WO2021038452A1 - New therapeutic agents for the treatment of haematological pathologies - Google Patents

New therapeutic agents for the treatment of haematological pathologies Download PDF

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WO2021038452A1
WO2021038452A1 PCT/IB2020/057952 IB2020057952W WO2021038452A1 WO 2021038452 A1 WO2021038452 A1 WO 2021038452A1 IB 2020057952 W IB2020057952 W IB 2020057952W WO 2021038452 A1 WO2021038452 A1 WO 2021038452A1
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Vincenzo CILIBRASI
Virginia SPANO'
Alessandra MONTALBANO
Paola BARRAJA
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Universita' Degli Studi Di Palermo
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D513/14—Ortho-condensed systems

Definitions

  • the present invention relates to the field of new tetracyclic molecules, having a tetracyclic system, and their use as medication for haematological pathologies, in particular for the treatment of acute myeloid leukemia (AML) in FLT3/ITD hemizygote patients resistant to conventional therapies.
  • AML acute myeloid leukemia
  • AML Acute myeloid leukemia
  • AML is the most common and aggressive form of leukaemia in adults, characterized by the rapid growth of white blood cells that accumulate in the bone marrow interfering with the production of normal blood cells.
  • AML is a relatively rare cancer, its incidence is destined to increase as the average age of the population increases.
  • the average age of diagnosis is 67 and the prognosis is poor; in fact the 5-year survival rate is 25%.
  • the malignant cell in AML is the myeloblast that is the immature precursor of white myeloid cells. Because of genetic mutations that hyperactivate the normal transduction pathways, the myeloblast does not encounter the normal differentiation processes.
  • the FLT3 receptor is a transmembrane protein that belongs to class III of the receptor tyrosine kinase family.
  • FLT3 FLT-3 ligand
  • FLT3 An aberrant expression of FLT3 has been observed in different haematology pathologies including acute myeloid leukemia in which mutations activating the FLT3 gene have been observed in about a third of patients.
  • One of the most common mutations is the Internal Tandem Duplication (ITD) observed in about 30% of patients, and associated with a poor prognosis and worse results with respect to patients who do not display this mutation.
  • ITD Internal Tandem Duplication
  • FLT3/ITD mutated FLT3
  • the survival rate is lower than that of fU2 WTi ⁇ patients and FLT3 ITD/WT heterozygote patients.
  • myeloblasts with FLT3/ITD mutant homodimers could activate the downstream signals of pathways continuously and aberrantly, compared to myeloblasts with the FLTS ⁇ or FLT3 ITD/WT genotype, thus increasing the survival of the myeloblasts and contributing to causing malignant transformations and chemoresistant phenomena.
  • the conventional therapeutic strategies in patients affected by leukaemia have not changed greatly and the results for many patients are poor. This makes the FLT3 receptor a potential target in therapy for AML and many pharmaceutical companies and research institutes have been strongly engaged in research into FLT3 inhibitors.
  • a common characteristic of first generation inhibitors such as Sorafenib, Lestaurtinib and Midostaurin is their poor selectivity, therefore they not only inhibit FLT3 but also other kinases. This causes the appearance of undesired toxic effects (gastrointestinal intolerances, prolonged cytopenia and palmar-plantar erythrodysesthesia) which have limited the clinical development of these inhibitors.
  • a group of compounds with an imidazo[2,1-b][1 ,3]benzothiazole structure have been shown to be powerful and selective FLT3 inhibitors, with good pharmacokinetic properties.
  • RTK kinase tyrosine receptors
  • Dovitinib induces G1 arrest and apoptosis on ALL (Acute Lymphoblastic Leukemia) SEM-K2 and HB1119 cell lines that express high levels of FTL3 with ICso in the nanomolar range (22 and 28 nM).
  • ALL acute Lymphoblastic Leukemia
  • HB1119 cell lines that express high levels of FTL3 with ICso in the nanomolar range (22 and 28 nM).
  • ICso in the nanomolar range
  • TCS 359 is a thiophene derivative able to inhibit enzymes with tyrosine-kinase activity such as KIT, PDGFR-a, AURORA-A and FLT3 (Flodge, C. N.; et al. W02005033102).
  • TCS 359 inhibits FLT3 with IC50 values equal to 42 nM and performs antiproliferative activity towards the human acute myeloid leukemia cell line MV4-11 with IC50 equal to 340 nM (Patch, R. J.; et al. Bioorg. Med. Chem. Lett. 2006, 16, 3282-3286).
  • Ar is an aromatic or heteroaromatic exatomic ring comprising 0, 1 or 2 N atoms
  • R is selected from the group consisting of H, Alki-6, cycloalkyl, heterocycloalkyl, aryl, aryl alkyl, heteroaryl, aryl sulfonyl and alkylamine, halogen, NO2, NH2, N3, wherein said Alki-6, cycloalkyl, heterocycloalkyl, aryl, aryl alkyl, heteroaryl, arylsulfonyl or alkylamine is optionally substituted with one or more substituents independently selected from linear or branched C1-C6 alkyl, nitro, amino, halogen, haloalkyl and alkoxy;
  • Ri and R2 are independently selected from the group consisting of H, COOH, carboxylic ester, carboxamide from primary, secondary or tertiary amine, aryl, halogen, NO2, NH2, N3, alkylamine and trifluoroalkyl, wherein said carboxylic acid, carboxylic ester, carboxamide from primary, secondary or tertiary amine, aryl, alkylamine or trifluorolalkyl is optionally substituted with one or more substituents independently selected from: linear or branched C1-C6 alkyl, nitro, amino, halogen haloalkyl and alkoxy;
  • R3 is selected from the group consisting of nitro, amino, ureidic wherein said amino or urea group is optionally substituted with one or more substituents independently selected from: Alki -6, nitro, amino, halogen, haloalkyl and heteroaryl optionally substituted with one or more substituents independently selected from linear or branched C1-C6 alkyl, nitro, amino, halogen and haloalkyl.
  • the compounds of the present invention in particular those having a tetracyclic 4- (2/-/-imidazo[2’,1’:2,3][1 ,3]thiazol[4,5-e]isoindole system, have expressed a powerful antiproliferative effect in vitro with specific selectivity towards the cell lines that overexpress FLT3/ITD. They have also been shown to selectively inhibit the vitality of blasts in hemizygote patients with mutated FLT3 (FLT3/ITD), who do not respond to conventional therapy, therefore they could have a significant impact on the treatment of AML. Furthermore, pyrrolic nitrogen is well suited to the introduction of chains that improve solubility in water in analogy with the study performed on compounds such as the aforementioned AC220, like ethylene morpholine or ethylene piperidine.
  • one aspect of the present invention relates to a compound of formula (I) as above described for use as medicament, in particular for the treatment of haematological pathologies and preferably for use in the treatment of AML, more preferably in FLT3/ITD hemizygote patients resistant to conventional therapies.
  • the subject matter of the present invention is also an amine compound of formula (I la) said Alk-i-6, cycloalkyl, heterocycloalkyl, aryl, aryl alkyl, heteroaryl, arylsulfonyl or alkylamine is optionally substituted with one or more substituents independently selected from linear or branched C1-C6 alkyl, nitro, amino, halogen, haloalkyl and alkoxy;
  • Ri and R2 are independently selected from the group consisting of H, COOH, carboxylic ester, carboxamide from primary, secondary or tertiary amine, halogen, NO2, NH2, N3, alkylamine and trifluoroalkyl, wherein said carboxylic acid, carboxylic ester, carboxamide from primary, secondary or tertiary amine, alkylamine or trifluorolalkyl is optionally substituted with one or more substituents independently selected from: linear or branched C1-C6 alkyl, nitro, amino, halogen and haloalkyl and alkoxy;
  • R3 is selected from the group consisting of nitro, amino, ureidic wherein said amino or urea group is optionally substituted with one or more substituents independently selected from: Alki -6, nitro, amino, halogen, haloalkyl and heteroaryl optionally substituted with one or more substituents independently selected from linear or branched C1-C6 alkyl, nitro, amino, halogen and haloalkyl.
  • the compounds of the present invention in particular those having a tetracyclic 4- (2/-/-imidazo[2’,1’:2,3][1 ,3]thiazol[4,5-e]isoindole system, have expressed a powerful antiproliferative effect in vitro with specific selectivity towards the cell lines that overexpress FLT3/ITD. They have also been shown to selectively inhibit the vitality of blasts in hemizygote patients with mutated FLT3 (FLT3/ITD), who do not respond to conventional therapy, therefore they could have a significant impact on the treatment of AML. Furthermore, pyrrolic nitrogen is well suited to the introduction of chains that improve solubility in water in analogy with the study performed on compounds such as the aforementioned AC220, like ethylene morpholine or ethylene piperidine.
  • one aspect of the present invention relates to a compound of formula (I) as above described for use as medicament, in particular for the treatment of haematological pathologies and preferably for use in the treatment of AML, more preferably in FLT3/ITD hemizygote patients resistant to conventional therapies.
  • the subject matter of the present invention is also an amine compound of formula
  • the amine derivatives of formula (lla) have been identified as key intermediates for the synthesis of the new tetracyclic system of formula (la) and at the same time they constitute a new chemical entity.
  • the subject matter of the present invention is also a process for preparing a compound of formula (I) comprising reacting a compound of formula (II) wherein A, B and C, Xi, n, m, R, Ri and R2 are as described above, with a compound of formula (IV). wherein Ar and R3 are as described above.
  • FIG. 1 - shows the docking of a compound according to the present invention in its crystalline structure of FLT3
  • Alki-6 means a linear or branched C1-C6 alkyl
  • Alki-4 means Ci-4-alkyls such as Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu; preferably Me.
  • Halogen includes F, Cl, Br, I; preferably Cl.
  • the ring A is preferably selected from the group consisting of
  • R is H, Aik, S0 2 Ph, Bn, 4-MeOBn, 3,5-(Me) 2 OBn, 3,4,5(MeO) 3 Bn, 2-Br-3,5-(Me) 2 OBn or
  • Z is halogen, where Y is absent, CH 2 , 0 or NMe.
  • Ri is H
  • R 2 is H or Br.
  • R 3 is
  • Ar 2 is selected from the group consisting of pyrazole, thiazole, pyridine, pyrimidine optionally substituted with one or more substituents independently selected from Alki -6, nitro, amino, halogen and haloalkyl.
  • Ar 2 is selected from the group consisting of pyrazole, thiazole, pyridine, pyrimidine optionally substituted with one or more substituents independently selected from Alki -6, nitro, amino, halogen and haloalkyl.
  • a compound having a tetracyclic 4-(2/-/-imidazo [2',1':2,3] [1 ,3] thiazole [4,5-e] isoindole system of formula (lc) wherein R, R1 and R3 are as described above, preferably R is H, Aik, S02Ph (CH2)nZ where n 2,3 and
  • Z is halogen, where Y is absent, CH2, 0 or NMe;
  • Ri is H, COOAIk
  • Rs is NO2, NH2, wherein Ar2 is selected from the group consisting of pyrazole, thiazole, pyridine, pyrimidine optionally substituted with one or more substituents independently selected from Alki -6, nitro, amino, halogen and haloalkyl.
  • Ri is preferably H.
  • Z is where Y is preferably CH2, NMe or 0.
  • R3 is NO2 or
  • X is where Y is preferably CH2 or NMe;
  • R3 is N02 or
  • Z is halogen, where Y is absent, CH 2 , 0 or NMe;
  • Ri is H, COOAIk, Ph, 3,4,5(MeO) 3 Ph; R2 is H.
  • the tetracyclic scaffold occupies the adenine binding pocket which prefers a planar and aromatic system, whereas the f-butyl- isoxazolyl portion lies in a lateral pocket mainly comprised of hydrophobic amino acids.
  • the hydrogen bonds with the ureidic function and p interactions of the edge- to-face type between the benzene ring and two phenylalanine residues (Figure 1) mainly contribute to stabilizing this conformation within the binding site.
  • A, B and C, m, R, Ri and R2 are as described above and where (a) Br2, CHClsiEtOH (1 :1 ) or CuBr 2 , EtOAc; ; (b) thiourea, NaCOs, DMF; (c) 2-bromo-p- nitroacetophenone, 2-methoxyethanol.
  • Subject matter of the present invention is also a process for preparing a compound of formula (lla) obtained by reacting a compound of formula (Ilia) wherein the A, B, m, r, R, Ri and R2 rings are as described above; with thiourea, preferably in DMF, THF, CFhCN, EtOH, MeOFI, in the presence of an excess of a base, preferably Na2C03. K2CO3, triethylamine.
  • synthesis for the preparation of a molecule of formula (lb) according to the present invention can be performed according to the following synthetic scheme: wherein A, B and C, m, R, Ri and R2 are as described above and (a) Br2, CHChiEtOH (1:1) orCuBr2, EtOAc; (b) guanidine nitrate, NaCCb, DMF; (c)2-bromo- p-nitroacetophenone, 2-methoxyethanol is as described above.
  • Subject matter of the present invention is also a process for preparing a compound of formula (Mb) obtained by reacting a compound of formula (lllb) wherein the A, B, m, r, R, Ri and R2 rings are as described above; with guanidine, preferably in DMF, THF, CFI3CN, EtOH, MeOFI, in the presence of an excess of a base, preferably Na2C03. K2CO3, triethylamine.
  • the synthetic strategy for the preparation of a molecule of formula (lc) envisaged: i) constructing the tetracyclic skeleton, 4-(2H- imidazo[2’,1’:2,3][1,3]thiazole[4,5-e]isoindole, by annulating the phenylamine substituted imidazole on the aminothiazole derivatives; ii) functionalizing the pyrrolic nitrogen with the appropriate chains; iii) introducing the ureidic function on the phenylamine group i
  • type 2 a-brominated ketone [compounds of formula (Ilia)] that represent the ideal building blocks for the new tetracyclic system was crucial.
  • the introduction of a phenyl sulfone group is crucial to obtain the desired bromination selectively in the a position to the carbonyl. Therefore, the ketones 1a,c,d appropriately prepared according to literature (Barraja, P.; et al. Bioorg. Med. Chem. Lett 2009, 19, 1711-1714; Barraja, P.; et al. Bioorg. Med. Chem.
  • Heterocycles 2003, 60, 1317-1328 were initially subjected to a phenyl sulfonylation reaction using NaH as a base in A/,/V-dimethylformamide (DMF) and phenyl sulfonyl chloride as the halide (Diagram 1).
  • the ketones 1a,c,d were further functionalized with a benzyl group and a 4-methoxybenzyl group through the use of benzyl bromide or 4-methoxybenzyl chloride and NaH as a base in L/,/V-dimethylformamide (DMF).
  • ketones 4 Starting from the cycloheptapyrrole ketones 4 the tricyclic pyrrolo[3',2':6,7]cyclohepta[1,2-d][1,3]thiazole derivatives 6 were also prepared (Scheme 2).
  • the ketones 4a-c were appropriately prepared according to literature (Spano, V.; et al. Eur. J. Med. Chem. 2016, 123, 447-461; Spano, V.; et al. Eur. J. Med. Chem. 2017, 128, 300-318).
  • the ketone 4b was functionalized at the pyrrolic nitrogen with a methyl group, a 4-methoxybenzyl group, a 3,5-dimethoxybenzyl group and a 3,4,5-trimethoxybenzyl group through the use of iodomethane, 4- methoxybenzylchloride, 3,5-dimethoxybenzylchloride or 3,4,5- trimethoxybenzylchloride, and NaH as a base in A/,/V-dimethylformamide (DMF).
  • the synthesis of the tricyclic derivatives was then performed in two steps without the isolation of the a-brominated intermediate.
  • the 4b-g ketones were subjected to bromination reaction using copper(ll) bromide in ethyl acetate under reflux. After verifying the disappearance of the starting ketone and the formation of the a- brominated product, the reaction mixture was filtered to remove the copper(l) bromide (CuBr) and the filtrate was evaporated under reduced pressure. The residue thus obtained was dissolved in DMF and K2CO3 and thiourea were added, allowing the isolation of the pyrrolocyclhepta [1 ,3]thiazoles 6b-g (40-92%) (Scheme 2, Table 2).
  • the proposed mechanism for the cyclization of the imidazole ring envisages the formation of an acyclic intermediate (A) by nucleophilic attachment of the nitrogen of the thiazole ring on the carbon atom that carries the bromine atom of the bromo- p-nitroacetophenone accompanied by elimination of HBr. Subsequently, the attachment of the iminic nitrogen to the carbonyl generates the cyclic intermediate (B) that dehydrates generating the imidazole system (Diagram 4).
  • the compound 7c was also functionalized at the pyrrolic nitrogen with different ethyl or propyl chains (Scheme 5).
  • the derivatives bearing a phenyl sulfone group 7a, b we used iron and catalytic quantities of H2SO4, obtaining the derivatives 9a, b (80-87%) (Procedure A) (Furlan, A.; et al. Eur. J. Med. Chem. 2012, 47, 239 - 254).
  • the introduction of the ureidic function on tetracyclic amino derivatives can be obtained through isocyanate (Dumas, J.; et al. US 20120046290) or via carbamate obtained from the commercial amine 3-amino-5-t-butyl-isoxazole 10. The latter approach is preferred considering that carbamates are easier to handle and store than isocyanates.
  • the phenyl carbamate 12 was obtained by reacting the 3-amino-5-f-butyl-isoxazole 10 with phenyl chloroformate 11 and K2CO3 in THF with high yields (Gross, T; et al. WO 2011056939).
  • the copulation reaction between the derivatives 9a-l and phenyl carbamate 12 was carried out in THF with DIPEA at 60 °C and catalytic quantities of DMAP enabling appropriately decorated ureidic compounds to be obtained 13a-l with yields from good to high (Diagram 5, Table 3).
  • the ethyl isoindol-1-carboxylate ketone (1b) was prepared by the modification of a method used for the preparation of the analogous carboxymethyl through a multistep sequence that involves the preparation of two reaction intermediates reported as follows.
  • the compound 7e with the chloropropyl chain and the NH derivative 7c display a certain selectivity towards KG-1 (0.536 and 3.868 mM respectively) and KG-1 a (0.876 and 2.985 pM respectively) with ICso values in the low micromolar range.
  • amino derivatives 9 seem to inhibit cell proliferation at micromolar concentrations, but only 9i (2.281 and 2.36 pM respectively) and 9d (4.39 and 4.558 pM), were shown to be selective towards the KG-1 and KG-1 a lines reaching the micromolar range.
  • TCS 359 100 100 100 0.31 0,322 100 100 100 100 100 100 100 100 100 100 38,306

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Abstract

The present invention relates to compounds having a tetracyclic system and the use thereof as new therapeutic agents in the treatment of acute myeloid leukemia (AML), preferably in FLT3/ITD hemizygote patients resistant to conventional therapies. The invention also relates to 5,7-dihydro-4H-[1,3]thiazolo[4,5-e]isoindol-2-amine compounds useful as intermediates for the synthesis of tetracyclic imidazo[2',1':2,3][1,3]thiazolo[4,5-e]isoindole compounds.

Description

NEW THERAPEUTIC AGENTS FOR THE TREATMENT OF HAEMATOLOGICAL PATHOLOGIES
FIELD OF THE INVENTION
The present invention relates to the field of new tetracyclic molecules, having a tetracyclic system, and their use as medication for haematological pathologies, in particular for the treatment of acute myeloid leukemia (AML) in FLT3/ITD hemizygote patients resistant to conventional therapies.
BACKGROUND
Acute myeloid leukemia (AML) is the most common and aggressive form of leukaemia in adults, characterized by the rapid growth of white blood cells that accumulate in the bone marrow interfering with the production of normal blood cells. Although AML is a relatively rare cancer, its incidence is destined to increase as the average age of the population increases. The average age of diagnosis is 67 and the prognosis is poor; in fact the 5-year survival rate is 25%. The malignant cell in AML is the myeloblast that is the immature precursor of white myeloid cells. Because of genetic mutations that hyperactivate the normal transduction pathways, the myeloblast does not encounter the normal differentiation processes. Therefore, uncontrolled growth of a clone of immature cells, called blasts, takes place, which lead to the development of AML. The most common mutation in AML takes place in the gene that promotes FLT3 cell growth and proliferation, FMS-like Tyrosine Kinase 3. The FLT3 receptor is a transmembrane protein that belongs to class III of the receptor tyrosine kinase family. The interaction of FLT3 with its natural ligand FL (FLT-3 ligand) determines the dimerization and autophosphorylation of the receptors which are involved in the pathways that regulate the proliferation of pluripotent stem cells, but which can also culminate in the survival and proliferation of leukaemic cells. An aberrant expression of FLT3 has been observed in different haematology pathologies including acute myeloid leukemia in which mutations activating the FLT3 gene have been observed in about a third of patients. One of the most common mutations is the Internal Tandem Duplication (ITD) observed in about 30% of patients, and associated with a poor prognosis and worse results with respect to patients who do not display this mutation. In particular, in hemizygote patients with mutated FLT3 (FLT3/ITD) the survival rate is lower than that of fU2WTi\ patients and FLT3ITD/WT heterozygote patients. Furthermore, myeloblasts with FLT3/ITD mutant homodimers could activate the downstream signals of pathways continuously and aberrantly, compared to myeloblasts with the FLTS^^ or FLT3ITD/WT genotype, thus increasing the survival of the myeloblasts and contributing to causing malignant transformations and chemoresistant phenomena. Despite the progress obtained in the understanding of the molecular biology of AML, the conventional therapeutic strategies in patients affected by leukaemia have not changed greatly and the results for many patients are poor. This makes the FLT3 receptor a potential target in therapy for AML and many pharmaceutical companies and research institutes have been strongly engaged in research into FLT3 inhibitors. Out of the first generation FLT3 inhibitors, Sunitinib (SU-11248), Sorafenib (BAY- 43-9006), Midostaurin (PKC412) and Lestaurtinib (CEP-701 ) (Figure 1 ), have shown to be promising in preclinical models of AML with mutated FLT3. Unfortunately many of these drugs have been shown to be non-optimal for the treatment of AML due to their poor power or an inadequate pharmacokinetic profile (Kayser, S.; et al. J. Leuk. Lymphoma 2014, 55, 243 -255; . Fiedler, W.; et al. Blood 2005, 105, 986 - 993; Ravandi, F.; J. Clin. Oncol. 2010, 28, 1856 - 1862). A common characteristic of first generation inhibitors such as Sorafenib, Lestaurtinib and Midostaurin is their poor selectivity, therefore they not only inhibit FLT3 but also other kinases. This causes the appearance of undesired toxic effects (gastrointestinal intolerances, prolonged cytopenia and palmar-plantar erythrodysesthesia) which have limited the clinical development of these inhibitors. A group of compounds with an imidazo[2,1-b][1 ,3]benzothiazole structure, have been shown to be powerful and selective FLT3 inhibitors, with good pharmacokinetic properties. In particular, the derivative AC220 (Quizartinib), analogous to AB530, without the carboxamide group and bearing a 2-morpholine tosyl chain for the purpose of improving the water solubility has been shown to be significantly powerful (IC5O=0.56 nM), selective towards FLT3 and with an excellent pharmacokinetic profile, but in clinical trials various problems have arisen, including cardiotoxicity. (Bhagwat, S.; et al WO 2007109120; Bhagwat, S. WO2011056764). In fact, it does not only cause a dose dependent extension of the QT interval, but is also responsible for greater risk of infection, neutropenia and haemorrhage (Cortes, J.; et al. Lancet Oncology 2018, 19, 889-903).
Recent studies have highlighted the ability of AC220 to induce the suppression of the normal haematopoietic progenitor cells, due to the inhibition of cKIT (or CD117) (Yamaura, T; et al. Blood 2018, 131, 426-438; Zhi, Y.; et al. Eur. J. Med. Chem., 2018, 155, 303-315).
