CN117466897A

CN117466897A - Highly selective FGFR2 inhibitors

Info

Publication number: CN117466897A
Application number: CN202310918418.XA
Authority: CN
Inventors: 朱程刚; 杨铉; 张朝春; 汪春牛; 王倩文; 陈超乐; 徐良亮
Original assignee: Shenzhen Forward Pharmaceuticals Co ltd
Current assignee: Shenzhen Forward Pharmaceuticals Co ltd
Priority date: 2022-07-27
Filing date: 2023-07-25
Publication date: 2024-01-30

Abstract

The invention relates to a high-selectivity FGFR2 inhibitor, a preparation method and application thereof. The compounds of the invention are useful in the treatment of tumors (particularly solid tumors such as, for example, intrahepatic cholangiocarcinoma, gastric cancer, etc.) and other disorders.

Description

Highly selective FGFR2 inhibitors

Technical Field

The invention belongs to the field of drug synthesis, and particularly relates to a high-selectivity FGFR2 inhibitor, and a preparation method and application thereof. The present disclosure relates to pyrrolopyrimidines and pharmaceutically acceptable salts thereof, which are useful in the treatment or prevention of diseases or conditions by modulating certain mutated forms of fibroblast growth factor receptor. Also disclosed herein are pharmaceutical compositions comprising the compounds or salts thereof, and methods of using the compounds and salts thereof for treating a variety of diseases mediated by various forms of FGFR2, including solid tumors, e.g., intrahepatic cholangiocarcinoma, gastric cancer, etc.

Background

There is a continuing need in the field of anticancer drugs for new anticancer compounds with better activity/selectivity. Fibroblast Growth Factor Receptor (FGFR) is a tyrosine kinase receptor that binds to fibroblast growth factor ligands. FGFR is a family of tyrosine kinase receptors consisting of an extracellular ligand binding domain and an intracellular tyrosine kinase domain, including FGFR1, FGFR2, FGFR3 and FGFR4 subtypes. Ligand FGF, when bound, results in receptor dimerization, phosphorylation and conformational changes in the intracellular domain, stimulating activation of protein kinase activity, and recruiting many intracellular protein binding. These protein interactions can aid in the activation of a range of intracellular signaling pathways, including Ras-MAPK, AKT-PI3K, and phosphatase C, signaling pathways important for cell growth, proliferation, and survival.

Aberrant activation of this pathway, such as overexpression of FGF ligands or activation mutations through FGFR, can lead to tumor growth, progression and resistance to traditional cancer therapies, which in turn lead to cell proliferation, growth, differentiation, migration and angiogenesis. In human tumors, it is possible to bring about ligand-independent receptor activation of genetic changes, including gene amplification, generation of unregulated FGFR signals by FGFR gene amplification or fusion, FGFR missense mutation, etc., overexpression of receptors caused by epigenetic and/or transcriptional regulator dysregulation, or upregulation of FGF ligands in tumor microenvironments. FGFR is expressed in a variety of cell types, and thus, aberrant FGFR signaling is associated with tumor formation, tumor progression, and therapeutic resistance to a variety of tumor types. ( Turner and R.Grose, nat.Rev.Cance 2010, 10:116-129 )

Known pan FGFR inhibitors (i.e. inhibitors that non-selectively inhibit FGFR 1-4) include Erdafitinib, pemigatinib, etc., but because of their low selectivity for FGFR2, they can respond clinically to a variety of cancers altered by FGFR, and these inhibitors have dose-limiting targeted toxicity. One of the most important adverse effects of pan FGFR inhibitors is hyperphosphatemia. The regulation of phosphate resorption is mediated by FGFR3 and FGFR 1. There is therefore a need for highly selective FGFR2 inhibitors, in particular inhibitors which have a weaker inhibitory activity on FGFR1, FGFR3 and/or FGFR4 (j. Gattineni et al, am. J. Physiol. Renal physiol.2014, 306: F351-F358; x.han et al, PLoS One 2016, 11: e 0147845). Pan FGFR inhibitors have been shown to be effective against cancers with FGFR2 gene fusion and FGFR2 amplification and/or FGFR2 activation mutations. However, low response rates and durations indicate that they are limited by toxicity. Accordingly, there is a need for FGFR2 selective inhibitor compounds for use in the treatment of tumors (in particular solid tumors, such as e.g. intrahepatic cholangiocarcinoma, gastric cancer, etc.) and other disorders.

Disclosure of Invention

The present invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof, which have good FGFR inhibition activity, in particular good FGFR2 selectivity, and are useful for the safe and effective treatment of related diseases.

In one aspect, provided herein are compounds of formula (I):

wherein the method comprises the steps of

R ⁵ Selected from the following groups: -R ^5A -L ⁵ -R ^5B ；

R ^5A Selected from the following groups:

R ^5A selected from C _3-14 Cycloalkyl, aryl, C _5-14 Heteroaryl, C _3-14 Saturated or partially unsaturated heterocycloalkyl, optionally substituted with at least one substituent R ^5C Substitution, C _3-14 Heterocycloalkyl and C _5-14 Heteroaryl groups each independently comprise 1, 2, 3 or 4 groups independently selected from-NH-, -heteroatoms or groups of heteroatoms of O-, -S-and N. R is R ^5C Selected from hydrogen, halogen (e.g., -F, -Cl or-Br), cyano, hydroxy, amino, nitro, alkyl, alkoxy, alkenyl, alkynyl, C _1-3 Haloalkyl, C _1-3 Haloalkoxy (e.g. -OCF) ₃ )；

L ⁵ Selected from-O-, -NH-, -C (=O) -, - (CH) ₂ ) _n -、-O(CH ₂ ) _n -、-S(CH ₂ ) _n -、-NH(CH ₂ ) _n -、-(CH ₂ ) _n NH-、-(CH ₂ ) _n O-、-(CH ₂ ) _n S-、-(CH ₂ ) _n C(＝O)-、-C(＝O)O(CH ₂ ) _n -、-OC(＝O)(CH ₂ ) _n -、-C(＝O)(CH ₂ ) _n -、-C(＝O)NH(CH ₂ ) _n -、-NHC(＝O)(CH ₂ ) _n -; preferably-O-, -NH-; -C (=o) -or-NHC (=o) -;

R ^5B selected from C _3-14 Cycloalkyl, aryl, C _5-14 Heteroaryl, C _3-14 Saturated or unsaturated heterocycloalkyl, optionally substituted with at least one substituent R ^5D Substitution, C _3-14 Heterocycloalkyl and C _5-14 Heteroaryl groups each independently comprise 1, 2, 3 or 4 groups independently selected from-NH-, -heteroatoms or groups of heteroatoms of O-, -S-and N. R is R ^5D Selected from hydrogen, halogen (e.g., -F, -Cl or-Br), cyano, hydroxy, amino, nitro, alkyl, alkoxy, alkenyl, alkynyl, C _1-3 Haloalkyl, C _1-3 Haloalkoxy (e.g. -OCF) ₃ )；

Cy ⁶ Selected from C _3-14 Cycloalkyl, aryl, C _5-14 Heteroaryl, saturated or partially unsaturatedC of (2) _3-14 Cycloalkyl, saturated or partially unsaturated C _3-14 Heterocycloalkyl, C _5-14 Heteroaryl, optionally substituted with at least one substituent R ^Cy6 Substitution, said C _3-14 Cycloalkyl, C _3-14 Heterocycloalkyl, C _3-14 Heterocycloalkyl and C _5-14 Heteroaryl groups each independently comprise 1, 2, 3 or 4 groups independently selected from-NH-, heteroatoms or groups of heteroatoms of O-, -S-and N, R is R ^Cy6 Selected from hydrogen, halogen (e.g., -F, -Cl or-Br), cyano, hydroxy, amino, nitro, alkyl, alkoxy, alkenyl, alkynyl, C _1-3 Haloalkyl, C _1-3 Haloalkoxy (e.g. -OCF) ₃ ) The method comprises the steps of carrying out a first treatment on the surface of the Wherein said amino, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, optionally further substituted;

L ⁶ selected from bonds, -O-, -NH-, -C (=O) -, - (CH) ₂ ) _n -、-O(CH ₂ ) _n -、-S(CH ₂ ) _n -、-NH(CH ₂ ) _n -、-(CH ₂ ) _n NH-、-(CH ₂ ) _n O-、-(CH ₂ ) _n S-、-(CH ₂ ) _n C(＝O)-、-C(＝O)O(CH ₂ ) _n -、-OC(＝O)(CH ₂ ) _n -、-C(＝O)(CH ₂ ) _n -、-C(＝O)NH(CH ₂ ) _n -、-NHC(＝O)(CH ₂ ) _n -; preferably-O-, -NH-; -C (=o) -or-NHC (=o) -;

R ⁷ is H or R ^B Wherein R is ⁷ Through t R ^7A Group substitution;

R ^W is considered a warhead group, particularly suited for covalent binding to thiol side chains of protein kinases, such as Cys491 of FGFR 2. Thus, in some embodiments, R ^W Characterized by being capable of covalently binding to cysteine residues, thereby irreversibly inhibiting a protein kinase. In some embodiments, the protein kinase is FGFR. In a particular embodiment, the protein kinase is FGFR2. In a particular embodiment, the protein kinase is FGFR2 and the cysteine residue is Cys491.

R ^W Selected from the following groups: a halogen atom,

R ^WA ，R ^WB and R is ^WC Independently selected from hydrogen, deuterium, halogen, -CN-, -C (O) R-, -C (O) OR, -C (O) NR ₂ (C (O) N (R) OR, OR optionally C _1-6 Aliphatic hydrocarbon groups (e.g. C _1-6 Alkyl or C _2-6 Alkenyl), phenyl, C _3-7 Saturated or partially unsaturated heterocycloalkyl and containing 1, 2 heteroatoms independently selected from-NH-, -O-, -S-, or heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from-NH-, -O-, -S-, wherein the ring is interrupted by w R ^C Group substitution; or (b)

R ^WA And R is ^WB ，R ^WB And R is ^WC Together with the atoms to which they are attached form C _4-7 Wherein the rings may each contain 0, 1 or 2 heteroatoms or groups of heteroatoms independently selected from-NH-, -O-, -S-; wherein the ring is covered by w R ^C Group substitution;

R ^WD selected from halogen or-OS (O) ₂ R；

R ^5C ，R ^5D And R7 ^A Independently selected from R ^A Or R is ^B And through u R ^C Substituted by radicals, or by two R ^5C A group, one R ^5C Radicals and one R ^5D A group, or two R ^5D The radicals together with the atoms to which they are attached form C _3-7 Or an aryl group, wherein said C _3-7 The saturated partially unsaturated group or heteroaryl group contains 0, 1, 2, 3 or 4 heteroatoms or groups of heteroatoms independently selected from-NH-, -O-, -S-, respectively; wherein the ring is covered by w R ^C Group substitution;

R ^A independently selected from oxygen, halogen, -CN, -NO ₂ ，-OR，-NR ₂ ，-S(O) ₂ R，-S(O) ₂ NR ₂ ，-S(O)R，-S(O)NR ₂ ，-C(O)R，-C(O)OR，-C(O)NR ₂ ，-C(O)N(R)OR，-OC(O)R，-OC(O)NR ₂ ，-N(R)C(O)OR，-N(R)C(O)R，-N(R)C(O)NR ₂ ，-N(R)C(NR)NR ₂ ，-N(R)S(O) ₂ NR ₂ or-N (R) S (O) ₂ R；

R ^B Independently selected from C _1-6 Aliphatic hydrocarbon groups (e.g. C _1-6 Alkyl or C _2-6 Alkenyl groups); a phenyl group; c (C) _5-6 A monocyclic heteroaryl group selected from a group consisting of heteroatoms or heteroatom groups comprising 1, 2, 3, or 4 heteroatoms independently selected from-NH-, -O-, -S-; c (C) _8-10 A bicyclic heteroaryl group selected from a group comprising 1, 2, 3, or 4 heteroatoms or heteroatom groups independently selected from-NH-, -O-, -S-; c (C) _3-7 Saturated or partially unsaturated cycloalkyl; c (C) _3-7 A saturated or partially unsaturated mono-heterocycloalkyl group selected from the group consisting of a heteroatom or a heteroatom group comprising 1 or 2 heteroatoms independently selected from-NH-, -O-, -S-; c (C) _7-12 A bicyclic heterocycloalkyl selected from the group consisting of a heteroatom or a heteroatom group comprising 1, 2, 3 or 4 heteroatoms independently selected from-NH-, -O-, -S-;

R ^C independently selected from oxygen, halogen, -CN, -NO ₂ ，-OR，-SR，-NR ₂ ，-S(O) ₂ R，-S(O) ₂ NR ₂ ，-S(O)R，-S(O)NR ₂ ，-S(O) ₂ F，-OS(O) ₂ F，-C(O)R，-C(O)OR，-C(O)NR ₂ ，-C(O)N(R)OR，-OC(O)R，-OC(O)NR ₂ ，-N(R)C(O)OR，-N(R)C(O)R，-N(R)C(O)NR ₂ ，-N(R)C(NR)NR ₂ ，-N(R)S(O) ₂ NR ₂ or-N (R) S (O) ₂ R；C _1-6 Aliphatic hydrocarbon groups (e.g. C ₁ - ₆ Alkyl or C _2-6 Alkenyl groups); a phenyl group; c (C) _3-7 A saturated or partially unsaturated heterocycloalkyl group selected from the group consisting of a heteroatom or a heteroatom group comprising 1 or 2 heteroatoms independently selected from-NH-, -O-, -S-; c (C) _5-6 Heteroaryl selected from the group consisting of heteroatoms or groups of heteroatoms comprising 1,2,3 or 4 groups independently selected from-NH-, -O-, -S-;

r is independently selected from hydrogen, or optionally C _1-6 Aliphatic hydrocarbon groups (e.g. C _1-6 Alkyl or C _2-6 Alkenyl groups); a phenyl group; c (C) _3-7 Saturated or partially unsaturated heterocycloalkyl selected from the group consisting ofContaining 1 or 2 heteroatoms or groups of heteroatoms independently selected from-NH-, -O-, -S-; c (C) _5-6 Heteroaryl selected from the group consisting of 1,2,3, or 4 heteroatoms or groups of heteroatoms independently selected from-NH-, -O-, -S-;

when two R groups are attached to the same nitrogen atom, the two R groups together with the nitrogen atom to which they are attached form C _4-7 A partially unsaturated heteroaryl group, wherein the heteroaryl group comprises 0,1,2 or 3 heteroatoms or groups of heteroatoms independently selected from-NH-, -O-, -S-;

m, n, p, q, r, t, u, v and w are independently selected from 0,1,2,3 or 4.

As described above, for Cy ⁶ In some preferred configurations, cy ⁶ Selected from phenylene, divalent saturated or partially unsaturated C _3-7 A monocyclic alkyl group; divalent saturated or partially unsaturated C _8-14 A bicycloalkyl group; divalent saturated or partially unsaturated C _3-7 Mono-heterocycloalkyl; the mono-heterocycloalkyl group contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from-N-, -O-, -S-; divalent saturated or partially unsaturated C _8-14 A bis-heterocycloalkyl; the bisheterocycloalkyl group contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from-N-, -O-, -S-; c (C) _5-6 A monocyclic heteroaryl group, said monocyclic heteroaryl group each comprising 1, 2, 3 or 4 heteroatoms or groups of heteroatoms independently selected from-N-, -O-, -S-; c (C) _9-10 A bicyclic heteroaryl group; the bicyclic heteroaryl groups each contain 1, 2, 3, or 4 heteroatoms or groups of heteroatoms independently selected from-N-, -O-, -S-; the Cy ⁶ De-L ⁶ -R ^W In addition, it is also subjected to p R ⁶ Group substitution;

in some preferred constructions, cy ⁶ Selected from divalent saturated or partially unsaturated C _3-14 Cycloalkyl; the Cy ⁶ De-L ⁶ -R ^W In addition, it is also subjected to p R ⁶ Group substitution; in some embodiments, cy ⁶ Selected from divalent saturated or partially unsaturated C _3-7 Monocycloalkyl, or divalent saturated or partially unsaturated C _8-14 Bicycloalkyl radicalsThe method comprises the steps of carrying out a first treatment on the surface of the The Cy ⁶ De-L ⁶ -R ^W In addition, it is also subjected to p R ⁶ Group substitution; cy (Cy) ⁶ Selected from divalent saturated or partially unsaturated C _3-7 Mono-heterocycloalkyl; the Cy ⁶ De-L ⁶ -R ^W In addition, it is also subjected to p R ⁶ Group substitution; cy (Cy) ⁶ Selected from divalent saturated or partially unsaturated C _8-14 A bis-heterocycloalkyl; the Cy ⁶ De-L ⁶ -R ^W In addition, it is also subjected to p R ⁶ Group substitution;

in some preferred constructions, cy ⁶ Selected from divalent saturated or partially unsaturated C _3-14 A heterocycloalkyl group; the heterocycloalkyl group contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from-N-, -O-, -S-; the Cy ⁶ De-L ⁶ -R ^W In addition, it is also subjected to p R ⁶ Group substitution; in some embodiments, cy ⁶ Selected from divalent saturated or partially unsaturated C _3-7 Mono-heterocycloalkyl; the mono-heterocycloalkyl group contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from-N-, -O-, -S-; or C _8-14 A bicycloalkyl group; the bicycloalkyl groups each contain 1, 2, 3 or 4 heteroatoms or groups of heteroatoms independently selected from-N-, -O-, -S-; the Cy ⁶ De-L ⁶ -R ^W In addition, it is also subjected to p R ⁶ Group substitution;

in some preferred constructions, cy ⁶ Selected from divalent saturated or partially unsaturated C _3-7 Mono-heterocycloalkyl; the mono-heterocycloalkyl group contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from-N-, -O-, -S-; the Cy ⁶ De-L ⁶ -R ^W In addition, it is also subjected to p R ⁶ Group substitution; in some embodiments, cy ⁶ Selected from divalent saturated or partially unsaturated C _5-6 Mono-heterocycloalkyl; the mono-heterocycloalkyl group contains 1 or 2 heteroatoms or hetero atom groups independently selected from-N-, -O-, -S-; the Cy ⁶ De-L ⁶ -R ^W In addition, it is also subjected to p R ⁶ Group substitution; in some embodiments, cy ⁶ Selected from pyrrolidinyl or dihydropyridineA pyrrolidinyl group; the Cy ⁶ De-L ⁶ -R ^W In addition, it is also subjected to p R ⁶ Group substitution;

in some preferred constructions, cy ⁶ Selected from C _5-14 Heteroaryl; the heteroaryl groups each contain 1, 2, 3 or 4 heteroatoms or groups of heteroatoms independently selected from-N-, -O-, -S-; the Cy ⁶ De-L ⁶ -R ^W In addition, it is also subjected to p R ⁶ Group substitution; in some embodiments, cy ⁶ Selecting C _5-6 A monocyclic heteroaryl group; the monocyclic heteroaryl groups each contain 1, 2, 3 or 4 heteroatoms or groups of heteroatoms independently selected from-N-, -O-, -S-; or C _9-10 A bicyclic heteroaryl group, each comprising 1, 2, 3, or 4 heteroatoms or groups of heteroatoms independently selected from-N-, -O-, -S-; the Cy ⁶ De-L ⁶ -R ^W In addition, it is also subjected to p R ⁶ Group substitution;

in some preferred constructions, cy ⁶ Selected from C _5-6 A monocyclic heteroaryl group; the monocyclic heteroaryl groups each contain 1, 2, 3 or 4 heteroatoms or groups of heteroatoms independently selected from-N-, -O-, -S-; the Cy ⁶ De-L ⁶ -R ^W In addition, it is also subjected to p R ⁶ Group substitution; in some embodiments, cy ⁶ Selecting C _5-6 A monocyclic heteroaryl group; the monocyclic heteroaryl groups each contain 1 or 2 heteroatoms or groups of heteroatoms independently selected from-N-, -O-, -S-; the Cy ⁶ De-L ⁶ -R ^W In addition, it is also subjected to p R ⁶ Group substitution; in some embodiments, cy ⁶ Selecting C ₅ A monocyclic heteroaryl group; the monocyclic heteroaryl groups each contain 1 or 2 independently selected nitrogen atoms; the Cy ⁶ De-L ⁶ -R ^W In addition, it is also subjected to p R ⁶ Group substitution;

in some preferred constructions, cy ⁶ Selected from C _9-10 A bicyclic heteroaryl group; the bicyclic heteroaryl groups each contain 1, 2, 3, or 4 heteroatoms or groups of heteroatoms independently selected from-N-, -O-, -S-; the Cy ⁶ De-L ⁶ -R ^W In addition, it is also subjected to p R ⁶ Group substitution; in some embodiments of the present invention, in some embodiments,Cy ⁶ selecting C _9-10 A bicyclic heteroaryl group; the C is _9-10 Bicyclic heteroaryl groups each contain 1, 2 or 3 independently selected nitrogen atoms; the Cy ⁶ De-L ⁶ -R ^W In addition, it is also subjected to p R ⁶ Group substitution;

in some specific embodiments, -Cy ⁶ -L ⁶ -R ^W Selected from:

R ⁶ are respectively and independently selected from R ^A Or R is ^B The R is ⁶ Through q R ^C Group substitution; or two R ⁶ A group, one R ⁶ Radicals and one R ^L The radicals together with the atoms to which they are attached form C _4-8 A partially unsaturated group or heteroaryl group, said C _4-8 The partially unsaturated group or heteroaryl group comprises 0, 1, 2, 3 or 4 heteroatoms or groups of heteroatoms independently selected from-NH-, -O-, -S-, respectively; the ring is covered by R R ^C A group substitution;

in some embodiments, two R ⁶ A group, one R ⁶ Radicals and one R ^L The radicals together with the atoms to which they are attached form C _4-8 A partially unsaturated group or heteroaryl group, said C _4-8 The partially unsaturated group or heteroaryl group comprises 0, 1, 2, 3 or 4 heteroatoms or groups of heteroatoms independently selected from-NH-, -O-, -S-, respectively; the ring is covered by R R ^C A group substitution;

in some preferred structures, R ⁵ (as shown in the specification, R ^5A -L ⁵ -R ^5B ) Selected from:

in some embodiments of the invention, the invention provides a compound of formula I-1, where R ^5A Selected from the group consisting of aromatic ring groups, aromatic heterocyclic rings, saturated or unsaturated cycloalkyl groups and their substituents including, but not limited to, phenylene, pyridylene, or cyclohexenylene and their substituents, Thus, compounds of the formula II-1, III-1, IV-1 or V-1 are formed:

or a pharmaceutically acceptable salt;

in some embodiments of the invention, the invention provides a compound of formula I-1, where R ^5A Selected from phenylene, pyridylene, or pyrimidinylene, thus forming a compound of formula VI-1, VII-1, VIII-1, or IX-1:

or a pharmaceutically acceptable salt;

in some embodiments of the invention, the invention provides a compound of formula II-1, III-1, IV-1 or V-1, said Cy ⁶ Selected from phenyl, thus forming a compound of formula X-1, XI-1, XII-1 or XIII-1:

or a pharmaceutically acceptable salt;

for example, in some embodiments of the invention, the invention provides compounds of formula X-1, XI-1, XII-1 or XIII-1:

or a pharmaceutically acceptable salt thereof, which R is as follows ⁵ Selected from the group consisting of

-Cy ⁶ -L ⁶ -R ^W Selected from the group consisting of

R ^5B Selected from hydrogen or R ^B The R is ^5B Through n R ^5D Group substitution;

R ^W selected from the following groups: a halogen atom,

R ⁶ are respectively and independently selected from R ^A Or R is ^B The R is ⁶ Through q R ^C Replacement; two R ⁶ A group, one R ⁶ Radicals and one R ^L The radicals being independently selected from C _4-7 A partially unsaturated group or an aryl group, said C _4-7 The partially unsaturated group or aryl group comprises 0, 1, 2, 3 or 4 heteroatoms or groups of heteroatoms independently selected from-NH-, -O-, -S-, respectively; the ring is covered by R R ^C A group substitution;

L ⁵ and L ⁶ Independently selected from a covalent bond, or C _1-4 Divalent saturated or unsaturated, straight or branched hydrocarbon chains in which one or two methylene units on the chain may be replaced by-CH (R ^L )-，-C(R ^L ) ₂ -，C _3-5 Cycloalkyl, C _3-5 Heterocycloalkyl, C _5-6 Heteroaryl, -NH-, -N (R) ^L )-，-NHC(O)-，-N(R ^L )C(O)-，-C(O)NH-，-C(O)N(R ^L )-，-NHS(O) ₂ -，-N(R ^L )S(O) ₂ -，-S(O) ₂ NH-，-S(O) ₂ N(R ^L ) -, -O-, -C (O) -, -OC (O) -, -C (O) O-, -S-, -S (O) -, or-S (O) ₂ -independent substitution;

-R ^WA ，R ^WB and R is ^WC Independently selected from hydrogen, deuterium, halogen, -CN-, -C (O) R-, -C (O) OR, -C (O) NR ₂ (C (O) N (R) OR, OR optionally C _1-6 Aliphatic hydrocarbon groups (e.g. C _1-6 Alkyl or C _2-6 Alkenyl), phenyl, C _3-7 Saturated or partially unsaturated heterocycloalkyl comprising 1,2 are independently selected from the group consisting of-NH-, -O-, the hetero atom of the-S-, and C _5-6 Heteroaryl comprising 1, 2, 3, or 4 heteroatoms independently selected from-NH-, -O-, -S-; or (b)

R ^WA And R is ^WB ，R ^WB And R is ^WC Or R ^WC And R is ^L Together with the atoms to which they are attached form C _4-7 A saturated, partially unsaturated ring of (a), said rings each comprising 0, 1 or 2 heteroatoms or groups of heteroatoms independently selected from-NH-, -O-, -S-;

R ^WD selected from halogen or-OS (O) ₂ R；

R ^5C ，R ^5D And R is ^7A Independently selected from R ^A Or R is ^B And is selected from u R ^C A substituent group;

R ^C independent selectionFrom oxygen, halogen, -CN, -NO ₂ ，-OR，-SR，-NR ₂ ，-S(O) ₂ R，-S(O) ₂ NR ₂ ，-S(O)R，-S(O)NR ₂ ，-S(O) ₂ F，-OS(O) ₂ F，-C(O)R，-C(O)OR，-C(O)NR ₂ ，-C(O)N(R)OR，-OC(O)R，-OC(O)NR ₂ ，-N(R)C(O)OR，-N(R)C(O)R，-N(R)C(O)NR ₂ ，-N(R)C(NR)NR ₂ ，-N(R)S(O) ₂ NR ₂ ，-N(R)S(O) ₂ R, or C _1-6 Aliphatic hydrocarbon groups (e.g. C _1-6 Alkyl or C _2-6 Alkenyl), phenyl, C _3-7 A saturated or partially unsaturated heterocycloalkyl group selected from the group consisting of a heteroatom or a heteroatom group comprising 1 or 2 heteroatoms independently selected from-NH-, -O-, -S-; c (C) _5-6 Heteroaryl selected from the group consisting of heteroatoms or groups of heteroatoms comprising 1, 2, 3 or 4 groups independently selected from-NH-, -O-, -S-;

r is independently selected from hydrogen, or optionally C _1-6 Aliphatic hydrocarbon groups (e.g. C _1-6 Alkyl or C _2-6 Alkenyl groups); a phenyl group; c (C) _3-7 A saturated or partially unsaturated heterocycloalkyl group selected from the group consisting of a heteroatom or a heteroatom group comprising 1 or 2 heteroatoms independently selected from-NH-, -O-, -S-; c (C) _5-6 Heteroaryl selected from the group consisting of heteroatoms or groups of heteroatoms comprising 1,2,3 or 4 groups independently selected from-NH-, -O-, -S-;

or R and R together with the nitrogen atom to which they are attached form C _4-7 A partially unsaturated heteroaryl group, wherein the heteroaryl group comprises 0,1,2 or 3 heteroatoms independently selected from nitrogen;

any of m, n, p, q, r, t, u, v and w is independently selected from 0,1,2,3 or 4.

In some embodiments of the invention, the invention provides a compound of formula II-1, III-1, IV-1 or V-1, said Cy ⁶ Selected from the group consisting of pyridylene groups, thus forming compounds of the formula XIV-1, XV-1, XVI-1, XVII-1, XVIII-1, XIX-1, XX-1, or XXI-1, respectively:

or a pharmaceutically acceptable salt;

in some embodiments of the invention, the invention provides a compound of formula II-1, III-1, IV-1 or V-1, said Cy ⁶ Selected from pyrimidinylene groups, thus forming a compound of formula XXII-1, XXIII-1, XXIV-1, or XXV-1, respectively:

or a pharmaceutically acceptable salt thereof, said L ⁵ ，L ⁶ ， ^R5B ，R ^5C ，R ^W ，R ⁶ Each variable in m and p is as defined in the embodiments, classes and subclasses herein.

In some embodiments of the invention, the invention provides compounds of formula I-1, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1, IX-1, X-1, XI-1, XII-1, XIII-1, XIV-1, XV-1, XVI-1, XVII-1, XVIII-1, XIX-1, XX-1, XXI-1, XXII-1, XXIII-1, XXIV-1, or XXV-1, the said compoundsWherein->Represents the connection R ⁵ Key of->Representing the linkage Cy ⁶ Is a key of (c). The L is ⁵ Selected from the group consisting of-O-, -C (O) -, -C (O) NH-, or-C (O) N (R) ^L ) -; in more preferred embodiments, the L ⁵ Selected from-C (O) -;

in more preferred embodiments, the L ⁵ Selected from-C (O) NH-; in more preferred embodiments, the L ⁵ Selected from-C (O) N (R) ^L ) -; in more preferred embodiments, the L ⁶ Selected from-NH-, -N (R) ^L )-；

In more preferred embodiments, m is selected from 0 or 1; in more preferred embodiments, p is selected from 0;

in more preferred embodiments, the R ^W Selected from the group consisting ofIn more preferred embodiments, the R ^W Selected from->In more preferred embodiments, the R ^W Selected from-C (O) -C ₂ H ₃ (vinylformyl).

Preferably, R ⁵ One or more (preferably all) of the following conditions are satisfied:

(1)m＝1，

(2)R ^5A Is a group consisting of 1, 4-phenylene,

(3) In the case where (1) and (2) are satisfied at the same time, R ^5C The substitution position is-L ⁵ The ortho-position of the group-the ortho-position,

(4)R ^5C selected from the group consisting of halogen, more preferably fluorine,

(5)R ^5B is C ^1-6 Alkyl (preferably methyl) substituted pyridinyl or pyrimidinyl.

More preferably, R ⁵ Is thatFurther preferably +.>Wherein m=1, r ^5C Selected from halogen (more preferably fluorine), X is CH or N.

at-Cy ⁶ -L ⁶ -R ^W Preferably, -Cy ⁶ -L ⁶ -part has nitrogen atoms, R ^W The tail end is carbonyl, and the nitrogen atom and the carbonyl form an amide group>N-C(＝O)-)。

More preferably, -Cy ⁶ -L ⁶ -R ^W Selected from:

even more preferably:

above-mentioned-Cy ⁶ -L ⁶ -R ^W The aromatic or heteroaromatic ring moiety in (2) may be substituted with p R ⁶ Group substitution, R ⁶ Selected from-H, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, -CN, -NH (C) _1-6 Alkyl), -N (C) _1-6 Alkyl group ₂ Preferably selected from the group consisting of-H, -F, -Cl and-CH ₃ 、-OCH ₃ P is selected from 0, 1, 2, 3 or 4.

Preferably, R ⁷ Selected from H, C _1-6 Alkyl, C _3-7 A saturated or partially unsaturated mono-heterocycloalkyl group selected from the group consisting of a heteroatom or a heteroatom group comprising 1 or 2 heteroatoms independently selected from-NH-, -O-, -S-; optionally R ⁷ Is selected from C _1-6 Alkyl, hydroxy, halogen groups.

In a particularly preferred embodiment, the present invention provides a compound of the formula XXVI-1 or XXVI-2, or a pharmaceutically acceptable salt thereof, as follows:

Wherein Cy ⁶ 、L ⁶ 、R ^WA Having the definition as described hereinbefore, X is CH or N, and-Cy ⁶ -L ⁶ -partly through nitrogen atoms withAnd part of the connection. Preferably, -Cy ⁶ -L ⁶ -part is optionally covered by C _1-6 Alkyl-or halogen-substituted phenyleneamino, pyridylamino, azetidinyl, azacyclopentyl, azacyclohexenyl, azapentenyl, azahexenyl, methyleneazetidinyl, methyleneazapentyl, methyleneazacyclohexenyl; r is R ^WA Is hydrogen or C _1-6 An alkyl group. R is R ⁷ Selected from C _1-6 Alkyl, trifluoromethyl, cyano, dimethylphosphoryl, 2-isopropanol-2-yl, methoxy, 1-hydroxyethyl, morpholinomethyl, (4-methylpiperazin-1-yl) -methyl.

In a further particularly preferred embodiment, the present invention provides a compound represented by the following formula XXVII:

wherein R is ^5C Selected from halogen and C _1-6 Alkoxy, preferably halogen (more preferably fluorine); r is R ⁶ Selected from-H, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, -CN, -NH (C) _1-6 Alkyl), -N (C) _1-6 Alkyl group ₂ The method comprises the steps of carrying out a first treatment on the surface of the X is CH or N; r is R ⁷ Selected from H, C _1-6 Alkyl (preferably methyl), C _3-7 A saturated or partially unsaturated mono-heterocycloalkyl group selected from the group consisting of a heteroatom or a heteroatom group comprising 1 or 2 heteroatoms independently selected from-NH-, -O-, -S-; optionally when R ⁷ When the R is not H, R ⁷ Is selected from C _1-6 Alkyl, hydroxy, halogen groups; m and p are independently selected from 0,1,2,3 or 4, preferably m=1 and/or p=0; r is R ^WA Selected from H or methyl.

In a still further particularly preferred embodiment, the present invention provides a compound represented by the following formula XXVIII-1 or XXVIII-2, or a pharmaceutically acceptable salt thereof:

wherein R is ⁶ Selected from-H, -F, -Cl、-CH ₃ 、-OCH ₃ X is CH or N, R ⁷ Selected from H, C _1-6 Alkyl (preferably methyl), C _3-7 A saturated or partially unsaturated mono-heterocycloalkyl group selected from the group consisting of a heteroatom or a heteroatom group comprising 1 or 2 heteroatoms independently selected from-NH-, -O-, -S-; optionally when R ⁷ When the R is not H, R ⁷ Is selected from C _1-6 Alkyl, hydroxy, halogen groups; p is selected from 0,1,2,3 or 4, preferably 0; r is R ^WA Selected from H or methyl.

The invention also provides a compound shown in the following formula or pharmaceutically acceptable salt thereof,

/>

the invention also provides a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to the above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The invention also provides application of the compound or pharmaceutically acceptable salt thereof or the composition in preparing FGFR inhibitor.

In some aspects of the invention, in the above use, the FGFR inhibitor is a medicament for solid tumors. Preferably, the solid tumor is selected from intrahepatic cholangiocarcinoma and gastric cancer.

Definition of the definition

The compounds of the present invention include those generally described herein, and are further described in terms of the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For the purposes of the present invention, chemical elements are identified according to the CAS version of the periodic Table of the elements (Manual of chemistry and physics (Handbook of Chemistry and Physics), 75 th edition). Furthermore, the general principle of organic chemistry is described in "organic chemistry (Organic Chemistry)", thomas sorrel (Thomas sorrel), university science press (University Science Books), soralito (sausalato): 1999 and "Ma Jigao grade organic chemistry (March's Advanced Organic Chemistry)", 5 th edition, editors: smith m.b. (Smith, m.b.) and Ma Ji j. (March, j.), john wili father company (John Wiley & Sons), new York (New York): 2001, the entire contents of which are incorporated herein by reference. Where the same structure is described, chemical names, common names, and chemical structures may be used interchangeably. If chemical structures and chemical names are used to refer to compounds and there is a divergence between the structures and names, the structures are subject to control.

As used herein, the term "aliphatic" or "aliphatic group" means a linear (i.e., unbranched) or branched hydrocarbon chain containing one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon having a single point of attachment to the remainder of the molecule, which is fully saturated or contains one or more unsaturated units, but which is not aromatic (also referred to herein as "carbocyclic" or "cycloaliphatic"). Unless otherwise specified, aliphatic groups contain 1 to 6 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1 to 5 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1 to 4 aliphatic carbon atoms. In still other embodiments, the aliphatic group contains 1 to 3 aliphatic carbon atoms, and in yet other embodiments, the aliphatic group contains 1 to 2 aliphatic carbon atoms. In some embodiments, the "cycloaliphatic group" is"(or" carbocycle ") means a monocyclic C that is fully saturated or contains one or more units of unsaturation, but which is not aromatic ₃ -C ₆ Hydrocarbons, which have a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, straight or branched chain, substituted or unsubstituted alkyl, alkenyl, alkynyl, and mixtures thereof, such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl, or (cycloalkyl) alkenyl.

As used herein, unless otherwise indicated, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon radical having a straight or branched chain, wherein the radical is optionally substituted at one or more carbon atoms of the straight, branched, monocyclic or polycyclic moiety or combination thereof with one or more substituents at each carbon, wherein the one or more substituents are independently C ₁ -C ₁₀ An alkyl group. Examples of "alkyl" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, and the like. Unless otherwise indicated, "alkyl" (including alkyl moieties in alkyl-containing groups) as defined herein refers to C _1-6 An alkyl group.

The term "alkenyl" refers to a monovalent aliphatic hydrocarbon group having at least one carbon-carbon double bond, either straight or branched. Unless otherwise indicated, "alkenyl" (including alkenyl moieties in alkenyl-containing groups) as defined in the definition of each group herein refers to C _2-6 Alkenyl groups.

The term "alkynyl" refers to a monovalent aliphatic hydrocarbon group having at least one carbon-carbon triple bond, either straight or branched. Unless otherwise indicated, "alkynyl" (including alkenyl moieties in alkenyl-containing groups) as defined in the definition of each group herein refers to C _2-6 Alkynyl groups.

The term "cycloalkyl" refers to a monovalent saturated aliphatic hydrocarbon group having a single or multiple ring structure. Examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl and the like. Unless otherwise indicated, "cycloalkyl" (including cycloalkyl moieties in cycloalkyl-containing groups) as defined herein in the definition of each group refers to C _3-14 Cycloalkyl groups.

The term "lower alkyl" refers to a C1-4 straight or branched chain alkyl. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

The term "lower haloalkyl" refers to a C1-4 straight or branched chain alkyl group substituted with one or more halogen atoms.

The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; quaternized forms of any basic nitrogen; or a heterocyclic substitutable nitrogen, such as N (as in 3, 4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR ⁺ (as in a substituted pyrrolidinyl group on N)).

As used herein, the term "unsaturated" means that a moiety has one or more unsaturated units.

As used herein, the term "C _1-8 (or C) _1-6 Or C _1-4 ) Saturated or unsaturated, straight or branched divalent hydrocarbon chain "refers to divalent alkylene, alkenylene, and alkynylene chains as defined herein as straight or branched chains.

The term "alkylene" refers to a divalent alkyl group. "alkylene chain" is polymethylene, i.e., - (CH) ₂ ) _n -wherein n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2 or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced by substituents. Suitable substituents include those described below with respect to the substituted aliphatic groups. Unless otherwise indicated, "alkylene" as defined in the definition of each group herein means C _1-6 An alkylene group.

The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below with respect to the substituted aliphatic groups. Unless otherwise indicated, "alkenylene" as defined in the definition of each group herein refers to C _2-6 Alkenylene radicals.

The term "halogen" means F, cl, br or I.

The term "aryl" used alone or as part of a larger moiety (such as "aralkyl", "aralkoxy" or "aryloxyalkyl") refers to a mono-or bi-cyclic system having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aromatic ring". In certain embodiments of the present invention, "aryl" refers to an aromatic ring system that may have one or more substituents, including, but not limited to, phenyl, biphenyl, naphthyl, anthracenyl, and the like.

As used herein, unless otherwise defined, the term "heteroaryl" or "heteroaromatic" refers to a 5-to 6-membered monocyclic aromatic ring containing one or more heteroatoms (e.g., one to three heteroatoms such as nitrogen, oxygen, and sulfur), or an 8-to 10-membered polycyclic ring system containing one or more heteroatoms, wherein at least one ring in the polycyclic ring system is aromatic and the point of attachment of the polycyclic ring system is via a ring atom on the aromatic ring. Heteroaryl rings may be attached to adjacent groups via carbon or nitrogen. Examples of heteroaryl rings include, but are not limited to, furan, thiophene, pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine, pyrimidine, indole, and the like. For example, unless otherwise defined, 1,2,3, 4-tetrahydroquinoline is a heteroaryl ring provided that its point of attachment is via a benzo ring, such as:

unless otherwise defined, the term "heterocyclyl" or "heterocyclic group" refers to a saturated or partially unsaturated 3-to 10-membered monocyclic or 7-to 14-membered polycyclic ring system, including bridged or fused rings, and which ring system includes one to four heteroatoms, such as nitrogen, oxygen and sulfur. The heterocyclyl ring may be linked to an adjacent group via carbon or nitrogen.

Unless otherwise defined, the term "partially unsaturated" in the context of a ring refers to a constituent ring within a monocyclic, or polycyclic (e.g., bicyclic, tricyclic, etc.) ring system, wherein the constituent ring contains at least one unsaturation other than that provided by the ring itself, but which is not aromatic. Examples of partially unsaturated rings include, but are not limited to, 3, 4-dihydro-2H-pyran, 3-pyrroline, 2-thiazoline, and the like. Where the partially unsaturated ring is part of a polycyclic ring system, the other constituent rings in the polycyclic ring system may be saturated, partially unsaturated, or aromatic, but the point of attachment of the polycyclic ring system is on the partially unsaturated constituent ring. For example, unless otherwise defined, 1,2,3, 4-tetrahydroquinoline is a partially unsaturated ring provided that its point of attachment is via a piperidinyl ring, such as:

unless otherwise defined, the term "saturated" in the context of a ring refers to a 3 to 10 membered monocyclic or 7 to 14 membered polycyclic (e.g., bicyclic, tricyclic, etc.) ring system wherein the monocyclic or the constituent rings that are points of attachment to the polycyclic ring system do not contain additional unsaturation beyond that provided by the ring itself. Examples of monocyclic saturated rings include, but are not limited to, azetidine, oxetane, cyclohexane, and the like. Where the saturated ring is part of a polycyclic ring system, the other constituent rings in the polycyclic ring system may be saturated, partially unsaturated, or aromatic, but the point of attachment of the polycyclic ring system is on the saturated constituent ring. For example, unless otherwise defined, 2-azaspiro [3.4] oct-6-ene is a saturated ring, provided that its point of attachment is via an N-azetidinyl ring, such as:

As used herein, the terms "alkylene", "arylene", "cycloalkylene", "heteroarylene", "heterocycloalkylene" and other like terms having the prefix "alkylene" refer to the divalent bonding form of the group modified by the prefix. For example, "alkylene" is a divalent alkyl group that connects a group to the person to which it is attached.

As used herein, the term "bridged bicyclic" refers to any saturated or partially unsaturated bicyclic ring system having at least one bridge, i.e., a carbocyclic or heterocyclic ring. As defined by IUPAC, "bridging" is a bond to multiple atoms or to an atom that is unbranched or connects two bridgeheads, where "bridgehead" is any backbone atom of a ring system that is bonded to three or more backbone atoms (except hydrogen). In some embodiments, the bridge Lian Shuanghuan group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridge Lian Shuanghuan groups are well known in the art and include those set forth below, wherein each group is attached to the remainder of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise indicated, the bridge Lian Shuanghuan groups are optionally substituted with one or more substituents as set forth with respect to aliphatic groups. Alternatively or additionally, any substitutable nitrogen of the bridge Lian Shuanghuan group is optionally substituted. Exemplary bridged bicyclic rings include:

As described herein, the compounds of the present invention may contain an "optionally substituted" moiety. In general, the term "substituted" means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have suitable substituents at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from the given group, the substituents at each position may be the same or different. Combinations of substituents contemplated by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to a compound that does not substantially change when subjected to conditions that allow it to be produced, detected, and (in some embodiments) recovered, purified, and used for one or more of the purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen; - (CH) ₂ ) _0-4 R ^o ；-(CH ₂ ) _0-4 OR ^o ；-O(CH ₂ ) _0-4 R ^o ；-O-(CH ₂ ) _0-4 C(O)OR ^o ；-(CH ₂ ) _0-4 CH(OR ^o ) ₂ ；-(CH ₂ ) _0-4 SR ^o The method comprises the steps of carrying out a first treatment on the surface of the Can pass through R ^o Substituted- (CH) ₂ ) _0-4 Ph; can pass through R ^o Substituted- (CH 2) _0-4 O(CH ₂ ) _0-1 Ph; can pass through R ^o Substituted-ch=chph; can pass through R ^o Substituted- (CH) ₂ ) _0-4 O(CH ₂ ) _0-1 -a pyridinyl group; -NO ₂ ；-CN；-N ₃ ；-(CH ₂ ) _0-4 N(R ^o ) ₂ ；-(CH ₂ ) _0-4 N(R ^o )C(O)R ^o ；-N(R ^o )C(S)R ^o ；-(CH ₂ ) _0-4 N(R ^o )C(O)NR ^o ₂ ；-N(R ^o )C(S)NR ^o ₂ ；-(CH ₂ ) _0-4 N(R ^o )C(O)OR ^o ；-N(R ^o )N(R ^o )C(O)R ^o ；-N(R ^o )N(R ^o )C(O)NR ^o ₂ ；-N(R ^o )N(R ^o )C(O)OR ^o ；-(CH ₂ ) _0-4 C(O)R ^o ；-C(S)R ^o ；-(CH ₂ ) _0- ₄ C(O)OR ^o ；-(CH ₂ ) _0-4 C(O)SR ^o ；-(CH ₂ ) _0-4 C(O)OSiR ^o ₃ ；-(CH ₂ ) _0-4 OC(O)R ^o ；-OC(O)(CH ₂ ) _0-4 SR ^o ；-SC(S)SR ^o ；-(CH ₂ ) _0-4 SC(O)R ^o ；-(CH ₂ ) _0-4 C(O)NR ^o ₂ ；-C(S)NR ^o ₂ ；-C(S)SR ^o ；-SC(S)SR ^o ；-(CH ₂ ) _0-4 OC(O)NR ^o ₂ ；-C(O)N(OR ^o )R ^o ；-C(O)C(O)R ^o ；-C(O)CH ₂ C(O)R ^o ；-C(NOR ^o )R ^o ；-(CH ₂ ) _0-4 SSR ^o ；-(CH ₂ ) _0- ₄ S(O) ₂ R ^o ；-(CH ₂ ) _0-4 S(O) ₂ OR ^o ；-(CH ₂ ) _0-4 OS(O) ₂ R ^o ；-S(O) ₂ NR ^o ₂ ；-(CH ₂ ) _0-4 S(O)R ^o ；-N(R ^o )S(O) ₂ NR ^o ₂ ；-N(R ^o )S(O) ₂ R ^o ；-N(OR ^o )R ^o ；-C(NH)NR ^o ₂ ；-P(O)(OR ^o )R ^o ；-P(O)R ^o ₂ ；-OP(O)R ^o ₂ ；-OP(O)(OR ^o ) ₂ ；-SiR ^o ₃ ；-(C _1-4 Linear or branched alkylene) O-N (R ^o ) ₂ The method comprises the steps of carrying out a first treatment on the surface of the Or- (C) _1-4 Straight-chain or branched alkylene) C (O) O-N (R) ^o ) ₂ Wherein each R is ^o May be substituted as defined below and independently hydrogen, C _1-6 Aliphatic, -CH ₂ Ph、-O(CH ₂ ) _0-1 Ph、-CH ₂ - (5-to 6-membered heteroaryl ring), or a 5-to 6-membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or two independently occurring R, regardless of the definition above ^o Together with intervening atoms, form a 3-to 12-membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, said ring may be substituted as defined below.

R ^o Suitable monovalent substituents on (or two independently occurring R ^o Ring formed with intervening atoms) is independently halogen, - (CH) ₂ ) _0-2 R ^· - (halo R) ^· )、-(CH ₂ ) _0-2 OH、-(CH ₂ ) _0-2 OR ^· 、-(CH ₂ ) _0-2 CH(OR ^· ) ₂ The method comprises the steps of carrying out a first treatment on the surface of the -O (halo R) ^· )、-CN、-N ₃ 、-(CH ₂ ) _0-2 C(O)R ^· 、-(CH ₂ ) _0-2 C(O)OH、-(CH ₂ ) _0-2 C(O)OR ^· 、-(CH ₂ ) _0-2 SR ^· 、-(CH ₂ ) _0- ₂ SH、-(CH ₂ ) _0-2 NH ₂ 、-(CH ₂ ) _0-2 NHR ^· 、-(CH ₂ ) _0-2 NR ^· ₂ 、-NO ₂ 、-SiR ^· ₃ 、-OSiR ^· ₃ 、-C(O)SR ^· 、-(C _1-4 Straight-chain OR branched alkylene) C (O) OR ^· or-SSR ^· Wherein each R is ^· Unsubstituted or substituted with only one or more halogen groups in the case of a crown "halo" and independently selected from C _1-4 Aliphatic, -CH ₂ Ph、-O(CH ₂ ) _0-1 Ph or a 5-to 6-membered saturated, partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. R is R ^o Suitable divalent substituents on saturated carbon atoms include =o and =s.

Suitable divalent substituents on the saturated carbon atoms of the "optionally substituted" group include the following: =o, =s, =nnr ^* ₂ 、＝NNHC(O)R ^* 、＝NNHC(O)OR ^* 、＝NNHS(O) ₂ R ^* 、＝NR ^* 、＝NOR ^* 、-O(C(R ^* ₂ )) _2-3 O-or-S (C (R) ^* ₂ )) _2-3 S-, wherein each R independently occurs ^* Is selected from hydrogen, C which may be substituted as defined below _1-6 Aliphatic, or unsubstituted 5-to 6-membered saturated, partially unsaturated, or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents bonded to the ortho-substitutable carbon of an "optionally substituted" group include: -O (CR) ^* ₂ ) _2-3 O-, wherein each R independently occurs ^* Is selected from hydrogen, C which may be substituted as defined below _1-6 Aliphatic groups, or unsubstituted 5-to 6-membered saturated, partially unsaturated, or aromatic rings having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

R ^* Suitable substituents on aliphatic radicals include halogen, -R ^· - (halo R) ^· )、-OH、-OR ^· (halo R) ^· )、-CN、-C(O)OH、-C(O)OR ^· 、-NH ₂ 、-NHR ^· 、-NR ^· ₂ or-NO ₂ Wherein each R is ^· Unsubstituted or substituted by one or more halogens only in the case of a "halo" group and independently C _1-4 Aliphatic, -CH ₂ Ph、-O(CH ₂ ) _0-1 Ph, or a 5-to 6-membered saturated, partially unsaturated, or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the substitutable nitrogen of an "optionally substituted" group include Each of which isIndependently hydrogen, C which may be substituted as defined below _1-6 Aliphatic, unsubstituted-OPh, or an unsubstituted 5-to 6-membered saturated, partially unsaturated, or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or, irrespective of the above definition, two independently occurring +.>Together with intervening atoms, form an unsubstituted 3 to 12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

Suitable substituents on aliphatic radicals are independently halogen, -R ^· - (halo R) ^· )、-OH、-OR ^· (halo R) ^· )、-CN、-C(O)OH、-C(O)OR ^· 、-NH ₂ 、-NHR ^· 、-NR ^· ₂ or-NO ₂ Wherein each R is ^· Unsubstituted or taken by one or more halogens only in the case of "halo" groupsInstead, and independently C _1-4 Aliphatic, -CH ₂ Ph、-O(CH ₂ ) _0-1 Ph, a 5-to 6-membered saturated, partially unsaturated, or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

As used herein, the term "isomer" refers to compounds of the same chemical formula but differing in structure or optical configuration. As used herein, the term "stereoisomer" refers to and includes isomeric molecules of the same molecular formula, but with atoms and/or functional groups positioned differently in space. All stereoisomers of the compounds of the invention (e.g., those stereoisomers that may exist due to asymmetric carbons on each substituent), including enantiomeric and diastereoisomeric forms, are contemplated within the scope of the present disclosure. Thus, unless otherwise indicated, single stereochemical isomers as well as mixtures of enantiomers, diastereomers and geometric (or conformational) isomers of the compounds of the invention are within the scope of the invention.

As used herein, the term "tautomer" is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. It is understood that tautomers encompass valence tautomers and proton tautomers (also known as proton-shifted tautomers). Valence tautomers include interconversions caused by recombination of some of the bound electrons. Proton tautomers include interconversions via proton transfer, such as keto-enol and imine-enamine isomerisation. Unless otherwise indicated, all tautomers of the compounds of the invention are within the scope of the invention.

As used herein, the term "isotopically substituted" refers to the substitution of an atom with its isotope. As used herein, the term "isotope" refers to an atom having the same atomic number as the atoms mainly present in nature, but having a mass number (neutron number) different from the mass number of the atoms mainly present in nature. It is understood that a compound having isotopic substitution refers to a compound in which at least one atom contained therein is isotopically substituted. Atoms that may be isotopically substituted include, but are not limited to, hydrogen, carbon, and oxygen. Hydrogen source Examples of daughter isotopes include ² H (also denoted as D) ³ H. Examples of isotopes of carbon atoms include ¹³ C, C is a metal alloy ¹⁴ C. Examples of isotopes of oxygen atoms include ¹⁸ O. Unless otherwise indicated, all isotopic substitutions of the compounds of the present invention are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the invention. In certain embodiments, for example, warhead portion R of the provided compounds ^W Comprising one or more deuterium atoms.

As used herein, the term "pharmaceutically acceptable salts" refers to those salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like commensurate with a reasonable benefit/_risk ratio. Exemplary pharmaceutically acceptable salts are found, for example, in Berge et al (J.Pharm. Sci.1977, 66 (1), 1; and Gould, P.L., int.J.Pharmaceutics 1986, 33, 201-217, (each of which is incorporated herein by reference in its entirety).

Pharmaceutically acceptable salts of the compounds of the invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups with inorganic acids (e.g., hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric) or with organic acids (e.g., acetic, oxalic, maleic, tartaric, citric, succinic or malonic) or by using other methods used in the art (e.g., ion exchange). Other pharmaceutically acceptable salts include adipic acid salts, alginates, ascorbates, aspartic acid salts, benzenesulfonic acid salts, benzoic acid salts, bisulfate salts, boric acid salts, butyric acid salts, camphoric acid salts, citric acid salts, cyclopentanepropionic acid salts, digluconate, dodecylsulfuric acid salts, ethanesulfonic acid salts, formic acid salts, fumaric acid salts, glucoheptonate, glycerophosphate, gluconic acid salts, hemisulfate, heptanoic acid salts, caproic acid salts, hydroiodides, 2-hydroxy-ethanesulfonic acid salts, lactobionic acid salts, lactic acid salts, lauric acid salts, lauryl sulfuric acid salts, malic acid salts, maleic acid salts, malonic acid salts, methanesulfonic acid salts, 2-naphthalenesulfonic acid salts, nicotinic acid salts, nitrate, oleic acid salts, oxalic acid salts, palmitic acid salts, pamoic acid salts, pectic acid salts, persulfates, 3-phenylpropionic acid salts, phosphate salts, pivalic acid salts, stearic acid salts, succinic acid salts, sulfuric acid salts, tartaric acid salts, thiocyanate salts, p-toluenesulfonic acid salts, undecanoic acid salts, valeric acid salts, and the like.

Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium and N ⁺ (C _1-4 Alkyl group ₄ And (3) salt. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium and amine cations formed using, for example, halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate counter ions.

Pharmaceutically acceptable salts are also intended to encompass hemi-salts, wherein the compound: the ratio of acids was 2:1, respectively. Exemplary hemi-salts are those derived from acids containing two carboxylic acid groups, such as malic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, glutaric acid, oxalic acid, adipic acid, and citric acid. Other exemplary semi-salts are those derived from a aprotic mineral acid (e.g., sulfuric acid). Preferred exemplary hemi-salts include, but are not limited to, hemi-maleate, hemi-fumarate, and hemi-succinate.

As used herein, the term "about" is used herein to refer to about, approximately, about, or near. When the term "about" is used in connection with a range of values, it modifies that range by extending the limits above and below that value. In general, the term "about" is used herein to modify a value above and below the stated value: deviation of 20% up or down (higher or lower).

As used herein, an "effective amount," "sufficient amount," or "therapeutically effective amount" is an amount of a compound sufficient to achieve a beneficial or desired result, including a clinical result. Thus, an effective amount may be sufficient, for example, to reduce or ameliorate the severity and/or duration of a disorder associated with FGFR2 signaling or one or more symptoms thereof; preventing progression of a condition or symptom associated with the disorder related to FGFR2 signaling; or enhance or otherwise improve the prophylactic or therapeutic effect of another therapy. An effective amount also includes an amount of the compound that avoids or substantially reduces undesired side effects.

As used herein and as is well understood in the art, a "treatment" is a route to achieve beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease or illness, stabilized (i.e., not worsening) state of disease or illness, prevention of spread of disease or illness, delay or slowing of progression of disease or illness, amelioration or palliation of the disease or illness state, and remission (whether partial or total), whether detectable or undetectable. "treatment" may also mean that the survival is prolonged compared to the expected survival without treatment. In some embodiments, the therapy may be administered after one or more symptoms have occurred. In other embodiments, the therapy may be administered in the absence of symptoms. For example, the therapy may be administered to a susceptible individual prior to onset of symptoms (e.g., based on a history of symptoms and/or based on genetic or other susceptibility factors). Treatment may also be continued after the symptoms have resolved, for example, to prevent or delay recurrence thereof.

The phrase "in need" refers to a need for symptomatic or asymptomatic relief from a condition associated with FGFR2 signaling activity, or may be otherwise alleviated by the compounds and/or compositions of the present disclosure.

The compounds described herein may be prepared from commercially available starting materials or synthesized using known organic, inorganic and/or enzymatic methods.

(1) From a compound of formula (IA) with a compound of formula (IA) ethynyl-Cy in the presence of an organic base, palladium catalyst ⁶ -L ⁶ Boc undergoes Sonogashira coupling to give intermediate (I)B)：

(2) From a compound of formula (IB) and a compound of formula (R) in the presence of an inorganic base or a palladium catalyst ⁵ ) The Buchwald reaction was carried out to afford Intermediate (IC):

(3) Intermediate (IC) gives Intermediate (ID) under high temperature action of 4-methoxybenzylamine:

(4) Reacting the Intermediate (ID) with acryloyl chloride, acryloyl anhydride, and acryloyl acid to obtain Intermediate (IE):

(5) Deprotection of Intermediate (IE) with a suitable acid affords compounds of formula (I):

(6) The compound of formula I is reacted with a corresponding acid to obtain a pharmaceutically acceptable salt of the compound of formula I, or the base of formula I is adjusted by a base.

Or undergo the following synthetic pathways:

(7) Intermediate (IC) is subjected to halogenation or other reactions to form Intermediate (IF), which is then suitably reacted to introduce the group R ⁷ Intermediate (IG) is generated, and Intermediate (IH) is generated after ammonia water high-temperature reaction:

(8) Reacting the Intermediate (IH) with acryloyl chloride, acryloyl anhydride or acrylic acid or 3- (benzenesulfonyl) propionic acid and removing potassium trimethylsiloxide to obtain a compound of formula (I):

also provided herein is a further method of preparing the above compound, comprising:

/>

(1) From a compound of formula (IIA) with a compound of formula (IIA) ethynyl-Cy in the presence of an inorganic base, palladium catalyst ⁶ -L ⁶ -Boc or-Cy ⁶ -L ⁶ Coupling reaction is carried out to obtain an intermediate (IIB):

(2) From a compound of formula (IIB) with a compound of formula R in the presence of an inorganic base, a palladium catalyst ⁷ Coupling reaction is carried out to obtain an intermediate (IIC):

(3) Reacting the Intermediate (IH) with acryloyl chloride, acryloyl anhydride, acrylic acid or 3- (benzenesulfonyl) propionic acid and removing potassium trimethylsiloxide to obtain a compound of formula (I):

in each step, the anhydrous solvent is selected from ethylene glycol dimethyl ether, dimethylbenzene and methylbenzeneN, N-dimethylformamide, dioxane, methylene chloride, methanol, acetonitrile, dimethyl sulfoxide and the like, and the catalyst is selected from methane sulfonic acid (2-di-bad hexyl phosphine) -3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (BrettPhos Pd G3), tetrakis (triphenylphosphine) palladium (Pd (PPh) ₃ ) ₄ ) [1,1' -bis (diphenylphosphorus) ferrocene]Palladium dichloride (Pd (dppf) Cl) ₂ ) Tris (dibenzyl acetone) dipalladium (0) (Pd) ₂ (dba) ₃ ) Bis dibenzylidene acetone palladium (0) (Pd (dba)) ₂ ) [1,1' -bis (di-t-butylphosphine) ferrocene]Palladium (II) dichloride (Pd (dtbpf) Cl ₂ ) (4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene)][2' -amino-2-biphenylyl group][ (methylsulfonyl) oxy group]Palladium (II) (XantphosPdG 3); copper iodide (CuI); bromosuccinimide (NBS), iodosuccinimide (NIS); the suitable acid is selected from dioxane solution (4M), ethyl acetate solution (4M), acetic acid, toluene sulfonic acid, hydrochloric acid and hydrobromic acid, preferably dioxane solution (4M) and acetic acid; the suitable base is selected from organic or inorganic bases, preferably ammonia, potassium carbonate, cesium carbonate, sodium t-butoxide, potassium phosphate, triethylamine, diisopropylethylamine, (1R, 2R) - (-) -N, N' -dimethylcyclohexane-1, 2-diamine, pyridine, sodium hydride and calcium hydride; the reducing agent is selected from lithium aluminum hydride, sodium borohydride acetate (NaBH (OAc) ₃ ) Sodium cyanoborohydride (NaBH (CN) ₃ ) The method comprises the steps of carrying out a first treatment on the surface of the Sodium cyanoborohydride (NaBH (CN) is preferred ₃ ). The condensing agent is Dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDCI), 1-propylphosphoric anhydride (T) ₃ P), 2- (7-azobenzotriazole) -N, N '-tetramethyluronium Hexafluorophosphate (HATU), benzotriazol-N, N' -tetramethyluronium Hexafluorophosphate (HBTU), and the like. In order to prevent undesired reactions of certain groups (e.g., amino groups, hydroxyl groups, etc.), it is necessary to protect the corresponding groups, while removing the protecting groups when appropriate.

Detailed Description

The following examples are further described herein with the understanding that the examples are included merely for purposes of further illustration and explanation and are not intended to limit the scope of the present disclosure.

Unless defined otherwise, technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the materials and methods are described herein below. In case of conflict, the present specification, including definitions therein, will control and materials, methods, and examples, will control and be in no way limiting. The following describes further the present disclosure in connection with specific examples, but is not intended to limit the scope thereof.

Example 1:

synthesis of N- (6- (4-amino-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) acrylamide:

the synthetic route is as follows:

step one: synthesis of (6-bromo-5-methoxypyridin-3-yl) carbamic acid tert-butyl ester

/>

6-bromo-5-methoxypyridin-3-amine (5.00 g,24.6 mmol) was added to 50mL of tetrahydrofuran, sodium bis (trimethylsilyl) amide (9.93 g,54.1 mmol) was added at-10℃followed by di-tert-butyl dicarbonate (5.37 g,24.6 mmol) and reacted at-10℃for 1 hour. LCMS detected completion of the reaction, quenched the reaction mixture by adding aqueous ammonium chloride, extracted with ethyl acetate, dried, filtered and spin-dried to give tert-butyl (6-bromo-5-methoxypyridin-3-yl) carbamate (5.80 g, 77.6% yield).

¹ H NMR(400MHz，CHLOROFORM-d)δ＝7.84(br s，1H)，7.73(d，J＝2.3Hz，1H)，6.67(br s，1H)，3.94(s，3H)，1.53(s，9H).

Step two: synthesis of tert-butyl (5-methoxy-6- ((trimethylsilyl) ethynyl) pyridin-3-yl) carbamate

Tert-butyl (6-bromo-5-methoxypyridin-3-yl) carbamate (5.00 g,16.4 mmol) was added to 50mL of tetrahydrofuran, and trimethylsilylethylene (2.11 g,21.4 mmol), bis (triphenylphosphine) palladium (II) dichloride (578 mg, 284 umol), cuprous iodide (94.2 mg,494 umol) and triethylamine (5.01 g,49.4 mmol) were added in this order and reacted at 50℃for 1 hour. LCMS detection of reaction completion gave crude tert-butyl (5-methoxy-6- ((trimethylsilyl) ethynyl) pyridin-3-yl) carbamate (5.50 g, crude) by direct spin-drying.

LCMS：m/z 321.1[M+H] ⁺ .

Step three: synthesis of tert-butyl (6-ethynyl-5-methoxypyridin-3-yl) carbamate

Tert-butyl (5-methoxy-6- ((trimethylsilyl) ethynyl) pyridin-3-yl) carbamate (5.50 g,17.1 mmol) was added to 55mL of methanol and potassium carbonate (4.47 g,4.71 mmol) was added and reacted at 25℃for 2 hours. LCMS detection of completion of reaction, spin-drying was isolated by column chromatography to give tert-butyl (6-ethynyl-5-methoxypyridin-3-yl) carbamate (1.50 g, yield 35.2%).

¹ H NMR(400MHz，CHLOROFORM-d)δ＝7.98(br s，1H)，7.94(s，1H)，6.96(br s，1H)，3.96(s，3H)，3.40(s，1H)，1.54(s，9H).

Step four: synthesis of 3-fluoro-4- ((6-methylpyridin-2-yl) oxy) aniline

4-amino-2-fluorophenol (5.00 g,39.3 mmol) was added to 50mL of N, N-dimethylformamide, 2-fluoro-6-methylpyridine (4.37 g,39.3 mmol) and cesium carbonate (25.6 g,78.6 mmol) were added and reacted at 100℃for 2 hours. LCMS detected completion of the reaction, water was added and extracted with ethyl acetate, the organic phase was washed with brine, dried, and the filtrate was spin-dried to give 3-fluoro-4- ((6-methylpyridin-2-yl) oxy) aniline (5.55 g, 60.1% yield) by column chromatography separation.

¹ H NMR(400MHz，DMSO-d6)δ＝7.71-7.61(m，1H)，6.95-6.85(m，2H)，6.68(d，J＝8.1Hz，1H)，6.44(dd，J＝2.6，13.1Hz，1H)，6.36(dd，J＝2.1，8.5Hz，1H)，5.27(s，2H)，2.28(s，3H).

Step five: synthesis of 4-chloro-5-nitro-6- (2, 2-trifluoroethoxy) pyrimidine

2, 2-trifluoroethanol (20.6 g,206 mmol) was dissolved in 200mL of tetrahydrofuran, then sodium hydrogen (8.25 g,206 mmol) was added at 0℃and after stirring for 30 minutes, 4, 6-dichloro-5-nitropyrimidine (40 g,206 mmol) was dissolved in 500mL of tetrahydrofuran and added to the reaction solution for 1 hour, after completion of LCMS detection, the reaction solution was quenched with ice water and stirred for 30 minutes, then extracted with ethyl acetate, the organic phase was washed with brine, dried over Na2SO4, filtered, concentrated and column chromatographed to give 4-chloro-5-nitro-6- (2, 2-trifluoroethoxy) pyrimidine (56.0 g, yield 74.8%).

¹ H NMR(400MHz，CHLOROFORM-d)δ＝8.71(s，1H)，5.00-4.94(m，2H).

Step six: synthesis of 4-chloro-6- (2, 2-trifluoroethoxy) pyrimidin-5-amine

4-chloro-5-nitro-6- (2, 2-trifluoroethoxy) pyrimidine (48.0 g,186 mmol) was dissolved in 400mL of ethanol, 80mL of water, ammonium chloride (19.9 g,372 mmol), reduced iron powder (52.0 g,931 mmol) was added, the reaction was carried out at 80℃for 2 hours, after completion of LCMS detection, the reaction solution was cooled to about 25℃and filtered, concentrated and column chromatographed to give 4-chloro-6- (2, 2-trifluoroethoxy) pyrimidin-5-amine (20.0 g, yield 26.8%).

LCMS：m/z 228.1[M+H] ⁺ .

Step seven: synthesis of 4-iodo-6- (2, 2-trifluoroethoxy) pyrimidin-5-amine

4-chloro-6- (2, 2-trifluoroethoxy) pyrimidin-5-amine (16.0 g,70.3 mmol) was dissolved in 240mL of hydroiodic acid at 25℃and sodium iodide (52.6 g,351 mmol) solution was added, the reaction was checked at 25℃for 3 hours, the reaction was ended by LCMS, aqueous sodium bicarbonate was added to adjust the pH to 7 and extracted with ethyl acetate, the organic phase was washed with brine, filtered, dried by spinning and column chromatography to give 4-iodo-6- (2, 2-trifluoroethoxy) pyrimidin-5-amine (20.7 g, yield 62.7%).

LCMS：m/z 320.0[M+H] ⁺ .

Step eight: synthesis of 5-bromo-4-iodo-6- (2, 2-trifluoroethoxy) pyrimidine

Isoamyl nitrite (17.4 g,148 mmol) was dissolved in 140mL acetonitrile, cuprous bromide (17.9 g,119 mmol), cupric bromide (13.3 g,59.5 mmol) and 4-iodo-6- (2, 2-trifluoroethoxy) pyrimidin-5-amine (19.0 g,59.5 mmol) were added to the mixture at 0deg.C and stirred for 1 hour, LCMS and TLC detection reaction ended, filtration, spin-dry and column chromatography afforded 5-bromo-4-iodo-6- (2, 2-trifluoroethoxy) pyrimidine (10.2 g, 39.0% yield).

¹ H NMR(400MHz，CHLOROFORM-d)δ＝8.40(s，1H)，4.88-4.81(m，2H).

Step nine: synthesis of tert-butyl (6- ((5-bromo-6 (2, 2-trifluoroethoxy) pyrimidin-4-yl) ethynyl) -5-methoxypyridin-3-yl) carbamate

5-bromo 4-iodo-6- (2, 2-trifluoroethoxy) pyrimidine (1.80 g,4.71 mmol) was added to 10mL of N, N-dimethylformamide, and tert-butyl (6-ethynyl-5-methoxypyridin-3-yl) carbamate (1.17 g,4.7 lmmol), 1-bis (diphenylphosphorus) ferrocene palladium chloride (344 mg,47 lumol), cuprous iodide (719 mg,942 umol) and triethylamine (1.19 g,11.7 mmol) were added to react at 20℃for 1 hour. LCMS checked for completion of the reaction, water was added and extracted with ethyl acetate, the organic phase was washed with brine, dried, and the filtrate was dried by spin-on column chromatography to give tert-butyl (6- ((5-bromo-6 (2, 2-trifluoroethoxy) pyrimidin-4-yl) ethynyl) -5-methoxypyridin-3-yl) carbamate (700 mg, 23.6% yield).

