WO2022213932A1

WO2022213932A1 - Pyrrolopyrimidinone compound and application thereof

Info

Publication number: WO2022213932A1
Application number: PCT/CN2022/085088
Authority: WO
Inventors: 蔡雄; 卿远辉; 何其捷; 翁运幄; 刘怡婷; 刘斌; 林明生; 封巧; 吴少槟; 范福顺; 戈平; 钱长庚
Original assignee: 广州必贝特医药股份有限公司
Priority date: 2021-04-06
Filing date: 2022-04-02
Publication date: 2022-10-13

Abstract

Provided are a pyrrolopyrimidinone compound having a structure represented by general formula (I) and an application thereof. The pyrrolopyrimidinone compound may effectively inhibit the activity of BTK C481 mutations, also has a strong inhibitory effect on the proliferation of wild-type BTK cell lines, and has the potential to be used as drugs for the treatment of B-cell lymphoma, autoimmune diseases and inflammation.

Description

Pyrrolopyrimidinones and their applications

technical field

The invention relates to the technical field of chemical medicine, in particular to a pyrrolopyrimidone compound and an application thereof.

Background technique

Bruton's tyrosine kinase (BTK) belongs to the TEC family of non-receptor tyrosine kinases and is an important part of the B cell receptor (BCR) signaling pathway (Smith, C.I., et al., The Tec family of cytoplasmic tyrosine kinases: mammalian Btk, Bmx, Itk, Tec, Txk and homologs in other species. Bioessays, 2001.23(5):p.436-46.). After initiation of BCR signaling, BTK phosphorylates and activates phospholipase Cγ2 (PLCγ2), which in turn activates the nuclear transcription factor NF-κB (Xia, B., et al., Targeting Bruton's tyrosine kinase signaling as an emerging therapeutic agent of B -cell malignancies. Oncol Lett, 2015.10(6):p.3339-3344.). BTK is expressed in all cell lines of the hematopoietic system except T cells and terminally differentiated plasma cells (Smith, C.I., et al., Expression of Bruton's agammaglobulinemia tyrosine kinase gene, BTK, is selectively down-regulated in T lymphocytes and plasma cells. J Immunol, 1994. 152(2): p. 557-65.). Normally expressed BTK is essential at all stages of B lymphocyte development. Abnormally activated BTK usually promotes clonal proliferation and accumulation of malignant B lymphocytes in the bone marrow, secondary lymphoid organs, and blood, and is considered to be one of the major mechanisms of B-cell lymphoma disease progression (Vetrie, D., et al. ., Thegene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature, 1993.361(6409):p.226-33.), so BTK inhibitors are a common treatment option for B-cell lymphomas . B-cell malignancies include non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL), with the most common subtypes being chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell Lymphoma (DLBCL), Follicular Lymphoma (FL), Multiple Myeloma (MM), Marginal Zone Lymphoma (MZL), Mantle Cell Lymphoma (MCL), and Waldenstrom's Macroglobulinemia (WM) (Wen , T., et al., Inhibitors targeting Bruton's tyrosine kinase in cancers: drug development advancements. Leukemia, 2021.35(2):p.312-332.). In addition to hematological tumors, more and more clinical trials are exploring the application of BTK inhibitors in the fields of non-hematological malignancies such as lung cancer, breast cancer, prostate cancer, kidney cancer, gastric cancer, liver cancer, pancreatic cancer, ovarian cancer, and colon cancer (Campbell , R., G. Chong, and E.A. Hawkes, Novel Indications for Bruton's Tyrosine Kinase Inhibitors, beyond Hematological Malignancies. J Clin Med, 2018.7(4).

After the abnormal activation of BCR signaling pathway caused by the massive expression of BTK, B cells can become dysfunctional, change the state of immune tolerance, transform into autoreactive B cells, and secrete a large number of autoantibodies to induce autoimmune diseases. BTK is also expressed on myeloid cells, including monocytes, macrophages, neutrophils and mast cells. These cells infiltrate lubricating lumen and produce inflammatory cytokines that exacerbate arthritis symptoms. BTK inhibitors can block B cell receptor-dependent cell proliferation and reduce inflammatory cytokine production (Whang, J.A. and B.Y. Chang, Bruton's tyrosine kinase inhibitors for the treatment of rheumatoid arthritis. Drug Discov Today, 2014.19(8):p. 1200-4.). Therefore, more and more BTK inhibitors are conducting clinical trials related to autoimmune diseases or inflammation such as rheumatoid arthritis, psoriasis, lupus erythematosus, lupus nephritis, multiple sclerosis, Sjogren's syndrome and asthma. (Szilveszter, K.P., T. Nemeth, and A. Mocsai, Tyrosine Kinases in Autoimmune and Inflammatory Skin Diseases. Front Immunol, 2019.10:p.1862.).

The first small-molecule BTK inhibitor approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) is ibrutinib, which binds to cysteine 481 of the BTKATP-binding pocket The cysteine residue (Cys481) in the active site selectively covalently binds to irreversibly inhibits the activity of BTK, thereby inhibiting the activation of the BCR signaling pathway, effectively preventing tumor migration to lymphoid tissues suitable for tumor growth, and reducing BTK. Malignant proliferation of cells and induction of apoptosis (Food and Drug Administration (FDA). Highlights of Prescribing Information. IMBRUVICA TM (ibrutinib) capsules, for oral use. 2019. (accessed 25 Nov 2019).). Approved indications for ibrutinib include mantle cell lymphoma (MCL) with at least one prior therapy; chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL); with del(17p) CLL/SLL; Waldenström's macroglobulinemia (WM); marginal zone lymphoma (MZL) with at least one prior anti-CD20-based therapy requiring systemic therapy and chronic transplant after failure of ≥1 systemic therapy Object-versus-host disease (cGVHD). In addition to targeting BTK, ibrutinib inhibits receptors including IL-2-induced T-cell kinase (ITK), tec protein tyrosine kinase (tec), BMX non-receptor tyrosine kinase, and epidermal growth factor receptors. Other kinases including EGFR (EGFR), which lead to toxic side effects such as rash and diarrhea (Wu, J., et al., Second-generation inhibitors of Bruton tyrosine kinase. J Hematol Oncol, 2016.9(1):p.80. ). With the progress of clinical trials, due to the controllable side effects of ibrutinib, more and more clinical trials have begun to explore the possibility of combined treatment of ibrutinib and other drugs. Ibrutinib in combination with lenalidomide and rituximab for the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) (Goy, A., et al., Ibrutinib plus lenalidomide and rituximab has promising activity in relapsed/refractory non-germinal center B-cell-like DLBCL.Blood, 2019.134(13):p.1024-1036.). In 2020, the Chinese Society of Clinical Oncology (CSCO) reported a phase III randomized controlled clinical study called PHOENIX, and the results confirmed that in patients less than 60 years old, rituximab, cyclophosphamide, doxorubicin can be seen. , Vincristine and prednisone (RCHOP) on the basis of adding ibrutinib, EFS (disease-free survival) was significantly benefited, and there is a trend of improvement, PFS and OS also have a clear trend of benefit. In addition, clinical trials exploring the combination of PD1/PD-L1 antibody and ibrutinib for the treatment of hematological malignancies and some solid tumors are also underway (Campbell, R., G. Chong, and E.A. Hawkes, Novel Indications for Bruton's Tyrosine Kinase Inhibitors, beyond Hematological Malignancies. J Clin Med, 2018.7(4).).

Acalabrutinib is the second novel, irreversible BTK inhibitor approved by the FDA for the treatment of mantle cell lymphoma (MCL) and CLL/small lymphocytic leukemia (Byrd, J.C., et al., Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med, 2016.374(4):p.323-32.). Compared with ibrutinib, acalabrutinib has higher selectivity and greatly reduces the off-target activity of EGFR and Tec, resulting in a lower incidence of adverse reactions and drug resistance. EGFR inhibition is considered to be related to rash. In association with severe diarrhea, Tec inhibition results in platelet dysfunction and increased risk of bleeding (Clinicaltrials.gov.NCT02477696.). In addition to the above two drugs, BeiGene's Zanubrutinib and InnoCare's Orelabrutinib have also been approved for marketing by the FDA and NMPA (Wen, T., et al., Inhibitors targeting Bruton's tyrosine kinase in cancers: drug development advancements. Leukemia, 2021.35(2):p.312-332.). None of the approved BTK inhibitors binds reversibly to cysteine 481 in the BTK binding pocket; based on biochemical binding kinetics, ibrutinib is the most potent BTK inhibitor, followed by zanubrutinib and acalabib tinib. In clinical practice, differences in pharmacodynamics and pharmacokinetics may affect inhibitor dose, efficacy, and adverse events (AEs). The half-life of acalatinib is shorter than that of once-daily ibrutinib, and the balance between rapid absorption and rapid elimination can lead to rapid on-target inhibition and reduce the potential risk of off-target problems or drug interactions.

Although BTK inhibitors have proven to be one of the most effective drugs in the treatment of several B-cell malignancies, cases of primary and secondary resistance have also emerged, often resulting in poor prognosis. IGHV mutations with CD79A/B wild-type WM or MYD88 mutations in ABC-DLBCL may be associated with primary resistance to ibrutinib (Xia, B., et al., Targeting Bruton's tyrosine kinase signaling as an emerging therapeutic agent of B-cell malignancies. Oncol Lett, 2015.10(6):p.3339-3344.). In CLL/SLL patients taking ibrutinib, mutations in the ibrutinib-binding (BTK Cys481), gatekeeper (BTK Thr474) and SH2 (BTK Thr316) domains of BTK have been found (Woyach, J.A., et al. , Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib. N Engl J Med, 2014.370(24):p.2286-94.). BTK Cys481 mutation is common in patients who progressed on ibrutinib therapy (Xu, L., et al., Acquired mutations associated with ibrutinib resistance in Waldenstrom macroglobulinemia. Blood, 2017.129(18):p.2519-2525.) . The most common mutation in BTK Cys481 is the substitution of cysteine (C) at position 481 of BTK with serine (S), which prevents covalent binding of BTK inhibitors to the sulfhydryl group of the ATP-binding site. BTK mutants C481F, C481G, C481R and C481Y were also found to be enriched in some CLL patients, leading to drug resistance, but the frequency was much lower than that of C481S (Woyach, J.A., et al., BTK(C481S)-Mediated Resistance to Ibrutinib in Chronic Lymphocytic Leukemia. J Clin Oncol, 2017. 35(13): p. 1437-1443.). Some studies have also found that PLCγ2 mutations (R665W, S707Y and L845F) can also lead to the activation of the B cell receptor (BCR) pathway and cause drug resistance (Liu, T.M., et al., Hypermorphic mutation of phospholipase C, gamma2 acquired in ibrutinib-resistant CLL confers BTK independency upon B-cell receptor activation. Blood, 2015.126(1):p.61-8.). To address the BTK resistance problem, second-generation BTK inhibitors targeting the C481 mutation were developed.

LOXO-305 is a highly selective and reversible BTK inhibitor with the fastest clinical progress. It does not covalently bind to C481, so C481 mutation will not lead to a decrease in the activity of LOXO-305, which can overcome the human body's response to covalent BTK inhibitors. (LOXO-305, A Next Generation Non-Covalent BTK Inhibitor, for Overcoming Acquired Resistance to Covalent BTK Inhibitors.). In the latest data from a Phase 1/2 clinical trial called BRUIN (NCT03740529), LOXO-305 demonstrated an ORR of 62% (95%) in 121 efficacy-evaluable BTK inhibitor-treated patients with CLL and SLL CI: 53-71). The ORR for patients with the BTK C481 mutation (71% [17/24]) was similar to that for patients without the mutation (66% [43/65]). Among 56 patients with MCL evaluable for response, 29 patients responded, including 14 patients with complete response (CR) and 15 patients with partial response (PR), with an overall response rate (ORR) of 52% (95% CI). :38-65). The ORR was also achieved in 52% (95% CI: 38-66) in 52 patients previously treated with a covalent BTK inhibitor.

ARQ 531 is an oral, potent and reversible BTK inhibitor with good bioavailability, which can inhibit the activity of wild-type and C481 mutant BTK (Reiff, S.D., et al., The BTK Inhibitor ARQ 531 Targets Ibrutinib-Resistant CLL and Richter Transformation. Cancer Discov, 2018.8(10):p.1300-1315.). Phase 1 data (NCT03162536) of AQR 531 were presented at the American Society of Hematology Annual Meeting (ASH) in December 2019, with 8 of 9 evaluable CLL patients achieving partial responses (PRs) at doses >65 mg QD. ), the remission rate was as high as 89%. Seven of the eight PR patients carried the BTK C481 mutation.

SUMMARY OF THE INVENTION

Based on the fact that C481 mutation accounts for a large proportion of first-generation BTK inhibitor resistance, and no drug has been approved for marketing at present, the present invention provides a new class of pyrrolopyrimidone compounds, which can effectively inhibit BTK C481 mutation Moreover, these compounds also have a strong inhibitory effect on wild-type BTK, and have the potential to be used as drugs for the treatment of B-cell lymphoma, autoimmune diseases and inflammation, and have great application value.

The present invention includes the following technical solutions.

The pyrrolopyrimidone compound represented by formula (I) or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule:

in:

The dashed line within the oxygen-containing six-membered ring indicates that it is a single bond or not;

n is selected from: 0, 1, 2, 3 or 4;

p is selected from: 0, 1, 2 or 3;

W is selected from: -O-, -S-, -CR ₄ R ₅ -;

Ring A is selected from: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted 8-10 membered heteroaryl, substituted or unsubstituted 8-10 membered benzo Heterocyclyl;

And, when ring A is selected from substituted or unsubstituted 8-10 membered heteroaryl, substituted or unsubstituted 8-10 membered benzoheterocyclyl, R ₁ is selected from: H, halogen, -OH, -OR ₆ , -NR ₇ R ₈ , -SR ₉ , -S(O)R ₉ , -S(O) ₂ R ₉ ;

When Ring A is selected from substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, R ₁ is selected from: -OR ₆ , -NR ₇ R ₁₀ , -SR ₉ , -S(O ) R ₉ , -S(O) ₂ R ₉ ;

R ₂ is selected from: H, halogen, C1-C6 alkyl;

Each R ₃ is independently selected from: H, halogen, nitro, cyano, ester, acyl, C1-C6 alkyl;

R ₄ , R ₅ are independently selected from: H, halogen, C1-C6 alkyl, C3-C8 cycloalkyl;

Each R ₆ is independently selected from: R ₉ S-substituted C1-C6 alkyl, R ₉ S(O)-substituted C1-C6 alkyl, R ₉ S(O) ₂ -substituted C1-C6 alkyl , R ₂₁ OC(O)O-substituted C1-C6 alkyl, aminocarbonyl, C1-C6 alkylaminocarbonyl, C1-C6 alkanoyl, amino-substituted C1-C6 alkanoyl, -(M ₁ )( M ₂ ) P=O; M ₁ and M ₂ are independently selected from: -OH, C1-C3 alkyl;

Each R ₇ is independently selected from: H, C1-C6 alkyl;

R ₈ is selected from: H, C1-C6 alkyl, CN, hydroxy-substituted C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, -SR ₉ , -S(O)R ₉ , -S(O) ₂ R ₉ ;

Each R _is independently selected from: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen substituted C1-C6 Alkyl, hydroxy substituted C1-C6 alkyl, C1-C6 alkoxy substituted C1-C6 alkyl, amino substituted C1-C6 alkyl, C1-C6 alkylamino substituted C1-C6 alkyl, C6-C10 aryl, one or more R ₁₂ substituted C6-C10 aryl, 3-10 membered heterocyclic group, amino, C1-C6 alkylamino;

R ₁₀ is selected from: CN, hydroxy-substituted C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, -SR ₁₁ , -S(O)R ₁₁ , -S(O) ₂ R ₁₁ ;

Each R ₁₁ is independently selected from: amino, hydroxy-substituted C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, phenyl, halogen-substituted phenyl;

Each R ₁₂ is independently selected from the group consisting of: halogen, nitro, cyano, C1-C6 alkyl;

R ₂₀ is selected from: H, R ₂₁ OC(O)O-substituted C1-C6 alkyl, R ₂₁ C(O)O-substituted C1-C6 alkyl, 1 or more R ₂₂ substituted 5- 8-membered heterocyclyl, R ₂₁ C(O)NH-substituted C1-C6 alkyl, 1 or more R ₂₃ substituted C1-C6 alkanoyl, (M ₁ )(M ₂ )P(O)O -Substituted C1-C6 alkyl; M ₁ and M ₂ are independently selected from: -OH, C1-C3 alkyl;

R ₂₁ is selected from: C1-C6 alkyl, C3-C8 cycloalkyl, amino-substituted C1-C6 alkyl;

Each R ₂₂ is independently selected from: C1-C6 alkyl, hydroxyl, halogen, nitro, cyano;

Each R ₂₃ is independently selected from: carboxyl, amino, hydroxyl, aminocarbonyl.

In some of these embodiments, the pyrrolopyrimidone compound has the structure represented by formula (II) or formula (III):

In some of these embodiments, Ring A is selected from:

in:

m is selected from: 0, 1 or 2;

X ₁ , X ₂ , X ₃ , X ₄ , X ₅ , X ₆ , X ₇ are independently selected from CR ₁₅ or N;

Each of R ₁₃ and R ₁₅ is independently selected from: H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen Substituted C1-C6 alkyl, hydroxy substituted C1-C6 alkyl, C1-C6 alkoxy substituted C1-C6 alkyl, amino substituted C1-C6 alkyl, C1-C6 alkylamino substituted C1 -C6 alkyl, C6-C10 aryl, 5-10 membered heteroaryl, nitro, cyano, -OR, -N(R) ₂ , -SR, -C(O)OR, -C(O) N(R) ₂ , -C(O)R, -S(O)R, -S(O) ₂ R, -S(O) ₂ N(R) ₂ , -N(R)C(O)R ;

Each R ₁₄ is independently selected from: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen substituted C1-C6 alkyl;

Each R is independently selected from: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen-substituted C1-C6 alkane group, C1-C6 alkyl substituted by hydroxy, C1-C6 alkyl substituted by C1-C6 alkoxy, C1-C6 alkyl substituted by amino, C1-C6 alkyl substituted by C1-C6 alkylamino.

In some of these embodiments, Ring A is selected from:

Wherein, X ₁ , X ₂ , and X ₃ are each independently selected from CR ₁₅ ; X ₄ , X ₅ , X ₆ , and X ₇ are each independently selected from CR ₁₅ or N.

In some of these embodiments, Ring A is selected from:

In some of these embodiments, each of R ₁₃ and R ₁₅ is independently selected from: H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, halogen substituted C1-C3 alkyl, hydroxy substituted C1-C3 Alkyl, C1-C3 alkyl substituted by C1-C3 alkoxy, C1-C3 alkoxy, cyano, -C(O)OR, -C(O)N(R) ₂ ; each R is independently selected From: H, C1-C6 alkyl.

In some of these embodiments, each of R ₁₃ and R ₁₅ is independently selected from: hydrogen, methyl, cyclopropyl, hydroxymethyl, ethyl, isopropyl, methoxymethyl, methoxycarbonyl, methoxy group, cyano group, aminocarbonyl group, monofluoromethyl group, difluoromethyl group, trifluoromethyl group, fluorine, chlorine.

In some of these embodiments, Ring A is selected from:

Wherein, each R ₁₃ is independently selected from: hydrogen, methyl, cyclopropyl, hydroxymethyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, fluorine, chlorine;

Each R ₁₅ is independently selected from: hydrogen, fluorine, chlorine.

In some of these embodiments, each R ₁₄ is independently selected from: H, C1-C3 alkyl.

In some of these embodiments, each R ₉ is independently selected from: H, C1-C3 alkyl, C3-C6 cycloalkyl, halogen-substituted C1-C3 alkyl, hydroxy-substituted C1-C3 alkyl, C1- C3 alkoxy substituted C1-C3 alkyl, amino substituted C1-C3 alkyl, C1-C3 alkylamino substituted C1-C3 alkyl, phenyl, halogen substituted phenyl, amino, C1-C3 Alkylamine group.

In some of these embodiments, each R ₉ is independently selected from: H, methyl, ethyl, dimethylamino, hydroxyethyl, isopropyl, amino, methylamino, methoxyethyl, phenyl , fluorophenyl.

In some of these embodiments, R ₈ is selected from: H, C1-C3 alkyl, -CN, hydroxy substituted C1-C3 alkyl, C1-C3 alkoxy substituted C1-C3 alkyl, -SR _{9- 1} , -S(O)R _9-1 , -S(O) ₂ R _9-1 ;

Wherein, each R _9-1 is independently selected from: hydroxy-substituted C1-C3 alkyl group, C1-C3 alkoxy-substituted C1-C3 alkyl group, amino group, phenyl group, and halogen-substituted phenyl group.

In some of these embodiments, R ₈ is selected from: H, methyl, -CN, hydroxyethyl, -S(O) ₂ R _9-1 ; wherein, R _9-1 is selected from: hydroxyethyl, methoxy ethyl, amino, phenyl, p-fluorophenyl.

In some of these embodiments, R ₁₀ is selected from: -CN, hydroxy substituted C1-C3 alkyl, C1-C3 alkoxy substituted C1-C3 alkyl, -SR ₁₁ , -S(O)R ₁₁ , -S(O) ₂ R ₁₁ ;

Each R ₁₁ is independently selected from: hydroxy-substituted C1-C3 alkyl, amino, C1-C3 alkoxy-substituted C1-C3 alkyl, phenyl, halogen-substituted phenyl.

In some of these embodiments, R ₁₀ is selected from: CN, hydroxyethyl, -S(O) ₂ R ₁₁ ; wherein each R ₁₁ is independently selected from: hydroxyethyl, amino, methoxyethyl, benzene base, p-fluorophenyl.

In some of these embodiments, each R ₆ is independently selected from: R ₉ S(O) ₂ -substituted methyl, R ₉ S(O) ₂ -substituted ethyl, R ₉ S(O) ₂ -substituted C1-C3 alkyl, aminocarbonyl, C1-C3 alkylaminocarbonyl, C1-C3 alkanoyl, amino-substituted C1-C6 alkanoyl;

Wherein, each R _9-2 is independently selected from: C1-C3 alkyl group, C1-C3 alkylamino group, hydroxy-substituted C1-C3 alkyl group, and amino group.

In some of these embodiments, each R ₆ is independently selected from: mesylmethyl, mesylethyl, ethylsulfonylethyl, mesylpropyl, dimethylaminosulfonylethyl, isopropyl Sulfonylethyl, hydroxyethylsulfonylethyl, aminosulfonylethyl, methylaminosulfonylethyl, aminocarbonyl, acetyl, 2-methyl-3-amino-butyryl, aminoacetyl.

In some of these embodiments, when Ring A is selected from substituted or unsubstituted 8-10 membered heteroaryl, substituted or unsubstituted 8-10 membered benzoheterocyclyl,

R ₁ is selected from: -OH, -OR ₆ , methanesulfonyl, -NR ₇ R ₈ , fluorine, chlorine;

R ₆ is selected from: R ₉ S(O) ₂ -substituted methyl, R ₉ S(O) ₂ -substituted ethyl, R ₉ S(O) ₂ -substituted propyl, C1-C3 alkanoyl, Amino-substituted C1-C6alkanoyl;

R ₇ is selected from: H, C1-C3 alkyl;

R ₈ is selected from: H, C1-C3 alkyl;

Each R ₉ is independently selected from: methyl, ethyl.

In some of these embodiments, Ring A is phenyl,

R ₁ is selected from: -OR ₆ , -NHR ₁₀ , -S(O) ₂ CH ₃ ;

R ₆ is selected from: R ₉ S(O) ₂ -substituted methyl, R ₉ S(O) ₂ -substituted ethyl; R ₉ S(O) ₂ -substituted propyl;

Each R ₉ is independently selected from: methyl, ethyl, amino, methylamino, dimethylamino,

R ₁₀ is selected from: -S(O) ₂ R ₁₁ ;

R ₁₁ is selected from the group consisting of: methaneoxy-substituted ethyl, amino.

In some of these embodiments, R ₂ is H; and/or, R ₃ is selected from the group consisting of: H, chlorine, fluorine.

In some of these embodiments, R ₂₀ is selected from: H, R ₂₁ OC(O)O-substituted C1-C3 alkyl, R ₂₁ C(O)O-substituted C1-C3 alkyl, (OH) ₂ P(O)O-substituted C1-C3 alkyl;

R ₂₁ is selected from: C1-C4 alkyl, C5-C6 cycloalkyl.

In some of these embodiments, the pyrrolopyrimidone compound is selected from:

The present invention also provides the use of the above-mentioned pyrrolopyrimidone compounds or their pharmaceutically acceptable salts or their stereoisomers or their prodrug molecules.

Including specific technical programs under the post.

Use of the above-mentioned pyrrolopyrimidone compounds or their pharmaceutically acceptable salts or their stereoisomers or their prodrug molecules in the preparation of BTK inhibitors.

In some of these embodiments, the BTK is wild-type BTK and/or C481 mutant BTK.

The application of above-mentioned pyrrolopyrimidone compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule in preparing the medicine for preventing and/or treating diseases and/or symptoms related to BTK hyperactivation .

In some of these embodiments, the BTK is wild-type BTK and/or C481 mutant BTK.

In some of these embodiments, the disease associated with BTK overactivation is a tumor, inflammation, or autoimmune disease.

In some of these embodiments, the tumor is a hematological tumor or a solid tumor.

In some of these embodiments, the hematological tumor is lymphoma, myeloma, lymphocytic leukemia, acute myeloid leukemia.

In some of these embodiments, the solid tumor is lung cancer, breast cancer, prostate cancer, kidney cancer, gastric cancer, liver cancer, pancreatic cancer, ovarian cancer, colon cancer.

In some of these embodiments, the inflammatory or autoimmune disease is rheumatoid arthritis, lupus erythematosus, lupus nephritis, multiple sclerosis, Sjogren's syndrome, asthma.

The present invention also provides a pharmaceutical composition for preventing and/or treating diseases and/or symptoms associated with BTK overactivation.

The specific technical solutions are as follows:

A pharmaceutical composition for preventing and/or treating diseases and/or symptoms related to BTK overactivation, comprising an active ingredient and a pharmaceutically acceptable adjuvant and/or carrier, the active ingredient comprising the above-mentioned pyrrolopyrimidone compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule.

In some of these embodiments, the active ingredient further comprises one or more second therapeutic agents capable of preventing and/or treating neoplastic, inflammatory or autoimmune diseases.

In some of these embodiments, the second therapeutic agent is selected from the group consisting of rituximab, lenalidomide, fludarabine, cyclophosphamide, doxorubicin, vincristine, prednisone, and PD-1 /PD-L1 antibody.

In some of these embodiments, the BTK is wild-type BTK and/or C481 mutant BTK.

The new pyrrolopyrimidone compounds provided by the present invention can effectively inhibit the mutation of BTK C481, and these compounds also have a strong inhibitory effect on wild-type BTK, and have the potential to be used for the treatment of B-cell lymphoma, autoimmune Drugs for sexually transmitted diseases and inflammation have greater application value.

Instruction drawings

Figure 1 is a graph of the mean drug duration of compound ARQ531, 1, 2, 10, 13, 14, 20 and 21 in rats administered by gavage (20 mg/kg).

Figure 2 is a graph of the mean drug time of compounds 23, 27, 34, 37, 60, 61 and 62 administered by gavage (20 mg/kg) to rats.

Figure 3 is a graph of the mean drug duration of the prodrug compound 110 administered by gavage to rats (20 mg/kg).

Figure 4 shows the antitumor activity of

compounds

13, 21 and 23 in TMD-8 transplanted tumor model.

Figure 5 shows the anti-tumor dose-response activity of compound 21 in the TMD-8 transplanted tumor model.

Detailed ways

In the compounds of the present invention, when any variable (eg, R, etc.) occurs more than once in any component, its definition at each occurrence is independent of the definition at each other occurrence. Likewise, combinations of substituents and variables are permissible so long as such combinations stabilize the compound. A line drawn into a ring system from a substituent indicates that the indicated bond may be attached to any substitutable ring atom. If the ring system is polycyclic, it means that such bonds are only attached to any suitable carbon atoms adjacent to the ring. It will be appreciated that one of ordinary skill in the art can select substituents and substitution patterns for the compounds of the present invention to provide compounds that are chemically stable and readily synthesized from readily available starting materials by the skill of the art and the methods set forth below. If a substituent is itself substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms, so long as the structure is stabilized.

The term "alkyl" as used herein is meant to include branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, the definition of "C1-C6" in "C1-C6 alkyl" includes groups having 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a straight or branched chain. For example, "C1-C6 alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl.

The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and the like.

The term "alkoxy" refers to a group in which an alkyl group is directly attached to oxygen, that is, a group having an -O-alkyl structure, such as -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₃ , -O -CH2CH( _CH3 ) ₂ , _{-OCH2CH2CH2CH3} , -O _- _CH ₍ _CH3 ₎ ₂ , etc.

The term "heterocyclyl" is a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent wherein one or more ring atoms are selected from N, O or S(O)m (where m is an integer from 0 to 2 ), the remaining ring atoms are carbon, such as: morpholinyl, piperidinyl, tetrahydropyrrolyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydro oxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl , dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidine, tetrahydrofuranyl, tetrahydrothienyl, etc., and their N-oxides, the connection of heterocyclic substituents can be Carbon atoms or through heteroatoms.

The term "heteroaryl" refers to an aromatic ring containing one or more heteroatoms selected from O, N or S. Heteroaryl groups within the scope of the present invention include, but are not limited to: quinolinyl, pyrazolyl, pyrrolyl , thienyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridazinyl, benzofuranyl, benzothienyl, benzoyl Oxazole, indolyl, etc.; "heteroaryl" is also understood to include the N-oxide derivative of any nitrogen-containing heteroaryl.

The term "substituted" refers to the replacement of a hydrogen group in a particular structure with a group of the designated substituent.

As understood by those skilled in the art, "halo" ("halo") or "halo" as used herein means chlorine, fluorine, bromine and iodine.

Unless otherwise defined, alkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl substituents can be unsubstituted or substituted. For example, a C1-C6 alkyl group can be substituted with one, two, or three substituents selected from OH, halogen, alkoxy, dialkylamino, or heterocyclyl groups such as morpholinyl, piperidinyl, and the like.

The present invention includes free forms of compounds of formula (I), formula (II) or formula (III), as well as pharmaceutically acceptable salts and stereoisomers thereof. Some of the specific exemplary compounds herein are protonated salts of amine compounds. The term "free form" refers to the amine compound in non-salt form. Included pharmaceutically acceptable salts include not only exemplary salts of the particular compounds described herein, but also typical pharmaceutically acceptable salts of all compounds of formula (I), formula (II), or formula (III) in free form . The free forms of specific salts of the compounds can be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a suitable dilute aqueous base, such as dilute aqueous NaOH, dilute aqueous potassium carbonate, dilute aqueous ammonia, and dilute aqueous sodium bicarbonate. The free forms differ somewhat from their respective salt forms in certain physical properties such as solubility in polar solvents, but for the purposes of the invention such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms.

The pharmaceutically acceptable salts of the present invention can be synthesized from compounds of the present invention containing a basic or acidic moiety by conventional chemical methods. Generally, salts of basic compounds are prepared by ion exchange chromatography or by reacting the free base and a stoichiometric amount or excess of an inorganic or organic acid in the desired salt form in a suitable solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reaction with a suitable inorganic or organic base.

Accordingly, pharmaceutically acceptable salts of the compounds of the present invention include conventional non-toxic salts of the compounds of the present invention formed by reacting a basic compound of the present invention with an inorganic or organic acid. For example, conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, as well as those derived from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, hard Fatty acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetyl Salts prepared from oxymonobenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, etc.

If the compound of the present invention is acidic, appropriate "pharmaceutically acceptable salts" refer to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic and organic bases. Salts derived from inorganic bases include aluminum salts, ammonium salts Salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganous salts, potassium salts, sodium salts, zinc salts, etc. Ammonium, calcium, magnesium, potassium and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as Amino acid, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethyl Diamine, N-Ethylmorpholine, N-Ethylpiperidine, Glucosamine, Glucosamine, Histidine, Hydroxocobalamin, Isopropylamine, Lysine, Methylglucamine, Morpholine, Piperazine , Piperidine, quack, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

Berg et al., "Pharmaceutical Salts," J. Pharm. Sci. '1977:66:1-19 describes the preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts in more detail.

Since deprotonated acidic moieties such as carboxyl groups in compounds can be anionic under physiological conditions, such charged charges can then be replaced by internally cationic protonated or alkylated basic moieties such as tetravalent The nitrogen atoms balance out, so it should be noted that the compounds of the present invention are potential inner salts or zwitterions.

In one embodiment, the present application provides a compound with the structure of formula (I), formula (II) or formula (III) and pharmaceutically acceptable salts thereof for the treatment of human or other mammalian tumors, inflammation or Autoimmune disease or symptoms.

In one embodiment, the compounds of the present application and their pharmaceutically acceptable salts can be used for the treatment or control of hematological tumors or solid tumors; wherein, the hematological tumors can be lymphoma, myeloma, lymphocytic leukemia, acute myeloid leukemia; The solid tumor can be lung cancer, breast cancer, prostate cancer, kidney cancer, stomach cancer, liver cancer, pancreatic cancer, ovarian cancer, colon cancer.

In one embodiment, the compounds of the present application and pharmaceutically acceptable salts thereof may be used for the treatment or control of inflammatory or autoimmune diseases such as: rheumatoid arthritis, lupus erythematosus, lupus nephritis, multiple sclerosis, Glenn Syndrome and Underlying Disease Asthma.

Drug metabolites and prodrugs: the metabolites of the compounds involved in the application and their pharmaceutically acceptable salts, as well as prodrugs that can be converted into the structures of the compounds involved in the application and their pharmaceutically acceptable salts in vivo, also Included in the claims of this application.

Combinations: Compounds of formula (I), formula (II) or formula (III) may be used in combination with other drugs known to treat or ameliorate similar conditions. When combined administration, the original drug administration mode & dosage remain unchanged, while the compound of formula (I), formula (II) or formula (III) is administered simultaneously or subsequently. When the compound of formula (I), formula (II) or formula (III) is taken at the same time with other one or more drugs, it is preferable to use one or more known drugs together with formula (I), formula (II) Or a pharmaceutical composition of a compound of formula (III). Drug combinations also include administration of a compound of formula (I) with one or more other known drugs at overlapping time periods. When the compound of formula (I), formula (II) or formula (III) is used in combination with one or more other drugs, the dosage of the compound of formula (I), formula (II) or formula (III) or known drugs Possibly lower doses than when they are taken alone.

Drugs or active ingredients that can be used in combination with a compound of formula (I), formula (II) or formula (III) include, but are not limited to:

Estrogen receptor modulators, androgen receptor modulators, retinal-like receptor modulators, cytotoxic/cytostatics, antiproliferative agents, protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protein kinase inhibitors agents, reverse transcriptase inhibitors, angiogenesis inhibitors, cell proliferation and survival signal inhibitors, drugs that interfere with cell cycle checkpoints and apoptosis inducers, cytotoxic drugs, tyrosine protein inhibitors, EGFR inhibitors, VEGFR inhibitors, serine/threonine protein inhibitors, Bcr-Abl inhibitors, c-Kit inhibitors, Met inhibitors, Raf inhibitors, MEK inhibitors, MMP inhibitors, topoisomerase inhibitors, histidine Acid deacetylase inhibitors, proteasome inhibitors, CDK inhibitors, Bcl-2 family protein inhibitors, MDM2 family protein inhibitors, IAP family protein inhibitors, STAT family protein inhibitors, PI3K inhibitors, AKT inhibitors , integrin blocker, interferon-α, interleukin-12, COX-2 inhibitor, p53, p53 activator, VEGF antibody, EGF antibody, cytotoxic T lymphocyte-associated antigen 4 (CTLA4) antibody, programmed Cell death 1 (PD-1) antibody, programmed cell death-ligand 1 (PD-L1) antibody, etc.

In one embodiment, the drugs or active ingredients that can be used in combination with the compound of formula (I), formula (II) or formula (III) include but are not limited to: aldesleukin, alendronate, interferon, Altranoin, Allopurinol, Sodium Allopurinol, Palonosetron Hydrochloride, Hexamelamine, Aminoglutide, Amifostine, Amrubicin, Amridine, Anastrozole , dolasetron, aranesp, arglabin, arsenic trioxide, arsenic, 5-azacytidine, azathioprine, BCG or tic BCG, betadine, betamethasone acetate, betamethasone sodium phosphate preparation, bexaro Ting, bleomycin sulfate, bromouridine, bortezomib, busulfan, calcitonin, alezolizumab injection, capecitabine, carboplatin, costo, cefesone, simoleukin, daunorubicin , chlorambucil, cisplatin, cladribine, cladribine, clodronate, cyclophosphamide, cytarabine, dacarbazine, actinomycin D, daunorubicin liposome, Dexamethasone, Dexamethasone Phosphate, Estradiol Valerate, Denisole-2, Dipomet, Deslorelin, Delazoxan, Diethylstilbestrol, Diflucan, Docetaxel, Deoxyfluridine, Adderall Mycin, dronabinol, chin-166-chitosan complex, eligard, rasburicase, epirubicin hydrochloride, aprepitant, epirubicin, epoetin alfa, erythropoietin, Eplatin, levamisole tablets, estradiol preparations, 17-beta-estradiol, estramustine sodium phosphate, ethinyl estradiol, amifostine, hydroxyphosphate, fenbifu, etoposide, fadrozole, Tamoxifen preparations, filgrastim, finasteride, filgrastin, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil, Fluoxymesterone, Flutamide, Formestan, 1-β-D-arabinofuranocythidine-5'-stearoyl phosphate, Formustine, Fulvestrant, Gammaglobulin, Gemcitabine , gemtuzumab ozogamicin, imatinib mesylate, carbazide wax paper capsules, goserelin, granisilone hydrochloride, histrelin, and methoxine, hydrocortisone, erythro-hydroxyl Nonyladenine, hydroxyurea, tetanibemumab, idarubicin, ifosfamide, interferon alpha, interferon-alpha2, interferon alpha-2A, interferon alpha-2B, interferon alpha -nl, interferon alpha-n3, interferon beta, interferon gamma-la, interleukin-2, intron A, Iressa, irinotecan, keteri, lentinan sulfate, letrozole, formazan leucovorin, leuprolide, leuprolide acetate, levothyroxine, levothyroxine calcium salt, levothyroxine sodium, levothyroxine sodium preparations, lomustine, lonidamine, drosophila Cannabidiol, nitrogen mustard, mecobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, esterified estrogen, 6-mercaptopurine, mesna, methotrexate, aminolevulinic Methyl ester, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrine, trolostam, doxorubicin citrate liposome, nedaplatin, pegylated Filgrastim, Oprel, Neupogen, Niru Mitre, tamoxifen, NSC-631570, recombinant human interleukin-1-beta, octreotide, ondansetron hydrochloride, dehydrocortisone oral solution, oxaliplatin, paclitaxel, prednisone sodium phosphate preparation, Peaspargase, Pegasys, Pentostatin, Streptolyticum, Pilocarpine Hydrochloride, Pirarubicin, Pukamycin, Porfimer Sodium, Prednimustine, Steprednib Solone, Prednisone, Premarin, Procarba, Recombinant Human Erythropoietin, Raltitrexed, Ribi, Etidronate, Rhenium-186, Rituxan, Strength-A, Romotide, Pilocarpine Hydrochloride Tablets, Octreotide, Samostim, Semustine, Sizoran, Sobuzoxan, Methylprednisolone, Paphos Acid, Stem Cell Therapy, Streptozocin, Strontium-89 Chloride, Levothyroxine Sodium, tamoxifen, tansulosin, tamoxifen, tastolactone, taxotere, ticetiazine, temozolomide, teniposide, testosterone propionate, methyltestosterone, thioguanine, thiotepa, Thyroid-stimulating hormone, tiludronic acid, topotecan, toremifene, tosilimumab, trastuzumab, triosulfan, tretinoin, methotrexate tablets, trimethoprim Amine, trimetrexate, triptorelin acetate, triptorelin pamoate, eufradine, uridine, valrubicin, vesrinone, vinblastine, vincristine, vincristine, vinorelbine Bing, velulizine, dextropropimide, net statin, zofenin, paclitaxel protein stabilizer, acolbifene, interferon r-lb, affinitak, aminopterin, azoxifene, asoprisnil, Tamestane, Atrasentan, BAY43-9006, Avastin, CCI-779, CDC-501, Celebrex, Cetuximab, Crinator, Cyproterone Acetate, Decitabine, DN-101, doxorubicin-MTC, dSLIM, dutasteride, edotecarin, eflunomine, ixitecan, fenretinide, histamine dihydrochloride, histidine hydrogel plant Insect, holmium-166DOTMP, ibandronic acid, interferon gamma, intron-PEG, ixabepilone, keyhole limpet hemocyanin, L-651582, lanreotide, lasoxifene, libra, lonafamib, mipo Xifene, Minodex, MS-209, Liposome MTP-PE, MX-6, Nafarelin, Nemrubicin, Novastat, Nolatroxide, Olimerson, onco-TCS, osidem, paclitaxel polyglutamate, sodium bromide, PN-401, QS-21, quasiyang, R-1549, raloxifene, leopard enzyme, 13-cis-retinoic acid, sand Platinum, siocalcidol, T-138067, tarceva, docosahexaenoate paclitaxel, thymosin al, gazofurine, tipifarnib, tirapazamine, TLK-286, toremifene, trans MID-lo7R, valspoda, vapretide, vatalanib, verteporfin, vinflunine, Z-100 and zolelinic acid or their combination.

In one embodiment, drugs or active ingredients that can be used in combination with a compound of formula (I), formula (II) or formula (III) include, but are not limited to: rituximab, lenalidomide, fluoride Darabine, cyclophosphamide, doxorubicin, vincristine, prednisone and PD-1/PD-L1 antibody.

Synthetic Methods: In addition to standard methods known in the literature or exemplified in experimental procedures, the compounds of the present invention can be prepared using the methods in the following synthetic schemes (Schemes 1-6). Combined with the following synthetic schemes, the compounds and synthetic methods described in the present invention can be better understood. The described synthetic schemes describe methods that can be used to prepare the compounds described in the present invention, and the described methods are merely illustrative scheme descriptions for illustrative purposes and do not limit the scope of the present invention.

plan 1

Scenario 2

Scenario 3

Scenario 4

Scenario 5

Option 6

Example 1: (4-(benzofuran-7-yloxy)-2-chlorophenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran Preparation of -3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 1) (prepared according to Scheme 1)

Step 1a: Preparation of Benzofuran-7-ol (Compound 0101-1):

To a solution of o-vanillin (5 g, 32.86 mmol, 1.0 equiv) in N,N-dimethylformamide (100 mL) was added ethyl bromoacetate (8.23 g, 49.29 mmol, 1.5 equiv) under nitrogen ), cesium carbonate (21.4 g, 65.72 mmol, 2.0 equiv), and the mixture was stirred at room temperature for 0.5 h, then at 120 °C for 3.0 h. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether/ethyl acetate=30/1 to 20/1) to obtain methyl 7-methoxybenzofuran-2-carboxylate (5.3 g, yield: 78.28 g) as a white solid product %).

To a solution of methyl 7-methoxybenzofuran-2-carboxylate (5.3 g, 25.73 mmol, 1.0 equiv) in tetrahydrofuran (10 mL) was added 2M sodium hydroxide solution (20 mL) and the mixture was cooled at room temperature Stir overnight. The reaction solution was adjusted to pH=4 with 4M hydrochloric acid, and extracted with ethyl acetate. The resulting organic phase was dried and concentrated under reduced pressure. The residue was used directly in the next step without further purification. LCMS (ESI): m/z=193[M+1]+.

To a solution of 7-methoxybenzofuran-2-carboxylic acid (4.2 g, 21.87 mmol, 1.0 equiv) in quinoline (50 mL) under nitrogen was added copper powder (4.2 g, 65.61 mmol, 3.0 equiv.), the mixture was stirred at 120°C overnight. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether/ethyl acetate=100/1 to 80/1) to obtain 7-methoxybenzofuran (2.5 g, yield: 77.40%) as a colorless oily product.

To a solution of 7-methoxybenzofuran (4.5 g, 30.4 mmol, 1.0 equiv) in dichloromethane was added dropwise boron tribromide (11.4 g, 45.6 mmol, 1.5 equiv) under nitrogen protection, and the mixture was Stir at 0°C for 1.5 hours. The reaction solution was quenched with methanol, diluted with water and extracted with dichloromethane, the organic phase was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether/ethyl acetate=100/1 to 50/1) to obtain benzofuran-7-ol (3.2 g, yield: 78.62%) as a yellow oily product.

Step 1b: Preparation of methyl 4-(benzofuran-7-yloxy)-2-chlorobenzoate (compound 0103-1): under nitrogen protection, to benzofuran-7-ol (0101-1) (1.39 g, 10.37 mmol, 1.5 equiv) in N,N-dimethylformamide (25 mL) was added methyl 2-chloro-4-fluorobenzoate (0102-1) (1.3 g, 6.91 mL) mol, 1.0 equiv) and potassium carbonate (1.9 g, 13.82 mmol, 2.0 equiv), and the mixture was stirred at 90°C overnight. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether/ethyl acetate = 30/1 to 10/1) to obtain methyl 4-(benzofuran-7-yloxy)-2-chlorobenzoate (1.9%) as a white solid product g, yield: 91.08%). LCMS (ESI): m/z=303[M+1]+.

Step 1c: Preparation of 4-(benzofuran-7-yloxy)-2-chlorobenzoic acid (compound 0104-1): To 4-(benzofuran-7-yloxy)-2-chlorobenzene To a solution of methyl formate (0103-1) (1.9 g, 6.29 mmol, 1.0 equiv) in tetrahydrofuran (5 mL) was added 2M sodium hydroxide solution (15 mL), and the mixture was stirred at room temperature overnight. The reaction solution was adjusted to pH=4 with 4M hydrochloric acid, and extracted with ethyl acetate. The resulting organic phase was dried and concentrated under reduced pressure. The residue was used directly in the next step without further purification. LCMS(ESI): m/z=289[M+1]+.

Step 1d: Preparation of 4-(benzofuran-7-yloxy)-2-chlorobenzoyl chloride (compound 0105-1): under nitrogen protection, at 0 °C, to 4-(benzofuran-7- Oxalyl chloride (2.25 g, 17.70 mmol, 3.0 equiv), N , N-dimethylformamide (1 mg), and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure. The residue was used directly in the next step without further purification.

Step 1e: (4-(benzofuran-7-yloxy)-2-chlorophenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (compound Preparation of 0107-1): under nitrogen protection, at 0 °C, 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0106-1) (1.45 g, 6.25 mmol, 1.05 equiv. ) in tetrahydrofuran (15 mL) was added sodium hydride (750 mg, 18.75 mmol, 3.0 equiv), and the mixture was stirred for half an hour. Then n-butyllithium (3.25 mL, 8.12 mmol, 1.3 equiv) was slowly added dropwise at -70°C and stirred for 1.0 h. A solution of 4-(benzofuran-7-yloxy)-2-chlorobenzoyl chloride (0105-1) (1.6 g, crude product) in 5 mL of tetrahydrofuran was added dropwise to the reaction solution at -70°C and stirred for 1.5 hours. The reaction solution was quenched with ammonium chloride solution and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether/ethyl acetate = 15/1 to 2/1) to give the product (4-(benzofuran-7-yloxy)-2-chlorophenyl) (4-(benzofuran-7-yloxy)-2-chlorophenyl) as a yellow solid -Chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (700 mg, yield: 28.0%). LCMS(ESI): m/z=424[M+1] ⁺ .

Step 1f: Preparation of ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol hydrochloride (compound 0108-1): ((3R,6S)-6-(hydroxyl) A mixture of tert-butyl methyl)tetrahydro-2H-pyran-3-yl)carbamate (80 mg, 0.346 mmol, 1.0 equiv) in methanol with hydrogen chloride (4M solution, 2.5 mL) was stirred at room temperature for 1 hour , the solvent was removed under reduced pressure and dried under vacuum, and the residue was used directly in the next step without further purification. LCMS (ESI): m/z=132[M+1] ⁺ .

Step 1g: (4-(benzofuran-7-yloxy)-2-chlorophenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran- Preparation of 3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 1): To (4-(benzofuran-7-yloxy)-2 -Chlorophenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (0107-1) (600 mg, 1.41 mmol, 1.0 equiv) and ((2S, 5R)-5-Aminotetrahydro-2H-pyran-2-yl)methanol hydrochloride (0108-1) (282 mg, 1.69 mmol, 1.2 equiv) was added to a mixture of tert-butanol (20 mL) N,N-Diisopropylethylamine (1.5 mL). The mixture was heated at 90°C overnight. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified with a silica gel column (dichloromethane/methanol=100/1 to 10/1) to give a yellow solid product (4-(benzofuran-7-yloxy)-2-chlorophenyl)(4- (((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone ( 360 mg, yield: 49.3%). MS(ES ⁺ ): m/z=519(M+H) ⁺ . ¹ H NMR(500MHz, DMSO) δ 8.57(d, J=5.6Hz, 1H), 8.23(s, 1H), 8.01(s ,1H),7.56(d,J＝12.5Hz,3H),7.32(t,J＝7.2Hz,1H),7.22-7.12(m,2H),7.10-6.93(m,2H),4.67(s, 1H), 4.14(s, 2H), 3.63(s, 2H), 3.12(d, J=10.6Hz, 2H), 2.17(s, 1H), 1.77(d, J=12.3Hz, 1H), 1.56( d,J＝11.8Hz,1H),1.38(d,J＝11.8Hz,1H).

Example 2: (2-Chloro-4-((2-methylbenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrakis Preparation of Hydrogen-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 2) (prepared according to Scheme 1)

Step 2a: Preparation of 2-methylbenzofuran-7-ol (compound 0101-2)

To a solution of 2-methoxyphenol (5 g, 40.3 mmol, 1.0 equiv) in N,N-dimethylformamide (120 mL) was added 3-bromopropyne (5.75 g, 48.3 mmol) under nitrogen mol, 1.2 equiv) and potassium carbonate (8.3 g, 60.4 mmol, 1.5 equiv). The mixture was stirred at room temperature for 0.5 hours and then at 50°C for 5.0 hours. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether/ethyl acetate = 40/1 to 20/1) to give 1-methoxy-2-(prop-2-yn-1-yloxy)benzene ( 6.3 g, yield: 96.47%). LCMS (ESI): m/z=163[M+1] ⁺ .

