33 (dd, j=16.5,8.0hz, 2h), 2.19 (dd, j=15.0,5.8hz, 2h), 1.83 1.66 (m, 2h), 1.12 (t, j=7.5hz, 3h)；
13c nmr(150mhz,dmso-d6):δ(ppm)172.6,161.6,146.1,141.6,140.7,137.7, 136.1,135.7,135.1,129.8,121.4,120.1,117.7,109.2,43.9,31.5,30.0,15.2,10.0.
Embodiment 96
5- (4- ((1,1- dioxy thiomorpholine) methyl) phenyl)-n- isopropyl -1h- pyrrolo- [2,3-b] pyridine -3- first Amide
Step 1: compound 5- (4- ((1,1- dioxy thiomorpholine) methyl) phenyl)-n- isopropyl -1- ((2- (trimethyl Silicon substrate) ethyoxyl) methyl) and -1h- pyrrolo- [2,3-b] pyrazine -3- Methanamide synthesis
By 4- (4- bromobenzyl) dioxy thiomorpholine (16mg, 0.05mmol), n- isopropyl -5- borate -1- ((2- (three Methylsilyl) ethyoxyl) methyl) -1h- pyrrolo- [2,3-b] pyridine-3-carboxamide (20mg, 0.04mmol), potassium carbonate (15mg, 0.11mmol) and pd (dppf) cl2(6.4mg, 0.01mmol) mixes, and adds Isosorbide-5-Nitrae-dioxane (8ml), blanket of nitrogen Under enclosing, 115 DEG C heat 4 hours, filter, kieselguhr filter, filtrate concentrate mix sample column chromatography (petrol ether/ethyl acetate (v/v)= 2/1) obtain 12.7mg yellow oil, yield: 52.4%.
ms(esi,pos.ion)m/z:557.1[m+1]+.
Step 2: compound 5- (4- ((1,1- dioxy thiomorpholine) methyl) phenyl)-n- isopropyl -1h- pyrrolo- [2, 3-b] pyridine-3-carboxamide synthesis
By 5- (4- ((1,1- dioxy thiomorpholine) methyl) phenyl)-n- isopropyl -1- ((2- (trimethyl silicon substrate) ethoxy Base) methyl) -1h- pyrrolo- [2,3-b] pyridine-3-carboxamide (140mg, 0.25mmol) is dissolved in dichloromethane (6ml), plus Enter trifluoroacetic acid (2ml), 2h, concentrated solvent are stirred at room temperature, add oxolane (6ml) dissolving, Deca lithium hydroxide solution (2n) to ph > 7,2h is stirred at room temperature, add water (20ml) dilution, dichloromethane extracts (15mlx3), anhydrous sodium sulfate drying concentrates Column chromatography (petrol ether/ethyl acetate (v/v)=1/1) obtains 63mg white solid, yield: 58.75%.
ms(esi,pos.ion)m/z:427.0[m+1]+；
1h nmr(600mhz,dmso-d6): δ (ppm) 12.13 (s, 1h), 8.65 (t, j=9.2hz, 1h), 8.56 (d, j =1.7hz, 1h), 8.21 (d, j=2.3hz, 1h), 7.83 (d, j=7.7hz, 1h), 7.68 (d, j=8.0hz, 2h), 7.47 (d, j=7.8hz, 2h), 4.12 (dt, j=13.5,6.7hz, 1h), 3.75 (d, j=25.8hz, 2h), 3.13 (s, 4h), 2.92 (s, 4h), 1.19 (d, j=6.5hz, 6h)；
13c nmr(150mhz,dmso-d6):δ(ppm)163.6,148.4,142.7,138.2,137.1,130.0, 129.7,129.1,127.6,127.3,119.1,110.4,59.7,50.8,50.6,40.6,23.1.
Embodiment 97
5- (3- ((1,1- dioxy thiomorpholine) methyl) phenyl)-n- isopropyl -1h- pyrrolo- [2,3-b] pyridine -3- first Amide
Step 1: compound 5- (3- ((1,1- dioxy thiomorpholine) methyl) phenyl)-n- isopropyl -1- ((2- (trimethyl Silicon substrate) ethyoxyl) methyl) and -1h- pyrrolo- [2,3-b] pyrazine -3- Methanamide synthesis
4- (3- bromobenzyl) dioxy thiomorpholine (175mg, 0.57mmol), n- isopropyl -5- borate -1- ((2- (three Methylsilyl) ethyoxyl) methyl) -1h- pyrrolo- [2,3-b] pyridine-3-carboxamide (220mg, 0.47mmol), potassium carbonate (165mg,1.19mmol)、pd(dppf)cl2(73mg, 0.09mmol) and 1,4- dioxane (10ml) are according to embodiment 20 step Rapid 1 synthetic method prepares 190mg yellow solid, yield: 71.3%.
ms(esi,pos.ion)m/z:557.1[m+1]+.
