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HK1260454B - N-(substituted-phenyl)-sulfonamide derivatives as kinase inhibitors - Google Patents

N-(substituted-phenyl)-sulfonamide derivatives as kinase inhibitors Download PDF

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Publication number
HK1260454B
HK1260454B HK19120273.8A HK19120273A HK1260454B HK 1260454 B HK1260454 B HK 1260454B HK 19120273 A HK19120273 A HK 19120273A HK 1260454 B HK1260454 B HK 1260454B
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Hong Kong
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compound
fluoro
methyl
phenyl
formula
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HK19120273.8A
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Chinese (zh)
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HK1260454A1 (en
Inventor
S·宾迪
D·卡兰兹
I·莫托
M·普里希
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内尔维阿诺医学科学有限公司
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Publication of HK1260454B publication Critical patent/HK1260454B/en

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Description

N- (substituted-phenyl) -sulfonamide derivatives as kinase inhibitors
The present invention relates to N- (substituted-phenyl) -sulfonamide compounds that are particularly useful as inhibitors of protein kinases (e.g. PERK kinase) and, thus, may be used for the treatment of cell proliferative diseases, such as cancer, or diseases associated with an activated unfolded protein response pathway, such as alzheimer's disease. The invention also provides processes for preparing these compounds, pharmaceutical compositions comprising these compounds and methods of treating diseases using pharmaceutical compositions comprising these compounds.
The Endoplasmic Reticulum (ER) represents a major subcellular compartment involved in the folding and maturation of proteins targeted to organelles and extracellular spaces. Several types of stress can alter the function of ER, including hypoxia, changes in protein glycosylation, consumption of ER calcium in the lumen, or changes in the redox state of ER (Wang m. and Kaufman r.j., Nat Rev cancer.2014 (9): 581-97). These events cause the accumulation of unfolded or misfolded proteins within the ER, eventually activating a series of adaptive mechanisms, called Unfolded Protein Response (UPR) (Hetz c., Chevet e. and Harding h.p., nat. rev. drug discov.2013, 12, 703-. These include increases in chaperone protein levels to promote protein refolding, degradation of misfolded proteins and cessation of translation to reduce the burden of protein entry into the ER. However, if cell damage is severe enough or prolonged, UPR signaling leads to apoptosis through apoptosis (Kim I., Xu W. and Reed J.C., Nat Rev Drug disc.2008 (7): 1013-1030).
UPRs are generally associated with maintaining cellular homeostasis in specific secretory cells, such as pancreatic beta cells, salivary glands, and plasma B cells, where high demand for protein synthesis and secretion requires effective and tightly controlled protein homeostasis. However, UPR is involved in many other physiological processes, including lipid and cholesterol metabolism, energy control, inflammation and cell differentiation (Wang M. and Kaufman R.J., Nat Rev cancer.2014 (9): 581-97). The large number of activities mediated by UPR reflects the role of ER stress in disease progression, such as cancer, neurodegenerative diseases and diabetes.
In mammals, there are three classes of ER stress sensors (Hetz c., Chevet e. and Harding h.p., nat. rev. drug discov.2013, 12, 703-: dimerization and autophosphorylation of IRE1 α means that conformational changes activate its RNase activity, resulting in the excision of the 26-nucleotide intron of mRNA encoding the transcription factor X-box binding protein 1(XBP1), which ultimately leads to the expression of a more stable and active form of the protein, termed XBP1s, which transactivates a set of target genes involved in protein folding, ER associated protein degradation (ERAD), protein translocation to ER and protein (Chen, Y. and Brandizi, F.trends Cell biol.2013, 547 Across 555).
ATF6 α is a transmembrane protein located in the ER that, upon ER stress, translocates to the golgi complex where it is processed, releasing the cytoplasmic fragment ATF6 f. This is a transcription factor that regulates the expression of ERAD pathway genes (Haze, k., Yoshida, h., Yanagi, h., Yura, T. & Mori, k., mol.biol.cell 1999, 10, 3787-.
Activation of PERK, such as activation of IRE1, is involved in dimerization, trans autophosphorylation, and formation of large clusters. Upon activation, PERK phosphorylates the eukaryotic translation initiation factor 2 α (eIF2 α), thereby inhibiting protein synthesis and thereby reducing the amount of nascent protein entering the ER. This has an important pro-survival effect on the cell itself, but in addition, it allows the translation of mRNA, for example of the activated transcription factor 4(ATF4), which controls the expression of genes encoding proteins involved in redox processes and amino acid metabolism. ATF4 also regulates the expression of important genes involved in apoptosis, including the transcription factor C/EBP homologous protein (CHOP) and growth inhibition and DNA damage induction 34(GADD34), which are involved in the feedback loop to dephosphorylate eIF2 α, thereby restoring protein synthesis. (Pytel D., Majsterek I. and Diehl J.A., Oncogene 2015 (35): 1207-1215).
Tumor cells are likely to rely on active UPR signaling because during their growth they are often hypoxic and starved for nutrients due to inadequate blood supply and abnormal vascular function (Rzymski t. and Harris a.l., clin.cancer res.2007, 13 (9): 2537-. Indeed, activation of UPR has been observed in clinical specimens. Human tumors, including those derived from cervical Cancer, glioblastoma (Bi m., Naczki c., kortzsky m., Fels d., Blais j., Hu n., Harding h., Novoa l., Varia m., Raleigh j., et al, EMBO j 2005 (24): 3470-81), hepatocellular tumors (Nakagawa h., Umemura a., Taniguchi k., Burgada j., Dhar d., oga h., Zhong z., Valasek m.a., Seki e, hidalogo j., Koike k., and Kaufman r.j., Cancer Cell-343 and breast Cancer (Andruska n., Yang x., shang g g.3734, g., h., kl g., kl h., kl g.k., kl h., kl k., kl h., kl, h., kl, h., kl h., tissue g, p.
In addition, aberrant activation of the unfolded protein response is implicated in a variety of other disorders, such as ocular diseases, obesity, diabetes (e.g., type 1 diabetes), stroke, myocardial infarction, cardiovascular diseases, atherosclerosis, cardiac arrhythmias, viral infections, inflammatory diseases, neurodegenerative diseases (e.g., prion-related diseases, amyotrophic lateral sclerosis, alzheimer's disease, huntington's disease and parkinson's disease), and the like. (Wang M. and Kaufman R.J., Nature 2016 (529): 326-335). Thus, inhibition of UPR with small molecules capable of blocking PERK activity and other components of UPR will lead to anticancer effects, as well as the possibility of treating diseases with activated unfolded protein responses.
Summary of The Invention
Three examples of the PERK compound inhibitor class are represented by substituted indoline derivatives disclosed in application WO2011/119663 and substituted pyrrolidone derivatives disclosed in application WO2015/136463 (both of which are applications by Glaxosmithkline LLC) and substituted quinazoline derivatives disclosed in application WO2014/161808 (application by Janssen Pharmaceutica NV).
The new classes of pyrrolo [2,3d ] pyrimidines and 4-aminopyrrolopyrimidines useful as serine/threonine or tyrosine kinase inhibitors are disclosed in WO98/41525 to Knoll AG and WO00/17202 to Basf AG, respectively.
Other kinase inhibitors represented by fused ring heteroaryl compounds are described in WO2010/045542 of the regents of the University of California.
However, there is a strong need for new compounds inhibiting PERK kinase activity which are useful in the treatment or prevention of cancer, in particular secretory cancer types, neurodegenerative diseases (e.g. amyotrophic lateral sclerosis, prion-related diseases, huntington's disease, alzheimer's disease and parkinson's disease) and the like, as well as diabetes, obesity, ocular diseases, stroke, myocardial infarction, cardiovascular diseases, atherosclerosis, cardiac arrhythmias, viral infections and inflammatory diseases. It is therefore an object of the present invention to provide such compounds.
Detailed Description
The present invention has now found that compounds of formula (I) as described below are kinase inhibitors and in particular PERK inhibitors and are therefore useful in therapy as anti-cancer agents.
Accordingly, a first aspect of the present invention provides N- (substituted-phenyl) -sulfonamides represented by formula (I),
wherein:
n is 0, 1 or 2;
r1 is an optionally substituted group selected from linear or branched (C)1-C8) Alkyl, (C)2-C8) Alkenyl, (C)2-C8) Alkynyl, (C)3-C8) Cycloalkyl group, (C)3-C8) Cycloalkenyl, heterocyclyl, aryl and heteroaryl;
r2 and R3 are independently halogen, cyano, OR4 OR an optionally substituted group selected from linear OR branched (C)1-C8) Alkyl, (C)2-C8) Alkenyl, (C)2-C8) Alkynyl and (C)3-C8) Cycloalkyl radicals, in which
R4 is an optionally substituted group selected from linear or branched (C)1-C8) Alkyl, (C)2-C8) Alkenyl, (C)2-C8) Alkynyl and (C)3-C8) A cycloalkyl group;
E1and E2Independently CH or N;
a is O, S or NR5, wherein
R5 is hydrogenOr an optionally substituted group selected from linear or branched (C)1-C8) Alkyl, (C)2-C8) Alkenyl, (C)2-C8) Alkynyl, (C)3-C8) Cycloalkyl group, (C)3-C8) Cycloalkenyl, heterocyclyl, aryl and heteroaryl;
and tautomers, hydrates, solvates, N-oxides, and pharmaceutically acceptable salts thereof.
The invention also provides methods for preparing N- (substituted-phenyl) -sulfonamide compounds of formula (I), by methods consisting of standard synthetic transformations.
The present invention also provides a method for the treatment of a disease caused by and/or associated with a deregulated protein kinase activity, in particular a protein kinase RNA-like ER kinase (PERK or EIF2AK3), which method comprises administering to a mammal in need thereof an effective amount of an N- (substituted-phenyl) -sulfonamide compound represented by formula (I) as defined above.
Preferred methods of the invention consist in treating diseases caused by and/or associated with deregulated protein kinase activity selected from the group consisting of cancer, cell proliferative disorders, viral infections, autoimmune diseases and neurodegenerative disorders.
Another preferred method of the invention is to treat certain types of cancer, including, but not limited to: cancers, including bladder, breast, colon, kidney, liver, lung, including small cell lung, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkitt's lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome, and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytomas, neuroblastomas, gliomas, and schwannomas; other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma (keratoxanthoma), thyroid follicular cancer, and kaposi's sarcoma.
In addition, the methods of the invention provide for inhibition of tumor angiogenesis and metastasis and methods of treating organ transplant rejection and host versus graft disease.
Another preferred method of the invention is for the treatment of specific cell proliferative disorders such as, for example, benign prostate hyperplasia, familial adenomatous polyposis, neurofibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and post-operative stenosis and restenosis.
Another preferred method of the invention is for the treatment of viral infections, in particular for the prevention of AIDS development in HIV-infected individuals.
Another preferred method of the invention is to treat autoimmune diseases and neurodegenerative diseases, in particular transplant rejection, skin diseases including psoriasis, allergic diseases, asthma, Rheumatoid Arthritis (RA), multiple sclerosis, Systemic Lupus Erythematosus (SLE), crohn's disease, prion-related diseases, alzheimer's disease, degenerative neurological diseases, encephalitis, stroke, parkinson's disease, amyotrophic lateral sclerosis, huntington's disease and pick's disease.
Another preferred method of the invention consists in treating alzheimer's disease, said method comprising administering to a subject in need thereof an effective amount of a compound of formula (I).
Another preferred method of the invention resides in treating stroke, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (I).
Another preferred method of the invention resides in the treatment of type 1 diabetes, said method comprising administering to a subject in need thereof an effective amount of a compound of formula (I).
Another preferred method of the invention resides in treating a disease state selected from the group consisting of: myocardial infarction, cardiovascular diseases, atherosclerosis, cardiac arrhythmias, obesity, ocular diseases and inflammatory diseases, the method comprising administering an effective amount of a compound of formula (I) to a subject in need thereof.
In addition, the methods of the present invention further comprise subjecting the mammal in need thereof to a radiation or chemotherapy regimen in combination with at least one cytostatic or cytotoxic agent.
The present invention also provides a pharmaceutical composition comprising one or more compounds of formula (I) as defined above or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, carrier and/or diluent.
The invention also provides pharmaceutical compositions comprising a compound of formula (I), and further comprising one or more chemotherapeutic agents, e.g., cell proliferation inhibiting or cytotoxic agents, antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents, cyclooxygenase inhibitors (e.g., COX-2 inhibitors), matrix metalloproteinase inhibitors, telomerase inhibitors, tyrosine kinase inhibitors, anti-growth factor receptor agents, anti-HER agents, anti-EGFR agents, anti-angiogenic agents (e.g., angiogenesis inhibitors), farnesyl transferase inhibitors, ras-raf signal transduction pathway inhibitors, cell cycle inhibitors, cdks inhibitors, tubulin binding agents, topoisomerase I inhibitors, topoisomerase II inhibitors, and the like.
Furthermore, the present invention provides an in vitro method for inhibiting the activity of a protein kinase RNA-like ER kinase (PERK or EIF2AK3), said method comprising contacting said protein with an effective amount of a compound of formula (I) as defined above.
In addition, the present invention provides a product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above and one or more chemotherapeutic agents as a combined preparation for simultaneous, separate or sequential use in anticancer therapy.
In a further aspect of the invention there is provided a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use as a medicament.
Furthermore, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above in the treatment of cancer.
Finally, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above for the manufacture of a medicament having anti-cancer activity.
Unless otherwise specified, when referring to the compounds of formula (I) themselves and any pharmaceutical compositions thereof or any therapeutic treatment involving them, the present invention includes all hydrates, solvates, complexes, metabolites, prodrugs, carriers, N-oxides and pharmaceutically acceptable salts of the compounds of the present invention.
A metabolite of a compound of formula (I) is any compound that is converted in vivo to the same compound of formula (I), e.g., upon administration to a mammal in need thereof. Typically, but not representing a limiting example, after administration of a compound of formula (I), the same derivative may be converted into various compounds, for example, including more soluble derivatives, such as hydroxylated derivatives, which are readily excreted. Thus, depending on the metabolic pathway that occurs, any of these hydroxylated derivatives may be considered a metabolite of the compound of formula (I).
Prodrugs are any covalently bonded compounds that release the active parent drug of formula (I) in vivo.
N-oxides are compounds of formula (I) in which nitrogen and oxygen are bonded via a dative bond.
If a stereogenic center or another form of an asymmetric center is present in the compounds of the present invention, it is intended herein to encompass all forms of such isomers, including enantiomers and diastereomers. Compounds containing a stereogenic center can be used in the form of a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture can be separated using well-known techniques and the individual enantiomers can be used individually. In the case of compounds having unsaturated carbon-carbon double bonds, the cis (Z) and trans (E) isomers are within the scope of the present invention.
In the case where a compound may exist in tautomeric forms, each tautomeric form is contemplated as being within the scope of the invention, whether existing in equilibrium or predominantly in one form.
As such, when in compounds of formula (I), E, unless otherwise provided2Is nitrogen, a is NR5 and R5 is hydrogen, showing only one of the tautomeric forms of formula (Ia) or (Ib), the remainder still being intended to be comprised within the scope of the invention:
where a compound may exist in tautomeric forms (e.g., keto-enol tautomers), each tautomeric form is contemplated as being within the scope of the invention, whether existing in equilibrium or predominantly in one form.
By the term "straight or branched chain (C)1-C8) By alkyl we mean any of the groups mentioned, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, n-hexyl and the like.
Unless otherwise provided, the term "(C)3-C8) By cycloalkyl "we mean a 3-to 8-membered all carbon monocyclic ring which may contain one or more double bonds but which does not have a fully conjugated pi-electron system. Examples of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene and cyclohexadiene, but are not limited thereto.
By the term "heterocyclyl" we mean a 3-to 7-membered saturated or partially unsaturated carbocyclic ring in which one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclic groups are, for example, pyran, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, thiazoline, thiazolidine, dihydrofuran, tetrahydrofuran, 1, 3-dioxolane, piperidine, piperazine, morpholine, and the like. The heterocyclic ring may optionally be further fused or linked to aromatic and non-aromatic carbocyclic and heterocyclic rings.
By the term "(C)2-C8) By alkenyl "we mean aliphatic (C)2-C8) A hydrocarbon chain comprising at least one carbon-carbon double bond and which may be straight or branched. Representative examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, and the like.
By the term "(C)2-C8) By alkynyl we mean aliphatic (C)2-C8) A hydrocarbon chain comprising at least one carbon-carbon triple bond and which may be straight or branched. Representative examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and the like.
The term "aryl" refers to a mono-, bi-or multi-carbocyclic hydrocarbon having 1 to 4 ring systems, which are optionally further fused or linked to each other by single bonds, wherein at least one of the carbocyclic rings is "aromatic", wherein the term "aromatic" refers to a completely conjugated pi-electron bond system. Non-limiting examples of such aryl groups are phenyl, alpha-naphthyl or beta-naphthyl or biphenyl.
The term "heteroaryl" refers to an aromatic heterocycle, typically a 5-to 7-membered heterocycle, having 1-3 heteroatoms selected from N, O or S; heteroaryl rings may optionally be further fused or linked to aromatic and non-aromatic carbocyclic and heterocyclic rings. Non-limiting examples of such heteroaryl groups are, for example, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl, thiazolyl, isothiazolyl, pyrrolyl, phenyl-pyrrolyl, furanyl, phenyl-furanyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, benzothienyl, isoindolinyl, benzimidazolyl, quinolinyl, isoquinolinyl, 1,2, 3-triazolyl, 1-phenyl-1, 2, 3-triazolyl, 2, 3-dihydroindolyl, 2, 3-dihydrobenzofuranyl, 2, 3-dihydrobenzothienyl, benzopyranyl, 2, 3-dihydrobenzoxazinyl, 2, 3-dihydroquinoxalinyl, and the like.
According to the present invention and unless otherwise provided, any one of the above R1, R2, R3, R4 and R5 groups may optionally be substituted at any of its free positions with one or more groups, such as 1-6 groups, independently selected from: halogen, nitreAn oxo group (═ O), a cyano group, and (C)1-C8) Alkyl, polyfluorinated (C)1-C8) Alkyl, polyfluorinated (C)1-C8) Alkoxy group, (C)2-C8) Alkenyl, (C)2-C8) Alkynyl, hydroxyalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, (C)3-C8) Cycloalkyl, hydroxy, (C)1-C8) Alkoxy, aryloxy, heterocyclyloxy, methylenedioxy, alkylcarbonyloxy, arylcarbonyloxy, cycloalkenyloxy, heterocyclylcarbonyloxy, alkyleneaminooxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, heterocyclylalkyloxycarbonyl-amino, ureido, alkylamino, dialkylamino, arylamino, diarylamino, heterocyclylamino, formylamino, alkylcarbonylamino, arylcarbonylamino, heterocyclylcarbonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, heterocyclylaminocarbonyl, alkoxycarbonylamino, hydroxyaminocarbonyloxyimino, alkylsulfonylamino, arylsulfonylamino, heterocyclylsulfonylamino, formyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyloxy, alkylcarbonyloxy, cycloalkyloxycarbonylamino, alkylcarbonyloxy, arylcarbonylamino, cycloalkyloxycarbonylamino, alkoxycarbonylamino, ureido, alkylamino, dialkylamino, arylcarbonylamino, heterocyclylsulfonylamino, formyl, alkylcarbonylamino, aminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkoxycarbonyl, ureido, where the like, where the appropriate to be substituted or combinations of the appropriate to the appropriate amounts of the appropriate to the appropriate amount of the amount of, Heterocyclylcarbonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, heterocyclylaminosulfonyl, arylthio, alkylthio, phosphonate, and alkylphosphonate. Thus, each of the above substituents may be further substituted, if appropriate, with one or more of the above groups.
By the term halogen atom we mean a fluorine, chlorine, bromine or iodine atom.
By the term cyano we mean the residue — CN.
By the term nitro we mean-NO2A group.
By the term polyfluorinated alkyl or polyfluorinated alkoxy we mean the above mentioned linear or branched (C)1-C8) Either alkyl or alkoxy substituted by more than one fluorine atom, e.g. trifluoromethyl, trifluoroethyl1,1,1,3,3, 3-hexafluoropropyl, trifluoromethoxy and the like.
By the term hydroxyalkyl we mean the above (C) with hydroxy1-C8) Any of the alkyl groups, for example, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, and the like.
From all of the above descriptions, it will be apparent to those skilled in the art that any group named a compound name, such as "arylamino", is necessarily intended to be conventionally construed as a moiety derived therefrom, such as amino further substituted with an aryl group, where aryl is as defined above.
Likewise, any of the terms, such as alkylthio, alkylamino, dialkylamino, alkoxycarbonyl, alkoxycarbonylamino, heterocyclylcarbonyl, heterocyclylcarbonylamino, cycloalkyloxycarbonyl, and the like, include groups wherein the alkyl, alkoxy, aryl, cycloalkyl, and heterocyclic moieties are as defined herein above.
Pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts with inorganic or organic acids, for example nitric, hydrochloric, hydrobromic, sulfuric, perchloric, phosphoric, acetic, trifluoroacetic, propionic, glycolic, lactic, oxalic, malonic, maleic, tartaric, citric, benzoic, cinnamic, mandelic, methanesulfonic, isethionic and salicylic acids.
Pharmaceutically acceptable salts of the compounds of formula (I) also include salts with inorganic or organic bases, for example hydroxides, carbonates or bicarbonates, acyclic or cyclic amines of alkali or alkaline earth metals, especially sodium, potassium, calcium, ammonium or magnesium.
Preferably, the present invention is directed to compounds of formula (I) wherein n is 0 or 1; r1 is an optionally substituted group selected from (C)3-C8) Cycloalkyl, aryl and heteroaryl; r2 is halogen or (C)1-C8) An alkyl group; a is S or NR5, and R3, R4, E1、E2And R5 is as defined above.
More preferably, the present invention is directed to compounds of formula (I) wherein n is 0; r1 is optionally substituted aryl or heteroaryl;r2 is halogen; a is NR5, and R3, R4, E1、E2And R5 is as defined above.
Even more preferably, the present invention is directed to compounds of formula (I) wherein n is 0; r1 is optionally substituted aryl; r2 is halogen; e1Is N; e2Is CH; a is NR5, wherein R5 is an optionally substituted group selected from linear or branched (C)1-C8) Alkyl and (C)3-C8) A cycloalkyl group; and R3 and R4 are as defined above.