Under nitrogen, a solution of 1-methoxy-2-(prop-2-yn-1-yloxy)benzene (6.3 g, 38.88 mmol, 1.0 equiv) in N,N-diethylaniline (60 mL) was added cesium fluoride (7.68 g, 50.55 mmol, 1.3 equiv). The mixture was stirred at 220°C for 7 hours. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether/ethyl acetate = 100/1 to 80/1) to obtain 7-methoxy-2-methylbenzofuran (4.3 g, yield: 68.25%) as a colorless oily product ).

To a solution of 7-methoxy-2-methylbenzofuran (1.7 g, 10.49 mmol, 1.0 equiv) in dichloromethane (30 mL) was added dropwise boron tribromide (3.95 g, 15.74 g) under nitrogen mmol, 1.5 equiv), the mixture was stirred at 0 °C for 1.5 h. The reaction solution was quenched with methanol, diluted with water and extracted with dichloromethane. The organic phase was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether/ethyl acetate=100/1 to 50/1) to obtain 2-methylbenzofuran-7-ol (1.1 g, yield: 73.33%) as a yellow oily product.

Step 2b: Preparation of methyl 2-chloro-4-((2-methylbenzofuran-7-yl)oxy)benzoate (compound 0103-2): under nitrogen To a solution of furan-7-ol (0101-2) (1.1 g, 7.43 mmol, 1.4 equiv) in N,N-dimethylformamide (30 mL) was added methyl 2-chloro-4-fluorobenzoate ( 0102-1) (1.0 g, 5.3 mmol, 1.0 equiv) and potassium carbonate (1.1 g, 7.85 mmol, 1.5 equiv). The mixture was stirred at 90°C for 4 hours. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether/ethyl acetate=30/1 to 10/1) to obtain 2-chloro-4-((2-methylbenzofuran-7-yl)oxy) as a white solid product Methyl benzoate (1.1 g, yield: 65.86%). LCMS (ESI): m/z=317[M+1]+.

Step 2c: Preparation of 2-chloro-4-((2-methylbenzofuran-7-yl)oxy)benzoic acid (compound 0104-2): To 2-chloro-4-((2-methyl) To a solution of methyl benzofuran-7-yl)oxy)benzoate (0103-2) (500 mg, 1.57 mmol, 1.0 equiv) in tetrahydrofuran (20 mL) was added 2M sodium hydroxide solution (10 mL), The mixture was stirred at room temperature overnight. The reaction solution was adjusted to pH=4 with 4M hydrochloric acid solution, and extracted with ethyl acetate. The resulting organic phase was dried and concentrated under reduced pressure. The residue was used directly in the next step without further purification. LCMS (ESI): m/z=303[M+1]+.

Step 2d: Preparation of 2-chloro-4-((2-methylbenzofuran-7-yl)oxy)benzoyl chloride (compound 0105-2): under nitrogen, at 0°C, to 2-chloro Oxalyl chloride ( 504 mg, 3.97 mmol, 3.0 equiv), N,N-dimethylformamide (1 mg). The mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure. The residue was used directly in the next step without further purification.

Step 2c: (2-Chloro-4-((2-methylbenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5- (0106-1) (300 mg, To a solution of 1.29 mmol, 1.0 equiv) in tetrahydrofuran was added sodium hydride (154 mg, 3.87 mmol, 3.0 equiv), and the mixture was stirred at room temperature for 1 hour. Then n-butyllithium (1.12 mL, 2.78 mmol, 1.3 equiv) was slowly added dropwise at -70°C and stirred for 1.0 h. Then, a solution of 2-chloro-4-((2-methylbenzofuran-7-yl)oxy)benzoyl chloride (0105-2) (450 mg, crude product) in tetrahydrofuran (5 mL) was added dropwise to the reaction solution. ) and stirred for 1.5 hours. The reaction solution was quenched with ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether/ethyl acetate = 15/1 to 2/1) to obtain (2-chloro-4-((2-methylbenzofuran-7-yl)oxy) as a yellow solid product )phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (60 mg, yield: 10.6%).

Step 2d: (2-Chloro-4-((2-methylbenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro Preparation of -2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 2): To (2-chloro-4-((2) -methylbenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (0107-2) (60 mg, 0.137 mmol, 1.0 equiv) and ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol hydrochloride (0108-1) (282 mg, 1.69 mmol, 1.2 equiv) To a mixture of tert-butanol (20 mL) was added N,N-diisopropylethylamine (1.5 mL). The mixture was heated at 90°C overnight. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified with a silica gel column (dichloromethane/methanol=100/1 to 10/1) to obtain a yellow solid product (2-chloro-4-((2-methylbenzofuran-7-yl)oxy) Phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5 -yl)methanone (23 mg, yield: 31.5%). MS (ES+): m/z=533 (M+H) ⁺ . Melting point: 135-146°C. ¹ HNMR(500MHz,DMSO)δ12.71(s,1H),8.58(d,J=7.1Hz,1H),8.25(s,1H),7.60(s,1H),7.57(d,J=8.5Hz ,1H),7.44(d,J＝7.7Hz,1H),7.30–7.16(m,2H),7.05(d,J＝7.9Hz,1H),7.00(dd,J＝8.5,2.3Hz,1H) ,6.69(s,1H),4.62(t,J＝5.5Hz,1H),4.15(dd,J＝12.9,10.5Hz,2H),3.43(dd,J＝11.8,6.4Hz,1H),3.35( d, J=7.9Hz, 2H), 3.17–3.08 (m, 1H), 2.44 (s, 3H), 2.19 (d, J=11.9Hz, 1H), 1.78 (d, J=13.2Hz, 1H), 1.57(qd,J=12.4,3.8Hz,1H),1.43–1.35(m,1H).

Example 3: (2-Chloro-4-((2-ethylbenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrakis Preparation of Hydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 3) (prepared according to Scheme 1)

Step 3a: Preparation of 2-ethylbenzofuran-7-ol (compound 0101-3):

To a solution of o-vanillin (4 g, 26.29 mmol, 1.0 equiv) in N,N-dimethylformamide (100 mL) was added ethyl 2-bromobutyrate (6.67 g, 34.17 mmol) under nitrogen , 1.3 equiv), cesium carbonate (17.14 g, 52.58 mmol, 2.0 equiv). The mixture was stirred at room temperature for 0.5 hours and then at 120°C for 2.0 hours. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether/ethyl acetate = 10/1 to 5/1) to obtain ethyl 2-(2-formyl-6-methoxyphenoxy)butanoate (7.0 g, yield: 100%).

To a mixed solution of ethyl 2-(2-formyl-6-methoxyphenoxy)butanoate (7.0 g, 26.29 mmol, 1.0 equiv) in methanol (30 mL), water (10 mL) was added hydrogen Sodium oxide solid (2.1 g, 52.63 mmol, 2.0 equiv) and the mixture was stirred at 60°C overnight. The reaction solution was adjusted to pH=4 with 4M hydrochloric acid, and extracted with ethyl acetate. The resulting organic phase was dried and concentrated under reduced pressure. The residue was used directly in the next step without further purification. LCMS(ESI): m/z=239[M+1]+.

To a solution of 2-(2-formyl-6-methoxyphenoxy)butyric acid (5.6 g, 23.53 mmol, 1.0 equiv) in acetic anhydride (60 mL) was added sodium acetate (5.79 g) under nitrogen , 70.59 mmol, 3.0 equiv), and the mixture was stirred at 140 °C overnight. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether/ethyl acetate=10/1) to obtain 2-ethyl-7-methoxybenzofuran (1.5 g, yield: 77.40%) as a yellow oily product.

To a solution of 2-ethyl-7-methoxybenzofuran (1.4 g, 7.95 mmol, 1.0 equiv) in dichloromethane under nitrogen was added dropwise boron tribromide (2.98 g, 11.93 mmol, 1.5 equiv), the mixture was stirred at 0°C for 1.5 hours. The reaction solution was quenched with methanol, diluted with water and extracted with dichloromethane. The organic phase was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether/ethyl acetate=25/1 to 15/1) to obtain 2-ethylbenzofuran-7-ol (890 mg, yield: 69.10%) as a yellow oily product.

Step 3b: Preparation of methyl 2-chloro-4-((2-ethylbenzofuran-7-yl)oxy)benzoate (compound 0103-3): under nitrogen To a solution of furan-7-ol (0101-3) (890 mg, 5.49 mmol, 1.5 equiv) in N,N-dimethylformamide (15 mL) was added methyl 2-chloro-4-fluorobenzoate ( 0102-1) (688 mg, 3.66 mmol, 1.0 equiv), potassium carbonate (3.58 g, 10.98 mmol, 3.0 equiv), the mixture was stirred at 90°C overnight. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether/ethyl acetate=20/1 to 10/1) to obtain 2-chloro-4-((2-ethylbenzofuran-7-yl)oxy) as a white solid product Methyl benzoate (890 mg, yield: 46.35%). LCMS(ESI): m/z=331[M+1]+.

Step 3c: Preparation of 2-chloro-4-((2-ethylbenzofuran-7-yl)oxy)benzoic acid (compound 0104-3): To 2-chloro-4-((2-ethyl To a solution of methyl benzofuran-7-yl)oxy)benzoate (0103-3) (560 mg, 1.70 mmol, 1.0 equiv) in tetrahydrofuran (5 mL) was added 2M sodium hydroxide solution (15 mL), The mixture was stirred at room temperature overnight. The reaction solution was adjusted to pH=4 with 4M hydrochloric acid, and extracted with ethyl acetate. The resulting organic phase was dried and concentrated under reduced pressure. The residue was used directly in the next step without further purification. LCMS (ESI): m/z=317[M+1]+.

Step 3d: Preparation of 2-chloro-4-((2-ethylbenzofuran-7-yl)oxy)benzoyl chloride (compound 0105-3): under nitrogen, at 0°C, to 2-chloro Oxalyl chloride ( 615 mg, 4.84 mmol, 3.0 equiv), N,N-dimethylformamide (1 mg), the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure. The residue was used directly in the next step without further purification.

Step 3e: (2-Chloro-4-((2-ethylbenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrro[2,3-d]pyrimidin-5-yl ) preparation of ketone (compound 0107-3): under nitrogen protection, 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0106-1) (420 mg, 1.81 mmol, 1.0 equiv) in tetrahydrofuran (20 mL) was added sodium hydride (217 mg, 5.43 mmol, 3.0 equiv), and the mixture was stirred at room temperature for 1 hour. Then n-butyllithium (0.94 mL, 2.35 mmol, 1.3 equiv) was slowly added dropwise at -70°C and stirred for 1.0 h. 2-Chloro-4-((2-ethylbenzofuran-7-yl)oxy)benzoyl chloride (0105-3) (520 mg, crude) in 3 mL of tetrahydrofuran was added dropwise at -70°C into the reaction solution and stirred for 1.5 hours. The reaction solution was quenched with ammonium chloride solution and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether/ethyl acetate = 15/1 to 2/1, 10% dichloromethane) to give a yellow solid product (2-chloro-4-((2-ethylbenzofuran- 7-yl)oxy)phenyl)(4-chloro-7H-pyrro[2,3-d]pyrimidin-5-yl)methanone (390 mg, yield: 53.0%). LCMS(ESI): m/z=452[M+1]+.

Step 3f: (2-Chloro-4-((2-ethylbenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro Preparation of -2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 3): To (2-chloro-4-((2) -Ethylbenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrro[2,3-d]pyrimidin-5-yl)methanone (0107-3) (100 mg, 0.221 mmol, 1.0 equiv) and ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol hydrochloride (0108-1) (34.8 mg, 0.265 mmol, 1.2 equiv) in To a mixture of tert-butanol (10 mL) was added N,N-diisopropylethylamine (0.5 mL). The mixture was heated at 90°C overnight. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (dichloromethane/methanol=12/1) to give (2-chloro-4-((2-ethylbenzofuran-7-yl)oxy)phenyl as a yellow solid product )(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl ) ketone (65 mg, yield: 53.8%). MS(ES ⁺ ): m/z=547(M+H) ⁺ . ¹ H NMR(500MHz, DMSO) δ 12.72(s, 1H), 8.58(d, J=7.1Hz, 1H), 8.25(s ,1H),7.59–7.54(m,2H),7.44(d,J=7.7Hz,1H),7.24(dd,J=12.9,5.0Hz,2H),7.08–6.98(m,2H),6.69( s, 1H), 4.61 (t, J=5.6Hz, 1H), 4.15 (dd, J=12.8, 10.2Hz, 2H), 3.47–3.39 (m, 1H), 3.34 (dd, J=11.7, 6.3Hz) ,2H),3.18–3.07(m,1H),2.78(q,J＝7.4Hz,2H),2.19(d,J＝11.9Hz,1H),1.78(d,J＝13.1Hz,1H),1.64 –1.49(m,1H),1.39(dd,J=16.9,6.5Hz,1H),1.24(t,J=7.5Hz,3H).

Example 4: (2-Chloro-4-((2-isopropylbenzofuran-7-yl)oxy)phenyl))4-(((3R,6S)-6-(hydroxymethyl) Preparation of tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (compound 4) (prepared according to Scheme 1)

Step 4a: Preparation of 2-isopropylbenzofuran-7-ol (compound 0101-4):

To a solution of 2-hydroxy-3-methoxybenzaldehyde (1.52 g, 10.0 mmol, 1.0 equiv) in 50 mL of dimethylformamide was added methyl 2-bromoisovalerate (2.05 g, 10.5 mmol, 1.05 equiv) and potassium carbonate (4.89 g, 15.0 mmol, 1.5 equiv). The mixture was stirred at 90°C for 8 hours, the mixture was filtered through celite, 30 ml of 2M aqueous sodium hydroxide solution was added to the filtrate, and the mixture was stirred at 70°C for 3 hours. Ethyl acetate was added, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2-(2-formyl-6-methoxyphenoxy)-3-methylbutanoic acid as a brown solid ( 3.0 g, crude). MS(ES ⁺ ): m/z 253(M+H) ⁺ .

To a solution of 2-(2-formyl-6-methoxyphenoxy)-3-methylbutanoic acid (3.0 g, 11.9 mmol, 1.0 equiv) in 30 mL of acetic anhydride was added sodium acetate (2.93 g, 35.7 mmol, 3.0 equiv). The mixture was stirred at 140°C overnight. The mixture was concentrated under reduced pressure, ethyl acetate was added, washed with saturated brine, the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=30/1 to 20/1) 2-isopropyl-7-methoxybenzofuran (243 mg, yield: 10%) was obtained as a white solid. MS(ES ⁺ ): m/z 191(M+H) ⁺ .

To a solution of 2-isopropyl-7-methoxybenzofuran (240 mg, 1.2 mmol, 1.0 equiv) in 10 mL of dichloromethane was added dropwise 1.2 mL of 2M tribromide at 0°C under nitrogen. Boronide in dichloromethane. The mixture was stirred at room temperature for 1 hour, quenched with methanol and water, added with dichloromethane, and washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2-isopropylbenzofuran-7-ol (227 mg, crude) as a yellow solid. MS(ES ⁺ ): m/z 177(M+H) ⁺ .

Step 4b: Preparation of methyl 2-chloro-4-((2-isopropylbenzofuran-7-yl)oxy)benzoate (compound 0103-4): under nitrogen, 2-chloro-4 - Methyl fluorobenzoate (0102-1) (195 mg, 1.03 mmol, 0.8 equiv), 2-isopropylbenzofuran-7-ol (0101-4) (227 mg, 1.29 mmol, 1.0 equiv) ) and potassium carbonate (539 mg, 3.90 mmol, 3.0 equiv) in 5 mL of dimethylformamide and stirred overnight at 90°C. Ethyl acetate was added, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 30/1 to 20/ 1) to obtain methyl 2-chloro-4-((2-isopropylbenzofuran-7-yl)oxy)benzoate (314 mg, yield: 88%) as a yellow solid. MS(ES ⁺ ): m/z 345(M+H) ⁺ .

Step 4c: Preparation of 2-chloro-4-((2-isopropylbenzofuran-7-yl)oxy)benzoic acid (compound 0104-4): 2-chloro-4-((2-isopropyl) Methyl propylbenzofuran-7-yl)oxy)benzoate (0103-4) (314 mg, 0.91 mmol, 1.0 equiv) was dissolved in 5 mL of tetrahydrofuran and 8 mL of 2M aqueous sodium hydroxide was added. The mixture was stirred at 60°C for 6 hours. 3M aqueous hydrogen chloride solution was added to adjust the pH to 2. Ethyl acetate was added for extraction, washed with water and saturated brine, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2-chloro-4-((2-isopropylbenzofuran-7-yl)oxygen as a yellow solid yl)benzoic acid (298 mg, yield: 99%). MS(ES ⁺ ): m/z 331(M+H) ⁺ .

Step 4d: 2(2-Chloro-4-((2-isopropylbenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidine- Preparation of 5-yl)methanone (compound 0107-4): under nitrogen protection, 2-chloro-4-((2-isopropylbenzofuran-7-yl)oxy)benzoic acid (0104- 4) (232 mg, 0.67 mmol, 1.0 equiv) was dissolved in 9 mL of dichloromethane and 1.0 mL of tetrahydrofuran. 0.01 mL of dimethylformamide was added. Oxalyl chloride (254 mg, 2.0 mmol, 3.0 equiv) was dissolved in 0.5 mL dichloromethane and added to the above mixture at room temperature. The mixture was stirred at room temperature for 3 hours. The mixture was concentrated to dryness under reduced pressure. 5-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0106-1) (226 mg, 1.0 mmol, 1.5 equiv) was dissolved in 25 mL of dry tetrahydrofuran under nitrogen and cooled to 0°C. Sodium hydride (144 mg, 3.0 mmol, 4.5 equiv) was added and the mixture was stirred at room temperature for 30 minutes. The mixture was cooled to -70°C and 1.6M n-butyllithium in n-hexane (0.82 mL, 1.3 mmol, 1.95 equiv) was added dropwise. The mixture was stirred at -70°C for 1 hour. The acid chloride obtained above was dissolved in 1 ml of anhydrous tetrahydrofuran, and then added dropwise to the above mixture. The mixture was stirred at -70°C for 1 hour. The reaction was quenched by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1 to 1/1) to obtain 2(2-chloro) as a yellow solid -4-((2-Isopropylbenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (164 mg, yield: 40%). MS(ES ⁺ ): m/z 466(M+H) ⁺ .

Step 4e: (2-Chloro-4-((2-isopropylbenzofuran-7-yl)oxy)phenyl))4-(((3R,6S)-6-(hydroxymethyl)tetrakis Preparation of hydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (compound 4): 2(2-chloro-4-( (2-Isopropylbenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (0107-4)( 80 mg, 0.17 mmol, 1.0 equiv), ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol hydrochloride (0108-1) (32 mg, 0.19 mmol, 1.1 equiv) and diisopropylethylamine (89 mg, 0.69 mmol, 4.0 equiv) were added to 10 mL of tert-butanol, and the mixture was stirred at 90°C overnight. The mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with water and saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (developing solvent: dichloromethane/methanol= 30/1) to give (2-chloro-4-((3-methylbenzofuran-7-yl)oxy)phenyl))4-(((3R,6S)-6-(hydroxyl) as a yellow solid Methyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (53 mg, yield: 54%). MS (ES ⁺ ): m/z 561 (M+H) ⁺ ; melting point 198-200°C. ¹ H NMR (500MHz, DMSO) δ 12.72(s, 1H), 8.57(d, J=7.2Hz, 1H), 8.24(s, 1H), 7.62-7.54(m, 2H), 7.43(dd, J =7.7,0.9Hz,1H),7.26-7.20(m,2H),7.08-7.00(m,2H),6.67(d,J=1.0Hz,1H),4.61(t,J=5.6Hz,1H) ,4.21-4.06(m,2H),3.46-3.38(m,1H),3.37-3.30(m,2H),3.12(t,J＝11.6Hz,1H),3.06(td,J＝13.4,7.2Hz ,1H),2.18(d,J＝12.4Hz,1H),1.78(d,J＝13.7Hz,1H),1.63-1.49(m,1H),1.45-1.34(m,1H),1.27(t, J=11.2Hz, 6H).

Example 5: (2-Chloro-4-((2-cyclopropylbenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl) Preparation of tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (compound 5) (prepared according to Scheme 1)

Step 5a: Preparation of 2-Cyclopropylbenzofuran-7-ol (Compound 0101-5):

To 2-hydroxy-3-methoxybenzaldehyde (1.0 g, 6.57 mmol, 1.0 equiv) and cesium carbonate (2.57 g, 7.88 mmol, 1.2 equiv) in N,N-dimethylformamide (5 mL) was added ethyl 2-bromo-2-cyclopropylacetate (1.43 g, 6.90 mmol, 1.2 equiv). The mixture was stirred at room temperature for 5 hours. The mixture was diluted with water (40 mL), then extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated to give 2-cyclopropyl-2-(2-formyl-6-methoxybenzene as a pale yellow oily substance). oxy)ethyl acetate (1.87 g, crude). LCMS (ESI): m/z 279 [M+1] ⁺ ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=5:1).

To ethyl 2-cyclopropyl-2-(2-formyl-6-methoxyphenoxy)acetate (1.83 g, 6.57 mmol, 1.0 equiv) in tetrahydrofuran (15 mL) and water (5 mL) To the mixture was added sodium hydroxide (788 mg, 19.71 mmol, 3.0 equiv). The mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (20 mL). 1N dilute hydrochloric acid was added to adjust pH=3. The aqueous layer was extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated to give 2-cyclopropyl-2-(2-formyl-6-methoxyphenoxy) as a white solid ) acetic acid (1.60 g, yield: 98%). LCMS (ESI): m/z 251 [M+1] ⁺ ; TLC: Rf 0.3 (dichloromethane:methanol=10:1).

To a mixture of 2-cyclopropyl-2-(2-formyl-6-methoxyphenoxy)acetic acid (1.60 g, 6.40 mmol, 1.0 equiv) in acetic anhydride (12 mL) was added sodium acetate ( 1.57 g, 19.20 mmol, 3.0 equiv). The mixture was heated to 140°C under nitrogen atmosphere for 3.5 hours. The mixture was diluted with water (60 mL), then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 30:1) to give 2-cyclopropyl-7-methoxybenzofuran (864 mg, yield: 72%) as a pale yellow oil. LCMS (ESI): m/z 189[M+1] ⁺ ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=20:1).

To a mixture of sodium hydride (60%, 745 mg, 18.62 mmol, 5.0 equiv) in N,N-dimethylformamide (10 mL) was added ethanethiol (1.38 mL, 18.62 mmol, 5.0 equiv) . The mixture was stirred at room temperature for 5 minutes. 2-Cyclopropyl-7-methoxybenzofuran (700 mg, 3.72 mmol, 1.0 equiv) was added, and the mixture was heated to 155°C under nitrogen for 1.5 hours. The mixture was diluted with saturated ammonium chloride solution (30 mL), then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated to give 2-cyclopropylbenzofuran-7-ol (647 mg, crude) as a pale yellow oil. LCMS (ESI): m/z 175 [M+1] ⁺ ; TLC: Rf 0.5 (PE:ethyl acetate=10:1).

Step 5b: Preparation of methyl 2-chloro-4-((2-cyclopropylbenzofuran-7-yl)oxy)benzoate (compound 0103-5): To 2-cyclopropylbenzofuran- 7-ol (0101-5) (648 mg, 3.72 mmol, 1.0 equiv) and potassium carbonate (616 mg, 4.46 mmol, 1.2 equiv) in N,N-dimethylformamide (5 mL) Methyl 2-chloro-4-fluorobenzoate (0102-1) (1.05 g, 5.58 mmol, 1.5 equiv) was added. The mixture was heated to 90°C under nitrogen atmosphere and reacted overnight. The mixture was diluted with water (30 mL), then extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 20:1) to give methyl 2-chloro-4-((2-cyclopropylbenzofuran-7-yl)oxy)benzoate as a white solid (1.27 g, yield: 100%). LCMS (ESI): m/z 343 [M+1] ⁺ ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=8:1).

Step 5c: Preparation of 2-chloro-4-((2-cyclopropylbenzofuran-7-yl)oxy)benzoic acid (compound 0104-5): To 2-chloro-4-((2-cyclo Methyl propylbenzofuran-7-yl)oxy)benzoate (0103-5) (1.32 g, 3.86 mmol, 1.0 equiv) in a mixture of methanol (10 mL) and water (5 mL) was added hydrogen Sodium oxide (310 mg, 7.72 mmol, 2.0 equiv). The mixture was stirred at room temperature overnight. The mixture was diluted with water (30 mL). 1N diluted hydrochloric acid was added to adjust pH=3. The aqueous layer was extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated to give 2-chloro-4-((2-cyclopropylbenzofuran-7-yl)oxygen as a white solid yl)benzoic acid (1.11 g, yield: 87%). LCMS (ESI): m/z 329 [M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol=10:1).

Step 5d: Preparation of 2-chloro-4-((2-cyclopropylbenzofuran-7-yl)oxy)benzoyl chloride (compound 0105-5): to 2-chloro-4-((2- Cyclopropylbenzofuran-7-yl)oxy)benzoic acid (0104-5) (200 mg, 0.61 mmol, 1.0 equiv) and N,N-dimethylformamide (2.2 mg, 0.03 mmol, 0.1 equiv) To a mixture of dichloromethane (8 mL) and tetrahydrofuran (1 mL) was added oxalyl chloride (0.10 mL, 1.22 mmol, 2.0 equiv). The mixture was stirred at room temperature for 5 hours. The solvent was removed under reduced pressure and dried under vacuum to give 2-chloro-4-((2-cyclopropylbenzofuran-7-yl)oxy)benzoyl chloride (212 mg, crude) as a pale yellow oil. TLC: Rf 0.5 (petroleum ether:ethyl acetate=20:1).

Step 5e: (2-Chloro-4-((2-cyclopropylbenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5 -yl)methanone (compound 0107-5) preparation: To a mixture of sodium hydride (60%, 61 mg, 1.52 mmol, 2.0 equiv) in tetrahydrofuran (4 mL) was added 5-bromo-4 under nitrogen atmosphere -Chloro-7H-pyrrolo[2,3-d]pyrimidine (0106-1) (177 mg, 0.76 mmol, 1.0 equiv). The mixture was stirred at room temperature for 10 minutes and then cooled to -78°C. n-Butyllithium (2.5M in hexanes, 0.37 mL, 0.91 mmol, 1.2 equiv) was added dropwise and stirred for 1 hour. A solution of 2-chloro-4-((2-cyclopropylbenzofuran-7-yl)oxy)benzoyl chloride (212 mg, 0.61 mmol, 0.8 equiv) in tetrahydrofuran (1 mL) was added dropwise, followed by Stirring was continued for 1 hour at -78°C. The reaction was quenched by the addition of saturated aqueous ammonium chloride (30 mL). The aqueous layer was extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was subjected to column chromatography on silica gel (petroleum ether:ethyl acetate 2:1) to give (2-chloro-4-((2-cyclopropylbenzofuran-7-yl)oxy)benzene as a white solid yl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (145 mg, yield: 41%). LCMS (ESI): m/z 464 [M+1] ⁺ ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=1:1).

Step 5f: (2-Chloro-4-((2-cyclopropylbenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrakis Preparation of Hydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 5): To (2-chloro-4-(( 2-Cyclopropylbenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 0107-5)( 80 mg, 0.17 mmol, 1.0 equiv) and ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol hydrochloride (0108-1) (38 mg, 0.22 mmol, 1.3 equiv.) To a mixture of tert-butanol (8 mL) was added N,N-diisopropylethylamine (0.15 mL, 0.86 mmol, 5.0 equiv). The mixture was heated at 90°C under nitrogen atmosphere overnight. The mixture was diluted with water (30 mL), then extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (ethyl acetate:dichloromethane:methanol=10:10:2) to give (2-chloro-4-((2-cyclopropylbenzofuran-7-yl) as a white solid )oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d ]pyrimidin-5-yl)methanone (40 mg, yield: 42%). LCMS (ESI): m/z 559 [M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol=10:1); melting point: 142-145°C. ¹ H NMR(500MHz, DMSO)δ12.72(s,1H),8.57(d,J=7.1Hz,1H),8.24(s,1H),7.56(d,J=8.2Hz,2H),7.38( d, J=7.6Hz, 1H), 7.27–7.12 (m, 2H), 7.07–6.97 (m, 2H), 6.66 (s, 1H), 4.60 (t, J=5.6Hz, 1H), 4.15 (d , J=7.8Hz, 2H), 3.57–3.39 (m, 1H), 3.33 (dd, J=11.7, 6.3Hz, 2H), 3.23–3.08 (m, 1H), 2.18 (d, J=12.5Hz, 1H), 2.14–2.03 (m, 1H), 1.78 (d, J=13.1Hz, 1H), 1.65–1.50 (m, 1H), 1.45–1.32 (m, 1H), 1.07–0.91 (m, 2H) ,0.87–0.72(m,2H).

Example 6: (2-Chloro-4-((2-(hydroxymethyl)benzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl) (base) tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (compound 6) preparation (prepared according to scheme 1)

Step 6a: Preparation of 2-(hydroxymethyl)benzofuran-7-ol (compound 0101-6):

Under nitrogen protection, to a mixture of 7-methoxybenzofuran-2-carboxylic acid ethyl ester (2.9 g, 13.18 mmol, 1.0 equiv) in dichloromethane (30 mL) was added 2 mol/L of ethyl 7-methoxybenzofuran-2-carboxylate at 0°C. Boron tribromide (10 mL, 19.77 mmol, 1.5 equiv). The mixture was stirred at 0°C for 2 hours. The mixture was quenched with methanol. The mixture was diluted with water (50 mL) and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with saturated brine (50 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate=3:1) to give a yellow solid ethyl 7-hydroxybenzofuran-2-carboxylate (2.5 g, yield: 92.6%) LCMS (ESI): m /z 207[M+1] ⁺ .

Under nitrogen protection, 1 mol/L lithium aluminum hydride was added to a mixture of ethyl 7-hydroxybenzofuran-2-carboxylate (1.95 g, 9.47 mmol, 1.0 equiv) in tetrahydrofuran (20 mL) at 0°C. (18.9 mL, 18.93 mmol, 2.0 equiv). The mixture was stirred at room temperature for 3 hours. Water (2 mL) was added to the reaction solution. Sodium hydroxide solution (2 mL) and water (6 mL) were then added to the mixture. The mixture was stirred at room temperature for 15 minutes. Anhydrous sodium sulfate was added to the mixture and stirring was continued for 15 minutes. The mixture was then filtered and washed with ethyl acetate (20 mL x 3). The filtrate was concentrated to give 2-(hydroxymethyl)benzofuran-7-ol as a yellow solid (1.07 g, yield: 69%) LCMS (ESI): m/z 165 [M+1] ⁺ .

Step 6b: Preparation of methyl 2-chloro-4-((2-(hydroxymethyl)benzofuran-7-yl)oxy)benzoate (compound 0103-6): under nitrogen To a mixture of hydroxymethyl)benzofuran-7-ol (0101-6) (1.35 g, 8.23 mmol, 1.0 equiv) in N,N-dimethylformamide (20 mL) was added 2-chloro-4 - Methyl fluorobenzoate (0102-1) (2.02 g, 10.70 mmol, 1.3 equiv) and potassium carbonate (1.7 g, 12.35 mmol, 1.5 equiv). The mixture was stirred at 90°C overnight. The mixture was diluted with water (100 mL), then extracted with ethyl acetate (75 mL x 3). The combined organic layers were washed with saturated brine (75 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (methanol:dichloromethane=1:20) to obtain methyl 2-chloro-4-((2-(hydroxymethyl)benzofuran-7-yl)oxy)benzoate as a yellow solid Ester (1.75 g, yield: 69%) LCMS (ESI): m/z 333 [M+1] ⁺ .

Step 6c: (2-Chloro-4-((2-((methoxymethoxy)methyl)benzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[ Preparation of 2,3-d]pyrimidin-5-yl)methanone (compound 0107-6): 2-chloro-4-((2-(hydroxymethyl)benzofuran) at 0°C under nitrogen protection Methyl-7-yl)oxy)benzoate (0103-6) (500 mg, 1.506 mmol, 1.0 equiv) and N,N-diisopropylethylamine (389 mg, 3.012 mmol, 2.0 equiv) To a mixture of dichloromethane (8 mL) was added bromomethyl methyl ether (226 mg, 1.807 mmol, 1.2 equiv). The mixture was stirred at 45°C overnight. The mixture was diluted with water (15 mL) and extracted with dichloromethane (15 mL x 3). The combined organic layers were washed with saturated brine (15 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate=10:1) to give 2-chloro-4-((2-(((methoxymethoxy)methyl)benzofuran-7 as a yellow solid) -yl)oxy)benzoic acid methyl ester (420 mg, yield: 74%) LCMS (ESI): m/z 377 [M+1] ⁺ . Under nitrogen protection, at 0 °C, to 5-bromo- To a mixture of 4-chloro-7H-pyrrole[2,3-d]pyrimidine (286 mg, 1.229 mmol, 1.1 equiv) in tetrahydrofuran (10 mL) was added sodium hydride (89 mg, 2.234 mmol, 2.0 equiv) The mixture was stirred at room temperature for 1 hour. To the mixture was added dropwise n-butyllithium (0.9 mL, 1.452 mmol, 1.3 equiv) at -70°C, and the mixture was stirred at -70°C for 1 hour. Then to the mixture was added slowly Methyl 2-chloro-4-((2-(((methoxymethoxy)methyl)benzofuran-7-yl)oxy)benzoate prepared above (420 mg, 1.117 mmol, 1.0 equiv) in tetrahydrofuran (2 mL), and the mixture was stirred at -70°C for 1 hour. The reaction was quenched with saturated ammonium chloride solution (5 mL). The mixture was diluted with water (15 mL), then ethyl acetate ( 15 mL×3). The combined organic layers were washed with saturated brine (15 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate=2:1 ) to give (2-chloro-4-((2-((methoxymethoxy)methyl)benzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo) as a yellow solid [2,3-d]pyrimidin-5-yl)methanone (80 mg, yield: 14.4%), LCMS (ESI): m/z 498[M+1] ⁺ .

Step 6d: (2-Chloro-4-((2-(hydroxymethyl)benzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl) ) preparation of tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (compound 6): under nitrogen protection, to (2- Chloro-4-((2-((methoxymethoxy)methyl)benzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d] Pyrimidin-5-yl)methanone (0107-6) (80 mg, 0.161 mmol, 1.0 equiv) and ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol hydrochloric acid Salt (0108-1) (32 mg, 0.193 mmol, 1.2 equiv) To a mixture of tert-butanol (5 mL) was added N,N-diisopropylethylamine (1 mL). The mixture was heated at 90°C overnight. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (15 mL×1), dried over anhydrous sodium sulfate and concentrated to give a yellow solid (2-chloro-4-((2-((methoxymethoxy)methyl)) Benzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrole and [2,3-d]pyrimidin-5-yl)methanone (126 mg, crude). LCMS (ESI): m/z 593 [M+1] ⁺ . (2-chloro-4-((2-((methoxymethoxy)methyl)benzofuran-7-yl)oxy)phenyl)(4-(((3R, 6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (126 mg, 0.212 mg mol, 1.0 equiv) in methanol of hydrogen chloride (4M solution, 3 mL) was stirred at 45°C for 1 hour. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (15 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (dichloromethane:methanol=10:1) to give a yellow solid (2-chloro-4-((2-(hydroxymethyl)benzofuran-7-yl)oxy) Phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5 -yl)methanone (20 mg, yield: 17.2%). LCMS (ESI): m/z 549 [M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol=10:1). ¹ HNMR(500MHz,DMSO)δ8.60(d,J=7.2Hz,1H),8.18(s,1H),7.55-7.47(m,3H),7.27(t,J=7.9Hz,1H),7.20 (d, J=2.3Hz, 1H), 7.09 (d, J=7.9Hz, 1H), 7.00 (dd, J=8.5, 2.4Hz, 1H), 6.86 (s, 1H), 5.55 (s, 1H) ,4.64(s,1H),4.55(s,2H),4.13(dd,J＝20.3,6.9Hz,3H),3.40(d,J＝4.5Hz,2H),3.10(t,J＝10.0Hz, 1H), 2.17(d, J＝11.9Hz, 1H), 1.77(d, J＝12.6Hz, 1H), 1.55(dd, J＝12.1, 3.6Hz, 1H), 1.37(d, J＝13.4Hz, 1H).

Example 7: (2-Chloro-4-((2-(fluoromethyl)benzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl) yl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 10) (prepared according to Scheme 1)

Step 7a: Preparation of methyl 2-chloro-4-((2-(fluoromethyl)benzofuran-7-yl)oxy)benzoate (compound 0103-10): under nitrogen protection at 0°C, To 25 mL of methyl 2-chloro-4-((2-(hydroxymethyl)benzofuran-7-yl)oxy)benzoate (0103-6) (178 mg, 0.54 mmol, 1.0 equiv) To the dichloromethane solution was added diethylaminosulfur trifluoride (131 mg, 0.81 mol, 1.5 equiv). The mixture was stirred for 2 hours, water was added, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=4/1) to obtain a white color Solid methyl 2-chloro-4-((2-(fluoromethyl)benzofuran-7-yl)oxy)benzoate (89 mg, yield: 49%). MS(ES ⁺ ): m/z 335(M+H) ⁺ .

Step 7b: Preparation of 2-chloro-4-((2-(fluoromethyl)benzofuran-7-yl)oxy)benzoic acid (compound 0104-10): 2-chloro-4-((2 Methyl -(fluoromethyl)benzofuran-7-yl)oxy)benzoate (0103-10) (89 mg, 0.27 mmol, 1.0 equiv) was dissolved in 4 mL of tetrahydrofuran and 8 mL of 2M sodium hydroxide was added aqueous solution. The mixture was stirred at 40°C for 8 hours. Aqueous 3M hydrochloric acid was added to adjust the pH to 2. Ethyl acetate was added for extraction, washed with water and saturated brine, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2-chloro-4-((2-(fluoromethyl)benzofuran-7-yl) as a white solid )oxy)benzoic acid (84 mg, yield: 97%). MS(ES ⁺ ): m/z 321(M+H) ⁺ .

Step 7c: (2-Chloro-4-((2-(fluoromethyl)benzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidine Preparation of -5-yl)methanone (compound 0107-10): under nitrogen protection, 2-chloro-4-((2-(fluoromethyl)benzofuran-7-yl)oxy)benzoic acid (0104-10) (84 mg, 0.26 mmol, 1.0 equiv) was dissolved in 5 mL dichloromethane and 1 mL tetrahydrofuran. 0.01 mL of N,N-dimethylformamide was added. Oxalyl chloride (100 mg, 0.79 mmol, 3.0 equiv) was dissolved in 1.0 mL of dichloromethane and added to the above mixture at room temperature. The mixture was stirred at room temperature for 3 hours. The mixture was concentrated to dryness under reduced pressure. 5-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (89 mg, 0.39 mmol, 1.5 equiv) was dissolved in 10 mL of dry tetrahydrofuran under nitrogen and cooled to 0°C. Sodium hydride (114 mg, 4.4 mmol, 6.0 equiv) was added and the mixture was stirred at room temperature for 30 minutes. The mixture was cooled to -70°C and 1.6M n-butyllithium in n-hexane (0.48 mL, 0.77 mmol, 1.95 equiv) was added dropwise. The mixture was stirred at -70°C for 1 hour. The acid chloride obtained above was dissolved in 1.5 ml of anhydrous tetrahydrofuran, and then added dropwise to the above mixture. The mixture was stirred at -70°C for 1 hour. The reaction was quenched by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (eluent: petroleum ether/ethyl acetate=2/1) to obtain a yellow solid (2-chloro-4-(( 2-(Fluoromethyl)benzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (52 mg, received rate: 43%). MS(ES ⁺ ): m/z 456(M+H) ⁺ .

Step 7d: (2-Chloro-4-((2-(fluoromethyl)benzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl) ) tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (compound 10) preparation: (2-chloro-4- ((2-(Fluoromethyl)benzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (52 mg , 0.11 mmol, 1.0 equiv) (0107-10), ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol hydrochloride (0108-1) (21 mg, 0.13 mmol, 1.1 equiv) and diisopropylethylamine (89 mg, 0.69 mmol, 6.0 equiv) were added to 10 mL of tert-butanol, and the mixture was stirred at 90°C overnight. The mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with water and saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (developing solvent: dichloromethane/methanol) =30/1) to give a yellow solid (2-chloro-4-((2-(fluoromethyl)benzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)- 6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (29 mg, yield: 47% ). MS (ES ⁺ ): m/z 551 (M+H) ⁺ ; melting point 144-146°C. ¹ H NMR (500MHz, DMSO) δ12.72(s, 1H), 8.58(d, J=7.2Hz, 1H), 8.25(s, 1H), 7.70-7.53(m, 3H), 7.35(t, J =7.9Hz,1H),7.30–7.17(m,3H),7.05(dd,J=8.5,2.4Hz,1H),5.55(d,J=48.3Hz,2H),4.61(s,1H),4.24 –4.02(m, 2H), 3.40(dd, J=22.6, 15.5Hz, 3H), 3.12(t, J=11.6Hz, 1H), 2.19(d, J=12.2Hz, 1H), 1.78(d, J=13.8Hz, 1H), 1.64–1.51 (m, 1H), 1.45–1.35 (m, 1H).

Example 8: (2-Chloro-4-((2-(difluoromethyl)benzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxy Preparation of methyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 11) (prepared according to Scheme 1)

Step 8a: Preparation of methyl 2-chloro-4-((2-(difluoromethyl)benzofuran-7-yl)oxy)benzoate (compound 0103-11): To 2-chloro-4- To a solution of methyl ((2-(hydroxymethyl)benzofuran-7-yl)oxy)benzoate (0103-6) (300 mg, 0.9 mmol, 1.0 equiv) in 40 mL of dichloromethane was added dichloromethane Manganese oxide (1.18 g, 13.5 mol, 15.0 equiv). The mixture was stirred at room temperature for 24 hours, filtered through celite, and the filtrate was concentrated under reduced pressure to give methyl 2-chloro-4-((2-formylbenzofuran-7-yl)oxy)benzoate (289) as a white solid mg, crude). MS (ES ⁺ ): m/z 331 (M+H) ⁺ . To methyl 2-chloro-4-((2-formylbenzofuran-7-yl)oxy)benzoate prepared above ( To a solution of 289 mg, 0.87 mmol, 1.0 equiv) in 15 mL of dichloromethane was added diethylaminosulfur trifluoride (565 mg, 3.5 mol, 4.0 equiv). The mixture was stirred at room temperature for 2 hours, water was added, the layers were separated, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 40/1 to 15/1) Purification gave methyl 2-chloro-4-((2-(difluoromethyl)benzofuran-7-yl)oxy)benzoate (286 mg, yield: 93%) as a white solid. MS(ES ⁺ ): m/z 353(M+H) ⁺ .

Step 8b: Preparation of 2-chloro-4-((2-(difluoromethyl)benzofuran-7-yl)oxy)benzoic acid (compound 0104-11): 2-chloro-4-(( Methyl 2-(difluoromethyl)benzofuran-7-yl)oxy)benzoate (0103-11) (286 mg, 0.81 mmol, 1.0 equiv) was dissolved in 10 mL of tetrahydrofuran and 8 mL of 2M hydrogen was added Sodium oxide aqueous solution. The mixture was stirred at 50°C for 16 hours. 3M aqueous hydrogen chloride solution was added to adjust the pH to 2. Ethyl acetate was added for extraction, washed with water and saturated brine, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2-chloro-4-((2-(difluoromethyl)benzofuran-7-) as a white solid yl)oxy)benzoic acid (293 mg, crude). MS(ES ⁺ ): m/z 339(M+H) ⁺ .

Step 8c: (2-Chloro-4-((2-(difluoromethyl)benzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d] Preparation of pyrimidin-5-yl)methanone (compound 0107-11): under nitrogen protection, 2-chloro-4-((2-(difluoromethyl)benzofuran-7-yl)oxy) Benzoic acid (0104-11) (100 mg, 0.30 mmol, 1.0 equiv) was dissolved in 5 mL of dichloromethane and 1 mL of tetrahydrofuran. 0.01 mL of dimethylformamide was added. Oxalyl chloride (113 mg, 0.89 mmol, 3.0 equiv) was dissolved in 1.0 mL of dichloromethane and added to the above mixture at room temperature. The mixture was stirred at room temperature for 3 hours. The mixture was concentrated to dryness under reduced pressure. 5-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0106-1) (101 mg, 0.44 mmol, 1.5 equiv) was dissolved in 8 mL of dry tetrahydrofuran under nitrogen protection, and Cool to 0°C. Sodium hydride (86 mg, 1.78 mmol, 6.0 equiv) was added and the mixture was stirred at room temperature for 30 minutes. The mixture was cooled to -70°C and 1.6M n-butyllithium in n-hexane (0.54 mL, 0.87 mmol, 1.95 equiv) was added dropwise. The mixture was stirred at -70°C for 1 hour. The acid chloride obtained above was dissolved in 1.5 ml of anhydrous tetrahydrofuran, and then added dropwise to the above mixture. The mixture was stirred at -70°C for 1 hour. The reaction was quenched by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (eluent: petroleum ether/ethyl acetate=1/1) to obtain a yellow solid (2-chloro-4-(( 2-(Difluoromethyl)benzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (59 mg, Yield: 42%). MS(ES ⁺ ): m/z 474(M+H) ⁺ .

Step 8d: (2-Chloro-4-((2-(difluoromethyl)benzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl) yl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (compound 11): (2-chloro-4 -((2-(difluoromethyl)benzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone ( 0107-11) (59 mg, 0.13 mmol, 1.0 equiv), ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol hydrochloride (0108-1) (23 mg , 0.14 mmol, 1.1 equiv) and diisopropylethylamine (82 mg, 0.63 mmol, 5.0 equiv) were added to 10 mL of tert-butanol, and the mixture was stirred at 90 °C overnight. The mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with water and saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (developing solvent: dichloromethane/methanol= 15/1) to give (2-chloro-4-((2-(difluoromethyl)benzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)- 6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (40 mg, yield: 55% ). MS (ES ⁺ ): m/z 569 (M+H) ⁺ ; melting point 139-141°C. ¹ H NMR(500MHz, DMSO)δ12.73(s,1H),8.58(d,J=7.2Hz,1H),8.25(s,1H),7.66(d,J=7.8Hz,1H),7.59( d, J=8.5Hz, 2H), 7.51 (t, J=2.1Hz, 1H), 7.43–7.17 (m, 4H), 7.09 (dd, J=8.5, 2.4Hz, 1H), 4.62 (t, J = 5.6Hz, 1H), 4.22–4.00 (m, 2H), 3.47–3.39 (m, 1H), 3.39–3.33 (m, 2H), 3.13 (t, J=11.6Hz, 1H), 2.19 (d, J=12.1Hz, 1H), 1.79 (d, J=13.5Hz, 1H), 1.58 (ddd, J=24.1, 12.4, 3.9Hz, 1H), 1.46–1.32 (m, 1H).

Example 9: (2-Chloro-4-((2-fluorobenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro Preparation of -2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 13) (prepared according to Scheme 1)

Step 9a: Preparation of tert-butyl 2-chloro-4-((2-fluorobenzofuran-7-yl)oxy)benzoate (compound 0103-13): To 7-hydroxybenzofuran (0101-1 ) (0.60 g, 4.44 mmol, 1.0 equiv) and potassium carbonate (0.92 g, 6.66 mmol, 1.5 equiv) in N,N-dimethylformamide (5 mL) was added 2-chloro-4- tert-Butyl fluorobenzoate (0102-1) (1.03 g, 4.44 mmol, 102 equiv). The mixture was heated at 95°C overnight under nitrogen atmosphere. The mixture was diluted with water (30 mL), then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 30:1) to give tert-butyl 4-(benzofuran-7-yloxy)-2-chlorobenzoate (1.23 g, 4-(benzofuran-7-yloxy)-2-chlorobenzoate) as a pale yellow oil. Yield: 80%). LCMS (ESI): m/z 345 [M+1] ⁺ ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=10:1). To a mixture of diisopropylamine (0.61 mL, 4.34 mmol, 1.3 equiv) in tetrahydrofuran (5 mL) was added n-butyllithium (2.5M in hexanes, 1.74 mL) dropwise under nitrogen at -78°C , 4.34 mmol, 1.3 equiv). The mixture was stirred for 5 minutes and then warmed to 0°C and stirred for 5 minutes. The mixture was recooled to -78°C. A solution of tert-butyl 4-(benzofuran-7-yloxy)-2-chlorobenzoate (1.15 g, 3.34 mmol, 1.0 equiv) prepared above in tetrahydrofuran (5 mL) was added dropwise and the The mixture was stirred for 1.5 hours. A solution of N-fluorobisbenzenesulfonamide (1.37 g, 4.34 mmol, 1.3 equiv) in tetrahydrofuran (5 mL) was added dropwise. The mixture was stirred at -78°C for 0.5h, then warmed to room temperature for 1 hour. The reaction was quenched by the addition of saturated aqueous ammonium chloride (30 mL). The aqueous layer was extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was subjected to column chromatography on silica gel (petroleum ether:ethyl acetate 60:1) to give 2-chloro-4-((2-fluorobenzofuran-7-yl)oxy)benzoic acid as a pale yellow oil tert-Butyl ester (783 mg, yield: 65%). LCMS (ESI): m/z 363 [M+1] ⁺ ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=10:1).

Step 9b: Preparation of 2-chloro-4-((2-fluorobenzofuran-7-yl)oxy)benzoic acid (compound 0104-13): To 2-chloro-4-((2-fluorobenzoic acid) To a mixture of furan-7-yl)oxy)benzoate (0103-13) (525 mg, 1.45 mmol, 1.0 equiv) in dichloromethane (10 mL) was added trifluoroacetic acid (3 mL). The mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was dried under vacuum to give 2-chloro-4-((2-fluorobenzofuran-7-yl)oxy)benzoic acid (427 mg, yield: 96%) as a white solid. LCMS (ESI): m/z 307 [M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol=10:1).

