EA043772B1 - BUMETANIDE DERIVATIVES FOR THE TREATMENT OF HYPERHIDROSIS - Google Patents

Description

The present invention relates to bumetanide derivatives of formula (I), as well as pharmaceutical compositions containing these compounds, intended for use in the treatment or prevention of diseases/disorders involving Na ⁺ -K ⁺ -2Cl ^- cotransporters (NKCC), and preferably for use in the treatment or prevention of hyperhidrosis.

Na ⁺ -K ⁺ -Cl ^- cotransporters.

The concentration of intracellular chloride ions ([Cl ^- ]i) is mainly regulated by chloride ion cotransporters with cations (CCC) of the SLC12 family genes (Maa et al., 2011). These transporters are among the most important ion transporters in multicellular organisms and are critical for survival (Alessi et al., 2014). Na ⁺ -K ⁺ -2CF cotransporters (NKCC) transport Cl ⁻ into the cell and K+ -CT cotransporters (KCC) mediate transport out of the cell (Munoz, DeFelipe, & AlvarezLeefmans, 2007). These CCCs are intrinsic membrane proteins that use energetically favorable transmembrane gradients of potassium and sodium ions to transport Cl ^- ions across membranes. These gradients arise from active primary transport of the ouabain-sensitive Na ⁺ -K ⁺ -ATPase (adenosine triphosphatase) (Alessi et al., 2014). The transfer of Cl ^- across the membrane occurs in an electrically neutral manner and therefore without any change in net charge (Payne et al., 2003). NKCC1 and NKCC2 use the incoming sodium current to transport Cl ^- into the cell to provide a concentration above equilibrium. KCC1, KCC2, KCC3 and KCC4 use the potassium gradient to transport Cl ^- out of the cell and reduce the Cl ^- concentration to below equilibrium (Maa et al., 2011). NKCC1 is widely distributed in the body and is expressed in neurons, glial cells, choroid plexus and vascular endothelium, while NKCC2 is expressed mainly in the kidney (Maa et al., 2011). At the protein level, NKCC1 and NKCC2 share 60% homology (Markadieu, N., Delpire, E., 2014). Cl ^- efflux from and into the cell is also regulated by two serine threonine kinases, SPAK, and by OSR1, which phosphorylates critical N- and C-residues contained in NKCC and KCC. Thus, they activate NKCC and induce Cl ^- influx, however, they simultaneously inhibit KCC and Cl ^- efflux (Alessi et al., 2014). In the mammalian central nervous system (CNS), the concentration of intracellular Cl ^- ([Cl ^- ]i) is determined by the strength and direction of GABAergic neuronal (GABA - gamma-aminobutyric acid) transport (Kahle & Staley, 2008). In the adult central nervous system, [Cl ^- ]i concentrations are extremely low and activation of the GABAa receptor results in an influx of Cl ^- into the cell, resulting in hyperpolarization and inhibition (Khanna, Walcott, & Kahle, 2013). On the other hand, in the immature neonatal brain, the concentration of [Cl ^- ]i is much higher, thus activation of the GABAa receptor causes Cl ^- efflux, leading to neuronal depolarization and excitation at the synapse (Kahle & Staley, 2008).

NKCC2.

NKCC2 is expressed on the apical side of the epithelial cell membrane in the ascending limb of the loop of Henle, in which approximately 20-30% of glomerular filtered NaCl is reabsorbed (Ares G., Caceres P., Ortiz P., 2011). The main function of the ascending loop of Henle is the reabsorption of NaCl, not water. This leads to additional dilution of the resulting urine in the lumens of the tubules. NKCC2 is also expressed in the macula densa. Macula densa cells act as NaCl sensors and can regulate glomerular filtration by constricting blood vessels or dilating blood vessels of the afferent arteriole. A decrease in the concentration of NaCl in the tubules leads to dilation of the blood vessels of the afferent arteriole and the release of renin by granule cells. In contrast, an increase in the concentration of NaCl in the tubules leads to a constriction of the blood vessels of the afferent arteriole and thus a decrease in glomerular filtration. This mechanism is known as tubuloglomerular feedback, and NKCC2 has been shown to play a critical role in sensing high concentrations of NaCl (Peti-Peterdi, J., Harris, R., 2010).

NKCC1.

Unlike NKCC2, NKCC1 is widely distributed in the body and has many different functions. It is highly expressed in the spiral of the inner ear and temporal ganglion. It is believed that regulation of [Cl ^- ]i concentration is an important function of NKCC1 in mature neurons that are not located in the CNS. However, increased expression of NKCC1 is observed in the mammalian brain and these increased concentrations of [Cl ^- ]i are believed to have developmental effects (Dzhala et al., 2005). NKCC1 is also highly expressed in the salivary gland, where it is involved in fluid and mucin secretion. It is also expressed in the intestine, where it is also involved in fluid secretion. The most prominent lesions in mice lacking NKCC1 are deafness and balance disorders, resulting from the fact that NKCC1 is highly expressed in the inner ear. It plays a major role in afferent neurons. In the CNS, its amount is increased only in immature neurons and it plays an important role in neuronal maturation. Mice lacking NKCC1 also suffer from hypotension and male infertility. Hypotension occurs due to decreased vascular tone (Markadieu, N., Delpire, E., 2014).

GABA.

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the adult mammalian brain (Dzhala et al., 2005). However, GABA-mediated transmission

- 1 043772 signals also play a key role in all important stages of development, such as cell proliferation (Owens & Kriegstein, 2002). The GABAa receptor is a ligand-gated chloride channel that is opened by GABA binding to its binding site. This receptor mediates a conformational change that allows Cl ^- to passively flow either into or out of the cell, depending on the equilibrium chloride concentration (Maa et al., 2011). The channel also allows bicarbonate to pass through the channel pores, but with less efficiency than for chloride (Owens & Kriegstein, 2002). The influx of Cl ^- causes hyperpolarization, on the other hand, the outflow of Cl ^- leads to depolarization. In the mammalian brain, GABA has a depolarizing effect, which leads to neuronal excitation and can therefore cause seizures (Dzhala et al., 2005). The depolarizing effects of GABA are critical for brain development. The GABA _a receptor has been shown to influence DNA (deoxyribonucleic acid) synthesis, proliferation and neuronal migration (Owens & Kriegstein, 2002). In an immature neuron, there is a delicate balance between inhibition and excitation. This balance plays an important role in the early stages of brain development. Excessive suppression results in impaired neuronal growth and synaptic maturation, while excessive excitation can cause seizures and even excitotoxic death (Maa et al., 2011).

Alarm disorders.

Anxiety disorders affect approximately 18% of adults and are the most common class of mental disorders (Le'pine, J., 2002). Anxiety disorders are currently treated with psychotherapy and medications such as serotonin reuptake inhibitors (SSRIs), antidepressants, monoamine oxidase inhibitors, benzodiazepines, and anticonvulsants. However, 20-40% of patients do not respond to any of these drugs listed above (Denys D., de Geus F. 2005). Another disadvantage of these drugs is the severe side effects that these drugs can cause in the central nervous system. Long-term use of SSRIs can cause sexual dysfunction and weight gain (Hirschfeld, R., 2003). Because a significant proportion of patients suffering from anxiety disorders do not respond to treatment, and because of the severe side effects that can be caused by currently used medications, new medications are urgently needed. In rat models of conditioned anxiety, bumetanide has been shown to have a calming effect. In the contextual fear model, rats treated with bumetanide had a significantly shorter percentage of torpor than rats treated with vehicle alone. Bumetanide also had significant effects in a fear-intensified startle model (Krystal AD, Sutherl and J, Hochman DW 2012).

Autism spectrum disorder.

Autism spectrum disorder (ASD) is a range of complex neurodevelopmental disorders that are characterized by repetitive and characteristic patterns of behavior and difficulties with social interaction and communication. ASD consists of a number of different disorders, the most severe form of which is autism. Other forms include Asperger's syndrome, childhood disintegrative disorder, and profound developmental disorders as part of ASD. One in 68 children is affected by ASD, and boys are more likely to develop ASD than girls. The disorder occurs in all racial and ethnic groups and at all socioeconomic levels (NINDS Autism Spectrum Disorder Fact Sheet 2016). Parturition in rodents plays an extremely important role, providing neuroprotective and analgesic effects on newborns. These effects are caused by an oxytocin-mediated decrease in [Cl']j concentration. In two rodent models of autism (VPA (valproic acid)-treated rats and fragile X (FRX) mice), this sequence is disrupted in CA3 pyramidal neurons. It can be restored by administration of bumetanide, which restores the sequence of GABA effects and the offspring of these rats do not exhibit an autism phenotype (Tyzio R. et al. 2014). Bumetanide was also used in an open-label study of 7 patients diagnosed with autism. Patients were treated with bumetanide for 10 months, and bumetanide caused improvement in emotion recognition and improved activation of brain regions involved in social and emotional perception (Hadjikhani N., et al. 2015). Since there is no cure for ASD and only very limited treatment options available, improved treatments are urgently needed.

Hyperhidrosis.

Hyperhidrosis is a medical condition that causes excessive sweating. It is classified as primary or secondary hyperhidrosis. Primary hyperhidrosis is idiopathic and is caused by excessive activity of the sympathetic nerves. It affects only limited areas of the body, mainly the armpits, palms, soles or head. While most of the body remains dry, sweat drips from one or two areas of the body. Secondary hyperhidrosis occurs due to side effects of certain medications or an underlying medical condition such as diabetes or gout (Website of American Academy of Dermatology (2016)). Hyperhidrosis can significantly affect daily life, e.g.

- 2 043772 cause restrictions in work activity, social interactions, physical activities, and on mental and emotional health. Available treatments include topical aluminum chloride hexahydrate, oral anticholinergics, botulinum toxin by injection, or surgery. All of these products have different effectiveness, side effects, cost and ease of use. In the United States, 15.3 million people have hyperhidrosis, representing 4.8% of the population. Only 51% of sufferers discuss their condition with medical professionals. 75% of people surveyed report that their condition has some adverse impact on their social life, well-being and emotional or mental health. A significant proportion of people report that excessive sweating is embarrassing and causes them anxiety (Doolittle J., et al. 2016). Considering the adverse effects reported by patients, it is clear that a better understanding and treatment of hyperhidrosis is needed. By blocking NKCC in the sweat glands, excessive sweating can be treated. Bumetanide has been shown to be partially effective for the treatment of hyperhidrosis (Louie, et al., 2016).

Spinal cord injury.

Each year, between 250,000 and 500,000 people worldwide suffer from spinal cord injury (SCI). In 90% of cases, SCI occurs due to trauma, such as traffic accidents, falls or beatings. People with SCI have a 2- to 5-fold increased risk of premature death and poorer chances of enrolling in school and participating in the economy. Symptoms of SCI depend on the severity of the injury and its location, but most patients experience chronic pain (WHO (2013) Spinal Cord Injury Fact Sheet No. 384). Damage and harm can lead to a long-lasting increase in the excitability of spinal cord neurons, which can cause chronic pain. Spinal cord injury (SCI) can result in a change in the mechanism of GABA channel activation from hyperpolarization to depolarization. The effects of SCI have been associated with downregulation of KCC2 resulting in high concentrations of [Cl']i, which leads to abnormalities in the activation of the GABAergic system. It appears that neuronal damage causes the spinal system to enter an early developmental state where GABA has a depolarizing effect. This depolarizing effect can cause the development of chronic pain and spasticity. Bumetanide can restore the normal function of the GABAergic system by blocking NKCC and restoring normal [Cl'] concentration (Huang Y., et al. 2016). Improved treatments for patients suffering from chronic pain due to SCI are urgently needed.

Recovery after an impact.

Stroke is the fifth leading cause of death in the United States and stroke affects 795,000 people in the United States each year. A stroke is caused by a blockage or damage to a blood vessel supplying blood to the brain. Stroke is also a leading cause of disability, reducing mobility in more than half of stroke survivors over the age of 65 (Centers for Disease Control and Prevention, (2016) Stroke Fact Sheet). Ischemic stroke promotes neurogenesis in adults, but it appears that these new neurons have a rather limited ability to survive over the long term. Ischemic stroke can cause an imbalance in the expression of NKCC and KCC, leading to an increase in [Cl-] concentration and, ultimately, a change in the mechanism of activation of the GABAergic system from hyperpolarization to depolarization. Chronic follow-up treatment with bumetanide may improve the trafficking of neuroblasts to the injured striatum and may also improve the survival of these newly generated neurons. In addition, a behavioral study showed an improvement in the narrower path walking test. Therefore, bumetanide and its derivatives can create a favorable microenvironment for newly formed neurons, which promotes their formation and survival (Xu W., et al. 2016). Thus, derivatives can be used to improve recovery and reduce damage after ischemic stroke, as well as in other diseases (for example, Alzheimer's disease) to improve memory.

Schizophrenia.

Schizophrenia is characterized by distortions of emotions, sensations, thinking, behavior, self-perception and speech. Many patients hear voices or suffer from hallucinations. The condition affects more than 21 million people worldwide and is associated with significant disability. Patients have a 2-2.5 times increased risk of premature death and discrimination and stigma are very common (WHO (2016) Schizophrenia Fact Sheet). The neurophysiological basis of schizophrenia remains poorly understood, but many studies have shown that dysregulation of cortical GABA transmission may be a cause of schizophrenia. A recent study in human schizophrenia identified a gain-of-function missense variant in SLC12A2 encoding the bumetanide-sensitive transporter NKCC1. Results from functional studies indicate that this NKCC1 variant is a gain-of-function variant that increases Cl-dependent activity even under conditions where the transporter is normally silent (hypotonic) (Merner, N.D., et al.

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2016). Another study found the KCC to have lost function in human schizophrenia (Merner, N.D., et al. 2015). In both cases (gained NKCC function, lost KCC function) the concentration of [Cl'] increases, which can lead to disruption of neurotransmission

GABA. Blocking NKCC may normalize [Cl-]i concentrations and change the GABA signaling mechanism back to hyperpolarization.

Parasites.

A recent study showed that furosemide (another NKCC-blocking loop diuretic) inhibits rAceMIF tautomerase activity at concentrations in the submicromolar range and may have beneficial effects in various studies (Cho Y., et al. 2011). Since bumetanide and its derivatives are also NKCC inhibitors, it is believed that these compounds will have the same effect as furosemide, or even greater effect.

Soil-transmitted helminthiasis.

More than 1.5 billion people are infected with soil-transmitted helminthiases. This represents 24% of the world's population. These helminth infections are caused by three types of parasitic worms: hookworms, nematodes and trichocephalus. Adult worms live in the intestines of infected people, where they produce thousands of eggs per day. These eggs, which are passed into the feces of infected people, cause contamination, for example by attaching to vegetables that are not cooked or peeled. Other routes of infection include drinking from a contaminated water source, or children who play in contaminated soil may become infected. In addition, hookworms lay eggs in the soil, which hatch into larvae that can burrow through the skin, and people can become infected by walking barefoot on contaminated soil. Symptoms and incidence vary greatly depending on the number of worms people are infected with. Mild infestations usually cause no symptoms, while more severe infestations can cause diarrhea, abdominal pain, general weakness, impaired cognitive and physical development, and blood loss, which can lead to anemia (WHO (2016) Soil-transmitted helminth infections Fact Sheet). A recent study found that furosemide, another arylsulfonamide derivative also used as a strong loop diuretic that blocks NKCC, has anthelmintic activity. Human MIF (macrophage migration inhibitory factor) is a proinflammatory protein with various functions. Furosemide targets AceMIF, which is similar to human MIF, and is believed to help the worm evade the host immune response (Cho Y., et al. 2011). Bumetanide derivatives may be effective inhibitors of hookworm MIF and may have superior worm killing properties. Lipophilic derivatives with improved pharmacokinetic characteristics are particularly promising derivatives for providing better treatment of helminth infections.

Other parasites.

The new compounds may also be useful for treating infections with other parasitic worms such as tapeworms, trichocephalus, guinea worms, pinworms, Toxocara, Strongyloides stercoralis and Ascaris lumbricoides. In addition to treating parasitic worm infections, they can be used to treat diseases caused by flukes, such as schistosomiasis, gnathostomiasis, paragonimiasis, fascioliasis or Swimmers' syndrome. In addition, the compounds can be used to treat diseases caused by protozoa, such as malaria, amoebiasis, giardiasis, sleeping sickness, toxoplasmosis, acanthamoeba keratitis, leishmaniasis, babesiosis, granulomatous amoebic encephalitis, cryptosporidiosis, cyclosporiasis or primary amoebic meningoencephalitis. The compounds can also be used to treat infections by ectoparasites such as Sarcoptes scabiei, Pediculus humanus capitis, Phthirus pubis, dermatobiasis, Tunga penetrans infection, Ixodoidea and others. The compounds can also be used to control plant pests such as nematodes, arthropods, ectoparasites and molluscs.

Edema.

Edema is the result of an imbalance in capillary and intestinal volumes. The kidneys regulate extracellular volume by regulating the excretion of sodium and water. Edema may be caused by venous occlusion, increased plasma volume, and increased capillary permeability. Treatment of edema includes limiting sodium intake, using a diuretic, and treating the underlying disorder. The swelling may be localized only to a limb, or it may be generalized and massive throughout the body. Because bumetanide is a loop diuretic and blocks the NKCC, it prevents sodium reuptake in the loop of Henle and results in the release of sodium and water. Bumetanide and its derivatives can be used to treat edema (O'Brien, O.G., et al. 2005).

Brain swelling.

Cerebral edema (swelling of the brain) causes intracranial hypertension (ICH), which has severe consequences when treating patients in clinical settings. Effective treatment of edema can significantly reduce mortality in a range of neurological conditions. Currently, drug treatment is the cornerstone of the treatment of cerebral edema. Osmotherapy was the basis of drug treatment. Mannitol and hypertonic saline (HS) are the most commonly used osmotic agents. Na/H exchanger inhibitors, NKCC, reduce the formation of cerebral edema by inhibiting the transfer of excess ion and water from the blood into the brain tissue (Deng Y., et al. 2016). Thus, NKCC inhibitors can be used to treat cerebral edema.

Down syndrome.

Down syndrome is the most common genetic cause of intellectual disability. Adults and children who have Down syndrome have lower than normal intelligence scores, learning disabilities, and memory impairment. This is caused by the presence of extra genetic material on chromosome 21. This may result from a process called nondisjunction, where the genetic material fails to separate, resulting in the formation of an extra chromosome (trisomy 21). The worldwide incidence is approximately 1 in 1000 births, meaning that approximately 3000 to 5000 children are born each year with this disorder (WHO (2017), Genes and chromosomal diseases). Mouse models have shown that altered GABAergic transmission is a significant contributor to learning and memory impairment. A recent publication showed that bumetanide can restore normal GABAergic transmission and improve cognitive impairment (Deidda, G., et al. 2015). The results of this study suggest that the use of bumetanide and its derivatives is a promising approach for the treatment of dementia in patients suffering from Down syndrome.

Glaucoma.

Glaucoma is the second leading cause of blindness worldwide as the average age of the population increases. Glaucoma is a term that describes a group of different diseases: In primary open-angle glaucoma, there is no outflow of intraocular fluid due to the fact that the channels are blocked. This leads to increased pressure in the eye and causes blindness. Because there are only a few symptoms, patients do not initially notice the slow loss of vision. The cause of closed-angle glaucoma is similar to that of open-angle glaucoma, but it occurs much more quickly and is accompanied by symptoms such as headache, blurred vision and eye pain. Due to the aging of the world population, the need for additional treatments increases every year (WHO (2004) Glaucoma is the second leading cause of blindness globally).

Bumetanide and its derivatives.

Bumetanide, i.e. 3-(Butylamino)-4-phenoxy-5-sulfamoylbenzoic acid, is a loop diuretic (strong diuretic) that blocks both NKCC1 and NKCC2, and which is approved by the FDA (Food and Drug Administration) and EMA ( European Medicines Agency) for the treatment of edema, preferably edema associated with congestive heart failure, liver disease and kidney disease, including nephrotic syndrome; bumetanide and/or and some of its derivatives have also been proposed for various other therapeutic uses (Lykke K et al., Br J Pharmacol. 2015, 172(18): 4469-80; Tollner K et al., Eur J Pharmacol. 2015 , 746:78-88; Tollner K et al., Ann Neurol. 2014, 75(4):550-62; Erker T et al., Epilepsia. 2016, 57(5):698-705; Louie JC et al. ., Physiol Rep. 2016, 4(22). pii: e13024). However, due to the presence of an extremely polar carboxy group, bumetanide has difficulty permeating the cell membrane, which significantly limits the therapeutic effectiveness of this drug. Thus, due to the low therapeutic activity and undesirably strong diuretic effect of bumetanide, there is a pressing and unmet need for new and/or improved therapeutic agents that can be used to treat disorders in which NKCC is involved and that do not have the disadvantages of bumetanide.

Several other (hetero)arylsulfonamides, benzoic acids, thiophenes, pyrazolopyrimidines or other derivatives are described, for example, in Feit PW et al., J Med Chem. 1976, 19(3):402-6; Feit PW et al., J Med Chem. 1977, 20(12): 1687-91; Consiglio G et al., ARKIVOC. 2002, 11:104-17; Hauck S et al., Bioorg Med Chem. 2016, 24(22):5717-29; Moni L et al., Synthesis. 2016, 48(23):4050-9; Moni L et al., Molecules. 2016, 21(9): 1153/1-1153/9; Palfrey HC et al., American Journal of Physiology. 1984, 246(3, Pt. 1):C242-C246; Englert H et al., Archiv der Pharmazie (Weinheim, Germany). 1983, 316(5):460-3; Nielsen OT et al., Am Chem Soc Symp Ser, Diuretic Agents. 1978, 83:12-23; Petzinger E et al., Am J Physiol. 1993, 265(5 Pt 1):G942-54; AU-A-521892; CN-A-104926804, DE-A-1966878; DE-A-2654795; GB-A-1523632; US 3985777; US 4010273; US 2014/066504; WO 2008/052190; WO 2010/083442; WO 2010/085352; WO 2012/018635; WO 2013/087090; WO 2014/157635; WO 2014/196793 and WO 2014/039454.

It is therefore an object of the present invention to provide new and/or improved active agents for the treatment of hyperhidrosis or other diseases/disorders in which NKCC, preferably NKCC1, are involved.

According to the present invention, it has been found that the bumetanide derivatives of formula (I),

- 5 043772 described and defined in the present invention can be used as Na ⁺ -K ⁺ -2Cl ^- cotransporter (NKCC) inhibitors, preferably as NKCC1 inhibitors. Moreover, according to the invention, it has been found that the bumetanide derivatives of formula (I) have significantly improved characteristics, in particular penetration, diuresis and metabolic stability. Thus, the compounds of the present invention have increased lipophilicity and improved skin penetration, significantly reduced diuretic activity, improved metabolic stability and overall improved therapeutic efficacy. This makes the compounds of the present invention extremely useful for therapeutic use, including use for the treatment or prevention of diseases or disorders in which NKCCs, preferably NKCC1, are involved. Therefore, the compounds of formula (I) proposed in the present invention can be successfully used for the treatment or prevention of hyperhidrosis (Louie JC et al., Physiol Rep. 2016, 4(22). pii: e13024; Bovell DL et al., Exp Dermatol 2011, 20(12): 1017-20; Cui CY et al., J Dermatol Sci. 2016, 81(2): 129-31) or other diseases/disorders in which NKCC are involved, including any diseases/disorders described above in the present invention in the introductory part of the present description. The present invention also relates to compounds of formula (I) which are selective inhibitors of NKCC1, in particular to compounds which inhibit NKCC1 more effectively than NKCC2, making these compounds particularly suitable for the treatment or prevention of diseases/disorders in which NKCC1 is involved , as well as for therapeutic uses in which a strong diuretic effect is undesirable, including, in particular, use for the treatment or prevention of hyperhidrosis. In addition, some of the compounds of the present invention have favorable solubility in water. The present invention also relates to compounds of formula (I) which contain an ester group and which can be hydrolyzed by esterases in the patient's skin to form more polar therapeutically active compounds which, due to their increased polarity, will not be easily transferred back to the surface of the skin and, thus, will accumulate at the desired target site (metabolic uptake), providing a more pronounced and/or longer-lasting therapeutic effect. All these characteristics make the compounds of the present invention extremely suitable for use as drugs for inhibiting NKCC, preferably NKCC1, and thus for therapeutically affecting diseases/disorders in which NKCC are involved, and preferably for treatment or prevention of hyperhidrosis.

Accordingly, the present invention relates to a compound of the following formula (I) or a pharmaceutically acceptable salt or solvate thereof,

X

II I

for use in the treatment or prevention of hyperhidrosis.

R ^{2 r} JA< ^{r3 R} S__S ^xz JT li j

In formula (I), the ring fragment 4L .lX, is or .

R ^x denotes R ¹ or R ³ .

R ¹ is selected from the group consisting of -COOH, -COO-(C1-C15-alkyl), -COO-(C0-C15alkylene)carbocyclyl, -COO-(C0-C15-alkylene)heterocyclyl, -O-CHO, -O -CO-(C1-C15-alkyl), -O-CO-(C0C15-alkylene)carbocyclyl, -O-CO-(C0-C15-alkylene)heterocyclyl, -CHO, -CO-(C1-C15-alkyl) , -CO-(C0-C15-alkylene)carbocyclyl, -CO-(C0-C15-alkylene)heterocyclyl, -CO-NH2, -CO-N(R ¹¹ )-(C1-C ₁₅ -alkyl), -CON(R ¹¹ )-(C0-C15-alkylene)carbocyclyl, -CO-N(R ¹¹ )-(C0-C ₁₅ -alkylene)heterocyclyl, -N(R11)-CHO, -N(R11)CO-(C ₁ - C ₁₅ -alkyl), -N(R ¹¹ )-CO-(C0-C15-αalkylene)carbocyclyl, -N(R ¹¹ )-CO-(C0-C ₁₅ -alkylene)heterocyclyl, C1-C ₁₅ -alkyl, -(C ₀ -C ₁₅ -alkylene)carbocyclyl, -(C ₀ -C ₁₅ -alkylene)heterocyclyl, C ₂ -C ₁₅ -alkenyl, -(C ₂ -C ₁₅ alkenylene)carbocyclyl, -(C ₂ -C ₁₅ -alkenylene)heterocyclyl, C ₂ -C ₁₅ -alkynyl, -(C ₂ -C ₁₅ alkynylene)carbocyclyl and -(C ₂ -C ₁₅ -alkynylene)heterocyclyl, where the alkyl fragment contained in any of the above groups is an alkylene fragment , contained in any of the above groups, an alkenylene fragment contained in any of the above groups, an alkynylene fragment contained in any of the above groups, the specified C ₁ -C ₁₅ -alkyl, the specified C ₂ -C ₁₅ alkenyl and the specified C _{The 2} -C ₁₅ -alkynyl is each optionally substituted with one or more groups independently selected from halogen, -CF ₃ , -CN, -NO2, -N(R ¹¹ )(R ¹¹ ), -O(R11), -S(R11 ) and -SO ₃ H, where one or more -CH2- units included in an alkyl fragment contained in any of the above groups, in an alkylene fragment contained in any of the above groups, in an alkenylene fragment contained in any of the above above groups, into an alkynylene moiety contained in any of

- 6 043772 of the above groups, to the specified C1-C ₁₅ -alkyl, to the specified C ₂ -C ₁₅ -alkenyl or to the specified C ₂ -C ₁₅ alkynyl, each optionally replaced by a group independently selected from -O-, -CO- , -СОО-, -О-СО-, -NCR ¹¹ )-, -N(R ¹¹ )-CO-, -CO-N(R ⁿ )-, -S-, -SO-, -SO2-, - SO2-N(R ¹¹ )- and -N(R ¹¹ )-SO2-, and wherein additionally a carbocyclyl moiety contained in any of the above groups, and a heterocyclyl moiety contained in any of the above groups, each optionally substituted by one or more groups independently selected from C1-C6 alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogen, 01-C6-haloalkyl, -CN, -NO ₂ , -N(R ¹¹ )(R ¹¹ ), -O(R), -S(R ¹¹ ), -SO ₃ H, carbocyclyl and heterocyclyl.

Each R ¹¹ is independently hydrogen or C1-C ₆ -alkyl.

R ² is selected from the group consisting of hydrogen, C1-C ₆ -alkyl, C ₂ -Cb-alkenyl, C ₂ -Cb-alkynyl, -OH, -O(C1-C ₆ -alkyl), -O(C ₁ - C ₆ -alkylene)-OH, -O(C ₁ -Cb-alkylene)-O(C ₁ -Cb-alkyl), -SH, -S(C ₁ -C6-alkyl), -NH2, -NH(C ₁ -C6-alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, C1-C ₆ -haloalkyl, -O-(C ₁ -C ₆ -haloalkyl), -CN, -NO2, -CHO, -CO-(C1-Cb-alkyl), -COOH, -COO-(C1-Cb-alkyl), -O-CO-(C1-Cb-alkyl), -CO- NH2, -CONH(C ₁ -C ₆ -alkyl), -CO-N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), -NH-CO-(C ₁ -C ₆ -alkyl ), -N(C1-C ₆ -alkyl)-CO-(C ₁ -C ₆ alkyl), -SO2-NH2, -SO ₂ -NH(C ₁ -C ₆ -alkyl), -SO ₂ -N( C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), -NH-SO ₂ -(C ₁ -C ₆ -alkyl) and -N(C ₁ -C ₆ -alkyl)-SO ₂ -( C ₁ -C ₆ -alkyl).

R ³ is selected from the group consisting of -SO2-NH2, -SO ₂ -NH(C ₁ -C ₆ -alkyl), -SO ₂ -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), -SO ₂ -N=(C ₁ -C ₆ -alkylidene) and -SO ₂ -halogen, where the alkyl moiety contained in said -SO ₂ -NH(C ₁ -C ₆ -alkyl) is one or both of the alkyl moieties, contained in said -SO ₂ -N(C ₁ -C ₆ alkyl)(C 1 -C ₆ -alkyl), and the alkylidene moiety contained in said -SO ₂ -N=(C ₁ -C ₆ alkylidene), each optionally substituted one or more groups independently selected from halogen, -CF ₃ , -CN, -NO ₂ , -NH ₂ , -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), -OH, -O(C1-C ₆ -alkyl), -SH and -S(C ₁ -C ₆ -alkyl).

R ⁴ is an R ^4a group and R ⁵ is an R ^5a group, or R ⁴ and R ⁵ are linked together to form a -R ^5b - group.

R ^4a is selected from -OR ⁴¹ , -SR ⁴¹ , -NH-R ⁴¹ , -N(C ₁ -C ₆ -alkyl)-R ⁴¹ , halogen, hydrogen, carbocyclyl and heterocyclyl, wherein said carbocyclyl and said heterocyclyl are each optionally substituted one or more R ⁴² groups.

R ⁴¹ is selected from the group consisting of -(C0-C4-alkylene)carbocyclyl, -(C0-C4-alkylene)heterocyclyl, C1-C6-alkyl, C2-C6-alkenyl and C2-C6-alkynyl, where the carbocyclyl moiety contained in said -(C0-C4-alkylene)carbocyclyl, and a heterocyclyl moiety contained in said -(C0-C4-alkylene)heterocyclyl, each optionally substituted with one or more R ⁴² groups, and wherein said C1-C6 alkyl, said C2-C6 -alkenyl, said C2-C6-alkynyl, an alkylene moiety contained in said -(C0-C4-alkylene)carbocyclyl, and an alkylene moiety contained in said -(C0-C4-alkylene)heterocyclyl, each optionally substituted with one or more groups R43 _.

Each R ⁴² is independently selected from the group consisting of C1- _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, -OH, -O(C1- _C6 alkyl), -O( _C1 -C ₆ -alkylene)-OH, -O(C ₁ -C ₆ -alkylene)-O(C ₁ -C ₆ -alkyl), -SH, -S(C1-C ₆ alkyl), -NH ₂ , - NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, C1-C ₆ -haloalkyl, -O-(C ₁ -C ₆ haloalkyl), -CN, -NO ₂ , -CHO, -CO-(C ₁ -C ₆ -alkyl), -COOH, -COO-(C ₁ -C ₆ -alkyl), -O-CO-(C ₁ -C ₆ -alkyl), -CO-NH2, -CO-NH(C ₁ -C ₆ -alkyl), -CO-N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), - NH-CO-(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ alkyl)-CO-(C ₁ -C ₆ -alkyl), -SO2-NH2, -SO ₂ -NH(C ₁ -C ₆ -alkyl), -SO ₂ -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), -NH-SO2(C1-C ₆ -alkyl) and -N(C ₁ - C ₆ -alkyl)-SO ₂ -(C ₁ -C ₆ -alkyl).

Each R ⁴³ is independently selected from the group consisting of -OH, -O(C ₁ -C ₆ alkyl), -SH, -S(C1-C ₆ alkyl), -NH ₂ , -NH(C ₁ -C ₆ - alkyl), -N(c ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, -CF ₃ , -CN, -NO ₂ , -CHO, -CO-(C1C ₆ -alkyl), -COOH, -COO-(C ₁ -C ₆ -alkyl), -O-CO-(C ₁ -C ₆ -alkyl), -CO-NH2, -CO-NH(C ₁ -C ₆ -alkyl), -CO-N(C ₁ C ₆ -alkyl)(C1-C ₆ -alkyl), -NH-CO-(C ₁ -C ₆ -alkyl) and -N(C ₁ -C ₆ -alkyl)-CO- (C ₁ -C ₆ -alkyl).

R ^5a is selected from -NH ₂ , -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), -NO2 and hydrogen, where the alkyl fragment, contained in said -NH(C ₁ -C ₆ -alkyl), and one or both of the alkyl moieties contained in said -M(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), each optionally substituted by one or more groups independently selected from halogen, -CF ₃ , -CN, -NO ₂ , -NH ₂ , -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C1-C ₆ -alkyl), -OH, -O(C1-C ₆ -alkyl), -SH, -S(C ₁ -C ₆ -alkyl), carbocyclyl and heterocyclyl, wherein said carbocyclyl and said heterocyclyl are each optionally substituted by one or more R ⁵¹ groups.

Each R ⁵¹ is independently selected from the group consisting of C1- _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, -OH, -O(C1- _C6 alkyl), -O( _C1 -C ₆ -alkylene)-OH, -O(C ₁ -C ₆ -alkylene)-O(C ₁ -C ₆ -alkyl), -SH, -S(C1-C ₆ alkyl), -NH ₂ , - NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, C1-C ₆ -haloalkyl, -O-(C ₁ -C ₆ haloalkyl), -CN, -NO ₂ , -CHO, -CO-(C ₁ -C ₆ -alkyl), -COOH, -COO-(C ₁ -C ₆ -alkyl), -O-CO-(C ₁ -C ₆ -alkyl), -CO-NH2, -CO-NH(C ₁ -C ₆ -alkyl), -CO-N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), - NH-CO-(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ alkyl)-CO-(C ₁ -C ₆ -alkyl), -SO2-NH2, -SO ₂ -NH(C ₁ -C6-alkyl), -SO ₂ -N(C ₁ -C6-alkyl)(C ₁ -C6-alkyl), -NH-SO2(C1-C ₆ -alkyl) and -N(C ₁ -C6-alkyl )-SO ₂ -(C ₁ -C6-alkyl).

R ^5b selected from -R ^5b1 -R ^5b2 -R ^5b1 -, -N=C(R ⁵³ )-R ^5b3 -R ^5b1 -, -R ^5b1 -R ^5b3 -C(R ⁵³ )=N- and -N= C(R ⁵³ )-R ^5b4 -C(R ⁵³ )=N-.

Each R ^5b1 is independently selected from -N(R ⁵² )-, -O- and -S-.

- 7 043772

R ^5b2 selected from -C(R ⁵³ )(R ⁵³ )-, -C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R 53 )-, -C(R ⁵³ )=C(R ^{53 )} -, -C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )=C(R ⁵³ )- and

-C(R ⁵³ )=C(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-.

R ^5b3 is selected from a covalent bond, -C(R ⁵³ )(R ⁵³ )-, -C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )- and -C(R ⁵³ )=C( R ⁵³ )-.

R ^5b4 is selected from a covalent bond and -C(R ⁵³ )(R ⁵³ )-.

Each R ⁵² is independently selected from the group consisting of hydrogen, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C _{2 -C 6} -kynyl, -(C ₀ -C ₄ -alkylene)aryl and -(Co- C ₄ -alkylene)heteroaryl.

Each R ⁵³ is independently selected from the group consisting of hydrogen, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C _{2 -C 6} -kynyl, -OH, -O(C ₁ -C ₆ -alkyl), - SH, -S(C ₁ -C ₆ -alkyl), -NH ₂ , -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, Cl-C6-haloalkyl, -O-(C ₁ -C ₆ -haloalkyl), -CN, -NO ₂ , -CHO, -CO-(Cl-C6-alkyl), -COOH, -COO-(C1 -C6-alkyl), -O-CO-(C1-C6-alkyl), -CO-NH2, -CO-NH(C1-C6-alkyl), -CO-N(Ci-C ₆ alkyl)(C ₁ -C ₆ -alkyl), -NH-CO-(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)-CO-(C ₁ -C ₆ -alkyl), -SO ₂ - NH ₂ , -SO ₂ -NH(C ₁ C ₆ -alkyl), -SO ₂ -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), -NH-SO ₂ -(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)-SO ₂ -(C ₁ -C ₆ -alkyl), -(C ₀ -C ₄ -alkylene)aryl and -(C ₀ -C ₄ -alkylene)heteroaryl, and any two R ⁵³ groups that are attached to the same carbon atom can also together form an =O group, and any two R ⁵³ groups that are attached to adjacent carbon atoms connected by a double bond can also can be linked together to form the group -C(R ⁵⁴ )=C(R ⁵⁴ )-C(R ⁵⁴ )=C(R ⁵⁴ )-.

Each R ⁵⁴ is independently selected from the group consisting of hydrogen, C1- _C6 alkyl, _C2 - _C6 alkenyl, _{C2C6 alkynyl} , -OH, -O( _C1 - _C6 alkyl), -SH , -S(C ₁ -C ₆ -alkyl), -NH ₂ , -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen , C1-C ₆ -haloalkyl, -O-(C ₁ -C ₆ -haloalkyl), -CN, -NO ₂ , -CHO, -CO-(C ₁ -C ₆ -alkyl), -COOH, -COO- (C ₁ -C ₆ -alkyl), -O-CO-(C ₁ -C ₆ -alkyl), -CO-NH2, -CO-NH(C ₁ -C ₆ -alkyl), -CO-N(C ₁ -C ₆ alkyl)(C1-C ₆ -alkyl), -NH-CO-(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)-CO-(C ₁ -C ₆ -alkyl), -SO ₂ -NH ₂ , -SO ₂ -NH(C1C ₆ -alkyl), -SO ₂ -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), -NH- SO ₂ -(C ₁ -C ₆ -alkyl) and -N(C ₁ -C ₆ -alkyl)-SO ₂ -(C ₁ -C ₆ -alkyl).

R ⁶ is selected from the group consisting of hydrogen, C1- _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, -OH, -O( _C1 - _C6 alkyl), -O( C ₁ -C ₆ -alkylene) -OH, -O(C ₁ -C ₆ -alkylene) -O(C ₁ -C ₆ -alkyl), -SH, -S(C ₁ -C ₆ -alkyl), - NH ₂ , -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, C1-C ₆ -haloalkyl, -O-(C ₁ -C ₆ -haloalkyl), -CN, -NO ₂ , -CHO, -CO-(C ₁ -C ₆ -alkyl), -COOH, -COO-(C ₁ -C ₆ -alkyl), -O- CO-(C ₁ -C ₆ -alkyl), -CO-NH2, -CONH(C ₁ -C ₆ -alkyl), -CO-N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl ), -NH-CO-(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)-CO-(C ₁ -C ₆ -alkyl), -SO2-NH2, -SO ₂ -NH (C ₁ -C ₆ -alkyl), -SO ₂ -N(c ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), -NH-SO ₂ -(C ₁ -C ₆ -alkyl) and -N(C ₁ -C ₆ -alkyl)-SO ₂ -(C ₁ -C ₆ -alkyl).

Alternatively, R ¹ and R ⁶ are linked together to form the group -R ¹⁶ -, where:

R ¹⁶ denotes the group -C(K ⁶ 'U/' ⁶ 'gC(K ⁶ 'nA ⁶ 'gC(K ⁶ 'nA ⁶ 'gC(1G^ where one or two units

-C(R ¹⁶¹ )(R ¹⁶¹ )- contained in the said group are each replaced by -R ¹⁶³ -;

each R ¹⁶¹ is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2C6 alkynyl, halogen, C1-C6 haloalkyl, -(C0-C6 alkylene)-CF3, -(C0- C6-alkylene)-CN, -(C0-C6-alkylene)NO2, -(Co-C6-alkylene)-N(R ¹⁶² )(R ¹⁶² ), -(Co-C6-alkylene)-O(R ¹⁶² ) , -(Co-C6-alkylene)-S(R ¹⁶² ), -(C0-C6-alkylene)SO3H, -( _C0 - _C6 -alkylene)carbocyclyl and -( _C0 - _C6 -alkylene)heterocyclyl; each R ¹⁶² independently represents hydrogen or C1- _C6 alkyl; and each R ¹⁶³ is independently selected from -N(R ¹⁶¹ )-, -O- and -S-. In accordance with R ² _γ

J| This invention is worthwhile if in formula (I) the ring moiety 4L is . R ² is hydrogen, R ³ is -SO2-NH2, R ⁴ is -O-phenyl, R ⁵ is -NH-CH2CH ₂ CH ₂ CH ₃ and R ⁶ is hydrogen, then R ¹ is different from -COOH.

The present invention also relates to a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in combination with a pharmaceutically acceptable excipient for use in the treatment or prevention of hyperhidrosis.

Furthermore, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for the preparation of a medicament for the treatment or prevention of hyperhidrosis.

The present invention also relates to a method of treating or preventing hyperhidrosis, which includes administering to a subject in need thereof (preferably a human) a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition containing any of the above substances in combination with a pharmaceutical acceptable inert filler. It should be understood that in accordance with this method, the compound of formula (I) or a pharmaceutically acceptable salt or solvate or pharmaceutical composition thereof must be administered in a therapeutically effective amount.

Furthermore, the present invention relates to the use of a compound of formula (I) or a pharmaceutically/physiologically acceptable salt or solvate thereof for suppressing or reducing non-pathological sweating in a subject (eg, a human). Accordingly, the present invention relates to the non-therapeutic use of a compound of formula (I) or a pharmaceutically/physiologically acceptable salt or solvate thereof to suppress or reduce sweating in a subject (eg, a human). The present invention also relates to a method (preferably

- 8 043772 non-therapeutic method) of suppressing or reducing sweating in a subject (eg, a human), which includes administering to the subject a compound of formula (I) or a pharmaceutically/physiologically acceptable salt thereof. Preferably, the subject in whom sweating is to be suppressed or reduced is a healthy subject, more preferably a subject who does not suffer from hyperhidrosis. The present invention preferably relates to suppressing or reducing sweating in a subject where sweating is caused by or occurs during physical activity or exercise (eg, sports).

For the treatment or prevention of hyperhidrosis, as well as for the suppression or reduction of non-pathological sweating, it is preferable that the compound of formula (I) or a pharmaceutically/physiologically acceptable salt or solvate thereof is administered topically, preferably applied to such areas of the skin that are susceptible (or significantly susceptible) to sweating , and/or on areas of the skin where it is necessary to reduce sweating. When administered topically, a compound of formula (I) or a pharmaceutically/physiologically acceptable salt or solvate thereof may be provided in pure form or, for example, in the form of a composition (for example, in the form of a pharmaceutical composition containing said compound and a pharmaceutically acceptable excipient intended for use for the treatment or prevention of hyperhidrosis, or in the form of a cosmetic composition containing the specified compound and a cosmetically/physiologically acceptable excipient intended to suppress or reduce non-pathological sweating). The compound of formula (I) or a pharmaceutically/physiologically acceptable salt or solvate thereof may also be provided in the form of a wipe (or cloth) containing said compound, in the form of an insole (or shoe insert or arch support; including, but not limited to, an orthopedic insole , orthopedic shoe insert or orthopedic instep support) containing the specified compound, or in the form of an article of clothing (or part of clothing) containing the specified compound. Each of the above articles (ie, a napkin, a cloth napkin, an insole, a shoe insert, an instep support, a garment or a piece of clothing) can, for example, be treated, coated or impregnated with the specified compound. Preferably, at least one surface (preferably at least one body-facing surface) of the above articles is treated, coated or impregnated (or has been treated, coated or impregnated) with a compound of formula (I) or a pharmaceutically/physiologically acceptable salt thereof, or solvate. The present invention also relates to such articles containing the compound of the present invention. Thus, the scope of the present invention includes, in particular, an article containing a compound of formula (I) or a pharmaceutically/physiologically acceptable salt or solvate thereof, where the article is (i) a napkin (or cloth), (ii) an insole (or a shoe insert or arch support; for example, an orthotic insole, an orthotic shoe insert, or an orthotic arch support), or (iii) an article of clothing (or piece of clothing).

According to the present invention, not only hyperhidrosis, but also other diseases/disorders in which NKCC is involved (or which are mediated by them), can be treated or prevented by a compound of formula (I), preferably diseases/disorders in which NKCC1 is involved (or which mediated by it).

Thus, the present invention also relates to a compound of formula (I) described and defined above in the present invention, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition containing any of the above and a pharmaceutically acceptable excipient intended for use for treating or preventing a disease or disorder in which NKCC is involved, preferably a disease or disorder in which NKCC1 is involved.

The present invention also relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for the preparation of a medicament for the treatment or prevention of a disease or disorder involving NKCC, preferably a disease or disorder involving NKCC1.

The present invention also provides a method of treating or preventing a disease or disorder in which NKCC is involved (preferably a disease or disorder in which NKCC1 is involved), comprising administering to a subject in need thereof (preferably a human) a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate or pharmaceutical composition containing any of the above substances in combination with a pharmaceutically acceptable excipient. It will be understood that in this method, the compound of formula (I) or a pharmaceutically acceptable salt or solvate or pharmaceutical composition thereof must be administered in a therapeutically effective amount.

In accordance with the present invention, the disease or disorder being treated or prevented, more specifically the disease or disorder in which NKCC (preferably NKCC1) is involved, is not particularly limited and is preferably selected from the group consisting of hyperhidrosis (e.g., primary hyperhidrosis, secondary hyperhidrosis or nocturnal hyperhidrosis), anxiety disorder, autism spectrum disorder (eg, autism, AS

- 9 043772 pergera, childhood disintegrative disorder or pervasive developmental disorder as a component of autism spectrum disorder), traumatic brain injury, spinal cord injury (including also chronic pain caused by spinal cord injury), peripheral nerve injury, stroke (for example, ischemic stroke; including, but not limited to, the use of the compounds of the present invention to promote recovery from stroke, or the use of said compounds to reduce the extent of brain damage and/or neurological disorders following stroke), Alzheimer's disease, schizophrenia, asthma, edema (e.g., cerebral edema brain), Down syndrome (especially dementia in patients with Down syndrome), glaucoma (eg, primary open-angle glaucoma or closed-angle glaucoma), or parasitic infection. The parasitic infection may be, for example, (i) helminthiasis, including also soil-transmitted helminthiasis, preferably infection by hookworms, nematodes, trichocephalus, tapeworms, guinea worms, pinworms, Toxocara, by Strongyloides stercoralis or Ascaris lumbricoides (or a disease caused by them); (ii) infection with sucking worms or a disease caused by sucking worms, preferably schistosomiasis, gnathostomiasis, paragonimiasis, fascioliasis or Swimmers' syndrome; (iii) protozoal infection or disease caused by protozoa, such as, for example, malaria, amoebiasis, giardiasis, sleeping sickness, toxoplasmosis, acanthamoeba keratitis, leishmaniasis, babesiosis, granulomatous amoebic encephalitis, cryptosporidiosis, cyclosporiasis or primary amoebic meningoencephalitis; or (iv) ectoparasitic infection, preferably Sarcoptes scabiei, Pediculus humanus capitis, Phthirus pubis, dermatobiasis, Tunga penetrans or Ixodoidea infection (or disease caused by them).

Accordingly, it is preferred that the disease or disorder treated or prevented in accordance with the present invention is selected from the group consisting of hyperhidrosis, primary hyperhidrosis, secondary hyperhidrosis, nocturnal hyperhidrosis, anxiety disorder, autism spectrum disorder, autism, Asperger's syndrome, childhood disintegrative disorder , pervasive developmental disorder as a component of autism spectrum disorder, traumatic brain injury, spinal cord injury (including also chronic pain due to spinal cord injury), peripheral nerve damage, stroke (eg, ischemic stroke), Alzheimer's disease, schizophrenia, asthma, edema (eg, cerebral edema), Down syndrome, dementia in patients with Down syndrome, glaucoma, primary open-angle glaucoma, closed-angle glaucoma, or parasitic infection. Preferably, the parasitic infection is selected from the group consisting of: (i) helminthiasis, preferably hookworm, hookworm, trichuriasis, taeniasis, dracunculiasis, enterobiasis, toxocariasis, Strongyloides stercoralis infection or Ascaris lumbricoides infection; (ii) trematodiasis, preferably schistosomiasis, gnathostomiasis, paragonimiasis, fascioliasis or Swimmers' syndrome; (iii) protozoal infection, preferably malaria, amoebiasis, giardiasis, sleeping sickness, toxoplasmosis, acanthamoeba keratitis, leishmaniasis, babesiosis, granulomatous amoebic encephalitis, cryptosporidiosis, cyclosporiasis or primary amoebic meningoencephalitis; or (iv) ectoparasitic infection, preferably Sarcoptes scabiei, Pediculus humanus capitis, Phthirus pubis, dermatobiasis, Tunga penetrans or Ixodoidea infection (or a disease caused by them). Particularly preferably, the disease or disorder being treated or prevented in accordance with the present invention is hyperhidrosis (eg, primary hyperhidrosis, secondary hyperhidrosis or nocturnal hyperhidrosis).

In accordance with the present invention, the disease or disorder being treated or prevented may be, for example, a neurological disease or disorder involving (or mediated by) NKCC, preferably a neurological disease or disorder involving (or mediated by) NKCC1. Relevant examples include, but are not limited to, stroke (eg, ischemic stroke), traumatic brain injury, spinal cord injury, peripheral nerve injury, or cerebral edema.

The compounds of formula (I) can further be used as pest control agents, preferably for the control of plant pests (such as, for example, nematodes, arthropods, ectoparasites and/or molluscs), for example by applying a compound of formula (I) or its salt or solvate on the plant or applied to the soil.

In addition, the present invention also relates to new compounds, described in more detail below, that can be used as drugs, and to a pharmaceutical composition containing such a compound and a pharmaceutically acceptable excipient.

Furthermore, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as an NKCC inhibitor in assays, preferably as an assay compound for inhibiting NKCC (preferably NKCC1). Accordingly, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in vitro as an NKCC inhibitor (preferably as an NKCC1 inhibitor), as well as the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or solvate as a research compound acting as an NKCC inhibitor (preferably as an inhibitor

- 10 043772

NKCC1). The present invention also relates to a method of inhibiting NKCC (preferably NKCC1) in vitro, comprising the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. The present invention also relates to a method of inhibiting NKCC (preferably NKCC1) in vitro, comprising the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as an NKCC inhibitor (preferably as an NKCC1 inhibitor). It should be understood that the term in vitro when used in this specific context means outside a living human or animal body, this includes, but is not limited to, experiments conducted using cells, cellular or intracellular extracts and/or biological molecules in an artificial environment such as aqueous solution or cell medium, which can be carried out, for example, in a flask, test tube, Petri dish, microtiter plate, etc.

The compound of formula (I), as well as its pharmaceutically acceptable salt or solvate, is described in more detail below:

X^Z

In formula (I), the ring fragment X X is

X

It should be understood that if the ring fragment 4L X- is a unit of formula (I) has the following structure:

R ² > then coR

R ³

R' R ⁴

R γ ^R \__ _s ^{x z} P

On the other hand, if the ring fragment X* X* is ’ then the compound of formula (I) has the following structure:

R ¹ is selected from the group consisting of -COOH, -COO-(C1-C15-alkyl), -COO-(C0-C15alkylene)carbocyclyl, -COO-(C0-C15-alkylene)heterocyclyl, -O-CHO, -O -CO-(C1-C15-alkyl), -O-SODSch C15-alkylene)carbocyclyl, -O-CO-(C0-C15-alkylene)heterocyclyl, -CHO, -CO-(C1-C15-alkyl), - CO-(C0-C15alkylene)carbocyclyl, -CO-(C0-C15-alkylene)heterocyclyl, -CO-NH2, -CO-N( ^R11 )-(C1- _C15 -alkyl), -CON( ^R11 ) -(C0-C15-alkylene)carbocyclyl, -CO-N(R1 ¹ )-(C0-C ₁₅ -alkylene)heterocyclyl, -N(R1 1)-CHO, -N(R1 1)CO-(C ₁ - C ₁₅ -alkyl), -N(R ¹¹ )-CO-(C0-C15-alkylene)carbocyclyl, -N(R ¹¹ )-CO-(C0-C ₁₅ -alkylene)heterocyclyl, C1-C ₁₅ -alkyl, -(C ₀ -C ₁₅ -alkylene)carbocyclyl, -(C ₀ -C ₁₅ -alkylene)heterocyclyl, C ₂ -C ₁₅ -alkenyl, -(C ₂ -C ₁₅ alkenylene)carbocyclyl, -(C ₂ -C ₁₅ -alkenylene)heterocyclyl, C ₂ -C ₁₅ -alkynyl, -(C ₂ -C ₁₅ alkynylene)carbocyclyl and -(C2-C15-alkynylene)heterocyclyl, where the alkyl fragment contained in any of the above groups, the alkylene fragment contained in any of the above groups, an alkenylene fragment contained in any of the above groups, an alkynylene fragment contained in any of the above groups, the specified C ₁ -C ₁₅ -alkyl, the specified C ₂ -C ₁₅ -alkenyl and the specified C ₂ -C ₁₅ -alkynyl is each optionally substituted with one or more ((eg, one, two or three)) groups independently selected from halogen, -CF3, -CN, -NO2, -N(R ¹¹ )(R ¹¹ ), - O(R11), -S(R11) and -SO3H, where one or more ((for example, one or two)) -CH2- units included in the alkyl moiety contained in any of the above groups, in the alkylene moiety contained in any of the above groups, in the alkenylene fragment contained in any of the above groups, in the alkynylene fragment contained in any of the above groups, in the specified C ₁ -C ₁₅ -alkyl, in the specified C ₂ -C ₁₅ -alkenyl or said C ₂ -C ₁₅ -alkynyl, each optionally replaced by a group independently selected from -O-, -CO-, -COO-, -O-CO-, -N(R ¹¹ )-, -N(R ¹¹ )-CO-, -CO-N(R ¹¹ )-, -S-, -SO-, -SO2-, -SO2-N(R ¹¹ )- and -N(R ¹¹ )-SO2-, and where additionally carbocyclyl moiety contained in any of the above

- 11 043772 groups, and a heterocyclyl moiety contained in any of the above groups, each optionally substituted with one or more ((for example, one, two or three)) groups independently selected from C ₁ -C ₆ -alkyl, C ₂ - C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, halogen, C ₁ -C ₆ -haloalkyl, -CN, -NO2,

-N(R ¹¹ )(R ¹¹ ), -O(R ⁿ ), -S(R ⁿ ), -SO ₃ H, carbocyclyl and heterocyclyl.

Each R ¹¹ is independently hydrogen or C1-C6 alkyl. Preferably, each R ¹¹ is independently hydrogen or C1- _C4 alkyl (eg methyl or ethyl).

R ¹ may represent, for example, any of the specific R ¹ groups contained in any of the compounds described in the examples section.