Both Quizartinib and Sorafenib induce TDK (Tyrosine kinase Domain) mutations responsible for the onset of acquired resistance (Larrosa-Garcia, et al. Mol Cancer Ther, 2017, 16, 991-1001) and the efficacy of both compounds is reduced by the protective effect that the microenvironment of the stroma exerts on the AML cells, providing an advantage in the proliferation of the FLT3-ITD+ progenitors with respect to healthy progenitor cells. (Parmar, A.; et al. Cancer Research 2011, 71, 4696- 4706; Karjalainen, R.; et al. Blood, 2017, 130, 789-802). Dovitinib or TKI258, in clinical phase II for the treatment of relapsing multiple myeloma, is a competitive inhibitor of the kinase tyrosine receptors (RTK) involved in tumour growth and in the angiogenesis processes of solid and liquid tumours. It is a powerful inhibitor of RTK associated with FGFR (fibroblast growth factor receptor), VEGFR (vascular endothelial growth factor), c-KIT (Tyrosine-protein kinase kit) as well as FLT3. Dovitinib induces G1 arrest and apoptosis on ALL (Acute Lymphoblastic Leukemia) SEM-K2 and HB1119 cell lines that express high levels of FTL3 with ICso in the nanomolar range (22 and 28 nM). However, like other TKI inhibitors, in monotherapy they can lead to the onset of resistance phenomena. (Eucker, J.; et al. Anticancer Research 2014, 34, 4899-4907).
TCS 359 is a thiophene derivative able to inhibit enzymes with tyrosine-kinase activity such as KIT, PDGFR-a, AURORA-A and FLT3 (Flodge, C. N.; et al. W02005033102). In particular, TCS 359 inhibits FLT3 with IC50 values equal to 42 nM and performs antiproliferative activity towards the human acute myeloid leukemia cell line MV4-11 with IC50 equal to 340 nM (Patch, R. J.; et al. Bioorg. Med. Chem. Lett. 2006, 16, 3282-3286).
Therefore, it is clear that there is a need for new chemical entities potentially useful for medical purposes, in particular in the treatment of haematology pathologies, and that are preferably powerful and selective FLT3 inhibitors, in particular mutated FLT3 (FLT3/ITD) for use in the treatment of acute myeloid leukemia (AML) in FLT3/ITD hemizygote patients resistant to conventional therapies, and that also and preferably have good pharmacokinetic properties and are possibly free from side effects.
SUMMARY OF THE INVENTION
The present invention solves the aforesaid problems by means of a tetracyclic compound of formula (I)
Figure imgf000006_0001
wherein the ring A is a pentatomic aromatic heterocyclic ring, comprising one, two N atoms; the ring B is an aromatic or non-aromatic cycloalkyl, aryl, heterocycloalkyl or heteroaryl ring, where m=1 ,2, wherein said heterocycloalkyl or heteroaryl ring comprises at least one heteroatom from N, O and S; the ring C is a pentatomic aromatic heterocyclic ring with n=0 when Xi=S or exatomic with n=1 when Xi=N;
Ar is an aromatic or heteroaromatic exatomic ring comprising 0, 1 or 2 N atoms;
R is selected from the group consisting of H, Alki-6, cycloalkyl, heterocycloalkyl, aryl, aryl alkyl, heteroaryl, aryl sulfonyl and alkylamine, halogen, NO2, NH2, N3, wherein said Alki-6, cycloalkyl, heterocycloalkyl, aryl, aryl alkyl, heteroaryl, arylsulfonyl or alkylamine is optionally substituted with one or more substituents independently selected from linear or branched C1-C6 alkyl, nitro, amino, halogen, haloalkyl and alkoxy;
Ri and R2, if present, are independently selected from the group consisting of H, COOH, carboxylic ester, carboxamide from primary, secondary or tertiary amine, aryl, halogen, NO2, NH2, N3, alkylamine and trifluoroalkyl, wherein said carboxylic acid, carboxylic ester, carboxamide from primary, secondary or tertiary amine, aryl, alkylamine or trifluorolalkyl is optionally substituted with one or more substituents independently selected from: linear or branched C1-C6 alkyl, nitro, amino, halogen haloalkyl and alkoxy;
R3 is selected from the group consisting of nitro, amino, ureidic wherein said amino or urea group is optionally substituted with one or more substituents independently selected from: Alki -6, nitro, amino, halogen, haloalkyl and heteroaryl optionally substituted with one or more substituents independently selected from linear or branched C1-C6 alkyl, nitro, amino, halogen and haloalkyl.
The compounds of the present invention, in particular those having a tetracyclic 4- (2/-/-imidazo[2’,1’:2,3][1 ,3]thiazol[4,5-e]isoindole system, have expressed a powerful antiproliferative effect in vitro with specific selectivity towards the cell lines that overexpress FLT3/ITD. They have also been shown to selectively inhibit the vitality of blasts in hemizygote patients with mutated FLT3 (FLT3/ITD), who do not respond to conventional therapy, therefore they could have a significant impact on the treatment of AML. Furthermore, pyrrolic nitrogen is well suited to the introduction of chains that improve solubility in water in analogy with the study performed on compounds such as the aforementioned AC220, like ethylene morpholine or ethylene piperidine.
Therefore, one aspect of the present invention relates to a compound of formula (I) as above described for use as medicament, in particular for the treatment of haematological pathologies and preferably for use in the treatment of AML, more preferably in FLT3/ITD hemizygote patients resistant to conventional therapies.
The subject matter of the present invention is also an amine compound of formula (I la) said Alk-i-6, cycloalkyl, heterocycloalkyl, aryl, aryl alkyl, heteroaryl, arylsulfonyl or alkylamine is optionally substituted with one or more substituents independently selected from linear or branched C1-C6 alkyl, nitro, amino, halogen, haloalkyl and alkoxy;
Ri and R2, if present, are independently selected from the group consisting of H, COOH, carboxylic ester, carboxamide from primary, secondary or tertiary amine, halogen, NO2, NH2, N3, alkylamine and trifluoroalkyl, wherein said carboxylic acid, carboxylic ester, carboxamide from primary, secondary or tertiary amine, alkylamine or trifluorolalkyl is optionally substituted with one or more substituents independently selected from: linear or branched C1-C6 alkyl, nitro, amino, halogen and haloalkyl and alkoxy;
R3 is selected from the group consisting of nitro, amino, ureidic wherein said amino or urea group is optionally substituted with one or more substituents independently selected from: Alki -6, nitro, amino, halogen, haloalkyl and heteroaryl optionally substituted with one or more substituents independently selected from linear or branched C1-C6 alkyl, nitro, amino, halogen and haloalkyl.
The compounds of the present invention, in particular those having a tetracyclic 4- (2/-/-imidazo[2’,1’:2,3][1 ,3]thiazol[4,5-e]isoindole system, have expressed a powerful antiproliferative effect in vitro with specific selectivity towards the cell lines that overexpress FLT3/ITD. They have also been shown to selectively inhibit the vitality of blasts in hemizygote patients with mutated FLT3 (FLT3/ITD), who do not respond to conventional therapy, therefore they could have a significant impact on the treatment of AML. Furthermore, pyrrolic nitrogen is well suited to the introduction of chains that improve solubility in water in analogy with the study performed on compounds such as the aforementioned AC220, like ethylene morpholine or ethylene piperidine.
Therefore, one aspect of the present invention relates to a compound of formula (I) as above described for use as medicament, in particular for the treatment of haematological pathologies and preferably for use in the treatment of AML, more preferably in FLT3/ITD hemizygote patients resistant to conventional therapies.
The subject matter of the present invention is also an amine compound of formula
(Ha)
Figure imgf000009_0001
wherein m, R, Ri and R2 are as described above and when m=1 , A is chosen from the group consisting of
Figure imgf000009_0002
when m=2, A is chosen from the group consisting of
Figure imgf000009_0003
(A4) and (As).
The amine derivatives of formula (lla) have been identified as key intermediates for the synthesis of the new tetracyclic system of formula (la) and at the same time they constitute a new chemical entity. The subject matter of the present invention is also a process for preparing a compound of formula (I) comprising reacting a compound of formula (II)
Figure imgf000010_0001
wherein A, B and C, Xi, n, m, R, Ri and R2 are as described above, with a compound of formula (IV).
Figure imgf000010_0002
wherein Ar and R3 are as described above.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 - shows the docking of a compound according to the present invention in its crystalline structure of FLT3
DETAILED DESCRIPTION OF THE INVENTION For the purpose of the present invention:
Alki-6 means a linear or branched C1-C6 alkyl
Alki-4 means Ci-4-alkyls such as Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu; preferably Me. Halogen includes F, Cl, Br, I; preferably Cl.
According to the present invention, is preferred a compound of formula (I), wherein Xi=S, n=0 , that is a compound of formula (la) wherein A, B and C, m, R, Ri and R2 are as described above.
According to the present invention, is preferred a compound of formula (I), wherein Xi=N and n=1 , that is a compound of formula (lb)
Figure imgf000011_0001
wherein A, B and C, m, R, Ri and R2 are as described above.
In a compound of formula (I) according to the present invention, the ring A is preferably selected from the group consisting of
Figure imgf000011_0002
Figure imgf000012_0001
Preferably in the compounds of formula (I) according to the present invention R is H, Aik, S02Ph, Bn, 4-MeOBn, 3,5-(Me)2OBn, 3,4,5(MeO)3Bn, 2-Br-3,5-(Me)2OBn or
Figure imgf000012_0002
Z is halogen, where Y is absent, CH2, 0 or NMe.
Preferably in compounds of formula (I) according to the present invention Ri is H,
COOAIk, Ph, 3,4,5(MeO)3Ph.
Preferably, in the compounds of formula (I) according to the present invention R2 is H or Br.
Preferably in the compounds of formula (I) according to the present invention R3 is
Figure imgf000012_0003
N02, NH2, wherein Ar2 is selected from the group consisting of pyrazole, thiazole, pyridine, pyrimidine optionally substituted with one or more substituents independently selected from Alki -6, nitro, amino, halogen and haloalkyl. According to the present invention, is particularly preferred a compound having a tetracyclic 4-(2/-/-imidazo [2',1':2,3] [1 ,3] thiazole [4,5-e] isoindole system of formula (lc)
Figure imgf000013_0001
wherein R, R1 and R3 are as described above, preferably R is H, Aik, S02Ph (CH2)nZ where n=2,3 and
Figure imgf000013_0002
Z is halogen, where Y is absent, CH2, 0 or NMe;
Ri is H, COOAIk;
Figure imgf000013_0003
Rs is NO2, NH2, wherein Ar2 is selected from the group consisting of pyrazole, thiazole, pyridine, pyrimidine optionally substituted with one or more substituents independently selected from Alki -6, nitro, amino, halogen and haloalkyl.
In the compounds of formula (lc) according to the present invention Ri is preferably H. In the compounds of formula (lc) according to the present invention R is H, Me or (CH2)nZ where n=2,3 and
Figure imgf000013_0004
Z is where Y is preferably CH2, NMe or 0. In the compounds according to formula (lc) according to the present invention
Figure imgf000014_0001
preferably R3 is NO2 or
Compounds are particularly preferred in which: Ri is H;
R is H, Me or (CH2)nX where n=2,3 and
Figure imgf000014_0002
X is where Y is preferably CH2 or NMe; and
Figure imgf000014_0003
R3 is N02 or
Of the compounds of formula (lla) according to the present invention the preferred ones are those in which
Figure imgf000014_0004
when m=2, A is (A2).
Of the compounds of formula (lla) according to the present invention the preferred ones are those in which R is H, Aik, S02Ph, Bn, 4-MeOBn, 3,5-(Me)2OBn, 3,4,5(MeO)3Bn, 2-Br-3,5- (Me)2OBn or (CH2)nZ where n=2,3 and
Figure imgf000015_0001
Z is halogen, where Y is absent, CH2, 0 or NMe;
Ri is H, COOAIk, Ph, 3,4,5(MeO)3Ph; R2 is H.
With the aim of directing the synthesis towards more promising derivatives, a first attempt was made through an approach to molecular modelling in which in a preliminary step the capacity of the model to reproduce the placement of quizartinib was evaluated by comparing it with that detected in the crystalline structure of FLT3 (Smith, C. C.; et al. Cancer Discov. 2015, 5, 668 - 679). A RMSD value of less than 1A was evaluated as an index of good model reliability, therefore the ureidic compounds were subjected to a docking study. As the calculations showed a common binding mode and orientation for all the derivatives, the one not substituted with pyrrolic nitrogen was considered as a representative compound for a more in- depth analysis of the interactions. The tetracyclic scaffold occupies the adenine binding pocket which prefers a planar and aromatic system, whereas the f-butyl- isoxazolyl portion lies in a lateral pocket mainly comprised of hydrophobic amino acids. The hydrogen bonds with the ureidic function and p interactions of the edge- to-face type between the benzene ring and two phenylalanine residues (Figure 1) mainly contribute to stabilizing this conformation within the binding site.
The synthesis for the preparation of a molecule of formula (la) according to the present invention can be performed according to the following synthetic scheme:
Figure imgf000016_0001
wherein A, B and C, m, R, Ri and R2 are as described above and where (a) Br2, CHClsiEtOH (1 :1 ) or CuBr2, EtOAc; ; (b) thiourea, NaCOs, DMF; (c) 2-bromo-p- nitroacetophenone, 2-methoxyethanol.
Subject matter of the present invention is also a process for preparing a compound of formula (lla) obtained by reacting a compound of formula (Ilia)
Figure imgf000016_0002
wherein the A, B, m, r, R, Ri and R2 rings are as described above; with thiourea, preferably in DMF, THF, CFhCN, EtOH, MeOFI, in the presence of an excess of a base, preferably Na2C03. K2CO3, triethylamine.
The synthesis for the preparation of a molecule of formula (lb) according to the present invention can be performed according to the following synthetic scheme:
Figure imgf000017_0001
wherein A, B and C, m, R, Ri and R2 are as described above and (a) Br2, CHChiEtOH (1:1) orCuBr2, EtOAc; (b) guanidine nitrate, NaCCb, DMF; (c)2-bromo- p-nitroacetophenone, 2-methoxyethanol is as described above. Subject matter of the present invention is also a process for preparing a compound of formula (Mb) obtained by reacting a compound of formula (lllb)
Figure imgf000017_0002
wherein the A, B, m, r, R, Ri and R2 rings are as described above; with guanidine, preferably in DMF, THF, CFI3CN, EtOH, MeOFI, in the presence of an excess of a base, preferably Na2C03. K2CO3, triethylamine. The synthetic strategy for the preparation of a molecule of formula (lc) according to the present invention envisaged: i) constructing the tetracyclic skeleton, 4-(2H- imidazo[2’,1’:2,3][1,3]thiazole[4,5-e]isoindole, by annulating the phenylamine substituted imidazole on the aminothiazole derivatives; ii) functionalizing the pyrrolic nitrogen with the appropriate chains; iii) introducing the ureidic function on the phenylamine group i
Figure imgf000018_0001
The synthesis of type 2 a-brominated ketone [compounds of formula (Ilia)] that represent the ideal building blocks for the new tetracyclic system was crucial. In fact, the introduction of the second electrophilic centre, in a to the carbonyl through selective bromination, enabled the subsequent annulation of the thiazole amine cycle. The introduction of a phenyl sulfone group is crucial to obtain the desired bromination selectively in the a position to the carbonyl. Therefore, the ketones 1a,c,d appropriately prepared according to literature (Barraja, P.; et al. Bioorg. Med. Chem. Lett 2009, 19, 1711-1714; Barraja, P.; et al. Bioorg. Med. Chem. 2011, 19, 2326-2341, Spano, V.; et al. Eur. J. Med. Chem. 2014, 74, 340-357, Spano, V.; et al. J. Med. Chem. 2016, 59, 7223-7238) and 1b, obtained by the reaction of the ethyl {[(2,6-dioxo cyclohexylidene)methyl]amino}acetate (Selic, L; et al. Heterocycles 2003, 60, 1317-1328), were initially subjected to a phenyl sulfonylation reaction using NaH as a base in A/,/V-dimethylformamide (DMF) and phenyl sulfonyl chloride as the halide (Diagram 1). The ketones 1a,c,d were further functionalized with a benzyl group and a 4-methoxybenzyl group through the use of benzyl bromide or 4-methoxybenzyl chloride and NaH as a base in L/,/V-dimethylformamide (DMF). The bromination of /V-phenyl sulfonyl substituted ketones 1e-h was obtained with good yields using copper(ll) bromide in ethyl acetate at reflux (79-90%), whereas for the ketones 1i-n, the same reaction was performed using Br2 in a chloroform- ethanol mixture (65-78%) (Scheme 1 ).
Scheme 1
Figure imgf000019_0001
Conditions and reactants: (i) NaH, DMF, RT 1 h then benzene sulphonyl chloride and aryl alkyl halide,
RT 1-24 h, 60-90%; (ii) Br2, CHCI3:EtOH (1 :1), RT 1 h, 45-78% or CuBr2, EtOAc, reflux 2 h, 79-90%;
(iii) thiourea, NaCOs, DMF, RT 16 h, 80-99%.
The cyclization of the a-bromoketones 2e-n [compounds of formula (Ilia)] was obtained through reaction with thiourea in DMF in the presence of an excess of Na2C03. After dispersing the reaction solvent in water, the desired products 3e-n [compounds of formula (lla)] are recovered (80-99%) by filtration in a sufficiently pure form for the subsequent steps (Scheme 1 , Table 1 ).
Table 1
Cpd Sbt R R1 R2
3e 2e SOzPh H H
3f 2f SOzPh COOEt H
3g 2g SOzPh Ph H
3h 2h SOzPh 3,4,5-(OMe)3Ph H 3i 2i Bn Br Br
3j 2j Bn Ph Br
3k 2k Bn 3.4.5-(OMe)3Ph
Br
3I 2I 4-OMeBn Br
Br
3m 2m 4-OMeBn Ph
Br
3n 2n 4-OMeBn 3.4.5-(OMe)sPh
Br
Starting from the cycloheptapyrrole ketones 4 the tricyclic pyrrolo[3',2':6,7]cyclohepta[1,2-d][1,3]thiazole derivatives 6 were also prepared (Scheme 2). The ketones 4a-c were appropriately prepared according to literature (Spano, V.; et al. Eur. J. Med. Chem. 2016, 123, 447-461; Spano, V.; et al. Eur. J. Med. Chem. 2017, 128, 300-318). The ketone 4b was functionalized at the pyrrolic nitrogen with a methyl group, a 4-methoxybenzyl group, a 3,5-dimethoxybenzyl group and a 3,4,5-trimethoxybenzyl group through the use of iodomethane, 4- methoxybenzylchloride, 3,5-dimethoxybenzylchloride or 3,4,5- trimethoxybenzylchloride, and NaH as a base in A/,/V-dimethylformamide (DMF). The synthesis of the tricyclic derivatives was then performed in two steps without the isolation of the a-brominated intermediate. The 4b-g ketones were subjected to bromination reaction using copper(ll) bromide in ethyl acetate under reflux. After verifying the disappearance of the starting ketone and the formation of the a- brominated product, the reaction mixture was filtered to remove the copper(l) bromide (CuBr) and the filtrate was evaporated under reduced pressure. The residue thus obtained was dissolved in DMF and K2CO3 and thiourea were added, allowing the isolation of the pyrrolocyclhepta [1 ,3]thiazoles 6b-g (40-92%) (Scheme 2, Table 2). From the reaction of the ketone 4f it was possible to isolate the expected tricyclic derivative 6f (40%) as well as a secondary reaction product, which was the derivative tricyclic ethyl 2-amino-9-(2-bromo-3,5-dimethoxybenzyl)-4, 5,6,9- tetrahydropyrrolo [3',2':6,7] cyclohepta[1 ,2-d][1 ,3]thiazol-8-carboxylate 6h (25%), in which the presence of a bromine atoms is highlighted in position 2 of the 3,5- dimethoxybenzyl substituent. Diagram 2
Figure imgf000021_0001
Conditions and reactants: (i) NaH, DMF, RT 1 h and 30 min. then alkyl or aryl alkyl halide, RT or 80°C 3-16 h, 79-94%; (ii) CuBr2, EtOAc, reflux 2 h; (iii) thiourea, NaCOs, DMF, RT 16 h, 40-92%.
Table 2
CPD sbt R R1
~6b 4b H COOEt
6c 4c S02Ph H
6d 4d Me COOEt
6e 4e 4-MeOBn COOEt
6f 4f 3,5-(Me)2OBn COOEt
6g 4g 3,4,5-(Me)3OBn COOEt
6h 4f 2-Br-3,5-(Me)2OBn COOEt The [1 ,3]thiazolo[4,5-e]isoindol-2-amines 3e,f [compounds of formula (lie)] were used as precursors for the synthesis of the tetracyclic core (lc) by reaction with bromo p-nitroacetophenone.
The phenyl sulfone derivatives 3e,f [compounds of formula (lie)] successfully cyclicize in various solvents (ethanol, acetone, 2-methoxyethanol, acetonitrile, DMF) with the bromo p-nitroacetophenone preferably at a temperature of 60-100°C for a maximum of 48h, although in many cases without excellent yields. The best yields were obtained using 2-methoxyethanol at 80 °C for about 12h. In fact, under these conditions the desired products 7a, b (48-64%) [compounds of formula (lc) wherein R3 is NO2, Ri=H, COOEt, R=S02Ph] separate during heating from the reaction mixture as yellow solids in pure form.
Scheme 3
Figure imgf000022_0001
Conditions and reactants: (i) 2-bromo-p-nitroacetofenone, 2-methoxyethanol, 70°C 13 h, 48-64%; (ii) DDQ, 1 ,4-dioxane, reflux 3 h, 10%; (iii) KOH, methanol, reflux 16 h, 90%; (iv) NaH, DMF, RT 2 h then iodomethane, RT 3 h, 85%. The proposed mechanism for the cyclization of the imidazole ring envisages the formation of an acyclic intermediate (A) by nucleophilic attachment of the nitrogen of the thiazole ring on the carbon atom that carries the bromine atom of the bromo- p-nitroacetophenone accompanied by elimination of HBr. Subsequently, the attachment of the iminic nitrogen to the carbonyl generates the cyclic intermediate (B) that dehydrates generating the imidazole system (Diagram 4).
Diagram 4
Figure imgf000023_0001
This would justify the fact that part of the starting product is recovered from the reactions in salt form by the HBr produced by the reaction. Oxidation attempts of the compounds 7a, b using 2,3-dichloro-5,6-dicyano benzoquinone (DDQ) in dioxane under reflux have produced only the aromatic derivative 8 with poor yields (10%). Therefore, it was decided to proceed with the synthesis on the not completely aromatic scaffold, supported by some preliminary docking computational studies on the quizartinib inside the kinase domain FLT3, (Smith, C. C.; et al. Nature 20'\2, 485, 260 - 263.) which had highlighted that a completely aromatic system was not a strictly necessary condition for appropriate binding, as it is the imidazothiazolic core that is mainly involved in p interactions within a large hydrophobic pocket. Therefore, the synthetic plan of the present invention proceeds on the dihydro derivatives 7 [compounds of formula (lc) in which R3=N02], subjecting them to the subsequent removal of the phenyl sulfone group in the presence of a large excess of KOH (1 : 35), in order to introduce the alkyl amine chains. However, such conditions have enabled only the derivative 7c [compound of formula (lc) to be isolated in which R3— NO2, Ri=H and R=H] The ethoxycarbonyl compound under the same reaction conditions decomposes and the use of different bases or B NF have only led to the recovery of the unreacted starting product. The pyrrolic nitrogen was subsequently alkylated with iodomethane in DMF using NaH as a base to provide the corresponding N-Me derivative 7d [compound of formula (lc) in which R3=N02, Ri=H and R=Me] with excellent yields.
The compound 7c was also functionalized at the pyrrolic nitrogen with different ethyl or propyl chains (Scheme 5).
In the case of propyl chains, which are not commercially available in form of halides, firstly 1-bromo-3-chloropropane was reacted in DMF in the presence of Kl, obtaining the derivative 7e [compound of formula (lc) in which R3=N02, Ri=H and R=(CH2)3CI] bearing the pyrrolic nitrogen and the chloropropyl chain. The nucleophilic substitution by secondary cyclic amines such as pyrrolidine, piperidine, /V-methyl- piperazine and morpholine in DMF and Bu4NI enabled the compounds 7f-i to be obtained with excellent yields. The compounds 7f-i are compounds of formula (lc)
Figure imgf000024_0001
in which R3=N02, Ri=H and R=(CFl2)3X where X= where Y=absent,
CM2, O, NMe.