Step 9c: Preparation of 2-chloro-4-((2-fluorobenzofuran-7-yl)oxy)benzoyl chloride (compound 0105-13)): To 2-chloro-4-((2-fluoro Benzofuran-7-yl)oxy)benzoic acid (0104-13) (200 mg, 0.65 mmol, 1.0 equiv) and N,N-dimethylformamide (1.9 mg, 0.03 mmol, 0.04 equiv) To a mixture of dichloromethane (7 mL) was added oxalyl chloride (0.11 mL, 1.30 mmol, 2.0 equiv). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and dried under vacuum to give 2-chloro-4-((2-fluorobenzofuran-7-yl)oxy)benzoyl chloride (212 mg, crude) as a pale yellow oil.

Step 9d: (2-Chloro-4-((2-fluorobenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl ) preparation of methyl ketone (compound 0107-13): To a mixture of sodium hydride (60%, 65 mg, 1.64 mmol, 2.0 equiv) in tetrahydrofuran (3.5 mL) was added 5-bromo-4-chloro under nitrogen atmosphere -7H-Pyrrolo[2,3-d]pyrimidine (0106-1) (190 mg, 0.82 mmol, 1.0 equiv). The mixture was stirred at room temperature for 10 minutes and then cooled to -78°C. n-Butyllithium (2.5M in hexanes, 0.39 mL, 0.98 mmol, 1.2 equiv) was added dropwise and stirred for 1 hour. 2-Chloro-4-((2-fluorobenzofuran-7-yl)oxy)benzoyl chloride (0105-13) (212 mg, 0.65 mmol, 0.8 equiv) in tetrahydrofuran (1.5 mL) was added dropwise The solution was then stirred at -78°C for 1 hour. The reaction was quenched by the addition of saturated aqueous ammonium chloride (30 mL). The aqueous layer was extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was subjected to column chromatography on silica gel (petroleum ether:ethyl acetate 2:1) to give (2-chloro-4-((2-fluorobenzofuran-7-yl)oxy)phenyl as a pale yellow solid ) (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (56 mg, yield: 19%). LCMS (ESI): m/z 442[M+1] ⁺ ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=1:1).

Step 9e: (2-Chloro-4-((2-fluorobenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro- Preparation of 2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 13): To (2-chloro-4-((2- Fluorobenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (0107-13) (56 mg, 0.13 mg mol, 1.0 equiv) and (3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-amine hydrochloride (0108-1) (28 mg, 0.17 mmol, 1.3 equiv) in To a mixture of tert-butanol (8 mL) was added N,N-diisopropylethylamine (0.11 mL, 0.64 mmol, 5.0 equiv). The mixture was heated to 90°C under nitrogen atmosphere and reacted overnight. The mixture was diluted with water (20 mL), then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by Pre-HPLC (acetonitrile-0.1% trifluoroacetic acid system) to give (2-chloro-4-((2-fluorobenzofuran-7-yl)oxy)phenyl)(4-chloro-4-((2-fluorobenzofuran-7-yl)oxy)phenyl)(4- (((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone ( 35 mg, yield: 51%). LCMS (ESI): m/z 537 [M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol=10:1); melting point: 151-153°C. ¹ H NMR (500MHz, DMSO) δ 12.72(s, 1H), 8.57(d, J=7.0Hz, 1H), 8.25(s, 1H), 7.70-7.55(m, 2H), 7.49(d, J =7.7Hz,1H),7.40–7.21(m,2H),7.14(d,J=8.0Hz,1H),7.07(dd,J=8.4,2.1Hz,1H),6.47(d,J=6.4Hz ,1H),4.63(t,J＝5.4Hz,1H),4.16(d,J＝7.6Hz,2H),3.42(dd,J＝11.7,6.0Hz,3H),3.11(dd,J＝21.0, 9.4Hz, 1H), 2.19 (d, J=11.7Hz, 1H), 1.78 (d, J=12.8Hz, 1H), 1.58 (dt, J=20.8, 10.4Hz, 1H), 1.38 (dt, J= 21.1, 10.5Hz, 1H).

Example 10: ((2-Chloro-4-((2-chlorobenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrakis Preparation of Hydrogen-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 14) (prepared according to Scheme 1)

Step 10a: Preparation of 2-chlorobenzofuran-7-ol (compound 0101-14):

Under nitrogen atmosphere, n-butyllithium (3.24 mL, 2.5 mol/L in n-hexane, 8.107 mmol, 1.2 equiv) was added dropwise to diisopropylamine (887 mg, 8.783 mmol, 1.3 equiv.) in 20 mL of tetrahydrofuran. The mixture was stirred at -30°C for 30 minutes. The mixture was cooled to room temperature. A solution of 7-methoxybenzofuran (1.0 g, 6.756 mmol, 1 equiv) in 2 mL of tetrahydrofuran was added dropwise. The mixture was stirred for a further 2 hours at -70°C. A solution of hexachloroethane (1.92 g, 8.107 mmol, 1.2 equiv) in 2 mL of tetrahydrofuran was added dropwise. The mixture was stirred at -70°C for 1 hour. Then, the reaction was quenched with aqueous ammonium chloride. The mixture was extracted with ethyl acetate. The organic phase was washed with aqueous sodium bisulfite. The organic phase is dried over sodium sulfate. The organic phase was concentrated and purified by silica gel column chromatography (eluent: petroleum ether) to give 2-chloro-7-methoxybenzofuran (1.18 g, crude product) as a white solid product. MS(ESI): m/z 183(M+H) ⁺ .

Under an atmosphere of nitrogen, boron tribromide (19 mL, 1.0 mol/L in dichloromethane, 19.35 mmol, 3.0 equiv) was added dropwise to 2-chloro-7-methoxybenzone under an ice bath. Furan (1.18 g, 6.45 mmol, 1.0 equiv) in 5 mL tetrahydrofuran. The mixture was stirred at room temperature for 2 hours. The reaction was quenched with ice-water solution. The mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine. The organic phase is dried over sodium sulfate. The organic phase was concentrated and purified by silica gel column chromatography (eluent: petroleum ether) to give 2-chlorobenzofuran-7-ol as a white solid product (1.0 g, crude). MS (ESI): m/z 169 ( M+H) ⁺ .

Step 10b: Preparation of methyl 2-chloro-4-((2-chlorobenzofuran-7-yl)oxy)benzoate (compound 0103-14): To 2-chlorobenzofuran- To a solution of 7-ol (0101-14) (927 mg, 4.92 mmol, 1.0 equiv) in N,N-dimethylformamide (10 mL) was added methyl 2-chloro-4-fluorobenzoate (0102- 1) (831 mg, 4.92 mmol, 1.0 equiv), potassium carbonate (1.35 g, 9.84 mmol, 2.0 equiv), the mixture was stirred at 90°C overnight. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether/ethyl acetate=100/1 to 30/1) to obtain 2-chloro-4-((2-chlorobenzofuran-7-yl)oxy)benzene as a yellow solid product Methyl formate (1.01 g, crude). LCMS (ESI): m/z=338[M+1] ⁺ .

Step 10c: Preparation of 2-chloro-4-((2-chlorobenzofuran-7-yl)oxy)benzoic acid (compound 0104-14): To 2-chloro-4-((2-chlorobenzoic acid) To a solution of methyl furan-7-yl)oxy)benzoate (0103-14) (1.01 g, 2.99 mmol, 1.0 equiv) in tetrahydrofuran (8 mL) was added 2M sodium hydroxide solution (2 mL), and the mixture was Stir overnight at 40°C. The reaction solution was adjusted to pH=1 with 4M hydrochloric acid, and filtered. The residue was washed with water and dried. The residue was used directly in the next step without further purification. LCMS(ESI): m/z=342[M+1] ⁺ .

Step 10d: (2-Chloro-4-((2-chlorobenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl ) preparation of ketone (compound 0107-14): under nitrogen protection, at 0 ℃, to 2-chloro-4-((2-chlorobenzofuran-7-yl)oxy)benzoic acid (0104-14) (736 mg, 2.278 mmol, 1.0 equiv) in dichloromethane/tetrahydrofuran (5/5 mL) was added oxalyl chloride (868 mg, 6.834 mmol, 3.0 equiv), N,N-dimethylformamide ( 1 drop) and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure. The residue was used without further purification. To a solution of 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0106-1) (529 mg, 2.278 mmol, 1.0 equiv) in tetrahydrofuran was added hydrogenation at 0 °C under nitrogen. Sodium (273 mg, 6.834 mmol, 3.0 equiv) and the mixture was stirred at room temperature for 1.0 h. Then n-butyllithium (1.1 mL, 2.5 mol per liter in n-hexane, 2.73 mmol, 1.2 equiv) was slowly added dropwise at -70°C and stirred for 1.0 h. The above-obtained residue was dissolved in 5 ml of tetrahydrofuran and added dropwise to the reaction solution. The reaction solution was quenched with ammonium chloride solution and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether/ethyl acetate = 15/1 to 2/1) to give a yellow solid product (2-chloro-4-((2-chlorobenzofuran-7-yl)oxy) phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (470 mg, crude). LCMS (ESI): m/z=459[M+1] ⁺ .

Step 10e: ((2-Chloro-4-((2-chlorobenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro Preparation of -2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 14): ((3R,6S)-6-( Hydroxymethyl)tetrahydro-2H-pyran-3-yl)carbamate tert-butyl ester (100 mg, 0.433 mmol, 1.0 equiv) in hydrogen chloride dioxane (4 mol per L solution, 5 mL) The mixture was stirred at room temperature for 1 hour, the solvent was removed under reduced pressure and dried under vacuum, the residue was used without further purification. To the residue and (2-chloro-4-((2-chlorobenzofuran-7-yl )oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (0107-14) (165 mg, 0.36 mmol, 1.0 equiv) in tert-butyl To the mixture of alcohols (20 mL) was added N,N-diisopropylethylamine (0.5 mL). The mixture was heated at 90° C. overnight. The reaction was diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to give the product ((2-chloro-4-((2-chlorobenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S) as a yellow solid. )-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (50 mg, yield: 25.12%). MS (ES ⁺ ): m/z=554 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO) δ 12.71 (s, 1H), 8.58 (d, J=7.2 Hz, 1H) ,8.24(s,1H),7.64–7.55(m,2H),7.50(dd,J=7.8,0.9Hz,1H),7.35(t,J=7.9Hz,1H),7.30(d,J=2.4 Hz, 1H), 7.18–7.12 (m, 2H), 7.07 (dd, J=8.5, 2.4Hz, 1H), 4.63 (s, 1H), 4.25–4.00 (m, 2H), 3.43 (dd, J= 12.7,7.7Hz,3H),3.12(t,J=11.6Hz,1H),2.20(dd,J=8.9,6.2Hz,1H),1.78(d,J=13.4Hz,1H),1.62–1.50( m,1H),1.42–1.34(m,1H).

Example 11: (2-Chloro-4-((3-methylbenzofuran-7-yl)oxy)phenyl))4-(((3R,6S)-6-(hydroxymethyl)tetrakis Preparation of Hydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 16) (prepared according to Scheme 1)

Step 11a: Preparation of 3-methylbenzofuran-7-ol (compound 0101-16):

To a solution of 2-methoxyphenol (2.0 g, 16.0 mmol, 1.0 equiv) in 50 mL of acetonitrile was added bromoacetone (2.6 g, 19.2 mmol, 1.2 equiv) and potassium carbonate (4.4 g, 32.0 mmol, 2.0 equiv) ). The mixture was stirred at 60°C for 3 hours, ethyl acetate was added, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 1-(2-methyl) as a yellow oil. Oxyphenoxy)propan-2-one (1.9 g, yield: 65%). MS(ES ⁺ ): m/z 181(M+H) ⁺ .

To a solution of 1-(2-methoxyphenoxy)propan-2-one (1.9 g, 10.6 mmol, 1.0 equiv) in 250 mL of toluene was added polyphosphoric acid (300 mg, 0.89 mmol, 0.08 equiv). The mixture was stirred at 120°C overnight. The reaction was quenched with water, extracted with ethyl acetate, washed with saturated brine, the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=30/1 to 20/1 ) to give 7-methoxy-3-methylbenzofuran (741 mg, yield: 43%) as a white solid. MS(ES ⁺ ): m/z 163(M+H) ⁺ .

To a solution of 7-methoxy-3-methylbenzofuran (741 mg, 4.58 mmol, 1.0 equiv) in 30 mL of dichloromethane was added dropwise 4.1 mL of 2M tribromide at 0 °C under a gas atmosphere. Boron in dichloromethane. The mixture was stirred at room temperature for 1 hour, quenched with methanol and water, added with dichloromethane, and washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 3-methylbenzofuran-7-ol (660 mg, yield: 97%) as a yellow solid. MS(ES ⁺ ): m/z 149(M+H) ⁺ .

Step 11b: Preparation of methyl 2-chloro-4-((3-methylbenzofuran-7-yl)oxy)benzoate (compound 0103-16): under nitrogen, 2-chloro-4- Methyl fluorobenzoate (0102-1) (690 mg, 3.69 mmol, 1.0 equiv), 3-methylbenzofuran-7-ol (0101-16) (818 mg, 5.53 mmol, 1.5 equiv) and A mixture of potassium carbonate (1.53 g, 11.1 mmol, 3.0 equiv) in 10 mL of dimethylformamide was stirred at 90°C overnight. Ethyl acetate was added, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 30/1 to 20/ 1) to obtain methyl 2-chloro-4-((3-methylbenzofuran-7-yl)oxy)benzoate (885 mg, yield: 75%) as a yellow solid. MS(ES ⁺ ): m/z 317(M+H) ⁺ .

Step 11c: Preparation of 2-chloro-4-((3-methylbenzofuran-7-yl)oxy)benzoic acid (compound 0104-16): 2-chloro-4-((3-methyl Methyl benzofuran-7-yl)oxy)benzoate (0103-16) (885 mg, 2.80 mmol, 1.0 equiv) was dissolved in 14 mL of tetrahydrofuran and 14 mL of 2M aqueous sodium hydroxide solution was added. The mixture was stirred at 40°C for 6 hours. 3M aqueous hydrogen chloride solution was added to adjust the pH to 2. Ethyl acetate was added for extraction, washed with water and saturated brine, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2-chloro-4-((3-methylbenzofuran-7-yl)oxy as a yellow solid ) benzoic acid (820 mg, yield: 96%). MS(ES ⁺ ): m/z 303(M+H) ⁺ .

Step 11d: 2(2-Chloro-4-((3-methylbenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5 Preparation of -yl)methanone (compound 0107-16): under nitrogen protection, 2-chloro-4-((3-methylbenzofuran-7-yl)oxy)benzoic acid (0104-16) (60 mg, 0.198 mmol, 1.0 equiv) was dissolved in 3 mL dichloromethane and 0.5 mL tetrahydrofuran. 0.01 mL of dimethylformamide was added. Oxalyl chloride (76 mg, 0.594 mmol, 3.0 equiv) was dissolved in 0.5 mL dichloromethane and added to the above mixture at room temperature. The mixture was stirred at room temperature for 3 hours. The mixture was concentrated to dryness under reduced pressure. 5-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0106-1) (55 mg, 0.24 mmol, 1.23 equiv) was dissolved in 5 mL of dry tetrahydrofuran under nitrogen protection, and cooled to 0°C. Sodium hydride (29 mg, 0.72 mmol, 3.69 equiv) was added and the mixture was stirred at room temperature for 30 minutes. The mixture was cooled to -70°C and 1.6M n-butyllithium in n-hexane (0.24 mL, 0.38 mmol, 1.9 equiv) was added dropwise. The mixture was stirred at -70°C for 1 hour. The acid chloride obtained above was dissolved in 1 ml of anhydrous tetrahydrofuran, and then added dropwise to the above mixture. The mixture was stirred at -70°C for 1 hour. The reaction was quenched by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1 to 1/1) to obtain 2(2-chloro) as a yellow solid -4-((3-Methylbenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (51 mg , yield: 57%). MS(ES ⁺ ): m/z 438(M+H) ⁺ .

Step 11e: (2-Chloro-4-((3-methylbenzofuran-7-yl)oxy)phenyl))4-(((3R,6S)-6-(hydroxymethyl)tetrahydro Preparation of -2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 16): 2(2-chloro-4-(( 3-Methylbenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (0107-16) (50 mg , 0.139 mmol, 1.0 equiv), ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol hydrochloride (0108-1) (23 mg, 0.139 mmol, 1.0 equiv ) and diisopropylethylamine (89 mg, 0.69 mmol, 5.0 equiv) were added to 10 mL of tert-butanol, and the mixture was stirred at 90°C overnight. The mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with water and saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (developing solvent: dichloromethane/methanol= 30/1) to give (2-chloro-4-((3-methylbenzofuran-7-yl)oxy)phenyl))4-(((3R,6S)-6-(hydroxyl) as a yellow solid Methyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (37 mg, yield: 50%). MS (ES ⁺ ): m/z 533 (M+H) ⁺ ; melting point 136-138°C.

¹ H NMR (500MHz, DMSO) δ12.71(s, 1H), 8.57(d, J=7.2Hz, 1H), 8.24(s, 1H), 7.81(d, J=1.3Hz, 1H), 7.59( s, 1H), 7.56 (d, J=8.5Hz, 1H), 7.53 (dd, J=7.8, 0.9Hz, 1H), 7.33 (t, J=7.8Hz, 1H), 7.19 (dd, J=13.2 ,5.1Hz,2H),6.99(dd,J=8.5,2.4Hz,1H),4.62(t,J=5.6Hz,1H),4.19–4.08(m,2H),3.47–3.39(m,1H) ,3.35(dd,J=9.0,2.8Hz,2H),3.16-3.07(m,1H),2.25(d,J=1.2Hz,3H),2.21-2.14(m,1H),1.78(t,J =10.3Hz,1H),1.65–1.49(m,1H),1.39(ddd,J=23.3,13.3,3.8Hz,1H).

Example 12: (2-Chloro-4-((6-methylbenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrakis Preparation of Hydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 17) (prepared according to Scheme 1)

Step 12a: Preparation of 6-methylbenzofuran-7-ol (compound 0101-17):

To a solution of 2-bromo-3-methylphenol (1.5 g, 8.02 mmol, 1.0 equiv) and potassium carbonate (1.66 g, 12.03 mmol, 1.5 equiv) in N,N-dimethylformamide (8 mL) To the mixture was added 2-bromo-1,1-diethoxyethane (1.98 g, 10.03 mmol, 1.25 equiv). The mixture was heated at 110°C overnight under nitrogen. The mixture was diluted with water (30 mL), then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated to give 2-bromo-1-(2,2-diethoxyethoxy)-3 as a brown oily substance - methylbenzene (2.63 g, crude). TLC: Rf 0.5 (petroleum ether:ethyl acetate=10:1).

To a mixture of 2-bromo-1-(2,2-diethoxyethoxy)-3-methylbenzene (2.60 g, 8.58 mmol, 1.0 equiv) in toluene (30 mL) was added polyphosphoric acid (3.20 g, 9.44 mmol, 1.1 equiv). The mixture was heated at 110°C for 1.5 hours under nitrogen atmosphere. The mixture was diluted with water (30 mL), then extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with saturated brine (30 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether) to give 7-bromo-6-methylbenzofuran (1.14 g, yield: 63%) as a pale yellow oil. TLC: Rf 0.7 (petroleum ether).

To a mixture of 7-bromo-6-methylbenzofuran (2.17 g, 10.28 mmol, 1.0 equiv) in dimethylsulfoxide (30 mL) was added _Pin2B2 (3.92 _g , 15.43 mmol, 1.5 equiv. ), potassium acetate (3.03 g, 30.84 mmol, 3.0 equiv)) and Pd(dppf)Cl2 (752 _mg , 1.03 mmol, 0.1 equiv). The mixture was heated at 115°C for 22 hours under nitrogen atmosphere. The mixture was diluted with water (200 mL), then extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (30 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 30:1) to give 4,4,5,5-tetramethyl-2-(6-methylbenzofuran-7-yl) as a pale green solid -1,3,2-dioxaborolane (2.0 g, yield: 75%). LCMS (ESI): m/z 259 [M+1] ⁺ ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=10:1).

To 4,4,5,5-tetramethyl-2-(6-methylbenzofuran-7-yl)-1,3,2-dioxaborolane (1.0 g, 3.88 mmol, 1.0 equiv.) To a mixture of methanol (15 mL) was added hydrogen peroxide (30%, 5 mL) dropwise. The mixture was stirred at room temperature for two days. The reaction was quenched by the addition of saturated sodium sulfite solution (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 10:1) to give 6-methylbenzofuran-7-ol (0.294 g, yield: 51%) as a pale yellow oil. LCMS (ESI): m/z 149 [M+1] ⁺ ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=6:1).

Step 12b: Preparation of methyl 2-chloro-4-((6-methylbenzofuran-7-yl)oxy)benzoate (compound 0103-17): To 6-methylbenzofuran-7- To a mixture of alcohol (0101-17) (294 mg, 1.986 mmol, 1.0 equiv) and potassium carbonate (329 mg, 2.384 mmol, 1.2 equiv) in N,N-dimethylformamide (5 mL) was added 2 - Methyl chloro-4-fluorobenzoate (0102-1) (450 mg, 2.384 mmol, 1.2 equiv). The mixture was heated at 90°C for 7 hours under nitrogen atmosphere. The mixture was diluted with water (40 mL), then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 30:1) to give methyl 2-chloro-4-((6-methylbenzofuran-7-yl)oxy)benzoate ( 467 mg, yield: 74%). LCMS (ESI): m/z 317 [M+1] ⁺ ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=10:1).

Step 12c: Preparation of 2-chloro-4-((6-methylbenzofuran-7-yl)oxy)benzoic acid (compound 0104-17): To 2-chloro-4-((6-methyl) Benzofuran-7-yl)oxy)benzoic acid methyl ester (0103-17) (467 mg, 1.48 mmol, 1.0 equiv) to a mixture of tetrahydrofuran (5 mL) and water (2 mL) was added sodium hydroxide (177 mg, 4.43 mmol, 3.0 equiv). The mixture was stirred at room temperature overnight. The mixture was diluted with water (20 mL). 1N dilute hydrochloric acid was added to adjust pH=3. The aqueous layer was extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated to give 2-chloro-4-((6-methylbenzofuran-7-yl)oxy as a white solid ) benzoic acid (410 mg, yield: 92%). LCMS (ESI): m/z 303 [M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol=10:1).

Step 12d: Preparation of 2-chloro-4-((6-methylbenzofuran-7-yl)oxy)benzoyl chloride (compound 0105-17): To 2-chloro-4-((6-methyl) benzofuran-7-yl)oxy)benzoic acid (0104-17) (200 mg, 0.66 mmol, 1.0 equiv) and N,N-dimethylformamide (2.4 mg, 0.033 mmol, 0.1 equiv) ) to a mixture of dichloromethane (8 mL) was added oxalyl chloride (0.11 mL, 1.32 mmol, 2.0 equiv). The mixture was stirred at room temperature for 5 hours. The solvent was removed under reduced pressure and dried under vacuum to give 2-chloro-4-((6-methylbenzofuran-7-yl)oxy)benzoyl chloride (212 mg, crude) as a pale yellow oil. TLC: Rf 0.5 (petroleum ether:ethyl acetate=20:1).

Step 12e: (2-Chloro-4-((6-methylbenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5- yl)methanone (compound 0107-17): To a mixture of sodium hydride (60%, 66 mg, 1.66 mmol, 2.0 equiv) in tetrahydrofuran (3.5 mL) was added 5-bromo-4- Chloro-7H-pyrrolo[2,3-d]pyrimidine (0106-1) (192 mg, 0.83 mmol, 1.0 equiv). The mixture was stirred at room temperature for 10 minutes and then cooled to -78°C. n-Butyllithium (2.5M in hexanes, 0.40 mL, 1.0 mmol, 1.2 equiv) was added dropwise and stirred for 1 hour. 2-Chloro-4-((6-methylbenzofuran-7-yl)oxy)benzoyl chloride (0105-17) (212 mg, 0.66 mmol, 1.0 equiv) in tetrahydrofuran (1.5 mL) was added dropwise ) solution, then stirring was continued at -78°C for 1 hour. The reaction was quenched by the addition of saturated aqueous ammonium chloride (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was subjected to column chromatography on silica gel (petroleum ether:ethyl acetate 3:1) to give (2-chloro-4-((6-methylbenzofuran-7-yl)oxy)phenyl)( 4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (150 mg, yield: 41%). LCMS (ESI): m/z 438 [M+1] ⁺ ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=1:1).

Step 12f: (2-Chloro-4-((6-methylbenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro Preparation of -2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 17): To (2-chloro-4-((6) -methylbenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (0107-17) (80 mg, 0.18 mmol, 1.0 equiv) and ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol hydrochloride (0108-1) (39.8 mg, 0.24 mmol, 1.3 equiv) To a mixture of tert-butanol (8 mL) was added N,N-diisopropylethylamine (0.16 mL, 0.92 mmol, 5.0 equiv). The mixture was heated at 90°C under nitrogen atmosphere overnight. The mixture was diluted with water (30 mL), then extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (ethyl acetate:dichloromethane:methanol=10:10:2) to give (2-chloro-4-((6-methylbenzofuran-7-yl)) as a white solid oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d] pyrimidin-5-yl)methanone (42 mg, yield: 43%). LCMS (ESI): m/z 533 [M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol=10:1); melting point: 175-178°C. ¹ HNMR (DMSO-d ₆ , 500MHz): δ 12.68 (s, 1H), 5.57 (d, J=7.0 Hz, 1H), 8.24 (s, 1H), 7.93 (d, J=2.0 Hz, 1H) ,7.58(s,1H),7.53(d,J＝8.5Hz,2H),7.26(d,J＝8.0Hz,1H),7.08(d,J＝2.5Hz,1H),7.01(d,J＝ 2.5Hz,1H),6.84-6.82(m,1H),4.63-4.60(m,1H),4.16-4.14(m,2H),3.43-3.40(m,1H),3.36-3.30(m,2H) ,3.13-3.09(m,1H),2.30(s,3H),2.19-2.17(m,1H),1.79-1.77(m,1H),1.60-1.52(m,1H),1.42-1.35(m, 1H).

Example 13: (2-Chloro-4-((6-fluorobenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro Preparation of -2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 18) (prepared according to Scheme 1)

Step 13a: Preparation of 6-fluorobenzofuran-7-ol (compound 0101-18): To 2-(6-fluorobenzofuran-7-yl)-4,4,5,5-tetramethyl- To a solution of 1,3,2-dioxaborane (1.0 g, 3.8 mmol, 1.0 equiv) in methanol (8 mL) was added 30% H2O2 ₍ ₂ mL). The mixture was stirred at room temperature overnight. The reaction was quenched with sodium bisulfite solution and extracted with ethyl acetate. The organic layer was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 100/1 to 30/1) to give 6-fluorobenzofuran-7-ol (580 mg, crude) as a yellow oil. LCMS (ESI): m/z 313 [M+1] ⁺ .

Step 13b: Preparation of methyl 2-chloro-4-((6-fluorobenzofuran-7-yl)oxy)benzoate (compound 0103-18): To 6-fluorobenzofuran- To a solution of 7-ol (0101-18) (796 mg, 5.17 mmol, 1.3 equiv) in N,N-dimethylformamide (5 mL) was added methyl 2-chloro-4-fluorobenzoate (0102- 1) (750 mg, 3.976 mmol, 1.0 equiv), potassium carbonate (1.1 g, 7.952 mmol, 2.0 equiv), the mixture was stirred at 90°C overnight. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether/ethyl acetate=100/1 to 30/1) to obtain 2-chloro-4-((6-fluorobenzofuran-7-yl)oxy)benzene as a white solid product Methyl formate (389 mg, yield: 30.63%). LCMS(ESI): m/z=321[M+1] ⁺ .

Step 13c: Preparation of 2-chloro-4-((6-fluorobenzofuran-7-yl)oxy)benzoic acid (compound 0104-18): To 2-chloro-4-((6-fluorobenzoic acid) To a solution of methyl furan-7-yl)oxy)benzoate (0103-18) (389 mg, 1.2 mmol, 1.0 equiv) in tetrahydrofuran (8 mL) was added 2M sodium hydroxide solution (2 mL) and the mixture was Stir overnight at 40°C. The reaction solution was adjusted to pH=1 with 4M hydrochloric acid, and filtered. The residue was washed with water and dried. The residue was used directly in the next step without further purification. LCMS (ESI): m/z=307[M+1] ⁺ .

Step 13d: (2-Chloro-4-((6-fluorobenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl ) preparation of ketone (compound 0107-18): under nitrogen protection, at 0 ℃, to 2-chloro-4-((6-fluorobenzofuran-7-yl)oxy)benzoic acid (0104-18) (400 mg, 1.307 mmol, 1.0 equiv) in dichloromethane/tetrahydrofuran (5/5 mL) was added oxalyl chloride (498 mg, 3.921 mmol, 3.0 equiv), N,N-dimethylformamide ( 1 drop) and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure. The residue was used without further purification. To a solution of 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0106-1) (303.8 mg, 1.307 mmol, 1.0 equiv) in tetrahydrofuran at 0°C under nitrogen was added hydrogenation Sodium (157 mg, 3.921 mmol, 3.0 equiv) and the mixture was stirred at room temperature for 1.0 h. Then n-butyllithium (1.06 mL, 1.6 mol per liter in n-hexane, 1.699 mmol, 1.3 equiv) was slowly added dropwise at -70°C and stirred for 1.0 h. A solution of the above obtained residue in 5 ml of tetrahydrofuran was then added dropwise. The reaction solution was quenched with ammonium chloride solution, diluted with water and extracted with ethyl acetate, the organic phase was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether/ethyl acetate = 15/1 to 2/1) to give the product (2-chloro-4-((6-fluorobenzofuran-7-yl)oxy) as a yellow solid Phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (80 mg, yield: 13.85%). LCMS (ESI): m/z=443[M+1] ⁺ .

Step 13e: (2-Chloro-4-((6-fluorobenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro- Preparation of 2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 18): ((3R,6S)-6-(hydroxyl) A mixture of tert-butyl methyl)tetrahydro-2H-pyran-3-yl)carbamate (50 mg, 0.217 mmol, 1.2 equiv) in hydrogen chloride dioxane (4 mol per L solution, 4 mL) After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure and dried under vacuum, and the residue was used without further purification. To the residue and (2-chloro-4-((6-fluorobenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5- yl)methanone (0107-18) (80 mg, 0.181 mmol, 1.0 equiv) To a mixture of tert-butanol (5 mL) was added N,N-diisopropylethylamine (0.5 mL). The mixture was heated at 90°C overnight. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to give the product (2-chloro-4-((6-fluorobenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S) as a yellow solid. -6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (54 mg, yield: 55.67 %). MS(ES ⁺ ): m/z=537(M+H) ⁺ 1H NMR(500MHz, DMSO) δ12.70(s, 1H), 8.56(d, J=7.2Hz, 1H), 8.24(s, 1H), 8.07(d, J＝2.2Hz, 1H), 7.64(dd, J＝8.6, 4.7Hz, 1H), 7.59(s, 1H), 7.56(d, J＝8.5Hz, 1H), 7.39( dd,J＝11.1,8.6Hz,1H),7.25(d,J＝2.5Hz,1H),7.09(d,J＝2.2Hz,1H),6.99(dd,J＝8.5,2.5Hz,1H), 4.61 (t, J=5.7Hz, 1H), 4.22–4.09 (m, 2H), 3.41 (dd, J=7.2, 5.3Hz, 1H), 3.35 (d, J=4.0Hz, 2H), 3.17–3.09 (m,1H),2.16(dd,J=20.4,17.7Hz,1H),1.78(d,J=13.4Hz,1H),1.57(tt,J=10.5,5.3Hz,1H),1.38(ddd, J=16.8,13.4,3.9Hz,1H).

Example 14: (2-Chloro-4-((5-fluorobenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro Preparation of -2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 20) (prepared according to Scheme 1)

Step 14a: Preparation of 5-fluorobenzofuran-7-ol (compound 0101-20):

To a mixture of 2-bromo-4-fluorophenol (2.5 g, 13.09 mmol, 1.0 equiv) and potassium carbonate (2.71 g, 19.64 mmol, 1.5 equiv) in N,N-dimethylformamide (20 mL) To this was added 2-bromo-1,1-diethoxyethane (3.87 g, 19.64 mmol, 1.5 equiv). The mixture was heated at 115°C overnight under nitrogen. The mixture was diluted with water (80 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was subjected to column chromatography on silica gel (petroleum ether:ethyl acetate 20:1) to give 2-bromo-1-(2,2-diethoxyethoxy)-4-fluorobenzene as a pale yellow oil (4.02 g, yield: 100%). TLC: Rf 0.5 (petroleum ether:ethyl acetate=10:1).

To a mixture of 2-bromo-1-(2,2-diethoxyethoxy)-4-fluorobenzene (4.02 g, 13.09 mmol, 1.0 equiv) in toluene (30 mL) was added polyphosphoric acid ( 4.87 g, 14.40 mmol, 1.1 equiv). The mixture was heated at 110°C for 1.5 hours under nitrogen atmosphere. The mixture was diluted with water (50 mL), then extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether) to give 7-bromo-5-fluorobenzofuran (0.391 g, yield: 14%) as a pale yellow oil. TLC: Rf 0.7 (petroleum ether).

To a mixture of 7-bromo-5-fluorobenzofuran (391 mg, 1.819 mmol, 1.0 equiv) in dimethyl sulfoxide (5 mL) was added bispinacol borate (600 mg, 2.364 mmol) , 1.3 equiv), potassium acetate (536 mg, 5.457 mmol, 3.0 equiv)) and Pd(dppf)Cl2 (133 _mg , 0.182 mmol, 0.1 equiv). The mixture was heated at 90°C for 10 hours under nitrogen atmosphere. The mixture was diluted with water (30 mL), then extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 20:1) to give 2-(5-fluorobenzofuran-7-yl)-4,4,5,5-tetramethyl- 1,3,2-Dioxaborolane (476 mg, yield: 100%). LCMS (ESI): m/z 263 [M+1] ⁺ ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=10:1).

Step 14b: Preparation of methyl 2-chloro-4-((5-fluorobenzofuran-7-yl)oxy)benzoate (compound 0103-20): To 5-fluorobenzofuran-7-ol ( 0101-20) (277 mg, 1.819 mmol, 1.0 equiv) and potassium carbonate (301 mg, 2.183 mmol, 1.2 equiv) in N,N-dimethylformamide (5 mL) was added 2-chloro -4-Fluorobenzoic acid methyl ester (0102-1) (343 mg, 1.819 mmol, 1.0 equiv). The mixture was heated at 90°C for 5 hours under nitrogen atmosphere. The mixture was diluted with water (30 mL), then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 20:1) to give methyl 2-chloro-4-((5-fluorobenzofuran-7-yl)oxy)benzoate (355) as a white solid mg, yield: 61%). LCMS (ESI): m/z 321 [M+1] ⁺ ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=8:1).

Step 14c: Preparation of 2-chloro-4-((5-fluorobenzofuran-7-yl)oxy)benzoic acid (compound 0104-20): To 2-chloro-4-((5-fluorobenzoic acid) Furan-7-yl)oxy)benzoic acid methyl ester (0103-20) (355 mg, 1.109 mmol, 1.0 equiv) to a mixture of tetrahydrofuran (5 mL) and water (2 mL) was added sodium hydroxide (133 mg, 3.328 mmol, 3.0 equiv). The mixture was stirred at room temperature overnight. The mixture was diluted with water (20 mL). 1N dilute hydrochloric acid was added to adjust pH=3. The aqueous layer was extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated to give 2-chloro-4-((5-fluorobenzofuran-7-yl)oxy) as a white solid Benzoic acid (200 mg, yield: 59%). LCMS (ESI): m/z 307 [M+1] ⁺ ; TLC: Rf 0.3 (dichloromethane:methanol=20:1).

Step 14d: Preparation of 2-chloro-4-((5-fluorobenzofuran-7-yl)oxy)benzoyl chloride (compound 0105-20): To 2-chloro-4-((5-fluorobenzene furan-7-yl)oxy)benzoic acid (0104-20) (200 mg, 0.654 mmol, 1.0 equiv) and N,N-dimethylformamide (4.8 mg, 0.065 mmol, 0.1 equiv) in To a mixture of dichloromethane (10 mL) and tetrahydrofuran (1.5 mL) was added oxalyl chloride (0.11 mL, 1.307 mmol, 2.0 equiv). The mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and dried under vacuum to give 2-chloro-4-((5-fluorobenzofuran-7-yl)oxy)benzoyl chloride (212 mg, crude) as a pale yellow oil. TLC: Rf 0.5 (petroleum ether:ethyl acetate=20:1).

Step 14e: (2-Chloro-4-((5-fluorobenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl ) Preparation of methyl ketone (compound 0107-20): To a mixture of sodium hydride (60%, 65 mg, 1.636 mmol, 2.0 equiv) in tetrahydrofuran (3.5 mL) was added 5-bromo-4-chloro under nitrogen atmosphere -7H-Pyrrolo[2,3-d]pyrimidine (0106-1) (190 mg, 0.818 mmol, 1.0 equiv). The mixture was stirred at room temperature for 10 minutes and then cooled to -78°C. n-Butyllithium (2.5M in hexanes, 0.39 mL, 0.982 mmol, 1.2 equiv) was added dropwise and stirred for 1 hour. 2-Chloro-4-((5-fluorobenzofuran-7-yl)oxy)benzoyl chloride (0105-20) (212 mg, 0.654 mmol, 1.0 equiv) in tetrahydrofuran (1.5 mL) was added dropwise The solution was then stirred for 1 hour at -78°C. The reaction was quenched by the addition of saturated aqueous ammonium chloride (20 mL). The aqueous layer was extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was subjected to column chromatography on silica gel (petroleum ether:ethyl acetate 2:1) to give (2-chloro-4-((5-fluorobenzofuran-7-yl)oxy)phenyl)(4 -Chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (99 mg, yield: 27%). LCMS (ESI): m/z 442[M+1] ⁺ ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=1:1).

Step 14f: (2-Chloro-4-((5-fluorobenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro- Preparation of 2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 20): To (2-chloro-4-((5- Fluorobenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (0107-20) (99 mg, 0.224 mm moles, 1.0 equiv) and ((2S,5R)-5-aminotetrahydro-2H-pyran 2-yl)methanol hydrochloride (0108-1) (48.8 mg, 0.291 mmol, 1.3 equiv) in tert-butyl To the mixture of alcohols (10 mL) was added N,N-diisopropylethylamine (0.20 mL, 1.12 mmol, 5.0 equiv). The mixture was heated at 90°C under nitrogen atmosphere overnight. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (ethyl acetate:dichloromethane:methanol=10:10:2) to give (2-chloro-4-((5-fluorobenzofuran-7-yl)oxy) as a white solid yl)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine -5-yl)methanone (56 mg, yield: 47%). LCMS (ESI): m/z 537 [M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol=10:1); melting point: 153-156°C. ¹ HNMR (DMSO-d ₆ , 500MHz): δ 12.72 (s, 1H), 8.57 (d, J=7.0 Hz, 1H), 8.25 (s, 1H), 8.10 (d, J=2.0 Hz, 1H) ,7.64(s,1H),7.59(d,J＝8.0Hz,1H),7.40-7.38(m,1H),7.35(d,J＝2.0Hz,1H),7.13-7.09(m,2H), 7.07(d, J＝2.5Hz, 1H), 4.63-4.61(m, 1H), 4.18-4.13(m, 2H), 3.43-3.40(m, 1H), 3.36-3.33(m, 2H), 3.14- 3.10(m,1H), 2.21-2.18(m,1H), 1.80-1.77(m,1H), 1.61-1.53(m,1H), 1.43-1.35(m,1H).

Example 15: (2-Chloro-4-((5-fluoro-2-methylbenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxy Preparation of methyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (compound 21) (prepared according to Scheme 1)

Step 15a: Preparation of 5-fluoro-2-methylbenzofuran-7-ol (compound 0101-21):

Combine 4-fluoro-2-methoxyphenol (3.0 g, 21.11 mmol, 1.0 equiv) and potassium carbonate (4.37 g, 31.67 mmol, 1.5 equiv) in N,N-dimethylformamide (15 mL) To the mixture was added 3-bromopropyne (3.01 g, 25.33 mmol, 1.2 equiv). The mixture was heated to 50°C under nitrogen atmosphere for overnight reaction. The mixture was diluted with water (80 mL), then extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (30 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=60:1) to give 4-fluoro-2-methoxy-1-(prop-2-yn-1-yloxy) as a pale yellow oily substance Benzene (3.57 g, yield: 94%). TLC: Rf 0.5 (petroleum ether:ethyl acetate=30:1).

To 4-fluoro-2-methoxy-1-(prop-2-yn-1-yloxy)benzene (3.57 g, 19.83 mmol, 1.0 equiv) in N,N-diethylaniline (25 mL ) was added cesium fluoride (3.92 g, 25.78 mmol, 1.3 equiv). The mixture was heated to 220°C under nitrogen atmosphere for 6 hours. The mixture was diluted with water (80 mL). Concentrated hydrochloric acid was added to adjust pH=3, and then extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with saturated brine (30 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=60:1) to give 5-fluoro-7-methoxy-2-methylbenzofuran (2.06 g, yield: 58) as a pale yellow oil. %). TLC: Rf 0.6 (petroleum ether:ethyl acetate=30:1).

To a mixture of 5-fluoro-7-methoxy-2-methylbenzofuran (2.0 g, 11.11 mmol, 1.0 equiv) in dichloromethane (50 mL) was added boron tribromide dropwise at 0°C (2M in dichloromethane, 7.2 mL, 14.4 mmol, 1.3 equiv). The mixture was warmed to room temperature and stirred for 4 hours. The reaction was quenched by the addition of methanol (10 mL). Water (50 mL) was added and extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with saturated brine (30 mL×1), dried over anhydrous sodium sulfate and concentrated to give 5-fluoro-2-methylbenzofuran-7-ol (2.04 g, crude) as a brown oil. . LCMS (ESI): m/z 167 [M+1] ⁺ ; TLC: Rf 0.3 (petroleum ether:ethyl acetate=10:1).

Step 15b: Preparation of methyl 2-chloro-4-((5-fluoro-2-methylbenzofuran-7-yl)oxy)benzoate (compound 0103-21): To 5-fluoro-2- Methylbenzofuran-7-ol (0101-21) (1.90 g, 11.44 mmol, 1.0 equiv) and potassium carbonate (1.89 g, 13.73 mmol, 1.2 equiv) in N,N-dimethylformamide ( 10 mL) was added methyl 2-chloro-4-fluorobenzoate (0102-1) (2.16 g, 11.44 mmol, 1.0 equiv). The mixture was heated to 90°C under nitrogen atmosphere and reacted overnight. The mixture was diluted with water (50 mL), then extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (30 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 50:1) to give 2-chloro-4-((5-fluoro-2-methylbenzofuran-7-yl)oxy)benzene as a white solid Methyl formate (2.13 g, yield: 56%). LCMS (ESI): m/z 335 [M+1] ⁺ ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=20:1).

Step 15c: (2-Chloro-4-((5-fluoro-2-methylbenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d] Preparation of pyrimidin-5-yl)methanone (compound 0107-21): To a mixture of sodium hydride (60%, 34 mg, 0.86 mmol, 2.0 equiv) in tetrahydrofuran (3 mL) was added 5- Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0106-1) (100 mg, 0.43 mmol, 1.0 equiv). The mixture was stirred at room temperature for 10 minutes and then cooled to -78°C. n-Butyllithium (2.5M in hexanes, 0.21 mL, 0.52 mmol, 1.2 equiv) was added dropwise and stirred for 1 hour. Methyl 2-chloro-4-((5-fluoro-2-methylbenzofuran-7-yl)oxy)benzoate (0103-21) (100 mg, 0.30 mmol, 0.7 equiv) was added dropwise solution in tetrahydrofuran (1 mL), then stirred at -78 °C for 1 h. The reaction was quenched by the addition of saturated aqueous ammonium chloride (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was subjected to column chromatography on silica gel (petroleum ether:ethyl acetate 2:1) to give a pale yellow solid (2-chloro-4-((5-fluoro-2-methylbenzofuran-7-yl)) oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (80 mg, yield: 58%). LCMS (ESI): m/z 456[M+1] ⁺ ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=1:1).

Step 15d: (2-Chloro-4-((5-fluoro-2-methylbenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl) yl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 21): To (2-chloro-4 -((5-Fluoro-2-methylbenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone ( 0107-21) (80 mg, 0.175 mmol, 1.0 equiv) and (3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-amine hydrochloride (0108-1)(38 mg, 0.23 mmol, 1.3 equiv) to a mixture of tert-butanol (8 mL) was added N,N-diisopropylethylamine (0.15 mL, 0.88 mmol, 5.0 equiv). The mixture was heated to 90°C under nitrogen atmosphere and reacted overnight. The mixture was diluted with water (30 mL), then extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (dichloromethane:methanol=10:1) to give (2-chloro-4-((5-fluoro-2-methylbenzofuran-7-yl)oxy) as a white solid )phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-yl)methanone (36 mg, yield: 38%). LCMS (ESI): m/z 551 [M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol=10:1); melting point: 145-148°C. ¹ H NMR (500MHz, DMSO) δ 12.73(s, 1H), 8.57(d, J=6.9Hz, 1H), 8.24(s, 1H), 7.63(s, 1H), 7.58(d, J=8.5 Hz, 1H), 7.33(s, 1H), 7.25(d, J＝7.0Hz, 1H), 7.10(d, J＝8.3Hz, 1H), 6.97(d, J＝10.2Hz, 1H), 6.69( s, 1H), 4.62(d, J=5.3Hz, 1H), 4.15(d, J=7.5Hz, 2H), 3.45–3.41(m, 1H), 3.35(s, 2H), 3.12(t, J =11.3Hz,1H),2.44(s,3H),2.19(d,J=11.3Hz,1H),1.78(d,J=13.3Hz,1H),1.62–1.48(m,1H),1.39(dd ,J=23.2,10.0Hz,1H).

Example 16: (4-(Benzo[b]thiophen-7-yloxy)-2-chlorophenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H Preparation of -pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 25) (prepared according to Scheme 1)

Step 16a: Preparation of Benzo[b]thiophen-7-ol (Compound 0101-25):

To a solution of 2-methoxythiophenol (2.4 g, 17.1 mmol, 1.0 equiv) in 20 mL of dimethylformamide was added 2-bromo-1,1-diethoxyethane (4.4 g, 22.2 mmol) mol, 1.3 equiv) and potassium carbonate (4.7 g, 34.2 mmol, 2.0 equiv). The mixture was stirred at room temperature for 4 hours, ethyl acetate was added, washed with water and saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a colorless oil (2,2- Diethoxyethyl)(2-methoxyphenyl)sulfide (4.5 g, crude). MS(ES ⁺ ): m/z 257(M+H) ⁺ .

To a solution of (2,2-diethoxyethyl)(2-methoxyphenyl)sulfide (2.28 g, 8.9 mmol, 1.0 equiv) in 250 mL of toluene was added polyphosphoric acid (300 mg, 0.89 mmol) moles, 0.08 equiv). The mixture was stirred at 120°C overnight. The reaction was quenched with water, extracted with ethyl acetate, washed with saturated brine, the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=50/1 to 30/1 ) to give 7-methoxybenzo[b]thiophene (470 mg, yield: 32%) as a yellow solid. MS(ES ⁺ ): m/z 165(M+H) ⁺ .

325 mg of 7-methoxybenzo[b]thiophene were added to 5.1 g of pyridine hydrochloride and the mixture was heated in a sealed jar at 160°C for 8 hours. The mixture was cooled to room temperature, ethyl acetate was added, and the organic phase was washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give benzo[b]thiophen-7-ol (303 mg, crude) as a yellow solid. MS(ES ⁺ ): m/z 151(M+H) ⁺ .

Step 16b: Preparation of methyl 4-(benzo[b]thiophen-7-yloxy)-2-chlorobenzoate (compound 0103-25): 2-chloro-4-fluorobenzoic acid under nitrogen Methyl ester (0102-1) (227 mg, 1.2 mmol, 1.0 equiv), benzo[b]thiophen-7-ol (0101-25) (270 mg, 1.8 mmol, 1.5 equiv) and potassium carbonate (497 mg, 3.6 mmol, 3.0 equiv.) in 10 mL of dimethylformamide and stirred overnight at 90°C. Ethyl acetate was added, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 30/1 to 20/ 1) to give methyl 4-(benzo[b]thiophen-7-yloxy)-2-chlorobenzoate (422 mg, crude) as a yellow solid. MS(ES ⁺ ): m/z 319(M+H) ⁺ .

Step 16c: Preparation of 4-(benzo[b]thiophen-7-yloxy)-2-chlorobenzoic acid (compound 0104-25): 4-(benzo[b]thiophen-7-yloxy )-methyl 2-chlorobenzoate (0103-25) (422 mg, 1.3 mmol, 1.0 equiv) was dissolved in 5 mL of tetrahydrofuran and 10 mL of 2M aqueous sodium hydroxide solution was added. The mixture was stirred at 50°C for 6 hours. 3M aqueous hydrogen chloride solution was added to adjust the pH to 2. Ethyl acetate was added for extraction, washed with water and saturated brine, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 4-(benzo[b]thiophen-7-yloxy)-2-chlorobenzoic acid as a yellow solid (378 mg, yield: 93%). MS(ES ⁺ ): m/z 305(M+H) ⁺ .

Step 16d: (4-(Benzo[b]thiophen-7-yloxy)-2-chlorophenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methan Preparation of ketone (compound 0107-25): under nitrogen protection, 4-(benzo[b]thiophen-7-yloxy)-2-chlorobenzoic acid (0104-25) (306 mg, 1.0 mmol) , 1.0 equiv) was dissolved in 15 mL of dichloromethane and 2 mL of tetrahydrofuran. 0.01 mL of dimethylformamide was added. Oxalyl chloride (381 mg, 3.0 mmol, 3.0 equiv) was dissolved in 2.0 mL of dichloromethane and added to the above mixture at room temperature. The mixture was stirred at room temperature for 3 hours. The mixture was concentrated to dryness under reduced pressure. 5-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0106-1) (249 mg, 1.1 mmol, 1.13 equiv) was dissolved in 25 mL of dry tetrahydrofuran under nitrogen and cooled to 0°C. Sodium hydride (213 mg, 4.4 mmol, 4.4 equiv) was added and the mixture was stirred at room temperature for 30 minutes. The mixture was cooled to -70°C and 1.6M n-butyllithium in n-hexane (0.9 mL, 1.43 mmol, 1.43 equiv) was added dropwise. The mixture was stirred at -70°C for 1 hour. The acid chloride obtained above was dissolved in 1.5 ml of anhydrous tetrahydrofuran, and then added dropwise to the above mixture. The mixture was stirred at -70°C for 1 hour. The reaction was quenched by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1 to 1/1) to obtain a yellow solid (4-(benzene) [b]thiophen-7-yloxy)-2-chlorophenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (248 mg, yield: 56%). MS(ES ⁺ ): m/z 440(M+H) ⁺ .