In particular, R ¹ may represent, for example, -COO-(C1-C15-alkyl), wherein the alkyl moiety contained in said -COO-(C1-C15-alkyl) is optionally substituted with one or more (for example, one, two or three) groups independently selected from halogen, -CF3, -CN, -NO2, -NH2, -NH(Ci-C4alkyl), -N(C1-C4-alkyl)(C1-C4-alkyl), -OH, -O(C1-C4-alkyl), -SH and -S(C1-C4-alkyl), and where additionally one or two -CH2- units included in the alkyl fragment contained in the specified -COO-(C1-C15alkyl) , each optionally replaced by a group independently selected from -O-, -CO-, -COO-, -O-CO-, -NH-, -N(C1-C4-alkyl)-, -NH-CO-, -N (C1-C4-alkyl)-CO-, -CO-NH-, -CO-N(C1-C4-alkyl)-, -S-, -SO-, -SO2-, -SO2-NH-, -SO2 -N(C1-C4-alkyl)-, -NH-SO2- and -N(C1-C4-alkyl)-SO2-. The alkyl moiety contained in said -COO-(C1-C15-alkyl) contains from 1 to 15 carbon atoms, preferably from 1 to 10 carbon atoms. Preferred examples of such R ¹ groups include the corresponding R ¹ groups contained in the compounds described in the examples section (including, for example, -COOCH3 or -COO-CH ₂ CH ₃ ; preferably -COO-CH3).

Another preferred example of R ¹ is -COOH.

Other preferred examples of R ¹ are -(C1-C4-alkylene)-NH-(C1-C4-alkylene)-R ¹² (such as, for example, -CH2-NH-CH2-R ¹² ), -COO-(C1- C ₄ -alkylene)-R ¹² (for example, -COO-CH2-R ¹² ), -O-CO-(C1C4-alkylene)-R ¹² , -CO-(C1-C ₄ -alkylene)-R ¹² , - Co-NH-(C1-C4-alkylene)-R ¹² (for example, -CO-NH-CH2-R ¹² ), -CO-N(C1-C ₄ -alkyl)-(C ₁ -C ₄ -alkylene) -R ¹² , -NH-CO-(C1-C4 alkylene)-R ¹² or -N(C1-C ₄ alkyl)-CO-(C ₁ -C ₄ alkylene)^ ¹² , where R ¹² is independently selected from -CF3, -CN and halogen (eg -F, -Cl, -Br or -I); preferably, R ¹² is independently selected from -CF3 and -CN; more preferably, R ¹² is -CF3. Specific examples of such R ¹ groups include the corresponding R ¹ groups contained in the compounds described in the examples section. A particularly preferred example of R ¹ is -(C 1 -C ₄ -alkylene)-NH-(C ₁ -C ₄ -alkylene)-CF ₃ and an even more preferred example is -CH2-NHCH2-CF3.

Another example of R ¹ is -(C1-C4-alkylene)-S-heterocyclyl, preferably -(C1-C4-alkylene)S-heteroaryl (such as, for example, -CH2-S-heteroaryl), wherein the heterocyclyl moiety contained in said The -(C1-C4-alkylene)-S-heterocyclyl, or heteroaryl moiety contained in said -(C1-C4-alkylene)-S-heteroaryl or said -CH2-S-heteroaryl is optionally substituted with one or more (e.g. one, two or three) groups independently selected from C1-C6 alkyl, C2C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -CN, -NO2, -N(R ¹¹ )(R ¹¹ ), -O(R ⁿ ), -S(R ⁿ ), -SO3H, carbocyclyl and heterocyclyl. Specific examples of such R ¹ groups include the corresponding R ¹ groups contained in the compounds described in the examples section.

Another example of R ¹ is -(C ₁ -C ₄ -alkylene)-O-(C ₀ -C ₄ -alkylene)carbocyclyl, preferably -(C ₁ -C ₄ -alkylene)-O-(C ₀ -C ₄ - alkylene)phenyl (such as, for example, -CH ₂ -O-phenyl or -CH ₂ -O-CH ₂ -phenyl), wherein the carbocyclyl moiety contained in said -(C ₁ -C ₄ -alkylene)-O-( C ₀ -C ₄ alkylene)carbocyclyl, or phenyl fragment contained in the specified -(C ₁ -C ₄ -alkylene)-O-(C ₀ -C ₄ alkylene)phenyl (or in the specified -CH2-O-phenyl or - CH2-O-CH2-phenyl), optionally substituted with one or more (for example, one, two or three) groups independently selected from C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ - alkynyl, halogen, C ₁ -C ₆ -haloalkyl, -CN, -NO2, -N(R ¹¹ )(R ¹¹ ), -O(R ⁿ ), -S(R ⁿ ), -SO3H, carbocyclyl and heterocyclyl. Specific examples of such R ¹ groups include the corresponding R ¹ groups contained in the compounds described in the examples section.

Another example of R ¹ is -(C1-C4-alkylene)heterocyclyl, preferably -CH2-heterocyclyl, wherein the heterocyclyl moiety contained in said -(C1-C4-alkylene)heterocyclyl or in said -CH2-heterocyclyl is optionally substituted with one or more (for example, one, two or three) groups independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1C6 haloalkyl, -CN, -NO2, -N(R ¹¹ ) (R ¹¹ ), -O(R ⁿ ), -S(R ⁿ ), -SO3H, carbocyclyl and heterocyclyl. The heterocyclyl moiety may be, for example, heterocycloalkyl (such as, for example, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl), heterocycloalkenyl (such as, for example, tetrahydropyridinyl) or heteroaryl. Specific examples of such R ¹ groups include the corresponding R ¹ groups contained in the compounds described in the examples section.

R ² is selected from the group consisting of hydrogen, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, -OH, -O (C ₁ -C ₆ -alkyl), -O (C ₁ -C ₆ -alkylene)-OH, -O(C ₁ -C ₆ -alkylene)-O(C ₁ -C ₆ -alkyl), -SH, -S(C ₁ -C ₆ -alkyl), -NH2, -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, C ₁ -C ₆ -haloalkyl, -O-( C ₁ -C ₆ -haloalkyl), -CN, -NO2, -CHO, -CO-(C ₁ -C ₆ -alkyl), -COOH, -COO-(C ₁ -C ₆ -alkyl), -O- CO-(C ₁ -C ₆ -alkyl), -CO-NH2, -CONH(C ₁ -C ₆ -alkyl), -CO-N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl ), -NH-СО-(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)-СО-(C ₁ -C ₆ - 12 043772 alkyl), -SO2-NH2, -SO ₂ -NH(C ₁ -C ₆ -alkyl), -SO ₂ -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), -NH-SO ₂ -(C ₁ -C ₆ - alkyl) and

-N(C ₁ -C ₆ -alkyl)-SO ₂ -(C ₁ -C ₆ -alkyl).

Preferably, R ² is selected from the group consisting of hydrogen, C1-C6 alkyl, -OH, -O(C1-C6 alkyl), -O(C1-C6 alkylene)-OH, -O(C1-C6 alkylene) -O(C1-C6-alkyl), -SH, -S(C1-C6-alkyl), -NH2, -NH(C1-C6-alkyl), -N(C1-C6-alkyl)(C1-C6-alkyl) , halogen, C1-C6-haloalkyl, -O-(C1-C6-haloalkyl) and -CN. More preferably, R ² is hydrogen or C1-C ₄ alkyl. Even more preferably, R ² is hydrogen.

R ³ is selected from the group consisting of -SO2-NH2, -SO ₂ -NH(C ₁ -C ₆ -alkyl), -SO ₂ -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), -SO ₂ -N=(C ₁ -C ₆ -alkylidene) and -SO ₂ -halogen, where the alkyl moiety contained in said -SO ₂ -NH(C ₁ -C ₆ -alkyl) is one or both of the alkyl moieties, contained in said -SO ₂ -N(C1-C ₆ alkyl)(C ₁ -C ₆ -alkyl), and the alkylidene moiety contained in said -SO2-N=(C1-C ₆ alkylidene), each optionally substituted with one or more (for example, one, two or three) groups independently selected from halogen, -CF ₃ , -CN, -NO2, -NH2, -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ C ₆ -alkyl), -OH, -O(C ₁ -C ₆ -alkyl), -SH and -S(C ₁ -C ₆ -alkyl).

Preferably, R ³ is selected from -SO2-NH2, -SO2-NH(C1-C4-alkyl), -SO2-N(C1-C4-alkyl)(C1-C4-alkyl) and -SO2-N=(C1-C4 -alkylidene), wherein the alkyl moiety contained in said -SO2-NH(C1C4-alkyl), one or both of the alkyl moieties contained in said -SO2-N(C1-C4-alkyl)(C1-C4-alkyl), and the alkylidene moiety contained in said -SO2-N=(C1-C4-alkylidene), each optionally substituted with one or more groups (preferably one group) independently selected from halogen, -CF3, -CN, -NO2, -NH2, -NH( C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -OH, -O(C1-C6 alkyl), -SH and -S(C1-C6 alkyl). More preferably, R ³ is selected from -SO2-NH2, -SO2NH(C1- _C4 -alkyl), -SO2 _- N( _C1 - _C4- alkyl)( _C1 - _C4 -alkyl) and -SO ₂ -N=(C ₁ -C ₄ -alkylidene), where the alkyl fragment contained in the specified -SO ₂ -NH(C ₁ -C ₄ -alkyl), one or both of the alkyl fragments contained in the specified -SO ₂ -N (C ₁ -C ₄ -alkyl)(C ₁ -C ₄ -alkyl), and the alkylidene moiety contained in said -SO ₂ -N=(C ₁ -C ₄ -alkylidene), each optionally substituted with one group selected from -NH2, -NH(C ₁ -C ₄ -alkyl) and -N(C ₁ -C ₄ -alkyl)(C ₁ -C ₄ -alkyl). Even more preferably, R ³ is selected from -SO2NH2, -SO2-NH(C1-C4-alkyl), -SO2-N(C1-C4-alkyl)(C1-C4-alkyl), -SO2-NH-(C1 -C4-alkylene)-NH2, -SO2-NH(C1-C4-alkylene)-NH(C1-C4-alkyl), -SO2-NH-(C1-C4-alkylene)-N(c1-C4-alkyl) (C1-C4-alkyl), -SO2-N=(C1-C4alkylidene)-NH2, -SO2-N=(C1-C4-alkylidene)-NH(C1-C4-alkyl) and -SO2-N=(C1 -C4-alkylidene)-N(C1-C4alkyl)(C1-C4-alkyl). Even more preferably, R ³ is selected from -SO2-NH2, -SO2-NH-CH3, -SO2N(CH3)2, -SO ₂ -NH-(C ₁ -C ₄ -alkylene)-NH ₂ , -SO ₂ -NH-(C ₁ -C ₄ -alkylene)-NH-CH ₃ , -SO ₂ -NH-(C ₁ -C ₄ -alkylene)N(CH3)2 (for example, -SO2-NH-CH2CH2-N( CH3)2), -SO2-N=(C1-C4-alkylidene)-NH2, -SO2-N=(Ci-C4alkylidene)-NH-CH ₃ and -SO ₂ -N=(C ₁ -C ₄ -alkylidene )-N(CH ₃ ) ₂ (for example, -SO2-N=CH-N(CH ₃ )2). A particularly preferred example of R ³ is -SO2-NH2. Another particularly preferred example of R ³ is -SO2-N=CH-N(CH3)2.

R ^x is R ¹ or R ³ (as defined above, including also the preferred definitions of R ¹ and R ³ ).

Preferably, R ^x is selected from -COOH, -COO-(C1-C6-alkyl), -SO2-NH2, -SO2-NH(C1-C4-alkyl), -SO2-N(C1-C4-alkyl)( C1-C4-alkyl) and -SO2-N=(C1-C4-alkylidene), where the alkyl fragment contained in the specified -SO2-NH(C1-C4-alkyl), one or both of the alkyl fragments contained in the specified -SO2 -N(C1-C4-alkyl)(C1-C4-alkyl), and the alkylidene moiety contained in said -SO2-N=(C1C4-alkylidene), each optionally substituted with one group selected from -NH2, -NH(C1 -C4-alkyl) and -N(C1-C4-alkyl)(C1-C4-alkyl). More preferably, R ^x is selected from -COOH, -COOCH3, -SO2-NH2 and -SO2-N=CH-N(CH3)2.

R ⁴ is an R ^4a group and R ⁵ is an R ^5a group; or alternatively, R ⁴ and R ⁵ are linked together to form the group -R ^5b -.

R ^4a is selected from -OR ⁴¹ , -SR ⁴¹ , -NH-R ⁴¹ , -N(C ₁ -C ₆ -alkyl)-R ⁴¹ , halogen (eg -Cl), hydrogen, carbocyclyl and heterocyclyl, wherein said carbocyclyl and said heterocyclyl is each optionally substituted with one or more (eg, one, two or three) R ⁴² groups.

Preferably, R ^4a is selected from -OR ⁴¹ , -SR ⁴¹ , -NH-R ⁴¹ , -N(C1-C6-alkyl)-R ⁴¹ , halogen, carbocyclyl and heterocyclyl, wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more R ⁴² groups. More preferably, R ^4a is selected from -OR ⁴¹ , -SR ⁴¹ , -NHR ⁴¹ , -N(C1-C ₆ -alkyl)-R ⁴¹ , carbocyclyl (eg aryl, cycloalkyl or cycloalkenyl) and heterocyclyl (eg heteroaryl , heterocycloalkyl or heterocycloalkenyl), wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more R ⁴² groups. Even more preferably, R ^4a is selected from -OR ⁴¹ , -SR ⁴¹ , -NH-R ⁴¹ , -N(C ₁ -C ₄ -alkyl)-R ⁴¹ , aryl and heteroaryl, wherein said aryl and said heteroaryl are each optional substituted with one or more R ⁴² groups.

R ⁴¹ is selected from the group consisting of -(Co-C ₄ -alkylene)carbocyclyl, -(Co-C ₄ -alkylene)heterocyclyl, C ₁ -C ₆ -alkyl, C2-C ₆ -alkenyl and C2-C ₆ -alkynyl wherein the carbocyclyl fragment contained in the specified -(C ₀ -C ₄ -alkylene)carbocyclyl, and the heterocyclyl fragment contained in the specified -(C ₀ -C ₄ -alkylene)heterocyclyl, each is optionally substituted with one or more (for example, one, two or

- 13 043772 three) R ⁴² groups, and where the specified CrQ-alkyl, the specified C ₂ -C ₆ -alkenyl, the specified C ₂ -C ₆ alkynyl, alkylene fragment contained in the specified -(C ₀ -C ₄ -alkylene)carbocyclyl , and the alkylene moiety contained in said -(C ₀ -C ₄ -alkylene)heterocyclyl, each optionally substituted with one or more (eg, one, two or three) R ⁴³ groups.

Preferably, R ⁴¹ is selected from the group consisting of -(C0-C4-alkylene)carbocyclyl, -(Co-C4alkylene)heterocyclyl, C1-C6-alkyl, C2-C6-alkenyl and C2-C6-alkynyl, wherein the carbocyclyl moiety, contained in said -(C0-C4-alkylene)carbocyclyl is selected from cycloalkyl, cycloalkenyl and aryl, wherein the heterocyclyl moiety contained in said -(C0-C4-alkylene)heterocyclyl is selected from heterocycloalkyl, heterocycloalkenyl and heteroaryl, wherein the carbocyclyl moiety, contained in said -(C0-C4-alkylene)carbocyclyl, and a heterocyclyl moiety contained in said -(C0-C4-alkylene)heterocyclyl, each optionally substituted with one or more (for example, one, two or three) R ⁴² groups, and where additionally the specified C1-C ₆ -alkyl, the specified C ₂ -C ₆ alkenyl, the specified C2-C6-alkynyl, the alkylene fragment contained in the specified -(C0-C4alkylene)carbocyclyl, and the alkylene fragment contained in the specified -(C0- C4alkylene)heterocyclyl, each optionally substituted with one or more (eg, one, two or three) R ⁴³ groups. More preferably, R ⁴¹ is selected from the group consisting of -(C0-C4alkylene)aryl and -(C0-C4-alkylene)heteroaryl, wherein the aryl moiety contained in said -(C0-C4alkylene)aryl and the heteroaryl moiety contained in said -(C0-C4-alkylene)heteroaryl, each optionally substituted with one or more (for example, one, two or three) R ⁴² groups, and wherein additionally an alkylene moiety contained in said -(C0- _C4 -alkylene)aryl, and an alkylene moiety contained in said -(C0-C4-alkylene)heteroaryl, each optionally substituted with one or more (eg, one, two or three) R ⁴³ groups. Even more preferably, R ⁴¹ is selected from -(C0-C4-alkylene)aryl and -(C0-C4-alkylene)heteroaryl, wherein the aryl moiety contained in said -(C0-C4-alkylene)aryl moiety and the heteroaryl moiety, contained in said -(C0-C4alkylene)heteroaryl, each is optionally substituted with one or more (eg, one, two or three) R ⁴² groups. A preferred example _of the aryl moiety contained in said -( _C0C4 -alkylene)aryl is phenyl. A preferred example of a heteroaryl moiety contained in said -( _C0 - _C4 -alkylene)heteroaryl is a 5- or 6-membered monocyclic heteroaryl containing 1 or 2 ring heteroatoms independently selected from oxygen, nitrogen and sulfur (where the remaining ring atoms are carbon atoms), such as, for example, imidazolyl, thiophenyl or pyrimidinyl. Even more preferably, R ⁴¹ is selected from phenyl and heteroaryl, wherein said heteroaryl is a 5- or 6-membered monocyclic heteroaryl containing 1 or 2 ring heteroatoms independently selected from oxygen, nitrogen and sulfur (the remaining ring atoms of the monocyclic heteroaryl are carbon atoms ), and wherein further said phenyl or said heteroaryl is optionally substituted with one or more (eg, one, two or three) R ⁴² groups.

Each R ⁴² is independently selected from the group consisting of C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, -OH, -O(C ₁ -C ₆ -alkyl), -O( C ₁ -C ₆ -alkylene)-OH, -O(C ₁ -C ₆ -alkylene)-O(C ₁ -C ₆ -alkyl), -SH, -S(C ₁ -C ₆ alkyl), -NH ₂ , -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, C ₁ -C ₆ -haloalkyl, -O-(C ₁ -C ₆ haloalkyl), -CN, -NO ₂ , -CNO, -CO-(C ₁ -C ₆ -alkyl), -COOH, -COO-(C ₁ -C ₆ -alkyl), -O-CO -(C ₁ -C ₆ -alkyl), -CO-NH2, -CO-NH(C ₁ -C ₆ -alkyl), -CO-N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ - alkyl), -NH-CO-(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ alkyl)-CO-(C ₁ -C ₆ -alkyl), -SO2-NH2, -SO ₂ - NH(C ₁ -C ₆ -alkyl), -SO ₂ -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), -NH-SO2(C ₁ -C ₆ -alkyl) and - N(C ₁ -C ₆ -alkyl)-SO ₂ -(C ₁ -C ₆ -alkyl).

Preferably, each R ⁴² is independently selected from the group consisting of C ₁ -C ₆ -alkyl, -OH, -O(C ₁ -C ₆ -alkyl), -O(C ₁ -C ₆ -alkylene)-OH, - O(C ₁ -C ₆ -alkylene) -O(C ₁ -C ₆ -alkyl), -SH, -S(C ₁ -C ₆ -alkyl), -NH ₂ , -NH(C ₁ -C ₆ - alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, C ₁ -C ₆ -haloalkyl, -O-(C ₁ -C ₆ -haloalkyl) and -CN.

Each R ⁴³ is independently selected from the group consisting of -OH, -O(C ₁ -C ₆ alkyl), -SH, -S(C ₁ -C ₆ alkyl), -NH ₂ , -NH(C ₁ -C ₆ -alkyl), -N(c ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, -CF ₃ , -CN, -NO ₂ , -CHO, -CO-(C ₁ C ₆ - alkyl), -COOH, -COO-(C ₁ -C ₆ -alkyl), -O-CO-(C ₁ -C ₆ -alkyl), -CO-NH2, -CO-NH(C ₁ -C ₆ - alkyl), -CO-N(C ₁ C ₆ -alkyl)(C ₁ -C ₆ -alkyl), -NH-CO-(C ₁ -C ₆ -alkyl) and -N(C ₁ -C ₆ -alkyl )-CO-(C ₁ -C ₆ -alkyl).

Preferably, each R ⁴³ is independently selected from the group consisting of -OH, -O(C ₁ -C ₆ alkyl), -SH, -S(C ₁ -C ₆ -alkyl), -NH2, -NH(C ₁ - C ₆ -alkyl), -M(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, -CF ₃ and -CN.

In accordance with the above definitions, it is particularly preferred if R ^4a is selected from the group consisting of -O-(Co-C4-alkylene)aryl, -O-(C0-C4-alkylene)heteroaryl, -S-(Co-C4-alkylene) )aryl, -S-(Co-C4-alkylene)heteroaryl, -NH-(Co-C4-alkylene)aryl, -NH-(Co-C4-alkylene)heteroaryl, -N(C1-C4alkyl)-(C0- C4-alkylene)aryl, -N(C1-C4-alkyl)-(Co-C4-alkylene)heteroaryl, aryl and heteroaryl, where the aryl fragment contained in any of the above groups, heteroaryl fragment contained in any of the above groups, said aryl and said heteroaryl are each optionally substituted with one or more (eg, one, two or three) R ⁴² groups. Even more preferably, R ^4a is selected from the group consisting of -O-aryl, -O-heteroaryl, -S-aryl, -S-heteroaryl, -NHaryl, -NH-heteroaryl, -N(C1- _C4 -alkyl) aryl, -N(C ₁ -C ₄ -alkyl)heteroaryl, aryl and heteroaryl, where aryl

- 14 043772 fragment contained in any of the above groups, heteroaryl fragment contained in any of the above groups, said aryl and said heteroaryl are each optionally substituted with one or more groups independently selected from C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ alkynyl, -OH, -O(C1-C ₆ -alkyl), -O(C ₁ -C ₆ -alkylene)-OH, -O(C ₁ -C ₆ - alkylene)-O(C ₁ -C ₆ -alkyl), -SH, -S(C ₁ -C ₆ alkyl), -NH2, -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, C ₁ -C ₆ -haloalkyl and -CN. Even more preferably, R ^4a is selected from the group consisting of -O-phenyl, -O-heteroaryl, -S-phenyl, -Sheteroaryl, -NH-phenyl, -NH-heteroaryl, -N(C ₁ -C ₄ -alkyl )phenyl, -N(C ₁ -C ₄ -alkyl)heteroaryl, phenyl and heteroaryl, wherein said heteroaryl or heteroaryl moiety contained in any of the above groups is a 5- or 6-membered monocyclic heteroaryl containing 1 or 2 ring heteroatom independently selected from oxygen, nitrogen and sulfur (the remaining ring atoms of a monocyclic heteroaryl are carbon atoms), and wherein additionally a phenyl moiety contained in any of the above groups, a heteroaryl moiety contained in any of the above groups, said phenyl and said heteroaryl is each optionally substituted with one or more groups independently selected from C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, -OH, -O(C1-C ₆ -alkyl), -O(C ₁ -C ₆ -alkylene)-OH, -O(C ₁ -C ₆ -alkylene)-O(C ₁ -C ₆ -alkyl), -SH, -S(C1-C ₆ -alkyl), -NH2, -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, C ₁ -C ₆ -haloalkyl and -CN. A particularly preferred example of R ^4a is -O-phenyl.

R ^5a is selected from the group consisting of -NH2, -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), -NO2 and hydrogen, where alkyl moiety contained in said -NH(C ₁ -C ₆ -alkyl), and one or both of the alkyl moieties contained in said -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -αalkyl), each optional substituted with one or more (for example, one, two or three) groups independently selected from halogen, -CF ₃ , -CN, -NO2, -NH2, -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), -OH, -O(C1-C ₆ -alkyl), -SH, -S(C ₁ -C ₆ -alkyl), carbocyclyl and heterocyclyl, where said carbocyclyl and said heterocyclyl are each optionally substituted with one or more (eg, one, two or three) R ⁵¹ groups.

Preferably, R ^5a is selected from -NH2, -NH(C1-C6-alkyl), -N(C1-C6-alkyl)(C1-C6-alkyl) and -NO2, wherein the alkyl moiety contained in said -NH( C1-C6 alkyl), and one or both of the alkyl moieties contained in said -N(C1-C6 alkyl)(C1-C6 alkyl), each optionally substituted with one or more (e.g., one, two or three) groups , independently selected from halogen, -CF3, -CN, -NO2, -NH2, -NH(C1-C6-alkyl), -N(C1-C6-alkyl)(C1-C6-alkyl), -OH, -O (C1-C6-alkyl), -SH and -S(C1-C6-alkyl). More preferably, R ^5a is selected from -NH2, -NH(C1- _C6 -alkyl), -N( _C1 - _C6 -alkyl)(C1 _{- C6} -alkyl) and -NO2. Particularly preferred examples of R ^5a are -NH2, -NH-CH ₂ CH ₂ CH ₂ CH ₃ or -NO2.

Each R ⁵¹ is independently selected from the group consisting of C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, -OH, -O(C ₁ -C ₆ -alkyl), -O( C ₁ -C ₆ -alkylene)-OH, -O(C ₁ -C ₆ -alkylene)-O(C ₁ -C ₆ -alkyl), -SH, -S(C1-C ₆ alkyl), -NH ₂ , -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, C ₁ -C ₆ -haloalkyl, -O-(C ₁ -C ₆ haloalkyl), -CN, -NO ₂ , -CNO, -CO-(C ₁ -C ₆ -alkyl), -COOH, -COO-(C ₁ -C ₆ -alkyl), -O-CO- (C ₁ -C ₆ -alkyl), -CO-NH2, -CO-NH(C ₁ -C ₆ -alkyl), -CO-N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl ), -NH-CO-(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ alkyl)-CO-(C ₁ -C ₆ -alkyl), -SO2-NH2, -SO ₂ -NH (C ₁ -C ₆ -alkyl), -SO ₂ -N (C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), -NH-SO2 (C ₁ -C ₆ -alkyl) and -N (C ₁ -C ₆ -alkyl)-SO ₂ -(C ₁ -C ₆ -alkyl).

Preferably, each R ⁵¹ is independently selected from the group consisting of C ₁ -C ₆ -alkyl, -OH, -O(C ₁ -C ₆ -alkyl), -O(C ₁ -C ₆ -alkylene)-OH, - O(C ₁ -C ₆ -alkylene) -O(C ₁ -C ₆ -alkyl), -SH, -S(C ₁ -C ₆ -alkyl), -NH2, -NH(C ₁ -C ₆ -alkyl ), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, C ₁ -C ₆ -haloalkyl, -O-(C ₁ -C ₆ -haloalkyl) and -CN.

R ^5b selected from -R ^5b1 -R ^5b2 -R ^5b1 -, -N=C(R ⁵³ )-R ^5b3 -R ^5b1 -, -R ^5b1 -R ^5b3 -C(R ⁵³ )=N- and -N= C(R ⁵³ )-R ^5b4 -C(R ⁵³ )=N-. Each R ^5b1 is independently selected from -N(R ⁵² )-, -O- and -S-.

R ^5b2 selected from -C(R ⁵³ )(R ⁵³ )-, -C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R 53 )-, -C(R ⁵³ )=C(R ^{53 )} -, -C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )=C(R ⁵³ )- and -C(R ⁵³ )=C(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-.

R ^5b3 is selected from a covalent bond, -C(R ⁵³ )(R ⁵³ )-, -C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )- and -C(R ⁵³ )=C( R ⁵³ )-.

R ^5b4 is selected from a covalent bond and -C(R ⁵³ )(R ⁵³ )-.

Each R ⁵² is independently selected from the group consisting of hydrogen, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C _{2 -C 6} -kynyl, -(C ₀ -C ₄ -alkylene)aryl and -(C ₀ -C ₄ -alkylene)heteroaryl.

Preferably, each R ⁵² is independently selected from the group consisting of hydrogen, C 1 -C ₄ alkyl (eg, n-butyl), C ₂ -C ₄ -alkenyl, and C ₂ -C ₄ -alkynyl (eg -CH ₂ -C =CH). Even more preferably, each R ⁵² is hydrogen.

Each R ⁵³ is independently selected from the group consisting of hydrogen, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -kynyl, -OH, -O(C 1 -C ₆ -alkyl), -SH , -S(C ₁ -C ₆ -alkyl), -NH ₂ , -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ alkyl), halogen , C ₁ -C ₆ -haloalkyl, -O-(C ₁ -C ₆ -haloalkyl), -CN, -NO ₂ , -CHO, -CO-(C ₁ -C ₆ -alkyl), -COOH, -COO -(C1-C6-alkyl), -O-CO-(C1-C6-alkyl), -CO-NH2, -CO-NH(C1-C6-alkyl), -CO-N(Ci-C6-alkyl)(C1 -C ₆ -alkyl), -NH-CO-(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)-CO-(C ₁ -C ₆ -alkyl), -SO2-NH2 , -SO ₂ -NH(C ₁ C ₆ -alkyl), -SO ₂ -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), -NH-SO ₂ -(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)-SO ₂ -(C ₁ -C ₆ -alkyl), -(C ₀ -C ₄ -alkylene)aryl and -(C ₀ -C ₄ - alkylene)heteroaryl; In addition, any two ^R53 groups that are attached to the same carbon atom can also together form an =O group, and any two ^R53 groups that are attached to adjacent carbon atoms connected by a double bond (t that is, any two R ⁵³ groups contained in the fragment -C(R ⁵³ )=C(R ⁵³ )-) can also be linked together to form the group -C(R ⁵⁴ )=C(R ⁵⁴ )-C( R ⁵⁴ )=C(R ⁵⁴ )-.

Preferably, each R ⁵³ is independently selected from the group consisting of hydrogen, C1-C6 alkyl, -OH, -O(C1-C6 alkyl), -SH, -S(C1-C6 alkyl), -NH2, -NH( C1-C6-alkyl), -N(C1-C6-alkyl)(C1-C6alkyl), halogen, C1-C6-haloalkyl, -O-(C1-C6-haloalkyl) and -CN, and any two R ⁵³ groups that are attached to the same carbon atom can also together form an =O group, and any two ^R53 groups that are attached to adjacent carbon atoms connected by a double bond can also be bonded together to form a -C( ^R54 )=C(R ⁵⁴ )-C(R ⁵⁴ )=C(R ⁵⁴ )-. More preferably, each R ⁵³ is independently selected from the group consisting of hydrogen, C1- _C6 alkyl, -OH, -O( _C1 - _C6 alkyl), -SH, -S( _C1 - _C6 alkyl ), -NH2, -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, C ₁ -C ₆ -haloalkyl, -O -(C ₁ -C ₆ -haloalkyl) and -CN, and any two R ⁵³ groups that are attached to the same carbon atom can also together form an =O group. Even more preferably, each R ⁵³ is independently selected from the group consisting of hydrogen, C1- _C4 -alkyl, -OH, -O( _C1C4 -alkyl), -NH2, -NH( _C1 - _C4 -alkyl), -N(C ₁ -C ₄ -alkyl)(C ₁ -C ₄ -alkyl), halogen, C1-C ₄ -haloalkyl, -O-(C1C ₄ -haloalkyl), and -CN, and any two R ⁵³ groups , which are attached to the same carbon atom can also together form an =O group.

Each R ⁵⁴ is independently selected from the group consisting of hydrogen, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C _{2 -C 6} -kynyl, -OH, -O(C 1 -C ₆ -alkyl), -SH , -S(C ₁ -C ₆ -alkyl), -NH2, -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, C ₁ -C ₆ -haloalkyl, -O-(C1-C ₆ -haloalkyl), -CN, -NO2, -CHO, -CO-(C1-C ₆ -alkyl), -COOH, -COO-(C1- C6-alkyl), -O-CO-(C1-C6-alkyl), -CO-NH2, -CO-NH(C1-C6-alkyl), -CO-N(Ci-C ₆ alkyl)(C1-C ₆ -alkyl), -NH-CO-(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)-CO-(C ₁ -C ₆ -alkyl), -SO2-NH2, - SO2-NH(C1C ₆ -alkyl), -SO ₂ -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), -NH-SO ₂ -(C ₁ -C ₆ -alkyl) and -N(C ₁ -C ₆ -alkyl)-SO ₂ -(C ₁ -C ₆ -alkyl).

Preferably, each R ₅₄ is independently selected from the group consisting of hydrogen, C1-C6 alkyl, -OH, -O(C1- _C6 alkyl), -SH, -S( _C1 - _C6 alkyl), -NH2, -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ alkyl), halogen, C ₁ -C ₆ -haloalkyl, -O-(C1-C ₆ -haloalkyl) and -CN. More preferably, each R ⁵⁴ is hydrogen.

It is particularly preferred if R ^5b is selected from -N(R ⁵² )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -N=C(R ⁵³ )-N(R ⁵² )-, -N (R ⁵² )-C(R ⁵³ )=N-, -N(R ⁵² )-C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -N =C(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -N(R ⁵² )C(R ⁵³ )=C(R ⁵³ )-N(R ⁵² )-, - N(R ⁵² )-C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )=N-, -N=C(R ⁵³ )-C(R ⁵³ )=N-, -N(R ⁵² )- C(R ⁵³ )(R ⁵³ )C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -N=C(R ⁵³ )-C(R ⁵³ ) (R ⁵³ )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -N(R ⁵² )-C(R ⁵³ )(R ⁵³ )C(R ⁵³ )=C(R ⁵³ )- N(R ⁵² )-, -N(R ⁵² )-C(R ⁵³ )=C(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -N(R ⁵² )- C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )C(R ⁵³ )=N-, -N=C(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )=N-, -OC(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -OC(R ⁵³ )(R 53 )-C(R ⁵³ )(R ⁵³ )-N( ^{R 52 )} -, -OC(R ⁵³ )=C(R ⁵³ )-N(R ⁵² )-, -OC(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -OC(R ⁵³ )(R ⁵³ )-C(R ⁵³ )=C(R ⁵³ )-N(R ⁵² )-, -OC(R ⁵³ )=C(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -N(R ⁵² )-C(R ^{53 )(R 53 )} -O-, -N(R ⁵² )-C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-O-, -N(R ⁵² )C(R ⁵³ )=C(R ⁵³ )-O-, -N(R ⁵² )-C( R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-O-, -N(R ⁵² )-C(R ⁵³ )(R ⁵³ )-C( R ⁵³ )=C(R ⁵³ )-O-, -N(R ⁵² )-C( ^{R 53} )=C(R 53 )-C(R ⁵³ )(R ⁵³ )-O-, -SC(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -SC(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -SC(R ⁵³ )=C( R ⁵³ )-N(R ⁵² )-, -SC(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, - SC(R ⁵³ )(R ⁵³ )-C(R ⁵³ )=C(R ⁵³ )-N(R ⁵² )-, -SC(R ⁵³ )=C(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -N(R ⁵² )-C(R ⁵³ )(R ⁵³ )-S-, -N(R ⁵² )-C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-S-, -N(R ⁵² )C(R ⁵³ )=C(R ⁵³ )-S-, -N(R ⁵² )-C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-S-, -N(R ⁵² )-C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )=C(R ⁵³ )-S -, -N(R ⁵² )-C(R ⁵³ )=C(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-S-, -N(R ⁵² )-C(R ⁵³ )(R ⁵³ ) -N(R ⁵² )-, -N(R ⁵² )-C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -N(R ⁵² )-C (R ⁵³ )=C(R ⁵³ )-N(R ⁵² )-, -N(R ⁵² )-C(R ⁵³ )(R 53 )-C(R ⁵³ )(R ⁵³ )-C( ^{R 53 )} (R ⁵³ )-N(R ⁵² )-, -N(R ⁵² )-C(R ⁵³ )(R ⁵³ )C(R ⁵³ )=C(R ⁵³ )-N(R ⁵² )-HN(R ⁵² )-C(R ⁵³ )=C(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-.

R ²

Λ ^κ γγ

Moreover, if the ring moiety 4L F is > and if R ⁴ and R ⁵ are linked together to form a group -R ^5b -, then even more preferably if R ^5b is selected such that the compound of formula (I) has any of following structures:

- 16 043772

R ⁶ is selected from the group consisting of hydrogen, C1-C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, -OH, -O(C1-Cb-alkyl), -O(C1- C6-alkylene)-OH, -O(C1-C6-alkylene)-O(C1-C6-alkyl), -SH, -S(C1-C6-alkyl), -NH2,

-NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, C ₁ -C ₆ -haloalkyl, -O-(C1-C ₆ -haloalkyl), -CN, -NO2, -CHO, -CO-(C1-C6-alkyl), -COOH, -COO-(C _g C ₆ -alkyl), -O-CO-(C1-C6- alkyl), -CO-NH2, -CONH(C1-C6-alkyl), -CO-N(C1-C6-alkyl)(C1-C6-alkyl), -NH-CO-(C1-C6-alkyl), ^(C _g C ₆ -alkyl)-CO-(C _g C6 alkyl), -SO2-NH2, -SO2-NH(C1-C6-alkyl), -SO2-N(C1-C6-alkyl)(C1-C6 -alkyl), -NH-SO2-(C1-C6-αalkyl) and -N(C ₁ -C ₆ -alkyl)-SO ₂ -(C ₁ -C ₆ -alkyl).

Preferably, R ⁶ is selected from the group consisting of hydrogen, C1-C6 alkyl, -OH, -O(C1-C6 alkyl), -O(C1-C6 alkylene)-OH, -O(C1-C6 alkylene) -O(C1-C6-alkyl), -SH, -S(C1-C6-alkyl), -NH2, -NH(C1-C6-alkyl), -N(C1-C6-alkyl)(C1-C6-alkyl) , halogen, C1-C6 haloalkyl, -O-(C1-C6 haloalkyl) and -CN. More preferably, R ⁶ is hydrogen or C1-C4 alkyl. Even more preferably, R ⁶ is hydrogen.

Alternatively (i.e., as an alternative to the meanings of ^R1 and ^R6 described above), the ^R1 and ^R6 groups are linked together to form the ^-R16- group, where:

R ¹⁶ denotes the group -C(R ¹⁶¹ XR ¹⁶¹ )-C(R ¹⁶¹ XR ¹⁶¹ )-C(R ¹⁶¹ )(R1^^^ where one or two units

-C(R ¹⁶¹ )(R ¹⁶¹ )- contained in the said group are all replaced by -R ¹⁶³ -;

each R ¹⁶¹ is independently selected from the group consisting of hydrogen, C1-C6-αalkyl, C2-C6-alkenyl, C2C6-alkynyl, halogen, C1-C6-haloalkyl, -(C0-C6-alkylene)-CF3, -(C0- C6-alkylene)-CN, -(C0-C6-alkylene)NO2, -(C0-C6-alkylene)-N(R ¹⁶² )(R ¹⁶² ), -(C0- _C6 -alkylene)-O(R ¹⁶² ), -(C0-C6-alkylene)-S(R ¹⁶² ), -(C0- _C6 -alkylene)SO ₃ H, -( _C0 - _C6- alkylene)carbocyclyl and -( _C0 - _C6- alkylene)heterocyclyl;

each R ¹⁶² independently represents hydrogen or C ₁ -C ₆ -alkyl; and each R ¹⁶³ is independently selected from -N(R ¹⁶¹ )-, -O- and -S-.

Preferably, R ¹⁶ represents the group -CH2-CH2-CH2-CH2-, wherein one or more -CH2- units included in said group are each replaced by -R ¹⁶³ -. More preferably, R ¹⁶ represents a -CH2-CH ₂ -CH ₂ -CH ₂ - group, where one -CH ₂ - unit included in said group is replaced by -R ¹⁶³ -. Even more preferably, R ¹⁶ is -CH2-R ¹⁶³ -CH2-CH ₂ - or -CH ₂ -CH ₂ -R ¹⁶³ -CH ₂ -.

Preferably, each R ¹⁶³ is independently -N(R ¹⁶¹ )-. A preferred example of a corresponding R ¹⁶³ group is -N(-CH2-CF3)-. Accordingly, it is particularly preferred if R ¹⁶ is -CH2-N(R ¹⁶¹ )-CH2-CH2- or -CH2-CH2-N(R ¹⁶¹ )-CH2- (for example -CH ₂ -N(-CH ₂ -CF ₃ )-CH ₂ CH2- or -CH2-CH2-N(-CH2-CF3)-CH2-).

- 17 043772 x

According to the present invention, if in formula (I) the ring moiety is ' R ² is hydrogen, R ³ is -SO ₂ -NH ₂ , ^{R 4} is -O-phenyl, R ⁵ is -NH-CH ₂ CH ₂ CH ₂ CH ₃ and R ⁶ denotes hydrogen, then R ¹ differs from -COOH.

So, in other words, R ¹ is different from -COOH (i.e. R ¹ is not -COOH) if you-

all the following conditions are met:

X ^x (i) the ring moiety is (ii) R ² is hydrogen, (iii) R ³ is -SO ₂ -NH ₂ , (iv) R ⁴ is -O-phenyl, (v) R ⁵ is -NH- CH ₂ CH ₂ CH ₂ CH ₃ , and (vi) R ⁶ is hydrogen.

The compound of formula (I) may be, for example, any of the specific compounds described herein in the examples section, in non-salt form (eg, free base/free acid form), or a pharmaceutically acceptable salt or solvate of the corresponding compound .

In particular, the compound of formula (I) may be a compound having any of the following formulas, or a pharmaceutically acceptable salt or solvate thereof:

- 18 043772

- 19 043772

- 20 043772

- 21 043772

- 22 043772

- 23 043772

- 24 043772

contained in a compound of formula (I) is

R ²

Accordingly, in this first embodiment, the compound of formula (I) is a compound of the following formula (1a) or a pharmaceutically acceptable salt or solvate thereof:

-25 043772

(la) wherein in formula (Ia) the groups and variables, including, but not limited to, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ , have the same meanings, including the same preferred meanings, as described and defined above in the present invention for the compound of formula (I).

In a second embodiment, the ring fragment .zvllw ΛΛ/lw contained in the compound of formula (I) is

RV

Ίγ~ι

Accordingly, in this second embodiment, the compound of formula (I) is a compound of the following formula (Ib) or a pharmaceutically acceptable salt or solvate thereof:

(lb) wherein in formula (Ib) the groups and variables, including, in particular, R ^x , R ⁴ , R ⁵ and R ⁶ , have the same meanings, including the same preferred meanings, as described and defined above in the present invention for compounds of formula (I).

In a third embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

R ²

R\J\/R ³

T _R 6/ ^A ^x ^A x _R 4

R ⁵ (la) in which R ⁴ represents the group R ^4a , in which R ⁵ represents the group R ^5a and where in formula (Ia) other groups and variables including, in particular, R ¹ , R ² , R ³ and R ⁶ , have the same meanings, including the same preferred meanings, as described and defined above in the present invention for the compound of formula (I).

In this third embodiment, R ^4a is selected from -OR ⁴¹ , -SR ⁴¹ , -NH-R ⁴¹ , -N(C1-C6-alkyl)-R ⁴¹ , halogen (eg -Cl), carbocyclyl and heterocyclyl, wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more (eg, one, two or three) R ⁴² groups. Preferably, R ^4a is selected from -OR ⁴¹ , -SR ⁴¹ , -NH-R ⁴¹ , -N(C1-C ₆ -alkyl)-R ⁴¹ , carbocyclyl (eg aryl, cycloalkyl or cycloalkenyl) and heterocyclyl (eg heteroaryl, heterocycloalkyl or heterocycloalkenyl), wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more R ⁴² groups. More preferably, R ^4a is selected from -OR ⁴¹ , -SR ⁴¹ , -NH-R ⁴¹ , -N(C ₁ -C ₄ -alkyl)-R ⁴¹ , aryl and heteroaryl, wherein said aryl and said heteroaryl are each optionally substituted one or more R ⁴² groups.

R ⁴¹ is selected from the group consisting of -(C0-C4-alkylene)carbocyclyl, -(C0-C4-alkylene)heterocyclyl, C1-C6-alkyl, C2-C6-alkenyl and C2-C6-alkynyl, where the carbocyclyl moiety contained in said -(C0-C4-alkylene)carbocyclyl, and a heterocyclyl moiety contained in said -(C0-C4-alkylene)heterocyclyl, each optionally substituted with one or more (for example, one, two or three) R ⁴² groups, and wherein said C1 -C ₆ -alkyl, the specified C ₂ -C ₆ -alkenyl, the specified C ₂ -C ₆ alkynyl, the alkylene fragment contained in the specified -(C ₀ -C ₄ -alkylene)carbocyclyl, and the alkylene fragment contained in the specified -( C ₀ -C ₄ -alkylene)heterocyclyl, each optionally substituted with one or more (eg, one, two or three) R ⁴³ groups. Preferably, R ⁴¹ is selected from the group consisting of -(C ₀ -C ₄ -alkylene)carbocyclyl, -(C ₀ -C ₄ -alkylene)heterocyclyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ -alkenyl and C ₂ -C _b -alkynyl, where the carbocyclyl fragment contained in the specified - (C ₀ - 26 043772

C ₄ -alkylene)carbocyclyl, selected from cycloalkyl, cycloalkenyl and aryl, where the heterocyclyl fragment contained in the specified - (C ₀ -C ₄ -alkylene)heterocyclyl, selected from heterocycloalkyl, heterocycloalkenyl and heteroaryl, where the carbocyclyl fragment contained in the specified - (C ₀ -C ₄ alkylene)carbocyclyl, and the heterocyclyl moiety contained in said -(C ₀ -C ₄ alkylene)heterocyclyl, each optionally substituted with one or more (for example, one, two or three) R ⁴² groups, and where additionally said C1-C6 alkyl, said C2-C6 alkenyl, said C2-C6 alkynyl, an alkylene moiety contained in said -(C0-C4-alkylene)carbocyclyl, and an alkylene moiety contained in said -(C0-C4- alkylene)heterocyclyl, each optionally substituted with one or more (eg, one, two or three) R ⁴³ groups. More preferably, R ⁴¹ is selected from -(C0- _C4 -alkylene)aryl and -( _C0 - _C4 -alkylene)heteroaryl, wherein the aryl moiety contained in said -(C0-C4-alkylene)aryl and heteroaryl moiety contained in said -(C0-C4-alkylene)heteroaryl, each optionally substituted with one or more (for example, one, two or three) R ⁴² groups, and wherein additionally an alkylene moiety contained in said -(C0-C4-alkylene)aryl , and the alkylene moiety contained in said -(C0-C4-alkylene)heteroaryl, each optionally substituted with one or more (eg, one, two or three) R ⁴³ groups. Even more preferably, R ⁴¹ is selected from -(C0-C4-alkylene)aryl and -(C0-C4-alkylene)heteroaryl, wherein the aryl moiety contained in said -(C0-C4-alkylene)aryl moiety and the heteroaryl moiety, contained in said -(C0-C4-alkylene)heteroaryl, each is optionally substituted with one or more (eg, one, two or three) R ⁴² groups. A preferred example of the aryl moiety contained in said -(C0-C ₄ -alkylene)aryl is phenyl. A preferred example of a heteroaryl moiety contained in said -( _C0 - _C4 -alkylene)heteroaryl is a 5- or 6-membered monocyclic heteroaryl containing 1 or 2 ring heteroatoms independently selected from oxygen, nitrogen and sulfur (where the remaining ring atoms are carbon) such as, for example, imidazolyl, thiophenyl or pyrimidinyl. Even more preferably, R ⁴¹ is selected from phenyl and heteroaryl, wherein said heteroaryl is a 5- or 6-membered monocyclic heteroaryl containing 1 or 2 ring heteroatoms independently selected from oxygen, nitrogen and sulfur (the remaining ring atoms of the monocyclic heteroaryl are carbon atoms ), and wherein further said phenyl or said heteroaryl is optionally substituted with one or more (eg, one, two or three) R ⁴² groups.

Each R ⁴² is independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OH, -O(C1-C6 alkyl), -O(C1-C6 alkylene)-OH, -O(C1-C6-alkylene)-O(C1-C6-alkyl), -SH, -S(C1-C6-alkyl), -NH2, -NH(C1-C6-alkyl), -N(C1-C6- alkyl)(C1-C6-alkyl), halogen, C1-C6-haloalkyl, -O-(C1-C6haloalkyl), -CN, -NO2, -CHO, -CO-(C1-C6-alkyl), -COOH, -COO-(C1-C6-alkyl), -O-CO-(C1-C6-alkyl), -CO-NH2, -CO-NH(C1-C6-alkyl), -CO-N(C1-C6- alkyl)(C1-C6-alkyl), -NH-CO-(C1-C6-alkyl), -N(C1-C6alkyl)-CO-(C1-C6-alkyl), -SO2-NH2, -SO2-NH (C1-C6-alkyl), -SO2-N(C1-C6-alkyl)(C1-C6-alkyl), -NH-SO2(C1-C6-alkyl) and -N(C1-C6-alkyl)-SO2 -(C1-C6-alkyl). Preferably, each R ⁴² is independently selected from the group consisting of C1- _C6- alkyl, -OH, -O(C1- _C6- alkyl), -O( _C1 - _C6 -alkylene)-OH, -O( C ₁ -C ₆ alkylene)-O(C1-C ₆ -alkyl), -SH, -S(C ₁ -C ₆ -alkyl), -NH ₂ , -NH(C ₁ -C ₆ -alkyl), - N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, C ₁ -C ₆ -haloalkyl, -O-(C ₁ -C ₆ -haloalkyl) and -CN.

Each R ⁴³ is independently selected from the group consisting of -OH, -O(C1-C6-alkyl), -SH, -S(C1-C6-alkyl), -NH2, -NH(C1-C6-alkyl), -N(c1 -C6-alkyl)(C1-C6-alkyl), halogen, -CF3, -CN, -NO2, -CHO, -CO-(C1C6-alkyl), -COOH, -COO-(C1-C6-alkyl), -O-CO-(C1-C6-alkyl), -CO-NH2, -CO-NH(C1-C6-alkyl), -CO-N(C1C6-alkyl)(C1-C6-alkyl), -NH- CO-(C1-C6-alkyl) and -N(C1-C6-alkyl)-CO-(C1-C6-alkyl). Preferably, each R ⁴³ is independently selected from the group consisting of -OH, -O(C1-C6 alkyl), -SH, -S(C ₁ -C ₆ alkyl), -NH ₂ , -NH(C ₁ - C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, -CF ₃ and -CN.

In accordance with the above definitions, it is particularly preferred if R ^4a is selected from the group consisting of -O-(C0-C4-alkylene)aryl, -O-(C0-C4-alkylene)heteroaryl, -S-(C0-C4-alkylene) )aryl, -S-(C0-C4-alkylene)heteroaryl, -NH-(C0-C4-alkylene)aryl, -NH-(C0-C4-alkylene)heteroaryl, -N(C1-C4alkyl)-(C0- C4-alkylene)aryl, -N(C1-C4-alkyl)-(C0-C4-alkylene)heteroaryl, aryl and heteroaryl, where the aryl fragment contained in any of the above groups, heteroaryl fragment contained in any of the above groups, said aryl and said heteroaryl are each optionally substituted with one or more (eg, one, two or three) R ⁴² groups. Even more preferably, R ^4a is selected from the group consisting of -O-aryl, -O-heteroaryl, -S-aryl, -S-heteroaryl, -NHaryl, -NH-heteroaryl, -N(C1- _C4 -alkyl) aryl, -N(C ₁ -C ₄ -alkyl)heteroaryl, aryl and heteroaryl, wherein an aryl moiety contained in any of the above groups, a heteroaryl moiety contained in any of the above groups, said aryl and said heteroaryl are each optionally substituted one or more groups independently selected from C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ alkynyl, -OH, -O(C1-C ₆ -alkyl), -O(C ₁ -C ₆ -alkylene)-OH, -O(C ₁ -C ₆ -alkylene)-O(C ₁ -C ₆ -alkyl), -SH, -S(C ₁ -C ₆ alkyl), -NH ₂ , -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, C ₁ -C ₆ -haloalkyl and -CN. Even more preferably, R ^4a is selected from the group consisting of -O-phenyl, -O-heteroaryl, -S-phenyl, -Sheteroaryl, -NH-phenyl, -NH-heteroaryl, -N(C ₁ -C ₄ -alkyl )phenyl, -N(C ₁ -C ₄ -alkyl)heteroaryl, phenyl and heteroaryl, where the specified heteroaryl or heteroaryl fragment contained in any of the above

- 27 043772 above groups, is a 5- or 6-membered monocyclic heteroaryl containing 1 or 2 ring heteroatoms independently selected from oxygen, nitrogen and sulfur (the remaining ring atoms of the monocyclic heteroaryl are carbon atoms), and wherein additionally a phenyl moiety contained in any of the above groups, a heteroaryl moiety contained in any of the above groups, said phenyl and said heteroaryl are each optionally substituted with one or more groups independently selected from C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ alkynyl, -OH, -O(C1-C ₆ -alkyl), -O(C1-C ₆ -alkylene)-OH, -O(C ₁ -C ₆ -alkylene)-O(C ₁ -C ₆ -alkyl), -SH, -S(C1-C ₆ alkyl), -NH2, -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ - C ₆ -alkyl), halogen, C ₁ -C ₆ -haloalkyl and -CN. A particularly preferred example of R ^4a is -O-phenyl.

In this third embodiment, R ^5a is selected from the group consisting of -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)(C1-C6alkyl), -NO2 and hydrogen, wherein the alkyl moiety contained in said -NH(C1-C6-alkyl), and one or both of the alkyl moieties contained in said -N(C1-C6-alkyl)(C1-C6-alkyl), each optionally substituted with one or more (for example, one, two or three) groups independently selected from halogen, -CF3, -CN, -NO2, -NH2, -NH(C1-C6-alkyl), -N(C1C6-alkyl)(C1-C6-alkyl), -OH, - O(C1-C6-alkyl), -SH, -S(C1-C6-alkyl), carbocyclyl and heterocyclyl, wherein said carbocyclyl and said heterocyclyl are all optionally substituted with one or more (for example, one, two or three) R ⁵¹ groups . Preferably, R ^5a is selected from the group consisting of -NH2, -NH(C1- _C6 -alkyl), -N( _C1 - _C6- alkyl)( _C1 - _C6 -alkyl) and -NO2, where alkyl moiety contained in said -NH(C ₁ -C ₆ -alkyl), and one or both of the alkyl moieties contained in said -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), each optionally substituted with one or more (for example, one, two or three) groups independently selected from halogen, -CF3, -CN, -NO2, _-NH2 , -NH( _C1 - _C6 -alkyl), N( _C1- C ₆ -alkyl)(C ₁ -C ₆ -alkyl), -OH, -O(C ₁ -C ₆ -alkyl), -SH and -S(C ₁ -C ₆ -alkyl). More preferably, R ^5a is selected from -NH2, -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl) and -NO2. Particularly preferred examples of R ^5a are -NH2, -NH-CH2CH2CH2CH3 or -NO2.

Each R ⁵¹ is independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OH, -O(C1-C6 alkyl), -O(C1-C6 alkylene)-OH, -O(C1-C6-alkylene)-O(C1-C6-alkyl), -SH, -S(C1-C6-alkyl), -NH2, -NH(C1-C6-alkyl), -N(C1-C6- alkyl)(C1-C6-alkyl), halogen, C1-C6-haloalkyl, -O-(C1-C6haloalkyl), -CN, -NO2, -CHO, -CO-(C1-C6-alkyl), -COOH, -COO-(C1-C6-alkyl), -O-CO-(C1-C6-alkyl), -CO-NH2, -CO-NH(C1-C6-alkyl), -CO-N(C1-C6- alkyl)(C1-C6-alkyl), -NH-CO-(C1-C6-alkyl), -N(C1-C6alkyl)-CO-(C1-C6-alkyl), -SO2-NH2, -SO2-NH (C1-C6-alkyl), -SO2-N(C1-C6-alkyl)(C1-C6-alkyl), -NH-SO2(C1-C6-alkyl) and -N(C1-C6-alkyl)-SO2 -(C1-C6-alkyl). Preferably, each R ⁵¹ is independently selected from the group consisting of C1- _C6 alkyl, -OH, -O(C1- _C6 alkyl), -O(C1- _C6 alkylene)-OH, -O(C1 -C ₆ alkylene)-O(C1-C ₆ -alkyl), -SH, -S(C ₁ -C ₆ -alkyl), -NH2, -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, C ₁ -C ₆ -haloalkyl, -O-(C1-C ₆ -haloalkyl) and -CN.