¹ H NMR(400MHz，DMSO-d6)δ＝10.03(s，1H)，8.80(s，1H)，8.25(s，1H)，7.84(s，1H)，5.18(q，J＝9.0Hz，2H)，3.89(s，3H)，1.50(s，9H).

Step ten: synthesis of tert-butyl (6- (5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) carbamate

Tert-butyl (6- ((5-bromo-6 (2, 2-trifluoroethoxy) pyrimidin-4-yl) ethynyl) -5-methoxypyridin-3-yl) carbamate (700 mg,1.39 mmol) was dissolved in 14mL dioxane, 3-fluoro-4- ((6-methylpyridin-2-yl) oxy) aniline (333 mg,1.39 mmol), [9, 9-dimethyl-4, 5-bis (diphenylphosphino) xanthene ] [ 2-amino-1, 1-diphenyl ] palladium (II) methanesulfonate dichloromethyl adduct (13lmg, 139 umol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (80.4 mg,139 umol) and cesium carbonate (906 mg,2.78 mmol) were added and reacted at 100℃for 6 hours. TLC monitored completion of the reaction and crude product after concentration was separated by silica gel column to give tert-butyl (6- (5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) carbamate (430 mg, yield 45.8%).

¹ H NMR(400MHz，DMSO-d6)δ＝9.82(s，1H)，8.55(s，1H)，8.23(d，J＝1.4Hz，1H)，7.73(t，J＝7.8Hz，1H)，7.69(s，1H)，7.38(dd，J＝2.3，11.2Hz，1H)，7.16(t，J＝8.6Hz，1H)，6.99(t，J＝3.6Hz，2H)，6.91-6.84(m，2H)，5.04(q，J＝8.3Hz，2H)，3.57(s，3H)，2.27(s，3H)，1.48(s，9H).

Step eleven: synthesis of 6- (5-amino-3-methoxypyridin-2-yl) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

Tert-butyl (6- (5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -4- (2, 2-trifluoroethoxy) -5-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) carbamate (1.50 g,2.34 mmol) was added to p-methylbenzylamine (3.21 g,23.4 mmol), after completion of the reaction at 190 ℃ for 2 hours, the reaction was concentrated and column chromatographed to give crude product which was then purified by reverse phase HPLC to give 6- (5-amino-3-methoxypyridin-2-yl) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (320 mg, yield 22.2%).

LCMS：m/z 578.2[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.27(s，1H)，7.74(t，J＝7.8Hz，1H)，7.49(d，J＝2.0Hz，1H)，7.31(dd，J＝2.5，11.0Hz，1H)，7.25(t，J＝8.6Hz，1H)，7.15(d，J＝8.6Hz，2H)，7.07-6.98(m，2H)，6.84-6.78(m，3H)，6.63(s，1H)，6.50(d，J＝2.0Hz，1H)，5.62(s，2H)，5.14(t，J＝5.6Hz，1H)，5.93-5.05(m，1H)，4.54(d，J＝5.6Hz，2H)，3.68(s，3H)，3.52(s，3H)，2.24(s，3H).

Step twelve: synthesis of N- (6- (5- (3-fluoro-4- ((6-methoxypyridin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) -3- (benzenesulfonyl) propanamide

6- (5-amino-3-methoxypyridin-2-yl) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (170 mg, 254 mol) was dissolved in 1mL of pyridine, 3- (benzenesulfonyl) propionic acid (63.0 mg, 254 mol) was added, phosphorus oxychloride (67.6 mg,441 mol) was added at 0 ℃, then after reaction at 20℃for 1 hour, LCMS detection reaction ended, aqueous sodium bicarbonate solution was added to quench and adjust pH to 7, and N- (6- (5- (3-fluoro-4- ((6-methoxypyridin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) -3- (benzenesulfonyl) propionamide (140 mg, 48.5%) was obtained by reverse phase HPLC purification.

LCMS：m/z 774.3[M+H] ⁺ .

¹ H NMR(400MHz，ACETONITRILE-d3)δ＝8.99(br d，J＝4.6Hz，1H)，8.31(s，1H)，8.09(d，J＝1.8Hz，1H)，7.91-7.82(m，2H)，7.70(d，J＝1.6Hz，1H)，7.67-7.60(m，2H)，7.58-7.51(m，2H)，7.21(dd，J＝2.2，10.8Hz，1H)，7.18-7.06(m，4H)，6.92(d，J＝7.3Hz，1H)，6.81-6.75(m，3H)，6.73(d，J＝8.3Hz，1H)，4.82(t，J＝5.5Hz，1H)，4.54(d，J＝5.5Hz，2H)，3.69(s，3H)，3.60(s，3H)，3.52(t，J＝7.3Hz，2H)，2.72(t，J＝7.3Hz，2H)，2.21(s，3H).

Step thirteen: synthesis of N- (6- (4-amino-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) -3- (benzenesulfonyl) propylamine

N- (6- (5- (3-fluoro-4- ((6-methoxypyridin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) -3- (benzenesulfonyl) propanamide (140 mg,467 mol) was dissolved in 1mL of trifluoroacetic acid, 0.5mL of trifluoromethanesulfonic acid was added, the reaction was reacted at 35℃for 2.5 hours, TLC detection was ended, the pH was adjusted to 7 by adding aqueous sodium bicarbonate and extracted with ethyl acetate, and the organic phase was concentrated and column chromatographed to give N- (6- (4-amino-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3- (benzenesulfonyl) propanamine (120 mg, yield 93.3%).

LCMS：m/z 654.3[M+H] ⁺ .

¹ H NMR(400MHz，ACETONITRILE-d3)δ＝8.65(br s，1H)，8.34(s，1H)，8.12(s，1H)，7.94-7.87(m，2H)，7.74(d，J＝1.8Hz，1H)，7.70(q，J＝7.3Hz，2H)，7.63-7.57(m，2H)，7.29-7.22(m，2H)，7.13(td，J＝1.0，8.5Hz，1H)，6.98(d，J＝7.4Hz，1H)，6.88-6.82(m，2H)，5.62-5.28(m，2H)，3.65(s，3H)，3.53(t，J＝7.3Hz，2H)，2.73(t，J＝7.3Hz，2H)，2.29(s，3H).

Step fourteen: synthesis of N- (6- (4-amino-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) acrylamide

6- (5-bromo-3-methoxypyridin-2-yl) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (120 mg, 183umol) was dissolved in 1mL of tetrahydrofuran, potassium trimethylsiloxide (23.55 mg,183.58 umol) was added, stirring was carried out at 20℃for 1 hour, and the completion of the reaction was detected by LCMS and the spin-dry was purified by reverse phase HPLC to give N- (6- (4-amino-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) acrylamide (17.5 mg, yield 18.4%).

LCMS：m/z 512.4[M+H]+。

¹ H NMR(400MHz，DMSO-d6)δ＝10.50(s，1H)，8.37(d，J＝1.6Hz，1H)，8.24(s，1H)，7.90(d，J＝1.6Hz，1H)，7.76(t，J＝7.7Hz，1H)，7.36(dd，J＝2.3，10.9Hz，1H)，7.30(t，J＝8.6Hz，1H)，7.12-7.05(m，1H)，7.02(d，J＝7.3Hz，1H)，6.90(d，J＝8.1Hz，1H)，6.78(s，1H)，6.48-6.38(m，1H)，6.35-6.26(m，1H)，5.91-5.67(m，3H)，3.64(s，3H)，2.27(s，3H).

Example 2:

synthesis of N- (4- (4-amino-5- (1- ((6-methylpyrimidin-2-yl) methyl) piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-methoxyphenyl) acrylamide:

the synthetic route is as follows:

step one: synthesis of 4-iodo-3-methoxyaniline

2-iodo-5-nitroanisole (80.0 g,286.71mmol,1 eq) was dissolved in ethanol (700 mL) and water (140 mL), fe powder (80.06 g,1.43mol,5 eq) and ammonium chloride (30.67 g,573.41mmol,2 eq) were added and reacted at 80℃for 4 hours, after completion of LCMS detection, concentrated and extracted with ethyl acetate to give crude 4-iodo-3-methoxyaniline (60.0 g, crude).

LCMS：m/z 249.9[M+H] ⁺ .

¹ H NMR(400MHz，CHLOROFORM-d)δ＝7.45(d，J＝8.4Hz，1H)，6.21(d，J＝2.4Hz，1H)，6.12(dd，J＝2.4，8.3Hz，1H)，3.81(s，3H)，3.77(s，2H).

Step two: synthesis of tert-butyl 4-iodo-3-methoxyphenylcarbamate

4-iodo-3-methoxyaniline (21.0 g,84.3mmol,1.00 eq) was dissolved in 200ml tetrahydrofuran, sodium bis (trimethylsilyl) amide (1M, 185mL,2.20 eq) was added at 0deg.C for 1 hour, then di-tert-butyl dicarbonate (18.4 g,84.3mmol,19.3mL,1.00 eq) was added, and reacted at 20deg.C for 1 hour. LCMS detected completion of the reaction, quenched the reaction mixture by adding aqueous ammonium chloride, extracted with ethyl acetate, dried, and filtered to give tert-butyl 4-iodo-3-methoxyphenylcarbamate (29.0 g,83.0mmol, 98.5% yield) by column chromatography.

LCMS：m/z 293.8[M+H] ⁺ .

¹ H NMR(400MHz，CHLOROFORM-d)δ＝7.80(d，J＝2.8Hz，1H)，7.57(d，J＝8.8Hz，1H)，6.84(br s，1H)，6.41(dd，J＝2.8，8.8Hz，1H)，3.81(s，3H)，1.55(s，9H).

Step three: synthesis of tert-butyl (3-methoxy-4-trimethylsilyl) ethynyl) phenylcarbamate

Tert-butyl 4-iodo-3-methoxyphenylcarbamate (20.0 g,57.3mmol,1.00 eq) was added to 200mL of tetrahydrofuran, and trimethylsilylethylene (11.2 g,114mmol,15.8mL,2.00 eq), bis (triphenylphosphine) palladium (II) dichloride (2.01 g,2.86mmol,0.05 eq), cuprous iodide (1.09 g,5.73mmol,0.10 eq) and triethylamine (17.4 g,172mmol,23.9mL,3.00 eq) were added in sequence and reacted at 40℃for 3 hours. LCMS detection was complete and direct spin-drying gave crude (3-methoxy-4-trimethylsilyl) phenylcarbamic acid tert-butyl ester (18.5 g, crude).

LCMS：m/z 264.0[M+H] ⁺ .

Step four: synthesis of (4-ethynyl-3-methoxyphenyl) carbamic acid tert-butyl ester

Tert-butyl (3-methoxy-4-trimethylsilyl) ethynyl) phenylcarbamate (28.0 g,87.6mmol,1.00 eq) was added to 200mL of methanol and potassium carbonate (36.3 g,262.9mmol,3.00 eq) was added to react at 20℃for 2 hours. LCMS detection of completion of reaction, spin-drying afforded (4-ethynyl-3-methoxyphenyl) carbamic acid tert-butyl ester (12.0 g,48.5mmol, 55.4% yield) by column chromatography.

LCMS：m/z 192.1[M+H] ⁺ .

¹ H NMR(400MHz，CHLOROFORM-d)δ＝7.83(d，J＝1.6Hz，1H)，7.33(d，J＝8.4Hz，1H)，7.30(br s，1H)，6.52(dd，J＝2.6，8.6Hz，1H)，3.84(s，3H)，3.43(s，1H)，1.54(s，9H).

Step five: synthesis of tert-butyl (4- ((5-bromo-6- (2, 2-trifluoroethoxy) pyrimidin-4-yl) ethynyl) -3-methoxyphenyl) carbamate

Tert-butyl (4-ethynyl-3-methoxyphenyl) carbamate (7.00 g,28.3mmol,1.00 eq) was added to 70mL tetrahydrofuran, and 5-bromo 4-iodo-6- (2, 2-trifluoroethoxy) pyrimidine (10.84 g,28.31mmol,1.0 eq), 1-bis (diphenylphosphorus) ferrocene palladium chloride (1.99 g,2.83mmol,0.1 eq), cuprous iodide (1.08 g,5.66mmol,0.2 eq) and triethylamine (8.59 g,84.9mmol,11.8mL,3 eq) were added and reacted at 50℃for 3 hours. LCMS checked the completion of the reaction, water was added and extracted with ethyl acetate, the organic phase was washed with brine, dried, and the filtrate was spin-dried and isolated by column chromatography to give tert-butyl (4- ((5-bromo-6- (2, 2-trifluoroethoxy) pyrimidin-4-yl) ethynyl) -3-methoxyphenyl) carbamate (8.40 g,16.7mmol, 59.1% yield).

LCMS：m/z 504.1[M+H] ⁺ .

¹ H NMR(400MHz，CHLOROFORM-d)δ＝8.80(s，1H)，8.26(s，1H)，7.59(d，J＝8.6Hz，1H)，7.53(br d，J＝1.8Hz，1H)，6.77(dd，J＝2.4，8.7Hz，1H)，5.20(q，J＝8.8Hz，2H)，3.82(s，3H)，1.48(s，9H).

Step six: synthesis of tert-butyl 4- (6- (4- ((tert-butylyl) amino) -2-methoxyphenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-5-yl) piperidine-carbamate

Tert-butyl (4- ((5-bromo-6- (2, 2-trifluoroethoxy) pyrimidin-4-yl) ethynyl) -3-methoxyphenyl) carbamate (500 mg,995 mol,1.00 eq) was dissolved in 15mL dioxane, 1-tert-butyl-4-aminopiperidine (199mg, 995 mol,1.00 eq), [9, 9-dimethyl-4, 5-bis (diphenylphosphino) xanthene ] [ 2-amino-1, 1-diphenyl ] palladium (II) methanesulfonate dichloromethyl adduct (189 mg, 199mol, 0.2 eq) and cesium carbonate (648 mg,1.99mmol,2.00 eq) were added and reacted at 110 ℃ for 3 hours. LCMS monitored completion of the reaction and the crude product after concentration was separated by silica gel column to give tert-butyl 4- (6- (4- ((tert-butylsulfanyl) amino) -2-methoxyphenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-5-yl) piperidine-carbamate (490 mg,788umol, 16.33% yield).

LCMS：m/z 622.2[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.71(br s，1H)，8.47(s，1H)，7.25(br d，J＝8.4Hz，1H)，7.19(br s，1H)，6.87(dd，J＝2.1，8.4Hz，1H)，6.51(s，1H)，5.46-4.99(m，2H)，3.82(s，3H)，3.34(s，9H)，1.39(s，9H)，1.28(br s，9H).

Step seven: synthesis of 3-methoxy-4- (5- (piperidin-4-yl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) aniline

Tert-butyl 4- (6- (4- ((tert-butylyl) amino) -2-methoxyphenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-5-yl) piperidine-carbamate was dissolved in 3.00ml 4M methanol hydrochloride, LCMS monitored for completion of the reaction, and concentrated to give crude 3-methoxy-4- (5- (piperidin-4-yl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) aniline (468 mg, crude).

LCMS：m/z 422.2[M+H] ⁺ .

Step eight: synthesis of 3-methoxy-4- (5- (1- ((6-methylpyridin-2-yl) piperidin-4-yl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) aniline

3-methoxy-4- (5- (piperidin-4-yl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) aniline (4638 mg,1.11mmol,1.00 eq) was dissolved in 4.00ml acetonitrile, and 2-bromomethyl-6-methylpyridine (227.28 mg,1.22mmol,1.1 eq) and potassium carbonate (460 mg,3.33mmol,3.00 eq) were added and reacted at 20℃for 12 hours. LCMS monitors the completion of the reaction, and after concentration the crude product is separated by a silica gel column to give 3-methoxy-4- (5- (1- ((6-methylpyridin-2-yl) piperidin-4-yl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) aniline (500 mg,949.57umol, 85.51% yield)

LCMS：m/z 527.3[M+H] ⁺ .

¹ H NMR(400MHz，CHLOROFORM-d)δ＝8.49(s，1H)，7.60(br d，J＝4.9Hz，2H)，7.05(br d，J＝8.0Hz，2H)，6.54(s，1H)，6.42-6.26(m，2H)，5.33-4.95(m，2H)，4.05-3.89(m，2H)，3.88-3.77(m，1H)，3.74(s，3H)，3.18-3.00(m，2H)，2.54(s，3H)，2.25-1.87(m，4H).

Step nine: synthesis of 6- (4-amino-2-methoxyphenyl) -5- (1- ((6-methylpyridin-2-yl) methyl) piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amino

3-methoxy-4- (5- (1- ((6-methylpyridin-2-yl) piperidin-4-yl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) aniline (300 mg, 569. Mu. Mol,1.00 eq) and aqueous ammonia (798 mg,5.70mmol, 877. Mu.L, 25% purity,10 eq) were dissolved in 2mL dioxane and stirred at 130℃for 48 hours after completion of the LCMS detection reaction, the reaction mixture was concentrated and purified by column on silica gel to give 6- (4-amino-2-methoxyphenyl) -5- (1- ((6-methylpyridin-2-yl) methyl) piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amino (160 mg, 360.73. Mu. Mol, 63.3%).

LCMS：m/z 444.1[M+H] ⁺ .

Step ten: synthesis of N- (4- (4-amino-5- (1- ((6-methylpyridin-2-yl) methyl) piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-methoxyphenyl) -3- (benzenesulfonyl) acrylamide

6- (4-amino-2-methoxyphenyl) -5- (1- ((6-methylpyridin-2-yl) methyl) piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amino (120 mg, 270. Mu. Mol,1.00 eq) was dissolved in 2mL of dichloromethane, 3- (benzenesulfonyl) propionic acid (52.1 mg, 243. Mu. Mol,0.9 eq) was added, N-diisopropylethylamine (45.5 mg, 352. Mu. Mol, 61.3. Mu. L,1.00 eq) was added at 0℃and reacted with a 50% ethyl acetate solution of tri-N-propylcyclic anhydride (172 mg, 270. Mu. Mol, 160. Mu. L,50.0% purity,1 eq) at 0℃and after completion of the S detection reaction, the mixture was spin-dried and purified by reverse phase HPLC to give N- (4- (4-amino-5- (1- ((6-methylpyridin-2-yl) methyl) piperidin-4-yl) -5H-pyrrolo [3, 6-methoxy ] pyrimidine-3- (166. Mu. Mol, 110 mg) amino) -3-d ] pyrimidine (110 mg, 1%).

LCMS：m/z 640.3[M+H] ⁺ .

Step eleven: synthesis of N- (4- (4-amino-5- (1- ((6-methylpyridin-2-yl) methyl) piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-methoxyphenyl) acrylamide

N- (4- (4-amino-5- (1- ((6-methylpyridin-2-yl) methyl) piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-methoxyphenyl) -3- (benzenesulfonyl) propenamide (110 mg,171 mol,1.00 eq) was dissolved in 1mL tetrahydrofuran, trimethylpotassium oxide (22.0 mg,171 mol,1.00 eq) was added, stirring was performed at 20℃for 1 hour, and the reaction was terminated by LCMS detection, and the mixture was purified by reverse phase HPLC to give N- (4- (4-amino-5- (1- ((6-methylpyridin-2-yl) methyl) piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-methoxyphenyl) acrylamide (15.0 mg,29.9 mol, yield 17.4%, purity 99.3%).

LCMS：m/z 527.3[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.39(s，1H)，8.14(s，1H)，7.68-7.59(m，2H)，7.34(br d，J＝8.0Hz，1H)，7.22(br dd，J＝7.8，15.9Hz，2H)，7.10(br d，J＝7.5Hz，1H)，6.61(br s，2H)，6.48(br dd，J＝10.1，16.9Hz，1H)，6.35-6.27(m，1H)，6.24-6.17(m，1H)，5.81(br d，J＝10.0Hz，1H)，4.17(br s，1H)，3.80-3.66(m，4H)，3.54(br s，3H)，2.86(br s，2H)，2.42(s，3H)，2.08(br s，4H).

The preparation of the compounds of the examples in Table 1 can be carried out by reference to the procedure analogous to the procedure for the preparation of example 1, except that the starting materials are replaced in the intermediate step to give the corresponding compounds.

TABLE 1

Example 6:

synthesis of N- (4- (4-amino-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-methoxyphenyl) acrylamide:

The synthetic route is as follows:

/>

step one: synthesis of tert-butyl (4- (5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-methoxyphenyl) carbamate

Tert-butyl (4- ((5-bromo-6- (2, 2-trifluoroethoxy) pyrimidin-4-yl) ethynyl) -3-methoxyphenyl) carbamate (4 g,7.96mmol,1 eq) and 3-fluoro-4- ((6-methylpyrimidin-2-yl) oxy) aniline (2.26 g,10.4mmol,1.3 eq) are dissolved in dioxane (70 mL) and [9, 9-dimethyl-4, 5-bis (diphenylphosphino) xanthene ] [ 2-amino-1, 1-diphenyl ] palladium (II) methanesulfonate (906 mg,955umol,0.12 eq), cesium carbonate (5.9 g,15.9mmol,2 eq) and 9, 9-dimethyl-4, 5-bis (diphenylphosphino) xanthene (922 mg,1.59mmol,0.2 eq) are added. The reaction solution was reacted under a nitrogen atmosphere at 100℃for 6 hours. After completion of the reaction, the mixture was concentrated and purified by column chromatography to give tert-butyl 4- (5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-methoxyphenyl) carbamate (4.5 g,88.4% yield) as a yellow solid.

LCMS：m/z 640.2[M+H] ⁺ .

Step two: synthesis of 6- (4-amino-2-methoxyphenyl) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidine-4-ammonia

Tert-butyl (4- (5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-methoxyphenyl) carbamate (1.0 g,1.56mmol,1 eq) was added to 10mL of aqueous ammonia and the reaction mixture was allowed to react at 100℃for 12 hours in a closed pot. LCMS and TLC detected completion of the reaction. The column chromatography was concentrated to give 6- (4-amino-2-methoxyphenyl) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidine-4-ammonia (300 mg,42.0% yield) as a yellow solid.

LCMS：m/z 457.2[M+H] ⁺ .

Step three: synthesis of N- (4- (4-amino-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-methoxyphenyl) acrylamide

/>

6- (4-amino-2-methoxyphenyl) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidine-4-amino (200 mg,1.00 eq) was dissolved in 3.0mLN, N dimethylformamide, diisopropylethylamine (567 mg,10.0 eq) was added, and then acryloyl chloride (19.8 mg,0.50 eq) was reacted at 0℃for 1 hour. LCMS detects the end of the reaction and 0.5mL of water is added to the reaction. N- (4- (4-amino-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-methoxyphenyl) acrylamide (6.0 mg, yield 2.68%) was obtained by reverse phase separation and purification.

LCMS：m/z 511.2[M+H] ⁺ .

¹ H NMR(400MHz，ACETONITRILE-d3)δ＝8.31(s，1H)，8.02(br s，1H)，7.81-7.66(m，2H)，7.34-7.18(m，3H)，7.14(d，J＝8.5Hz，1H)，7.00(d，J＝7.4Hz，1H)，6.83(d，J＝8.3Hz，1H)，6.73-6.66(m，2H)，6.36-6.22(m，2H)，5.69(dd，J＝2.8，9.2Hz，1H)，4.96(br s，2H)，3.81(s，3H)，2.34(s，3H).

Example 7:

synthesis of N- (4- (4-amino-5- (3-fluoro-4- ((6-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide:

the synthetic route is as follows:

step one: synthesis of tert-butyl 4-iodophenyl carbamate

4-iodoaniline (30.0 g,137 mmol) was dissolved in 200mL tetrahydrofuran, lithium bis (trimethylsilyl) amide (1M, 301mL,2.2 eq) was slowly added at-10℃and reacted at-10℃for 0.5 hours, followed by di-tert-butyl dicarbonate (29.9 g,137 mmol) and reacted at 20℃for 1.5 hours. After completion of TLC detection, the reaction solution was poured into a saturated ammonium chloride solution, ethyl acetate was added to extract, the organic phase was washed with saturated brine, and the filtrate was dried by spin-drying, followed by separation and purification through a silica gel column to give tert-butyl 4-iodophenylcarbamate as a yellow solid (32.0 g, yield 73.2%).

¹ H NMR(400MHz，CHLOROFORM-d)δ＝7.58(d，J＝8.8Hz，2H)，7.15(br d，J＝8.5Hz，2H)，6.47(br s，1H)，1.52(s，9H).

Step two: synthesis of tert-butyl 4- ((trimethylsilyl) ethynyl) phenyl-carbamate

Tert-butyl 4-iodophenylcarbamate (20.0 g,1.00 eq), bis (triphenylphosphine) palladium (II) dichloride (2.20 g,0.05 eq), trimethylsilylacetylene (8.00 g,1.30 eq), cuprous iodide (1.19 g,0.10 eq) and triethylamine (12.7 g,2.00 eq) were dissolved in 200mL tetrahydrofuran and reacted at 40 ℃ for 4 hours. LCMS detection reaction was completed and cooled to 25 ℃. The reaction solution was concentrated to give tert-butyl 4- ((trimethylsilyl) ethynyl) phenylcarbamate (18.1 g, crude).

LCMS：m/z 234.1[M+1-56].

Step three: synthesis of 4-phenylacetylene-amino tert-butyl ester

Tert-butyl 4- ((trimethylsilyl) ethynyl) phenylcarbamate (18.1 g,1.00 eq) and potassium carbonate (26.0 g,3.00 eq) were dissolved in 200mL methanol and stirred for 1 hour at 20 ℃. After completion of the LCMS detection reaction, the reaction solution was filtered, and the filtrate was dried by spin-drying at low temperature, and separated and purified by silica gel column to give tert-butyl 4-phenylacetylene-carbamate (12.0 g, yield 88.1%).

LCMS：m/z 203.0[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝9.66-9.08(m，1H)，7.34-7.25(m，2H)，7.24-7.14(m，2H)，4.06-3.76(m，1H)，1.37-1.25(m，9H).

Step four: synthesis of tert-butyl 4- ((5-bromo-6- (2, 2-trifluoroethoxy) pyrimidin-4-yl) ethynyl) phenylcarbamate

5-bromo-4-iodo-6- (2, 2-trifluoroethoxy) pyrimidine (1.00 g,1.00 eq), tert-butyl 4-phenylethynyl carbamate (595 mg,1.0 eq) dichloro bis (triphenylphosphine) palladium (II) (91.6 mg,0.05 eq), cuprous iodide (49.7 mg,0.10 eq) and triethylamine (587 mg,2.00 eq) were dissolved in 10mL tetrahydrofuran and reacted at 40℃for 2 hours. LCMS detects the end of the reaction. The reaction solution was concentrated by filtration, and separated and purified by a silica gel column to give tert-butyl 4- ((5-bromo-6- (2, 2-trifluoroethoxy) pyrimidin-4-yl) ethynyl) phenylcarbamate (1.10 g, yield 62.3%, purity 70.0%).

LCMS：m/z 472.0[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.05-9.75(m，1H)，8.82-8.72(m，1H)，7.68-7.56(m，4H)，5.26-5.11(m，2H)，1.52-1.48(m，9H).

Step five: synthesis of tert-butyl (4- (5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenylcarbamate

4- ((5-bromo-6- (2, 2-trifluoroethoxy) pyrimidin-4-yl) ethynyl) phenyl-amino-tert-butyl ester (1.10 g,1.00 eq), 3-fluoro-4- ((6-methylpyridin-2-yl) oxy) aniline (399mg, 1.10 eq), [9, 9-dimethyl-4, 5-bis (diphenylphosphoryl) xanthene ] [ 2-amino-1, 1-diphenyl ] palladium (II) methanesulfonate dichloromethane complex (151 mg,0.10 eq), cesium carbonate (1.06 mg,2.00 eq) and bis-diphenylphosphine-9, 9-dimethyloxaxanthene (94.3 mg,0.10 eq) were dissolved in 10ml dioxane and reacted at 100℃for 6 hours. LCMS detects the end of the reaction. The reaction solution was concentrated, and separated and purified by a silica gel column to give tert-butyl (4- (5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxo) phenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenylcarbamate (900 mg, yield 90.5%).

LCMS：m/z 610.3[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝9.78-9.46(m，1H)，8.63-8.43(m，1H)，7.76(t，J＝7.8Hz，1H)，7.58(dd，J＝2.1，11.0Hz，1H)，7.45(br d，J＝8.5Hz，2H)，7.32-7.18(m，3H)，7.11(br d，J＝8.5Hz，1H)，7.05-6.96(m，2H)，6.87(d，J＝8.1Hz，1H)，5.10-4.96(m，2H)，2.30(s，2H)，1.47(s，9H).

Step six: synthesis of 6- (4-aminobenzene) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxo) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amino

(4- (5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenylamino tert-butyl ester (500 mg,820 mol,1 eq) and aqueous ammonia (9.10 g,70.1mmol,10mL,27% purity,85.5 eq) were reacted at 100℃for 24 hours, LCMS and TLC detection reaction ended purification of 6- (4-aminobenzene) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amino (200 mg, yield 57.2%) by silica gel column separation.

LCMS：m/z 427.1[M+H] ⁺ .

¹ H NMR(400MHz，METHANOL-d4)δ＝8.19(s，1H)，7.75(t，J＝7.8Hz，1H)，7.39-7.23(m，3H)，7.02(d，J＝8.4Hz，3H)，6.87(d，J＝8.3Hz，1H)，6.66-6.57(m，3H)，2.38(s，3H).

Step seven: synthesis of N- (4- (4-amino-5- (3-fluoro-4- ((6-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide.

6- (4-aminobenzene) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidine-4-amino (70 mg, 164.15. Mu. Mol,1 eq) was dissolved in tetrahydrofuran (4 mL) and added dropwise (13.4 mg, 147.73. Mu. Mol, 12.05. Mu.L, 0.9 eq) at 0 ℃. The reaction solution was stirred at 20℃for one hour. LCMS detected 53% product. After low temperature spin drying, the product N- (4- (4-amino-5- (3-fluoro-4- ((6-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide (8.1 mg,9.79% yield, 95.3% purity) was isolated as a white solid by HPLC and confirmed by two-dimensional nuclear magnetism.

LCMS：m/z 445.2[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.26(s，1H)，8.22(s，1H)，7.77(t，J＝7.8Hz，1H)，7.70-7.58(m，3H)，7.45-7.37(m，1H)，7.35-7.24(m，3H)，7.07-6.87(m，2H)，6.74(s，1H)，6.48-6.35(m，1H)，6.32-6.20(m，1H)，5.77(dd，J＝1.5，10.1Hz，1H)，5.67(br s，2H)，2.29(s，3H).

Example 8:

n- (4- (4-amino-5- (3-fluoro-4- ((6-methylpyridin-2-yl) amino) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide:

step one: synthesis of N- (2-fluoro-4-nitrophenyl) -6-methylpyridin-2-amine

2-fluoro-4-nitroaniline (10.0 g,64.0 mmol) was dissolved in 100mL of toluene, and 2-bromo-6-methylpyridine (11.0 g,64.0 mmol) was added to react for 1 hour, sodium tert-butoxide (7.39 g,76.8 mmol), 1 '-binaphthyl-2, 2' -bis-diphenylphosphine (1.99 g,3.20 mmol) and tris (dibenzylideneacetone) dipalladium (1.76 g,1.92 mmol) were reacted at 120℃for 2 hours, after completion of LCMS detection, concentrated and column chromatography gave N- (2-fluoro-4-nitrophenyl) -6-methylpyridin-2-amine (14.5 g, yield 79.6%).

LCMS：m/z 248.2[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝9.45(s，1H)，8.87(t，J＝8.7Hz，1H)，8.18-8.02(m，2H)，7.61(t，J＝7.8Hz，1H)，7.08(d，J＝8.3Hz，1H)，6.86(d，J＝7.4Hz，1H)，2.44(s，3H).

Step two: 2-fluoro-N ¹ Synthesis of- (6-methylpyridin-2-yl) benzene-1, 4-diamine

N- (2-fluoro-4-nitrophenyl) -6-methylpyridin-2-amine (14.5 g,58.6 mmol) was dissolved in 150mL of ethanol, 31.7mL of water, ammonium chloride (6.27 g,117 mmol) and reduced iron powder (16.3 g,293 mmol) were added, the reaction was carried out at 80℃for 6 hours, after completion of LCMS detection, the reaction solution was cooled to room temperature, filtered, concentrated and column chromatographed to give 2-fluoro-N ¹ - (6-methylpyridin-2-yl) benzene-1, 4-diamine (6.90 g, yield 51.9%).

LCMS：m/z 218.1[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝7.85(s，1H)，7.34-7.26(m，1H)，7.16(t，J＝8.9Hz，1H)，6.44(d，J＝7.1Hz，1H)，6.41-6.32(m，2H)，6.22(d，J＝8.3Hz，1H)，5.19(s，2H)，2.25(s，3H).

The remaining intermediate and final product, similar to the procedure of example 1, can afford N- (4- (4-amino-5- (3-fluoro-4- ((6-methylpyridin-2-yl) amino) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide (25 mg, yield: 32.0%).

LCMS：n/z 480.4[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.22(s，1H)，8.88(d，J＝2.0Hz，1H)，8.69(t，J＝9.0Hz，1H)，8.19(s，1H)，7.61(d，J＝8.6Hz，2H)，7.51(t，J＝7.8Hz，1H)，7.42(dd，J＝2.4，11.9Hz，1H)，7.29(d，J＝8.6Hz，2H)，7.23(dd，J＝1.8，8.6Hz，1H)，6.93(d，J＝8.3Hz，1H)，6.74-6.66(m，2H)，6.45-6.35(m，1H)，6.28-6.20(m，1H)，5.75(dd，J＝2.0，10.0Hz，1H)，5.56(br s，2H)，2.38(s，3H).

The preparation of the compounds of examples in Table 2 can be carried out by reference to the procedure analogous to the route of preparation examples 1 and 8 described previously, except that the starting materials are replaced in an intermediate step to give the corresponding compounds.

TABLE 2

Example 10:

synthesis of 6- (5-ethynyl-3-methoxypyridin-2-yl) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine:

the synthetic route is as follows:

step one: synthesis of 6- (5-bromo-3-methoxypyridin-2-yl) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

Isoamyl nitrite (152 mg,1.30 mmol) was dissolved in 2.5mL acetonitrile, copper bromide (149 mg,1.04 mmol) and copper bromide (116 mg, 719 umol) were added, and finally 6- (5-amino-3-methoxypyridin-2-yl) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (300 mg,519 umol) was added, and after completion of the TLC detection reaction at 20℃for 12 hours, filtration, concentration and column chromatography gave 6- (5-bromo-3-methoxypyridin-2-yl) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (300 mg, yield 55.8%).

LCMS：m/z 643.1[M+H] ⁺ .

Step two: synthesis of 6- (5-bromo-3-methoxypyridin-2-yl) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6- (5-bromo-3-methoxypyridin-2-yl) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (300 mg,467 mol) was dissolved in 1mL of trifluoroacetic acid and 0.5mL of trifluoromethanesulfonic acid was added, the reaction was completed at 40℃for 2 hours, aqueous sodium bicarbonate was added to adjust the pH to 7 and extracted with ethyl acetate, the organic phase was concentrated and the column chromatographed to give 6- (5-bromo-3-methoxypyridin-2-yl) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (150 mg, yield 41.2%).

LCMS：m/z 523.0[M+H] ⁺ .

Step three: synthesis of 5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -6- (3-methoxy-5- ((trimethylsilyl) ethynyl) pyridin-2-yl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6- (5-bromo-3-methoxypyridin-2-yl) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (50.0 mg,95.9 mol) was dissolved in 2mLN, N-dimethylformamide, trimethylsilylacetylene (4.13 mg,143 mol), bis (triphenylphosphine) palladium (II) dichloride (6.73 mg,9.59 mol), triethylamine (9.41 mg,191 mol) and cuprous iodide (1.83 mg,9.59 mol) were added, stirring was carried out at 60℃for 2 hours, LCMS was carried out to examine the end of the reaction, extracted with water and ethyl acetate, the organic phase was left to dry with anhydrous sodium sulfate, and filtered and dried to give 5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -6- (3-methoxy-5- ((trimethylethynyl) pyridin-2-yl) -5H-pyrrolo [3,2-d ] pyrimidine (50.96 mg, 96.0% yield.

LCMS：m/z 539.2[M+H] ⁺ .

Step four: synthesis of 6- (5-ethynyl-3-methoxypyridin-2-yl) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

Crude 5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -6- (3-methoxy-5- ((trimethylsilyl) ethynyl) pyridin-2-yl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (50.0 mg,92.8 umol) and cesium fluoride (14.1 mg,92.8 umol) were added to 1mL of tetrahydrofuran and reacted at 20℃for 1 hour. After completion of LCMS detection reaction, solvent was flash dried and immediately after spin drying was purified by reverse phase HPLC to give 6- (5-ethynyl-3-methoxypyridin-2-yl) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (10.4 mg, yield 23.5%).

LCMS：m/z 467.3[M+H] ⁺ .

1HNMR(400MHz，ACETONITRILE-d3)δ＝8.29(s，1H)，8.21(s，1H)，7.70(t，J＝7.8Hz，1H)，7.42(s，1H)，7.26-7.18(m，2H)，7.11(br d，J＝8.6Hz，1H)，6.97(d，J＝7.3Hz，1H)，6.90(s，1H)，6.84(d，J＝8.1Hz，1H)，5.00(br s，2H)，3.71(s，3H)，3.62(s，1H)，2.32(s，3H).

The preparation of the compounds of examples in Table 3 can be carried out by reference to the procedure analogous to the procedure of preparation example 10, except that starting materials are replaced in the intermediate step to give the corresponding compounds.

TABLE 3 Table 3

Example 14:

n- (6- (4-amino-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyridin-3-yl) acrylamide:

the synthetic route is as follows:

step one: synthesis of tert-butyl (6-bromopyridin-3-yl) carbamate

6-bromopyridin-3-amino was dissolved in tetrahydrofuran, di-t-butyl dicarbonate was added, and after completion of the LCMS detection reaction, the reaction was concentrated and column chromatographed to give crude product, which was then purified by reverse phase HPLC to give tert-butyl (6-bromopyridin-3-yl) carbamate (320 mg, yield 22.2%).

LCMS：m/z 272.9[M+1] ⁺ ，274.9[M+3] ⁺ .

¹ H NMR(400MHz，CHLOROFORM-d)δ＝8.23(d，J＝2.6Hz，1H)，7.89(br d，J＝6.4Hz，1H)，7.41(d，J＝8.6Hz，1H)，6.55(br s，1H)，1.53(s，9H).

Step two: synthesis of tert-butyl (6- ((trimethylsilyl) ethynyl) pyridin-3-yl) carbamate

Tert-butyl (6-bromopyridin-3-yl) carbamate (45.0 g,164mmol,1.00 eq) was added to 400mL of tetrahydrofuran, and trimethylsilylethylene (32.3 g, 309 mmol,45.6mL,2.00 eq), bis (triphenylphosphine) palladium (II) dichloride (2.31 g,3.30mmol,0.02 eq), cuprous iodide (6277 mg,3.30mmol,0.02 eq) and triethylamine (33.3 g, 309 mmol,45.8mL,2.00 eq) were added in sequence and reacted at 40℃for 3 hours. LCMS detection of reaction completion gave crude tert-butyl (6- ((trimethylsilyl) ethynyl) pyridin-3-yl) carbamate (48.0 g, crude) by direct spin-drying.

LCMS：m/z 291.1[M+H] ⁺ .

Step three: synthesis of tert-butyl (6-ethynylpyridin-3-yl) carbamate

Tert-butyl (6- ((trimethylsilyl) ethynyl) pyridin-3-yl) carbamate (48.0 g,165mmol,1.00 eq) was added to 400mL methanol and potassium carbonate (45.6 g,330mmol,2.00 eq) was added to react for 2 hours at 20 ℃. LCMS detected completion of the reaction and spin-dried was isolated by column chromatography to give tert-butyl (6-ethynylpyridin-3-yl) carbamate (24.0 g,109mmol, 66.5% yield).

LCMS：m/z 219.1[M+H] ⁺ .

¹ H NMR(400MHz，CHLOROFORM-d)δ＝8.42(br s，1H)，8.04(br d，J＝7.4Hz，1H)，7.45(br d，J＝8.3Hz，1H)，6.73(br s，1H)，3.12(s，1H)，1.53(s，9H).

Step four: synthesis of tert-butyl (6- ((5-amino-5-bromo-6- (2, 2-trifluoroethoxy) pyrimidin-4-yl) ethynyl) pyridin-3-yl) carbamate

Tert-butyl (6-ethynylpyridin-3-yl) carbamate (2.85 g,13.0mmol,1.00 eq) was added to 50mL tetrahydrofuran, and 5-bromo 4-iodo-6- (2, 2-trifluoroethoxy) pyrimidine (5.00 g,13.0mmol,1.00 eq), 1-bis (diphenylphosphorus) ferrocene palladium chloride (458 mg, 650 umol,0.05 eq), cuprous iodide (248 mg,1.31mmol,0.10 eq) and triethylamine (2.64 g,26.1mmol,3.64mL,2.00 eq) were added and reacted at 40℃for 3 hours. LCMS detects completion of the reaction, water was added and extracted with ethyl acetate, the organic phase was washed with brine, dried, and the filtrate was filtered and spin-dried to give tert-butyl (6- ((5-amino-5-bromo-6- (2, 2-trifluoroethoxy) pyrimidin-4-yl) ethynyl) pyridin-3-yl) carbamate (6.10 g,9.89mmol, 75.7% yield) by column chromatography.

LCMS m/z：472.9[M+1] ⁺ ，474.9[M+3] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ＝9.99(s，1H)，8.81(s，1H)，8.75-8.70(m，1H)，8.02(dd，J＝2.2，8.6Hz，1H)，7.72(br d，J＝8.5Hz，1H)，5.22-5.14(m，2H)，1.52-1.49(m，9H).

Step five: synthesis of tert-butyl (6- (5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyridin-3-yl) carbamate

Tert-butyl 6- ((5-amino-5-bromo-6- (2, 2-trifluoroethoxy) pyrimidin-4-yl) ethynyl) pyridin-3-yl) carbamate (3.00 g,4.44mmol,1.00 eq), 3-fluoro-4- ((6-methylpyridin-2-yl) oxyaniline (871 mg,3.99mmol,0.9 eq) and [9, 9-dimethyl-4, 5-bis (diphenylphosphino) xanthene ] [ 2-amino-1, 1-diphenyl ] palladium (II) methanesulfonate dichloromethane complex (420 mg,443umol,0.10 eq), cesium carbonate (2.89 g,8.87mmol,2.00 eq) and bis-diphenylphosphine-9, 9-dimethyloxaxanthene (256 mg,443umol,0.10 eq) were dissolved in 30ml dioxane and reacted at 100 ℃ for 6 hours. LCMS detects the end of the reaction. The reaction solution was concentrated, and separated and purified by a silica gel column to give tert-butyl (6- (5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyridin-3-yl) carbamate (1.00 g,1.64mmol, yield 36.9%).

LCMS：m/z 611.3[M+H] ⁺ .

¹ H NMR(400MHz，CHLOROFORM-d)δ＝8.60(s，1H)，8.37(d，J＝2.8Hz，1H)，7.99(br d，J＝8.0Hz，1H)，7.60(t，J＝7.8Hz，1H)，7.48(dd，J＝2.8，7.7Hz，1H)，7.22-7.15(m，3H)，7.06(td，J＝1.2，8.6Hz，1H)，6.90(d，J＝7.4Hz，1H)，6.71(d，J＝8.0Hz，1H)，6.64(s，1H)，4.82(q，J＝8.2Hz，2H)，2.43(s，3H)，1.53(s，9H).

Step six: synthesis of 6- (5-aminopyridin-2-yl) -5- (3-fluoro-4-methylpyridin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

Tert-butyl (6- (5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyridin-3-yl) carbamate (300 mg,491umol,1.00 eq) was added to p-methylbenzylamine (606 mg,4.42mmol,572ul,9.00 eq), after completion of the reaction at 190℃for 2 hours, LCMS detection, concentrated and column chromatographed to give the crude product, which was then purified by reverse phase HPLC to give 6- (5-aminopyridin-2-yl) -5- (3-fluoro-4-methylpyridin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (150 mg,264umol, yield 53.9%, purity 96.7%).

LCMS：m/z 548.4[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ＝8.27(s，1H)，7.80-7.73(m，2H)，7.61(dd，J＝2.4，10.9Hz，1H)，7.37-7.25(m，2H)，7.21(d，J＝8.4Hz，1H)，7.10(d，J＝8.8Hz，2H)，7.03(d，J＝7.4Hz，1H)，6.88-6.82(m，2H)，6.82-6.80(m，2H)，6.78(s，1H)，5.59(s，2H)，4.86(t，J＝5.6Hz，1H)，4.51(d，J＝5.4Hz，2H)，3.67(s，3H)，2.25(s，3H)ppm.

Step seven: synthesis of N- (6- (5-3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl-4- ((4-methoxybenzyl) amino) -5H-pyrrolo [3,2-d ] pyrimidin-3-yl) -3- (benzenesulfonyl) propenamine

6- (5-Aminopyridin-2-yl) -5- (3-fluoro-4-methylpyridin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (130 mg, 237.41. Mu. Mol,1.00 eq) was dissolved in 1.00mL of pyridine, 3- (benzenesulfonyl) propionic acid (50.8 mg,237. Mu. Mol,1.00 eq) was added, phosphorus oxychloride (36.40 mg,237. Mu. Mol, 22.0. Mu. L,1.00 eq) was added at 0deg.C and reacted for 1 hour at 20deg.C, after completion of LCMS detection reaction, the spin-dried was purified by reverse phase HPLC to give N- (6- (5-3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl-4- ((4-methoxybenzyl) amino) -5H-pyrrolo [3,2-d ] pyrimidin-3-yl) -3- (benzenesulfonyl) propenamide (180 mg, crude product).

LCMS：m/z 744.4[M+H] ⁺ .

Step eight: synthesis of N- (6- (4-amino-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyridin-3-yl) -3- (benzenesulfonyl) propanamide

N- (6- (5-3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl-4- ((4-methoxybenzyl) amino) -5H-pyrrolo [3,2-d ] pyrimidin-3-yl) -3- (benzenesulfonyl) propenamide (180 mg,242umol,1.00 eq) was dissolved in 1mL trifluoroacetic acid and 0.5mL trifluoromethanesulfonic acid was added, reacted at 40℃for 6 hours, the LCMS detection reaction ended, the pH was adjusted to 7 by adding aqueous sodium bicarbonate solution and extracted with ethyl acetate, the organic phase was concentrated and the column chromatographed to give N- (6- (4-amino-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-3-yl) -3- (benzenesulfonyl) propionamide (210 mg, crude).

LCMS：m/z 624.3[M+H] ⁺

Step nine: synthesis of N- (6- (4-amino-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyridin-3-yl) acrylamide

N- (6- (4-amino-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyridin-3-yl) -3- (benzenesulfonyl) propanamide (210 mg, 336. Mu. Mol,1.00 eq) was dissolved in 2mL tetrahydrofuran, trimethylpotassium silicate oxide (43.2 mg, 336. Mu. Mol,1.00 eq) was added, the reaction was stirred at 20℃for 1 hour, the reaction was terminated by LCMS detection, and the mixture was purified by reverse phase HPLC to give N- (6- (4-amino-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyridin-3-yl) acrylamide (20.5 mg, 41.9. Mu. Mol, yield 12.4%, purity 98.6%).

LCMS：m/z 482.4[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ＝10.44(s，1H)，8.69(d，J＝2.2Hz，1H)，8.23(s，1H)，8.09(dd，J＝2.4，8.5Hz，1H)，7.78(t，J＝7.8Hz，1H)，7.68-7.53(m，2H)，7.43-7.26(m，2H)，7.08-6.98(m，2H)，6.93(d，J＝8.0Hz，1H)，6.50-6.37(m，1H)，6.35-6.23(m，1H)，5.82(dd，J＝1.8，10.1Hz，1H)，5.77-5.52(m，2H)，2.31(s，3H).

Example 15:

synthesis of N- (5- (4-amino-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyridin-2-yl) acrylamide:

in analogy to example 1, N- (5- (4-amino-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyridin-2-yl) acrylamide (24.5 mg, yield: 17.4%) was obtained.

LCMS：m/z 482.4[M+H] ⁺ .

¹ H NMR(400MHz，ACETONITRILE-d3)δ＝8.89(br s，1H)，8.31(d，J＝2.3Hz，1H)，8.27(s，1H)，8.18(d，J＝8.8Hz，1H)，7.71(t，J＝7.8Hz，1H)，7.60(dd，J＝2.4，8.6Hz，1H)，7.39-7.26(m，3H)，6.98(d，J＝7.4Hz，1H)，6.86(d，J＝8.3Hz，1H)，6.78(s，1H)，6.50-6.41(m，1H)，6.40-6.34(m，1H)，5.79(dd，J＝2.3，9.6Hz，1H)，4.93(br s，2H)，2.31(s，3H).

Example 16:

synthesis of N- (4- (4-amino-5- (2-fluoro-4- ((6-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide:

step one: synthesis of 2-fluoro-4- ((6-methylpyridin-2-yl) oxyaniline

4-amino-3-fluorophenol (10.0 g,78.6mmol,1.00 eq) was dissolved in N, N-methylformamide (200 mL), 2-fluoro-6-methylpyridine (8.74 g,78.6mmol,8.09mL,1.00 eq) and cesium carbonate (51.3 g,157mmol,2.00 eq) were added and reacted at 100deg.C for 3 hours, after completion of LCMS detection, water was added and extracted with ethyl acetate, the organic phase washed with brine, dried, the filtrate was dried and purified by column chromatography to give 2-fluoro-4- ((6-methylpyridin-2-yl) oxyaniline (2.3 g,10.5mmol, yield 13.4%).

LCMS：m/z 219.1[M+H] ⁺ .

The remaining intermediates and final products, in a similar manner to that described in example 1, can afford the synthesis of N- (4- (4-amino-5- (2-fluoro-4- ((6-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide (8.1 mg, yield: 13.0%).

LCMS：m/z 481.4[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.25(s，1H)，8.22(s，1H)，7.88-7.73(m，2H)，7.64(d，J＝8.6Hz，2H)，7.35-7.20(m，3H)，7.17-7.05(m，2H)，6.90(d，J＝8.3Hz，1H)，6.76(s，1H)，6.54-6.34(m，1H)，6.31-6.16(m，1H)，5.77(br d，J＝11.8Hz，1H)，5.64(br s，2H)，2.36(s，3H).

Example 17:

synthesis of N- (4- (4-amino-5- (4- (pyrrolidine-1-carbonyl) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide:

the synthetic route is as follows:

step one: synthesis of (4-nitrophenyl) (pyrrolidin-1-yl) methanone

4-Nitrophenyl benzoic acid (10.0 g,1.00 eq), pyrrolidine (6.38 g,1.50 eq), O- (7-azabenzotriazol-1-yl) -N, N, N, N-tetramethylurea hexafluorophosphate (34.1 g,1.50 eq) and N, N-diisopropylethylamine (23.2 g,3.00 eq) were dissolved in 100mLN, N-dimethylformamide and stirred at 20℃for 2 hours. After completion of the reaction by LCMS and TLC, the reaction mixture was extracted with water and ethyl acetate, and the organic phase was concentrated to give (4-nitrophenyl) (pyrrolidin-1-yl) methanone (13.1 g, crude).

LCMS：m/z 221.2[M+H] ⁺ .

Step two: synthesis of (4-anilino) (pyrrolidin-1-yl) methanones

(4-nitrophenyl) (pyrrolidin-1-yl) methanone (13.0 g,1.00 eq), ammonium chloride (15.8 g,5.00 eq) and reduced iron powder (16.5 g,5.00 eq) were dissolved in 50mL ethanol and 50mL water and stirred at 80℃for 2 hours. After completion of the LCMS detection reaction, the reaction mixture was filtered, the filtrate was extracted with water and ethyl acetate, and the organic phase was concentrated to give (4-anilino) (pyrrolidin-1-yl) methanone (10.0 g, crude).

LCMS：m/z 191.1[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝7.27(d，J＝8.5Hz，2H)，6.53(d，J＝8.5Hz，2H)，5.50(br s，2H)，1.80(br s，4H)，1.27-1.24(m，4H).

Step three: synthesis of (4- (5- (4- (pyrrolidine-1-carbonyl) phenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) amino tert-butyl ester

/>

(4- ((5-bromo-6- (2, 2-trifluoroethoxy) pyrimidin-4-yl) ethynyl) phenyl) amino tert-butyl ester (1.00 g,1.00 eq), (4-anilino) (pyrrolidin-1-yl) (564 mg,1.40 eq), cesium carbonate (1.38 g,2.00 eq), 4, 5-bis-diphenylphosphine-99-dimethylxanthene (61.2 mg,0.05 eq) and [9, 9-dimethyl-4, 5-bis (diphenylphosphino) xanthene ] [ 2-amino-1, 1-diphenyl ] palladium (II) methanesulfonate dichloromethyl adduct (100 mg,0.05 eq) were dissolved in 10mL dioxane and stirred at 100 ℃ for 12 hours. After completion of the reaction by LCMS and TLC, the reaction mixture was concentrated and purified by silica gel column to give (4- (5- (4- (pyrrolidine-1-carbonyl) phenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) amino tert-butyl ester (700 mg, yield 56.8%).

LCMS：m/z 582.7[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝9.50(s，1H)，8.53(s，1H)，7.50(br d，J＝8.3Hz，2H)，7.42-7.32(m，4H)，7.18(br d，J＝8.5Hz，2H)，6.98(s，1H)，4.98(q，J＝8.8Hz，2H)，3.47(brt，J＝6.6Hz，2H)，2.70(d，J＝11.1Hz，2H)，1.94-1.79(m，4H)，1.45(s，9H).

Step four: synthesis of (4- (4-amino-6- (4-anilino) -5H-pyrrolo [3,2-d ] pyrimidin-5-yl) phenyl) (pyrrolidin-1-yl) methanone

(4- (5- (4- (pyrrolidine-1-carbonyl) phenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) amino tert-butyl ester (700 mg,1.00 eq) and aqueous ammonia (1.41 g,10.0 eq) were dissolved in 5mL dioxane and stirred at 100℃for 48 hours. After completion of the reaction by LCMS and TLC, the reaction mixture was concentrated and purified by silica gel column to give (4- (4-amino-6- (4-anilino) -5H-pyrrolo [3,2-d ] pyrimidin-5-yl) phenyl) (pyrrolidin-1-yl) methanone (290 mg, yield 60.4%).

LCMS：m/z 399.1[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.18(s，1H)，7.66-7.60(m，2H)，7.48-7.42(m，2H)，6.92-6.86(m，2H)，6.56(s，1H)，6.45-6.39(m，2H)，5.45(br s，2H)，5.38-5.29(m，2H)，3.48(t，J＝6.7Hz，2H)，3.42-3.38(m，2H)，1.86(br dd，J＝6.5，13.9Hz，4H).

Step five: synthesis of N- (4- (4-amino-5- (4- (pyrrolidine-1-carbonyl) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide

(4- (4-amino-6- (4-anilino) -5H-pyrrolo [3,2-d ] pyrimidin-5-yl) phenyl) (pyrrolidin-1-yl) methanone (70.0 mg,1.00 eq) was dissolved in 2mL dioxane and acryloyl chloride (15.9 mg,1.00 eq) was slowly added at 0deg.C and reacted at 20deg.C for 2 hours. LCMS detects the end of the reaction. Integration and SFC purification gave N- (4- (4-amino-5- (4- (pyrrolidine-1-carbonyl) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide (25.0 mg, yield 31.5%).

LCMS：m/z 453.4[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.23(s，1H)，8.21(s，1H)，7.60(dd，J＝8.4，17.6Hz，4H)，7.48(d，J＝8.3Hz，2H)，7.20(d，J＝8.5Hz，2H)，6.74(s，1H)，6.49-6.34(m，1H)，6.28-6.18(m，1H)，5.76(dd，J＝1.8，10.1Hz，1H)，5.53(br s，2H)，3.47(br t，J＝6.6Hz，2H)，3.38(br t，J＝6.3Hz，2H)，1.92-1.78(m，4H).

Example 18:

synthesis of N- (4- (4-amino-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide:

the synthetic route is as follows:

step one: synthesis of tert-butyl (4- (5- (3-fluoro-4- ((6-methylpyrimidin-2-yl) oxy) phenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate

Tert-butyl 6- ((5-amino-5-bromo-6- (2, 2-trifluoroethoxy) pyrimidin-4-yl) ethynyl) pyridin-3-yl) carbamate (1.00 g,2.12mmol,1.00 eq), 3-fluoro-4- ((6-methylpyridin-2-yl) oxyaniline (460 mg,2.12mmol,1.00 eq), [9, 9-dimethyl-4, 5-bis (diphenylphosphino) xanthene ] [ 2-amino-1, 1-diphenyl ] palladium (II) methanesulfonate dichloromethane complex (100 mg,106umol,0.05 eq), cesium carbonate (1.38 g,4.23mmol,2.00 eq) and bis-diphenylphosphine-9, 9-dimethyloxaxanthene (61.2 mg,106umol,0.05 eq) were dissolved in 10.0ml dioxane and reacted at 100 ℃ for 12 hours. LCMS detects the end of the reaction. The reaction solution was concentrated, and the concentrated solution was purified by a silica gel column to give tert-butyl (4- (5- (3-fluoro-4- ((6-methylpyrimidin-2-yl) oxy) phenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (1.00 g, yield 36.9%).

LCMS：m/z 611.3[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝9.55(s，1H)，8.54(s，1H)，7.76(t，J＝7.8Hz，1H)，7.58(dd，J＝2.4，11.0Hz，1H)，7.45(br d，J＝8.4Hz，2H)，7.25(br d，J＝8.6Hz，3H)，7.14-7.08(m，1H)，7.02(d，J＝7.4Hz，1H)，6.99(s，1H)，6.87(d，J＝8.1Hz，1H)，5.02(br d，J＝8.9Hz，2H)，2.30(s，3H)，1.47(s，9H).

Step two: synthesis of tert-butyl (4- (7-bromo-5- (3-fluoro-4- ((6-methylpyrimidin-2-yl) oxy) phenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate

Tert-butyl (4- (5- (3-fluoro-4- ((6-methylpyrimidin-2-yl) oxy) phenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (850 mg,1.39 mol,1.00 eq) was dissolved in 10.0mL acetonitrile, N-bromosuccinimide (248 mg,1.39mmol,1.00 eq) was added at 0deg.C, reacted at 20deg.C for 3 hours, after completion of LCMS detection reaction, concentrated and column chromatographed to give tert-butyl (4- (7-bromo-5- (3-fluoro-4- ((6-methylpyrimidin-2-yl) oxy) phenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (800 mg, yield 81.6%).

LCMS：m/z 548.4[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝9.58(s，1H)，8.63(s，1H)，7.74(t，J＝7.8Hz，1H)，7.57(dd，J＝2.4，11.0Hz，1H)，7.49(d，J＝8.6Hz，2H)，7.29(d，J＝8.8Hz，2H)，7.25-7.20(m，1H)，7.14(dd，J＝1.5，8.6Hz，1H)，7.00(d，J＝7.2Hz，1H)，6.83(d，J＝8.2Hz，1H)，5.05(br d，J＝1.6Hz，2H)，2.26(s，3H)，1.47(s，9H).

Step three: synthesis of tert-butyl (4- (5- (3-fluoro-4- ((6-methylpyrimidin-2-yl) oxy) phenyl-7-methyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate

Tert-butyl (4- (7-bromo-5- (3-fluoro-4- ((6-methylpyrimidin-2-yl) oxy) phenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (500 mg,726umol,1.00 eq) was dissolved in 12.0mL dioxane and 3.00mL of water, methylboronic acid (434 mg,7.26mmol,10.0 eq), potassium carbonate (200 mg,1.45mmol,2.00 eq) and tetrakis (triphenylphosphine) palladium (83.9 mg,72.6umol,0.10 eq) were added, after completion of the LCMS detection reaction, ethyl acetate was added to extract, organic phase was concentrated and column chromatographed to give (4- (5- (3-fluoro-4- ((6-methylpyrimidin-2-yl) oxy) phenyl-7-methyl-4- (2, 2-trifluoro-5H-pyrrolo [ 3.2-yl) pyrimidine-yl) carbamate (390 mg, 5.9-yl) yield.

LCMS：m/z 624.0[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝9.52(s，1H)，8.55(s，1H)，7.73(t，J＝7.8Hz，1H)，7.49-7.44(m，3H)，7.22-7.17(m，3H)，7.03-6.99(m，2H)，6.82(d，J＝8.1Hz，1H)，5.03(q，J＝8.7Hz，2H)，2.28(d，J＝6.6Hz，6H)，1.47(s，9H).

Step four: synthesis of (6- (4-aminobenzene-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyridin-4-amine

Tert-butyl (4- (5- (3-fluoro-4- ((6-methylpyrimidin-2-yl) oxy) phenyl-7-methyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (100 mg,160umol,1.00 eq) was dissolved in 1mL dioxane and 3.00mL ammonia, the reaction was checked for completion at 180 ℃ for 48 hours, LCMS, the reaction was concentrated and column chromatographed to give (6- (4-aminobenzene-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyridin-4-amine (30.0 mg, 40.5% yield).

LCMS：m/z 624.3[M+H] ⁺ .

Step five: synthesis of N- (4- (4-amino-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide

(6- (4-aminobenzene-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyridin-4-amine (30 mg,68.1 mol,1 eq) was dissolved in 3mL tetrahydrofuran, acryloyl chloride (4.93 mg,54.5 mol,4.44ul,0.8 eq) was slowly added at 0deg.C, reacted for 1 hour at 0deg.C, after completion of the LCMS detection reaction, the reaction solution was spin-dried and purified by reverse phase HPLC to give N- (4- (4-amino-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide (9.6 mg, yield 27.5%).

LCMS：m/z 495.1[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.25(s，1H)，8.24(s，1H)，7.74(t，J＝7.6Hz，1H)，7.67(br d，J＝8.0Hz，2H)，7.48(br d，J＝10.9Hz，1H)，7.36-7.28(m，1H)，7.28-7.16(m，3H)，7.00(br d，J＝7.3Hz，1H)，6.87(br d，J＝8.1Hz，1H)，6.47-6.37(m，1H)，6.31-6.21(m，1H)，5.77(br d，J＝10.1Hz，1H)，5.65(br s，2H)，2.25(s，3H)，2.20(s，3H).

The preparation of the compounds of the examples in Table 4 can be carried out by reference to the procedure analogous to the procedure of preparation example 18, except that the starting materials are replaced in the intermediate step to give the corresponding compounds.

TABLE 4 Table 4

Example 23:

n- (4- (4-amino-7- (dimethylphosphoryl) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide:

the synthetic route is as follows:

step one: synthesis of tert-butyl (4- (7-iodo-5- (3-fluoro-4-methylpyridin-2-yl) oxy) phenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate

N-iodosuccinimide (554 mg,2.46 mmol) was added to tert-butyl (4- (5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (1.00 g,1.64 mmol) in acetonitrile (20 mL) and the reaction stirred at 20℃for 2 hours. LCMS and TLC monitored the end of the reaction, the reaction was added to saturated brine (50 mL) and ethyl acetate (150 mL), the organic phase was concentrated by dryness and purified by flash column chromatography to give tert-butyl (4- (7-iodo-5- (3-fluoro-4-methylpyridin-2-yl) oxy) phenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (600 mg,49.7% yield).

1H NMR(400MHz，DMSO-d6)δ＝9.57(s，1H)，8.62(s，1H)，7.73(t，J＝7.8Hz，1H)，7.61-7.38(m，3H)，7.32-7.17(m，3H)，7.11(dd，J＝1.5，8.6Hz，1H)，7.00(d，J＝7.3Hz，1H)，6.83(d，J＝8.1Hz，1H)，5.04(br s，2H)，2.26(s，3H)，1.47(s，9H).

Step two: synthesis of tert-butyl (4- (7- (dimethylphosphoryl) -5- (3-fluoro-4- ((6-methylpyrimidin-2-yl) oxy) phenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate

Tert-butyl (4- (7-iodo-5- (3-fluoro-4-methylpyridin-2-yl) oxy) phenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (300 mg,408 mol) and dimethylphosphine (95.5 mg,1.22 mmol) were dissolved in N, N-dimethylformamide (10 mL) and 1,1' -bis-diphenylphosphino ferrocene palladium dichloride (59.7 mg,81.6 mol) and N, N-diisopropylethylamine (105 mg,816 mol) were added. The reaction mixture was reacted at 110℃for 8 hours. After completion of the reaction, TLC was followed by addition to saturated brine (50 mL) and ethyl acetate (150 mL), and the organic phase was concentrated by drying, followed by purification on a flash column of silica gel to give tert-butyl (4- (7- (dimethylphosphoryl) -5- (3-fluoro-4- ((6-methylpyrimidin-2-yl) oxy) phenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (200 mg,71.5% yield).

1H NMR(400MHz，CHLOROFORM-d)δ＝8.62(s，1H)，7.63-7.52(m，2H)，7.39(br d，J＝8.5Hz，2H)，7.31(d，J＝8.8Hz，2H)，7.21(br s，1H)，7.15-7.10(m，1H)，7.03-6.98(m，1H)，6.93-6.86(m，2H)，6.66(d，J＝8.1Hz，1H)，4.82(q，J＝8.3Hz，2H)，2.38(s，3H)，1.87(br d，J＝8.6Hz，6H)，1.50(s，9H).

Step three: synthesis of (4-amino-6- (4-aminophenyl) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) dimethylphosphine oxide

Tert-butyl (4- (7- (dimethylphosphoryl) -5- (3-fluoro-4- ((6-methylpyrimidin-2-yl) oxy) phenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (200 mg,292 umol) was dissolved in a 30ml closed reactor (9.10 g,72.7mmol,10mL,28% purity) and reacted at 100℃and a pressure of 40psi for 48 hours. After TLC monitoring the end of the reaction, the reaction solution was diluted with ethyl acetate, washed with brine, and the organic phase was concentrated and column chromatographed to give (4-amino-6- (4-aminophenyl) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) dimethylphosphino-oxide (130 mg,88.7% yield).

1H NMR(400MHz，DMSO-d6)δ＝8.29(s，1H)，7.81-7.52(m，5H)，7.34(brt，J＝8.6Hz，2H)，7.25(dd，J＝1.6，8.5Hz，1H)，7.06-6.97(m，5H)，6.87(d，J＝8.1Hz，1H)，6.45(dd，J＝2.3，8.4Hz，3H)，5.82-5.61(m，2H)，5.40(br s，5H)，2.29(s，3H).

Step four: synthesis of N- (4- (4-amino-7- (dimethylphosphoryl) -5- (3-fluoro-4- ((6-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl 1 acrylamide

(4-amino-6- (4-aminophenyl) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) dimethylphosphino oxide (130 mg, 319 umol) was dissolved in tetrahydrofuran (3 mL), and acryloyl chloride (9.37 mg,103 umol) was slowly added dropwise at 0 ℃. The reaction was stirred at 0 ℃ for 1 hour LCMS to monitor the reaction completion. The reaction mixture was concentrated and separated by preparative HPLC to give N- (4- (4-amino-7- (dimethylphosphoryl) -5- (3-fluoro-4- ((6-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide (18.5 mg,12.8% yield).

LCMS：m/z 557.2[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.27(s，1H)，8.32(s，1H)，7.74(t，J＝7.8Hz，1H)，7.67-7.50(m，3H)，7.42-7.21(m，4H)，7.00(br d，J＝7.4Hz，1H)，6.85(d，J＝8.0Hz，1H)，6.51-6.34(m，1H)，6.32-6.16(m，1H)，5.99-5.58(m，3H)，2.21(s，3H)，1.67(br d，J＝13.9Hz，6H).

Example 24:

n- (4- (4-amino-7-cyano-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide:

the synthetic route is as follows:

step one: synthesis of tert-butyl (4- (7-cyano-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -4- (2, 2-trifluoroethoxy) 5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate

(4- (7-bromo-5- (3-fluoro-4-methylpyridin-2-yl) oxy) phenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamic acid tert-butyl ester (1.00 g,1.45 mmol), zinc cyanide (1.86 g,15.8 mmol) and CATACXIUM (R) APDG3 (1.06 g,1.45 mmol) were added to DMF (10 mL), nitrogen was replaced three times, stirred at 130℃for 6 hours, LCMS and TLC were monitored for the end of the reaction, the reaction was added to saturated brine (50 mL) and ethyl acetate (150 mL), concentrated in organic phase, and purified by flash column to give (4- (7-cyano-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -4- (2, 2-trifluoroethoxy) 5H-pyrrolo [3,2-d ] pyrimidin-6-yl) carbamic acid tert-butyl ester (65 mg, 600% yield).

¹ H NMR(400MHz，CDCl3)δ＝8.62(s，1H)，7.54(t，J＝7.8Hz，1H)，7.39-7.33(m，2H)，7.32-7.26(m，2H)，7.03(dd，J＝2.5，10.1Hz，1H)，6.97-6.92(m，1H)，6.83(d，J＝7.4Hz，1H)，6.67(d，J＝8.3Hz，1H)，6.54(s，1H)，4.75(q，J＝8.3Hz，2H)，2.32(s，3H)，1.45(s，9H).

Step two: synthesis of 4-amino-6- (4-aminophenyl) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carbonitrile

Tert-butyl (4- (7-cyano-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -4- (2, 2-trifluoroethoxy) 5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (300 mg, 470 umol) was dissolved in 1, 4-dioxane (0.5 mL) and aqueous ammonia (2 mL), and the reaction was stirred at 130℃for 12 hours. LCMS and TLC monitored the reaction was complete, the reaction was diluted with ethyl acetate, washed with brine, and the organic phase concentrated and column chromatographed to give 4-amino-6- (4-aminophenyl) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carbonitrile (100 mg,46.8% yield).

1H NMR(400MHz，DMSO-d6)δ＝8.31(s，1H)，7.79(t，J＝7.8Hz，1H)，7.72(dd，J＝1.9，10.7Hz，1H)，7.47-7.38(m，2H)，7.09-7.03(m，3H)，6.93(d，J＝8.1Hz，1H)，6.54(d，J＝8.6Hz，2H)，5.94(br s，2H)，5.69(s，2H)，2.31(s，3H).

Step three: synthesis of N- (4- (4-amine-7-cyano-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide

Acryloyl chloride (14.3 mg, 1598 umol) was added dropwise to a solution of 4-amino-6- (4-aminophenyl) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carbonitrile (90.0 mg, 199umol) in THF (0.5 mL) at 0deg.C, and the reaction was continued at that temperature for 2 hours. LCMS monitored the end of the reaction, and the reaction mixture was concentrated under reduced pressure and separated by preparative HPLC to give N- (4- (4-amine-7-cyano-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide (32.0 mg,31.5% yield).