Step 16e: (4-(Benzo[b]thiophen-7-yloxy)-2-chlorophenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H- Preparation of pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 25): (4-(benzo[b]thiophene-7- yloxy)-2-chlorophenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (0107-25) (100 mg, 0.23 mmol, 1.0 equiv ), ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol hydrochloride (0108-1) (42 mg, 0.25 mmol, 1.1 equiv) and diisopropylethyl acetate The amine (136 mg, 1.05 mmol, 5.0 equiv) was added to 10 mL of tert-butanol and the mixture was stirred at 90°C overnight. The mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with water and saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (developing solvent: dichloromethane/methanol= 30/1) to give (4-(benzo[b]thiophen-7-yloxy)-2-chlorophenyl)(4-(((3R,6S)-6-(hydroxymethyl) Tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (63 mg, yield: 51%). MS (ES ⁺ ): m/z 535 (M+H) ⁺ ; melting point 230-232°C. ¹ H NMR(500MHz, DMSO)δ12.73(s,1H),8.57(d,J=7.2Hz,1H),8.25(s,1H),7.83(d,J=5.3Hz,1H),7.79( d, J=7.6Hz, 1H), 7.61 (s, 1H), 7.58 (dd, J=9.5, 6.9Hz, 2H), 7.46 (t, J=7.8Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 7.14 (d, J=7.8Hz, 1H), 7.09 (dd, J=8.5, 2.4Hz, 1H), 4.62 (t, J=5.6Hz, 1H), 4.15 (ddd, J=11.2 ,6.5,3.3Hz,2H),3.46–3.39(m,1H),3.36(s,2H),3.12(t,J=11.6Hz,1H),2.24–2.13(m,1H),1.78(d, J=13.4Hz, 1H), 1.62–1.51 (m, 1H), 1.39 (ddd, J=31.2, 18.8, 12.2Hz, 1H).

Example 17: (2-Chloro-4-((2,3-dihydrobenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl) ) Preparation of tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 26) (prepared according to Scheme 2)

Step 17a: Preparation of 2,3-dihydrobenzofuran-7-ol (compound 0201-26): To benzofuran-7-ol (700 mg, 6.25 mmol, 1.0 equiv) in methanol under nitrogen Palladium on carbon (140 mg, 20%) was added to the solution (10 mL), and the mixture was stirred at room temperature for 16.0 hours. After filtration, the resulting filtrate was concentrated under reduced pressure. The residue was used directly in the next step without further purification. LCMS (ESI): m/z=135[M-1] ^- .

Step 17b: Preparation of methyl 2-chloro-4-((2,3-dihydrobenzofuran-7-yl)oxy)benzoate (compound 0202-26): under nitrogen To a solution of dihydrobenzofuran-7-ol (0201-26) (830 mg, 6.10 mmol, 1.0 equiv) in N,N-dimethylformamide (15 mL) was added 2-chloro-4-fluorobenzene Methyl formate (0102-1) (1.15 g, 6.10 mmol, 1.0 equiv), potassium carbonate (1.68 g, 12.20 mmol, 2.0 equiv), the mixture was stirred at 90°C overnight. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether/ethyl acetate=20/1 to 10/1) to obtain 2-chloro-4-((2,3-dihydrobenzofuran-7-yl)oxy as a white solid product yl) methyl benzoate (1.4 g, yield: 75.51%). LCMS(ESI): m/z=305[M+1]+.

Step 17c: Preparation of 2-chloro-4-((2,3-dihydrobenzofuran-7-yl)oxy)benzoic acid (compound 0203-26): To 2-chloro-4-(((2, To a solution of methyl 3-dihydrobenzofuran-7-yl)oxy)benzoate (0202-26) (1.9 g, 6.29 mmol, 1.0 equiv) in tetrahydrofuran (5 mL) was added 2M sodium hydroxide solution ( 15 mL) and the mixture was stirred at room temperature overnight. The reaction solution was adjusted to pH=4 with 4M hydrochloric acid, and extracted with ethyl acetate. The resulting organic phase was dried and concentrated under reduced pressure. The residue was used directly in the next step without further purification. LCMS(ESI): m/z=291[M+1]+.

Step 17d: Preparation of 2-chloro-4-((2,3-dihydrobenzofuran-7-yl)oxy)benzoyl chloride (compound 0204-26): under nitrogen at 0°C, to 2 -Chloro-4-((2,3-dihydrobenzofuran-7-yl)oxy)benzoic acid (0203-26) (500 mg, 1.72 mmol, 1.0 equiv) in tetrahydrofuran (20 mL) Oxalyl chloride (657 mg, 5.17 mmol, 3.0 equiv), N,N-dimethylformamide (1 mg) were added and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure. The residue was used directly in the next step without further purification.

Step 17e: (2-Chloro-4-((2,3-dihydrobenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidine- Preparation of 5-yl)methanone (compound 0205-26): under nitrogen protection, 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0106-1) (400 mg, 1.72 mmol, 1.0 equiv) in tetrahydrofuran (15 mL) was added sodium hydride (207 mg, 5.17 mmol, 3.0 equiv), then slowly n-butyllithium (0.89 mL, 2.32 mmol) was added dropwise at -70°C mmol, 1.3 equiv) and stirred for 1.0 h. 2-Chloro-4-((2,3-dihydrobenzofuran-7-yl)oxy)benzoyl chloride (0204-26) (520 mg, crude) was dissolved in 3 mL of tetrahydrofuran at -70°C It was added dropwise to the reaction solution and stirred for 1.5 hours. The reaction solution was quenched with ammonium chloride solution, diluted with water and extracted with ethyl acetate, the organic phase was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether/ethyl acetate = 15/1 to 2/1) to give the product (2-chloro-4-((2,3-dihydrobenzofuran-7-yl)) as a yellow solid oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (400 mg, yield: 54.6%). LCMS(ESI): m/z=426[M+1]+

Step 17f: (2-Chloro-4-((2,3-dihydrobenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl) Preparation of tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 26): To (2-chloro-4-( (2,3-Dihydrobenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (0205-26) (100 mg, 0.235 mmol, 1.0 equiv) and ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol hydrochloride (0108-1) (37 mg, 0.282 mmol) , 1.2 equiv.) To a mixture of tert-butanol (10 mL) was added N,N-diisopropylethylamine (0.5 mL). The mixture was heated at 90°C overnight. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (dichloromethane/methanol=12/1) to give the product (2-chloro-4-((2,3-dihydrobenzofuran-7-yl)oxy) as a yellow solid Phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5 -yl)methanone (38 mg, yield: 31.1%). MS (ES ⁺ ): m/z=521 (M+H) ⁺ . ¹ H NMR (500MHz, DMSO) δ 12.69 (s, 1H), 8.58 (d, J=7.1 Hz, 1H), 8.24 (s ,1H),7.61–7.51(m,2H),7.19(d,J＝7.2Hz,1H),7.07(d,J＝2.2Hz,1H),7.00(d,J＝8.0Hz,1H),6.95 –6.87(m,2H),4.69–4.53(m,3H),4.18–4.05(m,2H),3.43(dd,J=11.8,6.5Hz,1H),3.35(s,2H),3.27(d , J＝8.7Hz, 2H), 3.12(t, J＝11.4Hz, 1H), 2.19(d, J＝11.4Hz, 1H), 1.79(d, J＝13.0Hz, 1H), 1.63–1.49(m ,1H),1.43–1.32(m,1H).

Example 18: (4-(benzofuran-4-yloxy)-2-chlorophenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran Preparation of -3-yl)amino)-7H-pyrro[2,3-d]pyrimidin-5-yl)methanone (Compound 27) (prepared according to Scheme 3)

Step 18a: Preparation of Benzofuran-4-ol (Compound 0301-27):

To 2,6-dihydroxybenzaldehyde (1.5 g, 11 mmol, 1.0 equiv) and diisopropylethylamine (2.84 g, 22 mmol, 2.0 equiv) in dichloromethane (30 mL) at 0 °C ) was added dropwise MOMBr (2.06 g, 16.5 mmol, 1.5 equiv). The mixture was stirred at 0°C for 30 minutes and at room temperature for 1 hour. Dichloromethane was added to extract and washed with water and brine. The organic phase was dried and concentrated, and purified by silica gel column (eluent: petroleum ether/ethyl acetate=20/1) to give the product. Under nitrogen, the product (1.8 g, 9.9 mmol, 1.0 equiv), ethyl 2-bromoacetate (2.5 g, 14.8 mmol, 1.5 equiv) and cesium carbonate (6.45 g, 619.8 mmol, 2.0 equiv) were combined A solution of N,N-dimethylformamide (50 mL) was stirred at 120 °C overnight. The reaction solution was cooled, diluted with water, and extracted with ethyl acetate. The organic phase was dried and concentrated in vacuo to give the product 4-(methoxymethoxy)benzofuran-2-carboxylic acid (1.8 g, yield: 81.9%) as a brown solid.

To a solution of 4-(methoxymethoxy)benzofuran-2-carboxylic acid (1.8 g, 8.1 mmol, 1.0 equiv) in quinoline (30 mL) was added copper powder (1.56 g, 24.3 g) under nitrogen mmol, 3.0 equiv), the mixture was stirred at 120 °C overnight. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure to give 4-(methoxymethoxy)benzofuran (1.4 g, crude product) as a yellow oily product.

Compound 4-(methoxymethoxy)benzofuran (1.4 g, crude) was dissolved in methanol (20 mL), and then 4N hydrochloric acid (20 mL) was added. The mixture was stirred at room temperature for 1.5 hours. The reaction was diluted with water and extracted with ethyl acetate, the organic phase was dried and concentrated in vacuo. The residue was purified by silica gel column (eluent: petroleum ether/ethyl acetate=10/1) to obtain the product benzofuran-4-ol (1.08 g, yield: 100%) as a yellow oil.

Step 18b: Preparation of methyl 4-(benzofuran-4-yloxy)-2-chlorobenzoate (compound 0302-27): To benzofuran-4-ol (0301-27) under nitrogen (0.6 g, 4.48 mmol, 1.0 equiv) in N,N-dimethylformamide (30 mL) was added methyl 2-chloro-4-fluorobenzoate (0102-1) (844 mg, 4.48 mmol) mol, 1.0 equiv), potassium carbonate (1.24 g, 8.96 mmol, 2.0 equiv), and the mixture was stirred at 90°C overnight. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether/ethyl acetate = 100/1 to 50/1) to obtain methyl 4-(benzofuran-4-yloxy)-2-chlorobenzoate (0.9 g, yield: 66.5%). LCMS (ESI): m/z=303[M+1]+.

Step 18c: Preparation of 4-(benzofuran-4-yloxy)-2-chlorobenzoic acid (compound 0303-27): To 4-(benzofuran-4-yloxy)-2-chlorobenzene To a solution of methyl formate (0302-27) (0.9 g, 2.97 mmol, 1.0 equiv) in tetrahydrofuran (2 mL) was added 2M sodium hydroxide solution (6 mL) and the mixture was stirred at room temperature overnight. The reaction solution was adjusted to pH=4 with 4M hydrochloric acid, and extracted with ethyl acetate. The resulting organic phase was dried and concentrated under reduced pressure. The residue was used directly in the next step without further purification. LCMS(ESI): m/z=289[M+1]+.

Step 18d: Preparation of 4-(benzofuran-4-yloxy)-2-chlorobenzoyl chloride (compound 0304-27): under nitrogen protection, at 0 °C, to 4-(benzofuran-4- oxy)-2-chlorobenzoic acid (0303-27) (0.59 g, 2.05 mmol, 1.0 equiv) in dichloromethane (10 mL) was added oxalyl chloride (520.7 mg, 4.1 mmol, 2.0 equiv) , N,N-dimethylformamide (5 mg), and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure. The residue was used directly in the next step without further purification.

Step 18e: (4-(benzofuran-4-yloxy)-2-chlorophenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (compound 0305-27): under nitrogen, 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0106-1) (475.6 mg, 2.05 mmol, 1.0 equiv) was added to To the mixture in tetrahydrofuran (10 mL) was added NaH (246 mg, 6.15 mmol at 0°C, 3.0 equiv). The mixture was stirred at room temperature for 1.0 hours. Then n-butyl (1.54 mL, 2.46 mmol, 1.2 equiv) was added dropwise at -70°C and stirred for 1.0 h. Then a tetrahydrofuran solution (1 mL) of 4-(benzofuran-4-yloxy)-2-chlorobenzoyl chloride (0304-27) was added dropwise to the reaction solution at -70°C, and stirred for 1.0 hours . The reaction solution was quenched with _NH4Cl solution and extracted with ethyl acetate, then the organic phase was dried and concentrated in vacuo. The residue was purified by silica gel column (eluent: petroleum ether/ethyl acetate=5/1) to give a yellow solid product (4-(benzofuran-4-yloxy)-2-chlorophenyl) (4 -Chloro-7H-pyrro[2,3-d]pyrimidin-5-yl)methanone (450 mg, yield: 51.9%). LCMS (ESI): m/z=424[M+1] ⁺ .

Step 18f: (4-(benzofuran-4-yloxy)-2-chlorophenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran- Preparation of 3-yl)amino)-7H-pyrro[2,3-d]pyrimidin-5-yl)methanone (Compound 27): To (4-(benzofuran-4-yloxy)-2- Chlorophenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (0305-27 (100 mg, 0.236 mmol, 0.54 equiv) and ((2S,5R) -5-Aminotetrahydro-2H-pyran-2-yl)methanol hydrochloride (0108-1) To a mixture of tert-butanol (10 mL) was added N,N-diisopropylethylamine (1.0 mL) ). The mixture was heated at 90°C overnight. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (dichloromethane/methanol=12/1) to give a yellow color Solid product (4-(benzofuran-4-yloxy)-2-chlorophenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3 -yl)amino)-7H-pyrrole[2,3-d]pyrimidin-5-yl)methanone (50 mg, yield: 40.9%). MS (ES ⁺ ): m/z=519 (M+H ) ⁺ . ¹ H NMR(500MHz, DMSO)δ12.72(s,1H),8.58(d,J=7.1Hz,1H),8.25(s,1H),8.02(d,J=2.2Hz,1H) ,7.62(s,1H),7.57(d,J＝8.5Hz,1H),7.53(d,J＝8.3Hz,1H),7.39(t,J＝8.1Hz,1H),7.25(d,J＝ 2.4Hz, 1H), 7.04 (dd, J=8.4, 2.5Hz, 2H), 6.86–6.80 (m, 1H), 4.61 (t, J=5.6Hz, 1H), 4.16 (dt, J=10.9, 6.4 Hz, 2H), 3.47–3.40 (m, 1H), 3.39–3.33 (m, 2H), 3.12 (t, J=11.6Hz, 1H), 2.19 (d, J=12.0Hz, 1H), 1.79 (d , J=13.6Hz, 1H), 1.57 (dd, J=11.9, 3.8Hz, 1H), 1.45–1.33 (m, 1H).

Example 19: (4-(benzo[d]oxazol-7-yloxy)-2-chlorophenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro- Preparation of 2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 28) (prepared according to Scheme 1)

Step 19a: Preparation of 7-hydroxybenzoxazole (compound 0101-28):

To a mixture of 2-methoxy-6-nitrophenol (1.0 g, 5.92 mmol, 1.0 equiv) in dichloromethane (30 mL) was added boron tribromide (2M in dichloromethane) dropwise at 0°C , 4.4 mL, 8.80 mmol, 1.5 equiv). The mixture was warmed to room temperature and stirred overnight. The reaction was quenched by the addition of methanol (10 mL). Water (50 mL) was added and extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated to give 3-nitrocatechol (1.06 g, crude product) as a brown oil. LCMS (ESI): m/z 156 [M+1] ⁺ ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=3:1).

To a mixture of 3-nitrocatechol (1.0 g, 6.45 mmol, 1.0 equiv) in methanol (15 mL) was added palladium on carbon (200 mg). The mixture was stirred at room temperature overnight under hydrogen balloon pressure. The mixture is filtered. The filtrate was concentrated under reduced pressure to give 3-aminocatechol ((806 mg, yield: 100%) as a brown solid. LCMS (ESI): m/z 126 [M+1] ⁺ ; TLC: Rf 0.3 ( Petroleum ether:ethyl acetate=3:1).

To a mixture of 3-aminocatechol (806 mg, 6.45 mmol, 1.0 equiv) and p-toluenesulfonic acid monohydrate (123 mg, 0.65 mmol, 0.1 equiv) in ethanol (15 mL) was added orthoformic acid Trimethyl ester (4.79 g, 45.15 mmol, 7.0 equiv). The mixture was heated to 90°C under nitrogen atmosphere for 3 hours. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 2:1) to obtain 7-hydroxybenzoxazole (575 mg, yield: 66%) as a pale yellow solid. LCMS (ESI): m/z 136 [M+1] ⁺ ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=1:1).

Step 19b: Preparation of tert-butyl 2-chloro-4-fluorobenzoate (compound 0102-28): To 2-chloro-4-fluorobenzoic acid (2.0 g, 11.46 mmol, 1.0 equiv) and N,N- To a mixture of dimethylformamide (2 drops) in dichloromethane (20 mL) was added oxalyl chloride (1.94 mL, 22.91 mmol, 2.0 equiv). The mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL) to give a solution of 2-chloro-4-fluorobenzoyl chloride. To a mixture of tert-butanol (1.32 mL, 13.75 mmol, 1.2 equiv) in tetrahydrofuran (15 mL) was added dropwise n-butyllithium (2.5M in hexanes, 5.04 mL, 12.61 mL) at 0°C under nitrogen mmol, 1.1 equiv). The mixture was stirred for 10 minutes. A solution of 2-chloro-4-fluorobenzoyl chloride in tetrahydrofuran was added dropwise, and the mixture was stirred at 0°C for 1 hour. The reaction was quenched by the addition of saturated ammonium chloride solution (30 mL). The aqueous layer was extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was subjected to column chromatography on silica gel (petroleum ether:ethyl acetate 50:1) to give tert-butyl 2-chloro-4-fluorobenzoate (1.88 g, yield: 71%) as a pale yellow oil. TLC: Rf 0.5 (petroleum ether:ethyl acetate=20:1).

Step 19c: Preparation of tert-butyl 4-(benzo[d]oxazol-7-yloxy)-2-chlorobenzoate (compound 0103-28): To 7-hydroxybenzoxazole (0101-28 ) (275 mg, 2.04 mmol, 1.0 equiv) and potassium carbonate (366 mg, 2.65 mmol, 1.3 equiv) in N,N-dimethylformamide (5 mL) was added 2-chloro-4- tert-Butyl fluorobenzoate (0102-28) (705 mg, 3.06 mmol, 1.5 equiv). The mixture was heated at 90°C under nitrogen atmosphere overnight. The mixture was diluted with water (30 mL), then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 8:1) to give tert-butyl 4-(benzo[d]oxazol-7-yloxy)-2-chlorobenzoate (390 wt ) as a white solid mg, yield: 49%). LCMS (ESI): m/z 346[M+1] ⁺ ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=4:1).

Step 19d: Preparation of 4-(benzo[d]oxazol-7-yloxy)-2-chlorobenzoic acid (compound 0104-28): To 4-(benzo[d]oxazol-7-yl oxy)-2-chlorobenzoic acid tert-butyl ester (0103-28) (390 mg, 1.13 mmol, 1.0 equiv) in dichloromethane (7.5 mL) was added trifluoroacetic acid (2.5 mL). The mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure. The residue was diluted with trimethyl orthoformate (8 mL), and the mixture was heated to 90°C for 2.5 hours. The solvent was removed under reduced pressure. The residue was diluted with dichloromethane (10 mL) and filtered. The solid was collected and dried under vacuum to give 4-(benzo[d]oxazol-7-yloxy)-2-chlorobenzoic acid (256 mg, yield: 78%) as a white solid. LCMS (ESI): m/z 290 [M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol=10:1).

Step 19e: Preparation of 4-(benzo[d]oxazol-7-yloxy)-2-chlorobenzoyl chloride (compound 0105-28): To 4-(benzo[d]oxazol-7- oxy)-2-chlorobenzoic acid (0104-28) (226 mg, 0.78 mmol, 1.0 equiv) and N,N-dimethylformamide (2.3 mg, 0.031 mmol, 0.04 equiv) in dichloro To a mixture of methane (15 mL) and tetrahydrofuran (15 mL) was added oxalyl chloride (0.13 mL, 1.56 mmol, 2.0 equiv). The mixture was stirred at room temperature for 5 hours. The solvent was removed under reduced pressure and dried under vacuum to give 4-(benzo[d]oxazol-7-yloxy)-2-chlorobenzoyl chloride (241 mg, crude) as a pale yellow oil.

Step 19f: (4-(Benzo[d]oxazol-7-yloxy)-2-chlorophenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl) Preparation of methyl ketone (compound 0107-28): To a mixture of sodium hydride (60%, 125 mg, 3.12 mmol, 2.0 equiv) in tetrahydrofuran (3.5 mL) was added 5-bromo-4-chloro- 7H-pyrrolo[2,3-d]pyrimidine (0106-1) (364 mg, 1.56 mmol, 1.0 equiv). The mixture was stirred at room temperature for 10 minutes and then cooled to -78°C. n-Butyllithium (2.5M in hexanes, 0.75 mL, 1.87 mmol, 1.2 equiv) was added dropwise and stirred for 1 hour. A solution of 4-(benzo[d]oxazol-7-yloxy)-2-chlorobenzoyl chloride (0105-28) (241 mg, 0.78 mmol, 1.0 equiv) in tetrahydrofuran (1.5 mL) was added dropwise , and then stirred at -78°C for 1 hour. The reaction was quenched by the addition of saturated aqueous ammonium chloride (30 mL). The aqueous layer was extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was subjected to column chromatography on silica gel (petroleum ether:ethyl acetate 1:1) to give (4-(benzo[d]oxazol-7-yloxy)-2-chlorophenyl)(4- Chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (110 mg, yield: 33%). LCMS (ESI): m/z 425 [M+1] ⁺ ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=1:3).

Step 19g: (4-(Benzo[d]oxazol-7-yloxy)-2-chlorophenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H Preparation of -pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 28): To 4-(benzo[d]oxazole-7 -yloxy)-2-chlorophenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (compound 0107-28) (90 mg, 0.21 mmol, 1.0 equiv) and ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol hydrochloride (0108-1) (36 mg, 0.28 mmol, 1.3 equiv) in dimethyl To the mixture of sulfoxide (3 mL) was added N,N-diisopropylethylamine (0.19 mL, 1.06 mmol, 5.0 equiv). The mixture was heated to 88°C under nitrogen atmosphere for 6 hours. The mixture was diluted with water (30 mL), then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (dichloromethane:methanol=10:1) to give (4-(benzo[d]oxazol-7-yloxy)-2-chlorophenyl)(4) as a white solid -(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (39 mg, yield: 35%). LCMS (ESI): m/z 520 [M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol=10:1); melting point: 156-159°C. ¹ H NMR (500MHz, DMSO) δ 12.73(s, 1H), 8.79(s, 1H), 8.57(d, J=7.1Hz, 1H), 8.25(s, 1H), 7.71(d, J=7.7 Hz, 1H), 7.62(s, 1H), 7.59(d, J=8.5Hz, 1H), 7.46(t, J=8.0Hz, 1H), 7.35(d, J=2.4Hz, 1H), 7.29( d, J=8.0Hz, 1H), 7.10 (dd, J=8.5, 2.4Hz, 1H), 4.62 (t, J=5.6Hz, 1H), 4.20–4.10 (m, 2H), 3.47–3.39 (m ,1H),3.39–3.34(m,2H),3.11(d,J＝11.8Hz,1H),2.19(d,J＝12.8Hz,1H),1.79(d,J＝13.5Hz,1H),1.61 –1.50(m,1H),1.39(ddd,J=30.5,16.8,7.1Hz,2H).

Example 20: (4-(((1H-Indol-7-yl)oxy)-2-chlorophenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro- Preparation of 2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 29) (prepared according to Scheme 1)

Step 20a: Preparation of tert-butyl 7-(3-chloro-4-(methoxycarbonyl)phenoxy)-1H-indole-1-carboxylate (compound 0103-29): under nitrogen Indol-7-ol (0101-29) (1.50 g, 11.27 mmol, 1.0 equiv) in N,N-dimethylformamide (15 mL) was added methyl 2-chloro-4-fluorobenzoate Ester (0102-1) (2.55 g, 13.52 mmol, 1.2 equiv) and potassium carbonate (2.46 g, 17.80 mmol, 1.5 equiv). The mixture was stirred at 90°C overnight. The mixture was diluted with water (75 mL) and extracted with ethyl acetate (75 mL x 3). The combined organic layers were washed with saturated brine (75 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate=8:1) to give methyl 4-((1H-indol-7-yl)oxy)-2-chlorobenzoate (1.55 g, Yield: 46%) LCMS (ESI): m/z 302 [M+1] ⁺ . The above obtained methyl 4-((1H-indol-7-yl)oxy)-2-chlorobenzoate (500 mg, 1.66 mmol, 1.0 equiv), di-tert-butyl dicarbonate (435 mg, 1.99 mmol, 1.2 equiv), N,N-diisopropylethylamine (430 mg, 3.32 mmol, 2.0 equiv) and 4-dimethylaminopyridine (4 mg, 0.02 mmol, 0.01 equiv) in dichloro A mixture of methane (8 mL) was stirred at room temperature overnight. The mixture was diluted with water (15 mL) and extracted with dichloromethane (15 mL x 3). The combined organic layers were washed with saturated brine (15 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate=10:1) to give 7-(3-chloro-4-(methoxycarbonyl)phenoxy)-1H-indole-1- as a yellow oil tert-Butyl formate (620 mg, yield: 93%) LCMS (ESI): m/z 402 [M+1] ⁺ .

Step 20b: 7-(3-Chloro-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenoxy)-1H-indole-1-carboxylic acid tert-butyl ester Preparation of (compound 0107-29): To 5-bromo-4-chloro-7H-pyrrole[2,3-d]pyrimidine (0106-1) (140 mg, 0.599 mmol, 1.2 equiv.) To a mixture of tetrahydrofuran solution (5 mL) was added sodium hydride (40 mg, 0.998 mmol, 2.0 equiv). The mixture was stirred at room temperature for 1 hour. To the mixture was added n-butyllithium (0.41 mL, 0.649 mmol, 1.3 equiv) dropwise at -70°C, and the mixture was stirred at -70°C for 1 hour. Then to the mixture was slowly added tert-butyl 7-(3-chloro-4-(methoxycarbonyl)phenoxy)-1H-indole-1-carboxylate (0103-29) (200 mg, 0.499 mmol, 1.0 equiv) in tetrahydrofuran (2 mL), and the mixture was stirred at -70°C for 1 hour. The reaction was quenched with saturated ammonium chloride solution (5 mL). The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (15 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate=1:3) to give 7-(3-chloro-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5) as a yellow solid -Carbonyl)phenoxy)-1H-indole-1-carboxylic acid tert-butyl ester (80 mg, yield: 31%), LCMS (ESI): m/z 523 [M+1] ⁺ .

Step 20c: (4-(((1H-Indol-7-yl)oxy)-2-chlorophenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H Preparation of -pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (compound 29): under nitrogen protection, transfer to 7-(3-chloro-4 -(4-Chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenoxy)-1H-indole-1-carboxylic acid tert-butyl ester (80 mg, 0.154 mmol, 1.0 equiv) and ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol hydrochloride (43 mg, 0.185 mmol, 1.2 equiv) in tert-butanol (5 mL) was added N,N-Diisopropylethylamine (2 mL). The mixture was heated at 90°C overnight. The mixture was diluted with water (15 mL), then extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with saturated common salt Washed with water (20 mL x 1), dried over anhydrous sodium sulfate and concentrated to give a yellow solid 7-(3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro- 2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenoxy)-1H-indole-1-carboxylic acid tert-butyl ester (100 mg, crude ). LCMS (ESI): m/z 618[M+1] ⁺ . The 7-(3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrakis obtained above were Hydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenoxy)-1H-indole-1-carboxylic acid tert-butyl ester (100 mg , 0.162 mmol, 1.0 equiv) in methanolic hydrogen chloride (4M solution, 3 mL) was stirred for 1 h at 45° C. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (dichloromethane:methanol=10:1) to give a yellow solid (4 -(((1H-Indol-7-yl)oxy)-2-chlorophenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3 -yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (19 mg, yield: 23%). LCMS (ESI): m/z 518 [M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane: methanol = 10: 1). ¹ H NMR (500 MHz, DMSO) δ 11.33 (s, 1H), 8.60 (d, J = 7.1 Hz, 1H), 8.20 (s ,1H),7.51(d,J＝8.5Hz,1H),7.47(d,J＝7.8Hz,2H),7.35(t,J＝2.7Hz,1H),7.14( d, J=2.3Hz, 1H), 7.04 (t, J=7.8Hz, 1H), 6.94 (dd, J=8.5, 2.4Hz, 1H), 6.89 (d, J=7.5Hz, 1H), 6.54– 6.47(m, 1H), 4.64(s, 1H), 4.18–4.01(m, 3H), 3.41(d, J=5.8Hz, 2H), 3.10(t, J=10.0Hz, 1H), 2.18(d , J=11.9Hz, 1H), 1.82–1.74 (m, 1H), 1.55 (dd, J=12.0, 3.8Hz, 1H), 1.37 (dd, J=14.7, 4.3Hz, 1H).

Example 21: (2-Chloro-4-((1-methyl-1H-indol-7-yl)oxy)phenyl)[4-(((3R,6S)-6-(hydroxymethyl ) Preparation of tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 30) (prepared according to Scheme 1)

Step 21a: Preparation of methyl 2-chloro-4-((1-methyl-1H-indol-7-yl)oxy)benzoate (compound 0103-30): under nitrogen -7-ol (0101-29) (1.50 g, 11.27 mmol, 1.0 equiv) To a mixture of N,N-dimethylformamide (15 mL) was added methyl 2-chloro-4-fluorobenzoate ( 0102-1) (2.55 g, 13.52 mmol, 1.2 equiv) and potassium carbonate (2.46 g, 17.80 mmol, 1.5 equiv). The mixture was stirred at 90°C overnight. The mixture was diluted with water (75 mL) and extracted with ethyl acetate (75 mL x 3). The combined organic layers were washed with saturated brine (75 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate=8:1) to give methyl 4-((1H-indol-7-yl)oxy)-2-chlorobenzoate (1.55 g, Yield: 46%) LCMS (ESI): m/z 302 [M+1] ⁺ . Under nitrogen, at 0 °C, methyl 4-((1H-indol-7-yl)oxy)-2-chlorobenzoate (500 mg, 1.66 mmol, 1.0 equiv) obtained above and carbonic acid were added To a mixture of potassium (457 mg, 3.31 mmol, 2.0 equiv) in N,N-dimethylformamide (10 mL) was added methyl iodide (353 mg, 2.48 mmol, 1.5 equiv). The mixture was stirred at room temperature for 3 hours. The mixture was diluted with water (50 mL), then extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (50 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (petroleum ether:dichloromethane=3:2) to give methyl 2-chloro-4-((1-methyl-1H-indol-7-yl)oxy)benzoate as a yellow solid Ester (460 mg, yield: 88%) LCMS (ESI): m/z 316 [M+1] ⁺ .

Step 21b: (2-Chloro-4-((1-methyl-1H-indol-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidine- Preparation of 5-yl)methanone (compound 0107-30): To 5-bromo-4-chloro-7H-pyrro[2,3-d]pyrimidine (0106-1) (88 mg, 0.380 mmol, 1.2 equiv) in tetrahydrofuran solution (5 mL) was added sodium hydride (25 mg, 0.633 mmol, 2.0 equiv). The mixture was stirred at room temperature for 1 hour. The mixture was added dropwise n-butyllithium (0.26 mL, 0.411 mmol, 1.3 equiv) at -70°C, and the mixture was stirred at -70°C for 1 hour. To the mixture was then slowly added methyl 2-chloro-4-((1-methyl-1H-indol-7-yl)oxy)benzoate (0103-30) (100 mg, 0.316 mmol, 1.0 equiv) tetrahydrofuran solution (2 mL), and the mixture was stirred at -70 °C for 1 hour. The reaction was quenched with saturated ammonium chloride solution (5 mL). The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (15 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate:dichloromethane=1:1:1) to give (2-chloro-4-((1-methyl-1H-indol-7-yl) as a yellow solid )oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (100 mg, yield: 73%), LCMS (ESI): m/z 437[M+1] ⁺ .

Step 21c: (2-Chloro-4-((1-methyl-1H-indol-7-yl)oxy)phenyl)[4-(((3R,6S)-6-(hydroxymethyl) Preparation of tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (compound 30): under nitrogen -4-((1-Methyl-1H-indol-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone ( 0107-30) (100 mg, 0.229 mmol, 1.0 equiv) and ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol hydrochloride (0108-1) (65 mg , 0.275 mmol, 1.2 equiv) to a mixture of tert-butanol (5 mL) was added N,N-diisopropylethylamine (2 mL). The mixture was heated at 90°C overnight. The mixture was diluted with water (15 mL), then extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (dichloromethane:methanol=10:1) to give (2-chloro-4-((1-methyl-1H-indol-7-yl)oxy)benzene as a yellow solid yl)[4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5- yl)methanone (67 mg, 55% yield). LCMS (ESI): m/z 532 [M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol=10:1). ¹ H NMR(500MHz,DMSO)δ12.96-12.28(m,1H),8.58(d,J=7.1Hz,1H),8.23(s,1H),7.61-7.53(m,2H),7.47(d ,J=7.5Hz,1H),7.32(d,J=3.0Hz,1H),7.14(d,J=2.4Hz,1H),7.05(t,J=7.8Hz,1H),6.95(dd,J =8.5,2.4Hz,1H),6.87(d,J=7.5Hz,1H),6.51(d,J=3.0Hz,1H),4.64(s,1H),4.14(ddd,J=16.6,8.0, 4.9Hz, 2H), 3.85(s, 3H), 3.41(d, J＝6.6Hz, 3H), 3.10(d, J＝11.9Hz, 1H), 2.18(d, J＝12.0Hz, 1H), 1.78 (d, J=13.5Hz, 1H), 1.62–1.49 (m, 1H), 1.38 (dt, J=9.9, 8.0Hz, 1H).

Example 22: 2-Chloro-4-(naphthalen-1-yloxy)phenyl)(4-((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl ) Amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 32) Preparation (prepared according to Scheme 4)

Step 22a: Preparation of methyl 2-chloro-4-(naphthalen-1-yloxy)benzoate (compound 0402-32): methyl 2-chloro-4-fluorobenzoate (0102-1) (1.09 g, 5.78 mmol, 1.0 equiv), 1-naphthol (1 g, 6.94 mmol, 1.2 equiv), potassium carbonate (1.20 g, 8.67 mmol, 1.5 equiv) were dissolved in 15 mL of N,N-dimethyl in formamide. Under nitrogen, the mixture was stirred at 90°C for four hours, and water and ethyl acetate were added. The layers were separated, the organic phase was washed with saturated brine, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=20/1) to obtain 2-chloro-4-(naphthalene) as a red liquid Methyl-1-yloxy)benzoate (1.64 g, yield: 90.7%).

Step 22b: (2-Chloro-4-(naphthalen-1-yloxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 0403- 32) Preparation: Under nitrogen protection, 5-bromo-4-chloro-7H-pyrrole[2,3-d]pyrimidine (0106-1) (372 mg, 1.6 mmol, 1.0 equiv) was dissolved in 12 mL In dry tetrahydrofuran, the reaction system was cooled in an ice bath, sodium hydride (purity: 60%) (128 mg, 3.2 mmol, 2.0 equiv) was added, and the mixture was stirred at room temperature for 1 hour under nitrogen protection. The reaction was cooled in a dry ice-ethanol bath. At -70°C, 1.6M n-butyllithium n-hexane solution (1.3 mL, 2.08 mmol, 1.3 equiv) was added dropwise to the above mixture and stirred at -70°C for 1 hour. Methyl 2-chloro-4-(naphthalen-1-yloxy)benzoate (500 mg, 1.6 mmol, 1.0 equiv) was dissolved in 3 mL of tetrahydrofuran and the solution was added dropwise to the mixture at -70°C , stir for 1 hour. The reaction was quenched with aqueous ammonium chloride solution, extracted with ethyl acetate and water, the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1 to 2/ 1) A yellow solid was obtained (2-chloro-4-(naphthalen-1-yloxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (289.5 mg, yield: 42%). MS(ES ⁺ ): m/z=434(M+H) ⁺ .

Step 22c: 2-Chloro-4-(naphthalen-1-yloxy)phenyl)(4-((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl) Preparation of amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (compound 32): (2-chloro-4-(naphthalen-1-yloxy)phenyl)( 4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (0403-32) (100 mg, 0.23 mmol, 1.0 equiv), ((2S,5R)-5-amino Tetrahydro-2H-pyran-2-yl)methanol hydrochloride (58 mg, 0.35 mmol, 1.5 equiv), 1 mL diisopropylethylamine was dissolved in 10 mL tert-butanol. Under nitrogen, the mixture was stirred at 80°C overnight. Thin layer chromatography indicated no starting material. Ethyl acetate was added, washed with water, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was prepared by high performance liquid chromatography (acetonitrile/0.1% formic acid solution=40% to 80%) to obtain 2-chloro as a yellow solid -4-(Naphthalen-1-yloxy)phenyl)(4-((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrole and [2,3-d]pyrimidin-5-yl)methanone (25.5 mg, yield: 21%). MS (ES ⁺ ): m/z = 529 (M+H) ⁺ . ¹ H NMR (500MHz, DMSO) δ 8.58 (d, J = 7.1 Hz, 1H), 8.23 (s, 1H), 8.07–7.99 (m, 2H), 7.85 (d, J=8.4Hz, 1H), 7.69–7.50 (m, 5H), 7.31–7.21 (m, 2H), 7.02 (d, J=8.5Hz, 1H), 4.65 ( s, 1H), 4.37(t, J=4.8Hz, 1H), 4.14(s, 2H), 3.58(s, 2H), 3.12(d, J=10.5Hz, 1H), 2.17(s, 1H), 1.78(d,J＝14.0Hz,1H),1.56(d,J＝11.2Hz,1H),1.38(d,J＝11.8Hz,1H).

Example 23: (2-Chloro-4-(quinolin-8-yloxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran- Preparation of 3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 33) (prepared according to Scheme 4)

Step 23a: Preparation of methyl 2-chloro-4-(quinolin-8-yloxy)benzoate (compound 0402-33): under nitrogen protection, to quinolin-8-ol (0401-33) (0.92 g, 6.36 mmol, 1.2 equiv) in a mixture of N,N-dimethylformamide (15 mL) was added methyl 2-chloro-4-fluorobenzoate (0102-1) (1.00 g, 5.30 mmol) , 1.0 equiv) and potassium carbonate (1.10 g, 7.95 mmol, 1.5 equiv). The mixture was stirred at 90°C overnight. The mixture was diluted with water (75 mL), then extracted with ethyl acetate (75 mL x 3). The combined organic layers were washed with saturated brine (75 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate=1:1) to give methyl 2-chloro-4-(quinolin-8-yloxy)benzoate (800 mg, yield: 48) as a yellow solid %) LCMS (ESI): m/z 314 [M+1] ⁺ .

Step 23b: (2-Chloro-4-(quinolin-8-yloxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 0403 -33) Preparation: under nitrogen protection, at 0 °C, to 5-bromo-4-chloro-7H-pyrrole[2,3-d]pyrimidine (0106-1) (149 mg, 0.629 mmol, 1.0 equiv. ) to a mixture of tetrahydrofuran solution (5 mL) was added sodium hydride (51 mg, 1.28 mmol, 2.0 equiv). The mixture was stirred at room temperature for 1 hour. At -70°C, n-butyllithium (0.52 mL, 0.831 mmol, 1.3 equiv) was added dropwise to the mixture, and the mixture was stirred at -70°C for 1 hour. To the mixture was then slowly added a solution of methyl 2-chloro-4-(quinolin-8-yloxy)benzoate (0402-33) (200 mg, 0.629 mmol, 1.0 equiv) in tetrahydrofuran (2 mL) and the mixture Stir at -70°C for 1 hour. The reaction was quenched with saturated ammonium chloride solution (5 mL). The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (15 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate=1:3) to give (2-chloro-4-(quinolin-8-yloxy)phenyl)(4-chloro-7H-pyrrole) as a yellow solid and [2,3-d]pyrimidin-5-yl)methanone (52 mg, yield: 19%), LCMS (ESI): m/z 435 [M+1] ⁺ .

Step 23c: ((2-Chloro-4-(quinolin-8-yloxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran- Preparation of 3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (compound 33): under nitrogen protection, transfer to (2-chloro-4-(quinoline-8) -yloxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (0403-33) (45 mg, 0.104 mmol, 1.0 equiv) and ( To a mixture of (2R,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol (0108-1) (29 mg, 0.124 mmol, 1.2 equiv) in tert-butanol (5 mL) was added N,N-Diisopropylethylamine (68 mg, 0.52 mmol, 5.0 equiv). The mixture was heated at 90° C. overnight. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (dichloromethane:methanol=10:1) to give a yellow solid ((( 2-Chloro-4-(quinolin-8-yloxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino )-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (20 mg, 37% yield). LCMS (ESI): m/z 530 [M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol=10: ¹ ).1H NMR (500MHz, DMSO) δ 8.89 (dd, J=4.1, 1.6Hz, 1H), 8.59 (d, J=7.0Hz, 1H), 8.49 (dd,J=8.4,1.6Hz,1H),8.21(s,1H),7.94(d,J=8.2Hz,1H),7.69(t,J=7.9Hz,1H),7.64–7.59(m, 2H), 7.53–7.45(m, 2H), 7.10(d, J=2.4Hz, 1H), 6.89(dd, J=8.5, 2.4Hz, 1H), 4.63(s, 1H), 4.13(dt, J ＝11.6, 5.0Hz, 2H), 3.41(d, J＝5.4Hz, 2H), 3.35(s, 2H), 3.11(t, J＝10.0Hz, 1H), 2.18(d, J＝11.7Hz, 1H) ),1.78(d,J＝12.9Hz,1H),1.56(dd,J＝12.4,3.3Hz,1H),1.37(dd,J＝11.3,7.8Hz,1H).

Example 24: (4-(Benzo[d][1,3]dioxol-4-yloxy)-2-chlorophenyl)(4-(((3R,6S)-6 Preparation of -(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (compound 34) (according to Scheme II line preparation)

Step 24a: Preparation of methyl 4-(benzo[d][1,3]dioxol-4-yloxy)-2-chlorobenzoate (compound 0202-34): To benzo[ d][1,3]dioxol-4-ol (0201-34) (500 mg, 3.62 mmol, 1.0 equiv) and potassium carbonate (600 mg, 4.34 mmol, 1.2 equiv) in N, To the mixture of N-dimethylformamide (5 mL) was added methyl 2-chloro-4-fluorobenzoate (0102-1) (717 mg, 3.80 mmol, 1.05 equiv). The mixture was heated to 90°C under nitrogen atmosphere for 3.5 hours. The mixture was diluted with water (30 mL), then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 20:1) to give 4-(benzo[d][1,3]dioxol-4-yloxy)-2 as a white solid - Methyl chlorobenzoate (583 mg, yield: 53%). LCMS (ESI): m/z 307 [M+1] ⁺ ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=8:1).

Step 24b: (4-(Benzo[d][1,3]dioxol-4-yloxy)-2-chlorophenyl)(4-chloro-7H-pyrrolo[2,3 Preparation of -d]pyrimidin-5-yl)methanone (compound 0205-34): to a mixture of sodium hydride (60%, 15 mg, 0.378 mmol, 2.0 equiv) in tetrahydrofuran (3 mL) under nitrogen atmosphere 5-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0106-1) (44 mg, 0.189 mmol, 1.0 equiv) was added. The mixture was stirred at room temperature for 10 minutes and then cooled to -78°C. n-Butyllithium (2.5M in hexanes, 0.1 mL, 0.25 mmol, 1.3 equiv) was added dropwise and stirred for 1 hour. Methyl 4-(benzo[d][1,3]dioxol-4-yloxy)-2-chlorobenzoate (0202-34) (58 mg, 0.189 mmol, ) was added dropwise 1.0 equiv) in tetrahydrofuran (0.5 mL) and stirring was continued at -78°C for 1 hour. The reaction was quenched by the addition of saturated aqueous ammonium chloride (20 mL). The aqueous layer was extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with saturated brine (15 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was subjected to column chromatography on silica gel (petroleum ether:ethyl acetate 3:1) to give (4-(benzo[d][1,3]dioxol-4-yloxy)- 2-Chlorophenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (48 mg, yield: 59%). LCMS (ESI): m/z 428 [M+1] ⁺ ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=1:1).

Step 24c: (4-(Benzo[d][1,3]dioxol-4-yloxy)-2-chlorophenyl)(4-(((3R,6S)-6- Preparation of (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (compound 34): To (4- (Benzo[d][1,3]dioxol-4-yloxy)-2-chlorophenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5 -yl)methanone (0205-34) (48 mg, 0.112 mmol, 1.0 equiv) and ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol hydrochloride ( 0108-1) (24 mg, 0.146 mmol, 1.3 equiv) To a mixture of tert-butanol (8 mL) was added N,N-diisopropylethylamine (72 mg, 0.56 mmol, 5.0 equiv). The mixture was heated at 90°C under nitrogen atmosphere overnight. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (ethyl acetate:dichloromethane:methanol=10:10:2) to give a white solid (4-(benzo[d][1,3]dioxolane- 4-yloxy)-2-chlorophenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo [2,3-d]pyrimidin-5-yl)methanone (35 mg, yield: 60%). LCMS (ESI): m/z 523 [M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol=10:1); melting point: 153-156°C. ¹ HNMR (DMSO-d ₆ , 500MHz): δ 12.70(s, 1H), 8.57(d, J=7.0Hz, 1H), 8.24(s, 1H), 7.57(s, 1H), 7.55(s, 1H), 7.19(d, J＝2.0Hz, 1H), 7.04-7.02(m, 1H), 6.95-6.88(m, 2H), 6.78-6.76(m, 1H), 6.07(s, 2H), 4.63 -4.60(m, 1H), 4.17-4.12(m, 2H), 3.45-3.40(m, 1H), 3.36-3.30(m, 2H), 3.14-3.10(m, 1H), 2.21-2.18(m, 1H), 1.80-1.77 (m, 1H), 1.61-1.53 (m, 1H), 1.43-1.35 (m, 1H).

Example 25: (2-Chloro-4-((2,3-dihydrobenzo[b][1,4]dioxen-5-yl)oxy)phenyl))(4- (((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone ( Preparation of compound 35) (prepared according to scheme two)

Step 25a: Preparation of 2,3-dihydrobenzo[b][1,4]dioxen-5-ol (compound 0201-35): To pyrogallol (1.0 g, 7.93 mmol) , 1.0 equiv) and potassium carbonate (2.74 g, 19.83 mmol, 2.5 equiv) in acetonitrile (30 mL) was added 1,2-dibromoethane (2.23 g, 11.90 mmol, 1.5 equiv). The mixture was heated at 85°C overnight under nitrogen atmosphere. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 6:1) to give 2,3-dihydrobenzo[b][1,4]dioxen-5-ol (232) as a white solid mg, yield: 19%). LCMS (ESI): m/z 153 [M+1] ⁺ ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=3:1).

Step 25b: Methyl 2-chloro-4-((2,3-dihydrobenzo[b][1,4]dioxen-5-yl)oxy)benzoate (Compound 0202-35 ) preparation from 2,3-dihydrobenzo[b][1,4]dioxen-5-ol (0201-35) (232 mg, 1.526 mmol, 1.0 equiv) and potassium carbonate (253 mg, 1.831 mmol, 1.2 equiv) To a mixture of N,N-dimethylformamide (5 mL) was added methyl 2-chloro-4-fluorobenzoate (0102-1) (302 mg, 1.602 mmol, 1.05 equiv). The mixture was heated to 90°C under nitrogen atmosphere for 3 hours. The mixture was diluted with water (30 mL), then extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 20:1) to give 2-chloro-4-((2,3-dihydrobenzo[b][1,4]dioxane) as a white solid Methyl hexen-5-yl)oxy)benzoate (180 mg, yield: 37%). LCMS (ESI): m/z 321 [M+1] ⁺ ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=8:1).

Step 25c: (2-Chloro-4-((2,3-dihydrobenzo[b][1,4]dioxen-5-yl)oxy)phenyl)phenyl)(4 - Preparation of chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (compound 0205-35) by adding sodium hydride (60%, 45 mg, 1.126 mmol, 2.0 equiv.) To a mixture of tetrahydrofuran (4 mL) was added 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0106-1) (131 mg, 0.563 mmol, 1.0 equiv). The mixture was stirred at room temperature for 15 minutes and then cooled to -78°C. n-Butyllithium (2.5M in hexanes, 0.29 mL, 0.732 mmol, 1.3 equiv) was added dropwise and stirred for 1 hour. Methyl 2-chloro-4-((2,3-dihydrobenzo[b][1,4]dioxen-5-yl)oxy)benzoate (0202-35) was added dropwise (180 mg, 0.563 mmol, 1.0 equiv) in tetrahydrofuran (1.5 mL) and stirring was continued at -78°C for 1 hour. The reaction was quenched by the addition of saturated aqueous ammonium chloride (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with saturated brine (15 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was subjected to column chromatography on silica gel (petroleum ether:ethyl acetate 3:1) to give (2-chloro-4-((2,3-dihydrobenzo[b][1,4]dioxa) Cyclohexen-5-yl)oxy)phenyl)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (147 mg, yield: 59%) ). LCMS (ESI): m/z 442[M+1] ⁺ ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=1:1).