In a fourth embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

R ²

(1a) wherein R ⁴ and R ⁵ are bonded together to form the group -R ^5b -, and wherein in formula (Ia) other groups and variables, including in particular R ¹ , R ² , R ³ and R ⁶ , have the same meanings, including the same preferred meanings, as described and defined above in the present invention for the compound of formula (I).

In this fourth embodiment, R ⁴ and R ⁵ are linked together to form the group -R ^5b -. Group R ^5b selected from -R ^5b1 -R ^5b2 -R ^5b1 -, -N=C(R ⁵³ )-R ^5b3 -R ^5b1 -, -R ^5b1 -R ^5b3 -C(R ⁵³ )=N- and -N =C(R ⁵³ )-R ^5b4 C(R ⁵³ )=N-.

Each R ^5b1 is independently selected from -N(R ⁵² )-, -O- and -S-. R ^5b2 selected from -C(R ⁵³ )(R ⁵³ )-, -C(R ⁵³ )(R ⁵³ )C(R ⁵³ )(R ⁵³ )-, -C(R ⁵³ )=C(R ⁵³ )- , -C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )=C(R ⁵³ )- and -C(R ⁵³ )=C(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-. R ^5b3 is selected from a covalent bond, -C(R ⁵³ )(R ⁵³ )-, -C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )- and -C(R ⁵³ )=C( R ⁵³ )-. R ^5b4 is selected from a covalent bond and -C(R ⁵³ )(R ⁵³ )-.

Each R ⁵² is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2C6 alkynyl, -(C0-C4 alkylene)aryl, and -(C0-C4 alkylene)heteroaryl. Preferably, each R ⁵² is independently selected from the group consisting of hydrogen, C1-C4 alkyl (eg n-butyl), C ₂ -C ₄ alkenyl and C ₂ C ₄ alkynyl (eg -CH2-C=CH ). Even more preferably, each R ⁵² is hydrogen.

Each R ⁵³ is independently selected from the group consisting of hydrogen, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C _{2 -C 6} -kynyl, -OH, -O(C 1 -C ₆ -alkyl), -SH , -S(C ₁ -C ₆ -alkyl), -NH2, -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ alkyl), halogen, C ₁ -C ₆ -haloalkyl, -O-(C1-C ₆ -haloalkyl), -CN, -NO ₂ , -CHO, -CO-(C1-C ₆ -alkyl),

- 28 043772

-COOH, -COO-(C1-Cb-alkyl), -O-CO-(C1-Cb-alkyl), -CO-NH2, -CO-NH(C1-C6-alkyl), -CO-N(Ci -C ₆ alkyl)(C1-C ₆ -alkyl), -NH-CO-(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)-CO-(C ₁ -C ₆ - alkyl), -SO2-NH2, -SO2-NH(C1C ₆ -alkyl), -SO ₂ -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), -NH-SO ₂ -( C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)-SO ₂ -(C ₁ -C ₆ -alkyl), -(C ₀ -C ₄ -alkylene)aryl and -(Co- C ₄ -alkylene)heteroaryl; in addition, any two R ⁵³ groups that are attached to the same carbon atom can also together form an =O group, and any two R ⁵³ groups that are attached to adjacent carbon atoms connected by a double bond (i.e., any the two R ⁵³ groups contained in the fragment -C(R ⁵³ )=C(R ⁵³ )-) can also be linked together to form the group -C(R ⁵⁴ )=C(R ⁵⁴ )-C(R ⁵⁴ )= C(R ⁵⁴ )-. Preferably, each R ⁵³ is independently selected from the group consisting of hydrogen, C1-C6 alkyl, -OH, -O(C1-C6 alkyl), -SH, -S(C1-C6 alkyl), -NH2, - NH(C1-C6-alkyl), -N(C1-C6-alkyl)(C1-C6-alkyl), halogen, C1-C6-haloalkyl, -O-(C1-Cb-haloalkyl) and -CN, and any two ^R53 groups that are attached to the same carbon atom can also together form an =O group, and any two ^R53 groups that are attached to adjacent carbon atoms connected by a double bond can also be bonded together to form a - group C(R ⁵⁴ )=C(R ⁵⁴ )-C(R ⁵⁴ )=C(R ⁵⁴ )-. More preferably, each R ⁵³ is independently selected from the group consisting of hydrogen, C 1 -C ₆ -alkyl, -OH, -O(C ₁ -C ₆ -alkyl), -SH, -S(C ₁ -C ₆ -alkyl ), -NH2, -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, C ₁ -C ₆ -haloalkyl, -O -(C ₁ -C ₆ -haloalkyl) and -CN, and any two R ⁵³ groups that are attached to the same carbon atom can also together form an =O group. Even more preferably, each R ⁵³ is independently selected from the group consisting of hydrogen, C 1 -C ₄ -alkyl, -OH, -O(C ₁ -C ₄ -alkyl), -NH2, -NH(C ₁ -C ₄ - alkyl), -N(C ₁ -C ₄ -alkyl)(C ₁ -C ₄ -alkyl), halogen, C1-C ₄ -haloalkyl, -O-(C ₁ -C ₄ -haloalkyl), and -CN, and any two R ⁵³ groups that are attached to the same carbon atom can also together form an =O group.

Each R ⁵⁴ is independently selected from the group consisting of hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2C6-alkynyl, -OH, -O(C1-C6-alkyl), -SH, -S(C1-C6- alkyl), -NH2, -NH(C1-C6-alkyl), -N(C1-C6-alkyl)(C1-C6alkyl), halogen, C1-C6-haloalkyl, -O-(C1-C6-haloalkyl), -CN, -NO2, -CHO, -CO-(C1-C6-alkyl), -COOH, -COO-(C1-C6-alkyl), -O-CO-(C1-C6-alkyl), -CO- NH2, -CO-NH(C1-C6-alkyl), -CO-N(C1-C6-alkyl)(C1-C6-alkyl), -NH-CO-(C1-C6-alkyl), -N(C1-C6 -alkyl)-CO-(C1-C6-alkyl), -SO2-NH2, -SO2-NH(C1C6-alkyl), -SO2-N(C1-C6-alkyl)(C1-C6-alkyl), -NH -SO2-(C1-C6-alkyl) and -N(C1-C6-alkyl)-SO2-(C1-C6-alkyl). Preferably, each R ⁵⁴ is independently selected from the group consisting of hydrogen, C1-C6alkyl, -On, -O(C1- _C6alkyl ), -SH, -S( _{C1- C6alkyl} ), -NH2, -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ alkyl), halogen, C ₁ -C ₆ -haloalkyl, -O-(C1-C ₆ -haloalkyl) and -CN. More preferably, each R ⁵⁴ is hydrogen.

It is particularly preferred if R ^5b is selected from -N(R ⁵² )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -N=C(R ⁵³ )-N(R ⁵² )-, -N (R ⁵² )-C(R ⁵³ )=N-, -N(R ⁵² )-C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -N =C(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -N(R ⁵² )C(R ⁵³ )=C(R ⁵³ )-N(R ⁵² )-, - N(R ⁵² )-C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )=N-, -N=C(R ⁵³ )-C(R ⁵³ )=N-, -N(R ⁵² )- C(R ⁵³ )(R ⁵³ )C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -N=C(R ⁵³ )-C(R ⁵³ ) (R ⁵³ )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -N(R ⁵² )-C(R ⁵³ )(R ⁵³ )C(R ⁵³ )=C(R ⁵³ )- N(R ⁵² )-, -N(R ⁵² )-C(R ⁵³ )=C(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -N(R ⁵² )- C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )C(R ⁵³ )=N-, -N=C(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )=N-, -OC(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -OC(R ⁵³ )(R 53 )-C(R ⁵³ )(R ⁵³ )-N( ^{R 52 )} -, -OC(R ⁵³ )=C(R ⁵³ )-N(R ⁵² )-, -OC(R ⁵³ )(R 53 )-C(R ⁵³ )(R ⁵³ )-C( ^{R 53 )} (R ⁵³ )-N(R ⁵² )-, -OC(R ⁵³ )(R ⁵³ )-C(R ⁵³ )=C(R ⁵³ )-N(R ⁵² )-, -OC(R ⁵³ )=C(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -N(R ⁵² )-C(R ^{53 )(R 53 )} -O-, -N(R ⁵² )-C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-O-, -N(R ⁵² )C(R ⁵³ )=C(R ⁵³ )-O-, -N(R ⁵² )-C( R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-O-, -N(R ⁵² )-C(R ⁵³ )(R ⁵³ )-C( R ⁵³ )=C(R ⁵³ )-O-, -N(R ⁵² )-C( ^{R 53} )=C(R 53 )-C(R ⁵³ )(R ⁵³ )-O-, -SC(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -SC(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -SC(R ⁵³ )=C( R ⁵³ )-N(R ⁵² )-, -SC(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, - SC(R ⁵³ )(R ⁵³ )-C(R ⁵³ )=C(R ⁵³ )-N(R ⁵² )-, -SC(R ⁵³ )=C(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -N(R ⁵² )-C(R ⁵³ )(R ⁵³ )-S-, -N(R ⁵² )-C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-S-, -N(R ⁵² )C(R ⁵³ )=C(R ⁵³ )-S-, -N(R ⁵² )-C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-S-, -N(R ⁵² )-C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )=C(R ⁵³ )-S -, -N(R ⁵² )-C(R ⁵³ )=C(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-S-, -N(R ⁵² )-C(R ⁵³ )(R ⁵³ ) -(R ⁵² )-, -N(R ⁵² )-C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -N(R ⁵² )-C( R ⁵³ )=C(R ⁵³ )-N(R ⁵² )-, -N(R ⁵² )-C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )( R ⁵³ )-N(R ⁵² )-, -N(R ⁵² )-C(R ⁵³ )(R ⁵³ )C(R ⁵³ )=C(R ⁵³ )-N(R ⁵² )- and -N(R ⁵² )-C(R ⁵³ )=C(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-.

In this fourth embodiment, it is even more preferable if R ^5b is selected such that the compound of formula (Ia) has any of the following structures:

- 29 043772

In a fifth embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

(1a) in which R ⁴ represents the group R ^4a , in which R ^4a represents -O-phenyl, in which R ⁵ represents the group R ^5a , and where in formula (Ia) other groups and variables, including, in particular, R ¹ , R ² , R ³ , R ^5a and R ⁶ have the same meanings, including the same preferred meanings, as described and defined above in the present invention for the compound of formula (I).

In a sixth embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

(1a) in which R ⁴ represents the group R ^4a in which R ⁵ represents the group R ^5a in which R ^5a represents

-NH ₂ , and wherein in formula (Ia) the other groups and variables, including in particular R ¹ , R ² , R ³ , R ^4a and R ⁶ , have the same meanings, including the same preferred meanings, as described and defined above in the present invention for the compound of formula (I).

In a seventh embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

- 30 043772

(la) in which R ⁴ represents the group R ^4a , in which R ⁵ represents the group R ^5a , in which R ^5a represents -NH-CH2CH2CH2CH3 , and where in formula (Ia) other groups and variables, including, in particular, R ¹ , R ² , R 3 , R ^4a and R ⁶ have the same meanings, including the same preferred meanings, as described and defined above in the present invention for the compound of formula (I).

In an eighth embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

(1a) in which R ⁴ represents the group R ^4a in which R ⁵ represents the group R ^5a in which R ^5a represents

-NO ₂ , and wherein in formula (Ia) the other groups and variables, including, but not limited to, R ¹ , R ² , R 3 , R ^4a and R ⁶ , have the same meanings, including the same preferred meanings, as described and defined above in the present invention for the compound of formula (I).

In a ninth embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

R ²

ΤΪ ρδ^^/^ρ ⁴

^R5 . „ 3 - .........g. .

in which R ³ denotes -SO2-NH2, and where in formula (Ia) other groups and variables, including, in particular, R ¹ , R ² , R ⁴ , R ⁵ and R ⁶ , have the same meanings, including the same preferred values are as described and defined above in the present invention for the compound of formula (I).

In a tenth embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

R ² rI^J^^R ³ TY

R ⁵ (la) in which R ³ denotes -SO ₂ -N=CH-N(CH ₃ ) ₂ , and where in formula (Ia) other groups and variables, including, in particular, R ¹ , R ² , R ⁴ , R ⁵ and R ⁶ have the same meanings, including the same preferred meanings, as described and defined above in the present invention for the compound of formula (I).

In an eleventh embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

R ²

R\J\^R ³

CT r6^V^R ⁴

R ⁵ (la) in which R ³ is -SO2-NH2, in which R ⁴ is a group R ^4a , in which R ^4a is -O-phenyl, in which R ⁵ is a group R ^5a , and where in formula (Ia) other groups and variables, including, in particular, R ¹ , R ² , R ^5a and R ⁶ , have the same meanings, including the same preferred meanings, as described and defined above in the present invention for the compound of formula (I).

In a twelfth embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

- 31 043772

(la) in which R ³ is -SO2-NH2, in which R ⁴ is a group R ^4a , in which R ⁵ is a group R ^5a , in which R ^5a is -NH2, and where in formula (Ia) other groups and variables , including in particular R ¹ , R ² , R ^4a and R ⁶ , have the same meanings, including the same preferred meanings, as described and defined above in the present invention for the compound of formula (I).

In a thirteenth embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

R ² _R 6/^y^ _R 4

R ⁵ (la) in which R ³ represents -SO2-NH2, in which R ⁴ represents the group R ^4a , in which R ⁵ represents the group R ^5a , in which R ^5a represents -NH-CH ₂ CH ₂ CH ₂ CH ₃ , and wherein in formula (Ia) other groups and variables, including, in particular, R ¹ , R ² , R ^4a and R ⁶ , have the same meanings, including the same preferred meanings, as described and defined above in the present invention for the compound formula (I).

In a fourteenth embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

R ² t t

R ⁵ (la) in which R ³ is -SO2-NH2, in which R ⁴ is a group R ^4a , in which R ⁵ is a group R ^5a , in which R ^5a is -NO2, and where in formula (Ia) other groups and the variables, including, in particular, R ¹ , R ² , R ^4a and R ⁶ , have the same meanings, including the same preferred meanings, as described and defined above in the present invention for the compound of formula (I).

In a fifteenth embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

R ² r6/^Y^r4

R ⁵ (la) in which R ³ represents -SO ₂ -N=CH-N(CH ₃ ) ₂ in which R ⁴ represents the group R ^4a in which R ^4a represents -O-phenyl in which R ⁵ represents the group R ^5a , and wherein in formula (Ia) the other groups and variables, including, but not limited to, R ¹ , R ² , R ^5a and R ⁶ , have the same meanings, including the same preferred meanings, as described and defined herein above invention for a compound of formula (I).

In a sixteenth embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

(1a) in which R ³ is -SO ₂ -N=CH-N(CH ₃ ) ₂ , in which R ⁴ is a group R ^4a , in which R ⁵ is a group R ^5a , in which R ^5a is -NH2 , and wherein in formula (Ia) the other groups and variables, including, in particular, R ¹ , R ² , R ^4a and R ⁶ , have the same meanings, including the same preferences

- 32 043772 meanings as described and defined above in the present invention for the compound of formula (I).

In a seventeenth embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

(1a) in which R ³ is -SO2-N=CH-N(CH3)2, in which R ⁴ is a group R ^4a , in which R ⁵ is a group R ^5a , in which R ^5a is -NH-CH2CH ₂ CH ₂ CH ₃ and wherein in formula (Ia) the other groups and variables, including, in particular, R ¹ , R ² , R ^4a and R ⁶ , have the same meanings, including the same preferred meanings, as described and defined above in the present invention for a compound of formula (I).

In an eighteenth embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

(1a) in which R ³ is -SO2-N=CH-N(CH3)2, in which R ⁴ is a group R ^4a , in which R ⁵ is a group R ^5a , in which R ^5a is -NO2, and where in formula (Ia), other groups and variables, including, in particular, R ¹ , R ² , R ^4a and R ⁶ , have the same meanings, including the same preferred meanings, as described and defined above in the present invention for the compound of formula (I ).

In a nineteenth embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

R ²

R^J^^R ³ t t

R ⁵ _ 4 .. .........

wherein R ⁴ is -O-phenyl, wherein R ⁵ is -NH2, and wherein in formula (Ia) other groups and variables, including in particular R ¹ , R ² , R ³ and R ⁶ , have the same values, including the same preferred values as described and defined above in the present invention for the compound of formula (I).

In a twentieth embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

R ² rL^L^^ ³

Ρθ-^γ^ρ ⁴

R ⁵ (la) in which R ⁴ is -O-phenyl, in which R ⁵ is -NH-CH ₂ CH ₂ CH ₂ CH ₃ , and where in formula (Ia) other groups and variables, including, in particular, R ¹ , R ² , R ³ and R ⁶ have the same meanings, including the same preferred meanings, as described and defined above in the present invention for the compound of formula (I).

In the twenty-first embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

(1a) wherein R ⁴ is -O-phenyl, wherein R ⁵ is -NO2, and where in formula (Ia) other groups and variables including, but not limited to, R ¹ , R ² , R ³ and R ⁶ have the same meanings, including the same preferred meanings, as described and defined above in the present invention for the compound of formula (I).

In a twenty-second embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

(1a) wherein R ¹ is as defined below, and wherein in formula (Ia) the other groups and variables, including in particular R ² , R ³ , R ⁴ , R ⁵ and R ⁶ , have the same meanings , including the same preferred values as described and defined above in the present invention for the compound of formula (I).

In this twenty-second embodiment, R ¹ is -COO-(C1-C15-alkyl), wherein the alkyl moiety contained in said -COO-(C1-C15-alkyl) is optionally substituted with one or more (for example, one, two or three) groups independently selected from halogen, -CF3, -CN, -NO2, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)(C1-C4-alkyl), -OH , -O(C1-C4-alkyl), -SH and -S(C1-C4-alkyl), and where additionally one or two -CH2- units included in the alkyl fragment contained in the specified -COO-(C1-C15 -alkyl), each optionally replaced by a group independently selected from -O-, -CO-, -COO-, -O-CO-, -NH-, -N(C1-C4-αalkyl)-, -NH-CO- , -N(C1-C4-alkyl)-СО-, -CO-NH-, -СО-N(С1-С4-alkyl)-, -S-, -SO-, -SO2-, -SO2-NH- , -SO2-N(C1-C4-alkyl)-, -NH-SO2- and -N(C1-C4-alkyl)-SO2-. The alkyl moiety contained in said -COO-(C1-C15-alkyl) contains from 1 to 15 carbon atoms, preferably from 1 to 10 carbon atoms. Preferred examples of such R ¹ groups include the corresponding R ¹ groups contained in the compounds described in the examples section, including, in particular, -COO-CH3 or -COO-CH ₂ CH ₃ . A particularly preferred R ¹ group is -COO-CH ₃ .

In a twenty-third embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

R ² r^J^^r ³ T Y

R ⁵ (la) in which R ¹ denotes -COOH, and where in formula (Ia) other groups and variables, including, in particular, R ² , R ³ , R ⁴ , R ⁵ and R ⁶ , have the same meanings, including the same preferred values as described and defined above in the present invention for the compound of formula (I).

In a twenty-fourth embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

R ²

I T

R ^6/ yS ⁴

R ⁵ (la) wherein R ¹ is as defined below, and wherein in formula (Ia) the other groups and variables, including in particular R ² , R ³ , R ⁴ , R ⁵ and R ⁶ , have such the same meanings, including the same preferred meanings, as described and defined above in the present invention for the compound of formula (I).

In this twenty-fourth embodiment, R ¹ is selected from the group consisting of -(C1-C4alkylene)-NH-(C1-C4-alkylene)-R ¹² (for example, -CH2-NH-CH ₂ -R ¹² ), -COO- (C1-C4-alkylene)-R ¹² (for example, -COO-CH2-R ¹² ), -O-CO-(C1-C4-alkylene)-R ¹² , -CO-(C1-C4-alkylene)-R ¹² , -CO-NH-(C1-C4-alkylene)-R ¹² (for example, -CO-NH-CH2-R ¹² ), -CO-N(C1-C ₄ -alkyl)-(C ₁ -C ₄ -alkylene)-R ¹² , -NH-CO-(C1-C4-alkylene)-R ¹² and -N(C1-C ₄ -alkyl)-CO-(C ₁ -C ₄ -alkylene)-R ¹² , where R ¹² is independently selected from the group consisting of -CF3, -CN and halogen (eg -F, -Cl, -Br or -I). Preferably, R ¹² is independently selected from the group consisting of -CF3 and -CN; more preferably, R ¹² is -CF3. Specific examples of such R ¹ groups include the corresponding R ¹ groups contained in the compounds described in the examples section. More preferably, R ¹ is -(C1-C ₄ -alkylene)-NH-(C ₁ -C ₄ -alkylene)- 34 043772

CF ₃ , and even more preferably, R ¹ is -CH2-NH-CH2-CF3.

Thus, according to this twenty-fourth embodiment, the present invention provides a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

R ²

(1a)

In this twenty-fourth embodiment, in formula (Ia), R ¹ is selected from the group consisting of -(C1-C4-alkylene)-NH-(C1-C4-alkylene)-R ¹² (for example, -CH2-NH-CH2-R ¹² ), -COO-(C1-C ₄ -alkylene)R ¹² (for example, -COO-CH2-R ¹² ), -O-CO-(C1-C ₄ -alkylene)-R ¹² , -CO-(C1 -C4-alkylene)-R ¹² , -CO-NH-(CrC ₄ alkylene)-R ¹² (for example, -CO-NH-CH2-R ¹² ), -CO-N(C1-C4-alkyl)-(C1 -C4-alkylene)-R ¹² , -NH-CO-(C1-C ₄ alkylene)-R ¹² and -N(C1-C4-alkyl)-CO-(C1-C4-alkylene)-R ¹² , where R ¹² is independently selected from -CF3, -CN and halogen (eg -F, -Cl, -Br or -I). Preferably, R ¹² is independently selected from -CF3 and -CN; more preferably, R ¹² is -CF3. Specific examples of such R ¹ groups include the corresponding R ¹ groups contained in the compounds described in the examples section. Particularly preferably, R ¹ is -(C ₁ -C ₄ -alkylene)-NH-(C ₁ -C ₄ -alkylene)-CF ₃ , and even more preferably, if R ¹ is -CH2-NH-CH2-CF3 .

In the twenty-fourth embodiment, R ² is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OH, -O(C1-C6 alkyl), -O(C1-C6- alkylene)-OH, -O(C1-C6-alkylene)O(C1-C6-alkyl), -SH, -S(C1-C6-alkyl), -NH2, -NH(C1-C6-alkyl), - N(C1-C6-alkyl)(C1-C6-alkyl), halogen, C1C6-haloalkyl, -O-(C1-C6-haloalkyl), -CN, -NO2, -CHO, -CO-(C1-C6- alkyl), -COOH, -COO-(C1-C6-alkyl), -O-CO-(C1-C6-alkyl), -CO-NH2, -CO-NH(C1-C6-alkyl), -CO-N( C1-C6-alkyl)(C1-C6-alkyl), -NHCO-(C1-C6-alkyl), -N(C1-C6-alkyl)-CO-(C1-C6-alkyl), -SO2-NH2, -SO2-NH(C1-C6-alkyl), -SO2-N(C1-C6-alkyl)(C1-C6-alkyl), -NH-SO2-(C1-C6-alkyl) and -N(C1-C6-alkyl )-SO2-(C1-C6-alkyl). Preferably, R ² is selected from the group consisting of hydrogen, C 1 -C ₆ -alkyl, -OH, -O(C ₁ -C ₆ -alkyl), -O(C ₁ -C ₆ -alkylene)-OH, -O (C ₁ -C ₆ -alkylene) -O(C ₁ -C ₆ -alkyl), -SH, -S(C ₁ -C ₆ -alkyl), -NH2, -NH(C ₁ -C ₆ -alkyl) , -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, C ₁ -C ₆ -haloalkyl, -O-(C ₁ -C ₆ -haloalkyl) and -CN. More preferably, R ² is hydrogen or C1- _C4 alkyl. Even more preferably, R ² is hydrogen.

In the twenty-fourth embodiment, R ³ is selected from the group consisting of -SO2-NH2, -SO2NH(C1-C6-alkyl), -SO2-N(C1-C6-alkyl)(C1-C6-alkyl), -SO2-N =(C1-C6-alkylidene) and -SO2-halogen, where the alkyl fragment contained in the specified -SO2-NH(C1-C6-alkyl), one or both of the alkyl fragments contained in the specified -SO2-N(C1-C6 -alkyl)(C1-C6-alkyl), and the alkylidene moiety contained in said -SO2-N=(C1-C6-alkylidene), each optionally substituted with one or more (e.g., one, two or three) groups independently selected from halogen, -CF3, -CN, -NO2, -NH2, -NH(C1-C6-alkyl), -N(C1-C6-alkyl)(C1-C6-alkyl), -OH, -O(C1- C6-alkyl), -SH and -S(C1-C6-alkyl). Preferably, R ³ is selected from -SO2-NH2, -SO2-NH(C ₁ -C ₄ -alkyl), -SO ₂ -N(C ₁ -C ₄ -alkyl)(C ₁ -C ₄ -alkyl) and -SO ₂ -N=(C ₁ -C ₄ -alkylidene), where the alkyl fragment contained in the specified -SO ₂ -NH(C ₁ -C ₄ alkyl), one or both of the alkyl fragments contained in the specified -SO ₂ - N(C ₁ -C ₄ -alkyl)(C ₁ -C ₄ -alkyl), and the alkylidene moiety contained in said -SO ₂ -N=(C ₁ -C ₄ -alkylidene), each optionally substituted with one or more groups ( preferably one group), independently selected from halogen, -CF ₃ , -CN, -NO2, -NH2, -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ - C ₆ -alkyl), -OH, -O (C ₁ -C ₆ -alkyl), -SH and -S (C ₁ -C ₆ -alkyl). More preferably, R ³ is selected from -SO2-NH2, -SO2NH(C1-C4-alkyl), -SO2-N(C1-C4-alkyl)(C1-C4-alkyl) and -SO2-N=(C1- C4-alkylidene), where the alkyl fragment contained in the specified -SO2-NH(C1-C4-alkyl), one or both alkyl fragments contained in the specified -SO2-N(C1-C4-alkyl)(C1-C4-alkyl) ), and the alkylidene moiety contained in said -SO2-N=(C1-C4-alkylidene), each optionally substituted with one group selected from -NH2, -NH(C1-C4-alkyl) and -N(C1-C4- alkyl)(C1-C4-alkyl). Even more preferably, R ³ is selected from -SO2NH2, -SO2-NH(C ₁ -C ₄ -alkyl), -SO ₂ -N(C ₁ -C ₄ -alkyl)(C ₁ -C ₄ -alkyl), -SO ₂ -NH- (C ₁ -C ₄ -alkylene) -NH ₂ , -SO2-NH (C ₁ -C ₄ -alkylene) -NH (C ₁ -C ₄ -alkyl), -SO ₂ -NH- (C ₁ -C ₄ -alkylene)-N(C ₁ -C ₄ -alkyl)(C ₁ -C ₄ -alkyl), -SO ₂ -N=(C ₁ -C ₄ alkylidene) -NH ₂ , -SO ₂ -N=(C ₁ -C ₄ -alkylidene)-NH(C ₁ -C ₄ -alkyl) and -SO ₂ -N=(C ₁ -C ₄ -alkylidene)-N(C ₁ -C ₄ -alkyl) (C ₁ -C ₄ -alkyl). Even more preferably, R ³ is selected from -SO2-NH2, -SO2-NH-CH3, -SO ₂ N(CH ₃ )2, -SO ₂ -NH-(C ₁ -C ₄ -alkylene)-NH ₂ , -SO ₂ -NH-(C ₁ -C ₄ -alkylene)-NH-CH ₃ , -SO ₂ -NH-(C ₁ -C ₄ -alkylene)N(CH ₃ ) ₂ (for example, -SO ₂ -NH -CH ₂ CH ₂ -N(CH ₃ ) ₂ ), -SO ₂ -N=(C ₁ -C ₄ -alkylidene)-NH ₂ , -SO ₂ -N=(C ₁ -C ₄ alkylidene)-NH- CH ₃ and -SO ₂ -N=(C ₁ -C ₄ -alkylidene)-N(CH ₃ ) ₂ (for example, -SO ₂ -N=CH-N(CH ₃ ) ₂ ). Even more preferably, R ³ is -SO2-NH2.

In the twenty-fourth embodiment, R ⁴ is selected from -OR ⁴¹ , -SR ⁴¹ , -NH-R ⁴¹ , -N(C ₁ -C ₆ alkyl)-R ⁴¹ , halogen (eg -Cl), hydrogen, carbocyclyl and heterocyclyl wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more (eg, one, two or three) R ⁴² groups. Preferably, R ⁴ is selected from the group consisting of -OR ⁴¹ , -SR ⁴¹ , -NHR ⁴¹ , -N(C1-C6-alkyl)-R ⁴¹ , halogen, carbocyclyl and heterocyclyl, wherein said carbocyclyl and said heterocyclyl are each optionally substituted one or more R ⁴² groups. More preferably, R ⁴ is selected from the group consisting of -OR ⁴¹ , -SR ⁴¹ , -NH-R ⁴¹ , -N(C1-C ₆ -alkyl)-R ⁴¹ , carbocyclyl (for example, aryl, cycloalkyl or cycloalkenyl) and heterocyclyl (eg, heteroaryl, heterocycloalkyl or heterocycloalkenyl), wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more R ⁴² groups. Even more preferably, R is selected from the group consisting of -OR ⁴¹ , -SR ⁴¹ , -NH-R ⁴¹ , -N(C ₁ -C ₄ -alkyl)-R ⁴¹ , aryl and heteroaryl, wherein said aryl and said heteroaryl each is optionally substituted with one or more R ⁴² groups.

In the twenty-fourth embodiment, R ⁴¹ is selected from the group consisting of -(C0-C4alkylene)carbocyclyl, -(C0-C4-alkylene)heterocyclyl, C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl, wherein carbocyclyl moiety contained in said -(C0-C4-alkylene)carbocyclyl, and heterocyclyl moiety contained in said -(C0-C4-alkylene)heterocyclyl, each optionally substituted with one or more (for example, one, two or three) R ⁴² groups , and where the specified C1-C6 alkyl, the specified C2-C ₆ -alkenyl, the specified C ₂ -C ₆ -alkynyl, the alkylene fragment contained in the specified -(C ₀ -C ₄ -alkylene)carbocyclyl, and the alkylene fragment contained in the specified -(C ₀ -C ₄ -alkylene)heterocyclyl, each optionally substituted with one or more (eg, one, two or three) R ⁴³ groups. Preferably, R ⁴¹ is selected from the group consisting of -(C0-C4alkylene)carbocyclyl, -(C0-C4-alkylene)heterocyclyl, C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl, wherein the carbocyclyl moiety, contained in said -(C0-C4-alkylene)carbocyclyl is selected from the group consisting of cycloalkyl, cycloalkenyl and aryl, wherein the heterocyclyl moiety contained in said -(C0-C4-alkylene)heterocyclyl is selected from the group consisting of heterocycloalkyl, heterocycloalkenyl and heteroaryl, wherein the carbocyclyl moiety contained in said -(C0-C4alkylene)carbocyclyl and the heterocyclyl moiety contained in said -(C0-C4alkylene)heterocyclyl are each optionally substituted with one or more (for example, one, two or three) R ⁴² groups , and where additionally the specified C1-C ₆ -alkyl, the specified C ₂ -C ₆ -alkenyl, the specified C ₂ -C ₆ -alkynyl, the alkylene fragment contained in the specified -(C ₀ -C ₄ -alkylene)carbocyclyl, and the alkylene moiety contained in said -(C ₀ -C ₄ -alkylene)heterocyclyl, each optionally substituted with one or more (eg, one, two or three) R ⁴³ groups. More preferably, R ⁴¹ is selected from the group consisting of -(C0-C4-alkylene)aryl and -(C0-C4-alkylene)heteroaryl, wherein the aryl moiety contained in said -(C0-C4-alkylene)aryl and heteroaryl moiety contained in said -(C0-C4-alkylene)heteroaryl, each optionally substituted with one or more (for example, one, two or three) R ⁴² groups, and wherein additionally an alkylene moiety contained in said -(C0-C4-alkylene) )aryl, and the alkylene moiety contained in said -(C0-C4alkylene)heteroaryl, each optionally substituted with one or more (eg, one, two or three) R ⁴³ groups. Even more preferably, R ⁴¹ is selected from the group consisting of -(C0-C4alkylene)aryl and -(C0- _C4alkylene )heteroaryl, wherein the aryl moiety contained in said -( _C0 - _C4alkylene )aryl, and the heteroaryl moiety contained in said -(C ₀ -C ₄ -alkylene) heteroaryl, each optionally substituted with one or more (eg, one, two or three) R ⁴² groups. A preferred example of the aryl moiety contained in said -(C ₀ -C ₄ -alkylene) aryl is phenyl. A preferred example of a heteroaryl moiety contained in said -( _C0 - _C4 -alkylene)heteroaryl is a 5- or 6-membered monocyclic heteroaryl containing 1 or 2 ring heteroatoms independently selected from oxygen, nitrogen and sulfur (where the remaining ring atoms are carbon atoms), such as, for example, imidazolyl, thiophenyl or pyrimidinyl. Even more preferably, R ⁴¹ is selected from phenyl and heteroaryl, wherein said heteroaryl is a 5- or 6-membered monocyclic heteroaryl containing 1 or 2 ring heteroatoms independently selected from oxygen, nitrogen and sulfur (the remaining ring atoms of the monocyclic heteroaryl are carbon atoms ), and wherein further said phenyl or said heteroaryl is optionally substituted with one or more (eg, one, two or three) R ⁴² groups.

In the twenty-fourth embodiment, each R ⁴² is independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OH, -O(C1-C6 alkyl), -O(C1- C6-alkylene)-OH, -O(C1C6-alkylene)-O(C1-C6-alkyl), -SH, -S(C1-C6-alkyl), -NH2, -NH(C1-C6-alkyl), -N(C1-C6-alkyl)(C1-C6-alkyl), halogen, C1-C6-haloalkyl, -O-(C1-C6-haloalkyl), -CN, -NO2, -CHO, -CO-(C1 -C6-alkyl), -COOH, -COO-(C1-C6-alkyl), -O-CO-(C1-C6-alkyl), -CO-NH2, -CO-NH(C1-C6-alkyl), -CO-N(C1-C6-alkyl)(C1-C6-alkyl), -NH-CO-(C1-C6-alkyl), -N(C1-C6-alkyl)-CO-(C1-C6-alkyl), -SO2-NH2, -sO2-NH(C1-C6-alkyl), -SO2-N(C1-C6-alkyl)(C1-C6-alkyl), -NH-SO2-(C1-C6-alkyl) and - N(C1-C6-alkyl)-SO2-(C1-C6-alkyl). Preferably, each R ⁴² is independently selected from the group consisting of C1- _C6 alkyl, -OH, -O(C1- _C6 alkyl), -O( _C1 - _C6 alkylene)-OH, -0(C ₁ -C ₆ -alkylene) -0 (C ₁ -C ₆ -alkyl), -SH, -S (C ₁ -C ₆ -alkyl), -NH ₂ , -Nh (C ₁ -C ₆ -alkyl), - N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, C ₁ -C ₆ -haloalkyl, -O-(C ₁ -C ₆ -haloalkyl) and -CN.

In the twenty-fourth embodiment, each R ⁴³ is independently selected from the group consisting of -OH, -O(C1- _C6 -alkyl), -SH, -S( _C1 - _C6 -alkyl), _-NH2 , -NH( C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ - 36 043772 alkyl), halogen, -CF ₃ , -CN, -NO2, -CHO, -CO- (C ₁ -C ₆ -alkyl), -COOH, -COO-(C ₁ -C ₆ -alkyl), -O-CO-(C ₁ -C ₆ alkyl),

-CO-NH2, -СО-NH(С ₁ -С ₆ -alkyl), -СО-N(С ₁ -С ₆ -alkyl)(С ₁ -С ₆ -alkyl), -NH-CO-(C ₁ -C ₆ -alkyl) and -N(C ₁ -C ₆ alkyl)-CO-(C ₁ -C ₆ -alkyl). Preferably, each R ⁴³ is independently selected from the group consisting of -OH, -O(C1- _C6 -alkyl), -SH, -S( _C1 - _C6 -alkyl), -NH2, -NH( _C1- C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, -CF ₃ and -CN.

In the twenty-fourth embodiment, in accordance with the above definitions, it is particularly preferred if R ⁴ is selected from the group consisting of -O-(C0-C4-alkylene)aryl, -O-(C0-C4-alkylene)heteroaryl, -S-(C0- C4-alkylene)aryl, -S-(C0-C4-alkylene)heteroaryl, -NH-(C0-C4-alkylene)aryl, -NH-(C0-C4-alkylene)heteroaryl, -N(C1-C4-alkyl) )-(C0-C4-alkylene)aryl, -N(C1-C4-alkyl)-(C0-C4alkylene)heteroaryl, aryl and heteroaryl, where the aryl fragment contained in any of the above groups, the heteroaryl fragment contained in any of the above groups, said aryl and said heteroaryl are each optionally substituted with one or more (eg, one, two or three) R ⁴² groups. Even more preferably, R ⁴ is selected from the group consisting of -O-aryl, -O-heteroaryl, -S-aryl, -S-heteroaryl, -NH-aryl, -NH-heteroaryl, -N(C1-C ₄ - alkyl)aryl, -N(C ₁ -C ₄ alkyl)heteroaryl, aryl and heteroaryl, wherein an aryl moiety contained in any of the above groups, a heteroaryl moiety contained in any of the above groups, said aryl and said heteroaryl each optionally substituted with one or more groups independently selected from C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, -OH, -O(C1-C ₆ -alkyl), -O( C1-C ₆ -alkylene)-OH, -O(C ₁ -C ₆ -alkylene)-O(C ₁ -C ₆ -alkyl), -SH, -S(C ₁ -C ₆ -alkyl), -NH2 , -NH(C ₁ -C ₆ -alkyl), -N(c ₁ -C ₆ -alkyl)(C ₁ -C ₆ alkyl), halogen, C ₁ -C ₆ -haloalkyl and -CN. Even more preferably, R ⁴ is selected from the group consisting of -O-phenyl, -O-heteroaryl, -S-phenyl, -S-heteroaryl, -NH-phenyl, -NH-heteroaryl, -N(C ₁ -C ₄ alkyl)phenyl, -N(C ₁ -C ₄ -alkyl)heteroaryl, phenyl and heteroaryl, where said heteroaryl or heteroaryl fragment contained in any of the above groups is a 5- or 6-membered monocyclic heteroaryl containing 1 or 2 ring heteroatom independently selected from oxygen, nitrogen and sulfur (the remaining ring atoms of the monocyclic heteroaryl are carbon atoms), and wherein additionally a phenyl moiety contained in any of the above groups, a heteroaryl moiety contained in any of the above groups, said phenyl and heteroaryl is each optionally substituted with one or more groups independently selected from C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, -OH, -O(C1-C ₆ -alkyl), -O(C ₁ -C ₆ alkylene)-OH, -O(C1-C ₆ -alkylene)-O(C1-C ₆ -alkyl), -SH, -S(C ₁ -C ₆ -alkyl), - NH2, -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C1-C ₆ -alkyl), halogen, C ₁ -C ₆ -haloalkyl and -CN. Even more preferably, R ⁴ is -O-phenyl.

In the twenty-fourth embodiment, R ⁵ is selected from the group consisting of -NH2, -NH(C1C6-alkyl), -N(C1-C6-alkyl)(C1-C6-alkyl), -NO2 and hydrogen, wherein the alkyl moiety contained in said -NH(C1-C6-alkyl), and one or both of the alkyl moieties contained in said -N(C1-C6-alkyl)(C1-C6-alkyl), each optionally substituted with one or more (for example, one, two or three) groups independently selected from halogen, -CF3, -CN, -NO2, -NH2, -NH(C1-C6-alkyl), -N(C1C6-alkyl)(C1-C6-alkyl), -OH, - O(C1-C6-alkyl), -SH, -S(C1-C6-alkyl), carbocyclyl and heterocyclyl, wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more (for example, one, two or three) R ⁵¹ groups . Preferably, R ⁵ is selected from the group consisting of -NH2, -NH(C1-C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl) and -NO2, where alkyl moiety contained in said -NH(C ₁ -C ₆ -alkyl), and one or both of the alkyl moieties contained in said -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), each optional substituted with one or more (for example, one, two or three) groups independently selected from halogen, -CF ₃ , -CN, -NO2, -NH2, -NH(C ₁ -C ₆ -alkyl), N(C ₁ - C ₆ -alkyl)(C ₁ -C ₆ -alkyl), -OH, -O(C ₁ -C ₆ -alkyl), -SH and -S(C ₁ -C ₆ -alkyl). More preferably, R ⁵ is selected from -NH2, -NH(C1-C6-alkyl), -N(C1-C6-alkyl)(C1-C6-alkyl) and -NO2. Even more preferably, R ⁵ is selected from the group consisting of -NH2, -NH(C1-C ₆ -alkyl) and -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl). Even more preferably, R ⁵ is -NH(C ₁ -C ₆ -alkyl). Even more preferably, R ⁵ is -NH-CH2CH2CH2CH3.

In the twenty-fourth embodiment, each R ⁵¹ is independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OH, -O(C1-C6 alkyl), -O(C1- C6-alkylene)-OH, -O(C1C6-alkylene)-O(C1-C6-alkyl), -SH, -S(C1-C6-alkyl), -NH2, -NH(C1-C6-alkyl), -N(C1-C6-alkyl)(C1-C6-alkyl), halogen, C1-C6-haloalkyl, -O-(C1-C6-haloalkyl), -CN, -NO2, -CHO, -CO-(C1 -C6-alkyl), -COOH, -COO-(C1-C6-alkyl), -O-CO-(C1-C6-alkyl), -CO-NH2, -CO-NH(C1-C6-alkyl), -CO-N(C1-C6-alkyl)(C1-C6-alkyl), -NH-CO-(C1-C6-alkyl), -N(C1-C6-alkyl)-CO-(C1-C6-alkyl), -SO2-NH2, -sO2-NH(C1-C6-alkyl), -SO2-N(C1-C6-alkyl)(C1-C6-alkyl), -NH-SO2-(C1-C6-alkyl) and - N(C1-C6-alkyl)-SO2-(C1-C6-alkyl). Preferably, each R ⁵¹ is independently selected from the group consisting of C1- _C6 alkyl, -OH, -O( _C1 - _C6 alkyl), -O( _C1 - _C6 alkylene)-OH, -O( C ₁ -C ₆ -alkylene) -O(C ₁ -C ₆ -alkyl), -SH, -S(C ₁ -C ₆ -alkyl), -NH2, -NH(C ₁ -C ₆ -alkyl), - N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, C ₁ -C ₆ -haloalkyl, -O-(C ₁ -C ₆ -haloalkyl) and -CN.

In the twenty-fourth embodiment, R ⁶ is selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, -OH, -O(C ₁ -C ₆ -alkyl ), -O(C ₁ -C ₆ -alkylene)-OH, -O(C ₁ -C ₆ -alkylene) - 37 043772

O(C1-C6-alkyl), -SH, -8(C _g C ₆ -alkyl), -NH2, -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)( C ₁ -C ₆ -alkyl), halogen, C1Cb-haloalkyl, -O-(C _g C6-haloalkyl), -CN, -NO2, -CHO, -CO-(C _g C6-alkyl), -COOH, - COO-(C1-Cbalkyl), -O-CO-(C1-C6-alkyl), -CO-NH2, -CO-NH(C1-C6-alkyl), -CO-N(C1-C6-alkyl)( C1-C6-alkyl), -NHCO-(C1-C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)-CO-(C ₁ -C ₆ -alkyl), -SO2-NH2, -SO ₂ -NH(C ₁ -C ₆ -alkyl), -SO ₂ -N(C _r C ₆ alkyl)(C1-C ₆ -alkyl), -NH-SO ₂ -(C ₁ -C ₆ -alkyl) and -N(C ₁ -C ₆ -alkyl)-SO ₂ -(C ₁ -C ₆ -alkyl). Preferably, R ⁶ is selected from the group consisting of hydrogen, C1-C6 alkyl, -OH, -O(C1-C6 alkyl), -O(C1-C6 alkylene)-OH, -O(C1-C6- alkylene)-O(C1-C6-alkyl), -SH, -S(C1-C6-alkyl), -NH2, -NH(C1-C6-alkyl), -N(C1-C6-alkyl)(C1- C6alkyl), halogen, C1-C6-haloalkyl, -O-(C1-C6-haloalkyl) and -CN. More preferably, R ⁶ is hydrogen or C1-C4 alkyl. Even more preferably, R ⁶ is hydrogen.

According to a twenty-fourth embodiment, the compound of formula (Ia) may be, in particular, a compound of any of the following formulas or a pharmaceutically acceptable salt or solvate thereof:

The present invention also provides a compound of formula (Ia) as defined in the twenty-fourth embodiment, or a pharmaceutically acceptable salt or solvate thereof for use as a drug. The present invention also relates to a pharmaceutical composition containing the specified compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. In addition, the present invention relates to the specified compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition containing any of the above substances and a pharmaceutically acceptable excipient, for use in the treatment or prevention of a disease or disorder in which involves NKCC (preferably diseases or disorders in which NKCC1 is involved), including, but not limited to, any specific diseases/disorders referred to herein. The present invention also relates to the use of said compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof for the preparation of a medicament for the treatment or prevention of a disease or disorder involving NKCC (preferably a disease or disorder involving NKCC1), including, in particular, any specific diseases/disorders mentioned herein. In addition, the present invention provides a method of treating or preventing a disease or disorder in which NKCC is involved (preferably a disease or disorder in which NKCC1 is involved), including, but not limited to, any specific diseases/disorders set forth herein, which includes administering to a subject in need thereof (preferably a human) a compound of formula (Ia) as defined in the twenty-fourth embodiment, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition containing any of the above in combination with a pharmaceutically acceptable excipient. It will be understood that in this method, the compound of formula (Ia) or a pharmaceutically acceptable salt or solvate or pharmaceutical composition thereof must be administered in a therapeutically effective amount.

In a twenty-fifth embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

R ² r^Jx^^ ³

R ⁵ (la) wherein R is as defined below, and where in formula (Ia) the other groups and variables, including in particular R ² , R ³ , R ⁴ , R ⁵ and R ⁶ , have the same values, including the same preferred values as described and defined above in the present invention for the compound of formula (I).

In this twenty-fifth embodiment, R ¹ is -(C ₁ -C ₄ -alkylene)-S-heterocyclyl, preferably -(C ₁ -C ₄ -alkylene)-S-heteroaryl (such as, for example, -CH ₂ -S -heteroaryl), where the heterocyclyl fragment contained in the specified -(C ₁ -C ₄ -alkylene)-S-heterocyclyl, or the heteroaryl fragment contained in the specified -(C ₁ -C ₄ -alkylene)-S-heteroaryl or in the specified -CH ₂ -Sheteroaryl, optionally substituted with one or more (for example, one, two or three) groups independently selected from C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, halogen , C1-C ₆ haloalkyl, -CN, -NO ₂ , -N(R ¹¹ )(R ¹¹ ), -O(R ¹¹ ), -S(R ¹¹ ), -SO3H, carbocyclyl and heterocyclyl. Specific examples of such R ¹ groups include the corresponding R ¹ groups contained in the compounds described in the examples section.

In a twenty-sixth embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

R ²

T T

R ⁵ (la) wherein R ¹ is as defined below, and wherein in formula (Ia) the other groups and variables, including in particular R ² , R ³ , R ⁴ , R ⁵ and R ⁶ , have such the same meanings, including the same preferred meanings, as described and defined above in the present invention for the compound of formula (I).

In this twenty-sixth embodiment, R ¹ is -(C ₁ -C ₄ -alkylene)-O-(C ₀ -C ₄ alkylene)carbocyclyl, preferably -(C ₁ -C ₄ -alkylene)-O-(C ₀ - C ₄ -alkylene)phenyl (such as, for example, -CH ₂ -O-phenyl or -CH ₂ -O-CH ₂ -phenyl), wherein the carbocyclyl moiety contained in said -(C1C ₄ -alkylene)-O-( C ₀ -C ₄ -alkylene)carbocyclyl, or phenyl fragment contained in the specified -(C1C ₄ -alkylene)-O-(C ₀ -C ₄ -alkylene)phenyl (or in the specified -CH ₂ -O-phenyl or - CH ₂ -O-CH ₂ -phenyl), optionally substituted with one or more (for example, one, two or three) groups independently selected from C 1 -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, halogen, C _g C ₆ -haloalkyl, -CN, -NO2, -N(R ¹¹ )(R ¹¹ ), -O(R ^h ), -S(R ^h ), -SO3H, carbocyclyl and heterocyclyl. Specific examples of such R ¹ groups include the corresponding R ¹ groups contained in the compounds described in the examples section.

In a twenty-seventh embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

_i (1a) wherein R ¹ is as defined below, and where in formula (Ia) the other groups and variables, including, but not limited to, R ² , R ³ , R ⁴ , R ⁵ and R ⁶ , have the same values, including the same preferred values as described and defined above in the present invention for the compound of formula (I).

In this twenty-seventh embodiment, R ¹ is -(C ₁ -C ₄ -alkylene)heterocyclyl, preferably -CH ₂ -heterocyclyl, wherein the heterocyclyl moiety contained in said -(C1—

C ₄ -alkylene)heterocyclyl or in said -CH ₂ -heterocyclyl, optionally substituted with one or more (for example, one, two or three) groups independently selected from C1 -C ₆ -alkyl, C2 -C6 - alkenyl, C ₂ - C ₆ -alkynyl, halogen, C ₁ -C ₆ -haloalkyl, -CN, -NO ₂ , -N(R ¹¹ )(R ¹¹ ), -O(R ^h ), -S(R ¹¹ ), -SO3H, carbocyclyl and heterocyclyl. The heterocyclyl moiety may be, for example, heterocycloalkyl (such as, for example, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl), heterocycloalkenyl (such as, for example, tetrahydropyridinyl) or heteroaryl. Specific examples of such R ¹ groups include the corresponding R ¹ groups contained in the compounds described in the examples section.

In a twenty-eighth embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

- 39 043772

(la) in which R ¹ is -COOH, in which R ³ is -SO2-NH2, in which R ⁴ is a group R ^4a , in which R ⁵ is a group R ^5a , in which R ^5a is -NH2, and where in In formula (Ia), other groups and variables, including, in particular, R ² , R ^4a and R ⁶ , have the same meanings, including the same preferred meanings, as described and defined above in the present invention for the compound of formula (I).

In a twenty-ninth embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

R ²

Rk^^^R ³ T T r ⁶ ^V^r ⁴

R ⁵ (la) in which R ¹ is -COOH, in which R ³ is -SO2-NH2, in which R ⁴ is a group R ^4a , in which R ⁵ is a group R ^5a , in which R ^5a is -NH-CH2CH2CH2CH3 and wherein in formula (Ia) other groups and variables, including, in particular, R ² , R ^4a and R ⁶ , have the same meanings, including the same preferred meanings, as described and defined above in the present invention for the compound of formula ( I).

In a thirtieth embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

(1a) in which R ¹ is -COOH, in which R ³ is -SO2-NH2, in which R ⁴ is a group R ^4a , in which R ⁵ is a group R ^5a , in which R ^5a is -NO2, and where in In formula (Ia), other groups and variables, including, in particular, R ² , R ^4a and R ⁶ , have the same meanings, including the same preferred meanings, as described and defined above in the present invention for the compound of formula (I).

In the thirty-first embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

R ²

R\J\^ ^r3 T T Re^^V^R ⁴

R ⁵ (la) in which R ¹ denotes -COOH, in which R ³ denotes -SO2-N=CH-N(CH3)2, in which R ⁴ denotes the group R ^4a , in which R ⁵ denotes the group R ^5a , in wherein R ^5a is -NH2, and wherein in formula (Ia) other groups and variables, including, in particular, R ² , R ^4a and R ⁶ , have the same meanings, including the same preferred meanings, as described and defined above in the present invention for a compound of formula (I).

In a thirty-second embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

- 40 043772

(la) in which R ¹ is -COOH, in which R ³ is -SO ₂ -N=CH-N(CH ₃ ) ₂ , in which R ⁴ is a group R ^4a , in which R ⁵ is a group R ^5a , in wherein R ^5a is -NH-CH2CH2CH2CH3, and wherein in formula (Ia) the other groups and variables, including in particular R ² , R ^4a and R ⁶ , have the same meanings, including the same preferred meanings, as described and defined above in the present invention for the compound of formula (I).

In a thirty-third embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

R ²

R ⁵ (la) in which R ¹ represents -COOH, in which R ³ represents -SO ₂ -N=CH-N(CH ₃ ) ₂ in which R ⁴ represents the group R ^4a in which R ⁵ represents the group R ^5a wherein R ^5a is -NO2, and wherein in formula (Ia) other groups and variables, including in particular R ² , R ^4a and R ⁶ , have the same meanings, including the same preferred meanings, as described and defined above in the present invention for the compound of formula (I).

In a thirty-fourth embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

R ² rJx^^L^R ³

R ⁵ (la) in which R ¹ is -COO-CH3, in which R ³ is -SO2-NH2, in which R ⁴ is a group R ^4a , in which R ⁵ is a group R ^5a , in which R ^a is -NH2 and wherein in formula (Ia) other groups and variables, including, in particular, R ² , R ^4a and R ⁶ , have the same meanings, including the same preferred meanings, as described and defined above in the present invention for the compound of formula ( I).

In a thirty-fifth embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

R ²

Rx^J^^^R ³

R ⁵ (la) in which R ¹ is -COO-CH3, in which R ³ is -SO2-NH2, in which R ⁴ is a group R ^4a , in which R ⁵ is a group R ^5a , in which R ^5a is -NH -CH ₂ CH ₂ CH ₂ CH ₃ , and wherein in formula (Ia) the other groups and variables, including in particular R ² , R ^4a and R ⁶ , have the same meanings, including the same preferred meanings, as described and defined above in the present invention for the compound of formula (I).

In a thirty-sixth embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

- 41 043772

(la) in which R ¹ is -COO-CH3, in which R ³ is -SO2-NH2, in which R ⁴ is an R ^4a group, in which R ⁵ is a R ^5a group, in which R ^5a is -NO2, and wherein in formula (Ia) the other groups and variables, including, in particular, R ² , R ^4a and R ⁶ , have the same meanings, including the same preferred meanings, as described and defined above in the present invention for the compound of formula (I) .

In a thirty-seventh embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

(1a) in which R ¹ is -COO-CH3, in which R ³ is -SO ₂ -N=CH-N(CH ₃ ) ₂ , in which R ⁴ is a group R ^4a , in which R ⁵ is a group R ^5a wherein R ^5a is -NH2, and wherein in formula (Ia) the other groups and variables, including in particular R ² , R ^4a and R ⁶ , have the same meanings, including the same preferred meanings, as described and defined above in the present invention for the compound of formula (I).

In a thirty-eighth embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

in which R ¹ is -COO-CH3, in which R ³ is -SO ₂ -N=CH-N(CH ₃ ) ₂ , in which R ⁴ is a group R ^4a , in which R ⁵ is a group R ^5a , in which ^R5a is -NH-CH2CH2CH2CH3, and wherein in formula (Ia) other groups and variables, including in particular ^R2 , ^R4a and ^R6 , have the same meanings, including the same preferred meanings, as described and defined above in the present invention for the compound of formula (I).

