CN103476776B - 2,4-diaminourea-6,7-dihydro-5H-pyrrolo-[2,3] pyrimidine derivatives as FAK/Pyk2 inhibitor - Google Patents

Abstract

The present invention is relevant to following: a series of new as FAK and/or Pyk2 inhibitor 2,4 diaminourea 6,7 dihydro 5H pyrrolo-[2,3] pyrimidine derivatives, their preparation, their pharmaceutical composition and their application in the disease for treating FAK and/or Pyk2 mediation or disease.

Description

As FAK/Pyk2 inhibitor 2,4-diaminourea-6,7-dihydro-5H-pyrrolo-[2, 3] pyrimidine derivatives

Technical field

The present invention relates to suppress the novel 2,4-diaminourea-6,7-dihydro-5H-pyrrolo-of focal adhesion kinase (FAK/Pyk2) [2,3] pyrimidine derivatives, its preparation method and combinations thereof thing, and described compound for suppress FAK and/or Pyk2 application and For treating disease or the method for disease of FAK and/or Pyk2 mediation.

Background technology

FAK (focal adhesion kinase) be transduce from multiple stimulus object (such as integral protein, cytokine, chemotactic factor and Somatomedin) signal thus control various kinds of cell path and process and (include cell proliferation, cell migration, cellular morphology and thin Born of the same parents survive) nonreceptor tyrosine kinase.FAK is activated by FAC (talin complex) relevant somatomedin and integral protein. The combination of ECM (extracellular matrix) and integral protein result in the activation of FAK.The somatomedin that ECM is relevant, such as bFGF, EGF Or PDGF can further enhance the activation of FAK by the common stimulation of somatomedin.The assembly and disassembly pair of talin complex Cell adhesion and motion are most important.FAK will not make other protein phosphorylation.But, the FAK autophosphorylation of activation and Src Kinases combines, other site of Src kinases phosphorylation FAK in turn and other FAK associated proteins (such as Cas and paxillin (paxillin)).The FAK of phosphorylation provides the docking site of mediation (mediator) of multiple signal event, and subsequently The tune that cell grows and survives is participated in by activating of PI3K/Akt/mTOR and Grb2/SOS/RAS/Raf/MEK/ERK path Joint.FAK process LAN is relevant with the deterioration of kinds cancer.

Have turned out suppression FAK and can suppress tumor growth (the Beviglia et al 2003, BioChem of multiple cancerous cell 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).But, Normal human fibroblast or immortalization mammary glandular cell The suppression of middle FAK does not cause forfeiture or apoptosis (the Xu et al 1996 Cell Growth and Diff.7:413-of adhesion 418).Additionally, the forfeiture of FAK activity (rebuilds FAK-/-cell (FAK-/-cells with kinase-of kinases-death FAK Dead FAK)) reduce the growth of v-Src tumor in mice and reduce angiogenesis.Therefore, suppression FAK is probably treatment Effective therapy of excess proliferative disease (such as cancer).

Pyk2 is the unique relevant member of FAK family, has the amino acid identities of 48%.Although Pyk2 generates in tumor In effect the most fully aware of, but some evidences have shown that Pyk2 plays compensatory effect in FAK knock-out mice model.Cause This, the double inhibition of FAK and Pyk2 can be significantly expanded anti-angiogenesis function.

Summary of the invention

The invention discloses series of new 2,4-diaminourea-6,7-dihydro-5H-pyrrolo-[2,3] pyrimidine compound or Its pharmaceutically acceptable salt, solvate, polymorph, tautomer or prodrug, it has FAK/Pyk2 inhibitory activity, And can be used for antiproliferative and/or apoptosis and/or anti-infect and/or anti-cell motion and/or angiogenesis inhibitor, and can be used in In treatment mammal (preferably people) or the method for animal disorders, such as, it is used for suppressing tumor growth and cancer metastasis.This Bright further relate to described 2,4-diaminourea-6,7-dihydro-5H-pyrrolo-[2,3] pyrimidine compound or its pharmaceutically acceptable salt, The preparation method of solvate, polymorph, tautomer or prodrug, relates to comprising described compound or it pharmaceutically can connect The pharmaceutical composition of the salt, solvate, polymorph, tautomer or the prodrug that are subject to, and described 2,4-diaminourea-6,7- Dihydro-5H-pyrrolo-[2,3] pyrimidine compound or its pharmaceutically acceptable salt, solvate, polymorph, tautomerism Body or prodrug have antiproliferative and/or apoptosis in preparation and/or anti-infect and/or anti-cell motion and/or angiogenesis inhibitor Application in medicine.

The invention also discloses and utilize 2,4-diaminourea-6,7-dihydro-5H-pyrrolo-[2,3] pyrimidine compound or its medicine Acceptable salt on, solvate, polymorph, tautomer or the disease of prodrug treatment FAK and/or Pyk2 mediation or The method of disorders such as cancers.

The invention provides compound or its pharmaceutically acceptable salt, solvate, polymorph, the change of formula (I) Isomer or prodrug,

Wherein:

R¹And R²The group constituted independently selected from following group: hydrogen, halogen, cyano group, nitro, hydroxyl, optionally substituted alkane Base, optionally substituted cycloalkyl, optionally substituted thiazolinyl, optionally substituted alkynyl and optionally substituted alkoxyl, or R¹、R² It is collectively forming optionally substituted cycloalkyl or optionally substituted Heterocyclylalkyl with coupled carbon atom；

R³And R⁴The group constituted independently selected from following group: hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, appoint Select substituted aryl, optionally substituted aryl alkyl, optionally substituted Heterocyclylalkyl, optionally substituted heteroaryl ,-COR⁷、- SO₂R⁸、-SOR⁹；

R⁵And R⁶The group constituted independently selected from following group: hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, appoint Select substituted aryl, optionally substituted Heterocyclylalkyl, optionally substituted heteroaryl ,-COR¹⁰、-SO₂R¹¹With-SOR¹²；

R⁷、R⁸、R⁹、R¹⁰、R¹¹And R¹²The group constituted independently selected from following group: optionally substituted alkyl, optionally substituted Cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl；

R^xAnd R^yThe group constituted independently selected from following group: hydrogen, halogen, cyano group, nitro, hydroxyl, optionally substituted alkane Base, optionally substituted cycloalkyl, optionally substituted thiazolinyl, optionally substituted alkynyl and optionally substituted alkoxyl；And

R " group that constitutes selected from following group: hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted Thiazolinyl, optionally substituted alkynyl and optionally substituted alkoxyl.

The compounds of this invention can also represent in order to following formula (Ia):

Wherein, R¹、R²、R³、R⁴、R⁵、R⁶、R^x、R^yWith R " identical with the definition of formula above I.Present invention description below In, not tubular type (I) or formula (Ia), they representative compounds all include all possible stereoisomer, regional isomerism Body, diastereomer, enantiomer or epimer and their mixture.

On the other hand, at formula (I) or formula (Ia), R¹And R²The group constituted independently selected from following group: hydrogen, halogen, cyanogen Base, nitro, hydroxyl, optionally substituted C₁-C₆Alkyl, optionally substituted C₃-C₈Cycloalkyl, optionally substituted C₂-C₆Thiazolinyl, optionally Substituted C₂-C₆Alkynyl and optionally substituted C₁-C₆Alkoxyl；Or R¹、R²It is collectively forming optionally with coupled carbon atom Substituted C₃-C₈Cycloalkyl or optionally substituted Heterocyclylalkyl；

R³And R⁴The group constituted independently selected from following group: hydrogen, optionally substituted C₁-C₆Alkyl, optionally substituted C₃-C₈ Cycloalkyl, optionally substituted C₆-C₁₀Aryl, optionally substituted C₆-C₁₀Aryl-C₁-C₆Alkyl, optionally substituted Heterocyclylalkyl, appoint Select substituted heteroaryl ,-COR⁷、-SO₂R⁸With-SOR⁹；

R⁵And R⁶The group constituted independently selected from following group: hydrogen, optionally substituted C₁-C₆Alkyl, optionally substituted C₃-C₆ Cycloalkyl, optionally substituted C₆-C₁₀Aryl, optionally substituted Heterocyclylalkyl, optionally substituted heteroaryl ,-COR¹⁰、-SO₂R¹¹ With-SOR¹²；

R⁷、R⁸、R⁹、R¹⁰、R¹¹And R¹²The group constituted independently selected from following group: optionally substituted C₁-C₆Alkyl, optionally Substituted C₃-C₈Cycloalkyl, optionally substituted C₆-C₁₀Aryl, optionally substituted heteroaryl；

R^xAnd R^yThe group constituted independently selected from following group: hydrogen, halogen, cyano group, nitro, hydroxyl, optionally substituted C₁- C₆Alkyl, optionally substituted C₃-C₈Cycloalkyl, optionally substituted C₂-C₆Thiazolinyl, optionally substituted C₂-C₆Alkynyl and optionally substituted C₁-C₆Alkoxyl；And

R " selected from following group constitute group: hydrogen, optionally substituted C₁-C₆Alkyl, optionally substituted C₃-C₈Cycloalkyl, appoint Select substituted C₂-C₆Thiazolinyl, optionally substituted C₂-C₆Alkynyl and optionally substituted C₁-C₆Alkoxyl.

On the other hand, the invention provides formula (I) or some preferred compounds of formula (Ia) or it is pharmaceutically acceptable Salt, solvate, polymorph, tautomer or prodrug, wherein, R¹And R²The group constituted independently selected from following group: Hydrogen, optionally substituted C₁-C₆Alkyl, optionally substituted C₃-C₈Cycloalkyl or C₃-C₆Cycloalkyl, optionally substituted C₂-C₆Thiazolinyl, appoint Select substituted C₂-C₆Alkynyl and optionally substituted C₁-C₆Alkoxyl；Or R¹、R²It is collectively forming with coupled carbon atom and appoints Select substituted C₃-C₈Cycloalkyl or C₃-C₆Cycloalkyl；

On the other hand, the invention provides formula (I) or some preferred compounds of formula (Ia) or it is pharmaceutically acceptable Salt, solvate, polymorph, tautomer or prodrug, wherein, R⁵And R⁶The group constituted independently selected from following group: Hydrogen, optionally substituted C₆-C₁₀Aryl, the optionally substituted 1-4 of comprising N, O or S heteroatomic 5-15 unit Heterocyclylalkyl, optionally take Generation comprise 1-4 N, O or S heteroatomic 5-10 unit heteroaryl.

On the other hand, the invention provides formula (I) or some preferred compounds of formula (Ia) or it is pharmaceutically acceptable Salt, solvate, polymorph, tautomer or prodrug, wherein, R⁵And R⁶The group constituted independently selected from following group: Hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl；It is highly preferred that R⁵And R⁶Constitute independently selected from following group Group: hydrogen, 5-7 unit aryl, substituted 5-7 unit aryl, there is one or more N, O or S heteroatomic 5-7 unit's heteroaryl and replacement 5-7 unit heteroaryl；Further, described substituted 5-7 unit aryl or heteroaryl are selected from following at least one group replacement: take Generation or unsubstituted C₁-C₆Alkyl, C₃-C₆Cycloalkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl and C₁-C₆Alkoxyl.

On the other hand, the invention provides formula (I) or some preferred compounds of formula (Ia) or it is pharmaceutically acceptable Salt, solvate, polymorph, tautomer or prodrug, wherein, R³And R⁴The group constituted independently selected from following group: Hydrogen, optionally substituted C₃-C₈Cycloalkyl, optionally substituted C₆-C₁₀Aryl, optionally substituted C₆-C₁₀Aryl-C₁-C₆Alkyl, appoint Select the substituted 1-4 of comprising N, O or S heteroatomic 5-15 unit Heterocyclylalkyl, optionally substituted comprise 1-4 N, O or S hetero atom 5-10 unit heteroaryl；

On the other hand, the invention provides formula (I) or some preferred compounds of formula (Ia) or it is pharmaceutically acceptable Salt, solvate, polymorph, tautomer or prodrug, wherein, R³And R⁴The group constituted independently selected from following group: Hydrogen, aryl, substituted aryl, C₁-C₆Alkylaryl, substituted C₁-C₆Alkylaryl, heteroaryl and substituted heteroaryl；More excellent Selection of land, R³And R⁴The group constituted independently selected from following group: hydrogen, 5-7 unit aryl, substituted 5-7 unit aryl, substituted or not Substituted C₁-C₆Alkyl phenyl, has one or more N, O or S heteroatomic 5-7 unit's heteroaryl and substituted 5-7 unit heteroaryl Base；Further, described substituted 5-7 unit aryl or heteroaryl are selected from following at least one group and replace: halogen, C₁-C₆Alcoxyl Base, C₁-C₆Alkyl, C₃-C₆Cycloalkyl, alkyl monosubstituted amino, dialkyl amido, ring amino, heterocyclic amino group, arylamino, heteroaryl Amino ,-NR²³C(O)R²⁴、-NR²³SO₂R²⁵、-CONR²³R²⁶With-SO₂NR²³R²⁶；Wherein, R²³And R²⁶Independently selected from following base The group that group is constituted: hydrogen, substituted or unsubstituted C₁-C₆Alkyl and substituted or unsubstituted C₃-C₆Cycloalkyl；Or R²³、R²⁶ Former with coupled nitrogen it is collectively forming substituted or unsubstituted 5-7 unit heterocycle；R²⁴And R²⁵Independently selected from following group structure The group become: substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted cycloalkyl, aryl, substituted aryl, heteroaryl With substituted heteroaryl；It is highly preferred that R²⁴And R²⁵The group constituted independently selected from following group: substituted or unsubstituted C₁- C₆Alkyl, substituted or unsubstituted C₃-C₆Cycloalkyl, 5-7 unit aryl, substituted 5-7 unit aryl, 5-7 unit heteroaryl and replacement 5-7 unit heteroaryl.

On the other hand, the invention provides formula (I) or some preferred compounds of formula (Ia) or it is pharmaceutically acceptable Salt, solvate, polymorph, tautomer or prodrug, wherein, R^xAnd R^yIt is all hydrogen.

On the other hand, the invention provides formula (II) or the subclass of the compound of formula (I) that formula (IIa) represents or its pharmacy Upper acceptable salt, solvate, polymorph, tautomer or prodrug,

Wherein:

R¹And R²Independently selected from hydrogen, halogen, trifluoromethyl, cyano group, nitro, hydroxyl, C₁-C₆Alkyl, C₃-C₆Cycloalkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, C₁-C₆Alkoxyl；Or R¹、R²It is collectively forming C with coupled carbon atom₃-C₄Cycloalkyl or Substituted C₃-C₄Cycloalkyl；

R¹³、R¹⁴、R¹⁵、R¹⁶、R¹⁷、R¹⁸、R¹⁹、R²⁰、R²¹And R²²Independently selected from hydrogen, halogen, optionally substituted C₁-C₆Alkane Epoxide, optionally substituted C₁-C₆Alkyl, optionally substituted C₃-C₆Cycloalkyl, optionally substituted alkyl monosubstituted amino, optionally substituted Dialkyl amido, optionally substituted ring amino, optionally substituted heterocyclic amino group, optionally substituted arylamino, optionally substituted Heteroaryl amino ,-C (O)-R²⁴、-NR²³C(O)R²⁴、-NR²³SO₂R²⁵、-NR²³SOR²⁵、-CONR²³R²⁶、-SO₂NR²³R²⁶、- SONR²³R²⁶With-P (=O)-R²⁵；；Or R¹³R¹⁴、R¹⁴R¹⁵、R¹⁵R¹⁶、R¹⁶R¹⁷、R¹⁸R¹⁹、R¹⁹R²⁰、R²⁰R²¹And R²¹R²²Independently With the carbon atom on coupled phenyl be collectively forming substituted or unsubstituted 5-8 ring (including aromatic ring or hetero-aromatic ring) or Heterocycle；Wherein, R²³And R²⁶Independently selected from hydrogen, substituted or unsubstituted C₁-C₆Alkyl, C₃-C₆Cycloalkyl and aryl are (such as C_6-10Aryl), or R²³、R²⁶It is collectively forming substituted or unsubstituted 5-7 unit heterocycle with coupled nitrogen-atoms, or R²³And R²⁶Central one and coupled nitrogen-atoms are collectively forming heterocycle (such as, 5-8 unit heterocycle)；R²⁴And R²⁵Independently Selected from optionally substituted C₁-C₆Alkyl, optionally substituted C₃-C₆Cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl. Not tubular type (I) or formula (Ia), they representative compounds all include all possible stereoisomer, regional isomer, Diastereomer, enantiomer or epimer and their mixture.

On the other hand, the invention provides formula (II) or the subclass of the compound of formula (I) that formula (IIa) represents or its pharmacy Upper acceptable salt, solvate, polymorph, tautomer or prodrug, wherein, R¹And R²Independently selected from following group The group constituted: hydrogen, halogen, cyano group, nitro, hydroxyl, optionally substituted C₁-C₆Alkyl, optionally substituted C₃-C₈Cycloalkyl, optionally Substituted C₂-C₆Thiazolinyl, optionally substituted C₂-C₆Alkynyl and optionally substituted C₁-C₆Alkoxyl；Or R¹、R²With coupled Carbon atom is collectively forming optionally substituted C₃-C₈Cycloalkyl (or C₃-C₆Cycloalkyl, C₃-C₄Cycloalkyl)；

R¹³、R¹⁴、R¹⁵、R¹⁶、R¹⁷、R¹⁸、R¹⁹、R²⁰、R²¹And R²²The group constituted independently selected from following group: hydrogen, halogen, Optionally substituted C₁-C₆Alkyl, optionally substituted C₃-C₈Cycloalkyl, optionally substituted C₂-C₆Thiazolinyl, optionally substituted C₂-C₆Alkynes Base, optionally substituted C₁-C₆Alkoxyl, optionally substituted C₆-C₁₀Aryl, optionally substituted to comprise 1-4 N, O or S heteroatomic 5-15 unit Heterocyclylalkyl, optionally substituted comprise 1-4 N, O or S heteroatomic 5-10 unit heteroaryl, optionally substituted list-C₁- C₆Alkyl amino, optionally substituted two-C₁-C₆Alkyl amino, optionally substituted list-C₁-C₆Alkylaminoacyl, optionally substituted Two-C₁-C₆Alkylaminoacyl, optionally substituted 1-3 N, O or S heteroatomic 5-12 unit Heterocyclylalkyl-acyl group, optionally of comprising Substituted C₁-C₆Alkylamidoalkyl, amino-sulfonyl, optionally substituted list-C₁-C₆Alkyl amino sulfonyl, optionally substituted Two-C₁-C₆Alkyl amino sulfonyl, amino sulfinyl, optionally substituted list-C₁-C₆Alkyl amino sulfinyl, optionally take Two-the C in generation₁-C₆Alkyl amino sulfinyl, optionally substituted C₁-C₆Alkylcarboxamido.

On the other hand, the invention provides lower formula (III) or the subclass of the compound of formula (I) that formula (IIIa) represents or its Pharmaceutically acceptable salt, solvate, polymorph, tautomer or prodrug,

Wherein:

R¹And R²Independently selected from hydrogen, halogen, trifluoromethyl, cyano group, nitro, hydroxyl, C₁-C₆Alkoxyl, C₁-C₆Alkyl, C₃-C₆Cycloalkyl, alkyl monosubstituted amino, dialkyl amido, ring amino, heterocyclic amino group, arylamino, heteroaryl amino ,-NR²³C (O)R²⁴,-NR²³SO₂R²5 ,-CONR²³R²⁶,-SO₂NR²³R²⁶；

R²³And R²⁶Independently selected from hydrogen, C₁-C₆Alkyl, C₃-C₆Cycloalkyl；And

R²⁴And R²⁵Independently selected from C₁-C₆Alkoxyl, C₃-C₆Cycloalkyl, aryl, substituted aryl, heteroaryl, substituted Heteroaryl；Moiety combinations is to R¹³R¹⁴、R¹⁴R¹⁵、R¹⁵R¹⁶、R¹⁶R¹⁷、R¹⁸R¹⁹、R¹⁹R²⁰、R²⁰R²¹And R²¹R²²Independently and with its phase Carbon atom on phenyl even is collectively forming substituted or unsubstituted 5-8 ring (including aryl or heteroaryl) or heterocycle.

In description after this patent, not tubular type (III) or formula (IIIa), they representative compounds all include institute Possible stereoisomer, regional isomer, diastereomer, enantiomer or epimer and theirs is mixed Compound.

On the other hand, the invention provides lower formula (III) or the subclass of the compound of formula (I) that formula (IIIa) represents or its Pharmaceutically acceptable salt, solvate, polymorph, tautomer or prodrug, wherein:

R¹And R²Independently selected from hydrogen, halogen, cyano group, nitro, hydroxyl, optionally substituted C₁-C₆Alkyl, optionally substituted C₃-C₈Cycloalkyl, optionally substituted C₂-C₆Thiazolinyl, optionally substituted C₂-C₆Alkynyl, optionally substituted C₁-C₆Alkoxyl；Or R¹、R²It is collectively forming optionally substituted C with coupled carbon atom₃-C₈Cycloalkyl；

R¹³、R¹⁴、R¹⁵、R¹⁶、R¹⁷、R¹⁸、R¹⁹、R²⁰、R²¹And R²²Independently selected from hydrogen, halogen, optionally substituted C₁-C₆Alkane Base, optionally substituted C₃-C₈Cycloalkyl, optionally substituted C₂-C₆Thiazolinyl, optionally substituted C₂-C₆Alkynyl, optionally substituted C₁-C₆ Alkoxyl, optionally substituted C₆-C₁₀Aryl, optionally substituted comprise 1-4 N, O or S heteroatomic 5-15 unit Heterocyclylalkyl, appoint Select and substituted comprise 1-4 N, O or S heteroatomic 5-10 unit heteroaryl, optionally substituted list-C₁-C₆Alkyl amino, optionally take Two-the C in generation₁-C₆Alkyl amino, optionally substituted list-C₁-C₆Alkylaminoacyl, optionally substituted two-C₁-C₆Alkyl amino Acyl group, optionally substituted comprise 1-3 N, O or S heteroatomic 5-12 unit Heterocyclylalkyl-acyl group, optionally substituted C₁-C₆Alkyl Amide groups, amino-sulfonyl, optionally substituted list-C₁-C₆Alkyl amino sulfonyl, optionally substituted two-C₁-C₆Alkyl amino Sulfonyl, amino sulfinyl, optionally substituted list-C₁-C₆Alkyl amino sulfinyl, optionally substituted two-C₁-C₆Alkyl Amino sulfinyl, optionally substituted C₁-C₆Alkylcarboxamido.

On the other hand, the invention provides some preferred compounds or its medicine of formula (II), (IIa), (III) and (IIIa) Acceptable salt, solvate, polymorph, tautomer or prodrug on, wherein, R¹³、R¹⁴、R¹⁵、R¹⁶And R¹⁷Independent Ground is selected from hydrogen ,-NR²³C(O)R²⁴、-NR²³SO₂R²⁵、-CONR²³R²⁶With-SO₂NR²³R²⁶。R²³-R²⁶Definition with the most identical.

On the other hand, the invention provides some preferred compounds or its medicine of formula (II), (IIa), (III) and (IIIa) Acceptable salt, solvate, polymorph, tautomer or prodrug on, wherein, R¹⁸、R¹⁹、R²⁰、R²¹And R²²Independent Ground is selected from hydrogen, optionally substituted C₁-C₆Alkoxyl, optionally substituted C₁-C₆Alkyl, optionally substituted C₃-C₆Cycloalkyl, optionally take Generation there is one or more N, O or S heteroatomic 5-7 unit Heterocyclylalkyl；Or R¹⁸R¹⁹、R¹⁹R²⁰、R²⁰R²¹And R²¹R²²Independent The carbon atom on phenyl that ground is coupled is collectively forming optionally substituted 5-15 (or 5-10,5-8) ring and (includes aromatic ring or miscellaneous Aromatic ring) or heterocycle, wherein, described substituted ring or heterocycle are by oxo (oxo), optionally substituted C₁-C₆Alkoxyl, C₁-C₆Alkane Base, C₃-C₆Cycloalkyl or 5-7 unit heterocycle-C₁-C₆Alkyl is replaced.

On the other hand, the invention provides the compound of formula (I) selected from following compound or it is pharmaceutically acceptable Salt, solvate, polymorph, tautomer or prodrug,

On the other hand, the invention provides the above-claimed cpd of the present invention or its pharmaceutically acceptable salt, solvate, Polymorph, tautomer or prodrug, it is used as medicine.Preferably, described medicine has antiproliferative and/or apoptosis activity.

On the other hand, the invention provides pharmaceutical composition, it comprises the compound of the present invention or it is pharmaceutically acceptable Salt, solvate, polymorph, tautomer or prodrug.In some embodiments, the pharmaceutical composition of the present invention enters One step comprises pharmaceutically acceptable carrier, diluent, excipient and/or accessory drugs, such as preservative, absorption delaying agent, filler, Binding agent, adsorbent, buffer agent, disintegrating agent, solubilizing agent, other carrier and other inert fraction.The compound method of compositions is Technology well known in the art.

On the other hand, the method that the invention provides suppression FAK and/or Pyk2, described method includes the change making the present invention Compound contacts with FAK and/or Pyk2.

On the other hand, the invention provides treatment or the disease of prevention FAK and/or Pyk2 mediation or the method for disease, institute The method of stating includes compound or the compositions of the present invention to individuals in need administering therapeutic effective dose.Preferably, described Disease or disease are cancer, infectious disease, diseases associated with inflammation or autoimmune disease.It is highly preferred that described disease or disease Disease is cancer.In some embodiments, described individuality is mammal, is more preferably people.

On the other hand, the invention provides the above-claimed cpd of the present invention or its pharmaceutically acceptable salt, solvate, Polymorph, tautomer or prodrug are used for the application suppressed in the pharmaceutical composition of FAK and/or Pyk2 in preparation.Preferably Ground, described pharmaceutical composition is for the disease treated or prevent FAK and/or Pyk2 to mediate or disease.It is highly preferred that described disease Or disease is 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 pharmacy and prepare, described preparation includes the compound of logical formula (I) and is different from formula (I) At least one other cytostatic or cytotoxic active substance, these active substances are optionally it Tautomer, racemic modification, enantiomer, diastereomer and their mixture or pharmaceutically can connect The salt of the acid adding being subject to.

In other side, the present invention relates to above-claimed cpd or its most acceptable salt, the solvation of the present invention The pharmaceutical composition of thing, polymorph, tautomer or prodrug.In some embodiments, described pharmaceutical composition is mouth Oral dosage form.In some embodiments, the dosage form of described pharmaceutical composition is tablet, capsule, pill, powder, slow releasing preparation, molten Liquid and suspension, for sterile solution, suspension or the emulsion of parental injection, for ointment or the emulsifiable paste of topical, or Person is for the suppository of rectally.In other embodiments, described pharmaceutical composition is to be suitable for single to bestow exact dose Unit dosage forms.In other embodiments, the amount of compound of formula I about 0.001mg/kg body weight/day-about 1000mg/kg body weight/ In the range of it.In other embodiments, the amount of compound of formula I is in the range of about 0.5mg/kg body weight/day-about 50mg/kg Body weight/day.In some embodiments, the amount of compound of formula I is about 0.001g/ days-about 7g/ days.In other embodiments, The amount of compound of formula I is about 0.002-about 6g/ days.In other embodiments, the amount of compound of formula I be about 0.005g/ days-about 5g/ days.In other embodiments, the amount of compound of formula I is about 0.01-about 5g/ days.In other embodiments, Formulas I chemical combination The amount of thing is about 0.02g/ days-about 5g/ days.In other embodiments, the amount of compound of formula I is about 0.05g/ days-about 2.5g/ My god.In other embodiments, the amount of compound of formula I is about 0.1g/ days-about 1g/ days.In other embodiments, less than upper The dosage level stating range lower limit may be enough.In other embodiments, it may be necessary to higher than in above-mentioned scope The dosage level of limit.In some embodiments, the compound of Formulas I is used with single dose, once a day.At other embodiment In, the compound of Formulas I is used with multiple dose, every day is more than once.In some embodiments, the change of daily twice Formulas I Compound.In other embodiments, the compound of daily cubic expression tertiary I.In other embodiments, daily quarternary quantic The compound of I.In other embodiments, the compound of daily four above formula I.In some embodiments, described Pharmaceutical composition is applied to mammal.In other embodiments, described mammal is people.In other embodiments, Described pharmaceutical composition also comprises pharmaceutical carrier, excipient and/or auxiliary agent.In other embodiments, described pharmaceutical composition Also comprise at least one therapeutic agent.In other embodiments, described therapeutic agent selected from cell toxicant material, anti-angiogenic and The group of antitumor agent composition.In other embodiments, antitumor agent choosing free alkylating agent, antimetabolite, teniposide (epidophyllotoxin), antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone (mitoxantrones), platinum complex, biological response modifier and growth inhibitor, hormone/antihormonal therapy agents and hemopoietic are raw The group of long factor composition.In other embodiments, described therapeutic agent is paclitaxel (taxol), bortezomib (bortezomib) or both.In other embodiments, described pharmaceutical composition use with other treatment combine into OK.In other embodiments, other treatment described is radiotherapy, chemotherapy or combination.In other embodiments, described The most acceptable salt of the contained I of pharmaceutical composition.

In other side, the method that the present invention relates to suppress FAK and/or Pyk2.Described method include making described FAK and/ Or Pyk2 contact be enough to suppress the compositions of described kinase whose amount, thus suppress FAK and/or Pyk2 enzyme, wherein said compositions Contained I or its most acceptable salt, hydrate, polymorph, tautomer or prodrug.Real at some Execute in mode, the method that the present invention relates to Selective depression FAK and/or Pyk2.

In other side, the present invention relates to compound of formula I or its most acceptable salt, solvate, polymorphic Thing, tautomer or prodrug are used for the application suppressed in the pharmaceutical composition of FAK and/or Pyk2 in preparation.

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 pressed down System at least about 4%.In other embodiments, described enzyme is suppressed at least about 5%.In other embodiments, described enzyme quilt Suppression 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%.At other embodiment In, described enzyme is suppressed at least about 60%.In other embodiments, described enzyme is suppressed at least about 70%.Implement at other In mode, described enzyme is suppressed at least about 75%.In other embodiments, described enzyme is suppressed at least about 80%.At other In embodiment, described enzyme is suppressed at least about 90%.In other embodiments, described enzyme is substantially completely suppressed.One In a little embodiments, described contact is in intracellular generation.In some embodiments, described cell is mammalian cell.? In some embodiments, described mammalian cell behaviour cell.In some embodiments, the compound of contained I is utilized Pharmaceutically acceptable salt compositions suppression FAK and/or Pyk2.In other side, the present invention relates to treatment and suffer from FAK And/or the method for the individual described disease of the disease of Pyk2 mediation, described method includes using effective dose to described individuality The compound of contained I or its most acceptable salt, solvate, polymorph, tautomer or prodrug.At it Its aspect, the present invention relates to compound or its most acceptable salt, solvate, polymorph, the change of contained I Isomer or prodrug are used for the application treating in the pharmaceutical composition of the disease of FAK and/or Pyk2 mediation in preparation.