Step 25d: 2-Chloro-4-((2,3-Dihydrobenzo[b][1,4]dioxen-5-yl)oxy)phenyl))(4-(( (3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 35 ) preparation: to (2-chloro-4-((2,3-dihydrobenzo[b][1,4]dioxen-5-yl)oxy)phenyl)phenyl) (4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (0205-35) (70 mg, 0.158 mmol, 1.0 equiv) and ((2S,5R)-5- To a mixture of aminotetrahydro-2H-pyran-2-yl)methanol hydrochloride (0108-1) (34 mg, 0.205 mmol, 1.3 equiv) in tert-butanol (8 mL) was added N,N-di Isopropylethylamine (0.14 mL, 0.79 mmol, 5.0 equiv). The mixture was heated to 90°C under nitrogen atmosphere and reacted overnight. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (ethyl acetate:dichloromethane:methanol=10:10:2) to give 2-chloro-4-((2,3-dihydrobenzo[b][1] as a white solid ,4]dioxen-5-yl)oxy)phenyl))(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl )amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (55 mg, yield: 65%). LCMS (ESI): m/z 537 [M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol=10:1); melting point: 161-163°C. ¹ HNMR (DMSO-d ₆ , 500MHz): δ 12.69(s, 1H), 8.58(d, J=6.5Hz, 1H), 8.24(s, 1H), 7.56-7.52(m, 2H), 7.08( s,1H),6.93-6.88(m,2H),6.84-6.82(m,1H),6.76-6.74(m,1H),4.62(s,1H),4.26-4.20(m,4H),4.16- 4.06(m, 3H), 3.42-3.40(m, 1H), 3.18-3.10(m, 2H), 2.20-2.18(m, 1H), 1.79-1.77(m, 1H), 1.60-1.54(m, 1H) ), 1.42-1.33 (m, 1H).

Example 26: (4-(benzofuran-7-yloxy)-2-chlorophenyl)(4-(((3R,6S)-6-(((methylsulfonyl)methoxy)methane yl)tetrahydrofuran-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (compound 37) (prepared according to scheme 1)

Step 26a: Preparation of (3R,6S)-6-(((methylsulfonyl)methoxy)methyl)tetrahydro-2H-pyran-3-amine hydrochloride (compound 0108-37): To acetic acid (0.7 mL) To a mixture of dimethyl sulfoxide (3.5 mL) was added acetic anhydride (2.2 mL). The mixture was stirred at room temperature for 2 hours. tert-Butyl ((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)carbamate (90 mg, 0.390 mmol, 1.0 equiv) was added and the mixture was stirred overnight. The mixture was diluted with water (30 mL). The pH=8 was adjusted by adding solid sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with saturated brine (15 mL×1), dried over anhydrous sodium sulfate and concentrated to give a pale yellow oil ((3R,6S)-6-(((methylthio)methoxy) Methyl)tetrahydro-2H-pyran-3-yl)carbamate tert-butyl ester (108 mg, yield: 95%). LCMS (ESI): m/z 292[M+1] ⁺ . To tert-butyl ((3R,6S)-6-(((methylthiomethoxy)methyl)tetrahydro-2H-pyran-3-yl)carbamate (108 mg, 0.371 mmol) obtained above , 1.0 equiv) to a mixture of dichloromethane (6 mL) was added m-chloroperoxybenzoic acid (85%, 166 mg, 0.815 mmol, 2.2 equiv). The mixture was stirred at room temperature for 2 h. The mixture was water (20 mL). ) was diluted. Solid sodium bicarbonate was added to adjust pH=8. The aqueous layer was extracted with dichloromethane (15 mL×3). The combined organic layers were washed with saturated brine (15 mL×1), dried over anhydrous sodium sulfate and Concentration gave tert-butyl ((3R,6S)-6-(((methylsulfonyl)methoxy)methyl)tetrahydro-2H-pyran-3-yl)carbamate (126 mg) as a pale yellow oil , crude product). LCMS (ESI): m/z 324[M+1] ⁺ . The above obtained ((3R,6S)-6-(((methylsulfonyl)methoxy)methyl)tetrahydro- A mixture of tert-butyl 2H-pyran-3-yl)carbamate (116 mg, 0.359 mmol, 1.0 equiv) in methanolic hydrogen chloride (4M solution, 2 mL) was stirred at room temperature for 1 h. The solvent was removed under reduced pressure and the Drying under vacuum gave (3R,6S)-6-(((methylsulfonyl)methoxy)methyl)tetrahydro-2H-pyran-3-amine hydrochloride (93 mg, crude) as a white solid .LCMS (ESI): m/z 224[M+1] ⁺ .

Step 26b: (4-(benzofuran-7-yloxy)-2-chlorophenyl)(4-(((3R,6S)-6-(((methylsulfonyl)methoxy)methyl) ) Preparation of tetrahydrofuran-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 37): To (3R,6S)-6- ((Methylsulfonyl)methoxy)methyl)tetrahydro-2H-pyran-3-amine hydrochloride (0108-37) (48 mg, 0.215 mmol, 1.3 equiv) and (4-(benzol) Furan-7-yloxy)-2-chlorophenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (0107-1) (70 mg, 0.165 mm mol, 1.0 equiv) to a mixture of tert-butanol (5 mL) was added N,N-diisopropylethylamine (1 mL). The mixture was heated at 90°C overnight. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (dichloromethane:methanol=10:1) to give (4-(benzofuran-7-yloxy)-2-chlorophenyl)(4-(((( 3R,6S)-6-(((methylsulfonyl)methoxy)methyl)tetrahydrofuran-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5- yl)methanone (45 mg, 45% yield). LCMS (ESI): m/z 611 [M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol=10:1), melting point: 230-233°C. ¹ HNMR(500MHz,DMSO)δ8.60(d,J=7.2Hz,1H),8.22(s,1H),8.04(d,J=2.0Hz,1H),7.56(dd,J=15.1,7.6Hz) ,3H),7.32(t,J＝7.8Hz,1H),7.21(d,J＝2.3Hz,1H),7.17(d,J＝7.8Hz,1H),7.07(d,J＝2.1Hz,1H) ),7.01(dd,J=8.5,2.3Hz,1H),4.72-4.61(m,2H),4.23-4.03(m,2H),3.86-3.73(m,2H),3.64-3.56(m,1H) ),3.13(d,J=9.9Hz,1H),2.94(s,3H),2.19(d,J=11.8Hz,1H),1.75(d,J=12.4Hz,1H),1.60(dt,J =12.3,8.4Hz,1H),1.46(dt,J=24.0,6.5Hz,1H).

Example 27: (2-Chloro-4-((2-methylbenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-((methylsulfonyl) ) methyl) tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (compound 42) preparation (prepared according to scheme one route )

Step 27a: Preparation of (3R,6S)-6-((methylsulfonyl)methyl)tetrahydro-2H-pyran-3-amine hydrochloride (compound 0108-42): mixture ((2S,5R )-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-yl)methanesulfonic acid methyl ester (150 mg, 0.485 mmol, 1.0 equiv), sodium methanethiolate (170 mg) , 2.427 mmol, 5.0 equiv) and N,N-dimethylformamide (5 mL) were stirred at room temperature overnight. The mixture was diluted with water (25 mL), then extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (15 mL×1), dried over anhydrous sodium sulfate and concentrated to give ((3R,6S)-6-((methylthio)methyl)tetrahydro-2H as a yellow oil - tert-butyl pyran-3-yl)carbamate (138 mg, crude). LCMS (ESI): m/z 262[M+1] ⁺ . tert-butyl ((3R,6S)-6-((methylthio)methyl)tetrahydro-2H-pyran-3-yl)carbamate (138 mg, 0.528 mmol, 1.0 equiv) prepared above ) and m-chloroperoxybenzoic acid (183 mg, 1.057 mmol, 2.0 equiv) in dichloromethane (5 mL) were stirred at room temperature for 3 hours. The reaction solution was adjusted to pH=8 with saturated sodium bicarbonate solution. The mixture was diluted with water (15 mL) and extracted with dichloromethane (15 mL x 3). The combined organic layers were washed with saturated brine (15 mL×1), dried over anhydrous sodium sulfate and concentrated to give ((3R,6S)-6-(((methylsulfonyl)methyl)tetrahydro -2H-pyran-3-yl)carbamate tert-butyl ester (100 mg, crude). LCMS (ESI): m/z 294 [M+1] ⁺ . ((3R,6S)-6 obtained above -(((methylsulfonyl)methyl)tetrahydro-2H-pyran-3-yl)carbamate tert-butyl ester (70 mg, 0.239 mmol, 1.0 equiv) in hydrogen chloride-dioxane (4M solution, 1.5 mL) of the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and dried under vacuum to give (3R,6S)-6-((methylsulfonyl)methyl)tetrahydro-2H- as a yellow solid Pyran-3-amine hydrochloride (54 mg, crude). LCMS (ESI): m/z 229 [M+1] ⁺ .

Step 27b: (2-Chloro-4-((2-methylbenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-((methylsulfonyl) Preparation of methyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 42): To (3R,6S) -6-((Methylsulfonyl)methyl)tetrahydro-2H-pyran-3-amine hydrochloride (0108-42) (105 mg, 0.239 mmol, 1.0 equiv) and (2-chloro-4 -((2-Methylbenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (0107-2) (105 mg, 0.239 mmol, 1.0 equiv) To a mixture of tert-butanol (5 mL) was added N,N-diisopropylethylamine (2 mL). The mixture was heated at 90°C overnight. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (15 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (dichloromethane:methanol=10:1) to give ((2-chloro-4-((2-methylbenzofuran-7-yl)oxy)phenyl) as a yellow solid )(4-(((3R,6S)-6-((methylsulfonyl)methyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d] Pyrimidin-5-yl)methanone (37 mg, 26.1% yield). LCMS (ESI): m/z 595 [M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol=10:1), Melting point: 160° C. ¹ H NMR (500MHz, DMSO) δ 8.59(d, J=7.2Hz, 1H), 8.21(s, 1H), 7.56-7.50(m, 2H), 7.42(d, J=7.7 Hz, 1H), 7.23 (t, J=7.8Hz, 1H), 7.19 (d, J=2.4Hz, 1H), 7.04 (d, J=7.9Hz, 1H), 6.98 (dd, J=8.5, 2.4 Hz, 1H), 6.67 (d, J=0.9Hz, 1H), 4.19 (dd, J=10.5, 2.6Hz, 1H), 4.16–4.04 (m, 1H), 3.85 (dd, J=10.9, 8.4Hz) ,1H),3.47–3.40(m,1H),3.20–3.15(m,2H),2.98(s,3H),2.42(s,3H),2.16(d,J=11.7Hz,1H),1.87( d, J=12.8Hz, 1H), 1.65 (dd, J=12.1, 3.6Hz, 1H), 1.53 (d, J=14.2Hz, 1H).

Example 28: (2-Chloro-4-((2-methylbenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-((((methylsulfonyl) Preparation of acyl)methoxy)methyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 43) ( Prepared according to scheme 1)

To (3R,6S)-6-((methylsulfonyl)methoxy)methyl)tetrahydro-2H-pyran-3-amine hydrochloride (0108-37) (85 mg, 0.331 mmol, 1.0 equiv.) and (2-chloro-4-((2-methylbenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5- yl)methanone (0107-2) (145 mg, 0.331 mmol, 1.0 equiv) to a mixture of tert-butanol (5 mL) was added N,N-diisopropylethylamine (2 mL). The mixture was heated at 90°C overnight. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (dichloromethane:methanol=10:1) to give a yellow solid (2-chloro-4-((2-methylbenzofuran-7-yl)oxy)phenyl) [4-(((3R,6S)-6-(((methylsulfonyl)methoxy)methyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2, 3-d]pyrimidin-5-yl)methanone (51 mg, 24.8% yield). LCMS (ESI): m/z 625 [M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol=10:1), melting point: 160°C. ¹ HNMR(500MHz,DMSO)δ8.60(d,J=6.8Hz,1H),8.23(s,1H),7.56(d,J=8.3Hz,2H),7.44(d,J=7.4Hz,1H) ), 7.25(t, J＝7.9Hz, 1H), 7.21(s, 1H), 7.06(d, J＝7.8Hz, 1H), 7.01(d, J＝7.9Hz, 1H), 6.70(s, 1H) ),4.68(s,2H),4.18(d,J＝8.5Hz,2H),3.82(d,J＝5.7Hz,2H),3.60(s,1H),3.14(d,J＝10.2Hz,1H ), 2.95(s, 3H), 2.44(s, 3H), 2.19(s, 1H), 1.76(d, J=11.5Hz, 1H), 1.61(d, J=11.4Hz, 1H), 1.47(d ,J=11.8Hz,1H).

Example 29: (2-Chloro-4-((2-methylbenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(((2-(methyl) sulfonyl)ethoxy)methyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 44) Preparation (prepared according to Scheme 1)

Step 29a: Preparation of (3R,6S)-6-((2-(methylsulfonyl)ethoxy)methyl)tetrahydro-2H-pyran-3-amine hydrochloride (compound 0108-44) : under nitrogen protection, at 0 °C, to ((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)carbamate tert-butyl ester (120 mg, 0.519 mmol, 1.0 equiv) in tetrahydrofuran (10 mL) was added potassium tert-butoxide (116 mg, .038 mmol, 2.0 equiv), (methylsulfonyl)ethylene (220 mg, 2.078 mmol, 4.0 equiv), and the mixture was cooled at room temperature under stirring for 2.0 hours. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified with a silica gel column (dichloromethane/methanol=100/1 to 30/1) to obtain (3R,6S)-6-(((2-(methylsulfonyl)ethoxy)methan as a yellow oily product) yl)tetrahydro-2H-pyran-3-yl)carbamate tert-butyl ester (115 mg, yield: 65.7%). LCMS (ESI): m/z=338[M+1] ⁺ . ((3R,6S)-6-(((2-(methylsulfonyl)ethoxy)methyl)tetrahydro-2H-pyran-3-yl)carbamic acid tert-butyl ester obtained above (115 mg, 0.341 mmol, 1.0 equiv) in methanol of hydrogen chloride (4M solution, 2.5 mL) was stirred at room temperature for 1 h. The solvent was removed under reduced pressure and dried under vacuum to give (3R,6S)-6- as a white solid ((2-(Methylsulfonyl)ethoxy)methyl)tetrahydro-2H-pyran-3-amine hydrochloride (80 mg, crude). LCMS (ESI): m/z = 238 [M +1] ⁺ .

Step 29b: (2-Chloro-4-((2-methylbenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(((2-(methyl) Preparation of sulfonyl)ethoxy)methyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 44) : To (2-chloro-4-((2-methylbenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl ) ketone (0107-2) (80 mg, 0.182 mmol, 1.0 equiv) and (3R,6S)-6-((2-(methylsulfonyl)ethoxy)methyl)tetrahydro-2H- Pyran-3-amine hydrochloride (0108-44) (64.7 mg, 0.273 mmol, 1.5 equiv) in tert-butanol (10 mL) was added N,N-diisopropylethylamine (1.5 mL) ). The mixture was heated at 90°C overnight. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (dichloromethane:methanol=12:1) to give the product (2-chloro-4-((2-methylbenzofuran-7-yl)oxy)phenyl as a yellow solid )(4-(((3R,6S)-6-((2-(methylsulfonyl)ethoxy)methyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo [2,3-d]pyrimidin-5-yl)methanone (50 mg, yield: 43.0%). MS (ES ⁺ ): m/z = 639 (M+H) ⁺ . ¹ H NMR (500MHz, DMSO) δ 8.61 (d, J = 7.0 Hz, 1H), 8.25 (s, 1H), 7.62–7.51 (m, 2H), 7.45 (d, J=7.6Hz, 1H), 7.30–7.16 (m, 2H), 7.06 (d, J=7.9Hz, 1H), 7.01 (dd, J=8.5, 2.3Hz, 1H), 6.70 (s, 1H), 4.17 (d, J=9.2Hz, 2H), 3.82 (dq, J=11.7, 5.7Hz, 2H), 3.58–3.52 (m, 1H), 3.51–3.46 (m ,2H),3.38(s,2H),3.15(t,J＝10.3Hz,2H),3.01(s,3H),2.45(s,3H),2.20(d,J＝12.0Hz,1H),1.77 (d, J=13.0Hz, 1H), 1.61 (d, J=12.2Hz, 1H), 1.52–1.40 (m, 1H).

Example 30: (2-Chloro-4-((2-methylbenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-((2-(ethyl) sulfonyl)ethoxy)methyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 45) Preparation (prepared according to Scheme 1)

To (2-chloro-4-((2-methylbenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H -pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (compound 2) (100 mg, 0.188 mmol, 1.0 equiv) and (ethylsulfonyl) Acyl)ethylene (90 mg, 0.751 mmol, 4.0 equiv) in tetrahydrofuran (10 mL) was added potassium tert-butoxide (42 mg, 0.376 mmol, 2.0 equiv). The mixture was heated at 40°C for 3 hours. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified with a silica gel column (dichloromethane/methanol=100/1 to 15/1) to give a yellow solid product (2-chloro-4-((2-methylbenzofuran-7-yl)oxy) Phenyl)(4-(((3R,6S)-6-((2-(ethylsulfonyl)ethoxy)methyl)tetrahydro-2H-pyran-3-yl)amino)-7H- Pyrrolo[2,3-d]pyrimidin-5-yl)methanone (43 mg, yield: 35.2%). MS(ES+): m/z=653(M+H)+. Melting point: 122～131℃ ¹ H NMR(500MHz, DMSO)δ12.72(s,1H),8.58(d,J=7.1Hz,1H ), 8.24(s, 1H), 7.60(s, 1H), 7.56(d, J=8.5Hz, 1H), 7.44(d, J=7.6Hz, 1H), 7.31–7.19(m, 2H), 7.05 (d, J=7.8Hz, 1H), 7.00 (dd, J=8.5, 2.3Hz, 1H), 6.69 (s, 1H), 4.14 (t, J=11.4Hz, 2H), 3.85–3.74 (m, 2H), 3.53 (dd, J=12.3, 6.3Hz, 1H), 3.50–3.41 (m, 2H), 3.34 (d, J=5.6Hz, 2H), 3.14 (ddd, J=19.4, 14.4, 6.6Hz ,3H),2.44(s,3H),2.19(d,J＝11.7Hz,1H),1.74(d,J＝12.6Hz,1H),1.60(dt,J＝12.0,8.5Hz,1H),1.45 (dt,J=12.5,6.5Hz,1H),1.23(d,J=7.4Hz,3H).

Example 31: N-((2S,5R)-5-((5-(2-chloro-4-(naphthalen-1-yloxy)benzoyl)-7H-pyrrolo[2,3-d ] pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)methyl)-2-hydroxyethane-1-sulfonamide (compound 59) preparation (prepared according to scheme four)

Step 31a: N-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)-2-hydroxyethane-1-sulfonamide hydrochloride (compound 0108-59 ): tert-butyl ((3R,6S)-6-(aminomethyl)tetrahydro-2H-pyran-3-yl)carbamate (70 mg, 0.304 mmol, 1.0 equiv) at 0°C and triethylamine (0.17 mL, 1.216 mmol, 4.0 equiv) in dichloromethane (4.5 mL) was added dropwise methyl 2-(chlorosulfonyl)acetate (105 mg, 0.609 mmol, 2.0 equiv) of dichloromethane (0.5 mL). The mixture was warmed to room temperature and stirred overnight. The reaction was quenched by the addition of saturated sodium bicarbonate solution (15 mL). The aqueous layer was extracted with dichloromethane (15 mL×3). The combined organic layers were washed with saturated brine (15 mL×1), dried over anhydrous sodium sulfate and concentrated to give 2-(N-(((2S,5R)-5-((tert-butoxylated as a pale yellow oil. Carbonyl)amino)tetrahydro-2H-pyran-2-yl)methyl)sulfamoyl)acetate methyl ester (125 mg, crude). LCMS (ESI): m/z 367[M+1] ⁺ . Methyl 2-(N-(((2S,5R)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-yl)methyl)sulfamoyl)acetate obtained above (111 mg, 0.304 mmol, 1.0 equiv) To a mixture of tetrahydrofuran (2.5 mL) and water (1 mL) was added sodium hydroxide (36.5 mg, 0.912 mmol, 3.0 equiv). The mixture was stirred at room temperature for 1.5 hours. The mixture was diluted with water (15 mL). 1N dilute hydrochloric acid was added to adjust pH=5. The aqueous layer was extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with saturated brine (15 mL×1), dried over anhydrous sodium sulfate and concentrated to give 2-(N-(((2S,5R)-5-((tert-butoxycarbonyl) as a white solid Amino)tetrahydro-2H-pyran-2-yl)methyl)sulfamoyl)acetic acid (100 mg, crude). LCMS (ESI): m/z 353 [M+1] ⁺ . 2-(N-(((2S,5R)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-yl)methyl)sulfamoyl)acetic acid (93) obtained above mg, 0.264 mmol, 1.0 equiv) in tetrahydrofuran (3 mL) was added dropwise borane dimethyl sulfide (10M solution in dimethyl sulfide, 0.066 mL, 0.66 mmol, 2.5 equiv). The mixture was stirred at room temperature for 5 hours. Water (15 mL) was added to quench the reaction. The aqueous layer was extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with saturated brine (10 mL×1), dried over anhydrous sodium sulfate and concentrated to give ((3R,6S)-6-(((2-hydroxyethyl)sulfonamide) as a pale yellow oil yl)methyl)tetrahydro-2H-pyran-3-yl)carbamate tert-butyl ester (80 mg, crude). LCMS (ESI): m/z 339 [M+1] ⁺ . The above obtained tert-butyl ((3R,6S)-6-(((2-hydroxyethyl)sulfonamido)methyl)tetrahydro-2H-pyran-3-yl)carbamate (80 mg, A mixture of 0.237 mmol, 1.0 equiv) of hydrogen chloride in methanol (4M solution, 1.5 mL) was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and dried under vacuum to give N-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)-2-hydroxyethane-1- as a white solid Sulfonamide hydrochloride (65 mg, crude). LCMS (ESI): m/z 239[M+1] ⁺ .

Step 31b: N-((2S,5R)-5-((5-(2-chloro-4-(naphthalen-1-yloxy)benzoyl)-7H-pyrrolo[2,3-d] Preparation of pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)methyl)-2-hydroxyethane-1-sulfonamide (compound 59): under nitrogen protection, transfer to N-( ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)-2-hydroxyethane-1-sulfonamide (0108-59) (56 mg, 0.237 mmol, 1.0 equiv.) and (2-chloro-4-(naphthalen-1-yloxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (0403-32 ) (103 mg, 0.237 mmol, 1.0 equiv) To a mixture of tert-butanol (5 mL) was added N,N-diisopropylethylamine (1 mL). The mixture was heated at 90°C overnight. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (dichloromethane:methanol=10:1) to give N-((2S,5R)-5-((5-(2-chloro-4-(naphthalene-1-) as a yellow solid yloxy)benzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)methyl)-2-hydroxyethane- 1-sulfonamide (28 mg, 19% yield). LCMS (ESI): m/z 636 [M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol=10:1), melting point: >200°C. ¹ H NMR(500MHz, DMSO)δ8.59(d,J=7.2Hz,1H),8.23(s,1H),8.04(d,J=8.2Hz,2H),7.85(d,J=8.3Hz, 1H), 7.68–7.49 (m, 5H), 7.35–7.18 (m, 2H), 7.02 (dd, J=8.5, 2.2Hz, 2H), 4.93 (s, 1H), 4.16 (t, J=11.9Hz) ,2H),3.74(t,J＝6.1Hz,2H),3.48-3.41(m,1H),3.21-3.12(m,3H),3.02(t,J＝5.6Hz,2H),2.19(d, J=11.4Hz, 1H), 1.81 (d, J=12.6Hz, 1H), 1.59 (dd, J=22.6, 10.7Hz, 1H), 1.40 (dd, J=27.2, 13.5Hz, 1H).

Example 32: (2-Chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-((methylsulfonyl)methyl)tetrahydrofuran-2H-pyran-3-yl)amino )-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 60) Preparation (prepared according to Scheme 5)

Step 32a: Preparation of methyl 2-chloro-4-phenoxybenzoate (compound 0502-60): To phenol (0501-60) (7.0 g, 74.47 mmol, 1.4 equiv) N under nitrogen, To a solution of N-dimethylformamide (100 mL) was added methyl 2-chloro-4-fluorobenzoate (0102-1) (10.0 g, 53.19 mmol, 1.0 equiv), potassium carbonate (14.6 g, 106.38 mmol) moles, 2.0 equiv). The mixture was stirred at 90°C overnight. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether/ethyl acetate=30/1 to 10/1) to obtain methyl 2-chloro-4-phenoxybenzoate (10.5 g, yield: 75.53%) as a colorless oily product ). LCMS(ESI): m/z=263[M+1]+.

Step 32b: Preparation of (2-chloro-4-phenoxyphenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (compound 0503-60): nitrogen A solution of 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0106-1) (3.0 g, 12.93 mmol, 1.0 equiv) in tetrahydrofuran (15 mL) was added at 0 °C under protection. Sodium hydride (1.55 g, 38.79 mmol, 3.0 equiv) was added and stirred for 0.5 hour, then n-butyllithium (6.72 mL, 16.81 mmol, 1.3 equiv) was slowly added dropwise at -70°C and stirred for 1.0 hour. At -70°C, methyl 2-chloro-4-phenoxybenzoate (0502-60) (3.39 g, 12.93 mmol, 1.0 equiv) dissolved in 8 mL of tetrahydrofuran was added dropwise to the reaction solution and stirred for 1.5 hours . The reaction solution was quenched with ammonium chloride solution, diluted with water and extracted with ethyl acetate, the organic phase was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether/ethyl acetate = 15/1 to 2/1) to give pink solid product (2-chloro-4-phenoxyphenyl)(4-chloro-7H-pyrrolo[ 2,3-d]pyrimidin-5-yl)methanone (2.8 g, yield: 56.4%). LCMS (ESI): m/z=384[M+1] ⁺ .

Step 32c: (2-Chloro-4-phenoxyphenyl)(4-((3R,6S)-6-(((methylsulfonyl)methyl)tetrahydrofuran-2H-pyran-3-yl)amino) Preparation of -7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 60): To (3R,6S)-6-((methylsulfonyl)methyl)tetrahydro-2H- Pyran-3-amine hydrochloride (0108-42) (83 mg, 0.52 mmol, 2.0 equiv) and (2-chloro-4-phenoxyphenyl)(4-chloro-7H-pyrrolo[2, 3-d]pyrimidin-5-yl)methanone (0503-60) (100 mg, 0.26 mmol, 1.0 equiv) in tert-butanol (10 mL) was added N,N-diisopropylethylamine (1 ml). The mixture was heated at 90°C overnight. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (dichloromethane:methanol=10:1) to give (2-chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-(( as a yellow solid Methylsulfonyl)methyl)tetrahydrofuran-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (70 mg, yield: 49.9%) . LCMS (ESI): m/z 571 [M+1] ⁺ ; melting point: 152-155°C. ¹ H NMR (500MHz, DMSO) δ 12.74(s, 1H), 8.60(d, J=7.2Hz, 1H), 8.25(s, 1H), 7.62(s, 1H), 7.57(d, J=8.5 Hz, 1H), 7.48(t, J＝7.9Hz, 2H), 7.25(t, J＝7.4Hz, 1H), 7.18(dd, J＝5.1, 2.6Hz, 3H), 7.02(dd, J＝8.4 , 2.3Hz, 1H), 4.25–4.19 (m, 1H), 4.18–4.10 (m, 1H), 3.88 (dd, J=10.8, 8.5Hz, 1H), 3.44 (dd, J=14.9, 8.7Hz, 1H), 3.25–3.18 (m, 2H), 2.99 (s, 3H), 2.19 (d, J=11.7Hz, 1H), 1.94–1.81 (m, 1H), 1.73–1.63 (m, 1H), 1.61 –1.49(m,1H).

Example 33: (2-Chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-(((methylsulfonyl)methoxy)methyl)tetrahydro-2H- Preparation of pyran-3-yl)amino)-7H-pyrro[2,3-d]pyrimidin-5-yl)methanone (Compound 61) (prepared according to Scheme 5)

To (2-chloro-4-phenoxyphenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (0503-60) (90 mg, 0.235 mmol , 1.0 equiv) and (3R,6S)-6-((((methylsulfonyl)methoxy)methyl)tetrahydro-2H-pyran-3-amine hydrochloride (0108-37) (93 mg, 0.359 mmol, 1.5 equiv) to a mixture of tert-butanol (8 mL) was added N,N-diisopropylethylamine (0.21 mL, 1.175 mmol, 5.0 equiv). The mixture was heated at 90°C under nitrogen atmosphere overnight. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (ethyl acetate:dichloromethane:methanol=10:10:2) to give (2-chloro-4-phenoxyphenyl)(4-(((3R, 6S)-6-(((methylsulfonyl)methoxy)methyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrro[2,3-d]pyrimidin-5-yl ) ketone (66 mg, yield: 49%). LCMS (ESI): m/z 571 [M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol=10:1); melting point: 108-111°C. ¹ HNMR (DMSO-d ₆ , 500MHz): δ 12.50(s, 1H), 8.59(d, J=7.0Hz, 1H), 8.25(s, 1H), 7.61(s, 1H), 7.57(d, J=8.5Hz, 1H), 7.49-7.46(m, 2H), 7.27-7.24(m, 1H), 7.19-7.17(m, 3H), 7.03-7.01(m, 1H), 4.70-7.65(m, 2H), 4.20-4.14(m, 2H), 3.85-3.79(m, 2H), 3.62-3.58(m, 1H), 3.18-3.13(m, 1H), 2.95(s, 3H), 2.21-2.19( m, 1H), 1.77-1.74 (m, 1H), 1.66-1.58 (m, 1H), 1.51-1.42 (m, 1H).

Example 34: (2-Chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-((2-(methylsulfonyl)ethoxy)methyl)tetrahydro- Preparation of 2H-pyran-3-yl)amino)-7H-pyrro[2,3-d]pyrimidin-5-yl)methanone (Compound 62) (prepared according to Scheme 5)

To (2-chloro-4-phenoxyphenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (0503-60) (93 mg, 0.243 mmol , 1.0 equiv) and (3R,6S)-6-((2-(methylsulfonyl)ethoxy)methyl)tetrahydro-2H-pyran-3-amine hydrochloride (0108-44) ( 80 mg, 0.0.292 mmol, 1.2 equiv) in tert-butanol (10 mL) was added N,N-diisopropylethylamine (1.0 mL). The mixture was heated at 90°C overnight. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (dichloromethane:methanol=12:1) to give the product (2-chloro-4-phenoxyphenyl)(4-(((3R,6S)-6- as a yellow solid) ((2-(Methylsulfonyl)ethoxy)methyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrro[2,3-d]pyrimidin-5-yl)methanone (50 mg, yield: 35.2%). MS(ES ⁺ ): m/z=586(M+H) ⁺ . ¹ H NMR (500MHz, DMSO) δ 8.58(d, J=6.9Hz, 1H), 8.24(s, 1H), 7.59(s ,1H),7.56(d,J＝8.4Hz,1H),7.47(t,J＝7.8Hz,2H),7.25(t,J＝7.3Hz,1H),7.17(d,J＝8.1Hz,3H) ),7.02(dd,J=8.4,1.8Hz,1H),4.15(d,J=6.4Hz,2H),3.86–3.74(m,2H),3.52(dd,J=11.7,7.0Hz,5H) ,3.14(dd,J＝19.9,8.8Hz,1H),2.99(s,3H),2.18(d,J＝12.4Hz,1H),1.75(d,J＝12.1Hz,1H),1.60(dd, J=22.1, 10.4Hz, 1H), 1.45 (dd, J=22.5, 11.1Hz, 1H).

Example 35: (2-Chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-((2-(ethylsulfonyl)ethoxy)methyl)tetrahydro- Preparation of 2H-pyran-3-yl)amino)-7H-pyrro[2,3-d]pyrimidin-5-yl)methanone (Compound 63) (prepared according to Scheme 5)

Step 35a: (2-Chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H - Preparation of pyrrolo[2,3-d]pyrimidin-5-yl)methanone (compound 0504-63): under nitrogen protection, transfer to ((2S,5R)-5-aminotetrahydro-2H-pyran- 2-yl)methanol hydrochloride (0108-1) (33 mg, 0.261 mmol, 1.0 equiv) and (2-chloro-4-phenoxyphenyl)(4-chloro-7H-pyrrolo[2, 3-d]pyrimidin-5-yl)methanone (0503-60) (100 mg, 0.261 mmol, 1.0 equiv) in tert-butanol (5 mL) was added N,N-diisopropylethylamine (2 ml). The mixture was heated at 90°C overnight. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (dichloromethane:methanol=10:1) to give (2-chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-() as a yellow solid Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (70 mg, 56% yield). LCMS (ESI): m/z477[M+1] ⁺ .

Step 35b: (2-Chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-((2-(ethylsulfonyl)ethoxy)methyl)tetrahydro-2H Preparation of -pyran-3-yl)amino)-7H-pyrro[2,3-d]pyrimidin-5-yl)methanone (Compound 63): To (2-chloro-4-phenoxyphenyl) (4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl) To a mixture of methyl ketone (0504-63) (40 mg, 0.083 mmol, 1.0 equiv) and (ethylsulfonyl)ethylene (40 mg, 0.33 mmol, 4.0 equiv) in tert-butanol (5 mL) was added tert. Potassium butoxide (19 mg, 0.166 mmol, 2.0 equiv). The mixture was heated at 50°C for 3 hours. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified with a silica gel column (dichloromethane/methanol=100/1 to 15/1) to give a yellow solid product (2-chloro-4-phenoxyphenyl)(4-(((3R,6S)- 6-((2-(Ethylsulfonyl)ethoxy)methyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrro[2,3-d]pyrimidin-5-yl) Methyl ketone (18 mg, yield: 36.1%). MS (ES+): m/z=599 (M+H)+. Melting point: 102-111°C. ¹ H NMR (500MHz, DMSO) δ12.72(s, 1H), 8.59(d, J=7.0Hz, 1H), 8.25(s, 1H), 7.61(s, 1H), 7.57(d, J=8.4 Hz, 1H), 7.48 (t, J=7.8Hz, 2H), 7.25 (t, J=7.3Hz, 1H), 7.22–7.12 (m, 3H), 7.02 (dd, J=8.4, 2.0Hz, 1H) ),4.16(d,J＝7.9Hz,2H),3.80(dd,J＝10.3,5.4Hz,2H),3.53(dd,J＝12.0,6.7Hz,1H),3.50–3.40(m,2H) ,3.34(t,J＝5.4Hz,2H),3.18–3.07(m,3H),2.19(d,J＝11.5Hz,1H),1.75(d,J＝12.7Hz,1H),1.61(d, J=12.0Hz, 1H), 1.45 (d, J=11.1Hz, 1H), 1.23 (d, J=7.3Hz, 3H).

Example 36: 2-((2S,5R)-5-(((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl ) amino) tetrahydro-2H-pyran-2-yl) methoxy) ethane-1-sulfonamide (compound 66) preparation (prepared according to scheme five routes)

To 1-(2,4-dimethoxyphenyl)methanamine (717 mg, 4.29 mmol, 1.0 equiv) and N,N-diisopropylethylamine (1.1 g, 8.59 equiv) at 0 °C mol, 2.0 equiv) in dichloromethane (10 mL) was added dropwise 2-chloroethane-1-sulfonyl chloride (700 mg, 4.29 mmol, 1.0 equiv). The mixture was stirred at room temperature overnight. The mixture was diluted with water (25 mL) and extracted with dichloromethane (25 mL x 3). The combined organic layers were washed with saturated brine (25 mL×1), dried over anhydrous sodium sulfate and concentrated, and purified by column (PE:EA=10:1 to 5:1) to obtain N-(2,4- as a yellow oil) Dimethoxybenzyl)ethylenesulfonamide (900 mg, yield: 83.3%) LCMS (ESI): m/z 258 [M+1] ⁺ . Add N-(2,4-dimethoxybenzyl)ethylenesulfonamide (547 mg, 2.13 mmol, 2.0 equiv) and (2-chloro-4-phenoxyphenyl) (4 -(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrro[2,3-d]pyrimidin-5-yl)methanone ( 0504-63)((510 mg, 1.065 mmol, 1.0 equiv) in tetrahydrofuran (5 mL) was added potassium tert-butoxide (238.5 mg, 4.26 mmol, 4.0 equiv). The mixture was stirred at room temperature overnight. The mixture was Diluted with water (15 mL), then extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with saturated brine (15 mL×1), dried over anhydrous sodium sulfate and concentrated, and purified by column (PE: Ethyl acetate = 10:1 to 5:1) to give a yellow solid 2-((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[ 2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)methoxy)-N-(2,4-dimethoxybenzyl)ethane-1- Sulfonamide (150 mg, ~30% pure crude). LCMS (ESI): m/z 736[M+1] ⁺ . 2-((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl obtained above )amino)tetrahydro-2H-pyran-2-yl)methoxy)-N-(2,4-dimethoxybenzyl)ethane-1-sulfonamide (150 mg, 0.2 mmol, 1.0 equiv.) in a mixture of dichloromethane (2 mL) and trifluoroacetic acid (2 mL) was stirred at room temperature for 1 hour. The mixture was diluted with water (15 mL) and extracted with dichloromethane (15 mL x 3). The combined organic layers were washed with saturated brine (15 mL×1), dried over anhydrous sodium sulfate and concentrated, and the residue was purified by preparative thin layer chromatography (dichloromethane:methanol=10:1) to obtain a yellow solid 2- ((2S,5R)-5-((5-(2-Chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro- 2H-pyran-2-yl)methoxy)ethane-1-sulfonamide (34 mg, yield: 12.8%). LCMS (ESI): m/z 586 [M+1] ⁺ ; ¹ H NMR (500 MHz, DMSO) δ 12.73 (s, 1H), 8.58 (d, J=7.1 Hz, 1H), 8.25 (s, 1H) ), 7.60(s, 1H), 7.57(d, J＝8.5Hz, 1H), 7.48(t, J＝8.0Hz, 2H), 7.25(t, J＝7.4Hz, 1H), 7.21–7.14(m ,3H),7.02(dd,J=8.4,2.4Hz,1H),6.74(s,2H),4.22-4.05(m,2H),3.85-3.74(m,2H),3.59-3.49(m,1H) ), 3.44(t, J＝5.4Hz, 2H), 3.27(s, 2H), 3.18–3.09(m, 1H), 2.19(d, J＝12.2Hz, 1H), 1.76(d, J＝12.7Hz ,1H),1.60(qd,J=12.3,3.8Hz,1H),1.51–1.39(m,1H).

Example 37: 2-(((2S,5R)-5-(((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4- (base)amino)tetrahydro-2H-pyran 2-yl)methoxy)-N,N-dimethylethane-1-sulfonamide (compound 67) (prepared according to scheme five)

To (2-chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrole [2,3-d]pyrimidin-5-yl)methanone (0504-63) (50 mg, 0.104 mmol, 1.0 equiv) and N,N-dimethylethylenesulfonamide (56 mg, 0.209 mmol) , 4.0 equiv) To a mixture of tetrahydrofuran (5 mL) was added potassium tert-butoxide (23 mg, 0.208 mmol, 2.0 equiv). The mixture was heated at 50°C for 3 hours. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified by silica gel column (dichloromethane/methanol=100/1 to 15/1) to obtain 2-(((2S,5R)-5-((5-(2-chloro-4-benzene as a yellow solid product oxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran 2-yl)methoxy)-N,N-dimethylethyl Alkane-1-sulfonamide (23 mg, yield: 36.1%). MS (ES+): m/z=614 (M+H)+. Melting point: 105-116°C. ¹ H NMR(500MHz, DMSO)δ12.72(s,1H),8.58(d,J=7.1Hz,1H),8.25(s,1H),7.61(s,1H),7.57(d,J=8.5 Hz, 1H), 7.48(t, J＝7.9Hz, 2H), 7.25(t, J＝7.4Hz, 1H), 7.18(dd, J＝5.1, 2.5Hz, 3H), 7.02(dd, J＝8.4 ,2.2Hz,1H),4.16(d,J=8.5Hz,2H),3.76(t,J=6.0Hz,2H),3.57–3.52(m,1H),3.49–3.42(m,2H),3.33 (d, J=6.1Hz, 2H), 3.18–3.07 (m, 1H), 2.76 (d, J=8.5Hz, 6H), 2.19 (d, J=11.8Hz, 1H), 1.76 (d, J= 12.0Hz, 1H), 1.61 (dt, J=11.9, 8.6Hz, 1H), 1.45 (dd, J=23.8, 9.8Hz, 1H).

Example 38: 2-((2S,5R)-5-(((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl )amino)tetrahydro-2H-pyran-2-yl)methoxy)-N-methylethane-1-sulfonamide (compound 68) preparation (prepared according to scheme five)

At 0 °C, 1-(2,4-dimethoxyphenyl)-N-methylmethylamine (1.0 g, 5.52 mmol, 1.0 equiv) and N,N-diisopropylethylamine ( To a mixture of 1.43 g, 11.04 mmol, 2.0 equiv) in dichloromethane (10 mL) was added 2-chloroethane-1-sulfonyl chloride (0.99 g, 6.07 mmol, 1.1 equiv) dropwise. The mixture was stirred at room temperature overnight. The mixture was diluted with water (25 mL) and extracted with dichloromethane (25 mL x 3). The combined organic layers were washed with saturated brine (25 mL×1), dried over anhydrous sodium sulfate and concentrated to obtain N-(2,4-dimethoxybenzyl)-N-methylethylenesulfonamide as a yellow oil (1.04 g, yield: 69%) LCMS (ESI): m/z 272[M+1] ⁺ . To N-(2,4-dimethoxybenzyl)-N-methylethylenesulfonamide (142 mg, 0.523 mmol, 2.5 equiv) and (2-chloro-4-phenoxy) at 0 °C Phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrro[2,3-d]pyrimidine-5- yl)methanone (0504-63) (100 mg, 0.209 mmol, 1.0 equiv) in tetrahydrofuran (5 mL) was added potassium tert-butoxide (47 mg, 0.418 mmol, 2.0 equiv). The mixture was stirred at room temperature overnight. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (15 mL×1), dried over anhydrous sodium sulfate and concentrated to give 2-((2S,5R)-5-(((5-(2-chloro-4) as a yellow oil. -Phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)methoxy)-N-(2, 4-Dimethoxybenzyl)-N-methylethane-1-sulfonamide (173 mg, crude). LCMS (ESI): m/z 750 [M+1] ⁺ . 2-((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl prepared above ) amino)tetrahydro-2H-pyran-2-yl)methoxy)-N-(2,4-dimethoxybenzyl)-N-methylethane-1-sulfonamide (165 mg, 0.22 mmol, 1.0 equiv) in a mixture of dichloromethane (3 mL) and trifluoroacetic acid (3 mL) was stirred at room temperature for 1 hour. The mixture was diluted with water (15 mL) and extracted with dichloromethane (15 mL x 3). The combined organic layers were washed with saturated brine (15 mL×1), dried over anhydrous sodium sulfate and concentrated, and the residue was purified by preparative thin layer chromatography (dichloromethane:methanol=10:1) to obtain a yellow solid 2- ((2S,5R)-5-((5-(2-Chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro- 2H-pyran-2-yl)methoxy)-N-methylethane-1-sulfonamide (34 mg, 26% yield). LCMS (ESI): m/z 600 [M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol=10:1); melting point: 135°C-138°C. ¹ H NMR (500MHz, DMSO) δ 12.67(s, 1H), 8.59(d, J=7.0Hz, 1H), 8.24(s, 1H), 7.87-7.82(m, 1H), 7.63-7.53(m ,2H),7.48(t,J＝7.9Hz,2H),7.25(t,J＝7.4Hz,1H),7.22–7.10(m,3H),7.02(dd,J＝8.4,2.2Hz,1H) ,6.74(d,J＝4.8Hz,1H),4.16(d,J＝5.5Hz,2H),3.75(dt,J＝17.1,8.4Hz,2H),3.61–3.49(m,1H),3.46( t, J＝7.9Hz, 2H), 3.31(s, 2H), 3.14(t, J＝11.4Hz, 1H), 2.59(d, J＝4.9Hz, 3H), 2.19(d, J＝11.5Hz, 1H), 1.76 (d, J=13.1Hz, 1H), 1.60 (dd, J=22.2, 10.3Hz, 1H), 1.45 (dd, J=22.5, 11.0Hz, 1H).

Example 39: (2-Chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-((3-(methylsulfonyl)propoxy)methyl)tetrahydro- Preparation of 2H-pyran-3-yl)amino)-7H-pyrro[2,3-d]pyrimidin-5-yl)methanone (Compound 69) (prepared according to Scheme 5)

Step 39a: ((2S,5R)-5-((5-(2-Chloro-4-phenoxybenzoyl)-7-(methylsulfonyl)-7H-pyrrolo[2,3-d ] pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)methyl methanesulfonate (compound 0504-69) preparation: (2-chloro-4-phenoxybenzene at 0°C) base)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5- yl)methanone (0504-63) (56 mg, 0.117 mmol, 1.0 equiv) and N,N-diisopropylethylamine (0.12 mL, 0.702 mmol, 6.0 equiv) in dichloromethane (3 mL) To the mixture was added methanesulfonyl chloride (54 mg, 0.468 mmol, 4.0 equiv). The mixture was warmed to room temperature and stirred for 4 hours. The solvent was removed under reduced pressure. The residue was dried under vacuum to give ((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7-(methylsulfonyl)-7H as a pale yellow oil -Methyl pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)methanesulfonate (150 mg, crude). LCMS (ESI): m/z 635 [M+1] ⁺⁺ ; TLC: Rf 0.5 (dichloromethane:methanol=10:1).

Step 39b: (2-Chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-((3-(methylsulfonyl)propoxy)methyl)tetrahydro-2H Preparation of -pyran-3-yl)amino)-7H-pyrro[2,3-d]pyrimidin-5-yl)methanone (Compound 69): To 3-(methylsulfonyl)propan-1-ol (143 mg, 1.037 mmol, 4.2 equiv) To a mixture of N-methylpyrrolidone (4 mL) was added KHMDS (1M solution in tetrahydrofuran, 1.04 mL, 1.04 mmol, 4.2 equiv) dropwise. The mixture was stirred at room temperature for 5 minutes. Add ((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7-(methylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine -4-yl)amino)tetrahydro-2H-pyran-2-yl)methylmethanesulfonate (0504-69) (157 mg, 00.247 mmol, 1.0 equiv). The mixture was stirred at room temperature for 1 hour and then heated to 100°C for a further 40 minutes. The mixture was diluted with saturated aqueous ammonium chloride (30 mL), then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (dichloromethane:methanol=10:1) to give (2-chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-() as a white solid (3-(Methylsulfonyl)propoxy)methyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrro[2,3-d]pyrimidin-5-yl)methanone ( 20 mg, yield: 14%). LCMS (ESI): m/z 599 [M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol=10:1); melting point: 118-121°C. ¹ HNMR (DMSO-d ₆ , 500MHz): δ 12.68(s, 1H), 8.58(d, J=7.0Hz, 1H), 8.52(s, 1H), 7.61(s, 1H), 7.57(d, J=8.5Hz, 1H), 7.49-7.46(m, 2H), 7.27-7.24(m, 1H), 7.19-7.17(m, 3H), 7.03-7.01(m, 1H), 4.21-4.10(m, 2H), 3.53-3.51(m, 3H), 3.43-3.39(m, 2H), 3.15-3.12(m, 3H), 2.98(s, 3H), 2.20-2.18(m, 1H), 1.96-1.90( m, 2H), 1.78-1.75 (m, 1H), 1.64-1.56 (m, 1H), 1.45-1.40 (m, 1H).

Example 40: Carbamate ((2S,5R)-5-(((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl ) amino) tetrahydro-2H-pyran-2-yl) methyl ester (compound 70) preparation (according to scheme five route preparation)

Step 40a: Preparation of ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl carbamate hydrochloride (compound 0108-70): to ((3R,6S)- A solution of tert-butyl 6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)carbamate (50 mg, 0.216 mmol, 1.0 equiv) in N,N-dimethylformamide (1.5 mL) To the mixture was added carbonyldiimidazole (53 mg, 0.325 mmol, 1.5 equiv). The mixture was stirred at room temperature for 2 hours. Aqueous ammonia (25% in water, 0.24 g, 1.728 mmol, 8.0 equiv) was added. The mixture was stirred for an additional 2 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (10 mL×1), dried over anhydrous sodium sulfate and concentrated to obtain ((3R,6S)-6-((carbamoyloxy)methyl)tetrahydro -2H-Pyran-3-yl)carbamate tert-butyl ester (52 mg, crude). LCMS (ESI): m/z 275[M+1] ⁺ . ((3R,6S)-6-((carbamoyloxy)methyl)tetrahydro-2H-pyran-3-yl)carbamic acid tert-butyl ester prepared above (52 mg, 0.190 mmol, 1.0 equiv) in methanolic hydrogen chloride (4M solution, 2 mL) was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and dried under vacuum to give ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl carbamate hydrochloride (40 mg, crude) as a white solid. LCMS (ESI): m/z 175[M+1] ⁺ .

Step 40b: Carbamate ((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl) Preparation of amino)tetrahydro-2H-pyran-2-yl)methyl ester (compound 70): To (2-chloro-4-phenoxyphenyl)(4-chloro-7H-pyrrolo[2, 3-d]pyrimidin-5-yl)methanone (0503-60) (73 mg, 0.19 mmol, 1.0 equiv) and carbamic acid ((2S,5R)-5-aminotetrahydro-2H-pyran-2 -yl)methyl ester hydrochloride (0108-70) (40 mg, 0.19 mmol, 1.0 equiv) in tert-butanol (8 mL) was added N,N-diisopropylethylamine (0.17 mL) , 0.95 mmol, 5.0 equiv). The mixture was heated at 90°C under nitrogen atmosphere overnight. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (ethyl acetate:dichloromethane:methanol = 10:10:2) to give carbamate ((2S,5R)-5-((5-(2-chloro-4) as a white solid -phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)methyl ester (53 mg, yield: 54%). LCMS (ESI): m/z 522 [M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol=10:1); melting point: 223-226°C. ¹ HNMR (DMSO-d ₆ , 500MHz): δ 12.71(s, 1H), 8.57(d, J=7.0Hz, 1H), 8.25(s, 1H), 7.61(s, 1H), 7.56(d, J=8.5Hz, 1H), 7.49-7.46(m, 2H), 7.26-7.23(m, 1H), 7.18-7.16(m, 3H), 7.02-7.00(m, 1H), 6.52(s, 2H) ,4.18-4.12(m,2H),3.95-3.87(m,2H),3.57-3.53(m,1H),3.15-3.10(m,1H),2.20-2.18(m,1H),1.76-1.74( m, 1H), 1.65-1.57 (m, 1H), 1.49-1.41 (m, 1H).

