RU2777596C2 - Heterocyclylsulfonyl-substituted pyridines and their use in treatment of cancer - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to a compound of the formula I or to its pharmaceutically acceptable salt, in which L is -S(O)_n-; n is 2 or 1; X is 5- or 6-element heterocyclyl attached to L via a carbon atom and optionally substituted with one or more groups independently selected from Y; R¹, R², and R³, each independently, are H or -OR¹¹; where each R¹¹ is independently C_1-6 alkyl optionally substituted with one or more fluorine atoms; each Y is independently methyl or -C(O)CH₃; where alkyl groups can be with an unbranched chain, with a branched chain or cyclic. The invention also relates to the use of a compound of the formula I and to a pharmaceutical composition based on it.

EFFECT: new compounds and a pharmaceutical composition based on them are obtained, which can be used in medicine for the treatment of cancer mediated by inhibition of cytosolic thioredoxin reductase (TrxR1).

(I)

9 cl, 6 ex

Description

Technical field

The present invention relates to new compounds and compositions, as well as their use in the treatment of cancer. In particular, the present invention relates to novel compounds, compositions and methods for treating cancer by specifically and effectively inhibiting thioredoxin reductase with minimal inhibition of glutathione reductase.

State of the art

In the present description, the listing or discussion of previously explicitly published documents should not necessarily be understood as an admission that this document is part of the prior art or general knowledge.

Although a growing understanding of the role of oncogenes and the development of new cancer treatments and diagnostics have increased the life expectancy of cancer patients, there is still a high medical need to find more effective and less toxic treatments for cancers such as breast cancer, head cancer and neck, melanoma, glioblastoma, leukemia and colon cancer, and lung cancer.

It is well known that excessive production of reactive oxygen species is a common feature of cancer cells due to their distorted metabolism and excessive replicative excitation. Cancer cells can survive their unnaturally high production of reactive oxygen species due to the concomitant activation of robust antioxidant defense mechanisms.

Radiotherapy and chemotherapy protocols compete with antioxidant defense mechanisms by further increasing reactive oxygen species above adapted thresholds by targeting multiple cellular compartments and targets. Thus, sensitization of cancer cells to their endogenous production of reactive oxygen species may further cause cancer cell death. In contrast, normal cells have a preserved ability to deal with oxidative stress. With this in mind, it has been suggested that if the levels of reactive oxygen species can be further increased, or if the protective ability of cells against reactive oxygen species can be specifically impaired, then these systems can serve for a possible therapeutic mechanism of action of anticancer therapy (Luo, J., Solimini, N. L. & Elledge, S. J., Cell, 136, 823 (2009); Trachootham, D., Alexandre, J. & Huang, P., Nat Rev Drug Discov, 8, 579 (2009)).

Increased tolerance of cancer cells to oxidative stress may result from the activation of two major antioxidant systems in humans and other mammals: the glutathione and thioredoxin systems. Thus, the simultaneous suppression of the glutathione and thioredoxin systems has been proposed as a mechanism for anticancer activity (Harris, I.S., et al., Cancer Cell 27, 211 (2015); Mandal, P.K., et al., Cancer Res, 70, 9505-9514 ( 2010); Fath, M.A., Ahmad, I.M., Smith, C.J., Spence, J. & Spitz, D.R., Clin Cancer Res., 17, 6206 (2011)).

Cytosolic thioredoxin reductase is the key enzyme for the entire cytosolic thioredoxin system, which in turn is responsible for the signaling cascade and antioxidant activity (Arnér, E. S. J., Biochim Biophys Acta, 1790, 495-526 (2009)). High levels of cytosolic thioredoxin reductase expression in various types of cancer correlate with more severe cancer phenotype, resistance to chemotherapy drugs, and poor prognosis.

However, since non-cancer cells normally require either a glutathione or a thioredoxin system to survive (Arnér, E.S. & Holmgren, A., Eur J Biochem, 267, 6102 (2000); Lillig, C.H., Berndt, C. & Holmgren, A., Biochim Biophys Acta, 1780, 1304 (2008); Prigge, J.R., et al., Free Radic Biol Med, 52, 803 (2012)), it is difficult to therapeutically target both of these antioxidant systems without causing major unwanted toxicity.

It has been suggested that some anticancer chemotherapeutic protocols involve the inhibition of cytosolic thioredoxin reductase along with other cellular components (Becker, K. et al. Eur. J. Biochem., 267, 6118 (2000)). For example, gadolinium motexafine, which is commercially available as a radiosensitizer and thioredoxin reductase inhibitor, is also an effective ribonucleotide reductase inhibitor (Hashemy, S. I., Ungerstedt, J. S., Zahedi Avval, F. & Holmgren, A., J Biol Chem, 281, 10691 (2006) ). Auranofin, an effective inhibitor of theoredoxin reductase, parallels and damages mitochondria (Cox, A.G., Brown, K.K., Arnér, E.S. & Hampton, M.B., Biochem Pharmacol, 76, 1097-1109 (2008); Krishnamurthy, D., et al. , J Med Chem, 51, 4790 (2008); Rigobello, M. P., Folda, A., Baldoin, M. C., Scutari, G. & Bindoli, A., Free Radic Res, 39, 687 (2005)).

The structure and function of thioredoxin reductase, the biological effects associated with its inhibition, such as its potential in the mechanism of cancer treatment, and compounds are previously described as effective inhibitors in a review by Zhang, B. et al., Expert Opinion on Therapeutic Patents (2016).

The present invention relates to the development and use of new compounds that specifically and effectively act on cytosolic thioredoxin reductase, without affecting the closely related flavoprotein glutathione reductase, which maintains the function of the glutathione system, as a means to obtain a new effective anti-cancer treatment, which at the same time has limited toxic effects. side effects.

In particular, the present inventors have surprisingly found that novel pyridinyl sulfone compounds can provide highly selective inhibition of cytosolic thioredoxin reductase by acting as highly binding (and in some cases effectively irreversible) inhibitors of this enzyme without causing significant inhibition of glutathione reductase.

In particular, through efficient and selective inhibition of thioredoxin reductase relative to glutathione reductase, the new pyridinyl sulfones can be effective against cancers having a dysfunctional redox status, with minimal overall toxic effects on normal cells. Such inhibitors may also be suitable adjuvant therapy for use in combination with radiation therapy or other chemotherapeutic approaches. Based on these unexpected results, the present invention is directed to providing new methods of treating cancer.

International patent application WO 2005/007621 describes certain compounds as ubiquitin ligase inhibitors and their use in the treatment of cell proliferative diseases. However, none of the present compounds contains a nitro-substituted pyridine that is linked via a sulfonyl moiety to an optionally substituted heterocyclyl group (as defined herein).

International patent application WO 95/29897 describes certain (H ⁺ /K ⁺ )ATPase inhibitors and their use in the treatment of viral infections. However, none of the present compounds contains a nitro-substituted pyridine linked via a sulfonyl moiety to an optionally substituted heterocyclyl group.

International patent application WO 98/54139 describes a process for preparing certain pyridines. However, none of the present compounds contains a nitro-substituted pyridine linked via a sulfonyl moiety to an optionally substituted heterocyclyl group.

International patent applications WO 99/18096 and WO 99/017777 describe certain compounds and their use in the treatment of pathological conditions such as cancer. However, none of the present compounds contains a nitro-substituted pyridine linked via a sulfonyl moiety to an optionally substituted heterocyclyl group.

International patent application WO 01/064642 describes certain compounds and their use in the treatment of bleeding disorders. However, none of the present compounds contains a nitro-substituted pyridine linked via a sulfonyl moiety to an optionally substituted heterocyclyl group.

Detailed description of the invention

Certain nitro-substituted pyridines linked via a sulfonyl moiety to an optionally substituted heterocyclyl group as defined herein have been found to have unexpected properties that render such compounds useful in the treatment of various cancers.

Compounds of the present invention

In a first aspect of the present invention, there is provided a compound of formula I

(I)

(I)

or a pharmaceutically acceptable salt thereof, wherein:

L is -S(O) _n -;

n is 2 or 1;

X is a heterocyclyl attached to L through a carbon atom and optionally substituted with one or more groups independently selected from Y;

R ¹ , R ² and R ³ are each independently H, halogen, R ^a1 , -CN, -A ^a1 -C(Q ^a1 )R ^b1 , -A ^b1 -C(Q ^b1 )N(R ^c1 ) R ^d1 , -A ^c1 -C(Q ^c1 )OR ^e1 , -A ^d1 -S(O) _p R ^f1 , -A ^e1 -S(O) _p N(R ^g1 )R ^h1 , -A ^f1 -S( O) _p OR ⁱ¹ , -N ₃ , -N(R ^j1 )R ^k1 , -N(H)CN, -NO ₂ , -ONO ₂ , -OR ^l1 , or -SR ^m1 ;

each A ^a1 –A ^f1 is independently a single bond, -N(R ^p1 )- or -O-;

each Q ^a1 - Q ^c1 is independently =O, =S, =NR ⁿ¹ or =N(OR ^o1 );

each R ^a1 and R ^f1 is independently C _1-6 alkyl, C _2-6 alkenyl, or C _2-6 alkynyl, each optionally substituted with one or more groups independently selected from G ^1a , heterocyclyl optionally substituted with one or more groups independently selected from G ^1b , aryl optionally substituted with one or more groups independently selected from G ^1c , or heteroaryl optionally substituted with one or more groups independently selected from G ^1d ;

each R ^b1 , R ^c1 , R ^d1 , R ^e1 , R ^g1 , R ^h1 , R ⁱ¹ , R ^j1 , R ^k1 , R ^l1 , R ^m1 , R ⁿ¹ , R ^o1 and R ^p1 independently represents H, C _{1- 6} alkyl, C _2-6 alkenyl or C _2-6 alkynyl, each optionally substituted with one or more groups independently selected from G ^1a , heterocyclyl optionally substituted with one or more groups independently selected from G ^1b , aryl optionally substituted one or more groups independently selected from G ^1c , or heteroaryl optionally substituted with one or more groups independently selected from G ^1d ; or

any of R ^c1 and R ^d1 , R ^g1 and R ^h1 and/or R ^j1 and R ^k1 are bonded to each other to form, together with the nitrogen atom to which they are attached, a 3-6 membered ring which optionally contains one additional heteroatom and which is optionally substituted with one or more groups independently selected from G ^1b , C _1-3 alkyl, C _2-3 alkenyl or C _2-3 alkynyl, each of which is optionally substituted with one or more G ^1a groups, and =O;

each G ^1a and G ^1b is independently halogen, -CN, -N(R ^a2 )R ^b2 , -OR ^c2 , -SR ^d2 or =O;

each R ^a2 , R ^b2 , R ^c2 and R ^d2 independently represents H or C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl, each of which is optionally substituted with one or more fluorine atoms; or

R ^a2 and R ^b2 are bonded to each other to form, together with the nitrogen atom to which they are attached, a 3-6 membered ring which optionally contains one additional heteroatom and which is optionally substituted with one or more groups independently selected from fluorine and C _{1 -3} alkyl, C _2-3 alkenyl or C _2-3 alkynyl, each of which is optionally substituted with one or more fluorine atoms;

each Y is independently halogen, R ^a3 , -CN, -A ^a2 -C(Q ^a2 )R ^b3 , -A ^b2 -C(Q ^b2 )N(R ^c3 )R ^d3 , -A ^c2 -C(Q ^c2 )OR ^e3 , -A ^d2 -S(O) _q R ^f3 , -A ^e2 -S(O) _q N(R ^g3 )R ^h3 , -A ^f2 -S(O) _q OR ⁱ³ , -N ₃ , - N(R ^j3 )R ^k3 , -N(H)CN, -NO ₂ , -ONO ₂ , -OR ^l3 , -SR ^m3 or =O;

each Q ^a2 - Q ^c2 is independently =O, =S, =NR ⁿ³ or =N(OR ^o3 );

each A ^a2 –A ^f2 is independently a single bond, -N(R ^p3 )- or -O-;

each R ^a3 and R ^f3 is independently C _1-6 alkyl, C _2-6 alkenyl, or C _2-6 alkynyl, each optionally substituted with one or more groups independently selected from G ^2a , heterocyclyl optionally substituted with one or more groups independently selected from G ^2b , aryl optionally substituted with one or more groups independently selected from G ^2c , or heteroaryl optionally substituted with one or more groups independently selected from G ^2d ;

each R ^b3 , R ^c3 , R ^d3 , R ^e3 , R ^g3 , R ^h3 , R ⁱ³ , R ^j3 , R ^k3 , R ^l3 , R ^m3 , R ⁿ³ , R ^o3 and R ^p3 is independently H, C _{1- 6} alkyl, C _2-6 alkenyl, or C _2-6 alkynyl, each optionally substituted with one or more groups independently selected from G ^2a , heterocyclyl optionally substituted with one or more groups independently selected from G ^2b , aryl optionally substituted one or more groups independently selected from G ^2c , or heteroaryl optionally substituted with one or more groups independently selected from G ^2d ; or