Step 2: compound 5- (3- ((1,1- dioxy thiomorpholine) methyl) phenyl)-n- isopropyl -1h- pyrrolo- [2, 3-b] pyridine-3-carboxamide synthesis
5- (3- ((1,1- dioxy thiomorpholine) methyl) phenyl)-n- isopropyl -1- ((2- (trimethyl silicon substrate) ethyoxyl) Methyl) -1h- pyrrolo- [2,3-b] pyrazine -3- Methanamide (190mg, 0.34mmol), trifluoroacetic acid (2ml) and Lithium hydrate molten Liquid (2n) prepares 71mg white solid according to the synthetic method of embodiment 20 step 2, yield: 48.78%.
ms(esi,pos.ion)m/z:427.20[m+1]+；
1h nmr(600mhz,dmso-d6):δ(ppm)12.16(s,1h),8.70(s,1h),8.59(s,1h),8.25(s, 1h), 7.86 (d, j=7.5hz, 1h), 7.68 (s, 1h), 7.62 (d, j=7.4hz, 1h), 7.46 (t, j=7.5hz, 1h), 7.34 (d, j=7.3hz, 1h), 4.14 (dq, j=13.1,6.4hz, 1h), 3.76 (s, 2h), 3.16 (d, j=24.8hz, 4h), 2.93 (s, 4h), 1.19 (d, j=6.4hz, 6h)；
13c nmr(150mhz,dmso-d6):δ(ppm)163.6,148.4,142.9,139.3,139.0,129.8, 129.5,129.1,128.1,127.8,127.6,126.3,119.1,110.3,60.0,50.7,50.6,40.6,23.1.
Embodiment 98
N- (3- (3- (1h- indole -5- base) -1h- pyrrolo- [2,3-b] pyridine -5- base) phenyl) -3- methoxypropionamide
Step 1: the bromo- 3- of compound 5- (1h- indole -5- base) -1- p-toluenesulfonyl -1h- pyrrolo- [2,3-b] pyridine Synthesis
Bromo- for 5- 3- iodo- 1- p-toluenesulfonyl -1h- pyrrolo- [2,3-b] pyridine (20mg, 0.04mmol) is dissolved in second In nitrile (4ml), sequentially add 5- pinacol borate -1h- indole (11.2mg, 0.04mmol), 1n aqueous sodium carbonate (0.11ml,0.11mmol)、pd(dppf)cl2(6.5mg, 0.01mmol), changes n2, 2h is stirred at room temperature, adds saturated aqueous common salt (10ml), dichloromethane (10ml x 3) extraction, with anhydrous sodium sulfate drying, removes solvent, concentrated solution carries out post separation (oil Ether/ethyl acetate (v/v)=6/1), obtain 7mg brown solid, yield: 35.8%.
ms(esi,pos.ion)m/z:466.0[m+1].
Step 2: compound n- (3- (3- (1h- indole -5- base) -1- p-toluenesulfonyl -1h- pyrrolo- [2,3-b] pyrrole Piperazine -5- base) phenyl) acrylamide synthesis
By bromo- for 5- 3- (1h- indole -5- base) -1- p-toluenesulfonyl -1h- pyrrolo- [2,3-b] pyridine (10mg, 0.02mmol), n- (3- phenylboric acid pinacol ester phenyl) acrylamide (8.8mg, 0.032mmol), pd (dppf) cl2 The compound of the sodium carbonate liquor (0.052ml, 0.052mmol) of (3.1mg, 0.004mmol) and 1mol/l is placed in single port bottle, Add dioxane (4ml), 115 DEG C are stirred at room temperature 5 hours, add saturated aqueous common salt (10ml), dichloromethane (10ml x 3) Extraction, with anhydrous sodium sulfate drying, removes solvent, and concentrated solution carries out post separation (petrol ether/ethyl acetate (v/v)=2/1) and obtains To 3mg brown solid, yield: 26.27%.
ms(esi,pos.ion)m/z:533.2[m+1]+.
Step 3: compound n- (3- (3- (1h- indole -5- base) -1h- pyrrolo- [2,3-b] pyridine -5- base) phenyl) -3- The synthesis of methoxypropionamide
By n- (3- (3- (1h- indole -5- base) -1- p-toluenesulfonyl -1h- pyrrolo- [2,3-b] pyrazine -5- base) benzene Base) acrylamide (7mg, 0.01mmol) is dissolved in methanol (3ml), adds 5n sodium hydroxide solution (13.1 μ l, 0.06mmol) Solution, 50 DEG C of reacting by heating 3 hours, dilute (10ml), dichloromethane extracts (15ml x 3), is done with anhydrous sodium sulfate Dry, remove solvent, concentrated solution carries out post separation, and (petrol ether/ethyl acetate (v/v)=2/1) obtains 2mg faint yellow solid, produce Rate: 37.07%.
ms(esi,pos.ion)m/z:411.15[m+1]+；
1h nmr(600mhz,cd3od):δ(ppm)8.49(s,1h),8.48(s,1h),7.91(s,1h),7.87(s, 1h), 7.65 7.58 (m, 2h), 7.47 (m, 4h), 7.28 (d, j=3.0hz, 1h), 6.53 (d, j=2.9hz, 1h), 3.81 3.70 (m, 3h), 3.39 (s, 3h), 2.66 (t, j=6.1hz, 2h)；
13c nmr(150mhz,cd3od):δ(ppm)171.0,148.0,140.9,140.0,139.1,135.3,129.1, 129.1,128.6,126.4,125.5,124.7,122.7,122.6,121.0,119.2,118.4,118.4,118.2, 117.9,111.2,101.1,68.2,57.5,37.0.
