Bumetanide Derivatives for Treating Hyperhidrosis

Abstract

The present invention is + -K + -2Cl - The present invention relates to bumetanide derivatives of formula (I) and pharmaceutical compositions containing said compounds for use in the treatment or prevention of diseases / disorders involving the NKCC (NK receptor cotransporter), in particular for use in the treatment or prevention of hyperhidrosis. [Formula 1]

Description

[Technical Field]

[0001] The present invention is + -K + -2Cl - The present invention relates to bumetanide derivatives of formula (I) and pharmaceutical compositions containing said compounds for use in the treatment or prevention of diseases / disorders involving the NKCC (NK receptor cotransporter), in particular for use in the treatment or prevention of hyperhidrosis. [Background technology]

[0002] [Na + -K + -Cl - cotransporter] Intracellular chloride concentration ([Cl - ] i ) are primarily regulated by chloride-cation symporters (CCCs) of the SLC12 gene family (Maa et al., 2011). These transporters are among the most important ion transporters in multicellular organisms and are crucial for survival (Alessi et al., 2014). + -K + -2Cl - The Cl transporter (NKCC) - transports K into the cell + -Cl - KCCs (K+ cotransporters) transport Cl out of the cell (Munoz, DeFelipe, & Alvarez-Leefmans, 2007). These CCCs are integral membrane proteins that utilize the energetically favorable transmembrane gradient of potassium and sodium ions to transport Cl across the membrane. - These gradients are ouabain-sensitive Na + -K + This is established by primary active transport of Cl-ATPase (Alessi et al., 2014). - Transport is electroneutral, so essentially no charge transfer across the membrane is involved (Payne et al., 2003). NKCC1 and NKCC2 utilize sodium influx into the cell to transport Cl above equilibrium levels.- KCC1, KCC2, KCC3, and KCC4 utilize the potassium gradient to transport Cl - transports Cl out of the cell - NKCC1 is widely distributed throughout the body and is expressed in neurons, glial cells, the choroid plexus, and vascular endothelium. NKCC2, on the other hand, is primarily expressed in the kidney (Maa et al., 2011). NKCC1 and NKCC2 share 60% homology at the protein level (Markadieu, N., Delpire, E., 2014). The Cl function in cells - The efflux of Cl is also regulated by two serine-threonine kinases (SPAK and OSR1). These kinases phosphorylate critical N- and C-residues in NKCC and KCC. In this way, these kinases activate NKCC to regulate Cl. - At the same time, it inhibits KCC and - In mammalian central nervous system (CNS), intracellular Cl - Concentration ([Cl - ] i ) determines the strength and directionality of GABAergic neurotransmission (Kahle & Staley, 2008). In the adult central nervous system, [Cl - ] i Very low levels of GABA A Activation of the receptor causes Cl to enter the cell - This causes hyperpolarization and inhibition (Khanna, Walcott, & Kahle, 2013). On the other hand, in the immature neonatal brain, [Cl - ] i is much higher than GABA A Activation of the receptor causes Cl - This causes the neuron to depolarize and synapse to become excited (Kahle & Staley, 2008).

[0003] [NKCC2] NKCC2 is expressed on the apical membrane of epithelial cells in the ascending limb of Henle's loop and reabsorbs approximately 20-30% of the NaCl filtered by the glomerulus (Ares G., Caceres P., Ortiz P., 2011). The primary function of the ascending limb of Henle's loop is to reabsorb NaCl but not water, further diluting the forming urine in the tubular lumen. NKCC2 is also expressed in the macula densa. Macula densa cells function as NaCl sensors and can regulate glomerular filtration by vasoconstriction or vasodilation of afferent arterioles. A decrease in intratubular NaCl concentration induces afferent arteriole dilation and granule cells release renin. Conversely, an increase in intratubular NaCl concentration induces afferent arteriole constriction, thereby decreasing glomerular filtration. This mechanism is known as tubuloglomerular feedback, and NKCC2 has been shown to play a crucial role in sensing high concentrations of NaCl (Peti-Peterdi, J., Harris, R., 2010).

[0004] [NKCC1] In contrast to NKCC2, NKCC1 is widely distributed throughout the body and has many different functions. NKCC1 is highly expressed in the spiral ganglion and vestibular ganglion. In adult neurons not located in the CNS, [Cl] is expressed in the NKCC1 receptor. - ] i Regulation of [Cl] is thought to be an important function of NKCC1. However, in the immature brain, there is an increase in NKCC1 expression and [Cl] - ] iIncreased levels of NKCC1 are thought to have developmental effects (Dzhala et al., 2005). NKCC1 is also highly expressed in the salivary glands and is involved in saliva and mucin secretion. NKCC1 is also expressed in the intestine and is involved in water excretion. The most prominent defects in NKCC1 knockout mice are hearing loss and imbalance, which are due to high NKCC1 expression in the inner ear. NKCC1 plays a major role in afferent neurons. In the CNS, NKCC1 is elevated only in immature neurons and plays an important role in neuronal maturation. NKCC1 knockout mice suffer from hypotension and male infertility. Hypotension is due to decreased vascular tone (Markadieu, N., Delpire, E., 2014).

[0005] [GABA] Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the adult mammalian brain (Dzhala et al., 2005). However, GABA-mediated signaling also plays a key role throughout important developmental stages, such as cell proliferation (Owens & Kriegstein, 2002). A The receptor is a ligand-gated chloride channel that opens when GABA binds to the binding site. The receptor changes its conformation, allowing Cl to enter and leave the body depending on the equilibrium chloride concentration. - The channel passively allows bicarbonate to pass through the pore, but less efficiently than chloride (Owens & Kriegstein, 2002). - The influx of Cl causes hyperpolarization, and conversely, - The outflow of GABA causes depolarization. In the immature brain, GABA has a depolarizing effect, which excites neurons. This can lead to seizures (Dzhala et al., 2005). The depolarizing effect of GABA is extremely important for brain development. AReceptors have been shown to affect DNA synthesis, proliferation, and neuronal migration (Owens & Kriegstein, 2002). Immature neurons maintain a delicate balance between inhibition and excitation. This balance plays a crucial role in the early stages of brain development. Excessive inhibition leads to impaired neuronal growth and synaptic maturation, while excessive excitation can lead to seizures and even excitotoxic death (Maa et al., 2011).

[0006] [Anxiety disorder] Anxiety disorders affect approximately 18% of adults and are one of the most common mental disorders (Le´pine, J., 2002). Currently, anxiety disorders are treated with psychotherapy and medications, including serotonin reuptake inhibitors (SSRIs), antidepressants, monoamine oxidase inhibitors, benzodiazepines, and anticonvulsants. However, 20–40% of patients do not respond to any of these medications (Denys D., de Geus F. 2005). Another drawback of these medications is the severe side effects they can have on the CNS. Long-term use of SSRIs can cause sexual dysfunction and weight gain (Hirschfeld, R., 2003). Because the majority of patients with anxiety disorders are non-responders and current medications can cause severe side effects, there is a growing demand for new medications. Bumetanide has been shown to have anxiolytic effects in a rat model of conditioned anxiety. Rats treated with bumetanide exhibited significantly lower rates of freezing during the test period compared with rats treated with vehicle alone in a contextual fear conditioning model. Bumetanide also had significant effects in a fear-potentiated startle model (Krystal AD, Sutherland J, Hochman DW 2012).

[0007] [Autism spectrum disorder] Autism spectrum disorder (ASD) is a range of complex neurodevelopmental disorders characterized by repetitive and distinctive behavioral patterns and difficulties with social interaction and communication. ASD comprises a spectrum of distinct disorders, with autism being the most severe form. Other forms include Asperger's syndrome, childhood disintegrative disorder, and pervasive developmental disorders as a subset of ASD. One in 68 children has ASD, and boys are significantly more likely to develop it than girls. ASD occurs across all racial and ethnic groups and at all socioeconomic levels (NINDS Autism Spectrum Disorder Fact Sheet 2016). Delivery in rodents plays a crucial role, causing neuroprotective and analgesic effects in newborns. These effects are mediated by oxytocin [Cl]. - ] i This is due to a decrease in GABAergic signaling. In two rodent models of autism (VPA rats and FRX mice), this signaling is lost in CA3 pyramidal neurons. This can be restored by administration of bumetanide. As a result, GABAergic developmental signaling is restored, and the offspring of bumetanide-treated rats do not exhibit autistic phenotypes (Tyzio R. et al. 2014). Bumetanide has also been used in an open-label study involving seven patients diagnosed with autism. After 10 months of treatment, bumetanide improved emotion recognition and increased activation in brain regions involved in social and emotional perception (Hadjikhani N., et al. 2015). Because ASD cannot be cured and available treatment options are very limited, improved treatments are desperately needed.

[0008] [Hyperhidrosis] Hyperhidrosis is a medical condition that causes excessive sweating. It is classified as either primary or secondary hyperhidrosis. Primary hyperhidrosis is an idiopathic disorder caused by overactivity of the sympathetic nervous system. It affects only limited areas of the body (primarily the armpits, palms, soles, or head). One or two areas experience excessive sweating while the majority of the body remains dry. Secondary hyperhidrosis results from the side effects of certain medications or from underlying conditions such as diabetes or gout (Website of the American Academy of Dermatology (2016)). Hyperhidrosis can significantly impact daily life, including limitations on work, social interactions, physical activity, and mental and emotional well-being. Available treatments include topical aluminum chloride hexahydrate, oral anticholinergics, botulinum toxin injections, and surgery. Each of these treatments varies in effectiveness, side effects, cost, and ease of use. Hyperhidrosis affects 15.3 million people in the United States, representing 4.8% of the population. Only 51% of affected individuals consult a health care professional about their condition. 75% of surveyed individuals reported that their condition had some negative impact on their social life, well-being, or emotional or mental health. Most individuals acknowledged that excessive sweating was bothersome and led to anxiety (Doolittle J., et al. 2016). Given the negative impact reported by patients, there is a clear need for greater understanding and better treatment of hyperhidrosis. Blocking NKCC in sweat glands can treat excessive sweating. Bumetanide has been shown to be partially effective in treating hyperhidrosis (Louie, et al., 2016).

[0009] [Spinal Cord Injury] Worldwide, 250,000 to 500,000 people suffer from spinal cord injury (SCI) each year. 90% of SCI cases are caused by traumatic factors, such as road traffic accidents, falls, and violence. SCI patients have a two to five times higher risk of early death and lower rates of school attendance and economic participation. Symptoms of SCI vary depending on the severity and location of the injury, but most patients experience chronic pain (WHO (2013) Spinal Cord Injury Fact Sheet N 384). Injury and noxious stimuli can lead to long-term enhanced excitability of spinal nerves, which can result in chronic pain. Spinal cord injury (SCI) can shift GABA channel activation from hyperpolarization to depolarization. The effects of SCI involve downregulation of KCC2, which leads to [Cl] downregulation. - ] i This leads to increased [Cl] activity, which then shifts to GABAergic activation. Nerve injury is thought to shift the spinal cord to a state earlier in development where GABA has a depolarizing effect. This depolarizing effect can lead to the development of chronic pain and spasticity. Blocking NKCC reduces normal [Cl] activity. - ] i By restoring these concentrations, bumetanide can restore normal GABAergic function (Huang Y., et al. 2016). Improved treatments are greatly needed for patients with chronic pain resulting from SCI.

[0010] [Recovery after stroke] Stroke is the fifth leading cause of death in the United States, with 795,000 strokes occurring in the United States each year. Stroke occurs when blood vessels supplying blood to the brain become blocked or rupture. Stroke is also a leading cause of disability, with half of stroke survivors over the age of 65 experiencing reduced mobility (Centers for Disease Control and Prevention, (2016) Stroke Fact Sheet). Although ischemic stroke promotes neurogenesis in adults, the newborn neurons appear to have very limited long-term survival. Ischemic stroke can cause an imbalance in the expression of NKCC and KCC, which can lead to [Cl] - ]i This increases GABAergic activity, ultimately shifting it from hyperpolarization to depolarization. Long-term post-treatment with bumetanide promotes neuroblast migration into the injured striatum and improves the survival of newly generated neurons. Furthermore, behavioral assessments showed improved walking ability on the trabecular plane. Therefore, bumetanide and its derivatives may provide a favorable microenvironment for newly generated neurons, enhancing their generation and survival (Xu W., et al. 2016). Thus, this derivative can be used to enhance regeneration and reduce damage after ischemic stroke. It can also be used in other diseases (e.g., Alzheimer's disease) to improve memory.

[0011] [Schizophrenia] Schizophrenia is characterized by distortions of emotions, perceptions, thoughts, behaviors, sense of self, and language. Many patients experience auditory hallucinations and delusions. Schizophrenia affects over 21 million people worldwide and is associated with significant disability. Patients with schizophrenia are 2-2.5 times more likely to die prematurely and frequently suffer from discrimination and stigma (WHO (2016) Schizophrenia Fact Sheet). The neurophysiological basis of schizophrenia remains poorly understood. However, numerous studies suggest that dysregulation of cortical GABA transmission may be a cause of schizophrenia. Recent studies have identified a gain-of-function missense variant in SLC12A2 (encoding the bumetanide-sensitive NKCC1 cotransporter) in humans with schizophrenia. Functional experiments have shown that this NKCC1 variant is a gain-of-function variant, allowing Cl transport even under hypotonic conditions where a normal transporter would not function. - Increased KCC-dependent activity (Merner, ND, et al. 2016). Other studies have found loss-of-function KCC mutations in humans with schizophrenia (Merner, ND, et al. 2015). In both cases (NKCC gain-of-function and KCC loss-of-function), [Cl - ] iThis may lead to disruption of GABA neurotransmission. Blocking NKCC increases [Cl - ] i normalizes, and GABA signaling returns to hyperpolarization.

[0012] [Parasites] A recent study found that furosemide (another loop diuretic that blocks NKCC) was able to inhibit rAceMIF tautomerase activity at submicromolar concentrations and demonstrate positive effects in various assays (Cho Y., et al. 2011). Bumetanide and its derivatives, which are also inhibitors of NKCC, may be less potent than furosemide but may demonstrate similar effects.

[0013] [Soil-transmitted helminthic infections] More than 1.5 billion people worldwide are infected with soil-transmitted helminthic infections, accounting for 24% of the world's population. Helminthic infections are caused by three different parasitic worms: hookworms, roundworms, and whipworms. Adult worms reside in the intestines of infected individuals and lay thousands of eggs per day. These eggs arrive in the feces of infected individuals and are transmitted, for example, by eating uncooked or unpeeled vegetables. Other routes of infection include drinking water from contaminated sources and children playing in contaminated soil. Furthermore, hookworm eggs hatch in the soil, producing larvae that can penetrate the skin. These larvae are then transmitted by walking barefoot through contaminated soil. Symptoms and pathology vary greatly depending on the number of parasites present. Mild infections usually cause no symptoms. On the other hand, severe infections can cause diarrhea, abdominal pain, general weakness, impaired cognitive and physical development, and blood loss that can lead to anemia (WHO (2016) Soil-Transmitted Helmhinth Infections Fact Sheet). Recent findings suggest that furosemide (and other arylsulfonamide derivatives, also used as high-ceiling loop diuretics that block NKCC) has anthelmintic activity. Human MIF is a pro-inflammatory protein with diverse functions. The target of furosemide is AceMIF, which is similar to human MIF and appears to help parasites evade the host immune response (Cho Y., et al. 2011). Bumetanide derivatives are potent inhibitors of hookworm MIF and may have excellent anthelmintic potential. In particular, lipophilic derivatives with improved pharmacokinetic properties are promising candidates for the better treatment of helminth infections.

[0014] [Other parasites] The novel compounds may also be useful in the treatment of other helminths (e.g., tapeworms, whipworms, Guinea worms, pinworms, Toxocara, Strongyloides stercoralis, Ascaris lumbricoides, etc.). In addition to helminths, they may be used to treat diseases caused by parasitic trematodes (e.g., schistosomiasis, gnathostomiasis, paragonimiasis, fascioliasis, swamp dermatosis, etc.). Furthermore, the compounds may be used to treat diseases caused by protozoa (e.g., malaria, amebiasis, giardiasis, African sleeping sickness, toxoplasmosis, acanthamoeba keratitis, leishmaniasis, babesiosis, granulomatous amebic encephalitis, cryptosporidiosis, cyclosporosis, primary amebic meningoencephalitis, etc.). The compounds may also be used to treat ectoparasites (e.g., Sarcoptes scabiei, Pediculus humanus capitis, Phthirus pubis, Dermatophagoides larvae, Tunga penetrans, Ixodoidea ticks, etc.) The compounds may also be used against plant pests (e.g., nematodes, arthropods, ectoparasites, mollusks, etc.).

[0015] [edema] Intestinal edema results from an imbalance between capillary and intestinal space. The kidneys regulate extracellular fluid volume by regulating sodium and water excretion. Edema can result from venous obstruction, increased plasma volume, and increased capillary permeability. Treatment for edema consists of sodium restriction, diuretics, and treatment of the underlying condition. Edema can be localized to the extremities or widespread and massive throughout the body. Bumetanide is a loop diuretic that blocks NKCC, preventing sodium reuptake in the loop of Henle and allowing sodium and water excretion. Bumetanide and its derivatives can be used to treat edema (O'Brien, OG, et al. 2005).

[0016] [Cerebral edema] Cerebral edema (brain edema) can lead to increased intracranial pressure (ICH) and has serious consequences for patients in clinical settings. Effective anti-edema treatment can significantly reduce mortality in various neurological conditions. Currently, drug therapy is the basis for the management of cerebral edema. Osmotic therapy is the mainstay of drug therapy. Mannitol and hypertonic saline (HS) are the most commonly used osmotic agents. Inhibitors of the Na / H exchanger NKCC reduce the formation of cerebral edema by inhibiting excessive transport of ions and water from the blood to cerebral tissue (Deng Y., et al. 2016). Thus, NKCC inhibitors can be used to treat cerebral edema.

[0017] [Down Syndrome] Down syndrome is the most common genetic cause of intellectual disability. Adults and children with Down syndrome have lower-than-normal IQs, learning disabilities, and memory impairments. Down syndrome is caused by extra genetic material on chromosome 21. This occurs due to a process called nondisjunction, in which the genetic material fails to separate, resulting in an extra chromosome (trisomy 21). The global prevalence is approximately 1 per 1,000 births, meaning that approximately 3,000 to 5,000 children are born with this disorder each year (WHO (2017), Genes and chromosomal diseases). Altered GABAergic transmission significantly contributes to learning and memory impairments in mouse models. Recent literature has shown that bumetanide can restore normal GABAergic transmission and reduce cognitive impairment (Deidda, G., et al. 2015). Based on this study, bumetanide and its derivatives are promising approaches for the treatment of psychiatric disorders in patients with Down syndrome.

[0018] [Glaucoma] As the population ages, glaucoma has become the second leading cause of blindness worldwide. Glaucoma is a general term for a variety of diseases. In primary open-angle glaucoma, the ducts become blocked, preventing fluid from draining from the eye. This increases intraocular pressure and leads to blindness. Because symptoms are minimal, patients initially do not notice a gradual loss of vision. The causes of closed-angle glaucoma are similar to those of open-angle glaucoma, but the onset is much earlier and symptoms include headaches, blurred vision, and eye pain. As the world's population ages, the need for further treatment increases every year (according to the WHO (2004), glaucoma is the second leading cause of blindness worldwide).

[0019] [Bumetanide and its derivatives] Bumetanide (3-(butylamino)-4-phenoxy-5-sulfamoylbenzoic acid) is a loop diuretic (high ceiling diuretic) that blocks both NKCC1 and NKCC2. Bumetanide is approved by the FDA and EMA for the treatment of edema, particularly edema associated with congestive heart failure, liver disease, and kidney disease (e.g., nephrotic syndrome). Bumetanide and / or certain of its derivatives have also been proposed for various other therapeutic applications (Lykke K et al., Br J Pharmacol. 2015, 172(18): 4469-80; Toellner K et al., Eur J Pharmacol. 2015, 746:78-88; Toellner 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 highly polar carboxylic acid group, bumetanide has poor permeability across cell membranes, severely limiting the therapeutic potential of this drug. Therefore, in view of the weak therapeutic activity and undesirably strong diuretic effect of bumetanide, there is an urgent and unmet need for new and / or improved therapeutic agents that can be used to treat NKCC-associated disorders and that do not suffer from the drawbacks associated with bumetanide.

[0020] Certain other (hetero)arylsulfonamides, benzoic acids, thiophenes, pyrazolopyrimidines or other derivatives are described, for example, in the following documents: 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 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;US3,985,777;US4,010,273;US2014 / 06650 4;WO2008 / 052190;WO2010 / 083442;WO2010 / 085352;WO2012 / 018635;WO2013 / 087090;WO2014 / 157635;WO2014 / 196793;WO2014 / 039454. DETAILED DESCRIPTION OF THE INVENTION

[0021] It is therefore an object of the present invention to provide new and / or improved active ingredients for the treatment of hyperhidrosis or other diseases / disorders in which NKCC (especially NKCC1) is involved.

[0022] In the context of the present invention, the bumetanide derivatives of formula (I) described and defined herein are + -K + -2Cl -It has been found that the bumetanide derivatives of Formula (I) can be used as inhibitors of the NKCC (NK cell transporter), particularly as NKCC1 inhibitors. Furthermore, it has been found that the bumetanide derivatives of Formula (I) exhibit significantly improved properties, particularly with respect to penetration, diuresis, and metabolic stability. Accordingly, the compounds provided herein exhibit increased lipophilicity, improved skin penetration, significantly reduced diuretic activity, improved metabolic stability, and overall enhanced therapeutic efficacy. This makes the compounds of the present invention highly useful for therapeutic applications, such as the treatment or prevention of diseases or disorders involving NKCC (particularly NKCC1). Therefore, the compounds of formula (I) according to the present invention are useful for treating or preventing 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). Alternatively, they are useful for treating or preventing other diseases / disorders involving NKCC (such as those described in the prior art section of this specification). The present invention also provides compounds of formula (I) that are selective inhibitors of NKCC1 (particularly, compounds that inhibit NKCC1 more potently than NKCC2). Therefore, these compounds are particularly suitable for treating or preventing diseases / disorders involving NKCC1. These compounds are also particularly suitable for therapeutic applications where a high ceiling diuretic effect is undesirable (e.g., in the treatment or prevention of hyperhidrosis). Some of the compounds of the present invention further exhibit useful water solubility. The present invention also provides compounds of formula (I) that contain a carboxylic acid ester group and can be hydrolyzed by esterases in a patient's skin to release a more polar therapeutically active ingredient. Because of their high polarity, these compounds are not readily transported to the skin surface, allowing them to accumulate at the desired target site (metabolic trapping), resulting in a more pronounced and / or prolonged therapeutic effect. All of these properties make the compounds provided herein highly suitable as pharmaceuticals that inhibit NKCC (particularly NKCC1).These compounds are therefore highly suitable for therapeutic intervention in diseases / disorders in which NKCC is involved, particularly for the treatment or prevention of hyperhidrosis.

[0023] Accordingly, the present invention provides a compound of formula (I) below, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention of hyperhidrosis.

[0024] [ka]

[0025] In formula (I), the ring moiety (shown on the left below) is one of the formulae shown on the right below.

[0026] [ka]

[0027] R x is R 1 or R 3 is.

[0028] R 1 -COOH, -COO-(C 1-15 alkyl), -COO-(C 0-15 alkylene)-carbocyclyl, -COO-(C 0-15 alkylene)-heterocyclyl, -O-CHO, -O-CO-(C 1-15 alkyl), -O-CO-(C 0-15 alkylene)-carbocyclyl, -O-CO-(C 0-15 alkylene)-heterocyclyl, -CHO, -CO-(C 1-15 alkyl), -CO-(C 0-15 alkylene)-carbocyclyl, -CO-(C 0-15 alkylene)-heterocyclyl, -CO-NH2, -CO-N(R 11 )-(C 1-15 alkyl), -CO-N(R 11 )-(C 0-15 alkylene)-carbocyclyl, -CO-N(R11 )-(C 0-15 alkylene)-heterocyclyl, -N(R 11 )-CHO, -N(R 11 )-CO-(C 1-15 alkyl), -N(R 11 )-CO-(C 0-15 alkylene)-carbocyclyl, -N(R 11 )-CO-(C 0-15 alkylene)-heterocyclyl, C 1-15 Alkyl, -(C 0-15 alkylene)-carbocyclyl, -(C 0-15 alkylene)-heterocyclyl, C 2-15 Alkenyl, -(C 2-15 alkenylene)-carbocyclyl, -(C 2-15 Alkenylene)-heterocyclyl, C 2-15 Alkynyl, -(C 2-15 alkynylene)-carbocyclyl, and -(C 2-15 alkynylene)-heterocyclyl.

[0029] In this case, any alkyl moiety in the above group, any alkylene moiety in the above group, any alkenylene moiety in the above group, any alkynylene moiety in the above group, 1-15 Alkyl, above C 2-15 Alkenyl and the above C 2-15 Alkynyl is a halogen, -CF3, -CN, -NO2, -N(R 11 )(R 11 ), -O(R 11 ), -S(R 11 ), and —SO 3 H.

[0030] In this case, any alkyl moiety in the above group, any alkylene moiety in the above group, any alkenylene moiety in the above group, any alkynylene moiety in the above group, 1-15 Alkyl, above C 2-15 Alkenyl or the above C 2-15One or more -CH2- units contained in the alkynyl are each 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 )—SO—; Further, in this case, any carbocyclyl moiety in the above group and any heterocyclyl moiety in the above group may each be C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, -CN, -NO2, -N(R 11 )(R 11 ), -O(R 11 ), -S(R 11 ), —SO 3 H, carbocyclyl, and heterocyclyl.

[0031] Each R 11 are independently hydrogen or C 1-6 It is alkyl.

[0032] R 2 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), -CN, -NO2, -CHO, -CO-(C 1-6alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), -N(C 1-6 alkyl)-CO-(C 1-6 alkyl), -SO2-NH2, -SO2-NH(C 1-6 alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl), and -N(C 1-6 alkyl)-SO2-(C 1-6 alkyl).

[0033] R 3 -SO2-NH2, -SO2-NH(C 1-6 alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -SO2-N=(C 1-6 In this case, the above-mentioned -SO2-NH(C 1-6 alkyl), the alkyl portion of -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), and the above -SO2-N=(C 1-6 The alkylidene moiety of alkylidene) is halogen, -CF3, -CN, -NO2, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -OH, -O(C 1-6 alkyl), -SH, and -S(C 1-6 and optionally substituted with one or more groups independently selected from alkyl.

[0034] R 4 is R 4a is a group, and R 5is R 5a group. Alternatively, R 4 and R 5 are combined together to form -R 5b -Forms the base.

[0035] R 4a -OR 41 , -SR 41 , -NH-R 41 , -N(C 1-6 alkyl)-R 41 , halogen, hydrogen, carbocyclyl, and heterocyclyl, wherein the carbocyclyl and the heterocyclyl are each selected from one or more R 42 The group is optionally substituted.

[0036] R 41 is -(C 0-4 alkylene)-carbocyclyl, -(C 0-4 alkylene)-heterocyclyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, wherein the above-(C 0-4 the carbocyclyl portion of the -(C alkylene)-carbocyclyl; 0-4 Each heterocyclyl portion of the (alkylene)-heterocyclyl may be one or more R 42 In this case, the above C 1-6 Alkyl, above C 2-6 Alkenyl, above C 2-6 Alkynyl, as defined above -(C 0-4 alkylene)-carbocyclyl, and the alkylene portion of the above-(C 0-4 Each alkylene portion of the (alkylene)-heterocyclyl may be one or more R 43 The group is optionally substituted.

[0037] Each R 42 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -O(C1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), -N(C 1-6 alkyl)-CO-(C 1-6 alkyl), -SO2-NH2, -SO2-NH(C 1-6 alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl), and -N(C 1-6 alkyl)-SO2-(C 1-6 alkyl).

[0038] Each R 43 -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, -CF3, -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), and -N(C 1-6 alkyl)-CO-(C 1-6 alkyl).

[0039] R 5a -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -NO2 and hydrogen. 1-6 alkyl) and the alkyl portion of the above -N(C 1-6 Alkyl)(C 1-6 One or both alkyl moieties of the alkyl group may be halogen, -CF3, -CN, -NO2, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), carbocyclyl, and heterocyclyl, each of which is optionally substituted with one or more groups independently selected from one or more R 51 The group is optionally substituted.

[0040] Each R 51 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6haloalkyl), -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), -N(C 1-6 alkyl)-CO-(C 1-6 alkyl), -SO2-NH2, -SO2-NH(C 1-6 alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl), and -N(C 1-6 alkyl)-SO2-(C 1-6 alkyl).

[0041] R 5b -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-

[0042] Each R 5b1 is -N(R 52 )—, —O—, and —S—.

[0043] R 5b2 is -C(R 53 )(R 53 )-, -C(R 53 )(R 53 )-C(R 53 )(R 53 )-, -C(R 53 )=C(R53 )-, -C(R 53 )(R 53 )-C(R 53 )=C(R 53 )-, and -C(R 53 )=C(R 53 )-C(R 53 )(R 53 )- is selected from.

[0044] R 5b3 is 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 )- is selected from.

[0045] R 5b4 is a covalent bond and -C(R 53 )(R 53 )- is selected from.

[0046] Each R 52 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(C 0-4 alkylene)-aryl, and -(C 0-4 alkylene)-heteroaryl.

[0047] Each R 53 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6haloalkyl), -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), -N(C 1-6 alkyl)-CO-(C 1-6 alkyl), -SO2-NH2, -SO2-NH(C 1-6 alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl), -N(C 1-6 alkyl)-SO2-(C 1-6 alkyl), -(C 0-4 alkylene)-aryl, and -(C 0-4 Any two R bonded to the same carbon atom are independently selected from the group consisting of alkylene, heteroaryl, and aryl. 53 The groups may be joined together to form a ═O group. Any two R groups attached to adjacent carbon atoms connected by a double bond may 53 The groups are linked together to form -C(R 54 )=C(R 54 )-C(R 54 )=C(R 54 )-group may be formed.

[0048] Each R 54 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6haloalkyl), -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), -N(C 1-6 alkyl)-CO-(C 1-6 alkyl), -SO2-NH2, -SO2-NH(C 1-6 alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl), and -N(C 1-6 alkyl)-SO2-(C 1-6 alkyl).

[0049] R 6 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C1-6 alkyl), -N(C 1-6 alkyl)-CO-(C 1-6 alkyl), -SO2-NH2, -SO2-NH(C 1-6 alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl), and -N(C 1-6 alkyl)-SO2-(C 1-6 alkyl).

[0050] Alternatively, R 1 and R 6 are interconnected to form -R 16 - group, and the following upper limits are satisfied: ·R 16 is -C(R 161 )(R 161 )-C(R 161 )(R 161 )-C(R 161 )(R 161 )-C(R 161 )(R 161 )-group. One or two -C(R 161 )(R 161 )-units are, respectively, -R 163 - has been replaced by Each R 161 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, -(C 0-6 alkylene)-CF3, -(C 0-6 alkylene)-CN, -(C 0-6 alkylene)-NO2, -(C 0-6 alkylene)-N(R 162 )(R 162 ), -(C 0-6 alkylene)-O(R 162 ), -(C 0-6 alkylene)-S(R 162 ), -(C 0-6 alkylene)-SO3H, -(C0-6 alkylene)-carbocyclyl, and -(C 0-6 alkylene)-heterocyclyl. Each R 162 are independently hydrogen or C 1-6 It is alkyl. Each R 163 is -N(R 161 )—, —O—, and —S—.

[0051] In the present invention, the ring moiety (shown on the left below) in formula (I) is the formula shown on the right below, and R 2 is hydrogen and R 3 is -SO2-NH2, and R 4 is -O-phenyl and R 5 is -NH-CH2CH2CH2CH3, and R 6 is hydrogen, R 1 is not -COOH.

[0052] [ka]

[0053] The present invention also relates to a pharmaceutical composition for use in treating or preventing hyperhidrosis, comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient.

[0054] The present invention also relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for treating or preventing hyperhidrosis.

[0055] Similarly, the present invention relates to a method for treating or preventing hyperhidrosis, which method comprises administering to a subject (preferably a human) in need thereof a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (or a pharmaceutical composition comprising any of the above elements and a pharmaceutically acceptable excipient). It will be understood that in this method, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (or a therapeutically effective amount of a pharmaceutical composition) is administered.

[0056] The present invention further relates to the use of a compound of formula (I) or a pharmaceutically / physiologically acceptable salt or solvate thereof for inhibiting or reducing non-pathological sweating in a subject (e.g., 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 for inhibiting or reducing sweating in a subject (e.g., human). Similarly, the present invention relates to a method (particularly a non-therapeutic method) for inhibiting or reducing sweating in a subject (e.g., human). The method comprises administering a compound of formula (I) or a pharmaceutically / physiologically acceptable salt or solvate thereof to the subject. The subject whose sweating is inhibited or reduced is preferably a healthy subject, particularly a subject who does not suffer from hyperhidrosis. The present invention particularly relates to the inhibition or reduction of sweating in a subject. The sweating is caused by or is generated by physical stress or physical exercise (e.g., sports).