any two R ^c3 and R ^d3 , R ^g3 and R ^h3 and/or R ^j3 and R ^k3 are bonded to each other to form, together with the nitrogen atom to which they are attached, a 3-6 membered ring which optionally contains one additional heteroatom and which is optionally substituted with one or more groups independently selected from heterocyclyl optionally substituted with one or more groups independently selected from G ^2b , aryl optionally substituted with one or more groups independently selected from G ^2c , or heteroaryl optionally substituted with one or more groups independently selected from G ^2d and ═O;

each G ^2a is independently -CN, -N(R ^j4 )R ^k4 , -OR ^l4 , -SR ^m4 , or ═O;

each G ^2b is independently halogen, R ^a4 , -CN, -N(R ^j4 )R ^k4 , -OR ^l4 , -SR ^m4 , or ═O;

each G ^2c and G ^2d is independently halogen, R ^a4 , -CN, -A ^a3 -C(Q ^a4 )R ^b4 , -A ^b3 -C(Q ^b3 )N(R ^c4 )R ^d4 , -A ^c3 - C(Q ^c3 )OR ^e4 , -A ^d3 -S(O) _q R ^f4 , -A ^e3 -S(O) _q N(R ^g4 )R ^h4 , -A ^f3 -S(O) _q OR ⁱ⁴ , - N ₃ , -N(R ^j4 )R ^k4 , -N(H)CN, -NO ₂ , -ONO ₂ , -OR ^l4 or -SR ^m4 ;

each Q ^a3 - Q ^c3 is independently =O, =S, =NR ⁿ⁴ or =N(OR ^o4 );

each A ^a3 –A ^f3 is independently a single bond, -N(R ^p4 )- or -O-;

each R ^a4 and R ^f4 is independently C _1-6 alkyl, C _2-6 alkenyl, or C _2-6 alkynyl, each optionally substituted with one or more groups independently selected from G ^3a , or heterocyclyl optionally substituted with one or more groups independently selected from G ^3b ;

each R ^b4 , R ^c4 , R ^d4 , R ^e4 , R ^g4 , R ^h4 , R ⁱ⁴ , R ^j4 , R ^k4 , R ^l4 , R ^m4 , R ⁿ⁴ , R ^o4 and R ^p4 independently represents H, C _{1- 6} alkyl, C _2-6 alkenyl, or C _2-6 alkynyl, each optionally substituted with one or more groups independently selected from G ^3a , or heterocyclyl optionally substituted with one or more groups independently selected from G ^3b ; or

any of R ^c4 and R ^d4 , R ^g4 and R ^h4 and/or R ^j4 and R ^k4 are bonded to each other to form, together with the nitrogen atom to which they are attached, a 3-6 membered ring which optionally contains one additional heteroatom and which is optionally substituted with one or more groups independently selected from G ^3b ;

each G ^3a and G ^3b is independently halogen, R ^a5 , -CN, -N(R ^b5 )R ^c5 , -OR ^d5 , -SR ^e5 or =O;

each R ^a5 is independently C _1-6 alkyl, C _2-6 alkenyl, or C _2-6 alkynyl, each of which is optionally substituted with one or more groups independently selected from G ⁴ ;

each R ^b5 , R ^c5 , R ^d5 and R ^e5 is independently H, C _1-6 alkyl, C _2-6 alkenyl, or C _2-6 alkynyl, each optionally substituted with one or more groups independently selected from G ⁴ ; or

each R ^b5 and R ^c5 are bonded to each other to form, together with the nitrogen atom to which they are attached, a 3-6 membered ring which optionally contains one additional heteroatom and which is optionally substituted with one or more groups independently selected from G ⁴ ;

each G ⁴ is independently halogen, R ^a6 , -CN, -N(R ^b6 )R ^c6 , -OR ^d6 or =O;

each R ^a6 is independently C _1-6 alkyl, C _2-6 alkenyl, or C _2-6 alkynyl, each optionally substituted with one or more fluorine atoms;

each R ^b6 , R ^c6 and R ^d6 independently represents H or C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl, each of which is optionally substituted with one or more fluorine atoms; and

each p and q is independently 1 or 2,

and said compounds and their pharmaceutically acceptable salts may be referred to as the compounds of the present invention,

but provided that the compound of formula I is not:

(A)

3-nitro-2-(piperidin-4-ylsulfonyl)pyridine,

tert-butyl-3-((3-nitropyridin-2-yl)sulfonyl)pyrrolidine-1-carboxylate,

tert-butyl-(R)-3-((3-nitropyridin-2-yl)sulfonyl)pyrrolidine-1-carboxylate,

tert-butyl-(S)-3-((3-nitropyridin-2-yl)sulfonyl)pyrrolidine-1-carboxylate,

tert-butyl-3-((3-nitropyridin-2-yl)sulfonyl)piperidine-1-carboxylate or

tert-butyl-4-((3-nitropyridin-2-yl)sulfonyl)piperidine-1-carboxylate;

or

(B)

3-nitro-2-(4-piperidinylsulfinyl)pyridine,

3-nitro-2-(3-pyrrolidinylsulfinyl)pyridine,

3-nitro-2-(3-piperidinylsulfinyl)pyridine,

4-[(3-nitro-2-pyridinyl)sulfinyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl ether,

3-[(3-nitro-2-pyridinyl)sulfinyl]-1-pyrrolidinecarboxylic acid 1,1-dimethylethyl ether,

3-[(3-nitro-2-pyridinyl)sulfinyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester or

3-[(3-nitro-2-pyridinyl)sulfinyl]-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid ethyl ester.

For the avoidance of doubt, the compounds of formula I and their pharmaceutically acceptable salts, except as noted above, may be referred to herein as the compounds of the present invention. Likewise, reference to compounds according to the first aspect of the present invention refers to the compounds of formula I as defined in the first aspect of the present invention, including the qualifications indicated, and their pharmaceutically acceptable salts. Thus, the compounds according to the first aspect of the present invention are a separate embodiment of the compounds according to the present invention.

Those skilled in the art will appreciate that reference in this context to compounds of the present invention (eg, compounds of the first aspect of the present invention) includes reference to all embodiments and specific forms thereof.

Unless otherwise indicated, all technical and scientific terms used in this context have the same meaning as is generally understood by a person skilled in the art to which the present invention pertains.

Pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts may be prepared by conventional means, for example, by reacting the free acid form or free base form of a compound of the present invention with one or more equivalents of the appropriate acid or base, optionally in a solvent or medium in which the salt is insoluble, followed by removal of said salt. solvent or specified medium using standard techniques (eg in vacuo, freeze drying or filtration). Salts can also be obtained by exchanging the counterion of a compound of the present invention in salt form for another counterion, for example using a suitable ion exchange resin.

Specific acid addition salts that may be mentioned include carboxylate salts (e.g., formate, acetate, trifluoroacetate, propionate, isobutyrate, heptanoate, decanoate, caprate, caprylate, stearate, acrylate, caproate, propiolate, ascorbate, citrate, glucuronate, glutamate, glycolate , α-hydroxybutyrate, lactate, tartrate, phenylacetate, mandelate, phenylpropionate, phenylbutyrate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate, o-acetoxybenzoate, salicylate, nicotinate, isonicotinate, cinnamate, oxalate, sesbaucinate, malonate , fumarate, malate, maleate, hydroxymaleate, hippurate, phthalate or terephthalate salts), halide salts (e.g. chloride, bromide or iodide salts), sulfonate salts (e.g. benzenesulfonate, methyl, bromo or chlorobenzenesulfonate, xylenesulfonate, methanesulfonate, ethanes sulfonate, propanesulfonate, hydroxyethanesulfonate, 1- or 2-naphthalenesulfonate or 1,5-naphthalenesulfonate salts) or sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrophosphate, dihydrogen phosphate, metaphosphate, pyrophosphate or nitrate salts, and the like.

Specific base addition salts that may be mentioned include alkali metal salts (such as Na and K salts), alkaline earth metal salts (such as Mg and Ca salts), organic base salts (such as ethanolamine, diethanolamine, triethanolamine, tromethamine and lysine) and salts of inorganic bases (such as ammonia and aluminum hydroxide). More specifically, base addition salts that may be mentioned include the Mg, Ca salts, and most specifically the K and Na salts.

For the avoidance of doubt, the compounds of the present invention may exist in solid form and, therefore, the scope of the present invention includes all of their amorphous, crystalline and partially crystalline forms, and they may also exist in the form of an oily substance. Where the compounds of the present invention exist in crystalline and partially crystalline forms, such forms may include solvates, which are within the scope of the present invention. The compounds of the present invention may also exist in solution.

The compounds of the present invention may contain double bonds and therefore may exist as E (entgegen) and Z (zusammen) geometric isomers with respect to each individual double bond. All such isomers and mixtures thereof are within the scope of the present invention.

The compounds of the present invention may also exhibit tautomerism. All tautomeric forms and mixtures thereof are within the scope of the present invention.

The compounds of the present invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical isomerism and/or diastereoisomerism. Diastereoisomers can be separated using conventional techniques such as chromatography or fractional crystallization. Various stereoisomers can be isolated by separation of a racemic or other mixture of compounds using conventional techniques such as fractional crystallization or HPLC. Alternatively, the desired optical isomers can be obtained by reacting the appropriate optically active starting materials under conditions that do not lead to racemization or epimerization (i.e., the "chiral pool" method), by reacting the appropriate starting material with a "chiral auxiliary agent" that can be then remove the appropriate stage, through derivatization (ie separation, including dynamic separation); for example, with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography or by reaction with an appropriate chiral reagent or chiral catalyst, each time under conditions known to those skilled in the art. All stereoisomers and mixtures thereof are within the scope of the present invention.

As used herein, reference to halo and/or halogen independently refers to fluorine, chlorine, bromine and iodine (eg fluorine and chlorine).

Unless otherwise noted, C _1-z alkyl groups (where z is the upper end of the range) as defined herein may be straight chain or, if there is a sufficient number (i.e., at least two or three, as the case may be) of atoms carbon, may be branched and/or cyclic (forming a C _3-z cycloalkyl group). If there are a sufficient number (ie, at least four) carbon atoms, such groups may also be partially cyclic (forming a C _3-z partially cycloalkyl group). Partially cyclic alkyl groups that may be mentioned include cyclopropylmethyl and cyclohexylethyl. If a sufficient number of carbon atoms exist, such groups may also be polycyclic (eg, bicyclic or tricyclic) or spirocyclic.

Unless otherwise noted, C _2-z alkenyl groups (where z is the upper end of the range) as defined herein may be straight chain or, if there is a sufficient number (i.e., at least three) carbon atoms, may be branched and/or cyclic (forming a C _4-z cycloalkenyl group). If there are a sufficient number (ie, at least five) carbon atoms, such groups may also be partially cyclic. Partially cyclic alkenyl groups that may be mentioned include cyclopentenylmethyl and cyclohexenylmethyl. If a sufficient number of carbon atoms exist, such groups may also be polycyclic (eg, bicyclic or tricyclic) or spirocyclic.

Unless otherwise noted, C _2-z alkynyl groups (where z is the upper end of the range) as defined herein may be straight chain or, if there are a sufficient number (i.e., at least four) carbon atoms, may be branched .

For the avoidance of doubt, those skilled in the art should understand that the term "alkyl" refers to saturated hydrocarbon moieties, and the term "alkenyl" refers to unsaturated hydrocarbon moieties containing at least one carbon-carbon double bond, and the term "alkynyl" refers to unsaturated hydrocarbon moieties containing at least one carbon-carbon triple bond, and alkyl, alkenyl and alkynyl groups may be collectively referred to as hydrocarbon groups. In addition, such unsaturated hydrocarbon moieties are referred to with reference to the highest degree of unsaturation they contain (for example, a hydrocarbon moiety containing at least one carbon-carbon double bond and at least one carbon-carbon triple bond is referred to as alkynyl, although such fragments may also be referred to using terms such as "alkenyl-alkynyl" and the like).