In a thirty-ninth embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

(1a) in which R ¹ is -COO-CH3, in which R ³ is -SO2-N=CH-N(CH3)2, in which R ⁴ is a group R ^4a , in which R ⁵ is a group R ^5a , in wherein R ^5a is -NO2, and wherein in formula (Ia) other groups and variables, including, in particular, R ² , R ^4a and R ⁶ , have the same meanings, including the same preferred meanings, as described and defined above in the present invention for a compound of formula (I).

In a fortieth embodiment, the compound of formula (I) is a compound of the following formula (Ib) or a pharmaceutically acceptable salt or solvate thereof:

(lb) in which R ⁴ represents the group R ^4a , in which R ⁵ represents the group R ^5a , and where in formula (Ib) other groups and variables, including, in particular, R ^X and R ⁶ , have the same meanings, including the same preferred values as those described and defined above in the present invention for the compound of formula (I).

In this fortieth embodiment, R ^4a is selected from -OR ⁴¹ , -SR ⁴¹ , -NH-R ⁴¹ , -N(C1-C6-alkyl)R ⁴¹ , halogen (eg -Cl), carbocyclyl and heterocyclyl, wherein said carbocyclyl and said heterocyclyl is each optionally substituted with one or more (eg, one, two or three) R ⁴² groups. Preferably, R ^4a is selected from -OR ⁴¹ , -SR ⁴¹ , -NH-R ⁴¹ , -N(C1-C ₆ -alkyl)-R ⁴¹ , halogen, carbocyclyl (eg aryl, cycloalkyl or cycloalkenyl) and heterocyclyl ( for example, heteroaryl, heterocycloalkyl or heterocycloalkenyl), wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more R ⁴² groups. More preferably, R ^4a is selected from -OR ⁴¹ , -SR ⁴¹ , -NH-R ⁴¹ , -N(C1-C4-alkyl)-R ⁴¹ , halogen, aryl and heteroaryl, wherein said aryl and said heteroaryl are each optionally substituted one or more R ⁴² groups. Even more preferably, R ^4a is selected from -OR ⁴¹ , -SR ⁴¹ , -NH-R ⁴¹ , -N(C1-C ₄ -alkyl)-R ⁴¹ and halogen. Even more preferably, R ^4a is -OR ⁴¹ or halogen.

R ⁴¹ is selected from the group consisting of -(Co-C4-alkylene)carbocyclyl, -(Co-C4-alkylene)heterocyclyl, C1-C6-alkyl, C2-C6-alkenyl and C2-C6-alkynyl, wherein the carbocyclyl moiety contained in said -(Co-C4-alkylene)carbocyclyl, and a heterocyclyl moiety contained in said -(Co-C4-alkylene)heterocyclyl, each optionally substituted with one or more (for example, one, two or three) R ⁴² groups, and wherein said C1 -C ₆ -alkyl, the specified C ₂ -C ₆ -alkenyl, the specified C ₂ -C ₆ alkynyl, the alkylene fragment contained in the specified -(C _o -C ₄ -alkylene)carbocyclyl, and the alkylene fragment contained in the specified -( C _o -C ₄ -alkylene)heterocyclyl, each optionally substituted with one or more (eg, one, two or three) R ⁴³ groups. Preferably, R ⁴¹ is selected from the group consisting of -(C0-C4-alkylene)carbocyclyl, -(C0-C4-alkylene)heterocyclyl, C1-C6alkyl, C2-C6-alkenyl and C2-C6-alkynyl, wherein the carbocyclyl moiety, contained in the specified -(CoC4-alkylene)carbocyclyl is selected from the group consisting of cycloalkyl, cycloalkenyl and aryl, where the heterocyclyl moiety contained in the specified -(C0-C4-alkylene)heterocyclyl is selected from the group consisting of heterocycloalkyl, heterocycloalkenyl and heteroaryl, wherein the carbocyclyl moiety contained in said -(C0-C4-alkylene)carbocyclyl and the heterocyclyl moiety contained in said -(C0-C4-alkylene)heterocyclyl are each optionally substituted with one or more (e.g., one, two or three) groups R ⁴² , and where additionally the specified C1-C ₆ -alkyl, the specified C ₂ -C ₆ alkenyl, the specified C ₂ -C ₆ -alkynyl, the alkylene fragment contained in the specified -(C ₀ -C ₄ alkylene)carbocyclyl, and the alkylene moiety contained in said -(C ₀ -C ₄ alkylene)heterocyclyl, each optionally substituted with one or more (eg, one, two or three) R ⁴³ groups. More preferably, R ⁴¹ is selected from the group consisting of -(C0-C4alkylene)aryl and -(C0-C4-alkylene)heteroaryl, wherein the aryl moiety contained in said -(C0-C4alkylene)aryl and the heteroaryl moiety contained in said -(C0-C4-alkylene)heteroaryl, each optionally substituted with one or more (for example, one, two or three) R ⁴² groups, and wherein additionally an alkylene moiety contained in said -(C0-C4-alkylene)aryl, and the alkylene moiety contained in said -(C0-C ₄ -alkylene)heteroaryl, each optionally substituted with one or more (eg, one, two or three) R ⁴³ groups. Even more preferably, R ⁴¹ is selected from the group consisting of -(C0-C4-alkylene)aryl and -(C0-C4-alkylene)heteroaryl, wherein the aryl moiety contained in said -(C0-C4-alkylene)aryl, and the heteroaryl moiety contained in said -(C0-C4-alkylene)heteroaryl, each optionally substituted with one or more (eg, one, two or three) R ⁴² groups. A preferred example of the aryl moiety contained in said -(C0-C4-alkylene)aryl is phenyl. A preferred example of a heteroaryl moiety contained in said -(C0-C ₄ -alkylene)heteroaryl is a 5- or 6-membered monocyclic heteroaryl containing 1 or 2 ring heteroatoms independently selected from oxygen, nitrogen and sulfur (where the remaining ring atoms are carbon atoms), such as, for example, imidazolyl, thiophenyl or pyrimidinyl. Even more preferably, R ⁴¹ is selected from the group consisting of phenyl and heteroaryl, wherein said heteroaryl is a 5- or 6-membered monocyclic heteroaryl containing 1 or 2 ring heteroatoms independently selected from oxygen, nitrogen and sulfur (the remaining ring atoms of the monocyclic heteroaryl are carbon atoms), and wherein further said phenyl or said heteroaryl is optionally substituted with one or more (eg, one, two or three) R ⁴² groups.

Each R ⁴² is independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OH, -O(C1-C6 alkyl), -O(C1-C6 alkylene)-OH, -O(C1-C6-alkylene)-O(C1-C6-alkyl), -SH, -S(C1-C6-alkyl), -NH2, -NH(C1-C6-alkyl), -N(C1-C6- alkyl)(C1-C6-alkyl), halogen, C1-C6-haloalkyl, -O-(Ci-C6haloalkyl), -CN, -NO2, -CHO, -CO-(C1-C6-alkyl), -COOH, -COO-(C1-C6-alkyl), -O-CO-(C1-C6-alkyl), -CO-NH2, -CO-NH(C1-C6-alkyl), -CO-N(C1-C6- alkyl)(C1-C6-alkyl), -NH-CO-(C1-C6-alkyl), -N(C1-C6alkyl)-CO-(C1-C6-alkyl), -SO2-NH2, -SO2-NH (C1-C6-alkyl), -SO2-N(C1-C6-alkyl)(C1-C6-alkyl), -NH-SO2(C1-C6-alkyl) and -N(C1-C6-alkyl)-SO2 -(C1-C6-alkyl). Preferably, each R ⁴² is independently selected from the group consisting of C1- _C6- alkyl, -OH, -O(C1- _C6- alkyl), -O( _C1 - _C6 -alkylene)-OH, -O( C ₁ -C ₆ alkylene)-O(C1-C ₆ -alkyl), -SH, -S(C ₁ -C ₆ -alkyl), -NH ₂ , -NH(C ₁ -C ₆ -alkyl), - N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl),

- 43 043772 halogen, C1-Cb-haloalkyl, -O-(C1-Cb-haloalkyl) and -CN.

Each R ⁴³ is independently selected from the group consisting of -OH, -O(C1-C6-alkyl), -SH, -S(C1-C6-alkyl), -NH2, -NH(C1-C6-alkyl), -N(c1 -C6-alkyl)(C1-C6-alkyl), halogen, -CF3, -CN, -NO2, -CHO, -CO-(C1C6-alkyl), -COOH, -COO-(C1-C6-alkyl), -O-CO-(C1-C6-alkyl), -CO-NH2, -CO-NH(C1-C6-alkyl), -CO-N(CiC6-alkyl)(C1-C6-alkyl), -NH- CO-(C1-C6-alkyl) and -N(C1-C6-alkyl)-CO-(C1-C6-alkyl). Preferably, each R ⁴³ is independently selected from the group consisting of -OH, -O(C1-C6-alkyl), -SH, -S( _{C1- C6} -alkyl), -NH2, -NH(C1 _- C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, -CF ₃ and -CN.

In accordance with the above definitions, it is particularly preferred if R ^4a is -O-aryl or halogen, wherein the aryl moiety contained in said -O-aryl is optionally substituted with one or more groups independently selected from C1-C6 alkyl, C2- Cb-alkenyl, C2-C6alkynyl, -OH, -O(C1-Cb-alkyl), -O(C1-Cb-alkylene)-OH, -O(C1-C6-alkylene)-O(C1-C6-alkyl) ), -SH, -8(C1-Cbalkyl), -NH2, -NH(C1-C6-alkyl), -N(C1-C6-alkyl)(C1-C6-alkyl), halogen, C1-C6-haloalkyl and -CN. Even more preferably, R ^4a is -O-phenyl or a halogen (such as, in particular, -Cl), wherein the phenyl moiety contained in said -O-phenyl is optionally substituted with one or more groups independently selected from C1-C _6- alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, -OH, -O(C1-C ₆ alkyl), -O(C ₁ -C ₆ -alkylene)-OH, -O( C ₁ -C ₆ -alkylene)-O(C ₁ -C ₆ -alkyl), -SH, -S(C ₁ -C ₆ -alkyl), -NH2, -NH(C1-C ₆ alkyl), -N (C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, C ₁ -C ₆ -haloalkyl and -CN.

In this fortieth embodiment, R ^5a is selected from the group consisting of -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)(C1-C6alkyl), -NO2 and hydrogen, wherein the alkyl moiety contained in said -NH(C1-C6-alkyl), and one or both of the alkyl moieties contained in said -N(C1-C6-alkyl)(C1-C6-alkyl), each optionally substituted with one or more (for example, one, two or three) groups independently selected from halogen, -CF3, -CN, -NO2, -NH2, -NH(C1-C6-alkyl), -N(CiC6-alkyl)(C1-C6-alkyl), -OH, - O(C1-C6-alkyl), -SH, -S(C1-C6-alkyl), carbocyclyl and heterocyclyl, wherein said carbocyclyl and said heterocyclyl are all optionally substituted with one or more (for example, one, two or three) R ⁵¹ groups . Preferably, R ^5a is selected from the group consisting of -NH2, -NH(C1- _C6 -alkyl), -N( _C1 - _C6- alkyl)( _C1 - _C6 -alkyl), -NO2 and hydrogen, where the alkyl fragment contained in the specified -MH(C1-C ₆ -alkyl), and one or both of the alkyl fragments contained in the specified -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), each optionally substituted with one or more (for example, one, two or three) groups independently selected from halogen, -CF ₃ , -CN, -NO ₂ , -NH ₂ , -NH(C ₁ -C ₆ -alkyl), -N (C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), -OH, -O(C ₁ -C ₆ -alkyl), -SH and -S(C ₁ -C ₆ -alkyl). More preferably, R ^5a is selected from -NH2, -NH(C1-C6-alkyl), -N(C1-C6-alkyl)(C1-C6-alkyl), -NO2 and hydrogen. Particularly preferred examples of R ^5a are -NH2, -NH-CH2CH ₂ CH ₂ CH ₃ , -NO2 or hydrogen.

Each R ⁵¹ is independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OH, -O(C1-C6 alkyl), -O(C1-C6 alkylene)-OH, -0(C1-C6-alkylene)-0(C1-C6-alkyl), -SH, -S(C1-C6-alkyl), -NH2, -NH(C1-C6-alkyl), -N(C1-C6- alkyl)(C1-C6-alkyl), halogen, C1-C6-haloalkyl, -O-(C1-C6haloalkyl), -CN, -NO2, -CHO, -CO-(C1-C6-alkyl), -COOH, -COO-(C1-C6-alkyl), -O-CO-(C1-C6-alkyl), -CO-NH2, -CO-NH(C1-C6-alkyl), -CO-N(C1-C6- alkyl)(C1-C6-alkyl), -NH-CO-(C1-C6-alkyl), -N(C1-C6alkyl)-CO-(C1-C6-alkyl), -SO2-NH2, -SO2-NH (C1-C6-alkyl), -SO2-N(C1-C6-alkyl)(C1-C6-alkyl), -NH-SO2(C1-C6-alkyl) and -N(C1-C6-alkyl)-SO2 -(C1-C6-alkyl). Preferably, each R ⁵¹ is independently selected from the group consisting of C1- _C6 alkyl, -OH, -O(C1- _C6 alkyl), -O(C1- _C6 alkylene)-OH, -O(C ₁ -C ₆ alkylene)-O(C1-C ₆ -alkyl), -SH, -S(C ₁ -C ₆ -alkyl), -NH2, -NH(C ₁ -C ₆ -alkyl), -N( C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, C ₁ -C ₆ -haloalkyl, -O-(C1-C ₆ -haloalkyl) and -CN.

In the forty-first embodiment, the compound of formula (I) is a compound of the following formula (Ib) or a pharmaceutically acceptable salt or solvate thereof:

(lb) where in formula (Ib) the groups and variables have the following meanings.

In this forty-first embodiment, R ^x is selected from -COOH, -COO-(C1-C ₆ -alkyl), -SO2-NH2, -SO ₂ -NH(C ₁ -C ₄ -alkyl), -SO ₂ -N (C ₁ -C ₄ -alkyl)(C ₁ -C ₄ -alkyl) and -SO ₂ -N=(C ₁ -C ₄ -alkylidene), where the alkyl fragment contained in the specified -SO ₂ -NH(C ₁ -C ₄ -alkyl), one or both of the alkyl moieties contained in said -SO ₂ -N(C ₁ -C ₄ -alkyl)(C ₁ -C ₄ -alkyl), and the alkylidene moiety contained in said -SO ₂ -N=(C ₁ -C ₄ -alkylidene), each optionally substituted with one group selected from -NH2, -NH(C ₁ -C ₄ -alkyl) and -N(C ₁ -C ₄ -alkyl)(C ₁ -C ₄ -alkyl). Preferably, R ^x is selected from -COOH, -COOCH3, -SO2-NH2 and -SO2-N=CH-N(CH3)2.

In this forty-first embodiment, R ⁴ is the group R ^4a .

R ^4a is selected from -OR ⁴¹ , -SR ⁴¹ , -NH-R ⁴¹ , -N(C ₁ -C ₆ -alkyl)-R ⁴¹ , halogen (eg -Cl), carbocyclyl and heterocyclyl, wherein said carbocyclyl and said heterocyclyl is each optionally substituted

- 44 043772 one or more (for example, one, two or three) R ⁴² groups. Preferably, R ^4a is selected from -OR ⁴¹ , -SR ⁴¹ , -NH-R ⁴¹ , -N(C1-C6-alkyl)-R ⁴¹ , halogen, carbocyclyl (eg aryl, cycloalkyl or cycloalkenyl) and heterocyclyl (eg , heteroaryl, heterocycloalkyl or heterocycloalkenyl), wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more R ⁴² groups. More preferably, R ^4a is selected from -OR ⁴¹ , -SR ⁴¹ , -NH-R ⁴¹ , -N(C1-C ₄ -alkyl)-R ⁴¹ , halogen, aryl and heteroaryl, wherein said aryl and said heteroaryl are each optional substituted with one or more R ⁴² groups. Even more preferably, R ^4a is selected from -OR ⁴¹ , -SR ⁴¹ , -NH-R ⁴¹ , -N(C ₁ -C ₄ -alkyl)-R ⁴¹ and halogen. Even more preferably, R ^4a is -OR ⁴¹ or halogen.

R ⁴¹ is selected from the group consisting of -(Co-C4-alkylene)carbocyclyl, -(Co-C4-alkylene)heterocyclyl, C1-C6-alkyl, C2-C6-alkenyl and C2-C6-alkynyl, wherein the carbocyclyl moiety contained in said -(Co-C4-alkylene)carbocyclyl, and a heterocyclyl moiety contained in said -(Co-C4-alkylene)heterocyclyl, each optionally substituted with one or more (for example, one, two or three) R ⁴² groups, and wherein said C1 -C ₆ -alkyl, the specified C ₂ -C ₆ -alkenyl, the specified C ₂ -C ₆ alkynyl, the alkylene fragment contained in the specified -(C _o -C ₄ -alkylene)carbocyclyl, and the alkylene fragment contained in the specified -( C _o -C ₄ -alkylene)heterocyclyl, each optionally substituted with one or more (eg, one, two or three) R ⁴³ groups. Preferably, R ⁴¹ is selected from the group consisting of -(C0-C4-alkylene)carbocyclyl, -(C0-C4-alkylene)heterocyclyl, €1-€6alkyl, C2-C6-alkenyl and C2-C6-alkynyl, where carbocyclyl the fragment contained in the specified -(CoC4-alkylene)carbocyclyl is selected from the group consisting of cycloalkyl, cycloalkenyl and aryl, where the heterocyclyl fragment contained in the specified -(C0-C4-alkylene)heterocyclyl is selected from the group consisting of heterocycloalkyl, heterocycloalkenyl and heteroaryl, wherein the carbocyclyl moiety contained in said -(C0-C4-alkylene)carbocyclyl and the heterocyclyl moiety contained in said -(C0-C4-alkylene)heterocyclyl are each optionally substituted with one or more (for example, one, two or three ) groups R ⁴² , and where additionally the specified C1-C ₆ -alkyl, the specified C ₂ -C ₆ alkenyl, the specified C ₂ -C ₆ -kynyl, the alkylene fragment contained in the specified -(C ₀ -C ₄ alkylene)carbocyclyl, and the alkylene moiety contained in said -(C ₀ -C ₄ alkylene)heterocyclyl, each optionally substituted with one or more (eg, one, two or three) R ⁴³ groups. More preferably, R ⁴¹ is selected from the group consisting of -(C0-C4alkylene)aryl and -(C0-C4-alkylene)heteroaryl, wherein the aryl moiety contained in said -(C0-C4alkylene)aryl and the heteroaryl moiety contained in said -(C0-C4-alkylene)heteroaryl, each optionally substituted with one or more (for example, one, two or three) R ⁴² groups, and wherein additionally an alkylene moiety contained in said -(C0-C4-alkylene)aryl, and the alkylene moiety contained in said -(C0-C4-alkylene)heteroaryl, each optionally substituted with one or more (eg, one, two or three) R ⁴³ groups. Even more preferably, R ⁴¹ is selected from the group consisting of -(C0-C4-alkylene)aryl and -(C0-C4-alkylene)heteroaryl, wherein the aryl moiety contained in said -(C0-C4-alkylene)aryl, and the heteroaryl moiety contained in said -(C0-C ₄ -alkylene)heteroaryl, each optionally substituted with one or more (eg, one, two or three) R ⁴² groups. A preferred example of the aryl moiety contained in said -(C ₀ -C ₄ -alkylene) aryl is phenyl. A preferred example of a heteroaryl moiety contained in said -( _C0 - _C4 -alkylene)heteroaryl is a 5- or 6-membered monocyclic heteroaryl containing 1 or 2 ring heteroatoms independently selected from oxygen, nitrogen and sulfur (where the remaining ring atoms are carbon atoms), such as, for example, imidazolyl, thiophenyl or pyrimidinyl. Even more preferably, R ⁴¹ is selected from the group consisting of phenyl and heteroaryl, wherein said heteroaryl is a 5- or 6-membered monocyclic heteroaryl containing 1 or 2 ring heteroatoms independently selected from oxygen, nitrogen and sulfur (the remaining ring atoms of the monocyclic heteroaryl are carbon atoms), and wherein further said phenyl or said heteroaryl is optionally substituted with one or more (eg, one, two or three) R ⁴² groups.

Each R ⁴² is independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OH, -O(C1-C6 alkyl), -O(C1-C6 alkylene)-OH, -O(C1-C6-alkylene)-O(C1-C6-alkyl), -SH, -S(C1-C6-alkyl), -NH2, -NH(C1-C6-alkyl), -N(C1-C6- alkyl)(C1-C6-alkyl), halogen, C1-C6-haloalkyl, -O-(C1-C6haloalkyl), -CN, -NO2, -CHO, -CO-(C1-C6-alkyl), -COOH, -COO-(C1-C6-alkyl), -O-CO-(C1-C6-alkyl), -CO-NH2, -CO-NH(C1-C6-alkyl), -CO-N(C1-C6- alkyl)(C1-C6-alkyl), -NH-CO-(C1-C6-alkyl), -N(C1-C6alkyl)-CO-(C1-C6-alkyl), -SO2-NH2, -SO2-NH (C1-C6-alkyl), -SO2-N(C1-C6-alkyl)(C1-C6-alkyl), -NH-SO2(C1-C6-alkyl) and -N(C1-C6-alkyl)-SO2 -(C1-C6-alkyl). Preferably, each R ⁴² is independently selected from the group consisting of C1- _C6- alkyl, -OH, -O(C1- _C6- alkyl), -O( _C1 - _C6 -alkylene)-OH, -O( C1- _C6 alkylene)-O( _C1 - _C6 -alkyl), -SH, -S( _{C1- C6-} alkyl), -NH2 _, -NH( _C1 - _C6 -alkyl), - N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, C ₁ -C ₆ -haloalkyl, -O-(C ₁ -C ₆ -haloalkyl) and -CN.

Each R ⁴³ is independently selected from the group consisting of -OH, -O(C ₁ -C ₆ alkyl), -SH, -S(C1-C ₆ alkyl), -NH ₂ , -NH(C ₁ -C ₆ - alkyl), -N(c ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, -CF ₃ , -CN, -NO ₂ , -CHO, -CO-(C ₁ C ₆ -alkyl ), -COOH, -COO-(C ₁ -C ₆ -alkyl), -O-CO-(C ₁ -C ₆ -alkyl), -CO-NH2, -CO-NH (C ₁ -C ₆ -alkyl ), -CO-N(C ₁ - 45 043772

Cb-alkyl)(C1-Cb-alkyl), -NH-CO-(Cl- _Cb -alkyl) and -N( _C1 - _C6 -alkyl)-CO-( _C1 - _C6 -alkyl). Preferably, each R ⁴³ is independently selected from the group consisting of -OH, -O(C1-C _b -alkyl), -SH, -S(C ₁ -C _b -alkyl),

-NH2, -NH(C ₁ -C _b -alkyl), -N(C ₁ -C _b -alkyl)(C ₁ -C _b -alkyl), halogen, -CF ₃ and -CN.

In accordance with the above definitions, it is particularly preferred if R ^4a is -O-aryl or halogen, wherein the aryl moiety contained in said -O-aryl is optionally substituted with one or more groups independently selected from C1-C6-alkyl, C2- C6-alkenyl, C2-C6alkynyl, -OH, -O(C1-C6-alkyl), -O(C1-C6-alkylene)-OH, -O(C1-Cb-alkylene)-O(C1-Cb-alkyl) ), -SH, -S(C1-C6alkyl), -NH2, -NH(C1-Cb-alkyl), -N(C1-Cb-alkyl)(C1-Cb-alkyl), halogen, C1-Cb-haloalkyl and -CN. Even more preferably, R ^4a is -O-phenyl or a halogen (such as, in particular, -Cl), wherein the phenyl moiety contained in said -O-phenyl is optionally substituted with one or more groups independently selected from C1-C _b -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, -OH, -O(C1-C ₆ alkyl), -O(C ₁ -C _b -alkylene)-OH, -O( C1-C ₆ -alkylene)-O(C1-C ₆ -alkyl), -SH, -S(C ₁ -C _b -alkyl), -NH2, -NH(C ₁ -C ₆ alkyl), -N( C ₁ -C _b -alkyl (C ₁ -C _b -alkyl), halogen, C ₁ -C _b -haloalkyl and -CN.

In this forty-first embodiment, R ⁵ is the group R ^5a .

R ^5a is selected from the group consisting of -NH2, -NH(C1-Cb-alkyl), -N(C1-Cb-alkyl)(C1-Cb-alkyl), -NO2 and hydrogen, where the alkyl moiety contained in said - NH(C1-Cb-alkyl), and one or both of the alkyl moieties contained in said -N(C1-Cb-alkyl)(C1-Cb-αalkyl), each optionally substituted with one or more (for example, one, two or three ) groups independently selected from halogen, -CF3, -CN, -NO2, -NH2, -NH(C1-Cb-alkyl), -N(C1-Cb-alkyl)(C1-Cb-alkyl), -OH, -O(C1-C6-alkyl), -SH, -S(C1-C6-alkyl), carbocyclyl and heterocyclyl, wherein said carbocyclyl and said heterocyclyl are all optionally substituted with one or more (for example, one, two or three) R groups ⁵¹ . Preferably, R ^5a is selected from the group consisting of -NH2, -NH(C1-C _b -alkyl), -N(C ₁ -C _b -alkyl)(C ₁ C ₆ -alkyl), -NO2 and hydrogen, where an alkyl moiety contained in said -NH(C ₁ -C _b -alkyl), and one or both of the alkyl moieties contained in said -N(C ₁ -C _b -alkyl)(C ₁ -C _b -alkyl), each optionally substituted with one or more (for example, one, two or three) groups independently selected from halogen, -CF ₃ , -CN, -NO2, -NH2, -NH(C ₁ -C _b -alkyl), -N(C ₁ -C _b -alkyl)(C ₁ -C _b -alkyl), -OH, -O(C1-C ₆ -alkyl), -SH and -S(C ₁ -C _b -alkyl). More preferably, R ^5a is selected from the group consisting of -NH2, -NH(C1-Cb-alkyl), -N(C1-Cb-alkyl)(C1-Cb-alkyl), -NO2 and hydrogen. Particularly preferred examples of R ^5a are -NH2, -NH-CH ₂ CH ₂ CH ₂ CH ₃ , -NO ₂ or hydrogen.

Each R is independently selected from the group consisting of C ₁ -C _b -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, -OH, -O(C1-C ₆ -alkyl), -O(C1 -C ₆ -alkylene)-OH, -O(C ₁ -C _b -alkylene) -O(C ₁ -C _b -alkyl), -SH, -S(C ₁ -C _b -alkyl), -NH2, -NH(C ₁ -C _b -alkyl), -N(C ₁ -C _b -alkyl)(C ₁ -C _b -alkyl), halogen, C ₁ -C _b -haloalkyl, -O-(C1-C ₆ haloalkyl), -CN, -NO2, -CNO, -CO-(C1-C ₆ -alkyl), -COOH, -COO-(C ₁ -C _b -alkyl), -O-CO-(C1-C ₆ -alkyl), -CO-NH2, -CO-NH(C ₁ -C _b -alkyl), -CO-N(C ₁ -C _b -alkyl)(C ₁ -C _b -alkyl), -NH- CO-(C ₁ -C _b -alkyl), -N(Ci-C ₆ alkyl)-CO-(C1-C ₆ -alkyl), -SO2-NH2, -SO ₂ -NH(C ₁ -C _b - alkyl), -SO ₂ -N(C ₁ -C _b -alkyl)(C ₁ -C _b -alkyl), -NH-SO2(C ₁ -C _b -alkyl) and -N(C ₁ -C _b - alkyl)-SO ₂ -(C ₁ -C _b -alkyl). Preferably, each R ⁵¹ is independently selected from the group consisting of C ₁ -C _b -alkyl, -OH, -O(C1-C ₆ -alkyl), -O(C1-C ₆ -alkylene)-OH, -O( C1-C ₆ alkylene)-O(C1-C ₆ -alkyl), -SH, -S(C ₁ -C _b -alkyl), -NH2, -NH(C ₁ -C _b -alkyl), -N( C ₁ -C _b -alkyl)(C ₁ -C _b -alkyl), halogen, C ₁ -C _b -haloalkyl, -O-(C1-C ₆ -haloalkyl) and -CN.

R ⁶ is selected from the group consisting of hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, -OH, -O(C1-C6-alkyl), -O(C1-C6-alkylene)- OH, -O(C1-C6-alkylene)-O(C1-C6-alkyl), -SH, -S(C1-Cb-alkyl), -NH2, -NH(C1-Cb-alkyl), -N( C1-C6-alkyl)(C1-C6-alkyl), halogen, C1-C6-haloalkyl, -O-(C1-C6-haloalkyl), -CN, -NO2, -CHO, -CO-(C1-C6- alkyl), -COOH, -COO-(C1-C6-alkyl), -O-CO-(C1-C6-alkyl), -CO-NH2, -CONH(C1-C6-alkyl), -CO-N( C1-C6-alkyl)(C1-C6-alkyl), -NH-CO-(C1-C6-alkyl), -N(C1-C6-alkyl)-CO-(C1-C6alkyl), -SO2-NH2, -SO2-NH(C1-C6-alkyl), -SO2-N(c1-C6-alkyl)(C1-C6-alkyl), -NH-SO2-(C1-C6-alkyl) and -N(C1-C6 -alkyl)-SO2-(C1-C6-alkyl). Preferably, R ⁶ is selected from the group consisting of hydrogen, C1-C ₆ -alkyl, -OH, -O(C1-C ₆ -alkyl), -O(C1-C ₆ -alkylene)-OH, -O(C ₁ -C ₆ -alkylene)-O(C ₁ -C ₆ -alkyl), -SH, -S(CiC ₆ -alkyl), -NH2, -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, C ₁ -C ₆ -haloalkyl, -O-(C1C ₆ -haloalkyl) and -CN. More preferably, R ⁶ is hydrogen or C1- _C4 alkyl. Even more preferably, R ⁶ is hydrogen.

In a forty-second embodiment, the compound of formula (I) is a compound of the following formula (Ib) or a pharmaceutically acceptable salt or solvate thereof:

(lb) in which R ^x is selected from the group consisting of -COOH, -COOCH3, -SO2-NH2 and -SO ₂ -N=CH-N(CH ₃ ) ₂ , and where in formula (Ib) other groups and variables, including, in particular, R ⁴ , R ⁵ and R ⁶ have the same meanings, including the same preferred meanings, as described and defined in the forty-first embodiment.

- 46 043772

In a forty-third embodiment, the compound of formula (I) is a compound of the following formula (Ib) or a pharmaceutically acceptable salt or solvate thereof:

(Ib) wherein R ^x is -COOH, and wherein in formula (Ib) other groups and variables, including in particular R ⁴ , R ⁵ and R ⁶ , have the same meanings, including the same preferred meanings, as opi stated and defined in the forty-first embodiment.

In a forty-fourth embodiment, the compound of formula (I) is a compound of the following formula (Ib) or a pharmaceutically acceptable salt or solvate thereof:

(Ib) wherein R ^x is -COOCH ₃ and wherein in formula (Ib) the other groups and variables, including in particular R ⁴ , R ⁵ and R ⁶ , have the same meanings, including the same preferred meanings as described and defined in the forty-first embodiment.

In a forty-fifth embodiment, the compound of formula (I) is a compound of the following formula (Ib) or a pharmaceutically acceptable salt or solvate thereof:

(Ib) wherein R ^x is -SO2-NH2, and wherein in formula (Ib) other groups and variables, including in particular R ⁴ , R ⁵ and R ⁶ , have the same meanings, including the same preferred meanings, as described and defined in the forty-first embodiment.

In a forty-sixth embodiment, the compound of formula (I) is a compound of the following formula (Ib) or a pharmaceutically acceptable salt or solvate thereof:

(Ib) in which R ^x denotes -SO2-N=CH-N(CH ₃ )2, and where in formula (Ib) other groups and variables, including, in particular, R ⁴ , R ⁵ and R ⁶ , have such the same meanings, including the same preferred meanings, as described and defined in the forty-first embodiment.

In a forty-seventh embodiment, the compound of formula (I) is a compound of the following formula (Ib) or a pharmaceutically acceptable salt or solvate thereof:

(Ib) in which R ⁴ represents -O-phenyl, wherein the phenyl moiety contained in said -Ophenyl is optionally substituted with one or more groups independently selected from C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, -OH, -O(C ₁ -C ₆ -alkyl), -O(C ₁ -C ₆ -alkylene)-OH, -O(C ₁ -C ₆ -alkylene)-O(C ₁ -C ₆ alkyl), -SH, -S(C ₁ -C ₆ -alkyl), -NH2, -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, C ₁ -C ₆ haloalkyl and -CN; and wherein in formula (Ib), other groups and variables, including, in particular, R ^x , R ⁵ and R ⁶ , have the same meanings, including the same preferred meanings, as described and defined in the forty-first embodiment.

In a forty-eighth embodiment, the compound of formula (I) is a compound of the following formula (Ib) or a pharmaceutically acceptable salt or solvate thereof:

- 47 043772

(lb) wherein R ⁴ is a halogen (such as, in particular, -Cl), and where in formula (Ib) other groups and variables, including, in particular, R ^x , R ⁵ and R ⁶ , have the same meanings , including the same preferred values as described and defined in the forty-first embodiment.

In a forty-ninth embodiment, the compound of formula (I) is a compound of the following formula (Ib) or a pharmaceutically acceptable salt or solvate thereof:

wherein ^Rx is -COOH, wherein ^R5 is _-NH2 , and wherein in formula (Ib) the other groups and variables, including in particular ^R4 and ^R6 , have the same meanings, including the same preferred values as described and defined in the forty-first embodiment.

In a fiftieth embodiment, the compound of formula (I) is a compound of the following formula (Ib) or a pharmaceutically acceptable salt or solvate thereof:

wherein R ^x is _-COOCH3 , wherein ^R5 is -NH2, and wherein in formula (Ib) the other groups and variables, including in particular ^R4 and ^R6 , have the same meanings, including the same preferred values as described and defined in the forty-first embodiment.

In the fifty-first embodiment, the compound of formula (I) is a compound of the following formula (Ib) or a pharmaceutically acceptable salt or solvate thereof:

(Ib) wherein R ^x is -SO2-NH2, wherein R ⁵ is -NH2, and wherein in formula (Ib) other groups and variables, including in particular R ⁴ and R ⁶ , have the same meanings, including the same preferred values as those described and defined in the forty-first embodiment.

In a fifty-second embodiment, the compound of formula (I) is a compound of the following formula (Ib) or a pharmaceutically acceptable salt or solvate thereof:

(lb) in which R ^x denotes -SO ₂ -N=CH-N(CH ₃ ) ₂ , in which R ⁵ denotes -NH2, and where in formula (Ib) other groups and variables, including, in particular, R ⁴ and R ⁶ have the same meanings, including the same preferred meanings, as described and defined in the forty-first embodiment.

In a fifty-third embodiment, the compound of formula (I) is a compound of the following formula (Ib) or a pharmaceutically acceptable salt or solvate thereof:

wherein R ^x is -COOH, wherein R ⁵ is -NH-CH ₂ CH ₂ CH ₂ CH ₃ , and wherein in formula (Ib) other groups and variables, including in particular R ⁴ and R ⁶ , have the following the same meanings, including the same

- 48 043772 preferred values as described and defined in the forty-first embodiment.

In a fifty-fourth embodiment, the compound of formula (I) is a compound of the following formula (Ib) or a pharmaceutically acceptable salt or solvate thereof:

(lb) in which R ^x is -COOCH3, in which R ⁵ is -NH-CH2CH ₂ CH ₂ CH ₃ , and where in formula (Ib) other groups and variables, including in particular R ⁴ and R ⁶ , have the same values, including the same preferred values, as described and defined in the forty-first embodiment.

In a fifty-fifth embodiment, the compound of formula (I) is a compound of the following formula (Ib) or a pharmaceutically acceptable salt or solvate thereof:

(Ib) wherein R ^x is -SO2-NH2, wherein R ⁵ is -NH-CH ₂ CH ₂ CH ₂ CH ₃ , and wherein formula (Ib) contains other groups and variables including, but not limited to, R ⁴ and R ⁶ have the same meanings, including the same preferred meanings, as described and defined in the forty-first embodiment.

In a fifty-sixth embodiment, the compound of formula (I) is a compound of the following formula (Ib) or a pharmaceutically acceptable salt or solvate thereof:

(Ib) wherein R ^x is -SO2-N=CH-N(CH3)2, wherein R ⁵ is -NH-CH2CH ₂ CH ₂ CH ₃ , and where in formula (Ib) other groups and variables including, in particular, R ⁴ and R ⁶ have the same meanings, including the same preferred meanings, as described and defined in the forty-first embodiment.

In a fifty-seventh embodiment, the compound of formula (I) is a compound of the following formula (Ib) or a pharmaceutically acceptable salt or solvate thereof:

(Ib) wherein R ^x is -COOH, wherein R ⁵ is -NO2, and wherein in formula (Ib) other groups and variables, including in particular R ⁴ and R ⁶ , have the same meanings, including the same preferred values are as described and defined in the forty-first embodiment.

In a fifty-eighth embodiment, the compound of formula (I) is a compound of the following formula (Ib) or a pharmaceutically acceptable salt or solvate thereof:

(Ib) wherein R ^x is -COOCH ₃ , wherein R ⁵ is -NO2, and wherein in formula (Ib) other groups and variables, including in particular R ⁴ and R ⁶ , have the same meanings, including such the same preferred values as described and defined in the forty-first embodiment.

In a fifty-ninth embodiment, the compound of formula (I) is a compound of the following formula (Ib) or a pharmaceutically acceptable salt or solvate thereof:

(lb) in which R ^x denotes -SO2-NH2, in which R ⁵ denotes -NO2, and where in formula (Ib) other groups and variables, including, in particular, R ⁴ and R ⁶ , have the same meanings, including the same preferred values as those described and defined in the forty-first embodiment.

In a sixtieth embodiment, the compound of formula (I) is a compound of the following formula (Ib) or a pharmaceutically acceptable salt or solvate thereof:

...... ............. < ^1b » . . ... .....

in which R is -SO2-N=CH-N(CH ₃ )2, in which R ⁵ is -NO2, and where in formula (Ib) other groups and variables, including in particular R ⁴ and R ⁶ , have the same values, including the same preferred values, as described and defined in the forty-first embodiment.

In a sixty-first embodiment, the compound of formula (I) is a compound of the following formula (Ib) or a pharmaceutically acceptable salt or solvate thereof:

(Ib) wherein R ^x is -COOH, wherein R ⁵ is hydrogen, and wherein in formula (Ib) other groups and variables, including in particular R ⁴ and R ⁶ , have the same meanings, including the same preferences values as described and defined in the forty-first embodiment.

In a sixty-second embodiment, the compound of formula (I) is a compound of the following formula (Ib) or a pharmaceutically acceptable salt or solvate thereof:

(Ib) wherein R ^x is -COOCH ₃ , wherein R ⁵ is hydrogen, and wherein in formula (Ib) other groups and variables, including in particular R ⁴ and R ⁶ , have the same meanings, including the same preferred values are as described and defined in the forty-first embodiment.

In a sixty-third embodiment, the compound of formula (I) is a compound of the following formula (Ib) or a pharmaceutically acceptable salt or solvate thereof:

wherein ^Rx is -SO2-NH2, wherein ^R5 is hydrogen, and wherein in formula (Ib) the other groups and variables, including in particular ^R4 and ^R6 , have the same meanings, including the same preferences values as described and defined in the forty-first embodiment.

In a sixty-fourth embodiment, the compound of formula (I) is a compound of the following formula (Ib) or a pharmaceutically acceptable salt or solvate thereof:

- 50 043772

II z>—R ⁴ R ^6/ ^Y

R ⁵ x 5 in which R is -SO2-N=CH-N(CH ₃ )2, in which R ⁵ is hydrogen, and where in formula (Ib) other groups and variables including, in particular, R ⁴ and R ⁶ have the same meanings, including the same preferred meanings, as described and defined in the forty-first embodiment.

In a sixty-fifth embodiment, the compound of formula (I) is a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

R ²

R\J\/R ³ g T

R ⁵ (la) in which R ¹ and R ⁶ are bonded together to form a group -R ¹⁶ -, in which R ⁴ is an R ^4a group and in which R ^4a is hydrogen, in which R ⁵ is a R ^5a group, and where in formula (Ia), other groups and variables, including, in particular, R ¹⁶ , R ² , R ³ and R ^5a , have the same meanings, including the same preferred meanings, as described and defined above in the present invention for the compound of formula (I ).

In each of the embodiments described above in the present invention, the corresponding compound can be used as a drug, preferably for the treatment or prevention of a disease or disorder in which NKCC (preferably NKCC1) is involved, including use for the treatment or prevention of any relevant specific diseases/ violations specified in this application. It is particularly preferred if the corresponding compound is used for the treatment or prevention of hyperhidrosis.

The present invention also relates to new compounds. In particular, the present invention relates to a compound of formula (I) described and defined herein, including any examples and embodiments of a compound of formula (I) described herein, or a pharmaceutically acceptable salt or solvate thereof. The present invention also relates to any such compound intended for use as a drug, and to a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in combination with a pharmaceutically acceptable excipient.

In particular, the present invention relates to a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof (and, in addition, the present invention also relates to the said compound for use as a drug, and to a pharmaceutical composition containing the said compound and pharmaceutically acceptable excipient):

R ²

Y T

R ⁶ ^Y^r4

R ⁵ (la)

In formula (Ia), R ¹ is selected from the group consisting of -COOH, -COO-(C1-C15-alkyl), -COO-(C0-C15alkylene)carbocyclyl, -COO-(C0-C15-alkylene)heterocyclyl, -O -CHO, -O-CO-(C1-C15-alkyl), -O-CO-(C0C15-alkylene)carbocyclyl, -O-CO-(C0-C15-alkylene)heterocyclyl, -CHO, -CO-(C1 -C15-alkyl), -CO-(C0-C15alkylene)carbocyclyl, -CO-(C0-C15-alkylene)heterocyclyl, -CO-NH2, -CO-N(R ¹¹ )-(C1-C ₁₅ -alkyl) , -CON(R ¹¹ )-(C0-C15-alkylene)carbocyclyl, -CO-N(R ¹¹ )-(C0-C ₁₅ -alkylene)heterocyclyl, -N(R ¹¹ )-CHO, -N(R ¹¹ )CO-(C1-C15-alkyl), -N(R ¹¹ )-CO-(C0-C ₁₅ -alkylene)carbocyclyl, -N(R ¹¹ )-CO-(C ₀ -C ₁₅ -alkylene)heterocyclyl, C ₁ -C ₁₅ -alkyl, -(C ₀ -C ₁₅ -alkylene)carbocyclyl, -(C ₀ -C ₁₅ -alkylene)heterocyclyl, C ₂ -C ₁₅ -alkenyl, -(C ₂ -C ₁₅ alkenylene)carbocyclyl , -(C ₂ -C ₁₅ -alkenylene)heterocyclyl, C ₂ -C ₁₅ -alkynyl, -(C ₂ -C ₁₅ alkynylene)carbocyclyl and -(C ₂ -C ₁₅ -alkynylene)heterocyclyl, where the alkyl fragment contained in any of the above groups, an alkylene moiety contained in any of the above groups, an alkenylene moiety contained in any of the above groups, an alkynylene moiety contained in any of the above groups, the above C ₁ -C ₁₅ -alkyl, the above C ₂ -C ₁₅ -alkenyl and said C ₂ -C ₁₅ -alkynyl each optional

- 51 043772 is substituted with one or more groups independently selected from halogen, -CF ₃ , -CN, -NO2, -N(R ¹¹ )(R ¹¹ ), O(R ⁿ ), -S(R ⁿ ) and -SO3H , where one or more -CH2- units included in an alkyl fragment contained in any of the above groups, in an alkylene fragment contained in any of the above groups, in an alkenylene fragment contained in any of the above groups, in an alkynylene fragment contained in any of the above groups, the specified C ₁ -C ₁₅ -alkyl, the specified C ₂ -C ₁₅ -alkenyl or the specified C ₂ -C ₁₅ -kynyl, each optionally replaced by a group independently selected from -O- , -СО-, -СОО-, -О-СО-, -N(R ¹¹ )-, -N(R ¹¹ )-CO-, -CO-N(R ¹¹ )-, -S-, -SO- , -SO2-, -SO2-N(R ¹¹ )- and -N(R ¹¹ )-SO2-, and where additionally a carbocyclyl fragment contained in any of the above groups, and a heterocyclyl fragment contained in any of the above groups , each optionally substituted with one or more groups independently selected from C ₁ -C6 alkyl, C ₂ C6 alkenyl, C ₂ -C ₆ alkynyl, halogen, C ₁ -C ₆ haloalkyl, -CN, -NO2, -N(R ¹¹ )(R ¹¹ ), -O(R ⁿ ), -S(R ⁿ ), -SO ₃ H, carbocyclyl and heterocyclyl.

Each R ¹¹ is independently hydrogen or C1-C6 alkyl. Preferably, each R ¹¹ is independently hydrogen or C1-C4 alkyl (eg methyl or ethyl).

R ¹ may represent, for example, any of the specific R ¹ groups contained in any of the compounds described in the examples section.

In particular, R ¹ may represent, for example, -COO-(C1-C15-alkyl), wherein the alkyl moiety contained in said -COO-(C1-C15-alkyl) is optionally substituted with one or more (for example, one, two or three) groups independently selected from halogen, -CF3, -CN, -NO2, -NH2, -NH(C1-C4alkyl), -N(C1-C4-alkyl)(C1-C4-alkyl), -OH, -O(C1-C4-alkyl), -SH and -S(C1-C4-alkyl), and where additionally one or two -CH2- units included in the alkyl fragment contained in the specified -COO-(C1-C15alkyl) , each optionally replaced by a group independently selected from -O-, -CO-, -COO-, -O-CO-, -NH-, -N(C1-C4-alkyl)-, -NH-CO-, -N (C1-C4-alkyl)-СО-, -CO-NH-, -СО-N(С1-С4-alkyl)-, -S-, -SO-, -SO2-, -SO2-NH-, -SO2 -N(C1-C4-alkyl)-, -NH-SO2- and -N(C1-C4-alkyl)-SO2-. The alkyl moiety contained in said -COO-(C1-C15-alkyl) contains from 1 to 15 carbon atoms, preferably from 1 to 10 carbon atoms. Preferred examples of such R ¹ groups include the corresponding R ¹ groups contained in the compounds described in the examples section (including, for example, -COOCH3 or -COO-CH ₂ CH ₃ ; preferably -COO-CH3).

Another preferred example of R ¹ is -COOH.

Other preferred examples of R ¹ are -(C1-C4-alkylene)-NH-(C1-C4-alkylene)-R ¹² (such as, for example, -CH2-NH-CH2-R ¹² ), -COO-(C1- C ₄ -alkylene)-R ¹² (for example, -COO-CH2-R ¹² ), -O-CO-(C1C4-alkylene)-D ¹² , -CO-(C1-C ₄ -alkylene)-R ¹² , - Co-NH-(C1-C4-alkylene)-R ¹² (for example, -CO-NH-CH2-R ¹² ), -CO-N(C1-C ₄ -alkyl)-(C ₁ -C ₄ -alkylene) -R ¹² , -NH-CO-(C1-C4 alkylene)-R ¹² , or -N(C1-C ₄ alkyl)-CO-(C ₁ -C ₄ alkylene)^ ¹² , where R ¹² is independently selected from -CF3, -CN and halogen (for example -F, -Cl, -Br or -I); preferably, R ¹² is independently selected from -CF3 and -CN; more preferably, R ¹² is -CF3. Specific examples of such R ¹ groups include the corresponding R ¹ groups contained in the compounds described in the examples section. A particularly preferred example of R ¹ is -(C 1 -C ₄ -alkylene)-NH-(C ₁ -C ₄ -alkylene)-CF ₃ and an even more preferred example is -CH2-NHCH2-CF3.

Another example of R ¹ is -(C ₁ -C ₄ -alkylene)-S-heterocyclyl, preferably -(C ₁ -C ₄ -alkylene)S-heteroaryl (such as, for example, -CH ₂ -S-heteroaryl), where a heterocyclyl fragment contained in the specified -(C ₁ -C ₄ -alkylene)-S-heterocyclyl, or a heteroaryl fragment contained in the specified -(C ₁ -C ₄ -alkylene)-S-heteroaryl or in the specified -CH ₂ -S -heteroaryl, optionally substituted with one or more (for example, one, two or three) groups independently selected from C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -kynyl, halogen, C ₁ - C ₆ -haloalkyl, -CN, -NO2, -N(R ¹¹ )(R ¹¹ ), -O(R ⁿ ), -S(R ⁿ ), -SO3H, carbocyclyl and heterocyclyl. Specific examples of such R ¹ groups include the corresponding R ¹ groups contained in the compounds described in the examples section.

Another example of R ¹ is -(C ₁ -C ₄ -alkylene)-O-(C ₀ -C ₄ -alkylene)carbocyclyl, preferably -(C ₁ -C ₄ -alkylene)-O-(C ₀ -C ₄ - alkylene)phenyl (such as, for example, -CH ₂ -O-phenyl or -CH ₂ -O-CH ₂ -phenyl), wherein the carbocyclyl moiety contained in said -(C ₁ -C ₄ -alkylene)-O-( C ₀ -C ₄ alkylene)carbocyclyl, or phenyl fragment contained in the specified -(C ₁ -C ₄ -alkylene)-O-(C ₀ -C ₄ alkylene)phenyl (or in the specified -CH ₂ -O-phenyl or -CH ₂ -O-CH ₂ -phenyl), optionally substituted with one or more (for example, one, two or three) groups independently selected from C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ - C ₆ -alkynyl, halogen, C ₁ -C ₆ -haloalkyl, -CN, -NO2, -N(R ¹¹ )(R ¹¹ ), -O(R ⁿ ), -S(R ⁿ ), -SO3H, carbocyclyl and heterocyclyl. Specific examples of such R ¹ groups include the corresponding R ¹ groups contained in the compounds described in the examples section.

Another example of R ¹ is -(C1-C4-alkylene)heterocyclyl, preferably -CH2-heterocyclyl, wherein the heterocyclyl moiety contained in said -(C1-C4-alkylene)heterocyclyl or in said -CH2-heterocyclyl is optionally substituted with one or more (for example, one, two or three) groups independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1C6 haloalkyl, -CN, -NO2, -N(R ¹¹ ) (R ¹¹ ), -O(R ⁿ ), -S(R ⁿ ), -SO3H, carbocyclyl and heterocyclyl. The heterocyclyl moiety may be, for example, heterocycloalkyl (such as, for example, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl), heterocycloalkenyl (such as, for example, tetrahydropyridinyl) or heteroaryl. Specific examples of such R ¹ groups include the corresponding R ¹ groups contained in the compounds described in the examples section.

R ² is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OH, -O(C1-C6 alkyl), -O(C1-C6 alkylene)- OH, -O(C1-C6-alkylene)-O(C1-C6-alkyl), -SH, -S(C1-C6-alkyl), -NH2, -NH(C1-C6-alkyl), -N( C1-C6-alkyl)(C1-C6-alkyl), halogen, C1-C6-haloalkyl, -O-(C1-C6-haloalkyl), -CN, -NO2, -CHO, -CO-(C1-C6- alkyl), -COOH, -COO-(C1-C6-alkyl), -O-CO-(C1-C6-alkyl), -CO-NH2, -SONH(C1-C6-alkyl), -CO-N( C1-C6-alkyl)(C1-C6-alkyl), -NH-CO-(C1-C6-alkyl), -N(C1-C6-alkyl)-CO-(C1-C6alkyl), -SO2-NH2, -SO2-NH(C1-C6-alkyl), -SO2-N(c1-C6-alkyl)(C1-C6-alkyl), -NH-SO2-(C1-C6-alkyl) and -N(C1-C6 -alkyl)-SO2-(C1-C6-alkyl). Preferably, R ² is selected from the group consisting of hydrogen, C1-C ₆ -alkyl, -OH, -O(C1-C ₆ -alkyl), -O(C ₁ -C ₆ -alkylene)-OH, -O( C ₁ -C ₆ -alkylene)-O(C ₁ -C ₆ -alkyl), -SH, -S(CiC ₆ -alkyl), -NH ₂ , -NH(C ₁ -C ₆ -alkyl), -N (C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, C ₁ -C ₆ -haloalkyl, -O-(C1C ₆ -haloalkyl) and -CN. More preferably, R ² is hydrogen or C1- _C4 alkyl. Even more preferably, R ² is hydrogen.

R ³ is selected from the group consisting of -SO2-NH2, -SO2-NH(C1-C6-alkyl), -SO2-N(C1-C6-alkyl)(C1-C6alkyl), -SO2-N=(C1-C6 -alkylidene) and -SO2-halogen, where the alkyl fragment contained in the specified SO2-NH(C1-C6-alkyl), one or both of the alkyl fragments contained in the specified -SO2-N(C1-C6alkyl)(C1-C6- alkyl), and the alkylidene moiety contained in said -SO2-N=(C1-C6alkylidene), each optionally substituted with one or more groups independently selected from halogen, -CF3, -CN, -NO2, -NH2, -NH(C1 -C6-alkyl), -N(C1-C6-alkyl)(C1-C6-alkyl), -OH, -O(C1-C6-alkyl), -SH and -S(C1-C6-alkyl). Preferably, R ³ is selected from the group consisting of -SO2-NH ₂ , -SO ₂ -NH(C1C ₄ -alkyl), -SO ₂ -N(C ₁ -C ₄ -alkyl)(C ₁ -C ₄ -alkyl ) and -SO ₂ -N=(C ₁ -C ₄ -alkylidene), where the alkyl fragment contained in the specified -SO ₂ -NH(C ₁ -C ₄ -alkyl), one or both of the alkyl fragments contained in the specified - SO ₂ -N(C ₁ -C ₄ -alkyl)(C ₁ -C ₄ -alkyl), and the alkylidene moiety contained in said -SO ₂ -N=(C ₁ -C ₄ -alkylidene), each optionally substituted with one or more groups (preferably one group) independently selected from halogen, -CF ₃ , -CN, -NO ₂ , -NH ₂ , -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ - alkyl)(C ₁ -C ₆ -alkyl), -OH, -O(C1-C ₆ -alkyl), -SH and -S(C ₁ -C ₆ -alkyl). More preferably, R ³ is selected from -SO2-NH2, -SO2-NH(C1-C4-alkyl), -SO2-N(C1-C4-alkyl)(C1-C4-alkyl) and -SO2-N=( C1-C4alkylidene), where the alkyl fragment contained in the specified -SO2-NH(C1-C4-alkyl), one or both alkyl fragments contained in the specified -SO2-N(C1-C4-alkyl)(C1-C4-alkyl ), and the alkylidene moiety contained in said -SO2-N=(C1-C4-alkylidene), each optionally substituted with one group selected from -NH2, -NH(C1-C4-alkyl) and -N(C1-C4- alkyl)(C1-C4-alkyl). Even more preferably, R ³ is selected from the group consisting of -SO2-NH2, -SO2-NH(C ₁ -C ₄ alkyl), -SO ₂ -N(C ₁ -C ₄ alkyl)(C1-C ₄ - alkyl), -SO ₂ -NH-(C ₁ -C ₄ -alkylene)-NH ₂ , -SO ₂ -NH-(C ₁ -C ₄ -alkylene)-NH(C ₁ -C ₄ -alkyl), - SO ₂ NH-(C ₁ -C ₄ -alkylene)-N(C ₁ -C ₄ -alkyl)(C ₁ -C ₄ -alkyl), -SO ₂ -N=(C ₁ -C ₄ -alkylidene)- NH ₂ , -SO ₂ -N=(C ₁ -C ₄ alkylidene)-NH(C ₁ -C ₄ -alkyl) and -SO ₂ -N=(C ₁ -C ₄ -alkylidene)-N(C ₁ - C ₄ -alkyl)(C ₁ -C ₄ -alkyl). Even more preferably, R ³ is selected from the group consisting of -SO2-NH2, -SO2-NH-CH3, -SO2-N(CH3)2, -SO2-NH(C1-C4-alkylene)-NH2, -SO2- NH-(C1-C4-alkylene)-NH-CH3, -SO2-NH-(C1-C4-alkylene)-N(CH3)2 (for example, -SO2-NH-CH2CH2-N(CH3)2), - SO2-N=(C1-C4-alkylidene)-NH2, -SO2-N=(C1-C4-alkylidene)-NH-CH3 and -SO2N=(C1-C4-alkylidene)-N(CH3)2 (for example, -SO2-N=CH-N(CH3)2). A particularly preferred example of R ³ is -SO2-NH2. Another particularly preferred example of R ³ is -SO2-N=CH-N(CH ₃ ) ₂ .