In some embodiments, by being administered orally, (including intravenous, subcutaneous, intramuscular, blood vessel through duodenum, parenteral In or by infusion), local application (topical administration) or per rectum use contained I Compositions.In some embodiments, described pharmaceutical composition is peroral dosage form.In other embodiments, described medicine group The dosage form of compound is tablet, capsule, pill, powder, slow release formulation, solution and suspension, aseptic molten for parental injection Liquid, suspension or emulsion, for ointment or the emulsifiable paste of topical, or the suppository for rectally.Other embodiment party In formula, described pharmaceutical composition is the unit dosage forms being suitable for bestowing single exact dose.In other embodiments, described medicine Compositions also comprises pharmaceutical carrier, excipient and/or auxiliary agent.In other embodiments, the amount of compound of formula I is about In the range of 0.001mg/kg body weight/day-about 1000mg/kg body weight/day.In other embodiments, the amount of compound of formula I Scope is about 0.5mg/kg body weight/day-about 50mg/kg body weight/day.In some embodiments, the amount of compound of formula I is about 0.001g/ days-about 7g/ days.In other embodiments, the amount of compound of formula I is about 0.01g/ days-about 7g/ days.Real at other Executing in mode, the amount of compound of formula I is about 0.02g/ days-about 5g/ days.In other embodiments, the amount of compound of formula I is about 0.05g/ days-about 2.5g/ days.In other embodiments, the amount of compound of formula I is about 0.1g/ days-about 1g/ days.Real at other Execute in mode, may be enough less than the dosage level of above-mentioned range lower limit.In other embodiments, it may be necessary to Dosage level higher than above-mentioned range limit.In other embodiments, the compound of Formulas I is bestowed with single dose, once a day. In other embodiments, bestowing the compound of Formulas I with multiple dose, every day is more than once.In other embodiments, execute every day With the compound of twice Formulas I.In other embodiments, the compound of daily cubic expression tertiary I.In other embodiments, The daily compound of quarternary quantic I.In other embodiments, the compound of daily four above formula I.Real at some Execute in mode, described in suffer from the individuality of disease of FAK and/or Pyk2 mediation be mammal.In other embodiments, described Individuality is people.In some embodiments, using of the compositions of contained I is combined carry out with other treatment.At it In its embodiment, other treatment described is radiotherapy, chemotherapy or combination.In some embodiments, by contained Iization The compositions of compound is used with at least one therapeutic combination.In some embodiments, described therapeutic agent is selected from cell toxicant The group of matter, anti-angiogenic and antitumor agent.In other embodiments, antitumor agent choosing free alkylating agent, antimetabolic Thing, teniposide, antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum complex, biological response are adjusted Joint agent and growth inhibitor, hormone/antihormonal therapy agents and the group of hemopoietic growth factor composition.In other embodiments, institute State therapeutic agent selected from paclitaxel, bortezomib or both.In some embodiments, described by FAK and/or Pyk2 mediation Disease selected from the group that consists of: diseases associated with inflammation, infection, autoimmune disease, apoplexy, ischemia, heart disease, nerve Systemic disease, fibrotic disease, proliferative disease, excess proliferative disease, the excess proliferative disease of non-cancer, tumor (tumor), leukemia, vegetation (neopalsms), cancer (cancer), malignant tumor (carcinoma), metabolic disease, pernicious Disease, vascular restenosis, psoriasis, arteriosclerosis, rheumatoid arthritis, osteoarthritis, heart failure, chronic pain, Neuropathic pain, xerophthalmia, angle closure glaucoma and wide-angle glaucoma.In other embodiments, described FAK and/or The disease of Pyk2 mediation is diseases associated with inflammation.In other embodiments, the disease of described FAK and/or Pyk2 mediation is propagation Property disease.In other embodiments, disease choosing free tumor, leukemia, vegetation, the cancer of described FAK and/or Pyk2 mediation Disease, malignant tumor and the group of malignant disease composition.In other embodiments, described cancer is the brain cancer, breast carcinoma, pulmonary carcinoma, ovary Cancer, cancer of pancreas, carcinoma of prostate, renal carcinoma, colorectal cancer or leukemia.In other embodiments, described fibrotic disease is hard Skin disease, polymyositis, systemic lupus erythematosus (sle), rheumatoid arthritis, liver cirrhosis, cicatrization, interstitial nephritis or lung Fibrosis.In some embodiments, use is the combination of the most acceptable salt of contained I of effective dose Thing.

In other side, the present invention relates to make the growth of cancerous cell degeneration (degrade), anticancer or kill cancerous cell Method, described method includes making its amount of described cells contacting can effectively make cancerous cell degenerate, anticancer growth or kill The compositions of cancerous cell, the contained I of described compositions or its most acceptable salt, solvate, polymorphic Thing, tautomer or prodrug.

In other side, the present invention relates to contained I or its most acceptable salt, solvate, many Crystal formation thing, tautomer or prodrug are used for making cancerous cell degenerate in preparation, anticancer grows or kills the medicine of cancerous cell Application on compositions.

In some embodiments, described cancerous cell includes that brain cancer cell, breast cancer cell, lung carcinoma cell, ovarian cancer are thin Born of the same parents, prostate gland cancer cell, kidney cancer cell or colorectal cancer cell.In some embodiments, described compositions and at least one Therapeutic agent is used together.In other embodiments, described therapeutic agent be paclitaxel, bortezomib or both.At other In embodiment, described therapeutic agent selects free cell toxicant material, anti-angiogenic and the group of antitumor agent composition.Real at other Execute in mode, antitumor agent choosing free alkylating agent, antimetabolite, teniposide, antitumor enzyme, topoisomerase enzyme level Agent, procarbazine, mitoxantrone, platinum complex, biological response modifier and growth inhibitor, hormone/antihormonal therapy agents and The group of hemopoietic growth factor composition.In some embodiments, cancerous cell is degenerated.In other embodiments, the cancer of 1% is thin Born of the same parents are degenerated.In other embodiments, the cancerous cell of 2% is degenerated.In other embodiments, the cancerous cell of 3% is moved back Change.In other embodiments, the cancerous cell of 4% is degenerated.In other embodiments, the cancerous cell of 5% is degenerated.At it In its embodiment, the cancerous cell of 10% is degenerated.In other embodiments, the cancerous cell of 20% is degenerated.Real at other Executing in mode, the cancerous cell of 25% is degenerated.In other embodiments, the cancerous cell of 30% is degenerated.Other embodiment party In formula, the cancerous cell of 40% is degenerated.In other embodiments, the cancerous cell of 50% is degenerated.In other embodiments, The cancerous cell of 60% is degenerated.In other embodiments, the cancerous cell of 70% is degenerated.In other embodiments, 75% Cancerous cell degenerated.In other embodiments, the cancerous cell of 80% is degenerated.In other embodiments, the cancer of 90% Cell is degenerated.In other embodiments, the cancerous cell of 100% is degenerated.In other embodiments, essentially all of cancer Cell is all degenerated.In some embodiments, cancerous cell is killed.In other embodiments, the cancerous cell of 1% is killed Extremely.In other embodiments, the cancerous cell of 2% is killed.In other embodiments, the cancerous cell of 3% is killed.At it In its embodiment, the cancerous cell of 4% is killed.In other embodiments, the cancerous cell of 5% is killed.Implement at other In mode, the cancerous cell of 10% is killed.In other embodiments, the cancerous cell of 20% is killed.At other embodiment In, the cancerous cell of 25% is killed.In other embodiments, the cancerous cell of 30% is killed.In other embodiments, The cancerous cell of 40% is killed.In other embodiments, the cancerous cell of 50% is killed.In other embodiments, 60% Cancerous cell be killed.In other embodiments, the cancerous cell of 70% is killed.In other embodiments, the cancer of 75% Cell is killed.In other embodiments, the cancerous cell of 80% is killed.In other embodiments, the cancerous cell of 90% It is killed.In other embodiments, the cancerous cell of 100% is all killed.In other embodiments, essentially all of cancer is thin Born of the same parents are killed.In some embodiments, the growth of cancerous cell is suppressed.In other embodiments, the growth of cancerous cell It is suppressed about 1%.In other embodiments, the growth of cancerous cell is suppressed about 2%.In other embodiments, cancerous cell Growth be suppressed about 3%.In other embodiments, the growth of cancerous cell is suppressed about 4%.In other embodiments, The growth of cancerous cell is suppressed about 5%.In other embodiments, the growth of cancerous cell is suppressed about 10%.Implement at other In mode, the growth of cancerous cell is suppressed about 20%.In other embodiments, the growth of cancerous cell is suppressed about 25%.? In other embodiment, the growth of cancerous cell is suppressed about 30%.In other embodiments, the growth of cancerous cell is suppressed about 40%.In other embodiments, the growth of cancerous cell is suppressed about 50%.In other embodiments, the growth of cancerous cell It is suppressed about 60%.In other embodiments, the growth of cancerous cell is suppressed about 70%.In other embodiments, cancer is thin The growth of born of the same parents is suppressed about 75%.In other embodiments, the growth of cancerous cell is suppressed about 80%.At other embodiment In, the growth of cancerous cell is suppressed about 90%.In other embodiments, the growth of cancerous cell is suppressed about 100%.At some In embodiment, use is the compositions of the most acceptable salt of contained I.

In other side, the present invention relates to treatment or the method for the individual proliferative disease of prevention, described method comprises to institute State individuality and use the pharmaceutical composition of effective dose, the contained I of described pharmaceutical composition or it is the most acceptable Salt, solvate, polymorph, tautomer or prodrug.

In other side, the present invention relates to compound of formula I or its most acceptable salt, solvate, polymorphic Thing, tautomer or prodrug are used for the application treated or prevent in the pharmaceutical composition of proliferative disease in preparation.

In some embodiments, described proliferative disease be cancer, psoriasis, restenosis, autoimmune disease or Arteriosclerosis.In other embodiments, described proliferative disease is excess proliferative disease.In other embodiments, Described proliferative disease selects free tumor, leukemia, vegetation, cancer, malignant tumor and the group of malignant disease composition.Implement at other In mode, described cancer is the brain cancer, breast carcinoma, pulmonary carcinoma, ovarian cancer, cancer of pancreas, carcinoma of prostate, renal carcinoma, colorectal cancer or white blood Sick.In other embodiments, described fibrotic disease is scleroderma, polymyositis, systemic lupus erythematosus (sle), rheumatoid Arthritis, liver cirrhosis, cicatrization, interstitial nephritis or pulmonary fibrosis.In other embodiments, described cancer be the brain cancer, Breast carcinoma, pulmonary carcinoma, ovarian cancer, cancer of pancreas, carcinoma of prostate, renal carcinoma, colorectal cancer or leukemia.In other embodiments, institute Stating cancer is the brain cancer or adrenocortical carcinoma.In other embodiments, described cancer is breast carcinoma.At other embodiment In, described cancer is ovarian cancer.In other embodiments, described cancer is cancer of pancreas.In other embodiments, described cancer Disease is carcinoma of prostate.In other embodiments, described cancer is renal carcinoma.In other embodiments, described cancer is straight for knot Intestinal cancer.In other embodiments, described cancer is myelocytic leukemia.In other embodiments, described cancer is glue Matter blastoma.In other embodiments, described cancer is follicular lymphoma.In other embodiments, described cancer For pre B lymphocyte acute leukemia.In other embodiments, described cancer is Type B lymphatic chronic leukemia.At it In its embodiment, described cancer is mesothelioma.In other embodiments, described cancer is minicell system cancer.Real at some Execute in mode, using of the compositions of contained I and other treatment are combined.In other embodiments, described Other treatment is radiotherapy, chemotherapy or combination.In other embodiments, by the compositions of contained I with extremely Few a kind of therapeutic combination is used.In other embodiments, described therapeutic agent selected from cell toxicant material, anti-angiogenic and The group of antitumor agent.In other embodiments, antitumor agent choosing free alkylating agent, antimetabolite, teniposide, antitumor Enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum complex, biological response modifier and growth inhibitor, Hormone/antihormonal therapy agents and the group of hemopoietic growth factor composition.In other embodiments, described therapeutic agent is selected from Ramulus et folium taxi cuspidatae Alcohol, bortezomib or both.In some embodiments, by oral, through duodenum, parenteral (include intravenous, Subcutaneous, intramuscular, Ink vessel transfusing or pass through infusion), local application or per rectum applying said compositions.In other embodiments, The amount of compound of formula I is in the range of about 0.001mg/kg body weight/day-about 1000mg/kg body weight/day.In other embodiments, The amount of compound of formula I is in the range of about 0.5mg/kg body weight/day-about 50mg/kg body weight/day.In other embodiments, Formulas I The amount of compound is about 0.001g/ days-about 7g/ days.In other embodiments, the amount of compound of formula I be about 0.01g/ days-about 7g/ days.In other embodiments, the amount of compound of formula I is about 0.02g/ days-about 5g/ days.In other embodiments, Formulas I The amount of compound is about 0.05g/ days-about 2.5g/ days.In other embodiments, the amount of compound of formula I be about 0.1g/ days-about 1g/ days.In other embodiments, may be enough less than the dosage level of above-mentioned range lower limit.Implement at other In mode, it may be necessary to higher than the dosage level of above-mentioned range limit.In other embodiments, the compound of Formulas I is with single dose Amount is administered, once a day.In other embodiments, the compound of Formulas I is with multiple dose administration, and every day is more than once.At other In embodiment, the daily compound of twice Formulas I.In other embodiments, the compound of daily cubic expression tertiary I. In other embodiments, the compound of daily quarternary quantic I.In other embodiments, daily four above formula I Compound.In some embodiments, the individuality suffering from proliferative disease is mammal.In other embodiments, institute Stating individuality is people.In some embodiments, use is the most acceptable salt of contained I of effective dose Compositions.

In other side, the present invention relates to treatment or the method for the individual diseases associated with inflammation of prevention, described method comprises to institute State individuality and use the pharmaceutical composition of effective dose, the contained I of described pharmaceutical composition or it is the most acceptable Salt, solvate, polymorph, tautomer or prodrug.

In other side, the present invention relates to contained I or its most acceptable salt, solvate, many The application in the pharmaceutical composition that preparation is used for treatment or preventing inflammatory disease of crystal formation thing, tautomer or prodrug.

In other embodiments, diseases associated with inflammation is selected from the group consisted of: chronic inflammation disease, rheumatoid Arthritis, SpA, gouty arthritis, osteoarthritis, juvenile arthritis, acute rheumatic arthritis, enteropathic Arthritis, neurarthropathy, psoriatic arthritis, suppurative arthritis, arteriosclerosis, systemic lupus erythematosus (sle), inflammation Property intestinal tract disease, irritable bowel syndrome, ulcerative colitis, reflux esophagitis, regional enteritis (Crohn's Disease), gastritis, asthma, anaphylaxis, respiratory distress syndrome, pancreatitis, chronic obstructive pulmonary disease, pulmonary fibrosis, silver bits Disease, eczema or scleroderma.In some embodiments, using of the compositions of contained I is connected with other treatment Close.In other embodiments, the compositions of contained I is used with at least one therapeutic combination.Real at some Execute in mode, by oral, through duodenum, parenteral (include intravenous, subcutaneous, intramuscular, Ink vessel transfusing or pass through infusion), office Portion uses or per rectum applying said compositions.In other embodiments, the amount of compound of formula I is in the range of about 0.001mg/ Kg body weight/day-about 1000mg/kg body weight/day.In other embodiments, the amount of compound of formula I is in the range of about 0.5mg/kg Body weight/day-about 50mg/kg body weight/day.In other embodiment, the amount of compound of formula I is about 0.001g/ days-about 7g/ days.? In his embodiment, the amount of compound of formula I is about 0.01g/ days-about 7g/ days.In other embodiments, the amount of compound of formula I It is about 0.02g/ days-about 5g/ days.In other embodiments, the amount of compound of formula I is about 0.05g/ days-about 2.5g/ days.? In other embodiment, the amount of compound of formula I is about 0.1g/ days-about 1g/ days.In other embodiments, less than above-mentioned scope The dosage level of lower limit may be enough.In other embodiments, it may be necessary to higher than the agent of above-mentioned range limit Amount level.In other embodiments, the compound of Formulas I is administered in a single dose, once a day.In other embodiments, Formulas I Compound with multiple dose administration, every day is more than once.In other embodiments, the compound of daily twice Formulas I.? In other embodiment, the daily compound of cubic expression tertiary I.In other embodiments, the chemical combination of daily quarternary quantic I Thing.In other embodiments, the compound of daily four above formula I.In some embodiments, suffers from struvite disease Sick individuality is mammal.In other embodiments, described individuality is people.In some embodiments, use is to have The compositions of the most acceptable salt of contained I of effect amount.

In other side, the present invention relates to treatment or the method for prevention individual cancer, described method comprises to described individuality Use the pharmaceutical composition of effective dose, the contained I of described pharmaceutical composition or its most acceptable salt, solvent Compound, polymorph, tautomer or prodrug.

In other side, the present invention relates to contained I or its most acceptable salt, solvate, many The application in the pharmaceutical composition that preparation is used for treatment or prophylaxis of cancer of crystal formation thing, tautomer or prodrug.

In other embodiments, described cancer is the brain cancer, breast carcinoma, pulmonary carcinoma, ovarian cancer, cancer of pancreas, carcinoma of prostate, kidney Cancer, colorectal cancer or leukemia.In other embodiments, described fibrotic disease is scleroderma, polymyositis, systematicness Lupus erythematosus, rheumatoid arthritis, liver cirrhosis, cicatrization, interstitial nephritis or pulmonary fibrosis.At other embodiment In, described cancer is the brain cancer, breast carcinoma, pulmonary carcinoma, ovarian cancer, cancer of pancreas, carcinoma of prostate, renal carcinoma, colorectal cancer or leukemia.? In other embodiment, described cancer is the brain cancer or adrenocortical carcinoma.In other embodiments, described cancer is mammary gland Cancer.In other embodiments, described cancer is ovarian cancer.In other embodiments, described cancer is cancer of pancreas.At other In embodiment, described cancer is carcinoma of prostate.In other embodiments, described cancer is renal carcinoma.At other embodiment In, described cancer is colorectal cancer.In other embodiments, described cancer is myelocytic leukemia.Other embodiment party In formula, described cancer is glioblastoma multiforme.In other embodiments, described cancer is follicular lymphoma.Real at other Executing in mode, described cancer is pre B lymphocyte acute leukemia.In other embodiments, described cancer is Type B lymphocyte Property chronic leukemia.In other embodiments, described cancer is mesothelioma.In other embodiments, described cancer is little Cell line cancer.In some embodiments, using of the compositions of contained I is combined with other treatment.At it In its embodiment, other treatment described is radiotherapy, chemotherapy or combination.In other embodiments, by contained Iization The compositions of compound is used with at least one therapeutic combination.In other embodiments, described therapeutic agent is selected from cell toxicant The group of matter, anti-angiogenic and antitumor agent.In other embodiments, antitumor agent choosing free alkylating agent, antimetabolic Thing, teniposide, antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum complex, biological response are adjusted Joint agent and growth inhibitor, hormone/antihormonal therapy agents and the group of hemopoietic growth factor composition.In other embodiments, institute State therapeutic agent selected from paclitaxel, bortezomib or both.In some embodiments, by oral, through duodenum, intestinal Stomach outer (include intravenous, subcutaneous, intramuscular, Ink vessel transfusing or pass through infusion), local application or per rectum applying said compositions.? In other embodiment, in other embodiments, the amount of compound of formula I is in the range of about 0.001mg/kg body weight/day-about 1000mg/kg body weight/day.In other embodiments, the amount of compound of formula I is in the range of about 0.5mg/kg body weight/day-about 50mg/kg body weight/day.In other embodiments, the amount of compound of formula I is about 0.001g/ days-about 7g/ days.Implement at other In mode, the amount of compound of formula I is about 0.01g/ days-about 7g/ days.In other embodiments, the amount of compound of formula I is about 0.02g/ days-about 5g/ days.In other embodiments, the amount of compound of formula I is about 0.05g/ days-about 2.5g/ days.At other In embodiment, the amount of compound of formula I is about 0.1g/ days-about 1g/ days.In other embodiments, less than above-mentioned range lower limit Dosage level may be enough.In other embodiments, it may be necessary to higher than the dosage water of above-mentioned range limit Flat.In other embodiments, the compound of Formulas I is administered in a single dose, once a day.In other embodiments, the change of Formulas I Compound is with multiple dose administration, and every day is more than once.In other embodiments, the compound of daily twice Formulas I.At other In embodiment, the daily compound of cubic expression tertiary I.In other embodiments, the compound of daily quarternary quantic I. In other embodiments, the compound of daily four above formula I.In some embodiments, suffers from the individuality of cancer For mammal.In other embodiments, described individuality is people.In some embodiments, use is the bag of effective dose Compositions containing the most acceptable salt of compound of formula I.

In other side, the present invention relates to reduce individual in-vivo tumour volume, suppression gross tumor volume increase, reduce tumor increasing The method grown or suppress tumor proliferation, described method includes the pharmaceutical composition to described individual administering therapeutic effective dose, described The contained I of pharmaceutical composition or its most acceptable salt, solvate, polymorph, tautomer or Prodrug.

In other side, the present invention relates to compound of formula I or its most acceptable salt, solvate, polymorphic The application in preparing pharmaceutical composition of thing, tautomer or prodrug, described pharmaceutical composition is used for reducing gross tumor volume, pressing down Gross tumor volume processed increases, reduces tumor proliferation or suppression tumor proliferation.

In some embodiments, gross tumor volume reduces.In other embodiments, gross tumor volume is reduced at least 1%.? In other embodiment, gross tumor volume is reduced at least 2%.In other embodiments, gross tumor volume is reduced at least 3%.At it In its embodiment, gross tumor volume is reduced at least 4%.In other embodiments, gross tumor volume is reduced at least 5%.At other In embodiment, gross tumor volume is reduced at least 10%.In other embodiments, gross tumor volume is reduced at least 20%.At other In embodiment, gross tumor volume is reduced at least 25%.In other embodiments, gross tumor volume is reduced at least 30%.At other In embodiment, gross tumor volume is reduced at least 40%.In other embodiments, gross tumor volume is reduced at least 50%.At other In embodiment, gross tumor volume is reduced at least 60%.In other embodiments, gross tumor volume is reduced at least 70%.At other In embodiment, gross tumor volume is reduced at least 75%.In other embodiments, gross tumor volume is reduced at least 80%.At other In embodiment, gross tumor volume is reduced at least 85%.In other embodiments, gross tumor volume is reduced at least 90%.At other In embodiment, gross tumor volume is reduced at least 95%.In other embodiments, described tumor is uprooted.Some embodiment party In formula, gross tumor volume no longer increases.In some embodiments, tumor proliferation declines.In some embodiments, tumor proliferation Decline at least 1%.In some embodiments, tumor proliferation declines at least 2%.In some embodiments, under tumor proliferation It is down to few 3%.In some embodiments, tumor proliferation declines at least 4%.In some embodiments, tumor proliferation declines At least 5%.In some embodiments, tumor proliferation declines at least 10%.In some embodiments, tumor proliferation drops to Few 20%.In some embodiments, tumor proliferation declines at least 25%.In some embodiments, tumor proliferation drops to Few 30%.In some embodiments, tumor proliferation declines at least 40%.In some embodiments, tumor proliferation drops to Few 50%.In some embodiments, tumor proliferation declines at least 60%.In some embodiments, tumor proliferation drops to Few 70%.In some embodiments, tumor proliferation declines at least 75%.In some embodiments, tumor proliferation drops to Few 80%.In some embodiments, tumor proliferation declines at least 90%.In some embodiments, tumor proliferation drops to Few 95%.In some embodiments, tumor proliferation is prevented from.In some embodiments, by the combination of contained I Use and other treatment of thing are combined.In other embodiments, other treatment described is radiotherapy, chemotherapy or the group of the two Close.In other embodiments, the compositions of contained I is used with at least one therapeutic combination.Real at other Executing in mode, described therapeutic agent is selected from cell toxicant material, anti-angiogenic and the group of antitumor agent.At other embodiment In, antitumor agent choosing free alkylating agent, antimetabolite, teniposide, antitumor enzyme, topoisomerase enzyme inhibitor, methyl Benzyl hydrazine, mitoxantrone, platinum complex, biological response modifier and growth inhibitor, hormone/antihormonal therapy agents and hematopoietic growth The group of factor composition.In other embodiments, described therapeutic agent selected from paclitaxel, bortezomib or both.At some In embodiment, by oral, through duodenum, parenteral (include intravenous, subcutaneous, intramuscular, Ink vessel transfusing or pass through infusion), Local application or per rectum applying said compositions.In other embodiments, in other embodiments, compound of formula I Amount is in the range of about 0.001mg/kg body weight/day-about 1000mg/kg body weight/day.In other embodiments, compound of formula I Amount is in the range of about 0.5mg/kg body weight/day-about 50mg/kg body weight/day.In other embodiment, the amount of compound of formula I is about 0.001g/ days-about 7g/ days.In his embodiment, the amount of compound of formula I is about 0.01g/ days-about 7g/ days.Implement at other In mode, the amount of compound of formula I is about 0.02g/ days-about 5g/ days.In other embodiments, the amount of compound of formula I is about 0.05g/ days-about 2.5g/ days.In other embodiments, the amount of compound of formula I was at about 0.1g/ days-about 1g/ days.Real at other Execute in mode, may be enough less than the dosage level of above-mentioned range lower limit.In other embodiments, it may be necessary to Dosage level higher than above-mentioned range limit.In other embodiments, the compound of Formulas I is administered in a single dose, once a day. In other embodiments, the compound of Formulas I is with multiple dose administration, and every day is more than once.In other embodiments, execute every day With the compound of twice Formulas I.In other embodiments, the compound of daily cubic expression tertiary I.In other embodiments, The daily compound of quarternary quantic I.In other embodiments, the compound of daily four above formula I.Real at some Executing in mode, the individuality suffering from cancer is mammal.In other embodiments, described individuality is people.Some embodiment party In formula, use is the compositions of the most acceptable salt of contained I of effective dose.

In other side, the method that the present invention relates to patient produces curative effect, wherein said curative effect is selected from suppressing multiple cancer Disease, suppression immune disease and/or diseases associated with inflammation, described method includes the drug regimen using effective dose to described patient Thing, the contained I of described pharmaceutical composition or its most acceptable salt, solvate, polymorph, makes a variation mutually Structure body or prodrug.In some embodiments, described curative effect is suppression kinds cancer.In other embodiments, described curative effect For suppression immune disease.In other embodiments, described curative effect is suppression diseases associated with inflammation.

In other side, the present invention relates to contained I or its most acceptable salt, solvate, many Crystal formation thing, tautomer or prodrug are used for suppressing the medicine of kinds cancer, immune disease and/or diseases associated with inflammation in preparation Application in compositions.

In some embodiments, using of the compositions of contained I is combined with other treatment.At other In embodiment, other treatment described is radiotherapy, chemotherapy or combination.In other embodiments, by contained I chemical combination The compositions of thing is used with at least one therapeutic combination.In some embodiments, by oral, through duodenum, the intestines and stomach (include intravenous, subcutaneous, intramuscular, Ink vessel transfusing or pass through infusion) outward, local application or per rectum applying said compositions.At it In its embodiment, in other embodiments, the amount of compound of formula I is in the range of about 0.001mg/kg body weight/day-about 1000mg/kg body weight/day.In other embodiments, the amount of compound of formula I is in the range of about 0.5mg/kg body weight/day-about 50mg/kg body weight/day.In other embodiments, the amount of compound of formula I is about 0.001g/ days-about 7g/ days.Implement at other In mode, the amount of compound of formula I is about 0.01g/ days-about 7g/ days.In other embodiments, the amount of compound of formula I is about 0.02g/ days-about 5g/ days.In other embodiments, the amount of compound of formula I is about 0.05g/ days-about 2.5g/ days.At other In embodiment, the amount of compound of formula I is about 0.1g/ days-about 1g/ days.In other embodiments, less than above-mentioned range lower limit Dosage level may be enough.In other embodiments, it may be necessary to higher than the dosage water of above-mentioned range limit Flat.In other embodiments, the compound of Formulas I is administered in a single dose, once a day.In other embodiments, the change of Formulas I Compound is with multiple dose administration, and every day is more than once.In other embodiments, the compound of daily twice Formulas I.At other In embodiment, the daily compound of cubic expression tertiary I.In other embodiments, the compound of daily quarternary quantic I. In other embodiments, the compound of daily four above formula I.In some embodiments, suffers from the individuality of cancer For mammal.In other embodiments, described individuality is people.In some embodiments, use is the bag of effective dose Compositions containing the most acceptable salt of compound of formula I.

In other side, the present invention relates to compound of formula I or its most acceptable salt, solvate, polymorphic The preparation method of thing, tautomer or prodrug.

Detailed Description Of The Invention

Claims of the present invention set forth the new feature of the present invention especially.Detailed Description Of The Invention below set forth profit By the illustrative embodiments of the principle of the invention.By being better understood inventive feature and excellent with reference to following summary of the invention Point.

While characterized as the preferred embodiment of the present invention, but these embodiments are only used as example and provide.Should Understand that the variant of invention as described herein embodiment can also be used for implementing the present invention.Those of ordinary skill in the art should manage Solve, may occur in which that multiple variant, variations and alternatives are without deviating from the scope of the present invention.It should be understood that the protection model of various aspects of the present invention Enclose and determined by claims, and the method and structure of method and structure in these right and its equivalence is equal Within the scope of the claims contains.

Chapter title used herein is only used for the purpose of organizational, and is not necessarily to be construed as the limit to described theme System.The all documents quoted in the application or literature department divide and include but not limited to patent, patent application, article, books, manipulator Volume and paper, be integrally incorporated herein the most by reference.

Some technical terms of chemistry

Unless otherwise defined, the connotation that the most all scientific and technical terminologies have and claim theme art technology The connotation that personnel are generally understood that is identical.Except as otherwise noted, all patents of quoting in full herein, patent application, open material It is integrally incorporated by reference herein.If herein term there to be multiple definition, it is as the criterion with the definition of this chapter.Quoting URL Or when other this class identifier or address, it should be understood that this class identifier can carry out changing and can entering with the specifying information on the Internet Row exchange, it is possible to obtain information of equal value by Internal retrieval or other reference material channel being suitable for.The reference obtained Data proves availability and the public propagation of this type of information.

