UA112076C2 - Heteroaryl derivatives - Google Patents

Abstract

A compound of formula I is disclosed: (I) wherein Z, m and R-R are as described herein as a modulator of nicotinic acetylcholine receptors, in particular the α7 subtype, in a subject in need thereof, as well as its analogs, prodrugs , isotopically substituted analogs, metabolites, pharmaceutically acceptable salts, polymorphs, solvates, isomers, clathrates and co-crystals for use alone or in combination with suitable other drugs and pharmaceutical compositions containing such compounds and analogues. Also disclosed is a method of producing compounds and their intended uses in therapy, especially in the prevention and treatment of disorders such as Alzheimer's disease, moderate cognitive impairment, senile dementia, etc.

Description

(in)

M ve)

Ku Z t

In in (in) in? uch 7 k

KI and 0 where 7, t and K'-Nb are as described herein as a modulator of nicotinic acetylcholine receptors, particularly of the o7 subtype, in a subject in need thereof, as well as analogs, prodrugs, isotopically substituted analogs thereof , metabolites, pharmaceutically acceptable salts, polymorphs, solvates, isomers, clathrates and co-crystals for use either alone or in combination with suitable other drugs and pharmaceutical compositions containing such compounds and analogues. Also disclosed is a method of preparing the compounds and their intended uses in therapy, particularly in the prevention and treatment of disorders such as disease

Alzheimer's disease, mild cognitive impairment, senile dementia, etc. 4 sq m in M 67 DC

And 6) vE2 about MY and

VZ

()

Field of invention

This invention relates to new compounds of the general formula Y,

ГФ) 4 vv Z Kv vot. and c) vE2 o

TV in

Fo. their tautomeric forms, their stereoisomers, their M-oxides, their pharmaceutically acceptable salts, polymorphs, solvates, optical isomers, combinations with a suitable drug, pharmaceutical compositions containing them, methods of preparation of the above-mentioned compounds, and their use as modulators of nicotinic subunits acetylcholine receptor a7 (pAcSp a7).

Prerequisites of the invention

Cholinergic transmission of nerve impulses, mediated mainly by the neurotransmitter acetylcholine (AC), is the predominant regulator of the body's physiological functions through the central and autonomic nervous systems. ASP acts on the synapses of neurons located in all autonomic ganglia, neuromuscular junctions, and the central nervous system. Two distinct classes of AS target receptors have been identified in the brain, namely muscarinic (tACi) and nicotinic (PAS), which form a significant component of receptors performing their mnemonic and other vital physiological functions.

The nicotinic ASP receptors (MMK) of the nervous system belong to the class of ligand-gated ion channels (IS), consisting of five subunits (402-410, B2-84), located in a heteropentameric (0482) or homopentameric (c7) configuration (Raiegeop O ei ai., Rgoad.

Meigobio!., 2000, 61, 75-111). a4p2 and pASp a7 are the predominant subtypes expressed in the mammalian brain. PASP a7 is known as a therapeutic target due to its excessive expression in the learning and memory centers of the brain, the hippocampus and the cerebral cortex (Aibboyi Eyi ai., Meshhospet. Ipi., 1994, 25, 69-71). In particular, pASP a7 is characterized by high permeability to Ca ions, which is responsible for the release of the neurotransmitter and the subsequent modulation of the excitatory and inhibitory transmission of nerve impulses (AIKopdop Mei ai., Eig. U.

Ripaptasoi!., 2000, 393, 59-67; Oa|az-Vaiyavdchog E ei a!., Ttepaz Riaptasoi. 5si., 2004, 25, 317-324).

In addition, high influx of Sag- ions also affects long-term potentiation of memory through changes in gene expression (Vipeg K5 ei ai., U. Meiygovzsi., 2007, 27, 10578-10587; MeKau VE eiai., Viospet. Rpaptasoi! ., 2007, 74, 1120-1133).

Some recent studies have confirmed the role of pAcSiP a7 in neural processes such as attention, memory and cognition (Mapz5meiYideg NO ei a, Rousporpagtasoioudu (Vegi), 2006, 184, 292-305; Spap

MUK eyi ai., Meshtorpagttaso!iodu, 2007, 52, 1641-1649; Moipdu M ei a!., Yeig. MeigorzusporNaptasoi., 2007, 17, 145-155). Gene polymorphisms associated with white SNRNA?7 pACI a?7 were involved in genetic transmission in schizophrenia, associated with deficits in neurophysiological filtering of sensory information and, as a result, in cognitive impairment (Rheyedtap Kei ai., VioiI. Rzupiatsgu, 1995, 38, 22-33; Tvtsapu OMU eyi aYi., At. ). Honey. Sepei., 2001, 105, 662-668). Also, preclinical studies on pASP a7 knockout mice treated with an antisense oligonucleotide demonstrated impaired attention and defective cognition, underscoring the important role of pPASP a7 in cognition (Syg2op Rei ai., Meshygovzsi. Hey, 2006, 410, 15-19; Moipdud UM/ hey ay.,

MetzgorzusporNnaptasoiiodu., 2004, 29, 891-900). In addition, pharmacological blockade of pASP a7 impairs memory, and its activation enhances memory in preclinical rodent models, suggesting pASP a7 as a target for improving cognitive functions (Nazpitoio Kei ai., Vioi.

Rzuspiaigu, 2008, 63, 92-97).

Pathological function of the brain in sensory information deficit disorders was associated with nicotinic cholinergic transmission, in particular, through a7 receptors (Egevatap Kei a!., Vio!i. Rvuspiatgu, 1995, 38, 22-33; Tviapu OM ei a!., At. U). May Sepei., 2001, 105, 662-668;

Sagzop V ei ai., Meigotoyesshciag, 2008, May. 10, 377-384; And eopaga 5 yei ai!., Rnaptasoi. Viospet.

Venam., 2001, 70, 561-570; Egeedtap RE ei ai., Art. Rzusnianu Ver., 2003, 5, 155-161; Sappop TO ei aiYi.,, Sit. Orip. RvusNniayu, 2005, 18, 135-140). It is assumed that defective processing of sensory information at the level of subthreshold attention is the basis of cognitive fragmentation in schizophrenia and family psychoneurological disorders (I eiseg ZS ei aiYi., Rpaptasoi. TNpeg., 2009,

122, 302-311). Studies of genetic linkage traced the connection between the locus of the gene and? and some affective disorders, attention disorders, anxiety and psychotic disorders (Geopaga 5 ei ai., Rnaptasoi. Viospet. Vepam., 2001, 70, 561-570; Ztsetagi K ei ai., Mirrop

UakipdakKy 7avzvni, 2002, 119, 295-300).

Disturbances in cholinergic and glutamatergic homeostasis have long been considered to be factors that cause a patient to develop a neurological disease, including dementia) (Miggy Eyi a!I., Ogyd

Mem Regzresi., 2007, 20, 421-429). Dementia is a severe, progressive, multifactorial cognitive disorder that affects memory, attention, language, and problem-solving abilities.

Nicotinic receptor AS, in particular, the interaction of receptor a7 with afVi-4g, is assumed to be a previous pathogenic event in Alzheimer's disease, the main causative factor of dementia (U/apod NU ei ai., U. Meshgovsi., 2009, 29, 10961-10973). Moreover, gene polymorphisms in SNRNA7 have been implicated in dementia with Lewy bodies (0 B) and Pick's disease (Bepeg A ei ai., Oetepi. Segiaig.

Sodp. Oizoga., 2009, 28, 56-62).

The ability of pASA, especially the a7 receptor, to modify the disease has been used in the modification of Alzheimer's disease (AD) and Parkinson's disease (PO) by improving the survival of neurons and preventing neurodegeneration (M/apd ei aI. 2009; MadeIe KO ei a)i., Mepygossiepse, 2002, 110, 199-211; deuagazazipdat S eyi a!., Meshtozsiepse, 2002, 109, 275-285). In addition, pASip-7-induced activation of anti-apoptotic (ALL-2) and anti-inflammatory pathways in the brain will have neuroprotective effects in neurodegenerative diseases (Magego MV ei ai., Vgaiip. Kev5., 2009, 1256, 1-7). Dopamine-containing neurons of the ventral tegmental area (MTA) and the laterodorsal tegmental nucleus (GOT) are known to express AC nicotinic receptors, in particular, subunits a4, a3, 82, BZ, B4 (Kiltip A ei ai.,

Rzuspornaptaso!oadu (Veti), 2009, 203, 99-108). AC a4p2 and a3p4 nicotinic receptors, as determined using the "candidate gene" approach, have a strong mechanistic connection with nicotine addiction (MuUeiii5 KV ei aiYi., Rio Sepei., 2008, 4, e1000125). In particular, the probable role of pASSI a7 in cannabinoid addiction was investigated (Zoiip5 Mei ai., "Meshgovsi., 2007, 27, 5615-5620). Varenicline, a 4p2 partial agonist, demonstrated better efficacy in reducing smoking dependence and preventing relapse compared to buproprion (Ebbegi U0 ei a!., Rayepi. Rgeieg. Adpegepse, 2010, 4, 355-362).

The presence of a high-affinity nicotine binding site in pASP a4r2 in the descending inhibitory pathways from the brainstem has sparked interest in the antinociceptive properties of agonists of the ASP nicotinic receptor, such as epibatidine (YuOesKeg MMU ei ai.,

Ekhrep Orip. Ipumesia Ogide, 2001, 10, 1819-1830). Some new developments have opened the field of application of nicotine modulators for the treatment of pain (Kozhm/roipat MS ei ai., Raip, 2009, 146, 245-252). Appropriate modulation of AC nicotinic receptors may provide a treatment approach for pain-related conditions.

Another important role of pASpP ca7 is the ability to modulate the production of pro-inflammatory cytokines such as interleukins (I), tumor necrosis factor alpha (TME-a) and high mobility group framework (HMOV-1) in the central nervous system. Therefore, an anti-inflammatory and antinociceptive effect in pain-related disorders (rata) was demonstrated. MI ei ai.,

Meshygorpaptasoi!odu, 2000, 39, 2785-2791). In addition, the "cholinergic anti-inflammatory pathway", as it is assumed, is a regulator of local and systemic inflammation and neuroimmune interactions with the help of nervous and humoral pathways (ZaiYom/y5sp-Riepa Me6yi ai.,!ie 5si., 2007, 80, 2325-2329 ; SaPomyvsp-Riepa apa Ramiom 2007; Vozaz-Vaiypa Mei ai., My. Med., 2009, 15, 195-202; Vozaz-Vaiyna Mei ai., U. Iyiet. Meia., 2009, 265, 663- 679). Selective modulators of nicotinic receptors of ASP, in particular, type a7, such as 5T5-21, weaken the production of cytokine and I-18 after exposure to endotoxin. In addition, pASpP a7 is believed to play a central role in the pathogenesis of arthritis and in an effective therapeutic strategy for the treatment of joint inflammation (U/ezitap Meyi ai., Zsapa. ). Ittipoi., 2009, 70, 136-140). A probable role

PAS a7 is also involved in severe sepsis, endotoxemic shock and systemic inflammation (ip Uei a. (2010) Ipi. 9). Ittipodepei., And to them S ei a!., Stii. Sage. Med., 2009, 37, 634-641).

Angiogenesis is an important physiological process for cell survival and has pathological significance in cancer proliferation; some ASI nicotinic receptors that do not belong to the nervous system are involved, in particular, a7, a5, "3, B2, B4 (Agia5 NE eiai., Ipi. 9. Viospet. Se.

Vio!., 2009, 41, 1441-1451; NeezsNep S ei ai., u). Siip. Ipmevi., 2002, 110, 527-536). The role of AC nicotinic receptors in the development of cervical cancer, lung carcinogenesis and children's lung disorders in the smoking-prone population (СаПе)а-Масяз Іе ей аі., Іі was also investigated.

U. Sapseg., 2009, 124, 1090-1096; 5st floor, step NM ei ai., Yeshg. U. Rnaptasoi., 2000, 393, 265-277). Some agonists of pACI a?7, partial agonists, have been described in connection with their effectiveness in clinical and 60 preclinical studies. EMR-6124, a PASP α7 agonist, showed significant improvement in sensory information processing and biomarkers of cognitive impairment in a phase II study in patients suffering from schizophrenia (Empimo Rpagtaseciisaii5 rge55 heIease 2009, dap 12). at5-21 (OMHV-Apabavzeipe), an agonist of pASP a, in phase II clinical trials showed effectiveness in improving cognitive function deficits in schizophrenia and inhibition of endotoxin-induced release of TME-a (Oiipsu A ei a!., Vioi. Rzuspiayu, 2005, 57(8, Zirri.), AbBvzi 44;

Oiipsu A ei ai., Ap. Sept. Rzuspiayu, 2006, 63, 630-638; Suoiavzieip AV ei aYi., Asad. Etegu Med., 2007, 14 (15, Birri. 1), Abvi 474). SR-810123, a pACE7 agonist, shows the ability to protect against scopolamine-induced dementia and inhibit amphetamine-induced auditory evoked potentials in preclinical studies. , 53, 1222-1237). 558-180711A, also an agonist of PASI a7, improves learning and memory, and protects against MK-801/scopolamine-induced memory loss and prepulse inhibition in preclinical studies (Keagobe UR ei ai. , Yeig.). Rpaptasoi., 2009, 602, 58-65;

U. Rpagtasoi. Ex. TNeg., 2009, ZZ28, 766-776; Risnai Rei aI., Meshtorzusporpaptasoiido, 2007, 32, 17-34). BEM-12333 protected against scopolamine-induced amnesia in the passive avoidance test in preclinical studies (Kopsagai! Kei ai., U. Rpagtasoi. Ehr. Tpeg., 2009, 329, 459-468). AV-B-17779, an agonist of PASyA 7, shows improvement in the social recognition test performed in rats (Map KM ei ai!., Rzusporpaptasiodu (Vetpi), 2004, 172, 375-383). AVVE, an agonist of pASSI a?7, shows improvement of social recognition memory and working memory in rats in the Morris water maze test (Voev55 BO ei ai., U. Rpaptasoi. Ehr. Tpeg., 2007, 321, 716 -725). TO-5619, a selective pPASP α7 agonist, has demonstrated efficacy in animal models in relation to positive and negative symptoms and cognitive dysfunction in schizophrenia (Nayyyzeg

TA vi ai., Viospet. Rpaptasoi., 2009, 78, 803-812).

An alternative strategy for strengthening or ensuring the possibility of endogenous cholinergic transmission of nerve impulses of the ASP without direct stimulation of the target receptor is positive allosteric modulation (RAM) of pASSI a7 (AIridiegdine EH eiai., AI2gpeiteg riv. Avzzos. Oizoga., 2001, 15 Birri 1, 519-525 ). Some RAMs have been described, although at the preclinical stages of research. A-86774, РАМ pАСП а7, improves the filtering of sensory information in OVA/2 mice due to a significant decrease in the T:C ratio in a preclinical model of schizophrenia (Radii Kei aiYi., U. Mei. Spet., 2009, 52, 3377-3384 ). HU-4083, RAM pASIP a?7,

Zo normalizes the deficit of sensorimotor filtering in OVA/2 mice and memorization in a radial maze with 8 branches without changing the kinetic indicators of receptor desensitization (Mu NU ei ai., Rhos. Mai. Asai. Zsi., Shyu. 5. A., 2007 , 104, 8059-8064). Another RAM,

RMY-120596 profoundly changes the kinetic indicators of PAS a7 desensitization and at the same time protects against the violation of prepulse inhibition with the help of MK-801. M5-1738, another RAM, showed the effectiveness of ip-mmo on animal models in relation to social recognition and acquisition of spatial memory in the "Morris water maze" test (Titteptapp OV ei ai., U. Rpaptasoi. Ehr.

TNeg., 2007, 323, 294-307). In addition, in some published patents/applications listed below: 0520060142349, 0520070142450, 0520090253691, M/O2007031440, M/O2009115547,

МО2009135944, M/О2009127678, МО2009127679, МО2009043780, МО2009043784, 0О57683084, 57741364, МО2009145996, О52гО100240707, МО201810820202020810648

О52О100227869, ЕР1866314, M/О2010130768, МУО2011036167, 00520100190819, the effectiveness of allosteric modulators of nicotinic receptors of AS is revealed and their therapeutic potential is emphasized.

Brief description of the invention

According to one aspect of the present invention, there are provided the compounds represented by the general formula I, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, their polymorphs, their solvates, their optical isomers, their combinations with a suitable drug, and pharmaceutical compositions containing them.

Thus, the present invention, in addition, relates to a pharmaceutical composition containing compounds of the general formula (I), defined in this document, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, their polymorphs, their solvates, their optical isomers in combinations with conventional pharmaceutically acceptable carriers, diluents, etc., which may be used for the treatment and/or prevention of a disease or disorder or condition such as Alzheimer's disease (A), mild cognitive impairment (MC), senile dementia, vascular dementia, dementia in Parkinson's disease, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), dementia associated with Lewy bodies, AIO5-dementia complex (AOS), Pick's disease, dementia associated with Down syndrome, Huntington's disease, cognitive deficit functions associated with traumatic brain injury (TBI), stroke-associated cognitive decline, neuroprotection after stroke, because deficits of cognitive and sensorimotor filtering associated with schizophrenia, cognitive deficits associated with bipolar disorder, cognitive impairment associated with depression, acute pain, post-surgical or postoperative pain, chronic pain, inflammation, inflammatory pain, neuropathic pain, smoking cessation, need for growth of new blood vessels associated with wound healing, need for new blood vessel growth associated with vascularization of skin grafts, and lack of circulation, arthritis, rheumatoid arthritis, psoriasis, Crohn's disease, ulcerative colitis, pouchitis, inflammatory bowel disease, celiac disease, periodontitis, sarcoidosis , pancreatitis, organ transplant rejection, acute immune disease associated with organ transplantation, chronic immune disease associated with organ transplantation, septic shock, toxic shock syndrome, septic syndrome, depression and rheumatoid spondylitis.

The present invention also relates to a pharmaceutical composition containing the compounds of the general formula (I) defined in this document, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, their polymorphs, their solvates, their optical isomers in combination with conventional pharmaceutical carriers , diluents, etc., applicable to the treatment and/or prevention of a disease, or disorder, or condition classified or diagnosed as major or minor neurocognitive disorders, or disorders resulting from neurodegeneration.

The present invention also relates to a method of administering a compound of formula I as defined herein in combination with or as an adjunct to medication used in the treatment of attention deficit hyperactivity disorder, schizophrenia and other cognitive disorders such as Alzheimer's disease, dementia in Parkinson's disease , vascular dementia or dementia associated with Lewy bodies, traumatic brain injury.

The present invention also relates to a method of administering a compound of formula I as defined herein in combination with or as an adjunct to acetylcholinesterase inhibitors, disease-modifying drugs or biologics for neurodegenerative disorders, dopaminergic drugs, antidepressants, typical or atypical antipsychotics .

The present invention also relates to the use of a compound of formula I defined herein in the preparation of a medicinal product for the treatment of a disease or disorder, or

From a condition selected from the group classified or diagnosed as minor or major neurocognitive disorders or disorders resulting from neurodegeneration.

The present invention also relates to the use of a compound of formula I as defined herein in the preparation of a medicinal product for the treatment of a disease or disorder or condition selected from the group consisting of attention deficit hyperactivity disorder, schizophrenia, cognitive disorders, Alzheimer's disease, dementia in Parkinson's disease, vascular dementia or dementia associated with Lewy bodies and traumatic brain injury.

The present invention also relates to the use of a compound of formula I as defined herein in combination with, or as an adjunct to, a disease-modifying acetylcholinesterase inhibitor drug or biologic for neurodegenerative disorders, a dopaminergic drug, an antidepressant, or a typical or atypical antipsychotic. .

Detailed description of the invention

The present invention relates to new compounds of the general formula I, their tautomeric forms, their stereoisomers, their sulfoxides, their M-oxides, their pharmaceutically acceptable salts, their polymorphs, their solvates, their optical isomers, their combinations with a suitable drug and pharmaceutical compositions, that contain them, about Dy a in M ve t o); c2 o M tyu c

FO. where in the compound of formula I 2 is selected from the group including -5-, -O- and -M(B2)-;

B2 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl,

optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl;

B' is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl;

IN? selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halogen, perhaloalkyl, optionally substituted cycloalkyl, cyano, nitro, (K7(BA8)M-, Ba( -О0)М(АЛ-, (А 7(ВА)МС(-АМ(ВУ)-, ВОос(-О)МАе-, Н"5О2М(НВ)-, ВА" - and KaС(-О)-);

BZ is selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, wherein each of said optionally substituted cycloalkyl and optionally of a substituted heterocyclyl optionally ringed or optionally connected by a bridging bond, (К7)(Н8)М-, (А7ЛХКОНВ)- and КА"-;

IVUCt is a repeated "n" times group "K", each KE" independently selected from the group consisting of halogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, K'/аСб(-0)-, H'a50O2-, B'A"-, (p2)0(-OM(BAU)-,. (А7 (АВ)М-, (А7(АВ)МС(-А")М(Н?)-; where т is 0-3; or two K" groups and the carbon atoms to which they are attached together form an optional substituted 5- - b-membered cyclic system, optionally containing 1-4 heteroatoms/groups selected from the group including -M-, -5-, -O-, -0(-0)- and-b (-5)-;

Vo and K9 are independently selected from the group consisting of hydrogen, CaC(-:0)-, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; or K» and Kb, together with the nitrogen atom to which they are attached, form a 3- to 10-membered optionally substituted saturated/unsaturated heterocyclic ring system containing from one to three heteroatoms/groups selected from the group consisting of includes -5-, -M-, -0-, -0(-0)- and -C(-5)-; where are B, B8 and E? independently selected from the group consisting of hydrogen, optionally substituted

Co) alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl and optionally substituted heterocyclyl;

AND! selected from the group consisting of O and 5;

B": selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl and optionally substituted heterocyclyl; wherein the term "optionally substituted alkyl" means an alkyl group unsubstituted or substituted with 1-6 substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, aryl, heteroaryl, cycloalkyl, B "ba5O"-, VAT. "aOs(-0)-, Vas -0)0-, (VEN)MSO(-0)-, (А"О)(alkyl/MS(-О0)-, B 'bas(-O)1M(H)-, (B'ESN)IM-, /(B'3(alkylum-, (B'(H)IMS(-AM(H)- and (B'(alkyl/ MS (FOR ЗМ(Н)И-; the expression "optionally substituted alkenyl" means an alkenyl group unsubstituted or substituted by 1-6 substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, aryl, heteroaryl, cycloalkyl .

In (B'X(alkyl/MS(-O)-, V'bas(-O)M(H)-, (B'ECH)M-, (B'(alkylum-, (B'EdHN)IMS( -A"M(H)-. and (B'Z(alkyl/MS (ZA M(H)O-); the term "optionally substituted alkynyl" means an alkynyl group, unsubstituted or substituted by 1-6 substituents, independently selected from the group consisting of oxo, halogen, nitro, cyano, aryl, heteroaryl, cycloalkyl, K'a5O2-, B'OdI-, Vas -O)-, B'acyl-O)O-, (B'EXH)IMSO (-0)-

In (B'Z(alkyl/MS(-0)-, Vas -O)M(H)-, (A'E(H)M-, (A'O)(alkylum-, (B'EKHN)IMS (-AZM(H)- and (8)(alkyl/uMC (A )M(NI-); the expression "optionally substituted heteroalkyl" means a heteroalkyl group unsubstituted or substituted by 1-6 substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, aryl, heteroaryl and cycloalkyl; the term "optionally substituted cycloalkyl" means a cycloalkyl group unsubstituted or substituted with 1-6 substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, aryl ) 0-. )M-,

(В'ХХН)ИМС(-А "M (H)I- and (А 9(alkyl/MS(-AM(H)-); the expression "optionally substituted aryl" means (ii) an aryl group, unsubstituted or substituted 1-3 substituents independently selected from the group consisting of halogen, nitro, cyano, hydroxy, C1-

Svalkyl, Ce-Svalkenyl, Cg-Svalkynyl, C3-Cvcycloalkyl, C-Ceperhaloalkyl, alkyl-O-, alkenyl-O-, alkynyl-O-, perhaloalkyl-O-, alkyl-M(alkyl)-, alkyl-M( H)-, HeM-, alkyl-5O2-, perhaloalkyl-

ZO2-, alkyl-C(-O)M(alkyl)-, alkyl-C(-O)M(H)-, alkyl-Alkyl)C(20)-, alkyl-Z(H)C(-0) -, NagMS(-0O)-, alkyl-M(alkyl)5O»2-, alkyl-M(H)BO»-, NaM5O»2-, 3- - b-membered heterocycle containing 1-2 heteroatoms, selected from the group consisting of M, O and 5, where the specified 3- - b--lene heterocycle is optionally substituted with alkyl, alkenyl, alkynyl or alkyl-C(-0)-, or (ii) specified substituted or unsubstituted aryl ring, optionally fused with a cycloalkane ring or a heterocyclic ring containing 1-3 heteroatoms selected from 5, 0, M, through a bond, where said cycloalkane ring or heterocyclic ring is optionally substituted by oxo, alkyl, alkenyl, alkynyl or alkyl-C(-0)-; the expression "optionally substituted heterocyclyl" means (i) a heterocyclyl group unsubstituted or substituted on ring carbons 1-6 with substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, aryl, heteroaryl, alkyl, alkenyl, alkynyl . V'bas(-O)M(H)-, (ВЭХ(Н)М-, (А"9)(alkyl)Mm-, (ВЭХНИМС(-А")М(Н)и ии ( K'(alkyl/uMcS(A")M(H)-; (ii) a heterocyclyl group optionally substituted on the ring nitrogen(s) by one or more substituents selected from the group consisting of heteroaryl, alkyl, alkenyl, alkynyl . and aryl unsubstituted or substituted with 1-3 substituents independently selected from halogen, alkyl, alkenyl, alkynyl, cyano or nitro; the term "optionally substituted heteroaryl" means a heteroaryl group unsubstituted or substituted with 1-3 substituents independently selected from , which includes halogen, nitro, cyano, hydroxy, Si-Svalkyl, Soe-C valkenyl, Ce-Svalkynyl, C3-Cvcycloalkyl, C-Ceperhaloalkyl, alkyl-O-; alkenyl-O-, alkynyl-O-, perhaloalkyl-O-, alkyl-M(alkyl)-, alkyl-M(H)-, HeM-, alkyl-5O"-, perhaloalkyl-5O2-, alkyl-C(- O)M(alkyl)-, alkyl-C(-O)M(H)-, alkyl-M(alkyl)uC(-O)-, alkyl-

M(HC-O)-, NaMO(-O)-, alkyl-M(alkyl)5O»2-, alkyl-M(H)ZO»-, NgM5O»- and 3- - b-membered heterocycle, containing 1-2 heteroatoms selected from the group consisting of M, O and 5, where the heterocycle is optional

Zo is substituted with one to four substituents selected from the group consisting of alkyl, alkenyl, alkynyl or alkyl-C(-0O)-; the expression "optionally substituted 5--β-membered ring system" means a 5--β-membered ring system unsubstituted or substituted with 1-3 substituents selected from the group consisting of oxo, halogen, nitro, cyano, aryl, heteroaryl, alkyl, alkenyl, alkynyl, K'bas(-0)-, B'ca5O"-, B'ODA-,

B'aOS(-0)-, b'sas-0)0-, (B'HN)IMS(-O)-, (B'(alkyl/MS(-O0)-, B'sas(-O) M(H)-, (B'EHN)M-, (B')(alkylum-, (A'EHNIMS(-A"M(H)- and (K'O))(alkyl/MS(-AM(H )-; the expression "3- to 10-membered optionally substituted saturated/unsaturated heterocyclic ring system" means a 3- to 10-membered saturated/unsaturated heterocyclic ring system, unsubstituted or substituted by 1-3 substituents selected from the group, including oxo, halogen, nitro, cyano, aryl, heteroaryl, alkyl, alkenyl, alkynyl, B'basb(-0)-, B'ca5O"2-, B'OA"-, b'cOs(-0)- , v'szas(-0)0-, (B'HN)IMO(-0)-, (B'O(alkyl)/mMS(-0)-, Vas -O)M(H)-, (B "ЭХ(Н)М-, (А9)(alkyl)m-, (В)ВЭХН)ИМС(-А"МН)И- and (Е'"Э(alkyluMC(А")М(НИ-); wherein CO is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl, and ba is selected from the group consisting of alkyl, alkenyl, alkynyl, perhaloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl.

Whenever a range of the number of atoms in a structure is specified (for example, Сч-12, Си-в, С1и-в or

C:.alkyl, alkylamino, etc.), in particular, it is assumed that any subrange or individual number of carbon atoms falling within the specified range can also be used. Such

BO way, for example, mentioning the range of 1-38 carbon atoms (eg, Si-Cv), 1-6 carbon atoms (eg, Si-Sv), 1-4 carbon atoms (eg, Si-C4), 1-3 atoms of carbon (e.g., C:-C3) or 2-8 carbon atoms (e.g., C2-Cv), as applied to any chemical group (e.g., alkyl, alkylamino, etc.) mentioned herein, includes and, in particular, characterizes 1,2, 3,4, 5,6, 7, 8, 9, 10, 11 and/or 12 carbon atoms as appropriate, as well as any subrange thereof (eg, 1-2 carbon atoms , 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 1-7 carbon atoms, 1-8 carbon atoms, 1-9 carbon atoms, 1-10 carbon atoms, 1 -11 carbon atoms, 1-12 carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms, 2-6 carbon atoms, 2-7 carbon atoms, 2-8 carbon atoms, 2-9 carbon atoms, 2-10 carbon atoms, 2-11 carbon atoms, 2-12 carbon atoms, 3-4 carbon atoms, 3-5 carbon atoms, 3-6 carbon atoms of carbon, 3-7 carbon atoms, 3-8 carbon atoms, 3-9 carbon atoms, 3-10 carbon atoms, 3-11 carbon atoms, 3-12 carbon atoms, 4-5 carbon atoms, 4-6 carbon atoms, 4-7 carbon atoms, 4-8 carbon atoms, 4-9 carbon atoms, 4-10 carbon atoms, 4-11 carbon atoms and/or 4-12 carbon atoms, etc. if necessary).

One embodiment of this invention is a compound of formula Ia; (o; EI input and em-8

With what in c) in? yo v'sE (pa, de K", V, VZ, VU, IV", Not ii t defined above.

Another embodiment of this invention is a compound of formula IB; (9) EI input and em-8

Sa I! in o in? and

M Kk (Iv) in: va de V", V, VU, VU, VU, Ne, Vaz and t are defined above.

Another embodiment of this invention is a compound of the formula Ic;

GF) 4 m-Z

With and! in c) MORE

DU.

Go) Kk yo de V", V, VU, VU, VU, Ne y t are defined above.

In any of the embodiments of the present invention described above, E" is, in particular, selected from the group consisting of pyridyl, furanyl, indolyl, M-methylisoindolyl, benzofuranyl, piperazinyl, 4-(4-fluorophenyl)piperazinyl, morpholinyl, indolinyl . methyl, ethyl, dimethylamino, monomethylamino, tert-butyl and 4-methylpiperazinyl.

In any of the embodiments described above, K2 is, in particular, selected from the group consisting of hydrogen, methyl, dimethylamino, and dimethylaminomethyl.

In any of the embodiments described above, CZ is, in particular, selected from the group consisting of methyl, ethyl, n-propyl, methoxy, ethoxy, dimethylamino, M-methoxy-M-methylamino, M-(2-hydroxyethyl) -M-propylamino, acetylaminomethyl and piperidinyl.

In any of the embodiments described above, E? and KZ, in particular, independently selected from the group consisting of hydrogen and methyl, or K- and E», together with the nitrogen atom to which they are attached, form a piperidine ring.

In any of the embodiments described above, m is, in particular, selected from 0, 1 or 2, and K- is selected from methyl, or two K" together with the carbon atoms to which they are attached form a six-membered carbocycle.

In any of the embodiments described above, Kg is, in particular, selected from the group consisting of hydrogen, methyl, ethyl, and cyclopropylmethyl.

In any of the embodiments of the present invention, compounds of formula I, E' are selected from the group consisting of pyridyl, furanyl, indolyl, M-methylisoindolyl, benzofuranyl, piperazinyl, 4-(4-fluorophenyl)piperazinyl, morpholinyl, indolinyl, 2- oxoindolinyl, 2,3-dihydrobenzoi|b5I/1,4|dioxynyl, benzopyranyl and phenyl, optionally substituted with 1-2 substituents selected from the group consisting of halogen, cyclopropyl, trifluoromethyl, methoxy, ethoxy,

trifluoromethoxy, methyl, ethyl, dimethylamino, monomethylamino and tert-butyl, 4-methylpiperazinyl;

IN? selected from the group consisting of hydrogen, methyl, dimethylamino and dimethylaminomethyl; KZ is selected from the group consisting of methyl, ethyl, n-propyl, methoxy, ethoxy, dimethylamino, M-methoxy-M-methylamino, M-(2-hydroxyethyl)-M-propylamino, acetylaminomethyl, piperidinyl; KE? and

ВЯ are independently selected from hydrogen and methyl, or Б» and BU, together with the nitrogen atom to which they are attached, form a piperidine ring; t is selected from 0, 1 or 2, and 2" is selected from methyl, or two K" together with the carbon atoms to which they are attached form a six-membered carbocycle; and Kg is selected from the group consisting of hydrogen, methyl, ethyl and cyclopropylmethyl.

In any of the embodiments described above, K' is, in particular, selected from the group consisting of 4-chlorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-fluorophenyl, 4-cyclopropylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 3-ethoxyphenyl, 4-tolyl, 4-tert-butyl-phenyl, 4-dimethylaminophenyl, 3-fluorophenyl, phenyl, 4-ethylphenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl, 2,4- difluorophenyl, 3-chloro-4-fluorophenyl, 3-chloro-4-methoxyphenyl, piperazin-1-yl, 4-(fluorophenyl)piperazinyl, morpholino, pyridin-4-yl, pyridin-3-yl, furan-3-yl . B51(/1,4|dioxin-b-il).

In any of the embodiments described above, 7 is particularly selected as 5.

Next, general expressions used in the formula are defined; however, the specified values should not be interpreted as limiting the scope of the expression reg 56.

The term "alkyl", as used herein, means a straight chain hydrocarbon or a branched hydrocarbon containing from 1 to 20 carbon atoms. Preferably, the alkyl chain may contain 1-10 carbon atoms. More preferably, the alkyl chain can contain up to 6 carbon atoms. Typical examples of alkyl include, without limitation, methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

The term "alkenyl", as used herein, means an "alkyl" group as defined above, containing 2-20 carbon atoms and containing at least one double bond.

The term "alkynyl", as used herein, means an "alkyl" group as defined above, containing 2-20 carbon atoms and containing at least one triple bond.

"Alkyl", "alkenyl" or "alkynyl" as defined above may be optionally substituted with one or more substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, aryl, heteroaryl, cycloalkyl, K' sa5O»-, VAT, ptaOo(-0)-, Vas -O)0-, (A'EKHN)IMO(-O)-, (A'O)(alkyl/MS(-0)-, vya -ОУМ(Н)-, (ВЭХН)М-, (Б'З)(alkyl)М-, (А(Н)ИМС(-АЗМН)-, (А'ЗХ(alkyl)МС(-А" )M(H)-; where K'' is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; and A" is selected from 5 and 0; and sa is selected from alkyl, alkenyl, alkynyl, perhaloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl.

The term "perhaloalkyl" as used herein means an alkyl group as defined above, wherein all hydrogen atoms of said alkyl group are replaced by halogen.

The perhaloalkyl group is represented by trifluoromethyl, pentafluoroethyl, etc.

The term "heteroalkyl", as used in this document, means a heteroatom-modified alkyl group, where the SNeg group is modified (or substituted) -O-, -5-, -5(O2)-, -5(0)- "-M( W)-, Z(A")BA-, where K" and K" are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl. The group includes bonds such as CH3-5-, СН3-СНе-О-,

СНіз-О-СНо-, СНаз-5-СНе2-, СНаз-М(А"7)-СНе-, СН3-5((А")В"-СНе-, etc.

The term "cycloalkyl", as used herein, means a monocyclic, bicyclic or tricyclic non-aromatic ring system containing from 3 to 14 carbon atoms, preferably a monocyclic cycloalkyl ring containing 3 to 6 carbon atoms.

Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Bicyclic ring systems are also represented by a bridged monocyclic ring system in which two nonadjacent carbon atoms of a monocyclic ring are connected by an alkylene bridge. Typical examples of bicyclic ring systems include, without limitation, bicyclo|3.1.1)heptane, bicyclo|2.2.1|heptane, bicyclo|2.2.2|octane, bicycloI3.2.2|nonane, bicycloI3.3.|nonane, and bicyclo|4.2.1Inonane , bicyclo|3.3.2|decane, bicyclo|3.1.O|hexane, bicyclo|41O|heptane, bicyclo|3.2.O|heptanes, octahydro-1H-indene. Tricyclic ring systems are also represented by a bicyclic ring system, in which two non-adjacent carbon atoms of the bicyclic ring are connected by a bond or an alkylene bridge. Typical examples of tricyclic ring systems include, without limitation, tricyclo[3.3.1.03-L]nonane and tricyclo[3.3.1.13-L]decane (adamantane). The expression cycloalkyl also includes spiro systems where one ring is fused to one carbon atom, such ring systems are represented by spiro(2.5|octane, spiro(4.5|decane, spiro|bicyclo(|4.1.O)heptane-2,1"- cyclopentanome, hexahydro-2'H-spiro-cyclopropane-1,1"-pentalene).

Cycloalkyl as defined above may be optionally substituted with one or more substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, aryl, heteroaryl, alkyl, alkenyl, alkynyl, K'bas(-0)-, B'aB5O»2-, B'OdT-, B'caOS(-0)-, B'sas(-O)0O-, (A(H)IMO(-0)-, (8'Z)(alkyl /MS(20)-, v'sas-O)M(NI-, (v")(H)M-, (A"9)(alkyl)Mm-, (B'XH)IMS(-ATZM(NI -, (B'EualkylMC(-A")M(H)-; where CO is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; and A' is selected from 5 and 0; and B'sba selected from alkyl, alkenyl, alkynyl, perhaloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl.

The term "aryl" refers to a monovalent monocyclic, bicyclic or tricyclic aromatic hydrocarbon ring system. Examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, etc. Aryl groups also include partially saturated bicyclic and tricyclic aromatic hydrocarbons, such as tetrahydronaphthalene.

Said aryl group also includes aryl rings fused to heteroaryl or heterocyclic rings, such as 2,3-dihydro-benzo|1,4|dioxin-b-yl; 2,3-dihydro-benzo|1,4|dioxin-5-yl;. 2,3-dihydro-benzofuran-5-yl;. 2,3-dihydro-benzofuran-4-yl; 2,3-dihydro-benzofuran-b-yl; 2,3-dihydro-benzofuran-b-yl; 2,3-dihydro-1H-indol-5-yl; 2,3-dihydro-1H-indol-4-yl; 2,3-dihydro-1H-indol-b-yl; 2,3-dihydro-1H-indol-7-yl; benzo/1,3|dioxol-4-yl; benzo|1,3|dioxol-

B-il; 1,2,3,4-tetrahydroquinolinyl; 1,2,3,4-tetrahydroisoquinolinyl; 2,3-dihydrobenzothien-4-yl, 2- oxoindolin-5-yl.

Aryl as defined above may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, nitro, cyano, hydroxy, C1-

Svalkyl, Ce-Svalkenyl, Cg-Svalkynyl, C3-Cvcycloalkyl, C-Ceperhaloalkyl, alkyl-O-, alkenyl-O-, alkynyl-O-, perhaloalkyl-O-, alkyl-M(alkyl)-, alkyl-M( H)-, HeM-, alkyl-5O2-, perhaloalkyl-

ZO2-, alkyl-C(-O)M(alkyl)-, alkyl-C(-O)M(H)-, alkyl-Alkyl)C(20)-, alkyl-Z(H)C(-0) -, NagMS(-0O)-, alkyl-M(alkyl)5O»2-, alkyl-M(H)BO»-, NeaM5O»-, 3-6-membered heterocycle containing 1-2 heteroatoms, selected from M, O and 5, optionally substituted with alkyl, alkenyl, alkynyl or alkyl-

F(-0)-.