Particularly preferred compounds (compounds) of the invention are the following compounds, but are not limited thereto and, if appropriate, may be in the form of pharmaceutically acceptable salts:
1) n- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -3-chloro-4-methoxy-benzenesulfonamide (compound 1);
2) n- [3- (4-amino-7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -3-chloro-4-methoxy-benzenesulfonamide (compound 2);
3) n- {3- [ 4-amino-7- (1-methyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -5-chloro-2-fluoro-4-methoxy-benzenesulfonamide (compound 3);
4) n- {3- [ 4-amino-7- (1-methyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -3-chloro-4-methoxy-benzenesulfonamide (compound 4);
5) n- {3- [ 4-amino-7- (1-cyclopropyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -3-chloro-4-methoxy-benzenesulfonamide (compound 5);
6) n- {3- [ 4-amino-7- (1-isopropyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -3-chloro-4-methoxy-benzenesulfonamide (compound 6);
7) n- [3- (4-amino-1-methyl-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -2-fluoro-phenyl ] -5-chloro-2-fluoro-4-methoxy-benzenesulfonamide (compound 9);
8) n- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -4-methoxy-3-methyl-benzenesulfonamide (compound 12);
9) n- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -3-chloro-benzenesulfonamide (compound 13);
10) n- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -4-bromo-2-fluoro-benzenesulfonamide (compound 22);
11) n- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -5-chloro-2-fluoro-4-methoxy-benzenesulfonamide (compound 24);
12) n- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -3, 4-dichloro-benzenesulfonamide (compound 25);
13) n- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -3, 5-dichloro-benzenesulfonamide (compound 26);
14) n- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -4-methoxy-3, 5-dimethyl-benzenesulfonamide (compound 29);
15) n- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -3,4, 5-trifluoro-benzenesulfonamide (compound 32);
16) 5-bromo-6-chloro-pyridine-3-sulfonic acid [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -amide (compound 33);
17) n- [3- (4-amino-1-methyl-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -2-fluoro-phenyl ] -4-methoxy-3-methyl-benzenesulfonamide (compound 34);
18) n- [3- (4-amino-1-methyl-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -2-fluoro-phenyl ] -3-chloro-4-methoxy-benzenesulfonamide (compound 35);
19) n- {3- [ 4-amino-7- (tetrahydro-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -4-methoxy-3-methyl-benzenesulfonamide (compound 36);
20) n- {3- [ 4-amino-7- (tetrahydro-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -3-chloro-4-methoxy-benzenesulfonamide (compound 37);
21) n- {3- [ 4-amino-7- (1-methyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -4-methoxy-3-methyl-benzenesulfonamide (compound 38);
22) n- {3- [ 4-amino-7- (1-cyclopropyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -4-methoxy-3-methyl-benzenesulfonamide (compound 39);
23) n- {3- [ 4-amino-7- (1-isopropyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -4-methoxy-3-methyl-benzenesulfonamide (compound 40);
24) n- {3- [ 4-amino-7- (1-ethyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -4-methoxy-3-methyl-benzenesulfonamide (compound 41);
25) n- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -2-fluoro-4-methoxy-5-methyl-benzenesulfonamide (compound 44);
26) n- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -4-bromo-2, 5-difluoro-benzenesulfonamide (compound 46);
27) 5-chloro-thiophene-2-sulfonic acid [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -amide (compound 47);
28) 5-bromo-thiophene-2-sulfonic acid [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -amide (compound 48);
29) n- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -4-bromo-3-methyl-benzenesulfonamide (compound 52);
30) n- {3- [ 4-amino-1- (1-methyl-piperidin-4-yl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl ] -2-fluoro-phenyl } -5-chloro-2-fluoro-4-methoxy-benzenesulfonamide (compound 61);
31) n- [3- (4-amino-1-piperidin-4-yl-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -2-fluoro-phenyl ] -5-chloro-2-fluoro-4-methoxy-benzenesulfonamide (compound 62);
32) n- [3- (4-amino-1-piperidin-4-yl-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -2-fluoro-phenyl ] -3-chloro-4-methoxy-benzenesulfonamide (compound 63);
33) n- [3- (4-amino-7-piperidin-4-yl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -4-methoxy-3-methyl-benzenesulfonamide (compound 64);
34) n- {3- [ 4-amino-7- (1-methyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -3, 4-dichloro-benzenesulfonamide (compound 71);
35) n- {3- [ 4-amino-7- (1-methyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -4-bromo-2-fluoro-benzenesulfonamide (compound 72);
36) n- {3- [ 4-amino-7- (1-methyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -2-fluoro-4-methoxy-5-methyl-benzenesulfonamide (compound 73);
37) 6-methoxy-pyridine-3-sulfonic acid [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -amide (compound 81);
38) n- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -4-chloro-2-fluoro-benzenesulfonamide (compound 85) and
39) n- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -3-bromo-4-methoxy-benzenesulfonamide (compound 87).
The present invention also provides a process for the preparation of the compounds of formula (I) as defined above by using the reaction routes and synthetic schemes described below, by using techniques available in the art and readily available starting materials. The preparation of certain embodiments of the present invention is described in the following examples, but one of ordinary skill in the art will recognize that the preparation may be readily adapted to prepare other embodiments of the present invention. For example, the synthesis of non-exemplified compounds according to the invention may be carried out by modifications apparent to those skilled in the art, for example by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by carrying out changes in conventional reaction conditions. Alternatively, other reactions mentioned herein or known in the art will be considered to be amenable to the preparation of other compounds of the present invention.
In one general synthetic approach, compounds of formula (I) as defined above may be prepared according to scheme 1 below:
scheme 1
In the above scheme 1A, E1、E2R1, R2, R3 and n are as defined above; x is a halogen atom, such as iodine or bromine, or a suitable leaving group, such as triflate; m is a suitable organometallic radical, e.g. B (OH)2、B(OAlk)2、Sn(Alk)3、Al(Alk)2ZnX, MgX or ZrCp2X, wherein X is halogen and Alk is (C)1-C8) Alkyl, and Pg is a suitable nitrogen protecting group such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, methoxymethyl, and the like.
In the synthetic method for preparing the compound of formula (I) described in step "a" of scheme 1, the compound of formula (II) is reacted with the compound of formula (IV) using any one of cross-coupling reactions suitable for forming carbon-carbon bonds. The reactions described are well known in the art and are meant to couple with suitable organometallic reagents such as organoboron, organotin, organozinc, organoaluminum or organozirconium compounds, and the like. In step "b", the same type of reaction is carried out to couple the compound of formula (II) with the compound of formula (VI) to give the compound of formula (VII). In step "c", the same type of reaction is carried out to couple the compound of formula (II) with the compound of formula (VIII) to give the compound of formula (I). In step "d", the same type of reaction is performed to couple the compound of formula (II) with the compound of formula (IX) to give the compound of formula (X). In step "e", the compound of formula (V) is subjected to selective removal of the group Pg to give a compound of formula (VII), which is reacted in step "f" with a sulfonyl chloride derivative of formula (XI) to give a compound of formula (I). In step "g", the protecting group is selectively removed from the compound of formula (X) to give the compound of formula (I).
In step "a 1", the compound of formula (III) is reacted with the compound of formula (IV) using any one of the cross-coupling reactions suitable for forming carbon-carbon bonds as reported above for step "a" to form the compound of formula (XII). In step "b 1", the same type of reaction is carried out to couple the compound of formula (III) with the compound of formula (VI) to give the compound of formula (XIII). In step "c 1", the same type of reaction is carried out to couple the compound of formula (III) with the compound of formula (VIII) to give the compound of formula (XIV). In step "d 1", the same type of reaction is carried out to couple the compound of formula (III) with the compound of formula (IX) to give the compound of formula (XV). In step "e 1", the compound of formula (XII) is subjected to selective removal of the group Pg to give a compound of formula (XIII), which is reacted in step "f 1" with a sulfonyl chloride derivative of formula (XI) to give a compound of formula (XIV). In step "g 1", the protecting group is selectively removed from the compound of formula (XV) to give the compound of formula (XIV).
In step "h", the compound of formula (XV) is reacted with ammonia or an ammonia equivalent, e.g. ammonium acetate, to give the compound of formula (X). In step "h 1", the same type of reaction performed on the compound of formula (XIV) gives the compound of formula (I). In step "h 2", the same type of reaction performed on compound of formula (XIII) gives compound of formula (VII). In step "h 3", the same type of reaction carried out on the compound of formula (XII) gives the compound of formula (V).
In step "a" according to scheme 1, a compound of formula (II) is reacted with a suitable organometallic derivative of formula (IV) such as an organoboron compound (Suzuki reaction), an organotin compound (Stille reaction), an organozinc, an organoaluminum or organozirconium compound (Negishi reaction), and the like. Such reactions are well known to those skilled in the art. A preferred reaction is the Suzuki reaction, if appropriate in a palladium-or nickel-based catalyst, for example palladium (tetratriphenyl) phosphine, and a suitable base, for example Cs2CO3、K2CO3、Rb2CO3Aryl or heteroaryl borates or acids are used in the presence of NaOH, CsF and the like. The reaction may be carried out in a solvent such as N, N-dimethylformamide, dimethylsulfoxide, water, dimethoxyethane, 1, 4-dioxane, tetrahydrofuran, and the like, and mixtures thereof, in a microwave apparatus or under conventional thermal conditions, at a temperature of 90-120 ℃, and for a time period of 30 minutes to about 24 hours.
The compounds of formula (II) are converted according to step "a" of scheme 1 into compounds of formulae (VII), (I) and (X) as defined above, respectively, by cross-coupling with derivatives of formulae (VI), (VIII) and (IX), respectively, as defined above, according to steps "b", "c" and "d" of scheme 1.
According to step "e" or "g" of scheme 1, selective removal of the Pg group can be performed using acid or reducing conditions to give a compound of formula (VII) from a compound of formula (V) or a compound of formula (I) from a compound of formula (X), respectively. For example, the reaction is carried out using a strong acid, such as trifluoroacetic acid, optionally in the presence of a suitable co-solvent, such as dichloromethane, at 20 ℃ to reflux temperature for a time period of 30 minutes to about 48 hours. Alternatively, when Pg is benzyl or benzyloxy, the reaction is carried out using reducing conditions, e.g. H2In the presence of a suitable hydrogenation catalyst. The hydrogenation catalyst is typically a metal, most commonly palladium, which may be used as such or supported on carbon, in a suitable solvent, for example tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, methanol, ethyl acetate or mixtures thereof.
The compound of formula (VII) is reacted with a sulfonyl chloride of formula (XI) according to scheme 1, step "f", to give the compound of formula (I). Such reactions are carried out in the presence of a suitable base such as pyridine, N-methylmorpholine or diisopropylethylamine in a suitable solvent such as pyridine, dichloromethane or tetrahydrofuran at 0 ℃ to reflux temperature and for a time period of about 1 hour to about 7 days.
The conversion of the compound of formula (III) to the compounds of formulae (XII), (XIII), (XIV) and (XV), respectively, according to steps "a 1", "b 1", "c 1" and "d 1" of scheme 1 is carried out as described in step "a" of scheme 1.
The conversion of compounds of formula (XII) and (XV) to formula (XIII) and (XIV), respectively, according to steps "e 1" and "g 1" of scheme 1 is performed as described in step "e" of scheme 1.
The conversion of compounds of formula (XIII) to compounds of formula (XIV), respectively, according to step "f 1" of scheme 1 is performed as described in step "f" of scheme 1.
According to scheme 1, step "h", the conversion of the compound of formula (XV) to the compound of formula (X) is carried out using a solution of ammonia in a suitable solvent such as tetrahydrofuran, 1, 4-dioxane, pyridine, methanol, ethanol, etc., in a solvent such as water, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, etc., and mixtures thereof, at 20 ℃ to reflux temperature, under conventional thermal conditions or using a microwave apparatus, for a time period of 30 minutes to about 24 hours.
Compounds of formula (XIV), (XIII) and (XII) are converted to compounds of formula (I), (VII) and (V), respectively, as described in step "h" of scheme 1, according to steps "h 1", "h 2" and "h 3" of scheme 1.
Preferably, a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, may be prepared according to a process as defined above, which process comprises the steps of:
reacting an intermediate of formula (II)
Wherein E1、E2A is as defined in claim 1 and X is halogen or a leaving group,
or cross-coupled with:
step a) derivatives of the formula (IV)
Wherein R2, R3 and n are as defined above, M is an organometallic group, and Pg is a nitrogen protecting group; followed by
Step e) Selective removal of the Pg group from the resulting intermediate of formula (V)
Wherein E1、E2A, R2, R3, n and Pg are as defined above; and
step f) bringing the resulting intermediate of formula (VII)
Wherein E1、E2A, R2, R3 and n are as defined above, with a derivative of formula (XI),
wherein R1 is as defined above, to give a compound of formula (I) as defined above;
or cross-coupled with:
step b) derivatives of the formula (VI)
Wherein R2, R3, n and M are as defined above; followed by
Step f) reacting the intermediate of formula (VII) obtained as defined above with a derivative of formula (XI) as defined above to obtain a compound of formula (I) as defined above;
or cross-coupled with:
step c) derivatives of the formula (VIII)
Wherein R1, R2, R3, n and M are as defined above;
or cross-coupled with:
step d) derivatives of the formula (IX)
Wherein R1, R2, R3, n, Pg and M are as defined above; subsequently:
step g) Selective removal of Pg groups from the resulting intermediate of formula (X)
Wherein E1、E2A, R1, R2, R3, n and Pg are as defined above, to give a compound of formula (I) as defined above;
optionally converting a compound of formula (I) to another compound of formula (I), and if desired, converting a compound of formula (I) to a pharmaceutically acceptable salt thereof or converting a salt to the free compound (I).
Alternatively, compounds of formula (I) as defined above may be prepared according to scheme 2 below:
scheme 2
In the above scheme 2A, E1、E2R1, R2, R3, n, X, M and Pg are as defined above.
In the synthetic method for preparing the compound of formula (I) described in scheme 2, in step "a 2", "b 2", "c 2" or "d 2", the compound of formula (XVI) is reacted with the compound of formula (XVIII), (XIX), (XX) or (XXI), respectively, using any one of cross-coupling reactions suitable for forming a carbon-carbon bond to give the compound of formula (V), (VII), (I) or (X), respectively. In step "e", the compound of formula (V) is subjected to selective removal of the group Pg to give a compound of formula (VII), which is reacted in step "f" with a sulfonyl chloride derivative of formula (XI) to give a compound of formula (I). In step "g", the protecting group is selectively removed from the compound of formula (X) to give the compound of formula (I).
In step "a 3", "b 3", "c 3" or "d 3", the compound of formula (XVII) is reacted with the compound of formula (XVIII), (XIX), (XX) or (XXI), respectively, using any one of the cross-coupling reactions suitable for the formation of a carbon-carbon bond, to give the compound of formula (XII), (XIII), (XIV) or (XV), respectively. In step "e 1", the compound of formula (XII) is subjected to selective removal of the group Pg to give a compound of formula (XIII), which is reacted in step "f 1" with a sulfonyl chloride derivative of formula (XI) to give a compound of formula (XIV). In step "g 1", the protecting group is selectively removed from the compound of formula (XV) to give the compound of formula (XIV).
In step "h", the compound of formula (XV) is reacted with ammonia or an ammonia equivalent, e.g. ammonium acetate, to give the compound of formula (X). In step "h 1", the same type of reaction performed on the compound of formula (XIV) gives the compound of formula (I). In step "h 2", the same type of reaction performed on compound of formula (XIII) gives compound (VII). In step "h 3", the same type of reaction carried out on the compound of formula (XII) gives the compound of formula (V).
The compound of formula (XVI) is converted to compounds of formulae (V), (VII), (I) and (X), respectively, as described in step "a" of scheme 1, according to steps "a 2", "b 2", "c 2" and "d 2" of scheme 2.
The compounds of formula (V) and (X) are converted to compounds of formula (VII) and (I), respectively, as described in step "e" of scheme 1, according to steps "e" and "g" of scheme 2.
The compound of formula (VII) is converted to the compound of formula (I) according to step "f" of scheme 2, as described in step "f" of scheme 1.
The compound of formula (XVII) is converted to compounds of formulae (XII), (XIII), (XIV) and (XV), respectively, as described in step "a" of scheme 1, according to steps "a 3", "b 3", "c 3" and "d 3" of scheme 2.
The compounds of formula (XII) and (XV) are converted to compounds of formula (XIII) and (XIV), respectively, as described in step "e" of scheme 1, according to steps "e 1" and "g 1" of scheme 2.
The compound of formula (XIII) is converted to the compound of formula (XIV) according to step "f 1" of scheme 2, as described in step "f" of scheme 1.
Compounds of formula (XV), (XIV), (XIII) and (XII) are converted to compounds of formula (X), (I), (VII) and (V), respectively, as described in step "h" of scheme 1, according to steps "h", "h 1", "h 2" and "h 3" of scheme 2.
Alternatively, compound a of formula (II) wherein X, E is prepared according to scheme 3 below1And E2And A is N-R5, wherein R5 is as defined above:
scheme 3
In the above scheme 3A, E1、E2R1, R2, R3, n, X, M are as defined above and L is OH or a group which can act as a leaving group, for example a halogen atom, tosylate, mesylate or triflate, or L is a group-B (OH)2。
In the synthetic method described in scheme 3 for the preparation of compounds of formula (II) a, in step "h 5", a compound of formula (III) is reacted with ammonia or an ammonia equivalent to give a compound of formula (II). When A is the group NH, in step "L", N-alkylation with a suitable alkylating agent of formula L-R5 affords compounds of formula (II) A. Alternatively, when A is the group NH, in step "L1", the compound of formula (III) is N-alkylated with a suitable alkylating agent of formula L-R5 to give the compound of formula (III) A. In step "h 5A", such compound of formula (III) a is treated with ammonia or an ammonia equivalent to give a compound of formula (II) a. In step "i", the compound of formula (II) is converted to an organometallic derivative of formula (XVI), e.g., an organo-boron or organo-tin derivative, which is N-alkylated in step "L2" with a suitable alkylating agent of formula L-R5 to give the compound of formula (XVI) A. Alternatively, in step "iA", the compound of formula (II) a is converted to an organometallic derivative of formula (XVI) a. In step "i 1", the compound of formula (III) is converted to an organometallic derivative of formula (XVII), which is N-alkylated in step "L3" with a suitable alkylating agent of formula L-R5 to give a compound of formula (XVI) A. Alternatively, in step "i 1A", the compound of formula (III) A is converted to an organometallic derivative of formula (XVII) A. In step "h 4", the compound of formula (XVII) is reacted with ammonia or an ammonia equivalent to give the compound of formula (XVI), while in step "h 4A", the compound of formula (XVII) a is reacted with ammonia or an ammonia equivalent to give the compound of formula (XI) a.
According to steps "h 5", "h 5A", "h 4" and "h 4A" of scheme 3, the compounds of formula (III), (III) a, (XVII) and (xviiia) are converted to the corresponding compounds of formula (II), (IIA), (XVI) and (XVIA), respectively, as described in step "h" of scheme 1.
According to step "L" of scheme 3, a compound of formula (II) can be converted to another compound of formula (IIA) using a compound of formula L-R5, wherein L is OH, in which case Mitsunobu reaction conditions can be used, or L is a group that can optionally act as a leaving group upon activation, such as a halogen atom, tosylate, mesylate or triflate. In the former case, i.e. when using the Mitsunobu scheme, a dialkyl azodicarboxylate such as diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD) or the like may be used, the reaction being carried out in the presence of a trialkyl or triaryl phosphine, preferably triphenylphosphine, in a suitable solvent such as tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane, acetonitrile. When L is a halogen atom or group such as tosylate, mesylate or triflate and the like, a suitable base such as NaH, K may be used2CO3、Cs2CO3NaOH, DBU, LiHMDS, etc., in a suitable solvent such as dichloromethane, tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane, methanol, ethanol, isopropanol, acetonitrile, acetic acid, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, etc. The reaction may be carried out at a temperature of from 0 ℃ to reflux temperature for a time period of from 30 minutes to about 48 hours. If desired, the compound of formula (IIA) can be isolated and purified by silica gel chromatography or preparative HPLC.
The compounds of formula (III), (XVI) and (XVII) were alkylated as described in step "l" of scheme 3, respectively, according to steps "l 1", "l 2" and "l 3" of scheme 3.
According to step "i" of scheme 3, the compound of formula (II) can be converted to a suitable organometallic derivative of formula (XVI), such as organoboron, organotin derivatives, and the like. For example, the compound of formula (II) is reacted with a suitable boron compound to give an organoboron derivative, e.g., bis (pinacolato) diboron, pinacolborane, and the like, in the presence of a suitable palladium catalyst, e.g., palladium acetate (Pd (OAc)2) 1,1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (Pd (dppf) Cl2·CH2Cl2) Or Pd (CH)3CN)2Cl2And a suitable base, such as KOAc, triethylamine, and the like, in a suitable solvent, such as N, N-dimethylformamide, dimethylsulfoxide, dimethoxyethane, 1, 4-dioxane, tetrahydrofuran, toluene, and the like, at 20 ℃ to reflux temperature for a time period of 30 minutes to about 24 hours. Organotin derivatives can be obtained by reaction with suitable organotin reagents, such as hexamethylditin and the like, in the presence of a suitable palladium catalyst, such as tetrakis (triphenylphosphine) palladium (Pd (PPh)3)4) Or palladium acetate (Pd (OAc)2) Optionally a suitable phosphine, such as triphenylphosphine, and optionally in the presence of a suitable base, such as KOAc, triethylamine, and the like, in a solvent, such as N, N-dimethylformamide, dimethylsulfoxide, dimethoxyethane, 1, 4-dioxane, tetrahydrofuran, toluene, and the like, at 20 ℃ to reflux temperature for a time period of 30 minutes to about 24 hours.
According to steps "iA", "i 1" and "i 1A" of scheme 3, compounds of formula (II) a, (III) and (III) a are converted to compounds of formula (XVI) a, (XVII) and (XVII) a, respectively, as described in step "i" of scheme 3.
When the compound of formula (I) is prepared according to any of the variations of this process, the optional functional groups, reagents or intermediates thereof in all of its starting materials are intended to be within the scope of the present invention, and may give rise to unwanted side reactions, requiring appropriate protection according to conventional techniques.
The starting materials, combinations of any of the possible variants of the process object of the invention and any of its reactants are known compounds which, if not commercially available, can be prepared according to well known methods.
Pharmacology of
The biochemical activity of the compounds was determined by incubation with PERK recombinase (cytoplasmic domain corresponding to residues 540-1115) and eIF2 alpha Peptide substrate (amino acid sequence: LLSELSRRRIRSINK-SEQ ID Nr: 1; purchased from American Peptide Company, product No. 341923). The following steps are carried out:
the method comprises the following steps: by ADP-GloTMKinase assay quantification of ADP formed by the kinase reaction (Promega catalog No. 9102). Ura Pure ATP is contained in ADP-GloTMA kinase detection kit.
Compounds were serially diluted 3-fold to obtain final concentrations of 3.333 to 0.000169 μ M, then incubated in 384-well plates (Perkin Elmer catalog No. 6007290) at room temperature in the presence of ATP, substrate and enzyme for 60 minutes in a final volume of 15 μ L kinase buffer.
The final concentrations of the different reagents were 52. mu.M ATP, 8nm PERK, 300. mu.M substrate, 50mM Hepes pH 7.5, 3mM MgCl2、1mM DTT、3μM Na3VO4、0.2mg/ml BSA、1％DMSO。
After 60 minutes, an equal volume (15. mu.L) of ADP-Glo was added to each wellTMReagents to terminate the kinase reaction and deplete the remaining ATP. After 40 minutes, 30 μ L of kinase detection reagent was added while converting ADP to ATP and allowing the newly synthesized ATP to be measured using the coupled luciferase/luciferin reaction. After a further 40 minutes, the luminescence was read by a ViewLux Instrument (Perkin Elmer).
Data were analyzed by GraphPad Prism software provided for IC using a 4-parameter logistic equation50Sigmoidal fitting of the measured curves:
y ═ bottom + (top-bottom)/(1 +10^ ((logIC)50-x)' slope)
Wherein x is the logarithm of the inhibitor concentration and y is the response; y starts at the bottom and returns to the top in an S-shape.
The method 2 comprises the following steps: quantification of phosphorylated products formed by the kinase reaction in the presence of ATP (Aldrich, Cat. No. A2620-9).
Serial dilutions of the compounds were made at room temperature at ATP/P33The gamma ATP mix, substrate and enzyme were incubated in 384-well plates (Thermo Scientific, cat. No. 4312) for 60 minutes in a 15 microliter volume of kinase buffer.
The reaction volume contained final concentrations of 52. mu.M ATP in 50mM Hepes pH 7.5, 8nm PERK and 300. mu.M substrate, 3mM MgCl2、1mM DTT、3μM Na3VO40.2mg/ml BSA. The final concentration of DMSO was 1%.
At the end of the incubation, 60 μ L of Dowex resin (Sigma, custom resin 1x 8200-400 mesh, Cat. No. 13858-U) in 150mM sodium formate buffer pH 3.0 was added to stop the reaction and capture unreacted ATP/P33Gamma ATP, which is separated from the phosphorylated substrate in solution. After standing for 60 minutes, the supernatant was transferred in a volume of 22. mu.L to 384-Optiplates (Perkin-Elmer, Cat. No. 6007290). After addition of 50. mu.L microscint 40(Perkin-Elmer, Cat. No. 6013641), radioactivity was calculated in TopCount (Perkin Elmer).
