CN103476776A - 2,4-diamino-6,7-dihydro-5H-pyrrolo[2,3]pyrimidine derivatives as FAK/Pyk2 inhibitors - Google Patents

2,4-diamino-6,7-dihydro-5H-pyrrolo[2,3]pyrimidine derivatives as FAK/Pyk2 inhibitors Download PDF

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CN103476776A
CN103476776A CN2012800048211A CN201280004821A CN103476776A CN 103476776 A CN103476776 A CN 103476776A CN 2012800048211 A CN2012800048211 A CN 2012800048211A CN 201280004821 A CN201280004821 A CN 201280004821A CN 103476776 A CN103476776 A CN 103476776A
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CN103476776B (en
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校登明
程靓
刘希杰
胡远东
许新合
刘志华
张立鹏
吴伟
王树龙
沈宇
李�根
王银
赵胜
李舂龙
唐佳
于洪灏
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Capital Pharmaceutical Holdings (Beijing) Co., Ltd.
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Centaurus Biopharma Co Ltd
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Abstract

The invention relates to a novel class of 2,4-diamino-6,7-dihydro-5H-pyrrolo[2,3]pyrimidine derivatives as a FAK and/or Pyk2 inhibitor, to a process for their preparation, and to a composition thereof, as well as to use of the compounds for the inhibiting FAK and/or Pyk2 and method for the treatment of a FAK and/ or Pyk2 mediated disorder or disease.

Description

As 2 of FAK/Pyk2 inhibitor, 4-diamino-6,7-dihydro-5H-pyrrolo-[2,3] pyrimidine derivatives
Technical field
The present invention relates to suppress novel 2 of focal adhesion kinase (FAK/Pyk2), 4-diamino-6,7-dihydro-5H-pyrrolo-[2,3] pyrimidine derivatives, its preparation method and composition thereof, and described compound is for suppressing the application of FAK and/or Pyk2 and being used for the treatment of FAK and/or the illness of Pyk2 mediation or the method for disease.
Background technology
FAK (focal adhesion kinase) be transduction for example, from multiple stimulator (integral protein, cytokine, chemokine and somatomedin) thus signal control the nonreceptor tyrosine kinase of various kinds of cell path and process (comprising cell proliferation, cell migration, cellular form and cell survival).The somatomedin that FAK is relevant by FAC (adhesion plaque mixture) and integral protein activate.The combination of ECM (extracellular matrix) and integral protein has caused the activation of FAK.The somatomedin that ECM is relevant, for example bFGF, EGF or PDGF can further strengthen by the common stimulation of somatomedin the activation of FAK.The assembling of adhesion plaque mixture and decomposition cell adhesion and motion are most important.FAK can not make other protein phosphorylation.Yet the FAK autophosphorylation of activation also is combined with the Src kinases, the Src kinases conversely other site of phosphorylation FAK and other FAK for example, in conjunction with albumen (Cas and paxillin (paxillin)).The FAK of phosphorylation provides the docking site of mediation (mediator) of a plurality of signal events, and participates in subsequently the adjusting of Growth of Cells and survival by the activation of PI3K/Akt/mTOR and Grb2/SOS/RAS/Raf/MEK/ERK path.It is relevant with the deterioration of kinds cancer that FAK crosses expression.
Proved and suppressed tumor growth (the Beviglia et al 2003 that FAK can suppress multiple cancer cells, BioChem J.373:201-210, Smith et al 2005, Melanoma Res.15:357-362, Haider et al 2005, Clin.Cancer Res.11:8829-8836, van Nimwegen et al 2005, Cancer Res.65:4698-4706, Mitra et al 2006, Oncogene 25:4429-4440).Yet in normal people inoblast or immortalization mammary gland cell, the inhibition of FAK does not cause forfeiture or the apoptosis (Xu et al 1996 Cell Growth and Diff.7:413-418) of adhesion.In addition, the forfeiture of FAK activity (rebuild the FAK-of kinases-dead FAK/-cell (FAK-/-cells with kinase-dead FAK)) has reduced the growth of v-Src tumour in the mouse and has reduced vasculogenesis.Therefore, suppressing FAK may be effective therapy of overmedication proliferative disease (for example cancer).
Pyk2 is the unique relevant member of FAK family, has 48% amino acid identity.Although the effect of Pyk2 in tumour generates is also not fully aware of, some evidences have shown that Pyk2 brings into play compensatory effect in the FAK knock-out mice model.Therefore, the double inhibition of FAK and Pyk2 can significantly enlarge anti-angiogenic action.
Summary of the invention
The invention discloses series of new 2,4-diamino-6,7-dihydro-5H-pyrrolo-[2,3] pyrimidine compound or its pharmacy acceptable salt, solvate, polymorphic form, tautomer or prodrug, it has FAK/Pyk2 and suppresses active, and can be used for antiproliferative and/or apoptosis and/or resist infecting and/or anti-cell motion and/or angiogenesis inhibitor, and can be used in the method for the treatment of Mammals (preferably people) or animal illness, for example, for suppressing tumor growth and cancer metastasis.The invention still further relates to described 2, 4-diamino-6, 7-dihydro-5H-pyrrolo-[2, 3] pyrimidine compound or its pharmacy acceptable salt, solvate, polymorphic form, the preparation method of tautomer or prodrug, relate to and comprise described compound or its pharmacy acceptable salt, solvate, polymorphic form, the pharmaceutical composition of tautomer or prodrug, and described 2, 4-diamino-6, 7-dihydro-5H-pyrrolo-[2, 3] pyrimidine compound or its pharmacy acceptable salt, solvate, polymorphic form, tautomer or prodrug preparation have antiproliferative and/or apoptosis and/or anti-infect and/or the medicine of anti-cell motion and/or angiogenesis inhibitor in application.
The invention also discloses and utilize 2,4-diamino-6,7-dihydro-5H-pyrrolo-[2,3] pyrimidine compound or its pharmacy acceptable salt, solvate, polymorphic form, tautomer or prodrug treatment FAK and/or the illness of Pyk2 mediation or the method for disorders such as cancers.
The invention provides compound or its pharmacy acceptable salt, solvate, polymorphic form, tautomer or the prodrug of formula (I),
Figure BPA00001751561000021
Wherein:
R 1and R 2the group formed independently selected from following group: hydrogen, halogen, cyano group, nitro, hydroxyl, the optional alkyl replaced, the optional cycloalkyl replaced, the optional thiazolinyl replaced, the optional alkynyl replaced and the optional alkoxyl group replaced, or R 1, R 2with the common optional cycloalkyl replaced or the optional Heterocyclylalkyl replaced of forming of coupled carbon atom;
R 3and R 4the group formed independently selected from following group: the heteroaryl of the alkyl of hydrogen, optional replacement, the optional cycloalkyl replaced, the optional aryl replaced, the arylalkyl optionally replaced, the optional Heterocyclylalkyl replaced, optional replacement ,-COR 7,-SO 2r 8,-SOR 9;
R 5and R 6group independently selected from following group formation: the heteroaryl of hydrogen, the optional alkyl replaced, the optional cycloalkyl replaced, the aryl optionally replaced, the optional Heterocyclylalkyl replaced, optional replacement ,-COR 10,-SO 2r 11with-SOR 12;
R 7, R 8, R 9, R 10, R 11and R 12the group formed independently selected from following group: the optional alkyl replaced, the optional cycloalkyl replaced, the optional aryl replaced, the optional heteroaryl replaced;
R xand R ythe group formed independently selected from following group: hydrogen, halogen, cyano group, nitro, hydroxyl, the optional alkyl replaced, the optional cycloalkyl replaced, the optional thiazolinyl replaced, the optional alkynyl replaced and the optional alkoxyl group replaced; And
R " be selected from the group that following group forms: hydrogen, the optional alkyl replaced, the optional cycloalkyl replaced, the optional thiazolinyl replaced, the optional alkynyl replaced and the optional alkoxyl group replaced.
The compounds of this invention also can mean in order to following formula (Ia):
Figure BPA00001751561000031
Wherein, R 1, R 2, R 3, R 4, R 5, R 6, R x, R ywith R " identical with the definition of above general formula I.In the description of back of the present invention, not tubular type (I) or formula (Ia), the compound of their representatives all comprises all possible steric isomer, regional isomer, diastereomer, enantiomer or epimer and their mixture.
On the other hand, at formula (I) or formula (Ia), R 1and R 2the group formed independently selected from following group: hydrogen, halogen, cyano group, nitro, hydroxyl, the optional C replaced 1-C 6alkyl, the optional C replaced 3-C 8cycloalkyl, the optional C replaced 2-C 6thiazolinyl, the optional C replaced 2-C 6alkynyl and the optional C replaced 1-C 6alkoxyl group; Perhaps R 1, R 2with the common C that forms optional replacement of coupled carbon atom 3-C 8cycloalkyl or the optional Heterocyclylalkyl replaced;
R 3and R 4the group formed independently selected from following group: hydrogen, the optional C replaced 1-C 6alkyl, the optional C replaced 3-C 8cycloalkyl, the optional C replaced 6-C 10aryl, the optional C replaced 6-C 10aryl-C 1-C 6the heteroaryl of alkyl, the optional Heterocyclylalkyl replaced, optional replacement ,-COR 7,-SO 2r 8with-SOR 9;
R 5and R 6the group formed independently selected from following group: hydrogen, the optional C replaced 1-C 6alkyl, the optional C replaced 3-C 6cycloalkyl, the optional C replaced 6-C 10the heteroaryl of aryl, the optional Heterocyclylalkyl replaced, optional replacement ,-COR 10,-SO 2r 11with-SOR 12;
R 7, R 8, R 9, R 10, R 11and R 12the group formed independently selected from following group: the optional C replaced 1-C 6alkyl, the optional C replaced 3-C 8cycloalkyl, the optional C replaced 6-C 10aryl, the optional heteroaryl replaced;
R xand R ythe group formed independently selected from following group: hydrogen, halogen, cyano group, nitro, hydroxyl, the optional C replaced 1-C 6alkyl, the optional C replaced 3-C 8cycloalkyl, the optional C replaced 2-C 6thiazolinyl, the optional C replaced 2-C 6alkynyl and the optional C replaced 1-C 6alkoxyl group; And
R " be selected from the group that following group forms: hydrogen, the optional C replaced 1-C 6alkyl, the optional C replaced 3-C 8cycloalkyl, the optional C replaced 2-C 6thiazolinyl, the optional C replaced 2-C 6alkynyl and the optional C replaced 1-C 6alkoxyl group.
On the other hand, the invention provides some preferred compounds or its pharmacy acceptable salt, solvate, polymorphic form, tautomer or the prodrug of formula (I) or formula (Ia), wherein, R 1and R 2the group formed independently selected from following group: hydrogen, the optional C replaced 1-C 6alkyl, the optional C replaced 3-C 8cycloalkyl or C 3-C 6cycloalkyl, the optional C replaced 2-C 6thiazolinyl, the optional C replaced 2-C 6alkynyl and the optional C replaced 1-C 6alkoxyl group; Perhaps R 1, R 2with the common C that forms optional replacement of coupled carbon atom 3-C 8cycloalkyl or C 3-C 6cycloalkyl;
On the other hand, the invention provides some preferred compounds or its pharmacy acceptable salt, solvate, polymorphic form, tautomer or the prodrug of formula (I) or formula (Ia), wherein, R 5and R 6the group formed independently selected from following group: hydrogen, the optional C replaced 6-C 10aryl, optional replace comprise 1-4 N, O or the heteroatomic 5-15 of S unit Heterocyclylalkyl, optional replace comprise 1-4 N, O or the first heteroaryl of the heteroatomic 5-10 of S.
On the other hand, the invention provides some preferred compounds or its pharmacy acceptable salt, solvate, polymorphic form, tautomer or the prodrug of formula (I) or formula (Ia), wherein, R 5and R 6the group formed independently selected from following group: the heteroaryl of the aryl of hydrogen, aryl, replacement, heteroaryl, replacement; More preferably, R 5and R 6the group formed independently selected from following group: hydrogen, 5-7 unit aryl, the 5-7 unit aryl of replacement, have the 5-7 unit heteroaryl of one or more N, O or the heteroatomic 5-7 unit's heteroaryl of S and replacement; And 5-7 unit's aryl of described replacement or heteroaryl are selected from least one following group and are replaced: C replacement or unsubstituted 1-C 6alkyl, C 3-C 6cycloalkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl and C 1-C 6alkoxyl group.
On the other hand, the invention provides some preferred compounds or its pharmacy acceptable salt, solvate, polymorphic form, tautomer or the prodrug of formula (I) or formula (Ia), wherein, R 3and R 4the group formed independently selected from following group: hydrogen, the optional C replaced 3-C 8cycloalkyl, the optional C replaced 6-C 10aryl, the optional C replaced 6-C 10aryl-C 1-C 6alkyl, optional replace comprise 1-4 N, O or the heteroatomic 5-15 of S unit Heterocyclylalkyl, optional replace comprise 1-4 N, O or the first heteroaryl of the heteroatomic 5-10 of S;
On the other hand, the invention provides some preferred compounds or its pharmacy acceptable salt, solvate, polymorphic form, tautomer or the prodrug of formula (I) or formula (Ia), wherein, R 3and R 4the group formed independently selected from following group: the aryl of hydrogen, aryl, replacement, C 1-C 6the C of alkylaryl, replacement 1-C 6the heteroaryl of alkylaryl, heteroaryl and replacement; More preferably, R 3and R 4the group formed independently selected from following group: hydrogen, 5-7 unit aryl, the 5-7 unit aryl of replacement, C replacement or unsubstituted 1-C 6alkyl phenyl, have the 5-7 unit heteroaryl of the heteroatomic 5-7 of one or more N, O or S unit's heteroaryl and replacement; And 5-7 unit's aryl of described replacement or heteroaryl are selected from least one following group and are replaced: halogen, C 1-C 6alkoxyl group, C 1-C 6alkyl, C 3-C 6cycloalkyl, alkyl monosubstituted amino, dialkyl amido, ring amino, heterocyclic amino group, arylamino, heteroaryl amino ,-NR 23c (O) R 24,-NR 23sO 2r 25,-CONR 23r 26with-SO 2nR 23r 26; Wherein, R 23and R 26the group formed independently selected from following group: C hydrogen, replacement or unsubstituted 1-C 6c alkyl and replacement or unsubstituted 3-C 6cycloalkyl; Perhaps R 23, R 265-7 that former common formation replaces with coupled nitrogen or unsubstituted unit heterocycle; R 24and R 25the group formed independently selected from following group: C replacement or unsubstituted 1-C 6the heteroaryl of aryl, heteroaryl and the replacement of cycloalkyl alkyl, replacement or unsubstituted, aryl, replacement; More preferably, R 24and R 25the group formed independently selected from following group: C replacement or unsubstituted 1-C 6c alkyl, replacement or unsubstituted 3-C 6the 5-7 unit heteroaryl of 5-7 unit aryl, 5-7 unit's heteroaryl and the replacement of cycloalkyl, 5-7 unit aryl, replacement.
On the other hand, the invention provides some preferred compounds or its pharmacy acceptable salt, solvate, polymorphic form, tautomer or the prodrug of formula (I) or formula (Ia), wherein, R xand R yall hydrogen.
On the other hand, the invention provides subclass or its pharmacy acceptable salt, solvate, polymorphic form, tautomer or the prodrug of the compound of the formula (I) that formula (II) or formula (IIa) mean,
Wherein:
R 1and R 2independently selected from hydrogen, halogen, trifluoromethyl, cyano group, nitro, hydroxyl, C 1-C 6alkyl, C 3-C 6cycloalkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 1-C 6alkoxyl group; Perhaps R 1, R 2jointly form C with coupled carbon atom 3-C 4the C of cycloalkyl or replacement 3-C 4cycloalkyl;
R 13, R 14, R 15, R 16, R 17, R 18, R 19, R 20, R 21and R 22independently selected from hydrogen, halogen, the optional C replaced 1-C 6alkoxyl group, the optional C replaced 1-C 6alkyl, the optional C replaced 3-C 6the heteroaryl amino of cycloalkyl, the optional alkyl monosubstituted amino replaced, the dialkyl amido optionally replaced, the optional ring replaced heterocyclic amino group amino, that optionally replace, the optional arylamino replaced, optional replacement ,-C (O)-R 24,-NR 23c (O) R 24,-NR 23sO 2r 25,-NR 23sOR 25,-CONR 23r 26,-SO 2nR 23r 26,-SONR 23r 26with-P (=O)-R 25; ; Perhaps R 13r 14, R 14r 15, R 15r 16, R 16r 17, R 18r 19, R 19r 20, R 20r 21and R 21r 22independently with coupled phenyl on carbon atom jointly form 5-8 ring replacement or unsubstituted (comprising aromatic ring or hetero-aromatic ring) or heterocycle; Wherein, R 23and R 26independently selected from C hydrogen, replacement or unsubstituted 1-C 6alkyl, C 3-C 6cycloalkyl and aryl (C for example 6-10or R aryl), 23, R 26jointly form the first heterocycle of 5-7 replacement or unsubstituted with coupled nitrogen-atoms, or R 23and R 26central one forms heterocycle (for example, 5-8 unit heterocycle) jointly with coupled nitrogen-atoms; R 24and R 25independently selected from the optional C replaced 1-C 6alkyl, the optional C replaced 3-C 6cycloalkyl, the optional aryl replaced, the optional heteroaryl replaced.Not tubular type (I) or formula (Ia), the compound of their representatives all comprises all possible steric isomer, regional isomer, diastereomer, enantiomer or epimer and their mixture.
On the other hand, the invention provides subclass or its pharmacy acceptable salt, solvate, polymorphic form, tautomer or the prodrug of the compound of the formula (I) that formula (II) or formula (IIa) mean, wherein, R 1and R 2the group formed independently selected from following group: hydrogen, halogen, cyano group, nitro, hydroxyl, the optional C replaced 1-C 6alkyl, the optional C replaced 3-C 8cycloalkyl, the optional C replaced 2-C 6thiazolinyl, the optional C replaced 2-C 6alkynyl and the optional C replaced 1-C 6alkoxyl group; Perhaps R 1, R 2with the common C that forms optional replacement of coupled carbon atom 3-C 8cycloalkyl (or C 3-C 6cycloalkyl, C 3-C 4cycloalkyl);
R 13, R 14, R 15, R 16, R 17, R 18, R 19, R 20, R 21and R 22the group formed independently selected from following group: hydrogen, halogen, the optional C replaced 1-C 6alkyl, the optional C replaced 3-C 8cycloalkyl, the optional C replaced 2-C 6thiazolinyl, the optional C replaced 2-C 6alkynyl, the optional C replaced 1-C 6alkoxyl group, the optional C replaced 6-C 10aryl, optional replace comprise 1-4 N, O or the heteroatomic 5-15 of S unit Heterocyclylalkyl, optional replace comprise 1-4 N, O or the heteroatomic 5-10 of S unit heteroaryl, the optional list-C of replacement 1-C 6alkylamino, the optional two-C replaced 1-C 6alkylamino, the optional list-C replaced 1-C 6alkylamino acyl group, the optional two-C replaced 1-C 6alkylamino acyl group, the optional C that comprises 1-3 N, O or the heteroatomic 5-12 of S unit Heterocyclylalkyl-acyl group, optional replacement replaced 1-C 6alkylamidoalkyl, amino-sulfonyl, the optional list-C replaced 1-C 6alkyl amino sulfonyl, the optional two-C replaced 1-C 6alkyl amino sulfonyl, amino sulfinyl, the optional list-C replaced 1-C 6alkylamino sulfinyl, the optional two-C replaced 1-C 6alkylamino sulfinyl, the optional C replaced 1-C 6the alkyl sulfenyl amido.
On the other hand, the invention provides subclass or its pharmacy acceptable salt, solvate, polymorphic form, tautomer or the prodrug of the compound of the formula (I) that following formula (III) or formula (IIIa) mean,
Figure BPA00001751561000071
Wherein:
R 1and R 2independently selected from hydrogen, halogen, trifluoromethyl, cyano group, nitro, hydroxyl, C 1-C 6alkoxyl group, C 1-C 6alkyl, C 3-C 6cycloalkyl, alkyl monosubstituted amino, dialkyl amido, ring amino, heterocyclic amino group, arylamino, heteroaryl amino ,-NR 23c (O) R 24,-NR 23sO 2r 25 ,-CONR 23r 26,-SO 2nR 23r 26;
R 23and R 26independently selected from hydrogen, C 1-C 6alkyl, C 3-C 6cycloalkyl; And
R 24and R 25independently selected from C 1-C 6alkoxyl group, C 3-C 6the heteroaryl of the aryl of cycloalkyl, aryl, replacement, heteroaryl, replacement; Moiety combinations is to R 13r 14, R 14r 15, R 15r 16, R 16r 17, R 18r 19, R 19r 20, R 20r 21and R 21r 22independently with coupled phenyl on carbon atom jointly form 5-8 ring replacement or unsubstituted (comprising aryl or heteroaryl) or heterocycle.
In description after this patent, not tubular type (III) or formula (IIIa), the compound of their representatives all comprises all possible steric isomer, regional isomer, diastereomer, enantiomer or epimer and their mixture.
On the other hand, the invention provides subclass or its pharmacy acceptable salt, solvate, polymorphic form, tautomer or the prodrug of the compound of the formula (I) that following formula (III) or formula (IIIa) mean, wherein:
R 1and R 2independently selected from hydrogen, halogen, cyano group, nitro, hydroxyl, the optional C replaced 1-C 6alkyl, the optional C replaced 3-C 8cycloalkyl, the optional C replaced 2-C 6thiazolinyl, the optional C replaced 2-C 6alkynyl, the optional C replaced 1-C 6alkoxyl group; Perhaps R 1, R 2with the common C that forms optional replacement of coupled carbon atom 3-C 8cycloalkyl;
R 13, R 14, R 15, R 16, R 17, R 18, R 19, R 20, R 21and R 22independently selected from hydrogen, halogen, the optional C replaced 1-C 6alkyl, the optional C replaced 3-C 8cycloalkyl, the optional C replaced 2-C 6thiazolinyl, the optional C replaced 2-C 6alkynyl, the optional C replaced 1-C 6alkoxyl group, the optional C replaced 6-C 10aryl, optional replace comprise 1-4 N, O or the heteroatomic 5-15 of S unit Heterocyclylalkyl, optional replace comprise 1-4 N, O or the heteroatomic 5-10 of S unit heteroaryl, the optional list-C of replacement 1-C 6alkylamino, the optional two-C replaced 1-C 6alkylamino, the optional list-C replaced 1-C 6alkylamino acyl group, the optional two-C replaced 1-C 6alkylamino acyl group, the optional C that comprises 1-3 N, O or the heteroatomic 5-12 of S unit Heterocyclylalkyl-acyl group, optional replacement replaced 1-C 6alkylamidoalkyl, amino-sulfonyl, the optional list-C replaced 1-C 6alkyl amino sulfonyl, the optional two-C replaced 1-C 6alkyl amino sulfonyl, amino sulfinyl, the optional list-C replaced 1-C 6alkylamino sulfinyl, the optional two-C replaced 1-C 6alkylamino sulfinyl, the optional C replaced 1-C 6the alkyl sulfenyl amido.
On the other hand, the invention provides formula (II), (IIa), (III) and some preferred compounds (IIIa) or its pharmacy acceptable salt, solvate, polymorphic form, tautomer or prodrug, wherein, R 13, R 14, R 15, R 16and R 17independently selected from hydrogen ,-NR 23c (O) R 24,-NR 23sO 2r 25,-CONR 23r 26with-SO 2nR 23r 26.R 23-R 26definition with above identical.
On the other hand, the invention provides formula (II), (IIa), (III) and some preferred compounds (IIIa) or its pharmacy acceptable salt, solvate, polymorphic form, tautomer or prodrug, wherein, R 18, R 19, R 20, R 21and R 22independently selected from hydrogen, the optional C replaced 1-C 6alkoxyl group, the optional C replaced 1-C 6alkyl, the optional C replaced 3-C 6cycloalkyl, optional replace there is one or more N, O or the heteroatomic 5-7 of S unit Heterocyclylalkyl; Perhaps R 18r 19, R 19r 20, R 20r 21and R 21r 22the common formation of carbon atom on coupled phenyl optionally replaces independently 5-15 (or 5-10,5-8) ring (comprising aromatic ring or hetero-aromatic ring) or heterocycle, wherein, the ring of described replacement or heterocycle are by oxo (oxo), the optional C replaced 1-C 6alkoxyl group, C 1-C 6alkyl, C 3-C 6cycloalkyl or the heterocycle-C of 5-7 unit 1-C 6alkyl replaces.
On the other hand, the invention provides compound or its pharmacy acceptable salt, solvate, polymorphic form, tautomer or the prodrug of the formula (I) that is selected from following compound,
Figure BPA00001751561000091
On the other hand, the invention provides above-claimed cpd of the present invention or its pharmacy acceptable salt, solvate, polymorphic form, tautomer or prodrug, it is as medicine.Preferably, described medicine has antiproliferative and/or apoptosis activity.
On the other hand, the invention provides pharmaceutical composition, it comprises compound of the present invention or its pharmacy acceptable salt, solvate, polymorphic form, tautomer or prodrug.In some embodiments, pharmaceutical composition of the present invention further comprises pharmaceutically acceptable carrier, thinner, vehicle and/or adjuvant, for example sanitas, absorption delay agent, filler, tackiness agent, sorbent material, buffer reagent, disintegrating agent, solubilizing agent, other carrier and other inert fraction.The compound method of composition is technology well known in the art.
On the other hand, the invention provides the method that suppresses FAK and/or Pyk2, described method comprises makes compound of the present invention contact with FAK and/or Pyk2.
On the other hand, the invention provides treatment or prevention FAK and/or the illness of Pyk2 mediation or the method for disease, described method comprises to compound of the present invention or the composition of the individual administering therapeutic significant quantity that these needs are arranged.Preferably, described illness or disease are cancer, infectious diseases, diseases associated with inflammation or autoimmune disorder.More preferably, described illness or disease are cancer.In some embodiments, described individuality is Mammals, is more preferably the people.
On the other hand, the invention provides the application in the pharmaceutical composition for the preparation of suppressing FAK and/or Pyk2 of above-claimed cpd of the present invention or its pharmacy acceptable salt, solvate, polymorphic form, tautomer or prodrug.Preferably, described pharmaceutical composition is used for the treatment of or prevents illness or the disease of FAK and/or Pyk2 mediation.More preferably, described illness or disease are proliferative disease.In one embodiment, described proliferative disease is cancer.In another embodiment, described proliferative disease is diseases associated with inflammation.
On the other hand, the present invention relates to the pharmacy preparation, described preparation comprises the compound and at least one the other cytostatic or cytotoxic active substance that is different from formula (I) of general formula (I), and these active substances are optionally the salt of their tautomer, racemic modification, enantiomer, diastereomer and their mixture or pharmaceutically acceptable acid adding.
In other side, the present invention relates to pharmaceutically pharmaceutical composition of acceptable salt, solvate, polymorphic form, tautomer or prodrug of above-claimed cpd of the present invention or its.In some embodiments, described pharmaceutical composition is oral dosage form.In some embodiments, the formulation of described pharmaceutical composition is tablet, capsule, pill, pulvis, sustained release preparation, solution and suspension, for sterile solution, suspension or the emulsion of parenteral injection, for ointment or the emulsifiable paste of topical, or for the suppository of rectal administration.In other embodiments, described pharmaceutical composition is bestowed the unit dosage of exact dosage desired for being applicable to single.In other embodiments, the amount of formula I compound is in the scope of the 1000mg/kg body weight/day of about 0.001mg/kg body weight/day-Yue.In other embodiments, the scope of the amount of formula I compound is the 50mg/kg body weight/day of about 0.5mg/kg body weight/day-Yue.In some embodiments, the amount of formula I compound is about 0.001g/ days-7g/ days Yue.In other embodiments, the amount of formula I compound is the about 6g/ days of about 0.002-.In other embodiments, the amount of formula I compound is about 0.005g/ days-5g/ days Yue.In other embodiments, the amount of formula I compound is the about 5g/ days of about 0.01-.In other embodiments, the amount of formula I compound is about 0.02g/ days-5g/ days Yue.In other embodiments, the amount of formula I compound is about 0.05g/ days-2.5g/ days Yue.In other embodiments, the amount of formula I compound is about 0.1g/ days-1g/ days Yue.In other embodiments, the dosage level lower than above-mentioned scope lower limit may be enough.In other embodiments, may be higher than the dosage level of above-mentioned range limit.In some embodiments, use the compound of formula I with single dose, once a day.In other embodiments, use the compound of formula I with multiple doses, every day more than once.In some embodiments, use the compound of twice formula I every day.In other embodiments, use the compound of cubic expression tertiary I every day.In other embodiments, use the compound of quarternary quantic I every day.In other embodiments, use the compound with above formula I every day four times.In some embodiments, described pharmaceutical composition is applied to Mammals.In other embodiments, described Mammals is the people.In other embodiments, described pharmaceutical composition also comprises pharmaceutical carrier, vehicle and/or auxiliary agent.In other embodiments, described pharmaceutical composition also comprises at least one therapeutical agent.In other embodiments, described therapeutical agent is selected from the group that cell toxicant material, anti-angiogenic forming agent and antineoplastic agent form.In other embodiments, antineoplastic agent selects the group that free alkylating agent, metabolic antagonist, teniposide (epidophyllotoxin), antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone (mitoxantrones), platinum complex, biological response modifier and growth inhibitor, hormone/hormone antagonist therapeutical agent and hemopoieticgrowth factor form.In other embodiments, described therapeutical agent be taxol (taxol), Velcade (bortezomib) or both.In other embodiments, using with other treatment of described pharmaceutical composition combined and carried out.In other embodiments, described other treatment is radiotherapy, chemotherapy or the combination of the two.In other embodiments, described pharmaceutical composition comprises pharmaceutically acceptable salt of formula I compound.
In other side, the present invention relates to suppress the method for FAK and/or Pyk2.Described method comprises the composition that makes described FAK and/or Pyk2 contact be enough to suppress described kinase whose amount, thereby suppress FAK and/or Pyk2 enzyme, wherein said composition comprises formula I compound or its pharmaceutically acceptable salt, hydrate, polymorphic form, tautomer or prodrug.In some embodiments, the present invention relates to the method that selectivity suppresses FAK and/or Pyk2.
In other side, the present invention relates to formula I compound or its pharmaceutically acceptable salt, solvate, polymorphic form, tautomer or prodrug application in the pharmaceutical composition for the preparation of suppressing FAK and/or Pyk2.
In some embodiments, described enzyme is suppressed at least about 1%.In other embodiments, described enzyme is suppressed at least about 2%.In other embodiments, described enzyme is suppressed at least about 3%.In other embodiments, described enzyme is suppressed at least about 4%.In other embodiments, described enzyme is suppressed at least about 5%.In other embodiments, described enzyme is suppressed at least about 10%.In other embodiments, described enzyme is suppressed at least about 20%.In other embodiments, described enzyme is suppressed at least about 25%.In other embodiments, described enzyme is suppressed at least about 30%.In other embodiments, described enzyme is suppressed at least about 40%.In other embodiments, described enzyme is suppressed at least about 50%.In other embodiments, described enzyme is suppressed at least about 60%.In other embodiments, described enzyme is suppressed at least about 70%.In other embodiments, described enzyme is suppressed at least about 75%.In other embodiments, described enzyme is suppressed at least about 80%.In other embodiments, described enzyme is suppressed at least about 90%.In other embodiments, described enzyme is substantially fully suppressed.In some embodiments, described contact occurs in cell.In some embodiments, described cell is mammalian cell.In some embodiments, described mammalian cell behaviour cell.In some embodiments, utilize the composition of the pharmacy acceptable salt of the compound that comprises formula I to suppress FAK and/or Pyk2.In other side, the present invention relates to treatment and suffer from the method for described disease of individuality of the illness of FAK and/or Pyk2 mediation, described method comprises to described individuality uses the compound that comprises formula I of significant quantity or its pharmaceutically acceptable salt, solvate, polymorphic form, tautomer or prodrug.In other side, the present invention relates to the compound or its pharmaceutically acceptable salt, solvate, polymorphic form, tautomer or the prodrug application in the pharmaceutical composition of the illness for the preparation for the treatment of FAK and/or Pyk2 mediation that comprise formula I.
In some embodiments, by oral, use through duodenum, parenteral (comprising in intravenously, subcutaneous, intramuscular, blood vessel or by the infusion mode), topical application (topical administration) or per rectum the composition that comprises formula I compound.In some embodiments, described pharmaceutical composition is oral dosage form.In other embodiments, the formulation of described pharmaceutical composition is tablet, capsule, pill, pulvis, slow release formulation, solution and suspension, for sterile solution, suspension or the emulsion of parenteral injection, for ointment or the emulsifiable paste of topical, or for the suppository of rectal administration.In other embodiments, described pharmaceutical composition is the unit dosage that is applicable to bestowing the single exact dosage desired.In other embodiments, described pharmaceutical composition also comprises pharmaceutical carrier, vehicle and/or auxiliary agent.In other embodiments, the amount of formula I compound is in the scope of the 1000mg/kg body weight/day of about 0.001mg/kg body weight/day-Yue.In other embodiments, the scope of the amount of formula I compound is the 50mg/kg body weight/day of about 0.5mg/kg body weight/day-Yue.In some embodiments, the amount of formula I compound is about 0.001g/ days-7g/ days Yue.In other embodiments, the amount of formula I compound is about 0.01g/ days-7g/ days Yue.In other embodiments, the amount of formula I compound is about 0.02g/ days-5g/ days Yue.In other embodiments, the amount of formula I compound is about 0.05g/ days-2.5g/ days Yue.In other embodiments, the amount of formula I compound is about 0.1g/ days-1g/ days Yue.In other embodiments, the dosage level lower than above-mentioned scope lower limit may be enough.In other embodiments, may be higher than the dosage level of above-mentioned range limit.In other embodiments, bestow the compound of formula I with single dose, once a day.In other embodiments, bestow the compound of formula I with multiple doses, every day more than once.In other embodiments, use the compound of twice formula I every day.In other embodiments, use the compound of cubic expression tertiary I every day.In other embodiments, use the compound of quarternary quantic I every day.In other embodiments, use the compound with above formula I every day four times.In some embodiments, the individuality of the disease of the described FAK of suffering from and/or Pyk2 mediation is Mammals.In other embodiments, described individuality is the people.In some embodiments, using with other treatment of the composition that comprises formula I compound combined and carried out.In other embodiments, described other treatment is radiotherapy, chemotherapy or the combination of the two.Composition and at least one therapeutic combination that in some embodiments, will comprise formula I compound are used.In some embodiments, described therapeutical agent is selected from the group of cell toxicant material, anti-angiogenic forming agent and antineoplastic agent.In other embodiments, antineoplastic agent selects the group that free alkylating agent, metabolic antagonist, teniposide, antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum complex, biological response modifier and growth inhibitor, hormone/hormone antagonist therapeutical agent and hemopoieticgrowth factor form.In other embodiments, described therapeutical agent be selected from taxol, Velcade or both.In some embodiments, the group formed below the described disease choosing freely by FAK and/or Pyk2 mediation: diseases associated with inflammation, infect, autoimmune disorder, apoplexy, ischemic, heart trouble, nervous system disorders, fibrotic disease, proliferative disease, excess proliferative disease, the excess proliferative disease of non-cancer, tumour (tumor), leukemia, vegetation (neopalsms), cancer (cancer), malignant tumor (carcinoma), metabolic trouble, malignant disease, vascular restenosis, psoriatic, arteriosclerosis, rheumatoid arthritis, osteoarthritis, in heart failure, chronic pain, neuropathic pain, xeropthalmus, angle closure glaucoma and wide-angle glaucoma.In other embodiments, the disease of described FAK and/or Pyk2 mediation is diseases associated with inflammation.In other embodiments, the disease of described FAK and/or Pyk2 mediation is proliferative disease.In other embodiments, the group that the disease of described FAK and/or Pyk2 mediation selects free tumour, leukemia, vegetation, cancer, malignant tumor and malignant disease to form.In other embodiments, described cancer is the cancer of the brain, mammary cancer, lung cancer, ovarian cancer, carcinoma of the pancreas, prostate cancer, kidney, colorectal cancer or leukemia.In other embodiments, described fibrotic disease is scleroderma, polymyositis, systemic lupus erythematous, rheumatoid arthritis, liver cirrhosis, cicatrization, interstitial nephritis or pulmonary fibrosis.In some embodiments, use be significant quantity comprise the pharmaceutically composition of acceptable salt of formula I compound.
In other side, the present invention relates to make the method for cancer cells degeneration (degrade), anticancer growth or kill cancer cell, described method comprises makes that its amount of described cells contacting can effectively make that cancer cells is degenerated, the composition of anticancer growth or kill cancer cell, and described composition comprises formula I compound or its pharmaceutically acceptable salt, solvate, polymorphic form, tautomer or prodrug.
In other side, the present invention relates to comprise formula I compound or its pharmaceutically acceptable salt, solvate, polymorphic form, tautomer or prodrug application on the pharmaceutical composition for the preparation of making cancer cells degeneration, anticancer growth or kill cancer cell.
In some embodiments, described cancer cells comprises brain cancer cell, breast cancer cell, lung carcinoma cell, ovarian cancer cell, prostate cancer cell, kidney cancer cell or colorectal cancer cell.In some embodiments, described composition is used together with at least one therapeutical agent.In other embodiments, described therapeutical agent be taxol, Velcade or both.In other embodiments, described therapeutical agent selects the group that free cell toxicant material, anti-angiogenic forming agent and antineoplastic agent form.In other embodiments, antineoplastic agent selects the group that free alkylating agent, metabolic antagonist, teniposide, antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum complex, biological response modifier and growth inhibitor, hormone/hormone antagonist therapeutical agent and hemopoieticgrowth factor form.In some embodiments, cancer cells is degenerated.In other embodiments, 1% cancer cells is degenerated.In other embodiments, 2% cancer cells is degenerated.In other embodiments, 3% cancer cells is degenerated.In other embodiments, 4% cancer cells is degenerated.In other embodiments, 5% cancer cells is degenerated.In other embodiments, 10% cancer cells is degenerated.In other embodiments, 20% cancer cells is degenerated.In other embodiments, 25% cancer cells is degenerated.In other embodiments, 30% cancer cells is degenerated.In other embodiments, 40% cancer cells is degenerated.In other embodiments, 50% cancer cells is degenerated.In other embodiments, 60% cancer cells is degenerated.In other embodiments, 70% cancer cells is degenerated.In other embodiments, 75% cancer cells is degenerated.In other embodiments, 80% cancer cells is degenerated.In other embodiments, 90% cancer cells is degenerated.In other embodiments, 100% cancer cells is degenerated.In other embodiments, substantially all cancer cells are all degenerated.In some embodiments, cancer cells is killed.In other embodiments, 1% cancer cells is killed.In other embodiments, 2% cancer cells is killed.In other embodiments, 3% cancer cells is killed.In other embodiments, 4% cancer cells is killed.In other embodiments, 5% cancer cells is killed.In other embodiments, 10% cancer cells is killed.In other embodiments, 20% cancer cells is killed.In other embodiments, 25% cancer cells is killed.In other embodiments, 30% cancer cells is killed.In other embodiments, 40% cancer cells is killed.In other embodiments, 50% cancer cells is killed.In other embodiments, 60% cancer cells is killed.In other embodiments, 70% cancer cells is killed.In other embodiments, 75% cancer cells is killed.In other embodiments, 80% cancer cells is killed.In other embodiments, 90% cancer cells is killed.In other embodiments, 100% cancer cells all is killed.In other embodiments, substantially all cancer cells all are killed.In some embodiments, the growth of cancer cells is suppressed.In other embodiments, the growth of cancer cells suppressed approximately 1%.In other embodiments, the growth of cancer cells suppressed approximately 2%.In other embodiments, the growth of cancer cells suppressed approximately 3%.In other embodiments, the growth of cancer cells suppressed approximately 4%.In other embodiments, the growth of cancer cells suppressed approximately 5%.In other embodiments, the growth of cancer cells suppressed approximately 10%.In other embodiments, the growth of cancer cells suppressed approximately 20%.In other embodiments, the growth of cancer cells suppressed approximately 25%.In other embodiments, the growth of cancer cells suppressed approximately 30%.In other embodiments, the growth of cancer cells suppressed approximately 40%.In other embodiments, the growth of cancer cells suppressed approximately 50%.In other embodiments, the growth of cancer cells suppressed approximately 60%.In other embodiments, the growth of cancer cells suppressed approximately 70%.In other embodiments, the growth of cancer cells suppressed approximately 75%.In other embodiments, the growth of cancer cells suppressed approximately 80%.In other embodiments, the growth of cancer cells suppressed approximately 90%.In other embodiments, the growth of cancer cells suppressed approximately 100%.What use in some embodiments, is to comprise the pharmaceutically composition of acceptable salt of formula I compound.
In other side, the method that the present invention relates to treatment or prevent individual proliferative disease, described method comprises pharmaceutical composition from significant quantity to described individuality that use, and described pharmaceutical composition comprises formula I compound or its pharmaceutically acceptable salt, solvate, polymorphic form, tautomer or prodrug.
In other side, the present invention relates to formula I compound or its pharmaceutically acceptable salt, solvate, polymorphic form, tautomer or prodrug application in the pharmaceutical composition for the preparation for the treatment of or prevention proliferative disease.
In some embodiments, described proliferative disease is cancer, psoriatic, restenosis, autoimmune disorder or arteriosclerosis.In other embodiments, described proliferative disease is excess proliferative disease.In other embodiments, described proliferative disease selects the group that free tumour, leukemia, vegetation, cancer, malignant tumor and malignant disease form.In other embodiments, described cancer is the cancer of the brain, mammary cancer, lung cancer, ovarian cancer, carcinoma of the pancreas, prostate cancer, kidney, colorectal cancer or leukemia.In other embodiments, described fibrotic disease is scleroderma, polymyositis, systemic lupus erythematous, rheumatoid arthritis, liver cirrhosis, cicatrization, interstitial nephritis or pulmonary fibrosis.In other embodiments, described cancer is the cancer of the brain, mammary cancer, lung cancer, ovarian cancer, carcinoma of the pancreas, prostate cancer, kidney, colorectal cancer or leukemia.In other embodiments, described cancer is the cancer of the brain or adrenocortical carcinoma.In other embodiments, described cancer is mammary cancer.In other embodiments, described cancer is ovarian cancer.In other embodiments, described cancer is carcinoma of the pancreas.In other embodiments, described cancer is prostate cancer.In other embodiments, described cancer is kidney.In other embodiments, described cancer is colorectal cancer.In other embodiments, described cancer is myelocytic leukemia.In other embodiments, described cancer is glioblastoma multiforme.In other embodiments, described cancer is follicular lymphoma.In other embodiments, described cancer is the impatient property of pre B cell leukemia.In other embodiments, described cancer is Type B lymphatic chronic leukemia.In other embodiments, described cancer is mesothelioma.In other embodiments, described cancer is that minicell is cancer.In some embodiments, will comprise formula I compound composition use with other treatment linked together.In other embodiments, described other treatment is radiotherapy, chemotherapy or the combination of the two.Composition and at least one therapeutic combination that in other embodiments, will comprise formula I compound are used.In other embodiments, described therapeutical agent is selected from the group of cell toxicant material, anti-angiogenic forming agent and antineoplastic agent.In other embodiments, antineoplastic agent selects the group that free alkylating agent, metabolic antagonist, teniposide, antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum complex, biological response modifier and growth inhibitor, hormone/hormone antagonist therapeutical agent and hemopoieticgrowth factor form.In other embodiments, described therapeutical agent be selected from taxol, Velcade or both.In some embodiments, by oral, through duodenum, parenteral (comprise in intravenously, subcutaneous, intramuscular, blood vessel or pass through infusion), topical application or per rectum applying said compositions.In other embodiments, the scope of the amount of formula I compound is the 1000mg/kg body weight/day of about 0.001mg/kg body weight/day-Yue.In other embodiments, the scope of the amount of formula I compound is the 50mg/kg body weight/day of about 0.5mg/kg body weight/day-Yue.In other embodiments, the amount of formula I compound is about 0.001g/ days-7g/ days Yue.In other embodiments, the amount of formula I compound is about 0.01g/ days-7g/ days Yue.In other embodiments, the amount of formula I compound is about 0.02g/ days-5g/ days Yue.In other embodiments, the amount of formula I compound is about 0.05g/ days-2.5g/ days Yue.In other embodiments, the amount of formula I compound is about 0.1g/ days-1g/ days Yue.In other embodiments, the dosage level lower than above-mentioned scope lower limit may be enough.In other embodiments, may be higher than the dosage level of above-mentioned range limit.In other embodiments, the compound of formula I is with single dose administration, once a day.In other embodiments, the compound of formula I is with multiple dose administration, and every day more than once.In other embodiments, use the compound of twice formula I every day.In other embodiments, use the compound of cubic expression tertiary I every day.In other embodiments, use the compound of quarternary quantic I every day.In other embodiments, use the compound with above formula I every day four times.In some embodiments, the individuality of suffering from proliferative disease is Mammals.In other embodiments, described individuality is the people.In some embodiments, use be significant quantity comprise the pharmaceutically composition of acceptable salt of formula I compound.
In other side, the method that the present invention relates to treatment or prevent individual diseases associated with inflammation, described method comprises pharmaceutical composition from significant quantity to described individuality that use, and described pharmaceutical composition comprises formula I compound or its pharmaceutically acceptable salt, solvate, polymorphic form, tautomer or prodrug.
In other side, the present invention relates to comprise formula I compound or its pharmaceutically acceptable salt, solvate, polymorphic form, tautomer or prodrug application in the pharmaceutical composition for the preparation for the treatment of or preventing inflammatory disease.
In other embodiments, the diseases associated with inflammation choosing is the following group formed freely: chronic inflammation disease, rheumatoid arthritis, SpA, urarthritis, osteoarthritis, property childhood sacroiliitis, acute rheumatic arthritis, enteropathic arthritis, neurarthropathy, psoriatic arthritis, suppurative arthritis, arteriosclerosis, systemic lupus erythematous, the inflammatory intestinal tract disease, irritable bowel syndrome, ulcerative colitis, reflux esophagitis, regional enteritis (Crohn ' s disease), gastritis, asthma, allergy, respiratory distress syndrome, pancreatitis, chronic obstructive pulmonary disease, pulmonary fibrosis, psoriatic, eczema or scleroderma.In some embodiments, will comprise formula I compound composition use with other treatment linked together.Composition and at least one therapeutic combination that in other embodiments, will comprise formula I compound are used.In some embodiments, by oral, through duodenum, parenteral (comprise in intravenously, subcutaneous, intramuscular, blood vessel or pass through infusion), topical application or per rectum applying said compositions.In other embodiments, the scope of the amount of formula I compound is the 1000mg/kg body weight/day of about 0.001mg/kg body weight/day-Yue.In other embodiments, the scope of the amount of formula I compound is the 50mg/kg body weight/day of about 0.5mg/kg body weight/day-Yue.In other embodiment, the amount of formula I compound is about 0.001g/ days-7g/ days Yue.In his embodiment, the amount of formula I compound is about 0.01g/ days-7g/ days Yue.In other embodiments, the amount of formula I compound is about 0.02g/ days-5g/ days Yue.In other embodiments, the amount of formula I compound is about 0.05g/ days-2.5g/ days Yue.In other embodiments, the amount of formula I compound is about 0.1g/ days-1g/ days Yue.In other embodiments, the dosage level lower than above-mentioned scope lower limit may be enough.In other embodiments, may be higher than the dosage level of above-mentioned range limit.In other embodiments, the compound of formula I is with single dose administration, once a day.In other embodiments, the compound of formula I is with multiple dose administration, and every day more than once.In other embodiments, use the compound of twice formula I every day.In other embodiments, use the compound of cubic expression tertiary I every day.In other embodiments, use the compound of quarternary quantic I every day.In other embodiments, use the compound with above formula I every day four times.In some embodiments, the individuality of suffering from diseases associated with inflammation is Mammals.In other embodiments, described individuality is the people.In some embodiments, use be significant quantity comprise the pharmaceutically composition of acceptable salt of formula I compound.
In other side, the present invention relates to the method for the treatment of or prevention individual cancer, described method comprises pharmaceutical composition from significant quantity to described individuality that use, and described pharmaceutical composition comprises formula I compound or its pharmaceutically acceptable salt, solvate, polymorphic form, tautomer or prodrug.
In other side, the present invention relates to comprise formula I compound or its pharmaceutically acceptable salt, solvate, polymorphic form, tautomer or prodrug application in the pharmaceutical composition for the preparation for the treatment of or preventing cancer.
In other embodiments, described cancer is the cancer of the brain, mammary cancer, lung cancer, ovarian cancer, carcinoma of the pancreas, prostate cancer, kidney, colorectal cancer or leukemia.In other embodiments, described fibrotic disease is scleroderma, polymyositis, systemic lupus erythematous, rheumatoid arthritis, liver cirrhosis, cicatrization, interstitial nephritis or pulmonary fibrosis.In other embodiments, described cancer is the cancer of the brain, mammary cancer, lung cancer, ovarian cancer, carcinoma of the pancreas, prostate cancer, kidney, colorectal cancer or leukemia.In other embodiments, described cancer is the cancer of the brain or adrenocortical carcinoma.In other embodiments, described cancer is mammary cancer.In other embodiments, described cancer is ovarian cancer.In other embodiments, described cancer is carcinoma of the pancreas.In other embodiments, described cancer is prostate cancer.In other embodiments, described cancer is kidney.In other embodiments, described cancer is colorectal cancer.In other embodiments, described cancer is myelocytic leukemia.In other embodiments, described cancer is glioblastoma multiforme.In other embodiments, described cancer is follicular lymphoma.In other embodiments, described cancer is the impatient property of pre B cell leukemia.In other embodiments, described cancer is Type B lymphatic chronic leukemia.In other embodiments, described cancer is mesothelioma.In other embodiments, described cancer is that minicell is cancer.In some embodiments, will comprise formula I compound composition use with other treatment linked together.In other embodiments, described other treatment is radiotherapy, chemotherapy or the combination of the two.Composition and at least one therapeutic combination that in other embodiments, will comprise formula I compound are used.In other embodiments, described therapeutical agent is selected from the group of cell toxicant material, anti-angiogenic forming agent and antineoplastic agent.In other embodiments, antineoplastic agent selects the group that free alkylating agent, metabolic antagonist, teniposide, antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum complex, biological response modifier and growth inhibitor, hormone/hormone antagonist therapeutical agent and hemopoieticgrowth factor form.In other embodiments, described therapeutical agent be selected from taxol, Velcade or both.In some embodiments, by oral, through duodenum, parenteral (comprise in intravenously, subcutaneous, intramuscular, blood vessel or pass through infusion), topical application or per rectum applying said compositions.In other embodiments, in other embodiments, the scope of the amount of formula I compound is the 1000mg/kg body weight/day of about 0.001mg/kg body weight/day-Yue.In other embodiments, the scope of the amount of formula I compound is the 50mg/kg body weight/day of about 0.5mg/kg body weight/day-Yue.In other embodiments, the amount of formula I compound is about 0.001g/ days-7g/ days Yue.In other embodiments, the amount of formula I compound is about 0.01g/ days-7g/ days Yue.In other embodiments, the amount of formula I compound is about 0.02g/ days-5g/ days Yue.In other embodiments, the amount of formula I compound is about 0.05g/ days-2.5g/ days Yue.In other embodiments, the amount of formula I compound is about 0.1g/ days-1g/ days Yue.In other embodiments, the dosage level lower than above-mentioned scope lower limit may be enough.In other embodiments, may be higher than the dosage level of above-mentioned range limit.In other embodiments, the compound of formula I is with single dose administration, once a day.In other embodiments, the compound of formula I is with multiple dose administration, and every day more than once.In other embodiments, use the compound of twice formula I every day.In other embodiments, use the compound of cubic expression tertiary I every day.In other embodiments, use the compound of quarternary quantic I every day.In other embodiments, use the compound with above formula I every day four times.In some embodiments, the individuality of suffering from cancer is Mammals.In other embodiments, described individuality is the people.In some embodiments, use be significant quantity comprise the pharmaceutically composition of acceptable salt of formula I compound.
In other side, the present invention relates to reduce individual in-vivo tumour volume, suppress the method that gross tumor volume increases, reduces tumor proliferation or suppresses tumor proliferation, described method comprises to the pharmaceutical composition of described individual administering therapeutic significant quantity, and described pharmaceutical composition comprises formula I compound or its pharmaceutically acceptable salt, solvate, polymorphic form, tautomer or prodrug.
In other side, the present invention relates to formula I compound or its pharmaceutically acceptable salt, solvate, polymorphic form, tautomer or prodrug application in pharmaceutical compositions, described pharmaceutical composition is for reducing gross tumor volume, suppress the gross tumor volume increase, reduce tumor proliferation or suppressing tumor proliferation.