For the ethyl chains the anion of 7c generated in situ with NaFI, was reacted directly with the appropriate chain obtained in the form of free bases by treatment of commercial salts with sodium hydroxide.
All the nitro derivatives 7a-l were subsequently reduced with different methods.
For the derivatives bearing a phenyl sulfone group 7a, b we used iron and catalytic quantities of H2SO4, obtaining the derivatives 9a, b (80-87%) (Procedure A) (Furlan, A.; et al. Eur. J. Med. Chem. 2012, 47, 239 - 254). The derivatives 9a, b are compounds of formula (lc) wherein R3 is NH2, Ri=H, COOEt, R=S02Ph.
In the other cases we found it more convenient in terms of yield to use iron and acetic acid (Procedure B) or hydrogen and 10% Pd/C (Procedure C) (Scheme 5) providing the corresponding amino-derivatives 9c-l, used in some cases as such in the subsequent step.
The introduction of the ureidic function on tetracyclic amino derivatives can be obtained through isocyanate (Dumas, J.; et al. US 20120046290) or via carbamate obtained from the commercial amine 3-amino-5-t-butyl-isoxazole 10. The latter approach is preferred considering that carbamates are easier to handle and store than isocyanates. The phenyl carbamate 12 was obtained by reacting the 3-amino-5-f-butyl-isoxazole 10 with phenyl chloroformate 11 and K2CO3 in THF with high yields (Gross, T; et al. WO 2011056939). The copulation reaction between the derivatives 9a-l and phenyl carbamate 12 was carried out in THF with DIPEA at 60 °C and catalytic quantities of DMAP enabling appropriately decorated ureidic compounds to be obtained 13a-l with yields from good to high (Diagram 5, Table 3). The compounds 13a-l are
Figure imgf000025_0001
compounds of formula (I) in which R3=
Scheme 5
Figure imgf000026_0001
Conditions and reactants: (i) NaH, DMF, RT 2 h then 1-bromo-3-chloropropane, Kl, 70°C 2 h, 100%; (ii) NaH, DMF, RT 2 h then RX, BiuNI, 70°C 3-18 h, 77-93%; (iii) NaH, DMF, RT 2 h then RX, BiuNI, RT-50°C 20 h 75-85%.; (iv) Procedure A: Fe, H2S04, ethanol/water (5:1), 60°C 6-20 h, 50-80%.; Procedure B: Fe, acetic acid, 60°C 1-5 h, 30-60%.; Procedure C: H2, Pd/C, ethanol, RT 24 h, 55%>; (v) K2C03, THF, RT 3 h, then ethanol/water (4:1), 10°C 2 h, 90%.; (vi) DIPEA, DMAP, THF, 60°C 1- 3 h, 30-87%..
Table 3
Cmp. Yield Cmp. Yield R
9a 50 % 13a 87 % -f-Q
9b 80 % 13b 80 % -f-Q
9c 53 % 13c 72 % -H 9d 44 % 13d 84 % -CHs
Figure imgf000027_0001
The present invention can be better understood in the light of the following embodiment examples.
EXPERIMENTAL PART All the melting points were determined with BCichi-Tottoli capillary apparatus. The IR spectra were determined in bromoform with a Shimadzu IR Affinity-1 spectrophotometer. The 1H and 13C NMR spectra were recorded in solutions of DMSO -de or CDCL, respectively at 200 and 50.3 MHz using a Bruker AC 200 Mhz spectrometer (TMS as internal standard). The column chromatography was performed using Merck silica gel 230-400 mesh ASTM or with SEPACORE BLJCHI or Biotage 40i chromatography apparatus.
Preparation of ethyl 4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-carboxylate (1b)
The ethyl isoindol-1-carboxylate ketone (1b) was prepared by the modification of a method used for the preparation of the analogous carboxymethyl through a multistep sequence that involves the preparation of two reaction intermediates reported as follows.
Preparation of 2-[(dimethylamino)methylidene]cyclohexane-1 ,3-dione. A solution of 1 ,3-cyclohexandione (70 mmoles) in A/,/V-dimethylformamide dimethyl acetal (20 mL) was heated to reflux for 1 h. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was agitated with diethyl ether and filtered. The solid was used in the next step without any further purification. Yield: 96%; brown solid, mp: 102-103 °C; IR: 1660 (CO), 1585 (CO) crrr1; 1H NMR (CDCIs) (ppm): 1.90-2.03 (2H, m, CH2), 2.46 (4H, s, CH2x 2), 3.18 (3H, s, CHs), 3.41 (3H, s, CHs), 8.05 (1 H, s, CH); 13C NMR (CDCIs) (ppm): 19.3 (t), 37.9 (q x 2), 44.4 (t), 48.3 (t), 109.1 (d), 162.1 (s), 162.1 (s), 195.8
(s). Anal Calcd. for C9HisN02: C, 64.65; H, 7.84; N, 8.38. Found: C, 64.78; H, 7.52; N, 8.60.
Preparation of ethyl {[(2,6-dioxocyclohexylidene)methyl]amino}acetate. To a solution of 2-[(dimethylamino)methylidene]cyclohexane-1 ,3-dione (50 mmoles) in glacial acetic acid (40 ml_) glycine ethyl ester hydrochloride (55 mmoles) was added and the reaction mixture was heated to reflux for 2 h. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was agitated with ethanol and filtered. The solid was used in the next step without any further purification. Yield: 90%; yellow solid; mp: 58.8-59.4 °C; IR: 3434 (NH), 1747 (CO), 1713 (CO), 1667 (CO) cm 1; 1H NMR (DMSO -d6) (ppm): 1.21 (3H, t, J = 7.1 Hz, CHs), 1.74-1.91 (2H, m, CH2), 2.27-2.48 (4H, m, CH2 x 2), 4.14 (2H, q, J = 7.1 Hz, CH2), 4.37 (2H, d, J = 5.6 Hz, CH2), 8.07 (1 H, d, J = 14.2 Hz, CH), 10.79-10.98 (1 H, m, NH); 13C NMR (DMSO -d6) (ppm): 14.0 (q), 19.4
(t), 37.0 (t), 37.4 (t), 50.0 (t), 61 .0 (t), 108.1 (s), 159.5 (d), 169.0 (s), 195.2 (s), 198.3 (s). Anal Calcd. for C11 H15NO4: C, 58.66; H, 6.71 ; N, 6.22. Found: C, 58.98; H, 6.56; N, 6.43.
To a solution of ethyl {[(2,6-dioxo cyclohexylidene)methyl]amino}acetate (10 mmoles) in acetonitrile anhydrous (15 ml_), A/,/V-dimethylformamide dimethyl acetal (6.7 ml_, 50 mmol) was added and the reaction mixture was heated to reflux for 2 h. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The oily ethyl-3-(dimethylamino)-2-{[(2,6- dioxocyclohexylidene)methyl]amino}prop-2-enoate residue was used directly in the next step without any further purification. To the crude residue solubilized in anhydrous DCM (5 ml_), trifluoroacetic anyhdride (11 mmoles) was added dropwise at 0°C and the reaction mixture was agitated at room temperature for 16 h. The solvent was evaporated under reduced pressure and the oily residue was neutralized with the addition of a saturated solution of NaHCCb dropwise at 0° C. The aqueous solution was extracted with EtOAc (3 x ml_). The organic phase was dried on Na2S04 and the solvent evaporated under reduced pressure. The residue was purified using a chromatography column (cyclohexane: EtOAc 50: 50) and further recrystallized by EtOAc. Yield: 50%; white solid; mp: 184-185 °C (EtOAc); IR: 3435 (NH), 1687 (CO), 1662 (CO) cm 1; 1H NMR (DMSO -d6) (ppm): 1.28 (3H, t, J = 7.0 Hz, CHs), 1.82-2.08 (2H, m, CH2), 2.30-2.45 (2H, m, CH2), 2.85-2.98 (2H, m, CH2), 4.26 (2H, q, J = 7.0 Hz, CH2), 7.44 (1 H, s, H-3), 12.42 (1 H, s, NH); 13C NMR (DMSO -d6) (ppm): 13.4 (q), 22.0 (t), 24.0 (t), 38.5 (t), 59.7 (t), 118.0 (s), 122.7 (s), 123.6 (d), 134.0 (s), 160.5 (s), 193.8 (s). Anal. Calcd. for C11H13NO3 C, 63.76;
H, 6.32; N, 6.76. Found: C, 63.62; H, 6.35; N, 6.66.
Preparation of 2-(phenylsulfonyl)-2,5,6,7-tetrahydro-4H-isoindol-4-one (1e)
To a solution of 1a (7 mmoles) in anhydrous DMF (5 ml_), NaH (7.7 mmoles) was added at 0 °C and the reaction mixture was agitated at room temperature for 1 h. Benzenesulfonyl chloride (7.7 mmoles) was added at 0°C, and the reaction mixture was agitated at room temperature for 3 h. Then the reaction mixture was poured into water and ice and the resulting precipitate was filtered under vacuum. The crude product was purified using chromatography column (DCM). Yield: 70%; light brown solid; mp: 115-116 °C; IR: 1664 (CO) cm 1; 1H NMR (DMSO-de) (ppm): 1.84-1.98 (2H, m, CH2), 2.34-2.47 (2H, m, CH2), 2.50-2.68 (2H, m, CH2), 7.27 (1 H, d, J = 1.5 Hz, H-1 ), 7.60-7.90 (4H, m, H-3’, H-4’, H-5’ and H-3), 8.06-8.15 (2H, m, H-2’ and H- 6’); 13C NMR (DMSO-de) (ppm): 20.7 (t), 23.6 (t), 39.0 (t), 116.4 (d), 120.8 (d), 125.2 (s), 127.3 (d x 2), 129.1 (s), 130.1 (d x 2), 135.1 (d), 137.3 (s), 194.4 (s). Anal Calcd. for C14H13NO3S: C, 61.07; H, 4.76; N, 5.09. Found: C, 60.98; H, 4.62; N, 4.94. Preparation of ethyl 4-oxo-2(phenylsulfonyl)-4,5,6,7-tetrahydro-2H-isoindol-1- carboxylate (1f)
To a solution of 1b (20 mmoles) in anhydrous DMF (15 ml_), NaH (22 mmoles) was added at 0 °C and the reaction mixture was agitated at room temperature for 1 h. Benzenesulfonyl chloride (30 mmoles) was added at 0°C and the reaction mixture was agitated at room temperature for 3 h. The reaction mixture was poured into water and ice and the resulting precipitate was filtered under vacuum. The crude product was purified using chromatography column (DCM). Yield: 80 %; pale yellow solid; mp: 135-136 °C; IR : 1720 (CO), 1680 (CO) cm 1; 1H NMR (DMSO-de) (ppm):
I .19 (3H, t, J = 7.0 Hz, CHs), 1.90-2.08 (2H, m, CH2), 2.40-2.55 (2H, m, CH2), 2.80- 2.90 (2H, m, CH2), 4.18 (2H, q, J = 7.0 Hz, CH2), 7.60-7.85 (3H, m, H-3’, H-4’ and H-5’), 8.06-8.15 (2H, m, H-2’ and H-6’), 8.27 (1 H, s, H-3); 13C NMR (DMSO -d6) (ppm): 14.0 (q), 22.2 (t), 22.9 (t), 38.5 (t), 60.8 (t), 120.4 (s), 122.6 (s), 128.0 (d), 128.1 (d x 2), 129.4 (d x 2), 134.8 (d), 137.4 (s), 138.0 (s), 158.6 (s), 193.7 (s). Anal. Calcd. for C17H17NO5S: C, 58.78; H, 4.93; N, 4.03. Found: C, 58.89; H, 4.99; N, 4.18. Preparation of 2-(benzenesulfonyl)-1 -phenyl-2, 5, 6, 7-tetrahydro-4H-isoindol-4- one (1g)
To a solution of 1c (7 mmoles) in anhydrous DMF (5 ml_), NaH (7.7 mmoles) was added at 0 °C and the reaction mixture was agitated at room temperature for 1 h. Benzenesulfonyl chloride (7.7 mmoles) was added at 0°C, and the reaction mixture was agitated at room temperature for 24 h. Then the reaction mixture was poured into water and ice and the resulting precipitate was filtered under vacuum. The crude product was purified using chromatography column (DCM). Yield: 76%; light brown solid; mp: 144-145°C; IR 1660 (CO) cm-1; 1H NMR (DMSO-de) (ppm): 1.82-1.94 (2H, m, CH2), 2.34 (2H, t, J= 6.2 Hz, CH2), 2.44 (2H, t, J= 6.2 Hz, CH2), 7.05-7.10 (2H, m, Ar), 7.32-7.56 (7H, m, Ar), 7.68-7.76 (1 H, m, Ar), 7.98 (1 H, s, H-3); 13C NMR (DMSO-de) (ppm): 20.7 (t), 23.5 (t), 39.0 (t), 122.4 (d), 123.0 (s), 127.2 (2xd), 127.7 (2xd), 128.3 (s), 128.8 (d), 128.9 (s), 129.3 (s), 129.7 (2xd), 131.1 (2xd), 135.0 (d), 137.0 (s), 194.4 (s). Anal calcd for 20H17NO3S: C, 68.36; H, 4.88; N, 3.99. Found: C, 68.54; H, 4.73; N, 4.06.
Preparation of 2-(benzenesulfonyl)-1 -(3,4,5-trimethoxyphenyl)-2,5,6,7- tetrahydro-4H-isoindol-4-one (1 h)
To a solution of 1d (7 mmoles) in anhydrous DMF (5 ml_), NaH (7.7 mmoles) was added at 0°C and the reaction mixture was agitated at room temperature for 1 h. Benzenesulfonyl chloride (7.7 mmoles) was added at 0°C, and the reaction mixture was agitated at room temperature for 24 h. Then the reaction mixture was poured into water and ice and the resulting precipitate was filtered under vacuum. The crude product was purified using chromatography column (DCM). Yield: 60%; light brown solid; m.p.: 113-114°C; IR 1676 (CO) crrr1; 1H NMR (DMSO-de) (ppm): 1.84-1.97 (2H, m, CH2), 2.37-2.47 (4H, m, 2xCH2), 3.65 (6H, s, 2xCHs), 3.73 (3H, s, CHs), 6.29 (2H, s, H-2’ and H-6’), 7.45-7.57 (4H, m, Ar), 7.68-7.77 (1 H, m, Ar), 7.96 (1 H, s, H-3); 13C NMR (DMSO-de) (ppm): 20.7 (t), 23.5 (t), 39.1 (t), 55.8 (2xq), 60.1 (q), 108.8 (2xd), 122.0 (d), 122.6 (s), 123.9 (s), 127.3 (2xd), 127.9 (s), 129.2 (s), 129.6 (2xd), 134.9 (d), 136.9 (s), 137.9 (s), 152.1 (2xs), 194.4 (s). Anal calcd for C23H23NO6S: C, 62.57; H, 5.25; N, 3.17. Found: C, 62.69; H, 5.13; N, 3.08.
General procedure for the preparation of 2-substituted 2,5,6,7-tetrahydro-4H- isoindol-4-one (1 i-n).
To a solution of 1a,c,d (1 .35 g, 10 mmoles) in DMF (15 ml_) NaFI (0.24 g, 10 mmoles) was added at 0 °C and the reaction was agitated for 1 h at room temperature. The appropriate benzyl halide (15 mmoles) was added at 0°C and the reaction mixture was agitated at room temperature until complete (TLC). Then the reaction mixture was poured into water and ice. The aqueous solution was extracted with dichloromethane (3 x 50 ml_). The organic phase was dried on Na2S04 and the solvent evaporated under reduced pressure. The crude product was purified using a chromatography column using dichloromethane/ethyl acetate (98/2) as the eluent. 2-Benzyl-2,5,6,7-tetrahydro-4H-isoindol-4-one (1i). This compound was obtained by reaction of 1a with benzyl bromide after 5 h. Yield: 65%; white solid; mp: 78- 79°C; IR 1651 (CO) crrr1; 1H NMR (DMSO -d6) (ppm): 1.86-1.95 (2H, m, CH2), 2.29 (2H, t, J= 5.8 Hz, CH2), 2.57 (2H, t, J= 5.8 Hz, CH2), 5.10 (2H, s, CH2), 6.67 (1 H, s, H-1 ), 7.30-7.34 (5H, m, Ar), 7.43 (1 H, s, H-3); 13C NMR (DMSO -d6) (ppm): 21 .1 (t),
24.8 (t), 38.8 (t), 52.6 (t), 117.3 (d), 121.3 (s), 122.0 (d), 126.4 (s), 127.6 (2xd), 127.7 (d), 128.6 (2xd), 137.8 (s), 193.6 (s). Anal calcd for C15H15NO: C, 79.97; H, 6.71 ; N, 6.22. Found: C, 80.15; H, 6.96; N, 5.99.
2-Benzyl-1 -phenyl-2, 5, 6, 7-tetrahydro-4H-isoindol-4-one (1j). This compound was obtained by reaction of 1c with benzyl bromide after 1 h. Yield: 90%; white solid; m.p.: 128-129°C; IR 1655 (CO) cm-1; 1H NMR (DMSO-de) (ppm): 1.88-1.99 (2H, m, CH2), 2.37 (2H, t, J= 6.1 Hz, CH2), 2.56 (2H, t, J= 6.1 Hz, CH2), 5.19 (2H, s, CH2), 6.88-6.93 (2H, m, Ar), 6.95-7.45 (8H, m, Ar), 7.54 (1 H, s, H-3); 13C NMR (DMSO- de) (ppm): 21.4 (t), 24.7 (t), 39.9 (t), 50.5 (t), 120.8 (s), 123.3 (d), 124.6 (s), 126.8 (2xd), 127.4 (d), 127.5 (d), 128.4 (2xd), 128.5 (2xd), 128.9 (s), 129.6 (2xd), 130.9 (s), 137.7 (s), 193.8 (s). Anal calcd for C21H19NO: C, 83.69; H, 6.35; N, 4.65. Found: C, 83.45; H, 6.01 ; N, 4.88. 2-Benzyl-1 -(3,4,5-trimethoxyphenyl)-2,5,6,7-tetrahydro-4H-isoindol-4-one (1 k).
This compound was obtained by reaction of 1d with benzyl bromide after 3 h. Yield: 76%; white solid; mp: 156-157°C; IR: 1653 (CO) cm 1; 1H NMR (DMSO-de) (ppm): 1.18-2.03 (2H, m, CH2), 2.38 (2H, t, J= 5.7 Hz, CH2), 2.62 (2H, t, J= 5.7 Hz, CH2), 3.63 (3H, s, 2xCHs), 3.67 (3H, s, CHs), 5.21 (2H, s, CH2), 6.47 (2H, s, H-2’ and H- 6’), 6.97-7.01 (2H, m, Ar), 7.20-7.36 (3H, m, Ar), 7.56 (1 H, s, H-3); 13C NMR (DMSO-de) (ppm): 21.5 (t), 24.7 (t), 39.0 (t), 50.7 (t), 55.6 (2xq), 60.0 (q), 106.9 (2xd), 120.6 (s), 123.3 (d), 124.4 (s), 126.2 (s), 126.6 (2xd), 127.3 (d), 128.6 (2xd), 128.9 (s), 136.8 (s), 138.2 (s), 152.7 (2xs), 193.8 (s). Anal calcd for C24H25NO4: C, 73.64; H, 6.44; N, 3.58. Found: C, 73.76; H, 6.31 ; N, 3.44.
2-(4-Methoxybenzyl)-2,5,6,7-tetrahydro-4H-isoindol-4-one (1i). This compound was obtained by reaction of 1a with 4-methoxybenzyl chloride after 2 h. Yield: 65%; white solid; mp: 61-62°C; IR 1655 (CO) crrr1; 1H NMR (DMSO-de) (ppm): 1.83-1.95 (2H, m, CH2), 2.28 (2H, t, J= 6.1 Hz, CH2), 2.56 (2H, t, J= 6.1 Hz, CH2), 3.73 (3H, s, CHs), 5.01 (2H, s, CH2), 6.64 (1 H, s, H-1 ), 6.90 (d, 2H, J= 8.6 Hz, H-3’ and H-5’), 7.26 (2H, d, J= 8.6 Hz, H-2’ and H-6’), 7.38 (1 H, s, H-3); 13C NMR (DMSO-de) (ppm): 21.1 (t), 24.8 (t), 38.8 (t), 52.1 (t), 55.1 (q), 114.0 (2xd), 117.1 (d), 121.2 (s), 121.7 (d), 126.4 (s), 129.2 (2xd), 129.7 (s), 158.9 (s), 193.5 (s). Anal calcd for C16H17NO2: C, 75.27; H, 6.71 ; N, 5.49. Found: C, 74.87; H, 6.92; N, 5.09. 2-(4-Methoxybenzyl)-1 -phenyl-2, 5, 6, 7-tetrahydro-4H-isoindol-4-one (1 m). This compound was obtained by reaction of 1c with 4-methoxybenzyl chloride after 1 h and 30 min. Yield: 85%; white solid; mp: 135-136 °C; IR 1655 (CO) cm-1; 1H NMR (DMSO -cfe) (ppm): 1.85-1.97 (2H, m, CH2), 2.36 (2H, t, J= 6.1 Hz, CH2), 2.55 (2H, t, J= 6.1 Hz, CH2), 3.68 (3H, s, CHs), 5.10 (2H, s, CH2), 6.79 (2H, d, J= 8.9 Hz, H-3’ and H-5’), 6.87 (2H, d, J= 8.9 Hz, H-2’ and H-6’), 7.28-7.47 (5H, m, Ar), 7.49 (1 H, s, H-3); 13C NMR (DMSO -d6) (ppm): 21.4 (t), 24.7 (t), 38.9 (t), 50.0 (t), 55.0 (q), 113.8 (2xd), 120.7 (s), 123.0 (d), 124.6 (s), 127.5 (d), 128.4 (2xd), 128.5 (2xd), 128.7 (s), 129.4 (s), 129.6 (2xd), 131.0 (s), 158.6 (s), 193.7 (s). Anal calcd for C22H21NO2: C, 79.73; H, 6.39; N, 4.23. Found: C, 80.01 ; H, 6.12; N, 4.45. 2-(4-Methoxybenzyl)-1-(3,4,5-trimethoxyphenyl)-2,5,6,7-tetrahydro-4H- isoindol-4-one (1n): This compound was obtained by reaction of 1d with 4- methoxybenzyl chloride after 1 h. Yield 88%; white solid; mp: 160-161 °C; IR 1691 (CO) cm-1; 1H NMR (DMSO -d6) (ppm): 1.87-1.99 (2H, m, CH2), 2.36 (2H, t, J= 6.1 Hz, CH2), 2.59 (2H, t, J= 6.1 Hz, CH2), 3.68 (6H, s, 2xCHs), 3.69 (3H, s, CHs), 3.70 (3H, s, CHs), 5.12 (2H, s, CH2), 6.50 (2H, s, H-2’ and H-6’), 6.84 (2H, d, J= 8.9 Hz, H-3” and H-5”), 6.92 (2H, d, J= 8.9 Hz, H-2” and H-6”), 7.49 (1 H, s, H-3); 13C NMR (DMSO-cfe) (ppm): 21.5 (t), 24.7 (t), 38.9 (t), 50.3 (t), 55.1 (q), 55.8 (2xq), 60.0 (q), 107.0 (2xd), 113.9 (2xd), 120.5 (s), 122.6 (d), 124.4 (s), 126.4 (s), 128.3 (2xd), 128.9 (s), 129.8 (s), 136.8 (s), 152.7 (2xs), 158.5 (s), 193.8 (s). Anal calcd for C25H27NO5: C, 71.24; H, 6.46; N, 3.32. Found: C, 71.32; H, 6.34; N, 3.46.