LCMS：m/z 505.9[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.37(s，1H)，8.35(s，1H)，7.80-7.69(m，4H)，7.44-7.34(m，4H)，7.02(d，J＝7.4Hz，1H)，6.91(d，J＝8.1Hz，1H)，6.48-6.37(m，1H)，6.32-6.23(m，1H)，6.06(br s，2H)，5.82-5.76(m，1H)，2.26(s，3H).

Example 25:

n- (4- (4-amino-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7- (2-hydroxypropan-2-yl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide:

the synthetic route is as follows:

step one: synthesis of tert-butyl (4- (5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7- (isopropenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate

Tert-butyl (4- (5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7-iodo-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (3.00 g,1.00 eq), potassium isopropenyl trifluoroborate (72.4 mg,1.20 eq), [1, 1-bis (di-tert-butylphosphine) ferrocene ] palladium dichloride (13.9 mg,0.05 eq), cesium fluoride (123 mg,2.00 eq) were dissolved in 15mL acetonitrile and stirred at 80℃for 2 hours. After completion of LCMS and TLC detection, the reaction mixture was concentrated and purified by silica gel column to give tert-butyl ester (140 mg, yield 52.8%) of (4- (5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7- (isopropenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) as a yellow solid.

LCMS：m/z 650.2[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝9.50(s，1H)，8.59(s，1H)，7.95(s，1H)，7.73(t，J＝7.8Hz，1H)，7.56(s，1H)，7.52-7.39(m，3H)，7.23-7.15(m，3H)，7.08(dd，J＝1.4，8.6Hz，1H)，7.00(d，J＝7.4Hz，1H)，6.81(d，J＝8.0Hz，1H)，5.03(br d，J＝7.1Hz，2H)，2.89(s，3H)，2.73(s，3H)，1.47(s，9H).

Step two: synthesis of tert-butyl (4- (5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7- (2-isopropanol) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate

Tert-butyl (4- (5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7- (isopropenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (130 mg,1.00 eq), tetraethylammonium borohydride (145 mg,5.00 eq) was dissolved in 1.0mL methanol. Cobalt tetraphenylporphyrin (67 mg,0.50 eq) was added in portions at 0deg.C and stirred at 20deg.C for 1 hour. After completion of LCMS detection reaction, filtration gave tert-butyl amino (100 mg, crude) carbamate as a white solid (4- (5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7- (2-isopropanol) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl).

LCMS：m/z 668.3[M+H] ⁺ .

Step three: synthesis of 2- (4-amino-6- (4-anilino) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) isopropanol-2-ol

(4- (5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7- (2-isopropanol) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamic acid tert-butyl ester (120 mg,1.00 eq), aqueous ammonia (180 mg,10.0 eq) was dissolved in 2mL dioxane and stirred at 100℃for 48 hours. After completion of LCMS detection, the reaction mixture was concentrated and purified by silica gel column to give 2- (4-amino-6- (4-anilino) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) isopropyl alcohol-2-ol as a red solid (20 mg,22.9% yield).

LCMS：m/z 485.2[M+H] ⁺ .

Step four: synthesis of N- (4- (4-amino-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7- (2-isopropanol-2-yl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide

2- (4-amino-6- (4-anilino) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) isopropanol-2-ol (20 mg,1.00 eq) was dissolved in 3mL tetrahydrofuran, and acryloyl chloride (2.64 mg,0.60 eq) was slowly added at 0deg.C for 2 hours at 20deg.C. LCMS detects the end of the reaction. Purification by reverse phase column gave N- (4- (4-amino-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7- (2-isopropanol-2-yl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide as a white solid (5.00 mg, yield 22.5%).

LCMS：m/z 539.3[M+H] ⁺ .

¹ H NMR(400MHz，ACETONITRILE-d3)δ＝8.79-8.58(m，1H)，8.31(s，1H)，7.77-7.56(m，3H)，7.39-7.12(m，5H)，6.97(d，J＝7.4Hz，1H)，6.80(d，J＝8.3Hz，1H)，6.38-6.32(m，3H)，5.77(dd，J＝3.6，8.4Hz，1H)，5.15(br s，2H)，2.24(br s，3H)，1.40(s，6H).

The preparation of the compounds of the examples in Table 5 can be carried out by reference to the procedure analogous to the procedure of preparation example 18, except that starting materials are replaced in the intermediate step to give the corresponding compounds.

TABLE 5

Example 27:

synthesis of N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide:

the synthetic route is as follows:

step one: synthesis of 4- (benzyloxy) -3-fluoroaniline

4-amino-2-fluorophenol (10.0 g,78.6 mmol) was dissolved in 50mL of N' N-dimethylformamide, then potassium t-butoxide (8.83 g,78.6 mmol) was added at 0deg.C, after stirring for 10 minutes benzyl bromide (13.4 g,78.6 mmol) was added to the reaction solution, reacted at 0deg.C for 1 hour, after completion of LCMS detection reaction, water and ethyl acetate were added, the organic phase was washed with saturated sodium bicarbonate, then brine, concentrated and column chromatographed to give 4- (benzyloxy) -3-fluoroaniline (4.80 g, yield 26.6%).

LCMS：m/z 217.9[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ＝7.45-7.35(m，4H)，7.34-7.28(m，1H)，6.88(t，J＝9.2Hz，1H)，6.40(dd，J＝2.6，13.7Hz，1H)，6.27(td，J＝1.3，8.6Hz，1H)，4.97(s，2H)，4.95(s，2H).

Step two: synthesis of tert-butyl (4- (5- (4- (benzyloxy) -3-fluorophenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate

Tert-butyl (4- ((5-bromo-2, 2-trifluoroethoxy) pyrimidin-4-yl) ethynyl) phenyl) carbamate (2.00 g,186 mmol) was dissolved in 10mL ethanol, 4- (benzyloxy) -3-fluoroaniline (1.01 g,4.66 mmol), cesium carbonate (2.76 g,8.47 mmol), [9, 9-dimethyl-4, 5-bis (diphenylphosphino) xanthene ] [ 2-amino-1, 1-diphenyl ] palladium (II) methanesulfonate dichloro methyl adduct (401 mg,423 umol) and 4, 5-bis-diphenylphosphine-9, 9-dimethyloxaxanthene (245 mg,423 umol) were added, after completion of the s detection reaction the reaction was concentrated and column chromatography gave (4- (5- (4- (benzyloxy) -3-fluorophenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3, 6-phenyl ] pyrimidine) carbamate (85.8 g) amino-butyl (85.81%).

LCMS：m/z 609.7[M+H] ⁺ .

1H NMR(400MHz，DMSO-d6)δ＝9.53(s，1H)，8.51(s，1H)，7.46-7.37(m，7H)，7.24(d，J＝8.8Hz，2H)，7.18(brt，J＝9.1Hz，1H)，6.98(br d，J＝7.9Hz，1H)，6.93(s，1H)，5.76(s，1H)，5.20(br s，2H)，4.97(br d，J＝5.0Hz，2H)，1.47(s，9H).

Step three: synthesis of tert-butyl (4- (5- (4- (benzyloxy) -3-fluorophenyl) -4-hydroxy-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate

Tert-butyl (4- (5- (4- (benzyloxy) -3-fluorophenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (1.66 g,2.73 mmol) was dissolved in 44mL of dimethyl sulfoxide at 25 ℃, 6M sodium hydroxide solution was prepared and 4.55mL of the solution was added to the mixture, the reaction was allowed to react at 60℃for 1 hour, LCMS detection was completed, extraction was performed with water and ethyl acetate, and the organic phase was washed with brine, dried and column chromatographed to give tert-butyl (4- (5- (4- (benzyloxy) -3-fluorophenyl) -4-hydroxy-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (550 mg, yield 33.3%).

LCMS：m/z 527.1[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝11.93(br s，1H)，9.47(s，1H)，7.85(s，1H)，7.50-7.46(m，2H)，7.42(t，J＝7.2Hz，2H)，7.39-7.29(m，4H)，7.19(t，J＝9.1Hz，1H)，7.11(d，J＝8.8Hz，2H)，6.95(br d，J＝8.5Hz，1H)，6.65(s，1H)，5.19(s，2H)，1.46(s，9H).

Step four: synthesis of tert-butyl (4- (5- (4- (benzyloxy) -3-fluorophenyl) -4- ((4-methoxybenzyl) amino) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate

Tert-butyl (4- (5- (4- (benzyloxy) -3-fluorophenyl) -4-hydroxy-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (550 mg,1.04 mmol) was dissolved in 25mL of N' N-dimethylformamide, benzotriazol-1-yl-oxy-tripyrrolidine hexafluorophosphate (2.72 g,5.22 mmol), p-methoxybenzylamine (716mg, 5.22 mmol) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (795 mg,5.22 mmol) were added, LCMS was stirred for 6 hours at 80 ℃, water and ethyl acetate were added for extraction, the organic phase thereof was concentrated in water and filtered, the column chromatography was performed to give crude product, which was purified by preparative HPLC to give tert-butyl (4- (5- (4- (benzyloxy) -3-fluorophenyl) -4- ((4-methoxybenzyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) carbamate (110 mg, yield 11.5%).

LCMS：m/z 646.1[M+H] ⁺ .

¹ H NMR(400MHz，ACETONITRILE-d3)δ＝8.28(s，1H)，7.58(br s，1H)，7.44-7.41(m，4H)，7.39-7.36(m，1H)，7.32(d，J＝8.6Hz，2H)，7.23(dd，J＝2.4，11.4Hz，1H)，7.20(d，J＝8.8Hz，2H)，7.17-7.14(m，1H)，7.13-7.08(m，3H)，6.86-6.81(m，2H)，6.62(s，1H)，5.22-5.16(m，1H)，5.10(br d，J＝16.0Hz，2H)，4.47(s，2H)，3.72(s，3H)，1.47(s，9H).

Step five: synthesis of tert-butyl (4- (5- (3-fluoro-4-hydroxyphenyl) -4- ((4-methoxybenzyl) amino) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate

Tert-butyl (4- (5- (4- (benzyloxy) -3-fluorophenyl) -4- ((4-methoxybenzyl) amino) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (100 mg,109 umol) was dissolved in 10mL of methanol, then 50mg of 10% wet palladium on carbon was added, reacted for 3 hours at 20℃in a hydrogen atmosphere, filtered and concentrated to give (4- (5- (3-fluoro-4-hydroxyphenyl) -4- ((4-methoxybenzyl) amino) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (60.0 mg, yield 70.7%) as crude product.

LCMS：m/z 556.6[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝9.44(s，1H)，8.23(s，1H)，7.37(br d，J＝8.5Hz，2H)，7.25(br d，J＝10.4Hz，1H)，7.18(d，J＝8.5Hz，2H)，7.05(d，J＝8.4Hz，2H)，7.02(br d，J＝8.6Hz，1H)，6.90-6.85(m，1H)，6.82(d，J＝8.4Hz，2H)，6.64(s，1H)，4.85(brt，J＝5.2Hz，1H)，4.48(br d，J＝5.4Hz，2H)，3.69(s，3H)，3.17(s，1H)，1.45(s，9H)ppm.

Step six: synthesis of tert-butyl (4- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate

(4- (5- (3-fluoro-4-hydroxyphenyl) -4- ((4-methoxybenzyl) amino) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamic acid tert-butyl ester (60.0 mg,107 umol) was dissolved in 0.5mL of N' -dimethylformamide, 2-chloro-4-methylpyrimidine (27.7 mg,215 umol) and cesium carbonate (70.3 mg,215 umol) were added, after completion of the LCMS detection reaction at 100℃for 5 hours, water and ethyl acetate were added to extract, the organic phase was dried, filtered, concentrated and column chromatographed to give (4- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4-methoxybenzyl) amino) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamic acid tert-butyl ester (80 mg, yield 74.3%).

LCMS：m/z 648.1[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝9.50(s，1H)，8.46(d，J＝4.9Hz，1H)，8.35-8.24(m，1H)，7.75-7.58(m，1H)，7.50-7.41(m，3H)，7.37(br d，J＝8.5Hz，1H)，7.24-7.17(m，3H)，7.13(br d，J＝8.4Hz，2H)，6.86-6.77(m，2H)，6.73(s，1H)，5.00(br t，J＝5.2Hz，1H)，4.59-4.45(m，2H)，3.68(s，3H)，2.38(s，3H)，1.47(s，9H).

Step seven: synthesis of 6- (4-aminophenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

Tert-butyl (4- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (160 mg,509.67 mmol) was dissolved in 2.5mL of dichloromethane and 0.5mL of trifluoroacetic acid was added, the reaction was checked at 20℃for 2 hours, the reaction was completed, flash dried and sodium bicarbonate was added to adjust the pH to 7, extraction was performed with ethyl acetate, the organic phase was dried, filtered and concentrated to give 6- (4-aminophenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (70.0 mg, yield 62.1%).

LCMS：m/z 548.1[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.26(s，1H)，7.63(dd，J＝2.3，10.8Hz，1H)，7.47-7.42(m，1H)，7.41-7.30(m，2H)，7.21(d，J＝5.0Hz，1H)，7.11(br d，J＝8.6Hz，2H)，6.96(d，J＝8.5Hz，2H)，6.79(d，J＝8.6Hz，2H)，6.62-6.56(m，1H)，6.48(d，J＝8.5Hz，2H)，5.37(br s，2H)，4.86(br t，J＝5.5Hz，1H)，4.51(br d，J＝5.5Hz，2H)，3.67(s，3H)，2.42-2.35(m，3H).

Step eight: synthesis of N- (4- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) -3- (benzenesulfonyl) propylamine

6- (4-Aminophenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (60 mg,109 mol) was dissolved in 3mL of dichloromethane, 3- (benzenesulfonyl) propionic acid (46.9 mg,219 mol), N, N-diisopropylethylamine (28.3 mg,219 mol) and O- (7-azabenzotriazol-1-yl) -N, N, N, N-tetramethylurea hexafluorophosphine salt (83.3 mg,219 mol) were added, the S detection reaction was completed, and spin-drying and column chromatography gave N- (4- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) -3- (benzenesulfonyl) propylamine (100 mg) in a yield of 77.3%).

LCMS：m/z 744.2[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.19(br s，1H)，8.61-8.32(m，2H)，7.94-7.87(m，3H)，7.80-7.62(m，6H)，7.51-7.47(m，2H)，7.36(br d，J＝8.8Hz，1H)，7.21(br d，J＝5.0Hz，2H)，7.13(br d，J＝8.3Hz，2H)，6.81(br d，J＝8.3Hz，2H)，4.58(br d，J＝5.0Hz，2H)，3.68(s，3H)，3.58(br d，J＝7.0Hz，2H)，3.17(s，1H)，2.67(br s，2H)，2.38(s，3H).

Step nine: synthesis of N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) -3- (benzenesulfonyl) propylamine

N- (4- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) -3- (benzenesulfonyl) propylamine (100 mg,84.70 mol) was dissolved in 1mL of trifluoroacetic acid, 0.5mL of trifluoromethanesulfonic acid was added, stirring was carried out at 20℃for 2 hours, LCMS detection was completed, saturated sodium bicarbonate solution was added to adjust pH to 7, ethyl acetate was extracted, the organic phase was dried and dried to give N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) -3- (benzenesulfonyl) propylamine (60.0 mg, yield 37.9%).

LCMS：m/z 624.3[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.16(s，1H)，8.55-8.46(m，1H)，8.22(s，1H)，7.94-7.87(m，3H)，7.78-7.69(m，2H)，7.68-7.61(m，4H)，7.49-7.45(m，2H)，7.33(brdd，J＝1.5，8.6Hz，1H)，7.25-7.19(m，3H)，6.72(s，1H)，3.60(br d，J＝6.5Hz，2H)，2.67(br d，J＝1.8Hz，2H)，2.43-2.40(m，3H).

Step ten: synthesis of N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide

N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) -3- (benzenesulfonyl) propylamine (60.0 mg,96.2 mol) was dissolved in 3mL tetrahydrofuran, trimethylpotassium silicate oxide (18.5 mg,144 mol) was added, the reaction was checked for end by LCMS at 20℃for 1 hour, and the mixture was spun-dried and N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide (9.1 mg, yield 19.4%) was obtained by preparative HPLC.

LCMS：m/z 482.4[M+H] ⁺ .

¹ H NMR(400MHz，ACETONITRILE-d3)δ＝8.65(br s，1H)，8.41(d，J＝5.0Hz，1H)，8.27(s，1H)，7.63(d，J＝8.6Hz，2H)，7.45-7.34(m，2H)，7.33-7.24(m，3H)，7.09(d，J＝5.0Hz，1H)，6.72(s，1H)，6.39-6.26(m，2H)，5.74(dd，J＝3.8，8.1Hz，1H)，4.99(br s，2H)，2.42(s，3H).

Example 28:

n- (4- (4-amino-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7- (1-hydroxyethyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide:

the synthetic route is as follows:

step one: synthesis of (4- (7-acetyl-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) amino tert-butyl ester

/>

(4- (5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) amino tert-butyl ester (300 mg,1.00 eq), tributyl (1-ethoxyethylene) tin (683 mg,1.30 eq), dichlorobis (triphenylphosphine) palladium (II) (95.0 mg,0.10 eq) were dissolved in 15mL toluene and stirred at 105℃for 10 hours. After completion of LCMS and TLC detection, the reaction mixture was concentrated and purified by silica gel column to give tert-butyl ester (500 mg, yield 56.3%) of 4- (7-acetyl-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) as a yellow solid.

LCMS：m/z 652.4[M+H] ⁺ .

H NMR(400MHz，DMSO-d6)δ＝9.70-9.34(m，1H)，8.77-8.39(m，1H)，7.75(td，J＝7.8，10.4Hz，1H)，7.61-7.50(m，1H)，7.43(br dd，J＝8.6，19.6Hz，2H)，7.30-7.08(m，4H)，7.05-6.95(m，1H)，6.92-6.78(m，1H)，5.30-4.92(m，2H)，2.82-2.67(m，3H)，2.33-2.21(m，3H)，1.47(s，9H).

Step two: synthesis of 1- (4-amino-6- (4-anilino) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) ketene

(4- (7-acetyl-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamic acid tert-butyl ester (490 mg,1.00 eq), aqueous ammonia (942 mg,10.0 eq) was dissolved in 2mL dioxane and stirred at 100℃for 48 hours. After completion of LCMS detection, the reaction mixture was concentrated and purified by silica gel column to give 1- (4-amino-6- (4-anilino) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) ketene as a red solid (100 mg,28.3% yield).

LCMS：m/z 470.2[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.54-8.11(m，1H)，7.84-7.72(m，1H)，7.58(br d，J＝10.3Hz，1H)，7.47-6.84(m，6H)，6.78-6.37(m，3H)，5.84-5.27(m，3H)，2.50-2.49(m，9H)，1.75(s，3H).

Step three: synthesis of 1- (4-amino-6- (4-anilino) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) hydroxyethyl

1- (4-amino-6- (4-anilino) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) hydroxyethyl (60 mg,1.00 eq) was dissolved in 0.1ml methanol. Sodium borohydride (9.69 mg,2.00 eq) was added in portions at 0deg.C and stirred for 1 hour at 20deg.C. After completion of LCMS detection reaction, filtration gave 1- (4-amino-6- (4-anilino) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) hydroxyethyl (60 mg, crude) as a white solid.

LCMS：m/z 470.2[M+H] ⁺ .

Step four: synthesis of N- (4- (4-amino-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7- (1-hydroxyethyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide

1- (4-amino-6- (4-anilino) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) hydroxyethyl (30 mg,1.00 eq) was dissolved in 3mL tetrahydrofuran, acryloyl chloride (3.46 mg,0.60 eq) was slowly added at 0deg.C and reacted at 20deg.C for 2 hours, and LCMS detection was complete. Purification by reverse phase column gave N- (4- (4-amino-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7- (1-hydroxyethyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide as a white solid (5.00 mg, yield 27.8%).

LCMS：m/z 525.2[M+H] ⁺ .

¹ H NMR(400MHz，ACETONITRILE-d3)δ＝8.55(br s，1H)，8.28(s，1H)，7.78-7.57(m，3H)，7.33-7.13(m，5H)，6.95(d，J＝7.4Hz，1H)，6.80(d，J＝8.1Hz，1H)，6.37-6.28(m，2H)，5.74(dd，J＝4.6，7.3Hz，1H)，4.99-4.77(m，3H)，4.16-3.80(m，1H)，2.25(s，3H)，1.59(d，J＝6.5Hz，3H).

Example 29:

n- (4- (4-amino-5- (1- (6-methylpyridin) piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide:

the synthetic route is as follows:

step one: synthesis of tert-butyl 4- (6- (4- ((tert-Ding Yangtan yl) amino) phenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-5-yl) piperidine-1-carbamate

(4- ((5-bromo-6- (2, 2-trifluoroethoxy) pyrimidin-4-yl) ethynyl) phenyl) amino tert-butyl ester (3.00 g,1.00 eq), 4-aminopiperidine-1-carboxylic acid tert-butyl ester (1.27 g,1.00 eq), cesium carbonate (4.14 g,2.00 eq), 45-bis-diphenylphosphine-99-dimethylxanthene (183mg, 0.05 eq) and [9, 9-dimethyl-4, 5-bis (diphenylphosphino) xanthene ] [ 2-amino-1, 1-diphenyl ] palladium (II) methanesulfonate dichloromethyl adduct (301 mg,0.05 eq) were dissolved in 10mL dioxane and stirred at 105 ℃ for 6 hours. After completion of the reaction by LCMS and TLC, the reaction mixture was concentrated and purified by silica gel column to give tert-butyl 4- (6- (4- ((tert-Ding Yangtan base) amino) phenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-5-yl) piperidine-1-carbamate (2.50 g, yield 66.5%).

LCMS：m/z 592.8[M+H] ⁺ .

Step two: synthesis of 4- (5- (piperidin-4-yl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) amino

Tert-butyl 4- (6- (4- ((tert-Ding Yangtan yl) amino) phenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-5-yl) piperidine-1-carboxylate (2.50 g,1.00 eq) was dissolved in 2mL of methanol, and 4M dioxane hydrochloride (4.24 mL,4.00 eq) was slowly added at 0deg.C. Stirred at 20℃for 10 hours. After completion of LCMS detection, the reaction mixture was concentrated to give 4- (5- (piperidin-4-yl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) amino (1.65 g, crude).

LCMS：m/z 392.2[M+H] ⁺ .

Step three: synthesis of (4- (6- (4-anilino) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-5-yl) piperidin-1-yl) (6-methylpyridin-2-yl) methanone

6-methylpyridinecarboxylic acid (315 mg,0.90 eq), triethylamine (775 mg,1.00 eq) and O- (7-azabenzotriazol-1-yl) -N, N, N, N-tetramethylurea hexafluorophosphine salt (1.46 g,1.50 eq) were dissolved in 2mL of methylene chloride, and 4- (5- (piperidin-4-yl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) amino (1.00 g,1.00 eq) was slowly added at-20 ℃. Stirred at 20℃for 10 hours. After completion of the LCMS detection reaction, LCMS and TLC detection reaction, the reaction solution was concentrated and purified by silica gel column to give (4- (6- (4-anilino) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-5-yl) piperidin-1-yl) (6-methylpyridin-2-yl) methanone (1.00 g, yield 76.7%).

LCMS：m/z 511.2[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.45(s，1H)，7.82(t，J＝7.8Hz，1H)，7.32(dd，J＝3.2，7.7Hz，2H)，7.21(d，J＝8.5Hz，2H)，6.71(d，J＝8.4Hz，2H)，6.53(s，1H)，5.59(s，2H)，5.42-5.14(m，2H)，4.67(br d，J＝12.8Hz，1H)，2.69(s，6H)，2.48(s，3H)，1.95-1.87(m，1H)，1.75(br d，J＝12.9Hz，1H).

Step four: synthesis of 6- (4-anilino) -5- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amino

(4- (6- (4-anilino) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-5-yl) piperidin-1-yl) (6-methylpyridin-2-yl) methanone (1.00 g,1.00 eq) and aqueous ammonia (2.29 g,10.0 eq) were dissolved in 5mL dioxane and stirred at 100℃for 48 hours. After completion of the reaction by LCMS and TLC, the reaction mixture was concentrated and purified by silica gel column to give 6- (4-anilino) -5- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amino (340 mg, yield 56.3%).

LCMS：m/z 309.1[M+H] ⁺ .

Step five: synthesis of (4- (4-amino-6- (4-anilino) -5H-pyrrolo [3,2-d ] pyrimidin-5-yl) piperidin-1-yl) (6-methylpyridin-2-yl) methanone

6-picolinic acid (53.3 mg,0.90 eq), N, N-diisopropylethylamine (188 mg,3.00 eq) and O- (7-azabenzotriazol-1-yl) -N, N, N, N-tetramethyluronium hexafluorophosphine salt (277 mg,1.50 eq) were dissolved in 2mL of dichloromethane and 4- (5- (piperidin-4-yl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) amino (150 mg,1.00 eq) was slowly added at-20 ℃. Stirred at 20℃for 10 hours. After completion of the LCMS detection reaction, LCMS and TLC detection reaction, the reaction solution was concentrated and purified by silica gel column to give (4- (6- (4-anilino) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-5-yl) piperidin-1-yl) (6-methylpyridin-2-yl) methanone (190 mg, yield 38.8%).

LCMS：m/z 428.1[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.15(s，1H)，7.81(t，J＝7.8Hz，1H)，7.33(d，J＝7.8Hz，1H)，7.20(d，J＝7.6Hz，1H)，7.12(d，J＝8.4Hz，2H)，6.66(d，J＝8.4Hz，2H)，6.53(br s，2H)，6.25(s，1H)，5.61-5.28(m，2H)，4.76-4.63(m，1H)，4.48(br d，J＝12.9Hz，1H)，3.53(br d，J＝13.6Hz，2H)，3.11(br t，J＝11.9Hz，1H)，2.92-2.79(m，1H)，2.49(s，3H)，2.08-1.93(m，3H).

Step six: synthesis of N- (4- (4-amino-5- (1- (6-methylpyridine) piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide

/>

(4- (6- (4-anilino) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-5-yl) piperidin-1-yl) (6-methylpyridin-2-yl) methanone (100 mg,1.00 eq) was dissolved in 2mL dioxane, and acryloyl chloride (28.0 mg,1.00 eq) was slowly added at 0deg.C for 2 hours at 20deg.C. LCMS detects the end of the reaction. Integration and SFC purification gave N- (4- (4-amino-5- (1- (6-methylpyridin) piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide (21.2 mg, yield 31.5%).

LCMS：m/z 482.2[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.39(s，1H)，8.15(s，1H)，7.82(d，J＝8.6Hz，2H)，7.72(t，J＝7.7Hz，1H)，7.46(d，J＝8.5Hz，2H)，7.31(d，J＝7.6Hz，1H)，7.13(d，J＝7.6Hz，1H)，6.54(br s，2H)，6.52-6.45(m，1H)，6.38-6.27(m，2H)，5.87-5.77(m，1H)，4.81-4.65(m，1H)，4.52-4.39(m，1H)，3.57-3.46(m，1H)，3.16-3.06(m，1H)，2.91-2.80(m，1H)，2.44(s，3H)，2.05-1.76(m，4H).

Example 30:

n- (4- (4-amino-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7- (morpholinomethyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide:

the synthetic route is as follows:

step one: synthesis of tert-butyl (4- (5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7-formyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate

DIBAL-H (1M, 7.09 mL) was slowly added dropwise to tert-butyl (4- (7-cyano-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate in tetrahydrofuran (5 mL) at-60℃and the reaction was stirred continuously at-60℃for 2 hours, TLC and LCMS monitored for the end of the reaction, the reaction was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, and the organic phase was concentrated and dried and purified by flash column to give tert-butyl (4- (5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7-formyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (600 mg, 941. Mu.7% yield.

¹ H NMR：(400MHz，DMSO-d6)δ＝10.02(s，1H)，9.62(s，1H)，8.74(s，1H)，7.75(t，J＝7.8Hz，1H)，7.64(dd，J＝2.1，11.0Hz，1H)，7.50(d，J＝8.5Hz，2H)，7.35(d，J＝8.6Hz，2H)，7.29-7.23(m，1H)，7.22-7.15(m，1H)，7.01(d，J＝7.4Hz，1H)，6.85(d，J＝8.1Hz，1H)，5.15-4.98(m，2H)，2.26(s，3H)，1.48(s，9H).

Step two: synthesis of tert-butyl (4- (5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7- (morpholinomethyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate

Tert-butyl (4- (5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7-formyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (500 mg,784 umol), morphine (3411 mg,3.92 mmol), sodium acetate (128 mg,1.57 mmol), magnesium sulfate (283 mg,2.35 mmol) were added to THF (5 mL), the reaction was replaced with nitrogen three times, stirred at 60℃for one hour, then sodium cyanoborohydride (197mg, 3.14 mmol) was added at 20℃and stirred at this temperature for one hour. TLC and LCMS monitored the reaction was completed, the reaction was quenched with saturated aqueous sodium bicarbonate, extracted with ethyl acetate, and the organic phase concentrated to dryness and purified by flash column on silica gel to give tert-butyl (4- (5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7- (morpholinomethyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (600 mg,90.4% yield).

LCMS：m/z＝709.3[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝9.54(s，1H)，8.58(s，1H)，7.74(t，J＝7.8Hz，1H)，7.52(dd，J＝2.4，11.1Hz，1H)，7.48-7.44(m，2H)，7.37(d，J＝8.8Hz，2H)，7.20(t，J＝8.6Hz，1H)，7.08-7.03(m，1H)，7.01(d，J＝7.4Hz，1H)，6.83(d，J＝8.1Hz，1H)，5.12-4.91(m，2H)，3.54-3.50(m，4H)，2.38(br s，4H)，2.27(s，3H)，1.47(s，9H).

Step three: synthesis of 6- (4-aminophenyl) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7- (morpholinomethyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

Tert-butyl (4- (5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7- (morpholinomethyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (250 mg,352 umol), aqueous ammonia (4.42 g,35.2mmol,28% purity) was added to dioxane (10 mL), nitrogen was displaced three times, stirring was carried out at 130℃for 12 hours, LCMS and TLC monitored for the end of the reaction, the reaction solution was added to saturated brine and ethyl acetate, concentrated by organic coherence, and purified via flash silica gel column to give 6- (4-aminophenyl) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7- (morpholinomethyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (100 mg,53.9% yield).

¹ H NMR(400MHz，CDCl3)δ＝8.22(s，1H)，7.81-7.74(m，1H)，7.50(dd，J＝2.3，10.9Hz，1H)，7.38-7.30(m，1H)，7.24-7.18(m，1H)，7.10-6.99(m，3H)，6.89(d，J＝8.3Hz，1H)，6.48(d，J＝8.5Hz，2H)，5.56(br s，2H)，5.36-5.29(m，2H)，3.54-3.50(m，4H)，3.46(s，2H)，2.79-2.59(m，4H)，2.32-2.26(m，3H).

Step four: synthesis of N- (4- (4-amino-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7- (morpholinomethyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide

Acryloyl chloride (60.2 mg, 665. Mu. Mol) in tetrahydrofuran (0.2 mL) was added dropwise to 6- (4-aminophenyl) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7- (morpholinomethyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (70.0 mg, 133. Mu. Mol) in tetrahydrofuran (0.5 mL) at 0deg.C, and the reaction stirred for 1 hour. LCMS monitored the end of the reaction, the reaction mixture was quenched with water, diluted with acetonitrile and filtered, and the filtrate was purified by preparative HPLC to give N- (4- (4-amino-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7- (morpholinylmethyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide (8.50 mg,10.9% yield).

LCMS：m/z＝580.0[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.23(s，1H)，8.25(s，1H)，7.75(t，J＝7.8Hz，1H)，7.65(d，J＝8.6Hz，2H)，7.54(dd，J＝2.4，10.9Hz，1H)，7.39(d，J＝8.6Hz，2H)，7.36-7.30(m，1H)，7.27-7.21(m，1H)，7.01(d，J＝7.4Hz，1H)，6.88(d，J＝8.3Hz，1H)，6.47-6.36(m，1H)，6.31-6.21(m，1H)，5.80-5.75(m，1H)，5.67(br s，2H)，3.56-3.49(m，6H)，2.36(br s，4H)，2.25(s，3H).

The preparation of the compounds of examples in Table 6 can be carried out by reference to the procedure analogous to the procedure of preparation example 30, except that starting materials are replaced in the intermediate step to give the corresponding compounds.

TABLE 6

Example 32:

n- (4- (4-amino-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7- (trifluoromethyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide:

the synthetic route is as follows:

step one: synthesis of (4- (5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -4- (2, 2-trifluoroethoxy) -7- (trifluoromethyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) amine

(4- (5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7-iodo-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) amino tert-butyl ester (100 mg,1.00 eq), potassium fluoride (39.5 mg,5.00 eq), cuprous iodide (129 mg,5.00 eq) was dissolved in 0.1mL of 1-methyl-2-pyrrolidone, followed by addition of (trifluoromethyl) trimethylsilane (58 mg,3.00 eq). Stirring is carried out for 2 hours at 160℃under microwaves. After completion of LCMS detection reaction, filtration gave (4- (5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -4- (2, 2-trifluoroethoxy) -7- (trifluoromethyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) amine (100 mg, crude) as a white solid.

LCMS：m/z 578.1[M+H] ⁺ .

Step two: synthesis of 6- (4-anilino) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7- (trifluoromethyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

(4- (5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -4- (2, 2-trifluoroethoxy) -7- (trifluoromethyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) amine (100 mg,1.00 eq), aqueous ammonia (180 mg,10.0 eq) was dissolved in 2mL dioxane and stirred at 100℃for 48 hours. After completion of LCMS detection, the reaction mixture was concentrated and purified by silica gel column to give 6- (4-anilino) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7- (trifluoromethyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (20 mg, crude) as a red solid.

LCMS：m/z 495.2[M+H] ⁺ .

Step three: synthesis of N- (4- (4-amino-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7- (trifluoromethyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide

6- (4-anilino) -5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxo) phenyl) -7- (trifluoromethyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (20 mg,1.00 eq) was dissolved in 3mL tetrahydrofuran, and acryloyl chloride (1.41 mg,0.60 eq) was slowly added at 0deg.C and reacted at 20deg.C for 2 hours. LCMS detects the end of the reaction. Purification by reverse phase column gave N- (4- (4-amino-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7- (trifluoromethyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide as a white solid (4.40 mg, yield 49.2%).

LCMS：m/z 549.2[M+H] ⁺ .

¹ H NMR(400MHz，ACETONITRILE-d3)δ＝8.62(br s，1H)，8.37(s，1H)，7.77-7.56(m，3H)，7.36-7.28(m，3H)，7.26-7.21(m，2H)，6.96(d，J＝7.4Hz，1H)，6.81(d，J＝8.1Hz，1H)，6.36-6.30(m，2H)，5.75(dd，J＝5.1，6.9Hz，1H)，5.03(br s，2H)，2.23(s，3H).

Example 33:

n- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide:

the synthetic route is as follows:

step one: synthesis of tert-butyl (4- (5- (4- (benzyloxy) -3-fluorophenyl) -7-bromo-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate

NBS (3.54 g,19.8 mmol) was added to tert-butyl (4- (5- (4- (benzyloxy) -3-fluorophenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (11.0 g,18.0 mmol) in acetonitrile (65 mL) at 20℃and stirring was continued for 2 hours at that temperature. LCMS and TLC monitored the end of the reaction, water and ethyl acetate were added to extract, the organic phase was concentrated and column chromatographed to give tert-butyl (4- (5- (4- (benzyloxy) -3-fluorophenyl) -7-bromo-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (5.20 g,7.56mmol,41.8% yield).

¹ H NMR(400MHz，DMSO-d ₆ )δ＝9.56(s，1H)，8.60(s，1H)，7.52-7.35(m，8H)，7.32-7.25(m，2H)，7.14(t，J＝9.1Hz，1H)，7.03(dd，J＝1.1，9.9Hz，1H)，5.26-5.11(m，2H)，5.10-4.88(m，2H)，1.47(s，9H).

Step two: synthesis of tert-butyl (4- (5- (4- (benzyloxy) -3-fluorophenyl) -7-methyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate

Tert-butyl (4- (5- (4- (benzyloxy) -3-fluorophenyl) -7-bromo-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (4.00 g,5.82 mmol), methylboronic acid (1.74 g,29.0 mmol), tetrakis (triphenylphosphine) palladium (67 mg, 581umol) and potassium carbonate (2.41 g,17.4 mmol) were dissolved in dioxane (20 mL) and water (15 mL), replaced three times with nitrogen and stirred at 90℃for 5 hours. LCMS and TLC monitored the end of the reaction, water and ethyl acetate were added to extract, the organic phase was concentrated and column chromatographed to give tert-butyl (4- (5- (4- (benzyloxy) -3-fluorophenyl) -7-methyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (3.60 g,5.78mmol,99.3% yield).

¹ H NMR(400MHz，DMSO-d ₆ )δ＝9.51(s，1H)，8.55-8.49(m，1H)，7.45(br s，1H)，7.43(br d，J＝1.9Hz，2H)，7.39(s，1H)，7.36-7.31(m，2H)，7.30-7.22(m，2H)，7.19(d，J＝8.8Hz，2H)，7.12(t，J＝9.1Hz，1H)，6.94-6.87(m，1H)，5.15(s，2H)，4.98(br d，J＝8.3Hz，2H)，2.25(s，3H)，1.47(s，9H).

Step three: synthesis of 6- (4-aminophenyl) -5- (4- (benzyloxy) -3-fluorophenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-ol

Tert-butyl (4- (5- (4- (benzyloxy) -3-fluorophenyl) -7-methyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (2.70 g,4.34 mmol), 18-crown-6-ether (2.87 g,10.8 mmol) and KOH (2.68 g,47.7 mmol) were dissolved in dimethyl sulfoxide (12 mL) and water (12 mL), nitrogen was replaced three times, the reaction was completed at 90℃and LCMS detection was completed, saturated aqueous ammonium chloride solution was added to quench to neutrality, ethyl acetate was extracted, and the organic phase was concentrated to give 6- (4-aminophenyl) -5- (4- (benzyloxy) -3-fluorophenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-ol (4.00 g, crude product).

Step four: synthesis of tert-butyl (4- (5- (4- (benzyloxy) -3-fluorophenyl) -4-hydroxy-7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate

6- (4-aminophenyl) -5- (4- (benzyloxy) -3-fluorophenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-ol (3.50 g,7.95 mmol) and Boc2O (3.47 g,15.8 mmol) were added to ethanol (20 mL), nitrogen was replaced three times, and the reaction was reacted at 75℃for 12 hours. After completion of the reaction by TLC and LCMS, the reaction solution was added to saturated brine, extracted with ethyl acetate, and subjected to column chromatography to give tert-butyl (4- (5- (4- (benzyloxy) -3-fluorophenyl) -4-hydroxy-7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (1.60 g,37.2% yield).

¹ H NMR(400MHz，DMSO-d ₆ )δ＝11.90(br d，J＝3.5Hz，1H)，9.46(s，1H)，7.86(d，J＝3.6Hz，1H)，7.66-7.56(m，1H)，7.47(br d，J＝1.4Hz，1H)，7.44-7.38(m，5H)，7.22(dd，J＝2.5，11.9Hz，1H)，7.10(t，J＝9.3Hz，3H)，6.88(br dd，J＝1.4，8.6Hz，1H)，5.15(s，2H)，2.15(s，3H)，1.47(s，9H).

Step five: synthesis of tert-butyl (4- (5- (4- (benzyloxy) -3-fluorophenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate

Tert-butyl (4- (5- (4- (benzyloxy) -3-fluorophenyl) -4-hydroxy-7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (1.50 g,2.77 mmol), p-methoxybenzylamine (2.66 g,19.4 mmol), DBU (633 mg,4.16 mmol) and BOP (1.60 g,3.16 mmol) were added to acetonitrile (10 mL), replaced with nitrogen three times, stirred at 20℃for 0.5 hours, then raised to 75℃and stirring continued for 16 hours. LCMS and TLC monitored the end of the reaction, extraction with water and ethyl acetate, concentration of the organic phase, and column chromatography gave tert-butyl (4- (5- (4- (benzyloxy) -3-fluorophenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (3.70 g,71.7% yield).

LCMS：MS(ESI)m/z＝660.3[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ＝9.57-9.40(m，1H)，8.38-8.22(m，1H)，7.47-7.33(m，8H)，7.24-7.17(m，2H)，7.14(br d，J＝8.6Hz，2H)，7.07(br d，J＝8.5Hz，2H)，6.85-6.79(m，2H)，5.23-5.04(m，2H)，4.72(q，J＝4.8Hz，1H)，4.46(br d，J＝5.1Hz，2H)，3.68(s，3H)，1.99(s，3H)，1.46(s，9H).

Step six: synthesis of tert-butyl (4- (5- (3-fluoro-4-hydroxyphenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate

Tert-butyl (4- (5- (4- (benzyloxy) -3-fluorophenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (3.50 g,5.31 mmol), pd/C (0.3 g,10% purity) was dissolved in ethanol (20 mL), the reaction was replaced three times with hydrogen, and the reaction was continued for 2 hours under a hydrogen atmosphere (15 psi) at 45℃with LCMS and TLC monitoring the end of the reaction. The reaction solution was filtered, and the filtrate was concentrated to give tert-butyl (4- (5- (3-fluoro-4-hydroxyphenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (1.70 g,56.2% yield).

Step seven: synthesis of tert-butyl (4- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate

Tert-butyl (4- (5- (3-fluoro-4-hydroxyphenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (1.70 g,2.98 mmol) and 2-chloro-4-methylpyrimidine (574 mg,4.47 mmol) were dissolved in DMF (10 mL), nitrogen was replaced three times, stirred at 70 ℃ for 6 hours, LCMS and TLC monitored the reaction was complete. Water and ethyl acetate were added to extract, and the organic phase was concentrated and subjected to column chromatography to give tert-butyl (4- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (230 mg,347umol,11.6% yield).

¹ H NMR(400MHz，DMSO-d6)δ＝9.47(s，1H)，8.42(d，J＝5.0Hz，1H)，8.31(s，1H)，7.50(dd，J＝2.4，10.9Hz，1H)，7.45(d，J＝8.6Hz，2H)，7.42-7.34(m，1H)，7.24(dd，J＝1.4，8.4Hz，1H)，7.21-7.08(m，5H)，6.79(d，J＝8.6Hz，2H)，4.96(br s，1H)，4.53(d，J＝5.6Hz，2H)，3.67(s，3H)，2.35(s，3H)，2.19(s，3H)，1.47(s，9H).

Step eight: synthesis of 6- (4-aminophenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine

To tert-butyl 4- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (200 mg,302 mol) in dichloromethane (8 mL) was added trifluoroacetic acid (2 mL), the reaction was stirred at 20 ℃ for 1 hour, LCMS was monitored for the end of the reaction, saturated aqueous sodium carbonate was added to adjust to p11=8, dichloromethane extraction was performed, and the organic phase was concentrated to give 6- (4-aminophenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (155 mg,91.3% yield).

¹ H NMR(400MHz，DMSO-d ₆ )δ＝8.42(d，J＝5.0Hz，1H)，8.29(s，1H)，7.48(dd，J＝2.4，10.9Hz，1H)，7.39(t，J＝8.6Hz，1H)，7.26-7.17(m，2H)，7.11(d，J＝8.6Hz，2H)，6.91(d，J＝8.4Hz，2H)，6.78(d，J＝8.6Hz，2H)，6.51(d，J＝8.5Hz，2H)，5.31(s，2H)，4.85(t，J＝5.4Hz，1H)，4.52(d，J＝5.8Hz，2H)，3.67(s，3H)，2.37(s，3H)，2.18(s，3H).

Step nine: synthesis of N- (4- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) -3- (benzenesulfonyl) propanamide

To a solution of 6- (4-aminophenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (140 mg, 319 mol), DIEA (80.5 mg, 630 mol) and 3- (benzenesulfonyl) propionic acid (106 mg,498 mol) in methylene chloride (5 mL) was added HATU (255 mg,673 mol), and the reaction was stirred at 25℃for 2 hours, followed by LCMS and TLC to monitor the end of the reaction. Water and dichloromethane were added to extract, and the organic phase was concentrated and column chromatographed to give N- (4- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) -3- (benzenesulfonyl) propanamide (180 mg,95.2% yield).

¹ H NMR(400MHz，DMSO-d ₆ )δ＝10.17(s，1H)，8.42(d，J＝5.0Hz，2H)，7.96-7.89(m，2H)，7.72(d，J＝7.4Hz，1H)，7.68-7.61(m，2H)，7.57-7.50(m，3H)，7.41(t，J＝8.6Hz，1H)，7.24(dd，J＝1.2，8.3Hz，1H)，7.21-7.16(m，3H)，7.13(d，J＝8.6Hz，2H)，6.80(d，J＝8.8Hz，2H)，4.57(br d，J＝5.0Hz，2H)，3.68(s，3H)，3.61(t，J＝7.4Hz，2H)，2.67(t，J＝7.4Hz，2H)，2.35(s，3H)，2.19(s，3H).

Step ten: synthesis of N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) -3- (benzenesulfonyl) propanamide

To a solution of N- (4- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) -3- (benzenesulfonyl) propanamide (160 mg,211 umol) in trifluoroacetic acid (1.5 mL) was slowly added trifluoromethanesulfonic acid (0.3 mL), and the reaction mixture was stirred at 25℃for 1 hour, and LCMS was monitored for the completion of the reaction. The reaction solution was adjusted to ph=8 with saturated aqueous sodium carbonate, extracted with dichloromethane, and the organic phase was concentrated to give N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) -3- (benzenesulfonyl) propanamide (120 mg,89.1% yield).

Step eleven: synthesis of N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide

N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) -3- (benzenesulfonyl) propanamide (120 mg,188 mol) and potassium trimethylsilyloxide (30.1 mg,235 mol) were added to tetrahydrofuran (1.2 mL), the mixture was replaced with nitrogen three times, and the reaction mixture was stirred at 25℃for 1 hour. LCMS monitored the end of the reaction, and the reaction was concentrated and purified by preparative HPLC to give N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide (45.0 mg,47.2% yield).

LCMS：MS(ESI)m/z＝496.4[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ＝10.25(s，1H)，8.48(d，J＝4.9Hz，1H)，8.24(s，1H)，7.67(d，J＝8.6Hz，2H)，7.51(dd，J＝2.3，10.8Hz，1H)，7.43(t，J＝8.6Hz，1H)，7.25(d，J＝8.6Hz，3H)，7.20(d，J＝5.0Hz，1H)，6.61-6.33(m，1H)，6.29-6.20(m，1H)，5.81-5.71(m，1H)，5.69-5.53(m，2H)，2.38(s，3H)，2.20(s，3H).

Example 34:

n- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenylmethacrylamide:

the synthetic route is as follows:

step one: synthesis of tert-butyl (4- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino-7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) carbamate

At 20 ℃, trifluoromethanesulfonic acid (0.2 mL) was added dropwise to tert-butyl (4- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino-7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (120 mg,181 umol) in trifluoroacetic acid (1 mL), LCMS monitored the end of the reaction, saturated aqueous sodium carbonate solution was added to the reaction solution to quench to ph=8, dichloromethane extraction, organic phase was dried, and concentrated to give tert-butyl (4- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino-7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) carbamate (80.0 mg, crude product).

Step two: synthesis of N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenylmethacrylamide

Methacryloyl chloride (49.7 mg,475 umol) was added dropwise to tert-butyl (4- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino-7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) carbamate (70.0 mg,158 umol) in tetrahydrofuran (0.5 mL) at 0deg.C), the reaction was stirred continuously for 1 hour at 25deg.C, LCMS was monitored for reaction completion, the reaction was concentrated, and purified by preparative HPLC to give N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl methacrylamide (9.00 mg, yield 11.0%).

LCMS：MS(ESI)m/z＝510.2[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ＝9.88(s，1H)，8.49(d，J＝5.0Hz，1H)，8.25(s，1H)，7.70(d，J＝8.5Hz，2H)，7.57-7.48(m，1H)，7.43(t，J＝8.5Hz，1H)，7.29-7.19(m，4H)，5.79(s，1H)，5.68-5.55(m，2H)，5.53(s，1H)，2.39(s，3H)，2.20(s，3H)，1.95(s，3H).

Example 35:

n- (4- (4-amino-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) methacrylamide:

the synthetic route is as follows:

step one: synthesis of N- (4- (4-amino-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) methacrylamide

(6- (4-aminobenzene-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyridin-4-amine (80 mg,181umol,1.0 eq) was dissolved in 0.5mL of tetrahydrofuran, methacryloyl chloride (18.9 mg,181umol,17.7uL,1.0 eq) was slowly added at 0℃and reacted at 0℃for 1 hour, after completion of the LCMS detection reaction, the reaction solution was spin-dried and purified by reverse phase HPLC to give N- (4- (4-amino-5- (3-fluoro-4- ((6-methylpyridin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) methacrylamide (26.0 mg) as a white solid in 27.9% yield.

LCMS：MS(ESI)m/z＝509.4[M+H] ⁺ .

¹ H NMR(400MHz，ACETONITRILE-d3)δ＝8.40(brs，1H)，8.29(s，1H)，7.73-7.62(m，3H)，7.28-7.22(m，4H)，7.20-7.16(m，1H)，6.96(d，J＝7.3Hz，1H)，6.82(d，J＝8.0Hz，1H)，5.77(s，1H)，5.49(s，1H)，4.83(br s，2H)，2.28(s，3H)，2.25(s，3H)，1.99(s，3H).

Example 36:

n- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) -2-fluoropropionamide:

the synthetic route is as follows:

step one: synthesis of N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) -2-fluoropropionamide

2-Fluoroacrylic acid was dissolved in methylene chloride (4.00 ml) at 0℃to which N, N-dimethylformamide was added, and the reaction mixture was reacted at 0℃for 10 minutes; to a solution of 6- (4-aminophenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (40.0 mg,90.6 mol) in tetrahydrofuran (1.0 mL) was slowly added a reaction solution of 2-fluoroacrylic acid (1.5 mL), the reaction solution was mixed and stirred at 0℃for 30 minutes, and LCMS was monitored to finish the reaction. The reaction solution was concentrated and subjected to preparative HPLC to give N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) -2-fluoropropionamide (5.00 mg,10.7% yield).

LCMS：MS(ESI)m/z＝514.2[M+H] ⁺ .

¹ H NMR(400MHz，ACETONITRILE-d ₃ )δ＝8.83(br s，1H)，8.48-8.20(m，2H)，7.68(br d，J＝8.3Hz，2H)，7.36-7.19(m，5H)，7.06(br d，J＝4.9Hz，1H)，5.84-5.59(m，1H)，5.29(dd，J＝3.3，15.4Hz，1H)，4.88(br s，2H)，2.40(s，3H)，2.27-2.25(m，3H).

Example 37:

n- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) butyl-2-alkynylamide:

The synthetic route is as follows:

step one: synthesis of N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) butyl-2-alkynylamide

6- (4-aminobenzene) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (100 mg, 227. Mu. Mol) was dissolved in 1.00mL of tetrahydrofuran, and 2-butynoyl chloride (30.2 mg, 294. Mu. Mol) was added. The reaction mixture was reacted at 20℃for 1 hour. LCMS monitored the end of the reaction. The reaction solution was diluted with water and purified by preparative HPLC to give N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) butyl-2-alkynylamide (27.0 mg,53.2 μmol,23.5% yield) and N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) butyl-2-alkynylamide (13.0 mg,11.6% yield).

LCMS：MS(ESI)m/z＝508.2[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.74(s，1H)，8.49(d，J＝5.0Hz，1H)，8.37(s，1H)，7.60(d，J＝8.6Hz，2H)，7.56-7.38(m，2H)，7.27-7.12(m，4H)，6.46-5.10(m，2H)，2.38(s，3H)，2.20(s，3H)，2.05(s，3H).

Example 38:

n- (6- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyridin-3-yl) acrylamide:

the synthetic route is as follows:

step one: synthesis of tert-butyl (6- (5- (4- (benzyloxy) -3-fluorophenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyridin-3-yl) carbamate

Tert-butyl (6- ((5-bromo-6- (2, 2-trifluoroethoxy) pyrimidin-4-yl) ethynyl) pyridin-3-yl) carbamate (5.70 g,12.0 mmol), 4- (benzyloxy) -3-fluoroaniline (2.88 g,13.2 mmol), pd ₂ (dba) ₃ (1.10 g,1.20 mmol), xantphos (766 mg,1.32 mmol) and cesium carbonate (7.85 g,24.0 mmol) were dissolved in dioxane, replaced with nitrogen three times, stirred at 100℃for 2 hours, TLC monitored the end of the reaction, extracted with water and ethyl acetate, the organic phase concentrated and purified by column chromatography to give (6- (5- (4- (benzyloxy) -3-fluorophenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3, 2-d)]Pyrimidin-6-yl) pyridin-3-yl) carbamic acid tert-butyl ester (4.00 g,43.8% yield).

LCMS：MS(ESI)m/z＝610.0[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ＝9.74(s，1H)，8.57-8.45(m，2H)，7.86(dd，J＝2.3，8.7Hz，1H)，7.47-7.33(m，7H)，7.22-7.13(m，2H)，7.04-6.95(m，1H)，5.21(br s，2H)，4.97(br d，J＝8.9Hz，2H)，1.48(s，9H).

Step two: synthesis of tert-butyl (6- (5- (4- (benzyloxy) -3-fluorophenyl) -7-bromo-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyridin-3-yl) carbamate

NBS (1.16 g,6.50 mmol) was added to tert-butyl (6- (5- (4- (benzyloxy) -3-fluorophenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyridin-3-yl) carbamate (3.60 g,5.91 mmol) in acetonitrile (30 mL) at 20℃and stirring was continued for 2 hours at this temperature. LCMS and TLC monitored the reaction was complete, the reaction was filtered directly and the filter cake was dried to give tert-butyl (6- (5- (4- (benzyloxy) -3-fluorophenyl) -7-bromo-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyridin-3-yl) carbamate (3.40 g,82.6% yield).

¹ H NMR(400MHz，DMSO-d ₆ )δ＝9.80(s，1H)，8.63(s，1H)，8.56(d，J＝2.3Hz，1H)，7.95(dd，J＝2.4，8.6Hz，1H)，7.55(d，J＝8.6Hz，1H)，7.47-7.42(m，1H)，7.42-7.28(m，5H)，7.12(t，J＝8.9Hz，1H)，7.02-6.95(m，1H)，5.17(br s，2H)，5.09-4.88(m，2H)，1.49(s，9H).

Step three: synthesis of tert-butyl (6- (5- (4- (benzyloxy) -3-fluorophenyl) -7-methyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyridin-3-yl) carbamate

(5- (4- (benzyloxy) -3-fluorophenyl) -7-bromo-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3, 2-d)]Pyrimidin-6-yl) pyridin-3-yl) aminesTert-butyl benzoate (3.20 g,4.65 mmol), methyl boronic acid (1.39 g,23.2 mmol), pd ₂ (dba} ₃ (340 mg,371 mmole), dppf (3836 mg,697 mmole) and cesium carbonate (3.03 g,9.30 mmole) were dissolved in dioxane (30 mL) and water (3 mL), replaced with nitrogen three times, and stirred at 100℃for 5 hours. LCMS and TLC monitor the end of the reaction, add water and ethyl acetate, extract, concentrate the organic phase, and column chromatography to give (6- (5- (4- (benzyloxy) -3-fluorophenyl) -7-methyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3, 2-d)]Pyrimidin-6-yl) pyridin-3-yl) carbamic acid tert-butyl ester (2.44 g,84.1% yield).

¹ H NMR(400MHz，DMSO-d ₆ )δ＝9.72(s，1H)，8.60(d，J＝2.3Hz，1H)，8.54(s，1H)，7.88(dd，J＝2.4，8.6Hz，1H)，7.46-7.40(m，3H)，7.40-7.33(m，3H)，7.30(s，1H)，7.11(t，J＝9.1Hz，1H)，6.92-6.82(m，1H)，5.16(s，2H)，4.99(q，J＝8.7Hz，2H)，2.33(s，3H)，1.48(s，9H).

Step four: synthesis of 6- (5-aminopyridin-2-yl) -5- (4- (benzyloxy) -3-fluorophenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-ol

(6- (5- (4- (benzyloxy) -3-fluorophenyl) -7-methyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyridin-3-yl) carbamic acid tert-butyl ester (2.20 g,3.53 mmol), 18-crown-6-ether (2.80 g,10.5 mmol) and KOH (2.77 g,49.3 mmol) were dissolved in dimethyl sulfoxide (20 mL) and water (20 mL), nitrogen was replaced three times, reacted at 90℃for 8 hours, LCMS and TLC were examined for the end of the reaction, saturated ammonium chloride aqueous solution was added to quench to neutrality, ethyl acetate was extracted, the organic phase was concentrated, and TBME was filtered to give the filter residue as 6- (5-aminopyridin-2-yl) -5- (4- (benzyloxy) -3-fluorophenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-ol (1.50 g,96.3% yield).

¹ H NMR(400MHz，DMSO-d ₆ )δ＝11.82(br s，1H)，7.86(d，J＝2.5Hz，1H)，7.84(s，1H)，7.50-7.44(m，2H)，7.43(s，2H)，7.39-7.33(m，1H)，7.16(dd，J＝2.4，11.9Hz，1H)，7.11(t，J＝9.1Hz，1H)，6.92-6.86(m，1H)，6.85-6.78(m，2H)，5.51(s，2H)，5.15(s，2H)，2.18(s，3H).

Step five: synthesis of 6- (5-aminopyridin-2-yl) -5- (4- (benzyloxy) -3-fluorophenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6- (5-Aminopyridin-2-yl) -5- (4- (benzyloxy) -3-fluorophenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-ol (1.50 g,3.40 mmol), DBU (775 mg,5.10 mmol) and BOP (2.10 g,4.76 mmol) were added to acetonitrile (10 mL), nitrogen was replaced three times, after stirring at 20℃for 5 hours, p-methoxybenzylamine (3.26 g,23.7 mmol) was added to the reaction, and stirring was continued for 8 hours at 75 ℃. LCMS and TLC monitored the end of the reaction, water and ethyl acetate were added to extract, the organic phase was concentrated and column chromatographed to give 6- (5-aminopyridin-2-yl) -5- (4- (benzyloxy) -3-fluorophenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (1.00 g,52.5% yield).

¹ H NMR(400MHz，DMSO-d ₆ )δ＝8.28(s，1H)，7.86(d，J＝2.5Hz，1H)，7.46-7.40(m，4H)，7.40-7.37(m，1H)，7.37-7.32(m，1H)，7.23-7.17(m，1H)，7.11-7.06(m，3H)，7.02(d，J＝8.4Hz，1H)，6.86-6.81(m，3H)，5.51(s，2H)，5.12(s，2H)，4.72(t，J＝5.4Hz，1H)，4.46(d，J＝5.3Hz，2H)，3.68(s，3H)，2.22(s，3H).

Step six: synthesis of 4- (6- (5-aminopyridin-2-yl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl) -2-fluorophenol

6- (5-Aminopyridin-2-yl) -5- (4- (benzyloxy) -3-fluorophenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (0.94 g,1.68 mmol), pd/C (0.2 g,10% purity) was dissolved in ethanol (10 mL), the reaction was replaced three times with hydrogen, and the reaction was continued under a hydrogen atmosphere (25 psi) at 45℃for 2 hours, and LCMS and TLC monitored for the end of the reaction. The reaction solution was filtered, and the filtrate was concentrated to give 4- (6- (5-aminopyridin-2-yl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl) -2-fluorophenol (700 mg,88.7% yield).

Step seven: synthesis of 6- (5-aminopyridin-2-yl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine

4- (6- (5-Aminopyridin-2-yl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl) -2-fluorophenol (640 mg,1.42 mmol) and 2-chloro-4-methylpyrimidine (365 mg,2.85 mmol) were dissolved in DMF (5 mL), nitrogen was replaced three times, stirred at 70℃for 6 hours, LCMS and TLC monitored for the end of the reaction. Water and ethyl acetate were added to the mixture to extract, and the organic phase was concentrated and subjected to column chromatography to give 6- (5-aminopyridin-2-yl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (600 mg,74.8% yield).

¹ H NMR(400MHz，DMSO-d ₆ )δ＝8.42(d，J＝5.0Hz，1H)，8.31(s，1H)，7.88(d，J＝2.6Hz，1H)，7.46(dd，J＝2.4，10.9Hz，1H)，7.40-7.33(m，1H)，7.21-7.17(m，2H)，7.12(d，J＝8.6Hz，2H)，7.07(d，J＝8.4Hz，1H)，6.88(dd，J＝2.7，8.4Hz，1H)，6.78(d，J＝8.6Hz，2H)，5.56(s，2H)，4.95(t，J＝4.4，8.8Hz，1H)，4.52(d，J＝5.5Hz，2H)，3.67(s，3H)，2.37(s，3H)，2.24(s，3H).

Step eight: synthesis of N- (6- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyridin-3-yl) -3- (benzenesulfonyl) propanamide

To a solution of 6- (5-aminopyridin-2-yl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (570 mg,101 mmol), DIEA (327 mg,2.53 mmol) and 3- (benzenesulfonyl) propionic acid (433 mg,2.03 mmol) in dichloromethane (10 mL) was added HATU (1.08 g,2.84 mmol), and the reaction stirred at 25℃for 2 hours, LCMS and TLC monitored for the end of the reaction. Water and dichloromethane were added to extract, and the organic phase was concentrated and column chromatographed to give N- (6- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyridin-3-yl) -3- (benzenesulfonyl) propanamide (550 mg,71.5% yield).

¹ H NMR(400MHz，DMSO-d ₆ )δ＝10.41(s，1H)，8.72-8.61(m，2H)，8.42(d，J＝5.0Hz，1H)，8.36(s，1H)，7.96(dd，J＝2.5，8.6Hz，1H)，7.92-7.89(m，2H)，7.74-7.69(m，1H)，7.67-7.60(m，2H)，7.54-7.50(m，1H)，7.38(td，J＝4.3，8.6Hz，2H)，7.24-7.18(m，2H)，7.13(d，J＝8.5Hz，2H)，6.79(d，J＝8.6Hz，2H)，5.19(m，1H)，4.55(d，J＝5.5Hz，2H)，3.61(br d，J＝2.4Hz，2H)，3.15-3.12(m，2H)，2.53(s，3H)，2.35(s，3H)，2.27(s，3H).

Step nine: synthesis of N- (6- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyridin-3-yl) -3- (benzenesulfonyl) propanamide

To a solution of N- (6- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyridin-3-yl) -3- (benzenesulfonyl) propanamide (500 mg, 618 umol) in trifluoroacetic acid (2 mL) was slowly added trifluoromethanesulfonic acid (2 mL), and the reaction mixture was stirred at 25℃for 12 hours, and LCMS was monitored for the completion of the reaction. The reaction solution was adjusted to ph=8 with saturated aqueous sodium carbonate, extracted with dichloromethane, and the organic phase was concentrated to give N- (6- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyridin-3-yl) -3- (benzenesulfonyl) propanamide (410 mg,97.4% yield).

¹ H NMR(400MHz，DMSO-d ₆ )δ＝10.44(s，1H)，8.76-8.64(m，2H)，8.49(d，J＝5.0Hz，1H)，8.26-8.09(m，1H)，7.99(dd，J＝2.5，8.6Hz，1H)，7.95-7.87(m，3H)，7.74-7.69(m，1H)，7.65-7.60(m，2H)，7.57(dd，J＝2.4，10.6Hz，1H)，7.49-7.41(m，1H)，7.38(d，J＝8.6Hz，1H)，7.24-7.21(m，2H)，3.14(dd，J＝4.3，7.4Hz，2H)，2.74-2.70(m，2H)，2.40-2.38(m，3H)，2.29(s，3H).

Step ten: synthesis of N- (6- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyridin-3-yl) acrylamide

N- (6- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyridin-3-yl) -3- (benzenesulfonyl) propionamide (360 mg,563 umol) and potassium trimethylsilicon oxide (90.3 mg,704 umol) were added to tetrahydrofuran (3 mL), the mixture was replaced with nitrogen three times, and the reaction mixture was stirred at 25℃for 1 hour. LCMS monitored the end of the reaction, the reaction was concentrated and preparative HPLC gave N- (6- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyridin-3-yl) acrylamide (32.4 mg,11.5% yield).

LCMS：MS(ESI)m/z＝497.0[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ＝10.46(s，1H)，8.77(d，J＝2.3Hz，1H)，8.49(d，J＝5.0Hz，1H)，8.26(s，1H)，8.19-8.09(m，1H)，7.50(dd，J＝2.4，10.8Hz，1H)，7.46-7.37(m，2H)，7.26-7.15(m，2H)，6.49-6.38(m，1H)，6.33-6.24(m，1H)，5.82(dd，J＝2.0，10.0Hz，1H)，5.77-5.55(m，2H)，2.39(s，3H)，2.29(s，3H).

Example 39:

n- (5- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyrimidin-2-yl) acrylamide:

the synthetic route is as follows:

step one: synthesis of tert-butyl (5-iodopyrimidin-2-yl) carbamate

5-iodopyrimidin-2-amino was dissolved in tetrahydrofuran (10.0 g,45.2mol, 1.00 eq), lithium bis (trimethylsilyl) amide (99 ml g,2.20 eq) was slowly added at-70℃and reacted at-70℃for 1 hour, after completion of LCMS detection, T was extracted with water and ethyl acetate, and the organic phase was concentrated to give tert-butyl (5-iodopyrimidin-2-yl) carbamate (11.0 g, 75.7% yield).

LCMS：m/z 322.0[M+H] ⁺ .

Step two: synthesis of tert-butyl (5- ((trimethylsilyl) ethynyl) pyrimidin-2-yl) carbamate

Tert-butyl 5-iodopyrimidin-2-yl) carbamate (10.0 g,31.1mmol,1.00 eq) was added to 100mL tetrahydrofuran, and trimethylsilylethylene (3.06 g,31.1mmol,1.00 eq), bis (triphenylphosphine) palladium (II) dichloride (2.19 g,3.3mmol,0.1 eq), cuprous iodide (1.19 mg,6.23mmol,0.2 eq) and triethylamine 6.30g,62.2mmol,45.8mL,2.00 eq) were added in sequence and reacted at 40℃for 3 hours. LCMS detection of reaction completion gave crude tert-butyl (5- ((trimethylsilyl) ethynyl) pyrimidin-2-yl) carbamate (9.00 g, crude) by direct spin-drying.

LCMS：m/z 292.1[M+H] ⁺ .

Step three: synthesis of tert-butyl (5-ethynyl pyrimidin-2-yl) carbamate

Tert-butyl (5- ((trimethylsilyl) ethynyl) pyrimidin-2-yl) carbamate (9.00 g,30.8mmol,1.00 eq) was added to 00mL methanol and potassium carbonate (8.88 g,61.7mmol,2.00 eq) was added to react for hours at 20 ℃. LCMS detection of reaction completed, spin-drying separated by column chromatography to give tert-butyl (5-ethynyl pyrimidin-2-yl) carbamate (5.00 g,22.8mmol, 73.8% yield).

LCMS：m/z 220.2[M+H] ⁺ .

Step four: synthesis of tert-butyl (5- ((5-bromo-6- (2, 2-trifluoroethoxy) pyrimidin-4-yl) ethynyl) pyrimidin-2-yl) carbamate

Tert-butyl (5-ethynylpyrimidin-2-yl) carbamate (3.22 g,14.6mmol,1.00 eq) was added to 50mL tetrahydrofuran, and 5-bromo 4-iodo-6- (2, 2-trifluoroethoxy) pyrimidine (4.50 g,11.7mmol,1.00 eq), 1-bis (diphenylphosphorus) ferrocene palladium chloride (254 mg,1.18 mol,0.1 eq), cuprous iodide (223 mg,1.18mmol,0.10 eq) and triethylamine (2.38 g,2.35mL,2.00 eq) were added and reacted at 40℃for 3 hours. LCMS checked the completion of the reaction, water was added and extracted with ethyl acetate, the organic phase was washed with brine, dried, and the filtrate was spin-dried and isolated by column chromatography to give tert-butyl (5- ((5-bromo-6- (2, 2-trifluoroethoxy) pyrimidin-4-yl) ethynyl) pyrimidin-2-yl) carbamate (6.10 g,9.89mmol, yield 46.8%).

LCMS：m/z 417.9[M+1-56] ⁺ ，417.9[M+3-56] ⁺ .

Step five: synthesis of tert-butyl (5- (5- (4- (benzyloxy) -3-fluorophenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyrimidin-yl) carbamate

Tert-butyl (5- ((5-bromo-6- (2, 2-trifluoroethoxy) pyrimidin-4-yl) ethynyl) pyrimidin-2-yl) carbamate (2.00 g,12.0 mmol), 4- (benzyloxy) -3-fluoroaniline (916 mg,4.22 mmol), pd2 (dba) ₃ (383 mg, 426. Mu. Mmol), xantphos (488 mg, 847. Mu. Mmol) and cesium carbonate (2.75 g,8.43 mmol) were dissolved in dioxane, replaced with nitrogen three times, stirred at 100℃for 2 hours, TLC monitored the end of the reaction, extracted with water and ethyl acetate, the organic phase concentrated and purified by column chromatography to give (5- (5- (4- (benzyloxy) -3-fluorophenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3, 2-d)]Pyrimidin-6-yl) pyrimidin-yl-carbamic acid tert-butyl ester (1.48 g,57.4% yield).

LCMS：m/z＝611.1[M+H] ⁺ .

Step six: synthesis of (5- (4- (benzyloxy) -3-fluorophenyl) -7-bromo-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyrimidin-2-ylcarboxylic acid tert-butyl ester

NBS (787 g,4.42 mmol) was added to tert-butyl (5- (5- (4- (benzyloxy) -3-fluorophenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyrimidin-yl) carbamate (1.80 g,2.95 mmol) in acetonitrile (30 mL) at 20℃and stirring was continued at that temperature for 2 hours. LCMS and TLC monitored the reaction was complete, the reaction was filtered directly and the filter cake was dried to give tert-butyl (5 (5- (4- (benzyloxy) -3-fluorophenyl) -7-bromo-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyrimidin-2-carboxylate (3.40 g,4.94mmol,82.6% yield).

LCMS：m/z＝688.8[M+1] ⁺ ，690.8[M+3] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ＝10.41(s，1H)，8.72-8.56(m，3H)，7.57(dd，J＝2.0，11.6Hz，1H)，7.47-7.30(m，5H)，7.26-7.11(m，2H)，5.19(br d，J＝10.9Hz，4H)，1.46(s，9H).

Step seven: synthesis of tert-butyl (5- (4- (benzyloxy) -3-fluorophenyl) -7-methyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyrimidinyl) carbamate

(5- (4- (benzyloxy) -3-fluorophenyl) -7-bromo-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyrimidine-2-ylcarboxylic acid tert-butyl ester (2.00 g,2.90 mmol), dimethyl zinc (7.25 mL,7.25 mmol), bis (tri-tert-butylphosphine) palladium (148 mg,290 umol), dissolved in dioxane (30 mL), was replaced with nitrogen three times and stirred at 80℃for 1 hour.

LCMS：m/z＝625.2[M+H] ⁺ .

