WO2022213932A1 - Composé de pyrrolopyrimidinone et son utilisation - Google Patents

Composé de pyrrolopyrimidinone et son utilisation Download PDF

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WO2022213932A1
WO2022213932A1 PCT/CN2022/085088 CN2022085088W WO2022213932A1 WO 2022213932 A1 WO2022213932 A1 WO 2022213932A1 CN 2022085088 W CN2022085088 W CN 2022085088W WO 2022213932 A1 WO2022213932 A1 WO 2022213932A1
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substituted
alkyl
equiv
mmol
chloro
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PCT/CN2022/085088
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Chinese (zh)
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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
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广州必贝特医药股份有限公司
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Priority to CN202280001109.XA priority Critical patent/CN114761410B/zh
Publication of WO2022213932A1 publication Critical patent/WO2022213932A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention relates to the technical field of chemical medicine, in particular to a pyrrolopyrimidone compound and an application thereof.
  • Bruton's tyrosine kinase 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.).
  • BTK phospholipase C ⁇ 2
  • PLC ⁇ 2 phospholipase C ⁇ 2
  • NF- ⁇ B nuclear transcription factor
  • 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.
  • BTK 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.
  • NHL non-Hodgkin's lymphoma
  • CLL/SLL chronic lymphocytic leukemia
  • DLBCL diffuse large B-cell Lymphoma
  • FL Follicular Lymphoma
  • MM Multiple Myelom
  • B cells 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.
  • 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.
  • 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
  • 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).
  • MCL mantle cell lymphoma
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • WM Waldenström's macroglobulinemia
  • MZL marginal zone lymphoma
  • ibrutinib 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.
  • ITK IL-2-induced T-cell kinase
  • tec tec protein tyrosine kinase
  • BMX non-receptor tyrosine kinase
  • epidermal growth factor receptors 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. ).
  • 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.).
  • 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.).
  • MCL mantle cell lymphoma
  • 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.
  • 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.
  • ibrutinib is the most potent BTK inhibitor, followed by zanubrutinib and acalabib tinib.
  • differences in pharmacodynamics and pharmacokinetics may affect inhibitor dose, efficacy, and adverse events (AEs).
  • AEs adverse events
  • 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.
  • 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.).
  • 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.).
  • 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.
  • 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]).
  • ORR overall response rate
  • 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.
  • 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 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;
  • 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 ;
  • 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 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.
  • the pyrrolopyrimidone compound has the structure represented by formula (II) or formula (III):
  • Ring A is selected from:
  • n 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;
  • 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
  • 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.
  • Ring A is selected from:
  • 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.
  • Ring A is selected from:
  • 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.
  • 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.
  • Ring A is selected from:
  • 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.
  • each R 14 is independently selected from: H, C1-C3 alkyl.
  • 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.
  • each R 9 is independently selected from: H, methyl, ethyl, dimethylamino, hydroxyethyl, isopropyl, amino, methylamino, methoxyethyl, phenyl , fluorophenyl.
  • 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 ;
  • 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.
  • 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.
  • 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.
  • 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.
  • 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;
  • 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.
  • 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.
  • 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.
  • 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.
  • R 2 is H; and/or, R 3 is selected from the group consisting of: H, chlorine, fluorine.
  • 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 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.
  • the BTK is wild-type BTK and/or C481 mutant BTK.
  • the BTK is wild-type BTK and/or C481 mutant BTK.
  • the disease associated with BTK overactivation is a tumor, inflammation, or autoimmune disease.
  • the tumor is a hematological tumor or a solid tumor.
  • the hematological 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.
  • 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.
  • 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.
  • the active ingredient further comprises one or more second therapeutic agents capable of preventing and/or treating neoplastic, inflammatory or autoimmune diseases.
  • the second therapeutic agent is selected from the group consisting of rituximab, lenalidomide, fludarabine, cyclophosphamide, doxorubicin, vincristine, prednisone, and PD-1 /PD-L1 antibody.
  • the BTK is wild-type BTK and/or C481 mutant BTK.
  • the disease associated with BTK overactivation is a tumor, inflammation, or autoimmune disease.
  • the tumor is a hematological tumor or a solid tumor.
  • the hematological 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.
  • the inflammatory or autoimmune disease is rheumatoid arthritis, lupus erythematosus, lupus nephritis, multiple sclerosis, Sjogren's syndrome, asthma.
  • 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.
  • 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.
  • any variable eg, R, etc.
  • its definition at each occurrence is independent of the definition at each other occurrence.
  • 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.
  • alkyl as used herein is meant to include branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • 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.
  • C1-C6 alkyl specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl.
  • cycloalkyl refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms.
  • cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and the like.
  • 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.
  • 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,
  • 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.
  • substituted refers to the replacement of a hydrogen group in a particular structure with a group of the designated substituent.
  • halo means chlorine, fluorine, bromine and iodine.
  • alkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl substituents can be unsubstituted or substituted.
  • 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.
  • 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.
  • 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.
  • 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.
  • salts of acidic compounds are formed by reaction with a suitable inorganic or organic base.
  • 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.
  • 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, methanes
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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:
  • 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, cefes
  • 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.
  • Step 1a Preparation of Benzofuran-7-ol (Compound 0101-1):
  • 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.
  • 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.