As used herein, the term "heterocyclyl" may refer to non-aromatic monocyclic and bicyclic heterocyclyl groups (and said groups may optionally be bridged) in which at least one (e.g., one to four) atom in the ring system is other than carbon (i.e., e. is a heteroatom), and in which the total number of atoms in the ring system is from three to twelve (for example, from five to ten, and most preferably from three to eight, for example, a 5- or 6-membered heterocyclyl group). In addition, such heterocyclyl groups may be saturated, forming heterocycloalkyl, or unsaturated, containing one or more double and/or triple carbon-carbon or, if possible, carbon-heteroatomic or heteroatom-heteroatomic bonds, forming, for example, C _{2- z} (eg C _4-z ) heterocycloalkenyl (where z is the upper end of the range) or C _7-z heterocycloalkynyl group. C _2-z heterocyclyl groups that may be mentioned include 7-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1] octanyl, aziridinyl, azetidinyl, 2,3-dihydroisothiazolyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including 1,3-dioxolanyl), dioxanyl (including 1,3-dioxanyl and 1,4-dioxanyl ), dithianyl (including 1,4-dithianyl), dithiolanyl (including 1,3-dithiolanyl), imidazolidinyl, imidazolinyl, isothiazolidinyl, morpholinyl, 7-oxabicyclo[2.2.1]heptanyl, 6-oxabicyclo[3.2.1]octanyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl, 3-sulfolenyl, tetrahydropyranyl, tetrahydrofuryl, tetrahydropyridyl (such as 1,2,3,4-tetrahydropyridyl and 1,2,3, 6-tetrahydropyridyl), thietanyl, thiiranil, thiolanil, tetrahydrothiopyranyl, thiomorpholinyl, trithianyl (including 1,3,5-trithianyl), tropanil, and the like. Substituents on heterocyclyl groups, if appropriate, may be located at any atom in the ring system, including a heteroatom. In addition, if the substituent is another cyclic compound, then this cyclic compound can be attached through one atom in the heterocyclyl group to form the so-called "spiro" compound. The point of attachment for heterocyclyl groups may be at any atom in the ring system, including (if appropriate) an additional heteroatom (such as a nitrogen atom) or any fused carbocyclic ring atom that may be present as part of that ring system. Heterocyclyl groups may also be in N- or S-oxidized form.

Whenever mentioned herein, specific heterocyclyl groups that may be mentioned include 3-8 membered heterocyclyl groups (eg, 4-6 membered heterocyclyl groups).

The term "aryl" which may be used in this context includes reference to C _6-14 (eg C _6-10 ) aromatic groups. Such groups may be monocyclic or bicyclic, and in the case of bicyclic groups, they may be fully or partially aromatic. C _6-10 aryl groups that may be mentioned include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indanyl, and the like. (eg phenyl, naphthyl and the like such as phenyl). For the avoidance of doubt, the point of attachment of substituents in aryl groups may be at any carbon atom of the ring system.

The term "heteroaryl" or (heteroaromatic), which may be used in this context, includes a reference to 5-14-membered (for example, 5-10-membered) heteroaromatic groups containing one or more heteroatoms selected from oxygen, nitrogen and/ or sulfur. Such heteroaryl groups may contain one, two or three rings, of which at least one is aromatic. Substituents on heteroaryl/heteroaromatic groups, if appropriate, may be located at any atom in the ring system, including a heteroatom. The point of attachment of heteroaryl/heteroaromatic groups may be at any atom in the ring system, including (if appropriate) a heteroatom. Bicyclic heteroaryl/heteroaromatic groups may contain a benzene ring fused to one or more additional aromatic or non-aromatic heterocyclic rings, in which case the point of attachment of the polycyclic heteroaryl/heteroaromatic group may be on any ring, including the benzene ring and/or heteroaryl/heteroaromatic or heterocyclyl ring. Examples of heteroaryl/heteroaromatic groups that may be mentioned include pyridinyl, pyrrolyl, furanyl, thiophenyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, imidazopyrimidinyl, imidazothiazolyl, thienothiophenyl, indolopyridinyl, pyrimidinyl , azaindolyl, pyrazinyl, pyrazolopyrimidinyl, indazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl and purinyl. The scope of the present invention also includes oxides of heteroaryl/heteroaromatic groups (eg N-oxide). As indicated above, heteroaryl includes polycyclic (eg, bicyclic) groups in which one ring is aromatic (and the other may or may not be aromatic). Thus, other heteroaryl groups that may be mentioned include, for example, benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, dihydrobenzo[d]isothiazole, 3,4-dihydrobenz[1,4]oxazinyl, dihydrobenzothiophenyl , indolinyl, 5H,6H,7H-pyrrolo[1,2-b]pyrimidinyl, 1,2,3,4-tetrahydroquinolinyl, thiochromanil, and the like.

For the avoidance of doubt, in this context, the reference to heteroatoms has the usual meaning implied by those skilled in the art. Specific heteroatoms that may be mentioned include phosphorus, selenium, tellurium, silicon, boron, oxygen, nitrogen, and sulfur (eg, oxygen, nitrogen, and sulfur).

For the avoidance of doubt, reference to polycyclic (e.g., bicyclic) groups (e.g., when used in the context of heterocyclyl groups) refers to ring systems in which more than two cuts are required to convert such rings to a straight chain, with the minimum number of such cuts corresponding to the number specified rings (for example, the term "bicyclic" may mean that at least two cuts are needed to convert these rings into a straight chain). For the avoidance of doubt, the term "bicyclic" (for example, when used in the context of heterocyclyl groups) may refer to groups in which the second ring of a two-ring system is formed between two adjacent atoms of the first ring, and may also refer to groups in which two non-adjacent atoms are bonded via an alkylene or heteroalkylene chain (as the case may be), the latter groups being referred to as bridged.

For the avoidance of doubt, if an aryl or heteroaryl group is substituted by any group via a double bond, e.g. such an aryl or heteroaryl group consists of at least two rings, at least one ring being non-aromatic.

The present invention also includes isotopically labeled compounds of the present invention which are identical to those described herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. (or the most common in nature). All isotopes of any particular atom or element referred to in this context are included within the scope of the compounds of the present invention. Thus, the compounds of the present invention also include deuterated compounds, i.e. compounds in which one or more hydrogen atoms have been replaced by the hydrogen isotope deuterium.

For the avoidance of doubt, in cases where the nature of two or more substituents in a compound of the present invention may be the same, the actual nature of the respective substituents is by no means interdependent. For example, if there are two or more Y groups, said Y groups may be the same or different. Similarly, if there are two or more Y groups, each of which is R ^a3 , the R ^a3 groups in question may be the same or different. Similarly, if there is more than one R ^a1 group, each of which is independently C _1-6 alkyl substituted with one or more G ^1a groups, the nature of each G ^1a group is by no means interdependent.

For the avoidance of doubt, when using the term "A ^a1 - A ^f1 " in this context, it will be understood by those skilled in the art to mean A ^a1 , A ^b1 , A ^c1 , A ^d1 , A ^e1 and A ^f1 inclusive. Unless otherwise stated, the same applies to other similar terms used in this context.

Those skilled in the art will recognize that the compounds of the present invention that are the subject of the present invention include stable compounds. That is, the compounds of the present invention include compounds that are strong enough to withstand isolation, for example from a reaction mixture, to an acceptable degree of purity.

All embodiments of the present invention and specific features mentioned in this context may be taken individually or in combination with any other implementation options and/or specific features mentioned in this context (thus, describing more specific implementation options and specific features, described in this document), without departing from the description of the present invention.

Specific compounds according to the present invention that may be mentioned include compounds in which n is 2.

Additional compounds according to the present invention that may be mentioned include compounds in which n is 1.

Specific compounds according to the present invention that may be mentioned include compounds in which X is a saturated heterocyclyl, which may be referred to as heterocycloalkyl.

More specific compounds according to the present invention include compounds in which X is a 3-7 membered heterocyclyl (eg, heterocycloalkyl).

Even more specific compounds according to the present invention include compounds in which X represents a 5 - or 6-membered heterocyclyl (for example, heterocycloalkyl).

Even more specific compounds according to the present invention include compounds in which X is a 5- or 6-membered heterocyclyl (e.g., heterocycloalkyl) containing (i.e., containing as an integral member of the ring) one heteroatom, in particular, in which one the heteroatom is selected from O and N (for example, if the heteroatom is N, then said N atom is substituted with a Y group).

Specific compounds according to the present invention that may be mentioned include compounds in which X is a saturated heterocyclyl (which may be referred to as heterocycloalkyl).

Particular compounds of formula I which may be mentioned include compounds in which X is unsubstituted tetrahydrofuranyl (eg tetrahydrofuran-3-yl), tetrahydro-2H-pyranyl (eg tetrahydro-2H-pyran-4-yl) or piperidinyl ( e.g. piperidin-4-yl) optionally substituted with one or more (e.g. one) Y groups.

More specific compounds of the present invention that may be mentioned include compounds in which X is unsubstituted tetrahydropyranyl (eg tetrahydropyran-4-yl).

Even more specific compounds of formula I which may be mentioned include those wherein X is tetrahydrofuranyl (eg tetrahydrofuran-3-yl) or piperidinyl (eg piperidin-4-yl) optionally substituted with one or more (eg one ) groups Y.

Specific compounds according to the present invention that may be mentioned include compounds in which:

X is heterocyclyl substituted with one or more groups independently selected from Y;

each Y is independently halogen, R ^a3 , -CN, -A ^a2 -C(Q ^a2 )R ^b3 , -A ^b2 -C(Q ^b2 )N(R ^c3 )R ^d3 , -A ^c2 -C(Q ^c2 )OR ^e3 , -A ^d2 -S(O) _q R ^f3 , -A ^e2 -S(O) _q N(R ^g3 )R ^h3 , -A ^f2 -S(O) _q OR ⁱ³ , -N(R ^j3 )R ^k3 , -OR ^l3 , -SR ^m3 or =O;

each Q ^a2 - Q ^c2 is independently =O, =S, =NR ⁿ³ or =N(OR ^o3 );

each A ^a2 –A ^e2 is independently a single bond, -N(R ^p3 )- or -O-;

each R ^a3 and R ^f2 is independently C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl (e.g. C _1-6 alkyl), each of which is optionally substituted with one or more groups independently selected from G ^2a , heterocyclyl optionally substituted with one or more groups independently selected from G ^2b , aryl optionally substituted with one or more groups independently selected from G ^2c , or heteroaryl optionally substituted with one or more groups independently selected from G ^2d ;

each R ^b3 , R ^c3 , R ^d3 , R ^e3 , R ^g3 , R ^h3 , R ^j3 , R ^k3 , R ^l3 , R ^m3 , R ⁿ³ , R ^o3 and R ^p3 is independently H, C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl (e.g. C _1-6 alkyl), each optionally substituted with one or more groups independently selected from G ^2a , heterocyclyl optionally substituted with one or more groups independently selected from G ^2b , aryl optionally substituted with one or more groups independently selected from G ^2c , or heteroaryl optionally substituted with one or more groups independently selected from G ^2d , or

any two R ^c3 and R ^d3 , R ^g3 and R ^h3 and/or R ^j3 and R ^k3 are bonded to each other to form, together with the nitrogen atom to which they are attached, a 3-6 membered ring which optionally contains one additional heteroatom and which is optionally substituted with one or more groups independently selected from heterocyclyl optionally substituted with one or more groups independently selected from G ^2b , aryl optionally substituted with one or more groups independently selected from G ^2c , or heteroaryl optionally substituted with one or more groups independently selected from G ^2d and ═O;

each G ^2a is independently -CN, -N(R ^j4 )R ^k4 , -OR ^l4 , -SR ^m4 , or ═O;

each G ^2b is independently halogen, R ^a4 , -CN, -N(R ^j4 )R ^k4 , -OR ^l4 , -SR ^m4 , or ═O;

each G ^2c and G ^2d is independently halogen, R ^a4 , -CN, -A ^a3 -C(Q ^a3 )R ^b4 , -A ^b3 -C(Q ^b3 )N(R ^c4 )R ^d4 , -A ^c3 - C(Q ^c4 )OR ^e4 , -A ^d3 -S(O) _q R ^f4 , -A ^e3 -S(O) _q N(R ^g4 )R ^h4 , -A ^f3 -S(O) _q OR ⁱ⁴ , - N ₃ , -N(R ^j4 )R ^k4 , -N(H)CN, -NO ₂ , -ONO ₂ , -OR ^l4 or -SR ^m4 ;

each Q ^a3 - Q ^c3 is independently =O, =S, =NR ⁿ⁴ or =N(OR ^o4 );

each A ^a3 –A ^f3 is independently a single bond, -N(R ^p4 )- or -O-;

each R ^a3 and R ^f3 is independently C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl (e.g. C _1-6 alkyl), each of which is optionally substituted with one or more groups independently selected from G ^3a or heterocyclyl optionally substituted with one or more groups independently selected from G ^3b ;

each R ^b4 , R ^c4 , R ^d4 , R ^e4 , R ^g4 , R ^h4 , R ⁱ⁴ , R ^j4 , R ^k4 , R ^l4 , R ^m4 , R ⁿ⁴ , R ^o4 and R ^p4 independently represents H, C _{1- 6} alkyl, C _2-6 alkenyl or C _2-6 alkynyl (eg C _1-6 alkyl) each optionally substituted with one or more groups independently selected from G ^3a , or heterocyclyl optionally substituted with one or more groups, independently selected from G ^3b , or

any of R ^c4 and R ^d4 , R ^g4 and R ^h4 and/or R ^j4 and R ^k4 are bonded to each other to form, together with the nitrogen atom to which they are attached, a 3-6 membered ring which optionally contains one additional heteroatom and which is optionally substituted with one or more groups independently selected from G ^3b ;

each G ^3a and G ^3b is independently halogen, R ^a5 , -CN, -N(R ^b5 )R ^c5 , -OR ^d5 , -SR ^e5 or =O;

each R ^a5 is independently C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl (eg C _1-6 alkyl), each of which is optionally substituted with one or more groups independently selected from G ⁴ ;

each R ^b5 , R ^c5 , R ^d5 and R ^e5 is independently H or C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl (e.g. C _1-6 alkyl), each of which is optionally substituted with one or more groups independently selected from G ⁴ , or

each R ^b5 and R ^c5 are bonded to each other to form, together with the nitrogen atom to which they are attached, a 3-6 membered ring which optionally contains one additional heteroatom and which is optionally substituted with one or more groups independently selected from G ⁴ ;

each G ⁴ is independently halogen, R ^a6 , -CN, -N(R ^b6 )R ^c6 , -OR ^d6 or =O;

each R ^a6 is independently C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl (eg C _1-6 alkyl), each of which is optionally substituted with one or more fluorine atoms;

each R ^b6 , R ^c6 and R ^d6 is independently H or C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl (e.g. C _1-6 alkyl), each of which is optionally substituted with one or more atoms fluorine; and/or (for example, and)

each p and q is independently 1 or 2.