R ⁴ and R ⁵ are linked together to form the group -R ^5b -.

R ^5b selected from -R ^5b1 -R ^5b2 -R ^5b1 -, -N=C(R ⁵³ )-R ^5b3 -R ^5b1 -, -R ^5b1 -R ^5b3 -C(R ⁵³ )=N- and -N= C(R ⁵³ )-R ^5b4 -C(R ⁵³ )=N-. Each R ^5b1 is independently selected from the group consisting of -N(R ⁵² )-, -O- and -S-.

R ^5b2 selected from -C(R ⁵³ )(R ⁵³ )-, -C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R 53 )-, -C(R ⁵³ )=C(R ^{53 )} -, -C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )=C(R ⁵³ )- and -C(R ⁵³ )=C(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-. R ^5b3 is selected from a covalent bond, -C(R ⁵³ )(R ⁵³ )-, -C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )- and -C(R ⁵³ )=C( R ⁵³ )-. R ^5b4 is selected from a covalent bond and -C(R ⁵³ )(R ⁵³ )-.

Each R ⁵² is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2C6 alkynyl, -(C0-C4 alkylene)aryl, and -(C0-C4 alkylene)heteroaryl. Preferably, each R ⁵² is independently selected from the group consisting of hydrogen, C1-C4 alkyl (eg n-butyl), C ₂ -C ₄ alkenyl and C ₂ C ₄ alkynyl (eg -CH ₂ -C= CH). Even more preferably, each R ⁵² is hydrogen.

Each R ⁵³ is independently selected from the group consisting of hydrogen, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C _{2 -C 6} -kynyl, -OH, -O(C 1 -C ₆ -alkyl), -SH , -S(C ₁ -C ₆ -alkyl), -NH ₂ , -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ alkyl), halogen , C ₁ -C ₆ -haloalkyl, -O-(C ₁ -C ₆ -haloalkyl), -CN, -NO ₂ , -CHO, -CO-(C ₁ -C ₆ -alkyl), -COOH, -COO -(C1-Cb-alkyl), -O-CO-(C1-Cb-alkyl), -CO-NH2, -CO-NH(C1-C6-alkyl), -CO-P(C1- _C6- alkyl) (C1-C ₆ -alkyl), -NH-CO-(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)-CO-(C ₁ -C ₆ -alkyl), -SO2 -NH2, -SO ₂ -NH(C ₁ C ₆ -alkyl), -SO ₂ -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), -NH-SO ₂ -(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)-SO ₂ -(C ₁ -C ₆ -alkyl), -(C0-C4-alkylene)aryl and -(C0-C4-alkylene) heteroaryl, and any two ^R53 groups that are attached to the same carbon atom can also together form an =O group, and any two ^R53 groups that are attached to adjacent carbon atoms connected by a double bond can also be bonded together to form the group -C(R ⁵⁴ )=C(R ⁵⁴ )-C(R ⁵⁴ )=C(R ⁵⁴ )-. It is preferable if each R

- 53 043772 independently selected from the group consisting of hydrogen, C1-C6 alkyl, -OH, -O(C1- _C6 alkyl), -SH, -8(C1- _C6 alkyl), -NH2, -NH( C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, C ₁ -C ₆ -haloalkyl, -O-(C1-C ₆ haloalkyl) and -CN, and any two R ⁵³ groups that are attached to the same carbon atom can also together form an =O group, and any two R ⁵³ groups that are attached to adjacent carbon atoms connected by a double bond can also be linked together to form the group -C(R ⁵⁴ )=C(R ⁵⁴ )-C(R ⁵⁴ )=C(R ⁵⁴ )-. More preferably, each R ⁵³ is independently selected from the group consisting of hydrogen, C1-C6 alkyl, -OH, -O(C1-C6 alkyl), -SH, -S(C1-C6 alkyl), -NH2, -NH(C1C6-alkyl), -N(C1-C6-alkyl)(C1-C6-alkyl), halogen, C1-C6-haloalkyl, -O-(C1-C6-haloalkyl) and -CN, and any two R ⁵³ groups that are attached to the same carbon atom can also together form an =O group. Even more preferably, each R ⁵³ is independently selected from the group consisting of hydrogen, C1-C4 alkyl, -OH, -O(C ₁ -C ₄ -alkyl), -NH2, -NI(C ₁ -C ₄ -alkyl ), -N(C ₁ -C ₄ -alkyl)(C ₁ C ₄ -alkyl), halogen, C1-C ₄ -haloalkyl, -O-(C ₁ -C ₄ -haloalkyl), and -CN, and any two R ⁵³ groups that are attached to the same carbon atom can also together form an =O group.

Each R ⁵⁴ is independently selected from the group consisting of hydrogen, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ Sb-alkynyl, -OH, -O(C _g Sb-alkyl), -SH, - S(C1-C6-alkyl), -NH ₂ , -NH(C1-C6-alkyl), ^(C1-Cb-alkyl)(C1-Cbalkyl), halogen, C ₁ -C ₆ -haloalkyl, -O- (C1-C ₆ -haloalkyl), -CN, -NO2, -CHO, -CO-(C ₁ -C ₆ -alkyl),

-COOH, -COO-(C ₁ -C ₆ -alkyl), -O-CO-(C ₁ -C ₆ -alkyl), -CO-NH2, -CO-NH(C ₁ -C ₆ -alkyl), -CO-N(C ₁ -C ₆ alkyl)(C1-C ₆ -alkyl), -NH-CO-(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)-CO- (C ₁ -C ₆ -alkyl), -SO2-NH2, -SO2-NH(C1C ₆ -alkyl), -SO ₂ -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), -NH-SO ₂ -(C ₁ -C ₆ -alkyl) and -N(C ₁ -C ₆ -alkyl)-SO ₂ -(C ₁ -C ₆ -alkyl). Preferably, each R ⁵⁴ is independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, -OH, -O(C 1 -C ₆ -alkyl), -SH, -S(C ₁ -C ₆ -alkyl), -NH2, -NI(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ alkyl), halogen, C ₁ -C ₆ -haloalkyl, -O-(C1 -C ₆ -haloalkyl) and -CN. More preferably, each R ⁵⁴ is hydrogen.

It is particularly preferred if R ^5b is selected from -N(R ⁵² )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -N=C(R ⁵³ )-N(R ⁵² )-, -N (R ⁵² )-C(R ⁵³ )=N-, -N(R ⁵² )-C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -N =C(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -N(R ⁵² )C(R ⁵³ )=C(R ⁵³ )-N(R ⁵² )-, - N(R ⁵² )-C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )=N-, -N=C(R ⁵³ )-C(R ⁵³ )=N-, -N(R ⁵² )- C(R ⁵³ )(R ⁵³ )C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -N=C(R ⁵³ )-C(R ⁵³ ) (R ⁵³ )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -N(R ⁵² )-C(R ⁵³ )(R ⁵³ )C(R ⁵³ )=C(R ⁵³ )- N(R ⁵² )-, -N(R ⁵² )-C(R ⁵³ )=C(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -N(R ⁵² )- C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )C(R ⁵³ )=N-, -N=C(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )=N-, -OC(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -OC(R ⁵³ )(R 53 )-C(R ⁵³ )(R ⁵³ )-N( ^{R 52 )} -, -OC(R ⁵³ )=C(R ⁵³ )-N(R ⁵² )-, -OC(R ⁵³ )(R 53 )-C(R ⁵³ )(R ⁵³ )-C( ^{R 53 )} (R ⁵³ )-N(R ⁵² )-, -OC(R ⁵³ )(R ⁵³ )-C(R ⁵³ )=C(R ⁵³ )-N(R ⁵² )-, -OC(R ⁵³ )=C(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -N(R ⁵² )-C(R ^{53 )(R 53 )} -O-, -N(R ⁵² )-C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-O-, -N(R ⁵² )C(R ⁵³ )=C(R ⁵³ )-O-, -N(R ⁵² )-C( R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-O-, -N(R ⁵² )-C(R ⁵³ )(R ⁵³ )-C( R ⁵³ )=C(R ⁵³ )-O-, -N(R ^{52 )} -C(R ⁵³ )=C(R 53 )-C(R ⁵³ )(R ⁵³ )-O-, -SC(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -SC(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -SC(R ⁵³ )=C( R ⁵³ )-N(R ⁵² )-, -SC(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, - SC(R ⁵³ )(R ⁵³ )-C(R ⁵³ )=C(R ⁵³ )-N(R ⁵² )-, -SC(R ⁵³ )=C(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -N(R ⁵² )-C(R ⁵³ )(R ⁵³ )-S-, -N(R ⁵² )-C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-S-, -N(R ⁵² )C(R ⁵³ )=C(R ⁵³ )-S-, -N(R ⁵² )-C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-S-, -N(R ⁵² )-C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )=C(R ⁵³ )-S -, -N(R ⁵² )-C(R ⁵³ )=C(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-S-, -N(R ⁵² )-C(R ⁵³ )(R ⁵³ ) -N(R ⁵² )-, -N(R ⁵² )-C(R ⁵³ )(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-, -N(R ⁵² )-C (R ⁵³ )=C(R ⁵³ )-N(R ⁵² )-, -N(R ⁵² )-C(R ⁵³ )(R 53 )-C(R ⁵³ )(R ⁵³ )-C( ^{R 53 )} (R ⁵³ )-N(R ⁵² )-, -N(R ⁵² )-C(R ⁵³ )(R ⁵³ )C(R ⁵³ )=C(R ⁵³ )-N(R ⁵² )-HN(R ⁵² )-C(R ⁵³ )=C(R ⁵³ )-C(R ⁵³ )(R ⁵³ )-N(R ⁵² )-.

Even more preferably, R ^5b is selected such that the compound of formula (Ia) has any of the following structures:

- 54 043772

R ⁶ is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OH, -O(C1-C6 alkyl), -O(C1-C6 alkylene)- OH, -O(C1-C6-alkylene)-O(C1-C6-alkyl), -SH, -S(C1-C6-alkyl), -NH2, -NH(C1-C6-alkyl), -N( C1-C6-alkyl)(C1-C6-alkyl), halogen, C1-C6-haloalkyl, -O-(C1-C6-haloalkyl), -CN, -NO2, -CHO, -CO-(C1-C6- alkyl), -COOH, -COO-(C1-C6-alkyl), -O-CO-(C1-C6-alkyl), -CO-NH2, -CONH(C1-C6-alkyl), -CO-N( C1-C6-alkyl)(C1-C6-alkyl), -NH-CO-(C1-C6-alkyl), -N(C1-C6-alkyl)-CO-(C1-C6alkyl), -SO2-NH2, -SO2-NH(C1-C6-alkyl), -SO2-N(C1-C6-alkyl)(C1-C6-alkyl), -NH-SO2-(C1-C6-alkyl) and -N(C1-C6 -alkyl)-SO2-(C1-C6-alkyl). Preferably, R ⁶ is selected from the group consisting of hydrogen, C1-C ₆ -alkyl, -OH, -O(C1-C ₆ -alkyl), -O(C1-C ₆ -alkylene)-OH, -O(C1 -C ₆ -alkylene)-O(C1-C ₆ -alkyl), -SH, -S(C ₁ C ₆ -alkyl), -NH2, -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, C ₁ -C ₆ -haloalkyl, -O-(C ₁ C ₆ -haloalkyl) and -CN. More preferably, R ⁶ is hydrogen or C1- _C4 alkyl. Even more preferably, R ⁶ is hydrogen.

Moreover, the present invention relates to a compound of the following formula (Ib) or a pharmaceutically acceptable salt or solvate thereof (and the present invention also relates to the said compound for use as a drug, and to a pharmaceutical composition containing the said compound and a pharmaceutically acceptable inert filler):

(lb)

In formula (Ib), R ^x is selected from the group consisting of -COOH, -COO-(C1-C6-alkyl), -SO2-NH2, -SO2NH(C1-C4-alkyl), -SO2-N(C1-C4- alkyl)(C1-C4-alkyl) and -SO2-N=(C1-C4-αalkylidene), where the alkyl fragment contained in the specified -SO2-NH(C1-C4-alkyl), one or both alkyl fragments contained in said -SO2-N(C1-C4-alkyl)(C1-C4-alkyl), and the alkylidene moiety contained in said -SO2-N=(C1-C4-alkylidene), each optionally substituted with one group selected from -NH2 , -NH(C1-C4-alkyl) and -N(C1-C4-alkyl)(C1-C4-alkyl). Preferably, R ^x is selected from the group consisting of -COOH, -COOCH3, -SO2-NH2 and -SO2-N=CH-N(CH ₃ ) ₂ .

R ⁴ is an R ^4a group, and R ⁵ is an R ^5a group.

R ^4a is selected from -OR ⁴¹ , -SR ⁴¹ , -NH-R ⁴¹ , -N(C1-C6-αalkyl)-R ⁴¹ , halogen (eg -Cl), carbocyclyl and heterocyclyl, wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more R ⁴² groups. Preferably, R ^4a is selected from -OR ⁴¹ , -SR ⁴¹ , -NH-R ⁴¹ , -N(C1-C ₆ alkyl)-R ⁴¹ , halogen, carbocyclyl (eg aryl, cycloalkyl or cycloalkenyl) and heterocyclyl (eg , heteroaryl, heterocycloalkyl or heterocycloalkenyl), wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more R ⁴² groups. More preferably, R ^4a is selected from -OR ⁴¹ , -SR ⁴¹ , -NH-R ⁴¹ , -N(C1-C4-alkyl)-R ⁴¹ , halogen, aryl and heteroaryl, wherein said aryl and said heteroaryl are each optionally substituted one or more R ⁴² groups. Even more preferably, R ^4a is selected from -OR ⁴¹ , -SR ⁴¹ , -NH-R ⁴¹ , -N(C1-C ₄ -alkyl)-R ⁴¹ and halogen. Even more preferably, R ^4a is -OR ⁴¹ or halogen.

R ⁴¹ is selected from the group consisting of -(C0-C4-alkylene)carbocyclyl, -(C0-C4-alkylene)heterocyclyl, C1-C6-alkyl, C2-C6-alkenyl and C2-C6-alkynyl, where the carbocyclyl moiety contained in said -(C0-C4-alkylene)carbocyclyl, and a heterocyclyl moiety contained in said -(C0-C4-alkylene)heterocyclyl, each optionally substituted with one or more R ⁴² groups, and wherein said C1-C ₆ alkyl, said C ₂ -C ₆ -alkenyl, said C ₂ -C ₆ -alkynyl, alkylene moiety contained in said -(C0-C4-alkylene)carbocyclyl, and alkylene moiety contained in

- 55 043772 the specified -(C ₀ -C ₄ -alkylene)heterocyclyl, each optionally substituted with one or more R ⁴³ groups. Preferably, R ⁴¹ is selected from the group consisting of -(C0-C4-alkylene)carbocyclyl, -(C0-C4-alkylene)heterocyclyl, C1-C6-alkyl, C2-C6-alkenyl and C2-C6-alkynyl, wherein the carbocyclyl moiety, contained in the specified -(C0-C4-alkylene)carbocyclyl is selected from the group consisting of cycloalkyl, cycloalkenyl and aryl, where the heterocyclyl moiety contained in the specified -(C0-C4-alkylene)heterocyclyl is selected from the group consisting of heterocycloalkyl, heterocycloalkenyl and heteroaryl, wherein the carbocyclyl moiety contained in said -(C0-C4-alkylene)carbocyclyl and the heterocyclyl moiety contained in said -(C0-C4-alkylene)heterocyclyl are each optionally substituted with one or more (e.g., one, two or three) groups R ⁴² , and where additionally the specified C1-C ₆ -alkyl, the specified C ₂ -C ₆ -alkenyl, the specified C ₂ -C ₆ -alkynyl, the alkylene fragment contained in the specified -(C0-C4-alkylene)carbocyclyl, and the alkylene moiety contained in said -(C0-C4-alkylene)heterocyclyl, each optionally substituted with one or more (eg, one, two or three) R ⁴³ groups. More preferably, R ⁴¹ is selected from the group consisting of -(C0-C4-alkylene)aryl and -(C0-C4-alkylene)heteroaryl, wherein the aryl moiety contained in said -(C0-C4-alkylene)aryl and heteroaryl moiety contained in said -(C0-C4alkylene)heteroaryl, each optionally substituted with one or more (for example, one, two or three) R ⁴² groups, and wherein additionally an alkylene moiety contained in said -(C0- _C4alkylene )aryl , and the alkylene moiety contained in said -(C ₀ -C ₄ -alkylene)heteroaryl, each optionally substituted with one or more (eg, one, two or three) R ⁴³ groups. Even more preferably, R ⁴¹ is selected from the group consisting of -(C ₀ -C ₄ -alkylene)aryl and -(C ₀ -C ₄ -alkylene)heteroaryl, wherein the aryl moiety contained in said -(C0 -C4 -alkylene) aryl, and the heteroaryl moiety contained in said -(C0-C4-alkylene)heteroaryl, each optionally substituted with one or more (eg, one, two or three) R ⁴² groups. A preferred example of the aryl moiety contained in said -(C0-C4-alkylene)aryl is phenyl. A preferred example of a heteroaryl moiety contained in said -(C0-C4alkylene)heteroaryl is a 5- or 6-membered monocyclic heteroaryl containing 1 or 2 ring heteroatoms independently selected from oxygen, nitrogen and sulfur (where the remaining ring atoms are carbon atoms) , such as, for example, imidazolyl, thiophenyl or pyrimidinyl. Even more preferably, R ⁴¹ is selected from phenyl and heteroaryl, wherein said heteroaryl is a 5- or 6-membered monocyclic heteroaryl containing 1 or 2 ring heteroatoms independently selected from oxygen, nitrogen and sulfur (the remaining ring atoms of the monocyclic heteroaryl are carbon atoms ), and wherein further said phenyl or said heteroaryl is optionally substituted with one or more (eg, one, two or three) R ⁴² groups.

Each R ⁴² is independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OH, -O(C1-C6 alkyl), -O(C1-C6 alkylene)-OH, -O(C1-C6-alkylene)-O(C1-C6-alkyl), -SH, -S(C1-C6-alkyl), -NH2, -NH(C1-C6-alkyl), -N(C1-C6- alkyl)(C1-C6-alkyl), halogen, C1-C6-haloalkyl, -O-(C1-C6haloalkyl), -CN, -NO2, -CHO, -CO-(C1-C6-alkyl), -COOH, -COO-(C1-C6-alkyl), -O-CO-(C1-C6-alkyl), -CO-NH2, -CO-NH(C1-C6-alkyl), -CO-N(C1-C6- alkyl)(C1-C6-alkyl), -NH-CO-(C1-C6-alkyl), -N(C1-C6alkyl)-CO-(C1-C6-alkyl), -SO2-NH2, -SO2-NH (C1-C6-alkyl), -SO2-N(C1-C6-alkyl)(C1-C6-alkyl), -NH-SO2(C1-C6-alkyl) and -N(C1-C6-alkyl)-SO2 -(C1-C6-alkyl). Preferably, each R ⁴² is independently selected from the group consisting of C1- _C6- alkyl, -OH, -O(C1- _C6- alkyl), -O( _C1 - _C6 -alkylene)-OH, -O( C ₁ -C ₆ alkylene)-O(C1-C ₆ -alkyl), -SH, -S(C ₁ -C ₆ -alkyl), -NH2, -NH(C ₁ -C ₆ -alkyl), -N (C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, C ₁ -C ₆ -haloalkyl, -O-(C ₁ -C ₆ -haloalkyl) and -CN.

Each R ⁴³ is independently selected from the group consisting of -OH, -O(C1-C6-alkyl), -SH, -S(C1-C6-alkyl), -NH2, -NH(C1-C6-alkyl), -N(c1 -C6-alkyl)(C1-C6-alkyl), halogen, -CF3, -CN, -NO2, -CHO, -CO-(C1C6-alkyl), -COOH, -COO-(C1-C6-alkyl), -O-CO-(C1-C6-alkyl), -CO-NH2, -CO-NH(C1-C6-alkyl), -CO-N(C1C6-alkyl)(C1-C6-alkyl), -NH- CO-(C1-C6-alkyl) and -N(C1-C6-alkyl)-CO-(C1-C6-alkyl). Preferably, each R ⁴³ is independently selected from the group consisting of -OH, -O(C1-C6-alkyl), -SH, -S(C ₁ -C ₆ -alkyl), -NH2, -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, -CF ₃ and -CN.

In accordance with the above definitions, it is particularly preferred if R ^4a is -O-aryl or halogen, wherein the aryl moiety contained in said -O-aryl is optionally substituted with one or more groups independently selected from C1-C6 alkyl, C2- C6-alkenyl, C2-C6alkynyl, -OH, -O(C1-C6-alkyl), -O(C1-C6-alkylene)-OH, -O(C1-C6-alkylene)-O(C1-C6-alkyl) ), -SH, -S(C1-C6-alkyl), -NH2, -NH(C1-C6-alkyl), -N(C1-C6-alkyl)(C1-C6-alkyl), halogen, C1-C6-haloalkyl and -CN. Even more preferably, R ^4a is -O-phenyl or a halogen (such as, in particular, -Cl), wherein the phenyl moiety contained in said -O-phenyl is optionally substituted with one or more groups independently selected from C1-C _6- alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, -OH, -O(C1-C ₆ alkyl), -O(C ₁ -C ₆ -alkylene)-OH, -O( C ₁ -C ₆ -alkylene) -O (C ₁ -C ₆ -alkyl), -SH, -S (C ₁ -C ₆ -alkyl), -NH ₂ , -NH (C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, C ₁ -C ₆ -haloalkyl and -CN.

R ^5a is selected from the group consisting of -NH2, -NH(C ₁ -C ₆ -alkyl) and -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), where the alkyl fragment contained in the specified -NH(C ₁ -C ₆ -alkyl), and one or both of the alkyl moieties contained in said -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), each optionally substituted by one or

- 56 043772 more groups independently selected from halogen, -CF ₃ , -CN, -NO2, -NH2, -MScC^alkyl), -N(CiCb-alkyl)(C1-Cb-alkyl), -OH, -O (C1-C6-alkyl), -SH, -S(C1 _- C6-alkyl), carbocyclyl and heterocyclyl, wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more R ⁵¹ groups. Preferably, R ^5a is selected from the group consisting of -NH2, -NH(C1-Cb-alkyl) and -N(C1-Cb-alkyl)(C1-Cb-alkyl), wherein the alkyl moiety contained in said -NH( C1-Cb-alkyl), and one or both of the alkyl moieties contained in said -N(C1-Cb-alkyl)(C1-Cb-alkyl), each optionally substituted with one or more (for example, one, two or three) groups , independently selected from halogen, -CF3, -CN, -NO2, -NH2, -NH(C1-Cb-alkyl), -N(C1-Cb-alkyl)(C1-Cb-alkyl), -OH, -O (C1-C6-alkyl), -SH and -S(C1-C6-alkyl). More preferably, R ^5a is selected from -NH2, -NH(C1-C6alkyl) and -N( _C1 - _Cb -alkyl)( _C1 - _Cb -alkyl). Particularly preferred examples of R ^5a are -NH2 or -NH-CH2CH2CH2CH3.

Each R ⁵¹ is independently selected from the group consisting of C1-C6-alkyl, C2-C6-alkenyl, C2-C6alkynyl, -OH, -O(C1-C6-alkyl), -O(C1-C6-alkylene)-OH, -O(C1-Cb-alkylene)-O(C1-Cb-alkyl), -SH, -S(Ci-C6alkyl), -NH2, -NH(C1-Cb-alkyl), -N(C1-Cb- alkyl)(C1-Cb-alkyl), halogen, C1-Cb-haloalkyl, -O-(C1-C6haloalkyl), -CN, -NO2, -CHO, -CO-(C1-C6-alkyl), -COOH, -COO-(C1-Cb-alkyl), -O-CO-(C1-C6-alkyl), -CO-NH2, -CO-NH(C1-Cb-alkyl), -CO-N(C1-Cb- alkyl)(C1-Cb-alkyl), -NH-CO-(C1-Cb-alkyl), -N(Ci-C6alkyl)-CO-(C1-C6-alkyl), -SO2-NH2, -SO2-NH (C1-Cb-alkyl), -SO2-N(C1-Cb-alkyl)(C1-Cb-alkyl), -NH-SO2(C1-Cb-alkyl) and -N(C1-Cb-alkyl)-SO2 -(C1-Cb-alkyl). Preferably, each R ⁵¹ is independently selected from the group consisting of C1-C _b -alkyl, -OH, -O(C1-C ₆ -alkyl), -O(C1-C ₆ -alkylene)-OH, -O(C ₁ -C ₆ alkylene)-O(C1-C ₆ -alkyl), -SH, -S(C ₁ -C _b -alkyl), -NH2, -NH(C ₁ -C _b -alkyl), -N( C ₁ -C _b -alkyl)(C ₁ -C _b -alkyl), halogen, C ₁ -C _b -haloalkyl, -O-(C1-C ₆ -haloalkyl) and -CN.

R ⁶ is selected from the group consisting of hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, -OH, -O(C1-C6-alkyl), -O(C1-C6-alkylene)- OH, -O(C1-C6-alkylene)-O(C1-C6-alkyl), -SH, -S(C1-C6-alkyl), -NH2, -NH(C1-C6-alkyl), -N( C1-C6-alkyl)(C1-C6-alkyl), halogen, C1-C6-haloalkyl, -O-(C1-C6-haloalkyl), -CN, -NO2, -CHO, -CO-(C1-C6- alkyl), -COOH, -COO-(C1-C6-alkyl), -O-CO-(C1-C6-alkyl), -CO-NH2, -SONH(C1-C6-alkyl), -CO-N( C1-C6-alkyl)(C1-C6-alkyl), -NH-CO-(C1-C6-alkyl), -N(C1-C6-alkyl)-CO-(C1-C6alkyl), -SO2-NH2, -SO2-NH(C1-C6-alkyl), -SO2-N(c1-C6-alkyl)(C1-C6-alkyl), -NH-SO2-(C1-C6-alkyl) and -N(C1-C6 -alkyl)-SO2-(C1-C6-alkyl). Preferably, R ⁶ is selected from the group consisting of hydrogen, C1-C ₆ -alkyl, -OH, -O(C1-C ₆ -alkyl), -O(C1-C ₆ -alkylene)-OH, -O(C ₁ -C ₆ -alkylene)-O(C ₁ -C ₆ -alkyl), -SH, -S(CiC ₆ -alkyl), -NH2, -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl)(C ₁ -C ₆ -alkyl), halogen, C ₁ -C ₆ -haloalkyl, -O-(C1C ₆ -haloalkyl) and -CN. More preferably, R ⁶ is hydrogen or C1- _C4 alkyl. Even more preferably, R ⁶ is hydrogen.

The present invention also relates to a compound of any of the following formulas or a pharmaceutically acceptable salt or solvate thereof (and the present invention also relates to the said compound for use as a drug, and to a pharmaceutical composition containing the said compound and a pharmaceutically acceptable excipient):

- 57 043772

- 58 043772

- 59 043772

- 60 043772

- 61 043772

- 62 043772

- 63 043772

- 64 043772

For a person skilled in the field of synthetic chemistry, different routes for preparing the compounds of formula (I) will be apparent. Thus, for example, compounds of formula (I) can be prepared by the synthetic procedures described in the examples section or by similar procedures.

The following definitions apply throughout this specification unless specifically stated otherwise.

The term hydrocarbon group means a group consisting of carbon atoms and hydrogen atoms.

The term alicyclic is used in relation to cyclic groups and means that the corresponding cyclic group is non-aromatic.

As used herein, the term alkyl means a monovalent saturated acyclic (ie, non-cyclic) hydrocarbon group, which may be straight or branched. Accordingly, the alkyl group does not contain any carbon-carbon double bond or any carbon-carbon triple bond. The term C ₁ -C ₆ -alkyl means an alkyl group containing from 1 to 6 carbon atoms. Preferred typical alkyl groups are methyl, ethyl, propyl (eg n-propyl or isopropyl) or butyl (eg n-butyl, isobutyl, sec-butyl or tert-butyl). Unless otherwise defined, the term alkyl preferably means C1- _C4 alkyl, more preferably methyl or ethyl, and even more preferably methyl.

As used herein, the term alkenyl means a monovalent unsaturated acyclic hydrocarbon group that may be straight or branched and contains one or more (eg, one or two) carbon-carbon double bonds but does not contain any carbon-carbon triple bond. The term C ₂ -C ₆ -alkenyl means an alkenyl group containing from 2 to 6 carbon atoms. Preferred typical alkenyl groups are ethenyl, propenyl (eg prop-1-en-1-yl, prop-1-en-2-yl or prop-2-en-1-yl), butenyl, butadienyl (eg buta- 1,3-dien-1-yl or buta-1,3-dien-2-yl), pentenyl or pentadienyl (eg isoprenyl). Unless otherwise defined, the term alkenyl preferably means C ₂ -C ₄ alkenyl.

As used herein, the term alkynyl means a monovalent unsaturated acyclic hydrocarbon group which may be straight or branched and

- 65 043772 contains one or more (eg one or two) carbon-carbon triple bonds and optionally one or more carbon-carbon double bonds. The term C ₂ -C ₆ -alkynyl means an alkynyl group containing from 2 to 6 carbon atoms. Preferred typical alkynyl groups are ethynyl, propynyl (eg propargyl) or butynyl. Unless otherwise defined, the term alkynyl preferably means C ₂ -C ₄ -alkynyl.

As used herein, the term alkylene means an alkanediyl group, i.e. a divalent saturated acyclic hydrocarbon group, which may be linear or branched. The term CpC^-alkylene means an alkylene group containing from 1 to 15 carbon atoms, and the term C ₀ -C ₁₅ -alkylene means that a covalent bond (corresponding to the term C ₀ -alkylene) or C 1 -C ₁₅ -alkylene is contained. Preferred typical alkylene groups are methylene (-CH2-), ethylene (eg -CH2-CH2- or -CH( _-CH3 )-), propylene (eg _-CH2CH2 -CH2-, -CH( _-CH2 -CH ₃ )-, -CH ₂ -CH(-CH ₃ )- or -CH(-CH ₃ )-CH ₂ -) or butylene (for example, -CH2-CH2-CH2CH ₂ -). Unless otherwise defined, the term alkylene preferably means C1- _C4 alkylene (including in particular linear C1-C4 alkylene), more preferably methylene or ethylene, and even more preferably methylene.

As used herein, the term alkenylene means an alkenediyl group, i.e. a divalent unsaturated acyclic hydrocarbon group, which may be straight or branched and contains one or more (eg, one or two) carbon-carbon double bonds, but does not contain any carbon-carbon triple bond. The term C ₂ C ₁₅ -alkenylene means an alkenylene group containing from 2 to 15 carbon atoms. Unless otherwise defined, the term alkenylene preferably means C ₂ -C ₄ alkenylene (including, in particular, linear C 2 -C 4 alkenylene).

As used in the present invention, the term alkynylene means an alkynediyl group, i.e. a divalent unsaturated acyclic hydrocarbon group, which may be straight or branched and contains one or more (eg, one or two) carbon-carbon triple bonds and optionally one or more carbon-carbon double bonds. The term C ₂ -C ₁₅ alkynylene means an alkynylene group containing from 2 to 15 carbon atoms. Unless otherwise defined, the term alkynylene preferably means C ₂ -C ₄ -alkynylene (including, in particular, linear C ₂ -C ₄ -alkynylene).

As used herein, the term alkylidene means a divalent acyclic hydrocarbon group, which may be straight or branched, which is linked to the remainder of the corresponding compound by a double bond and which does not contain any other double bond (i.e., which does not contain any double bond other than the one that connects the alkylidene group to the rest of the corresponding compound) or no triple bond. The alkylidene group may, for example, be attached to a carbon atom or to a nitrogen atom contained in the remainder of the corresponding compound. The term C ₁ -C ₆ -alkylidene means an alkylidene group containing from 1 to 6 carbon atoms. Preferred typical alkylidene groups are methylidene (=CH ₂ ), ethylidene (=CH-CH ₃ ), propylidene (for example, =CH-CH ₂ CH ₃ or =C(-CH ₃ )-CH ₃ ), or butylidene (for example, = CH-CH ₂ CH ₂ CH ₃ , =C(-CH ₃ )-CH ₂ CH ₃ or =CH-CH(-CH ₃ )CH ₃ ). Unless otherwise defined, the term alkylidene preferably means _CC4 alkylidene.

As used herein, the term carbocyclyl means a hydrocarbon ring group, including monocyclic rings, as well as bridged ring systems, spirocyclic ring systems, and/or fused ring systems (which may consist of, for example, 2 or 3 rings), wherein said ring group may be saturated, partially unsaturated (i.e. unsaturated but not aromatic) or aromatic. Unless otherwise defined, carbocyclyl preferably means aryl, cycloalkyl or cycloalkenyl.

As used herein, the term heterocyclyl means a ring group including monocyclic rings, as well as bridged ring systems, spirocyclic ring systems, and/or fused ring systems (which may consist of, for example, two or three rings), wherein said ring group contains one or more (for example, one, two, three or four) ring heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon atoms, where one or more S ring atoms (if present) and/or one or more than one ring N atom (if present) may optionally be oxidized, wherein one or more ring carbon atoms may optionally be oxidized (i.e., form an oxo group), and wherein further said ring group may be saturated, partially unsaturated (i.e. . unsaturated, but not aromatic) or aromatic. Thus, for example, each heteroatom-containing ring contained in said ring group may contain one or two O atoms and/or one or two S atoms (which may optionally be oxidized), and/or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms contained in the corresponding heteroatom-containing ring is from 1 to 4, and that the corresponding heteroatom-containing ring contains at least one

- 66 043772 ring carbon atom (which may optionally be oxidized). Unless otherwise defined, the term heterocyclyl preferably means heteroaryl, heterocycloalkyl or heterocycloalkenyl.

As used herein, the term aryl means an aromatic hydrocarbon ring group, including monocyclic aromatic rings, as well as bridged ring systems and/or fused ring systems containing at least one aromatic ring (for example, ring systems consisting of two or three fused rings , where at least one of these fused rings is aromatic; or bridged ring systems consisting of two or three rings, where at least one of these bridged rings is aromatic). The term aryl can mean, for example, phenyl, naphthyl, dialinyl (i.e. 1,2-dihydronaphthyl), tetralinyl (i.e. 1,2,3,4-tetrahydronaphthyl), indanyl, indenyl (e.g. 1H-indenyl ), anthracenyl, phenanthrenyl, 9H-fluorenyl or azulenil. Unless otherwise defined, aryl preferably contains from 6 to 14 ring atoms, more preferably from 6 to 10 ring atoms, even more preferably it is phenyl or naphthyl, and most preferably it is phenyl.

As used herein, the term heteroaryl means an aromatic ring group, including monocyclic aromatic rings, as well as bridged ring systems and/or fused ring systems containing at least one aromatic ring (for example, ring systems consisting of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems consisting of two or three rings, wherein at least one of these bridged rings is aromatic), wherein said aromatic ring group contains one or more (for example, one , two, three or four) ring heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon atoms, where one or more S ring atoms (if present) and/or one or more N ring atoms (if present) they are contained) may optionally be oxidized, and wherein additionally one or more ring carbon atoms may optionally be oxidized (i.e. form an oxo group). Thus, for example, each heteroatom-containing ring contained in said aromatic ring group may contain one or two O atoms and/or one or two S atoms (which may optionally be oxidized), and/or one, two, three or four atoms N (which may optionally be oxidized), provided that the total number of heteroatoms contained in the corresponding heteroatom-containing ring is from 1 to 4, and that the corresponding heteroatom-containing ring contains at least one ring carbon atom (which is optionally oxidizable) . The term heteroaryl may mean, for example, thienyl (i.e. thiophenyl), benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furanyl (i.e. furanyl), benzofuranyl, isobenzofuranyl, chromanyl, chromenyl (e.g. 2H-1-benzopyranyl or 4H-1-benzopyranyl), isochromenyl (e.g. 1H-2-benzopyranyl), chromonyl, xanthenyl, phenoxathiinyl, pyrrolyl (e.g. 1H-pyrrolyl), imidazolyl, pyrazolyl, pyridyl (i.e. e. pyridinyl; e.g. 2-pyridyl, 3-pyridyl or 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolyl (e.g. 3H-indolyl), isoindolyl, indazolyl, indolizinyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl (e.g., [1,10]phenanthrolinyl, [1,7]phenanthrolinyl, or [4,7]phenanthrolinyl), phenazinyl, thiazolyl, isothiazolyl , phenothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl (e.g. 1,2,4oxadiazolyl, 1,2,5-oxadiazolyl (i.e. furazanyl) or 1,3,4-oxadiazolyl), thiadiazolyl (e.g. 1,2,4 -thiadiazolyl, 1,2,5-thiadiazolyl or 1,3,4-thiadiazolyl), phenoxazinyl, pyrazolo[1,5a]pyrimidinyl (e.g. pyrazolo[1,5-a]pyrimidin-3-yl), 1,2 -benzoisoxazol-3-yl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzo[b]thiophenyl (i.e. benzothienyl), triazolyl (e.g. 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl or 4H-1,2,4triazolyl), benzotriazolyl, 1H- tetrazolyl, 2H-tetrazolyl, triazinyl (for example, 1,2,3-triazinyl, 1,2,4triazinyl, or 1,3,5-triazinyl), furo[2,3-c]pyridinyl, dihydrofuropyridinyl (for example, 2, 3dihydrofuro[2,3-c]pyridinyl or 1,3-dihydrofuro[3,4-c]pyridinyl), imidazopyridinyl (for example, imidazo[1,2-a]pyridinyl or imidazo[3,2-a]pyridinyl), or coumarinil. Unless otherwise defined, the term heteroaryl preferably means a 5-14 membered (more preferably 5-10 membered) monocyclic ring or fused ring system containing one or more (for example, one, two, three or four) ring heteroatoms, independently selected of O, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized; even more preferably, the term heteroaryl means a 5- or 6-membered monocyclic ring containing one or more (for example, one, two or three) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms ( if present) and/or one or more ring N atoms (if present) are optionally oxidized, and where one or

- 67 043772 more ring carbon atoms are not necessarily oxidized. Additionally, unless otherwise specified, particularly preferred examples of heteroaryl include pyridinyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), imidazolyl, thiazolyl, 1H-tetrazolyl, 2H-tetrazolyl, thienyl (i.e., thiophenyl ) or pyrimidinyl.

As used herein, the term cycloalkyl means a saturated hydrocarbon ring group including monocyclic rings, as well as bridged ring systems, spirocyclic ring systems, and/or fused ring systems (which may consist of, for example, two or three rings; such as, for example, fused ring system consisting of two or three fused rings). The term cycloalkyl can mean, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl (ie decahydronaphthyl) or adamantyl. Unless otherwise defined, the term cycloalkyl preferably means C ₃ -C ₁₁ cycloalkyl, and more preferably means C ₃ -C ₇ cycloalkyl. A particularly preferred cycloalkyl is a monocyclic saturated hydrocarbon ring containing from 3 to 7 ring units. Moreover, unless otherwise specified, particularly preferred examples of cycloalkyl include cyclohexyl or cyclopropyl, with cyclohexyl being preferred.

As used herein, the term heterocycloalkyl means a saturated ring group, including monocyclic rings, as well as bridged ring systems, spirocyclic ring systems, and/or fused ring systems (which may consist of, for example, two or three rings; such as, for example, fused a ring system consisting of two or three fused rings), wherein said ring group contains one or more (for example, one, two, three or four) ring heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon atoms wherein one or more ring S atoms (if present) and/or one or more ring N atoms (if present) may optionally be oxidized, and wherein additionally one or more ring carbon atoms may optionally be oxidized (i.e. form an oxo group). Thus, for example, each heteroatom-containing ring contained in said saturated ring group may contain one or two O atoms and/or one or two S atoms (which may optionally be oxidized), and/or one, two, three or four atoms N (which may optionally be oxidized), provided that the total number of heteroatoms contained in the corresponding heteroatom-containing ring is from 1 to 4, and that the corresponding heteroatom-containing ring contains at least one ring carbon atom (which is optionally oxidizable) . The term heterocyloalkil can mean, for example, aziridinyl, azetidinyl, pyrrolidyl, imidazolidinyl, piraisolidinyl, pyperidinyl, purezinyl, azeepanil, diazepanil (for example, 1.4-diazepanil), oxasolidinyl, Izoxazolidyl, thiazolidyl, isotiazolidinyl, morpholin- 4- yl), thiomorpholinyl (e.g. thiomorpholin-4-yl), oxazepanil, oxiranyl, oxetanyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanil, thiiranil, thietanyl, tetrahydrothiophenyl (i.e. thiolanyl) , 1,3dithiolanyl, thianyl, thiepanyl, decahydroquinolinyl, decahydroisoquinolinyl or 2-oxa-5azabicyclo[2.2.1]hept-5-yl. Unless otherwise defined, the term heterocycloalkyl preferably means a 3- to 11-membered saturated ring group that is a monocyclic ring or a fused ring system (e.g., a fused ring system consisting of two fused rings), wherein said ring group contains one or more (for example, one, two, three or four) ring heteroatoms independently selected from O, S and N, where one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more ring carbon atoms are optionally oxidized; more preferably, the term heterocycloalkyl means a 5-7 membered saturated monocyclic ring group containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms ( if present) and/or one or more ring N atoms (if present) are optionally oxidized, and where one or more ring carbon atoms are optionally oxidized. Additionally, unless otherwise specified, particularly preferred examples of heterocycloalkyl include tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, or tetrahydrofuranyl.

As used herein, the term cycloalkenyl means an unsaturated alicyclic (non-aromatic) hydrocarbon ring group, including monocyclic rings, as well as bridged ring systems, spirocyclic ring systems, and/or fused ring systems (which may consist of, for example, two or three rings; such such as, for example, a fused ring system consisting of two or three fused rings), wherein said hydrocarbon ring group contains one or more (eg, one or two) carbon-carbon double bonds and does not contain any carbon-carbon triple bond. The term cycloalkenyl can mean, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl or cycloheptadienyl. Unless otherwise defined,

- 68 043772 the term cycloalkenyl preferably means C ₃ -C ₁₁ -cycloalkenyl, and more preferably, it means C ₃ -C ₇ -cycloalkenyl. A particularly preferred cycloalkenyl is a monocyclic unsaturated alicyclic hydrocarbon ring containing from 3 to 7 ring units and containing one or more (eg, one or two; preferably one) carbon-carbon double bonds.

As used herein, the term heterocycloalkenyl means an unsaturated alicyclic (non-aromatic) ring group, including monocyclic rings, as well as bridged ring systems, spirocyclic ring systems, and/or fused ring systems (which may consist of, for example, two or three rings; such as e.g., a fused ring system consisting of two or three fused rings), wherein said ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S, and N, and the remaining ring members atoms are carbon atoms where one or more ring S atoms (if present) and/or one or more ring N atoms (if present) may optionally be oxidized, where one or more ring carbon atoms may optionally be oxidized (i.e. e. form an oxo group), and wherein further said ring group contains at least one double bond between adjacent ring atoms and does not contain any triple bond between adjacent ring atoms. Thus, for example, each heteroatom-containing ring contained in said unsaturated alicyclic ring group may contain one or two O atoms and/or one or two S atoms (which may optionally be oxidized), and/or one, two, three or four N atom (which may optionally be oxidized), provided that the total number of heteroatoms contained in the corresponding heteroatom-containing ring is from 1 to 4, and that the corresponding heteroatom-containing ring contains at least one ring carbon atom (which may optionally be oxidized ). The term heterocycloalkenyl may mean, for example, imidazolinyl (for example, 2-imidazolinyl (i.e. 4,5-dihydro-1H-imidazolyl), 3-imidazolinyl, or 4-imidazolinyl), tetrahydropyridinyl (for example, 1,2,3, 6-tetrahydropyridinyl), dihydropyridinyl (for example, 1,2-dihydropyridinyl or 2,3-dihydropyridinyl), pyranyl (for example, 2H-pyranyl or 4H-pyranyl), thiopyranyl (for example, 2H-thiopyranyl or 4H-thiopyranyl), dihydropyranyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrazinyl, dihydroisoindolyl, octahydroquinolinyl (eg 1,2,3,4,4a,5,6,7octahydroquinolinyl) or octahydroisoquinolinyl (eg 1,2,3,4,5,6,7,8-octahydroisoquinolinyl). Unless otherwise defined, the term heterocycloalkenyl preferably means a 311-membered unsaturated alicyclic ring group that is a monocyclic ring or a fused ring system (e.g., a fused ring system consisting of two fused rings), wherein said ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optional are oxidized, and wherein said ring group contains at least one double bond between adjacent ring atoms and does not contain any triple bond between adjacent ring atoms; more preferably, the term heterocycloalkenyl means a 5-7 membered monocyclic unsaturated non-aromatic ring group containing one or more (for example, one, two or three) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein said ring group contains at least one double bond between adjacent ring atoms and does not contain any triple bond between adjacent ring atoms.

As used herein, the term halogen means fluorine (-F), chlorine (-Cl), bromine (-Br) or iodine (-I).

As used herein, the term haloalkyl means an alkyl group substituted with one or more (preferably 1 to 6, more preferably 1 to 3) halogen atoms independently selected from the group consisting of fluorine, chlorine, bromine and iodine, and preferably all are fluorine atoms. It should be understood that the maximum number of halogen atoms is limited by the maximum number of attachment positions contained and thus depends on the number of carbon atoms contained in the alkyl moiety contained in the haloalkyl group. The term haloalkyl may mean, for example, -CF3, -CHF2, -CH2F, -CF2-CH3, -CH2-CF3, -CH2-CHF2, -CH2-CF2-CH3, -CH2-CF2-CF3 or -CH(CF ₃ )2. A particularly preferred haloalkyl group is -CF ₃ .

When used in the present invention, the terms optional, optional and may mean that the specified characteristic may or may not be present. Whenever the term optional, optional or may be used, the present invention refers to both possibilities, i.e. that the corresponding characteristic is present or, alternatively, that the corresponding characteristic is absent. Thus, for example, the expression X is optionally replaced by Y (or X may be replaced by Y) means that X is either replaced by Y or is unsubstituted. Likewise, if a component contained in the composition is specified as optional, then the present invention specifically applies to both possibilities, i.e. that the corresponding component is present (contained in the composition) or that the corresponding component is absent from the composition.

In the present description, various groups are indicated as optionally substituted. Typically these groups may contain one or more substituents, such as one, two, three or four substituents. It should be understood that the maximum number of substituents is limited by the maximum number of attachment positions contained in the substituted moiety. Unless otherwise defined, as used herein, optionally substituted groups preferably contain no more than two substituents and may in particular contain only one substituent. In addition, unless otherwise specified, it is preferred that optional substituents are absent, i.e. the corresponding groups are unsubstituted.

It will be apparent to one skilled in the art that the substituent groups contained in the compounds of the present invention may be attached to the remainder of the corresponding compound at a number of different positions on the respective particular substituent group. Unless otherwise defined, preferred attachment positions for various specific substituent groups are illustrated in the examples.

As used in the present invention, unless explicitly stated otherwise or contrary to context, the singular terms and plural terms are used interchangeably with the terms one or more and at least one. Thus, for example, a composition containing a compound of formula (I) may mean a composition containing one or more compounds of formula (I).

When used in the present invention, the term approximately preferably means the specified numerical value ±10%, more preferably the specified numerical value ±5%, and especially preferably the exact specified numerical value. When the term is approximately used in reference to range limits, it preferably means a range from a lower limit equal to its specified numerical value -10% to an upper limit value equal to its specified numerical value +10%, more preferably means a range a range from a lower limit value of -5%, to an upper limit value of +5%, and even more preferably a range defined by precise numerical values corresponding to the lower limit value and the upper limit value. When the term is approximately used to refer to the limit value of an open-ended range, it preferably means a corresponding range of -10% lower limit or +10% upper limit, more preferably a range of -5% lower limit or from an upper limit value of +5%, and even more preferably an open-ended range defined by the exact numerical value of the corresponding limit value. If the term is approximately used in relation to a parameter whose quantity is determined by integers, such as the number of nucleotides in a given nucleic acid, then values corresponding to the specified numerical value of ±10% or ±5% must be rounded to the nearest integer (using the bond breaking rule , called rounding half up).

When used in the present invention, the term including (or includes, includes, contains, contains or contains), unless expressly stated otherwise or contrary to context, means containing, in particular, i.e. containing, among other optional elements, .... In addition, this term also includes the more precise terms consisting primarily of and consisting of. Thus, for example, the term A including B and C means A including, in particular, B and C, where A may contain additional optional elements (for example, A containing B, C and D would also be included), but the term also includes a term A consisting primarily of B and C and a term A consisting of B and C (i.e., A does not contain other components other than B and C).

The present invention includes all pharmaceutically or physiologically acceptable salts of the compounds of formula (I), which can be formed, for example, by protonation of an atom containing a lone electron pair susceptible to protonation, such as an amino group, with an inorganic or organic acid or salt, formed by an acidic group (such as a carboxy group) and a physiologically acceptable cation. Typical base addition salts include, for example: alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dichlorhexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts or choline salts; arylalkylamine salts such as K,K-dibenzylethylenediamine salts, benzathine salts, benetamine salts; heterocyclic aromatic amine salts, such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts or tetrabutylammonium salts; and salts of basic amino acids, such as arginine salts, lysine salts or histidine salts. Typical addition salts with acids include, for example: salts of inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfates (such as, for example, sulfates or hydrogen sulfate), nitrates, phosphates (such as, for example, phosphates, hydrogen phosphates or dihydrogen phosphates), carbonates , bicarbonates, perchlorates, borates or thiocyanates; salts of organic acids, such as acetates, propionates, butyrates, pentanoates, hexanoates, heptanoates, octanoates, cyclopentane propionates, decanoates, undecanoates, oleates, stearates, lactates, maleates, oxalates, fumarates, tartrates, malates, citrates, succinates, adipates, gluconates, glycolates, nicotinates, benzoates, salicylates, ascorbates, pamoates (embonates), camphorates, glucoheptanoates or pivalates; sulfonates such as methanesulfonates (mesylates), ethanesulfonates (esylates), 2-hydroxyethanesulfonates (isethionates), benzenesulfonates (besylates), p-toluenesulfonates (tosylates), 2-naphthalene sulfonates (napsylates), 3-phenylsulfonates or camphorsulfonates; glycerophosphates and acidic amino acid salts such as aspartates or glutamates. Preferred pharmaceutically/physiologically acceptable salts of the compounds of formula (I) include hydrochloride, hydrobromide, mesylate, sulfate, tartrate, fumarate, acetate, citrate and phosphate. A particularly preferred pharmaceutically/physiologically acceptable salt of the compound of formula (I) is the hydrochloride.

Also included within the scope of the present invention are the compounds of formula (I) in any solvated form, including, for example, solvates with water (i.e., hydrate) or solvates with organic solvents, such as, for example, methanol, ethanol or acetonitrile (ie methanolate, ethanolate or acetonitrile), or being in any crystalline form (ie in any polymorphic form), or in amorphous form. It should be understood that such solvates of compounds of formula (I) also include solvates of pharmaceutically acceptable salts of compounds of formula (I).

In addition, the compounds of formula (I) may exist in the form of different isomers, in particular stereoisomers (including, for example, geometric isomers (or cis/trans isomers), enantiomers and diastereoisomers) or tautomers. All such isomers of the compounds of formula (I), whether in mixture form or in pure or substantially pure form, are intended to form part of the present invention. With regard to stereoisomers, the scope of the present invention includes the individual optical isomers of the compounds proposed in the present invention, as well as any mixtures thereof (including, in particular, racemic mixtures/racemates). Racemates can be separated using physical techniques, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation using chiral column chromatography. Individual optical isomers can also be prepared from racemates by salt formation with an optically active acid and subsequent crystallization. The scope of the present invention also includes any tautomers of the compounds proposed in the present invention.

Also included within the scope of the present invention are compounds of formula (I) in which one or more atoms are replaced by a specific isotope of the corresponding atom. Thus, for example, within the scope of the present invention are compounds of formula (I) in which one or more hydrogen atoms (or, for example, all hydrogen atoms) are replaced by deuterium atoms (ie, using ² H; also called D). Accordingly, also within the scope of the present invention are compounds of formula (I) that are enriched in deuterium. Naturally occurring hydrogen is a mixture of isotopes containing approximately 99.98 mol% hydrogen-1 (1H) and approximately 0.0156 mol% deuterium ( ^2H or D). The number of deuterium atoms present at one or more hydrogen atom positions contained in the compounds of formula (I) can be increased using deuteration techniques known in the art. Thus, for example, a compound of formula (I) or a reagent or precursor used to synthesize a compound of formula (I) can be subjected to an H/D exchange reaction using, for example, heavy water (D2O). Other suitable deuteration techniques are described in: Atzrodt J et al., Bioorg Med Chem, 20(18), 5658-5667, 2012; William JS et al., Journal of Labeled Compounds and Radiopharmaceuticals, 53(11-12), 635-644, 2010; Modvig A et al., J Org Chem, 79, 5861-5868, 2014. Deuterium content can be determined, for example, using mass spectrometry or NMR (nuclear magnetic resonance) spectroscopy. Unless specifically stated otherwise, it is preferred that the compound of formula (I) is not enriched in deuterium. Accordingly, it is preferred that the compounds of formula (I) contain naturally occurring hydrogen atoms or 1H hydrogen atoms.

Also included within the scope of the present invention are compounds of formula (I) in which one or more atoms are replaced by a positronically active isotope of the corresponding atom, such as, for example, ¹⁸ F, ^PS , ¹³ N, ¹⁵ O, ⁷⁶ Br, ⁷⁷ Br, ¹²⁰ I and/or ¹²⁴ I. Such compounds can be used as radioactive tracers, tracking agents or imaging agents for positron emission tomography (PET). Thus, within the scope of the present invention are (i) compounds of formula (I) in which one or more fluorine atoms (or, for example, all fluorine atoms)

- 71 043772 are replaced by ¹⁸ F atoms, (ii) compounds of formula (I), in which one or more carbon atoms (or, for example, all carbon atoms) are replaced by ^PS atoms, (iii) compounds of formula (I), in which one or more nitrogen atoms (or, for example, all nitrogen atoms) are replaced by ¹³ N atoms, (iv) compounds of formula (I) in which one or more oxygen atoms (or, for example, all oxygen atoms) are replaced by ¹⁵ O atoms , (v) compounds of formula (I) in which one or more bromine atoms (or, for example, all bromine atoms) are replaced by ⁷⁶ Br atoms, (vi) compounds of formula (I) in which one or more bromine atoms ( or, for example, all bromine atoms) are replaced by ⁷⁷ Br atoms, (vii) compounds of formula (I) in which one or more iodine atoms (or, for example, all iodine atoms) are replaced by I atoms, and (viii) compounds of formula ( I) in which one or more iodine atoms (or, for example, all iodine atoms) are replaced by ¹²⁴ I atoms. It is generally preferred that none of the atoms contained in the compounds of formula (I) are replaced by specific isotopes.