The term "heteroaryl" refers to a 5- to 14-membered monocyclic, bicyclic, or tricyclic ring system with 1 to 4 ring heteroatoms selected from 0, M, or 5, and the remaining ring atoms are carbon (with corresponding hydrogen atoms, unless specified other), where at least one ring in the ring system is aromatic. Heteroaryl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3 or 4 atoms of each ring of the heteroaryl group may be substituted with a substituent. Examples of heteroaryl groups include pyridyl, 1-oxopyridyl, furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, benzoxazolyl, benzofuryl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, azaindolyl, imidazopyridyl, quinazolinyl, purinyl, pyrrolo|2,3|pyrimidinyl, pyrazoloIII3,I|pyrimidinyl and benzo(p)thienyl, 2,3-thiadiazolyl, 1H-pyrazolo5,1-c|-1,2,4-triazolyl, pyrrolo|3,4-a4|-1,2,3-triazolyl, cyclopentatriazolyl, ZH-pyrrolo!3,4-c isoxazolyl, etc. .

Heteroaryl as defined above may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, nitro, cyano, hydroxy, C1-

Svalkyl, Ce-Svalkenyl, Cg-Svalkynyl, C3-Cvcycloalkyl, C-Ceperhaloalkyl, alkyl-O-, alkenyl-O-, alkynyl-O-, perhaloalkyl-O-, alkyl-M(alkyl)-, alkyl-M( H)-, HeM-, alkyl-5O2-, perhaloalkyl-

ZO2-, alkyl-C(-O)M(alkyl)-, alkyl-C(-O)M(H)-, alkyl-Alkyl)C(-0)-, alkyl-Z(H)C(-0 )-, NagMS(-0O)-, alkyl-M(alkyl)5O»2-, alkyl-M(H)BO»-, NeaM5O»-, 3-6-membered heterocycle containing 1-2

BO heteroatoms selected from M, O and 5, optionally substituted with alkyl, alkenyl, alkynyl or alkyl-C(-0O)-.

The term "heterocycle" or "heterocyclic", as used herein, means a cycloalkyl group where one or more carbon atoms are substituted with -O-, -5-, -5(O2)-, -5(0)- "-M (87)-, -5(А8)BA"-, where K" and КЕ" are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl. The heterocycle can be connected to the main molecular fragment through any carbon atom or any nitrogen atom contained in the heterocycle Typical examples of a monocyclic heterocycle include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, 60 isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl,

piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. Typical examples of a bicyclic heterocycle include, without limitation, 1,3-benzodioxolyl, 1,3-benzodithiolyl, 2,3-dihydro-1,4-benzodioxynyl, 2,3-dihydro-1-benzofuranyl, 2,3-dihydro-1-benzothienyl , 2,3-dihydro-1H-indolyl and 1,2,3,4-tetrahydroquinolinyl. The term heterocycle also includes bridged heterocyclic systems such as azabicycloyi3.2.1|octane, azabicycloyi3.3.1inonane, etc.

The heterocyclyl group may optionally be substituted on the ring carbon by one or more substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, aryl, heteroaryl, alkyl, alkenyl, alkynyl, K'OA!-, B'aZc (-0)-, V'as(-O)0-, (A'EN)IMS(-O)-, (B'O(alkyl/MS(O)-, vya -OH)-, ( B'HN)M-, (B'O)(alkyl)m-, (B'HNIMS(-AZM(NI-, (B'O)(alkylUMS(-A))M(H)-; where 9 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; and A' is selected from 5 and O; and Ka is selected from alkyl, alkenyl, alkynyl, perhaloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl.

The heterocyclyl group may optionally be additionally substituted on the ring nitrogen(s) with substituents selected from the group consisting of aryl, heteroaryl, alkyl, alkenyl, alkynyl, B'ba(0(-0)- , n'taBO"-, Б'аОс(-0)-, (ВЭХН)IMSO(-О)-, (ВЭ(alkyl/MS(20)-; where CO is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl, and B'ba is selected from alkyl, alkenyl, alkynyl, perhaloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl.

The term "oxo" means a divalent oxygen (0) attached to a parent group. For example, an oxo attached to a carbon forms a carbonyl, an oxo substituted on a cyclohexane forms a cyclohexanone, and so on.

The term "annealed" refers to the ring system in question that is annealed to another ring, either at a carbon atom of the ring system or through a bond of the ring system, as in the case of fused or spiro ring systems.

The term "bridged" means the considered ring system, which contains an alkylene bridge with 1-4 methylene units connecting two non-adjacent ring atoms.

A compound, its stereoisomers, racemates, a pharmaceutically acceptable salt thereof, as described above,

In this case, the compound represented by the general formula I is selected from: 1. 4-(5-(4-chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)ubenzenesulfonamide, 2. 4-(5-(2- chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)ubenzenesulfonamide, 3. 4-(5-(3-chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)ubenzenesulfonamide, 4. 4-(5 -(4-fluorophenyl)-4-methyl-2-propionylthiophen-3-yl)benzenesulfonamide, 5. 4-(5-(4-cyclopropylphenyl)-4-methyl-2-propionylthiophen-3-yl)benzenesulfonamide, 6. 4-(4-methyl-2-propionyl-5-(4-trifluoromethyl)phenyl)thiophen-3-yl)/benzenesulfonamide, 7. A-(5-(4-methoxyphenyl)-4-methyl-2-propionylthiophene -3-yl)ubenzenesulfonamide, 8. 4-(5-(4-ethoxyphenyl)-4-methyl-2-propionylthiophen-3-yl)/benzenesulfonamide, 9. 4-(4-methyl-2-propionyl-5- (4-«-trifluoromethoxy)phenyl)thiophen-3-yl)benzenesulfonamide, 10. 4-(4-methyl-2-propionyl-5-(4-tolyluthiophen-3-yl)benzenesulfonamide, 11. 4-(5- (4-(tert-butyl)phenyl)-4-methyl-2-propionylthiophen-3-yl)ubenzenesulfonamide, 12. 4-((5-(4-dimethylamino)phenyl)-4-methyl-2-propionylthiophene-Z3 -yl)benzenesulfonami yes, 13. 4-(5-(3-fluorophenyl)-4-methyl-2-propionylthiophen-3-yl)benzenesulfonamide, 14. 4-(4-methyl-5-phenyl-2-propionylthiophen-3-yl) /benzenesulfonamide, 15. 4-(5-(3-ethoxyphenyl)-4-methyl-2-propionylthiophen-3-yl)benzenesulfonamide, 16. 4-(5-(4-ethylphenyl)-4-methyl-2-propionylthiophene -3-yl)ubenzenesulfonamide, 17. 4-(5-(3,4-dichlorophenyl)-4-methyl-2-propionylthiophen-3-yl)ubenzenesulfonamide, 18. 4-(5-(2,4-dichlorophenyl) -4-methyl-2-propionylthiophen-3-yl)benzenesulfonamide, 19. 4-(5-(2,4-difluorophenyl)-4-methyl-2-propionylthiophen-3-yl/benzenesulfonamide, 20. 4-(5 -(3-chloro-4-fluorophenyl)-4-methyl-2-propionylthiophen-3-yl)/benzenesulfonamide, 21. 4-(5-(3-chloro-4-methoxyphenyl)-4-methyl-2-propionylthiophene -3-yl)/benzenesulfonamide, 22. A-(4-methyl-5-(piperazin-1-yl)-2-propionylthiophen-3-yl)/benzenesulfonamide, 23. 4-(5-(4-(4 -fluorophenyl)piperazin-1-yl)-4-methyl-2-propionylthiophen-3-yl)benzenesulfonamide, 24. A-(4-methyl-5-morpholino-2-propionylthiophen-3-yl)ubenzenesulfonamide, 25. 4 -(4-methyl-2-propionyl-5-(pyridin-4-iluthiophen-3-yl)benz olsulfonamide, 26. 4-(4-methyl-2-propionyl-5-(pyridin-3-yl)uthiophen-3-yl)benzenesulfonamide, 27. A4-(5-(furan-3-yl)-4-methyl -2-propionylthiophen-3-yl)benzenesulfonamide, 28. 4-(5-(1H-indol-5-yl)-4-methyl-2-propionylthiophen-3-yl)ubenzenesulfonamide, bo 29. 4-(4- methyl-5-(1-methyl-1H-indol-5-yl)-2-propionylthiophen-3-yl)benzenesulfonamide,

30. 4-(5-(benzofuran-5-yl)-4-methyl-2-propionylthiophen-3-yl)/benzenesulfonamide, 31. 4-(5-(indolin-5-yl)y-A-methyl- 2-propionylthiophen-3-yl)benzenesulfonamide, 32. 4-(4-methyl-5-(4-(4-methylpiperazin-1-yl)uphenyl)-2-propionylthiophen-3-yl)benzenesulfonamide, 33. 4- (5-(4-chlorophenyl)-2-propionylthiophen-3-yl)ubenzenesulfonamide, 34. 4-(5-(4-chlorophenyl)-4-(dimethylamino)-2-propionylthiophen-3-yl)benzenesulfonamide, 35. 4-(5-(4-chlorophenyl)-4-((dimethylamino)methyl)-2-propionylthiophen-3-yl)benzenesulfonamide, 36. 5-(4-chlorophenyl)-M,M,4-trimethyl-3- (4-sulfamoylphenyl)thiophene-2-carboxamide, 37. 5-(4-chlorophenyl)-M-methoxy-M,4-dimethyl-3-(4-sulfamoylphenyl)thiophene-2-carboxamide,

C8. 5-(4-chlorophenyl)-M-(2-hydroxyethyl)-4-methyl-M-propyl-3-(4-sulfamoylphenyl)thiophene-2-carboxamide, 39. 4-(5-(4-chlorophenyl)- 4-methyl-2-(piperidin-1-carbonyl)thiophen-3-yl)benzenesulfonamide, 40. 4-(2-acetyl-5-(4-chlorophenyl)-4-methylthiophen-3-yl)ubenzenesulfonamide, 41. 4-(5-(4-chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)-2-methylbenzenesulfonamide, 42. methyl-4-methyl-5-(2-oxoindolin-5-yl)-3- (4-sulfamoylphenyl)thiophene-2-carboxylate, 43. ethyl-4-methyl-5-(2-oxoiindolin-5-yl)-3-(4-sulfamoylphenyl)thiophene-2-carboxylate, 44. 4-(4 -methyl-5-(4-methylaminophenyl)-2-propionylthiophen-3-yl)benzenesulfonamide, 45. 4-(5-(4-chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)-M,M -dimethylbenzenesulfonamide. 46. 4-(5-(4-chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)-M-methylbenzenesulfonamide, 47. A4-(5-(3,4-difluorophenyl)-4-methyl-2 -propionylthiophen-3-yl)/benzenesulfonamide, 48. 1-(5-(4-chlorophenyl)-4-methyl-3-(4-(piperidin-1-ylsulfonyl)phenyl)thiophen-2-yl)upropan-1 - ona, 49. 4-(5-(4-chlorophenyl)-1,4-dimethyl-2-propionyl-1H-pyrrol-3-yl)ubenzenesulfonamide, 50. 5-(4-chlorophenyl)-M,M ,1,4-tetramethyl-3-(4-sulfamoylphenyl)-1H-pyrrole-2-carboxamide, 51. 4-(5-(4-chlorophenyl)-1-ethyl-4-methyl-2-propionyl-1H -pyrrol-3-yl)/benzenesulfonamide, 52. 4-(5-(4-chlorophenyl)-1-(cyclopropylmethyl)-4-methyl-2-propionyl-1H-pyrrol-3-yl)benzenesulfonamide, 53. 4-(5-(4-chlorophenyl)-4-methyl-2-propionyl-1H-pyrrol-3-yl)benzenesulfonamide,

Zo 54. 4-(5-(4-fluorophenyl)-1,4-dimethyl-2-propionyl-1H-pyrrol-3-yl/benzenesulfonamide, 55. 4-(5-(4-methoxyphenyl)-1, 4-dimethyl-2-propionyl-1H-pyrrol-3-yl)benzenesulfonamide, 56. 4-(2-butyryl-5-(4-chlorophenyl)-1,4-dimethyl-1H-pyrrol-3-yl )ubenzenesulfonamide, 57. 4-(5-(2,4-dichlorophenyl)-1,4-dimethyl-2-propionyl-1H-pyrrol-3-yl)ubenzenesulfonamide, 58. 4-(5-(2,3 -dihydrobenzo|b1/I1 4|dioxin-b-yl)-1,4-dimethyl-2-propionyl-1H-pyrrol-3-yl)/ubenzenesulfonamide, 59. ethyl-5-(4-chlorophenyl)-4 -methyl-3-(4-sulfamoyl-5,6,7,8-tetrahydronaphthalen-1-yl)thiophene-2-carboxylate, 60. ethyl-5-(4-chlorophenyl)-3-(4-sulfamoylphenyl)/ furan-2-carboxylate.

According to another aspect of the present invention, compounds of the general formula I, wherein all symbols are as defined previously, were prepared by the methods described below. However, the present invention is not limited to these methods; compounds can also be prepared using procedures described in the literature for structurally related compounds.

Scheme 1 shows the method of obtaining a compound according to an embodiment of the formula

Ia. A compound of formula Ia can be obtained from a compound of formula MI, where K", Be, VU, B", Vb and t are the same as described for the general formula Ia.

If 5 - No - hydrogen

8 rn Shi sk ov in She

ZA I and schu i Ve yati them py ro t ptn be Y new in dolav in che «vi yi chi x 5 m as in st Bena cha

Ex PT 5th;

Yakscha KO: In ho volen KE E; ий х / х / чо / м и "KA v kv A us h nyn y pre YAKzhchr SCHO v rov OO o Ma

A compound of formula MI can be converted to its corresponding anhydride using standard procedures known in organic synthesis chemistry, or preferably by reaction with oxalyl chloride in dichloromethane together with UOME followed by reaction with M,O-dimethylhydroxylamine hydrochloride in the presence of triethylamine in dichloromethane to provide a compound of the formula E.

The compound of the formula MI! reacts with the Grignard reagent E"MOX", where EZ is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, which may be optionally annelated or optionally bridged, and X' is halogen, to give a compound of formula Ia, where EZ is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, which can be optionally annelated or optionally connected by a bridging bond, and K? and K9 are the same as described for general formula I or Ia. The reaction of the compound of the formula MI with EZMaX' can be performed according to the procedure given in the literature, for example, in 9. Med.

Spnet., 2009, 52, 3377.

Compound of formula MI, where K? - NE - hydrogen, can be converted to anhydride using oxalyl chloride in dichloromethane together with UOME followed by reaction with M,O-dimethylhydroxylamine hydrochloride in the presence of triethylamine in dichloromethane to provide a compound of formula Miia, which can then be further converted to a compound of formula Ia by responding to the ESMOA', as described in this document above.

A compound of the formula Mi alternatively reacts with (K7(AZ)MN, (A'EOVUMN or KOH, where KK and 8 are defined in the definition for KZ in the general formula Ia or I) to obtain a compound of the formula Ia, where KE and Kb are the same, as described for a compound of formula I or Ia, and EZ is selected from the group consisting of (K")(A8)M-, (A"'HONAV)M- and K"O-, where K" and KU are defined in the definition for KZ in the general formula Ia or I. The reaction was carried out according to conditions known in the conversion of carboxylic acids to amides and esters, as known to a person skilled in the art. The reaction can be carried out in the presence of solvents, for example, OME, TNE, a halogenated hydrocarbon, such such as chloroform and dichloromethane, an aromatic hydrocarbon such as xylene, benzene, toluene or a mixture thereof, or the like, in the presence of a suitable base such as triethylamine, diisopropylethylamine, pyridine or the like, at a temperature of 0-50 "C using reagents such as 1-"3-Dimethylaminopropyl)-3-ethylcarbodimidyl hydrochloride (EOSI), 1,3-dicyclohexylcarb odiimide (OSS), and auxiliary reagents such as 1-hydroxy-7-azabenzotriazole (NOAT), hydroxybenzotriazole hydrate (HOT) or the like.

A compound of formula Ia, where EK", Bg, and KZ are the same as described for a compound of formula I or Ia, and EE and EC are described for formula I or Ia, except for hydrogen, were obtained by the following reaction of compounds of formula Ia, where НК» and К9 are hydrogen, with reagents selected from KR and КЯ', where 7 is a halogen or -B(OH): in the presence of a base or using the appropriate conditions given in the literature, for example, in

Temapedtop Iyeg 2005, 46(43), 7295-7298, Teyapeidgtop Iyeg5 2003, 44(16), 3385-3386,

О52О03236413, Zupijeys Sottipisayop5 2009, 39(12), 2082-2092, Teiganedgtop Ieige 2010, 51(15), 2048-2051, Teimapedgtop Ieige5 2008, 49(18), 2882-2885, and U. Ateg. Spent 5 people 2005, 127(36), 12640-12646.

Scheme 2 shows a method for obtaining a compound of the formula MI from a compound of the formula YII and an alternative method for a compound MI from a compound of the formula MIP. s i rya a y se Sha m tob oetti covered! myrtle nina me 1

Z Te SHY Ov v i " shi nn A i

A no zv r v nd t v What about U M o s, IV still o and I in es svyuny be here in IV. y pet A she A Y y

Shch g tv ryu doby a Ohema2

MN their about x

Compound of formula MI, where EK! is disclosed for the compound of the general formula Ia, and 22 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, perhaloalkyl, optionally substituted cycloalkyl, K/A"- and K'aC(-0) -, can be obtained from a compound represented by the general formula II, where AK is an alkyl group, K' is an optionally substituted optionally fused aryl; optionally substituted optionally fused heteroaryl; where aryl and heteroaryl include fused ring systems where the aryl or heteroaryl ring is fused to a saturated ring system; and K2 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, perhaloalkyl, optionally substituted cycloalkyl, B'A"- ii V'aSb(50)-. The compound of formula II, in turn, was obtained using the procedures described in the literature, for example, in 55608082 and UMO2007092751. Groups subject to K2 can be converted from one to another at any of the following stages of scheme 1 or 2 using the general method of group conversion.

A compound of formula II upon halogenation gives a compound of formula I, where Y is halogen and the other symbols are the same as previously defined for the compound of formula I.

Halogenation can be carried out under conditions commonly used in organic synthesis chemistry using halogenating agents such as bromine, phosphorus tribromide, bromine chloride, aluminum tribromide, hydrogen iodide/iodine, iodine chloride, M-iodosuccinimide, iodine/sulfuric acid and M- chlorsuccinimide. Bromination was performed using bromine in the presence of zinc chloride.

The compound of formula I, obtained in the previous step, was subjected to Suzuki coupling with the compound of formula IM, where VK", A", AN? E' and K? are the same as defined for the compound of formula II, and KE", VU, NE and t are the same as defined in the general formula Ia or I. The Suzuki coupling can be carried out under different conditions of addition with boronic acids and boron esters, well known in the art. Preferably, the Suzuki coupling is carried out in a mixture of water, ethanol, methanol and toluene in the presence of a base such as potassium phosphate or potassium carbonate or the like, a palladium catalyst such as tetrakiss(triphenylphosphine)palladium(0) at 50 C or at a higher temperature. The boronic acid used in this reaction can be prepared by methods well known in the art, by hydrolysis of the corresponding boronate.

Harrows are usually commercially available. In addition, such boronates can also be prepared by reacting the corresponding iodine- or bromine-containing compound with an alkyllithium, such as butyllithium, followed by reaction with a borate ester, or by methods well known in the art (EP 1012142; review article by M. Miuatsga and A. 5y2ikKi, Spet. German, 1995, 95, 2547).

Hydrolysis of the ester bond of the compound of the formula M gives the compound of the formula MI, where EB", B, B"

B", A and are the same as defined above for the compound of formula U. Hydrolysis of the ester bond can be carried out using a standard procedure, typically used in organic synthesis chemistry or well known in the art, with a reagent such as such as sodium hydroxide, potassium hydroxide, lithium hydroxide or the like, in solvents such as water, alcohol, TNE or the like, or mixtures thereof. An aqueous solution of sodium hydroxide and ethanol were mainly used for the reaction.

Alternatively, a compound of formula MI may be prepared from a compound of formula

MI, where is K? selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, perhaloalkyl, optionally substituted cycloalkyl, K/A"- and B/aC(50)-; AK is alkyl group; and 7" represents bromine or amino, as follows.

The compound of the formula MI with 2" in bromine form was obtained by converting the amino group (the specified amino compound is commercially available) to the corresponding bromine group under the conditions, as a rule, used in the Sandmeyer reaction. It involves diazotization by reacting the corresponding amino compound with a nitrite, for example, tert-butyl nitrite or the like, followed by halogen exchange, which may be conveniently accomplished by reaction with a copper halide, preferably copper bromide).

The compound of the formula MI with 27 in the form of bromine was subjected to Suzuki coupling with the compound of the formula IM to obtain the compound IX, where the symbol K? is the same as defined for the compound of the formula MI! above, and B", B", are not the same as defined in the general formula Ia.

The compound of the formula IX upon bromination gives the compound of the formula X. Bromination can be carried out under the conditions, as a rule, used in the chemistry of organic synthesis, using brominating agents. According to this invention, bromination was carried out using bromine.

The compound of formula X was subjected to Suzuki coupling with K'"B(OH)", where EK" is defined in the general formula Ia, which has a point of attachment on a carbon atom, to obtain a compound of formula Y, where all the symbols are K-, НУ, И", They are not the same as defined in the compound of formula IX, a

B' is defined in the general formula Ia, which has an attachment point on a carbon atom. Hydrolysis of the ester bond of the compound of the formula M to the compound of the formula MI is carried out according to the same procedure and under the reaction conditions as described earlier. The compound of formula MI thus obtained was then converted to the compound of formula Ia using the method described above in the scheme

From 1. The groups falling under K2 can be introduced or transformed from one to another to obtain the necessary groups falling under the compound of formula Ia, at the stage of the compound of formula M or also at subsequent stages.

Scheme C shows the method of obtaining a compound of the formula MI, where K2 is selected from the group consisting of (К7ХА8)М-, Бас(ОМ(К)-, (А"ХАУМС(-А"М(ВУ)-, Б"ОС (-O)M(AU)-, B"a502M(A)-, cyano, nitro and halogen, from the dibromine-containing compound of the formula XI, where AK is an alkyl group. dig i 7 j o he, m i i

І и х У и" 2 х m Ше ! ше божосут ия свіон в а

ZOV im oyu 20 20 OA Yur VOSV

Any db tv; o zhu du vyti: b xx a mch i i

Shk

With M

Scheme C connection Misde B selected zkh ХК, КВ ее ОВ» . oblique VOMU, chance, halogen or shtro

Compound of formula MI, where K? selected from (К7ХА8)М-, В'асС(-ОМ(АЛ)-, (А"ХАУИМС(-О)М(ВАЗУ)-,

vOob(-O)M(B8U)-, B a5OgM(B)-, cyano, nitro, and halogen, can be obtained starting from the dibromine-containing compound of formula XI as follows. Compound XI can be prepared according to the method presented in .). Spent wasps Regkip Tgap5.: Ogdapis apa Viogdapis spetivigu (1972-1999), 1973, pages 1766 - 1770.

The compound of the formula XI upon nitration gives the compound XII, which upon reduction of the nitro group to the amino group gives the compound of the formula XII. Nitration and its subsequent reduction can be carried out under conditions according to procedures, as a rule, known or used in the chemistry of organic synthesis. According to this invention, nitration is carried out using nitric acid and reduction by using iron powder and acetic acid.

The compound of the formula ХІІІ was further reacted with reagents selected from КІ, НІ, АУІ,, where В,

Wow, VV Her E? defined earlier, except that they are hydrogen, and I. is a halogen, and/or with reagents selected from the group including K/"ab(-0O0)Y, B'aM-C0-O, B' aM-C-5 and (ALO(VU)MS(-O)Y, VAZA" С(-O)Y, and Ka5O»Y, where K", Ba and KU were defined earlier for the general formula I or Ia, and Y is a halogen, with the formation of a compound of the formula KHIM with KZ: in the form (АЛ(в8)М-, В'яс(-ОМ(АЛ-, (А7(А)МОС(-АМ(АУ)-, Б gОб(- О0)MAe-, Бе5О2М(АЛ-, В'А"- or в'аб(-0)-. В? in the compound of the formula ХМ, where В? represents К"2ОС(-О)МА-, were conveniently converted into (К)(АУ)МС(-О)М(А?)- by reaction with an amine of the formula (К7)(АУМН in the presence of a suitable base, such as alkali metal alkoxides or triethylamine, or using aluminum amide | Geigapedhop 60 (2004 ) 3439-43| in a non-polar organic solvent such as toluene or in a polar solvent such as tetrahydrofuran.

A compound of the formula XIM or a compound of the formula XIII was subjected to Suzuki coupling with a boronic acid of the formula E'B(OH)", where K' is the same as defined in the general formula

Ia, under standard Suzuki coupling conditions in the presence of a base selected from potassium phosphate, potassium carbonate, etc., and the palladium catalyst tetrakis(triphenylphosphine)palladium(0). in a solvent selected from water, ethanol, methanol, toluene and their mixture in any suitable proportion, to obtain a compound of the formula ХУ, where the definition of КЕ! is the same as defined in the general formula Ia, and K? is (7) (В8)М-, В'С(-О(АЛ-, (А7(АВМС(-А)М(ВАУ)-, в"ОоФ(-О)МАе-, Н'5О2М(А -, B'A-, Nab(-O)- or nitro.

Then the compound of the formula XM was subjected to Suzuki coupling with the compound of the formula IM z

Ko) by obtaining a compound of formula M, where E', B", VU, Ve and are the same as defined in the general formula Ia, and K? represents (7) (B8)M-, BaC(-OM(AL -, (A7(AZMS(-AM(VAZ)-, v"gOob(-O)MA"-, H"e5O»M(AL-, B'A"-, Nabi(-O)- or nitro. Compounds Suzuki was carried out according to the same procedure as previously described. A compound of formula M was further converted to a compound of formula MI using the procedures described above. In a compound of formula M, where Kg is nitro, the nitro group of said compound may be further converted to cyano or halogen, using known methods of transforming functional groups.

Scheme 4 shows a method of obtaining a compound of the formula MI, where K2 is hydrogen, from a dibromine-containing compound of the formula Xi, where AK is an alkyl group. Тоши им и пок вкв версен я ур пр ОН" same web vyv p pazh vya and 5 x dk tja ky / bu / compound M, where VK" is itself

I am one of them 4 not) k a, where I

Le me

Scheme 4. The structure of the compound Misde V is hydrogen

The compound of the formula XI was first combined with the boronic acid of the formula K'B(OH)", where EK! is the same as defined in the general formula Ia with the point of attachment on the carbon atom, by Suzuki coupling to give a compound of formula HMI, which was then subjected to Suzuki coupling with a compound of formula IM to give a compound of formula MU, where K2 is hydrogen. A compound of the formula M was converted to a compound of the formula MI, where EK", VU, P", Nei are the same as defined in the general formula Ia, and K? is hydrogen, using the procedure described earlier. ee ziv As vk nn And vi and "ortiyu,

Needless to say, I tore off the web of my eyes. Oh. 7 with Ом зве сн, х, the compound У, В. shows itself

If Den Wei is a fixed methyl hydrogen in compound x and

M x Y n ;

En A te

Scheme 5 victory day; in a or in- Kk i

GI hmm

In another embodiment, a compound of formula Y, wherein the symbols KE", B", N are the same as defined in the general formula Ia; KE" is selected from the group consisting of halogen, cyano,

B"a5O2-, IV'AT-, (B/a)0-O)M(AU)-, (A7(B8)M- and (K7(A8ZIMS(-A")M(AU)-; AK Is the same as defined for the compound of formula II; II Kg is methyl, on bromination gives the compound of formula XMII (Scheme 5). general formula Ia; and EK" is selected from the group including halogen, cyano, va5O"-, В'А-, (8/2)0(-О)М(АУ)-, (А7(ВВ)М- and (K7AUMS(-А"M(AU)-; AK is defined for the compound of formula II, and Y represents bromine, in the reaction with (E")MH", (B'3)(alkyl/MH or B'ZA"H , where CO is the same as defined for a compound of formula I and/or Ia, and further hydrolysis of the ester bond gives a compound of formula MI, where K is alkyl (e.g., methyl) substituted (K'X(H )M-, (А"О)(alkyl/M- or K'OdD"-, The synthesis of the compound of the formula Ia from the compound of the formula MI was carried out according to the same procedure and reaction conditions described earlier. If the compound of the formula M is characterized by Co - NIA - hydrogen, then the sulfonamide group must be protected by Kk!v using an appropriate protecting group, such as M,M- dimethylformamide dimethylacetal to obtain a compound of the formula CHMIII, which was then reacted with (E"EHN)M-, (A'9)(alkylMm- or E'ZA"TH, where KE" is the same as defined for the compound of formula I and/or Ia.

Alternatively, compounds of formula Ia, wherein all substituents are the same as described for the general formula, except that K2 is selected from hydrogen or optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, perhaloalkyl, neoob necessarily substituted cycloalkyl, cyano, nitro, (К7Л(Б8)М-, в'с(-ОМ(АЛ-, (АЛ(ВАУМОС(-А"ЗМ(АЯ)-, В"гОС(-О)МА» -, B8a5O2M(HB)-, B'A"- or tesb(-O)-, can be obtained starting from the compounds represented by the general formula (a), as presented in the following scheme 6.

be br i viya

TAT i a IV I Che a! and a dream, a lake that tears into Evil in their necks. b. you bot! ru y :

Ha Ks Ko 8 kn i

And yannia in Grn - (1 I kyu about what OB about everything

My U V oguysnvvve iv o scheUE ok -o ovo otv to shAV svia zhh to still 'm she! start, I o OA and z o i vm in Neva o

DO NOT react OH rda Oh t vach ; z re Zir eV ia i l-vya i E Y 2 I 2

Xia on -- A ZeA ran in Bronya r

EE AyuStr 8 i BUT ih iii z yav di ta yak yad v: vi ! r Ff zho u i yo V nt De chosen from i i

She our (in em., lo Kemo shim A V KK o lehivt prod 7t Mk Ka shk KE scored novni y y vi g ; g 7 not DEN gl) ' 9 (v ia otr vya ! (dev Ko voden U m. peni on Vy she a ven sh pc

Goy B. owl. paradise in g i z i s; M ДН: Z І which is possible che o nin with pk Vul tn de evavevy o pa) where - as Z ve A A OM le A represents an osssoion 3 00- IO-membered optional Substituted 0 saturated/ unmixed monocyclic anionic 860 optional Yazkaneu bridge heseropycnic ring system, which bridges the VED of one of the lryoh heterobatoms of corpses, such. as ok M. SOU SU de heterocyclic. the ring may optionally be further defined as nicloalkyl, heterocyclyl; aryl: or heterocyclic ring systems

Scheme 6

Compounds of formula (a) and () were prepared by applying the procedure described in the literature, such as Viogdapis spetivigu, 22, 387-394 (1994). A compound of formula (a) wherein K2 is selected from hydrogen or optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, perhaloalkyl, optionally substituted cycloalkyl, cyano or nitro, was protected using M,M- of dimethylformamide acetal to obtain the compound of formula (B). Protection can be carried out using a procedure given in the literature, such as EP 1790640. According to this invention, protection was carried out using M,M-dimethylformamide dimethyl acetal in the presence of OME.

A compound of formula (B) was reacted with carbon disulfide and dibromoethane in the presence of a base such as potassium carbonate, potassium tert-butoxide or the like in a solvent such as acetone or the like to form a dithiethane ring represented by formula (c). . . And "

The compound of formula (c) was then subjected to a reaction with B'-H, where K' is a heterocycle "A" with a point of attachment on a nitrogen atom;

C i.e., where A is a 3-10-membered optionally substituted heterocyclic ring system containing one to three heteroatoms/groups such as 5, M, O, C(-O) or

FB(-5); where the heterocyclic ring may optionally be further fused with cycloalkyl, heterocyclyl, aryl or heteroaryl ring systems to give the compound of formula (49).

The compound of formula (4) was further cyclized to obtain the compound of formula (e). According to the present invention, cyclization was carried out by reacting compound (4) with ethyl iodoacetate in the presence of a base such as potassium carbonate or the like.

Hydrolysis of compounds of formula (e) gave a compound of formula MI with VE" selected as a heterocycle attached through a nitrogen atom, Kg, B" and t are defined previously for the general formula Ia or I, and AK is an alkyl group. The hydrolysis may be carried out according to a standard procedure commonly used in organic synthesis chemistry or well known in the art, with reagents such as sodium hydroxide, potassium hydroxide and lithium hydroxide in solvents such as alcohol or TNE or the like. Preferably, hydrolysis is carried out using an aqueous solution of sodium hydroxide and ethanol. The compounds of the formula MI obtained in this way were further converted to the compound of the formula Ia, where KE" is a heterocycle connected through a nitrogen atom, using the method described above.

In the compound of the formula Ia, where is B? is nitro, the nitro group of the indicated compound can be further transformed into (CL(B8)M-, -, в8г5О2М(НЗ)- using known methods of conversion of functional groups.

A compound of formula (i), where the nitrogen in the sulfonamide functional group contains substituents other than hydrogen thereof, may be similarly converted to a compound of formula MI according to the chemical reaction described for the conversion of a compound of formula (a) to a compound of formula MI, however, for such a conversion no protection of the sulfonamide functional group is required, as shown in Scheme 6.

According to another aspect of the present invention, the compounds of the general formula IB, where all the symbols are described previously, were prepared by the method described below in Scheme 7.

NV Z I a te vv I I ve : KE. - 9 c

R in and I in HIM; etan he wn SCHE DV CI nn nn chi

RODE I re zr

Ov: av o va chl I (i , ; io ! y 1 Bbeoaaki in ' g. University set

VN is not square,

KE U bo v bii oyu Iv i-sh i i i sho yati NO yah ochovy z na i vi Her her

B vv m I where yes |! (a) with hydrogen / them

Y and M Ya

KD. I ah! with what and 5: т шк я здо гы и яа И и

Eat and eat

Still still about her her-I pe oi z she o shiya sov zh t

I rya I y-y vyh z y y U k drinking Ko de zo a in TI y in Sa na de zh Ko voden yiv le K is an apkil, an incentive4 y) compound IV

MK eOmalkia or vlkil

Scheme 7

A compound of formula IB can be prepared starting from a compound represented by general formula (iii) where EC, B2 and Ka are the same as defined for general formula or IB, and 2? is alkyl or -O-alkyl; which in in turn, it can be obtained by applying the procedures described in the literature, such as Teigapeagop I etseg5 2005, 46, 4539-4542,

MO2005105789, Temanedgop I eyege 2010, 51, 1693-1695; U. Oga. Spent 2009, 74(2), 903-905;

Ogdapis I etsegz 2007, 9(25), 5191-5194; Temanediop 2006, 62, 8243-8255, or methods well known in the art. Groups falling under P can be introduced or transformed into a suitable group of choice in any of the following stages of scheme 7 using general methods of transforming functional groups known to a person skilled in the art.

The compound of formula (iii), where P? "alkyl or O-alkyl, and the other symbols are the same as defined in the general formula IB or I, upon bromination can give a compound of formula (its).

Bromination can be carried out provided the procedure is generally known in the literature using brominating agents such as bromine, M-bromosuccinimide, phosphorus tribromide or the like (Zupiei 2002, 7, 1152-1154).

A compound of formula (II) where all symbols are the same as previously defined in general formula IB or I is subjected to Suzuki coupling with a compound of formula IM where B", B", N are the same as defined for the general formula IB or I, to give a compound of formula (m). A compound of formula (m), where K is alkyl, is a compound of formula IB, where KZ is selected as an alkyl group. The Suzuki coupling can be carried out under suitable coupling conditions with boronic acids and boronic esters, as is well known in the art. Preferably, the coupling reaction is carried out in a mixture of water, ethanol, methanol and toluene, in the presence of a base such as potassium phosphate, potassium carbonate or the like, and with a palladium catalyst such as tetrakis(triphenylphosphine)palladium (0) at a temperature of about 50 "C or higher. The boronic acid used in this reaction can be prepared by methods well known in the art, for example, by hydrolysis of the corresponding boronate. Harrows are usually commercially available. In addition, such boronates can also be prepared by reacting the corresponding iodine- or bromine-containing compound with an alkyllithium compound such as butyllithium and then reacting with a borate ester or by methods well known in the art (M/O200530715; EP1012142;

Chemiem apisier ru M. Miuantsga and A. Zi2ikKi, Spet. Chem. 1995, 95, 2547).

Hydrolysis of the ester bond of the compound of formula (m), if KK? - O-alkyl gives a compound of formula (mi), where EK", B2, B", B", Ve and t are defined above for compounds of formula (ii) and (im). Hydrolysis of the ester bond can be carried out using standard procedures commonly used in organic synthesis chemistry or well known in the art, with reagents such as sodium hydroxide, potassium hydroxide, lithium hydroxide or the like, in solvents such as alcohol, TNE or similar An aqueous solution of sodium hydroxide and ethanol is mainly used for this reaction.

A compound of formula (mi), where all symbols are the same as previously defined, is converted to its corresponding amide of formula (mi) according to conditions known for the conversion of carboxylic acids to amides. The reaction can be carried out preferably with M,O-dimethylhydroxylamine hydrochloride and triethylamine in OME using reagents such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EHYOSI), benzotriazole hydrate (NOVT) or the like.

In the case of a compound of the formula (my), where KU - ФВ» - hydrogen, the sulfonamide group must be protected before processing at other stages of subsequent reactions to obtain a compound of the formula

IU The protection of the sulfonamide group can be performed under conditions known to those skilled in the art, or using the idea presented in Ogdapis Rgeragayop5 apa Rgosedigev5 Ipiegpaiiopai! 2002, 37(5), 545-549. According to this invention, the protection was carried out using M,M-dimethylformamide dimethyl acetal in the presence of OME to obtain the compound of formula (miii).

A compound of the formula (my) or a compound of the formula (my) that does not require the protection of the sulfonamide group was reacted with the Grignard reagent ZMO", where KZ is selected from the group,

Which includes optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl and optionally substituted heterocyclyl, where each of said optionally substituted cycloalkyl and optionally substituted heterocyclyl is is necessarily annealed or optionally bridged, and X' is a halogen, to give a compound of the formula II. The reaction can be carried out under suitable conditions known to a person skilled in the art, or using the idea presented in W. May. Spet., 2009, 52, 3377.

Alternatively, the reaction of the compound of formula (mi) with

V'ATN, where EK: and RU are defined in the definition for short circuit in the general formula IB or I, with the preparation of the compound of the formula IB, where KE? and BU are the same as previously defined in the general formula I or IB, and EZ is selected from the group consisting of (K")(B8)M-, (A)ZM(ONZ)- and B/A"-, where V is defined in the definition for KZ in the general formula IB or I. The reaction can be carried out according to the conditions known in the conversion of carboxylic acids to amides and esters, as known to a person skilled in the art. The reaction may be carried out in the presence of suitable solvents such as HME, TNE, a halogenated hydrocarbon such as chloroform and dichloromethane, an aromatic hydrocarbon such as xylene, benzene, toluene, or a mixture thereof, or the like, in the presence of a suitable base such as triethylamine , diisopropylethylamine, pyridine or the like, at a temperature of 0-50C using reagents such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EOCI), 1,3-dicyclohexylcarbodiimide (OSS), and auxiliary reagents such as 1 -hydroxy-7-azabenzotriazole (NOAT), hydroxybenzotriazole hydrate (HOT) or the like.

Compound of formula IB, where is KE? and/(or KZ represent hydrogen, can be converted into a compound of formula IB, where B? and/(or KU are the same as defined in the general formula II, except for hydrogen) by reaction with the corresponding alkyl halides, alkenyl halides, alkynyl halides, alkanoyl halides or anhydrides, aryl halides or boronic acids in the presence of a base or using appropriate conditions given in the technical literature.

A compound of formula Ic may also be prepared using a suitable starting material by using the chemistry presented for compounds of formula Ia and Ib above.

The term "room temperature" means any temperature ranging from about 60 20 "C to about 40 "C, except when specifically mentioned in the description.