Should be understood that above-mentioned summary and being specified as hereafter are exemplary and be only used for explaining, and present subject matter is not appointed What limits.In this application, unless otherwise expressly specified, plural number is also included when otherwise using odd number.It has to be noticed that unless in literary composition Separately having and clearly illustrate, singulative the most used includes the plural shape of referents Formula.It shall yet further be noted that unless otherwise stated, "or" used, " or " represent "and/or".Additionally, term used " include " with And other form, such as " comprise ", " containing " and " containing " non-limiting.

Can be at list of references (" the ADVANCED ORGANIC CHEMISTRY 4 that includes Carey and Sundberg^TH ED. " Vols.A (2000) and B (2001), Plenum Press, New York) in find the definition to standard chemistry terms. Unless otherwise stated, the conventional method in the range of employing art technology, as mass spectrum, NMR, IR and UV/Vis spectrographic method and Pharmacological method.Unless proposed to be specifically defined, otherwise herein at analytical chemistry, Synthetic Organic Chemistry and medicine and pharmaceutical chemistry Relevant description in use term be known in the art.Can prepare at chemosynthesis, chemical analysis, medicine, preparation and passing Send, and to the treatment of patient uses standard technique.Such as, the available manufacturer operation instruction to test kit, or according to The explanation of mode well known in the art or the present invention is implemented reaction and is purified.Generally can according to this specification is quoted and Discuss multiple summary and more specific document in description, according to conventional method well known in the art implement above-mentioned technology and Method.In this manual, can by those skilled in the art select group and substituent group thereof with provide stable structure division and Compound.

When the conventional chemical formulas by writing from left to right describes substituent group, this substituent group includes from right to left too The substituent group being equal in chemistry obtained when writing structural formula.For example, CH₂O is equal to OCH₂。

Unless otherwise stated, general chemical terms used, such as but not limited to, " alkyl ", " amine ", " aryl " etc. It is same as its optionally substituted form.Such as, used herein to " alkyl " optionally substituted alkyl is included.

Compound described herein can have one or more stereogenic centres, and each stereogenic centers can be with R or S structure Presented in type or a combination thereof.Similarly, compound described herein can have one or more double bond, and each double bond can be with Presented in E (trans) or Z (cis) configuration or a combination thereof.One specific stereoisomer, constitutional isomer (regioisomer), diastereomer, enantiomer or epimer should be read to include all possible solid Isomer, constitutional isomer, diastereomer, enantiomer or epimer and mixture thereof.Therefore, described herein Compound include stereoisomer different on all configurations, constitutional isomer, diastereomer, enantiomer or difference to Isomeric forms and its corresponding mixture.For converting particular stereoisomer or making particular stereoisomer maintain the original state Technology, and the technology splitting stereoisomer mixture is well known in the art, and those skilled in the art can be just concrete The method that situation selects to be suitable for.See, e.g. Fumiss et al. (eds.), 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.

Terms used herein " part ", " chemical part ", " group ", " chemical group " refer to the specific fragment in molecule or Functional group.Chemical part is typically considered the chemical entities being embedded or attached on molecule.

Term " key " or " singly-bound " refer to, make two atoms or two parts be connected by key and obtain bigger structure division Chemical bond.

Term " optionally/arbitrarily " or " optionally/at random " refer to the event described subsequently or situation it may happen that or can Can not occur, this description includes described event or situation occurring and described event or situation not occurring.Such as, according to determining hereafter Justice, " optionally substituted alkyl " refers to " unsubstituted alkyl " (the substituted alkyl of unsubstituted base) or " substituted alkyl " (quilt The substituted alkyl of substituent group).Additionally, optionally substituted group can be unsubstituted (such as CH₂CH₃), completely replace (as CF₂CF₃), monosubstituted (CH₂CH₂F) the replacement degree between or completely replacing and be monosubstituted is (such as CH₂CHF₂、CF₂CH₃、CFHCHF₂ Deng).Those skilled in the art it is understood that for any group comprising one or more substituent group, will not be introduced into any The replacement that spatially can not exist and/or can not synthesize or substitute mode (such as, replace alkyl and include optionally substituted cycloalkanes Base, otherwise, cycloalkyl is defined to include optionally substituted alkyl, the most repeatedly).Therefore, described substituent group generally should be managed Solving and be about 1 for maximum molecular weight, 000 dalton, more generally, the largest of about 500 dalton are (except having clearly a need for macromole substituent group Situation outside, such as polypeptide, polysaccharide, Polyethylene Glycol, DNA and RNA etc.).

C used herein₁-C_nIncluding C₁-C₂、C₁-C₃、……C₁-C_n.For example, described " C₁-C₄" group refers to this portion There is in Fen 1-4 carbon atom, i.e. group and comprise 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms.Scope C₁-C₂And C₁-C₃Definition similar.Therefore, for example " C₁-C₄Alkyl " refer to there is being the alkyl of 1-4 carbon atom, i.e. Described alkyl is selected from methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group, sec-butyl and the tert-butyl group.Digital model herein Enclosing, such as " 1-10 " refers to that each integer in given range, such as " 1-10 carbon atom " refer 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 Individual carbon atom or 10 carbon atoms.

The term " hetero atom " being used alone or in combination herein or " miscellaneous " refer to the atom outside de-carbon and hydrogen.Hetero atom is only On the spot selected from oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and stannum, but it is not limited to these atoms.Two or more heteroatomic embodiment party are occurring In formula, said two or more hetero atom can be mutually the same, or some or all in said two or more hetero atom that These are different.

The term " alkyl " being used alone or in combination herein refers to optionally substituted straight chain or the one of optionally substituted side chain Valency saturated hydrocarbons, it has 1-about 6 carbon atoms of about 10 carbon atoms, more preferably 1-.Example include but not limited to methyl, ethyl, N-pro-pyl, isopropyl, 2-methyl-l-propyl group, 2-methyl-2-propyl, 2-methyl-1-butene base, 3-methyl-l-butyl, 2-methyl- 3-butyl, 2,2-dimethyl-1-propyl group, 2-methyl-1-pentene base, 3-methyl-1-pentene base, 4-methyl-l-amyl group, 2-methyl-2- Amyl group, 3-methyl-2-amyl group, 4-methyl-2-amyl group, 2,2-dimethyl-l-butyl, 3,3-dimethyl-1-butyl, 2-ethyl- 1-butyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, isopentyl, neopentyl, tertiary pentyl and hexyl, and longer Alkyl group, such as heptyl and octyl group etc..Group defined herein, when digital scope occurring such as " alkyl ", such as " C₁-C₆Alkane Base " 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 The alkyl that carbon atom is constituted, alkyl herein also comprises the situation of not specified digital scope.

The term " alkylidene " being used alone or in combination herein refers to the bilvalent radical derived by univalent alkyl defined above Group.Example includes but not limited to methylene (-CH₂), ethylidene (-CH₂CH₂), propylidene (-CH₂CH₂CH₂) and isopropylidene (- CH(CH₃)CH₂) etc..

The term " thiazolinyl " being used alone or in combination herein refers to optionally substituted straight chain or the one of optionally substituted side chain Valency alkyl, it has one or more C=C double bond and has 2-about 6 carbon atoms of about 10 carbon atoms, more preferably 2-.These Double bond in group can be cis or trans conformation, and should be understood to comprise the two isomer.Example include but not It is limited to vinyl (CH=CH₂), 1-acrylic (CH₂CH=CH₂), isopropenyl (C (CH₃)=CH₂), cyclobutenyl and 1,3-fourth two Thiazolinyl etc..When there is digital scope in thiazolinyl defined herein, such as " C₂-C₆Thiazolinyl " or " C_2-6Thiazolinyl " referring to can be former by 2 carbon The thiazolinyl that son, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms are constituted, thiazolinyl herein is also covered by not specified The situation of digital scope.

The term " alkenylene " being used alone or in combination herein refers to the bilvalent radical derivative by monovalence thiazolinyl defined above Group.Example includes but not limited to that ethenylidene (CH=CH) and propenylene isomers are (such as CH₂CH=CH and C (CH₃)=CH) Deng.

The term " alkynyl " being used alone or in combination herein refers to the monovalent hydrocarbon of optionally substituted straight or branched, its tool There is one or more C ≡ C tri-key and there are 2-about 6 carbon atoms of about 10 carbon atoms, more preferably 2-.Example includes but not limited to Acetenyl, 2-propynyl, 2-butyne base and 1,3-diacetylene base etc..When digital scope occurs in alkynyl defined herein, such as “C₂-C₆Alkynyl " or " C_2-6Alkynyl " referring to can be former by 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon The alkynyl group that son is constituted, alkynyl herein is also covered by the situation of not specified digital scope.

The term " miscellaneous alkyl ", " miscellaneous thiazolinyl " and " miscellaneous alkynyl " being used alone or in combination herein refers to optionally substituted alkane respectively Base, thiazolinyl and alkynyl structure, as described above, wherein one or more skeletal chain carbon atoms (the most also include Be connected hydrogen atom) be separately replaced by hetero atom (that is, other atom outside de-carbon, such as but not limited to oxygen, Nitrogen, sulfur, silicon, phosphorus, stannum or a combination thereof).

The term " haloalkyl " that is used alone or in combination herein, " haloalkenyl group ", " halo alkynyl " refer to optionally take respectively The alkyl in generation, thiazolinyl and alkynyl structure, as described above, it is former that wherein one or more hydrogen atoms are replaced by fluorine, chlorine, bromine, iodine Son or a combination thereof.In some embodiments, mutually the same halogen atom is used to replace two or more hydrogen atoms (such as two Methyl fluoride)；The most identical halogen atom is used to replace two or more hydrogen atom (examples in other embodiments 1-as chloro-in 1-fluoro-1-iodine ethyl).The non-limiting example of haloalkyl is methyl fluoride and bromoethyl.Haloalkenyl group non-limiting Property example is bromo vinyl.The non-limiting example of halo alkynyl is chloroethene alkynyl.

The term " ring ", " ring-type ", " ring " and " ring " being used alone or in combination herein refers to appoint as described herein Anticipating covalence closed structure, it includes alicyclic ring, heterocycle, aromatic ring, hetero-aromatic ring and multi-ring condenses ring system or multi-ring non-condensed ring system.Ring Can be optionally substituted.Ring can form fused rings pastern and divide.Term " first " refers to the number of the skeletal atom of makeup ring.Therefore, lift For example, hexamethylene, pyridine, pyrans and pyrimidine are hexatomic ring, and Pentamethylene., pyrroles, oxolane and thiophene are five-membered ring.

The term being used alone or in combination herein " condenses " and refers to that two or more rings have one or more key jointly Ring structure.

The term " cycloalkyl " being used alone or in combination herein refers to the saturated hydrocarbon ring of optionally substituted monovalence, and it comprises 3-about 15 ring carbons or about 10 ring carbons of 3-, it is possible to include other non-ring carbons of alternatively base (such as, Methylcyclopropyl groups).

The term " aromatic radical " being used alone or in combination herein refers to a ring or the loop section of multiple ring of plane, its tool Having the delocalized electronics π-conjugated systems containing 4n+2n electronics, wherein n is integer.Aromatic ring can be by more than 5,6,7,8,9 or 9 Atom is formed.Aromatic compounds can be optionally substituted, and can be the multi-ring of monocycle or fused rings.Term aromatic compound includes All containing carbocyclic ring (such as phenyl ring) with containing one or more heteroatomic rings (such as pyridine).

The term " aryl " being used alone or in combination herein refers to optionally substituted aryl radical, and it has 6-about 20 one-tenth Ring carbon atom or 6-10 ring carbons, and include fused rings and non-condensed aromatic ring.Fused-aryl comprises 2-4 aromatic ring fusion Ring, other free ring can be alicyclic ring, heterocycle, aromatic ring, aromatic heterocycle or its combination in any.Additionally, term aryl also includes Fused rings and non-condensed ring containing 6 to about 12 ring carbons, and containing the fused rings of 6 to about 10 ring carbons and non- Fused rings.The non-limiting example of monocyclic aryl includes phenyl；Fused rings aryl includes naphthyl, phenanthryl, anthryl, base；Non-thick The double aryl closed include xenyl.

The term " heteroaryl " being used alone or in combination herein refers to any substituted monovalence aryl, and it comprises about 5 to about 20 or 5 to 10 skeleton ring member nitrogen atoms, wherein one or more ring member nitrogen atoms are hetero atom, described hetero atom independently selected from Hetero atom in oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and stannum, but it is not limited to this；Its premise be the ring of described group do not comprise two adjacent O or S atom.In ring, occur that, in two or more heteroatomic embodiments, said two or more hetero atom can be each other Identical, or some or all in said two or more hetero atom are different from each other.Term heteroaryl includes optionally substituted There is at least one heteroatomic monovalence condenses or the heteroaryl of non-condensed.Additionally, term heteroaryl also includes containing 5 to about 12 The heteroaryl with non-condensed condensed of individual skeleton ring member nitrogen atoms, and the sum condensed containing 5 to about 10 skeleton ring member nitrogen atoms The heteroaryl of non-condensed, as phenyl ring condenses with furan nucleus.Can be combined with heteroaryl by carbon atom or hetero atom.Therefore, citing For, imidazoles can pass through its arbitrary carbon atom (imidazoles-2-base, imidazol-4 yl or imidazoles-5-base) or its nitrogen-atoms (imidazoles- 1-base or imidazo-3-yl) it is connected with parent molecule.Similarly, can by its any or whole carbon atoms and/or arbitrarily or all Hetero atom is further substituted with heteroaryl groups.The heteroaryl condensed can comprise the fused rings that 2-4 aromatic heterocycle condenses mutually, other Free ring can be alicyclic ring, heterocycle, aromatic ring, aromatic heterocycle or its combination in any.The non-limiting example of bicyclic heteroaryl includes Pyridine radicals；Fused ring heteroaryl includes benzimidazolyl (benzimidazolyl), quinolyl (quinolinyl), acridinyl (acridinyl), double heteroaryls of non-condensed include bipyridyl (bipyridinyl).Other example of heteroaryl include but It is not limited to: furyl (furanyl), thienyl (thienyl), oxazolyl (oxazolyl), acridinyl (acridinyl), fen Piperazine base (phenazinyl), benzimidazolyl (benzimidazolyl), benzofuranyl (benzofuranyl), benzothiazole Base (benzoxazolyl), benzothiazolyl (benzothiazolyl), diazosulfide base (benzothiadiazolyl), Benzothienyl (benzothiophenyl), benzodiazole base (benzoxadiazolyl), benzotriazole base (benzotriazolyl), imidazole radicals (imidazolyl), indyl (indolyl), isoxazolyl (isoxazolyl), isoquinoline Quinoline base (isoquinolinyl), indyl (indolizinyl), isothiazolyl (isothiazolyl), isoindolyl (isoindolyl), di azoly (oxadiazolyl), indazolyl (indazolyl), pyridine radicals (pyridyl), pyridazinyl (pyridazyl), pyrimidine radicals (pyrimidyl), pyrazinyl (pyrazinyl), pyrrole radicals (pyrrolyl), pyrazolyl (pyrazolyl), purine radicals (purinyl), phthalazinyl (phthalazinyl), pteridyl (pteridinyl), quinolyl (quinolinyl), quinazolyl (quinazolinyl), quinolyl (quinoxalinyl), triazolyl (triazolyl), Tetrazole radical (tetrazolyl), thiazolyl (thiazolyl), triazine radical (triazinyl) and thiadiazolyl group Etc., and oxide, such as pyridinyl-N-oxide (pyridyl-N-oxide) (thiadiazolyl).

The term " heterocyclic radical/heterocycle " being used alone or in combination herein refers to aliphatic heterocycle.The carbon of heterocycle indicated herein (such as C during atom number₃-C₆Heterocycle), described ring certainly exists at least one non-carbon (hetero atom).Such as " C₃-C₆ Heterocycle " name only relate to the number of carbon atom in ring, without regard to the sum of ring Atom.Name such as " 4-6 unit heterocycle " It is that (i.e. four, five or hexatomic ring, at least one of which atom is carbon atom to total atom number contained in finger ring, at least one atom For hetero atom, and remaining 2-4 atom is carbon atom or hetero atom).For having two or more heteroatomic heterocycles and Speech, said two or more hetero atom can be same to each other or different to each other.Heterocycle can be optionally substituted." heterocyclic radical/miscellaneous herein Ring " preferably comprise about 5 to about 20 or 5 to 10 or 5-8 or 5-6 skeleton ring member nitrogen atoms.

The limiting examples of " heterocyclic radical " includes azine (azinyl), azetidinyl (azetidinyl), oxygen Heterocycle butyl (oxetanyl), thietanyl (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-pyranose (2H-pyranyl), 4H-pyranose (4H-pyranyl), dioxacyclohexyl (dioxanyl), 1,3-dioxolanyl (1,3-dioxolanyl), pyrazolinyl (pyrazolinyl), two sulfur cyclohexyl (dithianyl), two sulfur cyclopenta (dithiolanyl), dihydro pyranyl (dihydropyranyl), dihydro-thiophene base (dihydrothienyl), dihydrofuran base (dihydrofuranyl), pyrazolidinyl (pyrazolidinyl), imidazolinyl (imidazolinyl), imidazoles piperidinyl (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- And quinolyl (quinolizinyl) etc. indolyl).This term also includes all annular form of saccharide, includes but not limited to Monosaccharide, disaccharide and oligosaccharide.

The term " carbocylic radical, carbocyclic ring " being used alone or in combination herein is alcyl, the most all by carbon covalently closed circle Structure, it can be saturated (i.e. cycloalkyl), part unsaturated (i.e. cycloalkenyl group).Can be by more than 3,4,5,6,7,8,9 or 9 Atom formed carbocyclic ring.Carbocyclic ring can be optionally substituted." carbocylic radical, carbocyclic ring " herein preferably comprise about 5 to about 20 or 5 to 10 or 5-8 or 5-6 skeleton ring member nitrogen atoms.Difference between term carbocyclic ring and heterocycle be the ring skeleton of heterocycle comprise to A few atom different from carbon.

The term " halogen ", " halo " or " halogenide " being used alone or in combination herein refers to fluorine, chlorine, bromine and iodine.

The term " alkoxyl " being used alone or in combination herein refers to alkylether radicals O-alkyl, and it includes O-aliphatic radical and O-carbon Ring group, wherein alkyl, aliphatic radical and carbon ring group can be optionally substituted, and term alkyl therein, aliphatic radical and carbocylic radical are such as Definition above.The non-limiting example of alkoxyl include methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, Isobutoxy, sec-butoxy and tert-butoxy etc..

The term " sulfenyl " being used alone or in combination herein refers to divalent group-S (-O).

The term " sulphonyl " being used alone or in combination herein refers to divalent group-S (-O)₂。

The term " sulfonamide " being used alone or in combination herein and " sulfonamido " refer to divalent group-S (-O)₂-NH- With-NH-S (=O)₂。

Except as otherwise noted, herein for replacing individually or term " substituted alkyl " that a combination thereof uses, " substituted Cycloalkyl ", " substituted thiazolinyl ", " substituted alkynyl ", " substituted alkoxyl ", " substituted aryl ", " substituted alkyl virtue Base ", " substituted heteroaryl ", substituent group in " substituted sulfonyl " and " substituted amino " independently be hydrogen, halogen, cyanogen Base, nitro, hydroxyl, C₁-C₆Alkyl, C₃-C₆Cycloalkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl and C₁-C₆Alkoxyl, monocycle or two cyclophanes One or more substituent groups in base and 5-7 unit heteroaryl.

Some drugs term

Terms used herein " FAK and/or Pyk2 inhibitor " refers to according to FAK and/or Pyk2l kinase assay described herein Measurement, to FAK and/or Pyk2 activity IC₅₀It is not greater than about 100 μMs or the compound of no more than about 50 μMs.“IC₅₀" refer to The activity of enzyme (such as FAK and/or Pyk2) is reduced to the inhibitor concentration of the half of maximum horizontal.Have now found that described hereinization The compound inhibitory action to FAK and/or Pyk2.According to the measurement of FAK and/or Pyk2l kinase assay described herein, the present invention's Compound preferably shows the IC to FAK and/or Pyk2 activity₅₀It is not greater than about 10 μMs, no more than about 5 μMs, more preferably not greater than about 1 μM, and most preferably no greater than about 200nM.

Terms used herein " selects ", " selectively ", " selectivity " refer to compared with other enzyme, the compound pair of the present invention The IC of FAK and/or Pyk2 enzyme₅₀Be worth lower (such as, the lowest by 2,5,10 or more times).

Relevant term " experimenter ", " patient " or " individual " used herein refers to suffer from disease, disease or the patient's condition etc. Individuality, including mammal and nonmammalian.The example of mammal includes but not limited to any member of Class Mammalia: People, inhuman primate (such as chimpanzee and other apes and monkey)；Domestic animal, such as cattle, horse, sheep, goat, pig；Family Support animal, such as rabbit, Canis familiaris L. and cat；Laboratory animal, including rodent, such as rat, mice and Cavia porcellus etc..Inhuman suckling The example of animal includes but not limited to birds and Fish etc..At a method provided herein and the embodiment of compositions In, described mammal is behaved.

Term used herein " is treated " synonym similar with other and is included alleviating, alleviating or improve disease or disease disease Shape, prevents other symptom, improves or prevents to cause the potential metabolism reason of symptom, suppression disease or disease, such as, stop disease Or the development of disease, alleviate disease or disease, make disease or disease take a turn for the better, alleviate the symptom caused by disease or disease, or Stop disease or the symptom of disease, additionally, this term comprises the purpose of prevention.This term also include obtain therapeutic effect and/or Preventive effect.Described therapeutic effect refers to cure or improve the potential disease treated.Additionally, to relevant to potential disease one Kind or the healing of multiple physiological signs or improvement are also therapeutic effect, although such as patient may nevertheless suffer from the shadow of potential disease Ring, but observe that patient profiles improves.For preventive effect, described group can be used to having the patient suffering from specified disease risk Compound, even if or not yet make medical diagnosis on disease, but use institute to the patient of one or more physiological signs that this disease occurs State compositions.

Term used herein " effective dose ", " therapeutically effective amount " or " pharmacy effective dose " refers to take metapedes with at certain At least one medicament or the amount of compound of one or more symptoms of disease or the disease treated is alleviated in degree.Its result Can be abatement and/or the alleviation of sign, symptom or the cause of disease, or other required change any of biosystem.Such as, it is used for controlling " effective dose " treated is to provide the compositions comprising compound disclosed herein needed for significant remission effect clinically Amount.The technical measurement that can use such as dose escalation trial is suitable for the effective dose in any individual case.

Terms used herein " is taken ", " using ", " administration " etc. refer to be delivered to carry out by compound or compositions The method in the required site of biological agent.These methods include but not limited to oral route, through intraduodenal routes, parenteral note Penetrate (including intravenous, subcutaneous, intraperitoneal, intramuscular, intra-arterial injection or infusion), topical and per rectum to be administered.This area Technical staff knows the application technique that can be used for Compounds and methods for described herein, such as at Goodman and Gilman, The Pharmacological Basis of Therapeutics,current ed.；Pergamon；and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., discuss in Easton, Pa Those.In a preferred embodiment, compound discussed herein and compositions are by Orally administered.

Refer to dock the one of subject experimenter herein for term " acceptable " used by preparation, compositions or composition As health condition there is no long-term adverse effect.

Terms used herein " pharmaceutically acceptable " refers to not affect the biological activity of the compounds of this invention or character Material (such as carrier or diluent), and relative nontoxic, i.e. this material can be applied to individuality and not cause bad biological respinse Or interact with any component comprised in bad mode and compositions.

Terms used herein " pharmaceutical composition " refers to that being optionally mixed with at least one pharmaceutically acceptable chemistry becomes Point bioactive compound, described pharmaceutically acceptable chemical composition include but not limited to carrier, stabilizer, diluent, Dispersant, suspending agent, thickening agent and/or excipient.

Terms used herein " carrier " refers to chemical compound or the reagent of relative nontoxic, and it contributes to introducing compound In cell or tissue.

Terms used herein " agonist " refers to strengthen the molecule of the activity of the activity of other molecule or acceptor site, such as Compound, medicine, zymoexciter or hormone regulating and controlling agent.

Terms used herein " antagonist " refers to eliminate or suppress active the dividing of the activity of other molecule or acceptor site Son, such as compound, medicine, enzyme inhibitor or hormone regulating and controlling agent.

Terms used herein " regulates and controls " to refer to directly or indirectly to interact with target thus changes the activity of target, citing For, it includes strengthening target activity, suppression target activity, limiting target activity or extend target activity.

Terms used herein " adjusting control agent " refers to the molecule directly or indirectly interacted with target.The described bag that interacts Include but be not limited to the interaction of agonist and antagonist.

Terms used herein " pharmaceutically acceptable salt " refers to remain the free acid of appointed compound and free alkali Biopotency, and on biology or other side, there is no the salt of ill effect.Compound as herein described can have acidity Or basic group, therefore with arbitrary multiple inorganic base or organic base and mineral acid and organic acid reaction, thus medicine can be formed Acceptable salt on.These salt can be prepared by the following method: in final separation and the purge process of the compounds of this invention Prepared by situ, or individually reacted with the organic acid being suitable for or mineral acid by the free alkali form of the compounds of this invention, and Separate the salt being consequently formed.The example of pharmaceutically acceptable salt includes by compound described herein and mineral acid or organic acid Or reaction between inorganic base or organic base and the salt prepared.These salt include acetate, acrylates, adipate, Sargassum Hydrochlorate, aspartate, benzoate, benzene sulfonate, disulfate, bisulfite, bromide, butyrate, butine-1,4- Diacid salt, Camphora hydrochlorate, camsilate, caprylate, chloro-benzoate, chloride, citrate, cyclopentane propionate, Caprate, gluconate, dihydric phosphate, dinitro-benzoate, lauryl sulfate, esilate, formates, prolong Rhizoma Corydalis hydrochlorate, gluceptate, glycerophosphate, glycollate, Hemisulphate, enanthate, hexin-1,6-diacid salt (hexyne-1,6-dioate), hydroxy benzoate, y-hydroxybutyric acid salt, hydrochlorate, hydrobromate, hydriodate, 2-hydroxyl second Sulfonate, iodide, isobutyrate, lactate, maleate, malonate, mesylate, mandelate, metaphosphate, first P-methoxybenzoic acid salt, ar-Toluic acid salt, dibasic alkaliine, 1-naphthalene sulfonic aicd salt, 2-naphthalene sulfonate, nicotinate, nitrate, double hydroxyl Naphthoate, fruit jelly hydrochlorate (pectinate), persulfate, 3-phenpropionate, phosphate, picrate, pivalate, propanoic acid Salt, pyrosulfate, pyrophosphate, acetylenecarboxylic acid, phthalate, phenylacetate, benzenebutanoic acid salt, propane sulfonic acid salt, salicylate, Succinate, sulfate, sulphite, suberate, sebacate, sulfonate, tartrate, rhodanate, to toluene sulphur Hydrochlorate, undecylate (undeconate) and xylenesulfonate.Other acid (such as oxalic acid), although itself being pharmaceutically not Acceptable, but can use in the preparation process of salt as intermedium, to obtain the compound and pharmaceutically of the present invention Acceptable acid-addition salts (sees Berge et al., the embodiment in J.Pharm.Sci.1977,66,1-19).Additionally, this The compound of the included free acid group described in literary composition can be with suitable alkali reaction (the most pharmaceutically acceptable metal cation Hydroxide, carbonate or bicarbonate), react with ammonia, or anti-with pharmaceutically acceptable organic primary amine, secondary amine or tertiary amine Should.Representational alkali metal salt or alkali salt include lithium salts, sodium salt, potassium salt, calcium salt, magnesium salt and aluminium salt etc..The explanation of alkali Property example includes sodium hydroxide, potassium hydroxide, hydroxide ethoxy trimethylamine, sodium carbonate and IV'(C_1-4Alkyl)₄Deng.For shape The representative organic amine becoming base addition salts includes ethamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine and piperazine etc..Ying Li Solving, compound described herein also includes the quaternary ammonium compound of its any Basic nitrogen-containing groups that may comprise.Can by quaternized instead Water solublity or oil-soluble or dispersible product should be obtained.See, e.g. the document of Berge et al. above.

Terms used herein " solvate " refers to the compounds of this invention and the solvent molecule formed by solvation Combination.In some cases, solvate refers to hydrate, i.e. solvent molecule is hydrone, the compounds of this invention and the group of water Close and form hydrate.

Terms used herein " polymorph " or " polymorph " refer to the chemical combination of the present invention existed with different form crystal lattices Thing.

Terms used herein " tautomer " refers to be migrated by such as hydrogen atom migration or proton and be prone to by the present invention The isomer that compound change obtains.

Term used herein " pharmaceutically acceptable derivates or prodrug " refers to any pharmacy of the compounds of this invention Upper acceptable salt, ester, the salt of ester or other derivant, it can provide the present invention to receptor after using directly or indirectly Compound or its metabolite with pharmaceutical active or residue.Particularly preferred derivant or prodrug are when being applied to patient Those compounds of the compounds of this invention bioavailability can be improved (for example, it is possible to make the compound being administered orally be easier to be inhaled Receive in blood), or promote what parent compound delivered to biologic-organ or action site (such as brain or lymphsystem) Those compounds.

The pharmaceutically acceptable prodrug of compound described herein includes but not limited to ester, carbonate, thiocarbonate, N- Acyl derivative, N-acyloxyallcyl derivant, the quaternary ammonium derivative of tertiary amine, the strange alkali of N-Manny (N-Mannich bases), Schiff base (Schiff base), amino acid conjugates, phosphate ester, slaine and sulphonic acid ester.Various prodrug forms are this areas Known to.See, e.g. Design of Prodrugs, 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 ofDrug 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, document above is incorporated by reference into this Literary composition.Prodrug described herein includes but not limited to the combination of material in following group and these materials: the prodrug that amine is derivative；Before hydroxyl Medicine includes but not limited to acyloxyalkyl ether, alkoxy carbonyl yloxy Arrcostab, Arrcostab, aryl ester and the ester containing disulfide bond.

The similar vocabulary such as term used herein " enhancing/improve " refer to increase the effect of desirable effect or extend required effect The persistent period of fruit.Therefore, represent strengthen therapeutic agent effect time, term " strengthens " refer to increase or extend other therapeutic agent pair The effect of systemic effect or the ability of persistent period.

Term used herein " amount of reinforced effects the amount of potentiation (can effectively) " refer to be enough to strengthen other treatment The amount of agent effect in required system.

Term used herein " drug regimen ", " using other treatment ", " using other therapeutic agent " etc. refer to by mixed Closing or combination more than one active component and the Drug therapy that obtains, it includes the fixing of active component and not fixed Combination.Art Language " fixed Combination " refers to use at least one to patient with the form of single entity or single dosage form simultaneously as herein described Compound and at least one collaborative medicament.Term " not fixed Combination " refers to use to patient with the form of corpus separatum simultaneously, Share or sequentially to use at least one compound as herein described and at least one collaborative preparation variable interval time, wherein This type of is applied in the two or more compound providing effect level in the patient.These are also applied in HAART, example As used three kinds or more kind active component.

