Patent Grant
8895744
This application is a National Stage entry of International Application No. PCT/EP2009/006206, having an international filing date of Aug. 27, 2009, which claims priority to European Application No. 08015802.5, filed Sep. 8, 2008, the disclosure of each of which is hereby incorporated in its entirety by reference.
The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Jul. 12, 2011, is named 10050600.txt and is 888 bytes in size.
The present invention relates to compounds that are able to inhibit the activity of the oncogenic protein kinases, including tyrosine kinases such as Anaplastic Lymphoma Kinase (ALK), which is aberrantly expressed and activated in different types of cancers, such as anaplastic large cell lymphoma (ALCL), RET (Rearranged during Transfection), which is involved in the onset of hereditary and sporadic thyroid cancer, and Bcr-Abl an oncogenic fusion protein frequently observed in chronic myeloid leukaemia (CML) patients, and the use of such compounds for the preparation of a pharmaceutical composition.
The present invention relates to inhibitors of the oncogenic protein kinases, including ALK, RET and Bcr-Abl. The formula of the inhibitors is disclosed below (Formula I). Such inhibitors can be used for the treatment of hyper-proliferative diseases such as cancer, in particular for the treatment of ALK fusion protein positive cancers, such as anaplastic large cell lymphoma (ALCL), diffuse large B cell lymphoma (DLBCL), inflammatory myofibroblastic tumours (IMT) and non-small cell lung cancer (NSCLC), as well as T315I Bcr-Abl positive cancers such as Chronic Myeloid Leukemia (CML) and Ph+ Acute lymphoblastic leukemia (ALL), and thyroid cancer linked to RET, such as papillary thyroid carcinoma (PTC) and multiple endocrine neoplasia type 2 (MEN2).
Cancer results from the subversion of processes that control the normal growth, location and mortality of cells. This loss of normal control mechanisms arises from the acquisition of mutations that lead to the oncogenic activation of proteins that are involved in the normal regulation of such processes.
Protein kinases are enzymes that catalyse the transfer of phosphate from adenosine-5′-triphosphate (ATP) to specific amino acid residues in many proteins. Generally, the phosphorylation of a protein changes its functionality, from inactive to active in some cases, and from active to inactive in others. Protein kinases are thus involved in the regulation of many aspects of cell function, as most of the signal transduction pathways controlling cell growth, survival, differentiation and motility are mediated by phosphorylation. Abnormal activity of protein kinases has been implicated in many cancers as well as in other diseases. The human genome encodes at least 518 kinases, of which approximately 90 specifically phosphorylate the phenolic hydroxyl of tyrosine residues. Tyrosine kinases are particularly involved in cell proliferation and survival processes, and their aberrant activation most often leads to oncogenic transformation.
For example, structural alterations in ALK produced by the chromosomal rearrangement t(2q23;5q35) generates the NPM/ALK oncogenic fusion protein associated with ALCL.1 1 Rabbitss, T. H. Nature, 1994, 372, 143
Large cell lymphomas represent about 25% of all non-Hodgkin's lymphomas; about one-third of these tumors are anaplastic large cell lymphoma (ALCL). In turn, more than half the patients with ALCL possess a chromosomal translocation that leads to the in-frame juxtaposition of the 5′ portion of the nucleophosmin (NPM) gene with the sequence encoding for the catalytic domain of ALK kinase. The resulting chimaeric gene, under the control of the strong NPM promoter, drives the expression of the NPM/ALK oncogenic fusion protein. An additional 10% of ALCL patients carry other ALK fusion proteins. To date, 11 ALK fusions have been described. In all cases, the ALK kinase domain sequence is fused to an aminoterminal protein-protein interaction domain of a protein that is highly expressed in the target cell. Thus, the fusion partner provides constitutive expression (through its promoter) and activation (via oligomerisation). In addition, ALK fusion proteins show anomalous cellular localisation. For example, NPM/ALK is mainly found in the cytoplasm and the nucleus. By contrast, wild-type ALK is a tightly regulated, integral membrane protein that is only activated in the presence of a specific extracellular ligand. ALK is normally expressed in the nervous system during embryonic development and is strongly down-regulated at birth, resulting in barely detectable levels in adult tissues. It has been extensively demonstrated that constitutively active NPM/ALK is a potent oncogene with transforming and tumourigenic properties.2 Moreover, rearrangement of ALK kinase is a very early event in tumour formation and is necessary for survival of transformed cells. The high level of expression of NPM/ALK and other ALK fusion protein variants in lymphoma cells and their direct role in lymphomagenesis, combined with the fact that normal ALK is expressed at low levels in the human body, suggests that ALK could potentially be an ideal target for therapy. 2 Morris, S. W; Kirstein, M. N.; Valentine, M. B.; Dittmer, K. G.; Shapiro, D. N.; Saltman, D. L.; Look; A. T. Science, 1994, 263, 1281-1284
Chronic Myeloid Leukemia (CML) is a myeloproliferative disease, characterized by the presence of a modified chromosome, named Ph-chromosome. In the eighties, the molecular defect associated with this cytogenetic abnormality was identified and it was established that the Ph-chromosome results from the chromosomal rearrangement t(9q34;22q11) and leads to the formation of the hybrid gene BCR-ABL coding for the oncogenic Bcr-Abl fusion tyrosine kinase associated with CML and ALL3. In the late 1980s, the data accumulated on the role of BCR-ABL in onset and progression of CML indicated BCR-ABL as the most attractive target for molecularly targeted therapy approaches. Therefore attempts to inhibit the TK activity of the oncoprotein were initiated and this process finally led to the discovery and the development of imatinib mesylate. Imatinib has been under clinical investigation for almost 8 years (50.000 patients) with remarkable results in terms of durable remissions. During the successful clinical trials, resistance to imatinib emerged particularly in patients with acute leukemias, but it is a potential issue also in patients in chronic phase. The molecular mechanism of resistance has been identified in Bcr-Abl gene amplification and mutations in the catalytic kinase domain of the gene3. Mutations render the target kinase insensitive to the drug, either by altering the conformational equilibrium of the catalytic domain, or by changing the drug binding site. This has prompted intense research to find new compounds able to overcome the resistance problem, such as Dasatinib4, Bosutinib5 and Nilotinib.6 These second generation inhibitors show increased potency compared to imatinib and are able to target most of imatinib-resistant clones. However, none of them is able to inhibit efficiently the imatinib-resistant Bcr-Abl T315I mutant. Thus, under the selective pressure of molecularly targeted therapies, the mutation of the gatekeeper amino acid threonine into an isoleucine (T315I) has evolved as the predominant one in patients3 and has proved to be critical for the resistance of the tumour towards Bcr-Abl kinase selective therapies'. These facts indicate that the T315I mutant is a crucial target for the development of new selective therapies aimed at eradicating the disease. 3 Ben-Neriah, Y., Daley, G. Q., Mes-Masson, A. M., Witte, O. N. & Baltimore, D. Science. 1986, 233, 2124 Shah, N. P., Tran, C., Lee, F. Y., Chen, P., Norris, D. & Sawyers, C. L. Science 2004 305, 399-4015 Puttini, M.; Coluccia, A. M.; Boschelli, F.; Cleris, L.; Marchesi, E.; Donella-Deana, A.; Ahmed, S.; Redaelli, S.; Piazza, R.; Magistroni, V.; Andreoni, F.; Scapozza, L.; Formelli, F. & Gambacorti-Passerini, C. Cancer Res. 2006, 66, 11314-113226 Weisberg, E., Manley, P. W., Breitenstein, W., Bruggen, J., Cowan-Jacob, S. W., Ray, A., Huntly, B., Fabbro, D., Fendrich, G., Hall-Meyers, E., Kung, A. L., et al. Cancer Cell. 2005 7, 129-1417 Gambacorti-Passerini, C. B., Gunby, R. H., Piazza, R., Galietta, A., Rostagno, R. & Scapozza, L. Lancet Oncol. 2003, 4, 75-85.
RET (Rearranged during Transfection) proto-oncogene is involved in the onset of hereditary and sporadic thyroid cancer.8 Activating mutations have been described both in the extracellular and the catalytic domain. In addition, rearranged forms of RET have been identified, in which the kinase domain is fused to an activating gene. In all cases, RET kinase activity is switched on independently of ligand binding and induces malignant transformation of thyroid cells. RET uncontrolled activity is both sufficient and necessary to cause neoplastic phenotype. Therefore, it represents an ideal target for molecular therapy of thyroid neoplasias. 8 Jhiang S M. Oncogene 2000, 19:5590-7.
Several small molecule compounds have been described as RET inhibitors during the last few years.9 However, all these compounds were developed against other targets and indeed hit a number of other kinases. This fact is likely to cause significant toxicity in clinical practice. Therefore, RET-selective inhibitors are needed for the management of this group of malignancies. 9 Gunby et al. Anti-Cancer Agents in Medicinal Chemistry 2007, 7, 594.
The disclosed inhibition of ALK, RET, and Bcr-Abl mutant T315I has been demonstrated using an ELISA-based in vitro kinase assay that has been previously developed (EP1454992). Furthermore cellular activity of the compounds on NPM/ALK transformed cells has been demonstrated by tritiated thymidine based cell proliferation inhibition assay.
The inhibitors of the present invention have the following formula or pharmaceutical acceptable salts thereof.
In a first aspect, the invention provides a compound of formula (I):
wherein either R1 or R2 is a structure consisting of a linker, spacer, and functional group L-S—X, and the other is chosen from a halogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, arylvinyl, substituted arylvinyl, vinyl, substituted vinyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl, substituted acyl, substituted oxalyl, nitro, nitrovinyl, amino, substituted amino, formyl, carboxyl, or carboxyl derivative. R3 is either H, methyl, ethoxymethyl, or SO2Ph
wherein when R1 is a structure L-S—X:
and
and
or
and
and
or
L is NH or O
and
S is an aryl group
and
X is a functional group or a spacer (defined here as an aryl, heteroaryl, alkyl, heteroalkyl, substituted alkyl, substituted aryl, substituted heteroaryl, or substituted heteroalkyl, where a heteroalkyl group is defined as —[(CH2)nY]m(CH2)p— with Y═O, S, or NH, n, m=1 to 3, and p=0 to 4, with the proviso that when m is 2 or 3, n is not 1) bearing a functional group, comprising an ether, amine, alcohol, sulfoxide, sulfone, sulfonamide, tetrazole, carboxylic acid, amide, nitro, aryl, substituted aryl, alkyl, cycloalkyl, heterocycle, substituted heterocycle, heteroaryl, substituted heteroaryl, halogen, or the following structure at the 3-position (meta) of the aryl group:
where Ra and or Rb are independently a hydrogen or a group chosen from a C1-C10 alkyl group, a C3-C7 cycloalkyl group, an aryl group, a C3-C12 heterocycle, or Ra and Rb are linked to form with the nitrogen a heterocycle such as an optionally substituted piperidine, piperazine, or morpholine
or
and
and
wherein when R2 is a structure L-S—X:
As used herein, the terms “alkyl”, “alkenyl”, “alkynyl”, “acyl” refer to linear or branched aliphatic chains containing from 1 to 4 carbon atoms, whereas the terms “(hetero)aryl” preferably indicates a 5- to 10-membered (hetero)aromatic ring.
In a first preferred embodiment, the invention provides a compound of formula (Ia):
In a further preferred embodiment, the invention provides a compound of formula (Ib):
In a further preferred embodiment, the invention provides a compound of formula (IIa):
In a further preferred embodiment, the invention provides a compound of formula (IIb):
In a further preferred embodiment, the invention provides a compound of formula (IIIa):
In a further preferred embodiment, the invention provides a compound of formula (IIIb):
The compounds of the invention can be in the form of free bases or as acid addition salts, preferably salts with pharmaceutically acceptable acids. The invention also includes separated isomers and diastereomers of the compounds, or mixtures thereof (e.g. racemic mixtures).
In a further embodiment, the invention provides a pharmaceutical composition containing a compound as above described in association with physiologically acceptable carriers and excipients. The compositions can be in the form of solid, semi-solid or liquid preparations, preferably in form of solutions, suspensions, powders, granules, tablets, capsules, syrups, suppositories, aerosols or controlled delivery systems. The compositions can be administered by a variety of routes, including oral, transdermal, subcutaneous, intravenous, intramuscular, rectal and intranasal, and are preferably formulated in unit dosage form, each dosage containing from about 1 to about 1000 mg, preferably from 1 to 500 mg of active ingredient. The principles and methods for the preparation of pharmaceutical compositions are described for example in Remington's Pharmaceutical Science, Mack Publishing Company, Easton (PA).
In a yet further embodiment, the invention relates to a compound or a pharmaceutical composition as herein provided, for use in the treatment of tumors, especially of ALK-associated, RET-associated or Bcr-Abl-associated tumors. In a preferred embodiment, the compounds or compositions according to the invention are used in the treatment of anaplastic large cell lymphoma, diffuse large B cell lymphoma, inflammatory myofibroblastic tumors, chronic myeloid leukemia or Ph+ acute lymphoblastic leukemia. In a further preferred embodiment, the compounds or compositions are used for the treatment of chronic myeloid leukaemia (CML) resistant to Imatinib or Dasatinib or Nilotinib or Bosutinib.
The compounds were prepared by selective sequential derivatization of the α-carboline core. α-Carbolines bearing halo or simple alkyl substituents on the pyridine ring (R1 in structure I) can readily be prepared by Graebe-Ullman reactions from disubstituted pyridine precursors. Electrophilic aromatic substitution provides selective access to disubstituted α-carbolines bearing halo, acyl, carboxyl, carboxamido, oxalyl, nitro, methyl-oxo acetate, or amine at the 6-position (R2 in structure I)
Further elaboration was achieved by palladium catalyzed or nucleophilic substitution of the chloro group on the 2-, 3-, or 4-position of the pyridine ring or the bromo group at the 6-position, using a Buchwald amination (case where L=—NH— or —O—), Suzuki coupling (case where R1, R2, or L=aryl, alkyl, or vinyl), Sonogoshira coupling (case where L=alkynyl), or by nucleophilic aromatic substitution (case where L=—NH— or —O—). Unsymmetrical α-carbolines bearing complex groups on both rings can be prepared by sequential selective palladium catalyzed coupling reactions.
Further functionalisation of the substitutents on the α-carboline core can be achieved either by the use of highly functionalized boronic acids or ester, arylamines, acetylenes, or phenols, or by late-stage derivatization of the linker already on the α-carboline structure. Thus nucleophilic substitution of 6-bromoacetyl-α-carbolines or demethylation of methoxyphenyl-α-carbolines followed by nucleophilic substitution of substituted alkyl halides or substituted alcohols by Mitsunobu reaction, provide access to a wide variety of compounds bearing substituents of the structure L-S—X.
Deprotection of arylsulfonyl groups (R3 on structure 1) was achieved with tetrabutylammonium fluoride or sodium methoxide in methanol. Deprotection of the ethoxymethyl group can be performed under acidic conditions.
Molecules of the following structures have been prepared
wherein:
when R1 is attached in the 2 position of the α-carboline ring it is selected from:
When R1 is attached in the 3 position of the α-carboline ring it is selected from:
When R1 is attached in the 4 position of the α-carboline ring it is selected from:
R2 is selected from:
R3 is hydrogen, methyl, ethoxymethyl, or benzenesulfonyl.
In the above tables, a dashed line across a bond indicates the point of attachment of the group to the α-carboline ring.
Extensions
One knowledgeable in the art will recognize that:
A Suzuki, Buchwald, or Sonogashira coupling can be performed equally well at the 2, 3, 4, and 6-positions, and thus that any analog prepared at one of these positions by one of these reactions can be prepared equally well at the remaining positions.
Using the palladium-catalyzed procedures described herein, R1 and R2 can thus be chosen freely and independently from:
A Suzuki, Buchwald, or Sonogashira coupling can be performed equally well with any other boronic acid or boronic ester, phenol, arylamine, or acetylene, respectively, and that any substitution pattern achieved with one of these compounds can be done with any other one. These include any commercial boronic acids or esters, phenols, arylamines, or acetylenes. Furthermore, one knowledgeable in the art will recognize that more highly functionalized vinyl boronic acids or esters and acetylenes can readily be prepared from substituted benzaldehydes. Compounds where L is a substituted vinyl group and 3 is an aryl or heteroaryl group can be prepared in a regiocontrolled and stereospecific fashion by hydroboration of a substituted arylacetylene.
Where a compound having a sidechain of the type L-S—X, where S is an alkyl chain and X is an amine, S can be an alkyl chain of any length from 1 to 10, or a heteroalkyl chain, defined as —[CH2)nY]m(CH2)p— with Y═O, S, or NH, n, m=1 to 3, and p=2 to 4, with the proviso that when m is 2 or 3 n is not 1, and X can be any polar functional group. For example,
Reduction of a nitro group gives an arylamine, which can be functionalized with a spacer and a functional group, using for example the sidechain and conditions used with the aminothiazole described in section 5.
Synthesis of α-carbolines Substituted on the Pyridine Ring
α-Carbolines substituted on the pyridine ring with alkyl or halogen were prepared from substituted pyridines and benzotriazole by a modified Graebe-Ullman reaction. 4-Chloro-α-carbolines were prepared by N-oxidation followed by a MsCl-induced substitution/rearrangement.
Synthesis of Disubstituted α-carbolines by Electrophilic Aromatic Substitution
Compounds of structure (Ia or Ib) where R2 is halogen, acyl, nitro, amino, formyl, carboxyl, or carboxyamide were prepared from 3-chloro-α-carboline by electrophilic aromatic substitution.
Further functionalisation was achieved by reduction, Henry condensation, Suzuki coupling (case where R2 or L=heteroaryl, aryl, alkyl, or vinyl), Sonogashira coupling (case where L=acetylene), Buchwald coupling (case where L=NH or O), nucleophilic substitution (case where L=C(O)CH2S), or by amide formation (case where L-X═C(O)CH2CH2C(O)NRaRb).
Compounds of structure (IIa) or (IIb) where R2 is halogen, acyl, nitro, amino, formyl, carboxyl were prepared from 2-chloro-α-carboline or 2-methyl-α-carboline by electrophilic aromatic substitution. Further functionalisation at R1 and R2 was achieved by Suzuki coupling (case where R or L=heteroaryl, aryl, alkyl, or vinyl), by Sonogashira coupling (case where L acetylene), by nucleophilic substitution (case where L=C(O)CH2S), by amide formation (case where L-X=C(O)CH2CH2C(O)NRaRb), or by a Buchwald substitution (case where L=—NH— or —O—).
Compounds of structure (IIIa) or (IIIb) where R2 is halogen, acyl, nitro, amino, formyl, carboxyl were prepared from 4-chloro-α-carboline by electrophilic aromatic substitution. Further functionalisation at R1 and R2 was achieved by Suzuki coupling (case where R or L=heteroaryl, aryl, alkyl, or vinyl), by Sonogashira coupling (L=acetylene), by nucleophilic substitution (case where L=C(O)CH2S), by amide formation (case where L-X=C(O)CH2CH2C(O)NRaRb), or by a Buchwald substitution (case where L=—NH— or —O—).
(2 equiv.) (2.5 mL/mmol) 1,4-dioxane, ArB(OH)2 (1.1 equiv.), 100° C., 12 h; or Pd2(dba)3 (0.08 equiv.), X-Phos (0.16 equiv.), t-BuONa (3 equiv.), t-BuOH, ArNH2 (1.1 equiv.), 100° C., 12 h; viii) Pd2(dba)3 (0.08 equiv.), X-Phos (0.16 equiv.), K2CO3 (3 equiv.), t-BuOH, ArNH2 (1.1 equiv.), 100° C.
Compounds of structure (Ib) where L=heteroaryl, S=carboxyaryl, and X=a heterocyclic amine were prepared according to the following route:
Synthesis of Disubstituted α-carbolines by a Regioselective Double Palladium Coupling Sequence
Compounds of structure (Ia) where the group X—S-L- represents is heteroaryl, aryl, or and R2 is heteroaryl, aryl, alkyl, alkynyl, arylamino, or vinyl, were prepared by a regioselective double palladium coupling sequence on the 3-chloro-6-bromo-α-carboline, in which the first palladium catalyzed reaction is a Suzuki, Buchwald, or Sonogashira coupling, and the second palladium catalyzed reaction is a Suzuki coupling. Further functionalisation was achieved by demethylation, of the methoxy group or reduction of the nitro group on the newly added aryl group, followed by Mitsunobu substitution, sulfonamide, or amide formation, prior to the second palladium-catalyzed coupling.
Compounds of structure (IIa) where R1 is heteroaryl, aryl, or vinyl and R2 is heteroaryl, aryl, alkyl, acetylene, arylamino, or vinyl, were prepared by a regioselective double palladium coupling sequence on the 2-chloro-6-bromo-α-carboline, in which the first palladium catalyzed reaction is a Suzuki, Buchwald, or Sonogashira coupling, and the second palladium catalyzed reaction is a Suzuki coupling. Further functionalisation can be achieved by demethylation, of the methoxy group or reduction of the nitro group on the newly added aryl group, followed by Mitsunobu substitution, sulfonamide, or amide formation, prior to the second palladium-catalyzed coupling.
Compounds of structure (IIIa) where R is heteroaryl, aryl, or vinyl and R2 is heteroaryl, aryl, alkyl, acetylene, arylamino, or vinyl, were prepared by a regioselective double palladium coupling sequence on the 4-chloro-6-bromo-α-carboline, in which the first palladium catalyzed reaction is a Suzuki, Buchwald, or Sonogashira coupling, and the second palladium catalyzed reaction is a Suzuki coupling. Further functionalisation can be achieved by demethylation, of the methoxy group or reduction of the nitro group on the newly added aryl group, followed by Mitsunobu substitution, sulfonamide, or amide formation, prior to the second palladium-catalyzed coupling.
Compounds of structure (Ib, IIb, and IIIb) where R1 is heteroaryl, aryl, alkyl, acetylene, arylamino, or vinyl, and R2 is heteroaryl, aryl, or vinyl were prepared by a regioselective double palladium coupling sequence on the 2,3, or 4-chloro-6-bromo-□-carboline, in which the first palladium catalyzed reaction is a Suzuki coupling, and the second palladium catalyzed reaction is a Suzuki, Buchwald, or Sonogashira coupling. Further functionalisation can be achieved by demethylation of the methoxy group or reduction of the nitro group on the newly added aryl group, followed by Mitsunobu substitution, sulfonamide, or amide formation.
Compounds of structure (Ia) where X—S-L- represents arylamino or aryloxy and R2 is heteroaryl, aryl, alkyl, alkynyl, arylamino, or vinyl, were prepared by a regioselective double palladium coupling sequence on the 3-chloro-6-bromo-α-carboline in which the second palladium coupling reaction is a Buchwald reaction.
Compounds of structure (IIa) where X—S-L- represents arylamino or aryloxy and R2 is heteroaryl, aryl, alkyl, alkynyl, arylamino, or vinyl, were prepared by a regioselective double palladium coupling sequence on the 2-chloro-6-bromo-α-carboline in which the second palladium coupling reaction is a Buchwald reaction.
Compounds of structure (IIIa) where X—S-L- represents arylamino or aryloxy and R2 is heteroaryl, aryl, alkyl, alkynyl, arylamino, or vinyl, were prepared by a regioselective double palladium coupling sequence on the 4-chloro-6-bromo-α-carboline in which the second palladium coupling reaction is a Buchwald reaction.
Compounds of structure (Ia) where X—S-L represents alkynyl or alkyl and R2 is heteroaryl, aryl, alkyl, alkynyl, arylamino or vinyl, were prepared by a regioselective double palladium coupling sequence on the 3-chloro-6-bromo-α-carboline, in which the first palladium catalyzed reaction is a Suzuki, Buchwald, or Sonogashira coupling, and the second palladium catalyzed reaction is a Sonogashira coupling. The resulting acetylenes can be reduced by hydrogenation.
Compounds of structure (IIa) where X—S-L represents alkynyl or alkyl and R2 is heteroaryl, aryl, alkyl, alkynyl arylamino, or vinyl, were prepared by a regioselective double palladium coupling sequence on the 2-chloro-6-bromo-α-carboline, in which the first palladium catalyzed reaction is a Suzuki, Buchwald, or Sonogashira coupling, and the second palladium catalyzed reaction is a Sonogashira coupling. The resulting acetylenes can be reduced by hydrogenation.
Compounds of structure (IIIa) where X—S-L represents alkynyl or alkyl and R2 is heteroaryl, aryl, alkyl, alkynyl, arylamino, or vinyl, were prepared by a regioselective double palladium coupling sequence on the 4-chloro-6-bromo-α-carboline, in which the first palladium catalyzed reaction is a Suzuki, Buchwald, or Sonogashira coupling, and the second palladium catalyzed reaction is a Sonogashira coupling. The resulting acetylenes can be reduced by hydrogenation.
Compounds of structure (Ib, IIb, and IIIb) where R1 is heteroaryl, aryl, alkyl, alkynyl, arylamino, or vinyl, and X—S-L represents alkyl were prepared by a regioselective double palladium coupling sequence on the 2-, 3-, or 4-chloro-6-bromo-α-carboline, in which the first palladium catalyzed reaction is a Sonogashira coupling, and after hydrogenation of the resulting acetylenes, the second palladium catalyzed reaction is a Suzuki, Buchwald, or Sonogashira coupling.
Compounds of structure Ib in which L is aryl, S is —O(CH2)n— and X is a dialkylamine were prepared by deprotection of the aryl methoxy group and a Mitsunobu substitution, followed after deprotection by a palladium catalyzed Suzuki, Buchwald, or Sonogashira coupling.
Compounds of structure Ia in which L is aryl, S is NH, and X is SO2Ph were prepared by reduction of the aryl nitro group followed by sulfonylation.
Synthesis of Disubstituted α-Carbolines by a Palladium Coupling Reaction followed by an Electrophilic Substitution
Compounds of structure (IIb) where R1 is a substituted arylamine and X—S-L is acyl, were prepared from 2-chloro-α-carboline by Buchwald coupling, followed by electrophilic aromatic substitution. Further functionalisation at the X—S-L- group can be achieved by nucleophilic substitution (case where L=C(O)CH2S), or by amide formation (case where L-X═C(O)CH2CH2C(O)N RaRb).
Using these methods the following compounds have been synthesized:
α-carbolines were synthesized by modified Graebe-Ullman reaction.10 This approach was selected as the shortest route to access to chloropyrido[2,3-b]indoles from dichloropyridine in only two steps. The 4-chloro-α-carboline was prepared by chlorination of pyrido[2,3-b]indol-N-oxyde.11 10 a) Vera-Luque, P.; Alajarin, R.; Alvarez-Builla, J.; Vaquero, J. J. Org. Lett. 2006, 8, 415. (b) Katritzky, A. R.; Lan, X.; Yang, J. Z.; Denisko, O. V. Chem. Rev. 1998, 98, 409. (c) Mehta, L. K.; Parrick, J.; Payne, F. J. Chem. Soc., Perkin Trans. 1 1993, 1261. (d) Semenov A. A.; Tolstikhina V. V. Chem. Heterocycl. Compd. 1984, 20, 345.11 Antiviral and neuroleptic α-carbolines. FR patent FR 19691114; Chem. Abstr. 1969, 72, 111444.
To a 0.2 M stirred suspension of the α-carboline derivative (200 mg) in anhydrous CH2Cl2 was added AlCl3 (4.5 equiv.) and acetyl chloride (2 equiv.) at room temperature under inert atmosphere. The mixture was stirred at reflux until completion of the reaction (as shown by t.l.c.). The resulting mixture was then cautiously quenched at 0° C. with H2O. It was extracted with the mixture of EtOAc/DMF (99:1). The resulting organic layer was washed with a saturated aqueous solution of NaHCO3, and brine, dried over MgSO4, and filtered and the solvents were removed under reduced pressure.