Step eight: synthesis of 6- (2-aminopyrimidin-5-yl) -5- (benzyloxy) -3-fluorophenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-ol

(5- (4- (benzyloxy) -3-fluorophenyl) -7-methyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyrimidinyl) carbamic acid tert-butyl ester (3.60 g,5.76 mmol), 18-crown-6-ether (4.57 g,17.29 mmol) and KOH (3.56 g,63.4 mmol) were dissolved in dimethyl sulfoxide (20 mL) and water (20 mL), nitrogen was replaced three times, reacted at 90℃for 8 hours, LCMS and TLC were detected, saturated ammonium chloride aqueous solution was added to quench to neutrality, ethyl acetate was extracted, the organic phase was concentrated, TBME was slurried and filtered to give the residue as 6- (2-aminopyrimidin-5 yl) -5- (benzyloxy) -3-fluorophenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-ol (1.50 g,96.3% yield).

LCMS：m/z＝443.2[M+H] ⁺ .

Step nine: synthesis of 6- (2-aminopyrimidin-5-yl) -5- (4- (benzyloxy) -3-fluorophenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine group

6- (2-aminopyrimidin-5-yl) -5- (benzyloxy) -3-fluorophenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-ol (2.00 g,4.52 mmol), DBU (963 mg,6.33 mmol) and BOP (2.80 g,6.33 mmol) were added to acetonitrile (10 mL), nitrogen was replaced three times, after stirring at 20℃for 5 hours p-methoxybenzylamine (3.10 g,22.6 mmol) was added to the reaction, and stirring was continued for 8 hours at 75 ℃. LCMS and TLC monitored the end of the reaction, water and ethyl acetate were added to extract, the organic phase was concentrated and column chromatographed to give 6- (2 aminopyrimidin-5-yl) -5- (4- (benzyloxy) -3-fluorophenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine group (1.80 g,60.9% yield).

LCMS：m/z＝562.2[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ＝8.29(s，1H)，8.10(s，2H)，7.50-7.37(m，6H)，7.32-7.18(m，2H)，7.07(d，J＝8.8Hz，2H)，6.90(s，2H)，6.83(d，J＝8.8Hz，2H)，5.41-5.01(m，2H)，4.89-4.69(m，1H)，4.47(d，J＝5.5Hz，2H)，3.68(s，3H)，2.19(s，3H).

Step ten: synthesis of 4- (6- (2-aminopyrimidin-5-yl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl) -2-fluorophenol

/>

6- (2 aminopyrimidin-5-yl) -5- (4- (benzyloxy) -3-fluorophenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (1.80 g,3.21 mmol), pd/C (0.4 g,10% purity) was dissolved in ethanol (10 mL), the reaction was replaced three times with hydrogen, and the reaction was continued under a hydrogen atmosphere (25 psi) at 45℃for 2 hours, and LCMS and TLC monitored for the end of the reaction. The reaction solution was filtered and the filtrate was concentrated to give 4- (6- (2-aminopyrimidin-5-yl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl) -2-fluorophenol (1.10 g,2.33mmol,72.7% yield).

LCMS：m/z＝472.2[M+H] ⁺ .

Step eleven: synthesis of 6- (2-aminopyrimidin-5-yl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine group

4- (6- (2-aminopyrimidin-5-yl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl) -2-fluorophenol (1.10 g,2.33 mmol) and 2-chloro-4-methylpyrimidine (499 mg,3.50 mmol) cesium carbonate (1.52 g,4.67 mmol) were dissolved in DMF (5 mL), nitrogen was replaced three times, stirred at 70℃for 6 hours, LCMS and TLC monitored for the end of the reaction. Water and ethyl acetate were added to extract, and the organic phase was concentrated and subjected to column chromatography to give 6- (2-aminopyrimidin-5-yl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine group (500 mg,38.0% yield).

LCMS：m/z＝564.2[M+H] ⁺ .

Step twelve: synthesis of N- (5- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyrimidin-3-yl) -3- (benzenesulfonyl) propanamide

After 6- (2-aminopyrimidin-5-yl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (100 mg, 177. Mu. Mmol) and 3- (benzenesulfonyl) propionic acid (114 mg, 532. Mu. Mmol) were dissolved in 1.0mL of pyridine, phosphorus oxychloride (81.6 mg, 532. Mu. Mmol) was added at 0deg.C, the reaction stirred at 25deg.C for 2 hours, and LCMS and TLC monitored for the end of the reaction. Water and dichloromethane were added to extract, and the organic phase was concentrated and column chromatographed to give N- (5- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyrimidin-3-yl) -3- (benzenesulfonyl) propionamide (300 mg, crude).

LCMS：m/z＝760.3[M+H] ⁺ .

Step thirteen: synthesis of N- (5- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyrimidin-2-yl) -3- (benzenesulfonyl) propanamide

To a solution of N- (5- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyrimidin-3-yl) -3- (benzenesulfonyl) propionamide (300 mg,150 mol) in trifluoroacetic acid (2 mL) was slowly added trifluoromethanesulfonic acid (2 mL), and the reaction mixture was stirred at 25℃for 12 hours, and LCMS was monitored for the completion of the reaction. The reaction solution was adjusted to ph=8 with saturated aqueous sodium carbonate, extracted with dichloromethane, and the organic phase was concentrated to give N- (5- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyrimidin-2-yl) -3- (benzenesulfonyl) propionamide (100 mg,52.1% yield).

Step fourteen: synthesis of N- (5- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyrimidin-2-yl) acrylamide

N- (5- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyrimidin-2-yl) -3- (benzenesulfonyl) propionamide (100 mg,46.9 umol) and potassium trimethylsilicon oxide (9.06 mg,70.35 umol) were added to tetrahydrofuran (3 mL), nitrogen was replaced three times, and the reaction solution was stirred at 25℃for 1 hour. LCMS monitored the end of the reaction, and the reaction was concentrated and purified by preparative HPLC to give N- (5- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyrimidin-yl) acrylamide (32.4 mg,11.5% yield).

LCMS：m/z＝498.1[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ＝10.96(s，1H)，8.61(s，2H)，8.48(br d，J＝4.6Hz，1H)，8.27(s，1H)，7.63(br d，J＝10.4Hz，1H)，7.53-7.39(m，1H)，7.35(br d，J＝8.9Hz，1H)，7.20(br d，J＝4.6Hz，1H)，6.65(br dd,J＝10.6，16.8Hz，1H)，6.30(br d，J＝17.3Hz，1H)，5.87-5.61(m，3H)，2.36(s，3H)，2.24(s，3H).

Example 40:

n- (6- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-fluoropyridin-3-yl) acrylamide:

the synthetic route is as follows:

step one: synthesis of 5-fluoro-6-iodopyridin-3-amine

3-amino-5-fluoropyridine (40.0 g,356 mmol) was dissolved in 100mL of water, potassium carbonate (98.6 g, 719 mmol) and iodine (90.5 mg,356 mmol) were added, stirred at 20℃for 10 hours, and after completion of LCMS detection reaction, concentrated and column chromatographed to give 5-fluoro-6-iodopyridin-3-amine (84.9 g, yield 47.1%).

LCMS：m/z 239.0[M+H] ⁺ .

Step two: synthesis of (5-fluoro-6-iodopyridin-3-yl) carbamic acid tert-butyl ester

5-fluoro-6-iodopyridin-3-amine (35.0 g,147 mmol) was dissolved in 80mL tetrahydrofuran, 1M sodium bis (trimethylsilyl) amide 323mL was added dropwise at-65℃and stirred for 1 hour, then di-tert-butyl dicarbonate 33.7mL was added at-65℃and the reaction was continued for 2 hours, after which the reaction was quenched with saturated ammonium chloride solution after LCMS detection, and then the crude (5-fluoro-6-iodopyridin-3-yl) carbamic acid tert-butyl ester (41.3 g) was extracted, dried, filtered and concentrated.

LCMS：m/z 339.0[M+H] ⁺ .

Step three: synthesis of tert-butyl (5-fluoro-6- ((trimethylsilyl) ethynyl) pyridin-3-yl) carbamate

Tert-butyl (5-fluoro-6-iodopyridin-3-yl) carbamate (41.3 g,122 mmol) was dissolved in 230mL tetrahydrofuran and 17.7mL of trimethylsilylethynyl, dichlorobis (triphenylphosphine palladium) (II) (4.29 g,6.11 mmol), cuprous iodide (2.33 g,12.2 mmol) and 34.0mL of triethylamine were added and reacted at 40℃for 2 hours, the completion of which was detected by LCMS and dried by spin-drying to give crude tert-butyl (5-fluoro-6- ((trimethylsilyl) pyridin-3-yl) carbamate (37.6 g).

LCMS：m/z 309.0[M+H] ⁺ .

Step four: synthesis of tert-butyl (6-ethynyl-5-fluoropyridin-3-yl) carbamate

Tert-butyl (5-fluoro-6- ((trimethylsilyl) ethynyl) pyridin-3-yl) carbamate (36.0 g,116 mmol) was dissolved in 250mL methanol, potassium carbonate (32.2 g,233 mmol) was added, stirred at 20 ℃ for 1 hour, LCMS checked for reaction completion, spun-dried and purified by column chromatography to give tert-butyl (6-ethynyl-5-fluoropyridin-3-yl) carbamate (26.5 g, 66.3%).

LCMS：m/z 236.9[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.10(s，1H)，8.41(d，J＝1.1Hz，1H)，7.90(dd，J＝1.8，11.8Hz，1H)，4.57(s，1H)，1.48(s，9H).

Step five: synthesis of tert-butyl (6- ((5-bromo-6- (2, 2-trifluoroethoxy) pyrimidin-4-yl) ethyl) -5-fluoropyridin-3-yl) carbamate

5-bromo-4-iodo-6- (2, 2-trifluoroethoxy) pyrimidine (41.7 g,108 mmol) was dissolved in 250mL tetrahydrofuran, tert-butyl (6-ethynyl-5-fluoropyridin-3-yl) carbamate (25.7 g,108 mmol), bis (triphenylphosphine palladium) (II) (3.82 g,5.45 mmol), 16.6mL triethylamine and copper iodide (2.07 g,10.8 mmol) were added, stirring was carried out at 35℃for 1.5 hours, LCMS detection reaction ended, filtration, spin-drying and column chromatography gave tert-butyl (6- ((5-bromo-6- (2, 2-trifluoroethoxy) pyrimidin-4-yl) ethyl) -5-fluoropyridin-3-yl) carbamate (32.6 g, yield 54.2%).

LCMS：m/z 490.8[M+1] ⁺ ，492.8[M+3] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.30(s，1H)，8.83(s，1H)，8.57-8.48(m，1H)，8.01(dd，J＝1.8，11.7Hz，1H)，5.24-5.13(m，2H)，1.50(s，9H).

Step six: synthesis of tert-butyl (6- (5- (4- (benzyloxy) -3-fluorophenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-fluoropyridin-3-yl) carbamate

/>

Tert-butyl (6- ((5-bromo-6- (2, 2-trifluoroethoxy) pyrimidin-4-yl) ethyl) -5-fluoropyridin-3-yl) carbamate (14.6 g,29.7 mmol) was dissolved in 100mL dioxane, 4- (benzyloxy) -3-fluoroaniline (6.52 g,30.0 mmol), tris (dibenzylideneacetone) dipalladium (1.36 g,1.49 mmol), 4, 5-bis (diphenylphosphorus) -9, 9-dimethylxanthene (1.72 g,2.97 mmol) and cesium carbonate (19.3 g,59.4 mmol) were added, the LCMS detection reaction ended and spin-drying and column chromatography gave tert-butyl (6- (5- (4- (benzyloxy) -3-fluorophenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-fluoropyridin-3-yl) carbamate (10.5 g, 31% yield).

LCMS：m/z 628.2[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.05(s，1H)，8.56(s，1H)，8.33(s，1H)，7.88-7.82(m，1H)，7.57-7.54(m，1H)，7.34-7.27(m，6H)，7.09-7.07(m，1H)，6.91(br d，J＝8.0Hz，1H)，5.20-5.17(m，2H)，4.99(br d，J＝8.4Hz，2H)，1.49(s，9H).

Step seven: synthesis of (6- (5- (4- (benzyloxy) -3-fluorophenyl) -7-bromo-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-fluoropyridin-3-yl) carbamic acid tert-butyl ester

Tert-butyl (6- (5- (4- (benzyloxy) -3-fluorophenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-fluoropyridin-3-yl) carbamate (10.5 g,16.8 mmol) was dissolved in 100mL of acetonitrile, N-bromosuccinimide (2.99 g,16.8 mmol) was stirred at 20℃for 1 hour, LCMS detection reaction ended, spin-drying and column chromatography gave tert-butyl (6- (5- (4- (benzyloxy) -3-fluorophenyl) -7-bromo-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-fluoropyridin-3-yl) carbamate (2.55 g, yield 11.3%).

LCMS：m/z 705.9[M+1] ⁺ ，707.9[M+3] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.13(s，1H)，8.65(s，1H)，8.44(s，1H)，7.91(dd，J＝1.4，11.9Hz，1H)，7.44-7.33(m，6H)，7.14(t，J＝9.1Hz，1H)，6.96(br d，J＝8.9Hz，1H)，5.16(br s，2H)，5.01(br d，J＝4.0Hz，2H)，1.49(s，9H).

Step eight: synthesis of (6- (5- (4- (benzyloxy) -3-fluorophenyl) -7-methyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-fluoropyridin-3-yl) carbamic acid tert-butyl ester

(6- (5- (4- (benzyloxy) -3-fluorophenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-fluoropyridin-3-yl) carbamic acid tert-butyl ester (2.20 g,3.11 mmol) was dissolved in 10mL dioxane, methyl boric acid (559 mg,9.34 mmol), cesium carbonate (3.04 g,9.34 mmol), 1-bis (diphenylphosphino) ferrocene (345 mg, 622. Mu. Mol) and tris (dibenzylideneacetone) dipalladium (284 mg, 311. Mu. Mol) were added, the reaction was stirred at 120℃for 5 hours, the reaction was stopped by LCMS detection, and (6- (5- (4- (benzyloxy) -3-fluorophenyl) -7-methyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-fluoropyridin-3-yl) carbamic acid tert-butyl ester (1.15 g) was obtained by column chromatography in a yield of (1.4.15%).

LCMS：m/z 642.0[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.07(s，1H)，8.57(s，1H)，8.45(s，1H)，7.87(dd，J＝1.4，12.0Hz，1H)，7.44-7.26(m，6H)，7.11(t，J＝9.1Hz，1H)，6.84(br d，J＝9.4Hz，1H)，5.15(s，2H)，5.06-4.93(m，2H)，2.22(s，3H)，1.49(s，9H).

Step nine: synthesis of 6- (5-amino-3-fluoropyridin-2-yl) -5- (4- (benzyloxy) -3-fluorophenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-ol

Tert-butyl (6- (5- (4- (benzyloxy) -3-fluorophenyl) -7-methyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-fluoropyridin-3-yl) carbamate (1.65 g,2.57 mmol) was dissolved in 9mL of dimethyl sulfoxide, 9mL of water and potassium hydroxide (1.66 g,29.58 mmol) were added and stirred at 90℃for 12 hours, LCMS detection reaction ended and 6- (5-amino-3-fluoropyridin-2-yl) -5- (4- (benzyloxy) -3-fluorophenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-ol (850 mg, yield 64.0%) was obtained by extraction, drying, filtration, spin drying and column chromatography.

LCMS：m/z 459.9[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝11.96(br d，J＝3.3Hz，1H)，7.87(d，J＝3.5Hz，1H)，7.80-7.73(m，1H)，7.51-7.31(m，5H)，7.16-7.06(m，2H)，6.81(br d，J＝8.6Hz，1H)，6.67(dd，J＝2.1，12.1Hz，1H)，5.94(s，2H)，5.14(s，2H)，2.07(s，3H).

Step ten: synthesis of 6- (5-amino-3-fluoropyridin-2-yl) -5- (4- (benzyloxy) -3-fluorophenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6- (5-amino-3-fluoropyridin-2-yl) -5- (4- (benzyloxy) -3-fluorophenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-ol (800 mg,1.74 mmol) was dissolved in 16mL of acetonitrile, benzotriazole-1-oxo-tris (dimethylaminophosphorus) hexafluorophosphate salt (1.27 g,2.87 mmol) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (503 mg,3.31 mmol) were added, reacted at 20℃for 2 hours, then 4-methoxybenzylamine (1.67 g,12.1 mmol) was added, LCMS was stirred at 80℃for 8 hours, the reaction was stopped, and 6- (5-amino-3-fluoropyridin-2-yl) -5- (4- (benzyloxy) -3-fluorophenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (1.60 g) was obtained by column chromatography in 9.80% yield.

LCMS：m/z 579.1[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.29(s，1H)，7.75(t，J＝1.9Hz，1H)，7.39-7.37(m，1H)，7.44-7.35(m，4H)，7.23(br s，1H)，7.19(d，J＝9.0Hz，1H)，7.10(d，J＝8.5Hz，2H)，7.03(br d，J＝8.8Hz，1H)，6.83(d，J＝8.6Hz，2H)，6.71-6.67(m，1H)，5.94(s，2H)，5.12(br d，J＝13.1Hz，2H)，4.90(t，J＝5.4Hz，1H)，4.48(br d，J＝5.4Hz，2H)，3.68(s，3H)，2.10(s，3H).

Step eleven: synthesis of 4- (6- (5-amino-3-fluoropyridin-2-yl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl) -2-fluorophenol

6- (5-amino-3-fluoropyridin-2-yl) -5- (4- (benzyloxy) -3-fluorophenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (800 mg,1.38 mmol) was dissolved in 8mL of ethanol, 10% wet palladium on carbon was added to 1.47g, and the reaction was carried out at 20℃for 2 hours in a hydrogen atmosphere, after which the reaction was completed by LCMS, filtered, extracted and dried by spin-drying to give crude 4- (6- (5-amino-3-fluoropyridin-2-yl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl) -2-fluorophenol (1.50 g).

LCMS：m/z 489.0[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.28(s，1H)，7.80-7.72(m，1H)，7.13-7.00(m，3H)，6.85-6.78(m，5H)，6.69(dd，J＝2.0，12.0Hz，1H)，5.90(s，2H)，4.95(t，J＝5.6Hz，1H)，4.50(br d，J＝5.3Hz，2H)，3.71(s，3H)，2.13-2.06(m，3H).

Step twelve: synthesis of 6- (5-amino-3-fluoropyridin-2-yl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine

4- (6- (5-amino-3-fluoropyridin-2-yl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl) -2-fluorophenol (1.45 g,2.97 mmol) was dissolved in 15mL of N, N-dimethylformamide, 2-chloro-4-methylpyrimidine (572 mg,4.45 mmol) and cesium carbonate (1.93 g,5.94 mmol) were added and stirred at 80℃for 6 hours, LCMS detection reaction ended, extraction, drying, filtration, spin-drying and column chromatography gave 6- (5-amino-3-fluoropyridin-2-yl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (810 mg, yield 33.8%).

LCMS：m/z 581.0[M+H] ⁺ .

Step thirteen: synthesis of N- (5-fluoro-6- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- (4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyridin-3-yl) -3- (phenylsulfonyl) propanamide

6- (5-amino-3-fluoropyridin-2-yl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (700 mg,1.21 mmol) was dissolved in 3.5mL of pyridine, 3- (benzenesulfonyl) propionic acid (258 mg,1.21 mmol) and phosphorus oxychloride were added at 0deg.C, stirred at 20deg.C for 2 hours, LCMS was assayed at 0deg.C to end the reaction, the pH was adjusted to 7 using saturated sodium bicarbonate solution, and extracted, dried, filtered, and column chromatographed after spin-drying to give N- (5-fluoro-6- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- (4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-3-yl) -3- (phenylsulfonyl) propanamide (570 mg, yield 49.9%).

LCMS：m/z 777.0[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝11.00(br s，1H)，8.83(s，1H)，8.52(s，1H)，8.50-8.44(m，3H)，8.04(dd，J＝1.9，11.8Hz，1H)，7.93-7.89(m，2H)，7.70(d，J＝7.4Hz，1H)，7.65-7.60(m，2H)，7.53(dd，J＝2.4，10.6Hz，1H)，7.42(t，J＝8.6Hz，1H)，7.19(d，J＝2.9Hz，2H)，7.15(br t，J＝5.9Hz，1H)，6.85(s，1H)，6.83(s，1H)，4.73(br d，J＝5.8Hz，2H)，3.69(s，3H)，3.64(br s，2H)，2.76(br t，J＝7.1Hz，2H)，2.35(s，3H)，2.23(s，3H).

Step fourteen: synthesis of N- (6- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-fluoropyridin-3-yl) -3- (phenylsulfonyl) propanamide

N- (5-fluoro-6- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- (4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) pyridin-3-yl) -3- (phenylsulfonyl) propanamide (560 mg, 733. Mu. Mol) was dissolved in 3mL of trifluoroacetic acid, 1.5mL of trifluoromethanesulfonic acid was added, stirring was carried out at 35℃for 2 hours, LCMS detection was completed, the reaction was dried and the pH was adjusted to 7 with saturated sodium bicarbonate solution, then extracted, dried and dried to give N- (6- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-fluoropyridin-3- (phenylsulfonyl) propanamide (560 mg, yield 77.8%).

LCMS：m/z 657.2[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.69-10.59(m，1H)，8.49-8.45(m，1H)，8.42(s，1H)，8.30-8.26(m，1H)，7.97(dd，J＝1.8，11.7Hz，1H)，7.92-7.88(m，2H)，7.69(br d，J＝7.4Hz，1H)，7.65-7.59(m，2H)，7.43-7.36(m，2H)，7.19(d，J＝5.0Hz，1H)，7.13(br d，J＝9.0Hz，1H)，5.93-5.77(m，2H)，3.63(br t，J＝7.3Hz，2H)，2.73(br t，J＝7.3Hz，2H)，2.37(s，3H)，2.15(s，3H).

Fifteen steps: synthesis of N- (6- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-fluoropyridin-3-yl) acrylamide

N- (6- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-fluoropyridin-3-yl) -3- (phenylsulfonyl) propanamide (560 mg, 850 mol) was dissolved in 10mL tetrahydrofuran, trimethylpotassium silicate oxide (110 mg, 861. Mu. Mol) was added, stirring was carried out at 20℃for 1 hour, LCMS detection reaction ended, filtration, spin-drying and preparation HPLC gave N- (6- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-fluoropyridin-3-yl) acrylamide (100 mg, yield 22.4%).

LCMS：m/z 515.2[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.76(s，1H)，8.58(s，1H)，8.48(d，J＝5.0Hz，1H)，8.28(s，1H)，8.20(dd，J＝1.6，11.8Hz，1H)，7.47-7.34(m，2H)，7.19(d，J＝5.0Hz，1H)，7.17-7.08(m，1H)，6.49-6.28(m，2H)，5.91-5.70(m，3H)，2.36(s，3H)，2.16(s，3H).

Example 41:

n- (4- (4-amino-5- (2-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) -acrylamide:

the synthetic route is as follows:

step one: synthesis of 4- (benzyloxy) -2-fluoro-1-nitrobenzene

3-fluoro-4-nitrophenol (32.1 g,204 mmol) was dissolved in 170mL of N, N-dimethylformamide, potassium carbonate (28.8 g,208 mmol) and benzyl bromide (35.3 g,206 mmol) were added, stirred at 20℃for 12 hours, after completion of the LCMS detection reaction, 1500mL of water was added for rinsing and filtration to give 4- (benzyloxy) -2-fluoro-1-nitrobenzene (46.5 g, yield 85.6%).

LCMS：m/z 247.9[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.16(t，J＝9.2Hz，1H)，7.50-7.34(m，5H)，7.29(dd，J＝2.6，13.7Hz，1H)，7.06(dd，J＝1.9，9.3Hz，1H)，5.27(s，2H).

Step two: synthesis of 4- (benzyloxy) -2-fluoroaniline

4- (benzyloxy) -2-fluoro-1-nitrobenzene (20.0 g,80.9 mmol) was dissolved in 100mL of ethanol, 40mL of water, reduced iron powder (22.5 g,404 mmol) and ammonium chloride (12.9 g,242 mmol) were added and reacted at 80℃for 3 hours, after which the reaction was detected by LCMS, filtered, concentrated and column chromatographed to give 4- (benzyloxy) -2-fluoroaniline (15.5 g, 86.4% yield).

LCMS：m/z 217.9[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝7.44-7.28(m，5H)，6.80-6.68(m，2H)，6.61(dd，J＝1.9，8.7Hz，1H)，4.97(s，2H)，4.64(s，2H).

Step three: synthesis of tert-butyl (4- (5- (4- (benzyloxy) -2-fluorophenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate

(4- ((5-bromo-6- (2, 2-trifluoroethoxy) pyrimidin-4-yl) ethynyl) phenyl) carbamic acid tert-butyl ester (16.6 g,35.2 mmol) was dissolved in 90mL dioxane and 4- (benzyloxy) -2-fluoroaniline (7.66 g,35.2 mmol), cesium carbonate (22.9 g,70.5 mmol), tris (dibenzylideneacetone) dipalladium (1.62 g,1.76 mmol) and 4, 5-bis (diphenylphosphorus) -9, 9-dimethylxanthene (2.04 g,3.53 mmol) were added to the mixture to react at 90℃for 5 hours, LCMS detection was completed, after which the mixture was dried by spin-drying and column chromatography to give (4- (5- (4- (benzyloxy) -2-fluorophenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamic acid tert-butyl ester (13.6 g, 55.7%).

LCMS：m/z 609.3[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝9.54(s，1H)，8.53(s，1H)，7.48-7.32(m，8H)，7.25(d，J＝8.8Hz，2H)，7.05(dd，J＝2.6，12.0Hz，1H)，6.98(s，1H)，6.87(dd，J＝2.1，8.9Hz，1H)，5.16(s，2H)，5.11-4.87(m，2H)，1.47(s，9H).

Step four: synthesis of tert-butyl (4- (5- (4- (benzyloxy) -2-fluorophenyl) -7-bromo-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate

Tert-butyl (4- (5- (4- (benzyloxy) -2-fluorophenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (13.6 g,22.3 mmol) was dissolved in 70mL of acetonitrile, N-bromosuccinimide (4.06 g,22.7 mmol) was added, stirring was carried out at 20℃for 2 hours, and the completion of the reaction was detected by LCMS and filtered to give tert-butyl (4- (5- (4- (benzyloxy) -2-fluorophenyl) -7-bromo-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (12.7 g, yield 77.3%).

LCMS：m/z 686.9[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝9.57(s，1H)，8.62(s，1H)，7.52-7.30(m，8H)，7.26(d，J＝8.6Hz，2H)，6.99(dd，J＝2.6，12.0Hz，1H)，6.83(dd，J＝2.3，8.8Hz，1H)，5.18-4.88(m，4H)，1.47(s，9H).

Step five: synthesis of tert-butyl (4- (5- (4- (benzyloxy) -2-fluorophenyl) -7-methyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate

Tert-butyl (4- (5- (4- (benzyloxy) -2-fluorophenyl) -7-bromo-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (12.6 g,18.3 mmol) was dissolved in 125mL of dioxane, and methylboronic acid (3.84 g,64.1 mmol), 1-bis (diphenylphosphino) ferrocene (3.05 g,5.50 mmol), cesium carbonate (11.9 g,36.6 mmol) and tris (dibenzylideneacetone) dipalladium (2.52 g,2.75 mmol) were added, and the LCM detection reaction was completed at 120℃for 5 hours, concentrated, extracted and column chromatographed to give tert-butyl (4- (5- (4- (benzyloxy) -2-fluorophenyl) -7-methyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (10.9 g, yield 74.5%).

LCMS：m/z 623.2[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝9.51(s，1H)，8.53(s，1H)，7.46-7.28(m，8H)，7.18(d，J＝8.6Hz，2H)，6.97(dd，J＝2.6，11.9Hz，1H)，6.80(dd，J＝2.3，8.8Hz，1H)，5.16-4.87(m，4H)，2.27(s，3H)，1.47(s，9H).

Step six: synthesis of 6- (4- (aminophenyl) -5- (4- (benzyloxy) -2-fluorophenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-ol

Tert-butyl (4- (5- (4- (benzyloxy) -2-fluorophenyl) -7-methyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (10.8 g,17.3 mmol) was dissolved in 60mL of dimethyl sulfoxide and 30mL of water, octadecyl ether-6 (11.4 g,43.3 mmol) and potassium hydroxide (9.73 g,173 mmol) were added, stirring was performed at 80℃for 3 hours, LCMS detection of the end of the reaction, washing with 2000mL of water, filtration and beating to give 6- (4- (aminophenyl) -5- (4- (benzyloxy) -2-fluorophenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-ol (3.71 g, yield 35.4%).

LCMS：m/z 441.0[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝11.84(br d，J＝1.5Hz，1H)，7.83(s，1H)，7.55(br d，J＝10.8Hz，1H)，7.47(br d，J＝6.8Hz，2H)，7.41(br t，J＝6.9Hz，2H)，7.16(br t，J＝8.8Hz，1H)，6.95(br d，J＝12.3Hz，1H)，6.83(br d，J＝7.8Hz，2H)，6.77(br d，J＝8.4Hz，1H)，6.46(br d，J＝7.8Hz，2H)，5.29(br s，2H)，5.10(br s，2H)，2.15(br s，3H).

Step seven: synthesis of 6- (4- (aminophenyl) -5- (4- (benzyloxy) -2-fluorophenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6- (4- (aminophenyl) -5- (4- (benzyloxy) -2-fluorophenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-ol (3.00 g,6.81 mmol) was dissolved in 60mL of acetonitrile, benzotriazole-1-oxo-tris (dimethylaminophosphorus) hexafluorophosphate (7.53 g,17.0 mmol) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (2.07 g,13.6 mmol), p-methoxybenzylamine (8.97 g,65.3 mmol) was added after stirring for 1 hour at 20℃and stirring for 11 hours at 80℃the LCMS detection reaction was complete, and spin-dry and column chromatography gave 6- (4- (aminophenyl) -5- (4- (benzyloxy) -2-fluorophenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (3.55 g, 64.2%).

LCMS：m/z 560.2[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝9.48(br s，1H)，8.29(s，1H)，8.12-7.88(m，1H)，7.55(br t，J＝8.9Hz，1H)，7.45-7.40(m，3H)，7.40-7.34(m，2H)，7.05(br d，J＝8.5Hz，2H)，6.99(dd，J＝2.8，5.8Hz，1H)，6.90(br d，J＝8.4Hz，2H)，6.86-6.81(m，2H)，6.48(d，J＝8.4Hz，2H)，5.32(br d，J＝1.8Hz，2H)，5.06(s，2H)，4.51-4.42(m，2H)，3.67(s，3H)，2.16(s，3H).

Step eight: synthesis of 4- (6- (4- (aminophenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl) -3-fluorophenol

6- (4- (aminophenyl) -5- (4- (benzyloxy) -2-fluorophenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (3.55 g,6.34 mmol) was dissolved in 20mL of ethanol, 10% wet palladium on carbon (3.38 g,3.17 mmol) was added, stirring was performed at 20deg.C for 3 hours in a hydrogen atmosphere, and the reaction was terminated by LCMS, filtered, dried and purified by column chromatography to give 4- (6- (4- (aminophenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl) -3-fluorophenol (800 mg, yield 26.0%).

LCMS：m/z 470.0[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ＝10.32(s，1H)，8.25(s，1H)，7.38(t，J＝8.9Hz，1H)，7.04(d，J＝8.4Hz，2H)，6.84(dd，J＝8.4，18.4Hz，4H)，6.63-6.54(m，2H)，6.46(d，J＝8.4Hz，2H)，5.28(br s，2H)，4.72(brs，1H)，4.53-4.40(m，2H)，3.71(s，3H)，2.16(s，3H).

Step nine: synthesis of 6- (4- (aminophenyl) -5- (2-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine

4- (6- (4- (aminophenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl) -3-fluorophenol (400 mg, 851. Mu. Mol) was dissolved in 8mLN, N-dimethylformamide, cesium carbonate (416 mg,1.28 mmol) and 2-chloro-4-methylpyrimidine (131 mg,1.02 mmol) were added, stirring was carried out at 90℃for 5 hours, LCMS detection reaction ended, and 6- (4- (aminophenyl) -5- (2-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (250 mg, yield 52.2%) was obtained by extraction, drying, filtration, spin-drying and column chromatography.

LCMS：m/z 562.2[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.48(d，J＝5.0Hz，1H)，8.45(br s，1H)，7.70(t，J＝8.6Hz，1H)，7.34(dd，J＝2.4，10.7Hz，1H)，7.22(d，J＝5.1Hz，1H)，7.13-7.05(m，3H)，6.90(d，J＝8.6Hz，2H)，6.82(d，J＝8.4Hz，2H)，6.51(d，J＝8.5Hz，2H)，5.64-5.36(m，2H)，5.21(br s，1H)，4.56(br d，J＝5.3Hz，2H)，3.68(s，3H)，2.40(s，3H)，2.21(s，3H).

Step ten: synthesis of N- (4- (5- (2-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) -3- (phenylsulfonyl) propanamide

6- (4- (aminophenyl) -5- (2-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (60.0 mg, 106. Mu. Mol) was dissolved in 2mL of dichloromethane, 3- (benzenesulfonyl) propionic acid (22.8 mg, 106. Mu. Mol), O- (7-azabenzotriazol-1-yl) -N, N, N, N-tetramethylurea hexafluorophosphine salt (109 mg, 288. Mu. Mol) and N, N-diisopropylethylamine (34.5 mg, 267. Mu. Mol) were added, the reaction was terminated at 20℃with S detection, and N- (4- (5- (2-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-phenyl) -propionyl-amide (77.0 mg) was obtained by column chromatography in a yield of 0.70%.

LCMS：m/z 758.3[M+H] ⁺ .

Step eleven: synthesis of N- (4- (4-amino-5- (2-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) -3- (phenylsulfonyl) propanamide

N- (4- (5- (2-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) -3- (phenylsulfonyl) propanamide (70.0 mg, 92.3. Mu. Mol) was dissolved in 2mL of trifluoroacetic acid, 1mL of trifluoromethanesulfonic acid was added, the reaction was completed at 20℃for 1 hour, LCMS detection reaction was completed, saturated aqueous sodium bicarbonate solution was added to adjust pH to 7, extraction and spin-drying to give N- (4- (4-amino-5- (2-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) -3- (phenylsulfonyl) propanamide (60.0 mg, yield 51.9%).

LCMS：m/z 638.1[M+H] ⁺ .

Step twelve: synthesis of N- (4- (4-amino-5- (2-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) -acrylamide

N- (4- (4-amino-5- (2-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) -3- (phenylsulfonyl) propanamide (60.0 mg, 94.0. Mu. Mol) was dissolved in 3mL tetrahydrofuran, trimethylpotassium oxide (12.0 mg, 94.0. Mu. Mol) was added, stirring was carried out at 20℃for 0.5 hours, LCMS detection reaction ended, after concentration, saturated aqueous ammonium chloride solution was added, extraction, the organic phase was concentrated and N- (4- (4-amino-5- (2-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) -acrylamide (13.0 mg, yield 27.3%) was obtained by preparative HPLC.

LCMS：m/z 496.3[M+H] ⁺ .

¹ H NMR(400MHz，ACETONITRILE-d3)δ＝8.64(br s，1H)，8.39(d，J＝5.0Hz，1H)，8.29(s，1H)，7.65(d，J＝8.5Hz，2H)，7.60-7.54(m，1H)，7.27(d，J＝8.6Hz，2H)，7.16-7.03(m，3H)，6.38-6.30(m，2H)，5.74(dd，J＝4.0，7.9Hz，1H)，4.86(br s，2H)，2.41(s，3H)，2.25(s，3H).

Example 42:

n- [6- (4-amino-5- { 2-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methylpyrrolio [3,2-d ] pyrimidin-6-yl) -5-methylpyridin-3-yl ] prop-2-enamide:

the synthetic route is as follows:

step one: synthesis of [ (6-bromo-5-methylpyridin-3-yl) amino ] methanoic acid-2-methylpropan-2-yl ester

6-bromo-5-methylpyridin-3-amine (33.0 g,176.44 mmol) was dissolved in tetrahydrofuran (300 mL), and lithium bis (trimethylsilyl) amide (1.00M, 3838 mL) was added dropwise at-78℃under nitrogen protection, after stirring for 1 hour, di-tert-butyl dicarbonate (40.4 g,185mmol,42.5 mL) was added at-78℃and the reaction was continued for 1 hour, after LCMS detection the reaction was completed, the reaction solution was poured into saturated ammonium chloride solution to quench, then extracted with ethyl acetate, dried over organic phase, filtered and concentrated to give [ (6-bromo-5-methylpyridin-3-yl) amino ] methanoic acid-2-methylpropan-2-yl ester (48.0 g, crude).

LCMS：m/z 286.9[M+H] ⁺ .

Step two: synthesis of 2-methylpropan-2-yl ({ 5-methyl-6- [ (trimethylsilyl) ethynyl ] pyridin-3-yl } amino) methanoate

[ (6-bromo-5-methylpyridin-3-yl) amino ] methanoic acid-2-methylpropan-2-yl ester (43.0 g,149 mmol) was dissolved in tetrahydrofuran (500 mL) and trimethylsilylacethylene (44.1 g,449mmol,62.23 mL), dichlorobis (triphenylphosphine palladium) (II) (4.48 g,6.38 mmol), cuprous iodide (5.70 g,30.0 mmol) and triethylamine (45.5 g,449mmol,62.53 mL) were added and reacted at 50℃for 2 hours, and the LCMS detection was completed. After spin-drying, 2-methylpropan-2-yl ({ 5-methyl-6- [ [ (trimethylsilyl) ethynyl ] pyridin-3-yl } amino) methanoate (60.0 g, crude) was purified by silica gel column.

LCMS：m/z 305.3[M+H] ⁺ .

Step three: synthesis of [ (6-ethynyl-5-methylpyridin-3-yl) amino ] methanoic acid-2-methylpropan-2-yl ester

2-methylpropan-2-yl ({ 5-methyl-6- [ (trimethylsilyl) ethynyl ] pyridin-3-yl } amino) methanoate (60.0 g, 197 mmol) was dissolved in methanol (500 mL) and potassium carbonate (81.7 g,591 mmol) was added. After stirring at 20℃for 2 hours, LCMS detects the end of the reaction. Spin-drying and column chromatography gave [ (6-ethynyl-5-methylpyridin-3-yl) amino ] methanoic acid-2-methylpropan-2-yl ester (20.0 g, 43.7% yield).

LCMS：m/z 233.1[M+H] ⁺ .

Step four: synthesis of 2-methylpropan-2-yl { 6- ({ 5-bromo-6- [ (2, 2-trifluoroethyl) oxy ] pyrimidin-4-yl } ethynyl) -5-methylpyridin-3-yl ] amino } methanoate

5-bromo-4-iodo-6- (2, 2-trifluoroethoxy) pyrimidine (10.0 g,26.1 mmol) was dissolved in tetrahydrofuran (100 mL), [ (6-ethynyl-5-methylpyridin-3-yl) amino ] methanoic acid-2-methylpropan-2-yl ester (9.10 g,39.2 mmol), bis (triphenylphosphine palladium) (II) (1.83 g,2.61 mmol), triethylamine (7.93 g,78.4mmol,10.9 mL) and cuprous iodide (994 mg,5.22 mmol) were added, stirred at 20℃for 12 hours, the LCMS detection reaction was completed, filtered, spin-dried and column chromatographed to give { 6- ({ 5-bromo-6- [ (2, 2-trifluoroethyl) oxy ] pyrimidin-4-yl } ethynyl) -5-methylpyridin-3-yl ] amino } methanoic acid-2-methylpropan-2-yl ester (10.3 g, yield 80.9%).

LCMS：m/z 487.1[M+H] ⁺ .

¹ H NMR(400MHz，CHLOROFORM-d)δ＝8.66(s，1H)，8.29(br d，J＝1.5Hz，1H)，8.06(br s，1H)，6.75(br s，1H)，4.88(q，J＝8.3Hz，2H)，2.58(s，3H)，1.54(s，9H).

Step five: synthesis of 6- {5- [4- (benzyloxy) -2-fluorophenyl ] -4- [ (2, 2-trifluoroethyl) oxy ] pyrrolo [3,2-d ] pyrimidin-6-yl } -5-methylpyridin-3-amine

2-methylpropan-2-yl { [6- ({ 5-bromo-6- [ (2, 2-trifluoroethyl) oxy ] pyrimidin-4-yl } ethynyl) -5-methylpyridin-3-yl ] amino } methanoate (10.0 g,20.5 mmol) was dissolved in dioxane (100 mL), 4- (benzyloxy) -2-fluoroaniline (4.45 g,20.5 mmol), tris (dibenzylideneacetone) dipalladium (1.87 g,2.05 mmol), 4, 5-bis (diphenylphosphorus) -9, 9-dimethylxanthene (2.37 g,410 mmol) and cesium carbonate (20.1 g,61.6 mmol) were added, the S detection reaction ended, and spin-drying and column chromatography gave 6- {5- [4- (benzyloxy) -2-fluorophenyl ] -4- [ (2, 2-trifluoroethyl) oxy ] pyrrolo [3,2-d ] pyrimidin-6-yl } -pyridin-3-8.7.61 g, yield (7.0%).

LCMS：m/z 624.2[M+H] ⁺ .

Step six: synthesis of [ (6- {5- [4- (benzyloxy) -2-fluorophenyl ] -7-bromo-4- [ (2, 2-trifluoroethyl) oxy ] pyrrolo [3,2-d ] pyrimidin-6-yl } -5-methylpyridin-3-yl) amino ] methanesulfonic acid-2-methylpropan-2-yl ester

6- {5- [4- (benzyloxy) -2-fluorophenyl ] -4- [ (2, 2-trifluoroethyl) oxy ] pyrrolo [3,2-d ] pyrimidin-6-yl } -5-methylpyridin-3-amine (7.34 g,11.7 mmol) was dissolved in acetonitrile (70 mL), N-bromosuccinimide (2.51 g,14.1 mmol) was added, stirring was carried out at 0℃for 2 hours, LCMS detected the end of the reaction, and spin-dry and column chromatography gave [ (6- {5- [4- (benzyloxy) -2-fluorophenyl ] -7-bromo-4- [ (2, 2-trifluoroethyl) oxy ] pyrrolo [3,2-d ] pyrimidin-6-yl } -5-methylpyridin-3-yl) amino ] methanoic acid-2-methylpropan-2-yl ester (6.23 g, 75.3% yield).

LCMS：m/z 701.9[M+H] ⁺ .

Step seven: synthesis of [ (6- {5- [4- (benzyloxy) -2-fluorophenyl ] -7-methyl-4- [ (2, 2-trifluoroethyl) oxy ] pyrrolo [3,2-d ] pyrimidin-6-yl } -5-methylpyridin-3-yl) amino ] methanesulfonic acid-2-methylpropan-2-yl ester

[ (6- {5- [4- (benzyloxy) -2-fluorophenyl ] -7-bromo-4- [ (2, 2-trifluoroethyl) oxy ] pyrrolo [3,2-d ] pyrimidin-6-yl } -5-methylpyridin-3-yl) amino ] methanesulfonic acid-2-methylpropan-2-yl ester (5.00 g,7.12 mmol) was dissolved in dioxane (50 mL), methylboronic acid (1.28 g,21.3 mmol), cesium carbonate (6.96 g,21.3 mmol), 1-bis (diphenylphosphino) ferrocene palladium dichloride (345 mg, 622. Mu. Mol), and after stirring at 120℃for 2 hours, LCMS detection was completed, and was concentrated and purified by column chromatography to give [ (6- {5- [4- (benzyloxy) -2-fluorophenyl ] -7-methyl-4- [ (2, 2-trifluoroethyl) oxy ] pyrrolo [3,2-d ] pyrimidin-6-yl } -5-methylpyridin-3-yl) amino ] methyl ] propan-2-yl ester (20.20 g).

LCMS：m/z 638.2[M+H] ⁺ .

Step eight: synthesis of 6- (5-amino-3-methylpyridin-2-yl) -5- [4- (benzyloxy) -2-fluorophenyl ] -7-methylpyrrolo [3,2-d ] pyrimidin-4-ol

[ (6- {5- [4- (benzyloxy) -2-fluorophenyl ] -7-methyl-4- [ (2, 2-trifluoroethyl) oxy ] pyrrolo [3,2-d ] pyrimidin-6-yl } -5-methylpyridin-3-yl) amino ] methanesulfonic acid-2-methylpropan-2-yl ester (3.40 g,5.33 mmol) was dissolved in dimethyl sulfoxide (30.0 mL) and water (15.0 mL), potassium hydroxide (2.99 g,53.3 mmol) and 18-crown ether-6 (3.50 g,3.33 mmol) were added, and stirring was carried out at 80℃for 2 hours, and the reaction mixture was poured into water and filtered to give a cake of the product 6- (5-amino-3-methylpyridin-2-yl) -5- [4- (benzyloxy) -2-fluorophenyl ] -7-methylpyrrolidin [3,2-d ] pyrimidin-4-ol (2.10 g, yield 84.6%).

LCMS：m/z 456.0[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ＝12.06-11.65(m，1H)，7.90-7.84(m，1H)，7.76(d，J＝2.4Hz，1H)，7.49-7.30(m，5H)，7.15-6.83(m，2H)，6.79-6.59(m，2H)，5.06(s，2H)，2.10-1.82(m，6H).

Step nine: synthesis of 6- {5- [4- (benzyloxy) -2-fluorophenyl ] -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolo [3,2-d ] pyrimidin-6-yl } -5-methylpyridin-3-amine

6- (5-amino-3-methylpyridin-2-yl) -5- [4- (benzyloxy) -2-fluorophenyl ] -7-methylpyrrolidin-4-ol (500 mg,1.10 mmol), benzotriazole-1-oxo-tris (dimethylaminophosphorus) hexafluorophosphate (1.21 g,2.74 mmol) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (334 mg,2.20 mmol) were dissolved in acetonitrile 10m, then 4-methoxybenzylamine (1.51 g,11.0 mmol) was added and stirred for 12 hours at 80℃before the LCMS detection reaction was completed, dried by column chromatography to give 6- {5- [4- (benzyloxy) -2-fluorophenyl ] -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolidin-6-yl } -5-methylpyridin-3-amine (4.00 g, crude product).

LCMS：m/z 575.2[M+H] ⁺ .

Step ten: synthesis of 4- [6- (5-amino-3-methylpyridin-2-yl) -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolo [3,2-d ] pyrimidin-5-yl 1-2-fluorophenol

/>

6- {5- [4- (benzyloxy) -3-fluorophenyl ] -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolo [3,2-d ] pyrimidin-6-yl } -5-methylpyridin-3-amine (4.00 g,6.96 mmol) was dissolved in ethanol (40 mL), 10% wet palladium on carbon (3.70 g,3.48mmol,10% purity) was added, and reacted in a hydrogen atmosphere (15 psi) at 20℃for 2 hours. After completion of the reaction by LCMS, the reaction mixture was filtered and concentrated and purified by silica gel column to give 4- [6- (5-amino-3-methylpyridin-2-yl) -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolo [3,2-d ] pyrimidin-5-yl ] -2-fluorophenol (1.30 g, yield 31.2%).

LCMS：m/z 485.2[M+H] ⁺ .

Step eleven: synthesis of 6- (5- { 2-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolio [3,2-d ] pyrimidin-6-yl) -5-methylpyridin-3-amine

4- [6- (5-amino-3-methylpyridin-2-yl) -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolio [3,2-d ] pyrimidin-5-yl ] -2-fluorophenol (300 mg, 619. Mu. Mol) was dissolved in N, N-dimethylformamide (10 mL), 2-chloro-4-methylpyrimidine (578mg, 4.45 mmol) and cesium carbonate (161 mg, 495. Mu. Mol) were added, stirred at 60℃for 12 hours, LCMS was checked for reaction termination, extracted, dried, filtered, dried by spin-dry and 6- (5- { 2-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolio [3,2-d ] pyrimidin-6-yl) -5-methylpyridin-3-amine (170 mg, yield 47.6%) was obtained by column chromatography.

LCMS：m/z 577.4[M+H] ⁺ .

Step twelve: synthesis of 3- (dioxy-phenyl- λ6-thio) -N- [6- (5- { 2-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolo [3,2-d ] pyrimidin-6-yl) -5-methylpyridin-3-yl ] propionamide

6- (5- { 2-fluoro-4- [ (4-methylpyrimidin-2-YL) oxy ] phenyl } -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolino [3,2-d ] pyrimidin-6-YL) -5-methylpyridin-3-amine (170 mg, 294. Mu. Mol), 3- (dioxyphenyl- λ6-thio) propionic acid (63.1 mg, 294. Mu. Mol), O- (7-azabenzotriazol-1-YL) -N, N, N, N-tetramethylurea hexafluorophosphine salt (224 mg, 589. Mu. Mol) were dissolved in dichloromethane (5 mL), triethylamine (74.5 mg, 737. Mu. Mol) was added at 20 ℃, stirred at 20℃for 2 hours, the reaction was quenched by LCM, and the reaction solution was extracted, dried, filtered, and column chromatographed after spin-drying to give 3- (dioxyphenyl-6-thio) -N- [6- (5- { 2-fluoro-4- [ (4-methylpyrimidin-2-YL) oxy } -4- { [ -phenyl ] methyl ] amino } -4-methyl ] pyrrol-3-6-YL) at a yield of 3.82 mg.

LCMS：m/z 773.6[M+H] ⁺ .

Step thirteen: n- [6- (4-amino-5- { 2-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methylpyrrolio [3,2-d ] pyrimidin-6-yl) -5-methylpyridin-3-yl ] -3- (dioxy-phenylene- λ6-thio) propanamide

3- (Dioxyphenyl-. Lamda.6-thio) -N- [6- (5- { 2-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolo [3,2-d ] pyrimidin-6-yl) -5-methylpyridin-3-yl ] propionamide (82.0 mg, 106. Mu. Mol) was dissolved in trifluoroacetic acid (2.00 mL), trifluoromethanesulfonic acid (1.00 mL) was added, and the mixture was stirred at 20℃for 6 hours, after which the reaction was completed, dried by stirring with a saturated potassium carbonate solution to adjust the pH to 8, and then extracted, dried and dried to give N- [6- (4-amino-5- { 2-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methylpyrrolio [3,2-d ] pyrimidin-6-yl) -5-methylpyridin-3-yl ] -3- (dioxo-phenyl-. Lamda.6-thio) propionamide (45.0 mg, 65.0 mg, yield%).

LCMS：m/z 653.1[M+H] ⁺ .

Step fourteen: synthesis of N- [6- (4-amino-5- { 2-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methylpyrrolio [3,2-d ] pyrimidin-6-yl) -5-methylpyridin-3-yl ] prop-2-enamide

N- [6- (4-amino-5- { 2-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methylpyrrolino [3,2-d ] pyrimidin-6-yl) -5-methylpyridin-3-yl ] -3- (dioxy-phenyl- λ6-thio) propanamide (45.0 mg, 68.9. Mu. Mol) was dissolved in tetrahydrofuran (2.00 mL), potassium trimethylsilicon oxide (8.84 mg, 68.9. Mu. Mol) was added, stirred at 20℃for 0.5 h, LCMS detection reaction ended, filtered, dried and purified by reverse phase HPLC to give N- [6- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methylpyrrolino [3,2-d ] pyrimidin-6-yl) -5-methylpyridin-3-yl ] prop-2-enamide (26.0 mg, yield 73.8%).

LCMS：m/z 511.2[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ＝10.41(br s，1H)，8.70-8.41(m，2H)，8.27(s，1H)，8.07(br s，1H)，7.71-6.79(m，4H)，6.50-6.36(m，1H)，6.35-6.22(m，1H)，5.81(dd，J＝1.6，10.0Hz，1H)，5.67(br d，J＝9.3Hz，2H)，2.37(s，3H)，2.24-2.11(m，3H)，2.07(s，3H).

Example 43:

n- [6- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methylpyridin-3-yl ] acrylamide:

the synthetic route is as follows:

step one: synthesis of 6- {5- [4- (benzyloxy) -3-fluorophenyl ] -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl } -5-methylpyridin-3-yl-carbamic acid tert-butyl ester

Tert-butyl N- (6- {2- [ 5-bromo-6- (2, 2-trifluoroethoxy) pyrimidin-4-yl ] ethynyl } -5-methylpyridin-3-yl) carbamate (10.0 g,20.5 mmol) was dissolved in dioxane (100 mL), 4- (benzyloxy) -3-fluoroaniline (4.45 g,20.5 mmol), tris (dibenzylideneacetone) dipalladium (1.87 g,20.5 mmol), 4, 5-bis (diphenylphosphorus) -9, 9-dimethylxanthene (2.37 g,41.0 mmol) and cesium carbonate (20.1 g,61.6 mmol) were added, the S detection reaction was completed, concentrated and the 6- {5- [4- (benzyloxy) -3-fluorophenyl ] -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl } -5-methylpyridin-3-yl-carbamic acid tert-butyl ester (4.83 g, yield) was obtained by column chromatography.

LCMS：m/z 624.0[M+H] ⁺ .

Step two: synthesis of tert-butyl N- (6- {5- [4- (benzyloxy) -3-fluorophenyl ] -7-bromo-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl } -5-methylpyridin-3-yl) carbamate

6- {5- [4- (benzyloxy) -3-fluorophenyl ] -4- [ (2, 2-trifluoroethyl) oxy ] pyrrolo [3,2-d ] pyrimidin-6-yl } -5-methylpyridin-3-yl-carbamic acid tert-butyl ester (5.3 g,8.50 mmol) was dissolved in acetonitrile (50 mL), N-bromosuccinimide (1.51 g,8.50 mmol), stirred at 0℃for 2 hours, LCMS detected the end of the reaction, concentrated and purified by column chromatography to give tert-butyl N- (6- {5- [4- (benzyloxy) -3-fluorophenyl ] -7-bromo-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl } -5-methylpyridin-3-yl) carbamic acid tert-butyl ester (5.9 g, yield 98.8%).

LCMS：m/z 701.9[M+1] ⁺ ，m/z 703.9[M+3] ⁺ .

Step three: synthesis of tert-butyl N- (6- {5- [4- (benzyloxy) -3-fluorophenyl ] -7-methyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl } -5-methylpyridin-3-yl) carbamate

Tert-butyl N- (6- {5- [4- (benzyloxy) -3-fluorophenyl ] -7-bromo-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl } -5-methylpyridin-3-yl) carbamate (5.00 g,7.12 mmol) was dissolved in dioxane (50 mL), methylboronic acid (1.28 g,21.3 mmol), cesium carbonate (6.96 g,21.3 mmol), tris (dibenzylideneacetone) dipalladium (187 mg, 205. Mu. Mol), 4, 5-bis (diphenylphosphorus) -9, 9-dimethylxanthene (237 mg, 410. Mu. Mol), stirred at 100℃for 2 hours, LCMS detection was complete, concentrated and the tert-butyl N- (6- {5- [4- (benzyloxy) -3-fluorophenyl ] -7-methyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-methyl } -5-pyridin-3-yl) carbamate was obtained by column chromatography (70.70%).

LCMS：m/z 638.2[M+H] ⁺ .

Step four: synthesis of 6- (5-amino-3-methylpyridin-2-yl) -5- [4- (benzyloxy) -3-fluorophenyl ] -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-ol

Tert-butyl N- (6- {5- [4- (benzyloxy) -3-fluorophenyl ] -7-methyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl } -5-methylpyridin-3-yl) carbamate (2.9 g,4.55 mmol) was dissolved in dimethyl sulfoxide (30.0 mL) and water (15.0 mL), potassium hydroxide (2.55 g,45.48 mmol) and 18-crown ether-6 (841 mg,3.18 mmol) were added, stirred at 80℃for 10 hours, LCMS was examined for the end of the reaction, and the reaction solution was poured into water and filtered to give the filter cake as product 6- (5-amino-3-methylpyridin-2-yl) -5- [4- (benzyloxy) -3-fluorophenyl ] -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-ol (1.90 g, yield 91.7).

LCMS：m/z 456.0[M+H] ⁺ .

Step five: synthesis of 6- {5- [4- (benzyloxy) -3-fluorophenyl ] -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl } -5-methylpyridin-3-amine

6- (5-amino-3-methylpyridin-2-yl) -5- [4- (benzyloxy) -3-fluorophenyl ] -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-ol (1.9 g,4.17 mmol), benzotriazole-1-oxo-tris (dimethylaminophosphorus) hexafluorophosphate (4.06 g,9.18 mmol) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (1.27 g,8.34 mmol) were dissolved in acetonitrile (20 m), then 4-methoxybenzylamine (5.72 g,41.71 mmol) was added, stirred at 80℃for 10 hours, the S detection reaction ended, concentrated and purified by column chromatography to give 6- {5- [4- (benzyloxy) -3-fluorophenyl ] -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl } -5-methylpyridin-3-amine (5.50 g, crude).

LCMS：m/z 575.2[M+H] ⁺ .

Step six: synthesis of 4- [6- (5-amino-3-methylpyridin-2-yl) -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl ] -2-fluorophenol

6- {5- [4- (benzyloxy) -3-fluorophenyl ] -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl } -5-methylpyridin-3-amine (2.40 g,4.18 mmol) was dissolved in ethanol (20 mL), 10% wet palladium on carbon (2.22 g,2.09mmol,10% purity) was added, and reacted in an environment of hydrogen (15 psi) at 20℃for 2 hours. After completion of the reaction by LCMS, the reaction mixture was filtered and concentrated and purified by silica gel column to give 4- [6- (5-amino-3-methylpyridin-2-yl) -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl ] -2-fluorophenol (0.655 g, yield 32.1%).

LCMS：m/z 484.9[M+H] ⁺ .

Step seven: synthesis of 6- (5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methylpyridin-3-amine

/>

4- [6- (5-amino-3-methylpyridin-2-yl) -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl ] -2-fluorophenol (650 mg,1.34 mmol) was dissolved in N, N-dimethylformamide (10 mL), 2-chloro-4-methylpyrimidine (258 mg,2.01 mmol) and potassium carbonate (370 mg,2.68 mmol) were added, stirred at 25℃for 3 hours, LCMS was checked for reaction completion, extracted, dried, filtered, concentrated and purified by column chromatography to give 6- (5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methylpyridin-3-amine (170 mg, yield 47.6%).

LCMS：m/z 577.0[M+H] ⁺ .

Step eight: synthesis of 3- (benzenesulfonyl) -N- [6- (5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methylpyridin-3-yl ] propionamide

6- (5- { 3-fluoro-4- [ (4-methylpyrimidin-2-YL) oxy ] phenyl } -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-YL) -5-methylpyridin-3-amine (600 mg,1.04 mmol), 3- (dioxy phenyl-. Lamda.6-thio) propionic acid (222 mg,1.04 mmol), O- (7-azabenzotriazol-1-YL) -N, N, N, N-tetramethylurea hexafluorophosphine salt (435 mg,1.14 mmol) were dissolved in dichloromethane (5 mL), N, N-diisopropylethylamine (268 mg,2.08 mmol) was added at 25℃and stirred for 3 hours, after S detection the reaction was completed, the reaction liquid was extracted, dried, filtered, concentrated and then 3- (benzenesulfonyl) -N- [6- (5- { 3-fluoro-4- [ (4-methylpyrimidin-2-YL) oxy } -4-methyl ] phenyl ] pyrrol-3-YL ] amide (700 mg, 5- { [ -m-ethyl) was obtained by column chromatography.

LCMS：m/z 773.0[M+H] ⁺ .

Step nine: synthesis of N- [6- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methylpyridin-3-yl ] -3- (benzenesulfonyl) propanamide

3- (benzenesulfonyl) -N- [6- (5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methylpyridin-3-yl ] propionamide (700 mg, 905. Mu. Mol) was dissolved in trifluoroacetic acid (8.00 mL), trifluoromethanesulfonic acid (135 mg, 905. Mu. Mol) was added, and after stirring for 1 hour at 20 ℃, the reaction was ended, concentrated and pH was adjusted to 8 with a saturated potassium carbonate solution, and then extracted, dried and concentrated to give N- [6- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methylpyridin-3-yl ] -3- (benzenesulfonyl) propionamide (450 mg, crude product).

LCMS：m/z 653.0[M+H] ⁺ .

Step ten: synthesis of N- [6- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methylpyridin-3-yl ] prop-2-enamide

N- [6- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methylpyrrolino [3,2-d ] pyrimidin-6-yl) -5-methylpyridin-3-yl ] -3- (benzenesulfonyl) propionamide (450 mg, 689. Mu. Mol) was dissolved in tetrahydrofuran (20 mL), trimethylsilicon potassium oxide (88.4 mg, 689. Mu. Mol) was added, stirring at 20℃for 0.5H, LCMS detection reaction ended, filtration, concentration and purification by reverse phase HPLC gave N- [6- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methylpyridin-3-yl ] acrylamide (190 mg, yield 53.9%).

LCMS：m/z 511.2[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.42(s，1H)，8.64(d，J＝2.0Hz，1H)，8.46(d，J＝5.0Hz，1H)，8.28(s，1H)，8.05(d，J＝1.4Hz，1H)，7.40-7.28(m，2H)，7.18(d，J＝5.1Hz，1H)，7.10(br d，J＝9.3Hz，1H)，6.50-6.36(m，1H)，6.35-6.25(m，1H)，5.86-5.66(m，3H)，2.35(s，3H)，2.06(d，J＝11.9Hz，6H).

Example 44:

n- [6- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-ethyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methylpyridin-3-yl ] acrylamide:

the synthetic route is as follows:

/>

step one: synthesis of tert-butyl N- (6- {5- [4- (benzyloxy) -3-fluorophenyl ] -7-vinyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl } -5-methylpyridin-3-yl) carbamate

N- (6- {5- [4- (benzyloxy) -3-fluorophenyl)]-7-bromo-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d]Pyrimidin-6-yl } -5-methylpyridin-3-yl) carbamic acid tert-butyl ester (1.00 g,7.12 mmol), potassium vinyltrifluoroborate (381 mg,2.00 eq), cesium carbonate (927 mg,2.00 eq), (2-dicyclohexylphosphine-2, 4, 6-triisopropyl-1, 1-biphenyl) [2- (2-amino-1, 1-biphenyl)]Palladium methanesulfonate (208 mg,0.2 eq) was dissolved in dioxane (20 mL) and H ₂ O (2 mL) was stirred at 100deg.C for 2 hours, LCMS detected the end of the reaction, concentrated and chromatographed on a column to give N- (6- {5- [4- (benzyloxy) -3-fluorophenyl)]-7-vinyl-4- (2, 2-trifluoroethoxy) -511-pyrrolo [3,2-d]Pyrimidin-6-yl } -5-methylpyridin-3-yl) carbamic acid tert-butyl ester. (640 mg, yield 69.2%).

LCMS：m/z 650.1[M+H] ⁺ .

Step two: synthesis of 6- (5-amino-3-methylpyridin-2-yl) -5- [4- (benzyloxy) -3-fluorophenyl ] -7-vinyl-5H-pyrrolo [3,2-d ] pyrimidin-4-ol

Tert-butyl N- (6- {5- [4- (benzyloxy) -3-fluorophenyl ] -7-vinyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl } -5-methylpyridin-3-yl) carbamate (550 mg, 846. Mu. Mol) was dissolved in dimethyl sulfoxide (30.0 mL) and water (15.0 mL), potassium hydroxide (2.55 g,45.48 mmol) and 18-crown-6 (447 mg,1.69 mmol) were added, stirred at 80℃for 3 hours, LCMS detection reaction was completed, the reaction solution was poured into water and filtered to give a filter cake as the product 6- (5-amino-3-methylpyridin-2-yl) -5- [4- (benzyloxy) -3-fluorophenyl ] -7-vinyl-5H-pyrrolo [3,2-d ] pyrimidin-4-ol (340 mg, 85.9%).

LCMS：m/z 468.2[M+H] ⁺ .

Step three: synthesis of 6- {5- [4- (benzyloxy) -3-fluorophenyl ] -4- { [ (4-methoxyphenyl) methyl ] amino } -7-vinyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl } -5-methylpyridin-3-amine

6- (5-amino-3-methylpyridin-2-yl) -5- [4- (benzyloxy) -3-fluorophenyl ] -7-vinyl-5H-pyrrolo [3,2-d ] pyrimidine-4-ol (380 mg, 812. Mu. Mol), benzotriazole-1-oxy-tris (dimethylaminophosphorus) hexafluorophosphate (79mg, 1.79 mmol) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (247 mg,1.63 mmol) were dissolved in acetonitrile (4 mL), then 4-methoxybenzylamine (557 mg,4.06 mmol) was added and stirred for 10 hours at 80℃before the LCMS detection reaction ended, concentrated and purified by column chromatography to give 6- {5- [4- (benzyloxy) -3-fluorophenyl ] -4- { [ (4-methoxyphenyl) methyl ] amino } -7-5H-pyrrolo [3,2-d ] pyrimidin-6-yl } -5-methylpyridin-3-amine (1.20 g, crude product).

LCMS：m/z 587.2[M+H] ⁺ .

Step four: synthesis of 4- [6- (5-amino-3-methylpyridin-2-yl) -4- { [ (4-methoxyphenyl) methyl ] amino } -7-ethyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl ] -2-fluorophenol

6- {5- [4- (benzyloxy) -3-fluorophenyl ] -4- { [ (4-methoxyphenyl) methyl ] amino } -7-vinyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl } -5-methylpyridin-3-amine (1.00 g,1.70 mmol) was dissolved in ethanol (10 mL), 10% wet palladium on carbon (1.81 g,1.70mmol,10% purity) was added, and reacted in an environment of hydrogen (15 psi) at 20℃for 2 hours. After completion of the reaction by LCMS, the reaction mixture was filtered and concentrated and purified by silica gel column to give 4- [6- (5-amino-3-methylpyridin-2-yl) -4- { [ (4-methoxyphenyl) methyl ] amino } -7-ethyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl ] -2-fluorophenol (200 mg, yield 23.5%).

LCMS：m/z 499.0[M+H] ⁺ .

Step five: synthesis of 6- (5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -4- { [ (4-methoxyphenyl) methyl ] amino } -7-ethyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methylpyridin-3-amine

4- [6- (5-amino-3-methylpyridin-2-yl) -4- { [ (4-methoxyphenyl) methyl ] amino } -7-vinyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl ] -2-fluorophenol (240 mg, 481. Mu. Mol) was dissolved in N, N-dimethylformamide (2 mL), 2-chloro-4-methylpyrimidine (123 mg, 962. Mu. Mol) and potassium carbonate (199mg, 1.44 mmol) were added, stirred at 85℃for 3 hours, LCMS was assayed at the end of the reaction, extracted, dried, filtered, concentrated and purified by column chromatography to give 6- (5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -4- { [ (4-methoxyphenyl) methyl ] amino } -7-ethyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methylpyridin-3-amine (170 mg, yield 47.6%).

LCMS：m/z 591.2[M+H] ⁺ .

Step six: synthesis of 3- (benzenesulfonyl) -N- [6- (5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -4- { [ (4-methoxyphenyl) methyl ] amino } -7-ethyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methylpyridin-3-yl ] propionamide

6- (5- { 3-fluoro-4- [ (4-methylpyrimidin-2-YL) oxy ] phenyl } -4- { [ (4-methoxyphenyl) methyl ] amino } -7-ethyl-5H-pyrrolo [3,2-d ] pyrimidin-6-YL) -5-methylpyridin-3-amine (250 mg, 423. Mu. Mol), 3- (dioxy-phenyl-. Lamda.6-thio) propionic acid (136 mg, 634. Mu. Mol), O- (7-azabenzotriazol-1-YL) -N, N, N, N-tetramethylurea hexafluorophosphine salt (241 mg, 634. Mu. Mol) was dissolved in dichloromethane (5 mL), n, N-diisopropylethylamine (109 mg, 846. Mu. Mol) was added at 20℃and stirred at 25℃for 3 hours, LCMS detects the end of the reaction, and the reaction solution is extracted, dried, filtered, concentrated and then purified by column chromatography to give 3- (benzenesulfonyl) -N- [6- (5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -4- { [ (4-methoxyphenyl) methyl ] amino } -7-ethyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methylpyridin-3-yl ] propionamide (180 mg, yield 54.1%).

LCMS：m/z 787.2[M+H] ⁺ .

Step seven: synthesis of N- [6- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-ethyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methylpyridin-3-yl ] -3- (benzenesulfonyl) propanamide

3- (benzenesulfonyl) -N- [6- (5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -4- { [ (4-methoxyphenyl) methyl ] amino } -7-ethyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methylpyridin-3-yl ] propionamide (130 mg,165. Mu. Mol) was dissolved in trifluoroacetic acid (1.00 mL), trifluoromethanesulfonic acid (24.79 mg, 165.21. Mu. Mol) was added, the reaction was stirred at 20℃for 1 hour, the end was concentrated and the pH was adjusted to 8 with a saturated potassium carbonate solution, and then extracted, dried and concentrated to give N- [6- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-ethyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methylpyridin-3-yl ] -3- (benzenesulfonyl) propionamide (85 mg, 77.2%) in a yield of 77.2%).

LCMS：m/z 667.2[M+H] ⁺ .

Step eight: synthesis of N- [6- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-ethyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methylpyridin-3-yl ] acrylamide

N- [6- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-vinyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methylpyridin-3-yl ] -3- (benzenesulfonyl) propionamide (115 mg, 172. Mu. Mol) was dissolved in tetrahydrofuran (2.00 mL), potassium trimethylsilyloxide (22.1 mg, 172. Mu. Mol) was added, stirred at 20℃for 3 hours, the reaction was terminated by LCMS detection, filtered, concentrated and purified by reverse phase HPLC to give N- [6- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-ethyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methylpyridin-3-yl ] acrylamide (13.5 mg, yield 14.9%).

LCMS：m/z 525.2[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.42(s，1H)，8.67(s，1H)，8.46(d，J＝5.0Hz，1H)，8.27(s，1H)，8.03(s，1H)，7.37-7.27(m，2H)，7.18(d，J＝4.9Hz，1H)，7.09(br d，J＝8.0Hz，1H)，6.47-6.38(m，1H)，6.33-6.26(m，1H)，5.82(br d，J＝10.4Hz，1H)，5.74(br s，2H)，2.60-2.55(m，1H)，2.46-2.41(m，1H)，2.35(s，3H)，2.02(s，3H)，1.10(t，J＝7.4Hz，3H).

Example 45:

n- (6- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) acrylamide:

the synthetic route is as follows:

step one: synthesis of tert-butyl (6- (5- (4- (benzyloxy) -3-fluorophenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) carbamate

Tert-butyl (6- ((5-bromo-6- (2, 2-trifluoroethoxy) pyrimidin-4-yl) ethynyl) -5-methoxypyridin-3-yl) carbamate (4.00 g,7.95 mmol) was dissolved in 40mL dioxane and 4- (benzyloxy) -3-fluoroaniline (2.00 g,9.22 mmol), cesium carbonate (5.18 g,15.9 mmol), tris (dibenzylideneacetone) dipalladium (727 mg, 794. Mu. Mol) and 4, 5-bis (diphenylphosphorus) -9, 9-dimethylxanthene (919 mg,1.59 mmol) were added to the mixture, after completion of the LCMS detection reaction, the mixture was dried by spin-drying and column chromatography to give tert-butyl (6- (5- (4- (benzyloxy) -3-fluorophenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) carbamate (3.05 g, yield 51%).