Terms used herein " co-administered ", " with ... combined administration " and its synonym etc. are directed to same patient and use Selected therapeutic agent, and be intended to use medicine by identical or different route of administration or identical or different administration number of times The therapeutic strategy of agent.In some embodiments, compound as herein described is used with other drug combination.These terms are contained Lid uses two or more medicament to animal so that there is described medicament and/or its metabolite in animal body simultaneously.These terms Including using different compositionss simultaneously, different time is used different compositionss and/or uses containing different activities composition A kind of compositions.Therefore, in some embodiments, the compound of the present invention and other medicament are blended in a kind of compositions Use.

Terms used herein " metabolite " refers to the derivant of this compound formed when compound metabolism.

Terms used herein " active metabolite " refers to this compound active formed when compound metabolism Derivant.

Terms used herein " metabolism " refers to that all processes of organism conversion predetermined substance (include but not limited to hydrolysis Reaction and enzymic catalytic reaction).Therefore, enzyme can make compound produce special structure change.Such as, Cytochrome P450 catalysis is many Plant redox reaction, and the glucal acid molecule of UDPglucuronyl transferase catalytic activation is to fragrance The transfer of alcohol, fatty alcohol, carboxylic acid, amine and free thiohydroxy group.More information about metabolism can be found in 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 be prepared by following method Compound as herein described.Following methods and embodiment illustrate that these methods.These flow processs and embodiment not Ying Yiren Where formula is interpreted limitation of the present invention.It is used as Standard synthetic techniques well known by persons skilled in the art synthesis herein Described compound, or it is applied in combination means known in the art and methods described herein.

Formula (I) compound, wherein R¹And R²In one be hydrogen, R⁵And R⁶In one be hydrogen, and R " be hydrogen, as with Shown in lower formula, it is used for illustrating the preparation of formula (I) compound as an example.

The synthesis of universal synthesis method I:2,4-bis-chloro-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine

Universal synthesis method II:6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2, the General synthetic procedure of 4-diamidogen

Step A: be dividedly in some parts metallic sodium (1.5 equivalent) in dehydrated alcohol.After the complete loss for reaction of metallic sodium, to institute Obtain in alcohol sodium solution and be separately added into 1,1,2-tricarboxylic ester (intermediate i, 1.0 equivalents) and carbamide (1.0 equivalent).Reactant liquor returns Being cooled to room temperature after flowing through night, rotary evaporation falls ethanol.Residue is soluble in water, is acid with dilute hydrochloric acid (2N) regulation pH value. Rotary evaporation obtains intermediate ii by silica gel flash chromatography residue after removing solvent.

Step B: be slowly added dropwise N, N '-diisopropylethylamine in the phosphorus oxychloride solution of intermediate ii (1.0 equivalent) (2.0 equivalent).After being added dropwise to complete, reactant liquor is heated to 100 degree and continues reaction 1-12 hour.It is evaporated off under reduced pressure major part trichlorine oxygen Phosphorus, aqueous phase sodium bicarbonate regulation pH value is alkalescence, is extracted with ethyl acetate, merges organic facies.Organic facies saturated aqueous common salt It is dried with anhydrous sodium sulfate after washing.Rotary evaporation obtains intermediate by silica gel flash chromatography residue after removing solvent iii。

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 dropping, reactant liquor is slowly raised to room temperature and continues reaction 2-12 hour.Reaction dilute hydrochloric acid (1N) after cancellation, aqueous phase is extracted with ethyl acetate, and merges organic facies.Anhydrous sodium sulfate is used after the washing of organic facies saturated aqueous common salt It is dried.Rotary evaporation removes after solvent to obtain crude product iv, the most purified is directly used in the next step.

Step D: add mesyl chloride (2.0 equivalent), triethylamine in the dichloromethane solution of intermediate iv (1.0 equivalent) (2.0 equivalent) and the 4-dimethylamino pyridine of catalytic amount.After reactant liquor is stirred at room temperature 1-12 hour, after rotary evaporation removes solvent Intermediate v is obtained by silica gel flash chromatography residue.

Step E: add 4-methoxybenzylamine (1.5 in the solution of the N-Methyl pyrrolidone of intermediate v (1.0 equivalent) Equivalent) and triethylamine (10.0 equivalent).Reactant liquor is heated to 130 degree and reacts 1-3 hour.After being cooled to room temperature, reactant liquor is fallen Enter in water.It is extracted with ethyl acetate aqueous phase, merges organic facies.Organic facies is done with anhydrous sodium sulfate after washing with saturated aqueous common salt Dry.Rotary evaporation obtains intermediate vi (intermediate A 1-A3) by silica gel flash chromatography residue after removing solvent.

Intermediate A 1

2,4-bis-chloro-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine

Step A:2-(2,4,6-trihydroxy-pyrimidine-5-base) ethyl acetate

According to universal synthesis method I, with 1,1,2-triacetic acid ethoxycarbonyl ethane (10 grams, 41mmol) and carbamide (2.44 grams, 41mmol) be raw material prepare 2-(2,4,6-trihydroxy-pyrimidine-5-base) ethyl acetate (light yellow solid, 4.6 grams, productivity 35.0%).

Step B:2-(2,4,6-trichloropyrimidine-5-base) ethyl acetate

According to universal synthesis method I, with 2-(2,4,6-trihydroxy-pyrimidine-5-base) ethyl acetate (2.5 grams, 12mmol), Phosphorus oxychloride (20 milliliters) and DIPEA (4 milliliters) are that raw material prepares 2-(2,4,6-trichloropyrimidine-5-base) second Acetoacetic ester (light yellow oil, 860 milligrams, productivity 27%).¹H NMR (400MHz, CDCl₃) δ ppm 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-base) ethanol

According to universal synthesis method I, with 2-(2,4,6-trichloropyrimidine-5-base) ethyl acetate (860 milligrams, 3.2mmol) With diisobutyl aluminium hydride (hexane solution of 1.0M, 10 milliliters, 10mmol) be raw material prepare 2-(2,4,6-trichloropyrimidines- 5-yl) ethanol (colorless oil, 720 milligrams, productivity 99%).

Step D:2-(2,4,6-trichloropyrimidine-5-base) ethyl methane sulfonate

According to universal synthesis method I, with 2-(2,4,6-trichloropyrimidine-5-base) ethanol (720 milligrams, 3.2mmol), methyl Sulfonic acid chloride (814 milligrams, 7.1mmol) and triethylamine (1 milliliter) are that raw material prepares 2-(2,4,6-trichloropyrimidine-5-base) methanesulfonic acid Ethyl ester (light yellow oil, 66 milligrams, productivity 68%).¹H NMR (400MHz, CDCl₃) δ ppm 4.39-4.44 (m, 2H), 3.29-3.36 (m, 2H), 3.08 (s, 3H).

Step E/ intermediate A 1:

2,4-bis-chloro-7-(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-base) ethyl methane sulfonate (480 milligrams, 1.57mmol) and 4-methoxybenzylamine (325 milligrams, 2.37mmol) is that raw material prepares 2, the chloro-7-of 4-bis-(4-methoxy-benzyl)- 6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidines (yellow solid, 660 milligrams, productivity 68%).¹H NMR (400MHz, CDCl₃)δ Ppm 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

Step A:(±)-1,1,2-triacetic acid ethoxycarbonyl propane

Metallic sodium (9 grams, 0.39mol) it is dividedly in some parts in 500 milliliters of dehydrated alcohol, after metallic sodium reaction completely, 0 degree Under, in gained alcohol sodium solution, drip diethyl malonate (50 grams, 0.31mol), drip complete and reactant liquor continuation 0 degree Lower stirring reaction 30 minutes after, to its dropping (±)-2 bromopropionic acid ethyl ester (56.5 grams, 0.31mol).After reactant liquor is raised to room temperature It is heated to reflux 12 hours.After reactant liquor is cooled to room temperature, rotary evaporation falls solvent, and residue is poured in trash ice.Extract by ethyl acetate Water intaking three times mutually, merges organic facies.It is dried with anhydrous sodium sulfate after the washing of organic facies saturated aqueous common salt.Rotary evaporation removes molten After agent crude product (±)-1,1,2-triacetic acid ethoxycarbonyl propane (67.8 grams, productivity 83.4%), the most purified be directly used in down Step reaction.

Step B:(±)-2-(2,4,6-trihydroxy-pyrimidine-5-base) ethyl propionate

According to universal synthesis method I, with (±)-1,1,2-triacetic acid ethoxycarbonyl propane (14.2 grams, 55mmol), metallic sodium (1.9 grams, 83mmol) and carbamide (3.3 grams, 55mmol) be raw material prepare (±)-2-(2,4,6-trihydroxy-pyrimidine-5-base) third Acetoacetic ester (reddish yellow oil, 6 grams, productivity 48%), the most purified is directly used in the next step.

Step C:(±)-2-(2,4,6-trichloropyrimidine-5-base) ethyl propionate

According to universal synthesis method I, with (±)-2-(2,4,6-trihydroxy-pyrimidine-5-base) ethyl propionate (6 grams, 12mmol), phosphorus oxychloride (30 milliliters) and N, N '-diisopropylethylamine (7.5 milliliters) be raw material prepare (±)-2-(2,4,6- Trichloropyrimidine-5-base) ethyl propionate (yellow oily liquid, 2.3 grams, productivity 31%).¹H NMR (400MHz, CDCl₃)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-base) propanol

According to universal synthesis method I, with (±)-2-(2,4,6-trichloropyrimidine-5-base) ethyl propionate (2.3 grams, 8mmol) With diisobutyl aluminium hydride (hexane solution of 1.0M, 10 milliliters, 10mmol) be raw material prepare (±)-(2,4,6-trichlorines are phonetic Pyridine-5-base) propanol (light yellow oil, 260 milligrams, productivity 13%).¹H NMR (400MHz, CDCl₃)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-base) methanesulfonic acid propyl ester

According to universal synthesis method I, with 2-(2,4,6-trichloropyrimidine-5-base) propanol (260 milligrams, 1.1mmol), methyl Sulfonic acid chloride (247 milligrams, 2.1mmol) and triethylamine (0.2 milliliter) are that raw material prepares 2-(2,4,6-trichloropyrimidine-5-base) first sulphur Propyl propionate (light yellow oil, 300 milligrams, productivity 87%).¹H NMR (400MHz, CDCl₃) δ ppm 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 2-(2,4,6-trichloropyrimidine-5-base) methanesulfonic acid propyl ester (300 milligrams, 0.94mmol), 4-methoxybenzylamine (192 milligrams, 1.4mmol) and triethylamine (2 milliliters) be raw material prepare (±)-2,4-bis- Chloro-7-(4-methoxy-benzyl)-5-methyl-6, (yellow solid, produces 7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine by 190 milligrams Rate 63%).¹H NMR (400MHz, CDCl₃) δ ppm 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) the chloro-7-of-2,4-bis-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine

Step A:(S)-2-(sulfonyloxy methyl epoxide) ethyl propionate

At 10-15 DEG C, to Pfansteihl ethyl ester (124 grams, 1.05mol) and the tetrahydrochysene furan of triethylamine (126 grams, 1.25mol) Muttering and drip methylsufonyl chloride (124 grams, 1.08mol) in solution, dropping in about 2 hours is complete.After reactant liquor is raised to room temperature, mistake Filter, solid oxolane washs.Filtrate is dried after washing, is concentrated to give (S)-2-(sulfonyloxy methyl epoxide) ethyl propionate (199 Gram, productivity 96.7%).

Step B:(S)-1,1-diyl diethyl propane-1,1,2-tricarboxylic ester

Toward the N of (S)-ethyl-2-(methyl sulphonyl) propionic ester (28.4 grams, 0.1mol), N '-dimethyl Methanamide (400 Milliliter) solution adds malonic acid dibenzyl ester (23.5 grams, 0.12mol) and cesium fluoride (15.2 grams, 0.1mol), chemical combination will be reacted Thing stirs 2 days under 50 degree, after being cooled to room temperature, is poured into water by reactant liquor, is extracted with ethyl acetate.Merge organic facies, use Saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, and filters, is spin-dried for, silicagel column isolated product (S)-1, the double benzyl formate of 1- Base-2-methvl-propionic acid ethvl ester (23 grams, productivity 60%).

Step C:(S)-2-(1-ethyoxyl-1 oxo acrylate-2 base) malonic acid

Toward (S)-1, methanol solution (500 millis of double benzyl formate base-2-methvl-propionic acid ethvl ester (23 grams, 60mmol) of 1- Rise) middle addition palladium carbon (10%, 2 grams), reactant mixture stirs 12 hours under hydrogen, and Filtration of catalyst is spin-dried for filtrate Obtain thick product (S)-2-(1-ethyoxyl-1 oxo acrylate-2 base) malonic acid (10 grams, productivity 83%).

Step D:(S)-2-(2,4,6-trioxy-hexahydropyrimidine-5-base) ethyl propionate

By (S)-2-(1-ethyoxyl-1 oxo acrylate-2 base) malonic acid (5 grams, 25mmol) and carbamide (1.8 grams, 29.4mmol) under the inner suspension of acetic anhydride (15 milliliters) is at microwave, it is heated to 60 degree to stir 30 minutes, after being cooled to room temperature, React with saturated sodium bicarbonate aqueous solution cancellation, be extracted with ethyl acetate.Merge organic facies, wash with saturated aqueous common salt, anhydrous Sodium sulfate is dried, and filters, is spin-dried for, silicagel column isolated product (S)-2-(2,4,6-trioxy-hexahydropyrimidine-5-base) propanoic acid Ethyl ester (2.85 grams, productivity 50%).

Step E:(S)-2-(2,4,6-trichloropyrimidine-5-base) ethyl propionate

According to universal synthesis method I, with (S)-2-(2,4,6-trioxy-hexahydropyrimidine-5-base) ethyl propionate (5.6 grams, 25mmol), phosphorus oxychloride (20 milliliters), N, N '-diisopropylethylamine (5 milliliters) carries out chlorination, separated after purification To product (S)-2-(2,4,6-trichloropyrimidine-5-base) ethyl propionate (yellow oil, 2.8 grams, productivity 40%).¹H NMR (400MHz, CDCl₃) δ ppm 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-base)-1-propanol

According to universal synthesis method I, with (S)-2-(2,4,6-trichloropyrimidine-5-base) ethyl propionate (1.0 grams, 3.55mmol) and diisobutyl aluminium hydride (hexane solution of 1.0M, 10.6 milliliters, 10.6mmol) carries out reduction reaction, warp Obtain after isolated and purified product (S)-2-(2,4,6-trichloropyrimidine-5-base)-1-propanol (pale yellowish oil liquid, 200 milligrams, Productivity 25%).¹H NMR (400MHz, CDCl₃) δ ppm 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-base) propyl Methanesulfonate

According to universal synthesis method I, with (S)-2-(2,4,6-trichloropyrimidine-5-base)-1-propanol (200 milligrams, 0.83mmol), mesyl chloride (191 milligrams, 1.66mmol) and triethylamine (166 milligrams, 1.66mmol) carry out esterification, warp Isolated and purified obtain product (S)-2-(2,4,6-trichloropyrimidine-5-base) propyl Methanesulfonate (pale yellowish oil liquid, 185 milli Gram, productivity 70%).

Step H/ intermediate A 3:(S)-2, the chloro-7-of 4-bis-(4-methoxyphenyl)-5-methyl-6,7-dihydro-5H-pyrroles And [2,3-d] pyrimidine

According to universal synthesis method I, with (S)-2-(2,4,6-trichloropyrimidine-5-base) propyl Methanesulfonate (185 milligrams, 0.578mmol), 4-Methoxybenzylamine (120 milligrams, 0.867mmol) and triethylamine (117 milligrams, 1.156mmol) are cyclized Reaction, separated purification obtains product (S)-2, the chloro-7-of 4-bis-(4-methoxyphenyl)-5-methyl-6,7-dihydro-5H-pyrroles And [2,3-d] pyrimidine (yellow oily liquid, 120 milligrams, productivity 64%).¹H NMR (400MHz, CDCl₃)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

2,4-bis-chloro-7-(4-methoxyphenyl)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine

Intermediate A 4 synthesizes as follows:

Step A:2-(2,4-bis-chloro-6-(4-methoxyphenyl amido) pyrimidine-5-base) ethyl acetate

Toward 2-(2,4,6-trichloropyrimidine-5-base) ethyl acetate (200 milligrams, 0.74mmol) at N, N '-dimethyl formyl The solution of amine (5 milliliters) adds 4-Methoxybenzylamine (112 milligrams, 0.82mmol) and N, N '-diisopropylethylamine (115 millis Gram, 0.89mmol).Reactant mixture is heated to 60 degree, after stirring 1 hour, goes out with shrend, be extracted with ethyl acetate.Merge Organic facies, respectively with dilute hydrochloric acid (1N), water and saturated aqueous common salt washing, anhydrous sodium sulfate is dried, and filters, is spin-dried for, and silicagel column divides From obtaining product 2-(2,4-bis-chloro-6-(4-methoxyphenyl amido) pyrimidine-5-base) ethyl acetate.¹H NMR (400MHz, CDCl₃) δ ppm 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-methoxyphenyl)-5,5-dimethyl-5H-pyrrolo-[2,3-d] pyrimidine-6 (7H)-one

By 2-(2,4-bis-chloro-6-(4-methoxyphenyl amido) pyrimidine-5-base) ethyl acetate (370 milligrams, 1.0mol), Iodomethane (284 milligrams, 2.0mmol), the N of potassium carbonate (690 milligrams, 5.0mmol), N '-dimethyl Methanamide (10 milliliters) is molten Liquid is added in tube sealing, is filled with nitrogen, is heated to 80 degree, is cooled to room temperature after 1 hour, is poured into water (100 milliliters), uses acetic acid second Ester extracts.Merging organic facies, wash with saturated aqueous common salt, anhydrous sodium sulfate is dried, and filters, is spin-dried for, and silicagel column isolated is produced Product 2, the chloro-7-of 4-bis-(4-methoxyphenyl)-5,5-dimethyl-5H-pyrrolo-[2,3-d] pyrimidine-6 (7H)-one (270 milligrams, Productivity 77%).¹H NMR (400MHz, CDCl₃) δ ppm 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-methoxyphenyl)-5,5-dimethyl-6,7-dihydro-5H-pyrroles And [2,3-d] pyrimidine

Under nitrogen protection, toward 2, the chloro-7-of 4-bis-(4-methoxyphenyl)-5,5-dimethyl-5H-pyrrolo-[2,3-d] is phonetic The solution of the oxolane (10 milliliters) of pyridine-6 (7H)-one (270 milligrams, 0.77mol) is added dropwise over borine (the tetrahydrochysene furan of 1M Mutter solution, 3.85 milliliters, 3.85mmol), add post-heating and reflux overnight, after being cooled to room temperature, be added dropwise over methanol (2 milliliters) Carry out cancellation.Major part solvent is removed in rotation, and residue over silica gel post separates, and obtains product 2,4-bis-chloro-7-(4-methoxybenzene Base)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine (156 milligrams, productivity 60%).¹H NMR (400MHz, CDCl₃) δ ppm 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) the chloro-7-of-2,4-two (4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine

Intermediate A 5 synthesizes as follows:

Step A:(R)-2-acetyloxypropanoic acid

At 0 DEG C, in the acetum (400 milliliters) of (S)-2-alanine (60 grams, 0.67 mole), it is dividedly in some parts Asia Sodium nitrate (93 grams, 1.34 moles).After reactant liquor is raised to room temperature, reactant mixture is stirred at room temperature 12 hours.Will residue Acetic acid is spin-dried for, and adds water, and is extracted with ethyl acetate.Merging organic facies, anhydrous sodium sulfate is dried, and filters, is spin-dried for, and silicagel column separates To product (R)-2-acetyloxypropanoic acid (30 grams, productivity 35%).¹H NMR(400MHz,CDCl₃)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

At-40 DEG C, slow in the ethanol solution (500 milliliters) of (R)-2-acetyloxypropanoic acid (30 grams, 0.23 mole) Slowly thionyl chloride (54 grams, 0.45 mole) is dripped.After reactant liquor is raised to room temperature, reactant mixture be stirred at room temperature 24 little Time.Solvent in mixture is spin-dried for, adds water, be extracted with ethyl acetate.Merging organic facies, anhydrous sodium sulfate is dried, and filters, rotation Dry, silicagel column isolated product (R)-2 hydroxy propanoic acid ethyl ester (15 grams, productivity 58%).¹H NMR(400MHz,CDCl₃)δ Ppm, 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 epoxide) ethyl propionate

At 10-15 DEG C, to (R)-2 hydroxy propanoic acid ethyl ester (15 grams, 0.13 mole) and triethylamine, (15.4 grams, 0.15 rubs You) tetrahydrofuran solution (300 milliliters) in dropping methylsufonyl chloride (15 grams, 0.13 mole), about 30 minutes dropping complete. After reactant liquor is raised to room temperature, filtering, solid oxolane washs.Filtrate is dried after washing, is concentrated to give (R)-2-(methyl Sulfonyloxy) ethyl propionate (15 grams, productivity 60%).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) the double benzyl formate-2-methvl-propionic acid ethvl ester of-1,1-

DMF (300 toward (R)-2-(sulfonyloxy methyl epoxide) ethyl propionate (15 grams, 0.076 mole) Milliliter) solution adds malonic acid dibenzyl ester (21.5 grams, 0.076 mole) and cesium fluoride (11.5 grams, 0.076 mole).Will be anti- Answer compound to stir two days under 50 degree, after being cooled to room temperature, reactant liquor is poured into water, is extracted with ethyl acetate.It is associated with Machine phase, washs with saturated aqueous common salt, and anhydrous sodium sulfate is dried, and filters, is spin-dried for, silicagel column isolated product (R)-1, the double first of 1- Acid benzyl ester-2-methvl-propionic acid ethvl ester (11 grams, productivity 40%).

Step E:(R)-2-(1-ethyoxyl-1 oxo acrylate-2-yl) malonic acid

Toward (R)-1, the methanol (200 milliliters) of the double benzyl formate-2-methvl-propionic acid ethvl ester (11 grams, 0.029 mole) of 1-is molten Adding palladium carbon (2 grams) in liquid, reactant liquor stirs 12 hours under hydrogen, and Filtration of catalyst is spin-dried for filtrate and obtains thick product (R)-2-(1-ethyoxyl-1 oxo acrylate-2-yl) malonic acid (3.5 grams, productivity 60%).

Step F:(R)-2-(2,4,6-trioxy-hexahydropyrimidine-5-base) ethyl propionate

By (R)-2-(1-ethyoxyl-1 oxo acrylate-2-yl) malonic acid (3.5 grams, 0.017 mole) and carbamide (1.03 grams, 0.017 mole) under the inner suspension of acetic anhydride (20 milliliters) is at microwave, it is heated to 60 degree stirs 30 minutes, it is cooled to room temperature, Use saturated sodium bicarbonate aqueous solution cancellation, be extracted with ethyl acetate.Merge organic facies, wash with saturated aqueous common salt, anhydrous slufuric acid Sodium is dried, and filters, is spin-dried for, silicagel column isolated product (R)-2-(2,4,6-trioxy-hexahydropyrimidine-5-base) ethyl propionate (2.0 grams, productivity 52%)

Step G:(R)-2-(2,4,6-trichloropyrimidine-5-base) ethyl propionate

According to universal synthesis method I, with (R)-2-(2,4,6-trioxy-hexahydropyrimidine-5-base) ethyl propionate (2.0 grams, 8.87 mM), phosphorus oxychloride (50 milliliters), N, N ,-diisopropylethylamine (5 milliliters) carries out chlorination, separated purification Obtain product (R)-2-(2,4,6-trichloropyrimidine-5-base) ethyl propionate (1.0 grams, 40%).¹H NMR(400MHz,CDCl₃)δ Ppm 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-base)-1-propanol

According to universal synthesis method I, with (R)-2-(2,4,6-trichloropyrimidine-5-base) ethyl propionate, (1.0 grams, 3.55 in the least Mole) and diisobutyl aluminium hydride (hexane solution of 1.0M, 10.6 milliliters, 10.6 mMs) carry out reduction reaction, through dividing Product (R)-2-(2,4,6-trichloropyrimidine-5-base)-1-propanol (70 milligrams, 10%) is obtained from purification.¹H NMR(400MHz, CDCl₃) δ ppm 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-base) methanesulfonic acid propyl ester

According to universal synthesis method I, with (R)-2-(2,4,6-trichloropyrimidine-5-base)-1-propanol, (70 milligrams, 0.58 in the least Mole), methylsufonyl chloride (67 milligrams, 0.58 mM) and triethylamine (60 milligrams, 1.66 mMs) be raw material prepare (R)- 2-(2,4,6-trichloropyrimidine-5-base) methanesulfonic acid propyl ester (60 milligrams, 65%).¹H NMR(400MHz,CDCl₃)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) the chloro-7-of-2,4-two (4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrroles And [2,3-d] pyrimidine

According to universal synthesis method I, with (R)-2-(2,4,6-trichloropyrimidine-5-base) methanesulfonic acid propyl ester (60 milligrams, 0.188 mM), 4-methoxybenzylamine (39 milligrams, 0.28 mM) and triethylamine (38 milligrams, 0.375 mM) they are former Material prepares (R)-2,4-two chloro-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine (45 millis Gram, 74%).¹H NMR(400MHz,CDCl₃) δ ppm7.16 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 '-two chloro-7 '-(4-methoxyphenyls)-6 ', 7 '-dihydro spiral shell [cyclopropane-1,5 '-pyrroles [2,3-d] is phonetic Pyridine]

Step A:1,1,2-ethane tricarboxylic acids triethyl

Metallic sodium (23.0 grams, 1 mole) it is dividedly in some parts in dehydrated alcohol (1000 milliliters).The complete loss for reaction of metallic sodium After, reactant liquor ice bath cools to 0 DEG C, dropping diethyl malonate (160.2 grams, 1 mole), rises after continuing stirring 0.5 hour To room temperature, adding ethyl chloroacetate (122.6 grams, 1 mole) and continue to stir 1 hour, temperature rising reflux dropped to room temperature after 3 hours. Rotary evaporation is poured in frozen water after falling ethanol.It is extracted with ethyl acetate aqueous phase three times, merges organic facies, organic facies saturated common salt Being dried with anhydrous sodium sulfate after water washing, it is (light yellow that rotary evaporation obtains product 1,1,2-ethane tricarboxylic acids triethyl after falling solvent Grease, 180.0 grams, productivity 73.1%) the most purified direct plunge into next step reaction.

Step B:2-(2,4,6-trihydroxy-pyrimidine-5-replacement) ethyl acetate

Metallic sodium (25.2 grams, 1.1 moles) it is dividedly in some parts in dehydrated alcohol (1500 milliliters).Metallic sodium reacts disappear completely After mistake, in gained alcohol sodium solution, it is separately added into 1,1,2-ethane tricarboxylic acids triethyl (180.0 grams, 0.73 mole) and carbamide (43.9 grams, 0.73 mole).Reactant liquor backflow is cooled to room temperature the most afterwards, and rotary evaporation falls ethanol, and residue is dissolved in water, Be acid with dilute hydrochloric acid regulation pH, after rotary evaporation removes solvent, by silica gel flash chromatography residue obtain product 2-(2, 4,6-trihydroxy-pyrimidine-5-replace) ethyl acetate (light yellow solid, 82.8 grams, productivity 35.0%).

Step C:2-(2,4,6-trichloropyrimidine-5-replacement) ethyl acetate

Trichlorine oxygen to intermediate 2-(2,4,6-trihydroxy-pyrimidine-5-replace) ethyl acetate (50.0 grams, 0.24 mole) Phosphorus (400.0 milliliters) solution is slowly added dropwise DIPEA (80.0 milliliters).After dropping, reactant liquor is heated to 100 DEG C are continued reaction 2 hours.Reactant liquor is cooled to the phosphorus oxychloride of rotary evaporation excess after room temperature, and residue is poured in trash ice. It is alkalescence with sodium bicarbonate regulation pH value.It is extracted with ethyl acetate aqueous phase three times, merges organic facies.Organic facies saturated common salt It is dried with anhydrous sodium sulfate after water washing.After rotary evaporation falls solvent, obtain product 2-by silica gel flash chromatography residue (2,4,6-trichloropyrimidine-5-replace) ethyl acetate (light yellow solid, 34.4 grams, productivity 54.6%).¹H NMR(400MHz, CDCl₃) δ ppm 4.24 (q, J=7.1Hz, 2H), 3.95 (s, 2H), 1.29 (t, J=7.1Hz, 3H).

Step D:2-(2,4-bis-chloro-6-(4-methoxybenzylamine) pyrimidine-5-replacement) ethyl acetate

N, N-diformazan to intermediate 2-(2,4,6-trichloropyrimidine-5-replace) ethyl acetate (43.3 grams, 0.16 mole) Base Methanamide (500.0 milliliters) solution adds 4-methoxybenzylamine (24.2 grams, 0.17 mole) and DIPEA (24.9 grams, 0.19 mole), reactant liquor is heated to 60 DEG C and reacts 1 hour.The cancellation that adds water is reacted, and is extracted with ethyl acetate aqueous phase three Secondary, merge organic facies, organic facies is dried with anhydrous sodium sulfate after washing with dilute hydrochloric acid and saturated aqueous common salt successively.Rotary evaporation falls After solvent, (2,4-bis-chloro-6-(4-methoxybenzylamine) pyrimidine-5-takes to obtain product 2-by silica gel flash chromatography residue Generation) ethyl acetate (light yellow solid, 27.1 grams, productivity 45.6%).¹H NMR(400MHz,CDCl₃) δ ppm 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-methoxyphenyl)-5-spiral shell [1,3] cyclopropyl-5H-pyrroles [2,3-d] pyrimidine-6- Ketone

To intermediate 2-(2,4-bis-chloro-6-(4-methoxybenzylamine) pyrimidine-5-replacement) ethyl acetate under nitrogen protection DMF (800.0 millis of (27.1 grams, 73.2 mMs) and grinding potassium carbonate (101.1 grams, 732.4 moles) Rise) in solution in 40 DEG C of droppings glycol dibromide (27.5 grams, 146.4 mMs).After dropping, reactant liquor is heated to 80 React 1 hour.The cancellation that adds water is reacted, and is extracted with ethyl acetate aqueous phase three times, merges organic facies, and organic facies saturated common salt is washed It is dried with anhydrous sodium sulfate after washing.After rotary evaporation falls solvent, obtain product 2,4-bis-by silica gel flash chromatography residue Chloro-7-(4-methoxyphenyl)-5-spiral shell [1,3] cyclopropyl-5H-pyrroles [2,3-d] pyrimidine-6-ketone (white solid, 21.2 grams, Productivity 82.7%).¹H NMR(400MHz,CDCl₃) δ ppm7.53 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 '-two chloro-7 '-(4-methoxyphenyls)-6 ', 7 '-dihydro spiral shell [cyclopropane-1,5 '- Pyrroles [2,3-d] pyrimidine]

To the chloro-7-of intermediate 2,4-bis-(4-methoxyphenyl)-5-spiral shell [1,3] cyclopropyl-5H-pyrroles under nitrogen protection Oxolane (200.0 milliliters) solution of [2,3-d] pyrimidine-6-ketone (14.0 grams, 40.0 mMs) drips 94% borine two Dimethylsulfide complex (8.2 milliliters, 80.0 mMs).After dropping, reactant liquor is heated to 60 DEG C of reactions overnight.Reaction is completely After, in 0 DEG C of dropping methanol cancellation reaction, after concentrating under reduced pressure, residue obtains product by silica gel flash chromatography2 ', 4 '-two Chloro-7 '-(4-methoxyphenyl)-6 ', 7 '-dihydro spiral shell [cyclopropane-1,5 '-pyrroles [2,3-d] pyrimidine](white solid, 8.4 Gram, productivity 62.4%).¹H NMR(400MHz,CDCl₃) δ ppm 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

Step A:4-(3-methoxyl group-4-nitrobenzophenone) morpholine

Toward 4-fluoro-2-methoxyl group-1-Nitrobenzol (100 grams, 0.584mol) and the diformazan of morpholine (60 grams, 0.689mol) Adding potassium carbonate (120 grams, 0.870mol) in sulfoxide (60 milliliters) solution, mixture pours ice into after reacting 6 hours under 70 degree In water, filter, wash filter cake with water, be dried to obtain product 4-(3-methoxyl group-4-nitrobenzophenone) morpholine (100 grams, productivity 72%).