General procedure for the preparation of 5-bromo-tetrahydroisoindol-4-ones (2e-h).
To a suspension of CuBr2 (5.4 mmoles) in anhydrous EtOAc (30 ml_) the appropriate ketone 1e-h (3 mmoles) was added and the reaction mixture was heated to reflux for 2 h. After cooling the reaction mixture it was filtered to remove the CuBr formed and the filtrate was evaporated under reduced pressure. The residue was purified using a chromatography column (DCM).
5-Bromo-2-(phenylsulfonyl)-2,5,6,7-tetrahydro-4H-isoindol-4-one (2e). This compound was obtained by reaction of 1e. Yield: 90%; white solid; mp: 134-135 °C; IR: 1683 (CO) cm 1; 1H NMR (DMSO-de) (ppm): 2.15-2.50 (2H, m, CH2), 2.65-2.78 (2H, m, CH2), 4.85-4.85 (1 H, m, CH), 7.34 (1 H, s, H-1 ), 7.65-7.90 (3H, m, H-3’, H- 4’ and H-5’), 8.04 (1 H, s, H-3), 8.08-8.19 (2H, m, H-2’ and H-6’); 13C NMR (DMSO- d6) (ppm): 17.9 (t), 32.3 (t), 52.3 (d), 116.8 (d), 122.1 (s), 123.1 (d), 127.1 (s), 127.4 (d x 2), 130.2 (d x 2), 135.4 (d), 137.0 (s) 186.7 (s). Anal. Calcd. for Ci4Hi2BrNOsS: C, 47.47; H, 3.41 ; N, 3.95. Found: C, 47.56; H, 3.57; N, 4.03 Ethyl 5-bromo-4-oxo-2(phenylsulfonyl)-4,5,6,7-tetrahydro-2H-isoindol-1- carboxylate (2f). This compound was obtained by reaction of 1f. Yield: 80%; white solid; mp: 123-124 °C; IR: 1723 (CO), 1687 (CO) cm 1; 1H NMR (DMSO-de) (ppm): 1.21 (3H, t, J = 7.0 Hz, CHs), 2.25-2.65 (2H, m, CH2), 2.75-3.15 (2H, m, CH2), 4.17 (2H, q, J = 7.0 Hz, CH2), 4.85-4.98 (1 H, m, CH), 7.60-7.85 (3H, m, H-3’, H-4’ and H- 5’), 8.10-8.22 (2H, m, H-2’ and H-6’), 8.45 (1 H, s, H-3); 13C NMR (DMSO-de) (ppm): 13.9 (q), 19.7 (t), 31 .5 (t), 51.5 (d), 61.1 (t), 119.6 (s), 120.5 (s), 128.3 (d x 2), 129.4 (d x 2), 130.2 (d), 135.0 (d), 135.9 (s), 137.1 (s), 158.4 (s), 186.1 (s). Anal. Calcd. for CiyHieBrNOsS: C, 47.90; H, 3.78; N, 3.29. Found: C, 47.99; H, 3.57; N, 3.53. 2-(benzenesulfonyl)-5-bromo-1 -phenyl-2, 5, 6, 7-tetrahydro-4H-isoindol-4-one (2g):this compound was obtained by reaction of 1g. Yield: 82%; white solid; mp: 144-145°C; IR 1681 (CO) crrr1; 1H NMR (DMSO-de) (ppm): 2.19-2.40 (4H, m, 2XCH2), 4.88 (1 H, t, J= 3.0 Hz, CH), 7.07-7.11 (2H, m, Ar), 7.33-7.57 (7H, m, Ar), 7.70-7.79 (1 H, m, Ar), 8.16 (1 H, s, H-3); 13C NMR (DMSO-de) (ppm): 18.0 (t), 32.3 (t), 52.3 (d), 120.0 (s), 124.6 (d), 126.3 (s), 127.4 (2xd), 127.9 (2xd), 128.5 (s), 129.0 (d), 129.5 (s), 129.7 (2xd), 131.2 (2xd), 135.2 (d), 136.7 (s), 186.8 (s). Anal calcd for C2oHi6BrN03S: C, 55.82; H, 3.75; N, 3.25. Found: C, 55.98; H, 3.63; N, 3.09. 2-(benzenesulfonyl)-5-bromo-1-(3,4,5-trimethoxyphenyl)-2,5,6,7-tetrahydro- 4H-isoindol-4-one (2g):this compound was obtained by reaction of 1h. Yield: 79%; white solid; mp: 134-135°C; IR 1661 (CO) cm-1; 1H NMR (DMSO-de) (ppm): 2.19- 2.59 (4H, m, 2xCH2), 3.65 (6H, s, 2xCHs), 3.74 (3H, s, CHs), 4.87 (1 H, t, J= 5.6 Hz, CH), 6.31 (2H, s, H-2’ and H-6’), 7.52-1. IQ (5H, m, Ar), 8.14 (1 H, s, H-3); 13C NMR (DMSO-de) (ppm): 17.9 (t), 32.3 (t), 52.2 (d), 55.8 (2xq), 60.1 (q), 108.8 (2xd), 119.5 (s), 123.5 (s), 124.2 (d), 126.0 (s), 127.5 (2xd), 129.4 (s), 129.7 (2xd), 135.1 (d), 136.6 (s), 138.0 (s), 152.2 (2xs), 186.8 (s). Anal calcd for C23H22BrN06S: C, 53.08; H, 4.26; N, 2.69. Found: C, 52.95; H, 4.17; N, 2.80.
General procedure for the preparation of 5-bromo-2,5,6,7-tetrahydro-4H- isoindol-4-one (2i-n).
To a solution of 1 i-n (2.2 mmoles) in a mixture of anhydrous CHCh-EtOH (1 :1 , 6 ml_) HBr (45% in AcOH, 9 drops) was added at 0 °C and then dropwise a solution of Br2 (0.45 ml_, 8.8 mmoles) in anhydrous CHCh. After 1 h at room temperature, a saturated solution of NaHSCb was added to the reaction. The two phases were separated and the aqueous phase was extracted with dichloromethane (3 x 50 ml_). The organic phase was dried on Na2S04 and the solvent evaporated under reduced pressure. The crude product was purified using a chromatography column with dichloromethane as the eluent.
2-Benzyl-1 ,3,5-tribromo-2,5,6,7-tetrahydro-4H-isoindol-4-one (2i): this compound was obtained by reaction of 1i. Yield: 66%; light brown solid; mp: 139- 140°C; IR 1677 (CO) cm-1; 1H NMR (DMSO -d6) (ppm): 2.24-2.38 (2H, m, CH2),
2.63-2.75 (2H, m, CH2), 4.81 (1 H, t, J= 4.0 Hz, CH), 5.34 (2H, s, CH2), 7.05-7.15 (2H, m, Ar), 7.26-7.42 (3H, m, Ar); 13C NMR (DMSO -d6) (ppm): 18.9 (t), 31.6 (t),
49.8 (t), 52.5 (d), 101.0 (s), 107.0 (s), 116.5 (s), 125.2 (s), 126.2 (2xd), 127.7 (d),
128.8 (2xd), 135.5 (s), 184.5 (s). Anal calcd for Ci5Hi2Br3NO: C, 39.00; H, 2.62; N, 3.03. Found: C, 39.15; H, 2.76; N, 2.91.
2-Benzyl-3,5-dibromo-1 -phenyl-2, 5, 6, 7-tetrahydro-4H-isoindol-4-one (2j): this compound was obtained by reaction of 1j. Yield: 70%; light brown solid; mp: 156- 157°C; IR 1669 (CO) crrr1; 1H NMR (DMSO-de) (ppm): 2.22-2.40 (2H, m, CH2),
2.63-2.84 (2H, m, CH2), 4.83 (1 H, t, J= 4.0 Hz, CH), 5.24 (2H, s, CH2), 6.86 (2H, t, J= 6.4 Hz, Ar), 7.26-7.41 (8H, m, Ar); 13C NMR (DMSO-de) (ppm): 18.7 (t), 32.7 (t),
48.8 (t), 53.2 (d), 108.0 (s), 115.6 (s), 123.1 (s), 125.7 (2xd), 127.4 (d), 128.4 (d),
128.7 (2xd), 128.8 (2xd), 129.8 (2xd), 130.0 (s), 131.1 (s), 136.5 (s), 185.2 (s). Anal calcd for C2iHi7Br2NO: C, 54.93; H, 3.73; N, 3.05. Found: C, 54.79; H, 3.58; N, 3.26. 2-Benzyl-3,5-dibromo-1-(3,4,5-trimethoxyphenyl)-2,5,6,7-tetrahydro-4H- isoindol-4-one (2k): this compound was obtained by reaction of 1k. Yield: 78%; light brown solid; mp: 156-157°C; IR 1669 (CO) cm-1; 1H NMR (DMSO-de) (ppm): 2.18-2.34 (2H, m, CH2), 2.60-2.89 (2H, m, CH2), 4.83 (1 H, t, J= 4.0 Hz, CH), 5.24 (2H, s, CH2), 6.50 (2H, s, H-2’ and H-6’), 6.93-6.97 (2H, m, Ar), 7.23-7.40 (3H, m, Ar); 13C (DMSO-cfe) (ppm): 18.6 (t), 32.7 (t), 47.7 (t), 53.1 (d), 55.6 (2xq), 60.0 (q), 107.2 (2xd), 108.0 (s), 115.4 (s), 122.9 (s), 125.3 (s), 125.7 (2xd), 127.3 (d), 128.8 (2xd), 136.7 (s), 136.9 (s), 137.3 (s), 152.8 (2xs), 185.2 (s). Anal calcd for C24H23Br2N04: C, 52.48; H, 4.22; N, 2.55. Found: C, 52.35; H, 4.09; N, 2.64. 1,3,5-tribromo-2-(4-methoxybenzyl)-2,5,6,7-tetrahydro-4H-isoindol-4-one (2I): this compound was obtained by reaction of 11. Yield: 75%; light brown solid; mp: 109-110°C; IR 1653 (CO) crrr1; 1H (DMSO-de) (ppm): 2.26-2.45 (2H, m, CH2), 2.51-2.68 (2H, m, CH2), 3.73 (3H, s, CHs), 4.81 (1 H, t, J= 3.9 Hz, CH), 5.26 (2H, s, CH2), 6.93 (2H, d, J= 8.7 Hz, H-3’ and H-5’), 7.05 (2H, d, J= 8.7 Hz, H-2’ and H-6’); 13C NMR (DMSO -c/e) (ppm): 18.9 (t), 31.6 (t), 49.3 (t), 52.5 (d), 55.1 (q), 100.9 (s),
106.8 (s), 114.2 (2xd), 116.5 (s), 125.1 (s), 127.3 (s), 127.8 (2xd), 158.7 (s), 184.4 (s). Anal calcd for Ci6Hi Br3N02: C, 39.06; H, 2.87; N, 2.85. Found: C, 38.98; H, 2.99; N, 2.73. 3.5-Dibromo-2-(4-methoxybenzyl)-1 -phenyl-2, 5,6, 7-tetrahydro-4H-isoindol-4- one (2m): this compound was obtained by reaction of 1m. Yield: 65%; light brown solid; mp: 156-157°C; IR 1665 (CO) crrr1; 1H NMR (DMSO-de) (ppm): 2.22-2.45 (2H, m, CM2), 2.56-2.85 (2H, m, CH2), 3.70 (3H, s, CHs), 4.82 (1 H, t, J= 4.4 Hz, CH), 5.17 (2H, s, CM2), 6.77 (2H, d, J= 9.0 Hz, H-3’ and H-5’), 6.85 (2H, d, J= 9.0 Hz, H-2’ and H-6’), 7.30-7.47 (5H, m, Ar); 13C NMR (DMSO-de) (ppm): 18.6 (t), 32.6 (t), 48.2 (t), 53.2 (d), 55.0 (q), 107.9 (s), 114.0 (2xd), 115.6 (s), 123.1 (s), 127.2 (2xd), 128.3 (s), 128.4 (d), 128.8 (2xd), 129.8 (2xd), 130.1 (s), 131.0 (s), 158.4 (s),
185.1 (s). Anal calcd for C22Hi9Br2N02: C, 54.01 ; H, 3.91 ; N, 2.86. Found: C, 54.13; H, 4.02; N, 2.95.
3.5-dibromo-2-(4-methoxybenzyl)-1-(3,4,5-trimethoxyphenyl)-2,5,6,7- tetrahydro-4H-isoindol-4-one (2n): this compound was obtained by reaction of 1n. Yield: 65%; light brown solid; mp: 174-175°C; IR 1669 (CO) crrr1; 1H NMR (DMSO- cfe) (ppm): 2.25-2.43 (2H, m, CH2), 2.67-2.85 (2H, m, CH2), 3.63 (6H, s, 2xCHs), 3.68 (3H, s, CHs), 3.70 (3H, s, CHs), 4.81 (1 H, t, J= 4.0 Hz, CH), 5.17 (2H, s, CH2), 6.52 (2H, s, H-2’ and H-6’), 6.81-6.91 (4H, m, H-2”, H-3”, H-5” and H-6”); 13C NMR (DMSO-cfe) (ppm): 18.4 (t), 32.7 (t), 47.2 (d), 55.1 (q), 55.7 (2xq), 60.0 (q), 107.2 (2xd), 112.9 (s), 114.1 (2xd), 119.9 (s), 121.9 (s), 125.1 (s), 127.3 (2xd), 128.4 (s),
129.2 (s), 137.4 (s), 152.9 (2xs), 158.5 (s), 185.0 (s). Anal calcd for C25H25Br2N05: C, 51.83; H, 4.35; N, 2.42. Found: C, 51.99; H, 4.46; N, 2.29.
General procedure for the synthesis of 2-amino-5,7-dihydro-4H- [1 ,3]thiazolo[4,5-e]isoindol (3e-n)
To a solution of the appropriate bromo derivative 2e-n (0.5 mmoles) in anhydrous DMF (5 ml_), Na2C03 (1 mmoles) and thiourea (1 mmoles) were added and the reaction mixture was agitated at room temperature for 16 h. The reaction was poured into water and ice and the precipitate was filtered. The solid obtained did not require any further purification.
7-(Phenylsulfonyl)-5,7-dihydro-4H-[1,3]thiazolo[4,5-e]isoindol-2-amino (3e).
This compound was obtained by reaction of 2e. Yield: 99%; light grey solid; mp: 209-210 °C; IR: 3407-3276 (NH2) cm 1; 1H NMR (DMSO-de) (ppm): 2.65-2.75 (4H, m, CH2x 2), 6.91 (2H, s, NH2), 7.03 (1 H, d, J = 2.0 Hz, H-6), 7.11 (1 H, d, J = 2.0 Hz, H-8), 7.55-7.80 (3H, m, H-3’, H-4’ and H-5’), 7.95 (2H, d, J= 7.0 Hz, H-2’ and H-6’); 13C NMR (DMSO -d6) (ppm): 20.1 (t), 21.6 (t), 111.8 (d), 116.9 (d), 117.2 (s), 123.2
(s), 124.6 (s), 126.6 (d x 2), 129.8 (d x 2), 134.3 (d), 138.1 (s), 139.3 (s), 166.9 (s). Anal. Calcd. for C15H13N3O2S2: C, 54.36; H, 3.95; N, 12.68. Found: C, 54.22; H, 3.75; N, 12.78.
Ethyl 2-amino-7-(phenylsulfonyl)-5,7-dihydro-4H-[1,3]thiazolo[4,5-e]isoindol- 6-carboxylate (3f). This compound was obtained by reaction of 2f. Yield: 95%; light grey solid; mp: 212-213 °C; IR: 3450-3353 (NH2), 1698 (CO) cm 1; 1H NMR (DMSO- d6) (ppm): 1.18 (3H, t, J = 7.0 Hz, CHs), 2.70-3.10 (4H, m, CH2x 2), 4.16 (2H, q, J = 7.0 Hz, CH2), 7.04 (2H, s, NH2), 7.52 (1 H, s, H-8), 7.60-7.80 (3H, m, H-3’, H-4’ and H-5’), 7.95-8.10 (2H, m, H-2’ and H-6’); 13C NMR (DMSO-de) (ppm): 13.9 (q), 21.0
(t), 21.2 (t), 60.7 (t), 117.2 (s), 118.9 (d), 120.2 (s), 120.92 (s), 127.2 (d x 2), 129.3 (d x 2), 133.2 (s), 134.2 (d), 138.2 (s), 138.5 (s), 159.0 (s), 167.3 (s). Anal. Calcd. for C18H17N3O4S2: C, 53.58; H, 4.25; N, 10.41. Found: C, 53.82; H, 4.57; N, 10.29.
6-Phenyl-7-(phenylsulfonyl)-5,7-dihydro-4H-[1,3]thiazolo[4,5-e]isoindol-2- amine (3g). This compound was obtained by reaction of 2g. Yield: 85%; light grey solid; mp: 194-195°C; IR 3419-3302 (NH2), 1649 (CO) cm-1; 1H NMR (DMSO-de) (ppm): 2.44-2.51 (2H, m, CH2), 2.63-2.73 (2H, m, CH2), 6.98 (2H, s, NH2), 7.16- 7.22 (3H, m, Ar), 7.37-7.54 (7H, m, H-8 and Ar), 7.67 (1 H, t, J= 7.3 Hz, Ar); 13C NMR (DMSO-cfe) (ppm): 20.0 (t), 21.4 (t), 114.3 (d), 117.7 (s), 121.9 (s), 124.6 (s), 126.4 (2xd), 127.5 (2xd), 128.2 (d), 129.4 (2xd), 129.9 (s), 130.6 (s), 130.8 (2xd), 134.2 (d), 137.6 (s), 139.3 (s), 167.0 (s). Anal calcd for C21 H17N3O2S2: C, 61 .89; H, 4.20; N, 10.31. Found: C, 61.72; H, 4.07; N, 10.55.
7-(Phenylsulfonyl)-6-(3,4,5-trimethoxyphenyl)-5,7-dihydro-4H- [1,3]thiazolo[4,5-e]isoindol-2-amine (3h): this compound was obtained by reaction of 2h with thiourea. Yield: 80%; light grey solid; mp: 191-192°C; IR 3409- 3322 (NH2) cm-1; 1H NMR (DMSO-de) (ppm): 2.51-2.69 (4H, m, 2xCH2), 3.70 (6H, s, 2xCHs), 3.73 (3H, s, CHs), 6.38 (2H, s, H-2” and H-6”), 6.97 (1 H, s, NH2), 7.24 (1 H, s, H-8), 7.42-7.72 (5H, m, Ar); 13C NMR (DMSO-de) (ppm): 20.0 (t), 21.4 (t), 55.8 (2xq), 60.1 (q), 108.6 (2xd), 113.9 (d), 117.5 (s), 121 .4 (s), 124.1 (s), 124.9 (s), 126.6 (2xd), 129.4 (2xd), 130.4 (s), 134.1 (d), 137.6 (s), 137.7 (s), 139.3 (s), 151.9 (2xs), 167.0 (s). Anal calcd for C24H23N3O5S2: C, 57.93; H, 4.66; N, 8.44. Found: C, 58.05; H, 4.78; N, 8.32.
7-Benzyl-6,8-dibromo-5,7-dihydro-4H-[1,3]thiazolo[4,5-e]isoindol-2-amine (3i): this compound was obtained by reaction of 2i. Yield: 91 %; light grey solid; mp: 74- 75°C; IR 1621 (CO) crrr1; 1H NMR (DMSO-de) (ppm): 2.60 (2H, t, J= 6.4 Hz, CH2), 2.73 (2H, t, J= 6.4 Hz, CH2), 5.22 (2H, s, CH2), 6.91 (2H, s, NH2), 7.02 (2H, d, J=
6.6 Hz, Ar), 7.22-7.38 (3H, m, Ar); 13C NMR (DMSO-de) (ppm): 21.0 (t), 21.5 (t),
48.6 (t), 105.2 (s), 114.2 (s), 114.9 (s), 118.2 (s), 119.6 (s), 125.9 (2xd), 127.3 (d),
128.6 (2xd), 137.2 (s), 139.5 (s), 166.4 (s). Anal calcd for Ci6Hi3Br2N3S: C, 43.76; H, 2.98; N, 9.57. Found: C, 43.88; H, 3.09; N, 9.41.
7-Benzyl-8-bromo-6-phenyl-5,7-dihydro-4H-[1,3]thiazolo[4,5-e]isoindol-2- amine (3j): this compound was obtained by reaction of 2j. Yield: 95%; light grey solid; mp: 94-dec°C; IR 3472-3380 (NH2) crrr1; 1H NMR (DMSO-de) (ppm): 2.65- 2.79 (4H, m, 2xCH2), 5.13 (2H, s, CH2), 6.84-6.94 (4H, m, NH2 and Ar), 7.16-7.45 (8H, m, Ar); 13C NMR (DMSO-de) (ppm): 20.7 (t), 22.1 (t), 54.9 (t), 109.9 (s), 114.2
(s), 116.8 (s), 117.8 (s), 125.5 (2xd), 127.6 (d), 128.4 (d), 128.5 (2xd), 128.6 (2xd), 129.3 (s), 129.4 (2xd), 131.0 (s), 131.1 (s), 138.1 (s), 166.6 (s). Anal calcd for C22Hi8BrN3S: C, 60.55; H, 4.16; N, 9.63. Found: C, 60.64; H, 4.02; N, 9.75. 7-Benzyl-8-bromo-6-(3,4,5-trimethoxyphenyl)-5,7-dihydro-4H- [1,3]thiazolo[4,5-e] isoindol-2-amine (3k): this compound was obtained by reaction of 2k. Yield: 95%; light grey solid; mp: 95-96°C; IR: 3465-3377 (NH2) crrr 1; 1H NMR (DMSO-cfe) (ppm): 2.64-2.83 (2H, m, 2xCH2), 3.57 (6H, s, 2xCH3), 3.66 (3H, s, CHs), 5.15 (2H, s, CH2), 6.46 (2H, s, H-2’ and H-6’), 6.84-6.98 (4H, m, Ar and NH2), 7.19-7.36 (3H, m, Ar); 13C NMR (DMSO-de) (ppm): 20.9 (t), 22.1 (t), 48.5
(t), 55.6 (2xq), 60.0 (q), 97.2 (s), 106.8 (2xd), 114.4 (s), 116.9 (s), 117.6 (s), 125.6 (2xd), 126.4 (s), 126.6 (s), 126.9 (d), 128.5 (2xd), 131.0 (s), 136.9 (s), 138.7 (s),
152.6 (2xs), 166.1 (s). Anal calcd for C25H24BrN303S: C, 57.04; H, 4.60; N, 7.98. Found: C, 56.96; H, 4.79; N, 8.09.
6,8-Dibromo-7-(4-methoxybenzyl)-5,7-dihydro-4H-[1,3]thiazolo[4,5-e]isoindol- 2-amine (3I): this compound was obtained by reaction of 2I. Yield: 80%; light grey solid; mp: 175-176°C; IR 3408-3290 (NH2) crrr1; 1H NMR (DMSO-de) (ppm): 2.59- 2.66 (2H, m, CH2), 2.72-2.79 (2H, m, CH2), 3.71 (3H, s, CHs), 5.14 (2H, s, CH2), 6.88-7.02 (6H, m, NH2 and Ar); 13C NMR (DMSO -cfe) (ppm): 21.0 (t), 21.5 (t), 48.6 (t), 55.0 (q), 95.7 (s), 99.7 (s), 114.0 (2xd), 114.8 (s), 118.2 (s), 119.6 (s), 127.4 (2xd), 129.0 (s), 139.5 (s), 158.4 (s), 166.3 (s). Anal calcd for Ci7Hi5Br2N3OS: C, 43.52; H, 3.22; N, 8.96. Found: C, 43.39; H, 3.07; N, 9.11. 8-Bromo-7-(4-methoxybenzyl)-6-phenyl-5,7-dihydro-4H-[1,3]thiazolo[4,5- e]isoindol-2-amine (3m): this compound was obtained by reaction of 2m. Yield: 95%; light grey solid; mp: 75-dec°C; IR 3478-3361 (NHz) cm-1; 1H NMR (DMSO-de) (ppm): 2.62-2.69 (4H, m, 2xCH2), 3.68 (3H, s, CHs), 5.07 (2H, s, CH2), 6.76 (2H, d, J= 9.0 Hz, H-3’ and H-5’), 6.82 (2H, d, J= 9.0 Hz, H-2’ and H-6’), 6.90 (2H, s, NH2), 7.26-7.45 (5H, m, Ar); 13C NMR (DMSO-de) (ppm): 20.8 (t), 22.2 (t), 47.8 (t), 55.0 (q), 97.3 (s), 98.7 (s), 113.9 (2xd), 114.3 (s), 117.8 (s), 126.9 (2xd), 127.7 (d), 128.6 (2xd), 129.5 (2xd), 130.1 (s), 131.1 (s), 131.3 (s), 140.0 (s), 151.1 (s), 158.2 (s). Anal calcd for C23H2oBrN3OS: C, 59.23; H, 4.32; N, 9.01. Found: C, 59.16; H, 4.43; N, 9.22.