[0057] For the treatment or prevention of hyperhidrosis as well as the suppression or reduction of non-pathological sweating, it is preferable to administer the compound of formula (I) or its pharmaceutically / physiologically acceptable salt or solvate topically. It is particularly preferable to administer it to areas of the skin that are affected (or strongly affected) by sweating and / or areas of the skin where reduced sweating is desired. For topical administration, the compound of formula (I) or its pharmaceutically / physiologically acceptable salt or solvate may be provided, for example, in the form of a composition. For example, it may be provided in the form of a pharmaceutical composition for use in the prevention or treatment of hyperhidrosis, containing the compound and a pharmaceutically acceptable additive. Alternatively, it may be provided in the form of a cosmetic composition for suppressing or reducing non-pathological sweating, containing the compound and a cosmetically / physiologically acceptable additive. It may also be provided in the form of a cloth (or wipe) containing the compound. Alternatively, the compound may be provided in the form of an insole (or shoe insole or insole; particularly, an orthopedic insole, an orthopedic shoe insole, or an orthopedic insole, etc.) containing the compound. Alternatively, the compound may be provided in the form of an article of clothing (or a piece of clothing). The compound of formula (I) or its pharmaceutically / physiologically acceptable salt or solvate may be applied to the above-mentioned articles (i.e., wipes, insoles, shoe insoles, insole, clothing, or a piece of clothing), for example, by treating, coating, or impregnating the compound. Preferably, one or more surfaces of the above-mentioned article (particularly, one or more surfaces facing the body) are treated, coated, or impregnated (or have been treated, coated, or impregnated) with the compound of formula (I) or its pharmaceutically / physiologically acceptable salt or solvate. The present invention also relates to articles containing the compounds described herein. Thus, the present invention specifically includes articles containing a compound of formula (I) or a pharmaceutically / physiologically acceptable salt or solvate thereof, which are (i) wipes (or wipes), (ii) insoles (or shoe inserts or footplates; e.g., orthopedic insoles, orthopedic shoe inserts, or orthopedic footplates), or (iii) articles of clothing (or pieces of clothing).

[0058] According to the present invention, in addition to hyperhidrosis, other diseases / disorders in which NKCC is involved (or mediated) (particularly, diseases / disorders in which NKCC1 is involved (or mediated)) can also be treated or prevented using the compounds of formula (I).

[0059] Accordingly, the present invention also relates to a compound of formula (I) as described and defined herein above, or a pharmaceutically acceptable salt or solvate thereof (or a pharmaceutical composition comprising any of the aforementioned elements and a pharmaceutically acceptable excipient), for use in the treatment or prevention of a disease or disorder in which NKCC is involved (in particular a disease or disorder in which NKCC1 is involved).

[0060] The present invention further relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for treating or preventing a disease or disorder involving NKCC (particularly a disease or disorder involving NKCC1).

[0061] Similarly, the present invention provides a method for treating or preventing a disease or disorder involving NKCC (particularly a disease or disorder involving NKCC1). The method comprises the step of administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (or a pharmaceutical composition comprising any of the above-mentioned elements together with a pharmaceutically acceptable excipient) to a subject (preferably a human) in need thereof. It will be understood that in this method, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (or a therapeutically effective amount of a pharmaceutical composition) is administered.

[0062] The disease or disorder to be treated or prevented in the present invention (specifically, a disease or disorder involving NKCC (preferably NKCC1)) is not particularly limited. Preferably, the disease or disorder is selected from hyperhidrosis (e.g., primary hyperhidrosis, secondary hyperhidrosis, or nocturnal hyperhidrosis), anxiety disorder, autism spectrum disorder (e.g., autism, Asperger's syndrome, childhood disintegrative disorder, or pervasive developmental disorder as part of autism spectrum disorder), traumatic brain injury, spinal cord injury (including chronic pain due to spinal cord injury), peripheral nerve injury, stroke (e.g., ischemic stroke; particularly, including the use of the compound according to the present invention to promote recovery after stroke, or the use of the compound to reduce brain damage and / or neurological deficits after stroke), Alzheimer's disease, schizophrenia, asthma, edema (e.g., cerebral edema), Down's syndrome (particularly, psychiatric disorders in Down's syndrome patients), glaucoma (e.g., primary open-angle glaucoma or angle-closure glaucoma), or parasitic infection. Parasitic infections include, for example: (i) Helminth infections (including soil-transmitted helminth infections), in particular infections associated with (or diseases caused by) hookworms, roundworms, whipworms, tapeworms, Guinea worms, pinworms, Toxocara, Strongyloides stercoralis, or Ascaris lumbricoides. (ii) Parasitic fluke infections or diseases caused by parasitic flukes, in particular schistosomiasis, gnathostomiasis, paragonimiasis, fascioliasis, or swamp dermatosis. (iii) Protozoal infections or diseases caused by protozoa, such as malaria, amebiasis, giardiasis, African sleeping sickness, toxoplasmosis, acanthamoeba keratitis, leishmaniasis, babesiosis, granulomatous amebic encephalitis, cryptosporidiosis, cyclosporosis, or primary amebic meningoencephalitis. (iv) Ectoparasitic infections, in particular infections associated with (or diseases caused by) Sarcoptes scabiei, head lice (Pediculus humanus capitis), pubic lice, Dermatophyte larvae, sand fleas (Tunga penetrans), or Ixodoidea ticks.

[0063] Thus, the disease or disorder to be treated or prevented in the present invention is preferably selected from hyperhidrosis, primary hyperhidrosis, secondary hyperhidrosis, nocturnal hyperhidrosis, anxiety disorders, autism spectrum disorders, autism, Asperger's syndrome, childhood disintegrative disorder, pervasive developmental disorders as part of autism spectrum disorders, traumatic brain injury, spinal cord injury (including chronic pain due to spinal cord injury), peripheral nerve injury, stroke (e.g., ischemic stroke), Alzheimer's disease, schizophrenia, asthma, oedema (e.g., cerebral oedema), Down's syndrome, psychiatric disorders in Down's syndrome patients, glaucoma, primary open-angle glaucoma, angle-closure glaucoma, and parasitic infection. The parasitic infection is preferably selected from the group consisting of: (i) helminth infections (particularly hookworm infections, roundworm infections, whipworm infections, tapeworm infections, Guinea worm infections, pinworm infections, toxocara infections, Strongyloides stercoralis infections, or Ascaris lumbricoides infections); (ii) parasitic fluke infections (particularly schistosomiasis, gnathostomiasis, paragonimiasis, fascioliasis, or swamp worm disease); (iii) protozoan infections (particularly malaria, amebiasis, giardiasis, African sleeping sickness, toxoplasmosis, acanthamoeba keratitis, leishmaniasis, babesiosis, granulomatous amebic encephalitis, cryptosporidiosis, cyclosporosis, or primary amebic meningoencephalitis); (iv) ectoparasitic infections (particularly Sarcoptes scabiei The disease or disorder to be treated or prevented in the present invention is selected from infections associated with (or diseases caused by) human lice (Pediculus scabiei), head lice (Pediculus humanus capitis), pubic lice, Dermatophyte larvae, sand fleas (Tunga penetrans), or Ixodoidea ticks. It is particularly preferred that the disease or disorder to be treated or prevented in the present invention is hyperhidrosis (e.g., primary hyperhidrosis, secondary hyperhidrosis, or nocturnal hyperhidrosis).

[0064] In addition, the disease or disorder to be treated or prevented in the present invention may be, for example, a neurological disease or disorder involving (or mediated by) NKCC (particularly, a neurological disease or disorder involving (or mediated by) NKCC1). Corresponding examples include, in particular, stroke (e.g., ischemic stroke), traumatic brain injury, spinal cord injury, peripheral nerve injury, or cerebral edema.

[0065] Furthermore, the compound of formula (I) can be used as a control agent (particularly a control agent for suppressing plant pests (such as nematodes, arthropods, ectoparasites and / or mollusks)) by, for example, applying the compound of formula (I) or a salt or solvate thereof to plants or soil.

[0066] The present invention also provides novel compounds (described in further detail below) that can be used as pharmaceuticals, and pharmaceutical compositions containing the compounds and pharmaceutically acceptable excipients.

[0067] The present invention further relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as an NKCC inhibitor in research. In particular, it relates to use as a research compound for inhibiting NKCC (particularly NKCC1). Accordingly, the present invention relates to the in vitro use of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as an NKCC inhibitor (particularly an NKCC1 inhibitor). Similarly, the present invention relates to the in vitro use of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as an research compound acting as an NKCC inhibitor (particularly an NKCC1 inhibitor). The present invention also relates to an in vitro method for inhibiting NKCC (particularly NKCC1). The method comprises applying the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. The present invention further provides an in vitro method for inhibiting NKCC (particularly NKCC1). The method comprises using the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as an NKCC inhibitor (particularly an NKCC1 inhibitor). It is to be understood that in this particular context the term "in vitro" is used to mean "outside the living human or animal body", examples of which include, inter alia, experiments carried out using cells, cell or subcellular extracts and / or biological molecules in an artificial environment (such as an aqueous solution or medium, which may be provided in a flask, test tube, Petri dish, microtiter plate, etc.).

[0068] The compounds of formula (I) and their pharmaceutically acceptable salts or solvates are described in detail below.

[0069] [ka]

[0070] In formula (I), the structure of the left ring moiety is one of the structures shown on the right.

[0071] [ka]

[0072] It will be understood that when the ring moiety (below left) is of the formula in the middle below, the compound of formula (I) has the structure below right.

[0073] [ka]

[0074] Conversely, when the ring moiety (shown on the left below) is of the formula in the center below, the compound of formula (I) has the structure shown on the right below.

[0075] [ka]

[0076] R 1 -COOH, -COO-(C 1-15 alkyl), -COO-(C 0-15 alkylene)-carbocyclyl, -COO-(C 0-15 alkylene)-heterocyclyl, -O-CHO, -O-CO-(C 1-15 alkyl), -O-CO-(C 0-15 alkylene)-carbocyclyl, -O-CO-(C 0-15 alkylene)-heterocyclyl, -CHO, -CO-(C 1-15 alkyl), -CO-(C 0-15 alkylene)-carbocyclyl, -CO-(C 0-15 alkylene)-heterocyclyl, -CO-NH2, -CO-N(R 11 )-(C 1-15 alkyl), -CO-N(R 11 )-(C 0-15 alkylene)-carbocyclyl, -CO-N(R 11 )-(C 0-15 alkylene)-heterocyclyl, -N(R 11 )-CHO, -N(R 11 )-CO-(C 1-15 alkyl), -N(R 11 )-CO-(C0-15 alkylene)-carbocyclyl, -N(R 11 )-CO-(C 0-15 alkylene)-heterocyclyl, C 1-15 Alkyl, -(C 0-15 alkylene)-carbocyclyl, -(C 0-15 alkylene)-heterocyclyl, C 2-15 Alkenyl, -(C 2-15 alkenylene)-carbocyclyl, -(C 2-15 Alkenylene)-heterocyclyl, C 2-15 Alkynyl, -(C 2-15 alkynylene)-carbocyclyl, and -(C 2-15 alkynylene)-heterocyclyl.

[0077] In this case, any alkyl moiety in the above group, any alkylene moiety in the above group, any alkenylene moiety in the above group, any alkynylene moiety in the above group, 1-15 Alkyl, above C 2-15 Alkenyl and the above C 2-15 Alkynyl is a halogen, -CF3, -CN, -NO2, -N(R 11 )(R 11 ), -O(R 11 ), -S(R 11 ), and —SO 3 H.

[0078] In this case, any alkyl moiety in the above group, any alkylene moiety in the above group, any alkenylene moiety in the above group, any alkynylene moiety in the above group, 1-15 Alkyl, above C 2-15 Alkenyl or the above C 2-15 One or more (e.g., one or two) -CH2- units contained in the alkynyl may be selected from -O-, -CO-, -COO-, -O-CO-, -N(R 11 )-, -N(R 11 )-CO-, -CO-N(R 11 )-, -S-, -SO-, -SO2-, -SO2-N(R11 )-, and -N(R 11 Optionally substituted with groups independently selected from: —SO—;

[0079] Further, in this case, any carbocyclyl moiety in the above group and any heterocyclyl moiety in the above group may each be C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, -CN, -NO2, -N(R 11 )(R 11 ), -O(R 11 ), -S(R 11 ), —SO 3 H, carbocyclyl, and heterocyclyl.

[0080] Each R 11 are independently hydrogen or C 1-6 Preferably, each R 11 are independently hydrogen or C 1-4 alkyl (for example, methyl or ethyl).

[0081] R 1 is, for example, a specific R 1 It may be any one of the groups.

[0082] In particular, R 1 For example, -COO-(C 1-15 In this case, the above-mentioned —COO—(C alkyl) may be used. 1-15 The alkyl portion of alkyl) is halogen, -CF3, -CN, -NO2, -NH2, -NH(C 1-4 alkyl), -N(C 1-4 Alkyl)(C 1-4 alkyl), -OH, -O(C 1-4 alkyl), -SH, and -S(C 1-4alkyl) independently selected from the group consisting of -COO-(C 1-15 One or two -CH2- units contained in the alkyl portion of the alkyl) are -O-, -CO-, -COO-, -O-CO-, -NH-, -N(C 1-4 alkyl)-, -NH-CO-, -N(C 1-4 alkyl)-CO-, -CO-NH-, -CO-N(C 1-4 alkyl)-, -S-, -SO-, -SO2-, -SO2-NH-, -SO2-N(C 1-4 alkyl)-, -NH-SO2-, and -N(C 1-4 The above-mentioned -COO-(C alkyl)-SO2- is optionally substituted with a group independently selected from the group consisting of -COO-(C 1-15 The alkyl portion of the R has 1 to 15 (particularly, 1 to 10) carbon atoms. 1 Suitable examples of groups include the corresponding R 1 groups (e.g., —COO—CH3 or —COO—CH2CH3; especially —COO—CH3).

[0083] R 1 A more preferred example of is -COOH.

[0084] R 1 A more preferred example of -(C 1-4 alkylene)-NH-(C 1-4 alkylene)-R 12 (e.g., -CH2-NH-CH2-R 12 ), -COO-(C 1-4 alkylene)-R 12 (e.g., -COO-CH2-R 12 ), -O-CO-(C 1-4 alkylene)-R 12 , -CO-(C 1-4 alkylene)-R 12 , -CO-NH-(C 1-4 alkylene)-R 12 (e.g., -CO-NH-CH2-R 12 ), -CO-N(C1-4 alkyl)-(C 1-4 alkylene)-R 12 , -NH-CO-(C 1-4 alkylene)-R 12 , or -N(C 1-4 alkyl)-CO-(C 1-4 alkylene)-R 12 In this case, R 12 are independently selected from -CF, -CN and halogen (e.g., -F, -Cl, -Br or -I). Preferably, R 12 is independently selected from -CF3 and -CN. More preferably, R 12 is -CF3. Such R 1 Specific examples of groups include the corresponding R 1 R 1 A particularly preferred example of 1-4 alkylene)-NH-(C 1-4 An even more preferred example is —CH—NH—CH—CF.

[0085] R 1 Further examples of -(C 1-4 alkylene)-S-heterocyclyl, especially -(C 1-4 alkylene)-S-heteroaryl (e.g., -CH-S-heteroaryl). 1-4 alkylene)-S-heterocyclyl, or the heterocyclyl portion of the above-(C 1-4 The heteroaryl portion of the -CH-S-heteroaryl and -CH-S-heteroaryl is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, -CN, -NO2, -N(R 11 )(R 11 ), -O(R 11 ), -S(R 11 ), —SO3H, carbocyclyl, and heterocyclyl.1 Specific examples of groups include the corresponding R 1 Examples of such groups include:

[0086] R 1 Further examples of -(C 1-4 alkylene)-O-(C 0-4 alkylene)-carbocyclyl, especially -(C 1-4 alkylene)-O-(C 0-4 alkylene)-phenyl (e.g., —CH—O-phenyl or —CH—O—CH-phenyl). 1-4 alkylene)-O-(C 0-4 the carbocyclyl portion of the -(C alkylene)-carbocyclyl, or 1-4 alkylene)-O-(C 0-4 The phenyl moiety of the alkylene-phenyl (or the phenyl moiety of the above-mentioned -CH-O-phenyl or -CH-O-CH-phenyl) is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, -CN, -NO2, -N(R 11 )(R 11 ), -O(R 11 ), -S(R 11 ), —SO3H, carbocyclyl, and heterocyclyl. 1 Specific examples of groups include the corresponding R 1 Examples of such groups include:

[0087] R 1 Further examples of -(C 1-4 alkylene)-heterocyclyl, in particular -CH2-heterocyclyl, where -(C 1-4 The heterocyclyl moiety of the -CH-heterocyclyl or -CH-heterocyclyl is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, halogen, C 1-6 Haloalkyl, -CN, -NO2, -N(R 11 )(R 11 ), -O(R 11 ), -S(R 11 ), -SO3H, carbocyclyl, and heterocyclyl. The heterocyclyl moiety may be, for example, a heterocycloalkyl (such as pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl), a heterocycloalkenyl (such as tetrahydropyridinyl), or a heteroaryl. Such R 1 Specific examples of groups include the corresponding R 1 Examples of such groups include:

[0088] R 2 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), -N(C 1-6 alkyl)-CO-(C 1-6 alkyl), -SO2-NH2, -SO2-NH(C1-6 alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl), and -N(C 1-6 alkyl)-SO2-(C 1-6 alkyl).

[0089] Preferably, R 2 is hydrogen, C 1-6 Alkyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), and —CN. More preferably, R 2 is hydrogen or C 1-4 Even more preferably, R 2 is hydrogen.

[0090] R 3 -SO2-NH2, -SO2-NH(C 1-6 alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -SO2-N=(C 1-6 In this case, the above-mentioned -SO2-NH(C 1-6 alkyl), the alkyl portion of -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), and the above -SO2-N=(C 1-6 The alkylidene moiety of alkylidene) is halogen, -CF3, -CN, -NO2, -NH2, -NH(C 1-6 alkyl), -N(C 1-6Alkyl)(C 1-6 alkyl), -OH, -O(C 1-6 alkyl), -SH, and -S(C 1-6 alkyl).

[0091] Preferably, R 3 -SO2-NH2, -SO2-NH(C 1-4 alkyl), -SO2-N(C 1-4 Alkyl)(C 1-4 alkyl), and -SO2-N=(C 1-4 In this case, the above -SO2-NH(C 1-4 alkyl), the alkyl portion of -SO2-N(C 1-4 Alkyl)(C 1-4 alkyl), and the above -SO2-N=(C 1-4 The alkylidene moiety of alkylidene) is halogen, -CF3, -CN, -NO2, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -OH, -O(C 1-6 alkyl), -SH, and -S(C 1-6 alkyl). More preferably, R 3 -SO2-NH2, -SO2-NH(C 1-4 alkyl), -SO2-N(C 1-4 Alkyl)(C 1-4 alkyl), and -SO2-N=(C 1-4 In this case, the above -SO2-NH(C 1-4 alkyl), the alkyl portion of -SO2-N(C 1-4 Alkyl)(C 1-4 alkyl), and the alkyl moieties of either or both of the above -SO2-N=(C 1-4 The alkylidene moiety of the alkylidene is -NH2, -NH(C 1-4 alkyl), and -N(C1-4 Alkyl)(C 1-4 alkyl). Even more preferably, R 3 -SO2-NH2, -SO2-NH(C 1-4 alkyl), -SO2-N(C 1-4 Alkyl)(C 1-4 alkyl), -SO2-NH-(C 1-4 alkylene)-NH2, -SO2-NH-(C 1-4 alkylene)-NH(C 1-4 alkyl), -SO2-NH-(C 1-4 alkylene)-N(C 1-4 Alkyl)(C 1-4 alkyl), -SO2-N=(C 1-4 alkylidene)-NH2, -SO2-N=(C 1-4 alkylidene)-NH(C 1-4 alkyl), and -SO2-N=(C 1-4 alkylidene)-N(C 1-4 Alkyl)(C 1-4 Even more preferably, R 3 are -SO2-NH2, -SO2-NH-CH3, -SO2-N(CH3)2, -SO2-NH-(C 1-4 alkylene)-NH2, -SO2-NH-(C 1-4 alkylene)-NH-CH3, -SO2-NH-(C 1-4 alkylene)-N(CH3)2 (e.g., -SO2-NH-CH2CH2-N(CH3)2), -SO2-N=(C 1-4 alkylidene)-NH2, -SO2-N=(C 1-4 alkylidene)-NH-CH3 and -SO2-N=(C 1-4 R is selected from the group consisting of -SO-N=CH-N(CH) and -SO-N=CH-N(CH). 3 A particularly suitable example of R is -SO2-NH2. 3 A more particularly preferred example is -SO2-N=CH-N(CH3)2.

[0092] R x is R 1 or R3 (As mentioned above. R 1 and R 3 (This also includes the preferred definition of

[0093] Preferably, R x -COOH, -COO-(C 1-6 alkyl), -SO2-NH2, -SO2-NH(C 1-4 alkyl), -SO2-N(C 1-4 Alkyl)(C 1-4 alkyl), and -SO2-N=(C 1-4 In this case, the above -SO2-NH(C 1-4 alkyl), the alkyl portion of -SO2-N(C 1-4 Alkyl)(C 1-4 alkyl), and the alkyl moieties of either or both of the above -SO2-N=(C 1-4 The alkylidene moiety of the alkylidene is -NH2, -NH(C 1-4 alkyl), and -N(C 1-4 Alkyl)(C 1-4 alkyl). More preferably, R x is selected from -COOH, -COOCH3, -SO2-NH2, and -SO2-N=CH-N(CH3)2.

[0094] R 4 is R 4a is a group, and R 5 is R 5a group. Alternatively, R 4 and R 5 are bonded together to form -R 5b -Forms the base.

[0095] R 4a -OR 41 , -SR 41 , -NH-R 41 , -N(C 1-6 alkyl)-R 41, halogen (e.g., —Cl), hydrogen, carbocyclyl, and heterocyclyl, wherein the carbocyclyl and the heterocyclyl each have one or more (e.g., one, two, or three) R 42 The group is optionally substituted.

[0096] Preferably, -OR 41 , -SR 41 , -NH-R 41 , -N(C 1-6 alkyl)-R 41 , halogen, carbocyclyl, and heterocyclyl, wherein the carbocyclyl and the heterocyclyl are each selected from one or more R 42 More preferably, R 4a -OR 41 , -SR 41 , -NH-R 41 , -N(C 1-6 alkyl)-R 41 , carbocyclyl (e.g., aryl, cycloalkyl, or cycloalkenyl), and heterocyclyl (e.g., heteroaryl, heterocycloalkyl, or heterocycloalkenyl), wherein the carbocyclyl and the heterocyclyl each are selected from one or more R 42 Even more preferably, R 4a -OR 41 , -SR 41 , -NH-R 41 , -N(C 1-4 alkyl)-R 41 , aryl, and heteroaryl, wherein the aryl and heteroaryl are each selected from one or more R 42 is optionally substituted with a group of

[0097] R 41 is -(C 0-4 alkylene)-carbocyclyl, -(C 0-4 alkylene)-heterocyclyl, C 1-6 Alkyl, C 2-6 Alkenyl and C2-6 alkynyl. In this case, the above-mentioned -(C 0-4 the carbocyclyl portion of the -(C alkylene)-carbocyclyl; 0-4 The heterocyclyl portion of each alkylene-heterocyclyl may be one or more (e.g., one, two, or three) R 42 In this case, the above C 1-6 Alkyl, above C 2-6 Alkenyl, above C 2-6 Alkynyl, as defined above -(C 0-4 alkylene)-carbocyclyl, and the alkylene portion of the above-(C 0-4 Each alkylene portion of the alkylene-heterocyclyl may be one or more (e.g., one, two, or three) R 43 The group is optionally substituted.

[0098] Preferably, R 41 Ha-(C 0-4 alkylene)-carbocyclyl, -(C 0-4 alkylene)-heterocyclyl, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 alkynyl. In this case, the above-mentioned -(C 0-4 The carbocyclyl portion of the -(C alkylene)-carbocyclyl is selected from cycloalkyl, cycloalkenyl, and aryl. 0-4 The heterocyclyl moiety of the -(C alkylene)-heterocyclyl is selected from heterocycloalkyl, heterocycloalkenyl, and heteroaryl. 0-4 the carbocyclyl portion of the -(C alkylene)-carbocyclyl; 0-4 The heterocyclyl portion of each alkylene-heterocyclyl may be one or more (e.g., one, two, or three) R 42 Further, the above C 1-6 Alkyl, above C 2-6 Alkenyl, above C 2-6 Alkynyl, as defined above -(C 0-4 alkylene)-carbocyclyl, and the alkylene portion of the above-(C0-4 Each alkylene portion of the alkylene-heterocyclyl may be one or more (e.g., one, two, or three) R 43 More preferably, R 41 is -(C 0-4 alkylene)-aryl, and -(C 0-4 In this case, the above-mentioned -(C 0-4 the aryl portion of the -(C alkylene)-aryl; 0-4 The heteroaryl portion of each alkylene-heteroaryl may be one or more (e.g., one, two, or three) R 42 The above-mentioned -(C 0-4 alkylene)-aryl, and the alkylene portion of the above-(C 0-4 Each alkylene portion of the alkylene-heteroaryl may be one or more (e.g., one, two, or three) R 43 Even more preferably, R 41 is -(C 0-4 alkylene)-aryl, and -(C 0-4 In this case, the above-mentioned -(C 0-4 the aryl portion of the -(C alkylene)-aryl; 0-4 The heteroaryl portion of each alkylene-heteroaryl may be one or more (e.g., one, two, or three) R 42 The above -(C 0-4 A preferred example of the aryl moiety of the -(C alkylene)-aryl is phenyl. 0-4 Preferred examples of the heteroaryl moiety of the alkylene-heteroaryl are 5- or 6-membered monocyclic heteroaryls having 1 or 2 hetero ring atoms independently selected from oxygen, nitrogen, and sulfur, with the remaining ring atoms being carbon atoms, such as imidazolyl, thiophenyl, or pyrimidinyl. Even more preferred are R 41is selected from phenyl and heteroaryl, where the heteroaryl is a 5- or 6-membered monocyclic heteroaryl having one or two hetero ring atoms independently selected from oxygen, nitrogen, and sulfur (the remaining ring atoms of the monocyclic heteroaryl are carbon atoms). Additionally, the phenyl or heteroaryl may contain one or more (e.g., one, two, or three) R 42 The group is optionally substituted.

[0099] Each R 42 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), -N(C 1-6 alkyl)-CO-(C 1-6 alkyl), -SO2-NH2, -SO2-NH(C 1-6 alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl), and -N(C 1-6 alkyl)-SO2-(C 1-6alkyl).

[0100] Preferably, each R 42 is C 1-6 Alkyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), and —CN.

[0101] Each R 43 -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, -CF3, -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), and -N(C 1-6 alkyl)-CO-(C 1-6 alkyl).

[0102] Preferably, each R 43 -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6Alkyl)(C 1-6 alkyl), halogen, —CF 3 , and —CN.

[0103] With respect to the above definitions, particularly preferred are R 4a is -O-(C 0-4 alkylene)-aryl, -O-(C 0-4 alkylene)-heteroaryl, -S-(C 0-4 alkylene)-aryl, -S-(C 0-4 alkylene)-heteroaryl, -NH-(C 0-4 alkylene)-aryl, -NH-(C 0-4 alkylene)-heteroaryl, -N(C 1-4 alkyl)-(C 0-4 alkylene)-aryl, -N(C 1-4 alkyl)-(C 0-4 alkylene)-heteroaryl, aryl, and heteroaryl, wherein any aryl portion of the above groups, any heteroaryl portion of the above groups, the aryl, and the heteroaryl each may be selected from one or more (e.g., one, two, or three) R 42 Even more preferably, R 4a is -O-aryl, -O-heteroaryl, -S-aryl, -S-heteroaryl, -NH-aryl, -NH-heteroaryl, -N(C 1-4 alkyl)-aryl, -N(C 1-4 and (alkyl)-heteroaryl, aryl, and heteroaryl, wherein any aryl portion of the above groups, any heteroaryl portion of the above groups, the aryl, and the heteroaryl are each selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 and optionally substituted with one or more groups independently selected from haloalkyl, and —CN. Even more preferably, R 4a is -O-phenyl, -O-heteroaryl, -S-phenyl, -S-heteroaryl, -NH-phenyl, -NH-heteroaryl, -N(C 1-4 alkyl)-phenyl, -N(C 1-4 and (alkyl)-heteroaryl, phenyl, and heteroaryl, wherein the heteroaryl or any heteroaryl moiety of the above groups is a 5- or 6-membered monocyclic heteroaryl having one or two hetero ring atoms independently selected from oxygen, nitrogen, and sulfur (the remaining ring atoms of the monocyclic heteroaryl are carbon atoms). Furthermore, any phenyl moiety of the above groups, any heteroaryl moiety of the above groups, the phenyl, and the heteroaryl are each selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 R is optionally substituted with one or more groups independently selected from haloalkyl and -CN. 4a A particularly preferred example of is -O-phenyl.

[0104] R 5a -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -NO2 and hydrogen. 1-6alkyl) and the alkyl portion of the above -N(C 1-6 Alkyl)(C 1-6 One or both alkyl moieties of the alkyl group may be halogen, -CF3, -CN, -NO2, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 and optionally substituted with one or more (e.g., one, two, or three) groups independently selected from alkyl, carbocyclyl, and heterocyclyl, wherein the carbocyclyl and heterocyclyl are each optionally substituted with one or more (e.g., one, two, or three) R 51 The group is optionally substituted.

[0105] Preferably, R 5a -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), and -NO2. In this case, the above-mentioned -NH(C 1-6 alkyl) and the alkyl portion of the above -N(C 1-6 Alkyl)(C 1-6 One or both alkyl moieties of the alkyl group may be halogen, -CF3, -CN, -NO2, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -OH, -O(C 1-6 alkyl), -SH, and -S(C 1-6 alkyl). More preferably, R 5a -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), and —NO2. 5a Particularly suitable examples are -NH2, -NH-CH2CH2CH2CH3, or -NO2.

[0106] Each R 51 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), -N(C 1-6 alkyl)-CO-(C 1-6 alkyl), -SO2-NH2, -SO2-NH(C 1-6 alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl), and -N(C 1-6 alkyl)-SO2-(C 1-6 alkyl).

[0107] Preferably, each R 51 is C 1-6 Alkyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), and —CN.

[0108] R 5b -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-

[0109] Each R 5b1 is -N(R 52 )—, —O—, and —S—.

[0110] R 5b2 is -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 )- is selected from.

[0111] R 5b3 is a covalent bond, -C(R 53 )(R 53 )-, -C(R 53 )(R53 )-C(R 53 )(R 53 )-, and -C(R 53 )=C(R 53 )- is selected from.

[0112] R 5b4 is a covalent bond and -C(R 53 )(R 53 )- is selected from.

[0113] Each R 52 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(C 0-4 alkylene)-aryl, and -(C 0-4 alkylene)-heteroaryl.

[0114] Preferably, each R 52 is hydrogen, C 1-4 Alkyl (e.g., n-butyl), C 2-4 Alkenyl and C 2-4 alkynyl (e.g., —CH—C≡CH). Even more preferably, each R 52 is hydrogen.

[0115] Each R 53 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), -N(C 1-6 alkyl)-CO-(C 1-6 alkyl), -SO2-NH2, -SO2-NH(C 1-6 alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl), -N(C 1-6 alkyl)-SO2-(C 1-6 alkyl), -(C 0-4 alkylene)-aryl, and -(C 0-4 Any two R bonded to the same carbon atom are independently selected from the group consisting of alkylene, heteroaryl, and aryl. 53 The groups may be joined together to form a ═O group. Any two R groups attached to adjacent carbon atoms connected by a double bond may 53 Groups (i.e., -C(R 53 )=C(R 53 )-part contains any two R 53 groups) are linked together to form -C(R 54 )=C(R 54 )-C(R 54 )=C(R 54 )-group may be formed.

[0116] Preferably, each R 53 is hydrogen, C 1-6 Alkyl, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 Any two R bonded to the same carbon atom are independently selected from -(haloalkyl), -(haloalkyl), and -CN. 53The groups may be joined together to form a ═O group. Any two R groups attached to adjacent carbon atoms connected by a double bond may 53 The groups are linked together to form -C(R 54 )=C(R 54 )-C(R 54 )=C(R 54 )-group. More preferably, each R 53 is hydrogen, C 1-6 Alkyl, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), and —CN, where any two R 53 The groups may together form a =O group. Even more preferably, each R 53 is hydrogen, C 1-4 Alkyl, -OH, -O(C 1-4 alkyl), -NH2, -NH(C 1-4 alkyl), -N(C 1-4 Alkyl)(C 1-4 Alkyl), halogen, C 1-4 Haloalkyl, -O-(C 1-4 haloalkyl), and —CN, where any two R 53 The groups may together form a =O group.