The intermediates and compounds of this invention can be obtained in pure form by a method known to reg 5e, for example, by distillation of the solvent in vacuo and recrystallization of the residue obtained from a suitable solvent, such as pentane, diethyl ether, isopropyl ether, chloroform, dichloromethane, ethyl acetate, acetone or combinations thereof, or by subjecting them to one of the purification methods, such as column chromatography (e.g., flash chromatography) on a suitable support material, such as alumina or silica gel, using an eluent such as dichloromethane, ethyl acetate, hexane, methanol, acetone and their combinations. The preparative GS-M5 method is also used to purify the molecules described in this document.

Salts of a compound of formula I may be prepared by dissolving the compound in a suitable solvent, for example a chlorinated hydrocarbon such as methyl chloride or chloroform, or a low molecular weight aliphatic alcohol such as ethanol or isopropanol, followed by treatment with the desired acid or base as described in Wegde 5 .M. her a). "Rpaptaseshisa! Zav, a hemiem/ apisiye ip hibadda! oh RINAptaseshisa! v5siepse5 moYishte 6b, radé 1-19 (1977)" and in the handbook of properties of pharmaceutical salts, selection and use of R.N. Eipgispy eiFapapa SatiPye

Simueptysh, U/iIeu-MSN (2002). Lists of suitable salts can also be found in Ketipdop'5

Rpagtasetschiysai! bsiepsev, 181p unit., Mask Rybiihpipd Sotrapu, Eachiop, RA, 1990, r. 1445, and doigpai oi Rpaptaseshisa! Zsiepse, 66, 2-19 (1977). For example, it can be an alkali metal salt (eg sodium or potassium), an alkaline earth metal (eg calcium) or an ammonium salt.

A compound of the present invention or a composition thereof can be effectively administered as a pharmaceutically acceptable acid addition, base neutralized or addition salt formed by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid and phosphoric acid , and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, and fumaric acid, or by reaction with an inorganic base such as sodium hydroxide , potassium hydroxide. Conversion to a salt is carried out by treating the compound in base form with at least a stoichiometric amount of the appropriate acid. Generally, the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol, methanol, etc., and an acid in a similar solvent is added. The mixture is kept at a suitable temperature (for example, from 0 "C to 50 "C). The resulting salt precipitates spontaneously or can be removed from the solution by a less polar solvent.

Stereoisomers of compounds of the formula | of this invention can be obtained by stereospecific synthesis or re-dissolution of an achiral compound using an optically active amine, acid or complexing agent, and separation of the diastereomeric salt/complex by fractional crystallization or column chromatography.

The term "prodrug" refers to derivative compounds, while the derivative is converted into a compound (drug) when administered to warm-blooded animals, such as humans. Enzymatic and/or chemical hydrolytic cleavage of the compounds of this invention occurs in such a way that this form of drug is released (parent drug in the form of a carboxylic acid), and the cleaved fragment or fragments remain non-toxic or are metabolized to form non-toxic metabolic products. For example, a carboxylic acid group can be esterified with, for example, a methyl group or an ethyl group to form an ester. If the ester is administered to the subject, the ester is cleaved, enzymatically or non-enzymatically, reductively, oxidizingly, or hydrolytically, with the opening of the anionic group. The anionic group can be esterified with fragments (for example, acyloxymethyl esters) that are cleaved to give an intermediate compound, which is then decomposed to give the active compound.

Prodrugs can be obtained either during the isolation and purification of compounds or by carrying out a separate reaction of the purified compound with a suitable derivatizing agent. For example, hydroxy groups can be converted to esters by treatment with a carboxylic acid in the presence of a catalyst. Examples of cleavable alcohol moieties of prodrugs include substituted or unsubstituted, branched or unbranched ester moieties of lower alkyls, e.g., ethyl esters, lower alkenyl esters, lower dialkylamine esters, and lower alkyls, e.g., dimethylaminoethyl ester, lower aucylamine esters alkyl, adcyloxy esters of lower alkyl (for example, pivaloyloxymethyl ester), aryl esters, for example, phenyl ester, aryl-lower alkyl esters,

for example, a benzyl ester, optionally substituted, for example, with methyl, halogen or methoxy substituents, aryl and aryl-lower alkyl esters, amides, lower alkyl amides, lower dialkyl amides and hydroxy amides.

Modulation of nicotinic cholinergic receptors, in particular (7), can provide efficacy in a number of cognitive states, from subthreshold attention to attention, and then short-term, long-term memory, and cognitive memory. Therefore, this invention may find application in the treatment and prevention a variety of disease states including, either singly or in combination, schizophrenia, schizophrenia-like disorder, cognitive impairment in schizophrenia, transient psychotic disorder, delusional disorder, schizoaffective disorder, induced psychotic disorder, paranoid personality disorder, schizoid personality disorder, schizotypal personality disorder, attention deficit disorder, attention deficit hyperactivity disorder, depression, manic depression, major depressive disorder, post-traumatic stress disorder, generalized anxiety disorder, Tourette syndrome, cyclothymic disorder, dysthymic disorder, agoraphobia, panic disorder (with or without agoraphobia), phobias ( including social phobia) and bipolar disorders ady (TPotvzep M5 ei ai., Siit.

Rpagt. Oeev., 2010, 16, 323-343; Repd 27 evy aiI., 7popdptsa hUi Khie Ui Sptsap Khie 7a pi, 2008, 25, 154-158; Moypa LU ei ai., Yeig. MeigorzusporNattasoii., 2007, 17, 145-155; Mapip I E sei ai., At. in.

Honey. Sepei., In Mepygorzusniaig. Sepei., 2007, 1448, 611-614; Mapinp IE eg a)I., Ryeusporpattasyodu (Vet), 2004, 174, 54-64; Repeg A vi aI., Oetepi. Segiaig. Sodp. Oizoga., 2009, 28, 56-62; MMIep5 TE ei a)I., Viospet. РНаптасой., 2007, 74, 1212-1223; Metboyiv 51 ei a!., Meygorpaptasiodu, 2003, 44, 224-233; The harness RE ei ai., Rnaptasoi. TNeg., 1997, 74, 21-25). The cholinergic system, in particular through the α7 pAsp, appears to be involved in traumatic brain injury-induced psychosis. Chronic nicotine treatment has been shown to weaken it. Thus, this invention may also find application in the treatment of cholinergic deficiencies

PAS a7 after a traumatic brain injury (Vepposhtspa Mei ai., Epserpai!e, 2007, 33, 616-620; Metoizv 51 ei a!., Meshtornaptasoiadou, 2003, 44, 224-233).

Modulation of AC nicotinic receptors, in particular the c7 subtype, may also help to complement suppressed cholinergic receptor expression and transmission (as in dementias) and also slow disease progression through restoration

From complex formation and internalization "7-481-42 in AYU and Down's syndrome (Mogaregu A ei ai.,

Meishgoioch. Vev., 2000, 2, 157-165; Naudag 5M ei ai., Vioogd. Honey. Spet., 2009, 17, 5247-5258;

ORetsshivsy 51 ei ai., SiIip. Meihorpaptasoi., 2003, 26, 277-283). Accordingly, the present invention may find application in the treatment and prevention of a variety of disease states, including, either singly or in combination, dementia due to Alzheimer's disease, dementia with Lewy bodies, Down's syndrome, head injury, stroke, hypoperfusion, Parkinson's disease, the disease

Huntington's disease, prion disease, progressive supranuclear palsy, radiation therapy, brain tumors, normotensive hydrocephalus, subdural hematoma, human immunodeficiency virus (HIV) infection, vitamin deficiency, hypothyroidism, medications, alcohol, lead, mercury, aluminum, heavy metals, syphilis, Lyme's disease, viral encephalitis, fungal infection and cryptococcosis (2Ppao H ei aI., App. M. U. Asai. 5si., 2001, 939, 179-186; Regtu E ei ai., Yeig. 5 .

Riaptasoi!., 2000, 393, 215-222; Napipoayup SV eia!., YuOetepiia, 1994, 5, 215-228; Map "in ei ai., u.

Meshgovzsi Vez., 2010, 88, 807-815; Yuigiz K vi a!I., toKe 2011, 42(12), 3530-6). Thus, the present invention may also find application in prevention and preventive measures immediately after identification at an early stage of a neurodegenerative disease, such as

Alzheimer's and Parkinson's disease.

Modulation of AC nicotinic receptors, in particular, a4p2, azp4 and a7, can be used in the development of therapeutic agents for nicotine and cannabinoid addiction and to prevent relapses. Therefore, the present invention may find application in the prevention or therapy of nicotine addiction, cannabinoid addiction and in the prevention of relapses of nicotine or cannabinoid addiction. In addition, the present invention may also represent an alternative therapy for unresponsive patients with addiction, patients with intolerance to the side effects of anti-addiction therapeutics, or those who require long-term maintenance therapy (Kygtip A ei ai., Rzusporpaptasiodu (Vegi), 2009, 203, 99-108; MUvyivv VV ei ai., Ri o5

Sepei., 2008, 4, e1000125; Boiipav Mei ai.,.). Meshgovsi., 2007, 27, 5615-5620; Errep CHO ei ai.,

Rayienpi. Rgieieg. Adpegepse, 2010, 4, 355-362).

This invention may also find application in the treatment and prevention of a number of painful conditions, including, either individually or in combinations, pain arising from the peripheral nervous system (PM5), post-diabetic neuralgia (POM), post-herpetic neuralgia (PON), multiple sclerosis, Parkinson's disease, lower back pain, fibromyalgia, 60 postoperative pain, acute pain, chronic pain, mononeuropathy, primary lateral sclerosis,

pseudobulbar palsy, progressive muscular paralysis, progressive bulbar palsy, post-poliomyelitis syndrome, diabetes-induced polyneuropathy, acute demyelinating polyneuropathy (Guillen-Barré syndrome), acute spinal muscular atrophy (Werdnig's disease

Hoffmann) and secondary neurodegeneration (YuopePu-NKobegiv OI ei ai., U. Rpaptasoi. Ehr. TPeg., 1998, 285, 777-786; Nomieu TU ei ai., Ve. U. Apaevii., 2010, 105, 201- 207;

Iptet. Mea., 2010, 268, 94-101).

The present invention may find application in the treatment and prevention of a plethora of inflammatory and pain-related conditions involving TME, and thereby provide relief of symptoms, either singly or in combination, of rheumatoid arthritis, bone resorption diseases, atherosclerosis, inflammatory bowel disease, Crohn's disease, inflammation, cancer pain, muscle degeneration, osteoarthritis, osteoporosis, ulcerative colitis, rhinitis, pancreatitis, spondylitis, acute respiratory failure syndrome (AKO5), joint inflammation, anaphylaxis, ischemia-reperfusion injury, multiple sclerosis, cerebral malaria, septic shock, rejection of transplanted tissue, brain injury, toxic shock syndrome, herpes virus infection (NZM-1 and NBMU-2), shingles infection, sepsis, fever, myalgia, asthma, uveitis, contact dermatitis associated with obesity disease and endotoxicosis (Siebeiep IA Tei ai., ZposkK, 2007, 27, 443-447; Repa Sei ai., Yeshig. u. Ittipoi. , 2010, 40, 2580-2589).

Thus, the present invention, in addition, relates to a pharmaceutical composition containing compounds of the general formula (I), as defined above, their tautomeric forms, their stereoisomers, their analogs, their prodrugs, their isotopically substituted analogs, their metabolites, their pharmaceutical acceptable salts, polymorphs thereof, solvates thereof, optical isomers thereof, clathrates thereof and co-crystals thereof in combination with conventional pharmaceutically acceptable carriers, diluents, etc.

A pharmaceutically acceptable carrier (or excipient) is preferably one that is chemically inert to the compound of the present invention and that does not exhibit adverse side effects or toxicity under the conditions of use. Such pharmaceutically acceptable carriers preferably include saline (for example, 0.995 saline), Stetorpog EG. (which is a derivative of castor oil and ethylene oxide, and is available from Zidt Spetis! So., 5. I otsi5, MO)

Zo (e.g. 595 Stetorpog EI//595 ethanol/9095 saline, 1095 Stetorpog EG/9090 saline or 5095 Stetorpog EI/5095 ethanol), propylene glycol (e.g. 4095 propylene glycol/1095 ethanol/5095 water), polyethylene glycol (e.g. , 4095 RES 4000/6090 saline) and alcohol (for example, 4095 ethanol/b6095 water). A preferred pharmaceutical carrier is a polyethylene glycol such as PES 400, and especially a composition containing 4095 PES 400 and 6095 water or saline. The choice of carrier will be determined in part by the particular compound selected as well as the particular method used to administer the composition. Therefore, there is a wide variety of suitable compounds of the pharmaceutical composition according to the present invention.

The following compounds for oral, aerosol, parenteral, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, rectal and vaginal administration are purely illustrative and not limiting.

Pharmaceutical compositions can be administered parenterally, for example, intravenously, intraarterially, subcutaneously, intradermally, intrathecally, or intramuscularly. Thus, the present invention relates to compositions for parenteral administration, which contain a solution of a compound according to this invention, dissolved or suspended in an acceptable carrier suitable for parenteral administration, including aqueous and non-aqueous, isotonic sterile injection solutions.

In general, the requirements for effective pharmaceutical carriers for parenteral formulations are well known to those skilled in the art. See Riagtaseciis5 apa Rpagtasu Rgasiise, 9U.V. IPrripsoi

Sotrapu, RpyPaadeirpia, RA, Vapkeg and SpaItegv, ey5., pages 238-250 (1982), and ABNR Naparook op

Ipiestarie Ogydv, Goizzei, 44P ey., pages 622-630 (1986). Such compositions include solutions containing antioxidants, buffers, bacteriostatic factors and solutions that make the composition isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions that may include suspending agents, solubilizers, thickeners, stabilizers and preservatives.

The compound may be administered in a physiologically acceptable diluent in a pharmaceutical carrier such as a sterile liquid or a mixture of liquids including water, saline, aqueous dextrose and solutions of related sugars, an alcohol such as ethanol, isopropanol (for example, in topical applications) or hexadecyl alcohol, glycols such as propylene glycol or 60 polyethylene glycol, dimethyl sulfoxide, glycerol ketals such as 2,2-dimethyl-1,3-dioxolane-4-

methanol, esters such as poly(ethylene glycol) 400, oil, fatty acid, ester or glyceride of a fatty acid, or acetylated glyceride of a fatty acid, with or without the addition of a pharmaceutically acceptable surfactant such as a soap or detergent, a suspending agent , such as pectin, carbomer, methylcellulose, hydroxypropylmethylcellulose or carboxymethylcellulose, or emulsifying agents and other pharmaceutical excipients.

Oils useful in parenteral formulations include petroleum, animal, vegetable and synthetic oils. Specific examples of oils useful in such compounds include peanut, soybean, sesame, cottonseed, corn, olive, petroleum jelly, and mineral oil. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.

Suitable soaps for use in parenteral formulations include fatty acid and alkali metal salts, ammonium and triethanolamine, and suitable detergents include (a) cationic detergents such as, for example, dimethyldialkylammonium halides and alkylpyridinium halides, (b) anionic detergents such as, e.g. , alkyl-, aryl- and olefin sulfonates, alkyl-, olefin-, ether- and monoglyceride sulfates and sulfosuccinates, (c) nonionic detergents, such as, for example, fatty acid amine oxides, fatty acid alkanolamides, and copolymers of polyoxyethylene and polypropylene, (4) amphoteric detergents, such as, for example, alkyl-B-aminopropionates and 2-alkylimidazoline quaternary ammonium salts, and (are) their mixtures.

Parenteral formulations will generally contain from about 0.595 or less to about 2595 or more by weight of a compound of the present invention in solution. Preservatives and buffers can be used. To minimize or eliminate irritation at the injection site, such compositions may contain one or more nonionic surfactants with a hydrophilic-lipophilic balance (HIB) of about 12 to about 17. The amount of surfactant in such formulations will typically be vary from about 595 to about 1595 by weight. Suitable surfactants include polyethylene sorbitan and fatty acid esters such as sorbitan monooleate and high molecular weight adducts of ethylene oxide with a hydrophobic base formed by condensation of propylene oxide with

With propylene glycol. Parenteral formulations may be presented in sealed single-dose or multi-dose containers, such as ampoules and vials, and may be stored in a freeze-dried (lyophilized) state, requiring only the addition of a sterile liquid adjuvant, such as water, for direct injection. before use.

Extemporaneous injection solutions and suspensions can be obtained from sterile powders, granules and tablets.

Topical formulations, including those used for transdermal drug release, are well known to those skilled in the art and are acceptable in the context of this invention for application to the skin.

Formulations suitable for oral administration may consist of (a) liquid solutions, such as an effective amount of a compound of the present invention, diluted in diluents such as water, saline, or orange juice; (B) capsules, sachets, tablets, lozenges and lozenges, each of which contains a given amount of a compound according to this invention in the form of solids or granules; (c) powders; (4) suspensions in a suitable liquid and (e) suitable emulsions. Liquid compounds may include diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohol, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent. Capsule forms can be of the conventional hard or soft gelatin type, containing, for example, surfactants, lubricants and inert fillers such as lactose, sucrose, calcium phosphate and corn starch. Tablet forms may include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, gum arabic, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate. , stearic acid and other fillers, dyes, diluents, buffering agents, disintegrants, humectants, preservatives, flavoring agents and pharmacologically compatible fillers. Dosage forms in the form of lozenges may contain the compound ingredient in a flavoring agent, typically in sucrose and gum arabic or tragacanth, as well as lozenges containing the compound of the present invention in an inert base such as gelatin and glycerin or sucrose and gum arabic. emulsions, gels, etc. contain, in addition to the compound according to this 60 invention, such fillers as are known from the prior art.

The compound according to this invention, alone or in combination with other suitable components, can be included in aerosol compositions to be administered by inhalation. The compound or epimer according to this invention is preferably supplied in a powdered form together with a surfactant and a propellant. Generally, the percentage ratios of the compounds of this invention may be from about 0.0195 to about 2095 by weight, preferably from about 195 to about 1095 by weight.

The surfactant, of course, must be non-toxic and preferably soluble in the propellant. Typical of such surfactants are esters or partial esters of fatty acids containing from b to 22 carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic, linolenic, olesteric, and oleic acids, with an aliphatic polyatomic alcohol, or their cyclic anhydride. Mixed esters such as mixed or natural glycerides can be used. The surfactant can be from about 0.195 to about 2095 by weight of the composition, preferably from about 0.2595 to about 595. A propellant is typically used to balance the composition. If desired, a carrier such as lecithin for intranasal delivery may also be included. Such aerosol compounds may be placed in acceptable propellants under pressure, such as dichlorodifluoromethane, propane, nitrogen, etc. They can also be formulated as pharmaceutical products for non-pressurized preparations, such as in a nebulizer or atomizer. Such aerosol compounds can be used for spraying on the mucous membrane.

In addition, the compound according to this invention can be included in suppositories by mixing with various bases, such as emulsifying bases or water-soluble bases. Compounds suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or aerosol formulations containing, in addition to the compound ingredient, such carriers as are known in the art to be suitable.

The concentration of the compound in the pharmaceutical compositions can vary, for example, from less than about 195 to about 1095, from 2095 to 5095 or more by weight, and can be selected mainly depending on the bulk liquid and viscosities according to the particular of the selected input path.

For example, a typical pharmaceutical composition for intravenous infusion can be made containing 250 ml of sterile Ringer's solution and 100 mg of at least one compound according to the present invention. Effective methods of preparing the parenterally administered compounds of the present invention will be known or apparent to those skilled in the art and are described in more detail in, for example, Ketipdiopie Ripagtaseciis! Zsiepse (177 vd.,

Mask Rybiiznipd Sotrapu, Easiop, RA, 1985).

It will be apparent to one of ordinary skill in the art that, in addition to the pharmaceutical compositions described above, the compound of the present invention may be formulated as inclusion complexes, such as cyclodextrin inclusion complexes, or liposomes. Liposomes can serve to target a compound of the present invention to a specific tissue, such as lymphoid tissue or liver cancer cells. Liposomes may also be used to increase the half-life of a compound of the present invention. Many methods are available for obtaining liposomes, described, for example, in 520Ka ei ai., App. Chem. Viorpuvkh. Bioepo., 9, 467 (1980), and in U.S. Patent Nos. 4,235,871, 4,501,728, 4,837,028, and 5,019,369.

The compounds or pharmaceutical compositions are used in an embodiment for the treatment and/or prevention of a disease or disorder or condition such as Alzheimer's disease (AD), mild cognitive impairment (MC), senile dementia, vascular dementia, Parkinson's disease dementia, attention deficit disorder , attention deficit hyperactivity disorder (ADHD), dementia associated with Lewy bodies, AIU5-dementia complex (ADC), Pick's disease, dementia associated with Down syndrome, Huntington's disease, cognitive deficits associated with traumatic brain injury (TBI ), stroke-related cognitive decline, post-stroke neuroprotective effect, cognitive and sensorimotor filtering deficits associated with schizophrenia, cognitive deficits associated with bipolar disorder, cognitive impairment associated with depression, acute pain, post-surgical or postoperative pain, chronic pain, inflammation, inflammatory pain, neuropathic pain, termination of n tanning, need for new blood vessel growth associated with wound healing, need for new blood vessel growth associated with skin graft vascularization and lack of blood circulation, arthritis, rheumatoid arthritis, psoriasis, Crohn's disease, ulcerative colitis, pouchitis, inflammatory bowel disease, celiac disease, periodontitis , sarcoidosis, pancreatitis, rejection of transplanted organs, acute immune disease associated with organ transplantation, chronic immune disease associated with organ transplantation,

septic shock, toxic shock syndrome, septic syndrome, depression and rheumatoid spondylitis.

In another embodiment, the pharmaceutical compositions are used to treat and/or prevent a disease or disorder or condition classified or diagnosed as major or minor neurocognitive disorders or disorders resulting from neurodegeneration.

The present invention also relates to a method of administering a compound of formula Y, defined above, in combination with drugs used in the treatment of attention deficit hyperactivity disorder, schizophrenia and other cognitive disorders, such as Alzheimer's disease, dementia in Parkinson's disease, vascular dementia or dementia, associated with Lewy bodies, traumatic brain injury, or in addition to them.

The present invention also relates to a method of administering a compound of formula Y as defined above in combination with, or as an adjunct to, acetylcholinesterase inhibitors, disease-modifying drugs or biologics for neurodegenerative disorders, dopaminergic drugs, antidepressants, typical or atypical antipsychotics .

Accordingly, a compound of formula !/ is used to prevent or treat a disorder mediated by nicotinic acetylcholine receptors. Such compounds may be administered to a subject suffering from or susceptible to such a disorder in a therapeutically effective amount. The compounds, in particular, are used in a method of treating a mammal with a condition in which modulation of nicotinic acetylcholine receptor activity provides therapeutic benefit, the method being performed by administering a therapeutically effective amount of a compound of formula I! a subject suffering from such a disorder or susceptible to it.

The present invention also relates to a pharmaceutical composition containing compounds of the general formula (I), as defined above, their tautomeric forms, their stereoisomers, their analogs, their isotopes, their pharmaceutically acceptable salts, their polymorphs, their solvates, their optical isomers in combination with conventional pharmaceutically acceptable carriers, diluents, etc., for use in any of the ways described herein.

The compounds of this invention may be administered in a dose sufficient to treat a disease, condition or disorder. Such doses are known from the prior art (see, for example, She

RPuzisiapye" YuOe5K Keigepse (2004)). Compounds can be introduced using methods such as those described, for example, in Umazzegtap ei ai., Sapseg, 36, pp. 1258-1268 (1975) and RPuzisiape' rezk RNegipese, 58Ii ed. , Ppotzhop RON (2004).

Appropriate doses and dosing regimens can be determined by conventional ranging techniques known to those skilled in the art. As a rule, treatment begins with smaller dosages that are less than the optimal dose of the compound according to this invention.

Then, the dosage is increased in small steps to achieve the optimal effect under the given circumstances. This method may involve the administration of from about 0.1 μg to about 50 mg of at least one compound according to the present invention per kg of body weight of an individual.

For a 70-kg patient, dosages of from about 10 mcg to about 200 mg of a compound of the present invention will be more commonly used, depending on the physiological response of the patient.

By way of example, and not by way of limitation of the present invention, a dose of a pharmaceutically active agent(s) described herein for methods of treating or preventing a disease or condition described above may be from about 0.001 to about 1 mg/kg body weight of a subject. per day, for example, about 0.001 mg, 0.002 mg, 0.005 mg, 0.010 mg, 0.015 mg, 0.020 mg, 0.025 mg, 0.050 mg, 0.075 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0 .25 mg, 0.5 mg, 0.75 mg or 1 mg/kg of body weight per day. The dosage of the pharmaceutically active agent(s) described herein for the described methods may be from about 1 to about 1000 mg/kg body weight of the subject to be treated per day, for example, about 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 0.020 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 500 mg, 750 mg or 1000 mg/kg body weight per day.

According to variants of implementation, the present invention relates to methods of treatment, prevention, alleviation and/or suppression of a condition modulated by the nicotinic acetylcholine receptor, which involves the introduction of a compound of formula (I) or its salt.

The terms "treat", "prevent", "alleviate" and "inhibit" and similar words, as used herein, do not imply mandatory 10095 or complete treatment, prevention, alleviation or inhibition. Rather, there are varying degrees of prevention, relief, and suppression that one skilled in the art will recognize as such.

contributing to a potential benefit or therapeutic effect. In this regard, the methods according to the present invention can provide any amount of any level of treatment, prevention, alleviation or suppression of the disorder in a mammal. For example, a disorder, including its symptoms or conditions, may be reduced by, for example, 10095, 9095, 8095, t095, 6095, 5095, 4095, 3095, 2095, or 1095. In addition, treatment, prevention, relief, or inhibition provided by the method according to the present invention may involve the treatment, prevention, alleviation or inhibition of one or more conditions or symptoms of a disorder, for example, cancer. Also, for the purposes of the present invention, "treating", "preventing", "alleviating" or "suppressing" may include delaying the onset of a disorder or a symptom or condition thereof.

In accordance with the present invention, the term "subject" includes "animal", which in turn includes a mammal, such as, without limitation, from the order Codepia, such as mice, and from the order I Adotogrupia, such as rabbits. It is preferred that the mammals belong to the order Sagpimoga, including Reiipe5 (cats) and Sapipeh5 (dogs). More preferably, the mammals belong to the order Agpiodasiuia, including Vomipezh (cows) and Zu/ipe (pigs), or the order Reg55odasiuia, including Edpipez (horses).

The most preferred is that the mammals belong to the order Riiitaiech, Seboia5 or 5bitoiav5 (monkeys) or the order Apipgoroid5 (humans and apes). A particularly dominant mammal is man.

Below are the abbreviations used in this description and their meanings.

AC: acetylcholine.

AYU: Alzheimer's disease.

AOS: AIO5-dementia complex.

ARNO: attention deficit hyperactivity disorder.

AIr5: acquired immune deficiency syndrome.

AKOZ: acute respiratory failure syndrome.

ОСС: 1,3-dicyclohexylcarbodiimide.

OSE: dichloroethane.

OSM: dichloromethane.

PIREA: diisopropylethylamine

ORI .V: dementia with Lewy bodies.

OME: M,.M-dimethylformamide.

EOSI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

ESHIRE: a plate reader for fluorescence imaging.

NAT: 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate.

HB5B5: Hanks' balanced salt solution.

NEREZ5: 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid.

HMOV: High Mobility Group Framework.

NOAT: 1-hydroxy-7-azabenzotriazole.

NEW: hydroxybenzotriazole hydrate.

NRI C: high performance liquid chromatography.

And: interleukins.

HOT: laterodorsal tegmental nucleus.

And ICs: ligand-gated ion channels.

MS: moderate cognitive impairment.

MV: M-bromosuccinimide.

MO: M-chlorosuccinimide.

MI: M-iodosuccinamide.

MMK: neuronal nicotinic receptors of AS.

RAM: positive allosteric modulation.

RO: Parkinson's disease.

ROM: postdiabetic neuralgia.

RNM: postherpetic neuralgia.

RMVO: p-methoxybenzyloxy.

PM5: peripheral nervous system.

TBI: traumatic brain injury.

TNE: tetrahydrofuran.

TS: thin-layer chromatography.

TM5: tetramethylsilane.

TME-a: tumor necrosis factor alpha.

MTA: ventral region of the tire. bo a7 PASI: subunit a7 of the nicotinic acetylcholine receptor.

The following examples are provided to further illustrate the present invention and, therefore, should not be construed as limiting the scope of the present invention in any way. All spectra

I"NMR was determined in the indicated solvents, and the chemical shifts are expressed in units of the weak field b from tetramethylsilane (TM5) as an internal standard, and the interproton interaction constants are expressed in hertz (Hz).

Example 1: Preparation of 4-(5-(4-chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)benzenesulfonamide (compound 1)

NMO25

Ff SNz 3-7 at 5 no

Step 1: Methyl 3-bromo-5-(4-chlorophenyl)-4-methylthiophene-2-carboxylate (1a)

Nn

Ve. rz at 5 o'clock

To a shaking solution of methyl 5-(4-chlorophenyl)-4-methylthiophene-2-carboxylate (obtained according to the procedure described in UMO 2007092751, 4.0 g, 15.0 mmol) in chloroform (50 ml) at 25 "С, zinc chloride (2.06 g, 15.0 mmol) was added, followed by the addition of bromine (2.64 g, 0.85 ml, 16.5 mmol) drop by drop under a nitrogen atmosphere. The resulting mixture was shaken at 60-65 "C for 1.5 hours. The course of the reaction was monitored using TI.

The reaction mixture was cooled to 0 "C and quenched with water (30 ml). The resulting organic layer was washed with 1095% aqueous sodium bicarbonate solution (2 x 50 ml) and dried over anhydrous Ma»5O. The solvent in the organic layer was evaporated under reduced pressure to give crude product, which was then purified by column chromatography on silica gel (100-200 mesh) using 395 ethyl acetate in hexanes as eluent to give the title compound (2.2 g, 42.53965).

M5: mass/charge 345 (M'-1).

I"NMR (SOCIz, 400 MHz): b 7.43 (y, 9-8.4 Hz, 2H), 7.36 (y, 9U-8.4 Hz, 2H), 3.9 (5, ЗН ), 2.28 (5,

ZN).

The compounds below were prepared by a procedure similar to that described above for compound "Ia" with appropriate variations in reactants, reaction conditions, and amounts of reagents. 2a. Methyl 3-bromo-5-(2-chlorophenyl)-4-methylthiophene-2-carboxylate

M5: mass/charge 345 (M'-1). yes Methyl 3-bromo-5-(4-fluorophenyl)-4-methylthiophene-2-carboxylate

From M5: mass/charge 330 (M-n1). 11a. Methyl 3-bromo-5-(4-(tert-butyl)phenyl)-4-methylthiophene-2-carboxylate

M5: mass/charge 368 (M'-1). 17a. Methyl 3-bromo-5-(3,4-dichlorophenyl)-4-methylthiophene-2-carboxylate

M5: mass/charge 381 (M'-1). 18a. Methyl 3-bromo-5-(2,4-dichlorophenyl)-4-methylthiophene-2-carboxylate

M5: mass/charge 381 (M'-1). 19a. Methyl 3-bromo-5-(2,4-difluorophenyl)-4-methylthiophene-2-carboxylate

M5: mass/charge 370 (M.23). 20a. Methyl 3-bromo-5-(3-chloro-4-fluorophenyl)-4-methylthiophene-2-carboxylate

M5: mass/charge 365 (M-n1). 21a. Methyl 3-bromo-5-(3-chloro-4-methoxyphenyl)-4-methylthiophene-2-carboxylate

M5: mass/charge 377 (M'1). 47a. Ethyl 3-bromo-5-(3,4-difluorophenyl)-4-methylthiophene-2-carboxylate

M5: mass/charge 384 (M.23).

Step 2: Ethyl 5-(4-chlorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate (15)

No. MO, Z "Y sn, Fr. and g ns

To a solution of methyl-3-bromo-5-(4-chlorophenyl)-4-methylthiophene-2-carboxylate (compound Ta, 2.2 g, 6.3 mmol) in a mixture of toluene:ethanol (10:30 ml) was added 4 -aminosulfonylbenzeneboronic acid (obtained according to the procedure given in EP 1012142, 1.28 g, 6.3 mmol) and potassium carbonate (1.76 g, 12.7 mmol) at 25"C in a stoppered test tube and bubbled through nitrogen gas the reaction mixture for 15 minutes. To this was added tetrakis(triphenylphosphine)palladium(O) (0.370 g, 0.318 mmol) under nitrogen and the reaction mixture was heated from about 95 "C to about 100 "C for 18 hours with shaking. was observed using TI C. The reaction mixture was cooled to 25 °C and filtered through celite. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (100-200 mesh) using 4095 ethyl acetate in hexanes as eluent to give the title compound (1.3 g, 48965).

M5: mass/charge 436 (M'-1). "NMR (SOCIz, 400 MHz): b 8.01 (a, 9-84 Hz, 2H), 7.46-7.41 (t, 6H). 4.89 (rv, 2H), 4.17 ( ad, 9U-7.2 Hz, 2H), 1.99 (5, ZN), 1.9 (9-72 Gu, ZN).

The compounds below were prepared by a procedure similar to that described above for compound 1p, with appropriate variations in reactants, reaction conditions, and amounts of reagents. 25. Ethyl 5-(2-chlorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate

M5: mass/charge 436 (M-n1). 4 years Ethyl 5-(4-fluorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate

M5: mass/charge 420 (M'-1). 11 years Ethyl 5-(4-(tert-butyl)phenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate

M5: mass/charge 458 (M'-1). 17 years old Ethyl 5-(3,4-dichlorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate

M5: mass/charge 470 (M'-1). 18 years old Ethyl 5-(2,4-dichlorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate

M5: mass/charge 470 (M'-1). 190. Ethyl 5-(2,4-difluorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate

From M5: mass/charge 438 (M-n1). 20 years Ethyl 5-(3-chloro-4-fluorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate

M5: mass/charge 454 (M'-1). 21 years old Ethyl 5-(3-chloro-4-methoxyphenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate

M5: mass/charge 466 (M'-1). 47 years old Ethyl 5-(3,4-difluorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate

M5: mass/charge 438 (M'-1).

Stage 3: 5-(4-Chlorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid (1c) ee 3-0 o 5 on

Ethyl 5-(4-chlorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate (compound 165, 1.9 g, 4.36 mmol) was suspended in ethanol (40 mL) and treated for 1 n Mahon solution (0.9 ml) at 25 °C. The reaction mixture was heated to 50-55 °C with shaking for 30-40 minutes. The course of the reaction was observed with the help of TI C. Then the reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with a mixture of ethyl acetate:water (100:50 ml). Aqueous 1095 NCI was added to the resulting diluted mixture, adjusting the pH of the mixture from 5 to 6.

The aqueous layer was extracted with ethyl acetate (2 x 50 ml). The combined organic layer was dried over anhydrous NaCl. The solvent in the organic layer was evaporated under reduced pressure to give the title compound (1.72 g, 97905).

M5: mass/charge 408 (M--1).

NMR (0M5O, 400 MHz): b 12.87 (p5, 1H), 7.88 (y, 9-84 Hz, 2H), 7.56 (p5, 4H). 7.5 (a, 9U -8.4

Hz, 2H), 7.45 (5, 2H), 1.95 (5, ЗН).

The compounds below were prepared by a procedure similar to that described above for compound "1c" with appropriate variations in reactants, reaction conditions, and amounts of reagents. 2s. 5-(2-Chlorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid

M5: mass/charge 408 (M'-1). 4s. 5-(4-Fluorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid

M5: mass/charge 392 (M--1). 11 p. 5-(4-(T-butyl)phenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid

M5: mass/charge 430 (M-n1). 17 p. 5-(3,4-Dichlorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid

M5: mass/charge 442 (M'n1). 18 p. 5-(2,4-Dichlorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid

M5: mass/charge 442 (M'n1). 19s. 5-(2,4-Difluorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid

M5: mass/charge 410 (M'-1). 20s. 5-(3-Chloro-4-fluorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid

M5: mass/charge 426 (M'-1). 21 p. 5-(3-Chloro-4-methoxyphenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid

M5: mass/charge 438 (M-n1). 47 p. 5-(3,4-Difluorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid

M5: mass/charge 410 (M'-1).

Step 4: 5-(4-Chlorophenyl)-3-(4-(M-((dimethylamino)methylene)sulfamoyl)phenyl)-M-methoxy-M,4-dimethylthiophene-2-carboxamide (149)

MO25

Ff sleep 9-9 o'clock E)

NHS about M sn,

Oxalyl chloride (2.1 g, 1.4 mL, 16.2 mmol) was added dropwise at 0 °C to a solution of 5-(4-chlorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2 -carboxylic acid (compound 1c, 2.2 g, 5.mmol) in a mixture of dichloromethane (40 mL) and OME (0.8 g, 0.8 mL, 10.8 mmol). The resulting mixture was allowed to warm to room temperature temperature and shaken for 1.5

For an hour in a nitrogen atmosphere. The course of the reaction was monitored using TI C. The reaction mixture was concentrated under reduced pressure and used directly for the next reaction.

The resulting residue was dissolved in dry dichloromethane (40 mL) and triethylamine (2.8 g, 3.9 mL, 27.0 mmol) was added, followed by the addition of M,O-dimethylhydroxylamine hydrochloride (1.06 g, 10.8 mmol). ) during shaking. The reaction mixture was shaken at room temperature for 2 hours. The course of the reaction was monitored by TIS. The reaction mixture was washed with water (2 x 20 ml) and the resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was further purified by column chromatography on silica gel (100-200 mesh) using 8090 ethyl acetate in hexane as eluent to give the title compound (2.36 g, 8696).

M5: mass/charge 506 (M-n1).

I"NMR (SOSI"z, 400 MHz): b 8.14 (5, 1H), 7.95 (a, U-8.4 Hz, 2H), 7.42 (65, 4H), 7.37 (a, 9U-8.4 Gu, 2H), 3.68 (5, ЗН), 3.17 (5, ЗН), 3.13 (5, ЗН), 3.05 (5, ЗН), 1 ,98 (5, ZN).

The compounds below were prepared by a procedure similar to that described above for compound "1d", with appropriate variations in reactants, reaction conditions, and amounts of reagents. 2. 5-(2-Chlorophenyl)-3-(4-(M-((dimethylamino)methylene)sulfamoyl)phenyl)-M-methoxy-M,4-dimethylthiophene-2-carboxamide

M5: mass/charge 506 (M'-1). 44. 3-(4-(M-(Dimethylamino)methylene)sulfamoyl)phenyl)-5-(4-fluorophenyl)-M-methoxy-M,4-dimethylthiophene-2-carboxamide

M5: mass/charge 490 (M-n1). 1t1a. 5-(4-"tert-butyl)phenyl)-3-(4-(M-((dimethylamino)methylene)sulfamoyl)phenyl)-M-methoxy-

M,4-dimethylthiophene-2-carboxamide

Zo

M5: mass/charge 528 (M'-1). 17a. 5-(3,4-Dichlorophenyl)-3-(4-(M-((dimethylamino)methylene)sulfamoyl)phenyl)-M-methoxy-

M,4-dimethylthiophene-2-carboxamide

M5: mass/charge 540 (M'n1). 184. 5-(2,4-Dichlorophenyl)-3-(4-(M-((dimethylamino)methylene)sulfamoyl)phenyl)-M-methoxy-

M,4-dimethylthiophene-2-carboxamide

M5: mass/charge 540 (M'-1). 194. 5-(2,4-Difluorophenyl)-3-(4-(M-((dimethylamino)methylene)sulfamoyl)phenyl)-M-methoxy-

M,4-dimethylthiophene-2-carboxamide

M5: mass/charge 508 (M-n1). 204. 5-(3-Chloro-4-fluorophenyl)-3-(4-(M-((dimethylamino)methylene)sulfamoyl)phenyl)-M-methoxy-M,4-dimethylthiophene-2-carboxamide

M5: mass/charge 524 (M'n1). 214. 5-(3-Chloro-4-methoxyphenyl)-3-(4-(M-((dimethylamino)methylene)sulfamoyl)phenyl)-M-methoxy-M,4-dimethylthiophene-2-carboxamide

M5: mass/charge 536 (M'-1). 47a. 5-(3,4-Difluorophenyl)-3-(4-(M-((dimethylamino)methylene)sulfamoyl)phenyl)-M-methoxy-

M,4-dimethylthiophene-2-carboxamide

M5: mass/charge 508 (M'-1).