In some embodiments, gross tumor volume reduces.In other embodiments, gross tumor volume reduces at least 1%.In other embodiments, gross tumor volume reduces at least 2%.In other embodiments, gross tumor volume reduces at least 3%.In other embodiments, gross tumor volume reduces at least 4%.In other embodiments, gross tumor volume reduces at least 5%.In other embodiments, gross tumor volume reduces at least 10%.In other embodiments, gross tumor volume reduces at least 20%.In other embodiments, gross tumor volume reduces at least 25%.In other embodiments, gross tumor volume reduces at least 30%.In other embodiments, gross tumor volume reduces at least 40%.In other embodiments, gross tumor volume reduces at least 50%.In other embodiments, gross tumor volume reduces at least 60%.In other embodiments, gross tumor volume reduces at least 70%.In other embodiments, gross tumor volume reduces at least 75%.In other embodiments, gross tumor volume reduces at least 80%.In other embodiments, gross tumor volume reduces at least 85%.In other embodiments, gross tumor volume reduces at least 90%.In other embodiments, gross tumor volume reduces at least 95%.In other embodiments, described tumour is uprooted.In some embodiments, gross tumor volume no longer increases.In some embodiments, tumor proliferation descends.In some embodiments, tumor proliferation descends at least 1%.In some embodiments, tumor proliferation descends at least 2%.In some embodiments, tumor proliferation descends at least 3%.In some embodiments, tumor proliferation descends at least 4%.In some embodiments, tumor proliferation descends at least 5%.In some embodiments, tumor proliferation descends at least 10%.In some embodiments, tumor proliferation descends at least 20%.In some embodiments, tumor proliferation descends at least 25%.In some embodiments, tumor proliferation descends at least 30%.In some embodiments, tumor proliferation descends at least 40%.In some embodiments, tumor proliferation descends at least 50%.In some embodiments, tumor proliferation descends at least 60%.In some embodiments, tumor proliferation descends at least 70%.In some embodiments, tumor proliferation descends at least 75%.In some embodiments, tumor proliferation descends at least 80%.In some embodiments, tumor proliferation descends at least 90%.In some embodiments, tumor proliferation descends at least 95%.In some embodiments, tumor proliferation is prevented from.In some embodiments, will comprise formula I compound composition use with other treatment linked together.In other embodiments, described other treatment is radiotherapy, chemotherapy or the combination of the two.Composition and at least one therapeutic combination that in other embodiments, will comprise formula I compound are used.In other embodiments, described therapeutical agent is selected from the group of cell toxicant material, anti-angiogenic forming agent and antineoplastic agent.In other embodiments, antineoplastic agent selects the group that free alkylating agent, metabolic antagonist, teniposide, antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum complex, biological response modifier and growth inhibitor, hormone/hormone antagonist therapeutical agent and hemopoieticgrowth factor form.In other embodiments, described therapeutical agent be selected from taxol, Velcade or both.In some embodiments, by oral, through duodenum, parenteral (comprise in intravenously, subcutaneous, intramuscular, blood vessel or pass through infusion), topical application or per rectum applying said compositions.In other embodiments, in other embodiments, the scope of the amount of formula I compound is the 1000mg/kg body weight/day of about 0.001mg/kg body weight/day-Yue.In other embodiments, the scope of the amount of formula I compound is the 50mg/kg body weight/day of about 0.5mg/kg body weight/day-Yue.In other embodiment, the amount of formula I compound is about 0.001g/ days-7g/ days Yue.In his embodiment, the amount of formula I compound is about 0.01g/ days-7g/ days Yue.In other embodiments, the amount of formula I compound is about 0.02g/ days-5g/ days Yue.In other embodiments, the amount of formula I compound is about 0.05g/ days-2.5g/ days Yue.In other embodiments, the amount of formula I compound was at about 0.1g/ days-1g/ days Yue.In other embodiments, the dosage level lower than above-mentioned scope lower limit may be enough.In other embodiments, may be higher than the dosage level of above-mentioned range limit.In other embodiments, the compound of formula I is with single dose administration, once a day.In other embodiments, the compound of formula I is with multiple dose administration, and every day more than once.In other embodiments, use the compound of twice formula I every day.In other embodiments, use the compound of cubic expression tertiary I every day.In other embodiments, use the compound of quarternary quantic I every day.In other embodiments, use the compound with above formula I every day four times.In some embodiments, the individuality of suffering from cancer is Mammals.In other embodiments, described individuality is the people.In some embodiments, use be significant quantity comprise the pharmaceutically composition of acceptable salt of formula I compound.
In other side, the present invention relates to the patient is produced the method for curative effect, wherein said curative effect is selected from and suppresses kinds cancer, Immunosuppression disease and/or diseases associated with inflammation, described method comprises pharmaceutical composition from significant quantity to described patient that use, and described pharmaceutical composition comprises formula I compound or its pharmaceutically acceptable salt, solvate, polymorphic form, tautomer or prodrug.In some embodiments, described curative effect is for suppressing kinds cancer.In other embodiments, described curative effect is the Immunosuppression disease.In other embodiments, described curative effect is the inflammation-inhibiting disease.
In other side, the present invention relates to comprise formula I compound or its pharmaceutically acceptable salt, solvate, polymorphic form, tautomer or prodrug application in the pharmaceutical composition for the preparation of suppressing kinds cancer, immunological disease and/or diseases associated with inflammation.
In some embodiments, will comprise formula I compound composition use with other treatment linked together.In other embodiments, described other treatment is radiotherapy, chemotherapy or the combination of the two.Composition and at least one therapeutic combination that in other embodiments, will comprise formula I compound are used.In some embodiments, by oral, through duodenum, parenteral (comprise in intravenously, subcutaneous, intramuscular, blood vessel or pass through infusion), topical application or per rectum applying said compositions.In other embodiments, in other embodiments, the scope of the amount of formula I compound is the 1000mg/kg body weight/day of about 0.001mg/kg body weight/day-Yue.In other embodiments, the scope of the amount of formula I compound is the 50mg/kg body weight/day of about 0.5mg/kg body weight/day-Yue.In other embodiments, the amount of formula I compound is about 0.001g/ days-7g/ days Yue.In other embodiments, the amount of formula I compound is about 0.01g/ days-7g/ days Yue.In other embodiments, the amount of formula I compound is about 0.02g/ days-5g/ days Yue.In other embodiments, the amount of formula I compound is about 0.05g/ days-2.5g/ days Yue.In other embodiments, the amount of formula I compound is about 0.1g/ days-1g/ days Yue.In other embodiments, the dosage level lower than above-mentioned scope lower limit may be enough.In other embodiments, may be higher than the dosage level of above-mentioned range limit.In other embodiments, the compound of formula I is with single dose administration, once a day.In other embodiments, the compound of formula I is with multiple dose administration, and every day more than once.In other embodiments, use the compound of twice formula I every day.In other embodiments, use the compound of cubic expression tertiary I every day.In other embodiments, use the compound of quarternary quantic I every day.In other embodiments, use the compound with above formula I every day four times.In some embodiments, the individuality of suffering from cancer is Mammals.In other embodiments, described individuality is the people.In some embodiments, use be significant quantity comprise the pharmaceutically composition of acceptable salt of formula I compound.
In other side, the present invention relates to pharmaceutically preparation method of acceptable salt, solvate, polymorphic form, tautomer or prodrug of formula I compound or its.
Detailed Description Of The Invention
Claims of the present invention have been stated new feature of the present invention especially.Stated the illustrative embodiments of utilizing the principle of the invention in detailed Description Of The Invention hereinafter.Can understand better the features and advantages of the present invention by reference to following summary of the invention.
Although this paper describes the preferred embodiment of the present invention, these embodiments only provide as example.The variant that should understand embodiment of the present invention as herein described also can be used for implementing the present invention.Those of ordinary skills should be understood that and multiple variant, variation and replacement can occur and not depart from the scope of the present invention.The protection domain that should understand all respects of the present invention determines by claims, and the method and structure in these claim scopes with and the scope that all contains at these claims of method and structure of equal value within.
Chapter title used herein is only for organizing the purpose of article, and should not be interpreted as the restriction to described theme.All documents of quoting in the application or literature department divide and include but not limited to patent, patent application, article, books, operational manual and paper, and all integral body is incorporated to this paper by reference.
Some technical term of chemistry
Unless otherwise defined, otherwise the connotation that the connotation that all scientific and technical terminologies of this paper have and claim theme one of ordinary skill in the art understand usually is identical.Except as otherwise noted, all patents that this paper quotes in full, patent application, open material integral body by reference are incorporated to this paper.If this paper has a plurality of definition to term, with the definition of this chapter, be as the criterion.When quoting URL or other this class identifier or address, should understand this class identifier can change and can with internet on specifying information exchanged, also can obtain information of equal value by the bibliography channel that internet is retrieved or other is applicable.Availability and the public propagation of the bibliography proof this type of information obtained.
Should be understood that above-mentioned summary and being specified as hereinafter are exemplary and only for explaining, and theme of the present invention is not imposed any restrictions.In this application, unless separately illustrate, otherwise also comprise plural number while using odd number.Must be noted that, unless explanation is separately arranged in literary composition clearly, singulative used comprises the plural form of indication things in the present specification and claims.It shall yet further be noted that except as otherwise noted, otherwise "or" used, " or " expression " and/or ".In addition, term used " comprises " and other form, for example " comprises ", " containing " and " containing " non-limiting.
Can be at reference (" the ADVANCED ORGANIC CHEMISTRY 4 that comprises Carey and Sundberg tHeD. " Vols.A (2000) and B (2001), Plenum Press, New York) in find the definition to the standard chemical term.Except as otherwise noted, otherwise adopt the ordinary method in the art technology scope, as mass spectrum, NMR, IR and UV/Vis spectrography and pharmacological method.Unless the proposition specific definition, otherwise the term that this paper adopts in analytical chemistry, Synthetic Organic Chemistry and medicine and pharmaceutical chemical relevant the description is known in the art.Can and send at chemosynthesis, chemical analysis, medicine preparation, preparation, and to Application standard technology in patient's treatment.For example, can utilize the operation instruction of manufacturer to test kit, or implement reaction and carry out purifying according to mode well known in the art or explanation of the present invention.Usually can, according to the description in a plurality of summary of quoting in this specification sheets and discussing and more concrete document, according to ordinary method well known in the art, implement above-mentioned technology and method.In this manual, can select group and substituting group thereof so that stable structure part and compound to be provided by those skilled in the art.
When the conventional chemical formula by writing is from left to right described substituting group, this substituting group comprises the resulting substituting group chemically be equal to while writing structural formula from right to left too.For example, CH 2o is equal to OCH 2.
Except as otherwise noted, otherwise universalization technics used, such as but not limited to, " alkyl ", " amine ", " aryl " are equal to its optional form replaced.For example, " alkyl " used herein comprises the alkyl of optional replacement.
Compound described herein can have one or more stereogenic centres, and each isomery center can exist with the form of R or S configuration or its combination.Similarly, compound described herein can have one or more pairs of keys, and each pair of key can exist with the form of E (trans) or Z (cis) configuration or its combination.Specific steric isomer, constitutional isomer (regioisomer), diastereomer, enantiomer or an epimer should be understood to include all possible steric isomer, constitutional isomer, diastereomer, enantiomer or epimer and composition thereof.Therefore, compound described herein comprise steric isomers different on all configurations, constitutional isomer, diastereomer, enantiomer or epimer form with and corresponding mixture.For the technology that transforms particular stereoisomer or particular stereoisomer is maintained the original state, and the technology that splits stereoisomer mixture is well known in the art, and those skilled in the art can select applicable method with regard to particular case.Referring to, Fumiss et al. (eds.) for example, VOGEL ' S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991,809-816; And Heller, Acc.Chem.Res.1990,23,128.
Term used herein " part ", " chemical part ", " group ", " chemical group " refer to specific fragment or the functional group in molecule.Chemical part is considered to embed or append to the chemical entities on molecule usually.
Term " key " or " singly-bound " refer to, by key, two atoms or two parts are connected and obtain the more chemical bond of macrostructure part.
Term " optional/any " or " optionally/at random " refer to that event or the situation described subsequently may occur or may not occur, and this description comprises generation described event or situation and described event or situation do not occur.For example, according to definition hereinafter, " the optional alkyl replaced " refers to " unsubstituted alkyl " (not being substituted the alkyl that base replaces) or " alkyl of replacement " (being substituted the alkyl that base replaces).In addition, the optional group replaced can be not to be substituted (as CH 2cH 3), replace (as CF fully 2cF 3), monosubstituted (CH 2cH 2f) or fully replace and monosubstituted between the replacement degree (as CH 2cHF 2, CF 2cH 3, CFHCHF 2deng).Those skilled in the art can understand, for comprising one or more substituent any groups, (for example can not be introduced into any replacement that spatially can not exist and/or can not synthesize or substitute mode, substituted alkyl comprises the cycloalkyl of optional replacement, otherwise, cycloalkyl is defined as comprising the alkyl of optional replacement, so repeatedly).Therefore, described substituting group should be understood to that maximum molecular weight is about 1,000 dalton usually, more generally, and the most about 500 dalton (except obviously needing the substituent situation of macromole, such as polypeptide, polysaccharide, polyoxyethylene glycol, DNA and RNA etc.).
C used herein 1-C ncomprise C 1-C 2, C 1-C 3... C 1-C n.For example, described " C 1-C 4" group refers in this part to have 1-4 carbon atom, group comprises 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms.Scope C 1-C 2and C 1-C 3definition similarly.Therefore, " C for example 1-C 4alkyl " refer to that, at the alkyl that 1-4 carbon atom arranged, described alkyl is selected from methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, sec-butyl and the tertiary butyl.Digital scope herein, for example " 1-10 " refers to each integer in given range, and for example " 1-10 carbon atom " refers to that this group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.
The term that this paper is used alone or in combination " heteroatoms " or " mixing " refer to the atom outside de-carbon and hydrogen.Heteroatoms is independently selected from oxygen, nitrogen, sulphur, phosphorus, silicon, selenium and tin, but is not limited to these atoms.In two or more heteroatomic embodiments occurring, described two or more heteroatomss can be mutually the same, or some or all in described two or more heteroatomss differ from one another.
The term that this paper is used alone or in combination " alkyl " refers to the straight chain of optional replacement or the monovalence stable hydrocarbon of the optional side chain replaced, and it has approximately 10 carbon atoms of 1-, more preferably about 6 carbon atoms of 1-.Example includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, 2-methyl isophthalic acid-propyl group, the 2-methyl-2-propyl, the 2-methyl-1-butene base, 3-methyl isophthalic acid-butyl, 2-methyl-3-butyl, 2, 2-dimethyl-1-propyl group, 2-methyl-1-pentene base, 3-methyl-1-pentene base, 4-methyl-1-pentene base, 2-methyl-2-amyl group, 3-methyl-2-amyl group, 4-methyl-2-amyl group, 2, 2-dimethyl-1-butyl, 3, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, tert-pentyl and hexyl, and longer alkyl group, as heptyl and octyl group etc.Group defined herein, as " alkyl " while digital scope occurring, " C for example 1-C 6alkyl " or " C 1-6alkyl " referring to can be by 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 alkyl that carbon atom forms, and the alkyl of this paper also comprises the not situation of designation number scope.
The term that this paper is used alone or in combination " alkylidene group " refers to the divalent group derivative by univalent alkyl defined above.Example includes but not limited to methylene radical (CH 2), ethylidene (CH 2cH 2), propylidene (CH 2cH 2cH 2) and isopropylidene (CH (CH 3) CH 2) etc.
The term that this paper is used alone or in combination " thiazolinyl " refers to the straight chain of optional replacement or the monovalence alkyl of the optional side chain replaced, and it has the two keys of one or more C=C and has approximately 10 carbon atoms of 2-, more preferably about 6 carbon atoms of 2-.Two keys in these groups can be cis or transoid conformation, and should be understood to comprise described two kinds of isomer.Example includes but not limited to vinyl (CH=CH 2), 1-propenyl (CH 2cH=CH 2), pseudoallyl (C (CH 3)=CH 2), butenyl and 1,3-butadiene base etc.When digital scope appears in thiazolinyl defined herein, " C for example 2-C 6thiazolinyl " or " C 2-6thiazolinyl " referring to can be by 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 thiazolinyl that carbon atom forms, and the thiazolinyl of this paper is also contained the not situation of designation number scope.
The term that this paper is used alone or in combination " alkenylene " refers to by the derivative divalent group of monovalence thiazolinyl defined above.Example includes but not limited to that vinylidene (CH=CH) and propenylidene isomer are (as CH 2cH=CH and C (CH 3)=CH) etc.
The term that this paper is used alone or in combination " alkynyl " refers to the monovalence alkyl of the straight or branched of optional replacement, and it has one or more C ≡ C triple bonds and has approximately 10 carbon atoms of 2-, more preferably about 6 carbon atoms of 2-.Example includes but not limited to ethynyl, 2-propynyl, 2-butyne base and 1,3-diacetylene base etc.When digital scope appears in alkynyl defined herein, " C for example 2-C 6alkynyl " or " C 2-6alkynyl " referring to can be by 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 alkynyl group that carbon atom forms, and the alkynyl of this paper is also contained the not situation of designation number scope.
The term that this paper is used alone or in combination " assorted alkyl ", " assorted thiazolinyl " and " assorted alkynyl " refer to respectively optional alkyl, thiazolinyl and the alkynyl structure replaced, as described above, (wherein one or more skeletal chain carbon atoms (also comprising in appropriate circumstances connected hydrogen atom) are replaced by heteroatoms respectively independently, other atom outside de-carbon, such as but not limited to oxygen, nitrogen, sulphur, silicon, phosphorus, tin or its combination).
The term that this paper is used alone or in combination " haloalkyl ", " haloalkenyl group ", " halo alkynyl " refer to respectively optional alkyl, thiazolinyl and the alkynyl structure replaced, as described above, wherein one or more hydrogen atoms are replaced by fluorine, chlorine, bromine, iodine atom or its combination.In some embodiments, use mutually the same halogen atom to replace two or more hydrogen atoms (for example difluoromethyl); Use in other embodiments not identical halogen atom each other to replace two or more hydrogen atoms (for example fluoro-1-iodine of the chloro-1-of 1-ethyl).The non-limiting example of haloalkyl is methyl fluoride and bromotrifluoromethane.The non-limiting example of haloalkenyl group is bromo vinyl.The non-limiting example of halo alkynyl is the chloroethene alkynyl.
The term that this paper is used alone or in combination " ring ", " ring-type ", " ring " and " ring " refer to as described herein covalence closed structure arbitrarily, and it comprises that alicyclic ring, heterocycle, aromatic ring, hetero-aromatic ring and many rings condense ring system or encircle the non-condensed ring system more.Ring can be optionally substituted.Ring can form the fused rings pastern and divide.Term " unit " refers to the number of the skeletal atom of makeup ring.Therefore, for example, hexanaphthene, pyridine, pyrans and pyrimidine are six-ring, and pentamethylene, pyrroles, tetrahydrofuran (THF) and thiophene are five-ring.
The term that this paper is used alone or in combination " condenses " and refers to that two or more rings have the ring structure of one or more keys jointly.
The term that this paper is used alone or in combination " cycloalkyl " refers to the monovalence stable hydrocarbon ring of optional replacement, its comprise 3-approximately 15 become ring carbon atom or 3-approximately 10 become ring carbon atoms, for example also can comprise, as substituent other non-one-tenth ring carbon atom (, methyl cyclopropyl).
The term that this paper is used alone or in combination " aromatic base " refers to a ring on plane or the loop section of a plurality of rings, and it has containing the delocalization electronics of 4n+2n electronics grips system altogether, and wherein n is integer.Aromatic ring can be formed by the atom more than 5,6,7,8,9 or 9.Aromatic substance can be optionally substituted, and can be many rings of monocycle or fused rings.Term aromatic compound comprises all containing carbocyclic ring (as phenyl ring) with containing one or more heteroatomic rings (as pyridine).
The term that this paper is used alone or in combination " aryl " refers to the aryl radical of optional replacement, and it has 6-approximately 20 one-tenth ring carbon atoms or 6-10 one-tenth ring carbon atom, and comprises fused rings and non-condensed aromatic ring.Fused-aryl comprises the ring that 2-4 aromatic ring condenses, and other free ring can be alicyclic ring, heterocycle, aromatic ring, aromatic heterocycle or its arbitrary combination.In addition, term aryl also comprises containing 6 to about 12 fused rings and non-condensed rings that become ring carbon atoms, and containing 6 to about 10 fused rings and non-condensed rings that become ring carbon atoms.The non-limiting example of monocyclic aryl comprises phenyl; The fused rings aryl comprises naphthyl, phenanthryl, anthryl, Azulene base; Two aryl of non-condensed comprise xenyl.
The term that this paper is used alone or in combination " heteroaryl " refers to the monovalence aryl of any replacement, it comprises approximately 5 to approximately 20 or 5 to 10 skeletons become annular atoms, wherein one or more become annular atoms is heteroatoms, described heteroatoms is independently selected from the heteroatoms in oxygen, nitrogen, sulphur, phosphorus, silicon, selenium and tin, but is not limited to this; Its prerequisite is that the ring of described group does not comprise two adjacent O or S atom.Occur that in ring, in two or more heteroatomic embodiments, described two or more heteroatomss can be mutually the same, or some or all in described two or more heteroatomss differ from one another.What the term heteroaryl comprised optional replacement has that condense or heteroaryl non-condensed of at least one heteroatomic monovalence.In addition, the term heteroaryl also comprises containing 5 and becomes condense and heteroaryl non-condensed of annular atoms to about 12 skeletons, and becomes condense and heteroaryl non-condensed of annular atoms containing 5 to about 10 skeletons, as phenyl ring and furan nucleus condense.Can with heteroaryl, be combined by carbon atom or heteroatoms.Therefore, for example, imidazoles can by it, carbon atom (imidazoles-2-base, imidazol-4 yl or imidazoles-5-yl) or its nitrogen-atoms (imidazoles-1-base or imidazo-3-yl) be connected with parent molecule arbitrarily.Similarly, can pass through its any or whole carbon atoms and/or the further substituted heteroaryl group of any or whole heteroatoms.The heteroaryl condensed can comprise the fused rings that 2-4 aromatic heterocycle condenses mutually, and other free ring can be alicyclic ring, heterocycle, aromatic ring, aromatic heterocycle or its arbitrary combination.The non-limiting example of bicyclic heteroaryl comprises pyridyl; Fused ring heteroaryl comprises benzimidazolyl-(benzimidazolyl), quinolyl (quinolinyl), acridyl (acridinyl), and two heteroaryls of non-condensed comprise bipyridyl (bipyridinyl).Other example of heteroaryl includes but not limited to: furyl (furanyl), thienyl (thienyl), oxazolyl (oxazolyl), acridyl (acridinyl), phenazinyl (phenazinyl), benzimidazolyl-(benzimidazolyl), benzofuryl (benzofuranyl), benzoxazolyl (benzoxazolyl), benzothiazolyl (benzothiazolyl), diazosulfide base (benzothiadiazolyl), benzothienyl (benzothiophenyl), Ben Bing oxadiazolyl (benzoxadiazolyl), benzotriazole base (benzotriazolyl), imidazolyl (imidazolyl), indyl (indolyl), isoxazolyl (isoxazolyl), isoquinolyl (isoquinolinyl), indyl (indolizinyl), isothiazolyl (isothiazolyl), pseudoindolyl (isoindolyl), oxadiazolyl (oxadiazolyl), indazolyl (indazolyl), pyridyl (pyridyl), pyridazinyl (pyridazyl), pyrimidyl (pyrimidyl), pyrazinyl (pyrazinyl), pyrryl (pyrrolyl), pyrazolyl (pyrazolyl), purine radicals (purinyl), phthalazinyl (phthalazinyl), pteridyl (pteridinyl), quinolyl (quinolinyl), quinazolyl (quinazolinyl), quinoxalinyl (quinoxalinyl), triazolyl (triazolyl), tetrazyl (tetrazolyl), thiazolyl (thiazolyl), triazinyl (triazinyl) and thiadiazolyl group (thiadiazolyl) etc., and oxide compound, for example pyridyl N-oxide compound (pyridyl-N-oxide).
The term that this paper is used alone or in combination " heterocyclic radical/heterocycle " refers to aliphatic heterocycle.(C for example while pointing out the carbon atom number of heterocycle herein 3-C 6heterocycle), certainly exist at least one non-carbon atom (heteroatoms) in described ring." C for example 3-C 6heterocycle " name only relate to the number of carbon atom in ring, and do not relate to the sum that encircles Atom.As the name of " 4-6 unit heterocycle " is total atom number contained in finger ring (four, five or six-ring, wherein at least one atom is carbon atom, and at least one atom is heteroatoms, and a remaining 2-4 atom is carbon atom or heteroatoms).For having two or more heteroatomic heterocycles, described two or more heteroatomss can be same to each other or different to each other.Heterocycle can be optionally substituted." heterocyclic radical/heterocycle " herein preferably comprises approximately 5 and becomes annular atoms to approximately 20 or 5 to 10 or 5-8 or 5-6 skeleton.
The limiting examples of " heterocyclic radical " comprises azine group (azinyl), azetidinyl (azetidinyl), oxa-cyclobutyl (oxetanyl), thia cyclobutyl (thietanyl), homopiperidinyl (homopiperidinyl), oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydro pyridyl (1,2,3,6-tetrahydropyridinyl), 2-pyrrolinyl (2-pyrrolinyl), 3-pyrrolinyl (3-pyrrolinyl), indyl (indolinyl), 2H-pyranyl (2H-pyranyl), 4H-pyranyl (4H-pyranyl), dioxacyclohexyl (dioxanyl), the DOX base (1,3-dioxolanyl), pyrazolinyl (pyrazolinyl), two sulphur cyclohexyl (dithianyl), two sulphur cyclopentyl (dithiolanyl), dihydro pyranyl (dihydropyranyl), dihydro-thiophene base (dihydrothienyl), dihydrofuran base (dihydrofuranyl), pyrazolidyl (pyrazolidinyl), imidazolinyl (imidazolinyl), imidazolidine base (imidazolidinyl), 3-azabicyclo [3.1.0] hexyl (3-azabicyclo[3.1.0] hexyl), 3-azabicyclo [4.1.0] heptyl (3-azabicyclo[4.1.0] heptyl), 3H-indyl (3H-indolyl) and quinolyl (quinolizinyl) etc.This term also comprises all annular form of carbohydrate, includes but not limited to monose, disaccharides and oligosaccharides.
The term that this paper is used alone or in combination " carbocylic radical, carbocyclic ring " is alicyclic radical, all structures by the carbon covalently closed circle namely, and it can be saturated (being cycloalkyl), part unsaturated (being cycloalkenyl group).Can form carbocyclic ring by the atom more than 3,4,5,6,7,8,9 or 9.Carbocyclic ring can be optionally substituted." carbocylic radical, carbocyclic ring " herein preferably comprises approximately 5 and becomes annular atoms to approximately 20 or 5 to 10 or 5-8 or 5-6 skeleton.The term carbocyclic ring is that from the difference between heterocycle the ring skeleton of heterocycle comprises at least one atom different with carbon.
The term that this paper is used alone or in combination " halogen ", " halo " or " halogenide " refer to fluorine, chlorine, bromine and iodine.
The term that this paper is used alone or in combination " alkoxyl group " refers to alkylether radicals O-alkyl, it comprises O-fat base and O-carbocylic radical, wherein alkyl, fat base and carbon ring group can be optionally substituted, and term alkyl wherein, fat base and carbocylic radical are as definition above.The non-limiting example of alkoxyl group comprises methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert.-butoxy etc.
The term that this paper is used alone or in combination " sulfinyl " refers to divalent group-S (O).
The term that this paper is used alone or in combination " sulphonyl " refers to divalent group-S (O) 2.
The term that this paper is used alone or in combination " sulphonamide " and " sulfonamido " refer to divalent group-S (O) 2-NH-and-NH-S (=O) 2.
Except as otherwise noted, herein for replacing separately or the substituting group of its term be used in combination " alkyl of replacement ", " cycloalkyl of replacement ", " thiazolinyl of replacement ", " alkynyl of replacement ", " alkoxyl group of replacement ", " aryl of replacement ", " alkylaryl of replacement ", " heteroaryl of replacement ", " alkylsulfonyl of replacement " and " amino of replacement " is hydrogen, halogen, cyano group, nitro, hydroxyl, C independently 1-C 6alkyl, C 3-C 6cycloalkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl and C 1-C 6one or more substituting groups in alkoxyl group, monocycle or aryl bicyclic and 5-7 unit heteroaryl.
The some drugs term
Term used herein " FAK and/or Pyk2 inhibitor " refers to the measurement according to FAK described herein and/or Pyk2l kinase assay, to the IC of FAK and/or Pyk2 activity 50be not more than approximately 100 μ M or be not more than the approximately compound of 50 μ M." IC 50" refer to half the inhibitor concentration to maximum horizontal by the activity decreased of enzyme (as FAK and/or Pyk2).Have now found that the restraining effect of compound described herein to FAK and/or Pyk2.According to the measurement of FAK described herein and/or Pyk2l kinase assay, compound of the present invention preferably shows the IC to FAK and/or Pyk2 activity 50be not more than approximately 10 μ M, be not more than approximately 5 μ M, more preferably no more than about 1 μ M, and most preferably be not more than about 200nM.
Term used herein " selection ", " selectively ", " selectivity " refer to other enzyme and compare, the IC of compound of the present invention to FAK and/or Pyk2 enzyme 50be worth lower (for example, at least low 2,5,10 or more times).
Relational term used herein " experimenter ", " patient " or " individuality " refer to suffer from disease, the individuality of illness or patient's condition etc., comprise Mammals and nonmammalian.Mammiferous example includes but not limited to any member of class of mammals: people, inhuman primate (for example chimpanzee and other apes and monkey); Domestic animal, for example ox, horse, sheep, goat, pig; Domestic animal, for example rabbit, dog and cat; Laboratory animal, comprise rodent, such as rat, mouse and cavy etc.The example of non-human mammal includes but not limited to birds and fish etc.In the embodiment of a method provided herein and composition, described Mammals is behaved.
Term used herein " treatment " and other similar synonym comprise alleviation, alleviate or improve disease or condition symptoms, prevent other symptom, improve or prevent to cause the potential metabolism reason of symptom, suppress disease or illness, for example stop the development of disease or illness, alleviate disease or illness, disease or illness are taken a turn for the better, alleviate the symptom caused by disease or illness, or end the symptom of disease or illness, in addition, the purpose that this term comprises prevention.This term also comprises acquisition result for the treatment of and/or preventive effect.Described result for the treatment of refers to cures or improves the potential disease for the treatment of.In addition, to the healing of one or more physiological signs relevant to potential disease or to improve be also result for the treatment of, although for example the patient may still be subject to the impact of potential disease, observe patient's condition improved.With regard to preventive effect, can be to thering is patient's applying said compositions of suffering from the specified disease risk, even if or not yet make medical diagnosis on disease, but to patient's applying said compositions of the one or more physiological signs that this disease occurs.
Term that this paper is used " significant quantity ", " treatment significant quantity " or " pharmacy effective dose " refer to takes metapedes with at least one medicament of one or more symptoms of alleviating to a certain extent the disease of being treated or illness or the amount of compound.Its result can be the subduing and/or alleviate of sign, symptom or the cause of disease, or any other required variation of biosystem.For example, " significant quantity " be used for the treatment of is the come into the open amount of composition of compound of this paper that comprises that provides clinically significant illness remission effect required.Can use the technical measurement such as the dosage escalation test to be suitable for the significant quantity in any individual case.
Term used herein " is taken ", " using ", " administration " etc. refer to and compound or composition can be delivered to the method in the required site of carrying out biological action.These methods include but not limited to oral route, through duodenum approach, parenteral injection (comprising intravenously, subcutaneous, intraperitoneal, intramuscular, intra-arterial injection or infusion), topical and per rectum administration.Those skilled in the art know the application technique that can be used for Compounds and methods for described herein, for example, at Goodman and Gilman, and The Pharmacological Basis of Therapeutics, current ed.; Pergamon; And Remington ' s, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, those that discuss in Pa.In a preferred embodiment, the compound that this paper discusses and composition are by Orally administered.
This paper refers to that for preparation, composition or composition term used " acceptable " the subject experimenter's of docking general health situation does not have long-term harmful effect.
Term used herein " pharmaceutically acceptable " refers to the biological activity that do not affect the compounds of this invention or the material (as carrier or thinner) of character, and relatively nontoxic, this material can be applied to individuality and not cause bad biological respinse or any component interaction to comprise in bad mode and composition.
Term used herein " pharmaceutical composition " refers to the bioactive compounds that optionally is mixed with at least one pharmaceutically acceptable chemical composition, and described pharmaceutically acceptable chemical composition includes but not limited to carrier, stablizer, thinner, dispersion agent, suspension agent, thickening material and/or vehicle.
Term used herein " carrier " refers to relatively nontoxic chemical compound or reagent, and it contributes to compound is incorporated in cell or tissue.
Term used herein " agonist " refers to the molecule of the activity of the activity that strengthens other molecule or acceptor site, for example compound, medicine, zymoexciter or hormone regulating and controlling agent.
Term used herein " antagonist " refers to the molecule of eliminating or suppressing the activity of the activity of other molecule or acceptor site, for example compound, medicine, enzyme inhibitors or hormone regulating and controlling agent.
Term used herein " regulation and control " thus refer to and target directly or indirectly interacts and changes the activity of target, for example, it comprise strengthen target active, suppress that target is active, the restriction target is active or extend the target activity.
Term used herein " adjusting control agent " refers to and the direct or indirect interactional molecule of target.Described interaction includes but not limited to the interaction of agonist and antagonist.
Term used herein " pharmacy acceptable salt " refers to the free acid that retained appointed compound and the biopotency of free alkali, and there is no the salt of undesirable action on biology or other side.Compound as herein described can have acidity or basic group, therefore can with multiple mineral alkali or organic bases and mineral acid and organic acid reaction arbitrarily, thereby form pharmacy acceptable salt.Can prepare by the following method by these salt: in final separation and the preparation of purge process situ of the compounds of this invention, or react separately with applicable organic acid or mineral acid by the free alkali form of the compounds of this invention, and separate the salt formed thus.The example of pharmacy acceptable salt comprises by the salt prepared that reacts between compound described herein and mineral acid or organic acid or mineral alkali or organic bases.These salt comprise acetate, acrylate, adipate, alginates, aspartate, benzoate, benzene sulfonate, hydrosulfate, bisulfite, bromide, butyrates, butine-Isosorbide-5-Nitrae-diacid salt, camphorate, camsilate, octylate, chloro-benzoate, muriate, Citrate trianion, cyclopentane propionate, caprate, gluconate, dihydrogen phosphate, dinitro-benzoate, dodecyl sulfate, esilate, formate, fumarate, gluceptate, glycerophosphate, glycollate, Hemisulphate, enanthate, hexin-1,6-diacid salt (hexyne-1,6-dioate), hydroxy benzoate, y-hydroxybutyric acid salt, hydrochloride, hydrobromate, hydriodate, the 2-isethionate, iodide, isobutyrate, lactic acid salt, maleate, malonate, mesylate, mandelate, metaphosphate, methoxybenzoic acid salt, tolyl acid salt, monohydric phosphate, 1-naphthalene sulfonic aicd salt, the 2-naphthalenesulfonate, nicotinate, nitrate, embonate, jelly hydrochlorate (pectinate), persulphate, the 3-phenpropionate, phosphoric acid salt, picrate, pivalate, propionic salt, pyrosulphate, pyrophosphate salt, propynoic acid, phthalate, phenylacetate, benzenebutanoic acid salt, propanesulfonic acid salt, salicylate, succinate, vitriol, sulphite, suberate, sebacate, sulfonate, tartrate, thiocyanate-, tosilate, undecylate (undeconate) and xylenesulfonate.Other acid (as oxalic acid), although itself be pharmaceutically unacceptable, but can be used as intermediate uses in the preparation process of salt, with obtain compound of the present invention and pharmaceutically acceptable acid salt (referring to Berge et al., J.Pharm.Sci.1977, embodiment in 66,1-19).In addition, the compound that comprises free acid group as herein described can with suitable alkali reaction (for example oxyhydroxide of pharmaceutically acceptable metallic cation, carbonate or supercarbonate), with ammonia react, or with pharmaceutically acceptable organic primary amine, secondary amine or reactive tertiary amine.Representational an alkali metal salt or alkaline earth salt comprise lithium salts, sodium salt, sylvite, calcium salt, magnesium salts and aluminium salt etc.The illustrative example of alkali comprises sodium hydroxide, potassium hydroxide, hydroxide hydroxyethyl Trimethylamine 99, sodium carbonate and IV ' (C 1-4alkyl) 4deng.The representative organic amine that is used to form base addition salt comprises ethamine, diethylamine, quadrol, thanomin, diethanolamine and piperazine etc.Should be understood that the quaternary ammonium compound of any alkaline nitrogen-containing group that compound described herein also comprises that it may comprise.Can obtain water-soluble or oil soluble or dispersible product by quaterisation.Referring to, such as the people's such as Berge document above.
Term used herein " solvate " refers to the compounds of this invention that forms by solvation and the combination of solvent molecule.In some cases, solvate refers to hydrate, and solvent molecule is water molecules, the compounds of this invention and water be combined to form hydrate.
Term used herein " polymorphic form " or " polymorph " refer to the compounds of this invention existed with different form crystal lattices.
Term used herein " tautomer " refers to by as hydrogen atom migration or proton shifting, being easy to the isomer obtained by the compounds of this invention change.
Term that this paper is used " pharmaceutically acceptable derivates or prodrug " refers to any pharmacy acceptable salt, the ester of the compounds of this invention, salt or other derivative of ester, and it can provide directly or indirectly compound of the present invention or its to have metabolite or the residue of pharmaceutical active after using to acceptor.Particularly preferred derivative or prodrug be can improve the compounds of this invention bioavailability when being applied to the patient those compounds (for example, can make oral compound be easier to be absorbed in blood), or promote those compounds that parent compound for example, is sent to biologic-organ or action site (brain or lymphsystem).
The pharmaceutically acceptable prodrug of compound described herein includes but not limited to quaternary ammonium derivative, the strange alkali of N-Manny (N-Mannich bases), schiff base (Schiff base), amino acid conjugates, phosphoric acid ester, metal-salt and the sulphonate of ester, carbonate, thiocarbonate, N-acyl derivative, N-acyloxy alkyl derivative, tertiary amine.Various prodrug forms are well known in the art.Referring to, Design of Prodrugs for example, Bundgaard, A.Ed., Elseview, 1985 and Method in Enzymology, Widder, K.et al., Ed.; Academic, 1985, vol.42, p.309-396; Bundgaard, H. " Design and Application of Prodrugs " in A Textbook of Drug Design and Development, Krosgaard-Larsen and H.Bundgaard, Ed., 1991, chapter 5,113-191 page; And Bundgaard, H., Advanced Drug Delivery Review, 1992,8,1-38, above document is incorporated to this paper by reference.Prodrug described herein includes but not limited to the combination of material in following group and these materials: the prodrug that amine is derivative; The hydroxyl prodrug includes but not limited to acyloxy alkyl ester, alkoxy carbonyl yloxy alkyl ester, alkyl ester, aryl ester and the ester that contains disulfide bond.
The similar vocabulary such as term that this paper is used " enhancing/raising " refer to the effect that increases required effect or extend the time length of required effect.Therefore, when meaning to strengthen the therapeutical agent effect, term " enhancing " refers to and increases or extend other therapeutical agent to the effect of systemic effect or the ability of time length.
Term that this paper is used " amount of reinforced effects (the effectively amount of enhancement) " refers to the amount that is enough to strengthen the effect of other therapeutical agent in required system.
Term that this paper is used " drug regimen ", " using other treatment ", " using other therapeutical agent " etc. refer to by mixing or combining the pharmacological agent that more than a kind of activeconstituents obtains, and it comprises the fixing of activeconstituents and fixed combination not.Term " fixed combination " refers to the form with single entity or single formulation uses at least one compound as herein described and at least one collaborative medicament to the patient simultaneously.Term " not fixed combination " refers to the form of separate entity and uses simultaneously, share or, to use in turn at least one compound as herein described and at least one collaborative preparation variable interval time, wherein this type of is applied in patient body two or more compounds that level of significance is provided to the patient.These also are applied in drug cocktail therapy (treatment), for example use three kinds or more kinds of activeconstituents.
Term used herein " co-administered ", " with ... combined administration " and its synonym etc. are to point to same patient to use selected therapeutical agent, and are intended to contain the therapeutic strategy of using medicament by identical or different route of administration or identical or different administration number of times.In some embodiments, compound as herein described and other medicament is co-administered.These terms are contained to animal and are used two or more medicaments so that have described medicament and/or its metabolite in animal body simultaneously.These terms comprise uses different compositions simultaneously, and different time is used different compositions and/or used a kind of composition that contains the different activities composition.Therefore, in some embodiments, compound of the present invention and other medicament are blended in a kind of composition and use.
Term used herein " metabolite " refers to the derivative of this compound formed when the compound metabolism.
Term used herein " active metabolite " refers to the activated derivative of tool of this compound formed when the compound metabolism.
Term used herein " metabolism " refers to that organism transforms all processes (including but not limited to hydrolysis reaction and enzymic catalytic reaction) of predetermined substance.Therefore, enzyme can make compound produce special structural changes.For example, the multiple redox reaction of Cytochrome P450 catalysis, and the glucal acid molecule of UDPglucuronyl transferase catalytic activation is to the transfer of aromatic alcohol, fatty alcohol, carboxylic acid, amine and free thiohydroxy group.More information about metabolism can be referring to The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996).
Synthetic method and embodiment
The invention provides the synthetic method of above-claimed cpd.In some embodiments, can prepare compound as herein described by following method.Following methods and embodiment are for these methods are described.These flow processs and embodiment should not be interpreted as limitation of the present invention by any way.Also can use standard synthetic technology well known by persons skilled in the art to synthesize compound as herein described, or be used in combination means known in the art and methods described herein.
Formula (I) compound, wherein R 1and R 2in one be hydrogen, R 5and R 6in one be hydrogen, and R " be hydrogen, as shown in following general formula, be used for as an example the preparation of formula (I) compound.
Universal synthesis method I:2,4-bis-is chloro-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine synthetic
Figure BPA00001751561000351
Universal synthesis method II:6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2, the general synthesis step of 4-diamines
Figure BPA00001751561000361
Steps A: in dehydrated alcohol, in batches add sodium Metal 99.5 (1.5 equivalent).The sodium Metal 99.5 complete reaction adds respectively 1,1,2-tricarboxylic ester (intermediate i, 1.0 equivalents) and urea (1.0 equivalent) after disappearing in the gained alcohol sodium solution.The reaction solution rear cool to room temperature that spends the night that refluxes, rotary evaporation falls ethanol.Residue is soluble in water, and it is acid regulating the pH value with dilute hydrochloric acid (2N).Rotary evaporation obtains intermediate ii by flash chromatography on silica gel purifying residue after removing solvent.
Step B: in the phosphorus oxychloride solution of intermediate ii (1.0 equivalent), slowly drip N, N '-diisopropylethylamine (2.0 equivalent).After being added dropwise to complete, reaction solution is heated to 100 degree and continues reaction 1-12 hour.Reduction vaporization falls most of phosphorus oxychloride, and it is alkalescence that water is regulated the pH value with sodium bicarbonate, is extracted with ethyl acetate, and merges organic phase.Organic phase is with after the saturated common salt water washing, using anhydrous sodium sulfate drying.Rotary evaporation obtains intermediate iii by flash chromatography on silica gel purifying residue after removing solvent.
Under step C:0 degree, in the tetrahydrofuran solution of intermediate iii (1.0 equivalent), drip diisobutyl aluminium hydride (3.0-4.0 equivalent).After dropwising, reaction solution slowly is raised to room temperature and continues reaction 2-12 hour.Reaction is with after dilute hydrochloric acid (1N) cancellation, and water is extracted with ethyl acetate, and merges organic phase.Organic phase is with after the saturated common salt water washing, using anhydrous sodium sulfate drying.Rotary evaporation obtains crude product iv, the not purified the next step that is directly used in after removing solvent.
Step D: add methylsulfonyl chloride (2.0 equivalent) in the dichloromethane solution of intermediate iv (1.0 equivalent), the 4-dimethylamino pyridine of triethylamine (2.0 equivalent) and catalytic amount.After reaction solution stirring at room 1-12 hour, rotary evaporation obtains intermediate v by flash chromatography on silica gel purifying residue after removing solvent.
Step e: in the solution of the N-Methyl pyrrolidone of intermediate v (1.0 equivalent), add 4-methoxybenzylamine (1.5 equivalent) and triethylamine (10.0 equivalent).Reaction solution is heated to 130 degree reaction 1-3 hour.After cool to room temperature, reaction solution is poured into water.Be extracted with ethyl acetate water, merge organic phase.Organic phase is with after the saturated common salt water washing, using anhydrous sodium sulfate drying.Rotary evaporation obtains intermediate vi (intermediate A 1-A3) by flash chromatography on silica gel purifying residue after removing solvent.
intermediate A 1
the chloro-7-of 2,4-bis-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine
Figure BPA00001751561000371
Steps A: 2-(2,4,6-trihydroxy-pyrimidine-5-yl) ethyl acetate
Figure BPA00001751561000372
According to universal synthesis method I, with 1,1,2-nitrilotriacetic ethoxycarbonyl ethane (10 grams, 41mmol) and urea (2.44 grams, 41mmol) make 2-(2,4 for raw material, 6-trihydroxy-pyrimidine-5-yl) ethyl acetate (light yellow solid, 4.6 grams, productive rate 35.0%).
Step B:2-(2,4,6-trichloropyrimidine-5-yl) ethyl acetate
According to universal synthesis method I, with 2-(2,4,6-trihydroxy-pyrimidine-5-yl) ethyl acetate (2.5 grams, 12mmol), phosphorus oxychloride (20 milliliters) and N, N-diisopropylethylamine (4 milliliters) makes 2-(2,4,6-trichloropyrimidine-5-yl) ethyl acetate (light yellow oil for raw material, 860 milligrams, productive rate 27%). 1H?NMR(400MHz，CDCl 3)δppm?4.20-4.25(q，2H，J＝7.2Hz)，3.94(s，2H)，1.27-1.30(t，3H，J＝7.2Hz)。
Step C:2-(2,4,6-trichloropyrimidine-5-yl) ethanol
Figure BPA00001751561000381
According to universal synthesis method I, with 2-(2,4,6-trichloropyrimidine-5-yl) ethyl acetate (860 milligrams, 3.2mmol) and the diisobutyl aluminium hydride (hexane solution of 1.0M, 10 milliliters, 10mmol) for raw material, make 2-(2,4,6-trichloropyrimidine-5-yl) ethanol (colorless oil, 720 milligrams, productive rate 99%).
Step D:2-(2,4,6-trichloropyrimidine-5-yl) ethyl methane sulfonate
Figure BPA00001751561000382
According to universal synthesis method I, with 2-(2,4,6-trichloropyrimidine-5-yl) ethanol (720 milligrams, 3.2mmol), (814 milligrams of Methanesulfonyl chlorides, 7.1mmol) and triethylamine (1 milliliter) make 2-(2,4,6-trichloropyrimidine-5-yl) ethyl methane sulfonate (light yellow oil for raw material, 66 milligrams, productive rate 68%). 1H?NMR(400MHz，CDCl 3)δppm?4.39-4.44(m，2H)，3.29-3.36(m，2H)，3.08(s，3H)。
Step e/intermediate A 1:
The chloro-7-of 2,4-bis-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine
According to universal synthesis method I, with 2-(2,4,6-trichloropyrimidine-5-yl) ethyl methane sulfonate (480 milligrams, 1.57mmol) and (325 milligrams of 4-methoxybenzylamines, 2.37mmol) make 2 for raw material, the chloro-7-of 4-bis-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine (yellow solid, 660 milligrams, productive rate 68%). 1H?NMR(400MHz，CDCl 3)δppm?7.18-7.20(dd，2H，J＝2.0Hz，6.8Hz)，6.86-6.88(dd，2H，J＝2.0Hz，6.4Hz)，4.53(s，2H)，3.80(s，3H)，3.54-3.58(t，2H，J＝8.8Hz)，2.95-3.00(t，2H，J＝8.8Hz)。
intermediate A 2
(±)-2, the chloro-7-of 4-bis-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine
Figure BPA00001751561000391
Steps A: (±)-1,1,2-nitrilotriacetic ethoxycarbonyl propane
Figure BPA00001751561000392
Add sodium Metal 99.5 (9 grams in 500 milliliters of dehydrated alcohols in batches, 0.39mol), after sodium Metal 99.5 reacts completely, under 0 degree, to dripping diethyl malonate in the gained alcohol sodium solution, (50 grams, 0.31mol), dropwise and reaction solution continued the lower stirring reaction of 0 degree after 30 minutes, to its dropping (±)-2 bromopropionic acid ethyl ester (56.5 grams, 0.31mol).Reaction solution is raised to the room temperature post-heating and refluxes 12 hours.After the reaction solution cool to room temperature, rotary evaporation falls solvent, and resistates is poured in trash ice.Be extracted with ethyl acetate water three times, merge organic phase.Organic phase is with after the saturated common salt water washing, using anhydrous sodium sulfate drying.Rotary evaporation obtains crude product (±)-1,1,2-nitrilotriacetic ethoxycarbonyl propane (67.8 grams, productive rate 83.4%), the not purified the next step that is directly used in after removing solvent.
Step B:(±)-2-(2,4,6-trihydroxy-pyrimidine-5-yl) ethyl propionate
Figure BPA00001751561000393
According to universal synthesis method I, with (±)-1,1,2-nitrilotriacetic ethoxycarbonyl propane (14.2 grams, 55mmol), and sodium Metal 99.5 (1.9 grams, 83mmol) and urea (3.3 grams, 55mmol) for raw material, make (±)-2-(2,4,6-trihydroxy-pyrimidine-5-yl) ethyl propionate (reddish yellow oily matter, 6 grams, productive rate 48%), the not purified the next step that is directly used in.
Step C:(±)-2-(2,4,6-trichloropyrimidine-5-yl) ethyl propionate
Figure BPA00001751561000401
According to universal synthesis method I, with (±)-2-(2,4,6-trihydroxy-pyrimidine-5-yl) ethyl propionate (6 grams, 12mmol), phosphorus oxychloride (30 milliliters) and N, N '-diisopropylethylamine (7.5 milliliters) makes (±)-2-(2,4,6-trichloropyrimidine-5-yl) ethyl propionate (yellow oily liquid for raw material, 2.3 gram, productive rate 31%). 1H?NMR(400MHz，CDCl 3)δppm?4.31-4.37(m，1H)，4.17-4.25(m，2H)，1.55-1.57(m，3H)，1.22-1.26(m，3H)。
Step D:(±)-(2,4,6-trichloropyrimidine-5-yl) propyl alcohol
Figure BPA00001751561000402
According to universal synthesis method I, with (±)-2-(2,4,6-trichloropyrimidine-5-yl) ethyl propionate (2.3 grams, 8mmol) and the diisobutyl aluminium hydride (hexane solution of 1.0M, 10 milliliters, 10mmol) for raw material, make (±)-(2,4,6-trichloropyrimidine-5-yl) propyl alcohol (light yellow oil, 260 milligrams, productive rate 13%). 1H?NMR(400MHz，CDCl 3)δppm?4.17-4.11(m，1H)，3.97-3.93(m，1H)，3.89-3.83(m，1H)，1.54(s，1H)，1.40-1.38(d，3H，J＝7.2Hz)。
Step e: (±)-2-(2,4,6-trichloropyrimidine-5-yl) methylsulfonic acid propyl ester
Figure BPA00001751561000403
According to universal synthesis method I, with 2-(2,4,6-trichloropyrimidine-5-yl) propyl alcohol (260 milligrams, 1.1mmol), (247 milligrams of Methanesulfonyl chlorides, 2.1mmol) and triethylamine (0.2 milliliter) make 2-(2,4,6-trichloropyrimidine-5-yl) methylsulfonic acid propyl ester (light yellow oil for raw material, 300 milligrams, productive rate 87%). 1H?NMR(400MHz，CDCl 3)δppm?4.73-4.68(t，1H，J＝9.2Hz)，4.53-4.49(dd，1H，J＝6.8Hz，10.4Hz)，4.13-4.06(m，1H)，3.00(s，3H)，1.48-1.46(d，3H，J＝7.2Hz)。
Step F/intermediate A 2:
(±)-2, the chloro-7-of 4-bis-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine
According to universal synthesis method I, with (300 milligrams of 2-(2,4,6-trichloropyrimidine-5-yl) methylsulfonic acid propyl ester, 0.94mmol), the 4-methoxybenzylamine (192 milligrams, 1.4mmol) and triethylamine (2 milliliters) for raw material makes (±)-2, the chloro-7-of 4-bis-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine (yellow solid, 190 milligrams, productive rate 63%). 1H?NMR(400MHz，CDCl 3)δppm?7.18-7.16(d，2H，J＝8.4Hz)，6.88-6.86(dd，2H，J＝2.0Hz，6.4Hz)，4.53(s，2H)，3.80(s，3H)，3.70-3.65(t，1H，J＝10.0Hz)，3.35-3.34(m，1H)，3.11-3.07(q，1H，J＝4.8Hz)，1.31-1.29(m，3H)。
intermediate A 3
(S)-2, the chloro-7-of 4-bis-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine
Figure BPA00001751561000411
Steps A: (S)-2-(sulfonyloxy methyl oxygen base) ethyl propionate
Figure BPA00001751561000412
Under 10-15 ℃, to the Pfansteihl ethyl ester (124 grams, 1.05mol) and triethylamine (126 grams, (124 grams 1.08mol), dropwise in about 2 hours to drip Methanesulfonyl chloride in tetrahydrofuran solution 1.25mol).After reaction solution is raised to room temperature, filter, solid washs with tetrahydrofuran (THF).Filtrate is dry after washing, concentrates to obtain (S)-2-(sulfonyloxy methyl oxygen base) ethyl propionate (199 grams, productive rate 96.7%).
Step B:(S)-1,1-dibenzyl diethyl propane-1,1,2-tricarboxylic ester
Figure BPA00001751561000421
Toward (S)-ethyl-2-(methyl sulphonyl) propionic ester (28.4 grams; 0.1mol) N; add propanedioic acid dibenzyl ester (23.5 grams in N '-dimethyl formamide (400 milliliters) solution; 0.12mol) and cesium fluoride (15.2 grams; 0.1mol), compound of reaction is stirred 2 days under 50 degree, after being cooled to room temperature; reaction solution is poured into water, is extracted with ethyl acetate.Merge organic phase, use the saturated common salt water washing, anhydrous sodium sulfate drying, filter, and is spin-dried for, and the silicagel column separation obtains product (S)-1, the two benzyl formate bases of 1--2-methyl-ethyl propionate (23 grams, productive rate 60%).