Embodiment 99
3- ((4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5h- pyrrolo- [2,3-b] pyrazine -7- carbonyl) phenyl) amino) Propionitrile
Step 1: the synthesis of compound (2- bromo- 5h- pyrrolo- [2,3-b] pyrazine -7- base) (4- nitrobenzophenone) methanol
Under room temperature, to 2- bromo- 5h- pyrrolo- [2,3-b] pyrazine (3g, 15.15mmol) and paranitrobenzaldehyde (5.4g, In mixture 36mmol) add methanol (25ml), after being stirred at room temperature 10 minutes add add potassium hydroxide (5.4g, 96mmol), continue to be stirred at room temperature 48 hours, stopped reaction, add water (50ml) dilution, and dichloromethane extracts (50mlx3), anhydrous Sodium sulfate is dried, and concentrates column chromatography (petrol ether/ethyl acetate (v/v)=2/1) and obtains 1.35g faint yellow solid, yield: 25.3%.
ms(esi,pos.ion)m/z:348.8,350.8[m+1]+.
Step 2: the synthesis of compound (2- bromo- 5h- pyrrolo- [2,3-b] pyrazine -7- base) (4- nitrobenzophenone) ketone
To (2- bromo- 5h- pyrrolo- [2,3-b] pyrazine -7- base) (4- nitrobenzophenone) methanol (210mg, 0.60mmol) In oxolane (7ml) solution, add dess-martin oxidant (530mg, 1.23mmol), be stirred at room temperature 4 hours, add water (15ml) dilute, dichloromethane extracts (20mlx3), anhydrous sodium sulfate drying, concentrate column chromatography (petrol ether/ethyl acetate (v/ V)=2/1) obtain 170mg faint yellow solid, yield: 81.42%.
ms(esi,pos.ion)m/z:347.05,349.10[m+1]+.
Step 3: compound (the bromo- 5- of 2- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrrole Piperazine -7- base) (4- nitrobenzophenone) ketone synthesis
To (2- bromo- 5h- pyrrolo- [2,3-b] pyrazine -7- base) (4- nitrobenzophenone) ketone (170mg, 0.49mmol) Add sodium hydride (60%, 40mg, 1.0mmol) in dmf (8ml) solution, be stirred at room temperature 30 minutes, addition semcl (120 μ l, 0.67mmol), continue to be stirred at room temperature 4 hours, add water (30ml) be quenched, dichloromethane extract (30mlx3), anhydrous sodium sulfate do Dry, after concentration, column chromatography (petrol ether/ethyl acetate (v/v)=3/1), filters, is dried to obtain 180mg yellow solid, yield: 76.98%.
ms(esi,pos.ion)m/z:477.75.479.75[m+1]+.
Step 4: compound (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (trimethylsilyl) ethyoxyl) methyl) -5h- Pyrrolo- [2,3-b] pyrazine -7- base) (4- nitrobenzophenone) ketone synthesis
To (the bromo- 5- of 2- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrazine -7- base) (4- Nitrobenzophenone) ketone (180mg, 0.37mmol) Isosorbide-5-Nitrae-dioxane (6ml) solution in, sequentially add potassium carbonate (80mg, 0.57mmol), 1- methylpyrazole boric acid fat (106mg, 0.50mmol) and pd (dppf) cl2(30mg, 0.04mmol), water (1.5ml), nitrogen protection, 115 DEG C are heated at reflux reaction 5.5 hours, and add water (40ml) dilution, and dichloromethane extracts (55mlx3), anhydrous sodium sulfate drying, concentrates column chromatography (petrol ether/ethyl acetate (v/v)=2/1) and obtains 120mg yellow admittedly Body, yield: 66.50%.
ms(esi,pos.ion)m/z:479.30[m+1]+.
Step 5: compound (4- aminophenyl) (2- (1- methyl isophthalic acid h- pyrrolo- -4- base) -5- ((2- (trimethyl silicon substrate) Ethyoxyl) methyl) -5h- pyrrolo- [2,3-b] pyrazine -7- base) and ketone synthesis
To (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5- ((2- (trimethylsilyl) ethyoxyl) methyl) -5h- pyrrolo- [2, 3-b] pyrazine -7- base) (4- nitrobenzophenone) ketone (120mg, 0.25mmol) methanol (6ml) solution in add palladium carbon (10%, 10mg, 0.01mmol), hydrogen exchange, it is stirred at room temperature 1.5 hours, filters, concentrate column chromatography (petrol ether/ethyl acetate (v/v) =0/1) obtain 44mg pale yellow oil, yield: 39.12%.
ms(esi,pos.ion)m/z:448.90[m+1]+.