LCMS：m/z 640.9[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝9.77(s，1H)，8.53(s，1H)，8.14(d，J＝1.8Hz，1H)，7.64(s，1H)，7.44-7.33(m，5H)，7.26(dd，J＝2.5，11.9Hz，1H)，7.09(t，J＝9.1Hz，1H)，6.92(s，1H)，6.80(br d，J＝8.6Hz，1H)，5.17(s，2H)，5.06-4.92(m，2H)，3.55(s，3H)，1.49(s，9H).

Step two: synthesis of (6- (5- (4- (benzyloxy) -3-fluorophenyl) -7-bromo-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) carbamic acid tert-butyl ester

Tert-butyl (6- (5- (4- (benzyloxy) -3-fluorophenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) carbamate (3.05 g,4.77 mmol) was dissolved in 15mL of acetonitrile, N-bromosuccinimide (328 mg,5.10 mmol) was added, stirring was carried out at 20℃for 2 hours, and the reaction was checked for completion by LCMS and filtered to give tert-butyl (6- (5- (4- (benzyloxy) -3-fluorophenyl) -7-bromo-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) carbamate (3.39 g, yield 77.1%).

LCMS：m/z 717.9[M+1] ⁺ ，719.9[M+3 ^]+ .

¹ H NMR(400MHz，DMSO-d6)δ＝9.83(s，1H)，8.61(s，1H)，8.21(br s，1H)，7.70(br s，1H)，7.42-7.33(m，5H)，7.31-7.24(m，1H)，7.11(br t，J＝9.0Hz，1H)，6.93-6.80(m，1H)，5.16(s，2H)，5.02(br s，2H)，3.58(br s，3H)，1.49(s，9H).

Step three: synthesis of (6- (5- (4- (benzyloxy) -3-fluorophenyl) -7-methyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) carbamic acid tert-butyl ester

(6- (5- (4- (benzyloxy) -3-fluorophenyl) -7-bromo-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) carbamic acid tert-butyl ester (3.00 g,4.18 mmol) was dissolved in 30mL of dioxane, and methylboronic acid (1.50 g,25.0 mmol), 1-bis (diphenylphosphino) ferrocene (1.16 g,2.09 mmol), cesium carbonate (2.72 g,8.35 mmol) and tris (dibenzylideneacetone) dipalladium (95 mg,1.04 mmol) were added, and after completion of the LCMS detection reaction, the reaction was concentrated, extracted and column chromatographed to give (6- (5- (4- (benzyloxy) -3-fluorophenyl) -7-methyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3.67 g of tert-butyl ester at 120℃under stirring for 4 hours.

LCMS：m/z 654.1[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝9.78(s，1H)，8.53(s，1H)，8.21(s，1H)，7.65(s，1H)，7.41-7.32(m，5H)，7.17(br d，J＝11.6Hz，1H)，7.07(t，J＝9.0Hz，1H)，6.76(br d，J＝8.4Hz，1H)，5.15(s，2H)，5.01(q，J＝8.6Hz，2H)，3.52(s，3H)，2.14(s，3H)，1.49(s，9H).

Step four: synthesis of 6- (5-amino-3-methoxypyridin-2-yl) -5- (4- (benzyloxy) -3-fluorophenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-ol

Tert-butyl (6- (5- (4- (benzyloxy) -3-fluorophenyl) -7-methyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) carbamate (2.30 g,3.52 mmol) was dissolved in 12mL of N-methylpyrrolidone, 18-crown-6 (1.16 g,4.40 mmol), 6mL of water and potassium hydroxide (1.15 g,20.5 mmol) were added and stirred at 90℃for 2 hours, LCMS detection of the end of the reaction was performed by extraction, concentration and column chromatography to give 6- (5-amino-3-methoxypyridin-2-yl) -5- (4- (benzyloxy) -3-fluorophenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-ol (800 mg, yield 42.9%).

LCMS：m/z 472.0[M+H ^]+ .

¹ H NMR(400MHz，DMSO-d6)δ＝11.84(br d，J＝2.8Hz，1H)，7.83(d，J＝3.4Hz，1H)，7.53(s，1H)，7.46-7.33(m，5H)，7.08(t，J＝9.0Hz，1H)，6.99(dd，J＝1.8，12.1Hz，1H)，6.74(br d，J＝8.6Hz，1H)，6.47(s，1H)，5.57(s，2H)，5.13(s，2H)，3.42(s，3H)，2.01(s，3H).

Step five: synthesis of 6- (5-amino-3-methoxypyridin-2-yl) -5- (4- (benzyloxy) -3-fluorophenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6- (5-amino-3-methoxypyridin-2-yl) -5- (4- (benzyloxy) -3-fluorophenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-ol (750 mg,1.59 mmol) was dissolved in 15mL of acetonitrile, benzotriazole-1-oxo-tris (dimethylaminophosphorus) hexafluorophosphate salt (1.06 g,2.39 mmol) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (375 mg,2.47 mmol), p-methoxybenzylamine (763 mg,5.57 mmol) was added after stirring for 1 hour at 20℃and stirring for 7 hours at 80℃and the LCMS detection reaction ended, spin-drying and column chromatography gave 6- (5-amino-3-methoxypyridin-2-yl) -5- (4- (benzyloxy) -3-fluorophenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (375 mg,2.47 mmol) in a yield of 410.7 mg.

LCMS：m/z 591.2[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.26(s，1H)，7.52(d，J＝2.0Hz，1H)，7.42-7.39(m，3H)，7.24(d，J＝8.5Hz，1H)，7.20-7.08(m，4H)，6.97-6.91(m，1H)，6.89-6.79(m，3H)，6.48(d，J＝2.0Hz，1H)，5.57(s，2H)，5.16-5.04(m，2H)，4.87(br t，J＝5.5Hz，1H)，4.47(br d，J＝5.3Hz，2H)，3.68(s，3H)，3.47(s，3H)，2.03(s，3H).

Step six: synthesis of 4- (6- (5-amino-3-methoxypyridin-2-yl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl) -2-fluorophenol

6- (5-amino-3-methoxypyridin-2-yl) -5- (4- (benzyloxy) -3-fluorophenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (360 mg, 609. Mu. Mol) was dissolved in 18mL of methanol, 10% wet palladium on carbon (488 mg, 609. Mu. Mol) was added, and stirring was performed in a hydrogen atmosphere at 20℃for 2 hours, after which the reaction was completed by LCMS detection, and 4- (6- (5-amino-3-methoxypyridin-2-yl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl) -2-fluorophenol (300 mg, yield 90.4%) was obtained by filtration and spin drying.

LCMS：m/z 501.1[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.24(s，1H)，7.51(d，J＝2.1Hz，1H)，7.09(d，J＝8.6Hz，2H)，7.01-6.94(m，1H)，6.90-6.71(m，5H)，6.49(d，J＝2.0Hz，1H)，5.53(s，2H)，4.90(t，J＝5.5Hz，1H)，4.49(br d，J＝5.3Hz，2H)，3.70(s，3H)，3.51(s，3H)，2.02(s，3H).

Step seven: synthesis of 6- (5-amino-3-methoxypyridin-2-yl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine

4- (6- (5-amino-3-methoxypyridin-2-yl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl) -2-fluorophenol (280 mg, 559. Mu. Mol) was dissolved in 3mLN, N-dimethylformamide, cesium carbonate (182 mg, 559. Mu. Mol) and 2-chloro-4-methylpyrimidine (71.9 mg, 559. Mu. Mol) were added, and stirring was performed at 90℃for 2 hours, and LCMS was performed to detect the end of the reaction, followed by extraction, drying, filtration, spin-drying and column chromatography to give 6- (5-amino-3-methoxypyridin-2-yl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (210 mg, yield 58.9%).

LCMS：m/z 593.3[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.43(d，J＝5.0Hz，1H)，8.29(s，1H)，7.59(d，J＝2.0Hz，1H)，7.30(t，J＝8.7Hz，1H)，7.21-7.13(m，4H)，6.97(br d，J＝8.9Hz，1H)，6.80(d，J＝8.6Hz，2H)，6.51(d，J＝2.0Hz，1H)，5.60(s，2H)，5.19(t，J＝5.6Hz，1H)，4.54(br d，J＝5.4Hz，2H)，3.67(s，3H)，3.47(s，3H)，2.36(s，3H)，2.07(s，3H).

Step eight: synthesis of N- (6- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) -3- (phenylsulfonyl) propanamide

6- (5-amino-3-methoxypyridin-2-yl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (190 mg, 320. Mu. Mol) was dissolved in 2mL of dichloromethane, 3- (benzenesulfonyl) propionic acid (114 mg, 532. Mu. Mol), O- (7-azabenzotriazol-1-yl) -N, N, N-tetramethylurea hexafluorophosphine salt (380 mg,1.00 mol) and N, N-diisopropylethylamine (133 mg,1.03 mmol) were added, the reaction was terminated at 35℃for 5 hours, and N- (6- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-methoxy) -3-pyridinyl) -3-propionyl-amide was obtained by column chromatography in a yield of 250 mg.

LCMS：m/z 789.0[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.43(s，1H)，8.53(dd，J＝1.3，8.4Hz，1H)，8.43(d，J＝5.0Hz，1H)，8.28(d，J＝1.8Hz，1H)，7.93-7.89(m，2H)，7.74-7.68(m，2H)，7.67-7.61(m，2H)，7.36-7.24(m，2H)，7.20-7.16(m，3H)，7.00(br d，J＝8.5Hz，1H)，6.81(d，J＝8.6Hz，2H)，5.99-5.62(m，1H)，4.60(br d，J＝5.4Hz，2H)，3.68(s，3H)，3.63(br t，J＝7.3Hz，2H)，3.53(s，3H)，2.72(br t，J＝7.3Hz，2H)，2.34(s，3H)，2.10(s，3H).

Step nine: synthesis of N- (6- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) -3- (phenylsulfonyl) propanamide

N- (6- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) -3- (phenylsulfonyl) propanamide (250 mg, 316. Mu. Mol) was dissolved in 2.5mL of trifluoroacetic acid, 2.5mL of trifluoromethanesulfonic acid was added, the reaction was completed at 20℃for 12 hours, LCMS detection reaction was completed, saturated aqueous sodium bicarbonate solution was added to adjust pH to 7, extraction and spin-drying to give N- (6- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) propanamide (210 mg, yield 76.3%).

LCMS：m/z 669.2[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.41(s，1H)，8.47(d，J＝5.0Hz，1H)，8.30-8.23(m，2H)，7.91(d，J＝7.4Hz，2H)，7.74-7.68(m，2H)，7.66-7.61(m，2H)，7.38-7.32(m，1H)，7.26-7.21(m，1H)，7.19(d，J＝4.9Hz，1H)，6.98(br d，J＝8.9Hz，1H)，6.04-5.76(m，2H)，3.63(t，J＝7.3Hz，2H)，3.54(s，3H)，2.72(t，J＝7.3Hz，2H)，2.37(s，3H)，2.08(s，3H).

Step ten: synthesis of N- (6- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) acrylamide

N- (6- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) -3- (phenylsulfonyl) propanamide (100 mg, 149. Mu. Mol) was dissolved in 12mL tetrahydrofuran, trimethylpotassium silicate oxide (19.7 mg, 154. Mu. Mol) was added, stirred at 20℃for 1 hour, LCMS detected the end of the reaction, concentrated and purified by preparative HPLC to give N- (6- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) acrylamide (19.2 mg, yield 24.1%).

LCMS：m/z 527.7[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.52(s，1H)，8.54-8.38(m，2H)，8.25(s，1H)，7.91(s，1H)，7.34(br t，J＝8.6Hz，1H)，7.28-7.15(m，2H)，7.00(br d，J＝8.1Hz，1H)，6.50-6.37(m，1H)，6.36-6.25(m，1H)，5.90-5.63(m，3H)，3.58(s，3H)，2.37(s，3H)，2.10(s，3H).

Example 46:

n- (6- (4-amino-7-ethyl-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) acrylamide:

step one: synthesis of (6- (5- (4- (benzyloxy) -3-fluorophenyl) -7-ethyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) carbamic acid tert-butyl ester

(6- (5- (4- (benzyloxy) -3-fluorophenyl) -7-bromo-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) carbamic acid tert-butyl ester (3.36 g,4.68 mmol) was dissolved in 30mL of dioxane, and methylboronic acid (3.39 g,45.8 mmol), 1-bis (diphenylphosphino) ferrocene (1.30 g,2.34 mmol), cesium carbonate (3.05 g,9.35 mmol) and tris (dibenzylideneacetone) dipalladium (1.07 g,1.17 mmol) were added, and the LCMS detection reaction was completed and column chromatography was performed at 120℃for 2 hours to give (6- (5- (4- (benzyloxy) -3-fluorophenyl) -7-ethyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3.80 g of carbamic acid tert-butyl ester (1.51%).

LCMS：m/z 668.1[M+H] ⁺ .

Step two: synthesis of 6- (5-amino-3-methoxypyridin-2-yl) -5- (4- (benzyloxy) -3-fluorophenyl) -7-ethyl-5H-pyrrolo [3,2-d ] pyrimidin-4-ol

Tert-butyl (6- (5- (4- (benzyloxy) -3-fluorophenyl) -7-ethyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) carbamate (1.80 g,2.70 mmol) was dissolved in 9mL of N-methylpyrrolidone, 18-crown-6 (1.20 g,4.53 mmol), 4.5mL of water and potassium hydroxide (1.20 g,21.3 mmol) were added, stirring was carried out at 90℃for 5 hours, LCMS detection reaction ended, extraction, concentration and column chromatography gave 6- (5-amino-3-methoxypyridin-2-yl) -5- (4- (benzyloxy) -3-fluorophenyl) -7-ethyl-5H-pyrrolo [3,2-d ] pyrimidin-4-ol (650 mg, yield 44.6%).

LCMS：m/z 486.2[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝11.84(br s，1H)，7.83(s，1H)，7.53(d，J＝2.1Hz，1H)，7.47-7.32(m，5H)，7.12-7.04(m，1H)，6.99(dd，J＝2.4，12.1Hz，1H)，6.79-6.71(m，1H)，6.46(d，J＝2.1Hz，1H)，5.56(s，2H)，5.13(s，2H)，3.41(s，3H)，2.48-2.43(m，2H)，1.05(t，J＝7.4Hz，3H).

Step three: synthesis of 6- (5-amino-3-methoxypyridin-2-yl) -5- (4- (benzyloxy) -3-fluorophenyl) -7-ethyl-N- (4-methoxybenzyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6- (5-amino-3-methoxypyridin-2-yl) -5- (4- (benzyloxy) -3-fluorophenyl) -7-ethyl-5H-pyrrolo [3,2-d ] pyrimidin-4-ol (600 mg,1.24 mmol) was dissolved in 12mL of acetonitrile, benzotriazole-1-oxo-tris (dimethylaminophosphorus) hexafluorophosphate (901 mg,2.04 mmol) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (301 mg,1.98 mmol), p-methoxybenzylamine (601 mg,4.39 mmol) was added after stirring for 1 hour at 20℃and after stirring for 7 hours at 80℃the S detection reaction ended, and spin-drying and column chromatography gave 6- (5-amino-3-methoxypyridin-2-yl) -5- (4- (benzyloxy) -3-fluorophenyl) -7-ethyl-N- (4-methoxybenzyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (530 mg, 9.48%) in a yield.

LCMS：m/z 605.2[M+H] ⁺ .

1H NMR(400MHz，DMSO-d6)δ＝8.26(s，1H)，7.52(d，J＝2.0Hz，1H)，7.44-7.38(m，4H)，7.19-7.07(m，4H)，6.92-6.80(m，4H)，6.47(d，J＝2.1Hz，1H)，5.55(s，2H)，5.17-5.04(m，2H)，4.87(t，J＝5.4Hz，1H)，4.47(br d，J＝5.0Hz，2H)，3.68(s，3H)，3.45(s，3H)，2.53-2.52(m，2H)，1.08(t，J＝7.5Hz，3H).

Step four: synthesis of 4- (6- (5-amino-3-methoxypyridin-2-yl) -7-ethyl-4- ((4-methoxybenzyl) amino) -5H-pyrrolo [3,2-d ] pyrimidin-5-yl) -2-fluorophenol

6- (5-amino-3-methoxypyridin-2-yl) -5- (4- (benzyloxy) -3-fluorophenyl) -7-ethyl-N- (4-methoxybenzyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (480 mg, 793. Mu. Mol) was dissolved in 48mL of methanol, 10% wet palladium on carbon (481 mg, 452. Mu. Mol) was added, and the reaction was stirred in a hydrogen atmosphere at 20℃for 2 hours, and the reaction was terminated by LCMS detection, filtered and dried by spin to give 4- (6- (5-amino-3-methoxypyridin-2-yl) -7-ethyl-4- ((4-methoxybenzyl) amino) -5H-pyrrolo [3,2-d ] pyrimidin-5-yl) -2-fluorophenol (400 mg, yield 70.5%).

LCMS：m/z 515.2[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.24(s，1H)，7.52(d，J＝2.0Hz，1H)，7.10(d，J＝8.6Hz，2H)，6.98(br d，J＝11.1Hz，1H)，6.91-6.77(m，5H)，6.48(d，J＝2.0Hz，1H)，5.52(s，2H)，4.94-4.85(m，1H)，4.49(br d，J＝4.1Hz，2H)，3.71(s，3H)，3.50(s，3H)，2.54-2.52(m，2H)，1.10-1.05(m，3H).

Step five: synthesis of 6- (5-amino-3-methoxypyridin-2-yl) -7-ethyl-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

4- (6- (5-amino-3-methoxypyridin-2-yl) -7-ethyl-4- ((4-methoxybenzyl) amino) -5H-pyrrolo [3,2-d ] pyrimidin-5-yl) -2-fluorophenol (350 mg, 680. Mu. Mol) was dissolved in 3.5mL dioxane, cesium carbonate (350 mg,1.07 mmol) and 2-chloro-4-methylpyrimidine (105 mg, 823. Mu. Mol) were added, stirring was performed at 90℃for 2 hours, and the reaction was terminated by LCMS detection and column chromatography by spin-drying to give 6- (5-amino-3-methoxypyridin-2-yl) -7-ethyl-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (300 mg, yield 69.0%).

LCMS：m/z 607.2[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.43(d，J＝5.1Hz，1H)，8.29(s，1H)，7.59(d，J＝2.0Hz，1H)，7.30(t，J＝8.6Hz，1H)，7.21-7.15(m，4H)，6.97(br d，J＝8.0Hz，1H)，6.80(d，J＝8.6Hz，2H)，6.50(d，J＝2.1Hz，1H)，5.58(s，2H)，5.19(t，J＝5.7Hz，1H)，4.54(br d，J＝5.1Hz，2H)，3.67(s，3H)，3.45(s，3H)，2.54(br s，2H)，2.36(s，3H)，1.10(t，J＝7.5Hz，3H).

Step six: synthesis of N- (6- (7-ethyl-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) -3- (phenylsulfonyl) propanamide

/>

6- (5-amino-3-methoxypyridin-2-yl) -7-ethyl-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (275 mg, 453. Mu. Mol) was dissolved in 5.5mL of dichloromethane, 3- (benzenesulfonyl) propionic acid (200 mg, 933. Mu. Mol), O- (7-azabenzotriazol-1-yl) -N, N, N, N-tetramethylurea hexafluorophosphine salt (551 mg,1.45 mmol) and N, N-diisopropylethylamine (220 mg,1.70 mmol) were added, the reaction was terminated by LCMS detection and N- (6- (7-ethyl-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino) -5H-pyrrolo [3,2-d ] pyrrol-yl ] pyridin-3-yl) -3, 360.1-methoxy-yl ] propionyl-amide was obtained by column chromatography at 35℃for 3 hours.

LCMS：m/z 803.3[M+H] ⁺ .

¹ H NMR(400MHz，ACETONITRILE-d3)δ＝8.69(s，1H)，8.63(br d，J＝3.8Hz，1H)，8.45(s，1H)，8.33(d，J＝5.0Hz，1H)，8.19(d，J＝1.9Hz，1H)，7.91(d，J＝7.4Hz，2H)，7.76(d，J＝1.6Hz，1H)，7.62-7.55(m，2H)，7.28-7.22(m，1H)，7.18(br d，J＝8.5Hz，3H)，7.08(br d，J＝8.6Hz，1H)，7.05(d，J＝5.1Hz，1H)，6.83(d，J＝8.6Hz，2H)，5.63(br t，J＝5.3Hz，1H)，4.66(br d，J＝5.4Hz，2H)，3.72(s，3H)，3.57(s，3H)，3.53(t，J＝7.2Hz，2H)，2.76-2.72(m，2H)，2.63(q，J＝7.4Hz，2H)，2.36(s，3H)，1.10(t，J＝7.4Hz，3H).

Step seven: synthesis of N- (6- (4-amino-7-ethyl-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) -3- (phenylsulfonyl) propanamide

N- (6- (7-ethyl-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) -3- (phenylsulfonyl) propanamide (360 mg, 448. Mu. Mol) was dissolved in 3.5mL of trifluoroacetic acid, 3.5mL of trifluoromethanesulfonic acid was added, the reaction was completed for 12 hours at 20 ℃, LCMS detection reaction was completed, pH was adjusted to 7 by adding saturated aqueous sodium bicarbonate solution, extraction, drying and spin-drying to give N- (6- (4-amino-7-ethyl-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) propanamide (300 mg, yield 60.7%).

LCMS：m/z 683.2[M+H] ⁺ .

¹ H NMR(400MHz，ACETONITRILE-d3)δ＝8.68(s，1H)，8.39-8.34(m，1H)，8.33-8.29(m，1H)，8.19(d，J＝1.9Hz，1H)，7.95-7.87(m，2H)，7.75-7.64(m，2H)，7.63-7.54(m，2H)，7.25(br t，J＝8.6Hz，1H)，7.18-7.13(m，1H)，7.08-7.03(m，2H)，4.98(br s，2H)，3.58(s，3H)，3.54(s，2H)，2.74(t，J＝7.3Hz，2H)，2.62(br d，J＝7.5Hz，2H)，2.38(s，3H)，1.14(s，3H).

Step eight: synthesis of N- (6- (4-amino-7-ethyl-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) acrylamide

/>

N- (6- (4-amino-7-ethyl-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) -3- (phenylsulfonyl) propanamide (200 mg, 292. Mu. Mol) was dissolved in 10mL tetrahydrofuran, trimethylpotassium silicate oxide (37.9 mg, 295. Mu. Mol) was added, stirred at 20℃for 1 hour, LCMS was assayed for the end of the reaction, concentrated and N- (6- (4-amino-7-ethyl-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -5-methoxypyridin-3-yl) acrylamide (43.0 mg, yield 26.3%) was obtained by preparative HPLC.

LCMS：m/z 541.0[M+H] ⁺ .

¹ H NMR(400MHz，ACETONITRILE-d3)δ＝8.82(s，1H)，8.37(d，J＝5.0Hz，1H)，8.34(d，J＝2.0Hz，1H)，8.30(s，1H)，7.98(d，J＝2.0Hz，1H)，7.24(t，J＝8.6Hz，1H)，7.15(br d，J＝10.8Hz，1H)，7.10-7.03(m，2H)，6.39-6.34(m，2H)，5.79(dd，J＝5.4，6.4Hz，1H)，4.98(br s，2H)，3.62(s，3H)，2.63(q，J＝7.5Hz，2H)，2.38(s，3H)，1.15(t，J＝7.5Hz，3H).

Example 47:

n- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-methylphenyl) acrylamide:

the synthetic route is as follows:

step one: synthesis of 5- (4- (benzyloxy) -3-fluorophenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidine

4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidine (22.5 g,103 mmol) was dissolved in 120mL of dimethyl sulfoxide, 1- (benzyloxy) -4-bromo-2-fluorobenzene (45.1 g,160 mmol), potassium phosphate (45.0 g,212 mmol), iodomethylene (19.7 g,103 mmol) and (1S, 2S) - (+) -N, N' -dimethylcyclohexyl-1, 2-diamine (4.42 g,31.0 mmol) were added, after completion of LCMS detection reaction, the filter cake was filtered and washed with 200mL of dimethyl sulfoxide, 5000mL of an aqueous ammonia/water=5/1 solution was prepared, the filtrate was added, extracted with dichloromethane, and the organic phase was dried by spinning to give 5- (4- (benzyloxy) -3-fluorophenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidine (19.5 g, 42.8%).

LCMS：m/z 418.5[M+H] ⁺ .

¹ H 1H NMR(400MHz，DMSO-d6)δ＝8.53(s，1H)，7.97(d，J＝3.3Hz，1H)，7.58-7.51(m，1H)，7.50-7.46(m，2H)，7.42(t，J＝7.4Hz，2H)，7.38-7.30(m，3H)，6.83(d，J＝3.1Hz，1H)，5.27(s，2H)，5.07(q，J＝8.9Hz，2H).

Step two: synthesis of 5- (3-fluoro-4-hydroxyphenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-ol

5- (4- (benzyloxy) -3-fluorophenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidine (19.3 g,46.2 mmol) was dissolved in 100 mLN-methylpyrrolidone, potassium hydroxide (25.9 g, 463mmol) and 100mL of water were added and reacted at 80℃for 18 hours, after completion of the LCMS detection reaction, 5000mL of water was added to precipitate a solid and filtered, and the filter cake was rinsed with water to give 5- (3-fluoro-4 hydroxyphenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-ol (13.8 g, yield 82.7%).

LCMS：m/z 336.0[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝12.00(br s，1H)，7.87(s，1H)，7.63(d，J＝3.1Hz，1H)，7.54-7.40(m，5H)，7.39-7.24(m，3H)，6.57(d，J＝3.0Hz，1H)，5.25(s，2H).

Step three: synthesis of 5- (4-benzyloxy) -3-fluorophenyl) -N- (4-methoxybenzyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

5- (3-fluoro-4 hydroxyphenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-ol (13.5 g,40.4 mmol) was dissolved in 271mL of acetonitrile, a catter condensing agent (27.1 g,61.4 mmol) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (11.3 g,74.7 mmol) were added, after reacting at 20℃for 2 hours, p-methoxybenzylamine (41.5 g,303 mmol) was added, reacting at 80℃for 3 hours, after LCMS detection was completed, cooled to room temperature, filtered, and the filter cake was rinsed with water to give 5- (4-benzyloxy) -3-fluorophenyl) -N- (4-methoxybenzyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (14.4 g, yield 73.7%).

LCMS：m/z 455.2[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.27(s，1H)，7.62(d，J＝3.3Hz，1H)，7.55-7.35(m，7H)，7.26(dd，J＝1.2，8.7Hz，1H)，7.20(d，J＝8.5Hz，2H)，6.85(d，J＝8.6Hz，2H)，6.59(d，J＝3.1Hz，1H)，5.54(t，J＝5.6Hz，1H)，5.23(s，2H)，4.54(d，J＝5.6Hz，2H)，3.71(s，3H).

Step four: synthesis of 4- (4-amino-5H-pyrrolo [3,2-d ] pyrimidin-5-yl) -2-fluorophenol

5- (4- (benzyloxy) -3-fluorophenyl) -N- (4-methoxybenzyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (14.4 g,31.6 mmol) was dissolved in 30mL of trifluoroacetic acid, 15mL of trifluoromethanesulfonic acid was added, stirring was carried out at 20℃for 2 hours, after completion of LCMS detection reaction, the trifluoroacetic acid was removed, the pH was adjusted to 7 with 1000mL of saturated sodium bicarbonate solution, and 4- (4-amino-5H-pyrrolo [3,2-d ] pyrimidin-5-yl) -2-fluorophenol (7.72 g, yield 77.8%) was obtained by filtration.

LCMS：m/z 244.9[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.39(br s，1H)，8.65-8.20(m，1H)，7.75(s，1H)，7.43(dd，J＝1.9，11.6Hz，1H)，7.19-7.05(m，3H)，6.63(br s，2H).

Step five: synthesis of 5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

4- (4-amino-5H-pyrrolo [3,2-d ] pyrimidin-5-yl) -2-fluorophenol (7.72 g,31.6 mmol) was dissolved in 40mL of N, N-dimethylformamide, cesium carbonate (15.4 g,47.4 mmol) and 2-chloro-4-methylpyrimidine (5.08 g,39.5 mmol) were added and reacted at 80℃for 5 hours, after completion of the LCMS detection reaction, water was added to separate out the solid, the filter cake was obtained by filtration, and after drying, it was slurried to obtain 5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (7.65 g, yield 68.3%).

LCMS：m/z 336.9[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.51(d，J＝5.0Hz，1H)，8.24(br s，1H)，7.80(d，J＝3.1Hz，1H)，7.62(dd，J＝2.3，11.1Hz，1H)，7.57(t，J＝8.6Hz，1H)，7.34(br d，J＝7.9Hz，1H)，7.23(d，J＝5.0Hz，1H)，6.63(br d，J＝2.9Hz，1H)，6.03(br s，2H)，2.46(s，3H).

Step six: synthesis of 6, 7-dibromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

/>

5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (7.65 g,22.7 mmol) was dissolved in 40mL acetonitrile and N-bromosuccinimide (15.3 g,86.4 mmol) was added, the reaction was allowed to react at 35℃for 2 hours, LCMS detection was complete, filtered, and the filter cake was rinsed with water to give 6, 7-dibromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (4.76 g, yield 42.3%).

LCMS：m/z 494.7[M+3] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.53(d，J＝5.0Hz，1H)，8.26(s，1H)，7.81(dd，J＝1.9，10.8Hz，1H)，7.69-7.60(m，1H)，7.49(br d，J＝8.3Hz，1H)，7.25(d，J＝5.0Hz，1H)，6.10-5.77(m，2H)，2.46(s，3H).

Step seven: synthesis of 6- (4-amino-2-methylphenyl) -7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6, 7-dibromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (300 mg, 607. Mu. Mol) was dissolved in 6mL of dioxane, 4-amino-2-methylphenylboronic acid pinacol ester (155 mg, 667. Mu. Mol), potassium phosphate (255 mg,1.21 mmol), tetrakis (triphenylphosphine) palladium (210 mg, 182. Mu. Mol) and 4mL of water were added, stirred at 80℃for 5 hours, after completion of LCMS detection reaction, concentrated and column chromatography gave 6- (4-amino-2-methylphenyl) -7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (210 mg, yield 46.5%).

LCMS：m/z 520.0[M+1] ⁺ ，522.0[M+3] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.48(d，J＝5.0Hz，1H)，8.27(s，1H)，7.76-7.33(m，5H)，7.20(d，J＝5.0Hz，1H)，6.85(br d，J＝8.0Hz，1H)，6.38(s，1H)，6.35-6.30(m，1H)，5.26(br s，2H)，2.39(s，3H)，1.97(s，3H).

Step eight: synthesis of 6- (4-amino-2-methylphenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6- (4-amino-2-methylphenyl) -7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (200 mg, 384. Mu. Mol) was dissolved in 5mL of dioxane, methyl boric acid (115 mg,1.92 mmol), cesium carbonate (250 mg, 768. Mu. Mol), tris (dibenzylideneacetone) dipalladium (175 mg, 192. Mu. Mol) and 1, 1-bis (diphenylphosphino) ferrocene (213 mg, 384. Mu. Mol) were added, and after completion of the LCMS detection reaction, concentrated and column chromatographed as 6- (4-amino-2-methylphenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (110 mg, 23.2%).

LCMS：m/z 456.1[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.49(br d，J＝4.9Hz，1H)，8.25(s，1H)，7.90(br dd，J＝3.1，7.2Hz，1H)，7.42-7.36(m，2H)，7.20(br d，J＝4.9Hz，1H)，6.82(br d，J＝7.8Hz，1H)，6.39(br s，1H)，6.35(br d，J＝8.0Hz，1H)，5.73-5.52(m，2H)，5.31-5.14(m，2H)，2.40(s，3H)，2.06-1.96(m，6H).

Step nine: synthesis of N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-methylphenyl) acrylamide

6- (4-amino-2-methylphenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (100 mg, 219. Mu. Mol) was dissolved in 3mL of tetrahydrofuran, and acryloyl chloride (19.8 mg, 219. Mu. Mol) was added, the reaction was terminated at 0℃for 1 hour, LCMS detection reaction was completed, concentrated and purified by preparative HPLC to give N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-methylphenyl) acrylamide (10.5 mg, yield 9.01%).

LCMS：m/z 510.4[M+H] ⁺ .

¹ H NMR(400MHz，ACETONITRILE-d3)δ＝8.61(br s，1H)，8.35(d，J＝5.1Hz，1H)，8.30(s，1H)，7.55(s，1H)，7.48(dd，J＝1.3，8.3Hz，1H)，7.32-7.08(m，4H)，7.05(d，J＝5.0Hz，1H)，6.41-6.26(m，2H)，5.73(dd，J＝3.3，8.6Hz，1H)，4.93(br s，2H)，2.37(s，3H)，2.10-2.06(m，6H).

Example 48:

n- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-fluorophenyl) acrylamide:

the synthetic route is as follows:

step one: synthesis of 6- (4-amino-2-fluorophenyl) -7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6, 7-dibromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (480 mg, 971. Mu. Mol) was dissolved in 15mL of dioxane, 4-amino-2-fluorophenylboronic acid pinacol ester (230 mg, 971. Mu. Mol), potassium phosphate (412 mg,1.94 mmole), tetrakis (triphenylphosphine) palladium (560 mg, 485. Mu. Mol) and 10mL of water were added, stirred at 80℃for 5 hours, after completion of LCMS detection reaction, concentrated and column chromatography gave 6- (4-amino-2-fluorophenyl) -7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (120 mg, yield 15.0%).

LCMS：m/z 523.9[M+H] ⁺ ，525.9[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.50(d，J＝5.0Hz，1H)，8.28(s，1H)，7.53-7.41(m，2H)，7.26-7.20(m，2H)，6.97(t，J＝8.4Hz，1H)，6.36(dd，J＝2.1，8.4Hz，1H)，6.29(dd，J＝1.9，12.6Hz，1H)，5.94-5.65(m，4H)，2.41(s，3H).

Step two: synthesis of 6- (4-amino-2-fluorophenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6- (4-amino-2-fluorophenyl) -7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (120 mg, 228. Mu. Mol) was dissolved in 6mL dioxane, methyl boric acid (47.9 mg,80 mmol), potassium phosphate (48.5 mg, 228. Mu. Mol), tris (dibenzylideneacetone) dipalladium (104 mg, 114. Mu. Mol) and 1, 1-bis (diphenylphosphino) ferrocene were added, reacted at 120℃for 3.5 hours, concentrated and column chromatographed to 6- (4-amino-2-fluorophenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (110 mg, 23.0%) after completion of the LCMS detection reaction.

LCMS：m/z 460.0[M+H] ⁺ .

Step three: synthesis of N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-fluorophenyl) acrylamide

6- (4-amino-2-fluorophenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (110 mg, 239. Mu. Mol) was dissolved in 5mL tetrahydrofuran, and acryloyl chloride (4.77 mg, 52.6. Mu. Mol) was added, the reaction was checked for completion at 0℃for 1 hour, concentrated and purified by preparative HPLC to give N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-fluorophenyl) acrylamide (6.5 mg, yield 5.07%).

LCMS：m/z 514.2[M+H] ⁺ .

¹ H NMR(400MHz，ACETONITRILE-d ₃ )δ＝8.74(br s，1H)，8.37(d，J＝5.0Hz，1H)，8.31(s，1H)，7.70(br d，J＝12.3Hz，1H)，7.35-7.21(m，4H)，7.18(br d，J＝8.8Hz，1H)，7.06(d，J＝5.0Hz，1H)，6.34(d，J＝6.1Hz，2H)，5.77(t，J＝5.9Hz，1H)，4.87(br s，2H)，2.38(s，3H)，2.18(br s，3H).

Example 49:

n- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -2, 3-difluorophenyl) acrylamide:

the synthetic route is as follows:

step one: synthesis of 6- (4-amino-2, 3-difluorophenyl) -7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6, 7-dibromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (500 mg,1.01 mmol) was dissolved in 20mL dioxane, 2, 3-difluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (387 mg,1.52 mmol), potassium phosphate (429 mg,2.02 mmol), tetrakis (triphenylphosphine) palladium (760 mg, 657. Mu. Mol) and 10mL water were added, after completion of the LCMS detection reaction, concentrated and column chromatography gave 6- (4-amino-2, 3-difluorophenyl) -7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (120 mg, 15.0% yield).

LCMS：m/z 542.0[M+1] ⁺ ，544.0[M+3] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ＝8.49(d，J＝4.9Hz，1H)，8.32-8.18(m，1H)，7.65-7.59(m，2H)，7.58-7.52(m，2H)，7.48-7.43(m，1H)，7.21(d，J＝5.0Hz，1H)，6.83(br t，J＝7.6Hz，1H)，6.54(br t，J＝8.4Hz，1H)，5.88(s，2H)，2.39(s，3H).

Step two: synthesis of 6- (4-amino-2, 3-difluorophenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6- (4-amino-2, 3-difluorophenyl) -7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (230 mg, 424. Mu. Mol) was dissolved in 6mL of dioxane, methyl boric acid (228 mg,3.82 mmol), cesium carbonate (276 mg, 848. Mu. Mol) and tris (dibenzylideneacetone) dipalladium (116 mg, 127. Mu. Mol) were added, reacted at 120℃for 3 hours, after completion of LCMS detection, the crude product was concentrated and purified by preparative HPLC to give 6- (4-amino-2, 3-difluorophenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (30.0 mg, yield 14.5%).

LCMS：m/z 478.1[M+H] ⁺ .

Step three: synthesis of N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -2, 3-difluorophenyl) acrylamide

6- (4-amino-2, 3-difluorophenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (30.0 mg, 62.8. Mu. Mol) was dissolved in 6mL of tetrahydrofuran, and acryloyl chloride (5.69 mg, 62.8. Mu. Mol) was added, and the reaction was reacted at 0℃for 1 hour, after which the reaction was terminated by LCMS, concentrated and purified by preparative HPLC to give N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -2, 3-difluorophenyl) acrylamide (26.0 mg, yield 76.3%).

LCMS：m/z 532.1[M+H] ⁺ .

¹ H NMR(400MHz，ACETONITRILE-d3)δ＝8.55(br s，1H)，8.37(d，J＝5.0Hz，1H)，8.31(s，1H)，8.11-8.02(m，1H)，7.36-7.24(m，2H)，7.20(br d，J＝8.5Hz，1H)，7.10-7.02(m，2H)，6.53-6.43(m，1H)，6.41-6.33(m，1H)，5.81(dd，J＝1.9，10.0Hz，1H)，4.95(br s，2H)，2.38(s，3H)，2.20(br s，3H).

Example 50:

n- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-fluoro-2-methylphenyl) acrylamide:

the synthetic route is as follows:

step one: synthesis of 6- (4-amino-2-fluoro-3-methylphenyl) -7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6, 7-dibromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (500 mg,1.01 mmol) was dissolved in 7.5mL dioxane, 3-fluoro-2-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (304 mg,1.21 mmol), potassium phosphate (429 mg,2.02 mmol), tetrakis (triphenylphosphine) palladium (284 mg, 505. Mu. Mol) and 5mL water were added, after completion of the LCMS detection reaction, concentrated and column chromatography gave 6- (4-amino-2-fluoro-3-methylphenyl) -7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (190 mg, 29.3% yield).

LCMS：m/z 538.0[M+H] ⁺ ，540.0[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.48(d，J＝5.0Hz，1H)，8.27(s，1H)，7.49(br d，J＝6.9Hz，1H)，7.43(br t，J＝8.6Hz，1H)，7.27-7.17(m，2H)，6.86(t，J＝8.2Hz，1H)，6.42(d，J＝8.4Hz，1H)，5.82(br d，J＝2.5Hz，2H)，5.53(s，2H)，2.40(s，3H)，1.90(s，3H).

Step two: synthesis of 6- (4-amino-2-fluoro-3-methylphenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6- (4-amino-2-fluoro-3-methylphenyl) -7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (190 mg, 352. Mu. Mol) was dissolved in 9mL of dioxane, methylboronic acid (190 mg,3.18 mmol), cesium carbonate (229 mg, 705. Mu. Mol) and tris (dibenzylideneacetone) dipalladium (161 mg, 176. Mu. Mol) were added, reacted at 120℃for 3 hours, after completion of the LCMS detection reaction, the crude product was concentrated and chromatographed, and the crude product was purified by preparative HPLC to give 6- (4-amino-2-fluoro-3-methylphenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (35.0 mg, yield 18.6%).

LCMS：m/z 474.0[M+H] ⁺ .

Step three: synthesis of N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-fluoro-2-methylphenyl) acrylamide

6- (4-amino-2-fluoro-3-methylphenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (35.0 mg, 73.9. Mu. Mol) was dissolved in 9mL of tetrahydrofuran, and acryloyl chloride (6.69 mg, 73.9. Mu. Mol) was added, the reaction was allowed to react at 0℃for 1 hour, and the reaction was terminated by LCMS, dried by spin-drying and purified by preparative HPLC to give N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-fluoro-2-methylphenyl) acrylamide (15.0 mg, yield 38.0%).

LCMS：m/z 528.3[M+H] ⁺ .

¹ H NMR(400MHz，ACETONITRILE-d3)δ＝8.37(d，J＝4.9Hz，1H)，8.31(s，1H)，8.10(br s，1H)，7.63(br d，J＝8.4Hz，1H)，7.35-7.23(m，2H)，7.19(br d，J＝8.6Hz，1H)，7.13(br t，J＝8.1Hz，1H)，7.06(d，J＝5.1Hz，1H)，6.52-6.41(m，1H)，6.38-6.29(m，1H)，5.77(dd，J＝1.7，10.1Hz，1H)，4.89(br s，2H)，2.39(s，3H)，2.14(br d，J＝2.0Hz，6H).

Example 51:

n- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-methoxyphenyl) acrylamide:

the synthetic route is as follows:

step one: synthesis of 6- (4-amino-2-methoxyphenyl) -7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6, 7-dibromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (500 mg,1.01 mmol) was dissolved in 15mL dioxane, 3-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (277 mg,1.11 mmol), potassium phosphate (279 mg,2.02 mmol), tetrakis (triphenylphosphine) palladium (284 mg, 505. Mu. Mol) and 10mL of water were added, and after completion of the LCMS detection reaction, concentrated and column chromatography gave 6- (4-amino-2-methoxyphenyl) -7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (300 mg, 46.9%) in a yield of 46.9%).

LCMS：m/z 538.0[M+3] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.49(d，J＝5.0Hz，1H)，8.25(s，1H)，7.58-7.11(m，4H)，6.93(d，J＝8.1Hz，1H)，6.17(dd，J＝1.8，8.2Hz，1H)，6.10(d，J＝1.8Hz，1H)，5.98-5.69(m，2H)，5.45(br s，2H)，3.43(s，3H)，2.40(s，3H).

Step two: synthesis of 6- (4-amino-2-methoxyphenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6- (4-amino-2-methoxyphenyl) -7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (300 mg, 559. Mu. Mol) was dissolved in 15mL of dioxane, methyl boric acid (301 mg,5.03 mmol), cesium carbonate (366 mg,1.12 mmol) and tris (dibenzylideneacetone) dipalladium (256 mg, 279. Mu. Mol) were added, reacted at 120℃for 3 hours, LCMS was concentrated and column chromatographed to give crude product, which was purified by preparative HPLC to give 6- (4-amino-2-methoxyphenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (35.0 mg, yield 12.8%).

LCMS：m/z 472.3[M+H] ⁺ .

Step three: synthesis of N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-methoxyphenyl) acrylamide

6- (4-amino-2-methoxyphenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (35.0 mg, 74.2. Mu. Mol) was dissolved in 6mL tetrahydrofuran, and acryloyl chloride (6.72 mg, 74.2. Mu. Mol) was added, the reaction was allowed to react at 0℃for 1 hour, LCMS detection of the end of the reaction, spin-drying and purification by preparative HPLC gave N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-methoxyphenyl) acrylamide (13.5 mg, yield 33.9%).

LCMS：m/z 526.4[M+H] ⁺ .

¹ H NMR(400MHz，ACETONITRILE-d3)δ＝8.62(br s，1H)，8.38(d，J＝5.0Hz，1H)，8.30(s，1H)，7.50(s，1H)，7.39-6.91(m，6H)，6.39-6.31(m，2H)，5.75(dd，J＝4.5，7.4Hz，1H)，4.98(br s，2H)，3.57(br s，3H)，2.38(s，3H)，2.14(s，3H).

Example 52:

n- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -2-fluoro-5-methylphenyl) acrylamide:

the synthetic route is as follows:

/>

step one: synthesis of 2-fluoro-5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) aniline

4-bromo-2-fluoro-5-methylaniline (1.00 g,4.90 mmol) was dissolved in 6mLN, N-dimethylformamide, and bis-pinacolatoborate (2.50 g,9.85 mmol), potassium acetate (1.45 g,14.7 mmol) and 1, 1-bis (diphenylphosphorus) ferrocene palladium chloride (358 mg, 490. Mu. Mol) were added, and after stirring at 80℃for 3 hours, LCMS detection reaction was completed, 2-fluoro-5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) aniline (920 mg, yield 63.5%) was obtained by extraction, drying, filtration, concentration and column chromatography.

LCMS：m/z 252.2[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝7.10(d，J＝12.4Hz，1H)，6.51(d，J＝8.8Hz，1H)，5.44(s，2H)，2.29(s，3H)，1.25(s，12H).

Step two: synthesis of 6- (4-amino-5-fluoro-2-methylphenyl) -7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6, 7-dibromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (500 mg,1.01 mmol) was dissolved in 7.5mL dioxane, 2-fluoro-5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (279 mg,1.11 mmol), potassium phosphate (279 mg,2.02 mmol), tetrakis (triphenylphosphine) palladium (584 mg, 505. Mu. Mol) and 5mL water were added, and after completion of the S detection reaction, concentration and column chromatography gave 6- (4-amino-5-fluoro-2-methylphenyl) -7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (300 mg, 39% yield, 1.39%).

LCMS：m/z 537.0[M+1] ⁺ ，540.0[M+3] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.48(d，J＝5.0Hz，1H)，8.28(s，1H)，7.43(br s，3H)，7.20(d，J＝5.0Hz，1H)，6.92(br d，J＝12.3Hz，1H)，6.56(d，J＝9.3Hz，1H)，6.01-5.77(m，2H)，5.36(s，2H)，2.38(s，3H)，1.96(s，3H).

Step three: synthesis of 6- (4-amino-5-fluoro-2-methylphenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine

/>

6- (4-amino-5-fluoro-2-methylphenyl) -7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (300 mg, 557. Mu. Mol) was dissolved in 15mL of dioxane, and methylboronic acid (300 mg,5.02 mmol), cesium carbonate (803 mg,1.11 mmol) and tris (dibenzylideneacetone) dipalladium (255 mg, 278. Mu. Mol) were added to react at 120℃for 2 hours, after completion of the LCMS detection reaction, the crude product was concentrated and purified by preparative HPLC to give 6- (4-amino-5-fluoro-2-methylphenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (45.0 mg, 16.0% yield).

LCMS：m/z 474.3[M+H] ⁺ .

Step four: synthesis of N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -2-fluoro-5-methylphenyl) acrylamide

6- (4-amino-5-fluoro-2-methylphenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (45.0 mg, 95.0. Mu. Mol) was dissolved in 9mL of tetrahydrofuran, and acryloyl chloride (8.60 mg, 95.0. Mu. Mol) was added, and the reaction was reacted at 0℃for 1 hour, and the completion of LCMS detection was air-dried and purified by preparative HPLC to give N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -2-fluoro-5-methylphenyl) acrylamide (15.0 mg, yield 28.4%).

LCMS：m/z 528.2[M+H] ⁺ .

¹ H NMR(400MHz，ACETONITRILE-d3)δ＝8.40-8.25(m，3H)，8.17(br d，J＝8.0Hz，1H)，7.34-7.10(m，3H)，7.08-7.00(m，2H)，6.51-6.30(m，2H)，5.78(br d，J＝10.0Hz，1H)，4.84(br s，2H)，2.37(s，3H)，2.10(s，3H)，2.08(s，3H).

Example 53:

n- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -2-fluoro-3-methylphenyl) acrylamide:

the synthetic route is as follows:

/>

step one: synthesis of 2-fluoro-3-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) aniline

4-bromo-2-fluoro-3-methylaniline (500 mg,2.45 mmol) was dissolved in 5mLN, N-dimethylformamide, and bis-pinacolato borate (1.25 g,4.93 mmol), potassium acetate (721 mg,7.35 mmol) and 1, 1-bis (diphenylphosphorus) ferrocene palladium chloride (178 mg, 245. Mu. Mol) were added, followed by stirring at 80℃for 3 hours, and after completion of the LCMS detection reaction, 2-fluoro-3-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) aniline (700 mg, yield 93.2%) was obtained by extraction, drying, filtration, concentration and column chromatography.

LCMS：m/z 252.0[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ＝7.16(d，J＝8.0Hz，1H)，6.53(t，J＝8.4Hz，1H)，5.43(s，2H)，2.31(d，J＝2.8Hz，3H)，1.25(s，12H).

Step two: synthesis of 6- (4-amino-3-fluoro-2-methylphenyl) -7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6, 7-dibromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (500 mg,1.01 mmol) was dissolved in 15mL dioxane, 2-fluoro-3-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (279 mg,1.11 mmol), potassium phosphate (279 mg,2.02 mmol), tetrakis (triphenylphosphine) palladium (284 mg, 505. Mu. Mol) and 10mL water were added, after completion of the LCMS detection reaction, concentrated and column chromatography gave 6- (4-amino-3-fluoro-2-methylphenyl) -7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (270 mg, 36.6% yield).

LCMS：m/z 548.1[M+1] ⁺ ，540.1[M+3] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ＝8.48(d，J＝5.0Hz，1H)，8.29(s，1H)，7.52-7.29(m，3H)，7.20(d，J＝5.0Hz，1H)，6.76(br d，J＝8.1Hz，1H)，6.55(t，J＝8.6Hz，1H)，6.01-5.76(m，2H)，5.35(s，2H)，2.38(s，3H)，1.94(d，J＝2.0Hz，3H).

Step three: synthesis of 6- (4-amino-3-fluoro-2-methylphenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6- (4-amino-3-fluoro-2-methylphenyl) -7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (270 mg, 501. Mu. Mol) was dissolved in 15mL of dioxane, and methylboronic acid (270 mg,4.51 mmol), cesium carbonate (326 mg,1.00 mmol) and tris (dibenzylideneacetone) dipalladium (229 mg, 250. Mu. Mol) were added to react at 120℃for 3 hours, after completion of the LCMS detection reaction, the crude product was concentrated and purified by preparative HPLC to give 6- (4-amino-3-fluoro-2-methylphenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (45.0 mg, 18.5%).

LCMS：m/z 474.2[M+H] ⁺ .

Step four: synthesis of N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -2-fluoro-3-methylphenyl) acrylamide

6- (4-amino-3-fluoro-2-methylphenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (45.0 mg, 95.0. Mu. Mol) was dissolved in 6mL tetrahydrofuran, and acryloyl chloride (8.60 mg, 95.0. Mu. Mol) was added, and the reaction was allowed to react at 0℃for 1 hour, after which the LCMS detection reaction ended, dried and purified by preparative HPLC to give N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -2-fluoro-3-methylphenyl) acrylamide (8.0 mg, yield 15.9%).

LCMS：m/z 528.2[M+H] ⁺ .

¹ H NMR(400MHz，ACETONITRILE-d3)δ＝8.40-8.27(m，3H)，8.11(br t，J＝8.1Hz，1H)，7.32-7.08(m，3H)，7.07-6.99(m，2H)，6.53-6.42(m，1H)，6.40-6.30(m，1H)，5.77(br d，J＝10.0Hz，1H)，4.91(br s，2H)，2.37(s，3H)，2.09(s，3H)，2.04(br s，3H).

Example 54:

1- (3- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -1H-pyrazol-1-yl) pyrrolidin-1-yl) prop-2-en-1-one:

the synthetic route is as follows:

step one: synthesis of tert-butyl 3- (4- (4-amino-7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylate

6, 7-dibromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (700 mg,1.42 mmol) was dissolved in 21mL dioxane and 14mL water, 3- (4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (566 mg,1.56 mmol), potassium phosphate (602.83 mmol), tetrakis (triphenylphosphine) palladium (818 mg, 708. Mu. Mol), and after completion of LCMS detection reaction, concentrated and column chromatography gave 3- (4-amino-7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (601 mg,1.56 mmol), yield (601 mg, 7.37%).

LCMS：m/z 650.0[M+1] ⁺ ，652.0[M+3] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.50(d，J＝5.0Hz，1H)，8.26(s，1H)，7.83(br s，1H)，7.71(dd，J＝2.2，10.7Hz，1H)，7.58-7.48(m，2H)，7.47-7.40(m，2H)，7.22(d，J＝5.0Hz，1H)，5.82-5.75(m，1H)，4.98(br s，1H)，3.72-3.63(m，1H)，3.53-3.43(m，1H)，3.36(br d，J＝6.9Hz，2H)，2.43(s，3H)，2.35-2.27(m，1H)，2.17(td，J＝6.2，12.4Hz，1H)，1.38(br d，J＝11.4Hz，9H).

Step two: synthesis of tert-butyl 3- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylate

3- (4- (4-amino-7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (530 mg, 814. Mu. Mol) was dissolved in 8mL dioxane, and methylboronic acid (5306 mg,8.96 mmol), cesium carbonate (530 mg,1.63 mmol) and methanesulfonic acid (2-dicyclohexylphosphine-2 ',4',6' -triisopropyl-1, 1' -biphenyl) (2 ' -amino-1, 1' -biphenyl-2-yl) palladium (II) (344 mg, 407. Mu. Mol) were added, and after completion of the S detection reaction, concentrated and column chromatography gave 3- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-1-yl) pyrrole-1-yl) palladium (II) (34 mg, 1' -biphenyl-2-yl) at 120℃for 2 hours gave a yield of 3- (4-amino-5-methyl-pyrrol-2-yl) 1-yl) pyrrolidine-1-carboxylic acid of 50 mg.

LCMS：m/z 586.1[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.50(d，J＝4.9Hz，1H)，8.27-8.15(m，1H)，7.85-7.42(m，4H)，7.35-7.21(m，3H)，5.56(br d，J＝2.6Hz，1H)，4.95(br d，J＝5.6Hz，1H)，3.74-3.60(m，1H)，3.55-3.43(m，1H)，3.41-3.34(m，2H)，2.43(s，3H)，2.37-2.31(m，1H)，2.27(s，3H)，2.22-2.16(m，1H)，1.37(br d，J＝12.8Hz，9H).

Step three: synthesis of 5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-6- (1- (pyrrolidin-3-yl) -1H-pyrazol-4-yl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

3- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (190 mg, 324. Mu. Mol) was dissolved in 6mL of dichloromethane, 3mL of trifluoroacetic acid was added, after completion of the LCMS detection reaction, the reaction mixture was adjusted to pH 7 with saturated sodium bicarbonate solution and extracted, and the organic phase was concentrated to give 5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-6- (1- (pyrrolidin-3-yl) -1H-pyrazol-4-yl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (150 mg, yield 53.3%).

LCMS：m/z 486.3[M+H] ⁺ .

Step four: synthesis of 1- (3- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -1H-pyrazol-1-yl) pyrrolidin-1-yl) prop-2-en-1-one

5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-6- (1- (pyrrolidin-3-yl) -1H-pyrazol-4-yl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (150 mg, 308. Mu. Mol) was dissolved in 5mL tetrahydrofuran, and acryloyl chloride (27.9 mg, 308. Mu. Mol) was added, the reaction was checked for completion at 0℃for 1 hour, LCMS, and the mixture was dried by spin-drying and purified by preparative HPLC to give 1- (3- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -1H-pyrazol-1-yl) pyrrolidin-1-yl) prop-2-en-1-one (20.0 mg, yield 11.5%).

LCMS：m/z 540.0[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.50(t，J＝4.8Hz，1H)，8.20(s，1H)，7.75(d，J＝9.3Hz，1H)，7.58(dd，J＝2.3，10.7Hz，1H)，7.50(dt，J＝2.2，8.6Hz，1H)，7.35-7.28(m，2H)，7.22(dd，J＝1.3，5.1Hz，1H)，6.55(ddd，J＝10.3，16.8，19.8Hz，1H)，6.13(ddd，J＝2.4，8.8，16.8Hz，1H)，5.65(ddd，J＝2.4，10.3，18.8Hz，1H)，5.55(br s，2H)，5.10-4.96(m，1H)，3.81(br d，J＝13.1Hz，2H)，3.73-3.65(m，2H)，2.43(s，3H)，2.41-2.15(m，5H).

Example 55:

1- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3, 6-dihydropyridin-1 (2H) -yl) prop-2-en-1-one:

the synthetic route is as follows:

step one: synthesis of tert-butyl 4- (4-amino-7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate

6, 7-dibromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (300 mg,607 mmol) was dissolved in 6mL of dioxane and 4mL of water, N-t-butoxycarbonyl-1, 2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester (187 mg,607 mmol), 4mL of water, potassium phosphate (255 mg,1.21 mmol) and tetrakis (triphenylphosphine) palladium (210 mg,182 mmol) were added, the reaction was stirred at 80℃for 3 hours, the completion of the LCMS detection reaction, dried by spin and column chromatography to give 4- (4-amino-7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (220 mg, 43.7%).

LCMS：m/z 595.9[M+1] ⁺ ，597.9[M+3] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.51(d，J＝5.0Hz，1H)，8.26(s，1H)，7.70(br d，J＝10.8Hz，1H)，7.59-7.52(m，1H)，7.43(br s，1H)，7.23(br d，J＝4.9Hz，1H)，6.02-5.87(m，3H)，3.89(br s，2H)，3.30(br s，2H)，2.41(s，3H)，2.06(br s，2H)，1.38(s，9H).

Step two: synthesis of tert-butyl 4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate

4- (4-amino-7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3, 6-dihydropyridin-1 (2H) -carboxylic acid tert-butyl ester (210 mg, 352. Mu. Mol) was dissolved in 2mL of dioxane, and methylboronic acid (73.7 mg,1.23 mmol), cesium carbonate (229 mg, 704. Mu. Mol), bis (diphenylphosphino) ferrocene iron (107 mg, 193. Mu. Mol) and tris (dibenzylideneacetone) dipalladium (80.6 mg, 88.0. Mu. Mol) were added, the S detection reaction was completed at 120℃with spin-drying and column chromatography to give 4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3, 6-dihydropyridin-1 (155.5 mg, 5.5% tert-butyl ester (155.5 mg) in 50% yield).

LCMS：m/z 532.3[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.51(d，J＝5.0Hz，1H)，8.22(s，1H)，7.60-7.55(m，2H)，7.53-7.51(m，1H)，7.33(dd，J＝1.3，8.4Hz，1H)，7.23(d，J＝5.0Hz，1H)，5.91(br s，1H)，5.72(br d，J＝1.0Hz，1H)，3.92(br s，2H)，3.29-3.26(m，2H)，2.41(s，3H)，2.19(s，3H)，1.91(br s，2H)，1.38(s，9H).

Step three: synthesis of 5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-6- (1, 2,3, 6-tetrahydropyridin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

Tert-butyl 4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (155 mg, 291. Mu. Mol) was dissolved in 2mL of dichloromethane, 1m L trifluoroacetic acid was added, stirring was carried out at 20 ℃ for 2 hours, LCMS detection was completed, saturated sodium bicarbonate solution was added to adjust pH to 7, extraction, drying and spin-drying were carried out to give 5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-6- (1, 2,3, 6-tetrahydropyridin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (150 mg, yield 69.1%).

LCMS：m/z 432.3[M+H] ⁺ .

Step four: synthesis of 1- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3, 6-dihydropyridin-1 (2H) -yl) prop-2-en-1-one

5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-6- (1, 2,3, 6-tetrahydropyridin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (150 mg, 347. Mu. Mol) was dissolved in 3mL of tetrahydrofuran, acryloyl chloride (25.17 mg, 278. Mu. Mol) was added at 0deg.C, stirring was carried out at 0deg.C for 1 hour, the reaction was terminated by LCMS detection, and 1- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3, 6-dihydropyridin-1 (2H) -yl) prop-2-en-1-one (23.5 mg, yield 13.9%) was concentrated and obtained by preparative HPLC.

LCMS：m/z 486.2[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.50(d，J＝5.0Hz，1H)，8.20(s，1H)，7.59(br d，J＝10.8Hz，1H)，7.52(t，J＝8.6Hz，1H)，7.33(br d，J＝8.4Hz，1H)，7.21(d，J＝5.0Hz，1H)，6.84-6.66(m，1H)，6.09(br d，J＝17.0Hz，1H)，5.93(br d，J＝13.8Hz，1H)，5.72-5.59(m，3H)，4.24-4.04(m，2H)，3.54-3.48(m，2H)，2.40(s，3H)，2.19(s，3H)，1.98(br s，2H).

Example 56:

the synthetic route is as follows:

step one: synthesis of tert-butyl [4- (4-amino-7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) cyclohexen-3-en-1-yl ] carbamate

6, 7-dibromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (250 mg,1.00 eq), potassium phosphate (214 mg,2.00 eq), 4-amino-1-cyclohexene-1-boronic acid pinacol ester-4-methylpyrimidinecarboxylic acid tert-butyl ester (165 mg,0.90 eq) and tetrakis triphenylphosphine palladium (80.7 mg,0.15 eq) were dissolved in 3mL dioxane and 2mL water. Stirred at 100℃for 2 hours. After completion of LCMS detection, tert-butyl [4- (4-amino-7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) cyclohexen-3-en-1-yl ] carbamate (500 mg, yield 53.9%) was obtained as a yellow solid by column chromatography purification.

LCMS：m/z 610.2[M+1] ⁺ ，612.2[M+3] ⁺ .

Step two: synthesis of tert-butyl [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) cyclohexen-3-en-1-yl ] carbamate

Tert-butyl [4- (4-amino-7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) cyclohexen-3-en-1-yl ] carbamate (450 mg,1.00 eq), cesium carbonate (480 mg,2.00 eq), methylboronic acid (441 mg,10.0 eq) and (2-dicyclohexylphosphine-2, 4, 6-triisopropyl-1, 1-biphenyl) [2- (2-amino-1, 1-biphenyl ] methanesulfonic acid palladium (187 mg,0.3 eq) were dissolved in 9mL dioxane and 3mL water and stirred at 120℃for 3 hours after completion of the LCMS detection reaction, yellow solid [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [2- (2-amino-1, 1-biphenyl) 2-tri-n-yl ] methane sulfonate was purified by a reverse phase column to give (16.1 mg, 1-d ] cyclohex-1-enyl ] carbamate as a yield of 100.16 mg.

LCMS：m/z 546.3.[M+H] ⁺ .

Step three: synthesis of 6- (4-aminocyclohexatrien-1-en-1-yl) -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine

Tert-butyl [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) cyclohexen-3-en-1-yl ] carbamate (100 mg,1.00 eq) was dissolved in 2.0mL of methanol. Methanol hydrochloride (4M, 1.8 mL) was added at 0deg.C for an hour. After completion of LCMS detection, the extraction was adjusted and concentrated to give 6- (4-aminocyclohex-1-en-1-yl) -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (80 mg, yield 97.8%) as a yellow solid.

LCMS：m/z 446.0.[M+H] ⁺ .

Step four: synthesis of N- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) cyclohexen-3-en-1-yl ] prop-2-enamide

/>

6- (4-aminocyclohexatrien-1-en-1-yl) -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (80 mg,1.00 eq) was dissolved in 2mL of tetrahydrofuran, and acryloyl chloride (16.6 mg,1.00 eq) was slowly added at 0℃and reacted at 20℃for 2 hours. LCMS detects the end of the reaction. Purification by reverse phase column gave N- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) cyclohexen-3-en-1-yl ] prop-2-enamide as a white solid (13.3 mg, 16.6% yield).

LCMS：m/z 500.0[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ8.51(d，J＝5.0Hz，1H)，8.19(s，1H)，8.01(d，J＝7.6Hz，1H)，7.61-7.46(m，2H)，7.35-7.28(m，1H)，7.22(d，J＝5.1Hz，1H)，6.23-6.14(m，1H)，6.09-6.01(m，1H)，5.80(br s，1H)，5.68-5.51(m，3H)，3.90-3.73(m，1H)，2.39(s，3H)，2.35(br d，J＝18.6Hz，1H)，2.18(s，3H)，2.07-1.90(m，3H)，1.79-1.67(m，1H)，1.38(br dd，J＝6.1，9.4Hz，1H).

Example 57:

n- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) cyclohexen-3-en-1-yl ] -4- (dimethylamino) but-2-enamide:

the synthetic route is as follows:

step one: synthesis of N- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) cyclohexen-3-en-1-yl ] -4- (dimethylamino) but-2-enamide

6- (4-aminocyclohexatrien-1-en-1-yl) -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (25.0 mg,1.00 eq), 4- (dimethylamino) but-2-enoic acid (8.70 mg,1.20 eq), O- (7-azabenzotriazol-1-yl) -N, N, N, N-tetramethylurea hexafluorophosphine salt (32.0 mg,1.50 eq) was dissolved in 2mL of tetrahydrofuran, and N, N-diisopropylethylamine (21.7 mg,3.00 eq) was slowly added at 0℃and reacted at 20℃for 1 hour. LCMS detects the end of the reaction. Purification by reverse phase column gave N- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) cyclohexen-3-en-1-yl ] -4- (dimethylamino) but-2-enamide as a white solid (11.3 mg, yield 34.9%).

LCMS：m/z 557.1[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ8.51(d，J＝5.0Hz，1H)，8.19(s，1H)，7.87(d，J＝7.4Hz，1H)，7.60-7.48(m，2H)，7.31(d，J＝7.5Hz，1H)，7.21(d，J＝5.0Hz，1H)，6.51(td，J＝6.1，15.4Hz，1H)，6.00(d，J＝15.5Hz，1H)，5.83-5.58(m，3H)，3.85-3.72(m，1H)，2.94(d，J＝5.9Hz，2H)，2.40(s，3H)，2.37-2.31(m，1H)，2.18(s，3H)，2.12(s，6H)，2.05-1.91(m，3H)，1.78-1.66(m，1H)，1.45-1.33(m，1H).

Example 58:

1- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methylpyrrolio [3,2-d ] pyrimidin-6-yl) -3-methyl-1, 2,3, 6-tetrahydropyridin-1-yl ] prop-2-en-1-one:

the synthetic route is as follows:

step one: synthesis of 3-methyl-4- (trifluoromethanesulfonyl) -1,2,3, 6-tetrahydropyridine-1-carboxylic acid tert-butyl ester

3-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester (5.00 g,23.4 mmol) was dissolved in tetrahydrofuran (100 mL) and lithium bis (trimethylsilyl) amide (1.00M, 28.1 mL) was added at-78deg.C. N-phenyl bis (trifluoromethanesulfonyl) imide (10.1 g,28.1 mmol) in tetrahydrofuran (50 mL) was added and reacted at-78deg.C for 1.5 hours, half an hour and at 20℃for 2 hours. LCMS detects the end of the reaction. The reaction mixture was poured into ice water to be extracted, ethyl acetate was used for extraction, and after drying and concentration of the organic phase, 3-methyl-4- (trifluoromethanesulfonyl) -1,2,3, 6-tetrahydropyridine-1-carboxylic acid tert-butyl ester was obtained by purification by preparative HPLC (2.80 g, yield 34.6%).

¹ H NMR(400MHz，CHLOROFORM-d)δ＝5.73(s，1H)，4.32-3.85(m，2H)，3.77-3.25(m，2H)，2.60(s，1H)，1.50(s，9H)，1.15(br d，J＝6.8Hz，3H).

Step two: synthesis of 3-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,2,3, 6-tetrahydropyridine-1-carboxylic acid tert-butyl ester

3-methyl-4- (trifluoromethanesulfonyl) -1,2,3, 6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (2.80 g,8.11 mmol), potassium acetate (2.39 g,24.3 mmol), 1-bis (diphenylphosphorus) ferrocene (134 mg, 243. Mu. Mol) and 1, 1-bis (diphenylphosphorus) ferrocene palladium chloride (198mg, 243. Mu. Mol) were dissolved in dioxane (15.0 mL), and bis pinacolato borate (1.96 g,7.70 mmol) was added. The reaction was added at 90℃for 2 hours under nitrogen protection and the reaction was checked for completion by LCMS. The reaction solution was concentrated and purified by column chromatography to give tert-butyl 3-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,2,3, 6-tetrahydropyridine-1-carboxylate (1.70 g, yield 64.8%).

LCMS：m/z 268.1[M+H-56] ⁺ .

¹ H NMR(400MHz，CHLOROFORM-d)δ＝6.34(s，1H)，4.10-4.04(m，1H)，3.67(br d，J＝19.6Hz，1H)，3.51-3.47(m，1H)，3.10-3.05(m，1H)，2.39(s，1H)，1.39(s，9H)，1.39(s，12H)，0.96(br d，J＝7.2Hz，3H).

Step three: synthesis of 2-methylpropan-2-yl 4- (4-amino-7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } pyrrolo [3,2-d ] pyrimidin-6-yl) -3-methyl-1, 2,3, 6-tetrahydropyridine-1-carboxylate

6, 7-dibromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } pyrrolo [3,2-d ] pyrimidin-4-amine (620 mg,1.25 mmol) was dissolved in dioxane (18.0 mL) and water (12.0 mL), 3-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,2,3, 6-tetrahydropyridine-1-carboxylic acid-2-methylpropan-2-yl ester (324 mg,1.00 mmol), potassium phosphate (552 mg,2.51 mmol) and tetrakis triphenylphosphine palladium (724 mg, 627. Mu. Mol) were added, and the mixture was reacted at 100℃for 2 hours under nitrogen. After completion of LCMS detection, the reaction mixture was concentrated and purified by column chromatography to give 4- (4-amino-7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } pyrrolo [3,2-d ] pyrimidin-6-yl) -3-methyl-1, 2,3, 6-tetrahydropyridine-1-carboxylic acid-2-methylpropan-2-yl ester (500 mg, yield 65.3%).

LCMS：m/z 610.0[M+1] ⁺ ，612.0[M+3] ⁺ .