Specific compounds according to the present invention that may be mentioned include compounds in which each Y is independently halogen (eg, fluorine), fluorine, R ^a3 , -N(H)-C(O)R ^b3 , -C(O) OR ^e3 , -N(H)-S(O) ₂ R ^f3 , -S(O) ₂ R ^f3 , -N(H)-S(O) _q N(R ^g3 )R ^h3 , -N(R ^j3 )R ^k3 or -OR ^l3 .

More specific compounds of the present invention that may be mentioned include compounds in which each Y is independently halogen (eg, fluorine), R ^a3 , -C(O)OR ^e3 , -N(R ^j3 )R ^k3 , or -OR ^l3 .

Even more specific compounds of the present invention that may be mentioned include compounds in which each Y is independently halogen (eg fluorine), fluorine, R ^a3 or -C(O)OR ^e3 (such as R ^a3 or -C( O)OR ^e3 ), in particular, in which R ^a3 and/or (for example, and) -R ^e3 represent C _1-3 alkyl (for example, methyl), optionally substituted with one or more fluorine atoms (such as -CH ₃ ).

For example, compounds of the present invention that may be mentioned include compounds in which each Y is independently methyl or —C(O)CH ₃ .

More specific compounds according to the present invention that may be mentioned include compounds in which:

X is heterocyclyl (eg C _2-7 heterocyclyl such as C _2-7 heterocycloalkyl) substituted with one or more (eg one) groups independently selected from Y;

each Y is independently fluorine, R ^a3 , -N(H)-C(O)R ^b3 , -C(O)OR ^e3 , -N(H)-S(O) ₂ R ^f3 , -S(O) ₂ R ^f3 , -N(H)-S(O) _q N(R ^g3 )R ^h3 , -N(R ^j3 )R ^k3 , or -OR ^l3 ; and/or (for example, and)

each R ^b3 , R ^e3 , R ^f3 , R ^g3 , R ^h3 , R ^e3 , R ^j3 , R ^k3 and R ^l3 independently represents H or C _1-3 alkyl, C _2-3 alkenyl or C _2-3 alkynyl ( e.g. C _1-3 alkyl), or

any two R ^g3 and R ^h3 and/or R ^j3 and R ^k3 are bonded together to form, together with the nitrogen atom to which they are attached, a 3 to 6 membered ring which optionally contains one additional nitrogen atom and which is optionally substituted with one or more C _1-3 alkyls, C _2-3 alkenyls or C _2-3 alkynyls (eg C _1-3 alkyls).

Even more specific compounds according to the present invention that may be mentioned include compounds in which:

X is C _2-5 heterocyclyl (eg C _2-5 heterocyclyl such as C _2-5 heterocycloalkyl) substituted with one or more groups (eg one group) independently selected from Y;

each Y is independently halogen (eg, fluorine), R ^a3 , -C(O)OR ^e3 , -N(R ^j3 )R ^k3 , or -OR ^l3 ;

each R ^a3 , R ^e3 , R ^j3 , R ^k3 and R ^l3 independently represents H or C _1-3 alkyl (eg, -CH ₃ ), or

R ^j3 and R ^k3 are bonded to each other to form, together with the nitrogen atom to which they are attached, a 3-6 membered ring (e.g. a 5-6 membered ring) which optionally contains one additional nitrogen atom and which is optionally substituted with one or more (eg one) C _1-3 alkyls (eg -CH ₃ ).

Specific compounds according to the present invention that may be mentioned include compounds in which each R ¹ , R ² and R ³ independently represents H, halogen (for example, fluorine or chlorine such as chlorine), R ^a1 , -N(R ^j1 )R ^k1 or -OR ^l1 .

More specific compounds according to the present invention that may be mentioned include compounds in which:

each R ^a1 and R ^f1 is independently C _1-6 alkyl, C _2-6 alkenyl, or C _2-6 alkynyl, each optionally substituted with one or more groups independently selected from G ^1a , or heterocyclyl optionally substituted with one or more groups independently selected from G ^1b ; and

each R ^b1 , R ^c1 , R ^d1 , R ^e1 , R ^g1 , R ^h1 , R ⁱ¹ , R ^j1 , R ^k1 , R ^l1 , R ^m1 , R ⁿ¹ , R ^o1 and R ^p1 independently represents H, C _{1- 6} alkyl, C _2-6 alkenyl, or C _2-6 alkynyl, each optionally substituted with one or more groups independently selected from G ^1a , or heterocyclyl optionally substituted with one or more groups independently selected from G ^1b ; or

any of R ^c1 and R ^d1 , R ^g1 and R ^h1 and/or R ^j1 and R ^k1 are bonded to each other to form, together with the nitrogen atom to which they are attached, a 3-6 membered ring which optionally contains one additional heteroatom and which is optionally substituted with one or more groups independently selected from halogen and C _1-3 alkyl, C _2-3 alkenyl, or C _2-3 alkynyl, each of which is optionally substituted with one or more halogens and ═O.

More specific compounds according to the present invention that may be mentioned include compounds in which:

each R ¹ , R ² and R ³ independently represents H, halogen (for example, fluorine or chlorine), R ^a1 , -N(R ^j1 )R ^k1 , -OR ^l1 or -SR ^m1 (for example, H, halogen, such as chlorine or fluorine, R ^a1 , -N(R ^j1 )R ^k1 or -OR ^l1 ); and/or (for example, and)

each R ^a1 , R ^j1 , R ^k1 , R ^l1 and R ^m1 is independently C _1-6 alkyl, C _2-6 alkenyl or C _1-6 alkynyl (e.g. C _1-6 alkyl such as methyl), optionally substituted with one or more fluorine atoms (eg, -CH ₃ ).

In particular embodiments that may be mentioned, only R ^c1 and R ^d1 and/or R ^g1 and R ^h1 may alternatively be linked to each other in the manner described herein.

For example, compounds of the present invention that may be mentioned include compounds in which:

each R ¹ , R ² and R ³ independently represents H or -OR ^l1 ; and

each R ^l1 is independently C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, each of which is optionally substituted with one or more fluorine atoms (such as methyl, difluoromethyl, trifluoromethyl), or -N(R ^a2 )R ^b2 or heterocyclyl optionally substituted with one G ^1b ;

each R ^a2 and R ^b2 is independently H or C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl (eg C _1-6 alkyl such as methyl),

or R ^a2 and R ^b2 are bonded to each other to form, together with the nitrogen atom to which they are attached, a 3-6 membered ring which optionally contains one additional heteroatom and which is optionally substituted with one or more groups independently selected from C _{1- 3} alkyl; and/or (for example, and)

G ^1b is C _1-3 alkyl and ═O.

Additional compounds according to the present invention that may be mentioned include compounds in which each R ¹ , R ² and R ³ independently represents H, halogen (eg chlorine), -N(R ^j1 )R ^k1 or -OR ^l1 .

In particular, the compounds of the present invention that may be mentioned include compounds in which:

each R ¹ , R ² and R ³ independently represents H, halogen (eg chlorine), -N(R ^j1 )R ^k1 or -OR ^l1 ;

each R ^l1 is independently C _1-6 alkyl, C _2-6 alkenyl, or C _2-6 alkynyl, each optionally substituted with one or more fluorine atoms (such as methyl, difluoromethyl, trifluoromethyl), or -N(R ^a2 )R ^b2 or heterocyclyl optionally substituted with one G ^1b ; and/or (for example, and)

each R ^j1 and R ^k1 is independently C _1-6 alkyl, C _2-6 alkenyl, or C _2-6 alkynyl (e.g., C _1-6 alkyl such as methyl), each optionally substituted with one or more fluorine atoms (for example, -CH ₃ ).

Even more specific compounds according to the present invention that may be mentioned include compounds in which:

each R ¹ , R ² and R ³ independently represents H or -OR ^l1 ; and/or (for example, and)

each R ^l1 is independently C _1-6 alkyl (eg C _1-3 alkyl such as methyl) optionally substituted with one or more fluorine atoms (eg -CH ₃ ).

Specific compounds according to the present invention that may be mentioned include compounds in which R ¹ , R ² and R ³ are each H.

Specific compounds of the present invention that may be mentioned include compounds in which at least one (eg one) of R ¹ , R ² and R ³ (eg R ¹ ) is a group other than H and the remainder of R ¹ , R ² and R ³ are H, in particular where the group other than H is:

-OR ^l1 (such as -OR ^l1 where R ^l1 is C _1-6 alkyl (eg C _1-6 alkyl such as methyl) optionally substituted with one or more fluorine atoms);

a halogen such as chlorine; or

-N(R ^j1 )R ^k1 , such as -NMe ₂ .

For example, compounds of the present invention that may be mentioned include those wherein at least one (eg one) of R ¹ , R ² and R ³ (eg R ¹ ) is —OC _1-6 alkyl, optionally substituted with one or more fluorine atoms (eg, -OCH ₃ ), halogen (eg, chlorine), or -N(R ^j1 )R ^k1 (eg, -NMe ₂ ), and the rest of R ¹ , R ² and R ³ are H.

Thus, in a particular embodiment, there is provided a compound of the present invention wherein:

R ² and R ³ are H; and/or (for example, and)

R ¹ is H or in particular halogen (eg fluorine or chlorine such as chlorine), R ^a1 , -N(R ^j1 )R ^k1 , -OR ^l1 or -SR ^m1 (eg H, halogen such as chlorine, R ^a1 , -N(R ^j1 )R ^k1 or -OR ^l1 ).

In a more specific embodiment, compounds of the present invention are provided wherein:

R ² and R ³ are H; and/or (for example, and)

R ¹ is H or in particular halogen, R ^a1 , -N(R ^j1 )R ^k1 , -OR ^l1 or -SR ^m1 , for example H, halogen, R ^a1 , -N(R ^j1 )R ^k1 or -OR ^l1 ), where each R ^a1 , R ^j1 , R ^k1 , R ^l1 and R ^m1 independently represents C _1-6 alkyl (for example, C _1-3 alkyl, such as methyl), optionally substituted with one or more fluorine atoms (for example, -CH ₃ ).

In an even more specific embodiment, there is provided a compound of the present invention wherein:

R ² and R ³ are H; and/or (for example, and)

R ¹ is H or -OC _1-6 alkyl (eg -OC _1-3 alkyl) optionally substituted with one or more fluorine atoms (eg -OCH ₃ ).

For example, compounds of the present invention are provided wherein:

R ² and R ³ are H; and/or (for example, and)

R ¹ is -OCH ₃ .

Thus, specific compounds according to the present invention that may be mentioned include compounds in which R ¹ is —OCH ₃ .

As indicated above, the specific features and embodiments described herein may be combined without departing from the spirit of the present invention.

For example, in a specific embodiment, the invention provides a compound of formula I, where:

X is unsubstituted heterocyclyl (eg C _2-8 heterocyclyl); and

each R ¹ , R ² and R ³ independently represents H, halogen, R ^a1 , -N(R ^j1 )R ^k1 or -OR ^l1 .

Specific compounds of the present invention (including compounds of formula I and all embodiments and specific forms thereof) that may be mentioned include the compounds of the examples provided herein or their pharmaceutically acceptable salts.