The data for each molecule was analyzed by an internal custom version of the SW software package "Assay Explorer" or by GraphPad Prizm software, or it was provided for IC using a 4-parameter logistic equation50Sigmoidal fitting of the measured curves:
y ═ bottom + (top-bottom)/(1 +10^ ((logIC)50-x)' slope)
Wherein x is the logarithm of the inhibitor concentration and y is the response; y starts at the bottom and returns to the top in an S-shape.
Testing compounds according to any one of the above PERK enzyme assays and displaying pIC for PERK in at least one experimental run50Activity, as shown in table a below:
TABLE A
The results for each compound were recorded as pIC50Calculated as IC50The negative logarithm of the values (moles) and are represented by the code according to table B below:
TABLE B
Code pIC50Value of
AA 7.8<pIC50
A 7.3<pIC50<7.8
B 6.8<pIC50<7.3
C pIC50<6.8
From all the above descriptions it is apparent that the novel compounds of formula (I) of the present invention are particularly advantageous in the treatment of diseases resulting from dysregulated protein kinase activity, such as cancer.
The compounds of the invention may be administered as single agents or in combination with known anti-cancer treatments, such as radiotherapy or chemotherapy regimens in combination with: for example, anti-hormonal agents such as anti-estrogens, anti-androgens and aromatase inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule-targeting drugs, platinum-based drugs, alkylating agents, DNA damaging or intercalating agents, antineoplastic anti-metabolic drugs, other kinase inhibitors, other anti-angiogenic agents, kinesin inhibitors, therapeutic monoclonal antibodies, mTOR inhibitors, histone deacetylase inhibitors, farnesyl transferase inhibitors and inhibitors of hypoxia response.
If formulated as a fixed dose, such combination products employ the compounds of the present invention in the dosage ranges described below and other pharmaceutically active agents in approved dosage ranges.
When the combined preparation is not suitable, the compound of formula (I) may be used in combination with known anticancer agents.
The compounds of formula (I) of the present invention, suitable for administration to a mammal, e.g., a human, can be administered by conventional routes, and the dosage level depends on the age, weight, condition of the patient and the route of administration.
For example, a suitable dose of a compound of formula (I) suitable for oral administration may be from about 10g to about 1g per dose, 1-5 times per day. The compounds of the invention may be administered in various dosage forms, for example, orally, in the form of tablets, capsules, sugar-or film-coated tablets, liquid solutions or suspensions; in the form of suppositories through the rectum; by parenteral injection or infusion, for example by intramuscular or by intravenous and/or intrathecal and/or intraspinal injection.
The invention also includes a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable excipient, which may be a carrier or diluent.
Pharmaceutical compositions comprising the compounds of the invention are generally prepared according to conventional methods and administered in the form of suitable pharmaceutical dosage forms.
For example, a solid oral dosage form may comprise the following excipients and active compound: diluents, such as lactose, glucose, sucrose, cellulose, corn starch or potato starch; lubricants, for example silica, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycols; binders, such as starch, gum arabic, gelatin, methyl cellulose, carboxymethyl cellulose, or polyvinyl pyrrolidone; disintegrating agents, such as starch, alginic acid, alginates or sodium starch glycolate; an effervescent mixture; a dye; a sweetener; wetting agents, such as lecithin, polysorbates, lauryl sulfate; and generally non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. These pharmaceutical preparations can be prepared in a known manner, for example by mixing, granulating, tabletting, sugar-coating or film-coating.
Liquid dispersions for oral administration may be, for example, syrups, emulsions and suspensions.
As an example, a syrup may comprise sucrose or a mixture of sucrose with glycerol and/or mannitol and sorbitol as a carrier.
Suspensions and emulsions may contain natural gums, agar, sodium alginate, pectin, methyl cellulose, carboxymethyl cellulose or polyvinyl alcohol as examples of carriers.
Suspensions or solutions for intramuscular injections may contain a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols (e.g. propylene glycol), and if desired, a suitable amount of lidocaine hydrochloride, together with the active compound.
Solutions for intravenous injection or infusion may contain sterile water as the carrier, or preferably they may be in the form of sterile isotonic saline solutions, or they may contain propylene glycol as the carrier.
Suppositories may contain a pharmaceutically acceptable carrier, such as cocoa butter, polyethylene glycol, polyoxyethylene sorbitan fatty acid ester surfactant or lecithin, with the active compound.
Experimental part
For any particular compound of formula (I) of the present invention, optionally in the form of a pharmaceutically acceptable salt, see the experimental section and claims. With respect to the examples below, the compounds of the present invention were synthesized using the methods described herein or other methods well known in the art.
The abbreviations and acronyms used herein have the following meanings:
g (g) mg (mg)
mL (mL) mM (millimolar concentration)
μ M (micromolar) mmol (millimole)
h (hour) MHz (megahertz)
mm (millimeter) Hz (Hertz)
M (molarity) min (minutes)
mol (mol) TLC (thin layer chromatography)
r.t. (Room temperature) TEA (triethylamine)
TFA (trifluoroacetic acid) DMF (N, N-dimethylformamide)
DIPEA (N, N-diisopropyl-N-ethylamine) DCM (dichloromethane)
THF (tetrahydrofuran) AcOET (ethyl acetate)
Hex (Hexane) MeOH (methanol)
DMSO (dimethyl sulfoxide) TIPS (triisopropylsilyl)
Ac (acetyl) bs (broad singlet)
TBDMS (dimethyl-tert-butylsilyl) ESI (electrospray ionization)
BOC (tert-butoxycarbonyl) Ac2O (acetic anhydride)
NaH (sodium hydride, 60% solution in mineral oil)
TBTU (2- (1H-benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium tetrafluoroborate)
RP-HPLC (reverse phase high Performance liquid chromatography) to better illustrate the invention, the following examples are now given, without constituting any limitation thereto.
The symbols and designations used herein for the methods, protocols, and examples are consistent with those used in the contemporary scientific literature, such as the Journal of the American Chemical Society or Journal of Biological Chemistry.
Unless otherwise explained, all materials were obtained from commercial suppliers, had the best grade and were used without further purification. Anhydrous solvents such as DMF, THF, CH2Cl2And toluene from Aldrich chemical company. All reactions involving air or moisture sensitive compounds were carried out in a nitrogen or argon atmosphere.
General purification and analytical methods
Flash chromatography was performed using silica gel (Merck grade 9395, 60A).
Electrospray (ESI) mass spectra were obtained using a Thermo Finnigan LCQ Deca XP ion trap. HPLC-UV-MS analysis for evaluation of compound purity was performed, combining an ion trap MS instrument with an HPLC system, surveyor (thermo Finnigan), equipped with an autosampler and a diode array detector (UV detection 215-. Instrument control, data acquisition and processing were performed by using Xcalibur 1.4SR1 software (Thermo Finnigan). HPLC chromatography was performed at room temperature and 1ml/min flow rate using a Phenomenex Gemini NX C18 column (4.6X 50 mm; 3 μm). Mobile phase a is ammonium acetate 5mM buffer (ph5.5, containing acetic acid)/acetonitrile 95:5, mobile phase B is ammonium acetate 5mM buffer (ph5.5, containing acetic acid)/acetonitrile 5: 95; the gradient was 0-100% B over 7 minutes, then 100% B was held for 2 minutes, and then re-equilibrated.
Exact mass data ESI (+) were obtained using a Waters Q-Tof Ultima directly linked to the mini HPLC 1100Agilent [ M.Colombo, F.Ricccardi-Sirtori, V.Rizzo, Rapid Commun. Mass.sectrom.2004, 18, 511-.
Retention times (HPLC r.t.) are given in minutes at 220nm or 254 nm. The mass is specified as the m/z ratio.
When necessary, compounds were purified by preparative HPLC using Waters preparative HPLC600 equipped with 996Waters PDA detector and micromass mod.zmd single quadrupole mass spectrometer, electrospray ionization, positive mode with Waters Symmetry C18(19X 50mm, 5um) column or Waters X Terra RP 18(30X150mm, 5 μm) column. Mobile phase a was water-0.01% trifluoroacetic acid and mobile phase B was acetonitrile. Gradient 10-90% B in 8 min, holding 90% B for 2 min. The flow rate was 20 mL/min. In the alternative, flowPhase A is water-0.1% NH3And the mobile phase B is acetonitrile. Gradient 10-100% B in 8 min, hold 100% B for 2 min. The flow rate was 20 mL/min.
1H-NMR spectroscopy was performed using Mercury VX 400 equipped with a 5mm dual resonance probe [1H (15N-31P) ID _ PFG Varian ] operating at 400.45 MHz.
Preparation 1
5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-ylamine, compounds of formula (II) A
Scheme 3
4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidine, compounds of formula (III) A
Scheme 3, step l1
4-chloro-5-iodo-7H-pyrrolo [2,3-d in N, N-Dimethylformamide (DMF) (80mL) at 0 deg.C]To pyrimidine (2.38g, 8.5mmol) was added gradually 60% NaH (0.59g, 14.7 mmol). H2After bubbling ceased, iodomethane (0.66mL, 10.6mmol) was added and the reaction mixture was warmed at room temperature. After 3 hours, the reaction mixture was slowly poured onto water and crushed ice (about 400 mL; cautious: H2 evolved due to quenching excess NaH). Filtering the resulting white solid, washing with water, and vacuum drying to obtain 4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d]Pyrimidine (2.38 g).
HPLC(254nm)：Rt：8.62min。
HRMS (ESI) calculated value C7H5ClIN3[M+H]+293.929, found 293.9296.
1H NMR(401MHz，DMSO-d6)δppm：3.83(s，3H)7.98(s，1H)8.65(s，1H)。
The following compounds were obtained in a similar manner:
4-chloro-5-iodo-7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidine, compounds of formula (III) A
HPLC(254nm)：Rt：11.17min。
HRMS (ESI) calculated value C9H9ClIN3[M+H]+321.9603, found 321.9605.
1H NMR(401MHz，DMSO-d6)δppm：1.47(d，J＝6.71Hz，6H)4.92-5.15(m，1H)8.16(s，1H)8.63(s，1H)。
4-chloro-7-ethyl-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine, compounds of formula (III) A
HPLC(254nm)：Rt：6.16min。
HRMS (ESI) calculated value C8H7ClIN3[M+H]+307.9446, found 307.9455.
1H NMR(500MHz，DMSO-d6)δppm：1.37(t，J＝7.24Hz，3H)4.29(q，J＝7.22Hz，2H)8.07(s，1H)8.64(s，1H)。
5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-ylamine, compounds of formula (II) A
Scheme 3, step h5A
A suspension of 4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidine (1,16g, 3.96mmol) in ammonium hydroxide (10mL, 75.43mmol) and dioxane (5mL) was stirred in a sealed vessel at 125 ℃ for 1 day. The reaction was cooled to room temperature, poured into water and ice, and filtered. The collected solid was washed with water to give 5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-ylamine (0.93g) as a white solid.
HPLC(254nm)：Rt：4.06min。
HRMS (ESI) calculated value C7H7IN4[M+H]+274.9788, found 274.9796.
1H NMR(500MHz，DMSO-d6)δppm：3.67(s，3H)6.59(br.s.，2H)7.42(s，1H)8.10(s，1H)。
The following compounds were obtained in a similar manner:
5-iodo-7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-4-ylamine, compounds of formula (II) A
HPLC(254nm)：Rt：4.99min。
HRMS (ESI) calculated value C9H11IN4[M+H]+303.0101, found 303.0105.
1H NMR (401MHz, DMSO-d6) delta ppm: 1.40(d, J ═ 6.71Hz, 6H)4.89 (quintuple, J ═ 6.74Hz, 1H)6.55(br.s., 2H)7.57(s, 1H)8.08(s, 1H).
7-Ethyl-5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-4-ylamine, a compound of formula (II) A
HPLC(254nm)：Rt：3.27min。
HRMS (ESI) calculated value C8H9IN4[M+H]+288.9945, found 288.9957.
1H NMR(401MHz，DMSO-d6)δppm：1.31(t，J＝7.26Hz，3H)4.13(d，J＝7.20Hz，2H)6.38-6.72(m，2H)7.47-7.50(m，1H)8.09(s，1H)。
Preparation 2
3-iodo-1-methyl-1H-pyrazolo [3,4-d ] pyrimidin-4-ylamine, a compound of formula (II) A
Scheme 3, step l
To 3-iodo-1H-pyrazolo [3,4-d at 0 DEG C]To a solution of pyrimidin-4-ylamine (550mg, 2.044mmol) in DMF (20mL) was added Cs2CO3(770mg, 2.362mmol) and methyl iodide (0.16mL, 2.57 mmol). The reaction was warmed at room temperature and stirred overnight. The reaction mixture was poured onto water and extracted with DCM. The organic phase was washed with brine and Na2SO4Drying and evaporating. The crude product was purified by silica gel chromatography with DCM: MeOH 95:5 elution and the resulting solid was washed with Et2Grinding together O to obtain 3-iodo-1-methyl-1H-pyrazolo [3,4-d]Pyrimidin-4-ylamine (170mg) as a white solid.
HPLC(254nm)：Rt：3.55min。
HRMS (ESI) calculated C6H6IN5[ M + H ]]+275.9741, found 275.9743.
1H NMR(401MHz，DMSO-d6)δppm：3.88(s，3H)7.49(s，2H)8.21(s，1H)。
Preparation 3
5-iodo-7- (1-methyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-ylamine, compounds of formula (II) A
Scheme 3
4- (4-chloro-5-iodo-pyrrolo [2,3-d ] pyrimidin-7-yl) -piperidine-1-carboxylic acid tert-butyl ester, a compound of formula (III) A
Scheme 3, step l1
Adding 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] through a syringe]To a solution of pyrimidine (518mg, 1.857mmol), tert-butyl 4-hydroxy-piperidine-1-carboxylate (1.14g, 5.671mmol) and triphenylphosphine (984mg, 3.775mmol) in THF (10mL) was added DEAD (0.6mL, 3.669mmol) dropwise and stirred at room temperature for 3 h. The reaction was concentrated, diluted with AcOEt and washed with NaOH 1.0N. The organic layer was then washed with brine and Na2SO4Drying and evaporating. The crude product was purified by silica gel chromatography, eluting with hexane: AcOEt ═ 7:3 elution gave 4- (4-chloro-5-iodo-pyrrolo [2, 3-d)]Pyrimidin-7-yl) -piperidine-1-carboxylic acid tert-butyl ester (730mg) as a white solid.
HPLC(254nm)：Rt：7.38min。
HRMS (ESI) calculated value C16H20N4O2ICl[M+H]+463.0393, found 463.04.
1H NMR(401MHz，DMSO-d6)δppm：1.43(s，9H)1.82-1.92(m，2H)1.92-2.04(m，2H)2.94(br.s.，2H)4.11(m，J＝11.60Hz，2H)4.72-4.95(m，1H)8.19(s，1H)8.64(s，1H)。
The following compounds were obtained in a similar manner:
4-chloro-5-iodo-7- (tetrahydro-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine, compounds of formula (III) A
HPLC(254nm)：Rt：5.97min。
HRMS (ESI) calculated value C11H11N3OICl[M+H]+363.9708, found 363.9724.
1H NMR(401MHz，DMSO-d6)δppm：1.87(dd，J＝12.39，2.26Hz，2H)2.06-2.24(m，2H)3.52(td，J＝11.84，1.59Hz，2H)3.99(dd，J＝11.47，4.39Hz，2H)4.82-5.00(m，1H)8.18(s，1H)8.64(s，1H)。
4-chloro-5-iodo-7-piperidin-4-yl-7H-pyrrolo [2,3-d ] pyrimidine, Compound of formula (III) A scheme 3
To 4- (4-chloro-5-iodo-pyrrolo [2, 3-d) in dioxane (8mL)]Pyrimidin-7-yl) -piperidine-1-carboxylic acid tert-butyl ester (240mg, 0.519mmol) to a solution of HCl in 4M dioxane (4ml, 16mmol) was added and the reaction stirred at 45 ℃ overnight. Evaporation ofThe reaction system was diluted with DCM and NaOH 1.0N to obtain a white solid. The aqueous layer was extracted with DCM and the combined organic layers were washed with brine and Na2SO4Drying and evaporating to obtain 4-chloro-5-iodo-7-piperidin-4-yl-7H-pyrrolo [2,3-d]Pyrimidine (157mg) as a white solid.
HPLC(254nm)：Rt：4.29min。
HRMS (ESI) calculated value C11H12N4ICl[M+H]+362.9868, found 362.9874.
1H NMR(500MHz，DMSO-d6)δppm：1.90-2.00(m，2H)2.00-2.16(m，2H)2.79-2.94(m，2H)3.12-3.28(m，2H)4.74-4.87(m，1H)8.08(s，1H)8.65(s，1H)。
The following compounds were obtained in a similar manner:
5-iodo-7-piperidin-4-yl-7H-pyrrolo [2,3-d ] pyrimidin-4-ylamine, compounds of formula (II) A
HPLC(254nm)：Rt：3.17min。
HRMS (ESI) calculated value C11H14IN5[M+H]+344.0367, found 344.0369.
1H NMR(500MHz，DMSO-d6)δppm：1.60-1.90(m，4H)2.55-2.62(m，2H)3.03(d，J＝12.51Hz，2H)4.47-4.62(m，1H)5.71-7.16(m，2H)7.52(s，1H)8.07(s，1H)。
4-chloro-5-iodo-7- (1-methyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine, compounds of formula (III) A
Scheme 3
To 4-chloro-5-iodo-7-piperidin-4-yl-7H-pyrrolo [2,3-d ] in DCM (15mL)]To pyrimidine (518mg, 1.430mmol) was added AcOH (90 μ L, 1.575mmol) in 37 wt.% aqueous formaldehyde (550 μ L, 7.346mmol) and stirred at room temperature. After 15min, NaBH (OAc) was added stepwise3(1.62g, 7.412mmol) and the reaction was stirred at room temperature overnight. The mixture was diluted with DCM and washed with NaOH 2.0N. The organic layer was washed with brine, Na2SO4Drying and evaporating to obtain 4-chloro-5-iodo-7- (1-methyl-piperidin-4-yl) -7H-pyrrolo [2,3-d]Pyrimidine (491mg) as a white solid.
HPLC(254nm)：Rt：4.37min。
HRMS (ESI) calculated value C12H14N4ICl[M+H]+377.0025, found 377.0042.
1H NMR(401MHz，DMSO-d6)δppm：1.88(m，J＝8.91Hz，2H)2.03-2.18(m，4H)2.23(s，3H)2.91(m，J＝8.67Hz，2H)4.62(m，J＝11.63，11.63，4.33Hz，1H)8.15(s，1H)8.63(s，1H)。
The following compounds were obtained in a similar manner:
4-chloro-5-iodo-7- (1-isopropyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine, compounds of formula (III) A
HPLC(254nm)：Rt：4.63min。
HRMS (ESI) calculated value C14H18N4ICl[M+H]+405.0338, found 405.0346.
1H NMR(500MHz，DMSO-d6)δppm：1.00(d，J＝6.56Hz，6H)1.84-1.94(m，2H)1.98-2.13(m，2H)2.24-2.35(m，2H)2.76(br.s.，1H)2.92(d，J＝10.68Hz，2H)4.61(t，J＝12.35Hz，1H)8.16(s，1H)8.63(s，1H)。
4-chloro-7- (1-cyclopropyl-piperidin-4-yl) -5-iodo-7H-pyrrolo [2,3-d ] pyrimidine, compounds of formula (III) A
HPLC(254nm)：Rt：6.35min。
HRMS (ESI) calculated value C14H16N4ICl[M+H]+403.0181, found 403.0183.
1H NMR(500MHz，DMSO-d6)δppm：0.28-0.37(m，2H)0.40-0.48(m，2H)1.63-1.73(m，1H)1.81-1.93(m，2H)2.05(s，3H)2.31-2.42(m，2H)3.02-3.12(m，1H)4.61-4.74(m，1H)8.14(s，1H)8.63(s，1H)。
5-iodo-7- (1-methyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-ylamine, compounds of formula (II) A
Scheme 3, step h5A
To a 5mL microwave vial loaded with dioxane (4mL) was added 4-chloro-5-iodo-7- (1-methyl-piperidin-4-yl) -7H-pyrrolo [2,3-d]Pyrimidine (469mg, 1.247mmol), ammonium hydroxide (10mL, 76.46mmol), sealed. At 13The reaction was heated at 0 ℃ for 180min under microwave irradiation. The mixture was diluted with water and extracted with DCM. The combined organic phases were washed with brine, Na2SO4Drying and evaporating. The solid obtained is reacted with Et2Grinding together O to obtain 5-iodo-7- (1-methyl-piperidin-4-yl) -7H-pyrrolo [2,3-d]Pyrimidin-4-ylamine (374mg) as a white solid.
HPLC(254nm)：Rt：3.22min。
HRMS (ESI) calculated value C12H16N5I[M+H]+358.0523, found 358.0535.
1H NMR(401MHz，DMSO-d6)δppm：1.74-1.87(m，2H)1.94-2.12(m，4H)2.23(s，3H)2.89(m，J＝8.06Hz，2H)4.31-4.60(m，1H)6.57(br.s.，2H)7.56(s，1H)8.08(s，1H)。
The following compounds were obtained in a similar manner:
5-iodo-7- (1-isopropyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-ylamine, compounds of formula (II) A
HPLC(254nm)：Rt：3.50min。
HRMS (ESI) calculated value C14H20N5I[M+H]+386.0836, found 386.0845.
1H NMR(500MHz，DMSO-d6)δppm：0.99(d，J＝6.56Hz，6H)1.82(dt，J＝11.78，1.81Hz，2H)1.96(qd，J＝12.20，3.97Hz，2H)2.26(t，J＝11.21Hz，2H)2.74(spt，J＝6.60Hz，1H)2.89(d，J＝11.44Hz，2H)4.45(tt，J＝11.93，3.85Hz，1H)6.58(br.s.，2H)7.57(s，1H)8.08(s，1H)。
7- (1-cyclopropyl-piperidin-4-yl) -5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-4-ylamine, compounds of formula (II) A
HPLC(254nm)：Rt：4.04min。
HRMS (ESI) calculated value C14H18N5I[M+H]+384.068, found 384.0689.
1H NMR(500MHz，DMSO-d6)δppm：0.27-0.34(m，2H)0.41-0.48(m，2H)1.67(tt，J＝6.58，3.49Hz，1H)1.79(d，J＝11.59Hz，2H)1.95(qd，J＝12.23，3.43Hz，2H)2.32(t，J＝11.29Hz，2H)3.04(d，J＝11.90Hz，2H)4.51(tt，J＝11.95，3.98Hz，1H)6.59(br.s.，2H)7.55(s，1H)8.08(s，1H)。
5-iodo-7- (tetrahydro-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-ylamine, compounds of formula (II) A
HPLC(254nm)：Rt：4.42min。
HRMS (ESI) calculated value C11H13IN4O[M+H]+345.0207, found 345.0213.
1H NMR(401MHz，DMSO-d6)δppm：1.80(m，J＝12.27，2.38Hz，2H)1.98-2.12(m，2H)3.48(td，J＝11.93，1.77Hz，2H)3.97(dd，J＝11.35，4.27Hz，2H)4.63-4.86(m，1H)6.59(br.s.，2H)7.60(s，1H)8.09(s，1H)。
4- (4-amino-5-iodo-pyrrolo [2,3-d ] pyrimidin-7-yl) -piperidine-1-carboxylic acid tert-butyl ester, a compound of formula (II) A
To a 5mL microwave vial loaded with dioxane (1mL) was added 4- (4-chloro-5-iodo-pyrrolo [2, 3-d)]Pyrimidin-7-yl) -piperidine-1-carboxylic acid tert-butyl ester (115mg, 0.249mmol), ammonium hydroxide (2mL, 16.6mmol), sealed. The reaction was heated at 100 ℃ under microwave irradiation for 120 min. The mixture was diluted with water and extracted with DCM. The combined organic phases were washed with brine, Na2SO4Drying and evaporating. The crude product was purified by silica gel chromatography with DCM: MeOH, 90:10 elution to give 4- (4-amino-5-iodo-pyrrolo [2, 3-d)]Pyrimidin-7-yl) -piperidine-1-carboxylic acid tert-butyl ester (80mg) as a white solid.