Example 41: N-(((2S,5R)-5-(((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4- (base)amino)tetrahydro-2H-pyran 2-yl)methyl)-2-methoxyethane-1-sulfonamide (compound 71) (prepared according to scheme five)

Step 41a: N-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)-2-methoxyethane-1-sulfonamide hydrochloride (Compound 0108 -71) preparation: tert-butyl ((3R,6S)-6-(aminomethyl)tetrahydro-2H-pyran-3-yl)carbamate (58 mg, 0.25 mmol, 1.0 equiv) and triethylamine (0.14 mL, 1.0 mmol, 4.0 equiv) in dichloromethane (4.5 mL) was added 2-methoxyethane-1-sulfonyl chloride (79 mg, 0.5 mmol) dropwise , 2.0 equiv) in dichloromethane (0.5 mL). The mixture was warmed to room temperature and stirred overnight. The reaction was quenched by the addition of saturated sodium bicarbonate solution (15 mL). The aqueous layer was extracted with dichloromethane (15 mL x 3). The combined organic layers were washed with saturated brine (15 mL×1), dried over anhydrous sodium sulfate and concentrated to give a pale yellow oil ((3R,6S)-6-(((2-methoxyethyl) Sulfonamido)methyl)tetrahydro-2H-pyran-3-yl)carbamate tert-butyl ester (100 mg, crude). LCMS (ESI): m/z 353 [M+1] ⁺ . ((3R,6S)-6-(((2-methoxyethyl)sulfonylamino)methyl)tetrahydro-2H-pyran-3-yl)carbamic acid tert-butyl ester prepared above (88 mg, 0.25 mmol, 1.0 equiv) in methanol of hydrogen chloride (4M solution, 1.5 mL) was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and dried under vacuum to give N-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)-2-methoxyethyl as a pale yellow oil Alkane-1-sulfonamide hydrochloride (72 mg, crude). LCMS (ESI): m/z 253[M+1] ⁺ .

Step 41b: N-(((2S,5R)-5-(((5-(2-Chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl ) amino) tetrahydro-2H-pyran 2-yl) methyl)-2-methoxyethane-1-sulfonamide (compound 71) preparation: to (2-chloro-4-phenoxyphenyl) )(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (0503-60) (64 mg, 0.167 mmol, 1.0 equiv) and N-(((2S,5R )-5-aminotetrahydro-2H-pyran-2-yl)methyl)-2-methoxyethane-1-sulfonamide hydrochloride (0108-71) (72 mg, 0.25 mmol, 1.5 equiv.) To a mixture of tert-butanol (5 mL) was added N,N-diisopropylethylamine (0.15 mL, 0.835 mmol, 5.0 equiv). The mixture was heated at 90°C overnight under nitrogen. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (ethyl acetate:dichloromethane:methanol=15:15:2) to give N-(((2S,5R)-5-((5-(2-chloro- 4-Phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran 2-yl)methyl)-2-methoxyethyl Alkane-1-sulfonamide (47 mg, yield: 47%). LCMS (ESI): m/z 600 [M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol=10:1); melting point: 127-130°C. ¹ HNMR (DMSO-d ₆ , 500MHz): δ 12.69(s, 1H), 8.59(d, J=6.5Hz, 1H), 8.25(s, 1H), 7.61(s, 1H), 7.57(d, J=8.5Hz, 1H), 7.49-7.46(m, 2H), 7.27-7.24(m, 1H), 7.19-7.17(m, 3H), 7.14-7.11(m, 1H), 7.03-7.01(m, 1H), 4.19-4.15(m, 2H), 3.67-3.65(m, 2H), 3.43-3.41(m, 1H), 3.32-3.30(m, 2H), 3.27(s, 3H), 3.17-3.12( m, 1H), 3.04-3.02 (m, 2H), 2.20-2.18 (m, 1H), 1.82-1.79 (m, 1H), 1.63-1.56 (m, 1H), 1.45-1.34 (m, 1H).

Example 42: N-(((2S,5R)-5-(((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4- (base)amino)tetrahydro-2H-pyran 2-yl)methyl)-2-hydroxyethane-1-sulfonamide (compound 72) (prepared according to scheme five)

To (2-chloro-4-phenoxyphenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (0503-60) (60 mg, 0.157 mmol , 1.0 equiv) and N-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)-2-hydroxyethane-1-sulfonamide hydrochloride (0108- 59) (65 mg, 0.235 mmol, 1.5 equiv) To a mixture of tert-butanol (5 mL) was added N,N-diisopropylethylamine (0.14 mL, 0.785 mmol, 5.0 equiv). The mixture was heated at 90°C overnight under nitrogen. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (ethyl acetate:methanol=15:1) to give N-(((2S,5R)-5-((5-(2-chloro-4-phenoxybenzene) as a white solid Formyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran 2-yl)methyl)-2-hydroxyethane-1-sulfonamide (12 mg, yield: 13%). LCMS (ESI): m/z 586 [M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol=10:1); melting point: 123-126°C. ¹ HNMR (DMSO-d ₆ , 500MHz): δ 8.59 (d, J=7.0 Hz, 1H), 8.25 (s, 1H), 7.60 (s, 1H), 7.57 (d, J=8.5 Hz, 1H) ,7.49-7.46(m,2H),7.27-7.24(m,1H),7.19-7.17(m,3H),7.03-6.99(m,2H),4.89-4.87(m,1H),4.18-4.14( m, 2H), 3.76-3.73(m, 2H), 3.21-3.16(m, 3H), 3.14-3.12(m, 1H), 3.04-3.02(m, 2H), 2.20-2.18(m, 1H), 1.82-1.79 (m, 1H), 1.63-1.55 (m, 1H), 1.45-1.40 (m, 1H).

Example 43: N-(((2S,5R)-5-(((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4- (base)amino)tetrahydro-2H-pyran-2-yl)methyl)sulfonamide (compound 73) (prepared according to scheme five)

Step 43a: Preparation of N-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)sulfonamide hydrochloride (compound 0108-73): at 0°C To a mixture of chlorosulfonyl isocyanate (98.5 mg, 0.696 mmol, 2.0 equiv) in tetrahydrofuran (3.5 mL) was added dropwise a solution of benzyl alcohol (75 mg, 0.696 mmol, 2.0 equiv) in tetrahydrofuran (0.5 mL). The mixture was warmed to room temperature and stirred for 1.5 hours. Add tert-butyl ((3R,6S)-6-(aminomethyl)tetrahydro-2H-pyran-3-yl)carbamate (80 mg, 0.348 mmol, 1.0 equiv) and triethylamine (0.19 mL). , 1.392 mmol, 4.0 equiv). The mixture was stirred for an additional 3 hours. The reaction was quenched by the addition of saturated sodium bicarbonate solution (20 mL). The aqueous layer was extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with saturated brine (15 mL×1), dried over anhydrous sodium sulfate and concentrated to give a pale yellow oil ((3R,6S)-6-(((N-((benzyloxy) Carbonyl)sulfamoyl)amino)methyl)tetrahydro-2H-pyran-3-yl)carbamate tert-butyl ester (200 mg, crude). LCMS (ESI): m/z 444[M+1] ⁺ . ((3R,6S)-6-(((N-((benzyloxy)carbonyl)sulfamoyl)amino)methyl)tetrahydro-2H-pyran-3-yl)carbamic acid prepared above To a mixture of tert-butyl ester (200 mg, 0.451 mmol, 1.0 equiv) in methanol (5 mL) was added palladium on carbon (40 mg). The mixture was stirred at room temperature overnight under hydrogen balloon pressure. The mixture is filtered. The filtrate was concentrated under reduced pressure to give tert-butyl ((3R,6S)-6-(((sulfamoylamino)methyl)tetrahydro-2H-pyran-3-yl)carbamate ((168) as a white solid mg, crude). LCMS (ESI): m/z 310 [M+1] ⁺ . ((3R,6S)-6-(((sulfamoylamino)methyl)tetrahydro-2H- prepared above A mixture of tert-butyl pyran-3-yl)carbamate (168 mg, 0.54 mmol, 1.0 equiv) in methanolic hydrogen chloride (4M solution, 1.5 mL) was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the Drying under 25°C afforded N-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)sulfonyldiamide hydrochloride (135 mg, crude) as a white solid. LCMS ( ESI): m/z 210[M+1] ⁺ .

Step 43b: N-(((2S,5R)-5-(((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl ) amino) tetrahydro-2H-pyran-2-yl) methyl) sulfonamide (compound 73) preparation: to (2-chloro-4-phenoxyphenyl) (4-chloro-7H- Pyrrolo[2,3-d]pyrimidin-5-yl)methanone (0503-60) (70 mg, 0.183 mmol, 1.0 equiv) and N-(((2S,5R)-5-aminotetrahydro- 2H-Pyran-2-yl)methyl)sulfonamide hydrochloride (0108-73) (67 mg, 0.274 mmol, 1.5 equiv) in tert-butanol (5 mL) was added N,N - Diisopropylethylamine (0.16 mL, 0.915 mmol, 5.0 equiv). The mixture was heated at 90°C overnight under nitrogen. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol 20:1) to give N-(((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl) as a white solid )-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)methyl)sulfonamide (35 mg, yield: 34%) . LCMS (ESI): m/z 557 [M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol=10:1); melting point: 216-219°C. ¹ HNMR (DMSO-d ₆ , 500MHz): δ 12.72(s, 1H), 8.59(d, J=7.0Hz, 1H), 8.25(s, 1H), 7.62(s, 1H), 7.57(d, J=8.5Hz, 1H), 7.50-7.47(m, 2H), 7.27-7.24(m, 1H), 7.19-7.17(m, 3H), 7.04-7.01(m, 1H), 6.50(s, 2H) ,6.46-6.43(m,1H),4.18-4.16(m,2H),3.49-3.47(m,1H),3.16-3.11(m,1H),3.01-2.91(m,2H),2.21-2.19( m, 1H), 1.89-1.86 (m, 1H), 1.59-1.56 (m, 1H), 1.43-1.38 (m, 1H).

Example 44: N-(((2S,5R)-5-(((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4- (base)amino)tetrahydro-2H-pyran 2-yl)methyl)benzenesulfonamide (compound 74) (prepared according to scheme five)

Step 44a: Preparation of N-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)benzenesulfonamide hydrochloride (compound 0108-74): To ((3R) , 6S)-6-(aminomethyl)tetrahydro-2H-pyran-3-yl)carbamate tert-butyl ester (110 mg, 0.478 mmol, 1.0 equiv) and triethylamine (0.26 mL, 1.912 mmol , 4.0 equiv) to a mixture of dichloromethane (5 mL) was added benzenesulfonyl chloride (169 mg, 0.957 mmol, 2.0 equiv). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol 30:1) to give ((3R,6S)-6-(phenylsulfonamidomethyl)tetrahydro-2H-pyran-3-yl as a white solid ) tert-butyl carbamate (151 mg, yield: 85%). LCMS (ESI): m/z 371 [M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol=10:1). tert-butyl ((3R,6S)-6-(phenylsulfonamidomethyl)tetrahydro-2H-pyran-3-yl)carbamate (151 mg, 0.408 mmol, 1.0 equiv) in methanol of hydrogen chloride (4M solution, 1.5 mL) was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure and dried under vacuum to give N-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)benzenesulfonamide hydrochloride (125 mg) as a white solid ,Crude). LCMS (ESI): m/z 271 [M+1] ⁺ ; TLC: Rf 0.3 (dichloromethane:methanol=10:1).

Step 44b: N-(((2S,5R)-5-(((5-(2-Chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl ) amino) tetrahydro-2H-pyran 2-yl) methyl) benzenesulfonamide (compound 74) preparation: to (2-chloro-4-phenoxyphenyl) (4-chloro-7H-pyrrolo) [2,3-d]pyrimidin-5-yl)methanone (0503-60) (70 mg, 0.183 mmol, 1.0 equiv) and N-(((2S,5R)-5-aminotetrahydro-2H- Pyran-2-yl)methyl)benzenesulfonamide hydrochloride (0108-74) (74 mg, 0.275 mmol, 1.5 equiv) in tert-butanol (5 mL) was added N,N-diiso Propylethylamine (0.16 mL, 0.914 mmol, 5.0 equiv). The mixture was heated at 90°C overnight under nitrogen atmosphere. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (dichloromethane:methanol=10:1) to give N-(((2S,5R)-5-((5-(2-chloro-4-phenoxybenzene) as a white solid Formyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran2-yl)methyl)benzenesulfonamide (40 mg, yield: 35%) . LCMS (ESI): m/z 618 [M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol=10:1); melting point: 133-137°C. ¹ HNMR (DMSO-d ₆ , 500MHz): δ 12.75(s, 1H), 8.55-8.54(m, 1H), 8.24(s, 1H), 7.83-7.81(m, 2H), 7.78-7.76(m ,1H),7.66-7.56(m,5H),7.49-7.46(m,2H),7.27-7.24(m,1H),7.19-7.17(m,3H),7.03-7.01(m,1H),4.13 -4.08(m, 2H), 3.34-3.30(m, 1H), 3.04-2.99(m, 1H), 2.87-2.82(m, 2H), 2.18-2.13(m, 1H), 1.76-1.73(m, 1H), 1.55-1.47 (m, 1H), 1.37-1.26 (m, 1H).

Example 45: N-(((2S,5R)-5-(((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4- Preparation of (according to Scheme 5)

Step 45a: Preparation of N-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)-4-fluorobenzenesulfonamide hydrochloride (compound 0108-75): To ((3R,6S)-6-(aminomethyl)tetrahydro-2H-pyran-3-yl)carbamate tert-butyl ester (90 mg, 0.391 mmol, 1.0 equiv) and triethylamine (0.22 mL , 1.564 mmol, 4.0 equiv) in dichloromethane (5 mL) was added 4-fluorobenzenesulfonyl chloride (152 mg, 0.783 mmol, 2.0 equiv). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol 30:1) to give ((3R,6S)-6-(((4-fluorophenyl)sulfonamido)methyl)tetrahydro-2H as a white solid -pyran-3-yl)carbamate tert-butyl ester (123 mg, yield: 81%). LCMS (ESI): m/z 389 [M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol=10:1). ((3R,6S)-6-(((4-fluorophenyl)sulfonamido)methyl)tetrahydro-2H-pyran-3-yl)carbamic acid tert-butyl ester prepared above (123 mg, A mixture of 0.317 mmol, 1.0 equiv) in methanolic hydrogen chloride (4M solution, 1.5 mL) was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure and dried under vacuum to give N-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)-4-fluorobenzenesulfonamide as a pale yellow oil Hydrochloride salt (100 mg, crude). LCMS (ESI): m/z 289 [M+1] ⁺ ; TLC: Rf 0.3 (dichloromethane:methanol=10:1).

Step 45b: N-(((2S,5R)-5-(((5-(2-Chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl ) amino) tetrahydro-2H-pyran 2-yl) methyl)-4-fluorobenzenesulfonamide (compound 75) preparation: to (2-chloro-4-phenoxyphenyl) (4-chloro- 7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (0503-60) (60 mg, 0.157 mmol, 1.0 equiv) and N-(((2S,5R)-5-aminotetrakis A mixture of hydro-2H-pyran-2-yl)methyl)-4-fluorobenzenesulfonamide hydrochloride (0108-75) (76 mg, 0.235 mmol, 1.5 equiv) in tert-butanol (5 mL) To this was added N,N-diisopropylethylamine (0.14 mL, 0.785 mmol, 5.0 equiv). The mixture was heated at 90°C overnight under nitrogen atmosphere. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (ethyl acetate:dichloromethane:methanol=15::15:2) to give N-(((2S,5R)-5-((5-(2-chloro) as a white solid -4-Phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran2-yl)methyl)-4-fluorobenzenesulfone Amide (26 mg, yield: 26%). LCMS (ESI): m/z 636 [M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol=10:1); melting point: 140-143°C. ¹ HNMR (DMSO-d ₆ , 500MHz): δ 12.72(s, 1H), 8.55(d, J=7.0Hz, 1H), 8.24(s, 1H), 7.89-7.86(m, 2H), 7.82- 7.80(m, 1H), 7.61(s, 1H), 7.56(d, J=8.5Hz, 1H), 7.49-7.42(m, 4H), 7.27-7.24(m, 1H), 7.19-7.17(m, 3H), 7.03-7.02(m, 1H), 4.10-4.08(m, 2H), 3.36-3.32(m, 1H), 3.05-3.00(m, 1H), 2.90-2.82(m, 2H), 2.16- 2.13 (m, 1H), 1.75-1.73 (m, 1H), 1.57-1.49 (m, 1H), 1.39-1.31 (m, 1H).

Example 46: N-(((2S,5R)-5-(((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine-4- (base)amino)tetrahydro-2H-pyran2-yl)methyl)cyanamide (compound 76) (prepared according to scheme five)

Step 46a: Preparation of N-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)cyanamide hydrochloride (compound 0108-76): go to ( (3R,6S)-6-(Aminomethyl)tetrahydro-2H-pyran-3-yl)carbamate tert-butyl ester (100 mg, 0.435 mmol, 1.0 equiv) and sodium acetate (107 mg, 1.304 mmol) mol, 3.0 equiv) in methanol (4 mL) was added dropwise a solution of cyanogen bromide (92 mg, 0.870 mmol, 2.0 equiv) in methanol (1 mL). The mixture was warmed to room temperature and stirred overnight. The reaction was quenched by the addition of saturated sodium bicarbonate solution (20 mL). The aqueous layer was extracted with dichloromethane (20 mL×3). The combined organic layers were washed with brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated to give ((3R,6S)-6-(cyanamidomethyl)tetrahydro-2H-pyran as a white solid -3-yl) tert-butyl carbamate (75 mg, crude). LCMS (ESI): m/z 256[M+1] ⁺ . tert-Butyl ((3R,6S)-6-(cyanamidomethyl)tetrahydro-2H-pyran-3-yl)carbamate (75 mg, 0.294 mmol, 1.0 equiv) prepared above in hydrogen chloride A mixture of methanol solution (4M solution, 1.5 mL) was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and dried under vacuum to give N-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)cyanamide hydrochloride (56 mg, Crude). LCMS (ESI): m/z 156[M+1] ⁺ .

Step 46b: N-(((2S,5R)-5-(((5-(2-Chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl ) amino) tetrahydro-2H-pyran 2-yl) methyl) cyanamide (compound 76) preparation: To (2-chloro-4-phenoxyphenyl) (4-chloro-7H-pyrrolo[ 2,3-d]pyrimidin-5-yl)methanone (0503-60) (70 mg, 0.183 mmol, 1.0 equiv) and N-(((2S,5R)-5-aminotetrahydro-2H-pyridine To a mixture of pyran-2-yl)methyl)cyanamide hydrochloride (0108-76) (52 mg, 0.275 mmol, 1.5 equiv) in tert-butanol (5 mL) was added N,N-diisopropyl Ethylamine (0.16 mL, 0.915 mmol, 5.0 equiv). The mixture was heated at 90°C overnight under nitrogen atmosphere. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (ethyl acetate:dichloromethane:methanol=15::15:3) to give N-(((2S,5R)-5-((5-(2-chloro) as a white solid -4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran 2-yl)methyl)cyanamide (22 mg, Yield: 24%). LCMS (ESI): m/z 503 [M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol=10:1); melting point: 136-139°C. ¹ HNMR (DMSO-d ₆ , 500MHz): δ 12.73(s, 1H), 8.59(d, J=7.0Hz, 1H), 8.25(s, 1H), 7.61(s, 1H), 7.56(d, J=8.5Hz, 1H), 7.49-7.46(m, 2H), 7.26-7.25(m, 1H), 7.18-7.17(m, 3H), 7.03-7.01(m, 1H), 6.84-6.82(m, 1H), 4.19-4.14(m, 2H), 3.46-3.44(m, 1H), 3.18-3.14(m, 1H), 3.07-3.03(m, 1H), 2.97-2.93(m, 1H), 2.20- 2.18 (m, 1H), 1.78-1.76 (m, 1H), 1.65-1.58 (m, 1H), 1.48-1.42 (m, 1H).

Example 47: (2-Chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-(((2-hydroxyethyl)amino)methyl)tetrahydro-2H-pyridine Preparation of pyran-3-yl)amino)-7H-pyrro[2,3-d]pyrimidin-5-yl)methanone (Compound 77) (prepared according to Scheme 5)

To (2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7-(methylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)amino)tetrahydro-2H-pyran-2-yl)methyl methanesulfonate (054-6 (74 mg, 0.117 mmol, 1.0 equiv) and sodium iodide (9 mg, 0.059 mmol, 0.5 equiv) to a mixture of acetonitrile (6 mL) was added ethanolamine (71 mg, 1.17 mmol, 10.0 equiv). The mixture was heated at 80°C overnight under nitrogen atmosphere. The solvent was removed under reduced pressure. The residue was diluted with water (15 mL). and filtered. The solid was collected and then purified by preparative thin layer chromatography (ethyl acetate:methanol=5:1) to give (2-chloro-4-phenoxyphenyl)(4-(((3R,6S) as a white solid -6-(((2-hydroxyethyl)amino)methyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrro[2,3-d]pyrimidin-5-yl)methanone (30 mg, yield: 49%) LCMS (ESI): m/z 522 [M+1] ⁺ ; TLC: Rf 0.3 (dichloromethane:methanol=8:1); ¹ HNMR (DMSO-d ₆ , 500MHz): δ 8.62-8.61(m, 2H), 8.25(s, 1H), 7.62(s, 1H), 7.56(d, J=7.5Hz, 1H), 7.50- 7.47(m,2H),7.27-7.22(m,1H),7.19-7.17(m,3H),7.03-7.01(m,1H),5.12(s,1H),4.24-4.21(m,2H), 3.74-3.72(m, 1H), 3.66(s, 2H), 3.23-3.20(m, 2H), 3.11-3.09(m, 1H), 2.98-2.94(m, 3H), 2.22-2.20(m, 1H ), 1.83-1.80 (m, 1H), 1.67-1.62 (m, 1H), 1.51-1.46 (m, 1H).

Example 48: (2-Chloro-4-((2-(methoxymethyl)benzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-( Preparation of hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (compound 7) (prepared according to scheme one route) )

Step 48a: Preparation of 2-chloro-4-((2-(methoxymethyl)benzofuran-7-yl)oxy)benzoic acid (compound 0104-7): under nitrogen at 0°C To methyl 2-chloro-4-((2-(hydroxymethyl)benzofuran-7-yl)oxy)benzoate (0103-6) (250 mg, 0.753 mmol, 1.0 equiv) in N, To a mixture of N-dimethylformamide (5 mL) was added sodium hydride (61 mg, 1.503 mmol, 2.0 equiv) and iodomethane (161 mg, 1.130 mmol, 1.5 equiv). The mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (15 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate=2:1) to give 2-chloro-4-((2-(methoxymethyl)benzofuran-7-yl)oxy) as a yellow solid Methyl benzoate (150 mg, yield: 57.7%) LCMS (ESI): m/z 347 [M+1] ⁺ .

Hydroxide of methyl 2-chloro-4-((2-(methoxymethyl)benzofuran-7-yl)oxy)benzoate (150 mg, 0.753 mmol, 1.0 equiv) obtained above A mixture of sodium solution (4 mL) and tetrahydrofuran (2 mL) was stirred at room temperature overnight. The mixture was adjusted to pH=6. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (15 mL×1), dried over anhydrous sodium sulfate and concentrated to give 2-chloro-4-((2-(methoxymethyl)benzofuran-7-) as a yellow solid yl)oxy)benzoic acid (148 mg, crude) LCMS (ESI): m/z 333 [M+1] ⁺ .

Step 48b: (2-Chloro-4-((2-(methoxymethyl)benzofuran-7-yl)oxy)phenyl)(4-chloro-7-((2-(trimethyl) Preparation of silyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (compound 0107-7): 2-chloro-4 -((2-(methoxymethyl)benzofuran-7-yl)oxy)benzoic acid (0104-7) (240 mg, 0.723 mmol, 1.0 equiv), N,O-dimethylhydroxylamine hydrochloride (106 mg, 1.084 mmol, 1.5 equiv), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (330 mg , 0.867 mmol, 1.2 equiv), triethylamine (366 mg, 3.614 mmol, 5.0 equiv) and N,N-dimethylformamide (5 mL) were stirred at room temperature for 4 hours. The mixture was diluted with water (25 mL), then extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (15 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate=2:3) to give 2-chloro-N-methoxy-4-((2-(methoxymethyl)benzofuran-7) as a yellow solid -yl)oxy)-N-methylbenzamide (160 mg, yield: 59%) LCMS (ESI): m/z 376 [M+1] ⁺ . Under nitrogen, at 0 °C, 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0106-1) (2.0 g, 8.6 mmol, 1.0 equiv) was dissolved in N,N - To a mixture of dimethylformamide (40 mL) was added sodium hydride (688 mg, 17.2 mmol, 2.0 equiv). The mixture was stirred at room temperature for 0.5 h. To the mixture was added 2-(trimethylsilyl)ethoxymethyl chloride (1.9 g, 11.2 mmol, 1.3 equiv) at 0°C. Mix and react at room temperature for 1 hour. The mixture was diluted with water (200 mL), then extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (50 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate=4:1) to give 5-bromo-4-chloro-7-(((2-(trimethylsilyl)ethoxy)methan as a white solid yl)-7H-pyrrolo[2,3-d]pyrimidine (1.86 g, yield: 60%) LCMS (ESI): m/z 362 [M+1] ⁺ . Under nitrogen at -70°C , to 5-bromo-4-chloro-7-(((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (310 mg, 0.426 mmol, 2.0 equiv) in tetrahydrofuran solution (5 mL) was added dropwise n-butyllithium (0.7 mL, 1.107 mmol, 2.6 equiv) and the mixture was stirred at -70°C for 1 hour. Then slowly added to the mixture 2-Chloro-N-methoxy-4-((2-(methoxymethyl)benzofuran-7-yl)oxy)-N-methylbenzamide (160 mg, 0.426 g) obtained above mmol, 1.0 equiv) in tetrahydrofuran (2 mL), and the mixture was stirred at -70°C for 1 h. The reaction was quenched with saturated ammonium chloride solution (5 mL). The mixture was diluted with water (15 mL) and then Extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with saturated brine (15 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate) = 2:1) to give (2-chloro-4-((2-(methoxymethyl)benzofuran-7-yl)oxy)phenyl)(4-chloro-7-((2-chloro) as a yellow solid -(Trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (120 mg, yield: 47.2%), LCMS (ESI ): m/z 598[M+1] ⁺ .

Step 48c: (2-Chloro-4-((2-(methoxymethyl)benzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxyl Preparation of methyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (compound 7): under nitrogen protection, to ( 2-Chloro-4-((2-(methoxymethyl)benzofuran-7-yl)oxy)phenyl)(4-chloro-7-((2-(trimethylsilyl)) Ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (0107-7) (120 mg, 0.201 mmol, 1.0 equiv) and ((2S,5R) -5-Aminotetrahydro-2H-pyran-2-yl)methanol hydrochloride (0108-1) (40 mg, 0.241 mmol, 1.2 equiv) in tert-butanol (5 mL) was added N, N-Diisopropylethylamine (2 mL). The mixture was heated to 90°C for overnight reaction. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (15 mL×1), dried over anhydrous sodium sulfate and concentrated to give a yellow solid (2-chloro-4-(((2-(methoxymethyl)benzofuran- 7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7-(((2- (Trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (58 mg, crude). LCMS (ESI): m/z 693[M+1] ⁺ .

(2-chloro-4-(((2-(methoxymethyl)benzofuran-7-yl)oxy)phenyl)(4-(((((3R,6S)- 6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7-(((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[ To a mixture of 2,3-d]pyrimidin-5-yl)methanone (50 mg, 0.072 mmol, 1.0 equiv) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at room temperature 1 hour. After the reaction solution was concentrated, methanol and ammonia water were added to the residue. The mixture was stirred at room temperature overnight. The mixture was diluted with water (15 mL), and then extracted with ethyl acetate (15 mL×3). The combined organic layers were saturated with Washed with brine (15 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (dichloromethane:methanol=20:1) to give a yellow solid (2-chloro-4-( (2-(Methoxymethyl)benzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran- 3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (35 mg, yield: 87.5%). LCMS (ESI): m/z 563 [M+1 ] ⁺ ;TLC: Rf 0.5 (dichloromethane:methanol=20:1). ¹ H NMR (500 MHz, DMSO) δ 12.48 (s, 1H), 8.23 (s, 1H), 7.77 (d, J=6.8 Hz, 1H), 7.62(d, J＝8.4Hz, 1H), 7.57(d, J＝7.6Hz, 1H), 7.33(t, J＝7.7Hz, 1H), 7.25(s, 1H), 7.18– 7.11(m, 2H), 7.09–7.01(m, 2H), 4.64(s, 1H), 4.54(s, 2H), 4.14(d, J=21.1Hz, 1H), 3.98(d, J=8.5Hz ,1H),3.39(d,J＝5.3Hz,1H),3.29(s,3H),3.27–3.22(m,1H),3.17(d,J＝4.7Hz,1H),3.06(t,J＝ 10.5Hz, 1H), 2.02 (d, J=10.7Hz, 1H), 1.74 (d, J=12.7Hz, 1H), 1.53 (d, J=12.4Hz, 1H), 1.32 (d, J=12.8Hz) , 1H).

Example 49: 7-(3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo Preparation of [2,3-d]pyrimidine-5-carbonyl)phenoxy)benzofuran-2-carbonitrile (compound 9) (prepared according to Scheme VI)

Step 49a: Preparation of 7-hydroxybenzofuran-2-carboxamide (compound 0101-9):

To a solution of 2-hydroxy-3-methoxybenzaldehyde (912 mg, 6.0 mmol, 1.0 equiv) and bromoacetonitrile (792 mg, 6.6 mmol, 1.1 equiv) in 40 mL of N,N-dimethylformamide To the mixture was added cesium carbonate (5.8 g, 18.0 mmol, 3.0 equiv). The mixture was stirred at room temperature overnight, ethyl acetate was added, washed with water and saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate= 2/1 to 1/1) was purified to give 7-methoxybenzofuran-2-carboxamide (440 mg, yield: 38%) as a yellow solid. MS(ES ⁺ ): m/z 192(M+H) ⁺ .

To a solution of the above obtained 7-methoxybenzofuran-2-carboxamide (600 mg, 3.1 mmol, 1.0 equiv) in 50 mL dichloromethane was added 2M boron tribromide in dichloromethane under nitrogen Methane solution (2.82 mL, 5.6 mmol, 1.8 equiv). The mixture was stirred at room temperature for 3 hours. The reaction was quenched with ammonium chloride solution, extracted with dichloromethane, washed with saturated brine, the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=2/1 to 1/2) to give 7-hydroxybenzofuran-2-carboxamide (500 mg, yield: 90%) as a yellow solid. MS(ES ⁺ ): m/z 178(M+H) ⁺ .

Step 49b: Preparation of 7-(3-Chloro-4-formylphenoxy)benzofuran-2-carboxamide (Compound 0602-9): 7-Hydroxybenzofuran-2-methane under nitrogen Amide (0101-9) (500 mg, 2.8 mmol, 1.0 equiv), 2-chloro-4-fluorobenzaldehyde (0601-9) (533 mg, 3.36 mmol, 1.2 equiv) and potassium carbonate (1.16 g, 8.4 mmol, 3.0 equiv.) in 25 mL of N,N-dimethylformamide and stirred at 90°C for 3 hours. Ethyl acetate was added, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 3/1 to 1/ 1) to obtain 7-(3-chloro-4-formylphenoxy)benzofuran-2-carboxamide (740 mg, yield: 83%) as a yellow solid. MS(ES ⁺ ): m/z 316(M+H) ⁺ .

Step 49c: 7-(3-Chloro-4-((4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(hydroxy)methyl)phenoxy)benzofuran-2 - Preparation of carbonitrile (compound 0603-9): under nitrogen protection, 7-(3-chloro-4-formylphenoxy)benzofuran-2-carboxamide (0602-9) (300 mg, 0.95 mmol, 1.0 equiv) was dissolved in 10 mL of dry N,N-dimethylformamide. The mixture was cooled to 0°C. Cyanuric chloride (1.23 g, 6.66 mmol, 7.0 equiv) was added, followed by stirring at 0°C for 3 hours. Ethyl acetate was added, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1 to 3/ 1) to obtain 7-(3-chloro-4-formylphenoxy)benzofuran-2-carbonitrile (128 mg, yield: 45%) as a yellow solid. MS(ES ⁺ ): m/z 298(M+H) ⁺ .

Under nitrogen, 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0106-1) (114 mg, 0.50 mmol, 1.5 equiv) was dissolved in 10 mL of dry tetrahydrofuran, and the Cool to -70°C. A 1.6M solution of n-butyllithium in n-hexane (0.79 mL, 1.26 mmol, 3.8 equiv) was added dropwise. The mixture was stirred at -70°C for 1 hour. 7-(3-Chloro-4-formylphenoxy)benzofuran-2-carbonitrile (100 mg, 0.34 mmol, 1.0 equiv) obtained above was dissolved in 0.5 mL of anhydrous tetrahydrofuran and added dropwise to in the above mixture. The mixture was stirred at -70°C for 1 hour. The reaction was quenched by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1 to 1/1) to obtain a yellow solid 7-(3- Chloro-4-((4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(hydroxy)methyl)phenoxy)benzofuran-2-carbonitrile (41 mg, received rate: 26%). MS(ES ⁺ ): m/z 451(M+H) ⁺ .

Step 49d: 7-(3-Chloro-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenoxy)benzofuran-2-carbonitrile (Compound 0107- 9) Preparation: 7-(3-Chloro-4-((4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(hydroxy)methyl)phenoxy)benzofuran -2-Carboxonitrile (0603-9) (41 mg, 0.089 mmol, 1.0 equiv) was dissolved in 6 mL of dimethyl sulfoxide, followed by the addition of 2-iodoylbenzoic acid (125 mg, 0.443 mmol, 5.0 equiv) . The mixture was stirred at room temperature overnight. Water was added to quench the reaction, ethyl acetate was added for extraction, the organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow solid 7-(3-chloro-4-(4-chloro-7H-pyrrolo[ 2,3-d]Pyrimidine-5-carbonyl)phenoxy)benzofuran-2-carbonitrile (40 mg, crude). MS(ES ⁺ ): m/z 449(M+H) ⁺ .

Step 49e: 7-(3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[ Preparation of 2,3-d]pyrimidine-5-carbonyl)phenoxy)benzofuran-2-carbonitrile (compound 9): 7-(3-chloro-4-(4-chloro-7H-pyrrolo) [2,3-d]pyrimidine-5-carbonyl)phenoxy)benzofuran-2-carbonitrile (0107-9) (40 mg, 0.091 mmol, 1.0 equiv), ((2S,5R)-5 - Aminotetrahydro-2H-pyran-2-yl)methanol hydrochloride (0108-1) (18 mg, 0.11 mmol, 1.2 equiv) and diisopropylethylamine (35 mg, 0.27 mmol, 3.0 equiv.) was added to 10 mL of tert-butanol and the mixture was stirred at 90°C overnight. The mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with water and saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (developing solvent: dichloromethane/methanol= 25/1) to give a yellow solid 7-(3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)- 7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenoxy)benzofuran-2-carbonitrile (20 mg, yield: 33%). MS (ES ⁺ ): m/z 544 (M+H) ⁺ ; melting point: 135-137°C. ¹ H NMR (500MHz, DMSO) δ12.73(s, 1H), 8.57(d, J=7.2Hz, 1H), 8.24(d, J=11.4Hz, 2H), 7.75-7.70(m, 1H), 7.63(s, 1H), 7.60(d, J=8.5Hz, 1H), 7.48(t, J=7.9Hz, 1H), 7.41(dd, J=7.9, 0.8Hz, 1H), 7.36(d, J =2.4Hz,1H),7.11(dd,J=8.5,2.4Hz,1H),4.62(t,J=5.6Hz,1H),4.21–4.09(m,2H),3.42(dd,J=11.6, 6.2Hz, 1H), 3.40–3.34 (m, 2H), 3.13 (t, J=11.6Hz, 1H), 2.22–2.12 (m, 1H), 1.79 (d, J=13.6Hz, 1H), 1.58 ( dd,J=11.9,4.0Hz,1H),1.43–1.37(m,1H).

Example 50: ((2-Chloro-4-((4-fluorobenzofuran-7-yl)oxy)phenyl)(4-((3R,6S)-6-(hydroxymethyl)tetrahydro Preparation of -2H-pyran-3-yl)amino)-7Hpyrro[2,3-d]pyrimidin-5-yl)methanone (Compound 19) (prepared according to Scheme 1)

Step 50a: Preparation of 4-fluorobenzofuran-7-ol (compound 0101-19):

Under nitrogen, 5-fluoro-2-methoxyphenol (2.0 g, 14.08 mmol, 1.0 equiv), 2-bromo-1,1-diethoxyethane (3.6 g, 18.3 mmol, 1.3 equiv), potassium carbonate (3.89 g, 28.16 mmol, 2.0 equiv) and potassium iodide (0.2 g, 10 wt%) in N,N-dimethylformamide (30 mL) was stirred at 90°C overnight. After cooling to room temperature, the reaction was quenched with water (30 mL) and extracted with ethyl acetate (60 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product 2-(2,2-diethoxyethoxy)-4-fluoro-1-methoxybenzene (3.1 g, yield rate: 86.1%). This product was used in the next step without further purification.

Under nitrogen protection, 2-(2,2-diethoxyethoxy)-4-fluoro-1-methoxybenzene (3.1 g, 12.01 mmol, 1.0 equiv) obtained above, and polyphosphoric acid were combined (10.2 g, 30.03 mmol, 2.5 equiv) in 1,2-dichloroethane (50 mL) at reflux overnight. After cooling to room temperature, the reaction was quenched with water (50 mL) and extracted with dichloromethane (100 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether) to give 4-fluoro-7-methoxybenzofuran (1.1 g, yield: 55.3%) as a yellow oil. MS(ES ⁺ ): m/z=167(M+H) ⁺ .

To a solution of 4-fluoro-7-methoxybenzofuran obtained above (1.1 g, 6.62 mmol, 1.0 equiv) in dichloromethane (15 mL) was added boron tribromide (2.49 g) under nitrogen , 9.94 mmol, 1.5 equiv), and the mixture was stirred at 0 °C for 2 h. The reaction solution was quenched with methanol, diluted with water and extracted with dichloromethane. The organic phase was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether/ethyl acetate=120/1 to 50/1) to obtain 4-fluorobenzofuran-7-ol (880 mg, yield: 88.0%) as a yellow oily product. MS(ES ⁺ ): m/z=153(M+H) ⁺ .

Step 50b: Preparation of methyl 2-chloro-4-((4-fluorobenzofuran-7-yl)oxy)benzoate (compound 0103-19): under nitrogen To a solution of 7-ol (0101-19) (600 mg, 3.95 mmol, 1.0 equiv) in N,N-dimethylformamide (15 mL) was added methyl 2-chloro-4-fluorobenzoate (0102- 1) (1.12 g, 5.92 mmol, 1.5 equiv), potassium carbonate (1.09 g, 7.90 mmol, 2.0 equiv). The mixture was stirred at 90°C overnight. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether/ethyl acetate=40/1 to 5/1) to give 2-chloro-4-((4-fluorobenzofuran-7-yl)oxy)benzene as a white solid product Methyl formate (950 mg, yield: 75.2%). MS (ES ⁺ ): m/z=321[M+1]+.

Step 50c: Preparation of 2-chloro-4-((4-fluorobenzofuran-7-yl)oxy)benzoic acid (compound 0104-19): To 2-chloro-4-((4-fluorobenzoic acid) To a solution of methyl furan-7-yl)oxy)benzoate (0103-19) (950 mg, 2.97 mmol, 1.0 equiv) in tetrahydrofuran (5 mL) was added 2M sodium hydroxide solution (5 mL), followed by The mixture was stirred at room temperature overnight. The reaction solution was adjusted to pH=4 with 4M hydrochloric acid, and extracted with ethyl acetate. The resulting organic phase was dried and concentrated under reduced pressure. The residue was used directly in the next step without further purification. LCMS (ESI): m/z=307[M+1]+.

Step 50d: Preparation of 2-chloro-4-((4-fluorobenzofuran-7-yl)oxy)benzoyl chloride (compound 0105-19) by adding 2-chloro- To a solution of 4-((4-fluorobenzofuran-7-yl)oxy)benzoic acid (0104-19) (410 mg, 4.02 mmol, 1.0 equiv) in tetrahydrofuran (8 mL) was added oxalyl chloride (510 mg) , 4.02 mmol, 3.0 equiv), N,N-dimethylformamide (10 mg), and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure. The residue was used directly in the next step without further purification.

Step 50e: (2-Chloro-4-((4-fluorobenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrro[2,3-d]pyrimidin-5-yl) Preparation of ketone (compound 0107-19): under nitrogen protection, at 0 °C, to 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0106-1) (300 mg, 1.3 mmol, 0.9 equiv) in tetrahydrofuran (5 mL) was added sodium hydrogen (165 mg, 4.11 mmol, 3.0 equiv), then n-butyllithium was slowly added dropwise at -70°C and stirred for 1.0 h. At -70°C, a solution of 2-chloro-4-((4-fluorobenzofuran-7-yl)oxy)benzoyl chloride (0105-19) (400 mg, crude) in 5 mL of tetrahydrofuran was added dropwise to The reaction solution was stirred for 1.5 hours. The reaction solution was quenched with ammonium chloride solution, diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether/ethyl acetate = 20/1 to 1/1) to give a yellow solid product (2-chloro-4-((4-fluorobenzofuran-7-yl)oxy) Phenyl)(4-chloro-7H-pyrrole[2,3-d]pyrimidin-5-yl)methanone (120 mg, yield: 18.8%) LCMS (ESI): m/z=443 [M+1 ]+.

Step 50f: ((2-Chloro-4-((4-fluorobenzofuran-7-yl)oxy)phenyl)(4-((3R,6S)-6-(hydroxymethyl)tetrahydro- Preparation of 2H-pyran-3-yl)amino)-7Hpyrro[2,3-d]pyrimidin-5-yl)methanone (Compound 19): To (2-chloro-4-((4-fluorobenzene) (2,3-d]pyrimidin-5-yl)methanone (0107-19) (80 mg, 0.18 mmol, 1.0 equiv) and ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol hydrochloride (28.6 mg, 0.21 mmol, 1.2 equiv) in tert-butanol (5 mL) N,N-diisopropylethylamine (0.5 mL) was added. The mixture was heated at 90°C overnight. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified by silica gel column (dichloromethane/methanol=100/1 to 10/1) to obtain (2-chloro-4-((4-fluorobenzofuran-7-yl)oxy)benzene as a yellow solid product base)(4-((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7Hpyrro[2,3-d]pyrimidin-5-yl)methyl Ketone (65 mg, yield: 67.0%). MS(ES+): m/z=538(M+H)+. Melting point: 152-163℃; ¹ HNMR (500MHz, DMSO) δ12.70(s, 1H), 8.57(d, J=6.9Hz, 1H ),8.24(s,1H),8.10(s,1H),7.61–7.50(m,2H),7.20(ddd,J=29.5,13.3,5.3Hz,4H),7.05–6.95(m,1H), 4.61(s, 1H), 4.15(d, J=7.4Hz, 2H), 3.45–3.38(m, 1H), 3.34(d, J=7.5Hz, 2H), 3.12(t, J=11.3Hz, 1H) ),2.18(d,J＝11.5Hz,1H),1.78(d,J＝12.9Hz,1H),1.57(dd,J＝22.5,10.5Hz,1H),1.38(dd,J＝23.0,9.9Hz , 1H).

Example 51: (2-Chloro-4-((2-Chloro-5-fluorobenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl) (base)tetrahydro-2H-pyran-3-yl))amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (compound 23) (prepared according to Scheme 1)

Step 51a: Preparation of 2-chloro-4-((2-chloro-5-fluorobenzofuran-7-yl)oxy)benzoic acid (compound 0104-23):

To 2-chloro-4-((5-fluorobenzofuran-7-yl)oxy)benzoic acid (0104-20) (1.0 g, 3.27 mmol, 1.0 equiv) and N,N-dimethylmethane To a mixture of the amide (2 drops) in dichloromethane (12 mL) was added oxalyl chloride (0.55 mL, 6.54 mmol, 2.0 equiv). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL) to give a solution of 2-chloro-4-((5-fluorobenzofuran-7-yl)oxy)benzoyl chloride. To a mixture of tert-butanol (1.57 mL, 4.25 mmol, 1.3 equiv) in tetrahydrofuran (10 mL) was added dropwise n-butyllithium (2.5 M in hexane, 1.57 mL, 3.92 mol) at 0°C under nitrogen mmol, 1.2 equiv). The mixture was stirred for 15 minutes. A solution of 2-chloro-4-((5-fluorobenzofuran-7-yl)oxy)benzoyl chloride in tetrahydrofuran was added dropwise, and the mixture was stirred at 0°C for 0.5 hours. The reaction was quenched by the addition of saturated ammonium chloride solution (30 mL). The aqueous layer was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with saturated brine (30 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was subjected to column chromatography on silica gel (petroleum ether:ethyl acetate 60:1) to give 2-chloro-4-((5-fluorobenzofuran-7-yl)oxy)benzoic acid as a pale yellow oil tert-Butyl ester (0.629 g, yield: 53%). LCMS (ESI): m/z 363 [M+1] ⁺ ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=30:1).

To the above obtained tert-butyl 2-chloro-4-((5-fluorobenzofuran-7-yl)oxy)benzoate (407 mg, 1.12 mmol, 1.0 equiv.) under nitrogen atmosphere at -78°C ) To a mixture of tetrahydrofuran (7 mL) was added N,N-diisopropylamide lithium (2.0 M in tetrahydrofuran, 0.79 mL, 1.58 mmol, 1.4 equiv) dropwise. The mixture was stirred for 1 hour. A solution of hexachloroethane (373 mg, 1.58 mmol, 1.4 equiv) in tetrahydrofuran (1 mL) was added dropwise, and the mixture was stirred at -78°C for 1 hour. The reaction was quenched by the addition of saturated aqueous ammonium chloride (30 mL). The aqueous layer was extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was subjected to column chromatography on silica gel (petroleum ether:ethyl acetate 100:1) to give 2-chloro-4-((2-chloro-5-fluorobenzofuran-7-yl)oxyl as a pale yellow oil yl) tert-butyl benzoate (370 mg, yield: 83%). LCMS (ESI): m/z 397 [M+1] ⁺ ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=30:1).

To the above obtained tert-butyl 2-chloro-4-((2-chloro-5-fluorobenzofuran-7-yl)oxy)benzoate (370 mg, 0.93 mmol, 1.0 equiv) in dichloromethane (8 mL) was added trifluoroacetic acid (2.5 mL). The mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure. The residue was dried under vacuum to give 2-chloro-4-((2-chloro-5-fluorobenzofuran-7-yl)oxy)benzoic acid (252 mg, yield: 80%) as a white solid. LCMS (ESI): m/z 341 [M+1] ⁺ ; TLC: Rf 0.3 (dichloromethane:methanol=20:1).

Step 51b: Preparation of 2-chloro-4-((2-chloro-5-fluorobenzofuran-7-yl)oxy)benzoyl chloride (compound 0105-23): To 2-chloro-4-(( 2-Chloro-5-fluorobenzofuran-7-yl)oxy)benzoic acid (0104-23) (252 mg, 0.74 mmol, 1.0 equiv) and N,N-dimethylformamide (1.6 mg, 0.022 mmol, 0.03 equiv) to a mixture of dichloromethane (6 mL) and tetrahydrofuran (1 mL) was added oxalyl chloride (0.16 mL, 1.85 mmol, 2.5 equiv). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and dried under vacuum to give 2-chloro-4-((2-chloro-5-fluorobenzofuran-7-yl)oxy)benzoyl chloride (266 mg, crude) as a pale yellow oil .

Step 51c: (2-Chloro-4-((2-Chloro-5-fluorobenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidine Preparation of -5-yl)methanone (compound 0107-23): To a mixture of sodium hydride (60%, 76 mg, 1.90 mmol, 2.0 equiv) in tetrahydrofuran (4 mL) was added 5-bromo under nitrogen atmosphere -4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (0106-1) (220 mg, 0.95 mmol, 1.0 equiv). The mixture was stirred at room temperature for 10 minutes and then cooled to -78°C. n-Butyllithium (2.5M in hexanes, 0.57 mL, 1.42 mmol, 1.5 equiv) was added dropwise and stirred for 1 hour. 2-Chloro-4-((2-chloro-5-fluorobenzofuran-7-yl)oxy)benzoyl chloride (0105-23) (273 mg, 0.76 mmol, 0.8 equiv) in tetrahydrofuran was added dropwise (2 mL) solution, then stirred at -78°C for 1 hour. The reaction was quenched by the addition of saturated aqueous ammonium chloride (30 mL). The aqueous layer was extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was subjected to column chromatography on silica gel (petroleum ether:ethyl acetate 2:1) to give (2-chloro-4-((2-chloro-5-fluorobenzofuran-7-yl)oxy) as a pale yellow solid yl)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (119 mg, yield: 33%). LCMS (ESI): m/z 476 [M+1] ⁺ ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=1:1).