Step C:(S)-2-(1-oxyethyl group-1 oxo the third-2 base) propanedioic acid
Toward (S)-1, the two benzyl formate bases of 1--2-methyl-ethyl propionate (23 grams, add palladium carbon (10% in methanol solution 60mmol) (500 milliliters), 2 grams), reaction mixture stirs 12 hours under hydrogen, remove by filter catalyzer, be spin-dried for filtrate and obtain thick product (S)-2-(1-oxyethyl group-1 oxo the third-2 base) propanedioic acid (10 grams, productive rate 83%).
Step D:(S)-2-(2,4,6-trioxy-hexahydropyrimidine-5-yl) ethyl propionate
By (S)-2-(1-oxyethyl group-1 oxo the third-2 base) propanedioic acid (5 grams, 25mmol) and urea (1.8 grams, 29.4mmol) at diacetyl oxide (15 milliliters), inner suspension is heated to 60 degree stirring 30 minutes under microwave, after being cooled to room temperature, with saturated sodium bicarbonate aqueous solution cancellation reaction, be extracted with ethyl acetate.Merge organic phase, use the saturated common salt water washing, anhydrous sodium sulfate drying, filter, and is spin-dried for, and the silicagel column separation obtains product (S)-2-(2,4,6-trioxy-hexahydropyrimidine-5-yl) ethyl propionate (2.85 grams, productive rate 50%).
Step e: (S)-2-(2,4,6-trichloropyrimidine-5-yl) ethyl propionate
According to universal synthesis method I, with (S)-2-(2,4,6-trioxy-hexahydropyrimidine-5-yl) ethyl propionate (5.6 grams, 25m mol), phosphorus oxychloride (20 milliliters), N, N '-diisopropylethylamine (5 milliliters) carries out chlorination, obtain product (S)-2-(2,4,6-trichloropyrimidine-5-yl) ethyl propionate (yellow oil after separation and purification, 2.8 gram, productive rate 40%). 1H?NMR(400MHz，CDCl 3)δppm?4.30-4.36(q，1H，J＝7.2Hz)，4.16-4.25(m，2H)，1.54-1.56(d，3H，J＝7.6Hz)，1.22-1.25(m，3H)。
Step F: (S)-2-(2,4,6-trichloropyrimidine-5-yl)-1-propyl alcohol
Figure BPA00001751561000432
According to universal synthesis method I, with (S)-2-(2,4,6-trichloropyrimidine-5-yl) ethyl propionate (1.0 grams, 3.55mmol) and the diisobutyl aluminium hydride (hexane solution of 1.0M, 10.6 milliliter, 10.6mmol) carry out reduction reaction, obtains product (S)-2-(2 after separation and purification, 4,6-trichloropyrimidine-5-yl)-1-propyl alcohol (light yellow oily liquid, 200 milligrams, productive rate 25%). 1H?NMR(400MHz，CDCl 3)δppm?4.13-4.17(m，1H)，3.83-3.96(m，2H)，1.79(s，1H)，1.38-1.40(d，3H，J＝7.2Hz)。
Step G:(S)-2-(2,4,6-trichloropyrimidine-5-yl) propyl group methanesulfonates
Figure BPA00001751561000433
According to universal synthesis method I, with (S)-2-(2,4,6-trichloropyrimidine-5-yl)-(200 milligrams of 1-propyl alcohol, 0.83mmol), methylsulfonyl chloride (191 milligrams, 1.66mmol) and (166 milligrams of triethylamines, 1.66mmol) carry out esterification, obtain product (S)-2-(2,4,6-trichloropyrimidine-5-yl) propyl group methanesulfonates (light yellow oily liquid through separation and purification, 185 milligrams, productive rate 70%).
Step H/ intermediate A 3:(S)-2, the chloro-7-of 4-bis-(4-p-methoxy-phenyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine
According to universal synthesis method I, with (S)-2-(2,4,6-trichloropyrimidine-5-yl) the propyl group methanesulfonates is (185 milligrams, 0.578mmol), (120 milligrams of 4-Methoxybenzylamines, 0.867mmol) and (117 milligrams of triethylamines, 1.156mmol) carry out cyclization, obtain product (S)-2 through separation and purification, the chloro-7-of 4-bis-(4-p-methoxy-phenyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine (yellow oily liquid, 120 milligrams, productive rate 64%). 1H?NMR(400MHz，CDCl 3)δppm?7.16-7.19(d，2H，J＝8.8Hz)，6.86-6.88(d，2H，J＝8.4Hz)，4.54(s，2H)，3.80(s，3H)，3.66-3.71(t，1H，J＝6.0Hz)，3.33-3.36(m，1H)，3.08-3.12(dd，1H，J＝4.4Hz，10.0Hz)，1.29-1.31(d，3H，J＝6.8Hz)。
intermediate A 4
the chloro-7-of 2,4-bis-(4-p-methoxy-phenyl)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine
Figure BPA00001751561000441
Intermediate A 4 is synthetic as follows:
Figure BPA00001751561000442
Steps A: 2-(the chloro-6-of 2,4-bis-(4-p-methoxy-phenyl amido) pyrimidine-5-yl) ethyl acetate
Toward 2-(2,4,6-trichloropyrimidine-5-yl) ethyl acetate is (200 milligrams, 0.74mmol) at N, add (112 milligrams of 4-Methoxybenzylamines in the solution of N '-dimethyl formamide (5 milliliters), 0.82mmol) and N, and N '-diisopropylethylamine (115 milligrams, 0.89mmol).Reaction mixture is heated to 60 degree, and after stirring 1 hour, the water cancellation, be extracted with ethyl acetate.Merge organic phase, use respectively dilute hydrochloric acid (1N), water and saturated common salt water washing, anhydrous sodium sulfate drying, filter, and is spin-dried for, and the silicagel column separation obtains product 2-(the chloro-6-of 2,4-bis-(4-p-methoxy-phenyl amido) pyrimidine-5-yl) ethyl acetate. 1HNMR(400MHz，CDCl 3)δppm?7.26-7.28(m，2H)，6.88-6.90(dd，2H，J＝2.0Hz，6.4Hz)，6.15(s，1H)，4.60-4.62(d，2H，J＝5.2Hz)，4.11-4.16(q，2H，J＝7.2Hz)，3.81(s，3H)，3.60(s，2H)，1.21-1.26(t，3H，J＝6.4Hz)。
Step B:2, the chloro-7-of 4-bis-(4-p-methoxy-phenyl)-5,5-dimethyl-5H-pyrrolo-[2,3-d] pyrimidine-6 (7H)-one
Figure BPA00001751561000452
By 2-(the chloro-6-of 2,4-bis-(4-p-methoxy-phenyl amido) pyrimidine-5-yl) ethyl acetate (370 milligrams, 1.0mol), (284 milligrams of methyl iodide, 2.0mmol), salt of wormwood (690 milligrams, N 5.0mmol), N '-dimethyl formamide (10 milliliters) solution is added in tube sealing, be filled with nitrogen, be heated to 80 degree, after 1 hour, be cooled to room temperature, be poured into water (100 milliliters), be extracted with ethyl acetate.Merge organic phase, use the saturated common salt water washing, anhydrous sodium sulfate drying, filter, be spin-dried for, the silicagel column separation obtains product 2, the chloro-7-of 4-bis-(4-p-methoxy-phenyl)-5,5-dimethyl-5H-pyrrolo-[2,3-d] pyrimidine-6 (7H)-one (270 milligrams, productive rate 77%). 1H?NMR(400MHz，CDCl 3)δppm?7.37-7.39(d，2H，J＝8.8Hz)，6.84-6.86(d，2H，J＝8.8Hz)，4.86(s，2H)，3.78(s，3H)，1.48(s，6H)。
Step C/ intermediate A 4:2, the chloro-7-of 4-bis-(4-p-methoxy-phenyl)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine
Under nitrogen protection; toward 2; the chloro-7-of 4-bis-(4-p-methoxy-phenyl)-5; (270 milligrams dropwise add the borine (tetrahydrofuran solution of 1M in the solution of tetrahydrofuran (THF) 0.77mol) (10 milliliters) to 5-dimethyl-5H-pyrrolo-[2,3-d] pyrimidine-6 (7H)-one; 3.85 milliliter; 3.85mmol), add post-heating and reflux and to spend the night, dropwise add methyl alcohol (2 milliliters) to carry out cancellation after being cooled to room temperature.Revolve most of solvent, resistates is separated with silicagel column, obtains product 2, the chloro-7-of 4-bis-(4-p-methoxy-phenyl)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine (156 milligrams, productive rate 60%). 1HNMR(400MHz，CDCl 3)δppm?7.16-7.18(d，2H，J＝8.4Hz)，6.86-6.88(d，2H，J＝8.0Hz)，4.56(s，2H)，3.81(s，3H)，3.23(s，2H)，1.37(s，6H)。
intermediate A 5
(R)-2, the chloro-7-of 4-bis-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine
Figure BPA00001751561000461
Intermediate A 5 is synthetic as follows:
Figure BPA00001751561000471
Steps A: (R)-2-acetoxyl group propionic acid
Figure BPA00001751561000472
Under 0 ℃, in the acetum (400 milliliters) of (S)-2-alanine (60 grams, 0.67 mole), add Sodium Nitrite (93 grams, 1.34 moles) in batches.After reaction solution is raised to room temperature, reaction mixture at room temperature stirs 12 hours.To remain acetic acid and be spin-dried for, add water, be extracted with ethyl acetate.Merge organic phase, anhydrous sodium sulfate drying, filter, and is spin-dried for, and the silicagel column separation obtains product (R)-2-acetoxyl group propionic acid (30 grams, productive rate 35%). 1H?NMR(400MHz，CDCl 3)δppm，11.70(s，2H)，5.02-5.07(q，1H)，2.07(s，3H)，1.46-1.52(d，3H)。
Step B:(R)-2 hydroxy propanoic acid ethyl ester
Under-40 ℃, in the ethanolic soln (500 milliliters) of (R)-2-acetoxyl group propionic acid (30 grams, 0.23 mole), slowly drip thionyl chloride (54 grams, 0.45 mole).After reaction solution is raised to room temperature, reaction mixture at room temperature stirs 24 hours.Solvent in mixture is spin-dried for, adds water, be extracted with ethyl acetate.Merge organic phase, anhydrous sodium sulfate drying, filter, and is spin-dried for, and the silicagel column separation obtains product (R)-2 hydroxy propanoic acid ethyl ester (15 grams, productive rate 58%). 1H?NMR(400MHz，CDCl 3)δppm，4.22-4.27(m，3H)，2.87-2.87(q，1H)，1.41-1.43(d，3H，J＝7.6Hz)，1.30-1.32(m，3H)。
Step C:(R)-2-(sulfonyloxy methyl oxygen base) ethyl propionate
Figure BPA00001751561000481
Under 10-15 ℃, drip Methanesulfonyl chloride (15 grams in the tetrahydrofuran solution (300 milliliters) of (R)-2 hydroxy propanoic acid ethyl ester (15 grams, 0.13 mole) and triethylamine (15.4 grams, 0.15 mole), 0.13 mole), within about 30 minutes, dropwise.After reaction solution is raised to room temperature, filter, solid washs with tetrahydrofuran (THF).Filtrate is dry after washing, concentrated (R)-2-(the sulfonyloxy methyl oxygen base) ethyl propionate (15 grams, productive rate 60%) that obtains.1H?NMR(400MHz，CDCl3)δppm，5.11-5.14(q，1H，)，4.24-4.29(m，2H)，2.81-3.17(q，3H，J＝7.2Hz)，1.61-1.43(d，3H，J＝7.6Hz)，1.30-1.32(m，3H)。
Step D:(R)-1, the two benzyl formates of 1--2-methyl-ethyl propionate
Figure BPA00001751561000482
Toward (R)-2-(sulfonyloxy methyl oxygen base) ethyl propionate (15 grams, 0.076 mole) N ' dinethylformamide (300 milliliters) solution in add propanedioic acid dibenzyl ester (21.5 grams, 0.076 mole) and cesium fluoride (11.5 grams, 0.076 mole).Compound of reaction is stirred two days under 50 degree, after cool to room temperature, reaction solution is poured into water, be extracted with ethyl acetate.Merge organic phase, use the saturated common salt water washing, anhydrous sodium sulfate drying, filter, and is spin-dried for, and the silicagel column separation obtains product (R)-1, the two benzyl formates of 1--2-methyl-ethyl propionate (11 grams, productive rate 40%).
Step e: (R)-2-(1-oxyethyl group-1 oxo third-2-yl) propanedioic acid
Figure BPA00001751561000483
Toward (R)-1, the two benzyl formates of 1--2-methyl-ethyl propionate (11 grams, 0.029 mole) methyl alcohol (200 milliliters) solution in add palladium carbon (2 gram), reaction solution stirs 12 hours under hydrogen, remove by filter catalyzer, be spin-dried for filtrate and obtain thick product (R)-2-(1-oxyethyl group-1 oxo third-2-yl) propanedioic acid (3.5 grams, productive rate 60%).
Step F: (R)-2-(2,4,6-trioxy-hexahydropyrimidine-5-yl) ethyl propionate
Figure BPA00001751561000484
By (R)-2-(1-oxyethyl group-1 oxo third-2-yl) propanedioic acid (3.5 grams, 0.017 mole) and urea (1.03 grams, 0.017 mole) at diacetyl oxide (20 milliliters), inner suspension is heated to 60 degree stirring 30 minutes under microwave, cool to room temperature, use the saturated sodium bicarbonate aqueous solution cancellation, be extracted with ethyl acetate.Merge organic phase, use the saturated common salt water washing, anhydrous sodium sulfate drying, filter, and is spin-dried for, and the silicagel column separation obtains product (R)-2-(2,4,6-trioxy-hexahydropyrimidine-5-yl) ethyl propionate (2.0 grams, productive rate 52%)
Step G:(R)-2-(2,4,6-trichloropyrimidine-5-yl) ethyl propionate
Figure BPA00001751561000491
According to universal synthesis method I, with (R)-2-(2,4,6-trioxy-hexahydropyrimidine-5-yl) ethyl propionate (2.0 grams, 8.87 mmole), phosphorus oxychloride (50 milliliters), DIPEA (5 milliliters) carries out chlorination, obtain product (R)-2-(2 through separation and purification, 4,6-trichloropyrimidine-5-yl) ethyl propionate (1.0 grams, 40%). 1H?NMR(400MHz，CDCl 3)δppm?4.30-4.36(q，1H，J＝7.2Hz)，4.17-4.24(m，2H)，1.54-1.56(d，3H，J＝7.6Hz)，1.22-1.25(m，3H)。
Step H:(R)-2-(2,4,6-trichloropyrimidine-5-yl)-1-propyl alcohol
Figure BPA00001751561000492
According to universal synthesis method I, with (R)-2-(2,4,6-trichloropyrimidine-5-yl) ethyl propionate (1.0 grams, 3.55 mmoles) and the diisobutyl aluminium hydride (hexane solution of 1.0M, 10.6 milliliter, 10.6 mmole) carry out reduction reaction, through separation and purification, obtain product (R)-2-(2,4,6-trichloropyrimidine-5-yl)-1-propyl alcohol (70 milligrams, 10%). 1H?NMR(400MHz，CDCl 3)δppm?4.14-4.17(m，1H)，3.85-3.97(m，2H)，1.56(s，1H)，1.38-1.40(d，3H，J＝7.2Hz)。
Step I:(R)-2-(2,4,6-trichloropyrimidine-5-yl) methylsulfonic acid propyl ester
Figure BPA00001751561000493
According to universal synthesis method I, with (R)-2-(2,4,6-trichloropyrimidine-5-yl)-1-propyl alcohol (70 milligrams, 0.58 mmole), (67 milligrams of Methanesulfonyl chlorides, 0.58 mmole) and triethylamine (60 milligrams, 1.66 mmoles) make (R)-2-(2,4 for raw material, 6-trichloropyrimidine-5-yl) methylsulfonic acid propyl ester (60 milligrams, 65%). 1H?NMR(400MHz，CDCl 3)δppm?4.69-4.74(t，1H，J＝9.2Hz)，4.49-4.54(dd，1H，J＝6.8Hz，10.4Hz)，4.06-4.49(m，1H)，3.92(s，1H)，1.46-1.48(d，3H，J＝7.2Hz)。
Step J/ intermediate A 5:(R)-2, the chloro-7-of 4-bis-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine
According to universal synthesis method I, with (60 milligrams of (R)-2-(2,4,6-trichloropyrimidine-5-yl) methylsulfonic acid propyl ester, 0.188 mmole), 4-methoxybenzylamine (39 milligrams, 0.28 mmole) and triethylamine (38 milligrams, 0.375 mmole) make (R)-2 for raw material, the chloro-7-of 4-bis-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine (45 milligrams, 74%). 1H?NMR(400MHz，CDCl 3)δppm7.16-7.19(d，2H，J＝8.8Hz)，6.86-6.88(d，2H，J＝8.4Hz)，4.54(s，2H)，3.80(s，3H)，3.66-3.71(t，1H，J＝6.0Hz)，3.33-3.36(m，1H)，3.08-3.12(dd，1H，J＝4.4Hz，10.0Hz)，1.29-1.31(d，3H，J＝6.8Hz)。
intermediate A 6
2 ', 4 '-bis-chloro-7 '-(4-p-methoxy-phenyls)-6 ', 7 '-dihydro spiral shell [cyclopropane-1,5 '- pyrroles [2,3-d] pyrimidine]
Figure BPA00001751561000502
Figure BPA00001751561000511
Steps A: 1,1,2-ethane tricarboxylic acid triethyl
Figure BPA00001751561000512
Add sodium Metal 99.5 (23.0 grams, 1 mole) in dehydrated alcohol (1000 milliliters) in batches.After the sodium Metal 99.5 complete reaction disappears, reaction solution cools to 0 ℃ with ice bath, drip diethyl malonate (160.2 grams, 1 mole), continue to stir after 0.5 hour and be raised to room temperature, add ethyl chloroacetate (122.6 grams, 1 mole) and continue and stir 1 hour, temperature rising reflux dropped to room temperature after 3 hours.Rotary evaporation is poured in frozen water after falling ethanol.Be extracted with ethyl acetate water three times, merge organic phase, organic phase is with after the saturated common salt water washing, using anhydrous sodium sulfate drying, rotary evaporation obtains product 1 after falling solvent, 1, not purified next step reaction of direct input of 2-ethane tricarboxylic acid triethyl (light yellow oil, 180.0 grams, productive rate 73.1%).
Step B:2-(2,4,6-trihydroxy-pyrimidine-5-replaces) ethyl acetate
Figure BPA00001751561000513
Add sodium Metal 99.5 (25.2 grams, 1.1 moles) in dehydrated alcohol (1500 milliliters) in batches.The sodium Metal 99.5 complete reaction adds respectively 1,1,2-ethane tricarboxylic acid triethyl (180.0 grams, 0.73 mole) and urea (43.9 grams, 0.73 mole) after disappearing in the gained alcohol sodium solution.The reaction solution rear cool to room temperature that spends the night that refluxes, rotary evaporation falls ethanol, residue is dissolved in water, it is acid regulating pH with dilute hydrochloric acid, after rotary evaporation removes solvent, by flash chromatography on silica gel purifying residue, obtains product 2-(2,4,6-trihydroxy-pyrimidine-5-replaces) ethyl acetate (light yellow solid, 82.8 grams, productive rate 35.0%).
Step C:2-(2,4,6-trichloropyrimidine-5-replaces) ethyl acetate
Figure BPA00001751561000521
Slowly drip DIPEA (80.0 milliliters) in phosphorus oxychloride (400.0 milliliters) solution of intermediate 2-(2,4,6-trihydroxy-pyrimidine-5-replaces) ethyl acetate (50.0 grams, 0.24 mole).After dropwising, reaction solution is heated to 100 ℃ and continues reaction 2 hours.The excessive phosphorus oxychloride of rotary evaporation after the reaction solution cool to room temperature, resistates is poured in trash ice.Regulating the pH value with sodium bicarbonate is weakly alkaline.Be extracted with ethyl acetate water three times, merge organic phase.Organic phase is with after the saturated common salt water washing, using anhydrous sodium sulfate drying.After rotary evaporation falls solvent, by flash chromatography on silica gel purifying residue, obtain product 2-(2,4,6-trichloropyrimidine-5-replaces) ethyl acetate (light yellow solid, 34.4 grams, productive rate 54.6%). 1H?NMR(400MHz，CDCl 3)δppm?4.24(q，J＝7.1Hz，2H)，3.95(s，2H)，1.29(t，J＝7.1Hz，3H)。
Step D:2-(the chloro-6-of 2,4-bis-(4-methoxybenzylamine) pyrimidine-5-replaces) ethyl acetate
Figure BPA00001751561000522
To intermediate 2-(2,4,6-trichloropyrimidine-5-replaces) ethyl acetate (43.3 grams, 0.16 mole) N, add 4-methoxybenzylamine (24.2 grams, 0.17 mole) and DIPEA (24.9 grams in dinethylformamide (500.0 milliliters) solution, 0.19 mole), reaction solution is heated to 60 ℃ of reactions 1 hour.Add the shrend reaction of going out, be extracted with ethyl acetate water three times, merge organic phase, organic phase is successively with after dilute hydrochloric acid and saturated common salt water washing, using anhydrous sodium sulfate drying.After rotary evaporation falls solvent, by flash chromatography on silica gel purifying residue, obtain product 2-(the chloro-6-of 2,4-bis-(4-methoxybenzylamine) pyrimidine-5-replaces) ethyl acetate (light yellow solid, 27.1 grams, productive rate 45.6%). 1H?NMR(400MHz，CDCl 3)δppm?7.29(dd，J＝6.0，3.9Hz，1H)，6.93-6.85(m，1H)，6.14(s，1H)，4.63(d，J＝5.3Hz，2H)，4.15(q，J＝7.1Hz，2H)，3.83(s，3H)，3.62(s，2H)，1.23(t，J＝7.1Hz，2H)。
The chloro-7-of step e: 2,4-bis-(4-p-methoxy-phenyl)-5-spiral shell [1,3] cyclopropyl-5H-pyrroles [2,3-d] pyrimidine-6-ketone
Figure BPA00001751561000531
Under nitrogen protection to intermediate 2-(2; the chloro-6-of 4-bis-(4-methoxybenzylamine) pyrimidine-5-replaces) ethyl acetate (27.1 grams; 73.2 mmole) and grind salt of wormwood (101.1 grams; 732.4 mole) N; drip 1 in 40 ℃ in dinethylformamide (800.0 milliliters) solution; 2-ethylene dibromide (27.5 grams, 146.4 mmoles).After dropwising, reaction solution is heated to 80 reaction 1 hour.Add the shrend reaction of going out, be extracted with ethyl acetate water three times, merge organic phase, organic phase is with after the saturated common salt water washing, using anhydrous sodium sulfate drying.After rotary evaporation falls solvent, by flash chromatography on silica gel purifying residue, obtain product 2, the chloro-7-of 4-bis-(4-p-methoxy-phenyl)-5-spiral shell [1,3] cyclopropyl-5H-pyrroles [2,3-d] pyrimidine-6-ketone (white solid, 21.2 grams, productive rate 82.7%). 1H?MR(400MHz，CDCl 3)δppm7.53-7.38(m，2H)，6.86(dd，J＝8.4，1.3Hz，2H)，4.94(d，J＝0.8Hz，2H)，3.79(d，J＝1.6Hz，3H)，2.14(qd，J＝4.3，1.6Hz，2H)，1.79(qd，J＝4.3，1.6Hz，2H)。
Step F intermediate A 6: 2 ', 4 '-bis-chloro-7 '-(4-p-methoxy-phenyls)-6 ', 7 '-bis- hydrogen spiral shell [cyclopropane-1,5 '-pyrroles [2,3-d] pyrimidine]
Figure BPA00001751561000541
Under nitrogen protection to intermediate 2; the chloro-7-of 4-bis-(4-p-methoxy-phenyl)-5-spiral shell [1; 3] cyclopropyl-5H-pyrroles [2; 3-d] pyrimidine-6-ketone (14.0 grams; 40.0 drip 94% borine dimethyl sulphide complex compound (8.2 milliliters, 80.0 mmoles) in tetrahydrofuran (THF) mmole) (200.0 milliliters) solution.After dropwising, reaction solution is heated to 60 ℃ of reactions and spends the night.After reacting completely, drip the methyl alcohol cancellation in 0 ℃ and react, after concentrating under reduced pressure, residue obtains product by the flash chromatography on silica gel purifying 2 ', 4 '-bis-chloro-7 '- (4-p-methoxy-phenyl)-6 ', 7 '-dihydro spiral shell [cyclopropane-1,5 '-pyrroles [2,3-d] pyrimidine](white solid, 8.4 grams, productive rate 62.4%). 1H?NMR(400MHz，CDCl 3)δppm?7.20(d，J＝8.6Hz，2H)，6.91-6.86(m，2H)，4.59(s，2H)，3.81(s，3H)，3.48(s，2H)，1.71(q，J＝4.9Hz，2H)，0.82(q，J＝4.9Hz，2H)。
intermediate B 1
2-methoxyl group-4-morpholine aniline
Figure BPA00001751561000542
Steps A: 4-(3-methoxyl group-4-nitrophenyl) morpholine
Figure BPA00001751561000543
Toward the fluoro-2-methoxyl group of 4--1-oil of mirbane (100 grams, 0.584mol) and morpholine (60 grams, 0.689mol) methyl-sulphoxide (60 milliliters) solution in add salt of wormwood (120 grams, 0.870mol), during mixture reacts after 6 hours and pours frozen water under 70 degree, filter, wash filter cake with water, drying obtains product 4-(3-methoxyl group-4-nitrophenyl) morpholine (100 grams, productive rate 72%).
Step B/ intermediate B 1:2-methoxyl group-4-morpholine aniline
Toward 4-(3-methoxyl group-4-nitrophenyl) morpholine (100 grams, 0.42mol) tetrahydrofuran (THF) (2 liters) solution in add palladium carbon (10%, 10 grams), under atmosphere of hydrogen, stir after 12 hours, remove by filter catalyzer, be spin-dried for filtrate, obtain product 2-methoxyl group-4-morpholine aniline (87 grams, productive rate 100%).
intermediate B 2
2-((tertiary butyl dimethyl-silicon alcoxyl base) methyl)-4-morpholine aniline
Figure BPA00001751561000551
The chloro-2-nitrobenzaldehyde of steps A: 5-
The vitriol oil (150 milliliters) is cooled to-20 degree, carefully add the 3-chlorobenzaldehyde (15 grams, 107mmol) and saltpetre (11.9 grams, 117mmol), maintain the temperature at-10 spend below.After adding, continue to stir 30 minutes, then pour in frozen water, be extracted with ethyl acetate.Merge organic phase, use the saturated common salt water washing, anhydrous sodium sulfate drying, filter, and is spin-dried for, and the silicagel column separation obtains the chloro-2-nitrobenzaldehyde of product 5-(12.0 grams, productive rate 60.6%).
Step B:2-(the chloro-2-nitrophenyl of 5-)-DOX
Add chloro-2-nitrobenzaldehyde (12.0 grams of 5-in the round-bottomed flask that the Dean-Stark device is housed, 64.7mmol), ethylene glycol (8.0 grams, 129.3mmol), tosic acid (0.2 gram) and toluene (150 milliliters), reflux adds the methylene dichloride dilution after 8 hours, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, filter, be spin-dried for, the silicagel column separation obtains product 2-(the chloro-2-nitrophenyl of 5-)-1,3-dioxolane (13.4 grams, productive rate 90.0%).
Step C:4-(3-(DOX-2-yl)-4-nitrophenyl) morpholine
Figure BPA00001751561000561
By 2-(the chloro-2-nitrophenyl of 5-)-1, (13.4 grams, 58.4mmol) be dissolved in vlil in morpholine (150 milliliters) 16 hours to the 3-dioxolane, is cooled to room temperature, add the methylene dichloride dilution, organic phase washes with water, and anhydrous sodium sulfate drying filters, be spin-dried for, the silicagel column separation obtains product 4-(3-(DOX-2-yl)-4-nitrophenyl) morpholine (15.9 grams, productive rate 97.1%).
Step D:5-morpholine-2-nitrobenzaldehyde
Figure BPA00001751561000562
(3-(1 to add 4-in the mixed solvent (100 milliliters/100 milliliters) of acetone and water, 3-dioxolane-2-yl)-4-nitrophenyl) morpholine (15.9 grams, 56.7mmol) and tosic acid (2.0 gram), then reflux is 4 hours, adds the ethyl acetate dilution.Organic phase is used respectively saturated sodium bicarbonate aqueous solution and saturated common salt water washing, and anhydrous sodium sulfate drying filters, and is spin-dried for, and obtains product 5-morpholine-2-nitrobenzaldehyde, not purifiedly is directly used in next step reaction.
Step e: (5-morpholine-2-nitrophenyl) methyl alcohol
Figure BPA00001751561000563
5-morpholine-2-nitrobenzaldehyde is dispersed in the mixed solvent of tetrahydrofuran (THF) and ethanol (100 milliliters/100 milliliters), slowly add sodium borohydride (4.0 gram), stir at normal temperatures 1 hour, add the aqueous solution of ether and saturated ammonium chloride, then use extracted with diethyl ether.Merge organic phase, use the saturated common salt water washing, anhydrous sodium sulfate drying, filter, and is spin-dried for, and the silicagel column separation obtains product (5-morpholine-2-nitrophenyl) methyl alcohol (8.5 grams, two step productive rates 62.3%)
Step F: 4-(3-((tertiary butyl dimethyl-silicon alcoxyl base) methyl)-4-nitrophenyl) morpholine
Figure BPA00001751561000571
Toward (5-morpholine-2-nitrophenyl) methyl alcohol (3.0 grams, 12.6mmol), triethylamine (2.54 grams, 25.2mmol) and 4-N, add TERT-BUTYL DIMETHYL CHLORO SILANE (2.83g in methylene dichloride (100 milliliters) solution of N '-lutidine (0.2 gram), 18.9mmol), after adding, at room temperature stir 2 hours, by ethyl acetate, dilute.Organic phase saturated common salt water washing, anhydrous sodium sulfate drying, filter, and is spin-dried for, and the silicagel column separation obtains product 4-(3-((tertiary butyl dimethyl-silicon alcoxyl base) methyl)-4-nitrophenyl) morpholine (4.0 grams, productive rate 90.9%).
Step G/ intermediate B 2:2-((tertiary butyl dimethyl-silicon alcoxyl base) methyl)-4-morpholine aniline
Toward 4-(3-((tertiary butyl dimethyl-silicon alcoxyl base) methyl)-4-nitrophenyl) morpholine (4.0 grams, 0.11mol) methanol solution (250 milliliters) in add Raney nickel (1.0 gram), under atmosphere of hydrogen, stir 1 hour, remove by filter catalyzer, be spin-dried for filtrate, obtain product 2-((tertiary butyl dimethyl-silicon alcoxyl base) methyl)-4-morpholine aniline (3.48 grams, productive rate 95.1%). 1H?NMR(400MHz，CDCl 3)δppm?6.72-6.76(m，2H)，6.62-6.64(d，1H，J＝8.0Hz)，4.66(s，2H)，3.92(s，2H)，3.84-3.86(t，4H，J＝4.4Hz)，3.00-3.03(t，4H，J＝4.8Hz)，0.90-0.91(m，9H)，0.08-0.09(m，6H)。
intermediate B 3
2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] bis-Evil-5-amine
Steps A: 3-nitro-1,2-pyrocatechol
Figure BPA00001751561000582
By pyrocatechol, (60 grams, 0.54mol) be dissolved in ether (2 liters), and the lower nitrosonitric acid (24 milliliters) that drips of 0 degree, after adding, slowly rise to room temperature, places 20 minutes, pours in frozen water, uses extracted with diethyl ether.Merge organic phase, with the dilute sodium carbonate aqueous solution (10%) washing, anhydrous sodium sulfate drying, filter, and is spin-dried for, and the silicagel column separation obtains product 3-nitro-1,2-pyrocatechol (25 grams, productive rate 30%). 1H?NMR(400MHz，CDCl 3)δppm?10.62(s，1H)，7.64-7.67(dd，1H，J＝1.6Hz，8.8Hz)，7.23-7.26(m，1H)，6.89-6.93(t，1H，J＝8.4Hz)，5.79(br，1H)。
Step B:5-nitro-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin
Figure BPA00001751561000583
Toward 3-nitro-1,2-pyrocatechol (11 grams, 0.071mol) N, add successively salt of wormwood (29 grams, 0.213mol) He 1 in N '-dimethyl formamide (500 milliliters) solution, 2-ethylene dibromide (14.7 grams, 0.078mol), then be heated to 110 degree, stir after 2 hours and be cooled to room temperature, be poured into water, be extracted with ethyl acetate.Merge organic phase, use the saturated common salt water washing, anhydrous sodium sulfate drying, filter, and is spin-dried for, and the silicagel column separation obtains product 5-nitro-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin (8 grams, productive rate 62%). 1H?NMR(400MHz，CDCl 3)δppm?7.48-7.50(dd，1H，J＝1.6Hz，8.4Hz)，7.09-7.12(dd，1H，J＝1.6Hz，8.4Hz)，6.88-6.92(t，1H，J＝8.4Hz)，4.40-4.42(m，2H)，4.34-4.36(m，2H)。
Step C/ intermediate B 3:2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] bis-Evil-5-amine
Toward 5-nitro-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin (8 grams, 0.044mol) methanol solution (250 milliliters) in add palladium carbon (10%, 2 grams), under atmosphere of hydrogen, stir and spend the night, remove by filter catalyzer, be spin-dried for filtrate, purify with silicagel column, obtain target product 2,3-dihydrobenzo [b] [1,4] bis-Evil-5-amine (6.5 grams, productive rate 97%). 1H?NMR(400MHz，CDCl 3)δppm?6.61-6.65(t，1H，J＝8.0Hz)，6.30-6.33(dt，2H，J＝1.2Hz，2.4Hz)，4.22-4.27(m，4H)，3.75(s，2H)。
intermediate B 4
8-morpholine-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] bis-Evil-5-amine
Steps A: N-(2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] bis-Evil-5-yl) ethanamide
Figure BPA00001751561000592
Under room temperature, toward 2,3-dihydrobenzo [b] [1, (intermediate B 3,4.5 grams, slowly drip diacetyl oxide (3.0 grams to 4] bis-Evil-5-amine in ethanolic soln 30mmol) (50 milliliters), 30mmol), stir at normal temperatures after adding 5 minutes, be spin-dried for solvent, separate with silicagel column, obtain product N-(2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] bis-Evil-5-yl) ethanamide (5.5 grams, productive rate 95%). 1H?NMR(400MHz，CDCl 3)δppm9.12(s，1H)，7.44-7.46(d，1H，J＝8.0Hz)，6.71-6.75(t，1H，J＝8.0Hz)，6.59-6.61(d，1H，J＝7.6Hz)，4.23-4.30(m，4H)，2.06(s，3H)。
Step B:N-(8-is bromo-2, and 3-dihydrobenzo [b] [Isosorbide-5-Nitrae] bis-Evil-5-yl) ethanamide
By N-(2,3-dihydrobenzo [b] [1,4] bis-Evil-5-yl) ethanamide (5.5 grams, 28.5mmol) chloroformic solution (20 milliliters) be cooled to-20 the degree, slowly drip bromine (1.6 milliliters, chloroformic solution 30mmol) (5 milliliters), keep reacting liquid temperature below-10 degree, after adding, under 0 degree, stir 10 minutes that, water cancellation rapidly, use dichloromethane extraction.Merge organic phase, use respectively saturated sodium bicarbonate aqueous solution and saturated common salt water washing, anhydrous sodium sulfate drying, filter, be spin-dried for, the silicagel column separation obtains product N-, and (8-bromo-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] bis-Evil-5-yl) ethanamide (5 grams, productive rate 64%). 1HNMR(400MHz，CDCl 3)δppm?9.23(s，1H)，7.46-7.48(d，1H，J＝8.8Hz)，7.04-7.06(d，1H，J＝9.2Hz)，4.32-4.40(m，4H)，2.07(s，3H)。
Step C:N-(8-morpholine-2, and 3-dihydrobenzo [b] [Isosorbide-5-Nitrae] bis-Evil-5-yl) ethanamide
Figure BPA00001751561000601
Toward N-(8-is bromo-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] bis-Evil-5-yl) ethanamide (5 grams, in toluene solution 18.4mmol) (50 milliliters), add morpholine (1.9 grams, 22mmol), Pd 2(dba) 3(1.68 grams, 1.84mmol), X-Phos (1.75 grams, 3.68mmol) and potassium tert.-butoxide (4.1 grams, 36.8mmol), mixture is placed in to tube sealing and under 130 degree, reacts and spend the night, be cooled to room temperature, filter, be spin-dried for filtrate, with silicagel column, separated to obtain product N-(8-morpholine-2,3-dihydrobenzo [b] [1,4] bis-Evil-5-yl) ethanamide (2 grams, productive rate 40%).
Step D/ intermediate B 4:8-morpholine-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] bis-Evil-5-amine
Toward N-(8-morpholine-2,3-dihydrobenzo [b] [1,4] bis-Evil-5-yl) ethanamide (2 grams, 7.19mmol) methanol solution (100 milliliters) in add concentrated hydrochloric acid (5 milliliters), and then stir and spend the night under room temperature, revolve most of solvent, with sodium bicarbonate aqueous solution, regulate the pH value to 7-8, be extracted with ethyl acetate.Merge organic phase, use the saturated common salt water washing, anhydrous sodium sulfate drying, filter, and is spin-dried for, and the silicagel column separation obtains product 8-morpholine-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] two Evil-5-amine (1 gram, productive rate 60%). 1H?NMR(400MHz，CDCl 3)δppm?6.38-6.41(d，1H，J＝8.4Hz)，6.27-6.29(d，1H，J＝8.4Hz)，4.28-4.32(m，4H)，3.85-3.88(t，4H，J＝4.8Hz)，3.55(s，2H)，2.95-2.97(t，4H，J＝4.8Hz)。
intermediate B 5
7-amido-1-ethyl-6-methoxyl group-4,5-dihydro-1H-benzo [b] azatropylidene-2 (3H)-one hydrochloride
Steps A: 6-methoxyl group-4,5-dihydro-1H-benzo [b] azatropylidene-2 (3H)-one
Figure BPA00001751561000612
Under 0 degree, toward 5-methoxyl group-3,4-dihydronaphthalene-1 (2H)-one (8.3 grams, 47.15mmol) poly phosphoric acid solution in (100 milliliters) slowly add sodiumazide (3.6 grams in batches, 55.4mmol), add in 30 minutes, then slowly rise to room temperature, continue to stir 16 hours, pour in frozen water, filter and collect precipitate, drying obtains product 6-methoxyl group-4,5-dihydro-1H-benzo [b] azatropylidene-2 (3H)-one (6.8 grams, productive rate 75.5%). 1HNMR(400MHz，DMSO-d6)δppm?9.48(s，1H)，7.13-7.17(t，1H，J＝8.0Hz)，6.77-6.79(d，1H，J＝7.6Hz)，6.58-6.60(d，1H，J＝7.6Hz)，3.78(s，3H)，2.68-2.72(t，2H，J＝6.8Hz)，2.11-2.14(t，2H，J＝7.2Hz)，1.99-2.05(m，2H)。
Step B:6-methoxyl group-7-nitro-4,5-dihydro-1H-benzo [b] azatropylidene-2 (3H)-one
Figure BPA00001751561000613
By 6-methoxyl group-4,5-dihydro-1H-benzo [b] azatropylidene-2 (3H)-one (6.8 grams, 35.6mmol) acetonitrile solution (50 milliliters) be cooled to-10 the degree, slowly drip (15.0 milliliters of trifluoromethanesulfanhydride anhydrides, 106.8mmol), stir after 20 minutes, add saltpetre (3.94 grams in batches, 39.0mmol), slowly rise to room temperature, continue to stir 5 hours, pour in the solution of sodium bicarbonate and frozen water (100 milliliters), regulate pH value to 9, be extracted with ethyl acetate.Merge organic phase, use the saturated common salt water washing, anhydrous sodium sulfate drying, filter, be spin-dried for, the silicagel column separation obtains product 6-methoxyl group-7-nitro-4,5-dihydro-1H-benzo [b] azatropylidene-2 (3H)-one (yellow solid, 4.68 grams, productive rate 55.7%). 1HNMR(400MHz，DMSO-d6)δppm?10.01(s，1H)，7.80-7.83(d，1H，J＝8.8Hz)，6.88-6.90(d，1H，J＝8.8Hz)，3.85(s，3H)，2.73-2.77(t，2H，J＝7.2Hz)，2.25-2.27(t，2H，J＝6.8Hz)，2.15-2.20(m，2H)。
Step C:1-ethyl-6-methoxyl group-7-nitro-4,5-dihydro-1H-benzo [b] azatropylidene-2 (3H)-one
Figure BPA00001751561000621
By 6-methoxyl group-7-nitro-4, (N '-dimethyl formamide solution (30 milliliters) is cooled to 0 degree to 5-dihydro-1H-benzo [b] azatropylidene-2 (3H)-one for 4.5 grams, N 19.0mmol), slowly add sodium hydride (60% mineral oil mixture in batches, 1.15 gram, 28.5mmol), after stirring 30 minutes, slowly drip (1.84 milliliters of iodoethane, 22.9mmol), more slowly rise to normal temperature, continue to stir 2 hours.Reaction is poured in frozen water after finishing, and filters to obtain product 1-ethyl-6-methoxyl group-7-nitro-4, and 5-dihydro-1H-benzo [b] azatropylidene-2 (3H)-one is pale solid (3.77 grams, productive rate 78.5%). 1HNMR(400MHz，CDCl 3)δppm?7.81-7.84(dd，1H，J＝1.6Hz，8.8Hz)，7.08-7.10(dd，1H，J＝1.2Hz，8.8Hz)，3.76-3.94(s+m，5H)，2.89-2.96(m，2H)，2.22-2.32(m，4H)，1.16-1.26(m，3H)。
Step D/ intermediate B 5:7-amido-1-ethyl-6-methoxyl group-4,5-dihydro-1H-benzo [b] azatropylidene-2 (3H)-one hydrochloride
Toward 1-ethyl-6-methoxyl group-7-nitro-4, 5-dihydro-1H-benzo [b] azatropylidene-2 (3H)-one (4.6 grams, 18.0mmol) ethanol (45 milliliters) solution in add palladium carbon (10%, 0.45 gram) and hydrazine hydrate (85%, 8.78 milliliter, 0.18mol), be heated to 90 degree, be cooled to room temperature after 6 hours, revolve most of solvent, acetone diluted for resistates (40 milliliters), be cooled to add concentrated hydrochloric acid after 0 degree, revolve desolventizing, obtain target product 7-amido-1-ethyl-6-methoxyl group-4, 5-dihydro-1H-benzo [b] azatropylidene-2 (3H)-one hydrochloride (4.3 grams, productive rate 87.7%). 1H?NMR(400MHz，CDCl 3)δppm?10.65(br，2H)，7.64-7.67(d，1H，J＝8.4Hz)，7.07-7.09(d，1H，J＝8.4Hz)，4.03(s，3H)，3.50-3.82(m，2H)，2.71-2.92(m，2H)，2.24-2.30(m，2H)，2.17-2.22(m，2H)，1.12-1.15(t，3H，J＝7.2Hz)。
intermediate B 6
5-amido isoindole-1-ketone
Figure BPA00001751561000631
Steps A: 2-(brooethyl)-4-nitrobenzene methyl
Figure BPA00001751561000632
By 2-methyl-(696 milligrams of 4-nitrobenzene methyls, 3.57mmol), (58.6 milligrams of Diisopropyl azodicarboxylates, 0.357mmol) and (785 milligrams of N-bromosuccinimides, 4.46mmol) be placed in tube sealing, add tetracol phenixin (35 milliliters), pour the nitrogen post-heating to 80 degree, stir and be cooled to room temperature after 22 hours, solids removed by filtration, be spin-dried for filtrate, obtain thick product 2-(brooethyl)-4-nitrobenzene methyl, for the light brown solid, not purified, be directly used in next step reaction.
Step B:5-nitro isoindole-1-ketone
Figure BPA00001751561000633
2-(brooethyl)-4-nitrobenzene methyl is dissolved in to (7N in the methanol solution of ammonia, 5 milliliters), stir after 2 hours and be spin-dried under normal temperature, obtain yellow solid, with ethyl acetate (15 milliliters) making beating, be cooled to-20 degree, filter to obtain product 5-nitro isoindole-1-ketone, for yellow solid 1h NMR (400MHz, DMSO-d6) δ ppm 9.04 (br s, 1H), 8.48 (d, 1H, J=2.0Hz), 8.25 (dd, 1H, J=2.0Hz, 8.4Hz), 7.91 (d, 1H, J=8.4Hz), 4.51 (s, 2H).
Step C/ intermediate B 6:5-amido isoindole-1-ketone
By 5-nitro isoindole-(60 milligrams of 1-ketone, 0.337mmol) be dissolved in methyl alcohol (20 milliliters), add palladium carbon (10%, 50 milligrams), under atmosphere of hydrogen, stir 1 hour, remove by filter catalyzer, be spin-dried for filtrate and obtain target product 5-amido isoindole-1-ketone (38 milligrams, productive rate 76.2%).
intermediate B 7
cumarone-7-amine hydrochlorate
Figure BPA00001751561000641
Steps A: 2-hydroxyl-3-nitrobenzaldehyde
Figure BPA00001751561000642
Under 0 degree, by concentrated nitric acid (65%, 4 grams) (5.0 grams, in acetic acid 41mmol) (50 milliliters) solution, more slowly rise to room temperature slowly to be added drop-wise to Benzaldehyde,2-hydroxy, stir 2 hours post-heating to 40 degree, continue to stir 5 hours, pour in the mixture of ice (75 gram) and water (500 gram), filter and collect precipitate, after separating, silicagel column obtains product 2-hydroxyl-3-nitrobenzaldehyde (1.8 grams, productive rate 26%). 1HNMR(400MHz，CDCl 3)δppm?11.44(s，1H)，10.42(s，1H)，8.34-8.37(dd，1H，J＝2.0Hz，8.4Hz)，8.10-8.13(dd，1H，J＝2.0Hz，7.6Hz)，7.12-7.16(t，1H，J＝8.0Hz)。
Step B:7-nitrobenzofuran-2-carboxylate methyl ester
Figure BPA00001751561000643
Add 2-hydroxyl-3-nitrobenzaldehyde (4.3 grams in a round-bottomed flask with the Dean-Stark device, 25.7mmol), 2-bromalonic acid dimethyl ester (5.95 grams, 28.3mmol), salt of wormwood (5.32 grams, 38.6mmol) and Tetrabutyl amonium bromide (0.8 gram, 2.5mmol) toluene solution (100 milliliters), reflux 5 hours, be spin-dried for solvent after being cooled to room temperature, obtain product 7-nitrobenzofuran-2-methyl-formiate (4.6 grams, productive rate 81%) through the silicagel column separation and purification. 1HNMR(400MHz，CDCl 3)δppm?8.31-8.33(dd，1H，J＝1.2Hz，8.0Hz)，8.02-8.04(dd，1H，J＝1.2Hz，8.0Hz)，7.66(s，1H)，7.46-7.50(t，1H，J＝8.0Hz)，4.03(s，3H)。
Step C:7-nitrobenzofuran-2-carboxylic acid
By 7-nitrobenzofuran-2-methyl-formiate, (4.12 grams, 18.6mmol) be dissolved in (100 milliliters) in ethanol, and (2.08 grams, 37.1mmol), reflux 1 hour, be cooled to room temperature, is spin-dried for solvent to add potassium hydroxide.Residue diluted with water, regulate the pH value with concentrated hydrochloric acid, has insolubles to separate out, and stirs after 30 minutes and filter, and collects precipitate, washes with water, obtains product 7-nitrobenzofuran-2-carboxylic acid (3.54 grams, productive rate 92%) after drying. 1H?NMR(400MHz，CDCl 3)δppm?8.28-8.30(dd，1H，J＝0.8Hz，8.0Hz)，8.06-8.08(dd，1H，J＝0.8Hz，7.6Hz)，7.641-7.642(d，1H，J＝0.4Hz)，7.47-7.51(m，2H)。
Step D:7-nitrobenzofuran
Figure BPA00001751561000652
By 7-nitrobenzofuran-2-carboxylic acid (3.54 grams, 17.1mmol) and cupric oxide (0.16 gram, 2mmol) be suspended in quinoline (30 milliliters), is heated to 170 degree, after 1 hour, is cooled to room temperature, dilute with water, ethyl acetate extraction.Merge organic phase, use the saturated common salt water washing, anhydrous sodium sulfate drying, filter, and is spin-dried for, and the silicagel column separation obtains product 7-nitrobenzofuran (2.56 grams, productive rate 92%). 1H?NMR(400MHz，DMSO-d6)δppm?8.27-8.28(d，1H，J＝2.0Hz)，8.12-8.17(m，2H)，7.46-7.50(t，1H，J＝8.0Hz)，7.215-7.220(d，1H，J＝2.0Hz)。
Step e/intermediate B 7: cumarone-7-amine hydrochlorate
Toward the 7-nitrobenzofuran, (2.56 grams, (2.5 grams 50mmol), have obvious exothermic phenomenon to add Raney nickel (approximately 200 milligrams) and hydrazine hydrate in methanol solution 15.7mmol) (100 milliliters).This mixture is heated to 50 degree, after 1 hour, is cooled to room temperature, remove by filter catalyzer, be spin-dried for filtrate.Resistates dilutes by ethyl acetate, adds the methanol solution (1N) of hydrogenchloride, has insolubles to separate out, and filters and collects precipitate, obtains target product cumarone-7-amine hydrochlorate (2.025 grams, productive rate 76%) after drying. 1H?NMR(400MHz，DMSO-d6)δppm?8.12-8.13(d，1H，J＝2.0Hz)，7.57-7.59(dd，1H，J＝1.2Hz，8.0Hz)，7.35-7.37(m，1H)，7.24-7.28(t，1H，J＝8.0Hz)，7.047-7.053(d，1H，J＝2.4Hz)。
intermediate B 8
1,3-dimethyl-1H-pyrazoles-5-amine
Toward 2-amido propenyl cyanide, (16.5 grams, (12.9 grams, 0.28mol), reflux 3 hours, revolve unnecessary Pentyl alcohol and methyl hydrazine to add methyl hydrazine in Pentyl alcohol 0.2mol) (40 milliliters) solution.By gained heptane (150 milliliters) making beating for resistates, to filter and collect precipitate, the lower vacuum-drying of 40 degree, obtain target product 1,3-dimethyl-1H-pyrazoles-5-amine (13.5 grams, productive rate 60.4%).
intermediate B 9
3,4,5-trimethoxy-aniline
Figure BPA00001751561000662
Steps A: 1,2,3-trimethoxy-5-oil of mirbane
Figure BPA00001751561000663
Under 10 degree, by 3,4,5-trimethoxybenzoic acid (10 grams, 47mmol) be added in the mixed solvent of nitric acid (20 milliliters) and acetic acid (40 milliliters) in batches, stir at normal temperatures after 30 minutes and pour in frozen water, filter and collect precipitate, wash with water, recrystallization in ethanol, obtain product 1,2,3-trimethoxy-5-oil of mirbane (6.64 grams, productive rate 66.1%). 1H?NMR(400MHz，DMSO-d6)δppm?7.51(s，2H)，3.87(s，6H)，3.77(s，3H)。
Step B/ intermediate B 9:3,4,5-trimethoxy-aniline
Toward 1,2,3-trimethoxy-5-oil of mirbane (6.64 grams, 31.2mmol) ethanolic soln (250 milliliters) add palladium carbon (10%, 300 milligram) and hydrazine hydrate (85%, 5.7 milliliter), a large amount of air releases are arranged, then, by mixture reflux 1 hour, be cooled to room temperature, filter, revolve desolventizing and obtain product 3,4,5-trimethoxy-aniline (white solid, 5.5 gram, productive rate 96.4%). 1HNMR(400MHz，DMSO-d6)δppm?5.86(s，2H)，4.82(br，2H)，3.64(s，6H)，3.50(s，3H)。
intermediate B 10
1-(3-morpholine propyl group)-1H-indoles-4-amine
Steps A: 1-(3-bromopropyl)-4-nitro-1H-indoles
Figure BPA00001751561000672
By 4-nitroindoline (5 grams, 31mmol) be dissolved in anhydrous N, in N '-dimethyl formamide (200 milliliters), add in batches grinding potassium hydroxide (1.74 grams, 31mmol), then drip 1,3-dibromopropane (18 grams, N 89mmol), N '-dimethyl formamide solution, stir at normal temperatures thin up after 12 hours, be extracted with ethyl acetate.Merge organic phase, use the saturated common salt water washing, anhydrous sodium sulfate drying, filter, and is spin-dried for, and the silicagel column separation obtains product 1-(3-bromopropyl)-4-nitro-1H-indoles (8.18 grams, productive rate 94%).
Step B:4-(3-(4-nitro-1H-indoles-1-yl) propyl group) morpholine
Figure BPA00001751561000681
By 1-(3-bromopropyl)-4-nitro-1H-indoles (8.18 grams, 28.9mmol) be dissolved in anhydrous N, in N '-dimethyl formamide (200 milliliters), add in batches grinding salt of wormwood (12 grams, 87mmol), then drip morpholine (12.6 grams, 144.8mmol) N, N '-dimethyl formamide solution, be heated to 80 degree, stir thin up after 12 hours, be extracted with ethyl acetate.Merge organic phase, use the saturated common salt water washing, anhydrous sodium sulfate drying, filtration, be spin-dried for, and obtains product 4-(3-(4-nitro-1H-indoles-1-yl) propyl group) morpholine, not purifiedly is directly used in next step reaction.