When an exemplary compound is indicated as having been prepared in a specific salt form, it will be appreciated by those skilled in the art that particular compounds of the present invention that may be mentioned include the free base or free acid (as appropriate) of said compound, and vice versa. In addition, if an illustrative compound is indicated as having been prepared in a specific salt form, then specific compounds of the present invention that may be mentioned include other (ie, different) pharmaceutically acceptable salts of said compound.

Thus, for the avoidance of doubt, specific compounds of the present invention that may be mentioned include:

6-methoxy-2-((2-methyltetrahydrofuran-3-yl)sulfonyl)-3-nitropyridine,

6-methoxy-2-((1-methylpiperidin-4-yl)sulfonyl)-3-nitropyridine,

1-(4-((6-methoxy-3-nitropyridin-2-yl)sulfonyl)piperidin-1-yl)ethan-1-one and

6-methoxy-3-nitro-2-((tetrahydro-2H-pyran-4-yl)sulfonyl)pyridine

and their pharmaceutically acceptable salts.

Compositions and medical applications

As described above, the compounds of the present invention, and therefore compositions and kits containing them, are useful as pharmaceutical preparations.

According to a second aspect of the present invention, there is provided a compound of the present invention as defined above (i.e., in the first aspect of the present invention, including all embodiments and specific features, but without limitation) for use as a pharmaceutical preparation. In addition, the proposed compound according to the present invention, the definition of which is given above, for use in medicine.

In a specific embodiment of the second aspect of the present invention, the compound of the present invention is the compound of the first aspect of the invention (ie, including disclaimers).

As indicated herein, the compounds of the present invention may find particular use in the treatment of cancer.

Thus, in a third aspect of the present invention, there is provided a compound of the present invention as defined above (i.e., in the first aspect of the present invention, including but not limited to all embodiments and specific features) for use in the treatment of cancer.

In an alternative third aspect of the present invention, there is provided the use of a compound of the present invention as defined above for the preparation of a medicament for the treatment of cancer.

In a further alternative third aspect, the present invention provides a method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention.

In a specific embodiment of the third aspect of the present invention, the compound of the present invention is the compound of the first aspect of the invention (ie, including disclaimers).

Those skilled in the art will appreciate that reference to the treatment of a particular pathological condition (or also the therapy of said condition) has a conventional meaning in the medical field. In particular, these terms may refer to achieving a reduction in the severity of one or more clinical symptoms associated with a given condition. For example, in the case of cancer, the term may refer to achieving a reduction in the number of cancer cells present (eg, in the case of cancer forming a solid tumor, as indicated by a decrease in tumor volume).

In this context, the reference to patients refers to living patients undergoing treatment, including mammalian patients (eg, humans).

In this context, the term "effective amount" refers to the amount of the compound, which provides a therapeutic effect in the patient undergoing treatment. Said effect may be objective (eg, measurable by some test or marker) or subjective (ie, the subject shows signs and/or feels the effect).

While the compounds of the present invention may have pharmacological activity per se, certain pharmaceutically acceptable (e.g. "protected") derivatives of the compounds of the present invention may exist or be prepared which may not have such activity, but which can be administered parenterally. or orally, and which can then be metabolized in the body to form the compounds of the present invention. Therefore, such compounds (which may have some pharmacological activity, provided that such activity is significantly lower than the activity of the active compounds to which they are metabolized) can be described as "prodrugs" of the compounds according to the present invention.

In this context, reference to prodrugs includes compounds that form a compound of the present invention in an experimentally detectable amount, within a given time, after enteral or parenteral administration (eg, oral or parenteral administration). All prodrugs of the compounds of the present invention are within the scope of the present invention.

In addition, some compounds of the present invention may have no or minimal pharmacological activity per se, but they can be administered parenterally or orally, and thereafter they can be metabolized in the body to form compounds of the present invention that have pharmacological activity per se. Such compounds (which also include compounds that may have some pharmacological activity, but their activity is significantly lower than that of the active compounds of the present invention to which they are metabolized) can also be described as "prodrugs".

Thus, the compounds according to the present invention are useful because they have pharmacological activity and/or are metabolized in the body after oral or parenteral administration to form compounds that have pharmacological activity.

Without being limited by theory, it is believed that compounds of the present invention in which n is 1 can be metabolized in vivo to form the corresponding compounds of the present invention in which n is 2.

As indicated herein, the compounds of the present invention may be useful in the treatment of cancer (ie, certain types of cancer).

Specific types of cancer that may be mentioned include cancers selected from the group consisting of:

soft tissue cancer such as sarcoma (eg, angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma;

lung cancer such as bronchogenic carcinoma (eg, squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (or bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, including non-small cell lung cancer;

gastrointestinal cancers: such as esophageal cancer (eg squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach cancer (eg carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (eg ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), cancer of the small intestine (eg, adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colon cancer (eg, adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma );

cancer of the genitourinary system such as kidney cancer (eg adenocarcinoma, Wilms tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (eg squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (eg adenocarcinoma, sarcoma), testes (eg, seminoma, teratoma, embryonic carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma);

liver cancer such as hepatoma (eg, hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;

bone cancer such as osteogenic sarcoma (eg, osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (eg, reticular cell sarcoma), multiple myeloma, malignant giant cell chordoma, osteochronfromoma (eg, osteochondral exostoses ), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors;

cancers of the head and/or nervous system, such as cancer of the skull (eg, osteoma, hemangioma, granuloma, xanthoma, ostosis deformans), meninges (eg, meningioma, meningiosarcoma, gliomatosis), brain (eg, astrocytoma, meduloblastoma, glioma, ependymoma) , germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord (eg, neurofibroma, meningioma, glioma, sarcoma);

gynecological cancers such as uterine (eg, endometrial carcinoma), cervical (eg, cervical carcinoma, precancerous cervical dysplasia), ovarian (eg, ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulvar cancer (eg, squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vaginal (eg, clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma)), fallopian tubes (eg, carcinoma);

hematological cancers such as blood and bone marrow cancers (eg, myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphomas);

skin cancers such as malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevoid tumors, lipoma, angioma, dermatofibroma, keloids; neurofibromatosis and adrenal cancer; and

neuroblastoma.

In this context, the reference to cancer cells and similar terms include a reference to a cell affected by any of the above pathological conditions.

More specific cancers that may be mentioned include diseases corresponding to the cell lines used in the examples provided herein.

For example, specific cancers that may be mentioned include breast cancer (such as breast adenocarcinoma, eg metastatic breast adenocarcinoma) and/or glioblastoma (such as glioblastoma multiforme).

More specific types of cancer that might be mentioned include:

head and neck cancer (such as throat cancer, eg, pharyngeal squamous cell carcinoma);

colon cancer (such as colon and rectal carcinoma);

skin cancer (such as epidermoid (skin) carcinoma);

cancers of the gastrointestinal tract (such as pancreatic cancer, eg ductal carcinoma of the pancreas);

breast cancer (such as breast adenocarcinoma, eg metastatic breast adenocarcinoma);

lung cancer (such as carcinoma); and

hematologic cancers (such as leukemia, eg acute monocytic leukemia).

In specific embodiments, the cancer is a solid tumor.

In more specific embodiments, the cancer is selected from pancreatic cancer, ovarian cancer, and colon and rectal cancer.

For example, in some embodiments, the cancer is selected from colon and rectal cancer (including cancer that processes Ras mutations), small cell lung cancer, non-small cell lung cancer (NSCLC), and glioma.

In other embodiments, the cancer is selected from non-small cell lung cancer, ovarian cancer, metastatic breast cancer, pancreatic cancer, hepatobiliary cancer (including hepatocellular cancer, extrahepatic bile duct cancer, and cholangiocarcinoma), and gastric cancer.

In additional embodiments, the cancer is selected from colon and rectal cancer (including Ras mutations), small cell lung cancer, non-small cell lung cancer, ovarian cancer, hepatobiliary cancer (including hepatocellular cancer, extrahepatic bile duct cancer, and cholangiocarcinoma), gastric cancer, testicular cancer, and squamous cell carcinoma of the head and neck.

In some embodiments, the cancer is selected from leukemia (including acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, and chronic lymphoid leukemia), lymphomas (including mantle cell lymphoma, Hodgkin's lymphoma, and non-Hodgkin's lymphoma), and prostate cancer.

Those skilled in the art will appreciate that treatment with the compounds of the present invention may further comprise (ie, it may be combined with) additional method(s) for treating the same pathological condition. In particular, treatment with the compounds of the present invention may be combined with cancer treatments, such as treatment with one or more other therapeutic agents useful in the treatment of cancer and/or one or more physical methods used in the treatment of cancer (such as treatment by surgery) known to those skilled in the art.

In particular, treatment with the compounds of the present invention can be carried out in patients who are or have been undergoing (i.e., during treatment for the same condition, for example, within a month of treatment with the compounds of the present invention, for example, within two weeks eg within a week or in particular on the same day) with a therapeutic agent or physical method capable of causing (eg, it can be shown to cause) an increase in reactive oxygen species.

For the avoidance of doubt, it will be appreciated by those skilled in the art that therapeutic agents or physical methods capable of causing (e.g., can be shown to cause) an increase in reactive oxygen species may not necessarily be effective treatments per se, but become effective when used in combination with compounds according to the present invention.

For the avoidance of doubt, it will be understood by those skilled in the art that the compounds of the present invention may also be used in combination with one or more other therapeutic agents that are useful in the treatment of cancer and/or with one or more physical methods useful in the treatment of cancer. (such as treatment with surgery), and such methods do not cause an increase in reactive oxygen species.

In particular, treatment with the compounds of the present invention can be carried out in patients who are or have been treated with radiation therapy.

So it's also suggested:

a method of treating cancer in a patient in need thereof, wherein said patient is administered a therapeutically effective amount of a compound of the present invention in combination with radiation therapy (ie simultaneously or sequentially); and

a compound of the present invention for use in the treatment of cancer in a patient who is also being treated with radiation therapy.

The compounds of the present invention are generally administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, sublingually, intranasally, topically, by any other parenteral route or by inhalation, in a pharmaceutically acceptable dosage form.

The compounds of the present invention may be administered alone or may be administered by known pharmaceutical compositions/dosage forms, including tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like.

Thus, in accordance with the fourth aspect of the present invention, there is provided a pharmaceutical composition/dosage form containing the compound of the present invention as defined above (i.e., in the first aspect of the present invention, including all embodiments and specific features, but without limitation) , and optionally (eg, as a mixture) one or more pharmaceutically acceptable adjuvants, diluents, and/or carriers.

In a specific embodiment of the fourth aspect of the present invention, the compound of the present invention is the compound of the first aspect of the invention (ie, including reservations).

Those skilled in the art will recognize that, in this context, references to compounds of the present invention for a particular use (and, likewise, uses and uses relating to compounds of the present invention) may also refer to pharmaceutical compositions containing compounds of the present invention. the present invention described in this context.

The compounds of the present invention may be administered in the form of tablets or capsules, eg timed release capsules, which are taken orally. Alternatively, the compounds of the present invention may be in liquid form and may be administered orally or by injection. The compounds of the present invention may also take the form of suppositories or creams, gels and foams, for example, which can be applied to the skin. In addition, they may be in the form of an inhalant that is administered nasally or through the lungs.

Those skilled in the art will recognize that the compounds of the present invention may act systemically and/or locally (ie, at a specific site).

The compounds of the present invention may be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, by any other parenteral route, or by inhalation, in a pharmaceutically acceptable dosage form. Alternatively, in particular if the compounds of the present invention are intended for topical action, then the compounds of the present invention may be administered locally.

Thus, in a particular embodiment, a pharmaceutical dosage form is provided in a pharmaceutically acceptable dosage form, including tablets or capsules, oral or injectable liquid forms, suppositories, creams, gels, foams, or inhalants (e.g., for intranasal administration). For the avoidance of doubt, in such embodiments, the compounds of the present invention may be present in solid (eg, in the form of a dispersion of solid particles), liquid (eg, in solution), or other forms, eg, in the form of micelles.

In more specific embodiments, the pharmaceutical dosage form is in the form of tablets or capsules, in liquid forms for oral administration or injection (eg, in a form suitable for intravenous injection). In particular, the injection may be carried out by conventional means, and these may include the use of microneedles.

Depending on, for example, the potency and physical properties of the compound of the present invention (i.e. active ingredient), pharmaceutical dosage forms that may be mentioned include those in which the active ingredient is present in an amount of at least 1% (or at least at least 10%, at least 30% or at least 50%) by weight. That is, the ratio of active ingredient to other components (i.e. to additional adjuvant, diluent and carrier) of the pharmaceutical composition is at least 1:99 (or at least 10:90, at least 30:70 or at least 50 :50) by weight.