Step 6: compound 3- ((4- (2- (1- methyl isophthalic acid h- pyrroles's -4- base) -5- ((2- (trimethyl silicon substrate) ethyoxyl) Methyl) -5h- pyrrolo- [2,3-b] pyrazine -7- carbonyl) phenyl) amino) propionitrile synthesis
To (4- aminophenyl) (2- (1- methyl isophthalic acid h- pyrrolo- -4- base) -5- ((2- (trimethyl silicon substrate) ethyoxyl) first Base) -5h- pyrrolo- [2,3-b] pyrazine -7- base) ketone (100mg, 0.22mmol) acrylonitrile (10ml) solution in, add three Aluminum chloride (45mg, 0.33mmol), 85 DEG C of back flow reaction 24 hours, add a small amount of methanol (5ml) that reaction is quenched, filter, filtrate Add water (40ml) dilution, and dichloromethane extracts (55mlx3), and anhydrous sodium sulfate drying concentrates column chromatography (petrol ether/ethyl acetate (v/v)=2/1) obtain 70mg yellow oil, yield: 70.64%.
ms(esi,pos.ion)m/z:502.3[m+1]+.
Step 7: compound 3- ((4- (2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5h- pyrrolo- [2,3-b] pyrazine -7- carbonyl Base) phenyl) amino) and propionitrile synthesis
To 3- ((4- (2- (1- methyl isophthalic acid h- pyrroles's -4- base) -5- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5h- pyrrole Cough up simultaneously [2,3-b] pyrazine -7- carbonyl) phenyl) amino) and propionitrile (79mg, 0.15mmol) dichloromethane (6ml) solution in, plus Enter trifluoroacetic acid (2ml) to be stirred overnight at room temperature, concentrated solvent, add oxolane (6ml) dissolving, plus ethylenediamine is neutralized to ph > 7, it is stirred at room temperature 3 hours, add water (20ml) dilution, dichloromethane extracts (20ml x 3), anhydrous sodium sulfate drying, evaporating column layer 7mg yellow solid is obtained by preparing plate separation, yield: 11.97% after analysis (petrol ether/ethyl acetate (v/v)=0/1).
ms(esi,pos.ion)m/z:372.25[m+1]+；
1h nmr(600mhz,dmso-d6):δ(ppm)12.75(s,1h),8.69(s,1h),8.31(s,1h),8.26(s, 1h), 7.99 (s, 1h), 7.88 (d, j=8.7hz, 2h), 6.88 (t, j=6.0hz, 1h), 6.74 (d, j=8.7hz, 2h), 3.90 (s, 3h), 3.48 (dd, j=12.6,6.3hz, 2h), 2.79 (t, j=6.5hz, 2h)；
13c nmr(150mhz,dmso-d6):δ(ppm)207.0,152.1,143.1,140.4,137.3,136.8, 136.0,135.3,132.7,129.5,127.1,121.5,120.0,115.2,111.2,45.8,40.5,17.8.
Embodiment 100
3- ((4- (5- methyl -2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5h- pyrrolo- [2,3-b] pyrazine -7- base) phenyl) Amino) propionitrile
Step 1: the synthesis of the bromo- 7- of compound 2- iodo- 5- methyl -5h- pyrrolo- [2,3-b] pyrazine
At 0 DEG C, sodium hydride (550mg, 13.75mmol) is dividedly in some parts the bromo- 7- of 2- iodo- 5h- pyrrolo- [2,3-b] pyrrole The n of piperazine (3.00g, 8.37mmol), in n- dimethylformamide (20ml) mixed liquor.After stirring 1.5h under room temperature, then at 0 DEG C It is slowly added dropwise iodomethane (2.2g, 16.00mmol), after completion of dropping, stirring reaction 5h under room temperature.Add water (50ml) be quenched instead Should, ethyl acetate (50ml x 3) extracts, and organic layer is washed with saturated aqueous common salt (50ml), anhydrous sodium sulfate drying, and concentration removes Remove solvent, residue carries out column chromatography for separation (petrol ether/ethyl acetate (v/v)=3/1) and obtains 2.00g faint yellow solid, produce Rate: 64.2%.
ms(esi,pos.ion)m/z:337.7[m+1]+；
1h nmr(400mhz,dmso-d6): δ (ppm) 8.52 8.30 (m, 1h), 8.18 (d, j=1.8hz, 1h), 3.85 (s,3h).