Step 51d: (2-Chloro-4-((2-chloro-5-fluorobenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl) ) Preparation of tetrahydro-2H-pyran-3-yl))amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 23): To (2-chloro-4 -((2-Chloro-5-fluorobenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (0107 -23) (119 mg, 0.25 mmol, 1.0 equiv) and (3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-amine hydrochloride (54 mg, 0.33 mmol, 1.3 equiv.) To a mixture of tert-butanol (10 mL) was added N,N-diisopropylethylamine (0.22 mL, 1.25 mmol, 5.0 equiv). The mixture was heated at 90°C under nitrogen atmosphere overnight. The mixture was diluted with water (20 mL), then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (ethyl acetate:dichloromethane:methanol=10:10:2) to give (2-chloro-4-((2-chloro-5-fluorobenzofuran-7) as a white solid -yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl))amino)-7H-pyrrolo[2, 3-d]pyrimidin-5-yl)methanone (70 mg, yield: 49%). LCMS (ESI): m/z 571 [M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol=10:1); melting point: 163-166°C. ¹ H NMR (500MHz, DMSO) δ 12.74(s, 1H), 8.57(d, J=6.7Hz, 1H), 8.25(s, 1H), 7.77-7.57(m, 2H), 7.43(s, 1H) ), 7.33 (d, J=8.1Hz, 1H), 7.25–7.05 (m, 3H), 4.62 (d, J=5.5Hz, 1H), 4.16 (d, J=7.2Hz, 2H), 3.46–3.33 (m, 3H), 3.19–3.04 (m, 1H), 2.20 (d, J=11.6Hz, 1H), 1.79 (d, J=12.7Hz, 1H), 1.63–1.50 (m, 1H), 1.39 ( dd,J=27.9,15.8Hz,1H).

Example 52: (2-Chloro-4-((2-methylbenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(((3-(methyl) sulfonyl)propoxy)methyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 46) preparation

To (2-chloro-4-((2-methylbenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H -pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (compound 2) (146 mg, 0.27 mmol, 1.0 equiv) and N,N- To a mixture of diisopropylethylamine (0.20 mL, 1.10 mmol, 4.0 equiv) in dichloromethane (6 mL) was added methanesulfonyl chloride (78 mg, 0.69 mmol, 2.5 equiv). The mixture was stirred at room temperature for 2 hours. The reaction was quenched by the addition of saturated sodium bicarbonate solution (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated to give a pale yellow solid ((2S,5R)-5-((5-(2-chloro-4-( (2-Methylbenzofuran-7-yl)oxy)benzoyl)-7-(methylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrakis Hydrogen-2H-pyran-2-yl)methylmethanesulfonate (173 mg, yield: 92%). TLC: Rf 0.6 (dichloromethane:methanol=10:1).

To a mixture of 3-(methylsulfonyl)propan-1-ol (129 mg, 0.93 mmol, 4.2 equiv) in N-methylpyrrolidone (4 mL) was added potassium hexamethyldisilazide dropwise (KHMDS) (1M solution in tetrahydrofuran, 0.93 mL, 0.93 mmol, 4.2 equiv). The mixture was stirred at room temperature for 10 minutes. Add ((2S,5R)-5-((5-(2-chloro-4-((2-methylbenzofuran-7-yl)oxy)benzoyl)-7-(methylsulfonyl )-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)methylmethanesulfonate (153 mg, 0.22 mmol, 1.0 equiv) . The mixture was stirred at room temperature for 1 h and then heated to 100°C for 40 minutes. The reaction was quenched by the addition of saturated aqueous ammonium chloride (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (dichloromethane:methanol=10:1) to give 2-chloro-4-((2-methylbenzofuran-7-yl)oxy)phenyl)( 4-(((3R,6S)-6-((3-(methylsulfonyl)propoxy)methyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2 ,3-d]pyrimidin-5-yl)methanone (18 mg, yield: 13%). LCMS (ESI): m/z 653 [M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol=10:1); melting point: 136-139°C. ¹ H NMR (500MHz, DMSO) δ 12.36(s, 1H), 8.58(d, J=7.1Hz, 1H), 8.24(s, 1H), 7.64-7.52(m, 2H), 7.44(d, J =7.6Hz,1H),7.29–7.18(m,2H),7.05(d,J=7.9Hz,1H),7.00(dd,J=8.5,2.3Hz,1H),6.69(s,1H),4.15 (d, J=8.6Hz, 2H), 3.52 (t, J=6.2Hz, 3H), 3.40 (ddd, J=14.6, 10.4, 5.1Hz, 2H), 3.18–3.09 (m, 3H), 2.98 ( s, 3H), 2.19 (d, J=11.9Hz, 1H), 1.97–1.87 (m, 2H), 1.77 (d, J=12.4Hz, 1H), 1.59 (dd, J=12.1, 3.6Hz, 1H) ),1.50–1.38(m,1H).

Example 53: (2-Chloro-4-((5-fluoro-2-methylbenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(( 2-(Methylsulfonyl)ethoxy)methyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone ( Preparation of compound 49) (prepared according to scheme one)

To (2-chloro-4-((5-fluoro-2-methylbenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidine- 5-yl)methanone) (0107-21) (50 mg, 0.109 mmol, 1.0 equiv) and (3R,6S)-6-((2-(methylsulfonyl)ethoxy)methyl)tetrakis Hydrogen-2H-pyran-3-amine hydrochloride (0108-49) (44.6 mg, 0.163 mmol, 1.5 equiv) in tert-butanol (10 mL) was added N,N-diisopropylethyl acetate Amine (1.5 mL). The mixture was heated at 90°C overnight. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (dichloromethane:methanol=10:1) to give the product (2-chloro-4-((5-fluoro-2-methylbenzofuran-7-yl)oxy) as a yellow solid yl)phenyl)(4-(((3R,6S)-6-((2-(methylsulfonyl)ethoxy)methyl)tetrahydro-2H-pyran-3-yl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (41 mg, yield: 57.34%). MS(ES ⁺ ): m/z=657(M+H) ⁺ ^.1HNMR (500MHz,MeOD)δ8.89(d,J=7.3Hz,1H),8.22(s,1H),7.49(d, J=8.4Hz, 1H), 7.44 (s, 1H), 7.16 (d, J=1.5Hz, 1H), 7.11 (dd, J=8.3, 1.6Hz, 1H), 7.04 (dd, J=8.5, 1.5 Hz, 1H), 6.81(dd, J=9.9, 1.7Hz, 1H), 6.55(s, 1H), 4.26(dt, J=10.7, 7.9Hz, 2H), 3.98–3.86(m, 2H), 3.62 (d, J＝8.7Hz, 1H), 3.55 (d, J＝4.8Hz, 2H), 3.35 (dd, J＝12.4, 8.2Hz, 2H), 3.26 (t, J＝10.1Hz, 1H), 3.10 –2.96(m,3H),2.42(s,3H),2.31(d,J=12.3Hz,1H),1.82(d,J=13.8Hz,1H),1.77–1.66(m,1H),1.64– 1.54(m,1H).

Example 54: (2-Chloro-4-((2-chlorobenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-((((methylsulfonyl)) Preparation of ethoxy)methyl)-tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 52)

Under the protection of nitrogen, under an ice-water bath, add ((2-chloro-4-((2-chlorobenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)- 6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 14) (46 mg, 0.083 mmol, 1.0 equiv) and methyl vinyl sulfone (26.5 mg, 0.25 mmol, 3.0 equiv) in tetrahydrofuran (5 mL) was added potassium tert-butoxide (18.6 mg, 0.166 mmol, 2.0 equiv). The mixture was stirred. 1 hour. The reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was purified with a thick preparative thin layer chromatography plate to give the product (2-chloro-4-(2-chloro-4-( (2-Chlorobenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(((methylsulfonyl)ethoxy)methyl)-tetrahydro-2H -pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (27 mg, yield: 50.39%). MS (ES ⁺ ): m/z =643(M+H) ⁺ . ¹ H NMR (500MHz, DMSO) δ 12.73(s, 1H), 8.58(d, J=7.1Hz, 1H), 8.25(s, 1H), 7.67–7.56(m ,2H),7.50(dd,J＝7.8,0.9Hz,1H),7.41-7.27(m,2H),7.24-7.11(m,2H),7.07(dd,J＝8.5,2.4Hz,1H), 4.19–3.98 (m, 2H), 3.92–3.71 (m, 2H), 3.63–3.43 (m, 3H), 3.36 (t, J=5.7Hz, 2H), 3.22–3.11 (m, 1H), 2.96 ( d, J=45.9Hz, 3H), 2.26–2.06 (m, 1H), 1.75 (dd, J=11.1, 3.7Hz, 1H), 1.61 (dd, J=11.9, 3.8Hz, 1H), 1.51–1.40 (m,1H).

Example 55: (2-Chloro-4-((5-fluorobenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(((2-(methyl) Sulfonyl)ethoxy)methyl)tetrahydro-2H-pyran)-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 55) preparation

At 0 °C, to (2-chloro-4-((5-fluorobenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrakis Hydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 20) (60 mg, 0.11 mmol, 1.0 equiv) and methyl vinylsulfone (35 mg, 0.34 mmol, 3.0 equiv) in tetrahydrofuran (4.5 mL) was added potassium tert-butoxide (25 mg, 0.22 mmol, 2.0 equiv). The mixture was stirred at 0°C for 1 hour. The reaction was quenched by the addition of saturated aqueous ammonium chloride (20 mL). The aqueous layer was extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (dichloromethane:methanol=10:1) to give (2-chloro-4-((5-fluorobenzofuran-7-yl)oxy)phenyl)( 4-(((3R,6S)-6-((2-(methylsulfonyl)ethoxy)methyl)tetrahydro-2H-pyran)-3-yl)amino)-7H-pyrrolo[ 2,3-d]pyrimidin-5-yl)methanone (43 mg, yield: 60%). LCMS (ESI): m/z 643 [M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol=10:1); melting point: 132-135°C. ¹ H NMR(500MHz,DMSO)δ12.73(s,1H),8.58(d,J=7.1Hz,1H),8.25(s,1H),8.10(d,J=2.0Hz,1H),7.64( s, 1H), 7.59 (d, J=8.5Hz, 1H), 7.48–7.25 (m, 2H), 7.15–6.96 (m, 3H), 4.20–4.09 (m, 2H), 3.81 (dt, J= 11.5, 5.9Hz, 2H), 3.64–3.50 (m, 1H), 3.47 (dd, J=4.6, 3.2Hz, 2H), 3.36 (t, J=5.6Hz, 2H), 3.14 (t, J=11.7 Hz,1H),2.99(d,J＝7.3Hz,3H),2.20(d,J＝11.8Hz,1H),1.76(d,J＝13.0Hz,1H),1.71–1.50(m,1H), 1.50–1.39(m,1H).

Example 56: (2-Chloro-4-((5-methylbenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrakis Preparation of Hydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 78) (prepared according to Scheme VI)

Step 56a: Preparation of 5-Methylbenzofuran-7-ol (Compound 0101-78)

Under nitrogen, combine 2-bromo-4-methylphenol (7.0 g, 37.43 mmol, 1.0 equiv), 2-bromo-1,1-diethoxyethane 11.06 g, 56.14 mmol, 1.5 equiv) , a mixture of potassium carbonate (7.76 g, 56.14 mmol, 1.5 equiv) in N,N-dimethylformamide (50 mL) was stirred at 120 °C overnight. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2-bromo-1-(diethoxymethoxy)-4-methylbenzene (12.0 g, crude) as a yellow oil. This product did not require further purification and was used directly in the next step.

Under nitrogen protection, 2-bromo-1-(diethoxymethoxy)-4-methylbenzene (12.0 g, 38.18 mmol, 1.0 equiv) obtained above and polyphosphoric acid (32.0 g, 95.45 mmol) were combined mol, 2.5 equiv) in 1,2-dichloroethane (100 mL) was stirred at 90 °C overnight. After cooling to room temperature, the reaction was quenched with water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 50/1 to 20/1) to give 7-bromo-5-methylbenzofuran (5.3 g, yield) as a yellow oil : 65.79%).

Under nitrogen protection, 7-bromo-5-methylbenzofuran (2.20 g, 10.42 mmol, 1.0 equiv) obtained above, triisopropyl borate (2.94 g, 15.63 mmol, 1.5 equiv) in tetrahydrofuran ( 20 mL) The mixture was stirred at -78°C. n-Butyllithium (1.6 mol per liter, 9.8 mL, 15.63 mmol, 1.5 equiv) was added dropwise, followed by stirring at -78°C for 2 hours. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: petroleum ether/ethyl acetate = 5/1 to 4/1) to give (5-methylbenzofuran-7-yl)boronic acid (1.10 g, obtained as a yellow solid) rate: 59.98%)

Under nitrogen, the above-obtained (5-methylbenzofuran-7-yl)boronic acid (1.1 g, 6.25 mmol, 1.0 equiv), hydrogen peroxide solution (30%, 10 mL), methanol (20 mL) were combined ) was stirred at room temperature overnight. The reaction solution was diluted with water and quenched with sodium sulfite solution. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 5/1 to 4/1) to give 5-methylbenzofuran-7-ol (410 mg, yield: 5/1 to 4/1) as a brown solid 44.32%). LCMS (ESI): m/z=149[M+1] ⁺ .

Step 56b: Preparation of 2-chloro-4-((5-methylbenzofuran-7-yl)oxy)benzaldehyde (compound 0602-78): 5-methylbenzofuran-7 under nitrogen - alcohol (0101-78) (410 mg, 2.77 mmol, 1.0 equiv), 2-chloro-4-fluorobenzaldehyde (0601-9) (394 mg, 2.49 mmol l, 0.9 equiv), potassium carbonate (573 mg, 4.15 mmol, 1.5 equiv) in N,N-dimethylformamide (10 mL) was stirred at 90 °C for 1.5 h. The reaction solution was diluted with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 10/1) to obtain 2-chloro-4-((5-methylbenzofuran-7-yl)oxy as a yellow oily product yl)benzaldehyde (500 mg, yield: 69.97%). LCMS(ESI): m/z=287[M+1]+.

Step 56c: (2-Chloro-4-(5-methylbenzofuran-7-yl)oxyphenyl)(4-chloro-7H-pyrro[2,3-d]pyrimidin-5-yl)methanol ( Preparation of compound 0603-78): 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0106-1) (323 mg, 1.39 mmol, 1.0 equiv) under nitrogen The tetrahydrofuran mixture was stirred at -78°C. tert-Butyllithium (1.6 mol per liter, 2.6 mL, 4.18 mmol, 3.0 equiv) was added dropwise, followed by stirring at -78°C for 2 hours. 2-Chloro-4-((5-methylbenzofuran-7-yl)oxy)benzaldehyde (0602-78) (400 mg, 1.39 mmol, 1.0 equiv) in tetrahydrofuran ( 3 mL) solution was added dropwise to the reaction solution and stirred for 1 hour. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: petroleum ether/ethyl acetate = 2/1 to 1/1) to give (2-chloro-4-(5-methylbenzofuran-7-yl) as a pink solid )oxy)phenyl)(4-chloro-7H-pyrrole[2,3-d]pyrimidin-5-yl)methanol (240 mg, yield: 39.33%). LCMS (ESI): m/z=440[M+1] ⁺ .

Step 56d: (2-Chloro-4-(5-methylbenzofuran-7-yl)oxyphenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methan Preparation of ketone (compound 0107-78): (2-chloro-4-(5-methylbenzofuran-7-yl)phenyl)(4-chloro-7H-oxypyrrolo[2,3-d ] pyrimidin-5-yl)methanol (0603-78) (240 mg, 0.55 mmol, 1.0 equiv) and 2-iodoylbenzoic acid (764 mg, 2.73 mmol, 5.0 equiv) in N-methylpyrrolidone (10 mL) The mixture was stirred at room temperature for 6 hours. The mixture was diluted with water, washed with 2 molar sodium hydroxide solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=2/1) to obtain a yellow solid (2 -Chloro-4-(5-methylbenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (119 mg , the yield is 49.51%). LCMS (ESI): m/z=438[M+1] ⁺ .

Step 56e: (2-Chloro-4-((5-methylbenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro Preparation of -2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 78): under nitrogen protection, transfer to (2-chloro-4 -((5-Methylbenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (0107-78) (119 mg, 0.27 mmol, 1.0 equiv) and ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol hydrochloride (82 mg, 0.36 mmol, 1.3 equiv) in To a mixture of tert-butanol (5 mL) was added N,N-diisopropylethylamine (0.24 mL). The mixture was heated at 90°C overnight. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by thick preparative thin layer chromatography (eluent: dichloromethane/methanol = 10/1) to give (2-chloro-4-((5-methylbenzofuran-7-yl)oxy) as a yellow solid yl)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine -5-yl)methanone (103 mg, yield: 71.71%). LCMS (ESI): m/z=533[M+1] ⁺ . ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.82 (d, J=7.1 Hz, 1 H), 8.34 (s, 1 H), 7.58 (d , J=2.1Hz, 1H), 7.39(d, J=8.5Hz, 1H), 7.36(s, 1H), 7.27(s, 1H), 7.11(d, J=2.3Hz, 1H), 6.98(dd , J＝8.5, 2.3Hz, 1H), 6.88(s, 1H), 6.76(d, J＝2.1Hz, 1H), 4.37(t, J＝8.8Hz, 2H), 3.68(dd, J＝11.3, 2.8Hz, 1H), 3.63–3.46 (m, 2H), 3.38–3.25 (m, 1H), 2.34 (d, J=8.5Hz, 1H), 2.01 (dd, J=12.3, 6.4Hz, 1H), 1.62(d, J=3.5Hz, 2H), 1.33(s, 1H).

Example 57: (2-Chloro-4-((5-methoxybenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl) Preparation of tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (compound 79) (prepared according to Scheme 1)

Step 57a: Preparation of 5-Methoxybenzofuran-7-ol (Compound 0101-79):

To a solution of 3-bromo-2-hydroxy-5-methoxybenzaldehyde (5 g, 21.6 mmol, 1.0 equiv) in N,N-dimethylformamide (30 mL) under nitrogen was added 2- Ethyl bromoacetate (5.43 g, 32.5 mmol, 1.5 equiv), cesium carbonate (14.11 g, 43.3 mmol, 2.0 equiv). The mixture was stirred at room temperature for 2.0 hours and then at 120°C for 2.0 hours. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether/ethyl acetate=10/1 to 5/1) to obtain ethyl 7-bromo-5-methoxybenzofuran-2-carboxylate (3.34 g, obtained as a yellow solid) rate: 51.78%). LCMS(ESI): m/z=299[M-1] ^- .

To a solution of the above obtained ethyl 7-bromo-5-methoxybenzofuran-2-carboxylate (3.34 g, 11.21 mmol, 1.0 equiv) in tetrahydrofuran (8 mL) was added 4M NaOH solution (16 mL), The mixture was stirred at room temperature overnight. The reaction solution was adjusted to pH=4 with 4M hydrochloric acid, and extracted with ethyl acetate. The resulting organic phase was dried and concentrated under reduced pressure. The residue was used directly in the next step without further purification. LCMS (ESI): m/z=271[M-1] ^- .

To a solution of 7-bromo-5-methoxybenzofuran-2-carboxylic acid (2.71 g, 10.04 mmol, 1.0 equiv) in quinoline (30 mL) obtained above was added copper powder (3.22 g) under nitrogen protection. g, 50.19 mmol, 5.0 equiv), the mixture was stirred at 125°C overnight. The reaction solution was diluted with water, extracted with ethyl acetate, and filtered. The filtrate was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether) to obtain 7-bromo-5-methoxybenzofuran (1.35 g, yield: 59.73%) as a yellow oily product.

Under nitrogen protection, the mixture obtained above, 7-bromo-5-methoxybenzofuran (1.25 g, 5.53 mmol, 1.0 equiv), bis-borate pinacol ester (1.83 g, 5.53 mmol, 1.0 equiv. ), potassium acetate (1.63 g, 16.59 mmol, 3.0 equiv), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.4 g, 0.55 mmol, 0.1 equiv) in dichloromethane The methyl sulfoxide solution (20 mL) was stirred at 90°C overnight. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether/ethyl acetate=1/1) to obtain 2-(5-methoxybenzofuran-7-yl)-4,4,5,5-tetramethyl as a yellow solid product yl-1,3,2-dioxaboropentane (450 mg, crude). LCMS(ESI): m/z=275[M+1]+.

Under nitrogen protection, the mixture 2-(5-methoxybenzofuran-7-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaboropentane (450 mg, 1.28 mmol, 1.0 equiv), hydrogen peroxide (4 mL), methanol (8 mL) was stirred at room temperature overnight. The reaction solution was diluted with water and quenched with sodium sulfite solution. The mixture was extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure to give the product 5-methoxybenzofuran-7-ol (210 mg, crude) as a yellow solid. LCMS(ESI): m/z=165[M+1]+.

Step 57b: Preparation of methyl 2-chloro-4-((5-methoxybenzofuran-7-yl)oxy)benzoate (compound 0103-79): 2-chloro-4 - Methyl fluorobenzoate (0101-79) (345 mg, 1.83 mmol, 1.5 equiv), potassium carbonate (253 mg, 1.83 mmol, 1.5 equiv) was added to 5-methoxybenzofuran-7-ol (0102-1) (200 mg, 1.22 mmol, 1.0 equiv) in N,N-dimethylformamide (6 mL). The mixture was stirred at 90°C overnight. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether/ethyl acetate = 20/1 to 10/1) to obtain 2-chloro-4-((5-methoxybenzofuran-7-yl)oxy as a yellow oily product ) methyl benzoate (390 mg, yield: 96.53%). LCMS (ESI): m/z=333[M+1]+.

Step 57c: Preparation of 2-chloro-4-((5-methoxybenzofuran-7-yl)oxy)benzoic acid (compound 0104-79): To 2-chloro-4-((5-methyl) To a solution of methyl oxybenzofuran-7-yl)oxy)benzoate (380 mg, 1.15 mmol, 1.0 equiv) in tetrahydrofuran (6 mL) was added 2M sodium hydroxide solution (12 mL) and the mixture was cooled to room temperature under stirring overnight. The reaction solution was adjusted to pH=4 with 4M hydrochloric acid, and extracted with ethyl acetate. The resulting organic phase was dried and concentrated under reduced pressure. The residue was used directly in the next step without further purification. LCMS(ESI): m/z=319[M+1]+.

Step 57d: Preparation of 2-chloro-4-((5-methoxybenzofuran-7-yl)oxy)benzoyl chloride (compound 0105-79): under nitrogen, at 0°C, to 2- A solution of chloro-4-((5-methoxybenzofuran-7-yl)oxy)benzoic acid (0104-79) (200 mg, 0.63 mmol, 1.0 equiv) in dichloromethane (5 mL) Oxalyl chloride (240 mg, 1.89 mmol, 3.0 equiv), N,N-dimethylformamide (1 mg) was added dropwise. The mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure. The residue was used directly in the next step without further purification.

Step 57e: (2-Chloro-4-((5-methoxybenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5 -yl)methanone (compound 0107-79) was prepared by adding 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0106-1) (161 mg at 0°C under nitrogen protection) , 0.69 mmol, 1.1 equiv) in tetrahydrofuran (5 mL) was added sodium hydride (50 mg, 1.26 mmol, 2.0 equiv), and the mixture was stirred at room temperature for 1 hour. Then n-butyllithium (0.52 mL, 0.82 mmol, 1.3 equiv) was slowly added dropwise at -70°C and stirred for 1.0 h. A solution of 2-chloro-4-((5-methoxybenzofuran-7-yl)oxy)benzoyl chloride (0105-79) (211 mg, crude) in 3 mL of tetrahydrofuran at -70°C It was added dropwise to the reaction solution and stirred for 1.5 hours. The reaction solution was quenched with ammonium chloride solution, diluted with water and extracted with ethyl acetate, the organic phase was dried and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether/ethyl acetate = 10/1 to 2/1, 10% dichloromethane) to give yellow solid product (2-chloro-4-((5-methoxybenzofuran) -7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (51 mg, yield: 17.89%). LCMS(ESI): m/z=454[M+1]+.

Step 57f: (2-Chloro-4-((5-methoxybenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrakis Preparation of Hydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 79): To (2-chloro-4-(( 5-Methoxybenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (0107-79)(51 mg, 0.112 mmol, 1.0 equiv) and ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol hydrochloride (0108-1) (19 mg, 0.112 mmol, 1.0 equiv.) To a mixture of tert-butanol (5 mL) was added N,N-diisopropylethylamine (2 mL). The mixture was heated at 90°C overnight. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (dichloromethane/methanol=10/1) to give (2-chloro-4-((5-methoxybenzofuran-7-yl)oxy)phenyl as a yellow solid )(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl ) ketone (37 mg, yield: 60.66%). MS(ES ⁺ ): m/z=549(M+H) ⁺ . ¹ H NMR (500MHz, DMSO) δ 8.60(d, J=7.1Hz, 1H), 8.20(s, 1H), 8.02(d , J＝1.9Hz, 1H), 7.56–7.46(m, 2H), 7.15(d, J＝2.2Hz, 1H), 7.00(dd, J＝8.7, 2.1Hz, 2H), 6.95(d, J＝ 1.9Hz, 1H), 6.83(d, J=1.9Hz, 1H), 4.65(s, 1H), 4.14(t, J=9.5Hz, 2H), 3.94(s, 3H), 3.48–3.36(m, 3H), 3.11(t, J＝9.9Hz, 1H), 2.18(d, J＝12.2Hz, 1H), 1.78(d, J＝12.9Hz, 1H), 1.55(dd, J＝13.9, 10.1Hz, 1H),1.38(dd,J=23.1,9.6Hz,1H).

Example 58: 7-(3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo Preparation of [2,3-d]pyrimidine-5-carbonyl)phenoxy)benzofuran-5-carbonitrile (compound 80) (prepared according to Scheme VI)

Step 58a: Preparation of 7-hydroxybenzofuran-5-carbonitrile (compound 0101-80):

To a solution of 5-bromo-2-hydroxy-3-methoxybenzaldehyde (6 g, 25.97 mmol, 1.0 equiv) in N,N-dimethylformamide (100 mL) under nitrogen was added 2- Ethyl bromoacetate (5.2 g, 31.17 mmol, 1.2 equiv), cesium carbonate (16.93 g, 51.94 mmol, 2.0 equiv), the mixture was stirred at room temperature for 2.0 hours and then at 120°C for 2.0 hours. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether/ethyl acetate = 10/1 to 5/1) to obtain ethyl 5-bromo-7-methoxybenzofuran-2-carboxylate (3.64 g, obtained as a yellow solid product) rate: 46.9%).

To a solution of the above obtained ethyl 5-bromo-7-methoxybenzofuran-2-carboxylate (3.64 g, 26.29 mmol, 1.0 equiv) in tetrahydrofuran (8 mL) was added 4M NaOH solution (24 mL), The mixture was stirred at room temperature overnight. The reaction solution was adjusted to pPH=4 with 4M hydrochloric acid, and extracted with ethyl acetate. The resulting organic phase was dried and concentrated under reduced pressure. The residue was used directly in the next step without further purification. LCMS(ESI): m/z=269[M-1] ^- .

To a solution of 5-bromo-7-methoxybenzofuran-2-carboxylic acid (6.34 g, 23.39 mmol, 1.0 equiv) in quinoline (100 mL) obtained above was added copper powder (7.6 g, 116.97 mmol, 5.0 equiv), the mixture was stirred at 135 °C overnight. The reaction solution was diluted with water, extracted with ethyl acetate, and filtered. The filtrate was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether/ethyl acetate=100/1 to 10/1) to obtain 5-bromo-7-methoxybenzofuran (3.54 g, yield: 66.79%) as a yellow oily product.

To a solution of 5-bromo-7-methoxybenzofuran obtained above (2.21 g, 9.73 mmol, 1.0 equiv) in dichloromethane (300 mL) was added boron tribromide (3.66 g, under nitrogen) 14.60 mmol, 1.5 equiv), the mixture was stirred at 0 °C for 10 min and then at room temperature overnight. The reaction solution was quenched with methanol, diluted with water and extracted with dichloromethane. The organic phase was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether/ethyl acetate=10/1 to 3/1) to obtain 5-bromobenzofuran-7-ol (1.35 g, yield: 65.21%) as a yellow solid product.

To a dichloromethane solution (50 mL) of 5-bromobenzofuran-7-ol obtained above (1.66 g, 7.79 mmol, 1.0 equiv) was added imidazole (1.06 g, 15.58 mmol, 2.0 equiv) under nitrogen protection. equiv), tert-butyldimethylsilyl chloride (1.76 g, 11.68 mmol, 1.5 equiv). The mixture was stirred at room temperature for 3.0 hours. The reaction solution was diluted with water and extracted with dichloromethane, and the organic phase was dried and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether/ethyl acetate=10/1 to 4/1) to give ((5-bromobenzofuran-7-yl)oxy)(tert-butyl)dimethyl as a yellow oil Silane (2.0 g, yield: 78.5%).

Under nitrogen, a solution of ((5-bromobenzofuran-7-yl)oxy)(tert-butyl)dimethylsilane (2.3 g, 7.03 mmol, 1.0 equiv) obtained above in N,N-dimethylsilane was added. To the methylformamide (40 mL) solution was added zinc cyanide (2.06 g, 17.57 mmol, 2.5 equiv), tetrakistriphenylphosphine palladium (813 mg, 0.703 mmol, 0.1 equiv), and the mixture was stirred at 100°C overnight. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether/ethyl acetate=10/1 to 2/1) to obtain 7-hydroxybenzofuran-5-carbonitrile (1.12 g, yield: 100%) as a yellow solid product. LCMS (ESI): m/z=158[M-1] ^- .

Step 58b: Preparation of 7-(3-Chloro-4-formylphenoxy)benzofuran-5-carbonitrile (Compound 0602-80): To 7-hydroxybenzofuran-5-methane under nitrogen To a solution of nitrile (0101-80) (155 g, 0.97 mmol, 1.0 equiv) in N,N-dimethylformamide (20 mL) was added 2-chloro-4-fluorobenzaldehyde (0601-9) (184 mg, 1.16 mmol, 1.2 equiv), potassium carbonate (200 g, 1.46 mmol, 1.5 equiv). The mixture was stirred at 90°C for 2.5 hours. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether/ethyl acetate=20/1) to obtain 7-(3-chloro-4-formylphenoxy)benzofuran-5-carbonitrile (235 mg, 7-(3-chloro-4-formylphenoxy)benzofuran-5-carbonitrile) as a white solid product. Yield: 81.6%).

Step 58c: 7-(3-Chloro-4-((4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(hydroxy)methyl)phenoxy)benzofuran-5 - Preparation of carbonitrile (compound 0603-80): 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0106-1) (229 mg) at -70°C under nitrogen , 0.99 mmol, 1.0 equiv) in tetrahydrofuran (20 mL) was slowly added dropwise n-butyllithium (1.55 mL, 2.48 mmol, 2.5 equiv) and stirred for 1.0 h. 7-(3-Chloro-4-formylphenoxy)benzofuran-5-carbonitrile (0602-80) (235 mg, 0.79 mmol, 0.8 equiv) was dissolved in 1 mL of tetrahydrofuran at -70°C It was added dropwise to the reaction solution and stirred for 1.0 hour. The reaction solution was quenched with ammonium chloride solution, diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether/ethyl acetate = 10/1 to 1/1, 10% dichloromethane) to give 7-(3-chloro-4-((4-chloro-7H-) as a pink solid product Pyrrolo[2,3-d]pyrimidin-5-yl)(hydroxy)methyl)phenoxy)benzofuran-5-carbonitrile (95 mg, yield: 70.0%). LCMS(ESI): m/z=451[M+1]+.

Step 58d: 7-(3-Chloro-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenoxy)benzofuran-5-carbonitrile (Compound 0107- 80) preparation: to 7-(3-chloro-4-((4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(hydroxy)methyl)phenoxy)benzol Furan-5-carbonitrile (0603-80) (90 mg, 0.2 mmol, 1.0 equiv) in N-methylpyrrolidone (8 mL) was added 2-iodoylbenzoic acid (280 mg, 1.0 mmol, 5.0 equiv), the mixture was stirred at room temperature overnight. The reaction solution was adjusted to pH=8 by adding sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified by thick preparative thin layer chromatography (dichloromethane/methanol=10/1) to give the product 7-(3-chloro-4-(4-chloro-7H-pyrrolo[2,3-d) as a colorless oil ]pyrimidine-5-carbonyl)phenoxy)benzofuran-5-carbonitrile (88 mg, yield: 98.0%).

Step 58e: 7-(3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[ Preparation of 2,3-d]pyrimidine-5-carbonyl)phenoxy)benzofuran-5-carbonitrile (Compound 80): To 7-(3-chloro-4-(4-chloro-7H-pyrrolo) [2,3-d]pyrimidine-5-carbonyl)phenoxy)benzofuran-5-carbonitrile (0107-80) (80 mg, 0.178 mmol, 1.0 equiv) and ((2S,5R)-5 -Aminotetrahydro-2H-pyran-2-yl)methanol hydrochloride (0108-80) (28.2 mg, 0.214 mmol, 1.2 equiv) in tert-butanol (8 mL) was added N,N- Diisopropylethylamine (0.5 mL). The mixture was heated at 90°C overnight. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (dichloromethane/methanol=9/1) to give 7-(3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl) as a yellow solid product )tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenoxy)benzofuran-5-carbonitrile (46 mg, received rate: 47.6%). MS (ES ⁺ ): m/z = 544 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO) δ 12.72 (s, 1H), 8.57 (d, J = 7.2 Hz, 1H), 8.32–8.22 (m, 2H), 8.13 (d, J=1.3Hz, 1H), 7.75–7.51 (m, 3H), 7.42 (d, J=2.4Hz, 1H), 7.25–7.09 (m, 2H), 4.62 ( t, J=5.6Hz, 1H), 4.23–4.09 (m, 2H), 3.43 (t, J=5.4Hz, 1H), 3.39–3.32 (m, 2H), 3.22–3.09 (m, 1H), 2.20 (d, J=12.0Hz, 1H), 1.79 (d, J=13.6Hz, 1H), 1.58 (dd, J=11.9, 3.7Hz, 1H), 1.39 (dt, J=23.6, 14.9Hz, 1H) .

Example 59: (2-Chloro-4-((2-methyl-5-(trifluoromethyl)benzofuran-7-yl)oxy)phenyl)(4-(((3R,6S) -6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (2-chloro-4-( (2-methyl-5-(trifluoromethyl)benzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H - Preparation of pyrrolo[2,3-d]pyrimidin-5-yl)methanone (compound 81) (prepared according to Scheme 1)

Step 59a: Preparation of 2-methyl-5-(trifluoromethyl)benzofuran-7-ol (compound 0101-81):

To a solution of 2-bromo-4-(trifluoromethyl)phenol (4 g, 16.59 mmol, 1.0 equiv) in N,N-dimethylformamide (40 mL) under nitrogen was added 3-bromopropane -1-yne (2.37 g, 19.92 mmol, 1.2 equiv), potassium carbonate (3.44 g, 24.90 mmol, 1.5 equiv), the mixture was stirred at 50°C overnight. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether/ethyl acetate=10/1) to obtain 2-bromo-1-(prop-2-yn-1-yloxy)-4-(trifluoromethyl) as a yellow oily product ) benzene (4.57 g, yield: 99.13%).

Under nitrogen, a solution of 2-bromo-1-(prop-2-yn-1-yloxy)-4-(trifluoromethyl)benzene (4.56 g, 16.4 mmol, 1.0 equiv) obtained above was added to N , N-diethylaniline (40 mL) solution was added cesium fluoride (3.24 g, 21.32 mmol, 1.3 equiv), and the mixture was stirred at 220° C. for 8 hours. The reaction solution was diluted with water and adjusted to pH=6 with 1 molar hydrochloric acid solution. The mixture was extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether) to give 7-bromo-2-methyl-5-(trifluoromethyl)benzofuran (3.17 g, yield: 69.52%) as a yellow oily product.

To the above obtained 7-bromo-2-methyl-5-(trifluoromethyl)benzofuran (1.5 g, 5.40 mmol, 1.0 equiv), triisopropyl borate under nitrogen protection at -70°C To a solution of the ester (1.32 g, 7.01 mmol, 1.3 equiv) in tetrahydrofuran (15 mL) was slowly added n-butyllithium (3.4 mL, 8.63 mmol, 1.6 equiv) and stirred at -70°C for 1 hour. The mixture was then stirred at room temperature for 4 hours. The reaction solution was diluted with water and adjusted to pH=6 with 1 molar hydrochloric acid solution. The mixture was extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether/ethyl acetate = 5/1) to give (2-methyl-5-(trifluoromethyl)benzofuran-7-yl)boronic acid (910 mg, 910 mg, yellow oily product) Yield: 68.94%). LCMS(ESI): m/z=245[M+1]+.

Under nitrogen protection, the above obtained (2-methyl-5-(trifluoromethyl)benzofuran-7-yl)boronic acid (1.02 g, 4.18 mmol, 1.0 equiv), hydrogen peroxide (5 mL), methanol (10 mL) of the mixture was stirred at room temperature overnight. The reaction solution was diluted with water and quenched with sodium sulfite solution. The mixture was extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure to give the product 2-methyl-5-(trifluoromethyl)benzofuran-7-ol (210 mg, crude) as a yellow solid. LCMS(ESI): m/z=217[M+1]+.

Step 59b: Preparation of methyl 2-chloro-4-((2-methyl-5-(trifluoromethyl)benzofuran-7-yl)oxy)benzoate (compound 0103-81): under nitrogen 2-methyl-5-(trifluoromethyl)benzofuran-7-ol (0101-81) (930 mg, 4.31 mmol, 1.0 equiv) in N,N-dimethylformamide ( 10 mL) solution was added methyl 2-chloro-4-fluorobenzoate (0102-1) (810 mg, 4.74 mmol, 1.1 equiv), potassium carbonate (890 g, 6.46 mmol, 1.5 equiv), and the mixture was Stir overnight at 90°C. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified with silica gel column (petroleum ether/ethyl acetate=20/1 to 10/1) to give 2-chloro-4-((2-methyl-5-(trifluoromethyl)benzoic acid) as a white oily product Furan-7-yl)oxy)benzoic acid methyl ester (890 mg, yield: 46.35%). LCMS(ESI): m/z=385[M+1]+.

Step 59c: Preparation of 2-chloro-4-((2-methyl-5-(trifluoromethyl)benzofuran-7-yl)oxy)benzoic acid (compound 0104-81): To 2-chloro Methyl 4-((2-methyl-5-(trifluoromethyl)benzofuran-7-yl)oxy)benzoate (0103-81) (700 mg, 1.83 mmol, 1.0 equiv) To the tetrahydrofuran (15 mL) solution was added 2M sodium hydroxide solution (30 mL), and the mixture was stirred at room temperature overnight. The reaction solution was adjusted to pH=4 with 4M hydrochloric acid, and extracted with ethyl acetate. The resulting organic phase was dried and concentrated under reduced pressure. The residue was used directly in the next step without further purification. LCMS (ESI): m/z=371[M+1]+.

Step 59d: Preparation of 2-chloro-4-((2-methyl-5-(trifluoromethyl)benzofuran-7-yl)oxy)benzoyl chloride (compound 0105-81): under nitrogen , at 0 °C, to 2-chloro-4-((2-methyl-5-(trifluoromethyl)benzofuran-7-yl)oxy)benzoic acid (0104-81) (300 mg, 0.81 To a solution of oxalyl chloride (314 mg, 2.43 mmol, 3.0 equiv), N,N-dimethylformamide (1 mg) in tetrahydrofuran (8 mL) was added dropwise. The mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure. The residue was used directly in the next step without further purification.

Step 59e: (2-Chloro-4-((2-methyl-5-(trifluoromethyl)benzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2 Preparation of ,3-d]pyrimidin-5-yl)methanone (Compound 0107-81): under nitrogen protection, at 0 °C, 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine To a solution of (0106-1) (235 mg, 1.01 mmol, 1.0 equiv) in tetrahydrofuran (5 mL) was added sodium hydride (81 mg, 2.02 mmol, 2.0 equiv), and the mixture was stirred at room temperature for 1 hour. Then n-butyllithium (0.82 mL, 1.31 mmol, 1.3 equiv) was slowly added dropwise at -70°C and stirred for 1.0 h. 2-Chloro-4-((2-methyl-5-(trifluoromethyl)benzofuran-7-yl)oxy)benzoyl chloride (0105-81) (315 mg, at -70°C, Crude product) dissolved in 3 mL of tetrahydrofuran was added dropwise to the reaction solution and stirred for 1.5 hours. The reaction solution was quenched with ammonium chloride solution, diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether/ethyl acetate = 15/1 to 1/1, 10% dichloromethane) to give yellow solid product (2-chloro-4-((2-methyl-5-( Trifluoromethyl)benzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (140 mg, yield: 34.23%). LCMS(ESI): m/z=506[M+1]+.

Step 59f: (2-Chloro-4-((2-methyl-5-(trifluoromethyl)benzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)- Preparation of 6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 81): To ( 2-Chloro-4-((2-methyl-5-(trifluoromethyl)benzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d ]pyrimidin-5-yl)methanone (0107-81) (50 mg, 0.10 mmol, 1.0 equiv) and ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methoxide acid salt (0108-1) (19 mg, 0.11 mmol, 1.1 equiv) To a mixture of tert-butanol (5 mL) was added N,N-diisopropylethylamine (2 mL). The mixture was heated at 90°C overnight. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (dichloromethane/methanol = 12/1) to give a yellow solid (2-chloro-4-((2-methyl-5-(trifluoromethyl)benzofuran-7) -yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3 -d]pyrimidin-5-yl)methanone (45 mg, yield: 75.63%). MS(ES ⁺ ): m/z=601(M+H) ⁺ . ¹ H NMR(500MHz, DMSO) δ 12.70(s, 1H), 8.58(d, J=7.0Hz, 1H), 8.23(s ,1H),7.88(s,1H),7.61–7.55(m,2H),7.47–7.34(m,2H),7.13–7.03(m,1H),6.83(t,J=9.9Hz,1H), 4.64(s, 1H), 4.23–4.07(m, 2H), 3.41(d, J=6.9Hz, 3H), 3.11(dd, J=16.0, 6.4Hz, 1H), 2.48(d, J=8.9Hz ,3H),2.19(d,J＝12.0Hz,1H),1.78(d,J＝13.7Hz,1H),1.56(tt,J＝12.2,6.3Hz,1H),1.39(ddd,J＝20.0, 13.2, 6.5Hz, 1H).

Example 60: (2-Chloro-4-((2-methylbenzofuran-7-yl)oxy)phenyl)(4-((3R,6S)-6-(hydroxymethyl)-3 Preparation of ,6-dihydro-2H-pyran-3-yl)amino)-7H-pyrro[2,3-d]pyrimidin-5-yl)methanone (Compound 83)

tert-butyl ((3R,6S)-6-(hydroxymethyl)-3,6-dihydro-2H-pyran-3-yl)carbamate (0108-83) (200 mg, 0.873 mmol, A mixture of 1.0 equiv.) in hydrogen chloride-methanol solution (4M solution, 5 mL) was stirred at room temperature for 1 hour, the solvent was removed under reduced pressure and dried under vacuum. The residue was combined with (2-chloro-4-((2-methylbenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrro[2,3-d]pyrimidine-5- yl)methanone (0107-2) (100 mg, 0.228 mmol, 1.0 equiv) was dissolved in tert-butanol (5 mL) and N,N-diisopropylethylamine (0.3 mL) was added. The mixture was heated at 90°C overnight. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified with a silica gel column (dichloromethane/methanol=50/1 to 10/1) to give a yellow solid product (2-chloro-4-((2-methylbenzofuran-7-yl)oxy) Phenyl)(4-((3R,6S)-6-(hydroxymethyl)-3,6-dihydro-2H-pyran-3-yl)amino)-7H-pyrrole[2,3-d] pyrimidin-5-yl)methanone (60 mg, yield: 49.5%). MS (ES+): m/z=532 (M+H)+. Melting point: 212-220°C. ¹ H NMR (500MHz, DMSO) δ 12.73(s, 1H), 8.71(d, J=7.8Hz, 1H), 8.26(s, 1H), 7.67-7.52(m, 2H), 7.43(d, J = 7.7Hz, 1H), 7.32–7.16 (m, 2H), 7.11–6.91 (m, 2H), 6.69 (s, 1H), 6.00 (t, J=7.5Hz, 2H), 4.92–4.64 (m, 2H), 4.29–4.07(m, 2H), 3.46(dtd, J=16.1, 11.3, 6.3Hz, 3H), 2.43(s, 3H).

Example 61: (2-Chloro-4-((2-chlorobenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)-3 Preparation of ,6-dihydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 84)

tert-butyl ((3R,6S)-6-(hydroxymethyl)-3,6-dihydro-2H-pyran-3-yl)carbamate (0108-83) (24 mg, 0.105 mmol, A mixture of 1.0 equiv.) in hydrogen chloride-dioxane solution (4 mol per liter solution, 2 mL) was stirred at room temperature for 1 hour, the solvent was removed under reduced pressure and dried under vacuum, and the residue was used without further purification. To the residue and (2-chloro-4-((2-chlorobenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5- yl)methanone (0107-14) (40 mg, 0.078 mmol, 1.0 equiv) To a mixture of tert-butanol (10 mL) was added N,N-diisopropylethylamine (0.5 mL). The mixture was heated at 90°C overnight. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified with a thick preparative thin layer chromatography plate to give (2-chloro-4-((2-chlorobenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S) as a yellow solid -6-(Hydroxymethyl)-3,6-dihydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (13 mg , yield: 27.08%). MS (ES ⁺ ): m/z=551 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO) δ 12.74 (s, 1H), 8.71 (d, J=7.8 Hz, 1H), 8.27 (s ,1H),7.68–7.56(m,2H),7.50(dd,J=7.8,0.9Hz,1H),7.37–7.27(m,2H),7.21–7.11(m,2H),7.07(dd,J = 8.5, 2.4Hz, 1H), 6.15–5.85 (m, 2H), 4.94–4.71 (m, 2H), 4.36–4.10 (m, 2H), 3.54–3.38 (m, 3H).

Example 62: (2-Chloro-4-((5-fluorobenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)-3 Preparation of ,6-dihydro-2H-pyran-3-)yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 85)

To (2-chloro-4-((5-fluorobenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methan Ketone (0107-20) (80 mg, 0.18 mmol, 1.0 equiv) and ((2S,5R)-5-amino-5,6-dihydro-2H-pyran-2-yl)methanol hydrochloride ( 0108-83) (39 mg, 0.24 mmol, 1.3 equiv) To a mixture of tert-butanol (8 mL) was added N,N-diisopropylethylamine (0.16 mL, 0.91 mmol, 5.0 equiv). The mixture was heated to 90°C under nitrogen atmosphere and reacted overnight. The mixture was diluted with water (20 mL), then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (ethyl acetate:dichloromethane:methanol=10:10:2) to give (2-chloro-4-((5-fluorobenzofuran-7-yl)oxy) as a white solid yl)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)-3,6-dihydro-2H-pyran-3-)yl)amino)-7H-pyrrolo[2 ,3-d]pyrimidin-5-yl)methanone (45 mg, yield: 46%). LCMS (ESI): m/z 535 [M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol=10:1); melting point: 252-255°C. ¹ H NMR (500MHz, DMSO) δ12.74(s, 1H), 8.71(d, J=7.8Hz, 1H), 8.27(s, 1H), 8.10(d, J=2.0Hz, 1H), 7.66( s, 1H), 7.59 (d, J=8.5Hz, 1H), 7.45–7.23 (m, 2H), 7.18–6.89 (m, 3H), 6.14–5.85 (m, 2H), 4.93–4.63 (m, 2H), 4.25–4.00 (m, 2H), 3.50–3.39 (m, 3H).

Example 63: 1-(5-(2-Chloro-4-((5-fluoro-2-methylbenzofuran-7-yl)oxy)benzoyl)-4-((((3R,6S) )-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethylcyclohexyl carbonate (Compound 95 ) preparation

Under nitrogen protection, (2-chloro-4-((5-fluoro-2-methylbenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-( Hydroxymethyl)tetrahydro-2H-pyran-3-yl))amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 21) (100 mg, 0.182 mmol , 1.0 equiv) and 1-chloroethylcyclohexyl carbonate (76 mg, 0.364 mmol, 2.0 equiv), cesium carbonate (120 mg, 0.364 mmol, 2.0 equiv), potassium iodide (4 mg, 0.018 mmol, 0.1 equiv) in N,N-dimethylacetamide (5 mL) was stirred at 50°C overnight. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (dichloromethane:methanol=40:1) to give 1-(5-(2-chloro-4-((5-fluoro-2-methylbenzofuran-7) as a yellow solid -yl)oxy)benzoyl)-4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)ethylcyclohexyl carbonate (46 mg, yield: 35.11%). LCMS (ESI): m/z=721[M+1] ⁺ ^.1H NMR (500MHz, DMSO) δ 8.57(d, J=7.2Hz, 1H), 8.32(s, 1H), 7.92(s, 1H), 7.60(d, J＝8.5Hz, 1H), 7.35(d, J＝2.3Hz, 1H), 7.28(dd, J＝8.5, 2.3Hz, 1H), 7.11(dd, J＝8.5, 2.3 Hz, 1H), 7.04–6.93 (m, 2H), 6.71 (s, 1H), 4.62 (t, J=5.5Hz, 1H), 4.51 (dd, J=8.3, 4.1Hz, 1H), 4.21–4.08 (m, 2H), 3.42 (dd, J=11.4, 5.5Hz, 1H), 3.34 (dd, J=12.6, 5.9Hz, 2H), 3.13 (t, J=11.1Hz, 1H), 2.45 (s, 3H), 2.19 (d, J=11.5Hz, 1H), 1.78 (dd, J=36.4, 17.8Hz, 6H), 1.58 (dd, J=16.1, 7.5Hz, 3H), 1.31 (dddd, J=38.8 ,33.0,15.9,6.3Hz,9H).