[0117] Each R 54 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C1-6 Haloalkyl, -O-(C 1-6 haloalkyl), -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), -N(C 1-6 alkyl)-CO-(C 1-6 alkyl), -SO2-NH2, -SO2-NH(C 1-6 alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl), and -N(C 1-6 alkyl)-SO2-(C 1-6 alkyl).

[0118] Preferably, each R 54 is hydrogen, C 1-6 Alkyl, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), and —CN. More preferably, each R 54 is hydrogen.

[0119] Particularly preferably, R 5b is -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-、-O-C(R 53 )(R 53 )-N(R 52 )-、-O-C(R 53 )(R 53 )-C(R 53 )(R 53 )-N(R 52 )-、-O-C(R 53 )=C(R 53 )-N(R 52 )-、-O-C(R 53 )(R 53 )-C(R 53 )(R 53 )-C(R 53 )(R 53 )-N(R 52 )-、-O-C(R 53 )(R 53 )-C(R 53 )=C(R 53 )-N(R 52 )-、-O-C(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(R53 )-C(R 53 )(R 53 )-O-、-S-C(R 53 )(R 53 )-N(R 52 )-、-S-C(R 53 )(R 53 )-C(R 53 )(R 53 )-N(R 52 )-、-S-C(R 53 )=C(R 53 )-N(R 52 )-、-S-C(R 53 )(R 53 )-C(R 53 )(R 53 )-C(R 53 )(R 53 )-N(R 52 )-、-S-C(R 53 )(R 53 )-C(R 53 )=C(R 53 )-N(R 52 )-、-S-C(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 )-, and -N(R 52 )-C(R 53 )=C(R 53 )-C(R 53 )(R 53 )-N(R 52 )- is selected from.

[0120] In addition, the ring part (left) is the formula on the right below, and R 4 and R 5 are interconnected to form -R 5b - group,

[0121] [ka]

[0122] R is selected so that the compound of formula (I) has the following structure: 5bIt is more preferable to select

[0123] [ka]

[0124] R 6 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), -N(C 1-6 alkyl)-CO-(C 1-6 alkyl), -SO2-NH2, -SO2-NH(C 1-6 alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl), and -N(C 1-6 alkyl)-SO2-(C 1-6 alkyl).

[0125] Preferably, R 6 is hydrogen, C 1-6 Alkyl, -OH, -O(C1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), and —CN. More preferably, R 6 is hydrogen or C 1-4 Even more preferably, R 6 is hydrogen.

[0126] or (i.e., R 1 and R 6 (instead of the above meaning for 1 and R 6 are interconnected to form -R 16 The conditions for this are as follows: ·R 16 is -C(R 161 )(R 161 )-C(R 161 )(R 161 )-C(R 161 )(R 161 )-C(R 161 )(R 161 )-group. One or two -C(R 161 )(R 161 )-units are, respectively, -R 163 - has been replaced with Each R 161 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, -(C 0-6 alkylene)-CF3, -(C 0-6 alkylene)-CN, -(C 0-6 alkylene)-NO2, -(C 0-6alkylene)-N(R 162 )(R 162 ), -(C 0-6 alkylene)-O(R 162 ), -(C 0-6 alkylene)-S(R 162 ), -(C 0-6 alkylene)-SO3H, -(C 0-6 alkylene)-carbocyclyl, and -(C 0-6 alkylene)-heterocyclyl. Each R 162 are independently hydrogen or C 1-6 It is alkyl. Each R 163 is -N(R 161 )—, —O—, and —S—.

[0127] Preferably, R 16 is a -CH2-CH2-CH2-CH2- group. One or two -CH2- units contained in this group are each -R 163 -. More preferably, R 16 is a -CH2-CH2-CH2-CH2- group. One -CH2- unit in this group is -R 163 -. Even more preferably, R 16 is -CH2-R 163 -CH2-CH2- or -CH2-CH2-R 163 -CH2-.

[0128] Preferably, each R 163 are independently -N(R 161 )-. The corresponding R 163 A suitable example of the group is -N(-CH2-CF3)-. Therefore, particularly preferred is R 16 is -CH2-N(R 161 )-CH2-CH2-, or -CH2-CH2-N(R 161 )-CH2- (for example, -CH2-N(-CH2-CF3)-CH2-CH2- or -CH2-CH2-N(-CH2-CF3)-CH2-).

[0129] According to the present invention, the ring moiety (shown on the left) in formula (I) is the formula shown on the right, and R 2 is hydrogen and R 3 is -SO2-NH2, and R 4 is -O-phenyl and R 5 is -NH-CH2CH2CH2CH3, and R 6 is hydrogen, R 1 is not -COOH.

[0130] [ka]

[0131] In other words, if all of the following conditions are met, R 1 is different from -COOH (R 1 is not -COOH). (i) The ring part (left) is the formula shown on the right. (ii) R 2 is hydrogen. (iii) R 3 is -SO2-NH2. (iv) R 4 is -O-phenyl. (v) R 5 is -NH-CH2CH2CH2CH3. (vi) R 6 is hydrogen.

[0132] [ka]

[0133] The compound of formula (I) may be, for example, any one of the specific compounds described in the Examples herein, which may be in a non-salt form (e.g., free base / acid form) or in the form of a pharmaceutically acceptable salt or solvate of the respective compound.

[0134] In particular, the compound of formula (I) may be a compound of any one of the following formulae: or a pharmaceutically acceptable salt or solvate thereof:

[0135] [ka] TIFF0007611812000013.tif212169TIFF0007611812000014.tif208169TIFF000 7611812000015.tif208169TIFF0007611812000016.tif197169TIFF0007611812 000017.tif206169TIFF0007611812000018.tif194169TIFF0007611812000019. tif191169TIFF0007611812000020.tif211169TIFF0007611812000021.tif74169

[0136] In embodiment 1, the ring moiety of the compound of formula (I) (shown below on the left) is shown below on the right.

[0137] [ka]

[0138] Thus, in embodiment 1, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0139] [ka]

[0140] In this case, the groups and variables in formula (Ia) (particularly R 1 , R 2 , R 3 , R 4 , R 5 and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0141] In embodiment 2, the ring moiety of the compound of formula (I) (shown below on the left) is shown below on the right.

[0142] [ka]

[0143] Thus, in embodiment 2, the compound of formula (I) is a compound of formula (Ib): or a pharmaceutically acceptable salt or solvate thereof:

[0144] [ka]

[0145] In this case, the groups and variables in formula (Ib) (particularly R x , R 4 , R 5 and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0146] In embodiment 3, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0147] [ka]

[0148] At this time, R 4 is R 4a is a group, and R 5 is R 5a group, and other groups and variables in formula (Ia) (particularly R 1 , R 2 , R 3 and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0149] In embodiment 3, -OR 41 , -SR 41 , -NH-R 41 , -N(C 1-6 alkyl)-R 41 , halogen (e.g., —Cl), carbocyclyl, and heterocyclyl, wherein the carbocyclyl and the heterocyclyl each have one or more (e.g., one, two, or three) R 42 Preferably, R 4a -OR 41 , -SR 41 , -NH-R 41 , -N(C 1-6 alkyl)-R 41 , carbocyclyl (e.g., aryl, cycloalkyl, or cycloalkenyl), and heterocyclyl (e.g., heteroaryl, heterocycloalkyl, or heterocycloalkenyl), wherein the carbocyclyl and the heterocyclyl each are selected from one or more R 42 More preferably, R 4a -OR 41 , -SR 41 , -NH-R 41 , -N(C 1-4 alkyl)-R 41 , aryl, and heteroaryl, wherein the aryl and heteroaryl are each selected from one or more R 42 is optionally substituted with a group of

[0150] R 41 is -(C 0-4 alkylene)-carbocyclyl, -(C 0-4 alkylene)-heterocyclyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, wherein the above-mentioned -(C 0-4 the carbocyclyl portion of the -(C alkylene)-carbocyclyl; 0-4The heterocyclyl portion of each alkylene-heterocyclyl may be one or more (e.g., one, two, or three) R 42 Further, the above C 1-6 Alkyl, above C 2-6 Alkenyl, above C 2-6 Alkynyl, as defined above -(C 0-4 alkylene)-carbocyclyl, and the alkylene portion of the above-(C 0-4 Each alkylene portion of the alkylene-heterocyclyl may be one or more (e.g., one, two, or three) R 43 Preferably, R 41 is -(C 0-4 alkylene)-carbocyclyl, -(C 0-4 alkylene)-heterocyclyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl. In this case, the above-mentioned -(C 0-4 The carbocyclyl portion of the -(C alkylene)-carbocyclyl is selected from cycloalkyl, cycloalkenyl, and aryl. 0-4 The heterocyclyl moiety of the -(C alkylene)-heterocyclyl is selected from heterocycloalkyl, heterocycloalkenyl, and heteroaryl. 0-4 the carbocyclyl portion of the -(C alkylene)-carbocyclyl; 0-4 The heterocyclyl portion of each alkylene-heterocyclyl may be one or more (e.g., one, two, or three) R 42 Further, the above C 1-6 Alkyl, above C 2-6 Alkenyl, above C 2-6 Alkynyl, as defined above -(C 0-4 alkylene)-carbocyclyl, and the alkylene portion of the above-(C 0-4 Each alkylene portion of the alkylene-heterocyclyl may be one or more (e.g., one, two, or three) R 43 More preferably, R 41 is -(C 0-4alkylene)-aryl, and -(C 0-4 In this case, the above-mentioned -(C 0-4 the aryl portion of the -(C alkylene)-aryl; 0-4 The heteroaryl portion of each alkylene-heteroaryl may be one or more (e.g., one, two, or three) R 42 The above-mentioned -(C 0-4 alkylene)-aryl, and the alkylene portion of the above-(C 0-4 Each alkylene portion of the alkylene-heteroaryl may be one or more (e.g., one, two, or three) R 43 Even more preferably, R 41 is -(C 0-4 alkylene)-aryl and -(C 0-4 In this case, the above-mentioned -(C 0-4 alkylene)-aryl and the aryl portion of the above-(C 0-4 The heteroaryl portion of each alkylene-heteroaryl may be one or more (e.g., one, two, or three) R 42 The above -(C 0-4 A preferred example of the aryl moiety of the -(C alkylene)-aryl is phenyl. 0-4 Preferred examples of the heteroaryl moiety of the alkylene-heteroaryl are 5- or 6-membered monocyclic heteroaryls having 1 or 2 hetero ring atoms independently selected from oxygen, nitrogen, and sulfur, with the remaining ring atoms being carbon atoms, such as imidazolyl, thiophenyl, or pyrimidinyl. Even more preferred are R 41 is selected from phenyl and heteroaryl, where the heteroaryl is a 5- or 6-membered monocyclic heteroaryl having one or two hetero ring atoms independently selected from oxygen, nitrogen, and sulfur (the remaining ring atoms of the monocyclic heteroaryl are carbon atoms). Additionally, the phenyl or heteroaryl may contain one or more (e.g., one, two, or three) R 42The group is optionally substituted.

[0151] Each R 42 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), -N(C 1-6 alkyl)-CO-(C 1-6 alkyl), -SO2-NH2, -SO2-NH(C 1-6 alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl), and -N(C 1-6 alkyl)-SO2-(C 1-6 alkyl). Preferably, each R 42 is C 1-6 Alkyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), and —CN.

[0152] Each R 43 -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, -CF3, -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), and -N(C 1-6 alkyl)-CO-(C 1-6 alkyl). Preferably, each R 43 -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), halogen, —CF 3 , and —CN.

[0153] According to the above definition, particularly preferred are R 4a is -O-(C 0-4 alkylene)-aryl, -O-(C 0-4 alkylene)-heteroaryl, -S-(C 0-4 alkylene)-aryl, -S-(C 0-4 alkylene)-heteroaryl, -NH-(C 0-4alkylene)-aryl, -NH-(C 0-4 alkylene)-heteroaryl, -N(C 1-4 alkyl)-(C 0-4 alkylene)-aryl, -N(C 1-4 alkyl)-(C 0-4 alkylene)-heteroaryl, aryl, and heteroaryl, wherein any aryl portion of the above groups, any heteroaryl portion of the above groups, the aryl, and the heteroaryl each may be selected from one or more (e.g., one, two, or three) R 42 Even more preferably, R 4a is -O-aryl, -O-heteroaryl, -S-aryl, -S-heteroaryl, -NH-aryl, -NH-heteroaryl, -N(C 1-4 alkyl)-aryl, -N(C 1-4 alkyl)-heteroaryl, aryl, and heteroaryl, wherein any aryl portion of the above groups, any heteroaryl portion of the above groups, the aryl, and the heteroaryl are each selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 and optionally substituted with one or more groups independently selected from haloalkyl, and —CN. Even more preferably, R 4a is -O-phenyl, -O-heteroaryl, -S-phenyl, -S-heteroaryl, -NH-phenyl, -NH-heteroaryl, -N(C 1-4 alkyl)-phenyl, -N(C 1-4and (alkyl)-heteroaryl, phenyl, and heteroaryl, wherein the heteroaryl or any heteroaryl moiety of the above groups is a 5- or 6-membered monocyclic heteroaryl having one or two hetero ring atoms independently selected from oxygen, nitrogen, and sulfur (the remaining ring atoms of the monocyclic heteroaryl are carbon atoms). Furthermore, any phenyl moiety of the above groups, any heteroaryl moiety of the above groups, the phenyl, and the heteroaryl are each selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 R is optionally substituted with one or more groups independently selected from haloalkyl and -CN. 4a A particularly preferred example of is -O-phenyl.

[0154] In embodiment 3, R 5a -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -NO2 and hydrogen. 1-6 alkyl) and the alkyl portion of the above -N(C 1-6 Alkyl)(C 1-6 One or both alkyl moieties of the alkyl group may be halogen, -CF3, -CN, -NO2, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6and optionally substituted with one or more (e.g., one, two, or three) groups independently selected from alkyl, carbocyclyl, and heterocyclyl, wherein the carbocyclyl and heterocyclyl are each optionally substituted with one or more (e.g., one, two, or three) R 51 Preferably, R 5a -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), and -NO2. In this case, the above-mentioned -NH(C 1-6 alkyl) and the alkyl portion of the above -N(C 1-6 Alkyl)(C 1-6 One or both alkyl moieties of the alkyl group may be halogen, -CF3, -CN, -NO2, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -OH, -O(C 1-6 alkyl), -SH, and -S(C 1-6 alkyl). More preferably, R 5a -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), and —NO2. 5a Particularly suitable examples are -NH2, -NH-CH2CH2CH2CH3, or -NO2.

[0155] Each R 51 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), -N(C 1-6 alkyl)-CO-(C 1-6 alkyl), -SO2-NH2, -SO2-NH(C 1-6 alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl), and -N(C 1-6 alkyl)-SO2-(C 1-6 alkyl). Preferably, each R 51 is C 1-6 Alkyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), and —CN.

[0156] In embodiment 4, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0157] [ka]

[0158] At this time, R 4 and R 5 are interconnected to form -R 5b - group and other groups and variables in formula (Ia) (particularly R 1 , R 2 , R 3 and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0159] In embodiment 4, R 4 and R 5 are interconnected to form -R 5b - group is formed. 5b The group is -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-

[0160] Each R 5b1 is -N(R 52 )-, -O-, and -S-. R 5b2 is -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(R53 )-C(R 53 )(R 53 )-. R 5b3 is 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 a covalent bond and -C(R 53 )(R 53 )- is selected from.

[0161] Each R 52 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(C 0-4 alkylene)-aryl, and -(C 0-4 Preferably, each R is independently selected from the group consisting of alkylene, heteroaryl, and aryl. 52 is hydrogen, C 1-4 Alkyl (e.g., n-butyl), C 2-4 Alkenyl and C 2-4 alkynyl (e.g., —CH—C≡CH). Even more preferably, each R 52 is hydrogen.

[0162] Each R 53 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), -CN, -NO2, -CHO, -CO-(C 1-6alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), -N(C 1-6 alkyl)-CO-(C 1-6 alkyl), -SO2-NH2, -SO2-NH(C 1-6 alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl), -N(C 1-6 alkyl)-SO2-(C 1-6 alkyl), -(C 0-4 alkylene)-aryl, and -(C 0-4 In addition, any two R bonded to the same carbon atom are independently selected from the group consisting of alkylene, heteroaryl, and aryl. 53 The groups may be joined together to form a ═O group. Any two R groups attached to adjacent carbon atoms connected by a double bond may 53 Groups (i.e., -C(R 53 )=C(R 53 )-part contains any two R 53 groups) are linked together to form -C(R 54 )=C(R 54 )-C(R 54 )=C(R 54 )-group. Preferably, each R 53 is hydrogen, C 1-6 Alkyl, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 Any two R bonded to the same carbon atom are independently selected from -(haloalkyl), -(haloalkyl), and -CN. 53The groups may be joined together to form a ═O group. Any two R groups attached to adjacent carbon atoms connected by a double bond may 53 The groups are linked together to form -C(R 54 )=C(R 54 )-C(R 54 )=C(R 54 )-group. More preferably, each R 53 is hydrogen, C 1-6 Alkyl, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 Any two R bonded to the same carbon atom are independently selected from -(haloalkyl), -(haloalkyl), and -CN. 53 The groups may together form a =O group. Even more preferably, each R 53 is hydrogen, C 1-4 Alkyl, -OH, -O(C 1-4 alkyl), -NH2, -NH(C 1-4 alkyl), -N(C 1-4 Alkyl)(C 1-4 Alkyl), halogen, C 1-4 Haloalkyl, -O-(C 1-4 Any two R bonded to the same carbon atom are independently selected from -(haloalkyl), -(haloalkyl), and -CN. 53 The groups may together form a =O group.

[0163] Each R 54 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6Haloalkyl, -O-(C 1-6 haloalkyl), -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), -N(C 1-6 alkyl)-CO-(C 1-6 alkyl), -SO2-NH2, -SO2-NH(C 1-6 alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl), and -N(C 1-6 alkyl)-SO2-(C 1-6 alkyl). Preferably, each R 54 is hydrogen, C 1-6 Alkyl, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), and —CN. More preferably, each R 54 is hydrogen.

[0164] Particularly preferably, R 5b is -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 )(R53 )-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-、-O-C(R 53 )(R53 )-N(R 52 )-、-O-C(R 53 )(R 53 )-C(R 53 )(R 53 )-N(R 52 )-、-O-C(R 53 )=C(R 53 )-N(R 52 )-、-O-C(R 53 )(R 53 )-C(R 53 )(R 53 )-C(R 53 )(R 53 )-N(R 52 )-、-O-C(R 53 )(R 53 )-C(R 53 )=C(R 53 )-N(R 52 )-、-O-C(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-、-S-C(R 53 )(R 53 )-N(R 52 )-、-S-C(R 53 )(R 53 )-C(R 53 )(R 53 )-N(R 52 )-、-S-C(R 53 )=C(R 53 )-N(R 52 )-、-S-C(R 53 )(R 53 )-C(R 53 )(R 53 )-C(R 53 )(R 53 )-N(R 52 )-、-S-C(R 53 )(R 53 )-C(R 53 )=C(R 53 )-N(R 52 )-、-S-C(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(R53 )(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 )-, and -N(R 52 )-C(R 53 )=C(R 53 )-C(R 53 )(R 53 )-N(R 52 )- is selected from.

[0165] In embodiment 4, R is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 39 5b It is more preferable to select

[0166] [ka]

[0167] In embodiment 5, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0168] [ka]

[0169] At this time, R 4 is R 4a is a group, and R 4a is -O-phenyl and R 5 is R 5a group, and other groups and variables in formula (Ia) (particularly R 1 , R 2 , R 3 , R 5a and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0170] In embodiment 6, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0171] [ka]

[0172] At this time, R 4 is R 4a is a group, and R 5 is R 5a is a group, and R 5a is —NH2, and the other groups and variables in formula (Ia) (particularly R 1 , R 2 , R 3 , R 4a and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0173] In embodiment 7, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0174] [ka]

[0175] At this time, R 4 is R 4a is a group, and R 5 is R 5a is a group, and R 5a is —NH—CH2CH2CH2CH3, and the other groups and variables in formula (Ia) (particularly R 1 , R 2 , R 3 , R 4a and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0176] In embodiment 8, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0177] [ka]

[0178] At this time, R 4 is R 4a is a group, and R 5 is R 5a is a group, and R 5a is —NO2, and the other groups and variables in formula (Ia) (particularly R 1 , R 2 , R 3 , R 4a and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0179] In embodiment 9, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0180] [ka]

[0181] At this time, R 3 is —SO—NH, and the other groups and variables in formula (Ia) (particularly R 1 , R 2 , R 4 , R 5 and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0182] In embodiment 10, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0183] [ka]

[0184] At this time, R 3 is —SO2—N═CH—N(CH3)2, and the other groups and variables in formula (Ia) (particularly R 1 , R 2 , R 4 , R 5 and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0185] In embodiment 11, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0186] [ka]

[0187] At this time, R 3 is -SO2-NH2, and R 4 is R 4a is a group, and R 4a is -O-phenyl and R 5 is R 5agroup, and other groups and variables in formula (Ia) (particularly R 1 , R 2 , R 5a and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0188] In embodiment 12, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0189] [ka]

[0190] At this time, R 3 is -SO2-NH2, and R 4 is R 4a is a group, and R 5 is R 5a is a group, and R 5a is —NH2, and the other groups and variables in formula (Ia) (particularly R 1 , R 2 , R 4a and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0191] In embodiment 13, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0192] [ka]

[0193] At this time, R 3 is -SO2-NH2, and R 4 is R 4a is a group, and R 5 is R 5a is a group, and R 5ais —NH—CH2CH2CH2CH3, and the other groups and variables in formula (Ia) (particularly R 1 , R 2 , R 4a and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0194] In embodiment 14, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0195] [ka]

[0196] At this time, R 3 is -SO2-NH2, and R 4 is R 4a is a group, and R 5 is R 5a is a group, and R 5a is —NO2, and the other groups and variables in formula (Ia) (particularly R 1 , R 2 , R 4a and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0197] In embodiment 15, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0198] [ka]

[0199] At this time, R 3 is -SO2-N=CH-N(CH3)2, and R 4 is R 4a is a group, and R 4a is -O-phenyl and R 5is R 5a group, and other groups and variables in formula (Ia) (particularly R 1 , R 2 , R 5a and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0200] In embodiment 16, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0201] [ka]

[0202] At this time, R 3 is -SO2-N=CH-N(CH3)2, and R 4 is R 4a is a group, and R 5 is R 5a is a group, and R 5a is —NH2, and the other groups and variables in formula (Ia) (particularly R 1 , R 2 , R 4a and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0203] In embodiment 17, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0204] [ka]

[0205] At this time, R 3 is -SO2-N=CH-N(CH3)2, and R 4 is R 4a is a group, and R 5 is R 5ais a group, and R 5a is —NH—CH2CH2CH2CH3, and the other groups and variables in formula (Ia) (particularly R 1 , R 2 , R 4a and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0206] In embodiment 18, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0207] [ka]

[0208] At this time, R 3 is -SO2-N=CH-N(CH3)2, and R 4 is R 4a is a group, and R 5 is R 5a is a group, and R 5a is —NO2, and the other groups and variables in formula (Ia) (particularly R 1 , R 2 , R 4a and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0209] In embodiment 19, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0210] [ka]

[0211] At this time, R 4 is -O-phenyl and R 5 is —NH2, and the other groups and variables in formula (Ia) (particularly R 1, R 2 , R 3 , and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0212] In embodiment 20, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0213] [ka]

[0214] At this time, R 4 is -O-phenyl and R 5 is —NH—CH2CH2CH2CH3, and the other groups and variables in formula (Ia) (particularly R 1 , R 2 , R 3 , and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0215] In embodiment 21, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0216] [ka]

[0217] At this time, R 4 is -O-phenyl and R 5 is —NO2, and the other groups and variables in formula (Ia) (particularly R 1 , R 2 , R 3 , and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0218] In embodiment 22, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0219] [ka]

[0220] At this time, R 1 is as defined below, and the other groups and variables in formula (Ia) (particularly R 2 , R 3 , R 4 , R 5 and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0221] In embodiment 22, R 1 is -COO-(C 1-15 In this case, the above -COO-(C alkyl) 1-15 The alkyl portion of alkyl) is halogen, -CF3, -CN, -NO2, -NH2, -NH(C 1-4 alkyl), -N(C 1-4 Alkyl)(C 1-4 alkyl), -OH, -O(C 1-4 alkyl), -SH, and -S(C 1-4 alkyl). 1-15 One or two -CH2- units contained in the alkyl portion of the alkyl) are -O-, -CO-, -COO-, -O-CO-, -NH-, -N(C 1-4 alkyl)-, -NH-CO-, -N(C 1-4 alkyl)-CO-, -CO-NH-, -CO-N(C 1-4 alkyl)-, -S-, -SO-, -SO2-, -SO2-NH-, -SO2-N(C 1-4 alkyl)-, -NH-SO2-, and -N(C 1-4The above-mentioned -COO-(C alkyl)-SO2- is optionally substituted with a group independently selected from the group consisting of -COO-(C 1-15 The alkyl portion of such R has 1 to 15 (particularly, 1 to 10) carbon atoms. 1 Suitable examples of groups include the corresponding R 1 groups (especially -COO-CH or -COO-CHCH). Particularly preferred R 1 The group is -COO-CH3.

[0222] In embodiment 23, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0223] [ka]

[0224] At this time, R 1 is —COOH, and the other groups and variables in formula (Ia) (particularly R 2 , R 3 , R 4 , R 5 and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0225] In embodiment 24, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0226] [ka]

[0227] At this time, R 1 is as defined below, and the other groups and variables in formula (Ia) (particularly R 2 , R 3 , R 4 , R 5 and R6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0228] In embodiment 24, R 1 is -(C 1-4 alkylene)-NH-(C 1-4 alkylene)-R 12 (e.g., -CH2-NH-CH2-R 12 ), -COO-(C 1-4 alkylene)-R 12 (e.g., -COO-CH2-R 12 ), -O-CO-(C 1-4 alkylene)-R 12 , -CO-(C 1-4 alkylene)-R 12 , -CO-NH-(C 1-4 alkylene)-R 12 (e.g., -CO-NH-CH2-R 12 ), -CO-N(C 1-4 alkyl)-(C 1-4 alkylene)-R 12 , -NH-CO-(C 1-4 alkylene)-R 12 , and -N(C 1-4 alkyl)-CO-(C 1-4 alkylene)-R 12 In this case, R 12 are independently selected from -CF, -CN and halogen (e.g., -F, -Cl, -Br or -I). Preferably, R 12 is independently selected from -CF3 and -CN. More preferably, R 12 is -CF3. Such R 1 Specific examples of groups include the corresponding R 1 More preferably, R 1 is -(C 1-4 alkylene)-NH-(C 1-4 alkylene)-CF3. Even more preferably, R 1 is -CH2-NH-CH2-CF3.

[0229] Thus, according to embodiment 24, the present invention provides a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0230] [ka]

[0231] In embodiment 24, R in formula (Ia) 1 is -(C 1-4 alkylene)-NH-(C 1-4 alkylene)-R 12 (e.g., -CH2-NH-CH2-R 12 ), -COO-(C 1-4 alkylene)-R 12 (e.g., -COO-CH2-R 12 ), -O-CO-(C 1-4 alkylene)-R 12 , -CO-(C 1-4 alkylene)-R 12 , -CO-NH-(C 1-4 alkylene)-R 12 (e.g., -CO-NH-CH2-R 12 ), -CO-N(C 1-4 alkyl)-(C 1-4 alkylene)-R 12 , -NH-CO-(C 1-4 alkylene)-R 12 and -N(C 1-4 alkyl)-CO-(C 1-4 alkylene)-R 12 In this case, R 12 are independently selected from -CF, -CN and halogen (e.g., -F, -Cl, -Br or -I). Preferably, R 12 is independently selected from -CF3 and -CN. More preferably, R 12 is -CF3. Such R 1 Specific examples of groups include the corresponding R 1 Particularly preferred are groups such as R 1 is -(C 1-4alkylene)-NH-(C 1-4 alkylene)-CF3. Even more preferably, R 1 is -CH2-NH-CH2-CF3.

[0232] In embodiment 24, R 2 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), -N(C 1-6 alkyl)-CO-(C 1-6 alkyl), -SO2-NH2, -SO2-NH(C 1-6 alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl) and -N(C 1-6 alkyl)-SO2-(C 1-6 alkyl). Preferably, R 2 is hydrogen, C 1-6 Alkyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl) and —CN. More preferably, R 2 is hydrogen or C 1-4 Even more preferably, R 2 is hydrogen.

[0233] In embodiment 24, R 3 -SO2-NH2, -SO2-NH(C 1-6 alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -SO2-N=(C 1-6 In this case, the above-mentioned -SO2-NH(C 1-6 alkyl), the alkyl portion of -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), and the above -SO2-N=(C 1-6 The alkylidene moiety of alkylidene) is halogen, -CF3, -CN, -NO2, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -OH, -O(C 1-6 alkyl), -SH, and -S(C 1-6 alkyl). Preferably, R 3 -SO2-NH2, -SO2-NH(C 1-4 alkyl), -SO2-N(C 1-4 Alkyl)(C 1-4 alkyl), and -SO2-N=(C 1-4 In this case, the above -SO2-NH(C 1-4alkyl), the alkyl portion of -SO2-N(C 1-4 Alkyl)(C 1-4 alkyl), and the above -SO2-N=(C 1-4 The alkylidene moiety of alkylidene) is halogen, -CF3, -CN, -NO2, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -OH, -O(C 1-6 alkyl), -SH, and -S(C 1-6 alkyl). More preferably, R 3 -SO2-NH2, -SO2-NH(C 1-4 alkyl), -SO2-N(C 1-4 Alkyl)(C 1-4 alkyl), and -SO2-N=(C 1-4 In this case, the above -SO2-NH(C 1-4 alkyl), the alkyl portion of -SO2-N(C 1-4 Alkyl)(C 1-4 alkyl), and the above -SO2-N=(C 1-4 The alkylidene moiety of the alkylidene is -NH2, -NH(C 1-4 alkyl), and -N(C 1-4 Alkyl)(C 1-4 alkyl). Even more preferably, R 3 -SO2-NH2, -SO2-NH(C 1-4 alkyl), -SO2-N(C 1-4 Alkyl)(C 1-4 alkyl), -SO2-NH-(C 1-4 alkylene)-NH2, -SO2-NH-(C 1-4 alkylene)-NH(C 1-4 alkyl), -SO2-NH-(C 1-4 alkylene)-N(C 1-4 Alkyl)(C 1-4 alkyl), -SO2-N=(C1-4 alkylidene)-NH2, -SO2-N=(C 1-4 alkylidene)-NH(C 1-4 alkyl), and -SO2-N=(C 1-4 alkylidene)-N(C 1-4 Alkyl)(C 1-4 Even more preferably, R 3 are -SO2-NH2, -SO2-NH-CH3, -SO2-N(CH3)2, -SO2-NH-(C 1-4 alkylene)-NH2, -SO2-NH-(C 1-4 alkylene)-NH-CH3, -SO2-NH-(C 1-4 alkylene)-N(CH3)2 (e.g., -SO2-NH-CH2CH2-N(CH3)2), -SO2-N=(C 1-4 alkylidene)-NH2, -SO2-N=(C 1-4 alkylidene)-NH-CH3 and -SO2-N=(C 1-4 Even more preferably, R is selected from the group consisting of -SO-N=CH-N(CH) and -SO-N=CH-N(CH). 3 is -SO2-NH2.