HPLC(254nm)：Rt：5.98min。
HRMS (ESI) calculated value C16H22N5O2I[M+H]+444.0891, found 444.088.
1H NMR(500MHz，DMSO-d6)δppm：1.42(s，9H)1.69-1.94(m，4H)2.75-3.02(m，2H)4.04-4.23(m，2H)4.59-4.79(m，1H)6.59(br.s.，2H)7.61(s，1H)8.08(s，1H)。
Preparation 4
4- (4-amino-3-iodo-pyrazolo [3,4-d ] pyrimidin-1-yl) -piperidine-1-carboxylic acid tert-butyl ester, a compound of formula (II) A
Scheme 3, step l
To 3-iodo-1H-pyrazolo [3,4-d]To a solution of pyrimidin-4-ylamine (300mg, 1.115mmol), tert-butyl 4-hydroxy-piperidine-1-carboxylate (680mg, 3.383mmol) and triphenylphosphine (593mg, 2.263mmol) in THF (10mL) was added DEAD (0.37mL, 2.262mmol) dropwise via syringe and stirred at rt for 3 h. The reaction was concentrated, diluted with AcOEt and washed with NaOH 1.0N. The organic layer was washed with brine, Na2SO4Drying and evaporating. The crude product was purified by silica gel chromatography, eluting with hexane: AcOEt ═ 1:1 elution gave 4- (4-amino-3-iodo-pyrazolo [3,4-d]Pyrimidin-1-yl) -piperidine-1-carboxylic acid tert-butyl ester (300mg) as a white solid.
HPLC(254nm)：Rt：5.72min。
HRMS (ESI) calculated value C15H21N6O2I[M+H]+445.0844, found 445.0839.
1H NMR(401MHz，DMSO-d6)δppm：1.43(s，9H)1.79-1.93(m，4H)2.95(br.s.，2H)3.91-4.20(m，2H)4.81(tt，J＝10.51，5.23Hz，1H)5.91-7.38(m，2H)8.19(s，1H)。
Preparation 5
3-bromo-thieno [3,2-c ] pyridin-4-ylamine, a compound of formula (II)
Scheme 3, step h5
Reacting 3-bromo-4-chloro-thieno [3,2-c]Pyridine (300mg, 1.21mmol) was dissolved in NMP (3mL) and placed in a 20-mL microwave vial. Saturated NH was added to the vial4Cl solution (5mL) and the mixture was heated at 150 ℃ with a microwave for a total of 3 h. The mixture was then diluted with water and extracted with ethyl acetate. The aqueous solution was then basified with NaOH and extracted with AcOEt. With Na2SO4The subsequent solution was dried and evaporated to dryness. The crude product was purified by silica gel flash column chromatography eluting with DCM to afford 3-bromo-thieno [3,2-c]Pyridin-4-ylamine (84 mg).
HPLC(254nm)：Rt：4.38min。
HRMS (ESI) calculated value C7H5BrN2S[M+H]+228.9430, and a measured value 228.9441.
1H NMR(500MHz，DMSO-d6)δppm：6.49(s，2H)7.27(d，J＝5.64Hz，1H)7.78(s，1H)7.83(d，J＝5.64Hz，1H)。
The following compounds were obtained in a similar manner:
3-bromo-furo [3,2-c ] pyridin-4-ylamine, a compound of formula (II)
HPLC(254nm)：Rt：3.91min。
HRMS (ESI) calculated value C7H5BrN2S[M+H]+212.9658, found 212.9659.
1H NMR(500MHz，DMSO-d6)δppm：1H NMR(500MHz，DMSO-d6)6.19(br.s.，2H)6.92(d，J＝5.95Hz，1H)7.85(d，J＝5.95Hz，1H)8.12(s，1H)。
Preparation 6
2-fluoro-3- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -aniline, a compound of formula (VI)
Scheme 1
3-bromo-2-fluoro-aniline (6.52g, 33.63mmol), bis (pinacolato) diboron (10.45g, 41.14mmol), and [1, 1' -bis (diphenylphosphino) ferrocene complexed with dichloromethane (1:1)]A mixture of palladium (II) dichloride (1.12g, 1.37mmol) and potassium acetate (10.1g, 103.06mmol) in dry DMF (65mL) was heated at 100 ℃ for 7 hours under a nitrogen atmosphere. The reaction was cooled to room temperature, diluted with AcOEt and filtered through celite. The organic phase was washed with water, brine, Na2SO4Drying and evaporating. The crude product was purified by silica gel chromatography, eluting with hexane: AcOEt ═ 8: 2, eluting to obtain the 2-fluoro-3- (4,4,5, 5-tetramethyl- [1,3, 2)]Dioxolane-2-yl) -aniline (6.90g) as a white solid.
HPLC(254nm)：Rt：5.94min。
HRMS (ESI) calculated value C12H17BNO2F[M+H]+237.1446, found 237.1453.
1H NMR(401MHz，DMSO-d6)δppm：1.28(s，12H)4.99(s，2H)6.67-6.78(m，1H)6.80-6.92(m，2H)。
The following compounds were obtained in a similar manner:
2-chloro-3- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -aniline, a compound of formula (VI)
HRMS (ESI) calculated value C12H17BNO2Cl[M+H]+253.115, found 253.114.
1H NMR(500MHz，DMSO-d6)δppm：1.28(s，12H)5.27(s，2H)6.77(dd，J＝7.09，1.60Hz，1H)6.86(dd，J＝7.93，1.68Hz，1H)6.95-7.03(m，1H)。
2-methyl-3- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -aniline, a compound of formula (VI)
HPLC(254nm)：Rt：6.34min。
HRMS (ESI) calculated value C13H20BNO2[M+H]+233.1696, found 233.1698.
1H NMR(401MHz，DMSO-d6)δppm：1.28(s，12H)2.20(s，3H)4.70(s，2H)6.67-6.73(m，1H)6.83-6.90(m，2H)。
2-amino-6- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzonitrile, compounds of the formula (VI)
HRMS (ESI) calculated value C13H17BN2O2[M+Na]+266.1311, found 266.1307.
1H NMR(500MHz，DMSO-d6)δppm：1.29(s，12H)5.93(s，2H)6.90(ddd，J＝9.72，7.82，1.07Hz，2H)7.24-7.33(m，1H)。
Preparation 7
[ 2-fluoro-3- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl ] -carbamic acid tert-butyl ester, compound of formula (IV)
Scheme 1
(3-bromo-2-fluoro-phenyl) -carbamic acid tert-butyl ester
To a suspension of 3-bromo-2-fluoro-aniline (5.48g, 28.84mmol) in NaOH 2N (100mL, 200mmol) was added di-tert-butyl dicarbonate (10.07g, 46.19mmol), and the mixture was kept under mechanical stirringAnd (4) refluxing and heating. After 24 h, the reaction was cooled at room temperature, diluted with DCM (100mL) and the organic layer was separated. The aqueous layer was extracted with DCM and the combined organic phases were washed with brine and Na2SO4Drying and evaporating. The crude product was purified by silica gel chromatography (gradient: hexane: AcOEt ═ 100: 0-70: 30) to recover the unreacted starting material (1.10g) to give the title compound (6.43g) as a white solid.
HPLC(254nm)：Rt：7.37min。
HRMS (ESI) calculated value C13H20BNO2[M+Na]+312.0006, found 312.0004.
1H NMR(600MHz，DMSO-d6)δppm：1.46(s，9H)7.09(t，J＝7.69Hz，1H)7.29-7.44(m，1H)7.60(t，J＝7.51Hz，1H)9.16(s，1H)。
[ 2-fluoro-3- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl ] -carbamic acid tert-butyl ester, compound of formula (IV)
Scheme 1
To (3-bromo-2-fluoro-phenyl) -carbamic acid tert-butyl ester (4.08g, 14.07mmol), bis (pinacolato) diboron (5.55g, 21.85mmol) and potassium acetate (4.35g, 44.38mmol) in a sealed tube was added dioxane (100mL) with N2The mixture was degassed. [1, 1' -bis (diphenylphosphino) ferrocene complexed with dichloromethane (1:1) (559mg, 0.684mmol) was added]Palladium (II) dichloride, the reaction was stirred at 100 ℃ overnight. The mixture was cooled at room temperature, diluted with AcOEt, and passed through celite. The combined organics were evaporated and the crude product was purified by silica gel chromatography (gradient hexanes: AcOEt ═ 100: 0to 70: 30) to give the title compound (4.6g) as a solid.
HRMS (ESI) calculated value C17H25BFNO4[M+Na]+359.1789, found 359.1791.
1H NMR(600MHz，DMSO-d6)δppm：1.29(s，12H)1.46(s，9H)7.12(t，J＝7.60Hz，1H)7.33(ddd，J＝7.19，5.27，1.65Hz，1H)7.70(t，J＝7.51Hz，1H)8.86(s，1H)。
Preparation 8
3-chloro-N- [ 2-fluoro-3- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl ] -4-methoxy-N-methoxymethyl-benzenesulfonamide, compounds of the formula (IX)
Scheme 1
N- (3-bromo-2-fluoro-phenyl) -3-chloro-4-methoxy-benzenesulfonamide, compound of formula (XX)
Scheme 3
To 3-bromo-2-fluoro-aniline (1.10g, 5.67mmol) in DCM (50mL) was added pyridine (0.68mL, 8.51mmol), 3-chloro-4-methoxy-benzenesulfonyl chloride (1.37g, 5.70mmol) and stirred at rt overnight. The reaction mixture was diluted with DCM and saturated NaHCO3Aqueous solution, saturated NH4Washed with aqueous Cl solution, brine and Na2SO4And (5) drying. The organic solvent was removed under reduced pressure and the crude product was taken up with Et2O triturated together to give the title compound (1.63g) as a white solid.
HPLC(254nm)：Rt：5.74min。
HRMS (ESI) calculated value C13H10BrClFNO3S[M+Na]+415.9129, found 415.9135.
1H NMR(600MHz，DMSO-d6)δppm：3.93(s，3H)7.10(td，J＝8.10，1.19Hz，1H)7.22-7.25(m，1H)7.31(d，J＝8.79Hz，1H)7.47-7.52(m，1H)7.66(dd，J＝8.70，2.29Hz，1H)7.74(d，J＝2.38Hz，1H)10.37(s，1H)。
N- (3-bromo-2-fluoro-phenyl) -3-chloro-4-methoxy-N-methoxymethyl-benzenesulfonamide, compounds of the formula (XXI)
Scheme 3
To N- (3-bromo-2-fluoro-phenyl) -3-chloro-4-methoxy-benzenesulfonamide (505mg, 1.282mmol) in DCM (15mL) was added DIPEA (0.35mL, 2.048mmol) and chloro-methoxy-methane (0.16mL, 2.055mmol) and stirred at rt overnight. The reaction was diluted with DCM and saturated NH4Cl, brine, Na2SO4And (5) drying. The organic solvent was removed under reduced pressure to give the title compound (480mg) as a solid.
HPLC(254nm)：Rt：6.99min。
HRMS (ESI) calculated value C15H14BrClFNO4S[M+Na]+459.9391, found 459.9391.
1H NMR(600MHz，DMSO-d6)δppm：3.30(s，3H)3.97(s，3H)4.99(s，2H)7.07-7.23(m，2H)7.34(d，J＝8.79Hz，1H)7.64(dd，J＝8.79，2.38Hz，1H)7.72(d，J＝2.38Hz，1H)7.74-7.79(m，1H)。
The following compounds were obtained in a similar manner:
n- (3-bromo-2-cyano-phenyl) -5-chloro-2-fluoro-4-methoxy-N-methoxymethyl-benzenesulfonamide, compounds of the formula (XXI)
HPLC(254nm)：Rt：6.74min。
HRMS (ESI) calculated value C16H13BrClFN2O4S[M+Na]+484.9344, found 484.9331.
1H NMR(500MHz，DMSO-d6)δppm：3.40(s，3H)3.98(s，3H)5.09(s，2H)7.37(d，J＝8.08Hz，1H)7.43(d，J＝12.35Hz，1H)7.64(d，J＝7.47Hz，1H)7.67(t，J＝8.16Hz，1H)7.96(dd，J＝8.24，0.92Hz，1H)。
3-chloro-N- [ 2-fluoro-3- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl ] -4-methoxy-N-methoxymethyl-benzenesulfonamide, compounds of the formula (IX)
Scheme 1
To N- (3-bromo-2-fluoro-phenyl) -3-chloro-4-methoxy-N-methoxymethyl-benzenesulfonamide (479mg, 1.093mmol), bis (pinacolato) diboron (345mg, 1.358mmol) and potassium acetate (295mg, 3.010mmol) in a Schlenk tube was added dioxane (12mL) and the solution was diluted with N2The mixture was degassed. Adding [1, 1' -bis (diphenylphosphino) ferrocene ] complexed with dichloromethane (1:1)]Palladium (II) dichloride (47mg, 0.057mmol), the reaction was stirred at 100 ℃ overnight. The mixture was cooled to room temperature, diluted with AcOEt, and passed through celite. The combined organics were evaporated and the crude product was purified by silica gel chromatography (gradient hexanes: AcOEt ═ 80: 20-60: 40) to give the title compound (400mg) as a solid.
MS(ESI)C21H26BClFNO6S(MW：485.77)：[M+H]+Measured value 486
Preparation 9
3-chloro-N- [ 2-fluoro-3- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl ] -4-methoxy-benzenesulfonamide, a compound of formula (VIII)
Scheme 1
To 2-fluoro-3- (4,4,5, 5-tetramethyl- [1,3, 2)]To a solution of dioxaborolan-2-yl) -aniline (163mg, 0.685mmol) in DCM (10mL) was added pyridine (0.28mL, 3.484mmol), 3-chloro-4-methoxy-benzenesulfonyl chloride (197mg, 0.820mmol) and stirred at room temperature for 2 h. The reaction was diluted with DCM and saturated NaHCO3Washed with brine and Na2SO4And (5) drying. The organic solvent was evaporated in vacuo and the residue triturated with hexanes to give the title compound (250mg) as a solid.
HRMS (ESI) calculated value C19H22BClFNO5S[M+Na]+463.0913, found 463.0897.
1H NMR(500MHz，DMSO-d6)δppm：1.20-1.31(m，12H)3.91(s，3H)7.13(t，J＝7.63Hz，1H)7.29(d，J＝8.85Hz，1H)7.35-7.42(m，1H)7.65(dd，J＝8.85，2.29Hz，1H)7.69(d，J＝2.14Hz，1H)7.93(t，J＝7.63Hz，1H)10.09-10.21(m，1H)。
The following compounds were obtained in a similar manner:
5-chloro-2-fluoro-N- [ 2-fluoro-3- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl ] -4-methoxy-benzenesulfonamide, a compound of formula (VIII)
1H NMR(401MHz，DMSO-d6)δppm：1.27(s，12H)3.94(s，3H)7.14(t，J＝7.60Hz，1H)7.33-7.46(m，3H)7.63(d，J＝7.32Hz，1H)10.38(s，1H)。
3-chloro-N- [ 2-chloro-3- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl ] -4-methoxy-benzenesulfonamide, a compound of formula (VIII)
HRMS (ESI) calculated value C19H22BCl2NO5S[M+Na]+479.0617, found 479.0607.
1H NMR(500MHz，DMSO-d6)δppm：1.28(s，12H)3.93(s，3H)7.24-7.34(m，3H)7.42(dd，J＝6.94，2.06Hz，1H)7.65(dd，J＝8.69，2.29Hz，1H)7.74(d，J＝2.44Hz，1H)9.97(s，1H)。
5-chloro-N- [ 2-chloro-3- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl ] -2-fluoro-4-methoxy-benzenesulfonamide, a compound of formula (VIII)
1H NMR(500MHz，DMSO-d6)δppm：1.28(s，12H)3.95(s，3H)7.27-7.33(m，1H)7.34-7.39(m，2H)7.46(dd，J＝7.32，1.68Hz，1H)7.61(d，J＝7.32Hz，1H)10.29(s，1H)。
3, 4-dichloro-N- [ 2-fluoro-3- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl ] -benzenesulfonamide, a compound of formula (VIII)
1H NMR(500MHz，DMSO-d6)δppm：1.26(s，12H)7.16(t，J＝7.70Hz，1H)7.38(td，J＝7.85，1.68Hz，1H)7.44(ddd，J＝7.09，5.49，1.60Hz，1H)7.65(dd，J＝8.54，2.14Hz，1H)7.82(d，J＝2.14Hz，1H)7.87(d，J＝8.54Hz，1H)10.36(s，1H)。
4-bromo-2-fluoro-N- [ 2-fluoro-3- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl ] -benzenesulfonamide, a compound of formula (VIII)
HRMS (ESI) calculated value C18H19BBrF2NO4S[M+Na]+495.0208, found 495.0204.
1H NMR(500MHz，DMSO-d6)δppm：1.27(s，12H)7.14(t，J＝7.70Hz，1H)7.38(td，J＝7.82，1.60Hz，1H)7.44(ddd，J＝7.21，5.30，1.68Hz，1H)7.57(dd，J＝8.50，1.80Hz，1H)7.61(dd，J＝8.20，7.60Hz，1H)7.88(dd，J＝9.76，1.68Hz，1H)10.54(s，1H)。
2-fluoro-N- [ 2-fluoro-3- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl ] -4-methoxy-5-methyl-benzenesulfonamide, a compound of formula (VIII)
HRMS (ESI) calculated value C20H24BF2NO5S[M+Na]+461.1365, found 461.1362.
1H NMR(500MHz，DMSO-d6)δppm：1.27(s，12H)2.08(s，3H)3.85(s，3H)7.07(d，J＝12.35Hz，1H)7.11(t，J＝7.70Hz，1H)7.39(t，J＝6.94Hz，2H)7.44(d，J＝8.39Hz，1H)10.19(s，1H)。
The corresponding boronic acids were isolated for the following compounds:
(2-fluoro-3- { [ (4-fluoro-2-iodophenyl) sulfonyl ] amino } phenyl) boronic acid, compound of formula (VIII)
HRMS (ESI) calculated value C12H9BF2INO4S[M+Na]+460.9286, found 460.9297.
1H NMR(500MHz，DMSO-d6)δppm：7.10(t，J＝7.70Hz，1H)7.31(td，J＝7.85，1.68Hz，1H)7.35-7.45(m，2H)7.83(ddd，J＝7.63，4.96，1.14Hz，1H)7.96(dd，J＝8.92，5.72Hz，1H)8.06(dd，J＝8.24，2.59Hz，1H)8.80(d，J＝5.03Hz，1H)10.29(s，1H)。
The following compounds were isolated in a mixture containing the relevant boronic acids:
5-bromo-thiophene-2-sulfonic acid [ 2-fluoro-3- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl ] -amide, a compound of formula (VIII)
MS(ESI)C16H18BBrFNO4S2(MW：462.17)：[M+NH4]+The measured value 480.
Preparation 10
5-chloro-2-fluoro-4-methoxy-benzenesulfonyl chloride, compound of formula (XI)
Scheme 1
1-chloro-4-fluoro-2-methoxy-benzene
To 2-chloro-5-fluoro-phenol (959mg, 6.54mmol) in DMF (15mL) was added gradually 60% NaH (496mg, 12.4mmol) at 0 ℃. H2After bubbling ceased, iodomethane (0.43mL, 6.91mmol) was added and the reaction mixture was allowed to warm at room temperature overnight. The reaction mixture was slowly poured onto water and crushed ice, washed with saturated NaHCO3The aqueous solution was basified and extracted with DCM. The combined organic phases were washed with brine, Na2SO4Drying and vacuum evaporating. The crude product was purified by silica gel multiple times, eluting with hexane: AcOEt ═ 9: 1 eluting to obtain1-chloro-4-fluoro-2-methoxy-benzene (600mg) as a clear oil.
HPLC(254nm)：Rt：6.15min。
1H NMR(600MHz，DMSO-d6)δppm：3.86(s，3H)6.76-6.85(m，1H)7.10(dd，J＝10.90，2.84Hz，1H)7.45(dd，J＝8.70，6.14Hz，1H)。
5-chloro-2-fluoro-4-methoxy-benzenesulfonyl chloride, compound of formula (XI)
Scheme 1
To 1-chloro-4-fluoro-2-methoxy-benzene (355mg, 2.21mmol) in DCM (20mL) was added chlorosulfonic acid (0.59mL, 8.84mmol) at 0 deg.C and stirred at room temperature overnight. The reaction was diluted with DCM, washed with water, brine and Na2SO4Drying and vacuum evaporating. The crude product was purified by silica gel chromatography, eluting with hexane: AcOEt ═ 8: 2 to give the title compound (400mg) as a white solid.
1H NMR(600MHz，DMSO-d6)δppm：3.86(s，3H)7.02(d，J＝11.17Hz，1H)7.59(d，J＝7.33Hz，1H)。
The following compounds were obtained in a similar manner:
4, 5-dichloro-2-fluoro-benzenesulfonyl chloride, compound of formula (XI)
1H NMR(500MHz，DMSO-d6)δppm：7.63(d，J＝9.00Hz，1H)7.76(d，J＝6.71Hz，1H)。
2-fluoro-4-methoxy-5-methyl-benzenesulfonyl chloride, compound of formula (XI)
1H NMR(500MHz，DMSO-d6)δppm：2.07(s，3H)3.77(s，3H)6.72(d，J＝11.90Hz，1H)7.39(d，J＝8.54Hz，1H)。
4-chloro-2-fluoro-5-methoxy-benzenesulfonyl chloride, compound of formula (XI)
1H NMR(500MHz，DMSO-d6)δppm：3.82(s，3H)7.33(d，J＝6.10Hz，1H)7.34(d，J＝8.85Hz，1H)。
3-cyano-4-methoxy-benzenesulfonyl chloride, compound of formula (XI)
1H NMR(500MHz，DMSO-d6)δppm：3.92(s，3H)7.21(d，J＝8.85Hz，1H)7.76(d，J＝1.98Hz，1H)7.84(dd，J＝8.69，2.14Hz，1H)。
3-bromo-4-methoxy-benzenesulfonyl chloride, compound of formula (XI)
1H NMR(500MHz，DMSO-d6)δppm：3.85(s，3H)7.05(d，J＝8.54Hz，1H)7.54(dd，J＝8.46，2.06Hz，1H)7.69(d，J＝1.98Hz，1H)。
Preparation 11
N- (3-bromo-2-cyano-phenyl) -5-chloro-2-fluoro-4-methoxy-benzenesulfonamide, a compound of formula (XX)
To 2-amino-6-bromo-benzonitrile (501mg, 2.47mmol) in anhydrous DMF (20mL) at 0 deg.C was added gradually 60% NaH (176mg, 4.4 mmol). After 30min, 2-fluoro-4-methoxy-5-methyl-benzenesulfonyl chloride (703mg, 2.72mmol) was added and the reaction mixture was warmed at room temperature. After 3 hours, the reaction was diluted with AcOEt and saturated NH4Washed with aqueous Cl solution, brine and Na2SO4Drying and evaporating. The crude product was purified by silica gel chromatography, eluting with hexane: AcOEt ═ 7:3 elution. The resulting solid was mixed with hexane: et (Et)2Trituration with O1: 1 gave the title compound (479mg) as a white solid.
HPLC(254nm)：Rt：5.40min。
HRMS (ESI) calculated value C14H9BrClFN2O3S[M+Na]+440.9082, found 440.9075.