As described herein, the compounds of the present invention may also be combined with one or more other agents (ie, different agents, eg, agents other than the compounds of formula I) that are suitable for the treatment of cancer. Such combination products are provided for administering a compound of the present invention in combination with one or more other therapeutic agents, or may be presented as separate dosage forms, wherein at least one of such dosage forms contains a compound of the present invention and at least at least one contains another therapeutic agent, or may be presented (i.e., formulated) as a combination preparation (i.e., presented as a single dosage form containing a compound of the present invention and one or more other therapeutic agents).

Thus, in accordance with the fifth aspect of the present invention, there is provided a combined product containing:

- a compound according to the present invention, as defined above (ie in the first aspect of the invention, including all embodiments and specific features, but without reservation); and

- one or more other therapeutic agents suitable for the treatment of cancer,

wherein each of components (A) and (B) is formulated as a mixture, optionally with one or more pharmaceutically acceptable adjuvants, diluents or carriers.

In a sixth aspect of the present invention, there is provided a kit comprising:

(a) a pharmaceutical dosage form as defined above (ie in the fourth aspect of the invention); and

(b) one or more other therapeutic agents suitable for the treatment of cancer, optionally in admixture with one or more pharmaceutically acceptable adjuvants, diluents or carriers,

and both components (a) and (b) are presented in a form that is suitable for administration in combination (ie, simultaneously or sequentially) with another component.

In specific embodiments of the fourth and fifth aspects of the present invention, the compound of the present invention is the compound of the first aspect of the invention (ie, including disclaimers).

Those skilled in the art will recognize that the compounds of the present invention and their pharmaceutically acceptable salts may be administered (eg, in the dosage forms described above) at various dosages, and suitable dosages can be readily determined by one of skill in the art. Oral, pulmonary, and topical doses (and subcutaneous doses, although such doses may be relatively lower) can range from about 0.01 µg/kg body weight per day (µg/kg/day) to about 200 µg/kg/day, preferably from about 0.01 to about 10 μg/kg/day, and more preferably from about 0.1 to about 5.0 μg/kg/day. For example, when administered orally, treatment with such compounds may include administration of dosage forms typically containing from about 0.01 μg to about 2000 mg, for example, from about 0.1 μg to about 500 mg, or from 1 μg to about 100 mg (eg, from about 20 μg to about 80 μg) of the active ingredient(s). When administered intravenously, the most preferred doses are from about 0.001 to about 10 μg/kg/hour during infusion at a constant rate. Advantageously, treatment may include administering such compounds and compositions as a single daily dose, or the total daily dose may be administered in divided doses two, three, or four times daily (e.g., twice daily for the doses described herein, for example, doses of 10 mg, 20 mg, 30 mg, or 40 mg twice daily).

In any case, the physician or the skilled artisan can determine the actual dose that will be most appropriate for a particular patient, which will likely vary with the route of administration, the type and severity of the condition being treated, and the species, age, weight, sex, renal function. , hepatic function and response of the particular patient to be treated. The above doses are illustrative for the average case; of course, there may be individual cases in which higher or lower dosage ranges are appropriate, and these are within the scope of the present invention.

Preparation of compounds/compositions

Pharmaceutical compositions/dosage forms, combination products and kits described herein can be obtained in accordance with standard and/or accepted pharmaceutical practice.

Thus, in a further aspect of the present invention, there is provided a method for preparing a pharmaceutical composition/dosage form as defined above, which comprises contacting a compound of the present invention, as defined above, with one or more pharmaceutically acceptable adjuvants, diluents, or carriers.

In additional aspects, the present invention provides a method for preparing a combination product or kit as defined above, which comprises contacting a compound of the present invention as defined above, or a pharmaceutically acceptable salt thereof, with another therapeutic agent that is suitable for the treatment of cancer, and at least one pharmaceutically acceptable adjuvant, diluent or carrier.

In this context, the mention of bringing into contact means that the two components become suitable for introduction in combination with each other.

Thus, in relation to the method of obtaining a set, as defined above, by bringing "in contact" of two components with each other means that the two components of the set can be:

(i) presented as separate dosage forms (ie, independently of each other), which are then brought into contact for use in combination with each other in combination therapy; or

(ii) packaged and presented together as separate components of a "combination package" for use in combination with each other in combination therapy.

The compounds of the present invention described herein can be prepared according to methods well known to those skilled in the art, such as those described in the examples below.

According to the seventh aspect of the present invention, there is provided a process for the preparation of a compound according to the first aspect of the invention as defined above (i.e., the compounds of the present invention, but including qualifications), which comprises:

(i) if n is 2, reacting a compound of formula IIA

(IIA)

(IIA)

where R ¹ , R ² and R ³ are as defined herein (i.e. for compounds of the present invention or any particular feature or embodiment thereof) and LG ¹ is a suitable leaving group (such as halogen, e.g. chlorine), with a compound of formula IIIA

(IIIA)

(IIIA)

where X is as defined herein (i.e., for compounds of the present invention, or any particular feature or embodiment thereof), and M is an alkali metal ion (such as a Na ion),

in the presence of a suitable acid (such as a concentrated acid, such as a concentrated mineral acid, such as a concentrated HCl, such as a concentrated aqueous HCl) and in the presence of a suitable solvent (such as a polar organic solvent, such as N,N'-dimethylacetamide, N, N'-dimethylformamide or tetrahydrofuran), and optionally in the presence of a suitable phase transfer catalyst (such as a quaternary ammonium salt, eg tetrabutylammonium chloride);

(ii) if n is 2, reacting a compound of formula IIB

(IIB)

(IIB)

where R ¹ , R ² and R ³ are as defined herein (i.e. for compounds of the present invention or any particular feature or embodiment thereof) and M is an alkali metal ion (such as a Na ion) , with a compound of formula IIIB

(IIIB)

(IIIB)

where X is as defined herein for Formula I (i.e. for compounds of the present invention or any particular feature or embodiment thereof) and LG ² is a suitable leaving group (such as halogen, e.g. chlorine) , in the presence of a suitable acid (such as a concentrated acid, eg a concentrated mineral acid, eg a concentrated HCl, eg a concentrated aqueous HCl) and in the presence of a suitable solvent (such as a polar organic solvent, eg N,N'-dimethylacetamide, N ,N'-dimethylformamide or tetrahydrofuran), and optionally in the presence of a suitable phase transfer catalyst (such as a quaternary ammonium salt, eg tetrabutylammonium chloride);

(iii) if n is 2, reacting a compound of formula IIA as defined above with a compound of formula IIIA as defined above in the presence of a suitable metal halide (such as a suitable metal iodide, e.g. CuI, or a suitable metal bromide, e.g. , CuBr; and said metal halide may be present in excess, for example, in an amount corresponding to at least 2 molar equivalents of a compound of formula IIA and/or a compound of formula IIIA) and in the presence of a suitable solvent (such as a polar organic solvent, for example, N ,N'-dimethylacetamide, N,N'-dimethylformamide, tetrahydrofuran, or 3-dimethyl-2-imidazolidinone), under conditions known to those skilled in the art;

(iv) if n is 2, reacting a compound of formula IIB as defined above with a compound of formula IIIB as defined above in the presence of a suitable metal halide (such as a suitable metal iodide, e.g. CuI, or a suitable metal bromide, e.g. , CuBr; and said metal halide may be present in excess, e.g., in an amount corresponding to at least 2 molar equivalents of a compound of formula IIB and/or a compound of formula IIIB) and in the presence of a suitable solvent (such as a polar organic solvent, e.g., N ,N'-dimethylacetamide, N,N'-dimethylformamide, tetrahydrofuran, or 3-dimethyl-2-imidazolidinone), under conditions known to those skilled in the art;

(v) reacting a compound of formula IV

(IV)

(iv)

where R ¹ - R ³ and X are as defined herein (i.e., for compounds of the present invention or any particular feature or embodiment thereof), with a suitable oxidizing agent (i.e., an oxidizing agent selected and used as needed to achieve the desired oxidation state; such as a hypochlorite salt, such as sodium hypochlorite, a peroxymonosulfate salt, such as potassium peroxymonosulfate (Oxone), a percarboxylic acid, such as meta-chloroperoxybenzoic acid (mCPBA), or potassium permanganate) in the presence of a suitable solvent (such as a polar organic solvent, eg N,N'-dimethylacetamide, N,N'-dimethylformamide or tetrahydrofuran) and optionally in the presence of water, under conditions known to those skilled in the art;

(vi) if n is 2, reacting a compound of formula V

(V)

(V)

where R ¹ , R ² and R ³ are as defined herein (i.e. for compounds of the present invention or any particular feature or embodiment thereof) and LG ³ is a suitable leaving group (such as halogen, e.g. chlorine), with a compound of formula VI

(VI)

(VI)

where X is as defined above (i.e., for compounds of the present invention or any particular feature or embodiment thereof), in the presence of a suitable Lewis acid (such as AlCl ₃ ) and in the presence of a suitable solvent, such as an organic solvent, e.g. dichloromethane or dichloroethane).

Compounds of formulas IIA, IIB, IIIA, IIIB, IV, V, and VI are either commercially available or known from the literature, or can be prepared by analogy with the methods described herein or conventional synthetic methods according to standard procedures from available starting materials using appropriate reagents and reaction conditions. In this regard, those skilled in the art may refer, inter alia, to Comprehensive Organic Synthesis, BM Trost and I. Fleming, Pergamon Press, 1991. Additional sources that may be consulted include Heterocyclic Chemistry, JA Joule, K. Mills and GF Smith, ^3rd edition, published by Chapman & Hall, "Comprehensive Heterocyclic Chemistry II", AR Katritzky, CW Rees and EFV Scriven, Pergamon Press, 1996, and "Science of Synthesis", vols. 9-17 ( Hetarenes and Related Ring Systems), Georg Thieme Verlag, 2006.

In particular, compounds of formula IV can be prepared by reacting a compound of formula VII

(VII)

(VII)

where X is as defined herein (i.e., for compounds of the present invention or any particular feature or embodiment thereof), with a compound of formula IIA as defined above, under conditions known to those skilled in the art, for example, in the presence of a suitable base (such as a metal carbonate, such as potassium carbonate, a metal hydroxide, such as sodium hydroxide, or an amine base, such as triethylamine), and in the presence of a suitable solvent (such as a polar organic solvent, such as N, N'-dimethylacetamide, N,N'-dimethylformamide or tetrahydrofuran, or a mixture of a polar organic solvent and water), under conditions known to those skilled in the art.

In the same way, compounds of formula IV can be prepared by reacting a compound of formula VIII

(VIII)

(VIII)

where X is as defined herein (i.e., for compounds of the present invention or any particular feature or embodiment thereof), with a compound of formula IIA as defined above, under conditions known to those skilled in the art, for example, in the presence of a suitable base (such as a metal carbonate, such as potassium carbonate, a metal hydroxide, such as sodium hydroxide, or an amine base, such as triethylamine), and in the presence of a suitable solvent (such as a polar organic solvent, such as N, N'-dimethylacetamide, N,N'-dimethylformamide or tetrahydrofuran, or a mixture of a polar organic solvent and water), under conditions known to those skilled in the art.

In the same way, compounds of formula IV (in particular, in which at least one Y is present, and it is an electron withdrawing group, such as -NO ₂ ) can be prepared by reacting a compound of formula IX

(IX)

(IX)

where R ¹ , R ² and R ³ are as defined herein (i.e., for compounds of the present invention or any particular feature or embodiment thereof), with a compound of formula IIIB as described herein, under conditions known to those skilled in the art (for example, if the R ⁴ groups present in a compound of formula IIIB are not sufficiently electron withdrawing, then the reaction can be carried out in the presence of a suitable catalyst such as palladium (II) acetate or copper oxide, in which case a suitable the base may be an alkali metal t-butoxide such as Kt-OBu).

In the same way, the compounds of formulas VIII and IX are either commercially available or known from the literature, or can be prepared by analogy with the methods described herein or conventional synthetic methods according to standard procedures from available starting materials using appropriate reagents. and reaction conditions.

The substituents R ¹ - R ³ and Y, as defined above, may be modified one or more times, after or during the methods described above, to obtain compounds of formula I, using methods well known to specialists in this field of technology. Examples of such methods include substitution, reduction, oxidation, dehydrogenation, alkylation, dealkylation, acylation, hydrolysis, esterification, esterification, halogenation, and nitration. Precursor groups may be replaced by other such groups, or by groups defined in formula I, at any time during the course of the reaction sequence. Those skilled in the art may also refer to Comprehensive Organic Functional Group Transformations, AR Katritzky, O. Meth-Cohn and CW Rees, Pergamon Press, 1995, and/or Comprehensive Organic Transformations, RC Larock, Wiley-VCH , 1999.