Step 2: compound 3- ((4- (2- bromo- 5- methyl -5h- pyrrolo- [2,3-b] pyrazine -7- base) phenyl) amino) third The synthesis of nitrile
Acetonitrile (12ml)/water (4ml), the bromo- 7- of 2- iodo- 5- methyl -5h- pyrrolo- [2,3-b] pyrazine (350mg, 1.04mmol), 3- ((4- (4,4,5,5- tetramethyl -1,3,2- dioxy boron pentane -2- base) phenyl) amino) propionitrile (350mg, 1.03mmol), sodium carbonate (330mg, 3.11mmol) and two (triphenylphosphine) palladium chloride (pd (pph3)2cl2)(40mg, Mixture 0.05mmol) prepares 80mg yellow solid according to the synthetic method of embodiment 1 step 1, yield: 21.7%.
ms(esi,pos.ion)m/z:356.2[m+1]+.
Step 3: compound 3- ((4- (5- methyl -2- (1- methyl isophthalic acid h- pyrazoles -4- base) -5h- pyrrolo- [2,3-b] pyrrole Piperazine -7- base) phenyl) amino) and propionitrile synthesis
Under nitrogen protection, Isosorbide-5-Nitrae-dioxane (4ml)/water (1ml) is added to 3- ((4- (2- bromo- 5- methyl -5h- pyrrole Cough up simultaneously [2,3-b] pyrazine -7- base) phenyl) amino) propionitrile (75mg, 0.18mmol), 1- methyl -4- (4,4,5,5- tetramethyl - 1,3,2- dioxy boron pentane -2- base) -1h- pyrazoles (65mg, 0.31mmol), potassium carbonate (45mg, 0.33mmol) and 1,1'- be double Diphenyl phosphino ferrocene palladium chloride (pd (dppf) cl2) in (8mg, 0.06mmol) mixture, 110 DEG C of back flow reaction overnight, Reactant liquor is cooled to room temperature, and kieselguhr filters, and filtrate reduced in volume carries out post separation (petrol ether/ethyl acetate (v/v)=0/ 1) obtain 52mg yellow solid, yield: 81.3%.
ms(esi,pos.ion)m/z:358.0[m+1]+；
1h nmr(600mhz,dmso-d6):δ(ppm)8.64(s,1h),8.38(s,1h),8.14(s,1h),8.11(s, 1h), 8.00 (d, j=8.6hz, 2h), 6.73 (d, j=8.7hz, 2h), 3.94 (s, 3h), 3.85 (s, 3h), 3.82 (s, 1h), 3.40 (t, j=6.4hz, 2h), 2.76 (t, j=6.5hz, 2h)；
13c nmr(150mhz,dmso-d6):δ(ppm)146.4,141.5,140.0,137.1,136.3,136.2, 134.0,129.8,129.4,127.1,122.5,121.7,120.2,113.1,39.5,39.2,31.4,17.9.
Biologic activity
Biological Examples 1 jak1/2/3 external activity test method
The present invention carries out biologic test using following methods to shown compound:
1. adopt caliper mobility shift assay detection compound to jak1/2/3 enzyme inhibition.
2. prepare 1 times of kinase reaction liquid: jak2/3:50mm hepes, ph 7.5；0.0015%brij-35；10mm mgcl2；2mm dtt.Jak1:25mm hepes, ph 7.5；0.001%brij-35；0.01%triton；0.5mm egta； 10mm mgcl2.
3. prepare reaction terminating liquid: 100mm hepes, ph 7.5；0.0015%brij-35；0.2%coating Reagent#3 (caliper, article No. 760050)；50mm edta.
4. enzyme prepares (jak1/2/3): prepares enzymatic solution with 1 times of kinase reaction liquid, enzyme prepares final concentration of jak1 (30nm), jak2 (2nm), jak 3 (4nm).
5. substrate is prepared: prepares substrate solution with 1 times of kinase reaction liquid, substrate is prepared final concentration and is shown in Table 1.
Table 1 substrate prepares final concentration
According to experimental technique optimum results, experiment using 384 orifice plates (corning, cat.no.3573, Lot.no.12608008) detected, jak1/2/3 enzyme concentration is formulated as jak1 (75nm), jak2 (5nm), jak 3 (10nm), final concentration of jak1 (30nm), jak2 (2nm), jak 3 (4nm) are reacted；Substrate peptide fam-p22 concentration is joined It is made as 7.5 μm, react final concentration of 3 μm；Atp compound concentration is jak1 (225 μm), jak2 (50 μm), jak3 (15.5 μm), instead Should final concentration of jak1 (90 μm), jak2 (20 μm), jak3 (6.2 μm)；Peptide d (sequence 5-fam-c6- Kkhtddgympmspgva-nh2) concentration is formulated as 7.5 μm, reacts final concentration of 3 μm；Enzyme and substrate are all anti-using 1 times of kinases Liquid is answered to prepare.Reaction system is as shown in table 2.
Table 2 compound is to jak1/2/3 enzyme ic50Detection system
Detected using 384 orifice plates, Setup Experiments test sample sample wells, Positive control wells, negative control hole, each sample Detect the inhibitory action to jak1/2/3 enzyme for the compound under 8 concentration using duplicate hole, by the use of enzyme and substrate reactions hole as sun Property comparison, no enzyme hole (kinase reaction liquid) is as negative control.After table 2 order addition respective sample, buffer and enzyme are pressed in each hole, 25 DEG C of (rt) calorstats are incubated 10min, and then every hole adds configured good peptide solution, and incubates in 28 DEG C of constant temperature Educate 60min, after adding reaction terminating liquid, excited in fp485nm using caliper ez reader/525nm transmitted wave strong point enters Row detection, reading data is conversion ratio.Using graph pad prism 5 software under compound variable concentrations to jak1/2/3 Enzyme inhibition is mapped, and calculates ic50, experimental result is shown in Table 3.