A white powder was obtained in 78% yield (184 mg) after trituration of the crude product in MeOH and filtration and flash chromatography (eluent: EtOAc/PE 1:1 to EtOAc) of residual filtrate; mp>139° C.; 1H-NMR (300 MHz, DMSO-d6): δ 12.03 (bs, 1H), 8.82 (d, 1H, J=1.6 Hz), 8.51 (d, 1H, J=8.0 Hz), 8.03 (dd, 1H, J=1.6, 8.6 Hz), 7.52 (d, 1H, J=8.6 Hz), 7.15 (d, 1H, J=8.0 Hz), 2.69 (s, 3H), 2.60 (s, 3H); 13C-NMR (75 MHz, DMSO-d6): δ 196.9 (C), 155.8 (C), 152.5 (C), 141.5 (C), 129.2 (CH), 128.9 (C), 126.1 (CH), 122.4 (CH), 120.3 (C), 115.5 (CH), 112.9 (C), 110.9 (CH), 26.6 (CH3), 24.3 (CH3); MS
A white powder was obtained in 75% yield (184 mg) after trituration, filtration of crude product in THF and flash chromatography (CH2Cl2/AcOEt 9:1) of residual filtrate; 1H-NMR (300 MHz, DMSO-d6): δ 12.4 (bs, 1H), 8.97 (s, 1H), 8.86 (d, 1H, J=2.1 Hz), 8.49 (d, 1H, J=2.1 Hz), 8.14 (d, 1H, J=8.6 Hz), 7.58 (d, 1H, J=8.6 Hz), 2.66 (s, 3H); 13C-NMR (75 MHz, DMSO-d6): δ 196.8 (C), 161.9 (C), 144.7 (CH), 142.6 (C), 129.3 (C), 128.7 (CH), 127.3 (CH), 123.6 (CH), 122.5 (C), 119.3 (C), 116.8 (C), 111.3 (CH), 26.6 (CH3); GC-MS (EI) m/z 244 [M+]
To a 0.2 M stirred suspension of the α-carboline derivative (200 mg) in anhydrous CH2Cl2 was added AlCl3 (4.5 equiv.) and bromoacetyl bromide (1.1 equiv.), at room temperature under inert atmosphere. The mixture was stirred at reflux until completion of the reaction (as shown by t.l.c.). The resulting mixture was then cautiously quenched at 0° C. with H2O. It was extracted with the mixture of EtOAc/DMF (99:1). The resulting organic layer was washed with NaHCO3 a saturated aqueous solution of NaHCO3, and brine, dried over MgSO4, and filtered and the solvents were removed under reduced pressure.
A white powder was obtained in 69% yield (221 mg) after trituration of the crude product in MeOH and filtration and flash chromatography (CH2Cl2/EtOAc 9:1) of residual filtrate; 1H-NMR (300 MHz, DMSO-d6): δ 12.52 (bs, 1H), 9.04 (d, 1H, J=1.1 Hz), 8.84 (d, 1H, J=2.3 Hz), 8.51 (d, 1H, J=2.5 Hz), 8.15 (dd, 1H, 1.7, 8.5 Hz), 7.61 (d, 1H, J=8.7 Hz), 4.96 (s, 2H); 13C-NMR (75 MHz, DMSO-d6): δ 190.8 (C), 150.9 (C), 145.1 (CH), 142.9 (C), 128.8 (CH), 128.0 (CH), 126.2 (C), 124.3 (CH), 122.8 (C), 119.5 (C), 116.7 (C), 111.7 (CH), 33.7 (CH2); MS (EI) m/z 244 [M+-CH2Br];
A yellow powder was obtained in 31% yield (221 mg) after trituration of the crude product in MeOH and filtration; 1H NMR (300 MHz, DMSO-d6): δ=12.54 (bs, 1H); 8.99 (d, 1H, J=1.5 Hz); 8.70 (d, 1H, J=8.1 Hz); 8.14 (dd, 1H, J=1.7 Hz, J=8.7 Hz); 7.63 (d, 1H, J=8.7 Hz); 7.39 (d, 1H, J=8.1 Hz); 4.99 (s, 2H).
The following compound can be prepared by the same method:
To a 0.2 M stirred suspension of the α-carboline derivative (200 mg) in anhydrous CH2Cl2 was added AlCl3 (4.5 equiv.) and benzoyl chloride (2 equiv.), at room temperature under inert atmosphere. The mixture was stirred at reflux until completion of the reaction (followed by t.l.c.). The resulting mixture was then cautiously quenched at 0° C. with H2O. It was extracted with the mixture of EtOAc/DMF (99:1). The resulting organic layer was washed with NaHCO3 saturated aqueous solution and brine, dried over MgSO4, filtered and solvents were removed under reduced pressure.
A white powder was obtained in 87% yield (273 mg) after flash chromatography (eluent: EtOAc/PE 1:1 to EtOAc); mp 231° C.; 1H-NMR (300 MHz, DMSO-d6): δ 12.10 (bs, 1H), 8.58 (s, 1H), 8.51 (d, 1H, J=7.9 Hz), 7.86 (dd, 1H, J=1.7, 8.5 Hz), 7.77-7.75 (m, 2H), 7.70-7.65 (m, 1H), 7.60-7.55 (m, 3H), 7.13 (d, 1H, J=8.22 Hz), 2.60 (s, 3H); 13C-NMR (75 MHz, DMSO-d6): δ 195.4 (C), 161.8 (C), 155.9 (C), 152.5 (C), 141.4 (C), 138.3 (C), 131.8 (CH), 129.5 (CH), 129.4 (2 CH), 128.5 (2 CH), 128.1 (CH), 123.7 (CH), 120.3 (C), 115.9 (CH), 112.8 (C), 110.9 (CH), 24.4 (CH3); MS (ESI) m/z 287 [M+H+]
The following compounds can be prepared by the same method:
To a 0.2 M stirred suspension of the α-carboline derivative (200 mg) in anhydrous CH2Cl2 was added AlCl3 (4.5 equiv.) and methyl oxalyl chloride (2 equiv.), at room temperature under inert atmosphere. The mixture was stirred at reflux until completion of the reaction (followed by t.l.c.). The resulting mixture was then cautiously quenched at 0° C. with H2O. It was extracted with the mixture of EtOAc/DMF (99:1). The resulting organic layer was washed with NaHCO3 saturated aqueous solution and brine, dried over MgSO4, filtered and solvents were removed under reduced pressure.
A white powder was obtained in 83% yield (223 mg) after flash chromatography (eluent: CH2Cl2/EtOAc 8:2 to EtOAc); 1H-NMR (300 MHz, DMSO-d6): δ 12.3 (bs, 1H), 8.77 (d, 1H, J=1.6 Hz), 8.59 (d, 1H, J=7.9 Hz), 8.00 (dd, 1H, J=1.6, 8.7 Hz), 7.62 (d, 1H, J=8.7 Hz), 7.20 (d, 1H, J=7.9 Hz), 3.99 (s, 3H), 2.61 (s, 3H); 13C-NMR (75 MHz, DMSO-d6): δ 186.3 (C), 165.4 (C), 156.6 (C), 152.7 (C), 143.1 (C), 129.9 (CH), 127.4 (CH), 124.6 (CH), 123.3 (C), 120.9 (C), 116.1 (CH), 112.7 (C), 111.9 (CH), 52.9 (CH3), 24.4 CH3); MS (ESI) m/z 269.1 [M+H+]; Anal. Calcd for C15H12N2O3: C, 67.16; H, 4.51; N, 10.44. Found: C, 67.10; H, 4.49; N, 10.33.
A white powder was obtained in 70% yield (200 mg) after after flash chromatography (eluent: EtOAc/CH2Cl2 2:8); 1H-NMR (300 MHz, DMSO-d6): 12.7 (bs, 1H), 8.96 (d, 1H, J=2.4 Hz), 8.91 (d, 1H, J=1.3 Hz), 8.54 (d, 1H, J=2.4 Hz), 8.09 (dd, 1H, J=1.9, 8.6 Hz), 7.68 (d, 1H, J=8.6 Hz), 4.00 (s, 3H); 13C-NMR (75 MHz, DMSO-d6): δ 186.2 (C), 165.2 (C), 150.9 (C), 145.4 (CH), 143.9 (C), 129.3 (CH), 128.3 (CH), 125.9 (CH), 123.8 (C), 123.2 (C), 119.8 (C), 116.5 (CH), 112.3 (C), 52.9 (CH3); MS (ESI) m/z 287.1 [M+H+]
The following compounds can be prepared by the same method:
To a 0.02 M stirred suspension of the α-carboline derivative (200 mg) in anhydrous CH2Cl2 was added in portions AlCl3 (4.5 equiv.) at −78° C. After stirring for 5 min, α,α-dichloromethyl methyl ether (3 equiv.) was added dropwise to the mixture. The reaction mixture was stirred at −78° C. and then allowed to warm to room temperature for 12 hours. The resulting mixture was then cautiously quenched at 0° C. with H2O. It was extracted with the mixture of EtOAc/DMF (99:1). The combined organic layer was washed with aq. sat. NaHCO3, dried with MgSO4, filtered and solvents were removed under reduced pressure.
A white powder was obtained in 54% yield (123 mg) after after flash chromatography (eluent: CH2Cl2/EtOAc 85:15); 1H-NMR (300 MHz, DMSO-d6) δ 12.56 (bs, H), 10.06 (s, H), 8.87 (d, 1H, J=2.4 Hz), 8.84 (d, 1H, J=1.5 Hz), 8.52 (dd, 1H, J=2.4 Hz), 8.04 (dd, 1H, J=1.5, 8.5 Hz), 7.67 (d, 1H, J=8.5 Hz); 13C-NMR (75 MHz, DMSO-d6): δ 191.8 (CH), 150.8 (C), 145.1 (CH), 143.5 (C), 129.1 (C), 128.9 (CH), 128.2 (CH), 125.4 (CH), 122.8 (C), 119.8 (C), 116.6 (C), 112.0 (CH); MS (EI) m/z 230 [M+]
The following compounds can be prepared by the same method:
The crude product 6-formyl-2-methyl-9H-pyrido[2,3-b]indole (231 mg, 1.1 mmol) was prepared and diluted immediately in anhydrous MeCN (9 mL). To a stirred suspension was added DMAP (cat. amount) and Boc2O (361 mg, 1.5 equiv.). The mixture was stirred at room temperature overnight and then poured with 5% aqueous NaHCO3 and extracted with EtOAc. The combined organic layers were dried (MgSO4), and the solvent was removed under reduced pressure to give an oil. A white powder was obtained in 54% yield (185 mg) after after flash chromatography (eluent: PE/EtOAc 85:15); 1H-NMR (300 MHz, CDCl3): δ 10.06 (s, 1H), 8.46 (d, 1H, J=1.5 Hz), 8.43 (d, 1H, J=8.7 Hz), 8.22 (d, 1H, J=7.6 Hz), 8.00 (dd, 1H, J=1.5, 8.7 Hz), 7.24 (d, 1H, J=7.6 Hz), 2.75 (s, 3H), 1.78 (s, 9H); 13C-NMR (75 MHz, CDCl3): δ 191.4 (CH), 157.8 (C), 151.7 (C), 149.4 (C), 141.3 (C), 131.7 (C), 128.9 (CH), 128.4 (CH), 123.2 (C), 121.4 (CH), 118.9 (CH), 116.3 (CH), 115.2 (C), 84.9 (C), 28.3 (3 CH3), 25.2 (CH3); MS (EI) m/z 311 [M+H+], 333 [M+Na+], 643 [2M+Na+]
A solution of 18 (56 mg, 0.177 mmol) in CH2Cl2 (2.5 mL) was stirred under argon and treated with CF3CO2H (700 μL). After 90 min at room temperature, the resulting mixture was then cautiously quenched at 0° C. with H2O and a saturated aqueous NaHCO3 was added until pH 10. The solution was diluted with CH2Cl2, washed with H2O, dried with MgSO4, filtered and concentrated.
A white powder was obtained in 93% yield (35 mg) after trituration of the crude product in MeOH and filtration; 1H-NMR (300 MHz, DMSO-d6): δ 12.20 (bs, 1H), 10.04 (s, 1H), 8.71 (d, 1H, J=1.2 Hz), 8.53 (d, 1H, J=7.9 Hz), 7.96 (dd, 1H, J=1.2, 8.4 Hz), 7.61 (d, 1H, J=8.4 Hz), 7.18 (d, 1H, J=7.9 Hz), 2.61 (s, 3H); 13C-NMR (300 MHz, DMSO-d6): δ 192.1 (CH), 156.3 (C), 152.6 (C), 142.7 (C), 129.6 (CH), 128.8 (C), 126.9 (CH), 124.5 (CH), 120.9 (C), 115.9 (CH), 112.8 (C), 111.8 (C), 24.5 (CH3); MS (ESI) [M+H+]=211;
To a 0.2 M stirred suspension of the α-carboline derivative (200 mg) in anhydrous CH2Cl2 was added AlCl3 (4.5 equiv.) and 2.2 M oxalyl chloride (2 equiv.) in anhydrous CH2Cl2, at room temperature under inert atmosphere. The mixture was stirred at room temperature until completion of the reaction (followed by t.l.c.). The resulting mixture was then cautiously quenched at 0° C. with H2O. It was extracted with the mixture of EtOAc/DMF (99:1). The resulting organic layer was dried over MgSO4, filtered and solvents were removed under reduced pressure.
A white powder was obtained in 71% yield (181 mg) after trituration of the crude product in MeOH and filtration; mp>295° C. (MeOH); 1H-NMR (300 MHz, DMSO-d6): δ 12.73 (bs, 1H), 12.36 (bs, 1H), 8.89 (d, 1H, J=1.5 Hz), 8.86 (d, 1H, J=2.2 Hz), 8.47 (d, 1H, J=2.2 Hz), 8.09 (dd, 1H, J=1.5, 8.5 Hz), 7.57 (d, 1H, J=8.5 Hz); MS (EI) m/z 247 [M+H]+;
A white powder was obtained in 71% yield (181 mg) after trituration of the crude product in MeOH and filtration; mp>295° C. (MeOH); 1H-NMR (300 MHz, DMSO-d6): δ 12.73 (bs, 1H), 12.02 (bs, 1H), 8.75 (d, 1H, J=1.5 Hz), 8.52 (d, 1H, J=7.8 Hz), 8.02 (dd, 1H, J=1.5, 8.5 Hz), 7.52 (d, 1H, J=8.5 Hz), 7.14 (d, 1H, J=7.8 Hz), 2.60 (s, 3H); MS (EI) m/z 227 [M+H]+
The following compounds can be prepared by the same method:
To a 0.2 M stirred suspension of the α-carboline derivative (200 mg) in anhydrous CH2Cl2 was added AlCl3 (4.5 equiv.) and 2.2 M oxalyl chloride (2 equiv.) in anhydrous CH2Cl2, at room temperature under inert atmosphere. The mixture was stirred at room temperature until completion of the reaction (followed by t.l.c.). The resulting mixture was then cautiously quenched at 0° C. with secondary amine. It was extracted with the mixture of EtOAc. The resulting organic layer was dried over MgSO4, filtered and solvents were removed under reduced pressure. The product was purified by column chromatography (EtOAc) to afford product without protection. To a 0.5 M solution of this product in anhydrous DMF was added 60% sodium hydride (3 equiv.) at 0° C. After stirring at 0° C. for 20 min, iodomethane (2.5 equiv.) was added dropwise. The reaction mixture was stirred for 12 h and then poured with 5% aqueous saturated NaHCO3 solution and extracted with EtOAc (3×50 mL). The combined organic layers were dried (MgSO4), and the solvent was removed under reduced pressure.
The product was purified by column chromatography (EtOAc/PE 9:1) to afford 7 in 48% yield as an orange solid. 1H NMR (300 MHz, CDCl3): δ 8.49 (dd, 1H, J=1.5, 4.9 Hz), 8.27 (dd, 1H, J=1.5, 7.7 Hz), 8.12 (d, 1H, J=1.5 Hz), 7.55 (dd, 1H, J=1.5, 8.3 Hz), 7.42 (d, 1H, J=8.3 Hz), 7.15 (dd, 1H, J=4.9, 7.7 Hz), 3.93 (s, 3H), 3.47 (bs, 4H), 1.23 (bs, 6H).
The product was purified by column chromatography (EtOAc/PE 4:6) to afford 8 in 22% yield as an orange solid. 1H-NMR (300 MHz, CDCl3): δ 8.41 (dd, 1H, J=1.5, 4.9 Hz), 8.19 (dd, 1H, J=1.5, 7.2 Hz), 7.99 (bs, 1H), 7.42 (dd, 1H, J=1.3, 8.5 Hz), 7.34 (d, 1H, J=8.5 Hz), 7.06 (dd, 1H, J=4.9, 7.2 Hz), 3.84 (s, 3H), 3.70 (bs, 2H), 1.31 (bs, 12H).
The following compounds can be prepared by the same method:
At room temperature and under inert atmosphere, a solution of 0.7 M bromine (1.2 equiv.) in anhydrous CH2Cl2 was added to a 0.45 M suspension of 2-, 3- or 4-chloro-9H-pyrido[2,3-b]indole (1 equiv.) in anhydrous CH2Cl2. The mixture was stirred for 1 h at room temperature Excess bromine was destroyed by addition of sat. aq Na2S2O3 solution. The resulting mixture was extracted with EtOAc/DMF (99:1). The combined organic phases were washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure.
The compound 8a was obtained by trituration in MeOH. Yield: 75%; mp>220° C. (MeOH); IR 3135, 3053, 1626, 1597, 1574, 1404, 1273, 1202, 1128, 794, 771 cm−1; 1H-NMR (300 MHz, DMSO-d6): δ 12.21 (bs, 1H), 8.62 (d, 1H, J=8.1 Hz), 8.47 (d, 1H, J=1.5 Hz), 7.61 (dd, 1H, J=1.9, 8.7 Hz), 7.48 (d, 1H, J=8.7 Hz), 7.31 (d, 1H, J=8.1 Hz); 13C-NMR (75 MHz, DMSO-d6): δ 151.2 (C), 147.1 (C), 137.5 (C), 132.2 (CH), 129.3 (CH), 123.9 (CH), 121.8 (C), 115.0 (CH), 113.6 (CH), 113.4 (C), 112.1 (C); MS (ESI) m/z 279 [M−H; 79Br], 281 [M−H; 81Br]; HRMS (EI): Calcd for C11H6BrClN2: 279.9403. Found: 279.9405.
The compound R252 was obtained by trituration in MeOH. Yield: 78%; mp>220° C. (MeOH); IR: 3031, 3005, 2957, 1577, 1604, 1486, 1269, 1232, 1089, 803, 700 cm−1; 1H-NMR (300 MHz, DMSO-d6): δ 12.19 (bs, 1H), 8.75 (d, 1H, J=2.5 Hz), 8.48 (d, 1H, J=1.9 Hz), 8.46 (d, 1H, J=2.5 Hz), 7.62 (dd, 1H, J=1.9, 8.6 Hz), 7.48 (d, 1H, J=8.6 Hz); 13C-NMR (75 MHz, DMSO-d6): δ 150.3 (C), 145.0 (CH), 138.4 (C), 129.9 (CH), 128.8 (CH), 124.4 (CH), 122.1 (C), 121.5 (C), 115.4 (C), 113.6 (CH), 111.8 (C); MS (ESI) m/z 281 [M+H+; 79Br], 283 [M+H+; 81Br]; HRMS (EI): Calcd for C11H6BrClN2: 279.9403. Found: 279.9405.
The compound 10 was obtained by trituration in MeOH. Yield: 76%; mp>220° C. (MeOH); IR: 3123, 2950, 1603, 1569, 1442, 1276, 870, 795 cm−1; 1H-NMR (300 MHz, DMSO-d6): δ 12.40 (bs, 1H), 8.43 (d, 1H, J=1.5 Hz), 8.42 (d, 1H, J=5.3 Hz), 7.69 (dd, 1H, J=1.5, 8.6 Hz), 7.54 (d, 1H, J=8.6 Hz), 7.38 (d, 1H, J=5.3 Hz); 13C-NMR (75 MHz, DMSO-d6): δ 152.8 (C), 147.6 (CH), 137.6 (C), 136.9 (C), 129.9 (CH), 124.4 (CH), 120.7 (C), 115.9 (CH), 113.7 (CH), 111.9 (C), 111.7 (C); MS (ESI) m/z 281.1 [M+H+; 79Br], 283.1 [M+H+; 81Br]; HRMS (ESI): Calcd for C11H6BrClN2: 280.9481. Found: 280.9485.
At room temperature and under inert atmosphere, AlCl3 (4.5 equiv.) and succinic anhydride (1.2 equiv.) were added to a 0.2 M suspension of (R248) or (R297) (1 equiv.) in anhydrous CH2Cl2. The mixture was stirred at reflux until completion of the reaction (monitored by t.l.c.). The reaction was refluxed for 2 h 30. The resulting mixture was then cautiously quenched at 0° C. with H2O. The mixture was extracted with a mixture of EtOAc/DMF (99:1). The resulting organic layer was dried over MgSO4, filtered, and solvents were removed under reduced pressure. Trituration of the crude residue from MeOH then filtration afforded desired products.
Orange solid. Yield=66%. mp 243.0° C.; IR (KBr): 3118, 1664, 1623, 1587, 1484, 1443, 1382, 1346, 1269, 1228, 1080, 527, 440 cm−1; 1H-NMR (300 MHz, DMSO-d6): δ12.41 (bs, 1H), 12.17 (bs, 1H), 9.01 (s, 1H), 8.87 (d, 1H, J=2.2 Hz), 8.48 (d, 1H, J=2.4 Hz), 8.12 (dd, 1H, J=1.5, 8.7 Hz), 7.58 (d, 1H, J=6.3 Hz), 3.36-(m, 2H), 2.64 (t, 2H, J=6.3 Hz); 13C-NMR (75 MHz, DMSO-d6) 6197.4 (C), 174.0 (C), 150.8 (C), 144.8 (CH), 142.6 (C), 128.9 (CH), 128.8 (CH), 127.1 (CH), 123.4 (CH), 122.6 (C), 119.4 (C), 116.9 (C), 111.4 (CH), 32.9 (CH2), 28.0 (CH2); MS
Yellow solid. Yield 31%. mp 280.8° C., IR (KBr): 3205, 3139, 3062, 2965, 1705, 1674, 1616, 1566, 1408, 1351, 1341, 1254, 1218, 1177, 1126, 931, 803, 773, 527 cm−1, 1H NMR (300 MHz, DMSO-d6): δ 12.45 (bs, 1H), 12.16 (bs, 1H), 8.97 (s, 1H), 8.74 (d, 1H, J=8.1 Hz), 8.12 (d, 1H, J=8.3 Hz), 7.60 (d, 1H, J=8.5 Hz), 7.37 (d, 1H, J=8.5 Hz) 3.37 (m, 2H), 2.64 (t, 2H, J=5.6 Hz), 13C NMR (75 MHz, DMSO-d6): δ 197.4 (C), 173.9 (C), 151.7 (C), 146.9 (C), 141.7 (C), 132.1 (CH), 129.1 (C), 126.6 (CH), 122.7 (CH), 119.6 (C), 115.4 (CH), 114.6 (C), 111.4 (CH), 32.9 (CH2), 27.9 (CH2). MS (ESI) 303.0 [2M+H+], 626.8 [2M+Na+]
The following compound can be prepared by the same method:
To the appropriate thiol (1.1 equiv.) in anhydrous DMF under argon at 0° C. was introduced NaH (1.2-1.4 equiv.). After 30 min, (R251) or (R228) were introduced. This solution was stirred at room temperature for 4 hours and then the crude mixture was concentrated under vacuum. This mixture was poured with 5% aqueous NaHCO3 and extracted with EtOAc. The combined organic layers were dried (MgSO4), and the solvent was removed under reduced pressure. The crude product was purified either by recrystallization from CH2Cl2/PE to afford R263, R284 and R283, or trituration in MeOH and filtration to give R264, R272, R273, R274 and R275 or flash chromatography to afford R279 and R280.
Yield: 23%; mp 238-239° C. (MeOH); IR (KBr): 3436, 3200, 3113, 3026, 2995, 2847, 2749, 1669, 1618, 1592, 1454, 1382, 1264, 732, 522 cm−1; 1H-NMR (300 MHz, DMSO-d6): δ12.47 (bs, 1H), 9.05 (s, 1H), 8.83 (d, 1H, J=2.5 Hz), 8.50 (d, 1H, J=2.5 Hz), 8.16 (dd, 1H, J=1.5, 8.7 Hz), 7.60 (d, 1H, J=8.7 Hz), 7.35 (m, 4H), 7.20 (t, 1H, J=7.2 Hz), 4.74 (s, 2H); 13C-NMR (75 MHz, DMSO-d6): δ193.3 (C), 150.9 (C), 144.9 (CH) 142.8 (C), 135.6 (C), 129.5 (C), 128.9 (CH), 128.8 (CH), 128.3 (CH), 127.9 (CH), 125.9 (CH), 124.2 (CH), 122.7 (C), 119.42 (C), 116.8 (C), 111.5 (CH), signal for CH2 missing: must be behind DMSO 1H residual signal; MS (+ESI) 353.1 [M+H+], HRMS Calculated for C19H13ClN2OS: 352.0437. Found: 352.0437.
Yield: 67%; Mp 209-210° C. (Meoh); Ir (Kbr): 3400, 3200, 3113, 3031, 2842, 1669, 1572, 1413, 1259, 742 cm−1, 1H-NMR (300 MHz, DMSO-d6): δ12.47 (bs, 1H), 9.09 (s, 1H), 8.85 (s, 1H), 8.49 (s, 1H), 8.34 (d, 1H, J=3.6 Hz), 8.18 (d, 1H, J=8.3 Hz), 7.62 (m, 2H), 7.39 (d, 1H, J=7.9 Hz), 7.09 (t, 1H, J=5.7 Hz), 4.91 (s, 2H); 13C-NMR (75 MHz, DMSO-d6): 6192.9 (C), 157.4 (C), 150.9 (C) 149.3 (CH), 144.6 (CH), 142.8 (C), 136.7 (CH), 128.8 (CH), 128.2 (C), 123.9 (CH), 122.7 (C), 121.7 (CH), 119.9 (CH), 119.43 (C), 116.8 (C), 111.5 (CH), 36.9 (CH2); MS (+ESI) 354.1 [M+H+], HRMS Calculated for C18H12ClN3OS: 353.0390. Found: 353.0391.
Yield: 54%; mp 241-242° C. (MeOH); IR (KBr): 3451, 3205, 3113, 2995, 2908, 2852, 2760, 2703, 1669, 1602, 1413, 998, 747 cm−1; 1H-NMR (300 MHz, DMSO-d6): δ12.52 (bs, 1H), 9.15 (d, 1H, J=1.2 Hz), 8.88 (d, 1H, J=2.3 Hz), 8.52 (d, 1H, J=2.3 Hz), 8.22 (dd, 1H, J=1.2, 8.7 Hz), 8.01 (dd, 1H, J=0.7, 7.9 Hz), 7.78 (dd, 1H, J=0.8, 7.5 Hz), 7.65 (d, 1H, J=8.7 Hz), 7.44 (td, 1H, J=1.4, 7.7 Hz), 7.35 (td, 1H, J=1.2, 7.5 Hz), 5.27 (s, 2H); 13C-NMR (75 MHz, DMSO-d6): δ191.7 (C), 166.1 (C), 152.6 (C), 150.9 (C), 145.1 (CH), 143.0 (C), 134.8 (C), 128.9 (CH), 127.8 (CH), 127.7 (C), 126.4 (CH), 124.5 (CH), 124.1 (CH), 122.8 (C), 121.9 (CH), 121.1 (CH), 119.5 (C), 116.8 (C), 111.72 (CH), 41.07 (CH2); MS (ESI) 410.1 [M+H+]; HRMS Calculated for C20H12ClN3OS2: 409.0110. Found: 409.0110.