Step C/ intermediate B 10:1-(3-morpholine propyl group)-1H-indoles-4-amine
Add palladium carbon (10%) in the methanol solution (100 milliliters) of 4-(3-(4-nitro-1H-indoles-1-yl) propyl group) morpholine, under atmosphere of hydrogen, stir 12 hours, remove by filter catalyzer, be spin-dried for filtrate, obtain target product 1-(3-morpholine propyl group)-1H-indoles-4-amine, for brown solid (5 grams, two step productive rates 67%).
Intermediate C1
2-amido-N-methyl-benzamide
Figure BPA00001751561000682
Toward isatoic anhydride (10 grams, 61.3mmol) tetrahydrofuran (THF) (200 milliliters) suspension in drip the methanol solution (40%, 10 milliliter) of methylamine, stir after 16 hours and be spin-dried for solvent under room temperature, obtain product 2-amido-N-methyl-benzamide (9 grams, productive rate 97.8%). 1H?NMR(400MHz，CDCl 3)δppm?7.14-7.32(m，2H)，6.60-6.72(m，2H)，6.05(br?s，1H)，2.97(d，3H，J＝5.0Hz)。
intermediate C2
4-amido-N-methyl benzo [d] [1,3]-dioxa-5-methane amide
Figure BPA00001751561000691
Steps A: 4-nitro benzo [d] [1,3]-dioxole
Figure BPA00001751561000692
Toward add in hexamethyl three phosphamides (100 milliliters) sodium hydride (60% mineral oil mixture, 1.0 grams, 25mmol), then slowly drip 3-nitro-1, the 2-pyrocatechol (gets 1.55 grams from the synthetic of intermediate B3, hexamethyl three phosphamide solution (20 milliliters) 10mmol), add in 10 minutes, after adding, add (0.94 milliliter of methylene iodide, 11.6mmol), continue to stir 30 minutes, use the frozen water cancellation, use extracted with diethyl ether.Merge organic phase, use the saturated common salt water washing, anhydrous sodium sulfate drying, filter, and is spin-dried for, and the silicagel column separation obtains product 4-nitro benzo [d] [1,3]-dioxole (1.32 grams, productive rate 79%). 1H?NMR(400MHz，CDCl 3)δppm?7.59-7.62(dd，1H，J＝1.2Hz，8.8Hz)，7.06-7.09(dd，1H，J＝0.8Hz，8.0Hz)，6.91-6.96(dt，1H，J＝0.8Hz，8.4Hz)，6.219-6.221(d，2H，J＝0.8Hz)。
Step B: dioxa between benzo [d] [1,3]-4-amine
Figure BPA00001751561000693
Toward 4-nitro benzo [d] [1,3]-dioxole (2.0 grams, add Raney nickel (approximately 0.5 gram) in ethanolic soln 12mmol) (80 milliliters), stir after 4 hours and remove by filter catalyzer under atmosphere of hydrogen, be spin-dried for filtrate, separate with silicagel column, obtain product benzo [d] [1,3] dioxa between-4-amine (1.04 grams, productive rate 63%). 1H?NMR(400MHz，CDCl 3)δppm?6.64-6.68(t，1H，J＝8.0Hz)，6.29-6.35(dt，2H，J＝0.8Hz，6.4Hz)，5.90(s，2H)，3.52(br，2H)。
Dioxa step C:[1,3] [4 ', 5 ': 5,6] benzo [1,2-b] azet-6 (7H)-one
Figure BPA00001751561000701
Toward Chloral Hydrate (1.39 grams, 8.4mmol) and sodium sulfate (6.91 grams, add benzo [d] [1 in aqueous solution 48.7mmol) (23.1 milliliters), 3] dioxa between-4-amine (1.0 grams, 7.3mmol), oxammonium sulfate (6.24 grams, 38mmol) and dilute hydrochloric acid (1.2N, 7.7 milliliter), stir 1.5 hours under 60 degree, then under 25 degree, place and spend the night, filter and collect brown solid, wash vacuum-drying with water.Again it is dissolved in methylsulfonic acid, be heated to 45 degree, be cooled to 0 degree after 30 minutes, pour into (200 gram) in ice, there is dark red solid to separate out, filter to collect, after drying dioxa between product [1,3] [4 ', 5 ': 5,6] benzo [1,2-b] azet-6 (7H)-one (635 milligrams, productive rate 53%). 1H?NMR(400MHz，CDCl 3)δppm?7.68(br?s，1H)，7.35-7.37(d，1H，J＝8.0Hz)，6.59-6.61(d，1H，J＝8.0Hz)，6.13(s，2H)。
Dioxa between step D:4-amido benzo [d] [1,3]-5-carboxylic acid
Toward sodium hydroxide (4.6 grams, in aqueous solution 115mmol) (35 milliliters), add dioxa between [1,3] [4 ', 5 ': 5,6] benzo [1,2-b] azet-6 (7H)-one (2.35 grams, 14.4mmol), slowly drip superoxol (30%, 21 milliliter) in 30 minutes, then regulate pH value to 7 with dilute hydrochloric acid, filter and collect precipitate, drying obtains dioxa between product 4-amido benzo [d] [1,3]-5-carboxylic acid (1.68 grams, productive rate 64%). 1H?NMR(400MHz，DMSO-d6)δppm?7.40-7.42(d，1H，J＝8.4Hz)，6.25-6.27(d，1H，J＝8.4Hz)，6.04(s，2H)。
Dioxa-5-methane amide between step e/intermediate C2:4-amido-N-methyl benzo [d] [1,3]
At methylamine (0.43 gram, 13.9mmol) acetonitrile solution (20 milliliters) in add 4-amido benzo [d] [1,3] dioxa between-5-carboxylic acid (1.68 grams, 9.3mmol), 2-(7-azepine-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-urea phosphofluoric acid ester (HATU, 4.28 grams, 11.2mmol).Mixture stirs at normal temperatures after 12 hours and is spin-dried for, and the dilution that adds methylene chloride, wash with water, anhydrous sodium sulfate drying, filter, and is spin-dried for, the silicagel column separation obtains dioxa-5-methane amide between product 4-amido-N-methyl benzo [d] [1,3] (1.48 grams, productive rate 82%). 1HNMR(400MHz，CDCl 3)δppm6.95-6.98(d，1H，J＝8.4Hz)，6.24-6.26(d，1H，J＝8.0Hz)，5.97(s，2H)，2.94-2.95(m，3H)。
intermediate C3
(2-aminocarbonyl phenyl) (pyrrolidin-1-yl) methyl ketone
Figure BPA00001751561000711
Toward 2-amido phenylformic acid (5.0 grams, 36.5mol) tetrahydrofuran solution (50 milliliters) in add N, (6.5 grams, 40.1mol), stir 1 hour under normal temperature N '-carbonyl dimidazoles, then add tetramethyleneimine (3.5 grams, 40.1mmol), continue to stir and spend the night, revolve desolventizing, thin up, use dichloromethane extraction.Merge organic phase, use the saturated common salt water washing, anhydrous sodium sulfate drying, filter, and is spin-dried for and obtains product (2-aminocarbonyl phenyl) (pyrrolidin-1-yl) methyl ketone (5.4 grams, productive rate 66%), not purified, is directly used in next step reaction. 1H?NMR(400MHz，CDCl 3)δppm?7.12-7.21(m，2H)，6.66-6.71(m，2H)，4.62(br?s，2H)，3.63(br?s，2H)，3.47(br?s，2H)，1.87-1.94(m，4H)。
intermediate C4
2-amido-N-methyl benzenesulfonamide
Figure BPA00001751561000712
Steps A: N-methyl-2-nitrobenzene sulfonamide
Toward 2-nitro-1-benzene sulfonyl chloride (30 grams, 0.14mol) dichloromethane solution (500 milliliters) in slowly drip the aqueous solution (30% of methylamine, 15.3 gram) and (38 milliliters of triethylamines, 0.27mol), stir at normal temperatures after 1 hour and be spin-dried for solvent, resistates carries out separation and purification with silicagel column and obtains product N-methyl-2-nitrobenzene sulfonamide (26 grams, productive rate 90%).
Step B/ intermediate C4:2-amido-N-methyl benzenesulfonamide
Toward N-methyl-2-nitrobenzene sulfonamide (26 grams, 0.12mol) methanol solution (500 milliliters) in add palladium carbon (10%, 2 grams), stir after 3 hours and remove by filter catalyzer under atmosphere of hydrogen, be spin-dried for filtrate and obtain target product 2-amido-N-methyl benzenesulfonamide (22 grams, productive rate 98%). 1H?NMR(400MHz，CDCl 3)δppm?7.45-7.48(dd，1H，J＝1.6Hz，8.0Hz)，7.24-7.31(m，2H)，6.81-6.83(dd，1H，J＝0.6Hz，8.0Hz)，6.60-6.65(m，1H)，5.89(s，2H)，2.370-2.374(d，3H，J＝1.6Hz)。
intermediate C5
2-amido-N-propylbenzene sulfonamide hydrochloride
Steps A: 2-nitro-N-propylbenzene sulphonamide
Under 0 degree, toward Tri N-Propyl Amine (2.36 grams, 0.04mol) tetrahydrofuran solution (100 milliliters) in slowly add 2-nitro-1-benzene sulfonyl chloride (8.88 grams, 0.04mol) and triethylamine (4.05 grams, 0.04mol), stir at normal temperatures after 4 hours and be spin-dried for solvent and obtain thick product 2-nitro-N-propylbenzene sulphonamide (9.18 grams, productive rate 93.9%). 1H?NMR(400MHz，CDCl 3)δppm?8.11-8.16(m，1H)，7.84-7.89(m，1H)，7.74-7.79(m，2H)，5.26(s，1H)，3.05-3.10(t，2H，J＝6.4Hz)，1.51-1.60(m，2H)，0.89-0.92(t，3H，J＝7.6Hz)。
Step B/ intermediate C5:2-amido-N-propylbenzene sulfonamide hydrochloride
Toward 2-nitro-N-propylbenzene sulphonamide (8.64 grams, 0.035mol) methanol solution (100 milliliters) in add palladium carbon (10%, 3.5 gram), stir after 12 hours and remove by filter catalyzer under atmosphere of hydrogen, be spin-dried for filtrate, resistates is dissolved in ether, blast hydrogen chloride gas, obtain product 2-amido-N-propylbenzene sulfonamide hydrochloride (8.61 grams, productive rate 98.4%). 1H?NMR(400MHz，DMSO-d6)δppm?8.14(br?s，3H)，7.50-7.62(m，2H)，7.26-7.30(dt，1H，J＝1.6Hz，7.6Hz)，6.88-6.90(d，1H，J＝8.0Hz)，6.67-6.71(m，1H)，2.61-2.65(t，2H，J＝7.2Hz)，1.28-1.37(sext，2H，J＝7.2Hz)，0.72-0.76(t，3H，J＝7.6Hz)。
intermediate C6
2-amido-N-cyclobutyl benzsulfamide
Figure BPA00001751561000731
Steps A: N-cyclobutyl-2-nitrobenzene sulfonamide
Figure BPA00001751561000732
Under 0 degree, toward 2-nitro-1-benzene sulfonyl chloride (6.8 grams, 30.8mol) dichloromethane solution (100 milliliters) in slowly add ring butylamine (2.2 grams, 31mmol) and triethylamine (14 grams, 138.6mol), stir at normal temperatures after 4 hours and be spin-dried for solvent, resistates carries out separation and purification with silicagel column and obtains product N-cyclobutyl-2-nitrobenzene sulfonamide (7 grams, productive rate 88.9%). 1H?NMR(400MHz，CDCl 3)δppm?8.14-8.16(m，1H)，7.84-7.87(m，1H)，7.72-7.74(m，2H)，5.45-5.47(d，1H，J＝8.8Hz)，3.93-3.99(m，1H)，2.11-2.18(m，2H)，1.84-1.90(m，2H)，1.59-1.69(m，2H)。
Step B/ intermediate C6:2-amido-N-cyclobutyl benzsulfamide
Toward N-cyclobutyl-2-nitrobenzene sulfonamide (7 grams, 27.3mmol) methanol solution (100 milliliters) in add palladium carbon (10%), stir after 12 hours and remove by filter catalyzer under atmosphere of hydrogen, be spin-dried for filtrate, resistates carries out separation and purification with silicagel column and obtains product 2-amido-N-cyclobutyl benzsulfamide (6 grams, productive rate 97.1%). 1H?NMR(400MHz，CDCl 3)δppm?7.68-7.71(dd，1H，J＝1.6Hz，8.0Hz)，7.27-7.33(m，1H)，6.74-6.82(m，2H)，5.30(s，1H)，5.08(s，2H)，3.70-3.73(m，1H)，1.96-2.04(m，2H)，1.67-1.75(m，2H)，1.48-1.62(m，2H)。
intermediate C7
2-amido-N-cyclopentyl benzsulfamide
Figure BPA00001751561000741
Steps A: N-cyclopentyl-2-nitrobenzene sulfonamide
Figure BPA00001751561000742
Under 0 degree, toward 2-nitro-1-benzene sulfonyl chloride (22.1 grams, slowly add cyclopentamine (9 grams in dichloromethane solution 100mol) (500 milliliters), 105.9mmol) and triethylamine (14 grams, 138.6mol), stir at normal temperatures after 4 hours and be spin-dried for solvent, resistates carries out separation and purification with silicagel column and obtains product N-cyclopentyl-2-nitrobenzene sulfonamide (23 grams, productive rate 85.2%). 1H?NMR(400MHz，CDCl 3)δppm?8.16-8.18(m，1H)，7.84-7.87(m，1H)，7.40-7.78(m，2H)，5.25-5.27(d，1H，J＝7.6Hz)，3.76-3.81(m，1H)，1.79-1.87(m，2H)，1.62-1.70(m，2H)，1.39-1.58(m，4H)。
Step B/ intermediate C7:2-amido-N-cyclopentyl benzsulfamide
Toward N-cyclopentyl-2-nitrobenzene sulfonamide (23 grams, 85.2mmol) methanol solution (500 milliliters) in add palladium carbon (10%), stir after 12 hours and remove by filter catalyzer under atmosphere of hydrogen, be spin-dried for filtrate, resistates carries out separation and purification with silicagel column and obtains product 2-amido-N-cyclopentyl benzsulfamide (20 grams, productive rate 97.8%). 1H?NMR(400MHz，CDCl 3)δppm?7.71-7.74(dd，1H，J＝1.2Hz，8.0Hz)，7.30-7.34(m，1H)，6.75-6.82(m，2H)，4.86(br?s，3H)，3.50-3.53(m，1H)，1.67-1.69(m，2H)，1.55-1.62(m，2H)，1.42-1.50(m，2H)，1.22-1.36(m，2H)。
intermediate C8
2-amido-N-cyclohexyl benzene sulfonamide
Figure BPA00001751561000751
Steps A: N-cyclohexyl-2-nitrobenzene sulfonamide
Under 0 degree, toward 2-nitro-1-benzene sulfonyl chloride (22.1 grams, slowly add hexahydroaniline (11.9 grams in dichloromethane solution 100mol) (500 milliliters), 120.2mmol) and triethylamine (14 grams, 138.6mol), stir at normal temperatures after 1 hour and be spin-dried for solvent, resistates carries out separation and purification with silicagel column and obtains product N-cyclohexyl-2-nitrobenzene sulfonamide (25.7 grams, productive rate 90.5%). 1H?NMR(400MHz，CDCl 3)δppm?8.16-8.19(m，1H)，7.85-7.87(m，1H)，7.72-7.78(m，2H)，5.24-5.26(d，1H，J＝7.6Hz)，3.34-3.36(m，1H)，1.77-1.81(m，2H)，1.63-1.69(m，2H)，1.52-1.56(m，1H)，1.17-1.30(m，5H)。
Step B/ intermediate C8:2-amido-N-cyclohexyl benzene sulfonamide
Toward N-cyclohexyl-2-nitrobenzene sulfonamide (25.7 grams, 90.5mmol) methanol solution (500 milliliters) in add palladium carbon (10%), stir after 12 hours and remove by filter catalyzer under atmosphere of hydrogen, be spin-dried for filtrate, resistates carries out separation and purification with silicagel column and obtains product 2-amido-N-cyclohexyl benzene sulfonamide (22 grams, productive rate 95.7%). 1H?NMR(400MHz，CDCl 3)δppm?7.72-7.74(dd，1H，J＝1.2Hz，8.0Hz)，7.27-7.33(m，1H)，6.75-6.82(m，2H)，4.84(s，3H)，3.05-3.07(m，1H)，1.59-1.70(m，4H)，1.46-1.50(m，1H)，1.08-1.22(m，5H)。
intermediate C9
n-(2-aminocarbonyl phenyl) ethanamide
Under 0 degree, toward 1, the 2-O-Phenylene Diamine (100 grams, and the lower dropping of methylene dichloride 0.93mol) (1L) diacetyl oxide (87 milliliters, 0.92mol), under 0 degree, stir after 2 hours, standing 12 hours, solid collected by filtration, with methylene dichloride and ether washing, obtain product N-(2-aminocarbonyl phenyl) ethanamide (25 grams, productive rate 18%) after drying. 1H?NMR(400MHz，CDCl 3)δppm?7.14-7.26(m，2H)，7.04-7.08(m，1H)，6.78-6.81(m，2H)，3.86(br?s，2H)，2.20(s，3H)。
intermediate C10
n-(2-aminocarbonyl phenyl)-N-methyl Toluidrin
Figure BPA00001751561000761
Steps A: N-methyl-N-(2-nitrophenyl) Toluidrin
Figure BPA00001751561000762
Toward cesium carbonate (20.2 grams, 0.065mol) acetonitrile solution (500 milliliters) in add N-methyl Toluidrin (5.33 grams, 0.049mol) and fluoro-2-oil of mirbane (4.59 grams of 1-, 0.033mol), stir at normal temperatures after 12 hours and filter, be spin-dried for filtrate, resistates is through the silicagel column separation and purification, obtain product N-methyl-N-(2-nitrophenyl) Toluidrin (4.2 grams, productive rate 56.1%). 1H?NMR(400MHz，DMSO-d6)δppm?7.92-7.94(dd，1H，J＝1.2Hz，8.0Hz)，7.74-7.81(m，2H)，7.57-7.62(m，1H)，3.27(s，3H)，3.03(s，3H)。
Step B/ intermediate C10:N-(2-aminocarbonyl phenyl)-N-methyl Toluidrin
Toward N-methyl-N-(2-nitrophenyl) Toluidrin (3.90 grams, 0.017mol) methanol/dichloromethane solution (100 milliliters) in add palladium carbon (10%, 1.5 gram), stir after 8 hours and remove by filter catalyzer under atmosphere of hydrogen, be spin-dried for filtrate, resistates obtains product N-(2-aminocarbonyl phenyl)-N-methyl Toluidrin (3.3 grams, productive rate 97.4%) with the ether washing. 1H?NMR(400MHz，DMSO-d6)δppm?7.16-7.18(dd，1H，J＝1.2Hz，7.6Hz)，6.99-7.04(m，1H)，6.72-6.75(dd，1H，J＝1.2Hz，8.0Hz)，6.53-6.57(m，1H)，5.09(br，2H)，3.06(s，3H)，3.02(s，3H)。
intermediate C11
n-(2-(aminomethyl) phenyl)-N-methyl Toluidrin hydrochloride
Figure BPA00001751561000771
Steps A: N-(2-cyano-phenyl)-N-methyl Toluidrin
Figure BPA00001751561000772
Toward cesium carbonate (55.78 grams, add N-methyl Toluidrin (14.0 grams in acetonitrile solution 171mmol) (500 milliliters), 0.128mol) and 2-fluorophenyl acetonitrile (10.37 grams, 86mmol), stir at normal temperatures after 12 hours and filter, be spin-dried for filtrate, the resistates thin up, use dichloromethane extraction.Merge organic phase, use the saturated common salt water washing, anhydrous sodium sulfate drying, filter, and is spin-dried for, and the silicagel column separation obtains product N-(2-cyano-phenyl)-N-methyl Toluidrin (16.0 grams, productive rate 88.9%). 1H?NMR(400MHz，CDCl 3)δppm?7.62-7.73(m，2H)，7.54-7.56(m，1H)，7.45-7.50(m，1H)，3.40(s，3H)，3.14(s，3H)。
Step B/ intermediate C11:N-(2-(aminomethyl) phenyl)-N-methyl Toluidrin hydrochloride
Past N-(2-cyano-phenyl)-N-methyl Toluidrin (16.0 grams, and ammonia methanol solution 76mmol) (500 milliliters, 4molL -1) in add palladium carbon (10%, 4 grams), stir after 24 hours and remove by filter catalyzer under atmosphere of hydrogen, be spin-dried for filtrate, after being dissolved in to ether, resistates blasts hydrogen chloride gas, obtain product N-(2-(aminomethyl) phenyl)-N-methyl Toluidrin hydrochloride (15.0 grams, productive rate 90.4%). 1H?NMR(400MHz，CDCl 3)δppm?7.54-7.55(m，1H)，7.35-7.40(m，1H)，7.28-7.33(m，1H)，7.24-7.26(m，1H)，3.99(br?s，2H)，3.25(s，3H)，2.98(s，3H)。
Universal synthesis method II:6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2, the general synthesis step of 4-diamines
Figure BPA00001751561000781
Steps A: to containing the chloro-7-of 2,4-bis-(4-methoxy-benzyl)-6, in the anhydrous toluene solution of 7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine (vi, intermediate A 1-A4,1.0 equivalents), add respectively amine R 5r 6nH (intermediate B 1-B10,1.0-1.2 equivalent), three (dibenzalacetone) two palladium (Pd 2(dba) 3, 5-20mol%), (±)-BINAP or X-Phos (10-20mol%) and cesium carbonate or potassium tert.-butoxide or sodium tert-butoxide or salt of wormwood (1.5-4.0 equivalent).Mixture is heated to after 100-150 spends a few hours under microwave or in tube sealing be cooled to room temperature, rotary evaporation is removed most of solvent, the resistates acetic acid ethyl dissolution, use the saturated common salt water washing, after anhydrous sodium sulfate drying, filter, rotary evaporation is except desolventizing, and the silicagel column separation obtains the chloro-7-of 4-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine (vii).
Step B: to containing the chloro-7-of 4-(4-methoxy-benzyl)-6, in the anhydrous toluene solution of 7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine (vii, 1.0 equivalents), add respectively amine R 3r 4nH (intermediate C1-C11,1.0-1.2 equivalent), three (dibenzalacetone) two palladium (Pd 2(dba) 3, 5-20mol%), (±)-BINAP or X-Phos (10-20mol%) and cesium carbonate or potassium tert.-butoxide or sodium tert-butoxide or salt of wormwood (1.5-4.0 equivalent).Mixture is heated to after 100-150 spends a few hours under microwave or in tube sealing be cooled to room temperature, rotary evaporation is removed most of solvent, the resistates acetic acid ethyl dissolution, use the saturated common salt water washing, filter after anhydrous sodium sulfate drying, rotary evaporation is except desolventizing, the silicagel column separation obtains 7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2,4 diamines (viii).
Step C: to containing 7-(4-methoxy-benzyl)-6, in the anhydrous trifluoroacetic acid solution of 7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2,4 diamines (viii), carefully add the some vitriol oils.After mixture at room temperature stirs 2-12 hour, use the saturated sodium bicarbonate aqueous solution cancellation.Water is extracted with ethyl acetate, and merges organic phase, use the saturated common salt water washing, and anhydrous sodium sulfate drying filters to be spin-dried for and with the silicagel column separation, obtains 6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2,4 diamines (ix, embodiment 1-37) afterwards.
Embodiment 1
(2-(2-methoxyl group-4-morpholine base phenyl amido)-6, [2,3-d] is phonetic for 7-dihydro-5H-pyrrolo-for 2- pyridine-4-amido)-N-methyl-benzamide
The chloro-N-of steps A: 4-(2-methoxyl group-4-morpholine base phenyl)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine
According to universal synthesis method II, with the chloro-7-of 2,4-bis-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] and pyrimidine (1,200 milligram of intermediate A, 0.65mmol), 2-methoxyl group-4-morpholine aniline (intermediate B 1,160 milligrams, 0.77mmol), Pd 2(dba) 3(30 milligrams, 0.033mmol), (40 milligrams of (±)-BINAP, 0.064mmol) and cesium carbonate (315 milligrams, 0.97mmol) carry out linked reaction, separate and obtain the chloro-N-of product 4-(2-methoxyl group-4-morpholine base phenyl)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine (yellow solid, 100 milligrams, productive rate 32%). 1H?NMR(400MHz，CDCl 3)δppm?8.37-8.39(d，1H，J＝9.6Hz)，7.38(s，1H)，7.21-7.26(m，2H)，6.86-6.88(dd，2H，J＝2.0Hz，6.8Hz)，6.50-6.52(m，2H)，4.54(s，2H)，3.85-3.87(m，7H)，3.80(s，3H)，3.45-3.49(t，2H，J＝8.4Hz)，3.08-3.11(t，4H，J＝4.8Hz)，2.90-2.94(t，2H，J＝8.4Hz)。
Step B:2-(2-(2-methoxyl group-4-morpholine base phenyl amido)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide
According to universal synthesis method II, with the chloro-N-of 4-(2-methoxyl group-4-morpholine base phenyl)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-(100 milligrams of 2-amine, 0.21mmol), 2-amino-N-methyl-benzamide (intermediate C1,40 milligrams, 0.27mmol), Pd 2(dba) 3(10 milligrams, 0.011mmol), (15 milligrams of (±)-BINAP, 0.024mmol) and cesium carbonate (105 milligrams, 0.322mmol) carry out linked reaction, separate and obtain product 2-(2-(2-methoxyl group-4-morpholine base phenyl amido)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide (yellow solid, 60 milligrams, productive rate 48%). 1HNMR(400MHz，CDCl 3)δppm?10.00(s，1H)，8.63-8.65(d，1H，J＝8.0Hz)，8.39-8.41(d，1H，J＝8.8Hz)，7.38-7.40(m，2H)，7.24-7.26(m，1H)，7.19(s，1H)，6.85-6.90(m，3H)，6.526-6.532(d，1H，J＝2.4Hz)，6.47-6.49(dd，1H，J＝2.4Hz，8.8Hz)，6.22(s，1H)，4.52(s，2H)，3.86-3.88(t+s，7H)，380(s，3H)，3.40-3.45(t，2H，J＝8.8Hz)，3.09-3.11(t，4H，J＝4.8Hz)，2.96-2.98(d，3H，J＝5.2Hz)，2.89-2.93(t，2H，J＝8.8Hz)。
Step C:2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide
According to universal synthesis method II, two vitriol oils are added to 2-(2-(2-methoxyl group-4-morpholine base phenyl amido)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-(20 milligrams of N-methyl-benzamides, 0.034mmol) trifluoroacetic acid solution in (1 milliliter), stir after some hours and separate and obtain target product 2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide (yellow solid, 14 milligrams, productive rate 88%). 1H?NMR(400MHz，DMSO-d6)δppm?10.64(s，1H)，8.61-8.63(d，1H，J＝4.8Hz)，8.55-8.57(d，1H，J＝8.0Hz)，7.83-7.85(d，1H，J＝8.8Hz)，7.65-7.67(dd，1H，J＝1.2Hz，8.0Hz)，7.31-7.35(dt，1H，J＝1.2Hz，8.4Hz)，7.14(s，1H)，6.88-6.92(dt，1H，J＝0.8Hz，8.0Hz)，6.605-6.611(d，1H，J＝2.4Hz)，6.56(s，1H)，6.42-6.45(dd，1H，J＝2.4Hz，8.8Hz)，3.80(s，3H)，3.72-3.74(t，4H，J＝4.8Hz)，3.48-3.53(t，2H，J＝8.8Hz)，3.05-3.07(t，4H，J＝4.8Hz)，2.76-2.81(s+t，5H)。
embodiment 2
4-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine dioxa-5-methane amide between-4-amido)-N-methyl benzo [d] [1,3]
Figure BPA00001751561000811
Dioxa-5-methane amide between steps A: 4-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl benzo [d] [1,3]
Figure BPA00001751561000812
According to universal synthesis method II, by 2, the chloro-7-of 4-bis-(4-methoxy-benzyl)-6,7-dihydro-(80 milligrams of 5H-pyrrolo-[2,3-d] pyrimidines, 0.166mmol), dioxa-5-methane amide (intermediate C2,39 milligrams between 4-amino-N-methyl benzo [d] [1,3], 0.201mmol), Pd 2(dba) 3(30 milligrams, 0.033mmol), (16 milligrams of X-Phos, 0.034mmol) and (108 milligrams of cesium carbonates, 0.331mmol) toluene solution be heated to 130 degree stir and within 12 hours, to carry out linked reaction in tube sealing, separate and obtain product 4-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl benzo [d] [1,3] dioxa between-5-methane amide (yellow solid, 20 milligrams, productive rate 19%). 1H?NMR(400MHz，CDCl 3)δppm?8.27-8.29(d，1H，J＝8.8Hz)，7.22-7.27(m，3H)，7.09-7.11(d，1H，J＝8.4Hz)，6.84-6.87(m，2H)，6.65-6.67(d，1H，J＝8.4Hz)，6.48(s，1H)，6.34-6.36(m，2H)，5.90(s，2H)，4.49(s，2H)，3.81-3.87(m，7H)，3.78-3.80(m，3H)，3.37-3.41(t，2H，J＝8.0Hz)，3.07-3.08(m，4H)，2.888-2.891(d，3H，J＝1.2Hz)，2.79-2.83(t，3H，J＝8.0Hz)。
Dioxa-5-methane amide between step B:4-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl benzo [d] [1,3]
According to universal synthesis method II, toward 4-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-6, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido)-N-methyl benzo [d] [1, 3] dioxa between-(20 milligrams of 5-methane amides, 0.031mmol) trifluoroacetic acid solution (5 milliliters) in drip four vitriol oils, separate and obtain target product 4-(2-(2-methoxyl group-4-morpholine phenyl amido)-6 after reaction finishes, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido)-N-methyl benzo [d] [1, 3] dioxa between-5-methane amide (white solid, 6.3 milligram, productive rate 39%). 1H?NMR(400MHz，CDCl 3)δppm?8.29(s，1H)，8.15-8.17(d，1H，J＝8.8Hz)，7.12(s，1H)，7.07-7.09(d，1H，J＝8.0Hz)，6.67-6.69(d，1H，J＝8.0Hz)，6.46-6.47(d，1H，J＝2.4Hz)，6.30-6.33(dd，1H，J＝1.6Hz，8.4Hz)，6.21-6.22(d，1H，J＝4.4Hz)，5.87(s，2H)，4.41(s，1H)，3.85-3.87(t，4H，J＝4.8Hz)，3.82(s，3H)，3.61-3.65(t，2H，J＝8.4Hz)，3.04-3.07(t，4H，J＝4.8Hz)，2.90-2.97(m，5H)。
embodiment 3
((2-(2-methoxyl group-4-morpholine phenyl amido)-6, [2,3-d] is phonetic for 7-dihydro-5H-pyrrolo-for 2- pyridine-4-amido) phenyl) (pyrrolidin-1-yl) ketone
Figure BPA00001751561000831
Steps A: (2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) phenyl) (pyrrolidin-1-yl) ketone
According to universal synthesis method II, by 2, the chloro-7-of 4-bis-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine (120 milligrams, 0.25mmol), (2-aminophenyl) (pyrrolidin-1-yl) methyl ketone hydrochloride (intermediate C3,68 milligrams, 0.30mmol), Pd 2(dba) 3(92 milligrams, 0.101mmol), (62 milligrams of (±)-BINAP, 0.10mmol) and cesium carbonate (325 milligrams, toluene solution 1.0mmol) is heated to 130 degree and stirs 12 hours in tube sealing, is isolated to product (yellow solid, 60 milligrams, productive rate 38%). 1H?NMR(400MHz，CDCl 3)δppm?8.61(s，1H)，8.45-8.47(d，1H，J＝8.4Hz)，8.37-8.39(d，1H，J＝8.8Hz)，7.32-7.38(m，2H)，7.23-7.24(m，2H)，6.92-6.95(t，1H，J＝7.2Hz)，6.85-6.87(d，2H，J＝8.4Hz)，6.525-6.531(d，1H，J＝2.4Hz)，6.46-6.49(dd，1H，J＝2.4Hz，8.4Hz)，4.52(s，2H)，3.86-3.88(s+m，7H)，3.80(s，3H)，3.61-3.64(t，2H，J＝7.2Hz)，3.52-3.53(m，2H)，3.39-3.43(t，2H，J＝7.6Hz)，3.09-3.11(t，4H，J＝4.8Hz)，2.80-2.84(t，2H，J＝8.4Hz)，1.94-1.96(m，2H)，1.85-1.86(m，2H)。
Step B:(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) phenyl) (pyrrolidin-1-yl) methyl ketone
According to universal synthesis method II, toward (2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-6, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido) phenyl) (80 milligrams of (pyrrolidin-1-yl) ketones, 0.126mmol) trifluoroacetic acid solution (6 milliliters) in add five vitriol oils, under normal temperature, stir some hours, obtain target product through aftertreatment with separating, (2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido) phenyl) (pyrrolidin-1-yl) methyl ketone (white solid, 56 milligrams, productive rate 86%). 1H?NMR(400MHz，DMSO-d6)δppm?8.58(s，1H)，8.08-8.10(d，1H，J＝8.0Hz)，7.89-7.91(d，1H，J＝8.8Hz)，7.39-7.41(d，1H，J＝7.6Hz)，7.30-7.32(m，1H)，7.06(s，1H)，6.96-6.99(t，1H，J＝7.6Hz)，6.59-6.60(d，1H，J＝2.0Hz)，6.55(s，1H)，6.37-6.40(dd，1H，J＝2.4Hz，8.8Hz)，3.79(s，3H)，3.71-3.73(t，4H，J＝4.4Hz)，3.44-3.49(m，6H)，3.02-3.05(t，4H，J＝4.4Hz)，2.67-2.71(t，2H，J＝8.4Hz)，1.74-1.83(m，4H)。
embodiment 4
2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine -4-amido)-N-methyl benzenesulfonamide
Steps A: 2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl benzenesulfonamide
Figure BPA00001751561000851
According to universal synthesis method II, by the chloro-7-of 2,4-bis-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] and pyrimidine (100 milligrams, 0.208mmol), 2-amino-N-methyl benzenesulfonamide (intermediate C4,46 milligrams, 0.25mmol), Pd 2(dba) 3(38 milligrams, 0.042mmol), (26 milligrams of (±)-BINAP, 0.042mmol) and (136 milligrams of cesium carbonates, 0.416mmol) toluene solution be heated to 130 degree stir 24 hours in tube sealing, be isolated to product 2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl benzenesulfonamide (94 milligrams, productive rate 72%).
Step B:2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl benzenesulfonamide
According to universal synthesis method II, toward 2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-(94 milligrams of N-methyl benzenesulfonamides, 0.149mmol) trifluoroacetic acid solution (10 milliliters) in add 6 vitriol oils, obtain target product 2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6 through aftertreatment and separation and purification, 7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl benzenesulfonamide (white solid, 65 milligrams, productive rate 70%). 1H?NMR(400MHz，DMSO-d6)δppm?8.49(m，1H)，8.32(s，1H)，7.75-7.78(m，2H)，7.69-7.71(d，1H，J＝8.0Hz)，7.47-7.51(t，1H，J＝7.6Hz)，7.27(s，1H)，7.07(m，1H)，6.75(s，1H)，6.63-6.64(d，1H，J＝2.8Hz)，6.43-6.46(dd，1H，J＝2.4Hz，8.8Hz)，3.81(s，3H)，3.74-3.76(m，4H)，3.51-3.55(t，2H，J＝8.4Hz)，3.07-3.09(t，4H，J＝4.8Hz)，2.77-2.81(t，2H，J＝8.0Hz)，2.42-2.43(d，3H，J＝5.2Hz)。
embodiment 5
2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine -4-amido)-N-propylbenzene sulphonamide
Figure BPA00001751561000861
Steps A: 2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-propylbenzene sulphonamide
Figure BPA00001751561000862
According to universal synthesis method II, by the chloro-7-of 2,4-bis-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] and pyrimidine (100 milligrams, 0.207mmol), 2-amino-N-propylbenzene sulfonamide hydrochloride (intermediate C6,62 milligrams, 0.247mmol), Pd 2(dba) 3(38 milligrams, 0.042mmol), (26 milligrams of (±)-BINAP, 0.042mmol) and (271 milligrams of cesium carbonates, 0.831mmol) toluene solution be heated to 130 degree and stir 12 hours in tube sealing, obtain product 2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-6 through separation and purification, 7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-propylbenzene sulphonamide (40 milligrams of yellow solids, productive rate 29%). 1H?NMR(400MHz，CDCl 3)δppm?8.31-8.35(m，2H)，7.92(s，1H)，7.84-7.86(dd，1H，J＝1.2Hz，8.0Hz)，7.49-7.53(m，1H)，7.23-7.26(m，3H)，7.05-7.09(m，1H)，6.85-6.88(m，2H)，6.52-6.53(d，1H，J＝2.8Hz)，6.40-6.43(dd，1H，J＝2.8Hz，8.8Hz)，4.60-4.63(t，1H，J＝6.0Hz)，4.52(s，2H)，3.86-3.89(m，7H)，3.80(s，3H)，3.41-3.45(t，2H，J＝8.4Hz)，3.08-3.11(m，4H)，2.78-2.87(m，4H)，1.37-1.43(m，2H)，0.75-0.79(t，3H，J＝7.2Hz)。
Step B:2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-propylbenzene sulphonamide
According to universal synthesis method II, toward 2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-6, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido)-(40 milligrams of N-propylbenzene sulphonamide, 0.061mmol) trifluoroacetic acid solution (4 milliliters) in add 3 vitriol oils, stir at normal temperatures some hours, obtain target product 2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6 through aftertreatment and separation and purification, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido)-N-propylbenzene sulphonamide (white solid, 16 milligrams, productive rate 48%). 1HNMR(400MHz，DMSO-d6)δppm8.42-8.44(d，1H，J＝8.8Hz)，8.28(s，1H)，7.84-7.85(m，1H)，7.77-7.79(d，1H，J＝8.8Hz)，7.68-7.70(d，1H，J＝7.6Hz)，7.43-7.45(m，1H)，7.22(s，1H)，7.02-7.06(t，1H，J＝7.6Hz)，6.71(s，1H)，6.60-6.61(d，1H，J＝2.4Hz)，6.40-6.42(dd，1H，J＝2.4Hz，8.8Hz)，3.79(s，3H)，3.71-3.74(m，4H)，3.49-3.53(m，2H)，3.04-3.06(m，4H)，2.76-2.80(t，2H，J＝8.4Hz)，2.68-2.73(m，2H)，1.30-1.35(m，2H)，0.70-0.73(t，3H，J＝7.6Hz)。
embodiment 6
n-cyclobutyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo- [2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561000871
Steps A: N-cyclobutyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561000881
According to universal synthesis method II, by the chloro-7-of 2,4-bis-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] and pyrimidine (100 milligrams, 0.208mmol), 2-amino-N-cyclobutyl benzsulfamide (intermediate C11,56 milligrams, 0.248mmol), Pd 2(dba) 3(38 milligrams, 0.042mmol), (20 milligrams of X-Phos, 0.042mmol) and cesium carbonate (136 milligrams, toluene solution 0.416mmol) is heated to 130 degree and stirs 12 hours in tube sealing, through separation and purification, obtains product N-cyclobutyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide (white solid, 100 milligrams, productive rate 71%). 1H?NMR(400MHz，CDCl 3)δppm?8.28-8.35(dd，2H，J＝8.8Hz，19.2Hz)，7.83-7.89(m，2H)，7.48-7.52(t，1H，J＝8.0Hz)，7.25-7.27(m，3H)，7.04-7.08(t，1H，J＝7.6Hz)，6.86-6.88(m，2H)，6.53(s，1H)，6.38-6.40(d，1H，J＝8.8Hz)，4.87-4.89(d，1H，J＝8.8Hz)，4.54(s，2H)，3.86-3.89(m，7H)，3.80(s，3H)，3.71-3.73(m，1H)，3.43-3.47(t，2H，J＝8.4Hz)，3.08-3.10(m，4H)，2.80-2.84(t，2H，J＝8.0Hz)，1.95-2.02(m，2H)，1.69-1.76(m，2H)，1.45-1.52(m，2H)。
Step B:N-cyclobutyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
According to universal synthesis method II, toward N-cyclobutyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-6, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido) (100 milligrams of benzsulfamides, 0.181mmol) trifluoroacetic acid solution (6 milliliters) add 5 vitriol oils, stir at normal temperatures some hours, obtain target product N-cyclobutyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6 through aftertreatment and separation and purification, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido) benzsulfamide (white solid, 39.8 milligram, productive rate 49%). 1H?NMR(400MHz，DMSO-d6)δppm8.42-8.44(d，1H，J＝8.4Hz)，8.30(s，1H)，8.18-8.20(d，1H，J＝8.8Hz)，7.80-7.82(d，1H，J＝8.4Hz)，7.70-7.72(dd，1H，J＝1.6Hz，8.0Hz)，7.44-7.48(m，1H)，7.02-7.06(m，1H)，6.75(s，1H)，6.62-6.63(d，1H，J＝2.4Hz)，6.40-6.43(dd，1H，J＝2.4Hz，9.2Hz)，3.81(s，3H)，3.73-3.76(t，4H，J＝4.4Hz)，3.52-3.61(m，3H)，3.06-3.08(t，4H，J＝4.8Hz)，2.78-2.83(t，2H，J＝8.8Hz)，1.87-1.90(m，2H)，1.73-1.87(m，2H)，1.45-1.49(m，2H)。
embodiment 7
n-cyclopentyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo- [2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561000891
Steps A: N-cyclopentyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
According to universal synthesis method II, by the chloro-7-of 2,4-bis-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] and pyrimidine (80 milligrams, 0.166mmol), 2-amino-N-cyclopentyl benzsulfamide (intermediate C12,48 milligrams, 0.20mmol), Pd 2(dba) 3(30 milligrams, 0.033mmol), (16 milligrams of X-Phos, 0.034mmol) and cesium carbonate (108 milligrams, toluene solution 0.331mmol) is heated to 130 degree and stirs 12 hours in tube sealing, through separation and purification, obtains product N-cyclopentyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide (white solid, 90 milligrams, productive rate 79%). 1H?NMR(400MHz，CDCl 3)δppm?8.32-8.34(d，1H，J＝8.8Hz)，8.23-8.25(d，1H，J＝8.4Hz)，7.87-7.89(dd，1H，J＝1.2Hz，8.0Hz)，7.82(s，1H)，7.49-7.53(t，1H，J＝8.0Hz)，7.25-7.26(m，3H)，7.07-7.11(t，1H，J＝8.0Hz)，6.86-6.88(m，2H)，6.52(s，1H)，6.38-6.40(d，1H，J＝8.8Hz)，4.53-4.57(m，3H)，3.86-3.89(m，7H)，3.80(s，3H)，3.53-3.54(m，1H)，3.42-3.46(t，2H，J＝8.4Hz)，3.08-3.10(t，4H，J＝3.6Hz)，2.79-2.83(t，2H，J＝8.4Hz)，1.65-1.71(m，2H)，1.49-1.50(m，2H)，1.36-1.40(m，2H)，1.24-1.31(m，2H)。
Step B:N-cyclopentyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
According to universal synthesis method II, toward N-cyclopentyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-6, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido) (100 milligrams of benzsulfamides, 0.146mmol) trifluoroacetic acid solution (6 milliliters) in add 5 vitriol oils, stir at normal temperatures some hours, obtain target product N-cyclopentyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6 through aftertreatment and separation and purification, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido) benzsulfamide (19.6 milligrams of white solids, productive rate 24%). 1H?NMR(400MHz，DMSO-d6)δppm8.39-8.41(d，1H，J＝8.4Hz)，8.29(s，1H)，7.87-7.89(d，1H，J＝8.0Hz)，7.80-7.82(d，1H，J＝8.8Hz)，7.73-7.75(dd，1H，J＝1.6Hz，8.0Hz)，7.46-7.47(m，1H)，7.24(s，1H)，7.03-7.07(t，1H，J＝7.6Hz)，6.75(s，1H)，6.62-6.63(d，1H，J＝2.4Hz)，6.40-6.43(dd，1H，J＝2.4Hz，8.8Hz)，3.81(s，3H)，3.73-3.76(t，4H，J＝5.2Hz)，3.51-3.55(t，2H，J＝8.4Hz)，3.43-3.44(m，1H)，3.05-3.08(t，4H，J＝4.8Hz)，2.77-2.81(t，2H，J＝8.4Hz)，1.48-1.60(m，4H)，1.24-1.35(m，4H)。
Figure BPA00001751561000901
Steps A: N-cyclohexyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561000911
According to universal synthesis method II, by the chloro-7-of 2,4-bis-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] and pyrimidine (80 milligrams, 0.166mmol), 2-amino-N-cyclohexyl benzene sulfonamide (intermediate C13,51 milligrams, 0.201mmol), Pd 2(dba) 3(30 milligrams, 0.033mmol), (16 milligrams of X-Phos, 0.034mmol) and cesium carbonate (108 milligrams, toluene solution 0.331mmol) is heated to 130 degree and stirs 12 hours in tube sealing, through separation and purification, obtains product N-cyclohexyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide (white solid, 100 milligrams, productive rate 86%). 1HNMR(400MHz，CDCl 3)δppm?8.31-8.33(d，1H，J＝8.0Hz)，8.20-8.21(m，1H)，7.87-7.89(dd，1H，J＝1.6Hz，8.0Hz)，7.81(s，1H)，7.48-7.52(dt，1H，J＝1.2Hz，8.8Hz)，7.24-7.26(m，3H)，7.06-7.10(m，1H)，6.85-6.88(dd，1H，J＝2.0Hz，6.8Hz)，6.516-6.523(d，1H，J＝2.8Hz)，6.36-6.39(dd，1H，J＝2.8Hz，8.8Hz)，4.58-4.60(d，1H，J＝7.6Hz)，4.53(s，2H)，3.85-3.88(m，7H)，3.80(s，3H)，3.41-3.45(t，2H，J＝8.4Hz)，3.07-3.10(m，5H)，2.79-2.83(t，2H，J＝8.4Hz)，1.66-1.68(m，2H)，1.50-1.53(m，2H)，1.24-1.29(m，1H)，1.00-1.14(m，5H)。
Step B:N-cyclohexyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
According to universal synthesis method II, toward N-cyclohexyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-6, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido) (90 milligrams of benzsulfamides, 0.129mmol) trifluoroacetic acid solution (5 milliliters) add 4 vitriol oils, stir at normal temperatures some hours, obtain target product N-cyclohexyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6 through aftertreatment and separation and purification, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido) benzsulfamide (white solid, 20.1 milligram, productive rate 27%). 1H?NMR(400MHz，DMSO-d6)δppm8.32-8.34(d，1H，J＝7.6Hz)，8.23(s，1H)，7.82-7.88(m，2H)，7.75-7.77(m，1H)，7.46-7.48(m，1H)，7.22(s，1H)，7.05-7.09(t，1H，J＝7.6Hz)，6.75(s，1H)，6.63(s，1H)，6.39-6.42(d，1H，J＝8.8Hz)，3.81(s，3H)，3.75-3.76(m，4H)，3.51-3.55(t，2H，J＝8.4Hz)，3.07-3.08(m，4H)，2.95-2.96(m，1H)，2.78-2.82(t，2H，J＝8.0Hz)，1.52-1.54(m，4H)，1.40-1.42(m，1H)，0.99-1.08(m，4H)，0.84-0.86(m，1H)。
embodiment 9
n-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) phenyl) ethanamide
Figure BPA00001751561000921
Steps A: N-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) phenyl) ethanamide
Figure BPA00001751561000922
According to universal synthesis method II, by the chloro-7-of 2,4-bis-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] and pyrimidine (120 milligrams, 0.25mmol), N-(2-aminophenyl) ethanamide (intermediate C14,41 milligrams, 0.27mmol), Pd 2(dba) 3(46 milligrams, 0.05mmol), (31 milligrams of (±)-BINAP, 0.05mmol) and (163 milligrams of cesium carbonates, 0.5mmol) toluene solution be heated to 130 degree and stir 24 hours in tube sealing, obtain product N-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2 through separation and purification, 3-d] pyrimidine-4-amido) phenyl) ethanamide (108 milligrams, productive rate 51%).
Step B:N-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) phenyl) ethanamide
According to universal synthesis method II, toward N-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) phenyl) (60 milligrams of ethanamides, 0.1mmol) trifluoroacetic acid solution (10 milliliters) in add 5 vitriol oils, stir at normal temperatures some hours, obtain target product (white solid through aftertreatment and separation and purification, 10 milligrams, productive rate 21%). 1H?NMR(400MHz，DMSO-d6)δppm?9.75(s，1H)，7.72-7.76(br，1H)，7.42-7.54(m，3H)，7.20(m，3H)，6.63(s，1H)，6.38(br?s，1H)，3.81(s，3H)，3.73-3.74(m，5H)，3.52(s，3H)，3.08(m，4H)，2.06(s，3H)。
embodiment 10
n-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) phenyl)-N-methyl Toluidrin
Figure BPA00001751561000931
Steps A: N-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) phenyl)-N-methyl Toluidrin
According to universal synthesis method II, by the chloro-7-of 2,4-bis-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] and pyrimidine (100 milligrams, 0.208mmol), N-(2-aminophenyl)-N-methyl Toluidrin (intermediate C15,50 milligrams, 0.25mmol), Pd 2(dba) 3(38 milligrams, 0.042mmol), (26 milligrams of (±)-BINAP, 0.042mmol) and (271 milligrams of cesium carbonates, 0.831mmol) toluene solution be heated to 130 degree and stir 12 hours in tube sealing, obtain product N-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-6 through separation and purification, 7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) phenyl)-N-methyl Toluidrin (white solid, 70 milligrams, productive rate 52%). 1H?NMR(400MHz，CDCl 3)δppm?8.36-8.41(dd，2H，J＝8.4Hz，13.2Hz)，7.31-7.33(m，2H)，7.27-7.28(m，3H)，7.15(s，1H)，6.99-7.02(m，1H)，6.86-6.88(m，2H)，6.53(s，1H)，6.45-6.47(d，1H，J＝8.8Hz)，4.52(s，2H)，3.87-3.88(m，7H)，3.79(s，3H)，3.40-3.45(t，2H，J＝8.8Hz)，3.26-3.27(d，3H，J＝1.6Hz)，3.09-3.11(m，4H)，2.969-2.973(d，3H，J＝1.6Hz)，2.82-2.86(t，2H，J＝8.0Hz)。
Step B:N-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) phenyl)-N-methyl Toluidrin
According to universal synthesis method II, toward N-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-6, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido) phenyl)-(70 milligrams of N-methyl Toluidrins, 0.108mmol) trifluoroacetic acid solution (6 milliliters) in add 5 vitriol oils, stir at normal temperatures some hours, obtain target product N-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6 through aftertreatment and separation and purification, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido) phenyl)-N-methyl Toluidrin (white solid, 36.4 milligram, productive rate 64%). 1H?NMR(400MHz，DMSO-d6)δppm?8.13(m，1H)，7.79(m，1H)，7.51(m，1H)，7.04-7.29(m，4H)，6.61-6.63(m，2H)，6.22(m，1H)，3.81(s，3H)，3.73-3.76(t，4H，J＝4.8Hz)，3.50-3.54(t，2H，J＝7.6Hz)，3.17(s，3H)，3.07-3.08(m，7H)，2.71-2.72(m，3H)。
embodiment 11
n-(2-((2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) methyl) phenyl)-N-methyl Toluidrin
Steps A: N-(2-((2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) methyl) phenyl)-N-methyl Toluidrin
Figure BPA00001751561000952
According to universal synthesis method II, by 2, the chloro-7-of 4-bis-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine (120 milligrams, 0.25mmol), N-(2-(amino methyl) phenyl)-N-methyl Toluidrin hydrochloride (intermediate C16,62 milligrams, 0.25mmol), Pd 2(dba) 3(23 milligrams, 0.025mmol), (31 milligrams of X-Phos, 0.05mmol) and (325 milligrams of cesium carbonates, 1.0mmol) toluene solution be heated to 130 degree and stir 24 hours in tube sealing, obtain product N-(2-((2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-6 through separation and purification, 7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) methyl) phenyl)-N-methyl Toluidrin (white solid, 20 milligrams, productive rate 12%).