Enzyme (jak1/2/3) the suppression data of table 3 compound
Table 3 data display, part of compounds of the present invention all has certain inhibitory action to jak1, jak2 and jak3, particularly There is stronger inhibitory action to jak3, the treatment of multiple indications can be effectively used for.
Pk research in biological Examples 2 test compound rat body
Sd rat oral gavage gives 5mg/kg or the test compound through tail vein injection 1mg/kg.After administration temporally Point (0.083 hour, 0.25 hour, 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours and 24 hours) orbital vein Blood sampling, is collected in plus k2In the anticoagulant tube of edta.Plasma sample after liquid-liquid extraction, on triple quadrupole bar tandem mass spectrometer, Quantitative analyses are carried out in multiple reaction ion monitoring (mrm) mode.Using winnonlin 6.1 software with non-compartment model method meter Calculate pharmacokinetic parameters.
Conclusion: the compounds of this invention clearance rate is medium, after sd Oral Administration in Rats administration 5mg/kg, shows higher blood medicine Exposed amount, the half-life is reasonable simultaneously, possesses reasonable druggability.

Claims (10)

1. a kind of compound, it is the stereoisomer of the compound shown in compound or formula (i) as shown in formula (i), and geometry is different Structure body, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable salt Or prodrug:
Wherein:
A ring is c3-9Cycloalkyl, c5-9Cycloalkenyl group, c1-9Heterocyclic radical, c6-10Aryl, c1-9Heteroaryl, c6-12Condensed-bicyclic base, c5-12 Condense miscellaneous bicyclic group, c6-12Spiral shell bicyclic group or c5-12The miscellaneous bicyclic group of spiral shell；
A ring is further individually optionally by 1,2,3 or 4 r1Replace；
Each r1It independently is h, deuterium, f, cl, br, i, cn, alkyl, thiazolinyl, alkynyl, haloalkyl, r- (cr6r7)n- o-, r- (cr6r7)n1-, r8o-(cr6r7)n-, r8- c (=o)-n (r9)-, cn- (cr6r7)n-r0-(cr6r7)n-n(r9)-, cn- (cr6r7)n- s (=o)p-r0-(cr6r7)n-n(r9)-, r9a-n(r9)-c (=o)-, r or r-n (r9)-；
The subformula that e ring is as follows: Wherein, " * " represents and r5Connected one end；Wherein, when e ring isWhen, A ring is cyclopropyl；
Each r0It independently is c3-9Cycloalkyl, c5-9Cycloalkenyl group, c1-9Heterocyclic radical, c6-10Aryl, c1-9Heteroaryl, c6-12Condensed-bicyclic Base, c5-12Condense miscellaneous bicyclic group, c6-12Spiral shell bicyclic group or c5-12The miscellaneous bicyclic group of spiral shell；Each r0Individually optionally by 1,2,3 or 4 r6a Replace；
Each r independently is c3-9Cycloalkyl, c5-9Cycloalkenyl group, c1-9Heterocyclic radical, c6-10Aryl, c1-9Heteroaryl, c6-12Condensed-bicyclic Base, c5-12Condense miscellaneous bicyclic group, c6-12Spiral shell bicyclic group or c5-12The miscellaneous bicyclic group of spiral shell；Each r is individually optionally by 1,2,3 or 4 r6aTake Generation；
Each r6aIt independently is hydrogen, deuterium, c1-4Alkyl, c2-6Thiazolinyl, c2-6Alkynyl, f, cl, br, i, cn, r6b-(cr6r7)n- s (=o )p-, hydroxyl, nitro, amino, carboxyl or c1-4Alkoxyl；
Each r6b, r6And r7It independently is hydrogen, deuterium, c1-4Alkyl, c2-6Thiazolinyl, c2-6Alkynyl, f, cl, br, i, cn, hydroxyl, nitro, c1-4Haloalkyl, amino, carboxyl or c1-4Alkoxyl；
Each r8It independently is hydrogen, deuterium, c1-4Alkyl, c1-4Haloalkyl or ho- (cr6r7)n1-；