Yield: 50%; mp 209-210° C. (MeOH); IR (KBr): 3267, 3047, 2959, 2350, 1659, 1618, 1587, 1377, 1259, 1157, 732, 747 cm−1; 1H-NMR (300 MHz, DMSO-d6): δ12.64 (s, 1H), 12.49 (s, 1H), 9.10 (s, 1H), 8.82 (d, 1H, J=1.3 Hz), 8.50 (s, 1H), 8.19 (d, 1H, J=8.3 Hz), 7.62 (d, 1H, J=8.7 Hz), 7.46 (bs, 1H), 7.38 (d, 1H, J=4.3 Hz), 7.11 (m, 2H), 5.15 (s, 2H); 13C-NMR (75 MHz, DMSO-d6): δ192.4 (C), 150.9 (C), 149.7 (C) 145.0 (CH), 142.9 (CH), 132.2 (C), 128.9 (CH), 127.7 (CH), 124.0 (CH), 122.8 (C), 122.3 (C), 121.5 (CH), 119.4 (C), 116.8 (C), 111.6 (CH), 109.5 (C); signal for CH2 missing: must be behind DMSO 1H residual signal, MS (ESI) 393.1 [M+H+], 806.9 [2M+Na+]
Yield: 44%; mp 176-177° C. (CH2Cl2/PE); IR (KBr): 3441, 3103, 3057, 2945, 2781, 1654, 1613, 1588, 1449, 1372, 1260, 763 cm−1; 1H-NMR (300 MHz, DMSO-d6): δ12.44 (bs, 1H), 9.00 (d, 1H, J=1.3 Hz), 8.84 (d, 1H, J=2.2 Hz), 8.50 (d, 1H, J=2.2 Hz), 8.13 (dd, 1H, J=1.7, 8.6 Hz), 7.59 (d, 1H, J=8.6 Hz), 5.76 (s, 2H), 2.65 (t, 2H, J=6.6 Hz), 2.44 (t, 2H, J=6.6 Hz), 2.11 (s, 6H, CH3); 13C-NMR (75 MHz, DMSO-d6): δ194.2 (C), 150.9 (C), 144.9 (CH), 142.7 (C), 128.8 (CH), 127.9 (CH), 127.6 (C), 124.1 (CH), 122.7 (C), 119.4 (C), 116.8 (C), 111.5 (CH), 58.4 (CH2), 44.8 (CH3), 36.9 (CH2), 29.3 (CH2); MS (−ESI) 346.2 [M−H−]
Yield: 56%; mp 137-138° C. (CH2Cl2/PE); IR (KBr): 3462, 3114, 3037, 2970, 1659, 1618, 1593, 1444, 1270, 533 cm−1; 1H-NMR (300 MHz, DMSO-d6): δ 12.44 (bs, 1H), 8.99 (d, 1H, J=1.1 Hz), 8.83 (d, 1H, J=2.4 Hz), 8.49 (d, 1H, J=2.4 Hz), 8.13 (dd, 1H, J=1.7, 8.7 Hz), 7.59 (d, 1H, J=8.7 Hz), 4.07 (s, 2H), 2.63 (s, 2H), 2.49 (m, 4H), 0.93 (t, 6H, J=7.2 Hz); 13C-NMR (75 MHz, DMSO-d6): δ 194.3 (C), 150.9 (C), 144.9 (CH), 142.7 (C), 128.8 (CH), 128.0 (CH), 127.5 (C), 124.1 (CH), 122.7 (C), 119.4 (C), 116.8 (C), 111.5 (CFI), 51.9 (CH2), 46.2 (CH3), 36.7 (CH2), 28.9 (CH2), 11.7 (CR3); MS (ESI) 376.1 [M+H+]
Yield: 72%; mp 229-230° C.; IR (KBr): 3431, 3108, 3037, 2847, 1669, 1629, 1598, 1572, 1444, 1383, 1260, 758 cm−1; 1H-NMR (300 MHz, DMSO-d6): δ12.48 (bs, 1H), 9.06 (bs, 1H), 8.83 (d, 1H, J=2.3 Hz), 8.51 (d, 1H, J=2.2 Hz), 8.168 (d, 1H, J=8.7 Hz), 7.59-7.62 (m, 2H), 7.37-7.40 (m, 2H), 7.23-7.28 (m, 1H), 4.84 (s, 21-1); 13C-NMR (75 MHz, DMSO-d6): δ 193.1 (C), 150.8 (C), 145.0 (CH) 142.9 (C), 138.7 (C), 131.6 (C), 130.8 (CH), 129.8 (CH), 128.8 (CH), 128.6 (CH), 127.9 (CH), 126.9 (CH), 124.2 (CH), 122.7 (C), 122.16 (C), 119.4 (C), 116.8 (C), 111.5 (CH), signal for CH2 missing: must be behind DMSO 1H residual signal; MS (−ESI) 431.0 [M−H−], 466.7 [M+Cl−]
Yield: 41%; mp 167-168° C.; IR (KBr): 3436, 3200, 3113, 3026, 2995, 2847, 2749, 1669, 1618, 1592, 1454, 1382, 1264, 732, 522 cm−1; 1H-NMR (300 MHz, DMSO-d6): δ12.45 (bs, 1H), 9.02 (s, 1H), 8.82 (d, 1H, J=2.3 Hz), 8.50 (d, 1H, J=2.3 Hz), 8.15 (dd, 1H, J=1.5, 8.6 Hz), 7.59 (d, 1H, J=8.6 Hz), 7.24-7.30 (m, 2H), 6.89-6.94 (m, 3H); 13C-NMR (75 MHz, DMSO-d6): δ194.3 (C), 158.1 (C), 150.1 (C) 144.9 (CH), 142.7 (C), 129.5 (CH), 128.8 (CH), 128.8 (CH), 127.9 (CH), 124.1 (CH), 120.7 (CH), 114.5 (CH), 111.5 (CH), 66.7 (CH2), 37.2 (CH2), 116.8 (C), 30.8 (CH2), signal for CH2 missing: must be behind DMSO 1H residual signal; MS (−ESI) 395.1 [M−H−]
The crude product was purified by flash chromatography (CH2Cl2/EtOAc 3:1) to afford R282 in 57% yield as a yellow solid, 1H-NMR (300 MHz, DMSO-d6): δ 12.48 (bs, 1H), 9.06 (s, 1H), 8.88 (d, 1H, J=2.5 Hz), 8.50 (d, 1H, J=2.5 Hz), 8.14 (dd, 1H, J=1.5, 8.7 Hz), 7.60 (d, 1H, J=8.7 Hz), 4.93 (s, 2H), 4.09 (t, 2H, J=8.1 Hz), 3.46 (t, 2H, J=8.1 Hz); MS (ESI) m/z 361.9 [M+H+]
The crude product was purified by flash chromatography (EtOAc/PE 6:4) to afford R301 in 55% yield as a yellow solid, 1H-NMR (300 MHz, DMSO-d6): δ 12.5 (bs, 1H), 9.12 (s, 1H), 8.84 (s, 1H), 8.50 (s, 1H), 8.20 (d, 1H, J=9.0 Hz), 7.84 (d, 1H, J=8.9 Hz), 7.63 (d, 1H, J=8.5 Hz), 7.33 (s, 1H), 6.97 (dd, 114, J=2.1. 9.0 Hz), 5.24 (s, 2H), 2.64 (s, 3H); 13C-NMR (75 MHz, DMSO-d6): δ 191.7 (C), 167.0 (C), 161.8 (2C), 158.7 (C), 153.9 (C), 145.0 (CH), 142.9 (C), 128.9 (CH), 127.6 (CH), 126.3 (CH), 124.1 (CH), 122.7 (C), 122.0 (CH), 119.5 (C), 116.7 (C), 113.7 CH), 111.7 (CH), 104.4 (CH), 55.4 (CH3), 41.0 (CH2); MS (ESI) m/z 440.1 [M+H+]
The crude product was purified by trituration with methanol and filtration to afford R312 in 22% yield as a yellow solid, 1H-NMR (300 MHz, DMSO-d6): δ 12.45 (bs, 1H), 8.99 (d, 1H, J=1.3 Hz), 8.42 (d, 1H, J=2.5 Hz), 8.49 (d, 1H, J=2.4 Hz), 8.13 (dd, 1H, J=1.7, 8.7 Hz), 7.58 (d, 1H, J=8.7 Hz), 4.5 (bs, 1H), 4.05 (s, 2H), 3.45-3.43 (m, 2H), 2.58 (t, 2H, J=7.1 Hz), 1.71-1.66 (m, 2H); 13C-NMR (75 MHz, DMSO-d6): δ 194.2 (C), 144.9 (C), 142.7 (C), 128.7 (CH), 127.9 (CH), 127.5 (C), 124.1 (CH), 122.7 (C), 119.4 (C), 116.8 (C), 111.4 (CH), 59.4 (CH2), 36.8 (CH2), 31.9 (CH2), 28.3 (CH2), MS (ESI) m/z 335.1 [M+H+], 690.8 [2M+Na+]; HRMS (EI): Calcd for C16H15ClN2O2S: 335.0621. Found: 335.0624.
Purification of the crude solid performed by crystallization from CH2Cl2/PE to afford a yellow solid. Yield=67%. mp 177.7° C.; IR (KBr): 3446, 3195, 3139, 3052, 2965, 2801, 1659, 1623, 1592, 1403, 1331, 1254, 1203, 1123, 926, 814, 773, 537 cm−1; 1H-NMR (300 MHz, DMSO-d6): δ12.47 (bs, 1H), 8.96 (s, 1H), 8.70 (d, 1H, J=7.9 Hz), 8.12 (d, 1H, J=7.9 Hz), 7.60 (d, 1H, J=7.9 Hz), 7.38 (d, 1H, J=8.3 Hz), 4.08 (s, 2H), 3.33 (s, 2H), 2.60 (m, 4H), 2.43 (s, 2H), 0.92 (t, 6H, J=1.3 Hz); 13C-NMR (75 MHz, DMSO-d6): δ 194.3 (C), 151.7 (C), 146.9 (C), 141.7 (C), 132.0 (CFI), 127.7 (C), 127.4 (CH), 123.4 (CH), 119.7 (C), 115.5 (CH), 114.5 (C), 111.4 (CH), 51.9 (CH2), 46.1 (CH2), 36.7 (CH2), 29.0 (CH2), 11.7 (CH3).
Purification of the crude solid performed by trituration from Et2O to afford a yellow solid. Yield=60%; mp 255.9° C.; IR (KBr): 3190, 3129, 3052, 2975, 2893, 1659, 1918, 1597, 1571, 1479, 1397, 1280, 1172, 1126, 921, 732, 435 cm−1; 1H-NMR (300 MHz, DMSO-d6): δ12.50 (bs, 1H), 9.00 (s, 1H), 8.69 (d, 1H, J=8.1 Hz), 8.15 (dd, 1H, J=1.6, 8.6 Hz), 7.61 (d, 1H, J=8.7 Hz), 7.38 (m, 3H), 7.31 (t, 2H, J=7.6 Hz), 7.19 (t, 1H, J=7.2 Hz), 4.75 (s, 2H); 13C-NMR (75 MHz, DMSO-d6): δ193.4 (C), 151.8 (C), 147.1 (C) 141.9 (C), 135.6 (C), 132.2 (CH), 128.9 (CH), 128.3 (CH), 127.9 (C), 127.4 (CH), 125.9 (CH), 123.6 (CH), 119.7 (C), 115.7 (CH), 114.7 (C), 111.6 (CH), 39.8 (CH2); MS (−ESI) 726.8 [2M+Na+], (−ESI) 351.1 [M−H−], 740.6 [2M+Cl−]
The following compounds can be prepared by the same method:
To a 0.2 M stirred suspension of the α-carboline derivative (200 mg) in anhydrous CH2Cl2 was added AlCl3 (4.5 equiv.) and bromoacetyl bromide (2.1 equiv.), at room temperature under inert atmosphere. The mixture was stirred at reflux until completion of the reaction (followed by t.l.c.). The resulting mixture was then cautiously quenched at 0° C. with H2O. It was extracted with the mixture of EtOAc/DMF (99:1). The resulting organic layer was washed with NaHCO3 saturated aqueous solution and brine, dried over MgSO4, filtered and solvents were removed under reduced pressure. 2-Bromo-1-(9H-pyrido[2,3-b]indol-6-yl)ethanone was obtained in 61% yield after trituration of the crude product in MeOH and filtration
1H NMR (300 MHz, DMSO-d6): δ 8.99 (d, 1H, J=1.7 Hz), 8.80 (dd, 1H, J=1.5, 7.7 Hz), 8.66 (d, 1H, J=9.0 Hz), 8.64 (d, 1H, J=1.7, 3.7 Hz), 8.26 (dd, 1H, J=1.7, 9.0 Hz), 7.60 (dd, 1H, J=4.5, 7.7 Hz), 5.42 (s, 2H), 5.0 (s, 1H)
A solution of potassium thiocyanate (73 mg, 0.73 mmol, 2 equiv.) in Ethanol (1 mL), was added dropwise a solution of compound 2-Bromo-1-(9H-pyrido[2,3-b]indol-6-yl)ethanone (150 mg, 0.366 mmol) in ethanol (1 mL). The mixture was stirred at reflux for 1 hour. The resulting mixture was then cautiously quenched at 0° C. with H2O. It was extracted with EtOAc. The resulting organic layer was washed with NaCl saturated aqueous solution, dried over MgSO4, and filtered. Solvent was removed under reduced pressure The crude product was triturated and filtered. The resulting product (82 mg, 0276 mmol) was dissolved in glacial acetic acid (1 mL), 50% sulfuric acid (200 μL) was added, and then the mixture was heated to reflux for 1 hour. The resulting mixture was quenched at 0° C. with H2O. The aqueous layer is treated with Na2CO3 until pH=6 and then extracted with AcOEt (3×20 ml). The organic layers was washed with NaCl saturated aqueous solution, dried over MgSO4, and filtered. Solvent was removed under reduced pressure. A white powder was obtained in 23% yield after trituration of the crude product in MeOH and filtration; 1H NMR (300 MHz, DMSO-d6): δ 11.96 (bs, 1H), 11.78 (bs, 1H), 8.48-8.43 (m, 3H), 7.74 (dd, 1H, J=1.9, 8.5 Hz), 7.52 (d, 1H, J=8.5 Hz), 7.25 (dd, 1H, J=5.5, 7.2 Hz), 6.69 (d, 1H, J=1.9 Hz), 4.75 (bs, 1H); MS (ESI) m/z 268.1 [M+H+]
The following compounds can be prepared by the same method:
To a stirred suspension of 2-Bromo-1-(9H-pyrido[2,3-b]indol-6-yl)ethanone (100 mg, 0.346 mmol) in EtOH (2 mL) was added thiourea (26 mg, 1 equiv.) and the mixture was heated at 70° C. for 2 h. After cooling to room temperature, the solvent was evaporated to dryness. The resulting solid was stirred in a mixture of EtOAc/saturated aqueous NaHCO3 solution (2:1) until dissolution, and then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. Compound 13 was obtained as a white powder in 99% yield after trituration of the crude product in MeOH and filtration; 1H-NMR (300 MHz; DMSO-d6): δ 12.07 (bs, 1H), 8.57-8.45 (m, 2H), 8.47 (dd, 1H, J=1.5, 4.9 Hz), 7.85 (dd, 1H, J=1.7, 8.5 Hz), 7.57 (d, 1H, J=8.5 Hz), 7.28 (dd, 1H, J=5.0, 7.7 Hz), 7.08 (s, 1H); 13C-NMR (75 MHz; DMSO-d6): δ 170.1 (C), 150.9 (C), 145.1 (CH), 140.3 (C), 139.2 (C), 130.0 (CH), 125.0 (CH), 121.1 (C), 120.4 (C), 119.2 (CH), 116.0 (C), 115.6 (CH), 112.0 (CH), 100.7 (CH); MS (ESI) m/z 267.1 [M+H+]; HRMS (ESI): Calcd for C14H10N4S: 267.0704. Found: 267.0703
The following compounds can be prepared by the same method:
To a mixture of 4-(4-methylpiperazine)benzoic acid (741 mg, equiv.) in anhydrous DMF (1.6 mL) was added a solution of 4-(9H-pyrido[2,3-b]indol-6-yl)thiazol-2-amine (200 mg, 0.79 mmol) in anhydrous DMF (1.6 mL), a solution of EDCI (606 mg, equiv.) in dry DMF (1.6 mL) and DMAP (16 mg, equiv.). The reaction mixture was stirred at room temperature for 12 h and DMF was evaporated in vacuo. The product was purified by column chromatography (CH2Cl2/MeOH 9:1) to afford R222 in 13% yield. 1H-NMR (300 MHz; DMSO-d6): δ 12.74 (bs, 1H), 11.90 (bs, 1H), 8.73 (s, 1H), 8.49 (d, 1H, J=7.3 Hz), 8.44 (d, 1H, J=3.6 Hz), 8.14-8.06 (m, 3H), 7.62 (s, 1H), 7.55 (d, 1H, J=8.5 Hz), 7.48 (d, 2H, J=8.1 Hz), 7.24 (dd, 1H, J=5.1, 7.6 Hz), 3.57 (s, 3H), 2.50 (bs, 4H), 2.26 (bs, 4H); MS (ESI) m/z 483.2 [M+H+].
The following compounds can be prepared by the same method:
To the appropriate 4-(chloro-9H-pyrido[2,3-b]indol-6-yl)-4-oxo-butyric acid in anhydrous (0.2M) DMF were added amine (4 equiv.), N-Ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (4 equiv.) and a catalytic amount of DMAP under argon atmosphere. The reaction was stirred at room temperature for 12 h and then the resulting mixture was then cautiously quenched at 0° C. with H2O. The mixture was extracted with EtOAc. The resulting organic layer was washed with a saturated aqueous NaHCO3 solution and brine, dried over MgSO4, filtered, and solvents were removed under reduced pressure. Trituration of the crude residue from dichloromethane then filtration and washing with PE afforded desired compounds.
Yield=45%. mp 232.6° C.; IR (KBr): 3446, 3190, 3149, 2934, 2796, 1638, 1613, 1449, 1382, 1264, 1228, 1167, 527 cm−1; 1H-NMR (300 MHz, DMSO-d6): δ 12.40 (bs, 1H), 9.02 (s, 1H), 8.89 (d, 1H, J=2.2 Hz), 8.49 (d, 1H, J=2.4 Hz), 8.13 (dd, 1H, J=1.5, 8.7 Hz), 7.59 (d, 1H, J=8.6 Hz), 3.52 (t, 2H, J=4.5 Hz), 3.43 (t, 2H, J=4.2 Hz), 3.36 (m, 2H) 2.74 (t, 2H, J=5.9 Hz), 2.35 (t, 2H, J=3.9 Hz), 2.24 (t, 2H, J=4.9 Hz), 2.20 (s, 3H); 13C-NMR (75 MHz, DMSO-d6): δ 197.8 (C), 169.7 (C), 150.8 (C), 144.8 (CH), 142.5 (C), 129.2 (C), 128.8 (CH), 127.2 (CH), 123.3 (CH), 122.6 (C), 119.3 (C), 116.9 (C), 111.4 (CH), 54.8 (CH2), 54.3 (CH2), 45.7 (CH3), 44.6 (CH2), 41.1 (CH2), 32.9 (CH2), 26.8 (CH2); MS
Yield=55%. mp 236.4° C.; ER (KBr): 3451, 3200, 3149, 2934, 2790, 1643, 1592, 1442, 1397, 1356, 1254, 1177, 1121, 993, 927, 794, 773 cm−1; 1H-NMR (300 MHz, DMSO-d6): δ12.43 (bs, 1H), 8.96 (s, 1H), 8.73 (d, 1H, J=7.2 Hz), 8.11 (d, 1H, J=7.2 Hz), 7.59 (d, 1H, J=8.3 Hz), 7.36 (d, 1H, J=6.9 Hz), 3.52 (s, 2H), 3.43 (s, 2H), 3.36 (m, 2H), 2.73 (t, 2H, J=5.9 Hz), 2.34 (s, 2H), 2.23 (s, 2H), 2.19 (s, 3H); 13C-NMR (75 MHz, DMSO-d6): δ197.8 (C), 169.6 (C), 151.7 (C), 146.9 (C), 141.6 (C), 132.1 (CH), 129.4 (C), 126.6 (CH), 122.6 (CH), 119.6 (C), 115.4 (CH), 114.6 (C), 111.3 (CH), 54.7 (CH2), 54.3 (CH2), 45.6 (CH3), 44.6 (CH2), 41.0 (CH2), 32.8 (CH2), 26.7 (CH2); MS
Yield=47%. mp 227.5° C.; IR (KBr): 3272, 3108, 2898, 1669, 1643, 1618, 1505, 1479, 1449, 1377, 1239, 1162, 1024, 814, 527 cm−1; 1H-NMR (300 MHz, DMSO-d6): δ 12.39 (bs, 1H), 9.02 (s, 1H), 8.88 (s, 1H), 8.49 (s, 1H), 8.37 (bs, 1H), 8.13 (d, 1H, J=7.5 Hz), 7.59 (d, 1H, J=8.3 Hz), 7.19 (d, 2H, J=7.7 Hz), 6.87 (d, 2H, J=7.9 Hz), 4.21 (s, 2H), 3.72 (s, 3H), 3.38 (s, 2H), 2.58 (s, 2H); 13C-NMR (75 MHz, DMSO-d6): δ197.8 (C), 171.1 (C), 158.0 (C), 150.8 (C), 144.7 (CH), 142.5 (C), 132.5 (C), 128.9 (C), 128.7 (CH), 128.4 (CH), 127.1 (CH), 123.2 (CH), 122.5 (C), 119.3 (C), 116.8 (C), 113.5 (CH), 111.3 (CH), 54.9 (CH3), 41.5 (CH2), 33.2 (CH2), 29.4 (CH2); MS
The following compounds can be prepared by the same method:
Solid ammonium acetate (509 mg, 6.6 mmol, 15 equiv.) was added to solution of R267 (100 mg, 0.44 mmol) in nitromethane (25 mL). The mixture was vigorously stirred and boiled at 120-130° C. for 48 h. Then the mixture was cooled in an ice bath and concentrated under reduced pressure. Trituration of the crude residue from methanol followed by filtration afforded R266 (69 mg, 57%). 1H-NMR (300 MHz, DMSO-d6): δ 12.47 (bs, 1H), 8.76 (bs, 1H), 8.64 (d, 1H, J=2.1 Hz), 8.50 (d, 1H, J=2.5 Hz), 8.28 (d, 1H, J=13.5 Hz), 8.21 (d, 1H, J=13.5 Hz), 8.01 (bd, 1H, J=8.9 Hz), 7.58 (d, 1H, J=8.1 Hz); 13C-NMR (75 MHz, 80° C. DMSO-d6): δ 150.5 (C), 144.6 (CH), 141.8 (C), 139.9 (CH), 135.3 (CH), 128.5 (CH), 127.9 (CH), 124.0 (CH), 122.3 (C), 121.6 (C), 119.9 (C), 115.9 (C), 111.9 (CH); MS (ESI) m/z 272 [M−H−], HRMS (ESI): Calcd for C13H8ClN3O2: 274.0383. Found: 274.0386.
At 0° C., sodium hydride (60% in oil, 78 mg, 1.95 mmol 1.1 equiv.) was added to a stirred a solution of R266 (405 mg, 1.77 mmol) in anhydrous THF (12.4 mL). After stirring at 0° C. for 20 min, benzenesulfonyl chloride (273 μL, 2.13 mmol, 1.2 equiv.) was added dropwise. The reaction mixture was stirred for 12 h and then poured with 5% aqueous saturated NaHCO3 solution and extracted with EtOAc (3×20 mL). The combined organic layers were dried (MgSO4), and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (CH2Cl2/PE 8:2) to afford 13 in 80% yield as a white solid, 1H-NMR (300 MHz, CDCl3): δ 10.11 (s, 1H), 8.59 (d, 1.14, J=8.9 Hz), 8.51 (d, 1H, J=2.3 Hz), 8.41 (d, 1H, J=1.4 Hz), 8.20 (d, 1H, J=2.3 Hz), 8.17-8.14 (m, 2H), 8.09 (dd, 1H, J=1.4, 8.9 Hz), 7.57 (tt, 1H, J=1.1, 7.3 Hz), 7.47 (d, 1H, J=7.9 Hz), 7.45 (td, 1H, J=1.5, 7.5 Hz); 13C-NMR (75 MHz, CDCl3): δ 191.0 (C), 149.3 (C), 146.5 (CH), 141.9 (C), 138.2 (C), 134.7 (CH), 132.5 (C), 130.5 (CH), 129.3 (2 CH), 128.6 (CH), 128.1 (C), 127.9 (2 CH), 122.9 (CH), 122.2 (C), 119.0 (C), 115.4 (CH); MS (ESI) m/z 371 [M+H+]
Solid ammonium acetate (121 mg, 1.1 equiv. 1.56 mmol) was added to solution of 9-benzenesulfonyl-3-chloro-9H-pyrido[2,3-b]indole-6-carbaldehyde (524 mg, 1.42 mmol) in nitromethane (5.5 mL). The mixture was vigorously stirred and boiled at 100° C. for 2 h. Then the mixture was cooled in an ice bath and concentrated under reduced pressure. Trituration of the crude residue from ethanol followed by filtration afforded 14 (528 mg, 89.5%), 1H-NMR (300 MHz, CDCl3): δ 8.81 (d, 1H, J=1.6 Hz), 8.70 (d, 1H, J=2.3 Hz), 8.65 (d, 1H, J=2.3 Hz), 8.42 (d, 1H, J=8.8 Hz), 8.25 (s, 2H), 8.17 (dd, 1H, J=1.6, 8.9 Hz), 8.09 (d, 1H, J=7.2 Hz), 8.09 (d, 1H, J=8.8 Hz), 7.71 (t, 1H, J=7.4 Hz), 7.60 (d, 1H, J=8.1 Hz), 7.58 (t, 1H, J=7.4 Hz); 13C-NMR (75 MHz, DMSO-d6): δ 148.7 (C), 146.0 (CH), 139.4 (C), 138.7 (CH), 137.9 (CH), 137.3 (C), 135.2 (CH), 130.9 (CH), 129.8 (2 CH), 129.5 (CH), 127.3 (C), 127.1 (2 CH), 126.5 (C), 123.8 (CH), 122.2 (C), 118.9 (C), 115.0 (CH), MS (ESI) m/z 414 [M+H+]
NaBH4 (46 mg, 2.5 equiv.) was added in small portions to a suspension of 14 (200 mg, 0.48 mmol) and 240 mg of silica (40-60 mesh) in a solution of chloroform and isopropanol (11.6 mL, 8.6:3). The solution was stirred for 1 h 30 at room temperature and then filtered through celite. Solvents were removed under reduced pressure and the crude product was purified by flash chromatography (CH2Cl2/PE 7:3) to afford 15 in 73% yield as a white solid, 1H-NMR (300 MHz, CDCl3): δ 8.49 (d, 1H, J=1.2 Hz), 8.41 (d, 1H, J=8.6 Hz), 8.14-8.10 (m, 3H), 7.74 (bs, 1H), 7.55 (t, 1H, J=7.5 Hz), 7.45-7.40 (m, 3H), 4.70 (t, 2H, J=7.1 Hz), 3.46 (t, 1H, J=7.1 Hz), 13C-NMR (75 MHz, CDCl3): δ 162.4 (C), 149.0 (C), 145.8 (CH), 138.4 (C), 137.7 (C), 134.3 (CH), 131.9 (C), 129.9 (CH), 129.2 (2 CH), 128.2 (CH), 127.7 (2C), 122.3 (C), 121.0 (CH), 119.4 (C), 115.7 (CH), 76.4 (CH2), 33.2 (CH2), MS (ESI) m/z 416 [M+H+]
To a solution of 15 (72 mg, 0.17 mmol) in MeOH (1 mL) was added a catalytic amount of Ni Raney. This mixture was stirred overnight at 50° C. under nitrogen atmosphere. The solids were filtered off and the filtrate evaporated to give 16. 1H-NMR (300 MHz, DMSO-d6): δ 8.78 (d, 1H, J=2.4 Hz), 8.60 (d, 1H, J=2.4 Hz), 8.30 (d, 1H, J=8.7 Hz), 8.14 (bs, 1H), 8.04 (d, 1H, J=8.7 Hz); 8.02 (d, 1H, J=7.2 Hz), 7.70 (t, 1H, J=7.2 Hz), 7.59-7.54 (m, 3H), 6.74 (bs, 2H); 3.05 (m, 2H), 2.96 (m, 2H); MS (ESI) m/z 386 [M-NH3+], 386 [M+H+], 408 [M+Na+].