Step B:N-(2-((2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) methyl) phenyl)-N-methyl Toluidrin
According to universal synthesis method II, toward N-(2-((2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-6, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido) methyl) phenyl)-(20 milligrams of N-methyl Toluidrins, 0.303mmol) trifluoroacetic acid solution (4 milliliters) in add 1 vitriol oil, stir at normal temperatures some hours, obtain target product N-(2-((2-(2-methoxyl group-4-morpholine phenyl amido)-6 through aftertreatment and separation and purification, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido) methyl) phenyl)-N-methyl Toluidrin (white solid, 0.63 milligram, productive rate 4%). 1H?NMR(400MHz，CD 3OD)δppm?7.92-7.94(d，1H，J＝8.0Hz)，7.78-7.81(m，1H)，7.58-7.62(m，1H)，7.46-7.53(m，2H)，7.33-7.35(m，2H)，6.58-6.60(m，1H)，6.35-6.37(d，1H，J＝8.8Hz)，4.56(s，1H)，3.81-3.85(m，7H)，3.56-3.63(m，3H)，3.18(m，2H)，3.04-3.05(m，7H)，2.80-2.84(t，2H，J＝8.4Hz)。
embodiment 12
n 2 -(2-methoxyl group-4-morpholine phenyl)-N 4 -(6-picoline-2-yl)-6,7-dihydro-5H- pyrrolo-[2,3-d] pyrimidine-2, the 4-diamines
Figure BPA00001751561000961
Steps A: N 2-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-N 4-(6-picoline-2-yl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2,4-diamines
Figure BPA00001751561000962
According to universal synthesis method II, by the chloro-7-of 2,4-bis-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine (100 milligrams, 0.208mmol), 6-picoline-2-amine (29 milligrams, 0.266mmol), Pd 2(dba) 3(21 milligrams, 0.022mmol), (±)-BINAP (28 milligrams, 0.044mmol) and cesium carbonate (144 milligrams, toluene solution 0.44mmol) in tube sealing with microwave heating to 125 degree and stir 4 hours, obtain product N after separation and purification 2-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-N 4-(6-picoline-2-yl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2,4-diamines (40 milligrams, productive rate 33%). 1H?NMR(400MHz，CDCl 3)δppm?7.98-8.00(d，1H，J＝8.4Hz)，7.84(br，1H)，7.47-7.51(t，1H，J＝8.0Hz)，7.39-7.43(t，1H，J＝8.0Hz)，7.20-7.22(m，3H)，6.86-6.88(m，2H)，6.65-6.67(m，1H)，6.59-6.61(m，1H)，6.46-6.52(m，3H)，5.89(br?s，2H)，4.52(s，2H)，3.86-3.89(m，6H)，3.80(s，3H)，3.48-3.53(m，3H)，3.14-3.16(m，6H)，2.07-2.11(m，3H)。
Step B:N 2-(2-methoxyl group-4-morpholine phenyl)-N 4-(6-picoline-2-yl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2,4-diamines
According to universal synthesis method II, toward N 2-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-N 4-(6-picoline-2-yl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2, (40 milligrams of 4-diamines, 72.3mmmol) trifluoroacetic acid solution (5 milliliters) in add 2 vitriol oils, stir at normal temperatures some hours, obtain target product N through aftertreatment and separation and purification 2-(2-methoxyl group-4-morpholine phenyl)-N 4-(6-picoline-2-yl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2,4-diamines (white solid, 3.6 milligrams, productive rate 11.5%). 1H?NMR(400MHz，CDCl 3)δppm8.02-8.04(d，2H，J＝8.4Hz)，7.50-7.51(m，1H)，7.19(br?s，1H)，6.71-6.73(d，1H，J＝7.2Hz)，6.48-6.51(m，2H)，3.84-3.88(m，7H)，3.64-3.68(t，2H，J＝8.0Hz)，3.05-3.12(m，6H)，2.31(br，3H)。
embodiment 13
n 4 -(3,4-difluorophenyl)-N 2 -(2-methoxyl group-4-morpholine phenyl)-6,7-dihydro-5H-pyrrole cough up also [2,3-d] pyrimidine-2, the 4-diamines
Figure BPA00001751561000981
Steps A: N 4-(3,4-difluorophenyl)-N 2-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2,4-diamines
Figure BPA00001751561000982
According to universal synthesis method II, by the chloro-7-of 2,4-bis-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine (90 milligrams, 0.187mmol), 3,4-difluoroaniline (29 milligrams, 0.225mmol), Pd 2(dba) 3(34 milligrams, 0.037mmol), (±)-BINAP (23 milligrams, 0.037mmol) and cesium carbonate (122 milligrams, toluene solution 0.374mmol) is heated to 130 degree and stirs 12 hours in tube sealing, through separation and purification, obtains product N 4-(3,4-difluorophenyl)-N 2-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2,4-diamines (yellow solid, 46 milligrams, productive rate 43%). 1H?NMR(400MHz，CDCl 3)δppm?8.29-8.31(d，1H，J＝8.8Hz)，7.57-7.58(m，1H)，7.23-7.26(m，2H)，7.15(s，1H)，7.01-7.06(m，1H)，6.92-6.94(m，1H)，6.85-6.87(m，2H)，6.49-6.53(dt，2H，J＝2.4Hz，8.4Hz)，5.82(s，1H)，4.52(s，2H)，3.86-3.89(m，7H)，3.80(s，3H)，3.37-3.42(t，2H，J＝8.8Hz)，3.10-3.12(t，4H，J＝4.8Hz)，2.66-2.71(t，2H，J＝8.4Hz)。
Step B:N 4-(3,4-difluorophenyl)-N 2-(2-methoxyl group-4-morpholine phenyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2,4-diamines
According to universal synthesis method II, toward N 4-(3,4-difluorophenyl)-N 2-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2, (46 milligrams of 4-diamines, 0.080mmol) trifluoroacetic acid solution (5 milliliters) and three stir at normal temperatures some hours, obtain target product N through aftertreatment and separation and purification 4-(3,4-difluorophenyl)-N 2-(2-methoxyl group-4-morpholine phenyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2,4-diamines (white solid, 2.9 milligrams, productive rate 8%). 1H?NMR(400MHz，DMSO-d6)δppm?8.27(s，1H)，7.82-7.87(m，1H)，7.72-7.74(d，1H，J＝8.8Hz)，7.19-7.25(m，2H)，7.12(s，1H)，6.596-6.603(d，1H，J＝2.8Hz)，6.40-6.41(d，1H，J＝2.4Hz)，6.38-6.41(dd，1H，J＝2.4Hz，8.8Hz)，3.78(s，3H)，3.71-3.74(m，4H)，3.43-3.47(m，2H)，3.03-3.05(t，4H，J＝4.8Hz)，2.79-2.83(t，2H，J＝8.4Hz)。
embodiment 14
2-(2-(2-(methylol)-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide
Figure BPA00001751561000991
Steps A: N-(2-((tertiary butyl dimethyl-silicon alcoxyl base) methyl)-4-morpholine phenyl)-chloro-7-of 4-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine
Figure BPA00001751561000992
According to universal synthesis method II, by 2, the chloro-7-of 4-bis-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine (intermediate A 1,1g, 3.2mmol), 2-((tertiary butyl dimethyl-silicon alcoxyl base) methyl)-4-morpholine aniline (intermediate B 2,1.14g, 3.5mmol), Pd 2(dba) 3(146 milligrams, 0.16mmol), (200 milligrams of (±)-BINAP, 0.32mmol) and cesium carbonate (2.08g, 6.2mmol) toluene solution be heated to 110 degree and stir 6 hours under microwave, obtain product N-(2-((tertiary butyl dimethyl-silicon alcoxyl base) methyl)-4-morpholine phenyl)-chloro-7-of 4-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2 through separation and purification, 3-d] pyrimidine-2-amine (0.5g, productive rate 26.3%).
Step B:2-(2-(2-((tertiary butyl dimethyl-silicon alcoxyl base) methyl)-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide
Figure BPA00001751561001001
According to universal synthesis method II, by N-(2-((tertiary butyl dimethyl-silicon alcoxyl base) methyl)-4-morpholine phenyl)-chloro-7-of 4-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-(500 milligrams of 2-amine, 0.84mmol), 2-amino-N-methyl-benzamide (intermediate C1,151 milligrams, 1mmol), Pd 2(dba) 3(192 milligrams, 0.21mmol), (200 milligrams of X-Phos, 0.42mmol) and (546 milligrams of cesium carbonates, 1.7mmol) toluene solution be heated to 140 degree and stir 4 hours under microwave, obtain product 2-(2-(2-((tertiary butyl dimethyl-silicon alcoxyl base) methyl)-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-6 through separation and purification, 7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide (417 milligrams, productive rate 68.8%). 1H?NMR(400MHz，DMSO-d6)δppm?10.79(s，1H)，8.57-8.61(m，2H)，8.02(s，1H)，7.63-7.71(m，2H)，7.21-7.23(m，3H)，6.96-6.97(d，1H，J＝2.8Hz)，6.85-6.91(m，4H)，4.72(s，2H)，4.41(s，2H)，3.74-3.77(s+m，7H)，3.32-3.42(m，2H)，3.05-3.07(t，4H，J＝4.8Hz)，2.75-2.79(s+m，5H)，0.89(s，9H)，0.06(s，6H)。
Step C:2-(2-(2-(methylol)-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide
According to universal synthesis method II, toward 2-(2-(2-((tertiary butyl dimethyl-silicon alcoxyl base) methyl)-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-6, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido)-(200 milligrams of N-methyl-benzamides, 0.282mmol) trifluoroacetic acid solution (2 milliliters) in add 4 vitriol oils, stir at normal temperatures some hours, obtain target product 2-(2-(2-(methylol)-4-morpholine phenyl amido)-6 through aftertreatment and separation and purification, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido)-(30 milligrams of N-methyl-benzamides, productive rate 22.4%). 1H?NMR(400MHz，DMSO-d6)δppm?10.69(s，1H)，8.56-8.58(m，2H)，7.94(s，1H)，7.61-7.63(d，1H，J＝6.0Hz)，7.54-7.57(d，1H，J＝8.8Hz)，7.20-7.22(m，1H)，6.92-6.93(d，1H，J＝2.8Hz)，6.80-6.88(m，2H)，6.51(s，1H)，5.21-5.23(t，1H，J＝5.6Hz)，4.45-4.46(d，2H，J＝5.2Hz)，3.73-3.75(t，4H，J＝4.8Hz)，3.45-3.51(m，2H)，3.03-3.06(t，4H，J＝4.8Hz)，2.76-2.80(m，5H)。
embodiment 15
2-(2-(2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] bis-Evil-5-amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide
Figure BPA00001751561001011
The chloro-N-of steps A: 4-(2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] bis-Evil-5-yl)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine
Figure BPA00001751561001012
According to universal synthesis method II, by the chloro-7-of 2,4-bis-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine (intermediate A 1,310 milligrams, 1.0mmol), 2,3-dihydrobenzo [b] [1,4] bis-Evil-5-amine (3,151 milligrams of intermediate B, 1.0mmol), Pd 2(dba) 3(183 milligrams, 0.2mmol), (±)-BINAP (124 milligrams, 0.2mmol) and (192 milligrams of sodium tert-butoxides, 2.0mmol) toluene solution be heated to 100 degree and stir 10 minutes under microwave, obtain the chloro-N-of product 4-(2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] bis-Evil-5-yl)-7-(4-methoxy-benzyl)-6 through separation and purification, 7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine (yellow solid, 100 milligrams, productive rate 24%). 1H?NMR(400MHz，CDCl 3)δppm?8.10-8.12(dd，1H，J＝1.2Hz，8.4Hz)，7.22-7.24(d，2H，J＝8.8Hz)，6.86-6.88(dd，2H，J＝2.0Hz，6.8Hz)，6.78-6.83(t，1H，J＝8.4Hz)，6.51-6.53(dd，1H，J＝1.2Hz，8.0Hz)，6.31-6.33(d，1H，J＝8.0Hz)，4.54(s，2H)，4.25-4.32(m，7H)，3.80(s，3H)，3.47-3.51(t，2H，J＝8.4Hz)，2.91-2.96(t，2H，J＝8.4Hz)。
Step B:2-(2-(2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] bis-Evil-5-amido)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide
Figure BPA00001751561001021
According to universal synthesis method II, by the chloro-N-(2 of 4-, 3-dihydrobenzo [b] [Isosorbide-5-Nitrae] bis-Evil-5-yl)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-(100 milligrams of 2-amine, 0.236mmol), 2-amino-N-methyl-benzamide (intermediate C1,42 milligrams, 0.280mmol), Pd 2(dba) 3(43 milligrams, 0.047mmol), (22 milligrams of X-Phos, 0.046mmol) and (154 milligrams of cesium carbonates, 0.472mmol) toluene solution be heated to 130 degree and stir 12 hours in tube sealing, (2-(2 to obtain product 2-through separation and purification, 3-dihydrobenzo [b] [1,4] bis-Evil-5-amido)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide (yellow solid, 50 milligrams, productive rate 39%). 1H?NMR(400MHz，CDCl 3)δppm?10.03(s，1H)，8.62-8.64(d，1H，J＝8.4Hz)，8.12-8.14(dd，1H，J＝0.8Hz，8.0Hz)，7.39-7.42(m，2H)，7.22-7.26(m，2H)，6.85-6.91(m，3H)，6.74-6.79(t，1H，J＝8.4Hz)，6.48-6.50(dd，1H，J＝1.6Hz，8.4Hz)，6.21-6.22(m，1H)，4.52(s，2H)，4.33-4.35(m，2H)，4.26-4.28(m，2H)，3.78(s，3H)，3.42-3.46(t，2H，J＝8.4Hz)，2.971-2.974(d，3H，J＝1.2Hz)，2.90-2.94(t，2H，J＝8.4Hz)。
Step C:2-(2-(2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] bis-Evil-5-amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide
According to universal synthesis method II, toward 2-, (2-(2, 3-dihydrobenzo [b] [1, 4] bis-Evil-5-amido)-7-(4-methoxy-benzyl)-6, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido)-(60 milligrams of N-methyl-benzamides, 0.115mmol) trifluoroacetic acid solution (6 milliliters) in add 4 vitriol oils, stir at normal temperatures some hours, (2-(2 to obtain target product 2-through aftertreatment and separation and purification, 3-dihydrobenzo [b] [1, 4] bis-Evil-5-amido)-6, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido)-(27 milligrams of N-methyl-benzamides, productive rate 69%). 1h NMR (400MHz, DMSO-d6) δ ppm9.18 (s, 1H), 8.67 (s, 1H), 7.68-7.70 (d, 1H, J=7.6Hz), (7.36-7.38 m, 2H), 7.15-7.16 (m, 1H), (6.78-6.85 m, 2H), 6.74-6.76 (m, 1H), (6.21-6.32 m, 4H), 2.78-2.79 (d, 3H, J=4.4Hz), benzo [b] [(CH on Isosorbide-5-Nitrae] bis-Evil ring 2cH 2-) signal covered by the remaining peak of deuterated solvent.
embodiment 16
n-methyl-2-(2-(8-morpholine-2, and 3-dihydrobenzo [b] [Isosorbide-5-Nitrae] bis-Evil-5-amido)-6,7- dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzamide
Figure BPA00001751561001031
The chloro-7-of steps A: 4-(4-methoxy-benzyl)-N-(8-morpholine-2, and 3-dihydrobenzo [b] [Isosorbide-5-Nitrae] bis-Evil-5-yl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine
Figure BPA00001751561001041
According to universal synthesis method II, by the chloro-7-of 2,4-bis-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] and pyrimidine (1,200 milligram of intermediate A, 0.645mmol), 8-morpholine-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] bis-Evil-5-amine (4,152 milligrams of intermediate B, 0.644mmol), Pd 2(dba) 3(118 milligrams, 0.129mmol), (80 milligrams of (±)-BINAP, 0.129mmol) and (124 milligrams of sodium tert-butoxides, 1.292mmol) toluene solution be heated to 100 degree and stir 10 minutes under microwave, obtain the chloro-7-of product 4-(4-methoxy-benzyl)-N-(8-morpholine-2 through separation and purification, 3-dihydrobenzo [b] [1,4] bis-Evil-5-yl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine (yellow solid, 200 milligrams, productive rate 61%). 1H?NMR(400MHz，CDCl 3)δppm?8.01-8.03(d，1H，J＝8.8Hz)，7.21-7.24(d，2H，J＝8.4Hz)，6.86-6.88(d，2H，J＝8.8Hz)，6.51-6.54(d，1H，J＝8.8Hz)，4.54(s，2H)，4.30-4.34(m，4H)，3.86-3.89(m，4H)，3.80(s，3H)，3.46-3.50(m，2H)，3.00-3.03(m，4H)，2.91-2.95(m，2H)。
Step B:2-(7-(4-methoxy-benzyl)-2-(8-morpholine-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] bis-Evil-5-amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide
According to universal synthesis method II, by the chloro-7-of 4-(4-methoxy-benzyl)-N-(8-morpholine-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] bis-Evil-5-yl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-(200 milligrams of 2-amine, 0.39mmol), 2-amino-N-methyl-benzamide (intermediate C1,71 milligrams, 0.47mmol), Pd 2(dba) 3(72 milligrams, 0.079mmol), (37 milligrams of X-Phos, 0.078mmol) and (274 milligrams of cesium carbonates, 0.840mmol) toluene solution be heated to 130 degree and stir 2 hours under microwave, obtain product 2-(7-(4-methoxy-benzyl)-2-(8-morpholine-2 through separation and purification, 3-dihydrobenzo [b] [1,4] bis-Evil-5-amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide (white solid, 75 milligrams, productive rate 31%). 1H?NMR(400MHz，CDCl 3)δppm?10.03(s，1H)，8.62-8.64(d，1H，J＝8.4Hz)，8.02-8.04(d，1H，J＝8.8Hz)，7.38-7.42(m，2H)，7.23-7.25(m，2H)，7.09(s，1H)，6.85-6.92(m，3H)，6.47-6.50(d，1H，J＝8.8Hz)，6.27-6.29(d，1H，J＝8.4Hz)，4.52(s，2H)，4.27-4.34(m，4H)，3.85-3.90(m，4H)，3.80(s，3H)，3.41-3.45(t，2H，J＝8.4Hz)，3.01-3.03(m，3H)，2.95-2.97(m，4H)，2.89-2.93(t，2H，J＝8.4Hz)。
Step C:N-methyl-2-(2-(8-morpholine-2, and 3-dihydrobenzo [b] [Isosorbide-5-Nitrae] bis-Evil-5-amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzamide
According to universal synthesis method II, by 2-(7-(4-methoxy-benzyl)-2-(8-morpholine-2, 3-dihydrobenzo [b] [1, 4] bis-Evil-5-amido)-6, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido)-(75 milligrams of N-methyl-benzamides, 0.120mmol) trifluoroacetic acid solution (6 milliliters) in add 5 vitriol oils, stir at normal temperatures some hours, obtain target product N-methyl-2-(2-(8-morpholine-2 through aftertreatment and separation and purification, 3-dihydrobenzo [b] [1, 4] bis-Evil-5-amido)-6, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido) (60 milligrams of benzamide, productive rate 99%). 1H?MR(400MHz，DMSO-d6)δppm?11.98(s，1H)，10.68(s，1H)，8.63-8.64(m，2H)，7.66-7.67(d，1H，J＝7.6Hz)，7.47-7.49(d，1H，J＝6.8Hz)，7.33-7.37(t，1H，J＝8.0Hz)，6.93-6.97(t，1H，J＝7.6Hz)，6.72(br?s，1H)，6.42-6.44(d，1H，J＝8.8Hz)，4.25-4.28(m，4H)，3.71-3.73(t，4H，J＝4.4Hz)，3.53-3.57(t，2H，J＝8.4Hz)，2.92-2.94(t，4H，J＝4.4Hz)，2.78-2.81(m，5H)。
embodiment 17
2-(2-(1-ethyl-6-methoxyl group-2-oxo-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-7- amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide
Figure BPA00001751561001061
Steps A: 7-(the chloro-7-of 4-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amido)-1-ethyl-6-methoxyl group-4,5-dihydro-1H-benzo [b] azatropylidene-2 (3H)-one
Figure BPA00001751561001062
According to universal synthesis method II, by the chloro-7-of 2,4-bis-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine (intermediate A 1,310 milligrams, 1.0mmol), 7-amido-1-ethyl-6-methoxyl group-4,5-dihydro-1H-benzo [b] azatropylidene-2 (3H)-one hydrochloride (intermediate B 5,271 milligrams, 1.0mmol), Pd 2(dba) 3(183 milligrams, 0.2mmol), (124 milligrams of (±)-BINAP, 0.2mmol) and cesium carbonate (1.304g, 4.0mmol) toluene solution be heated to 130 degree and stir 2 hours under microwave, obtain product 7-(the chloro-7-of 4-(4-methoxy-benzyl)-6 through separation and purification, 7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amido)-1-ethyl-6-methoxyl group-4,5-dihydro-1H-benzo [b] azatropylidene-2 (3H)-one (yellow solid, 100 milligrams, productive rate 20%). 1h NMR (400MHz, CDCl 3) δ ppm8.45-8.48 (dd, 1H, J=2.0Hz, 9.2Hz), 7.48 (s, 1H), (7.23-7.27 m, 2H), 6.96-6.99 (d, 1H, J=8.8Hz), 6.88-6.90 (t, 2H, J=2.4Hz), 4.57 (s, 2H), 3.79-3.81 (m, 6H), (3.50-3.54 t, 3H, J=8.4Hz), (2.94-2.98 t, 2H, J=8.4Hz), (2.29 s, 3H), 1.11-1.17 (m, 4H), (CH on benzo [b] azatropylidene ring 2cH 2cH 2-) signal covered by the remaining peak of solvent.
Step B:2-(2-(1-ethyl-6-methoxyl group-2-oxo-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-7-amido)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide
Figure BPA00001751561001071
According to universal synthesis method II, by 7-(the chloro-7-of 4-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amido)-1-ethyl-6-methoxyl group-4, and 5-dihydro-1H-benzo [b] azatropylidene-2 (3H)-one (100 milligrams, 0.197mmol), 2-amino-N-methyl-benzamide (intermediate C1,35 milligrams, 0.233mmol), Pd 2(dba) 3(36 milligrams, 0.039mmol), (24 milligrams of (±)-BINAP, 0.039mmol) and (128 milligrams of cesium carbonates, 0.393mmol) toluene solution be heated to 130 degree and stir 12 hours in tube sealing, obtain product 2-(2-(1-ethyl-6-methoxyl group-2-oxo-2 through separation and purification, 3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-7-amido)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide (white solid, 30 milligrams, productive rate 25%). 1H?NMR(400MHz，CDCl 3)δppm?10.09(s，1H)，8.58-8.61(d，1H，J＝8.4Hz)，8.48-8.51(d，1H，J＝9.2Hz)，7.52-7.53(m，1H)，7.41-7.42(m，2H)，7.27-7.30(m，1H)，7.24-7.26(m，1H)，6.86-6.96(m，3H)，4.54(s，2H)，3.80-3.82(m，6H)，3.45-3.49(t，2H，J＝8.4Hz)，2.92-3.00(m，5H)，2.29-2.30(m，2H)，1.59-1.61(m，2H)，1.11-1.15(t，3H，J＝7.2Hz)，0.94-0.98(t，2H，J＝7.6Hz)。
Step C:2-(2-(1-ethyl-6-methoxyl group-2-oxo-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-7-amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide
According to universal synthesis method II, toward 2-(2-(1-ethyl-6-methoxyl group-2-oxo-2, 3, 4, 5-tetrahydrochysene-1H-benzo [b] azatropylidene-7-amido)-7-(4-methoxy-benzyl)-6, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido)-(30 milligrams of N-methyl-benzamides, 0.048mmol) trifluoroacetic acid solution (6 milliliters) in add 3 vitriol oils, stir at normal temperatures some hours, obtain target product 2-(2-(1-ethyl-6-methoxyl group-2-oxo-2 through aftertreatment and separation and purification, 3, 4, 5-tetrahydrochysene-1H-benzo [b] azatropylidene-7-amido)-6, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido)-(4.7 milligrams of N-methyl-benzamides, productive rate 20%). 1H?NMR(400MHz，CD 3OD)δppm?8.37-8.39(d，1H，J＝8.4Hz)，8.27-8.29(m，1H)，7.60-7.62(d，1H，J＝7.6Hz)，7.37-7.39(m，1H)，6.97-6.99(m，2H)，3.77-3.78(m，3H)，3.64-3.68(t，2H，J＝8.0Hz)，2.90-2.96(m，5H)，2.20-2.24(m，8H)，1.09-1.12(m，3H)。
embodiment 18
n-methyl-2-(2-(1-oxo isoindole-5-amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine -4-amido) benzamide
Figure BPA00001751561001081
Steps A: 5-(the chloro-7-of 4-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amido) isoindole-1-ketone
Figure BPA00001751561001082
According to universal synthesis method II, by the chloro-7-of 2,4-bis-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] and pyrimidine (1,310 milligram of intermediate A, 1.0mmol), 5-amido isoindole-1-ketone (intermediate B 6,148 milligrams, 1.0mmol), Pd 2(dba) 3(183 milligrams, 0.2mmol), (124 milligrams of (±)-BINAP, 0.2mmol) and cesium carbonate (654 milligrams, toluene solution 2.01mmol) is heated to 130 degree and stirs 3 hours under microwave, through separation and purification, obtains product 5-(the chloro-7-of 4-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amido) isoindole-1-ketone (yellow solid, 80 milligrams, productive rate 19%). 1H?NMR(400MHz，CDCl 3)δppm?8.05(s，1H)，7.72-7.73(m，1H)，7.46-7.48(d，2H，J＝8.4Hz)，7.22-7.24(m，2H)，6.87-6.89(d，2H，J＝6.8Hz)，6.09(s，1H)，4.54(s，2H)，4.41(s，2H)，3.805-3.809(d，3H，J＝1.6Hz)，3.54-3.55(m，2H)，2.96-2.97(m，2H)。
Step B:2-(7-(4-methoxy-benzyl)-2-(1-oxo isoindole-5-amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide
According to universal synthesis method II, by 5-(the chloro-7-of 4-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amido) (80 milligrams of isoindolin-1-one, 0.190mmol), 2-amino-N-methyl-benzamide (intermediate C1,34 milligrams, 0.227mmol), Pd 2(dba) 3(35 milligrams, 0.038mmol), (18 milligrams of X-Phos, 0.038mmol) and cesium carbonate (124 milligrams, toluene solution 0.380mmol) is heated to 130 degree and stirs 12 hours in tube sealing, through separation and purification, obtains product 2-(7-(4-methoxy-benzyl)-2-(1-oxo isoindole-5-amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide (yellow solid, 10 milligrams, productive rate 10%).
Step C:N-methyl-2-(2-(1-oxo isoindole-5-amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzamide
According to universal synthesis method II, toward 2-(7-(4-methoxy-benzyl)-2-(1-oxo isoindole-5-ylamino)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-(10 milligrams of N-methyl-benzamides, 0.019mmol) trifluoroacetic acid solution (3 milliliters) in add 2 vitriol oils, stir at normal temperatures some hours, obtain target product N-methyl-2-(2-(1-oxo isoindole-5-amido)-6 through aftertreatment and separation and purification, 7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzamide (white solid, 1.9 milligram, productive rate 26%). 1H?NMR(400MHz，CD 3OD)δppm?8.45-8.47(d，1H，J＝8.8Hz)，8.12(s，1H)，7.55-7.63(m，3H)，7.40-7.44(t，1H，J＝8.4Hz)，7.00-7.04(t，1H，J＝8.0Hz)，4.34(s，2H)，3.65-3.69(t，2H，J＝8.4Hz)，2.94-2.98(t，2H，J＝8.0Hz)，2.90(s，3H)。
embodiment 19
2-(2-(cumarone-7-amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N- methyl benzamide
Figure BPA00001751561001101
Steps A: N-(cumarone-7-yl)-chloro-7-of 4-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine
Figure BPA00001751561001102
According to universal synthesis method II, by the chloro-7-of 2,4-bis-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] and pyrimidine (1,310 milligram of intermediate A, 1.0mmol), cumarone-7-amine hydrochlorate (intermediate B 7,169.6 milligram, 1.0mmol), Pd 2(dba) 3(183 milligrams, 0.2mmol), (124 milligrams of (±)-BINAP, 0.2mmol) and cesium carbonate (1.304g, 4.0mmol) toluene solution be heated to 130 degree and stir 12 hours in tube sealing, obtain product N-(cumarone-7-yl)-chloro-7-of 4-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2 through separation and purification, 3-d] pyrimidine-2-amine (200 milligrams, productive rate 49%). 1H?NMR(400MHz，CDCl 3)δppm?8.35-8.37(dd，1H，J＝2.8Hz，6.4Hz)，7.596-7.601(d，1H，J＝2.0Hz)，7.46(s，1H)，7.20-7.26(m，3H)，6.86-6.88(dd，2H，J＝2.0Hz，6.4Hz)，6.768-6.774(d，1H，J＝2.4Hz)，4.56(s，2H)，3.80(s，3H)，3.49-3.54(t，2H，J＝8.4Hz)，2.94-2.98(t，2H，J＝8.4Hz)。
Step B:2-(2-(cumarone-7-amido)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide
According to universal synthesis method II, by N-(cumarone-7-yl)-chloro-7-of 4-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-(100 milligrams of 2-amine, 0.25mmol), 2-amino-N-methyl-benzamide (intermediate C1,44 milligrams, 0.293mmol), Pd 2(dba) 3(10 milligrams, 0.011mmol), (15 milligrams of (±)-BINAP, 0.049mmol) and (47 milligrams of potassium tert.-butoxides, 0.489mmol) toluene solution be heated to 130 degree and stir 12 hours in tube sealing, obtain product 2-(2-(cumarone-7-amido)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2 through separation and purification, 3-d] pyrimidine-4-amido)-N-methyl-benzamide (60 milligrams, productive rate 47%).
Step C:2-(2-(cumarone-7-amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide
According to universal synthesis method II, toward 2-(2-(cumarone-7-amido)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-(60 milligrams of N-methyl-benzamides, 0.115mmol) trifluoroacetic acid solution (8 milliliters) in add 4 vitriol oils, stir at normal temperatures some hours, obtain target product 2-(2-(cumarone-7-amido)-6 through aftertreatment and separation and purification, 7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide (10 milligrams, productive rate 22%). 1H?NMR(400MHz，DMSO-d6)δppm?10.73(s，1H)，8.58-8.59(d，1H，J＝4.4Hz)，8.36-8.39(m，2H)，7.94-7.95(d，1H，J＝2.4Hz)，7.61-7.63(t，2H，J＝7.6Hz)，7.32-7.34(d，1H，J＝7.6Hz)，7.10-7.18(m，2H)，6.956-9.962(d，1H，J＝2.4Hz)，6.83-6.87(t，1H，J＝7.6Hz)，6.65(s，1H)，3.52-3.57(t，2H，J＝8.8Hz)，2.81-2.85(t，2H，J＝8.8Hz)，2.77-2.78(d，3H，J＝4.4Hz)。
embodiment 20
(2-(1,3-di methyl isophthalic acid H-pyrazoles-5-amido)-6, [2,3-d] is phonetic for 7-dihydro-5H-pyrrolo-for 2- pyridine-4-amido)-N-methyl-benzamide
The chloro-N-of steps A: 4-(1,3-dimethyl-1H-pyrazoles-5-yl)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine
According to universal synthesis method II, by the chloro-7-of 2,4-bis-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] and pyrimidine (1,130 milligram of intermediate A, 0.421mmol), 1,3-dimethyl-1H-pyrazoles-5-amine (8,56 milligrams of intermediate B, 0.505mmol), Pd 2(dba) 3(20 milligrams, 0.022mmol), (26 milligrams of (±)-BINAP, 0.042mmol) and cesium carbonate (206 milligrams, toluene solution 0.632mmol) is heated to 130 degree and stirs 2.5 hours under microwave, through separation and purification, obtains the chloro-N-(1 of product 4-, 3-dimethyl-1H-pyrazoles-5-yl)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine (20 milligrams, productive rate 9.8%). 1H?NMR(400MHz，DMSO-d6)δppm9.16(s，1H)，6.25-6.27(d，2H，J＝8.4Hz)，6.95-6.98(d，2H，J＝8.8Hz)，6.02(s，1H)，4.50(s，2H)，3.79(s，3H)，3.62(s，3H)，3.53-3.57(t，2H，J＝8.4Hz)，2.92-2.96(t，2H，J＝8.4Hz)，2.14(s，3H)。
Step B:2-(2-(1,3-dimethyl-1H-pyrazoles-5-amino)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide
Figure BPA00001751561001131
According to universal synthesis method II, by the chloro-N-(1 of 4-, 3-dimethyl-1H-pyrazoles-5-yl)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine (75 milligrams, 0.155mmol), 2-amino-N-methyl-benzamide (intermediate C1,28 milligrams, 0.185mmol), Pd 2(dba) 3(28 milligrams, 0.031mmol), (19 milligrams of (±)-BINAP, 0.031mmol) and cesium carbonate (76 milligrams, toluene solution 0.233mmol) is heated to 130 degree stirring under microwave, and (2-(1 to obtain product 2-through separation and purification, 3-dimethyl-1H-pyrazoles-5-amino)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide (50 milligrams, productive rate 65%). 1HNMR(400MHz，CDCl 3)δppm?10.23(s，1H)，8.47-8.49(d，1H，J＝8.4Hz)，7.36-7.38(d，1H，J＝8.0Hz)，7.30-7.34(t，1H，J＝8.0Hz)，7.19-7.21(d，2H，J＝8.4Hz)，6.85-6.89(m，3H)，6.37(s，1H)，6.20-6.21(d，1H，J＝3.2Hz)，6.08(s，1H)，4.46(s，2H)，3.801(s，3H)，3.799(s，3H)，3.43-3.47(t，2H，J＝8.4Hz)，2.97-2.98(d，3H，J＝4.8Hz)，2.89-2.93(t，2H，J＝8.4Hz)。
Step C:2-(2-(1,3-dimethyl-1H-pyrazoles-5-amino)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide
According to universal synthesis method II, toward 2-, (2-(1,3-di methyl isophthalic acid H-pyrazoles-5-ylamino)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-(50 milligrams of N-methyl-benzamides, 0.1mmol) trifluoroacetic acid solution (5 milliliters) in add 3 vitriol oils, stir at normal temperatures some hours, (2-(1 to obtain target product 2-through aftertreatment and separation and purification, 3-dimethyl-1H-pyrazoles-5-amino)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide (3.8 milligrams, productive rate 10%). 1H?NMR(400MHz，DMSO-d6)δppm?10.83(s，1H)，8.67-8.69(d，2H，J＝8.0Hz)，8.54(s，1H)，7.71-7.73(m，1H)，7.31-7.32(m，1H)，6.95-6.97(m，1H)，6.72(s，1H)，5.98(s，1H)，3.57-3.60(m，5H)，2.84-2.89(m，5H)，2.05(s，3H)。
embodiment 21
n-methyl-2-(2-(3,4,5-tri p-methoxy-phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzamide
Figure BPA00001751561001141
The chloro-7-of steps A: 4-(4-methoxy-benzyl)-N-(3,4,5-trimethoxyphenyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine
Figure BPA00001751561001142
According to universal synthesis method II, by the chloro-7-of 2,4-bis-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine (intermediate A 1,200 milligrams, 0.645mmol), 3,4, the 5-trimethoxy-aniline (9,118 milligrams of intermediate B, 0.645mmol), Pd 2(dba) 3(118 milligrams, 0.129mmol), (±)-BINAP (80 milligrams, 0.129mmol) and (421 milligrams of cesium carbonates, 1.291mmol) toluene solution be heated to 130 degree and stir 2 hours under microwave, obtain the chloro-7-of product 4-(4-methoxy-benzyl)-N-(3,4,5-trimethoxyphenyl)-6 through separation and purification, 7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine (white solid, 100 milligrams, productive rate 68%). 1H?NMR(400MHz，CDCl 3)δppm?7.19-7.21(d，2H，J＝8.4Hz)，6.97(s，2H)，6.83-6.87(m，3H)，4.54(s，2H)，3.79-3.80(s+s，12H)，3.39-3.53(t，2H，J＝8.4Hz)，2.93-2.97(t，2H，J＝8.4Hz)。
Step B:2-(7-(4-methoxy-benzyl)-2-(3,4,5-trimethoxyphenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide
Figure BPA00001751561001151
According to universal synthesis method II, by the chloro-7-of 4-(4-methoxy-benzyl)-N-(3,4,5-trimethoxyphenyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-(100 milligrams of 2-amine, 0.219mmol), 2-amino-N-methyl-benzamide (intermediate C1,39 milligrams, 0.26mmol), Pd 2(dba) 3(40 milligrams, 0.044mmol), (±)-BINAP (27 milligrams, 0.043mmol) and (143 milligrams of cesium carbonates, 0.439mmol) toluene solution be heated to 130 degree and stir 12 hours in tube sealing, obtain product 2-(7-(4-methoxy-benzyl)-2-(3,4,5-trimethoxyphenyl amido)-6 through separation and purification, 7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide (yellow solid, 30 milligrams, productive rate 24%). 1H?NMR(400MHz，CDCl 3)δppm?10.11(s，1H)，8.63-8.65(d，1H，J＝8.4Hz)，7.37-7.40(m，1H)，7.17-7.30(m，3H)，6.96(s，2H)，6.85-6.88(m，2H)，6.62-6.69(m，2H)，6.19(s，1H)，6.04(s，1H)，4.53(s，2H)，3.79-3.80(m，6H)，3.72(s，6H)，3.45-3.49(t，2H，J＝8.4Hz)，2.92-2.98(m，5H)。
Step C:N-methyl-2-(2-(3,4,5-trimethoxyphenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzamide
According to universal synthesis method II, toward 2-(7-(4-methoxy-benzyl)-2-(3,4,5-trimethoxyphenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-(30 milligrams of N-methyl-benzamides, 0.053mmol) trifluoroacetic acid solution (6 milliliters) in add 3 vitriol oils, stir at normal temperatures some hours, (2-(3,4 to obtain target product N-methyl-2-through aftertreatment and separation and purification, 5-trimethoxyphenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzamide (5.8 milligrams, productive rate 24%). 1H?NMR(400MHz，DMSO-d6)δppm?10.60(s，1H)，8.60-8.69(m，3H)，7.64-7.66(d，1H，J＝8.0Hz)，7.30-7.34(t，1H，J＝8.0Hz)，7.08(s，2H)，6.89-6.93(t，1H，J＝7.6Hz)，6.65(s，1H)，3.64(s，6H)，3.58(s，3H)，3.51-3.55(t，2H，J＝8.4Hz)，2.77-2.84(m，5H)。
embodiment 22
n-methyl-2-(2-(1-(3-morpholine propyl group)-1H-indoles-4-amido)-6,7-dihydro-5H- pyrrolo-[2,3-d] pyrimidine-4-amido) benzamide
Figure BPA00001751561001161
The chloro-7-of steps A: 4-(4-methoxy-benzyl)-N-(1-(3-morpholine propyl group)-1H-indoles-4-yl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine
Figure BPA00001751561001162
According to universal synthesis method II, by 2, the chloro-7-of 4-bis-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine (intermediate A 1,309 milligrams, 1.0mmol), 1-(3-morpholine propyl group)-1H-indoles-4-amine (10,259 milligrams of intermediate B, 1.0mmol), Pd 2(dba) 3(183 milligrams, 0.2mmol), (124 milligrams of (±)-BINAP, 0.2mmol) and (652 milligrams of cesium carbonates, 2.0mmol) toluene solution be heated to 140 degree and stir 3 hours under microwave, obtain the chloro-7-of product 4-(4-methoxy-benzyl)-N-(1-(3-morpholine propyl group)-1H-indoles-4-yl)-6,7-dihydro-5H-pyrrolo-[2 through separation and purification, 3-d] pyrimidine-2-amine (135 milligrams, productive rate 25.4%).
Step B:2-(7-(4-methoxy-benzyl)-2-(1-(3-morpholine propyl group)-1H-indoles-4-amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide
Figure BPA00001751561001171
According to universal synthesis method II, by the chloro-7-of 4-(4-methoxy-benzyl)-N-(1-(3-morpholine propyl group)-1H-indol-4-yl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-(135 milligrams of 2-amine, 0.254mmol), 2-amino-N-methyl-benzamide (intermediate C1,38 milligrams, 0.253mmol), Pd 2(dba) 3(46 milligrams, 0.050mmol), (24 milligrams of X-Phos, 0.050mmol) and (124 milligrams of cesium carbonates, 0.380mmol) toluene solution be heated to 140 degree and stir 3.5 hours under microwave, obtain product 2-(7-(4-methoxy-benzyl)-2-(1-(3-morpholine propyl group)-1H-indoles-4-amido)-6,7-dihydro-5H-pyrrolo-[2 through separation and purification, 3-d] pyrimidine-4-amido)-N-methyl-benzamide (100 milligrams, productive rate 61%). 1H?NMR(400MHz，CDCl 3)δppm?10.06(s，1H)，8.68-8.70(d，1H，J＝8.4Hz)，8.09-8.10(d，1H，J＝6.8Hz)，7.40-7.42(m，2H)，7.14-7.18(m，1H)，7.02-7.06(m，2H)，6.86-6.93(m，3H)，6.58(s，1H)，6.16(s，1H)，4.55(s，2H)，4.19-4.22(m，2H)，3.80(s，3H)，3.72-3.80(m，5H)，3.44-3.49(m，3H)，2.94-2.99(m，5H)，2.40-2.42(m，4H)，2.22-2.28(m，2H)，1.99-2.04(m，4H)。
Step C:
N-methyl-2-(2-(1-(3-morpholine propyl group)-1H-indoles-4-amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzamide
According to universal synthesis method II, toward 2-(7-(4-methoxy-benzyl)-2-(1-(3-morpholine propyl group)-1H-indoles-4-amido)-6, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido)-(100 milligrams of N-methyl-benzamides, 0.155mmol) trifluoroacetic acid solution (5 milliliters) in add 4 vitriol oils, stir at normal temperatures some hours, obtain target product N-methyl-2-(2-(1-(3-morpholine propyl group)-1H-indoles-4-amido)-6 through aftertreatment and separation and purification, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido) (10 milligrams of benzamide, productive rate 12%). 1H?NMR(400MHz，CDCl 3)δppm10.18(s，1H)，8.69-8.72(d，1H，J＝8.4Hz)，7.95-7.97(d，1H，J＝7.6Hz)，7.37-7.42(m，2H)，7.13-7.17(m，1H)，7.03-7.05(m，2H)，6.82-6.94(m，2H)，6.51-6.52(d，1H，J＝2.8Hz)，6.19-6.20(d，1H，J＝4.8Hz)，4.49(s，1H)，4.18-4.21(t，2H，J＝6.8Hz)，3.65-3.74(m，7H)，2.99-3.07(m，5H)，2.39-2.40(m，4H)，2.17-2.19(m，2H)，1.95-1.99(m，3H)。
embodiment 23
(±)-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6,7-dihydro-5H-pyrrolo- [2,3-d] pyrimidine-4-amido)-N-methyl-benzamide
Figure BPA00001751561001181
According to universal synthesis method II, by (±)-2, the chloro-7-of 4-bis-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine (intermediate A 2,190 milligrams, 0.586mmol), 2-methoxyl group-4-morpholine aniline (1,146 milligram of intermediate B, 0.702mmol), Pd 2(dba) 3(27 milligrams, 0.03mmol), (36 milligrams of (±)-BINAP, 0.058mmol) and cesium carbonate (287 milligrams, the heated and stirred in tube sealing of toluene solution 0.88mmol), obtain the chloro-N-of product (±)-4-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-5-methyl-6 through separation and purification, 7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine (yellow solid, 100 milligrams, productive rate 35%). 1HNMR(400MHz，CDCl 3)δppm?8.37-8.39(d，1H，J＝9.2Hz)，7.39(s，1H)，7.20-7.22(dd，2H，J＝2.0Hz，6.8Hz)，6.86-6.88(m，2H)，6.49-6.52(m，2H)，4.54(s，2H)，3.85-3.87(t+s，7H)，3.80(s，3H)，3.57-3.62(t，1H，J＝9.6Hz)，3.29-3.31(m，1H)，3.08-3.11(m，4H)，3.00-3.03(dd，1H，J＝4.0Hz，9.6Hz)，1.24-1.28(m，3H)。
Step B:(±)-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide
Figure BPA00001751561001191
According to universal synthesis method II, by the chloro-N-of (±)-4-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-(65 milligrams of 2-amine, 0.131mmol), 2-amino-N-methyl-benzamide (intermediate C1,24 milligrams, 0.16mmol), Pd 2(dba) 3(6 milligrams, 0.007mmol), (9 milligrams of (±)-BINAP, 0.014mmol) and (64 milligrams of cesium carbonates, 0.196mmol) toluene solution heated and stirred in tube sealing, obtain product (±)-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6 through separation and purification, 7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide (yellow solid, 55 milligrams, productive rate 45%). 1H?NMR(400MHz，CDCl 3)δppm?9.98(s，1H)，8.61-8.63(d，1H，J＝8.4Hz)，8.38-8.40(d，1H，J＝8.8Hz)，7.38-7.42(m，2H)，7.23-7.25(m，2H)，7.18(s，1H)，6.85-6.92(m，3H)，6.52(s，1H)，6.46-6.48(d，1H，J＝8.8Hz)，6.15-6.16(d，1H，J＝4.8Hz)，4.46-4.60(dd，2H，J＝14.8Hz，42.8Hz)，3.86-3.88(t+s，7H)，3.798-3.802(d，3H，J＝1.6Hz)，3.51-3.53(m，1H)，3.35-3.38(m，1H)，3.09-3.11(t，4H)，2.97-3.00(s+m，4H)，1.28-1.32(m，3H)。
Step C:(±)-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide
According to universal synthesis method II, toward (±)-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido)-(55 milligrams of N-methyl-benzamides, 0.09mmol) trifluoroacetic acid solution (4 milliliters) in add 4 vitriol oils, stir at normal temperatures some hours, obtain target product (±)-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6 through aftertreatment and separation and purification, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido)-N-methyl-benzamide (yellow solid, 5 milligrams, productive rate 11%). 1HNMR(400MHz，DMSO-d6)δppm?10.62(br?s，1H)，8.63-8.64(d，1H，J＝4.8Hz)，8.40(br?s，1H)，7.71-7.73(d，1H，J＝8.4Hz)，7.62-7.65(dd，2H，J＝1.2Hz，8.0Hz)，7.31-7.35(t，1H，J＝7.6Hz)，6.94-6.97(t，1H，J＝7.6Hz)，6.62-6.63(d，1H，J＝2.4Hz)，6.43-6.45(dd，1H，J＝2.4Hz，8.8Hz)，3.80(s，3H)，3.68-3.74(m，5H)，3.31(m，2H)，3.09-3.11(m，5H)，2.76-2.77(d，3H，J＝4.4Hz)，1.20-1.21(m，3H)。
(±)-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide can be with (4.6 * 150 millimeters of Chiralcel AD-H, Daicel company) pillar splits, the ethanolic soln/normal hexane of the diethylamine that moving phase is 0.025% (1/1).The retention time of two enantiomers is respectively 7.213 minutes and 10.835 minutes.