[0234] In embodiment 24, R 4 -OR 41 , -SR 41 , -NH-R 41 , -N(C 1-6 alkyl)-R 41 , halogen (e.g., —Cl), hydrogen, carbocyclyl, and heterocyclyl, wherein the carbocyclyl and the heterocyclyl each have one or more (e.g., one, two, or three) R 42 Preferably, R 4 -OR 41 , -SR 41 , -NH-R 41 , -N(C 1-6 alkyl)-R 41, halogen, carbocyclyl, and heterocyclyl, wherein the carbocyclyl and the heterocyclyl are each selected from one or more R 42 More preferably, R 4 -OR 41 , -SR 41 , -NH-R 41 , -N(C 1-6 alkyl)-R 41 , carbocyclyl (e.g., aryl, cycloalkyl, or cycloalkenyl), and heterocyclyl (e.g., heteroaryl, heterocycloalkyl, or heterocycloalkenyl), wherein the carbocyclyl and the heterocyclyl each are selected from one or more R 42 Even more preferably, R 4 -OR 41 , -SR 41 , -NH-R 41 , -N(C 1-4 alkyl)-R 41 , aryl, and heteroaryl, wherein the aryl and heteroaryl are each selected from one or more R 42 is optionally substituted with a group of

[0235] In embodiment 24, R 41 is -(C 0-4 alkylene)-carbocyclyl, -(C 0-4 alkylene)-heterocyclyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl. In this case, the above-mentioned -(C 0-4 The carbocyclyl portion of the -(C alkylene)-carbocyclyl 0-4 The heterocyclyl portion of each alkylene-heterocyclyl may be one or more (e.g., one, two, or three) R 42 In this case, the above C 1-6 Alkyl, above C 2-6 Alkenyl, above C 2-6 Alkynyl, as defined above -(C0-4 alkylene)-carbocyclyl, and the alkylene portion of the above-(C 0-4 Each alkylene portion of the alkylene-heterocyclyl may be one or more (e.g., one, two, or three) R 43 Preferably, R 41 is -(C 0-4 alkylene)-carbocyclyl, -(C 0-4 alkylene)-heterocyclyl, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 alkynyl. In this case, the above-mentioned -(C 0-4 The carbocyclyl moiety of the -(C alkylene)-carbocyclyl is selected from cycloalkyl, cycloalkenyl, and aryl. 0-4 The heterocyclyl moiety of the -(C alkylene)-heterocyclyl is selected from heterocycloalkyl, heterocycloalkenyl, and heteroaryl. 0-4 The carbocyclyl portion of the -(C alkylene)-carbocyclyl 0-4 The heterocyclyl portion of each alkylene-heterocyclyl may be one or more (e.g., one, two, or three) R 42 Further, the above C 1-6 Alkyl, above C 2-6 Alkenyl, above C 2-6 Alkynyl, as defined above -(C 0-4 alkylene)-carbocyclyl, and the alkylene portion of the above-(C 0-4 Each alkylene portion of the alkylene-heterocyclyl may be one or more (e.g., one, two, or three) R 43 More preferably, R 41 is -(C 0-4 alkylene)-aryl, and -(C 0-4 In this case, the above-mentioned -(C 0-4 the aryl portion of the -(C alkylene)-aryl; 0-4The heteroaryl portion of each alkylene-heteroaryl may be one or more (e.g., one, two, or three) R 42 The above-mentioned -(C 0-4 alkylene)-aryl, and the alkylene portion of the above-(C 0-4 Each alkylene portion of the alkylene-heteroaryl may be one or more (e.g., one, two, or three) R 43 Even more preferably, R 41 is -(C 0-4 alkylene)-aryl, and -(C 0-4 In this case, the above-mentioned -(C 0-4 the aryl portion of the -(C alkylene)-aryl; 0-4 The heteroaryl portion of each alkylene-heteroaryl may be one or more (e.g., one, two, or three) R 42 The above -(C 0-4 A preferred example of the aryl moiety of the -(C alkylene)-aryl is phenyl. 0-4 Preferred examples of the heteroaryl moiety of the alkylene-heteroaryl are 5- or 6-membered monocyclic heteroaryls having 1 or 2 hetero ring atoms independently selected from oxygen, nitrogen, and sulfur, with the remaining ring atoms being carbon atoms, such as imidazolyl, thiophenyl, or pyrimidinyl. Even more preferred are R 41 is selected from phenyl and heteroaryl, where the heteroaryl is a 5- or 6-membered monocyclic heteroaryl having one or two hetero ring atoms independently selected from oxygen, nitrogen, and sulfur (the remaining ring atoms of the monocyclic heteroaryl are carbon atoms). Additionally, the phenyl or heteroaryl may contain one or more (e.g., one, two, or three) R 42 The group is optionally substituted.

[0236] In embodiment 24, each R 42 is C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), -N(C 1-6 alkyl)-CO-(C 1-6 alkyl), -SO2-NH2, -SO2-NH(C 1-6 alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl), and -N(C 1-6 alkyl)-SO2-(C 1-6 alkyl). Preferably, each R 42 is C 1-6 Alkyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C1-6 haloalkyl), and —CN.

[0237] In embodiment 24, each R 43 -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, -CF3, -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), and -N(C 1-6 alkyl)-CO-(C 1-6 alkyl). Preferably, each R 43 -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), halogen, —CF 3 , and —CN.

[0238] In embodiment 24, according to the above definition, particularly preferred are R 4 is -O-(C 0-4 alkylene)-aryl, -O-(C 0-4 alkylene)-heteroaryl, -S-(C 0-4 alkylene)-aryl, -S-(C 0-4 alkylene)-heteroaryl, -NH-(C 0-4 alkylene)-aryl, -NH-(C 0-4 alkylene)-heteroaryl, -N(C 1-4 alkyl)-(C0-4 alkylene)-aryl, -N(C 1-4 alkyl)-(C 0-4 alkylene)-heteroaryl, aryl, and heteroaryl, wherein any aryl portion of the above groups, any heteroaryl portion of the above groups, the aryl, and the heteroaryl each may be selected from one or more (e.g., one, two, or three) R 42 Even more preferably, R 4 is -O-aryl, -O-heteroaryl, -S-aryl, -S-heteroaryl, -NH-aryl, -NH-heteroaryl, -N(C 1-4 alkyl)-aryl, -N(C 1-4 and (alkyl)-heteroaryl, aryl, and heteroaryl, wherein any aryl portion of the above groups, any heteroaryl portion of the above groups, the aryl, and the heteroaryl are each selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 and optionally substituted with one or more groups independently selected from haloalkyl, and —CN. Even more preferably, R 4 is -O-phenyl, -O-heteroaryl, -S-phenyl, -S-heteroaryl, -NH-phenyl, -NH-heteroaryl, -N(C 1-4 alkyl)-phenyl, -N(C 1-4and (alkyl)-heteroaryl, phenyl, and heteroaryl, wherein the heteroaryl or any heteroaryl moiety of the above groups is a 5- or 6-membered monocyclic heteroaryl having one or two hetero ring atoms independently selected from oxygen, nitrogen, and sulfur (the remaining ring atoms of the monocyclic heteroaryl are carbon atoms). Furthermore, any phenyl moiety of the above groups, any heteroaryl moiety of the above groups, the phenyl, and the heteroaryl are each selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 and optionally substituted with one or more groups independently selected from haloalkyl and —CN. Even more preferably, R 4 is -O-phenyl.

[0239] In embodiment 24, R 5 -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -NO2 and hydrogen. 1-6 alkyl) and the alkyl portion of the above -N(C 1-6 Alkyl)(C 1-6 One or both alkyl moieties of the alkyl group may be halogen, -CF3, -CN, -NO2, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6and optionally substituted with one or more (e.g., one, two, or three) groups independently selected from alkyl, carbocyclyl, and heterocyclyl, wherein the carbocyclyl and heterocyclyl are each optionally substituted with one or more (e.g., one, two, or three) R 51 Preferably, R 5 -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), and -NO2. In this case, the above-mentioned -NH(C 1-6 alkyl) and the alkyl portion of the above -N(C 1-6 Alkyl)(C 1-6 One or both alkyl moieties of the alkyl group may be halogen, -CF3, -CN, -NO2, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -OH, -O(C 1-6 alkyl), -SH and -S(C 1-6 alkyl). More preferably, R 5 -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), and —NO. Even more preferably, R 5 is -NH2, -NH(C 1-6 alkyl), and -N(C 1-6 Alkyl)(C 1-6 Even more preferably, R 5 is -NH(C 1-6 alkyl). Even more preferably, R 5 is -NH-CH2CH2CH2CH3.

[0240] In embodiment 24, each R 51 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), -N(C 1-6 alkyl)-CO-(C 1-6 alkyl), -SO2-NH2, -SO2-NH(C 1-6 alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl), and -N(C 1-6 alkyl)-SO2-(C 1-6 alkyl). Preferably, each R 51 is C 1-6 Alkyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), and —CN.

[0241] In embodiment 24, R 6 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), -N(C 1-6 alkyl)-CO-(C 1-6 alkyl), -SO2-NH2, -SO2-NH(C 1-6 alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl), and -N(C 1-6 alkyl)-SO2-(C 1-6 alkyl). Preferably, R 6 is hydrogen, C 1-6 Alkyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), and —CN. More preferably, R 6 is hydrogen or C 1-4 Even more preferably, R 6 is hydrogen.

[0242] According to embodiment 24, the compound of formula (Ia) may in particular be a compound of any one of the following formulae: or a pharmaceutically acceptable salt or solvate thereof:

[0243] [ka]

[0244] The present invention also relates to a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof as described in embodiment 24 for use as a medicament. Similarly, the present invention relates to a pharmaceutical composition comprising the compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient. The present invention further relates to a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof (or a pharmaceutical composition comprising any of the above-mentioned elements and a pharmaceutically acceptable excipient) for use in the treatment or prevention of a disease or disorder involving NKCC (particularly a disease or disorder involving NKCC1, and particularly any one of the specific diseases / disorders described herein). The present invention also relates to the use of the compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for the treatment or prevention of a disease or disorder involving NKCC (particularly a disease or disorder involving NKCC1, and particularly any one of the specific diseases / disorders described herein). The present invention also provides a method for treating or preventing a disease or disorder involving NKCC (particularly a disease or disorder involving NKCC1, and particularly any one of the specific diseases / disorders described herein). The method comprises administering a compound of formula (Ia) as described in embodiment 24 or a pharmaceutically acceptable salt or solvate thereof (or a pharmaceutical composition comprising any of the aforementioned elements together with a pharmaceutically acceptable excipient) to a subject (preferably a human) in need thereof. It will be understood that in this method, a therapeutically effective amount of a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof (or a therapeutically effective amount of a pharmaceutical composition) is administered.

[0245] In embodiment 25, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0246] [ka]

[0247] At this time, R1 is as defined below, and the other groups and variables in formula (Ia) (particularly R 2 , R 3 , R 4 , R 5 and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0248] In embodiment 25, R 1 is -(C 1-4 alkylene)-S-heterocyclyl, preferably -(C 1-4 alkylene)-S-heteroaryl (e.g., -CH-S-heteroaryl). 1-4 alkylene)-S-heterocyclyl, or the heterocyclyl portion of the above-(C 1-4 The heteroaryl portion of the above-mentioned -CH2-S-heteroaryl is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, -CN, -NO2, -N(R 11 )(R 11 ), -O(R 11 ), -S(R 11 ), —SO3H, carbocyclyl, and heterocyclyl. 1 Specific examples of groups include the corresponding R 1 Examples of such groups include:

[0249] In embodiment 26, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0250] [ka]

[0251] At this time, R1 is as defined below, and the other groups and variables in formula (Ia) (particularly R 2 , R 3 , R 4 , R 5 and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0252] In embodiment 26, R 1 Ha-(C 1-4 alkylene)-O-(C 0-4 alkylene)-carbocyclyl, preferably -(C 1-4 alkylene)-O-(C 0-4 alkylene)-phenyl (e.g., —CH—O-phenyl or —CH—O—CH-phenyl). 1-4 alkylene)-O-(C 0-4 the carbocyclyl portion of the -(C alkylene)-carbocyclyl, or 1-4 alkylene)-O-(C 0-4 The phenyl portion of the alkylene)-phenyl (or the above-mentioned -CH2-O-phenyl or -CH2-O-CH2-phenyl) is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, -CN, -NO2, -N(R 11 )(R 11 ), -O(R 11 ), -S(R 11 ), —SO3H, carbocyclyl, and heterocyclyl. 1 Specific examples of groups include the corresponding R 1 Examples of such groups include:

[0253] In embodiment 27, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0254] [ka]

[0255] At this time, R 1 is as defined below, and the other groups and variables in formula (Ia) (particularly R 2 , R 3 , R 4 , R 5 and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0256] In embodiment 27, R 1 Ha-(C 1-4 alkylene)-heterocyclyl, preferably -CH2-heterocyclyl. 1-4 alkylene)-heterocyclyl, or the heterocyclyl moiety of the above-mentioned -CH2-heterocyclyl is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, -CN, -NO2, -N(R 11 )(R 11 ), -O(R 11 ), -S(R 11 ), -SO3H, carbocyclyl, and heterocyclyl. The heterocyclyl moiety may be, for example, a heterocycloalkyl (such as pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl), a heterocycloalkenyl (such as tetrahydropyridinyl), or a heteroaryl. Such R 1 Specific examples of groups include the corresponding R 1 Examples of such groups include:

[0257] In embodiment 28, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0258] [ka]

[0259] At this time, R 1 is -COOH and R 3 is -SO2-NH2, and R 4 is R 4a is a group, and R 5 is R 5a is a group, and R 5a is —NH2, and the other groups and variables in formula (Ia) (particularly R 2 , R 4a and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0260] In embodiment 29, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0261] [ka]

[0262] At this time, R 1 is -COOH and R 3 is -SO2-NH2, and R 4 is R 4a is a group, and R 5 is R 5a is a group, and R 5a is —NH—CH2CH2CH2CH3, and the other groups and variables in formula (Ia) (particularly R 2 , R 4a and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0263] In embodiment 30, the compound of Formula (I) is a compound of Formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0264] [ka]

[0265] At this time, R 1 is -COOH and R 3 is -SO2-NH2, and R 4 is R 4a is a group, and R 5 is R 5a is a group, and R 5a is —NO2, and the other groups and variables in formula (Ia) (particularly R 2 , R 4a and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0266] In embodiment 31, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0267] [ka]

[0268] At this time, R 1 is -COOH and R 3 is -SO2-N=CH-N(CH3)2, and R 4 is R 4a is a group, and R 5 is R 5a is a group, and R 5a is —NH2, and the other groups and variables in formula (Ia) (particularly R 2 , R 4a and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0269] In embodiment 32, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0270] [ka]

[0271] At this time, R 1 is -COOH and R 3 is -SO2-N=CH-N(CH3)2, and R 4 is R 4a is a group, and R 5 is R 5a is a group, and R 5a is —NH—CH2CH2CH2CH3, and the other groups and variables in formula (Ia) (particularly R 2 , R 4a and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0272] In embodiment 33, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0273] [ka]

[0274] At this time, R 1 is -COOH and R 3 is -SO2-N=CH-N(CH3)2, and R 4 is R 4a is a group, and R 5 is R 5a is a group, and R 5a is —NO2, and the other groups and variables in formula (Ia) (particularly R 2 , R 4a and R 6) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0275] In embodiment 34, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0276] [ka]

[0277] At this time, R 1 is -COO-CH3, and R 3 is -SO2-NH2, and R 4 is R 4a is a group, and R 5 is R 5a is a group, and R 5a is —NH2, and the other groups and variables in formula (Ia) (particularly R 2 , R 4a and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0278] In embodiment 35, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0279] [ka]

[0280] At this time, R 1 is -COO-CH3, and R 3 is -SO2-NH2, and R 4 is R 4a is a group, and R 5 is R 5a is a group, and R 5a is —NH—CH2CH2CH2CH3, and the other groups and variables in formula (Ia) (particularly R 2 , R4a and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0281] In embodiment 36, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0282] [ka]

[0283] At this time, R 1 is -COO-CH3, and R 3 is -SO2-NH2, and R 4 is R 4a is a group, and R 5 is R 5a is a group, and R 5a is —NO2, and the other groups and variables in formula (Ia) (particularly R 2 , R 4a and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0284] In embodiment 37, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0285] [ka]

[0286] At this time, R 1 is -COO-CH3, and R 3 is -SO2-N=CH-N(CH3)2, and R 4 is R 4a is a group, and R 5 is R 5a is a group, and R 5ais —NH2, and the other groups and variables in formula (Ia) (particularly R 2 , R 4a and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0287] In embodiment 38, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0288] [ka]

[0289] At this time, R 1 is -COO-CH3, and R 3 is -SO2-N=CH-N(CH3)2, and R 4 is R 4a is a group, and R 5 is R 5a is a group, and R 5a is —NH—CH2CH2CH2CH3, and the other groups and variables in formula (Ia) (particularly R 2 , R 4a and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0290] In embodiment 39, the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0291] [ka]

[0292] At this time, R 1 is -COO-CH3, and R 3 is -SO2-N=CH-N(CH3)2, and R 4 is R 4a is a group, and R5 is R 5a is a group, and R 5a is —NO2, and the other groups and variables in formula (Ia) (particularly R 2 , R 4a and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0293] In embodiment 40, the compound of formula (I) is a compound of formula (Ib): or a pharmaceutically acceptable salt or solvate thereof:

[0294] [ka]

[0295] At this time, R 4 is R 4a is a group, and R 5 is R 5a group, and other groups and variables in formula (Ib) (particularly R x and R 6 ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0296] In embodiment 40, R 4a -OR 41 , -SR 41 , -NH-R 41 , -N(C 1-6 alkyl)-R 41 , halogen (e.g., —Cl), carbocyclyl, and heterocyclyl, wherein the carbocyclyl and the heterocyclyl each have one or more (e.g., one, two, or three) R 42 Preferably, R 4a -OR 41 , -SR 41 , -NH-R 41 , -N(C 1-6 alkyl)-R 41, halogen, carbocyclyl (e.g., aryl, cycloalkyl, or cycloalkenyl), and heterocyclyl (e.g., heteroaryl, heterocycloalkyl, or heterocycloalkenyl), wherein the carbocyclyl and the heterocyclyl each are selected from one or more R 42 More preferably, R 4a -OR 41 , -SR 41 , -NH-R 41 , -N(C 1-4 alkyl)-R 41 , halogen, aryl, and heteroaryl, wherein the aryl and heteroaryl are each selected from one or more R 42 Even more preferably, R 4a -OR 41 , -SR 41 , -NH-R 41 , -N(C 1-4 alkyl)-R 41 and halogen. Even more preferably, R 4a -OR 41 Or a halogen.

[0297] R 41 is -(C 0-4 alkylene)-carbocyclyl, -(C 0-4 alkylene)-heterocyclyl, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 alkynyl, wherein the above-mentioned -(C 0-4 The carbocyclyl portion of the -(C alkylene)-carbocyclyl 0-4 The heterocyclyl portion of each alkylene-heterocyclyl may be one or more (e.g., one, two, or three) R 42 In this case, the above C 1-6 Alkyl, above C 2-6 Alkenyl, above C 2-6 Alkynyl, as defined above -(C 0-4alkylene)-carbocyclyl, and the alkylene portion of the above-(C 0-4 Each alkylene portion of the alkylene-heterocyclyl may be one or more (e.g., one, two, or three) R 43 Preferably, R 41 is -(C 0-4 alkylene)-carbocyclyl, -(C 0-4 alkylene)-heterocyclyl, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 alkynyl. In this case, the above-mentioned -(C 0-4 The carbocyclyl portion of the -(C alkylene)-carbocyclyl is selected from cycloalkyl, cycloalkenyl, and aryl. 0-4 The heterocyclyl moiety of the -(C alkylene)-heterocyclyl is selected from heterocycloalkyl, heterocycloalkenyl, and heteroaryl. 0-4 The carbocyclyl portion of the -(C alkylene)-carbocyclyl 0-4 The heterocyclyl portion of each alkylene-heterocyclyl may be one or more (e.g., one, two, or three) R 42 Further, the above C 1-6 Alkyl, above C 2-6 Alkenyl, above C 2-6 Alkynyl, as defined above -(C 0-4 alkylene)-carbocyclyl, and the alkylene portion of the above-(C 0-4 Each alkylene portion of the alkylene-heterocyclyl may be one or more (e.g., one, two, or three) R 43 More preferably, R 41 is -(C 0-4 alkylene)-aryl, and -(C 0-4 In this case, the above-mentioned -(C 0-4 the aryl portion of the -(C alkylene)-aryl; 0-4The heteroaryl portion of each alkylene-heteroaryl may be one or more (e.g., one, two, or three) R 42 The above-mentioned -(C 0-4 alkylene)-aryl, and the alkylene portion of the above-(C 0-4 Each alkylene portion of the alkylene-heteroaryl may be one or more (e.g., one, two, or three) R 43 Even more preferably, R 41 is -(C 0-4 alkylene)-aryl, and -(C 0-4 In this case, the above-mentioned -(C 0-4 the aryl portion of the -(C alkylene)-aryl; 0-4 The heteroaryl portion of each alkylene-heteroaryl may be one or more (e.g., one, two, or three) R 42 The above -(C 0-4 A preferred example of the aryl moiety of the -(C alkylene)-aryl is phenyl. 0-4 Preferred examples of the heteroaryl moiety of the alkylene-heteroaryl are 5- or 6-membered monocyclic heteroaryls having 1 or 2 hetero ring atoms independently selected from oxygen, nitrogen, and sulfur, with the remaining ring atoms being carbon atoms, such as imidazolyl, thiophenyl, or pyrimidinyl. Even more preferred are R 41 is selected from phenyl and heteroaryl, where the heteroaryl is a 5- or 6-membered monocyclic heteroaryl having one or two hetero ring atoms independently selected from oxygen, nitrogen, and sulfur (the remaining ring atoms of the monocyclic heteroaryl are carbon atoms). Additionally, the phenyl or heteroaryl may contain one or more (e.g., one, two, or three) R 42 The group is optionally substituted.

[0298] Each R 42 is C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), -N(C 1-6 alkyl)-CO-(C 1-6 alkyl), -SO2-NH2, -SO2-NH(C 1-6 alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl), and -N(C 1-6 alkyl)-SO2-(C 1-6 alkyl). Preferably, each R 42 is C 1-6 Alkyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6haloalkyl), and —CN.

[0299] Each R 43 -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, -CF3, -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), and -N(C 1-6 alkyl)-CO-(C 1-6 alkyl). Preferably, each R 43 -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), halogen, —CF 3 , and —CN.

[0300] According to the above definition, particularly preferred are R 4a is -O-aryl or halogen. In this case, the aryl portion of the -O-aryl is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 and optionally substituted with one or more groups independently selected from haloalkyl and -CN. Even more preferably, R 4a is -O-phenyl or halogen (especially, -Cl, etc.). In this case, the phenyl portion of the -O-phenyl is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Optionally substituted with one or more groups independently selected from haloalkyl, and -CN.

[0301] In embodiment 40, R 5a -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -NO2 and hydrogen. 1-6 alkyl) and the alkyl portion of the above -N(C 1-6 Alkyl)(C 1-6 One or both alkyl moieties of the alkyl group may be halogen, -CF3, -CN, -NO2, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6and optionally substituted with one or more (e.g., one, two, or three) groups independently selected from alkyl, carbocyclyl, and heterocyclyl, wherein the carbocyclyl and heterocyclyl are each optionally substituted with one or more (e.g., one, two, or three) R 51 Preferably, R 5a -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -NO2 and hydrogen. 1-6 alkyl) and the alkyl portion of the above -N(C 1-6 Alkyl)(C 1-6 One or both alkyl moieties of the alkyl group may be halogen, -CF3, -CN, -NO2, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -OH, -O(C 1-6 alkyl), -SH, and -S(C 1-6 alkyl). More preferably, R 5a -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -NO2 and hydrogen. 5a Particularly suitable examples of are -NH2, -NH-CH2CH2CH2CH3, -NO2 or hydrogen.

[0302] Each R 51 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), -N(C 1-6 alkyl)-CO-(C 1-6 alkyl), -SO2-NH2, -SO2-NH(C 1-6 alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl), and -N(C 1-6 alkyl)-SO2-(C 1-6 alkyl). Preferably, each R 51 is C 1-6 Alkyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), and —CN.

[0303] In embodiment 41, the compound of formula (I) is a compound of formula (Ib): or a pharmaceutically acceptable salt or solvate thereof:

[0304] [ka]

[0305] The meanings of the groups and variables of formula (Ib) are as follows:

[0306] In embodiment 41, R x -COOH, -COO-(C 1-6 alkyl), -SO2-NH2, -SO2-NH(C 1-4 alkyl), -SO2-N(C 1-4 Alkyl)(C 1-4 alkyl), and -SO2-N=(C 1-4 In this case, the above -SO2-NH(C 1-4 alkyl), the alkyl portion of -SO2-N(C 1-4 Alkyl)(C 1-4 alkyl), and the above -SO2-N=(C 1-4 The alkylidene moiety of the alkylidene is -NH2, -NH(C 1-4 alkyl), and -N(C 1-4 Alkyl)(C 1-4 alkyl). Preferably, R x is selected from -COOH, -COOCH3, -SO2-NH2, and -SO2-N=CH-N(CH3)2.

[0307] In embodiment 41, R 4 is R 4a It is the base.

[0308] R 4a -OR 41 , -SR 41 , -NH-R 41 , -N(C 1-6 alkyl)-R 41 , halogen (e.g., —Cl), carbocyclyl, and heterocyclyl, wherein the carbocyclyl and the heterocyclyl each have one or more (e.g., one, two, or three) R 42Preferably, R 4a -OR 41 , -SR 41 , -NH-R 41 , -N(C 1-6 alkyl)-R 41 , halogen, carbocyclyl (e.g., aryl, cycloalkyl, or cycloalkenyl), and heterocyclyl (e.g., heteroaryl, heterocycloalkyl, or heterocycloalkenyl), wherein the carbocyclyl and the heterocyclyl each are selected from one or more R 42 More preferably, R 4a -OR 41 , -SR 41 , -NH-R 41 , -N(C 1-4 alkyl)-R 41 , halogen, aryl, and heteroaryl, wherein the aryl and heteroaryl are each selected from one or more R 42 Even more preferably, R 4a -OR 41 , -SR 41 , -NH-R 41 , -N(C 1-4 alkyl)-R 41 and halogen. Even more preferably, R 4a -OR 41 Or a halogen.

[0309] R 41 is -(C 0-4 alkylene)-carbocyclyl, -(C 0-4 alkylene)-heterocyclyl, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 alkynyl. In this case, the above-mentioned -(C 0-4 The carbocyclyl portion of the -(C alkylene)-carbocyclyl 0-4 The heterocyclyl portion of each alkylene-heterocyclyl may be one or more (e.g., one, two, or three) R42 In this case, the above C 1-6 Alkyl, above C 2-6 Alkenyl, above C 2-6 Alkynyl, as defined above -(C 0-4 alkylene)-carbocyclyl, and the alkylene portion of the above-(C 0-4 Each alkylene portion of the alkylene-heterocyclyl may be one or more (e.g., one, two, or three) R 43 Preferably, R 41 is -(C 0-4 alkylene)-carbocyclyl, -(C 0-4 alkylene)-heterocyclyl, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 alkynyl. In this case, the above-mentioned -(C 0-4 The carbocyclyl portion of the -(C alkylene)-carbocyclyl is selected from cycloalkyl, cycloalkenyl, and aryl. 0-4 The heterocyclyl moiety of the -(C alkylene)-heterocyclyl is selected from heterocycloalkyl, heterocycloalkenyl, and heteroaryl. 0-4 The carbocyclyl portion of the -(C alkylene)-carbocyclyl 0-4 The heterocyclyl portion of each alkylene-heterocyclyl may be one or more (e.g., one, two, or three) R 42 Further, the above C 1-6 Alkyl, above C 2-6 Alkenyl, above C 2-6 Alkynyl, as defined above -(C 0-4 alkylene)-carbocyclyl, and the alkylene portion of the above-(C 0-4 Each alkylene portion of the alkylene-heterocyclyl may be one or more (e.g., one, two, or three) R 43 More preferably, R 41 is -(C 0-4 alkylene)-aryl and -(C 0-4In this case, the above-mentioned -(C 0-4 the aryl portion of the -(C alkylene)-aryl; 0-4 The heteroaryl portion of each alkylene-heteroaryl may be one or more (e.g., one, two, or three) R 42 The above-mentioned -(C 0-4 alkylene)-aryl, and the alkylene portion of the above-(C 0-4 Each alkylene portion of the alkylene-heteroaryl may be one or more (e.g., one, two, or three) R 43 Even more preferably, R 41 is -(C 0-4 alkylene)-aryl and -(C 0-4 In this case, the above-mentioned -(C 0-4 the aryl portion of the -(C alkylene)-aryl; 0-4 The heteroaryl portion of each alkylene-heteroaryl may be one or more (e.g., one, two, or three) R 42 The above -(C 0-4 A preferred example of the aryl moiety of the -(C alkylene)-aryl is phenyl. 0-4 Preferred examples of the heteroaryl moiety of the alkylene-heteroaryl are 5- or 6-membered monocyclic heteroaryls having 1 or 2 hetero ring atoms independently selected from oxygen, nitrogen, and sulfur, with the remaining ring atoms being carbon atoms, such as imidazolyl, thiophenyl, or pyrimidinyl. Even more preferred are R 41 is selected from phenyl and heteroaryl, where the heteroaryl is a 5- or 6-membered monocyclic heteroaryl having one or two hetero ring atoms independently selected from oxygen, nitrogen, and sulfur (the remaining ring atoms of the monocyclic heteroaryl are carbon atoms). Additionally, the phenyl or heteroaryl may have one or more (e.g., one, two, or three) R 42 The group is optionally substituted.

[0310] Each R 42 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), -N(C 1-6 alkyl)-CO-(C 1-6 alkyl), -SO2-NH2, -SO2-NH(C 1-6 alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl), and -N(C 1-6 alkyl)-SO2-(C 1-6 alkyl). Preferably, each R 42 is C 1-6 Alkyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), and —CN.

[0311] Each R 43 -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, -CF3, -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), and -N(C 1-6 alkyl)-CO-(C 1-6 alkyl). Preferably, each R 43 -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), halogen, —CF 3 , and —CN.

[0312] According to the above definition, R 4a is particularly preferably -O-aryl or halogen. In this case, the aryl portion of the -O-aryl is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 and optionally substituted with one or more groups independently selected from haloalkyl and —CN. Even more preferably, R 4a is -O-phenyl or halogen (especially, -Cl, etc.). In this case, the phenyl portion of the -O-phenyl is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Optionally substituted with one or more groups independently selected from haloalkyl, and -CN.

[0313] In embodiment 41, R 5 is R 5a It is the base.

[0314] R 5a -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -NO2 and hydrogen. 1-6 alkyl) and the alkyl portion of the above -N(C 1-6 Alkyl)(C 1-6 One or both alkyl moieties of the alkyl group may be halogen, -CF3, -CN, -NO2, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6alkyl), -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 and optionally substituted with one or more (e.g., one, two, or three) groups independently selected from alkyl, carbocyclyl, and heterocyclyl, wherein the carbocyclyl and heterocyclyl are each optionally substituted with one or more (e.g., one, two, or three) R 51 Preferably, R 5a -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -NO2 and hydrogen. 1-6 alkyl) and the alkyl portion of the above -N(C 1-6 Alkyl)(C 1-6 One or both alkyl moieties of the alkyl group may be halogen, -CF3, -CN, -NO2, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -OH, -O(C 1-6 alkyl), -SH, and -S(C 1-6 alkyl). More preferably, 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -NO2 and hydrogen. 5a Particularly suitable examples of are -NH2, -NH-CH2CH2CH2CH3, -NO2 or hydrogen.

[0315] Each R 51 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), -N(C 1-6 alkyl)-CO-(C 1-6 alkyl), -SO2-NH2, -SO2-NH(C 1-6 alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl) and -N(C 1-6 alkyl)-SO2-(C 1-6 alkyl). Preferably, each R 51 is C 1-6 Alkyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl) and —CN.

[0316] R 6 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), -N(C 1-6 alkyl)-CO-(C 1-6 alkyl), -SO2-NH2, -SO2-NH(C 1-6 alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl), and -N(C 1-6 alkyl)-SO2-(C 1-6 alkyl). Preferably, R 6 is hydrogen, C 1-6 Alkyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6haloalkyl), and —CN. More preferably, R 6 is hydrogen or C 1-4 Even more preferably, R 6 is hydrogen.

[0317] In embodiment 42, the compound of formula (I) is a compound of formula (Ib): or a pharmaceutically acceptable salt or solvate thereof:

[0318] [ka]

[0319] At this time, R x is selected from -COOH, -COOCH3, -SO2-NH2 and -SO2-N=CH-N(CH3)2, and the other groups and variables in formula (Ib) (particularly R 4 , R 5 and R 6 ) have the same meanings (and preferred meanings) as described and defined in embodiment 41.

[0320] In embodiment 43, the compound of formula (I) is a compound of formula (Ib): or a pharmaceutically acceptable salt or solvate thereof:

[0321] [ka]

[0322] At this time, R x is —COOH, and the other groups and variables in formula (Ib) (particularly R 4 , R 5 and R 6 ) have the same meanings (and preferred meanings) as described and defined in embodiment 41.

[0323] In embodiment 44, the compound of formula (I) is a compound of formula (Ib): or a pharmaceutically acceptable salt or solvate thereof:

[0324] [ka]

[0325] At this time, R x is —COOCH3, and the other groups and variables in formula (Ib) (particularly R 4 , R 5 and R 6 ) have the same meanings (and preferred meanings) as described and defined in embodiment 41.

[0326] In embodiment 45, the compound of formula (I) is a compound of formula (Ib): or a pharmaceutically acceptable salt or solvate thereof:

[0327] [ka]

[0328] At this time, R x is —SO—NH, and the other groups and variables in formula (Ib) (particularly R 4 , R 5 and R 6 ) have the same meanings (and preferred meanings) as described and defined in embodiment 41.

[0329] In embodiment 46, the compound of formula (I) is a compound of formula (Ib): or a pharmaceutically acceptable salt or solvate thereof:

[0330] [ka]

[0331] At this time, R x is —SO2—N═CH—N(CH3)2, and the other groups and variables in formula (Ib) (particularly R 4 , R 5 and R 6) have the same meanings (and preferred meanings) as described and defined in embodiment 41.