The compounds of the present invention can be administered as compounds themselves or they can be formulated as drugs. Drugs/pharmaceutical compositions may optionally contain one or more pharmaceutically acceptable excipients such as carriers, diluents, fillers, disintegrants, lubricants, binders, colorants, pigments, stabilizers, preservatives, antioxidants and/or solubility enhancers.

The pharmaceutical compositions may contain one or more solubility enhancers, such as, for example, poly(ethylene glycol), including poly(ethylene glycol) having a molecular weight ranging from about 200 to about 5000 Da (for example, PEG (PEG = polyethylene glycol) 200, PEG 300, PEG 400, or PEG 600), ethylene glycol, propylene glycol, glycerin, nonionic surfactant, tyloxapol, polysorbate 80, macrogol 15-hydroxystearate (e.g. Collifor® HS 15, CAS Registration No.: 70142-34 -6), phospholipid, lecithin, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, cyclodextrin, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-γ-cyclodextrin, hydroxypropyl- γ -cyclodextrin, dihydroxypropyl-b-cyclodextrin, β-cyclodextrin sulfobutyl ether, γ-cyclodextrin sulfobutyl ether, glucosyl-a-cyclodextrin, glucosyl-b-cyclodextrin, diglucosyl-b-cyclodextrin, maltosyl-a-cyclodextrin, maltosyl-b-cyclodextrin, maltosyl -γ-cyclodextrin, maltotriosyl-b-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-b-cyclodextrin, methyl-b-cyclodextrin, carboxyalkyl thioether, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, vinyl acetate copolymer, vinylpyrrolidone, lauryl sulfate sodium at, sodium dioctyl sulfosuccinate, or any combination of them.

Pharmaceutical compositions can be prepared by methods known to one skilled in the art, for example, by methods described in Remington: The Science and Practice of Pharmacy, Pharmaceutical Press, ^22nd edition. The pharmaceutical compositions can be formulated in dosage forms for oral, parenteral, eg, intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardiac, rectal, nasal, topical, aerosol, or vaginal administration. Oral dosage forms include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, lozenges, solutions, emulsions, suspensions, syrups, elixirs, reconstitutive powders and granules, dispersible powders, drug-containing granules gums, chewable tablets and effervescent tablets. Dosage forms for parenteral administration include solutions, emulsions, suspensions, dispersions, and powders and granules for reconstitution. Emulsions are the preferred dosage forms for parenteral administration. Dosage forms for rectal and vaginal administration include suppositories and egg-shaped suppositories. Nasal dosage forms can be administered by inhalation and insufflation, for example, using a metered inhaler. Dosage forms for topical administration include creams, gels, ointments, balms, patches, and transdermal delivery systems.

The compounds of formula (I) or the pharmaceutical compositions described above containing a compound of formula (I) can be administered to a subject by any convenient route systemically/peripherally or at the site of desired effect, including, but not limited to, one or more of the following routes: orally ( e.g., in tablet, capsule, or ingestible solution form), topically (e.g., transdermally, intranasally, ocularly, buccally, and sublingually), parenterally (e.g., injection or infusion techniques, and including, e.g., injection, for example, subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intravertebral, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid or epigastric, for example by depot implantation, for example subcutaneous or intramuscular), in lungs (for example, by treatment by inhalation or insufflation using, for example, an aerosol administered, for example, through the mouth or nose), by gastrointestinal administration, intrauterine, intraocular, subcutaneous, ocular (including intravitreal or into the chamber), rectal and vaginal administration.

If the compounds or pharmaceutical compositions are administered parenterally, examples of such administration include one or more of the following routes: intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, epigastric, intracardiac, intracranial, intramuscular or subcutaneous administration of the compound or pharmaceutical compositions, and/ or they are administered using infusion techniques. For parenteral administration, the compounds are best used in the form of a sterile aqueous solution, which may contain other substances, for example, sufficient salts or glucose to render the solution isotonic with blood. Aqueous solutions should be buffered if necessary (preferably to ensure a pH value between 3 and 9). The preparation of suitable parenteral preparations under sterile conditions is easily accomplished using conventional pharmaceutical techniques well known to those skilled in the art.

These compounds or pharmaceutical compositions may also be administered orally in the form of tablets, capsules, egg-shaped preparations, elixirs, solutions or suspensions, which may contain flavoring or coloring agents intended for immediate, delayed, modified, delayed, pulsed or controlled release use.

Tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, hydrogen calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or cassava starch), sodium starch glycolate, sodium croscarmellose and some complex silicates, and granulating binders such as polyvinylpyrrolidone, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. In addition, lubricants such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. Solid compositions of a similar type can also be used as fillers for gelatin capsules. In this case, preferred excipients include lactose, starch, cellulose or high molecular weight polyethylene glycols. To prepare aqueous suspensions and/or elixirs, the agent can be combined with various sweeteners or flavoring agents, coloring agents or dyes, emulsifying and/or suspending agents and diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

Alternatively, these compounds or pharmaceutical compositions can be administered in the form of a suppository or pessary, or they can be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or powder. The compounds of the present invention can also be administered cutaneously or transdermally, for example, through the use of a skin patch.

These compounds or pharmaceutical compositions can also be administered using sustained release systems. Suitable examples of sustained release compositions include semi-permeable polymer matrices in the form of molded articles, for example films, or microcapsules. Sustained release matrices include, for example, polylactides (see, for example, US 3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman, U. et al., Biopolymers 22:547-556 (1983) ), poly(2-hydroxyethyl methacrylate) (R. Langer et al., J. Biomed. Mater. Res. 15:167-277 (1981), and R. Langer, Chem. Tech. 12:98-105 (1982) ), ethylene vinyl acetate (R. Langer et al., Id.) or poly-D-(-)-3-hydroxybutyric acid (EP 133988). Sustained release pharmaceutical compositions also include liposomes with compounds included therein. Liposomes containing the compound of the present invention can be prepared according to methods known in the art, such as, for example, those described in any of the following publications: DE 3218121; Epstein et al., Proc. Natl. Acad. Sci. (USA) 82:3688-3692 (1985); Hwang et al., Proc. Natl. Acad. Sci. (USA) 77:4030-4034 (1980); EP 0052322; EP 0036676; EP 088046; EP 0143949; EP 0142641; JP 83118008; US 4485045; US 4544545 and EP 0102324.

These compounds or pharmaceutical compositions can also be administered into the lungs, rectally or into the eyes. For ophthalmic use, they can be formulated as micronized suspensions in isotonic, pH sterile saline, or preferably as solutions in isotonic, pH sterile saline, optionally in combination with a preservative such as benzalkonium chloride. Alternatively, they can be prepared as an ointment such as one containing petrolatum.

It is also possible to prepare dry powder preparations containing the compounds of formula (I) for administration into the lungs, preferably by inhalation. Such dry powders can be prepared by spray drying under conditions that provide a substantially amorphous glassy or substantially crystalline bioactive powder. Accordingly, dry powders of the compounds of the present invention can be prepared using the emulsification/spray drying technique disclosed in WO 99/16419 or WO 01/85136.

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Spray drying of drug solutions containing compounds of the present invention can be carried out, for example, as generally described in the Spray Drying Handbook,

5th ed., K. Masters, John Wiley & Sons, Inc., NY (1991), in WO 97/41833, or in WO 03/053411.

For topical application to the skin, the compounds or pharmaceutical compositions may be formulated as a suitable ointment containing the active compound suspended or dissolved, for example, in a mixture of one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifiable wax and water. Alternatively, they can be formulated as a suitable lotion or cream where they are suspended or dissolved, for example, in a mixture of one or more of the following: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl ester wax, 2-octyldodecanol , benzyl alcohol and water.

Thus, the present invention relates to compounds or pharmaceutical compositions proposed in the present invention, where the corresponding compound or pharmaceutical composition is administered by any of the following routes: orally; local routes, including transdermal, nasal, ocular, buccal or sublingual routes; parenterally by injection or infusion techniques, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intravertebral, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, epigastric, intraventricular, intraurethral, or intracranial path; pulmonary route, including treatment by inhalation or insufflation; gastrointestinal route; intrauterine route; intraocular route; subcutaneously; ocular route, including injection into the vitreous or into the chamber; rectally; or vaginally, particularly preferred routes of administration are topical administration, oral administration or parenteral administration. For the treatment or prevention of hyperhidrosis, topical administration is even more preferred.

Usually the physician will be able to determine the actual dosage that is most appropriate for a particular subject. The specific dosage and frequency of administration for any particular individual subject may vary and depend on a variety of factors, including the potency of the particular compound used, the metabolic stability and duration of action of that compound, age, body weight, general health, sex, diet, route and time of administration. the rate of elimination, the combination of drugs, the severity of the particular pathological condition and the particular subject being treated.

A recommended, but non-limiting, dose of the compounds of the present invention for oral administration to a human (approximately 70 kg body weight) may be from 0.05 to 2000 mg, preferably from 0.1 to 1000 mg of active ingredient per single dose. A single dose can be administered, for example, 1 to 3 times a day. A single dose can also be administered 1 to 7 times per week, for example, when administered no more than once per day. It should be understood that it may be necessary to make routine changes in dosage depending on the age and body weight of the patient/subject, as well as the severity of the pathological condition being treated. The exact dose, as well as the route of administration, ultimately depends on the judgment of the treating physician or veterinarian.

A compound of formula (I) or a pharmaceutical composition containing a compound of formula (I) can be administered in a monotherapy mode (for example, without the simultaneous administration of any additional therapeutic agents or without the simultaneous administration of any additional therapeutic agents intended to treat the same disease which is treated or prevented with a compound of formula (I)). However, a compound of formula (I) or a pharmaceutical composition containing a compound of formula (I) can also be administered in combination with one or more additional therapeutic agents, for example, one or more additional therapeutic agents selected from the group consisting of phenobarbital, phenytoin , valproate (or valproic acid), carbamazepine, lamotrigine, levetiracetam, ethosuximide and pharmaceutically acceptable salts of any of the above. If a compound of formula (I) is used in combination with a second therapeutic agent intended to treat the same disease or condition, the dose of each compound may be different from the dose used when the corresponding compound is used alone, in particular, a lower dose of each compound may be used . Combining a compound of formula (I) with one or more additional therapeutic agents (e.g., one or more of the corresponding exemplary therapeutic agents noted above) may involve co-administration of a compound of formula (I) and the additional therapeutic agent(s) (in one pharmaceutical preparation or in separate pharmaceutical preparations) or sequential/separate administration of a compound of formula (I) and additional therapeutic agent(s). If administration is carried out sequentially, either the compound of formula (I) of the present invention or one or more additional therapeutic agents may be administered first. If administered simultaneously, one or more additional therapeutic agents may be included in the same pharmaceutical preparation as the compound of formula (I), or they may be administered in one or more different (separate) pharmaceutical preparations.

The subject or patient being treated in accordance with the present invention may be an animal (eg, a non-human animal). Preferably, the subject/patient is a mammal. More preferably, the subject/patient is a human (such as a man or a female) or a non-human mammal (such as, for example, a guinea pig, hamster, rat, mouse, rabbit, dog, cat, horse, monkey, ape, marmoset , baboon, gorilla, chimpanzee, orangutan, gibbon, sheep, cattle or pig). Most preferably, the subject/patient being treated in accordance with the present invention is a human.

The term treatment of a disorder or disease used in the present invention (eg, treatment of hyperhidrosis) is well known in the art. Treatment of a disorder or disease implies that the disorder or disease is believed to be present or diagnosed in the patient/subject. A patient/subject who is believed to be suffering from a disorder or disease will typically exhibit specific clinical and/or pathological symptoms that can readily be attributed to a particular pathological condition by one skilled in the art (ie, diagnose the disorder or disease).

Treatment of a disorder or disease may, for example, result in stopping the progression of the disorder or disease (eg, stopping the worsening of symptoms) or delaying the progression of the disorder or disease (if the stop of progression is only temporary). Treatment of a disorder or disease may also result in a partial response (eg, relief of symptoms) or a complete response (eg, disappearance of symptoms) in a subject/patient suffering from the disorder or disease. Accordingly, treating a disorder or disease may also mean improving the course of the disorder or disease, which may, for example, result in stopping the progression of the disorder or disease or delaying the progression of the disorder or disease. Such a complete or partial response may be followed by a relapse. It should be understood that a subject/patient may exhibit a wide range of reactions to treatment (eg, typical reactions described above in the present invention). Treatment of a disorder or disease may particularly include curative treatment (preferably leading to a complete response and eventual cure of the disorder or disease) and palliative treatment (including relief of symptoms).

The term prevention of a disorder or disease used in the present invention (eg, prevention of hyperhidrosis) is also well known in the art. Thus, for example, a patient/subject suspected of being susceptible to a disorder or disease may experience a particularly beneficial effect from preventing the disorder or disease. The patient/subject may be susceptible or predisposed to a disorder or disease, including, but not limited to, hereditary predisposition. The presence of such a predisposition can be determined using standard tests using, for example, genetic markers or phenotypic indicators. It should be understood that the disorder or disease to be prevented in accordance with the present invention is not or cannot be diagnosed in the patient/subject (eg, the patient/subject does not exhibit any clinical or pathological symptoms). Thus, the term warning includes the use of a compound of the present invention before any clinical and/or pathological symptoms are diagnosed or established or can be diagnosed or established by the attending physician.

It should be understood that the present invention specifically relates to each and every combination of characteristics described in the present invention, including any combination of general and/or preferred characteristics. In particular, the present invention specifically relates to each combination of values (including common and/or preferred values) for different groups and variables contained in formula (I).

A number of documents are cited herein, including patent applications and scientific literature. The disclosure of these documents, although not considered relevant to the patentability of the present invention, is incorporated herein by reference in its entirety. More precisely, all documents cited are incorporated herein by reference to the same extent as if each individual document had been specifically and individually indicated as being incorporated by reference.

Reference herein to any prior art publication (or information derived therefrom) is not to be construed as an endorsement or admission, or any form of suggestion, that the corresponding prior art publication (or information derived therefrom) is part of the public knowledge in the technical field to which the present invention relates.

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The present invention is particularly characterized by the following embodiments.

(1) A compound of any of the following formulas or a pharmaceutically acceptable salt thereof, or a salt-

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for use in the treatment or prevention of a disease or disorder in which NKCC is involved.

(2) A pharmaceutical composition containing a compound as defined in embodiment (1) and a pharmaceutically acceptable excipient for use in treating or preventing a disease or disorder in which NKCC is involved.

(3) Use of a compound as defined in embodiment (1) for the preparation of a medicament for the treatment or prevention of a disease or disorder in which NKCC is involved.

(4) A method of treating or preventing a disease or disorder in which NKCC is involved, comprising administering to a subject in need thereof a compound as defined in embodiment (1) or a pharmaceutical composition as defined in embodiment (2).

(5) The method according to embodiment (4), in which the subject is a person.

(6) A compound for use according to embodiment (1), or a pharmaceutical composition for use according to embodiment (2), or use according to embodiment (3), or a method according to embodiment (4) or (5), wherein the disease or disorder in which NKCC is involved, is hyperhidrosis.

(7) Non-therapeutic use of the compound according to embodiment (1) to suppress or reduce sweating in a subject.

(8) A non-therapeutic method of suppressing or reducing sweating in a subject, where the method includes administering to the subject a compound as defined in embodiment (1).

(9) A non-therapeutic use according to embodiment (7), or a non-therapeutic method according to embodiment (8), wherein the compound is administered topically.

(10) A non-therapeutic use according to embodiment (7) or (9), or a non-therapeutic method according to embodiment (8) or (9), where the specified compound is provided in the form of an article containing the specified compound, where the article is a napkin, an insole or an article of clothing.

(11) An article containing a compound as defined in embodiment (1), where the article is a napkin, an insole, or a garment.

(12) A compound for use according to embodiment (1), or a pharmaceutical composition for use according to embodiment (2), or a use according to embodiment (3), or a method according to embodiment (4) or (5), wherein the disease or disorder in which participating NKCC, selected from the group including anxiety disorder, autism spectrum disorder, autism, Asperger's syndrome, childhood disintegrative disorder, pervasive developmental disorder as a component of the disorder

- 84 043772 autism spectrum, traumatic brain injury, spinal cord injury, peripheral nerve injury, stroke, Alzheimer's disease, schizophrenia, asthma, edema, Down syndrome, dementia in patients with Down syndrome, glaucoma, primary open-angle glaucoma, closed-angle glaucoma and a parasitic infection, wherein said parasitic infection is preferably selected from the group consisting of helminthiasis, hookworm, nematodiasis, trichuriasis, taeniasis, dracunculiasis, enterobiasis, toxocariasis, Strongyloides stercoralis infection, Ascaris lumbricoides infection, trematodiasis, schistosomiasis, gnathostomiasis, paragonimiasis, fascioliasis , Swimmers syndrome, protozoal infection, malaria, amoebiasis, giardiasis, sleeping sickness, toxoplasmosis, acanthamoeba keratitis, leishmaniasis, babesiosis, granulomatous amoebic encephalitis, cryptosporidiosis, cyclosporiasis, primary amoebic meningoencephalitis, ectoparasitic infection, Sarcoptes sc infection abiei, Pediculus humanus capitis infection, Phthirus pubis infection, dermatobiasis , Tunga penetrans infection and Ixodoidea infection.

(13) Use of the compound as defined in embodiment (1) in vitro as an NKCC inhibitor.

(14) A method of inhibiting NKCC in vitro, comprising using a compound as defined in embodiment (1).

(15) A compound of any of the following formulas or a pharmaceutically acceptable salt or solvate thereof:

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(16) A compound as defined in embodiment (15), for use as a drug.

- 91 043772 (17) A pharmaceutical composition containing a compound as defined in embodiment (15) and a pharmaceutically acceptable excipient.

The present invention has been described with reference to the following examples, which are illustrative only and should not be construed as limiting the scope of the present invention.

Examples

The compounds described in this section are identified by their chemical formulas and their corresponding chemical names. In case of conflict between any chemical formula and the corresponding chemical name specified in the present invention, it should be noted that the present invention relates to both the compound defined by the chemical formula and the compound defined by the chemical name, and preferably relates to the compound defined using a chemical formula.

Example 1. Synthesis of various compounds proposed in the present invention.

General techniques.

All chemicals and solvents were purchased from suppliers (Sigma Aldrich, Merck, Apollo Scientific and TCI Europe) and were analytical grade. Bumetanide was purchased from OChem Inc., Des Plaines, IL, US.

The reactions were monitored by thin layer chromatography using aluminum plates coated with silica gel F ₂₅₄ , available from Merck.

When carrying out column chromatography, silica gel 60, 70-230 mesh, meeting the ASTM standard, manufactured by Merck, was used as a stationary phase.

Melting points were determined using a microscope with a ThermoGalen Kofler heating stage.

1H- and ^13C -NMR spectra were recorded using Bruker Advance (200 and 50 MHz, respectively) and chemical shifts are given in ppm relative to the peak of the remaining solvent and tetramethylsilane used as an internal standard.

Mass spectra were recorded on a Shimadzu spectrometer (GC-17A; MS-QP5050A). Peak intensity is indicated as a percentage of the intensity of the most intense signal contained in the spectrum.

Elemental analysis was carried out at the University of Vienna in the laboratory Mag. Johannes Theiner and all values given correspond to calculated values of +/-0.4%.

Ethyl 3-(butylamino)-4-phenoxy-5-sulfamoyl benzoate (TEPS 1)

To a suspension of 5 mmol (1.82 g) of bumetanide in 3 ml of EtOH under an argon atmosphere, 11 mmol (0.8 ml) SOCl ₂ was added and stirred overnight. Once the conversion was complete (monitored by TLC, toluene/EtOAc, 6+4), the mixture was extracted several times with 5% NaHCO ₃ solution, saturated brine and water. Then, the organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was recrystallized from ethanol to give 1.67 g (85%) TEPS 1.

1H NMR (200 MHz, chloroform-d) δ 8.05-7.92 (m, 1H), 7.66-7.54 (m, 1H), 7.45-7.25 (m, 2H), 7.21-7.05 (m, 1H), 7.00-6.89 (m, 2H), 4.96 (s, 2H), 4.40 (q, J=7.1 Hz, 2H) , 4.03-3.45 (br s, 1H), 3.21-3.01 (m, 2H), 1.41 (t, J=7.1 Hz, 3H), 1.3 1-1 .07 (m, 4H), 0.95-0.76 (m, 3H).

N-benzyl-3-(butylamino)-4-phenoxy-5-sulfamoylbenzamide (TEPS 2)

mmol (1.09 g) bumetanide was dissolved in 20 ml dichloromethane and 3.38 mmol (0.65 g) EDC-HCl (N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride) was added. After 5 minutes, 3.37 mmol (0.52 g) of HOBt (N-hydroxybenzotriazole) was added and the reaction mixture was stirred for a further 5 minutes. 3 mmol (328 μl) of benzylamine was then added and the reaction mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was extracted three times with ethyl acetate and the combined organic layers were washed with brine and dried over Na ₂ SO ₄ . The solvent was then evaporated under reduced pressure and the crude product was purified by column chromatography (toluene/ethyl acetate, 6+4) and by recrystallization from 50% ethanol.

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1H NMR (200 MHz, chloroform-d): δ 7.55-7.45 (m, 2H), 7.40-7.20 (m, 7H), 7.14-7.02 (m, 1H) , 6.96-6.80 (m, 3H), 5.09 (s, 2H), 4.59 (d, J=5.8 Hz, 2H), 3.07 (t, J=6.9 Hz, 2H), 1.49-1.30 (m, 2H), 1.23-1.01 (m, 2H), 0.79 (t, J=7.2 Hz, 3H).

Methyl 3-(butylamino)-5-(dimethylsulfamoyl)-4-phenoxybenzoate (TEPS 3)

mmol (1.09 g) of bumetanide was dissolved in 5 ml of DMF (N,N-dimethylformamide) and 9.9 mmol (1.37 g) of K ₂ CO ₃ and 10 mmol (0.62 ml) of methyl iodide were added. The reaction mixture was stirred for 5 hours and poured into ice water. The resulting precipitate was filtered off and the crude product was purified by column chromatography (toluene/ethyl acetate, 8+2).

1H NMR (200 MHz, chloroform-d): δ 7.95 (d, J=1.9 Hz, 1H), 7.57 (d, J=1.9 Hz, 1H), 7.34-7, 22 (m, 2H), 7.06 (t, J=7.3 Hz, 1H), 6.83 (d, J=7.9 Hz, 2H), 3.94 (s, 3H), 3, 69 (s, 1H), 3.10 (t, J=6.9 Hz, 2H), 2.79 (s, 6H), 1.52-1.35 (m, 2H), 1.26-1 .06 (m, 2H), 0.82 (t, J=7.2 Hz, 3H).

3-(Butylamino)-5-(dimethylsulfamoyl)-4-phenoxybenzoic acid (TEPS 4)

mmol (1.09 g) bumetanide was dissolved in 20 ml dichloromethane, then 3.38 mmol (0.65 g) EDC-HCl was added. After 5 minutes, 3.37 mmol (0.52 g) HOBt was added and the reaction mixture was stirred for 5 minutes. 3.01 mmol (274 μl) of aniline was then added and the reaction mixture was stirred at room temperature overnight. The mixture was then extracted with ethyl acetate and washed with saturated NaHCO ₃ solution and dried over Na ₂ SO ₄ . The solvent was evaporated under reduced pressure and the crude product was recrystallized from EtOH to give 3-(butylamino)-4-phenoxy-N-phenyl5-sulfamoylbenzamide. 0.3 mmol (0.265 g) 3-(butylamino)-4-phenoxy-N-phenyl-5-sulfamoylbenzamide was dissolved in 4 ml methanol and 2 ml THF (tetrahydrofuran). Then 2 ml of 1 M LiOH solution was added and the mixture was stirred at room temperature until the reaction was completed. The reaction mixture was acidified with 2M HCl solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over Na ₂ SO ₄ . The solvent was then evaporated under reduced pressure.

1H NMR (200 MHz, chloroform-d): δ 8.05 (d, J=2.0 Hz, 1H), 7.63 (d, J=2.0 Hz, 1H), 7.37-7, 24 (m, 2H), 7.07 (t, J=7.3 Hz, 1H), 6.91-6.79 (m, 2H), 3.13 (t, J=6.9 Hz, 2H ), 2.81 (s, 6H), 1.53-1.37 (m, 2H), 1.29-1.08 (m, 2H), 0.83 (t, J=7.2 Hz, 3H).

3-(Butylamino)-5-(chloromethyl)-2-phenoxybenzenesulfonamide (TEPS 76)

mmol (0.35 g) 3-(butylamino)-5-(hydroxymethyl)-2-phenoxybenzenesulfonamide (Toellner K et al., Annals of Neurology (2014), 75(4), 550-562) was dissolved in 5 ml thionyl chloride and heated at 80°C for 3 hours. The thionyl chloride was evaporated under reduced pressure and the material was dried in vacuum for 1 hour. The product was purified by recrystallization from 70% MeOH to give 0.34 g of brown crystals (92% yield).

1H NMR (200 MHz, chloroform-d) δ 7.43-7.27 (m, 3H), 7.08 (t, J=7.3 Hz, 1H), 7.02-6.79 (m, 3H), 4.88 (s, 2H) δ 4.57 (s, 2H), 3.07 (t, J=6.9 Hz, 2H), 1.54-1.33 (m, 2H), 1.28-1.08 (m, 2H), 0.83, J=7.1 Hz (t, 3H). MS (mass spectrometry) m/z: 368/370 M+.

3-(Butylamino)-2-phenoxy-5-[(2,2,2-trifluoroethylamino)methyl]benzenesulfonamide (TEPS 5)

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General technique A.

mmol (369 mg) of 3-(butylamino)-5-(chloromethyl)-2-phenoxybenzene-sulfonamide (TEPS 76) was dissolved in 3 ml of dimethylformamide (DMF). 2 mmol (157 μl) of 2,2,2-trifluoroethylamine was added to the mixture, and the mixture was stirred at room temperature overnight. After completion of the reaction, the progress of which was checked by thin layer chromatography, the liquid substances were evaporated under reduced pressure to obtain a white crude product. This crude product was purified by column chromatography (ethyl acetate/petroleum ether, 6+4) and recrystallization from 70% MeOH to give 130 mg of white crystals (30% yield).

^1H NMR (200 MHz, methanol-I4) δ 7.34-7.18 (m, 3H), 7.09-6.96 (m, 2H), 6.94-6.83 (m, 2H) , 3.90 (s, 2H), 3.29-3.17 (m, 2H), 3.09 (t, J=6.8 Hz, 2H), 1.49-1.32 (m, 2H ), 1.26-1.06 (m, 2H), 0.81 (t, J=7.2 Hz, 3H). MS m/z: 431 M+.

3-(Butylamino)-5-(morpholinomethyl)-2-phenoxybenzenesulfonamide (TEPS 6)

TEPS 6 was prepared according to general procedure A, but instead of 2,2,2-trifluoroethylamine, 2 ml of morpholine was added. The crude product was purified by column chromatography (ethyl acetate/petroleum ether, 1 + 1) and recrystallization from EtOH to give 130 mg of beige crystals (31% yield).

1H NMR (200 MHz, chloroform-d) δ 7.38-7.23 (m, 3H), 7.20-6.80 (m, 4H), δ 5.10 (s, 2H), 3.98 -3.66 (m, 5H), 3.54 (s, 2H), 3.16-2.98 (m, 2H), 2.77-2.36 (m, 4H), 1.52-1 .30 (m, 2H), 1.27-1.08 (m, 2H), 0.82 (t, J=7.1 Hz, 3H). MC m/z: 419 M+.

3-(Butylamino)-5-(1H-imidazol-2-ylsulfanylmethyl)-2-phenoxybenzenesulfonamide (TEPS 7)

TEPS 7 was prepared according to General Procedure A, but instead of 2,2,2-trifluoroethylamine, 1 mmol (100 mg) of 2-mercaptoimidazole was added and the reaction mixture was stirred for 2 days. The crude product was purified by column chromatography (ethyl acetate/petroleum ether/triethylamine, 6+3+1) and recrystallization from 70% EtOH to give 0.22 g of white crystals (51% yield).

1H NMR (200 MHz, chloroform-d) δ 7.36-7.21 (m, 2H), 7.14 (s, 2H), 7.10-6.96 (m, 2H), 6.94- 6.80 (m, 2H), 6.63 (d, J=2.0 Hz, 1H), 4.17 (s, 2H), 2.95 (t, J=6.8 Hz, 2H), 1.42-1.26 (m, 2H), 1.22-1.02 (m, 2H), 0.80 (t, J=7.2 Hz, 3H). MC m/z: 432 M+.

3-(Butylamino)-2-phenoxy-5-(pyrimidin-2-ylsulfanylmethyl)benzenesulfonamide (TEPS 8)

TEPS 8 was prepared according to general procedure A, but instead of 2,2,2-trifluoroethylamine, 1 mmol (112 mg) of 2-mercaptopyrimidine was added. The crude product was purified by column chromatography (ethyl acetate/petroleum ether, 7+3) and recrystallization from 70% MeOH to give 210 mg of white crystals (47% yield).

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1H NMR (200 MHz, chloroform-d) δ 8.55 (d, J=4.8 Hz, 2H), 7.38 (d, J=1.8 Hz, 1H), 7.35-7.23 (m, 2H),

7.18-6.83 (m, 5H), 4.90 (s, 2H), 4.41 (s, 2H), 3.80 (t, J=5.3 Hz, 1H), 3.17 -2.91 (m, 2H), 1.49-1.31 (m, 2H), 1.261.05 (m, 2H), 0.81 (t, J=7.1 Hz, 3H). MC m/z: 444 M ⁺ .

3-(Butylamino)-5-[(1-methylimidazol-2-yl)sulfanylmethyl]-2-phenoxybenzenesulfonamide (TEPS

9)

TEPS 9 was prepared according to general procedure A, but instead of 2,2,2-trifluoroethylamine, 1 mmol (114 mg) of 2-mercapto-1-methylimidazole was added. The crude product was purified by column chromatography (ethyl acetate/petroleum ether/triethylamine, 6+3+1) and recrystallization from 70% MeOH to give 180 mg of white crystals (40% yield).

1H NMR (200 MHz, chloroform-d) δ 7.33-7.08 (m, 5H), 7.07-6.91(m, 3H), 6.81 (d, J=7.7 Hz, 2H), 6.65 (d, J=1.7 Hz, 1H), 4.75,(t, J=5.7 Hz, 1H), 4.17 (s, 2H), 3.43 (s , 3H), 2.98-2.81 (m, 2H), 2.98-2.81 (m, 2H), 1.17-0.99 (m, 2H), 0.77 (t, J =7.1 Hz, 3H). MC m/z: 446 M+.

-(Butylamino)-5-(1-hydroxy-1-methylethyl)-2-phenoxybenzenesulfonamide (TEPS 10)

To a solution of 4 mmol methyl 3-(butylamino)-4-phenoxy-5-sulfamoyl benzoate (WO 2013/087090) in 10 ml dry THF, 15 ml methylmagnesium bromide solution (1.4 M in THF) was added and the mixture was stirred at room temperature. At intervals of 30 minutes, another 3 ml of methylmagnesium bromide solution (1.4 M in THF) was added 5 times. After stirring for only 3 hours, the reaction was quenched with 5% aqueous NH ₄ Cl, which resulted in the precipitation of a white solid. The mixture was then extracted with ethyl acetate and washed twice with water and once with brine. The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (EtOAc/petroleum ether, 1 + 1) and recrystallization from 70% EtOH to give 1.06 g of a brown solid (70% yield).

^1H NMR (200 MHz, chloroform-d) δ 7.40-7.21 (m, 3H), CH (aromatic), 7.17-6.99 (m, 2H), 6.996.83 (m, 2H ), 5.07 (s, 2H), 3.78 (t, J=5.1 Hz, 1H), 3.16-2.97 (m, 2H), 2.33 (s, 1H), 1 .57(s, 6H), 1.49-1.32 (m, 2H), 1.29-1.10 (m, 2H), 0.81 (t, J=7.1 Hz, 3H). MS m/z: 378 M+.

3-(Butylamino)-5-isopropynyl-2-phenoxybenzenesulfonamide (TEPS 11)

0.5 mmol TEPS 10 was dissolved in 5 ml thionyl chloride and the mixture was stirred for 1 day. After completion of the reaction, thionyl chloride was evaporated under reduced pressure. The resulting crude product was purified by column chromatography (ethyl acetate/petroleum ether, 1+1) and recrystallization from 70% EtOH to give 120 mg of a beige solid (67% yield).

1H NMR (200 MHz, chloroform-d) δ 7.44-7.27 (m, 3H), 7.12-6.90 (m, 4H), 5.39 (s, 1H), 5.23- 5.10 (m, 1H), 4.89 (s, 2H), 3.78 (t, J=5.3 Hz, 1H), 3.16-3.00 (m, 2H), 2.17 (s, 3H), 1.51-1.35 (m, 2H), 1.24-1.11 (m, 2H), 0.83 (t, J=7.2 Hz, 3H). MS m/z: 360 M+.

3-(Butylamino)-5-[(4-hydroxy-4-phenyl-1-piperidyl)methyl]-2-phenoxybenzenesulfonamide (TEPS 12)

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TEPS 12 was prepared according to General Procedure A, but instead of 2,2,2-trifluoroethylamine, 1.2 mmol (213 mg) of 4-hydroxy-4-phenylpiperidine was added and the mixture was stirred at room temperature for 2 days. The crude product was purified by column chromatography (EtOAc/petroleum ether, 1+1) and recrystallization from 70% MeOH to give 210 mg of white crystals (41% yield).

^1H NMR (200 MHz, chloroform-d) δ 7.64-7.46 (m, 2H), 7.41-7.25 (m, 6H), 7.16-6.85 (m, 4H) , 4.95 (s, 2H), 5.21-4.72 (m, 1H), 3.57 (s, 2H), 5=3.20-2.99 (m, 2H), 2.97 -2.72 (m, 2H), 2.53 (t, J=10.8 Hz, 2H), 2.32-2.02 (m, 2H), 1.88-1.61 (m, 3H ), 1.51-1.32 (m, 2H), 1.28-1.12 (m, 2H), 0.83 (t, J= 7.1 Hz, 3H). MS m/z: 510 M+.

3-(Butylamino)-5-[(cyanomethylamino)methyl]-2-phenoxybenzenesulfonamide (TEPS 13)

TEPS 13 was prepared according to general procedure A, but instead of 2,2,2-trifluoroethylamine, 1.2 mmol (167 μl) triethylamine and 1.2 mmol (71 μl) aminoacetonitrile were added. The crude product was purified by column chromatography (EtOAc/petroleum ether, 1 + 1) and recrystallization from 70% EtOH to give 180 mg of a beige powder (46% yield).

^1H NMR (200 MHz, chloroform-d) δ 7.40-7.22 (m, 3H), 7.16-6.85 (m, 4H), 5.02 (s, 2H), 3.91 (s, 2H), 3.88-3.78 (m, 1H), 3.60 (s, 2H), 3.20-3.00 (m, 2H), 2.99-2.83 (d , 1H), 1.49-1.34 (m, 2H), 1.26-1.12 (m, 2H), 0.90-0.74 (m, 3H). MS m/z: 388 M+.

3-(Butylamino)-2-phenoxy-5-[(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)methyl]benzenesulfonamide (TEPS 14)

TEPS 14 was prepared according to general procedure A, but instead of 2,2,2-trifluoroethylamine, 1.2 eq was added. 4-phenyl-1,2,3,6-tetrahydropyridine. The resulting crude product was purified by column chromatography (ethyl acetate/petroleum ether, 3+7) to give 110 mg of TEPS 14 (29.3% yield).

1H NMR (200 MHz, chloroform-d) δ 7.54-7.21 (m, 9H), 7.07 (t, J=7.5 Hz, 1H), 7.00-6.83 (m, 2H),5 6.07 (s, 1H), 5.06 (s, 2H), 4.00-3.72 (m, 3H), 3.50-3.28 (m, 2H), 3, 17-3.03 (m, 2H), 3.00-2.80 (m, 2H), 2.80-2.56 (m, 2H), 1.54-1.32 (m, 2H), 1.28-1.06 (m, 2H), 0.81 (t, J=7.1 Hz, 3H). MS m/z: 491 M+.

N'-[3-(butylamino)-2-phenoxy-5-[(2-thienylmethylamino)methyl]phenyl]sulfonyl-N,Ndimethylformamidine hydrochloride (TEPS 15)

3-(Butylamino)-2-phenoxy-5-[(2-thienylmethylamino)methyl]benzenesulfonamide was prepared according to general procedure A, but instead of aniline, 1 mmol (104 μl) of 2-thiophenemethylamine was added. The crude product was purified by column chromatography (ethyl acetate/petroleum ether, 1+1) and recrystallization from 70% EtOH to give 0.23 g of beige crystals (52% yield). 0.22 mmol (0.100 g) 3-(butylamino)-2-phenoxy-5-[(2-thienylmethylamino)methyl]benzenesulfonamide was dissolved in 5 ml of dry THF and 0.48 mmol (0.068 ml) DMF-DMA (N) was added ,N-dimethylacetamide). The reaction mixture was stirred overnight and purified by column chromatography (ethyl acetate). The resulting brown solid was then dissolved in dry THF and 3 ml of a 1M solution was added

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HCl in diethyl ether. The precipitated salt with HCl was filtered off and beige crystals were obtained (yield 37.5%).

1H NMR (200 MHz, chloroform-d) δ 10.36 (s, 1H), 7.91 (s, 1H), 7.49 (d, J=l 1.9 Hz, 3H), 7.37- 7.20 (m, 3H), 7.11-6.70 (m, 4H), 4.30 (s, 2H), 4.10 (s, 2H), 3.74 (t, J=6, 6 Hz, 1H), 3.13 (s, 2H), 2.70 (d, J=43.2 Hz, 6H), 2.00-1.70 (m, 1H), 1.47-1, 25 (m, 2H), 1.23-1.00 (m, 2H), 0.76 (t, J=6.9 Hz, 3H).

Methyl 3-(butylamino)-5-[2-(dimethylamino)ethylsulfamoyl]-4-phenoxybenzoate (TEPS 16)

0.19 mmol (0.087 g) Methyl 3-(butylamino)-4-phenoxy-5-sulfamoyl benzoate (WO 2013/087090) was dissolved in 5 ml DMF and 1.3 mmol (0.188 g) 2-dimethylaminoethyl chloride HCl was added and 2.2 mmol (0.304 g) K ₂ CO ₃ . The reaction mixture was stirred at 40°C for 2 days and the resulting crude product was purified by column chromatography (ethyl acetate/petroleum ether/triethylamine, 3+6.5+0.5) to give a white powder (yield 39.6%) .

1H NMR (200 MHz, chloroform-d) δ 7.95 (d, J=1.8 Hz, 1H), 7.67-7.53 (m, 1H), 7.29 (t, J=7, 7 Hz, 2H), 7.06 (t, J=7.3 Hz, 1H), 6.88 (d, J=7.8 Hz, 2H), 3.93 (s, 3H), 3.88 (s, 1H), 3.26-3.07 (m, 2H), 3.05-2.90 (m, 2H), 2.44-2.29 (m, 2H), 2.16 (s , 6H), 1.51-1.35 (m, 2H), 1.21-1.05 (m, 2H), 0.81 (t, J=7.1 Hz, 3H). MS m/z: 449 M ⁺ .

Methyl 3-(butylamino)-5-[2-(dimethylamino)ethylsulfamoyl]-4-phenoxybenzoate (TEPS 17)

TEPS 16 was dissolved in dry THF and 3 ml of a 1 M solution of HCl in diethyl ether was added. The precipitated salt with HCl was filtered and a white powdery substance was obtained (yield 92.5%).

1H NMR (200 MHz, chloroform-d) δ 11.28 (s, 1H), 7.88 (s, 1H), 7.56 (s, 1H), 7.33-7.19 (m, 3H) , 7.02 (t, J=8.1 Hz, 2H), 3.93 (s, 3H), 3.31 (d, J=22.4 Hz, 4H), 3.09 (t, J= 6.8 Hz, 2H), 2.83 (s, 6H), 1.52-1.32 (m, 2H), 1.28-1.07 (m, 2H), 0.81 (t, J =7.1 Hz, 3H).

5-(Anilinomethyl)-3-(butylamino)-N-[2-(dimethylamino)ethyl]-2-phenoxybenzenesulfonamide (TEPS 18)

0.5 mmol (0.213 g) 5-(anilinomethyl)-3-(butylamino)-2-phenoxybenzenesulfonamide (Lykke K et al., British Journal of Pharmacology (2015), 172(18), 4469-4480) was dissolved in 5 ml of DMF and 2 mmol (0.288 g) 2-dimethylaminoethyl chloride HCl and 2 mmol (0.278 g) K ₂ CO ₃ were added. The reaction mixture was stirred at 40°C overnight and the resulting crude product was purified by column chromatography (ethyl acetate/petroleum ether/triethylamine, 3+6.5+0.5) to give a brown solid (38.3% yield).

^1H NMR (200 MHz, chloroform-d) δ 7.42-7.09 (m, 6H), 7.08-6.84 (m, 4H), 6.83-6.58 (m, 3H) , 5.33 (s, 1H), 4.33 (s, 2H), 3.83 (t, J=5.3 Hz, 1H), 3.13-3.00 (m, 2H), 2, 99-2.87 (m, 2H), 2.38-2.27 (m, 2H), 2.17 (s, 6H), 1.41-1.27 (m, 2H), 1.19- 1.03 (m, 2H), 0.79 (t, J=7.1 Hz, 3H). MS m/z: 496 M ⁺ .

3-(Butylamino)-5-(ethoxymethyl)-2-phenoxybenzenesulfonamide (TEPS 19)

0.27 mmol (100 mg) TEPS 76 was dissolved in acetonitrile and 0.44 mmol (34 μl) sodium ethoxide was added. The reaction mixture was stirred at room temperature overnight and then added

- 97 043772 another 0.15 mmol (12 µl) sodium ethoxide. After completion of the reaction, 5% aqueous NaHCO ₃ solution was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The resulting crude product was purified by recrystallization from EtOH to give 38 mg of a brown solid (22.7% yield).

1H NMR (200 MHz, chloroform-d) δ 7.39-7.23 (m, 3H), 7.20-6.80 (m, 4H), 4.92 (s, 2H), 4.49 ( s, 2H), 3.59 (q, J=7.0 Hz, 2H), 3.05 (t, J=7.0 Hz, 2H), 1.52-1.33 (m, 2H), 1.27 (t, J=7.0 Hz, 3H), 1.23-1.05 (m, 2H), 0.81 (t, J=6.8 Hz, 3H). MS m/z: 378 M+.

3-(Butylamino)-2-phenoxy-5-(phenoxymethyl)benzenesulfonamide (TEPS 20)

0.64 mmol (60 mg) Phenol was dissolved in 5 ml DMF and 0.54 mmol (200 mg) TEPS 76 was added in three portions over 15 min. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, 5% aqueous NaHCO ₃ solution was added and the mixture was extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (ethyl acetate/petroleum ether, 3+7) to give 43 mg of TEPS 20 (15.6% yield).

1H NMR (200 MHz, chloroform-d) δ 7.62-7.20 (m, 6H), 7.19-6.83 (m, 6H), 5.04 (s, 2H), 4.94 ( s, 2H), 3.04 (t, J=6.8 Hz, 2H), 1.53-1.30 (m, 2H), 1.29-1.01 (m, 2H), 0.81 (t, J=6.0 Hz, 3H). MS m/z: 426 M+.

3-(Butylamino)-2-phenoxy-5-(4-phenyl-3,6-dihydro-2H-pyridine-1-carbonyl)benzenesulfonamide (TEPS 21)

mmol (364 mg) bumetanide and 1.1 mmol (179 mg) CDI were added to dry THF. After a clear solution formed, 1.3 mmol (200 mg) of 4-phenyl-1,2,3,6-tetrahydropyridine was added and the reaction mixture was stirred at room temperature overnight. After completion of the reaction, 5% aqueous NaHCO ₃ solution was added and the mixture was extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The resulting crude product was recrystallized from EtOH to give 294 mg of a white powder (58% yield).

^1H NMR (200 MHz, chloroform-d) δ 7.59-7.21 (m, 8H), 7.20-6.79 (m, 4H), 6.39-5.78 (m, 1H) , 5.16 (s, 2H), 4.47-4.07 (m, 2H), 4.02-3.61 (m, 2H), 3.05 (t, J=6.8 Hz, 2H ), 2.63 (s-br, 2H), 1.52-1.29 (m, 2H), 1.29-1.03 (m, 2H), 0.80 (t, J=7.1 Hz, 3H). MS m/z: 505 M+.

-(Butylamino)-5 - [2-[2-[2-(2-methoxyethoxy)ethoxy] ethoxy] ethoxymethyl]-2 phenoxybenzenesulfonamide (TEPS 22)

0.27 mmol (100 mg) TEPS 76 was dissolved in 3 ml of dry THF, then 22 mg of NaH and 63 μl of tetraethylene glycol were added. After completion of the reaction, 5% aqueous NaHCO ₃ solution was added and the mixture was extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (ethyl acetate/petroleum ether, 3+7) to give 40 mg of TEPS 22 (27% yield).

1H NMR (200 MHz, chloroform-d) δ 7.28-7.14 (m, 3H), 7.06-6.73 (m, 4H), 5.19 (s, 2H), 4.46 ( s, 2H), 3.86-3.39 (m, 14H), 3.27 (m, 2H), 2.97 (t, J=6.8 Hz, 2H), 1.54-0.97 (m, 7H), 0.74(t, J=7.2 Hz, 3H). MS m/z: 540 M+.

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3-(Butylamino)-4-phenoxy-5-sulfamoyl-N-(2,2,2-trifluoroethyl)benzamide (TEPS 23)

To a solution of 1 mmol (364 mg) of bumetanide in 5 ml of dry THF, 1.2 mmol (194 mg) of 1,1carbonyldiimidazole (CDI) was added and the mixture was stirred for 2 hours. After TLC showed that the mixture no longer contained bumetanide , 2 mmol (157 μl) of trifluoroethylamine was added and the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was poured into 20 ml of 5% NaHCO ₃ solution and extracted with ethyl acetate. The organic phase was then dried over Na ₂ SO ₄ and the solvent was removed under reduced pressure. The crude product was then purified by recrystallization from EtOH to give 159 mg of a white powder (36% yield).

1H NMR (200 MHz, methanol-I4) δ 7.73 (d, J=2.1 Hz, 1H), 7.44 (d, J=2.1 Hz, 1H), 7.38-7.20 (m, 2H), 7.146.98 (m, 1H), 6.98-6.86 (m, 2H), 4.10 (q, J=9.3 Hz, 2H), 3.13 (t, J=6.8 Hz, 2H), 1.56-1.34 (m, 2H), 1.30-1.03 (m, 3H), 0.82 (t, J=7.2 Hz, 3H ). MS m/z: 445 M ⁺ .

4-Morpholino-3-nitro-5-sulfamoylbenzoic acid (TEPS 24)

mmol (280 mg) 4-chloro-3-nitro-5-sulfamoylbenzoic acid was dissolved in 2 ml of morpholine and stirred at reflux overnight. After completion of the reaction, the crude product was purified by recrystallization from water to obtain 222 mg of yellow crystals (67% yield).

1H NMR (200 MHz, DMSO-d6 (DMSO-dimethyl sulfoxide)) δ 14.02 (s, 1H), 8.86-8.71 (m, 1H), 8.618.43 (m, 1H), 7.69 (s, 2H), 4.18-3.57 (m, 4H), 3.28-3.07 (m, 4H).

Methyl 3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitro-4-(prop-2-ynylamino)benzoate (TEPS 25)

CH ₃ o o I

III ⁴⁴ n ₃ s A ch ₃

X NOj L mmol (350 mg) TEPS 28 was dissolved in 5 ml of acetonitrile and 2 mmol (276 mg) K ₂ CO ₃ and 1.1 mmol (70 μl) propargylamine were added. The mixture was stirred overnight and after TLC indicated that the mixture no longer contained TEPS 28, it was extracted with ethyl acetate and washed with brine. The combined organic layers were evaporated under reduced pressure and the resulting brown solid was recrystallized from 70% ethanol to give 108 mg of brown crystals (30% yield).

1H NMR (200 MHz, DMSO-d6) δ 8.53-8.39 (m, 2H), 8.31 (s, 1H), 7.29 (t, J=5.6 Hz, 1H), 4 ,31-4.07 (m, 2H), 3.85 (s, 3H), 3.32 (s, 1H), 3.26 (t, J=2.3 Hz, 1H), 3.15 ( s, 1H), 2.94 (s, 1H).

Methyl 3-(dibutylamino)-4-phenoxy-5-sulfamoyl benzoate (TEPS 26) (WO 2013/087090)

mmol (228 μl) Butyraldehyde was added to a solution of 1 mmol methyl 3-(butylamino)-4phenoxy-5-sulfamoyl benzoate (WO 2013/087090) in 10 ml 1,2-dichloroethane. 1.5 mmol (87 μl) of acetic acid was added to this solution. The reaction mixture was cooled to 0°C and 3 mmol (0.64 g) of sodium triacetoxyborohydride (NaBH(OAc) ₃ ) was added over 2 hours and the mixture was stirred overnight.

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After completion of the reaction, 10 ml of water was added and the mixture was stirred for 1 hour. The reaction mixture was extracted with 20 ml of dichloromethane and washed with brine. The organic phase was then dried over Na ₂ SO ₄ and evaporated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate/petroleum ether, 7+3) and recrystallized from EtOH to give 223 mg of white crystals (51% yield).

^1H NMR (200 MHz, chloroform-d) δ 8.23 (d, J=1.2 Hz, 1H), 7.87 (s, 1H), 7.37-7.15 (m, 2H), 7.14-6.97 (m, 1H), 6.93-6.73 (m, 2H), 4.99 (s, 2H), 4.12-3.79 (m, 3H), 3. 02 (t, J=7.2 Hz, 4H), 1.35-1.09 (m, 4H), 1.10-0.92 (m, 4H), 0.77 (t, J=6, 8 Hz, 6H). MC m/z: 434 M ⁺ .

3-(Dibutylamino)-5-(hydroxymethyl)-2-phenoxybenzenesulfonamide (TEPS 27) (WO 2013/087090)

mmol TEPS 26 was dissolved in 5 ml of anhydrous THF and stirred under argon at room temperature. Then 2 ml of a 1 M solution of DIBAL-N (diisobutylaluminum hydride) in toluene was added. After 1, 2, 3 and 4 hours, respectively, another 1 ml of 1 M solution of DIBAL-N in toluene was added and the reaction mixture was stirred overnight. Once the mixture no longer contained TEPS 26 by TLC, the mixture was cooled to 0°C and the reaction was stopped with a 5% aqueous NHCl ₄ solution, which resulted in the precipitation of a gel-like substance. Then the precipitate was dissolved in 2 N. HCl solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water, once with brine and dried over Na ₂ SO ₄ . The liquid substances were evaporated under reduced pressure and the residue was purified by recrystallization from ethanol to give 360 mg of a beige powder (89% yield).

1H NMR (200 MHz, methanol-d4) δ 7.63 (brs, 1H), 7.40 (brs, 1H), 7.32-7.14 (m, 2H), 7.00 (t, J= 7.3 Hz, 1H), 6.82 (d, J=7.5 Hz, 2H), 4.66 (s, 2H), 3.13 (t, J=7.4 Hz, 4H), 1 .43-0.92 (m, 8H), 0.78 (t, J=7.0 Hz, 6H). MS m/z: 406 M+.

3-(Butylamino)-5-[(N-butylanilino)methyl]-2-phenoxybenzenesulfonamide (TEPS 28)

CH ₃ mmol (180 μl) Butyraldehyde was added to a solution of 1 mmol 5-(anilinomethyl)-3(butylamino)-2-phenoxybenzenesulfonamide (Lykke K et al., British Journal of Pharmacology (2015), 172(18), 4469- 4480) in 10 ml of 1,2-dichloroethane. To this solution were added 2 mmol (116 μl) of acetic acid and 3 mmol (0.64 g) of sodium triacetoxyborohydride (NaBH(OAc) ₃ ) and the mixture was stirred overnight. The mixture was then diluted with 10 ml water and 20 ml dichloromethane. The organic phase was dried over Na ₂ SO ₄ and then evaporated under reduced pressure. The resulting crude product was purified by column chromatography (ethyl acetate/petroleum ether, 7+3) to give 312 mg of a white powder (58% yield).

1H NMR (200 MHz, chloroform-d) δ 7.89 (s, 1H), 7.45-7.15 (m, 5H), 7.00 (t, J=7.3 Hz, 1H), 6 ,89-6.59 (m, 6H), 4.52 (s, 2H), 3.41 (t, J=7.6 Hz, 2H), 2.88 (t, J=7.0 Hz, 2H), 2.75 (s, 3H), 2.58 (s, 3H), 1.64 (s, 1H), 1.491.17 (m, 6H), 1.18-0.87 (m, 4H ), 0.73 (t, J=7.2 Hz, 3H). MS m/z: 536 M+.

3-(Dibutylamino)-4-phenoxy-5-sulfamoylbenzoic acid (TEPS 29) (WO 2013/087090)

- 100 043772

mmol (434 mg) TEPS 26 was dissolved in 3 ml MeOH and 2 ml 2 N was added. NaOH solution. The reaction mixture was stirred at room temperature for 2 hours. After TLC showed that the mixture no longer contained TEPS 26, the solution was acidified with 2 N. HCl solution and the resulting precipitate was filtered and dried in vacuum to obtain 380 mg of a white powdery substance (90% yield).

1H NMR (200 MHz, methanol-d ₄ ) δ 8.22 (d, J=2.0 Hz, 1H), 7.91 (d, J=2.1 Hz, 1H), 7.37-7, 15 (m, 2H), 7.02 (t, J=7.3 Hz, 1H), 6.83 (d, J=7.5 Hz, 2H), 3.10 (t, J=7.2 Hz, 4H), 1.38-1.15 (m, 4H), 1.13-0.93 (m, 4H), 0.78 (t, J=7.1 Hz, 6H).

Methyl 7-[(E)-dimethylaminomethyleneamino]sulfonyl-2-methyl-1-prop-2-ynylbenzimidazole-5carboxylate (TEPS 30)

CH ₃ o o I Ih c IL V ^N ^ ^N -ch ^N ~4 ^CH

CH ₃ mmol TEPS 25 (368 mg) was added to 15 ml ethanol and 3 ml dioxane, this mixture was heated to 85°C and stirred until completely dissolved. Then 10 mmol ammonium chloride (535 mg) in 6 ml water was added. 4 mmol of powdered iron (223 mg) was added in three portions at 2 min intervals. The reaction mixture was stirred at 85°C for an additional 2.5 hours until the mixture no longer contained TEPS 25 by TLC. The mixture was cooled to 60°C and then extracted three times with 25 ml of dichloromethane. The combined organic layers were washed with water and dried over Na ₂ SO ₄ . The crude product was purified by flash chromatography (ethyl acetate) and recrystallization from methanol to give 90 mg of white crystals (25% yield).

1H NMR (200 MHz, chloroform-d) δ 8.56 (s, 1H), 8.48 (s, 1H), 8.16 (s, 1H), 5.80 (d, J=2.5 Hz , 2H), 3.95 (s, 3H), 3.15 (s, 3H), 3.12 (s, 3H), 2.85 (s, 3H), 2.38 (t, J=5, 0, 2.5 Hz, 2H). MS m/z: 362 M ⁺ .

Methyl 4-(butylamino)-3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitrobenzoate (TEPS 31) sn ₃ o o I |n ₃ s A sn ₃

[T'°

NOj L ^CH ₃

To a suspension of 3 mmol (842 mg) of 4-chloro-3-nitro-5-sulfamoylbenzoic acid in 3 ml of H ₂ O, 10.8 mmol (907 mg) of NaHCO ₃ was carefully added, then 6 mmol (595 μl) of butylamine. The resulting solution was stirred at 85°C for 16 hours. After completion of the reaction, 10 ml of H ₂ O was added and then the mixture was acidified by adding 2 N. HCl solution. The mixture was then cooled and the precipitate was filtered to obtain 825 mg of white crystals (86.6% yield).