Stage 5: Preparation of 4-(5-(4-chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)benzenesulfonamide (compound 1) n.mO.5 ee 3-5 o 5

To a solution of 5-(4-chlorophenyl)-3-(4-(M-«((dimethylamino)methylene)sulfamoyl)phenyl)-M-methoxy-

of M,4-dimethylthiophene-2-carboxamide (compound 14, 2.3 g, 4.55 mmol), shaking in anhydrous

Grignard reagent (ethylmagnesium bromide, 3.04 g, 22.8 ml, 22.77 mmol) was added dropwise to TNE (40 ml) at 25 "C, and the reaction mixture was heated at 70-75 "C for 1 hour. The progress of the reaction was monitored by TIS. After cooling the reaction mixture to 0 "C, the reaction mixture was quenched by adding a saturated solution of ammonium chloride (40 ml) and the resulting mixture was extracted with ethyl acetate (3 x 50 ml). The combined organic layer was dried over

With anhydrous Ma»5O5. The solvent was evaporated from the dry organic layer under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (100-200 mesh) using 30-3595 ethyl acetate in hexane as eluent to give the title compound, which was then purified by precipitation by dissolving 1, 1 g of the compound in dichloromethane (10 ml) and its precipitation by slow addition of diisopropyl ether (0.89 g, 47).

M5: mass/charge 420 (M'-1).

I"NMR (0M5O, 400 MHz): b 7.95 (a, U-8.4 Hz, 2H), 7.59 (p5, 4H), 7.56 (j, 9-84 Hz, 2H), 7.45 (5, 2H), 2.37 (a, U-6.8 Hz, 2H), 1.92 (5, ЗН), 0.88 (I, 9У-6.8 Hz, ЗН).

The following compounds were prepared according to the procedure described above, but with appropriate changes in the reactants. 4-(5-(2-Chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)/benzenesulfonamide (compound 2)

M5: mass/charge 420 (M'-1).

I"NMR (0M50O, 400 MHz): b 7.88 (y, 9U-8.4 Hz, 2H), 7.56-7.58 (t, 1H), 7.43-7.47 (t, 7H), 2.34 (9, 9U-7.2 Hz, 2H), 1.70 (5, ЗН), 0.89 (I, 9U-7.2 Hz, ЗН). 4-(5-( 4-Fluorophenyl)-4-methyl-2-propionylthiophen-3-yl)ubenzenesulfonamide (compound 4)

M5: mass/charge 404 (M'-1).

NMR (0M50O, 400 MHz): b 7.94 (a, 9-84 Hz, 2H), 7.56-7.64 (t, 4H), 7.49 (rz-exchanges with 020, 2H) , 7.36-7.40 (t, 2H), 2.38 (n, U9-7.2 Hz, 2H), 1.92 (5, ЗН), 0.89 (I, 9U-7.2 4-(5-(4-tert-butyl)phenyl)-4-methyl-2-propionylthiophen-3-yl)ubenzenesulfonamide (compound 11)

M5: mass/charge 442 (M-n1). "NMR (SOSI", 400 MHz): b 8.02 (y, 9U-8.4 Hz, 2H), 7.42-7.49 (t, 6H), 4.92 (rz-exchanges with 020, 2H), 2.56 (a, 9-7.2 Hz, 2H), 1.97 (5, ЗН), 1.36 (5, 9H), 1.06 (I, 9-7.2 Hz, 4-(5-(3,4-Dichlorophenyl)-4-methyl-2-propionylthiophen-3-yl)ubenzenesulfonamide (compound 17)

M5: mass/charge 454 (M'-1).

I"NMR (SOSI", 400 MHz): b 8.03 (y, 9-84 Hz, 2H), 7.59 (y, 9-2.0 Hz, 1H), 7.54 (a, 9U- 8.4 Hz, 1H), 7.42 (a, 9-8.4 Hz, 2H), 7.32 (yes, 9-84, 2.0 Hz, 1H), 4.91 (B5-exchanges with 020, 2H), 2.52 (a, 9-72 Gu, 2H), 1.95 (5, ЗН), 1.04 (I, 9-7.2 Hz, ЗН). 4-(5-( 2,4-Dichlorophenyl)-4-methyl-2-propionylthiophen-3-yl)ubenzenesulfonamide (compound 18)

M5: mass/charge 454 (M-n1). "NYMR (SOSI", 400 MHz): b 8.04 (y, 9U-8.4 Hz, 2H), 7.53-7.54 (t, 1H), 7.44 (a, 9-84 Hz , 2H), 7.32-7.42 (t, 2H), 4.89 (rz-exchanges with O2O, 2H), 2.55 (d, 9-72 Hz, 2H), 1.76 (5, ZN), 1.04 (9-72 Hz,

ZN). 4-(5-(2,4-Difluorophenyl)-4-methyl-2-propionylthiophen-3-yl)/benzenesulfonamide (compound 19)

M5: mass/charge 422 (M-n1).

I"NMR (SOSI", 400 MHz): b 8.04 (a, 9-8.4 Hz, 2H), 7.47 (y, 9-8.4 Hz, 2H), 7.38-7, 44 (t, 1H) 6.98-7.04 (t, 2H), 5.01 (re-exchange with O2O, 2H), 2.54 (d, 9-72 Hz, 2H), 1.83 ( 5, ZN), 1.05 (i, 9-72 Hz,

ZN). 4-(5-(3-Chloro-4-fluorophenyl)-4-methyl-2-propionylthiophen-3-yl)/benzenesulfonamide (compound 20)

M5: mass/charge 438 (M-n1). "NMR (SOSI", 400 MHz): b 8.04 (y, 9-84 Hz, 2H), 7.54 (da, 9-6.8, 2.4 Hz, 1H), 7.42 (a , 9-84

Hz, 2H), 7.35-7.38 (t, 1H), 7.25 (I, 9-84 Hz, 1H), 4.92 (B5-exchanges with O2O, 2H), 2.54 (d , 9U-7.2 Hz, 2H), 1.94 (5, ЗН), 1.04 (i, 9-7.2 Hz, ЗН). 4-(5-(3-Chloro-4-methoxyphenyl)-4-methyl-2-propionylthiophen-3-yl)/ubenzenesulfonamide (compound 21)

M5: mass/charge 450 (M'-1).

I"NMR (0M5O, 400 MHz): b 7.93 (a, U-8.4 Hz, 2H), 7.61 (y, 9-24 Gu, 1H), 7.54 (a, 9U-8 ,4 Hz, 2H), 7.50 (a, 9-24 Hz, 1H), 7.49 (rb5-exchanges with O2O, 2H), 7.29 (y, U-8.8 Hz, 1H), 3.92 (5, ZN), 2.35 (ad, 9-72

Hz, 2H), 1.91 (5, ZN), 0.87 (I, 9U-7.2 Hz, ZN). 4-(2-Acetyl-5-(4-chlorophenyl)-4-methylthiophen-3-yl)/benzenesulfonamide (compound 40)

M5: mass/charge 406 (M'-1). "NMR (0M5O, 400 MHz): b 7.95 (y, 9-84 Hz, 2H), 7.57-7.59 (t, 6H), 7.50 (re-exchanges with 020, 2H), 1.99 (5, 3H), 1.93 (5, 3H).4-(5-(3,4-Difluorophenyl)-4-methyl-2-propionylthiophen-3-yl)/benzenesulfonamide (compound 47)

From M5: mass/charge 422 (M-n1). "NYMR (SOSI", 400 MHz): b 8.03 (y, 9U-8.4 Hz, 2H), 7.42 (y, 9-84 Hz, 2H), 7.25-7.33 (t . 72 Hz, ZN).

Example 2: Preparation of 4-(4-methyl-5-morpholino-2-propionylthiophen-3-yl)benzenesulfonamide (compound 24) nm, in (c)

Fo) 8 m7 in vv c) So

Stage 1: Preparation of M,M-dimethyl-M'-((4-propionylphenyl)sulfonyl)/formimidamide (24a)

To a stirred solution of 4-propionylbenzenesulfonamide (prepared according to the procedure described in Viogdapis Spetivig 1994, 22, 387-394) (2.2 g, 10.3 mmol) in ethyl acetate (20 mL) was added UOME (2.0 ml) followed by the dropwise addition of M,M-dimethylformamidedimethylacetal (1.36 g, 1.51 ml, 11.36 mmol) at room temperature.

The resulting mixture was shaken at room temperature for 4 hours. The course of the reaction was monitored by TIS. The reaction mixture was concentrated under reduced pressure to give a solid product, which was washed with diisopropyl ether to give the title compound (2.6 g, 9490).

M5: mass/charge 269 (M'-1).

I"NMR (0M5O0O, 400 MHz): b 8.25 (5, 1H), 8.08 (y, 9U-8.8 Hz, 2H), 7.90 (y, 9U-8.4 Hz, 2H ), 3.15 (5,

ZN), 3.09 (ad, 9U-7.2 Hz, 2H), 2.91 (5, ZN), 1.08 (, U-7.2 Hz, ZN).

Stage 2: Preparation of /- M'-(4-(2-(1,3-dithiathan-2-ylidene)upropanoyl)phenyl)sulfonyl)-M, M- dimethylformimidamide (245) (F) z-8

And o-8-0

Shit

AND

To a stirring solution of M,M-dimethyl-M'-(4-propionylphenyl)sulfonyl)/formimidamide (compound 24a, 1.0 g, 3.73 mmol) in dry TNE (30 mL) was added potassium tert-butoxide (0.837 g, 7.46 mmol) at 0 "C in a nitrogen atmosphere. The resulting mixture was shaken at room temperature for 1 hour. The reaction mixture was cooled to 0 "C and carbon disulfide (0.425 g) was added dropwise to the cooled reaction mixture , 0.34 ml, 5.59 mmol) at 0"C. The resulting reaction mixture was shaken at room temperature for 30 minutes. The resulting reaction mixture was cooled to 0"C and dibromomethane (1 .3 g, 0.85 ml, 7.46 mmol) at 0 "C. The reaction mixture obtained as a result was shaken at room temperature for 20 hours. The course of the reaction was observed with the help of a TIS. The reaction mixture was poured into cold water (50 ml ) and extracted with ethyl acetate (3 x 50 mL).The combined organic layer was dried over anhydrous Mag5 A: 4. The solvent was evaporated under reduced pressure from the dry organic layer to give the crude product, which was further purified by column chromatography on silica gel (100-200 mesh) using 295 methanol in dichloromethane as eluent to give the title compound (0.65 g, 4990).

M5: mass/charge 357 (M-n1).

I"NMR (SOSI", 400 MHz): 6 8.13 (5, 1H), 7.93 (a, 9U-8.8 Hz, 2H), 7.59 (a, U-8.4 Hz, 2H), 4.16 (5, 2H), 3.15 (5, ЗН), 3.04 (5, ЗН), 1.83 (5, ЗН).

Stage C: Preparation of M,M-dimethyl-M'-(4-(2-methyl-Z3-morpholino-3-thioxopropanoyl)phenyl)sulfonyl)/formimidamide (24c) 97

Som av; and o-5-0

Shit

Am

To a solution of M'-((4-(2-(1,3-dithiathan-2-ylidene)propanoyl)phenyl)sulfonyl)-M,M-dimethylformimidamide (compound 24p, 0.53 g, 1.48 mmol), morpholine (0.39 g, 4.4 mmol) in toluene (20 mL) was added under stirring at room temperature. The reaction mixture was shaken at 115-120 "C for 3 hours. The course of the reaction was observed with the help of TI C. The reaction

The mixture was concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (100-200 mesh) using 295 methanol in dichloromethane as eluent to give the title compound (0.191 g, 32.3965).

M5: mass/charge 398 (M'-1). "NMR (0M5O, 400 MHz): b 8.23 (5, 1H), 7.85 (Yug5, 4H), 5.19 (d, U-6.4 Hz, 1H), 3.5-4, 0 (t, 8H), 3.14 (5, ЗН), 2.91 (5, ЗН), 1.33 (y, 9-6.4 Hz, ЗН).

The compounds below were prepared by a procedure similar to that described above for compound "24c" with appropriate variations in reactants, reaction conditions, and amounts of reagents. 226. Tert-butyl-4-(3-(4-(M-((dimethylamino)methylene)sulfamoyl)phenyl)-2-methyl-3-oxopropanethioyl)piperazine-1-carboxylate

M5: mass/charge 519 (Ma23).

23 Sat. 00M'-((4-(3-(4-(4-Fluorophenyl)piperazin-1-yl)-2-methyl-3-thioxopropanoyl)phenyl)sulfonyl)-

M,M-dimethylformimidamide

M5: mass/charge 491 (M'-1).

Step 4: Preparation of ethyl 3-(4-(M-((dimethylamino)methylene)sulfamoyl)phenyl)-4-methyl-5-morpholinothiophene-2-carboxylate (244)

Gays / x - ev tm (c) So

To a solution of M,M-dimethyl-M'-((4-(2-methyl-3-morpholino-3-thioxopropanoyl)uphenyl)usulfonyl/uformimidamide (compound 24c, 0.180 g, 0.45 mmol), which was shaken, in potassium carbonate (0.45 g, 3.17 mmol) was added to dry acetone (15 ml) at room temperature. The resulting mixture was shaken at 55-60 "C for 2 hours. The reaction mixture was cooled to 0 "C and a drop of ethyl iodoacetate (0.097 g, 0.053 mL, 0.45 mmol) was added dropwise. The reaction mixture was stirred at reflux temperature for 4 h. The reaction progress was monitored by TIS. The reaction mixture was allowed to warm to room temperature and filtered through a pad of celite. A pad of celite washed with acetone (2 x 10 ml). The filtrate was concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (100-200 mesh) using 50-5595 ethyl acetate in hexanes as eluent to give the title compound (0.091 g, 4390).

M5: mass/charge 466 (M'-1).

I"NMR (SOSI", 400 MHz): 6 8.19 (5, 1H), 7.90 (a, 9-8.4 Hz, 2H), 7.31 (a, 9U-8.4 Hz, 2H), 4.10 (ad, y7.2 Hz, 2H), 3.87-3.84 (t, 4H), 3.16 (5, ЗН), 3.07 (5, ЗН), 3, 07-3.04 (t, 4H), 1.88 (5, ZN), 1.15 (i, 9-72 Hz, ZN).

The compounds below were prepared by a procedure similar to that described above for compound "244" with appropriate variations in reactants, reaction conditions, and amounts of reagents. 224. Tert-butyl-4-(4-(4-(M-((dimethylamino)methylene)sulfamoyl)phenyl)-5-(ethoxycarbonyl)-3-methylthiophen-2-yl)piperazine-1-carboxylate

M5: mass/charge 565 (M'-1). 23a. Ethyl 3-(4-((M-«((dimethylamino)methylene)sulfamoyl)phenyl)-5-(4-(4-fluorophenyl)piperazin-1-yl)y4-methyl-thiophene-2-carboxylate

M5: mass/charge 559 (M'-1).

From Stage 5: Preparation of 4-methyl-5-morpholino-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid (24e) nM, in (c)

From no 5 to So

Ethyl 3-(4-(M-((dimethylamino)methylene)sulfamoyl)phenyl)-4-methyl-5-morpholinothiophene-2-carboxylate (compound 244, 0.36 g, 0.77 mmol) was suspended in ethanol ( 20 ml) and combined with 32 N Mahon solution (1.55 ml) at 25 "C. The reaction mixture was heated at 95-100 "C with shaking for 1 hour. The course of the reaction was observed with the help of TI C. The resulting reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with a mixture of ethyl acetate:water (30:15 ml). Aqueous 1095 NSI was added to it with pH adjustment to 5-6. The aqueous layer was extracted with ethyl acetate (2 x 20 ml). The combined organic layer was dried over anhydrous

Mag5O:. The solvent was evaporated under reduced pressure from the dried organic layer to give the title compound (0.196 g, 66965).

M5: mass/charge 383 (M'-1). NMR (0M5O, 400 MHz): b 12.44 (re, 1H), 7.83 (y, 9-84 Hz, 2H), 7.42 (5, 2H), 7.41 (a, 9U- 8.4

Hz, 2H), 3.75 (I, U-4.8 Hz, 4H), 2.98 (Her, 9-44 Hz, 4H), 1.79 (5, ЗН).

The compounds below were prepared by a procedure similar to that described above for compound "24e", with appropriate variations in reactants, reaction conditions, and amounts of reagents. 226. 5-(4-(Tert-butoxycarbonyl)piperazin-1-yl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid

M5: mass/charge 482 (M--1). 236. 5-(4-(4-Fluorophenyl)piperazin-1-yl)4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid

M5: mass/charge 476 (M'-1).

Stage 6: Preparation of 3-(4-(M-((dimethylamino)methylene)sulfamoyl)phenyl)-M-methoxy-M,4-dimethyl-5-morpholinothiophene-2-carboxamide (24) - / 4 (F) pc -6 5 m77y o So

Oxalyl chloride (0.19 g, 0.13 ml, 1.49 mmol) was added dropwise at 0 "C to a solution of 4-methyl-5-morpholino-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid (compound 24e, 0.19 g, 0.497 mmol) in a mixture of dichloromethane (15 mL) and OME (0.073 g, 0.08 mL, 0.99 mmol). The resulting mixture was allowed to warm to room temperature and shaken for 1.5 h in a nitrogen atmosphere.The course of the reaction was monitored by TI C. The reaction mixture was concentrated under reduced pressure and used directly for the next reaction.

The resulting residue was dissolved in dry dichloromethane (15 mL) and triethylamine (0.251 g, 0.35 mL, 2.48 mmol) was added, followed by the addition of M,O-dimethylhydroxylamine hydrochloride (0.098 g, 0.99 mmol) with shaking at 0 "С. The reaction mixture was shaken at room temperature for 2 hours. The course of the reaction was observed using TiIS.

The reaction mixture was washed with water (2 x 10 ml) and the resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography on silica gel (100-200 mesh) using 195% methanol in dichloromethane as eluent to give the title compound (0.127 g, 53965).

M: mass/charge 481 (M--1).

I"NMR (SOSI", 400 MHz): b 8.13 (5, 1H), 7.89 (a, 9U-8.4 Hz, 2H), 7.29 (j, 9U-8.4 Hz, 2H), 3.86 (Brg5,

AN), 3.65 (5, ZN), 3.14 (5, ZN), 3.13 (5, ZN), 3.03-3.05 (t, 7/Н), 1.85 (5 , ZN).

Z The compounds below were prepared by a procedure similar to that described above for compound "241" with appropriate variations in reactants, reaction conditions, and amounts of reagents. 221. Tert-butyl-4-(4-(4-(M-((dimethylamino)methylene)sulfamoyl)phenyl)-5-(methoxy(methyl)carbamoyl)-3-methylthiophen-2-yl)piperazin-1- carboxylate

M5: mass/charge 580 (M'-1). 23. 0 3-(4-(M-(Dimethylamino)methylene)sulfamoyl)phenyl)-5-(4-(4-fluorophenyl)piperazin-1-yl)-

M-methoxy-M,4-dimethylthiophene-2-carboxamide

M5: mass/charge 574 (M'n1).

Step 7: Preparation of 4-(4-methyl-5-morpholino-2-propionylthiophen-3-yl)/benzenesulfonamide (compound 24) nm y) (o)

Fo. 5 m o So

To a solution of 3-(4-(M-((dimethylamino)methylene)sulfamoyl)phenyl)-M-methoxy-M,4-dimethyl-5-morpholinothiophene-2-carboxamide (compound 241, 0.120 g, 0.25 mmol) , shaking, in anhydrous TNE (10 ml) at 25 "C, Grignard's reagent (ethylmagnesium bromide, 0.17 g, 1.25 ml, 1.25 mmol) was added drop by drop, and the reaction mixture was heated to 70-75 "C within 1 hour.

The course of the reaction was monitored by TIS. After cooling the reaction mixture to 0 "s, the reaction mixture was quenched by adding a saturated solution of ammonium chloride (10 ml) and the resulting mixture was extracted with ethyl acetate (2 x 20 ml). The combined organic layer was dried over anhydrous Mag50"h. The solvent in the dried organic layer was evaporated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (100-200 mesh) using 40-4595 ethyl acetate in hexane as eluent to give the title compound, which was further purified by precipitation by dissolving 0.056 g of this compound in ethyl acetate (1.0 mL) and precipitating it by slow addition of diisopropyl ether.The precipitate was filtered to give the title compound (0.047 g, 4890).

M5: mass/charge 395 (M'-1).

I"NMR (0M5O, 400 MHz): b 7.88 (a, 9U-8.4 Hz, 2H), 7.46-7.48 (t, 4H), 3.74-3.76 (t, 4H), 3.00-3.03 (t, 4H), 2.24 (4, 9-72 Hz, 2H), 1.75 (5, ЗН), 0.83 (Y, 9-72 Gu, ZN).

The following compounds were prepared according to the procedure described above, but with appropriate changes in the reactants. 4-(4-methyl-5-(piperazin-1-yl)-2-propionylthiophen-3-yl)/benzenesulfonamide (compound 22)

M5: mass/charge 394 (M'-1). "NMR (SOSI", 400 MHz): b 7.84 (y, 9U-8.4 Hz, 2H), 7.18 (a, 9-8.4 Hz, 2H), 6.31 (p5-exchanges with 020, 2H), 2.84-2.89 (t, 8H), 2.36 (rz-exchanges with 020, 1H), 2.16 (d, U-7.2 Hz, 2H), 1, 63 (5, ZN), 0.80 (I, 9-72

Gu, ZN). 4-(5-(4-(4-Fluorophenyl)piperazin-1-yl)-4-methyl-2-propionylthiophen-3-yl)ubenzenesulfonamide (compound 23)

M5: mass/charge 488 (M'-1).

NMR (0M5O, 400 MHz): b 7.88 (a, 9U-8.4 Hz, 2H), 7.47-7.49 (t, 4H), 7.00-7.10 (t, 4H), 3.34-3.36 (t, 4H), 3.24-3.26 (t, 2H), 3.16-3.19 (t, 2H), 2.24 (ad, 9- 7.2 Hz, 2H), 1.78 (5, ЗН), 0.83 (I, 9-72

Hz, ZN).

Example C: Preparation of 4-(5-(4-methoxyphenyl)-4-methyl-2-propionylthiophen-3-yl)benzenesulfonamide (compound 7) nmO»5

Ff SN

What is the United Nations" at 5

Nze

Zo Step 1: Methyl 3-bromo-4-methylthiophene-2-carboxylate (7a)

SN

Ve.

What; at 5 o'clock

To a stirring suspension of copper (I) bromide (14.3 g, 64.0 mmol) in acetonitrile (70 mL) was added tert-butyl nitrite (7.83 g, 9.21 mL, 76.0 mmol) under atmosphere of nitrogen at room temperature (2572). To this suspension was added dropwise a solution of methyl 3-amino-4-methylthiophene-2-carboxylate (10.0 g, 58.0 mmol) in acetonitrile (30 mL) at 20 "C for 2 hours. The reaction mixture was shaken at 25 "C for 2 hours. The course of the reaction was monitored by TIS. Then the reaction mixture was slowly added to 150 ml of 2 N HCl and extracted with ethyl acetate (2 x 150 ml). The resulting organic layer was washed with water (1 x 50 ml), brine (1 x 50 ml), dried over sodium sulfate and concentrated under reduced pressure to give the crude product as a semi-solid (10.5 g), which was then purified column chromatography on silica gel (100-200 mesh) using 795 ethyl acetate in hexanes as eluent to give the title compound (9.0 g, 65.5590).

M5: mass/charge 236 (M'-1).

I"NYMR (SOSI", 400 MHz): b 7.19 (5, 1H), 3.87 (5, ЗН), 2.24 (5, ЗН).

Step 2: Methyl 4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate (75)

there is

F, sn. in -

To a stirring suspension of methyl 3-bromo-4-methylthiophene-2-carboxylate (compound 7a, 9.0 g, 38.0 mmol) in ethanol:toluene (10030 mL) in a stoppered tube was added (4- sulfamoylphenyl)boronic acid (8.46 g, 42.0 mmol) and potassium carbonate (10.57 g, 76.0 mmol) under nitrogen at room temperature (ca. 2522). Nitrogen gas was blown through this suspension for an additional 15 minutes at room temperature (approximately 25°C) and tetrakis(triphenylphosphine)palladium(0) (2.21 g, 1.9 mmol) was added at 25°C and the stoppered tube was closed. The reaction mixture was shaken at 105 °C for 15 hours and the course of the reaction was observed with the help of TI!/C. The reaction mixture was filtered and washed with ethyl acetate (2 x 100 ml). The organic layer was concentrated under reduced pressure to obtain the crude product as a semi-solid substance (11.2 g); which was purified by column chromatography on silica gel (100-200 mesh) using 5095 ethyl acetate in hexanes as eluent to give the title compound (2095 ethyl ester was observed as a trans-esterified product) (8.8 g, 70.7090).

M5: mass/charge 312 (M-n1).

I"NMR (SOSI"z, 400 MHz): b 7.97 (y, 9U-8.4 Hz, 2H), 7.38 (y, 9U-8.4 Hz, 2H), 7.23 (5 , 1H), 4.91 (p5- exchanges with 020, 2H), 3.71 (in, ZN), 2.20 (in, ZN).

Stage 3: Methyl-5-bromo-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate (7 s) nmO.5 o Ve / -

To a stirring suspension of methyl-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate (compound 76, 8.80 g, 27.0 mmol) in OCM (150 mL) was added dropwise bromine ( 5.19 g, 1.67 ml, 32.0 mmol) at 0 "C. The reaction mixture was shaken at 25 "C for 2 hours and the course of the reaction was observed with the help of a TI C. Then the reaction mixture was completely concentrated and redissolved in OSM (250 ml). The resulting organic layer was washed with water (2 x 50 ml), brine (1 x 50 ml) and dried over sodium sulfate and concentrated under reduced pressure to give the crude product as a semi-solid (10.2 g), which was then purified by column chromatography on silica gel (100-200 mesh) using 5095 ethyl acetate in hexanes as eluent to give the title compound (2095 ethyl ester was observed as a trans-esterified product) (9.0 g, 82.3490).

From M5: mass/charge 391 (M-n1). "NMR (SOSI", 400 MHz): b 8.01 (a, 9U-8.4 Hz, 2H), 7.39 (y, 9-8.4 Hz, 2H), 4.93 (p5-exchanges with 020, 2H), 3.72 (5, ЗН), 1.95 (5, ЗН).

Step 4: Methyl 5-(4-methoxyphenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate (74) noMOo5 o. ; I have! 5 in -o and ost

To a solution of methyl-5-bromo-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate (compound 7o, 3.0 g, 7.69 mmol) in a mixture of toluene:ethanol (25:75 ml) was added (4-methoxyphenyl)boronic acid (1.28 g, 8.46 mmol) and potassium carbonate (3.18 g, 23.07 mmol) at 25 °C. Nitrogen gas was bubbled through the reaction mixture for 15 minutes. tetrakis(triphenylphosphine)palladium(O) (0.487 g, 0.422 mmol) in nitrogen and the reaction mixture was heated at 95-100 "C for 1 hour with shaking. The course of the reaction was monitored using

TS. The reaction mixture was cooled to 25 °C and filtered through celite, then washed with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure to give the crude product, which was then purified by column chromatography on silica gel (100-200 mesh) using 5095 ethyl acetate in hexanes as eluent to give the title compound (2095 ethyl ester was observed as a trans-esterified product) (2.69 g, 84965).

M5: mass/charge 418 (M-n1). "NYMR (SOSI", 400 MHz): b 8.01 (a, 9U-8.4 Hz, 2H), 7.41-7.46 (t, 4H), 7.00 (a, 9U-8, 4 Hz, 2H), 4.96 (re-exchanges with 020, 2H), 3.87 (in, ZN), 3.73 (5, ZN), 1.99 (in, ZN).

The compounds below were prepared by a procedure similar to that described above for compound 7a, with appropriate variations in reactants, reaction conditions, and amounts of reagents.

By. Ethyl 5-(33-chlorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate

M5: mass/charge 436 (M'-1). 50. Ethyl 5-(4-cyclopropylphenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate

M5: mass/charge 442 (M'n1). ba. Ethyl 4-methyl-3-(4-sulfamoylphenyl)-5-(4-trifluoromethyl)phenyl)thiophene-2-carboxylate

M5: mass/charge 468 (M-1). 8a. Ethyl 5-(4-ethoxyphenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate

M5: mass/charge 446 (M'-1). 94. Ethyl-4-methyl-3-(4-sulfamoylphenyl)-5-(4-trifluoromethoxy)phenyl)thiophene-2-carboxylate

M5: mass/charge 486 (M'-1). 104. Ethyl-4-methyl-3-(4-sulfamoylphenyl)-5-(p-tolyluthiophene-2-carboxylate)

M5: mass/charge 416 (M'-1). 124. Ethyl-5-(4-(dimethylamino)phenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate

M5: mass/charge 445 (M'-1). 13a. Ethyl 5-(3-fluorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate

From M5: mass/charge 420 (M-n1). 14d4. Ethyl 4-methyl-5-phenyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate

M5: mass/charge 402 (M'-1). 154. Ethyl 5-(3-ethoxyphenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate

M5: mass/charge 446 (M'-1). 164. Ethyl 5-(4-ethylphenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate

M5: mass/charge 430 (M'-1). 2540. Ethyl-4-methyl-5-(pyridin-4-yl)-3-(4-sulfamoylphenyl)thiophene-2-carboxylate

M5: mass/charge 403 (M'-1). 264. Ethyl-4-methyl-5-(pyridin-3-yl)-3-(4-sulfamoylphenyl)thiophene-2-carboxylate

M5: mass/charge 403 (M-n1). 274. Ethyl-5-(furan-3-yl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate

M5: mass/charge 392 (M'-1). 284. Ethyl 5-(1H-indol-5-yl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate

M5: mass/charge 441 (M'1). 294. Ethyl-4-methyl-5-(1-methyl-1H-indol-5-yl)-3-(4-sulfamoylphenyl)thiophene-2-carboxylate

M5: mass/charge 455 (M'-1). not Ethyl 5-(benzofuran-5-yl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate

M5: mass/charge 442 (M'n1). 314. Ethyl 5-(1-acetylindolin-5-yl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate

M5: mass/charge 485 (M-n1). 444. Ethyl-5-(4-(tert-butoxycarbonyl)methyl)amino)phenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate

M5: mass/charge 531 (M'-1).

Step 5: 5-(4-Methoxyphenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid (7e)

n.mOo,5 o what but Osn"

Methyl 5-(4-methoxyphenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate (compound 7, 3.02 g, 7.24 mmol) was suspended in ethanol (50 mL) and Mason added (1.44 g, 36.2 mmol) in 10 ml of water at 25 "C. The reaction mixture was heated at 50-55 "C with shaking for 2 hours.

The course of the reaction was observed with the help of TI C. Then the reaction mixture was concentrated under reduced pressure. 50 ml of water was added to the resulting residue and the mixture was cooled using an ice bath. Then aqueous hydrochloric acid (10965) was added to the mixture to bring the pH to 5-6. Then the mixture was extracted with ethyl acetate (2 x 75 ml). The combined organic layer was dried over anhydrous Mag5O5. The solvent was evaporated under reduced pressure to give the product (2.83 g, 9790).

M5: mass/charge 404 (M'-1). "NMR (0M5O, 400 MHz): b 12.85 (p5-exchanges with 020, 1H), 7.86 (y, 9U-8.4 Hz, 2H), 7.45-7.50 (t,

AN), 7.45 (p5-exchanges with 020, 2H), 7.07 (y, 9-84 Hz, 2H), 3.81 (5, ЗН), 1.90 (5, ЗН).

The compounds below were prepared by a procedure similar to that described above for compound Te, with appropriate variations in reactants, reaction conditions, and amounts of reagents.

Ze. 5-(3-Chlorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid

M5: mass/charge 408 (M'-1).

Be. 5-(4-Cyclopropylphenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid

M5: mass/charge 414 (M'-1). eh 4-Methyl-3-(4-sulfamoylphenyl)-5-(4-trifluoromethyl)phenyl)thiophene-2-carboxylic acid

M5: mass/charge 442 (M'n1). ve. 5-(4-Ethoxyphenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid

M5: mass/charge 418 (M'-1). where. 4-methyl-3-(4-sulfamoylphenyl)-5-(4-trifluoromethoxy)phenyl)thiophene-2-carboxylic acid

M5: mass/charge 458 (M.-n1). 10th 4-Methyl-3-(4-sulfamoylphenyl)-5-(p-tolyluthiophene-2-carboxylic acid)

M5: mass/charge 388 (M'-1). 12th century 5-(4-(Dimethylamino)phenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid

M5: mass/charge 417 (M'1).

From 1Ze. 5-(3-Fluorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid

M5: mass/charge 392 (M'-1). 14 4-methyl-5-phenyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid

M5: mass/charge 374 (M'-1). 15th century 5-(3-Ethoxyphenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid

M5: mass/charge 418 (Mn1). eh 5-(4-Ethylphenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid

M5: mass/charge 402 (M'-1). 25th 4-Methyl-5-(pyridin-4-yl)-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid

M5: mass/charge 375 (M'-1). 2be. 4-Methyl-5-(pyridin-3-yl)-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid

M5: mass/charge 375 (M'-1). 27th 5-(Furan-3-yl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid

M5: mass/charge 364 (M'-1). 28th 5-(1H-indol-5-yl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid

M5: mass/charge 413 (M-n1). 29th 4-methyl-5-(1-methyl-1H-indol-5-yl)-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid

M5: mass/charge 427 (M'1).

zabe 5-(Benzofuran-5-yl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid

M5: mass/charge 414 (M'-1).

Z1e. 5-(1-acetylindolin-5-yl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid

M5: mass/charge 457 (M'-1). 44e. 5-(4-(Tert-butoxycarbonyl)methyl)amino)phenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid

M5: mass/charge 503(M--1).

Step 6: 3-(4-(M-(Dimethylamino)methylene)sulfamoyl)phenyl)-M-methoxy-5-(4-methoxyphenyl)-

M,4-dimethylthiophene-2-carboxamide (71) in; 87 yo with A om, Osn"

Oxalyl chloride (1.77 g, 1.2 ml, 13.9 mmol) was added dropwise at 0 "C to a solution of 5-(4-methoxyphenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2 -carboxylic acid (compound 7e, 2.8 g, 6.94 mmol) in a mixture of dichloromethane (75 mL) and OME (1.01 g, 1.1 mL, 13.89 mmol). The resulting mixture was allowed to reach room temperature and was shaken for 1.5 hours under a nitrogen atmosphere. The progress of the reaction was monitored by TIS. The reaction mixture was then concentrated under reduced pressure. The resulting residue was dissolved in dry dichloromethane (75 mL) and triethylamine (2.8 g, 3, 9 ml, 27.76 mmol) followed by the addition of M,O-dimethylhydroxylamine hydrochloride (1.35 g, 13.89 mmol) with shaking.

Then the reaction mixture was shaken at room temperature for 2 hours. The course of the reaction was monitored by TIS. Then the reaction mixture was washed with water (2 x 25 ml), the resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography on silica gel (100-200 mesh) using 8095 ethyl acetate in hexane as eluent to give the title compound (2.73 g, 78965).

M5: mass/charge 502 (M'-1). "NMR (SOSI", 400 MHz): b 8.16 (5, 1H), 7.95 (y, 9U-8.4 Hz, 2H), 7.45 (a, 9-84 Hz, 2H), 7.39 (a, 928.4 Hu, 2H), 7.00 (a, 9-84 Hu, 2H), 3.88 (5, ЗН), 3.70 (5, ЗН), 3.19 ( 5, ZN), 3.17 (5, ZN), 3.07 (in,

ZN), 2.00 (5, ZN).

The compounds below were prepared by a procedure similar to that described above for compound "7" with appropriate variations in reactants, reaction conditions, and amounts of reagents

ZI. 5-(3-Chlorophenyl)-3-(4-(M-((dimethylamino)methylene)sulfamoyl)phenyl)-M-methoxy-M,4-dimethylthiophene-2-carboxamide

M5: mass/charge 506 (M'-1).

B. 5-(4-"Cyclopropylphenyl)-3-(4-"M-((dimethylamino)methylene)sulfamoyl)phenyl)-M-methoxy-

M,4-dimethylthiophene-2-carboxamide

M5: mass/charge 512 (M'-1).

From b. 3-(4-(M-(Dimethylamino)methylene)sulfamoyl)phenyl)-M-methoxy-M,4-dimethyl-5-(4-(trifluoromethyl)phenyl)thiophene-2-carboxamide

M5: mass/charge 540 (M'-1). 8. 3-(4-((M-((Dimethylamino)methylene)sulfamoyl)phenyl)-5-(4-ethoxyphenyl)-M-methoxy-M,4-dimethylthiophene-2-carboxamide

M5: mass/charge 516 (M-n1). 9. 3-(4-(M-(Dimethylamino)methylene)sulfamoyl)phenyl)-M-methoxy-M,4-dimethyl-phenyl)-5-(4-(trifluoromethoxy)phenyl)thiophene-2-carboxamide

M5: mass/charge 556 (M'-1). 10. 00 3-(4-(M-(Dimethylamino)methylene)sulfamoyl)phenyl)-M-methoxy-M,4-dimethyl-phenyl)-5- (4-(p-tolyluthiophene-2-carboxamide

M5: mass/charge 486 (M'-1). 121. 3-(4-(M-((Dimethylamino)methylene)sulfamoyl)phenyl)-5-(4-(dimethylamino)phenyl)-M-methoxy-M,4-dimethylthiophene-2-carboxamide

M5: mass/charge 515 (M'-1). 131. 3-(4-((M-((Dimethylamino)methylene)sulfamoyl)phenyl)-5-(3-fluorophenyl)-M-methoxy-M,4-dimethylthiophene-2-carboxamide

M5: mass/charge 490 (M'-1). 141. 3-(4-(M-(Dimethylamino)methylene)sulfamoyl)phenyl)-M-methoxy-M,4-dimethyl-5-phenylthiophene-2-carboxamide

M5: mass/charge 472 (M-n1).

15 00 3-(4-(M-(dimethylamino)methylene)sulfamoyl)phenyl)-5-(3-ethoxyphenyl)-M-methoxy-M,4-dimethylthiophene-2-carboxamide

M5: mass/charge 516 (M'-1). 161. 3-(4-(M-(Dimethylamino)methylene)sulfamoyl)phenyl)-5-(4-ethylphenyl)-M-methoxy-M,4-dimethylthiophene-2-carboxamide

M5: mass/charge 500 (M'-1). 2. 3-(4-(M-(Dimethylamino)methylene)usulfamoyl)phenyl)-M-methoxy-M,4-dimethyl-5-(pyridin-4-ylthiophene-2-carboxamide)

M5: mass/charge 473 (M'-1). 261. 3-(4--"M-"(Dimethylamino)methylene)usulfamoyl)phenyl)-M-methoxy-M,4-dimethyl-5-(pyridine-

Z-iluthiophene-2-carboxamide

M5: mass/charge 473 (M'-1). 2. 3-(4-(M-((Dimethylamino)methylene)sulfamoyl)phenyl)-5-(furan-3-yl)-M-methoxy-M,4-dimethylthiophene-2-carboxamide

M5: mass/charge 462 (M-n1). 28. 3-(4-((M-((Dimethylamino)methylene)sulfamoyl)phenyl)-5-(1H-indol-5-yl)-M-methoxy-M,4-dimethylthiophene-2-carboxamide

M5: mass/charge 511 (M'-1). 291. 3-(4-(M-(Dimethylamino)methylene)sulfamoyl)phenyl)-M-methoxy-M,4-dimethyl-5-(1-methyl-1H-indole-5-iluthiophene-2-carboxamide

M5: mass/charge 525 (M'-1).

ZOE. 5-(Benzofuran-5-yl)-3-(4-"M-((dimethylamino)methylene)sulfamoyl)phenyl)-M-methoxy-M,4-dimethylthiophene-2-carboxamide

M5: mass/charge 512 (M'-1).