[0332] In embodiment 47, the compound of formula (I) is a compound of formula (Ib): or a pharmaceutically acceptable salt or solvate thereof:

[0333] [ka]

[0334] At this time, R 4 is -O-phenyl. The phenyl portion of the above -O-phenyl is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 and optionally substituted with one or more groups independently selected from haloalkyl and —CN. Other groups and variables in formula (Ib) (particularly R x , R 5 and R 6 ) have the same meanings (and preferred meanings) as described and defined in embodiment 41.

[0335] In embodiment 48, the compound of formula (I) is a compound of formula (Ib): or a pharmaceutically acceptable salt or solvate thereof:

[0336] [ka]

[0337] At this time, R 4is a halogen (especially —Cl, etc.), and the other groups and variables in formula (Ib) (especially R x , R 5 and R 6 ) have the same meanings (and preferred meanings) as described and defined in embodiment 41.

[0338] In embodiment 49, the compound of formula (I) is a compound of formula (Ib): or a pharmaceutically acceptable salt or solvate thereof:

[0339] [ka]

[0340] At this time, R x is -COOH and R 5 is —NH2, and the other groups and variables in formula (Ib) (particularly R 4 and R 6 ) have the same meanings (and preferred meanings) as described and defined in embodiment 41.

[0341] In embodiment 50, the compound of Formula (I) is a compound of Formula (Ib): or a pharmaceutically acceptable salt or solvate thereof:

[0342] [ka]

[0343] At this time, R x is -COOCH3 and R 5 is —NH2, and the other groups and variables in formula (Ib) (particularly R 4 and R 6 ) have the same meanings (and preferred meanings) as described and defined in embodiment 41.

[0344] In embodiment 51, the compound of formula (I) is a compound of formula (Ib): or a pharmaceutically acceptable salt or solvate thereof:

[0345] [ka]

[0346] At this time, R x is -SO2-NH2, and R 5 is —NH2, and the other groups and variables in formula (Ib) (particularly R 4 and R 6 ) have the same meanings (and preferred meanings) as described and defined in embodiment 41.

[0347] In embodiment 52, the compound of Formula (I) is a compound of Formula (Ib): or a pharmaceutically acceptable salt or solvate thereof:

[0348] [ka]

[0349] At this time, R x is -SO2-N=CH-N(CH3)2, and R 5 is —NH2, and the other groups and variables in formula (Ib) (particularly R 4 and R 6 ) have the same meanings (and preferred meanings) as described and defined in embodiment 41.

[0350] In embodiment 53, the compound of formula (I) is a compound of formula (Ib): or a pharmaceutically acceptable salt or solvate thereof:

[0351] [ka]

[0352] At this time, R x is -COOH and R 5 is —NH—CH2CH2CH2CH3, and the other groups and variables in formula (Ib) (particularly R 4 and R6 ) have the same meanings (and preferred meanings) as described and defined in embodiment 41.

[0353] In embodiment 54, the compound of Formula (I) is a compound of Formula (Ib): or a pharmaceutically acceptable salt or solvate thereof:

[0354] [ka]

[0355] At this time, R x is -COOCH3 and R 5 is —NH—CH2CH2CH2CH3, and the other groups and variables in formula (Ib) (particularly R 4 and R 6 ) have the same meanings (and preferred meanings) as described and defined in embodiment 41.

[0356] In embodiment 55, the compound of Formula (I) is a compound of Formula (Ib): or a pharmaceutically acceptable salt or solvate thereof:

[0357] [ka]

[0358] At this time, R x is -SO2-NH2, and R 5 is —NH—CH2CH2CH2CH3, and the other groups and variables in formula (Ib) (particularly R 4 and R 6 ) have the same meanings (and preferred meanings) as described and defined in embodiment 41.

[0359] In embodiment 56, the compound of Formula (I) is a compound of Formula (Ib): or a pharmaceutically acceptable salt or solvate thereof:

[0360] [ka]

[0361] At this time, R x is -SO2-N=CH-N(CH3)2, and R 5 is —NH—CH2CH2CH2CH3, and the other groups and variables in formula (Ib) (particularly R 4 and R 6 ) have the same meanings (and preferred meanings) as described and defined in embodiment 41.

[0362] In embodiment 57, the compound of formula (I) is a compound of formula (Ib): or a pharmaceutically acceptable salt or solvate thereof:

[0363] [ka]

[0364] At this time, R x is -COOH and R 5 is —NO2, and the other groups and variables in formula (Ib) (particularly R 4 and R 6 ) have the same meanings (and preferred meanings) as described and defined in embodiment 41.

[0365] In embodiment 58, the compound of Formula (I) is a compound of Formula (Ib): or a pharmaceutically acceptable salt or solvate thereof:

[0366] [ka]

[0367] At this time, R x is -COOCH3 and R 5 is —NO2, and the other groups and variables in formula (Ib) (particularly R 4 and R 6) have the same meanings (and preferred meanings) as described and defined in embodiment 41.

[0368] In embodiment 59, the compound of Formula (I) is a compound of Formula (Ib): or a pharmaceutically acceptable salt or solvate thereof:

[0369] [ka]

[0370] At this time, R x is -SO2-NH2, and R 5 is —NO2, and the other groups and variables in formula (Ib) (particularly R 4 and R 6 ) have the same meanings (and preferred meanings) as described and defined in embodiment 41.

[0371] In embodiment 60, the compound of Formula (I) is a compound of Formula (Ib): or a pharmaceutically acceptable salt or solvate thereof:

[0372] [ka]

[0373] At this time, R x is -SO2-N=CH-N(CH3)2, and R 5 is —NO2, and the other groups and variables in formula (Ib) (particularly R 4 and R 6 ) have the same meanings (and preferred meanings) as described and defined in embodiment 41.

[0374] In embodiment 61, the compound of formula (I) is a compound of formula (Ib): or a pharmaceutically acceptable salt or solvate thereof:

[0375] [ka]

[0376] At this time, R x is -COOH and R 5 is hydrogen, and the other groups and variables in formula (Ib) (particularly R 4 and R 6 ) have the same meanings (and preferred meanings) as described and defined in embodiment 41.

[0377] In embodiment 62, the compound of formula (I) is a compound of formula (Ib): or a pharmaceutically acceptable salt or solvate thereof:

[0378] [ka]

[0379] At this time, R x is -COOCH3 and R 5 is hydrogen, and the other groups and variables in formula (Ib) (particularly R 4 and R 6 ) have the same meanings (and preferred meanings) as described and defined in embodiment 41.

[0380] In embodiment 63, the compound of formula (I) is a compound of formula (Ib): or a pharmaceutically acceptable salt or solvate thereof:

[0381] [ka]

[0382] At this time, R x is -SO2-NH2, and R 5 is hydrogen, and the other groups and variables in formula (Ib) (particularly R 4 and R 6 ) have the same meanings (and preferred meanings) as described and defined in embodiment 41.

[0383] In embodiment 64, the compound of formula (I) is a compound of formula (Ib): or a pharmaceutically acceptable salt or solvate thereof:

[0384] [ka]

[0385] At this time, R x is -SO2-N=CH-N(CH3)2, and R 5 is hydrogen, and the other groups and variables in formula (Ib) (particularly R 4 and R 6 ) have the same meanings (and preferred meanings) as described and defined in embodiment 41.

[0386] In embodiment 65, the compound of Formula (I) is a compound of Formula (Ia): or a pharmaceutically acceptable salt or solvate thereof:

[0387] [ka]

[0388] At this time, R 1 and R 6 are interconnected to form -R 16 -forming group, R 4 is R 4a is a group, and R 4a is hydrogen and R 5 is R 5a group, and other groups and variables in formula (Ia) (particularly R 16 , R 2 , R 3 and R 5a ) have the same meanings (and preferred meanings) as described and defined herein above for compounds of formula (I).

[0389] In each embodiment described hereinabove, the respective compounds may be used as pharmaceuticals. In particular, the compounds may be used as pharmaceuticals for treating or preventing diseases or disorders involving NKCC (preferably NKCC1) (e.g., pharmaceuticals for treating or preventing any of the corresponding specific diseases / disorders described herein). Particularly preferably, the compounds are used for treating or preventing hyperhidrosis.

[0390] The present invention also relates to novel compounds. In particular, the present invention relates to a compound of formula (I) as described and defined herein (e.g., any one of the examples and embodiments of the compound of formula (I) described herein), or a pharmaceutically acceptable salt or solvate thereof. Furthermore, the present invention relates to any of the above compounds for use as a medicine. The present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in combination with a pharmaceutically acceptable excipient.

[0391] In particular, the present invention relates to a compound of the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof: Furthermore, the present invention relates to said compound for use as a medicine, and also to a pharmaceutical composition comprising said compound and a pharmaceutically acceptable excipient.

[0392] [ka]

[0393] In formula (Ia), R 1 -COOH, -COO-(C 1-15 alkyl), -COO-(C 0-15 alkylene)-carbocyclyl, -COO-(C 0-15 alkylene)-heterocyclyl, -O-CHO, -O-CO-(C 1-15 alkyl), -O-CO-(C 0-15 alkylene)-carbocyclyl, -O-CO-(C 0-15 alkylene)-heterocyclyl, -CHO, -CO-(C 1-15 alkyl), -CO-(C0-15 alkylene)-carbocyclyl, -CO-(C 0-15 alkylene)-heterocyclyl, -CO-NH2, -CO-N(R 11 )-(C 1-15 alkyl), -CO-N(R 11 )-(C 0-15 alkylene)-carbocyclyl, -CO-N(R 11 )-(C 0-15 alkylene)-heterocyclyl, -N(R 11 )-CHO, -N(R 11 )-CO-(C 1-15 alkyl), -N(R 11 )-CO-(C 0-15 alkylene)-carbocyclyl, -N(R 11 )-CO-(C 0-15 alkylene)-heterocyclyl, C 1-15 Alkyl, -(C 0-15 alkylene)-carbocyclyl, -(C 0-15 alkylene)-heterocyclyl, C 2-15 Alkenyl, -(C 2-15 alkenylene)-carbocyclyl, -(C 2-15 Alkenylene)-heterocyclyl, C 2-15 Alkynyl, -(C 2-15 alkynylene)-carbocyclyl, and -(C 2-15 alkynylene)-heterocyclyl.

[0394] In this case, any alkyl moiety in the above group, any alkylene moiety in the above group, any alkenylene moiety in the above group, any alkynylene moiety in the above group, 1-15 Alkyl, above C 2-15 Alkenyl and the above C 2-15 Alkynyl is a halogen, -CF3, -CN, -NO2, -N(R 11 )(R 11 ), -O(R 11 ), -S(R 11 ), and —SO 3 H.

[0395] In this case, any alkyl moiety in the above group, any alkylene moiety in the above group, any alkenylene moiety in the above group, any alkynylene moiety in the above group, 1-15 Alkyl, above C 2-15 Alkenyl or the above C 2-15 One or more -CH2- units contained in the alkynyl are each 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 Optionally substituted with groups independently selected from: —SO—;

[0396] Further, in this case, any carbocyclyl moiety in the above group and any heterocyclyl moiety in the above group may be C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, -CN, -NO2, -N(R 11 )(R 11 ), -O(R 11 ), -S(R 11 ), —SO 3 H, carbocyclyl, and heterocyclyl.

[0397] Each R 11 are independently hydrogen or C 1-6 Preferably, each R 11 are independently hydrogen or C 1-4 alkyl (for example, methyl or ethyl).

[0398] R 1 is a specific R 1 It may be any one of the groups.

[0399] In particular, R 1For example, -COO-(C 1-15 In this case, the above-mentioned —COO—(C alkyl) may be used. 1-15 The alkyl portion of alkyl) is halogen, -CF3, -CN, -NO2, -NH2, -NH(C 1-4 alkyl), -N(C 1-4 Alkyl)(C 1-4 alkyl), -OH, -O(C 1-4 alkyl), -SH, and -S(C 1-4 alkyl). 1-15 One or two -CH2- units contained in the alkyl portion of the alkyl) are -O-, -CO-, -COO-, -O-CO-, -NH-, -N(C 1-4 alkyl)-, -NH-CO-, -N(C 1-4 alkyl)-CO-, -CO-NH-, -CO-N(C 1-4 alkyl)-, -S-, -SO-, -SO2-, -SO2-NH-, -SO2-N(C 1-4 alkyl)-, -NH-SO2-, and -N(C 1-4 The above-mentioned -COO-(C alkyl)-SO2- is optionally substituted with a group independently selected from the group consisting of -COO-(C 1-15 The alkyl portion of such R has 1 to 15 (particularly, 1 to 10) carbon atoms. 1 Suitable examples of groups include the corresponding R 1 groups (e.g., -COO-CH3 or -COO-CH2CH3; particularly, -COO-CH3).

[0400] R 1 A more preferred example of is -COOH.

[0401] R 1 A more preferred example of -(C 1-4 alkylene)-NH-(C 1-4 alkylene)-R 12 (e.g., -CH2-NH-CH2-R 12 ), -COO-(C 1-4alkylene)-R 12 (e.g., -COO-CH2-R 12 ), -O-CO-(C 1-4 alkylene)-R 12 , -CO-(C 1-4 alkylene)-R 12 , -CO-NH-(C 1-4 alkylene)-R 12 (e.g., -CO-NH-CH2-R 12 ), -CO-N(C 1-4 alkyl)-(C 1-4 alkylene)-R 12 , -NH-CO-(C 1-4 alkylene)-R 12 , or -N(C 1-4 alkyl)-CO-(C 1-4 alkylene)-R 12 In this case, R 12 are independently selected from -CF, -CN and halogen (e.g., -F, -Cl, -Br or -I). Preferably, R 12 is independently selected from -CF3 and -CN. More preferably, R 12 is -CF3. Such R 1 Specific examples of groups include the corresponding R 1 R 1 A particularly preferred example of 1-4 alkylene)-NH-(C 1-4 An even more preferred example is —CH—NH—CH—CF.

[0402] R 1 Further examples of -(C 1-4 alkylene)-S-heterocyclyl, in particular -(C 1-4 alkylene)-S-heteroaryl (e.g., -CH-S-heteroaryl). 1-4 alkylene)-S-heterocyclyl, or the heterocyclyl portion of the above-(C 1-4 The heteroaryl portion of the above-mentioned -CH2-S-heteroaryl is C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, -CN, -NO2, -N(R 11 )(R 11 ), -O(R 11 ), -S(R 11 ), —SO3H, carbocyclyl, and heterocyclyl. 1 Specific examples of groups include the corresponding R 1 Examples of such groups include:

[0403] R 1 Further examples of -(C 1-4 alkylene)-O-(C 0-4 alkylene)-carbocyclyl, in particular -(C 1-4 alkylene)-O-(C 0-4 alkylene)-phenyl (e.g., —CH—O-phenyl or —CH—O—CH-phenyl). 1-4 alkylene)-O-(C 0-4 the carbocyclyl portion of the -(C alkylene)-carbocyclyl, or 1-4 alkylene)-O-(C 0-4 The phenyl moiety of the alkylene-phenyl (or the phenyl moiety of the above-mentioned -CH-O-phenyl or -CH-O-CH-phenyl) is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, -CN, -NO2, -N(R 11 )(R 11 ), -O(R 11 ), -S(R 11 ), —SO3H, carbocyclyl, and heterocyclyl. 1 Specific examples of groups include the corresponding R 1 Examples of such groups include:

[0404] R 1 Further examples of -(C 1-4 alkylene)-heterocyclyl, particularly -CH2-heterocyclyl, where -(C 1-4 The heterocyclyl moiety of the -CH-heterocyclyl or -CH-heterocyclyl is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, -CN, -NO2, -N(R 11 )(R 11 ), -O(R 11 ), -S(R 11 ), -SO3H, carbocyclyl, and heterocyclyl. The heterocyclyl moiety may be, for example, heterocycloalkyl (such as pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl), heterocycloalkenyl (such as tetrahydropyridinyl), or heteroaryl. Such R 1 Specific examples of groups include the corresponding R 1 Examples of such groups include:

[0405] R 2 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), -N(C 1-6 alkyl)-CO-(C 1-6 alkyl), -SO2-NH2, -SO2-NH(C 1-6 alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl), and -N(C 1-6 alkyl)-SO2-(C 1-6 alkyl). Preferably, R 2 is hydrogen, C 1-6 Alkyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), and —CN. More preferably, R 2 is hydrogen or C 1-4 Even more preferably, R 2 is hydrogen.

[0406] R 3 -SO2-NH2, -SO2-NH(C 1-6 alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -SO2-N=(C 1-6 In this case, the above-mentioned -SO2-NH(C 1-6alkyl), the alkyl portion of -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), and the above -SO2-N=(C 1-6 The alkylidene moiety of alkylidene) is halogen, -CF3, -CN, -NO2, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -OH, -O(C 1-6 alkyl), -SH, and -S(C 1-6 alkyl). Preferably, R 3 -SO2-NH2, -SO2-NH(C 1-4 alkyl), -SO2-N(C 1-4 Alkyl)(C 1-4 alkyl), and -SO2-N=(C 1-4 In this case, the above -SO2-NH(C 1-4 alkyl), the alkyl portion of -SO2-N(C 1-4 Alkyl)(C 1-4 alkyl), and the above -SO2-N=(C 1-4 The alkylidene moiety of alkylidene) is halogen, -CF3, -CN, -NO2, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -OH, -O(C 1-6 alkyl), -SH, and -S(C 1-6 alkyl). More preferably, R 3 -SO2-NH2, -SO2-NH(C 1-4 alkyl), -SO2-N(C 1-4 Alkyl)(C 1-4 alkyl), and -SO2-N=(C 1-4 In this case, the above -SO2-NH(C 1-4 alkyl), the alkyl portion of -SO2-N(C1-4 Alkyl)(C 1-4 alkyl), and the above -SO2-N=(C 1-4 The alkylidene moiety of the alkylidene is -NH2, -NH(C 1-4 alkyl), and -N(C 1-4 Alkyl)(C 1-4 alkyl). Even more preferably, R 3 -SO2-NH2, -SO2-NH(C 1-4 alkyl), -SO2-N(C 1-4 Alkyl)(C 1-4 alkyl), -SO2-NH-(C 1-4 alkylene)-NH2, -SO2-NH-(C 1-4 alkylene)-NH(C 1-4 alkyl), -SO2-NH-(C 1-4 alkylene)-N(C 1-4 Alkyl)(C 1-4 alkyl), -SO2-N=(C 1-4 alkylidene)-NH2, -SO2-N=(C 1-4 alkylidene)-NH(C 1-4 alkyl), and -SO2-N=(C 1-4 alkylidene)-N(C 1-4 Alkyl)(C 1-4 Even more preferably, R 3 are -SO2-NH2, -SO2-NH-CH3, -SO2-N(CH3)2, -SO2-NH-(C 1-4 alkylene)-NH2, -SO2-NH-(C 1-4 alkylene)-NH-CH3, -SO2-NH-(C 1-4 alkylene)-N(CH3)2 (e.g., -SO2-NH-CH2CH2-N(CH3)2), -SO2-N=(C 1-4 alkylidene)-NH2, -SO2-N=(C 1-4 alkylidene)-NH-CH3 and -SO2-N=(C 1-4 R is selected from the group consisting of -SO-N=CH-N(CH) and -SO-N=CH-N(CH). 3A particularly suitable example of R is -SO2-NH2. 3 A further particularly suitable example is -SO2-N=CH-N(CH3)2.

[0407] R 4 and R 5 are interconnected to form -R 5b -Forms the base.

[0408] R 5b -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 -N(R 52 )—, —O—, and —S—.

[0409] R 5b2 is -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 a covalent bond, -C(R 53 )(R 53 )-, -C(R 53 )(R 53 )-C(R 53 )(R 53 )-, and -C(R53 )=C(R 53 )-. R 5b4 is a covalent bond and -C(R 53 )(R 53 )- is selected from.

[0410] Each R 52 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(C 0-4 alkylene)-aryl, and -(C 0-4 Preferably, each R is independently selected from the group consisting of alkylene, heteroaryl, and aryl. 52 is water hydrogen, C 1-4 Alkyl (e.g., n-butyl), C 2-4 Alkenyl, and C 2-4 alkynyl (e.g., —CH—C≡CH). Even more preferably, each R 52 is hydrogen.

[0411] Each R 53 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), -N(C 1-6 alkyl)-CO-(C1-6 alkyl), -SO2-NH2, -SO2-NH(C 1-6 alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl), -N(C 1-6 alkyl)-SO2-(C 1-6 alkyl), -(C 0-4 alkylene)-aryl, and -(C 0-4 Any two R bonded to the same carbon atom are independently selected from the group consisting of alkylene, heteroaryl, and aryl. 53 The groups may be joined together to form a ═O group. Any two R groups attached to adjacent carbon atoms connected by a double bond may 53 The groups are linked together to form -C(R 54 )=C(R 54 )-C(R 54 )=C(R 54 )-group. Preferably, each R 53 is hydrogen, C 1-6 Alkyl, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 Any two R bonded to the same carbon atom are independently selected from -(haloalkyl), -(haloalkyl), and -CN. 53 The groups may be joined together to form a ═O group. Any two R groups attached to adjacent carbon atoms connected by a double bond may 53 The groups are linked together to form -C(R 54 )=C(R 54 )-C(R 54 )=C(R 54 )-group. More preferably, each R 53 is hydrogen, C 1-6 Alkyl, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 Any two R bonded to the same carbon atom are independently selected from -(haloalkyl), -(haloalkyl), and -CN. 53 The groups may together form a =O group. Even more preferably, each R 53 is hydrogen, C 1-4 Alkyl, -OH, -O(C 1-4 alkyl), -NH2, -NH(C 1-4 alkyl), -N(C 1-4 Alkyl)(C 1-4 Alkyl), halogen, C 1-4 Haloalkyl, -O-(C 1-4 Any two R bonded to the same carbon atom are independently selected from -(haloalkyl), -(haloalkyl), and -CN. 53 The groups may together form a =O group.

[0412] Each R 54 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), -N(C 1-6 alkyl)-CO-(C1-6 alkyl), -SO2-NH2, -SO2-NH(C 1-6 alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl), and -N(C 1-6 alkyl)-SO2-(C 1-6 alkyl). Preferably, each R 54 is hydrogen, C 1-6 Alkyl, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), and —CN. More preferably, each R 54 is hydrogen.

[0413] Particularly preferably, R 5b is -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(R53 )=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-、-O-C(R 53 )(R 53 )-N(R 52 )-、-O-C(R 53 )(R 53 )-C(R 53 )(R 53 )-N(R 52 )-、-O-C(R 53 )=C(R 53 )-N(R 52 )-、-O-C(R 53 )(R 53 )-C(R 53 )(R 53 )-C(R 53 )(R53 )-N(R 52 )-、-O-C(R 53 )(R 53 )-C(R 53 )=C(R 53 )-N(R 52 )-、-O-C(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-、-S-C(R 53 )(R 53 )-N(R 52 )-、-S-C(R 53 )(R 53 )-C(R 53 )(R 53 )-N(R 52 )-、-S-C(R 53 )=C(R 53 )-N(R 52 )-、-S-C(R 53 )(R 53 )-C(R 53 )(R 53)-C(R 53 )(R 53 )-N(R 52 )-、-S-C(R 53 )(R 53 )-C(R 53 )=C(R 53 )-N(R 52 )-、-S-C(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 )-, and -N(R 52 )-C(R 53 )=C(R 53 )-C(R 53 )(R 53 )-N(R 52 )- is selected from.

[0414] Even more preferably, R is selected such that the structure of the compound of formula (Ia) is either 5b is selected.

[0415] [ka]

[0416] R 6 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), -N(C 1-6 alkyl)-CO-(C 1-6 alkyl), -SO2-NH2, -SO2-NH(C 1-6 alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl), and -N(C 1-6 alkyl)-SO2-(C 1-6 alkyl). Preferably, hydrogen, C 1-6 Alkyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), and —CN. More preferably, R 6 is hydrogen or C 1-4 Even more preferably, R 6 is hydrogen.

[0417] The present invention also provides a compound of the following formula (Ib) or a pharmaceutically acceptable salt or solvate thereof: The present invention also relates to the compound for use as a medicine, and to a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient.

[0418] [ka]

[0419] In formula (Ib), R x -COOH, -COO-(C 1-6 alkyl), -SO2-NH2, -SO2-NH(C 1-4 alkyl), -SO2-N(C 1-4 Alkyl)(C 1-4 alkyl), and -SO2-N=(C 1-4 In this case, the above -SO2-NH(C 1-4 alkyl), the alkyl portion of -SO2-N(C 1-4 Alkyl)(C 1-4 alkyl), and the above -SO2-N=(C 1-4 The alkylidene moiety of the alkylidene is -NH2, -NH(C 1-4 alkyl), and -N(C 1-4 Alkyl)(C 1-4 alkyl). Preferably, R x is selected from -COOH, -COOCH3, -SO2-NH2, and -SO2-N=CH-N(CH3)2.

[0420] R 4 is R 4a is a group, and R 5 is R 5a It is the base.

[0421] R 4a -OR 41 , -SR 41 , -NH-R 41 , -N(C 1-6 alkyl)-R 41 , halogen (e.g., —Cl), carbocyclyl, and heterocyclyl, wherein the carbocyclyl and the heterocyclyl are each selected from one or more R 42 Preferably, R 4a -OR 41 , -SR 41 , -NH-R 41 , -N(C 1-6 alkyl)-R41 , halogen, carbocyclyl (e.g., aryl, cycloalkyl, or cycloalkenyl), and heterocyclyl (e.g., heteroaryl, heterocycloalkyl, or heterocycloalkenyl), wherein the carbocyclyl and the heterocyclyl each are selected from one or more R 42 More preferably, R 4a -OR 41 , -SR 41 , -NH-R 41 , -N(C 1-4 alkyl)-R 41 , halogen, aryl, and heteroaryl, wherein the aryl and heteroaryl are each selected from one or more R 42 Even more preferably, R 4a -OR 41 , -SR 41 , -NH-R 41 , -N(C 1-4 alkyl)-R 41 and halogen. Even more preferably, R 4a HA-OR 41 Or a halogen.

[0422] R 41 is -(C 0-4 alkylene)-carbocyclyl, -(C 0-4 alkylene)-heterocyclyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl. In this case, the above-mentioned -(C 0-4 The carbocyclyl portion of the -(C alkylene)-carbocyclyl 0-4 Each heterocyclyl portion of the (alkylene)-heterocyclyl may be one or more R 42 In this case, the above C 1-6 Alkyl, above C 2-6 Alkenyl, above C 2-6 Alkynyl, as defined above -(C 0-4alkylene)-carbocyclyl, and the alkylene portion of the above-(C 0-4 Each alkylene portion of the (alkylene)-heterocyclyl may be one or more R 43 Preferably, R 41 is -(C 0-4 alkylene)-carbocyclyl, -(C 0-4 alkylene)-heterocyclyl, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 alkynyl. In this case, the above-mentioned -(C 0-4 The carbocyclyl portion of the -(C alkylene)-carbocyclyl is selected from cycloalkyl, cycloalkenyl, and aryl. 0-4 The heterocyclyl moiety of the -(C alkylene)-heterocyclyl is selected from heterocycloalkyl, heterocycloalkenyl, and heteroaryl. 0-4 The carbocyclyl portion of the -(C alkylene)-carbocyclyl 0-4 The heterocyclyl portion of each alkylene-heterocyclyl may be one or more (e.g., one, two, or three) R 42 Further, the above C 1-6 Alkyl, above C 2-6 Alkenyl, above C 2-6 Alkynyl, as defined above -(C 0-4 alkylene)-carbocyclyl, and the alkylene portion of the above-(C 0-4 Each alkylene portion of the alkylene-heterocyclyl may be one or more (e.g., one, two, or three) R 43 More preferably, R 41 is -(C 0-4 alkylene)-aryl, and -(C 0-4 In this case, the above-mentioned -(C 0-4 the aryl portion of the -(C alkylene)-aryl; 0-4 The heteroaryl portion of each alkylene-heteroaryl may be one or more (e.g., one, two, or three) R 42The above-mentioned -(C 0-4 alkylene)-aryl, and the alkylene portion of the above-(C 0-4 Each alkylene portion of the alkylene-heteroaryl may be one or more (e.g., one, two, or three) R 43 Even more preferably, R 41 is -(C 0-4 alkylene)-aryl, and -(C 0-4 In this case, the above-mentioned -(C 0-4 the aryl portion of the -(C alkylene)-aryl; 0-4 The heteroaryl portion of each alkylene-heteroaryl may be one or more (e.g., one, two, or three) R 42 The above -(C 0-4 A preferred example of the aryl moiety of the -(C alkylene)-aryl is phenyl. 0-4 Preferred examples of the heteroaryl moiety of the alkylene-heteroaryl are 5- or 6-membered monocyclic heteroaryls having 1 or 2 hetero ring atoms independently selected from oxygen, nitrogen, and sulfur, with the remaining ring atoms being carbon atoms, such as imidazolyl, thiophenyl, or pyrimidinyl. Even more preferred are R 41 is selected from phenyl and heteroaryl, where the heteroaryl is a 5- or 6-membered monocyclic heteroaryl having one or two hetero ring atoms independently selected from oxygen, nitrogen, and sulfur (the remaining ring atoms of the monocyclic heteroaryl are carbon atoms). Additionally, the phenyl or heteroaryl may contain one or more (e.g., one, two, or three) R 42 The group is optionally substituted.

[0423] Each R 42 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), -N(C 1-6 alkyl)-CO-(C 1-6 alkyl), -SO2-NH2, -SO2-NH(C 1-6 alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl), and -N(C 1-6 alkyl)-SO2-(C 1-6 alkyl). Preferably, each R 42 is C 1-6 Alkyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), and —CN.

[0424] Each R43 -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, -CF3, -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), and -N(C 1-6 alkyl)-CO-(C 1-6 alkyl). Preferably, each R 43 -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), halogen, —CF 3 , and —CN.

[0425] According to the above definition, particularly preferred are R 4a is -O-aryl or halogen. In this case, the aryl portion of the -O-aryl is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6and optionally substituted with one or more groups independently selected from haloalkyl, and —CN. Even more preferably, R 4a is -O-phenyl or halogen (especially, -Cl, etc.). In this case, the phenyl portion of the above -O-phenyl is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Optionally substituted with one or more groups independently selected from haloalkyl, and -CN.

[0426] R 5a is -NH2, -NH(C 1-6 alkyl), and -N(C 1-6 Alkyl)(C 1-6 In this case, the above-mentioned —NH(C 1-6 alkyl) and the alkyl portion of the above -N(C 1-6 Alkyl)(C 1-6 One or both alkyl moieties of the alkyl group may be halogen, -CF3, -CN, -NO2, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), carbocyclyl, and heterocyclyl, each of which is optionally substituted with one or more groups independently selected from one or more R 51 Preferably, R 5a -NH2, -NH(C 1-6 alkyl), and -N(C1-6 Alkyl)(C 1-6 In this case, the above-mentioned —NH(C 1-6 alkyl) and the alkyl portion of the above -N(C 1-6 Alkyl)(C 1-6 One or both alkyl moieties of the alkyl group may be halogen, -CF3, -CN, -NO2, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -OH, -O(C 1-6 alkyl), -SH, and -S(C 1-6 alkyl). More preferably, R 5a -NH2, -NH(C 1-6 alkyl), and -N(C 1-6 Alkyl)(C 1-6 alkyl). 5a Particularly suitable examples are -NH2 or -NH-CH2CH2CH2CH3.

[0427] Each R 51 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), -N(C 1-6 alkyl)-CO-(C 1-6 alkyl), -SO2-NH2, -SO2-NH(C 1-6 alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl), and -N(C 1-6 alkyl)-SO2-(C 1-6 alkyl). Preferably, each R 51 is C 1-6 Alkyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), and —CN.

[0428] R 6 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6haloalkyl), -CN, -NO2, -CHO, -CO-(C 1-6 alkyl), -COOH, -COO-(C 1-6 alkyl), -O-CO-(C 1-6 alkyl), -CO-NH2, -CO-NH(C 1-6 alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO-(C 1-6 alkyl), -N(C 1-6 alkyl)-CO-(C 1-6 alkyl), -SO2-NH2, -SO2-NH(C 1-6 alkyl), -SO2-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-SO2-(C 1-6 alkyl), and -N(C 1-6 alkyl)-SO2-(C 1-6 alkyl). Preferably, R 6 is hydrogen, C 1-6 Alkyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), halogen, C 1-6 Haloalkyl, -O-(C 1-6 haloalkyl), and —CN. More preferably, R 6 is hydrogen or C 1-4 Even more preferably, R 6 is hydrogen.

[0429] The present invention further relates to a compound of any one of the following formulae, or a pharmaceutically acceptable salt or solvate thereof: The present invention also relates to the compound for use as a medicament, and to a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient.

[0430] [ka]

[0431] TIFF0007611812000096.tif209169

[0432] TIFF0007611812000097.tif204169

[0433] TIFF0007611812000098.tif205169

[0434] TIFF0007611812000099.tif213169

[0435] TIFF0007611812000100.tif200169

[0436] TIFF0007611812000101.tif193169

[0437] TIFF0007611812000102.tif216169

[0438] TIFF0007611812000103.tif19169

[0439] It will be apparent to those skilled in the art of synthetic chemistry that compounds of formula (I) can be prepared in a variety of ways, for example, by following the synthetic routes described in the Examples (or by routes analogous to those synthetic routes).