1H NMR(500MHz，DMSO-d6)δppm：3.87(s，3H)6.81(br.s.，1H)6.97-7.18(m，3H)7.65-7.71(m，1H)。
Preparation 12
4-chloro-7-methyl-5- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine, a compound of formula (XVII) A
Scheme 3, step i1A
To 4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidine (1.16g, 3.96mmol) in dry THF (50mL) at-10 deg.C was slowly added a THF solution of i-prMgCl (2.0N, 2.4mL, 4.80 mmol). After 5min, 1-isopropoxy-3, 3,4, 4-tetramethyl-borolane (1.2mL, 5.94mmol) was added and stirred for 2 hours. The reaction was diluted with saturated aqueous NH4Cl solution and extracted with AcOEt. The combined organic phases were washed with brine, dried over Na2SO4 and evaporated. The crude product was purified by silica gel chromatography, eluting with hexane: AcOEt ═ 7:3 elution gave 4-chloro-7-methyl-5- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine (850mg) as a white solid.
HPLC(254nm)：Rt：5.99min。
HRMS (ESI) calculated value C13H17BClN3O2[M+H]+293.1212, found 293.1221.
1H NMR(500MHz，DMSO-d6)δppm：1.30(s，12H)3.84(s，3H)8.04(s，1H)8.65(s，1H)。
Example 1
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -3-chloro-4-methoxy-benzenesulfonamide, a compound of formula (I), (compound 1)
Scheme 1
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -3-chloro-4-methoxy-N-methoxymethyl-benzenesulfonamide, a compound of formula (X)
Scheme 1, step d
In a Schlenk tube, 5-iodo-7-methyl-7H-pyrrolo [2,3-d ] was reacted with]Pyrimidin-4-ylamine (88mg, 0.321mmol), 3-chloro-N- [ 2-fluoro-3- (4,4,5, 5-tetramethyl- [1,3, 2%]Dioxolane-2-yl-phenyl]-4-methoxy-N-methoxymethyl-benzenesulfonamide (244mg, 0.503mmol), Cs2CO3(308mg, 0.945mmol) and 1,1' -bis (diphenylphosphino) ferrocene complexed with dichloromethane (1:1)]1, 2-Dimethoxyethane (DME) (5mL) and water (0.55mL) in dichloropalladium (II) (21mg, 0.026 mmol). The reaction mixture was degassed with nitrogen and heated to 85 ℃ for 5 hours. Then filtered through a pad of celite. Evaporating the filtrate under reduced pressure; the crude product was dissolved in DCM and saturated NaHCO3Washing with aqueous solution, brine, and Na2And drying the SO 4. The organic layer was evaporated and the crude product was purified by crystallization with AcOEt to give the title compound (72mg) as a white solid.
MS(ESI)C22H21ClFN5O4S(MW：505.96)：[M+H]+The measured value 506.
The following compounds were obtained in a similar manner:
n- [3- (4-amino-7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -3-chloro-4-methoxy-N-methoxymethyl-benzenesulfonamide, a compound of formula (X)
MS(ESI)C24H25ClFN5O4S(MW：534.01)：[M+H]+The measured value 535.
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -3-chloro-4-methoxy-benzenesulfonamide, a compound of formula (I) (compound 1)
Scheme 1, step g
To N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ]]Pyrimidin-5-yl) -2-fluoro-phenyl]To a solution of-3-chloro-4-methoxy-N-methoxymethyl-benzenesulfonamide (50.5mg, 0.100mmol) in trifluoroacetic acid (TFA) (1mL) was added water (0.15mL), and heated to 50 ℃ for 5 hours. The reaction mixture was poured into saturated NaHCO3Aqueous solution, extracted with DCM. The combined organic phases were washed with brine, Na2SO4Drying and evaporating under reduced pressure. The crude product was purified by preparative HPLC to give the title compound (20mg) as a white solid.
HPLC(254nm)：Rt：7.59min。
HRMS (ESI) calculated value C20H17ClFN5O3S[M+H]+462.0798, found 462.0789.
1H NMR(401MHz，DMSO-d6)δppm：3.73(s，3H)3.91(s，3H)5.96(br.s.，2H)6.98-7.10(m，1H)7.10-7.20(m，2H)7.22(s，1H)7.28(d，J＝8.79Hz，1H)7.68(dd，J＝8.67，2.32Hz，1H)7.75(d，J＝2.32Hz，1H)8.14(s，1H)。
The following compounds were obtained in a similar manner:
n- [3- (4-amino-7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -3-chloro-4-methoxy-benzenesulfonamide, a compound of formula (I), (compound 2)
HPLC(254nm)：Rt：5.89min。
HRMS (ESI) calculated value C22H21ClFN5O3S[M+H]+490.1111, found 490.1114.
1H NMR(401MHz，DMSO-d6)δppm1.44(d，J＝6.71Hz，6H)3.92(s，3H)4.95(spt，J＝6.71Hz，1H)5.95(br.s.，2H)7.20(d，J＝3.66Hz，3H)7.28-7.36(m，2H)7.69(dd，J＝8.67，2.32Hz，1H)7.75(d，J＝2.32Hz，1H)8.13(s，1H)10.18(br.s.，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -3-chloro-4-hydroxy-benzenesulfonamide, a compound of formula (I), (compound 67)
Scheme 1, step g
BBr at room temperature3Treatment of N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] in DCM (3mL) with 1M solution of DCM (144. mu.L, 0.144mmol)]Pyrimidin-5-yl) -2-fluoro-phenyl]-3-chloro-4-methoxy-N-ethoxymethyl-benzenesulfonamide (9.3mg, 0.018 mmol). The reaction was quenched with MeOH and evaporated in vacuo. The crude product was purified by silica gel chromatography with DCM: MeOH ═ 95:5 elution gave the title compound (6.4mg) as a white solid.
HPLC(254nm)：Rt：4.94min。
HRMS (ESI) calculated value C19H15ClFN5O3S[M+H]+448.0641, found 448.0636.
1H NMR(401MHz，DMSO-d6)δppm：3.73(s，3H)5.96(br.s.，2H)7.07(d，J＝8.67Hz，1H)7.12-7.28(m，4H)7.53(dd，J＝8.67，2.32Hz，1H)7.69(d，J＝2.20Hz，1H)8.15(s，1H)10.09(br.s.，1H)11.32(br.s.，1H)。
Example 2
N- {3- [ 4-amino-7- (1-methyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -5-chloro-2-fluoro-4-methoxy-benzenesulfonamide, a compound of formula (I), (Compound 3) scheme 1, step c
In a Schlenk tube, 5-iodo-7- (1-methyl-piperidin-4-yl) -7H-pyrrolo [2,3-d]Pyrimidin-4-ylamine (36mg, 0.102mmol), 5-chloro-N- [ 2-chloro-3- (4,4,5, 5-tetramethyl- [1,3, 2%]Dioxolane-2-yl-phenyl]-2-fluoro-4-methoxy-benzenesulfonamide (90mg, 0.196mmol), Cs2CO3(119mg, 0.365mmol) and 1,1' -bis (diphenylphosphino) ferrocene complexed with dichloromethane (1:1)]To a solution of palladium (II) dichloride (6.7mg, 0.008mmol) were added 1, 2-Dimethoxyethane (DME) (1.8mL) and water (0.2 mL). The reaction mixture was degassed with nitrogen, heated to 85 ℃ for 5 hours, and then filtered through a pad of celite. Evaporating the filtrate under reduced pressure; the crude product was dissolved in DCM and saturated NaHCO3Washing with aqueous solution, brine, and Na2SO4And (5) drying. The organic layer was evaporated and the crude product was purified by silica gel chromatography with DCM: MeOH: NH3Elution was 90:10: 0.5% to give the title compound (33mg) as a white solid.
HPLC(254nm)：Rt：4.85min。
HRMS (ESI) calculated value C25H25ClF2N6O3S[M+H]+563.1438, found 563.1445.
1H NMR(401MHz，DMSO-d6)δppm：1.93(m，J＝12.69，2.56Hz，2H)2.02-2.16(m，2H)2.27(m，J＝11.41，11.41Hz，2H)2.33(s，3H)3.00(m，J＝11.35Hz，2H)3.93(s，3H)4.58(tt，J＝11.89，4.10Hz，1H)5.98(br.s.，2H)7.01-7.25(m，3H)7.32(t，J＝5.92Hz，2H)7.70(d，J＝7.32Hz，1H)8.13(s，1H)10.37(s，1H)。
The following compounds were obtained in a similar manner:
n- {3- [ 4-amino-7- (1-methyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -3-chloro-4-methoxy-benzenesulfonamide, a compound of formula (I), (compound 4)
HPLC(254nm)：Rt：4.74min。
HRMS (ESI) calculated value C25H26ClFN6O3S[M+H]+545.1533, found 545.1547.
1H NMR(401MHz，DMSO-d6)δppm：1.89(m，J＝9.52Hz，2H)1.98-2.11(m，2H)2.11-2.21(m，2H)2.27(s，3H)2.94(m，J＝11.11Hz，2H)3.92(s，3H)4.42-4.67(m，1H)5.97(br.s.，2H)7.10-7.24(m，3H)7.27-7.34(m，2H)7.69(dd，J＝8.67，2.32Hz，1H)7.74(d，J＝2.32Hz，1H)8.12(s，1H)9.52-10.46(m，1H)。
N- {3- [ 4-amino-7- (1-cyclopropyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -3-chloro-4-methoxy-benzenesulfonamide, a compound of formula (I), (compound 5)
HPLC(254nm)：Rt：5.69min。
HRMS (ESI) calculated value C27H28ClFN6O3S[M+H]+571.1689, found 571.1685.
1H NMR(500MHz，DMSO-d6)δppm：0.42-1.04(m，4H)2.07(s，3H)2.54(br.s.，4H)3.92(s，3H)4.65-4.82(m，1H)6.09(br.s.，2H)7.13-7.23(m，3H)7.28(br.s.，1H)7.31(d，J＝8.85Hz，1H)7.71(dd，J＝8.77，2.21Hz，1H)7.76(d，J＝2.29Hz，1H)8.15(s，2H)10.23(br.s.，1H)。
N- {3- [ 4-amino-7- (1-isopropyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -3-chloro-4-methoxy-benzenesulfonamide, a compound of formula (I), (compound 6)
HPLC(254nm)：Rt：4.93min。
HRMS (ESI) calculated value C27H30ClFN6O3S[M+H]+573.1846, found 573.1859.
1H NMR(500MHz，DMSO-d6)δppm：1.03(d，J＝6.56Hz，6H)1.82-2.10(m，4H)2.38(d，J＝14.18Hz，2H)2.84(br.s.，1H)2.97(m，J＝9.61Hz，2H)3.92(s，3H)4.48-4.61(m，1H)5.63-6.34(m，2H)7.05-7.23(m，3H)7.27-7.35(m，2H)7.69(dd，J＝8.92，2.06Hz，1H)7.74(d，J＝2.14Hz，1H)8.10-8.17(m，1H)9.69-10.45(m，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-chloro-phenyl ] -5-chloro-2-fluoro-4-methoxy-benzenesulfonamide, a compound of formula (I), (compound 7)
HPLC(254nm)：Rt：5.70min。
HRMS (ESI) calculated value C20H16Cl2FN5O3S[M+H]+496.0408, found 496.0417.
1H NMR(500MHz，DMSO-d6)δppm：3.72(s，3H)3.94(s，3H)5.79(br.s.，2H)7.23(s，1H)7.25-7.45(m，4H)7.70(d，J＝7.32Hz，1H)8.14(s，1H)10.37(br.s.，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-chloro-phenyl ] -3-chloro-4-methoxy-benzenesulfonamide, a compound of formula (I), (compound 8)
HPLC(254nm)：Rt：5.55min。
HRMS (ESI) calculated value C20H17Cl2N5O3S[M+H]+478.0502, found 478.05.
1H NMR(500MHz，DMSO-d6)δppm：3.72(s，3H)3.93(s，3H)5.28-6.34(m，2H)7.21(s，1H)7.24(d，J＝7.47Hz，2H)7.31(d，J＝8.85Hz，1H)7.33-7.39(m，1H)7.67(dd，J＝8.85，2.29Hz，1H)7.79(d，J＝2.29Hz，1H)8.13(s，1H)10.04(s，1H)。
N- [3- (4-amino-1-methyl-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -2-fluoro-phenyl ] -5-chloro-2-fluoro-4-methoxy-benzenesulfonamide, a compound of formula (I), (compound 9)
HPLC(254nm)：Rt：5.34min。
HRMS (ESI) calculated value C19H15ClF2N6O3S[M+H]+481.0656, found 481.064.
1H NMR(500MHz，DMSO-d6)δppm：3.93(s，3H)3.94(s，3H)7.23-7.32(m，1H)7.33-7.41(m，3H)7.73(d，J＝7.32Hz，1H)8.25(s，1H)10.59(s，1H)。
4- { 4-amino-3- [3- (5-chloro-2-fluoro-4-methoxy-benzenesulfonylamino) -2-fluoro-phenyl ] -pyrazolo [3,4-d ] pyrimidin-1-yl } -piperidine-1-carboxylic acid tert-butyl ester, a compound of formula (I), (compound 10)
HPLC(254nm)：Rt：6.64min。
HRMS (ESI) calculated value C28H30ClF2N7O5S[M+H]+650.1759, found 650.179。
1H NMR(401MHz，DMSO-d6)δppm：1.42(s，9H)1.83-2.05(m，4H)3.00(br.s.，2H)3.93(s，3H)4.08(m，J＝13.55Hz，2H)4.89(tt，J＝10.42，5.14Hz，1H)7.23-7.42(m，4H)7.73(d，J＝7.45Hz，1H)8.24(s，1H)10.56(s，1H)。
4- { 4-amino-3- [3- (3-chloro-4-methoxy-benzenesulfonylamino) -2-fluoro-phenyl ] -pyrazolo [3,4-d ] pyrimidin-1-yl } -piperidine-1-carboxylic acid tert-butyl ester, compound of formula (I), (compound 11)
HPLC(254nm)：Rt：6.53min。
HRMS (ESI) calculated value C28H31ClFN7O5S[M+H]+632.1853, found 632.184.
1H NMR(401MHz，DMSO-d6)δppm：1.42(s，9H)1.77-2.04(m，4H)2.98(br.s.，2H)3.92(s，3H)4.07(m，J＝12.45Hz，2H)4.89(m，J＝10.44，5.40，5.40Hz，1H)7.21-7.37(m，4H)7.71(dd，J＝8.79，2.32Hz，1H)7.80(d，J＝2.20Hz，1H)8.23(s，1H)10.24(s，1H)。
N- [3- (4-amino-furo [3,2-c ] pyridin-3-yl) -2-fluoro-phenyl ] -5-chloro-2-fluoro-4-methoxy-benzenesulfonamide, a compound of formula (I) (compound 69)
HPLC(254nm)：Rt：6.01min。
HRMS (ESI) calculated value C20H14ClF2N3O4S[M+H]+466.0435, found 466.0424.
1H NMR(500MHz，DMSO-d6)δppm：3.94(s，3H)5.42(s，2H)6.95(d，J＝5.95Hz，1H)7.22-7.41(m，4H)7.73(d，J＝7.47Hz，1H)7.87(d，J＝5.95Hz，1H)7.94(s，1H)10.62(br.s.，1H)。
N- [3- (4-amino-furo [3,2-c ] pyridin-3-yl) -2-fluoro-phenyl ] -3-chloro-4-methoxy-benzenesulfonamide, a compound of formula (I) (compound 70)
HPLC(254nm)：Rt：5.83min。
HRMS (ESI) calculated value C20H15ClFN3O4S[M+H]+448.0529, found 448.0519.
1H NMR(500MHz，DMSO-d6)δppm：3.92(s，3H)5.40(s，2H)6.95(d，J＝5.95Hz，1H)7.20-7.35(m，4H)7.68(dd，J＝8.69，2.29Hz，1H)7.78(d，J＝2.29Hz，1H)7.87(d，J＝5.95Hz，1H)7.92(s，1H)10.31(br.s.，1H)。
N- {3- [ 4-amino-7- (1-methyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -3, 4-dichloro-benzenesulfonamide, a compound of formula (I) (compound 71)
HPLC(254nm)：Rt：5.18min。
HRMS (ESI) calculated value C24H23Cl2FN6O2S[M+H]+549.1037, found 549.1042.
1H NMR(500MHz，DMSO-d6)δppm：1.95(d，J＝11.29Hz，2H)2.11(qd，J＝12.70，3.00Hz，2H)2.37(br.s，5H)3.06(d，J＝10.68Hz，2H)4.60(tt，J＝11.84，4.02Hz，1H)6.03(br.s.，1H)7.08(t，J＝6.70Hz，1H)7.13(t，J＝7.78Hz，1H)7.17(td，J＝7.50，1.70Hz，1H)7.31(s，1H)7.69(dd，J＝8.39，2.14Hz，1H)7.83(d，J＝8.39Hz，1H)7.91(d，J＝2.13Hz，1H)8.13(s，1H)。
N- {3- [ 4-amino-7- (1-methyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -4-bromo-2-fluoro-benzenesulfonamide, a compound of formula (I) (compound 72)
HPLC(254nm)：Rt：4.88min。
HRMS (ESI) calculated value C24H23BrF2N6O2S[M+H]+577.0828, found 577.0836.
1H NMR(500MHz，DMSO-d6)δppm：1.95(d，J＝10.83Hz，2H)2.12(qd，J＝12.20，3.05Hz，2H)2.37(br.s，5H)3.06(d，J＝10.83Hz，2H)4.60(t，J＝11.90Hz，1H)5.98(br.s，2H)7.06(br.s.，1H)7.11(t，J＝7.85Hz，1H)7.19(td，J＝7.66，1.60Hz，1H)7.32(s，1H)7.55(dd，J＝8.39，1.68Hz，1H)7.69(t，J＝8.08Hz，1H)7.80(d，J＝9.15Hz，1H)8.13(s，1H)。
N- {3- [ 4-amino-7- (1-methyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -2-fluoro-4-methoxy-5-methyl-benzenesulfonamide, a compound of formula (I) (compound 73)
HPLC(254nm)：Rt：4.97min。
HRMS (ESI) calculated value C26H28F2N6O3S[M+H]+543.1985, found 543.1978.
1H NMR(500MHz，DMSO-d6)δppm：1.88(d，J＝11.74Hz，2H)2.05(qd，J＝12.10，3.20Hz，2H)2.10(s，3H)2.13(t，J＝11.50Hz，2H)2.25(s，3H)2.93(d，J＝11.13Hz，2H)3.85(s，3H)4.54(tt，J＝11.61，4.18Hz，1H)5.98(br.s.，2H)7.07(d，J＝12.51Hz，1H)7.13-7.19(m，2H)7.19-7.26(m，1H)7.33(s，1H)7.51(d，J＝8.24Hz，1H)8.13(s，1H)10.30(br.s.，1H)。
N- [3- (4-amino-7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -5-chloro-2-fluoro-4-methoxy-benzenesulfonamide, a compound of formula (I) (compound 74)
HPLC(254nm)：Rt：5.98min。
HRMS (ESI) calculated value C22H20ClF2N5O3S[M+H]+508.1016, found 508.1014.
1H NMR(500MHz，DMSO-d6)δppm：1.44(d，J＝6.86Hz，6H)3.94(s，3H)4.95(spt，J＝6.81Hz，1H)5.99(br.s.，2H)7.16-7.31(m，3H)7.35(s，1H)7.38(d，J＝12.05Hz，1H)7.71(d，J＝7.32Hz，1H)8.13(s，1H)10.52(s，1H)。
N- [3- (4-amino-7-ethyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -5-chloro-2-fluoro-4-methoxy-benzenesulfonamide, a compound of formula (I) (compound 75)
HPLC(254nm)：Rt：8.66min。
HRMS (ESI) calculated value C21H18ClF2N5O3S[M+H]+494.086, found 494.0859.
1H NMR(500MHz，DMSO-d6)δppm：1.36(t，J＝7.24Hz，3H)3.94(s，3H)4.19(q，J＝7.17Hz，2H)6.00(br.s.，2H)7.17-7.28(m，3H)7.31(s，1H)7.38(d，J＝11.90Hz，1H)7.71(d，J＝7.47Hz，1H)8.14(s，1H)10.53(br.s.，1H)。
N- {3- [ 4-amino-7- (tetrahydro-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -5-chloro-2-fluoro-4-methoxy-benzenesulfonamide, a compound of formula (I) (compound 76)
HPLC(254nm)：Rt：5.68min。
HRMS (ESI) calculated value C24H22ClF2N5O4S[M+H]+550.1122, found 550.1123.
1H NMR(500MHz，DMSO-d6)δppm：1.87(dd，J＝12.20，2.59Hz，2H)1.99-2.14(m，2H)3.47-3.59(m，2H)3.94(s，3H)3.99(dd，J＝11.21，4.19Hz，2H)4.82(tt，J＝11.93，4.08Hz，1H)6.02(br.s.，1H)7.17-7.30(m，3H)7.38(s，1H)7.38(d，J＝11.90Hz，1H)7.71(d，J＝7.32Hz，1H)8.14(s，1H)10.53(s，1H)。
The following compounds were isolated as TFA salts by preparative HPLC:
5-bromo-thiophene-2-sulfonic acid {3- [ 4-amino-7- (1-methyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -amide, compound of formula (I) (compound 77)
HPLC(254nm)：Rt：4.8min。
HRMS (ESI) calculated value C22H22BrFN6O2S2[M+H]+565.0486, found 565.0497.
1H NMR(500MHz，DMSO-d6)δppm：2.17-2.26(m，2H)2.26-2.37(m，2H)2.83(br.s.，3H)4.86(tt，J＝11.82，4.19Hz，1H)6.88(br.s，2H)7.24-7.33(m，3H)7.35(d，J＝4.12Hz，1H)7.42(d，J＝4.12Hz，1H)7.44(s，1H)8.29(s，1H)9.57(br.s.，1H)10.60(br.s.，1H)。
Example 3
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -4-methoxy-3-methyl-benzenesulfonamide, a compound of formula (I), (compound 12)
Scheme 1
[3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -carbamic acid tert-butyl ester, compound of formula (V)
Scheme 1, step a
In a Schlenk tube, 5-iodo-7-methyl-7H-pyrrolo [2,3-d ] was reacted with]Pyrimidin-4-ylamine (395mg, 1.442mmol), [ 2-fluoro-3- (4,4,5, 5-tetramethyl- [1,3, 2-]Dioxolane-2-yl-phenyl]Tert-butyl carbamate (790mg, 2.344mmol), Cs2CO3(1.42g, 4.356mmol) and 1,1' -bis (diphenylphosphino) ferrocene complexed with dichloromethane (1:1)]To palladium (II) dichloride (86.3mg, 0.106mmol) was added 1, 2-Dimethoxyethane (DME) (22.5mL) and water (2.5 mL). The reaction mixture was degassed with nitrogen, heated to 85 ℃ for 5 hours, and then filtered through a pad of celite. Evaporating the filtrate under reduced pressure; the crude product was dissolved in DCM and saturated NaHCO3Washing with aqueous solution, brine, and Na2SO4And (5) drying. The organic layer was evaporated and the crude product was purified by silica gel chromatography, eluting with AcOEt, to give the title compound (247mg) as a white solid.
HPLC(254nm)：Rt：7.63min。
HRMS (ESI) calculated value C18H20FN5O2[M+H]+358.1674, found 358.1667.
1H NMR(500MHz，DMSO-d6)δppm：1.47(s，9H)3.75(s，3H)5.51-6.34(m，2H)7.06-7.15(m，1H)7.20(t，J＝7.85Hz，1H)7.32(s，1H)7.58(t，J＝7.17Hz，1H)8.15(s，1H)9.05(s，1H)。
The following compounds were obtained in a similar manner:
[3- (4-amino-1-methyl-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -2-fluoro-phenyl ] -carbamic acid tert-butyl ester, compound of formula (V)
HPLC(254nm)：Rt：5.29min。
HRMS (ESI) calculated value C17H19FN6O2[M+H]+359.1627, found 359.1631.