  • 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.
  • 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-Diisopropyleth
  • Step 2a Preparation of 2-methylbenzofuran-7-ol (compound 0101-2)
  • 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.
  • 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.
  • 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-
  • Step 3a Preparation of 2-ethylbenzofuran-7-ol (compound 0101-3):
  • 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.
  • 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.
  • 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.
  • 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
  • Step 4a Preparation of 2-isopropylbenzofuran-7-ol (compound 0101-4):
  • 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.
  • 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.
  • Step 4d 2(2-Chloro-4-((2-isopropylbenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-
  • 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.
  • 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.
  • Step 5a Preparation of 2-Cyclopropylbenzofuran-7-ol (Compound 0101-5):
  • 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.
  • 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).
  • 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 (2M 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).
  • 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-butan
  • 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.
  • Step 6a Preparation of 2-(hydroxymethyl)benzofuran-7-ol (compound 0101-6):
  • 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.
  • 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.
  • 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).
  • 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
  • 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.
  • 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.
  • Step 7c (2-Chloro-4-((2-(fluoromethyl)benzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidine
  • 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.
  • 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
  • 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).
  • 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.
  • Step 8c (2-Chloro-4-((2-(difluoromethyl)benzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]
  • pyrimidin-5-yl)methanone compound 0107-11
  • 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.
  • 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 diisopropylethyl
  • 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.
  • 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 (2M 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).
  • 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-
  • 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.
  • Step 10a Preparation of 2-chlorobenzofuran-7-ol (compound 0101-14):
  • 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.
  • 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.
  • 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 °C, 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.
  • 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.
  • Step 11a Preparation of 3-methylbenzofuran-7-ol (compound 0101-16):
  • 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.
  • 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.
  • Step 11d 2(2-Chloro-4-((3-methylbenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5
  • 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.
  • 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 m
  • Step 12a Preparation of 6-methylbenzofuran-7-ol (compound 0101-17):
  • 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.
  • 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.
  • 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 (2M 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).
  • 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
  • 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.
  • 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.
  • 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.
  • 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 °C, 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.
  • 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.
  • Step 14a Preparation of 5-fluorobenzofuran-7-ol (compound 0101-20):
  • 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.
  • 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).
  • Step 14e (2-Chloro-4-((5-fluorobenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl )
  • methyl ketone compound 0107-20
  • 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 m
  • 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.
  • Step 15a Preparation of 5-fluoro-2-methylbenzofuran-7-ol (compound 0101-21):
  • 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.
  • Step 15c (2-Chloro-4-((5-fluoro-2-methylbenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]
  • pyrimidin-5-yl)methanone compound 0107-21
  • sodium hydride 60%, 34 mg, 0.86 mmol, 2.0 equiv
  • 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 (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).
  • 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-but
  • 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.
  • Step 16a Preparation of Benzo[b]thiophen-7-ol (Compound 0101-25):
  • 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.
  • 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.
  • Step 16d (4-(Benzo[b]thiophen-7-yloxy)-2-chlorophenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methan
  • ketone compound 0107-25
  • 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.
  • 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
  • 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.
  • 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-
  • 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.
  • 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-but
  • Step 18a Preparation of Benzofuran-4-ol (Compound 0301-27):
  • 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.
  • 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.
  • n-butyl (1.54 mL, 2.46 mmol, 1.2 equiv) was added dropwise at -70°C and stirred for 1.0 h.
  • 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.
  • 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) ).
  • Step 19a Preparation of 7-hydroxybenzoxazole (compound 0101-28):
  • 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.
  • 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.
  • 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.
  • 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).
  • Step 19f (4-(Benzo[d]oxazol-7-yloxy)-2-chlorophenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)
  • methyl ketone compound 0107-28
  • sodium hydride 50%, 125 mg, 3.12 mmol, 2.0 equiv
  • 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 (2M 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).
  • 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
  • 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.
  • 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.
  • 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
  • (compound 0107-29) To 5-bromo-4-chloro-7H-pyrrole[2,3-d]pyrimidine (0106-1) (140 mg, 0.599 mmol, 1.2 equiv.)
  • sodium hydride 40 mg, 0.998 mmol, 2.0 equiv. The mixture was stirred at room temperature for 1 hour.
  • 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.
  • tert-butyl 7-(3-chloro-4-(methoxycarbonyl)phenoxy)-1H-indole-1-carboxylate (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).
  • Step 20c (4-(((1H-Indol-7-yl)oxy)-2-chlorophenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H
  • compound 29 4-(((1H-Indol-7-yl)oxy)-2-chlorophenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H
  • 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
  • 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.
  • Step 21b (2-Chloro-4-((1-methyl-1H-indol-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-
  • 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.
  • 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
  • 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.
  • Step 22b (2-Chloro-4-(naphthalen-1-yloxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 0403- 32)
  • 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