[0440] Unless specifically stated otherwise, the following definitions apply throughout this specification.

[0441] The term "hydrocarbon group" refers to a group consisting of carbon and hydrogen atoms.

[0442] The term "alicyclic" is used in reference to a cyclic group to mean that the corresponding cyclic group is not aromatic.

[0443] As used herein, the term "alkyl" refers to a monovalent saturated acyclic (non-cyclic) hydrocarbon group, which may be straight-chain or branched. Thus, an "alkyl" group does not have any carbon-carbon double or triple bonds. 1-6 "Alkyl" means an alkyl group having 1 to 6 carbon atoms. Suitable examples of alkyl groups include methyl, ethyl, propyl (e.g., n-propyl or isopropyl), or butyl (e.g., n-butyl, isobutyl, sec-butyl, or tert-butyl). Unless otherwise defined, the term "alkyl" preferably refers to a C 1-4 It represents alkyl, more preferably methyl or ethyl, and even more preferably methyl.

[0444] As used herein, the term "alkenyl" refers to a monovalent unsaturated acyclic hydrocarbon group, which may be straight-chained or branched, having one or more (e.g., one or two) carbon-carbon double bonds, but no carbon-carbon triple bonds. 2-6 The term "alkenyl" refers to an alkenyl group having 2 to 6 carbon atoms. Suitable examples of alkenyl groups include ethenyl, propenyl (e.g., prop-1-en-1-yl, prop-1-en-2-yl, or prop-2-en-1-yl), butenyl, butadienyl (e.g., buta-1,3-dien-1-yl, or buta-1,3-dien-2-yl), pentenyl, or pentadienyl (e.g., isoprenyl). Unless otherwise defined, the term "alkenyl" preferably refers to an alkenyl group having 2 to 6 carbon atoms. 2-4 represents alkenyl.

[0445] As used herein, the term "alkynyl" refers to a monovalent unsaturated acyclic hydrocarbon group, which may be straight-chained or branched, having one or more (e.g., one or two) carbon-carbon triple bonds and, optionally, one or more carbon-carbon double bonds. 2-6 The term "alkynyl" means an alkynyl group having 2 to 6 carbon atoms. Suitable examples of alkynyl groups include ethynyl, propynyl (e.g., propargyl), or butynyl. Unless otherwise defined, the term "alkynyl" preferably refers to an alkynyl group having 2 to 6 carbon atoms. 2-4 It represents alkynyl.

[0446] As used herein, the term "alkylene" refers to an alkanediyl group, i.e., a divalent saturated acyclic hydrocarbon group, which may be straight-chain or branched. 1-15 "Alkylene" means an alkylene group having 1 to 15 carbon atoms. 0-15 The term "alkylene" refers to either a covalent bond (corresponding to the "C alkylene" alternative) or a C 1-15 indicates the presence of alkylene. Suitable examples of alkylene groups include methylene (-CH-), ethylene (e.g., -CH-CH- or -CH(-CH)-), propylene (e.g., -CH-CH-CH-, -CH(-CH-CH)-, -CH-CH(-CH)- or -CH(-CH)-CH-), or butylene (e.g., -CH-CH-CH-CH-). Unless otherwise defined, the term "alkylene" preferably refers to a C 1-4 Alkylene (especially linear C 1-4 alkylene, etc.), more preferably methylene or ethylene, and even more preferably methylene.

[0447] As used herein, the term "alkenylene" refers to an alkenediyl group, i.e., a divalent unsaturated acyclic hydrocarbon group, which may be linear or branched, and which has one or more (e.g., one or two) carbon-carbon double bonds and no carbon-carbon triple bonds. 2-15 "Alkenylene" means an alkenylene group having 2 to 15 carbon atoms. Unless otherwise defined, the term "alkenylene" preferably refers to a C 2-4 Alkenylene (especially linear C 2-4 alkenylene, etc.

[0448] As used herein, the term "alkynylene" refers to an alkynediyl group, i.e., a divalent unsaturated acyclic hydrocarbon group, which may be linear or branched, and which has one or more (e.g., one or two) carbon-carbon triple bonds and, optionally, one or more carbon-carbon double bonds. 2-15 "Alkynylene" means an alkynylene group having 2 to 15 carbon atoms. Unless otherwise defined, the term "alkynylene" preferably refers to a C 2-4 Alkynylene (especially linear C 2-4 alkynylene, etc.

[0449] As used herein, the term "alkylidene" refers to a divalent acyclic hydrocarbon group, which may be straight-chain or branched. An alkylidene group is attached to the residue of a compound through a double bond and has no other double bonds (i.e., no double bonds other than the double bond that attaches the alkylidene group to the residue of a compound). Alternatively, an alkylidene group does not have a triple bond. An alkylidene group may be attached, for example, to a carbon atom or a nitrogen atom of the residue of a compound. "C 1-6"Alkylidene" means an alkylidene group having 1 to 6 carbon atoms. Suitable examples of alkylidene groups include methylidene (=CH2), ethylidene (=CH-CH3), propylidene (e.g., =CH-CH2CH3 or =C(-CH3)-CH3), or butylidene (e.g., =CH-CH2CH2CH3, =C(-CH3)-CH2CH3, or =CH-CH(-CH3)-CH3). Unless otherwise defined, the term "alkylidene" preferably refers to a C 1-4 Represents alkylidene.

[0450] As used herein, the term "carbocyclyl" refers to a hydrocarbon ring group, including monocyclic, bridged, spirocyclic, and / or fused ring systems (e.g., consisting of two or three rings), which may be saturated, partially unsaturated (unsaturated but not aromatic), or aromatic. Unless otherwise defined, "carbocyclyl" preferably refers to aryl, cycloalkyl, or cycloalkenyl.

[0451] As used herein, the term "heterocyclyl" refers to a ring group having a monocyclic, bridged, spirocyclic, and / or fused ring system (e.g., composed of two or three rings). The ring group has one or more (e.g., one, two, three, or four) heteroatoms independently selected from O, S, and N, and the remaining ring atoms are carbon atoms. One or more S ring atoms (if present) and / or one or more N ring atoms (if present) may be optionally oxidized. One or more carbon ring atoms may be optionally oxidized (forming an oxo group). Furthermore, the ring group may be saturated, partially unsaturated (unsaturated but not aromatic), or aromatic. For example, each heteroatom-containing ring in the ring group may have one or two O atoms, one or two S atoms (optionally oxidized), and / or one, two, three, or four N atoms (optionally oxidized). provided that the total number of heteroatoms in the heteroatom-containing ring is 1 to 4, and that one or more carbon ring atoms (which may be optionally oxidized) are present in the heteroatom-containing ring. Unless otherwise defined, "heterocyclyl" preferably refers to heteroaryl, heterocycloalkyl, or heterocycloalkenyl.

[0452] As used herein, the term "aryl" refers to an aromatic hydrocarbon ring group, including monocyclic aromatic rings, bridged rings and / or fused ring systems with one or more aromatic rings (e.g., a ring system consisting of two or three fused rings, one or more of which are aromatic; or a bridged ring system consisting of two or three rings, one or more of which are aromatic). "Aryl" may refer to, for example, phenyl, naphthyl, diarylnyl (1,2-dihydronaphthyl), tetralinyl (1,2,3,4-tetrahydronaphthyl), indanyl, indenyl (e.g., 1H-indenyl), anthracenyl, phenanthrenyl, 9H-fluorenyl, or azulenyl. Unless otherwise defined, "aryl" preferably has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms, even more preferably phenyl or naphthyl, and most preferably phenyl.

[0453] As used herein, the term "heteroaryl" refers to an aromatic ring group, including monocyclic aromatic rings, bridged rings and / or fused ring systems having one or more aromatic rings (e.g., a ring system consisting of two or three fused rings, one or more of which is aromatic; or a bridged ring system consisting of two or three rings, one or more of which is aromatic). In this case, the aromatic ring group has one or more (e.g., one, two, three, or four) heteroatoms independently selected from O, S, and N, and the remaining ring atoms are carbon atoms. In this case, one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may be optionally oxidized. Furthermore, in this case, one or more carbon ring atoms may be optionally oxidized (may form an oxo group). For example, each heteroatom-containing ring in the aromatic ring group may have one or two O atoms, and / or one or two S atoms (which may be optionally oxidized), and / or one, two, three, or four N atoms (which may be optionally oxidized), provided that the total number of heteroatoms in the heteroatom-containing ring is 1 to 4, and that one or more carbon ring atoms (which may be optionally oxidized) are present in the heteroatom-containing ring. "Heteroaryl" includes, for example, thienyl (thiophenyl), benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (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 (pyridyl), indolyl; for example, 2-pyridyl, 3-pyridyl, or 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolyl (for example, 3H-indolyl), isoindolyl, indazolyl, indolizinyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl (for example, [1,10]phenanthrolinyl, [1,

[0033] phenanthrolinyl or [4,7]phenanthrolinyl), phenazinyl, thiazolyl, isothiazolyl, phenothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl (furazanyl) or 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl or 1,3, 4-thiadiazolyl), phenoxazinyl, pyrazolo[1,5-a]pyrimidinyl (e.g., pyrazolo[1,5-a]pyrimidin-3-yl), 1,2-benzisoxazol-3-yl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzo[b]thiophenyl (benzothienyl), triazolyl (e.g., 1H-1,2,3-triazolyl, 2H-1 ,2,3-triazolyl, 1H-1,2,4-triazolyl or 4H-1,2,4-triazolyl), benzotriazolyl, 1H-tetrazolyl, 2H-tetrazolyl, triazinyl (e.g., 1,2,3-triazinyl, 1,2,4-triazinyl or 1,3,5-triazinyl), furo[2,3-c]pyridinyl, dihydrofuropyridinyl (e.g., 2,3-dihydrofuro[2,3-c]pyridinyl or 1,3-dihydrofuro[2,3-c]pyridinyl hydrofuro[3,4-c]pyridinyl), imidazopyridinyl (e.g., imidazo[1,2-a]pyridinyl or imidazo[3,2-a]pyridinyl), quinazolinyl, thienopyridinyl, tetrahydrothienopyridinyl (e.g., 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl), dibenzofuranyl, 1,3-benzodioxolyl, benzodioxanyl (e.g., 1,3-benzodioxanyl or 1,

[0023] Unless otherwise defined, the term "heteroaryl" preferably refers to a 5- to 14-membered (more preferably 5- to 10-membered) monocyclic or fused ring system having one or more (e.g., 1, 2, 3, or 4) hetero ring atoms 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 one or more carbon ring atoms are optionally oxidized. Even more preferably, "heteroaryl" refers to a 5- or 6-membered monocyclic ring having one or more (e.g., 1, 2, or 3) hetero ring atoms 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 one or more carbon ring atoms are optionally oxidized. Furthermore, unless otherwise specified, particularly suitable examples of "heteroaryl" include pyridinyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), imidazolyl, thiazolyl, 1H-tetrazolyl, 2H-tetrazolyl, thienyl (thiophenyl), or pyrimidinyl.

[0454] As used herein, the term "cycloalkyl" refers to a saturated hydrocarbon ring group, including monocyclic, bridged, spirocyclic, and / or fused ring systems (e.g., may be composed of two or three rings; fused ring systems composed of two or three fused rings, etc.). "Cycloalkyl" may refer to, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl (decahydronaphthyl), or adamantyl. Unless otherwise defined, "cycloalkyl" preferably refers to C 3-11 represents cycloalkyl, more preferably C 3-7 It represents cycloalkyl. Particularly preferred "cycloalkyl" is a monocyclic saturated hydrocarbon ring having 3 to 7 ring members. Unless otherwise specified, particularly preferred examples of "cycloalkyl" include cyclohexyl or cyclopropyl (particularly cyclohexyl).

[0455] As used herein, the term "heterocycloalkyl" refers to a saturated ring group, including monocyclic, bridged, spirocyclic, and / or fused ring systems (e.g., composed of two or three rings; fused rings composed of two or three fused rings, etc.). The ring group has one or more (e.g., one, two, three, or four) heteroatoms independently selected from O, S, and N, and the remaining ring atoms are carbon atoms. One or more S ring atoms (if present) and / or one or more N ring atoms (if present) may be optionally oxidized. Furthermore, one or more carbon ring atoms may be optionally oxidized (i.e., form an oxo group). For example, each heteroatom-containing ring in the saturated ring group may have one or two O atoms, one or two S atoms (optionally oxidized), and / or one, two, three, or four N atoms (optionally oxidized). provided that the total number of heteroatoms in the heteroatom-containing ring is 1 to 4, and one or more carbon ring atoms (which may be optionally oxidized) are present in the heteroatom-containing ring. "Heterocycloalkyl" includes, for example, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl (e.g., 1,4-diazepanyl), oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, morpholinyl (e.g., morpholin-4-yl), thiomorpholinyl (e.g., thiomorpholin-4- ... It may represent sazepanyl, oxiranyl, oxetanyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, thiiranyl, thietanyl, tetrahydrothiophenyl (thiolanyl), 1,3-dithiolanyl, thianyl, thiepanyl, decahydroquinolinyl, decahydroisoquinolinyl, or 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl. Unless otherwise defined, "heterocycloalkyl" preferably represents a 3- to 11-membered saturated ring group, and is a monocyclic or fused ring system (e.g., a fused ring system composed of two fused rings).In this case, the ring group has one or more (e.g., one, two, three, or four) hetero ring atoms independently selected from O, S, and N. In this case, one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized. In this case, one or more carbon ring atoms are optionally oxidized. More preferably, "heterocycloalkyl" represents a 5- to 7-membered saturated monocyclic group having one or more (e.g., one, two, or three) hetero ring atoms independently selected from O, S, and N. In this case, one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized. In this case, one or more carbon ring atoms are optionally oxidized. Furthermore, unless otherwise defined, particularly preferred examples of "heterocycloalkyl" include tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, and tetrahydrofuranyl.

[0456] As used herein, the term "cycloalkenyl" refers to an unsaturated alicyclic (non-aromatic) hydrocarbon ring group, including monocyclic, bridged, spirocyclic, and / or fused ring systems (e.g., may be composed of two or three rings; fused ring systems composed of two or three fused rings, etc.). In this case, the hydrocarbon ring group has one or more (e.g., one or two) carbon-carbon double bonds and does not have a carbon-carbon triple bond. "Cycloalkenyl" may refer to, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, or cycloheptadienyl. Unless otherwise defined, "cycloalkenyl" preferably refers to C 3-11 represents cycloalkenyl, more preferably C 3-7 It represents cycloalkenyl. Particularly preferably, "cycloalkenyl" is a monocyclic unsaturated alicyclic hydrocarbon ring having 3 to 7 ring members and having one or more (e.g., one or two; preferably one) carbon-carbon double bonds.

[0457] As used herein, the term "heterocycloalkenyl" refers to an unsaturated alicyclic (non-aromatic) ring group, including monocyclic, bridged, spirocyclic, and / or fused ring systems (e.g., composed of two or three rings; fused ring systems composed of two or three fused rings, etc.). The ring group has one or more (e.g., one, two, three, or four) heteroatoms independently selected from O, S, and N, and the remaining ring atoms are carbon atoms. One or more S ring atoms (if present) and / or one or more N ring atoms (if present) may be optionally oxidized. One or more carbon ring atoms may be optionally oxidized (i.e., form an oxo group). Furthermore, the ring group has one or more double bonds between adjacent ring atoms and no triple bonds between adjacent ring atoms. For example, each heteroatom-containing ring contained in the unsaturated alicyclic ring group may have one or two O atoms, and / or one or two S atoms (which may be optionally oxidized), and / or one, two, three, or four N atoms (which may be optionally oxidized), provided that the total number of heteroatoms in the heteroatom-containing ring is 1 to 4, and one or more carbon ring atoms (which may be optionally oxidized) are present in the heteroatom-containing ring. Examples of "heterocycloalkenyl" include imidazolinyl (e.g., 2-imidazolinyl (4,5-dihydro-1H-imidazolyl), 3-imidazolinyl, or 4-imidazolinyl), tetrahydropyridinyl (e.g., 1,2,3,6-tetrahydropyridinyl), dihydropyridinyl (e.g., 1,2-dihydropyridinyl or 2,3-dihydropyridinyl), pyranyl (e.g., 2H-pyranyl or 4H-pyranyl), and the like. thiopyranyl (e.g., 2H-thiopyranyl or 4H-thiopyranyl), dihydropyranyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrazinyl, dihydroisoindolyl, octahydroquinolinyl (e.g., 1,2,3,4,4a,5,6,7-octahydroquinolinyl) or octahydroisoquinolinyl (e.g., 1,2,3,4,5,6,7,8-octahydroisoquinolinyl).Unless otherwise defined, "heterocycloalkenyl" preferably refers to a 3- to 11-membered unsaturated alicyclic ring group, which is a monocyclic or fused ring system (e.g., a fused ring system consisting of two fused rings). The ring group has one or more (e.g., one, two, three, or four) hetero ring atoms independently selected from O, S, and N. One or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized. One or more carbon ring atoms are optionally oxidized. The ring group has one or more double bonds between adjacent ring atoms and no triple bonds between adjacent ring atoms. More preferably, "heterocycloalkenyl" refers to a 5- to 7-membered monocyclic unsaturated non-aromatic ring group, which has one or more (e.g., one, two, or three) hetero ring atoms 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, wherein one or more carbon ring atoms are optionally oxidized, wherein the ring group has one or more double bonds between adjacent ring atoms and no triple bonds between adjacent ring atoms.

[0458] As used herein, the term "halogen" refers to fluoro (-F), chloro (-Cl), bromo (-Br) or iodo (-I).

[0459] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more (preferably 1 to 6, more preferably 1 to 3) halogen atoms. The halogen atoms are independently selected from fluoro, chloro, bromo, and iodo, and are preferably all fluorine atoms. It is understood that the maximum number of halogen atoms is limited by the number of available bonding sites and, therefore, depends on the number of carbon atoms contained in the alkyl portion of the haloalkyl group. "Haloalkyl" may refer to, for example, -CF3, -CHF2, -CH2F, -CF2-CH3, -CH2-CF3, -CH2-CHF2, -CH2-CF2-CH3, -CH2-CF2-CF3, or -CH(CF3)2. A particularly preferred "haloalkyl" group is -CF3.

[0460] As used herein, the terms "optional" and "may" mean that the indicated feature may or may not be present. When the terms "optional" and "may" are used, the invention particularly relates to both possibilities; that is, to both the possibility that a feature is present and the possibility that the feature is absent. For example, the phrase "X is optionally substituted with Y" (or "X may be substituted with Y") means that X is either substituted with Y or is not substituted. Similarly, when a component of a composition is described as "optional," the invention particularly relates to both possibilities; that is, to both the possibility that a component is present (included in the composition) and the possibility that the component is not included in the composition.

[0461] In this specification, various groups are described as "optionally substituted." Generally, these groups may have one or more substituents (e.g., one, two, three, or four substituents). It will be understood that the maximum number of substituents is limited by the number of available bonding sites on the substituted moiety. Unless otherwise defined, "optionally substituted" groups described herein preferably have two or less substituents, and in particular may have only one substituent. Also, unless otherwise defined, it is preferred that there are no optional substituents (i.e., the corresponding group is not substituted).

[0462] Those skilled in the art will recognize that the substituents on the compounds of the present invention can be attached to the remainder of the compound through a number of different positions on the particular substituent. Unless otherwise specified, preferred positions of attachment for various particular substituents are as shown in the Examples.

[0463] As used herein, unless expressly indicated otherwise or contradicted by context, the terms "a," "an," and "the" are used interchangeably with "one or more" and "at least one." Thus, for example, a composition containing "a compound of formula (I)" can be interpreted as referring to a composition containing "one or more compounds of formula (I)."

[0464] As used herein, the term "about" preferably refers to ±10% of the stated numerical value, more preferably ±5% of the stated numerical value, and especially the stated numerical value itself. When the term "about" is used in reference to the endpoints of a range, it preferably refers to "-10% of the stated lower limit to +10% of the stated upper limit," more preferably refers to "-5% ​​of the lower limit to +5% of the upper limit," and even more preferably refers to "the defined lower limit to the defined upper limit." When the term "about" is used in reference to one of the endpoints of an open-ended range, it preferably indicates that the range begins at -10% of the lower limit or +10% of the upper limit, more preferably indicates that the range begins at -5% of the lower limit or +5% of the upper limit, and even more preferably indicates that the open-ended range is defined by the numerical endpoint itself. When the term "about" is used in reference to a parameter that takes an integer value (such as the number of nucleotides in a particular nucleic acid), a number corresponding to ±10% or ±5% of the stated numerical value is rounded to the nearest integer (with intermediate values ​​rounded up or down).

[0465] As used herein, the term "comprising, comprising, comprises, contain, contains, containing" has the meaning "including, among other things" (i.e., "including, among other optional additional elements"), unless expressly indicated otherwise or contradicted by context. In addition, this term also has the narrower meanings of "consisting essentially of" and "consisting of." For example, the term "A comprising B and C" means "A including, among other things, B and C," and A may contain optional additional elements (e.g., "A comprising B, C, and D" is also included). However, this term also has the meanings "A consisting essentially of B and C" and "A consisting of B and C" (i.e., A does not include any components other than B and C).

[0466] The scope of the present invention encompasses all pharmaceutically or physiologically acceptable salt forms of the compounds of formula (I). The salt forms can be formed, for example, by protonating an atom having a lone pair of electrons susceptible to protonation (such as an amino group) with an inorganic or organic acid. Alternatively, the salts can be formed as salts of physiologically acceptable cations with acid groups (such as a carboxylic acid group). Examples of base addition salts include 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 salts, triethylamine salts, dicyclohexylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, procaine salts, meglumine salts, ethylenediamine salts, or choline salts); aralkylamine salts (such as N,N-dibenzylethylenediamine salts, benzathine salts, or benethamine 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 basic amino acid salts (such as arginine salts, lysine salts, or histidine salts).Examples of acid addition salts include, for example, mineral acid salts (hydrochloride, hydrobromide, hydroiodide, sulfate (e.g., sulfate or hydrogen sulfate), nitrate, phosphate (e.g., phosphate, hydrogen phosphate, or dihydrogen phosphate), carbonate, hydrogen carbonate, perchlorate, borate, or thiocyanate); organic acid salts (acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, adipate, gluconate, etc.). , glycolate, nicotinate, benzoate, salicylate, ascorbate, pamoate (embonate), camphorate, glucoheptanoate, or pivalate; sulfonate (methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate (isethionate), benzenesulfonate (besylate), p-toluenesulfonate (tosylate), 2-naphthalenesulfonate (napsylate), 3-phenylsulfonate, or camphorsulfonate; glycerophosphate; acidic amino acid salts (aspartate or glutamate). Preferably, the pharmaceutically / physiologically acceptable salt of the compound of formula (I) is hydrochloride, hydrobromide, mesylate, sulfate, tartrate, fumarate, acetate, citrate, or phosphate. Particularly preferably, the pharmaceutically / physiologically acceptable salt of the compound of formula (I) is hydrochloride.

[0467] The scope of the present invention also encompasses any solvated form of the compound of formula (I). Examples of solvates include solvates with water (hydrates), solvates with organic solvents (e.g., solvates with methanol, ethanol, or acetonitrile (methanolate, ethanolate, or acetonitrileate)), any crystalline form (any polymorph), or amorphous form. It will be understood that solvates of the compound of formula (I) also include solvates of pharmaceutically acceptable salts of the compound of formula (I).

[0468] Furthermore, compounds of formula (I) may exist in various isomeric forms. In particular, compounds of formula (I) may exist in stereoisomers (such as geometric isomers (or cis / trans isomers), enantiomers, diastereomers, etc.) or tautomeric forms. All isomers of compounds of formula (I), whether in admixture or in pure or substantially pure form, are intended to be part of the present invention. With respect to stereoisomers, the present invention includes both isolated optical isomers of the compounds of the present invention as well as any mixtures thereof (e.g., racemic mixtures / racemates). Racemates can be separated by physical methods (such as fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography). Individual optical isomers can also be obtained by salt formation of racemates with optically active acids followed by crystallization. The present invention further encompasses any tautomers of the compounds herein.

[0469] The scope of the present invention also includes compounds of formula (I) in which one or more atoms are replaced with a particular isotope of that atom. For example, the present invention includes compounds of formula (I) in which one or more hydrogen atoms (or, for example, all hydrogen atoms) are replaced with a deuterium atom ( 2 The present invention also encompasses compounds of formula (I) that are substituted with hydrogen atoms (H; sometimes written as "D"). Therefore, the present invention also encompasses compounds of formula (I) that have a high concentration of deuterium. Naturally occurring hydrogen is approximately 99.98 mol% hydrogen 1 ( 1 H) and approximately 0.0156 mol% deuterium ( 2The compound of formula (I) is an isotopic mixture containing hydrogen and hydrogen (H or D). The deuterium content at one or more hydrogen positions in the compound of formula (I) can be increased by deuteration methods known in the art. For example, the compound of formula (I), reactants, or precursors used in the synthesis of the compound of formula (I) can be subjected to an H / D exchange reaction (e.g., using heavy water (DO)). Other suitable deuteration methods are disclosed 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). The deuterium content can be measured, for example, by mass spectrometry or NMR spectroscopy. Unless otherwise specifically indicated, it is preferred that the compounds of formula (I) do not have a large number of deuterium atoms. 1 Preferably, a H hydrogen atom is present in the compound of formula (I).

[0470] The present invention also encompasses compounds of formula (I) in which one or more atoms are substituted with a positron-emitting isotope of that atom ( 18 F, 11 C. 13 N, 15 O. 76 Br, 77 Br, 120 I and / or 124 Such compounds can be used as tracers, trackers, or imaging probes in positron emission tomography (PET). Accordingly, the present invention encompasses compounds in which: (i) one or more fluorine atoms (or, for example, all fluorine atoms) are 18 (ii) a compound of formula (I) in which one or more carbon atoms (or, for example, all carbon atoms) are substituted with a F atom; 11(iii) compounds of formula (I) in which one or more nitrogen atoms (or, for example, all nitrogen atoms) are substituted with 13 (iv) a compound of formula (I) in which one or more oxygen atoms (or, for example, all oxygen atoms) are substituted with an N atom; 15 (v) a compound of formula (I) in which one or more bromine atoms (or, for example, all bromine atoms) are substituted with an O atom; 76 (vi) compounds of formula (I) in which one or more bromine atoms (or, for example, all bromine atoms) are substituted with Br atoms; 77 (vii) compounds of formula (I) in which one or more iodine atoms (or, for example, all iodine atoms) are substituted with Br atoms; 120 (viii) compounds of formula (I) in which one or more iodine atoms (or, for example, all iodine atoms) are substituted with 1 atom; 124 Compounds of formula (I) substituted with I atoms. Generally, it is preferred that none of the atoms in compounds of formula (I) are substituted with any particular isotope.

[0471] The compounds herein may be administered as the compound itself or may be formulated as a medicament. The medicament / pharmaceutical composition 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).

[0472] The pharmaceutical composition may also include one or more solubility enhancers. Examples of the solubility enhancer include poly(ethylene glycol) (poly(ethylene glycol) having a molecular weight of about 200 to about 5,000 Da (e.g., PEG200, PEG300, PEG400, or PEG600)), ethylene glycol, propylene glycol, glycerol, nonionic surfactants, tyloxapol, polysorbate 80, macrogol-15-hydroxystearate (e.g., Kolliphor® HS15, CAS70142-34-6), phospholipids, lecithin, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, cyclodextrin, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-γ-cyclodextrin, hydroxypropyl propyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, sulfobutylether-γ-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl-β-cyclodextrin, carboxyalkyl thioether, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, vinyl acetate copolymer, vinylpyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, or any combination thereof.

[0473] Pharmaceutical compositions can be formulated by methods well known to those skilled in the art (see "Remington: The Science and Practice of Pharmacy", Pharmaceutical Press, 22 nd(e.g., methods described in the '999 edition). Pharmaceutical compositions may be formulated in dosage forms for oral administration, parenteral administration (e.g., intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardiac, rectal, nasal, topical, aerosol, or vaginal administration). Dosage forms for oral administration include coated or uncoated tablets, soft gelatin capsules, hard gelatin capsules, buccal tablets, troches, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules, medicated gums, chewable tablets, and effervescent tablets. Dosage forms for parenteral administration include solutions, emulsions, suspensions, dispersions, powders and granules for reconstitution. Emulsions are preferred dosage forms for parenteral administration. Dosage forms for rectal and vaginal administration include suppositories and pessaries. Dosage forms for nasal administration can be administered by inhalation (e.g., via a metered-dose inhaler) and insufflation. Dosage forms for topical administration include creams, gels, ointments, salves, patches and transdermal delivery systems.

[0474] The compounds of formula (I) or pharmaceutical compositions containing them can be administered to a subject by any convenient route of administration, whether systemic or peripheral, or at the desired site of action. Routes of administration include, but are not limited to, one or more of oral (e.g., tablet, capsule, or ingestible solution), topical (e.g., transdermal, intranasal, ophthalmic, buccal, and sublingual), parenteral (e.g., using injection or infusion techniques (such as subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, small subcutaneous, intraarticular, intrathecal, or intrasternal injection), for example, by implantation of a depot (such as subcutaneously or intramuscularly)), pulmonary (e.g., via the mouth or nose, by inhalation or insufflation therapy, such as with an aerosol), gastrointestinal, intrauterine, intraocular, subcutaneous, ophthalmic (such as intravitreal or intracameral), rectal, or vaginal administration.

[0475] When the compound or pharmaceutical composition is administered parenterally, examples of administration include one or more of intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracardiac, intracranial, intramuscular, or subcutaneous administration of the compound or pharmaceutical composition, and / or use of infusion techniques. For parenteral administration, the most commonly used form of the compound is a sterile aqueous solution (which may contain other substances, such as sufficient salts or glucose, to make the solution isotonic with blood). The aqueous solution is suitably buffered (preferably pH 3-9) if necessary. Suitable sterile parenteral formulations are readily prepared by standard pharmaceutical methods well known to those skilled in the art.

[0476] The compounds or pharmaceutical compositions can also be administered orally in the form of tablets, capsules, suppositories, elixirs, solutions or suspensions, which may contain flavoring or coloring agents for immediate, delayed, modified, sustained, pulsed or controlled release.

[0477] Tablets may contain excipients (such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, and glycine), disintegrants (such as starches (preferably corn, potato, or tapioca starch), sodium starch glycolate, croscarmellose sodium, and certain complex silicates), and granule binders (such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin, and acacia). Additionally, they may contain lubricants (such as magnesium stearate, stearic acid, glyceryl behenate, and talc). Solid compositions of the same type can also be used as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, cellulose, or high molecular weight polyethylene glycols. For aqueous suspensions and / or elixirs, the drug may be combined with various sweeteners or flavoring agents, coloring agents or dyes, emulsifying and / or suspending agents, diluents (such as water, ethanol, propylene glycol, and glycerin), and combinations thereof.

[0478] The compound or pharmaceutical composition can be administered in the form of a suppository or pessary. Alternatively, it can be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder. The compound of the present invention can also be administered dermally or transdermally (for example, by using a skin patch).

[0479] The compound or pharmaceutical composition can also be administered by sustained release system.Suitable examples of sustained release compositions include semi-permeable polymer matrices in the form of shaped articles (for example, films or microcapsules).Sustained release matrices include, for example, polylactide (see, for example, US 3,773,919), copolymers of L-glutamic acid and γ-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 (EP133988). In addition, the sustained-release pharmaceutical composition also includes the compound encapsulated in liposome.The liposome containing the compound of the present invention can be prepared by methods well known in the art.For example, it can be prepared by any one of the following methods: DE3218121; Epstein et al., Proc. Natl. Acad. Sci. (USA) 82:3688-3692 (1985); Hwang et al., Proc. Natl. Acad. Sci. (USA) 77:4030-4034 (1980); EP0052322; EP0036676; EP088046; EP0143949; EP0142641; JP83-118008; US4,485,045; US4,544,545; and EP0102324.

[0480] The compound or pharmaceutical composition may be administered via the pulmonary, rectal, or ocular routes. For ophthalmic use, the compound or pharmaceutical composition may be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline (preferably as a solution in isotonic, pH-adjusted, sterile saline), optionally in combination with a preservative such as benzalkonium chloride. Alternatively, the compound or pharmaceutical composition may be formulated in an ointment such as petrolatum.

[0481] It is also contemplated to prepare dry powder formulations of compounds of formula (I) for pulmonary administration (particularly inhalation). Such dry powders can be prepared by spray drying under conditions that yield a substantially amorphous, glassy or substantially crystalline bioactive powder. Thus, dry powders of the compounds of the invention can be produced by the emulsification / spray drying process disclosed in WO 99 / 16419 or WO 01 / 85136. Spray drying of solution formulations of the compounds of the invention can be carried out, for example, as generally disclosed in "Spray Drying Handbook," 5th ed., K. Masters, John Wiley & Sons, Inc., NY (1991), WO 97 / 41833, or WO 03 / 053411.