Example 64: Pivalic acid (5-(2-chloro-4-((5-fluoro-2-methylbenzofuran-7-yl)oxy)benzoyl)-4-((3R,6S )-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrro[2,3-d]pyrimidin-7-yl)methyl ester (Compound 96)

Under nitrogen protection, (2-chloro-4-((5-fluoro-2-methylbenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-( Hydroxymethyl)tetrahydro-2H-pyran-3-yl))amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 21) (35 mg, 0.064 mmol , 1.0 equiv) and chloromethyl pivalate (20 mg, 0.127 mmol, 2.0 equiv), potassium carbonate (120 mg, 0.191 mmol, 3.0 equiv), potassium iodide (2 mg, 0.006 mmol, 0.1 equiv) The N,N-dimethylacetamide (5 mL) mixture was stirred at 50°C for 3 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (dichloromethane:methanol=40:1) to give pivalic acid (5-(2-chloro-4-((5-fluoro-2-methylbenzofuran- 7-yl)oxy)benzoyl)-4-((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrole[2,3 -d]pyrimidin-7-yl)methyl ester (24 mg, yield: 57.14%). LCMS (ESI): m/z=665[M+1] ⁺ ^.1H NMR (500MHz, DMSO) δ 8.53(d, J=7.1Hz, 1H), 8.34(s, 1H), 7.84(s, 1H), 7.62 (d, J=8.5Hz, 1H), 7.36 (d, J=2.2Hz, 1H), 7.29 (dd, J=8.4, 2.2Hz, 1H), 7.11 (dd, J=8.5, 2.2 Hz, 1H), 6.99(dd, J＝10.1, 2.2Hz, 1H), 6.71(s, 1H), 6.11(s, 2H), 4.64(t, J＝5.5Hz, 1H), 4.16(d, J = 6.7Hz, 2H), 3.46–3.40 (m, 1H), 3.36 (s, 2H), 3.18–3.11 (m, 1H), 2.44 (s, 3H), 2.20 (d, J=11.9Hz, 1H) ,1.79(d,J＝13.3Hz,1H),1.59(d,J＝12.2Hz,1H),1.39(d,J＝13.6Hz,1H),1.07(s,9H).

Example 65: (5-(2-Chloro-4-((5-fluoro-2-methylbenzofuran-7-yl)oxy)benzoyl)-4-(((3R,6S)- Preparation of 6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyldihydrogenphosphoric acid (Compound 97)

Under nitrogen protection, to (2-chloro-4-((5-fluoro-2-methylbenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6- (Hydroxymethyl)tetrahydro-2H-pyran-3-yl))amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 21) (100 mg, 0.18 mM mol, 1.0 equiv) and di-tert-butyl chloromethylphosphate (95 mg, 0.36 mmol, 2.0 equiv) in 3 mL of N-methylpyrrolidone was added cesium carbonate (178 mg, 0.55 mmol, 3.0 equiv) and potassium iodide (30 mg, 0.18 mmol, 1.0 equiv). The mixture was stirred at room temperature overnight. Ethyl acetate was added, and the mixture was washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (developing solvent: dichloromethane/methanol=13/1) to obtain a yellow solid ((5-(2-chloro-4-( (5-Fluoro-2-methylbenzofuran-7-yl)oxy)benzoyl)-4-(((3R,6S)-6-(hydroxymethyl))tetrahydro-2H-pyran -3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)di-tert-butyl phosphate (64 mg, yield: 45%). MS(ES ⁺ ): m/z 773(M+H) ⁺ .

The above obtained ((5-(2-chloro-4-((5-fluoro-2-methylbenzofuran-7-yl)oxy)benzoyl)-4-(((3R,6S) -6-(hydroxymethyl))tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)di-tert-butyl phosphate ( 64 mg, 0.083 mmol, 1.0 equiv) was dissolved in 4 mL of dichloromethane and 0.5 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 3 hours. The mixture was concentrated to dryness under reduced pressure. The residue was stirred with water and filtered with suction to collect the solid. The solid was dried under reduced pressure to give (5-(2-chloro-4-((5-fluoro-2-methylbenzofuran-7-yl)oxy)benzoyl)-4-(( (3R,6S)-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyldihydrogenphosphoric acid (35 mg, yield: 63%). MS (ES ⁺ ): m/z 661 (M+H) ⁺ ; melting point: 170-172°C. ¹ H NMR(500MHz, DMSO)δ8.56(d,J=7.1Hz,1H),8.33(s,1H),7.82(s,1H),7.60(d,J=8.5Hz,1H),7.34( d, J＝1.9Hz, 1H), 7.28 (dd, J＝8.4, 2.0Hz, 1H), 7.09 (dd, J＝8.5, 1.9Hz, 1H), 7.00 (dd, J＝10.2, 2.0Hz, 1H) ), 6.70(s, 1H), 5.85(d, J=10.0Hz, 2H), 4.62(s, 1H), 4.16(d, J=6.7Hz, 2H), 3.53(s, 3H), 3.11(s ,1H),2.44(s,3H),2.20(d,J＝11.7Hz,1H),1.79(d,J＝12.8Hz,1H),1.59(d,J＝15.5Hz,1H),1.39(d , J=19.1Hz, 1H).

Example 66: Acetic acid ((2S,5R)-5-((5-(2-chloro-4-((5-fluoro-2-methylbenzofuran-7-yl)oxy)benzoyl) Preparation of -7H-pyrro[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)methyl ester (compound 106)

Under nitrogen protection, add (2-chloro-4-(5-fluoro-2-methylbenzofuran-7-yl)oxyphenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidine -5-yl)methanone (0107-21) (50 mg, 0.11 mmol, 1.0 equiv) and ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl acetate Trifluoroacetate (0108-106) (crude, 0.28 mmol, 2.5 equiv) In a mixture of tert-butanol (5 mL) was added N,N-diisopropylethylamine (85 mg, 0.66 mmol, 6.0 equiv). The mixture was heated to 90°C and reacted overnight. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by thick preparative thin layer chromatography (dichloromethane/methanol=10/1) to give acetic acid ((2S,5R)-5-((5-(2-chloro-4-(((5- Fluoro-2-methylbenzofuran-7-yl)oxy)benzoyl)-7H-pyrro[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2- yl) methyl ester (32 mg, yield: 49.06%). LCMS (ESI): m/z=593[M+1] ⁺ . ¹ H NMR (500MHz, DMSO) δ 12.75(s, 1H), 8.58(d, J=7.0Hz, 1H), 8.25(s, 1H), 7.64(s, 1H), 7.59(d, J=8.5Hz, 1H), 7.34(d, J=2.2Hz, 1H), 7.26(dd, J=8.5, 2.3Hz, 1H), 7.10( dd,J＝8.5,2.3Hz,1H),6.98(dd,J＝10.3,2.3Hz,1H),6.70(s,1H),4.16(dd,J＝14.3,7.6Hz,2H),4.06–3.97 (m, 2H), 3.66–3.57(m, 1H), 3.16(t, J=11.7Hz, 1H), 2.44(s, 3H), 2.20(d, J=12.1Hz, 1H), 2.04(s, 3H), 1.77 (d, J=12.5Hz, 1H), 1.62 (dd, J=11.9, 3.6Hz, 1H), 1.53–1.39 (m, 1H).

Example 67: (2S,5R)-5-(5-(2-Chloro-4-(5-fluoro-2-methylbenzofuran-7-yl)oxy)-7-yl)oxy) Preparation of Benzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)tetrahydro-2H-pyran-2-yl)methyl L-valine ester (Compound 109)

(2-chloro-4-(5-fluoro-2-methylbenzofuran-7-yl)oxyphenyl)(4-((3r,6s)-6-(hydroxymethyl)tetrahydro-2H -pyran-3-yl)amino)-7-(2-trimethylsilylethoxy)methyl)-7H-pyrro[2,3-d]pyrimidin-5-yl)methanone (Compound 21 ) (100 mg, 0.15 mmol, 1.0 equiv) with N-tert-butoxycarbonyl-L-valine (64 mg, 0.29 mmol, 2.0 equiv), N,N'-dicyclohexylcarbodiimide ( A mixture of 47 mg, 0.225 mmol, 1.5 equiv) and 4-dimethylaminopyridine (28 mg, 0.225 mmol, 1.5 equiv) in dichloromethane (8 mL) was stirred at room temperature overnight. The reaction solution was diluted with water and extracted with dichloromethane. The organic phase was dried and concentrated under reduced pressure. The residue was purified by thick preparative thin layer chromatography (petroleum ether/ethyl acetate=2/1) to give the product (2S,5R)-5-(5-(2-chloro-4-(5-fluoro-2) as a white solid -Methylbenzofuran-7-yl)oxy)-7-(2-trimethylsilylethoxy)-methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl )amino)tetrahydro-2H-pyran-2-yl)methyl(tert-butoxycarbonyl)-L-valine (86 mg, yield: 65.23%). LCMS (ESI): m/z=880[M+1] ⁺ .

(2S,5R)-5-(5-(2-chloro-4-(5-fluoro-2-methylbenzofuran-7-yl)oxy)-7-(2-trimethyl) obtained above Silylethoxy)-methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)methyl(tert-butoxycarbonyl) A solution of -L-valine (86 mg, 0.098 mmol, 1.0 equiv) in dichloromethane (3 mL) was added trifluoroacetic acid (3 mL) and the reaction was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, methanol (6 mL) and ammonia water (1.5 mL) were added to the mixture, followed by stirring at room temperature for 1 hour. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by thick preparative thin layer chromatography (dichloromethane/methanol=12/1) to give the product (2S,5R)-5-(5-(2-chloro-4-(5-fluoro-2-) as a yellow solid Methylbenzofuran-7-yl)oxy)-7-yl)oxy)benzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)tetrahydro-2H-pyridine Furan-2-yl)methyl L-valine ester (56 mg, yield: 87.90%). LCMS (ESI): m/z=650[M+1] ⁺ ^.1H NMR (500MHz, DMSO) δ 8.58(d, J=6.8Hz, 1H), 8.25(s, 1H), 7.63(s, 1H), 7.58(d, J＝8.4Hz, 1H), 7.33(d, J＝2.0Hz, 1H), 7.26(dd, J＝8.5, 2.3Hz, 1H), 7.10(dd, J＝8.4, 2.3 Hz, 1H), 6.98 (dd, J=10.3, 2.3Hz, 1H), 6.70 (s, 1H), 4.23–4.04 (m, 4H), 3.60 (d, J=5.5Hz, 1H), 3.18–3.14 (m, 2H), 2.44 (s, 3H), 2.21 (d, J=11.3Hz, 1H), 1.86 (dd, J=12.5, 6.5Hz, 1H), 1.78 (d, J=12.2Hz, 1H) ,1.62(d,J＝12.1Hz,1H),1.50(d,J＝14.6Hz,1H),0.87(dd,J＝24.1,6.8Hz,6H).

Example 68: ((2S,5R)-5-((5-(2-chloro-4-((5-fluoro-2-methylbenzofuran-7-yl)oxy)benzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)methylglycinate 2,2,2-trifluoroacetate (Compound 110) preparation

To a solution of (tert-butoxycarbonyl)glycine (150 mg, 0.856 mmol, 1.0 equiv) in tetrahydrofuran (8 mL) was added N,N'-carbonyldiimidazole (166 mg, 1.03 mmol, 1.2 equiv) under nitrogen ), the mixture was stirred at 75°C for 3.0 hours, and the solvent was removed under reduced pressure. To a solution of the residue (crude) in N,N-dimethylformamide (4 mL) was added (2-chloro-4-((5-fluoro-2-methylbenzofuran-7-) under nitrogen protection yl)oxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl))amino)-7H-pyrrolo[2,3 -d]pyrimidin-5-yl)methanone (compound 21) (100 mg, 0.182 mmol, 0.21 equiv) and potassium carbonate (75.3 mg, 0.545 mmol, 0.63 equiv), then the mixture was stirred at 65°C for 1.5 Hour. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified with silica gel column (dichloromethane/methanol=60/1 to 20/1) to give ((2S,5R)-5-((5-(2-chloro-4-((5-fluoro) as a yellow oil -2-Methylbenzofuran-7-yl)oxy)benzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino)tetrahydro-2H-pyran-2 -yl)methyl(tert-butoxycarbonyl)glycinate (115 mg, yield: 65.7%). LCMS (ESI): m/z=708[M+1]+.

To ((2S,5R)-5-((5-(2-chloro-4-((5-fluoro-2-methylbenzofuran-7-yl)oxy)benzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino)tetrahydro-2H-pyran-2-yl)methyl(tert-butoxycarbonyl)glycinate (120 mg, 0.169 mmol , 1.0 equiv) in dichloromethane (10 mL) was added trifluoroacetic acid (2.0 mL). The mixture was reacted at room temperature for 1.0 hours. The reaction solution was concentrated under reduced pressure to obtain a yellow solid ((2S,5R)-5-((5-(2-chloro-4-((5-fluoro-2-methylbenzofuran-7-yl)oxy) Benzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)methylglycinate 2,2,2-trifluoroacetic acid salt (102 mg, yield: 83.6%). MS(ES ⁺ ): m/z=608(M+H) ⁺ . ¹ H NMR (500MHz, DMSO) δ 12.85(s, 1H), 8.70(d, J=6.8Hz, 1H), 8.26(d , J＝22.8Hz, 4H), 7.69(s, 1H), 7.58(d, J＝8.5Hz, 1H), 7.35(d, J＝2.0Hz, 1H), 7.26(dd, J＝8.5, 2.1Hz) ,1H),7.11(dd,J＝8.5,2.2Hz,1H),6.97(dd,J＝10.2,2.1Hz,1H),6.70(s,1H),4.19(dd,J＝19.5,7.5Hz, 4H), 3.90(d, J＝3.8Hz, 2H), 3.75-3.56(m, 1H), 3.19(t, J＝11.5Hz, 1H), 2.44(s, 3H), 2.23(d, J＝11.2 Hz,1H),1.80(d,J＝12.3Hz,1H),1.66(d,J＝12.1Hz,1H),1.55(d,J＝11.2Hz,1H).

Example 69: (4-(((3R,6S)-6-(aminomethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- Preparation of 5-yl)(2-chloro-4-((5-fluoro-2-methylbenzofuran-7-yl)oxy)phenyl)methanone (Compound 111)

Under nitrogen protection, the mixture (2-chloro-4-((5-fluoro-2-methylbenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6- (Hydroxymethyl)tetrahydro-2H-pyran-3-yl))amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 21) (70 mg, 0.127 mM mol, 1.0 equiv) and N,N-diisopropylethylamine (83 mg, 0.636 mmol, 5.0 equiv) in dichloromethane (5 mL) was added dropwise methanesulfonyl chloride (75 mg, 0.636 mmol, 5.0 equiv) and the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (dichloromethane:methanol=20:1) to obtain (2S,5R)-5-((5-(2-chloro-4-((5-fluoro-methanesulfonic acid) as a yellow solid) 2-Methylbenzofuran-7-yl)oxy)benzoyl)-7-(methylsulfonyl)-7H-pyrro[2,3-d]pyrimidin-4-yl)amino)tetrahydrofuran-2H -pyran-2-yl)methyl ester (100 mg, crude). LCMS (ESI): m/z=707[M+1] ⁺ .

The above-obtained methanesulfonic acid (2S,5R)-5-((5-(2-chloro-4-((5-fluoro-2-methylbenzofuran-7-yl)oxy)benzoyl )-7-(methylsulfonyl)-7H-pyrro[2,3-d]pyrimidin-4-yl)amino)tetrahydrofuran-2H-pyran-2-yl)methyl ester (80 mg, 0.113 mmol , 1.0 equiv) and ammonia (3 mL) in N-methylpyrrolidone (3 mL) were stirred overnight at 90 °C in a smothered tank. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (dichloromethane:methanol=10:1) to give (4-(((3R,6S)-6-(aminomethyl)tetrahydro-2H-pyran-3-yl) )amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-((5-fluoro-2-methylbenzofuran-7-yl)oxy)benzene yl)methanone (25 mg, yield: 40.32%). LCMS (ESI): m/z=550[M+1] ⁺ ^.1H NMR (500MHz, DMSO) δ 12.81(s, 1H), 8.61(d, J=7.2Hz, 1H), 8.26(s, 1H), 8.02(s, 2H), 7.65(s, 1H), 7.58(d, J=8.5Hz, 1H), 7.35(d, J=2.3Hz, 1H), 7.26(dd, J=8.4, 2.3 Hz, 1H), 7.18–7.02 (m, 1H), 6.98 (dd, J=10.3, 2.3Hz, 1H), 6.70 (s, 1H), 4.21 (dt, J=11.6, 8.6Hz, 2H), 3.64 (t, J=9.6Hz, 1H), 3.20(dd, J=18.5, 8.5Hz, 1H), 2.99(s, 1H), 2.82(s, 1H), 2.45(s, 3H), 2.22(d, J=11.9Hz, 1H), 1.82 (d, J=11.4Hz, 1H), 1.72–1.58 (m, 1H), 1.58–1.41 (m, 1H).

Example 70: (2-Chloro-4-((5-fluoro-2-methylbenzofuran-7-yl)oxy)phenyl)(4-(((3R,6S)-6-(( Preparation of dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (compound 113)

Under nitrogen protection, (3R,6S)-6-((dimethylamino)methyl)tetrahydro-2H-pyran-3-amine hydrochloride (0108-113) (61.2 mg, 0.315 mmol, 1.2 equiv), (2-chloro-4-((5-fluoro-2-methylbenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d ]pyrimidin-5-yl)methanone (0107-21) (70 mg, 0.154 mmol, 1.0 equiv) and N,N-diisopropylethylamine (59 mg, 0.462 mmol, 3.0 equiv) in tert-butyl The mixture in alcohol (5 mL) was stirred at 90°C overnight. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (dichloromethane:methanol=10:1) to give (2-chloro-4-((5-fluoro-2-methylbenzofuran-7-yl)oxy) as a yellow solid )phenyl)(4-(((3R,6S)-6-((dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3 -d]pyrimidin-5-yl)methanone (38 mg, 42.6% yield). LCMS (ESI): m/z 578 [M+1] ⁺¹ H NMR (500 MHz, DMSO) δ 12.71 (s, 1H), 8.58 (d, J=7.0 Hz, 1H), 8.25 (s, 1H) ,7.64(s,1H),7.59(d,J＝8.5Hz,1H),7.34(d,J＝2.3Hz,1H),7.26(dd,J＝8.5,2.3Hz,1H),7.10(dd, J=8.5, 2.3Hz, 1H), 6.98 (dd, J=10.2, 2.3Hz, 1H), 6.70 (s, 1H), 4.15 (d, J=6.6Hz, 2H), 3.52 (d, J=9.8 Hz, 1H), 3.16(t, J＝11.8Hz, 1H), 2.46–2.35(m, 5H), 2.26(s, 6H), 2.19(d, J＝9.6Hz, 1H), 1.81(d, J = 13.1Hz, 1H), 1.65–1.53 (m, 1H), 1.43–1.36 (m, 1H).

Example 71: (2-Chloro-4-((5-fluoro-2-methylbenzofuran-7-yl)oxy)phenyl)(4-((3R,6S)-6-(fluoromethyl) Preparation of tetrahydro-2H-pyran-3-yl)amino)-7Hpyrro[2,3-d]pyrimidin-5-yl)methanone (Compound 114)

Under nitrogen protection, transfer to (2-chloro-4-((5-fluoro-2-methylbenzofuran-7-yl)oxy)phenyl)(4-((3R,6S)-6-(hydroxyl) Methyl)tetrahydro-2H-pyran-3-yl)amino)-7Hpyrro[2,3-d]pyrimidin-5-yl)methanone (Compound 21) (50 mg, 0.09 mmol, 1.0 equiv) To a mixture of dichloromethane (5 mL) was added dropwise diethylaminosulfur trifluoride (14 mg, 0.18 mmol, 2.0 equiv), and the mixture was stirred at room temperature for 4 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (dichloromethane:methanol=30:1) to give (2-chloro-4-((5-fluoro-2-methylbenzofuran-7-yl)oxy) as a yellow solid )phenyl)(4-((3R,6S)-6-(fluoromethyl)tetrahydro-2H-pyran-3-yl)amino)-7Hpyrro[2,3-d]pyrimidin-5-yl ) ketone (14 mg, yield: 28.%). LCMS (ESI): m/z=553[M+1] ⁺ ^.1H NMR (500MHz, DMSO) δ 12.74(s, 1H), 8.59(d, J=7.0Hz, 1H), 8.26(s, 1H), 7.64(s, 1H), 7.59(d, J=8.4Hz, 1H), 7.34(d, J=2.0Hz, 1H), 7.25(dd, J=8.5, 2.1Hz, 1H), 7.10( dd, J=8.4, 2.2Hz, 1H), 6.98 (dd, J=10.2, 2.1Hz, 1H), 6.70 (s, 1H), 4.57–4.27 (m, 2H), 4.25–4.08 (m, 2H) ,3.75–3.57(m,1H),3.19(t,J＝10.1Hz,1H),2.44(s,3H),2.22(d,J＝12.2Hz,1H),1.75(d,J＝12.7Hz, 1H), 1.64 (qd, J=12.2, 3.6Hz, 1H), 1.48 (qd, J=12.8, 3.7Hz, 1H).

Biological activity test

The contrast compound used in the present invention is ARQ 531, and the structure is as follows:

1. Enzyme activity inhibition test

1. Experimental materials

2. Experimental method

1) Construction of BTK-C481S enzyme (Methods Mol Biol. 2011; 722:157-66)

a. Entrust Suzhou Jinweizhi Biotechnology Co., Ltd. to synthesize the full-length sequence of BTK-C481S and connect it with the pcDNA3.1-3xFLAG vector;

b. The pcDNA3.1-3xFLAG plasmid linked with the full-length sequence of BTK-C481S was transfected into 293T cells to express 3X FLAG-BTK-C481S protein;

c. Utilize

M2 Affinity Gel and 3X

The BTK-C481S protein was purified by Peptide and stored in buffer (50 mM Tris-HCl, pH 7.4, 150 mM NaCl, 0.1 nM EDTA, 2 mM DTT, 0.1 mM PMSF, 25% glycerol).

2) BTK-C481S enzyme activity inhibition experiment

Using the ADP-Glokinase Kinase Assay Kit, its activity was determined by quantifying the amount of ADP produced during the kinase reaction. First, after the kinase reaction, an equal volume of ADP-Glo ^™ reagent was added to stop the kinase reaction and deplete the remaining ATP. Second, the kinase detection reagent is added while converting ADP to ATP and the newly synthesized ATP is measured using the luciferase/luciferin reaction. By using the ATP to ADP conversion curve, the intensity of the luminescent signal can be linked to the concentration of ADP, and the resulting luminescent signal is proportional to the concentration of ADP produced and correlated with kinase activity.

The experimental method is to dissolve the compounds to be tested in DMSO and then dilute them with kinase buffer (40 mM Tris, pH 7.4, 10 mM MgCl ₂ , 0.1 mg/ml BSA, 1 mM DTT), and add 1 ul of different concentrations of the tested compounds to a 96-well microplate. Compound (initial concentration of 1000nM, 4-fold dilution, 6 concentrations in total) and 2ul of BTK-C481S enzyme, and control wells without compound and without kinase were set at the same time. After incubation at room temperature for 30 minutes, add 1 ul of 125 μM ATP and 1 ul of 0.2 mg/ml Poly(Glu,Tyr) substrate mixed in advance, and incubate at 30°C for 1 hour after mixing. Add 5ul of ADP-Glo ^TM reagent to stop the kinase reaction, after 40 minutes of incubation at room temperature, add 10ul of kinase detection reagent, and incubate at room temperature for 30-60 minutes. Luminescence signal was measured with a BioTek Synergy H1 Microplate Reader.

Taking the luminescence signal intensity of the control well without compound as the maximum signal value and the luminescence signal intensity of the control well without kinase as the minimum signal value, the inhibition rate of the compound to the kinase was calculated, the inhibition rate %=(maximum signal value-signal value of compound well)/ (maximum signal value - minimum signal value) x 100%. Taking compound concentration as abscissa and inhibition rate as ordinate, sigmoidal dose-response curve was fitted using Graphpad prism7 software and IC ₅₀ was calculated.

3. Experimental results

The median inhibitory concentration (IC ₅₀ ) of each compound in the above experiment was calculated, and the results are shown in Table 1.

2. Tumor cell proliferation inhibition experiment

1. Experimental materials

RPMI1640培养基RPMI1640 medium	GIBCO，#C11875500BTGIBCO, #C11875500BT
胎牛血清(FBS)Fetal Bovine Serum (FBS)	Biological Industries，#040011ACSBiological Industries, #040011ACS
IL-3IL-3	PEPROTECH,#213-13PEPROTECH, #213-13
CellTiter-Glo发光细胞活力检测试剂盒CellTiter-Glo Luminescent Cell Viability Assay Kit	Promega，#G7573Promega, #G7573
Scepter自动细胞计数仪Scepter Automated Cell Counter	Millipore，#PHCC00000Millipore, #PHCC00000

2. Cell line (all origin cells have been identified by STR data)

细胞株名称cell line name	突变位点Mutation site	种属species	来源source
TMD-8TMD-8	WTWT	人people	上海翰森生物医药科技有限公司Shanghai Hansen Biomedical Technology Co., Ltd.

3. Experimental method

Tumor cell proliferation inhibition assay

After the cells were centrifuged and resuspended, the cell density was determined with a Scepter automatic cell counter. The density of TMD-8 cells was adjusted to 44,000 cells per ml, 90 μl was added to each well of a 96-well culture plate, and the cells were placed in a 37° C., 5% CO ₂ incubator for 24 hours. Add different concentrations of the compounds to be tested. Cells were incubated with compounds in the presence of 10% fetal bovine serum for 72 hours. Cell growth inhibition was assessed by measuring ATP levels using a luminescent cell viability assay kit (see manufacturer's instructions for details). Briefly, 30 μl of CellTiter-Glo reagent was added to each well, and the plate was shaken for 10 minutes to induce cell lysis, and the fluorescent signal was detected and recorded with a microplate detector. Maximum signal values were obtained from cells treated with DMSO for 72 hours. Minimum signal values were obtained from medium alone (zero cell number). Inhibition rate %=(maximum signal value-compound signal value)/(maximum signal value-minimum signal value)×100%. Taking compound concentration as abscissa and inhibition rate as ordinate, sigmoidal dose-response curve was fitted using Graphpad prism7 software and IC ₅₀ was calculated.

4. Experimental results

Table 1. Inhibitory activity of compounds on enzymes and tumor cell proliferation

化合物compound	BTK-C481S酶(IC50nM)BTK-C481S enzyme (IC50nM)	TMD-8细胞(IC50nM)TMD-8 cells (IC50nM)
11	IVIV	IIIIII
22	VV	IVIV
33	IIIIII	IIII
44	IIII	IIII
55	IVIV	IIII
66	VV	IVIV
77	II	II
99		IIII
1010	VV	IVIV
1111	IVIV	IVIV
1313	IVIV	IIIIII
1414	VV	IVIV
1616	IIIIII	IIII
1717	IVIV	IVIV
1818	VV	IVIV
1919	IIIIII	II
2020	VV	IVIV
21twenty one	IVIV	VV
23twenty three	VV	IVIV
2525	IVIV	IIIIII
2626	VV	IIIIII
2727	IVIV	IIII
2828	IVIV	II
2929	IIII	IIII
3030	IIIIII	IIII
3232	IVIV	IIII
3333	IVIV	IIII
3434	IVIV	IIIIII
3535	VV	IIIIII
3737	IVIV	IIIIII
4242	IVIV	IVIV
4343	IIIIII	IIIIII
4444	IVIV	VV

4545	IVIV	IVIV
4646	IVIV	IIIIII
4949		IVIV
5252	IVIV	IIIIII
5555	IVIV	IIIIII
5959	IIII	II
6060	IVIV	IIII
6161	IVIV	IIII
6262	IVIV	IIII
6363	IVIV	IIIIII
6666	VV	IIII
6767	IIIIII	IIII
6868	IIIIII	IIIIII
6969	IVIV	IIIIII
7070	IVIV	II
7171	IVIV	IIIIII
7272	IIIIII	IIII
7373	IVIV	IIII
7474	II	II
7575	II	II
7676	IIIIII	IIII
7777	IIII	IIIIII
7878		IIII
7979	IIII	II
8080		IIII
8181		IIII
8383		IVIV
8484	IVIV	IIIIII
8585	IVIV	IIIIII
111111		IVIV
113113		IVIV
114114		IIII
ARQ531ARQ531	IVIV	IIII

Among them: I>300nM, 300nM>II>100nM, 100nM>III>50nM, 50nM>IV>20nM, V<20nM.

As can be seen from the above table, some compounds of the present invention have stronger inhibitory effect on the enzymatic activity of BTK-C481S mutation compared with ARQ 531, and some compounds of the present invention have a stronger inhibitory effect on BTK wild-type tumors than ARQ 531. Stronger anti-tumor proliferative activity.

3. Pharmacokinetic (PK) Experiment

1. Experimental method

Male SD rats, weighing 180-350 g, were fasted overnight before the test. The compounds to be tested were dissolved in 30% sulfobutyl-beta-cyclodextrin (SBE-beta-CD) and 1N HCl and administered by single gavage at 20 mg/kg. 15 minutes, 30 minutes and 1, 2, 4, 6, 8 and 24 hours after administration, blood was taken from the tail end fracture, about 0.3 ml per time point, placed in a centrifuge tube containing K2-EDTA, and centrifuged (2000 g, 10 minutes, 4°C) to take the plasma and store it in an ultra-low temperature freezer at -70°C to -80°C. 50 μL of plasma samples were vortexed with 135 μL acetonitrile (containing 1 μg/mL internal standard) for protein precipitation, centrifuged, and the supernatant was collected for LC-MS/MS analysis.

2. Experimental results

After oral administration of the pyrrolopyrimidone compounds provided by the present invention to rats, the absorption is good and the blood exposure is high. The results are shown in Figures 1, 2 and Table 2. The _Tmax of the pyrrolopyrimidone compound of the present invention is 0.67-4.67 hours, the _Cmax is 936.3-5843.3 ng/ml, and the AUC _0-24h is 3260.8-92108.8 ng/ml*h. After oral administration of the prodrug compound 110 to rats, the exposure to blood was low, but the exposure of the active metabolite compound 21 was high, indicating that the prodrug had good absorption and was metabolized to generate active metabolites after absorption (Table 3, image 3). _Cmax refers to the maximum plasma concentration, T _1/2 is the half-life, AUC _0-24 refers to the area under the 0-24 hour time-concentration curve, and AUC _0-inf refers to the area under the 0-Inf time-concentration curve.

Table 2. Pharmacokinetic parameters of rats administered by gavage (20 mg/kg)

Table 3. Pharmacokinetic parameters of prodrug compound 110 after intragastric administration (20 mg/kg) to rats

4. Efficacy experiment

1. Experimental method

1.1 Experiment of antitumor activity of compounds 13, 21 and 23 in the subcutaneous model of TMD-8 human diffuse large B lymphoma cell xenograft mice.

NOD-SCID mice were purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. and housed in the barrier system animal room. When sufficient number of TMD-8 cells were cultured, cells were collected and washed twice with DPBS, and finally cells were inoculated in suspension with serum-free RPMI1640 medium and Matrigel 1:1 (v/v) (sigma, E1270). Only single cell suspensions with greater than 90% viability (trypan blue exclusion) were used for injection. Using a 1 mL syringe and a 26G syringe needle, 4 million cells suspended in 0.2 mL of serum-free medium and Matrigel were injected into the subcutaneous region of the right flank of each mouse, carefully avoiding blood vessels. Tumor size was measured 2 weeks after implantation. The size of the tumor was measured using a vernier caliper, and the tumor volume was calculated using the following formula: tumor volume = (length x width ² )/2. When the TMD-8 tumor volume reached an average of about 237 mm, the animals were divided into ⁵ oral administration groups, namely vehicle control group, ARQ531 positive control group (maximum tolerated dose 70 mg/kg) and compound 13 administration treatment group, compound 21 administration treatment group, compound 23 administration treatment group, the dose of compound 13 was 100 mg/kg from day 1 to day 5, 70 mg/kg from day 6 to day 28, and the dose of compound 21 and 23 was 100 mg/kg. The doses were all 100 mg/kg (n=3/group), administered once a day. Compounds were dissolved in 30% sulfobutyl-β-cyclodextrin (SBE-β-CD) and 1.0 molar equivalent hydrochloric acid (pH 4-5), respectively, at a final concentration of 10/7 mg/mL by gavage, respectively. The drug was administered continuously for 28 days.

1.2 Dose-dependent experiments of compound 21 in a subcutaneous mouse model of TMD-8 human diffuse large B lymphoma cells.

NOD-SCID mice were purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. and housed in the barrier system animal room. When sufficient number of TMD-8 cells were cultured, cells were collected and washed twice with DPBS, and finally cells were inoculated in suspension with serum-free RPMI1640 medium and Matrigel 1:1 (v/v) (sigma, E1270). Only single cell suspensions with greater than 90% viability (trypan blue exclusion) were used for injection. Using a 1 mL syringe and 26G syringe needle, 10 million cells suspended in 0.2 mL of serum-free medium and Matrigel were injected into the subcutaneous region of the right flank of each mouse, carefully avoiding blood vessels. Tumor size was measured 2 weeks after implantation. The size of the tumor was measured using a vernier caliper, and the tumor volume was calculated using the following formula: tumor volume = (length x width ² )/2. When the TMD-8 tumor volume reached an average ^of about 184 mm, the animals were divided into 5 oral administration groups, namely the vehicle control group, the ARQ531 positive control group (maximum tolerated dose of 70 mg/kg) and the compound 21 dose of 25/kg 50/100 mg/kg administration group (n=8/group), administered once a day. Compounds were dissolved in 30% sulfobutyl-β-cyclodextrin (SBE-β-CD) and 1.0 molar equivalent hydrochloric acid (pH 4-5), respectively, at final concentrations of 7/2.5/5.0/10.0 mg, respectively Administered by gavage/mL for 19 consecutive days.

2. Experimental results

2.1 Anticancer activity of compounds 13, 21, 23 in TMD-8 xenograft mouse subcutaneous tumor model. The dose of positive control compound ARQ531 was 70 mg/kg, the dose of compound 13 was 100 mg/kg from day 1 to day 5, and the dose of compound 21 and 23 was 100 mg/kg from day 6 to day 28. , 28 days of continuous administration, once a day, the excipient control group ended the animal experiment on the 15th day because the tumor volume was too large, and the animals in the other administration groups reached the maximum tumor inhibition rate on the 21st day, ARQ531 positive The T/C values of the control compound and compound 13, 21, and 23 administration groups were -96.2%, -99.6%, -100.0%, and -98.8%, respectively, and the relative tumor proliferation rate was continued until the 29th day. The T/C values were -79.0% and -96.8%, -97.9% and -75.6%, respectively. The drug was stopped and the tumor growth was continued to be observed until the end of the experiment on the 39th day. During the administration, except that the animals in the ARQ531 positive control compound and the compound 13 administration group discontinued the drug due to weight loss, the animals in the compound 21 and 23 administration groups had no obvious clinical symptoms or weight loss (the results are shown in Table 4 and Figure 4). 4).

The results showed that compounds 13, 21 and 23 could significantly inhibit the growth of TMD-8 tumor, and compound 21 had the best inhibitory effect and good tolerance.

2.2 The dose-response relationship of compound 21 in inhibiting the growth of TMD-8 xenograft tumors. Compound 21 was administered once a day and after continuous oral administration for 19 days, the T/C values of the relative tumor proliferation rates of the 25 mg/kg, 50 mg/kg and 100 mg/kg groups were 51.5% (p<0.05) and -43.6%, respectively. (p<0.001), -98.3% (p<0.001), tumor weight inhibition rates were 46.3%, 96.0%, and 99.8%, respectively; ARQ531 positive control compound was administered at a dose of 70 mg/kg once a day, and after continuous oral administration for 19 days , the relative tumor proliferation rate T/C value was -67.6% (p<0.001), and the tumor weight inhibition rate was 98.4%. One animal in the compound 21 dose 50mg/kg administration group was found to be dead on the 15th day of administration, and there was no abnormality in the gross anatomy, and the other animals and the doses of 25mg/kg and 100mg/kg animals were not compared with the vehicle control group in the same period. Obvious clinical symptoms appeared and no significant changes in body weight (results are shown in Table 5 and Figure 5).

The results showed that compound 21 inhibited the growth of TMD-8 tumor in a dose-dependent manner and was well tolerated.

Table 4. Antitumor activity of compounds 12, 21, 23 in TMD-8 xenograft tumor model and effect on animal body weight

Remark 1: BWC=body weight changed (body weight change rate), the calculation formula is: body weight change rate (%)=(W _T -W ₀ )/W ₀ x 100. _WT : animal body weight on the day of measurement, W0 _: animal body weight before administration.

Table 5. Antitumor dose-response relationship of compound 21 in TMD-8 xenograft tumor model and its effect on animal body weight

The technical features of the above-described embodiments can be combined arbitrarily. For the sake of brevity, all possible combinations of the technical features in the following embodiments are not described. However, as long as there is no contradiction between the combinations of these technical features, All should be regarded as the scope described in this specification.

The above-mentioned embodiments only represent several embodiments of the present invention, and the descriptions thereof are specific and detailed, but should not be construed as a limitation on the scope of the patent of the present invention. It should be pointed out that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can also be made, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention should be subject to the appended claims.

Claims

The pyrrolopyrimidone compound represented by formula (I) or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule:

in:

The dashed line within the oxygen-containing six-membered ring indicates that it is a single bond or not;

n is selected from: 0, 1, 2, 3 or 4;

p is selected from: 0, 1, 2 or 3;

W is selected from: -O-, -S-, -CR 4 R 5 -;

Ring A is selected from: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted 8-10 membered heteroaryl, substituted or unsubstituted 8-10 membered benzo Heterocyclyl;

And, when ring A is selected from substituted or unsubstituted 8-10 membered heteroaryl, substituted or unsubstituted 8-10 membered benzoheterocyclyl, R 1 is selected from: H, halogen, -OH, -OR 6 , -NR 7 R 8 , -SR 9 , -S(O)R 9 , -S(O) 2 R 9 ;

When Ring A is selected from substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, R 1 is selected from: -OR 6 , -NR 7 R 10 , -SR 9 , -S(O ) R 9 , -S(O) 2 R 9 ;

R 2 is selected from: H, halogen, C1-C6 alkyl;

Each R 3 is independently selected from: H, halogen, nitro, cyano, ester, acyl, C1-C6 alkyl;

R 4 , R 5 are independently selected from: H, halogen, C1-C6 alkyl, C3-C8 cycloalkyl;

Each R 6 is independently selected from: R 9 S-substituted C1-C6 alkyl, R 9 S(O)-substituted C1-C6 alkyl, R 9 S(O) 2 -substituted C1-C6 alkyl , R 21 OC(O)O-substituted C1-C6 alkyl, aminocarbonyl, C1-C6 alkylaminocarbonyl, C1-C6 alkanoyl, amino-substituted C1-C6 alkanoyl, -(M 1 )( M 2 ) P=O; M 1 and M 2 are independently selected from: -OH, C1-C3 alkyl;

Each R 7 is independently selected from: H, C1-C6 alkyl;

R 8 is selected from: H, C1-C6 alkyl, CN, hydroxy-substituted C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, -SR 9 , -S(O)R 9 , -S(O) 2 R 9 ;

Each R is independently selected from: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen substituted C1-C6 Alkyl, hydroxy substituted C1-C6 alkyl, C1-C6 alkoxy substituted C1-C6 alkyl, amino substituted C1-C6 alkyl, C1-C6 alkylamino substituted C1-C6 alkyl, C6-C10 aryl, one or more R 12 substituted C6-C10 aryl, 3-10 membered heterocyclic group, amino, C1-C6 alkylamino;

R 10 is selected from: CN, hydroxy-substituted C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, -SR 11 , -S(O)R 11 , -S(O) 2 R 11 ;

Each R 11 is independently selected from: amino, hydroxy-substituted C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, phenyl, halogen-substituted phenyl;

Each R 12 is independently selected from the group consisting of: halogen, nitro, cyano, C1-C6 alkyl;

R 20 is selected from: H, R 21 OC(O)O-substituted C1-C6 alkyl, R 21 C(O)O-substituted C1-C6 alkyl, 1 or more R 22 substituted 5- 8-membered heterocyclyl, R 21 C(O)NH-substituted C1-C6 alkyl, 1 or more R 23 substituted C1-C6 alkanoyl, (M 1 )(M 2 )P(O)O -Substituted C1-C6 alkyl; M 1 and M 2 are independently selected from: -OH, C1-C3 alkyl;

Each R 21 is independently selected from: C1-C6 alkyl, C3-C8 cycloalkyl, amino-substituted C1-C6 alkyl;

Each R 22 is independently selected from: C1-C6 alkyl, hydroxyl, halogen, nitro, cyano;

Each R 23 is independently selected from: carboxyl, amino, hydroxyl, aminocarbonyl.
The pyrrolopyrimidone compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule according to claim 1, wherein the pyrrolopyrimidone compound has the formula (II ) or the structure shown in formula (III):
The pyrrolopyrimidone compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule according to claim 1 or 2 is characterized in that, ring A is selected from:

in:

m is selected from: 0, 1 or 2;

X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 are independently selected from CR 15 or N;

Each of R 13 and R 15 is independently selected from: H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen Substituted C1-C6 alkyl, hydroxy substituted C1-C6 alkyl, C1-C6 alkoxy substituted C1-C6 alkyl, amino substituted C1-C6 alkyl, C1-C6 alkylamino substituted C1 -C6 alkyl, C6-C10 aryl, 5-10 membered heteroaryl, nitro, cyano, -OR, -N(R) 2 , -SR, -C(O)OR, -C(O) N(R) 2 , -C(O)R, -S(O)R, -S(O) 2 R, -S(O) 2 N(R) 2 , -N(R)C(O)R ;

Each R 14 is independently selected from: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen substituted C1-C6 alkyl;

Each R is independently selected from: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen-substituted C1-C6 alkane group, C1-C6 alkyl substituted by hydroxy, C1-C6 alkyl substituted by C1-C6 alkoxy, C1-C6 alkyl substituted by amino, C1-C6 alkyl substituted by C1-C6 alkylamino.
The pyrrolopyrimidone compound according to claim 3 or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule, is characterized in that, ring A is selected from:

Wherein, X 1 , X 2 , and X 3 are each independently selected from CR 15 ; X 4 , X 5 , X 6 , and X 7 are each independently selected from CR 15 or N.
The pyrrolopyrimidone compound according to claim 4 or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule, is characterized in that, ring A is selected from:
The pyrrolopyrimidone compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule according to claim 3 is characterized in that,

Each of R 13 and R 15 is independently selected from: H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, halogen-substituted C1-C3 alkyl, hydroxy-substituted C1-C3 alkyl, C1-C3 alkane Oxy-substituted C1-C3 alkyl, C1-C3 alkoxy, cyano, -C(O)OR, -C(O)N(R) 2 ;

Each R is independently selected from: H, C1-C6 alkyl.
The pyrrolopyrimidone compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule according to claim 6, wherein each R 13 and R 15 are independently selected from: hydrogen, Methyl, cyclopropyl, hydroxymethyl, ethyl, isopropyl, methoxymethyl, methoxycarbonyl, methoxy, cyano, aminocarbonyl, monofluoromethyl, difluoromethyl, trifluoro Methyl, Fluorine, Chlorine.
The pyrrolopyrimidone compound according to claim 3 or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule, is characterized in that, ring A is selected from:

Wherein, each R 13 is independently selected from: hydrogen, methyl, cyclopropyl, hydroxymethyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, fluorine, chlorine;

Each R 15 is independently selected from: hydrogen, fluorine, chlorine.
The pyrrolopyrimidone compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule according to claim 3, wherein each R 14 is independently selected from: H, C1-C3 alkyl.
The pyrrolopyrimidone compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof, wherein each R 9 is independently selected from: H, C1 -C3 alkyl, C3-C6 cycloalkyl, halogen substituted C1-C3 alkyl, hydroxy substituted C1-C3 alkyl, C1-C3 alkoxy substituted C1-C3 alkyl, amino substituted C1-C3 Alkyl, C1-C3 alkylamino substituted C1-C3 alkyl, phenyl, halogen substituted phenyl, amino, C1-C3 alkylamino.
The pyrrolopyrimidone compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule according to claim 10, wherein each R 9 is independently selected from: H, methyl, Ethyl, dimethylamino, hydroxyethyl, isopropyl, amino, methylamino, methoxyethyl, phenyl, fluorophenyl.
The pyrrolopyrimidone compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule according to claim 1 or 2, wherein R 8 is selected from: H, C1-C3 alkane base, CN, hydroxy-substituted C1-C3 alkyl, C1-C3 alkoxy-substituted C1-C3 alkyl, -SR 9-1 , -S(O)R 9-1 , -S(O) 2 R 9-1 ;

Wherein, each R 9-1 is independently selected from: hydroxy-substituted C1-C3 alkyl group, C1-C3 alkoxy-substituted C1-C3 alkyl group, amino group, phenyl group, and halogen-substituted phenyl group.
The pyrrolopyrimidone compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule according to claim 12, characterized in that, R 8 is selected from: H, methyl, -CN, Hydroxyethyl, -S(O) 2 R 9-1 ; wherein, each R 9-1 is independently selected from: hydroxyethyl, methoxyethyl, amino, phenyl, p-fluorophenyl.
The pyrrolopyrimidone compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule according to claim 1 or 2, wherein R 10 is selected from: -CN, hydroxy-substituted C1-C3 alkyl, C1-C3 alkoxy substituted C1-C3 alkyl, -SR 11 , -S(O)R 11 , -S(O) 2 R 11 ;

Each R 11 is independently selected from: hydroxy-substituted C1-C3 alkyl, amino, C1-C3 alkoxy-substituted C1-C3 alkyl, phenyl, halogen-substituted phenyl.
The pyrrolopyrimidone compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule according to claim 14, wherein R 10 is selected from: -CN, hydroxyethyl, - S(O) 2 R 11 ; wherein, R 11 is selected from: hydroxyethyl, amino, methoxyethyl, phenyl, p-fluorophenyl.
The pyrrolopyrimidone compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule according to claim 1 or 2, wherein each R 6 is independently selected from: R 9- 2 S-substituted C1-C3 alkyl, R 9-2 S(O)-substituted C1-C3 alkyl, R 9-2 S(O) 2 -substituted C1-C3 alkyl, aminocarbonyl, C1 -C3 alkylaminocarbonyl, C1-C3 alkanoyl, amino-substituted C1-C6 alkanoyl;

Wherein, each R 9-2 is independently selected from: C1-C3 alkyl group, C1-C3 alkylamino group, hydroxy-substituted C1-C3 alkyl group, amino group.
The pyrrolopyrimidone compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof according to claim 16, wherein each R 6 is independently selected from: methanesulfonylmethyl , methanesulfonylethyl, ethanesulfonylethyl, methanesulfonylpropyl, dimethylaminosulfonylethyl, isopropylsulfonylethyl, hydroxyethylsulfonylethyl, aminosulfonylethyl, methyl Aminosulfonylethyl, aminocarbonyl, acetyl, 2-methyl-3-amino-butyryl, aminoacetyl.
The pyrrolopyrimidone compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule according to claim 1 or 2, characterized in that when ring A is selected from substituted or unsubstituted 8 -10-membered heteroaryl, substituted or unsubstituted 8-10-membered benzoheterocyclyl,

R 1 is selected from: -OH, -OR 6 , methanesulfonyl, -NR 7 R 8 , fluorine, chlorine;

R 6 is selected from: R 9 S(O) 2 -substituted methyl, R 9 S(O) 2 -substituted ethyl, R 9 S(O) 2 -substituted propyl, C1-C3 alkanoyl, Amino-substituted C1-C6alkanoyl;

R 7 is selected from: H, C1-C3 alkyl;

R 8 is selected from: H, C1-C3 alkyl;

Each R 9 is independently selected from: methyl, ethyl.
The pyrrolopyrimidone compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule according to claim 1 or 2 is characterized in that, ring A is phenyl,

R 1 is selected from: -OR 6 , -NHR 10 , -S(O) 2 CH 3 ;

R 6 is selected from: R 9 S(O) 2 -substituted methyl, R 9 S(O) 2 -substituted ethyl; R 9 S(O) 2 -substituted propyl;

Each R 9 is independently selected from: methyl, ethyl, amino, methylamino, dimethylamino,

R 10 is selected from: -S(O) 2 R 11 ;

R 11 is selected from the group consisting of: methaneoxy-substituted ethyl, amino.
The pyrrolopyrimidone compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof, characterized in that R 2 is H; and/or R 3 Selected from: H, chlorine, fluorine.
The pyrrolopyrimidone compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule according to claim 1 or 2, wherein R 20 is selected from: H, R 21 OC ( O) O-substituted C1-C3 alkyl, R 21 C(O)O-substituted C1-C3 alkyl, (OH) 2 P(O)O-substituted C1-C3 alkyl;

R 21 is selected from: C1-C4 alkyl, C5-C6 cycloalkyl.
The pyrrolopyrimidone compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule according to claim 1, wherein the pyrrolopyrimidone compound is selected from:
Use of the pyrrolopyrimidone compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof in the preparation of a BTK inhibitor.
The use according to claim 23, wherein the BTK is wild-type BTK and/or C481 mutant BTK.
The pyrrolopyrimidone compound according to any one of claims 1-22 or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule is used in the preparation of preventing and/or treating diseases related to BTK overactivation and/or symptomatic drug use.
The use according to claim 25, wherein the BTK is wild-type BTK and/or C481 mutant BTK.
The use according to claim 25, wherein the disease related to BTK overactivation is tumor, inflammation or autoimmune disease.
The application according to claim 27, wherein the tumor is a hematological tumor or a solid tumor; the inflammatory or autoimmune disease is rheumatoid arthritis, lupus erythematosus, lupus nephritis, multiple sclerosis, Glenn Syndrome, Asthma
The application according to claim 28, wherein the blood tumor is lymphoma, myeloma, lymphocytic leukemia, acute myeloid leukemia; the solid tumor is lung cancer, breast cancer, prostate cancer, kidney cancer, gastric cancer , liver cancer, pancreatic cancer, ovarian cancer, colon cancer.
A pharmaceutical composition for preventing and/or treating diseases and/or symptoms related to BTK overactivation, characterized in that it comprises an active ingredient and a pharmaceutically acceptable adjuvant and/or carrier, wherein the active ingredient includes claims The pyrrolopyrimidone compound of any one of 1-22 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof.
The pharmaceutical composition according to claim 30, wherein the active ingredient further comprises one or more second therapeutic agents capable of preventing and/or treating tumors, inflammation or autoimmune diseases.
The pharmaceutical composition of claim 31, wherein the second therapeutic agent is selected from the group consisting of rituximab, lenalidomide, fludarabine, cyclophosphamide, doxorubicin, vincristine , Prednisone and PD-1/PD-L1 antibodies.