^1H NMR (200 MHz, chloroform-d) δ 8.56 (d, J=2.2 Hz, 1H), 8.43 (d, J=2.2 Hz, 1H), 8.10 (s, 1H), 7.03 (s, 1H), 3.89 (s, 3H), 3.18 (s, 3H), 3.05 (s, 3H), 3.02-2.90 (m, 2H ), 1.77-1.57 (m, 2H), 1.55-1.35 (m, 2H), 0.93 (t, J=7.1 Hz, 3H). ¹³ C NMR (50 MHz, CDCl ₃ ) δ 164.7, 159.1, 143.7, 136.8, 133.1, 132.2, 129.5, 116.1, 52.3, 46.6 , 41.8, 35.8, 32.1, 19.9, 13.7. MC m/z: 387 M ⁺ .

Methyl 3-[(E)-dimethylaminomethyleneamino]sulfonyl-4-(1-methylimidazol-2-yl)sulfanyl-5nitrobenzoate (TEPS 32)

- 101 043772

To 10 ml of acetonitrile was added mmol (1.05 g) methyl-4-chloro-3-[(E)-

dimethylaminomethyleneamino]sulfonyl-5-nitrobenzoate (WO 2012/018635), 3.3 mmol (376 mg) 2-mercapto-1-methylimidazole and 6.6 mmol (910 mg) K ₂ CO ₃ . The solution was stirred at room temperature overnight. Once the mixture no longer contained methyl 4-chloro-3-[(E)dimethylaminomethyleneamino]sulfonyl-5-nitrobenzoate by TLC, the reaction mixture was diluted with 10 ml of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and evaporated under reduced pressure. The crude product was then purified by recrystallization from ethanol to give 1.04 g of yellow crystals (81% yield).

1H NMR (200 MHz, DMSO-d ₆ ) δ 8.66 (d, J=1.9 Hz, 1H), 8.34 (d, J=1.8 Hz, 2H), 7.28 (s, 1H), 6.87 (s, 1H), 3.91 (s, 3H), 3.51 (s, 3H), 3.10 (s, 3H), 2.92 (s, 3H). MS m/z: not found.

Methyl 3-amino-5-[(E)-dimethylaminomethyleneamino]sulfonyl-4-(1-methylimidazol-2yl)sulfanyl benzoate (TEPS 33)

mmol TEPS 32 (428 mg) was added to 15 ml ethanol and 3 ml dioxane, this mixture was heated to 85°C and stirred until completely dissolved. Then 10 mmol ammonium chloride (535 mg) in 6 ml water was added. 4 mmol of powdered iron (223 mg) was added in three portions at 2 min intervals. The reaction mixture was stirred at 85°C for an additional 2.5 hours until the mixture no longer contained TEPS 32 by TLC. The mixture was cooled to 60°C and then extracted three times with 25 ml of dichloromethane. The combined organic layers were washed with water and dried over Na ₂ SO ₄ . The crude product was purified by flash chromatography (ethyl acetate) to give 290 mg of a yellow solid (73% yield).

1H NMR (200 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.79 (d, J=1.9 Hz, 1H), 7.50 (d, J=2.0 Hz, 1H ), 7.27 (d, J=1.3 Hz, 1H), 6.93 (d, J=1.3 Hz, 1H), 6.07 (s, 2H), 3.85 (s, 3H ), 3.54 (s, 3H), 3.10 (s, 3H), 2.85 (s, 3H). MS m/z: cannot be determined using IED-MS (IED - electron impact ionization).

Methyl 3-(butylamino)-5-[(E)-dimethylaminomethyleneamino]sulfonyl-4-(1-methylimidazol-2yl)sulfanyl benzoate (TEPS 34)

mmol (228 μl) Butyl iodide was added to a solution of 1 mmol TEPS 33 in 10 ml 1,2-dichloroethane. 1.5 mmol (87 μl) of acetic acid was added to this solution. 3 mmol (0.64 g) of sodium triacetoxyborohydride (NaBH(OAc) ₃ ) was then added over 2 hours and the mixture was stirred overnight. After completion of the reaction, the mixture was poured into 30 ml of water. The reaction mixture was extracted twice with 20 ml of dichloromethane and the combined organic layers were washed with brine. The organic phase was then dried over Na ₂ SO ₄ and evaporated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate) to give 234 mg of a yellow powder (52% yield).

^1H NMR (200 MHz, chloroform-d) δ 8.16 (s, 1H), 8.09 (d, J=1.8 Hz, 1H), 7.36 (d, J=1.8 Hz, 1H), 7.10 (d, J=1.4 Hz, 1H), 6.96 (d, J=1.4 Hz, 1H), 5.79 (s, 1H), 3.91 (s, 3H), 3.59 (s, 3H), 3.10 (d, J=17.3 Hz, 8H), 1.62-1.44 (m, 2H), 1.43-1.15 (m , 2H), 0.92 (t, J=7.2 Hz, 3H). MS m/z: 453 M ⁺ .

3-(Butylamino)-4-(1-methylimidazol-2-yl)sulfanyl-5-sulfamoyl-benzoic acid (TEPS 35)

- 102 043772

mmol (454 mg) TEPS 34 was dissolved in 3 ml MeOH and 2 ml 2 N was added. NaOH solution. The reaction mixture was stirred at room temperature for 2 hours. After TLC showed that the mixture no longer contained TEPS 34, the solution was acidified with 2 N. HCl solution and the resulting precipitate was filtered off and recrystallized from EtOH to obtain 346 mg of yellow crystals (90% yield).

^1H NMR (200 MHz, methanol-I4) δ 8.78 (s, 1H), 8.03 (dd, J=4.7, 1.7 Hz, 1H), 7.56 (s, 1H), 7.37 (s, 1H), 7.18 (s, 1H), 3.69 (s, 3H), 3.28-3.10 (m, 2H), 1.68-1.43 (m, 2H), 1.41-1.18 (m, 2H), 0.92 (t, J=6.9 Hz, 3H). MS: cannot be determined using the IED.

Methyl 4-(4,5-dihydrothiazol-2-ylsulfanyl)-3-[(E)-dimethylaminomethyleneamino]sulfonyl-5nitrobenzoate (TEPS 36)

In a three-neck flask, 1 mmol of methyl 4-chloro-3-[(E)-dimethylaminomethyleneamino]sulfonyl-5nitrobenzoate (350 mg) was dissolved in acetonitrile (10 ml). Then 1.2 mmol of 2mercaptothiazoline (MW = 119.21 g/mol; 143 mg) and 2 mmol of K ₂ CO ₃ (MW = 138 g/mol; 276 mg) were added to the flask. The reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture and it was extracted with ethyl acetate three times and washed with brine. The organic layers were dried over Na ₂ SO ₄ and the solvent was removed under reduced pressure. The crude product was then purified by column chromatography (ethyl acetate/petroleum ether, 7+3). 283 mg of a yellow crystalline solid was obtained (78.0% yield).

Methyl 3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitro-4-(3-thienyl)benzoate (TEPS 39)

mmol of methyl 4-chloro-3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitrobenzoate (320 mg) was dissolved in 3 ml of dioxane. 1.3 mmol (167 mg) of 3-thienylboronic acid, 3 mmol (414 mg) of potassium carbonate and 100 mg of tetrakis(triphenylphosphine)palladium(0) were then added. The reaction vessel was purged with argon, the mixture was heated to 90°C and stirred overnight. The mixture was then cooled to room temperature and diluted with ethyl acetate and washed with water and brine. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (ethyl acetate/petroleum ether, 7+3) to give 278 mg of a brown solid (70% yield).

Ή NMR (200 MHz, chloroform-d) δ 9.13 (d, J=1.8 Hz, 1H), 8.46 (d, J=1.8 Hz, 1H), 7.60-7.29 (m, 2H), 7.22-7.07 (m, 2H), 4.01 (s, 3H), 2.90 (s, 3H), 2.84 (s, 3H). MS m/z: 398 M+.

Methyl 3-amino-5-[(E)-dimethylaminomethyleneamino]sulfonyl-4-(3-thienyl)benzoate (TEPS 40)

mmol TEPS 39 (397 mg) was added to 15 ml ethanol and 3 ml dioxane and the mixture was heated to 85°C and stirred until completely dissolved. Then 10 mmol ammonium chloride (535 mg) in 6 ml water was added. 4 mmol of powdered iron (223 mg) was added in three portions at 2 min intervals. The reaction mixture was stirred at 85°C for an additional 2.5 hours until the mixture no longer contained TEPS 39 by TLC. The mixture was cooled to 60°C and then extracted three times with 25 ml of dichloromethane. The combined organic layers were washed with water and dried over Na ₂ SO ₄ . The crude product was purified by flash chromatography (ethyl acetate/petroleum ether, 7+3) to give 334 mg of a yellow solid (90% yield).

- 103 043772

1H NMR (200 MHz, chloroform-d) δ 8.43 (d, J=1.6 Hz, 1H), 7.73 (d, J=1.7 Hz, 1H), 7.47-7.35 (m, 2H),

7.18-7.02 (m, 2H), 3.93 (s, 3H), 2.88 (s, 3H), 2.84 (s, 3H). MS m/z: 367 M ⁺ .

Methyl 3-(butylamino)-5-[(E)-dimethylaminomethyleneamino]sulfonyl-4-(3-thienyl)benzoate (TEPS

41)

mmol (367 mg) TEPS 40 was dissolved in 5 ml of acetonitrile. Then 3 mmol (408 mg) K ₂ CO ₃ and 3 mmol (3418 μl) butyl iodide were added. The reaction mixture was stirred at 90°C for 2 days. After completion of the reaction, the reaction mixture was poured into 20 ml of water and extracted with ethyl acetate three times. The combined organic layers were washed with brine and dried over Na ₂ SO ₄ . The solvent was then evaporated under reduced pressure, and the resulting crude product was purified by column chromatography (ethyl acetate/toluene, 1 + 1) to obtain 90 mg of a white powder (21.0% yield).

1H NMR (200 MHz, chloroform-d) δ 8.37 (d, J=1.6 Hz, 1H), 7.66 (d, J=1.7 Hz, 1H), 7.52-7.36 (m, 2H), 7.12 (s, 1H), 7.13-7.00 (m, 1H), 3.94 (s, 3H), 3.13-2.99 (m, 2H), 2.89 (s, 3H), 2.85 (s, 3H), 1.56-1.35 (m, 2H), 1.32-1.12 (m, 2H), 0.86 (t, J=7.2 Hz, 3H). MS m/z: 424 M ⁺ .

Methyl 3-(dibenzylamino)-5-[(E)-dimethylaminomethyleneamino]sulfonyl-4-(3-thienyl)benzoate (TEPS 42)

mmol (367 mg) TEPS 40 was dissolved in 5 ml of acetonitrile. Then 2 mmol (276 mg) K ₂ CO ₃ and 2 mmol (238 μl) benzyl bromide were added. The reaction mixture was stirred at 70°C overnight. After completion of the reaction, the reaction mixture was poured into 20 ml of water and extracted with ethyl acetate three times. The combined organic layers were washed with brine and dried over Na ₂ SO ₄ . The solvent was then evaporated under reduced pressure and the resulting crude product was purified by column chromatography (ethyl acetate/toluene, 1.5+8.5) to obtain 193 mg of a white powder (35% yield).

1H NMR (200 MHz, chloroform-d) δ 8.70 (d, J=1.7 Hz, 1H), 8.01 (d, J=1.7 Hz, 1H), 7.43-7.28 (m, 1H), 7.30-7.15 (m, 8H), 7.07 (s, 1H), 7.03-6.88 (m, 5H), 4.04-3.80 (m , 7H), 2.87 (s, 3H), 2.79 (s, 3H). MS m/z: 547 M ⁺ .

5-(Benzyloxymethyl)-3-(butylamino)-2-phenoxybenzenesulfonamide (TEPS 43)

To 10 ml of dry THF, 1.5 mmol (37 mg) of NaH and 1.1 mmol (114 μl) of benzyl alcohol were added. The solution was stirred for 10 minutes and then 1 mmol (369 mg) TEPS 76 was added. The reaction mixture was stirred at room temperature overnight. Once the mixture no longer contained TEPS 76 by TLC, the reaction mixture was dried under reduced pressure and purified by column chromatography (ethyl acetate/petroleum ether, 3+7) to obtain 100 mg of a white powder (22% yield).

^1H NMR (200 MHz, chloroform-d) δ 7.51-7.20 (m, 8H), 7.06 (t, J=7.4 Hz, 1H), 7.00-6.88 (m , 3H), 4.85 (s, 2H), 4.60 (s, 2H), 4.53 (s, 2H), 3.83 (s, 1H), 3.05 (t, J=6, 9 Hz, 2H), 1.57-1.29 (m, 2H), 1.29-1.05 (m, 2H), 0.81 (t, J=7.2 Hz, 3H). MS m/z: 440 M+.

Methyl 3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitro-4-pyrimidin-2-ylsulfanyl benzoate (TEPS 44)

- 104 043772

In a three-neck flask, 1 mmol of methyl 4-chloro-3-[(E)-dimethylaminomethyleneamino]sulfonyl-5nitrobenzoate (350 mg) was dissolved in acetonitrile (10 ml). Then 1.2 mmol of 2mercaptopyrimidine (MW = 112.15 g/mol; 135 mg) and 2 mmol of K ₂ CO ₃ (MW = 138 g/mol; 276 mg) were added to the flask. The reaction mixture was stirred at room temperature overnight and the reaction progress was monitored by thin layer chromatography (ethyl acetate/petroleum ether, 7+3). The mixture was extracted three times with ethyl acetate and washed with water (2x15 ml) and brine (1x20 ml). The organic layer was dried over Na ₂ SO ₄ and the solvent was removed under reduced pressure. The crude product was then purified by column chromatography (ethyl acetate/petroleum ether, 7+3). 408 mg of a yellow crystalline solid was obtained (95.9% yield).

1H NMR (200 MHz, DMSO-d6) δ 8.84 (d, J=1.9 Hz, 1H), 8.68 (d, J=1.9 Hz, 1H), 8.59 (d, J =4.8 Hz, 2H), 8.24 (d, J=2.6 Hz, 2H), 7.31 (d, J=4.9 Hz, 1H), 3.96 (s, 3H), 3.33 (s, 3H), 2.99 (s, 3H). ¹³ C NMR (50 MHz, CDCl ₃ ) δ 163.6, 161.1, 154.1, 147.2, 133.0, 132.9, 128.3, 63.4, 53.3, 42.0 , 36.2, 36.0. MS m/z: 426 M ⁺ .

Methyl 3-amino-5-[(E)-dimethylaminomethyleneamino]sulfonyl-4-pyrimidin-2ylsulfanyl benzoate (TEPS 45)

In a three-neck flask, 0.96 mmol TEPS 44 (408 mg) was dissolved in 20 ml EtOH and 10 ml dioxane at reflux. Then, 9.8 mmol NH ₄ Cl (MM=53.49 g/mol; 524 mg) was dissolved in 12.5 ml H ₂ O and added to the reaction vessel. After 5 minutes, 3.84 mmol Fe (MW = 55.85 g/mol; 215 mg) was added in three portions. The reaction mixture was then stirred at reflux for 1 hour. EtOH and dioxane were removed under reduced pressure, then dichloromethane and H ₂ O were added. The product was extracted with dichloromethane and the organic layer was washed with 2x15 ml H ₂ O and brine. The organic layer was dried over Na ₂ SO ₄ and dichloromethane was removed under reduced pressure. The crude product was then purified by column chromatography (ethyl acetate/petroleum ether, 7+3) to obtain 144 mg of orange crystals (37.9% yield).

1H NMR (200 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.56 (d, J=4.8 Hz, 1H), 8.33 (d, J=4.7 Hz, 2H ), 8.07 (d, J=2.0 Hz, 1H), 6.88 (t, J=4.8 Hz, 1H), 3.88 (s, 5H), 3.18 (s, 2H ), 2.93 (d, J=12.3 Hz, 2H). ¹³ C NMR (50 MHz, DMSO) δ 164.8, 160.8, 157.8, 146.2, 143.8, 130.7, 122.0, 114.0, 66.3, 52.7, 41.1, 35.4. MS m/z:397 M ⁺ .

Methyl 3-(butylamino)-5-[(E)-dimethylaminomethyleneamino]sulfonyl-4-pyrimidin-2ylsulfanyl benzoate (TEPS 46)

In a round bottom flask, 0.36 mmol TEPS 45 (144 mg) was dissolved in DMF. Then 0.45 mmol K ₂ CO ₃ (63 mg) and 0.45 mmol butyl iodide (51.1 μl) were added to the reaction vessel. The reaction mixture was stirred at room temperature overnight. DMF was then removed under reduced pressure. The product was extracted with ethyl acetate and the organic layer was washed with H ₂ O and brine. The crude product was purified by column chromatography (ethyl acetate/petroleum ether, 7+3) to give 143 mg of orange crystals (87.9% yield).

1H NMR (200 MHz, chloroform-d) δ 9.42 (d, J=1.9 Hz, 1H), 8.98 (s, 1H), 8.68-8.44 (m, 3H), 8 .34 (s, 1H),

6.87 (t, J=4.9 Hz, 1H), 3.95 (s, 3H), 3.20 (s, 3H), 3.04 (s, 2H), 2.87 (t, J =7.5 Hz, 2H), 1.60 (t, J=7.9 Hz, 1H), 1.39 (dd, J=15,l, 7.0 Hz, 2H), 0.85 (t , J=7.2 Hz, 3H). ¹³ C NMR (50 MHz, CDCl ₃ ) δ 166.0, 161.2, 159.2, 158.1, 146.4,

143.6, 131.0, 125.3, 123.6, 123.0, 113.8, 52.5, 41.6, 37.0, 35.6, 31.5, 22.2, 13, 6. MS m/z: 451 M ⁺ .

3-(Butylamino)-4-pyrimidin-2-ylsulfanyl-5-sulfamoylbenzoic acid (TEPS 47)

- 105 043772

In a round bottom flask, 0.28 mmol TEPS 46 (136 mg) was dissolved in 20 ml MeOH and 7 ml 2N. NaOH solution. The reaction mixture was stirred at 50°C for 2 hours. MeOH was removed under reduced pressure. The aqueous layer was poured into a glass and acidified with 2 N. HCl solution. The resulting precipitate was then extracted with ethyl acetate. The organic layer was washed with H ₂ O and brine, and the solvent was removed under reduced pressure to obtain 104 mg of a beige powder (89% yield).

1H NMR (200 MHz, DMSO-d ₆ ) δ 13.43 (s, 1H), 9.36-8.88 (m, 2H), 8.59 (d, J=4.9 Hz, 2H), 8.23 (d, J=1.9 Hz, 1H), 7.52 (s, 2H), 7.01 (t, J=4.8 Hz, 1H), 2.82 (t, J=7 .2 Hz, 2H), 1.46 (q, J=7.6 Hz, 2H), 1.34-1.05 (m, 3H), 0.73 (t, J=7.2 Hz, 3H ). ¹³ C NMR (50 MHz, DMSO) δ 166.2, 159.3, 158.5, 148.5, 143.6, 131.2, 126.0, 123.7, 121.7, 114.2, 35.8, 30.8, 21.4, 13.3. MS m/z: 382 M ⁺ .

Methyl 3-(benzylamino)-5-[(E)-dimethylaminomethyleneamino]sulfonyl-4-pyrimidin-2ylsulfanyl benzoate (TEPS 83)

In a round bottom flask, 0.36 mmol TEPS 45 (144 mg) was dissolved in DMF and 0.43 mmol K2CO3 (MW=138 g/mol; 60 mg) and 0.43 mmol benzyl bromide (MW=171.04 g) were added to the reaction vessel /mol; 5=1.44 g/ ^cm3 ; 51.3 µl). The reaction mixture was stirred at room temperature overnight. The reaction was monitored by thin layer chromatography (ethyl acetate/petroleum ether, 7+3) and DMF was removed under reduced pressure. The product was extracted with 2x15 ml ethyl acetate and the organic layer was washed with 2x15 ml H2O and 1x20 ml brine. The crude product was purified by column chromatography (ethyl acetate/petroleum ether, 7+3) to give 144 mg of beige/brown crystals (82.4% yield).

1H NMR (200 MHz, chloroform-d) δ 9.33 (d, J=1.9 Hz, 1H), 8.69 (s, 1H), 8.57 (d, J=1.9 Hz, 1H ), 8.44 (d, J=4.8 Hz, 2H), 8.34 (s, 1H), 7.23-7.00 (m, 5H), 6.81 (t, J=4, 8 Hz, 1H), 4.12 (s, 2H), 3.95 (s, 3H), 3.11 (s, 3H), 3.02 (s, 3H). ¹³ C NMR (50 MHz, CDCl ₃ ) δ 166.0, 161.3, 159.1, 157.9, 146.8, 144.4, 136.7, 131.5, 129.1, 128.6 , 127.3, 123.4, 123.1, 113.9, 52.6, 41.9, 41.6, 35.8, 29.8. MS m/z: 485 M ⁺ .

3-(Benzylamino)-4-pyrimidin-2-ylsulfanyl-5-sulfamoylbenzoic acid (TEPS 48)

In a round bottom flask, 0.28 mmol TEPS 83 (136 mg) was dissolved in 20 ml MeOH and 7 ml 2N. NaOH solution. The reaction mixture was stirred at 50°C for 2 hours. MeOH was removed under reduced pressure. The aqueous layer was poured into a glass and acidified with 2 N. HCl solution. The resulting precipitate was then extracted with ethyl acetate and washed with H2O and brine. The solvent was removed under reduced pressure to obtain 104 mg of a beige powder (89.2% yield).

¹ H NMR (200 MHz, DMSO-d ₆ ) δ 9.10 (d, J=1.9 Hz, 1H), 8.80 (s, 1H), 8.54 (d, J=4.8 Hz , 2H), 8.23 (d, J=1.9 Hz, 1H), 7.58 (s, 2H), 7.24-6.92 (m, 5H), 4.09 (s, 2H) . ¹³ C NMR (50 MHz, DMSO) δ 166.2, 158.8, 158.2, 149.0, 144.3, 136.5, 131.8, 128.9, 128.3, 127.1, 123.3, 122.8, 121.3, 114.2, 29.0. MS m/z: cannot be determined using an IED.

- 106 043772

Methyl 3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitro-4-prop-2-inoxybenzoate (TEPS 49)

Under argon, 1.5 mmol (60 mg) NaH was washed at 5 min intervals with three portions of dry THF (6 mL). After THF was added a third time, 1.1 mmol (64 μl) of propargyl alcohol and 1 mmol (320 mg) of methyl 4-chloro-3-[(E)dimethylaminomethyleneamino]sulfonyl-5-nitrobenzoate were added. The mixture was stirred at room temperature overnight. After completion of the reaction, which was monitored by thin layer chromatography, the mixture was extracted three times with ethyl acetate and washed with brine. The combined organic layers were evaporated under reduced pressure and the resulting orange solid was recrystallized from 96% ethanol to give 83 mg of orange crystals (15% yield).

1H NMR (200 MHz, chloroform-d) δ 8.96 (d, J=2.2 Hz, 1H), 8.70 (d, J=2.2 Hz, 1H), 8.33 (s, 1H ), 5.04 (d, J=2.5 Hz, 2H), 3.98 (s, 3H), 3.23 (s, 3H), 3.04 (s, 3H), 2.69 (t , J=2.5 Hz, 1H). ¹³ C NMR (50 MHz, CDCI3) δ 163.7, 161.4, 151.7, 144.9, 139.9, 135.3, 130.5, 127.3, 77.8, 77.5, 64.7, 53.2, 42.0, 35.9. MS m/z: 370 M ⁺ .

Methyl 4-(allylamino)-3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitrobenzoate (TEPS 50)

mmol (320 mg) methyl 4-chloro-3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitrobenzoate was dissolved in 5 ml of acetonitrile and 2 mmol (276 mg) K ₂ CO ₃ and 1.1 mmol (70 μl ) allylamine. The mixture was stirred overnight and once the mixture no longer contained methyl 4-chloro-3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitrobenzoate by TLC, it was extracted with ethyl acetate and washed with brine. The combined organic layers were evaporated under reduced pressure and the resulting yellow solid was recrystallized from 70% ethanol to give 78 mg of yellow crystals (21.1% yield).

'H NMR (200 MHz, chloroform-d) δ 8.59 (d, J=2.1 Hz, 1H), 8.46 (d, J=2.1 Hz, 1H), 8.10 (s, 1H), 7.15 (s, 1H), 6.04-5.71 (m, 1H), 5.49-5.30 (m, 1H), 5.29-5.18 (m, 1H) , 3.90 (s, 3H), 3.69 (d, J=5.7 Hz, 2H), 3.18 (s, 3H), 3.04 (s, 3H). ¹³ C NMR (50 MHz, CDCI3) δ 164.6, 159.1, 143.3, 137.3, 133.1, 132.8, 132.2, 130.3, 118.8, 116.9, 52.4, 49.1, 41.8, 35.9. MS m/z: 371 M ⁺ .

Methyl 4-anilino-3-nitro-5-sulfamoyl benzoate (TEPS 51)

To a solution of 10 mmol (2.947 g) of methyl 3-(benzylamino)-5-[(E)-dimethylaminomethyleneamino]sulfonyl-4-phenylsulfanyl benzoate in 50 ml of acetonitrile was added 24 mmol of aniline (2.191 ml) and 20 mmol of K ₂ CO ₃ ( 2.764 g). The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the progress of which was monitored using thin layer chromatography, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over Na ₂ SO ₄ and then evaporated under reduced pressure. The resulting crude product was purified by recrystallization from EtOH (70%) to give 3.40 g of orange crystals (97% yield).

1H NMR (200 MHz, DMSO-d6) δ 8.60 (d, J=2.1 Hz, 1H), 8.46 (s, 1H), 8.41 (d, J=2.1 Hz, 1H ), 8.11 (s, 2H), 7.37-7.22 (m, 2H), 7.09 (t, J=7.3 Hz, 1H), 7.03-6.89 (m, 2H), 3.90 (s, 3H) ¹³ C NMR (50 MHz, DMSO) δ 163.8, 140.2, 139.3, 137.7, 133.9, 133.2, 131.1, 129 ,3, 124.5, 119.4, 119.3, 52.6. MS m/z: 351 M ⁺ .

Methyl 3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitro-4-phenylsulfanyl benzoate (TEPS 52)

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To a solution of 2 mmol (700 mg) methyl 4-chloro-3-[(E)-dimethylaminomethyleneamino]sulfonyl-5nitrobenzoate in 10 ml of acetonitrile was added 4 mmol K ₂ CO ₃ (553 mg) and 2.4 mmol thiophenol (245 μl ). The mixture was stirred at room temperature for 1 day and after completion of the reaction, which was monitored by thin layer chromatography, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over Na ₂ SO ₄ and then evaporated under reduced pressure. The resulting crude product was purified by column chromatography (first using 300 ml petroleum ether, then using 300 ml ethyl acetate) to give 723 mg of yellow crystals (85% yield).

1H NMR (200 MHz, chloroform-d) δ 9.10 (d, J=1.9 Hz, 1H), 8.36-8.25 (m, 2H), 7.34-7.18 (m, 3H), 7.167.03 (m, 2H), 3.98 (s, 3H), 2.96 (s, 3H), 2.87 (s, 3H) ¹³ C NMR (50 MHz, CDCh) δ 163, 8, 161.3, 154.2, 147.0, 133.5, 132.6, 131.3, 129.90, 129.4, 128.4, 128.0, 77.2, 53.2, 41.6, 35.6. MS m/z: 423 M ⁺ .

Methyl 3-amino-5-[(E)-dimethylaminomethyleneamino]sulfonyl-4-phenylsulfanyl benzoate (TEPS 53)

To a solution of 1 mmol (423 mg) TEPS 52 in 10 ml EtOH was added a solution of 10 mmol (535 mg) NH ₄ Cl in 30 ml H ₂ O. The mixture was stirred and refluxed. After adding 10 ml of dioxane, 4 mmol (223 mg) of iron was added at 3-minute intervals in three portions. This mixture was heated for 8 hours. After completion of the reaction, the progress of which was monitored using thin layer chromatography, the mixture was diluted with water and extracted with dichloromethane. The organic phase was dried over Na ₂ SO ₄ and then evaporated under reduced pressure to obtain 390 mg of light yellow crystals (99% of compound 4).

^1H NMR (200 MHz, chloroform-d) δ 8.39 (s, 1H), 8.22 (s, 1H), 7.65 (s, 1H), 7.26-7.06 (m, 3H ), 6.99-6.84 (m, 2H), 4.25 (brs, 2H), 3.92 (s, 3H), 2.75 (s, 3H), 2.49 (s, 3H) ¹³ C NMR (50 MHz, CDCl ₃ ) δ 165.9, 161.0, 150.1, 146.7, 134.7, 132.2, 129.3, 129.3, 125.7, 120.0 , 119.9, 114.3, 77.2, 52.6, 41.2, 34.9. MS m/z: 493 M ⁺ .

Methyl 3-(butylamino)-5-[(E)-dimethylaminomethyleneamino]sulfonyl-4-phenylsulfanyl benzoate (TEPS 54)

To a solution of 1.5 mmol (135 μl) of butyraldehyde in 10 ml of 1,2 dichloroethane was added 1 mmol (393 mg) TEPS 53. To this solution was added 1 mmol acetic acid (58 μl) and 1.5 mmol (318 mg) sodium triacetoxyborohydride (NaBH(OAc) ₃ ) and the mixture was stirred at room temperature overnight. After completion of the reaction, which was monitored by thin layer chromatography, the mixture was diluted with water and extracted with dichloromethane. The organic phase was dried over Na ₂ SO ₄ and then evaporated under reduced pressure. The resulting crude product was purified by column chromatography (ethyl acetate/petroleum ether, 1+1) to give 60 mg of a beige powder (13% yield).

1H NMR (200 MHz, chloroform-d) δ 8.31 (s, 1H), 8.22 (s, 1H), 7.49 (s, 1H), 7.33-7.04 (m, 3H) , 7.01-6.83 (m, 2H), 3.93 (s, 3H), 3.11 (t, J=6.9 Hz, 2H), 2.74 (s, 3H), 2, 49 (s, 3H), 1.51-1.28 (m, 2H), 1.21-0.98 (m, 2H), 0.77 (t, J=7.2 Hz, 3H) ¹³ C NMR (50 MHz, CDCl ₃ ) δ 166.4, 161.0, 150.2, 146.7, 134.8, 132.3, 129.2, 129.2, 125.9, 125.8, 117 ,9, 114.8, 77.2, 52.6, 43.44, 41.1, 34.9, 31.0, 19.9, 13.7. MS m/z: 449 M ⁺ .

3-(Butylamino)-4-phenylsulfanyl-5-sulfamoylbenzoic acid (TEPS 55)

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To a solution of 0.5 mmol (225 mg) TEPS 54 in 3 ml MeOH was added 2 ml of 2 N. NaOH solution and stirred at room temperature overnight. After completion of the reaction, which was monitored by thin layer chromatography, the mixture was acidified with 2 ml of 2N. HCl solution. The precipitate was filtered off to give 80 mg of a beige solid (40% compound 6).

1H NMR (200 MHz, DMSO- _d6 ) δ 7.86 (s, 1H), 7.45 (s, 2H), 7.35 (s, 1H), 7.31-7.06 (m, 4H ), 5.53 (t, J=5.6 Hz, 1H), 3.20-2.98 (m, 2H), 1.41-1.18 (m, 3H), 1.12-0, 88 (m, 2H), 0.72 (t, J=7.2 Hz, 3H) ¹³ C NMR (50 MHz, DMSO) δ 166.7, 149.9, 148.8, 134.4, 133, 1, 129.0, 127.4, 126.6, 114.9, 114.1, 113.5, 42.3, 39.9, 39.52, 39.1, 30.1, 19.1, 13.6. MS m/z: IED not possible.

Methyl 3-[(E)-dimethylaminomethyleneamino]sulfonyl-4-[[(18)-2-methoxy-1-methyl-2oxoethyl]amino]-5-nitrobenzoate (TEPS 56)

mmol (1049 mg) of methyl 4-chloro-3-[(E)-dimethylaminomethyleneamino]-sulfonyl-5-nitrobenzoate and 6 mmol (839 mg) of L-alanine methyl ester hydrochloride were suspended in 15 ml of N,Ndimethylformamide. 1.5 ml of triethylamine was added to this mixture and it was stirred at 100°C for 2 hours. After completion of the reaction, the solution was washed with water and extracted with ethyl acetate three times. The combined organic phases were washed with brine. The organic phase was dried over sodium sulfate and the filtrate was evaporated under reduced pressure. The resulting crude product was purified by column chromatography (ethyl acetate/petroleum ether, 7+3) and evaporated under reduced pressure to give 2.21 mmol (920 mg) of yellow crystals (73.6% yield).

[a] ²⁰ D=+ 67.668° (c=0.5; methanol).

1H NMR (200 MHz, chloroform-d) δ 8.70 (d, J=2.1 Hz, 1H), 8.48 (d, J=2.3 Hz, 1H), 8.18 (s, 1H ), 7.60 (d, J=7.8 Hz, 1H), 4.34-4.11 (m, 1H), 3.91 (s, 2H), 3.75 (s, 3H), 3 .18 (s, 3H), 3.07 (s, 3H), 1.45 (d, J=6.9 Hz, 3H). MS m/z: 417 M+.

Methyl 3-[(E)-dimethylaminomethyleneamino]sulfonyl-4-[[(1R)-2-methoxy-1-methyl-2oxoethyl]amino]-5-nitrobenzoate (TEPS 57)

mmol (350 mg) of methyl 4-chloro-3-[(E)-dimethylaminomethyleneamino]-sulfonyl-5-nitrobenzoate and 2 mmol (280 mg) of D-alanine methyl ester hydrochloride were suspended in 10 ml of N,Ndimethylformamide. 1 ml of triethylamine was added to this mixture and it was stirred at 100°C for 2 hours. After completion of the reaction, the solution was washed with water and extracted three times with ethyl acetate. The combined organic phases were washed with brine. The organic phase was dried over sodium sulfate and the filtrate was evaporated under reduced pressure. The resulting crude product was purified by column chromatography (ethyl acetate/petroleum ether, 7+3) and evaporated under reduced pressure to give 0.67 mmol (280 mg) of yellow crystals (67.0% yield).

[a] ²⁰ D=- 68.895° (c=0.5; methanol).

1H NMR (200 MHz, chloroform-d) δ 8.70 (d, J=2.1 Hz, 1H), 8.48 (d, J=2.2 Hz, 1H), 8.18 (s, 1H ), 4.17 (dd, J=18.0, 7.0 Hz, 1H), 3.91 (s, 3H), 3.75 (s, 3H), 3.18 (s, 3H), 3 .07 (s, 3H), 1.45 (d, J=6.9 Hz, 3H). ¹³ C NMR (50 MHz, CDCl ₃ ) δ 173.0, 164.6, 159.4, 141.9, 138.2, 134.0, 132.0, 131.7, 118.4, 53.5 , 52.8, 52.6, 41.9, 36.0, 19.3. MS m/z: 417 M ⁺ .

Methyl (2S)-8-[(E)-dimethylaminomethyleneamino]sulfonyl-2-methyl-3-oxo-2,4-dihydro-1Hquinoxaline-6-carboxylate (TEPS 58)

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mmol (833 mg) TEPS 56 was dissolved in 15 ml ethanol. 2 ml of dioxane was added and the mixture was heated to 85°C and stirred until completely dissolved. A solution of 24 mmol ammonium chloride (1284 mg) in 6 ml water was then added. 14 mmol of powdered iron (781 mg) was added in four portions at 5 min intervals. The mixture was cooled to 60°C and then extracted three times with 25 ml of dichloromethane. The combined organic layers were washed with water and dried over sodium sulfate. The filtrate was evaporated under reduced pressure and the resulting crude product was purified by column chromatography (ethyl acetate/petroleum ether, 7+3, and ethyl acetate only) to give 1.16 mmol (410 mg) of yellow crystals (57.8% yield).

[a] ²⁰ D=+ 15.353° (c=0.5; methanol).

1H NMR (200 MHz, DMSO-d6) δ 10.69 (s, 1H), 8.29 (s, 1H), 7.88 (d, J=2.0 Hz, 1H), 7.47 (d , J=2.0 Hz, 1H), 6.63 (s, 1H), 4.19 (d, J=8.8 Hz, 1H), 3.80 (s, 3H), 3.13 (s , 3H), 2.91 (s, 3H), 1.25 (d, J=6.9 Hz, 3H). ¹³ C NMR (50 MHz, DMSO) δ 166.8, 165.2, 159.4, 134.6, 126.8, 124.2, 123.2, 117.7, 117.0, 51.9, 50.8, 40.8, 35.1, 29.0, 19.5. MS m/z: 354 M ⁺ .

3-(Butylamino)-2-phenoxy-5-(pyrrolidin-1-ylmethyl)benzenesulfonamide (TEPS 59)% / y g |f ⁰ mmol (369 mg) TEPS 76 was dissolved in 5 ml of pyrrolidine and the mixture was stirred at room temperature in during the night. After completion of the reaction, the progress of which was checked using thin layer chromatography, the liquid substances were evaporated under reduced pressure. The crude product was purified by column chromatography (toluene/triethylamine, 8+2) and recrystallization from 70% EtOH to give 220 mg of a white powder (55% yield).

1H NMR (200 MHz, DMSO-ds) δ 7.39-6.62 (m, 9H), 4.67 (s, 1H), 3.56 (s, 2H), 3.14-2.91 ( m, 2H), 2.30 (s, 1H), 1.84-1.61 (m, 4H), 1.52-1.24 (m, 2H), 1.27-1.00 (m, 2H), 0.77 (t, J=7.1 Hz, 3H). ¹³ C NMR (50 MHz, DMSO) δ 156.9, 142.0, 137.2, 137.0, 134.9, 129.0, 121.9, 115.5, 114.7, 113.7, 59.5, 53.6, 42.1, 30.4, 23.2, 19.3, 13.7. MS m/z: 403 M ⁺ .

3-(Butylamino)-5-(imidazole-1-carbonyl)-2-phenoxybenzenesulfonamide (TEPS 60)

To a solution of 2.5 mmol (913 mg) of bumetanide in 10 ml of dry THF, 2.75 mmol (447 mg) of 1,1carbonyldiimidazole (CDI) was added and the mixture was stirred at 67°C for 3 hours. The mixture was then cooled to room temperature and after adding 15 ml of diethyl ether, a white precipitate formed. The precipitate was filtered and dried under reduced pressure to obtain 0.98 g of white powder (94.30% yield).

1H NMR (200 MHz, ) δ 8.10 (d, J=1.4 Hz, 1H), 7.78 (d, J=2.0 Hz, 1H), 7.49 (d, J=2, 0 Hz, 1H), 7.29-7.12 (m, 4H), 7.08-6.69 (m, 3H), 3.00 (t, J=6.7 Hz, 2H), 1, 41-1.23 (m, 2H), 1.19-0.93 (m, 2H), 0.70 (t, J=7.1 Hz, 3H). ¹³ C NMR (50 MHz, MeOH) δ 171.6, 158.4, 144.0, 141.1, 138.4, 133.3, 131.0, 124.3, 122.1, 117.7, 117.6, 117.1, 69.3, 44.2, 32.5, 21.3, 14.5.

N'-[3-(butylamino)-5-(hydroxymethyl)-2-phenoxyphenyl]sulfonyl-N,N-dimethylformamidine (TEPS 61)

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To a solution of 1 mmol 3-(butylamino)-5-(hydroxymethyl)-2-phenoxybenzenesulfonamide (Toellner K et al., Annals of Neurology (2014), 75(4), 550-562) in 2.5 ml DMF was added 1 .2 mmol (iodomethyl)cyclopropane and 1 mmol (124 mg) AgO and stirred for 2 days. The mixture was then evaporated under reduced pressure and the resulting crude product was purified by column chromatography (toluene/triethylamine, 8+2). According to the spectrum, no ether was formed, but DMF bound to the sulfonamide group to form the desired compound, yielding 200 mg of yellow crystals (49% yield).

¹ H NMR (200 MHz, DMSO-d ₆ ) δ 7.85 (s, 1H), 7.37-7.20 (m, 2H), 7.18-6.87 (m, 3H), 6, 77-6.54 (m, 2H), 5.31 (t, J=5.8 Hz, 1H), 4.72-4.56 (m, 1H), 4.51 (d, J=5, 6 Hz, 2H), 4.20-3.93 (m, 1H), 3.06-2.94 (m, 2H), 2.86 (s, 3H), 1.42-1.25 (m , 2H), 1.16-1.00 (m, 2H), 0.75 (t, J=7.2 Hz, 3H). ¹³ C NMR (50 MHz, DMSO) δ= 160.2, 156.3, 141.7, 140.3, 135.3, 134.5, 129.3, 121.9, 115.0. 113.0, 112.7, 62.7, 42.2, 40.7, 34.5, 30.4, 19.3, 13.6. MS m/z: 406 M ⁺ .

5-Chlorothiophene-2-carboxylic acid (TEPS 62) (Moni, L et al., 2016)

ABOUT

300 mmol (12 g) NaOH was dissolved in 60 ml H ₂ O and the solution was cooled to 0-10°C. Then 90 mmol (4.65 ml) bromine was added. 30 mmol (4.8 g) of 2-acetyl-5-chlorothiophene (T1) was dissolved in 30 ml of dioxane and added at a temperature of 0-10°C. The solution was stirred at room temperature for 1 hour, this led to the formation of bromoform. Bromoform was removed using a separatory funnel and 3 g of sodium pyrosulfite in 45 ml of H ₂ O was added to the aqueous phase. The solution was acidified with concentrated HCl, which formed a beige precipitate. The precipitate was collected by vacuum filtration to obtain 3.72 g of the substance. (76.1%).

1H NMR (200 MHz, chloroform-d) δ 7.69 (d, J=4.1 Hz, 1H), 7.26 (s, 1H), 6.98 (d, J=4.1 Hz, 1H ).

Methyl 5-chlorothiophene-2-carboxylate (TEPS 63) (Hauck, S. et al., 2016)

3.716 g (22.9 mmol) TEPS 62 was dissolved in 30 ml MeOH and 1.5 ml concentrated H ₂ SO ₄ was added. After stirring at reflux for 28 hours, NaOH was added to make the solution alkaline. The solution was then extracted three times with ethyl acetate and dried over Na ₂ SO ₄ . The solvent was then removed by rotary evaporation to obtain 2.157 g of a brown liquid product (53.3%).

^1H NMR (200 MHz, chloroform-d) δ 7.59 (d, J=4.0 Hz, 1H) δ 6.93 (d, J=4.0 Hz, 1H) δ 3.87 (s, 3H). ¹³ C NMR (50 MHz, DMSO-d ₆ ) δ 160.8, 135.6, 133.8, 131.3, 128.6, 52.5. MS m/z: 176 M ⁺ .

Methyl 5-chloro-4-nitrothiophene-2-carboxylate (TEPS 64) (Park, Chan L. et al., 2014)

NO2 o

12.2 mmol (2.157 g) TEPS 63 was dissolved in 3.9 ml concentrated H2SO4 and then cooled to 0-10°C. A cold (0-5°C) mixture of 3 ml of concentrated H ₂ SO ₄ and 1.7 ml of concentrated HNO ₃ was slowly added and stirred at 0° C for 1 hour. The mixture was then poured into ice water, and a precipitate formed. The precipitate was collected by vacuum filtration and washed three times, first with H ₂ O, then with 5% sodium bicarbonate solution and washed again with H ₂ O. A yellow product was obtained in a yield of 1.502 g (54.9%).

1H NMR (200 MHz, chloroform-d) δ 8.18 (s, 1H), 3.94 (s, 3H). ¹³ C NMR (50 MHz, chloroform-d) δ 128.6, 53.1. MC m/z: 221 M ⁺ .

Methyl 4-nitro-5-phenoxythiophene-2-carboxylate (TEPS 65) (Consiglio, G., et al., 2002)

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1.502 g (6.8 mmol) TEPS 64 was dissolved in 22.4 ml of dimethylformamide, then 0.694 g of phenol and 1.86 g of K2CO3 were added. The mixture was stirred at room temperature overnight. Then added

H2O and product were collected by extraction with ethyl acetate (done three times). The organic layers were dried over Na ₂ SO ₄ and the solvent was removed on a rotary evaporator to give 1.805 g of beige crystals (95.6%).

L NMR (200 MHz, chloroform-d) δ 8.11 (s, 1H) δ 7.64-7.16 (m, 5H) δ 3.85 (s, 3H). ¹³ C NMR (50 MHz, chloroform-d) δ 161.3, 156.8, 130.8, 128.3, 127.8, 120.0, 117.3, 52.9. MS m/z: 279 M ⁺ .

Methyl 4-amino-5-phenoxythiophene-2-carboxylate (TEPS 66)

1.805 g (6.5 mmol) TEPS 65 was added to 65 ml EtOH, the mixture was heated to 85°C and stirred until completely dissolved. Then 2.249 g of ammonium chloride was dissolved in 25 ml of H ₂ O and added to the solution. Then 0.937 g of powdered iron was added in three portions at intervals of several minutes. The solution was stirred at 85°C for 2 hours until the mixture no longer contained TEPS 65 by TLC. The mixture was then cooled to 60°C and the reaction product was collected by extraction with dichloromethane. The organic layers were washed with H2O and brine and dried over Na ₂ SO ₄ . The dichloromethane was then removed by rotary evaporation to obtain 1.25 g of a brown liquid (76.9%).

^1H NMR (200 MHz, chloroform-d) δ 7.78-6.65 (m, 6H) 5 3.84 (s, 3H) 5 2.92 (s, 3H). ¹³ C NMR (50 MHz, chloroform-d) δ 162.6, 157.9, 133.1, 129.9, 125.9, 123.8, 116.2, 62.2, 52.1. MS m/z: 249 M ⁺ .

Methyl 4-(butylamino)-5-phenoxythiophene-2-carboxylate (TEPS 67)

1.25 g (5.0 mmol) TEPS 66 was dissolved in 20 ml of dimethylformamide, then 0.453 g of K ₂ CO ₃ and 792 μl of butyl iodide were added and the mixture was stirred at reflux for 3 hours. Then H ₂ O and the product were added collected by extraction with ethyl acetate. The organic layers were dried over Na ₂ SO ₄ and then the solvent was removed in a rotary evaporator. The product was then purified by column chromatography (ethyl acetate/petroleum ether, 3+7) to give 0.702 g of a light yellow solid (4.6%).

^1H NMR (200 MHz, chloroform-d) δ 7.64-6.76 (m, 6H) 5 3.82 (s, 3H), 3.10 (t, J=7.0 Hz, 1H) δ 1.66-1.13 (m, 4H) δ 0.87 (t, J=7.1 Hz, 3H). ¹³ C NMR (50 MHz, chloroform-d) δ 129.8, 123.7, 116.2, 52.1, 46.4, 32.1, 20.0, 13.8. MS m/z: 318 M ⁺ .

4-(Butylamino)-5-phenoxythiophene-2-carboxylic acid (TEPS 68)

1.98 mmol (0.7 g) TEPS 67, 2 mmol (0.218 g) KOH were dissolved in 30 ml EtOH and 10 ml H ₂ O. The reaction mixture was then refluxed for 3 hours. The solvent was removed under reduced pressure and the residue was diluted with H2O. NaOH solution was then added to increase the pH to 10. The aqueous layer was then washed with ethyl acetate and acidified with concentrated HCl. The product was then extracted with ethyl acetate, washed with water, dried over Na ₂ SO ₄ and then concentrated under reduced pressure. The product was then purified by column chromatography (ethyl acetate/petroleum ether, 3+7, 10% CH3COOH) to give 0.045 g (7.5%).

^1H NMR (200 MHz, chloroform-d) δ 8.20 (s, 1H) δ 7.56-6.95 (m, 6H) δ 3.13 (t, J=6.9 Hz, 1H) δ 1.42 (m, 4H) δ 0.90 (t, J=7.1 Hz, 3H). ¹³ C NMR (50 MHz, chloroform-d) δ 167.5, 157.9, 136.5, 129.9, 125.0, 124.0, 116.5, 46.6, 31.9, 20, 0, 13.8. MS m/z: 291 M ⁺ .

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5-Chloro-4-nitrothiophene-2-sulfonyl chloride (TEPS 69) (Yang, J. et al., 2015)

In a three-neck flask, 6.16 ml (46.1 mmol) of 5-chlorothiophene-2-sulfonyl chloride was added dropwise to 55.6 ml of fuming nitric acid.

First, the solution was cooled to ensure a temperature below 60°C. After stirring for 3 hours, the reaction was completed and the solution was poured into ice water. The product was collected by vacuum filtration to give 11.161 g of yellow crystals (92.4%).

1H NMR (200 MHz, chloroform-d) δ 8.30 (s, 1H). ¹³ C NMR (50 MHz, chloroform-d) δ 129.8. MS m/z: 263 M ⁺ .

5-chloro-4-nitrothiophene-2-sulfonamide (TEPS 70) (Kunzer, A.R., et al., 2010)

11.31 g (42.6 mmol) TEPS 69 at 0°C was added to 44.2 ml NH4OH. After addition was complete, the reaction mixture was stirred at room temperature until the solid dissolved. The clear orange solution was cooled with ice, diluted with H ₂ O and acidified with concentrated HCl to precipitate a solid. The product was collected by vacuum filtration to give 4.566 g of a yellow powder (44.1%).

1H NMR (200 MHz, DMSO-d ₆ ) δ 8.14 (s, 1H) 5 7.97 (s, 2H). ¹³ C NMR (50 MHz, DMSO-d ₆ ) δ 141.7, 124.8. MS m/z: 242 M ⁺ .

N'-[(5-chloro-4-nitro-2-thienyl)sulfonyl]-N,N-dimethylformamidine (TEPS 71)

4.566 g (18.8 mmol) of TEPS 70 was dissolved in 22.5 ml of acetonitrile and then 2.8 ml of N,N-dimethylformαmide dimethyl acetal was added slowly. The reaction mixture was stirred overnight, then the mixture was extracted with ethyl acetate three times and the organic layer was dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to obtain 1.95 g of yellow product (35.1%).

^1H NMR (200 MHz, DMSO-d6) δ 8.29 (s, 1H) 5 8.00 (s, 1H) δ 3.20 (s, 3H) δ 2.98 (s, 3H). ¹³ C NMR (50 MHz, DMSO-d6) δ 160.6, 124.8, 41.3, 35.4. MS m/z: 297 M ⁺ .

N,N-dimethyl-N'-[(4-nitro-5-phenoxy-2-thienyl)sulfonyl]formamidine (TEPS 72)

6.6 mmol (1.95 g) TEPS 71 was dissolved in 17 ml of acetonitrile and then 0.55 g of phenol and 1.85 g of K ₂ CO ₃ were added. The mixture was stirred for 4 hours, then water was added and extracted three times with ethyl acetate and once with brine. The organic layer was dried over Na ₂ SO ₄ and the solvent was removed under reduced pressure to obtain 0.4 g of brown crystals. The product was purified by column chromatography (ethyl acetate/petroleum ether, 3+7) to give 2.2 g of orange product (92.4%).

1H NMR (200 MHz, DMSO-d6) δ 8.22 (s, 1H) 5 7.82 (s, 1H) 5 7.70-7.37 (m, 5H) 5 3.16 (s, 3H) 5 2.92 (s, 3H). ¹³ C NMR (50 MHz, chloroform-d) δ 159.5, 156.8, 130.8, 128.7, 127.8, 124.7, 119.9, 41.9, 36.0. MC m/z: 378 M ⁺ .

N'-[(4-amino-5-phenoxy-2-thienyl)sulfonyl]-N,N-dimethylformamidine (TEPS 73)

2.2 g (6.1 mmol) TEPS 72 was added to 40 ml EtOH, the mixture was heated to 85°C and stirred until completely dissolved. Then 4.4 g of ammonium chloride was dissolved in H ₂ O and added to the solution. Then three

- 113 043772 0.61 g of powdered iron was added in portions at intervals of several minutes. The solution was stirred at 85°C for 2 hours until the mixture no longer contained TEPS 72 by TLC. The mixture was cooled to 60°C and the reaction product was collected by extraction with dichloromethane. The combined organic phases were washed with brine and the organic phase was dried over Na ₂ SO ₄ . The solvent was then removed under reduced pressure. The product was purified by column chromatography (ethyl acetate/petroleum ether, 1 + 1) to give 0.709 g of a yellow liquid (36.1%).

^1H NMR (200 MHz, DMSO-Y6) δ 8.17 (s, 1H) δ 7.46-6.92 (m, 6H) δ 4.86 (s, 2H) δ 3.16 (s, 3H ) δ 2.94 (s, 3H). ¹³ C NMR (50 MHz, DMSO-66) δ 159.6, 158.0, 135.3, 134.6, 132.2, 129.8, 123.3, 123.0, 115.8, 40, 9, 35.2. MS m/z: 325 M ⁺ .

N'-[[4-(butylamino)-5-phenoxy-2-thienyl]sulfonyl]-N,N-dimethylformamidine (TEP S 74)

0.7 g (2.2 mmol) TEPS 73 was dissolved in 3.9 ml dimethylformamide, then 0.31 g K2CO3 and 531 μl butyl iodide were added and the mixture was stirred at reflux for 3 hours. Then H2O was added and the product was collected by extraction with ethyl acetate. The organic layers were dried over Na ₂ SO ₄ and then the solvent was removed in a rotary evaporator. The product was then purified by column chromatography (ethyl acetate/petroleum ether, 3+7) to give 0.101 g of a light yellow solid (11.8%).

^1H NMR (200 MHz, chloroform-d) δ 8.09 (s, 1H) δ 7.45-6.99, 6H) δ 3.20-2.98 (m, 8H) δ 1.70-1 .15 (m, 4H) δ 0.89 (t, J=7.2 Hz, 1H). ¹³ C NMR (50 MHz, chloroform-d) δ 159.2, 158.0, 131.7, 129.8, 123.9, 121.4, 116.3, 60.4, 46.8, 41, 6, 35.7, 31.7, 19.9, 13.8. MS m/z: 381 M ⁺ .

Methyl-1-butyl-7-[(E)-dimethylaminomethyleneamino]sulfonyl-2-propylbenzimidazole-5carboxylate (TEPS 77)

0.5 mmol (193 mg) TEPS 31 was added to 7.5 ml ethanol and 1.5 ml dioxane and the mixture was heated to 85°C and stirred until completely dissolved. Then 0.5 mmol ethyl acetate (25 μl), 0.5 mmol concentrated acetic acid (14 μl) and 5 mmol ammonium chloride (267.5 mg) in 3 ml water were added. 2 mmol of powdered iron (111.5 mg) was added in three portions at 2-minute intervals. The reaction mixture was stirred at 85°C for an additional 2.5 hours until the mixture no longer contained BUM131 by TLC. The mixture was cooled and then extracted three times with dichloromethane. The combined organic layers were washed with water and dried over Na ₂ SO ₄ . The crude product was purified by column chromatography (ethyl acetate/petroleum ether, 8+2) to give 43 mg of a yellow solid (21.1% yield).

^1H NMR (200 MHz, chloroform-d) δ 8.55 (s, 2H), 8.15 (s, 1H), 4.95-4.65 (m, 2H), 3.94 (s, 3H ), 3.16 (s, 3H), 3.07 (s, 3H), 2.99-2.85 (m, 2H), 2.15-1.90 (m, 2H), 1.90- 1.71 (m, 2H), 1.61-1.37 (m, 2H), 1.26 (s, 1H), 1.12 (t, J=7.4 Hz, 3H), 0.99 (t, J=7.3 Hz, 3H). ¹³ C NMR (50 MHz, CDCl ₃ ) δ 166.6, 159.7, 159.2, 144.3, 133.3, 126.7, 125.1, 124.2, 122.9, 52.4 , 45.8, 41.8, 35.8, 33.3, 29.8, 21.1, 20.1, 14.2, 13.9. MS m/z: 408 M ⁺ .