C11. 5-(1-acetylindolin-5-yl)-3-(4-(M-((dimethylamino)methylene)sulfamoyl)phenyl)-M-methoxy-

M,4-demethylthiophene-2-carboxamide

M5: mass/charge 555 (M'-1).

HELL. tert-butyl-(4-(4-(4-(M-((dimethylamino)methylene)sulfamoyl)phenyl)-5-(methoxy(methyl)carbamoyl)-3-methylthiophene-2-ylphenylmethyl)carbamate

From M5: mass/charge 601 (M-n1).

Step 7: 4-(5-(4-Methoxyphenyl)-4-methyl-2-propionylthiophen-3-yl)benzenesulfonamide (compound 7)

NoMmO»5 o) / x more

Osn"

Grignard's reagent (ethylmagnesium bromide, 3.59 g, 26.8 ml, 26.94 mmol) was added drop by drop to a solution of /3-(4-(M-«((dimethylamino)methylene)sulfamoyl)phenyl)-M- of methoxy-5-(4-methoxyphenyl)-M,4-dimethylthiophene-2-carboxamide (compound 71, 2.7 g, 5.8 mmol) with shaking in anhydrous TNE (100 mL) at 25 "C and reaction the mixture was heated at from about 70 "C to about 75 "C for 1 hour. The course of the reaction was monitored by TI C. After cooling the reaction mixture to 0 "C, the reaction mixture was quenched by adding a saturated solution of ammonium chloride (50 ml) and obtained in the resulting mixture was extracted with ethyl acetate (2 x 100 ml).

The combined organic layer was dried over anhydrous Ma»25O:. The solvent was evaporated from the dried organic layer under reduced pressure to give the crude product, which was purified by preparative NRI C to give the title compound (0.84 g, 37905).

M5: mass/charge 416 (M'-1).

I"NMR (SOS, 400 MHz): b 8.00 (a, 9-84 Hz, 2H), 7.40-7.43 (t, 4H), 6.97 (j, 9U-8.4 Hz , 2H), 4.87 (p5-exchanges with O2O, 2H), 3.85 (5, ZN), 2.53 (d, 9U-7.2 Hz, 2H), 1.93 (5, ZN) , 1.03 (, 9U-7.2 Hz, ZN).

The following compounds were prepared according to the procedure described above, but with appropriate changes in the reactants. 4-(5-(3-Chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)/benzenesulfonamide (compound 3)

M5: mass/charge 420 (M-n1). "NMR (0M5O, 400 MHz): b 7.93 (a, 9U-8.4 Hz, 2H), 7.62 (Her, 9-24 Hz, 1H), 7.53-7.56 (t, 5H), 7.49 (re-exchanges with 020, 2H), 2.38 (4, U9-7.2 Hz, 2H), 1.93 (5, ЗН), 0.88 (I, 9U-7 ,2 Hz, ЗН. 4-(5-(4-Cyclopropylphenyl)-4-methyl-2-propionylthiophen-3-yl)/benzenesulfonamide (compound 5)

M5: mass/charge 426 (M.-n1).

I"NMR (SOSI", 400 MHz): b 8.01 (a, 9-84 Hz, 2H), 7.43 (y, 9-8.4 Hz, 2H), 7.38 (a, 9- 8.0 Hz, 2H), 7.15 (a, 9U-8.0 Hz, 2H), 4.87 (p5-exchanges with 020, 2H), 2.55 (d, 9U-7.2 Hz, 2H), 1.91-1.97 (t, 4H), 1.01-1.06 (t, 5H), 0.75-0.78 (t, 2H). 4-(4-methyl-2 -propionyl-5-(4-«(trifluoromethyl)phenyl)thiophen-3-yl)/ubenzenesulfonamide (compound 6)

M5: mass/charge 454 (M'-1). "NMR (SOSI", 400 MHz): b 8.03 (a, 9-84 Hz, 2H), 7.72 (9, 9-8.0 Hz, 2H), 7.61 (a, U-8 .4 Hz, 2H), 7.43 (a, 9-8.0 Hz, 2H), 5.02 (rB5-exchanges with 020, 2H), 2.54 (d, 9-72 Hz, 2H), 1.97 (5, ZN), 1.04 (I, 20-72

Gu, ZN). 4-(5-(4-Ethoxyphenyl)-4-methyl-2-propionylthiophen-3-yl)ubenzenesulfonamide (compound 8)

M5: mass/charge 430 (M'-1).

I"NMR (SOSI"z, 400 MHz): b 8.01 (a, 9-88 Hz, 2H), 7.42 (y, 9-8.4 Hz, 2H), 7.40 (a, 9 -8.4 Hz, 2H), 6.95 (y, 9U-8.8 Hz, 2H), 4.88 (p5-exchanges with 020, 2H), 4.08 (ad, U-6.8 Hz , 2H), 2.54 (4, 9-72 Hz, 2H), 1.93 (5, ZN), 1.44 (I, 9-68 Hz, ZN), 1.03 (I, 9-7 4-(4-methyl-2-propionyl-5-(4-(trifluoromethoxy)phenyl)thiophen-3-yl)benzenesulfonamide (compound 9)

M5: mass/charge 470 (M'-1). "NMR (SOSI", 400 MHz): b 8.04 (a, 9-84 Hz, 2H), 7.52 (0.9-8.0 Hz, 2H), 7.44 (a, 9-8 .4 Hz, 2H), 7.31 (a, 9U-8.0 Hz, 2H), 4.98 (b5-exchanges with 020, 2H), 2.55 (d, U-7.2 Hz, 2H ), 1.95 (5, ZN), 1.05 (I, 9-72

Hz, ZN). 4-(4-methyl-2-propionyl-5-(4-tolyluthiophen-3-yl)ubenzenesulfonamide (compound 10)

M5: mass/charge 400 (M'-1).

I"NMR (0M50O, 400 MHz): b 7.92 (y, 9-8.4 Hz, 2H), 7.55 (y, 9U-8.4 Hz, 2H), 7.49 (B5-exchanges with rgo, 2H), 7.45 (a, 9-8.4 Hz, 2H), 7.33 (a, 9-84 Hz, 2H), 2.33-2.36 (t, 5H), 1 .92 (5, ZN), 0.87 (I, 9-72

Hz, ZN). 4-(5-(4-tert-butylphenyl)-4-methyl-2-propionylthiophen-3-yl)ubenzenesulfonamide (compound 11)

M5: mass/charge 442 (M'n1). "NMR (SOSI", 400 MHz): b 8.02 (y, 9U-8.4 Hz, 2H), 7.42-7.49 (t, 6H), 4.92 (rz-exchanges with 020, 2H), 2.56 (d, 9-72 Hz, 2H), 1.97 (5, ЗН), 1.36 (5, 9Н), 1.06 (I, 9-7.2 Hz, ЗН) 4-(5-(4-Dimethylamino)phenyl)-4-methyl-2-propionylthiophen-3-yl)benzenesulfonamide (compound 12)

M5: mass/charge 429 (M'-1).

I"NMR (SOSI", 400 MHz): b 8.01 (a, 9-84 Hz, 2H), 7.44 (y, 9-8.4 Hz, 2H), 7.40 (a, 9- 88 Hz, 2H), 6.77 (a, 9-8.8 Hz, 2H), 4.83 (p5-exchanges with O2O, 2H), 3.03 (5, 6H), 2.55 (ad, 9U-7.2 Hz, 2H), 1.97 (5, ЗН), 1.05 (, 9-72 Hu, ЗН). 4-(5-(3-Fluorophenyl)-4-methyl-2-propionylthiophene -3-yl)ubenzenesulfonamide (compound 13)

M5: mass/charge 404 (M--1).

I"NYMR (SOSI"z, 400 MHz): b 8.02 (a, 9U-8.4 Hz, 2H), 7.40-7.46 (t, ЗН), 7.26-7.29 ( t, 1H), 7.18-7.21 (t, 1H), 7.09-7.14 (t, 1H), 5.09 (re-exchange with 020, 2H), 2.55 (d, 9U-7.2 Hz, 2H), 1.96 (5, ZN), 1.03 (and 9U-7.2 Hz, ZN). 4-(4-methyl-5-phenyl-2-propionylthiophene-3 -yl)benzenesulfonamide (compound 14)

M5: mass/charge 386 (M'-1).

I"NMR (0M50, 400 MHz): b 7.93 (a, 9-84 Hz, 2H), 7.45-7.57 (t, 9H), 2.36 (4, 9-7.2 Hz , 2H), 1.93 (5, ЗН), 0.88 (I, 9-7.2 Hz, ЗН). 4-(5-(3-Ethoxyphenyl)-4-methyl-2-propionylthiophene-3- yl)ubenzenesulfonamide (compound 15)

M5: mass/charge 430 (M'-1).

I"NMR (SOSI"z, 400 MHz): b 8.01 (4, 9-8.4 Hz, 2H), 7.42 (a, 9-84 Hz, 2H), 7.34 (I, 9U -8.0 Hz, 1H), 7.05 (yes, 9U-8.0, 2.0 Hz, 1TN), 6.99 (Her, 9U-2.0 Hz, 1H), 6.92 (yes , 9U-8.0, 2.0 Hz, 1H), 5.07 (B5-exchanges with 020, 2H), 4.06 (a, 9-7.2 Hz, 2H), 2.53 (d, 9-7.2 Hz, 2H), 1.95 (5, ZN), 1.42 (I, 9-72 Hz, ZN), 1.02 (i, 9-72 Hz, ZN). 4-( 5-(4-Ethylphenyl)-4-methyl-2-propionylthiophen-3-yl)benzenesulfonamide (compound 16)

M5: mass/charge 414 (M'-1). NMR (SOSI»z, 400 MHz): 6 8.02 (a, 9U-8.4 Hz, 2H), 7.45 (a, 9U-8.0 Hz, 2H), 7.42 (I, 9U-8.0 Hz, 2H), 7.29 (y, 9-8.4 Hz, 2H), 5.00 (B5-exchanges with 020, 2H), 2.72 (4, 9-7.6 Hz, 2H), 2.54 (4, 9U-7.2 Hz, 2H), 1.96 (5, ZN), 1.28 (Her, U-7.6 Hz, ZN), 1.04 ( I, 9U-7.2 Hz, ЗН. 4-(4-methyl-2-propionyl-5-(pyridin-4-iluthiophen-3-yl)ubenzenesulfonamide (compound 25)

M5: mass/charge 387 (M'-1).

I"NMR (0M50, 400 MHz): b 8.71 (a, 9-84 Hz, 2H), 7.93 (a, 9U-8.4 Hz, 2H), 7.57-7.59 (t , 4H), because 7.50 (rz-exchange with O2O, 2H), 2.39 (ad, 9-7.2 Hz, 2H), 1.98 (5, ЗН), 0.88 (I, 9U -7.2 Hz, ZN).

4-(4-methyl-2-propionyl-5-(pyridin-3-iluthiophen-3-yl)ubenzenesulfonamide (Compound 26)

M5: mass/charge 387 (M'-1).

I"NMR (0M50O, 400 MHz): b 8.77-8.78 (t, 1H), 8.66 (ai, 9U-8.8, 1.6 Hz, 1H), 7.99-8, 02 (t, 1H), 7.94 (a, U-8.8 Hz, 2H), 7.54-7.58 (t, ЗН), 7.50 (re-exchanges with 020, 2H), 2 .38 (d, 9-7.2 Hz, 2H), 1.94 (5, ЗН), 0.688 (I, 9-7.2 Hz, ЗН). 4-(5-(Furan-3-yl) -4-methyl-2-propionylthiophen-3-yl)/benzenesulfonamide (compound 27)

M5: mass/charge 376 (M'-1).

I"NMR (SOSI", 400 MHz): 6 8.01 (a, U-8.8 Hz, 2H), 7.68-7.69 (t, 1H), 7.51 (Her, 9-16 Hz, 1H), 7.38 (a, 9U-8.4 Hz, 2H), 6.64-6.65 (t, 1H), 4.88 (re-exchanges with 020, 2H), 2.49 (d, 9-7.2 Hz, 2H), 1.96 (5, ЗН), 1.02 (, 9-7.2 Hu, ЗН). 4-(5-(1H-indol-5-yl) )-4-methyl-2-propionylthiophen-3-yl)/ubenzenesulfonamide (compound 28)

M5: mass/charge 425 (M.-H1). NMR (0M5O, 400 MHz): b 11.3 (p5-exchanges with 020, 1H), 7.92 (a, 9U-8.4 Hz, 2H), 7.74-7.75 (t, 1H ), 7.58 (9, U-8.4 Hz, 2H), 7.52 (y, 9U-8.4 Hz, 1H), 7.49 (b5-exchanges with 020, 2H), 7.45 (I, 9U-2.8 Hz, 1H), 7.27 (aa, 9-8.4, 1.6 Gu, 1H), 6.52-6.53 (t, 1H), 2.36 ( 4, 9-7.2 Hz, 2H), 1.96 (5, ЗН), 0.85 (I, 9-7.2 Hz,

ZN). 4-(4-methyl-5-(1-methyl-1H-indol-5-yl)-2-propionylthiophen-3-yl)/benzenesulfonamide (compound 29)

M5: mass/charge 439 (M'-1). "NMR (0M5O, 400 MHz): b 7.92 (a, 9-84 Hz, 2H), 7.75 (5, 1H), 7.56-7.58 (t, ЗН), 7.49 ( rv- exchanges with 020, 2H), 7.43 (a, U-2.8 Hz, 1H), 7.34 (a, 9U-8.4 Hz, 1H), 6.52 (j, 9-28 Hz, 1H), 3.83 (5, ЗН), 2.37 (a, U9-7.2 Hz, 2Н), 1.96 (5, ЗН), 0.88 (I, 9У-7.2 4-(5-(Benzofuran-5-yl)-4-methyl-2-propionylthiophen-3-yl)/'benzenesulfonamide (compound 30)

M5: mass/charge 426 (M'-1).

I"NMR (0M50O, 400 MHz): 6 8.10 (5, 1H), 7.93 (a, 9U-8.0 Hz, 2H), 7.86 (5, 1H), 7.75 (y , U-8.4 Hz, 1H), 7.58 (y, 9-8.0 Hz, 2H), 7.48 (t, ЗН), 7.05 (5, 1H), 2.37 ( . -2-propionylthiophen-3-yl)ubenzenesulfonamide (compound 31)

M5: mass/charge 427 (M'1).

I"NMR (SOSI", 400 MHz): b 7.99 (y, 9U-8.4 Hz, 2H), 7.40 (a, 9-84 Hz, 2H), 7.23 (5, 1H) , 7,14-7,16

Zo (t, 1H), 6.66 (a, 9U-8.0 Hz, 1H), 5.72 (rb5-exchanges with 020, 2H), 3.63 (I, U-8.4 Hz, 2H ), 3.08 (i, 9U-8.4 Hz, 2H), 2.46 (a, 9-7.2 Hz, 2H), 2.01 (p5-exchanges with 020, 1H), 1.93 (5, ZN), 1.01 (I, 9U-7.2 Gu, ZN). 4-(4-methyl-5-(4-(4-methylpiperazin-1-yl)uphenyl)-2-propionylthiophen-3-yl)benzenesulfonamide (compound 32)

M5: mass/charge 484 (M'-1).

I"NMR (0M5O, 400 MHz): b 7.90 (a, U-8.4 Hz, 2H), 7.49 (y, 9-84 Hz, 2H), 7.41 (a, 9U-8 .4 Hz, 2H), 7.04 (y, 9-84 Hz, 2H), 5.04 (p5-exchanges with 020, 2H), 3.28-3.29 (t, 4H), 2.74 -2.75 (t, 4H), 2.41 (5,

ЗН), 2.33 (а, 9У-7.2 Hz, 2Н), 1.88 (5, ЗН), 0.85 (I, 9У-7.2 Hz, ЗН). 4-(4-methyl-5-(4-methylaminophenyl)-2-propionylthiophen-3-yl)ubenzenesulfonamide (compound 44)

M5: mass/charge 415 (M'-1). "NMR (0M5O, 400 MHz): b 7.90 (a, 9-84 Hz, 2H), 7.52 (y, 9-8.4 Hz, 2H), 7.47 (re-exchanges with

Wow, 2H) 7.31 (y, 9U-8.4 Hz, 2H), 6.63 (0, 9-84 Hz, 2H), 6.11 (d, U-4.8 Hz, exchanges with Yu2O . -7.2 Gu, ZN).

Example 4: Preparation of methyl-4-methyl-5-(2-oxoindolin-5-yl)-3--4-sulfamoylphenyl)thiophene-2-carboxylate (compound 42) and ethyl-4-methyl-5-(2- oxoindolin-5-yl)-3-(4-sulfamoylphenyl)thiophene-2-carboxylate (compound 43)

The following procedure, similar to that presented for the compound of formula 7 (step 4 of example 3), and the replacement of 4-methoxyphenylboronic acid with the corresponding boronic acid or a similar reagent, compounds of formula 42 and 43 were obtained.

Methyl-4-methyl-5-(2-oxoindolin-5-yl)-3-(4-sulfamoylphenyl)thiophene-2-carboxylate (compound 5BO 42)

M5: mass/charge 443 (M'-1).

NMR (0M5O, 400 MHz): b 10.60 (p5-exchanges with 020, 1H), 7.88 (a, 9U-8.4 Hz, 2H), 7.49 (y, 9U-8, 4

Hz, 2H), 7.40 (p5-exchanges with 020, 2H), 7.37-7.39 (t, 2H), 6.94 (y, 9U-8.0 Hz, 1H), 3.64 (5, ZN), 3.56 (5, 2H), 1.96 (5, ZN).

Ethyl 4-methyl-5-(2-oxoindolin-5-yl)-3-(4-sulfamoylphenyl)thiophene-2-carboxylate (compound 4Z)

M5: mass/charge 457 (M.-H1). "NMR (0ОМ50О, 400 MHzu): 6 10.59 (p5-exchanges with 020, 1Н), 7.86 (y, 9У-8.4 Hz, 2Н), 7.49 (а, 9-84

Hz, 2H), 7.41 (p5-exchanges with 020, 2H), 7.37-7.39 (t, 2H), 6.94 (y, 9U-8.0 Hz, 1H), 4.08 (d, 9-72 Hz, 2H), 60 3.56 (5, 2H), 1.96 (5, ЗН), 1.07 (I, 9-7.2 Hz, ЗН).

Example 5: Preparation of 4-(5-(4-chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)-M,M-dimethylbenzenesulfonamide (compound 45) -

IN

(c) 39-

WITH

(o) and 4-(5-(4-chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)-M-methylbenzenesulfonamide (compound 46)

NM. o rya (e)

Ua with Fr

To a solution of 4-(5-(4-chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)/'benzenesulfonamide (compound 1, 0.50 g, 1.19 mmol) in acetonitrile (15 ml) was added KCO3 (0.25 g, 1.84 mmol) at room temperature and shaken for 15 minutes. Methyl iodide (0.20 g, 0.08 ml, 1.42 mmol) was added to it. The resulting mixture was shaken at room temperature for 15 hours. The course of the reaction was monitored with TI! C. Then the reaction mixture was concentrated under reduced pressure. The concentrated mass was diluted with water (20 ml). The resulting mixture was extracted with ethyl acetate (3 x 30 ml). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product.

The resulting crude product was purified by column chromatography on silica gel (100-200 mesh) using 4095 ethyl acetate in hexanes as eluent to give the first title compound (0.05 g, 9.38905) and the second title compound (0.045 g, 8.790).

The first title compound: 4-(5-(4-chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)-M,M-dimethylbenzenesulfonamide (compound 45) and in / 5 2-4 5 (9)

M5: mass/charge 448 (M'-1). "NMR (0M50O, 400 MHz): b 7.86 (y, 9-84 Hz, 2H), 7.60-7.65 (t, 6H), 2.65 (v, 6H), 2.32 ( ad, 9U-7.2 Hz, 2H), 1.94 (5, ZN), 0.86 (I, 9U-7.2 Hz, ZN).

The second title compound: 4-(5-(4-chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)-M-methylbenzenesulfonamide (compound 46)

Her father

NM. / in / 5 7-4 5 o;

M5: mass/charge 434 (M'-1). "NMR (0M5O, 400 MHz): b 7.87 (y, 9-84 Hz, 2H), 7.55-7.65 (t, 7H), 2.46 (y, 9-48 Hz, ЗН) ,

Зо 2.34 (а, 9-7.2 Hz, 2Н), 1.93 (5, ЗН), 0.86 (И, 9-7.2 Hz, ЗН).

Example 6: Preparation of 4-(5-(4-chlorophenyl)-4-(dimethylamino)methyl)-2-propionylthiophen-3-yl/ubenzenesulfonamide (compound 35)

NMO,»5 / sha

M

3-7 at 5

Nzo

Step 1: Ethyl 4-(bromomethyl)-5-(4-chlorophenyl)-3-(4-sulfamoylphenyl)thiophene-2-carboxylate (Zba)

PA e us Vg zmo /x v o si

To a solution of / ethyl 5-(4-chlorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate (compound 16, 4.0 g, 9.17 mmol), which was shaken, in chlorobenzene ( 50 ml) was added MV5 (1.77 g, 10.09 mmol) and AIVM (1.65 g, 10.09 mmol) at 25 "C. Then the reaction mixture was shaken at 857 for 4 hours. The progress of the reaction was monitored using TI C. Then the reaction mixture was cooled to room temperature and quenched with an aqueous solution of sodium chloride (50 ml).

Then the resulting mixture was extracted with ethyl acetate (2 x 50 ml). The organic layer was washed with saline (1 x 50 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the crude product (4.0 g). The crude product was then purified by column chromatography on silica gel (100-200 mesh) using 4095 ethyl acetate in hexanes as eluent to give the title compound (2.8 g, 59.32965).

M5: mass/charge 516 (M'-1). "NMR (0M5O, 400 MHz): b 7.90 (y, 9-84 Hz, 2H), 7.59-7.71 (t, 4H), 7.58 (y, 9U-8.4 Hz, 2H), 7.51 (rz-exchanges with O2O, 2H) 4.29 (5, 2H), 4.10 (d, U-6.8 Hz, 2H), 1.06 (Her, 9U-6, 8 Hz, ZN).

Step 2: Ethyl 4-(bromomethyl)-5-(4-chlorophenyl)-3-(4-(M- ((dimethylamino)methylene)sulfamoyl)phenyl)thiophene-2-carboxylate (356)

MIND

-m tu o

I'm sorry

To a suspension of ethyl 4-(bromomethyl)-5-(4-chlorophenyl)-3-(4-sulfamoylphenyl)thiophene-2-carboxylate (compound 35a, 2.7 g, 5.24 mmol) in ethyl acetate (30 ml) was added

OME (1.91 g, 2.01 mL, 26.2 mmol) and M,M-dimethylformamide dimethyl acetal (OME acetal) (0.69 g, 0.76 mL, 5.76 mmol) under nitrogen at room temperature (approximately 25 C).

Then the reaction mixture was shaken at room temperature (approximately 25 "C) for 4 hours. The progress of the reaction was monitored by TIS. The reaction mixture was concentrated under reduced pressure to obtain 2.9 g of the crude product. Then the obtained crude

The product was purified by column chromatography on silica gel (100-200 mesh) using 1.595 methanol in OSM as eluent to give the title compound (2.2 g, 73.82960).

M5: mass/charge 571 (M'1).

I"NMR (0M5O, 400 MHz): 6 8.23 (5, 1H) 7.85 (y, 9U-8.4 Hz, 2H), 7.62-7.75 (t, 4H), 7, 52 (y, 9-84

Hz, 2H), 4.29 (5, 2H), 4.07 (ad, 9U-7.2 Hz, 2H), 3.15 (5, ЗН) 2.94 (5, ЗН), 1.01 (1.9U-7.2 Hz, ZN).

Step C: Ethyl 5-(4-chlorophenyl)-4-((dimethylamino)methyl)-3-(4-(M- ((dimethylamino)methylene)sulfamoyl)phenyl)thiophene-2-carboxylate (35c)

EM

M ooh- xY,

M

And about that

To the suspension of ethyl-4-(bromomethyl)-5-(4-chlorophenyl)-3-(4-(M- ((dimethylamino)methylene)sulfamoyl)phenyl)thiophene-2-carboxylate (compound 35B, 2.20 g, 3.86 mmol), stirring in benzene (30 ml), dimethylamine (0.69 g, 7.6 ml of a 2 M solution in TNE, 15.4 mmol) was added dropwise at 0 "C. Then the reaction mixture was shaken at room temperature (approximately 25 "C) for 16 hours. The course of the reaction was monitored using

TS. The reaction mixture was then concentrated to obtain the crude product as a semi-solid substance (2.38 g). The resulting crude product was purified by column chromatography on silica gel (100-200 mesh) using 1.295 methanol in OSM as eluent to give the title compound (1.1 g, 53.39965).

M5: mass/charge 534 (M'-1).

I"NMR (SOSI", 400 MHz): b 8.16 (5, 1H), 7.93 (y, 9U-8.4 Hz, 2H), 7.66 (y, 9-84 Hz, 2H) , 7.39-7.42 (t, 4H), 4.14 (ad, 9-7.2 Hz, 2H), 3.15 (5, ЗН), 3.07 (5, 2H), 3, 04 (5, ZN), 1.85 (5, 6H), 1.13 (I, 9-72 Gu,

ZN).

Step 4: 5-(4-Chlorophenyl)-4-((dimethylamino)methyl)-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid (354)

N.M. your o)

AND,

M no0 Z even more

Ethyl 5-(4-chlorophenyl)-4-((dimethylamino)methyl)-3-(4-(M- ((dimethylamino)methylene)sulfamoyl)phenyl)thiophene-2-carboxylate (compound C35c, 1.0 g , 1.87 mmol) was suspended in ethanol (20 ml) and a solution of Mahon (0.37 g, 9.36 mmol) in water (2 ml) was added to it at 25 °C. The reaction mixture was heated at 75 °C with shaking within 2 hours. The course of the reaction was observed using TI C. The reaction mixture was concentrated under reduced pressure. Then the obtained residue was diluted with water (5 ml) and cooled using an ice bath. Then, aqueous 1095 NCI was added to the cooled mixture, bringing the pH of the mixture to 5-6. The resulting solid was filtered and dried under reduced pressure to give the title compound (0.8 g, 94.78905).

M5: mass/charge 451 (M'-1).

From I"NMR (0M50O, 400 MHz): b 12.85 (rz-exchanges with 020, 1H), 7.86 (a, 9U-8.0 Hz, 2H), 7.70 (a, 9U-8 ,0

Hz, 2H) 7.52-7.60 (t, 4H), 7.49 (rz-exchanges with 20, 2H), 3.61 (v, 2H), 1.97 (v, 6H).

Step 5: 5-(4-Chlorophenyl)-4-((dimethylamino)methyl)-3-(4-(M- ((dimethylamino)methylene)sulfamoyl)phenyl)-M-methoxy-M-methylthiophene-2-carboxamide (Z35e)

ish ey and M

Y x o-M / 8 C and si

Oxalyl chloride (0.39 g, 0.26 ml, 3.1 mmol) was added dropwise at 0 "C to a solution of /5-(4-chlorophenyl)-4-((dimethylamino)methyl)-3-(4 -sulfamoylphenyl)thiophene-2-carboxylic acid (compound 354, 0.7 g, 1.55 mmol) in a mixture of dichloromethane (25 mL) and OME (0.27 g, 0.24 mL, 3.10 mmol). the mixture was allowed to reach room temperature and shaken for 1.5 hours under a nitrogen atmosphere. The course of the reaction was monitored by TI C. Then the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in dry dichloromethane (25 ml), cooled to 0 "C and triethylamine (0.94 g, 1.3 mL, 9.31 mmol) was added to it, followed by the addition of M,O-dimethylhydroxylamine hydrochloride (0.3 g, 3.1 mmol) with stirring. Then the reaction mixture was shaken at room temperature for 2 hours. The course of the reaction was observed with the help of TI C. Then the reaction mixture was diluted

ORSM (25 ml) and washed with water (2 x 25 ml), the obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product.

The obtained crude product was purified by column chromatography on silica gel (100-200 mesh) using 69% methanol in OSM as eluent to give the title compound (0.45 g, 52.8196).

M5: mass/charge 549 (M'-1).

I"NMR (0M50, 400 MHz): 5 8.28 (5, 1H), 7.78 (a, 9-8.0 Hz, 2H), 7.72 (a, 9U-8.4 Hz, 2H ), 7.58 (y, 3-8.0 Hz, 2H), 7.46 (y, 9U-8.4 Hz, 2H), 3.63 (5, ЗН), 3.47 (5, ЗН ), 3.38 (5, 2H), 3.17 (5, ЗН), 3.09 (5,

ЗН), 2.94 (5, 6Н).

Step 6: 4-(5-(4-Chlorophenyl)-4-((dimethylamino)methyl)-2-propionylthiophen-3-yl)benzenesulfonamide (compound 35)

N.MO,5 x, x us /x what about si

Grignard's reagent (ethyl magnesium bromide, 0.48 g, 3.6 ml of a 1 M solution in TNE, 3.64 mmol) was added drop by drop to the solution of /5-(4-chlorophenyl)-4-«((dimethylamino)methyl) -3-(4-(M- ((dimethylamino)methylene)sulfamoyl)phenyl)-M-methoxy-M-methylthiophene-2-carboxamide (compound

ZBe, 0.4 g, 0.72 mmol) with shaking in anhydrous TNE (20 mL) at 25 °C. The reaction mixture was then heated at about 70 °C to about 75 °C for 2 hours. was observed using TI C. After cooling the reaction mixture to 0 "C, the reaction mixture

It was quenched by adding a saturated solution of ammonium chloride (15 ml). Then the resulting mixture was extracted with ethyl acetate (2 x 30 ml). The combined organic layer was dried over anhydrous

Mag5O.. The solvent from the dried organic layer was evaporated under reduced pressure to give the crude product, which was then purified by column chromatography on silica gel (100-200 mesh) using 6095 ethyl acetate in hexanes as eluent to give the title compound (0.065 g, 19.2890 ).

M5: mass/charge 463 (M'-1).

I"NMR (SOSI"z, 400 MHz): b 7.99 (y, 9-84 Hz, 2H), 7.63 (y, 9U-8.4 Hz, 2H), 7.48 (a, 9U -8.4 Hz, 2H), 7.42 (a, 9-8.4 Hz, 2H), 4.95 (p5-exchanges with 020, 2H), 3.05 (5, 2H), 2.51 (ad, 9-7.2 Hz, 2H), 1.85 (5, 6H), 1.05 (, 9-72 Gu, ZN).

Example 7: Preparation of 4-(5-(4-chlorophenyl)-2-propionylthiophen-3-yl)/benzenesulfonamide (compound 33)

N.MO»5 oo oo» o 5 nze

Step 1: Ethyl 3-bromo-5-(4-chlorophenyl)thiophene-2-carboxylate (ZZa)

Ve. Is. 2)

To a solution of ethyl-3,5-dibromothiophene-2-carboxylate (obtained according to the procedure described in U. Spet. Zos. RegKkip Tgap5-1: Ogdapis apa Vioogdapis Spetivigu (1972-1999), 1973, r 1766-1770), (2.0 g, 6.36 mmol) in a mixture of toluene:water (35:22 ml) was added (4-chlorophenyl)boronic acid (0.99 g, 6.36 mmol) and potassium carbonate (1.76 g, 12.73 mmol) at 25 "C. Nitrogen gas was bubbled through the reaction mixture for 15 minutes. Then tetrakis(triphenylphosphine)palladium(0) (0.37 g, 0.31 mmol) was added to the reaction mixture under a nitrogen atmosphere and the reaction mixture heated at from about 95 to about 100 °C for 3 hours with shaking. The progress of the reaction was monitored by TIS. The reaction mixture was then cooled to 25 °C and filtered through celite and the celite pad was washed with ethyl acetate (50 ml). The resulting filtrate was concentrated under reduced pressure to give the crude product, which was then purified by flash column chromatography with using 695 ethyl acetate in hexanes as an eluent to give the title compound (1.5 g, 68.189605).

M5: mass/charge 347 (M'-1).

I"NMR (SOSI", 400 MHz): 6 7.52 (y, 9U-8.4 Hz, 2H), 7.39 (y, 9U-8.4 Hz, 2H), 7.26 (5, 1H), 4.38 (a, 9U-7.2 Hz, 2H), 1.40 (1, 9-72 Hz, ЗН).

Step 2: Ethyl 5-(4-chlorophenyl)-3-(4-sulfamoylphenyl)thiophene-2-carboxylate (330)

НМО»5 o // (e) 5 (A SI go I.

(4-Sulfamoylphenyl )boronic acid (0.84 g, 4.19 mmol) and potassium carbonate (1.16 g, 8.39 mmol) at 25 °C. Nitrogen gas was bubbled through the reaction mixture for 15 minutes. Tetrakis was then added to the reaction mixture ( triphenylphosphine)palladium(O) (0.24 g, 0.20 mmol) under a nitrogen atmosphere and the reaction mixture was heated at about 95 to about 100 °C for 16 hours with shaking. The course of the reaction was monitored by TIS. Then the reaction mixture was cooled to 25 °C and filtered through celite, the celite pad was washed with ethanol (2 x 25 ml). The resulting filtrate was concentrated under reduced pressure to obtain a crude product, which was then

Zo was purified by column chromatography on silica gel (100-200 mesh) using 5090 ethyl acetate in hexanes as eluent to give the title compound (1.35 g, 76.2790).

M5: mass/charge 422 (M'n1).

I"NMR (0M50O, 400 MHz): b 7.83-7.87 (t, 4H), 7.68-7.70 (t, ЗН), 7.54 (a, U-8.4 Hz, 2H), 7.54 (rz-exchanges with O2O, 2H), 4.19 (d, 9U-7.2 Hz, 2H), 1.17 (9-72 Hz, ЗН).

Step 3: 5-(4-Chlorophenyl)-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid (33c)

NMmOo»5 o // and no SI

Ethyl 5-(4-chlorophenyl)-3-(4-sulfamoylphenyl)thiophene-2-carboxylate (compound 33B, 1.3 g, 3.08 mmol) was suspended in ethanol (30 mL) and Mahon's solution ( 0.61 g, 15.4 mmol) in water (3 ml) at 25 °C. Then the reaction mixture was heated at approximately 75 °C with shaking for 3 hours. The course of the reaction was observed with the help of TI C. Then the reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with water (5 ml) and cooled using an ice bath. Then, aqueous 1095 NCI was added to the cooled mixture, bringing the pH to 5-6. The resulting mixture was extracted with ethyl acetate (3 x 25 ml).

The combined organic layer was dried over anhydrous Ma»25O:. The solvent was evaporated from the dried organic layer under reduced pressure to give the title compound (1.10 g, 90.99).

M5: mass/charge 394 (M-n1).

I"NMR (0М50О, 400 MHz): 6 12.85 (B5-exchanges with 020, 1Н), 7.81-7.86 (t, 4Н), 7.70-7.72 (t, ЗН), 7.53 (a, 9U-8.4 Hz, 2H), 7.44 (p5-exchanges with 020, 2H).

Step 4: 5-(4-Chlorophenyl)-3-(4-«"M-(dimethylamino)methylene)sulfamoyl)phenyl)-M-methoxy-M-methylthiophene-2-carboxamide (334) / -M y; vo o7 (o, / x

M 5 o-m (a

M Ge

Oxalyl chloride (0.70 g, 0.48 mL, 5.58 mmol) was added dropwise at 0 "C to a solution of 5-(4-chlorophenyl)-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid ( compound 33c, 1.10 g, 2.79 mmol) in a mixture of dichloromethane (30 mL) and OME (0.40 g, 0.43 mL, 5.58 mmol). The mixture was then allowed to warm to room temperature and shaken for 1 .5 hours in a nitrogen atmosphere. The course of the reaction was monitored with the help of TI C. Then the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in dry dichloromethane (30 ml), and then the mixture was cooled to 0 "C. Triethylamine (1.69 g, 2.32 mL, 16.75 mmol) was added to the cooled mixture, followed by the addition of M,O-dimethylhydroxylamine hydrochloride (0.54 g, 5.58 mmol) with stirring. Then the reaction mixture was shaken at room temperature for 2 hours. The course of the reaction was monitored by TIS. Then the reaction mixture was diluted with PCM (25 ml), washed with water (2 x 25 ml), the resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product.

The crude product was then purified by flash column chromatography using 0.890 methanol in OSM as eluent to give the title compound (0.9 g, 65.6990).

M5: mass/charge 492 (M'-1).

I"NMR (SOSI"z, 400 MHz): b 8.14 (5, 1H), 7.91 (a, U-8.4 Hz, 2H), 7.51-7.58 (t, 4H) , 7.38 (y, 9-8.4

Hz, 2H), 7.26 (5, 1H), 3.65 (5, ЗН), 3.22 (5, ЗН), 3.13 (5, ЗН), 3.02 (5, ЗН).

Step 5: 4-(5-(4-Chlorophenyl)-2-propionylthiophen-3-yl/benzenesulfonamide (compound 33)

NMO,5 (o) / x still si

Grignard's reagent (ethylmagnesium bromide, 0.67 g, 5.0 ml of a 1 M solution in TNE, 5.08 mmol) was added drop by drop to a solution of 5-(4-chlorophenyl)-3-(4-(M- ( dimethylamino)methylene)sulfamoyl)phenyl)-M-methoxy-M-methylthiophene-2-carboxamide (compound

Zza, 0.5 g, 1.01 mmol) stirred in anhydrous TNE (15 mL) at 25 °C. The reaction mixture was then heated from about 70 to about 75 °C for 2 hours. The course of the reaction was monitored with the help of TI C. After cooling the reaction mixture to 0 "C, the reaction mixture was quenched by adding a saturated solution of ammonium chloride (10 ml). The resulting mixture was extracted with ethyl acetate (2 x 30 ml). The combined organic layer was dried over anhydrous Mag"5O".

The solvent was evaporated from the dried organic layer under reduced pressure to give the crude product, which was then purified by column chromatography on silica gel (100-200 mesh) using 4095 ethyl acetate in hexanes as eluent to give the title compound (0.06 g, 14.690).

M5: mass/charge 406 (M'-1).

I"NMR (0M50O, 400 MHz): b 7.88 (y, 9U-8.4 Hz, 2H), 7.85 (a, U-8.8 Hz, 2H), 7.69-7.71 (t, ZN) 7.55 (a, 9U-8.4 Hz, 2H), 7.48 (p5-exchanges with 020, 2H), 2.58 (d, 9-72 Hz, 2H), 0, 95 (I, 9U-7.2 Hz, ZN).

Example 8: Preparation of /4-(5-(4-chlorophenyl)-4-(dimethylamino)-2-propionyl o thiophen-3-yl)benzenesulfonamide (compound 34)

N.mOO5 sh

Pho cheese" at 5

Nze

Stage 1: Ethyl 3,5-dibromo-4-nitrothiophene-2-carboxylate (C4a)

Ve. MO, at // 5 Vg

Go

Sulfuric acid (27.6 g, 15.0 mL, 281.0 mmol) was added dropwise to ethyl 3,5-dibromothiophene-2-carboxylate (obtained according to the procedure described in US5 Recap

Tgap5-1: Ogdapis apa Vioogdapis Spetivigu (1972-1999), 1973, r 1766-1770) (5.0 g, 15.92 mmol) at room temperature (approximately 25 "C). Then the reaction mixture was cooled to -5 C and nitric acid (2.0 g, 2.04 mL, 31.84 mmol) was slowly added to the cooled mixture. The reaction mixture was then stirred at 0 "C for 1 hour. The course of the reaction was observed with the help of TI C. Then the reaction mixture was poured into ice water (150 ml). The resulting mixture was extracted with ethyl acetate (2 x 100 ml). The combined organic layer was dried over sulfate

of sodium and concentrated under reduced pressure to give the crude product, which was then purified by column chromatography on silica gel (100-200 mesh) using 295 ethyl acetate in hexanes as eluent to give the title compound (3.40 g, 59.5490).

M5: mass/charge 359 (M'-1).

I"NMR (SOSI", 400 MHz): b 4.40 (d, 9-7.2 Hz, 2H), 1.40 (i, 9-7.2 Hz, ЗН).