  • sodium hydride purity: 60%
  • 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.
  • 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.
  • Step 23b (2-Chloro-4-(quinolin-8-yloxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 0403 -33)
  • 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.
  • 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).
  • 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-Diisopropyle
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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).
  • 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 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.
  • 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.
  • 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.
  • 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.
  • Step 26b (4-(benzofuran-7-yloxy)-2-chlorophenyl)(4-(((3R,6S)-6-(((methylsulfonyl)methoxy)methyl) )
  • 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 e
  • 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.
  • 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.
  • 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)
  • 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.
  • 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)
  • 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.
  • 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.
  • 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,
  • 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).
  • Step 31b N-((2S,5R)-5-((5-(2-chloro-4-(naphthalen-1-yloxy)benzoyl)-7H-pyrrolo[2,3-d]
  • 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
  • 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.
  • 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.
  • 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.
  • Step 32c (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: 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 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.
  • Step 35a (2-Chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H -
  • 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).
  • 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
  • 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)
  • reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure.
  • 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
  • Step 39b (2-Chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-((3-(methylsulfonyl)propoxy)methyl)tetrahydro-2H
  • Compound 69 To 3-(methylsulfonyl)propan-1-ol (143 mg, 1.037 mmol, 4.2 equiv)
  • KHMDS (1M solution in tetrahydrofuran, 1.04 mL, 1.04 mmol, 4.2 equiv
  • 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.
  • 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,
  • 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.
  • 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).
  • 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 m
  • 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 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.
  • Step 43a Preparation of N-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)sulfonamide hydrochloride (compound 0108-73): at 0°C
  • chlorosulfonyl isocyanate 98.5 mg, 0.696 mmol, 2.0 equiv
  • benzyl alcohol 75 mg, 0.696 mmol, 2.0 equiv
  • tetrahydrofuran 0.5 mL
  • 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
  • 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.
  • 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).
  • 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.
  • 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.
  • 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).
  • 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,
  • 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.
  • 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).
  • 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 m
  • 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.
  • 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.
  • 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
  • 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,
  • Step 49a Preparation of 7-hydroxybenzofuran-2-carboxamide (compound 0101-9):
  • 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.
  • 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.
  • 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) .
  • 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
  • Step 50a Preparation of 4-fluorobenzofuran-7-ol (compound 0101-19):
  • 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.
  • 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)
  • ketone compound 0107-19
  • 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.
  • 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.
  • Step 51a Preparation of 2-chloro-4-((2-chloro-5-fluorobenzofuran-7-yl)oxy)benzoic acid (compound 0104-23):
  • 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).
  • Step 51c (2-Chloro-4-((2-Chloro-5-fluorobenzofuran-7-yl)oxy)phenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidine
  • -5-yl)methanone compound 0107-273: 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).
  • 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-butano
  • 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.
  • 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)
  • 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.
  • Step 56a Preparation of 5-Methylbenzofuran-7-ol (Compound 0101-78)
  • 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.
  • Step 56c (2-Chloro-4-(5-methylbenzofuran-7-yl)oxyphenyl)(4-chloro-7H-pyrro[2,3-d]pyrimidin-5-yl)methanol
  • Step 56c (2-Chloro-4-(5-methylbenzofuran-7-yl)oxyphenyl)(4-chloro-7H-pyrro[2,3-d]pyrimidin-5-yl)methanol
  • 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.
  • 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
  • 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.
  • 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.
  • 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
  • Step 58a Preparation of 7-hydroxybenzofuran-5-carbonitrile (compound 0101-80):
  • 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.
  • reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure.
  • Step 58c 7-(3-Chloro-4-((4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(hydroxy)methyl)phenoxy)benzofuran-5 -
  • 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.
  • 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.
  • 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- Diisopropylethyl
  • 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):
  • 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.
  • 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
  • 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.
  • 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
  • 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)
  • 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.
  • 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
  • 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)
  • 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)
  • 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.
  • 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.
  • 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)
  • the contrast compound used in the present invention is ARQ 531, and the structure is as follows:
  • 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;
  • 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).
  • 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 TM 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.
  • kinase buffer 40 mM Tris, pH 7.4, 10 mM MgCl 2 , 0.1 mg/ml BSA, 1 mM DTT
  • sigmoidal dose-response curve was fitted using Graphpad prism7 software and IC 50 was calculated.
  • 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 ⁇ l 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).
  • compound BTK-C481S enzyme (IC50nM) TMD-8 cells (IC50nM) 1 IV III 2 V IV 3 III II 4 II II 5 IV II 6 V IV 7 I I 9 II 10 V IV 11 IV IV 13 IV III 14 V IV 16 III II 17 IV IV 18 V IV 19 III I 20 V IV twenty one IV V twenty three V IV 25 IV III 26 V III 27 IV II 28 IV I 29 II II 30 III II 32 IV II 33 IV II 34 IV III 35 V III 37 IV III 42 IV 43 III III 44 IV V
  • 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.