The compounds of the present invention can be isolated from their reaction mixtures and, if necessary, purified using conventional techniques known to those skilled in the art. Thus, the methods for preparing compounds of the present invention described herein may include, as a last step, isolation and optional purification of a compound of the present invention (eg, isolation and optional purification of a compound of formula I).

Those skilled in the art will appreciate that in the methods described above and below, the functional groups of intermediates may need to be protected with protecting groups. Protection and deprotection of functional groups can be carried out before or after the reaction in the above schemes.

Protecting groups can be installed and removed in accordance with techniques well known to those skilled in the art and described below. For example, the protected compounds/intermediates described herein can be chemically converted to unprotected compounds using standard deprotection techniques. The type of chemical transformation determines the need and type of protective groups, as well as the sequence of the synthesis. The use of protecting groups is described in detail in "Protective Groups in Organic Synthesis", 3rd Edition, T.W. Greene & P.G.M. Wutz, Wiley-Interscience (1999).

In a further aspect of the present invention, there is provided a compound of formula IV as defined herein (i.e., wherein R ¹ , R ² , R ³ and X are as defined herein, including all specific features and embodiments thereof) , or a pharmaceutically acceptable salt thereof.

Particular compounds of formula IV that may be mentioned include those prepared in the examples provided herein and their pharmaceutically acceptable salts.

The compounds of the present invention may have the advantage that they may be more effective, less toxic, longer acting, more potent, may cause fewer side effects, may be more easily absorbed, and/or may have a better pharmacokinetic profile (e.g., higher oral bioavailability and/or lower clearance), and/or may have other useful pharmacological, physical or chemical properties compared to prior art compounds when used for the above indications or otherwise. In particular, the compounds of the present invention may have the advantage of being more effective and/or showing advantageous properties in vivo.

Without being limited by theory, it is believed that inhibition of thyroidoxin reductase is achieved through the use of the high electrophilicity of small molecule inhibitors in combination with the pronounced intrinsic nucleophilicity of NADPH-reduced, but not oxidized thioredoxin reductase, which leads to selective and effective inhibition of this enzyme without significant impact on other cellular pathways or enzymes.

In addition, it is believed that normal non-cancer cells can survive without a functional cytosolic thioredoxin-reductase enzyme due to the preserved function of the glutathione system, while cancer cells cannot survive with specific inhibition of cytosolic thioredoxin-reductase.

Examples

The present invention is illustrated by the following examples, in which the following abbreviations may be used.

aq. water

BSA bovine serum albumin

conc. concentrated

DMA N,N'-dimethylacetamide

DMF N,N'-dimethylformamide

DMSO dimethyl sulfoxide

DTNB 5,5'-dithio-bis-(2-nitrobenzoic acid)

EDTA ethylenediaminetetraacetic acid

GSSG glutathione disulfide

HPLC high performance liquid chromatography

HRMS high resolution mass spectrometry

mCPBA meta-chloroperbenzoic acid

NADPH nicotinamide adenine dinucleotide phosphate

NMR nuclear magnetic resonance

PBS phosphate buffered saline

room t-ra room temperature

The starting materials and chemicals indicated in the syntheses described below are commercially available from many vendors such as Sigma Aldrich.

In the event that there is a discrepancy between the name and the structure of the compounds shown graphically, the latter should be followed (if this does not contradict the experimental data that can be given, and / or if this does not obviously follow from the context). The names of end compounds can be translated into structures, for example, using ChemBioDraw Ultra 14.

Example 1: 6-Methoxy-2-((2-methyltetrahydrofuran-3-yl)sulfonyl)-3-nitropyridine

(a) 6-Methoxy-2-((2-methyltetrahydrofuran-3-yl)thio)-3-nitropyridine

A mixture of 2-chloro-6-methoxy-3-nitropyridine (250 mg, 1.33 mmol), 2-methyltetrahydrofuran-3-thiol (172 mg, 1.46 mmol), K ₂ CO ₃ (220 mg, 1.59 mmol) and DMF (5 ml) were stirred at room temperature overnight. Water was added and the mixture was extracted with EtOAc. The combined extracts were washed with H ₂ O, brine and dried over Na ₂ SO ₄ . Concentration and purification by chromatography gave the sub-title compound (99 mg, 29%).

(b) 6-Methoxy-2-((2-methyltetrahydrofuran-3-yl)sulfonyl)-3-nitropyridine

mCPBA (224 mg, 1.28 mmol) was added to a stirred mixture of 6-methoxy-2-((2-methyltetrahydrofuran-3-yl)thio)-3-nitropyridine (99 mg, 0.37 mmol) and CH ₂ Cl ₂ (10 ml) at room temperature. The mixture was stirred at room temperature overnight, diluted with CH ₂ Cl ₂ (10 ml) and washed with aq. Na ₂ S ₂ O ₃ solution (aqueous, saturated) and brine, and dried over Na ₂ SO ₄ . Purification by chromatography gave the title compound (21 mg, 19%).

The following compounds were obtained using the method described above.

Example Chemical structure MS [m/z (M+H) ⁺ ] Name ¹ H-NMR [solvent, δ] 2

MS [m/z (M+H) ⁺ = (calculated for C ₁₃ H ₁₇ N ₃ O ₆ S+H: 344.09), found: 343.6] 1-(4-((6-methoxy-3-nitropyridin-2-yl)sulfonyl)piperidin-1-yl)ethan-1-one ¹ H-NMR [CDCl ₃ , δ 8.08 (d, J= 8.56 Hz, 1H), 7.07 (d, J= 8.76 Hz, 1H), 4.75-4.71 (m , 1H), 4.07 (s, 3H), 4.01-3.99 (m, 2H), 3.19-3.16 (m, 1H), 2.68-2.65 (m, 1H ), 2.21-2.17 (m, 1H), 2.11 (s, 3H), 2.02-1.88 (m, 3H)] 3

MS [m/z (M+H) ⁺ = (calculated for C ₁₁ H ₁₄ N ₂ O ₆ S+H: 303.07), found: 303.1] 6-methoxy-3-nitro-2-((tetrahydro-2H-pyran-4-yl)sulfonyl)pyridine ¹ H-NMR [DMSO-d ₆ , δ 8.48 (d, J= 9 Hz, 1H), 7.39 (d, J= 9 Hz, 1H), 4.26-4.20 (m, 1H ), 4.02 (s, 3H), 3.97-3.94 (m, 2H), 3.45-3.39 (m, 2H), 1.88-1.84 (m, 2H), 1.74-1.68 (m, 2H)]

Example 4: 6-Methoxy-2-(2-methyltetrahydrofuran-3-ylsulfinyl)-3-nitropyridine

- 6-Methoxy-2-(2-methyltetrahydrofuran-3-ylsulfanyl)-3-nitropyridine

To a solution of 6-methoxy-2-chloro-3-nitropyridine (1 g, 5.319 mmol) in dimethylformamide (5 ml) was added potassium carbonate (880 mg, 6.382 mmol) and 2-methyloxolane-3-thiol (690 mg, 5.851 mmol ) at room temperature. The reaction mixture was stirred for 12 hours at room temperature. The progress of the reaction was monitored by LCMS. The reaction mixture was quenched with ice water (20 ml) and extracted with ethyl acetate (50 ml). The organic layer was washed with water (3 x 30 ml) then brine (1 x 50 ml). The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give a crude product which was purified by column chromatography eluting with 7% ethyl acetate in hexane to give the sub-title compound as a yellow solid (700 mg, 48%).

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.51-8.48 (m, 1H), 6.79-6.76 (m, 1H), 4.56-3.85 (m, 6H ), 3.78-3.63 (m, 1H), 2.71-2.62 (m, 1H), 1.98-1.92 (m, 1H), 1.28-1.14 (m , 3H);

¹³ C NMR (DMSO-d ₆ , 100 MHz) δ 164.2, 164.1, 157.5, 157.5, 137.4, 136.0, 107.0, 106.9, 78.1, 78 .1, 75.8, 65.9, 65.1, 54.9, 54.8, 47.7, 45.9, 33.6, 32.2, 19.5, 16.8;

LCMS [m/z (M+H) ⁺ ] 271 (MW calc = 270); diastereomeric mixture, R _t = 2.42, 2.45;

HPLC purity at λ=210 nm: diastereomeric mixture, R _t =8.84, 22.98%; R _t =8.81, 75.37%.

- 6-Methoxy-2-(2-methyltetrahydrofuran-3-ylsulfinyl)-3-nitropyridine

To a solution of 6-methoxy-2-(2-methyltetrahydrofuran-3-ylsulfanyl)-3-nitropyridine (450 mg, 1.666 mmol) in dichloromethane (10 ml) was added m-chloroperbenzoic acid (343.86 mg, 1.999 mmol) at 0 °C. The reaction mixture was stirred at the same temperature for 3 hours. The progress of the reaction was monitored by LCMS. The reaction mixture was quenched with a solution of sodium sulfite and sodium bicarbonate (1:1) for 20 minutes. The reaction mixture was extracted with dichloromethane (3 x 20 ml) and the combined organic layer was washed with brine (1 x 20 ml). The organic layer was separated and dried over anhydrous sodium sulfate and evaporated under reduced pressure to give a crude product which was purified by column chromatography eluting with 2% methanol in dichloromethane to give the title compound as a yellow solid (190 mg, 40%) .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.59-8.54 (m), 7.21-7.13 (m), 4.53-3.38 (m), 4.09 ( s), 2.8-2.6 (m), 2.49-2.25 (m), 1.75-1.58 (m), 1.61 (d, J=6.4 Hz), 1.49 (d, J=6.5 Hz), 1.40 (d, J=6.1 Hz), 0.76 (d, J=6.3 Hz);

¹³ C NMR (DMSO-d ₆ , 100 MHz) δ 165.7, 165.6, 165.6, 161.5, 160.4, 159.6, 137.6, 137.1, 137.0, 136 .8, 136.7, 113.8, 112.9, 112.5, 112.3, 76.3, 70.34, 67.2, 66.3, 66.3, 65.8, 65.6 , 65.4, 64.1, 63.5, 55.2, 55.15, 30.37, 26.45, 21.7, 21.0, 20.1, 18.8, 16.6;

LCMS [m/z (M+H) ⁺ ] 287 (MW calc = 286); diastereomeric mixture, R _t = 7.29, 7.59, 7.71, 8.02;

HPLC purity at λ=210 nm: diastereomeric mixture, R _t =8.54, 7.4%; R _t =8.84, 56.8%; R _t =8.95, 16.3%; R _t =9.25, 18.4%

Example 5: 6-Methoxy-3-nitro-2-(tetrahydropyran-4-ylsulfinyl)pyridine

- 6-Methoxy-3-nitro-2-(tetrahydropyran-4-ylsulfanyl)pyridine

To a solution of 6-methoxy-2-chloro-3-nitropyridine (1 g, 5.319 mmol) in dimethylformamide (5 ml) was added potassium carbonate (880 mg, 6.382 mmol) and oxane-4-thiol (690 mg, 5.851 mmol) at room temperature. The reaction mixture was stirred for 12 hours at room temperature. The progress of the reaction was monitored by LCMS. The reaction mixture was quenched with ice water (20 ml) and extracted with ethyl acetate (50 ml). The organic layer was washed with water (3 x 30 ml) then brine (1 x 50 ml). The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give a crude product which was purified by column chromatography eluting with 10% ethyl acetate in hexane to give the sub-title compound as an off-white solid (1.2 g, 83.5%.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.48 (d, J= 9.0 Hz, 1H), 6.75 (d, J= 9.0 Hz, 1H), 4.21-4 .11 (m, 1H), 4.02 (s, 3H), 3.91-3.86 (m, 2H), 3.53-3.47 (m, 2H), 2.05-2.02 (m, 2H), 1.70-1.65 (m, 2H);

¹³ C NMR (DMSO-d ₆ , 100 MHz) δ 164.0, 157.0, 137.3, 135.5, 106.7, 66.6 (2C), 54.6, 39.4, 32, 0(2C);

LCMS [m/z (M+H) ⁺ ] 271 (MW calc = 270); _Rt = 1.66

- 6-Methoxy-3-nitro-2-(tetrahydropyran-4-ylsulfinyl)pyridine

To a solution of 6-methoxy-3-nitro-2-(tetrahydropyran-4-ylsulfanyl)pyridine (800 mg, 2.962 mmol) in dichloromethane (10 ml) was added m-chloroperbenzoic acid (611.55 mg, 3.555 mmol) at 0° C. The reaction mixture was stirred at room temperature for 4 hours. The progress of the reaction was monitored by LCMS. The reaction mixture was quenched with a solution of sodium sulfite and sodium bicarbonate (1:1) for 20 minutes. The reaction mixture was extracted with dichloromethane (3 x 20 ml) and the combined organic layer was washed with brine (1 x 20 ml). The organic layer was separated and dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give a crude product which was purified by column chromatography eluting with 1.5% methanol in dichloromethane to give the title compound as a light yellow solid (270 mg , 32%).