8-Bromo-7-(4-methoxybenzyl)-6-(3,4,5-trimethoxyphenyl)-5,7- dihydro-4H- [1,3]thiazolo[4,5-e] isoindol-2-amine (3n): this compound was obtained by reaction of 2n. Yield: 96%; light grey solid; mp: 182-183°C; IR 3459-3352 (NH2) crrr 1; 1H NMR (DMSO-cfe) (ppm): 2.67-2.78 (2H, m, 2xCH2), 3.61 (6H, s, 2xCH3), 3.67 (3H, s, CHs), 3.70 (3H, s, CHs), 5.08 (2H, s, CH2), 6.48 (2H, s, H-2’ and H-6’), 6.83- 6.87 (6H, m, Ar and NH2); 13C NMR (DMSO-de) (ppm): 21.7 (t), 22.1 (t), 46.7 (t), 55.1 (q), 55.7 (2xq), 60.0 (q), 97.1 (s), 106.9 (2xd), 109.8 (s), 113.9 (2xd), 116.6 (s), 117.9 (s), 126.9 (2xd), 129.2 (s), 130.3 (s), 136.9 (s), 152.6 (s), 152.7 (s), 158.2 (s), 158.3 (s), 166.1 (s). Anal calcd for C26H26BrN304S: C, 56.12; H, 4.71 ; N, 7.55. Found: C, 56.29; H, 4.59; N, 7.42.
General procedure for the synthesis of 1 -substituted ethyl 8-oxo-1,4,5,6,7,8- hexahydrocycloepta[b]pyrrole-2-carboxylate (4d-g).
To a solution of ketone 4b (9 mmoles) in anhydrous DMF (17 ml_), NaH (10 mmoles) was added at 0 °C and the reaction was agitated for 1 h and 30 minutes at room temperature. The appropriate alkyl or aryl alkyl halide (13.5 mmoles) was added at 0°C and the reaction mixture was agitated at room temperature or heated until complete (TLC). The reaction was then poured into water, ice and salt and if a precipitate formed the solid was filtered. In the absence of precipitate, the aqueous solution was extracted with dichloromethane (3 x 50 ml_). The organic phase was dried on Na2S04 and the solvent evaporated under reduced pressure. The crude product was purified using chromatography column (dichloromethane).
Ethyl 1 -methyl-8-oxo-1 ,4,5,6,7,8-hexahydrocyclohepta[b]pyrrole-2- carboxylate (d). This compound was obtained by reaction of 4b with iodomethane in 2 h at room temperature. Yield: 94%; white solid; mp: 51 .3-51 .5 °C; IR: 1705 (CO), 1642 (CO) cm 1; 1H NMR (DMSO-de) (ppm): 1.28 (3H, t, J = 7.1 Hz, CHs), 1.68 - 1.77 (4H, m, CH2 x 2), 2.64 (2H, t, J = 6.6 Hz, CH2), 2.75 (2H, t, J = 6.6 Hz, CH2), 4.06 (3H, s, CHs), 4.25 (2H, q, J = 7.1 Hz, CH2), 6.74 (1 H, s, H-3); 13C NMR (DMSO- de) (ppm): 14.1 (q), 20.8 (t), 24.4 (t), 24.8 (t), 34.3 (q), 41.4 (t), 60.2 (t), 116.6 (d), 126.3 (s), 132.8 (s), 133.5 (s), 160.3 (s), 194.1 (s). Anal calcd for C13H17NO3: C, 66.36; H, 7.28; N, 5.95. Found: C, 66.48; H, 7.37; N, 5.79.
Ethyl 1 -(4-methoxybenzyl)-8-oxo-1 ,4,5,6,7,8-hexahydrocyclohepta[b]pyrrole- 2-carboxylate (4e). This compound was obtained by reaction of 4b with 4- methoxybenzyl chloride in 6 h at room temperature. Yield: 79%; white solid; mp: 73.2 - 73.6 °C; IR: 1709 (CO), 1645 (CO) cm 1; 1H NMR (DMSO-de) (ppm): 1.23 (3H, t, J = 7.1 Hz, CHs), 1 .63 - 1 .79 (4H, m, CH2 x 2), 2.60 (2H, t, J = 5.6 Hz, CH2), 2.79 (2H, t, J = 5.6 Hz, CH2), 3.69 (3H, s, CHs), 4.20 (2H, q, J = 7.1 Hz, CH2), 5.93 (2H, s, CH2), 6.78 - 6.81 (4H, m, Ar), 6.83 (1 H, s, H-3); 13C NMR (DMSO-de) (ppm): 14.0 (q), 20.7 (t), 24.2 (t), 24.7 (t), 41.4 (t), 47.6 (t), 54.9 (q), 60.4 (t), 113.6 (d x 2), 117.7 (d), 126.1 (s), 127.2 (d x 2), 131.0 (s), 132.9 (s), 133.9 (s), 158.0 (s), 160.2 (s), 194.4 (s). Anal calcd for C2OH23N04: C, 70.36; H, 6.79; N, 4.10. Found: C, 70.55; H, 6.64; N, 3.95.
Ethyl 1 -(3,5-dimethoxybenzyl)-8-oxo-1 , 4, 5, 6,7,8- hexahydrocyclohepta[b]pyrrole-2-carboxylate (4f). This compound was obtained by reaction of 4b with 3,5-dimethoxybenzyl chloride in 16 h at room temperature. Yield: 83%; white solid; mp: 71 .8 - 72.0 °C; IR: 1707 (CO), 1647 (CO) cm-1; 1H NMR (DMSO-de) (ppm): 1.22 (3H, t, J = 7.1 Hz, CHs), 1.72 (4H, m, CH2 x 2), 2.61 (2H, t, J = 6.9 Hz, CH2), 2.82 (2H, t, J = 6.9 Hz, CH2), 3.65 (6H, s, CHs x 2), 4.19 (2H, q, J = 7.1 Hz, CH2), 5.94 (4H, s, CH2, H-2’ and H-6’), 6.32 (1 H, s, H-4’), 6.88 (1 H, s, H-3); 13C NMR (DMSO-de) (ppm): 14.1 (q), 20.8 (t), 24.4 (t), 24.8 (t), 41.4 (t), 48.2 (t), 55.0 (q x 2), 60.4 (t), 97.8 (d), 103.7 (d x 2), 117.8 (d), 126.3 (s),
133.1 (s), 133.9 (s), 141.9 (s), 160.1 (CO), 160.5 (s x 2), 194.3 (s). Anal calcd for C21 H25NO5: C, 67.91 ; H, 6.78; N, 3.77. Found: C, 68.02; H, 6.67; N, 3.89.
Ethyl 1 -(3,4,5-trimethoxybenzyl)-8-oxo-1 , 4, 5, 6,7,8- hexahydrocyclohepta[b]pyrrole-2-carboxylate (4g). This compound was obtained by reaction of 4b with 3,4,5-trimethoxybenzyl chloride in 5 h at 80°C. Yield: 80%; white solid; mp: 70 -70.2 °C; IR: 1709 (CO), 1646 (CO) cm 1; 1H NMR (DMSO- de) (ppm): 1 .24 (3H, t, J = 7.1 Hz, CHs), 1 .66 - 1 .80 (4H, m, CH2 x 2), 2.64 (2H, t, J = 5.6 Hz, CH2), 2.82 (2H, t, J = 5.6 Hz, CH2), 3.60 (3H, s, CHs), 3.64 (6H, s, CHs x 2), 4.22 (2H, q, J = 7.1 Hz, CH2), 5.97 (2H, s, CH2), 6.16 (2H, s, H-2’ and H-6’), 6.88 (1 H, s, H-3); 13C NMR (DMSO -d6) (ppm): 14.0 (q), 20.8 (t), 24.3 (t), 24.7 (t), 41 .4 (t),
48.1 (t), 55.6 (q x 2), 59.9 (q), 60.4 (t), 102.9 (d x 2), 117.8 (d), 126.3 (s), 133.1 (s), 133.9 (s), 135.0 (s), 136.2 (s), 152.8 (s x 2), 160.2 (s), 194.4 (s). Anal calcd for C22H27NO6: C, 65.82; H, 6.78; N, 3.49. Found: C, 65.99; H, 6.85; N, 3.37.
General procedure for the synthesis of the 2-amino- pyrrole[3',2':6,7]cyclohepta[1,2-c/][1,3]thiazoles (6b-g)
To a suspension of CuBr2 (5.4 mmoles) in anhydrous ethyl acetate (12 ml_) the appropriate ketone 4 (3 mmoles) was added and the reaction mixture was heated to reflux for 2 h. After cooling, the reaction mixture was filtered under vacuum for removing the CuBr formed. The solvent evaporated under reduced pressure and the residue was dissolved in anhydrous DMF (12 ml_). Then K2CO3 (6 mmoles) and thiourea (6 mmoles) were added and the new reaction mixture was agitated at room temperature for 16 h. The reaction was then poured into water, ice and salt (30 ml_) and if a precipitate formed the solid was filtered. In the absence of precipitate, the aqueous solution was extracted with dichloromethane (3 x 40 ml_). The organic phase was dried on Na2S04 and the solvent evaporated under reduced pressure. The crude product was purified using a chromatography column (dichloromethane:ethyl acetate 8:2).
Ethyl 2-amino-4,5,6,9-tetrahydropyrrole[3',2':6,7]cyclohepta[1,2- c/][1,3]thiazole-8-carboxylate (6b) This compound was obtained by reaction of 4b. Yield: 52%; white solid; mp: 190 - 191 °C; IR: 3370 (NH), 3202 - 3156 (NH2) 1692 (CO) crrr1; 1H NMR (DMSO-de) (ppm): 1.27 (3H, t, J = 7.1 Hz, CHs), 1.85 - 1.99 (2H, m, CH2), 2.75 - 2.85 (4H, m, CH2 x 2), 4.22 (2H, q, J = 7.1 Hz, CH2), 6.63 (1 H, s, H-7), 6.88 (2H, s, NH2), 9.64 (1 H, s, NH); 13C NMR (DMSO-de) (ppm): 14.3 (q), 23.9 (t), 27.0 (t), 27.6 (t), 59.5 (t), 116.4 (d), 118.9 (s), 119.3 (s), 121.6 (s), 129.8 (s), 137.8 (s), 159.9 (s), 165.5 (s). Anal. Calcd. for Ci3Hi5N302S: C, 56.30; H, 5.45; N, 15.15. Found: C, 56.38; H, 5.56; N, 15.14.
9-(Phenylsulfonyl)-4,5,6,9-tetrahydropyrrole[3',2':6,7]cyclohepta[1,2- c/][1,3]thiazole-2-amine (6b) This compound was obtained by reaction of 4c. Yield: 45%; yellow solid; mp: 173 - 174 °C; IR: 3252 - 3143 (NH2) cm 1; 1H NMR (CDCIs) (ppm): 2.01 - 2.11 (2H, m, CH2), 2.41 (2H, t, J = 6.7 Hz, CH2), 2.45 (2H, t, J = 6.7 Hz, CH2), 4.68 (2H, s, NH2), 6.17 (1 H, d, J = 3.0 Hz, H-7), 7.35 (1 H, d, J = 3.0 Hz, H-8), 7.40 - 7.55 (3H, m, H-3’, H-4’ and H-5’), 7.86 (2H, d, J = 7.0 Hz, H-2’ and H- 6’); 13C NMR (CDCIs) (ppm): 24.0 (t), 25.0 (t), 31.8 (t), 113.5 (d), 123.2 (d), 125.3 (s), 126.7 (s), 127.2 (d x 2), 128.4 (d x 2), 130.5 (s), 133.0 (d), 138.3 (s), 140.1 (s), 162.7 (s). Anal. Calcd. for Ci6Hi5N302S2: C, 55.63; H, 4.38; N, 12.16. Found: C, 55.77; H, 4.26; N, 12.08.
Ethyl 2-amino-9-methyl-4,5,6,9-tetrahydropyrrole[3',2':6,7]cyclohepta[1,2- c/][1,3]thiazol-8-carboxylate (6d). This compound was obtained by reaction of 4d. Yield: 65 %; yellow solid; mp: 113 - 114 °C; IR: 3255 - 3188 (NH2), 1690 (CO) cm 1; 1H NMR (CDCIs) (ppm): 1 .34 (3H, t, J = 7.1 Hz, CHs), 2.05 -2.09 (2H, m, CH2), 2.61 (2H, t, J = 6.4 Hz, CH2), 2.76 (2H, t, J = 6.4 Hz, CH2), 4.16 (3H, s, CHs), 4.27 (2H, q, J = 7.1 Hz, CH2), 4.86 (2H, s, NH2), 6.79 (1 H, s, H-7); 13C NMR (CDCIs) (ppm):
14.5 (q), 25.7 (t), 25.8 (t), 29.9 (t), 35.2 (q), 59.6 (t), 117.3 (d), 121.8 (s), 124.2 (s), 126.2 (s), 132.7 (s), 139.0 (s), 161.5 (s), 163.3 (s). Anal. Calcd. for Ci4Hi7Ns02S: C, 57.71 ; H, 5.88; N, 14.42. Found: C, 57.84; H, 5.76; N, 14.52.
Ethyl 2-amino-9-(4-methoxybenzyl)-4,5,6,9- tetrahydropyrrole[3',2':6,7]cyclohepta[1,2-c/l[1,3]thiazol-8-carboxylate (6e). This compound was obtained by reaction of 4e. Yield: 60%; yellow solid; mp: 59°C; IR: 3253 - 3175 (NH2), 1715 (CO) cm 1; 1H NMR (CDCIs) (ppm): 1.27 (3H, t, J = 7.1 Hz, CHs), 2.05 - 2.12 (2H, m, CH2), 2.63 (2H, t, J = 6.5 Hz, CH2), 2.73 (2H, t, J =
6.5 Hz, CH2), 3.73 (3H, s, CHs), 4.17 (2H, q, J = 7.1 Hz, CH2), 4.73 (2H, s, NH2), 6.09 (2H, s, CH2), 6.73 (2H, d, J = 8.6 Hz, H-3’ and H-5’), 6.86 (1 H, s, H-7) 6.89 (2H, d, J = 8.6 Hz, H-2’ and H-6’); 13C NMR (CDC ) (ppm): 14.4 (q), 25.5 (t), 25.7 (t), 30.2 (t), 48.6 (t), 55.1 (q), 59.6 (t), 113.5 (d x 2), 118.6 (d), 121.4 (s), 124.7 (s), 126.3 (s), 127.5 (d x 2), 132.5 (s), 132.6 (s), 139.1 (s), 158.1 (s), 161.1 (s), 163.4 (s). Anal. Calcd. for C21 H23N3O3S: C, 63.45; H, 5.83; N, 10.57. Found: C, 63.32; H, 5.98; N, 10.68.
Ethyl 2-amino-9-(3,5-dimethoxybenzyl)-4,5,6,9- tetrahydropyrrole[3',2':6,7]cyclohepta[1,2-c/l[1,3]thiazol-8-carboxylate (6f).
This compound was obtained by reaction of 4f. Yield: 40%; brown solid; mp: 140.6
- 141.0 °C; IR: 3377 - 3253 (NH2), 1696 (CO) cm 1; 1H NMR (CDCIs) (ppm): 1.27
(3H, t, J = 7.1 Hz, CHs), 2.03 - 2.13 (2H, m, CH2), 2.63 (2H, t, J = 6.6 Hz, CH2), 2.73 (2H, t, J = 6.6 Hz, CH2), 3.66 (6H, s, CHs x 2), 4.19 (2H, q, J = 7.1 Hz, CH2), 4.77
(2H, s, NH2), 6.08 (2H, s, CH2), 6.14 (2H, s, H-2’ and H-6’), 6.23 (1 H, s, H-4’), 6.87
(1 H, s, H-7); 13C NMR (CDCIs) (ppm): 14.4 (q), 25.6 (t), 25.7 (t), 30.2 (t), 49.1 (t),
55.1 (q), 59.6 (t), 98.6 (d), 104.1 (d x 2), 118.6 (d), 121.7 (s), 124.7 (s), 126.1 (s),
132.7 (s), 139.1 (s), 142.9 (s), 160.5 (s x 2), 161.1 (s), 163.5 (s). Anal. Calcd. for C22H25N3O4S: C, 61.81 ; H, 5.89; N, 9.83. Found: C, 61.97; H, 5.75; N, 10.01.
Ethyl 2-amino-9-(3,4,5-trimethoxybenzyl)-4,5,6,9- tetrahydropyrrole[3',2':6,7]cyclohepta[1,2-c/l[1,3]thiazol-8-carboxylate (6g). This compound was obtained by reaction of 4g. Yield: 92 %; yellow solid; mp: 149.5
- 150.3 °C; IR: 3408 - 3357 (NH2), 1701 (CO) cm 1; 1H NMR (CDCIs) (ppm): 1.30
(3H, t, J = 7.1 Hz, CHs), 2.03 - 2.11 (2H, m, CH2), 2.63 (2H, t, J = 6.4 Hz, CH2), 2.73 (2H, t, J = 6.4 Hz, CH2), 3.70 (6H, s, CHs x 2), 3.76 (3H, s, CHs), 4.22 (2H, q, J =
7.1 Hz, CH2), 4.78 (2H, s, NH2), 6.14 (2H, s, CH2), 6.23 (2H, s, H-2’ and H-6’), 6.86
(1 H, s, H-7); 13C NMR (CDCIs) (ppm): 14.4 (q), 25.5 (t), 25.6 (t), 30.4 (t), 48.8 (t),
55.7 (q x 2), 59.7 (t), 60.7 (q), 103.6 (d x 2), 118.7 (d), 121.6 (s), 124.9 (s), 126.1 (s), 132.6 (s), 135.9 (s), 136.3 (s), 139.3 (s), 152.8 (s x 2), 161 .2 (s), 163.6 (s). Anal. Calcd. for CzsH^NsOsS: C, 60.38; H, 5.95; N, 9.18. Found: C, 60.44; H, 6.07; N, 9.08.
Ethyl 2-amino-9-(2-bromo-3,5-dimethoxybenzyl)-4,5,6,9- tetrahydropyrrole[3',2':6,7]cyclohepta[1,2-c/l[1,3]thiazol-8-carboxylate (6h).
This compound was obtained by reaction of 4f. Yield: 25%; brown solid; mp: 189.3
- 189.9 °C; IR: 3334 - 3227 (NH2), 1695 (CO) cm 1; 1H NMR (CDCIs) (ppm): 1.25 (3H, t , J = 7.1 Hz, CHs), 2.00 - 2.09 (2H, m, CH2), 2.69 - 2.84 (4H, m, CH2 x 2), 3.56 (3H, s, CHs), 3.84 (3H, s, CHs), 4.18 (2H, q, J = 7.1 Hz, CH2), 4.62 (2H, s, NH2), 5.43 (1 H, s, H-4’), 6.21 (2H, s, CH2), 6.28 (1 H, s, H-6’), 6.91 (1 H, s, H-7); 13C NMR (CDCIs) (ppm): 14.3 (q), 26.6 (t), 26.7 (t), 28.4 (t), 51.1 (t), 55.1 (q), 56.2 (q), 59.7 (t), 97.2 (d), 101.3 (s), 103.2 (d), 118.7 (d), 121.9 (s), 124.6 (s), 126.0 (s), 132.4 (s), 138.3 (s), 142.4 (s), 156.1 (s), 159.7 (s), 160.9 (s), 162.9 (s). Anal. Calcd. for C22H2 BrNs04S: C, 52.18; H, 4.78; N, 8.30. Found: C, 52.25; H, 4.69; N, 8.22.
General procedure for the synthesis of nitro-derivatives (7a, b)
A mixture of the appropriate 2-aminothiazole 3e,f (4.5 mmoles) and 2-bromo-p- nitroacetophenone (4.95 mmoles) in anhydrous 2-methoxyethanol was heated to 70 °C for 13 h. The reaction mixture was cooled to 0°C and the solid formed was collected by filtration and washed with 2-methoxyethanol for providing the desired product without any further purification. 8-(4-Nitrophenyl)-2-(phenylsulfonyl)-4,5-dihydro-2H- imidazo[2',T:2,3][1,3]thiazolo[4,5-e]isoindol (7a). This compound was obtained by reaction of 3e. Yield: 64%; yellow solid; mp: 261-262 °C; IR: 1505-1333 (N02) cm-1; 1H NMR (DMSO-cfe) (ppm): 2.80-3.07 (4H, m, CH2 x 2), 7.36 (1 H, s, H-3), 7.55- 7.90 (3H, m, H-3’, H-4’ and H-5’), 8.05 (2H, d, J = 7.2 Hz, H-2’ and H-6’), 8.03 (1 H, s, H-1 ), 8.18 (2H, d, J = 8.5 Hz, H-2” and H-6”), 8.30 (2H, d, J = 8.5 Hz, H-3” and H-5”), 9.07 (1 H, s, H-imidaz); 13C NMR (DMSO-de) (ppm): 19.6 (t), 23.2 (t), 112.1 (d), 113.6 (d), 116.0 (s), 117.8 (d), 121 .4 (s), 123.0 (s), 124.1 (d x 2), 125.2 (d x 2), 126.7 (d x 2), 128.9 (s), 130.0 (d x 2), 134.7 (d), 137.9 (s), 140.8 (s), 143.9 (s), 145.8 (s), 148.1 (s). Anal. Calcd. for C2sHi6N404S2: C, 57.97; H, 3.38; N, 11 .76. Found: C, 58.10; H, 3.65; N, 11.66.
Ethyl 8-(4-nitrophenyl)-2-(phenylsulfonyl)-4,5-dihydro-2H- imidazo[2',T:2,3][1,3]thiazolo[4,5-e]isoindole-3-carboxylate(7b). This compound was obtained by reaction of 3f. Yield: 48%; pale yellow solid; mp: 249- 250 °C; IR: 1726 (CO), 1505-1333 (N02) cm 1; 1H NMR (DMSO-cfe) (ppm): 1.22 (3H, t, J = 7.0 Hz, CHs), 2.97-3.19 (4H, m, CH2 x 2), 4.22 (2H, q, J = 7.0 Hz, CH2), 7.59- 7.84 (3H, m, H-3’, H-4’ and H-5’), 8.05 (2H, d, J = 6.8 Hz, H-2’ and H-6’), 8.20 (2H, d, J = 8.6 Hz, H-2” and H-6”), 8.30 (2H, d, J = 8.6 Hz, H-3” and H-5”), 8.51 (1 H, s, H-1 ), 9.16 (1 H, s, H-imidaz); 13C NMR (DMSO -d6) (ppm): 13.9 (q), 20.6 (t), 22.6 (t), 61.1 (t), 113.8 (s), 120.6 (d), 121.7 (s), 123.3 (s), 124.2 (d x 2), 125.3 (d x 2), 127.7 (d x 2), 129.5 (d x 2), 132.1 (d), 134.4 (d), 138.4 (s), 140.9 (s), 143.9 (s), 145.9 (s), 147.6 (s), 148.3 (s), 157.1 (s), 158.8 (s). Anal. Calcd. for C26H20N4O6S2: C, 56.92; H, 3.67; N, 10.21. Found: C, 56.70; H, 3.75; N, 10.56.