[0482] For topical administration to the skin, the compound or pharmaceutical composition can be formulated into a suitable ointment, which contains the active ingredient suspended or dissolved in a mixture of, for example, one or more of mineral oil, liquid paraffin, white petrolatum, propylene glycol, emulsifying wax, and water. Alternatively, the compound or pharmaceutical composition can be formulated into a suitable lotion or cream, which can be suspended or dissolved in a mixture of, for example, 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.

[0483] Therefore, the present invention relates to the compound or pharmaceutical composition provided herein, wherein the compound or pharmaceutical composition is administered by any one of the following routes: oral; topical route (such as transdermal, intranasal, ocular, buccal or sublingual); parenteral route using injection or infusion technique (such as subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, intrathecal, intrasternal, intraventricular, intraurethral or intracranial); pulmonary route (such as by inhalation therapy or insufflation therapy); gastrointestinal; intrauterine; intraocular; subcutaneous; ophthalmic route (such as intravitreal or intracameral); rectal; or intravaginal. Particularly preferred administration routes are topical, oral or parenteral administration. For the treatment or prevention of hyperhidrosis, topical administration is more preferred.

[0484] A physician will typically determine the actual dosage that will be most suitable for an individual subject. The specific dosage level and frequency of administration for any particular individual subject may vary and will depend on a variety of factors, such as the activity of the particular compound used, the metabolic stability and length of action of that compound, age, body weight, general health, sex, diet, mode and time of administration, excretion rate, concurrent drug use, the severity of the particular medical condition, and the individual subject being treated.

[0485] A suggested (but non-limiting) dosage for oral administration of the compounds of the present invention to humans (body weight approximately 70 kg) is 0.05 to 2000 mg, particularly 0.1 mg to 1000 mg, of active ingredient per unit dose. The unit dose may be administered, for example, 1 to 3 times per day. The unit dose may also be administered 1 to 7 times per week (e.g., no more than once per day). It will be understood that it may be necessary to vary the dose routinely depending on the age and weight of the patient / subject and the severity of the condition being treated. The exact dose and route of administration are ultimately at the discretion of the attending physician or veterinarian.

[0486] The compound of formula (I) or a pharmaceutical composition containing it can be administered as a monotherapy (e.g., without the simultaneous administration of an additional therapeutic agent, or without the simultaneous administration of an additional therapeutic agent for the same disease being treated or prevented with the compound of formula (I)). However, the compound of formula (I) or a pharmaceutical composition containing it may also be administered in combination with an additional therapeutic agent (e.g., one or more selected from phenobarbital, phenytoin, valproate (or valproic acid), carbamazepine, lamotrigine, levetiracetam, ethosuximide, and pharmaceutically acceptable salts of any of the above-mentioned agents). When the compound of formula (I) is used in combination with a second therapeutic agent effective against the same disease or condition, the dosage of each compound may differ from that when the compound is used alone (particularly, each compound may be used in a lower dosage). The combination of the compound of formula (I) with one or more additional therapeutic agents (e.g., one or more of the exemplary therapeutic agents described above) may be simultaneous administration of the compound of formula (I) and the additional therapeutic agents (in a single pharmaceutical formulation or in separate pharmaceutical formulations). Alternatively, the combination may be sequential / separate administration of the compound of formula (I) and the additional therapeutic agents. When sequentially administered, either the compound of formula (I) according to the present invention or the one or more additional therapeutic agents may be administered first. When simultaneously administered, the one or more additional therapeutic agents may be included in the same pharmaceutical formulation as the compound of formula (I) or may be administered in one or more different (separate) pharmaceutical formulations.

[0487] The subject or patient to be treated by the present invention may be an animal (e.g., a non-human animal). Preferably, the subject / patient is a mammal. More preferably, the subject / patient is a human (e.g., a male or female human) or a non-human mammal (guinea pig, hamster, rat, mouse, rabbit, dog, cat, horse, monkey, ape, marmoset, baboon, gorilla, chimpanzee, orangutan, gibbon, sheep, cow, pig, etc.). Most preferably, the subject / patient to be treated by the present invention is a human.

[0488] As used herein, the term "treatment" of a disorder or disease (e.g., "treatment" of hyperhidrosis) is well known in the art. "Treatment" of a disorder or disease implies that the disorder or disease has been suspected or diagnosed in a patient / subject. A patient / subject suspected of suffering from a disorder or disease usually exhibits specific clinical and / or pathological symptoms. Those skilled in the art can easily attribute these symptoms to a specific pathological state (i.e., a diagnosis of a disorder or disease).

[0489] "Treatment" of a disorder or disease may, for example, result in the cessation of the progression of the disorder or disease (e.g., symptoms do not worsen) or a slowing of the progression of the disorder or disease (where the cessation of progression is only transient). "Treatment" of a disorder or disease may also result in a partial response (e.g., improvement of symptoms) or a complete response (e.g., disappearance of symptoms) to a subject / patient suffering from a disorder or disease. Thus, "treatment" of a disorder or disease may also imply an improvement of the disorder or disease. An improvement of a disorder or disease may, for example, result in the cessation of the progression of the disorder or disease or a slowing of the progression of the disorder or disease. Such a partial or complete response may be followed by a relapse. It is understood that a subject / patient may experience a wide range of responses to treatment (such as the exemplary responses described above in this specification). Treatment of a disorder or disease may include, inter alia, curative treatment (preferably resulting in a complete response and ultimately curing the disorder or disease) and palliative treatment (such as alleviation of symptoms).

[0490] As used herein, the term "prevention" of a disorder or disease (e.g., "prevention" of hyperhidrosis) is also well known in the art. For example, a patient / subject suspected of being prone to a disorder or disease may particularly benefit from the prevention of the disorder or disease. The subject / patient may have a susceptibility or predisposition to the disorder or disease (including, but not limited to, a genetic predisposition). Such a predisposition can be determined by standard methods or assays, for example, using genetic markers or phenotypic indicators. It should be understood that the disorder or disease prevented by the present invention has not been diagnosed or cannot be diagnosed in the patient / subject (e.g., the patient / subject does not exhibit any clinical or pathological symptoms). Thus, the term "prevention" encompasses the use of the compounds of the present invention before any clinical and / or pathological symptoms are diagnosed or determined, or can be diagnosed or determined by the attending physician.

[0491] It is to be understood that the present invention relates to each and every combination of the features described herein (including any combination of general and / or preferred features). In particular, the present invention relates to each and every combination of meanings (such as general and / or preferred meanings) for the various groups and variables contained in formula (I).

[0492] Many documents, including patent applications and scientific papers, are cited in this specification. The disclosures of these documents are not believed to be relevant to the patentability of this invention, but are incorporated by reference in their entirety. More specifically, all documents are incorporated by reference to the same extent as if they were specifically and individually indicated to be incorporated by reference.

[0493] Reference herein to any prior art document (or information based thereon) is not and should not be construed as an acknowledgment, admission, or any form of suggestion that the prior art document (or information based thereon) forms part of the common general knowledge in the art to which this specification pertains.

[0494] The present invention particularly relates to the following:

[0495] 1. A compound of any one of the following formulae, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention of a disease or disorder in which NKCC is involved.

[0496] [ka] TIFF0007611812000105.tif211169TIFF0007611812000106.tif208169TIFF000 7611812000107.tif208169TIFF0007611812000108.tif197169TIFF0007611812 000109.tif206169TIFF0007611812000110.tif194169TIFF0007611812000111. tif191169TIFF0007611812000112.tif213169TIFF0007611812000113.tif75169

[0497] 2. A pharmaceutical composition for use in treating or preventing a disease or disorder involving NKCC, comprising the compound according to item 1 and a pharmaceutically acceptable excipient.

[0498] 3. Use of a compound according to item 1 in the preparation of a medicament for treating or preventing a disease or disorder in which NKCC is involved.

[0499] 4. A method for treating or preventing a disease or disorder involving NKCC, comprising administering to a subject in need thereof a compound according to item 1 or a pharmaceutical composition as defined in item 2.

[0500] 5. The method according to item 4, wherein the subject is a human.

[0501] 6. The compound for use according to item 1, the pharmaceutical composition for use according to item 2, the use according to item 3, or the method according to item 4 or 5, wherein the disease or disorder involving NKCC is hyperhidrosis.

[0502] 7. Non-therapeutic use of a compound according to item 1 to inhibit or reduce sweating in a subject.

[0503] 8. A non-therapeutic method for inhibiting or reducing sweating in a subject, comprising administering to said subject a compound according to item 1.

[0504] 9. The non-therapeutic use according to item 7 or the non-therapeutic method according to item 8, wherein the compound is administered topically.

[0505] 10. The non-therapeutic use according to item 7 or 9 or the non-therapeutic method according to item 8 or 9, wherein the compound is provided in the form of an article containing the compound, the article being a wipe, an insole or an article of clothing.

[0506] 11. An article containing the compound according to item 1, the article being a wipe, an insole or an article of clothing.

[0507] 12. The disease or disorder in which NKCC is involved is selected from anxiety disorders, autism spectrum disorders, autism, Asperger's syndrome, childhood disintegrative disorder, pervasive developmental disorders as part of autism spectrum disorders, traumatic brain injury, spinal cord injury, peripheral nerve injury, stroke, Alzheimer's disease, schizophrenia, asthma, edema, Down's syndrome, psychiatric disorders in patients with Down's syndrome, glaucoma, primary open-angle glaucoma, angle-closure glaucoma, and parasitic infection; The parasitic infection is preferably a helminth infection, a hookworm infection, a roundworm infection, a whipworm infection, a tapeworm infection, a Guinea worm infection, a pinworm infection, a toxocara infection, a Strongyloides stercoralis infection, an Ascaris lumbricoides infection, a parasitic fluke infection, schistosomiasis, gnathostomiasis, paragonimiasis, fascioliasis, swamp dermatitis, a protozoan infection, malaria, amebiasis, giardiasis, African sleeping sickness, toxoplasmosis, acanthamoeba keratitis, leishmaniasis, babesiosis, granulomatous amebic encephalitis, cryptosporidiosis, cyclosporosis, primary amebic meningoencephalitis, an ectoparasitic infection, an infection associated with Sarcoptes scabiei, a head lice (Pediculus humanus), or a parasitic worm infection. Item 6. The compound for use according to item 1, the pharmaceutical composition for use according to item 2, the use according to item 3, or the method according to item 4 or 5, wherein the compound for use according to item 1, the pharmaceutical composition for use according to item 2, the use according to item 3, or the method according to item 4 or 5, is selected from infections associated with Dermatophyte pubis (Phthirus capitis), infections associated with pubic lice (Phthirus pubis), infections associated with Dermatophyte larvae, infections associated with sand fleas (Tunga penetrans), and infections associated with ixodid ticks (Ixodoidea).

[0508] 13. In vitro use of the compounds according to item 1 as NKCC inhibitors.

[0509] 14. An in vitro method for inhibiting NKCC, comprising the step of applying a compound according to item 1.

[0510] 15. A compound of any one of the following formulae: or a pharmaceutically acceptable salt or solvate thereof:

[0511] [ka] TIFF0007611812000115.tif212169TIFF0007611812000116.tif204169TIFF0007611812000117.tif205169TIFF0007611812000118.tif21516 9TIFF0007611812000119.tif200169TIFF0007611812000120.tif192169TIFF0007611812000121.tif218169TIFF0007611812000122.tif20169

[0512] 16. A compound according to item 15 for use as a medicine.

[0513] 17. A pharmaceutical composition comprising the compound according to item 15 and a pharmaceutically acceptable excipient. [Example]

[0514] The present invention will now be described with reference to the following examples, which are merely illustrative and should not be construed as limiting the scope of the invention.

[0515] The compounds described in the present examples are defined by chemical formulas and corresponding chemical names. In the event of a discrepancy between the chemical formulas described in the present examples and the corresponding chemical names, the present invention relates to both the compounds defined by the chemical formulas and chemical names (particularly, to the compounds defined by the chemical formulas).

[0516] Example 1: Synthesis of various compounds according to the present invention [General method] All chemicals and solvents were of analytical grade and purchased from commercial suppliers (Sigma Aldrich, Merck, Apollo Scientific, and TCI Europe). Bumetanide was obtained from OChem Inc., Des Plaines, IL, US.

[0517] Silica Gel F 254The reaction was monitored by thin layer chromatography using coated aluminum sheets (Merck).

[0518] Silica gel 60 (70-230 mesh ASTM; manufactured by Merck) was used as the stationary phase for column chromatography.

[0519] Melting points were determined with a ThermoGalen Kofler microscope.

[0520] 1 H-NMR and 13 C-NMR spectra were measured at a Bruker Advance ( 1 H is 200MHz, 13 C is 50 MHz). Chemical shifts are reported in ppm relative to the residual solvent line or to tetramethylsilane as an internal standard.

[0521] Mass spectra were measured on a Shimadzu (GC-17A; MS-QP5050A) spectrophotometer. Peak intensities are reported as percentages based on the maximum signal in the spectrum.

[0522] Elemental analyses were performed by Mag. Johannes Theiner of the University of Vienna. All reported values ​​are within ±0.4% of the calculated values.

[0523] Ethyl 3-(butylamino)-4-phenoxy-5-sulfamoyl-benzoate (TEPS1)

[0524] [ka]

[0525] To a suspension of 5 mmol of bumetanide (1.82 g) in 3 mL of EtOH, 11 mmol (0.8 mL) of SOCl2 was added under argon and stirred overnight. Upon complete conversion (monitored by TLC T / EtOAc:6+4), the mixture was extracted several times with 5% NaHCO3, saturated brine, and water. The organic layer was then dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was recrystallized in ethanol to give 1.67 g (85%) of TEPS1. 1 H NMR (200 MHz, chloroform-d) δ 8.05-7.92 (m, 1H), δ 7.66-7.54 (m, 1H), δ 7.45-7.25 (m, 2H), δ 7.21-7.05 (m, 1H), δ 7.00-6.89 (m, 2H), δ 4.96 (s, 2H), δ 4.40 (q, J=7.1 Hz, 2H), δ 4.03-3,45 (br s, 1H), δ 3.21-3.01 (m, 2H), δ 1.41 (t, J=7.1 Hz, 3H), δ 1.31-1.07 (m, 4H), δ 0.95-0.76 (m, 3H).

[0526] N-benzyl-3-(butylamino)-4-phenoxy-5-sulfamoyl-benzamide (TEPS2)

[0527] [ka]

[0528] 3 mmol (1.09 g) of bumetanide was dissolved in 20 mL of dichloromethane and 3.38 mmol (0.65 g) of EDC.HCl was added. After 5 min, 3.37 mmol (0.52 g) of HOBt was added, and the reaction mixture was stirred for another 5 min. Next, 3 mmol (328 μL) of benzylamine was added, and the reaction mixture was stirred at room temperature overnight. After the reaction was complete, it was extracted three times with ethyl acetate, and the combined organic layers were washed with brine and dried over Na2SO4. The solvent was then evaporated under reduced pressure, and the crude product was purified by column chromatography (toluene / ethyl acetate: 6 + 4) and recrystallization in 50% ethanol. 1 H-NMR (200 MHz, chloroform-d): δ 7.55- 7.45 (m, 2H), δ 7.40- 7.20 (m, 7H), δ 7.14- 7.02 (m, 1H), δ 6.96- 6.80 (m, 3H), δ 5.09 (s, 2H), δ 4.59 (d, J = 5.8 Hz, 2H), δ 3.07 (t, J = 6.9 Hz, 2H), δ 1.49- 1.30 (m, 2H), δ 1.23 - 1.01 (m, 2H), δ 0.79 (t, J = 7.2 Hz, 3H).

[0529] Methyl 3-(butylamino)-5-(dimethylsulfamoyl)-4-phenoxybenzoate (TEPS3)

[0530] [ka]

[0531] 3 mmol (1.09 g) of bumetanide was dissolved in 5 mL of DMF, and 9.9 mmol (1.37 g) of K2CO3 and 10 mmol (0.62 mL) of methyl iodide were added. The reaction mixture was stirred for 5 h 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), δ 7.57 (d, J = 1.9 Hz, 1H), 7.34- 7.22 (m, 2H), δ 7.06 (t, J = 7.3 Hz, 1H), δ 6.83 (d, J = 7.9 Hz, 2H), δ 3.94 (s, 3H), δ 3.69 (s, 1H), δ 3.10 (t, J = 6.9 Hz, 2H), δ 2.79 (s, 6H), 1.52- 1.35 (m, 2H), δ 1.26- 1.06 (m, 2H), δ 0.82 (t, J = 7.2 Hz, 3H).

[0532] 3-(Butylamino)-5-(dimethylsulfamoyl)-4-phenoxybenzoic acid (TEPS4)

[0533] [ka]

[0534] 3 mmol (1.09 g) of bumetanide was dissolved in 20 mL of dichloromethane. Next, 3.38 mmol (0.65 g) of EDC.HCl was added. After 5 minutes, 3.37 mmol (0.52 g) of HOBt was added, and the reaction mixture was stirred for 5 minutes. Next, 3.01 mmol (274 μL) of aniline was added, and the reaction mixture was stirred at room temperature overnight. The mixture was then extracted with ethyl acetate, washed with saturated NaHCO3 solution, and dried over Na2SO4. The solvent was evaporated under reduced pressure, and the crude product was recrystallized in EtOH to give 3-(butylamino)-4-phenoxy-N-phenyl-5-sulfamoyl-benzamide. 0.3 mmol (0.265 g) of 3-(butylamino)-4-phenoxy-N-phenyl-5-sulfamoyl-benzamide was dissolved in 4 mL of methanol and 2 mL of THF. Then, 2 mL of 1 M LiOH solution was added, and the mixture was stirred at room temperature until the reaction was complete. The reaction mixture was acidified with 2 M HCl and extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over Na2SO4. The solvent was then evaporated under reduced pressure. 1 H-NMR (200 MHz, chloroform-d): δ 8.05 (d, J = 2.0 Hz, 1H), δ 7.63 (d, J = 2.0 Hz, 1H), δ 7.37- 7.24 (m, 2H), δ 7.07 (t, J = 7.3 Hz, 1H), δ 6.91- 6.79 (m, 2H), δ 3.13 (t, J = 6.9 Hz, 2H), δ 2.81 (s, 6H), δ 1.53 - 1.37 (m, 2H), δ 1.29- 1.08 (m, 2H), δ 0.83 (t, J = 7.2 Hz, 3H).

[0535] 3-(Butylamino)-5-(chloromethyl)-2-phenoxy-benzenesulfonamide (TEPS76)

[0536] [ka]

[0537] 1 mmol (0.35 g) of 3-(butylamino)-5-(hydroxymethyl)-2-phenoxy-benzenesulfonamide (Toellner K et al., Annals of Neurology (2014), 75(4), 550-562) was dissolved in 5 mL of thionyl chloride and heated at 80 °C for 3 h. The thionyl chloride was evaporated under reduced pressure, and the resulting material was dried in vacuum for 1 h. The product was purified by recrystallization in 70% MeOH to give 0.34 g of brown crystals (yield: 92%). 1H NMR (200 MHz, chloroform-d) δ 7.43 - 7-27 (m, 3H), δ 7.08 (t, J = 7.3 Hz, 1H), δ 7.02 - 6.79 (m, 3H), δ 4.88 (s, 2H) δ 4.57 (s, 2H), δ 3.07 (t, J = 6.9 Hz, 2H), δ 1.54 - 1.33 (m, 2H), δ 1.28 - 1.08 (m, 2H), δ 0.83, J = 7.1 Hz (t, 3H). MS m / z: 368 / 370 M + .

[0538] 3-(Butylamino)-2-phenoxy-5-[(2,2,2-trifluoroethylamino)methyl]benzenesulfonamide (TEPS5)

[0539] [ka]

[0540] [General Method A] 1 mmol (369 mg) of 3-(butylamino)-5-(chloromethyl)-2-phenoxy-benzenesulfonamide (TEPS76) was dissolved in 3 mL of dimethylformamide (DMF). 2 mmol (157 μL) of 2,2,2-trifluoroethylamine was added, and the mixture was stirred at room temperature overnight. After the reaction was complete (confirmed by thin-layer chromatography), the liquid was 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 recrystallized in 70% MeOH to obtain 130 mg of white crystals (yield: 30%). 1H NMR (200 MHz, Methanol-d4) δ 7.34 - 7.18 (m, 3H), δ 7.09 - 6.96 (m, 2H), δ 6.94 - 6.83 (m, 2H), δ 3.90 (s, 2H), δ 3.29 - 3.17 (m, 2H), δ 3.09 (t, J = 6.8 Hz, 2H), δ 1.49 - 1.32 (m, 2H), δ 1.26 - 1.06 (m, 2H), δ 0.81 (t, J = 7.2 Hz, 3H). MS m / z: 431 M + .

[0541] 3-(Butylamino)-5-(morpholinomethyl)-2-phenoxy-benzenesulfonamide (TEPS6)

[0542] [ka]

[0543] TEPS6 was prepared according to general method A, except that 2 mL of morpholine was added instead of 2,2,2-trifluoroethylamine. The crude product was purified by column chromatography (ethyl acetate / petroleum ether: 1+1) and recrystallized in EtOH to give 130 mg of beige crystals (yield: 31%). 1 H NMR (200 MHz, Methanol-d4) δ 7.34 - 7.18 (m, 3H), δ 7.09 - 6.96 (m, 2H), δ 6.94 - 6.83 (m, 2H), δ 3.90 (s, 2H), δ 3.29 - 3.17 (m, 2H), δ 3.09 (t, J = 6.8 Hz, 2H), δ 1.49 - 1.32 (m, 2H), δ 1.26 - 1.06 (m, 2H), δ 0.81 (t, J = 7.2 Hz, 3H). MS m / z: 431 M + .

[0544] 3-(Butylamino)-5-(1H-imidazol-2-ylsulfanylmethyl)-2-phenoxy-benzenesulfonamide (TEPS7)

[0545] [ka]

[0546] TEPS7 was prepared according to general procedure A, except that 1 mmol (100 mg) of 2-mercaptoimidazole was added instead of 2,2,2-trifluoroethylamine and the reaction was stirred for 2 days. The crude product was purified by column chromatography (ethyl acetate / petroleum ether / triethylamine: 6+3+1) and recrystallized in 70% EtOH to give 0.22 g of white crystals (yield: 51%). 1 H NMR (200 MHz, chloroform-d) δ 7.36 - 7.21 (m, 2H), δ 7.14 (s, 2H), δ 7.10 - 6.96 (m, 2H), δ 6.94 - 6.80 (m, 2H), δ 6.63 (d, J = 2.0 Hz, MS m / z: 432M + .

[0547] 3-(Butylamino)-2-phenoxy-5-(pyrimidin-2-ylsulfanylmethyl)benzenesulfonamide (TEPS8)

[0548] [ka]

[0549] TEPS8 was prepared according to general method A, except that 1 mmol (112 mg) of 2-mercaptopyrimidine was added instead of 2,2,2-trifluoroethylamine. The crude product was purified by column chromatography (ethyl acetate / petroleum ether: 7+3) and recrystallized in 70% MeOH to give 210 mg of white crystals (yield: 47%). 1 H NMR (200 MHz, chloroform-d) δ 8.55 (d, J = 4.8 Hz, 2H), δ 7.38 (d, J = 1.8 Hz, 1H), δ 7.35 - 7.23 (m, 2H), δ 7.18 - 6.83 (m, 5H), δ 4.90 (s, 2H), δ 4.41 (s, 2H), δ 3.80 (t, J = 5.3 Hz, 1H), δ 3.17 - 2.91 (m, 2H), δ 1.49 - 1.31 (m, 2H), δ 1.26 - 1.05 (m, 2H), δ 0.81 (t, J = 7.1 Hz, 3H). MS m / z: 444 M + .

[0550] 3-(Butylamino)-5-[(1-methylimidazol-2-yl)sulfanylmethyl]-2-phenoxy-benzenesulfonamide (TEPS9)

[0551] [ka]

[0552] TEPS9 was prepared according to general method A, except that 1 mmol (114 mg) of 2-mercapto-1-methylimidazole was added instead of 2,2,2-trifluoroethylamine. The crude product was purified by column chromatography (ethyl acetate / petroleum ether / triethylamine: 6+3+1) and recrystallized in 70% MeOH to give 180 mg of white crystals (yield: 40%). 1H NMR (200 MHz, chloroform-d) δ 7.33 - 7.08 (m, 5H), δ 7.07 - 6.91(m, 3H), δ 6.81 (d, J = 7.7 Hz, 2H), δ 6.65 (d, J = 1.7 Hz, 1H), δ 4.75,(t, J = 5.7 Hz, 1H), δ 4.17 (s, 2H), δ 3.43 (s, 3H), δ 2.98 - 2.81 (m, 2H), δ 2.98 - 2.81 (m, 2H), δ 1.17 - 0.99 (m, 2H), δ 0.77 (t, J = 7.1 Hz, 3H). MS m / z: 446 M + .

[0553] 3-(Butylamino)-5-(1-hydroxy-1-methyl-ethyl)-2-phenoxy-benzenesulfonamide (TEPS10)

[0554] [ka]

[0555] To a solution of 4 mmol of methyl 3-(butylamino)-4-phenoxy-5-sulfamoylbenzoate (WO 2013 / 087090) in 10 mL of anhydrous THF, 15 mL of methylmagnesium bromide solution (1.4 M in THF) was added, and the mixture was stirred at room temperature. Five additional 3 mL portions of methylmagnesium bromide solution (1.4 M in THF) were added at 30-minute intervals. After a total of 3 hours of stirring, the mixture was quenched with 5% aqueous NH4Cl solution, precipitating a white solid. The mixture was then extracted with ethyl acetate, washed twice with water, and once with brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (EtOAc / petroleum ether: 1+1) and recrystallized in 70% EtOH to give 1.06 g of a brown solid (yield: 70%).

[0556] 3-(Butylamino)-5-isopropenyl-2-phenoxy-benzenesulfonamide (TEPS11)

[0557] [ka]

[0558] 0.5 mmol of TEPS10 was dissolved in 5 mL of thionyl chloride, and the mixture was stirred for 1 day. After the reaction was completed, the thionyl chloride was evaporated under reduced pressure. The resulting crude product was purified by column chromatography (ethyl acetate / petroleum ether: 1+1) and recrystallized in 70% EtOH to give 120 mg of a beige solid (yield: 67%). 1 H NMR (200 MHz, chloroform-d) δ 7.44 -7.27 (m, 3H), δ 7.12 - 6.90 (m, 4H), δ 5.39 (s, 1H), δ 5.23 - 5.10 (m, 1H), δ 4.89 (s, 2H), δ 3.78 (t, J = 5.3 Hz, 1H), δ 3.16 - 3.00 (m, 2H), δ 2.17 (s, 3H), δ 1.51 - 1.35 (m, 2H), δ 1.24 - 1.11 (m, 2H), δ 0.83 (t, J = 7.2 Hz, 3H).MS m / z: 360M + .

[0559] 3-(Butylamino)-5-[(4-hydroxy-4-phenyl-1-piperidyl)methyl]-2-phenoxy-benzenesulfonamide (TEPS12)

[0560] [ka]

[0561] TEPS12 was prepared according to general procedure A, except that 1.2 mmol (213 mg) of 4-hydroxy-4-phenylpiperidine was added instead of 2,2,2-trifluoroethylamine 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 recrystallized in 70% MeOH to give 210 mg of white crystals (yield: 41%). 1 H NMR (200 MHz, chloroform-d) δ 7.64 - 7.46 (m, 2H), δ 7.41 - 7.25 (m, 6H), δ 7.16 - 6.85 (m, 4H), δ 4.95 (s, 2H), δ 5.21 - 4.72 (m, 1H), δ 3.57 (s, 2H), δ = 3.20 - 2.99 (m, 2H), δ 2.97 - 2.72 (m, 2H), δ 2.53 (t, J = 10.8 Hz, 2H), δ 2.32 - 2.02 (m, 2H), δ 1.88 - 1.61 (m, 3H), δ 1.51 -1.32 (m, 2H), δ 1.28 - 1.12 (m, 2H), δ 0.83 (t, J= 7.1 Hz, 3H). MS m / z: 510 M + .

[0562] 3-(Butylamino)-5-[(cyanomethylamino)methyl]-2-phenoxy-benzenesulfonamide (TEPS13)

[0563] [ka]

[0564] TEPS13 was prepared according to general method A, except that 1.2 mmol (167 μL) of triethylamine and 1.2 mmol (71 μL) of aminoacetonitrile were added instead of 2,2,2-trifluoroethylamine. The crude product was purified by column chromatography (EtOAc / petroleum ether: 1+1) and recrystallized in 70% EtOH to give 180 mg of a beige powder (yield: 46%). 1 H NMR (200 MHz, chloroform-d) δ 7.40 - 7.22 (m, 3H), δ 7.16 - 6.85 (m, 4H), δ 5.02 (s, 2H), δ 3.91 (s, 2H), δ 3.88 - 3.78 (m, 1H), δ 3.60 MS m / z: 388M + .

[0565] 3-(Butylamino)-2-phenoxy-5-[(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)methyl]benzenesulfonamide (TEPS14)

[0566] [ka]

[0567] TEPS14 was prepared according to general method A, except that 1.2 equivalents of 4-phenyl-1,2,3,6-tetrahydropyridine was added instead of 2,2,2-trifluoroethylamine. The resulting crude product was purified by column chromatography (ethyl acetate / petroleum ether: 3+7) to give 110 mg of TEPS14 (yield: 29.3%). 1H NMR (200 MHz, chloroform-d) δ 7.54 - 7.21 (m, 9H), δ 7.07 (t, J = 7.5 Hz, 1H), δ 7.00 - 6.83 (m, 2H), δ6.07 (s, 1H), δ 5.06 (s, 2H), δ 4.00 - 3.72 (m, 3H), δ 3.50 - 3.28 (m, 2H), δ 3.17 - 3.03 (m, 2H), δ 3.00 - 2.80 (m, 2H), δ 2.80 - 2.56 (m, 2H), δ 1.54 - 1.32 (m, 2H), δ 1.28 - 1.06 (m, 2H), δ 0.81 (t, J = 7.1 Hz, 3H). MS m / z: 491 M + .

[0568] N'-[3-(butylamino)-2-phenoxy-5-[(2-thienylmethylamino)methyl]phenyl]sulfonyl-N,N-dimethyl-formamidine hydrochloride (TEPS15)

[0569] [ka]

[0570] 3-(butylamino)-2-phenoxy-5-[(2-thienylmethylamino)methyl]benzenesulfonamide was prepared according to general procedure A, except that 1 mmol (104 μL) of 2-thiophenemethylamine was added instead of aniline. The crude product was purified by column chromatography (ethyl acetate / petroleum ether: 1+1) and recrystallized in 70% EtOH to give 0.23 g of beige crystals (yield: 52%). 0.22 mmol (0.100 g) of 3-(butylamino)-2-phenoxy-5-[(2-thienylmethylamino)methyl]benzenesulfonamide was dissolved in 5 mL of anhydrous THF and 0.48 mmol (0.068 mL) of DMF-DMA was added. The reaction was stirred overnight and purified by column chromatography (ethyl acetate). The resulting brown solid was then dissolved in anhydrous THF and 3 mL of 1 M HCl (in diethyl ether) was added. The precipitated HCl salt was filtered off to give beige crystals (yield: 37.5%). 1 H NMR (200 MHz, chloroform-d) δ 10.36 (s, 1H), δ 7.91 (s, 1H), δ 7.49 (d, J = 11.9 Hz, 3H), δ 7.37 - 7.20 (m, 3H), δ 7.11 - 6.70 (m, 4H), δ 4.30 (s, 2H), δ 4.10 (s, 2H), δ3.74 (t, J = 6.6 Hz, 1H), δ3.13 (s, 2H), δ 2.70 (d, J = 43.2 Hz, 6H), δ 2.00 - 1.70 (m, 1H), δ 1.47 - 1.25 (m, 2H), δ 1.23 - 1.00 (m, 2H), δ 0.76 (t, J = 6.9 Hz, 3H).

[0571] Methyl 3-(butylamino)-5-[2-(dimethylamino)ethylsulfamoyl]-4-phenoxybenzoate (TEPS16)

[0572] [ka]

[0573] 0.19 mmol (0.087 g) of methyl 3-(butylamino)-4-phenoxy-5-sulfamoylbenzoate (WO2013 / 087090) was dissolved in 5 mL of DMF, and 1.3 mmol (0.188 g) of 2-dimethylaminoethyl HCl and 2.2 mmol (0.304 g) of K2CO3 were added. 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%). 1 H NMR (200 MHz, chloroform-d) δ 7.95 (d, J = 1.8 Hz, 1H), δ 7.67 - 7.53 (m, 1H), δ 7.29 (t, J = 7.7 Hz, 2H), δ 7.06 (t, J = 7.3 Hz, 1H), δ 6.88 (d, J = 7.8 Hz, 2H), δ 3.93 (s, 3H), δ 3.88 (s, 1H), δ 3.26 - 3.07 (m, 2H), δ 3.05 - 2.90 (m, 2H), δ 2.44 - 2.29 (m, 2H), δ 2.16 (s, 6H ), δ 1.51 - 1.35 (m, 2H), δ 1.21 - 1.05 (m, 2H), δ 0.81 (t, J = 7.1 Hz, 3H). MS m / z: 449 M + .