embodiment 24
(±)-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6,7-dihydro-5H-pyrroles and [2,3-d] pyrimidine-4-amido) phenyl) (pyrrolidin-1-yl) methyl ketone
Steps A: (±)-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) phenyl) (pyrrolidin-1-yl) methyl ketone
Figure BPA00001751561001202
According to universal synthesis method II, by the chloro-N-of (±)-4-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-(70 milligrams of 2-amine, 0.141mmol), (2-aminocarbonyl phenyl) (pyrrolidin-1-yl) methyl ketone hydrochloride (intermediate C3,39 milligrams, 0.172mmol), Pd 2(dba) 3(13 milligrams, 0.014mmol), (18 milligrams of (±)-BINAP, 0.029mmol) and (92 milligrams of cesium carbonates, 0.282mmol) toluene solution be heated to 130 degree and stir 12 hours in tube sealing, obtain product (±)-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6 through separation and purification, 7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) phenyl) (pyrrolidin-1-yl) methyl ketone (90 milligrams, productive rate 98%). 1HNMR(400MHz，CDCl 3)δppm?8.63(s，1H)，8.40-8.44(t，2H，J＝8.8Hz)，7.31-7.38(m，2H)，7.19-7.24(m，3H)，6.93-6.95(dd，1H，J＝0.8Hz，7.2Hz)，6.86-6.92(dd，2H，J＝1.6Hz，20.4Hz)，6.518-6.524(d，1H，J＝2.4Hz)，6.45-6.47(dd，1H，J＝2.0Hz，8.8Hz)，4.47-4.58(dd，2H，J＝14.8Hz，23.6Hz)，3.86-3.88(m，7H)，3.80(s，3H)，3.62-3.63(m，2H)，3.50-3.54(m，3H)，3.27-3.28(m，1H)，3.09-3.11(t，4H，J＝4.8Hz)，2.94-2.98(dd，1H，J＝4.4Hz，9.6Hz)，1.84-1.95(m，4H)，1.24-1.27(m，3H)。
Step B:(±)-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) phenyl) (pyrrolidin-1-yl) methyl ketone
According to universal synthesis method II, toward (±)-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido) phenyl) (90 milligrams of (pyrrolidin-1-yl) methyl ketone, 0.138mmol) trifluoroacetic acid solution (8 milliliters) in add 4 vitriol oils, stir at normal temperatures some hours, obtain target product (±)-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6 through aftertreatment and separation and purification, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido) phenyl) (pyrrolidin-1-yl) methyl ketone (yellow solid, 44.4 milligram, productive rate 60%). 1H?NMR(400MHz，DMSO-d6)δppm?8.67(s，1H)，8.21-8.23(d，1H，J＝8.8Hz)，7.86-7.88(d，1H，J＝8.0Hz)，7.42-7.44(d，1H，J＝7.6Hz)，7.31-7.35(t，1H，J＝8.0Hz)，7.13(s，1H)，6.97-7.01(t，1H，J＝7.6Hz)，6.61-6.62(m，2H)，6.39-6.42(dd，1H，J＝2.0Hz，8.4Hz)，3.81(s，3H)，3.73-3.76(t，4H，J＝4.4Hz)，3.62-3.67(t，1H，J＝9.2Hz)，3.35-3.52(m，5H)，3.01-3.05(m，5H)，1.75-1.87(m，4H)，1.16-1.18(d，3H，J＝6.4Hz)。
embodiment 25
(±)-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6,7-dihydro-5H-pyrrolo- [2,3-d] pyrimidine-4-amido)-N-methyl benzenesulfonamide
Figure BPA00001751561001221
Steps A: (±)-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl benzenesulfonamide
Figure BPA00001751561001222
According to universal synthesis method II, by the chloro-N-of (±)-4-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-(80 milligrams of 2-amine, 0.161mmol), 2-amino-N-methyl benzenesulfonamide (intermediate C4,36 milligrams, 0.194mmol), Pd 2(dba) 3(15 milligrams, 0.016mmol), (20 milligrams of (±)-BINAP, 0.032mmol) and (105 milligrams of cesium carbonates, 0.322mmol) toluene solution be heated to 130 degree and stir 12 hours in tube sealing, obtain product (±)-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6 through separation and purification, 7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl benzenesulfonamide (95 milligrams, productive rate 91%). 1H?NMR(400MHz，CDCl 3)δppm?8.32-8.38(dd，2H，J＝8.4Hz，15.2Hz)，8.00(s，1H)，7.85-7.87(dd，1H，J＝1.6Hz，8.0Hz)，7.50-7.54(m，1H)，7.22-7.27(m，3H)，7.07-7.10(t，1H，J＝8.0Hz)，6.86-6.88(m，2H)，6.52-6.53(d，1H，J＝2.4Hz)，6.40-6.43(dd，1H，J＝1.2Hz，8.8Hz)，4.49-4.60(m，2H)，4.44-4.46(m，1H)，3.87-3.89(m，7H)，3.81(s，3H)，3.54-3.59(m，1H)，3.27-3.28(m，1H)，3.09-3.11(t，4H，J＝4.4Hz)，2.99-3.02(dd，1H，J＝4.0Hz，9.6Hz)，2.59-2.61(d，3H，J＝5.6Hz)，1.22-1.28(m，3H)。
Step B:(±)-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl benzenesulfonamide
According to universal synthesis method II, toward (±)-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido)-(95 milligrams of N-methyl benzenesulfonamides, 0.147mmol) trifluoroacetic acid solution (8 milliliters) in add 4 vitriol oils, stir at normal temperatures some hours, obtain target product (±)-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6 through aftertreatment and separation and purification, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido)-(54 milligrams of N-methyl benzenesulfonamides, productive rate 70%). 1HNMR(400MHz，DMSO-d6)δppm?8.48-8.50(d，1H，J＝8.0Hz)，8.36(s，1H)，7.74-7.79(m，2H)，7.68-7.71(dd，1H，J＝1.6Hz，7.6Hz)，7.46-7.48(m，1H)，7.26(s，1H)，7.05-7.09(m，1H)，6.74(s，1H)，6.62-6.63(d，1H，J＝2.8Hz)，6.42-6.45(dd，1H，J＝2.4Hz，8.8Hz)，3.81(s，3H)，3.74-3.76(t，4H，J＝4.8Hz)，3.66-3.67(t，1H)，3.30-3.31(m，1H)，3.05-3.09(m，5H)，2.43-2.45(d，3H，J＝5.2Hz)，1.16-1.18(d，3H，J＝7.2Hz)。
embodiment 26
(±)-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6,7-dihydro-5H-pyrrolo- [2,3-d] pyrimidine-4-amido)-N-propylbenzene sulphonamide
Figure BPA00001751561001231
Steps A: (±)-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-propylbenzene sulphonamide
Figure BPA00001751561001241
According to universal synthesis method II, by the chloro-N-of (±)-4-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-(70 milligrams of 2-amine, 0.141mmol), 2-amino-N-propylbenzene sulfonamide hydrochloride (intermediate C5,43 milligrams, 0.171mmol), Pd 2(dba) 3(13 milligrams, 0.014mmol), (18 milligrams of (±)-BINAP, 0.029mmol) and (138 milligrams of cesium carbonates, 0.423mmol) toluene solution be heated to 130 degree and stir 12 hours in tube sealing, obtain product (±)-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6 through separation and purification, 7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-propylbenzene sulphonamide (60 milligrams, productive rate 63%). 1H?NMR(400MHz，CDCl 3)δppm?8.30-8.34(dd，2H，J＝4.8Hz，10.4Hz)，7.96(s，1H)，7.85-7.88(dd，1H，J＝1.2Hz，8.0Hz)，7.49-7.54(t，1H，J＝7.6Hz)，7.23-7.25(m，2H)，7.07-7.11(t，1H，J＝7.6Hz)，6.86-6.88(d，2H，J＝8.4Hz)，6.518-6.524(d，1H，J＝2.4Hz)，6.38-6.41(dd，1H，J＝2.4Hz，8.8Hz)，4.45-4.60(m，3H)，3.86-3.89(m，7H)，3.81(s，3H)，3.54-3.59(t，1H，J＝9.2Hz)，3.26-3.29(m，1H)，3.08-3.11(t，4H，J＝4.8Hz)，2.99-3.02(dd，1H，J＝4.0Hz，9.6Hz)，2.82-2.90(m，2H)，1.36-1.43(m，2H)，1.23-1.26(m，3H)，0.75-0.79(t，3H，J＝7.2Hz)。
Step B:(±)-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-propylbenzene sulphonamide
According to universal synthesis method II, toward (±)-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido)-(60 milligrams of N-propylbenzene sulphonamide, 0.089mmol) trifluoroacetic acid solution (5 milliliters) in add 4 vitriol oils, stir at normal temperatures some hours, obtain target product (±)-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6 through aftertreatment and separation and purification, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido)-(24.5 milligrams of N-propylbenzene sulphonamide, productive rate 49.7%). 1H?NMR(400MHz，DMSO-d6)δppm?8.42-8.44(d，1H，J＝8.4Hz)，8.35(s，1H)，7.85-7.88(t，1H，J＝6.0Hz)，7.76-7.78(d，1H，J＝8.8Hz)，7.68-7.70(dd，1H，J＝1.2Hz，8.0Hz)，7.42-7.46(m，1H)，7.24(s，1H)，7.02-7.05(m，1H)，6.73(s，1H)，6.60-6.61(d，1H，J＝2.4Hz)，6.38-6.41(dd，1H，J＝2.4Hz，8.8Hz)，3.79(s，3H)，3.71-3.74(t，4H，J＝4.8Hz)，3.63-3.68(t，1H，J＝9.2Hz)，3.25-3.27(m，1H)，3.04-3.06(m，5H)，2.68-2.76(m，2H)，1.32-1.37(q，2H，J＝7.2Hz)，1.14-1.16(d，3H，J＝6.4Hz)，0.71-0.74(t，3H，J＝7.6Hz)。
embodiment 27
(±)-N-cyclobutyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6,7-dihydro-5H- pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Steps A: (±)-N-cyclobutyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001252
According to universal synthesis method II, by the chloro-N-of (±)-4-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-(50 milligrams of 2-amine, 0.101mmol), 2-amino-N-cyclobutyl benzsulfamide (intermediate C6,28 milligrams, 0.124mmol), Pd 2(dba) 3(10 milligrams, 0.011mmol), (13 milligrams of (±)-BINAP, 0.021mmol) and (66 milligrams of cesium carbonates, 0.202mmol) toluene solution be heated to 130 degree and stir 12 hours in tube sealing, obtain product (±)-N-cyclobutyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6 through separation and purification, 7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide (55 milligrams, productive rate 79.4%). 1HNMR(400MHz，CDCl 3)δppm?8.29-8.32(d，2H，J＝8.8Hz)，7.90(s，1H)，7.84-7.86(d，1H，J＝6.4Hz)，7.48-7.52(t，1H，J＝8.0Hz)，7.24-7.26(m，2H)，7.05-7.09(t，1H，J＝7.6Hz)，6.87-6.90(m，2H)，6.51-6.52(d，1H，J＝2.4Hz)，6.33-6.36(dd，1H，J＝2.8Hz，8.8Hz)，4.66-4.68(d，1H，J＝5.2Hz)，4.49-4.60(dd，2H，J＝14.8Hz，29.6Hz)，3.86-3.89(m，7H)，3.81(s，3H)，3.71-3.73(m，1H)，3.55-3.60(t，1H，J＝9.2Hz)，3.27-3.30(m，1H)，3.07-3.10(t，4H，J＝4.4Hz)，2.99-3.03(dd，1H，J＝4.0Hz，9.6Hz)，1.96-2.05(m，2H)，1.66-1.75(m，2H)，1.30-1.52(m，2H)，1.25-1.27(m，3H)。
Step B:(±)-N-cyclobutyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
According to universal synthesis method II, toward (±)-N-cyclobutyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido) (55 milligrams of benzsulfamides, 0.08mmol) trifluoroacetic acid solution (5 milliliters) in add 4 vitriol oils, stir at normal temperatures some hours, obtain target product (±)-N-cyclobutyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6 through aftertreatment and separation and purification, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido) benzsulfamide (yellow solid, 41.1 milligram, productive rate 90.8%). 1H?NMR(400MHz，DMSO-d6)δppm?8.51-8.53(d，1H，J＝8.4Hz)，8.42(s，1H)，8.27-8.29(d，1H，J＝8.8Hz)，7.84-7.86(d，1H，J＝8.8Hz)，7.75-7.78(dd，1H，J＝1.6Hz，8.4Hz)，7.49-7.52(t，1H，J＝7.2Hz)，7.32(s，1H)，7.08-7.12(m，1H)，6.83(s，1H)，6.68-6.69(d，1H，J＝2.0Hz)，6.45-6.48(dd，1H，J＝1.6Hz，8.8Hz)，3.87(s，3H)，3.79-3.81(t，4H，J＝4.4Hz)，3.65-3.77(m，2H)，3.33-3.35(m，1H)，3.12-3.15(m，5H)，2.02-2.06(m，1H)，1.87-1.92(m，2H)，1.77-1.81(m，1H)，1.48-1.55(m，2H)，1.23-1.25(d，3H，J＝6.4Hz)。
embodiment 28
(±)-N-cyclopentyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001271
Steps A: (±)-N-cyclopentyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001272
According to universal synthesis method II, by the chloro-N-of (±)-4-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-(50 milligrams of 2-amine, 0.101mmol), 2-amino-N-cyclopentyl benzsulfamide (intermediate C7,29 milligrams, 0.121mmol), Pd 2(dba) 3(10 milligrams, 0.011mmol), (13 milligrams of (±)-BINAP, 0.021mmol) and (66 milligrams of cesium carbonates, 0.202mmol) toluene solution be heated to 130 degree and stir 12 hours in tube sealing, obtain product (±)-N-cyclopentyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6 through separation and purification, 7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide (55 milligrams, productive rate 77.9%). 1HNMR(400MHz，CDCl 3)δppm?8.27-8.30(dd，2H，J＝4.8Hz，7.6Hz)，7.86-7.89(m，2H)，7.50-7.53(t，1H，J＝7.6Hz)，7.23-7.25(m，2H)，7.07-7.11(t，1H，J＝7.6Hz)，6.86-6.88(dd，2H，J＝2.0Hz，6.4Hz)，6.51-6.52(d，1H，J＝2.4Hz)，6.34-6.37(dd，1H，J＝2.8Hz，8.4Hz)，4.49-4.59(dd，2H，J＝14.8Hz，26.8Hz)，4.41-4.43(d，1H，J＝7.6Hz)，3.86-3.89(m，7H)，3.81(s，3H)，3.52-3.59(m，2H)，3.28-3.30(m，1H)，3.07-3.10(t，4H，J＝4.8Hz)，2.99-3.02(dd，1H，J＝4.4Hz，9.6Hz)，1.66-1.71(m，2H)，1.47-1.50(m，2H)，1.22-1.39(7H)。
Step B:(±)-N-cyclopentyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
According to universal synthesis method II, toward (±)-N-cyclopentyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido) (55 milligrams of benzsulfamides, 0.079mmol) trifluoroacetic acid solution (5 milliliters) in add 4 vitriol oils, stir at normal temperatures some hours, obtain target product (±)-N-cyclopentyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6 through aftertreatment and separation and purification, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido) (47 milligrams of benzsulfamides, productive rate 100%). 1H?NMR(400MHz，DMSO-d6)δppm?8.43-8.45(d，1H，J＝8.8Hz)，8.38(s，1H)，7.89-7.91(d，1H，J＝7.6Hz)，7.78-7.81(d，1H，J＝8.8Hz)，7.72-7.75(dd，1H，J＝1.2Hz，8.0Hz)，7.43-7.47(m，1H)，7.26(s，1H)，7.03-7.07(t，1H，J＝7.6Hz)，6.76(s，1H)，6.62-6.63(d，1H，J＝2.4Hz)，6.39-6.42(dd，1H，J＝2.4Hz，8.8Hz)，3.81(s，3H)，3.73-3.76(t，4H，J＝4.8Hz)，3.65-3.69(t，1H，J＝9.2Hz)，3.43-3.45(m，1H)，3.26-3.30(m，1H)，3.06-3.08(m，5H)，1.64-1.66(m，1H)，1.51-1.56(m，4H)，1.16-1.39(m，3H)，0.83-0.85(d，3H，J＝8.0Hz)。
embodiment 29
(±)-N-cyclohexyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001281
Steps A: (±)-N-cyclohexyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001291
According to universal synthesis method II, by the chloro-N-of (±)-4-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-(50 milligrams of 2-amine, 0.101mmol), 2-amino-N-cyclohexyl benzene sulfonamide (intermediate C8,31 milligrams, 0.121mmol), Pd 2(dba) 3(10 milligrams, 0.011mmol), (13 milligrams of (±)-BINAP, 0.021mmol) and (66 milligrams of cesium carbonates, 0.202mmol) toluene solution be heated to 130 degree and stir 12 hours in tube sealing, obtain product (±)-N-cyclohexyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6 through separation and purification, 7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide (55 milligrams, productive rate 97.4%). 1H?NMR(400MHz，CDCl 3)δppm?8.25-8.29(t，2H，J＝7.6Hz)，7.88-7.90(dd，1H，J＝1.6Hz，8.0Hz)，7.85(s，1H)，7.49-7.53(m，1H)，7.23-7.27(m，3H)，7.08-7.12(t，1H，J＝7.6Hz)，6.86-6.88(m，2H)，6.508-6.514(d，1H，J＝2.4Hz)，6.32-6.35(dd，1H，J＝2.4Hz，8.8Hz)，4.49-4.59(dd，2H，J＝14.8Hz，24.0Hz)，4.37-4.39(d，1H，J＝7.6Hz)，3.86-3.88(m，7H)，3.81(s，3H)，3.54-3.59(t，1H，J＝9.6Hz)，3.28-3.31(m，1H)，3.07-3.09(m，5H)，2.99-3.02(dd，1H，J＝4.0Hz，9.2Hz)，1.68-1.70(m，2H)，1.49-1.50(m，2H)，1.39-1.43(m，1H)，1.26-1.28(m，3H)，0.98-1.11(m，5H)。
Step B:(±)-N-cyclohexyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
According to universal synthesis method II, toward (±)-N-cyclohexyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido) (70 milligrams of benzsulfamides, 0.098mmol) trifluoroacetic acid solution (5 milliliters) in add 4 vitriol oils, stir at normal temperatures some hours, obtain target product (±)-N-cyclohexyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6 through aftertreatment and separation and purification, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido) (38.3 milligrams of benzsulfamides, productive rate 65.4%). 1H?NMR(400MHz，DMSO-d6)δppm?8.32-8.36(m，2H)，7.83-7.85(d，1H，J＝8.0Hz)，7.78-7.80(d，1H，J＝8.8Hz)，7.72-7.74(m，1H)，7.42-7.44(m，1H)，7.21(s，1H)，7.03-7.07(t，1H，J＝8.0Hz)，6.73(s，1H)，6.597-6.603(d，1H，J＝2.4Hz)，6.35-6.37(dd，1H，J＝2.0Hz，8.8Hz)，3.79(s，3H)，3.71-3.73(t，4H，J＝4.8Hz)，3.63-3.68(t，1H，J＝9.2Hz)，3.05-3.07(m，5H)，3.03-3.04(m，1H)，1.21-1.61(m，4H)，0.94-1.18(m，7H)，0.81-0.83(m，2H)。
embodiment 30
(±)-N-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6,7-dihydro-5H-pyrrole cough up also [2,3-d] pyrimidine-4-amido) phenyl) ethanamide
Figure BPA00001751561001301
Steps A: (±)-N-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) phenyl) ethanamide
Figure BPA00001751561001302
According to universal synthesis method II, by the chloro-N-of (±)-4-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-(70 milligrams of 2-amine, 0.141mmol), N-(2-aminocarbonyl phenyl) ethanamide (intermediate C9,26 milligrams, 0.173mmol), Pd 2(dba) 3(15 milligrams, 0.016mmol), (20 milligrams of (±)-BINAP, 0.032mmol) and (105 milligrams of cesium carbonates, 0.322mmol) toluene solution be heated to 130 degree and stir 12 hours in tube sealing, obtain product (±)-N-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6 through separation and purification, 7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) phenyl) ethanamide (yellow solid, 80 milligrams, productive rate 93%). 1H?NMR(400MHz，CDCl 3)δppm?8.75(s，1H)，8.11-8.13(d，1H，J＝8.4Hz)，7.74-7.76(d，1H，J＝8.0Hz)，7.31-7.33(m，1H)，7.13-7.26(m，5H)，6.86-6.88(d，2H，J＝8.4Hz)，6.49-6.50(d，1H，J＝2.4Hz)，6.37-6.39(dd，1H，J＝2.4Hz，8.8Hz)，4.48-4.58(dd，2H，J＝15.2Hz，28.4Hz)，3.86-3.89(m，7H)，3.80(s，3H)，3.51-3.55(t，1H，J＝9.2Hz)，3.07-3.10(m，5H)，2.95-2.98(dd，1H，J＝4.0Hz，9.6Hz)，2.02(s，3H)，0.86-0.89(m，3H)。
Step B:(±)-N-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) phenyl) ethanamide
According to universal synthesis method II, toward (±)-N-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido) phenyl) (80 milligrams of ethanamides, 0.131mmol) trifluoroacetic acid solution (8 milliliters) in add 3 vitriol oils, stir at normal temperatures some hours, obtain target product (±)-N-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6 through aftertreatment and separation and purification, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido) phenyl) ethanamide (yellow solid, 45 milligrams, productive rate 70%). 1H?NMR(400MHz，DMSO-d6)δppm?10.00(s，1H)，7.97-7.99(d，1H，J＝8.8Hz)，7.68-7.69(d，1H，J＝7.2Hz)，7.59(s，1H)，7.36-7.38(d，1H，J＝8.0Hz)，7.24-7.27(t，1H，J＝7.2Hz)，7.08-7.15(m，2H)，6.65-6.66(d，2H，J＝2.4Hz)，6.35-6.37(d，1H，J＝7.6Hz)，3.86(s，3H)，3.78-3.81(t，4H，J＝4.4Hz)，3.67-3.71(t，1H，J＝9.2Hz)，3.23(m，1H)，3.08-3.10(m，5H)，2.12(s，3H)，1.12-1.14(d，3H，J＝6.4Hz)。
embodiment 31
(±)-N-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6,7-dihydro-5H-pyrrole cough up also [2,3-d] pyrimidine-4-amido) phenyl)-N-methyl Toluidrin
Figure BPA00001751561001321
Steps A: (±)-N-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) phenyl)-N-methyl Toluidrin
According to universal synthesis method II, by the chloro-N-of (±)-4-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-(80 milligrams of 2-amine, 0.161mmol), N-(2-aminocarbonyl phenyl)-N-methyl Toluidrin (intermediate C10,39 milligrams, 0.195mmol), Pd 2(dba) 3(15 milligrams, 0.016mmol), (20 milligrams of (±)-BINAP, 0.032mmol) and (105 milligrams of cesium carbonates, 0.322mmol) toluene solution be heated to 130 degree and stir 12 hours in tube sealing, obtain product (±)-N-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6 through separation and purification, 7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) phenyl)-N-methyl Toluidrin (80 milligrams, productive rate 75%). 1H?NMR(400MHz，CDCl 3)δppm8.38-8.40(d，2H，J＝8.8Hz)，7.32-7.36(t，1H，J＝8.4Hz)，7.20-7.26(m，4H)，7.00-7.04(m，1H)，6.86-6.88(d，2H，J＝8.8Hz)，6.518-6.524(d，1H，J＝2.4Hz)，6.44-6.46(dd，1H，J＝2.8Hz，8.8Hz)，4.46-4.60(dd，2H，J＝14.8Hz，41.6Hz)，3.86-3.89(m，7H)，3.80(s，3H)，3.52-3.56(t，1H，J＝9.6Hz)，3.27-3.28(m，1H)，3.27(s，3H)，3.09-3.11(t，4H，J＝4.4Hz)，2.97-3.00(m，4H)，1.26-1.27(m，3H)。
Step B:(±)-N-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) phenyl)-N-methyl Toluidrin
According to universal synthesis method II, toward (±)-N-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido) phenyl)-(80 milligrams of N-methyl Toluidrins, 0.121mmol) trifluoroacetic acid solution (8 milliliters) in add 3 vitriol oils, stir at normal temperatures some hours, obtain target product (±)-N-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6 through aftertreatment and separation and purification, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido) phenyl)-(28.4 milligrams of N-methyl Toluidrins, productive rate 43%). 1H?NMR(400MHz，DMSO-d6)δppm?8.26-8.28(d，1H，J＝8.0Hz)，7.80-7.82(d，1H，J＝8.8Hz)，7.51-7.53(d，1H，J＝8.4Hz)，7.25-7.26(m，2H)，7.17(s，1H)，7.03-7.04(m，1H)，6.61-6.62(m，2H)，6.41-6.43(d，1H，J＝8.0Hz)，3.81(s，3H)，3.74-3.75(m，4H)，3.66-3.67(m，1H)，3.16-3.17(m，1H)，3.10(s，3H)，3.03-3.07(m，8H)，1.20-1.23(t，3H，J＝6.4Hz)。
embodiment 32
(±)-N-(2-((2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6,7-dihydro-5H- pyrrolo-[2,3-d] pyrimidine-4-amido) methyl) phenyl)-N-methyl Toluidrin
Steps A: (±)-N-(2-((2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) methyl) phenyl)-N-methyl Toluidrin
Figure BPA00001751561001341
According to universal synthesis method II, by the chloro-N-of (±)-4-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-(60 milligrams of 2-amine, 0.121mmol), N-(2-(amino methyl) phenyl)-N-methyl Toluidrin hydrochloride (intermediate C11,37 milligrams, 0.147mmol), Pd 2(dba) 3(13 milligrams, 0.014mmol), (15 milligrams of (±)-BINAP, 0.024mmol) and (118 milligrams of cesium carbonates, 0.362mmol) toluene solution be heated to 130 degree and stir 24 hours in tube sealing, obtain product (±)-N-(2-((2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6 through separation and purification, 7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) methyl) phenyl)-N-methyl Toluidrin (50 milligrams, productive rate 60.8%). 1H?NMR(400MHz，CDCl 3)δppm?8.49-8.51(m，1H)，7.65-7.68(t，1H，J＝4.4Hz)，7.32-7.34(m，2H)，7.18-7.24(m，3H)，6.84-6.86(m，2H)，6.516-6.522(d，1H，J＝1.6Hz)，6.44-6.46(d，1H，J＝8.8Hz)，5.19(br，1H)，4.87(br?s，1H)，4.41-4.54(dd，2H，J＝14.4Hz，40.0Hz)，3.85-3.88(m，7H)，3.80(s，3H)，3.40-3.41(m，1H)，3.30(s，2H)，3.06-3.09(m，4H)，3.00(s，3H)，2.86-2.89(dd，1H，J＝4.0Hz，8.8Hz)，1.26-1.28(m，3H)。
Step B:(±)-N-(2-((2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) methyl) phenyl)-N-methyl Toluidrin
According to universal synthesis method II, toward (±)-N-(2-((2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido) methyl) phenyl)-(50 milligrams of N-methyl Toluidrins, 0.074mmol) trifluoroacetic acid solution (4 milliliters) in add 1 vitriol oil, stir at normal temperatures some hours, obtain target product (±)-N-(2-((2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6 through aftertreatment and separation and purification, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido) methyl) phenyl)-(18.3 milligrams of N-methyl Toluidrins, productive rate 44.5%). 1H?NMR(400MHz，DMSO-d6)δppm?7.83(s，1H)，7.48-7.50(m，1H)，7.29-7.36(m，3H)，6.89(br，1H)，6.54-6.58(m，2H)，6.22-6.23(m，2H)，4.44-4.78(m，2H)，3.77(s，3H)，3.69-3.71(t，4H，J＝4.8Hz)，3.55-3.59(t，1H，J＝4.8Hz)，3.20-3.23(m，4H)，3.09(s，3H)，2.96-2.98(m，5H)，1.12-1.14(d，3H，J＝6.0Hz)。
embodiment 33
(±)-N 2 -(2-methoxyl group-4-morpholine phenyl)-5-methyl-N 4 -(6-picoline-2-yl)-6, 7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2, the 4-diamines
Figure BPA00001751561001351
Steps A: (±)-N 2-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-5-methyl-N 4-(6-picoline-2-yl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2,4-diamines
Figure BPA00001751561001352
According to universal synthesis method II, by the chloro-N-of (±)-4-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-(70 milligrams of 2-amine, 0.141mmol), 6-picoline-2-amine (19 milligrams, 0.176mmol), Pd 2(dba) 3(13 milligrams, 0.014mmol), (±)-BINAP (18 milligrams, 0.029mmol) and (92 milligrams of cesium carbonates, 0.282mmol) toluene solution be heated to 130 degree and stir 12 hours in tube sealing, obtain product (±)-N through separation and purification 2-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-5-methyl-N 4-(6-picoline-2-yl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2,4-diamines (70 milligrams, productive rate 87%). 1H?NMR(400MHz，CDCl 3)δppm?8.08-8.10(d，1H，J＝8.4Hz)，7.48-7.52(t，1H，J＝8.0Hz)，7.33-7.38(m，2H)，7.22-7.25(m，2H)，7.12(s，1H)，6.86-6.88(d，2H，J＝8.4Hz)，6.70-6.72(d，1H，J＝7.2Hz)，6.50-6.54(m，2H)，4.61(s，1H)，4.46-4.61(dd，2H，J＝14.8Hz，44.4Hz)，3.87-3.88(m，7H)，3.80(s，3H)，3.54-3.59(t，1H，J＝9.2Hz)，3.11-3.14(t，4H，J＝4.4Hz)，2.99-3.02(dd，1H，J＝2.0Hz，9.2Hz)，2.33(m，4H)，1.23-1.26(m，3H)。
Step B:(±)-N 2-(2-methoxyl group-4-morpholine phenyl)-5-methyl-N 4-(6-picoline-2-yl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2,4-diamines
According to universal synthesis method II, toward (±)-N 2-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-5-methyl-N 4-(6-picoline-2-yl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2, (70 milligrams of 4-diamines, 0.123mmol) trifluoroacetic acid solution (5 milliliters) in add 4 vitriol oils, stir at normal temperatures some hours, through aftertreatment and separation and purification, obtain target product (±)-N 2-(2-methoxyl group-4-morpholine phenyl)-5-methyl-N 4-(6-picoline-2-yl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2,4-diamines (43.2 milligrams, productive rate 78.5%). 1HNMR(400MHz，DMSO-d6)δppm?8.46(s，1H)，7.82-7.83(m，1H)，7.70-7.71(m，1H)，7.44-7.45(m，1H)，7.10-7.11(m，1H)，6.61-6.73(m，2H)，6.40-6.41(m，1H)，3.72-3.79(m，7H)，3.49-3.51(m，3H)，2.97-3.15(m，7H)，2.20(m，4H)，0.87-0.91(m，3H)。
embodiment 34
(±)-N 4 -(3,4-difluorophenyl)-N 2 -(2-methoxyl group-4-morpholine phenyl)-5-methyl-6,7- dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2, the 4-diamines
Figure BPA00001751561001361
Steps A: (±)-N 4-(3,4-difluorophenyl)-N 2-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2,4-diamines
Figure BPA00001751561001371
According to universal synthesis method II, by the chloro-N-of (±)-4-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-(90 milligrams of 2-amine, 0.181mmol), (28 milligrams of 3,4-difluoroanilines, 0.217mmol), Pd 2(dba) 3(17 milligrams, 0.019mmol), (±)-BINAP (23 milligrams, 0.037mmol) and (120 milligrams of cesium carbonates, 0.368mmol) toluene solution be heated to 130 degree and stir 12 hours in tube sealing, obtain product (±)-N through separation and purification 4-(3,4-difluorophenyl)-N 2-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2,4-diamines (70 milligrams, productive rate 66%). 1H?NMR(400MHz，CDCl 3)δppm?8.27-8.29(d，1H，J＝8.4Hz)，7.58-7.61(m，1H)，7.22-7.25(m，2H)，7.15(s，1H)，7.04-7.06(m，1H)，6.93-6.94(m，1H)，6.86-6.88(dd，2H，J＝2.0Hz，6.8Hz)，6.48-6.53(dt，2H，J＝2.8Hz，8.8Hz)，5.84(s，1H)，4.52-4.58(dd，2H，J＝14.4Hz，24.0Hz)，3.86-3.89(m，7H)，3.80(s，3H)，3.50-3.55(t，1H，J＝9.2Hz)，3.10-3.12(m，5H)，2.94-2.97(dd，1H，J＝4.0Hz，9.6Hz)，1.13-1.15(d，3H，J＝6.8Hz)。
Step B:(±)-N 4-(3,4-difluorophenyl)-N 2-(2-methoxyl group-4-morpholine phenyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2,4-diamines
According to universal synthesis method II, toward (±)-N 4-(3,4-difluorophenyl)-N 2-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2, (70 milligrams of 4-diamines, 0.119mmol) trifluoroacetic acid solution (5 milliliters) in add 4 vitriol oils, stir at normal temperatures some hours, through aftertreatment and separation and purification, obtain target product (±)-N 4-(3,4-difluorophenyl)-N 2-(2-methoxyl group-4-morpholine phenyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2,4-diamines (51.7 milligrams, productive rate 93%). 1H?NMR(400MHz，DMSO-d6)δppm?8.20(s，1H)，7.82-7.88(m，1H)，7.73-7.75(d，1H，J＝8.8Hz)，7.21-7.24(m，2H)，7.16(s，1H)，6.615-6.622(d，1H，J＝2.8Hz)，6.55(s，1H)，6.40-6.42(dd，1H，J＝2.0Hz，8.8Hz)，3.80(s，3H)，3.73-3.76(t，4H，J＝4.4Hz)，3.57-3.62(t，1H，J＝8.4Hz)，3.02-3.07(m，5H)，1.10-1.12(d，3H，J＝6.8Hz)。
embodiment 35
(S)-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6,7-dihydro-5H-pyrroles and [2,3-d] pyrimidine-4-amido)-N-methyl-benzamide
Figure BPA00001751561001381
Steps A: the chloro-N-of (S)-4-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine
Figure BPA00001751561001382
According to universal synthesis method II, by (S)-2, the chloro-7-of 4-bis-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine (intermediate A 3,120 milligrams, 0.37mmol), 2-methoxyl group-4-morpholine aniline (1,85 milligram of intermediate B, 0.41mmol), Pd 2(dba) 3(34 milligrams, 0.04mmol), (46 milligrams of (±)-BINAP, 0.74mmol) and (181 milligrams of cesium carbonates, 0.56mmol) toluene solution heated and stirred under microwave, obtain product (S)-chloro-N-of 4-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2 through separation and purification, 3-d] pyrimidine-2-amine (88 milligrams, productive rate 48%). 1H?NMR(400MHz，CDCl 3)δppm?8.37-8.40(d，1H，J＝9.6Hz)，7.40(s，1H)，7.20-7.25(m，2H)，6.83-6.88(m，2H)，6.49-6.52(dd，2H，J＝2.8Hz，6.0Hz)，4.55(s，2H)，3.85-3.88(s+m，7H)，3.80(s，3H)，3.58-3.62(t，1H，J＝9.6Hz)，3.28-3.30(m，1H)，3.08-3.11(t，4H，J＝4.8Hz)，3.00-3.03(dd，1H，J＝4.0Hz，9.6Hz)，1.24-1.27(m，3H)。
Step B:(S)-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide
Figure BPA00001751561001391
According to universal synthesis method II, by the chloro-N-of (S)-4-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-(88 milligrams of 2-amine, 0.18mmol), 2-amino-N-methyl-benzamide (intermediate C1,27 milligrams, 0.18mmol), Pd 2(dba) 3(16 milligrams, 0.02mmol), (22 milligrams of (±)-BINAP, 0.04mmol) and (87 milligrams of cesium carbonates, 0.27mmol) toluene solution be heated to 130 degree and stir 12 hours in tube sealing, obtain product (S)-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6 through separation and purification, 7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide (50 milligrams, productive rate 46%). 1H?NMR(400MHz，CDCl 3)δppm?10.00(s，1H)，8.61-8.63(d，1H，J＝8.4Hz)，8.39-7.42(d，1H，J＝8.8Hz)，7.38-7.43(m，2H)，7.20-7.27(m，3H)，6.86-6.93(m，3H)，6.46-6.49(m，2H)，6.22(s，1H)，4.46-4.61(dd，2H，J＝10.8Hz，43.2Hz)，3.87-3.88(s+m，7H)，3.81(s，3H)，3.51-3.54(m，1H)，3.36(s，1H)，3.10-3.12(t，4H，J＝3.2Hz)，2.97-3.01(m，4H)，1.27-1.33(m，3H)。
Step C:(S)-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide
According to universal synthesis method II, toward (S)-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido)-(50 milligrams of N-methyl-benzamides, 0.082mmol) trifluoroacetic acid solution (10 milliliters) in add 4 vitriol oils, stir at normal temperatures some hours, obtain target product (S)-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6 through aftertreatment and separation and purification, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido)-(20 milligrams of N-methyl-benzamides, productive rate 50%). 1HNMR(400MHz，DMSO-d6)δppm?10.08(s，1H)，8.60-8.63(dd，1H，J＝1.2Hz，8.4Hz)，8.24-8.26(d，1H，J＝8.8Hz)，7.38-7.42(m，2H)，7.10(s，1H)，6.91-6.95(m，1H)，6.51-6.52(d，1H，J＝2.4Hz)，6.45-6.48(dd，1H，J＝3.2Hz，8.8Hz)，6.18-6.19(d，1H，J＝4.4Hz)，4.49(s，1H)，3.85-3.89(s+m，7H)，3.76-3.81(t，1H，J＝9.2Hz)，3.47-3.49(m，1H)，3.20-3.23(dd，1H，J＝4.4Hz，8.8Hz)，3.09-3.11(t，4H，J＝4.8Hz)，2.98-2.99(d，3H，J＝4.8Hz)，1.38-1.40(d，3H，J＝6.4Hz)。E.e. pH-value determination pH: 92.70%.
embodiment 36
(S) (2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6,7-bis-for-N-cyclobutyl-2- hydrogen-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001401
Steps A: (S)-N-cyclobutyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001402
According to universal synthesis method II, by the chloro-N-of (S)-4-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-(32 milligrams of 2-amine, 0.065mmol), 2-amino-N-cyclobutyl benzsulfamide (intermediate C6,17 milligrams, 0.077mmol), Pd 2(dba) 3(12 milligrams, 0.013mmol), (6 milligrams of X-Phos, 0.013mmol) and (42 milligrams of cesium carbonates, 0.129mmol) toluene solution be heated to 130 degree and stir 12 hours in tube sealing, obtain product (S)-N-cyclobutyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6 through separation and purification, 7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide (20 milligrams, productive rate 45%). 1H?NMR(400MHz，CDCl 3)δppm?8.30-8.32(d，2H，J＝8.4Hz)，7.90(s，1H)，7.84-7.86(m，1H)，7.48-7.52(t，1H，J＝7.6Hz)，7.24-7.26(m，2H)，7.05-7.09(t，1H，J＝7.6Hz)，6.87-6.89(d，2H，J＝8.4Hz)，6.51-6.52(d，1H，J＝2.4Hz)，6.34-6.36(dd，1H，J＝2.4Hz，8.4Hz)，4.66-4.68(d，1H，J＝9.2Hz)，4.49-4.60(dd，2H，J＝14.8Hz，29.2Hz)，3.86-3.89(m，7H)，3.81(s，3H)，3.71-3.74(m，1H)，3.55-3.60(t，1H，J＝9.6Hz)，3.28-3.31(m，1H)，3.07-3.10(t，4H，J＝4.8Hz)，3.00-3.03(dd，1H，J＝4.0Hz，9.2Hz)，1.96-2.02(m，2H)，1.66-1.75(m，2H)，1.45-1.52(m，2H)，1.22-1.24(m，3H)。
Step B:(S)-N-cyclobutyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
According to universal synthesis method II, toward (S)-N-cyclobutyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido) (20 milligrams of benzsulfamides, 0.029mmol) trifluoroacetic acid solution (10 milliliters) in add 3 vitriol oils, stir at normal temperatures some hours, obtain target product (S)-N-cyclobutyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6 through aftertreatment and separation and purification, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido) (14 milligrams of benzsulfamides, productive rate 85%). 1H?NMR(400MHz，CDCl 3)δppm?8.29-8.31(d，1H，J＝8.4Hz)，8.15-8.17(d，1H，J＝8.8Hz)，8.02(s，1H)，7.86-7.88(d，1H，J＝8.0Hz)，7.48-7.52(t，1H，J＝8.0Hz)，7.18(s，1H)，7.08-7.12(t，1H，J＝7.6Hz)，6.496-6.501(d，1H，J＝2.0Hz)，6.32-6.35(dd，1H，J＝2.0Hz，8.8Hz)，4.89-4.90(d，1H，J＝8.8Hz)，4.69(s，1H)，3.70-3.88(m，8H)，3.38-3.43(m，1H)，3.21-3.24(dd，1H，J＝4.0Hz，8.8Hz)，3.07-3.09(t，4H，J＝4.4Hz)，1.97-2.01(m，2H)，1.64-1.75(m，2H)，1.42-1.51(m，2H)，1.26-1.33(m，3H)。
embodiment 37
2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5,5-dimethyl-6,7-dihydro-5H-pyrroles and [2,3-d] pyrimidine-4-amido)-N-methyl-benzamide
Figure BPA00001751561001421
The chloro-N-of steps A: 4-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine
Figure BPA00001751561001422
According to universal synthesis method II, by the chloro-7-of 2,4-bis-(4-methoxy-benzyl)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo-[2,3-d] and pyrimidine (4,156 milligrams of intermediate A, 0.46mmol), 2-methoxyl group-4-morpholine aniline (intermediate B 1,115 milligrams, 0.55mmol), Pd 2(dba) 3(42 milligrams, 0.046mmol), (±)-BINAP (57 milligrams, 0.092mmol) and salt of wormwood (225 milligrams, toluene solution 0.69mmol) is heated to 130 degree and stirs 3 hours under microwave, obtain the chloro-N-of product 4-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-5 through separation and purification, 5-dimethyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine (white solid, 86 milligrams, productive rate 37%). 1H?NMR(400MHz，CDCl 3)δppm?8.36-8.38(d，1H，J＝9.2Hz)，7.39(s，1H)，7.20-7.22(d，2H，J＝8.4Hz)，6.86-6.88(d，2H，J＝8.8Hz)，6.50-6.51(m，2H)，4.57(s，2H)，3.85-3.87(m，7H)，3.80(s，3H)，3.16(s，2H)，3.08-3.11(t，4H，J＝4.8Hz)，1.35(s，6H)。
Step B:2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide
Figure BPA00001751561001431
According to universal synthesis method II, by the chloro-N-of 4-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine (86 milligrams, 0.169mol), 2-amino-N-methyl-benzamide (intermediate C1,51 milligrams, 0.338mmol), Pd 2(dba) 3(16 milligrams, 0.017mmol), (22 milligrams of (±)-BINAP, 0.035mmol) and (110 milligrams, salt of wormwood, 0.338mmol) toluene solution be heated to 150 degree and stir 3 hours under microwave, obtain product 2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5 through separation and purification, 5-dimethyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide (white solid, 70 milligrams, productive rate 67%). 1H?NMR(400MHz，CDCl 3)δppm?9.76(s，1H)，8.52-8.54(d，1H，J＝8.0Hz)，8.36-8.38(d，1H，J＝8.8Hz)，7.37-7.41(t，2H，J＝7.6Hz)，7.23-7.25(m，2H)，7.17(s，1H)，6.90-6.94(t，1H，J＝6.8Hz)，6.86-6.90(m，2H)，6.51-6.52(d，1H，J＝2.8Hz)，6.42-6.44(dd，1H，J＝2.0Hz，8.8Hz)，6.19(m，1H)，4.54(s，2H)，3.86-3.88(m，7H)，3.80(s，3H)，3.08-3.10(m，6H)，2.97-2.98(d，3H，J＝4.8Hz)，1.46(s，6H)。
Step C:2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide
According to universal synthesis method II, toward 2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5, 5-di methyl-6, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido)-(70 milligrams of N-methyl-benzamides, 0.112mmol) trifluoroacetic acid solution (3 milliliters) in add 5 vitriol oils, stir at normal temperatures some hours, obtain target product 2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5 through aftertreatment and separation and purification, 5-dimethyl-6, 7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido)-N-methyl-benzamide (yellow solid, 30 milligrams, productive rate 53.3%). 1H?NMR(400MHz，CDCl 3)δppm?9.84(s，1H)，8.52-8.54(dd，1H，J＝1.2Hz，8.8Hz)，8.23-8.25(d，1H，J＝8.8Hz)，7.37-7.41(m，2H)，7.09(s，1H)，6.96-7.00(m，1H)，6.50-6.51(d，1H，J＝2.8Hz)，6.41-6.44(dd，1H，J＝2.8Hz，8.8Hz)，6.11(s，1H)，4.43(s，1H)，3.85-3.89(m，7H)，3.336-3.339(d，3H，J＝1.2Hz)，3.08-3.11(t，4H，J＝4.8Hz)，2.99-3.00(d，3H，J＝4.8Hz)，1.52(s，6H)。
embodiment 38
2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine -4-amido)-N, the N-dimethyl benzene sulfonamide
Figure BPA00001751561001441
1H?NMR(400MHz，DMSO-d6)δppm?8.53-8.55(dd，1H，J＝0.8Hz，8.0Hz)，8.41(s，1H)，7.74-7.76(d，1H，J＝8.4Hz)，7.66-7.68(m，1H)，7.54-7.55(m，1H)，7.28(s，1H)，7.10-7.14(t，1H，J＝7.2Hz)，6.79(s，1H)，6.625-6.631(d，1H，J＝2.4Hz)，6.43-6.46(dd，1H，J＝6.4Hz，8.8Hz)，3.82(s，3H)，3.74-3.76(m，4H)，3.47-3.55(m，2H)，3.07-3.09(m，4H)，2.78-2.82(t，2H，J＝8.4Hz)，2.64(s，6H)。
embodiment 39
n-butyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
1H?NMR(400MHz，DMSO-d6)δppm?8.41-8.43(d，1H，J＝8.0Hz)，8.27(s，1H)，7.79-7.82(m，2H)，7.69-7.71(d，1H，J＝8.0Hz)，7.45-7.46(m，1H)，7.21(s，1H)，7.04-7.06(m，1H)，6.72(s，1H)，6.61(s，1H)，6.40-6.42(d，1H，J＝8.8Hz)，3.79(s，3H)，3.72-3.73(m，4H)，3.49-3.53(t，2H，J＝8.4Hz)，3.05-3.06(m，4H)，2.72-2.80(m，4H)，1.27-1.30(m，2H)，1.11-1.17(m，2H)，0.69-0.73(t，3H，J＝6.8Hz)。
embodiment 40
n-sec.-propyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo- [2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001452
1H?NMR(400MHz，DMSO-d6)δppm?8.38-8.40(d，1H，J＝8.4Hz)，8.23(s，1H)，7.78-7.83(m，2H)，7.72-7.74(d，1H，J＝8.0Hz)，7.43-7.47(t，1H，J＝7.6Hz)，7.23(s，1H)，7.01-7.05(t，1H，J＝7.6Hz)，6.73(s，1H)，6.61(s，1H)，6.39-6.41(d，1H，J＝8.8Hz)，3.788-3.791(d，3H，J＝1.2Hz)，3.72-3.73(m，4H)，3.49-3.53(t，2H，J＝8.4Hz)，3.23-3.28(m，1H)，3.05-3.06(m，4H)，2.76-2.80(t，2H，J＝8.0Hz)，0.91-0.93(m，6H)。
embodiment 41
2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine -4-amido) benzsulfamide
Figure BPA00001751561001461
1H?NMR(400MHz，DMSO-d6)δppm?8.51-8.53(d，1H，J＝8.4Hz)，8.39(s，1H)，7.89-7.91(d，1H，J＝8.8Hz)，7.82-7.84(dd，1H，J＝1.2Hz，8.0Hz)，7.68(s，2H)，7.49-7.53(m，1H)，7.29(s，1H)，7.09-7.13(m，1H)，6.78(s，1H)，6.69-6.70(d，1H，J＝2.4Hz)，6.48-6.51(dd，1H，J＝2.4Hz，8.8Hz)，3.88(s，3H)，3.80-3.82(t，4H，J＝4.8Hz)，3.57-3.61(t，2H，J＝8.4Hz)，3.13-3.15(t，4H，J＝4.8Hz)，2.83-2.88(t，2H，J＝8.4Hz)。
embodiment 42
n-cyclopropyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo- [2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001462
1H?NMR(400MHz，DMSO-d6)δppm?8.49-8.51(d，1H，J＝8.0Hz)，8.19(s，1H)，8.14(s，1H)，7.79-7.81(d，1H，J＝8.8Hz)，7.73-7.76(dd，1H，J＝1.6Hz，8.0Hz)，7.47-7.50(t，1H，J＝7.6Hz)，7.25(s，1H)，7.05-7.09(t，1H，J＝8.0Hz)，6.75(s，1H)，6.627-6.634(d，1H，J＝2.8Hz)，6.42-6.45(dd，1H，J＝2.4Hz，8.8Hz)，3.81(s，3H)，3.74-3.76(t，4H，J＝4.8Hz)，3.50-3.55(t，2H，J＝8.4Hz)，3.07-3.09(t，4H，J＝4.8Hz)，2.78-2.82(t，2H，J＝8.4Hz)，2.07-2.11(m，1H)，0.43-0.46(m，2H)，0.38-0.39(m，2H)。
execute example 43
n-ethyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001471
1H?NMR(400MHz，CDCl 3)δppm?8.32(s，1H)，8.18(d，J＝8.6Hz，1H)，8.05(s，1H)，7.88(d，J＝7.8Hz，1H)，7.52(t，J＝7.8Hz，1H)，7.21-7.05(m，2H)，6.51(d，J＝2.5Hz，1H)，6.42(d，J＝9.0Hz，1H)，4.63(s，1H)，4.56(s，1H)，3.92-3.82(m，7H)，3.67(t，J＝8.2Hz，2H)，3.15-3.06(m，4H)，3.01-2.83(m，4H)，1.04(t，J＝7.2Hz，3H)。
embodiment 44
n-sec-butyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
1H?NMR(400MHz，CDCl 3)δppm?8.27(d，J＝8.0Hz，1H)，8.20(d，J＝8.2Hz，1H)，7.97(s，1H)，7.90(d，J＝7.8Hz，1H)，7.51(s，1H)，7.17(s，1H)，7.11(t，J＝7.9Hz，1H)，6.51(s，1H)，6.37(d，J＝9.3Hz，1H)，4.52(s，1H)，4.38(d，J＝7.9Hz，1H)，3.86(s，7H)，3.68(t，J＝8.1Hz，2H)，3.18(s，1H)，3.09(s，4H)，2.94(t，J＝8.5Hz，2H)，1.35-1.30(m，2H)，0.97(d，J＝6.2Hz，3H)，0.71(t，J＝7.0Hz，3H)。
embodiment 45
n-isobutyl--2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001481
1H?NMR(400MHz，DMSO-d 6)δppm?8.48(s，1H)，7.86(t，J＝6.4Hz，1H)，7.76(d，J＝6.8Hz，1H)，7.48-7.60(m，2H)，7.14-7.47(m，2H)，6.64(s，1H)，6.49-6.51(m，1H)，3.79(s，3H)，3.72-3.74(m，4H)，3.51-3.61(m，2H)，3.24-3.31(m，2H)，3.05-3.14(m，2H)，2.53(t，J＝6.4Hz，2H)，1.54-1.61(m，1H)，0.75(d，J＝5.2Hz，6H)。
embodiment 46
n-sec.-propyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001482
1H?NMR(400MHz，DMSO-d 6)δppm?8.46(d，J＝8.6Hz，1H)，8.36(s，1H)，7.84(d，J＝7.8Hz，1H)，7.79(d，J＝8.8Hz，1H)，7.74(dd，J＝8.0，1.5Hz，1H)，7.44(t，J＝7.9Hz，1H)，7.25(s，1H)，7.04(t，J＝7.2Hz，1H)，6.75(s，1H)，6.62(d，J＝2.5Hz，1H)，6.40(dd，J＝8.7，2.5Hz，1H)，3.80(s，3H)，3.76-3.71(m，4H)，3.67(t，J＝9.1Hz，1H)，3.31-3.25(m，2H)，3.11-3.01(m，4H)，1.17(d，J＝6.7Hz，3H)，1.01(d，J＝6.5Hz，3H)，0.90(d，J＝6.5Hz，3H)。
embodiment 47
the N-tertiary butyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
1H?NMR(400MHz，CDCl 3)δppm?8.18(dd，J＝13.6，8.8Hz，2H)，7.93(d，J＝7.9Hz，1H)，7.81(s，1H)，7.51(t，J＝7.7Hz，1H)，7.14(dd，J＝18.7，11.1Hz，2H)，6.51(s，1H)，6.37(d，J＝8.6Hz，1H)，4.56(d，J＝13.0Hz，2H)，3.92-3.79(m，7H)，3.68(t，J＝8.4Hz，2H)，3.10(d，J＝4.8Hz，4H)，2.92(t，J＝8.2Hz，2H)，1.16(s，9H)。
embodiment 48
n-(3-methoxyl group) propyl group-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H- pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001492
1H?NMR(400MHz，DMSO-d 6)δppm?8.43(d，J＝8.8Hz，1H)，8.25(s，1H)，7.85(t，J＝5.8Hz，1H)，7.78(d，J＝8.7Hz，1H)，7.69(dd，J＝8.0，1.3Hz，1H)，7.46(t，J＝7.3Hz，1H)，7.23(s，1H)，7.05(t，J＝7.6Hz，1H)，6.73(s，1H)，6.61(d，J＝2.3Hz，1H)，6.41(dd，J＝8.7，2.3Hz，1H)，3.79(s，3H)，3.75-3.68(m，4H)，3.51(t，J＝8.5Hz，2H)，3.18(t，J＝6.1Hz，2H)，3.09-3.00(m，7H)，2.79(dd，J＝13.2，6.5Hz，4H)，1.59-1.46(m，2H)。
embodiment 49
n-(2-dimethylin) ethyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro -5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001501
1H?NMR(400MHz，DMSO-d 6)δppm?8.41(d，J＝8.6Hz，1H)，8.24(s，1H)，7.79(d，J＝8.7Hz，1H)，7.72(d，J＝6.5Hz，1H)，7.47(t，J＝7.2Hz，1H)，7.22(s，1H)，7.06(t，J＝7.5Hz，1H)，6.73(s，1H)，6.61(d，J＝2.4Hz，1H)，6.40(dd，J＝8.8，2.5Hz，1H)，3.79(s，3H)，3.76-3.66(m，4H)，3.51(t，J＝8.1Hz，2H)，3.12-3.00(m，4H)，2.89(s，2H)，2.78(t，J＝8.5Hz，2H)，2.14(s，6H)。
embodiment 50
n-(3-methoxyl group) ethyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H- pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
1H?NMR(400MHz，DMSO-d 6)δppm?8.44(d，J＝8.5Hz，1H)，8.26(s，1H)，8.08(d，J＝5.9Hz，1H)，7.80(d，J＝8.6Hz，1H)，7.71(d，J＝7.6Hz，1H)，7.46(s，1H)，7.23(s，1H)，7.05(d，J＝7.7Hz，1H)，6.72(s，1H)，6.62(s，1H)，6.42(d，J＝8.4Hz，1H)，3.80(s，3H)，3.74(m，4H)，3.51(t，J＝8.2Hz，2H)，3.25(t，J＝5.6Hz，2H)，3.10(s，2H)，3.06(s，3H)，2.96-2.87(m，2H)，2.79(t，J＝8.6Hz，2H)。
embodiment 51
n-phenyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001511
1H?NMR(400MHz，CDCl 3)δppm?8.14(d，J＝8.7Hz，1H)，8.04(d，J＝8.5Hz，1H)，7.80(s，1H)，7.73(d，J＝7.7Hz，1H)，7.47(t，J＝7.8Hz，1H)，7.23(s，1H)，7.11-6.99(m，5H)，6.51(d，J＝2.2Hz，1H)，6.34(d，J＝8.7Hz，1H)，4.57(s，1H)，3.91-3.83(m，7H)，3.61(t，J＝8.3Hz，2H)，3.13-3.05(m，4H)，2.78(t，J＝8.4Hz，2H)。
embodiment 52
n-sec.-propyl-2-(2-(4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4- amido) benzsulfamide
Figure BPA00001751561001512
1H?NMR(400MHz，DMSO-d 6)δppm?8.61(s，1H)，8.45(d，J＝8.5Hz，1H)，8.23(s，1H)，7.83(d，J＝8.0Hz，1H)，7.73(dd，J＝8.0，1.6Hz，1H)，7.49(dd，J＝11.2，8.1Hz，3H)，7.03(t，J＝7.1Hz，1H)，6.79(d，J＝9.1Hz，2H)，6.71(s，1H)，3.75-3.64(m，4H)，3.51(t，J＝8.6Hz，2H)，3.29-3.20(m，1H)，3.02-2.91(m，4H)，2.78(t，J＝8.6Hz，2H)，0.92(d，J＝6.5Hz，6H)。
embodiment 53
n-sec.-propyl-2-(2-(4-(N-methyl) formylphenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001521
1H?NMR(400MHz，DMSO-d 6)δppm?9.18(s，1H)，8.33(d，J＝8.6Hz，1H)，8.23-8.10(m，2H)，7.85(d，J＝7.7Hz，1H)，7.81-7.70(m，3H)，7.64(d，J＝8.8Hz，2H)，7.55(t，J＝7.7Hz，1H)，7.10(t，J＝7.7Hz，1H)，6.89(s，1H)，3.55(t，J＝8.4Hz，2H)，2.82(t，J＝8.6Hz，2H)，2.74(d，J＝4.5Hz，3H)，1.98(d，J＝7.9Hz，1H)，0.92(d，J＝6.5Hz，6H)。
embodiment 54
n-sec.-propyl-2-(2-(4 hydroxymethyl phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4- amido) benzsulfamide
Figure BPA00001751561001522
1H?NMR(400MHz，CDCl 3)δppm?8.14(d，J＝8.4Hz，1H)，7.88(s，1H)，7.81(d，J＝7.8Hz，1H)，7.42(t，J＝6.9Hz，3H)，7.12(d，J＝8.4Hz，2H)，7.03(t，J＝7.6Hz，1H)，6.77(s，1H)，4.52(s，2H)，4.40(d，J＝8.0Hz，1H)，3.65(t，2H)，，3.34-3.21(m，1H)，2.85(t，J＝8.4Hz，2H)，0.91(d，J＝6.5Hz，6H)。
embodiment 55
n-sec.-propyl-2-(2-(the fluoro-4-morpholine of 2-phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
1H?NMR(400MHz，DMSO-d 6)δppm?8.46(d，J＝8.3Hz，1H)，8.31(s，1H)，8.01(s，1H)，7.82(d，J＝7.9Hz，1H)，7.48-7.28(m，2H)，6.98(t，J＝7.6Hz，1H)，6.80(dd，J＝14.0，2.5Hz，1H)，6.72-6.61(m，2H)，3.83-3.66(m，4H)，3.50(t，J＝8.6Hz，2H)，3.30-3.24(m，1H)，3.16-3.00(m，4H)，2.74(dd，J＝31.1，22.6Hz，2H)，0.87(dd，J＝38.0，6.7Hz，6H)。
embodiment 56
n-sec.-propyl-2-(2-(2-methoxyl group-6-morpholine pyridine-3-amido)-6,7-dihydro-5H-pyrrolo- [2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001531
1H?NMR(400MHz，CDCl 3)δppm?8.39(d，1H，J＝8.4Hz)，8.25(s，1H)，7.85(d，1H，J＝8.4Hz)，7.82(d，1H，J＝8.0Hz)，7.71(dd，1H，J＝8.0Hz，1.2Hz)，7.40(t，1H，J＝7.6Hz)，7.33(s，1H)，7.01(t，1H，J＝7.6Hz)，6.72(s，1H)，6.27(d，1H，J＝8.4Hz)，3.80(s，1H)，3.69-3.71(m，4H)，3.50(t，2H，J＝8.4Hz)，3.33-3.36(m，4H)，3.21-3.27(m，1H)，2.77(t，2H，J＝8.8Hz)，0.94(d，1H，J＝6.8Hz)。
embodiment 57
(2-(6-morpholine pyridine-3-amido)-6, [2,3-d] is phonetic for 7-dihydro-5H-pyrrolo-for N-sec.-propyl-2- pyridine-4-amido) benzsulfamide
Figure BPA00001751561001532
1H?NMR(400MHz，CDCl 3)δppm?8.66(s，1H)，8.40(d，1H，J＝8.4Hz)，8.36(d，1H，J＝2.4Hz)，8.23(s，1H)，7.84-7.87(m，2H)，7.33(dd，1H，J＝8.0Hz，1.2Hz)，7.46(t，1H，J＝7.2Hz)，7.03(t，1H，J＝7.6Hz)，6.78(s，1H)，6.74(d，1H，J＝9.2Hz)，3.67-3.70(m，4H)，3.52(t，2H，J＝8.8Hz)，3.26-3.31(m，5H)，2.78(t，2H，J＝8.4Hz)，0.92(d，1H，J＝6.4Hz)。
embodiment 58
(2-(3-morpholine pyridine-2-amido)-6, [2,3-d] is phonetic for 7-dihydro-5H-pyrrolo-for N-sec.-propyl-2- pyridine-4-amido) benzsulfamide
Figure BPA00001751561001541
1H?NMR(400MHz，CDCl 3)δppm?8.99(s，1H)，8.11(m，2H)，8.03-7.74(m，3H)，7.50(t，J＝7.0Hz，1H)，7.12(d，J＝8.2Hz，2H)，6.54(s，1H)，4.49(s，1H)，4.07-3.78(m，4H)，3.72(s，2H)，3.42(d，J＝5.6Hz，1H)，3.13-2.95(m，4H)，2.92(s，2H)，1.01(d，J＝6.5Hz，6H)。
embodiment 59
n-sec.-propyl-2-(2-(2-oxyethyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001542
1H?NMR(400MHz，CDCl 3)δppm?8.21(d，J＝9.3Hz，2H)，7.91(d，J＝6.6Hz，2H)，7.52(t，J＝7.3Hz，1H)，7.21(s，1H)，7.13(d，J＝7.3Hz，1H)，6.50(d，J＝2.5Hz，1H)，6.37(d，J＝9.0Hz，1H)，4.57(s，1H)，4.40(s，1H)，4.08(q，J＝7.0Hz，2H)，3.91-3.83(m，4H)，3.68(t，J＝8.2Hz，2H)，3.41(d，J＝7.1Hz，1H)，3.14-3.01(m，4H)，2.93(s，2H)，1.45(t，J＝7.0Hz，3H)，1.01(d，J＝6.5Hz，6H)。
embodiment 60
n-sec.-propyl-2-(2-(2-trifluoromethyl-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo- [2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001551
1H?NMR(400MHz，CDCl 3)δppm?8.11(d，J＝8.3Hz，1H)，7.95(s，1H)，7.88(d，J＝9.0Hz，1H)，7.77(dd，J＝8.0，1.6Hz，1H)，7.30(td，J＝8.4，4.0Hz，1H)，7.08-6.92(m，2H)，6.89(dd，J＝9.1，2.9Hz，1H)，6.61(s，1H)，4.55(s，1H)，4.38(d，J＝7.7Hz，1H)，3.98-3.71(m，4H)，3.57(t，J＝8.5Hz，2H)，3.31(dq，J＝13.2，6.6Hz，1H)，3.13-2.86(m，4H)，2.82(t，J＝8.5Hz，2H)，0.97-0.82(m，6H)。
embodiment 61
(2-(4-trifluoromethyl amido)-6, [2,3-d] is phonetic for 7-dihydro-5H-pyrrolo-for N-sec.-propyl-2- pyridine-4-amido) benzsulfamide
Figure BPA00001751561001552
1H?NMR(400MHz，DMSO-d 6)δppm?9.35(s，1H)，8.29(d，J＝8.2Hz，1H)，8.19(s，1H)，7.89(d，J＝8.7Hz，2H)，7.84(d，J＝8.1Hz，1H)，7.77(dd，J＝8.0，1.4Hz，1H)，7.56(t，J＝7.8Hz，1H)，7.47(d，J＝8.7Hz，2H)，7.10(t，J＝7.6Hz，1H)，6.93(s，1H)，3.56(t，J＝8.5Hz，2H)，3.28-3.14(m，1H)，2.83(t，J＝8.5Hz，2H)，0.92(d，J＝6.5Hz，6H)。
embodiment 62
n-sec.-propyl-2-(2-(4-(N-dimethyl) formylphenyl amido)-6,7-dihydro-5H-pyrrolo- [2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001561
1H?NMR(400MHz，CDCl 3)δppm?8.11(dd，J＝8.3，0.8Hz，1H)，7.90(s，1H)，7.84(dd，J＝8.0，1.5Hz，1H)，7.54-7.41(m，3H)，7.26-7.21(m，2H)，7.06(dd，J＝11.2，4.0Hz，2H)，4.67(d，J＝7.8Hz，1H)，4.59(s，1H)，3.59(t，J＝8.5Hz，2H)，3.35(dq，J＝13.2，6.5Hz，1H)，2.99(s，6H)，2.86(t，J＝8.5Hz，2H)，0.91(dd，J＝18.9，6.6Hz，6H)。
embodiment 63
(2-(4-acetamido phenyl amido)-6, [2,3-d] is phonetic for 7-dihydro-5H-pyrrolo-for N-sec.-propyl-2- pyridine-4-amido) benzsulfamide
Figure BPA00001751561001562
1H?NMR(400MHz，DMSO-d 6)δppm?9.70(s，1H)，8.76(s，1H)，8.40(d，J＝8.4Hz，1H)，8.20(s，1H)，7.82(d，J＝7.8Hz，1H)，7.75(dd，J＝8.0，1.5Hz，1H)，7.55(d，J＝9.0Hz，2H)，7.47(t，J＝7.1Hz，1H)，7.35(d，J＝9.0Hz，2H)，7.05(t，J＝7.6Hz，1H)，6.75(s，1H)，3.52(dd，J＝16.0，7.5Hz，2H)，3.29-3.21(m，1H)，2.80(t，J＝8.5Hz，2H)，1.97(d，J＝3.2Hz，3H)，0.92(d，J＝6.5Hz，6H)。
embodiment 64
n-sec.-propyl-2-(2-(4-(N-methyl) alkylsulfonyl phenyl amido)-6,7-dihydro-5H-pyrrolo- [2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001563
1H?NMR(400MHz，DMSO-d 6)δppm?8.14(d，J＝8.3Hz，1H)，8.00(s，1H)，7.94(d，J＝7.9Hz，1H)，7.75-7.61(m，4H)，7.56(t，J＝7.8Hz，1H)，7.18(dd，J＝14.2，6.3Hz，2H)，4.71(s，1H)，4.65(d，J＝7.7Hz，1H)，4.37(t，J＝17.6Hz，1H)，3.71(t，J＝8.5Hz，2H)，3.45(dd，J＝13.4，6.7Hz，1H)，2.96(t，J＝8.5Hz，2H)，2.62(t，J＝16.5Hz，3H)，0.99(dd，J＝24.1，7.1Hz，6H)。
embodiment 65
n-sec.-propyl-2-(2-(4-morpholine formyl radical phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001571
1H?NMR(400MHz，DMSO-d 6)δppm?9.14(s，1H)，8.33(d，J＝8.2Hz，1H)，8.20(s，1H)，7.83(d，J＝8.0Hz，1H)，7.79-7.73(m，3H)，7.57-7.49(m，1H)，7.23(d，J＝8.7Hz，2H)，7.09(t，J＝7.6Hz，1H)，6.86(s，1H)，3.62-3.52(m，6H)，3.48(s，4H)，3.24(dd，J＝13.8，7.1Hz，1H)，2.82(t，J＝8.6Hz，2H)，0.92(d，J＝6.5Hz，6H)。
embodiment 66
n-sec.-propyl-2-(2-(2-methyl-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001572
1H?NMR(400MHz，CDCl 3)δppm?8.27(d，J＝8.4Hz，1H)，8.16(s，1H)，7.85(d，J＝8.0Hz，1H)，7.66(d，J＝8.4Hz，1H)，7.37(t，J＝8.0Hz，1H)，7.04(t，J＝7.6Hz，1H)，6.77(s，1H)，6.72(d，J＝8.8Hz，1H)，6.38(s，1H)，4.58(s，1H)，4.44(d，J＝6.8Hz，1H)，3.87-3.89(m，4H)，3.66(t，J＝8.4Hz，2H)，3.44-3.38(m，1H)，3.11-3.13(m，4H)，2.90(t，J＝8.4Hz，2H)，2.26(s，3H)，1.02(d，J＝6.8Hz，6H)。
embodiment 67
n-sec.-propyl-2-(2-(2-methoxyl group-4-pyrroles's phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001581
1H?NMR(400MHz，DMSO-d 6)δppm?8.48(d，J＝8.0Hz，1H)，8.27(s，1H)，7.83(d，J＝8.0Hz，1H)，7.73(dd，J＝8.0Hz，1.6Hz，1H)，7.58(d，J＝8.8Hz，1H)，7.41(t，J＝8.4Hz，1H)，7.17(s，1H)，7.02(t，J＝8.0Hz，1H)，6.66(s，1H)，6.20(d，J＝2.4Hz，1H)，6.06(dd，J＝8.8Hz，2.4Hz，1H)，3.78(s，3H)，3.51(t，J＝8.8Hz，2H)，3.25-3.32(m，1H)，3.21-3.24(m，4H)，2.78(t，J＝8.4Hz，2H)，1.94-1.97(m，4H)，0.94(d，J＝6.4Hz，6H)。
embodiment 68
n-sec.-propyl-2-(2-(2-methoxyl group-4-piperidines phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001582
1H?NMR(400MHz，DMSO-d 6)δppm?8.41(d，J＝8.4Hz，1H)，8.25(s，1H)，7.83(d，J＝8.0Hz，1H)，7.77(d，J＝8.8Hz，1H)，7.74(dd，J＝8.8Hz，1.6Hz，1H)，7.46(t，J＝8.8Hz，1H)，7.22(s，1H)，7.05(t，J＝8.0Hz，1H)，6.73(s，1H)，6.59(d，J＝2.4Hz，1H)，6.41(dd，J＝8.8Hz，2.4Hz，1H)，3.80(s，3H)，3.53(t，J＝8.4Hz，2H)，3.24-3.31(m，1H)，3.05-3.08(m，4H)，2.79(t，J＝8.4Hz，2H)，1.61-1.67(m，4H)，1.51-1.54(m，2H)，0.94(d，J＝6.4Hz，6H)。
embodiment 69
n-sec.-propyl-2-(2-(4-(1-hydroxyl) ethylphenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
1H?NMR(400MHz，CDCl 3)δppm?8.25(d，J＝8.1Hz，1H)，7.98(s，1H)，7.90(dd，J＝8.0，1.5Hz，1H)，7.69-7.39(m，3H)，7.31-7.22(m，2H)，7.12(t，J＝7.1Hz，1H)，6.77(s，1H)，4.86(q，J＝6.4Hz，1H)，4.55(s，1H)，4.45(d，J＝7.2Hz，1H)，3.69(t，J＝8.5Hz，2H)，3.42(dd，J＝14.0，6.6Hz，1H)，2.94(t，J＝8.5Hz，2H)，1.47(t，J＝13.5Hz，3H)，1.01(d，J＝6.5Hz，6H)。
embodiment 70
n-sec.-propyl-2-(2-(2-methoxyl group-4-(2-morpholine) ethoxyl phenenyl amido)-6,7-dihydro -5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001592
1H?NMR(400MHz，CDCl 3)δppm?8.24(d，J＝8.4Hz，1H)，8.18(d，J＝8.9Hz，1H)，7.96-7.74(m，2H)，7.57-7.43(m，1H)，7.08(dd，J＝29.7，22.6Hz，2H)，6.52(t，J＝10.3Hz，1H)，6.34(dd，J＝8.9，2.6Hz，1H)，4.55(s，1H)，4.47(d，J＝7.7Hz，1H)，4.08(t，J＝5.8Hz，2H)，3.94-3.79(m，3H)，3.79-3.70(m，4H)，3.67(t，J＝8.5Hz，2H)，3.41(dq，J＝13.2，6.6Hz，1H)，2.93(t，J＝8.4Hz，2H)，2.80(t，J＝5.8Hz，2H)，2.66-2.49(m，4H)，0.99(t，J＝11.8Hz，6H)。
embodiment 71
n-sec.-propyl-2-(2-(4-Trifluoromethoxyphen-l amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
1H?NMR(400MHz，DMSO-d 6)δppm?9.11(s，1H)，8.33(d，J＝8.4Hz，1H)，8.22(s，1H)，7.85(d，J＝8.0Hz，1H)，7.76-7.79(m，3H)，7.54(t，J＝8.8Hz，1H)，7.16(d，J＝8.8Hz，2H)，7.09(t，J＝8.0Hz，1H)，6.87(s，1H)，3.56(t，J＝8.4Hz，2H)，3.28-3.31(m，1H)，2.83(t，J＝8.4Hz，2H)，0.94(d，J＝6.4Hz，6H)。
embodiment 72
n-sec.-propyl-2-(2-(4-(1-sec.-propyl amido) ethylphenyl amido)-6,7-dihydro-5H-pyrrole cough up also [2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001602
1H?NMR(400MHz，DMSO-d 6)δppm?9.17-9.23(brs，2H)，8.86-8.89(brs，1H)，8.32-8.38(brs，1H)，8.28(s，1H)，7.86(d，J＝7.6Hz，1H)，7.78(d，J＝7.6Hz，1H)，7.73(d，J＝8.8Hz，2H)，7.56(t，J＝7.6Hz，1H)，7.43(d，J＝8.8Hz，2H)，7.12(t，J＝7.6Hz，1H)，4.36-4.40(m，1H)，3.57(t，J＝8.4Hz，2H)，3.26-3.31(m，1H)，2.87-2.92(m，1H)，2.82(t，J＝8.0Hz，2H)，1.55(d，J＝6.8Hz，3H)，1.22(d，J＝6.8Hz，6H)，0.94(d，J＝6.4Hz，6H)。
embodiment 73
(2-(3-Toluidrin phenyl amido)-6, [2,3-d] is phonetic for 7-dihydro-5H-pyrrolo-for N-sec.-propyl-2- pyridine-4-amido) benzsulfamide
Figure BPA00001751561001611
1H?NMR(400MHz，CDCl 3)δppm?8.21(d，J＝8.3Hz，1H)，8.01(d，J＝7.8Hz，2H)，7.73(s，1H)，7.64(t，J＝7.8Hz，1H)，7.30-7.14(m，3H)，6.91(d，J＝8.7Hz，2H)，6.32(s，1H)，4.73(s，1H)，4.59(d，J＝7.8Hz，1H)，3.77(t，J＝8.5Hz，2H)，3.51(dd，J＝13.0，6.6Hz，1H)，3.06(d，J＝1.4Hz，3H)，3.00(d，J＝9.1Hz，2H)，1.09(dd，J＝6.5，1.3Hz，6H)。
embodiment 74
n-sec.-propyl-2-(2-(3-(N-methyl) formyl radical phenyl amido)-6,7-dihydro-5H-pyrrolo- [2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001612
1H?NMR(400MHz，DMSO-d 6)δppm?8.99(s，1H)，8.47(d，J＝8.4Hz，1H)，8.31(s，1H)，8.20(q，J＝4.8Hz，1H)，7.99(s，1H)，7.83-7.88(m，2H)，7.75(dd，J＝8.4Hz，1.6Hz，1H)，7.46(t，J＝8.4Hz，1H)，7.23-7.29(m，2H)，7.06(t，J＝8.4Hz，1H)，6.82(s，1H)，3.56(t，J＝8.4Hz，2H)，3.25-3.31(m，1H)，2.83(t，J＝8.0Hz，2H)，2.74(d，J＝4.4Hz，3H)，0.94(d，J＝6.4Hz，6H).