Step B/ intermediate B 1:2-methoxyl group-4-morpholine aniline

Add in oxolane (2 liters) solution of 4-(3-methoxyl group-4-nitrobenzophenone) morpholine (100 grams, 0.42mol) Enter palladium carbon (10%, 10 grams), after stirring 12 hours under an atmosphere of hydrogen, Filtration of catalyst, it is spin-dried for filtrate, obtains product 2-first Epoxide-4-morpholine aniline (87 grams, productivity 100%).

Intermediate B 2

2-((t-butyldimethyl silane epoxide) methyl)-4-morpholine aniline

Step A:5-chloro-2-nitrobenzaldehyde

Concentrated sulphuric acid (150 milliliters) is cooled to-20 degree, is carefully added into 3-chlorobenzaldehyde (15 grams, 107mmol) and potassium nitrate (11.9 grams, 117mmol), maintain the temperature at below-10 degree.After adding, continue stirring 30 minutes, then pour in frozen water, use second Acetoacetic ester extracts.Merging organic facies, wash with saturated aqueous common salt, anhydrous sodium sulfate is dried, and filters, is spin-dried for, and silicagel column separates To product 5-chloro-2-nitrobenzaldehyde (12.0 grams, productivity 60.6%).

Step B:2-(5-chloro-2-nitrobenzophenone)-DOX

In the round-bottomed flask equipped with Dean-Stark device add 5-chloro-2-nitrobenzaldehyde (12.0 grams, 64.7mmol), ethylene glycol (8.0 grams, 129.3mmol), p-methyl benzenesulfonic acid (0.2 gram) and toluene (150 milliliters), it is heated to reflux 8 Adding dchloromethane after hour, organic facies saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, and filters, is spin-dried for, silicagel column Isolated product 2-(5-chloro-2-nitrobenzophenone)-DOX (13.4 grams, productivity 90.0%).

Step C:4-(3-(DOX-2-base)-4-nitrobenzophenone) morpholine

2-(5-chloro-2-nitrobenzophenone)-DOX (13.4 grams, 58.4mmol) is dissolved in morpholine (150 millis Rise) in solution be heated to reflux 16 hours, be cooled to room temperature, add dchloromethane, organic phase washed with water, anhydrous sulfur Acid sodium is dried, and filters, is spin-dried for, silicagel column isolated product 4-(3-(DOX-2-base)-4-nitrobenzophenone) morphine Quinoline (15.9 grams, productivity 97.1%).

Step D:5-morpholine-2-nitrobenzaldehyde

Acetone and water mixed solvent (100 milliliters/100 milliliters) in add 4-(3-(DOX-2-base)- 4-nitrobenzophenone) morpholine (15.9 grams, 56.7mmol) and p-methyl benzenesulfonic acid (2.0 grams), then it is heated to reflux 4 hours, adds second Acetoacetic ester dilutes.Organic facies is washed with saturated sodium bicarbonate aqueous solution and saturated aqueous common salt respectively, and anhydrous sodium sulfate is dried, mistake Filter, is spin-dried for, and obtains product 5-morpholine-2-nitrobenzaldehyde, the most purified is directly used in next step reaction.

Step E:(5-morpholine-2-nitrobenzophenone) methanol

5-morpholine-2-nitrobenzaldehyde is dispersed in the mixed solvent of oxolane and ethanol (100 milliliters/100 millis Rise), it is slowly added into sodium borohydride (4.0 grams), at normal temperatures stirring 1 hour, adds ether and the aqueous solution of saturated ammonium chloride, then Extract with ether.Merging organic facies, wash with saturated aqueous common salt, anhydrous sodium sulfate is dried, and filters, is spin-dried for, and silicagel column separates To product (5-morpholine-2-nitrobenzophenone) methanol (8.5 grams, two step productivity 62.3%)

Step F:4-(3-((t-butyldimethyl silane epoxide) methyl)-4-nitrobenzophenone) morpholine

Toward (5-morpholine-2-nitrobenzophenone) methanol (3.0 grams, 12.6mmol), triethylamine (2.54 grams, 25.2mmol) and 4-N, adds tert-butyl chloro-silicane in dichloromethane (100 milliliters) solution of N '-dimethyl pyridine (0.2 gram) (2.83g, 18.9mmol), is stirred at room temperature after adding 2 hours, uses diluted ethyl acetate.Organic facies saturated common salt is washed Washing, anhydrous sodium sulfate is dried, and filters, is spin-dried for, silicagel column isolated product 4-(3-((t-butyldimethyl silane epoxide) first Base)-4-nitrobenzophenone) morpholine (4.0 grams, productivity 90.9%).

Step G/ intermediate B 2:2-((t-butyldimethyl silane epoxide) methyl)-4-morpholine aniline

Toward 4-(3-((t-butyldimethyl silane epoxide) methyl)-4-nitrobenzophenone) morpholine (4.0 grams, 0.11mol) Methanol solution (250 milliliters) in add Raney nickel (1.0 grams), under an atmosphere of hydrogen stirring 1 hour, Filtration of catalyst, Be spin-dried for filtrate, obtain product 2-((t-butyldimethyl silane epoxide) methyl)-4-morpholine aniline (3.48 grams, productivity 95.1%).¹H NMR (400MHz, CDCl₃) δ ppm 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-dihydrobenzos [b] [Isosorbide-5-Nitrae] two-5-amine

Step A:3-nitro-1,2-catechol

Catechol (60 grams, 0.54mol) is dissolved in ether (2 liters), under 0 degree, drips fuming nitric aicd (24 milliliters), After adding, it is slowly increased to room temperature, places 20 minutes, pour in frozen water, extract with ether.Merge organic facies, use dilute sodium carbonate water Solution (10%) washs, and anhydrous sodium sulfate is dried, and filters, is spin-dried for, silicagel column isolated product 3-nitro-1,2-catechol (25 grams, productivity 30%).¹H NMR (400MHz, CDCl₃) δ ppm 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] two English

Toward 3-nitro-1, the N of 2-catechol (11 grams, 0.071mol), N '-dimethyl Methanamide (500 milliliters) solution In be sequentially added into potassium carbonate (29 grams, 0.213mol) and glycol dibromide (14.7 grams, 0.078mol), be then heated to 110 Degree, is cooled to room temperature after stirring 2 hours, is poured into water, is extracted with ethyl acetate.Merge organic facies, wash with saturated common salt Washing, anhydrous sodium sulfate is dried, and filters, is spin-dried for, silicagel column isolated product 5-nitro-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] two English (8 grams, productivity 62%).¹H NMR (400MHz, CDCl₃) δ ppm 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] two-5-amine

Toward 5-nitro-2, the methanol solution (250 milliliters) of 3-dihydrobenzo [b] [Isosorbide-5-Nitrae] two English (8 grams, 0.044mol) Middle addition palladium carbon (10%, 2 grams), is stirred overnight under an atmosphere of hydrogen, Filtration of catalyst, is spin-dried for filtrate, pure with silicagel column Change, obtain target product 2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] two-5-amine (6.5 grams, productivity 97%).¹H NMR (400MHz, CDCl₃) δ ppm 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] two-5-amine

Step A:N-(2,3-dihydrobenzos [b] [Isosorbide-5-Nitrae] two-5-base) acetamide

Under room temperature, toward 2, the ethanol of 3-dihydrobenzo [b] [Isosorbide-5-Nitrae] two-5-amine (intermediate B 3,4.5 grams, 30mmol) is molten Liquid (50 milliliters) is slowly added dropwise acetic anhydride (3.0 grams, 30mmol), stirs at normal temperatures after adding 5 minutes, be spin-dried for solvent, use Silicagel column separates, and obtains product N-(2,3-dihydrobenzos [b] [Isosorbide-5-Nitrae] two-5-base) acetamide (5.5 grams, productivity 95%).¹H NMR (400MHz, CDCl₃) δ ppm9.12 (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-bromo-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] two-5-base) acetamide

Chloroformic solution by N-(2,3-dihydrobenzos [b] [Isosorbide-5-Nitrae] two-5-base) acetamide (5.5 grams, 28.5mmol) (20 milliliters) are cooled to-20 degree, are slowly added dropwise the chloroformic solution (5 milliliters) of bromine (1.6 milliliters, 30mmol), keep reactant liquor Temperature-10 spend below, after adding under 0 degree stirring 10 minutes that, go out with shrend rapidly, extract with dichloromethane.Merge Organic facies, respectively with saturated sodium bicarbonate aqueous solution and saturated aqueous common salt washing, anhydrous sodium sulfate is dried, and filters, is spin-dried for, silica gel Post isolated product N-(8-bromo-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] two-5-base) acetamide (5 grams, productivity 64%).¹H NMR (400MHz, CDCl₃) δ ppm 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-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] two-5-base) acetamide

Molten toward the toluene of N-(8-bromo-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] two-5-base) acetamide (5 grams, 18.4mmol) Liquid (50 milliliters) adds morpholine (1.9 grams, 22mmol), Pd₂(dba)₃(1.68 grams, 1.84mmol), X-Phos (1.75 grams, 3.68mmol) with potassium tert-butoxide (4.1 grams, 36.8mmol), mixture is placed in tube sealing and reacts overnight under 130 degree, cooling To room temperature, filter, be spin-dried for filtrate, carry out separating to obtain product N-(8-morpholine-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] two with silicagel column -5-base) acetamide (2 grams, productivity 40%).

Step D/ intermediate B 4:8-morpholine-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] two-5-amine

First toward N-(8-morpholine-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] two-5-base) acetamide (2 grams, 7.19mmol) Adding concentrated hydrochloric acid (5 milliliters) in alcoholic solution (100 milliliters), be stirred overnight under room temperature the most again, major part solvent is removed in rotation, uses carbonic acid Hydrogen sodium water solution regulation pH value, to 7-8, is extracted with ethyl acetate.Merge organic facies, wash with saturated aqueous common salt, anhydrous sodium sulfate It is dried, filters, be spin-dried for, silicagel column isolated product 8-morpholine-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] two-5-amine (1 gram, Productivity 60%).¹H NMR (400MHz, CDCl₃) δ ppm 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 hydrochlorate

Step A:6-methoxyl group-4,5-dihydro-1H-benzo [b] azatropylidene-2 (3H)-one

Under 0 degree, toward 5-methoxyl group-3, in the poly phosphoric acid solution of 4-dihydronaphthalene-1 (2H)-one (8.3 grams, 47.15mmol) (100 milliliters) are slowly added to Hydrazoic acid,sodium salt (3.6 grams, 55.4mmol) in batches, add, be then slowly increased to room temperature in 30 minutes, Continue stirring 16 hours, pour in frozen water, precipitate is collected by filtration, be dried to obtain product 6-methoxyl group-4,5-dihydro-1H- Benzo [b] azatropylidene-2 (3H)-one (6.8 grams, productivity 75.5%).¹H NMR (400MHz, DMSO-d6) δ ppm 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

By 6-methoxyl group-4, the acetonitrile of 5-dihydro-1H-benzo [b] azatropylidene-2 (3H)-one (6.8 grams, 35.6mmol) is molten Liquid (50 milliliters) is cooled to-10 degree, is slowly added dropwise trifluoromethanesulfanhydride anhydride (15.0 milliliters, 106.8mmol), after stirring 20 minutes, It is dividedly in some parts potassium nitrate (3.94 grams, 39.0mmol), is slowly increased to room temperature, continue stirring 5 hours, pour sodium bicarbonate and ice into In the solution of water (100 milliliters), regulation pH value, to 9, is extracted with ethyl acetate.Merge organic facies, wash with saturated aqueous common salt, nothing Aqueous sodium persulfate is dried, and filters, is spin-dried for, silicagel column isolated product 6-methoxyl group-7-nitro-4,5-dihydro-1H-benzo [b] Azatropylidene-2 (3H)-one (yellow solid, 4.68 grams, productivity 55.7%).¹H NMR (400MHz, DMSO-d6) δ ppm 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

By 6-methoxyl group-7-nitro-4,5-dihydro-1H-benzo [b] azatropylidene-2 (3H)-one (4.5 grams, 19.0mmol) N, N '-dimethyl formamide solution (30 milliliters) is cooled to 0 degree, is slowly dividedly in some parts the sodium hydride (mineral oil of 60% Thing, 1.15 grams, 28.5mmol), after stirring 30 minutes, it is slowly added dropwise iodoethane (1.84 milliliters, 22.9mmol), then is slowly increased to Room temperature, continues stirring 2 hours.After reaction terminates, pour in frozen water, filter to obtain product 1-ethyl-6-methoxyl group-7-nitro-4, 5-dihydro-1H-benzo [b] azatropylidene-2 (3H)-one, for pale solid (3.77 grams, productivity 78.5%).¹H NMR (400MHz, CDCl₃) δ ppm 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 hydrochlorate

Toward 1-ethyl-6-methoxyl group-7-nitro-4,5-dihydro-1H-benzo [b] azatropylidene-2 (3H)-one (4.6 grams, In ethanol (45 milliliters) solution 18.0mmol) add palladium carbon (10%, 0.45 gram) and hydrazine hydrate (85%, 8.78 milliliters, 0.18mol), being heated to 90 degree, be cooled to room temperature after 6 hours, rotation goes major part solvent, residue acetone to dilute (40 millis Rise), add concentrated hydrochloric acid after being cooled to 0 degree, rotation is removed solvent, is obtained target product 7-amido-1-ethyl-6-methoxyl group-4,5-bis- Hydrogen-1H-benzo [b] azatropylidene-2 (3H)-one hydrochlorate (4.3 grams, productivity 87.7%).¹H NMR (400MHz, CDCl₃)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 iso-indoles-1-ketone

Step A:2-(bromomethyl)-4-nitrobenzene methyl

By 2-methyl-4-nitrobenzene methyl (696 milligrams, 3.57mmol), azodiisobutyronitrile (58.6 milligrams, 0.357mmol) it is placed in tube sealing with N-bromosuccinimide (785 milligrams, 4.46mmol), adds carbon tetrachloride (35 millis Rise), pour nitrogen post-heating to 80 degree, be cooled to room temperature, solids removed by filtration after stirring 22 hours, be spin-dried for filtrate, obtain and slightly produce Product 2-(bromomethyl)-4-nitrobenzene methyl, for light tan solid, the most purified, it is directly used in next step reaction.

Step B:5-nitro iso-indoles-1-ketone

2-(bromomethyl)-4-nitrobenzene methyl is dissolved in the methanol solution of ammonia (7N, 5 milliliters), under room temperature It is spin-dried for after stirring 2 hours, obtains yellow solid, pull an oar by ethyl acetate (15 milliliters), be cooled to-20 degree, filter to obtain product 5-nitre Base iso-indoles-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 iso-indoles-1-ketone

5-nitro iso-indoles-1-ketone (60 milligrams, 0.337mmol) is dissolved in methanol (20 milliliters), adds palladium carbon (10%, 50 milligrams), stirs 1 hour under atmosphere of hydrogen, Filtration of catalyst, is spin-dried for filtrate and obtains the target product different Yin of 5-amido Diindyl-1-ketone (38 milligrams, productivity 76.2%).

Intermediate B 7

Benzofuran-7-amine hydrochlorate

Step A:2-hydroxyl-3-nitrobenzaldehyde

Under 0 degree, concentrated nitric acid (65%, 4 grams) is slowly dropped to the acetic acid (50 of Benzaldehyde,2-hydroxy (5.0 grams, 41mmol) Milliliter) in solution, then it is slowly increased to room temperature, stir 2 hours post-heating to 40 degree, continuation is stirred 5 hours, pours ice (75 grams) into With in the mixture of water (500 grams), precipitate is collected by filtration, after silicagel column separates, obtains product 2-hydroxyl-3-nitrobenzoyl Aldehyde (1.8 grams, productivity 26%).¹H NMR (400MHz, CDCl₃) δ ppm 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

In a round-bottomed flask with Dean-Stark device add 2-hydroxyl-3-nitrobenzaldehyde (4.3 grams, 25.7mmol), 2-dibromomalonic acid dimethyl ester (5.95 grams, 28.3mmol), potassium carbonate (5.32 grams, 38.6mmol) and tetrabutyl bromine Change the toluene solution (100 milliliters) of ammonium (0.8 gram, 2.5mmol), be heated to reflux 5 hours, after being cooled to room temperature, be spin-dried for solvent, Obtain product 7-nitrobenzofuran-2-methyl formate (4.6 grams, productivity 81%) through silicagel column is isolated and purified.¹H NMR (400MHz, CDCl₃) δ ppm 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

7-nitrobenzofuran-2-methyl formate (4.12 grams, 18.6mmol) is dissolved in ethanol (100 milliliters), adds Enter potassium hydroxide (2.08 grams, 37.1mmol), be heated to reflux 1 hour, be cooled to room temperature, be spin-dried for solvent.Residue with water is dilute Release, regulate pH value with concentrated hydrochloric acid, have insoluble matter to separate out, filter after stirring 30 minutes, collect precipitate, wash with water, after drying Obtain product 7-nitrobenzofuran-2-carboxylic acid (3.54 grams, productivity 92%).¹H NMR (400MHz, CDCl₃)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

7-nitrobenzofuran-2-carboxylic acid (3.54 grams, 17.1mmol) and copper oxide (0.16 gram, 2mmol) are suspended in In quinoline (30 milliliters), being heated to 170 degree, be cooled to room temperature, dilute with water after 1 hour, ethyl acetate extracts.Merge organic Phase, washs with saturated aqueous common salt, and anhydrous sodium sulfate is dried, and filters, is spin-dried for, silicagel column isolated product 7-nitrobenzofuran (2.56 grams, productivity 92%).¹H NMR (400MHz, DMSO-d6) δ ppm 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: benzofuran-7-amine hydrochlorate

Raney nickel is added (about in the methanol solution (100 milliliters) of 7-nitrobenzofuran (2.56 grams, 15.7mmol) 200 milligrams) and hydrazine hydrate (2.5 grams, 50mmol), there is obvious exothermic phenomenon.This mixture is heated to 50 degree, cold after 1 hour But to room temperature, Filtration of catalyst, it is spin-dried for filtrate.Residue with ethyl acetate dilutes, and adds the methanol solution of hydrogen chloride (1N), there is insoluble matter to separate out, precipitate is collected by filtration, obtain target product benzofuran-7-amine hydrochlorate (2.025 after drying Gram, productivity 76%).¹H NMR (400MHz, DMSO-d6) δ ppm 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 crotonic nitrile (16.5 grams, 0.2mol) n-amyl alcohol (40 milliliters) solution in add methyl hydrazine (12.9 grams, 0.28mol), being heated to reflux 3 hours, unnecessary n-amyl alcohol and methyl hydrazine are removed in rotation.By gained residue with heptanes (150 milliliters) Making beating, is collected by filtration precipitate, and 40 degree lower is vacuum dried, and obtains target product 1,3-dimethyl-1H-pyrazoles-5-amine (13.5 grams, Productivity 60.4%).

Intermediate B 9

3,4,5-trimethoxy-anilines

Step A:1,2,3-trimethoxy-5-Nitrobenzol

Under 10 degree, by 3,4,5-trimethoxybenzoic acids (10 grams, 47mmol) are added to nitric acid (20 milliliters) and acetic acid in batches In the mixed solvent of (40 milliliters), stirring at normal temperatures was poured in frozen water after 30 minutes, precipitate is collected by filtration, washes with water, Recrystallization in ethanol, obtains product 1,2,3-trimethoxy-5-Nitrobenzol (6.64 grams, productivity 66.1%).¹H NMR (400MHz, DMSO-d6) δ ppm 7.51 (s, 2H), 3.87 (s, 6H), 3.77 (s, 3H).

Step B/ intermediate B 9:3,4,5-trimethoxy-anilines

Ethanol solution (250 milliliters) toward 1,2,3-trimethoxy-5-Nitrobenzol (6.64 grams, 31.2mmol) adds palladium carbon (10%, 300 milligrams) and hydrazine hydrate (85%, 5.7 milliliters), have a large amount of gas to discharge, then mixture is heated to reflux 1 little Time, it being cooled to room temperature, filter, rotation goes solvent to obtain product 3,4,5-trimethoxy-anilines (white solid, 5.5 grams, productivity 96.4%).¹H NMR (400MHz, DMSO-d6) δ ppm 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-indole-4-amine

Step A:1-(3-bromopropyl)-4-nitro-1H-indole

4-nitroindoline (5 grams, 31mmol) is dissolved in anhydrous N, in N '-dimethyl Methanamide (200 milliliters), adds in batches Enter the potassium hydroxide (1.74 grams, 31mmol) ground, then drip 1, the N, N ' of 3-dibromopropane (18 grams, 89mmol)-diformazan Base formamide solution, dilute after stirring 12 hours at normal temperatures, it is extracted with ethyl acetate.Merge organic facies, use saturated food Saline washs, and anhydrous sodium sulfate is dried, and filters, is spin-dried for, silicagel column isolated product 1-(3-bromopropyl)-4-nitro-1H-Yin Diindyl (8.18 grams, productivity 94%).

Step B:4-(3-(4-nitro-1H-indole-1-base) propyl group) morpholine

1-(3-bromopropyl)-4-nitro-1H-indole (8.18 grams, 28.9mmol) is dissolved in anhydrous N, N '-dimethyl first In amide (200 milliliters), be dividedly in some parts the potassium carbonate (12 grams, 87mmol) of grinding, then drip morpholine (12.6 grams, N 144.8mmol), N '-dimethyl formamide solution, it is heated to 80 degree, dilute after stirring 12 hours, use acetic acid second Ester extracts.Merging organic facies, wash with saturated aqueous common salt, anhydrous sodium sulfate is dried, and filters, is spin-dried for, obtains product 4-(3-(4- Nitro-1H-indole-1-base) propyl group) morpholine, the most purified be directly used in next step reaction.

Step C/ intermediate B 10:1-(3-morpholine propyl group)-1H-indole-4-amine

Palladium carbon is added in the methanol solution (100 milliliters) of 4-(3-(4-nitro-1H-indole-1-base) propyl group) morpholine (10%), stirring 12 hours, Filtration of catalyst, be spin-dried for filtrate, obtain target product 1-(3-morphine under an atmosphere of hydrogen Quinoline propyl group)-1H-indole-4-amine, for brown solid (5 grams, two step productivity 67%).

Intermediate C1

2-amido-N-methyl-benzamide

The methanol dripping methylamine in oxolane (200 milliliters) suspension of isatoic anhydride (10 grams, 61.3mmol) is molten Liquid (40%, 10 milliliters), stirs after 16 hours under room temperature and is spin-dried for solvent, obtain product 2-amido-N-methyl-benzamide (9 grams, Productivity 97.8%).¹H NMR (400MHz, CDCl₃) δ ppm 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-Methanamide

Step A:4-nitro benzo [d] [1,3]-dioxole

Past hexamethyl three phosphamide (100 milliliters) middle addition sodium hydride (mineral oil mixture of 60%, 1.0 grams, 25mmol), then it is slowly added dropwise 3-nitro-1,2-catechol (getting from the synthesis of intermediate B3,1.55 grams, 10mmol) Hexamethyl three phosphamide solution (20 milliliters), added in 10 minutes, after adding, addition diiodomethane (0.94 milliliter, 11.6mmol), continue stirring 30 minutes, use frozen water cancellation, extract with ether.Merge organic facies, wash with saturated aqueous common salt, nothing Aqueous sodium persulfate is dried, and filters, is spin-dried for, silicagel column isolated product 4-nitro benzo [d] [1,3]-dioxole (1.32 grams, productivity 79%).¹H NMR (400MHz, CDCl₃) δ ppm 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-4-amine between benzo [d] [1,3]

In the ethanol solution (80 milliliters) of 4-nitro benzo [d] [1,3]-dioxole (2.0 grams, 12mmol) Add Raney nickel (about 0.5 gram), Filtration of catalyst after stirring 4 hours under an atmosphere of hydrogen, be spin-dried for filtrate, use silicagel column Separate, obtain dioxa-4-amine (1.04 grams, productivity 63%) between product benzo [d] [1,3].¹H NMR (400MHz, CDCl₃)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)。

Step C:[1,3] dioxa [4', 5':5,6] benzo [1,2-b] azet-6 (7H)-one between

Toward chloral hydrate (1.39 grams, 8.4mmol) and the aqueous solution (23.1 milliliters) of sodium sulfate (6.91 grams, 48.7mmol) Dioxa-4-amine (1.0 grams, 7.3mmol) between middle addition benzo [d] [1,3], oxammonium sulfate. (6.24 grams, 38mmol) and dilute salt Acid (1.2N, 7.7 milliliters), stirs 1.5 hours under 60 degree, stands overnight the most at 25 degrees c, brown solid is collected by filtration, and uses Water washs, vacuum drying.It is dissolved in again in methanesulfonic acid, is heated to 45 degree, is cooled to 0 degree after 30 minutes, pours in ice (200 grams), have dark red solid to separate out, are collected by filtration, dioxa [4', 5':5,6] benzo between dried product [1,3] [1, 2-b] azet-6 (7H)-one (635 milligrams, productivity 53%).¹H NMR (400MHz, CDCl₃) δ ppm 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-5-carboxylic acid between step D:4-amido benzo [d] [1,3]

Add in the aqueous solution (35 milliliters) of sodium hydroxide (4.6 grams, 115mmol) dioxa between [1,3] [4', 5':5, 6] benzo [1,2-b] azet-6 (7H)-one (2.35 grams, 14.4mmol), were slowly added dropwise hydrogenperoxide steam generator in 30 minutes (30%, 21 milliliters), then with dilute hydrochloric acid regulation pH value to 7, precipitate is collected by filtration, is dried to obtain product 4-amido benzo [d] Dioxa-5-carboxylic acid (1.68 grams, productivity 64%) between [1,3].¹H NMR (400MHz, DMSO-d6) δ ppm 7.40-7.42 (d, 1H, J=8.4Hz), 6.25-6.27 (d, 1H, J=8.4Hz), 6.04 (s, 2H).

Dioxa-5-Methanamide between step E/ intermediate C2:4-amido-N-methyl benzo [d] [1,3]

Two are added between 4-amido benzo [d] [1,3] in the acetonitrile solution (20 milliliters) of methylamine (0.43 gram, 13.9mmol) Oxa--5-carboxylic acid (1.68 grams, 9.3mmol), 2-(7-azepine-1H-BTA-1-base)-1,1,3,3-tetramethylurea six Fluorophosphoric acid ester (HATU, 4.28 grams, 11.2mmol).Mixture is spin-dried for after stirring 12 hours at normal temperatures, and add methylene chloride dilution, Washing with water, anhydrous sodium sulfate is dried, and filters, is spin-dried for, silicagel column isolated product 4-amido-N-methyl benzo [d] [1,3] Between dioxa-5-Methanamide (1.48 grams, productivity 82%).¹H NMR (400MHz, CDCl₃) δ ppm6.95-6.98 (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

N, N'-carbonyl diurethane is added in the tetrahydrofuran solution (50 milliliters) of 2-amido benzoic acid (5.0 grams, 36.5mol) Imidazoles (6.5 grams, 40.1mol), stirs 1 hour under room temperature, is subsequently adding pyrrolidine (3.5 grams, 40.1mmol), continues stirred At night, rotation is removed solvent, dilute, is extracted with dichloromethane.Merging organic facies, wash with saturated aqueous common salt, anhydrous sodium sulfate is done Dry, filter, be spin-dried for obtaining product (2-aminocarbonyl phenyl) (pyrrolidin-1-yl) methyl ketone (5.4 grams, productivity 66%), the most purified, It is directly used in next step reaction.¹H NMR (400MHz, CDCl₃) δ ppm 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

Step A:N-methyl-2-nitrobenzene sulfonamide

It is slowly added dropwise first in the dichloromethane solution (500 milliliters) of 2-nitro-1-benzene sulfonyl chloride (30 grams, 0.14mol) The aqueous solution (30%, 15.3 grams) of amine and triethylamine (38 milliliters, 0.27mol), stirring at normal temperatures was spin-dried for solvent after 1 hour, Residue over silica gel post carries out isolated and purified obtaining product N-methyl-2-nitrobenzene sulfonamide (26 grams, productivity 90%).