Synthesis of 8-(4-nitrophenyl)-4,5-dihydro-2H- imidazo[2',1':2,3][1,3]thiazolo[4,5-e]isoindole (7c)
To a suspension of 7a (1 .5 mmoles) in methanol (120 ml_), KOH (52.5 mmoles) was added and the reaction mixture was heated to reflux for 16 h. After cooling, the solvent was removed under reduced pressure and the residue was suspended in water and the solid formed was filtered. The crude product was purified using chromatography column (DCM). Yield: 90%; orange solid; mp: 277-278 °C; IR: 3270 (NH), 1503-1335 (NO2) cm 1; 1H NMR (DMSO-de) (ppm): 2.80-3.05 (4H, m, CH2 x 2), 6.75 (1 H, s, H-3), 7.52 (1 H, s, H-1 ), 8.17 (2H, d, J = 8.8 Hz, H-2” and H-6”), 8.29 (2H, d, J = 8.8 Hz, H-3” and H-5”), 8.88 (1 H, s, H-imidaz), 11.02 (1 H, s, NH); 13C NMR (DMSO -d6) (ppm): 20.3 (t), 24.0 (t), 110.4 (s), 111.6 (d), 112.1 (d), 115.0 (d),
115.9 (s), 116.5 (s), 124.1 (d x 2), 124.2 (s), 125.1 (d x 2), 141.1 (s), 143.5 (s), 145.7
(s), 148.4 (s). Anal. Calcd. for C17H12N4O2S: C, 60.70; H, 3.60; N, 16.66. Found: C, 61.05; H, 3.55; N, 16.85.
Synthesis of 2-methyl-8-(4-nitrophenyl)-4,5-dihydro-2H- imidazo[2',1':2,3][1,3]thiazolo[4,5-e]isoindole (7d)
To a solution of 7c (0.5 mmoles) in anhydrous DMF (5 ml_), NaH (0.55 mmoles) was added at 0 °C and the reaction mixture was agitated at room temperature for 2 h. Then, iodomethane (0.75 mmoles) was added at 0 °C and the reaction mixture was agitated at room temperature for 3 h. The reaction mixture was poured into water and ice and the solid formed was filtered and purified using a chromatography column (DCM). Yield: 85%; orange solid; mp: 272-273 °C; IR: 1509-1339 (NO2) crrr 1; 1H NMR (DMSO-cfe) (ppm): 2.75-3.00 (4H, m, CH2 x 2), 3.69 (3H, s, CHs), 6.70 (1 H, s, H-3), 7.46 (1 H, s, H-1 ), 8.16 (2H, d, J = 8.4 Hz, H-2” and H-6”), 8.29 (2H, d, J = 8.4 Hz, H-3” and H-5”), 8.81 (1 H, s, H-imidaz); 13C NMR (DMSO -d6) (ppm): 20.2
(t), 23.9 (t), 35.9 (q), 110.5 (s), 111.3 (d), 115.6 (d), 115.9 (s), 116.9 (s), 119.3 (d),
123.9 (s), 124.3 (d x 2), 125.2 (d x 2), 141 .1 (s), 143.7 (s), 145.7 (s), 148.4 (s). Anal. Calcd. for C18H14N4O2S: C, 61.70; H, 4.03; N, 15.99. Found: C, 61.68; H, 4.12; N, 16.14.
Synthesis of 2-(3-chloropropyl)-8-(4-nitrophenyl)-4,5-dihydro-2H- iinidazo[2\1':2,3][1,3]thiazolo[4,5-e]isoindole (7e)
To a solution of 7c (1.5 mmoles) in anhydrous DMF (15 ml_), NaFI (1.65 mmoles) was added at 0 °C and the reaction mixture was agitated at room temperature for 2 h. Then Kl (0.5 mmoles) and 1-bromo-3-chloropropane (4.5 mmoles) were added and the reaction mixture was heated to 70° C in an ultrasound bath for 2 h. The reaction mixture was poured into water and ice and the solid formed was filtered and purified using a chromatography column (DCM). Yield: 100%; yellow solid; mp: 227- 228 °C; IR: 1509-1339 (NO2) cm 1; 1H NMR (DMSO-de) (ppm): 2.10-2.40 (2H, m, CH2), 2.75-3.08 (4H, m, CH2 x 2), 3.60-3.68 (2H, t, J = 6.2 Hz, CH2), 4.07 (2H, t, J = 6.6 Hz, CH2), 6.78 (1 H, s, H-3), 7.54 (1 H, s, H-1 ), 8.15 (2H, d, J = 8.8 Hz, H-2” and H-6”), 8.29 (2H, d, J = 8.8 Hz, H-3” and H-5”), 8.82 (1 H, s, H-imidaz); 13C NMR (DMSO -d6) (ppm): 20.2 (t), 23.8 (t), 33.5 (t), 42.3 (t), 46.2 (t), 110.7 (s), 111.4 (d), 114.6 (d), 116.2 (s), 117.0 (s), 118.3 (d), 123.7 (s), 124.2 (d x 2), 125.1 (d x 2), 141.0 (s), 143.6 (s), 145.7 (s), 148.4 (s). Anal. Calcd. for C20H17CIN4O2S: C, 58.18; H, 4.15; N, 13.57. Found: C, 58.35; H, 4.23; N, 13.74.
General procedure for the synthesis of nitro derivatives 7f-i To a solution of 7e (1 mmoles) in anhydrous DMF (8 ml_), tetrabutylammonium iodide (1 .5 mmoles) were added and the appropriate heterocyclic amide (4 mmoles). The reaction mixture was heated to 70°C until complete (TLC). Then the reaction mixture was poured into water and ice and the solid formed was filtered. The crude product was purified using chromatography column. 8-(4-Nitrophenyl)-2-[3-(pyrrolidin-1-yl)propyl]-4,5-dihydro-2H- imidazo[2',T:2,3][1,3]thiazolo[4,5-e]isoindol (7a). This compound was obtained by reaction of 7e with pyrrolidine in 3 h. The purification was obtained by chromatography column (DCM: MeOH 95: 5). Yield: 77%; orange solid; mp: 171- 172 °C; IR: 1511-1340 (NO2) cm 1; 1H NMR (DMSO-de) (ppm): 1.83-1.94 (4H, m, CH2 X 2), 2.02-2.20 (2H, m, CH2), 2.50-2.75 (6H, m, CH2 x 3), 2.3 (4H, s, CH2 x 2), 4.03 (2H, t, J = 6.8 Hz, CH2), 6.55 (1 H, s, H-3), 6.98 (1 H, s, H-1 ), 7.94 (1 H, s, H- imidaz), 8.02 (2H, d, J= 9.0 Hz, H-2” and H-6”), 8.24 (2H, d, J = 9.0 Hz, H-3” and H-5”); 13C NMR (DMSO -d6) (ppm): 20.8 (t), 23.5 (t x 2), 24.7 (t), 30.0 (t), 47.6 (t),
52.9 (t), 54.1 (t x 2), 109.0 (d), 111.8 (s), 113.1 (d), 117.6 (s), 117.6 (s), 118.1 (d),
123.9 (s), 124.2 (d x 2), 125.2 (d x 2), 141 .0 (s), 144.4 (s), 146.4 (s), 149.9 (s). Anal. Calcd. for C24H25N5O2S: C, 64.41 ; H, 5.63; N, 15.65. Found: C, 64.45; H, 5.78; N, 15.92.
8-(4-Nitrophenyl)-2-[3-(piperidin-1-yl)propyl]--4,5-dihydro-2H- imidazo[2',1':2,3][1,3]thiazolo[4,5-e]isoindol (7g). This compound was obtained by reaction of 7e with piperidine in 16 h. The purification was obtained by chromatography column (DCM: MeOH 97: 3). Yield: 93%; yellow solid; mp: 290-291 °C; IR: 1510-1340 (NO2) cm-1; 1H NMR (DMSO-cfe) (ppm): 1.25-1.63 (6H, m, CH2 x 3), 1 .83-2.02 (2H, m, CH2), 2.20-2.50 (6H, m, CH2 x 3), 2.72-3.00 (4H, m, CH2 x 2), 3.93 (2H, t, J = 6.9 Hz, CH2), 6.74 (1 H, s, H-3), 7.50 (1 H, s, H-1 ), 8.13 (2H, d, J = 9.0 Hz, H-2” and H-6”), 8.27 (2H, d, J = 9.0 Hz, H-3” and H-5”), 8.78 (1 H, s, H- imidaz); 13C NMR (DMSO-de) (ppm): 20.2 (t x 2), 23.9 (t x 2), 25.3 (t), 28.0 (t), 47.2 (t), 53.9 (t x 2), 55.3 (t), 110.4 (s), 111.3 (d), 114.5 (d), 115.9 (s), 116.6 (s), 118.3 (d), 123.8 (s), 124.1 (d x 2), 125.0 (d x 2), 141.0 (s), 143.5 (s), 145.6 (s), 148.4 (s). Anal. Calcd. for C25H27N5O2S: C, 65.05; H, 5.90; N, 15.17. Found: C, 65.31 ; H, 5.82; N, 15.02.
2-[3-(4-Methylpiperazin-1-yl)propyl]-8-(4-nitrophenyl)-4,5-dihydro-2H-imidazo [2',T:2,3][1,3]thiazolo[4,5-e]isoindole (7h). This compound was obtained by reaction of 7e with 1-methylpiperidine in 18 h. The purification was obtained by chromatography column (DCM: MeOH 96: 4). Yield: 90%; orange solid; mp: 194- 195 °C; IR: 1512-1340 (NO2) cm 1; 1H NMR (CDCIs) (ppm): 1.90-2.09 (2H, m, CH2), 2.27-2.70 (13H, m, CH2 x 5 and CHs), 2.92 (4H, m, CH2 x 2), 3.98 (2H, t, J =6.8 Hz, CH2), 6.54 (1 H, s, H-3), 6.89 (1 H, s, H-1 ), 7.85 (1 H, s, H-imidaz), 7.98 (2H, d, J = 7.1 Hz, H-2” and H-6”), 8.22 (2H, d, J = 7.1 Hz, H-3” and H-5”); 13C NMR (CDCIs) (ppm): 20.8 (t), 24.7 (t), 28.5 (t), 46.0 (q), 47.6 (t), 53.0 (t x 2), 54.8 (t), 55.1 (t x 2), 108.8 (d), 111.6 (s), 113.1 (d), 117.5 (s), 117.9 (s), 118.1 (d), 123.9 (s), 124.1 (d x 2), 125.1 (d x 2), 140.9 (s), 144.3 (s), 146.3 (s), 149.9 (s). Anal. Calcd. for C25H28N6O2S: C, 63.00; H, 5.92; N, 17.63. Found: C, 63.31 ; H, 6.13; N, 17.75. 2-[3-(Morpholin-4-yl)propyl]-8-(4-nitrophenyl)-4,5-dihydro-2H-imidazo [2',T:2,3][1,3]thiazolo[4,5-e]isoindole (7o). This compound was obtained by reaction of 7e with morpholine in 8 h. The purification was obtained by chromatography column (DCM: MeOH 98: 2). Yield: 80%; orange solid; mp: 203- 204 °C; IR: 1511-1340 (NO2) cm 1; 1H NMR (CDCh) (ppm): 1.92-2.09 (2H, m, CH2), 2.23-2.50 (6H, m, CH2 x 3), 2.86-3.00 (4H, m, CH2 x 2), 3.68-3.82 (4H, m, CH2 x 2), 3.95-4.10 (2H, t, J = 6.8 Hz, CH2), 6.55 (1 H, s, H-3), 6.88 (1 H, s, H-1), 7.82 (1 H, s, H-imidaz), 7.97 (2H, d, J = 8.9 Hz, H-2” and H-6”), 8.22 (2H, d, J = 8.9 Hz, H-3” and H-5”); 13C NMR (CDCh) (ppm): 20.7 (t), 24.6 (t), 28.3 (t), 47.5 (t), 53.7 (t x 2), 55.3 (t), 67.0 (t x 2), 108.7 (d), 111.6 (s), 113.0 (d), 117.6 (s), 117.9 (s), 118.1 (d), 123.9 (s), 124.1 (d x 2), 125.1 (d x 2), 140.9 (s), 144.3 (s), 146.3 (s), 149.9 (s). Anal. Calcd. for C24H25N5O3S: C, 62.18; H, 5.44; N, 15.11. Found: C, 61.97; H, 5.41 ; N, 15.18. General procedure for the synthesis of nitro derivatives 7j-l To a solution of 7c (1 .2 mmoles) in anhydrous DMF (8 ml_), NaH (1 .32 mmoles) was added at 0 °C and the reaction mixture was agitated at room temperature for 2 h. Then, tetrabutylammonium iodide (1.32 mmoles) was added and the appropriate alkyl halide in the form of a free base (4.8 mmoles) in DMF (2 ml_) and the reaction mixture was agitated at room temperature or heated to 50 °C until complete (TLC). (The free bases of alkyl halides were prepared extemporaneously from the salts commercially available for treatment with an NaOH solution and extraction with DCM). The reaction mixture was poured into water and ice and the solid formed was filtered and purified using a chromatography column. 8-(4-Nitrophenyl)-2-[2-(pyrrolidin-1-yl)ethyl]-4,5-dihydro-2H- imidazo[2',T:2,3][1,3]thiazolo[4,5-e]isoindol (7j). This compound was obtained by reaction of 7c with 1-(2-chloroethyl)pyrrolidine in 20 h at room temperature. The purification was obtained by chromatography column (DCM:MeOH 98:2) and further crystallization from ethanol. Yield: 77%; orange solid; mp: 171-172 °C (EtOH); IR: 1512-1340 (NO2) cm-1 ; 1 H NMR (DMSO-de) (ppm): 1 .63-1 .72 (4H, m, CH2 x 2), 2.45- 2.53 (4H, m, CH2 x 2), 2.77-3.00 (6H, m, CH2 x 3), 4.03 (2H, t, J = 6.9 Hz, CH2), 6.78 (1 H, s, H-3), 7.53 (1 H, s, H-1 ), 8.16 (2H, d, J = 9.0 Hz, H-2” and H-6”), 8.30 (2H, d, J = 9.0 Hz, H-3” and H-5”), 8.82 (1 H, s, H-imidaz); 13C NMR (DMSO-de) (ppm): 20.2 (t), 23.1 (t x 2), 23.9 (t), 48.4 (t), 53.6 (t x 2), 56.5 (t), 110.4 (d), 111.3 (s), 114.8 (d), 115.9 (s), 116.6 (s), 118.5 (d), 123.8 (s), 124.2 (d x 2), 125.1 (d x 2), 141.0 (s), 143.6 (s), 145.7 (s), 148.4 (s). Anal. Calcd. for C23H23N5O2S: C, 63.72; H, 5.35; N, 16.15. Found: C, 64.01 ; H, 5.28; N, 16.33. 8-(4-Nitrophenyl)-2-[2-(piperidin-1-yl)ethyl]-4,5-dihydro-2H- imidazo[2',1':2,3][1,3]thiazolo[4,5-e]isoindol (7k). This compound was obtained by reaction of 7c with 1-(2-chloroethyl)piperidine in 20 h at room temperature. The purification was obtained by chromatography column (DCM: MeOH 99: 1 ) and further crystallization from ethanol. Yield: 85%; yellow solid; mp: 231-232 °C (EtOH); IR: 1505-1340 (NO2) cm 1; 1H NMR (CDCIs) (ppm): 1 .32-1 .62 (6H, m, CH2 x 3), 2.37- 2.50 (4H, m, CH2 x 2), 2.68 (2H, t, J = 6.8 Hz, CH2), 2.85 (4H, s, CH2 x 2), 4.00 (2H, t, J = 6.8 Hz, CH2), 6.52 (1 H, s, H-3), 6.89 (1 H, s, H-1 ), 7.79 (1 H, s, H-imidaz), 7.91 (2H, d, J = 8.6 Hz, H-2” and H-6”), 8.16 (2H, d, J= 8.6 Hz, H-3” and H-5”); 13C NMR (CDCIs) (ppm): 20.8 (t), 24.1 (t), 24.7 (t), 25.9 (t x 2), 47.6 (t), 54.9 (t x 2), 60.0 (t), 108.8 (d), 111.7 (s), 113.3 (d), 117.6 (s), 118.0 (s), 118.3 (d), 123.9 (s), 124.2 (d x 2), 125.2 (d x 2), 140.9 (s), 144.4 (s), 146.4 (s), 149.9 (s). Anal. Calcd. for C24H25N5O2S: C, 64.41 ; H, 5.63; N, 15.65. Found: C, 64.83; H, 5.81 ; N, 15.90. 2-[2-(Morpholin-4-yl)ethyl]-8-(4-nitrophenyl)-4,5-dihydro-2H-imidazo [2',T:2,3][1,3]thiazolo[4,5-e]isoindole (7I). This compound was obtained by reaction of 7c with 4-(2-chloroethyl)morpholine in 20 h at 50 °C. Purification was obtained through chromatography column (DCM:MeOH 98:2). Yield: 75%; orange solid; mp: 258-259 °C; IR: 1511-1340 (NO2) cm-1; 1H NMR (DMSO-de) (ppm): 2.38- 2.50 (4H, m, CH2 x 2), 2.70 (2H, t, J = 6.7 Hz, CH2), 2.76-3.00 (4H, m, CH2 x 2), 3.53-3.63 (4H, m, CH2 x 2), 4.05 (2H, t, J = 6.7 Hz, CH2), 6.79 (1 H, s, H-3), 7.53 (1 H, s, H-1 ), 8.15 (2H, d, J = 9.0 Hz, H-2” and H-6”), 8.30 (2H, d, J = 9.0 Hz, H-3” and H-5”), 8.80 (1 H, s, H-imidaz); 13C NMR (DMSO -d6) (ppm): 20.2 (t), 23.9 (t), 46.4 (t), 53.3 (t x 2), 58.9 (t), 66.1 (t x 2), 110.4 (s), 111.3 (d), 114.8 (d), 116.0 (s), 116.6 (s), 118.6 (d), 123.8 (s), 124.2 (d x 2), 125.1 (d x 2), 141.0 (s), 143.6 (s), 145.7 (s), 148.4 (s). Anal. Calcd. for C23H23N5O3S: C, 61.45; H, 5.16; N, 15.58. Found: C, 61.37; H, 5.41 ; N, 15.77.
Synthesis of 8-(4-nitrophenyl)-2-(phenylsulfonyl)-2H- imidazo[2',1':2,3][1,3]thiazolo[4,5-e]isoindole (8)
To a suspension of 7a (0.2 mmoles) in 1 ,4-dioxane anhydrous (30 ml_), DDQ (0.4 mmoles) was added and the reaction mixture was heated to reflux for 3 h. Then the solvent was removed under reduced pressure and the residue was purified through chromatography column (DCM:EtOAc 98:2). Yield: 10%; brown solid; mp: 289-290 °C; IR: 1503-1335 (NO2) crrr1; 1H NMR (DMSO -cfe) (ppm): 7.53 (1 H, d, J = 7.6 Hz, H-5), 7.74 (1 H, d, J = 7.6 Hz, H-4), 8.01 -8.26 (1 OH, m, Ar), 8.80 (1 H, s, H-1 ), ), 9.37 (1 H, s, H-imidaz); 13C NMR (DMSO-de) (ppm): 109.1 (d), 112.7 (d), 114.1 (d), 114.3 (s), 118.9 (d), 119.3 (d), 121.6 (s), 122.6 (s), 124.1 (d x 2), 124.9 (s), 125.2 (d x 2), 127.2 (d x 2), 130.2 (d x 2), 135.4 (d), 137.3 (s), 140.5 (s), 144.4 (s), 145.8 (s), 148.3 (s). Anal. Calcd. for C23H14N4O4S2: C, 58.22; H, 2.97; N, 11.81. Found: C, 58.13; H, 3.16; N, 11.79.
General procedure for the synthesis of amino derivative 9a-l Procedure A
To a suspension of 7a or 7b (0.45 mmoles) in an ethanol/water mixture (5:1 , 15 ml_), powered iron (9 mmoles) and H2SO4 (12 N, 0.5 ml_) were added and the reaction mixture was heated to 60 °C until complete (TLC). The solution was filtered through celite and washed with ethanol. The solvent was removed under reduced pressure and to the crude residue a saturated solution of NaHCCbwas added and extracted with EtOAc (3 x 20 ml_). The organic phase was dried on Na2S04 and the solvent was removed under reduced pressure. The crude product was purified using chromatography column.
Procedure B
To a solution of the appropriate nitro derivative 7 (0.5 mmoles) in glacial acetic acid (5 ml) powdered iron was added (5 mmoles). The reaction mixture was heated to 60°C in an ultrasound bath until complete (TLC). The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was neutralized with NaHCCb (or Na2C03) and extracted with EtOAc (3 x 20 mL). The organic phase was washed with brine, dried on Na2S04 and the solvent was removed under reduced pressure. The crude product was purified using chromatography column.
Procedure C
To a solution/suspension of the appropriate nitro derivative 7 (0.5 mmoles) in ethanol (20 mL), Pd/C (10% w/w) was added and the reaction mixture was agitated under H2 atmosphere for 24 h. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified using chromatography column (9f) or used directly in the subsequent step without any further purification (9e, 9j,k).
4-[2-(phenylsulfonyl)-4,5-dihydro-2H-imidazo[2',1':2,3][1,3]thiazolo[4,5- e]isoindol-8-yl]aniline (9a). This compound was obtained by reaction of 7a according to procedure A in 20 h. Purification was obtained through chromatography column (cyclohexane: EtOAC 60:40). Yield: 50%; pink solid; mp: 223-224 °C; IR: 3461-3472 (NH2) cm-1; 1H NMR (DMSO-de) (ppm): 2.80-3.00 (4H, m, CH2 x 2), 5.19 (2H, s, NH2), 6.61 (2H, d, J = 7.9 Hz, H-3” and H-5”), 7.33 (1 H, s, H-3), 7.58-7.85 (5H, m, H-3’, H-4’, H-5’, H-2” and H-6”), 8.02 (2H, d, J = 7.0 Hz, H-2’ and H-6’), 8.13 (1 H, s, H-1 ), 8.53 (1 H, s, H-imidaz); 13C NMR (DMSO-de) (ppm): 19.7 (t), 23.1 (t), 106.8 (d), 108.6 (d), 113.4 (s), 113.7 (d x 2), 116.4 (s), 117.7 (d), 120.7 (s), 121.4 (s), 122.1 (s), 123.3 (s), 125.7 (d x 2), 126.7 (d x 2), 130.0 (d x 2), 134.6 (s), 137.9 (d), 147.3 (s), 147.9 (s). Anal. Calcd. for C23Hi8N 02S2: C, 61.86; H, 4.06; N, 12.55. Found: C, 61.97; H, 4.30; N, 12.41.
Ethyl 8-(4-aminophenyl)-2-(phenylsulfonyl)-4,5-dihydro-2H- imidazo[2',T:2,3][1,3]thiazolo[4,5-e]isoindol-3-carboxylate (9b). This compound was obtained by reaction of 7b according to procedure A heating to 60°C in an ultrasound bath for 6 h. Purification was obtained through chromatography column (DCM: EtOAc 90:10). Yield: 80%; light yellow solid; mp: 259-260 °C; IR: 3486-3398 (NH2), 1715 (CO) cm 1; 1H NMR (DMSO-de) (ppm): 1.22 (3H, t, J = 7.0 Hz, CHs ) 2.93-3.19 (4H, m, CH2 x 2), 4.22 (2H, q, J = 7.0 Hz, CH2), 5.18 (2H, s, NH2), 6.61 (2H, d, J = 8.4 Hz, H-3” and H-5”), 7.58-7.85 (5H, m, H-3’, H-4’, H-5’, H- 2” and H-6”), 8.11 (2H, d, Jn = 6.7 Hz, H-2’ and H-6’), 8.47 (1 H, s, H-1 ), 8.62 (1 H, s, H-imidaz); 13C NMR (DMSO -d6) (ppm): 13.9 (q), 20.7 (t), 22.5 (t), 61.1 (t), 106.9 (d), 113.7 (d x 2), 114.1 (s), 119.7 (d), 120.6 (s), 121 .0 (s), 121 .5 (s), 122.1 (s), 125.8 (d x 2), 127.4 (d x 2), 129.4 (d x 2), 131.3 (s), 134.4 (d) 138.4 (s), 146.3 (s), 147.4 (s), 148.0 (s), 158.9 (s). Anal. Calcd. for C26H22N 04S2: C, 60.21 ; H, 4.28; N, 10.80. Found: C, 60.57; H, 4.30; N, 11.01.