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.57 (d, J= 8.96 Hz, 1H), 7.16 (d, J= 8.96 Hz, 1H), 4.07 (s , 3H), 3.96-3.86 (m, 2H), 3.51-3.25 (m, 3H), 1.91-1.81 (m, 3H), 1.25-1.18 (m, 1H);

¹³ C NMR (CDCl ₃ , 100 MHz) δ 166.3, 160.4, 137.7, 136.0, 112.9, 67.0, 66.6, 58.6, 55.7, 28.0 , 23.1;

LCMS [m/z (M+H) ⁺ ] 287 (MW calc = 286); _Rt = 1.32

HPLC purity at λ=220 nm: 99.53%.

Example 6 1-[4-(6-Methoxy-3-nitropyridin-2-ylsulfinyl)piperidin-1-yl]ethanone

- 1-[4-(6-Methoxy-3-nitropyridin-2-ylsulfanyl)piperidin-1-yl]ethanone

Potassium carbonate (880 mg, 6.382 mmol) and 1-(4-sulfanylpiperidin-1-yl)ethan- 1-one (930 mg, 5.851 mmol) at room temperature. The reaction mixture was stirred for 12 hours at room temperature. The progress of the reaction was monitored by LCMS. The reaction mixture was filtered. The filtrate was evaporated under reduced pressure to give a crude product which was purified by column chromatography eluting with 2% methanol in dichloromethane and triturated with ether to give the sub-title compound as a yellow solid (1.2 g, 72.5%) .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.49 (d, J= 9.1 Hz, 1H), 6.77 (d, J= 9.1 Hz, 1H), 4.27-4 .24 (m, 1H), 4.16-4.09 (m, 1H), 4.03 (s, 3H), 3.84-3.80 (m, 1H), 3.27-3.23 (m, 1H), 2.92-2.86 (m, 1H), 2.13-2.07 (m, 2H), 2.01 (s, 3H), 1.69-1.59 (m , 1H), 1.54-1.50 (m, 1H);

¹³ C NMR (DMSO-d ₆ , 100 MHz) δ 167.9, 164.1, 156.9, 137.4, 135.5, 106.7, 54.7, 45.5, 40.6, 40 .4, 31.6, 31.0, 21.2;

LCMS [m/z (M+H) ⁺ ] 312 (MW calc = 311); _Rt = 1.57

- 1-[4-(6-Methoxy-3-nitropyridin-2-ylsulfinyl)-piperidin-1-yl]ethanone

To a solution of 1-[4-(6-methoxy-3-nitropyridin-2-ylsulfanyl)-piperidin-1-yl]ethanone (850 mg, 2.733 mmol) in dichloromethane (10 ml) 3.279 mmol) at 0 °C. The reaction mixture was stirred at the same temperature for 3 hours. The progress of the reaction was monitored by LCMS. The reaction mixture was quenched with a solution of sodium sulfite and sodium bicarbonate (1:1) for 20 minutes. The reaction mixture was extracted with dichloromethane (3 x 20 ml) and the combined organic layer was washed with brine (1 x 20 ml). The organic layer was separated and dried over anhydrous sodium sulfate and evaporated under reduced pressure to give a crude product which was purified by column chromatography eluting with 4% methanol in dichloromethane to give the title compound (250 mg, 28%) as a yellow solid .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.60-8.57 (m, 1H), 7.18-7.15 (m, 1H), 4.5-4.4 (m, 1H ), 4.07 (s, 3H), 3.95-3.85 (m, 1H), 3.55-3.45 (m, 1H), 3.15-2.95 (m, 1H), 2.65-2.53(m, 1H), 2.11-1.95(m, 4H), 1.85-1.55(m, 2H), 1.39-1.33(m, 1H );

¹³ C NMR (DMSO-d ₆ , 100 MHz) δ 167.9, 165.4, 159.8, 159.7 137.8, 137.13, 137.09, 112.5, 57.47, 57, 35, 55.22, 55.21, 45.0, 44.4, 40.2, 39.5, 27.9, 27.2, 22.4, 21.5, 21.12, 21.08;

MS [m/z (M+H) ⁺ ] 328 (MM calc = 327); R _t = 1.85;

HPLC purity at λ=200 nm: 97.72%.

Biological examples

Biological example 1: Inhibition of recombinant TrxR1 and GR

Inhibition of recombinant thioredoxin reductase 1 (TrxR1) and glutathione reductase (GR) by small molecule compounds was studied in a 96-well plate format. 30 nM TrxR1 was incubated in the presence of 250 μM NADPH, 0.1 mg/ml BSA and various concentrations of the compound (final DMSO concentration 1%) in 50 mM Tris buffer (pH 7.5) and 2 mM EDTA for 15 minutes. After an incubation period, 2 mM DTNB was added to each well and a change in optical density (OD) was observed at 412 nm. Percent activity was determined using controls with DMSO carrier and without TrxR1 (blank). Incubated with 2 nM GR in the presence of 250 μM NADPH, 0.1 mg/ml BSA and various concentrations of compounds (final concentration DMSO 1%) in a buffer of 50 mm Tris (pH 7.5) and 2 mm EDTA for 15 minutes. After an incubation period, 1 mM GSSG was added to each well and the change in optical density (OD) at 340 nm was observed. Percent activity was determined using controls with DMSO vehicle and without GR (blank).

Using the assays described in Biological Example 1, the following IC ₅₀ values were obtained. The results obtained are presented below in table 1.

Example No. IC50 in TrxR assay (nM) IC50 in GR assay (µM) one 93.0 >100 µM 2 391 >100 µM 3 39.06 >100 µM four 1010 >100 µM 5 4330 >100 µM 6 4060 >100 µM

Biological Example 2: Breast Cancer Cell Viability Assay

MDA-MB-231 cells were seeded at a density of 2000 cells per well in 96-well black optical plates in the presence of 10% FBS medium containing 25 nM selenite. The next day, cells were treated with different concentrations of compounds (0.1% DMSO final concentration) and incubated for 72 hours. After incubation, Alamar Blue reagent was added to each well and incubated for an additional 3 hours. Fluorescence was read at an excitation wavelength of 530 nm/emission wavelength of 590 nm, and the percent viability was determined using DMSO-vehicle and cell-free controls (blank).

Using the assays described in Biological Example 2, the following IC ₅₀ values were obtained. The results obtained are presented below in table 2.

Example No. IC50 cell viability MDA-MB-231 (µM) one 4.53 2 12.29 3 5.08

Biological Example 3: Cancer cell viability assay

Breast cancer and glioblastoma cell lines were seeded at a density of 4000 cells per well in 96-well plates in the presence of 10% FBS medium. The next day, cells were treated with various concentrations of exemplary compounds (final DMSO concentration 0.1%) and incubated for 72 hours. After incubation, An MTT analysis was performed to assess cell viability. Percent viability was determined using control samples with DMSO carrier and without cells (blank).

Using the assays described in Biological Example 3, the following IC ₅₀ values were obtained. The results obtained are presented below in table 3.

Example No. IC50 U-87 MG (µM) IC50 MDA-MB-231 (µM) IC50 MDA-MB-468 (µM) one 8.89 8.94 4.14 2 10.59 9.97 four 3 6.11 7.53 4.34 four 9.27 3.54 2.10 5 - 3.57 2.40 6 - 11.56 5.58

Claims (80)

1. Compound of formula I

(I) or a pharmaceutically acceptable salt thereof, wherein L is -S(O) _n -; n is 2 or 1; X is a 5- or 6-membered heterocyclyl attached to L via a carbon atom and optionally substituted with one or more groups independently selected from Y; R ¹ , R ² and R ³ are each independently H or —OR ^l1 where each R ^l1 is independently C _1-6 alkyl optionally substituted with one or more fluorine atoms; each Y is independently methyl or -C(O)CH ₃ ; where the alkyl groups may be straight chain, branched or cyclic; but provided that the compound of formula I is not: (A) 3-nitro-2-(piperidin-4-ylsulfonyl)pyridine, or (B) 3-nitro-2-(4-piperidinylsulfinyl)pyridine, 3-nitro-2-(3-pyrrolidinylsulfinyl)pyridine, or 3-nitro-2-(3-piperidinylsulfinyl)pyridine. 2. The compound according to claim 1, characterized in that R ¹ is -OCH ₃ . 3. Use of a compound of formula I

(I) or a pharmaceutically acceptable salt thereof, wherein L is -S(O) _n -; n is 2 or 1; X is a 5- or 6-membered heterocyclyl attached to L via a carbon atom and optionally substituted with one or more groups independently selected from Y; R ¹ , R ² and R ³ are each independently H or —OR ^l1 where each R ^l1 is independently C _1-6 alkyl optionally substituted with one or more fluorine atoms; each Y is independently methyl or -C(O)CH ₃ ; where the alkyl groups may be straight chain, branched or cyclic; as a pharmaceutical agent having inhibitory activity against cytosolic thioredoxin-reductase. 4. Use of a compound of formula I

(I) or a pharmaceutically acceptable salt thereof, wherein L is -S(O) _n -; n is 2 or 1; X is a 5- or 6-membered heterocyclyl attached to L via a carbon atom and optionally substituted with one or more groups independently selected from Y; R ¹ , R ² and R ³ are each independently H or —OR ^l1 where each R ^l1 is independently C _1-6 alkyl optionally substituted with one or more fluorine atoms; each Y is independently methyl or -C(O)CH ₃ ; where the alkyl groups may be straight chain, branched or cyclic; for the treatment of cancer mediated by inhibition of cytosolic thioredoxin reductase. 5. Use of a compound of formula I

(I) or a pharmaceutically acceptable salt thereof, wherein L is -S(O) _n -; n is 2 or 1; X is a 5- or 6-membered heterocyclyl attached to L via a carbon atom and optionally substituted with one or more groups independently selected from Y; R ¹ , R ² and R ³ are each independently H or —OR ^l1 where each R ^l1 is independently C _1-6 alkyl optionally substituted with one or more fluorine atoms; each Y is independently methyl or -C(O)CH ₃ ; where the alkyl groups may be straight chain, branched or cyclic; to obtain a drug for the treatment of cancer mediated by inhibition of cytosolic thioredoxin reductase. 6. A method of treating cancer mediated by inhibition of cytosolic thioredoxin reductase, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula I

(I) or a pharmaceutically acceptable salt thereof, wherein L is -S(O) _n -; n is 2 or 1; X is a 5- or 6-membered heterocyclyl attached to L via a carbon atom and optionally substituted with one or more groups independently selected from Y; R ¹ , R ² and R ³ are each independently H or —OR ^l1 where each R ^l1 is independently C _1-6 alkyl optionally substituted with one or more fluorine atoms; each Y is independently methyl or -C(O)CH ₃ ; where the alkyl groups may be straight chain, branched or cyclic. 7. Application or method according to paragraphs. 4-6, characterized in that the cancer is selected from the group consisting of: soft tissue cancer such as sarcoma, myxoma, rhabdomyoma, fibroma, lipoma and teratoma; lung cancer such as bronchogenic carcinoma, alveolar or bronchiolar carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal cancers such as esophageal cancer, gastric cancer, pancreatic cancer, small intestine cancer, colon cancer; cancer of the genitourinary system, such as cancer of the kidneys, bladder and urethra, prostate, testis; liver cancer such as hepatoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bone cancer such as osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, multiple myeloma, malignant giant cell chordoma, osteochronfromoma, benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumors; cancers of the head and/or nervous system such as cancer of the skull, meninges, brain, spinal cord; gynecological cancers such as cancer of the uterus, cervix, ovary, vulva, vagina, fallopian tubes; hematological cancers such as blood and bone marrow cancer, Hodgkin's disease, non-Hodgkin's lymphoma; skin cancers such as malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevoid tumors, lipoma, angioma, dermatofibroma, keloids; neurofibromatosis and adrenal cancer; and neuroblastoma. 8. Application or method according to paragraphs. 4-7, characterized in that the cancer is a solid tumor. 9. Pharmaceutical composition for the treatment of cancer mediated by inhibition of cytosolic thioredoxin reductase (TrxR1) containing a therapeutically effective amount of a compound of formula I

(I) or a pharmaceutically acceptable salt thereof, wherein L is -S(O) _n -; n is 2 or 1; X is a 5- or 6-membered heterocyclyl attached to L via a carbon atom and optionally substituted with one or more groups independently selected from Y; R ¹ , R ² and R ³ are each independently H or —OR ^l1 where each R ^l1 is independently C _1-6 alkyl optionally substituted with one or more fluorine atoms; each Y is independently methyl or -C(O)CH ₃ ; where the alkyl groups may be straight chain, branched or cyclic; and optionally one or more pharmaceutically acceptable adjuvants, diluents and/or carriers.