1H NMR(401MHz，DMSO-d6)δppm：1.48(s，9H)3.96(s，3H)6.98-7.36(m，2H)7.61-7.82(m，1H)8.25(s，1H)9.09(s，1H)。
5- (3-amino-2-fluoro-phenyl) -7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-ylamine hydrochloride, compound of formula (VIII)
Scheme 1, step e
Reacting [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ]]Pyrimidin-5-yl) -2-fluoro-phenyl]Tert-butyl carbamate (247mg, 0.692mmol) is dissolved in dioxane (8mL) and treated with 4M HCl in dioxane (4mL, 16mmol) at 40 ℃ overnight. Evaporate the solvent and combine the residue with Et2Trituration of O together afforded the title compound (215mg) as the hydrochloride salt.
HPLC(254nm)：Rt：3.33min。
HRMS (ESI) calculated value C13H12FN5[M+H]+258.115, found 258.1149.
1H NMR(500MHz，DMSO-d6)δppm：3.85(s，3H)6.58(t，J＝6.94Hz，1H)6.86(t，J＝8.08Hz，1H)6.94-7.05(m，1H)7.63(s，1H)8.47(s，1H)。
The following compounds were obtained in a similar manner:
3- (3-amino-2-fluoro-phenyl) -1-methyl-1H-pyrazolo [3,4-d ] pyrimidin-4-ylamine, a compound of formula (VIII)
MS(ESI)C12H11FN6(MW：258.26)：[M+H]+The measurement 259.
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -4-methoxy-3-methyl-benzenesulfonamide, a compound of formula (I) (compound 12)
Scheme 1, step f
In a screw cap test tube, 5- (3-amino-2-fluoro-phenyl) -7-methyl-7H-pyrrolo [2,3-d]Pyrimidin-4-ylamine hydrochloride (48mg, 0.145mmol) was suspended in DCM (4 mL). Pyridine (232. mu.L, 2.887mmol) and 4-methoxy-3-methyl-benzenesulfonyl chloride (64mg, 0.290mmol) were added and the reaction was stirred at room temperature overnight. The mixture was diluted with DCM and saturated NaHCO3Washing with aqueous solution, brine, and Na2SO4Drying and vacuum evaporating. The crude product was purified by silica gel chromatography, eluting with DCM: MeOH ═ 95: 5. The solid obtained is reacted with Et2Grinding together O to obtain the targetThe title compound (33mg) was a white solid.
HPLC(254nm)：Rt：7.43min。
HRMS (ESI) calculated value C21H20FN5O3S[M+H]+442.1344, found 442.1352.
1H NMR(401MHz，DMSO-d6)δppm：2.15(s，3H)3.73(s，3H)3.84(s，3H)5.96(br.s.，2H)7.08(d，J＝8.67Hz，1H)7.10-7.21(m，3H)7.22(s，1H)7.53-7.62(m，2H)8.14(s，1H)10.04(br.s.，1H)。
The following compounds were obtained in a similar manner:
n- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -3-chloro-benzenesulfonamide, a compound of formula (I), (compound 13)
HPLC(254nm)：Rt：7.46min。
HRMS (ESI) calculated value C19H15ClFN5O2S[M+H]+432.0692, found 432.0695.
1H NMR(401MHz，DMSO-d6)δppm：3.76(s，3H)6.45(br.s.，2H)7.12-7.26(m，3H)7.32(s，1H)7.59-7.64(m，1H)7.69-7.77(m，2H)7.78-7.81(m，1H)8.23(s，1H)10.40(br.s.，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -4-methoxy-benzenesulfonamide, a compound of formula (I), (compound 14)
HPLC(254nm)：Rt：6.44min。
HRMS (ESI) calculated value C20H18FN5O3S[M+H]+428.1187, found 428.1196.
1H NMR(401MHz，DMSO-d6)δppm：3.73(s，3H)3.81(s，3H)5.95(br.s.，2H)7.08(d，J＝8.91Hz，2H)7.13-7.28(m，4H)7.70(d，J＝8.91Hz，2H)8.15(s，1H)10.07(s，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -4-trifluoromethyl-benzenesulfonamide, a compound of formula (I), (compound 15)
HPLC(254nm)：Rt：8.35min。
HRMS (ESI) calculated value C20H15F4N5O2S[M+H]+466.0956, found 466.0955.
1H NMR(401MHz，DMSO-d6)δppm：3.70-3.79(m，3H)6.61(br.s.，2H)7.14-7.26(m，3H)7.31(s，1H)7.90-8.04(m，4H)8.25(s，1H)10.52(br.s.，1H)。
Pyridine-3-sulfonic acid [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -amide, compound of formula (I), (compound 16)
HPLC(254nm)：Rt：4.34min。
HRMS (ESI) calculated value C18H15FN6O2S[M+H]+399.1034, found 399.1029.
1H NMR(401MHz，DMSO-d6)δppm：3.72(s，3H)5.96(br.s.，2H)6.99-7.34(m，4H)7.63(ddd，J＝8.06，4.88，0.73Hz，1H)8.13(m，J＝2.32，1.59Hz，1H)8.14(s，1H)8.82(dd，J＝4.76，1.59Hz，1H)8.86-9.00(m，1H)10.49(br.s.，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -3, 4-dimethoxy-benzenesulfonamide, a compound of formula (I), (compound 17)
HPLC(254nm)：Rt：4.89min。
HRMS (ESI) calculated value C21H20FN5O4S[M+H]+458.1293, found 458.1304.
1H NMR(401MHz，DMSO-d6)δppm：3.73(s，3H)3.73(s，3H)3.81(s，3H)5.95(br.s.，2H)7.09(d，J＝8.54Hz，1H)7.13-7.21(m，3H)7.22(s，1H)7.27(d，J＝2.20Hz，1H)7.33(dd，J＝8.48，2.14Hz，1H)8.15(s，1H)10.03(s，1H)。
4-methyl-3, 4-dihydro-2H-benzo [1,4] oxazine-7-sulfonic acid [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -amide, compound of formula (I), (compound 18)
HPLC(254nm)：Rt：5.24min。
HRMS (ESI) calculated value C22H21FN6O3S[M+H]+469.1453, found 469.1463.
1H NMR(401MHz，DMSO-d6)δppm：2.78(s，3H)3.24-3.28(m，2H)3.73(s，3H)4.19-4.34(m，2H)5.95(br.s.，2H)6.78(d，J＝8.91Hz，1H)6.96-7.01(m，1H)6.98(s，1H)7.12-7.25(m，3H)7.23(s，1H)8.15(s，1H)9.96(s，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -4-nitro-benzenesulfonamide, a compound of formula (I), (compound 19)
HPLC(254nm)：Rt：5.21min。
HRMS (ESI) calculated value C19H15FN6O4S[M+H]+443.0933, found 443.0944.
1H NMR(401MHz，DMSO-d6)δppm：3.72(s，3H)5.97(br.s.，2H)7.15-7.29(m，4H)7.98-8.06(m，2H)8.14(s，1H)8.35-8.44(m，2H)10.63(br.s.，1H)。
Naphthalene-2-sulfonic acid [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -amide, compound of formula (I), (compound 20)
HPLC(254nm)：Rt：5.62min。
HRMS (ESI) calculated value C23H18FN5O2S[M+H]+448.1238, found 448.1242.
1H NMR(401MHz，DMSO-d6)δppm：3.68(s，3H)5.92(br.s.，2H)7.08(s，1H)7.10-7.27(m，3H)7.62-7.68(m，1H)7.68-7.75(m，1H)7.82(dd，J＝8.73，1.89Hz，1H)8.03(d，J＝8.18Hz，1H)8.13(t，J＝4.27Hz，3H)8.40(d，J＝1.46Hz，1H)10.33(s，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -2, 5-difluoro-benzenesulfonamide, a compound of formula (I), (compound 21)
HPLC(254nm)：Rt：5.21min。
HRMS (ESI) calculated value C19H14F3N5O2S[M+H]+434.0893, found 434.0901.
1H NMR(401MHz，DMSO-d6)δppm：3.73(s，3H)5.96(br.s.，2H)7.13-7.32(m，4H)7.51-7.67(m，3H)8.15(s，1H)10.70(br.s.，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -4-bromo-2-fluoro-benzenesulfonamide, a compound of formula (I), (compound 22)
HPLC(254nm)：Rt：5.57min。
HRMS (ESI) calculated value C19H14BrF2N5O2S[M+H]+494.0093, found 494.0105.
1H NMR(401MHz，DMSO-d6)δppm：3.73(s，3H)5.96(br.s.，2H)7.09-7.32(m，4H)7.59(dd，J＝8.42，1.59Hz，1H)7.65-7.73(m，1H)7.88(dd，J＝10.01，1.34Hz，1H)8.15(s，1H)10.64(br.s.，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -2, 6-difluoro-benzenesulfonamide, a compound of formula (I), (compound 23)
HPLC(254nm)：Rt：5.01min。
HRMS (ESI) calculated value C19H14F3N5O2S[M+H]+434.0893, found 434.0902.
1H NMR(401MHz，DMSO-d6)δppm：3.74(br.s.，3H)5.92(br.s.，2H)7.05-7.37(m，6H)7.65-7.78(m，1H)8.15(s，1H)10.82(br.s.，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -5-chloro-2-fluoro-4-methoxy-benzenesulfonamide, a compound of formula (I), (compound 24)
HPLC(254nm)：Rt：5.56min。
HRMS (ESI) calculated value C20H16ClF2N5O3S[M+H]+480.0703, found 480.0711。
1H NMR(401MHz，DMSO-d6)δppm：3.71-3.76(m，3H)3.94(s，3H)5.98(br.s.，2H)7.15-7.28(m，4H)7.36(d，J＝12.08Hz，1H)7.71(d，J＝7.45Hz，1H)8.15(s，1H)10.50(s，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -3, 4-dichloro-benzenesulfonamide, a compound of formula (I), (compound 25)
HPLC(254nm)：Rt：5.85min。
HRMS (ESI) calculated value C19H14Cl2FN5O2S[M+H]+466.0302, found 466.0309.
1H NMR(401MHz，DMSO-d6)δppm：3.73(s，3H)6.00(br.s.，2H)7.10-7.27(m，4H)7.71(dd，J＝8.48，2.14Hz，1H)7.88(d，J＝8.42Hz，1H)7.95(d，J＝2.07Hz，1H)8.15(s，1H)10.45(br.s.，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -3, 5-dichloro-benzenesulfonamide, a compound of formula (I), (compound 26)
HPLC(254nm)：Rt：5.91min。
HRMS (ESI) calculated value C19H14Cl2FN5O2S[M+H]+466.0302, found 466.0304.
1H NMR(401MHz，DMSO-d6)δppm：3.73(s，3H)6.00(br.s.，2H)7.13-7.30(m，4H)7.73(d，J＝1.95Hz，2H)7.96(t，J＝1.71Hz，1H)8.15(s，1H)10.52(br.s.，1H)。
2, 3-dihydro-benzofuran-5-sulfonic acid [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -amide, compound of formula (I), (compound 27)
HPLC(254nm)：Rt：5.08min。
HRMS (ESI) calculated value C21H18FN5O3S[M+H]+440.1187, found 440.1205.
1H NMR(401MHz，DMSO-d6)δppm：3.21(t，J＝8.79Hz，2H)3.73(s，3H)4.62(t，J＝8.85Hz，2H)5.96(br.s.，2H)6.89(d，J＝8.42Hz，1H)7.10-7.23(m，3H)7.24(s，1H)7.53(dd，J＝8.54，2.08Hz，1H)7.63(d，J＝1.71Hz，1H)8.15(s，1H)10.01(s，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -4-ethoxy-3-methyl-benzenesulfonamide, a compound of formula (I), (compound 28)
HPLC(254nm)：Rt：10.44min。
HRMS (ESI) calculated value C22H22FN5O3S[M+H]+456.15, found 456.1511.
1H NMR(401MHz，DMSO-d6)δppm：1.34(t，J＝6.96Hz，3H)2.15(s，3H)3.73(s，3H)4.09(q，J＝6.96Hz，2H)5.95(br.s.，2H)7.02-7.09(m，1H)7.12-7.20(m，3H)7.22(s，1H)7.52-7.60(m，2H)8.15(s，1H)10.00(s，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -4-methoxy-3, 5-dimethyl-benzenesulfonamide, a compound of formula (I), (compound 29)
HPLC(254nm)：Rt：5.55min。
HRMS (ESI) calculated value C22H22FN5O3S[M+H]+456.15, found 456.1505.
1H NMR(401MHz，DMSO-d6)δppm：2.24(s，6H)3.68(s，3H)3.73(s，3H)5.97(br.s.，2H)7.09-7.21(m，3H)7.23(s，1H)7.47(s，2H)8.15(s，1H)10.08(s，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -4-isopropoxy-3-methyl-benzenesulfonamide, a compound of formula (I), (compound 30)
HPLC(254nm)：Rt：7.93min。
HRMS (ESI) calculated C23H24FN5O3S [ M + H ]]+470.1657, found 470.1643.
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -3, 4-dimethyl-benzenesulfonamide, a compound of formula (I), (compound 31)
HPLC(254nm)：Rt：5.55min。
HRMS (ESI) calculated value C21H20FN5O2S[M+H]+426.1395, found 426.1385.
1H NMR(500MHz，DMSO-d6)δppm：2.25(s，3H)2.27(s，3H)3.72(s，3H)5.98(br.s.，2H)7.06-7.20(m，3H)7.23(s，1H)7.32(d，J＝7.93Hz，1H)7.44-7.51(m，1H)7.55(s，1H)8.14(s，1H)10.15(s，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -3,4, 5-trifluoro-benzenesulfonamide, a compound of formula (I), (compound 32)
HPLC(254nm)：Rt：5.56min。
HRMS (ESI) calculated value C19H13F4N5O2S[M+H]+452.0799, found 452.0786.
1H NMR(500MHz，DMSO-d6)δppm：3.73(s，3H)6.04(br.s.，2H)7.10-7.24(m，3H)7.27(s，1H)7.74(t，J＝6.56Hz，2H)8.15(s，1H)10.54(br.s.，1H)。
5-bromo-6-chloro-pyridine-3-sulfonic acid [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -amide, compound of formula (I), (compound 33)
HPLC(254nm)：Rt：5.49min。
HRMS (ESI) calculated value C18H13BrClFN6O2S[M+H]+510.975, found 510.9738.
1H NMR(500MHz，DMSO-d6)δppm：3.73(s，3H)6.07(br.s.，2H)7.12-7.27(m，4H)8.15(s，1H)8.49(d，J＝2.14Hz，1H)8.72(d，J＝2.29Hz，1H)10.65(br.s.，1H)。
N- [3- (4-amino-1-methyl-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -2-fluoro-phenyl ] -4-methoxy-3-methyl-benzenesulfonamide, a compound of formula (I), (compound 34)
HPLC(254nm)：Rt：5.23min。
HRMS (ESI) calculated value C20H19FN6O3S[M+H]+443.1296, found 443.1299.
1H NMR(401MHz，DMSO-d6)δppm：2.15(s，3H)3.84(s，3H)3.93(s，3H)7.07(d，J＝8.67Hz，1H)7.20-7.26(m，1H)7.26-7.36(m，2H)7.57(d，J＝1.59Hz，1H)7.61(dd，J＝8.54，2.32Hz，1H)8.24(s，1H)10.07(s，1H)。
N- [3- (4-amino-1-methyl-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -2-fluoro-phenyl ] -3-chloro-4-methoxy-benzenesulfonamide, a compound of formula (I) (compound 35)
HPLC(254nm)：Rt：5.22min。
HRMS (ESI) calculated value C19H16ClFN6O3S[M+H]+463.075, found 463.0749.
1H NMR(401MHz，DMSO-d6)δppm：3.92(s，3H)3.93(s，3H)7.23-7.28(m，1H)7.28-7.36(m，3H)7.71(dd，J＝8.67，2.32Hz，1H)7.81(d，J＝2.32Hz，1H)8.24(s，1H)10.24(s，1H)。
Example 4
N- {3- [ 4-amino-7- (tetrahydro-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -4-methoxy-3-methyl-benzenesulfonamide, a compound of formula (I) (compound 36)
Scheme 1
5- (3-amino-2-fluoro-phenyl) -7- (tetrahydro-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-ylamine, compound of formula (VIII)
Scheme 1, step b
In a Schlenk tube, 5-iodo-7- (tetrahydro-pyran-4-yl) -7H-pyrrolo [2,3-d ] is added]Pyrimidin-4-ylamine (70mg, 0.203mmol), 2-fluoro-3- (4,4,5, 5-tetramethyl- [1,3, 2)]Dioxolane-2-yl-aniline (104mg, 0.439mmol), Cs2CO3(250mg, 0.767mmol) and 1,1' -bis (diphenylphosphino) ferrocene complexed with dichloromethane (1:1)]To palladium (II) dichloride (14mg, 0.017mmol) were added 1, 2-Dimethoxyethane (DME) (3.6mL) and water (0.4 mL). With nitrogen gas supplyThe reaction mixture was degassed, heated to 85 ℃ for 5 hours, and then filtered through a pad of celite. Evaporating the filtrate under reduced pressure; the crude product was dissolved in DCM and saturated NaHCO3Washing with aqueous solution, brine, and Na2SO4And (5) drying. The solvent was evaporated and the crude product was purified by silica gel chromatography with DCM: MeOH 95:5 elution. The solid obtained is reacted with Et2O trituration together afforded the title compound (39mg) as a white solid.
HPLC(254nm)：Rt：4.30min。
HRMS (ESI) calculated value C17H18FN5O[M+H]+328.1568, found 328.1575.
1H NMR(401MHz，DMSO-d6)δppm：1.87(dd，J＝12.33，2.44Hz，2H)2.02-2.18(m，2H)3.53(t，J＝11.17Hz，2H)4.00(dd，J＝11.23，4.03Hz，2H)4.83(tt，J＝11.93，3.94Hz，1H)5.23(br.s.，2H)5.99(br.s.，2H)6.41-6.61(m，1H)6.77(td，J＝8.24，1.59Hz，1H)6.88-7.02(m，1H)7.42(s，1H)8.13(s，1H)。
The following compounds were obtained in a similar manner:
5- (3-amino-2-fluoro-phenyl) -7- (1-methyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-ylamine, a compound of formula (VII)
HPLC(254nm)：Rt：3.32min。
HRMS (ESI) calculated value C18H21FN6[M+H]+341.1885, found 341.1895.
1H NMR(401MHz，DMSO-d6)δppm：1.77-1.96(m，2H)2.00-2.15(m，4H)2.22(s，3H)2.79-3.00(m，2H)4.42-4.63(m，1H)5.22(s，2H)5.97(br.s.，2H)6.52(ddd，J＝7.50，6.70，1.60Hz，1H)6.77(td，J＝8.21，1.65Hz，1H)6.95(ddd，J＝7.90，7.50，0.60Hz，1H)7.37(s，1H)8.12(s，1H)。
5- (3-amino-2-fluoro-phenyl) -7- (1-isopropyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-ylamine, compounds of formula (VII)
MS(ESI)C20H25FN6(MW：368.46)：[M+H]+Found 369.
5- (3-amino-2-fluoro-phenyl) -7- (1-cyclopropyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-ylamine, compounds of formula (VII)
MS(ESI)C20H26FN6(MW：366.24)：[M+H]+And a measured value 367.
4- [ 4-amino-5- (3-amino-2-fluoro-phenyl) -pyrrolo [2,3-d ] pyrimidin-7-yl ] -piperidine-1-carboxylic acid tert-butyl ester, a compound of formula (VII)
HPLC(254nm)：Rt：5.69min。
HRMS (ESI) calculated value C22H27FN6O2[M+H]+427.2253, found 427.2245.
1H NMR(500MHz，DMSO-d6)δppm：1.42(s，9H)1.84-2.01(m，4H)2.94(br.s.，2H)4.11(br.s.，2H)4.67-4.80(m，1H)5.25(s，2H)6.51(t，J＝6.48Hz，1H)6.76(t，J＝7.55Hz，1H)6.94(t，J＝7.85Hz，1H)7.43(s，1H)8.12(s，1H)。
5- (3-amino-2-fluoro-phenyl) -7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-ylamine, a compound of formula (VII)
HPLC(254nm)：Rt：4.03min。
HRMS (ESI) calculated value C13H12FN5[M+H]+258.115, found 258.1154.
1H NMR(500MHz，DMSO-d6)δppm：3.74(s，3H)5.26(s，2H)5.76(s，2H)6.45-6.57(m，1H)6.76(td，J＝8.24，1.53Hz，1H)6.87-7.00(m，1H)7.27(s，1H)8.14(s，1H)。
5- (3-amino-2-methyl-phenyl) -7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-ylamine, a compound of formula (VII)
HPLC(254nm)：Rt：4.05min。
HRMS (ESI) calculated value C14H15N5[M+H]+254.14, found 254.1397.
1H NMR(500MHz，DMSO-d6)δppm：1.92(s，3H)3.73(s，3H)4.95-5.06(m，2H)5.11-6.29(m，2H)6.46(dd，J＝7.32，0.92Hz，1H)6.61-6.71(m，1H)6.87-6.98(m，1H)7.07(s，1H)8.11(s，1H)。
5- (3-amino-2-chloro-phenyl) -7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-ylamine, a compound of formula (VII)
HPLC(254nm)：Rt：4.25min。
HRMS (ESI) calculated value C13H12ClN5[M+H]+274.0854, found 274.0852.
1H NMR(500MHz，DMSO-d6)δppm：3.74(s，3H)5.50(s，2H)5.55-6.38(m，2H)6.56(dd，J＝7.47，1.53Hz，1H)6.83(dd，J＝8.16，1.60Hz，1H)7.08(t，J＝7.70Hz，1H)7.21(s，1H)8.13(s，1H)。
N- {3- [ 4-amino-7- (tetrahydro-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -4-methoxy-3-methyl-benzenesulfonamide, a compound of formula (I) (compound 36)
Scheme 1, step f
To 5- (3-amino-2-fluoro-phenyl) -7- (tetrahydro-pyran-4-yl) -7H-pyrrolo [2,3-d ] in DCM (1.5mL)]To pyrimidin-4-ylamine (15mg, 0.046mmol) was added pyridine (6. mu.L, 0.074mmol) and 4-methoxy-3-methyl-benzenesulfonyl chloride (14mg, 0.063 mmol). The reaction was stirred at room temperature overnight. The reaction was then diluted with DCM and saturated NaHCO3Washing with aqueous solution, brine, and Na2SO4Drying and evaporating. The crude product was purified by silica gel chromatography with DCM: MeOH ═ 95:5 elution gave the title compound (24mg) as a white solid.
HPLC(254nm)：Rt：5.54min。
HRMS (ESI) calculated value C25H26FN5O4S[M+H]+512.1763, found 512.1758.
1H NMR(401MHz，DMSO-d6)δppm：1.87(dd，J＝12.14，2.62Hz，2H)1.97-2.13(m，2H)2.15(s，3H)3.52(m，J＝11.11，11.11Hz，2H)3.85(s，3H)3.99(dd，J＝11.35，4.15Hz，2H)4.82(tt，J＝11.92，3.89Hz，1H)5.97(br.s.，2H)7.09(d，J＝8.79Hz，1H)7.13-7.24(m，3H)7.33(s，1H)7.54(d，J＝1.71Hz，1H)7.59(dd，J＝8.67，2.20Hz，1H)8.13(s，1H)10.00(s，1H)。
The following compounds were obtained in a similar manner:
n- {3- [ 4-amino-7- (tetrahydro-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -3-chloro-4-methoxy-benzenesulfonamide, a compound of formula (I) (compound 37)
HPLC(254nm)：Rt：5.55min。
HRMS (ESI) calculated value C24H23ClFN5O4S[M+H]+532.1216, found 532.1213.