To a cooled mixture (0° C.) of 16 (65 mg, 0.17 mmol) in CH2Cl2 (3 mL) were added Et3N (100 μL, 4.2 equiv.) and benzoyl chloride (30 μL, 1.5 equiv.). The mixture was stirred for 12 h at room temperature. The resulting mixture was then quenched at 0° C. with NaHCO3. It was extracted with the mixture of EtOAc. The resulting organic layer was washed with saturated aqueous NaHCO3 solution and brine, dried over MgSO4, filtered and solvents were removed under reduced pressure. The crude product was purified by flash chromatography (EtOAc/PE 1:1) to afford 17 in 48% yield as a white solid, 1H NMR (300 MHz, CDCl3): δ 8.48 (d, 1H, J=2.3 Hz), 8.41 (d, 1H, J=8.5 Hz), 8.13-8.11 (m, 3H), 7.77 (bs, 1H), 7.70 (d, 1H, J=7.5 Hz), 7.57-7.41 (m, 7H), 6.19 (bs, 1H), 3.05 (q, 2H, J=6.9 Hz), 3.09 (t, 2H, J=6.9 Hz); MS (ESI) m/z 490 [M+H+]
At room temperature and under inert atmosphere, 1.0 M TBAF in THF (310 μL, 5 equiv.) was added a solution of 17 (30 mg, 0.061 mmol) in anhydrous THF (2.5 mL). The solution was refluxed for 2 h. The resulting mixture was then cautiously quenched at 0° C. with H2O. The mixture was extracted with EtOAc (3×10 mL). The resulting organic layers were dried over MgSO4, filtered, and solvents were removed under reduced pressure. The crude product was purified by flash chromatography (EtOAc) to afford R265 in 61% yield. 1H-NMR (300 MHz, DMSO-d6): δ 11.91 (bs, 1H), 8.65 (d, 1H, J=2.3 Hz), 8.61 (bt, 1H, J=5.5 Hz), 8.39 (d, 1H, J=2.3 Hz), 8.07 (bs, 1H), 7.82 (d, 1H, J=7.5 Hz), 7.54-7.37 (m, 5H), 3.55 (q, 2H, J=7.7 Hz), 2.98 (t, 2H, J=7.7 Hz); MS (ESI) m/z 350.2 [M+H+], 698.9 [2M+H+], 721.0 [2M+Na+], HRMS (ESI): Calcd for C20H16ClN3O: 350.1060. Found: 350.10631.
The following compounds can be prepared by the same method
Sodium hydride (60% in oil; 1.1 equiv.) was added to a stirred 0.15 M suspension of 8a-c (1 equiv.) in anhydrous THF at 0° C. After stirring at 0° C. for 20 min, benzenesulfonyl chloride (1.2 equiv.) was added dropwise. The reaction mixture was stirred for 12 h and then poured with 5% aqueous saturated NaHCO3 solution and extracted with EtOAc (3×20 mL). The combined organic layers were dried (MgSO4), and the solvent was removed under reduced pressure.
The crude product was purified by flash chromatography (CH2Cl2) to afford 19 in 88% yield as a solid. Mp 204-206° C. (CH2Cl2/PE 3:7); IR: 3060, 1614, 1573, 1448, 1380, 1371, 1187, 1173, 1128, 1088, 813, 727, 682 cm−1; 1H-NMR (300 MHz, CDCl3): δ 8.37 (d, 1H, J=8.9 Hz), 8.20 (d, 1H, J=7.2 Hz), 8.19 (d, 1H, J=8.7 Hz), 8.08 (d, 1H, J=8.1 Hz), 8.02 (d, 1H, J=1.8 Hz), 7.68 (dd, 1H, J=1.8, 8.9 Hz), 7.58-7.56 (m, 1H), 7.50-7.45 (m, 2H), 7.31 (d, 1H, J=8.1 Hz); 13C-NMR (75 MHz, CDCl3): δ 149.2 (C), 138.1 (C), 136.5 (C), 134.5 (CH), 131.4 (CH), 130.7 (CH), 129.1 (2 CH), 128.2 (2 CH), 123.8 (C), 123.6 (CH), 119.8 (CH), 117.5 (C), 116.6 (CH), 115.9 (C); MS (ESI) m/z 421 [M+H+, 79Br], 422.9 [M+H+, 81Br]; HRMS (ESI): Calcd for C17H10BrClN2O2S: [M+Na]+=442.9233. Found [M+Na]+=442.9229.
The crude product was purified by flash chromatography (CH2Cl2/PE 1:1) to afford 20 in 91% yield as a white solid; mp 242° C. (MeOH); IR: 3061, 1584, 1569, 1447, 1384, 1356, 1184, 1091, 970, 847, 815, 724 cm−1; 1H-NMR (300 MHz, CDCl3): δ 8.35 (d, 1H, J=8.9 Hz), 8.20 (s, 1H), 8.18 (s, 1H), 8.05 (d, 1H, J=8.1 Hz), 7.99 (d, 1H, J=1.5 Hz), 7.65 (dd, 1H, J=1.7, 8.9 Hz), 7.58 (t, 1H, J=7.4 Hz), 7.49-7.44 (m, 2H), 7.28 (d, 1H, J=8.1 Hz); 13C-NMR (75 MHz, CDCl3): 149.2 (C), 138.1 (C), 136.4 (C), 134.5 (CH), 131.4 (CH), 130.7 (CH), 129.2 (2 CH), 128.2 (2 CH), 123.8 (C), 123.6 (CH), 119.8 (CH), 117.5 (CH), 116.6 (C); 115.9 (C); MS (ESI) 421.0 [M+H+], 443.1 [M+Na+]; HRMS (ESI): Calcd for C17H10BrClN2O2S: [M+Na+]=442.9233. Found: [M+Na]+=442.9229.
The crude product was purified by flash chromatography (CH2Cl2/PE 1:1) to afford 21 in 85% yield as a white solid; mp 212-214° C. (CH2Cl2/PE 1:1); IR (KBr): 3122, 3059, 1607, 1579, 1558, 1432, 1384, 1349, 1193, 1183, 995, 806, 722 cm−1; 1H NMR (300 MHz, CDCl3): δ 8.50 (d, 1H, J=2.1 Hz), 8.45 (d, 1H, J=5.3 Hz), 8.40 (d, 1H, J=8.9 Hz), 8.14-8.11 (m, 2H), 7.71 (dd, 1H, J=2.1 Hz, J=8.9 Hz), 7.55 (tt, 1H, J=1.3, 7.3 Hz), 7.45-7.40 (m, 2H), 7.29 (d, 1H, J=5.3 Hz); 13C-NMR (75 MHz, CDCl3): δ 151.6 (C), 147.5 (CH), 138.8 (C), 138.3 (C), 136.4 (C), 134.5 (CH), 131.9 (CH), 129.2 (2 CH), 127.8 (2 CH), 125.9 (CH), 123.4 (C), 120.5 (CH), 117.4 (C), 116.4 (CH); 115.6 (C); MS (ESI) m/z 422.9 [M+H+], 449.2 [M+Na+]; HRMS (ESI): Calcd for C17H10BrClN2O2S: [M+Na]+=442.9233. Found: [M+Na+]=442.9233.
The crude product was purified by flash chromatography (CH2Cl2) to afford 22 in 72% yield as a white solid; 1H-NMR (300 MHz, CDCl3): δ 8.59 (dd, 1H, J=1.5, 4.9 Hz), 8.38 (d, 1H, J=9.0 Hz), 8.16 (dd, 1H, J=1.5, 7.9 Hz), 8.13 (d, 3H, J=7.9 Hz), 8.06 (d, 1H, J=2.1 Hz), 7.67 (dd, 1H, J=2.1, 9.0. Hz), 7.53 (t, 1H, J=7.4 Hz), 7.44-7.39 (m, 2H), 7.31 (dd, 1H, J=4.9, 7.9 Hz); MS (ESI) m/z 388 [M+H+];
60% sodium hydride (3 equiv.) was added to a stirred 0.4M suspension of chloro-α-carboline (1 equiv.) in anhydrous DMF at 0° C. After stirring at 0° C. for 20 min, EOM-Cl (2.5 equiv.) was added dropwise. The reaction mixture was stirred for 12 hours and then poured with 5% aqueous saturated NaHCO3 solution and extracted with EtOAc (3×20 mL). The combined organic layers were dried (MgSO4), and the solvent was removed under reduced pressure.
The product was purified by column chromatography on silica gel (CH2Cl2) to afford 23 in 89% yield as a yellow solid; 1H NMR (300 MHz, CDCl3): δ 8.42 (d, 1H, J=2.3 Hz); 8.28 (d, 1H, J=2.3 Hz); 8.03 (d, 1H, J=7.7 Hz); 7.62 (d, 1H, J=8.3 Hz); 7.56 (ddd, 1H, J=1.1, 7.1 Hz); 7.34 (ddd, 1H, J=1.1, 8.1 Hz), 5.90 (s, 2H); 3.54 (q, 2H, J=6.9 Hz); 1.15 (t, 3H, J=6.9 Hz).
The product was purified by column chromatography on silica gel (CH2Cl2/EP 9/1) to afford 24 in 55% yield as a white solid; 1H NMR (300 MHz, CDCl3): δ 8.47 (d, 1H, J=7.9 Hz); 8.34 (d, 1H, J=5.3 Hz); 7.67 (d, 1H, J=8.3 Hz); 7.57 (td, 1H, J=1.3, 7.3 Hz); 7.37 (td, 1H, J=1.1, 8.1 Hz); 7.19 (d, 1H, J=5.3 Hz), 5.92 (s, 2H); 3.54 (q, 2H, J=6.9 Hz); 1.15 (t, 3H, J=6.9 Hz); 13C-NMR (75 MHz, CDCl3): δ 152.8 (C), 146.0 (C), 139.5 (C), 138.2 (C), 127.7 (CH), 123.4 (CH), 121.3 (CH), 120.0 (C), 116.9 (CH), 114.2 (CH), 110.4 (CH), 71.3 (CH2), 64.5 (CH2), 15.1 (CH3);
The product was purified by column chromatography on silica gel (CH2Cl2/EP 1/1) to afford 25 in 99% yield as a white solid; 1H NMR (300 MHz, CDCl3): δ 8.17 (d, 1H, J=7.9 Hz); 7.99 (d, 1H, J=7.7 Hz); 7.64 (d, 1H, J=8.3 Hz); 7.53 (td, 1H, J=1.0, 7.3 Hz); 7.33 (td, 1H, J=1.0, 7.7 Hz); 7.18 (d, 1H, J=7.9 Hz), 5.92 (s, 2H); 3.54 (q, 2H, J=6.9 Hz); 1.15 (t, 3H, J=6.9 Hz); 13C-NMR (75 MHz, CDCl3): δ 151.2 (C), 147.6 (C), 139.4 (C), 130.4 (CH) 127.2 (CH), 121.3 (CH), 120.8 (CH), 120.4 (C), 115.8 (CH), 114.6 (C), 110.8 (CH), 71.1 (CH2), 64.4 (CH2), 15.0 (CH3);
At room temperature and under inert atmosphere, Pd(PPh3)4 (0.08 equiv.), boronic acid (1.1 equiv.), and a 0.3M solution of K2CO3 (3 equiv.) in H2O was added to a 0.1M suspension of 9a-c in anhydrous 1,4-dioxane or THF. This solution was stirred at 100° C. or 70° C. respectively for 12 h. After cooling to room temperature, the solution was filtered through celite and solvents were removed under reduced pressure.
The crude product was purified by flash chromatography (CH2Cl2/PE 7:3) to afford 26 in 75% yield as a yellow solid; mp>220° C. (CH2Cl2/PE 6:4); IR: 3016, 1607, 1683, 1520, 1473, 1361, 1216, 1182, 1091, 978, 822, 725 cm−1; 1H-NMR (300 MHz, CDCl3): δ 8.50 (d, 1H, J=8.9 Hz), 8.50 (d, 1H, J=2.3 Hz), 8.19 (d, 1H, J=2.3 Hz), 8.15-8.12 (m, 2H), 8.02 (d, 1H, J=1.5 Hz), 7.78 (dd, 1H, J=1.5, 8.9 Hz), 7.60-7.51 (m, 3H), 7.45-7.40 (m, 2H), 7.02 (dt, 1H, J=2.8, 8.9 Hz), 7.01 (d, 1H, J=8.9 Hz), 3.87 (s, 3H); 13C-NMR (75 MHz, CDCl3): δ 159.5 (C), 159.0 (C), 150.7 (C), 149.2 (C), 145.7 (CH), 138.6 (C), 137.5 (C), 134.3 (CH), 132.9 (C) 129.2 (2 CH), 128.4 (2 CH), 128.3 (CH), 128.1 (CH), 127.6 (2 CH), 122.4 (C), 120.1 (C), 118.8 (CH), 115.5 (CH), 114.6 (2 CH), 54.5 (CH3); MS (ESI) m/z 449.0 [M+H+], 471.0 [M+Na+], 918.8 [2M+Na+]; HRMS (ESI): Calcd for C24H17ClN2O3S: [M+Na+]=471.0546. Found: [M+Na+]=471.0546.
The crude product was purified by flash chromatography (CH2Cl2/PE 6:4) to afford 11b in 71% yield as a yellow solid; mp 190-192° C. (MeOH); IR (KBr): 3025, 1568, 1474, 1433, 1366, 1176, 1090, 972, 727, 683 cm−1; 1H-NMR (300 MHz, CDCl3): δ 8.50 (d, 1H, J=2.4 Hz), 8.45 (d, 1H, J=8.9 Hz), 8.18 (d, 1H, J=2.4 Hz), 8.14-8.11 (m, 2H), 8.00 (d, 1H, J=1.7 Hz), 7.76 (dd, 1H, J=1.7, 8.9 Hz), 7.57-7.52 (m, 3H), 7.45-7.36 (m, 4H), 7.29 (tt, 1H, J=1.2, 7.4 Hz), 7.23 (d, 1H, J=16.4 Hz), 7.16 (d, 1H, J=16.4 Hz); 13C NMR (75 MHz, CDCl3): δ 145.7 (CH), 138.5 (C), 137.8 (C), 137.1 (C), 134.3 (CH), 133.9 (C), 129.3 (CH), 129.2 (2 CH), 128.9 (2 CH), 128.4 (CH), 128.0 (CH), 127.8 (CH), 127.7 (CH), 127.6 (C) 127.6 (2 CH), 126.7 (2 CH), 122.4 (C), 119.9 (C), 118.6 (CH), 115.5 (CH); MS (ESI) m/z 445.0 [M+H+], 466.9 [M+Na+], 910.9 [2M+Na+]; HRMS (ESI): Calcd for C25H17ClN2O2S: [M+Na+]=467.0597. Found: [M+Na+]=467.0598.
To a solution of 9-benzenesulfonyl-6-bromo-3-chloro-9H-pyrido[2,3-b]indole (250 mg, 0.59 mmol, 1 equiv.) in anhydrous dioxane (25 ml) under Argon, Pd(PPh3)4 (102 mg, 0.09 mmol, 0.15 equiv.), K2CO3 (244 mg, 1.77 mmol, 3 equiv.), (E)-2′-(4-methoxyphenyl)ethenylboronic acid (110 mg, 0.77 mmol, 1.3 equiv.) and H2O (5 ml) are added respectively. The mixture is stirred at 100° C. overnight and then filtered over celite which is washed with AcOEt (20 ml) and THF (10 ml). The filtrate is concentrated under reduced pressure and the crude residue is purified over silica gel column (eluant CH2Cl2/PE 7:3). The product is obtained as a white solid (212 mg, 0.40 mmol) in 68% yield.
1H-NMR (300 MHz CDCl3) δ 8.50 (d, 1H, J=2.5 Hz), 8.43 (d, 1, J=8.9 Hz), 8.18 (d, 1H, J=2.3 Hz), 8.13 (d, 1H, J=7.2 Hz), 8.12 (d, 1H, J=8.7 Hz), 7.97 (d, 1H, J=1.7 Hz), 7.74 (dd, 1H, J=1.7, 8.9 Hz), 7.57-7.40 (m, 5H), 7.11 (d, 2H, J=6.8 Hz), 6.93 (d, 2H, J=8.6 Hz), 3.85 (s, 3H).
The crude product was purified by flash chromatography (CH2Cl2/PE 1:1) to afford 29 in 61% yield as a white solid; 1H-NMR (300 MHz, CDCl3): 8.61 (d, 1H, J=8.9 Hz), 8.53 (t, 1H, J=2.1 Hz), 8.26-8.24 (m, 3H), 8.21 (d, 1H, J=8.1 Hz), 8.14 (d, 1H, J=1.3 Hz), 8.01-7.97 (m, 1H), 7.84 (d, 1H, J=1.9, 8.9 Hz), 7.67 (t, 1H, J=8.1 Hz), 7.58 (dd, 1H, J=2.4, 9.8 Hz), 7.50 (d, 1H, J=7.9 Hz), 7.35 (d, 1H, J=8.1 Hz); 13C-NMR (75 MHz, CDCl3): δ 149.9 (C), 149.0 (C), 148.9 (CH), 142.3 (C), 138.3 (C), 137.7 (C), 134.9 (C), 134.5 (CH), 133.3 (CH), 130.7 (CH), 130.1 (CH), 129.1 (2 CH), 128.2 (2 CH), 127.7 (CH), 122.9 (C), 122.3 (CH), 122.2 (Cu), 119.8 (CH), 119.4 (CH), 116.8 (C), 115.7 (CH). MS (ESI) m/z 464.0 [M+H+], 485.9 [M+Na+], 948.3 [2M+Na+]; HRMS (EI): Calcd for C23H14ClN3O4S: [M+]=463.0394. Found: [M+]=463.0394.
The crude product was purified by flash chromatography (CH2Cl2/EtOAc 8:2) to afford 30 in 78% yield as a white solid; 1H-NMR (300 MHz, CDCl3): δ 8.53 (d, 1H, J=8.9 Hz), 8.51 (d, 1H, J=2.3 Hz), 8.20 (d, 1H, J=2.3 Hz), 8.15 (d, 1H, J=7.2 Hz), 8.07 (d, 1H, J=1.7 Hz), 7.82 (dd, 1H, J=1.7, 8.9 Hz), 7.61 (d, 2H, J=7.5 Hz), 7.55 (tt, 1H, J=1.3, 8.3 Hz), 7.46-7.41 (m, 4H), 3.76 (bs, 4H), 3.59 (bs, 2H), 2.52 (bs, 4H); 13C-NMR (75 MHz, CDCl3): δ 149.2 (C), 145.7 (CH), 139.3 (C), 138.5 (C), 137.7 (CH), 137.4 (C), 137.3 (C), 134.2 (CH), 129.9 (2 CH), 129.1 (2 CH), 128.4 (CH), 128.1 (CH), 127.7 (CH), 127.6 (C), 127.2 (2 CH), 122.4 (C), 119.9 (C), 119.2 (CH), 115.5 (CH), 67.1 (2 CH2), 63.1 (CH2), 53.7 (2 CH2); MS (ESI) m/z 518 [M+H+];
The crude product was purified by flash chromatography (CH2Cl2) to afford 31 in 42% yield as a white solid; 1H-NMR (300 MHz, CDCl3): δ 8.54-8.51 (m, 3H), 8.20 (d, 1H, J=2.3 Hz), 8.15-8.12 (m, 2H), 8.00 (d, 1H, J=1.7 Hz), 7.84-7.81 (m, 1H), 7.74 (dd, 1H, J=1.9, 8.7 Hz), 7.54 (d, 1H, J=7.5 Hz), 7.46-7.41 (m, 2H), 6.78 (d, 1H, J=9.2 Hz), 3.88-3.85 (m, 4H), 3.63-3.61 (m, 4H); 13C-NMR (75 MHz, CDCl3): δ 158.7 (C), 149.7 (C), 149.3 (C), 146.0 (CH), 145.8 (CH), 138.5 (C), 137.5 (C), 136.6 (CH), 164.7 (C), 134.3 (CH), 129.2 (2 CH), 128.1 (2 CH), 127.7 (CH), 127.6 (3 CH), 126.0 (C), 122.6 (C), 119.8 (C), 118.3 (CH), 115.7 (CH), 10′7.1 (CH), 66.8 (2 CH2), 45.7 (2 CH2); MS (ESI) m/z 505.1 [M+H+]; HRMS (EI): Calcd for C26H21ClN4O3S: 505.1101. Found: 505.1098.
The crude product was purified by flash chromatography (CH2Cl2/PE 3:7) to afford 32 in 58% yield as a white solid; mp 176-178° C. (CH2Cl2/PE 3:7); IR: 2932, 1606, 1587, 1567, 1519, 1465, 1450, 1369, 1172, 1039, 813, 732, 683 cm−1; 1H-NMR (300 MHz, CDCl3): δ 8.48 (d, J=8.6 Hz), 8.22 (d, 1H, J=7.5 Hz), 8.22 (d, 1H, J=8.9 Hz) 8.12 (d, 1H, J=8.1 Hz), 8.01 (d, 1H, J=1.5 Hz), 7.74 (dd, 1H, J=1.9, 8.9 Hz), 7.57 (d, 2H, 8.7 Hz), 7.56 (td, 1H, J=1.1, 8.1 Hz), 7.48-7.43 (m, 2H), 7.28 (d, 1H, J=8.1 Hz), 6.98 (d, 2H, J=8.7 Hz), 3.83 (s, 3H); 13C-NMR (75 MHz, CDCl3): δ 162.4 (C), 159.4 (C), 148.4 (C), 138.4 (C), 137.3 (C), 136.7 (C), 134.3 (CH), 133.0 (C), 130.5 (CH), 129.1 (2 CH), 128.4 (2 CH), 128.1 (2 CH), 127.6 (CH), 122.7 (C), 119.5 (CH), 118.5 (CH), 117.3 (C), 115.3 (CH), 114.5 (2 CH), 55.5 (CH3); MS (ESI) m/z 448.9 [M+H+], 471 HRMS (ESI): Calcd for C24H17ClN2O3S: [M+Na+]=471.0546. Found: [M+Na+]=471.0543.
The crude product was purified by flash chromatography (CH2Cl2/PE 3:7) to afford 33 in 64% yield as a white solid; nip 180-182° C. (CH2Cl2/PE 3:7); IR: 3022, 1587, 1571, 1470, 1447, 1380, 1172, 980, 807, 753, 728, 682 cm−1; 1H-NMR (300 MHz, CDCl3): δ 8.46 (d, 1H, J=8.9 Hz), 8.22 (d, 1H, J=7.5 Hz), 8.22 (d, 1H, J=9.0 Hz), 8.11 (d, 1H, J=8.1 Hz), 8.00 (d, 1H, J=1.8 Hz), 7.75 (dd, 1H, J=1.8, 9.0 Hz), 7.57-7.54 (m, 3H), 7.47 (t, 2H, J=7.9 Hz), 7.39 (t, 2H, J=7.1 Hz), 7.31 (d, 1H, J=8.1 Hz), 7.31 (td, 1H, J=1.1, 7.2 Hz), 7.23 (d, 1H, J=16.3 Hz), 7.17 (d, 1H, J=16.3 Hz); 13C-NMR (75 MHz, CDCl3): δ 162.4 (C), 148.5 (C), 138.4 (C), 137.2 (C), 137.1 (C); 134.3 (CH), 133.8 (C), 130.5 (CH), 129.2 (CH), 129.1 (2 CH); 128.9 (2 CH), 128.2 (2 CH), 127.9 (CH), 127.8 (CH), 127.1 (CH), 126.6 (2 CH), 122.6 (C), 119.6 (CH), 118.4 (CH), 117.1 (C), 115.3 (CH); MS (ESI) m/z 445.0 [M+H+], 467.0 [M+Na+], 910.6 [2M+Na+]; HRMS (ESI): Calcd for C25H17ClN2O2S: [M+Na+]=467.0597. Found: [M+Na+]=467.0597.
The crude product was purified by flash chromatography (CH2Cl2/PE 1:1) to afford 34 in 70% yield as a white solid; mp 209-211° C. (CH2Cl2/PE); IR: 3022, 2835, 1607, 1583, 1521, 1467, 1441, 1375, 1234, 1172, 1020, 834, 770, 690 cm−1; 1H-NMR (300 MHz, CDCl3): δ 8.56 (d, 1H, J=9.0 Hz), 8.55 (d, 1H, J=7.4 Hz), 8.43 (d, 1H, J=5.5 Hz), 8.18-8.15 (m, 2H), 7.80 (dd, 1H, J=2.1, 8.7 Hz), 7.61 (d, 2H, J=8.7 Hz), 7.54 (tt, 1H, J=1.3, 7.4 Hz), 7.45-7.40 (m, 2H), 7.29 (d, 1H, J=5.5 Hz), 7.03 (d, 2H, J=8.7 Hz), 3.87 (s, 3H); 13C-NMR (75 MHz, CDCl3): δ 159.4 (C), 151.9 (C), 146.8 (CH), 138.6 (C), 138.5 (C), 137.3 (C), 136.7 (C), 134.3 (CH), 133.2 (C), 129.1 (2 CH), 128.5 (2 CH), 128.0 (CH), 127.8 (2 CH), 122.5 (C), 121.2 (CH), 120.4 (CH), 116.8 (C), 115.0 (CH), 114.5 (2 CH); 55.5 (CH3); MS (ESI) m/z 449.0 [M+H+], 471.0 [M+Na+], 918.8 [2M+Na+]; FIRMS (ESI): Calcd for C24H17ClN2O3S: [M+Na+] 471.0546. Found: [M+Na+]=471.0545.