Step 2: Ethyl 4-amino-3,5-dibromothiophene-2-carboxylate (345) 5О0

VE. MN. o // in Vg th

To a solution of ethyl 3,5-dibromo-4-nitrothiophene-2-carboxylate (compound 34a, 10.0 g, 27.85 mmol) in acetic acid (100 ml) was added iron powder (7.77 g, 139.27 mmol). Then the reaction mixture was heated at 60 "C for 35 minutes with shaking. The course of the reaction was observed with the help of TC. Then the reaction mixture was cooled to 25 "C. Then, acetic acid was evaporated from the reaction mixture under reduced pressure. The pH of the resulting reaction mass was adjusted to 8-9 by adding to it a saturated solution of sodium bicarbonate. Ethyl acetate (150 ml) was added to the resulting mixture, the resulting emulsion was filtered, and then the organic layer was separated. The remaining aqueous layer was then re-extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over sodium sulfate and the dried organic layer was concentrated under reduced pressure to give the crude product, which was then purified by column chromatography on silica gel (100-200 mesh) using 295 ethyl acetate in hexanes as eluent to give the title compound (6 .00 g, 65.5090).

M5: mass/charge 330 (M-n1).

I"NYMR (SOSI", 400 MHz): b 4.34 (d, 9U-7.2 Hz, 2H), 4.03 (B5-exchanges with 020, 2H), 1.36 (I, 9-7 ,2 Gu,

ZN).

Step 3: Ethyl 3,5-dibromo-4-(dimethylamino)thiophene-2-carboxylate (34c)

H

Ve. M. v. in Vg ge

Man (6095 suspension in mineral oil) (1, 82 g, 45.49 mmol) at a temperature of approximately -5 "C. Then the reaction mixture was shaken at -5 "C for 20 minutes. Then, iodomethane (6.47 g, 2.83 ml, 45.59 mmol) was added to the reaction mixture, and the shaking was continued for 40 minutes at -5 "C. The course of the reaction was monitored using

TS. Then the reaction mixture was quenched by adding cold water (50 ml). Then the resulting mixture was extracted with ethyl acetate (3 x 100 ml). The combined organic layer was then dried over sodium sulfate and concentrated under reduced pressure to give the crude product, which was then purified by flash column chromatography using 2.595 ethyl acetate in hexanes as eluent to give the title compound (3.2 g, 58.9790) .

From M5: mass/charge 358 (M-n1).

I"NMR (SOSI", 400 MHz): b 4.33 (d, U9-7.2 Gu, 2H), 2.89 (5, 6H), 1.35 (I, 9U-7.2 Hz, ZN).

Step 4: Ethyl 3-bromo-5-(4-chlorophenyl)-4-(dimethylamino)thiophene-2-carboxylate (344)

Ve.

M. o // from the SI

To a solution of ethyl 3,5-dibromo-4-(dimethylamino)thiophene-2-carboxylate (compound 34c, 3.0 g, 8.40 mmol) in a mixture of toluene:ethanol (5 ml:30 ml) was added (4 -chlorophenyl)boronic acid (1.44 g, 9.24 mmol) and potassium carbonate (2.32 g, 16.80 mmol) at 25 "С. Nitrogen gas was bubbled through the reaction mixture for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.48 g, 0.42 mmol) was then added to the reaction mixture under a nitrogen atmosphere and the reaction mixture was heated at approximately 95 to 100 °C for 3 hours with shaking. The progress of the reaction was monitored by with the help of TI C. Then the reaction mixture was cooled to 25 "C and filtered through celite, then the celite pad was washed with ethyl acetate (50 ml). The resulting filtrate was then concentrated under reduced pressure to give the crude product, which was then purified by flash column chromatography using 1295 ethyl acetate in hexanes as eluent to give the title compound (2.5 g, 76.5690).

M5: mass/charge 389 (M'-1). "NMR (SOSIz, 400 MHz): 6 7.47 (a, 9-8.8 Hz, 2H), 7.40 (y, 9-8.8 Hz, 2H) 4.38 (d, 9-7 ,2 Hz, 2H), 2.78 (5, 6H), 1.40 (1, 9-72 Hz, ЗН).

Step 5: Ethyl 5-(4-chlorophenyl)-4-(dimethylamino)-3-(4-sulfamoylphenyl)thiophene-2-carboxylate (C4e)

NMO,"5 de

M. about // about.

To a solution of ethyl 3-bromo-5-(4-chlorophenyl)-4-(dimethylamino)thiophene-2-carboxylate (compound 344, 2.20 g, 5.65 mmol) in a mixture of toluene ethanol (10 ml:30 ml) (4-sulfamoylphenyl)boronic acid (1.25 g, 6.22 mmol) and potassium carbonate (1.56 g, 11.30 mmol) were added at 25 °C. Nitrogen gas was bubbled through the reaction mixture for 15 minutes. Then to to the reaction mixture was added tetrakistriphenylphosphine)palladium(O) (0.32 g, 0.28 mmol) under nitrogen and the reaction mixture was heated at about 95 to about 100 °C for 16 hours with shaking. The course of the reaction was observed with the help of TI!S. The reaction mixture was then cooled to 25°C and filtered through celite. The celite pad was then washed with ethanol (2 x 25 mL). The combined filtrate was concentrated under reduced pressure to give the crude product, which was then purified by flash column chromatography using 5595 ethyl acetate in hexanes as an eluent to give the title compound (2.0 g, 76.05965).

M5: mass/charge 465 (M-n1). "NMR (0M5O, 400 MHz): b 7.85 (y, 9U-8.4 Hz, 2H), 7.60 (y, 9-8.8 Hz, 2H), 7.52-7.55 ( t, AN), 7.44 (rz-exchanges with O2O, 2H), 4.07 (d, 9-7.2 Hz, 2H) 2.33 (5, 6H), 1.07 (I, 9- 7.24 Hz, ZN).

Step 6: 5-(4-Chlorophenyl)-4-(dimethylamino)-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid (34 u) nMmO,5 where

M. o // 87 A no SI

Ethyl 5-(4-chlorophenyl)-4-(dimethylamino)-3-(4-sulfamoylphenyl)thiophene-2-carboxylate (compound C4e, 2.00 g, 4.30 mmol) was suspended in ethanol (30 mL) and solution was added to it

Mmaone (0.86 g, 21.5 mmol) in water (4 ml) at 25 "C. Then the reaction mixture was heated at 75 "C with shaking for 2 hours. The course of the reaction was monitored using TI S. Then

The reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with water (10 ml) and cooled using an ice bath. Aqueous 10 95 NCI was added to the cooled mixture, bringing the pH of the solution to about b. The resulting mixture was extracted with ethyl acetate (3 x 30 ml). The combined organic layer was then dried over anhydrous Mag5Ox.

The solvent was evaporated from the dried organic layer under reduced pressure to give the title compound (1.60 g, 85.1905).

M5: mass/charge 437 (M'-1). NMR (0M5O, 400 MGu): b 12.97 (p5-exchanges with 020, 1H), 7.84 (y, 9-8.4 Hz, 2H), 7.58 (a, 9-84

Hz, 2H), 7.52-7.54 (t, AN), 7.44 (re-exchange with 020, 2H), 2.32 (in, 6H).

Step 7: 5-(4-Chlorophenyl)-4-(dimethylamino)-3-(4-(("M-((dimethylamino)methylene) sulfamoyl)phenyl)-M-methoxy-M-methylthiophene-2-carboxamide (349 )

/ - in;

M 57O o

KI and

M. o) / X with A

M si

Oxalyl chloride (0.58 g, 0.39 mL, 4.57 mmol) was added dropwise to a solution of 5-(4-chlorophenyl)-4-(dimethylamino)-3-(4-sulfamoylphenyl)thiophene-2-carbon acid (compound C4i, 1.00 g, 2.28 mmol) in a mixture of dichloromethane (30 ml) and OME (0.33 g, 0.35 ml, 4.57 mmol) at 0 "С.

Then the reaction mixture was allowed to warm to room temperature and shaken for 1.5 hours under nitrogen atmosphere. The course of the reaction was observed using TI C. Then the mixture was concentrated under reduced pressure. The obtained residue was dissolved in dry dichloromethane (30 ml) and cooled to 0 "C. Then triethylamine (1.38 g, 1.90 ml, 13.68 mmol) was added to the cooled reaction mixture, followed by the addition of M,O-dimethylhydroxylamine hydrochloride ( 0.40 g, 4.57 mmol) with shaking. Then the reaction mixture was shaken at room temperature for 2 hours. The progress of the reaction was monitored by TIS. Then the reaction mixture was diluted with OSM (25 ml) and washed with water (2 x 25 ml ).The combined organic layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was then purified by column chromatography on silica gel (100-200 mesh) using 1.695 methanol in OSM as eluent to give the title compound ( 0.8 g, 65.35905).

M: mass/charge 535 (M'-1).

I"NMR (0M50, 400 MHz): 6 8.27 (5, 1H), 7.77 (a, 9-84 Hz, 2H), 7.54 (t, 4H) 7.44 (y, 9- 8.4 Gu, 2H), 3.62 (5, ZN), 3.17 (5, ZN), 3.08 (5, ZN), 2.94 (5, ZN), 2.34 (5, 6H).

Step 8: 4-(5-(4-Chlorophenyl)-4-(dimethylamino)-2-propionylthiophen-3-yl)/benzenesulfonamide (compound 34)

NoMmO; 5

KI

M. about; / X what

SI

Grignard's reagent (ethyl magnesium bromide, 0.62 g, 4.66 ml of a 1 M solution in TNE, 4.67 mmol) was added drop by drop to the solution of 5-(4-chlorophenyl)-4-(dimethylamino)-3-(4 -(M-((dimethylamino)methylene)sulfamoyl)phenyl)-M-methoxy-M-methylthiophene-2-carboxamide (compound 349, 0.5 g, 0.93 mmol) was stirred in anhydrous TNE (30 mL ) at 25 "C. Then the reaction mixture was heated at approximately 70 to 75 "C for 2 hours. The course of the reaction was monitored with TI! C. After cooling the reaction mixture to 0 "С, the reaction mixture was quenched by adding a saturated solution of ammonium chloride (10 ml). Then the resulting mixture was extracted

With ethyl acetate (2 x 30 ml). The combined organic layer was dried over anhydrous Mag»5O».

The solvent was evaporated from the dried organic layer under reduced pressure to give the crude product, which was then purified by column chromatography on silica gel (100-200 mesh) using 4095 ethyl acetate in hexanes as eluent to give the title compound (0.27 g, 64.4395) . The title compound was then purified by preparative NRIS (0.135 g, 32.29).

M5: mass/charge 449 (M'-1).

I"NMR (0M50, 400 MHz): b 7.90 (a, 9-84 Hz, 2H), 7.60-7.62 (t, 4H), 7.54 (y, 9-8.4 Hz , 2H), 7.48 (rz-exchanges with O2O, 2H), 2.32-2.36 (5, 8H), 0.86 (I, 9-72 Hz, ЗН).

Example 9: 5-(4-Chlorophenyl)-M,M,4-trimethyl-3-(4-sulfamoylphenyl)thiophene-2-carboxamide (compound Zb)

Nam, 8; O yo o / X o

M SI

Dimethylamine (0.055 g, 0.61 mL of a 2M solution in TNE, 1.22 mmol) was added dropwise to a solution of 5-(4-chlorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid (compound 1c, 0.25 g, 0.61 mmol) in dry TNE (15 ml) in a nitrogen atmosphere at 0 "C. NATO (0.26 g, 0.67 mmol) and SIREA (0, 16 g, 0.21 ml, 1.24 mmol) at 0 "C with shaking. Then the mixture was allowed to warm up to 10 "C and shaken for 2 hours. The course of the reaction was observed with the help of TI!C. Then the reaction mixture was concentrated under reduced pressure. The resulting concentrated mass was diluted with ethyl acetate (30 ml) and washed with a saturated solution of sodium bicarbonate (2 x 15 ml) and saline solution (1 x 15 ml).

The resulting organic layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was then purified by flash column chromatography using 2595 ethyl acetate in hexanes as eluent to give the title compound (0.06 g, 22.50965 ).

M5: mass/charge 435 (M'-1). NMR (0M5O, 400 MHz): b 7.89 (y, 9-8.4 Hz, 2H), 7.57 (5, 4H), 7.49 (a, 9U-8.4 Hz, 2H) .

The following compounds were prepared according to the procedure described above, but with appropriate changes in the reactants. 5-(4-Chlorophenyl)-M-methoxy-M,4-dimethyl-3-(4-sulfamoylphenyl)thiophene-2-carboxamide (compound 37)

M5: mass/charge 451 (M'-1).

I"NMR (0M50, 400 MHz): b 7.85 (a, U-8.4 Hz, 2H), 7.58 (5, AN), 7.44 (a, 9U-8.4 Hz, 2H), 7.43 (p5- exchanges with 020, 2H), 3.64 (5, ЗН), 3.09 (5, ЗН), 2.01 (в, ЗН). 5-(4-Chlorophenyl)-M- (2-hydroxyethyl)-4-methyl-N-propyl-3-(4-sulfamoylphenyl)thiophene-2-carboxamide (compound 38)

M5: mass/charge 493 (M'-1). "NMR (0M5O, 400 MHz): b 7.87 (y, 9-84 Hz, 2H), 7.55-7.57 (t, 4H), 7.52 (y, 9-8.4 Hz, 2H), 7.45 (rz-exchanges with O2O, 2H), 4.71 (rz-exchanges with O2O, 1H), 3.25-3.30 (t, 4H), 3.16-3.21 ( t, 2H), 2.11 (5, ZN), 1.27-1.29 (t, 2H), 1.02 (a.9 -6.0 Hu, ЗN).

Zo 4-(5-(4-Chlorophenyl)-4-methyl-2-(piperidin-1-carbonyl)thiophen-3-yl)benzenesulfonamide (compound 39)

M5: mass/charge 475 (M'-1).

I"NMR (0M50, 400 MHz): b 7.89 (a, 9-84 Hz, 2H), 7.56-7.60 (t, 4H), 7.54 (j, 9-8.4 Hz , 2H), 7.46 (rz-exchanges with 020, 2H), 3.59-3.64 (t, 2H), 3.12-3.16 (t, 2H), 2.12 (5, ЗН ), 1.22-1.27 (t, 6H).

Example 10: Preparation of 4-(5-(4-chlorophenyl)-1,4-dimethyl-2-propionyl-1H-pyrrol-3-yl/ubenzenesulfonamide (compound 49) n.mO.5

From 9-2 o'clock M

Sleep

Step 1: Methyl 5-(4-chlorophenyl)-1,4-dimethyl-1H-pyrrole-2-carboxylate (494) sn,

WITH

! CVD

A solution of methyl-5-(4-chlorophenyl)-4-methyl- 1 of H-pyrrole-2-carboxylate (obtained according to the procedure described in .). Ogd. Spec., 2009, 74(2), 903-905, Og9. I ey. 2007, 9(25), 5191-5194 , 2.20 g, 8.81 mmol) in OME (10 mL), followed by the addition of methyl iodide (1.88 g, 0.83 mL, 13.22 mmol). The resulting reaction mixture was stirred at room temperature for 45 minutes. The progress of the reaction was monitored by TLC. The reaction mixture was then quenched with water (10 mL). The resulting mixture was then extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over anhydrous

Mag5O.. The solvent was evaporated from the dried organic layer under reduced pressure to give the crude product, which was then purified by column chromatography on silica gel (100-200 mesh) using 15-20 95 ethyl acetate in hexanes as eluent to give the title compound (1 .9 g, 81.9 U).

M5: mass/charge 264 (M'-1).

I"NMR (0M50O, 400 MHz): b 7.55 (a, 9U-8.4 Hz, 2H), 7.39 (j, 9U-8.4 Hz, 2H), 6.48 (5, 1H ), 3.74 (5,

ZN), 3.67 (5, ZN), 1.94 (in, ZN).

Step 2: Methyl 3-bromo-5-(4-chlorophenyl)-1,4-dimethyl-1H-pyrrole-2-carboxylate (494)

CH"

Ve. about M

M sn o. sleep and

Bromine (1.69 g, 0.54 mL, 10.54 mmol) was added dropwise to a solution of methyl 5-(4-chlorophenyl)-1,4-dimethyl-1H-pyrrole-2-carboxylate (compound 49a , 1.85 g, 7.03 mmol), which was shaken in acetic acid (20 ml) at 10 "C. The resulting reaction mixture was stirred at room temperature for 15 hours. The course of the reaction was monitored by TI C. From the reaction mixture acetic acid was removed under reduced pressure and the resulting residue was diluted in ethyl acetate (150 mL). The resulting mixture was washed with saturated sodium bicarbonate solution (50 mL) followed by brine (50 mL). The combined organic layer was dried over anhydrous Mag5O4. The solvent was evaporated from the dried organic layer under reduced pressure to give the crude product, which was washed with a mixture of ethyl acetate in hexanes (10:90) to give the title compound (2.1 g, 87.5 Vol).

I"NMR (SOSI", 400 MHz): b 7.43 (y, 9U-8.4 Hz, 2H), 7.20 (y, 9-8.4 Hz, 2H), 3.88 (5, ZN), 3.67 (5,

ZN), 1.94 (5, ZN).

Zo Stage 3: Methyl 5-(4-chlorophenyl)-1,4-dimethyl-3-(4-sulfamoylphenyl)-1H-pyrrole-2-carboxylate (49u) nH.mO,5

FI, SN Fr. vd:

Nesto Sn

To a solution of methyl-3-bromo-5-(4-chlorophenyl)-1,4-dimethyl-1H-pyrrole-2-carboxylate (compound 4963, 2.0 g, 5.84 mmol) in a mixture of toluene:ethanol ( 15:40 mL) were added 4-aminosulfonylbenzene boronic acid (1.41 g, 7.01 mmol) and potassium carbonate (2.42 g, 17.52 mmol) at 25 °C in a stoppered test tube and bubbled nitrogen gas through the resulting mixture for 15 minutes.

Tetrakis(triphenylphosphine)palladium(O) (0.349 g, 0.29 mmol) was then added to the reaction mixture under nitrogen and the reaction mixture was heated from about 95 to about 100 °C for 15 hours with shaking. The progress of the reaction was monitored by TI! C. Then the reaction mixture was cooled to 25 "C and filtered through celite. The celite pad was washed with ethanol (100 mL) and ethyl acetate (50 mL). The combined filtrate was concentrated under reduced pressure to give the crude product, which was then purified by column chromatography on silica gel (100-200 mesh) using 40 95 ethyl acetate in hexanes as eluent to give the title compound (1.7 g, 69, 6 b).

M5: mass/charge 419 (M-n1).

NMR (SOSI»z, 400 MHz): b 7.92 (a, 9U-8.4 Hz, 2H), 7.46 (y, 9-8.8 Hz, 2H), 7.42 (a, 9 -8.4 Hz, 2H), 7.29 (a, 9U-8.8 Hz, 2H), 4.86 (65, exchange with O2O, 2H), 3.74 (5, ЗН), 3.58 (in, ZN), 1.79 (in, ZN).

Stage 4: 5-(4-chlorophenyl)-1,4-dimethyl-3-(4-sulfamoylphenyl)-1H-pyrrole-2-carboxylic acid n.mOo,5

Z ee 9-0» at M h

Methyl 5-(4-chlorophenyl)-1,4-dimethyl-3-(4-sulfamoylphenyl)-1H-pyrrole-2-carboxylate (compound 49u, 1.6 g, 3.82 mmol) was suspended in ethanol ( 100 ml) and treated with a solution of Mahon (0.76 g, 19.13 mmol) in water (20 ml) at 0 "C. Then the reaction mixture was heated at 80 "C with shaking for 15 hours. The course of the reaction was observed with the help of TI C. Then the reaction mixture was concentrated under reduced pressure. The reaction mixture was then treated with diluted HCl to adjust the pH of the mixture from b to 7. The resulting mixture was then extracted with ethyl acetate (2 x 100 ml). The combined organic layer was then dried over anhydrous Mg5Ox.

The solvent was evaporated from the dried organic layer under reduced pressure to give the title compound (1.3 g, 84.4 U).

M5: mass/charge 405 (M'-1).

I"NMR (0OM50, 400 MHz): b 11.89 (65, exchanges with 020, 1H), 7.79 (a, 9-84 Hz, 2H), 7.59 (a, U-8.4

Hz, 2H), 7.47 (y, 9U-8.4 Hz, 2H), 7.42 (y, 9U-8.4 Hz, 2H), 7.31 (65, exchanges with 020, 2H), 3.67(5, ZN), 1.77 (5, ZN).

Step 5: 5-(4-Chlorophenyl)-N-methoxy-N,1,4-trimethyl-3-(4-sulfamoylphenyl)-1H-pyrrole-2-carboxamide (496)

НМО»С Coll. o a o M

M

SNz

Nose. M sleep

To a solution of / 5-(4-chlorophenyl)-1,4-dimethyl-3-(4-sulfamoylphenyl)-1H-pyrrole-2-carboxylic acid (compound 49e, 0.800 g, 1.98 mmol), which is shaken, in To OME (15 mL) was added NOVT (0.333 g, 2.17 mmol) at room temperature, followed by the addition of M, O-dimethylhydroxylamine hydrochloride (0.386 g, 3.96 mmol). Then the reaction mixture was cooled to 0 "C and EOS (0.570 g, 2.97 mmol) and triethylamine (0.80 g, 1.10 ml, 7.92 mmol) were added to the cooled reaction mixture. Then the reaction mixture was shaken at room temperature for 15 hours. The progress of the reaction was monitored by TSC. The reaction mixture was then concentrated under reduced pressure. The resulting residue was taken up in ethyl acetate (100 mL) and washed with saturated sodium bicarbonate (20 mL) followed by brine (20 mL). The resulting organic the layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product.

The product was then purified by column chromatography on silica gel (100-200 mesh) using 50 95 ethyl acetate in hexanes as eluent to give the title compound (0.680 g, 76.8 U).

M5: mass/charge 448 (M'-1).

I"NMR (0M5O, 400 MHz): b 7.83 (a, U-8.4 Hz, 2H), 7.59 (y, 9U-8.8 Hz, 2H), 7.46 (a, 9U -8.4 Hz, 2H), 7.42 (a, 9-8.8 Hz, 2H), 7.35 (65, exchanges with 020, 2H), 3.43(5, 6H), 2.99 (5, ZN), 1.96 (in, ZN).

Step 6: 5-(4-Chlorophenyl)-3-(4-(M-«((dimethylamino)methylene)sulfamoyl)phenyl)-M-methoxy-M,1,4-trimethyl-1H-pyrrole-2-carboxamide (4903) sn» us

MOo»5 902 9-0 (o) M sn ns. di sn" Z

To a solution of 5-(4-chlorophenyl)-M-methoxy-M, 1,4-trimethyl-3-(4-sulfamoylphenyl)-1H-pyrrole-2-

Carboxamide (compound 496f, 0.650 g, 1.45 mmol) stirred in ethyl acetate (12 mL) was sequentially added HOME (0.65 mL) and OME acetal (0.207 g, 0.233 mL, 1.74 mmol) at room temperature . Then the reaction mixture was shaken at room temperature for 15 hours under a nitrogen atmosphere. The course of the reaction was monitored by TIS. The precipitated product was filtered and washed with ether (10 ml) to give the title compound (0.600 g, 82.19 g).

M5: mass/charge 503 (M'-1). "NMR (0M5O, 400 MHz): b 8.24 (5, 1H), 7.77 (9, 9-8.4 Hz, 2H), 7.57 (y, 9-84 Hz, 2H), 7 ... .00 (5, ZN), 2.92 (5, ZN), 1.95 (5, ZN).

Step 7: 4-(5-(4-Chlorophenyl)-1,4-dimethyl-2-propionyl-1H-pyrrol-3-yl)benzenesulfonamide (compound 49) n.mO.5 ee 9-0 o M

Sleep is not

Grignard's reagent (ethylmagnesium bromide, 0.531 g, 3.98 ml, 1M solution in TNE, 3.98 mmol) was added dropwise under a nitrogen atmosphere to a solution of 5-(4-chlorophenyl)-3-(4-(M- ( (Dimethylamino)methylene)sulfamoyl)phenyl)-M-methoxy-M,1,4-trimethyl-1H-pyrrole-2-carboxamide (compound 490), 0.400 g, 0.79 mmol) shaken in anhydrous TNE ( 15 ml) at 2576 and then the reaction mixture was heated from about 70 to about 75 °C for 1 hour.

The progress of the reaction was monitored by TIS. After cooling the reaction mixture to 0 "s, the cooled reaction mixture was quenched by adding a saturated solution of ammonium chloride (10 ml). The resulting mixture was extracted with ethyl acetate (2 x 50 ml). The combined organic layer was dried over anhydrous Mag50"5. The solvent from the dried organic solution was evaporated under reduced pressure to give the crude product, which was then purified using preparative NRI C to give the title compound (0.070 g, 21.08 Vol).

M5: mass/charge 417 (M--1).

I"NMR (SOSI", 400 MHz): b 8.01 (a, 9-84 Hz, 2H), 7.47 (y, 9-8.4 Hz, 2H), 7.45 (y, 9- 8.4 Hz, 2H), 7.28 (8, 9U-8.4 Hz, 2H), 4.93 (p5, exchanges with Yu2O, 2H), 3.69 (5, ЗН), 2.16 ( d, 9-7.2 Hz, 2H), 1.76 (5, ZN), 0.93 (I, U-7.2 Hz, ZN).

Example 11: Preparation of 4-(5-(4-chlorophenyl)-1,4-dimethyl-2-propionyl-1H-pyrrol-3-yl)benzenesulfonamide (compound 49) (alternative method)

N.mO,5

Le 9-2 at M

I don't sleep

Zo Step 1: 1-(5-(4-Chlorophenyl)-1,4-dimethyl-1H-pyrrol-2-yl)upropan-1-one (49a)

SNU at about Snz

M,M-Dimethylpropionamide (3.24 g, 3.52 mL, 32.08 mmol) was cooled at 0-5 "C and ROS Is (4.9 g, 2.9 mL, 32 .08 mmol).The resulting mixture was then shaken at room temperature (approximately 25 "C) for 20 minutes. Then the reaction mixture was diluted with 1,2-dichloroethane (60 ml) and cooled to 0 "C. A solution of 2-(4-chlorophenyl)-1,3-dimethyl-1H-pyrrole (obtained according to to the procedure given in Teigapeagop I eChseg5 46 (2005) 4539-4542, 6.0 g, 29.17 mmol) in 1,2-dichloroethane (60 mL). The reaction mixture was then heated under reflux for 30 minutes. reactions were observed using TiCs.

The resulting mixture was allowed to cool to room temperature and diluted with an aqueous solution of sodium acetate trihydrate (21.8 g, 160.4 mmol in 45 ml of water). The resulting mixture was additionally heated under reflux for 30 minutes, the two layers were separated.

The aqueous layer was extracted with dichloromethane (3x100 ml). The combined organic layer was washed with water (1x100 ml) and dried over anhydrous Mag5O»4. The solvent from the reaction mixture was evaporated under reduced pressure to obtain the crude product. This crude product was purified by column chromatography on silica gel (100-200 mesh) using 4-6 95 ethyl acetate in hexanes as eluent to give the title compound (6.55 g, 85.8 95).

M5: mass/charge 262 (M'-1). "NMR (SOSI", 400 MHz): b 7.45 (a, 9-8.8 Hz, 2H), 7.24 (y, 9-8.8 Hz, 2H), 6.89 (5, 1H ), 3.76 (5,

ZN), 2.83(4, 9U-7.6 Hz, 2H), 2.02 (5, ZN), 1.21 (I, 9-76 Hz, ZN).

The compounds below were prepared using a procedure similar to that described above for compound "49a" with appropriate variations in reactants, reaction conditions, and amounts of reagents.

Baa. 1-(5-(4-Fluorophenyl)-1,4-dimethyl-1H-pyrrol-2-yl)upropan-1-one

M5: mass/charge 246(M-1).

BB 1-(5-(4-Methoxyphenyl)-1,4-dimethyl-1H-pyrrol-2-yl)upropan-1-one

M5: mass/charge 258 (M-n1).

Bba 1-(5-(4-Chlorophenyl)-1,4-dimethyl-1H-pyrrol-2-yl)butan-1-one

M5: mass/charge 276 (M'n1).

B7a. 1-(5-(2,4-Dichlorophenyl)-1,4-dimethyl-1H-pyrrol-2-yl/upropan-1-one

M5: mass/charge 297 (M'-1).

Wow 1-(5-(2,3-Dihydrobenzoyl(/1,4|dioxin-6b-yl)-1,4-dimethyl-!H-pyrrole-2-ylpropan-1-one)

M5: mass/charge 286 (M'-1).

Step 2: 1-(3-bromo-5-(4-chlorophenyl)-1,4-dimethyl-1H-pyrrol-2-yl)upropan-1-one (495)

SN

Ve.

More; si o; M

SN

A solution of M-bromosuccinimide (4.42 g, 24.83 mmol) in TNE (62.5 mL) was added dropwise to a solution of 1-(5-(4-chlorophenyl)-1,4-dimethyl-1H-pyrrole -2-yl)upropan-1-one (compound 49a, 6.5 g, 24.83 mmol) stirred in TNE (100 ml) at -78 °C. The resulting reaction mixture was then stirred at -78 °C C for 5 hours. The reaction mixture was allowed to slowly warm up to 25 °C for an additional 3-4 hours. The progress of the reaction was monitored using

TS. The solvent from the reaction mixture was evaporated under reduced pressure to obtain a residue

Zo was mixed in ethyl acetate (200 ml). The resulting mixture was washed with a saturated solution of sodium bicarbonate (1x100 ml), followed by washing with water (1x100 ml). The combined organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated from the dried organic layer under reduced pressure to give the crude product, which was then purified by flash column chromatography using 10 95 ethyl acetate in hexanes to give the title compound (7.58 g, 90 b).

M5: mass/charge 342 (M'-1).

I"NMR (SOSI", 400 MHz): b 7.45 (y, 9-84 Hz, 2H), 7.22 (y, 9-8.4 Hz, 2H), 3.67 (5, ЗН) , 3.12 (a4, 9U-7.2 Hz, 2H), 1.96 (5, ZN), 1.21 (1, 9U-7.2 Gu, ZN).

The compounds below were prepared using a procedure similar to that described above for compound "49p" with appropriate variations in reactants, reaction conditions, and amounts of reagents. 54 years old 1-(3-bromo-5-(4-fluorophenyl)-1,4-dimethyl-1H-pyrrol-2-yl)upropan-1-one

M5: mass/charge 325 (M'-1). 55 years old 1-(3-bromo-5-(4-methoxyphenyl)-1,4-dimethyl-1H-pyrrol-2-yl)upropan-1-one

M5: mass/charge 336 (M-n1). 56B. 1-(3-bromo-5-(4-chlorophenyl)-1,4-dimethyl-1H-pyrrol-2-yl)butan-1-one

M5: mass/charge 356 (M'-1). 575. 1-(3-bromo-5-(2,4-dichlorophenyl)-1,4-dimethyl-1H-pyrrole-2-ilupropan-1-one

M5: mass/charge 376 (M'-1). 580. 1-(3-bromo-5-(2,3-dihydrobenzo|B1/11,4|dioxin-b-yl)-1,4-dimethyl-1H-pyrrol-2-yl)u. propane-1-one

M5: mass/charge 365 (M'-1).

Step 3: 4-(5-(4-Chlorophenyl)-1,4-dimethyl-2-propionyl-1H-pyrrol-3-yl)benzenesulfonamide (compound 49)

nN.mO.5 more about.

Ha

SNz

To a solution of 1-(3-bromo-5-(4-chlorophenyl)-1,4-dimethyl-1H-pyrrol-2-yl)upropan-1-one (compound 496, 3.0 g, 8.81 mmol ) 4-aminosulfonylbenzeneboronic acid (1.947 g, 9.69 mmol) and potassium carbonate (2.43 g, 17.61 mmol) were added to a mixture of toluene ethanol (15 ml: 45 ml) at 25 "C in a stoppered test tube, and nitrogen gas was bubbled through it for 15 min. To the reaction mixture under nitrogen was added tetrakis(triphenylphosphine)palladium(0) (0.51 g, 0.44 mmol) and the reaction mixture was heated from about 90 to about 95°C for 18 hours with shaking. The progress of the reaction was monitored by TIS. The reaction mixture was then cooled to 25 °C and filtered through celite. The celite pad was washed with 1095 methanol in dichloromethane. The resulting combined filtrate was concentrated under reduced pressure to give the crude product, which was then purified using a column flash chromatography using 40 95 ethyl acetate in hexanes as eluent to give the title compound (1.22 g, 33.2 Ov).

M5: mass/charge 417 (M'1). "NMR (SOSI", 400 MHz): b 8.02 (y, 9-84 Hz, 2H), 7.48 (y, 9-84 Hz, 2H), 7.47 (a, 9U-8.4 Hz, 2H), 7.30 (a, 9U-8.4 Hz, 2H), 5.11 (65, exchanges with 020, 2H), 3.71 (5, ЗН), 2.17 (4, 9 -7.2 Hz, 2H), 1.75 (5, ZN), 0.94(, 9U-7.2 Hz, ZN).

The following compounds were prepared according to the procedure described above, but with appropriate changes in the reactants. 4-(5-(4-Fluorophenyl)-1,4-dimethyl-2-propionyl-1H-pyrrol-3-yl)/benzenesulfonamide (compound 54)

M5: mass/charge 401 (M--1).

I"NMR (SOSIz, 400 MHz): b 8.01 (a, 9U-8.4 Hz, 2H), 7.48 (a, 9U-8.4 Hz, 2H), 7.31-7.35 (t, 2H), 7.21 (I, 9-84 Hz, 2H), 4.98 (p5-exchanges with 20, 2H), 3.70 (5, ЗН), 2.18 (4, 9- 72 Hz, 2H), 1.74 (5, ЗН), 0.94 (I, 9U-7.2 Hz, ЗН). 4-(5-(4-Methoxyphenyl)-1,4-dimethyl-2- propionyl-1H-pyrrole-Z-yl/ubenzenesulfonamide (compound 55)

M5: mass/charge 413(M--1).

I"NMR (SOSI", 400 MHz): b 8.01 (a, 9-84 Hz, 2H), 740 (y, 9-8.4 Hz, 2H), 7.29 (y, U-8, 4 Hz, 2H), 7.03 (9, 9-8.4 Hz, 2H), 4.89 (p5-exchanges with 020, 2H), 3.88 (5, ЗН), 3.71 (5, ЗН), 2.18 (а, У-7.2 Hz, 2Н),

Зо 1.76 (5, ZN), 0.92 (I, 9U-7.2 Hz, ZN). 4-(2-butyryl-5-(4-chlorophenyl)-1,4-dimethyl-1H-pyrrol-3-yl)/benzenesulfonamide (compound 56)

M5: mass/charge 431 (M--1).

I"NMR (SOSI", 400 MHz): b 8.01 (a, 9U-8.4 Hz, 2H), 7.46-7.49 (t, 4H), 7.31 (a, 9-84 Hz, 2H), 4.96 (re-exchanges with 020, 2H), 3.71 (5, ZN), 2.13 (I, 9-7.2 Hz, 2H), 1.76 (5, ZN ), 1.45-1.52 (t, 2H), 0.71 (, 9U-7.2 Hz, ЗН). 4-(5-(2,4-Dichlorophenyl)-1,4-dimethyl-2 -propionyl-1H-pyrrol-3-yl/ubenzenesulfonamide (compound 57)

M5: mass/charge 452(M-1). "NMR (SOSIz, 400 MHz): b 8.01 (a, 9-84 Hz, 2H), 7.58 (0.9-2.0 Hz, 1H), 7.49 (a, U-8, 4 Hz, 2H), 7.39 (yes, 9U-8.4, 2.0 Hz, 1H), 7.26-7.28 (t, 1H), 4.93 (re-exchanges with 020, 2H ), 3.64 (in, ЗН), 2.19 (а, 9У-7.2 Hz, 2Н), 1.66 (5, ЗН), 0.95 (I, 9У-7.2 Hz, ЗН ). 4-(5-(2,3-Dihydrobenzoyl|B1/1 4|dioxin-6b-yl)-1,4-dimethyl-2-propionyl-1H-pyrrol-3-yl)benzenesulfonamide (compound 58)

M5: mass/charge 441(M--1). "NMR (0M50O, 400 MHz): b 7.89 (a, 9-8.0 Hz, 2H), 7.49 (a, 9U-8.0 Hz, 2H), 7.44 (B5-exchanges with

Wow, 2H), 6.99 (y, 9U-8.4 Hz, 1H), 6.86-6.91 (t, 2H), 4.30 (5, 4H), 3.61 (5, ЗН ), 2.12 (а, 9-7.2 Hz, 2Н), 1.71 (5, ЗН), 0.83 (Her, 9У-7.2 Hz, ЗН).

Example 12: Preparation of 4-(5-(4-chlorophenyl)-4-methyl-2-propionyl-1H-pyrrol-3-yl)benzenesulfonamide (compound 53)

noMO.,5

F, SN Fr. //

M KA si

Step 1: 1-(5-(4-Chlorophenyl)-4-methyl-1H-pyrrol-2-yl)propan-1-one (53a)

SN

M

N

(at)

Phosphorus oxychloride (1.496 g, 0.896 mL, 9.76 mmol) was added dropwise to precooled (0-57) M,M-dimethylpropionamide (0.987 g, 1.073 mL, 9.76 mmol), maintaining the temperature from about 0 " C to about 5 "C. The resulting reaction mixture was then allowed to warm to room temperature (approximately 25 °C) and then stirred at room temperature (approximately 25 °C) for 15 minutes. The reaction mixture was then diluted with 1,2-dichloroethane (17 mL), the resulting mixture was cooled to 0 "C, then drop by drop 2-(4-chlorophenyl)-3-methyl-1H-pyrrole was added to it (obtained according to the procedure given in Teigapedop I eyeg5 46 (2005) 4539-4542, 1.7 g, 8 .87 mmol) in 1,2-dichloroethane (17 ml). The resulting reaction mixture was heated under reflux for 30 minutes. The progress of the reaction was monitored by TI C. The reaction mixture was then allowed to cool to room temperature and then a solution of sodium acetate trihydrate (6.64 g, 48.8 mmol) in 14 mL of water was added to it. The resulting reaction mixture was heated under reflux for 30 minutes. Then the two phases formed in the reaction mixture were separated.

The aqueous layer was extracted with dichloromethane (3x50 ml). The combined organic layer was washed with saturated sodium bicarbonate solution (1x50 ml) followed by water (1x50 ml) and then the organic layer was dried over anhydrous Mag25O0.5. The solvent was evaporated from the dried organic layer under reduced pressure to give the crude product. The crude product was then purified by flash column chromatography using 10 95 ethyl acetate in hexanes as eluent to give the title compound (1.82 g, 83 Vol).

M5: mass/charge 247 (M'n1).

I"NMR (SOSIz, 400 MHz): b 9.75 (65, exchanges with 020, 1H), 7.47 (a, 9-8.8 Hz, 2H), 7.41 (a, 9-88

Hz, 2H), 6.814, 9-24 Hz, 1H), 2.79 (ad, 9U-7.2 Hz, 2H), 2.26 (5, ЗН), 1.21 (1, 9-72 Hz , ZN).

Step 2: 1-(3-bromo-5-(4-chlorophenyl)-4-methyl-1H-pyrrole-2-ylpropan-1-one (5360)

SNz

Ve. io; M

N

A solution of M-bromosuccinimide (1.25 g, 7.06 mmol) in TNE (20 mL) was added dropwise to a solution of 1-(5-(4-chlorophenyl)-4-methyl-1H-pyrrol-2-yl )upropan-1-one (compound 53a, 1.75 g, 7.06 mmol),

It was shaken in TNE (40 ml) at about -78 "C. The resulting reaction mixture was shaken at about -78 "C for 5 hours. The reaction mixture was then allowed to slowly warm to 25°C for an additional 3-4 hours. The progress of the reaction was monitored by TICS.

The solvent was evaporated from the reaction mixture under reduced pressure and ethyl acetate (200 ml) was added to the resulting residue. The resulting mixture was washed with a saturated solution of sodium bicarbonate (1x50 ml) followed by washing with water (1x50 ml). The combined organic layer was then dried over anhydrous Ma»5O4. The solvent was evaporated from the dried organic layer under reduced pressure to give the crude product, which was then purified by flash column chromatography using 10 95 ethyl acetate in hexanes to give the title compound (1.77 g, 77 Fo).