[0574] Methyl 3-(butylamino)-5-[2-(dimethylamino)ethylsulfamoyl]-4-phenoxybenzoate (TEPS17)

[0575] [ka]

[0576] TEPS16 was dissolved in anhydrous THF and 3 mL of 1 M HCl (in diethyl ether) was added. The precipitated HCl salt was filtered off to give a white powder (yield: 92.5%). 1 H NMR (200 MHz, chloroform-d) δ 11.28 (s, 1H), δ 7.88 (s, 1H), δ 7.56 (s, 1H), δ 7.33 - 7.19 (m, 3H), δ 7.02 (t, J = 8.1 Hz, 2H), δ 3.93 (s, 3H), δ3.31 (d, J = 22.4 Hz, 4H), δ3.09 (t, J = 6.8 Hz, 2H), δ2.83 (s, 6H), δ 1.52 - 1.32 (m, 2H), δ 1.28 - 1.07 (m, 2H), δ 0.81 (t, J = 7.1 Hz, 3H).

[0577] 5-(Anilinomethyl)-3-(butylamino)-N-[2-(dimethylamino)ethyl]-2-phenoxy-benzenesulfonamide (TEPS18)

[0578] [ka]

[0579] 0.5 mmol (0.213 g) of 5-(anilinomethyl)-3-(butylamino)-2-phenoxy-benzenesulfonamide (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) of 2-dimethylaminoethyl HCl and 2 mmol (0.278 g) of K2CO3 were added. The reaction mixture was stirred overnight at 40 °C, 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 (yield: 38.3%). 1H NMR (200 MHz, chloroform-d) δ 7.42 - 7.09 (m, 6H), δ 7.08 - 6.84 (m, 4H), δ 6.83 - 6.58 (m, 3H), δ 5.33 (s, 1H), δ 4.33 (s, 2H), δ3.83 (t, J = 5.3 Hz, 1H), δ3.13 - 3.00 (m, 2H), δ 2.99 - 2.87 (m, 2H), δ 2.38 - 2.27 (m, 2H), δ 2.17 (s, 6H), δ 1.41 - 1.27 (m, 2H), δ 1.19 - 1.03 (m, 2H), δ 0.79 (t, J = 7,1 Hz, 3H). MS m / z: 496 M + .

[0580] 3-(Butylamino)-5-(ethoxymethyl)-2-phenoxy-benzenesulfonamide (TEPS19)

[0581] [ka]

[0582] 0.27 mmol (100 mg) of TEPS76 was dissolved in acetonitrile, and 0.44 mmol (34 μL) of sodium ethoxide was added. The reaction mixture was stirred at room temperature overnight. Then, 0.15 mmol (12 μL) of sodium ethoxide was further added. After the reaction was completed, 5% aqueous NaHCO3 was added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The resulting crude product was purified by recrystallization in EtOH to give 38 mg of a brown solid (yield: 22.7%). 1H NMR (200 MHz, chloroform-d) δ 7.39 - 7.23 (m, 3H), δ 7.20 - 6.80 (m, 4H), δ 4.92 (s, 2H), δ 4.49 (s, 2H), δ 3.59 (q, J = 7.0 Hz, 2H), δ 3.05 (t, J = 7.0 Hz, 2H), δ 1.52 - 1.33 (m, 2H), δ 1.27 (t, J = 7.0 Hz, 3H), δ 1.23 - 1.05 (m, 2H), δ 0.81 (t, J = 6.8 Hz, 3H). 378M + .

[0583] 3-(Butylamino)-2-phenoxy-5-(phenoxymethyl)benzenesulfonamide (TEPS20)

[0584] [ka]

[0585] 0.64 mmol (60 mg) of phenol was dissolved in 5 mL of DMF, and 0.54 mmol (200 mg) of TEPS 76 was added in three portions over 15 minutes. The reaction was stirred overnight at room temperature. After the reaction was complete, 5% aqueous NaHCO3 was added, and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, 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 (yield: 15.6%). 1H NMR (200 MHz, chloroform-d) δ 7.62 - 7.20 (m, 6H), δ 7.19 - 6.83 (m, 6H), δ 5.04 (s, 2H), δ 4.94 (s, 2H), δ 3.04 (t, J = 6.8 Hz, 2H), δ 1.53 - 1.30 (m, 2H), δ 1.29 - 1.01 (m, 2H), δ 0.81 (t, J = 6.0 Hz, 3H). MS m / z: 426 M + .

[0586] 3-(Butylamino)-2-phenoxy-5-(4-phenyl-3,6-dihydro-2H-pyridine-1-carbonyl)benzenesulfonamide (TEPS21)

[0587] [ka]

[0588] 1 mmol (364 mg) of bumetanide and 1.1 mmol (179 mg) of CDI were added to anhydrous THF. After a clear solution was formed, 1.3 mmol (200 mg) of 4-phenyl-1,2,3,6-tetrahydropyridine was added, and the reaction was stirred at room temperature overnight. After the reaction was complete, 5% aqueous NaHCO3 was added, and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The resulting crude product was recrystallized in EtOH to give 294 mg of a white powder (yield: 58%). 1H NMR (200 MHz, chloroform-d) δ 7.59 - 7.21 (m, 8H), δ 7.20 - 6.79 (m, 4H), δ 6.39 - 5.78 (m, 1H), δ 5.16 (s, 2H), δ 4.47 - 4.07 (m, 2H), δ 4.02 - 3.61 (m, 2H), δ 3.05 (t, J = 6.8 Hz, 2H), δ 2.63 (s-br, 2H), δ1.52 - 1.29 (m, 2H), δ 1.29 - 1.03 (m, 2H), δ 0.80 (t, J = 7.1 Hz, 3H). MS m / z: 505 M + .

[0589] 3-(Butylamino)-5-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxymethyl]-2-phenoxy-benzenesulfonamide (TEPS22)

[0590] [ka]

[0591] 0.27 mmol (100 mg) of TEPS76 was dissolved in 3 mL of anhydrous THF. Then, 22 mg of NaH and 63 μL of tetraethylene glycol were added. After the reaction was completed, 5% aqueous NaHCO3 was added, and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, 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 TEPS22 (yield: 27%). 1H NMR (200 MHz, chloroform-d) δ 7.28 - 7.14 (m, 3H), δ 7.06 - 6.73 (m, 4H), δ 5.19 (s, 2H), δ 4.46 (s, 2H), δ 3.86 - 3.39 (m, 14H), δ 3.27 (m, 2H), δ2.97 (t, J = 6.8 Hz, 2H), δ1.54 - 0.97 (m, 7H), δ 0.74(t, J = 7.2 Hz, 3H). MS m / z: 540 M + .

[0592] 3-(Butylamino)-4-phenoxy-5-sulfamoyl-N-(2,2,2-trifluoroethyl)benzamide (TEPS23)

[0593] [ka]

[0594] To a solution of 1 mmol (364 mg) bumetanide in 5 mL of anhydrous THF, 1.2 mmol (194 mg) of 1,1-carbonyldiimidazole (CDI) was added, and the mixture was stirred for 2 hours. After no residual bumetanide was detected by TLC, 2 mmol (157 μL) of trifluoroethylamine was added, and the mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was poured into 20 mL of 5% NaHCO3 and extracted with ethyl acetate. The organic phase was then dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was then purified by recrystallization in EtOH to give 159 mg of a white powder (36% yield). 1H NMR (200 MHz, Methanol-d4) δ 7.73 (d, J = 2.1 Hz, 1H), 7.44 (d, J = 2.1 Hz, 1H), 7.38 - 7.20 (m, 2H), 7.14 - 6.98 (m, 1H), 6.98 - 6.86 (m, MS m / z: 445 M + .

[0595] 4-Morpholino-3-nitro-5-sulfamoyl-benzoic acid (TEPS24)

[0596] [ka]

[0597] 1 mmol (280 mg) of 4-chloro-3-nitro-5-sulfamoylbenzoic acid was dissolved in 2 mL of morpholine and stirred overnight under reflux. After the reaction was completed, the crude product was purified by recrystallization in water to give 222 mg of yellow crystals (yield: 67%). 1 H NMR (200 MHz, DMSO-d6) δ 14.02 (s, 1H), δ 8.86 - 8.71 (m, 1H), δ 8.61 - 8.43 (m, 1H), δ 7.69 (s, 2H), δ4.18 - 3.57 (m, 4H), δ 3.28 - 3.07 (m, 4H).

[0598] Methyl 3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitro-4-(prop-2-ynylamino)benzoate (TEPS25)

[0599] [ka]

[0600] 1 mmol (350 mg) of TEPS28 was dissolved in 5 mL of acetonitrile, and 2 mmol (276 mg) of K2CO3 and 1.1 mmol (70 μL) of propargylamine were added. The mixture was stirred overnight, and after TLC showed no residual TEPS28, the reaction mixture was extracted with ethyl acetate and washed with brine. The combined organic layer was evaporated under reduced pressure, and the resulting brown solid was recrystallized in 70% ethanol to give 108 mg of brown crystals (yield: 30%). 1 H NMR (200 MHz, DMSO-d6) δ8.53 - 8.39 (m, 2H), δ 8.31 (s, 1H), δ 7.29 (t, J = 5.6 Hz, 1H), δ 4.31 - 4.07 (m, 2H), δ 3.85 (s, 3H), δ 3.32 (s, 1H), δ3.26 (t, J = 2.3 Hz, 1H), δ 3.15 (s, 1H), δ2.94 (s, 1H).

[0601] Methyl 3-(dibutylamino)-4-phenoxy-5-sulfamoyl-benzoate (TEPS26) (WO2013 / 087090)

[0602] [ka]

[0603] To a solution of 1 mmol of methyl 3-(butylamino)-4-phenoxy-5-sulfamoylbenzoate (WO 2013 / 087090) in 10 mL of 1,2-dichloroethane was added 2 mmol (228 μL) of butyraldehyde. To this solution was added 1.5 mmol (87 μL) of acetic acid. 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. The mixture was stirred overnight. After the reaction was complete, 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 Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate / petroleum ether: 7+3) and recrystallized in EtOH to give 223 mg of white crystals (yield: 51%). 1 H NMR (200 MHz, chloroform-d) δ 8.23 ​​(d, J = 1.2 Hz, 1H), δ 7.87 (s, 1H), 7.37 - 7.15 (m, 2H), δ7.14 - 6.97 (m, 1H), δ 6.93 - 6.73 (m, 2H), δ 4.99 (s, 2H), δ 4.12 - 3.79 (m, 3H), δ 3.02 (t, J = 7.2 Hz, 4H), δ 1.35 - 1.09 (m, 4H), δ 1.10 - 0.92 (m, 4H), δ 0.77 (t, J = 6.8 Hz, 6H). MS m / z: 434 M + .

[0604] 3-(Dibutylamino)-5-(hydroxymethyl)-2-phenoxy-benzenesulfonamide (TEPS27) (WO2013 / 087090)

[0605] [ka]

[0606] 1 mmol of TEPS26 was dissolved in 5 mL of anhydrous THF and stirred at room temperature under an argon atmosphere. Next, 2 mL of 1 M DIBAL-H in toluene was added. After 1, 2, 3, and 4 hours, 1 mL of the 1 M DIBAL-H in toluene solution was added, and the reaction was stirred overnight. After TLC confirmed that no TEPS26 remained, the mixture was cooled to 0 °C and quenched with 5% aqueous NH4 to precipitate a gel-like substance. The precipitate was then dissolved in 2 N HCl and extracted three times with ethyl acetate. The combined organic layer was washed three times with water, once with brine, and dried over Na2SO4. The liquid was evaporated under reduced pressure and purified by recrystallization in ethanol to give 360 ​​mg of a beige powder (yield: 89%). 1 H NMR (200 MHz, Methanol-d4) δ 7.63 (brs, 1H), δ7.40 (brs, 1H), 7.32 - 7.14 (m, 2H), δ 7.00 (t, J = 7.3 Hz, 1H), δ 6.82 (d, J = 7.5 Hz, 2H), δ δ 4.66 (s, 2H), 3.13 (t, J = 7.4 Hz, 4H), δ1.43 - 0.92 (m, 8H), δ 0.78 (t, J = 7.0 Hz, 6H). MS m / z: 406 M + .

[0607] 3-(Butylamino)-5-[(N-butylanilino)methyl]-2-phenoxy-benzenesulfonamide (TEPS28)

[0608] [ka]

[0609] 2 mmol (180 μL) of butyraldehyde was added to a solution of 1 mmol of 5-(anilinomethyl)-3-(butylamino)-2-phenoxy-benzenesulfonamide (Lykke K et al., British Journal of Pharmacology (2015), 172(18), 4469-4480) dissolved in 10 mL of 1,2-dichloroethane. 2 mmol (116 μL) of acetic acid and 3 mmol (0.64 g) of sodium triacetoxyborohydride (NaBH(OAc)3) were added to this solution, and the mixture was stirred overnight. The mixture was then diluted with 10 mL of water and 20 mL of dichloromethane. The organic phase was dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate / petroleum ether: 7+3) to give 312 mg of a white powder (yield: 58%). 1 H NMR (200 MHz, chloroform-d) δ 7.89 (s, 1H), 7.45 - 7.15 (m, 5H), δ7.00 (t, J = 7.3 Hz, 1H), δ6.89 - 6.59 (m, 6H), δ 4.52 (s, 2H), δ 3.41 (t, J = 7.6 Hz, 2H), δ 2.88 (t, J = 7.0 Hz, 2H), δ 2.75 (s, 3H), δ 2.58 (s, 3H), δ 1.64 (s, 1H), δ1.49 - 1.17 (m, 6H), δ 1.18 - 0.87 (m, 4H), δ 0.73 (t, J = 7.2 Hz, 3H). MS m / z: 536 M + .

[0610] 3-(Dibutylamino)-4-phenoxy-5-sulfamoyl-benzoic acid (TEPS29) (WO2013 / 087090)

[0611] [ka]

[0612] 1 mmol (434 mg) of TEPS26 was dissolved in 3 mL of MeOH and 2 mL of 2N NaOH was added. The reaction was stirred at room temperature for 2 hours. After TLC showed that no TEPS26 remained, the solution was acidified with 2N HCl, and the resulting precipitate was filtered off and dried under vacuum to give 380 mg of a white powder (yield: 90%). 1 H NMR (200 MHz, Methanol-d4) δ 8.22 (d, J = 2.0 Hz, 1H), δ 7.91 (d, J = 2.1 Hz, 1H), δ 7.37 - 7.15 (m, 2H), δ 7.02 (t, J = 7.3 Hz, 1H), δ 6.83 (d, J = 7.5 Hz, 2H), δ 3.10 (t, J = 7.2 Hz, 4H), δ 1.38 - 1.15 (m, 4H), δ 1.13 - 0.93 (m, 4H), δ 0.78 (t, J = 7.1 Hz, 6H).

[0613] Methyl 7-[(E)-dimethylaminomethyleneamino]sulfonyl-2-methyl-1-prop-2-ynyl-benzimidazole-5-carboxylate (TEPS30)

[0614] [ka]

[0615] 1 mmol of TEPS25 (368 mg) was added to 15 mL of ethanol and 3 mL of dioxane, and the mixture was heated to 85 °C and stirred until completely dissolved. Next, a solution of 10 mmol of ammonium chloride (535 mg) in 6 mL of water was added. 4 mmol of iron powder (223 mg) was added in three portions at 2-minute intervals. The reaction was further stirred at 85 °C for 2.5 h until TEPS25 was no longer detected 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 brine and dried over Na2SO4. The crude product was purified by flash chromatography (ethyl acetate) and recrystallized in methanol to give 90 mg of white crystals (yield: 25%). 1 H NMR (200 MHz, chloroform-d) δ 8.56 (s, 1H), δ 8.48 (s, 1H), δ 8.16 (s, 1H), δ 5.80 (d, J = 2.5 Hz, 2H), δ 3.95 (s, 3H), δ3.15 (s, 3H), δ 3.12 (s, 3H), δ 2.85 (s, 3H), δ 2.38 (t, J = 5.0, 2.5 Hz, 2H). MS m / z: 362 M + .

[0616] Methyl 4-(butylamino)-3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitrobenzoate (TEPS31)

[0617] [ka]

[0618] To a suspension of 3 mmol (842 mg) of 4-chloro-3-nitro-5-sulfamoylbenzoic acid in 3 mL of HO, 10.8 mmol (907 mg) of NaHCO was carefully added, followed by 6 mmol (595 μL) of butylamine. The resulting solution was stirred at 85 °C for 16 hours. After the reaction was complete, 10 mL of HO was added. The mixture was then acidified by adding 2 N HCl. The mixture was then cooled, and the precipitate was filtered off to give 825 mg of white crystals (yield: 86.6%). 1 H 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, CDCl3) 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. m / z: 387M + .

[0619] Methyl 3-[(E)-dimethylaminomethyleneamino]sulfonyl-4-(1-methylimidazol-2-yl)sulfanyl-5-nitrobenzoate (TEPS32)

[0620] [ka]

[0621] To 10 mL of acetonitrile, 3 mmol (1.05 g) of methyl 4-chloro-3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitrobenzoate (WO 2012 / 018635), 3.3 mmol (376 mg) of 2-mercapto-1-methylimidazole, and 6.6 mmol (910 mg) of K2CO3 were added. The solution was stirred overnight at room temperature. When TLC showed that no methyl 4-chloro-3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitrobenzoate remained, 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 Na2SO4, and evaporated under reduced pressure. The crude product was then purified by recrystallization in ethanol to give 1.04 g of yellow crystals (yield: 81%). 1 H NMR (200 MHz, DMSO-d6) δ8.66 (d, J = 1.9 Hz, 1H), δ8.34 (d, J = 1.8 Hz, 2H), δ7.28 (s, 1H), δ 6.87 (s, 1H), δ 3.91 (s, 3H), 3.51 (s, 3H), δ 3.10 (s, 3H), δ 2.92 (s, 3H). MS m / z: not found.

[0622] Methyl 3-amino-5-[(E)-dimethylaminomethyleneamino]sulfonyl-4-(1-methylimidazol-2-yl)sulfanyl-benzoate (TEPS33)

[0623] [ka]

[0624] 1 mmol of TEPS32 (428 mg) was added to 15 mL of ethanol and 3 mL of dioxane, and the mixture was heated to 85 °C and stirred until completely dissolved. Next, a solution of 10 mmol of ammonium chloride (535 mg) in 6 mL of water was added. 4 mmol of iron powder (223 mg) was added in three portions at 2-minute intervals. The reaction was further stirred at 85 °C for 2.5 h until TEPS32 was no longer detected 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 brine and dried over Na2SO4. The crude product was purified by flash chromatography (ethyl acetate) to give 290 mg of a yellow solid (yield: 73%). 1 H NMR (200 MHz, DMSO-d6) δ8.25 (s, 1H), δ 7.79 (d, J = 1.9 Hz, 1H), δ 7.50 (d, J = 2.0 Hz, 1H), δ 7.27 (d, J = 1.3 Hz, 1H), δ 6.93 (d, J = MS m / z: not possible EI-MS.

[0625] Methyl 3-(butylamino)-5-[(E)-dimethylaminomethyleneamino]sulfonyl-4-(1-methylimidazol-2-yl)sulfanyl-benzoate (TEPS34)

[0626] [ka]

[0627] To a solution of 1 mmol of TEPS33 in 10 mL of 1,2-dichloroethane was added 2 mmol (228 μL) of butyl iodide. To this solution was added 1.5 mmol (87 μL) of acetic acid. Next, 3 mmol (0.64 g) of sodium triacetoxyborohydride (NaBH(OAc)3) was added over 2 h, and the mixture was stirred overnight. After the reaction was complete, it 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 Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate) to give 234 mg of a yellow powder (yield: 52%). 1 H NMR (200 MHz, chloroform-d) δ 8.16 (s, 1H), δ 8.09 (d, J = 1.8 Hz, 1H), δ 7.36 (d, J = 1.8 Hz, 1H), δ 7.10 (d, J = 1.4 Hz, 1H), δ 6.96 (d, J = 1.4 Hz, 1H), δ 5.79 (s, 1H), δ 3.91 (s, 3H), δ 3.59 (s, 3H), δ3.10 (d, J = 17.3 Hz, 8H), δ1.62 - 1.44 (m, 2H), δ 1.43 - 1.15 (m, 2H), δ 0.92 (t, J = 7.2 Hz, 3H). MS m / z: 453 M + .

[0628] 3-(Butylamino)-4-(1-methylimidazol-2-yl)sulfanyl-5-sulfamoyl-benzoic acid (TEPS35)

[0629] [ka]

[0630] 1 mmol (454 mg) of TEPS34 was dissolved in 3 mL of MeOH, and 2 mL of 2 N NaOH was added. The reaction mixture was stirred at room temperature for 2 hours. After TLC confirmed that no TEPS34 remained, the solution was acidified with 2 N HCl, and the resulting precipitate was filtered off and recrystallized in EtOH to give 346 mg of yellow crystals (yield: 90%). 1 H NMR (200 MHz, Methanol-d4) δ 8.78 (s, 1H), δ8.03 (dd, J = 4.7, 1.7 Hz, 1H), δ 7.56 (s, 1H), δ7.37 (s, 1H), δ 7.18 (s, 1H), δ 3.69 (s, MS: not possible in EI.

[0631] Methyl 4-(4,5-dihydrothiazol-2-ylsulfanyl)-3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitrobenzoate (TEPS36)

[0632] [ka]

[0633] In a three-neck flask, 1 mmol of methyl 4-chloro-3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitrobenzoate (350 mg) was dissolved in acetonitrile (10 mL). Next, 1.2 mmol of 2-mercaptothiazoline (MW = 119.21 g / mol; 143 mg) and 2 mmol of K2CO3 (MW = 138 g / mol; 276 mg) were added to the flask. The reaction mixture was stirred overnight at room temperature. Water was added to the reaction mixture, which was then extracted three times with ethyl acetate and washed with brine. The organic layer was dried over Na2SO4, 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 (yield: 78.0%).

[0634] Methyl 3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitro-4-(3-thienyl)benzoate (TEPS39)

[0635] [ka]

[0636] 1 mmol of methyl 4-chloro-3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitrobenzoate (320 mg) was dissolved in 3 mL of dioxane. Next, 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 added. The reaction vial was filled with argon, heated to 90 °C, and stirred overnight. The mixture was then cooled to room temperature, 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 (yield: 70%). 1H NMR (200 MHz, chloroform-d) δ 9.13 (d, J = 1.8 Hz, 1H), δ 8.46 (d, J = 1.8 Hz, 1H), δ 7.60 - 7.29 (m, 2H), δ 7.22 - 7.07 (m, 2H), δ 4.01 (s, 3H), δ 2.90 (s, 3H), δ 2.84 (s, 3H). MS m / z: 398 M + .

[0637] Methyl 3-amino-5-[(E)-dimethylaminomethyleneamino]sulfonyl-4-(3-thienyl)benzoate (TEPS40)

[0638] [ka]

[0639] 1 mmol of TEPS39 (397 mg) was added to 15 mL of ethanol and 3 mL of dioxane, and the mixture was heated to 85 °C and stirred until completely dissolved. Next, a solution of 10 mmol of ammonium chloride (535 mg) in 6 mL of water was added. 4 mmol of iron powder (223 mg) was added in three portions at 2-minute intervals. The reaction was further stirred at 85 °C for 2.5 h until TEPS39 was no longer detected 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 brine and dried over Na2SO4. The crude product was purified by flash chromatography (ethyl acetate / petroleum ether: 7 + 3) to give 334 mg of a yellow solid (yield: 90%). 1 H NMR (200 MHz, chloroform-d) δ 8.43 (d, J = 1.6 Hz, 1H), δ 7.73 (d, J = 1.7 Hz, 1H), δ 7.47 - 7.35 (m, 2H), δ 7.18 - 7.02 (m, 2H), δ 3.93 (s, 3H), δ 2.88 (s, 3H), δ 2.84 (s, 3H). MS m / z: 367 M +.

[0640] Methyl 3-(butylamino)-5-[(E)-dimethylaminomethyleneamino]sulfonyl-4-(3-thienyl)benzoate (TEPS41)

[0641] [ka]

[0642] 1 mmol (367 mg) of TEPS40 was dissolved in 5 mL of acetonitrile. Then, 3 mmol (408 mg) of K2CO3 and 3 mmol (3418 μL) of butyl iodide were added. The reaction mixture was stirred at 90 °C for 2 days. After the reaction was completed, the reaction mixture was poured into 20 mL of water and extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over Na2SO4. The solvent was then evaporated under reduced pressure, and the resulting crude product was purified by column chromatography (ethyl acetate / toluene: 1+1) to give 90 mg of a white powder (yield: 21.0%). 1 H NMR (200 MHz, chloroform-d) δ 8.37 (d, J = 1.6 Hz, 1H), δ 7.66 (d, J = 1.7 Hz, 1H), δ 7.52 - 7.36 (m, 2H), δ 7.12 (s, 1H), δ 7.13 - 7.00 (m, 1H), δ 3.94 (s, 3H), δ 3.13 - 2.99 (m, 2H), δ 2.89 (s, 3H), δ2.85 (s, 3H), δ 1.56 - 1.35 (m, 2H), δ 1.32 - 1.12 (m, 2H), δ 0.86 (t, J = 7.2 Hz, 3H). MS m / z: 424 M + .

[0643] Methyl 3-(dibenzylamino)-5-[(E)-dimethylaminomethyleneamino]sulfonyl-4-(3-thienyl)benzoate (TEPS42)

[0644] [ka]

[0645] 1 mmol (367 mg) of TEPS40 was dissolved in 5 mL of acetonitrile. Then, 2 mmol (276 mg) of K2CO3 and 2 mmol (238 μL) of benzyl bromide were added. The reaction mixture was stirred at 70 °C overnight. After the reaction was complete, the reaction mixture was poured into 20 mL of water and extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over Na2SO4. 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 give 193 mg of a white powder (yield: 35%). 1 H NMR (200 MHz, chloroform-d) δ 8.70 (d, J = 1.7 Hz, 1H), δ 8.01 (d, J = 1.7 Hz, 1H), δ 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 + .

[0646] 5-(benzyloxymethyl)-3-(butylamino)-2-phenoxy-benzenesulfonamide (TEPS43)

[0647] [ka]

[0648] To 10 mL of anhydrous THF was added 1.5 mmol (37 mg) of NaH and 1.1 mmol (114 μL) of benzyl alcohol. The solution was stirred for 10 minutes, and then 1 mmol (369 mg) of TEPS76 was added. The reaction was stirred overnight at room temperature. When TLC confirmed that no TEPS76 remained, the reaction mixture was evaporated to dryness under reduced pressure and purified by column chromatography (ethyl acetate / petroleum ether: 3+7) to give 100 mg of a white powder (yield: 22%). 1 H NMR (200 MHz, chloroform-d) δ 7.51 - 7.20 (m, 8H), δ 7.06 (t, J = 7.4 Hz, 1H), δ 7.00 - 6.88 (m, 3H), δ 4.85 (s, 2H), 4.60 (s, 2H), δ 4.53 MS m / z: 440M + .

[0649] Methyl 3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitro-4-pyrimidin-2-ylsulfanyl-benzoate (TEPS44)

[0650] [ka]

[0651] In a three-neck flask, 1 mmol of methyl 4-chloro-3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitrobenzoate (350 mg) was dissolved in acetonitrile (10 mL). Next, 1.2 mmol of 2-mercaptopyrimidine (MW = 112.15 g / mol; 135 mg) and 2 mmol of K2CO3 (MW = 138 g / mol; 276 mg) were added to the flask. The reaction mixture was stirred overnight at room temperature and controlled by thin-layer chromatography (ethyl acetate / petroleum ether: 7 + 3). The mixture was extracted three times with ethyl acetate and washed with water (2 × 15 mL) and brine (1 × 20 mL). The organic layer was dried over Na2SO4, 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 (yield: 95.9%). 1 H NMR (200 MHz, DMSO-d6) δ8.84 (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, CDCl3) 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 + .

[0652] Methyl 3-amino-5-[(E)-dimethylaminomethyleneamino]sulfonyl-4-pyrimidin-2-ylsulfanyl-benzoate (TEPS45)

[0653] [ka]

[0654] In a three-neck flask, 0.96 mmol of TEPS44 (408 mg) was dissolved in 20 mL of EtOH and 10 mL of dioxane under reflux. Next, 9.8 mmol of NH4Cl (MW = 53.49 g / mol; 524 mg) was dissolved in 12.5 mL of HO and added to the reaction vial. After 5 min, 3.84 mmol of Fe 2+ (MW=55.85 g / mol; 215 mg) was added in three portions. The reaction mixture was then stirred under reflux for 1 h. EtOH and dioxane were removed under reduced pressure, followed by the addition of dichloromethane and H2O. The product was extracted with dichloromethane, and the organic layer was washed with 2 x 15 mL of H2O and brine. The organic layer was dried over Na2SO4, and the dichloromethane was removed under reduced pressure. The crude product was then purified by column chromatography (ethyl acetate / petroleum ether: 7+3) to give 144 mg of orange crystals (yield: 37.9%). 1 H NMR (200 MHz, DMSO-d6) δ8.80 (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 + .

[0655] Methyl 3-(butylamino)-5-[(E)-dimethylaminomethyleneamino]sulfonyl-4-pyrimidin-2-ylsulfanyl-benzoate (TEPS46)

[0656] [ka]

[0657] In a round-bottom flask, 0.36 mmol of TEPS45 (144 mg) was dissolved in DMF. Then, 0.45 mmol of K2CO3 (63 mg) and 0.45 mmol of butyl iodide (51.1 μL) were added to the reaction vial. The reaction mixture was stirred at room temperature overnight. Then, DMF was removed under reduced pressure. The product was extracted with ethyl acetate, and the organic layer was washed with HO and brine. The crude product was purified by column chromatography (ethyl acetate / petroleum ether: 7 + 3) to give 143 mg of orange crystals (yield: 87.9%). 1 H 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 = 15.1, 7.0 Hz, 2H), 0.85 (t, J = 7.2 Hz, 3H). 13 C NMR (50 MHz, CDCl3) δ166.0, 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 + .

[0658] 3-(Butylamino)-4-pyrimidin-2-ylsulfanyl-5-sulfamoyl-benzoic acid (TEPS47)

[0659] [ka]

[0660] In a round-bottom flask, 0.28 mmol of TEPS46 (136 mg) was dissolved in 20 mL of MeOH and 7 mL of 2N NaOH. The reaction mixture was stirred at 50 °C for 2 h. MeOH was removed under reduced pressure. The aqueous layer was poured into a beaker and acidified with 2N HCl. The resulting precipitate was then extracted with ethyl acetate. The organic layer was washed with HO and brine, and the solvent was removed under reduced pressure to give 104 mg of a beige powder (yield: 89%). 1 H NMR (200 MHz, DMSO-d6) δ13.43 (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 (50MHz, 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: 382M + .

[0661] Methyl 3-(benzylamino)-5-[(E)-dimethylaminomethyleneamino]sulfonyl-4-pyrimidin-2-ylsulfanyl-benzoate (TEPS83)

[0662] [ka]

[0663] In a round-bottom flask, 0.36 mmol of TEPS45 (144 mg) was dissolved in DMF and 0.43 mmol of KCO (MG = 138 g / mol; 60 mg) and 0.43 mmol of benzyl bromide (MG = 171.04 g / mol; δ = 1.44 g / cm3 ; 51.3 μL) was added to the reaction vial. The reaction mixture was stirred at room temperature overnight. The progress was controlled by thin layer chromatography (ethyl acetate / petroleum ether: 7+3) and DMF was removed under reduced pressure. The product was extracted with 2 × 15 mL of ethyl acetate and the organic layer was washed with 2 × 15 mL of HO and 1 × 20 mL of brine. The crude product was purified by column chromatography (ethyl acetate / petroleum ether: 7+3) to give 144 mg of beige / brown crystals (yield: 82.4%). 1 H 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, CDCl3) 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 + .

[0664] 3-(Benzylamino)-4-pyrimidin-2-ylsulfanyl-5-sulfamoyl-benzoic acid (TEPS48)

[0665] [ka]

[0666] In a round-bottom flask, 0.28 mmol of TEPS83 (136 mg) was dissolved in 20 mL of MeOH and 7 mL of 2N NaOH. The reaction mixture was stirred at 50 °C for 2 hours. The MeOH was removed under reduced pressure. The aqueous layer was poured into a beaker and acidified with 2N HCl. The resulting precipitate was then...

Claims

1. A compound of any one of the following formulae: or a pharma- ceutically acceptable salt or solvate thereof: 【Chemistry 1】

2. 10. A compound according to claim 1 for use as a medicine.

3. A pharmaceutical composition comprising a compound of claim 1 and a pharma- ceutically acceptable excipient.

4. A compound of any one of the following formulae, or a pharma- ceutically acceptable salt or solvate thereof: A pharma- ceutically acceptable excipient; A therapeutic agent for neurological diseases comprising the compound. 【Chemistry 2】

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