The crude product was purified by flash chromatography (CH2Cl2/PE 6:4) to afford 35 in 68% yield as a white solid; mp 216-218° C. (CH2Cl2/PE); IR: 3063, 2924, 1614, 1583, 1562, 1442, 1371, 1170, 1006, 995, 814, 684 cm−1; 1H-NMR (300 MHz, CDCl3): δ 8.51 (d, 1H, J=8.6 Hz), 8.51 (d, 1H, J=1.5 Hz), 8.43 (d, 1H, J=5.5 Hz), 8.15 (d, 2H, J=8.6 Hz), 7.81 (dd, 1H, J=1.5, 8.6 Hz), 7.58-7.52 (m, 3H), 7.45-7.36 (m, 4H), 7.31-7.28 (m, 1H), 7.30 (d, 1H, J=5.5 Hz), 7.27 (d, 1H, J=16.4 Hz), 7.18 (d, 1H, J=16.4 Hz); 13C-NMR (75 MHz, CDCl3): δ 162.4 (C), 149.8 (C), 146.9 (CH), 138.5 (C), 137.2 (C), 137.1 (C), 134.3 (CH), 133.8 (C), 129.2 (CH), 129.1 (2 CH), 128.9 (2 CH), 128.1 (CH), 127.9 (CH), 127.8 (2 CH), 127.3 (CH), 126.7 (2 CH), 122.4 (C), 121.2 (CH), 120.4 (CH), 116.7 (C), 115.0 (CH); MS (ESI) m/z 445.0 [M+H+], 466.9 [M+Na+], 910.8 [2M+Na+]; HRMS (ESI): Calcd for C25H17ClN2O2S: [M+Na+]=467.0597. Found: [M+Na+]=467.0598.
The following compounds can be prepared by the same method:
At room temperature and under inert atmosphere, Pd(PPh3)4 (0.08 equiv.), 4-methoxyphenyl boronic acid (2.2 equiv.), and a 0.3M solution of K2CO3 in H2O were added to a solution of 19 or 21 in anhydrous 1,4-dioxane. This solution stirred at reflux for 12 h. After cooling to room temperature, solution was filtered through celite and solvents were removed under reduced pressure.
The crude product was purified by flash chromatography (CH2Cl2/PE 1/1) to afford 36 in 90% yield as a white solid; mp 206-208° C. (CH2Cl2/PE 6:4); IR: 2993, 1607, 1591, 1518, 1464, 1167, 1039, 978, 807 cm−1; 1H-NMR (300 MHz, CDCl3): δ 8.51 (d, 1H, J=8.7 Hz), 8.22 (d, 2H, J=7.4 Hz), 8.16 (d, 1H, J=7.7 Hz), 8.15 (d, 2H, J=8.9 Hz), 8.02 (d, 1H, J=1.5 Hz), 7.72 (dd, 1H, J=1.5, 8.7 Hz), 7.66 (d, 1H, J=8.1 Hz), 7.60 (d, 2H, J=8.9 Hz), 7.48 (t, 1H, J=7.4 Hz), 7.41-7.36 (m, 2H), 7.04 (d, 2H, J=8.6 Hz), 7.02 (d, 2H, J=8.6 Hz), 3.89 (s, 3H), 3.87 (s, 3H); 13C-NMR (75 MHz, CDCl3): δ 160.8 (C), 159.3 (C), 154.6 (C), 151.3 (C), 139.9 (C), 136.9 (2×C), 133.9 (CH), 133.4 (C), 131.6 (C), 128.9 (2 CH), 128.5 (2 CH), 128.4 (2 CH), 127.8 (2 CH), 126.9 (CH), 123.7 (C), 118.4 (CH), 116.6 (C), 115.2 (CH), 115.1 (CH), 114.5 (3 CH), 114.3 (2 CH); 55.5 (2 CH3); MS (ESI) m/z 521.1 [M+H+], 543.0 [M+Na+]; HRMS (ESI): Calcd for C31H24N2O3S: [M+Na]+=543.1354. Found: [M+Na]+=543.1355.
The crude product was purified by flash chromatography (CH2Cl2/PE 1:1) to afford 37 in 89% yield as a white solid; mp 162-164° C. (CH2Cl2/PE 1:1); IR: 3010, 2965, 1608, 1515, 1464, 1232, 1170, 822 cm−1; 1H-NMR (300 MHz, CDCl3): δ 8.55 (d, 1H, J=5.0 Hz), 8.53 (dd, 1H, J=0.8, 8.5 Hz), 8.22-8.20 (m, 2H), 7.72 (d, 1H, J=1.9 Hz), 7.70 (dd (H, J=1.9, 8.5 Hz), 7.54-7.36 (m, 7H), 7.14 (d, 1H, J=5.0 Hz), 7.07 (d, 2H, J=8.7 Hz), 6.94 (d, 2H, J=8.7 Hz), 3.90 (s, 3H), 3.84 (s, 3H); 13C-NMR (75 MHz, CDCl3): δ 160.5 (C), 159.2 (C), 151.7 (C), 149.5 (2C), 146.6 (CH), 145.7 (C), 138.9 (C), 136.7 (C), 136.3 (C), 134.0 (CH), 133.2 (C), 130.0 (2 CH), 129.0 (2 CH), 128.1 (2 CH), 127.8 (2 CH), 126.9 (CH), 123.5 (C), 120.7 (CH), 120.5 (CH), 115.0 (CH), 114.5 (2 CH), 114.3 (2 CH); 55.6 (CH3), 55.5 (CH3); MS (ESI) m/z 521.1 [M+H+], 1062.9 [2M+Na+]; HRMS (ESI): Calcd for C31H24N2O3S: 521.1535. Found: 521.1537.
The following compounds can be prepared by the same method:
To a solution of 3-chloro-6-(4-methoxyphenyl)-9-(benzenesulfonyl)-9H-pyrido[2,3-b]indole (222 mg, 1.11 mmol, 1eq.) in CH2Cl2 at 0° C., BBr3 (4.46 ml, 1M in CH2Cl2 4.46 mmol) was added dropwise. After 3 h at room temperature, the reaction mixture is hydrolysed with H2O and extracted with AcOEt (3×50 ml), dried with MgSO4, then filtered. The solvents were removed under reduced pressure and the crude material was purified by flash chromatography (CH2Cl2 then AcOEt) to afford 4-(3-chloro-9-(benzenesulfonyl)-9H-pyrido[2,3-b]indol-6-yl)phenol (409 mg, 0.94 mmol, 85% yield. 1H NMR 1H ((CD3)2CO, 300 MHz), δ 8.67 (d, 1H, J=2.3 Hz), 8.45-8.51 (m, 4H), 8.16-8.20 (m, 2H), 7.93 (dd, 1H, J=2.1 Hz, 8.9 Hz), 7.54-7.68 (m, 5H), 6.98 (d, 2H, J=8.6 Hz).
The following compounds can be prepared by the same method:
Typical procedure for the Mitsunobu substitution of the phenol group
To a solution of 4-(3-chloro-9-(benzenesulfonyl)-9H-pyrido[2,3-b]indol-6-yl)phenol (180 mg, 0.41 mmol, 1 eq.), triphenylphosphine (430 mg, 1.64 mmol, 4 eq.) and 3-(diethylamino)propan-1-ol (264 mg, 2.05 mmol, Seq.) in THF (10 ml) was added diisopropyldiazodicarboxylate (DIAD, 332 mg, 1.64 mmol, 4 eq.). The resulting solution was stirred at room temperature under Ar for 20 h and concentrated under reduced pressure. The crude residue was chromatographed over silica gel column (eluted with mixtures of AcOEt and EP and then AcOEt and MeOH). The product was then dissolved in dichloromethane and precipitated with EP. The solid was then filtered and washed with EP to give 3-(4-(3-chloro-9-(benzenesulfonyl)-9H-pyrido[2,3-b]indol-6-yl)phenoxy)-N,N-diethylpropan-1-amine (113 mg, 0.21 mmol, 51% yield). 1H NMR (CDCl3 300 MHz) δ ppm 8.47 (dd, 2H, J=2.6 Hz, 8.3 Hz), 8.18 (d, 1H, J=2.3 Hz), 8.13 (d, 2H, J=7.4 Hz), 8.01 (d, 1H, J=1.5 Hz), 7.77 (dd, 1H, J=1.8 Hz, 8.7 Hz), 7.54 (dd, 3H, J=8.7 Hz, 9.0 Hz), 7.42 (dd, 2H, J=7.3 Hz, 7.9 Hz), 7.01 (d, 2H, J=8.6 Hz), 4.08 (t, 2H, J=6.1 Hz), 2.58-2.72 (m, 6H), 2.00 (dd, 2H, J=6.8 Hz, 7.5 Hz), 1.08 (t, 6H, J=7.2 Hz). NMR 13C 75 MHz CDCl3 δ ppm 162.5 (C), 158.9 (C), 149.3 (C), 145.6 (CH), 138.6 (C), 137.5 (C), 137.4 (C), 134.3 (CH), 129.1 (2×CH), 128.3 (2×CH), 128.3 (C), 128.1 (CH), 127.6 (2×CH), 122.4 (C), 120.1 (C), 118.8 (CH), 115.5 (CH), 115.1 (2×CH), 66.5 (CH2), 49.5 (CH2), 47.1 (2×CH2), 26.8 (CH2), 11.6 (2×CH3). MS [ESI] 548 [M+H 35Cl], 550 [M+H 37Cl].
HRMS: calc. 548.1775; observed: 548.1776.
To a solution of 4-(3-chloro-9-(benzenesulfonyl)-9H-pyrido[2,3-b]indol-6-yl)phenol (240 mg, 0.55 mmol, 1 equiv.) in anhydrous THF (14 ml), triphenylphosphin (577 mg, 2.2 mmol, 4 equiv.) and 2-(4-methylpiperazin-1-yl)ethanol (397 mg, 2.75 mmol, 5 equiv.) are added. DIAD (445 mg, 2.2 mmol, 4 equiv.) is then added dropwise to the solution which is stirred at room temperature for 12 hours. The mixture is then extracted with a solution of HCl 0.1M (3×10 ml). The aqueous layer is treated with Na2CO3 until pH=9 and then extracted with AcOEt (3×20 ml). The organic layers are dried over MgSO4, filtered and concentrated under reduced pressure. The residue (yellow solid) is purified over silica chromatography (eluted with AcOEt/MeOH 9:1 and then THF/MeOH 9:1) to give the product as a white solid (259 mg, 0.44 mmol) in 80% yield. 1H NMR (300 MHz, CDCl3) δ 8.47 (dd, 2H, J=2.5, 7.7 Hz), 8.17 (d, 1H, J=2.1 Hz), 8.13 (d, 2H, J=7.5 Hz), 8.00 (d, 1H, J=0.9 Hz), 7.76 (dd, 1H, J=1.5, 8.6 Hz), 7.57-7.39 (m, 5H), 7.55 (d, 2H, J=8.6 Hz), 7.01 (d, 2H, J=8.5 Hz), 4.17 (t, 2H, J=5.6 Hz), 2.87 (t, 2H, J=5.6 Hz), 2.70-2.58 (br d, 8H), 2.35 (s, 3H).
The following compounds can be prepared by the same method:
To a 1 M mixture of compound in anhydrous THF was added 4 equiv. of TBAF (1.0 M solution in THF), under inert atmosphere. The mixture was refluxed until completion of the reaction (followed by T.L.C, 2-3 hours). Solvent was removed and the residue was dissolved in CH2Cl2. The organic layer was washed with water, brine, dried over anhydrous MgSO4, filtered and the solvent was removed under reduced pressure.
To a Solution of (E)-9-Benzenesulfonyl-3-Chloro-6-(2′-(4-methoxyphenyl)ethenyl)-9H-pyrido[2,3-b]indole (127 mg, 0.25 mmol, 1 equiv.) in anhydrous THF (11 ml) under Argon, TBAF 1M in THF (1.26 ml, 1.26 mmol, 5 equiv.) is added dropwise. The reaction is carried out at reflux for 4 hours and then concentrated under reduced pressure. The crude product is washed with MeOH and then filtered. The product R350 is obtained as a white solid (17 mg, 0.04 mmol) in 21% yield. 1H NMR (300 MHz, DMSO d6) δ 12.05 (br s, 1H), 8.68 (d, 1H, J=2.1 Hz), 8.42 (d, 1H, J=2.3 Hz), 8.41 (s, 1H), 7.74 (d, 1H, J=8.3 Hz), 7.55 (d, 2H, J=8.5 Hz), 7.50 (d, J=8.3 Hz), 7.21 (d, 2H, J=1.5 Hz), 6.97 (d, 2H, J=8.5 Hz), 3.78 (s, 3H).
At room temperature and under inert atmosphere, 1.0 M TBAF in THF (1.9 mL, 5 equiv.) was added a solution of 9-benzenesulfonyl-3-chloro-6-(4-methoxyphenyl)-9H-pyrido[2,3-b]indole (26) (169 mg, 0.376 mmol) in anhydrous THF (17 mL). The solution was refluxed for 2 h. The resulting mixture was then cautiously quenched at 0° C. with H2O. The mixture was extracted with EtOAc (3×10 mL). The resulting organic layers were dried over MgSO4, filtered, and solvents were removed under reduced pressure. The crude product was purified by flash chromatography (CH2Cl2/EtOAc 9:1) to afford R277 in 85% yield as a yellow solid; mp>220° C. (MeOH); IR: 3109, 3035, 2935, 2848, 1630, 1603, 1578, 1483, 1232, 1090, 1033, 800, 778, 700 cm−1; 1H-NMR (300 MHz, DMSO-d6): δ 12.02 (bs, 1H), 8.74 (d, 1H, J=2.4 Hz), 8.49 (d, 1H, J=1.8 Hz), 8.42 (d, 1H, J=2.4 Hz), 7.76 (dd, 1H, J=1.8, 8.6 Hz), 7.55 (d, 1H, J=8.5 Hz), 7.06 (d, 1H, J=8.7 Hz), 3.81 (s, 3H); 13C-NMR (75 MHz, DMSO-d6): δ 158.4 (C), 150.7 (C), 144.1 (CH), 138.8 (C), 133.2 (C), 132.1 (C), 128.3 (CH), 127.7 (2 CH), 126.2 (CH), 121.7 (C), 120.2 (C), 119.3 (CH), 126.6 (C), 114.4 (2 CH), 111.8 (CH), 55.2 (CH3); MS (ESI) m/z 309.1 [M+H]+; HRMS (EI): Calcd for C18H13ClN2O: 308.0716. Found: 308.0714.
At Room Temperature and Under Inert Atmosphere, 1.0 M TBAF in Ti-if (0.94 mL, 5 equiv.) was added a solution of R308 (95 mg, 0.0.188 mmol) in anhydrous THF (8.5 mL). The solution was refluxed for 2 h. The resulting mixture was then cautiously quenched at 0° C. with H2O. The mixture was extracted with EtOAc (3×10 mL). The resulting organic layers were dried over MgSO4, filtered, and solvents were removed under reduced pressure. The crude product was purified by flash chromatography (PE/EtOAc 1:1 to EtOAc) to afford R308 in 85% yield as a yellow solid; 1H-NMR (300 MHz, DMSO-d6): δ 12.02 (bs, 1H), 8.72 (d, 1H, J=2.1 Hz), 8.55 (d, 1H, J=2.4 Hz), 8.50 (d, 1H, J=1.5 Hz), 8.43 (d, 1H, J=2.3 Hz), 7.96 (dd, 1H, J=2.6, 8.9 Hz), 7.77 (dd, 1H, J=1.7, 8.5 Hz), 7.56 (d, 1H, J=8.5 Hz), 6.97 (d, 1H, J=8.9 Hz), 3.73 (t 4H, J=4.6 Hz), 3.49 (t, 4H, J=4.6 Hz); 13C-NMR (75 MHz, DMSO-d6): δ 158.2 (C), 150.5 (C), 145.3 (CH), 144.2 (C), 138.8 (C), 135.8 (CH), 129.6 (C), 128.2 (CH), 126.1 (C), 125.7 (CH), 121.7 (C), 120.3 (C), 118.8 (CH), 116.5 (C), 111.9 (CH), 107.1 (CH), 65.9 (2 CH2), 45.3 (2 CH2); MS (ESI) m/z 365.2 [M+H+]; HRMS (EI): Calcd for C20H17ClN4O: 365.1169. Found: 365.1169.
At room temperature and under inert atmosphere, 1.0 M TBAF in THF (1.6 mL, 5 equiv.) was added a solution of 11a (140 mg, 0.315 mmol) in anhydrous THE (15 mL). The solution was refluxed for 4 h. The resulting mixture was then cautiously quenched at 0° C. with H2O. The mixture was extracted with EtOAc (3×20 mL). The resulting organic layers were dried over MgSO4, filtered, and solvents were removed under reduced pressure. Solvent was removed. The crude product was purified by flash chromatography (eluent: PE/EtOAc 1:1 to EtOAc) to afford 42 in 73% yield as a yellow solid; 1H-NMR (300 MHz, DMSO-d6): δ 12.12 (bs, 1H), 8.57 (d, 1H, J=8.1 Hz), 8.43 (bs, 1H), 7.77 (dd, 114, J=1.1, 8.5 Hz), 7.61 (d, 2H, J=7.1 Hz), 7.52 (d, 1H, J=8.3 Hz), 7.40 (d, 1H, J=16.4 Hz), 7.40 (d, 1H, J=7.5 Hz), 7.38 (d, 1H, J=7.9 Hz), 7.29 (d, 1H, J=7.9 Hz), 7.27 (d 1H, J 7.5 Hz), 7.26 (d, 1H, J=16.4 Hz); 13C-NMR (75 MHz, DMSO-d6): δ 151.4 (C), 146.5 (C), 138.5 (C), 137.4 (C), 131.5 (CH), 129.5 (CH), 129.0 (C), 128.7 (2 CH), 126.3 (CH), 126.2 (2 CH), 125.9 (CH), 120.3 (C), 119.3 (CH), 114.7 (CH), 114.3 (C), 111.8 (CH); MS (ESI) m/z 304 [M+H+];
At Room Temperature and Under Inert Atmosphere, 1.0 M TBAF in THF (1.75 mL, 5 equiv.) was added a solution of 30 (181 mg, 0.35 mmol) in anhydrous THF (16 mL). The solution was refluxed for 4 h. The resulting mixture was then cautiously quenched at 0° C. with H2O. The mixture was extracted with EtOAc (3×20 mL). The resulting organic layers were dried over MgSO4, filtered, and solvents were removed under reduced pressure. The crude product was purified by flash chromatography (eluent: CH2Cl2/EtOAc 7:3 to EtOAc) to afford R313 in 61% yield as a yellow solid; 1H-NMR (300 MHz, DMSO-d6): δ 12.05 (bs, 1H), 8.75 (d, 1H, J=2.4 Hz), 8.55 (d, 1H, J=1.7 Hz), 8.43 (d, 1H, J=2.4 Hz), 7.81 (dd, 1H, J=1.7, 8.7 Hz), 7.70 (d, 2H, J=8.1 Hz), 7.58 (d, 1H, J=8.7 Hz), 7.41 (d, 2H, J=8.1 Hz), 3.59 (t, 4H, J=4.4 Hz), 3.51 (s, 2H), 2.39 (t, 4H, J=4.4 Hz); 13C-NMR (75 MHz, DMSO-d6): δ 150.6 (C), 144.2 (C), 139.5 (C), 139.2 (C), 136.3 (C), 132.3 (C), 129.6 (2 CH), 128.3 (C), 126.5 (2 CH), 126.4 (CH), 121.8 (C), 120.2 (C), 119.8 (CH), 116.7 (C), 111.9 (CH), 66.2 (2 CH2), 62.1 (CH2), 53.2 (2 CH2); MS (ESI) m/z 378 [M+H+]
The crude product was purified by flash chromatography (eluent: CH2Cl2/EtOAc 9:1) to afford R311 in 95% yield as brown solid; 1H-NMR (300 MHz, DMSO-d6): δ 11.81 (s, 1H), 8.59 (d, 1H, J=8.1 Hz), 8.40 (d, 1H, J=1.1 Hz), 8.15 (d, 2H, J=8.7 Hz), 7.76 (d, 1H, J=8.1 Hz), 7.71-7.68 (m, 3H), 7.52 (d, 1H, J=8.5 Hz), 7.08 (d, 2H, J=8.7 Hz), 7.05 (d, 2H, J=8.7 Hz), 3.84 (s, 3H), 3.82 (s, 3H); 13C-NMR (75 MHz, DMSO-d6): δ 159.9 (C), 158.3 (C), 153.0 (C), 152.5 (C), 138.3 (C), 133.5 (C), 131.9 (C), 131.7 (C), 129.4 (CH), 128.0 (2 CH), 127.7 (2 CH), 125.0 (CH), 121.2 (C), 118.5 (CH), 114.3 (2 CH), 114.3 (2 CH), 113.8 (C), 111.5 (CH), 111.3 (CH), 55.2 (CH3), 55.1 (CH3); MS (ESI) m/z 381.2 [M+H]+;
HRMS (EI): Calcd for C25H20N2O2: 380.1525. Found: 380.1527.
The following compounds can be prepared by the same method:
Typical Procedure for the Sodium Methoxide-catalyzed Deprotection of the Benzenesulfonyl Group
3-(4-(3-chloro-9-(benzenesulfonyl)-9H-pyrido[2,3-b]indol-6-yl)phenoxy)-N,N-diethylpropan-1-amine (57 mg, 0.10 mmol) is added to a solution of Na° (23 mg, 1 mmol, 10 eq) in methanol (0.1 ml). The reaction is carried out at 65° C. for 2 hours, the mixture is then hydrolysed with ethanol and H2O and extracted with ethyl acetate (3×20 ml). The organic layers are dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue (orange solid) is purified over flash chromatography (eluted with THF/MeOH 9:1) to give the product R337 as a white solid (29 mg, 0.07 mmol) with a 70% yield. 1H NMR (CDCl3 300 MHz) δ ppm 8.42 (br s, 1H), 8.28 (br. s, 1H), 8.14 (br.s, 1H), 7.70 (dd, 1H, J=1.7, 8.5 Hz); 7.60-7.45 (m, 3H), 7.57 (d, 21-1, J=8.6 Hz), 7.01 (d, 21-1, J=8.7 Hz), 4.08 (t, 2H, J=6.3 Hz), 2.67 (t, 2H, J=7.3 Hz), 2.59 (q, 4H, J=7.1 Hz), 1.98 (p, 2H, J=6.8 Hz), 1.07 (t, 6H, J=7.1 Hz).
3-chloro-6-(4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-9-(benzenesulfonyl)-9H-pyrido[2,3-b]indole (203 mg, 0.36 mmol) is added to a solution of Na (83 mg, 3.6 mmol, 10 equiv.) in anhydrous MeOH (3.6 ml). The reaction is carried out at 65° C. for 2 hours, the mixture is then hydrolysed with ethanol and H2O and extracted with ethyl acetate (3×20 ml). The organic layers are dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue (orange solid) is purified over flash chromatography (eluted with THF/MeOH 9:1) to give the product R347 as a white solid (124 mg, 0.30 mmol) in 83% yield. 1H NMR (300 MHz, (CD3)2C0) δ 12.01 (br s, 1H), 8.74 (d, 1H, J=2.3 Hz), 8.49 (d, 1H, J=1.7 Hz), 8.42 (d, 1H, J=2.5 Hz), 7.76 (dd, 1H, J=1.8, 8.5 Hz), 7.66 (d, 2H, J=8.9 Hz), 7.55 (d, 1H, J=8.5 Hz), 7.06 (d, 2H, J=8.9 Hz), 4.13 (t, 2H, J=5.8 Hz), 2.72 (t, 2H, J=5.8 Hz), 2.38 (br s, 8H).
The following compounds can be prepared by the same method:
A sealed pressure tube with stir bar was charged with Pd(OAc)2 (0.08 equiv.), 2-dicyclohexylphosphino-2′,6′-dimethoxyphenyl (0.16 equiv.), R248 (1 equiv.), boronic acid (1.2 equiv.) and K3PO4 (2.5 equiv.). The tube was evacuated and back-filled with argon (this was repeated three additional times). 1,4-Dioxane (2.5 mL/mmol) was added (when degassed solvent was used) and the reaction mixture was allowed to stir at 100° C. overnight. After cooling to room temperature, the products were extracted from the water layer with ethyl acetate, dried over MgSO4, filtered through celite and solvents were removed under reduced pressure.
The product was purified by column chromatography (CH2Cl2/EtOAc 9:1) to afford R278 in 73% yield as a yellow solid; mp>220° C. (MeOH); IR:3125, 2979, 1607, 1587, 1570, 1519, 1455, 1244, 1231, 1034, 742 cm−1; 1H-NMR (300 MHz, DMSO-d6): δ 11.80 (bs, 1H), 8.75 (d, 1H, J=2.1 Hz), 8.67 (d, 1H, J=2.1 Hz), 8.23 (d, 1H, J=7.9 Hz), 7.72 (d, 2H, J=8.6 Hz), 7.51-7.43 (m, 2H), 7.23 (td, 1H, J=1.5, 8.1 Hz), 7.07 (d, 2H, J=8.6 Hz), 3.82 (s, 3H); 13C-NMR (75 MHz, DMSO-d6): 158.6 (C), 151.1 (C), 144.4 (CH), 139.4 (C), 130.9 (C), 127.9 (2 CH), 127.4 (C), 126.7 (CH), 126.0 (CH), 121.4 (CH), 120.5 (C), 119.3 (CH), 115.3 (C), 114.5 (2 CH), 111.3 (CH), 55.2 (CH3); MS (ESI) m/z 275.2 [M+H]+; HRMS (ESI): Calcd for C18H14N2: 275.1184. Found: 275.1186.
The product was purified by column chromatography (CH2Cl2/EtOAc 9:1) to afford R281 in 68% yield as a white solid. Mp>220° C. (MeOH); IR 2973, 1604, 1496, 1456, 1403, 1243, 1109, 961, 741, 685 cm−1; 1H-NMR (300 MHz, DMSO-d6): δ 11.85 (bs, 1H), 8.84 (d, 1H, J=2.1 Hz), 8.62 (d, 1H, J=2.1 Hz), 8.19 (d, 1H, J=7.7 Hz), 7.64 (d, 2H, J=7.4 Hz), 7.51-7.34 (m, 6H), 7.30-7.22 (m, 2H); 13C-NMR (75 MHz, DMSO-d6): δ 151.6 (C), 146.2 (CH), 139.4 (C), 137.4 (C), 128.7 (2 CH), 127.3 (C), 126.9 (CH), 126.8 (CH), 126.4 (CH), 126.2 (2 CH), 124.8 (CH), 124.7 (C), 121.3 (CH), 120.4 (C), 119.7 (CH), 115.5 (C), 111.4 (CH); MS (ESI) m/z 271.2 [M+H]+; HRMS (ESI): Calcd for C19H14N2: 271.1235. Found: 271.1236.
The product was purified by column chromatography on silica gel (CH2Cl2/EtOAc 8/2) to afford R 328 in 70% yield as a yellow solid. mp>220° C. (MeOH); 1H NMR (300 MHz, DMSO-d6): δ 11.99 (bs, NH); 9.02 (d, 1H, J=2.3 Hz); 8.85 (d, 1H, J=2.3 Hz); 8.62 (t, 1H, J=1.9 Hz); 830 (t, 2H, J=7.7 Hz); 8.23 (dd, 1H, J=1.0, 2.3 Hz); 7.81 (t, 1H, J=8.1 Hz); 7.55-7.46 (m, 2H); 7.27 (td, 1H, J=1.5, 7.2 Hz); 13C NMR (75 MHz, DMSO-d6): δ 152.2 (C), 148.8 (C), 145.3 (CH), 140.7 (C), 139.8 (C), 133.6 (CH), 130.8 (CH), 127.3 (2×CH), 125.6 (C), 122.0 (C14), 121.9 (CH), 121.4 (CH), 120.9 (C), 120.1 (CH), 115.8 (C), 111.8 (CH); MS (ESI) m/z 290.1 [M+H]+; HRMS (ESI): Calcd for C17H11N3O2: 290.0930. Found: 290.0934.