1H NMR(401MHz，DMSO-d6)δppm：1.87(dd，J＝12.08，2.44Hz，2H)1.96-2.13(m，2H)3.45-3.61(m，2H)3.93(s，3H)3.99(dd，J＝11.29，4.09Hz，2H)4.82(tt，J＝11.90，4.09Hz，1H)5.99(br.s.，2H)7.11-7.25(m，3H)7.28-7.36(m，2H)7.70(dd，J＝8.67，2.32Hz，1H)7.75(d，J＝2.32Hz，1H)8.13(s，1H)10.18(s，1H)。
N- {3- [ 4-amino-7- (1-methyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -4-methoxy-3-methyl-benzenesulfonamide, a compound of formula (I) (compound 38)
HPLC(254nm)：Rt：4.85min。
HRMS (ESI) calculated value C26H29FN6O3S[M+H]+525.2079, found 525.207.
1H NMR(500MHz，DMSO-d6)δppm：1.89(d，J＝10.99Hz，2H)2.05(qd，J＝12.08，3.28Hz，2H)2.15(br.s，2H)2.15(s，3H)2.27(br.s.，3H)2.94(d，J＝9.46Hz，2H)3.84(s，3H)4.55(tt，J＝11.88，4.06Hz，1H)5.99(br.s.，2H)7.09(d，J＝8.70Hz，1H)7.13-7.23(m，3H)7.30(s，1H)7.54(dd，J＝2.37，0.69Hz，1H)7.59(dd，J＝8.62，2.37Hz，1H)8.12(s，1H)10.01(br.s.，1H)。
N- {3- [ 4-amino-7- (1-cyclopropyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -4-methoxy-3-methyl-benzenesulfonamide, a compound of formula (I) (compound 39)
HPLC(254nm)：Rt：5.69min。
HRMS (ESI) calculated value C28H31FN6O3S[M+H]+551.2235, found 551.2244.
1H NMR(500MHz，DMSO-d6)δppm：0.27-0.35(m，2H)0.39-0.51(m，2H)1.62-1.73(m，1H)1.79-1.90(m，2H)1.95(qd，J＝12.02，3.58Hz，2H)2.14(s，3H)2.30-2.42(m，2H)3.05(d，J＝11.44Hz，2H)3.83(s，3H)4.56(tt，J＝11.90，3.97Hz，1H)5.96(br.s.，2H)7.08(d，J＝8.85Hz，1H)7.11-7.23(m，3H)7.28(s，1H)7.52(dd，J＝2.44，0.76Hz，1H)7.58(dd，J＝8.54，2.29Hz，1H)8.12(s，1H)10.04(br.s.，1H)。
N- {3- [ 4-amino-7- (1-isopropyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -4-methoxy-3-methyl-benzenesulfonamide, a compound of formula (I), (compound 40)
HPLC(254nm)：Rt：5.03min。
HRMS (ESI) calculated value C28H33FN6O3S[M+H]+553.2392, found 553.2408.
1H NMR(500MHz，DMSO-d6)δppm：1.00(d，J＝6.56Hz，6H)1.84-1.93(m，2H)1.98(qd，J＝11.90，2.90Hz，2H)2.14(s，3H)2.25-2.35(m，2H)2.76(spt，J＝6.60Hz，1H)2.92(d，J＝11.59Hz，2H)3.84(s，3H)4.51(tt，J＝11.93，4.31Hz，1H)5.96(br.s.，2H)7.06(d，J＝8.69Hz，2H)7.11(t，J＝7.70Hz，1H)7.18(td，J＝7.90，1.70Hz，1H)7.29(s，1H)7.52(d，J＝1.68Hz，1H)7.58(dd，J＝8.62，2.21Hz，1H)8.12(s，1H)9.86(br.s，1H)。
N- {3- [ 4-amino-7- (1-ethyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -4-methoxy-3-methyl-benzenesulfonamide, a compound of formula (I), (compound 41)
HPLC(254nm)：Rt：4.72min。
HRMS (ESI) calculated value C27H31FN6O3S[M+H]+539.2235, found 539.2239.
4- { 4-amino-5- [ 2-fluoro-3- (4-methoxy-3-methyl-benzenesulfonylamino) -phenyl ] -pyrrolo [2,3-d ] pyrimidin-7-yl } -piperidine-1-carboxylic acid tert-butyl ester, compound of formula (I), (compound 42)
MS(ESI)C30H35FN6O5S(MW：610.71)：[M+H]+The measured value 611.
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -4, 5-dichloro-2-fluoro-benzenesulfonamide, a compound of formula (I), (compound 43)
HPLC(254nm)：Rt：5.84min。
HRMS (ESI) calculated value C19H13Cl2F2N5O2S[M+H]+484.0208, found 484.0219.
1H NMR(500MHz，DMSO-d6)δppm：3.73(s，3H)6.05(br.s.，2H)7.14-7.30(m，4H)7.93(d，J＝6.86Hz，1H)8.05(d，J＝9.61Hz，1H)8.16(s，1H)10.84(br.s.，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -2-fluoro-4-methoxy-5-methyl-benzenesulfonamide, a compound of formula (I), (compound 44)
HPLC(254nm)：Rt：5.52min。
HRMS (ESI) calculated value C21H19F2N5O3S[M+H]+460.125, found 460.1243.
1H NMR(500MHz，DMSO-d6)δppm：2.10(s，3H)3.73(s，3H)3.85(s，3H)5.99(br.s.，2H)7.08(d，J＝12.35Hz，1H)7.14-7.24(m，3H)7.25(s，1H)7.51(d，J＝8.08Hz，1H)8.15(s，1H)10.30(s，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -2, 5-dichloro-benzenesulfonamide, a compound of formula (I), (compound 45)
HPLC(254nm)：Rt：5.67min。
HRMS (ESI) calculated value C19H14Cl2FN5O2S[M+H]+466.0302, found 466.0294.
1H NMR(401MHz，DMSO-d6)δppm：3.73(s，3H)5.97(br.s.，2H)7.18-7.25(m，3H)7.26(s，1H)7.67-7.78(m，2H)7.92(dd，J＝2.08，0.85Hz，1H)8.15(s，1H)10.67(br.s.，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -4-bromo-2, 5-difluoro-benzenesulfonamide, a compound of formula (I), (compound 46)
HPLC(254nm)：Rt：5.65min。
HRMS (ESI) calculated value C19H13BrF3N5O2S[M+H]+511.9998, found 511.9978.
1H NMR(401MHz，DMSO-d6)δppm：3.73(s，3H)5.98(br.s.，2H)7.10-7.30(m，4H)7.73(dd，J＝7.63，6.04Hz，1H)8.06(dd，J＝9.03，5.37Hz，1H)8.15(s，1H)10.77(br.s.，1H)。
5-chloro-thiophene-2-sulfonic acid [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -amide, a compound of formula (I), (compound 47)
HPLC(254nm)：Rt：5.46min。
HRMS (ESI) calculated value C17H13ClFN5O2S2[M+H]+438.0256, found 438.0244.
1H NMR(401MHz，DMSO-d6)δppm：3.74(s，3H)5.99(br.s.，2H)7.07-7.33(m，5H)7.43(d，J＝4.03Hz，1H)8.15(s，1H)10.57(br.s.，1H)。
5-bromo-thiophene-2-sulfonic acid [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -amide, compound of formula (I), (compound 48)
HPLC(254nm)：Rt：5.50min。
HRMS (ESI) calculated value C17H13BrFN5O2S2[M+H]+481.9751, found 481.9739.
1H NMR(401MHz，DMSO-d6)δppm：3.74(s，3H)5.99(br.s.，2H)7.25(d，J＝5.13Hz，4H)7.31-7.36(m，1H)7.36-7.41(m，1H)8.15(s，1H)10.56(br.s.，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -3, 5-bis-trifluoromethyl-benzenesulfonamide, a compound of formula (I), (compound 49)
HPLC(254nm)：Rt：6.17min。
HRMS (ESI) calculated value C21H14F7N5O2S[M+H]+534.0829, found 534.0824.
1H NMR(401MHz，DMSO-d6)δppm：3.72(s，3H)6.01(br.s.，2H)7.12-7.30(m，4H)8.14(s，1H)8.30(s，2H)8.51(s，1H)10.67(br.s.，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -3-chloro-4-trifluoromethoxy-benzenesulfonamide, a compound of formula (I), (compound 50)
HPLC(254nm)：Rt：6.14min。
HRMS (ESI) calculated value C20H14ClF4N5O3S[M+H]+516.0515, found 516.0507.
1H NMR(401MHz，DMSO-d6)δppm：3.72(s，3H)6.01(br.s.，2H)7.04-7.29(m，4H)7.72-7.88(m，2H)8.02(d，J＝2.07Hz，1H)8.15(s，1H)10.50(br.s.，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -4-bromo-3-trifluoromethyl-benzenesulfonamide, a compound of formula (I), (compound 51)
HPLC(254nm)：Rt：6.03min。
HRMS (ESI) calculated value C20H14BrF4N5O2S[M+H]+544.0061, found 544.0071.
1H NMR(401MHz，DMSO-d6)δppm：3.73(s，3H)6.01(br.s.，2H)7.05-7.31(m，4H)7.91(dd，J＝8.36，2.26Hz，1H)8.09(d，J＝2.20Hz，1H)8.11-8.17(m，2H)10.53(br.s.，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -4-bromo-3-methyl-benzenesulfonamide, a compound of formula (I), (compound 52)
HPLC(254nm)：Rt：5.83min。
HRMS (ESI) calculated value C20H17BrFN5O2S[M+H]+490.0343, found 490.033.
1H NMR(401MHz，DMSO-d6)δppm：2.39(s，3H)3.73(s，3H)5.98(br.s.，2H)6.97-7.34(m，4H)7.41-7.59(m，1H)7.74(d，J＝1.95Hz，1H)7.81(d，J＝8.42Hz，1H)8.15(s，1H)10.29(s，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -3-fluoro-4-methoxy-benzenesulfonamide, a compound of formula (I), (compound 53)
HPLC(254nm)：Rt：5.19min。
HRMS (ESI) calculated value C20H17F2N5O3S[M+H]+446.1093, found 446.1084.
1H NMR(401MHz，DMSO-d6)δppm：3.73(s，3H)3.90(s，3H)5.97(br.s.，2H)7.16-7.21(m，3H)7.23(s，1H)7.30-7.36(m，1H)7.53-7.62(m，2H)8.15(s，1H)10.18(s，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -4-bromo-benzenesulfonamide, a compound of formula (I), (compound 54)
HPLC(254nm)：Rt：7.95min。
HRMS (ESI) calculated value C19H15BrFN5O2S[M+H]+476.0187, found 476.0184.
1H NMR(500MHz，DMSO-d6)δppm：3.72(s，3H)5.99(br.s.，2H)7.14-7.23(m，3H)7.21(s，1H)7.65-7.71(m，2H)7.80(d，J＝8.69Hz，2H)8.14(s，1H)10.37(br.s.，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -4-chloro-benzenesulfonamide, a compound of formula (I), (compound 55)
HPLC(254nm)：Rt：7.70min。
HRMS (ESI) calculated value C19H15ClFN5O2S[M+H]+432.0692, found 432.0701.
1H NMR(500MHz，DMSO-d6)δppm：3.72(s，3H)5.99(br.s.，2H)7.22(s，1H)7.13-7.24(m，3H)7.62-7.69(m，2H)7.73-7.80(m，2H)8.14(s，1H)10.37(br.s.，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -4-iodo-benzenesulfonamide, a compound of formula (I), (compound 56)
HPLC(254nm)：Rt：8.32min。
HRMS (ESI) calculated valueC19H15FIN5O2S[M+H]+524.0048, found 524.0042.
1H NMR(500MHz，DMSO-d6)δppm：3.73(s，3H)6.06(br.s.，2H)7.15-7.23(m，3H)7.22(s，1H)7.49-7.54(m，2H)7.92-8.01(m，2H)8.16(s，1H)10.34(s，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -methanesulfonamide, a compound of formula (I), (compound 68)
HPLC(254nm)：Rt：4.02min。
HRMS (ESI) calculated value C14H14FN5O2S[M+H]+336.0925, found 336.0921.
1H NMR(500MHz，DMSO-d6)δppm：3.05(s，3H)3.75(s，3H)6.07(br.s.，2H)7.17-7.23(m，1H)7.25(t，J＝7.80Hz，1H)7.34(s，1H)7.37(td，J＝7.63，1.83Hz，1H)8.15(s，1H)9.67(br.s，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-methyl-phenyl ] -5-chloro-2-fluoro-4-methoxy-benzenesulfonamide, a compound of formula (I), (compound 57)
HPLC(254nm)：Rt：5.63min。
HRMS (ESI) calculated value C21H19ClFN5O3S[M+H]+476.0954, found 476.095.
1H NMR(500MHz，DMSO-d6)δppm：2.03(s，3H)3.72(s，3H)3.95(s，3H)5.06-6.53(m，2H)6.99(dd，J＝7.85，1.45Hz，1H)7.09-7.18(m，2H)7.19(d，J＝7.63Hz，1H)7.37(d，J＝11.90Hz，1H)7.66(d，J＝7.32Hz，1H)8.13(s，1H)10.00(s，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-methyl-phenyl ] -3-chloro-4-methoxy-benzenesulfonamide, a compound of formula (I), (compound 58)
HPLC(254nm)：Rt：5.50min。
HRMS (ESI) calculated value C21H20ClN5O3S[M+H]+458.1048, found 458.105.
1H NMR(500MHz，DMSO-d6)δppm：1.95(s，3H)3.72(s，3H)3.93(s，3H)5.08-6.41(m，2H)6.91(dd，J＝7.85，1.30Hz，1H)7.03-7.15(m，2H)7.17(d，J＝7.78Hz，1H)7.31(d，J＝8.85Hz，1H)7.57(dd，J＝8.69，2.29Hz，1H)7.70(d，J＝2.14Hz，1H)8.12(s，1H)9.67(br.s.，1H)。
Propane-1-sulfonic acid [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -amide, compound of formula (I) (compound 78)
HPLC(254nm)：Rt：4.65min。
HRMS (ESI) calculated value C16H18FN5O2S[M+H]+364.1238, found 364.1232.
1H NMR(500MHz，DMSO-d6)δppm：0.98(t，J＝7.47Hz，3H)1.76(sxt，J＝7.53Hz，2H)3.10-3.18(m，2H)3.77(s，3H)6.34(br.s.，2H)7.19-7.29(m，2H)7.36-7.44(m，2H)8.20(s，1H)9.69(s，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -4-chloro-2-fluoro-5-methoxy-benzenesulfonamide, a compound of formula (I) (compound 79)
HPLC(254nm)：Rt：5.43min。
HRMS (ESI) calculated value C20H16ClF2N5O3S[M+H]+480.0703, found 480.07.
1H NMR(401MHz，DMSO-d6)δppm：3.73(s，3H)3.83(s，3H)5.65-6.18(m，2H)7.07-7.21(m，1H)7.23(s，1H)7.36-7.43(m，1H)8.14(s，1H)。
5-methyl-thiophene-2-sulfonic acid [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -amide, a compound of formula (I) (compound 80)
HPLC(254nm)：Rt：5.1min。
HRMS (ESI) calculated value C18H16FN5O2S2[M+H]+418.0802, found 418.0806.
1H NMR(500MHz，DMSO-d6)δppm：2.47(d，J＝0.76Hz，3H)3.73(s，3H)5.96(br.s.，2H)6.87(dq，J＝3.79，1.02Hz，1H)7.17-7.30(m，3H)7.26(s，1H)7.36(d，J＝3.81Hz，1H)8.15(s，1H)10.35(s，1H)。
6-methoxy-pyridine-3-sulfonic acid [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -amide, compound of formula (I) (compound 81)
HPLC(254nm)：Rt：4.84min。
HRMS (ESI) calculated value C19H17FN6O3S[M+H]+429.114, found 429.1146.
1H NMR(500MHz，DMSO-d6)δppm：3.72(s，3H)3.91(s，3H)6.01(br.s.，2H)7.01(dd，J＝8.85，0.61Hz，1H)7.17-7.25(m，3H)7.23(s，1H)8.00(dd，J＝8.77，2.67Hz，1H)8.14(s，1H)8.51(dd，J＝2.59，0.61Hz，1H)10.32(s，1H)。
3-methyl-3H-imidazole-4-sulfonic acid [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -amide, compound of formula (I) (compound 82)
HPLC(254nm)：Rt：3.78min。
HRMS (ESI) calculated value C17H16FN7O2S[M+H]+402.1143, found 402.114.
1H NMR(500MHz，DMSO-d6)δppm：3.67(s，3H)3.74(s，3H)5.98(br.s.，2H)7.13-7.17(m，1H)7.16-7.21(m，1H)7.29(s，1H)7.36(td，J＝7.44，2.21Hz，1H)7.77(d，J＝1.22Hz，1H)7.80(d，J＝0.92Hz，1H)8.15(s，1H)10.05(s，1H)。
Furan-2-sulfonic acid [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -amide, compound of formula (I) (compound 83)
HPLC(254nm)：Rt：5.22min。
HRMS (ESI) calculated value C17H14FN5O3S[M+H]+388.0874, found 388.0884.
1H NMR(500MHz，DMSO-d6)δppm：3.74(s，3H)5.98(br.s.，2H)6.66(dd，J＝3.43，1.75Hz，1H)7.09(d，J＝3.36Hz，1H)7.18-7.27(m，3H)7.28(s，1H)8.00(dd，J＝1.68，0.76Hz，1H)8.15(s，1H)10.58(br.s.，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -benzenesulfonamide, a compound of formula (I) (compound 84)
HPLC(254nm)：Rt：4.91min。
HRMS (ESI) calculated value C19H16FN5O2S[M+H]+398.1082, found 398.1087.
1H NMR(500MHz，DMSO-d6)δppm：3.72(s，3H)5.94(br.s.，2H)7.12-7.25(m，3H)7.21(s，1H)7.53-7.61(m，2H)7.61-7.69(m，1H)7.73-7.80(m，2H)8.14(s，1H)10.27(s，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -4-chloro-2-fluoro-benzenesulfonamide, a compound of formula (I) (compound 85)
HPLC(254nm)：Rt：5.47min。
HRMS (ESI) calculated value C19H14ClF2N5O2S[M+H]+450.0598, found 450.0593.
1H NMR(500MHz，DMSO-d6)δppm：3.73(s，3H)5.99(br.s.，2H)7.19-7.28(m，4H)7.46(dd，J＝8.54，1.83Hz，1H)7.73-7.81(m，2H)8.15(s，1H)10.67(br.s.，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -3-cyano-4-methoxy-benzenesulfonamide, a compound of formula (I) (compound 86)
HPLC(254nm)：Rt：5.01min。
HRMS (ESI) calculated value C21H17FN6O3S[M+H]+453.114, found 453.1136.
1H NMR(500MHz，DMSO-d6)δppm：3.73(s，3H)3.99(s，3H)6.03(br.s.，2H)7.13-7.23(m，3H)7.24(s，1H)7.43(d，J＝9.15Hz，1H)8.01(dd，J＝9.00，2.29Hz，1H)8.10(d，J＝2.44Hz，1H)8.15(s，1H)10.30(s，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -3-bromo-4-methoxy-benzenesulfonamide, a compound of formula (I) (compound 87)
HPLC(254nm)：Rt：5.47min。
HRMS (ESI) calculated value C20H17BrFN5O3S[M+H]+506.0292, found 506.0297.
1H NMR(500MHz，DMSO-d6)δppm：3.73(s，3H)3.91(s，3H)6.01(br.s.，2H)7.14-7.22(m，3H)7.23(s，1H)7.27(d，J＝8.85Hz，1H)7.73(dd，J＝8.69，2.29Hz，1H)7.91(d，J＝2.29Hz，1H)8.15(s，1H)10.21(s，1H)。
Pyridine was used as a solvent for the following compounds:
cyclopropanesulfonic acid [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -amide, a compound of formula (I) (compound 88)
HPLC(254nm)：Rt：4.43min。
HRMS (ESI) calculated value C16H16FN5O2S[M+H]+362.1082, found 362.1079.
1H NMR(500MHz，DMSO-d6)δppm：0.86-0.94(m，2H)0.93-1.01(m，2H)2.67-2.75(m，1H)3.75(s，3H)6.05(br.s.，2H)7.21-7.30(m，2H)7.35(s，1H)7.37-7.44(m，1H)8.15(s，1H)9.67(s，1H)。
Cyclohexanesulfonic acid [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -amide, a compound of formula (I) (Compound 89)
HPLC(254nm)：Rt：5.3min。
HRMS (ESI) calculated value C19H22FN5O2S[M+H]+404.1551, found 404.1548.
1H NMR(500MHz，DMSO-d6)δppm：1.14(tt，J＝12.80，3.00Hz，1H)1.26(qt，J＝12.70，3.15Hz，2H)1.42(qd，J＝12.38，3.13Hz，2H)1.61(d，J＝12.20Hz，1H)1.78(dt，J＝12.96，3.13Hz，2H)2.11(d，J＝10.83Hz，2H)3.06(tt，J＝11.71，3.09Hz，1H)3.75(s，3H)6.06(br.s.，2H)7.18-7.23(m，1H)7.22-7.26(m，1H)7.33(s，1H)7.41(td，J＝7.51，2.21Hz，1H)8.15(s，1H)9.64(s，1H)。
N- [3- (4-amino-thieno [3,2-c ] pyridin-3-yl) -2-fluoro-phenyl ] -5-chloro-2-fluoro-4-methoxy-benzenesulfonamide, a compound of formula (I), (compound 59)
Scheme 1
3- (3-amino-2-fluoro-phenyl) -thieno [3,2-c ] pyridin-4-ylamine, a compound of formula (VII)
Scheme 1, step b
To 3-bromo-thieno [3,2-c ]]Solution of pyridin-4-ylamine (80mg, 0.35mmol) in DME (3.2mL) and water (0.32mL) was added Cs2CO3(342mg, 1.05mmol) and 2-fluoro-3- (4,4,5, 5-tetramethyl- [1,3, 2)]Dioxolane-2-yl) -aniline (207mg, 0.87 mmol). The mixture was sonicated for 5 minutes, then Pd (dppf) Cl was added2(20mg) and heated at 100 ℃ for 1.5h with a microwave. The mixture was diluted with AcOEt and saturated NaHCO3The solution and brine washes. With Na2SO4The organic layer was dried and evaporated to dryness. The crude product was purified by flash chromatography on silica, eluting with DCM-MeOH 2%. Thereby isolating 3- (3-amino-2-fluoro-phenyl) -thieno [3,2-c]pyridin-4-ylamine (68 mg).
HPLC(254nm)：Rt：4.55min。
HRMS (ESI) calculated value C13H11FN3S[M+H]+260.0652, found 260.0654.
1H NMR(500MHz，DMSO-d6)δppm 5.38(s，4H)6.52(ddd，J＝7.44，6.37，1.45Hz，1H)6.88(td，J＝8.27，1.60Hz，1H)6.99(t，J＝7.70Hz，1H)7.26(d，J＝5.64Hz，1H)7.51(s，1H)7.81(d，J＝5.64Hz，1H)。
N- [3- (4-amino-thieno [3,2-c ] pyridin-3-yl) -2-fluoro-phenyl ] -5-chloro-2-fluoro-4-methoxy-benzenesulfonamide, a compound of formula (I) (compound 59)
Scheme 1, step f
To 3- (3-amino-2-fluoro-phenyl) -thieno [3,2-c]To a solution of pyridin-4-ylamine (40mg, 0.15mmol) in DCM (2.5mL) was added pyridine (15. mu.L) and 5-chloro-2-fluoro-4-methoxysulfonyl chloride (50mg, 0.19 mmol). The mixture was stirred at room temperature for 1 day, then refluxed for 15 hours. After dilution with DCM, saturated NaHCO3The solution and water wash the solution. Then using Na2SO4The organic layer was dried and evaporated to dryness. The crude residue was purified by silica gel flash column chromatography using a 1: 1-4: elution with a 6 hexane/AcOEt gradient gave the title compound (12.3 mg).
HPLC(254nm)：Rt：6.20min。
HRMS (ESI) calculated value C20H15ClF2N3O3S2[M+H]+482.0206, found 482.0202.