M5: mass/charge 327 (M-n1).

I"NMR (SOSI", 400 MHz): 6 9.67 (65, exchanged with 020, 1H) 7.43 (t, 4H), 3.05 (d, 9-72 Hz, 2H), 2.21 (5, ZN), 1.20 (I, 9-7.2 Hz, ZN).

Step 3: 4-(5-(4-Chlorophenyl)-4-methyl-2-propionyl-1H-pyrrol-3-yl)benzenesulfonamide (compound 53) bo n.MmOo,5

KY sn o. // from:

To a solution of 1-(3-bromo-5-(4-chlorophenyl)-4-methyl-1H-pyrrol-2-yl)upropan-1-one (compound 536, 1.0 g, 3.06 mmol) in a mixture Toluene:ethanol (5:15 mL) was added 4-aminosulfonylbenzeneboronic acid (0.67 g, 3.37 mmol) and potassium carbonate (1.26 g, 9.19 mmol) at about 25°C in a stoppered tube. , and nitrogen gas was bubbled through the resulting reaction mixture for 15 minutes. Tetrakis(triphenylphosphine)palladium(O) (0.17 g, 0.153 mmol) was then added to the reaction mixture under nitrogen and the reaction mixture was heated from about 90 "C to 95 " C for 18 hours with shaking. The course of the reaction was monitored by TI C. Then the reaction mixture was cooled to 25 "C and filtered through celite. The celite pad was washed with 1095 methanol in dichloromethane (3x25 mL).

The combined filtrate was concentrated under reduced pressure to give the crude product, which was then purified by flash column chromatography using 40 95 ethyl acetate in hexanes as eluent to give the title compound (0.082 g, 6.65 g).

M5: mass/charge 403 (M'-1). "NMR (0OM5O, 400 MHz): b 11.83 (p5, exchanges with 020, 1H) 7.87 (y, 9U-8.4 Hz, 2H), 7.61 (a, 9-84

Hz, 2H), 7.53 (y, 9U-8.4 Hz, 2H), 7.51 (a, 9U-8.4 Hz, 2H), 7.42 (65, exchanges with 020, 2H), 2.40 (d, U-7.2 Hz, 2H), 1.91 (5, ЗН), 0.914, 9-7.2 Hz, ЗН).

Example 13: 4-(5-(4-Chlorophenyl)-1-ethyl-4-methyl-2-propionyl-1H-pyrrol-3-yl)benzenesulfonamide (compound 51)

NmO.5

FI, SNU o // eh: ho x

Step 1: 2-(4-chlorophenyl)-1-ethyl-3-methyl-1H-pyrrole (51a)

SN

/

A solution of /2-(4-chlorophenyl)-3-methyl-1H-pyrrole (obtained according to the procedure given in Teigapeadgop I eChCeg5 46 (2005) 4539-4542, 1.0 g, 5.22 mmol) in OME (10 mL) was added dropwise to a shaking suspension of sodium hydride (0.23 g, 5.74 mmol, 60 95 dispersion in mineral oil) in 20 mL of OME at 0 °C under a nitrogen atmosphere. The reaction mixture was then stirred at approx. 0 "C for 30 minutes. Then ethyl iodide (0.89 g, 0.47 ml, 5.74 mmol) was added to the reaction mixture, maintaining the temperature at 0 "C. Then the reaction mixture was shaken at 25 "C for 3 hours. The course of the reaction was monitored using TI.

Z The reaction mixture was slowly quenched with cold water (30 mL) and the resulting mixture was then extracted with ethyl acetate (2 x 30 mL). The combined organic layer was then washed with brine (1 x mL) and dried over sodium sulfate. The dried organic layer was then concentrated under reduced pressure to give the crude product as a semi-solid mass (0.8 g), which was then purified by flash column chromatography using 5 95 ethyl acetate in hexanes as eluent to give the title compound (0.6 g, 52.3 95).

M5: mass/charge 220 (M.-n1).

I"NMR (SOSI"z, 400 MHz): b 7.42 (y, 9-84 Hz, 2H), 7.24 (y, 9-8.4 Hz, 2H), 6.71 (a, 9U -2.8 Hz, 1H), 6.10 (a, 9-2.8 Hz, 1H), 3.83 (d, 9-7.2 Hz, 2H), 2.05 (5, ЗН), 1.24 (I, 9-72 Hz, ZN).

Step 2: 1-(5-(4-Chlorophenyl)-1-ethyl-4-methyl-1H-pyrrol-2-yl)upropan-1-one (5165)

SN.

M and (in;

Phosphorus oxychloride (0.47 g, 0.28 mL, 3.00 mmol) was added dropwise to precooled (0-57) M,M-dimethylpropionamide (0.30 g, 0.27 mL, 3.00 mmol ), maintaining the temperature from about 0 "C to about 5 "C. The resulting reaction mixture was then allowed to warm to room temperature (approximately 25°C), after which it was shaken at room temperature (approximately 25°C) for 20 minutes. Then the reaction mixture was diluted with 1,2-dichloroethane (15 ml), the resulting mixture was cooled to 0 "С, then 2-(4-chlorophenyl)-1-ethyl-3-methyl-1H-pyrrole (compound 51a, 0.6 g, 2.13 mmol) in 1,2-dichloroethane (15 mL). The resulting reaction mixture was heated under reflux for 30 minutes. The progress of the reaction was monitored by TIS. Then the reaction mixture was allowed to cool to room temperature temperature, and then a solution of sodium acetate trihydrate (1.23 g, 15.0 mmol) in 14 mL of water was added to it. The resulting reaction mixture was heated under reflux for 30 minutes. The two phases formed in the reaction mixture were then separated. The aqueous layer was extracted dichloromethane (3 x 30 mL). The combined organic layer was washed with water (1 x 30 mL) and dried over anhydrous Mg 5 O 4 . The solvent was evaporated from the dried organic layer under reduced pressure to give the crude product, which was then purified by flash column chromatography using 10 95 ethyl acetate in hexanes as an eluent to give the title compound (0.5 g, 66.4 Vol).

M5: mass/charge 276 (M'n1).

I"NMR (SOSI", 400 MHz): b 7.46 (y, 9U-8.4 Hz, 2H), 7.23 (y, 9-8.4 Hz, 2H), 6.90 (5, 1H), 4.23 (a, 9U-7.2 Hz, 2H), 2.85 (4, 9-7.2 Hz, 2H), 1.95 (5, ЗН), 1.22 (1, 9-7.2 Hz, ZN), 1.16 (Her, 9U-7.2 Hz, ZN).

Step 3: 1-(3-bromo-5-(4-chlorophenyl)-1-ethyl-4-methyl-1H-pyrrole-2-ylpropan-1-one (51c)

SN

Ve.

More; si o M

IN.

A solution of M-bromosuccinimide (0.35 g, 1.99 mmol) in TNE (10 mL) was added dropwise to a solution of 1-(5-(4-chlorophenyl)-1-ethyl-4-methyl-1H-pyrrole -2-yl)upropan-1-one (compound 516, 0.5 g, 1.81 mmol) stirred in TNE (25 mL) at about -78 "C. The resulting reaction mixture was stirred at about -78 " C for 5 hours. The reaction mixture was then allowed to slowly warm to 25 °C for an additional 3-4 hours. The progress of the reaction was monitored using

TS. The solvent was evaporated from the reaction mixture under reduced pressure to the obtained residue

Ethyl acetate (50 ml) was added. The resulting mixture was washed with a saturated solution of sodium bicarbonate (1x30 ml) followed by washing with water (1x30 ml). The combined organic layer was then dried over anhydrous Ma»5O4. The solvent was evaporated from the dried organic layer under reduced pressure to give the crude product, which was then purified by flash column chromatography with 10 95 ethyl acetate in hexanes as eluent to give the title compound (0.5 g, 78.0 Fo). "NYMR (SOSI", 400 MHz): b 7.45 (a, 9-84 Hz, 2H), 7.22 (0.9-84 Hz, 2H), 4.20 (d, 9-6.8 Hz, 2H), 3.14 (ad, 9U-7.2 Hz, 2H), 1.91 (5, ЗН), 1.22 (1, 9-7.2 Hz, ЗН), 1.12 ( I, 9U-6.8 Hz, ZN).

Step 4: 4-(5-(4-Chlorophenyl)-1-ethyl-4-methyl-2-propionyl-1H-pyrrol-3-yl)/benzenesulfonamide (compound 51)

NoMO2"5 "Y St. about Liakh (3

M si zo 5

To a solution of 1-(3-bromo-5-(4-chlorophenyl)-1-ethyl-4-methyl-1H-pyrrol-2-yl)upropan-1-one (compound 51c, 0.5 ppm, 1.41 mmol) in a mixture of tolueneethanol (3:12 ml), 4-aminosulfonylbenzeneboronic acid (0.34 g, 1.69 mmol) and potassium carbonate (0.48 g, 3.52 mmol) were added at a temperature of approximately 25 "С in a test tube , which is capped, and nitrogen gas was bubbled through the reaction mixture for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.16 g, 0.14 mmol) was then added to the reaction mixture under nitrogen and the reaction mixture was heated from about 90 "C to 95 "C for 18 hours with shaking. The course of the reaction was monitored by TI C. Then the reaction mixture was cooled to 25 "C and filtered through celite. The celite pad was washed with 10 95 methanol in dichloromethane (2 x 20 ml). The combined filtrate was concentrated under reduced pressure to give the crude product, which was then purified by column chromatography on silica gel (100-200 mesh) using 30-35 95 ethyl acetate in hexanes as eluent to give the title compound (0.2 g, 32.9 Fo).

M5: mass/charge 431 (M'-1).

I"NMR (SOSI", 400 MHz): b 8.02 (a, 9U-8.4 Hz, 2H), 7.47-7.49 (t, 4H), 7.29 (y, 9U-8 ,4 Hz, 2H), 4.94 (re-exchanges with O2O, 2H), 4.21 (ad, U9-6.8 Hz, 2H), 2.18 (d, 9-7.2 Hz, 2H ), 1.69 (5, ZN), 1.16 (i, 9-68

Hz, ZN), 0.95 (I, U-7.2 Hz, ZN).

Similarly, the following compound 4-(5-(4-Chlorophenyl)-1-(cyclopropylmethyl)-4-methyl-2-propionyl-1H-pyrrol-3-yl) was obtained by practical application of the above procedure with appropriate changes in reactants benzenesulfonamide (compound 52)

M5: mass/charge 457 (M--1). "NYMR (SOSI", 400 MHz): b 8.01 (a, 9U-8.4 Hz, 2H), 7.46-7.50 (t, 4H), 7.30 (a, 9-8, 4 Hz, 2H), 4.97 (re-exchanges with O2O, 2H), 4.14 (d, U-6.8 Hz, 2H), 2.20 (d, 9-7.2 Hz, 2H) , 1.72 (5, ZN), 0.96 (Her, 9-72

Hu, ZN), 0.86-0.87 (t, 1H), 0.31-0.34 (t, 2H), -0.08- -0.04 (t, 2H).

Example 14: Preparation of 4-(5-(4-chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)-2-methylbenzenesulfonamide (compound 41) nomO,5

FI DREAM

3-7 at 5 ns

Step 1: Methyl 3-(4-(M-(tert-butyl)usulfamoyl)-3-methylphenyl)-4-methylthiophene-2-carboxylate (Aa)

CHz o // 5 -o 4-bromo-M-(tert-butyl)-2-methylbenzenesulfonamide (obtained according to the procedure described in the literature Teigapedgop, 2006, 62, 7902-7910, 1.43 g, 4.68 mmol ) and potassium phosphate (2.25 g, 10.63 mmol) were added to a suspension of methyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-

From dioxaborolan-2-yl)thiophene-2-carboxylate (obtained according to the procedure described in the literature U. Ogd. Spet., 2010, 75, 3855-3858, 1.2 g, 4.25 mmol), which is shaken, in a mixture of 20 ml

TNE and 4 ml of water in a test tube in a nitrogen atmosphere at room temperature (25 "C). Nitrogen purging was continued for this suspension for 15 minutes at room temperature (25 "C).

Triphenylphosphine (0.056 g, 0.21 mmol) and palladium(II) acetate (0.02 g, 0.08 mmol) were then added

C5 to it at 25"C and the test tube was closed with a stopper. The reaction mixture was shaken at 70C for 20 hours. The course of the reaction was monitored with the help of TIS. The reaction mixture was then filtered and washed with ethyl acetate (2 x 30 ml). The organic layer was concentrated at reduced pressure to give the crude product, which was then purified by flash column chromatography using 40 95 ethyl acetate in hexanes as eluent to give the title compound (0.7 g, 43.10 U).

M5: mass/charge 382 (M'-1). "NYMR (SOSI", 400 MHz): b 8.09 (y, 9U-8.0 Hz, 1H), 7.16-7.23 (t, ZN), 4.52 (p5-exchanges with 020, 1H), 3.69 (5, ЗН), 2.70 (5, ЗН), 2.00 (5, ЗН), 1.27 (5, 9Н).

Step 2: Methyl 5-bromo-4-methyl-3-(3-methyl-4-sulfamoylphenyl)thiophene-2-carboxylate (41B)

n.mOo,5

SN

) and in another -0

Bromine (0.35 g, 0.11 mL, 2.2 mmol) was added dropwise to a suspension of methyl-3-(4-(M-(tert-butyl)usulfamoyl)-3-methylphenyl)-4-methylthiophene- 2-carboxylate (41a, 0.70 g, 1.83 mmol), which was stirred in OCM (15 mL) at 0 °C. The reaction mixture was then stirred at 257 for 3 hours. The progress of the reaction was monitored by TI C. The reaction mixture was then concentrated. OSM (50 mL) was added to the residue. The resulting mixture was washed with water (2 x 20 mL), brine (1 x 20 mL), and dried over sodium sulfate. The dried organic layer was then concentrated under reduced pressure to give crude product in the form of a semi-solid substance (0.7 g), which was then purified by flash column chromatography using 40 95 ethyl acetate in hexanes as eluent to give the title compound (0.63 g, 85.13 Vol).

M5: mass/charge 405 (M'-1). "NMR (SOSI", 400 MHz): b 8.09 (a, 9U-8.0 Gu, 1H), 7.17-7.23 (t, 2H), 4.91 (re-exchanges with 020, 2H), 3.73 (5, ZN), 2.72 (5, ZN), 1.95 (5, ZN).

Step 3: Ethyl 5-(4-chlorophenyl)-4-methyl-3-(3-methyl-4-sulfamoylphenyl)thiophene-2-carboxylate (41c) n.mOo»5 o

(d4-chlorophenyl)boronic acid (0.29 g, 1.85 mmol) and potassium carbonate (0.43 g, 3.09 mmol) were added to a solution of methyl 5-bromo-4-methyl-3-( 3-methyl-4-sulfamoylphenyl)thiophene-2-carboxylate (4160, 0.62 g, 1.54 mmol) in a mixture of 5 ml of toluene and 20 ml of ethanol at 25 "C. Nitrogen gas was bubbled through the reaction mixture for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.09 g, 0.08 mmol) was then added to the reaction mixture under a nitrogen atmosphere and the reaction mixture was heated at a temperature from about 95 °C to 100 °C for 3 hours with shaking. the reaction was observed with the help of TI!C. Then the reaction mixture was cooled to 25 "C and filtered through celite. The celite pad was washed with ethyl acetate (20 mL). The combined filtrate was then concentrated under reduced pressure to give the crude product, which was then purified by flash column chromatography using 30 95 ethyl acetate in hexanes as eluent to give the title compound (0.53 g, 76.8 U).

From M5: mass/charge 450 (M-n1). "NMR (SOSI", 400 MHz): b 8.09 (a, 9-8.4 Hz, 1H), 7.41-7.46 (t, 4H), 7.21-7.24 (t, 2H), 4.88 (rz-exchanges with O2O, 2H), 4.17 (d, U-6.8 Hz, 2H), 2.73(5, ЗН), 1.99 (5, ЗН), 1.19 (I, 9U-6.8 Hz, ZN).

Step 4: 5-(4-Chlorophenyl)-4-methyl-3-(3-methyl-4-sulfamoylphenyl)thiophene-2-carboxylic acid (414)

NMO"5 and 5-0

Ethyl 5-(4-chlorophenyl)-4-methyl-3-(3-methyl-4-sulfamoylphenyl)thiophene-2-carboxylate (41c, 0.6 g, 1.33 mmol) was suspended in ethanol (20 mL) and a solution of sodium hydroxide (0.1 g, 2.66 mmol) in water (2 ml) was added to it at 25 "C. Then the reaction mixture was heated to 75 "C with shaking for 2 hours. The course of the reaction was observed using TI C. The reaction mixture was concentrated under reduced pressure. The resulting residue was then diluted with water (5 ml) and the mixture was cooled using an ice bath. 10 95 aqueous HCl was added to the cooled mixture, adjusting the pH of the mixture from approximately 5 to 6. Then the mixture was extracted with ethyl acetate (2 x 35 ml). The combined organic layer was then dried over anhydrous NaOH.

The solvent was evaporated from the dried organic layer under reduced pressure to give the title compound (0.53 g, 94 Vol).

M5: mass/charge 422 (M-n1).

NMR (0M5O, 400 MHz): b 12.52 (rz-exchanges with 020, 1H), 7.89 (a, 9-8.4 Hz, 1H), 7.54-7.58 (t,

AN), 7.46 (p5-exchanges with 020, 2H), 7.27-7.32 (t, 2H), 2.62 (5, ZN), 1.98 (v, ZN).

Step 5: 5-(4-Chlorophenyl)-3-(4-((M-(dimethylamino)methylene)sulfamoyl)-3-methylphenyl)-M-methoxy-M,4-dimethylthiophene-2-carboxamide (41e)

AND

Mo o) / X with A o si

Oxalyl chloride (0.47 g, 0.32 mL, 3.7 mmol) was added dropwise to a solution of 5-(4-chlorophenyl)-4-methyl-3-(3-methyl-4-sulfamoylphenyl)thiophene-2- carboxylic acid (414, 0.52 g, 1.23 mmol) in a mixture of dichloromethane (20 mL) and OME (0.18 g, 0.19 mL, 2.46 mmol) at 0 "C. Then the mixture was allowed to warm to at room temperature and shaken for 1.5 hours under a nitrogen atmosphere. The course of the reaction was monitored by TI C. The reaction mixture was then concentrated under reduced pressure. The resulting residue was then dissolved in dry dichloromethane (20 mL) and cooled to 0"C. Triethylamine (0.74 g, 1.03 mL, 7.39 mmol) was then added to the resulting cooled solution, followed by the addition of M,O-dimethylhydroxylamine hydrochloride (0.24 g, 2.46 mmol) with shaking. Then the reaction mixture was shaken at room temperature for 2 hours. The course of the reaction was observed with the help of TI C. Then the reaction mixture was diluted with OSM (20 ml) and the resulting mixture was washed with water (2 x 10 ml). The resulting organic layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was then purified by column chromatography on silica gel (100-200 mesh) using 0.8 9% methanol in OSM as eluent to afford the title compound (0.34 g, 53 vol).

M5: mass/charge 520 (M'-1). "NMR (SOSI", 400 MHz): b 8.15 (5, 1H), 8.01 (a, 9-84 Hz, 1H), 7.43-7.44 (t, 4H), 7.15 -7.19 (t, 2H), 3.70 (5, ЗН), 3.20 (5, ЗН), 3.16 (5, ЗН), 3.06 (5, ЗН), 2.70( 5, ZN), 1.98 (5, ZN).

Zo Step 6: 4-(5-(4-Chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)-2-methylbenzenesulfonamide (compound 41) nMO,5 a e 9-0 o 5 nNzs

Grignard's reagent (ethylmagnesium bromide, 0.42 g, 3.17 ml of a 1M solution in TNE, 3.17 mmol) was added dropwise to a solution of (5-(4-chlorophenyl)-3-(4-(M- ( dimethylamino)methylene)sulfamoyl)-3-methylphenyl)-M-methoxy-M,4-dimethylthiophene-2-carboxamide (41e, 0.33 g, 0.63 mmol) in shaking anhydrous TNE (20 mL) at 25 76.

Then the reaction mixture was heated from about 70 "C to 75 "C for 1 hour. The course of the reaction was monitored with TI! C. Then the reaction mixture was cooled to 0°C.

The cooled reaction mixture was quenched by adding saturated ammonium chloride solution (10 mL) and then the mixture was extracted with ethyl acetate (2 x 30 mL). The combined organic layer was dried over anhydrous Ma»5O4. The solvent was evaporated from the dried organic layer under reduced pressure to give the crude product, which was then purified using preparative NRI C to give the title compound (0.05 g, 18.1 95).

M5: mass/charge 434 (M'-1).

"NMR (0M50O, 400 MHz): b 7.93 (a, 9U-8.0 Hz, 1H), 7.56-7.59 (t, 4H), 7.51 (rz-exchanges with 020, 2H ), 7.35-7.38 (t, 2H), 2.64 (5, ЗН), 2.32 (d, 927.2 Hz, 2Н), 1.92 (5, ЗН), 0.87 (I, 9U-7.2 Hz, ZN).

Example 15: Preparation of 1-(5-(4-chlorophenyl)-4-methyl-3-(4-(piperidin-1-ylsulfonyl)phenyl)thiophen-2-yl)upropan-1-one (compound 48)

FU;

M. in; where x f si 5 0)

Step 1: Ethyl 4-methyl-3-(4-(piperidin-1-ylsulfonyl)phenyl)thiophene-2-carboxylate (48a) (e)

SN. o 5 t (4-(Piperidin-1-ylsulfonyl)/phenyl)boronic acid (obtained according to the procedure described in O520060258670, 4.41 g, 16.38 mmol) and potassium carbonate (5.15 g, 37.2 mmol) was added to a suspension of methyl 3-bromo-4-methylthiophene-2-carboxylate (7a, 3.5 g, 14.89 mmol), which was being shaken, in a mixture of 100 ml of ethanol and 30 ml of toluene in a test tube under a nitrogen atmosphere at room temperature (257). This suspension was purged with nitrogen for 15 minutes at room temperature (2572). Tetrakis(triphenylphosphine)palladium(0) (0.86 g, 0.74 mmol) was then added to the reaction mixture at a temperature of approximately 25 °C and the tube was capped. The reaction mixture was then shaken at 105 °C for 15 hours. The course of the reaction was observed with the help of TI C. Then the reaction mixture was filtered and washed with ethyl acetate (2 x 50 ml).

The combined organic layer was then concentrated under reduced pressure to give the crude product, which was then purified by column chromatography on silica gel (100-200 mesh) using 4595 ethyl acetate in hexanes as eluent to give the title compound (3.5 g, 62 ,0 95).

M5: mass/charge 394 (M'-1).

I"NMR (0M50, 400 MHz): b 7.76 (y, 9-8.4 Hz, 2H), 7.68 (5, 1H), 7.50 (a, 9U-8.4 Hz, 2H ), 4.06 (4, 9-6.6 Hu, 2H), 2.93 (I, 9-4.2 Hu, 4H), 1.98 (5, ЗН), 1.54-1.59 (t, 4H), 1.36-1.39 (t, 2H), 1.01 (I, 9U-6.8

Hz, ZN).

Step 2: Ethyl 5-bromo-4-methyl-3-(4-(piperidin-1-ylsulfonyl)phenyl)thiophene-2-carboxylate (486) ha -Z 07

SNz about Y in Vg 5 t

Obtained using the following method presented in example C in step 3, using 48a as a starting material.

From M5: mass/charge 473 (M-n1).

Step 3: Ethyl 5-(4-chlorophenyl)-4-methyl-3-(4-(piperidin-1-ylsulfonyl)phenyl)thiophene-2-carboxylate (48c)

Fe; rya 9-7 cho 5 (e)

Obtained using the following method presented in example C at step 4, using 4865 and (4-chlorophenyl)boronic acid as reactants.

M5: mass/charge 504 (M'-1). 5 Step 4: 5-(4-Chlorophenyl)-4-methyl-3-(4-(piperidin-1-ylsulfonyl)phenyl)thiophene-2-carboxylic acid (484)

Fe.

M. "

IN

IN

-- but 5 (e)

Obtained using the following method presented in example C at step 5, using 48c as a starting material.

M5: mass/charge 476 (M-n1).

Step-3: 5-(4-Chlorophenyl)-M-methoxy-M,4-dimethyl-3-(4-(piperidin-1-ylsulfonyl)phenyl)thiophene-2-carboxamide (48e)

Fe;

M. I 5 2-6

M 5 - 1 o (o)

Obtained using the following method presented in example C in step 6, using 484 as a starting material.

M5: mass/charge 519 (M'-1).

Step-4: 1-(5-(4-Chlorophenyl)-4-methyl-3-(4-(piperidin-1-ylsulfonyl)phenyl)thiophen-2-yl)upropan-1-one (compound 48)

Fe.

M. i 5 9- 5 (c)

Obtained using the following method presented in example C at step 7 using 48e as a starting material.

M5: mass/charge 488 (M'-1). "NMR (0M5O, 400 MHz): b 7.84 (y, 9-8.0 Hz, 2H), 7.63 (y, 9-8.0 Hz, 2H), 7.46 (t, 4H) . , 1.36-1.38 (t, 2H), 0.86 (y, y7.2 Hz, ZN).

Example 16: Preparation of 5-(4-chlorophenyl)-M,M,1,4-tetramethyl-3-(4-sulfamoylphenyl)-1H-pyrrole-2-carboxamide (compound 50)

nm // where 3-9: (o) M

M

M

/

To a solution of / 5-(4-chlorophenyl)-1,4-dimethyl-3-(4-sulfamoylphenyl)-1H-pyrrole-2-carboxylic acid (496, 1.00 g, 2.47 mmol), which is being shaken, in OME (15 mL) was added NOVT (0.41 g, 2.72 mmol) at room temperature, followed by the addition of dimethylamine hydrochloride (0.40 g, 4.94 mmol). The reaction mixture was cooled to 0 °C, and then EOS (0.71 g, 3.70 mmol) and triethylamine (1.00 g, 1.37 mL, 9.88 mmol) were added to the cooled reaction mixture. The reaction mixture was then shaken at at room temperature for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. Ethyl acetate (100 mL) was added to the resulting residue. The resulting mixture was then washed with saturated sodium bicarbonate solution (20 mL) followed by brine solution (20 mL). The resulting organic layer was dried over anhydrous sodium sulfate. The dried organic layer was then concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 90 95 ethyl acetate in hexanes as an eluent to give the title compound (0.94 g, 88.1 95).

M5: mass/charge 432 (M'-1).

I"NMR (0M50O, 400 MHz): 6 7.82 (y, 9-84 Hz, 2H), 7.57 (y, 9-84 Hz, 2H), 7.46 (a, 9-84 Hz, 2H), 7.A1 (a, 9-84 Hz, 2H), 7.36 (B5-exchanges with 020, 2H), 3.40 (5, ЗН), 2.87 (c, ЗН), 2, 56 (5, ZN), 1.98 (in,

ZN).

Example 17: Preparation of ethyl 5-(4-chlorophenyl)-4-methyl-3-(4-sulfamoyl-5,6,7,8-tetrahydronaphthalen-1-yl)thiophene-2-carboxylate (compound 59) n. mO,5 F se 3-7 o 5 7

Stage 1: 4-bromo-5,6,7,8-tetrahydronaphthalene-1-sulfonyl chloride (59a) so; 0

Hg

Chlorosulfonic acid (13.80 g, 7.93 ml, 118.00 mmol) was added dropwise to a solution of 5-bromo-1,2,3,4-tetrahydronaphthalene (obtained according to the procedure described in the literature M/O2004/ 792, 10.0 g, 47.4 mmol), which is shaken, in 50 ml of chloroform at 0 s.

The reaction mixture was then allowed to warm to approximately 25°C and shaken at the same temperature for 45 minutes. The course of the reaction was monitored using TI S. Then

The reaction mixture was poured into ice water (50 ml) and the resulting mixture was extracted with chloroform (2 x 150 ml). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the title compound (12.0 g, 81.6 95), which was taken as such without further work-up for the next step.

M5: mass/charge Z310(M-1).

I"NMR (SOSI", 400 MHz): b 7.81 (a, 9U-8.8 Hu, 1H), 7.64 (a, 9U-8.8 Hu, 1H), 2.72-7, 81 (t, 4H), 1.683-1.89 (t, 4H).

Step 2: 4-bromo-N-(tert-butyl)-5,6,7,8-tetrahydronaphthalene-1-sulfonamide (595)

what

Hg

Tert-butylamine (8.5 g, 12.32 mL, 116.0 mmol) was added dropwise to a suspension of 4-bromo-5,6,7,8-tetrahydronaphthalene-1-sulfonyl chloride (59a, 12.0 g, 38.8 mmol), which is shaken, in 150 ml of tetrahydrofuran at 0 "C. Then the reaction mixture was shaken at a temperature of approximately 25 "C for 2 hours. The progress of the reaction was monitored by TIS. Water (100 ml) was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate (2 x 150 ml). The combined organic layer was then dried over sodium sulfate and the dried organic layer was concentrated under reduced pressure to give the crude product, which was then purified by column chromatography on silica gel (100-200 mesh) using 95% ethyl acetate in hexanes as eluent to give the title compounds (2.34 g, 17.4 95).

M5: mass/charge 347 (M'-1). "NMR (SOSI", 400 MHz): b 7.79 (a, 9U-8.8 Hz, 1H), 7.52 (a, 9-8.8 Hz, 1H), 4.53 (p5-exchanges with 020, 1H), 2.76-7.63 (t, 4H), 1.80-1.85 (t, 4H), 1.22 (5, 9H).

Step C: Methyl 3-(4-(N-(tert-butyl)sulfamoyl)-5,6,7,8-tetrahydronaphthalen-1-yl)-4-methylthiophene-2-carboxylate (59c)

SN about 5-co 4-bromo-M-(tert-butyl)-5,6,7,8-tetrahydronaphthalene-1-sulfonamide (596, 1.35 g, 3.90 mmol) and potassium phosphate (0.75 g, 3.54 mmol) ) was added to a suspension of methyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (obtained according to the procedure described in the literature 9 . Ogd. Spet., 2010, 75, 3855-3858, 1.0 g, 3.54 mmol), which is shaken, in a mixture of 20 ml of TNE and 4 ml of water in a test tube under a nitrogen atmosphere at room temperature (approximately 25 C) .

This suspension was purged with nitrogen gas for 15 minutes at room temperature (approximately 25 °C). Triphenylphosphine (0.028 g, 0.10 mmol) and palladium acetate (II) (0.016 g, 0.07 mmol) were then added to the reaction mixture at 25 "C and the test tube was closed with a cork. The reaction mixture was then stirred at approximately 75°C for 20 hours. The progress of the reaction was monitored by TLC. The reaction mixture was then filtered and the resulting substrate was washed with ethyl acetate (2 x 30 mL). The combined filtrate was then concentrated under reduced pressure to give the crude product, which was then purified by flash column chromatography using 30 95 ethyl acetate in hexanes as eluent to give the title compound (0.11 g, 7.7 95).

M5: mass/charge 422 (M'n1).

I"NMR (SOCIz, 400 MHz): b 7.99 (a, 9-8.0 Hz, 1H), 7.26 (5, 1H), 6.98 (a, 9-8.0 Hz, 1H ), 4.43 (p5- exchanges with O2O, 1H), 3.66 (5, ЗН), 3.23 (I, 9U-6.4 Hz, 2H), 2.21-2.43 (t, 2H), 1.87 (5, ZN), 1.69-1.81 (t,

AN), 1.27 (5, 9Н).

Step 4: Methyl 5-bromo-4-methyl-3-(4-sulfamoyl-5,6,7,8-tetrahydronaphthalen-1-yl)thiophene-2-carboxylate (594)

NoMO, 5

SN o and vi Vi -o

Bromine (0.045 g, 0.015 mL, 0.28 mmol) was added dropwise to a suspension of methyl-3-(4-(N-(tert-butyl)sulfamoyl)-5,6,7,8-tetrahydronaphthalen-1-yl )-4-methylthiophene-2-carboxylate

(59c, 0.10 g, 0.24 mmol), which was shaken, in 15 ml of dichloromethane at a temperature of about 0 "C. Then the reaction mixture was shaken at about 25 "C for 2 hours. The course of the reaction was observed with the help of TI C. Then the reaction mixture was concentrated. 20 ml of dichloromethane was added to the obtained residue. The resulting mixture was washed with water (2 x 10 ml), saline solution (1 x 10 ml) and the resulting organic layer was dried over sodium sulfate. The dried organic layer was then concentrated under reduced pressure to give the crude product, which was then purified by flash column chromatography using 20 95 ethyl acetate in hexanes as eluent to give the title compound (0.08 g, 67.4 Ubv).

M5: mass/charge 445 (M'-1).

I"NMR (SOSI", 400 MHz): 6 7.97 (y, 9-8.4 Hz, 1H), 6.97 (a, 9U-8.4 Hz, 1H), 4.43 (p5- exchanges with 020, 2H), 3.73 (5, ЗН), 3.22-3.28 (t, 2H), 2.24-2.А46 (t, 2H), 1.69-1.82 ( t, 7H).

Step 5: Ethyl 5-(4-chlorophenyl)-4-methyl-3-(4-sulfamoyl-5,6,7,8-tetrahydronaphthalen-1-yl)thiophene-2-carboxylate (compound 59) pe F, (4-Chlorophenyl)boronic acid (0.027 g, 0.17 mmol) and potassium carbonate (0.043 g, 0.31 mmol) were added to a solution of methyl-5-bromo-4-methyl-3-(4- sulfamoyl-5,6,7,8-tetrahydronaphthalene-1-yl)thiophene-2-carboxylate (594, 0.07 g, 0.16 mmol) in a mixture of 1 ml of toluene and 4 ml of ethanol at 2576. Nitrogen gas was bubbled through the reaction mixture for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.009 g, 0.008 mmol) was then added to the reaction mixture under a nitrogen atmosphere and the reaction mixture was heated at a temperature from about 95 °C to about 100 °C for 3 hours with shaking. The progress of the reaction was monitored using TI C. Then the reaction mixture was cooled to 25"C and filtered through celite, the celite pad was washed with 10 ml of ethyl acetate. The resulting combined filtrate was then concentrated under reduced pressure to give the crude product, which was then purified by flash column chromatography using 30% ethyl acetate in hexanes as eluent to give the title compound (0.027 g, 35.0 v).

M5: mass/charge 490 (M'-1).

I"NMR (SOSIz, 400 MHz): b 7.97 (y, 9U-8.0 Gu, 1H), 7.45 (5, 4H), 7.05 (a, 9U-8.0 Hz, 1H ), 5.31 (p5- exchanges with 020, 2H), 4.10-4.20 (t, 2H), 3.25-3.28 (t, 2H), 2.51-2.57 (t , 1H), 2.31-2.37 (t, 1H), 1.78-

Zo 1.90 (t, 7H), 1.13 (her, 9-7.2 Hz, ZN).

Example 18: Preparation of ethyl 5-(4-chlorophenyl)-3-(4-sulfamoylphenyl)/furan-2-carboxylate (compound 60) n.mOo,5 iso. io» o o

IS

Stage 1: Ethyl-3-(4-sulfamoylphenyl)furan-2-carboxylate (bba) n.mO,5 o. // (o)

Gee)

G

(4-Sulfamoylphenyl)boronic acid (1.76 g, 8.77 mmol) and potassium carbonate (2.52 g, 18.26 mmol) were added to a suspension of ethyl 3-bromofuran-2-carboxylate (obtained according to the procedure described in the literature EP1I489077A1, 2004, 1.6 g, 7.30 mmol), which is shaken, in a mixture of 80 ml of ethanol and 20 ml of toluene (80 ml:20 ml) in a nitrogen atmosphere at room temperature

(25'C) in a test tube. The suspension was purged with nitrogen gas for 15 minutes at room temperature (approximately 25°C). Tetrakis(triphenylphosphine)palladium(0) (0.422 g, 0.365 mmol) was then added to the reaction mixture at 25 °C and the tube was closed with a stopper. Then the reaction mixture was shaken at 100 °C for 18 hours. The course of the reaction was observed with the help of TI C. The reaction mixture was then filtered and washed with ethyl acetate (2 x 100 ml). The combined organic layer was then concentrated under reduced pressure to give the crude product as a semi-solid (11.2 g), which was then purified by column chromatography on silica gel (100-200 mesh) using 50 95 ethyl acetate in hexanes as eluent. to obtain the title compound (1.2 g, 55.60 9b).

M5: mass/charge 296 (M-n1).

I"NMR (SOCIz, 400 MHz): b 7.99 (y, U-8.8 Hz, 2H), 7.76 (a, 9U-8.8 Hz, 2H), 7.23 (0.9 -2.0 Hz 1H), 6.65 (y, U-2.0 Hz, 1H), 4.85 (B5-exchanges with O2O, 2H), 4.35 (ad, 9-7.2 Hz 2H ), 1.33 (i, 9-72 Hz, ZN).

Step 2: Ethyl 5-(4-chlorophenyl)-3-(4-sulfamoylphenyl)furan-2-carboxylate (compound 60) noMO,5

1-Bromo-4-chlorobenzene (0.214 g, 1.11 mmol) and potassium acetate (0.199 g, 2.03 mmol) were added to a solution of ethyl 3-(4-sulfamoylphenyl)furan-2-carboxylate. (ba, 0.3 g, 1.01 mmol) in dimethylacetamide (5 mL) at 25 °C in a test tube. Nitrogen gas was bubbled through the reaction mixture for 15 minutes. Palladium(II) acetate (0.023 g, 0.102 mmol) in a nitrogen atmosphere and the tube was closed with a stopper. Then the reaction mixture was heated at 150 "C for 20 hours with shaking. The course of the reaction was monitored using

TS. Then the reaction mixture was cooled to 25 °C and concentrated under reduced pressure.

The obtained residue was dissolved in ethyl acetate (30 ml). The resulting solution was then washed with water (2 x 10 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the crude product, which was then purified by flash column chromatography using 50,906 ethyl acetate in hexanes as eluent to give the title compound ( 0.040 g, 9.70 Fo).

M5: mass/charge 406 (M'-1).

I"NMR (SOSIZ, 400 MHz): b 8.00 (a, 9-8.8 Hz, 2H), 7.75-7.77 (t, 4H), 7.43 (j, 9-8, 8 Hz, 2H), 6.85 (5, 1H), 5.2 (p5-exchanges with 020, 2H), 4.35 (d, 9U-7.2 Hz 2H), 1.34 (I, 9 -72 Hz, ZN).

From Example 19: Pharmacological screening

The compounds were investigated in a real-time cell kinetic assay on human IMC-32 cells with intrinsic a/pASP expression. An increase in the levels of intracellular Ca? were measured on a fluorescence imaging plate reader (EGIRK). Solutions of the tested compound and the agonist were prepared in a buffer for analysis (HB55, p 7.4, 20 mM NEREZ and 10 mM Sasi"). Briefly, cells were seeded onto poly-U-lysine-coated 9b-well microplates with black walls and a clear bottom at a density of 80,000-100,000 cells/well and incubated at 37 C/595 C for 40-48 hours before the experiment. To assess compound-mediated potentiation of the agonist response, the growth medium was removed from the wells and 200 μl of the calcium-binding dye 4 for B IRK (Moeschag Oemise5) resuspended in assay buffer and added to the wells. After loading the dye, the microplates were incubated for 30 minutes at 37 "С and 30 minutes at room temperature and then directly transferred to EGIRK. The background fluorescence was monitored during the first 10-30 seconds, followed by the addition of 25 μl of the solution of the studied compound and the subsequent monitoring of changes in fluorescence for up to 10 minutes

Next was the addition of 25 μl of agonist solution (RMO-282987, 10 μM) and fluorescence measurement for 4 minutes (Raodpiy K. eyi a. 2009, U. Med. Spet., 52, 3377 - 84).

The compound-induced increase in the agonist response (fold increase in PAM activity) was calculated by dividing the maximum effect (maximum-minimum fluorescence value) obtained with the test compound in the presence of an agonist by the effect of the agonist by itself. ECs of the compounds were calculated using the SgarpRai Rgicht software, version 5.0, when plotting the concentration of the compound in relation to the multiplicity of the increase in RAM activity.