Step four: synthesis of 2-methylpropan-2-yl 4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methylpyrrolio [3,2-d ] pyrimidin-6-yl) -3-methyl-1, 2,3, 6-tetrahydropyridine-1-carboxylate

4- (4-amino-7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } pyrrolo [3,2-d ] pyrimidin-6-yl) -3-methyl-1, 2,3, 6-tetrahydropyridin-1-carboxylic acid 2-methylpropan-2-yl ester (500 mg, 819. Mu. Mol) was dissolved in dioxane (5.00 mL) and methylboronic acid (475 mg,7.94 mmol), (2-dicyclohexylphosphine-2, 4, 6-triisopropyl-1, 1-biphenyl) [2- (2-amino-1, 1-biphenyl ] methanesulfonic acid palladium (138 mg, 163. Mu. Mol) and cesium carbonate (533 mg,1.64 mmol) were added, and the reaction was performed under nitrogen for 2 hours at 120℃to give 4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methylpyrimidin-2, 1-yl) 2-methyl-1-biphenyl ] methanesulfonic acid palladium (138 mg, 163. Mu. Mol) and cesium carbonate (533 mg,1.64 mmol) after drying by silica gel column purification, 4- (4-amino-5- { 3-fluoro-4-2-methyl-oxy) phenyl } -7-methylpyrimidin-2-yl) 2-methyl-1-4-yl ] methanesulfonate was obtained.

LCMS：m/z 546.4[M+H] ⁺ .

Step five: synthesis of 5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-6- (3-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) pyrrolo [3,2-d ] pyrimidin-4-amine

4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methylpyrrolo [3,2-d ] pyrimidin-6-yl) -3-methyl-1, 2,3, 6-tetrahydropyridine-1-carboxylic acid 2-methylpropan-2-yl ester (70.0 mg, 128. Mu. Mol) was dissolved in dioxane hydrochloride (4.00M, 3.50 mL). The reaction was stirred at 20℃for 0.5 h and was checked for completion by LCMS. Spin-drying gives 5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-6- (3-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) pyrrolo [3,2-d ] pyrimidin-4-amine (50.0 mg, crude).

LCMS：m/z 446.0[M+H] ⁺ .

Step six: synthesis of 1- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methylpyrrolio [3,2-d ] pyrimidin-6-yl) -3-methyl-1, 2,3, 6-tetrahydropyridin-1-yl ] prop-2-en-1-one

5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-6- (3-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) pyrrolo [3,2-d ] pyrimidin-4-amine (50 mg, 112. Mu. Mol) was dissolved in tetrahydrofuran (1.00 mL), and acryloyl chloride (6.09 mg, 67.3. Mu. Mol) was added at 0 ℃. The reaction was carried out at 20℃for 1 hour, and the completion of the reaction was detected by LCMS. The reaction solution was concentrated and purified by preparative HPLC to give 1- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methylpyrrolio [3,2-d ] pyrimidin-6-yl) -3-methyl-1, 2,3, 6-tetrahydropyridin-1-yl ] prop-2-en-1-one (8.60 mg, yield 15.3%).

LCMS：m/z 500.6[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.73-8.36(m，1H)，8.21(br s，1H)，7.73-7.10(m，4H)，6.96-6.59(m，1H)，6.25-6.04(m，1H)，6.02-5.87(m，1H)，5.78-5.44(m，3H)，4.45-4.21(m，1H)，4.17-3.85(m，1H)，3.64-3.52(m，2H)，2.39(br s，3H)，2.16(br s，3H)，1.92(br s，1H)，0.75(br s，3H).

Example 59:

1- (3- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -2, 5-dihydro-1H-pyrrol-1-yl) prop-2-en-1-one:

the synthetic route is as follows:

step one: synthesis of tert-butyl 4- (4-amino-7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylate

6, 7-dibromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (700 mg,1.42 mmol) was dissolved in 15mL dioxane, 1-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-boronic acid pinacol ester (426 mg,1.45 mmol), potassium phosphate (601 mg,2.83 mmol), tetrakis (triphenylphosphine) palladium (812 mg, 708. Mu. Mol) and 10mL water were added, and after completion of the LCMS detection reaction, concentrated and column chromatography afforded 4- (4-amino-7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (420 mg, 36.6%) in a yield of 36.6%.

LCMS：m/z 582.0[M+1] ⁺ ，584.0[M+3] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.52(d，J＝5.0Hz，1H)，8.33-8.22(m，1H)，7.88-7.77(m，1H)，7.63-7.58(m，1H)，7.56-7.50(m，1H)，7.24(br d，J＝4.6Hz，1H)，6.14-6.03(m，1H)，6.02-5.55(m，2H)，4.10(br s，4H)，2.42(br d，J＝5.3Hz，3H)，1.39(br d，J＝7.8Hz，9H).

Step two: synthesis of tert-butyl 4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylate

4- (4-amino-7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (370 mg, 635. Mu. Mol) was dissolved in 6mL dioxane, methyl boric acid (68.8 mg,6.16 mmol), cesium carbonate (413 mg,1.27 mmol) and methanesulfonic acid (2-dicyclohexylphosphine-2 ',4',6' -triisopropyl-1, 1' -biphenyl) (2 ' -amino-1, 1' -biphenyl-2-yl) palladium (II) (268 mg, 317. Mu. Mol), after completion of the S detection reaction, the crude product was concentrated and column chromatographed to give 4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [ 2-yl) palladium (2, 8 ',6' -triisopropyl-1, 1' -biphenyl-2-yl) 2, tert-butyl ester, yield of 4- (4-amino-5- (3-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-pyrrol-2-yl ] 2, 1-H-yl by preparative HPLC.

LCMS：m/z 518.6[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.51(d，J＝4.9Hz，1H)，8.21(s，1H)，7.75-7.66(m，1H)，7.58(dt，J＝3.6，8.5Hz，1H)，7.42(br t，J＝7.6Hz，1H)，7.23(t，J＝4.6Hz，1H)，5.94(br d，J＝16.1Hz，1H)，5.83-5.37(m，2H)，4.11(br s，2H)，3.89(br s，2H)，2.42(br d，J＝7.4Hz，3H)，2.28(br d，J＝2.9Hz，3H)，1.37(d，J＝14.5Hz，9H).

Step three: synthesis of 6- (4, 5-dihydro-1H-pyrrol-3-yl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine

4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -2, 3-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (100 mg, 193. Mu. Mol) was dissolved in 5mL of dichloromethane, 2mL of trifluoroacetic acid was added, after completion of the reaction at 20℃for 1 hour, the pH was adjusted to 7 with saturated aqueous sodium bicarbonate solution after completion of the reaction, and extracted and concentrated to give 6- (4, 5-dihydro-1H-pyrrol-3-yl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (80.0 mg, yield 90.2%).

LCMS：m/z 418.3[M+H] ⁺ .

Step four: synthesis of 1- (3- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -2, 5-dihydro-1H-pyrrol-1-yl) prop-2-en-1-one

6- (4, 5-dihydro-1H-pyrrol-3-yl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (80.0 mg, 191.65. Mu. Mol) was dissolved in 8mL tetrahydrofuran, and acryloyl chloride (17.3 mg,191. Mu. Mol) was added, reacted at 0℃for 1 hour, and the LCMS detection reaction ended, concentrated and purified by preparative HPLC to give 1- (3- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -2, 5-dihydro-1H-pyrrol-1-yl) prop-2-en-1-one (35.0 mg, yield 37.9%).

LCMS：m/z 472.3[M+H] ⁺ .

¹ H NMRlH NMR(400MHz，DMSO-d6)δ＝8.48(dd，J＝5.0，18.5Hz，1H)，8.27-8.16(m，1H)，7.75-7.65(m，1H)，7.62-7.52(m，1H)，7.47-7.37(m，1H)，7.21(br d，J＝4.9Hz，1H)，6.58-6.37(m，1H)，6.15(ddd，J＝2.1，4.8，16.8Hz，1H)，5.99(br d，J＝11.1Hz，1H)，5.76-5.57(m，3H)，4.48(br s，1H)，4.25(br d，J＝6.0Hz，2H)，4.02(br s，1H)，2.44-2.36(m，3H)，2.30(br d，J＝2.6Hz，3H).

Example 60:

1- [ (1 r,5 s) -6- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-azabicyclo [3.1.0] hex-3-yl ] prop-2-enamide:

the synthetic route is as follows:

step one: synthesis of 2- (diiodomethyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolane

2- (Dichloromethyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolane (1.78 g,1.00 eq) sodium iodide (3.16 g,2.50 eq) was dissolved in 10mL acetonitrile. Stirred at 55℃for 72 hours. After LCMS detection reaction was completed, 2- (diiodomethyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan was purified by column chromatography to give a yellow solid. (2.40 g, yield 72.2%)

¹ H NMR(400MHz，CHLOROFORM-d)δ＝4.31(s，1H)，1.31(s，12H).

Step two: synthesis of (1R, 5S) -6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester

Tetramethyl ethylenediamine (3.85 g,8.00 eq) and chromium chloride (4.07 g,8.00 eq) were dissolved in 70mL tetrahydrofuran. Stirred at 20℃for 0.5 h. Then, tert-butyl N-2, 5-dihydro-1H-pyrrole-1-carboxylate (700 mg,1.00 eq) was dissolved in 27mL of tetrahydrofuran, slowly added to the reaction flask, and finally, 2- (diiodomethyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (2.44 g,1.50 eq) was dissolved in 27mL of tetrahydrofuran, and slowly added to the reaction flask. After LCMS detection reaction was completed, white solid (1 r,5 s) -6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester was obtained by purification by column chromatography. (725 mg, yield 56.6%).

¹ H NMR(400MHz，CHLOROFORM-d)δ3.66-3.41(m，2H)，3.33-3.19(m，2H)，1.59-1.48(m，2H)，1.35(s，9H)，1.15(s，12H)，-0.35(t，J＝4.4Hz，1H).

Step three: synthesis of tert-butyl (1R, 5S) -6- (4-amino-7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-azabicyclo [3.1.0] hexane-3-carboxylate

Potassium phosphate (214 mg,2.00 eq), (1R, 5S) -6- (4, 5-tetramethyl-1, 3-dioxaborolan-2-yl) -3-azabicyclo [3.1.0] hexane-3-carboxylate (436mg, 2.90 eq) and tetrakis triphenylphosphine palladium (224 mg,0.4 eq) were dissolved in 1mL dioxane and 0.3 mL water. Stirred at 100℃for 2 hours. After completion of LCMS detection reaction, purified by column chromatography to give (1 r,5 s) -6- (4-amino-7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester as a yellow solid (200 mg, yield 29.6%).

LCMS：m/z 595.8[M+1] ⁺ ，597.8[M+3] ⁺ .

Step four: synthesis of tert-butyl (1R, 5S) -6- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-azabicyclo [3.1.0] hexane-3-carboxylate

(1R, 5S) -6- (4-amino-7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester (200 mg,1.00 eq), methylboronic acid (200 mg,10.0 eq) cesium carbonate (219 mg,2.00 eq) and (2-dicyclohexylphosphine-2, 4, 6-triisopropyl-1, 1-biphenyl) [2- (2-amino-1, 1-biphenyl ] methanesulfonic acid palladium (84 mg,0.3 eq) in 9mL dioxane and 3mL water were stirred at 100℃for 1 hour, and after completion of the LCMS detection reaction, the crude product of (1R, 5S) -6- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-pyrrolo [ 3-d ] pyrrole ] 3-carboxylic acid was purified by column chromatography to give a yellow solid (1R, 5S) -6- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl ] methanesulfonic acid.

LCMS：m/z 531.9[M+H] ⁺ .

Step five: synthesis of 6- [ (1R, 5S) -3-azabicyclo [3.1.0] hexane-6-yl ] -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine

(1R, 5S) -6- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester (80 mg,1.00 eq) was dissolved in 2.0mL of methanol. Methanol hydrochloride (4M, 1.8 mL) was added at 0deg.C for an hour. After completion of LCMS detection reaction, the concentrate was give 6- [ (1 r,5 s) -3-azabicyclo [3.1.0] hexane-6-yl ] -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (64 mg, crude) as a yellow solid.

LCMS：m/z 432.1[M+H] ⁺ .

Step six: synthesis of 1- [ (1R, 5S) -6- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-azabicyclo [3.1.0] hexane-3-yl ] prop-2-enamide

6- [ (1R, 5S) -3-azabicyclo [3.1.0] hexane-6-yl ] -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (64 mg,1.00 eq) was dissolved in 2mL of tetrahydrofuran, and acryloyl chloride (12.5 mg,1.00 eq) was slowly added at 0deg.C and reacted at 20deg.C for 2 hours. LCMS detects the end of the reaction. Purification by reverse phase column and normal phase purification gave 1- [ (1R, 5S) -6- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-azabicyclo [3.1.0] hex-3-yl ] prop-2-enamide as a white solid (15.3 mg, 99.3% yield).

LCMS：m/z 485.9[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ8.56(d，J＝4.9Hz，1H)，8.17(s，1H)，7.71(d，J＝11.0Hz，1H)，7.56(t，J＝8.6Hz，1H)，7.36(d，J＝8.6Hz，1H)，7.24(d，J＝5.1Hz，1H)，6.46(dd，J＝10.3，16.6Hz，1H)，6.09(dd，J＝2.3，16.8Hz，1H),5.77-5.45(m，3H)，3.77-3.67(m，1H)，3.66-3.59(m，1H)，3.53(d，J＝12.4Hz，1H)，3.27(s，1H)，2.47(s，3H)，2.25(s，3H)，2.00-1.89(m，1H)，1.64-1.63(m，2H).

Example 61:

1- [3- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) piperidin-1-yl ] prop-2-enamide:

the synthetic route is as follows:

step one: synthesis of tert-butyl 5- (4-amino-7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -1,2,3, 6-tetrahydropyridine-1-carboxylate

6, 7-dibromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (800 mg,1.00 eq), potassium phosphate (687 mg,2.00 eq), tert-butyl 5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (500 mg,1.00 eq) and tetrakis triphenylphosphine palladium (467 mg,0.25 eq) were dissolved in 5.0mL dioxane and 2.0 mL water. Stirred at 100℃for 2 hours. After completion of LCMS detection, 5- (4-amino-7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -1,2,3, 6-tetrahydropyridine-1-carboxylic acid tert-butyl ester was purified by column chromatography as a yellow solid (1.00 g, yield 67.3%).

LCMS：m/z 595.7[M+1] ⁺ ，597.6[M+3] ⁺ .

Step two: synthesis of tert-butyl 3- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) piperidine-1-carboxylate

5- (4-amino-7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -1,2,3, 6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (600 mg,1.00 eq) and wet palladium on carbon (214 mg,0.60 eq) were dissolved in 3mL of methanol. Stirred at 80℃and hydrogen (50 psi) for 12 hours. After completion of LCMS detection, the reaction was concentrated to give tert-butyl 3- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) piperidine-1-carboxylate as a yellow solid (400 mg, yield 76.5%).

LCMS：m/z 519.9.[M+H] ⁺ .

Step three: synthesis of tert-butyl 3- (4-amino-7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) piperidine-1-carboxylate

Tert-butyl [4- (4-amino-7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) cyclohexen-3-en-1-yl ] carbamate (340 mg,1.00 eq) was dissolved in 5mL acetonitrile. N-bromosuccinimide (151 mg,1.30 eq) was slowly added at 0deg.C, followed by stirring at 20deg.C for 1 hour. After completion of LCMS detection, water and ethyl acetate were added to extract, and the organic phase was concentrated to give 3- (4-amino-7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) piperidine-1-carboxylic acid tert-butyl ester (400 mg, crude product) as a yellow solid.

LCMS：m/z 597.9.[M+1] ⁺ ，599.9.[M+3] ⁺ .

Step four: synthesis of tert-butyl 3- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) piperidine-1-carboxylate

3- (4-amino-7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) piperidine-1-carboxylic acid tert-butyl ester (400 mg,1.00 eq), cesium carbonate (404 mg,2.00 eq), methylboronic acid (400 mg,10.0 eq) and (2-dicyclohexylphosphino-2, 4, 6-triisopropyl-1, 1-biphenyl) [2- (2-amino-1, 1-biphenyl ] methanesulfonic acid palladium (168 mg,0.3 eq) were dissolved in 6mL dioxane and 2mL water after 3 hours at 120 ℃ after completion of the S detection reaction, 3- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) piperidine-1-carboxylic acid was purified by reverse phase column as a yellow solid (60 mg, 16.6%).

LCMS：m/z 533.9.[M+H] ⁺ .

Step five: synthesis of 5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-6- (piperidin-3-yl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

3- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) piperidine-1-carboxylic acid tert-butyl ester (60 mg,1.00 eq) was dissolved in 2.0mL of methanol. Methanol hydrochloride (4M, 1.8 mL) was added at 0deg.C for an hour. After completion of LCMS detection, concentration gave 5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-6- (piperidin-3-yl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (40 mg, yield 82.0%) as a yellow solid.

LCMS：m/z 433.8.[M+H] ⁺ .

Step six: synthesis of 1- [3- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) piperidin-1-yl ] prop-2-enamide

5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-6- (piperidin-3-yl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (40 mg,1.00 eq) was dissolved in 2mL of tetrahydrofuran, and acryloyl chloride (16.6 mg,1.00 eq) was slowly added at 0deg.C and reacted at 20deg.C for 2 hours. LCMS detects the end of the reaction. Purification by reverse phase column gave 1- [3- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) piperidin-1-yl ] prop-2-enamide as a white solid (12.2 mg, yield 26.8%).

LCMS：m/z 488.3[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ＝8.50(br s，1H)，8.17(s，1H)，7.90-7.39(m，3H)，7.23(d，J＝5.0Hz，1H)，6.85-6.53(m，1H)，6.10-5.91(m，1H)，5.70-5.50(m，1H)，5.48-5.29(m，2H)，4.58-4.37(m，1H)，4.21-3.98(m，1H)，3.43-3.37(m，1H)，3.13-2.90(m，1H)，2.76-2.58(m，1H)，2.40(s，3H)，2.38(s，3H)，2.18-2.04(m，1H)，1.97-1.90(m，1H)，1.79-1.69(m，1H)，1.28-1.16(m，1H).

Example 62:

1- [3- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -8-azabicyclo [3.2.1] oct-2-en-8-yl ] prop-2-enamide:

the synthetic route is as follows:

step one: synthesis of tert-butyl 3- (4-amino-7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -8-azabicyclo [3.2.1] oct-2-ene-8-carboxylate

6, 7-dibromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (600 mg,1.00 eq), potassium phosphate (514 mg,2.00 eq), 4-Boc-amino-1-cyclohexene-1-boronic acid pinacol ester-4-methylpyrimidine (406 mg,1.00 eq) and tetrakis triphenylphosphine palladium (420 mg,0.15 eq) were dissolved in 12mL dioxane and 6mL water. Stirred at 100℃for 2 hours. After completion of LCMS detection, 3- (4-amino-7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -8-azabicyclo [3.2.1] oct-2-ene-8-carboxylic acid tert-butyl ester was purified by column chromatography to give a yellow solid (750 mg, yield 55.5%).

LCMS：m/z 621.8[M+1] ⁺ ，623.8[M+3] ⁺ .

Step two: synthesis of tert-butyl 3- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -8-azabicyclo [3.2.1] oct-2-ene-8-carboxylate

Tert-butyl [4- (4-amino-7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) cyclohexen-3-en-1-yl ] carbamate (400 mg,1.00 eq), cesium carbonate (418 mg,2.00 eq), methylboronic acid (284 mg,10.0 eq) and (2-dicyclohexylphosphine-2, 4, 6-triisopropyl-1, 1-biphenyl) [2- (2-amino-1, 1-biphenyl ] methanesulfonic acid palladium (185 mg,0.3 eq) were dissolved in 6mL dioxane and 2mL water after stirring for 1 hour at 100℃LCMS detection, the resulting yellow solid 3- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidine-2, 6-yl) was purified by a reverse phase column to give (260 mg, 1-dioxan-1, 2-yl) and (2.3 mg, 0-eq) was obtained.

LCMS：m/z 558.1.[M+H] ⁺ .

Step three: synthesis of 6- { 8-azabicyclo [3.2.1] oct-2-en-3-yl } -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine

3- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -8-azabicyclo [3.2.1] oct-2-ene-8-carboxylic acid tert-butyl ester (200 mg,1.00 eq) was dissolved in 5.0mL of methanol. Methanol hydrochloride (4M, 1.8 mL) was added at 0deg.C for an hour. After completion of LCMS detection, 6- { 8-azabicyclo [3.2.1] oct-2-en-3-yl } -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (60 mg, yield 97.8%) was obtained as a yellow solid by reverse phase column purification.

LCMS：m/z 458.0.[M+H] ⁺ .

Step four: synthesis of 1- [3- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -8-azabicyclo [3.2.1] oct-2-en-8-yl ] prop-2-enamide

6- { 8-azabicyclo [3.2.1] oct-2-en-3-yl } -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (30 mg,1.00 eq) was dissolved in 2mL of tetrahydrofuran, and acryloyl chloride (5.93 mg,1.00 eq) was slowly added at 0deg.C and reacted at 20deg.C for 2 hours. LCMS detects the end of the reaction. Purification by reverse phase column gave 1- [3- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -8-azabicyclo [3.2.1] oct-2-en-8-yl ] prop-2-enamide as a white solid (13.4 mg, 39.3% yield).

LCMS：m/z 512.1[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ＝8.49(d，J＝5.0Hz，1H)，8.18(s，1H)，7.65-7.45(m，2H)，7.33(br d，J＝8.5Hz，1H)，7.22(d，J＝5.0Hz，1H)，6.69(dd，J＝10.4，16.6Hz，1H)，6.22-6.10(m，2H)，5.69-5.57(m，3H)，4.73(br s，1H)，4.52(br s，1H)，2.73-2.58(m，1H)，2.43(s，3H)，2.06(d，J＝4.4Hz，3H)，2.01-1.60(m，4H)，1.44-1.23(m，1H).

Example 63:

n- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -2- ((dimethylamino) methyl) phenyl) acrylamide:

the synthetic route is as follows:

step one: synthesis of 6- (4-amino-3- ((dimethylamino) methyl) phenyl) -7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6, 7-dibromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (450 mg, 910. Mu. Mol) was dissolved in 15mL of dioxane and 10mL of water, 2- ((dimethylamino) methyl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (450 mg,1.63 mmol), potassium phosphate (383 mg,1.82 mmol), tetrakis (triphenylphosphine) palladium (526 mg, 455. Mu. Mol), and after completion of LCMS detection reaction, concentrated and column chromatography gave 6- (4-amino-3- ((dimethylamino) methyl) phenyl) -7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (200 mg, yield, 31.5%).

LCMS：m/z 563.2[M+1] ⁺ ，565.2[M+3] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.47(d，J＝5.0Hz，1H)，8.26(s，1H)，7.61-7.58(m，1H)，7.44(s，1H)，7.32(dd，J＝1.6，8.6Hz，1H)，7.21(d，J＝5.1Hz，1H)，7.07(dd，J＝2.0，8.3Hz，1H)，6.92-6.84(m，1H)，6.63(d，J＝8.4Hz，1H)，5.75(s，4H)，3.29(br s，2H)，2.41(s，3H)，2.15-1.98(m，6H).

Step two: synthesis of 6- (4-amino-3- ((dimethylamino) methyl) phenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6- (4-amino-3- ((dimethylamino) methyl) phenyl) -7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (180 mg, 319. Mu. Mol) was dissolved in 9mL of dioxane, methyl boric acid (181 mg,3.04 mmol), cesium carbonate (208 mg, 638. Mu. Mol) and methanesulfonic acid (2-dicyclohexylphosphine-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (135 mg, 159. Mu. Mol) were added, after completion of the S detection reaction, concentrated and purified by preparative HPLC to give 6- (4-amino-3- ((dimethylamino) methyl) phenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-amine (35.0 mg, yield (21.0%).

LCMS：m/z 499.1[M+H] ⁺ .

Step three: synthesis of N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -2- ((dimethylamino) methyl) phenyl) acrylamide

6- (4-amino-3- ((dimethylamino) methyl) phenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (35.0 mg, 70.2. Mu. Mol) was dissolved in 9mL tetrahydrofuran, and acryloyl chloride (6.35 mg, 70.2. Mu. Mol) was added, reacted at 0deg.C for 1 hour, LCMS detected the end of the reaction, concentrated and purified by preparative HPLC to give N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -2- ((dimethylamino) methyl) phenyl) acrylamide (20.5 mg, yield 52.3%).

LCMS：m/z 553.3[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ＝10.78(br s，1H)，8.46(d，J＝5.0Hz，1H)，8.25(s，1H)，8.14(br d，J＝7.4Hz，1H)，7.50(dd，J＝2.3，10.8Hz，1H)，7.41(t，J＝8.6Hz，1H)，7.29(br d，J＝8.3Hz，1H)，7.26-7.18(m，2H)，7.08(br s，1H)，6.39-6.26(m，1H)，6.24-6.15(m，1H)，5.80(dd，J＝1.4，10.1Hz，1H)，5.63(br s，2H)，3.45(br s，2H)，2.39(s，3H)，2.22(s，3H)，2.12(br s，6H).

Example 64:

n- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-fluoro-5-methylphenyl ] acrylamide:

the synthetic route is as follows:

step one: synthesis of 2- (2-bromo-5-nitrophenyl) -1, 3-dioxolane

2-bromo-5-nitrobenzaldehyde (5.00 g,1.00 eq), p-toluenesulfonic acid (375 mg,0.1 eq), ethylene glycol (13.5 g,1.00 eq) were dissolved in 10mL toluene. Stirred at 110℃for 1 hour. After completion of LCMS detection, 2- (2-bromo-5-nitrophenyl) -1, 3-dioxolane (5.96 g, crude) was purified by column chromatography as a white solid.

LCMS：m/z 273.9[M+1] ⁺ ，273.9[M+3] ⁺ .

Step two: synthesis of 4-bromo-3- (oxetan-3-oxy) aniline

2- (2-bromo-5-nitrophenyl) -1, 3-dioxolane (5.96 g,1.00 eq), iron powder (6.07 g,5.00 eq), ammonium chloride (5.82 g,5.00 eq) were dissolved in 20mL ethanol, and 20mL water was added. Stirred at 80℃for 2 hours. After the TLC detection reaction was completed, it was filtered, concentrated and purified by column chromatography to give 4-bromo-3- (1, 3-dioxolan-2-yl) aniline as a yellow solid (4.70 g, yield 88.5%).

Step three: synthesis of 3- (1, 3-dioxolan-2-yl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline

Tert-butyl N- (4-bromo-3-fluoro-5-methylphenyl) aminomethyl ester (3.0 g,1.00 eq), potassium acetate (2.4 g,2.00 eq), bis-pinacolatoborate (2.96 g,0.95 eq) and palladium (2-amino-1, 1-biphenyl) methanesulfonate (2.7 g,0.20 eq) were dissolved in 30mL dioxane after completion of the LCMS detection reaction, and 3- (1, 3-dioxolan-2-yl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (3.40 g, crude product) was purified by column chromatography.

LCMS：m/z 292.0[M+H] ⁺ .

Step four: synthesis of 6- [ 4-amino-2- (1, 3-dioxolan-2-yl) phenyl ] -7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

3- (1, 3-Dioxapent-2-yl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (882 mg,2.00 eq), potassium phosphate (516 mg,2.00 eq), 6, 7-dibromo-5- { 3-fluoro-4- [ (4-methylpyridin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (600 mg,1.00 eq) and tetra-triphenylphosphine palladium (420 mg,0.20 eq) were dissolved in 6mL dioxane and 3mL water. Stirred at 100℃for 1 hour. After completion of LCMS detection reaction, 6- [ 4-amino-2- (1, 3-dioxolan-2-yl) phenyl ] -7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (530 mg, crude) was purified by column chromatography as a yellow solid.

LCMS：m/z 577.6[M+1] ⁺ ，579.6[M+3] ⁺ .

Step five: synthesis of 6- [ 4-amino-2- (1, 3-dioxolan-2-yl) phenyl ] -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6- [ 4-amino-2- (1, 3-dioxolan-2-yl) phenyl ] -7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (500 mg,1.00 eq), cesium carbonate (281.5 mg,2.00 eq), methylboronic acid (515 mg,10.0 eq) and (2-dicyclohexyl-2, 4, 6-triisopropyl-1, 1-biphenyl) [2- (2-amino-1, 1-biphenyl ] methanesulfonic acid palladium (147 mg,0.2 eq) were dissolved in 15mL dioxane and 5mL water after completion of the LCMS detection reaction, 6- [ 4-amino-2- (1, 3-dioxolan-2-yl) phenyl ] -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-d ] pyrrole was purified by reverse phase column to give yellow solid (83 mg, 5.2 eq) and yield of [2- (2-amino-1, 1-biphenyl ] methanesulfonic acid palladium (147 mg,0.2 eq) in water at 110 ℃ for 3 hours.

LCMS：m/z 513.9.[M+H] ⁺ .

Step six: synthesis of 6- (4-amino-2-fluoro-6-methylphenyl) -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6- [ 4-amino-2- (1, 3-dioxolan-2-yl) phenyl ] -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (200 mg,1.00 eq) was dissolved in 2mL tetrahydrofuran. Hydrochloric acid (142 mg,5.00 eq) was slowly added at 0deg.C. Stirred at 20℃for 10 hours. After completion of LCMS detection reaction, 6- (4-amino-2-fluoro-6-methylphenyl) -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (300 mg, crude product) was obtained as a white solid by column chromatography purification.

LCMS：m/z 470.0.[M+H] ⁺ .

Step seven: synthesis of 6- { 4-amino-2- [ (dimethylamino) methyl ] phenyl } -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6- (4-amino-2-fluoro-6-methylphenyl) -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (200 mg,1.00 eq), dimethylamine hydrochloride (347 mg,10 eq) were dissolved in 2mL of methanol, acetic acid (76.7 mg,3.00 eq), sodium acetate (174 mg,5.00 eq), sodium cyanoborohydride (53.5 mg,2.00 eq) were added. Stirred at 20℃for 10 hours. After completion of TLC detection the reaction was purified by HPLC (column: xtime C18 150*40mm*10um;mobile phase: [ water (NH 4HCO 3) -ACN ]; gradient:4% -44% B over 32 min) to give 6- { 4-amino-2- [ (dimethylamino) methyl ] phenyl } -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine as a white solid (200 mg, white solid).

LCMS：m/z 499.0[M+H] ⁺ .

Step eight: synthesis of N- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-fluoro-5-methylphenyl ] acrylamide

66- { 4-amino-2- [ (dimethylamino) methyl ] phenyl } -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (80 mg,1.00 eq) was dissolved in 2mL of tetrahydrofuran, and acryloyl chloride (14.1 mg,1.00 eq) was slowly added at 0deg.C and reacted at 20deg.C for 2 hours. LCMS detects the end of the reaction. Purification by reverse phase column gave N- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-fluoro-5-methylphenyl ] acrylamide as a white solid (13.5 mg, yield 24.3%).

LCMS：m/z 553.0[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ＝10.4(s，1H)，8.46(d，J＝5.0Hz，1H)，8.30(s，1H)，7.83-7.03(m，7H)，6.57-6.39(m，1H)，6.33-6.20(m，1H)，6.02-5.60(m，3H)，3.44(br s，2H)，2.50-2.49(m，3H)，2.35(s，3H)，2.15-1.96(s，6H).

Example 65:

n- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3- (hydroxymethyl) phenyl ] acrylamide:

the synthetic route is as follows:

step one: synthesis of methyl 5-amino-2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate

Methyl 2-bromo-5-aminobenzoate (2.00 g,1.00 eq), potassium acetate (1.77 g,2.00 eq), bis-pinacolatoborate (8.87 g,1.30 eq) [1, 1-bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane (1.04 g,0.20 eq) were dissolved in 30mL dioxane. Stirred at 90℃for 1 hour. After completion of LCMS detection reaction, 5-amino-2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoic acid methyl ester (1.50 g, yield 62.2%) was obtained as a yellow solid by column chromatography purification.

LCMS：m/z 278.1[M+H] ⁺ .

1H NMR(400MHz，DMSO-d6)δ7.18(d，J＝8.0Hz，1H)，6.95(d，J＝2.0Hz，1H)，6.69(dd，J＝2.1，8.0Hz，1H)，5.56(s，2H)，3.76(s，3H)，1.26(s，12H).

Step two: synthesis of methyl 5-amino-2- (4-amino-7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) benzoate

6, 7-dibromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (800 mg,1.00 eq), potassium phosphate (684 mg,2.00 eq), methyl 5-amino-2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate (1.1 g,1.00 eq) and palladium tetraphenylphosphine (560 mg,0.30 eq) were dissolved in 16mL dioxane and 4mL water. Stirred at 100℃for 3 hours. After completion of LCMS detection, 5-amino-2- (4-amino-7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) benzoic acid methyl ester (600 mg, yield 52.5%) was obtained as a yellow solid by column chromatography purification.

LCMS：m/z 563.7[M+1] ⁺ ，565.7[M+3] ⁺ .

Step three: synthesis of methyl 5-amino-2- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) benzoate

Methyl 5-amino-2- (4-amino-7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) benzoate (500 mg,1.00 eq), cesium carbonate (545 mg,2.00 eq), methylboronic acid (530 mg,10.0 eq) and palladium (2-dicyclohexylphosphino-2, 4, 6-triisopropyl-1, 1-biphenyl) [2- (2-amino-1, 1-biphenyl ] methanesulfonate (225 mg,0.3 eq) were dissolved in 20mL of dioxane and 5mL of water after stirring at 100℃for 1 hour, LCMS detection gave 5-amino-2- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) benzoate (300 mg) as a yellow solid in 54.54% yield.

LCMS：m/z 500.0[M+H] ⁺ .

Step four: synthesis of [ 5-amino-2- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] methanol

Methyl 5-amino-2- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) benzoate (200 mg,1.00 eq) was dissolved in 3mL of tetrahydrofuran and reacted at 20℃for 1 hour. A solution of lithium aluminum hydride in tetrahydrofuran (160 uL,1.00 eq) was slowly added at 0deg.C. After completion of LCMS detection reaction, ethyl acetate and water were added to extract, concentrate, and purify via reverse phase column to give [ 5-amino-2- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] methanol (20 mg, crude) as a yellow solid.

LCMS：m/z 472.0[M+H] ⁺ .

Step five: synthesis of N- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3- (hydroxymethyl) phenyl ] acrylamide

[ 5-amino-2- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] methanol (80 mg,1.00 eq) was dissolved in 2mL of tetrahydrofuran, and acryloyl chloride (3.84 mg,1.00 eq) was slowly added at 0deg.C and reacted at 20deg.C for 1 hour. LCMS detects the end of the reaction. Purification by reverse phase column gave N- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3- (hydroxymethyl) phenyl ] acrylamide as a white solid (4.00 mg, yield 17.2%).

LCMS：m/z 525.8[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ10.24(s，1H)，8.46(d，J＝5.0Hz，1H)，8.25(s，1H)，7.78(s，1H)，7.69-7.58(m，1H)，7.53-7.28(m，2H)，7.25-7.08(m，3H)，6.50-6.39(m，1H)，6.31-6.15(m，1H)，5.76(dd，J＝1.9，10.2Hz，1H)，5.69-5.50(m，2H)，5.22(t，J＝5.2Hz，1H),4.33-4.16(m，2H)，2.36(s，3H)，2.01(s，3H).

Example 66:

n- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3- [2- (dimethylamino) ethoxy ] phenyl ] acrylamide:

the synthetic route is as follows:

step one: synthesis of [2- (2-bromo-5-nitrophenoxy) ethyl ] dimethylamine

Sodium hydride (3.64 g,2.00 eq) was dissolved in 30mL anhydrous tetrahydrofuran, 2-dimethylaminoethanol (8.10 g,2.00 eq) was slowly added at 20℃and stirred for 1 hour at 20 ℃. Then, 1-bromo-2-fluoro-4-nitrobenzene (10.0 g,1.00 eq) was slowly added. Stirred at 20℃for 1 hour. After completion of the LCMS detection reaction, the yellow solid [2- (2-bromo-5-nitrophenoxy) ethyl ] dimethylamine (4.60 g, yield 35.0%) was obtained by column purification.

LCMS：m/z 289.0[M+H] ⁺ ，291.0[M+H] ⁺ .

Step two: synthesis of 4-bromo-3- [2- (dimethylamino) ethoxy ] aniline

[2- (2-bromo-5-nitrophenoxy) ethyl ] dimethylamine (4.60 g,1.00 eq), ammonium chloride (4.24 g,5.00 eq), and iron powder (4.44 g,5.00 eq) were dissolved in 20mL ethanol and 20mL water. Stirred at 80℃for 1 hour. After completion of the TLC detection reaction, 4-bromo-3- [2- (dimethylamino) ethoxy ] aniline (2.30 g, yield 54.1%) was obtained as a yellow solid by column chromatography purification.

LCMS：m/z 258.8[M+H] ⁺ ，260.8[M+H] ⁺ .

Step three: synthesis of 3- [2- (dimethylamino) ethoxy ] -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) aniline

4-bromo-3- [2- (dimethylamino) ethoxy ] aniline (1.00 g,1.00 eq), cesium carbonate (2.51 g,2.00 eq), bis-pinacolatoborate (1.18 g,1.20 eq) and palladium (653 mg,0.20 eq) 2- (2-amino-1, 1-biphenyl) methanesulfonate (2-amino-1, 1-biphenyl) were dissolved in 30mL dioxane after completion of the LCMS detection reaction, and 3- [2- (dimethylamino) ethoxy ] -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) aniline (700 mg, yield 45.0%) was purified by column chromatography as a yellow solid.

LCMS：m/z 307.0[M+H] ⁺ .

Step four: synthesis of 6- { 4-amino-2- [2- (dimethylamino) ethoxy ] phenyl } -7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine group

/>

6, 7-dibromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (400 mg,1.00 eq), cesium carbonate (526 mg,2.00 eq), 3- [2- (dimethylamino) ethoxy ] -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) aniline (496 mg,1.60 eq) and 1, 1-bis (diphenylphosphorus) ferrocene palladium chloride (0.2 g,0.20 eq) were dissolved in 8mL dioxane and 2mL water. Stirred at 100℃for 1 hour. After completion of LCMS detection, 6- { 4-amino-2- [2- (dimethylamino) ethoxy ] phenyl } -7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (350 mg, yield 72.8%) was obtained as a yellow solid by column chromatography purification.

LCMS：m/z 592.8[M+H] ⁺ ，594.8[M+H] ⁺ .

Step five: synthesis of 6- { 4-amino-2- [2- (dimethylamino) ethoxy ] phenyl } -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6- { 4-amino-2- [2- (dimethylamino) ethoxy ] phenyl } -7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (200 mg,1.00 eq), cesium carbonate (220 mg,2.00 eq), methylboronic acid (202 mg,10.0 eq) and (2-dicyclohexylphosphine-2, 4, 6-triisopropyl-1, 1-biphenyl) [2- (2-amino-1, 1-biphenyl ] methanesulfonic acid palladium (84 mg,0.3 eq) were dissolved in 12mL of dioxane and 3mL of water after completion of the reaction, which was stirred at 110℃for 1 hour, LCMS was purified by reverse phase column to give 6- { 4-amino-2- [2- (dimethylamino) ethoxy ] phenyl } -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [2, 1-biphenyl ] (84 mg,0.3 eq) and (60 mg, 33.60%).

LCMS：m/z 529.1.[M+H] ⁺ .

Step six: synthesis of N- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3- [2- (dimethylamino) ethoxy ] phenyl ] acrylamide

6- { 4-amino-2- [2- (dimethylamino) ethoxy ] phenyl } -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (50 mg,1.00 eq) was dissolved in 2mL of tetrahydrofuran, and acryloyl chloride (8.57 mg,1.00 eq) was slowly added at 0deg.C and reacted at 20deg.C for 2 hours. LCMS detects the end of the reaction. Purification by reverse phase column gave N- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3- [2- (dimethylamino) ethoxy ] phenyl ] acrylamide as a white solid (20.0 mg, yield 35.7%).

LCMS：m/z 582.9[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ10.26(s，1H)，8.47(d，J＝5.0Hz，1H)，8.24(s，1H)，7.50(s，1H)，7.41-7.28(m，2H)，7.26-7.18(m，3H)，7.14-7.03(m，1H)，6.51-6.34(m，1H)，6.31-6.19(m，1H)，5.78(dd，J＝1.8，10.1Hz，1H)，5.67(s，2H)，4.02-3.87(m，1H)，3.83-3.67(m，1H)，2.57(dd，J＝3.1，5.4Hz，2H)，2.38(s，3H)，2.16-2.05(m，9H).

Example 67:

n- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3- (2-hydroxyethoxy) phenyl ] acrylamide:

the synthetic route is as follows:

step one: synthesis of 2- [2- (benzyloxy) ethoxy ] -1-bromo-4-nitrobenzene

2-bromo-5-nitrophenol (500 mg,2.29 mmol) and [ (2-bromoethoxy) methyl ] benzene (500 mg,2.32 mmol) were dissolved in acetonitrile (5.00 mL), and potassium carbonate (950 mg,6.88 mmol) was added. Stirred at 90℃for 2 hours, and TLC checked for reaction completion. Extraction with dichloromethane and water and concentration of the organic phase afforded 2- [2- (benzyloxy) ethoxy ] -1-bromo-4-nitrobenzene (750 mg, 92.8% yield).

Step two: synthesis of 3- [2- (benzyloxy) ethoxy ] -4-bromoaniline

/>

2- [2- (benzyloxy) ethoxy ] -1-bromo-4-nitrobenzene (3.00 g,8.52 mmol) was dissolved in ethanol (14.0 mL) and water (3.00 mL), and iron powder (2.38 g,42.6 mmol) and acetic acid (2.56 g,42.6 mmol) were added. After stirring at 90℃for 2 hours, LCMS detects the end of the reaction. The reaction solution was filtered, and after adjusting the base, extracted with water and ethyl acetate, the organic phase was dried and concentrated to give 3- [2- (benzyloxy) ethoxy ] -4-bromoaniline (2.80 g, crude).

LCMS：m/z 322.0[M+H] ⁺ ，324.0[M+H] ⁺ .

Step three: synthesis of 3- [2- (benzyloxy) ethoxy ] -4-bromoaniline

3- [2- (benzyloxy) ethoxy ] -4-bromoaniline (2.80 g,8.69 mmol) was dissolved in tetrahydrofuran (30 mL) and di-tert-butyldicarbonate (2.84 g,13.0 mmol) and triethylamine (1.76 g,17.4 mmol) were added. After stirring at 60℃for 2 hours, LCMS detects the end of the reaction. Spin-drying was separated and purified by column chromatography to give 3- [2- (benzyloxy) ethoxy ] -4-bromoaniline (1.90 g, yield 51.78%).

LCMS：m/z 365.9[M+H-56] ⁺ .

Step four: synthesis of tert-butyl N- {3- [2- (benzyloxy) ethoxy ] -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl } carbamate

3- [2- (benzyloxy) ethoxy ] -4-bromoaniline (1.3 g,3.08 mmol), bis-pinacolato borate (859 mg,3.39 mmol) was dissolved in dioxane (5.00 mL) and potassium acetate (906 mg,9.23 mmol), 1-bis (diphenylphosphorus) ferrocene palladium chloride (225 mg, 307. Mu. Mol) was added. The reaction was stirred at 115℃for 12 hours under nitrogen and was checked for end by LCMS. Spin-drying was separated by column chromatography to give tert-butyl N- {3- [2- (benzyloxy) ethoxy ] -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl } carbamate (550 mg, yield 38.1%).

LCMS：m/z 470.0[M+H] ⁺ .

Step five: n- [4- (4-amino-7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3- [2- (benzyloxy) ethoxy ] phenyl ] carbamic acid tert-butyl ester

6, 7-dibromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } pyrrolo [3,2-d ] pyrimidin-4-amine (550 mg,1.11 mmol) was dissolved in dioxane (9.00 mL) and water (3.00 mL), tert-butyl N- {3- [2- (benzyloxy) ethoxy ] -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl } carbamate (522 mg,1.11 mmol), potassium carbonate (463mg, 3.34 mmol) and tetrakis triphenylphosphine palladium (257 mg, 222. Mu. Mol) were added and reacted at 100℃for 2 hours under nitrogen. After completion of the LCMS detection reaction, the reaction mixture was concentrated and purified by column chromatography to give tert-butyl N- [4- (4-amino-7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3- [2- (benzyloxy) ethoxy ] phenyl ] carbamate (900 mg, yield 21.4%).

LCMS：m/z 756.0[M+1] ⁺ ，758.0[M+3] ⁺ .

Step six: synthesis of tert-butyl N- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3- [2- (benzyloxy) ethoxy ] phenyl ] carbamate

Tert-butyl N- [4- (4-amino-7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3- [2- (benzyloxy) ethoxy ] phenyl ] carbamate (900 mg,1.19 mmol) was dissolved in dioxane (10.0 mL) and methylboronic acid (460 mg,11.5 mmol), (2-dicyclohexylphosphine-2, 4, 6-triisopropyl-1, 1-biphenyl) [2- (2-amino-1, 1-biphenyl ] methanesulfonic acid palladium (201 mg, 238. Mu. Mol) and cesium carbonate (775 mg,2.38 mmol) were added, and the reaction was reacted at 120℃for 3 hours under nitrogen, after which the LCMS detection reaction was completed, the mixture was dried by column chromatography and purified on silica gel to give N- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [2- (2-amino-1, 1-biphenyl ] methanesulfonic acid, 2-yl) 2- (5 mg, 5-ethoxy) ethoxy ] 3- [ 3-phenyl ] sulfonate (490 mg, 5mg, 3-d ] ethoxy ] phenyl ] carboxylate.

LCMS：m/z 692.1[M+H] ⁺ .

Step seven: synthesis of 2- [ 5-amino-2- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenoxy ] ethan-1-ol

Tert-butyl N- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3- [2- (benzyloxy) ethoxy ] phenyl ] carbamate (400 mg, 578. Mu. Mol) was dissolved in dichloromethane (50.0 mL), and boron trichloride (1.00M, 5.78 mL) was added at 0deg.C. Stirred at 0℃for 2 hours. LCMS detects the end of the reaction. Spin-drying gives 2- [ 5-amino-2- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenoxy ] ethan-1-ol (230 mg, yield 66.1%).

LCMS：m/z 502.0[M+H] ⁺ .

Step eight: synthesis of N- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3- (2-hydroxyethoxy) phenyl ] acrylamide

2- [ 5-amino-2- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenoxy ] ethan-1-ol (100 mg, 199. Mu. Mol) was dissolved in tetrahydrofuran (5.00 mL), and acryloyl chloride (20 mg, 220. Mu. Mol) was added at 0deg.C. The reaction was carried out at 0℃for 1 hour, and the completion of the reaction was detected by LCMS. The reaction mixture was concentrated and purified by preparative HPLC to give N- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3- (2-hydroxyethoxy) phenyl ] acrylamide (20 mg, yield 17.5%).

LCMS：m/z 556.2[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ＝10.26(s，1H)，8.47(d，J＝5.0Hz，1H)，8.23(s，1H)，7.47(s，1H)，7.40-7.21(m，3H)，7.20-7.01(m，3H)，6.46-6.35(m，1H)，6.31-6.19(m，1H)，5.86-5.74(m，1H)，5.65(br s，2H)，4.81(br s，1H)，3.88(td，J＝5.1，10.0Hz，1H)，3.68(td，J＝5.1，10.1Hz，1H)，3.58(br s，2H)，2.37(s，3H)，2.08(s，3H).

Example 68:

n- [7- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -2H-1, 3-benzodioxol-4-yl ] acrylamide:

the synthetic route is as follows:

step one: synthesis of 7-bromo-2H-1, 3-benzodioxolan-4-amino group

2H-1, 3-Benzodioxolan-4-amino (1.00 g,1.00 eq) was dissolved in 10mL acetonitrile. (1.30 g,1.00 eq) of N-bromosuccinimide was slowly added at 0deg.C. After completion of the TLC detection reaction, 7-bromo-2H-1, 3-benzodioxolan-4-amino (800 mg, yield 50.7%) was obtained as a white solid by column chromatography purification.

LCMS：m/z 215.5[M+1] ⁺ ，217.5[M+3] ⁺ .

1H NMR(400MHz，DMSO-d ₆ )δ6.72(d，J＝8.8Hz，1H)，6.24(d，J＝8.8Hz，1H)，6.00(s，2H)，5.09(s，2H).

Step two: synthesis of 7- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2H-1, 3-benzodioxolan-4-amino group

7-bromo-2H-1, 3-benzodioxolan-4-amino (800 mg,1.00 eq), potassium acetate (726 mg,2.00 eq), bis-pinacolato borate (1.41 g,1.50 eq) and 1, 1-bis (diphenylphosphorus) ferrocene palladium chloride (541 mg,0.20 eq) were dissolved in 10mL dioxane. Stirred at 100℃for 10 hours. After completion of LCMS detection reaction, 7- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2H-1, 3-benzodioxolan-4-amino (600 mg, yield 61.5%) was obtained as yellow solid by column chromatography purification.

LCMS：m/z 264.1[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ6.84(d，J＝8.1Hz，1H)，6.22(d，J＝8.3Hz，1H)，5.90(s，2H)，5.31(s，2H)，1.24(s，12H).

Step three: synthesis of 6- (7-amino-2H-1, 3-benzodioxol-4-yl) -7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amino

6, 7-dibromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (500 mg,1.00 eq), potassium phosphate (433 mg,2.00 eq), 7- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2H-1, 3-benzodioxolan-4-amine (266 mg,1.00 eq) and tetrakis triphenylphosphine palladium (232 mg,0.20 eq) were dissolved in 8mL dioxane and 4mL water. Stirred at 100℃for 2 hours. After completion of LCMS detection reaction, 6- (7-amino-2H-1, 3-benzodioxol-4-yl) -7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amino (250 mg, yield 44.7%) was obtained as a yellow solid by column chromatography purification.

LCMS：m/z 550.0[M+1] ⁺ ，552.0[M+3] ⁺ .

Step four: synthesis of 6- (7-amino-2H-1, 3-benzodioxol-4-yl) -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6- (7-amino-2H-1, 3-benzodioxolan-4-yl) -7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amino (200 mg,1.00 eq), cesium carbonate (240 mg,2.00 eq), methylboronic acid (217 mg,10.0 eq) and (2-dicyclohexylphosphin-2, 4, 6-triisopropyl-1, 1-biphenyl) [2- (2-amino-1, 1-biphenyl ] methanesulfonic acid palladium (92 mg,0.3 eq) were dissolved in 12mL dioxane and 4mL of water after completion of the LCMS detection reaction, 6- (7-amino-2H-1, 3-benzodioxolan-4-yl) -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy } -7-methyl-5H-pyrrolo [ 6-5-2-yl ] pyrimidine was obtained in a yellow solid (180 mg,0.3 eq) by reverse phase column purification after stirring for 1 hour at 120 ℃.

LCMS：m/z 486.2.[M+H] ⁺ .

Step five: synthesis of N- [7- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -2H-1, 3-benzodioxol-4-yl ] acrylamide

6- (7-amino-2H-1, 3-benzodioxol-4-yl) -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (100 mg,1.00 eq) was dissolved in 2mL of tetrahydrofuran, and acryloyl chloride (18.64 mg,1.00 eq) was slowly added at 0deg.C and reacted at 20deg.C for 2 hours. LCMS detects the end of the reaction. Purification by reverse phase column gave N- [7- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -2H-1, 3-benzodioxol-4-yl ] acrylamide as a white solid (32.0 mg, yield 27.7%).

LCMS：m/z 539.9[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ9.97(s，1H)，8.49(d，J＝5.0Hz，1H)，8.25(s，1H)，7.49-7.38(m，3H)，7.20(d，J＝5.0Hz，1H)，7.15(dd，J＝1.4，8.6Hz，1H)，6.77(d，J＝8.6Hz，1H)，6.57(dd，J＝10.2，16.9Hz，1H)，6.24(dd，J＝1.9，17.1Hz，1H)，5.96-5.86(m，2H)，5.80-5.67(m，3H)，2.39(s，3H)，2.18(s，3H).

Example 69:

n- [7- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -2, 3-dihydro-1-benzofuran-4-yl ] acrylamide:

the synthetic route is as follows:

step one Synthesis of 7-bromo-2, 3-dihydro-1-benzofuran-4-amine

2, 3-dihydro-1-benzofuran-4-amine (3.00 g,1.00 eq) was dissolved in 10mL of acetonitrile. (3.95 g,1.00 eq) N-bromosuccinimide was slowly added at 0deg.C. Stirred at 20℃for 1 hour. After completion of TLC detection, 7-bromo-2, 3-dihydro-1-benzofuran-4-amine (2.20 g, yield 46.3%) was obtained as a white solid by column chromatography.

¹ H NMR(400MHz，DMSO-d ₆ )δ6.89(d，J＝8.4Hz，1H)，6.06(dd，J＝3.6Hz，1H)，5.17(s，2H)，4.53(t，J＝8.8Hz，2H)，3.02(t，J＝8.8Hz，2H).

Step two: synthesis of 7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1-benzofuran-4-amine

7-bromo-2, 3-dihydro-1-benzofuran-4-amine (2.0 g,1.00 eq), potassium acetate (1.83 g,2.00 eq), bis-pinacolato borate (2.84 g,1.20 eq) and 1, 1-bis (diphenylphosphorus) ferrocene palladium chloride (2.05 g,0.20 eq) were dissolved in 10mL dioxane. Stirred at 100℃for 3 hours. After completion of LCMS detection reaction, 7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1-benzofuran-4-amine (530 mg, yield 21.7%) was obtained as a yellow solid by column chromatography.

LCMS：m/z 261.9[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ7.06(d，J＝8.1Hz，1H)，6.06(d，J＝8.0Hz，1H)，5.39(s，2H)，4.45(t，J＝8.8Hz，2H)，2.86(t，J＝8.8Hz，2H)，1.21(s，12H).

Step three: synthesis of 6- (4-amino-2, 3-dihydro-1-benzofuran-7-yl) -7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6, 7-dibromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (720 mg,2.00 eq), potassium phosphate (618 mg,2.00 eq), 7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1-benzofuran-4-amine (762 mg,1.00 eq) and tetrakis triphenylphosphine palladium (504 mg,0.20 eq) were dissolved in 12mL dioxane and 6mL water. Stirred at 100℃for 3 hours. After completion of LCMS detection, 6- (4-amino-2, 3-dihydro-1-benzofuran-7-yl) -7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (120 mg, yield 15.0%) was purified by column chromatography as a yellow solid.

LCMS：m/z 547.6[M+1] ⁺ ，549.6[M+3] ⁺ .

Step four: synthesis of 6- (4-amino-2, 3-dihydro-1-benzofuran-7-yl) -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6- (4-amino-2, 3-dihydro-1-benzofuran-7-yl) -7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (150 mg,1.00 eq), cesium carbonate (178 mg,2.00 eq), methylboronic acid (163 mg,10.0 eq) and (2-dicyclohexylphosphino-2, 4, 6-triisopropyl-1, 1-biphenyl) [2- (2-amino-1, 1-biphenyl ] methanesulfonic acid palladium (46.2 mg,0.2 eq) were dissolved in 2mL dioxane.after completion of the reaction, stirred at 100℃for 1 hour, LCM was purified by reverse phase column to give 6- (4-amino-2, 3-dihydro-1-benzofuran-7-yl) -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidine (120 mg, 90% yield).

LCMS：m/z 484.0.[M+H] ⁺ .

Step five: synthesis of N- [7- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -2, 3-dihydro-1-benzofuran-4-yl ] acrylamide

6- (4-amino-2, 3-dihydro-1-benzofuran-7-yl) -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (110 mg,1.00 eq) was dissolved in 2mL of tetrahydrofuran, and acryloyl chloride (20.6 mg,1.00 eq) was slowly added at 0deg.C and reacted at 20deg.C for 2 hours. LCMS detects the end of the reaction. Purification by reverse phase column gave N- [7- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -2, 3-dihydro-1-benzofuran-4-yl ] acrylamide as a white solid (23.7 mg, yield 19.1%).

LCMS：m/z 538.1[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ9.65(s，1H)，8.48(d，J＝5.0Hz，1H)，8.23(s，1H)，7.40-7.31(m，3H)，7.20(d，J＝4.9Hz，1H)，7.14-7.07(m，1H)，7.04(d，J＝8.3Hz，1H)，6.54(dd，J＝10.1，16.9Hz，1H)，6.26(dd，J＝1.9，16.9Hz，1H)，5.76(dd，J＝1.6，10.3Hz，1H)，5.66(s，2H)，4.55-4.16(m，2H)，3.16-3.07(m，2H)，2.39(s，3H)，2.13(s，3H).

Example 70:

n- [8- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxo ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -2, 3-dihydro-1, 4-benzodioxan-5-yl ] acrylamide:

the synthetic route is as follows:

step one: synthesis of 8-bromo-2, 3-dihydro-1, 4-benzodioxan-5-amine

2, 3-dihydro-1, 4-benzodioxan-5-amine (2.10 g,13.9 mmol) was dissolved in acetonitrile (30 mL), and a solution of N-bromosuccinimide (2.60 g,14.6 mmol) in acetonitrile (10 mL) was added at 0deg.C. The reaction was then stirred at 20℃for 1 hour under nitrogen and checked for completion by LCMS. Spin drying and column chromatography separation gave 8-bromo-2, 3-dihydro-1, 4-benzodioxane-5-amine (3.00 g, 93.8% yield).

LCMS：m/z 229.8[M+1] ⁺ ，231.8[M+3] ⁺ .

Step two: synthesis of 8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1, 4-benzodioxan-5-amine

8-bromo-2, 3-dihydro-1, 4-benzodioxan-5-amine (600 mg,2.61 mmol) and bis-pinacolato borate (668mg, 2.61 mmol) were dissolved in dioxane (5.00 mL), and potassium acetate (767 mg,7.82 mmol), 1-bis (diphenylphosphorus) ferrocene palladium chloride (381 mg, 521. Mu. Mol) was added. The reaction was then stirred at 100deg.C for 2 hours under nitrogen and checked for completion by LCMS. Spin-drying and column chromatography separation to obtain 8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1, 4-benzodioxan-5-amine (1.20 g, crude product).

LCMS：m/z 279.9[M+H] ⁺ .

Step three: synthesis of 6- (8-amino-2, 3-dihydro-1, 4-benzodioxan-5-yl) -7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxo ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6, 7-dibromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxo ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (100 mg, 202. Mu. Mol) was dissolved in dioxane (5 mL) and water (2.5 mL), 8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1, 4-benzodioxan-5-amine (70.0 mg, 252. Mu. Mol), potassium carbonate (83.9 mg, 607. Mu. Mol) and tetrakis triphenylphosphine palladium (46.8 mg, 40.5. Mu. Mol) were added and reacted at 100℃for 2 hours under nitrogen protection. After LCMS detection reaction was completed, the reaction mixture was concentrated and purified by column chromatography to give 6- (8-amino-2, 3-dihydro-1, 4-benzodioxan-5-yl) -7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxo ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (630 mg, crude).

LCMS：m/z 563.8[M+1] ⁺ ，565.8[M+3] ⁺ .

Step four: synthesis of 6- (8-amino-2, 3-dihydro-1, 4-benzodioxan-5-yl) -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxo ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6- (8-amino-2, 3-dihydro-1, 4-benzodioxan-5-yl) -7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxo ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (100 mg, 177. Mu. Mol) was dissolved in dioxane (5.00 mL) and methylboronic acid (106 mg,1.77 mmol), (2-dicyclohexyl-2, 4, 6-triisopropyl-1, 1-biphenyl) [2- (2-amino-1, 1-biphenyl ] methanesulfonic acid palladium (30.0 mg, 35.4. Mu. Mol) and cesium carbonate (173 mg, 531. Mu. Mol) were added, and the reaction was performed at 120℃for 1 hour under nitrogen, after which the completion of the LCMS detection reaction, the reaction was dried over a silica gel column to give 6- (8-amino-2, 3-dihydro-1, 4-benzodioxan-5-yl) -5- { 3-fluoro-4-methylpyrimidin-2, 1-biphenyl ] methanesulfonic acid palladium (30.0 mg, 35.4-mmol) and cesium carbonate (173 mg, 531. Mu. Mol) and the reaction was purified by silica gel column to give 6- (8-amino-2, 3-dihydro-1, 4-benzodioxan-5-yl) -5- { 3-fluoro-4-methyl-pyrimidine-2-methyl-2-1-hydroxy ] pyrimidine-2-1-methyl-2-hydroxy-1-methyl-32-methyl-carboxylate (170 mg, 32.3 mg).

LCMS：m/z 500.1[M+H] ⁺ .

Step five: synthesis of N- [8- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxo ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -2, 3-dihydro-1, 4-benzodioxan-5-yl ] acrylamide

6- (8-amino-2, 3-dihydro-1, 4-benzodioxan-5-yl) -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxo ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (170 mg, 340. Mu. Mol) was dissolved in tetrahydrofuran (10.0 mL), and acryloyl chloride (30.8 mg, 340. Mu. Mol) was added at 0deg.C. The reaction was carried out at 0℃for 1 hour, and the completion of the reaction was detected by LCMS. The reaction mixture was concentrated and purified by preparative HPLC to give N- [8- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxo ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -2, 3-dihydro-1, 4-benzodioxan-5-yl ] acrylamide (30.0 mg, yield 15.8%).

LCMS：m/z 554.6[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ＝9.45(s，1H)，8.48(d，J＝5.0Hz，1H)，8.24(s，1H)，7.74(br d，J＝8.4Hz，1H)，7.49-6.82(m，5H)，6.70(br dd，J＝10.2，16.9Hz，1H)，6.24(dd，J＝1.3，16.9Hz，1H)，5.93-5.50(m，3H)，4.34-4.22(m，1H)，4.14(br d，J＝9.6Hz，2H)，3.85-3.71(m，1H)，2.38(s，3H)，2.13(s，3H).

Example 71:

n- (7- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) benzo [ d ] oxazol-4-yl) acrylamide:

the synthetic route is as follows:

step one: synthesis of 7-bromobenzo [ d ] oxazol-4-amine

4-aminobenzoxazole (900 mg,6.71 mmol) was dissolved in 8mL of acetonitrile, N-bromosuccinimide (1.19 g,6.71 mmol) was added, stirred at 20℃for 1 hour, and after completion of the LCMS detection reaction, concentrated and column chromatographed to give 7-bromobenzo [ d ] oxazol-4-amine (1.32 g, yield 85.8%).

LCMS：m/z 213.0[M+H] ⁺ ，215.0[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.58(s，1H)，7.24(d，J＝8.5Hz，1H)，6.50(d，J＝8.5Hz，1H)，5.86(s，2H).

Step two: synthesis of 7- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzo [ d ] oxazol-4-amine

7-bromobenzo [ d ] oxazol-4-amine (1.22 g,5.73 mmol) was dissolved in 12mL dioxane, pinacol ester of biboronate (2.91 g,11.4 mmol), 1-bis (diphenylphosphino) ferrocene ] palladium dichloride (6278 mg, 859. Mu. Mol) and potassium acetate (1.69 g,17.1 mmol) were added and stirred at 100deg.C for 2 hours, after completion of LCMS detection reaction, concentrated and column chromatographed to give 7- (4, 5-tetramethyl-1, 3, 2-dioxaboran-2-yl) benzo [ d ] oxazol-4-amine (670 mg, yield 41.3%).

LCMS：m/z 260.9[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.47(s，1H)，7.36(d，J＝8.0Hz，1H)，6.50(d，J＝8.1Hz，1H)，6.12(s，2H)，1.28(s，12H).

Step three: synthesis of 7- (4-amino-7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) benzo [ d ] oxazol-4-amine

6, 7-dibromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (600 mg,1.21 mmol) was dissolved in 9mL dioxane, 7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ d ] oxazol-4-amine (803 mg,1.40 mmol), potassium phosphate (515 mg,2.43 mmol), tetrakis (triphenylphosphine) palladium (701 mg, 607. Mu. Mol) and 6mL water were added, after completion of the LCMS detection reaction, concentrated and column chromatography gave 7- (4-amino-7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) benzo [ oxazol-4-amine (420 mg, 54.9% yield).

LCMS：m/z 546.9[M+H] ⁺ ，548.9[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.48-8.43(m，2H)，8.30(s，1H)，7.53(br d，J＝9.5Hz，1H)，7.47(brd，J＝7.5Hz，1H)，7.25-7.17(m，2H)，7.05(d，J＝8.3Hz，1H)，6.52(d，J＝8.3Hz，1H)，6.06(s，2H)，5.89(brs，2H)，2.39(s，3H).

Step four: synthesis of 7- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) benzo [ d ] oxazol-4-amine

7- (4-amino-7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) benzo [ d ] oxazol-4-amine (420 mg, 767. Mu. Mol) was dissolved in 8mL dioxane, methyl boric acid (420 mg,7.02 mmol), cesium carbonate (500 mg,1.53 mmol) and methanesulfonic acid (2-dicyclohexylphosphine-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (162 mg, 191. Mu. Mol) were added, and after completion of the LCMS detection reaction, the reaction was concentrated and column chromatographed to give 7- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) benzo [ 4-amine (300 mg, 60%).

LCMS：m/z 483.0[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.47(d，J＝5.0Hz，1H)，8.42(s，1H)，8.26(s，1H)，7.40(dd，J＝2.1，10.9Hz，1H)，7.33(t，J＝8.7Hz，1H)，7.19(d，J＝5.0Hz，1H)，7.13(br d，J＝8.9Hz，1H)，6.96(d，J＝8.3Hz，1H)，6.51(d，J＝8.3Hz，1H)，5.94(s，2H)，5.67(br s，2H)，2.39(s，3H)，2.13(s，3H).

Step five: synthesis of N- (7- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) benzo [ d ] oxazol-4-yl) acrylamide

7- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) benzo [ d ] oxazol-4-amine (150 mg, 310. Mu. Mol) was dissolved in 9mL tetrahydrofuran and acryloyl chloride (25.3 mg, 279. Mu. Mol) was added, the reaction was checked for end by LCMS at 0℃for 1 hour, concentrated and purified by preparative HPLC to give N- (7- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) benzo [ d ] oxazol-4-yl) acrylamide (32.5 mg, yield 18.1%).

LCMS：m/z 555.2[M+H ₂ 0+H] ⁺ .

¹ H NMR(400MHz，CHLOROFORM-d)δ＝9.33-9.11(m，1H)，8.63-8.44(m，1H)，8.41(s，1H)，8.34-8.33(m，1H)，8.36(d，J＝5.0Hz，1H)，8.30(s，1H)，7.14-7.00(m，2H)，6.99-6.93(m，2H)，6.53-6.45(m，1H)，6.41-6.31(m，1H)，5.87(br d，J＝10.5Hz，1H)，4.80(br s，2H)，2.48(s，3H)，2.20(s，3H).

Example 72:

n- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3- (difluoromethoxy) phenyl ] acrylamide:

the synthetic route is as follows:

step one: synthesis of 1-bromo-2- (difluoromethoxy) -4-nitrobenzene

2-bromo-5-nitrophenol (6.00 g,1.00 eq), sodium difluorochloroacetate (4.20 g,2.00 eq) and sodium hydroxide (1.10 g,1.00 eq) were dissolved in 30 mLN-methylpyrrolidone ring and 0.5mL of water. Stirred at 120℃for 1 hour. After completion of TLC detection, water and ethyl acetate were added and extracted to give 1-bromo-2- (difluoromethoxy) -4-nitrobenzene (7.00 g, yield 94.9%) as a yellow oil.

Step two: synthesis of 4-bromo-3- (difluoromethoxy) aniline

1-bromo-2- (difluoromethoxy) -4-nitrobenzene (5.00 g,1.00 eq), ammonium chloride (4.99 g,5.00 eq), and iron powder (5.21 g,5.00 eq) were dissolved in 20mL ethanol and 20mL water. Stirred at 80℃for 1 hour. After completion of the TLC detection reaction, 4-bromo-3- (difluoromethoxy) aniline (3.50 g, yield 78.8%) was obtained as a yellow solid by column chromatography purification.

Step three: synthesis of 3- (difluoromethoxy) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) amino

4-bromo-3- (difluoromethoxy) aniline (2.50 g,1.00 eq), potassium acetate (171 mg,2.00 eq), bis-pinacolato borate (2.93 g,1.10 eq) and 1, 1-bis (diphenylphosphorus) ferrocene palladium chloride (1.54 g,0.20 eq) were dissolved in 30mL dioxane. Stirred at 90℃for 12 hours. After completion of LCMS detection, 3- (difluoromethoxy) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) amino (1.00 g, 33.3% yield) was purified by column chromatography as a yellow solid.

¹ H NMR(400MHz，DMSO-d ₆ )δ7.33(d，J＝8.1Hz，1H)，7.11-6.61(m，1H)，6.41(dd，J＝1.6，8.1Hz，1H)，6.29(s，1H)，5.85-5.68(m，2H)，1.24(s，12H).

Step four: synthesis of 6- [ 4-amino-2- (difluoromethoxy) phenyl ] -7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6, 7-dibromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (200 mg,1.00 eq), cesium carbonate (263 mg,2.00 eq), 3- (difluoromethoxy) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) amino (115 mg,1.00 eq) and 1, 1-bis (diphenylphosphorus) ferrocene palladium chloride (66.3 mg,0.20 eq) were dissolved in 4mL dioxane and 1mL water. Stirred at 100℃for 2 hours. After completion of LCMS detection, 6- [ 4-amino-2- (difluoromethoxy) phenyl ] -7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (350 mg, yield 50.3%) was obtained as a yellow solid by column chromatography purification.

LCMS：m/z 571.5[M+1] ⁺ ，573.5[M+3] ⁺ .

Step five: synthesis of 6- [ 4-amino-2- (difluoromethoxy) phenyl ] -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6- [ 4-amino-2- (difluoromethoxy) phenyl ] -7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (50 mg,1.00 eq), cesium carbonate (56.9 mg,2.00 eq), methylboronic acid (52 mg,10.0 eq) and palladium (2-dicyclohexylphosphine-2, 4, 6-triisopropyl-1, 1-biphenyl) [2- (2-amino-1, 1-biphenyl ] methanesulfonate (22.1 mg,0.3 eq) were dissolved in 3mL dioxane after 3 hours stirring at 120℃S detection gave 6- [ 4-amino-2- (difluoromethoxy) phenyl ] -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidine-amine (50 mg, crude product).

LCMS：m/z 508.1.[M+H] ⁺ .

Step six: synthesis of N- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3- (difluoromethoxy) phenyl ] acrylamide

6- [ 4-amino-2- (difluoromethoxy) phenyl ] -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (50 mg,1.00 eq) was dissolved in 2mL of tetrahydrofuran, and acryloyl chloride (8.92 mg,1.00 eq) was slowly added at 0deg.C and reacted at 20deg.C for 2 hours. LCMS detects the end of the reaction. Purification by reverse phase column gave N- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3- (difluoromethoxy) phenyl ] acrylamide as a white solid (17.8 mg, yield 31.5%).

LCMS：m/z 562.0[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ＝10.45(s，1H)，8.47(d，J＝4.9Hz，1H)，8.26(s，1H)，7.75(s，1H)，7.56-7.29(m，4H)，7.19(d，J＝4.9Hz，1H)，7.10(d，J＝0.9Hz，1H)，7.00-6.58(m，1H)，6.39(d，J＝10.0Hz，1H)，6.33-6.26(m，1H)，5.86-5.67(m，3H)，2.36(s，3H)，2.08(s，3H).