Methyl (2R)-8-[(E)-dimethylaminomethyleneamino]sulfonyl-2-methyl-3-oxo-2,4-dihydro-1Hquinoxaline-6-carboxylate (TEPS 78)

- 114 043772

mmol (833 mg) TEPS 57 was dissolved in 15 ml ethanol. 2 ml of dioxane was added and the mixture was heated to 85°C and stirred until completely dissolved. A solution of 24 mmol ammonium chloride (1284 mg) in 6 ml water was then added. 14 mmol of powdered iron (781 mg) was added in four portions at 5 min intervals. The mixture was cooled to 60°C and then extracted three times with 25 ml of dichloromethane. The combined organic layers were washed with water and dried over sodium sulfate. The filtrate was evaporated under reduced pressure and the resulting crude product was purified by column chromatography (ethyl acetate/petroleum ether, 7+3, and ethyl acetate only) to give 1.49 mmol (530 mg) of yellow crystals (74.7% yield).

[a] ²⁰ D=- 14.159° (c=0.5; methanol).

1H NMR (200 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 8.29 (s, 1H), 7.88 (d, J=1.9 Hz, 1H), 7.47 ( s, 1H), 6.64 (s, 1H), 4.19 (dd, J=6.8, 2.3 Hz, 1H), 3.80 (s, 3H), 3.56 (s, 1H ), 3.13 (s, 3H), 2.91 (s, 3H), 1.25 (d, J=6.8 Hz, 3H). ¹³ C NMR (50 MHz, DMSO) δ 166.8, 165.2, 159.4, 134.6, 126.8, 124.2, 123.3, 117.7, 117.0, 66.4, 51.9, 50.9, 40.9, 35.1, 19.5. MC m/z: 354 M ⁺ .

Methyl (2R)-4-butyl-8-[(E)-dimethylaminomethyleneamino]sulfonyl-2-methyl-3-oxo-1,2dihydroquinoxaline-6-carboxylate (TEPS 79)

mmol (354 mg) TEPS 78 was dissolved in 9 ml of N,N-dimethylformamide. 2 mmol (276 mg) of potassium carbonate and 6 mmol (687 μl) of butyl iodide were added to the mixture and stirred at 90°C for 16 hours. After completion of the reaction, the mixture was washed with water and extracted with ethyl acetate three times. The combined organic phases were washed with brine. The organic phase was dried over sodium sulfate and the filtrate was evaporated under reduced pressure. The resulting crude product was purified by column chromatography (ethyl acetate) and evaporated under reduced pressure to give 0.34 mmol (139 mg) of yellow crystals (33.9% yield).

[a] ²⁰ D=- 11.163° (c=0.5; methanol).

1H NMR (200 MHz, chloroform-d) δ 8.37-8.02 (m, 2H), 7.66 (s, 1H), 6.62 (s, 1H), 4.19 (dd, J= 6.7, 1.9 Hz, 1H), 4.07-3.76 (m, 5H), 3.15 (s, 3H), 3.03 (s, 3H), 1.67 (s, 2H ), 1.74-1.57 (m, 1H), 1.56-1.31 (m, 5H), 0.97 (t, J=6.9 Hz, 3H). ¹³ C NMR (50 MHz, CDOj) δ 166.3, 166.1, 158.9, 137.6, 128.2, 124.7, 124.5, 118.8, 118.3, 52.1, 51.4, 42.1,41.6, 35.7, 28.9, 20.1, 19.1, 13.8. MS m/z: 410 M ⁺ .

(2R)-4-butyl-2-methyl-3-oxo-8-sulfamoyl-1,2-dihydroquinoxaline-6-carboxylic acid (TEPS 80)

0.48 mmol (200 mg) TEPS 79 was dissolved in 1.5 ml methanol and 1.5 ml 2 N. sodium hydroxide solution and the mixture was stirred at 40°C for 2 hours. After completion of the reaction and cooling of the mixture to room temperature, the methanol was evaporated under reduced pressure. After adding 1.5 ml of 2 N. hydrochloric acid solution, a light yellow precipitate was formed. The precipitate was filtered and dried under reduced pressure to obtain 0.43 mmol (150 mg) of a light yellow powder (yield 91.5%)

[a] ²⁰ _D = - 38.303° (c = 0.5; methanol).

- 115 043772

1H NMR (200 MHz, DMSO- _d6 ) δ 12.89 (s, 1H), 8.02 (s, 1H), 7.70 (s, 2H), 7.60 (s, 1H), 6, 64 (s, 1H), 4.314.07 (m, 1H), 3.95 (t, J=7.3 Hz, 2H), 1.65-1.44 (m, 2H), 1.43-1 .10 (m, 5H), 0.91 (t, J=7.1 Hz, 3H).

¹³ C NMR (50 MHz, DMSO) δ 166.8, 166.6, 136.8, 128.2, 126.4, 124.8, 119.2, 118.3, 51.1,41.2, 28.9, 19.9, 18.8, 14.1.

MS m/z: IED not possible.

Methyl (2S)-4-butyl-8-[(E)-dimethylaminomethyleneamino]sulfonyl-2-methyl-3-oxo-1,2dihydroquinoxaline-6-carboxylate (TEPS 81)

mmol (354 mg) TEPS 58 was dissolved in 9 ml of N,N-dimethylformamide. 2 mmol (276 mg) of potassium carbonate and 6 mmol (687 μl) of butyl iodide were added to the mixture and stirred at 90°C for 16 hours. After completion of the reaction, the mixture was washed with water and extracted with ethyl acetate three times. The combined organic phases were washed with brine. The organic phase was dried over sodium sulfate and the filtrate was evaporated under reduced pressure. The resulting crude product was purified by column chromatography (ethyl acetate) and evaporated under reduced pressure to give 0.32 mmol, 131 mg of yellow crystals (31.9% yield).

[a] ²⁰ D=+ 12.083° (c=0.5; methanol).

1H NMR (200 MHz, DMSO-d ₆ ) δ 8.29 (s, 1H), 7.97 (d, J=1.7 Hz, 1H), 7.57 (d, J=1.8 Hz, 1H), 6.76 (s, 1H), 4.26 (dd, J=6.8, 1.9 Hz, 1H), 4.09-3.85 (m, 2H), 3.83 (s , 3H), 3.14 (s, 3H), 2.91 (s, 3H), 1.63-1.44 (m, 2H), 1.381.08 (m, 6H), 0.91 (t, J=7.1 Hz, 3H). ¹³ C NMR (50 MHz, DMSO) δ 166.0, 165.3, 159.4, 136.4, 127.6, 125.1, 123.5, 117.5, 117.3, 52.1, 50.8, 40.9, 35.1,28.4, 19.4, 19.0, 13.6. MS m/z: 410 M ⁺ .

(2S)-4-butyl-2-methyl-3-oxo-8-sulfamoyl-1,2-dihydroquinoxaline-6-carboxylic acid (TEPS 82)

0.12 mmol (50 mg) TEPS 81 was dissolved in 1.5 ml methanol and 1.5 ml 2 N. sodium hydroxide solution and the mixture was stirred at 40°C for 2 hours. After completion of the reaction and cooling of the mixture to room temperature, the methanol was evaporated under reduced pressure. After adding 1.5 ml of 2 N. hydrochloric acid solution, a light yellow precipitate was formed.

The precipitate was filtered and dried under reduced pressure to obtain 0.117 mmol (40 mg) of a light yellow powder (97.5% yield).

[a] ²⁰ D=+ 35.405° (c=0.5; methanol).

1H NMR (200 MHz, DMSO- _d6 ) δ 12.90 (s, 1H), 8.06-7.96 (m, 1H), 7.71 (s, 1H), 7.60 (s, 1H ), 6.65 (s, 1H), 4.30-4.07 (m, 1H), 3.95 (t, J=7.2 Hz, 2H), 1.65-1.42 (m, 2H), 1.30 (d, J=6.7 Hz, 5H), 0.90 (t, J=7.1 Hz, 3H). ¹³ C NMR (50 MHz, DMSO) δ 166.3, 166.2, 136.4, 127.7, 125.9, 124.4, 118.7, 117.8, 50.7, 40.9, 28.4, 19.4, 18.3, 13.6. MS m/z: IED not possible.

3-(Butylamino)-2-phenoxy-5-(2,2,2-trifluoroethoxymethyl)benzenesulfonamide (TEPS 83)

mg of sodium hydride dispersion in mineral oil (2 mmol) was washed twice with dry THF. 3 mL of THF was added to the sodium hydride, followed by 1.5 mmol (108 μL) of 2,2,2-trifluoroethanol and 0.5 mmol (184 mg) of TEPS 76. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, it was stopped with 3 ml of water. The mixture was then extracted three times with ethyl acetate, and the combined organic layers were washed with brine and dried over Na ₂ SO ₄ . The organic layers were dried under reduced pressure to give a white crude product. The crude product was further purified by column chromatography (ethyl acetate/petroleum ether,

3+7) and recrystallization from EtOH to obtain 78 mg of white powder (yield 36%).

1H NMR (200 MHz, DMSO-d6) δ 7.40-7.03 (m, 5H), 7.07-6.72 (m, 4H), 4.67 (s, 2H), 4.14 ( q, J=9.4 Hz, 2H), 3.03 (t, J=6.9 Hz, 2H), 1.48-1.24 (m, 2H), 1.26-0.98 (m , 2H), 0.77 (t, J=7.2 Hz, 3H). ¹³ C NMR (50 MHz, DMSO-d ₆ ) δ 156.7, 142.2, 137.3, 135.8, 134.7, 129.0, 124.5 (d, J=279.2 Hz) , 121.9, 115.5, 113.9, 113.0, 72.9, 66.6 (q, J=32.8 Hz), 42.0, 30.3, 19.3, 13.6 . MS m/z 443.

4-(4-Fluorophenoxy)-3-nitro-5-sulfamoylbenzoic acid (TEPS 84) (WO 2012/018635)

To a suspension of 20 mmol (5.61 g) 4-chloro-3-nitro-5-sulfamoylbenzoic acid (561 mg) in 30 ml water, 80 mmol NaHCO ₃ (6.8 g) was carefully added, then 40 mmol (4.77 d) 4-fluorophenol. This solution was stirred at 85°C for 16 hours. After cooling to room temperature, the precipitate was filtered off and dissolved in 10 ml of hot water. Then 6 N was added. The HCl solution and the resulting precipitate were filtered and dried to give 4.35 g of a yellow solid (61% yield).

^1H NMR (200 MHz, DMSO) δ 14.01 (brs, 1H), 8.83-8.54 (m, 2H), 7.88 (s, 2H), 7.15 (t, J=8 ,8 Hz, 2H), 7.05-6.86 (m, 3H). ¹³ C NMR (50 MHz, DMSO) δ 164.7, 158.56 (d, J=239.5 Hz), 153.25 (d, J=2.3 Hz), 148.2, 143.4, 140.3, 133.6, 130.9, 128.6, 118.24 (d, J=8.5 Hz), 116.56 (d, J=23.7 Hz). MS m/z 356.

3-Amino-4-(4-fluorophenoxy)-5-sulfamoylbenzoic acid (TEPS 85)

To an aqueous LiOH solution (pH set to 11) was added 10 mmol (3.56 g) TEPS 84 and 350 mg palladium on activated charcoal (5% Pd/C). The resulting mixture was hydrogenated at room temperature. After the uptake of _H2 became negligible, the mixture was filtered and the filtrate was acidified with 6N. HCl solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and dried under reduced pressure to obtain 2.15 g of a brown solid (66% yield).

1H NMR (200 MHz, DMSO) δ 7.78-7.47 (m, 2H), 7.30 (s, 2H), 7.19-7.00 (m, 2H), 6.99-6, 76 (m, 2H), 5.32 (s, 2H). ¹³ C NMR (50 MHz, DMSO) δ 166.9, 157.8 (d, J=236.9 Hz), 152.8 (d, J=2.0 Hz), 143.2, 139.3, 138.3, 128.3, 120.7, 117.3 (d, J=8.4 Hz), 116.1, 115.7. MC m/z 326.

Methyl 3-(benzylamino)-4-(4-fluorophenoxy)-5-sulfamoyl benzoate (TEPS 86)

5 mmol (0.6 ml) of benzyl bromide was added to a suspension of 2 mmol (652 mg) TEPS 85 in 10 ml MeOH. The mixture was then refluxed for 16 hours to obtain a solution. After completion of the reaction, MeOH was removed under reduced pressure and 20 ml of 5% NaHCO ₃ solution was added. This mixture was extracted three times with ethyl acetate and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (ethyl acetate/petroleum ether, 3+7) to give 351 mg of a white solid

- 117 043772 substances (yield 41%).

¹ H NMR (200 MHz, DMSO) δ 7.67 (d, J=1.9 Hz, 1H), 7.40 (s, 2H), 7.35-7.04 (m, 8H), 6, 96-6.80 (m, 2H),

6.21 (t, J=6.0 Hz, 1H), 4.35 (d, J=6.0 Hz, 2H), 3.81 (s, 3H). ¹³ C NMR (50 MHz, DMSO) δ 165.8, 158.0 (d,

J=237.2 Hz), 153.1 (d, J=2.0 Hz), 142.8, 140.5, 139.5, 138.3, 128.8, 127.3, 127.3, 127.1, 117.4 (d, J=8.3 Hz),

116.1, 115.7, 52.9, 46.2. MC m/z 430.

3-(Benzylamino)-2-(4-fluorophenoxy)-5-(hydroxymethyl)benzenesulfonamide (TEPS 87)

In a three-neck flask under argon, 2 mmol TEPS 86 (860 mg) was dissolved in 8 ml anhydrous THF. Then 4 ml of a 1 M solution of DIBAL-N in toluene was added. After 1, 2, 3 and 4 hours, another 2 ml of 1 M solution of DIBAL-N in toluene was added and the reaction mixture was stirred overnight. Once the mixture no longer contained TEPS 86 by TLC, the mixture was cooled to 0° C. and the reaction was stopped with 5% aqueous NHCl ₄ solution, which resulted in the precipitation of a gel-like substance. Then the precipitate was dissolved in 2 N. HCl solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water, once with brine and dried over Na ₂ SO ₄ . The liquids were evaporated under reduced pressure and purified by recrystallization from ethanol to give 665 mg of a beige powder (83% yield).

^1H NMR (200 MHz, DMSO) δ 7.34-7.00 (m, 10H), 6.92-6.74 (m, 3H), 5.86-5.69 (m, 1H), 4 .38 (s, 2H), 4.30 (d, J=5.2 Hz, 2H). ¹³ C NMR (50 MHz, DMSO) δ 157.7 (d, J=236.5 Hz), 153.7, 140.6, 140.0, 137.4, 135.5, 128.7, 128, 1, 127.2, 117.2 (d, J=8.1 Hz), 115.7 (d, J=23.3 Hz), 113.5, 112.6, 63.0, 46.3. MC m/z 402.

3-(Benzylamino)-2-(4-fluorophenoxy)-5-[(2,2,2-trifluoroethylamino)methyl]benzenesulfonamide (TEPS 88)

1.5 mmol (604 mg) TEPS 87 was dissolved in 5 ml of thionyl chloride and heated at 80°C for 3 hours. The thionyl chloride was evaporated under reduced pressure. The product was purified by column chromatography (ethyl acetate/petroleum ether, 7+3) to give 470 mg of a brown solid (74% yield). 1 mmol (420 mg) of this benzyl chloride intermediate was dissolved in 5 ml of DMF, to this solution was added 2 mmol (157 μl) of 2,2,2-trifluoroethylamine and the mixture was stirred in a sealed vessel at room temperature overnight. After completion of the reaction, the progress of which was checked using thin layer chromatography, the liquid substances were evaporated under reduced pressure. This crude product was purified by column chromatography (ethyl acetate/petroleum ether, 3+7) and recrystallization from ethanol to give 86 mg of white crystals (18% yield).

1H NMR (200 MHz, MeOd) δ 7.32-7.11 (m, 6H), 7.09-6.71 (m, 5H), 4.34 (d, J=3.8 Hz, 2H) , 3.84 (d, J=26.0 Hz, 2H), 3.05 (q, J=9.8 Hz, 2H). ¹³ C NMR (50 MHz, MeOD) δ 142.0, 139.0, 137.3, 128.1, 126.7, 116.5, 116.4, 115.5, 115.4, 115.0, 114.2, 52.1, 46.4. MS m/z 483.

3-(Butylamino)-2-phenoxy-5-(2,2,2-trifluoroethylsulfanylmethyl)benzenesulfonamide (TEPS 89)

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mg of sodium hydride dispersion in mineral oil (2 mmol) was washed twice with dry THF. 3 ml of THF was added to the sodium hydride, then 1 ml of 2,2,2-trifluoroethanethiol and 1 mmol (369 mg) TEPS 76 were added and the vessel was sealed. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, it was stopped with 3 ml of water. The mixture was then extracted three times with ethyl acetate, and the combined organic layers were washed with brine and dried over Na2SO4. The organic layers were dried under reduced pressure and purified by column chromatography (ethyl acetate/petroleum ether, 4+6) and recrystallization from ethanol to give 257 mg of a white powder (57% yield).

^1H NMR (200 MHz, CDCl3) δ 7.38-7.18 (m, 3H), 7.08 (t, J=7.3 Hz, 1H), 6.99-6.75 (m, 3H ), 4.89 (s, 2H), 3.83 (s, 2H), 3.16-2.82 (m, 4H), 1.59-1.28 (m, 2H), 1.31- 1.03 (m, 2H), 0.82 (t, J=7.1 Hz, 3H). ¹³ C NMR (50 MHz, CDCl3) δ 156.2, 142.5, 136.1, 136.0, 135.1, 130.2, 126.1 (d, J=276.9 Hz), 123, 6, 116.3, 115.4, 43.2, 36.8, 33.4 (q, J=32.6 Hz), 31.2, 31.1, 19.9, 13.8. MC m/z 448.

3-(Butylamino)-2-phenoxy-5-(2,2,2-trifluoroethylsulfinylmethyl)benzenesulfonamide (TEPS 90)

While stirring, a solution of 0.35 mmol oxon (53 mg) in 2 ml of water was added to a solution of 0.5 mmol TEPS 89 (224 mg) in 5 ml of acetonitrile. The reaction mixture was stirred at room temperature for 2 days until the mixture no longer contained TEPS 89 by TLC, and then poured into 10 ml of ice water. The solid was filtered and recrystallized from ethanol to give 162 mg of a white powder (70% yield).

^1H NMR (200 MHz, DMSO) δ 7.39-7.12 (m, 4H), 7.11-6.75 (m, 5H), 4.91 (t, J=5.8 Hz, 1H ), 4.28 (q, J=12.8 Hz, 2H), 4.14-3.75 (m, 2H), 3.03 (q, J=6.5 Hz, 2H), 1.50 -1.22 (m, 2H), 1.24-0.95 (m, 2H), 0.77 (t, J=7.2 Hz, 3H). ¹³ C NMR (50 MHz, DMSO) δ 156.6, 142.3, 137.4, 136.2, 129.0, 128.3, 127.6, 122.0, 116.5, 115.5, 115.5, 57.4, 53.3 (d, J=26.9 Hz), 42.1, 30.2, 19.3, 13.6. MC m/z 464.

3-(2,2,2-Trifluoroethylsulfanylmethyl)benzenesulfonamide (TEPS 91)

mg of sodium hydride dispersion in mineral oil (2 mmol) was washed twice with dry THF. 3 ml of THF was added to the sodium hydride, then 1 ml of 2,2,2-trifluoroethanethiol and 1 mmol (250 mg) of 3bromomethylbenzenesulfonamide were added. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, it was stopped with 3 ml of water. The mixture was then extracted three times with ethyl acetate, and the combined organic layers were washed with brine and dried over Na ₂ SO ₄ . The organic layers were dried under reduced pressure to obtain a white crude product. The crude product was further purified by column chromatography (ethyl acetate/petroleum ether, 1+1) and recrystallization from EtOH to give 135 mg of a white powder (61% yield).

^1H NMR (200 MHz, MeOD) δ 7.90 (s, 1H), 7.90-7.75 (m, 1H), 7.65-7.41 (m, 2H), 3.97 (s , 2H), 3.16 (q, J=10.2 Hz, 2H). ¹³ C NMR (50 MHz, MeOD) δ 145.5, 139.9, 133.8, 130.4, 127.7 (d, J=275.4 Hz), 127.6, 126.2, 37, 2, 33.85 (q, J=32.7 Hz). MS m/z 285.

3-(Butylamino)-2-phenoxy-5-(3,3,3-trifluoropropylsulfanylmethyl)benzenesulfonamide (TEPS 92)

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mg of sodium hydride dispersion in mineral oil (2 mmol) was washed twice with dry THF. 3 ml of THF was added to the sodium hydride, then 1 ml of 2,2,2-trifluoropropanethiol and 1 mmol (369 mg) TEPS 76 were added and the vessel was sealed. The reaction mixture was stirred at room temperature for 2 days. After completion of the reaction, it was stopped with 3 ml of water. The mixture was then extracted three times with ethyl acetate, and the combined organic layers were washed with brine and dried over Na ₂ SO ₄ . The organic layers were dried under reduced pressure and purified by column chromatography (ethyl acetate/petroleum ether, 4+6) and recrystallization from ethanol to give 137 mg of a white powder (30% yield).

1H NMR (200 MHz, CDO3) δ 7.44-7.18 (m, 3H), 7.08 (t, J=7.3 Hz, 1H), 6.98-6.80 (m, 3H) , 4.89 (s, 2H), 3.73 (s, 2H), 3.05 (t, J=6.9 Hz, 2H), 2.74-2.50 (m, 2H), 2, 51-2.17 (m, 2H), 1.54-1.30 (m, 2H), 1.31-1.01 (m, 2H), 0.82 (t, J=7.2 Hz, 3H). ¹³ C NMR (50 MHz, MeOD) δ 156.2, 142.4, 136.2, 135.9, 135.8, 134.3, 130.1, 126.1 (d, J=277.2 Hz ), 123.6, 117.4, 116.0, 115.3, 115.2, 43.2, 36.5, 34.6 (q, J=28.7 Hz), 31.1, 23, 8 (q, J=3.3 Hz), 19.9, 13.8. MC m/z 462.

3-(Butylamino)-5-[[2-(dimethylamino)ethylamino]methyl]-2-phenoxybenzenesulfonamide hydrochloride (TEPS 93)

mmol (740 mg) TEPS 76 was dissolved in a solution containing 5 ml DMF and 1 ml TEA (triethylamine). 2 mmol (440 μl) of 98% N,N'-dimethylethylenediamine was added to the mixture and the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was purified by column chromatography (ethyl acetate/triethylamine/EtOH, 6+3+1). The crude product was dissolved in dry THF and 1 ml of a 1.0 M solution of hydrogen chloride in diethyl ether was added. The resulting precipitate was filtered and 123 mg of a yellow powdery substance was obtained (yield 13%).

^1H NMR (200 MHz, MeOd) δ 7.42 (d, J=2.0 Hz, 1H), 7.37-7.18 (m, 3H), 7.05 (t, J=7.3 Hz, 1H), 6.91 (d, J=7.6 Hz, 2H), 4.40-4.23 (m, 2H), 3.65 (d, J=10.5 Hz, 4H), 3.15 (t, J=6.8 Hz, 2H), 3.00 (s, 6H), 1.57-1.27 (m, 2H), 1.30-1.00 (m, 2H) , 0.81 (t, J=7.2 Hz, 3H). ¹³ C NMR (50 MHz, MeOD) δ 156.6, 142.7, 137.9, 137.4, 129.2, 128.7, 122.6, 116.7, 115.8, 115.2, 52.9, 51.2, 42.7, 42.6, 41.9, 30.5, 19.5, 12.6. MC IED is not possible.

5-(1,3-Benzothiazolyl-2-sulfanylmethyl)-3-(butylamino)-2-phenoxybenzenesulfonamide (TEPS 93)

mmol (368 mg) TEPS 76 was dissolved in a solution containing 3 ml DMF and 1 ml TEA. 2 mmol (338 mg) of 2-mercaptobenzothiazole was then added and the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was purified by column chromatography (ethyl acetate/petroleum ether, 3+7). The crude product was then purified by recrystallization from EtOH to give 140 mg of white crystals (28% yield).

1H NMR (200 MHz, DMSO) δ 8.01 (d, J=7.8 Hz, 1H), 7.89 (d, J=7.8 Hz, 1H), 7.54-7.32 (m , 2H), 7.30-7.07 (m, 6H), 6.97 (t, J=7.3 Hz, 1H), 6.88-6.62 (m, 2H), 4.83 ( t, J=5.9 Hz, 1H), 4.67 (s, 2H), 3.10-2.79 (m, 2H), 1.411.15 (m, 2H), 1.13-0.87 (m, 2H), 0.68 (t, J=7.1 Hz, 3H). ¹³ C NMR (50 MHz, DMSO) δ 166.5, 157.1, 153.0, 142.6, 137.8, 136.0, 136.0, 135.2, 135.0, 129.5, 126.9, 125.1, 122.4, 122.3, 121.6, 115.9, 114.7, 42.5, 36.9, 30.7,

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19.7, 14.0. MS m/z 499.

3-(Butylamino)-2-phenoxy-5-(2-pyridylsulfanylmethyl)benzenesulfonamide (TEPS 95)

To 3 ml of DMF and 2 ml of triethylamine were added 1 mmol (369 mg) TEPS 76 and 1 mmol (114 mg) 2mercaptopyridine and stirred at room temperature overnight. After completion of the reaction, DMF was evaporated and water was added. The mixture was extracted three times with ethyl acetate, washed three times with water and once with brine. The mixture was purified by column chromatography (ethyl acetate/petroleum ether, 4+6). The product was then recrystallized from 70% isopropanol to give 221 mg of light yellow crystals.

^1H NMR (200 MHz, chloroform-d) δ 8.46 (d, J=3.4 Hz, 1H), 7.59-7.41 (m, 1H), 7.39-7.13 (m , 4H), 7.136.83 (m, 5H), 4.87 (s, 2H), 4.43 (s, 2H), 3.00 (t, J=6.9 Hz, 2H), 1.45 -1.25 (m, 2H), 1.24-1.03 (m, 2H), 0.80 (t, J=7.2 Hz, 3H). ¹³ C NMR (50 MHz, chloroform-d) δ 158.1, 156.2, 149.4, 142.1, 136.8, 136.2, 135.5, 129.9, 123.3, 122, 3, 119.9, 116.5, 115.4, 115.2, 100.0, 100.0, 43.0, 34.0, 31.0, 19.8, 13.7. MS m/z 444.

3-(Butylamino)-5-(1H-imidazol-2-ylsulfanylmethyl)-2-phenoxybenzenesulfonamide (TEPS 96)

mmol (369 mg) 3-(butylamino)-5-(chloromethyl)-2-phenoxybenzenesulfonamide (TEPS 76) was dissolved in 3 ml DMF and 1 ml TEA. To this mixture was added 2 mmol (205 mg) of 2-mercaptoimidazole and the mixture was stirred at room temperature overnight. After completion of the reaction, which was verified by thin layer chromatography, the mixture was purified by column chromatography using a mobile phase containing ethyl acetate and petroleum ether (9+1). The product-containing fractions were combined and the mobile phase was evaporated under reduced pressure to give 308 mg of a whitish-brown powder (71% yield).

1H NMR (200 MHz, MeOd) δ 7.35-7.17 (m, 2H), 7.14-6.93 (m, 4H), 6.93-6.77 (m, 2H), 6, 62-6.59 (m, 1H), 4.14 (s, 1H), 2.94 (t, J=6.7 Hz, 2H), 1.46-1.22 (m, 2H), 1 .23-0.98 (m, 2H), 0.80 (t, J=7.1 Hz, 3H). ¹³ C NMR (50 MHz, MeOD) δ 156.8, 142.2, 138.4, 136.5, 136.0, 135.8, 129.1, 122.3, 115.3, 115.1, 114.4, 42.3, 39.1, 30.6, 19.5, 12.6. MC m/z 432.

3-(Butylamino)-2-phenoxy-5-[(2-pyridylamino)methyl]benzenesulfonamide (TEPS 97)

mmol (348 mg) of 3-(butylamino)-5-formyl-2-phenoxybenzenesulfonamide was dissolved in 10 ml of 1,2dichloroethane and 1 mmol (29 μl) of acetic acid and 1.2 mmol of 2-aminopyridine were added. After stirring the mixture for 2 hours, 1.5 mmol of triacetoxyborohydride (NaBH(OAc) ₃ ) was added and the mixture was stirred overnight. The product was diluted with 40 ml dichloromethane and 10 ml saturated NaHCO ₃ solution. After washing with brine, the mixture was evaporated under reduced pressure. Purification was carried out by column chromatography (ethyl acetate/petroleum ether, 6+4) and recrystallization from 70% EtOH to give 130 mg of white crystals (30% yield).

1H NMR (200 MHz, DMSO) δ 8.06-7.88 (m, 1H), 7.51-6.30 (m, 12H), 4.76-4.61 (m, 1H), 4, 55-4.41 (m, 2H), 3.13-2.87 (m, 2H), 1.40-1.20 (m, 2H), 1.19-0.97 (m, 2H), 0.74 (t, J=7.0 Hz, 3H). ¹³ C NMR (50 MHz, DMSO) δ 159.0, 157.3, 147.9, 142.4, 138.9, 137.3, 137.3, 135.2, 129.5, 122.4, 115.9, 114.2, 112.8, 112.4, 108.6, 44.4, 42.6, 30.8, 19.8, 14.1. MS m/z 427.

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3-(Butylamino)-N-(4-fluorophenyl)-4-phenoxy-5-sulfamoylbenzamide (TEPS 98)

mmol (364 mg) of bumetanide was dissolved in 5 ml of THF, then 1.2 mmol (194 mg) of 1,1carbonyldiimidazole was added and the mixture was stirred for 3 hours. Then 2 mmol (222 mg) of 4fluoroaniline was added and the mixture was stirred at room temperature for nights. After completion of the reaction, 20 ml of 5% sodium bicarbonate solution was added and the reaction mixture was extracted with ethyl acetate three times. The collected organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by recrystallization from EtOH to give 200 mg of a yellow powder (44% yield).

^1H NMR (200 MHz, DMSO) δ 10.40 (s, 1H), 7.86-7.69 (m, 2H), 7.68 (d, J=1.9 Hz, 1H), 7, 45 (d, J=1.9 Hz, 1H), 7.41-7.10 (m, 6H), 7.02 (t, J=7.3 Hz, 1H), 6.96-6.77 (m, 2H), 4.97 (t, J=5.6 Hz, 1H), 3.12 (q, J=6.5 Hz, 2H), 1.49-1.28 (m, 2H) , 1.23-0.97 (m, 2H), 0.78 (t, J=7.2 Hz, 3H). ¹³ C NMR (50 MHz, DMSO) δ 164.7, 158.41 (d, J=240.4 Hz) 156.4, 142.2, 138.5, 137.5, 135.32 (d, J =2.5 Hz), 132.2, 129.1, 122.54 (d, J=7.9 Hz), 122.2, 115.6, 115.19 (d, J=22.2 Hz) , 113.6, 42.1, 30.3, 19.3, 13.6. MC m/z 347.

3-(Butylamino)-5-[(4-fluoroanilino)methyl]-2-phenoxybenzenesulfonamide (TEPS 99)

0.33 mmol (150 mg) TEPS 98 was dissolved in 20 ml of tetrahydrofuran. 1.32 mmol (4 eq., 100 mg) of borane dimethyl sulfide complex was added. The mixture was stirred at reflux at 86°C overnight. Once the mixture no longer contained any starting material by TLC, the mixture was cooled to room temperature and the reaction was quenched with 20 mL of halved aqueous NaHCO ₃ solution. The mixture was then extracted three times with ethyl acetate, washed with saturated sodium chloride solution and dried over sodium sulfate. The solvent was removed under reduced pressure and the crude product was purified by recrystallization from EtOH. Yield: 56 mg (38%) 1H NMR (200 MHz, DMSO) δ 7.25 (t, J=7.7 Hz, 2H), 7.15-7.04 (m, 3H), 7.06- 6.76 (m, 6H), 6.67-6.50 (m, 2H), 6.24 (t, J=6.0 Hz, 1H), 4.72 (t, J=5.7 Hz , 1H), 4.24 (d, J=5.9 Hz, 2H), 2.99 (q, J=6.2 Hz, 2H), 1.40-1.18 (m, 2H), 1 .21-0.93 (m, 2H), 0.74 (t, J=7.1 Hz, 3H). ¹³ C NMR (50 MHz, DMSO) δ 156.8, 154.32 (d, J=241.5 Hz), 145.3 145.29 (d, J=1.4 Hz), 137.9, 137 ,1, 134.9, 129.0, 121.8, 115.5, 115.20 (d, J=21.9 Hz), 113.5, 112.98 (d, J=7.3 Hz) , 112.4, 46.8, 42.1, 39.5, 30.3, 19.3, 13.6. MC m/z 333.

N-(2,7a-dihydro-1H-benzimidazol-2-yl)-3-(butylamino)-4-phenoxy-5-sulfamoylbenzamide (TEPS 100)

mmol (728 mg) of bumetanide was dissolved in 5 ml of dry tetrahydrofuran. 2.4 mmol (388 mg) of 1,1-carbonyldiimidazole was added and the mixture was stirred for 2 hours. Once the mixture no longer contained bumetanide by thin layer chromatography, 4 mmol (532 mg) of trifluoropropan-1-amine and the mixture was stirred at room temperature overnight. After completion of the reaction, 20 ml of 5% NaHCO3 solution was added and the mixture was extracted with ethyl acetate three times. The collected organic phase was washed with brine and dried over Na ₂ SO ₄ . Then the solvent was removed at

- 122 043772 low pressure. The crude product was purified by recrystallization from MeOH. Yield: 413 mg (43%).

1H NMR (200 MHz, DMSO) δ 12.38 (brs, 1H), 7.95 (d, J=1.7 Hz, 1H), 7.74 (d, J=1.7 Hz, 1H), 7.50-7.40 (m, 2H), 7.35-7.22 (m, 4H), 7.20-7.13 (m, 2H), 7.01 (t, J=7.3 Hz, 1H), 6.88 (d, J=7.8 Hz, 2H), 4.90 (t, J=5.5 Hz, 1H), 3.13 (q, J=6.4 Hz, 2H), 1.41 (p, J=6.9 Hz, 2H), 1.25-1.04 (m, 2H), 0.79 (t, J=7.2 Hz, 3H). ¹³ C NMR (50 MHz, DMSO) δ 156.5, 142.1, 138.8, 137.4, 129.2, 122.3, 121.9, 115.6, 114.8, 114.3, 42.2, 30.4, 19.4, 13.7. MS m/z 481.

3-(Butylamino)-4-phenoxy-5-sulfamoyl-N-(3,3,3-trifluoropropyl)benzamide (TEPS 101)

mmol (364 mg) of bumetanide was dissolved in 5 ml of dry tetrahydrofuran. 1.2 mmol (194 mg) of 1,1-carbonyldiimidazole was added and the mixture was stirred for 3 hours. After thin layer chromatography showed that all bumetanide had reacted, 2 mmol (300 mg) of trifluoropropan-1-amine and the mixture were added stirred at room temperature overnight. After completion of the reaction, 20 ml of 5% NaHCO ₃ solution was added and the mixture was extracted with ethyl acetate three times. The collected organic phase was washed with brine and dried over Na ₂ SO ₄ . The solvent was then removed under reduced pressure. The crude product was purified by recrystallization from EtOH. Yield: 220 mg (47%).

1H NMR (200 MHz, MeOd) δ 7.74-7.61 (m, 2H), 7.40 (d, J=2.0 Hz, 1H), 7.29 (t, J=7.9 Hz , 2H), 7.10-7.03 (m, 2H), 6.96-6.85 (m, 2H), 3.64 (t, J=7.0 Hz, 2H), 3.12 ( t, J=6.8 Hz, 2H), 2.70-2.37 (m, 2H), 1.42 (p, J=6.8 Hz, 2H), 1.24-1.05 (m , 2H), 0.81 (t, 3H). ¹³ C NMR (50 MHz, MeOD) δ 169.1, 157.8, 144.0, 140.6, 138.4, 132.9, 130.7, 127.96 (d, J=276.2 Hz ), 124.0, 116.6, 114.9, 114.5, 43.7, 34.60 (q, J=4.0 Hz), 34.03 (q, J=27.8 Hz), 32.0, 20.8, 14.0. MC m/z 459.

3-(Butylamino)-2-phenoxy-5-[(3,3,3-trifluoropropylamino)methyl]benzenesulfonamide (TEPS 102)

1.56 mmol (363 mg) TEPS 101 was dissolved in 20 ml THF and 5.8 mmol (0.556 ml) borane complex with dimethyl sulfide was added. The reaction mixture was then stirred at 86°C overnight. Once the mixture no longer contained starting material by TLC, the mixture was cooled to room temperature and then the reaction was quenched with 20 ml of halved aqueous NaHCO ₃ solution. The mixture was extracted three times with 25 ml of ethyl acetate, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the crude product was purified by column chromatography (ethyl acetate/petroleum ether and TEA, 1:1+20 ml TEA) and recrystallized from 70% EtOH to give 178 mg of material (yield: 26%).

1H NMR (200 MHz, CDCl3) δ 7.38-7.16 (m, 3H), 7.06 (t, J=7.3 Hz, 1H), 6.91 (d, J=7.3 Hz , 3H), 4.90 (s, 1H), 3.79 (s, 2H), 3.06 (q, J=6.7 Hz, 2H), 2.91 (t, J=7.1 Hz , 2H), 2.34 (qt, J=10.9, 7.1 Hz, 2H), 1.41 (p, J=6.8 Hz, 2H), 1.17 (dq, J=13, 7, 6.9 Hz, 2H), 0.82 (t, J=7.2 Hz, 3H). ¹³ C NMR (50 MHz, CDCl ₃ ) δ 156.4, 142.4, 138.2, 135.7, 135.6, 133.0, 130.1, 126.79 (d, J=276.8 Hz), 123.5, 120.5, 115.5, 115.3, 114.3, 53.4, 43.2, 42.23 (q, J=3.3 Hz), 34.41 (q , J=27.7 Hz), 31.2, 19.9, 13.8. MC m/z 445.

3-(Butylamino)-N-(2-morpholinoethyl)-4-phenoxy-5-sulfamoylbenzamide (TEPS 103)

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To a solution of 1 mmol (364 mg) of bumetanide in 5 ml of dry THF, 1.2 mmol (194 mg) of 1,1carbonyldiimidazole (CDI) was added and the mixture was stirred for 3 hours. After TLC showed that all of the bumetanide had reacted, 2 mmol (0.262 ml) 4-(2-aminoethyl)morpholine was added and the mixture was stirred at room temperature overnight. After completion of the reaction, 20 ml of 5% NaHCO ₃ solution was added and the mixture was extracted three times with 25 ml of ethyl acetate. The organic phase was washed with brine and then dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure. The crude product was purified by flash column chromatography (TEA/ethyl acetate, 1:9). The resulting substance was dried in vacuum to obtain 385 mg of a white powdery substance (yield 80%).

^1H NMR (200 MHz, MeOd) δ 7.69 (d, J=2.0 Hz, 1H), 7.42 (d, J=2.0 Hz, 1H), 7.29 (t, J= 7.9 Hz, 2H), 7.097.00 (m, 2H), 6.96-6.87 (m, 2H), 3.76-3.67 (m, 4H), 3.56 (t, J =6.6 Hz, 2H), 3.13 (t, J=6.8 Hz, 2H), 2.67-2.50 (m, 6H), 1.43 (p, J=6.9 Hz , 2H), 1.28-1.09 (m, 2H), 0.82 (t, J=7.2 Hz, 3H). ¹³ C NMR (50 MHz, MeOD) δ 169.0, 157.8, 143.9, 140.4, 138.3, 130.6, 124.0, 116.6, 115.0, 114.5, 67.7, 58.6, 54.7, 43.7, 37.8, 32.0, 20.8, 14.0. MC m/z 476.

3-(Butylamino)-4-phenoxy-N-[2-(1-piperidyl)ethyl]-5-sulfamoylbenzamide (TEPS 104)

To a solution of 1 mmol (364 mg) of bumetanide in 5 ml of dry THF, 1.2 mmol (194 mg) of 1,1carbonyldiimidazole (CDI) was added and the mixture was stirred for 2 hours. After TLC showed that all of the bumetanide had reacted, 2 mmol (0.285 ml) 4-(2-aminoethyl)piperidine was added and the mixture was stirred at room temperature overnight. After completion of the reaction, 20 ml of 5% NaHCO3 solution was added and the mixture was extracted three times with 25 ml of ethyl acetate. The organic phase was washed with brine and then dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure. The crude product was purified by recrystallization from 70% EtOH to give 302 mg (yield: 67%).

1H NMR (200 MHz, MeOd) δ 7.69 (d, J=2.0 Hz, 1H), 7.42 (d, J=2.0 Hz, 1H), 7.29 (t, J=7 .9 Hz, 2H), 7.05 (t, J=7.3 Hz, 1H), 6.97-6.84 (m, 2H), 3.56 (t, J=6.8 Hz, 2H ), 3.13 (t, J=6.8 Hz, 2H), 2.67-2.45 (m, 6H), 1.73-1.33 (m, 8H), 1.26-1, 05 (m, 2H), 0.82 (t, J=7.2 Hz, 3H). ¹³ C NMR (50 MHz, MeOD) δ 169.0, 157.8, 143.9, 140.5, 138.3, 133.3, 130.6, 124.0, 116.6, 115.0, 114.5, 58.9, 55.5, 43.7, 38.0, 32.0, 26.6, 25.1, 20.9, 14.0. MC m/z 474.

3-(Butylamino)-2-phenoxy-5-(3,3,3-trifluoropropoxymethyl)benzenesulfonamide (TEPS 105)

In a three-neck round-bottom flask, 4 mmol (168 mg) of a dispersion of sodium hydride in mineral oil (60%) was washed twice with dry THF. 5 ml THF, 4.5 mmol (0.4 ml) 3,3,3-trifluoro-1propanol and 1 mmol (368 mg) TEPS 76 were then added. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, it was stopped with 10 ml of water. The mixture was then extracted three times with ethyl acetate, the combined organic layers were washed with brine, dried over Na2SO4 and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (ethyl acetate/petroleum ether, 4+6) and recrystallization from toluene to give 122 mg of a white powder (27% yield).

1H NMR (200 MHz, MeOd) δ 7.37-7.15 (m, 3H), 7.10-6.81 (m, 4H), 4.55 (s, 2H), 3.76 (t, J=6.3 Hz, 2H),

3.07 (t, J=6.8 Hz, 2H), 2.66-2.37 (m, 2H), 1.53-1.27 (m, 2H), 1.30-1.02 ( m, 2H), 0.81 (t, J=7.2 Hz, 3H). ¹³ C NMR (50 MHz, MeOD) δ 158.2, 143.8, 137.8, 137.5, 130.5, 123.7, 116.5, 115.4, 114.5, 73.5, 64.32 (q, J=3.6 Hz), 43.8, 35.04 (q, J=28.3 Hz), 32.1, 20.9, 14.0. MC m/z 446.

3-[(2,2,2-trifluoroethylamino)methyl]benzenesulfonamide

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mmol (1.41 g) 2,2,2-trifluoro-N-[(4-sulfamoylphenyl)methyl]acetamide (Augurusa, A., et al., 2016) was dissolved in 10 ml of dry tetrahydrofuran (THF). The mixture was cooled to 0-4°C and purged with argon. 25 mmol (12.5 ml) LiAlH ₄ (2.0 M solution in THF) was carefully added in three portions every 30 minutes, then the solution was heated at 60°C for 3 hours. The mixture was stirred at room temperature overnight. The mixture was cooled again, cooled to 0-4°C and the reaction was stopped with a 5% aqueous solution of NH ₄ Cl. Added 2 N. HCl solution until the mixture became completely clear and it was extracted twice with ethyl acetate. The aqueous phase was neutralized by adding 2 M NaOH and re-extracted twice with ethyl acetate. The second organic phase was dried over sodium sulfate and evaporated under reduced pressure. The product was then recrystallized from isopropanol. The product was obtained - 387 mg of white crystals (yield 28.9%).

Ή NMR (200 MHz, DMSO-d ₆ ) δ 7.79 (part A of the AB system, J _AB =8.3 Hz, 2H), 7.52 (part B of the AB system, J _ab =8.3 Hz, 2H ), 7.31 (s, 2H), 3.86 (d, J=5.7 Hz, 2H), 3.32-3.11 (m, 2H), 3.09-2.96 (m, 1H). ¹³ C NMR (50

MHz, DMSO-d ₆ ) δ 144.3, 142.6, 126.2 (q, J=279.3 Hz), 128.1, 125.6, 51.8, 48.7 (q, J= 30.3 Hz). MS m/z: 269 M ⁺ .

2-(2,2,2-trifluoroethyl)-3,4-dihydro-1H-isoquinoline-7-sulfonamide

2-(2,2,2-trifluoroethyl)-3,4-dihydro-1H-isoquinoline-6-sulfonamide .νη ₂

Example 2. Inhibitory activity of the compounds proposed in the present invention in relation to NKCC 1.

The compounds of formula (I) proposed in the present invention are inhibitors of Na ⁺ -K ⁺ -2Cl- (NKCC) cotransporters, in particular NKCC1. The inhibitory activity of the compounds of the present invention on NKCC1 can be determined, for example, using the following NKCCIA activity assay.

To activate NKCC1A, prior to incorporation experiments, oocytes expressing hNKCC1A (Lykke, K., et al. 2016) or uninjected control oocytes were preincubated in a K-free solution at room temperature for 30 min. To study K influx, oocytes were treated with an isosmotic assay solution in which KCl was used instead of choline chloride and ⁸⁶ Rb ⁺ was added as an indicator for K ⁺ . Bumetanide (positive control), a compound of formula (I) of the present invention (drug) or a control diluent (negative control) was added to the test solution. Incorporation experiments were then performed with gentle stirring at room temperature for 5 min. The influx experiments were stopped and the radioisotope content was determined by liquid scintillation β-particle counting using an Opti-Fluor scintillation mixture and a liquid scintillation analyzer. hNKCC1A-mediated K ⁺ incorporation was then determined as ([flux _{of NKCC1-expressing oocytes} in the presence of x μM drug]-[flux _{of uninjected oocytes} in the presence of x μM drug]), to correct for endogenous NKCC activity. The reduction in hNKCCIA-mediated K ⁺ incorporation observed with the test compound indicates that the compound inhibits NKCC1. When examining the representative compounds of formula (I) described in the examples, they are shown to have NKCC1 inhibitory activity through this assay.

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Publications

Alessi, D., Zhang, J., Khanna, A., Hochdorfer, T., Shang, Y., & Kahle, K. T. (2014). The WNKSPAK/ OSR1 pathway: Master regulator of cation-chloride cotransporters. Science Signaling(334).

Ares G., Caceres P., Ortiz P. (2011) Molecular regulation of NKCC2 in the thick ascending limb. Am J Physiol Renal Physiol 301:F1143–F1159.

Augurusa, A., Mehta, M., Perez, M., Zhu, J., Stephan, D. (2016) Catalytic Reduction of Amides by Electrophilic Phosphonium Cations via FLP Hydrosilylation. The Royal Society of Chemistry 52: 12195–12198.

Cho Y., et al. (2011) Drug Repositioning and Pharmacophore Identification in the Discovery of Hookworm MIF Inhibitors. Chemistry & Biology 18, 1089-1101.

Consiglio, Giovanni; Frenna, Vincenzo; Guernelli, Susanna; Macaluso, Gabriella. (2002). Analysis of substituent effects in the reactions of some 3-nitro-5-Xthiophenes with aniline in benzene. A new interpretation of the 'element effect'. ARKIVOC (Gainesville, FL, United States), Issue 11, Pages 104-117.

Deidda, G., et al. (2015) Reversing excitatory GAB AAR signaling restores synaptic plasticity and memory in a mouse model of Down syndrome. Nature Medicine 21, 318-326.

Deng Y., et al. (2016) Progress in Drug Treatment of Cerebral Edema. MiniReviews in Medicinal Chemistry 16: 917-925.

Denys D., de Geus F. (2005) Predictors of pharmacotherapy response in anxiety disorders. Curr Psychiatry Rep 7:252–257.

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Doolittle J., et al. (2016) Hyperhidrosis: an update on prevalence and severity in the United States. Archives of Dermatological Research 1-7).

Dzhala, V. I., Talos, D. M., Sdrulla, D. A., Brumback, A. C., Mathews, G. C., Benke, T. A., & Staley, K. J. (November 2005). NKCC1 transporter facilitates seizures in the developing brain. Nature Medicine(l 1), pp. 1205-1213.

Hadjikhani N., et al. (2015) Improving emotional face perception in autism with diuretic bumetanide: A proof-of-concept behavioral and functional brain imaging pilot study. Autism Vol. 19(2) 149-157).

Hauck, Stefanie; Hiesinger, Kerstin; Khageh Hosseini, Sabrina; Achenbach, Janosch; Biond, Ricardo M.; Proschak, Ewgenij; Zoernig, Martin; Odadzic, Dalibor. (2016). Pyrazolo[l,-5a]-pyrimidines as a new class of FUSE binding protein 1 (FUBP1) inhibitors. Bioorganic & Medicinal Chemistry Volume 24, Issue 22, Pages 5717-5729.

Hirschfeld, R., 2003 Long-term side effects of SSRIs: sexual dysfunction and weight gain. The Journal of Clinical Psychiatry 64 Suppl 18: 20–24.

Huang Y., et al. (2016) Acute spinal cord injury (SCI) transforms how GABA affects nociceptive sensitization. Experimental Neurology 285 82-95).

Kahle, K. T., & Staley, K. J. (2008, September). The bumetanide-sensitive NaK-2C1 cotransporter NKCC1 as a potential target of a novel mechanism-based treatment strategy for neonatal seizures. Neurosurg Focus, pp. 1-7.

Kunzer, Aaron R.; Elmore, Steven W.; Hexamer, Laura; Park, Cheol-Min; Sowers, Andrew J.; Sullivan, Gerard M.; Wang, Gary T.; Wang, Xilu; Wendt, Michael D. (2010). Preparation of heterocyclic apoptosis-inducing agents for treatment of cancer and immune disorders. PCTInt. ApplAIS^., Patent 2010, WO 2010083442.

Krystal AD, Sutherland J, Hochman DW (2012) Loop Diuretics Have Anxiolytic Effects in Rat Models of Conditioned Anxiety. PLoS ONE 7(4): e35417).

Lepine, J., (2002) The epidemiology of anxiety disorders: prevalence and societal costs. The Journal of Clinical Psychiatry 63 Suppl 14: 4-8.

Louie JC et al., Physiol Rep. 2016, 4(22). pii: el3024).

Lykke, K., et al. (2016) The search for NKCC1-selective drugs for the treatment of epilepsy: Structure-function relationship of bumetanide and various bumetanide derivatives in inhibiting the human cation-chloride cotransporter NKCC1 A. Epilepsy & Behavior, 59:42-49.

- 127 043772

Maa, E. H., Kahle, K. T., Walcott, W. P., Spitz, M. C., & Staley, K. J. (2011). Diuretics and epilepsy: Will the past and present meet? Epilepsy(52), pp. 1559-1669.

Markadieu, N., Delpire, E. (2014) Physiology and pathophysiology of SLC12A1/2 transporters Pflugers Arch-Eur J Physiol 466:91–105.

Merner, N.D., et al. (2016) Gain-of-function missense variant in SLC12A2, encoding the bumetanidesensitive NKCC1 cotransporter, identified in human schizophrenia. Journal of Psychiatric Research 77 22-26.

Merner, N.D., et al. (2015) Regulatory domain or CPG site variation in SLC12A5, encoding the chloride transporter KCC2, in human autism and schizophrenia. Frontiers in Cellular Neuroscience 9, 386.

Moni, L.; Banfi, L.; Basso, A.; Bozzano, A.; Spallarossa, M.; Wessjohann, L.; Riva R. (2016). Molecules, Volume 21, Issue 9, Pages 1153/1-1153/9.

Munoz, A., DeFelipe, J., & Alvarez-Leefmans, F. J. (2007). Cation-Chloride Cotransporters and GABAergic Innervation in the Human Epileptic Hippocampus. Epilepsy(48), pp. 663-673.

O'Brien, O. G., et al. (2005) Treatment of edema. American Family Physician 71, 2111-2117.

Owens, D. F., & Kriegstein, A. R. (September 2002). Is there more to GABA than synaptic inhibition. Nature Reviews Neuroscience(3), pp. 715-727.

Park, Chan Hee; Lee, Sang Hwi; Im, Junhwan; Lee, Soon Ok; Kim, Hoe Moon; Moon, Sung Hyun; Kim, Seunghee; Kim, Jongmin; Ko, Kwang Seok; Choi, Bu Young; Kim, Byungho (2014). Heterocyclic derivatives as STAT3 protein inhibitors and their preparation. PCTInt. Appl. 293pp., Patent 2014. WO 2014196793.

Payne, J. A., Rivera, C., Voipio, J., & Kaila, K. (April 2003). Cation-chloride co-transporters in neuronal communication, development and trauma. Trends in Neurosciences(26), pp. 199-206.

Peti-Peterdi J., Harris R. (2010) Macula densa sensing and signaling mechanisms of renin release. J Am Soc Nephrol 21:1093–1096.

Tyzio R. et al. (2014) Oxytocin-Mediated GABA Inhibition During Delivery Attenuates Autism Pathogenesis in Rodent Offspring Science 343 (6171), 675-679).

Xu W., et al. (2016) Chloride Co-transporter NKCC1 Inhibitor Bumetanide Enhances Neurogenesis and Behavioral Recovery in Rats After Experimental Stroke. Mol Neurobiol DOI 10.1007/sl2035-016-9819-0).

Yang, Jing; Sun, Hao; Zhao, Jing (2015). Preparation of piperazine derivatives as antitumor agents. Faming Zhuanli Shenqing 14pp. Patent 2015, CN 104926804.

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Claims (8)

CLAIM 1. A compound of any of the following formulas or a pharmaceutically acceptable salt thereof: - 129 043772 - 130 043772 - 131 043772 - 132 043772 - 133 043772 - 134 043772 2. Use of a compound according to claim 1 as a medicament for the treatment or prevention of diseases/disorders involving Na-K ⁺ -2C1' cotransporters (NKCC). 3. A pharmaceutical composition containing a compound according to claim 1 and a pharmaceutically acceptable excipient. 4. The use of a pharmaceutical composition containing a compound according to claim 1 and a pharmaceutically acceptable excipient for the treatment or prevention of a disease or disorder selected from the group consisting of anxiety disorder, autism spectrum disorder, autism, Asperger's syndrome, childhood disintegrative disorder, pervasive developmental disorder as a component of autism spectrum disorder, traumatic brain injury, spinal cord injury, peripheral nerve damage, stroke, Alzheimer's disease, schizophrenia, asthma, edema, Down syndrome, dementia in patients suffering from Down syndrome, glaucoma. 5. Use of a compound according to claim 1 for the preparation of a medicinal product for the treatment or prevention of a disease or disorder selected from the group consisting of anxiety disorder, autism spectrum disorder, autism, Asperger's syndrome, childhood disintegrative disorder, pervasive developmental disorder as a component of autism spectrum disorder, traumatic brain injury, spinal cord injury, peripheral nerve injury, stroke, Alzheimer's disease, schizophrenia, asthma, edema, Down syndrome, dementia in patients with Down syndrome, glaucoma. 6. Use according to claim 4 or 5, wherein the disease or disorder is primary open-angle glaucoma or closed-angle glaucoma. 7. Use of a compound according to claim 1 in vitro as an NKCC inhibitor. 8. A method for inhibiting NKCC in vitro, comprising using a compound according to claim 1. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2 - 135 -