embodiment 75
(2-(3-acetamido phenyl amido)-6, [2,3-d] is phonetic for 7-dihydro-5H-pyrrolo-for N-sec.-propyl-2- pyridine-4-amido) benzsulfamide
Figure BPA00001751561001621
1H?NMR(400MHz，DMSO-d 6)δppm?9.80(s，1H)，8.90-9.00(brs，1H)，8.41-8.50(brs，1H)，8.34(s，1H)，7.84(d，J＝8.0Hz，1H)，7.76(d，J＝7.2Hz，1H)，7.66(s，1H)，7.46-7.49(m，2H)，7.00-7.19(m，3H)，6.84-6.89(brs，1H)，3.56(t，J＝8.4Hz，2H)，3.24-3.33(m，1H)，2.70-2.89(brs，1H)，2.02(s，3H)，0.95(d，J＝6.8Hz，6H)。
embodiment 76
n-sec.-propyl-2-(2-(2-methoxyl group-4-(4-(N, N-dimethyl)) piperidyl phenyl amido) -6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001622
1H?NMR(400MHz，DMSO-d 6)δppm?8.39(d，J＝8.4Hz，1.6Hz，1H)，8.25(s，1H)，7.83(d，J＝8.0Hz，1H)，7.81(d，J＝8.8Hz，1H)，7.74(dd，J＝8.8Hz，1H)，7.46(t，J＝8.8Hz，1H)，7.24(s，1H)，7.05(t，J＝8.0Hz，1H)，6.73(s，1H)，6.63(d，J＝2.4Hz，1H)，6.45(dd，J＝8.8Hz，2.4Hz，1H)，3.81(s，3H)，3.76(d，J＝12.8Hz，2H)，3.53(t，J＝8.8Hz，2H)，3.23-3.31(m，1H)，3.05-3.19(m，1H)，2.79(t，J＝8.8Hz，2H)，2.62-2.75(m，8H)，2.03(d，J＝12.8Hz，2H)，1.64-1.72(m，2H)，0.94(d，J＝6.8Hz，6H)。
embodiment 77
n-sec.-propyl-2-(2-(2-methoxyl group-4-1H-imidazolyl phenyl amido)-6,7-dihydro-5H-pyrroles and [2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001631
1H?NMR(400MHz，DMSO-d 6)δppm?8.30(d，J＝8.8Hz，1H)，8.27(d，J＝6.4Hz，1H)，8.21(d，J＝6.8Hz，2H)，7.84(d，J＝8.4Hz，1H)，7.75(d，J＝8.0Hz，1H)，7.71(s，1H)，7.55(t，J＝8.0Hz，1H)，7.44(s，1H)，7.24(s，1H)，7.04-7.09(m，3H)，6.90(s，1H)，3.93(s，3H)，3.55(t，J＝8.4Hz，2H)，3.21-3.31(m，1H)，2.81(t，J＝8.8Hz，2H)，0.92(d，J＝6.8Hz，6H)。
embodiment 78
n-sec.-propyl-2-(2-(4-pyrroyl group phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001632
1H?NMR(400MHz，CDCl 3)δppm?8.15(d，J＝8.5Hz，1H)，8.02(s，1H)，7.91(d，J＝8.0Hz，1H)，7.62-7.50(m，3H)，7.42(d，J＝8.6Hz，2H)，7.14(t，J＝7.6Hz，1H)，4.79(m，2H)，3.67(dd，J＝17.5，8.4Hz，4H)，3.53-3.35(m，3H)，2.91(t，J＝8.3Hz，2H)，2.01-1.79(m，4H)，1.00(t，J＝8.1Hz，6H)。
embodiment 79
n-sec.-propyl-2-(2-(2-methoxyl group-4-(4-methylol) piperidyl phenyl amido)-6,7-dihydro -5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001633
1H?NMR(400MHz，CDCl 3)δppm?8.26(d，J＝8.2Hz，1H)，8.15(d，J＝8.8Hz，1H)，8.00-7.78(m，2H)，7.52(t，J＝7.9Hz，1H)，7.12(dd，J＝15.7，7.6Hz，2H)，6.54(d，J＝2.5Hz，1H)，6.41(dd，J＝8.8，2.5Hz，1H)，4.54(s，1H)，4.44(d，J＝7.6Hz，1H)，3.84(d，J＝6.7Hz，3H)，3.67(t，J＝8.5Hz，2H)，3.63-3.48(m，4H)，3.40(dq，J＝13.0，6.6Hz，1H)，2.92(t，J＝8.5Hz，2H)，2.67(dd，J＝12.0，9.7Hz，2H)，1.86(d，J＝11.6Hz，2H)，1.56-1.38(m，2H)，1.02(dd，J＝12.2，6.6Hz，6H)。
embodiment 80
n-sec.-propyl-2-(2-(2-methoxyl group-4-(3-hydroxyl) pyrryl phenyl amido)-6,7-dihydro-5H- pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001641
1H?NMR(400MHz，CDCl 3)δppm?8.26(s，1H)，7.97-8.05(m，2H)，7.88(d，J＝8.3Hz，1H)，7.50-7.55(m，2H)，7.26(s，5H)，7.09(m，2H)，6.14(s，1H)，6.05(d，J＝8.8Hz，1H)，3.84(s，3H)，3.64(t，J＝8.0Hz，2H)，3.56-3.19(m，5H)，2.87(s，2H)，2.27-2.10(m，2H)，2.07-1.94(m，4H)，1.00(d，J＝6.5Hz，6H)。
embodiment 81
n-sec.-propyl-2-(2-(2-methoxyl group-4-(3-hydroxyl) piperidyl phenyl amido)-6,7-dihydro-5H- pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
1H?NMR(400MHz，DMSO-d 6)δppm?8.34(s，1H)，7.79(d，J＝7.6Hz，1H)，7.73-7.75(m，1H)，7.45-7.53(m，1H)，7.05-7.11(m，1H)，6.61(s，1H)，6.37-6.42(m，1H)，4.13-4.21(m，1H)，3.78(s，3H)，3.62-3.71(m，1H)，3.52(t，J＝8.0Hz，2H)，3.34-3.45(m，2H)，2.63-2.85(m，4H)，1.88-1.94(m，1H)，1.68-1.74(m，1H)，1.38-1.58(m，2H)，0.92(d，J＝6.4Hz，6H)。
embodiment 82
n-sec.-propyl-2-(2-(4-(1-piperidines) ethylphenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001651
1H?NMR(400MHz，CDCl 3)δppm?8.22(d，J＝8.3Hz，1H)，8.01(s，1H)，7.90(dd，J＝7.9，1.4Hz，1H)，7.60-7.49(m，3H)，7.24(s，1H)，7.12(t，J＝7.6Hz，1H)，6.85(s，1H)，4.59(d，J＝7.1Hz，2H)，3.67(t，J＝8.3Hz，2H)，3.52-3.30(m，1H)，2.91(dd，J＝18.1，9.7Hz，2H)，2.65-2.19(m，3H)，1.91-1.53(m，10H)，1.08-0.94(m，6H)。
embodiment 83
(2-(2-methoxyl group-4-(2-oxygen) pyridine-1 (2H) phenyl amido)-6,7-bis-for N-sec.-propyl-2- hydrogen-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001652
1H?NMR(400MHz，DMSO-d 6)δppm?8.29(t，J＝8.0Hz，2H)，8.21(s，1H)，7.81(d，J＝7.7Hz，1H)，7.76(d，J＝7.9Hz，1H)，7.61(d，J＝4.9Hz，1H)，7.55(t，J＝7.8Hz，1H)，7.51-7.36(m，2H)，7.13-6.95(m，2H)，6.90(s，1H)，6.82(dd，J＝8.5，2.2Hz，1H)，6.45(d，J＝8.8Hz，1H)，6.28(t，J＝6.7Hz，1H)，3.85(s，3H)，3.55(t，J＝8.8Hz，2H)，2.82(t，J＝8.6Hz，2H)，0.90(t，J＝19.2Hz，6H)。
embodiment 84
(2-(2-methoxyl group-4-(3,5-dimethyl) morpholine phenyl amido)-6,7-bis-for N-sec.-propyl-2- hydrogen-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001661
1H?NMR(400MHz，CDCl 3)δppm?8.26(d，J＝8.2Hz，1H)，8.17(d，J＝8.8Hz，1H)，7.98-7.87(m，2H)，7.51(dd，J＝12.0，5.0Hz，1H)，7.12(dd，J＝15.4，7.5Hz，2H)，6.49(d，J＝2.5Hz，1H)，6.36(dd，J＝8.8，2.5Hz，1H)，4.56(d，J＝11.7Hz，2H)，3.90-3.78(m，5H)，3.65(t，J＝8.4Hz，2H)，3.41(td，J＝13.4，6.7Hz，1H)，3.32(d，J＝10.7Hz，2H)，2.91(t，J＝8.4Hz，2H)，2.44-2.32(m，2H)，1.25(t，1.8Hz，6H)，1.01(d，J＝6.5Hz，6H)。
embodiment 85
(2-(2-methoxyl group-4-(2-morpholine) ethyl amido phenyl amine base)-6,7-bis-for N-sec.-propyl-2- hydrogen-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001662
1H?NMR(400MHz，DMSO-d 6)δppm?8.47(d，J＝8.7Hz，1H)，8.27(s，1H)，7.82(d，J＝7.8Hz，1H)，7.73(dd，J＝8.0，1.6Hz，1H)，7.51(d，J＝8.5Hz，1H)，7.41(t，J＝7.7Hz，1H)，7.14(s，1H)，7.02(t，J＝7.6Hz，1H)，6.65(s，1H)，6.32(d，J＝2.3Hz，1H)，6.12(dd，J＝8.5，2.3Hz，1H)，5.15(m，1H)，3.73(s，3H)，3.67-3.55(m，4H)，3.51(t，J＝8.6Hz，2H)，3.39-3.25(m，1H)，3.13(d，J＝6.3Hz，2H)，2.78(t，J＝8.5Hz，2H)，2.43(s，4H)，0.95(d，J＝6.5Hz，6H)。
embodiment 86
n-sec.-propyl-2-(2-(2-methoxyl group-4-(4-hydroxyl) piperidyl phenyl amido)-6,7-dihydro-5H- pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001671
1H?NMR(400MHz，DMSO-d 6)δppm?8.42(d，J＝8.3Hz，2H)，8.26(s，1H)，7.77(t，J＝8.4Hz，3H)，7.47(t，J＝7.9Hz，1H)，7.22(s，2H)，7.06(t，J＝7.6Hz，1H)，6.74(s，2H)，6.61(d，J＝2.5Hz，1H)，6.43(d，J＝8.7Hz，1H)，4.67(d，J＝4.2Hz，1H)，3.81(s，3H)，3.543.30(m，6H)，2.78(m，4H)，2.01(d，J＝8.0Hz，1H)，1.83(d，2H)，1.51(d，J＝9.9Hz，2H)，0.95(d，J＝6.5Hz，6H)。
embodiment 87
n-sec.-propyl-2-(2-(2-methoxyl group-4-sulfone is for morpholine phenyl amido)-6,7-dihydro-5H-pyrroles and [2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001672
1H?NMR(400MHz，CDCl 3)δppm?8.25(d，J＝8.7Hz，2H)，8.04-7.76(m，2H)，7.51(s，1H)，7.20(s，1H)，7.12(t，1H)，6.50(s，1H)，6.49(s，1H)，6.42(d，J＝9.2Hz，1H)，4.55(s，1H)，4.39(d，J＝7.6Hz，1H)，3.86(s，3H)，3.69(t，J＝9.3Hz，7H)，3.69(t，J＝9.3Hz，6H)，3.42(dd，J＝14.0，6.6Hz，1H)，3.18-3.04(m，4H)，2.94(d，J＝8.3Hz，2H)，1.01(d，J＝6.5Hz，6H)。
embodiment 88
n-sec.-propyl-2-(2-(2-methoxyl group-4-tetrazolium-2-base phenyl amido)-6,7-dihydro-5H-pyrrolo- [2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001681
1H?NMR(400MHz，CDCl 3)δppm?8.59(d，J＝9.2Hz，2H)，8.18(d，J＝8.4Hz，1H)，7.97-7.91(m，2H)，7.66-7.49(m，4H)，7.18(t，J＝7.6Hz，1H)，4.63(s，1H)，4.43(d，J＝7.6Hz，1H)，3.99(s，3H)，3.73(t，J＝8.5Hz，2H)，3.47-3.39(m，1H)，2.97(dd，J＝20.2，11.9Hz，2H)，1.01(d，J＝6.5Hz，6H)。
embodiment 89
(2-(2-methoxyl group-4-(3-N, N-dimethyl) pyrroles's phenyl amido)-6,7-bis-for N-sec.-propyl-2- hydrogen-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001682
1H?NMR(400MHz，CDCl 3)δppm?8.33(s，1H)，8.13-7.94(m，2H)，7.89(d，J＝8.0Hz，1H)，7.50(t，J＝7.9Hz，1H)，7.09(t，J＝7.8Hz，1H)，7.00(s，1H)，6.13(d，J＝2.2Hz，1H)，6.05(d，J＝8.6Hz，1H)，4.51(d，J＝30.1Hz，2H)，3.85(s，3H)，3.65(t，J＝8.4Hz，2H)，3.55-3.37(m，4H)，3.21(s，1H)，2.37(s，6H)，2.13(d，J＝67.2Hz，2H)，2.11-1.78(m，2H)，1.01(s，6H)。
embodiment 90
n-sec.-propyl-2-(2-(2-methoxyl group-4-(2,4-dimethyl)-1H-imidazoles phenyl amido)-6,7- dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001691
1H?NMR(400MHz，CDCl 3)δppm?8.49(d，J＝8.4Hz，1H)，8.21(d，J＝8.3Hz，1H)，8.05-7.77(m，2H)，7.73-7.48(m，1H)，7.43(s，1H)，7.15(dd，J＝11.1，4.1Hz，1H)，6.81-6.55(m，3H)，4.65(s，1H)，4.56(d，J＝7.8Hz，1H)，3.90(s，3H)，3.73(t，J＝8.4Hz，2H)，3.63-3.33(m，1H)，3.15-2.79(m，2H)，2.34(s，3H)，2.29-2.15(m，3H)，1.01(dd，J＝17.8，6.5Hz，6H)。
embodiment 91
n-sec.-propyl-2-(2-(4-methyl) thiazole amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4- amido) benzsulfamide
Figure BPA00001751561001692
1H?NMR(400MHz，CDCl 3)δppm?12.30(s，1H)，9.47(s，1H)，7.91(dd，J＝13.7，8.2Hz，2H)，7.62(s，1H)，7.53(t，J＝7.8Hz，1H)，7.15(t，J＝7.7Hz，1H)，6.21(s，1H)，4.46(d，J＝7.7Hz，1H)，3.80(t，J＝8.2Hz，2H)，3.40(dd，J＝12.8，6.6Hz，1H)，2.96(t，J＝8.2Hz，2H)，2.52-2.10(m，3H)，1.01(dd，J＝6.5，1.4Hz，6H)。
embodiment 92
n-sec.-propyl-2-(2-(2-methoxyl group-4-1,4-connection piperidines phenyl amido)-6,7-dihydro-5H-pyrroles and [2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001693
1H?NMR(400MHz，CDCl 3)δppm?8.22(d，J＝8.4Hz，1H)，8.17(d，J＝8.8Hz，1H)，7.85-7.92(m，2H)，7.52(t，J＝7.6Hz，1H)，7.17(s，1H)，7.12(t，J＝7.6Hz，1H)，6.51(s，1H)，6.38(d，J＝8.8Hz，1H)，4.56(s，1H)，4.43-4.49(brs，1H)，3.85(s，3H)，3.62-3.70(m，4H)，3.39-3.44(m，1H)，3.28-3.21(m，7H)，2.72(t，J＝8.4Hz，2H)，2.06-2.09(m，2H)，1.81-1.95(m，6H)，1.61-1.65(m，2H)。
embodiment 93
n-sec.-propyl-2-(2-(2-methoxyl group-4-(4-pyrryl) piperidines phenyl amido)-6,7-dihydro-5H- pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001701
1H?NMR(400MHz，DMSO-d 6)δppm?8.38(d，J＝8.4Hz，1H)，8.23(s，1H)，7.80(dd，J＝8.3，4.2Hz，2H)，7.73(d，J＝8.0Hz，1H)，7.45(t，J＝7.8Hz，1H)，7.20(s，1H)，7.03(t，J＝7.6Hz，1H)，6.70(s，1H)，6.61(d，J＝2.2Hz，1H)，6.50-6.37(m，1H)，3.79(s，3H)，3.65(s，2H)，3.51(t，J＝8.4Hz，2H)，2.78(t，J＝8.5Hz，2H)，2.64(t，J＝11.5Hz，2H)，1.99(d，J＝15.1Hz，2H)，1.82(m，4H)，1.66(s，2H)，0.93(d，J＝6.5Hz，6H)。
embodiment 94
n-sec.-propyl-2-(2-(2-methoxyl group-4-pyrazole phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
1H?NMR(400MHz，CDCl 3)δppm?8.45(d，J＝8.8Hz，1H)，8.22(d，J＝8.0Hz，1H)，8.00-7.90(m，2H)，7.87(d，J＝2.4Hz，1H)，7.71(d，J＝1.5Hz，1H)，7.57(t，J＝7.0Hz，1H)，7.40(s，1H)，7.30(d，J＝2.3Hz，1H)，7.16(t，J＝7.7Hz，1H)，7.01(dd，J＝8.8，2.4Hz，1H)，6.52-6.37(m，1H)，4.61(s，1H)，4.42(d，J＝8.0Hz，1H)，3.95(d，J＝18.6Hz，3H)，3.73(t，J＝8.5Hz，2H)，3.43(dd，J＝13.2，7.0Hz，1H)，2.98(t，J＝8.4Hz，2H)，1.00(dd，J＝13.0，7.0Hz，6H)。
embodiment 95
n-sec.-propyl-2-(2-(2-methoxyl group-4-(4-morpholine) piperidines phenyl amido)-6,7-dihydro-5H- pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001711
1H?NMR(400MHz，CDCl 3)δppm?8.25(s，1H)，8.15(d，J＝8.7Hz，1H)，7.93(d，J＝6.8Hz，1H)，7.54(t，J＝7.1Hz，1H)，7.21(s，1H)，7.14(t，J＝7.7Hz，1H)，6.56(t，J＝4.0Hz，1H)，6.46-6.32(m，1H)，4.65(s，1H)，4.52(s，1H)，3.98(s，1H)，3.87-3.72(m，7H)，3.71-3.49(m，4H)，3.43(dd，J＝13.4，6.6Hz，1H)，2.94(m，2H)，2.81-2.56(m，6H)，2.38(s，2H)，1.98(d，J＝11.7Hz，2H)，1.72(d，J＝11.8Hz，2H)，1.03(d，J＝6.5Hz，6H)。
embodiment 96
(2-(2-methoxyl group-4-(4-N-methylpiperazine) piperidines phenyl amido)-6,7-bis-for N-sec.-propyl-2- hydrogen-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001712
1H?NMR(400MHz，DMSO-d 6)δppm?8.40(d，J＝8.4Hz，1H)，8.24(s，1H)，7.83(d，J＝8.0Hz，1H)，7.78-7.65(m，2H)，7.45(t，J＝7.9Hz，1H)，7.21(s，1H)，7.04(t，J＝7.6Hz，1H)，6.72(s，1H)，6.59(d，J＝2.2Hz，1H)，6.46-6.31(m，1H)，3.79(s，3H)，3.65(d，J＝12.1Hz，2H)，3.52(t，J＝8.3Hz，2H)，3.28-3.16(m，3H)，2.78(t，J＝8.5Hz，2H)，2.69-2.55(m，8H)，2.27(m，4H)，1.83(s，2H)，1.52(d，J＝10.6Hz，2H)，0.93(d，J＝6.5Hz，6H)。
embodiment 97
n-sec.-propyl-2-(2-(2-methoxyl group-4-(4-piperazine) piperidines phenyl amido)-6,7-dihydro-5H- pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001721
1H?NMR(400MHz，DMSO-d 6)δppm?8.82-9.03(m，2H)，7.79(t，J＝7.6Hz，2H)，7.43-7.58(m，1H)，7.15-7.22(m，1H)，7.11-7.14(m，1H)，6.68(s，1H)，6.51-6.56(m，1H)，3.88-3.92(m，2H)，3.80(s，3H)，3.21-3.67(m，12H)，2.74(t，J＝7.6Hz，2H)，2.57-2.65(m，2H)，1.61-1.71(m，2H)，0.93(d，J＝6.4Hz，6H)。
embodiment 98
n-sec.-propyl-2-(2-(2-methoxyl group-4-(2-carbonyl) piperidines phenyl amido)-6,7-dihydro-5H- pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001722
1H?NMR(400MHz，DMSO-d 6)δppm?8.41(d，J＝8.2Hz，1H)，8.25(s，1H)，7.78(m，3H)，7.47(t，J＝7.1Hz，1H)，7.23(s，1H)，7.05(t，J＝7.6Hz，1H)，6.74(s，1H)，6.62(d，J＝2.5Hz，1H)，6.44(dd，J＝8.7，2.5Hz，1H)，4.42(d，J＝12.2Hz，1H)，3.82(d，J＝9.3Hz，3H)，3.76-3.62(m，2H)，3.53(t，J＝8.2Hz，2H)，3.29-3.19(m，1H)，3.18(t，J＝5.6Hz，2H)，2.80(t，J＝8.5Hz，2H)，2.69(t，J＝11.2Hz，2H)，2.25(t，J＝6.4Hz，2H)，1.90-1.77(m，2H)，1.68(d，J＝4.7Hz，2H)，1.57(d，J＝9.8Hz，2H)，0.94(d，J＝6.5Hz，6H)。
embodiment 99
n-sec.-propyl-2-(2-(2-methoxyl group-4-(3,4-2 (1H))-quinolinone phenyl amido)-6,7- dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001731
1H?NMR(400MHz，CDCl 3)δppm?8.26(d，J＝8.0Hz，1H)，8.16(d，J＝8.8Hz，1H)，7.93(s，1H)，7.90(dd，J＝8.0Hz，1.2Hz，1H)，7.52(t，J＝8.8Hz，1H)，7.16-7.25(s，1H)，7.12(t，J＝7.6Hz，1H)，7.02(t，J＝8.0Hz，1H)，6.57(d，J＝2.4Hz，1H)，6.43(dd，J＝8.8Hz，2.0Hz，1H)，4.54-4.61(m，2H)，4.43-4.50(m，1H)，3.86(s，3H)，3.65-3.69(m，4H)，3.39-3.44(m，1H)，2.92(t，J＝8.8Hz，2H)，2.79-2.86(m，6H)，2.58-2.62(m，1H)，1.82-1.84(m，2H)，1.01(d，J＝6.4Hz，6H)。
embodiment 100
n 4 -(2-(sec.-propyl sulphonyl) phenyl)-N 2 -(2-methoxyl group-4-morpholinyl phenyl)-6,7 -dihydro-5H-pyrrolo-[2,3-D] pyrimidine-2, the 4-diamines
1H?NMR(400MHz，DMSO-d 6)δppm?8.53(s，1H)，8.50(d，J＝8.4Hz，1H)，7.75(d，J＝8.8Hz，1H)，7.71(dd，J＝8.0Hz，1.6Hz，1H)，7.58(t，J＝8.4Hz，1H)，7.27(s，1H)，7.14(t，J＝8.0Hz，1H)，6.76(s，1H)，6.62(d，J＝2.4Hz，1H)，6.44(dd，J＝8.8Hz，2.8Hz，1H)，3.80(s，3H)，3.74-3.76(m，4H)，3.51(t，J＝8.4Hz，2H)，3.38-3.42(m，1H)，3.07-3.09(m，4H)，2.78(t，J＝8.4Hz，2H)，1.17(d，J＝6.8Hz，6H)。
embodiment 101
(±)-N-sec.-propyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6,7-dihydro -5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001741
1H?NMR(400MHz，DMSO-d 6)δppm?8.46(d，J＝8.3Hz，1H)，8.36(s，1H)，7.77(ddd，J＝13.5，9.5，4.7Hz，3H)，7.44(t，J＝7.9Hz，1H)，7.25(s，1H)，7.04(t，J＝7.2Hz，1H)，6.75(s，1H)，6.62(d，J＝2.5Hz，1H)，6.40(dd，J＝8.7，2.5Hz，1H)，3.80(s，3H)，3.77-3.71(m，4H)，3.67(t，J＝9.1Hz，1H)，3.27(d，J＝6.9Hz，1H)，3.11-3.03(m，5H)，1.17(d，J＝6.7Hz，3H)，1.01(d，J＝6.5Hz，3H)，0.90(d，J＝6.5Hz，3H)。
embodiment 102
(R)-N-methyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6,7-dihydro-5H- pyrrolo-[2,3-d] pyrimidine-4-amido) benzamide
Figure BPA00001751561001742
1H?NMR(400MHz，DMSO-d 6)δppm?10.08(s，1H)，8.60-8.63(dd，1H，J＝1.2Hz，8.4Hz)，8.24-8.26(d，1H，J＝8.8Hz)，7.39-7.42(m，2H)，7.10(s，1H)，6.91-6.95(m，1H)，6.50-6.51(d，1H，J＝2.4Hz)，6.45-6.48(dd，1H，J＝3.2Hz，8.8Hz)，6.18-6.19(d，1H，J＝4.4Hz)，4.13(s，1H)，3.85-3.89(s+m，7H)，3.76-3.81(t，1H，J＝9.2Hz)，3.47-3.49(m，1H)，3.20-3.23(dd，1H，J＝4.4Hz，8.8Hz)，3.00-3.10(t，4H，J＝4.8Hz)，2.90-3.00(d，3H，J＝4.8Hz)，1.38-1.40(d，3H，J＝6.4Hz)。
embodiment 103
n-methyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5,5-dimethyl-6,7-dihydro-5H- pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001751
1H?NMR(400MHz，CDCl 3)δppm?8.32(d，1H，J＝8.4Hz)，8.13(d，1H，J＝8.8Hz)，8.32(s，1H)，7.88(dd，1H，J＝8.0Hz，1.6Hz)，7.52(t，1H，J＝8.4Hz)，7.17(s，1H)，7.11(t，1H，J＝7.2Hz)，6.50(d，1H，J＝2.8Hz)，6.33(dd，1H，J＝8.8Hz，2.4Hz)，4.71(s，1H)，4.49(q，1H，J＝4.8Hz)，3.85-3.88(m，7H)，3.35(s，2H)，3.07-3.10(m，4H)，2.59(d，3H，J＝5.2Hz)，1.47(s，6H)。
embodiment 104
n-cyclobutyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5,5-dimethyl-6,7-dihydro -5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001752
1H?NMR(400MHz，CDCl 3)δppm?8.22(d，1H，J＝8.4Hz)，8.13(d，1H，J＝8.8Hz)，7.88(dd，1H，J＝8.8Hz，1.2Hz)，7.87(s，1H)，7.50(t，1H，J＝7.2Hz)，7.17(s，1H)，7.12(t，1H，J＝7.2Hz)，6.49(d，1H，J＝2.4Hz)，6.26(dd，1H，J＝8.8Hz，2.4Hz)，4.63(d，1H，J＝9.6Hz)，4.57(s，1H)，3.85-3.87(m，7H)，3.70-3.76(m，1H)，3.37(s，2H)，3.05-3.08(m，4H)，1.93-2.00(m，2H)，1.62-1.70(m，2H)，1.47(s，6H)，1.41-1.49(m，2H)。
embodiment 105
n-sec.-propyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5,5-dimethyl-6,7-dihydro -5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001761
1H?NMR(400MHz，CDCl 3)δppm?8.21(d，1H，J＝8.4Hz)，8.13(d，1H，J＝8.8Hz)，7.92(dd，1H，J＝8.0Hz，1.2Hz)，7.83(s，1H)，7.51(t，1H，J＝7.2Hz)，7.17(s，1H)，7.14(t，1H，J＝7.2Hz)，6.49(d，1H，J＝2.0Hz)，6.27(dd，1H，J＝8.8Hz，2.4Hz)，4.58(s，1H)，4.29(d，1H，J＝4.0Hz)，3.85-3.88(m，7H)，3.36-3.40(m，1H)，3.36(s，2H)，3.06-3.07(m，4H)，1.49(s，6H)，0.97(d，6H)，J＝6.8Hz)。
embodiment 106
n-n-propyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5,5-dimethyl-6,7-dihydro -5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001762
1H?NMR(400MHz，CDCl 3)δppm?8.26(d，1H，J＝8.4Hz)，8.12(d，1H，J＝8.8Hz)，7.93(s，1H)，7.89(dd，1H，J＝8.0Hz，1.6Hz)，7.52(t，1H，J＝8.4Hz)，7.17(s，1H)，7.14(t，1H，J＝8.0Hz)，6.49(d，1H，J＝2.4Hz)，6.31(dd，1H，J＝8.8Hz，2.8Hz)，4.61(s，1H)，4.46(t，1H，J＝6.4Hz)，3.85-3.88(m，7H)，3.36(s，1H)，3.07-3.09(m，4H)，2.86(q，2H，J＝6.4Hz)，1.47(s，6H)，1.28-1.39(m，2H)，0.72(t，3H，J＝7.6Hz)。
embodiment 107
n-isobutyl--2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5,5-dimethyl-6,7-dihydro -5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001771
1H?NMR(400MHz，CDCl 3)δppm?8.25(d，1H，J＝8.0Hz)，8.11(d，1H，J＝8.8Hz)，7.88-7.90(m，2H)，7.52(t，1H，J＝8.8Hz)，7.16(s，1H)，7.14(t，1H，J＝8.4Hz)，6.49(d，1H，J＝2.8Hz)，6.29(dd，1H，J＝8.8Hz，2.4Hz)，4.57(s，1H)，4.44(t，1H，J＝6.4Hz)，3.85-3.88(m，7H)，3.36(s，2H)，3.07-3.09(m，4H)，2.70(t，2H，J＝6.8Hz)，1.55-1.63(m，1H)，1.48(s，6H)，0.72(d，6H，J＝6.8Hz)。
embodiment 108
n-cyclopentyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5,5-dimethyl-6,7-dihydro -5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001772
1H?NMR(400MHz，DMSO-d6)δppm?8.35(d，J＝8.0Hz，1H)，8.32(s，1H)，7.83(d，J＝7.6Hz，1H)，7.78(d，J＝8.8Hz，1H)，7.70(dd，J＝8.0Hz，1.6Hz，1H)，7.41(t，J＝8.4Hz，1H)，7.17(s，1H)，7.05(t，J＝8.0Hz，1H)，6.76(s，1H)，6.59(d，J＝2.8Hz，1H)，6.32(dd，J＝8.8Hz，2.4Hz，1H)，3.79(s，3H)，3.71-3.73(m，4H)，3.43-3.47(m，1H)，3.19(s，2H)，3.02-3.05(m，4H)，1.55-1.69(m，2H)，1.41-1.53(m，2H)，1.30-1.35(m，10H)。
embodiment 109
n-cyclohexyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5,5-dimethyl-6,7-dihydro -5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001781
1H?NMR(400MHz，DMSO-d 6)δppm?8.30(s，1H)，8.25(d，J＝8.8Hz，1H)，7.79(d，J＝8.8Hz，1H)，7.72(d，J＝8.6Hz，1H)，7.42(t，J＝8.0Hz，1H)，7.14(s，1H)，7.07(t，J＝8.0Hz，1H)，6.76(s，1H)，6.59(s，1H)，6.28(d，J＝8.8Hz，1H)，3.79(s，3H)，3.70-3.72(m，4H)，3.20(s，2H)，2.95-3.03(m，5H)，1.55-1.61(m，2H)，1.45-1.52(m，2H)，1.35(s，6H)，1.19-1.24(m，2H)，1.05-1.12(m，2H)，0.94-1.09(m，2H)。
embodiment 110
n-normal-butyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5,5-dimethyl-6,7-dihydro -5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
1H?NMR(400MHz，CDCl 3)δppm?8.28(d，J＝8.2Hz，1H)，8.13(d，J＝8.8Hz，1H)，7.93-7.86(m，2H)，7.52(s，1H)，7.14(d，J＝5.5Hz，2H)，6.49(d，J＝2.5Hz，1H)，6.31(dd，J＝8.8，2.4Hz，1H)，4.53(s，1H)，4.36(s，1H)，3.86(dd，J＝8.1，3.2Hz，7H)，3.36(s，2H)，3.11-3.03(m，4H)，2.90(dd，J＝13.6，6.8Hz，2H)，1.47(s，6H)，1.31(dd，J＝14.8，7.3Hz，4H)，1.13(dd，J＝15.0，7.3Hz，2H)，0.72(t，J＝7.3Hz，3H)。
embodiment 111
n, N-dimethyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5,5-dimethyl-6,7- dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001791
1H?NMR(400MHz，CDCl 3)δppm?8.42(s，1H)，8.35(d，1H，J＝8.8Hz)，8.20(d，1H，J＝8.8Hz)，7.77(dd，1H，J＝8.0Hz，1.6Hz)，7.50(t，1H，J＝8.4Hz)，7.16(s，1H)，7.10(t，1H，J＝8.0Hz)，6.50(d，1H，J＝2.4Hz)，6.35(dd，1H，J＝8.8Hz，2.4Hz)，4.54(s，1H)，3.86-3.88(m，7H)，3.35(s，2H)，3.08-3.10(m，4H)，2.72(s，6H)，1.48(s，2H)。
embodiment 112
n-sec-butyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5,5-dimethyl-6,7-dihydro -5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001792
1H?NMR(400MHz，CDCl 3)δppm?8.21(d，J＝8.3Hz，1H)，8.14(d，J＝8.8Hz，1H)，7.92(dd，J＝7.8，1.6Hz，2H)，7.53-7.46(m，1H)，7.18(s，1H)，7.15-7.09(m，1H)，6.49(d，J＝2.5Hz，1H)，6.26(dd，J＝8.8，2.5Hz，1H)，4.67(s，1H)，4.32(d，J＝8.1Hz，1H)，3.91-3.81(m，7H)，3.35(s，2H)，3.17(dt，J＝14.6，6.6Hz，1H)，3.10-3.03(m，4H)，1.45(d，J＝12.4Hz，6H)，1.38-1.19(m，2H)，0.96(d，J＝6.6Hz，3H)，0.67(t，J＝7.4Hz，3H)。
embodiment 113
n-ethyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5,5-dimethyl-6,7-dihydro-5H- pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001801
1H?NMR(400MHz，CDCl 3)δppm?8.29(d，J＝7.9Hz，1H)，8.14(d，J＝8.8Hz，1H)，7.95(s，1H)，7.89(dd，J＝8.0，1.5Hz，1H)，7.54-7.48(m，1H)，7.17-7.09(m，2H)，6.50(d，J＝2.5Hz，1H)，6.32(dd，J＝8.9，2.6Hz，1H)，4.54(s，1H)，4.37(t，J＝6.1Hz，1H)，3.89-3.83(m，7H)，3.36(d，J＝0.9Hz，2H)，3.11-3.05(m，4H)，3.02-2.91(m，2H)，1.47(s，6H)，1.00(t，J＝7.2Hz，3H)。
embodiment 114
n-(3-methoxyl group) propyl group-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5,5-diformazan base-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001802
1H?NMR(400MHz，CDCl 3)δppm?8.32(d，J＝8.3Hz，1H)，8.19(d，J＝8.8Hz，1H)，7.96(s，1H)，7.90(d，J＝8.0Hz，1H)，7.52(t，J＝7.8Hz，1H)，7.21-7.08(m，2H)，6.51(d，J＝2.5Hz，1H)，6.33(dd，J＝8.8，2.4Hz，1H)，5.50(t，J＝5.6Hz，1H)，4.51(s，1H)，3.95-3.78(m，7H)，3.36(s，2H)，3.24(t，J＝5.5Hz，2H)，3.13-3.06(m，4H)，3.04-2.97(m，5H)，1.48(s，6H)。
embodiment 115
n-(2-methoxyl group) ethyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5,5-diformazan base-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001811
1H?NMR(400MHz，CDCl 3)δppm?8.29(d，J＝8.0Hz，1H)，8.04(s，2H)，7.90(d，J＝8.1Hz，1H)，7.51(t，J＝7.2Hz，1H)，7.15(t，J＝7.6Hz，1H)，6.49(s，1H)，6.32(d，J＝6.4Hz，1H)，4.93(s，1H)，3.87(d，J＝9.9Hz，7H)，3.41(s，2H)，3.26(t，J＝5.1Hz，2H)，3.09(dd，J＝12.5，7.7Hz，9H)，1.48(s，6H)。
embodiment 116
n-phenyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5,5-dimethyl-6,7-dihydro-5H- pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001812
1H?NMR(400MHz，CDCl 3)δppm?8.11(d，J＝8.8Hz，1H)，8.05(d，J＝8.2Hz，1H)，7.73(s，1H)，7.63(d，J＝8.0Hz，1H)，7.46(t，J＝7.0Hz，1H)，7.23(s，1H)，7.02(m，J＝7.3Hz，6H)，6.51(d，J＝2.5Hz，1H)，6.43(s，1H)，6.20(d，J＝8.8Hz，1H)，4.64(s，1H)，3.88(d，J＝6.6Hz，7H)，3.38(s，2H)，3.11-3.04(m，4H)，1.49(s，6H)。
embodiment 117
the N-tertiary butyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5,5-dimethyl-6,7-dihydro -5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001821
1H?NMR(400MHz，CDCl 3)δppm?8.44(s，1H)，8.19(s，1H)，7.96(d，J＝7.6Hz，1H)，7.88(t，J＝9.3Hz，2H)，7.50(t，J＝7.7Hz，1H)，7.31(d，J＝7.6Hz，1H)，6.88(s，1H)，6.56(d，J＝8.3Hz，1H)，4.43(s，1H)，4.04(s，4H)，3.88(d，J＝19.0Hz，3H)，3.60(s，2H)，3.37(s，4H)，1.52(s，6H)，1.16(d，J＝17.1Hz，9H)。
embodiment 118
n-encircles the third methyl-2-, and (7-bis-for 2-(2-methoxyl group-4-morpholine phenyl amido)-5,5-dimethyl-6 hydrogen-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001822
1H?NMR(400MHz，CDCl 3)δppm?8.28(d，J＝8.3Hz，1H)，8.13(d，J＝8.8Hz，1H)，7.95(d，J＝6.4Hz，1H)，7.89(s，1H)，7.57(t，J＝7.1Hz，1H)，7.23-7.15(m，2H)，6.54(d，J＝2.5Hz，1H)，6.32(d，J＝9.0Hz，1H)，4.60-4.53(m，2H)，3.98-3.85(m，7H)，3.41(s，2H)，3.14-3.07(m，4H)，2.83-2.74(m，2H)，1.53(s，6H)，0.082-0.072(m，1H)，0.35-0.25(m，2H)，-0.05--0.09(m，2H)。
embodiment 119
n-hydroxyethyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5,5-dimethyl-6,7-dihydro -5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001831
1H?NMR(400MHz，CDCl 3)δppm?9.10(s，1H)，8.20(s，1H)，8.10(d，J＝8.7Hz，1H)，7.95(d，J＝8.0Hz，1H)，7.58(d，J＝5.5Hz，1H)，7.32(s，1H)，7.04(s，1H)，6.92(s，1H)，4.17-4.07(m，4H)，3.87(s，3H)，3.61(s，3H)，3.57-3.49(m，6H)，3.11(s，2H)，1.53(s，6H)。
embodiment 120
n-(N, N-dimethyl) ethyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5,5- dimethyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide
Figure BPA00001751561001832
1H?NMR(400MHz，CDCl 3)δppm?8.17(s，1H)，8.03(d，1H，J＝8.8Hz)，8.01(s，1H)，7.82(dd，1H，J＝8.0Hz，1.2Hz)，7.53(t，1H，J＝8.4Hz)，7.16(t，1H，J＝7.2Hz)，6.48(d，1H，J＝2.4Hz)，6.30(dd，1H，J＝8.8Hz，2.4Hz)，4.99(brs，1H)，3.85-3.88(m，7H)，3.37(s，2H)，3.20-3.25(m，2H)，3.08-3.11(m，4H)，2.71-2.75(m，2H)，2.37(s，6H)，1.48(s，6H)。
embodiment 121
2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo- [2,3-d] pyrimidine-4-amido) benzoyl cyclopentamine
Figure BPA00001751561001841
1H?NMR(400MHz，CDCl 3)δppm?8.71(s，1H)，8.42(d，J＝8.3Hz，1H)，8.28(d，J＝8.8Hz，1H)，7.35(dd，J＝12.2，8.1Hz，2H)，7.13(s，1H)，6.97(t，J＝7.5Hz，1H)，6.52(s，1H)，6.45(d，J＝8.8Hz，1H)，4.45(s，1H)，3.95-3.78(m，7H)，3.64(t，J＝6.7Hz，2H)，3.54(t，J＝6.2Hz，2H)，3.33(s，2H)，3.11(d，J＝4.5Hz，4H)，2.04-1.90(m，2H)，1.89-1.79(m，2H)，1.47(s，6H)。
embodiment 122
n-methyl-N-methylsulfonyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5,5-dimethyl -6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) aniline
Figure BPA00001751561001842
1H?NMR(400MHz，CDCl3)δppm?8.42(d，J＝8.7Hz，1H)，8.16(d，J＝8.5Hz，1H)，7.40-7.30(m，2H)，7.15-7.04(m，2H)，6.51(s，1H)，6.42(d，J＝8.6Hz，1H)，5.35(m，2H)，3.88(m，4H)，3.85(s，3H)，3.35(s，2H)，3.27(d，J＝2.4Hz，3H)，3.10(m，4H)，2.99(s，3H)。
embodiment 123
n 2 -(2-methoxyl group-4-morpholinyl phenyl)-5,5-dimethyl-N 4 -(6-picoline-2)-6,7 -dihydro-5H-pyrroles [2,3-d] pyrimidine 2-1, the 4-diamines
Figure BPA00001751561001843
1H?NMR(400MHz，CDCl 3)δppm?8.09(t，J＝8.2Hz，2H)，7.48(t，J＝7.9Hz，1H)，7.10(s，1H)，6.75(d，J＝7.3Hz，1H)，6.52(d，J＝2.5Hz，1H)，6.47(dd，J＝8.7，2.5Hz，1H)，4.82(s，1H)，3.94-3.80(m，7H)，3.35(s，2H)，3.15-3.09(m，4H)，2.44(s，3H)，1.49(s，6H)。
embodiment 124
n-ethanoyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5,5-dimethyl-6,7-dihydro -5H-pyrrolo-[2,3-d] pyrimidine-4-amido) aniline
Figure BPA00001751561001851
1H?NMR(400MHz，CDCl 3)δppm?8.52(s，1H)，7.87(d，J＝8.8Hz，1H)，7.47(t，J＝9.8Hz，2H)，7.24-7.08(m，3H)，6.53-6.40(m，2H)，6.28(d，J＝8.7Hz，1H)，4.74(s，1H)，3.91-3.83(m，4H)，3.81(s，3H)，3.36(s，2H)，3.12-3.00(m，4H)，1.97(s，3H)，1.45(s，6H)。
embodiment 125
the fluoro-2-of 3,4-bis-(2-(2-methoxyl group-4-morpholine phenyl amido)-5,5-dimethyl-6,7-dihydro-5H- pyrrolo-[2,3-d] pyrimidine-4-amido) benzene
Figure BPA00001751561001852
1H?NMR(400MHz，CDCl 3)δppm?8.05(d，J＝8.6Hz，1H)，7.73(ddd，J＝12.8，7.3，2.7Hz，1H)，7.11-6.98(m，2H)，6.95(d，J＝9.0Hz，1H)，6.52-6.41(m，2H)，5.94(s，1H)，4.59(s，1H)，3.91-3.81(m，7H)，3.34(s，2H)，3.15-3.06(m，4H)，1.42(s，6H)。
embodiment 126
n-methyl 2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5,5-dimethyl-6,7-dihydro-5H- pyrrolo-[2,3-d] pyrimidine-4-amido) benzo [d] [3,4] dioxole methane amide
Figure BPA00001751561001861
1H?NMR(400MHz，CDCl 3)δppm?8.79(s，1H)，8.09(d，J＝8.8Hz，1H)，7.22(s，1H)，7.08(d，J＝8.2Hz，1H)，6.70(d，J＝8.1Hz，1H)，6.50(d，J＝2.5Hz，1H)，6.32(dd，J＝8.8，2.5Hz，1H)，6.12(d，J＝4.8Hz，1H)，5.84(s，2H)，4.80-4.60(s，1H)，3.94-3.88(m，4H)，3.86(s，3H)，3.38(s，2H)，3.14-3.06(m，4H)，2.96(d，J＝4.9Hz，3H)，1.54(s，6H)。
embodiment 127
n-methyl-N-methylsulfonyl 2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5,5-dimethyl -6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) hexahydroaniline
Figure BPA00001751561001862
1H?NMR(400MHz，CDCl 3)δppm?8.00(d，J＝8.4Hz，1H)，6.48(s，1H)，6.43(d，J＝8.4Hz，2H)，3.96-3.78(m，7H)，3.38(s，2H)，3.18-3.05(m，4H)，2.85(s，3H)，2.75(m，3H)，2.52(m，1H)，2.38-2.28(t，1H)，2.24-2.18(t，2H)，2.08-1.96(m，4H)，1.60(s，6H)，1.40-1.30(m，4H)。
embodiment 128
n-methyl-2-(2-(2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxygen assorted oneself-5-amido)-5,5-dimethyl-6,7- dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzamide
Figure BPA00001751561001871
1H?NMR(400MHz，CDCl 3)δppm?9.87(s，1H)，8.50(d，1H，J＝8.0Hz)，7.99(dd，1H，J＝8.4Hz，1.2Hz)，7.39-7.43(m，2H)，7.12(s，1H)，6.95(t，1H，J＝8.4Hz)，6.72(t，1H，J＝8.0Hz)，6.48(dd，1H，J＝8.4Hz，1.6Hz)，6.12-6.14(brs，1H)，4.48(s，1H)，4.25-4.31(m，4H)，3.34(s，2H)，2.99(d，3H，J＝5.2Hz)，1.53(s，6H)。
embodiment 129
n-methyl-2-(2-(8-morpholine-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxygen mix hexene-5-amido)-5, 5-dimethyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzamide
Figure BPA00001751561001872
1H?NMR(400MHz，DMSO-d 6)δppm?10.97-10.64(m，1H)，8.79(s，1H)，8.44(s，1H)，7.69(d，J＝7.7Hz，1H)，7.35(s，2H)，7.08(s，1H)，6.47(d，J＝8.8Hz，1H)，4.31(s，4H)，3.80-3.73(m，4H)，3.40(s，4H)，2.99(s，4H)，2.82(d，J＝4.5Hz，3H)，1.47(s，6H)。
embodiment 130
n-methyl-2-(2-(3,4,5-trimethoxyphenyl amido)-5,5-dimethyl-6,7-dihydro-5H-pyrrole cough up also [2,3-d] pyrimidine-4-amido) benzamide
1H?NMR(400MHz，CDCl 3)δppm?10.14(s，1H)，8.50(d，J＝8.5Hz，1H)，7.43(d，J＝6.5Hz，1H)，7.35(d，J＝7.4Hz，1H)，6.96(t，J＝7.5Hz，1H)，6.82(s，2H)，6.18(s，1H)，3.85(s，3H)，3.71(s，6H)，3.41(s，2H)，3.04(d，J＝4.9Hz，3H)，1.55(s，6H)。
embodiment 131
n-methyl-2-(2-(cumarone-7-amido)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzamide
Figure BPA00001751561001881
1H?NMR(400MHz，CDCl 3)δppm?9.91(s，1H)，8.50(d，1H，J＝8.8Hz)，8.23(d，1H，J＝7.6Hz)，7.59(d，1H，J＝2.0Hz)，7.39-7.42(m，2H)，7.21(s，1H)，7.18(dd，1H，J＝8.0Hz，1.2Hz)，7.12(t，1H，J＝8.0Hz)，6.96(t，1H，J＝8.0Hz)，6.76(d，1H，J＝2.0Hz)，6.13-6.14(brs，1H)，4.54(s，1H)，3.37(s，1H)，2.99(d，3H，J＝5.2Hz)，1.54(s，6H)。
embodiment 132
n-methyl-2-(2-(1,3-dimethyl-1H-pyrazoles-5-amino)-5,5-dimethyl-6,7-dihydro -5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzamide
Figure BPA00001751561001882
1H?NMR(400MHz，CDCl 3)δppm?10.09(s，1H)，8.37(d，1H，J＝8.8Hz)，7.36(dd，1H，J＝8.0Hz，1.6Hz)，7.30(t，1H，J＝8.0Hz)，6.91(t，1H，J＝7.2Hz)，6.53(brs，1H)，6.11-6.14(brs，1H)，6.01(s，1H)，4.63(s，1H)，3.66(s，3H)，3.56(s，2H)，2.99(d，3H，J＝4.8Hz)，2.25(s，3H)，1.52(s，6H)。
embodiment 133
n-methyl-2-(2-(N-ethyl-6-methoxyl group-4,5-dihydro-1H-benzo [B] ring heptamide- 2 (3H)-7-amidos)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzene methane amide
Figure BPA00001751561001891
1H?NMR(400MHz，DMSO-d 6)δppm?10.35(s，1H)，8.64(d，J＝4.6Hz，1H)，8.48(d，J＝8.4Hz，1H)，8.07(d，J＝8.8Hz，1H)，7.60(d，J＝7.7Hz，1H)，7.46(s，1H)，7.33(t，J＝7.9Hz，1H)，7.01(d，J＝8.8Hz，1H)，6.94(t，J＝7.5Hz，1H)，6.76(s，1H)，3.70(s，3H)，3.23(s，2H)，2.78(d，J＝4.4Hz，3H)，2.12(s，3H)，1.98(s，1H)，1.44(s，6H)，0.99(t，J＝7.1Hz，3H)。
embodiment 134
n-methyl-2-(2-(1-(3-morpholine propyl group)-1H-indoles-5-amido)-5,5-diformazan base-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzamide
Figure BPA00001751561001892
1H?NMR(400MHz，CDCl 3)δppm?10.04(s，1H)，8.53(d，J＝8.9Hz，1H)，7.88(s，1H)，7.43-7.30(m，2H)，7.09-7.12(m，3H)，6.97(d，J＝7.4Hz，1H)，6.57(s，1H)，6.12(s，1H)，4.20(t，J＝6.6Hz，2H)，3.73(s，4H)，3.40(s，2H)，2.99(s，J＝4.6Hz，3H)，2.41(m，4H)，2.28(s，2H)，2.01(m，J＝6.3Hz，2H)，1.55(s，6H)。
embodiment 135
n-methyl-2-(2 '-(2-methoxyl group-4-morpholine phenyl amido)-6 ', 7 '-dihydro spiral shell [cyclopropane-1,5 '- pyrrolo-[2,3-d] pyrimidine]-4 '-amido) benzsulfamide
Figure BPA00001751561001901
1H?NMR(400MHz，CDCl 3)δppm?8.11(dd，J＝8.5，5.3Hz，2H)，7.87(dd，J＝8.0，1.4Hz，1H)，7.52(t，J＝7.8Hz，1H)，7.42(s，1H)，7.20-7.08(m，2H)，6.55-6.44(m，1H)，6.29(dd，J＝8.8，2.4Hz，1H)，4.76(brs，2H)，3.96-3.77(m，7H)，3.56(s，2H)，3.17-3.00(m，4H)，2.59(d，J＝5.0Hz，3H)，1.52(t，J＝6.1Hz，2H)，0.84(t，J＝6.1Hz，2H)。
embodiment 136
the N-tertiary butyl-2-(2 '-(2-methoxyl group-4-morpholine phenyl amido)-6 ', 7 '-dihydro spiral shell [cyclopropane -1,5 '-pyrrolo-[2,3-d] pyrimidine]-4 '-amido) benzsulfamide