The product was purified by column chromatography on silica gel (CH2Cl2/EtOAc 9/1) to afford R325 in 65% yield as a yellow solid. mp>220° C. (MeOH); 1H NMR (300 MHz, DMSO-d6): δ 11.91 (bs, NH); 8.80 (s, 2H); 8.23 (d, 1H, J=7.9 Hz); 7.79 (dd, 1H, J=0.5, 1.7 Hz); 7.52-7.44 (m, 2H); 7.24 (td, 1H, J=1.9, 7.2 Hz); 6.99 (d, 1H, J=0.8, 3.4 Hz); 6.64 (dd, 1H, J=1.9, 3.4 Hz); 13C NMR (75 MHz, DMSO-d6): δ 152.2 (C), 151.1 (C), 142.5 (CH), 142.4 (CH), 139.4 (C), 126.9 (CH), 123.3 (CH), 121.5 (CH), 120.4 (C), 119.7 (CH), 118.7 (C), 115.1 (C), 112.0 (CH), 111.4 (CH), 104.6 (CH); MS (EI) m/z 234.0 [M+]; HRMS (EI): Calcd for C15H10N2O: 234.0793. Found: 234.0792.
The product was purified by column chromatography (CH2Cl2/EtOAc 8:2) to afford R329 in 63% yield as a white solid. 1H-NMR (300 MHz, DMSO-d6): δ 11.89 (bs, 1H); 8.89 (d, 1H, J=2.1 Hz); 8.80 (d, 1H, J=2.3 Hz); 8.26 (d, 1H, J=7.7 Hz); 7.92 (d, 1H, J=8.5 Hz); 7.82 (d, 1H, J=8.3 Hz); 7.75 (d, 1H, J=8.3 Hz); 7.53-7.45 (m, 3H); 7.41-7.36 (m, 1H); 7.04 (ddd, 1H, J=1.3, 6.6 Hz).
The product was purified by column chromatography (CH2Cl2) to afford R299 in 70% yield as a white solid. mp>220° C. (MeOH); IR 3136, 3083, 2958, 1596, 1583, 1572, 1457, 1415, 1028, 818 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 11.80 (br s, 1H), 8.52 (d, 1H, J=8.1 Hz), 8.14 (d, 2H, J=8.9 Hz), 8.13 (d, 1H, J=7.9 Hz), 7.74 (d, 1H, J=8.1 Hz), 7.48 (d, 1H, 7.3 Hz), 7.42 (td, 1H, J=1.3 and 6.9 Hz), 7.21 (td, 1H, J=1.3 and 7.9 Hz), 7.07 (d, 2H, J=8.9 Hz), 3.83 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 159.8 (C), 152.8 (C), 152.0 (C), 139.1 (C), 131.9 (C), 129.1 (CH), 128.0 (2 CH), 126.2 (CH), 120.9 (CH), 120.5 (C), 119.4 (CH), 114.1 (2 CH), 113.5 (C), 111.2 (CH), 111.1 (CH), 55.2 (CH3); MS (ESI) m/z 275.2 [M+H]+; HRMS (ESI): Calcd for C18H14N2O: 275.1184. Found: 275.1186.
The product was purified by column chromatography (CH2Cl2) to afford R300 in 72% yield as a yellow solid. mp>220° C. (MeOH); IR 3159, 3089, 3041, 2888, 1601, 1579, 1458, 1413, 1227, 954, 726, 685 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 11.75 (br s, 1H), 8.48 (d, 1H, J=7.7 Hz), 8.12 (d, 1H, J=8.1 Hz), 7.72 (d, 1H, J=16.0 Hz), 7.69 (d, 2H, J=7.2 Hz), 7.46-7.40 (m, 6H), 7.34-7.29 (m, 1H), 7.21 (td, 1H, J=1.3, 8.1 Hz); 13C NMR (75 MHz, DMSO-d6) δ 152.0 (C), 151.8 (C), 139.4 (C), 136.5 (C), 131.0 (CH), 128.9 (CH), 128.8 (2 CH), 128.8 (CH), 128.1 (CH), 126.9 (2 CH), 126.5 (CH), 120.9 (CH), 120.5 (C), 119.5 (CH), 114.9 (CH), 114.6 (C), 111.1 (CH); MS (ESI) m/z 271.2 [M+H]+; HRMS (ESI): Calcd for C19H14N2: 271.1235. Found: 271.1236.
The product was purified by column chromatography (CH2Cl2/EtOAc 9:1) to afford R309 in 70% yield as a yellow solid. Mp 208-210° C. (MeOH); IR 3062, 2968, 2835, 1599, 1560, 1515, 1456, 1252, 1176, 1029, 809, 745, 724 cm−1; 1H-NMR (300 MHz, DMSO-d6): δ 11.93 (bs, 1H), 8.41 (d, 1H, J=−4.9 Hz), 7.64-7.60 (m, 3H), 7.5 (d, 1H, J=8.1 Hz), 7.40 (ddd, 1H, J=0.9, 7.2 Hz), 7.17 (d, 2H, J=8.7 Hz), 7.06 (d, 1H, J=5.1 Hz), 7.04 (td, 1H, J=1.1, 7.5 Hz), 3.88 (s, 3H); 13C-NMR (75 MHz, DMSO-d6): δ 159.6 (C), 149.2 (C), 145.9 (CH), 144.1 (C), 138.9 (C), 130.6 (C), 129.8 (2 CH), 126.4 (CH), 121.9 (CH), 119.9 (C), 119.0 (CH), 115.9 (CH), 114.2 (2 CH), 112.1 (C), 111.3 (CH), 55.3 (CH3); MS (ESI) m/z 275.2 [M+H+]; HRMS (EI): Calcd for C18H14N2: 274.1106. Found: 274.1105.
The product was purified by column chromatography (CH2Cl2/EtOAc 9:1) to afford R310 in 72% yield as a yellow solid. Mp>220° C. (MeOH); IR: 3059, 2972, 1633, 1599, 1580, 1561, 1455, 1397, 1255, 957, 730, 690 cm−1; 1H-NMR (300 MHz, DMSO-d6): δ 11.87 (bs, 1H), 8.39 (d, 1H, J=5.3 Hz), 8.32 (d, 1H, J=8.0 Hz), 8.07 (d, 1H, J=16.3 Hz), 7.85 (d, 2H, J=7.2 Hz), 7.65 (d, 1H, J=16.3 Hz), 7.54-7.45 (m, 5H), 7.41-7.36 (m, 1H), 7.27 (td, 1H, J=1.5, 8.0 Hz); 13C-NMR (75 MHz, DMSO-d6): δ 152.7 (C), 145.9 (CH), 139.8 (C), 139.0 (C), 136.3 (C), 134.5 (CH), 128.9 (2 CH), 128.8 (CH), 127.4 (2 CH), 126.3 (CH), 123.7 (CH), 123.4 (CH), 120.4 (C), 119.7 (CH), 112.3 (C), 111.2 (CH), 110.9 (CH); MS (ESI) m/z 270 [M+]; HRMS (ESI): Calcd for C19H14N2: 271.1235. Found: 271.1235.
At room temperature and under an inert atmosphere, Pd(PPh3)4 (0.08 equiv.), boronic acid (1.1 equiv.), and a 0.3 M solution of K2CO3 (3 equiv.) in H2O were added to a 0.1M solution of R297 or R296 in anhydrous 1,4-dioxane. This solution was stirred at 100° C. for 12 h. After cooling to room temperature, the solution was filtered through celite and solvents were removed under reduced pressure.
The product was purified by column chromatography on silica gel (CH2Cl2/EP 9/1) to afford 42 in 83% yield as a yellow solid. mp 185.187° C. (MeOH); 1H NMR (300 MHz, DMSO-d6): δ 12.01 (bs, NH); 9.06 (t, 1H, J=1.9 Hz); 8.62 (d, 1H, J=8.0 Hz); 8.60 (d, 1H J=8.1 Hz); 8.25 (dd, 1H, J=1.5, 8.1 Hz); 8.19 (d, 1H, J=7.7 Hz); 7.96 (d, 1H, J=18.0 Hz); 7.79 (t, 1H, J=8.1 Hz); 7.51 (d, 1H, J=8.9 Hz); 7.47 (td, 1H, J=0.8, 8.9 Hz); 7.25 (td, 1H, J=1.5, 7.9 Hz); 13C NMR (75 MHz, DMSO-d6): δ 152.0 (C), 150.0 (C), 148.5 (C), 141.0 (C), 139.6 (C), 132.7 (CH), 130.3 (CH), 128.9 (CH), 129.5 (CH), 127.0 (CH), 123.1 (CH), 121.4 (CH), 120.9 (CH), 120.1 (C), 119.7 (CH), 115.4 (C), 112.2 (C), 111.3 (CH); MS (ESI) m/z 290.2, 244.3 [M+H]+, [M-NO2+H]+; HRMS (ESI): Calcd for C17H11N3O2: 290.0930. Found:290.09314.
The product was purified by column chromatography on silica gel (CH2Cl2) to afford R326 in 81% yield as a brown solid. mp=208-210° C. (MeOH); 1H-NMR (300 MHz, DMSO-d6): δ 11.85 (bs, 1H), 8.54 (d, 1H, J=7.9 Hz), 8.13 (d, 1H, J=7.7 Hz), 7.85 (dd, 1H, J=1.1, 1.7 Hz), 7.62 (d, 1H, J=8.1 Hz), 7.48-7.41 (m, 2H), 7.22 (ddd, 1H, J=1.9, 6.8, 8.1 Hz), 7.13 (d, 1H, J=3.4 Hz), 6.68 (dd, 1H, J=1.7, 3.4 Hz); 13C NMR (75 MHz, DMSO-d6): δ 154.0 (C), 151.8 (C), 145.3 (CH), 143.8 (C), 139.3 (C), 129.1 (CH), 126.5 (CH), 120.9 (CH), 120.4 (C), 119.6 (CH), 114.3 (C), 112.3 (CH), 111.2 (CH), 110.2 (CH), 108.3 (CH); MS (CI) m/z 235 [M+H]+ 100° C.; HRMS (CI): Calcd for C15H10N2O: 235.0871. Found: 235.08727.
At room temperature and under an inert atmosphere, Pd(PPh3)4 (0.08 equiv.), boronic acid (1.1 equiv.), and a 0.3 M solution of K2CO3 (3 equiv.) in H2O were added to a 0.1M solution of 2-chloro-α-carboline in anhydrous 1,4-dioxane. This solution was stirred at 100° C. for 12 h. After cooling to room temperature, the solution was filtered through celite and solvents were removed under reduced pressure. A solution of crude product in CH2Cl2 (3.5 mL) was stirred under argon and treated with CF3CO2H (1 mL). After 90 min at room temperature, the resulting mixture was then cautiously quenched at 0° C. with H2O and a saturated aqueous NaHCO3 was added until pH 10. The solution was diluted with CH2Cl2, washed with H2O, dried with MgSO4, filtered and concentrated. The product was purified by column chromatography on silica gel (CH2Cl2) to afford R355 in 10% yield as a yellow solid. 1H-NMR (300 MHz, CDCl3): δ 9.90 (bs, 1H), 8.89 (bs, NH), 8.28 (d, 1H, J=8.0 Hz), 7.98 (d, 1H, J=8.0 Hz), 7.51 (d, 1H, J=8.1 Hz), 7.43-7.40 (m, 1H); 7.33-7.27 (m, 2H), 6.97 (s, 1H), 6.85 (s, 1H), 6.34 (dd, 1H, J=2.6, 5.5 Hz).
The product was purified by column chromatography on silica gel (CH2Cl2/EtOAc 8/2) to afford R331 in 77% yield as a yellow solid. mp>220° C. (MeOH); 1H-NMR (300 MHz, DMSO-d6): δ 12.11 (bs, 1H), 8.52 (d, 1H, J=5.0 Hz), 8.48 (t, 1H, J=1.8 Hz), 8.43 (ddd, 1H, J=1.1, 2.3, 7.9 Hz), 8.18 (ddd, 1H, J=1.0, 1.7, 7.9 Hz), 7.93 (t, 1H, J=8.1 Hz), 7.55 (d, 1H, J=7.9 Hz), 7.46 (d, 1H, J=7.9 Hz), 7.45 (td, 1H, J=1.0, 7.9 Hz 7.21 (d, 1H, J=5.0 Hz), 7.04 (td, 1H, J=1.0, 7.9 Hz); 13C-NMR (75 MHz, DMSO-d6): δ 152.3 (C), 148.1 (C), 146.2 (CH), 141.6 (C), 139.9 (C), 139.2 (C), 135.2 (CH), 130.6 (CH), 126.8 (CH), 123.5 (CH), 123.1 (CH), 121.7 (CH), 119.4 (CH), 119.2 (C), 115.8 (CH), 111.9 (C), 111.6 (CH); MS (ESI) m/z 290.2, 244.3 [M+H]+, [M-NO2+H]+; HRMS (ESI): Calcd for C17H11N3O2: 290.0930. Found: 290.09255; Anal. Calcd for C17H11N3O2:: C, 70.58; H, 3.83; N, 14.52. Found: C, 70.30; H, 3.85; N, 14.20.
The product was purified by column chromatography on silica gel (CH2Cl2/EtOAc 8/2) to afford R327 in 76% yield as a green solid. mp>220° C. (MeOH); 1H NMR (300 MHz, DMSO-d6): δ 12.00 (bs, NH); 8.50 (d, 1H, J=8.5 Hz); 8.42 (d, 1H, J=5.3 Hz); 8.13 (dd, 1H, J=0.6, 1.7 Hz); 7.54-7.51 (m, 1H); 7.48 (td, 1H, J=1.1, 6.9 Hz); 7.43 (d, 1H, J=5.1 Hz); 7.31 (dd, 1H, J=0.8, 3.4 Hz); 7.21 (ddd, 1H, J=1.5, 6.8, 8.2 Hz). 13C NMR (75 MHz, DMSO-d6): δ 153.0 (C), 151.7 (C), 145.8 (CH), 144.5 (CH), 139.2 (C2), 131.7 (C), 126.7 (CH), 123.7 (CH), 119.7 (C), 119.5 (CH), 112.5 (2×CH), 111.2 (CH), 111.1 (CH), 109.8 (C); MS (CI) m/z 235 [M+H]+; HRMS (CI): Calcd for C15H10N2O: 235.0871. Found: 235.0872.
The product was purified by column chromatography (CH2Cl2/EtOAc 7:3) to afford R330 in 58% yield as a green solid. 1H-NMR (300 MHz, DMSO-d6): δ 12.00 (bs, 1H), 8.47 (d, 1H, J=5.1 Hz), 7.93 (d, 1H, J=8.2 Hz), 7.83 (d, 1H, J=7.3 Hz), 7.79 (d, 1H, J=7.8 Hz), 7.64 (d, 1H, J=8.7 Hz), 7.56-7.51 (m, 3H), 7.45-7.40 (m, 2H), 7.15 (d, 1H, J=4.9 Hz), 7.04 (ddd, 1H, J=0.5, 6.8 Hz).
At room temperature and under an inert atmosphere, Pd(PPh3)4, (0.08 equiv.), trans vinyl phenyl boronic acid (1.1 equiv.), and a 0.3M solution of K2CO3 (3 equiv.) in H2O were added to a 0.1M solution of 32 or 34 in 1,4-dioxane. This solution was stirred at 100° C. for 12 h. After cooling to room temperature, solution was filtered through celite and solvents were removed under reduced pressure.
The crude product was purified by flash chromatography (CH2Cl2/PE 1:1) to afford 43 in 84% yield as a yellow solid; mp 193-195° C. (CH2Cl2/PE); IR: 2926, 1607, 1586, 1518, 1465, 1382, 1172, 1090, 967, 812 cm−1; 1H-NMR (300 MHz, CDCl3): δ 8.58 (d, 1H, J=8.9 Hz), 8.33 (d, 1H, J=7.4 Hz), 8.32 (d, 1H, J=8.9 Hz), 8.14 (d, 1H, J=7.9 Hz), 8.06 (d, 1H, J=1.7 Hz), 7.91 (d, 1H, J=16.0 Hz), 7.78 (dd, 1H, J=1.9, 8.6 Hz), 7.71 (d, 2H, J=7.4 Hz), 7.66 (d, 2H, J=8.7 Hz), 7.60-7.36 (m, 6H), 7.34 (d, 1H, J=2.6 Hz), 7.28 (d, 1H, J=16.0 Hz), 7.09 (d, 2H, J=8.6 Hz), 3.94 (s, 3H); 13C-NMR (75 MHz, CDCl3): δ 159.3 (C), 153.5 (C), 151.2 (C), 139.0 (C), 137.1 (C), 136.9 (C), 136.8 (C), 134.0 (CH), 133.4 (CH), 133.2 (C), 128.9 (4 CH), 128.6 (CH), 128.5 (CH); 128.3 (2 CH), 127.9 (3 CH), 127.3 (2 CH), 127.0 (CH), 123.6 (C), 118.5 (CH), 118.3 (CH), 117.4 (C), 115.2 (CH), 114.4 (2 CH); 55.4 (CH3); MS (ESI) m/z 517.1 [M+H+], 539 [M+Na+]; HRMS (ESI): Calcd for C32H24N2O3S: 517.1586. Found: 517.1589.
The crude product was purified by flash chromatography (CH2Cl2/PE 6:4) to afford 44 in 81% yield as a white solid; 1H-NMR (300 MHz, CDCl3): δ 8.59 (d, 1H, J=8.6 Hz), 8.53 (m, 1H), 8.28-8.21 (m, 4H), 8.12 (d, 1H, J=1.9 Hz), 8.00 (dd, 1H, J=16 Hz), 7.78 (dd, J=1.0, 7.7 Hz), 7.78 (dd, 1H, J=1.9, 8.6 Hz), 7.72 (d, 1H, J=8.1 Hz), 7.66 (t, 1H, J=7.9 Hz), 7.57-7.51 (m, 2H), 7.46 (d, 1H, J=8.1 Hz), 7.43 (d, 1H, J=8.5 Hz), 7.26 (d, 1H, J=5.6 Hz), 6.61 (dd, 1H, J=1.7, 3.4 Hz).
The crude product was purified by flash chromatography (CH2Cl2/PE 7:3) to afford 45 in 87% yield as a yellow solid; mp 190-192° C. (CH2Cl2/PE); IR: 3073, 2838, 1633, 1607, 1587, 1517, 1462, 1443, 1377, 1179, 1047, 810, 728, 688 cm−1; 1H-NMR (300 MHz, CDCl3): δ 8.59 (d, 1H, J=8.7 Hz), 8.52 (d, 1H, J=5.1 Hz), 8.23 (d, 1H, J=1.7 Hz), 8.20-8.17 (m, 2H), 7.84 (d, 1H, J=16.2 Hz), 7.75 (dd, 1H, J=1.8, 8.7 Hz), 7.62-7.57 (m, 4H), 7.55-7.50 (m, 1H), 7.45-7.36 (m, 5H), 7.35 (d, 1H, J=16.2 Hz), 7.02 (d, 2H, J=8.9 Hz), 3.88 (s, 3H); 13C-NMR (75 MHz, CDCl3): δ 162.4 (C), 159.4 (C), 146.7 (CH), 141.6 (C), 138.9 (C), 137.1 (C), 136.8 (C), 136.2 (C), 135.8 (CH), 134.0 (CH), 133.5 (C), 129.2 (3 CH), 129.0 (2 CH), 128.4 (2 CH), 127.7 (2 CH), 127.3 (2 CH), 127.1 (CH), 124.0 (C), 123.4 (CH), 121.2 (CH), 116.0 (CH), 115.9 (C), 115.3 (CH), 114.6 (2 CH), 55.5 (CH3); MS (ESI) m/z 517.1 [M+H+], 1055.0 [2M+Na+]; HRMS (EI): Calcd for C31H24N2O3S: 517.1586. Found: 517.1585.
The following compounds can be prepared by the same method:
In sealed pressure tube and stir bar was charged Pd(OAc)2 (5 mg, 0.08 equiv.), 2-dicyclohexylphosphino-2′,6′-dimethoxyphenyl 1 (18 mg, 0.16 equiv.), a-carbolines (83 mg, 0.267 mmol), trans vinyl phenyl boronic acid (119 mg, 3.0 equiv.) and K3PO4 (142 mg, 2.5 equiv.). The tube was evacuated and back-filled with argon (this was repeated three additional times). 700 μl of anhydrous 1,4-dioxane was added (when degassed solvent was used) and the reaction mixture was allowed to stir at 100° C. overnight. After cooling to room temperature, the products were extracted from the water layer with ethyl acetate, dried over MgSO4, filtered through celite and solvents were removed under reduced pressure. The crude product was purified by flash chromatography (CH2Cl2/EtOAc 9:1) to afford R315 in 65% yield as a white solid; mp>220° C. (MeOH); IR: 3060, 2994, 2833, 1606, 1517, 1485, 1460, 1232, 957, 813, 740, 692 cm−1; 1H-NMR (300 MHz, DMSO-d6): δ 11.86 (bs, 1H), 8.95 (d, 1H, J=2.1 Hz), 8.61 (d, 1H, J=2.1 Hz), 8.47 (d, 1H, J=1.3 Hz), 7.74 (dd, 1H, J=1.9, 8.5 Hz), 7.71 (d, 214, J=8.9 Hz), 7.63 (d, 2H, J=7.1 Hz), 7.54 (d, 1H, J=8.5 Hz), 7.46 (d, 1H, J=16.4 Hz), 7.43-7.39 (m, 2H), 7.37 (d, 1H, J=16.4 Hz), 7.27 (t, 1H, J=7.4 Hz), 7.07 (d, 2H, J=8.9 Hz), 3.82 (s, 3H); 13C-NMR (75 MHz, DMSO-d6): δ 158.4 (C), 152.0 (C), 146.5 (CH), 138.5 (C), 137.4 (C), 133.4 (C), 131.9 (C), 128.8 (2 CH), 127.7 (2 CH), 127.4 (CH), 126.8 (CH), 126.3 (CH), 126.2 (2 CH), 125.6 (CH), 124.9 (CH), 127.8 (C), 121.1 (C), 118.9 (CH), 115.8 (C), 114.4 (2 CH), 111.7 (CH), 55.2 (CH3); MS (ESI) m/z 377.3 [M+H+]; HRMS (ESI): Calcd for C26H20N2O: 377.1654. Found: 377.1653.
In sealed pressure tube and stir bar was charged Pd(OAc)2 (2.5 mg, 0.08 equiv.), 2-dicyclohexylphosphino-2′,6′-dimethoxyphenyl 1 (9 mg, 0.16 equiv.), α-carbolines (50 mg, 0.137 mmol), trans vinyl phenyl boronic acid (41 mg, 3 equiv.) and K3PO4 (117 mg, 4 equiv.). The tube was evacuated and back-filled with argon (this was repeated three additional times). 200 μL of anhydrous 1,4-dioxane was added (when degassed solvent was used) and the reaction mixture was allowed to stir at 100° C. overnight. After cooling to room temperature, the products were extracted from H2O layer with EtOAc, dried over MgSO4, filtered through celite and solvents were removed under reduced pressure. The crude product was purified by flash chromatography (eluent: EtOAc/PE 1:1 to EtOAc) to afford R307 in 72% yield as a yellow solid; 1H-NMR (300 MHz, DMSO-d6): δ 11.89 (bs, 1H), 8.92 (d, 1H, 2.1 Hz), 8.63 (d, 1H, J=2.1 Hz), 8.57 (d, 1H, J=2.5 Hz), 8.49 (bs, 1H), 7.99 (dd, 1H, J=2.5, 8.9 Hz), 7.74 (dd, 1H, J=1.9, 8.5 Hz), 7.64 (d, 2H, J=7.6 Hz), 7.55 (d, 1H, J=8.5 Hz), 7.46 (d, 1H, J=16.4 Hz), 7.43-7.39 (m, 2H), 7.36 (d, 1H, J=16.4 Hz), 7.30-7.25 (m, 1H), 6.98 (d, 1H, J=8.9 Hz), 3.76-3.73 (m, 4H), 3.52-3.49 (m, 4H); 13C-NMR (75 MHz, DMSO-d6): δ 158.1 (C), 152.0 (C), 146.5 (CH), 145.3 (C), 138.5 (C), 137.3 (C) 135.7 (CH), 129.4 (C), 128.8 (2 CH), 127.4 (CH), 126.8 (CH), 126.4 (CH), 126.3 (C), 126.2 (2 CH), 125.1 (CH), 124.9 (CH), 124.7 (C), 121.2 (C), 118.5 (CH), 115.7 (C), 111.9 (CH), 107.1 (CH), 66.2 (2 CH2), 45.3 (2 CH2); MS (ESI) m/z 433.3 [M+H+]; HRMS (ESI): Calcd for C28H24N4O: 433.2028. Found: 433.2029.
In sealed pressure tube and stir bar was charged Pd(OAc)2 (0.08 equiv., 2 mg, 0.08 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxyphenyl 1 (0.16 equiv., 7 mg, 0.16 mmol), R313 (40 mg, 0.106 mmol), trans vinyl phenyl boronic acid (3 equiv., 48 mg, 0.318 mmol) and K3PO4 (4 equiv., 90 mg, 0.424 mmol). The tube was evacuated and back-filled with argon (this was repeated three additional times). 270 μL of anhydrous 1,4-dioxane was added (when degassed solvent was used) and the reaction mixture was allowed to stir at 100° C. overnight. After cooling to room temperature, the products were extracted from the water layer with EtOAc, dried over MgSO4, filtered through celite and solvents were removed under reduced pressure. The crude product was purified by flash chromatography (EtOAc) to afford R314 in 72% yield as a yellow solid; 1H-NMR (300 MHz, DMSO-d6): δ 11.91 (bs, 1H), 8.95 (d, 1H, J=2.1 Hz), 8.63 (d, 1H, J=2.1 Hz), 8.54 (d, 1H, J=1.3 Hz), 7.80 (dd, 1H, J=1.9, 8.7 Hz), 7.73 (d, 2H, J=8.5 Hz), 7.63 (d, 2H, J=7.4 Hz), 7.57 (d, 2H, J=8.4 Hz), 7.46 (d, 1H, J=16.0 Hz), 7.39 (d, 1H, J=16.0 Hz), 7.44-7.39 (m, 3H), 7.29 (m, 1H), 3.60 (bs, 4H), 3.52 (s, 2H), 2.40 (bs, 4H); 13C-NMR (75 MHz, DMSO-d6): δ 152.0 (C), 146.5 (CH), 139.7 (C), 138.9 (C), 137.3 (C), 136.2 (C) 131.8 (C), 129.6 (2 CH), 128.8 (2 CH), 127.4 (CH), 126.8 (CH), 126.4 (2 CH), 126.3 (CH), 126.2 (2 CH), 125.8 (CH), 124.9 (CH), 124.8 (C), 121.1 (C), 119.4 (CH), 115.7 (C), 111.8 (CH), 66.2 (2 CH), 62.1 (CH2), 53.2 (2 CH2); MS (ESI) m/z 446 [M+H+]
3-chloro-6-(4-methoxyphenyl)-9H-pyrido[2,3-b]indole (50 mg, 0.16 mmol, 1 equiv.), (E)-2′-(3-fluorophenyl)ethenylboronic acid (80 mg, 0.48 mmol, 3 equiv.), K3PO4 (136 mg, 0.64 mmol, 4 equiv.), S-PHOS (13.1 mg, 0.032 mmol, 0.2 equiv.), Pd(OAc)2 (3.6 mg, 0.016 mmol, 0.1 equiv.) are introduced in a schlenk tube which is flushed with N2. Freshly distilled dioxan (0.433 ml) is then injected and the reaction is carried out at 100° C. overnight. The mixture is filtered through celite and concentrated under reduced pressure. The crude product is purified over silica gel chromatography (eluant CH2Cl2/AcOEt 9:1). The slightly yellow solid obtained is washed with methanol to give the product as a white solid (51 mg, 0.13 mmol) in 81% yield. 1H NMR (300 MHz, DMSO-d6) δ 11.91 (br s, 1H), 8.94 (d, 1H, J=1.5 Hz), 8.62 (d, 1H, J=1.9 Hz), 8.47 (s, 1H), 7.75-7.68 (m, 3H), 7.57-7.36 (m, 6H), 7.10-7.05 (m, 3H), 3.82 (s, 3H).