Step B/ intermediate C4:2-amido-N-methyl benzenesulfonamide

Palladium carbon is added in the methanol solution (500 milliliters) of N-methyl-2-nitrobenzene sulfonamide (26 grams, 0.12mol) (10%, 2 grams), under an atmosphere of hydrogen stirring 3 hours after Filtration of catalyst, be spin-dried for filtrate obtain target product 2-amido- N-methyl benzenesulfonamide (22 grams, productivity 98%).¹H NMR (400MHz, CDCl₃) δ ppm 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-propylbenzenesulfonamide hydrochlorate

Step A:2-nitro-N-propylbenzenesulfonamide

Under 0 degree, in the tetrahydrofuran solution (100 milliliters) of n-propylamine (2.36 grams, 0.04mol), it is slowly added to 2-nitre Base-1-benzene sulfonyl chloride (8.88 grams, 0.04mol) and triethylamine (4.05 grams, 0.04mol), stirring at normal temperatures was spin-dried for after 4 hours Solvent obtains thick product 2-nitro-N-propylbenzenesulfonamide (9.18 grams, productivity 93.9%).¹H NMR (400MHz, CDCl₃)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-propylbenzenesulfonamide hydrochlorate

Palladium carbon is added in the methanol solution (100 milliliters) of 2-nitro-N-propylbenzenesulfonamide (8.64 grams, 0.035mol) (10%, 3.5 grams), Filtration of catalyst after stirring 12 hours under an atmosphere of hydrogen, it is spin-dried for filtrate, residue is dissolved in second In ether, blast hydrogen chloride gas, obtain product 2-amido-N-propylbenzenesulfonamide hydrochlorate (8.61 grams, productivity 98.4%).¹H NMR (400MHz, DMSO-d6) δ ppm 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

Step A:N-cyclobutyl-2-nitrobenzene sulfonamide

Under 0 degree, in the dichloromethane solution (100 milliliters) of 2-nitro-1-benzene sulfonyl chloride (6.8 grams, 30.8mol) slowly Adding ring butylamine (2.2 grams, 31mmol) and triethylamine (14 grams, 138.6mol), stirring at normal temperatures was spin-dried for solvent after 4 hours, Residue over silica gel post carries out isolated and purified obtaining product N-cyclobutyl-2-nitrobenzene sulfonamide (7 grams, productivity 88.9%).¹H NMR (400MHz, CDCl₃) δ ppm 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

Palladium carbon is added in the methanol solution (100 milliliters) of N-cyclobutyl-2-nitrobenzene sulfonamide (7 grams, 27.3mmol) (10%), Filtration of catalyst after stirring 12 hours under an atmosphere of hydrogen, it is spin-dried for filtrate, residue over silica gel post separates Purification obtains product 2-amido-N-cyclobutyl benzsulfamide (6 grams, productivity 97.1%).¹H NMR (400MHz, CDCl₃)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-cyclopenta benzsulfamide

Step A:N-cyclopenta-2-nitrobenzene sulfonamide

Under 0 degree, in the dichloromethane solution (500 milliliters) of 2-nitro-1-benzene sulfonyl chloride (22.1 grams, 100mol) slowly Adding Aminocyclopentane (9 grams, 105.9mmol) and triethylamine (14 grams, 138.6mol), stirring at normal temperatures was spin-dried for solvent after 4 hours, Residue over silica gel post carries out isolated and purified obtaining product N-cyclopenta-2-nitrobenzene sulfonamide (23 grams, productivity 85.2%).¹H NMR (400MHz, CDCl₃) δ ppm 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-cyclopenta benzsulfamide

Palladium carbon is added in the methanol solution (500 milliliters) of N-cyclopenta-2-nitrobenzene sulfonamide (23 grams, 85.2mmol) (10%), Filtration of catalyst after stirring 12 hours under an atmosphere of hydrogen, it is spin-dried for filtrate, residue over silica gel post separates Purification obtains product 2-amido-N-cyclopenta benzsulfamide (20 grams, productivity 97.8%).¹H NMR (400MHz, CDCl₃)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

Step A:N-cyclohexyl-2-nitrobenzene sulfonamide

Under 0 degree, in the dichloromethane solution (500 milliliters) of 2-nitro-1-benzene sulfonyl chloride (22.1 grams, 100mol) slowly Adding cyclohexylamine (11.9 grams, 120.2mmol) and triethylamine (14 grams, 138.6mol), stirring at normal temperatures is spin-dried for molten after 1 hour Agent, residue over silica gel post carry out isolated and purified obtain product N-cyclohexyl-2-nitrobenzene sulfonamide (25.7 grams, productivity 90.5%).¹H NMR (400MHz, CDCl₃) δ ppm 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

Palladium is added in the methanol solution (500 milliliters) of N-cyclohexyl-2-nitrobenzene sulfonamide (25.7 grams, 90.5mmol) Carbon (10%), Filtration of catalyst after stirring 12 hours, is spin-dried for filtrate under an atmosphere of hydrogen, and residue over silica gel post is carried out point Product 2-amido-N-cyclohexyl benzene sulfonamide (22 grams, productivity 95.7%) is obtained from purification.¹H NMR (400MHz, CDCl₃)δ Ppm 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) acetamide

Under 0 degree, toward 1, drip under the dichloromethane (1L) of 2-o-phenylenediamine (100 grams, 0.93mol) acetic anhydride (87 milliliters, 0.92mol), after stirring 2 hours under 0 degree, stand 12 hours, solid is collected by filtration, wash with dichloromethane and ether, be dried After obtain product N-(2-aminocarbonyl phenyl) acetamide (25 grams, productivity 18%).¹H NMR (400MHz, CDCl₃)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-methylmethanesulfonamide

Step A:N-methyl-N-(2-nitrobenzophenone) Methanesulfomide

N-methylmethanesulfonamide (5.33 is added in the acetonitrile solution (500 milliliters) of cesium carbonate (20.2 grams, 0.065mol) Gram, 0.049mol) and 1-fluoro-2-Nitrobenzol (4.59 grams, 0.033mol), stirring at normal temperatures is filtered after 12 hours, is spin-dried for filter Liquid, residue by silicagel column is isolated and purified, obtain product N-methyl-N-(2-nitrobenzophenone) Methanesulfomide (4.2 grams, productivity 56.1%).¹H NMR (400MHz, DMSO-d6) δ ppm 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-methylmethanesulfonamide

Methanol/dichloromethane solution toward N-methyl-N-(2-nitrobenzophenone) Methanesulfomide (3.90 grams, 0.017mol) (100 milliliters) add palladium carbon (10%, 1.5 grams), Filtration of catalyst after stirring 8 hours under an atmosphere of hydrogen, is spin-dried for filter Liquid, residue with diethyl ether washing obtains product N-(2-aminocarbonyl phenyl)-N-methylmethanesulfonamide (3.3 grams, productivity 97.4%).¹H NMR (400MHz, DMSO-d6) δ ppm 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-methylmethanesulfonamide hydrochlorate

Step A:N-(2-cyano-phenyl)-N-methylmethanesulfonamide

N-methylmethanesulfonamide (14.0 is added in the acetonitrile solution (500 milliliters) of cesium carbonate (55.78 grams, 171mmol) Gram, 0.128mol) and 2-fluorophenyl acetonitrile (10.37 grams, 86mmol), stirring at normal temperatures is filtered after 12 hours, is spin-dried for filtrate, residual Excess dilute, extracts with dichloromethane.Merging organic facies, wash with saturated aqueous common salt, anhydrous sodium sulfate is dried, and filters, It is spin-dried for, silicagel column isolated product N-(2-cyano-phenyl)-N-methylmethanesulfonamide (16.0 grams, productivity 88.9%).¹H NMR (400MHz, CDCl₃) δ ppm 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-methylmethanesulfonamide hydrochlorate

Toward N-(2-cyano-phenyl)-N-methylmethanesulfonamide (16.0 grams, 76mmol) ammonia methanol solution (500 milliliters, 4mol.L^-1Add palladium carbon (10%, 4 grams), Filtration of catalyst after stirring 24 hours under an atmosphere of hydrogen in), be spin-dried for filtrate, Blast hydrogen chloride gas after residue is dissolved in ether, obtain product N-(2-(aminomethyl) phenyl)-N-methylmethanesulfonamide Hydrochlorate (15.0 grams, productivity 90.4%).¹H NMR (400MHz, CDCl₃) δ ppm 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 synthetic procedure of 4-diamidogen

Step A: to containing 2, the chloro-7-of 4-bis-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine (vi, Intermediate A 1-A4,1.0 equivalents) anhydrous toluene solution in be separately added into amine R⁵R⁶(intermediate B 1-B10,1.0-1.2 works as NH Amount), three (dibenzalacetone) two palladium (Pd₂(dba)₃, 5-20mol%), (±)-BINAP or X-Phos (10-20mol%) and Cesium carbonate or potassium tert-butoxide or sodium tert-butoxide or potassium carbonate (1.5-4.0 equivalent).Mixture is heated under microwave or in tube sealing Being cooled to room temperature to the 100-150 number of degrees hour, rotary evaporation removes major part solvent, and residue with ethyl acetate dissolves, and uses Saturated aqueous common salt washs, and anhydrous sodium sulfate filters after drying, and rotary evaporation removes solvent, silicagel column isolated 4-chloro-7-(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)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine The anhydrous toluene solution of (vii, 1.0 equivalents) is separately added into amine R³R⁴NH (intermediate C1-C11,1.0-1.2 equivalent), three (two BENZYLIDENE ACETONE) two palladium (Pd₂(dba)₃, 5-20mol%), (±)-BINAP or X-Phos (10-20mol%) and cesium carbonate or Potassium tert-butoxide or sodium tert-butoxide or potassium carbonate (1.5-4.0 equivalent).Mixture is heated to 100-150 under microwave or in tube sealing Being cooled to room temperature after the number of degrees hour, rotary evaporation removes major part solvent, and residue with ethyl acetate dissolves, uses saturated aqueous common salt Washing, anhydrous sodium sulfate filters after drying, rotary evaporation removing solvent, silicagel column isolated 7-(4-methoxy-benzyl)-6, 7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2,4 diamidogen (viii).

Step C: to containing 7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2,4 diamidogen (viii) anhydrous trifluoroacetic acid solution is carefully added into some concentrated sulphuric acids.After mixture is stirred at room temperature 2-12 hour, Use saturated sodium bicarbonate aqueous solution cancellation.Aqueous phase is extracted with ethyl acetate, and merges organic facies, washs with saturated aqueous common salt, anhydrous Sodium sulfate is dried, and filters after being spin-dried for silicagel column isolated 6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2,4 diamidogen (ix, embodiment 1-37).

Embodiment 1

2-(2-(2-methoxyl group-4-morpholine base phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amine Base)-N-methyl-benzamide

The chloro-N-of step 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 2, the chloro-7-of 4-bis-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine (intermediate A 1,200 milligrams, 0.65mmol), 2-methoxyl group-4-morpholine aniline (intermediate B 1,160 milligrams, 0.77mmol), Pd₂(dba)₃(30 milligrams, 0.033mmol), (±)-BINAP (40 milligrams, 0.064mmol) and cesium carbonate (315 Milligram, 0.97mmol) carry out coupling reaction, the chloro-N-of isolated 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, productivity 32%).¹H NMR (400MHz, CDCl₃) δ ppm 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-methoxybenzyl Base)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine (100 milligrams, 0.21mmol), 2-Amino-N-methyl benzoyl Amine (intermediate C1,40 milligrams, 0.27mmol), Pd₂(dba)₃(10 milligrams, 0.011mmol), (±)-BINAP (15 milligrams, 0.024mmol) carry out coupling reaction with cesium carbonate (105 milligrams, 0.322mmol), isolated 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, productivity 48%).¹H NMR (400MHz, CDCl₃) δ ppm 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), 3.80 (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 concentrated sulphuric acids are added to 2-(2-(2-methoxyl group-4-morpholine base phenyl amine Base)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide (20 Milligram, 0.034mmol) trifluoroacetic acid solution in (1 milliliter), isolated target product 2-(2-(2-after stirring some hours Methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide (yellow solid, 14 milligrams, productivity 88%).¹H NMR (400MHz, DMSO-d6) δ ppm 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-4-amine Base) dioxa-5-Methanamide between-N-methyl benzo [d] [1,3]

Step 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) dioxa-5-Methanamide between-N-methyl benzo [d] [1,3]

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 (80 milligrams, 0.166mmol), dioxa-5-Methanamide (intermediate between 4-Amino-N-methyl benzo [d] [1,3] C2,39 milligrams, 0.201mmol), Pd₂(dba)₃(30 milligrams, 0.033mmol), X-Phos (16 milligrams, 0.034mmol) and carbon The toluene solution of acid caesium (108 milligrams, 0.331mmol) is heated to 130 degree of stirrings in tube sealing and carries out coupling reaction in 12 hours, point From obtaining product 4-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrroles And [2,3-d] pyrimidine-4-amido) between-N-methyl benzo [d] [1,3] dioxa-5-Methanamide (yellow solid, produces by 20 milligrams Rate 19%).¹H NMR (400MHz, CDCl₃) δ ppm 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).

Step B:4-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine- 4-amido) dioxa-5-Methanamide between-N-methyl benzo [d] [1,3]

According to universal synthesis method II, toward 4-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxybenzyl Base)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) dioxa-5-Methanamide between-N-methyl benzo [d] [1,3] Four concentrated sulphuric acids of dropping in the trifluoroacetic acid solution (5 milliliters) of (20 milligrams, 0.031mmol), reaction terminates rear isolated mesh Mark product 4-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)- Dioxa-5-Methanamide between N-methyl benzo [d] [1,3] (white solid, 6.3 milligrams, productivity 39%).¹H NMR (400MHz, CDCl₃) δ ppm 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-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amine Base) phenyl) (pyrrolidin-1-yl) ketone

Step 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 hydrochlorate (intermediate C3,68 Milligram, 0.30mmol), Pd₂(dba)₃(92 milligrams, 0.101mmol), (±)-BINAP (62 milligrams, 0.10mmol) and cesium carbonate The toluene solution of (325 milligrams, 1.0mmol) is heated to 130 degree in tube sealing and stirs 12 hours, is isolated to product (yellow Color solid, 60 milligrams, productivity 38%).¹H NMR (400MHz, CDCl₃) δ ppm 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).

(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] is phonetic for step B:(2- Pyridine-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-methoxybenzyl Base)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) phenyl) (pyrrolidin-1-yl) ketone (80 milligrams, Trifluoroacetic acid solution (6 milliliters) 0.126mmol) adds five concentrated sulphuric acids, stirs under room temperature some hours, post-treated and Isolated target product, (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, productivity 86%).¹H NMR (400MHz, DMSO-d6) δ ppm 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-amine Base)-N-methyl benzenesulfonamide

Step 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

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 (100 milligrams, 0.208mmol), 2-Amino-N-methyl benzsulfamide (intermediate C4,46 milligrams, 0.25mmol), Pd₂(dba)₃(38 milligrams, 0.042mmol), (±)-BINAP (26 milligrams, 0.042mmol) and cesium carbonate (136 milligrams, Toluene solution 0.416mmol) is heated to 130 degree in tube sealing and stirs 24 hours, is isolated to product 2-(2-(2-first Epoxide-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amine Base)-N-methyl benzenesulfonamide (94 milligrams, productivity 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-methoxybenzyl Base)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl benzenesulfonamide (94 milligrams, 0.149mmol) Trifluoroacetic acid solution (10 milliliters) adds 6 concentrated sulphuric acids, post-treated and isolated and purified obtain target product 2-(2-(2-first Epoxide-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl benzenesulfonamide (white solid, 65 milligrams, productivity 70%).¹H NMR (400MHz, DMSO-d6) δ ppm 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-amine Base)-N-propylbenzenesulfonamide

Step 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-propylbenzenesulfonamide

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 (100 milligrams, 0.207mmol), 2-amino-N-propylbenzenesulfonamide hydrochlorate (intermediate C6,62 milligrams, 0.247mmol), Pd₂(dba)₃(38 milligrams, 0.042mmol), (±)-BINAP (26 milligrams, 0.042mmol) and cesium carbonate The toluene solution of (271 milligrams, 0.831mmol) is heated to 130 degree in tube sealing and stirs 12 hours, and separated purification obtains 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-propylbenzenesulfonamide (yellow solid 40 milligrams, productivity 29%).¹H NMR (400MHz, CDCl₃)δ Ppm 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-propylbenzenesulfonamide

According to universal synthesis method II, toward 2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxybenzyl Base)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-propylbenzenesulfonamide (40 milligrams, 0.061mmol) Trifluoroacetic acid solution (4 milliliters) adds 3 concentrated sulphuric acids, stirs at normal temperatures some hours, post-treated and isolated and purified To target product 2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amine Base)-N-propylbenzenesulfonamide (white solid, 16 milligrams, productivity 48%).¹H NMR (400MHz, DMSO-d6) δ ppm8.42- 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

(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] is phonetic for N-cyclobutyl-2- Pyridine-4-amido) benzsulfamide

Step 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

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 (100 milligrams, 0.208mmol), 2-amino-N-cyclobutyl benzsulfamide (intermediate C11,56 milligrams, 0.248mmol), Pd₂(dba)₃(38 milligrams, 0.042mmol), X-Phos (20 milligrams, 0.042mmol) and cesium carbonate (136 millis Gram, 0.416mmol) toluene solution in tube sealing, be heated to 130 degree and stir 12 hours, separated purification obtains product N-ring Butyl-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, productivity 71%).¹H NMR (400MHz, CDCl₃)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) benzsulfamide (100 milligrams, 0.181mmol) Trifluoroacetic acid solution (6 milliliters) add 5 concentrated sulphuric acids, stir at normal temperatures some hours, post-treated and isolated and purified must To target product N-cyclobutyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] Pyrimidine-4-amido) benzsulfamide (white solid, 39.8 milligrams, productivity 49%).¹H NMR (400MHz, DMSO-d6) δ Ppm8.42-8.44 (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

(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] is phonetic for N-cyclopenta-2- Pyridine-4-amido) benzsulfamide

Step A:N-cyclopenta-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 2, the chloro-7-of 4-bis-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine (80 milligrams, 0.166mmol), 2-amino-N-cyclopenta benzsulfamide (intermediate C12,48 milligrams, 0.20mmol), Pd₂(dba)₃(30 milligrams, 0.033mmol), X-Phos (16 milligrams, 0.034mmol) and cesium carbonate (108 millis Gram, 0.331mmol) toluene solution in tube sealing, be heated to 130 degree and stir 12 hours, separated purification obtains product N-ring Amyl group-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, productivity 79%).¹H NMR (400MHz, CDCl₃)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-cyclopenta-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-cyclopenta-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 (100 milligrams, 0.146mmol) Trifluoroacetic acid solution (6 milliliters) in add 5 concentrated sulphuric acids, stir at normal temperatures some hours, post-treated and isolated and purified Obtain target product N-cyclopenta-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3- D] pyrimidine-4-amido) benzsulfamide (white solid 19.6 milligrams, productivity 24%).¹H NMR (400MHz, DMSO-d6) δ Ppm8.39-8.41 (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).

Embodiment 8

(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] is phonetic for N-cyclohexyl-2- Pyridine-4-amido) benzsulfamide

Step 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

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 (80 milligrams, 0.166mmol), 2-amino-N cyclohexyl benzsulfamide (intermediate C13,51 milligrams, 0.201mmol), Pd₂(dba)₃(30 milligrams, 0.033mmol), X-Phos (16 milligrams, 0.034mmol) and cesium carbonate (108 millis Gram, 0.331mmol) toluene solution in tube sealing, be heated to 130 degree and stir 12 hours, separated purification obtains product N-ring Hexyl-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, productivity 86%).¹H NMR (400MHz, CDCl₃)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) benzsulfamide (90 milligrams, 0.129mmol) Trifluoroacetic acid solution (5 milliliters) adds 4 concentrated sulphuric acids, stirs at normal temperatures some hours, post-treated and isolated and purified obtain (2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] is phonetic for target product N-cyclohexyl-2- Pyridine-4-amido) benzsulfamide (white solid, 20.1 milligrams, productivity 27%).¹H NMR (400MHz, DMSO-d6) δ Ppm8.32-8.34 (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) acetamide

Step 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) acetamide

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-aminophenyl) acetamide (intermediate C14,41 milligrams, 0.27mmol), Pd₂(dba)₃(46 milligrams, 0.05mmol), (±)-BINAP (31 milligrams, 0.05mmol) and cesium carbonate (163 milligrams, Toluene solution 0.5mmol) is heated to 130 degree in tube sealing and stirs 24 hours, and separated purification obtains product 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) acetamide (108 milligrams, productivity 51%).

((2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] is phonetic for 2-for step B:N- Pyridine-4-amido) phenyl) acetamide

According to universal synthesis method II, toward N-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxyl group Benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) phenyl) trifluoro of acetamide (60 milligrams, 0.1mmol) Acetic acid solution (10 milliliters) adds 5 concentrated sulphuric acids, stirs at normal temperatures some hours, post-treated and isolated and purified obtain mesh Mark product (white solid, 10 milligrams, productivity 21%).¹H NMR (400MHz, DMSO-d6) δ ppm 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-methylmethanesulfonamide

Step 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-methylmethanesulfonamide

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 (100 milligrams, 0.208mmol), N-(2-aminophenyl)-N-methylmethanesulfonamide (intermediate C15,50 milligrams, 0.25mmol), Pd₂(dba)₃(38 milligrams, 0.042mmol), (±)-BINAP (26 milligrams, 0.042mmol) and cesium carbonate (271 Milligram, 0.831mmol) toluene solution in tube sealing, be heated to 130 degree and stir 12 hours, separated purification obtains product 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-methylmethanesulfonamide (white solid, 70 milligrams, productivity 52%).¹H NMR (400MHz, CDCl₃) δ ppm 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).

((2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] is phonetic for 2-for step B:N- Pyridine-4-amido) phenyl)-N-methylmethanesulfonamide

According to universal synthesis method II, toward N-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxyl group Benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) phenyl)-N-methylmethanesulfonamide (70 milligrams, Trifluoroacetic acid solution (6 milliliters) 0.108mmol) adds 5 concentrated sulphuric acids, stirs at normal temperatures some hours, post-treated Target product N-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-is obtained with isolated and purified [2,3-d] pyrimidine-4-amido) phenyl)-N-methylmethanesulfonamide (white solid, 36.4 milligrams, productivity 64%).¹H NMR (400MHz, DMSO-d6) δ ppm 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-methylmethanesulfonamide

Step 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-methylmethanesulfonamide

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-methylmethanesulfonamide hydrochlorate (intermediate C16,62 milligrams, 0.25mmol), Pd₂(dba)₃(23 milligrams, 0.025mmol), X-Phos (31 milligrams, 0.05mmol) and carbonic acid The toluene solution of caesium (325 milligrams, 1.0mmol) is heated to 130 degree in tube sealing and stirs 24 hours, and separated purification is produced Product 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-methylmethanesulfonamide (white solid, 20 milligrams, productivity 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-methylmethanesulfonamide

According to universal synthesis method II, toward N-(2-((2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxyl group Benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) methyl) phenyl)-N-methylmethanesulfonamide (20 milligrams, Trifluoroacetic acid solution (4 milliliters) 0.303mmol) adds 1 concentrated sulphuric acid, stirs at normal temperatures some hours, post-treated Target product N-(2-((2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-is obtained with isolated and purified [2,3-d] pyrimidine-4-amido) methyl) phenyl)-N-methylmethanesulfonamide (white solid, 0.63 milligram, productivity 4%).¹H NMR (400MHz, CD₃OD) δ ppm 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-base)-6,7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-2,4-diamidogen

Step A:N²-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-N⁴-(6-picoline-2- Base)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2,4-diamidogen

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 (100 milligrams, 0.208mmol), 6-picoline-2-amine (29 milligrams, 0.266mmol), Pd₂(dba)₃(21 millis Gram, 0.022mmol), (±) toluene of-BINAP (28 milligrams, 0.044mmol) and cesium carbonate (144 milligrams, 0.44mmol) is molten Liquid with microwave heating to 125 degree and stir 4 hours, separated obtains product N in tube sealing after purification²-(2-methoxyl group-4- Coffee quinoline phenyl)-7-(4-methoxy-benzyl)-N⁴-(6-picoline-2-base)-6,7-dihydro-5H-pyrrolo-[2,3-d] is phonetic Pyridine-2,4-diamidogen (40 milligrams, productivity 33%).¹H NMR (400MHz, CDCl₃) δ ppm 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:N²-(2-methoxyl group-4-morpholine phenyl)-N⁴-(6-picoline-2-base)-6,7-dihydro-5H-pyrroles And [2,3-d] pyrimidine-2,4-diamidogen

According to universal synthesis method II, toward N²-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-N⁴- (6-picoline-2-base)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2,4-diamidogen (40 milligrams, 72.3mmmol) Trifluoroacetic acid solution (5 milliliters) adds 2 concentrated sulphuric acids, stirs at normal temperatures some hours, post-treated and isolated and purified To target product N²-(2-methoxyl group-4-morpholine phenyl)-N⁴-(6-picoline-2-base)-6,7-dihydro-5H-pyrrolo- [2,3-d] pyrimidine-2,4-diamidogen (white solid, 3.6 milligrams, productivity 11.5%).¹H NMR (400MHz, CDCl₃)δ Ppm8.02-8.04 (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-pyrrolo-[2,3-d] Pyrimidine-2,4-diamidogen

Step A:N⁴-(3,4-difluorophenyl)-N²-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-6, 7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2,4-diamidogen

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 (90 milligrams, 0.187mmol), 3,4-difluoroanilines (29 milligrams, 0.225mmol), Pd₂(dba)₃(34 milligrams, 0.037mmol), (±)-BINAP (23 milligrams, 0.037mmol) and the toluene solution of cesium carbonate (122 milligrams, 0.374mmol) Being heated to 130 degree in tube sealing and stir 12 hours, separated purification obtains product N⁴-(3,4-difluorophenyl)-N²-(2-methoxy Base-4-morpholine phenyl)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2,4-diamidogen (yellow Solid, 46 milligrams, productivity 43%).¹H NMR (400MHz, CDCl₃) δ ppm 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:N⁴-(3,4-difluorophenyl)-N²-(2-methoxyl group-4-morpholine phenyl)-6,7-dihydro-5H-pyrrolo- [2,3-d] pyrimidine-2,4-diamidogen

According to universal synthesis method II, toward N⁴-(3,4-difluorophenyl)-N²-(2-methoxyl group-4-morpholine phenyl)-7- (4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2, the trifluoro of 4-diamidogen (46 milligrams, 0.080mmol) Acetic acid solution (5 milliliters) and three stirs some hours at normal temperatures, post-treated and isolated and purified obtain target product N⁴-(3,4-difluorophenyl)-N²-(2-methoxyl group-4-morpholine phenyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2, 4-diamidogen (white solid, 2.9 milligrams, productivity 8%).¹H NMR (400MHz, DMSO-d6) δ ppm 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-amine Base)-N-methyl-benzamide

Step A:N-(2-((t-butyldimethyl silane epoxide) methyl)-4-morpholine phenyl)-4-chloro-7-(4-methoxy Base benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine

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-((t-butyldimethyl silane epoxide) methyl)-4-morpholine aniline (in Mesosome B2,1.14g, 3.5mmol), Pd₂(dba)₃(146 milligrams, 0.16mmol), (±)-BINAP (200 milligrams, 0.32mmol) Under microwave, it is heated to 110 degree with the toluene solution of cesium carbonate (2.08g, 6.2mmol) and stirs 6 hours, separated purification Obtain product N-(2-((t-butyldimethyl silane epoxide) methyl)-4-morpholine phenyl)-4-chloro-7-(4-methoxybenzyl Base)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine (0.5g, productivity 26.3%).

Step B:2-(2-(2-((t-butyldimethyl silane epoxide) methyl)-4-morpholine phenyl amido)-7-(4-first Oxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide

According to universal synthesis method II, by N-(2-((t-butyldimethyl silane epoxide) methyl)-4-morpholine phenyl)- The chloro-7-of 4-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine (500 milligrams, 0.84mmol), 2- Amino-N-methyl Benzoylamide (intermediate C1,151 milligrams, 1mmol), Pd₂(dba)₃(192 milligrams, 0.21mmol), X-Phos The toluene solution of (200 milligrams, 0.42mmol) and cesium carbonate (546 milligrams, 1.7mmol) is heated to 140 degree under microwave and stirs Mixing 4 hours, separated purification obtains product 2-(2-(2-((t-butyldimethyl silane epoxide) methyl)-4-morpholine phenyl Amido)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide (417 milligrams, productivity 68.8%).¹H NMR (400MHz, DMSO-d6) δ ppm 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).

(2-(2-(methylol)-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] is phonetic for step C:2- Pyridine-4-amido)-N-methyl-benzamide

According to universal synthesis method II, toward 2-(2-(2-((t-butyldimethyl silane epoxide) methyl)-4-morpholine benzene Base amido)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide The trifluoroacetic acid solution (2 milliliters) of (200 milligrams, 0.282mmol) adds 4 concentrated sulphuric acids, stirs at normal temperatures some hours, Post-treated and isolated and purified obtain target product 2-(2-(2-(methylol)-4-morpholine phenyl amido)-6,7-dihydro-5H- Pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide (30 milligrams, productivity 22.4%).¹H NMR (400MHz, DMSO-d6) δ ppm 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-dihydrobenzos [b] [Isosorbide-5-Nitrae] two-5-amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine- 4-amido)-N-methyl-benzamide

The chloro-N-of step A:4-(2,3-dihydrobenzos [b] [Isosorbide-5-Nitrae] two-5-base)-7-(4-methoxy-benzyl)-6,7-bis- Hydrogen-5H-pyrrolo-[2,3-d] pyrimidine-2-amine

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] and pyrimidine (intermediate A 1,310 milligrams, 1.0mmol), 2,3-dihydrobenzos [b] [Isosorbide-5-Nitrae] two-5-amine (intermediate B 3,151 Milligram, 1.0mmol), Pd₂(dba)₃(183 milligrams, 0.2mmol), (±)-BINAP (124 milligrams, 0.2mmol) and sodium tert-butoxide The toluene solution of (192 milligrams, 2.0mmol) is heated to 100 degree under microwave and stirs 10 minutes, and separated purification obtains product The chloro-N-of 4-(2,3-dihydrobenzos [b] [Isosorbide-5-Nitrae] two-5-base)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-2-amine (yellow solid, 100 milligrams, productivity 24%).¹H NMR (400MHz, CDCl₃)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-dihydrobenzos [b] [Isosorbide-5-Nitrae] two-5-amido)-7-(4-methoxy-benzyl)-6,7-bis- Hydrogen-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide

According to universal synthesis method II, by chloro-for 4-N-(2,3-dihydrobenzos [b] [Isosorbide-5-Nitrae] two-5-base)-7-(4-methoxy Base benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine (100 milligrams, 0.236mmol), 2-Amino-N-methyl benzene Methanamide (intermediate C1,42 milligrams, 0.280mmol), Pd₂(dba)₃(43 milligrams, 0.047mmol), X-Phos (22 milligrams, 0.046mmol) toluene solution with cesium carbonate (154 milligrams, 0.472mmol) is heated to 130 degree in tube sealing and stirs 12 Hour, separated purification obtains product 2-(2-(2,3-dihydrobenzos [b] [Isosorbide-5-Nitrae] two-5-amido)-7-(4-methoxybenzyl Base)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide (yellow solid, 50 milligrams, productivity 39%).¹H NMR (400MHz, CDCl₃) δ ppm 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-dihydrobenzos [b] [Isosorbide-5-Nitrae] two-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-dihydrobenzos [b] [Isosorbide-5-Nitrae] two-5-amido)-7-(4-methoxy Base benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide (60 milligrams, Trifluoroacetic acid solution (6 milliliters) 0.115mmol) adds 4 concentrated sulphuric acids, stirs at normal temperatures some hours, post-treated Target product 2-(2-(2,3-dihydrobenzos [b] [Isosorbide-5-Nitrae] two-5-amido)-6,7-dihydro-5H-pyrroles is obtained with isolated and purified And [2,3-d] pyrimidine-4-amido)-N-methyl-benzamide (27 milligrams, productivity 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), the (-CH on benzo [b] [Isosorbide-5-Nitrae] bicyclo-₂CH₂-) signal covered by the remaining peak of deuterated solvent.