Each r9And r9aIt independently is hydrogen, deuterium, c1-4Alkyl, c1-4Haloalkyl or ho- (cr6r7)n-；
Each r2、r3And r4It independently is h, deuterium, f, cl, br, i, cn, c1-4Alkyl, c2-6Thiazolinyl, c2-6Alkynyl, c1-4Haloalkyl, r8o-(cr6r7)n-, r8- c (=o)-n (r9)-, r9a-n(r9)-c (=o)-or r9a-n(r9)-；
r5For cn- (cr10r11)n1-n(r12)-, cn- (cr10r11)n1- c (=o)-n (r12)-, cn- (cr10r11)n-c3-9Cycloalkyl- n(r12)-, r13-o-(cr10r11)n1-n(r12)-, cn- (cr10r11)n1-c1-9Heterocyclic radical-c (=o)-n (r12)-, cn- (cr10r11)n- c (=o)-c1-9Heterocyclic radical-(cr10r11)n-n(r12)-, r13-(cr10r11)n1- s (=o)p-(cr10r11)n-n (r12)-, r13-(cr10r11)n- s (=o)p-(r12a)n-c3-9Cycloalkyl-n (r12)-, r13-(cr10r11)n-n(r12)-c (=o)- (cr10r11)n-(r12a) n-, cn- (cr10r11)n-n(r12)-c (=o)-(cr10r11)n-(r12a) n-, cn- (cr10r11)n-c1-9 Heterocyclic radical-(cr10r11)n-n(r12)-, cn- (cr10r11)n1- s (=o)p-(r12a) n-, cn- (cr10r11)n- c (=o)-c1-9Miscellaneous Ring group-(cr10r11)n-, cn- (cr10r11)n-c3-9Cycloalkyl-(cr10r11)n1-, ho- (cr10r11)n-c3-9Cycloalkyl- (cr10r11)n1-, cn- (cr10r11)n-c1-9Heterocyclic radical-(cr10r11)n1-, cn- (cr10r11)n1-n(r12)-c (=o)-, cn- (cr10r11)n1-, c6-10Aryl-(cr10r11)n1-, (r12a)n(r12)-c (=o)-(cr10r11)n1-, cn- (cr10r11)n-c1-9Miscellaneous Ring group-(cr10r11)n-n(r12)-s (=o)p-, cn- (cr10r11)n-c1-9Heterocyclic radical-(cr10r11)n- s (=o)p-, cn- (cr10r11)n- s (=o)p-, r13-(cr10r11)n-(r12a) n-s (=o)p-, r13-(cr10r11)n-n(r12)-c (=o)- (cr10r11)n-(r12a) n-s (=o)p- or cn- (cr10r11)n1-(r12a) n-s (=o)p-；Wherein r5Described in aryl, heterocycle Base and cycloalkyl are individually optionally by 1,2,3 or 4 r6cReplace；
Each r10, r11And r13It independently is hydrogen, deuterium, c1-4Alkyl, c2-6Thiazolinyl, c2-6Alkynyl or c1-4Haloalkyl；
Each r12And r12aIt independently is hydrogen, deuterium, c1-4Alkyl, c2-6Thiazolinyl, c2-6Alkynyl, or c1-4Haloalkyl；
Each r6cIt independently is hydrogen, deuterium, c1-4Alkyl, f, cl, br, i, cn, hydroxyl, nitro, amino, carboxyl or c1-4Alkoxyl；
Wherein each n independently is 0,1,2 or 3；
Each n1 independently is 1,2,3 or 4；
M is 0,1,2,3 or 4；
Each p independently is 0,1 or 2.
2. compound according to claim 1, wherein
A ring is
Wherein, x1And x2It is each independently-c (r14r14a)-,-n (r15)-,-o- ,-s (=o)p- or-c (=o)-；
x3, x4, x5And x6It is each independently cr14Or n；
Each r14And r14aIt independently is hydrogen, deuterium, c1-4Alkyl, c2-6Thiazolinyl, c2-6Alkynyl or c1-4Haloalkyl；
Each r15It independently is hydrogen, deuterium, c1-4Alkyl, c2-6Thiazolinyl, c2-6Alkynyl or c1-4Haloalkyl.
3. compound according to claim 1, wherein
A ring is
4. the compound according to claim 1,2 or 3, wherein
Each r1It independently is h, deuterium, f, cl, br, i, cn, c1-4Alkyl, c2-6Thiazolinyl, c2-6Alkynyl, c1-4Haloalkyl, cn- (cr6r7)n-r0-(cr6r7)n-n(r9)-, r- (cr6r7)n- o-, r- (cr6r7)n-, r8o-(cr6r7)n-, r8- c (=o)-n (r9)-, r9a-n(r9)-c (=o)-, cn- (cr6r7)n- s (=o)p-r0-(cr6r7)n-n(r9)-, r or r-n (r9)-；
Each r0It independently is
Each r independently is
Wherein, y1And y2It is each independently-c (r16r16a)-,-n (r17)-,-o- ,-s (=o)p- or-c (=o)-；
y3, y4And y5It is each independently cr16Or n；
Each r16And r16aIt independently is hydrogen, deuterium, c1-4Alkyl, c2-6Thiazolinyl, c2-6Alkynyl or c1-4Haloalkyl；
Each r17It independently is hydrogen, deuterium, c1-4Alkyl, c2-6Thiazolinyl, c2-6Alkynyl or c1-4Haloalkyl.