Example 73:

n- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3- (oxetan-3-oxy) phenyl ] acrylamide:

the synthetic route is as follows:

step one: synthesis of 3- (2-bromo-5-nitrophenoxy) oxetane

Sodium hydride (1.82 g,2.00 eq) was dissolved in 30mL anhydrous tetrahydrofuran, 3-oxetane alcohol (3.37 g,2.00 eq) was slowly added at 20℃and stirred for 1 hour at 20 ℃. Then, 1-bromo-2-fluoro-4-nitrobenzene (5.00 g,1.00 eq) was slowly added. Stirred at 20℃for 1 hour. After completion of the TLC detection, 3- (2-bromo-5-nitrophenoxy) oxetane (5.00 g, yield 80.2%) was obtained as a yellow solid by column purification.

Step two: synthesis of 4-bromo-3- (oxetan-3-oxy) aniline

3- (2-bromo-5-nitrophenoxy) oxetane (4.00 g,1.00 eq), ammonium chloride (3.90 g,5.00 eq), and iron powder (4.08 g,5.00 eq) were dissolved in 20mL ethanol and 20mL water. Stirred at 80℃for 1 hour. After completion of the TLC detection reaction, 4-bromo-3- (oxetan-3-oxy) aniline (3.50 g, yield 98.2%) was obtained as a yellow solid by column chromatography purification.

LCMS：m/z 244.0[M+1] ⁺ .246.0[M+3] ⁺ .

Step three: synthesis of 3- (oxetan-3-oxy) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) aniline

4-bromo-3- (oxetan-3-oxy) aniline (1.50 g,1.00 eq), cesium carbonate (2.51 g,2.00 eq), bis-pinacolatoborate (1.87 g,1.20 eq) and palladium (1.04 g,0.20 eq) 2- (2-amino-1, 1-biphenyl) methanesulfonate (2-amino-1, 1-biphenyl) were dissolved in 30mL of dioxane after stirring at 85℃for 2 hours after completion of LCMS detection reaction, 3- (oxetan-3-oxy) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) aniline (600 mg, 33.5% yield) was purified by column chromatography as a yellow solid.

LCMS：m/z 292.0[M+H] ⁺ .

Step four: synthesis of 6- [ 4-amino-2- (oxetan-3-oxy) phenyl ] -7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6, 7-dibromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (400 mg,1.00 eq), cesium carbonate (227 mg,2.00 eq), 3- (oxetan-3-oxy) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) aniline (235 mg,1.00 eq) and 1, 1-bis (diphenylphosphorus) ferrocene palladium chloride (132 mg,0.20 eq) were dissolved in 4mL dioxane and lmL water. Stirred at 100℃for 1 hour. After completion of LCMS detection, 6- [ 4-amino-2- (oxetan-3-yloxy) phenyl ] -7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (250 mg, yield 53.3%) was purified by column chromatography as a yellow solid.

LCMS：m/z 578.0[M+1] ⁺ ，580.0[M+3] ⁺ .

Step five: synthesis of 6- [ 4-amino-2- (oxetan-3-oxy) phenyl ] -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6- [ 4-amino-2- (oxetan-3-yloxy) phenyl ] -7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (200 mg,1.00 eq), cesium carbonate (219.6 mg,2.00 eq), methylboronic acid (207.6 mg,10.0 eq) and (2-dicyclohexylphosphino-2, 4, 6-triisopropyl-1, 1-biphenyl) [2- (2-amino-1, 1-biphenyl ] methanesulfonic acid palladium (87.6 mg,0.3 eq) were dissolved in 12mL of dioxane 3mL of water after stirring 1 hour at 120℃LCMS detection reaction, 6- [ 4-amino-2- (oxetan-3-oxy) phenyl ] -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-H-pyrrolo [3, 4-d ] amine was purified by reverse phase column to give a yellow solid (4.0.45 mg, yield).

LCMS：m/z 514.2.[M+H] ⁺ .

Step six: synthesis of N- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3- (oxetan-3-oxy) phenyl ] acrylamide

/>

6- [ 4-amino-2- (oxetan-3-oxy) phenyl ] -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (80 mg,1.00 eq) was dissolved in 2mL of tetrahydrofuran, and acryloyl chloride (14.1 mg,1.00 eq) was slowly added at 0deg.C and reacted at 20deg.C for 2 hours. LCMS detects the end of the reaction. Purification by reverse phase column gave N- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3- (oxetan-3-oxy) phenyl ] acrylamide as a white solid (10.0 mg, yield 10.4%).

LCMS：m/z 568.0[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ10.28(s，1H)，8.49(d，J＝4.9Hz，1H)，8.25(s，1H)，7.48-6.82(m，7H)，6.50-6.16(m，2H)，5.82-5.68(m，3H)，4.88-4.74(m，2H)，4.67(t，J＝6.4Hz，1H)，4.55-4.42(m，1H)，4.22(s，1H)，2.40(s，3H)，2.13(s，3H).

Example 74:

n- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-cyanophenyl ] acrylamide:

the synthetic route is as follows:

step one: synthesis of 5-amino-2- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzonitrile

5-amino-2-bromoxynil (500 mg,1.00 eq), potassium acetate (498 mg,2.00 eq), bis-pinacolato borate (773 mg,1.10 eq) and 1, 1-bis (diphenylphosphorus) ferrocene palladium chloride (278 mg,0.15 eq) were dissolved in 3mL dioxane. Stirred at 90℃for 12 hours. After completion of LCMS detection, 5-amino-2- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzonitrile (200 mg, yield 32.2%) was obtained as a yellow solid by column chromatography.

LCMS：m/z 245.1[M+H] ⁺ .

Step two: synthesis of 5-amino-2- (4-amino-7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxo ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) benzonitrile

6, 7-dibromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (450 mg,1.00 eq), cesium carbonate (594 mg,2.00 eq), 5-amino-2- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzonitrile (222 mg,1.00 eq) and 1, 1-bis (diphenylphosphorus) ferrocene palladium chloride (198 mg,0.20 eq) were dissolved in 4mL dioxane and 1mL water. Stirred at 100℃for 1 hour. After completion of LCMS detection, 5-amino-2- (4-amino-7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxo ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) benzonitrile (200 mg, yield 41.3%) was obtained as a yellow solid by column chromatography purification.

LCMS：m/z 531.1[M+1] ⁺ ，533.1[M+3] ⁺ .

Step three: synthesis of 5-amino-2- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) benzonitrile

5-amino-2- (4-amino-7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) benzonitrile (200 mg,1.00 eq), cesium carbonate (245 mg,2.00 eq), methylboronic acid (225 mg,10.0 eq) and palladium (2-dicyclohexylphosphino-2, 4, 6-triisopropyl-1, 1-biphenyl) [2- (2-amino-1, 1-biphenyl ] methanesulfonate (96 mg,0.3 eq) were dissolved in 6mL dioxane and 2mL water after stirring at 120℃for 1 hour LCMS detection the end of the reaction to give 5-amino-2- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) benzonitrile as a yellow solid (100 mg) in a yield of 9.9%.

LCMS：m/z 467.2.[M+H] ⁺ .

Step four: synthesis of N- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-cyanophenyl ] acrylamide

5-amino-2- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) benzonitrile (100 mg,1.00 eq) was dissolved in 2mL of tetrahydrofuran, and acryloyl chloride (19.4 mg,1.00 eq) was slowly added at 0deg.C and reacted at 20deg.C for 2 hours. LCMS detects the end of the reaction. Purification by reverse phase column gave N- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-cyanophenyl ] acrylamide as a white solid (26.9 mg, yield 23.8%).

LCMS：m/z 520.9[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ10.60(s，1H)，8.48(d，J＝5.0Hz，1H)，8.35-8.21(m，2H)，7.84(dd，J＝2.1，8.6Hz，1H)，7.75-6.84(m，5H)，6.53-6.18(m，2H)，5.98-5.71(m，3H)，2.35(s，3H)，2.15(s，3H).

Example 75:

n- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3- (cyanomethyl) phenyl ] acrylamide:

the synthetic route is as follows:

step one: synthesis of (2-bromo-5-nitrophenyl) methanol

2-bromo-5-nitrobenzoic acid (25.0 g,2.00 eq) was dissolved in 200mL anhydrous tetrahydrofuran, borane (203 mL,2.00 eq) was slowly added at 0deg.C and stirred at 70deg.C for 1 hour. After completion of TLC detection, the reaction was purified by column chromatography to give (2-bromo-5-nitrophenyl) methanol (18.0 g, yield 76.3%) as a yellow solid.

¹ H NMR(400MHz，DMSO-d6)δ8.32-8.22(m，1H)，8.02(d，J＝8.0Hz，1H)，7.86(d，J＝8.8Hz，1H)，5.85(s，1H)，4.60(s，2H).

Step two: synthesis of 1-bromo-2- (bromomethyl) -4-nitrobenzene

(2-bromo-5-nitrophenyl) methanol (16.0 g,1.00 eq) was dissolved in 50.0ml of dichloromethane, and triphenylphosphine (27.1 g,1.50 eq) and carbon tetrabromide (34.3 g,1.50 eq) were added. Stirred at 20℃for 10 hours. After completion of LCMS detection, 1-bromo-2- (bromomethyl) -4-nitrobenzene (9.00 g, 44.2% yield) was purified by column chromatography as a white solid.

¹ H NMR(400MHz，CHLOROFORM-d)δ8.34(d，J＝2.4Hz，1H)，8.04(dd，J＝2.7，8.8Hz，1H)，7.79(d，J＝8.8Hz，1H)，4.64(s，2H).

Step three: synthesis of 2- (2-bromo-5-nitrophenyl) acetonitrile

1-bromo-2- (bromomethyl) -4-nitrobenzene (7.00 g,1.00 eq) was dissolved in 50.0m dimethyl sulfoxide, 25.0ml water was added, and sodium cyanide (2.53 g,2.18 eq) was added at 20 ℃. Stirred at 60℃for 6 hours. After completion of LCMS detection, the reaction was quenched by addition of saturated sodium bicarbonate solution and extracted with ethyl acetate and water after completion of the quench. The crude product was purified by column chromatography to give 2- (2-bromo-5-nitrophenyl) acetonitrile (5.00 g, crude) as a yellow solid.

¹ H NMR(400MHz，CHLOROFORM-d)δ8.45-8.40(m，1H)，8.12(dd，J＝1.9，8.8Hz，1H)，7.87-7.83(m，1H)，3.95(s，2H).

Step four: synthesis of 2- (5-amino-2-bromophenyl) acetonitrile

2- (2-bromo-5-nitrophenyl) acetonitrile (5.00 g,1.00 eq), iron powder (5.79 g,5.00 eq), ammonium chloride (5.55 g,5.00 eq) were dissolved in 20mL ethanol, and 20mL water was added. Stirred at 80℃for 1 hour. After completion of LCMS detection reaction, 2- (5-amino-2-bromophenyl) acetonitrile (2.70 g, yield 61.6%) was purified by column chromatography as a yellow solid.

LCMS：m/z 210.9[M+H] ⁺ ，m/z 212.9[M+H] ⁺ .

Step five: synthesis of 2- [ 5-amino-2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetonitrile

2- (5-amino-2-bromophenyl) acetonitrile (2.5 g,1.00 eq), potassium acetate (2.33 g,2.00 eq), bis -oxo borate (1.27 g,1.00 eq) and 1, 1-bis (diphenylphosphorus) ferrocene palladium chloride (194 mg,0.20 eq) were dissolved in 25mL dioxane. Stirred at 100℃for 1 hour. After the completion of the TLC detection reaction, 2- [ 5-amino-2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetonitrile (2.40 g, yield 78.5%) was obtained as a yellow solid by column chromatography.

LCMS：m/z 259.0[M+H] ⁺ .

Step six: synthesis of 2- [ 5-amino-2- (4-amino-7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] acetonitrile

6, 7-dibromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (1.0 g,1.00 eq), cesium carbonate (1.32 g,2.00 eq), 2- [ 5-amino-2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetonitrile (1.04 g,2.00 eq) and 1, 1-bis (diphenylphosphorus) ferrocene palladium chloride (292 mg,0.20 eq) were dissolved in 10mL dioxane and 3mL water. Stirred at 100℃for 1 hour. After completion of LCMS detection reaction, 2- [ 5-amino-2- (4-amino-7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] acetonitrile (710 mg, crude) was purified by column chromatography to give a grey solid.

LCMS：m/z 544.8[M+H] ⁺ ，546.8[M+H] ⁺ .

Step seven: synthesis of 2- [ 5-amino-2- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] acetonitrile

2- [ 5-amino-2- (4-amino-7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] acetonitrile (600 mg,1.00 eq), cesium carbonate (178 mg,1.5 eq), methylboronic acid (254 mg,10.0 eq) and (2-dicyclohexylphosphine-2, 4, 6-triisopropyl-1, 1-biphenyl) [2- (2-amino-1, 1-biphenyl ] methanesulfonic acid palladium (185 mg,0.2 eq) were dissolved in 18mL of dioxane and 6mL of water, and after completion of the LCMS detection reaction, 2- [ 5-amino-2- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] phenyl ] acetonitrile was purified by reverse phase column (19 mg, yield) of 1.38 mg.

LCMS：m/z 480.8[M+H] ⁺ .

Step eight: synthesis of N- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3- (cyanomethyl) phenyl ] acrylamide

2- [ 5-amino-2- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] acetonitrile (38.0 mg,1.00 eq) was dissolved in 2mL of tetrahydrofuran, and acryloyl chloride (5.73 mg,1.00 eq) was slowly added at 0deg.C and reacted at 20deg.C for 1 hour. LCMS detects the end of the reaction. Purification by reverse phase column gave N- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3- (cyanomethyl) phenyl ] acrylamide as a white solid (11.0 mg, yield 21.9%).

LCMS：m/z 534.9[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.39(br s，1H),8.46(br d，J＝4.8Hz，1H)，8.27(s，1H)，7.86(br s，1H),7.66(br d，J＝7.9Hz，1H)，7.51(br d，J＝10.6Hz，1H)，7.42-7.35(m，1H)，7.28(br d，J＝7.9Hz，2H)，7.17(br d，J＝4.6Hz，1H)，6.47-6.38(m，1H)，6.32-6.24(m，1H)，5.79(br d，J＝10.1Hz，1H)，5.65(br s，2H)，3.77(brs，2H)，2.34(s，3H)，2.05(s，3H).

Example 76:

n- [4- (4-amino-5- { 5-fluoro-2-methyl-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methylpyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] acrylamide:

the synthetic route is as follows:

step one: synthesis of tert-butyl N- [4 (4- (benzyloxy) -5-fluoro-2-methylphenyl) carbamate

Benzyloxy-4-bromo-2-fluoro-5-methyl-benzene (15 g,50.82 mmol) and tert-butyl carbamate (8.34 g,71.1 mmol) were dissolved in dioxane (20 mL) and palladium acetate (1.14 g,5.08 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (5.88 g,10.16 mmol) and cesium carbonate (33.1 g,102 mmol) were added. The reaction solution was reacted at 100℃for 6 hours. After completion of the reaction, inorganic salts were removed by filtration, and the filtrate was concentrated and purified by column chromatography to give tert-butyl N- [4 (4- (benzyloxy) -5-fluoro-2-methylphenyl) carbamate (12.0 g,71.3% yield).

¹ H NMR(400MHz，CHLOROFORM-d)δ＝7.61(br d，J＝9.5Hz，1H)，7.49-7.30(m，5H)，6.79(d，J＝9.0Hz，1H)，6.13(br s，1H)，5.09(s，2H)，2.17(s，3H)，1.52(s，9H).

Step two: synthesis of 4- (benzyloxy) -5-fluoro-2-methylaniline

Tert-butyl N- [4 (4- (benzyloxy) -5-fluoro-2-methylphenyl) carbamate (12 g,36.2 mmol) was added to methanol hydrochloride (4M, 40.00 mL) and the reaction was allowed to react at 20℃for 2 hours. After the completion of the reaction, the reaction mixture was concentrated, and was slurried with ethyl acetate (50 ml) and filtered to obtain 8.50g of a white solid in 85.9% yield.

LCMS：m/z 232.1[M+H] ⁺ .

Step three: synthesis of [ (4- {5- [4- (benzyloxy) -5-fluoro-2-methylphenyl ] -4- [ (2, 2-trifluoroethyl) oxy ] pyrrolo [3,2-d ] pyrimidin-6-yl } phenyl) amino ] carboxylic acid tert-butyl ester

Tert-butyl { [4- ({ 5-bromo-6- [ (2, 2-trifluoroethyl) oxy ] pyrimidin-4-yl } ethynyl) phenyl ] amino } carboxylate (6.86 g,14.5 mmol) was dissolved in dioxane (120 ml), 4-benzyloxy-2, 5-difluoroaniline (4.08 g,15.2 mmol), tris (dibenzylideneacetone) dipalladium (1.06 g,1.16 mmol), 4,5 bis-diphenylphosphine-9, 9-dimethylxanthene (1.34 g,2.32 mmol) and cesium carbonate (10.4 g,31.9 mmol) were added and stirred at 110℃for 12 hours. LCMS monitored the end of the reaction. The reaction mixture was extracted with water and ethyl acetate, and the organic phase was dried over saturated brine, filtered and concentrated by column chromatography to give tert-butyl [ (4- {5- [4- (benzyloxy) -5-fluoro-2-methylphenyl ] -4- [ (2, 2-trifluoroethyl) oxy ] pyrrolo [3,2-d ] pyrimidin-6-yl } phenyl) carbamate (5.59 g, yield 59.7%).

LCMS：m/z 623.3[M+H] ⁺ .

¹ H NMR(400MHz，CHLOROFORM-d)δ＝8.53(s，1H)，7.50-7.45(m，2H)，7.42(t，J＝7.3Hz，2H)，7.39-7.30(m，3H)，7.26-7.21(m，2H)，7.00(d，J＝11.0Hz，1H)，6.89-6.77(m，2H)，6.60(s，1H)，5.16(s，2H)，4.81(qd，J ₁ ＝8.3，J ₂ ＝12.4Hz，1H)，4.62(qd，J ₁ ＝8.4，J ₂ ＝12.4Hz，1H)，1.80(s，3H)，1.52(s，9H).

Step four: synthesis of [ (4- {5- [4- (benzyloxy) -5-fluoro-2-methylphenyl ] -7-bromo-4- [ (2, 2-trifluoroethyl) oxy ] pyrrolo [3,2-d ] pyrimidin-6-yl } phenyl) amino ] carboxylic acid tert-butyl ester

Tert-butyl [ (4- {5- [4- (benzyloxy) -5-fluoro-2-methylphenyl ] -4- [ (2, 2-trifluoroethyl) oxy ] pyrrolo [3,2-d ] pyrimidin-6-yl } phenyl) amino ] carboxylate (5.49 g,8.82 mmol) was dissolved in acetonitrile (5 mL), and N-bromosuccinimide (1.57 g,8.82 mmol) was slowly added dropwise at 0℃and stirred for 1 hour. LCMS monitored the end of the reaction. The reaction mixture was extracted with water and ethyl acetate, and the organic phase was dried over saturated brine, filtered and concentrated by column chromatography to give tert-butyl [ (4- {5- [4- (benzyloxy) -5-fluoro-2-methylphenyl ] -7-bromo-4- [ (2, 2-trifluoroethyl) oxy ] pyrrolo [3,2-d ] pyrimidin-6-yl } phenyl) carbamate (4.92 g, yield 79.5%).

LCMS：m/z 700.8[M+H] ⁺ ，702.8[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝9.57(s，1H)，8.60(s，1H)，7.54-7.29(m，10H)，7.11(d，J＝9.1Hz，1H)，5.20-5.06(m,2H)，5.05-4.92(m，2H)，1.72(s，3H)，1.47(s，9H).

Step five: synthesis of [ (4- {5- [4- (benzyloxy) -5-fluoro-2-methylphenyl ] -7-methyl-4- [ (2, 2-trifluoroethyl) oxy ] pyrrolo [3,2-d ] pyrimidin-6-yl } phenyl) amino ] carboxylic acid tert-butyl ester

Tert-butyl [ (4- {5- [4- (benzyloxy) -5-fluoro-2-methylphenyl ] -7-bromo-4- [ (2, 2-trifluoroethyl) oxy ] pyrrolo [3,2-d ] pyrimidin-6-yl } phenyl) carbamate (5.0 g, 712. Mu. Mol) was dissolved in dioxane (50 mL) and water (10 mL) and methylboronic acid (4.26 g,71.3 mmol) and [1, 1-bis (diphenylphosphino) ferrocene ] palladium (II) dichloride (521 mg, 712. Mu. Mol) dichloromethane adduct and cesium carbonate (6.96 g,21.4 mmol) were added and the mixture stirred at 110℃for 1 hour. LCMS monitored the end of the reaction. The reaction mixture was extracted with water and ethyl acetate, and the organic phase was dried over saturated brine, filtered and concentrated by column chromatography to give tert-butyl [ (4- {5- [4- (benzyloxy) -5-fluoro-2-methylphenyl ] -7-methyl-4- [ (2, 2-trifluoroethyl) oxy ] pyrrolo [3,2-d ] pyrimidin-6-yl } phenyl) carbamate (1.90 g, yield 40.8%).

LCMS：m/z 637.3[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝9.51(s，1H)，8.55-8.47(m，1H),7.53-7.29(m，8H)，7.24(d，J＝8.8Hz，2H)，7.08(d，J＝9.1Hz，1H)，5.14(q，J＝11.8Hz，2H)，5.05-4.88(m，2H)，2.28(s，3H)，1.73-1.64(m，3H)，1.47(s，9H).

Step six: synthesis of 6- (4-aminophenyl) -5- [4- (benzyloxy) -5-fluoro-2-methylphenyl ] -7-methylpyrrolo [3,2-d ] pyrimidin-4-ol

Tert-butyl [ (4- {5- [4- (benzyloxy) -5-fluoro-2-methylphenyl ] -7-methyl-4- [ (2, 2-trifluoroethyl) oxy ] pyrrolo [3,2-d ] pyrimidin-6-yl } phenyl) amino ] carboxylate (1.90 g,2.98 mmol) and stearyl crown ether-6 (2.37 g,8.95 mmol) were dissolved in dimethyl sulfoxide (20 mL) and water (10 mL) followed by potassium hydroxide (1.67 g,29.8 mmol). Stirred at 90℃for 1 hour. LCMS monitored the end of the reaction. The reaction solution was extracted with water and ethyl acetate, and the organic phase was dried over saturated brine, concentrated over sodium sulfate and poured into water (20 m 1) and stirred for 20 minutes to give 6- (4-aminophenyl) -5- [4- (benzyloxy) -5-fluoro-2-methylphenyl ] -7-methylpyrrolo [3,2-d ] pyrimidin-4-ol (1.30 g, yield 93.3%).

LCMS：m/z 455.1[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝7.81(s，1H)，7.49-7.32(m，5H)，7.21-7.04(m，2H)，6.85(d，J＝8.4Hz，2H)，6.45(d，J＝8.5Hz，2H)，5.26(s，2H)，5.12(s，2H)，3.51(s，1H)，2.15(s，3H)，1.74(s，3H).

Step seven: synthesis of 4- {5- [4- (benzyloxy) -5-fluoro-2-methylphenyl ] -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolo [3,2-d ] pyrimidin-6-yl } aniline

6- (4-aminophenyl) -5- [4- (benzyloxy) -5-fluoro-2-methylphenyl ] -7-methylpyrrolo [3,2-d ] pyrimidin-4-ol (1.0 g,2.20 mmol) was dissolved in acetonitrile (10 mL) followed by the addition of benzotriazole-1-tris (trimethylamino) -trifluorophosphate (2.92 g,6.60 mmol), 1.8-diazabicyclo [5.4.0] undec-7-ene (1.04 g,6.60 mmol) 4-methoxybenzylamine (3.02 g,22.0 mmol). The mixture was stirred at 80℃for 2 hours. LCMS monitored the end of the reaction. The reaction solution was extracted with water and dichloromethanol, and the organic phase was dried over saturated brine, filtered and concentrated by column chromatography to give 4- {5- [4- (benzyloxy) -5-fluoro-2-methylphenyl ] -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolo [3,2-d ] pyrimidin-6-yl } aniline (2.74 g, yield 39.0%).

LCMS：m/z 574.1[M+H] ⁺ .

Step eight: synthesis of 4- [6- (4-aminophenyl) -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolo [3,2-d ] pyrimidin-5-yl ] -2-fluoro-5-methylphenol

After dissolving 4- {5- [4- (benzyloxy) -5-fluoro-2-methylphenyl ] -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrro-lo [3,2-d ] pyrimidin-6-yl } aniline (2.20 g,3.84 mmol) in methanol (20 mL), palladium on carbon was added. The reaction solution was stirred at 20℃for 2 hours after three substitutions under an atmosphere of hydrogen (15 psi). LCMS monitored the end of the reaction. The reaction solution was purified by filtration, concentrated, and column chromatography to give 4- [6- (4-aminophenyl) -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolo [3,2-d ] pyrimidin-5-yl ] -2-fluoro-5-methylphenol (400 mg, yield 21.3%).

LCMS：m/z 484.2[M+H] ⁺ .

Step nine: synthesis of 4- (5- { 5-fluoro-2-methyl-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolio [3,2-d ] pyrimidin-6-yl) aniline

4- [6- (4-aminophenyl) -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolo [3,2-d ] pyrimidin-5-yl ] -2-fluoro-5-methylphenol (200 mg, 413. Mu. Mol) was dissolved in N, N-dimethylformamide (6 mL) cesium carbonate (399 mg, 827. Mu. Mol) was added to 2-chloro-4-methylpyrimidine (79.7 mg, 620. Mu. Mol). The reaction solution was stirred at 80℃for 2 hours. LCMS monitored the end of the reaction. The reaction mixture was extracted with water and dichloromethane, and the organic phase was dried over saturated brine, sodium sulfate and purified by filtration and concentrated column chromatography to give 4- (5- { 5-fluoro-2-methyl-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolio [3,2-d ] pyrimidin-6-yl) aniline (200 mg, yield 79.5%).

LCMS：m/z 576.2[M+H] ⁺ .

Step ten: synthesis of 3- (dioxy-phenyl- λ6-thio) -N- [4- (5- { 5-fluoro-2-methyl-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolio [3,2-d ] pyrimidin-6-yl) phenyl ] propanamide

4- (5- { 5-fluoro-2-methyl-4- [ (4-methylpyrimidin-2-YL) oxy ] phenyl } -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolo [3,2-d ] pyrimidin-6-YL) aniline (150 mg, 260. Mu. Mol) and 3- (benzenesulfonyl) propionic acid (139 mg, 651. Mu. Mol) were dissolved in dichloromethane (4 mL) and then O- (7-azabenzotriazol-1-YL) -N, N, N, N-tetramethylurea hexafluorophosphine salt (247 mg, 651. Mu. Mol) and N, N-diisopropylethylamine (101 mg, 781. Mu. Mol) were added. The reaction solution was stirred at 25℃for 1 hour. LCMS monitored the end of the reaction. The reaction solution was extracted with water and ethyl acetate, and the organic phase was washed with saturated brine, dried over sodium sulfate, and purified by filtration and concentration column chromatography to give 3- (dioxy-phenyl-. Lamda.6-thio) -N- [4- (5- { 5-fluoro-2-methyl-4- [ (4-methylpyrimidin-2-yl) oxy) phenyl ] phenyl } -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] propionamide (190 mg, yield 79.9%).

LCMS：m/z 772.4[M+H] ⁺ .

Step eleven: synthesis of N- [4- (4-amino-5- { 5-fluoro-2-methyl-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methylpyrrolio [3,2-d ] pyrimidin-6-yl) phenyl ] -3- (dioxy-phenylene- λ6-thio) propanamide

3- (Dioxyphenyl-. Lamda.6-thio) -N- [4- (5- { 5-fluoro-2-methyl-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolio [3,2-d ] pyrimidin-6-yl) phenyl ] propionamide (80.0 mg, 103. Mu. Mol) was dissolved in trifluoroacetic acid (0.5 mL) under nitrogen, and trifluoromethanesulfonic acid (1 mL) was slowly added, followed by stirring at 25℃for 2 hours. LCMS monitored the end of the reaction. The reaction solution was adjusted to pH 7-8 with saturated sodium bicarbonate solution at 0deg.C, extracted with water and dichloromethane, and the organic phase was washed with saturated brine, dried over sodium sulfate, filtered and concentrated to give N- [4- (4-amino-5- { 5-fluoro-2-methyl-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methylpyrrolio [3,2-d ] pyrimidin-6-yl) phenyl ] -3- (dioxy-phenyl-. Lamda.6-thio) propanamide (50.0 mg, yield 74.0%).

LCMS：m/z 652.2[M+H] ⁺ .

Step twelve: synthesis of N- [4- (4-amino-5- { 5-fluoro-2-methyl-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methylpyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] acrylamide

N- [4- (4-amino-5- { 5-fluoro-2-methyl-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methylpyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] -3- (dioxy-phenyl-. Lamda.6-thio) propanamide (50.0 mg,76. Mu. Mol) was dissolved in tetrahydrofuran (1 mL) under a nitrogen atmosphere, and the reaction solution was stirred at 25℃for 1 hour. LCMS monitored the end of the reaction. The reaction mixture was extracted with water and ethyl acetate, and the organic phase was dried over saturated brine, filtered and concentrated and purified by reverse phase separation to give N- [4- (4-amino-5- { 5-fluoro-2-methyl-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methylpyrrolio [3,2-d ] pyrimidin-6-yl) phenyl ] acrylamide (8.60 mg, yield 21.5%).

LCMS：m/z 510.2[M+H] ⁺ .

¹ H NMR(400MHz，ACETONITRILE-d3)δ＝8.57(br s，1H)，8.38(d，J＝5.0Hz，1H)，8.28(s，1H),7.65(d，J＝8.5Hz，2H)，7.45(d，J＝10.5Hz，1H)，7.30(d，J＝8.5Hz，2H)，7.18(d，J＝8.5Hz，1H),7.06(d，J＝5.0Hz，1H)，6.35-6.31(m，2H)，5.77-5.72(m，1H)，4.72(br s，2H)，2.39(s，3H)，2.27(s，3H)，1.79(s，3H).

Example 77:

n- [4- (4-amino-5- {2, 5-difluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methylpyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] acrylamide:

the synthetic route is as follows:

step one: synthesis of 1- (benzyloxy) -2, 5-difluoro-4-nitrobenzene

1,2, 4-trifluoro-5-nitro-benzene (24.5 g,138mmol,15.8 mL) was dissolved in N, N-dimethylformamide (250 mL), and benzyl alcohol (14.9 g,138mmol,14.3 mL) and potassium carbonate (38.2 g,277 mmol) were added sequentially. The reaction solution was stirred at 25℃for 6 hours. TLC detection was complete and purification by column chromatography gave 1- (benzyloxy) -2, 5-difluoro-4-nitrobenzene (22.3 g,60.4% yield) as a yellow solid.

¹ H NMR(400MHz，DMSO-d6)δ＝8.15(dd，J＝7.3，10.8Hz，1H)，7.61(dd，J＝7.0，13.1Hz，1H)，7.51-7.35(m，5H)，5.32(s，2H).

Step two: synthesis of 4- (benzyloxy) -2, 5-difluoroaniline

1- (benzyloxy) -2, 5-difluoro-4-nitrobenzene (10 g,37.7 mmol), iron powder (10.5 g,188 mmol), acetic acid (11.3 g,188mmol,10.8 mL) were dissolved in ethanol (100 mL) and water (20 mL) and stirred at 80℃for 1 hour. After completion of TLC detection reaction, water-washed extraction, purification by column chromatography gave a brown solid (5.5 g,62.0% yield).

¹ H NMR(400MHz，DMSO-d6)δ＝7.46-7.30(m，5H)，7.02(dd，J＝7.9，12.3Hz，1H)，6.61(dd，J＝8.5，12.9Hz，1H)，5.01(s，2H)，4.94(s，2H).

Step three: synthesis of [ (4- {5- [4- (benzyloxy) -2, 5-difluorophenyl ] -4- [ (2, 2-trifluoroethyl) oxy ] pyrrolo [3,2-d ] pyrimidin-6-yl } phenyl) amino ] carboxylic acid tert-butyl ester

Tert-butyl { [4- ({ 5-bromo-6- [ (2, 2-trifluoroethyl) oxy ] pyrimidin-4-yl } ethynyl) phenyl ] amino } carboxylate (6.50 g,13.7 mmol) was dissolved in dioxane (120 ml), 4- (benzyloxy) -2, 5-difluoroaniline (3.40 g,14.4 mmol), tris (dibenzylideneacetone) dipalladium (1.01 g,1.10 mmol), 4,5 bis-diphenylphosphine-9, 9-dimethylxanthene (1.27 g,2.20 mmol) and cesium carbonate (9.87 g,30.2 mmol) were added under nitrogen, and then stirred at 110℃for 12 hours. LCMS monitored the end of the reaction. The reaction mixture was extracted with water and ethyl acetate, and the organic phase was dried over saturated brine, filtered and concentrated by column chromatography to give tert-butyl [ (4- {5- [4- (benzyloxy) -2, 5-difluorophenyl ] -4- [ (2, 2-trifluoroethyl) oxy ] pyrrolo [3,2-d ] pyrimidin-6-yl } phenyl) amino ] carboxylate (6.04 g, yield 68.1%).

LCMS：m/z 627.1[M+H] ⁺ .

1HNMR(400MHz，CHLOROFORM-d)δ＝9.72-9.46(m，1H)，8.57-8.50(m，1H)，7.69(dd，J ₁ ＝7.4，J ₂ ＝11.3Hz，1H)，7.54-7.24(m，10H)，7.02-6.91(m，1H)，5.29-5.16(m，2H)，5.08-4.95(m，2H)，1.48(s，9H).

Step four: synthesis of [ (4- {5- [4- (benzyloxy) -2, 5-difluorophenyl ] -7-bromo-4- [ (2, 2-trifluoroethyl) oxy ] pyrrolo [3,2-d ] pyrimidin-6-yl } phenyl) amino ] carboxylic acid tert-butyl ester

/>

Tert-butyl [ (4- {5- [4- (benzyloxy) -2, 5-difluorophenyl ] -4- [ (2, 2-trifluoroethyl) oxy ] pyrrolo [3,2-d ] pyrimidin-6-yl } phenyl) amino ] carboxylate (6.00 g,9.58 mmol) was dissolved in acetonitrile (60 mL), and N-bromosuccinimide (1.57 g,8.82 mmol) was slowly added dropwise thereto at 0℃and stirred for 1 hour. LCMS monitored the end of the reaction. The reaction mixture was extracted with water and ethyl acetate, and the organic phase was dried over saturated brine, filtered and concentrated by column chromatography to give tert-butyl [ (4- {5- [4- (benzyloxy) -2, 5-difluorophenyl ] -7-bromo-4- [ (2, 2-trifluoroethyl) oxy ] pyrrolo [3,2-d ] pyrimidin-6-yl } phenyl) carbamate (3.00 g, yield 42.5%).

LCMS：m/z 704.9[M+H] ⁺ ，706.9[M+H] ⁺ .

¹ HNMR(400MHz，DMSO-d6)δ＝9.59(s，1H)，8.63(s，1H)，7.70(dd，J ₁ ＝7.3，J ₂ ＝11.2Hz，1H)，7.54-7.16(m，10H)，5.25-4.99(m，4H)，1.47(s，9H).

Step five: synthesis of [ (4- {5- [4- (benzyloxy) -2, 5-difluorophenyl ] -7-methyl-4- [ (2, 2-trifluoroethyl) oxy ] pyrrolo [3,2-d ] pyrimidin-6-yl } phenyl) amino ] carboxylic acid tert-butyl ester

Tert-butyl [ (4- {5- [4- (benzyloxy) -2, 5-difluorophenyl ] -7-bromo-4- [ (2, 2-trifluoroethyl) oxy ] pyrrolo [3,2-d ] pyrimidin-6-yl } phenyl) amino ] carboxylate (3.00 g,42.5 mmol) was dissolved in dioxane (40 mL) and water (20 mL) followed by the addition of methylboronic acid (2.54 g,425 mmol) and [1, 1-bis (diphenylphosphino) ferrocene ] palladium (II) dichloride dichloromethane adduct (3.11 g,4.25 mmol) and cesium carbonate (41.5 g,128 mmol). The mixture was stirred at 110℃for 1 hour. LCMS monitored the end of the reaction. The reaction mixture was extracted with water and ethyl acetate, and the organic phase was dried over saturated brine, filtered and concentrated by column chromatography to give tert-butyl [ (4- {5- [4- (benzyloxy) -2, 5-difluorophenyl ] -7-methyl-4- [ (2, 2-trifluoroethyl) oxy ] pyrrolo [3,2-d ] pyrimidin-6-yl } phenyl) carbamate (1.80 g, yield 65.2%).

LCMS：m/z 641.1[M+H] ⁺ .

¹ HNMR(400MHz，DMSO-d6)δ＝9.55(s，1H)，8.55(s，1H)，7.63-7.20(m，11H)，5.27-5.12(m，2H)，5.08-4.93(m，2H)，2.27(s，3H)，1.47(s，9H).

Step six: synthesis of 6- (4-aminophenyl) -5- [4- (benzyloxy) -2, 5-difluorophenyl ] -7-methylpyrrolo [3,2-d ] pyrimidin-4-ol

Tert-butyl [ (4- {5- [4- (benzyloxy) -2, 5-difluorophenyl ] -7-methyl-4- [ (2, 2-trifluoroethyl) oxy ] pyrrolo [3,2-d ] pyrimidin-6-yl } phenyl) amino ] carboxylate (2.70 g,4.21 mmol) and octadecyl-ether-6 (3.34 g,12.6 mmol) were dissolved in dimethyl sulfoxide (20 mL) and water (10 mL) and potassium hydroxide (2.36 g,42.1 mmol) was added. Stirred at 90℃for 1 hour. LCMS monitored the end of the reaction. The reaction mixture was extracted with water and ethyl acetate, and the organic phase was dried over saturated brine, concentrated over sodium sulfate and poured into water (20 ml) and stirred for 20 minutes to give 6- (4-aminophenyl) -5- [4- (benzyloxy) -2, 5-difluorophenyl ] -7-methylpyrrolo [3,2-d ] pyrimidin-4-ol (1.08 g, yield 55.8%).

LCMS：m/z 459.1[M+H] ⁺ .

Step seven: synthesis of 4- {5- [4- (benzyloxy) -2, 5-difluorophenyl ] -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolo [3,2-d ] pyrimidin-6-yl } aniline

6- (4-aminophenyl) -5- [4- (benzyloxy) -2, 5-difluorophenyl ] -7-methylpyrro-o [3,2-d ] pyrimidin-4-ol (1.00 g,2.18 mmol) was dissolved in acetonitrile (10 mL) followed by the addition of benzotriazole-1-tris (trimethylamino) -trifluorophosphate (2.89 g,6.54 mmol), 1.8-diazabicyclo [5.4.0] deca-7-ene (996 mg,6.54mmol, 986. Mu.L), 4-methoxybenzylamine (2.99 g,21.8mmol,2.83 mL). The mixture was stirred at 80℃for 2 hours. LCMS monitored the end of the reaction. The reaction solution was extracted with water and dichloromethanol, and the organic phase was washed with saturated brine, dried over sodium sulfate, filtered and concentrated by column chromatography to give 4- {5- [4- (benzyloxy) -2, 5-difluorophenyl ] -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolo [3,2-d ] pyrimidin-6-yl } aniline (2.34 g, crude product).

LCMS：m/z 578.2[M+H] ⁺ .

Step eight: synthesis of 4- [6- (4-aminophenyl) -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolo [3,2-d ] pyrimidin-5-yl ] -2, 5-difluorophenol

After dissolving 4- {5- [4- (benzyloxy) -2, 5-difluorophenyl ] -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrro-lo [3,2-d ] pyrimidin-6-yl } aniline (2.34 g,4.05 mmol) in methanol (20 mL), palladium on carbon was added. The reaction solution was stirred at 20℃for 2 hours after three substitutions under an atmosphere of hydrogen (15 psi). LCMS monitored the end of the reaction. The reaction solution was purified by filtration, concentrated, and column chromatography to give 4- [6- (4-aminophenyl) -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolo [3,2-d ] pyrimidin-5-yl ] -2, 5-difluorophenol (550 mg, yield 27.8%).

LCMS：m/z 488.1[M+H] ⁺ .

Step nine: synthesis of 4- (5- {2, 5-difluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolio [3,2-d ] pyrimidin-6-yl) aniline

/>

4- [6- (4-aminophenyl) -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolo [3,2-d ] pyrimidin-5-yl ] -2, 5-difluorophenol (420 mg, 861. Mu. Mol) was dissolved in N, N-dimethylformamide (6 mL) and cesium carbonate (280 mg, 861. Mu. Mol), 2-chloro-4-methylpyrimidine (886 mg,6.89 mmol) was added. The reaction solution was stirred at 80℃for 2 hours. LCMS monitored the end of the reaction. The reaction mixture was extracted with water and dichloromethane, and the organic phase was dried over saturated brine, sodium sulfate and purified by filtration and concentrated column chromatography to give 4- (5- {2, 5-difluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolio [3,2-d ] pyrimidin-6-yl) aniline (220 mg, yield 44.0%).

LCMS：m/z 580.2[M+H] ⁺ .

Step ten: synthesis of N- [4- (5- {2, 5-difluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolio [3,2-d ] pyrimidin-6-yl) phenyl ] -3- (dioxy-phenyl-. Lamda.6-thio) propanamide

4- (5- {2, 5-difluoro-4- [ (4-methylpyrimidin-2-YL) oxy ] phenyl } -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolo [3,2-d ] pyrimidin-6-YL) aniline (200 mg, 345. Mu. Mol) and 3- (benzenesulfonyl) propionic acid (369 mg,1.73 mmol) were dissolved in dichloromethane (1 mL) and O- (7-azabenzotriazol-1-YL) -N, N, N, N-tetramethylurea hexafluorophosphine salt (656 mg,1.73 mmol) and N, N-diisopropylethylamine (267 mg,2.07 mmol) were added. The reaction solution was stirred at 25℃for 1 hour. LCMS monitored the end of the reaction. The reaction solution was extracted with water and ethyl acetate, and the organic phase was dried over saturated brine, and concentrated by filtration and column chromatography to give N- [4- (5- {2, 5-difluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolio [3,2-d ] pyrimidin-6-yl) phenyl ] -3- (dioxy-phenyl-. Lamda.6-thio) propanamide (260 mg, yield 53.4%).

LCMS：m/z 776.2[M+H] ⁺ .

Step eleven: synthesis of N- [4- (4-amino-5- {2, 5-difluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methylpyrrolio [3,2-d ] pyrimidin-6-yl) phenyl ] -3- (dioxy-phenyl- λ6-thio) propanamide

N- [4- (5- {2, 5-difluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolio [3,2-d ] pyrimidin-6-yl) phenyl ] -3- (dioxy-phenylene- λ6-thio) propanamide (190 mg, 244. Mu. Mol) was dissolved in trifluoroacetic acid (0.5 mL) under nitrogen, and then trifluoromethanesulfonic acid (1 mL) was slowly added, followed by stirring at 25℃for 2 hours. LCMS monitored the end of the reaction. The reaction solution was adjusted to pH 7-8 with saturated sodium bicarbonate solution at 0deg.C, extracted with water and dichloromethane, the organic phase was washed with saturated brine, dried over sodium sulfate, filtered and concentrated to give N- [4- (4-amino-5- {2, 5-difluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methylpyrrolio [3,2-d ] pyrimidin-6-yl) phenyl ] -3- (dioxy-phenylene- λ6-thio) propanamide (160 mg, yield 99.6%)

LCMS：m/z 656.1[M+H] ⁺ .

Step twelve: synthesis of N- [4- (4-amino-5- {2, 5-difluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methylpyrrolio [3,2-d ] pyrimidin-6-yl) phenyl ] acrylamide

N- [4- (4-amino-5- {2, 5-difluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methylpyrrolino [3,2-d ] pyrimidin-6-yl) phenyl ] -3- (dioxy-phenyl-. Lamda.6-thio) propanamide (160 mg, 244. Mu. Mol) was dissolved in tetrahydrofuran (1 mL) under nitrogen atmosphere, and the reaction solution was stirred at 20℃for 1 hour. LCMS monitored the end of the reaction. The reaction mixture was extracted with water and ethyl acetate, and the organic phase was washed with saturated brine, dried over sodium sulfate, filtered and concentrated and separated in reverse phase to give N- [4- (4-amino-5- {2, 5-difluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methylpyrrolio [3,2-d ] pyrimidin-6-yl) phenyl ] acrylamide (21.4 mg, yield 16.7%).

LCMS：m/z 514.3[M+H] ⁺ .

¹ HNMR(400MHz，DMSO-d6)δ＝10.29(s，1H)，8.50(d，J＝5.0Hz，1H)，8.26(s，1H)，7.87(dd，J ₁ ＝7.2，J ₂ ＝10.1Hz，1H)，7.70(br d，J＝8.5Hz，2H)，7.52(dd，J ₁ ＝7.3，J ₂ ＝9.6Hz，1H)，7.27-7.18(m，3H)，6.48-6.38(m，1H)，6.31-6.22(m，1H)，5.85-5.72(m，3H)，2.38(s，3H)，2.20(s，3H).

Example 78:

n- [4- (4-amino-5- {3, 5-difluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methylpyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] acrylamide:

the synthetic route is as follows:

step one: synthesis of [ (4- {5- [4- (benzyloxy) -2, 5-difluorophenyl ] -4- [ (2, 2-trifluoroethyl) oxy ] pyrrolo [3,2-d ] pyrimidin-6-yl } phenyl) amino ] carboxylic acid tert-butyl ester

LCMS：m/z 627.1[M+H] ⁺ .

¹ HNMR(400MHz，CHLOROFORM-d)δ＝9.72-9.46(m，1H)，8.57-8.50(m，1H)，7.69(dd，J ₁ ＝7.4，J ₂ ＝11.3Hz，1H)，7.54-7.24(m，10H)，7.02-6.91(m，1H)，5.29-5.16(m，2H)，5.08-4.95(m，2H)，1.48(s，9H).

Step two: synthesis of [ (4- {5- [4- (benzyloxy) -3, 5-difluorophenyl ] -7-bromo-4- [ (2, 2-trifluoroethyl) oxy ] pyrrolo [3,2-d ] pyrimidin-6-yl } phenyl) amino ] carboxylic acid tert-butyl ester

Tert-butyl [ (4- {5- [4- (benzyloxy) -2, 5-difluorophenyl ] -4- [ (2, 2-trifluoroethyl) oxy ] pyrrolo [3,2-d ] pyrimidin-6-yl } phenyl) amino ] carboxylate (6.29 g,10.0 mmol) was dissolved in acetonitrile (60 mL), and N-bromosuccinimide (1.79 g,10.0 mmol) was slowly added dropwise thereto at 0℃and stirred for 1 hour. LCMS monitored the end of the reaction. The reaction solution was extracted with water and ethyl acetate, and the organic phase was dried over saturated brine, filtered and concentrated by column chromatography to give tert-butyl [ (4- {5- [4- (benzyloxy) -3, 5-difluorophenyl ] -7-bromo-4- [ (2, 2-trifluoroethyl) oxy ] pyrrolo [3,2-d ] pyrimidin-6-yl } phenyl) carbamate (6.90 g, yield 97.4%).

LCMS：m/z 704.9[M+1] ⁺ ，706.9[M+3] ⁺ .

¹ HNMR(400MHz，DMSO-d6)δ＝9.61(s，1H)，8.62(s，1H)，7.49(d，J＝8.6Hz，2H)，7.40-7.18(m，9H)，5.13(s，2H)，5.01(q，J＝8.8Hz，2H)，1.48(s，9H).

Step three: synthesis of [ (4- {5- [4- (benzyloxy) -3, 5-difluorophenyl ] -7-methyl-4- [ (2, 2-trifluoroethyl) oxy ] pyrrolo [3,2-d ] pyrimidin-6-yl } phenyl) amino ] carboxylic acid tert-butyl ester

Tert-butyl [ (4- {5- [4- (benzyloxy) -3, 5-difluorophenyl ] -7-bromo-4- [ (2, 2-trifluoroethyl) oxy ] pyrrolo [3,2-d ] pyrimidin-6-yl } phenyl) amino ] carboxylate (5.40 g,7.65 mmol) was dissolved in dioxane (4 mL) followed by the addition of methylboronic acid (4.58 g,76.5 mmol), [1, 1-bis (diphenylphosphino) ferrocene ] palladium (II) dichloride (560 mg, 765. Mu. Mol) and cesium carbonate (7.48 g,22.9 mmol). The mixture was stirred at 110℃for 1 hour. LCMS monitored the end of the reaction. The reaction mixture was extracted with water and ethyl acetate, and the organic phase was dried over saturated brine, filtered and concentrated by column chromatography to give tert-butyl [ (4- {5- [4- (benzyloxy) -3, 5-difluorophenyl ] -7-methyl-4- [ (2, 2-trifluoroethyl) oxy ] pyrrolo [3,2-d ] pyrimidin-6-yl } phenyl) carbamate (2.00 g, yield 31.4%).

LCMS：m/z 641.1[M+H] ⁺ .

¹ HNMR(400MHz，DMSO-d6)δ＝9.56(s，1H)，8.54(s，1H)，7.48(br d，J＝8.4Hz，2H)，7.35(s，5H)，7.24-7.07(m，4H)，5.12(s，2H)，4.99(q，J＝8.8Hz，2H)，2.25(s，3H)，1.48(s，9H).

Step four: synthesis of 6- (4-aminophenyl) -5- [4- (benzyloxy) -3, 5-difluorophenyl ] -7-methylpyrrolo [3,2-d ] pyrimidin-4-ol

Tert-butyl [ (4- {5- [4- (benzyloxy) -3, 5-difluorophenyl ] -7-methyl-4- [ (2, 2-trifluoroethyl) oxy ] pyrrolo [3,2-d ] pyrimidin-6-yl } phenyl) amino ] carboxylate (2.00 g,3.12 mmol) and octadecyl-ether-6 (2.48 g,9.37 mmol) were dissolved in dimethyl sulfoxide (20 mL) and water (10 mL) and potassium hydroxide (1.75 g,31.2 mmol) was added. Stirred at 90℃for 1 hour. LCMS monitored the end of the reaction. The reaction mixture was extracted with water and ethyl acetate, and the organic phase was dried over saturated brine, concentrated over sodium sulfate, and poured into water (20 ml) and stirred for 20 minutes to give 6- (4-aminophenyl) -5- [4- (benzyloxy) -3, 5-difluorophenyl ] -7-methylpyrrolo [3,2-d ] pyrimidin-4-ol (1.20 g, yield 79.6%).

LCMS：m/z 459.1[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝11.89(br d，J＝1.3Hz，1H)，7.85(br s，1H)，7.38(br s，5H)，7.00(br d，J＝8.8Hz，2H)，6.81(br d，J＝7.4Hz，2H)，6.50(br d，J＝7.1Hz，2H)，5.35(br s，2H)，5.15(br s，2H)，2.13(br s，3H).

Step five: synthesis of 4- {5- [4- (benzyloxy) -3, 5-difluorophenyl ] -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolo [3,2-d ] pyrimidin-6-yl } aniline

6- (4-aminophenyl) -5- [4- (benzyloxy) -3, 5-difluorophenyl ] -7-methylpyrro-o [3,2-d ] pyrimidin-4-ol (500 mg,1.09 mmol) was dissolved in acetonitrile (10 mL) followed by the addition of benzotriazole-1-tris (trimethylamino) -trifluorophosphate (1.50 g,10.9 mmol), 1.8-diazabicyclo [5.4.0] undec-7-ene (1.45 g,3.27 mmol) and 4-methoxybenzylamine (498 mg,3.27 mmol). The mixture was stirred at 80℃for 2 hours. LCMS monitored the end of the reaction. The reaction solution was extracted with water and dichloromethanol, and the organic phase was washed with saturated brine, dried over sodium sulfate, filtered and concentrated by column chromatography to give 4- {5- [4- (benzyloxy) -3, 5-difluorophenyl ] -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolo [3,2-d ] pyrimidin-6-yl } aniline (3.86 g, crude product).

LCMS：m/z 578.3[M+H] ⁺ .

Step six: synthesis of 4- [6- (4-aminophenyl) -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolo [3,2-d ] pyrimidin-5-yl ] -2, 6-difluorophenol

4- {5- [4- (benzyloxy) -3, 5-difluorophenyl ] -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolo [3,2-d ] pyrimidin-6-yl } aniline (3.86 g,330 mmol) was dissolved in methanol (20 mL) and palladium on carbon was added. The reaction solution was replaced three times under an atmosphere of hydrogen (15 psi) and stirred at 20℃for 2 hours. LCMS monitored the end of the reaction. The reaction solution was purified by filtration, concentrated, and column chromatography to give 4- [6- (4-aminophenyl) -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolo [3,2-d ] pyrimidin-5-yl ] -2, 6-difluorophenol (760 mg, yield 27.8%).

LCMS：m/z 488.1[M+H] ⁺ .

Step seven: synthesis of 4- (5- {3, 5-difluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolio [3,2-d ] pyrimidin-6-yl) aniline

4- [6- (4-aminophenyl) -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolo [3,2-d ] pyrimidin-5-yl ] -2, 6-difluorophenol (610 mg,1.25 mmol) was dissolved in N, N-dimethylformamide (6 mL back) cesium carbonate (1.63 g,5.01 mmol) and 2-chloro-4-methylpyrimidine (643 mg,5.01 mmol) were added. The reaction solution was stirred at 80℃for 2 hours. LCMS monitored the end of the reaction. The reaction mixture was extracted with water and dichloromethane, and the organic phase was dried over saturated brine, filtered and concentrated by column chromatography to give 4- (5- {3, 5-difluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolio [3,2-d ] pyrimidin-6-yl) aniline (380 mg, yield 26.7%).

LCMS：m/z 580.2[M+H] ⁺ .

Step eight: synthesis of 4- (5- {3, 5-difluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolio [3,2-d ] pyrimidin-6-yl) aniline

4- (5- {3, 5-difluoro-4- [ (4-methylpyrimidin-2-YL) oxy ] phenyl } -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolo [3,2-d ] pyrimidin-6-YL) aniline (320 mg, 552. Mu. Mol) and 3- (benzenesulfonyl) propionic acid (236 mg,1.10 mmol) were dissolved in dichloromethane (1 mL) and O- (7-azabenzotriazol-1-YL) -N, N, N, N-tetramethylurea hexafluorophosphine salt (524 mg,1.38 mmol) and N, N-diisopropylethylamine (214 mg,1.66 mmol) were added. The reaction solution was stirred at 25℃for 1 hour. LCMS monitored the end of the reaction. The reaction solution was extracted with water and ethyl acetate, and the organic phase was washed with saturated brine, dried over sodium sulfate, and purified by filtration and concentration column chromatography to give 4- (5- {3, 5-difluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolio [3,2-d ] pyrimidin-6-yl) aniline (550 mg, crude product).

LCMS：m/z 776.2[M+H] ⁺ .

Step nine: synthesis of N- [4- (4-amino-5- {3, 5-difluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methylpyrrolio [3,2-d ] pyrimidin-6-yl) phenyl ] -3- (dioxy-phenyl- λ6-thio) propanamide

4- (5- {3, 5-difluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methylpyrrolio [3,2-d ] pyrimidin-6-yl) aniline (250 mg, 322. Mu. Mol) was dissolved in trifluoroacetic acid (0.5 mL) under nitrogen, then trifluoromethanesulfonic acid (1 mL) was slowly added, and finally stirred at 25℃for 2 hours. LCMS monitored the end of the reaction. The reaction solution was adjusted to pH 7-8 with saturated sodium bicarbonate solution at 0deg.C, extracted with water and dichloromethane, and the organic phase was washed with saturated brine, dried over sodium sulfate, filtered and concentrated to give N- [4- (4-amino-5- {3, 5-difluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methylpyrrolio [3,2-d ] pyrimidin-6-yl) phenyl ] -3- (dioxy-phenylene- λ6-thio) propanamide (211 mg, yield 99.8%).

LCMS：m/z 656.3[M+H] ⁺ .

Step ten: synthesis of N- [4- (4-amino-5- {3, 5-difluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methylpyrrolio [3,2-d ] pyrimidin-6-yl) phenyl ] acrylamide

N- [4- (4-amino-5- {3, 5-difluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methylpyrrolino [3,2-d ] pyrimidin-6-yl) phenyl ] -3- (dioxy-phenyl-. Lamda.6-thio) propanamide (210 mg, 320. Mu. Mol) was dissolved in tetrahydrofuran (1 mL) under a nitrogen atmosphere, and the reaction solution was stirred at 20℃for 1 hour. LCMS monitored the end of the reaction. The reaction mixture was extracted with water and ethyl acetate, and the organic phase was washed with saturated brine, dried over sodium sulfate, filtered and concentrated and separated by preparative HPLC to give N- [4- (4-amino-5- {3, 5-difluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methylpyrrolio [3,2-d ] pyrimidin-6-yl) phenyl ] acrylamide (35.8 mg, yield 21.4%).

LCMS：m/z 514.2[M+H] ⁺ .

¹ HNMR(400MHz，DMSO-d6)δ＝10.29(s，1H)，8.51(d，J＝5.0Hz，1H)，8.26(s，1H)，7.70(d，J＝8.5Hz,2H)，7.38(d，J＝8.1Hz，2H)，7.29-7.21(m，3H)，6.50-6.36(m，1H),6.32-6.21(m，1H)，5.95-5.70(m,3H)，2.39(s，3H)，2.18(s，3H).

Example 79:

n- (4- (4-amino-5- (2, 6-difluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide:

the synthetic route is as follows:

step one: synthesis of 3, 5-difluoro-4-nitrophenol

3, 5-difluorophenol (19.5 g,149 mmol) was dissolved in 200mL of methylene chloride, 90% concentrated nitric acid (16.6 g,237 mmol) was added at 0deg.C for 1 hour, and after completion of TLC detection, the reaction solution was added to water, extracted with methylene chloride, dried, concentrated and column-chromatographed to give 3, 5-difluoro-4-nitrophenol (7.05 g, yield 26.8%).

¹ H NMR(400MHz，DMSO-d6)δ＝11.8(s，1H)，6.87-6.56(m，2H).

Step two: synthesis of 5- (benzyloxy) -1, 3-difluoro-2-nitrobenzene

3, 5-difluoro-4-nitrophenol (7.05 g,40.2 mmol) was dissolved in 7mLN, N-dimethylformamide, potassium carbonate (5.62 g,40.6 mmol) and benzyl bromide (7.02 g,41.0 mmol) were added, the reaction was allowed to react at 20℃for 12 hours, after completion of the TLC detection, the reaction solution was added to 700mL of water, and the filter cake was obtained as 5- (benzyloxy) -1, 3-difluoro-2-nitrobenzene (9.50 g, yield 88.9%).

¹ H NMR(400MHz，DMSO-d6)δ＝7.51-7.35(m，5H)，7.22(d，J＝11.0Hz，2H)，5.25(s，2H).

Step three: synthesis of 4- (benzyloxy) -2, 6-difluoroaniline

5- (benzyloxy) -1, 3-difluoro-2-nitrobenzene (9.50 g,35.8 mmol) was dissolved in 50mL of ethanol, 10mL of water, reduced iron powder (10.0 g, 178 mmol) and ammonium chloride (5.00 g,93.4 mmol) were added, reacted at 80℃for 3 hours, after which the reaction was completed by LCMS, filtered, concentrated and column chromatographed to give 4- (benzyloxy) -2, 6-difluoroaniline (5.05 g, 59.9% yield).

LCMS：m/z 236.1[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝7.45-7.28(m，5H)，6.73-6.65(m，2H)，4.99(s，2H)，4.63(s，2H).

Step four: synthesis of tert-butyl (4- (5- (4- (benzyloxy) -2, 6-difluorophenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate

(4- ((5-bromo-6- (2, 2-trifluoroethoxy) pyrimidin-4-yl) ethynyl) phenyl) carbamic acid tert-butyl ester (4.28 g,9.06 mmol) was dissolved in 21mL dioxane and 4- (benzyloxy) -2, 6-difluoroaniline (2.13 g,9.06 mmol), cesium carbonate (5.91 g,18.1 mmol), tris (dibenzylideneacetone) dipalladium (829 mg, 906. Mu. Mol) and 4, 5-bis (diphenylphosphorus) -9, 9-dimethylxanthene (1.05 g,1.81 mmol) were added to the solution to react at 90℃for 3 hours, LCMS detection was completed, and spin-dry and column chromatography gave (4- (5- (4- (benzyloxy) -2, 6-difluorophenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamic acid tert-butyl ester (3.80 g, 58.8%).

LCMS：m/z 627.6[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝9.58(s，1H)，8.56(s，1H)，7.52-7.33(m，7H)，7.26(d，J＝8.6Hz，2H)，7.07-6.94(m，3H)，5.16(s，2H)，5.03(q，J＝8.8Hz，2H)，1.47(s，9H).

Step five: synthesis of tert-butyl (4- (5- (4- (benzyloxy) -2, 6-difluorophenyl) -7-bromo-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate

Tert-butyl (4- (5- (4- (benzyloxy) -2, 6-difluorophenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (3.50 g,5.59 mmol) was dissolved in 35mL acetonitrile, N-bromosuccinimide (1.00 g,5.64 mmol) was added and stirring was carried out at 20℃for 2 hours, LCMS detected the end of the reaction and filtered to give tert-butyl (4- (5- (4- (benzyloxy) -2, 6-difluorophenyl) -7-bromo-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (3.50 g, yield 84.3%).

LCMS：m/z 704.8[M+H] ⁺ ，706.8[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝9.63(s，1H)，8.66(s，1H)，7.52(d，J＝8.8Hz，2H)，7.45-7.33(m，5H)，7.26(d，J＝8.8Hz，2H)，6.97(d，J＝9.8Hz，2H)，5.13(s，2H)，5.07(q，J＝8.8Hz，2H)，1.48(s，9H).

Step six: synthesis of tert-butyl (4- (5- (4- (benzyloxy) -2, 6-difluorophenyl) -7-methyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate

(4- (5- (4- (benzyloxy) -2, 6-difluorophenyl) -7-bromo-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamic acid tert-butyl ester (3.35 g,4.75 mmol) was dissolved in 33.5mL dioxane, methyl boric acid (1.68 g,28.0 mmol), 1-bis (t-butylphosphorus) ferrocene palladium chloride (928 mg,1.42 mmol) and cesium fluoride (1.85 g,12.1 mmol) were added and stirred at 100℃for 2 hours, LCMS was checked for the end of the reaction, concentrated and column chromatographed to give (4- (5- (4- (benzyloxy) -2, 6-difluorophenyl) -7-methyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamic acid tert-butyl ester (2.85 g, yield 91.8%).

LCMS：m/z 641.1[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝9.57(s，1H)，8.58(s，1H)，7.50(d，J＝8.6Hz，2H)，7.46-7.33(m，5H)，7.20(d，J＝8.6Hz，2H)，6.93(d，J＝9.6Hz，2H)，5.13(s，2H)，5.04(q，J＝8.8Hz，2H)，2.29(s，3H)，1.48(s，9H).

Step seven: synthesis of 6- (4-aminophenyl) -5- (4- (benzyloxy) -2, 6-difluorophenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-ol

Tert-butyl (4- (5- (4- (benzyloxy) -2, 6-difluorophenyl) -7-methyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) carbamate (2.85 g,4.45 mmol) was dissolved in 12 mLN-methylpyrrolidinone, 18-crown ether-6 (1.91 g,7.21 mmol), 6mL of water and potassium hydroxide (1.90 g,33.9 mmol) were added, stirred at 90℃for 12 hours, after completion of the LCMS detection reaction, extracted, concentrated and column chromatographed to give 6- (4-aminophenyl) -5- (4- (benzyloxy) -2, 6-difluorophenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-ol (1.61 g, yield 74.2%).

LCMS：m/z 459.0[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝11.93(s，1H)，7.86(s，1H)，7.48-7.34(m，5H)，6.90-6.79(m，4H)，6.49(d，J＝8.5Hz，2H)，5.33(s，2H)，5.10(s，2H)，2.15(s，3H).

Step eight: synthesis of 6- (4-aminophenyl) -5- (4- (benzyloxy) -2, 6-difluorophenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6- (4-aminophenyl) -5- (4- (benzyloxy) -2, 6-difluorophenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-ol (1.50 g,3.27 mmol) was dissolved in 28mL acetonitrile, benzotriazole-1-oxo-tris (dimethylaminophosphorus) hexafluorophosphate salt (3.65 g,8.25 mmol) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (1.03 g,6.77 mmol), p-methoxybenzylamine (4.28 g,31.1 mmol) was added after stirring for 1 hour at 20℃and 9 hours at 80℃and the S detection reaction ended, which was spin-dried and column chromatographed to give 6- (4-aminophenyl) -5- (4- (benzyloxy) -2, 6-difluorophenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (1.88 g, 61.6%) in 61% yield.

LCMS：m/z 578.2[M+H] ⁺ .

¹ H NMR(400MHz，ACETONITRILE-d3)δ＝8.46(s，1H)，7.36(d，J＝8.8Hz，2H)，7.16(d，J＝8.8Hz，2H)，6.97(d，J＝8.8Hz，2H)，6.93(br d，J＝8.5Hz，3H)，6.88(d，J＝8.8Hz，2H)，6.75(br d，J＝9.6Hz，2H)，6.61-6.57(m，2H)，5.99-5.92(m，1H)，5.05(s，2H)，4.69(d，J＝5.8Hz，2H)，3.80(s，2H)，3.74(s，3H)，2.25(s，3H).

Step nine: synthesis of 4- (6- (4-aminophenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl) -3, 5-difluorophenol

6- (4-aminophenyl) -5- (4- (benzyloxy) -2, 6-difluorophenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (1.58 g,2.74 mmol) was dissolved in 32mL of methanol, 10% wet palladium on carbon (960 mg, 902. Mu. Mol) was added, stirring was performed at 20deg.C for 2 hours in a hydrogen atmosphere, and the reaction was terminated by LCMS, filtered and dried to give 4- (6- (4-aminophenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl) -3, 5-difluorophenol (1.32 g, yield 51.4%).

LCMS：m/z 488.1[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.97(s，1H)，8.70(s，1H)，8.00(br s，2H)，7.13(d，J＝8.6Hz，2H)，6.96(br d，J＝3.4Hz，1H)，6.87(d，J＝8.6Hz，2H)，6.81(d，J＝8.5Hz，2H)，6.59(br d，J＝9.8Hz，2H)，6.51(d，J＝8.5Hz，2H)，4.70(br d，J＝5.8Hz，2H)，3.72(s，3H)，2.20(s，3H).

Step ten: synthesis of 6- (5-aminophenyl) -5- (2, 6-difluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine

4- (6- (4-aminophenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl) -3, 5-difluorophenol (1.17 g,2.40 mmol) was dissolved in 10mLN, N-dimethylformamide, potassium carbonate (351 mg,2.54 mmol) and 2-chloro-4-methylpyrimidine (700 mg,5.45 mmol) were added, stirring was performed at 90℃for 6 hours, LCMS detection was completed, and 6- (5-aminophenyl) -5- (2, 6-difluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (920 mg, yield 46.3%) was obtained by extraction, drying, filtration, spin-drying and column chromatography.

LCMS：m/z 580.1[M+H] ⁺ .

¹ H NMR(400MHz，ACETONITRILE-d3)δ＝8.46-8.37(m，2H)，7.26(br d，J＝8.6Hz，1H)，7.21-7.10(m，4H)，7.04(d，J＝8.8Hz，2H)，6.98(d，J＝8.5Hz，2H)，6.83(d，J＝8.6Hz，2H)，6.62(d，J＝8.5Hz，2H)，5.53-5.45(m，1H)，4.64(d，J＝5.6Hz，2H)，3.72(s，3H)，2.43(s，3H)，2.22(s，3H).

Step eleven: synthesis of N- (4- (5- (2, 6-difluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) -3- (phenylsulfonyl) propanamide

6- (5-aminophenyl) -5- (2, 6-difluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (850 mg,1.47 mmol) was dissolved in 15mL of dichloromethane, 3- (benzenesulfonyl) propionic acid (631 mg,2.95 mmo), O- (7-azabenzotriazol-1-yl) -N, N, N-tetramethylurea hexafluoro-phosphine salt (1.68 g,4.43 mmo) and N, N-diisopropylethylamine (676 mg,5.24 mmol) were added, the reaction was terminated by LCMS detection and N- (4- (5- (2, 6-difluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] phenyl) -propanamide was obtained by column chromatography in a yield of (12.45 g, 3.12 mg).

LCMS：m/z 776.3[M+H] ⁺ .

Step twelve: synthesis of N- (6- (4-amino-5- (2, 6-difluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) -3- (phenylsulfonyl) propanamide

/>

N- (4- (5- (2, 6-difluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) -3- (phenylsulfonyl) propanamide (1.12 g,1.44 mmol) was dissolved in 6mL of trifluoroacetic acid, 6mL of trifluoromethanesulfonic acid was added, the reaction was allowed to react at 20℃for 2 hours, LCMS detection was completed, saturated aqueous sodium bicarbonate solution was added to adjust the pH to 7, and N- (6- (4-amino-5- (2, 6-difluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) -3- (phenylsulfonyl) propanamide (930 mg, yield 71.7%) was extracted and dried.

LCMS：m/z 656.0[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.19(s，1H)，8.52(d，J＝5.0Hz，1H)，8.26(s，1H)，7.94-7.87(m，2H)，7.76-7.70(m，1H)，7.68-7.61(m，2H)，7.53(d，J＝8.6Hz，2H)，7.28(br d，J＝8.6Hz，2H)，7.23(d，J＝5.0Hz，1H)，7.18-7.11(m，2H)，5.87(br s，2H)，3.61(br t，J＝7.4Hz，2H)，2.75-2.69(m，2H)，2.40(s，3H)，2.18(s，3H).

Step thirteen: synthesis of N- (4- (4-amino-5- (2, 6-difluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide

N- (6- (4-amino-5- (2, 6-difluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) -3- (phenylsulfonyl) propanamide (300 mg, 457. Mu. Mol) was dissolved in 15mL tetrahydrofuran, trimethylpotassium oxide (59.8 mg, 466. Mu. Mol) was added, stirring was carried out at 20℃for 1 hour, LCMS detection reaction ended, spin-dried and N- (4- (4-amino-5- (2, 6-difluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) acrylamide (39.5 mg, 16.6%) was obtained by preparative HPLC.

LCMS：m/z 513.9[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.31(s，1H)，8.52(d，J＝5.0Hz，1H)，8.29(s，1H)，7.71(d，J＝8.5Hz，2H)，7.28(br d，J＝8.8Hz，2H)，7.24-7.16(m，3H)，6.49-6.38(m，1H)，6.31-6.21(m，1H)，6.00(br s，2H)，5.77(dd，J＝1.4，10.2Hz，1H)，2.39(s，3H)，2.20(s，3H).