Embodiment 16

N-methyl-2-(2-(8-morpholine-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] two-5-amido)-6,7-dihydro-5H-pyrrole Cough up also [2,3-d] pyrimidine-4-amido) Benzoylamide

The chloro-7-of step A:4-(4-methoxy-benzyl)-N-(8-morpholine-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] two-5- Base)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine

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 1,200 milligrams, 0.645mmol), 8-morpholine-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] two-5-amine (intermediate B 4,152 milligrams, 0.644mmol), Pd₂(dba)₃(118 milligrams, 0.129mmol), (±)-BINAP (80 milligrams, 0.129mmol) and sodium tert-butoxide (124 milligrams, 1.292mmol) toluene solution under microwave, be heated to 100 degree and stir 10 minutes, separated purification obtain the chloro-7-of product 4-(4-methoxy-benzyl)-N-(8-morpholine-2,3-dihydrobenzo [b] [1, 4] two-5-base)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine (yellow solid, 200 milligrams, productivity 61%).¹H NMR (400MHz, CDCl₃) δ ppm 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] two-5-amine Base)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide

According to universal synthesis method II, by chloro-for 4-7-(4-methoxy-benzyl)-N-(8-morpholine-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] two-5-base)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine (200 milligrams, 0.39mmol), 2-ammonia Base-N-methyl-benzamide (intermediate C1,71 milligrams, 0.47mmol), Pd₂(dba)₃(72 milligrams, 0.079mmol), X-Phos (37 milligrams, 0.078mmol) and cesium carbonate (274 milligrams, 0.840mmol) toluene solution under microwave, be heated to 130 degree And stir 2 hours, separated purification obtains product 2-(7-(4-methoxy-benzyl)-2-(8-morpholine-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] two-5-amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) (white is solid for-N-methyl-benzamide Body, 75 milligrams, productivity 31%).¹H NMR (400MHz, CDCl₃) δ ppm 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-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] two-5-amido)-6,7-bis- Hydrogen-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) Benzoylamide

According to universal synthesis method II, by 2-(7-(4-methoxy-benzyl)-2-(8-morpholine-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] two-5-amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide (75 millis Gram, 0.120mmol) trifluoroacetic acid solution (6 milliliters) in add 5 concentrated sulphuric acids, stir at normal temperatures some hours, through after place Reason obtains target product N-methyl-2-(2-(8-morpholine-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] two-5-amine with isolated and purified Base)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) Benzoylamide (60 milligrams, productivity 99%).¹H NMR (400MHz, DMSO-d6) δ ppm 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-amidos)-6, 7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide

Step 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

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 1,310 milligrams, 1.0mmol), 7-amido-1-ethyl-6-methoxyl group-4,5-dihydro-1H-benzo [b] Azatropylidene-2 (3H)-one hydrochlorate (intermediate B 5,271 milligrams, 1.0mmol), Pd₂(dba)₃(183 milligrams, 0.2mmol), The toluene solution of (±)-BINAP (124 milligrams, 0.2mmol) and cesium carbonate (1.304g, 4.0mmol) is heated under microwave 130 degree and stir 2 hours, separated purification obtains product 7-(the chloro-7-of 4-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrroles And [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, productivity 20%).¹H NMR (400MHz, CDCl₃) 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), the (-CH on benzo [b] azatropylidene ring₂CH₂CH₂-) signal is by solvent Remaining peak covers.

Step B:2-(2-(1-ethyl-6-methoxyl group-2-oxo-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-7-amine Base)-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 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 (100 milligrams, 0.197mmol), and 2-Amino-N-methyl Benzoylamide (intermediate C1,35 milligrams, 0.233mmol), Pd₂(dba)₃(36 milligrams, 0.039mmol), (±)-BINAP (24 milligrams, 0.039mmol) and cesium carbonate (128 milligrams, 0.393mmol) toluene molten Liquid is heated to 130 degree in tube sealing and stirs 12 hours, and separated purification obtains product 2-(2-(1-ethyl-6-methoxyl group-2- Oxo-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-7-amidos)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrroles And [2,3-d] pyrimidine-4-amido)-N-methyl-benzamide (white solid, 30 milligrams, productivity 25%).¹H NMR (400MHz, CDCl₃) δ ppm 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-amine Base)-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-benzene And [b] azatropylidene-7-amido)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N- The trifluoroacetic acid solution (6 milliliters) of methyl benzamide (30 milligrams, 0.048mmol) adds 3 concentrated sulphuric acids, stirs at normal temperatures Mix some hours, post-treated and isolated and purified obtain target product 2-(2-(and 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 Benzoylamide (4.7 milligrams, productivity 20%).¹H NMR (400MHz, CD₃OD) δ ppm 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-amine Base) Benzoylamide

Step A:5-(the chloro-7-of 4-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amido) Iso-indoles-1-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 (intermediate A 1,310 milligrams, 1.0mmol), 5-amido iso-indoles-1-ketone (intermediate B 6,148 milligrams, 1.0mmol), Pd₂(dba)₃(183 milligrams, 0.2mmol), (±)-BINAP (124 milligrams, 0.2mmol) and cesium carbonate (654 millis Gram, 2.01mmol) toluene solution under microwave, be heated to 130 degree and stir 3 hours, separated purification obtains product 5-(4- Chloro-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amido) (yellow is solid for iso-indoles-1-ketone Body, 80 milligrams, productivity 19%).¹H NMR (400MHz, CDCl₃) δ ppm 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) isoindolin-1-one (80 milligrams, 0.190mmol), 2-Amino-N-methyl Benzoylamide (intermediate C1,34 milligrams, 0.227mmol), Pd₂(dba)₃(35 milligrams, 0.038mmol), X-Phos (18 milligrams, 0.038mmol) and carbon The toluene solution of acid caesium (124 milligrams, 0.380mmol) is heated to 130 degree in tube sealing and stirs 12 hours, and separated purification obtains To product 2-, (7-(4-methoxy-benzyl)-2-(1-oxo isoindole-5-amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] is phonetic Pyridine-4-amido)-N-methyl-benzamide (yellow solid, 10 milligrams, productivity 10%).

(2-(1-oxo isoindole-5-amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] is phonetic for step C:N-methyl-2- Pyridine-4-amido) Benzoylamide

According to universal synthesis method II, past 2-(7-(4-methoxy-benzyl)-2-(1-oxo isoindole-5-ylamino)- 6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amidos) trifluoro of-N-methyl-benzamide (10 milligrams, 0.019mmol) Acetic acid solution (3 milliliters) adds 2 concentrated sulphuric acids, stirs at normal temperatures some hours, post-treated and isolated and purified obtain mesh Mark product N-methyl-2-(2-(1-oxo isoindole-5-amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) Benzoylamide (white solid, 1.9 milligrams, productivity 26%).¹H NMR (400MHz, CD₃OD) δ ppm 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-(benzofuran-7-amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methylbenzene Methanamide

Step A:N-(benzofuran-7-base) the chloro-7-of-4-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3- D] pyrimidine-2-amine

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 1,310 milligrams, 1.0mmol), benzofuran-7-amine hydrochlorate (intermediate B 7,169.6 milligrams, 1.0mmol), Pd₂(dba)₃(183 milligrams, 0.2mmol), (±)-BINAP (124 milligrams, 0.2mmol) and cesium carbonate The toluene solution of (1.304g, 4.0mmol) is heated to 130 degree in tube sealing and stirs 12 hours, and separated purification obtains product N-(benzofuran-7-base) the chloro-7-of-4-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine (200 milligrams, productivity 49%).¹H NMR (400MHz, CDCl₃) δ ppm 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-(benzofuran-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-(benzofuran-7-base) the chloro-7-of-4-(4-methoxy-benzyl)-6,7-bis- Hydrogen-5H-pyrrolo-[2,3-d] pyrimidine-2-amine (100 milligrams, 0.25mmol), 2-Amino-N-methyl Benzoylamide (intermediate C1,44 milligrams, 0.293mmol), Pd₂(dba)₃(10 milligrams, 0.011mmol), (±)-BINAP (15 milligrams, 0.049mmol) In tube sealing, it is heated to 130 degree with the toluene solution of potassium tert-butoxide (47 milligrams, 0.489mmol) and stirs 12 hours, separated Purification obtains product 2-(2-(benzofuran-7-amido)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] Pyrimidine-4-amido)-N-methyl-benzamide (60 milligrams, productivity 47%).

Step C:2-(2-(benzofuran-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-(benzofuran-7-amido)-7-(4-methoxy-benzyl)-6,7-bis- Hydrogen-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) trifluoroacetic acid of-N-methyl-benzamide (60 milligrams, 0.115mmol) is molten Liquid (8 milliliters) adds 4 concentrated sulphuric acids, stirs at normal temperatures some hours, post-treated and isolated and purified obtain target product 2-(2-(benzofuran-7-amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide (10 milligrams, productivity 22%).¹H NMR (400MHz, DMSO-d6) δ ppm 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-(2-(1,3-di methyl isophthalic acid H-pyrazoles-5-amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amine Base)-N-methyl-benzamide

The chloro-N-of step 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 2, the chloro-7-of 4-bis-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine (intermediate A 1,130 milligrams, 0.421mmol), 1,3-dimethyl-1H-pyrazoles-5-amine (intermediate B 8,56 milligrams, 0.505mmol), Pd₂(dba)₃(20 milligrams, 0.022mmol), (±)-BINAP (26 milligrams, 0.042mmol) and cesium carbonate The toluene solution of (206 milligrams, 0.632mmol) is heated to 130 degree under microwave and stirs 2.5 hours, and separated purification obtains The chloro-N-of product 4-(1,3-dimethyl-1H-pyrazoles-5-yl)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo-[2,3- D] pyrimidine-2-amine (20 milligrams, productivity 9.8%).¹H NMR (400MHz, DMSO-d6) δ ppm9.16 (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

According to universal synthesis method II, by chloro-for 4-N-(1,3-dimethyl-1H-pyrazoles-5-base)-7-(4-methoxybenzyl Base)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine (75 milligrams, 0.155mmol), 2-Amino-N-methyl benzoyl Amine (intermediate C1,28 milligrams, 0.185mmol), Pd₂(dba)₃(28 milligrams, 0.031mmol), (±)-BINAP (19 milligrams, 0.031mmol) toluene solution with cesium carbonate (76 milligrams, 0.233mmol) is heated to 130 degree under microwave and stirs, through dividing Product 2-(2-(1,3-dimethyl-1H-pyrazoles-5-amino)-7-(4-methoxy-benzyl)-6,7-dihydro-5H-is obtained from purification Pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide (50 milligrams, productivity 65%).¹H NMR (400MHz, CDCl₃) δ ppm 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-methoxyl group Benzyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide (50 milligrams, 0.1mmol) Trifluoroacetic acid solution (5 milliliters) adds 3 concentrated sulphuric acids, stirs at normal temperatures some hours, post-treated and isolated and purified To target product 2-(2-(1,3-dimethyl-1H-pyrazoles-5-amino)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amine Base)-N-methyl-benzamide (3.8 milligrams, productivity 10%).¹H NMR (400MHz, DMSO-d6) δ ppm 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 methoxyphenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine- 4-amido) Benzoylamide

The chloro-7-of step A:4-(4-methoxy-benzyl)-N-(3,4,5-trimethoxyphenyl)-6,7-dihydro-5H-pyrrolo- [2,3-d] pyrimidine-2-amine

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 1,200 milligrams, 0.645mmol), 3,4,5-trimethoxy-anilines (intermediate B 9,118 milligrams, 0.645mmol), Pd₂(dba)₃(118 milligrams, 0.129mmol), (±)-BINAP (80 milligrams, 0.129mmol) and cesium carbonate The toluene solution of (421 milligrams, 1.291mmol) is heated to 130 degree under microwave and stirs 2 hours, and separated purification is produced The chloro-7-of product 4-(4-methoxy-benzyl)-N-(3,4,5-trimethoxyphenyl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine- 2-amine (white solid, 100 milligrams, productivity 68%).¹H NMR (400MHz, CDCl₃) δ ppm 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-pyrroles And [2,3-d] pyrimidine-4-amido)-N-methyl-benzamide

According to universal synthesis method II, by chloro-for 4-7-(4-methoxy-benzyl)-N-(3,4,5-trimethoxyphenyl)-6, 7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine (100 milligrams, 0.219mmol), 2-Amino-N-methyl Benzoylamide (in Mesosome C1,39 milligrams, 0.26mmol), Pd₂(dba)₃(40 milligrams, 0.044mmol), (±)-BINAP (27 milligrams, 0.043mmol) and the toluene solution of cesium carbonate (143 milligrams, 0.439mmol) is heated to 130 degree in tube sealing and to stir 12 little Time, separated purification obtain product 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 (yellow solid, 30 milligrams, productivity 24%).¹H NMR (400MHz, CDCl₃) δ ppm 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) Benzoylamide

According to universal synthesis method II, past 2-(7-(4-methoxy-benzyl)-2-(3,4,5-trimethoxyphenyl amido)- 6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amidos) trifluoro of-N-methyl-benzamide (30 milligrams, 0.053mmol) Acetic acid solution (6 milliliters) adds 3 concentrated sulphuric acids, stirs at normal temperatures some hours, post-treated and isolated and purified obtain mesh Mark product N-methyl-2-(2-(3,4,5-trimethoxyphenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amine Base) Benzoylamide (5.8 milligrams, productivity 24%).¹H NMR (400MHz, DMSO-d6) δ ppm 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-indole-4-amido)-6,7-dihydro-5H-pyrrolo-[2,3- D] pyrimidine-4-amido) Benzoylamide

The chloro-7-of step A:4-(4-methoxy-benzyl)-N-(1-(3-morpholine propyl group)-1H-indole-4-base)-6,7-bis- Hydrogen-5H-pyrrolo-[2,3-d] pyrimidine-2-amine

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-indole-4-amine (intermediate B 10, 259 milligrams, 1.0mmol), Pd₂(dba)₃(183 milligrams, 0.2mmol), (±)-BINAP (124 milligrams, 0.2mmol) and carbonic acid The toluene solution of caesium (652 milligrams, 2.0mmol) is heated to 140 degree under microwave and stirs 3 hours, and separated purification is produced The chloro-7-of product 4-(4-methoxy-benzyl)-N-(1-(3-morpholine propyl group)-1H-indole-4-base)-6,7-dihydro-5H-pyrrolo- [2,3-d] pyrimidine-2-amine (135 milligrams, productivity 25.4%).

Step B:2-(7-(4-methoxy-benzyl)-2-(1-(3-morpholine propyl group)-1H-indole-4-amido)-6,7-bis- Hydrogen-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide

According to universal synthesis method II, by chloro-for 4-7-(4-methoxy-benzyl)-N-(1-(3-morpholine propyl group)-1H- Indol-4-yl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine (135 milligrams, 0.254mmol), 2-amino-N-first Yl-benzamide (intermediate C1,38 milligrams, 0.253mmol), Pd₂(dba)₃(46 milligrams, 0.050mmol), X-Phos (24 millis Gram, 0.050mmol) and the toluene solution of cesium carbonate (124 milligrams, 0.380mmol) under microwave, be heated to 140 degree and stir 3.5 hours, separated purification obtained product 2-(7-(4-methoxy-benzyl)-2-(1-(3-morpholine propyl group)-1H-indole-4- Amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide (100 milligrams, productivity 61%) 。¹H NMR (400MHz, CDCl₃) δ ppm 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-indole-4-amido)-6,7-dihydro-5H-pyrrolo-[2,3- D] pyrimidine-4-amido) Benzoylamide

According to universal synthesis method II, past 2-(7-(4-methoxy-benzyl)-2-(1-(3-morpholine propyl group)-1H-indole- 4-amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide (100 milligrams, Trifluoroacetic acid solution (5 milliliters) 0.155mmol) adds 4 concentrated sulphuric acids, stirs at normal temperatures some hours, post-treated With isolated and purified obtain target product N-methyl-2-(2-(1-(3-morpholine propyl group)-1H-indole-4-amido)-6,7-dihydro- 5H-pyrrolo-[2,3-d] pyrimidine-4-amido) Benzoylamide (10 milligrams, productivity 12%).¹H NMR (400MHz, CDCl₃)δ Ppm10.18 (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

Step A:(±) 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-2-amine

According to universal synthesis method II, will (±)-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 (intermediate B1,146 milligrams, 0.702mmol), Pd₂(dba)₃(27 milligrams, 0.03mmol), (±)-BINAP (36 milligrams, 0.058mmol) With toluene solution heated and stirred in tube sealing of cesium carbonate (287 milligrams, 0.88mmol), separated purification obtain product (±)- 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-2-amine (yellow solid, 100 milligrams, productivity 35%).¹H NMR (400MHz, CDCl₃) δ ppm 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-amidos)-N-methyl-benzamide

According to universal synthesis method II, will (±) the chloro-N-of-4-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxyl group Benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine (65 milligrams, 0.131mmol), 2-amino-N-first Yl-benzamide (intermediate C1,24 milligrams, 0.16mmol), Pd₂(dba)₃(6 milligrams, 0.007mmol), (±)-BINAP (9 millis Gram, 0.014mmol) and toluene solution heated and stirred in tube sealing of cesium carbonate (64 milligrams, 0.196mmol), separated purification Obtain product (±)-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-methyl-6,7-bis- Hydrogen-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide (yellow solid, 55 milligrams, productivity 45%).¹H NMR (400MHz, CDCl₃) δ ppm 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 Base benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide (55 milligrams, Trifluoroacetic acid solution (4 milliliters) 0.09mmol) adds 4 concentrated sulphuric acids, stirs at normal temperatures some hours, post-treated and Isolated and purified obtain target product (±)-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 (yellow solid, 5 milligrams, productivity 11%).¹H NMR (400MHz, DMSO-d6) δ ppm 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 use Chiralcel AD-H (4.6 × 150 millimeters, Daicel company) post Son splits, and flowing is the ethanol solution/normal hexane (1/1) of the diethylamine of 0.025% mutually.The retention time of two enantiomers It 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-pyrrolo-[2,3- D] pyrimidine-4-amido) phenyl) (pyrrolidin-1-yl) methyl ketone

Step 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-amidos) phenyl) (pyrrolidin-1-yl) methyl ketone

According to universal synthesis method II, will (±) the chloro-N-of-4-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxyl group Benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine (70 milligrams, 0.141mmol), (2-amido benzene Base) and (pyrrolidin-1-yl) methyl ketone hydrochlorate (intermediate C3,39 milligrams, 0.172mmol), Pd₂(dba)₃(13 milligrams, 0.014mmol), (±) toluene solution of-BINAP (18 milligrams, 0.029mmol) and cesium carbonate (92 milligrams, 0.282mmol) exists Be heated to 130 degree in tube sealing and stir 12 hours, separated purification obtain product (±)-(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 (90 milligrams, productivity 98%).¹H NMR (400MHz, CDCl₃) δ ppm 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-pyrroles And [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 Base benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) phenyl) (pyrrolidin-1-yl) methyl ketone The trifluoroacetic acid solution (8 milliliters) of (90 milligrams, 0.138mmol) adds 4 concentrated sulphuric acids, stirs at normal temperatures some hours, Post-treated and isolated and purified obtain target product (±)-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl- 6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amidos) phenyl) (pyrrolidin-1-yl) methyl ketone (yellow solid, 44.4 millis Gram, productivity 60%).¹H NMR (400MHz, DMSO-d6) δ ppm 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

Step 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-amidos)-N-methyl benzenesulfonamide

According to universal synthesis method II, will (±) the chloro-N-of-4-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxyl group Benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine (80 milligrams, 0.161mmol), 2-amino-N-first Base benzsulfamide (intermediate C4,36 milligrams, 0.194mmol), Pd₂(dba)₃(15 milligrams, 0.016mmol), (±)-BINAP The toluene solution of (20 milligrams, 0.032mmol) and cesium carbonate (105 milligrams, 0.322mmol) is heated to 130 degree also in tube sealing Stir 12 hours, separated purification obtain product (±)-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy Base benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl benzenesulfonamide (95 milligrams, produce Rate 91%).¹H NMR (400MHz, CDCl₃) δ ppm 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 Base benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl benzenesulfonamide (95 milligrams, Trifluoroacetic acid solution (8 milliliters) 0.147mmol) adds 4 concentrated sulphuric acids, stirs at normal temperatures some hours, post-treated With isolated and purified obtain target product (±)-2-(and 2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6,7-dihydro- 5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl benzenesulfonamide (54 milligrams, productivity 70%).¹H NMR (400MHz, DMSO-d6) δ ppm 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-propylbenzenesulfonamide

Step 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-amidos)-N-propylbenzenesulfonamide

According to universal synthesis method II, will (±) the chloro-N-of-4-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxyl group Benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine (70 milligrams, 0.141mmol), 2-amino-N-third Base benzenesulfonamide, hydrochloride (intermediate C5,43 milligrams, 0.171mmol), Pd₂(dba)₃(13 milligrams, 0.014mmol), (±)- The toluene solution of BINAP (18 milligrams, 0.029mmol) and cesium carbonate (138 milligrams, 0.423mmol) is heated to 130 in tube sealing Spend and stir 12 hours, separated purification obtain product (±)-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-propylbenzenesulfonamide (60 millis Gram, productivity 63%).¹H NMR (400MHz, CDCl₃) δ ppm 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-propylbenzenesulfonamide

According to universal synthesis method II, toward (±)-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy Base benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-propylbenzenesulfonamide (60 milligrams, Trifluoroacetic acid solution (5 milliliters) 0.089mmol) adds 4 concentrated sulphuric acids, stirs at normal temperatures some hours, post-treated With isolated and purified obtain target product (±)-2-(and 2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6,7-dihydro- 5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-propylbenzenesulfonamide (24.5 milligrams, productivity 49.7%).¹H NMR (400MHz, DMSO-d6) δ ppm 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-pyrrole Cough up also [2,3-d] pyrimidine-4-amido) benzsulfamide

Step A:(±)-N-cyclobutyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxybenzyl Base)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide

According to universal synthesis method II, will (±) the chloro-N-of-4-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxyl group Benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine (50 milligrams, 0.101mmol), 2-amino-N-ring Butyl benzene sulfonamide (intermediate C6,28 milligrams, 0.124mmol), Pd₂(dba)₃(10 milligrams, 0.011mmol), (±)-BINAP The toluene solution of (13 milligrams, 0.021mmol) and cesium carbonate (66 milligrams, 0.202mmol) is heated to 130 degree in tube sealing and stirs Mix 12 hours, separated purification obtain product (±)-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 (55 milligrams, produce Rate 79.4%).¹H NMR (400MHz, CDCl₃) δ ppm 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 amine Base)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide (55 Milligram, 0.08mmol) trifluoroacetic acid solution (5 milliliters) in add 4 concentrated sulphuric acids, stir at normal temperatures some hours, through after Process and isolated and purified obtain target product (±)-N-cyclobutyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-first Base-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide (yellow solid, 41.1 milligrams, productivity 90.8%).¹H NMR (400MHz, DMSO-d6) δ ppm 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-cyclopenta-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) benzsulfamide

Step A:(±)-N-cyclopenta-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxybenzyl Base)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide

According to universal synthesis method II, will (±) the chloro-N-of-4-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxyl group Benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine (50 milligrams, 0.101mmol), 2-amino-N-ring Amylbenzene sulfonamide (intermediate C7,29 milligrams, 0.121mmol), Pd₂(dba)₃(10 milligrams, 0.011mmol), (±)-BINAP The toluene solution of (13 milligrams, 0.021mmol) and cesium carbonate (66 milligrams, 0.202mmol) is heated to 130 degree in tube sealing and stirs Mix 12 hours, separated purification obtain product (±)-N-cyclopenta-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 (55 milligrams, produce Rate 77.9%).¹H NMR (400MHz, CDCl₃) δ ppm 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-cyclopenta-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 amine Base)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide (55 Milligram, 0.079mmol) trifluoroacetic acid solution (5 milliliters) in add 4 concentrated sulphuric acids, stir at normal temperatures some hours, through after Process and isolated and purified obtain target product (±)-N-cyclopenta-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-first Base-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide (47 milligrams, productivity 100%).¹H NMR (400MHz, DMSO-d6) δ ppm 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-pyrrole Cough up also [2,3-d] pyrimidine-4-amido) benzsulfamide

Step A:(±)-N-cyclohexyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxybenzyl Base)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide

According to universal synthesis method II, will (±) the chloro-N-of-4-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxyl group Benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine (50 milligrams, 0.101mmol), 2-amino-N-ring Hexyl benzene sulfonamide (intermediate C8,31 milligrams, 0.121mmol), Pd₂(dba)₃(10 milligrams, 0.011mmol), (±)-BINAP The toluene solution of (13 milligrams, 0.021mmol) and cesium carbonate (66 milligrams, 0.202mmol) is heated to 130 degree in tube sealing and stirs Mix 12 hours, separated purification obtain product (±)-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 (55 milligrams, produce Rate 97.4%).¹H NMR (400MHz, CDCl₃) δ ppm 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 amine Base)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide (70 Milligram, 0.098mmol) trifluoroacetic acid solution (5 milliliters) in add 4 concentrated sulphuric acids, stir at normal temperatures some hours, through after Process and isolated and purified obtain target product (±)-N-cyclohexyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-first Base-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide (38.3 milligrams, productivity 65.4%).¹H NMR (400MHz, DMSO-d6) δ ppm 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-pyrrolo-[2, 3-d] pyrimidine-4-amido) phenyl) acetamide

Step A:(±)-N-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-first Base-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) phenyl) acetamide

According to universal synthesis method II, will (±) the chloro-N-of-4-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxyl group Benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine (70 milligrams, 0.141mmol), N-(2-amido benzene Base) and acetamide (intermediate C9,26 milligrams, 0.173mmol), Pd₂(dba)₃(15 milligrams, 0.016mmol), (±)-BINAP (20 Milligram, 0.032mmol) and the toluene solution of cesium carbonate (105 milligrams, 0.322mmol) in tube sealing, be heated to 130 degree and stir 12 hours, separated purification obtain product (±)-N-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxyl group Benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) phenyl) acetamide (yellow solid, 80 millis Gram, productivity 93%).¹H NMR (400MHz, CDCl₃) δ ppm 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-pyrrole Cough up also [2,3-d] pyrimidine-4-amido) phenyl) acetamide

According to universal synthesis method II, toward (±)-N-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-first Oxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) phenyl) acetamide (80 milligrams, Trifluoroacetic acid solution (8 milliliters) 0.131mmol) adds 3 concentrated sulphuric acids, stirs at normal temperatures some hours, post-treated With isolated and purified obtain target product (±)-N-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6,7-bis- Hydrogen-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) phenyl) acetamide (yellow solid, 45 milligrams, productivity 70%).¹H NMR (400MHz, DMSO-d6) δ ppm 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-pyrrolo-[2, 3-d] pyrimidine-4-amido) phenyl)-N-methylmethanesulfonamide

Step A:(±)-N-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-first Base-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) phenyl)-N-methylmethanesulfonamide

According to universal synthesis method II, will (±) the chloro-N-of-4-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxyl group Benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine (80 milligrams, 0.161mmol), N-(2-amido benzene Base) and-N-methylmethanesulfonamide (intermediate C10,39 milligrams, 0.195mmol), Pd₂(dba)₃(15 milligrams, 0.016mmol), The toluene solution of (±)-BINAP (20 milligrams, 0.032mmol) and cesium carbonate (105 milligrams, 0.322mmol) heats in tube sealing To 130 degree and stir 12 hours, separated purification obtain product (±)-N-(2-(2-(2-methoxyl group-4-morpholine phenyl amine Base)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) phenyl)-N-methyl Methanesulfomide (80 milligrams, productivity 75%).¹H NMR (400MHz, CDCl₃) δ ppm8.38-8.40 (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-pyrrole Cough up also [2,3-d] pyrimidine-4-amido) phenyl)-N-methylmethanesulfonamide

According to universal synthesis method II, toward (±)-N-(2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-first Oxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) phenyl)-N-methylmethanesulfonamide (80 Milligram, 0.121mmol) trifluoroacetic acid solution (8 milliliters) in add 3 concentrated sulphuric acids, stir at normal temperatures some hours, through after Process and isolated and purified obtain target product (±)-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-methylmethanesulfonamide (28.4 milligrams, productivity 43%).¹H NMR (400MHz, DMSO-d6) δ ppm 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-methylmethanesulfonamide

Step A:(±)-N-(2-((2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-methoxy-benzyl)-5-first Base-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) methyl) phenyl)-N-methylmethanesulfonamide

According to universal synthesis method II, will (±) the chloro-N-of-4-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxyl group Benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine (60 milligrams, 0.121mmol), N-(2-(amino Methyl) phenyl)-N-methylmethanesulfonamide hydrochlorate (intermediate C11,37 milligrams, 0.147mmol), Pd₂(dba)₃(13 milligrams, 0.014mmol), (±)-BINAP (15 milligrams, 0.024mmol) and the toluene solution of cesium carbonate (118 milligrams, 0.362mmol) In tube sealing, be heated to 130 degree and stir 24 hours, separated purification obtain product (±)-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-methylmethanesulfonamide (50 milligrams, productivity 60.8%).¹H NMR (400MHz, CDCl₃)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-pyrrole Cough up also [2,3-d] pyrimidine-4-amido) methyl) phenyl)-N-methylmethanesulfonamide

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)-N-methyl first sulphur The trifluoroacetic acid solution (4 milliliters) of amide (50 milligrams, 0.074mmol) adds 1 concentrated sulphuric acid, stirs some little at normal temperatures Time, post-treated and isolated and purified obtain target product (±)-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-methylmethanesulfonamide (18.3 milligrams, Productivity 44.5%).¹H NMR (400MHz, DMSO-d6) δ ppm 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-base)-6,7-dihydro- 5H-pyrrolo-[2,3-d] pyrimidine-2,4-diamidogen

Step A:(±)-N²-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-5-methyl-N⁴-(6-first Yl pyridines-2-base)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2,4-diamidogen