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Abstract

L'invention concerne un composé de pyrrolopyrimidinone ayant une structure représentée par la formule générale (I) et son utilisation. Le composé de pyrrolopyrimidinone peut inhiber de manière efficace l'activité de mutations de BTK C481, a également un puissant effet inhibiteur sur la prolifération de lignées cellulaires de BTK de type sauvage, et a le potentiel d'être utilisé en tant que médicaments pour le traitement d'un lymphome à cellules B, de maladies auto-immunes et d'une inflammation.
PCT/CN2022/085088 2021-04-06 2022-04-02 Composé de pyrrolopyrimidinone et son utilisation WO2022213932A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115894500A (zh) * 2022-11-02 2023-04-04 中国药科大学 一种作为btk激酶抑制剂的化合物及其制备方法与用途
WO2024193509A1 (fr) * 2023-03-18 2024-09-26 山东新时代药业有限公司 Dérivé de benzoyl pyrrolopyrimidine, son utilisation et son procédé de préparation

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110152258A1 (en) * 2009-11-18 2011-06-23 Ibrahim Prabha N Compounds and Methods for Kinase Modulation, and Indications Therefor
WO2014188173A1 (fr) * 2013-05-20 2014-11-27 Redx Pharma Limited Dérivés pyrazolopyrimidine utiles comme inhibiteurs de la tyrosine kinase de bruton
WO2018088780A1 (fr) * 2016-11-08 2018-05-17 Daewoong Pharmaceutical Co., Ltd. Nouveaux dérivés de pyrrolopyrimidine et compositions pharmaceutiques les contenant
CN108699062A (zh) * 2015-12-23 2018-10-23 艾科尔公司 四氢吡喃基氨基-吡咯并嘧啶酮及其使用方法
CN109890821A (zh) * 2016-08-24 2019-06-14 艾科尔公司 氨基-吡咯并嘧啶酮化合物及其使用方法
CN112608318A (zh) * 2019-12-16 2021-04-06 成都海博为药业有限公司 一种作为蛋白质激酶抑制剂的化合物及其用途
WO2021093839A1 (fr) * 2019-11-13 2021-05-20 南京明德新药研发有限公司 Composé pyrrolopyrimidine utilisé comme inhibiteur de btk et son utilisation

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110152258A1 (en) * 2009-11-18 2011-06-23 Ibrahim Prabha N Compounds and Methods for Kinase Modulation, and Indications Therefor
WO2014188173A1 (fr) * 2013-05-20 2014-11-27 Redx Pharma Limited Dérivés pyrazolopyrimidine utiles comme inhibiteurs de la tyrosine kinase de bruton
CN108699062A (zh) * 2015-12-23 2018-10-23 艾科尔公司 四氢吡喃基氨基-吡咯并嘧啶酮及其使用方法
CN109890821A (zh) * 2016-08-24 2019-06-14 艾科尔公司 氨基-吡咯并嘧啶酮化合物及其使用方法
WO2018088780A1 (fr) * 2016-11-08 2018-05-17 Daewoong Pharmaceutical Co., Ltd. Nouveaux dérivés de pyrrolopyrimidine et compositions pharmaceutiques les contenant
WO2021093839A1 (fr) * 2019-11-13 2021-05-20 南京明德新药研发有限公司 Composé pyrrolopyrimidine utilisé comme inhibiteur de btk et son utilisation
CN112608318A (zh) * 2019-12-16 2021-04-06 成都海博为药业有限公司 一种作为蛋白质激酶抑制剂的化合物及其用途

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115894500A (zh) * 2022-11-02 2023-04-04 中国药科大学 一种作为btk激酶抑制剂的化合物及其制备方法与用途
CN115894500B (zh) * 2022-11-02 2024-05-28 中国药科大学 一种作为btk激酶抑制剂的化合物及其制备方法与用途
WO2024193509A1 (fr) * 2023-03-18 2024-09-26 山东新时代药业有限公司 Dérivé de benzoyl pyrrolopyrimidine, son utilisation et son procédé de préparation

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