1H NMR(500MHz，DMSO-d6)δppm 3.93(s，3H)5.15-5.32(m，2H)7.23-7.33(m，3H)7.38(d，J＝11.90Hz，1H)7.39-7.44(m，1H)7.52(s，1H)7.73(d，J＝7.32Hz，1H)7.83(d，J＝5.64Hz，1H)10.67(br.s.，1H)
The following compounds were obtained in a similar manner:
n- [3- (4-amino-thieno [3,2-c ] pyridin-3-yl) -2-fluoro-phenyl ] -4-methoxy-3-methyl-benzenesulfonamide, a compound of formula (I), (compound 60)
HPLC(254nm)：Rt：6.15min。
HRMS (ESI) calculated value C21H19FN3O3S2[M+H]+444.0847, found 444.0847.
1H NMR(500MHz，DMSO-d6)δppm 2.19(s，3H)3.87(s，3H)5.22(br.s.，2H)7.12(d，J＝8.39Hz，1H)7.22-7.30(m，2H)7.32(d，J＝5.64Hz，1H)7.41(td，J＝7.32，2.59Hz，1H)7.53(s，1H)7.57-7.61(m，2H)7.86(d，J＝5.64Hz，1H)10.19(br.s.，1H)。
Example 5
N- {3- [ 4-amino-1- (1-methyl-piperidin-4-yl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl ] -2-fluoro-phenyl } -5-chloro-2-fluoro-4-methoxy-benzenesulfonamide, a compound of formula (I), (compound 61)
Scheme 1
N- [3- (4-amino-1-piperidin-4-yl-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -2-fluoro-phenyl ] -5-chloro-2-fluoro-4-methoxy-benzenesulfonamide, a compound of formula (I), (compound 62)
Scheme 1
To 4- { 4-amino-3- [3- (5-chloro-2-fluoro-4-methoxy-benzenesulfonylamino) -2-fluoro-phenyl in dioxane (4mL) was added]-pyrazolo [3,4-d]Pyrimidin-1-yl } -piperidine-1-carboxylic acid tert-butyl ester (155mg, 0.239mmol) was added HCl in 4M dioxane (4mL, 16mmol) and stirred at room temperature overnight. The organic layer was removed in vacuo, the residue was dissolved in water and treated with aqueous NaOH 2N to a pH of the solution>9. The resulting solid was filtered with Et2Grinding together O to obtainThe title compound (100mg) was a white solid.
HPLC(254nm)：Rt：4.64min。
HRMS (ESI) calculated value C23H22ClF2N7O3S[M+H]+550.1234, found 550.1238.
1H NMR(401MHz，DMSO-d6)δppm：1.92(m，J＝10.74Hz，2H)2.03-2.24(m，2H)2.80(td，J＝12.42，1.65Hz，2H)3.18(m，J＝12.57Hz，2H)3.86(s，3H)4.81(tt，J＝11.52，4.23Hz，1H)6.62(td，J＝6.87，1.53Hz，1H)6.88(t，J＝7.69Hz，1H)7.05(d，J＝11.35Hz，1H)7.18(td，J＝8.27，1.65Hz，1H)7.68-7.72(m，1H)8.21(s，1H)。
The following compounds were obtained in a similar manner:
n- [3- (4-amino-1-piperidin-4-yl-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -2-fluoro-phenyl ] -3-chloro-4-methoxy-benzenesulfonamide, a compound of formula (I), (compound 63)
HPLC(254nm)：Rt：4.57min。
HRMS (ESI) calculated value C23H23ClFN7O3S[M+H]+532.1329, found 532.1341.
1H NMR(401MHz，DMSO-d6)δppm：1.97-2.07(m，2H)2.12-2.29(m，2H)3.01(td，J＝12.76，2.56Hz，2H)3.88(s，3H)4.94(tt，J＝11.31，4.32Hz，1H)6.81(t，J＝6.77Hz，1H)6.98(t，J＝7.81Hz，1H)7.18(d，J＝8.67Hz，1H)7.21-7.27(m，1H)7.67(dd，J＝8.54，2.20Hz，1H)7.69-7.72(m，1H)8.22-8.24(m，1H)。
N- [3- (4-amino-7-piperidin-4-yl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -4-methoxy-3-methyl-benzenesulfonamide, a compound of formula (I), (compound 64)
HPLC(254nm)：Rt：4.79min。
HRMS (ESI) calculated value C25H27FN6O3S[M+H]+511.1922, found 511.1918.
1H NMR(500MHz，DMSO-d6)δppm：2.11-2.18(m，5H)2.23-2.34(m，2H)3.06-3.21(m，2H)3.85(s，3H)4.91-5.01(m，1H)7.09(d，J＝8.69Hz，1H)7.17-7.28(m，4H)7.55(s，2H)7.60(d，J＝1.83Hz，1H)7.65(dd，J＝8.62，2.36Hz，1H)8.45(s，1H)8.78(m，J＝9.46Hz，1H)8.99(d，J＝9.91Hz，1H)10.12(s，1H)。
N- {3- [ 4-amino-1- (1-methyl-piperidin-4-yl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl ] -2-fluoro-phenyl } -5-chloro-2-fluoro-4-methoxy-benzenesulfonamide, a compound of formula (I) (compound 61)
Scheme 1
To N- [3- (4-amino-1-piperidin-4-yl-1H-pyrazolo [3, 4-d) in DCM (2mL)]Pyrimidin-3-yl) -2-fluoro-phenyl]-5-chloro-2-fluoro-4-methoxy-benzenesulfonamide (26mg, 0.047mmol) was added aqueous formaldehyde solution 37% (21. mu.L, 0.280mmol), AcOH (3. mu.L, 0.052mmol) and stirred at room temperature for 10 min. Then NaBH (OAc) is added3(66mg, 0.302mmol) and the mixture was stirred at room temperature for 5 h. The reaction was diluted with DCM and saturated NaHCO3And (4) treating with an aqueous solution. The aqueous layer was extracted with DCM and the combined organic layers were washed with brine and Na2SO4Drying and evaporating. The crude product was purified by silica gel chromatography with DCM: MeOH: NH (NH)395: 5: 0.5% elution gave the title compound (17mg) as a white solid.
HPLC(254nm)：Rt：4.75min。
HRMS (ESI) calculated value C24H24ClF2N7O3S[M+H]+564.1391, found 564.1385.
1H NMR(401MHz，DMSO-d6)δppm：1.98(m，J＝10.86Hz，2H)2.14-2.31(m，2H)2.34-2.48(m，5H)3.10(m，J＝10.86Hz，2H)3.91(s，3H)4.74(m，J＝11.11，11.11Hz，1H)4.70-4.70(m，0H)7.18(d，J＝6.47Hz，2H)7.22-7.38(m，2H)7.73(d，J＝7.45Hz，1H)8.23(s，1H)9.37-10.81(m，1H)。
The following compounds were obtained in a similar manner:
n- {3- [ 4-amino-1- (1-isopropyl-piperidin-4-yl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl ] -2-fluoro-phenyl } -5-chloro-2-fluoro-4-methoxy-benzenesulfonamide, a compound of formula (I), (compound 65)
HPLC(254nm)：Rt：4.99min。
HRMS (ESI) calculated value C26H28ClF2N7O3S[M+H]+592.1704, found 592.1702.
1H NMR(401MHz，DMSO-d6)δppm：1.09-1.19(m，6H)2.07(br.s.，2H)2.27(m，J＝9.89Hz，2H)2.70-3.25(m，5H)3.91(s，3H)4.84(br.s.，1H)7.15(br.s.，2H)7.20-7.35(m，2H)7.73(d，J＝7.45Hz，1H)8.13-8.33(m，1H)。
N- {3- [ 4-amino-1- (1-methyl-piperidin-4-yl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl ] -2-fluoro-phenyl } -3-chloro-4-methoxy-benzenesulfonamide, a compound of formula (I), (compound 66)
HPLC(254nm)：Rt：4.61min。
HRMS (ESI) calculated value C24H25ClFN7O3S[M+H]+546.1485, found 546.1485.
1H NMR(500MHz，DMSO-d6)δppm：1.93(m，J＝10.98Hz，2H)2.12-2.24(m，2H)2.26-2.42(m，5H)3.02(m，J＝9.00Hz，2H)3.91(s，3H)4.59-4.79(m，1H)7.07-7.36(m，4H)7.71(dd，J＝8.77，2.21Hz，1H)7.79(d，J＝2.29Hz，1H)8.22(s，1H)9.58-10.49(m，1H)。
Example 6
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-cyano-phenyl ] -5-chloro-2-fluoro-4-methoxy-benzenesulfonamide, a compound of formula (I), (compound 90)
Scheme 2
5-chloro-N- [3- (4-chloro-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-cyano-phenyl ] -2-fluoro-4-methoxy-benzenesulfonamide, compound of formula (XIV)
Scheme 2, step c3
To 4-chloro-7-methyl-5- (4,4,5, 5-tetramethyl- [1,3,2] in a Schlenk tube]Dioxolane-2-yl) -7H-pyrrolo [2,3-d]Pyrimidine (118mg, 0.403mmol), N- (3-bromo-2-cyano-phenyl) -5-chloro-2-fluoro-4-methoxy-benzenesulfonamide (85mg, 0.202mmol), Cs2CO3(217mg, 0.666mmol) and 1,1' -bis (diphenylphosphino) ferrocene complexed with dichloromethane (1:1)]To palladium (II) dichloride (17mg, 0.020mmol) was added DMF (5 mL). The reaction mixture was degassed with nitrogen, heated to 100 ℃ overnight, and then filtered through a pad of celite. Evaporating the filtrate under reduced pressure; the crude product was dissolved in DCM and saturated NaHCO3Washing with aqueous solution, brine, and Na2SO4And (5) drying. The organic layer was evaporated and the crude product was purified by silica gel chromatography with AcOEt: hexane-7: 3 elution gave the title compound (40mg) as a white solid.
HPLC(254nm)：Rt：5.55min。
HRMS (ESI) calculated value C21H14Cl2FN5O3S[M+H]+506.0251, found 506.0251.
1H NMR(500MHz，DMSO-d6)δppm：3.92(s，3H)3.95(s，3H)7.22-7.35(m，1H)7.38(d，J＝11.90Hz，1H)7.44-7.54(m，1H)7.63(d，J＝7.32Hz，1H)7.70(t，J＝7.85Hz，1H)7.96(s，1H)8.72(s，1H)11.00(br.s.，1H)。
N- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-cyano-phenyl ] -5-chloro-2-fluoro-4-methoxy-benzenesulfonamide, a compound of formula (I), (compound 90)
Scheme 2, step h1
To a 5mL microwave vial loaded with dioxane (0.5mL) was added 5-chloro-N- [3- (4-chloro-7-methyl-7H-pyrrolo [2,3-d ]]Pyrimidin-5-yl) -2-cyano-phenyl]-2-fluoro-4-methoxy-benzenesulfonamide (21mg, 0.041mmol), ammonium hydroxide (2.5mL, 19.11mmol), sealed. The reaction vessel was heated at 130 ℃ for 180min under microwave irradiation. The mixture was diluted with water and extracted with DCM. The combined formed bodies were washed with brine, Na2SO4Drying and evaporating. The solid obtained is reacted with Et2O triturated together to give the title compound (6.8mg) as a white solid.
HPLC(254nm)：Rt：4.79min。
HRMS (ESI) calculated value C21H16ClFN5O3S[M+H]+487.075, found 487.0754.
1H NMR(500MHz，DMSO-d6)δppm：3.74(s，3H)3.87(s，3H)4.93-6.30(m，1H)6.51(d，J＝6.86Hz，1H)7.08-7.16(m，1H)7.16-7.23(m，1H)7.31(s，1H)7.74(d，J＝7.32Hz，1H)8.14(s，1H)。
Sequence listing
<110> Nerviano Medical Sciences S.r.l.
<120> N- (substituted-phenyl) -sulfonamide derivatives as kinase inhibitors
<130> NMS 105
<150> EP 16175386
<151> 2016-06-21
<160> 1
<170> PatentIn version 3.3
<210> 1
<211> 15
<212> PRT
<213> Artificial
<220>
<223> peptide substrate
<400> 1
Leu Leu Ser Glu Leu Ser Arg Arg Arg Ile Arg Ser Ile Asn Lys
1 5 10 15

Claims (24)

1. A compound of formula (I)
Wherein:
n is 0;
r1 is a group selected from: straight or branched chain (C)1-C8) An alkyl group; (C)3-C8) A cycloalkyl group; phenyl, optionally substituted in any of its free positions by one or more groups selected from halogen, methyl, (C)1-C8) Alkoxy, trifluoromethyl, trifluoromethoxy, nitro, hydroxy, and cyano; heteroaryl selected from furanyl, thienyl, imidazolyl and pyridyl, optionally substituted at any of its free positions with one or more halogen atoms, methyl or methoxy; a naphthyl group; 2, 3-dihydro-benzofuranyl;
r2 is halogen, cyano or methyl;
E1and E2Independently CH or N;
a is O, S or NR5, wherein
R5 is hydrogen or a group selected from linear or branched (C)1-C8) An alkyl group; piperidinyl group optionally substituted with (C)1-C8) Alkyl or (C)3-C8) Cycloalkyl substitution; a pyridyl group; and pyrrolidinyl optionally substituted with (C)1-C8) Alkyl substitution;
and pharmaceutically acceptable salts thereof.
2. A compound of formula (I) according to claim 1, wherein R1 is selected from phenyl, optionally substituted in any of its free positions by one or more groups selected from halogen, methyl, (C)1-C8) Alkoxy, trifluoromethyl, trifluoromethoxy, nitro, hydroxy, and cyano; and heteroaryl selected from furanAryl, thienyl, imidazolyl and pyridyl, which are optionally substituted at any of their free positions by one or more halogen atoms, methyl or methoxy; r2 is halogen or methyl; and A is S or NR 5.
3. The compound of claim 2 of formula (I) wherein R2 is halogen and a is NR 5.
4. A compound of formula (I) according to claim 3, wherein R1 is phenyl, optionally substituted in any of its free positions by one or more groups selected from halogen, methyl, (C)1-C8) Alkoxy, trifluoromethyl, trifluoromethoxy, nitro, hydroxy and cyano, and a is NR 5.
5. A compound, or a pharmaceutically acceptable salt thereof, selected from:
n- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -3-chloro-4-methoxy-benzenesulfonamide (compound 1);
n- [3- (4-amino-7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -3-chloro-4-methoxy-benzenesulfonamide (compound 2);
n- {3- [ 4-amino-7- (1-methyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -5-chloro-2-fluoro-4-methoxy-benzenesulfonamide (compound 3);
n- {3- [ 4-amino-7- (1-methyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -3-chloro-4-methoxy-benzenesulfonamide (compound 4);
n- {3- [ 4-amino-7- (1-cyclopropyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -3-chloro-4-methoxy-benzenesulfonamide (compound 5);
n- {3- [ 4-amino-7- (1-isopropyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -3-chloro-4-methoxy-benzenesulfonamide (compound 6);
n- [3- (4-amino-1-methyl-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -2-fluoro-phenyl ] -5-chloro-2-fluoro-4-methoxy-benzenesulfonamide (compound 9);
n- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -4-methoxy-3-methyl-benzenesulfonamide (compound 12);
n- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -3-chloro-benzenesulfonamide (compound 13);
n- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -4-bromo-2-fluoro-benzenesulfonamide (compound 22);
n- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -5-chloro-2-fluoro-4-methoxy-benzenesulfonamide (compound 24);
n- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -3, 4-dichloro-benzenesulfonamide (compound 25);
n- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -3, 5-dichloro-benzenesulfonamide (compound 26);
n- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -4-methoxy-3, 5-dimethyl-benzenesulfonamide (compound 29);
n- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -3,4, 5-trifluoro-benzenesulfonamide (compound 32);
5-bromo-6-chloro-pyridine-3-sulfonic acid [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -amide (compound 33);
n- [3- (4-amino-1-methyl-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -2-fluoro-phenyl ] -4-methoxy-3-methyl-benzenesulfonamide (compound 34);
n- [3- (4-amino-1-methyl-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -2-fluoro-phenyl ] -3-chloro-4-methoxy-benzenesulfonamide (compound 35);
n- {3- [ 4-amino-7- (tetrahydro-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -4-methoxy-3-methyl-benzenesulfonamide (compound 36);
n- {3- [ 4-amino-7- (tetrahydro-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -3-chloro-4-methoxy-benzenesulfonamide (compound 37);
n- {3- [ 4-amino-7- (1-methyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -4-methoxy-3-methyl-benzenesulfonamide (compound 38);
n- {3- [ 4-amino-7- (1-cyclopropyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -4-methoxy-3-methyl-benzenesulfonamide (compound 39);
n- {3- [ 4-amino-7- (1-isopropyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -4-methoxy-3-methyl-benzenesulfonamide (compound 40);
n- {3- [ 4-amino-7- (1-ethyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -4-methoxy-3-methyl-benzenesulfonamide (compound 41);
n- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -2-fluoro-4-methoxy-5-methyl-benzenesulfonamide (compound 44);
n- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -4-bromo-2, 5-difluoro-benzenesulfonamide (compound 46);
5-chloro-thiophene-2-sulfonic acid [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -amide (compound 47);
5-bromo-thiophene-2-sulfonic acid [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -amide (compound 48);
n- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -4-bromo-3-methyl-benzenesulfonamide (compound 52);
n- {3- [ 4-amino-1- (1-methyl-piperidin-4-yl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl ] -2-fluoro-phenyl } -5-chloro-2-fluoro-4-methoxy-benzenesulfonamide (compound 61);
n- [3- (4-amino-1-piperidin-4-yl-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -2-fluoro-phenyl ] -5-chloro-2-fluoro-4-methoxy-benzenesulfonamide (compound 62);
n- [3- (4-amino-1-piperidin-4-yl-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -2-fluoro-phenyl ] -3-chloro-4-methoxy-benzenesulfonamide (compound 63);
n- [3- (4-amino-7-piperidin-4-yl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -4-methoxy-3-methyl-benzenesulfonamide (compound 64);
n- {3- [ 4-amino-7- (1-methyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -3, 4-dichloro-benzenesulfonamide (compound 71);
n- {3- [ 4-amino-7- (1-methyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -4-bromo-2-fluoro-benzenesulfonamide (compound 72);
n- {3- [ 4-amino-7- (1-methyl-piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -2-fluoro-phenyl } -2-fluoro-4-methoxy-5-methyl-benzenesulfonamide (compound 73);
6-methoxy-pyridine-3-sulfonic acid [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -amide (compound 81);
n- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -4-chloro-2-fluoro-benzenesulfonamide (compound 85) and
n- [3- (4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -2-fluoro-phenyl ] -3-bromo-4-methoxy-benzenesulfonamide (compound 87).
6. A process for the preparation of a compound as defined in claim 1, or a pharmaceutically acceptable salt thereof, which process comprises the steps of:
reacting an intermediate of formula (II)
Wherein E1、E2A is as defined in claim 1, and X is a leaving group;
or cross-coupled with:
step a) derivatives of the formula (IV)
Wherein R2, R3 and n are as defined in claim 1, M is an organometallic group, and Pg is a nitrogen protecting group; followed by
Step e) selectively removing the Pg group from the resulting intermediate of formula (V)
Wherein E1、E2A, R2, R3, n and Pg are as defined above; and
step f) bringing the resulting intermediate of formula (VII)
Wherein E1、E2A, R2, R3 and n are as defined above, with a derivative of formula (XI),
wherein R1 is as defined in claim 1, to give a compound of formula (I) as defined in claim 1;
or cross-coupled with:
step b) derivatives of the formula (VI)
Wherein R2, R3, n and M are as defined above; followed by
Step f) reacting the intermediate of formula (VII) obtained as defined above with a derivative of formula (XI) as defined above to obtain a compound of formula (I) as defined in claim 1;
or cross-coupled with:
step c) derivatives of the formula (VIII)
Wherein R1, R2, R3, n and M are as defined above;
or cross-coupled with:
step d) derivatives of the formula (IX)
Wherein R1, R2, R3, n, Pg and M are as defined above; subsequently:
step g) selectively removing the Pg group from the resulting intermediate of formula (X),
wherein E1、E2A, R1, R2, R3, n and Pg are as defined above, to give a compound of formula (I) as defined in claim 1;
optionally converting a compound of formula (I) to another compound of formula (I) and, if desired, converting a compound of formula (I) to a pharmaceutically acceptable salt thereof or converting a salt to the free compound (I).
7. The method of claim 6, wherein the leaving group is a halogen.
8. A pharmaceutical composition comprising one or more compounds as defined in claim 1 or 5 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.
9. The pharmaceutical composition of claim 8, further comprising one or more chemotherapeutic agents.
10. An in vitro method for inhibiting the activity of a protein kinase RNA-like ER kinase, comprising contacting said protein kinase RNA-like ER kinase with an effective amount of a compound as defined in claim 1 or 5.
11. A product comprising a compound as defined in claim 1 or 5, or a pharmaceutically acceptable salt thereof, and one or more chemotherapeutic agents, as a combined preparation for simultaneous, separate or sequential use in anticancer therapy.
12. A compound as defined in claim 1 or 5, or a pharmaceutically acceptable salt thereof, for use as a medicament.
13. Use of a compound as defined in claim 1 or 5, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease caused by and/or associated with deregulated protein kinase RNA-like ER kinase activity.
14. The use of claim 13, wherein the disease is selected from the group consisting of a cell proliferative disease, a viral infection, an autoimmune disease, and a neurodegenerative disease.
15. The use of claim 14, wherein the cell proliferative disorder is cancer.
16. The use of claim 15, wherein the cancer is selected from hematopoietic tumors of lymphoid lineage, hematopoietic tumors of myeloid lineage, tumors of mesenchymal origin, tumors of the central and peripheral nervous system, and other tumors.
17. The use of claim 15, wherein the cancer is selected from the group consisting of bladder, breast, colon, kidney, liver, lung, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin.
18. The use of claim 16, wherein the hematopoietic tumor of lymphoid lineage is selected from leukemia, B-cell lymphoma, T-cell lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma, hairy cell lymphoma and burkitt's lymphoma; said tumor of mesenchymal origin is selected from fibrosarcoma and rhabdomyosarcoma; the central and peripheral nervous system tumors are selected from gliomas and schwannomas; and the other tumor is selected from melanoma, seminoma, teratocarcinoma, osteosarcoma, keratoacanthoma, thyroid follicular cancer, and kaposi's sarcoma.
19. The use of claim 18, wherein the leukemia is acute lymphocytic leukemia or acute lymphoblastic leukemia.
20. The use of claim 14, wherein the viral infection is AIDS.
21. The use of claim 14, wherein the autoimmune disease and neurodegenerative disease are selected from transplant rejection, psoriasis, allergic diseases, asthma, Rheumatoid Arthritis (RA), multiple sclerosis, Systemic Lupus Erythematosus (SLE), crohn's disease, prion-related diseases, alzheimer's disease, degenerative neurological diseases, parkinson's disease, amyotrophic lateral sclerosis, huntington's disease, and pick's disease.
22. The use of claim 14 or 15, which provides tumor angiogenesis and metastasis inhibition.
23. The use of claim 14 or 15, further comprising contacting the mammal in need thereof with a combination of radiation therapy or chemotherapy regimen and at least one cytostatic or cytotoxic agent.
24. The use of claim 13, wherein the disease is selected from the group consisting of type 1 diabetes, myocardial infarction, cardiovascular disease, atherosclerosis, cardiac arrhythmia, obesity, ocular disease, and inflammatory disease.
HK19120273.8A 2016-06-21 2017-06-19 N-(substituted-phenyl)-sulfonamide derivatives as kinase inhibitors HK1260454B (en)

Applications Claiming Priority (1)

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HK1260454A1 HK1260454A1 (en) 2019-12-20
HK1260454B true HK1260454B (en) 2022-12-16

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