According to universal synthesis method II, will (±) the chloro-N-of-4-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxyl group Benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine (70 milligrams, 0.141mmol), 6-picoline- 2-amine (19 milligrams, 0.176mmol), Pd₂(dba)₃(13 milligrams, 0.014mmol), (±)-BINAP (18 milligrams, 0.029mmol) and the toluene solution of cesium carbonate (92 milligrams, 0.282mmol) is heated to 130 degree in tube sealing and to stir 12 little Time, separated purification obtain product (±)-N²-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-5-methyl- N⁴-(6-picoline-2-base)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2,4-diamidogen (70 milligrams, productivity 87%).¹H NMR (400MHz, CDCl₃) δ ppm 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:(±)-N²-(2-methoxyl group-4-morpholine phenyl)-5-methyl-N⁴-(6-picoline-2-base)-6,7- Dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2,4-diamidogen

According to universal synthesis method II, toward (±)-N²-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxybenzyl Base)-5-methyl-N⁴-(6-picoline-2-base)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2,4-diamidogen (70 millis Gram, 0.123mmol) trifluoroacetic acid solution (5 milliliters) in add 4 concentrated sulphuric acids, stir at normal temperatures some hours, through after place Reason and isolated and purified obtain target product (±)-N²-(2-methoxyl group-4-morpholine phenyl)-5-methyl-N⁴-(6-picoline- 2-yl)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2,4-diamidogen (43.2 milligrams, productivity 78.5%).¹H NMR (400MHz, DMSO-d6) δ ppm 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-2,4-diamidogen

Step A:(±)-N⁴-(3,4-difluorophenyl)-N²-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxybenzyl Base)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2,4-diamidogen

According to universal synthesis method II, will (±) the chloro-N-of-4-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxyl group Benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine (90 milligrams, 0.181mmol), 3,4-difluorobenzenes Amine (28 milligrams, 0.217mmol), Pd₂(dba)₃(17 milligrams, 0.019mmol), (±)-BINAP (23 milligrams, 0.037mmol) In tube sealing, it is heated to 130 degree with the toluene solution of cesium carbonate (120 milligrams, 0.368mmol) and stirs 12 hours, separated pure Change obtain product (±)-N⁴-(3,4-difluorophenyl)-N²-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)- 5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2,4-diamidogen (70 milligrams, productivity 66%).¹H NMR (400MHz, CDCl₃) δ ppm 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:(±)-N⁴-(3,4-difluorophenyl)-N²-(2-methoxyl group-4-morpholine phenyl)-5-methyl-6,7-bis- Hydrogen-5H-pyrrolo-[2,3-d] pyrimidine-2,4-diamidogen

According to universal synthesis method II, toward (±)-N⁴-(3,4-difluorophenyl)-N²-(2-methoxyl group-4-morpholine benzene Base)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2,4-diamidogen (70 milligrams, Trifluoroacetic acid solution (5 milliliters) 0.119mmol) adds 4 concentrated sulphuric acids, stirs at normal temperatures some hours, post-treated With isolated and purified obtain target product (±)-N⁴-(3,4-difluorophenyl)-N²-(2-methoxyl group-4-morpholine phenyl)-5-first Base-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2,4-diamidogen (51.7 milligrams, productivity 93%).¹H NMR (400MHz, DMSO-d6) δ ppm 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-pyrrolo-[2,3-d] Pyrimidine-4-amido)-N-methyl-benzamide

Step A:(S) 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-2-amine

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 (intermediate B1,85 milligrams, 0.41mmol), Pd₂(dba)₃(34 milligrams, 0.04mmol), (±)-BINAP (46 milligrams, 0.74mmol) and carbon Toluene solution heated and stirred under microwave of acid caesium (181 milligrams, 0.56mmol), it is chloro-that separated purification obtains product (S)-4- N-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] is phonetic Pyridine-2-amine (88 milligrams, productivity 48%).¹H NMR (400MHz, CDCl₃) δ ppm 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

According to universal synthesis method II, by the chloro-N-of (S)-4-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxybenzyl Base)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine (88 milligrams, 0.18mmol), 2-Amino-N-methyl Benzoylamide (intermediate C1,27 milligrams, 0.18mmol), Pd₂(dba)₃(16 milligrams, 0.02mmol), (±)-BINAP (22 millis Gram, 0.04mmol) and the toluene solution of cesium carbonate (87 milligrams, 0.27mmol) is heated to 130 degree in tube sealing and to stir 12 little Time, separated purification obtains product (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 (50 milligrams, productivity 46%).¹H NMR (400MHz, CDCl₃) δ ppm 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-methoxyl group Benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide (50 milligrams, Trifluoroacetic acid solution (10 milliliters) 0.082mmol) adds 4 concentrated sulphuric acids, stirs at normal temperatures some hours, post-treated With isolated and purified obtain target product (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 (20 milligrams, productivity 50%).¹H NMR (400MHz, DMSO-d6) δ ppm 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)-N-cyclobutyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5-methyl-6,7-dihydro-5H-pyrroles And [2,3-d] pyrimidine-4-amido) benzsulfamide

Step 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

According to universal synthesis method II, by the chloro-N-of (S)-4-(2-methoxyl group-4-morpholine phenyl)-7-(4-methoxybenzyl Base)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-2-amine (32 milligrams, 0.065mmol), 2-amino-N-ring fourth Base benzsulfamide (intermediate C6,17 milligrams, 0.077mmol), Pd₂(dba)₃(12 milligrams, 0.013mmol), X-Phos (6 millis Gram, 0.013mmol) and the toluene solution of cesium carbonate (42 milligrams, 0.129mmol) in tube sealing, be heated to 130 degree and stir 12 Hour, separated purification obtains product (S)-N-cyclobutyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-7-(4-first Oxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide (20 milligrams, productivity 45%).¹H NMR (400MHz, CDCl₃) δ ppm 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 amine Base)-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide (20 Milligram, 0.029mmol) trifluoroacetic acid solution (10 milliliters) in add 3 concentrated sulphuric acids, stir some hours at normal temperatures, warp Post processing and isolated and purified obtain target product (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 (14 milligrams, productivity 85%).¹H NMR (400MHz, CDCl₃) δ ppm 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-pyrrolo-[2,3-d] Pyrimidine-4-amido)-N-methyl-benzamide

The chloro-N-of step 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

According to universal synthesis method II, by 2, the chloro-7-of 4-bis-(4-methoxy-benzyl)-5,5-dimethyl-6,7-dihydro- 5H-pyrrolo-[2,3-d] pyrimidine (intermediate A 4,156 milligrams, 0.46mmol), 2-methoxyl group-4-morpholine aniline (intermediate B1,115 milligrams, 0.55mmol), Pd₂(dba)₃(42 milligrams, 0.046mmol), (±)-BINAP (57 milligrams, 0.092mmol) Under microwave, it is heated to 130 degree with the toluene solution of potassium carbonate (225 milligrams, 0.69mmol) and stirs 3 hours, separated purification Obtain the chloro-N-of product 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 (white solid, 86 milligrams, productivity 37%).¹H NMR (400MHz, CDCl₃)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

According to universal synthesis method II, by chloro-for 4-N-(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 Benzoylamide (intermediate C1,51 milligrams, 0.338mmol), Pd₂(dba)₃(16 milligrams, 0.017mmol), (±)-BINAP (22 Milligram, 0.035mmol) and the toluene solution of potassium carbonate (110 milligrams, 0.338mmol) under microwave, be heated to 150 degree and stir 3 hours, separated purification obtain product 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 (white solid, 70 millis Gram, productivity 67%).¹H NMR (400MHz, CDCl₃) δ ppm 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-methoxybenzyl Base)-5,5-di methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido)-N-methyl-benzamide (70 milligrams, Trifluoroacetic acid solution (3 milliliters) 0.112mmol) adds 5 concentrated sulphuric acids, stirs at normal temperatures some hours, post-treated With isolated and purified obtain target product 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 (yellow solid, 30 milligrams, productivity 53.3%).¹H NMR (400MHz, CDCl₃) δ ppm 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-amine Base)-N, N-dimethyl benzene sulfonamide

1H NMR (400MHz, DMSO-d6) δ ppm 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

(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] is phonetic for N-butyl-2- Pyridine-4-amido) benzsulfamide

¹H NMR (400MHz, DMSO-d6) δ ppm 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

(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] is phonetic for N-isopropyl-2- Pyridine-4-amido) benzsulfamide

¹H NMR (400MHz, DMSO-d6) δ ppm 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-amine Base) benzsulfamide

¹H NMR (400MHz, DMSO-d6) δ ppm 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

(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] is phonetic for N-cyclopropyl-2- Pyridine-4-amido) benzsulfamide

¹H NMR (400MHz, DMSO-d6) δ ppm 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

(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] is phonetic for N-ethyl-2- Pyridine-4-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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

(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] is phonetic for N-sec-butyl-2- Pyridine-4-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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

(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] is phonetic for N-isobutyl group-2- Pyridine-4-amido) benzsulfamide

¹H NMR(400MHz,DMSO-d₆) δ ppm 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

(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] is phonetic for N-isopropyl-2- Pyridine-4-amido) benzsulfamide

¹H NMR(400MHz,DMSO-d₆) δ ppm 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

(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] is phonetic for the N-tert-butyl group-2- Pyridine-4-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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

¹H NMR(400MHz,DMSO-d₆) δ ppm 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-dimethylamino) ethyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrroles And [2,3-d] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,DMSO-d₆) δ ppm 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-d₆) δ ppm 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

(2-(2-methoxyl group-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] is phonetic for N-phenyl-2- Pyridine-4-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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-isopropyl-2-(2-(4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amine Base) benzsulfamide

¹H NMR(400MHz,DMSO-d₆) δ ppm 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-isopropyl-2-(2-(4-(N-methyl) formylphenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine- 4-amido) benzsulfamide

¹H NMR(400MHz,DMSO-d₆) δ ppm 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-isopropyl-2-(2-(4 hydroxymethyl phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) Benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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-isopropyl-2-(2-(2-fluoro-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine- 4-amido) benzsulfamide

¹H NMR(400MHz,DMSO-d₆) δ ppm 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-isopropyl-2-(2-(2-methoxyl group-6-morpholine pyridine-3-amido)-6,7-dihydro-5H-pyrrolo-[2,3- D] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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

N-isopropyl-2-(2-(6-morpholine pyridine-3-amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4- Amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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

N-isopropyl-2-(2-(3-morpholine pyridine-2-amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4- Amido) benzsulfamide

¹H NMR(400MHz,CDCl₃)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

(2-(2-ethyoxyl-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] is phonetic for N-isopropyl-2- Pyridine-4-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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-isopropyl-2-(2-(2-trifluoromethyl-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] Pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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

N-isopropyl-2-(2-(4-trifluoromethyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amine Base) benzsulfamide

¹H NMR(400MHz,DMSO-d₆) δ ppm 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

(2-(4-(N-dimethyl) formylphenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] is phonetic for N-isopropyl-2- Pyridine-4-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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

N-isopropyl-2-(2-(4-acetamidophenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amine Base) benzsulfamide

¹H NMR(400MHz,DMSO-d₆) δ ppm 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

(2-(4-(N-methyl) sulfonvlphenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] is phonetic for N-isopropyl-2- Pyridine-4-amido) benzsulfamide

¹H NMR(400MHz,DMSO-d₆) δ ppm 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-isopropyl-2-(2-(4-morpholine Fonnylphenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine- 4-amido) benzsulfamide

¹H NMR(400MHz,DMSO-d₆) δ ppm 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

(2-(2-methyl-4-morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] is phonetic for N-isopropyl-2- Pyridine-4-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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

(2-(2-methoxyl group-4-pyrroles's phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] is phonetic for N-isopropyl-2- Pyridine-4-amido) benzsulfamide

¹H NMR(400MHz,DMSO-d₆) δ ppm 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

(2-(2-methoxyl group-4-piperidines phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] is phonetic for N-isopropyl-2- Pyridine-4-amido) benzsulfamide

¹H NMR(400MHz,DMSO-d₆) δ ppm 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-isopropyl-2-(2-(4-(1-hydroxyl) ethylphenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine- 4-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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-isopropyl-2-(2-(2-methoxyl group-4-(2-morpholine) ethoxyl phenenyl amido)-6,7-dihydro-5H-pyrroles And [2,3-d] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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-isopropyl-2-(2-(4-Trifluoromethoxyphen-l amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4- Amido) benzsulfamide

¹H NMR(400MHz,DMSO-d₆) δ ppm 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-isopropyl-2-(2-(4-(1-isopropyl amido) ethylphenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3- D] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,DMSO-d₆) δ ppm 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

N-Isopropyl-2-(2-(3-Methanesulfomide phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amine Base) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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

(2-(3-(N-methyl) Fonnylphenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] is phonetic for N-isopropyl-2- Pyridine-4-amido) benzsulfamide

¹H NMR(400MHz,DMSO-d₆) δ ppm 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

N-isopropyl-2-(2-(3-acetamidophenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amine Base) benzsulfamide

¹H NMR(400MHz,DMSO-d₆) δ ppm 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-isopropyl-2-(2-(2-methoxyl group-4-(4-(N, N-dimethyl)) piperidinophenyl amido)-6,7-dihydro- 5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,DMSO-d₆) δ ppm 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-isopropyl-2-(2-(2-methoxyl group-4-1H-imidazolylphenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3- D] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,DMSO-d₆) δ ppm 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-isopropyl-2-(2-(4-pyrroyl group phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4- Amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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-isopropyl-2-(2-(2-methoxyl group-4-(4-methylol) piperidinophenyl amido)-6,7-dihydro-5H-pyrroles And [2,3-d] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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-isopropyl-2-(2-(2-methoxyl group-4-(3-hydroxyl) pyrrole radicals phenyl amido)-6,7-dihydro-5H-pyrrolo- [2,3-d] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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-isopropyl-2-(2-(2-methoxyl group-4-(3-hydroxyl) piperidinophenyl amido)-6,7-dihydro-5H-pyrrolo- [2,3-d] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,DMSO-d₆) δ ppm 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-isopropyl-2-(2-(4-(1-piperidines) ethylphenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine- 4-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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

N-isopropyl-2-(2-(2-methoxyl group-4-(2-oxygen) pyridine-1 (2H) phenyl amido)-6,7-dihydro-5H-pyrroles And [2,3-d] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,DMSO-d₆) δ ppm 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

N-isopropyl-2-(2-(2-methoxyl group-4-(3,5-dimethyl) morpholine phenyl amido)-6,7-dihydro-5H-pyrrole Cough up also [2,3-d] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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

N-isopropyl-2-(2-(2-methoxyl group-4-(2-morpholine) ethyl amido phenyl amine base)-6,7-dihydro-5H-pyrrole Cough up also [2,3-d] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,DMSO-d₆) δ ppm 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-isopropyl-2-(2-(2-methoxyl group-4-(4-hydroxyl) piperidinophenyl amido)-6,7-dihydro-5H-pyrrolo- [2,3-d] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,DMSO-d₆) δ ppm 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-isopropyl-2-(2-(2-methoxyl group-4-sulfone is for morpholine phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3- D] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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-isopropyl-2-(2-(2-methoxyl group-4-tetrazolium-2-base phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3- D] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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

N-isopropyl-2-(2-(2-methoxyl group-4-(3-N, N-dimethyl) pyrroles's phenyl amido)-6,7-dihydro-5H-pyrrole Cough up also [2,3-d] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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-isopropyl-2-(2-(2-methoxyl group-4-(2,4-dimethyl)-1H-imidazolylphenyl amido)-6,7-dihydro-5H- Pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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-isopropyl-2-(2-(4-methyl) thiazole amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) Benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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-isopropyl-2-(2-(2-methoxyl group-4-1,4-joins piperidines phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3- D] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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-isopropyl-2-(2-(2-methoxyl group-4-(4-pyrrole radicals) piperidines phenyl amido)-6,7-dihydro-5H-pyrrolo- [2,3-d] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,DMSO-d₆) δ ppm 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

(2-(2-methoxyl group-4-pyrazole phenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] is phonetic for N-isopropyl-2- Pyridine-4-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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-isopropyl-2-(2-(2-methoxyl group-4-(4-morpholine) piperidines phenyl amido)-6,7-dihydro-5H-pyrrolo- [2,3-d] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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

N-isopropyl-2-(2-(2-methoxyl group-4-(4-N-methyl piperazine) piperidines phenyl amido)-6,7-dihydro-5H-pyrrole Cough up also [2,3-d] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,DMSO-d₆) δ ppm 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-isopropyl-2-(2-(2-methoxyl group-4-(4-piperazine) piperidines phenyl amido)-6,7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,DMSO-d₆) δ ppm 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-isopropyl-2-(2-(2-methoxyl group-4-(2-carbonyl) piperidines phenyl amido)-6,7-dihydro-5H-pyrrolo-[2, 3-d] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,DMSO-d₆) δ ppm 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-isopropyl-2-(2-(2-methoxyl group-4-(3,4-2 (1H))-quinolinone phenyl amido)-6,7-dihydro-5H-pyrrole Cough up also [2,3-d] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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-(isopropyl sulphonyl) phenyl)-N ² -(2-methoxyl group-4-morpholino phenyl)-6,7-dihydro-5H-pyrrolo- [2,3-D] pyrimidine-2,4-diamidogen

¹H NMR(400MHz,DMSO-d₆) δ ppm 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-isopropyl-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) benzsulfamide

¹H NMR(400MHz,DMSO-d₆) δ ppm 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) Benzoylamide

¹H NMR(400 MHz,DMSO-d₆) δ ppm 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

¹H NMR(400MHz,CDCl₃) δ ppm 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-pyrroles And [2,3-d] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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-isopropyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5,5-dimethyl-6,7-dihydro-5H-pyrroles And [2,3-d] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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-pro-pyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5,5-dimethyl-6,7-dihydro-5H-pyrroles And [2,3-d] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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 group-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5,5-dimethyl-6,7-dihydro-5H-pyrroles And [2,3-d] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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-cyclopenta-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5,5-dimethyl-6,7-dihydro-5H-pyrroles And [2,3-d] pyrimidine-4-amido) benzsulfamide

¹H NMR (400MHz, DMSO-d6) δ ppm 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-pyrroles And [2,3-d] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,DMSO-d₆) δ ppm 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-pyrroles And [2,3-d] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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-pyrrole Cough up also [2,3-d] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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-pyrroles And [2,3-d] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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

¹H NMR(400MHz,CDCl₃) δ ppm 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-dimethyl-6,7-bis- Hydrogen-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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-dimethyl-6,7-bis- Hydrogen-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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

¹H NMR(400MHz,CDCl₃) δ ppm 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-tert-butyl group-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5,5-dimethyl-6,7-dihydro-5H-pyrroles And [2,3-d] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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-ring the third methyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5,5-dimethyl-6,7-dihydro-5H-pyrrole Cough up also [2,3-d] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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-ethoxy-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5,5-dimethyl-6,7-dihydro-5H-pyrroles And [2,3-d] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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-bis- Hydrogen-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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 Aminocyclopentane

¹H NMR(400MHz,CDCl₃) δ ppm 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-mesyl-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5,5-dimethyl-6,7-bis- Hydrogen-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) aniline

¹H NMR (400MHz, CDCl3) δ ppm 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 2-1,4-diamidogen

¹H NMR(400MHz,CDCl₃) δ ppm 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-acetyl group-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5,5-dimethyl-6,7-dihydro-5H-pyrroles And [2,3-d] pyrimidine-4-amido) aniline

¹H NMR (400MHz, CDCl₃) δ ppm 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

3,4-bis-fluoro-2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5,5-dimethyl-6,7-dihydro-5H-pyrroles And [2,3-d] pyrimidine-4-amido) benzene

¹H NMR(400MHz,CDCl₃) δ ppm 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 Methanamide

¹H NMR(400MHz,CDCl₃) δ ppm 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-mesyl 2-(2-(2-methoxyl group-4-morpholine phenyl amido)-5,5-dimethyl-6,7-bis- Hydrogen-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) cyclohexylamine

¹H NMR(400MHz,CDCl₃) δ ppm 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-dihydrobenzos [b] [Isosorbide-5-Nitrae] dioxygen miscellaneous hex-5-amido)-5,5-dimethyl-6,7-bis- Hydrogen-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) Benzoylamide

¹H NMR(400MHz,CDCl₃) δ ppm 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 miscellaneous hexene-5-amido)-5,5-diformazan Base-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) Benzoylamide

¹H NMR(400MHz,DMSO-d₆)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-pyrrolo-[2, 3-d] pyrimidine-4-amido) Benzoylamide

¹H NMR(400MHz,CDCl₃) δ ppm 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

(2-(benzofuran-7-amido)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo-[2,3-d] is phonetic for N-methyl-2- Pyridine-4-amido) Benzoylamide

¹H NMR(400MHz,CDCl₃) δ ppm 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) Benzoylamide

¹H NMR(400MHz,CDCl₃) δ ppm 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] cycloheptyl amide-2 (3H)-7-amine Base)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) Benzoylamide

¹H NMR(400MHz,DMSO-d₆) δ ppm 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-indole-5-amido)-5,5-dimethyl-6,7-dihydro-5H- Pyrrolo-[2,3-d] pyrimidine-4-amido) Benzoylamide

¹H NMR(400MHz,CDCl₃) δ ppm 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 ', and 7 '-dihydro spiral shell [cyclopropane-1,5 '-pyrrole Cough up also [2,3-d] pyrimidine]-4 '-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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-tert-butyl 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

¹H NMR(400MHz,CDCl₃) δ ppm 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 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

¹H NMR(400MHz,CDCl₃) δ ppm 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-isopropyl-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

¹H NMR(400MHz,CDCl₃) δ ppm 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 ', and 7 '-dihydro spiral shell [cyclopropane-1,5 '-pyrrole Cough up also [2,3-d] pyrimidine]-4 '-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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-ring the third 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

¹H NMR(400MHz,CDCl₃) δ ppm 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

¹H NMR(400MHz,CDCl₃) δ ppm 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

¹H NMR(400MHz,CDCl₃) δ ppm 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 ', and 7 '-dihydro spiral shell [cyclopropane-1,5 '-pyrrole Cough up also [2,3-d] pyrimidine]-4 '-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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-pi-allyl-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

¹H NMR(400MHz,CDCl₃) δ ppm 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-cyclopenta-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

¹H NMR(400MHz,CDCl₃) δ ppm 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

¹H NMR(400MHz,CDCl₃) δ ppm 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

¹H NMR(400MHz,CDCl₃) δ ppm 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-pro-pyl-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

¹H NMR(400MHz,CDCl₃) δ ppm 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

¹H NMR(400MHz,CDCl₃) δ ppm 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

¹H NMR(400MHz,CDCl₃) δ ppm 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, N-dimethyl-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

¹H NMR(400MHz,CDCl₃) δ ppm 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

¹H NMR(400MHz,CDCl₃) δ ppm 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 '-diamidogen

¹H NMR(400MHz,CDCl₃) δ ppm 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-base)-6 ', 7 '-dihydro spiral shell [cyclopropane- 1,5 '-pyrrolo-[2,3-d] pyrimidine]-2 ', 4 '-diamidogen

¹H NMR(400MHz,CDCl₃) δ ppm 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 ', and 7 '-dihydro spiral shell [cyclopropane-1,5 '-pyrrolo- [2,3-d] pyrimidine]-4 '-amido) phenyl) acetamide

¹H NMR(400MHz,CDCl₃) δ ppm 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 ', and 7 '-dihydro spiral shell [cyclopropane-1,5 '-pyrrolo- [2,3-d] pyrimidine]-4 '-amido) phenyl)-N-methylmethanesulfonamide

¹H NMR(400MHz,CDCl₃) δ ppm 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 ', and 7 '-dihydro spiral shell [cyclopropane-1,5 '-pyrrolo- [2,3-d] pyrimidine]-4 '-amido) benzsulfamide

¹H NMR(400MHz,CDCl₃) δ ppm 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) Benzoylamide

¹H NMR(400MHz,DMSO-d₆) δ ppm 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-methoxyphenyl amido)-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-amido) Benzoylamide

¹H NMR (400MHz, DMSO-d6) δ ppm 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) Benzoic acid

¹H NMR(400MHz,DMSO-d₆) δ ppm 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) Benzaldehyde

¹H NMR(400MHz,DMSO-d₆) δ ppm 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) Phenethanol

¹H NMR(400MHz,CDCl₃) δ ppm 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) pheiiyldimetliyl oxygen phosphorus

¹H NMR(400MHz,CDCl₃) δ ppm 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

FAK with GST label is purchased from Invitrogen (PV3832).PYK2 with GST label is purchased from Invitrogen(PV4567).By monitoring fluorogen labelling from Perkin Elmer (TRF0101) in the presence of ATP The phosphorylation of ULight-poly-Glu, Ala, Tyr (1:1:1) peptide substrates, measures the activity of FAK/PYK2.By from Perkin The anti phosphotyrosine antibody (PY20) of the LANCE europium chelating labelling of Elmer (AD0066) identifies that the tyrosine of phosphorylation is residual Base.This makes described fluorogen and Europium chelate close proximity (> 10nm), thus upon Envision (PerkinElmer) When 320nm excites, energy can be transferred to acceptor fluorescence group from donor Europium chelate.This causes launches light, and energy at 665nm Enough captured by Envision.Therefore, the intensity of described signal is directly proportional to FAK/PYK2 activity.

In order to measure the inhibitory activity of FAK/PYK2 inhibitor, first prepare the 100%DMSO conduct of compound containing 1mM Storing solution, and in 96 orifice plates (Corning, 3897), make 3 times of serial dilutions to obtain the 100X storing solution of 12 variable concentrations. The 100X storing solution of the 5 each concentration of μ l is joined containing 95 μ l 1X reaction buffer (40mM Tris, pH7.5,10mM MgCl₂, 1mM DTT and 1mM CHAPS) hole in, thus obtain 5X storing solution.Then the 5X storing solution of 2 μ each concentration of l is joined In 384 hole OptiPlate (PerkinElmer, 6007299).

The experiment of FAK: by 4 μ l 2.5nM FAK, the 1ul 8 μ g/ μ l BSA and 1.5 of preparation in above-mentioned reaction buffer μ l 666nM ULight-poly-Glu, Ala, Tyr (1:1:1) peptide substrates joins in each hole.By adding 1.5 μ l 33.3 μMs ATP initiation reaction.Make reaction carry out 120 minutes, then be formulated in 1X LANCE detection buffer (PerkinElmer, CR97-100) 5 μ l 40mM EDTA stop buffer cancellation reactions in.

The experiment of PYK2: by the 5 μ l 2nM PYK2 and 1.5 μ l 666nM of configuration in above-mentioned reaction buffer ULight-poly-Glu, Ala, Tyr (1:1:1) peptide substrates joins in each hole.Cause by adding 46.6 μMs of ATP of 1.5 μ l Reaction.Reaction is made to carry out 40 minutes, then with being formulated in 1X LANCE detection buffer (PerkinElmer, CR97-100) 5 μ l 40mM EDTA stop buffer cancellation reaction.

After reaction cancellation, in each hole, add 5 μ l 8nM anti phosphotyrosine antibody, and incubation 60 minutes.According to Above-mentioned principle utilizes Envision (PerkinElmer) to detect flat board.

Form 1: some have the biologically active data of pyrrolo-[2,3-d] pyrimidines of structure formula (I)

Claims (5)

1. compound or its pharmaceutically acceptable salt, described compound is represented by below general formula (IIa):

Wherein:

R¹And R²Independent selected from hydrogen and C₁-C₆Alkyl, or R¹、R²It is collectively forming C with coupled carbon atom₃-C₈Cycloalkanes Base；

R¹⁶、R¹⁷、R²²For H；

R¹⁴、R¹⁵Independent selected from hydrogen and halogen；

R²¹Selected from H and C₁-C₆Alkoxyl；

R¹⁹Selected from H, C₁-C₆Alkoxyl, list-C₁-C₆Alkylaminoacyl, C₁-C₆Alkylamidoalkyl, C₁-C₆Alkylsulfonamido；

R¹⁸Selected from H, halogen, be optionally substituted by halogen or unsubstituted C₁-C₆Alkyl and C₁-C₆Alkoxyl；

R²⁰Selected from H；Halogen；By halogen, hydroxyl, list-C₁-C₆Alkyl amino, comprise the 5-7 unit heterocycle alkane of 1-2 N, O or S atom The substituted or unsubstituted C of base₁-C₆Alkyl；The 5-7 unit heteroaryl that by halogen, comprises 1-4 N, O or S atom, comprise 1-2 The 5-7 unit substituted or unsubstituted C of Heterocyclylalkyl of N, O or S atom₁-C₆Alkoxyl；Comprise the 5-8 unit of 1-4 N, O or S atom Heteroaryl；By hydroxyl, two-C₁-C₆Alkyl amino, hydroxyl-C₁-C₆Alkyl, (=O), by C₁-C₆The substituted or unsubstituted bag of alkyl 5-7 unit Heterocyclylalkyl containing 1-2 N, O or S atom the substituted or unsubstituted 5-7 unit comprising 1-2 N, O or S atom Heterocyclylalkyl；Comprise the 5-7 unit Heterocyclylalkyl-acyl group of 1-2 N, O or S atom；Comprised the 5-7 unit of 1-2 N, O or S atom Heterocyclylalkyl substituted or unsubstituted list-C₁-C₆Alkyl amino, list-C₁-C₆Alkylaminoacyl, two-C₁-C₆Alkyl amino acyl Base, C₁-C₆Alkylamidoalkyl, list-C₁-C₆Alkyl amino sulfonyl；S atom on described 5-7 unit Heterocyclylalkyl is optionally Oxidized；

R¹³Selected from H, halogen, by halogen, the substituted or unsubstituted C of hydroxyl₁-C₆Alkyl, C₁-C₆Alkoxyl, list-C₁-C₆Alkyl Aminoacyl, two-C₁-C₆Alkylaminoacyl, C₁-C₆Alkylamidoalkyl, amino-sulfonyl, by C₂-C₆Thiazolinyl, C₁-C₆Alkoxyl Or two-C₁-C₆Alkyl amino substituted or unsubstituted list-C₁-C₆Alkyl amino sulfonyl, two-C₁-C₆Alkyl sulfonyl amino Base, list-C₃-C₆Cycloalkyl amino sulfonyl, C₁-C₆Alkyl sulfonyl amino, C₁-C₆Alkyl sulphonyl.

2. compound or its pharmaceutically acceptable salt, described compound is selected from following

3. pharmaceutical composition, it comprises a) compound according to any one of claim 1-2 or its pharmaceutically acceptable salt, And b) pharmaceutically acceptable carrier, diluent, excipient and/or accessory drugs.

4. compound according to any one of claim 1-2 or its pharmaceutically acceptable salt preparation be used for suppressing FAK and/ Or the application in the pharmaceutical composition of Pyk2.

5. compound or its pharmaceutically acceptable salt according to any one of claim 1-2 are used for treating or preventing in preparation Application in the pharmaceutical composition of cancer or diseases associated with inflammation.