1H NMR (300 MHz, DMSO-d6) δ 11.91 (br s, 1H), 8.94 (d, 1H, J=1.5 Hz), 8.62 (d, 1H, J=1.9 Hz), 8.47 (s, 1H), 7.75-7.68 (m, 3H), 7.57-7.36 (m, 6H), 7.10-7.05 (m, 3H).
(E)-3-chloro-6-(2-(phenyl)ethenyl)-9H-pyrido[2,3-b]indole (50 mg, 0.16 mmol, 1 equiv.), (E)-2′-(3-fluorophenyl)ethenylboronic acid (81 mg, 0.49 mmol, 3 equiv.), K3PO4 (136 mg, 0.64 mmol, 4 equiv.), S-PHOS (13.1 mg, 0.032 mmol, 0.2 equiv.), Pd(OAc)2 (4.0 mg, 0.016 mmol, 0.1 equiv.) are introduced in a schlenk tube which is flushed with N2. Freshly distilled dioxane (0.433 ml) is then injected and the reaction is carried out at 100° C. overnight. The mixture is filtered through celite and concentrated under reduced pressure. The crude product is purified over silica gel chromatography (eluant CH2Cl2/AcOEt 6:4). The white solid obtained is washed with methanol to give the product as a white solid (44 mg, 0.11 mmol) in 69% yield.
1H NMR (300 MHz, DMSO-d6) δ 11.98 (br s, 1H), 8.87 (s, 1H), 8.65 (s, 1H), 8.45 (s, 1H), 7.77-7.10 (m, 15H); 13C NMR (75 MHz, DMSO-d6) δ 164.3 (C), 161.1 (C), 152.1 (C), 146.6 (CH), 140.1 (C), 139.2 (C), 137.5 (C), 130.7 (CH), 129.2 (CH), 128.7 (2×CH), 128.0 (CH), 127.2 (CH), 126.2 (2×CH), 126.1 (CH), 126.0 (CH), 125.6 (CH), 125.1 (CH), 124.6 (C), 122.7 (CH), 120.9 (C), 119.3 (CH), 115.6 (C), 114.1 (CH), 112.3 (CH), 111.7 (CH).
3-chloro-6-(4-methoxyphenyl)-9H-pyrido[2,3-b]indole (50 mg, 0.16 mmol, 1 equiv.), 3-nitrophenylboronic acid (81 mg, 0.48 mmol, 3 equiv.), K3PO4 (136 mg, 0.64 mmol, 4 equiv.), S-PHOS (13.1 mg, 0.032 mmol, 0.2 equiv.), Pd(OAc)2 (4.0 mg, 0.016 mmol, 0.1 equiv.) are introduced in a schlenk tube which is flushed with N2. Freshly distilled dioxane (0.433 ml) is then injected and the reaction is carried out at 100° C. overnight. The mixture is filtered through celite and concentrated under reduced pressure. The crude product is purified over silica gel chromatography (eluant CH2Cl2/AcOEt 6:4). The white solid obtained is washed with methanol to give the product as a white solid (43 mg, 0.11 mmol) in 69% yield.
1H NMR (300 MHz, DMSO-d6) δ 12.00 (br s, 1H), 9.12 (d, 1H, J=2.1 Hz), 8.88 (d, 1H, J=2.3 Hz), 8.64 (t, 1H, J=2.0 Hz), 8.59 (d, 1H, J=1.7 Hz), 8.34-8.22 (m, 2H), 7.85-7.70 (m, 4H), 7.58 (d, 1H, J=8.6 Hz), 7.07 (d, 2H, J=8.6 Hz), 3.82 (s, 3H); MS (+ESI) [M+H+]=396.2.
6-(4-methoxyphenyl)-3-(3-nitrophenyl)-9H-pyrido[2,3-b]indole (35 mg, 0.09 mmol, 1 equiv.), is dissolved in anhydrous THF (1 ml), MeOH (8 ml), and palladium on charcoal (10 mg, 0.009 mmol, 0.1 equiv.), are then added in an autoclave which is flushed with argon and then pressurized with H2 (10 bar). The reaction is carried out at room temperature for 16 hours. The mixture is then filtered over Mite and washed with AcOEt. The green solid obtained is washed with methanol to afford the product as a slightly green solid (26 mg, 0.07 mmol), in 79% yield.
1H NMR (300 MHz, DMSO-d6) δ 11.82 (hr s, 1H), 8.78 (d, 1H, J=2.3 Hz), 8.62 (d, 1H, J=2.3 Hz), 8.53 (d, 1H, J=1.5 Hz), 7.75-7.69 (m, 3H), 7.55 (d, 1H, J=8.5 Hz), 7.16 (dd, 1H, J=7.7, 7.9 Hz), 7.05 (d, 2H, J=8.9 Hz), 6.98-6.90 (m, 2H), 6.59 (dd, 1H, J=1.3, 7.9 Hz), 3.82 (s, 3H).
To a solution of 3-(6-(4-methoxyphenyl)-9H-pyrido[2,3-b]indol-3-yl)benzenamine (23 mg, 0.06 mmol, 1 equiv.), in anhydrous pyridine (0.300 ml), benzenesulfonyl chloride (0.009 ml) is added under argon. The reaction is carried out at room temperature for 3 hours and is then quenched with H2O (5 ml). The aqueous layer is extracted with AcOEt (3×5 ml) and CH2Cl2 (5 ml). The organic layers are dried over MgSO4 and concentrated under reduced pressure. The crude product is purified over silica gel chromatography (eluant CH2Cl2/AcOEt 7:3) to afford the product as a white solid (15 mg, 0.03 mmol) in 50% yield.
1H NMR (300 MHz, DMSO-d6) δ 11.98 (br s, 1H), 10.50 (br s, 1H), 8.83 (d, 1H, J=2.1 Hz), 8.60 (d, 1H, J=2.3 Hz), 8.59 (d, 1H, J=1.5 Hz), 7.92 (d, 1H, J=1.5 Hz), 7.89 (d, H, J=1.7 Hz), 7.82 (dd, 1H, J=1.9, 8.6 Hz), 7.77 (d, 1H, J=8.9 Hz), 7.70-7.67 (m, 2H), 7.62 (d, 2H, J=8.7 Hz), 7.53 (d, 1H, J=1.7 Hz), 7.52 (d, 1H, J=3.0 Hz), 7.44 (dd, 1H, J=7.9, 8.1 Hz), 7.17 (d, 1H, J=1.7 Hz), 7.13 (d, 2H, J=8.9 Hz), 3.82 (s, 3H).
To a solution of 3-(4-(3-chloro-9H-pyrido (100 mg, mmol, 1 eq) in anhydrous dioxane (50 ml), Pd(PPh3)4 (mg, mmol, 0.15 eq), K2CO3 (mg, mmol, eq), (E)-2′-(phenyl)ethenylboronic acid (mg, mmol, eq) and H2O (ml) are respectively added under argon. The mixture is stirred at 100° C. overnight, filtered over Mite which is washed with AcOEt and THF. The crude product (brown oil) is purified over silica chromatography (eluted with CH2Cl2/PE 7:3) to give the product R338 as a white solid (39 mg, 0.08 mmol) with a 77% yield. 1HNMR (CDCl3 300 MHz) δ ppm 8.60 (br s, 1H), 8.56 (br. s, 1H), 8.25 (br.s, 1H), 7.70 (br. d, 1H, J=8.7 Hz); 7.62 (d, 2H, J=5.9 Hz), 7.60-7.52 (m, 3H), 7.40 (br. t, 2H, J=7.1 Hz), 7.33-7.16 (3H, m), 7.01 (d, 2H, J=5.9 Hz), 4.11 (t, 2H, J=5.5 Hz), 2.75 (br. s, 6H), 2.11 (br. s, 2H), 1.17 (br. s, 6H).
The following compounds can be prepared by the same method
A solution of R296 or R297, aniline (1.2 equiv.), tris(dibenzylideneacetone)palladium (0.05 equiv.), dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.1 equiv.), and K2CO3 (3 equiv.) in degassed t-BuOH (1.5 mL/mmol R296 or R297) was stirred overnight at 100° C. in a sealed tube. After cooling at room temperature, the mixture was quenched with water and extracted with EtOAc. The organic layer was dried over MgSO4, filtered through Celite and concentrated under reduced pressure.
C—N Coupling at C2
The crude product was purified by flash chromatography (CH2Cl2/PE 9:1) to afford R317 in 55% yield as a red solid; 1H-NMR (300 MHz, DMSO-d6): δ 11.62 (bs, 1H), 9.76 (bs, 1H), 8.93 (t, 1H, J=2.3 Hz), 8.31 (d, 1H, J=8.3 Hz), 8.15 (ddd, 1H, J=0.8, 2.3, 8.2 Hz), 7.95 (d, 1H, J=7.5 Hz), 7.73 (ddd, 1H, J=0.8, 2.3, 8.2 Hz), 7.56 (t, 1H, J=8.2 Hz), 7.43 (d, 1H, J=7.9 Hz), 7.30 (td, 1H, J=1.0, 7.4 Hz), 7.15 (td, 1H, J=1.0, 7.4 Hz), 6.74 (d, 1H, J=8.3 Hz); MS (ESI) m/z 304 [M+H+].
The crude product was purified by flash chromatography (CH2Cl2/PE 9:1) to afford R319 in 53% yield as a red solid; 1H-NMR (300 MHz, DMSO-d6): δ 10.38 (bs, 1H), 8.87 (d, 1H, J=8.7 Hz), 8.53 (bs, 1H), 8.25 (t, 2H, J=8.5 Hz), 7.96 (d, 1H, J=7.9 Hz), 7.57 (td, 1H, J=1.5, 8.9 Hz), 7.42-7.37 (m, 3H), 6.95 (td, 1H, J=1.1, 8.5 Hz), 6.87 (d, 1H, J=8.3 Hz); MS (ESI) m/z 304 [M+H+].
Using the general procedure, R297 (100 mg, 0.498 mmol), Pd2dba3 (37.0 mg, 0.04 mmol, 0.08 equiv.), X-Phos (37.0 mg, 0.080 mmol, 0.16 equiv.), aniline (60 μL, 0.650 mmol, 1.3 equiv.) and LiN(TMS)2 (1.5 mL, 1.0 M in THF, 3.00 mmol, 6 equiv.) were heated to 65° C. overnight. The crude material was purified by column chromatography (CH2Cl2) to give the desired product as a white solid (80 mg, 62%). 1H-NMR (300 MHz, acetone-d6): δ 10.56 (bs, 1H), 8.40 (bs, 1H), 8.20 (d, 1H, J=8.5 Hz), 7.91 (d, 1H, J=7.7 Hz), 7.85 (d, 2H, 17.7 Hz), 7.48 (d, 1H, J=8.1 Hz), 7.31-7.25 (m, 3H), 7.15 (t, 1H, J=7.5 Hz), 6.92 (t, 1H, J=7.2 Hz), 6.73 (d, 1H, J=8.5 Hz); MS (ESI) m/z 258 [M+H+].
C—N Coupling at C4
The crude product was purified by flash chromatography (CH2Cl2/PE 9:1) to afford R322 in 80% yield as a yellow solid; 1H-NMR (300 MHz, DMSO-d6): δ 11.62 (bs, 1H), 9.76 (bs, 1H), 8.23 (d, 1H, J=5.5 Hz), 8.06 (t, 1H, J=2.2 Hz), 8.00 (d, 1H, J=7.4 Hz), 7.82 (ddd, 1H, J=0.8, 2.5, 8.3 Hz), 7.67 (dt, 1H, J=0.9, 7.5 Hz), 7.58 (t, 1H, J=7.9 Hz), 7.39 (td, 1H, J=1.1, 7.5 Hz), 7.15 (td, 1H, J=1.1, 7.5 Hz), 6.98 (d, 1H, J=5.5 Hz); MS (ESI) m/z 305.2 [M+H+], HRMS (ESI): Calcd for C17H11N3O2: 305.1039. Found: 305.1041.
The crude product was purified by flash chromatography (CH2Cl2/PE 9:1) to afford R323 in 73% yield as a red solid, 1H-NMR (300 MHz, DMSO-d6): δ 11.93 (bs, 1H), 9.71 (bs, 1H), 8.31 (d, 1H, J=5.5 Hz), 8.24 (dd, 1H, J=1.3, 8.0 Hz), 7.86 (d, 1H, J=7.9 Hz), 7.61 (td, 1H, J=1.5, 7.9 Hz), 7.53-7.40 (m, 3H), 7.19-7.10 (m, 3H); 13C-NMR (75 MHz, DMSO-d6): δ 153.6 (C), 147.0 (CH), 142.2 (C), 138.3 (C), 138.2 (C), 136.6 (C), 135.8 (CH), 126.3 (CH), 125.9 (CH), 121.8 (CH), 121.0 (CH), 119.9 (CH), 119.5 (CH), 119.2 (C), 111.1 (CH), 106.1 (C), 105.8 (CH); MS (ESI) m/z 305.2 [M+H+], HRMS (ESI): Calcd for C17H11N3O2: 305.1039. Found: 305.1036.
The crude product was purified by flash chromatography (CH2Cl2/EtOAc 6:4) to afford R324 in 64% yield as a red solid, 1H-NMR (300 MHz, DMSO-d6): δ 11.64 (bs, 1H), 8.5 (bs, 1H), 8.11-8.07 (m, 2H), 7.44 (d, 1H, J=7.7 Hz), 7.36 (td, 1H, 0.9, 7.5 Hz), 7.25 (t, 1H, J=8.5 Hz), 7.14 (td, 1H, J=0.9, 7.5 Hz), 6.89-6.86 (m, 2H), 6.85 (d, 1H, J=5.6 Hz), 6.63 (dt, 1H, J=1.7, 8.3 Hz); 13C-NMR (75 MHz, DMSO-d6): δ 153.7 (C), 146.8 (C), 145.9 (C), 142.7 (C), 137.6 (C), 129.9 (CH), 124.9 (CH), 122.7 (CH), 120.0 (C), 118.8 (CH), 112.9 (CH), 110.5 (CH), 108.1 (CH), 106.4 (CH), 103.6 (C), 102.3 (CH), 54.9 (CH3); MS (ESI) m/z 290.3 [M+H+],
HRMS (ESI): Calcd for C18H14N2O: 290.1293. Found: 290.1288.
C—N Coupling at C3
A solution of the corresponding 3-chloro α-carboline(1 equiv.), aniline (1.2 equiv.), tris(dibenzylideneacetone)palladium (0.05 equiv.), dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.1 equiv.), and NaOtBu (3 equiv.) in degassed t-BuOH (1.5 mL/mmol R 248) was stirred overnight at 100° C. in a sealed tube. After cooling at room temperature, the mixture was quenched with water and extracted with EtOAc. The organic layer was dried over MgSO4, filtered through celite and concentrated under reduced pressure.
The crude product was purified by flash chromatography (CH2Cl2/EtOAc 8:2) to afford R344 in 82% yield as a yellow solid, 1H-NMR (300 MHz, DMSO-d6): δ 11.62 (bs, NH), 8.30 (d, 1H, J=2.3 Hz); 8.23 (d, 1H, J=2.3 Hz), 8.14 (d, 1H, J=7.7 Hz), 8.01 (bs, NH), 7.46 (d, 1H, J=7.5 Hz); 7.42 (td, 1H, J=0.8, 8.1 Hz), 7.16 (td, 1H, J=1.3, 7.7 Hz), 7.08 (t, 1H, J=7.9 Hz), 6.48 (dd, 1H, J=1.7, 7.9 Hz), 6.45 (t, 1H, J=2.3 Hz), 6.31 (dd, 1H, J=2.3, 8.1 Hz), 3.68 (s, 3H);
The crude product was purified by flash chromatography (CH2Cl2/EtOAc 6:4) to afford 47 in 64% yield as a red solid, 1H-NMR (300 MHz, DMSO-d6): δ 11.61 (bs, 1H), 8.30 (d, 1H, J=2.4 Hz), 8.24 (d, 1H, J=2.4 Hz), 8.13 (d, 1H, J=7.7 Hz), 8.01 (bs, NH), 7.47-7.73 (m, 1H), 7.41 (td, 1H, J=1.1, 8.1 Hz), 7.19 (d, 2H, J=7.5 Hz), 7.16 (td, 1H, J=1.5, 6.57 Hz), 6.93 (d, 2H, J=7.7 Hz), 6.72 (t, 1H, J=7.1 Hz); MS (ESI) m/z 260.3 [M+H+], HRMS (ESI): Calcd for C17H13N3: 260.1188. Found 260.1189.
C—N Coupling at C2 with 6-substituted-α-carbolines:
Using the general procedure, 2-chloro-6-(2′-phenylethyenyl)-9H-pyrido[2,3-b]indole (54 mg, 0.178 mmol), Pd2dba3 (13.0 mg, 0.014 mmol, 0.08 equiv.), X-Phos (13.0 mg, 0.029 mmol, 0.16 equiv.), aniline (21 μL, 0.231 mmol, 1.3 equiv.), K2CO3 (74 mg, 0.53 mmol, 3 equiv.) and t-BuOH (0.4 mL) were heated to 65° C. overnight. The crude material was purified by column chromatography (EtOAc/PE 15:85) to give the desired product as a yellow solid (40 mg, 62%). 1H-NMR (300 MHz, DMSO-d6): δ 11.59 (bs, 1H), 9.23 (bs, 1H), 8.24 (d, 1H, J=8.5 Hz), 8.15 (d, 1H, J=0.8 Hz), 7.84 (d, 2H, J=7.5 Hz), 7.60 (d, 2H, J=7.3 Hz), 7.55 (d, 1H, J=1.3, 8.3 Hz), 7.40-7.18 (m, 8H), 6.93-6.88 (m, 1H), 6.71 (d, 1H, J=8.5 Hz); 13C-NMR (75 MHz, DMSO-d6): δ 154.4 (C), 151.4 (C), 141.8 (C), 137.6 (C), 137.3 (C), 130.1 (CH), 129.7 (CH), 128.7 (2 CH), 128.6 (2 CH), 128.5 (C), 126.9 (CH), 126.0 (2 CH), 125.3 (CH), 122.8 (CH), 122.0 (C), 120.3 (CH), 118.0 (2 CH), 117.3 (CH), 110.9 (CH), 106.5 (C), 103.7 (CFI); MS (ESI) m/z 362 [M+H+], HRMS (ESI): Calcd for C25H19N3: 362.1657. Found: 362.1653.
Using the general procedure, 2-Chloro-6-(2′-phenylethyenyl)-9H-pyrido[2,3-b]indole (43 mg, 0.142 mmol), Pd2 dba3 (11.0 mg, 0.011 mmol, 8 mol % Pd), L (11.0 mg, 0.023 mmol, 16 mol %), 2-nitro-aniline (23 μL, 0.185 mmol, 1.3 equiv.), K2CO3 (59 mg, 0.426 mmol, 3 equiv.) and t-BuOH (0.3 mL) were heated to 100° C. overnight. The crude material was purified by column chromatography (CH2Cl2/PE 7:3) to give the desired product as a yellow solid (40 mg, 62%). 1H-NMR (300 MHz, DMSO-d6): δ 11.68 (bs, 1H), 9.90 (bs, 1H), 8.39 (d, 1H, J=8.3 Hz), 8.33 (d, 1H, J=8.5 Hz), 8.25 (d, 1H, J=0.6 Hz), 8.09 (dd, 1H, J=1.3, 8.5 Hz), 7.69 (td, 1H, J=1.1, 8.1 Hz), 7.62-7.59 (m, 3H), 7.41-7.35 (m, 4H), 7.27-7.19 (m, 3H), 7.13 (td, 1H, J=1.0, 8.3 Hz), 6.94 (d, 1H, J=8.3 Hz)
C—N Coupling at C3 with 6-substituted-α-carbolines:
3-chloro-6-(2′-phenylethyl)-9H-pyrido[2,3-b]indole (50 mg, 0.16 mmol, 1 equiv.), Pd2 dba3 (8.2 mg, 0.008 mmol, 0.05 equiv.), 2-Dicyclohexyl phosphino-2′,4′,6′-Triisopropylbiphenyl (L2)(8.1 mg, 0.016 mmol, 0.1 equiv.), sodium tert-butoxide (36 mg, 0.37 mmol, 2.2 equiv.) are introduced in a schlenk tube and flushed with N2. tert-butanol (0.255 ml) and m-Anisidine (25 mg, 0.20 mmol, 1.2 equiv.) are then added. The reaction is carried out at 100° C. overnight and then filtered over celite and evaporated under reduced pressure. The crude product (yellow oil) is purified over silica gel chromatography (eluant AcOEt/PE 4:6, 6:4) to afford the product as a green solid (18 mg, 0.046 mmol) in 29% yield. mp=161-165; IR 3359, 3145, 3022, 1595, 1494, 1467, 1383, 1218, 1151, 1038, 968, 891, 809, 771, 685 cm−1; 1H NMR (300 MHz, CDCl3) 9.94 (br s, 1H, H9), 8.18 (s, 1H, H2), 7.78 (s, 1H, H4), 7.41 (d, 1H, J=8.3 Hz, H8), 7.32-7.14 (m, 71-1, CHPh+CHAn), 6.52 (d, 1H, J=8.1 Hz, H7), 6.47-6.44 (m, 2H, H5+CHPh or CHAn), (br s, 1H, NHAn), 3.77 (s, 3H, OCH3), 3.12-2.97 (m, 4H, 2CH2); MS (+ESI) [M+H+]=394.3
The Following Compounds can be Prepared by the Same Method
To a solution of R317 (104 mg, 0.343 mmol) in anhydrous CH2Cl2 (3 mL) was added AlCl3 (206 mg, 1.54 mmol, 4.5 equiv.) and bromoacetyl bromide (33 μL, 0.377 mmol, 1.1 equiv.) diluted in CH2Cl2 (1 mL) at room temperature under inert atmosphere. The mixture was stirred at reflux until completion of the reaction (followed by t.l.c.). The resulting mixture was then cautiously quenched at 0° C. with H2O. It was extracted with the mixture of EtOAc/DMF (99:1). The resulting organic layer was washed with saturated aqueous NaHCO3 solution and brine, dried over MgSO4, filtered and solvents were removed under reduced pressure. To diethylamino)ethylthiol (64 mg, 0.376 mmol, 1.1 equiv.) in anhydrous DMF (700 μL) under argon at 0° C. was introduced NaH (17 mg, 0.414 mmol). After 30 min, the product obtained in the previous step (80 mg, 0.188 mmol) was introduced. This solution was stirred at room temperature for 4 h and then the crude mixture was concentrated under vacuum. This mixture was poured with 5% aqueous NaHCO3 and extracted with EtOAc. The combined organic layers were dried (MgSO4), and the solvent was removed under reduced pressure. The crude product was purified by recrystallization from CH2Cl2/PE to furnish desired compound R321. 1H-NMR (300 MHz, DMSO-d6): δ 12.07 (bs, 1H), 9.87 (bs, 1H), 8.93-8.92 (m, 1H), 8.71 (s, 1H), 8.44 (d, 1H, J=8.7 Hz), 8.17-8.14 (m, 1H), 7.97 (dd, 1H, J=1.7, 8.5 Hz), 7.76 (d, 1H, J=6.8 Hz), 7.58 (t, 1H, J=8.3 Hz), 7.49 (d, 1H, J=8.3 Hz), 4.07 (s, 2H), 2.61 (s, 4H), 2.44 (s, 2H), 0.92 (t, 6H, J=Hz), 0.83 (bs, 2H), MS (ESI) m/z 478 [M+H+];
A solution of 9-EOM protected 2- or 4-chloro α-carbolines, the appropriate phenol (1.3 equiv), tris(dibenzylideneacetone)dipalladium (0.08 equiv), dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.16 equiv), and K2CO3 (2.2 equiv) in degassed toluene (1.5 mL per mmol) was stirred overnight at 110° C. in a sealed tube. After cooling to r.t., the products were extracted from the water layer with ethyl acetate, dried over MgSO4, filtered through celite and solvents were removed under reduced pressure.
The product was purified by column chromatography on silica gel (CH2Cl2/EP 1/1) and recrystallisation in EtOH to afford 47 in 62% yield as a yellow solid; 1H NMR (300 MHz, CDCl3): δ 8.35 (d, 1H, J=8.1 Hz); 8.16-8.15 (m, 1H); 8.08 (ddd, 1H, J=2.1, 3.2, 5.85 Hz); 8.00 (d, 1H, J=7.7 Hz); 7.63-7.55 (m, 3H); 7.48 (td, 1H, J=1.1, 7.4 Hz); 7.32 (td, 1H, J=1.1, 8.3 Hz), 5.68 (s, 2H); 3.41 (q, 2H, J=6.9 Hz); 1.06 (t, 3H, J=6.9 Hz); 13C NMR (75 MHz, CDCl3) δ=160.6 (C), 155.3 (CH), 150.1 (C), 149.0 (C), 139.2 (C), 132.1 (CH), 130.0 (CH), 127.3 (CH), 126.2 (CH), 121.2 (CH), 121.0 (C), 120.2 (CH), 119.1 (CH), 116.3 (CH), 112.2 (C), 110.6 (CH), 104.0 (CH), 70.9 (CH2), 64.4 (CH2), 14.9 (CH3); MS (SIMS) m/z 363 [M+]; HRMS (LSIMS): Calcd for C18H13N3O3: 363.1219. Found: 363.1218.
The product was purified by column chromatography on silica gel (CH2Cl2) to afford 48 in 89% yield as a yellow solid; 1H NMR (300 MHz, CDCl3): δ 8.42 (d, 1H, J=2.3 Hz); 8.28 (d, 1H, J=2.3 Hz); 8.03 (d, 1H, J=7.7 Hz); 7.62 (d, 1H, J=8.3 Hz); 7.56 (ddd, 1H, J=1.1, 7.1 Hz); 7.34 (ddd, 1H, J=1.1, 8.1 Hz), 5.90 (s, 2H); 3.54 (q, 2H, J=6.9 Hz); 1.15 (t, 3H, J=6.9 Hz);
The product was purified by column chromatography on silica gel (CH2Cl2/EP 9/1) to afford 49 in 86% yield as a white solid; 1H NMR (300 MHz, CDCl3): δ 8.37 (d, 1H, J=5.6 Hz); 8.13 (d, 2H, J=7.9 Hz); 8.08 (t, 1H, J=2.1 Hz); 7.68 (d, 1H, J=8.3 Hz); 7.62 (d, 1H, J=7.9 Hz); 7.58-7.51 (m, 2H); 7.31 (td, 1H, J=1.0, 7.9 Hz); 6.59 (d, 1H, J=5.6 Hz); 5.96 (s, 2H); 3.59 (q, 2H, J=6.9 Hz); 1.17 (t, 3H, J=6.9 Hz);
The product was purified by column chromatography on silica gel (CH2Cl2) to afford 50 in 78% yield as a yellow oil; 1H NMR (300 MHz, CDCl3): δ 8.29 (d, 1H, J=5.6 Hz); 8.26 (d, 1H, J=7.7 Hz); 7.66 (d, 1H, J=8.1 Hz); 7.52 (td, 1H, J=1.3, 7.3 Hz); 7.38-7.29 (m, 2H); 6.85-6.79 (m, 1H); 6.55 (d, 1H, J=5.9 Hz); 5.94 (s, 2H); 3.82 (s, 3H); 3.58 (q, 2H, J=6.9 Hz); 1.16 (t, 3H, J=6.9 Hz);
A Schlenk tube with stir bar was charged with Pd(Cl)2(CH3CN)2 (8 mg, 0.08 equiv), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (30 mg, 0.16 equiv), chloro-α-carbolines (100 mg, 1 equiv), Cs2CO3 (325 mg, 2.6 equiv.). The tube was evacuated and back-filled with argon (this was repeated three additional times). A anhydrous acetonitrile (700 μL) was added (when degassed solvent was used) and then the alkyne (1.3 equiv.) was injected and the reaction mixture was allowed to stir at desired temperature overnight. After cooling to r.t., the products were extracted from the water layer with ethyl acetate, dried over MgSO4, filtered through celite and solvents were removed under reduced pressure.