5. compound according to claim 4, wherein
Each r1It independently is h, deuterium, f, cl, br, i, cn, methyl, ethyl, n-pro-pyl, isopropyl, trifluoromethyl, cn- (cr6r7)n- r0-(cr6r7)n-n(r9)-, cn- (cr6r7)n- s (=o)p-r0-(cr6r7)n-n(r9)-, r- (cr6r7)n- o-, r- (cr6r7)n1-, r8o-(cr6r7)n-, r8- c (=o)-n (r9)-, r9a-n(r9)-c (=o)-, r or r-n (r9)-；
Each r0It independently is
Each r independently is
6. compound according to claim 1, wherein
r5For cn- (cr10r11)n1-n(r12)-, cn- (cr10r11)n1- c (=o)-n (r12)-, cn- (cr10r11)n-c3-6Cycloalkyl- n(r12)-, r13-o-(cr10r11)n1-n(r12)-, cn- (cr10r11)n1-c3-6Heterocyclic radical-c (=o)-n (r12)-, cn- (cr10r11)n- c (=o)-c3-6Heterocyclic radical-(cr10r11)n-n(r12)-, r13-(cr10r11)n- s (=o)p-(r12a)n-c3-6Cycloalkanes Base-n (r12)-, r13-(cr10r11)n-n(r12)-c (=o)-(cr10r11)n-(r12a) n-, cn- (cr10r11)n-n(r12)-c (= o)-(cr10r11)n-(r12a) n-, r13-(cr10r11)n1- s (=o)p-(cr10r11)n-n(r12)-, cn- (cr10r11)n-c3-6Heterocycle Base-(cr10r11)n-n(r12)-, cn- (cr10r11)n1- s (=o)p-(r12a) n-, cn- (cr10r11)n- c (=o)-c3-6Heterocycle Base-(cr10r11)n-, cn- (cr10r11)n-c3-6Cycloalkyl-(cr10r11)n1-, ho- (cr10r11)n-c3-6Cycloalkyl- (cr10r11)n1-, cn- (cr10r11)n-c3-6Heterocyclic radical-(cr10r11)n1-, cn- (cr10r11)n1-, phenyl-(cr10r11)n1-, (r12a)n(r12)-c (=o)-(cr10r11)n1-, cn- (cr10r11)n1-n(r12)-c (=o)-, cn- (cr10r11)n-c3-6Heterocycle Base-(cr10r11)n- s (=o)p-, cn- (cr10r11)n- s (=o)p-, cn- (cr10r11)n-c3-6Heterocyclic radical-(cr10r11)n-n (r12)-s (=o)p-, r13-(cr10r11)n-(r12a) n-s (=o)p-, r13-(cr10r11)n-n(r12)-c (=o)- (cr10r11)n-(r12a) n-s (=o)p- or cn- (cr10r11)n1-(r12a) n-s (=o)p-；
Each r10, r11And r13It independently is hydrogen, deuterium, methyl, ethyl, n-pro-pyl, isopropyl, 2,2,2- trifluoroethyls or fluoroform Base；
Each r12And r12aIt independently is hydrogen, deuterium, methyl, n-pro-pyl, ethyl or isopropyl；
Each r6cIt independently is hydrogen, deuterium, methoxyl group, f, cl, br, i, cn, hydroxyl, nitro, amino, methyl, n-pro-pyl, ethyl or different Propyl group.
7. compound according to claim 1, wherein
r5For
8. a kind of compound, its be have one of following structure compound or have one of following structural compounds solid different Structure body, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt Or prodrug:
9. a kind of pharmaceutical composition, it comprises compound and pharmaceutically acceptable load described in claim 1-8 any one At least one in body, excipient, diluent, adjuvant or vehicle；
Preferably, wherein said pharmaceutical composition, it optionally further comprises additional therapeutic agent, described additional therapeutic agent choosing From chemotherapeutics or antiproliferative, anti-inflammatory agent, immunomodulator or immunosuppressant, neurotrophic factor, for treating cardiovascular The activating agent of disease, for treating the activating agent of diabetes and the activating agent for treating autoimmune disease.
10. the compound described in claim 1-8 any one or the pharmaceutical composition described in claim 9 are in preparing medicine Purposes, wherein said medicine is used for preventing, process, treat or mitigate autologous patient immunological diseases or proliferative disease；
And/or wherein said medicine is used for suppression or regulatory protein kinase activity；
Preferably, wherein autoimmune disease is lupus, multiple sclerosiss, muscle contracting lateral sclerosis, rheumatoid arthritiss, Psoriasises, i patients with type Ⅰ DM, the complication leading to because of organ transplantation, foreign body is transplanted, diabetes, cancer, asthma, atopic dermatitiss, Autoimmune thyroid disease, ulcerative colitiss, Crohn disease, Alzheimer, leukemia and lymphoma；
Preferably, wherein 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, myelosises Disease, atherosclerosiss or pulmonary fibrosiss；
Preferably, wherein said protein kinase is jak1, jak2, jak3, btk, egfr or egfr t790m.
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