Example 80:

n- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7- (hydroxymethyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] acrylamide:

the synthetic route is as follows:

step one: synthesis of 6- (4-amino-phenyl) -7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6, 7-dibromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (300 mg, 607. Mu. Mol) was dissolved in 6mL of dioxane, 4-amino-2-methylphenylboronic acid pinacol ester (146 mg, 667. Mu. Mol), potassium phosphate (255 mg,1.21 mmol), tetrakis (triphenylphosphine) palladium (210 mg, 182. Mu. Mol) and 4mL of water were added, stirred at 90℃for 2 hours, after completion of LCMS detection reaction, concentrated and column chromatography gave 6- (4-amino-2-methylphenyl) -7-bromo-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (190 mg, yield 61.8%).

LCMS：m/z 505.9[M+1] ⁺ ，507.9[M+3] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ8.50(d，J＝5.0Hz，1H)，8.26(s，1H)，7.59(dd，J＝2.3，10.8Hz，1H)，7.46(t，J＝8.6Hz，1H)，7.33(dd，J＝1.3，8.6Hz，1H)，7.22(d，J＝5.0Hz，1H)，7.00(d，J＝8.5Hz，2H)，6.51(d，J＝8.5Hz，2H)，5.80-5.64(m，2H)，5.48-5.32(m，2H)，2.42(s，3H).

Step two: synthesis of [ 4-amino-6- (4-aminophenyl) -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl ] methanol

6- (4-aminophenyl) -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7- (prop-1-en-2-yl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (70 mg,1.00 eq), 1- (tributyltin) -methanol (133 mg,3.00 eq) and (2-dicyclohexylphosphino-2, 4, 6-triisopropyl-1, 1-biphenyl) [2- (2-amino-1, 1-biphenyl) ] palladium (II) (32.0 mg,0.3 eq) were dissolved in 3mL dioxane. Stirred at 100℃for 3 hours. After completion of LCMS detection, purification by reverse phase column afforded [ 4-amino-6- (4-aminophenyl) -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl ] methanol (60 mg, crude) as a yellow solid.

LCMS：m/z 458.0[M+H] ⁺ .

Step three: synthesis of N- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7- (hydroxymethyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] acrylamide

[ 4-amino-6- (4-aminophenyl) -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl ] methanol (60 mg,1.00 eq) was dissolved in 2mL of tetrahydrofuran, and acryloyl chloride (11.8 mg,1.00 eq) was slowly added at 0deg.C and reacted at 20deg.C for 2 hours. LCMS detects the end of the reaction. Purification by reverse phase column gave N- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7- (hydroxymethyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] acrylamide as a white solid (33.0 mg, yield 47.2%).

LCMS：m/z 511.7[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ10.25(s，1H)，8.49(d，J＝5.0Hz，1H)，8.27(s，1H)，7.66(d，J＝8.8Hz，2H)，7.54(dd，J＝2.4，10.8Hz，1H)，7.45(t，J＝8.6Hz，1H)，7.34(d，J＝8.6Hz，2H)，7.25(td，J＝1.3，8.5Hz，1H)，7.20(d，J＝5.0Hz，1H)，6.48-6.37(m，1H)，6.31-6.23(m，1H)，5.80-5.74(m，1H)，5.64(br s，2H)，4.85(t，J＝4.8Hz，1H)，4.51(d，J＝4.5Hz，2H)，2.39(s，3H).

Example 81:

n- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7- (methoxymethyl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] acrylamide:

the synthetic route is as follows:

step one: synthesis of tributyl (methoxymethyl) stannane

Diisopropylamine (691 mg,1.10 eq) was dissolved in 10 ml of anhydrous tetrahydrofuran, then n-butyllithium (2.73 ml,1.10 eq) was slowly added to the reaction flask at-78 ℃ and stirred for 0.5 hours at-78 ℃. Subsequently, tributyltin hydrogen was slowly added to the reaction flask at-78 ℃ and stirred at 0 ℃ for 0.5 hours. The reaction mixture was cooled to-78℃and bromomethyl ether (776 mg,1.00 eq) was then added slowly to the flask and stirred at 20℃for 1 hour. After completion of the TLC detection reaction, tributyl (methoxymethyl) stannane (500 mg, yield 24.0%) was obtained as a white liquid by column purification.

¹ H NMR(400MHz，CHLOROFORM-d)δ3.63(s，2H)，3.22(s，3H)，1.49-1.38(m，6H)，1.24(J＝7.3，14.7Hz，6H)，0.88-0.79(m，15H).

Step two: synthesis of 6- (4-aminophenyl) -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7- (methoxymethyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6- (4-aminophenyl) -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7- (prop-1-en-2-yl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (200 mg,1.00 eq), tributyl (methoxymethyl) stannane (198mg, 15.0 eq), and chloro (2-dicyclohexylphosphino-2, 4, 6-triisopropyl-1, 1-biphenyl) [2- (2-amino-1, 1-biphenyl) ] palladium (II) (9.20 mg,0.3 eq) were dissolved in 3mL dioxane. Stirred at 100℃for 3 hours. After completion of LCMS detection, 6- (4-aminophenyl) -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7- (methoxymethyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (190 mg, crude) was obtained as a yellow solid by column purification.

LCMS：m/z 472.0[M+H] ⁺ .

Step three: synthesis of N- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7- (methoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] acrylamide

6- (4-aminophenyl) -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7- (methoxymethyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (40 mg,1.00 eq) was dissolved in 2mL of tetrahydrofuran, and acryloyl chloride (16.7 mg,1.00 eq) was slowly added at 0deg.C and reacted at 20deg.C for 2 hours. LCMS detects the end of the reaction. Purification by reverse phase column gave N- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7- (methoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] acrylamide as a white solid (16.7 mg, yield 37.2%).

LCMS：m/z 526.0[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ10.27(s，1H),8.49(d，J＝4.9Hz，1H)，8.27(s，1H)，7.70-7.64(m，2H)，7.61-7.55(m，1H)，7.45(t，J＝8.6Hz，1H)，7.30(d，J＝8.6Hz，3H)，7.22-7.18(m，1H)，6.48-6.38(m，1H)，6.31-6.22(m，1H)，5.81-5.60(m，3H)，4.40(s，2H)，3.27(s，3H)，2.38(s，3H).

Example 82:

n- [4- (4-amino-7-ethyl-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] acrylamide:

the synthetic route is as follows:

step one: synthesis of 6- (4-aminophenyl) -7-ethyl-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6- (4-aminophenyl) -7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (200 mg,1.00 eq), cesium carbonate (258.8 mg,2.00 eq), ethylboronic acid (289.6 mg,10.0 eq) and palladium (2-dicyclohexylphosphine-2, 4, 6-triisopropyl-1, 1-biphenyl) [2- (2-amino-1, 1-biphenyl ] methanesulfonate (66.8 mg,0.3 eq) were dissolved in 12mL of dioxane and 4mL of water, stirred at 120℃for 2 hours after the end of the S detection reaction, 6- (4-aminophenyl) -7-ethyl-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidine-4-amine (60 mg, 33.3% yield) was obtained as a yellow solid by reverse phase column purification.

LCMS：m/z 456.0.[M+H] ⁺ .

Step two: synthesis of N- [4- (4-amino-7-ethyl-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] acrylamide

6- (4-aminophenyl) -7-ethyl-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (60 mg,1.00 eq) was dissolved in 2mL of tetrahydrofuran, and acryloyl chloride (11.9 mg,1.00 eq) was slowly added at 0deg.C and reacted at 20deg.C for 2 hours. LCMS detects the end of the reaction. Purification by reverse phase column gave N- [4- (4-amino-7-ethyl-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] acrylamide as a white solid (12.4 mg, yield 18.1%).

LCMS：m/z 510.1[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ10.25(s，1H)，8.47(d，J＝5.0Hz，1H)，8.24(s，1H)，7.67(br d，J＝8.4Hz，2H)，7.51(dd，J＝2.2，10.7Hz，1H)，7.44-7.36(m，1H)，7.27-7.16(m，4H)，6.48-6.37(m，1H)，6.32-6.22(m，1H)，5.77(dd，J＝1.7，10.1Hz，1H)，5.65-5.51(m，2H)，2.63(q，J＝7.3Hz，2H)，2.37(s，3H)，1.18(br t，J＝7.4Hz，3H).

Example 83:

n- [4- (4-amino-7-ethyl-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-methoxyphenyl ] acrylamide:

the synthetic route is as follows:

step one: synthesis of 6- (4-amino-2-methoxyphenyl) -7-ethyl-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6- (4-amino-2-methoxyphenyl) -7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (1.8 g,1.00 eq), cesium fluoride (1.02 g,2.00 eq), ethylboronic acid (2.48 g,10.0 eq) and 1, 1-bis (t-butylphosphorus) ferrocene palladium chloride (650 mg,0.3 eq) were dissolved in 54mL dioxane and 18mL water. Stirred at 110℃for 2 hours. After completion of LCMS detection reaction, 6- (4-amino-2-methoxyphenyl) -7-ethyl-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (300 mg, crude) was obtained as a yellow solid by reverse phase column purification.

LCMS：m/z 486.0[M+H] ⁺ .

Step two: synthesis of N- [4- (4-amino-7-ethyl-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-methoxyphenyl ] acrylamide

6- (4-amino-2-methoxyphenyl) -7-ethyl-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (30 mg,1.00 eq) was dissolved in 2mL of tetrahydrofuran, and acryloyl chloride (11.9 mg,1.00 eq) was slowly added at 0deg.C and reacted at 20deg.C for 2 hours. LCMS detects the end of the reaction. Purification by reverse phase column gave N- [4- (4-amino-7-ethyl-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-methoxyphenyl ] acrylamide as a white solid (3.20 mg, yield 9.60%).

LCMS：m/z 540.0[M+H] ⁺ .

¹ H NMR(400MHz，ACETONITRILE-d3)δ8.60(s，1H)，8.38(d，J＝5.0Hz，1H)，8.29(s，1H)，7.49(s，1H)，7.38-6.91(m，6H)，6.42-6.29(m，2H)，5.75(dd，J＝4.9，6.9Hz，1H)，5.07-4.72(m，2H)，3.58(s，3H)，2.70-2.49(m，2H)，2.38(s，3H)，1.16(t，J＝7.5Hz，3H).

Example 84:

n- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7- (propan-2-yl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] acrylamide:

the synthetic route is as follows:

step one: synthesis of 6- (4-aminophenyl) -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7- (prop-1-en-2-yl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6- (4-aminophenyl) -7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-yl (1.25 g,1.00 eq), cesium carbonate (1.61 g,2.00 eq), pinacol isopropenylborate (635 mg,3.00 eq) and palladium (2-dicyclohexylphosphino-2, 4, 6-triisopropyl-1, 1-biphenyl) [2- (2-amino-1, 1-biphenyl ] methanesulfonate (417.5 mg,0.3 eq) were dissolved in 15mL of dioxane and 5mL of water after completion of the S detection reaction, 6- (4-aminophenyl) -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7- (prop-1-en-2-yl) -5H-pyrrolo [3,2-d ] pyrimidine (200 mg, 3.75% yield) was obtained by reverse phase column purification.

LCMS：m/z 468.0[M+H] ⁺ .

Step two: synthesis of 6- (4-aminophenyl) -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7- (propan-2-yl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6- (4-aminophenyl) -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7- (prop-1-en-2-yl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (50 mg,1.00 eq) and Pd/C (91.0 mg,0.2 eq) were dissolved in 10mL of methanol. Stirred at 20℃for 2 hours. After completion of LCMS detection, filtration and concentration gave 6- (4-aminophenyl) -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7- (propan-2-yl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (120 mg, yield 59.7%) as a yellow solid.

LCMS：m/z 470.0[M+H] ⁺ .

Step three: synthesis of N- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7- (propan-2-yl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] acrylamide

6- (4-aminophenyl) -7-cyclopropyl-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (100 mg,1.00 eq) was dissolved in 2mL of tetrahydrofuran, and acryloyl chloride (19.2 mg,1.00 eq) was slowly added at 0deg.C and reacted at 20deg.C for 2 hours. LCMS detects the end of the reaction. Purification by reverse phase column gave N- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7- (propan-2-yl) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] acrylamide as a white solid (26.0 mg, yield 23.2%).

LCMS：m/z 523.9[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ10.24(s，1H)，8.47(d，J＝5.0Hz，1H)，8.24(s，1H)，7.66(d，J＝8.5Hz，2H)，7.50(dd，J＝2.4，10.9Hz，1H)，7.42-7.33(m，1H)，7.26-7.14(m，4H)，6.48-6.37(m，1H)，6.31-6.21(m，1H)，5.81-5.70(m，1H)，5.55(s，2H)，2.93(J＝7.0Hz，1H)，2.36(s，3H)，1.39(d，J＝7.0Hz，6H).

Example 85:

n- [4- (4-amino-7-cyclopropyl-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] acrylamide:

the synthetic route is as follows:

step one: synthesis of 6- (4-aminophenyl) -7-cyclopropyl-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6- (4-aminophenyl) -7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (200 mg,1.00 eq), cesium carbonate (255 mg,2.00 eq), cyclopropylboronic acid (338 mg,10.0 eq) and palladium (2-dicyclohexylphosphino-2, 4, 6-triisopropyl-1, 1-biphenyl) [2- (2-amino-1, 1-biphenyl ] methanesulfonate (66.8 mg,0.3 eq) were dissolved in 12mL dioxane and 4mL water, stirred at 120℃for 2 hours after completion of the detection reaction, LCM was purified by reverse phase column to give 6- (4-aminophenyl) -7-cyclopropyl-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (110 mg, 5.59%) in a yield of yellow solid.

LCMS：m/z 468.2[M+H] ⁺ .

Step three: synthesis of N- [4- (4-amino-7-cyclopropyl-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] acrylamide

6- (4-aminophenyl) -7-cyclopropyl-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (80 mg,1.00 eq) was dissolved in 2mL of tetrahydrofuran, and acryloyl chloride (15.5 mg,1.00 eq) was slowly added at 0deg.C and reacted at 20deg.C for 2 hours. LCMS detects the end of the reaction. Purification by reverse phase column gave N- [4- (4-amino-7-cyclopropyl-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] acrylamide as a white solid (23.2 mg, yield 25.7%).

LCMS：m/z 522.0[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ10.25(s，1H)，8.48(d，J＝5.0Hz，1H)，8.17(s，1H)，7.67(d，J＝8.5Hz，2H)，7.55-7.36(m，2H)，7.32-7.23(m，3H)，7.19(d，J＝4.9Hz，1H)，6.47-6.36(m，1H)，6.31-6.22(m，1H)，5.81-5.73(m，1H)，5.65-5.12(m，2H)，2.37(s，3H)，1.80-1.68(m，1H)，1.24-1.18(m，2H)，0.77-0.65(m，2H).

Example 86:

the synthetic route is as follows:

step one: synthesis of 4-bromo-3-fluoro-5-methylaniline

3-fluoro-5-methylaniline (3.00 g,1.00 eq) was dissolved in 10mL acetonitrile. N-bromosuccinimide (3.95 g,1.00 eq) was slowly added at 0deg.C. Stirred at 20℃for 1 hour. After completion of the TLC detection reaction, 4-bromo-3-fluoro-5-methylaniline was obtained as a white solid (2.20 g, yield 46.3%).

LCMS：m/z 203.8[M+1] ⁺ ，205.8[M+3] ⁺ .

¹ H NMR(400MHz，DMSO-d 6)δ＝6.37(s，1H)，6.32(dd，J＝2.5，11.3Hz，1H)，5.47(br s，2H)，2.22(s，3H).

Step two: synthesis of tert-butyl N- (4-bromo-3-fluoro-5-methylphenyl) carbamate

4-bromo-3-fluoro-5-methylaniline (4.00 g,1.00 eq) was dissolved in 20mL tetrahydrofuran and sodium bis (trimethylsilyl) amide (3.95 g,1.00 eq) and di-tert-butyl dicarbonate (3.00 g,1.00 eq) were slowly added at 0deg.C. Stirred at 20℃for 1 hour. After completion of the TLC detection reaction, N- (4-bromo-3-fluoro-5-methylphenyl) carbamic acid tert-butyl ester (3.50 g, yield 98.2%) was obtained as a yellow solid by column chromatography purification.

LCMS：m/z 247.8[M+1-56] ⁺ ，249.8[M+3-56] ⁺ .

Step three: synthesis of tert-butyl N- [ 3-fluoro-5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] carbamate

Potassium N- (4-bromo-3-fluoro-5-methylphenyl) carbamate (6.00 g,1.00 eq) acetate (2.51 g,2.00 eq), bis-pinacolato borate (4.51 g,0.90 eq) and cyclopentadiene [ (1, 2, 3-. Eta. -1-phenyl-2-propenyl ] palladium (2.89 g,0.20 eq) were dissolved in 30mL dioxane. Stirred at 100℃for 2 hours. After completion of LCMS detection, N- [ 3-fluoro-5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] carbamate (2.83 g, 40.8% yield) was obtained as a yellow solid by column chromatography.

LCMS：m/z 295.9[M+H-56] ⁺ .

Step four: synthesis of tert-butyl N- [4- (4-amino-7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-fluoro-5-methylphenyl ] carbamate

Potassium phosphate (515 mg,2.00 eq), tert-butyl 6, 7-dibromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-4-amine (600 mg,1.00 eq), N- [ 3-fluoro-5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] carbamate (852 mg,2.00 eq) and tetra-triphenylphosphine palladium (280 mg,0.20 eq) were dissolved in 12mL dioxane and 6mL water. Stirred at 100℃for 1 hour. After completion of LCMS detection, N- [4- (4-amino-7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-fluoro-5-methylphenyl ] carbamic acid tert-butyl ester (1.10 g, crude product) was obtained as a yellow solid by column chromatography purification.

LCMS：m/z 637.9[M+1] ⁺ ，639.9[M+3] ⁺ .

Step five: synthesis of tert-butyl N- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-fluoro-5-methylphenyl ] carbamate

Tert-butyl N- [4- (4-amino-7-bromo-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-fluoro-5-methylphenyl ] carbamate (1.0 g,1.00 eq), cesium carbonate (1.1 g,2.00 eq), methylboronic acid (935 mg,10.0 eq) and palladium (2-dicyclohexylphosphine-2, 4, 6-triisopropyl-1, 1-biphenyl) [2- (2-amino-1, 1-biphenyl ] methanesulfonate (265 mg,0.2 eq) were dissolved in 15mL dioxane and 5mL water after stirring for 1 hour at 100℃LCMS detection, the resulting solid N- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [2- (2-amino-1, 1-biphenyl ] methanesulfonic acid was purified by reverse phase column to give a yellow solid (41 mg, yield of tert-butyl) 3-fluoro-4- [ 2-methyl ] pyrimidine-2-yl ] phenyl ] sulfonate.

LCMS：m/z 574.0.[M+H] ⁺ .

Tert-butyl N- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-fluoro-5-methylphenyl ] carbamate (200 mg,1.00 eq) was dissolved in 2mL of tetrahydrofuran. Hydrochloric acid/dioxane (3.95 g,1.00 eq) was slowly added at 0 ℃. Stirred at 20℃for 1 hour. After the completion of the TLC detection, 6- (4-amino-2-fluoro-6-methylphenyl) -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (43.0 mg, yield 26.0%) was obtained as a white solid by column chromatography purification.

LCMS：m/z 474.3.[M+H] ⁺ .

Step seven: synthesis of N- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-fluoro-5-methylphenyl ] acrylamide

6- (4-amino-2-fluoro-6-methylphenyl) -5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (40 mg,1.00 eq) was dissolved in 2mL of tetrahydrofuran, and acryloyl chloride (7.65 mg,1.00 eq) was slowly added at 0deg.C and reacted at 20deg.C for 2 hours. LCMS detects the end of the reaction. Purification by reverse phase column gave N- [4- (4-amino-5- { 3-fluoro-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3-fluoro-5-methylphenyl ] acrylamide as a white solid (13.8 mg, yield 30.9%).

LCMS：m/z 528.0[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ10.37(s，1H)，8.46(d，J＝5.2Hz，1H)，8.27(s，1H)，7.54(d，J＝12.1Hz，1H)，7.42-7.37(m，1H)，7.29(s，1H)，7.18(d，J＝4.8Hz，1H)，7.12(d，J＝8.4Hz，1H)，6.42-6.36(m，1H)，6.30-6.24(m，1H)，5.80(d，J＝10.0Hz，2H)，5.72(s，2H)，2.34(s，3H)，2.04(d，J＝8.0Hz，6H).

Example 87:

n- [4- (4-amino-5- { 3-methoxy-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] acrylamide:

the synthetic route is as follows:

step one: synthesis of 1- (benzyloxy) -2-methoxy-4-nitrobenzene

4-nitro-2-methoxyphenol (5.00 g,29.5 mmol) was dissolved in acetonitrile (50.0 mL), and potassium carbonate (8.17 g,59.1 mmol) and benzyl bromide (10.1 g,59.1 mmol) were added. Stirring was carried out at 80℃for 3 hours, and the reaction was checked for completion by LCMS. Concentrated, and subjected to column chromatography to give yellow 1- (benzyloxy) -2-methoxy-4-nitrobenzene (5.70 g, yield 74.3%).

Step two: synthesis of 4- (benzyloxy) -3-methoxyaniline

1- (benzyloxy) -2-methoxy-4-nitrobenzene (5.00 g,19.2 mmol) was dissolved in ethanol (20.0 mL) and water (20.0 mL), and ammonium chloride (5.16 g,96.4 mmol) and iron powder (5.39 g,96.4 mmol) were added. After stirring at 80℃for 2 hours, LCMS detects the end of the reaction. Filtration, extraction and concentration of the organic phase afforded 1- (benzyloxy) -2-methoxy-4-nitrobenzene as a red solid (4.10 g, 92.7% yield).

LCMS：m/z 229.6[M+H] ⁺ .

¹ H NMR(400MHz，CHLOROFORM-d)δ＝7.45-7.09(m，5H)，6.69(d，J＝8.4Hz，1H)，6.29(d，J＝2.4Hz，1H)，6.04(dd，J＝2.4，8.4Hz，1H)，4.88(s，2H)，4.70(s，2H)，3.70(s，3H).

Step three: synthesis of tert-butyl N- (4- {5- [4- (benzyloxy) -3-methoxyphenyl ] -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl } phenyl) carbamate

Tert-butyl N- (4- {2- [ 5-bromo-6- (2, 2-trifluoroethoxy) pyrimidin-4-yl ] ethynyl } phenyl) carbamate (1.00 g,2.12 mmol) was dissolved in dioxane (3.00 mL), 4- (benzyloxy) -3-methoxyaniline (284 mg,2.33 mmol), tris (dibenzylideneacetone) dipalladium (193 mg, 211. Mu. Mol), 4, 5-bis (diphenylphosphorus) -9, 9-dimethylxanthene (245 mg, 423. Mu. Mol) and cesium carbonate (1.38 g,4.23 mmol) were added, and the LCMS detection reaction was completed and the reaction mixture was concentrated by column chromatography to give tert-butyl N- (4- {5- [4- (benzyloxy) -3-methoxyphenyl ] -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl } phenyl) carbamate (6.00 g, 91.3%) as a yellow solid. 5 reactions in parallel.

LCMS：m/z 621.0[M+H] ⁺ .

Step four: synthesis of tert-butyl N- (4- {5- [4- (benzyloxy) -3-methoxyphenyl ] -7-bromo-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl } phenyl) carbamate

Tert-butyl N- (4- {5- [4- (benzyloxy) -3-methoxyphenyl ] -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl } phenyl) carbamate (5.30 g,8.54 mmol) was dissolved in acetonitrile (50 mL), N-bromosuccinimide (1.98 g,11.1 mmol), stirred at 20℃for 1 hour, LCMS detected the end of the reaction, the reaction concentrated, and column chromatographed to give tert-butyl N- (4- {5- [4- (benzyloxy) -3-methoxyphenyl ] -7-bromo-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl } phenyl) carbamate as a yellow solid (6.00 g, crude product).

LCMS：m/z 699.0[M+H] ⁺ ，701.0[M+H] ⁺ .

Step five: synthesis of tert-butyl N- (4- {5- [4- (benzyloxy) -3-methoxyphenyl ] -7-methyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl } phenyl) carbamate

Tert-butyl N- (4- {5- [4- (benzyloxy) -3-methoxyphenyl ] -7-bromo-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl } phenyl) carbamate (3.00 g,4.29 mmol) was dissolved in dioxane (30 mL) and 10mL of water, methylboronic acid (2.57 g,42.9 mmol), cesium carbonate (2.79 g,8.43 mmol), 1-bis (diphenylphosphino) ferrocene palladium dichloride (1.09 g,1.28 mmol) and stirred at 120℃for 2 hours, LCMS was detected at the end of the reaction and the reaction concentrated to give tert-butyl N- (4- {5- [4- (benzyloxy) -3-methoxyphenyl ] -7-methyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl } phenyl) carbamate (2.00 g, 73.4%) as a yellow solid.

LCMS：m/z 635.2[M+H] ⁺ .

Step six: synthesis of 6- (4-aminophenyl) -5- [4- (benzyloxy) -3-methoxyphenyl ] -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-ol

Tert-butyl N- (4- {5- [4- (benzyloxy) -3-methoxyphenyl ] -7-methyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl } phenyl) carbamate (1.80 g,2.84 mmol) was dissolved in dimethyl sulfoxide (6.0 mL) and water (6.0 mL), potassium hydroxide (1.59 g,28.3 mmol) and 18-crown-6 (7.50 g,28.3 mmol) were added, stirred at 90℃for 10 hours, LCMS detection reaction ended, the reaction solution was poured into water and extracted to give 6- (4-aminophenyl) -5- [4- (benzyloxy) -3-methoxyphenyl ] -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-ol (900 mg, yield 70.1%) as a yellow solid.

LCMS：m/z 452.9[M+H] ⁺ .

Step seven: synthesis of 6- (4-aminophenyl) -5- [4- (benzyloxy) -3-methoxyphenyl ] -N- [ (4-methoxyphenyl) methyl ] -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6- (4-aminophenyl) -5- [4- (benzyloxy) -3-methoxyphenyl ] -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-ol (900 mg,1.99 mmol), benzotriazole-1-oxo-tris (dimethylaminophosphorus) hexafluorophosphate (2.64 g,5.97 mmol) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (908 mg,5.97 mmol) were dissolved in acetonitrile 8.0m, then 4-methoxybenzylamine (1.36 g,9.94 mmol) was added and stirred at 90℃for 2 hours, LCMS detection was completed and the reaction concentrated and passed through a column to give 6- (4-aminophenyl) -5- [4- (benzyloxy) -3-methoxyphenyl ] -N- [ (4-methoxyphenyl) methyl ] -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (1.00 g, crude product) as a yellow solid.

LCMS：m/z 572.0[M+H] ⁺ .

Step eight: synthesis of 4- [6- (4-aminophenyl) -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl ] -2-methoxyphenol

6- (4-aminophenyl) -5- [4- (benzyloxy) -3-methoxyphenyl ] -N- [ (4-methoxyphenyl) methyl ] -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (1.00 g,1.75 mmol) was dissolved in methanol (10 mL), 10% wet palladium on carbon (1.86 g,1.75mmol,10% purity) was added, and reacted in a hydrogen atmosphere at 20℃for 3 hours (15 psi). After completion of the reaction by LCMS, the reaction mixture was filtered and concentrated and purified by silica gel column to give 4- [6- (4-aminophenyl) -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl ] -2-methoxyphenol as a yellow oil (150 mg, yield 17.8%).

LCMS：m/z 481.8[M+H] ⁺ .

Step nine: synthesis of 6- (4-aminophenyl) -5- { 3-methoxy-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -N- [ (4-methoxyphenyl) methyl ] -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine

4- [6- (4-aminophenyl) -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl ] -2-methoxyphenol (150 mg, 311. Mu. Mol) was dissolved in N, N-dimethylformamide (2.0 mL), 2-chloro-4-methylpyrimidine (80.0 mg, 6235. Mu. Mol) and potassium carbonate (129 mg, 934. Mu. Mol) were added, stirred at 90℃for 12 hours, and the reaction was checked for completion by LCMS, and 6- (4-aminophenyl) -5- { 3-methoxy-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -N- [ (4-methoxyphenyl) methyl ] -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (120 mg, 67.1% yield) was obtained.

LCMS：m/z 574.3[M+H] ⁺ .

Step ten: synthesis of 3- (benzenesulfonyl) -N- [4- (5- { 3-methoxy-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] propanamide

6- (4-Aminophenyl) -5- { 3-methoxy-4- [ (4-methylpyrimidin-2-YL) oxy ] phenyl } -N- [ (4-methoxyphenyl) methyl ] -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (120 mg, 209. Mu. Mol), 3- (dialkylenylphenyl-. Lamda.6-thio) propionic acid (53.1 mg, 251. Mu. Mol), O- (7-azabenzotriazol-1-YL) -N, N, N, N-tetramethylurea hexafluorophosphine salt (238 mg, 627. Mu. Mol) were dissolved in dichloromethane (0.5 mL), triethylamine (81.1 mg, 627. Mu. Mol) was added at 20 ℃, the reaction was terminated by LCMS detection, and the reaction mixture was concentrated and purified to give yellow oil 3- (benzenesulfonyl) -N- [4- (5- { 3-methoxy-4- [ (4-methylpyrimidin-2-YL) oxy ] phenyl } -4- { [4- (4-methoxyphenyl) methyl ] amino ] 7-pyrrolo [3, 6-d ] pyrimidine-2-amine (0.5 mg,62 mg) in a column under stirring at 20℃for 1 hour.

LCMS：m/z 770.1[M+H] ⁺ .

Step eleven: synthesis of N- [4- (4-amino-5- { 3-methoxy-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] -3- (benzenesulfonyl) propanamide

3- (benzenesulfonyl) -N- [4- (5- { 3-methoxy-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] propionamide (90.0 mg, 116. Mu. Mol) was dissolved in trifluoroacetic acid (1.00 mL), trifluoromethanesulfonic acid (1.00 mL) was added, stirring was performed at 40℃for 1 hour, LCMS detection was completed, a saturated potassium carbonate solution was added to adjust pH to 8, and then extraction, drying and concentration were performed to give N- [4- (4-amino-5- { 3-methoxy-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] -3- (benzenesulfonyl) propionamide (70.0 mg, crude product) as a yellow solid.

LCMS：m/z 650.0[M+H] ⁺ .

Step twelve: synthesis of N- [4- (4-amino-5- { 3-methoxy-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] acrylamide

N- [4- (4-amino-5- { 3-methoxy-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] -3- (benzenesulfonyl) propanamide (70.0 mg,107 methanol) was dissolved in tetrahydrofuran (2.00 mL), trimethylpotassium silicate oxide (16.5 mg, 129. Mu. Mol) was added, stirring was carried out at 20℃for 1 hour, LCMS detection was completed, saturated ammonium chloride solution was added to adjust pH to 7, extraction was carried out, and purification by reverse phase HPLC afforded N- [4- (4-amino-5- { 3-methoxy-4- [ (4-methylpyrimidin-2-yl) oxy ] phenyl } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] acrylamide (6.50 mg, yield 11.8%) as a white solid.

LCMS：m/z 508.0[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ＝10.22(s，1H)，8.41(d，J＝5.0Hz，1H)，8.23(s，1H)，7.66(d，J＝8.5Hz，2H)，7.28(d，J＝8.5Hz，2H)，7.21(d，J＝8.4Hz，1H)，7.15(d，J＝2.3Hz，1H)，7.10(d，J＝5.0Hz，1H)，6.97(dd，J＝2.3，8.3Hz，1H)，6.46-6.38(m，1H)，6.30-6.23(m，1H)，5.77(dd，J＝1.9，10.1Hz，1H)，5.67-5.43(m，2H)，3.56(s，3H)，2.36(s，3H)，2.24-2.19(s，3H).

Example 88:

4- { 4-amino-7-methyl-6- [4- (prop-2-enoylamino) phenyl ] -5H-pyrrolo [3,2-d ] pyrimidin-5-yl } -2-methoxy-N- (2, 2-trifluoroethyl) benzamide:

the synthetic route is as follows:

step one: synthesis of 4-amino-2-methoxy-N- (2, 2-trifluoroethyl) benzamide

4-amino-2-methoxybenzoic acid (4.00 g,23.9 mmol), 2-trifluoroethan-1-amine (4.74 g,47.8 mmol), O- (7-azabenzotriazol-1-YL) -N, N, N, N-tetramethylurea hexafluorophosphine salt (13.6 g,35.8 mmol) was dissolved in dichloromethane (20 mL), N, N-diisopropylethylamine (9.28 g,71.7 mmol) was added at 20℃and stirred at 20℃for 3 hours, LCMS detection reaction was completed, the reaction solution was concentrated and purified by column to give 4-amino-2-methoxy-N- (2, 2-trifluoroethyl) benzamide (4.00 g, yield 67.3%) as a yellow oil.

LCMS：m/z 248.6[M+H] ⁺ .

¹ H NMR(400MHz，CHLOROFORM-d)δ＝8.23(t，J＝6.4Hz，1H)，7.65(d，J＝8.5Hz，1H)，6.29-6.13(m，2H)，5.85(s，2H)，4.18-4.04(m，2H)，3.84(s，3H).

Step two: synthesis of tert-butyl N- [4- (5- { 3-methoxy-4- [ (2, 2-trifluoroethyl) aminocarbonyl ] phenyl } -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] carbamate

Tert-butyl N- (4- {2- [ 5-bromo-6- (2, 2-trifluoroethoxy) pyrimidin-4-yl ] ethynyl } phenyl) carbamate (2.30 g,4.87 mmol) was dissolved in dioxane (20.0 mL), 1.33g,5.36 mmol) of 4-amino-2-methoxy-N- (2, 2-trifluoroethyl) benzamide, tris (dibenzylideneacetone) dipalladium (445 mg, 487. Mu. Mol), 4, 5-bis (diphenylphosphorus) -9, 9-dimethylxanthene (563 mg, 974. Mu. Mol) and cesium carbonate (3.17 g,9.74 mmol) were added, and the LCMS detection reaction was completed and the reaction mixture was concentrated by column chromatography to give tert-butyl N- [4- (5- { 3-methoxy-4- [ (2, 2-trifluoroethyl) aminocarbonyl ] phenyl } -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] phenyl ] carbamate as a yellow solid (1.90 g, yield of 3.17g,9.74 mmol) and 6.74 mmol) at 100 ℃.

LCMS：m/z 640.1[M+H] ⁺ .

¹ H NMR(400MHz，CHLOROFORM-d)δ＝9.49(s，1H)，8.68(br t，J＝6.4Hz，1H)，8.53(s，1H)，7.75(d，J＝8.1Hz，1H)，7.44-7.32(m，3H)，7.24(d，J＝8.6Hz，2H)，6.97(s，1H)，6.88(dd，J＝1.6，8.3Hz，1H)，5.09-4.88(m，2H)，4.18-4.07(m，2H)，3.83-3.80(m，3H)，1.45(s，9H).

Step three: synthesis of tert-butyl N- [4- (7-bromo-5- { 3-methoxy-4- [ (2, 2-trifluoroethyl) aminocarbonyl ] phenyl } -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] carbamate

Tert-butyl N- [4- (5- { 3-methoxy-4- [ (2, 2-trifluoroethyl) aminocarbonyl ] phenyl } -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] carbamate (2.00 g,3.13 mmol) was dissolved in acetonitrile (20 mL), N-bromosuccinimide (723 mg,4.07 mmol) was stirred at 20℃for 1 hour, LCMS detection was completed, the reaction mixture was concentrated, extracted, and concentrated to give tert-butyl N- [4- (7-bromo-5- { 3-methoxy-4- [ (2, 2-trifluoroethyl) aminocarbonyl ] phenyl } -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] carbamate (2.50 g, crude product) as a yellow solid.

LCMS：m/z 717.9[M+1] ⁺ ，719.9[M+3] ⁺ .

Step four: synthesis of tert-butyl N- [4- (5- { 3-methoxy-4- [ (2, 2-trifluoroethyl) aminocarbonyl ] phenyl } -7-methyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] carbamate

Tert-butyl N- [4- (7-bromo-5- { 3-methoxy-4- [ (2, 2-trifluoroethyl) aminocarbonyl ] phenyl } -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] carbamate (2.0 g,2.78 mmol) was dissolved in dioxane (20 mL) and water (5 mL), methylboronic acid (1.66 g,27.84 mmol), cesium carbonate (1.82 g,5.56 mmol), 1-bis (diphenylphosphino) ferrocene palladium dichloride (4638 mg, 556. Mu. Mol) was added, stirring was carried out at 110℃for 1 hour, LCMS detection was completed, and the reaction mixture was concentrated to give N- [4- (5- { 3-methoxy-4- [ (2, 2-trifluoroethyl) aminocarbonyl ] phenyl } -7-methyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] carbamate as a yellow solid (1.10 g, yield) and 60.10% yield.

LCMS：m/z 654.0[M+H] ⁺ .

Step five: synthesis of 4- [6- (4-aminophenyl) -4-hydroxy-7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl ] -2-methoxy-N- (2, 2-trifluoroethyl) benzamide

Tert-butyl N- [4- (5- { 3-methoxy-4- [ (2, 2-trifluoroethyl) aminocarbonyl ] phenyl } -7-methyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl ] carbamate (700 mg,1.07 mmol) was dissolved in dimethyl sulfoxide (2.0 mL) and water (2.0 mL), potassium hydroxide (600 mg,10.7 mmol) and 18-crown ether-6 (1.13 g,4.28 mmol) were added, stirred at 90℃for 5 hours, LCMS was performed to detect the end of the reaction, and the reaction solution was poured into water and extracted to give 4- [6- (4-aminophenyl) -4-hydroxy-7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl ] -2-methoxy-N- (2, 2-trifluoroethyl) benzamide (400 mg, 79.2%).

LCMS：m/z 472.0[M+H] ⁺ .

Step six: synthesis of 4- [6- (4-aminophenyl) -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl ] -2-methoxy-N- (2, 2-trifluoroethyl) benzamide

4- [6- (4-aminophenyl) -4-hydroxy-7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl ] -2-methoxy-N- (2, 2-trifluoroethyl) benzamide (400 mg,848 mol), benzotriazole-1-oxo-tris (dimethylaminophosphorus) hexafluorophosphate salt (1.13 g,2.55 mmol) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (387 mg,2.55 mmol) were dissolved in acetonitrile 10.0mL, 4-methoxybenzylamine (698 mg,677 mol) was then added and the reaction was concentrated at 90℃for 5 hours after stirring, affording crude 4- [6- (4-aminophenyl) -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl ] -2-methoxy-N- (2, 2-trifluoroethyl) benzamide (1.00 g) as a yellow solid.

LCMS：m/z 591.0[M+H] ⁺ .

Step seven: synthesis of 4- (4-amino-6- (4-aminophenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl) -2-methoxy-N- (2, 2-trifluoroethyl) benzamide

4- [6- (4-aminophenyl) -4- { [ (4-methoxyphenyl) methyl ] amino } -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl ] -2-methoxy-N- (2, 2-trifluoroethyl) benzamide (300 mg, 507. Mu. Mol) was dissolved in trifluoroacetic acid (1.00 mL), trifluoromethanesulfonic acid (1.00 mL) was added, stirring was carried out at 40℃for 1 hour, LCMS detection was completed, saturated potassium carbonate solution was added to adjust pH to 8, followed by extraction, drying, concentration, and column chromatography purification to give 4- (4-amino-6- (4-aminophenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl) -2-methoxy-N- (2, 2-trifluoroethyl) benzamide (150 mg, crude product) as a yellow solid.

LCMS：m/z 470.9[M+H] ⁺ .

Step eight: synthesis of 4- { 4-amino-7-methyl-6- [4- (prop-2-enoylamino) phenyl ] -5H-pyrrolo [3,2-d ] pyrimidin-5-yl } -2-methoxy-N- (2, 2-trifluoroethyl) benzamide

4- (4-amino-6- (4-aminophenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl) -2-methoxy-N- (2, 2-trifluoroethyl) benzamide (150 mg, 285. Mu. Mol) was dissolved in tetrahydrofuran (5.00 mL), acrylamide (25.8 mg, 285. Mu. Mol) was added, and the reaction was stirred for 1 hour at 20℃and purified by reverse phase HPLC to give 4- { 4-amino-7-methyl-6- [4- (prop-2-enylamino) phenyl ] -5H-pyrrolo [3,2-d ] pyrimidin-5-yl } -2-methoxy-N- (2, 2-trifluoroethyl) benzamide (50.0 mg, yield 31.5%) as a white solid.

LCMS：m/z 525.0[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )δ＝10.22(s，1H)，8.70(t，J＝6.4Hz，1H)，8.24(s，1H)，7.72-7.60(m，3H)，7.23(d，J＝8.6Hz，2H)，7.13(d，J＝1.8Hz，1H)，6.94(dd，J＝1.9，8.1Hz，1H)，6.46-6.36(m，1H)，6.30-6.20(m，1H)，5.79-5.72(m，1H)，5.63(br s，2H)，4.16-3.99(m，2H)，3.75(s，3H)，2.19(s，3H).

Example 89:

the synthetic route is as follows:

step one: synthesis of 3, 5-difluoro-4-iodoaniline

3, 5-difluoroaniline (10.0 g,77.4 mmol) was dissolved in 500mL of water, iodine (23.5 g,92.9 mmol) and sodium bicarbonate (9.96 g,118 mmol) were added and reacted for 12 hours, after completion of LCMS detection reaction, 3, 5-difluoro-4-iodoaniline (18.3 g, yield 75.0%) was obtained by filtration.

LCMS：m/z 256.0[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝6.28(d，J＝9.3Hz，2H)，5.91(s，2H).

Step two: synthesis of tert-butyl (3, 5-difluoro-4-iodophenyl) carbamate

3, 5-difluoro-4-iodoaniline (15.0 g,58.8 mmol) was dissolved in 300mL of tetrahydrofuran, lithium bis (trimethylsilyl) amide (19.7 g,118 mmol) was added at 0deg.C, di-tert-butyl dicarbonate (12.8 g,58.8 mmol) was added after room temperature was restored to react for 2 hours, saturated ammonium chloride solution was added to quench the reaction after LCMS detection, and the reaction was extracted, dried and column chromatographed to give tert-butyl (3, 5-difluoro-4-iodophenyl) carbamate (15.9 g, yield 57.0%).

LCMS：m/z 356.1[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝9.88(s，1H)，7.23(d，J＝9.0Hz，2H)，1.47(s，9H).

Step three: synthesis of tert-butyl (3, 5-difluoro-4- (trimethylsilyl) ethynyl) phenyl) carbamate

(3, 5-difluoro-4-iodophenyl) carbamic acid tert-butyl ester (14.9 g,41.9 mmol) was dissolved in 100mL of tetrahydrofuran, and trimethylsilylethylene (14.8 g,151 mmol), triethylamine (8.49 g,83.9 mmol), dichlorobis (triphenylphosphine) palladium (II) (4.42 g,6.29 mmol) and cuprous iodide (2.40 g,12.5 mmol) were added to the solution, and after completion of the LCMS detection reaction, the solution was concentrated to give (3, 5-difluoro-4- (trimethylsilyl) ethynyl) phenyl) carbamic acid tert-butyl ester crude product (13.6 g, yield 74.9%).

LCMS：m/z 326.1[M+H] ⁺ .

Step four: synthesis of tert-butyl (4-ethynyl-3, 5-difluorophenyl) carbamate

Tert-butyl (3, 5-difluoro-4- (trimethylsilyl) ethynyl) phenyl) carbamate (13.6 g,41.9 mmol) was dissolved in 100mL of methanol, potassium carbonate (17.3 g,125 mmol) was added, the reaction was carried out at 20℃for 2 hours, and after completion of the LCMS detection reaction, tert-butyl (4-ethynyl-3, 5-difluorophenyl) carbamate (8.41 g, yield 68.0%) was concentrated and column chromatographed.

LCMS：m/z 253.9[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.00(s，1H)，7.24(br d，J＝10.1Hz，2H)，4.62(s，1H)，1.47(s，9H).

Step five: synthesis of tert-butyl (4- ((5-bromo-6- (2, 2-trifluoroethoxy) pyrimidin-4-yl) ethynyl) -3, 5-difluorophenyl) carbamate

(4-ethynyl-3, 5-difluorophenyl) carbamic acid tert-butyl ester (2.00 g,7.90 mmol) was dissolved in 20mL of tetrahydrofuran, 5-bromo-4-iodo-6- (2, 2-trifluoroethoxy) pyrimidine (17.3 g,125 mmol), triethylamine (1.60 g,15.8 mmol), bis (triphenylphosphine) palladium (II) dichloride (554 mg, 789. Mu. Mol) and cuprous iodide (300 mg,1.58 mmol) were added, after completion of the LCMS detection reaction at 40℃for 2 hours, concentrated and column chromatographed to give (4- ((5-bromo-6- (2, 2-trifluoroethoxy) pyrimidin-4-yl) ethynyl) -3, 5-difluorophenyl) carbamic acid tert-butyl ester (3.16 g, 58.2% yield).

LCMS：m/z 507.8[M+1] ⁺ ，509.8[M+3] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.21(br s，1H)，8.79(s，1H)，7.34(br d，J＝10.4Hz，2H)，5.17(brd，J＝8.8Hz，2H)，1.49(s，9H).

Step six: synthesis of (4- (5- (4- (benzyloxy) -3-fluorophenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3, 5-difluorophenyl) carbamic acid tert-butyl ester

Tert-butyl (4- ((5-bromo-6- (2, 2-trifluoroethoxy) pyrimidin-4-yl) ethynyl) -3, 5-difluorophenyl) carbamate (3.16 g,6.22 mmol) was dissolved in 20mL dioxane and 4- (benzyloxy) -3-fluoroaniline (1.35 g,6.22 mmol), cesium carbonate (4.05 g,12.4 mmol), tris (dibenzylideneacetone) dipalladium (569 mg, 621. Mu. Mol) and 4, 5-bis (diphenylphosphorus) -9, 9-dimethylxanthene (719 mg,1.24 mmol) were added to the mixture to react at 90℃for 3 hours, LCMS detection was completed, which was dried by spin-drying and column chromatography to give tert-butyl (4- (5- (4- (benzyloxy) -3-fluorophenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3, 5-difluorophenyl) carbamate (2.50 g, 54.9% yield.

LCMS：m/z 645.1[M+H] ⁺ .

Step seven: synthesis of tert-butyl (4- (5- (4- (benzyloxy) -3-fluorophenyl) -7-bromo-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3, 5-difluorophenyl) carbamate

Tert-butyl (4- (5- (4- (benzyloxy) -3-fluorophenyl) -4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3, 5-difluorophenyl) carbamate (2.40 g,3.72 mmol) was dissolved in 24mL acetonitrile, N-bromosuccinimide (841 mg,4.73 mmol) was added, and stirring was carried out at 20℃for 2 hours, LCMS detected the end of the reaction and filtered to give tert-butyl (4- (5- (4- (benzyloxy) -3-fluorophenyl) -7-bromo-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3, 5-difluorophenyl) carbamate (2.68 g, yield 81.5%).

LCMS：m/z 722.7[M+1] ⁺ ，724.7[M+3] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.03(s，1H)，8.65(s，1H)，7.44-7.30(m，7H)，7.20(br t，J＝9.0Hz，2H)，6.98(br d，J＝8.6Hz，1H)，5.17(br d，J＝5.8Hz，2H)，5.01(br d，J＝6.5Hz，2H)，1.48(s，9H).

Step eight: synthesis of tert-butyl (4- (5- (4- (benzyloxy) -3-fluorophenyl) -7-methyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3, 5-difluorophenyl) carbamate

Tert-butyl (4- (5- (4- (benzyloxy) -3-fluorophenyl) -7-bromo-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3, 5-difluorophenyl) carbamate (2.50 g,3.46 mmol) was dissolved in 28mL of dioxane, and methylboronic acid (1.25 g,20.9 mmol), cesium carbonate (2.25 g,6.91 mmol), 1-bis (diphenylphosphino) ferrocene (957 mg,1.73 mmol) and tris (dibenzylideneacetone) dipalladium (791 mg, 863. Mu. Mol) were added, stirred at 120℃for 2 hours, the LCMS detection reaction ended, and column chromatography afforded (4- (5- (4- (benzyloxy) -3-fluorophenyl) -7-methyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3, 5-difluorophenyl) carbamate (1.68 g) in a tert-butyl (1.68%).

LCMS：m/z 659.2[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝9.98(s，1H)，8.57(s，1H)，7.46-7.31(m，5H)，7.29-7.13(m，4H)，6.89(br d，J＝8.8Hz，1H)，5.17(s，2H)，5.07-4.94(m，2H)，2.18(s，3H)，1.49(s，9H).

Step nine: synthesis of 6- (4-amino-2, 6-difluorophenyl) -5- (4- (benzyloxy) -3-fluorophenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-ol

/>

Tert-butyl (4- (5- (4- (benzyloxy) -3-fluorophenyl) -7-methyl-4- (2, 2-trifluoroethoxy) -5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3, 5-difluorophenyl) carbamate (1.48 g,2.25 mmol) was dissolved in 15 mLN-methylpyrrolidinone, 18-crown ether-6 (740 mg,2.81 mmol), 7.5mL of water and potassium hydroxide (1.51 g,26.9 mmol) were added and stirred at 90℃for 24 hours after completion of LCMS detection reaction, 6- (4-amino-2, 6-difluorophenyl) -5- (4- (benzyloxy) -3-fluorophenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-ol (1.05 g, 88.2% yield) was obtained by extraction, concentration and column chromatography.

LCMS：m/z 477.0[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝11.95(br s，1H)，7.86(d，J＝3.1Hz，1H)，7.53-7.31(m，5H)，7.17(br t，J＝9.1Hz，1H)，7.06(dd，J＝2.0，11.9Hz，1H)，6.84(br d，J＝8.6Hz，1H)，6.16(br d，J＝10.6Hz，2H)，6.00(s，2H)，5.15(s，2H)，2.03(s，3H).

Step ten: synthesis of 6- (4-amino-2, 6-difluorophenyl) -5- (4- (benzyloxy) -3-fluorophenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine

6- (4-amino-2, 6-difluorophenyl) -5- (4- (benzyloxy) -3-fluorophenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-ol (1.00 g,2.10 mmol) was dissolved in 15mL of acetonitrile, benzotriazole-1-oxo-tris (dimethylaminophosphorus) hexafluorophosphate (2.04 g,4.62 mmol) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (702 mg,4.62 mmol) were added, after stirring for 1 hour at 20℃p-methoxybenzylamine (2.02 g,14.6 mmol), stirring for 9 hours at 80℃was complete, LCMS detection was performed and column chromatography was performed to give 6- (4-amino-2, 6-difluorophenyl) -5- (4- (benzyloxy) -3-fluorophenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4.88 g (1.88 g, yield, 6%).

LCMS：m/z 596.1[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.40-8.21(m，1H)，7.38-7.36(m，1H)，7.28(d，J＝8.8Hz，2H)，7.25-7.15(m，2H)，7.09(d，J＝8.6Hz，2H)，7.02(br d，J＝8.9Hz，1H)，6.92-6.87(m，2H)，6.82(d，J＝8.6Hz，2H)，6.15(br d，J＝10.9Hz，2H)，5.98(s，2H)，4.91(t，J＝5.4Hz，1H)，4.46(br d，J＝5.4Hz，2H)，3.76(s，2H)，3.67(s，3H)，2.05(s，3H).

Step eleven: synthesis of 4- (6- (4-amino-2, 6-difluorophenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl) -2-fluorophenol

6- (4-amino-2, 6-difluorophenyl) -5- (4- (benzyloxy) -3-fluorophenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (1.15 g,1.93 mmol) was dissolved in 12mL of methanol, 10% wet palladium on carbon (575 mg, 540. Mu. Mol) was added, and stirring was performed at 20deg.C for 2 hours in a hydrogen atmosphere, LCMS detected the end of the reaction, filtered, and dried by spin to give 4- (6- (4-amino-2, 6-difluorophenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl) -2-fluorophenol (1.00 g, 51.4%).

LCMS：m/z 506.6[M+H] ⁺ .

Step twelve: synthesis of 6- (4-amino-2, 6-difluorophenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine

4- (6- (4-amino-2, 6-difluorophenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-5-yl) -2-fluorophenol (900 mg,1.78 mmol) was dissolved in 9mL dioxane, cesium carbonate (1.16 g,3.56 mmol) and 2-chloro-4-methylpyrimidine (457 mg,3.56 mmol) were added, stirring was performed at 90℃for 3 hours, LCMS detection of the end of the reaction, spin-dry and column chromatography gave 6- (4-amino-2, 6-difluorophenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (520 mg, yield 46.3%).

LCMS：m/z 598.2[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝8.42(d，J＝5.0Hz，1H)，8.32(s，1H)，7.40(t，J＝8.6Hz，1H)，7.31(dd，J＝2.0，10.8Hz，1H)，7.19(d，J＝5.0Hz，1H)，7.14(br d，J＝8.5Hz，2H)，7.10(br d，J＝8.6Hz，1H)，6.79(d，J＝8.6Hz，2H)，6.19(d，J＝10.9Hz，2H)，6.01(s，2H)，5.14(br t，J＝5.6Hz，1H)，4.53(br d，J＝5.5Hz，2H)，3.67(s，3H)，2.36(s，3H)，2.08(s，3H).

Step thirteen: synthesis of N- (3, 5-difluoro-4- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) -3- (phenylsulfonyl) propanamide

6- (4-amino-2, 6-difluorophenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -N- (4-methoxybenzyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-4-amine (500 mg, 836. Mu. Mol) was dissolved in 10mL of dichloromethane, 3- (benzenesulfonyl) propionic acid (356 mg,1.67 mmol), O- (7-azabenzotriazol-1-yl) -N, N, N-tetramethylurea hexafluorophosphine salt (954 mg,2.51 mmol) and N, N-diisopropylethylamine (324 mg,2.51 mmol) were added, the reaction was terminated by LCMS detection and N- (3, 5-difluoro-4- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3, 2-phenyl) -propionyl-3- (4.660 mg) propionyl-yl) amide was obtained by column chromatography.

LCMS：m/z 794.1[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.59(s，1H)，8.43(d，J＝5.0Hz，1H)，7.93-7.87(m，3H)，7.81-7.60(m，5H)，7.29(br d，J＝11.0Hz，2H)，7.22-7.14(m，4H)，6.94(s，1H)，6.83(d，J＝8.6Hz，2H)，4.68(br d，J＝5.4Hz，2H)，3.69(s，3H)，3.63-3.59(m，2H)，2.72-2.68(m，2H)，2.33(s，3H)，2.15(s，3H).

Step fourteen: synthesis of N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3, 5-difluorophenyl) -3- (phenylsulfonyl) propanamide

N- (3, 5-difluoro-4- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- ((4-methoxybenzyl) amino) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) phenyl) -3- (phenylsulfonyl) propanamide (660 mg, 831. Mu. Mol) was dissolved in 3mL of trifluoroacetic acid, 3mL of trifluoromethanesulfonic acid was added, the reaction was allowed to react at 40℃for 2 hours, LCMS detection was completed, saturated aqueous sodium bicarbonate solution was added to adjust pH to 7, and the mixture was extracted, dried and spun dry to give N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3, 5-difluorophenyl) -3- (phenylsulfonyl) propanamide (560 mg, yield 72.9%).

LCMS：m/z 674.2[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.54(s，1H)，8.47(d，J＝5.0Hz，1H)，8.27(s，1H)，7.72-7.59(m，4H)，7.51-7.33(m，3H)，7.26(br d，J＝10.4Hz，2H)，7.19(d，J＝5.0Hz，1H)，7.12(br d，J＝8.1Hz，1H)，5.81(br s，2H)，3.54-3.43(m，2H)，2.72-2.67(m，2H)，2.36(s，3H)，2.09(s，3H).

Fifteen steps: synthesis of N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3, 5-difluorophenyl) acrylamide

N- (4- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3, 5-difluorophenyl) -3- (phenylsulfonyl) propanamide (280 mg, 415. Mu. Mol) was dissolved in 10mL of tetrahydrofuran, trimethylpotassium oxide (53.3 mg, 415. Mu. Mol) was added, stirring was carried out at 20℃for 0.5 hours, LCMS detection was completed, the reaction mixture was added to a saturated ammonium chloride solution, extracted, dried, spun-dried and N- (4-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-5H-pyrrolo [3,2-d ] pyrimidin-6-yl) -3, 5-difluorophenyl) acrylamide (45.0 mg, yield 20.7%) was obtained by preparative HPLC.

LCMS：m/z 532.0[M+H] ⁺ .

¹ H NMR(400MHz，DMSO-d6)δ＝10.64(s，1H)，8.47(br d，J＝4.9Hz，1H)，8.27(s，1H)，7.53-7.31(m，4H)，7.25-7.06(m，2H)，6.45-6.27(m，2H)，5.96-5.69(m，3H)，2.35(s，3H)，2.11(s，3H).

Biological test data:

test example 1: SNU-16 cell proliferation assay

The human gastric cancer cell line SNU-16 (ATCC, CRL-5974) is a cell line amplified by FGFR2 gene. SNU-16 cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum and grown at 37℃in a humidified incubator with 5% CO 2.

The number of living cells in the culture was examined according to the protocol described in CellTiter-Glo Luminescent cell Viability Assav (Promega catalog # G7570) from Promega corporation. mu.L of cells (8,000 cells/well) were cultured in a growth medium in a Corning black clear bottom 96-well plate and incubated overnight at 37℃in a 5% CO2 humidified incubator. Serial dilutions of compound in 100% dmso were added to the cells using a pipette and the cells were cultured for an additional 72 hours. mu.L of the mixed Cell Titer-Glo reagent was added to cells in a 96-well plate to lyse the cells, and gently mixed. Subsequently, the autofluorescence was detected on an Envision microplate detector, and data for each compound were obtained. Finally, the data is entered into a suitable software package (e.g., prism) for curve fitting analysis. IC was determined based on this data and by calculating the concentration of compound required to obtain 50% inhibition ₅₀ Values.

Test example 2: KATO III cell proliferation assay

The human gastric cancer cell line KATOIII (ATCC, HTB-103) is a cell line amplified by FGFR2 gene. KATOIII cells were grown in RPMI 1640 medium containing 10% fetal bovine serum in a humidified incubator with 5% co2 at 37 ℃.

The number of living cells in the culture was examined according to the protocol described in CellTiter-Glo Luminescent cell Viability Assay (Promega catalog # G7570) from Promega corporation. mu.L of cells (8,000 cells/well) were cultured in a growth medium in a Corning black clear bottom 96-well plate and incubated overnight at 37℃in a 5% CO2 humidified incubator. Serial dilutions of compound in 100% dmso were added to the cells using a pipette and the cells were cultured for an additional 72 hours. mu.L of the mixed CellTiter-Glo reagent was added to cells in 96-well plates to lyse the cells and gently mixed. Subsequently, the autofluorescence was detected on an Envision microplate detector, and data for each compound were obtained. Finally, the data is entered into a suitable software package (e.g., prism) for curve fitting analysis. Based on this data and calculated to obtain 50% inhibition required Determination of IC by Compound concentration ₅₀ Values.

Test example 3: AN3 CA cell proliferation assay

The human endometrial cancer cell line AN3 CA (ATCC, HTB-111) is a FGFR 2N 550K mutant cell line. AN3 CA cells were grown in MEM medium containing 10% fetal bovine serum in a humidified incubator with 5% CO2 at 37 ℃.

The number of living cells in the culture was examined according to the protocol described in CellTiter-Gli Luminescent cell Viability Assay (Promega catalog # G7570) from Promega corporation. mu.L of cells (8,000 cells/well) were cultured in a growth medium in a Corning black clear bottom 96-well plate and incubated overnight at 37℃in a 5% CO2 humidified incubator. Serial dilutions of compound in 100% dmso were added to the cells using a pipette and the cells were cultured for an additional 72 hours. mu.L of the mixed CellTiter-Glo reagent was added to cells in 96-well plates to lyse the cells and gently mixed. Subsequently, the autofluorescence was detected on an Envision microplate detector, and data for each compound were obtained. Finally, the data is entered into a suitable software package (e.g., prism) for curve fitting analysis. IC was determined based on this data and by calculating the concentration of compound required to obtain 50% inhibition ₅₀ Values.

The FGFR2 inhibition activity data for each of the compounds obtained in test example 1, test example 2 and test example 3 are shown in table 8.

TABLE 8

/>

Remarks: * Erdafitinib (catalog number: HY-18708) and Pemigatib (catalog number: HY-109099) are available from MedChemexpress.

In the following test examples, cell proliferation inhibition tests were performed using cell lines that highly expressed different fgfrls, 3, and 4, respectively. The results show that the inhibition activity of the compound of the invention on FGFR1, 3 and 4 is obviously weaker than that of FGFR2, thereby proving that the compound has high selectivity on FGFR 2.

Test example 4: li-7 cell proliferation assay

The human liver cancer cell line Li-7 (TCHul 83) is a cell line amplified by FGFR1 gene. Lu-7 cells were grown in RPMI 1640 medium containing 10% fetal bovine serum in a humidified incubator with 5% CO2 at 37 ℃.

The number of living cells in the culture was examined according to the protocol described in CellTiter-Glo Luminescent cell Viability Assay (Promega catalog # G7570) from Promega corporation. mu.L of cells (8,000 cells/well) were cultured in a growth medium in a Corning black clear bottom 96-well plate and incubated overnight at 37℃in a 5% CO2 humidified incubator. Serial dilutions of compound in 100% dmso were added to the cells using a pipette and the cells were cultured for an additional 72 hours. mu.L of the mixed CellTiter-Glo reagent was added to cells in 96-well plates to lyse the cells and gently mixed. Subsequently, the autofluorescence was detected on an Envision microplate detector, and data for each compound were obtained. Finally, the data is entered into a suitable software package (e.g., prism) for curve fitting analysis. IC was determined based on this data and by calculating the concentration of compound required to obtain 50% inhibition ₅₀ Values.

Test example 5: RT4 cell proliferation assay

The human bladder cancer cell line RT4 (ATCC, HTB-2) is a cell line in which the FGFR3 gene is amplified. RT4 cells were cultured in McCoy's 5a medium containing 10% fetal bovine serum and placed in a humidified incubator with 5% CO2 at 37.C, growth.

The number of living cells in the culture was examined according to the protocol described in CellTiter-Glo Luminescent cell Viability Assay (Promega catalog # G7570) from Promega corporation. mu.L of cells (8,000 cells/well) were cultured in a Corning black transparent bottom 96-well plate in a growth medium at 37 DEG CThe cells were incubated overnight in a 5% CO2 humidified incubator. Serial dilutions of compound in 100% dmso were added to the cells using a pipette and the cells were cultured for an additional 72 hours. mu.L of the mixed CellTiter-Glo reagent was added to cells in 96-well plates to lyse the cells and gently mixed. Subsequently, the autofluorescence was detected on an Envision microplate detector, and data for each compound were obtained. Finally, the data is entered into a suitable software package (e.g., prism) for curve fitting analysis. IC was determined based on this data and by calculating the concentration of compound required to obtain 50% inhibition ₅₀ Values.

Test example 6: MDA-MB-453 cell proliferation assay

The human breast cancer cell line MDA-MB-453 (ATCC, HTB-131) is a cell line amplified by FGFR4 gene. MDA-MB-453 cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum and grown at 37℃in a humidified incubator with 5% CO 2.

The number of living cells in the culture was examined according to the protocol described in CellTiter-Glo Luminescent cell Viability Assay (Promega catalog # G7570) from Promega corporation. mu.L of cells (8,000 cells/well) were cultured in a growth medium in a Corning black clear bottom 96-well plate and incubated overnight at 37℃in a humidified incubator. Serial dilutions of compound in 100% dmso were added to the cells using a pipette and the cells were cultured for an additional 72 hours. mu.L of the mixed Cell Titer-Glo reagent was added to cells in a 96-well plate to lyse the cells, and gently mixed. Subsequently, the autofluorescence was detected on an Envision microplate detector, and data for each compound were obtained. Finally, the data is entered into a suitable software package (e.g., prism) for curve fitting analysis. IC was determined based on this data and by calculating the concentration of compound required to obtain 50% inhibition ₅₀ Values.

Table 9 shows the data of FGFR1, FGFR3 and FGFR4 inhibition activity obtained for each of the compounds of test example 4, test example 5 and test example 6. The results show that the inhibition activity of the compound of the invention on FGFR1, 3 and 4 is obviously weaker than that of FGFR2, thereby proving that the compound has high selectivity on FGFR 2.

TABLE 9

/>

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein the method comprises the steps of

R ⁵ Selected from the following groups: -R ^5A -L ⁵ -R ^5B ；

R ^5A Selected from the following groups:

Cy ⁶ Selected from C _3-14 Cycloalkyl, aryl, C _5-14 Heteroaryl, saturated or partially unsaturated C _3-14 Cycloalkyl, saturated or partially unsaturated C _3-14 Heterocycloalkyl, C _5-14 Heteroaryl, optionally substituted with at least one substituent R ^Cy6 Substitution, said C _3-14 Cycloalkyl, C _3-14 Heterocycloalkyl, C _3-14 Heterocycloalkyl and C _5-14 Heteroaryl groups each independently comprise 1, 2, 3 or 4 groups independently selected from-NH-, heteroatoms or groups of heteroatoms of O-, -S-and N, R is R ^Cy6 Selected from hydrogen, halogen (e.g., -F, -Cl or-Br), cyano, hydroxy, amino, nitro, alkyl, alkoxy, alkenyl, alkynyl, C _1-3 Haloalkyl, C _1-3 Haloalkoxy (e.g. -OCF) ₃ ) The method comprises the steps of carrying out a first treatment on the surface of the Wherein said amino, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, optionally further substituted;

R ⁷ is H or R ^B Wherein R is ⁷ Through t R ^7A Group substitution;

R ^W selected from the following groups: a halogen atom,

-CN，

R ^WA ，R ^WB and R is ^WC Independently selected from hydrogen, deuterium, halogen, -CN-, -C (O) R-, -C (O) OR, -C (O) NR ₂ (C (O) N (R) OR, OR optionally C _1-6 Aliphatic hydrocarbon groups (e.g. C _1-6 Alkyl or C _2-6 Alkenyl), phenyl, C _3-7 Saturated or partially unsaturated heterocycloalkyl and containing 1, 2 heteroatoms independently selected from-NH-, -O-, -S-, or heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from-NH-, -O-, -S-, wherein the ring is interrupted by w R ^C Group substitution; or R is ^WA And R is ^WB ，R ^WB And R is ^WC Together with the atoms to which they are attached form C _4-7 Wherein the rings may each contain 0, 1 or 2 heteroatoms or groups of heteroatoms independently selected from-NH-, -O-, -S-; wherein the ring is covered by w R ^C Group substitution;

R ^WD selected from halogen or-OS (O) ₂ R；

R ^5C ，R ^5D And R is ^7A Independently selected from R ^A Or R is ^B And through u R ^C Substituted by radicals, or by two R ^5C A group, one R ^5C Radicals and one R ^5D A group, or two R ^5D The radicals together with the atoms to which they are attached form C _3-7 Or an aryl group, wherein said C _3-7 The saturated partially unsaturated group or heteroaryl group contains 0, 1, 2, 3 or 4 heteroatoms or groups of heteroatoms independently selected from-NH-, -O-, -S-, respectively; wherein the ring is covered by w R ^C Group substitution;

R ^C independently selected from oxygen, halogen, -CN, -NO ₂ ，-OR，-SR，-NR ₂ ，-S(O) ₂ R，-S(O) ₂ NR ₂ ，-S(O)R，-S(O)NR ₂ ，-S(O) ₂ F，-OS(O) ₂ F，-C(O)R，-C(O)OR，-C(O)NR ₂ ，-C(O)N(R)OR，-OC(O)R，-OC(O)NR ₂ ，-N(R)C(O)OR，-N(R)C(O)R，-N(R)C(O)NR ₂ ，-N(R)C(NR)NR ₂ ，-N(R)S(O) ₂ NR ₂ or-N (R) S (O) ₂ R；C _1-6 Aliphatic hydrocarbon groups (e.g. C _1-6 Alkyl or C _2-6 Alkenyl groups); a phenyl group; c (C) _3-7 A saturated or partially unsaturated heterocycloalkyl group selected from the group consisting of a heteroatom or a heteroatom group comprising 1 or 2 heteroatoms independently selected from-NH-, -O-, -S-; c (C) _5-6 Heteroaryl selected from the group consisting of heteroatoms or groups of heteroatoms comprising 1,2,3 or 4 groups independently selected from-NH-, -O-, -S-;

r is independently selected from hydrogen, or optionally C _1-6 Aliphatic hydrocarbon groups (e.g. C _1-6 Alkyl or C _2-6 Alkenyl groups); a phenyl group; c (C) _3-7 A saturated or partially unsaturated heterocycloalkyl group selected from the group consisting of a heteroatom or a heteroatom group comprising 1 or 2 heteroatoms independently selected from-NH-, -O-, -S-; c (C) _5-6 Heteroaryl selected from the group consisting of 1,2,3, or 4 heteroatoms or groups of heteroatoms independently selected from-NH-, -O-, -S-;

m, n, p, q, r, t, u, v and w are independently selected from 0,1,2,3 or 4.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula XXVI-1 or XXVI-2:

wherein X is CH or N, -Cy ⁶ -L ⁶ -partly through nitrogen atoms withPartial ligation (preferably, -Cy) ⁶ -L ⁶ -part is optionally covered by C _1-6 Alkyl-or halogen-substituted subunits Phenylamino, pyridylamino, azetidinyl, azapyrrolidinyl, azacyclohexenyl, azapentenyl, azacyclohexenyl, methyleneazetidinyl, methyleneazapyrrolidinyl, methyleneazacyclohexenyl); r is R ^WA Is hydrogen or C _1-6 An alkyl group. R is R ⁷ Selected from C _1-6 Alkyl, trifluoromethyl, cyano, dimethylphosphoryl, 2-isopropanol-2-yl, methoxy, 1-hydroxyethyl, morpholinomethyl, (4-methylpiperazin-1-yl) -methyl.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula XXVII:

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula XXVIII-1 or XXVIII-2:

wherein R is ⁶ Selected from the group consisting of-H, -F, -Cl, -CH ₃ 、-OCH ₃ X is CH or N, R ⁷ Selected from H, C _1-6 Alkyl (preferably methyl), C _3-7 A saturated or partially unsaturated mono-heterocycloalkyl group selected from the group consisting of a heteroatom or a heteroatom group comprising 1 or 2 heteroatoms independently selected from-NH-, -O-, -S-; optionally when R ⁷ When the R is not H, R ⁷ Is selected from C _1-6 Alkyl, hydroxy, halogen groups; p is selected from 0,1,2,3 or 4, preferably 0; r is R ^WA Selected from H or methyl.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein,

the compound is selected from the following compounds:

6. a pharmaceutical composition comprising a compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

7. Use of a compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, in the preparation of an FGFR inhibitor.

8. The use of claim 7, wherein the FGFR inhibitor is a medicament for the treatment or prevention of solid tumors.

9. The use of claim 8, wherein the solid tumor is selected from intrahepatic cholangiocarcinoma and gastric cancer.