The product was purified by column chromatography on silica gel (CH2Cl2) to afford R342 in 64% yield as a yellow solid; 1H NMR (300 MHz, DMSO-d6): δ 11.87 (bs, NH); 8.54 (d, 1H, J=7.9 Hz); 8.19 (d, 1H, J=7.7 Hz); 7.66-7.62 (m, 2H); 7.52-7.46 (m, 6H); 7.25 (ddd, 1H, J=1.5, 6.8 Hz).
The product was purified by column chromatography on silica gel (CH2Cl2/EtOAc 9/1) to afford R341 in 61% yield as a yellow solid; 1H NMR (300 MHz, Acetone-d6): δ 11.75 (bs, NH); 8.45 (d, 1H, J=7.7 Hz); 8.14 (d, 1H, J=7.7 Hz); 7.50 (d, 1H, J=7.5 Hz); 7.45 (ddd, 1H, J=1.1, 6.8 Hz); 7.27 (d, 1H, J=7.8 Hz); 7.22 (ddd, 1H, J=1.7, 8.1 Hz), 2.47 (t, 2H, J=7.0 Hz); 1.62-1.57 (m, 2H); 1.04 (t, 3H, J=7.8 Hz).
A Schlenk tube with stir bar was charged with Pd(Cl)2(CH3CN)2 (0.08 equiv), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.16 equiv), N-EOM protected chloro-α-carbolines (1 equiv), Cs2CO3 (2.6 equiv.). The tube was evacuated and back-filled with argon (this was repeated three additional times). An anhydrous acetonitrile (0.6 mmol/mL) was added (when degassed solvent was used) and then the alkyne (1.3 equiv.) was injected and the reaction mixture was allowed to stir at desired temperature overnight. After cooling to r.t., the products were extracted from the water layer with ethyl acetate, dried over MgSO4, filtered through celite and solvents were removed under reduced pressure.
C—C(sp) at C2
The product was purified by column chromatography on silica gel (CH2Cl2/EP 7/3) to afford 64 in 80% yield as a yellow solid; 1H NMR (300 MHz, CDCl3): δ 8.28 (d, 1H, J=7.9 Hz); 8.05 (d, 1H, J=7.7 Hz); 7.69-7.64 (m, 3H); 7.54 (td, 1H, J=1.1, 7.3 Hz); 7.49 (d, 1H, 7.7 Hz); 7.39-7.37 (m, 3H); 7.33 (td, 1H, J=1.0, 7.1 Hz); 5.97 (s, 1H); 3.57 (q, 2H, J=6.9 Hz); 1.16 (t, 3H, J=6.9 Hz);
The product was purified by column chromatography on silica gel (CH2Cl2/EP 6/4) to afford 65 in 85% yield as a yellow solid; 1H NMR (300 MHz, CDCl3): δ 8.21 (d, 1H, J=7.9 Hz); 8.02 (d, 1H, J=7.7 Hz); 8.15 (d, 1H, J=8.1 Hz); 7.51 (td, 1H, J=1.3, 7.4 Hz); 7.33 (d, 1H, J=7.9 Hz); 7.31 (td, 1H, J=1.0, 8.3 Hz); 5.94 (s, 1H); 3.53 (q, 2H, J=7.0 Hz); 2.48 (t, 2H, J=7.3 Hz); 1.71 (sex, 2H, J=7.3 Hz); 1.13 (t, 3H, J=7.0 Hz); 1.09 (t, 3H, J=7.3 Hz)
The product was purified by column chromatography on silica gel (CH2Cl2/EP 4/6) to afford 66 in 87% yield as a yellow oil; 1H NMR (300 MHz, CDCl3): 8.22 (d, 1H, J=7.9 Hz); 8.02 (d, 1H, J=7.9 Hz); 7.65 (d, 1H, J=8.3 Hz); 7.51 (ddd, 1H, J=1.1, 7.1, 8.3 Hz); 7.36 (d, 1H, J=7.9 Hz); 7.31 (d, 1H, J=1.1, 7.9 Hz); 6.36 (sept, 1H, J=1.9 Hz); 5.94 (s, 2H); 3.54 (q, 2H, J=7.1 Hz); 2.33-2.28 (m, 2H); 2.20-2.15 (m, 2H); 1.73-1.61 (m, 4H); 1.13 (t, 3H, J=7.1 Hz).
The product was purified by column chromatography on silica gel (CH2Cl2/EP 4/6) to afford 67 in 79% yield brown oil; 1H NMR (300 MHz, CDCl3): δ 8.20 (d, 1H, J=7.9 Hz); 8.01 (d, 1H, J=7.9 Hz); 7.64 (d, 1H, J=8.3 Hz); 7.51 (td, 1H, J=1.1, 7.2 Hz); 7.33 (d, 1H, J=7.9 Hz); 7.30 (td, 1H, J=0.75, 7.9 Hz); 5.93 (s, 2H); 3.53 (q, 2H, J=7.1 Hz); 2.72-2.63 (m, 1H); 1.98-1.94 (m, 2H); 1.82-1.78 (m, 2H); 1.68-1.56 (m, 3H); 1.44-1.33 (m, 3H); 1.13 (t, 3H, J=7.0 Hz); 13C-NMR (75 MHz, CDCl3): δ 151.7 (C), 139.9 (C), 139.9 (C), 128.1 (CH), 127.2 CH), 120.9 (CH), 120.9 (CH), 120.8 (C), 120.1 (CH), 115.2 (C), 110.7 (CH), 94.7 (C), 81.5 (C), 71.1 (CH2), 64.2 (2×CH2), 32.5 (2×CH2), 29.9 (CH2), 26.0 (CH), 25.1 (CH2), 15.1 (CH3).
C—C(sp) at C3
A Schlenk tube with stir bar was charged with Pd(Cl)2(CH3CN)2 (0.08 equiv), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.16 equiv), chloro-α-carbolines (1 equiv), Cs2CO3 (2.6 equiv.). The tube was evacuated and back-filled with argon (this was repeated three additional times). An anhydrous acetonitrile (0.6 mmol/mL) was added (when degassed solvent was used) and then the alkyne (1.3 equiv.) was injected and the reaction mixture was allowed to stir at desired temperature overnight. After cooling to r.t., the products were extracted from the water layer with ethyl acetate, dried over MgSO4, filtered through celite and solvents were removed under reduced pressure.
The product was purified by column chromatography on silica gel (CH2Cl2/EP 8/2) to afford 68 in 96% yield as a yellow solid; 1H NMR (300 MHz, CDCl3): δ 8.66 (d, 1H, J=1.9 Hz); 8.45 (d, 1H, J=1.9 Hz); 8.06 (d, 1H, J=7.7 Hz); 7.66 (d, 1H, J=8.31 Hz); 7.60-7.53 (m, 3H); 7.41-7.32 (m, 4H); 5.93 (s, 1H); 3.57 (q, 2H, J=6.9 Hz); 1.16 (t, 3H, J=6.9 Hz); MS (ESI) m/z 281.3, 327.0 [M+H+-EtOH]+, [M+H]+;
C—C(sp) at C4
A Schlenk tube with stir bar was charged with Pd(Cl)2(CH3CN)2 (0.08 equiv), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.16 equiv), chloro-α-carbolines (1 equiv), Cs2CO3 (2.6 equiv.). The tube was evacuated and back-filled with argon (this was repeated three additional times). An anhydrous acetonitrile (0.6 mmol/mL) was added (when degassed solvent was used) and then the alkyne (1.3 equiv.) was injected and the reaction mixture was allowed to stir at desired temperature overnight. After cooling to r.t., the products were extracted from the water layer with ethyl acetate, dried over MgSO4, filtered through celite and solvents were removed under reduced pressure
The product was purified by column chromatography on silica gel (CH2Cl2/EP 9/1) to afford 69 in 96% yield as a yellow solid; NMR (300 MHz, CDCl3): δ 8.61 (d, 1H, J=7.7 Hz); 8.45 (d, 1H, J=5.1 Hz); 7.72 (dd, 1H, J=3.8, 7.5 Hz); 7.68 (d, 1H, J=8.1 Hz); 7.57 (td, 1H, J=1.0, 7.1 Hz); 7.48-7.43 (m, 3H); 7.37 (d, 1H, J=1.0, 7.9 Hz); 7.30 (d, 1H, J=5.3 Hz); 5.95 (s, 2H); 3.52 (q, 2H, J=6.9 Hz); 1.16 (t, 3H, J=6.9 Hz);
The product was purified by column chromatography on silica gel (CH2Cl2) to afford 70 in 90% yield as a yellow oil; 1H NMR (300 MHz, CDCl3): δ 8.52 (d, 1H, J=7.7 Hz); 8.38 (d, 1H, J=5.2 Hz); 7.65 (d, 1H, J=8.3 Hz); 7.54 (td, 1H, J=1.1, 7.2 Hz); 7.33 (td, 1H, J=1.1, 8.2 Hz); 7.17 (d, 1H, J=5.2 Hz); 5.92 (s, 2H); 3.54 (q, 2H, J=7.0 Hz); 2.63 (t, 2H, J=7.3 Hz); 1.81 (sex, 2H, J=7.3 Hz); 1.16 (t, 3H, J=7.3 Hz); 1.14 (t, 3H, J=7.0 Hz).
The product was purified by column chromatography on silica gel (CH2Cl2/EP 8/2) to afford 71 in 77% yield as a yellow oil; NMR (300 MHz, CDCl3): δ 8.52 (d, 1H, J=7.7 Hz); 8.39 (d, 1H, J=5.1 Hz); 7.65 (d, 1H, J=8.3 Hz); 7.55 (td, 1H, J=1.1, 7.1 Hz); 7.34 (td, 1H, J=1.1, 8.2 Hz); 7.18 (d, 1H, J=5.1 Hz); 6.46 (sept, 1H, J=1.9 Hz), 5.92 (s, 2H); 3.54 (q, 2H, J=7.0 Hz); 2.39-2.37. (m, 2H); 2.28-2.22 (m, 2H); 1.81-1.65 (m, 4H); 1.14 (t, 3H, J=7.0 Hz).
C—C(sp) at C6
To a solution of 9-benzenesulfonyl-6-bromo-3-chloro-9-9H-pyrido[2,3-b]indole (100 mg, 0.24 mmol, 1 equiv.) in anhydrous DMF (1.5 ml) under argon, Pd(Cl)2(PPh3)2 (17 mg, 0.024 mmol, 0.1 equiv.), CuI (9 mg, 0.048 mmol, 0.2 equiv.), PPh3 (6 mg, 0.024 mmol, 0.1 equiv.), 1-ethynylbenzene (0.079 ml, 0.72 mmol, 3 equiv.) and triethylamine (3 ml) are respectively added. The mixture is stirred at 80° C. overnight and then poured over water (5 ml) and extracted with CH2Cl2 (3×10 ml). The combined organic layers are washed with brine (3×10 ml) and concentrated under reduced pressure. The crude residue is purified over silica gel column (eluant CH2Cl2/PE 1:1) to afford the product 59 as a white solid (98 mg, 0.28 mmol) in 92% yield. NMR (300 MHz, CDCl3) δ 8.51 (d, 1H, J=2.3 Hz), 8.46 (d, 1H, J=8.9 Hz), 8.15 (d, 2H, J=2.3 Hz), 8.10 (dd, 2H, J=1.6, 15 Hz), 7.76 (dd, 1H, J=1.7, 8.9 Hz), 7.58-7.54 (m, 3H), 7.44 (dd, 2H, J=7.3, 8.3 Hz), 7.38 (d, 1H, J=1.7 Hz), 7.36 (d, 2H, J=2.3 Hz).
The following compound can be prepared by the same method:
To a solution of 9-benzenesulfonyl-3-chloro-6-(2-phenylethynyl)-9H-pyrido[2,3-b]indole (88 mg, 0.20 mmol, 1 equiv.) in anhydrous THF under argon, TBAF 1M in THF (1 ml, 1 mmol, 5 equiv.) is added dropwise. The reaction is carried out at reflux for 4 hours and then evaporated. The crude product (yellow solid) is purified over silica gel chromatography (CH2Cl2/AcOEt 9:1) to afford the product 60 as a white solid (53 mg, 0.18 mmol) in 88% yield. 1H NMR (300 MHz, DMSO d6) δ 12.25 (br s, 1H), 8.77 (d, 1H, J=2.5 Hz), 8.49 (br s, 1H), 8.47 (d, 1H, J=2.5 Hz), 7.67 (dd, 1H, J=1.5, 8.5 Hz), 7.59-7.54 (m, 3H), 7.45-7.42 (m, 3H).
The following compound can be prepared by the same method:
A solution of 9-benzenesulfonyl-3-chloro-6-(2-phenylethynyl)-9H-pyrido[2,3-b]indole (200 mg, 0.45 mmol, 1 equiv.) in anhydrous ethanol (25 ml) was treated with 10% palladium on carbon (50 mg, 0.047 mmol, 0.1 equiv.) and then stirred at room temperature under an atmosphere of H2 overnight. The reaction mixture was filtered through celite and then concentrated under reduced pressure. The crude product (pale yellow solid) was purified over silica gel chromatography (eluant CH2Cl2/PE 7:3) to afford the product 61 as a white solid (183 mg, 0.41 mmol) in 91% yield. mp=158-162° C.; IR 3057, 3023, 2926, 1494, 1475, 1432, 1376, 1366, 1255, 1182, 1712, 1090, 977, 908, 713, 683 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.48 (d, 1H, J=2.3 Hz, H2), 8.36 (d, 1H, J==8.7 Hz, H8), 8.12 (m, 3H, H4+H7+CHP), 7.67 (s, 1H, H5), 7.56-7.52 (m, 1H, CHP+CHPh), 7.45-7.38 (m, 3H, 3CHP or CHPh), 7.32-7.18 (m, 5H, CHP+CHPh), 3.12-2.97 (m, 4H, 2CH2); 13C NMR (75 MHz, CDCl3) δ 149.2 (C), 145.4 (CH), 141.4 (C), 138.7 (C), 138.1 (C), 137.0 (C), 134.2 (CH), 130.0 (CH), 129.1 (2×CH), 128.6 (2×CH), 128.6 (2×CH), 128.9 (2×CH), 127.6 (CH), 127.5 (C), 126.3 (CH), 122.0 (C), 120.6 (CH), 120.0 (C), 115.1 (CH), 38.2 (CH2), 38.8 (CH2); MS (+ESI) [M+H+]=447.1
To a solution of 9-(benzenesulfonyl)-3-chloro-6-(2′-phenylethyl)-9H-pyrido[2,3-b]indole (170 mg, 0.38 mmol, 1 equiv.) in THF (18 ml) under argon TBAF 1M in THF (1.91 ml, 1.91 mmol, 5 equiv.) was added dropwise. The reaction was carried out at reflux for 4 hours and then evaporated. The crude product (brown oil) was purified over silica gel chromatography (eluant AcOEt/PE 1:1) to afford the product R351 as a white solid (108 mg, 0.35 mmol) in 91% yield. mp=216-220° C.; IR 3111, 3028, 2921, 2851, 1600, 1490, 1453, 1389, 1271, 1236, 1087, 1030, 931, 732, 682 cm−1; 1H NMR (300 MHz, DMSO d6) δ 12.31 (br s, 1H, H9), 9.02 (d, 1H, J=2.5 Hz, H2), 8.80 (d, 1H, J=2.4 Hz, H4), 8.48 (s, 1H, H5), 7.85-7.77 (m, 2H, H8+H7), 7.72 (m, 4H, CHPh), 7.61-7.57 (m, 1H, CHPh), 3.46-3.36 (m, 4H, 2CH2); 13C NMR (75 MHz, DMSO d6) δ 150.3 (C), 143.8 (CH), 141.6 (C), 138.2 (C), 133.0 (C), 128.4 (2×CH), 128.3 (CH), 128.2 (2×CH), 127.8 (CH), 125.8 (CH), 121.5 (C), 120.9 (CH), 119.6 (C), 116.3 (C), 111.2 (CH), 37.7 (CH2), 37.3 (CH2); MS (+ESI) [M+H+]=307.2
The following compound can be prepared by the same method:
3-chloro-6-(2′-phenylethyl)-9H-pyrido[2,3-b]indole (31 mg, 0.10 mmol, 1 equiv.), Pd(OAc)2 (2.3 mg, 0.01 mmol, 0.1 equiv.), 2-Dicyclohexyl phosphino-2′,6′-dimethoxylbiphenyl (L) (8.2 mg, 0.02 mmol, 0.2 equiv.), K3PO4 (43 mg, 0.20 mmol, 2 equiv.) and benzo[d][1,3]dioxol-5-ylboronic acid (24.9 mg, 0.15 mmol, 1.5 equiv.) are introduced in a schlenk tube and flushed with N2. Freshly distilled dioxane (0.40 ml) is then injected and the reaction is carried out at 100° C. overnight. The mixture is filtered over Mite and evaporated under reduced pressure. The crude product is purified over silica gel chromatography (eluant AcOEt/PE 4:6, 6:4). The resulting solid is washed with methanol and filtered under vacuum to give the product as a white solid (12 mg, 0.03 mmol) in 30% yield. mp=231-235° C.; IR 3028, 2901, 2837, 1610, 1512, 1490, 1466, 1446, 1396, 1279, 1225, 1034, 800, 697 cm−1; 1H NMR (300 MHz, DMSO d6) δ 11.71 (br s, 1H, H9), 8.71 (d, 1H, J=2.3 Hz, H2), 8.64 (d, 1H, J=2.3 Hz, H4), 8.10 (s, 1H, HO, 7.42-7.16 (m, 9H, H7+CHPh+CHAn), 7.05 (d, 1H, J=8.1 Hz, H8); 6.08 (s, 2H, OCH2O), 3.06-2.96 (m, 4H, CH2); 13C NMR (75 MHz, DMSO d6) δ 151.3 (C), 148.1 (C), 146.5 (C), 144.2 (CH), 141.7 (C), 137.9 (C), 132.9 (C), 132.7 (C), 128.4 (2×CH), 128.3 (2×CH), 127.3 (C), 126.3 (CH), 125.8 (CH), 120.7 (CH), 120.5 (CH), 120.4 (C), 120.2 (CH), 115.3 (C), 111.1 (C), 108.8 (CH), 107.3 (CH), 101.1 (CH2), 37.8 (CH2), 37.4 (CH2); MS (+ESI) [M+H+]=393.3
36. Alk Kinase Inhibitory Activity
Method: ELISA-Based In Vitro Kinase Assay
Recombinant ALK kinase was expressed in Sf9 insect cells using the pBlueBacHis2C baculovirus vector system and purified using an anion exchange Fast Flow Q-sepharose column (Amersham-Pharmacia Biotech) followed by HiTrap™-nickel affinity column (Amersham-Pharmacia Biotech). Purified ALK protein was used to screen inhibitors in the ELISA-based kinase assay. A Nunc Immuno 96 well plate was incubated overnight at 37° C. with coating solution (125 μL/well) containing ALK peptide substrate (ARDIYRASFFRKGGCAMLPVK) (SEQ ID NO: 1) at various concentrations in PBS. Wells were then washed with 200 μL of wash buffer (PBS-Tween 0.05%) and left to dry for at least 2 h at 37° C. The kinase reaction was performed in the presence of 50 mM Tris pH 7.5, 5 mM MnCl2, 5 mM MgCl2, 0.3 mM ATP and purified rALK in a total volume of 100 μL/well at 30° C. for 15 min. For inhibitor testing the reaction mix was preincubated with the inhibitor or solvent control for 10 min at room temperature before transferring to the ELISA plate. After the reaction wells were washed 5 times with 200 μL of wash buffer. Phosphorylated peptide was detected using 100 μL/well of a mouse monoclonal anti-phosphotyrosine antibody (clone 4G10 Upstate Biotech Ltd) diluted 1:2000 in PBS+4% BSA. After 30 min incubation at room temperature the antibody was removed and wells were washed as described above. 100 μL of a secondary antibody (anti-mouse IgG, Horseradish Peroxidase linked whole antibody, Amersham Pharmacia Biotech) diluted 1:1000 in PBS+4% BSA was added to each well and the plate was incubated again for 30 min at room temperature before washing as above. The plate was developed using 100 μL/well TMB Substrate Solution (Endogen) and the reaction was stopped by adding an equiv.ual volume of H2SO4 0.36 M. Finally, the absorbance was read at 450 nm using an Ultrospec® 300 spectrophotometer (Amersham-Pharmacia Biotech). The concentration of the test solution showing 50% inhibition as compared with the control was expressed as IC50 (μM).
37. Abl T315I Mutant Kinase Inhibitory Activity
Method: ELISA-Based In Vitro Kinase Assay
Recombinant Abl T315I protein was expressed in Sf9 cells using the pBlueBacHis2C baculovirus expression vector. Abl T315I was purified using an anion exchange Fast Flow Q-sepharose column (Amersham-Pharmacia Biotech) followed by HiTrap™-nickel affinity column (Amersham-Pharmacia Biotech). Purified Abl T315I was used in the ELISA-based kinase assay to screen inhibitors as described above. The kinase reaction was performed in the presence of 50 mM Tris pH 7.5, 1 mM MnCl2, 5 mM MgCl2, 0.3 mM ATP, peptide substrate (ARDIYRASFFRKGGCAMLPVK) (SEQ ID NO: 1) and purified Abl T315I. The concentration of the test solution showing 50% inhibition as compared with the control was expressed as IC50 (μM).
38. RET Kinase Inhibitory Activity
Method: ELISA-Based In Vitro Kinase Assay
Recombinant Ret protein was expressed in Sf9 cells using the pBlueBacHis2C baculovirus expression vector. Ret was purified using an anion exchange Fast Flow Q-sepharose column (Amersham-Pharmacia Biotech) followed by HiTrap™-nickel affinity column (Amersham-Pharmacia Biotech). Purified Ret was used in the ELISA-based kinase assay to screen inhibitors as described above. The kinase reaction was performed in the presence of 50 mM Tris pH 7.5, 1 mM MnCl2, 5 mM MgCl2, 0.3 mM ATP, peptide substrate (ARDIYRASFFRKGGCAMLPVK) (SEQ ID NO: 1) and purified Ret. The concentration of the test solution showing 50% inhibition as compared with the control was expressed as IC50 (μM).
Method: Tritiated Thymidine Uptake Cell Proliferation Assay
The following procedure was used with parent untransformed BaF3 cells, BaF3 cells transformed with the oncogenic fusion protein NPM/ALK, NPM/ALK positive SUDHL-1 cells, ALK-negative U937 cells, NPM/ALK positive KARPAS-299 cells. The parent untransformed BaF3 cells and Alk-negative U937 cells are used as controls. Cells were seeded in U-bottomed 96-well plates at 10 000 cells/well in a volume of 100 μL in supplemented medium. In the case of the parent untransformed BaF3 cells, the medium was supplemented with IL-3. Serial dilutions of inhibitors were added to the appropriate wells and volumes adjusted to 200 μL. Controls were treated with the equivalent volume of vehicle, DMSO, alone. Plates were incubated at 37° C. for 72 h. 3[H]-thymidine (1 μCi/well) was added for the last 16 h of incubation. Cells were harvested on to paper filters and 3[H]-thymidine incorporation was measured using a β scintillation counter (1430 MicroBeta, Wallac, Turku, Finland). The 50% inhibitory concentration (IC50) was defined as the concentration of inhibitor, expressed in micromolar, that gave a 50% decrease in 3[H]-thymidine uptake compared with controls.
Method: Tritiated Thymidine Uptake Cell Proliferation Assay
The following procedure was used with parent untransformed BaF3 cells, BaF3 cells transformed with the oncogenic fusion protein bcr-abl, Abl-negative U937 cells, or Bcr-abl positive LAMA-84 cells. The parent untransformed BaF3 cells and Abl-negative U937 cells are used as controls. Cells were seeded in U-bottomed 96-well plates at 10 000 cells/well in a volume of 100 μL in supplemented medium. In the case of the parent untransformed BaF3 cells, the medium was supplemented with IL-3. Serial dilutions of inhibitors were added to the appropriate wells and volumes adjusted to 200 μL. Controls were treated with the equivalent volume of vehicle, DMSO, alone. Plates were incubated at 37° C. for 72 h. 3[H]-thymidine (1 μCi/well) was added for the last 16 h of incubation. Cells were harvested on to paper filters and 3[H]-thymidine incorporation was measured using a β scintillation counter (1430 MicroBeta, Wallac, Turku, Finland). The 50% inhibitory concentration (IC50) was defined as the concentration of inhibitor, expressed in micromolar, that gave a 50% decrease in 3H-thymidine uptake compared with controls.
Method: Tritiated Thymidine Uptake Cell Proliferation Assay
The following procedure was used with parent untransformed BaF3 cells, BaF3 cells transformed with the oncogenic fusion protein RET-PTC2, or RET-negative 11937 cells. The parent untransformed BaF3 cells and RET-negative U937 cells are used as controls. Cells were seeded in U-bottomed 96-well plates at 10 000 cells/well in a volume of 100 μL in supplemented medium. In the case of the parent untransformed BaF3 cells, the medium was supplemented with IL-3. Serial dilutions of inhibitors were added to the appropriate wells and volumes adjusted to 200 μL. Controls were treated with the equivalent volume of vehicle, DMSO, alone. Plates were incubated at 37° C. for 72 h. 3[H]-thymidine (1 μCi/well) was added for the last 16 h of incubation. Cells were harvested on to paper filters and 3[H]-thymidine incorporation was measured using a β scintillation counter (1430 MicroBeta, Wallac, Turku, Finland). The 50% inhibitory concentration (IC50) was defined as the concentration of inhibitor, expressed in micromolar, that gave a 50% decrease in 3[H]-thymidine uptake compared with controls.
| Number | Date | Country | Kind |
|---|---|---|---|
| 08015802 | Sep 2008 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP2009/006206 | 8/27/2009 | WO | 00 | 6/9/2011 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2010/025872 | 3/11/2010 | WO | A |
| Number | Name | Date | Kind |
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| 2690441 | Burtner et al. | Sep 1954 | A |
| 5532261 | DiNinno et al. | Jul 1996 | A |
| 20050049265 | Adams | Mar 2005 | A1 |
| Number | Date | Country |
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| 1 367 058 | Dec 2003 | EP |
| 2 876 377 | Apr 2006 | FR |
| 1 268 772 | Mar 1972 | GB |
| 1 268 773 | Mar 1972 | GB |
| WO 2006131552 | Dec 2006 | WO |
| WO 2007097981 | Aug 2007 | WO |
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| J. Wieczorek, et al.: “Antineoplastic Activity of Azacarbazoles I. Synthesis and Antitumor Properties of Alpha-Carboline and Its Selected Derivative”, Jan. 1, 1986, Archivum Immunologiae et Therapiae Experimentalis, Polish Academy of Sciences, Wroclaw, PL, pp. 315-321 (XP009048570). |
| EPO Communication issued Jul. 29, 2014; Application No. 08 015 802.5. |
| Number | Date | Country | |
|---|---|---|---|
| 20110281862 A1 | Nov 2011 | US |