4-(4,5-dihydro-2H-imidazo[2',1,:2,3][1,3]thiazolo[4,5-e]isoindol-8-yl)aniline (9c). This compound was obtained by reaction of 7c according to procedure B in 3 h. Purification was obtained through chromatography column (DCM: EtOAC 80:20). Yield: 53%; pink solid; mp: 264-265 °C; IR: 3462-3368 (NH2), 3209 (NH) crrr1; 1H NMR (DMSO-cfe) (ppm): 2.80-2.95 (4H, m, CH2 x 2), 5.14 (2H, s, NH2), 6.59 (2H, d, J = 8.5 Hz, H-3” and H-5”), 6.72 (1 H, s, H-3), 7.46 (1 H, s, H-1 ), 7.60 (2H, d, J = 8.5 Hz, H-2” and H-6”), 7.82 (1 H, s, H-imidaz), 10.96 (1 H, bs, NH); 13C NMR (DMSO- de) (ppm): 20.4 (t), 24.0 (t), 106.1 (d), 110.8 (s), 111.9 (d), 113.7 (s), 113.8 (d x 2), 114.9 (d), 116.5 (s), 122.4 (s), 124.3 (s), 125.7 (d x 2), 146.5 (s), 146.9 (s), 147.8 (s). Anal. Calcd. for C17H14N4S: C, 66.64; H, 4.61 ; N, 18.29. Found: C, 66.58; H, 4.92; N, 18.55.
4-(2-methyl-4,5-dihydro-2H-imidazo[2,,1':2,3][1,3]thiazolo[4,5-e]isoindol-8- yl)aniline (9d). This compound was obtained by reaction of 7d according to procedure B in 1 h. Purification was obtained through chromatography column (DCM:EtOAC 85:15). Yield: 44%; light orange solid; mp: 110-111 °C; IR: 3451-3370 (NH2) cm-1; 1H NMR (DMSO-de) (ppm): 2.73-2.98 (4H, m, CH2 x 2), 3.66 (1 H, s, CHs), 5.20 (2H, bs, NH2), 6.60 (2H, d, J = 8.5 Hz, H-3” and H-5”), 6.67 (1 H, s, H-3), 7.45 (1 H, s, H-1 ), 7.58 (2H, d, J = 8.5 Hz, H-2” and H-6”), 8.22 (1 H, s, H-imidaz); 13C NMR (DMSO-de) (ppm): 20.3 (t), 23.8 (t), 35.9 (q), 106.0 (d), 110.9 (s), 113.6 (s), 113.8 (d x 2), 115.6 (d), 117.0 (s), 119.1 (d), 122.4 (s), 123.9 (s), 125.6 (d x 2), 146.5 (s), 146.9 (s), 147.7 (s). Anal. Calcd. for Ci8Hi6N S: C, 67.47; H, 5.03; N, 17.49. Found: C, 67.67; H, 5.31 ; N, 17.71. 4-{2-[3-(pyrrolidin-1-yl)propyl]-4,5-dihydro-2H- imidazo[2',T:2,3][1,3]thiazolo[4,5-e]isoindol-8-yl}aniline (9f). This compound was obtained by reaction of 7f according to procedure C. Purification was obtained by chromatography column (DCM:MeOH 95:5) and further crystallization from diethyl ether. Yield: 55%; light brown solid; mp: 165-166 °C (Et20); IR: 3415-3387 (NH2) crrr1; 1H NMR (DMSO-cfe) (ppm): 1.73-1.89 (4H, m, CH2 x 2), 1.97-2.20 (2H, m, CH2), 2.65-3.00 (10H, m, CH2 x 5), 3.99 (2H, t, J = 6.6 Hz, CH2), 5.16 (2H, bs, NH2), 6.60 (2H, d, J = 8.5 Hz, H-3” and H-5”), 6.76 (1 H, s, H-3), 7.53 (1 H, s, H-1 ), 7.58 (2H, d, J = 8.5 Hz, H-2” and H-6”), 8.23 (1 H, s, H-imidaz); 13C NMR (DMSO- d6) (ppm): 20.3 (t), 22.9 (t x 2), 22.9 (t), 23.8 (t), 46.6 (t), 51 .9 (t), 53.2 (t x 2), 106.0 (d), 111.0 (s), 113.8 (d x 2), 113.8 (s), 114.5 (d), 116.8 (s), 118.1 (d), 122.3 (s), 123.9 (s), 125.6 (d x 2), 146.6 (s), 147.0 (s), 147.9 (s). Anal. Calcd. for C24H27N5S: C, 69.03; H, 6.52; N, 16.77. Found: C, 69.28; H, 6.43; N, 16.65. 4-{2-[3-(piperidin-1-yl)propyl]-4,5-dihydro-2H- imidazo[2',1':2,3][1,3]thiazolo[4,5-e]isoindol-8-yl}aniline (9g). This compound was obtained by reaction of 7g according to procedure B in 2 h. Purification was obtained through chromatography column (DCM:MeOH 95:5). Yield: 38%; light orange solid; mp: 201-202 °C; IR: 3446-3380 (NHz) cm 1; 1H NMR (DMSO-de) (ppm): 1.25-1.53 (6H, m, CH2 x 3), 1.83-2.02 (2H, m, CH2), 2.10-2.50 (6H, m, CH2 x 3), 2.62-2.98 (4H, m, CH2 x 2), 3.80-4.00 (2H, m, CH2), 5.13 (2H, bs, NH2), 6.59 (2H, d, J = 8.1 Hz, H-3” and H-5”), 6.71 (1 H, s, H-3), 7.48 (1 H, s, H-1 ), 7.57 (2H, d, J = 8.1 Hz, H-2” and H-6”), 8.22 (1 H, s, H-imidaz); 13C NMR (CDCIs) (ppm): 20.4 (t), 23.8 (t), 24.1 (t), 25.5 (t x 2), 28.1 (t), 47.1 (t), 54.0 (t x 2), 55.4 (t), 106.0 (d), 110.8 (s), 113.6 (s), 113.7 (d x 2), 114.5 (d), 116.6 (s), 118.2 (d), 122.3 (s), 123.9 (s), 125.6 (d x 2), 146.5 (s), 147.0 (s), 147.8 (s). Anal. Calcd. for C25H29N5S: C, 69.57; H, 6.77; N, 16.23. Found: C, 69.84; H, 6.93; N, 16.51. 4-{2-[3-(4-methylpiperazin-1-yl)propyl]-4,5-dihydro-2H- imidazo[2',T:2,3][1,3]thiazolo [4,5-e]isoindol-8-yl}aniline (9h). This compound was obtained by reaction of 7h according to procedure B in 3 h. Purification was obtained through chromatography column (DCM:MeOH 95:5). Yield: 30%; light brown solid; mp: 219-220 °C; IR: 3443-3374 (NH2) cm 1; 1H NMR (CDCIs) (ppm): 1.88-2.00 (2H, m, CH2), 2.30-2.40 (5H, m, CH2 and CHs), 2.42-2.68 (8H, m, CH2 x 4), 2.90 (4H, s, CH2 X 2), 3.95 (2H, t, J = 6.8 Hz, CH2), 4.60 (2H, bs, NH2), 6.50 (1 H, s, H-3), 6.73 (2H, d, J = 8.6 Hz, H-3” and H-5”), 6.86 (1 H, s, H-1 ), 7.61 (1 H, s, H- imidaz), 7.67 (2H, d, J = 8.6 Hz, H-2” and H-6”); 13C NMR (CDCIs) (ppm): 20.9 (t),
24.6 (t), 28.4 (t), 45.5 (q), 47.4 (t), 52.5 (t x 2), 54.6 (t x 3), 105.2 (d), 112.1 (s), 113.1 (d), 115.3 (d x 2), 115.9 (s), 117.7 (d), 118.0 (s), 123.9 (s), 125.2 (s), 126.2 (d x 2),
145.6 (s), 147.1 (s), 148.5 (s). Anal. Calcd. for C^HsoNeS: C, 67.23; H, 6.77; N, 18.82. Found: C, 67.51 ; H, 6.83; N, 18.95. 4-{2-[3-(morpholin-4-yl)propyl]-4,5-dihydro-2H- imidazo[2',T:2,3][1,3]thiazolo[4,5-e]isoindol-8-yl}aniline (9i). This compound was obtained by reaction of 7i according to procedure B in 5 h. The purification was obtained by chromatography column (DCM:MeOH 98:2) and further crystallization from EtOAc. Yield: 60%; light yellow solid; mp: 207-208 °C (AcOEt); IR: 3410-3324 (NH2) cm-1; 1H NMR (DMSO-de) (ppm): 1.83-2.02 (2H, m, CH2), 2.20-2.43 (6H, m, CM2 X 3), 2.73-3.00 (4H, m, CH2 x 2), 3.52-3.58 (4H, m, CH2 x 2), 3.83-3.98 (2H, t, J = 6.8 Hz, CH2), 5.15 (2H, s, NH2), 6.60 (2H, d, J = 8.4 Hz, H-3” and H-5”), 6.72 (1 H, s, H-3), 7.49 (1 H, s, H-1 ), 7.58 (2H, d, J = 8.5 Hz, H-2” and H-6”), 8.23 (1 H, s, H-imidaz); 13C NMR (DMSO -d6) (ppm): 20.4 (t), 23.8 (t), 27.7 (t), 47.0 (t), 53.3 (t x 2), 55.1 (t), 66.2 (t x 2), 106.0 (d), 110.8 (s), 113.6 (s), 113.7 (d x 2), 114.5 (d), 116.6 (s), 118.2 (d), 122.3 (s), 123.9 (s), 125.6 (d x 2), 146.5 (s), 147.0 (s), 147.8 (s). Anal. Calcd. for C24H27N5OS: C, 66.48; H, 6.28; N, 16.15. Found: C, 66.75; H, 6.43; N, 16.27.
4-{2-[2-(morpholin-4-yl)ethyl]-4,5-dihydro-2H- imidazo[2',1':2,3][1,3]thiazolo[4,5-e]isoindol-8-yl}aniline (9I). This compound was obtained by reaction of 7I according to procedure B in 3 h. Purification was obtained through chromatography column (DCM:MeOH 98:2). Yield: 33%; light brown solid; mp: 225-226 °C; IR: 3443-3375 (NH2) cm 1; 1H NMR (CDCIs) (ppm): 2.43-2.55 (4H, m, CH2 x 2), 2.73 (2H, t, J = 6.7 Hz, CH2), 2.89 (4H, s, CH2 x 2), 3.47 (2H, s, NH2), 3.65-3.75 (4H, m, CH2 x 2), 4.01 (2H, t, J = 6.7 Hz, CH2), 6.56 (1 H, s, H-3), 6.73 (2H, d, J = 8.5 Hz, H-3” and H-5”), 6.88 (1 H, s, H-1 ), 7.59 (1 H, s, H- imidaz), 7.66 (2H, d, J = 8.5 Hz, H-2” and H-6”); 13C NMR (CDCIs) (ppm): 20.9 (t), 24.6 (t), 47.4 (t), 53.8 (t x 2), 59.2 (t), 67.0 (t x 2), 105.3 (d), 112.3 (s), 113.1 (d), 115.3 (d x 2), 116.1 (s), 118.0 (d), 118.2 (s), 123.9 (s), 125.2 (s), 126.3 (d x 2), 145.7 (s), 147.2 (s), 148.5 (s). Anal. Calcd. for CzsH^NsOS: C, 65.84; H, 6.01 ; N, 16.69. Found: C, 65.79; H, 6.21 ; N, 16.56.
Preparation of phenyl 5-terf-butylisoxazole-3-ylcarbamate (12).
To a suspension of 5-fe/f-butylisoxazole-3-amine 10 (3.5 mmoles) and potassium carbonate anhydrous (7 mmoles) in THF anhydrous (10 ml_), a solution of phenyl chloroformate 11 (5.25 mmoles) in THF anhydrous (5 ml_) was added at 0 °C dropwise and under N2 atmosphere. The reaction mixture was left in agitation at room temperature for 3 h. The suspension was filtered and the filter was washed with THF. The filtrate was evaporated under reduced pressure. To the residue water and ethanol (4: 1 ) were added and the mixture was agitated at 10°C for 2 h. The resulting solid was collected by filtration and washed with a mixture of water: ethanol (4 : 1 ). The solid obtained did not require any further purification. Yield: 90%. The spectroscopic data are in accordance with those reported in literature. General procedure for the synthesis of ureido derivatives 13a-l
To a solution of pure or crude amino derivatives 9 (0.3 mmoles) in anhydrous THF (5 ml_) phenyl 5-fe/f-butylisoxazol-3-ylcarbamate (0.33 mmoles), DIPEA (0.45 mmoles) and DMAP (0.15 mmoles) were added. The solution was heated to 60°C until complete (TLC). The reaction mixture was concentrated under reduced pressure and the crude residue was purified through chromatography column or crystallization.
1-(5-ferf-Butyl-1,2-oxazol-3-yl)-3-{4-[2-(phenylsulfonyl)-4,5-dihydro-2H- imidazo [2',T:2,3][1,3]thiazolo[4,5-e]isoindol-8-yl]phenyl}urea (13a). This compound was obtained by reaction of 9a in 2 h and the crude residue was purified by crystallization from THF. Yield: 87%; pink solid; mp: 259-260 °C (THF); IR: 3315 (NH), 3287 (NH), 1690 (CO) cm 1; 1H NMR (DMSO-cfe) (ppm): 1.31 (9H, s, CH3 x 3), 2.80-3.03 (4H, m, CH2 x 2), 6.54 (1 H, s, CH-isoxaz), 7.35 (1 H, s, H-3), 7.52 (2H, d, J = 8.6, H-2” and H-6”), 7.58-7.83 (3H, m, H-3’, H-4’ and H-5’), 7.89 (2H, d, J = 8.6 Hz, H-3” and H-5”), 8.02-8.11 (2H, m, H-2’ and H-6’), 8.16 (1 H, s, H-1 ), 8.75 (1 H, s, CH-imidaz), 8.90 (1 H, s, NH), 9.56 (1 H, s, NH); 13C NMR (DMSO-de) (ppm): 23.0 (t), 25.0 (t), 28.3 (q x 3), 32.4 (s), 92.4 (d), 108.5 (d), 113.3 (d), 116.2 (s), 117.6 (d), 118.5 (d x 2), 121.3 (s), 121.8 (s), 123.3 (s), 125.3 (d x 2), 126.7 (d x 2), 128.6 (s), 130.0 (d x 2), 134.7 (d), 137.6 (s), 137.8 (s), 145.8 (s), 147.0 (s), 151.2 (s), 158.2 (s), 180.4 (s). Anal. Calcd. for C31H28N6O4S2: C, 60.77; H, 4.61 ; N, 13.72. Found: C, 60.81 ; H, 4.52; N, 13.68.
Ethyl 8-(4-{[(5-ferf-butyl-1,2-oxazol-3-yl)carbamoyl]amino}phenyl)-2-
(phenylsulfonyl)-4,5-dihydro-2H-imidazo[2',T:2,3][1,3]thiazolo[4,5-e]isoindol- 3-carboxylate (13b). This compound was obtained by reaction of 9b in 1 h and the crude residue was purified by crystallization from ethanol. Yield: 80%; pale yellow solid; mp: 264-265 °C (EtOH); IR: 3315 (NH), 3278 (NH), 1719 (CO), 1689 (CO) crrr 1; 1H NMR (DMSO-cfe) (ppm): 1.28 (3H, t, J = 7.0 Hz, CHs), 1.37 (9H, s, CHs x 3), 3.02-3.25 (4H, m, CH2 x 2), 4.29 (2H, q, J = 7.0 Hz, CH2), 6.60 (1 H, s, CH-isossaz), 7.58 (2H, d, J = 8.7 Hz, H-2” and H-6”), 7.70-7.92 (3H, m, H-3’, H-4’ and H-5’), 7.97 (2H, d, J = 8.7 Hz, H-3” and 5”), 8.02-8.11 (2H, m, H-2’ and H-6’), 8.56 (1 H, s, H- 1 ), 8.91 (1 H, s, CH-imidaz), 8.96 (1 H, s, NH), 9.61 (1 H, s, NH); 13C NMR (DMSO- d6) (ppm): 13.9 (q), 20.8 (t), 22.6 (t), 28.3 (q x 3), 32.5 (s), 61.1 (t), 92.5 (d), 106.9 (s), 108.8 (d), 114.0 (s), 118.5 (d x 2), 120.6 (d), 121.9 (s), 125.3 (d x 2), 127.4 (d x 2), 128.7 (s), 129.4 (d x 2), 131.3 (s), 134.4 (d), 137.9 (s), 138.4 (s), 146.0 (s), 146.9 (s), 149.7 (s), 151.3 (s), 158.4 (s), 158.9 (s), 180.2 (s). Anal. Calcd. for C34H32N6O6S2: C, 59.63; H, 4.71 ; N, 12.27. Found: C, 59.89; H, 4.79; N, 12.52.
1 -(5-ferf-Butyl-1 ,2-oxazol-3-yl)-3-[4-(4,5-dihydro-2H-imidazo [2',1':2,3][1,3]thiazolo[4,5-e]isoindol-8-yl)phenyl]urea (13c). This compound was obtained by reaction of 9c in 1 h and the crude residue was purified by crystallization from ethanol. Yield: 72%; pink solid; mp: > 400 °C (EtOH); IR: 3315 (NH), 3285 (NH), 3142 (NH), 1654 (CO) cm 1; 1H NMR (DMSO-de) (ppm): 1.31 (9H, s, CHs x 3), 2.80-3.00 (4H, m, CH2 x 2), 6.54 (1 H, s, CH-isossaz), 6.74 (1 H, s, H-3), 7.47-7.53 (3H, m, H-1 , H-2” and H-6”), 7.87 (2H, d, J = 8.5 Hz, H-3” and 5”), 8.75 (1 H, s, CH-imidaz), 8.90 (1 H, s, NH), 9.56 (1 H, s, NH), 10.99 (1 H, s, NH); 13C NMR (DMSO-de) (ppm): 20.4 (t), 24.0 (t), 28.3 (q x 3), 32.5 (s), 92.4 (d), 108.0 (d), 110.7 (s), 112.0 (d), 114.4 (s), 114.9 (d), 116.5 (s), 118.5 (d x 2), 124.3 (s), 125.2 (d x 2), 128.9 (s), 137.7 (s), 145.6 (s), 147.1 (s), 151.2 (s), 158.4 (s), 180.1 (s). Anal. Calcd. for C25H24N6O2S: C, 63.54; H, 5.12; N, 17.78. Found: C, 63.85; H, 5.42; N, 18.03. 1-(5-ferf-Butyl-1,2-oxazol-3-yl)-3-[4-(2-methyl-4,5-dihydro-2H- imidazo[2',T:2,3][1,3] thiazolo[4,5-e]isoindol-8-yl)phenyl]urea (13d). This compound was obtained by reaction of 9d in 1 h and the crude residue was purified by crystallization from THF. Yield: 84%; light yellow solid; mp: 243-244 °C (THF); IR: 3335 (NH), 3278 (NH), 1711 (CO) cm 1; 1H NMR (DMSO-cfe) (ppm): 1.31 (9H, s, CHs x 3), 2.77-2.98 (4H, m, CH2 x 2), 3.68 (3H, s, CHs), 6.54 (1 H, s, CH-isossaz), 6.68 (1 H, s, H-3), 7.46-7.53 (3H, m, H-1 , H-2” and H-6”), 7.85 (2H, d, J = 8.5 Hz, H- 3” and H-5”), 8.45 (1 H, s, CH-imidaz), 8.89 (1 H, s, NH), 9.57 (1 H, s, NH); 13C NMR (DMSO-de) (ppm): 20.3 (t), 23.9 (t), 28.3 (q x 3), 32.4 (s), 35.9 (q), 92.4 (d), 107.7 (d), 110.8 (s), 114.4 (s), 115.6 (d), 117.0 (s), 118.5 (d x2), 119.1 (d), 123.9 (s), 125.1 (d x 2), 128.9 (s), 137.7 (s), 145.7 (s), 147.1 (s), 151.3 (s), 158.4 (s), 180.1 (s). Anal. Calcd. for C26H26N6O2S: C, 64.18; H, 5.39; N, 17.27. Found: C, 64.45; H, 5.24; N, 17.53.
1-(5-ferf-Butyl-1,2-oxazol-3-yl)-3-{4-[2-(3-chloropropyl)-4,5-dihydro-2H- imidazo [2',T:2,3][1,3]thiazolo[4,5-e]isoindol-8-yl]phenyl}urea (13e). This compound was obtained by reaction of 9e (crude) in 1 h and the crude residue was purified through chromatography column (petroleum ether: EtOAC 70:30). Yield: 43%; light yellow solid; mp: 253-254 °C; IR: 3325 (NH), 3284 (NH), 1720 (CO) crrr 1; 1H NMR (DMSO-cfe) (ppm): 1.31 (9H, s, CHs x 3), 2.20-2.40 (2H, m, CH2), 2.82- 3.02 (4H, m, CH2 x 2), 3.69 (2H, t, J = 6.2 Hz, CH2), 4.06-2.20 (2H, m, CH2), 6.59 (1 H, s, CH-isossaz), 6.82 (1 H, s, H-3), 7.52-7.61 (3H, m, H-1 , H-2” and H-6”), 7.91 (2H, d, J = 8.3 Hz, H-3” and H-5”), 8.52 (1 H, s, CH-imidaz), 8.93 (1 H, s, NH), 9.60 (1 H, s, NH); 13C NMR (DMSO -d6) (ppm): 20.3 (t), 23.9 (t), 28.3 (q x 3), 32.5 (s), 33.5 (t), 42.4 (t), 46.2 (t), 92.4 (d), 107.8 (d), 111.0 (s), 114.7 (d), 117.0 (s), 118.3 (s), 118.5 (d x 2), 118.5 (d), 123.8 (s), 125.1 (d x 2), 128.9 (s), 137.7 (s), 145.6 (s), 147.1 (s), 151.2 (s), 158.4 (s), 180.2 (s). Anal. Calcd. for C28H29CIN602S: C, 61.25; H, 5.32; N, 15.31. Found: C, 61.53; H, 5.54; N, 15.25.
1 -(5-ferf-Butyl-1 ,2-oxazol-3-yl)-3-(4-{2-[3-(pyrrolidin-1 -yl)propyl]-4,5-dihydro- 2H-imidazo[2',1':2,3][1,3]thiazolo[4,5-e]isoindol-8-yl}phenyl)urea (13f). This compound was obtained by reaction of 9f in 2 h and the crude residue was purified by chromatography column (DCM:MeOH 95:5) and further crystallized from ethanol. Yield: 42%; white solid; mp: 230-231 °C (EtOH); IR: 3341 (NH), 3303 (NH), 1718 (CO) cm-1; 1H NMR (DMSO-cfe) (ppm): 1.31 (9H, s, CHs x 3), 1.64-1.78 (4H, m, CH2 x 2), 1.90-2.10 (2H, m, CH2), 2.40-2.60 (6H, m, CH2 x 3), 2.80-3.00 (4H, m, CH2 x 2), 3.96 (2H, t, J = 6.6 Hz, CH2), 6.53 (1 H, s, CH-isossaz), 6.74 (1 H, s, H-3), 7.47- 7.55 (3H, m, H-1 , H-2” and H-6”), 7.85 (2H, d, J = 8.6 Hz, H-3” and H-5”), 8.46 (1 H, s, CH-imidaz), 8.96 (1 H, s, NH), 9.57 (1 H, s, NH); 13C NMR (DMSO-de) (ppm): 13C NMR (DMSO-de) (ppm): 20.3 (t), 23.1 (t x 2), 23.9 (t), 28.3 (q x 3), 30.0 (t), 32.4 (s), 47.2 (t), 52.5 (t), 53.5 (t x 2), 92.4 (d), 107.8 (s), 110.7 (d), 114.4 (s), 114.5 (d), 116.7 (s), 118.2 (d), 118.5 (d x 2), 123.9 (s), 125.1 (d x 2), 128.9 (s), 137.8 (s), 145.6 (s), 147.1 (s), 151 .3 (s), 158.4 (s), 180.1 (s). Anal. Calcd. for C32H37N702S: C, 65.84; H, 6.39; N, 16.80. Found: C, 65.99; H, 6.66; N, 17.07.