Figure BPA00001751561001902
1H?NMR(400MHz，CDCl 3)δppm?8.03(d，J＝8.9Hz，1H)，7.88(dd，J＝19.7，8.1Hz，2H)，7.43(t，J＝7.8Hz，1H)，7.09(dd，J＝15.0，7.0Hz，3H)，6.41(d，J＝2.4Hz，1H)，6.14(dd，J＝8.9，2.4Hz，1H)，4.60(s，1H)，4.34(s，1H)，3.87-3.71(m，7H)，3.52(s，2H)，3.13-2.86(m，5H)，1.60-1.30(m，3H)，1.04(s，9H)，0.79(t，J＝6.1Hz，2H)。
embodiment 137
n-isobutyl--2-(2 '-(2-methoxyl group-4-morpholine phenyl amido)-6 ', 7 '-dihydro spiral shell [cyclopropane -1,5 '-pyrrolo-[2,3-d] pyrimidine]-4 '-amido) benzsulfamide
Figure BPA00001751561001911
1H?NMR(400MHz，CDCl 3)δppm?8.07(t，J＝9.1Hz，2H)，7.86(d，J＝8.2Hz，1H)，7.53-7.46(m，1H)，7.33(s，1H)，7.17-7.09(m，2H)，6.48(d，J＝2.4Hz，1H)，6.25(d，J＝11.5Hz，1H)，4.64(s，1H)，4.44(s，1H)，3.90-3.80(m，7H)，3.58(s，2H)，3.11-3.00(m，4H)，2.67(t，J＝6.6Hz，2H)，1.52(d，J＝6.2Hz，2H)，0.86(d，J＝6.2Hz，2H)，0.71(d，J＝6.7Hz，6H)。
embodiment 138
n-sec.-propyl-2-(2 '-(2-methoxyl group-4-morpholine phenyl amido)-6 ', 7 '-dihydro spiral shell [cyclopropane -1,5 '-pyrrolo-[2,3-d] pyrimidine]-4 '-amido) benzsulfamide
Figure BPA00001751561001912
1H?NMR(400MHz，CDCl 3)δppm?8.12(d，J＝8.8Hz，1H)，8.04(d，J＝8.3Hz，1H)，7.92(d，J＝6.9Hz，1H)，7.52(t，J＝7.9Hz，1H)，7.16(dd，J＝16.4，9.0Hz，2H)，6.50(d，J＝2.3Hz，1H)，6.24(d，J＝8.9Hz，1H)，4.68(s，1H)，4.33(d，J＝7.9Hz，1H)，3.88(d，J＝8.6Hz，7H)，3.60(s，2H)，3.37(dd，J＝13.8，6.7Hz，1H)，3.14-3.01(m，4H)，1.53(t，J＝6.2Hz，2H)，0.93(d，6H)，0.84-0.87(m，2H)。
embodiment 139
n-ethyl-2-(2 '-(2-methoxyl group-4-morpholine phenyl amido)-6 ', 7 '-dihydro spiral shell [cyclopropane-1,5 '- pyrrolo-[2,3-d] pyrimidine]-4 '-amido) benzsulfamide
Figure BPA00001751561001921
1H?NMR(400MHz，CDCl 3)δppm?8.09(dd，J＝8.5，4.1Hz，1H)，7.87(d，J＝6.9Hz，1H)，7.50(t，J＝7.4Hz，1H)，7.35(s，1H)，7.20-7.08(m，2H)，6.48(d，J＝2.3Hz，1H)，6.26(d，J＝8.8Hz，1H)，4.69(s，1H)，4.51(t，J＝5.8Hz，1H)，3.94-3.76(m，7H)，3.57(s，2H)，3.18-2.98(m，4H)，2.98-2.87(m，2H)，1.51(d，J＝6.0Hz，2H)，0.97(t，J＝7.2Hz，3H)，0.90-0.77(m，2H)。
embodiment 140
n-encircles the third methyl-2-, and (2 '-(2-methoxyl group-4-morpholine phenyl amido)-6 ', 7 '-dihydro spiral shell [encircles third alkane-1,5 '-pyrrolo-[2,3-d] pyrimidine]-4 '-amido) benzsulfamide
Figure BPA00001751561001922
1H?NMR(400MHz，CDCl 3)δppm?8.05(d，J＝9.1Hz，2H)，7.90(d，J＝8.0Hz，1H)，7.53(t，J＝7.7Hz，1H)，7.21-7.02(m，2H)，6.50(d，J＝2.3Hz，1H)，6.24(d，J＝8.9Hz，1H)，4.66(s，1H)，4.56(s，1H)，3.99-3.79(m，7H)，3.61(s，2H)，3.19-2.95(m，4H)，2.84-2.59(m，2H)，1.55(dd，J＝12.9，6.6Hz，2H)，0.88(t，J＝6.1Hz，1H)，0.74(m，2H)，0.34-0.13(m，2H)。
embodiment 141
2-(2 '-(2-methoxyl group-4-morpholine phenyl amido)-6 ', 7 '-dihydro spiral shell [cyclopropane-1,5 '-pyrrolo- [2,3-d] pyrimidine]-4 '-amido)-N-(2-methoxy ethyl)-benzsulfamide
Figure BPA00001751561001931
1H?NMR(400MHz，CDCl 3)δppm?8.25-8.02(m，2H)，7.86(dd，J＝8.0，1.4Hz，1H)，7.56-7.46(m，1H)，7.41(s，1H)，7.16(s，1H)，7.10(dd，J＝11.2，4.0Hz，1H)，6.49(d，J＝2.5Hz，1H)，6.29(dd，J＝8.8，2.5Hz，1H)，5.12(s，1H)，4.69(s，1H)，3.94-3.77(m，7H)，3.55(s，2H)，3.25(t，J＝5.1Hz，2H)，3.16-3.01(m，9H)，1.51(t，J＝6.1Hz，2H)，0.82(t，J＝6.2Hz，2H)。
embodiment 142
n-(2-hydroxyethyl)-2-(2 '-(2-methoxyl group-4-morpholine phenyl amido)-6 ', 7 '-dihydro spiral shell [cyclopropane-1,5 '-pyrrolo-[2,3-d] pyrimidine]-4 '-amido) benzsulfamide
Figure BPA00001751561001932
1H?NMR(400MHz，CDCl 3)δppm?8.08(d，J＝8.2Hz，1H)，7.69(d，J＝7.6Hz，1H)，7.26(s，9H)，6.77(s，1H)，6.70(d，J＝8.3Hz，1H)，6.52(m，2H)，5.65(brs，1H)，4.79(s，2H)，4.58(s，1H)，4.25(s，2H)，3.87(s，7H)，3.52(d，J＝18.3Hz，4H)，3.21(s，2H)，3.11(s，4H)，1.21(s，2H)，0.67(s，2H)。
embodiment 143
n-phenyl-2-(2 '-(2-methoxyl group-4-morpholine phenyl amido)-6 ', 7 '-dihydro spiral shell [cyclopropane-1,5 '- pyrrolo-[2,3-d] pyrimidine]-4 '-amido) benzsulfamide
Figure BPA00001751561001941
1H?NMR(400MHz，CDCl 3)δppm?8.12(t，J＝25.8Hz，1H)，7.89(d，J＝8.3Hz，1H)，7.59(t，J＝22.1Hz，1H)，7.44(t，J＝7.8Hz，1H)，7.18(m，2H)，6.99(t，J＝5.8Hz，6H)，6.50(d，J＝2.4Hz，1H)，6.26-6.08(m，1H)，4.66(s，1H)，3.87(d，J＝7.1Hz，7H)，3.58(s，2H)，3.24-2.96(m，4H)，1.51(t，J＝6.2Hz，2H)，0.86(t，J＝6.1Hz，2H)。
embodiment 144
n-allyl group-2-(2 '-(2-methoxyl group-4-morpholine phenyl amido)-6 ', 7 '-dihydro spiral shell [cyclopropane -1,5 '-pyrrolo-[2,3-d] pyrimidine]-4 '-amido) benzsulfamide
Figure BPA00001751561001942
1H?NMR(400MHz，CDCl 3)δppm?8.10(dd，J＝14.2，8.6Hz，2H)，7.88(d，J＝7.9Hz，1H)，7.52(t，J＝7.2Hz，1H)，7.33(s，1H)，7.15(dd，J＝15.0，7.3Hz，2H)，6.50(d，J＝2.4Hz，1H)，6.28(dd，J＝8.9，2.4Hz，1H)，5.74-5.39(m，1H)，4.99(dd，J＝34.0，13.6Hz，2H)，4.68-4.52(m，2H)，4.02-3.77(m，7H)，3.55(dd，J＝16.6，10.6Hz，4H)，3.25-2.93(m，4H)，1.52(t，J＝6.1Hz，2H)，0.86(t，J＝6.1Hz，2H)。
embodiment 145
n-cyclopentyl-2-(2 '-(2-methoxyl group-4-morpholine phenyl amido)-6 ', 7 '-dihydro spiral shell [cyclopropane -1,5 '-pyrrolo-[2,3-d] pyrimidine]-4 '-amido) benzsulfamide
Figure BPA00001751561001951
1H?NMR(400MHz，CDCl 3)δppm?8.19(d，J＝8.8Hz，1H)，8.10(d，J＝8.2Hz，1H)，8.00(d，J＝8.0Hz，1H)，7.61(t，J＝7.3Hz，1H)，7.36(d，J＝7.9Hz，8H)，7.16(dd，J＝14.6，6.8Hz，2H)，6.59(d，J＝2.2Hz，1H)，6.32(d，J＝8.8Hz，1H)，4.80(s，1H)，4.51(d，J＝7.8Hz，1H)，3.97(d，J＝8.6Hz，7H)，3.70(s，2H)，3.83-3.53(m，1H)，3.26-3.07(m，4H)，1.62(m，10H)，)，0.87(t，J＝6.2Hz，2H)。
embodiment 146
n-cyclopropyl-2-(2 '-(2-methoxyl group-4-morpholine phenyl amido)-6 ', 7 '-dihydro spiral shell [cyclopropane -1,5 '-pyrrolo-[2,3-d] pyrimidine]-4 '-amido) benzsulfamide
Figure BPA00001751561001952
1H?NMR(400MHz，CDCl 3)δppm?8.11(s，1H)，7.85(s，1H)，7.60(d，J＝7.5Hz，1H)，7.16(s，1H)，6.77(d，J＝7.5Hz，1H)，6.54-6.36(m，2H)，6.18(s，1H)，4.96-4.80(m，2H)，3.87(d，J＝10.6Hz，7H)，3.56(d，J＝13.8Hz，2H)，3.05(s，4H)，2.48(d，J＝22.6Hz，2H)，2.20(d，J＝20.0Hz，2H)，1.29(d，J＝26.4Hz，5H)，0.89(s，4H)。
embodiment 147
n-sec-butyl-2-(2 '-(2-methoxyl group-4-morpholine phenyl amido)-6 ', 7 '-dihydro spiral shell [cyclopropane -1,5 '-pyrrolo-[2,3-d] pyrimidine]-4 '-amido) benzsulfamide
Figure BPA00001751561001961
1H?NMR(400MHz，CDCl 3)δppm?8.11(d，J＝8.8Hz，1H)，8.02(d，J＝8.3Hz，1H)，7.88(dd，J＝8.0，1.4Hz，1H)，7.47(t，J＝7.8Hz，1H)，7.34(s，1H)，7.17(s，1H)，7.11(t，J＝7.6Hz，1H)，6.47(d，J＝2.5Hz，1H)，6.20(dd，J＝8.9，2.5Hz，1H)，4.64(s，1H)，4.31(d，J＝8.2Hz，1H)，3.91-3.79(m，7H)，3.57(s，2H)，3.18-2.95(m，5H)，1.62(s，1H)，1.50(t，J＝6.1Hz，2H)，0.93(d，J＝6.6Hz，3H)，0.83(d，J＝6.1Hz，2H)，0.65(t，J＝7.4Hz，3H)。
embodiment 148
n-n-propyl-2-(2 '-(2-methoxyl group-4-morpholine phenyl amido)-6 ', 7 '-dihydro spiral shell [cyclopropane -1,5 '-pyrrolo-[2,3-d] pyrimidine]-4 '-amido) benzsulfamide
Figure BPA00001751561001962
1H?NMR(400MHz，CDCl 3)δppm?8.08(t，J＝9.0Hz，2H)，7.87(d，J＝7.9Hz，1H)，7.51(t，J＝7.2Hz，1H)，7.33(s，1H)，7.20-7.10(m，2H)，6.48(d，J＝2.4Hz，1H)，6.26(d，J＝8.9Hz，1H)，4.64(s，1H)，4.44(t，J＝6.0Hz，1H)，3.93-3.79(m，7H)，3.58(s，2H)，3.13-3.01(m，4H)，2.84(dd，J＝13.6，6.8Hz，2H)，1.52(t，J＝6.1Hz，2H)，1.33(dd，J＝14.5，7.2Hz，3H)，0.86(dd，J＝11.9，6.0Hz，2H)，0.70(t，J＝7.4Hz，3H)。
embodiment 149
n-cyclohexyl-2-(2 '-(2-methoxyl group-4-morpholine phenyl amido)-6 ', 7 '-dihydro spiral shell [cyclopropane -1,5 '-pyrrolo-[2,3-d] pyrimidine]-4 '-amido) benzsulfamide
Figure BPA00001751561001971
1H?NMR(400MHz，CDCl 3)δppm?8.09(d，J＝8.8Hz，1H)，7.99(d，J＝8.3Hz，1H)，7.91(dd，J＝7.9，1.4Hz，1H)，7.51(t，J＝7.8Hz，1H)，7.17(dd，J＝13.8，5.8Hz，2H)，6.49(d，J＝2.4Hz，1H)，6.21(dd，J＝8.9，2.4Hz，1H)，4.69(s，1H)，4.44(d，J＝7.9Hz，1H)，3.94-3.77(m，7H)，3.60(s，2H)，3.13-2.98(m，5H)，1.64(d，J＝8.6Hz，3H)，1.53(t，J＝6.1Hz，2H)，1.45(s，2H)，1.36-1.22(m，7H)，1.12-0.94(m，5H)，0.88(dd，J＝11.2，5.1Hz，3H)。
embodiment 150
n-cyclobutyl-2-(2 '-(2-methoxyl group-4-morpholine phenyl amido)-6 ', 7 '-dihydro spiral shell [cyclopropane -1,5 '-pyrrolo-[2,3-d] pyrimidine]-4 '-amido) benzsulfamide
Figure BPA00001751561001972
1H?NMR(400MHz，CDCl 3)δppm?8.11(d，J＝8.8Hz，1H)，8.03(d，J＝8.3Hz，1H)，7.86(d，J＝7.8Hz，1H)，7.49(t，J＝7.7Hz，1H)，7.31(s，1H)，7.18(s，1H)，7.11(t，J＝7.6Hz，1H)，6.48(d，J＝2.2Hz，1H)，6.28-6.15(m，1H)，4.80(d，J＝9.4Hz，1H)，4.74(s，1H)，3.93-3.78(m，7H)，3.78-3.64(m，1H)，3.58(s，2H)，3.10-2.96(m，4H)，2.12-1.86(m，4H)，1.74-1.59(m，3H)，1.51(t，J＝6.1Hz，2H)，1.48-1.36(m，2H)，1.26(t，J＝7.0Hz，6H)，0.92-0.78(m，3H)。
embodiment 151
n, (2 '-(2-methoxyl group-4-morpholine phenyl amido)-6 ', 7 '-dihydro spiral shell [encircles third to N-dimethyl-2- alkane-1,5 '-pyrrolo-[2,3-d] pyrimidine]-4 '-amido) benzsulfamide
Figure BPA00001751561001981
1H?NMR(400MHz，CDCl 3)δppm?8.16(dd，J＝11.7，8.8Hz，2H)，7.83(s，1H)，7.75(d，J＝7.4Hz，1H)，7.51(dd，J＝18.2，9.9Hz，2H)，7.19(s，1H)，7.11(t，J＝7.6Hz，1H)，6.51(d，J＝2.3Hz，1H)，6.32(d，J＝8.9Hz，1H)，4.67(s，1H)，3.87(d，J＝8.9Hz，7H)，3.58(s，2H)，3.14-3.02(m，4H)，2.70(s，6H)，1.58(t，J＝6.0Hz，2H)，0.84(s，2H)。
embodiment 152
2-(2 '-(2-methoxyl group-4-morpholine phenyl amido)-6 ', 7 '-dihydro spiral shell [cyclopropane-1,5 '-pyrrolo- [2,3-d] pyrimidine]-4 '-amido)-N-methyl-benzamide
Figure BPA00001751561001982
1H?NMR(400MHz，CDCl 3)δppm?9.39(s，1H)，8.34(s，1H)，8.25(d，J＝8.8Hz，1H)，7.38(d，J＝7.8Hz，2H)，7.12(s，1H)，6.94(t，J＝7.5Hz，1H)，6.51(d，J＝2.5Hz，1H)，6.40(dd，J＝8.8，2.5Hz，1H)，6.11(s，1H)，3.90-3.83(m，7H)，3.57(s，2H)，3.11-3.07(m，4H)，2.99(d，J＝4.9Hz，3H)，1.75(t，J＝6.0Hz，2H)，0.83(t，J＝6.1Hz，2H)。
embodiment 153
n 4 ' -(3,4-difluorophenyl)-N 2 '-(2-methoxyl group-4-morpholine phenyl)-6 ', 7 '-dihydro spiral shell [cyclopropane -1,5 '-pyrrolo-[2,3-d] pyrimidine]-2 ', 4 '-diamines
1H?NMR(400MHz，CDCl 3)δppm?8.07(d，J＝8.8Hz，1H)，7.69-7.45(m，1H)，7.14-6.93(m，2H)，6.87(s，1H)，6.54-6.31(m，2H)，5.35(s，1H)，4.55(s，1H)，3.87(dd，J＝10.3，5.7Hz，7H)，3.56(s，2H)，3.21-2.91(m，4H)，1.31(m，2H)，0.89(m，2H)。
embodiment 154
n 2 '-(2-methoxyl group-4-morpholine phenyl)-N 4 ' -(6-picoline-2-yl)-6 ', 7 '-dihydro spiral shell [ring propane-1,5 '-pyrrolo-[2,3-d] pyrimidine]-2 ', 4 '-diamines
Figure BPA00001751561001992
1H?NMR(400MHz，CDCl 3)δppm?8.17(d，J＝8.7Hz，1H)，7.98(d，J＝8.3Hz，1H)，7.46(dd，J＝21.9，14.2Hz，1H)，7.02(d，J＝20.3Hz，1H)，6.72(d，J＝7.3Hz，1H)，6.58-6.35(m，2H)，6.17(s，1H)，4.60(s，1H)，3.87(dd，J＝8.6，3.6Hz，7H)，3.67(s，2H)，3.34-2.98(m，4H)，2.40(s，3H)，1.57-1.41(m，2H)，0.87(t，J＝6.2Hz，2H)。
embodiment 155
n-(2-(2 '-(2-methoxyl group-4-morpholine phenyl amido)-6 ', 7 '-dihydro spiral shell [cyclopropane-1,5 '-pyrrole cough up also [2,3-d] pyrimidine]-4 '-amido) phenyl) ethanamide
1H?NMR(400MHz，CDCl 3)δppm?8.41(s，1H)，7.86(d，J＝8.8Hz，1H)，7.48(s，1H)，7.36(d，J＝4.9Hz，1H)，7.23-7.14(m，2H)，7.05(s，1H)，6.44(d，J＝15.2Hz，1H)，6.26(d，J＝9.0Hz，1H)，5.84(s，1H)，4.60(s，1H)，3.90-3.83(m，4H)，3.81(s，3H)，3.57(s，2H)，3.13-3.01(m，4H)，1.98(s，3H)，1.42(s，2H)，0.87(d，J＝7.0Hz，2H)。
embodiment 156
n-(2-(2 '-(2-methoxyl group-4-morpholine phenyl amido)-6 ', 7 '-dihydro spiral shell [cyclopropane-1,5 '-pyrrole cough up also [2,3-d] pyrimidine]-4 '-amido) phenyl)-N-methyl Toluidrin
1H?NMR(400MHz，CDCl 3)δppm?8.11(d，J＝8.8Hz，1H)，8.03(d，J＝8.3Hz，1H)，7.86(d，J＝7.8Hz，1H)，7.49(t，J＝7.7Hz，1H)，7.31(s，1H)，7.18(s，1H)，7.11(t，J＝7.6Hz，1H)，6.70)s，1H)，6.48(d，J＝2.2Hz，1H)，6.28-6.15(m，1H)，4.74(s，1H)，3.93-3.78(m，7H)，3.58(s，2H)，3.25(s，2H)，3.10-2.96(m，4H)，1.74-1.59(m，3H)，1.51(t，J＝6.1Hz，2H)，1.26(t，J＝7.0Hz，2H)，0.92-0.78(m，2H)。
embodiment 157
n-methyl-2-(2 '-(3,4,5-trimethoxyphenyl amido)-6 ', 7 '-dihydro spiral shell [cyclopropane-1,5 '- pyrrolo-[2,3-d] pyrimidine]-4 '-amido) benzsulfamide
1H?NMR(400MHz，CDCl 3)δppm?8.05(d，J＝8.4Hz，1H)，7.83(dd，J＝8.0，1.4Hz，1H)，7.54-7.36(m，2H)，7.04(dd，J＝19.5，12.2Hz，1H)，6.79(s，2H)，6.74(s，1H)，4.80-4.44(m，2H)，3.85-3.74(s，3H)，3.62(m，7H)，2.58(d，J＝4.9Hz，3H)，1.54-1.41(m，2H)，0.84(t，J＝6.1Hz，2H)。
embodiment 158
n-methyl-2-(2-(4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4- amido) benzamide
Figure BPA00001751561002012
1H?NMR(400MHz，DMSO-d 6)δppm?10.66(s，1H)，8.62(dd，J＝22.0，17.5Hz，3H)，7.82-7.18(m，4H)，6.94-6.68(m，3H)，6.59(s，1H)，3.72(s，4H)，3.49(dd，J＝23.3，14.7Hz，2H)，3.00(s，4H)，2.82-2.56(m，5H)。
embodiment 159
n-methyl-2-(2-(2-p-methoxy-phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4- amido) benzamide
Figure BPA00001751561002013
1H?NMR(400MHz，DMSO-d6)δppm?10.67(d，J＝34.1Hz，1H)，8.63(d，J＝4.5Hz，1H)，8.52(d，J＝8.4Hz，1H)，8.22(dd，J＝7.8，1.6Hz，1H)，7.65(d，J＝6.8Hz，1H)，7.35(dd，J＝18.9，11.7Hz，2H)，7.05-6.77(m，4H)，6.71(s，1H)，4.01-3.72(m，3H)，3.68-3.40(m，2H)，2.89-2.59(m，5H)。
embodiment 160
2-(2-(2-methoxyl group 4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4- amido) phenylformic acid
Figure BPA00001751561002021
1H?NMR(400MHz，DMSO-d 6)δppm?11.54-10.76(m，1H)，8.69(d，J＝8.2Hz，1H)，7.91(d，J＝8.0Hz，1H)，7.80(d，J＝8.7Hz，1H)，7.32(d，J＝7.4Hz，1H)，7.19(s，1H)，6.85(s，2H)，6.61(d，2H)，6.46(d，J＝8.8Hz，1H)，3.79(s，3H)，3.76-3.62(m，6H)，3.58-3.45(m，2H)，3.13-2.97(m，4H)，2.81(t，2H)。
embodiment 161
2-(2-(2-methoxyl group 4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4- amido) phenyl aldehyde
1H?NMR(400MHz，DMSO-d 6)δppm?10.31(s，1H)，9.93(s，1H)，8.70(d，J＝8.6Hz，1H)，7.78(d，J＝7.7Hz，1H)，7.68(d，J＝8.7Hz，1H)，7.46(d，J＝8.5Hz，1H)，7.32(s，1H)，7.05(t，J＝7.1Hz，1H)，6.76(s，1H)，6.62(d，J＝2.5Hz，1H)，6.46(dd，J＝8.7，2.5Hz，1H)，3.85-3.66(m，7H)，3.53(dd，J＝18.5，10.1Hz，2H)，3.15-3.02(m，4H)，2.86(t，J＝8.4Hz，2H)。
embodiment 162
2-(2-(2-methoxyl group 4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4- amido) phenylethyl alcohol
Figure BPA00001751561002031
1H?NMR(400MHz，CDCl 3)δppm?8.26(d，J＝8.8Hz，1H)，7.94(d，J＝8.2Hz，1H)，7.36(d，J＝8.3Hz，2H)，7.31-7.25(m，1H)，7.21(s，1H)，7.10(s，1H)，6.54(d，J＝2.6Hz，1H)，6.47(d，J＝8.8Hz，1H)，4.79(s，2H)，4.55(s，1H)，3.90(dd，J＝9.7，4.8Hz，7H)，3.66(t，J＝8.5Hz，2H)，3.19-3.06(m，1H)，2.83(t，J＝8.4Hz，2H)。
embodiment 163
2-(2-(2-methoxyl group-(4-piperazine) morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) phenyl dimethyl oxygen phosphorus
1H?NMR(400MHz，CDCl 3)δppm?10.08(s，1H)，8.26(dd，J＝8.0Hz，4.4Hz，1H)，8.22(d，J＝8.8Hz，1H)，7.43(t，J＝8.4Hz，1H)，8.26(ddd，J＝14.4Hz，8.0Hz，1.6Hz，1H)，7.06(s，1H)，6.97(t，J＝8.8Hz，1H)，6.54(d，J＝2.8Hz，1H)，6.50(dd，J＝8.8Hz，2.4Hz，1H)，4.43(s，1H)，3.85(s，3H)，3.61-3.65(m，4H)，3.01(t，J＝8.0Hz，2H)，2.64-2.71(m，6H)，2.41-2.58(m，4H)，2.34-2.40(m，1H)，2.31(s，3H)，1.94(d，J＝13.2Hz，2H)，1.81(d，J＝13.2Hz，6H)，1.70-1.74(m，2H)。
The biochemical test of FAK/Pyk2 activity
With the FAK of GST label purchased from Invitrogen (PV3832).With the PYK2 of GST label purchased from Invitrogen (PV4567).By monitoring under ATP exists from ULight-poly-Glu, the Ala of the fluorophore mark of Perkin Elmer (TRF0101), the phosphorylation of Tyr (1: 1: 1) peptide substrates, measure the activity of FAK/PYK2.Identify the tyrosine residues of phosphorylation by the anti-phosphorylated tyrosine antibody (PY20) of the LANCE europium chelating mark from Perkin Elmer (AD0066).This makes described fluorophore and europium inner complex close proximity (>10nm), thereby, once excite at 320nm by Envision (PerkinElmer), energy can be transferred to acceptor fluorescence group from donor europium inner complex.This causes the utilizing emitted light at 665nm, and can be caught by Envision.Therefore, the intensity of described signal is directly proportional to the FAK/PYK2 activity.
In order to measure the inhibition activity of FAK/PYK2 inhibitor, at first prepare the 100%DMSO of the compound that contains 1mM as storing solution, and make 3 times of serial dilutions to obtain the 100X storing solution of 12 different concns in 96 orifice plates (Corning, 3897).The 100X storing solution of 5 each concentration of μ l is joined containing 95 μ l 1X reaction buffer (40mM Tris, pH7.5,10mM MgCl 2, 1mM DTT and 1mMCHAPS) hole in, thereby obtain the 5X storing solution.Then the 5X storing solution of 2 each concentration of μ l is joined in 384 hole OptiPlate (PerkinElmer, 6007299).
The experiment of FAK: the 4 μ l 2.5nM FAK that will prepare in above-mentioned reaction buffer, 1ul 8 μ g/ μ lBSA and 1.5 μ l 666nM ULight-gather Glu, Ala, Tyr (1: 1: 1) peptide substrates joins in each hole.By adding 1.5 μ l 33.3 μ M ATP initiation reactions.Reaction is carried out 120 minutes, then with being formulated in 1X LANCE, detected 5 μ l 40mM EDTA stop buffer cancellation reactions in damping fluid (PerkinElmer, CR97-100).
The experiment of PYK2: the 5 μ l 2nM PYK2 that will configure in above-mentioned reaction buffer and 1.5 μ l666nM ULight-gather Glu, Ala, Tyr (1: 1: 1) peptide substrates joins in each hole.By adding 1.5 μ l46.6 μ MATP initiation reactions.Reaction is carried out 40 minutes, then with being formulated in 1X LANCE, detected 5 μ l 40mM EDTA stop buffer cancellation reactions in damping fluid (PerkinElmer, CR97-100).
After the reaction cancellation, in each hole, add the anti-phosphorylated tyrosine antibody of 5 μ l 8nM, and incubation 60 minutes.According to above-mentioned principle, utilize Envision (PerkinElmer) to detect dull and stereotyped.
Form 1: some have the biologically active data of pyrrolo-[2, the 3-d] pyrimidines of structural formula (I)
Figure BPA00001751561002041
Figure BPA00001751561002061
Figure BPA00001751561002071
Figure BPA00001751561002091
Figure BPA00001751561002101
Figure BPA00001751561002111
Figure BPA00001751561002121
Figure BPA00001751561002141
Figure BPA00001751561002151
Figure BPA00001751561002161
Figure BPA00001751561002171
Figure BPA00001751561002181
Figure BPA00001751561002191
Figure BPA00001751561002201
Figure BPA00001751561002211
Figure BPA00001751561002221
Figure BPA00001751561002241
Figure BPA00001751561002261
Figure BPA00001751561002271
Figure BPA00001751561002281
Figure BPA00001751561002291
Figure BPA00001751561002301
Figure BPA00001751561002311
Figure BPA00001751561002321
Figure BPA00001751561002331
Figure BPA00001751561002341
Figure BPA00001751561002351
Figure BPA00001751561002361
Figure BPA00001751561002371

Claims (19)

1. the compound of general formula I or its pharmacy acceptable salt, solvate, polymorphic form, tautomer or prodrug,
Figure FPA00001751560900011
Wherein:
R 1and R 2the group formed independently selected from following group: hydrogen, halogen, cyano group, nitro, hydroxyl, the optional alkyl replaced, the optional cycloalkyl replaced, the optional thiazolinyl replaced, the optional alkynyl replaced and the optional alkoxyl group replaced, or R 1, R 2with the common optional cycloalkyl replaced or the optional Heterocyclylalkyl replaced of forming of coupled carbon atom;
R 3and R 4the group formed independently selected from following group: the heteroaryl of the alkyl of hydrogen, optional replacement, the optional cycloalkyl replaced, the optional aryl replaced, the arylalkyl optionally replaced, the optional Heterocyclylalkyl replaced, optional replacement ,-COR 7,-SO 2r 8with-SOR 9;
R 5and R 6group independently selected from following group formation: the heteroaryl of hydrogen, the optional alkyl replaced, the optional cycloalkyl replaced, the aryl optionally replaced, the optional Heterocyclylalkyl replaced, optional replacement ,-COR 10,-SO 2r 11with-SOR 12;
R 7, R 8, R 9, R 10, R 11and R 12the group formed independently selected from following group: the optional alkyl replaced, the optional cycloalkyl replaced, the optional aryl replaced, the optional heteroaryl replaced;
R xand R ythe group formed independently selected from following group: hydrogen, halogen, cyano group, nitro, hydroxyl, the optional alkyl replaced, the optional cycloalkyl replaced, the optional thiazolinyl replaced, the optional alkynyl replaced and the optional alkoxyl group replaced; And
R " be selected from the group that following group forms: hydrogen, the optional alkyl replaced, the optional cycloalkyl replaced, the optional thiazolinyl replaced, the optional alkynyl replaced and the optional alkoxyl group replaced.
2. compound as claimed in claim 1 or its pharmacy acceptable salt, solvate, polymorphic form, tautomer or prodrug, wherein, R xand R yall hydrogen.
3. compound as claimed in claim 1 or 2 or its pharmacy acceptable salt, solvate, polymorphic form, tautomer or prodrug, wherein,
R 1and R 2the group formed independently selected from following group: hydrogen, halogen, cyano group, nitro, hydroxyl, the optional C replaced 1-C 6alkyl, the optional C replaced 3-C 8cycloalkyl, the optional C replaced 2-C 6thiazolinyl, the optional C replaced 2-C 6alkynyl and the optional C replaced 1-C 6alkoxyl group; Perhaps R 1, R 2with the common C that forms optional replacement of coupled carbon atom 3-C 8cycloalkyl or the optional Heterocyclylalkyl replaced;
R 3and R 4the group formed independently selected from following group: hydrogen, the optional C replaced 1-C 6alkyl, the optional C replaced 3-C 8cycloalkyl, the optional C replaced 6-C 10aryl, the optional C replaced 6-C 10aryl-C 1-C 6the heteroaryl of alkyl, the optional Heterocyclylalkyl replaced, optional replacement ,-COR 7,-SO 2r 8with-SOR 9;
R 5and R 6the group formed independently selected from following group: hydrogen, the optional C replaced 1-C 6alkyl, the optional C replaced 3-C 6cycloalkyl, the optional C replaced 6-C 10the heteroaryl of aryl, the optional Heterocyclylalkyl replaced, optional replacement ,-COR 10,-SO 2r 11with-SOR 12;
R 7, R 8, R 9, R 10, R 11and R 12the group formed independently selected from following group: the optional C replaced 1-C 6alkyl, the optional C replaced 3-C 8cycloalkyl, the optional C replaced 6-C 10aryl, the optional heteroaryl replaced;
R xand R ythe group formed independently selected from following group: hydrogen, halogen, cyano group, nitro, hydroxyl, the optional C replaced 1-C 6alkyl, the optional C replaced 3-C 8cycloalkyl, the optional C replaced 2-C 6thiazolinyl, the optional C replaced 2-C 6alkynyl and the optional C replaced 1-C 6alkoxyl group; And
R " be selected from the group that following group forms: hydrogen, the optional C replaced 1-C 6alkyl, the optional C replaced 3-C 8cycloalkyl, the optional C replaced 2-C 6thiazolinyl, the optional C replaced 2-C 6alkynyl and the optional C replaced 1-C 6alkoxyl group.
4. compound as described as any one in claim 1-3 or its pharmacy acceptable salt, solvate, polymorphic form, tautomer or prodrug, wherein, R 1and R 2the group formed independently selected from following group: hydrogen, the optional C replaced 1-C 6alkyl, the optional C replaced 3-C 8cycloalkyl, the optional C replaced 2-C 6thiazolinyl, the optional C replaced 2-C 6alkynyl and the optional C replaced 1-C 6alkoxyl group; Perhaps R 1, R 2with the common C that forms optional replacement of coupled carbon atom 3-C 8cycloalkyl;
5. compound as described as any one in claim 1-4 or its pharmacy acceptable salt, solvate, polymorphic form, tautomer or prodrug, wherein, R 5and R 6the group formed independently selected from following group: hydrogen, the optional C replaced 6-C 10aryl, optional replace comprise 1-4 N, O or the heteroatomic 5-15 of S unit Heterocyclylalkyl, optional replace comprise 1-4 N, O or the first heteroaryl of the heteroatomic 5-10 of S.
6. compound as described as any one in claim 1-5 or its pharmacy acceptable salt, solvate, polymorphic form, tautomer or prodrug, wherein, R 3and R 4the group formed independently selected from following group: hydrogen, the optional C replaced 3-C 8cycloalkyl, the optional C replaced 6-C 10aryl, the optional C replaced 6-C 10aryl-C 1-C 6alkyl, optional replace comprise 1-4 N, O or the heteroatomic 5-15 of S unit Heterocyclylalkyl, optional replace comprise 1-4 N, O or the first heteroaryl of the heteroatomic 5-10 of S.
7. compound as claimed in claim 1 or its pharmacy acceptable salt, solvate, polymorphic form, tautomer or prodrug, described compound is meaned by following general formula (IIa):
Figure FPA00001751560900031
Wherein:
R 1and R 2the group formed independently selected from following group: hydrogen, halogen, cyano group, nitro, hydroxyl, the optional C replaced 1-C 6alkyl, the optional C replaced 3-C 8cycloalkyl, the optional C replaced 2-C 6thiazolinyl, the optional C replaced 2-C 6alkynyl and the optional C replaced 1-C 6alkoxyl group; Perhaps R 1, R 2with the common C that forms optional replacement of coupled carbon atom 3-C 8cycloalkyl;
R 13, R 14, R 15, R 16, R 17, R 18, R 19, R 20, R 21and R 22the group formed independently selected from following group: hydrogen, halogen, the optional C replaced 1-C 6alkyl, the optional C replaced 3-C 8cycloalkyl, the optional C replaced 2-C 6thiazolinyl, the optional C replaced 2-C 6alkynyl, the optional C replaced 1-C 6alkoxyl group, the optional C replaced 6-C 10aryl, optional replace comprise 1-4 N, O or the heteroatomic 5-15 of S unit Heterocyclylalkyl, optional replace comprise 1-4 N, O or the heteroatomic 5-10 of S unit heteroaryl, the optional list-C of replacement 1-C 6alkylamino, the optional two-C replaced 1-C 6alkylamino, the optional list-C replaced 1-C 6alkylamino acyl group, the optional two-C replaced 1-C 6alkylamino acyl group, the optional C that comprises 1-3 N, O or the heteroatomic 5-12 of S unit Heterocyclylalkyl-acyl group, optional replacement replaced 1-C 6alkylamidoalkyl, amino-sulfonyl, the optional list-C replaced 1-C 6alkyl amino sulfonyl, the optional two-C replaced 1-C 6alkyl amino sulfonyl, amino sulfinyl, the optional list-C replaced 1-C 6alkylamino sulfinyl, the optional two-C replaced 1-C 6alkylamino sulfinyl, the optional C replaced 1-C 6the alkyl sulfenyl amido.
8. compound as claimed in claim 1 or its pharmacy acceptable salt, solvate, polymorphic form, tautomer or prodrug, described compound is meaned by following general formula (IIIa):
Figure FPA00001751560900041
Wherein:
R 1and R 2the group formed independently selected from following group: hydrogen, halogen, cyano group, nitro, hydroxyl, the optional C replaced 1-C 6alkyl, the optional C replaced 3-C 8cycloalkyl, the optional C replaced 2-C 6thiazolinyl, the optional C replaced 2-C 6alkynyl, the optional C replaced 1-C 6alkoxyl group; Perhaps R 1, R 2with the common C that forms optional replacement of coupled carbon atom 3-C 8cycloalkyl;
R 13, R 14, R 15, R 16, R 17, R 18, R 19, R 20, R 21and R 22the group formed independently selected from following group: hydrogen, halogen, the optional C replaced 1-C 6alkyl, the optional C replaced 3-C 8cycloalkyl, the optional C replaced 2-C 6thiazolinyl, the optional C replaced 2-C 6alkynyl, the optional C replaced 1-C 6alkoxyl group, the optional C replaced 6-C 10aryl, optional replace comprise 1-4 N, O or the heteroatomic 5-15 of S unit Heterocyclylalkyl, optional replace comprise 1-4 N, O or the heteroatomic 5-10 of S unit heteroaryl, the optional list-C of replacement 1-C 6alkylamino, the optional two-C replaced 1-C 6alkylamino, the optional list-C replaced 1-C 6alkylamino acyl group, the optional two-C replaced 1-C 6alkylamino acyl group, the optional C that comprises 1-3 N, O or the heteroatomic 5-12 of S unit Heterocyclylalkyl-acyl group, optional replacement replaced 1-C 6alkylamidoalkyl, amino-sulfonyl, the optional list-C replaced 1-C 6alkyl amino sulfonyl, the optional two-C replaced 1-C 6alkyl amino sulfonyl, amino sulfinyl, the optional list-C replaced 1-C 6alkylamino sulfinyl, the optional two-C replaced 1-C 6alkylamino sulfinyl, the optional C replaced 1-C 6the alkyl sulfenyl amido.
9. compound as described as any one in claim 1-8 or its pharmacy acceptable salt, solvate, polymorphic form, tautomer or prodrug, it is as medicine.
10. compound as claimed in claim 9 or its pharmacy acceptable salt, solvate, polymorphic form, tautomer or prodrug, wherein, described medicine has antiproliferative and/or apoptosis activity.
11. pharmaceutical composition, it comprises a) the described compound of any one or its pharmacy acceptable salt, solvate, polymorphic form, tautomer or prodrug in claim 1-9, and b) pharmaceutically acceptable carrier, thinner, vehicle and/or adjuvant.
12. suppress the method for FAK and/or Pyk2, described method comprises makes the described compound of any one in claim 1-9 contact with FAK and/or Pyk2.
13. the illness for the treatment of or prevention FAK and/or Pyk2 mediation or the method for disease, described method comprises to the described compound of any one or the described composition of claim 11 in the claim 1-8 of patient's administering therapeutic significant quantity that these needs are arranged.
14. method as claimed in claim 13, wherein, described illness or disease are proliferative disease, infectious diseases or autoimmune disorder.
15. method as claimed in claim 14, wherein, described proliferative disease is selected from cancer and diseases associated with inflammation.
16. the described compound of any one or its pharmacy acceptable salt, solvate, polymorphic form, tautomer or the prodrug application in the pharmaceutical composition for the preparation of suppressing FAK and/or Pyk2 in claim 1-8.
17. the described compound of any one or its pharmacy acceptable salt, solvate, polymorphic form, tautomer or the prodrug application in the pharmaceutical composition of the illness for the preparation for the treatment of or prevention FAK and/or Pyk2 mediation or disease in claim 1-8.
18. application as claimed in claim 17, wherein, described illness or disease are proliferative disease, infectious diseases or autoimmune disorder.
19. application as claimed in claim 18, wherein, described proliferative disease is selected from cancer and diseases associated with inflammation.
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