1 -(5-ferf-Butyl-1 ,2-oxazol-3-yl)-3-(4-{2-[3-(piperidin-1 -yl)propyl]-4,5-dihydro- 2H-imidazo[2',T:2,3][1,3]thiazolo[4,5-e]isoindol-8-yl}phenyl)urea (13g). This compound was obtained by reaction of 9g in 2 h and the crude residue was purified by chromatography column (DCM:MeOH 93:7). Yield: 60%; light yellow solid; mp: 255-256 °C; IR: 3342 (NH), 3280 (NH), 1701 (CO) cm 1; 1H NMR (DMSO-de) (ppm): 1.20-1.68 (15H, m, CHs x 3 and CH2 x 3), 1.90-2.13 (2H, m, CH2), 2.32-2.50 (6H, m, CM2 x 3), 2.75-3.00 (4H, m, CH2 x 2), 3.86-4.03 (2H, m, CH2), 6.54 (1 H, s, CH- isossaz), 6.74 (1 H, s, H-3), 7.48-7.54 (3H, m, H-2”, H-6” and H-1 ), 7.85 (2H, d, J = 8.4 Hz, H-3” and H-5”), 8.46 (1 H, s, CH-imidaz), 9.10 (1 H, s, NH), 9.64 (1 H, s, NH); 13C NMR (DMSO-de) (ppm): 20.3 (t ), 23.4 (t), 23.9 (t), 24.8 (t x 2), 27.5 (t), 28.3 (q x 3), 32.4 (s), 47.0 (t), 53.6 (t x 2), 55.0 (t), 92.4 (d), 107.7 (d), 110.8 (s), 114.4 (d),
114.5 (s), 116.7 (s), 118.2 (d), 118.4 (d x 2), 123.9 (s), 125.1 (d x 2), 128.8 (s), 137.8 (s), 145.7 (s), 147.1 (s), 151.3 (s), 158.3 (s), 180.1 (s). Anal. Calcd. for CssHsgNyO^: C, 66.30; H, 6.58; N, 16.40. Found: C, 66.12; H, 6.53; N, 16.73.
1 -(5-ferf-Butyl-1 ,2-oxazol-3-yl)-3-(4-{2-[3-(4-methylpiperazin-1 -yl)propyl]-4,5- dihydro-2H-imidazo[2',1':2,3][1,3]thiazolo[4,5-e]isoindol-8-yl}phenyl)urea (13h). This compound was obtained by reaction of 9h in 2 h and the crude residue was purified by crystallization from ethanol. Yield: 53%; light yellow solid; mp: 227- 228 °C (EtOH); IR: 3334 (NH), 3279 (NH), 1719 (CO) cm 1; 1H NMR (DMSO-de) (ppm): 1 .30 (9H, s, CHs x 3), 1 .80-2.50 (15H, m, CH2 x 6 and CHs), 2.75-3.00 (4H, m, CH2 X 2), 3.86-3.98 (2H, m, CH2), 6.54 (1 H, s, CH-isossaz), 6.74 (1 H, s, H-3), 7.49-7.54 (3H, m, H-2”, H-6” and H-1 ), 7.85 (2H, d, J = 7.9 Hz, H-3” and H-5”), 8.46 (1 H, s, CH-imidaz), 8.88 (1 H, s, NH), 9.56 (1 H, s, NH); 13C NMR (DMSO -d6) (ppm): 20.3 (t), 23.9 (t), 28.1 (t), 28.3 (q x 3), 32.4 (s), 45.7 (q), 47.1 (t), 52.7 (t x 2), 54.7 (t x 2), 54.7 (t), 92.4 (d), 107.8 (d), 110.7 (s), 114.4 (s), 114.5 (d), 116.6 (s), 118.2 (d),
118.5 (d x 2), 123.9 (s), 125.1 (d x 2), 128.9 (s), 137.7 (s), 145.6 (s), 147.1 (s), 151.2 (s), 158.4 (s), 180.1 (s). Anal. Calcd. for C33H oN802S: C, 64.68; H, 6.58; N, 18.29. Found: C, 64.89; H, 6.73; N, 18.53.
1-(5-ferf-Butyl-1,2-oxazol-3-yl)-3-(4-{2-[3-(morpholin-4-yl)propyl]-4, 5-dihydro- 2tf-imidazo[2,,1':2,3][1,3]thiazolo[4,5-e]isoindol-8-yl}phenyl)urea (13i). This compound was obtained by reaction of 9i in 2 h and the crude residue was purified by crystallization from ethanol. Yield: 75%; light yellow solid; mp: 238-239 °C (EtOH); IR: 3340 (NH), 3280 (NH), 1720 (CO) cm 1; 1H NMR (DMSO-cfe) (ppm): 1.34 (9H, s, CHs x 3), 1 .87-2.00 (2H, m, CH2), 2.20-2.40 (6H, m, CH2 x 3), 2.80-3.00 (4H, m, CH2 x 2), 3.52-3.68 (4H, m, CH2 x 2), 3.86-4.03 (2H, m, CH2), 6.54 (1 H, s, CH- isossaz), 6.73 (1 H, s, H-3), 7.47-7.54 (3H, m, H-2”, H-6” and H-1 ), 7.85 (2H, d, J = 7.9 Hz, H-3” and H-5”), 8.46 (1 H, s, CH-imidaz), 8.88 (1 H, s, NH), 9.55 (1 H, s, NH); 13C NMR (DMSO-de) (ppm): 20.3 (t), 23.8 (t), 27.8 (t), 28.3 (q x 3), 32.5 (s), 47.1 (t), 53.3 (t x 2), 55.1 (t), 66.2 (t x 2), 92.4 (d), 107.8 (d), 110.7 (s), 114.4 (s), 114.5 (d), 116.6 (s), 118.3 (d), 118.5 (d x 2), 123.9 (s), 125.1 (d x 2), 128.9 (s), 137.7 (s), 145.6
(s), 147.1 (s), 151 .2 (s), 158.4 (s), 180.1 (s). Anal. Calcd. for C32H37N7O3S: C, 64.08; H, 6.22; N, 16.35. Found: C, 64.09; H, 6.44; N, 16.53.
1 -(5-ferf-Butyl-1 ,2-oxazol-3-yl)-3-(4-{2-[2-(pyrrolidin-1 -yl)ethyl]-4,5-dihydro- 2H-imidazo[2',1':2,3][1,3]thiazolo[4,5-e]isoindol-8-yl}phenyl)urea (13j). This compound was obtained by reaction of 9j (crude) in 3 h and the crude residue was purified by chromatography column (DCM:MeOH 95:5). Yield: 60%; light yellow solid; mp: 250-251 °C; IR: 3347 (NH), 3296 (NH), 1726 (CO) cm 1; 1H NMR (DMSO- cfe) (ppm): 1 .37 (9H, s, CHs x 3), 1 .71-1 .78 (4H, m, CH2 x 2), 2.50-2.60 (2H, m, CH2 x 2), 2.80-3.05 (6H, m, CH2 x 3), 4.08 (2H, t, J = 6.7 Hz, CH2), 6.59 (1 H, s, CH- isossaz), 6.83 (1 H, s, H-3), 7.52-7.61 (3H, m, H-1 , H-2” and H-6”), 7.92 (2H, d, J = 8.5 Hz, H-3” and H-5”), 8.51 (1 H, s, CH-imidaz), 8.96 (1 H, s, NH), 9.62 (1 H, s, NH); 13C NMR (DMSO-de) (ppm): 20.3 (t), 23.1 (t x 2), 23.8 (t), 28.3 (q x 3), 32.5 (s), 48.5
(t), 53.6 (t x 2), 56.5 (t), 92.4 (d), 107.8 (d), 110.6 (s), 114.4 (s), 114.8 (d), 116.6 (s), 118.4 (d x 2), 118.5 (d), 123.9 (s), 125.1 (d x 2), 128.9 (s), 137.7 (s), 145.6 (s), 147.1 (s), 151.3 (s), 158.4 (s), 180.1 (s). Anal. Calcd. for C31 H35N7O2S: C, 65.35; H, 6.19; N, 17.21. Found: C, 65.29; H, 6.21 ; N, 17.53.
1 -(5-ferf-Butyl-1 ,2-oxazol-3-yl)-3-(4-{2-[2-(piperidin-1 -yl)ethyl]-4,5-dihydro-2H- imidazo[2',T:2,3][1,3]thiazolo[4,5-e]isoindol-8-yl}phenyl)urea (13k). This compound was obtained by reaction of 9k (crude) in 1 h and the crude residue was purified by chromatography column (DCM:MeOH 98:2) and further crystallized from diethyl ether. Yield: 30%; yellow solid; mp: 230-231 °C (EbO); IR: 3326 (NH), 3284 (NH), 1712 (CO) cm-1; 1H NMR (DMSO-de) (ppm): 1.31 (9H, s, CHs x 3), 1.30-1.58 (6H, m, CH2 X 3), 2.38-2.50 (4H, m, CH2 x 2), 2.60-2.75 (2H, m, CH2), 2.80-3.00 (4H, m, CH2 x 2), 4.02 (2H, t, J = 6.3 Hz, CH2), 6.53 (1 H, s, CH-isossaz), 6.76 (1 H, s, H-3), 7.48-7.54 (3H, m, H-2”, H-6” and H-1 ), 7.85 (2H, d, J = 8.6 Hz, H-3” and H- 5”), 8.44 (1 H, s, CH-imidaz), 8.88 (1 H, s, NH), 9.55 (1 H, s, NH); 13C NMR (DMSO- de) (ppm): 20.3 (t), 23.9 (t), 25.5 (t x 2), 28.3 (q x 3), 32.4 (s), 46.7 (t), 54.1 (t x 2), 54.2 (t), 59.33 (t), 92.4 (d), 107.7 (d), 110.7 (s), 114.4 (s), 114.8 (d), 116.6 (s), 118.4 (d), 118.5 (d x 2), 123.9 (s), 125.1 (d x 2), 128.9 (s), 137.7 (s), 145.6 (s), 147.2 (s), 151.3 (s), 158.4 (s), 180.2 (s). Anal. Calcd. for C32H37N7O2S: C, 65.84; H, 6.39; N, 16.80. Found: C, 66.12; H, 6.28; N, 16.98.
1-(5-ferf-Butyl-1,2-oxazol-3-yl)-3-(4-{2-[2-(morpholin-4-yl)ethyl]-4, 5-dihydro- 2H-imidazo[2',1':2,3][1,3]thiazolo[4,5-e]isoindol-8-yl}phenyl)urea (131). This compound was obtained by reaction of 91 in 2 h and the crude residue was purified by crystallization from ethanol. Yield: 45%; white solid; mp: 247-248 °C (EtOH); IR: 3326 (NH), 3286 (NH), 1712 (CO) cm 1; 1H NMR (DMSO-de) (ppm): 1 .31 (9H, s, CHs x 3), 2.42-2.50 (4H, m, CH2 x 2), 2.70 (2H, t, J = 6.4 Hz, CH2), 2.75-2.97 (4H, m, CH2 X 2), 3.52-3.62 (4H, m, CH2 x 2), 4.04 (2H, t, J = 6.4 Hz, CH2), 6.53 (1 H, s, CH- isossaz), 6.78 (1 H, s, H-3), 7.47-7.54 (3H, m, H-2”, H-6” and H-1 ), 7.85 (2H, d, J = 8.5 Hz, H-3” and H-5”), 8.44 (1 H, s, CH-imidaz), 8.88 (1 H, s, NH), 9.55 (1 H, s, NH); 13C NMR (DMSO-de) (ppm): 20.3 (t), 23.8 (t), 28.3 (q x 3), 32.5 (s), 46.3 (t), 53.3 (t x 2), 58.9 (t), 66.2 (t x 2), 92.4 (d), 107.7 (d), 110.7 (s), 114.4 (s), 114.8 (d), 116.6 (s), 118.5 (d x 3), 123.9 (s), 125.1 (d x 2), 128.9 (s), 137.7 (s), 145.6 (s), 147.2 (s), 151.3 (s), 158.4 (s), 180.2 (s). Anal. Calcd. for C31H35N7O3S: C, 63.57; H, 6.02; N, 16.74. Found: C, 63.42; H, 6.30; N, 16.80.
Biology. Anti -proliferative activity in vitro
A series of 30 derivatives (Table 4) with tetracyclic core variously decorated in form of nitro 7a-l, amine 9a-d,f,i and ureidic compounds 13a-l, were subjected to screening in vitro to evaluate the antiproliferative activity on 12 haematological lines, one derivative from ALL (MOLT-4), nine from AML (HL-60, KG-1 , KG-1a, MOLM- 13, MV4-11 , NOMO-1 , OCI-AML2, PL-21 , THP-1 ) and 2 from CML (K-562, KCL- 22). Dovitinib, Quizartinib and TCS 359 selective towards FLT3-ITD, were used as reference drugs.
Table 4
Figure imgf000061_0001
Figure imgf000061_0002
Figure imgf000062_0001
Figure imgf000063_0001
The results were expressed as ICso and the geometric mean was calculated to prevent the incidence of very high or very low values of activity being levelled (Table 5). Of the 30 derivatives, five (7h, 13c, 13d, 13g, 13h) demonstrated notable power, with a geometric mean of ICso less than 1 mM. By analysing the results from a structure-activity relationship point of view, it can be noted that among the ureidic derivatives, compound 13c, with NH free pyrrole is the most powerful compound of the whole series. Like Quizartinib, it was shown to be particularly effective against MOLM-13 and MV4-11, which actually overexpress the FLT3-ITD mutation, reaching nanomolar values (0.011- 0.014 pM). It also provided positive responses on the other cell lines with ICso values from the submicro to micromolar range (0.265-1.582 pM). The same behaviour is noted for the N-Methyl derivative 13d, which is equipotent with respect to 13c maintaining selectivity towards the MOLM- 13 and MV4-11 lines (0.035-0.058 pM) with activity at submicro/micromolar concentrations (0.812-4.783 pM). The presence of alkyl amine chains seems to produce a reduction of the activity although the compounds 13e-l (0.101-17.15 pM) maintain selectivity towards the MOLM-13 and MV4-11 (0.101 -0.578 pM) lines with ICso values at submicromolar level and good power towards the other cell lines. Instead, the presence of the phenylsufonyl group extinguishes the activity leading to almost inactive derivatives even if 13a displays selectivity in the low micromolar range towards MOLM-13 (5.468 pM) and MV4-11 (14.9 pM). In relation to the nitro derivatives the compounds 7f, 7g, 7h, 7j and 7k are noteworthy which, surprisingly, despite losing their selectivity, display a geometric mean of ICso lower than Quizartinib. The compound 7e with the chloropropyl chain and the NH derivative 7c display a certain selectivity towards KG-1 (0.536 and 3.868 mM respectively) and KG-1 a (0.876 and 2.985 pM respectively) with ICso values in the low micromolar range. Finally, amino derivatives 9 seem to inhibit cell proliferation at micromolar concentrations, but only 9i (2.281 and 2.36 pM respectively) and 9d (4.39 and 4.558 pM), were shown to be selective towards the KG-1 and KG-1 a lines reaching the micromolar range.
Table 5
Figure imgf000065_0001
Dovitinib 0,266 0,911 0,035 0,033 0,005 0,004 1,493 0,568 2.85 1,936 2,018 2,552 0,268 Quizartinib 50.28 100 33.53 100 0,003 0,003 100 0.45 100 100 100 100 9,687
TCS 359 100 100 100 100 0.31 0,322 100 100 100 100 100 100 38,306
13c 0,591 0,608 0,265 0,904 0,014 0,011 1,541 0,519 0,616 1,454 1,582 0,709 0,385
7h 1,842 1,318 0,415 0,587 0,358 0,378 0,409 0,375 0.94 1,985 1,373 1.36 0,769
13h 0,586 1,432 0,677 1,345 0,169 0,111 2,483 0,691 1.1 2,539 1,309 1,478 0,845
13d 1,008 1,761 0,812 4,783 0,058 0,035 2,499 0,799 0.86 2,271 4,151 2,229 0,945
13g 0,644 1,437 0,821 1,756 0,262 0,116 1,389 1,644 1,618 2,438 I,633 1,454 0,988
13k 0,943 1,672 1,533 2,585 0.42 0.29 1,749 1,096 1,882 2,798 3,332 3,046 1,438
13f 0,711 2,624 1,747 3,243 0,355 0,353 2,064 1,517 1,798 2,675 3,237 2,563 1,531
7k 0,498 4,306 2,229 1,362 1,502 1,152 3,448 1,253 1,362 1,361 6,416 2,459 1,831
13j 1,088 2,818 2,367 3,772 0.39 0,394 2,565 1,919 3,492 5,201 3,866 3,747 2,048
131 1,983 4,128 1,969 7,007 0,105 0,157 6,857 2,311 2,145 4,519 13.2 4,438 2,249
7f 0,407 4,063 3,015 2,525 3,259 2,108 3,962 1,272 1,653 1,375 5,328 4.79 2,328
13e 1,877 4,619 1,258 13.58 0,578 0,469 3,769 1,074 1.37 8,288 100 8,258 3,275
7g 2,433 4,256 2,529 2,685 2,687 4,431 4.3 3,041 6,284 14.62 4,168 4,314 4,025
7j 1,927 4,173 2,507 1,282 5,292 2,249 5,135 2,108 5,062 6,945 19.33 9.95 4,099
13i 9,356 13.89 7,389 25.1 0,242 0,101 22.37 9.82 15.33 25.4 13.86 17.15 6,916
9i 11.57 14.45 2,281 2.36 9,759 7,775 14.07 17.58 15.34 20.93 12.52 22.79 10,370
9f 7,799 19.92 6,146 7,289 7.65 8,714 17.35 9,612 12.98 12.92 II.85 16.46 10,800
9d 14.12 27.46 4.39 4,558 5,654 2,959 29.94 25.98 18.32 19.64 11 18.71 11,824
9c 18.14 37.01 8,552 7,605 4,085 8,522 13.28 19.77 28.39 53.75 16.97 37.23 16,421
7e 0,743 100 0,536 0,876 15.36 48.66 90 100 100 100 50.63 100 21,857
9a 62.75 100 25.22 18.48 13.29 26.88 87.66 73.57 100 100 70.4 70.97 51,357
7c 100 62.22 3,868 2,985 58.36 100 100 100 100 100 100 100 52,305
13a 100 100 100 100 5,468 14.9 100 100 100 100 17.14 100 57,820

Claims

1. A tetracyclic compound of formula (I)
Figure imgf000066_0001
wherein the ring A is a pentatomic aromatic heterocyclic ring, comprising one, two N atoms; the ring B is an aromatic or non-aromatic cycloalkyl, aryl, heterocycloalkyl or heteroaryl ring, where m=1 ,2, wherein said heterocycloalkyl or heteroaryl ring comprises at least one heteroatom from N, O and S; the ring C is a pentatomic aromatic heterocyclic ring with n=0 when Xi=S or exatomic with n=1 when Xi=N;
Ar is an aromatic or heteroaromatic exatomic ring comprising 0, 1 or 2 N atoms;
R is selected from the group consisting of H, Alki-6, cycloalkyl, heterocycloalkyl, aryl, aryl akyl, heteroaryl, aryl sulfonyl and alkylamine, halogen, NO2, NH2, N3, wherein said Alki-6, cycloalkyl, heterocycloalkyl, aryl, aryl alkyl, heteroaryl, aryl sulfonyl or alkylamine is optionally substituted with one or more substituents independently selected from linear or branched C1-C6 alkyl, nitro, amino, halogen, haloalkyl and alkoxy;
Ri and R2, if present, are independently selected from the group consisting of H, COOH, carboxylic ester, carboxamide from primary, secondary or tertiary amine, aryl, halogen, NO2, NH2, N3, alkylamine and trifluoroalkyl, wherein said carboxylic acid, carboxylic ester, carboxamide from primary, secondary or tertiary amine, aryl, alkylamine or trifluorolalkyl is optionally substituted with one or more substituents independently selected from: linear or branched C1-C6 alkyl, nitro, amino, halogen haloalkyl and alkoxy; R3 is selected from the group consisting of nitro, amino, ureidic wherein said amino or ureidic group is optionally substituted with one or more substituents independently selected from: Alki -6, nitro, amino, halogen and haloalkyl and heteroaryl optionally substituted with one or more substituents independently selected from linear or branched C1-C6 alkyl, nitro, amino, halogen and haloalkyl.
2. A compound of formula (I) according to claim 1 wherein Xi=S, n=0, which is a compound of formula (la)
Figure imgf000067_0001
wherein A, B and C, m, R, Ri and R2 are as defined in claim 1.
3. A compound of formula (I) according to claim 1 wherein Xi=N, n=1, which is a compound of formula (lb)
Figure imgf000067_0002
wherein A, B and C, m, R, Ri and R2 are as defined in claim 1.
4. A compound of formula (I) according to any one of the preceding claims in which ring A is selected from the group consisting of
Figure imgf000068_0001
5. A compound of formula (I) according to any one of the preceding claims having a tetracyclic 4-(2/-/-imidazo[2’,1’:2,3][1 ,3]thiazolo[4,5-e]isoindole system of formula (lc)
Figure imgf000068_0002
wherein R, Ri and R3 are as defined in the previous claims.
6. A compound of formula (I) according to claim 5 wherein:
R is H, Aik, S02Ph, Bn, 4-MeOBn, 3,5-(Me)2OBn, 3,4,5-(MeO)3Bn, 2-Br-3,5- (Me)20Bn or (CH2)nZ where n=2,3 and
Figure imgf000069_0001
Z is halogen, where Y is absent, CH2, 0 or NMe;
Ri is H, Br, COOAIk, Ph, 3,4,5-(MeO)3Ph;
R2 is H or Br;
Figure imgf000069_0002
Rs is NO2, NH2, in which AG2 is selected from the group consisting of pyrazole, thiazole, pyridine, pyrimidine optionally substituted with one or more substituents independently selected from Alki -6, nitro, amino, halogen and haloalkyl.
7. A compound of formula (I) according to any one of the preceding claims for use as a medicament.
8. A compound of formula (I) according to any one of claims 1-6 for use in the treatment of haematological pathologies.
9. A compound of formula (I) according to any one of claims 1-6 for use according to claim 8 wherein said haematological pathology is acute myeloid leukemia (AML), preferably in FLT3/ITD hemizygote patients resistant to conventional therapies.
10. A compound of formula (lla)
Figure imgf000070_0001
wherein m, R, Ri and R2 are as defined in claims 1-6 and when m=1 , A is chosen from the group consisting of
Figure imgf000070_0002
when m=2, A is chosen from the group consisting of
Figure imgf000070_0003
(A4) and (As).
11. Use of a compound of formula (I la) according to claim 10 as an intermediate for the synthesis of a compound of formula (I) according to any one of claims 1-6.
12. A process for the preparation of a compound of formula (I) according to any one of claims 1-6 comprising contacting a compound of formula (II)
Figure imgf000071_0001
wherein A, B and C, Xi, n, m, R, Ri and R2 are as defined in claims 1-6, with a compound of formula (IV).
Figure imgf000071_0002
wherein Ar and R3 are as defined in claims 1-6.
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