Multiplicity of increase in activity at a concentration of 1 μM: compounds with which the activity increases less than 5 times are combined into group A, compounds with which the activity is increased by 5.1-15 times are combined into group B, and compounds , with which the activity increases more than 15 times, are combined into group C.

The following Table 1 shows the fold increase in activity with compounds according to the present invention.

Table 1

Multiplicity of activation increase 2,3, 11, 13, 14,15, 17, 20, 21, 22, 23, 24, 25, 26, 27, 28, 1 AND 29, 31, 32, 33, 34, 35, Zb , 37, 38, 39, 42, 43, 48, 50, 52, 53, 54, 57, 58 2 | In 77771711 14.5,8,9,18,19,30,40,51,55,56...: K::/ :!;,.:S:K(2E:(In DC

Claims (1)

FORMULA OF THE INVENTION 1. The compound of formula I, its tautomeric forms, its stereoisomers or its pharmaceutically acceptable salts uch 7 k КИ и (0) where, in the compound of formula I, 2 is selected from the group including -5-, -О- and -М(Б2)-; B is selected from the group consisting of hydrogen, optionally substituted C1-Swalkyl, optionally substituted C1-Swalkenyl, optionally substituted C1-Swalquinyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted 5-10-membered heteroaryl containing 1-3 heteroatoms selected from M, O and 5, and optionally substituted 4-10-membered heterocyclyl containing 1-3 heteroatoms selected from M, O and 5; B' is selected from the group consisting of optionally substituted aryl, optionally substituted 5- to 10-membered heteroaryl containing 1-3 heteroatoms selected from M, O, and 5, optionally substituted cycloalkyl, and optionally optionally substituted 4-10-membered heterocyclyl containing 1-3 heteroatoms selected from M, O and 5; B2 is selected from the group consisting of hydrogen, optionally substituted C1-Salkyl, optionally substituted Co-Salkyl, optionally substituted C2-Salkyl, halogen, C1-Swiperhaloalkyl, optionally substituted cycloalkyl, cyano, nitro . А!- and веф(-0)-; BZ is selected from the group consisting of optionally substituted C-Svalkyl, optionally Zo-substituted Co-Svalkenyl, optionally substituted Cg2-Svalkynyl, optionally substituted cycloalkyl, optionally substituted 4-10 membered heterocyclyl, which contains 1-3 heteroatoms selected from M, O and 5, wherein each of said optionally substituted cycloalkyl and optionally substituted heterocyclyl is optionally annelated or necessarily connected by a bridging bond, (K7)(A8)IM-, (ALM(ONB)- and K"A"-; IVUCHt is repeated "t" times of the "K7" group, and each K" independently selected from the group consisting of halogen, cyano, optionally substituted C.i-Svalkyl, optionally by substituted Cg2-Svalkenyl, optionally substituted Co2-Svalkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted 4-10-membered heterocyclyl, which contains 1-3 heteroatoms selected from M, O and 5, ВаС(-0)-, В'а502-, В'А"-, (8"2)0(-О)М(РУ)-, (А8Л(В8)М-, (А7Л( AB)MS(-АМ(АУ)-; where t-0-3; or two groups K" and the carbon atoms to which they are attached together form an optionally substituted 5-b--lene cyclic system, optionally containing 1-4 heteroatoms/groups selected from the group consisting of -M- , -5-, -O-, -C(-0)- and -F(-5)-; Vo and 29 are independently selected from the group consisting of hydrogen, K/2C(-0)-, optionally substituted C1-Salkyl, optionally substituted Co-Salkylenyl, optionally substituted C2-Salkyl, optionally substituted cycloalkyl, optionally substituted 4-10 membered heterocyclyl, which contains 1-3 heteroatoms selected from M, O and 5, optionally substituted aryl and optionally substituted 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from M, O, and 5; or Ki A, together with the nitrogen atom to which they are attached, form a 3- A 10-membered optionally substituted saturated/unsaturated heterocyclic ring system containing from one to three heteroatoms/groups selected from the group consisting of -5-, -M-, -O-, -C(20)- and- C(-5)-; where is K", B8 and KE? independently selected from the group consisting of hydrogen, optionally substituted C1-Swalkyl, optionally substituted Co-Swalkenyl, optionally substituted C2-Swalkynyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted 5 -10-membered heteroaryl containing 1-3 heteroatoms selected from M, O and 5, optionally substituted cycloalkyl and optionally substituted 4-10-membered heterocyclyl containing 1-3 heteroatoms selected from M, O and 5; AND! selected from the group consisting of c and 5; B is selected from the group consisting of optionally substituted C:-Svalkyl, optionally substituted Co-Svalkenyl, optionally substituted C2-Svalkynyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted 5 -10-membered heteroaryl containing 1-3 heteroatoms selected from M, O and 5, optionally substituted cycloalkyl and optionally substituted 4-10-membered heterocyclyl containing 1-3 heteroatoms selected from M, O and 5; where optionally substituted C1-Salkyl is a C1-Salkyl group unsubstituted or substituted with 1-6 substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, aryl, 5-10 membered heteroaryl, which contains 1-3 heteroatoms selected from M, O and 5, cycloalkyl, "a5(O"-, BOA!-, rab c(-0)-, B'basI-O)0-, (B'(H) IMOS(-0)-, (V'GS-Svalkil)mMS(-0)-, Vsasi-O)M(H)-, (АЕХН)М-, (ВЭХС:-Svalkil) M -, (ВХХ)ИМС(-АМН)- and (ХХ(С1- Coo) Svalkyl)MS(-AM(NI-; optionally substituted C2o-Svalkenyl is a C2o-Svalkenyl group, unsubstituted or substituted by 1- 6 substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from M, O and 5, cycloalkyl, 'ba5O'-, ВТОдТ -, V'baOS(-0)-, vas(-0)0-, (BA'(NIMS(-O)-, (V'KS- Svalkil/MS(-0)-, Vas -OM(H) -, (А'ЕХН)М-, (В'Х(C1-Svalkyl)Mm-, (ВІХНИМС(-AZM(Н)- and (Х(Сч1- Svalkyl/uMS(-AZM(HO-) necessarily substituted Co-Svalkinyl is a Co-Svalkinyl group, unsubstituted or substituted with 1-6 substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from M, O and 5, cycloalkyl, 'a5 (O»-, OJSC. p'aZs(-0)-, V'basI-0)0-, (B'(H)MOS(-0)-, (V'EDS- Svalkil)mMS(-0)-, V'sasi-O )M(H)-, (АЭХН)М-, (ВЭХС:-Svalkyl) M-, (ВЭХН)IMS(-АМН)- and (ВХ(С1- Svalkyl)MS(-AM( NO-; optionally substituted heteroalkyl is a heteroalkyl group unsubstituted or substituted with 1-6 substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, aryl, 5-10-membered heteroaryl containing 1 -3 heteroatoms selected from M, O and 5, and cycloalkyl; optionally substituted cycloalkyl is a cycloalkyl group unsubstituted or substituted with 1-6 substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, aryl, A 5-10-membered heteroaryl containing 1-3 heteroatoms selected from M, O and 5, C- Svalkyl, Co-Svalkenyl, Cg2-Svalkynyl, K'basb(-O)-, B'ba5O"- . 'bas(-O)M(H)-, (B'H)M-, (A '(C:-Svalkil)M-, (A'Z(NMS(-AZMN)O- and (K2)3( C1-Svalkyl/MS(A )M(NI-; optionally substituted aryl is an aryl group, n substituted or substituted by 1-3 substituents independently selected from the group consisting of halogen, nitro, cyano, hydroxy, Ci-Svalkyl, Co-Svalkenyl, Cg-Svalkynyl, C3-Cvcycloalkyl, Ci-Svperhaloalkyl, Ci-Svalkyl-O-, Co-Svalkenyl-O-, Co-Svalkynyl-O, Si-Sweperhaloalkyl-O-, Si-Svalkyl-M(Si-Svalkyl)-, Si-Svalkyl- M(H)-, NeM-, Si-Svalkyl-50 »5-, Ci-Superhaloalkyl-5O2-, Ci-Svalkyl-C(O)M(Si-Svalkyl)-, Si-Svalkyl-C(-O)M(H)-, Si-Svalkyl-M(C1- Svalkyl)C(20)-, Si-Svalkyl-M(H)C(-0)-, NaMS(-0)-, C- Svalkyl-M(С1-Svalkyl)ZO»-, Si-Svalkyl-M( H)ZO»-, NagM5O»-, 3-6--lene heterocycle containing 1- or 2 heteroatoms selected from the group including M, O and 5, where the specified 3-be--lene heterocycle is optional substituted with Si-Svalkyl, Co-Svalkenyl, Co-Svalkynyl or C:i-Svalkyl-C(:0O)-, or (ii) the specified substituted or unsubstituted aryl ring, optionally fused to a cycloalkane ring or 3-b-- by a linoleic heterocyclic ring containing 1-3 heteroatoms selected from 5, 0, M, through a bond, where the specified cycloal kan ring or 3-6-membered heterocyclic ring is optionally substituted with oxo, Si-Svalkyl, Cg-Svalkenyl, C2-Svalkynyl or Si-Svalkyl-C(-0O)-; an optionally substituted 4-10-membered heterocyclyl containing 1-3 heteroatoms selected from M, O and 5 is (ii) a 4-10-membered heterocyclyl group containing 1-3 heteroatoms selected from M, O and 5, unsubstituted or substituted on ring carbons 1-6 with substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from M, O and 5, S:i-Svalkil, So-Svalkenil, Sgo-Svalkinil, K'OD"-, всегОС(-0)-, Vas -О)0-, (ВЭХН)IMO(-О) -, (ВЕ(С1-Svalkyl)MS(О0)-, Vasi -О)М(Н)-, (А'(Н)М-, (ВЕС-SvalkyluMm-, (В'ХН)ИМС (-АМ(Н)А- ой (КОС -SvalkyluМС(-А"М(Н)-; (its) 4-10-membered heterocyclyl group, which contains 1-3 heteroatoms selected from M, O and 5, neoobov optionally substituted on the ring nitrogen(s) with one or more substituents selected from the group consisting of 5-10-membered heteroaryl containing 1-3 heteroatoms selected from M, O and 5, C:i-Salkyl, Co- Svalkenil, Cg2-Svalkinil, K'basb(-0)-, B'aBO"-, b'aOS(-O0)-, (B'(H)MS(-0)-, ( B'(C- Svalkyl/MS(-O)- and aryl, unsubstituted or substituted with 1-3 substituents independently selected from halogen, C-Svalkyl, C-Svalkenyl, C-Svalkynyl, cyano or nitro; optionally substituted 5-10 membered heteroaryl which contains 1-3 heteroatoms selected from M, O and 5 is a 5-10 membered heteroaryl group which contains 1-3 heteroatoms selected from M, O and 5 , unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of halogen, nitro, cyano, hydroxy, C:i-Salkyl, C6-Salkyl, C6-Salkyl, C3-C6cycloalkyl, C1-C6 perhaloalkyl, C6-Salkyl- O-, Co-Svalkenyl-O-, Co-Svalkynyl-O-, Si-Swperhaloalkyl-O-, Si-Svalkyl-M(Si-Svalkyl)-, Si-Svalkyl-M(H)-, NeaM-, Si -Svalkyl-5O2-, Si-Sulfarhaloalkyl-5O2-, C1-Svalkyl-C(-O)M(Si-Svalkyl)-, Si-Svalkyl-C(O)M(H)-, Si-Svalkyl-M( Si-Svalkyl)C(-0)-, C- Svalkyl-M(H)C(-0)-, NagMS(-0)-, C1-Svalkyl-M(Si-Svalkyl)5O»-, C1-Svalkyl -M(H)ZO"-, HgM5O"- and a 3-b-membered heterocycle containing 1-2 heteroatoms selected from the group consisting of M, O and 5, where the 3-b-membered heterocycle is optionally substituted with one to four substituents selected from the group consisting of Si-Svalkyl, Se-Svalkenyl, Co-Svalkinyl or Si-Svalky l-C(-O)-; an optionally substituted 5-6-membered ring system is a 5-6 membered ring system unsubstituted or substituted with 1-3 substituents selected from the group consisting of oxo, halogen, nitro, cyano, aryl, 5-10- one-membered heteroaryl containing 1-3 heteroatoms selected from M, O and 5, C-Svalkyl, Co-Svalkenyl, Co-Svalkynyl, K'ba(C(-0)-, B'aB5O"-, BOdI -, riaOS(-0)-, Vas -O)0-, (АЯХН)IMO(-О)-, (В'ОХ(Si-SvalkyluMS(-О0)-, Va с(-ОУМ(Н) -, (VYEDN)IM-, (V'O(S-Svalkil)um-, (VYAHN)IMS(-А"M(H)O- and (K'OH(S-Svalkil)/MS (-AM(H)-; 3-10-membered optionally substituted saturated/unsaturated heterocyclic ring system is a 3-10-membered saturated/unsaturated heterocyclic ring system, unsubstituted or substituted with 1-3 substituents selected from the group, which includes oxo, halogen, nitro, cyano, aryl, 5-10 membered heteroaryl, which contains 1-3 heteroatoms selected from M, O and 5, C-Svalkyl, Co-Svalkenyl, C0-Svalkynyl, V'bas( -0)-, B'saB5O"-, B'OdI-, B'baZo(-0)-, B'sas(-O)0-, (АЕХН)IMO(-О)-, (А" )(C1-Svalkil/MS(20)-, vya -O)M(H)-, (B'XHN)M-, (B')(C1-Svalkilum-, (АЭХНИМС(-АМ(Н))- and (В'ХС-Svalkilum)/ MS(-AM(NI-; where Co is selected from hydrogen, C:1-Salkyl, Co-Salkylenyl, Co-Salkylynyl, aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from M, O and 5, cycloalkyl or 4- 10-membered heterocyclyl containing 1-3 heteroatoms selected from M, O and 5; and C'ba is selected from the group consisting of C1-Salkyl, C2-Salkyl, C2-Salkyl, C1-Swiperhaloalkyl, aryl, 5-10 membered heteroaryl, which contains 1-3 heteroatoms selected from M, O and 5, cycloalkyl or 4-10 membered heterocyclyl containing 1-3 heteroatoms selected from M, O and 5. 2. The compound of formula I, its tautomeric forms, its stereoisomers or its pharmaceutically acceptable salts according to claim 1, where VK? selected from the group consisting of hydrogen, optionally substituted alkyl and (AHA) M-. 3. The compound of formula I, its tautomeric forms, its stereoisomers or its pharmaceutically acceptable salts according to claim 1 or claim 2, where K2 is selected from the group consisting of hydrogen, methyl, dimethylamino and dimethylaminomethyl. 4. The compound of formula I, its tautomeric forms, its stereoisomers or its pharmaceutically acceptable salts according to any one of claims 1-3, where EE" is selected from the group including optionally substituted C1- alkyl, optionally substituted 4- A 10-membered heterocyclyl containing 1-3 heteroatoms, 60 selected from M, O and 5, K'/A-, (B(B8)M- and (KLLM(ON3)-. 5. The compound of formula I, its tautomeric forms, its stereoisomers or its pharmaceutically acceptable salts according to any of claims 1-4, where EZ is selected from the group including methyl, ethyl, n-propyl, methoxy, ethoxy, dimethylamino, M -methoxy-M-methylamino, M-(2-hydroxyethyl)-M-propylamino and piperidinyl. 6. The compound of formula I, its tautomeric forms, its stereoisomers or its pharmaceutically acceptable salts according to any of claims 1-5, where KK? and K9U are independently selected from the group consisting of hydrogen, optionally substituted C:-Svalkyl, or both EK", and K9, together with the nitrogen atom to which they are attached, form a 3-10-part lene optionally substituted saturated /unsaturated heterocyclic ring system containing from one to three heteroatoms/groups selected from the group consisting of -5-, -M-, -O-, -(20)- and -C(-5)-. 7. The compound of formula I, its tautomeric forms, its stereoisomers or its pharmaceutically acceptable salts according to any of claims 1-6, where E and KU are independently selected from the group consisting of hydrogen, methyl, or and, and 9 together with the atom nitrogen, to which they are attached, form a piperidine ring. 8. The compound of formula I, its tautomeric forms, its stereoisomers or its pharmaceutically acceptable salts according to any one of claims 1-7, where t is 0, 1 or 2, and K" is selected or selected from optionally substituted Si-Svalkyl group or groups, or two K" together with the carbon atoms to which they are attached, form an optionally substituted 5-6 membered cyclic system, optionally containing 1-4 heteroatoms/groups selected from the group consisting of - M-, -5-, -O-, -C(-0)- and -0(-5)-. 9. The compound of formula I, its tautomeric forms, its stereoisomers or its pharmaceutically acceptable salts according to any one of claims 1-8, where t is 0, 1 or 2, and E" is selected from a metal group or groups, or two K" together with the carbon atoms to which they are attached form a six-membered carbocycle. 10. The compound of formula I, its tautomeric forms, its stereoisomers or its pharmaceutically acceptable salts according to any one of claims 1-9, where Kg is selected from hydrogen and optionally substituted Si-Svalkyl. 11. The compound of formula I, its tautomeric forms, its stereoisomers or its pharmaceutically acceptable salts according to any of claims 1-10, where Ka is selected from the group consisting of hydrogen, methyl, ethyl and cyclopropylmethyl. 12. The compound of formula I, its tautomeric forms, its stereoisomers or its pharmaceutically acceptable salts according to any of claims 1-11, where BC? selected from the group consisting of hydrogen, optionally substituted Si-Svalkyl and (A7)(A8)M-; BZ is selected from the group consisting of optionally substituted Z0 C-Salkyl, optionally substituted 4-10 membered heterocyclyl containing 1-3 heteroatoms selected from M, O and 5, K'"A"-, ( В"ХАУ)М- and (Е7ОМ(ОНВЗ)-; Во and КУ are independently selected from the group including hydrogen, optionally substituted S.i-Svalkyl, or ЕК», и К9 together with a nitrogen atom to which they are attached, form a 3-10 membered optionally substituted saturated/unsaturated heterocyclic ring system containing from one to three heteroatoms/groups selected from the group consisting of -5-, -M-, -O-, -C (250)- and -С(-5)-; t is 0, 1 or 2, and КЕ" is selected from an optionally substituted C-Salkyl group or groups, or two K" together with carbon atoms to which they are attached, form an optionally substituted 5-6-linked cyclic system, optionally containing 1-4 heteroatoms/groups selected from the group consisting of -M-, -5-, -0-, -6( -9)- and -0(-5)-; and Kg is selected from the group consisting of hydrogen and optionally substituted Ci1-Svalkyl. 13. The compound of formula I, its tautomeric forms, its stereoisomers or its pharmaceutically acceptable salts according to any of claims 1-12, where E! selected from the group consisting of pyridyl, furanyl, indolyl, M-methylisoindolyl, benzofuranyl, piperazinyl, 4-(4-fluorophenyl)piperazinyl, morpholinyl, indolinyl, 2-oxoindolinyl, 2,3-dihydrobenzoi|B1(1,4|dioxynyl , benzopyranyl and phenyl, optionally substituted with 1-2 substituents selected from the group consisting of halogen, cyclopropyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, methyl, ethyl, dimethylamino, monomethylamino, tert-butyl and 4-methylpiperazinyl; MK? selected from the group consisting of hydrogen, methyl, dimethylamino and dimethylaminomethyl, KZ selected from the group consisting of methyl, ethyl, n-propyl, methoxy, ethoxy, dimethylamino, M-methoxy-M-methylamino, M-(2-hydroxyethyl) -M-propylamino and piperidinyl; B" and Kb are independently selected from the group consisting of hydrogen, methyl, or E? and R, together with the nitrogen atom to which they are attached, form a piperidine ring; t is 0, 1 or 2, and KE" selected from methyl groups, or two BK" together with the carbon atoms to which they are attached, form a six-membered carbocycle; and Ka? selected the first selected from the group consisting of hydrogen, methyl, ethyl and cyclopropylmethyl. 14. The compound of formula I, its tautomeric forms, its stereoisomers or its pharmaceutically acceptable salts according to any one of claims 1-13, where K' is selected from the group consisting of 4-chlorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4- fluorophenyl, 4-cyclopropylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 3-ethoxyphenyl, 4-tolyl, 4-tert-butylphenyl, 4-dimethylaminophenyl, 3-fluorophenyl, phenyl, 4-ethylphenyl, 3,4- dichlorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 3-chloro-4-fluorophenyl, 3-chloro-4-methoxyphenyl, piperazin-1-yl, 4-(fluorophenyl)piperazinyl, morpholino, pyridine-4- sil, pyridin-Z-yl, furan-Z-yl, 1H-indol-5-yl, 1-methyl-1H-indol-5-yl, benzofuran-5-yl, indolin-5-yl, 4-(4-methylpiperazine -1-yl)phenyl and 2,3-dihydrobenzoi|51(11,4|dioxin-b-yl. 15. The compound of formula I, its tautomeric forms, its stereoisomers or its pharmaceutically acceptable salts according to any one of claims 1-14, where 7 represents 5. 16. The compound of formula I, its tautomeric forms, its stereoisomers or its pharmaceutically acceptable salts according to any of claims 1-15, where the compound is selected from the group consisting of: 4-(5-(4-chlorophenyl)-4-methyl -2-propionylthiophene-3-yl)benzenesulfonamide; 4-(5-(2-chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)benzenesulfonamide; 4-(5-(3-chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)benzenesulfonamide; 4-(5-(4-fluorophenyl)-4-methyl-2-propionylthiophen-3-yl)ubenzenesulfonamide; 4-(5-(4-cyclopropylphenyl)-4-methyl-2-propionylthiophen-3-yl)ubenzenesulfonamide; 4-(4-methyl-2-propionyl-5-(4-«(trifluoromethyl)phenyl)thiophen-3-yl)/benzenesulfonamide; 4-(5-(4-Methoxyphenyl)-4-methyl-2-propionylthiophen-3-yl)ubenzenesulfonamide; 4-(5-(4-ethoxyphenyl)-4-methyl-2-propionylthiophen-3-yl/benzenesulfonamide; 4-(4-methyl-2-propionyl-5-(4-«(trifluoromethoxy)phenyl)thiophene-3 -yl)/benzenesulfonamide; 4-(4-methyl-2-propionyl-5-(4-tolyluthiophen-3-yl)ubenzenesulfonamide; 4-(5-(4-(tert-butylphenyl)-4-methyl-2- propionylthiophen-3-yl)ubenzenesulfonamide; 4-(5-(4-dimethylamino)phenyl)-4-methyl-2-propionylthiophen-3-yl)ubenzenesulfonamide; 4-(5-(3-fluorophenyl)-4-methyl- 2-propionylthiophen-3-yl)ubenzenesulfonamide; 4-(4-methyl-5-phenyl-2-propionylthiophen-3-yl)benzenesulfonamide; 4-(5-(3-ethoxyphenyl)-4-methyl-2-propionylthiophen- 3-yl/benzenesulfonamide; 4-(5-(4-ethylphenyl)-4-methyl-2-propionylthiophen-3-yl)/ubenzenesulfonamide; 4-(5-(3,4-dichlorophenyl)-4-methyl-2 -propionylthiophen-3-yl)/'benzenesulfonamide; 4-(5-(2,4-dichlorophenyl)-4-methyl-2-propionylthiophen-3-yl)/'benzenesulfonamide; 4-(5-(2,4- difluorophenyl)-4-methyl-2-propionylthiophen-3-yl)/benzenesulfonamide; 4-(5-(3-chloro-4-fluorophenyl)-4-methyl-2-propionylthiophen-3-yl)/benzenesulfonamide; 4- (5-(3-chloro-4-methoxyphenyl)-4-methyl-2-propionyl thiophene-3-yl)benzenesulfonamide; 4-(4-methyl-5-(piperazin-1-yl)-2-propionylthiophen-3-yl)/benzenesulfonamide; 4-(5-(4-(4-fluorophenyl)piperazin-1-yl)-4-methyl-2-propionylthiophen-3-yl)ubenzenesulfonamide; Zo 4-(4-methyl-5-morpholino-2-propionylthiophen-3-yl)ubenzenesulfonamide; 4-(4-methyl-2-propionyl-5-(pyridin-4-iluthiophen-3-yl)ubenzenesulfonamide; 4-(4-methyl-2-propionyl-5-(pyridin-3-iluthiophen-3-yl) ubenzenesulfonamide; 4-(5-(furan-3-yl)-4-methyl-2-propionylthiophen-3-yl)ubenzenesulfonamide; 4-(5-(1H-indol-5-yl)-4-methyl-2- propionylthiophen-3-yl)/benzenesulfonamide; 4-(4-methyl-5-(1-methyl-1 H-indol-5-yl)-2-propionylthiophen-3-yl)/benzenesulfonamide; 4-(5-( benzofuran-5-yl)-4-methyl-2-propionylthiophen-3-yl)/benzenesulfonamide 4-(5-(indolin-5-yl)y-A-methyl-2-propionylthiophen-3-yl)ybenzenesulfonamide; 4-(4-methyl-5-(4-(4-methylpiperazin-1-yl)uphenyl)-2-propionylthiophen-3-yl)benzenesulfonamide; 4-(5-(4-chlorophenyl)-2-propionylthiophen-3 -yl)/benzenesulfonamide; 4-(5-(4-chlorophenyl)-4-(dimethylamino)-2-propionylthiophen-3-yl)/benzenesulfonamide; 4-(5-(4-chlorophenyl)-4-((dimethylamino )methyl)-2-propionylthiophen-3-yl)ubenzenesulfonamide; 5-(4-chlorophenyl)-M,M,4-trimethyl-3-(4-sulfamoylphenyl)thiophene-2-carboxamide; 5-(4-chlorophenyl) -M-methoxy-M,4-dimethyl-3-(4-sulfamoylphenyl)thiophene-2-carboxamide; 5-(4-chlorophenyl)-M -(2-hydroxyethyl)-4-methyl-N-propyl-3-(4-sulfamoylphenyl)thiophene-2-carboxamide; 4-(5-(4-chlorophenyl)-4-methyl-2-(piperidin-1-carbonyl)thiophen-3-yl)/benzenesulfonamide; 4-(2-acetyl-5-(4-chlorophenyl)-4-methylthiophen-3-yl)/benzenesulfonamide; 4-(5-(4-chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)y-2-methylbenzenesulfonamide; methyl-4-methyl-5-(2-oxoindolin-5-yl)-3-(4-sulfamoylphenyl)thiophene-2-carboxylate; ethyl 4-methyl-5-(2-oxoindolin-5-yl)-3-(4-sulfamoylphenyl)thiophene-2-carboxylate; 4-(4-methyl-5-(4-methylaminophenyl)-2-propionylthiophen-3-yl)ubenzenesulfonamide; 4-(5-(4-chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)-M,M-dimethylbenzenesulfonamide; 4-(5-(4-chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)-M-methylbenzenesulfonamide; 4-(5-(3,4-difluorophenyl)-4-methyl-2-propionylthiophen-3-yl)/benzenesulfonamide; 1-(5-(4-chlorophenyl)-4-methyl-3-(4-(piperidin-1-ylsulfonyl)phenyl)thiophen-2-yl)propan-1-one; 4-(5-(4-chlorophenyl)-1,4-dimethyl-2-propionyl-1H-pyrrol-3-yl)ubenzenesulfonamide; 5-(4-chlorophenyl)-M,M,1,4-tetramethyl-3-(4-sulfamoylphenyl)-1H-pyrrole-2-carboxamide; 4-(5-(4-chlorophenyl)-1-ethyl-4-methyl-2-propionyl-1H-pyrrol-3-yl)benzenesulfonamide; 4-(5-(4-chlorophenyl)-1-(cyclopropylmethyl)-4-methyl-2-propionyl-1H-pyrrol-3-yl/benzenesulfonamide; because 4-(5-(4-chlorophenyl)-4- methyl-2-propionyl-1H-pyrrol-3-yl/benzenesulfonamide; 4-(5-(4-fluorophenyl)-1,4-dimethyl-2-propionyl-1H-pyrrol-3-yl)/'benzenesulfonamide; 4-(5-(4-methoxyphenyl)-1,4-dimethyl-2-propionyl-1H-pyrrol-3-yl)/'benzenesulfonamide; 4-(2-butyryl-5-(4-chlorophenyl)-1,4-dimethyl-1H-pyrrol-3-yl)benzenesulfonamide; 4-(5-(2,4-dichlorophenyl)-1,4-dimethyl-2-propionyl-1H-pyrrol-3-yl)/benzenesulfonamide; 4-(5-(2,3-dihydrobenzoyl)-1,1-4-dioxin-6-yl)-1,4-dimethyl-2-propionyl-1H-pyrrol-3-yl)benzenesulfonamide; ethyl 5-(4-chlorophenyl)-4-methyl-3-(4-sulfamoyl-5,6,7,8-tetrahydronaphthalen-1-yl)thiophene-2-carboxylate and ethyl 5-(4-chlorophenyl) -3-(4-sulfamoylphenyl)furan-2-carboxylate. 17. A pharmaceutical composition containing a compound according to any one of claims 1-16 and a pharmaceutically acceptable carrier. 18. A method of preventing or treating a disease or symptom or disorder mediated in part or in whole by nicotinic acetylcholine receptors, said method comprising the steps of administering to a subject having or at risk of said disease or symptom or disorder a therapeutically effective amount compounds according to any of claims 1-16. 19. A method of treating a disease or disorder or condition partially or fully mediated by nicotinic acetylcholine receptors in a subject in need thereof, comprising the steps of administering to the subject a therapeutically effective amount of a compound of formula I, its tautomeric forms, its stereoisomers or its pharmaceutically acceptable salts (c) nu ve) Ku Z t ВЯЙ в (c) в? M, 7 k КИ and (0) where in the compound of formula 2 is selected from the group including -5-, -О- and -М(В2)-; B is selected from the group consisting of hydrogen, optionally substituted C1-Swalkyl, optionally substituted C1-Swalkenyl, optionally substituted C1-Swalquinyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted 5-10-membered heteroaryl containing 1-3 heteroatoms selected from M, O and 5, and optionally substituted 4-10-membered heterocyclyl containing 1-3 heteroatoms selected from M, O and 5; B' is selected from the group consisting of optionally substituted aryl, optionally substituted 5- to 10-membered heteroaryl containing 1-3 heteroatoms selected from M, O, and 5, optionally substituted cycloalkyl, and optionally optionally substituted 4-10-membered heterocyclyl containing 1-3 heteroatoms selected from M, O and 5; IN? selected from the group consisting of hydrogen, optionally substituted C:-Swalkyl, optionally substituted C0-Swalkenyl, optionally substituted C2-Swalquinyl, halogen, C1-Swperhaloalkyl, optionally substituted cycloalkyl, cyano, nitro, ( KHAVM-, v'ee(-OM(A-, (A7(VAUIMOS(-А"M(AU)-, B"2ОС(-О)МА-, Na5О2M(VVZ)-, В'А"- and K /aC(-0)-; BZ is selected from the group consisting of optionally substituted C1-Salkyl, optionally substituted C0-Salkyl, optionally substituted C1-Salkyl, optionally substituted cycloalkyl, optionally a substituted 4-10 membered heterocyclyl containing 1-3 heteroatoms selected from M, O and 5, wherein each of said optionally substituted cycloalkyl and optionally substituted heterocyclyl is optionally ringed or optionally bridged connection, (K7)(AZ)M-, (B"LMZH(ONB)- and BA"-; IVUt is a repeated "t" times group "B", and each EC" is independently selected from the group that includes halogen, cyano, optionally substituted Si-Svalkyl, optionally substituted Cg2-Svalkenyl, optionally substituted Co2-Svalkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted 4-10 membered heterocyclyl, which contains 1-3 heteroatoms selected from M, O and 5, В/аб(-0)-, ВН"а5О»2-, В'А-, (В"2)С(-О)М(АУ)-, (АЛ(В)М-, (А7АЗИМС( -A")M(AU)-; where t-0-3; or two K" groups and the carbon atoms to which they are attached together form an optionally substituted 5-b--lene ring system optionally containing 1-4 heteroatoms/groups selected from the group consisting of -M- , -5-, -O-, -C(-0)- and -F(-5)-; Vo and 29 are independently selected from the group consisting of hydrogen, K/2C(-0)-, optionally substituted C-Svalkyl, optionally substituted C-Svalkenyl, optionally substituted Cg2-Svalkynyl, optionally substituted cycloalkyl, optionally substituted 4-10-membered heterocyclyl, which contains 1-3 heteroatoms selected from M, O and 5, optionally substituted aryl and optionally substituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from M, O and 5; or Ki AA together with the nitrogen atom to which they are attached form 3-10 membered optionally substituted saturated/unsaturated heterocyclic ring system containing from one to three heteroatoms/groups selected from the group consisting of -5-, -M-, -O-, -C(20)- i-C(-5)-; where is K", B8 and KE? independently selected from the group consisting of hydrogen, optionally substituted C1-Swalkyl, optionally substituted Co-Swalkenyl, optionally substituted C2-Swalkynyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted 5 -10-membered heteroaryl containing 1-3 heteroatoms selected from M, O and 5, optionally substituted cycloalkyl and optionally substituted 4-10-membered heterocyclyl containing 1-3 heteroatoms selected from M, O and 5; AND! selected from the group consisting of c and 5; B is selected from the group consisting of optionally substituted C:-Svalkyl, optionally substituted Co-Svalkenyl, optionally substituted C2-Svalkynyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted 5 -10-membered heteroaryl containing 1-3 heteroatoms selected from M, O and 5, optionally substituted cycloalkyl and optionally substituted 4-10-membered heterocyclyl containing 1-3 heteroatoms selected from M, O and 5; where optionally substituted C1-Salkyl is a C1-Salkyl group unsubstituted or substituted with 1-6 substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, aryl, 5-10 membered heteroaryl, which contains 1-3 heteroatoms selected from M, O and 5, cycloalkyl, "a5(O"-, BOA!-, rab c(-0)-, B'basI-O)0-, (B'(H) IMOS(-0)-, (V'GS-Svalkil)mMS(-0)-, Vsasi-O)M(H)-, (АЕХН)М-, (ВЭХС:-Svalkil) M -, (ВХХ)ИМС(-АМН)- and (ХХ(С1- Coo) Svalkyl)MS(-AM(NI-; optionally substituted C2o-Svalkenyl is a C2o-Svalkenyl group, unsubstituted or substituted by 1- 6 substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from M, O and 5, cycloalkyl, 'ba5O'-, ВТОдТ -, V'baOS(-0)-, vas(-0)0-, (BA'(NIMS(-O)-, (V'KS- Svalkil/MS(-0)-, Vas -OM(H) -, (А'ЕХН)М-, (В'Х(C1-Svalkyl)Mm-, (ВІХНИМС(-AZM(Н)- and (Х(Сч1- Svalkyl/uMS(-AZM(HO-) necessarily substituted Co-Svalkinyl is a Co-Svalkinyl group, unsubstituted or substituted with 1-6 substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from M, O and 5, cycloalkyl, 'a5 (O»-, OJSC. p'aZs(-0)-, V'basI-0)0-, (B'(H)MOS(-0)-, (V'EDS- Svalkil)mMS(-0)-, V'sasi-O )M(H)-, (АЭХН)М-, (ВЭХС:-Svalkyl) M-, (ВЭХН)IMS(-АМН)- and (ВХ(С1- Svalkyl)MS(-AM( NO-; optionally substituted heteroalkyl is a heteroalkyl group unsubstituted or substituted with 1-6 substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, aryl, 5-10-membered heteroaryl containing 1 -3 heteroatoms selected from M, O and 5, and cycloalkyl; optionally substituted cycloalkyl is a cycloalkyl group unsubstituted or substituted with 1-6 substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, aryl, A 5-10-membered heteroaryl containing 1-3 heteroatoms selected from M, O and 5, C- Svalkyl, Co-Svalkenyl, Cg2-Svalkynyl, K'basb(-O)-, B'ba5O"- . 'bas(-O)M(H)-, (B'H)M-, (A '(C:-Svalkil)M-, (A'Z(NMS(-AZMN)O- and (K2)3( C1-Svalkyl/MS(A")M(NI-; optionally substituted aryl is an aryl group, not substituted or substituted by 1-3 substituents independently selected from the group consisting of halogen, nitro, cyano, hydroxy, C1-Salkyl, Co-Swalkenyl, Cg-Swalkynyl, C3-Cvcycloalkyl, Ci-Swperhaloalkyl, Ci-Swalalkyl-O-, Co-Svalkenyl-O-, Co-Svalkynyl-O-, Si-Swperhaloalkyl-O-, Si-Svalkyl-M(Si-Svalkyl)-, Si-Svalkyl- M(HO-, NeM-, C:-Svalkyl- 5O2-, C-Superhaloalkyl-5O2, C:i-Svalkyl-C(O)M(C:i-Svalkyl)-, C-Svalkyl-C(-O)M(H)-, C-Svalkyl-M( C1-Svalkyl)/C(-0)-, Si-Svalkyl-M(H)C(-0)-, NaMS(-0)-, C- Svalkyl-M(C1-Svalkyl)ZO»-, Si- Svalkyl-M(H)ZO»-, NagM5O»-, 3-6-ene heterocycle containing 1 or 2 heteroatoms selected from the group including M, O and 5, where the specified 3-6-ene the heterocycle is optionally substituted with C-Svalkyl, Cg-Svalkenyl, Co-Svalkynyl or C:i-Svalkyl-C(:0O)-, or (ii) the specified substituted or unsubstituted aryl ring, optionally fused with a cycloalkane ring or 3 -b--lene heterocyclic ring containing 1-3 heteroatoms selected from 5, 0, M, through a bond, where the indicated cycloal kan ring or 3-6-membered heterocyclic ring is optionally substituted with oxo, Si-Svalkyl, C5-Svalkenyl, C2-Svalkynyl or Si-Svalkyl-C(-0O)-; an optionally substituted 4-10-membered heterocyclyl containing 1-3 heteroatoms selected from M, O and 5 is (ii) a 4-10-membered heterocyclyl group containing 1-3 heteroatoms selected from M, O and 5, unsubstituted or substituted on ring carbons 1-6 with substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from M, O and 5, S:i-Svalkil, So-Svalkenil, Sgo-Svalkinil, K'OD"-, всегОС(-0)-, Vas -О)0-, (ВЭХН)IMO(- О)-, (В'Е(С1-Svalkyl)МС(О0)-, Vasi -О)М(Н)-, (А'(Н)М-, (В'ЕС-SvalkyluMm-, (В'ХН )IMS(-АМ(Н)А- ой (КОС -SvalkyluМС(-А"М(Н)-; (its) 4-10-membered heterocyclyl group, which contains 1-3 heteroatoms selected from M, O and 5 , optionally substituted on the ring nitrogen(s) with one or more substituents selected from the group consisting of 5-10-membered heteroaryl containing 1-3 heteroatoms selected from M, O and 5, C:i-Cylalkyl, Co- Svalkenyl, Cg2-Svalkenyl, K'basb(-0)-, B'aBO"-, b'aOS(-O0)-, (B'(H)MS(-0)-, (B'(C- Svalkyl/MS(-O)- and aryl, unsubstituted or substituted with 1-3 substituents independently selected from halogen, C-Svalkyl, Co-Svalkenyl, Co-Svalkynyl, cyano or nitro; optionally substituted 5-10 membered heteroaryl which contains 1-3 heteroatoms selected from M, O and 5 is a 5-10 membered heteroaryl group which contains 1-3 heteroatoms selected from M, O and 5 , unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of halogen, nitro, cyano, hydroxy, C:i-Salkyl, C6-Salkyl, C6-Salkyl, C3-C6cycloalkyl, C1-C6 perhaloalkyl, C6-Salkyl- O-, Co-Svalkenyl-O-, Co-Svalkynyl-O-, Si-Swperhaloalkyl-O-, Si-Svalkyl-M(Si-Svalkyl)-, Si-Svalkyl-M(H)-, NeM-, Si -Svalkyl-5O», Si-Superhaloalkyl-5O2-, C1-Svalkyl-C(-O)M(Si-Svalkyl)-, Si-Svalkyl-C(O)M(H)-, Si-Svalkyl-M( Si-Svalkyl)C(-0)-, C- Svalkyl-M(H)C(-0)-, NagMS(-0)-, C1-Svalkyl-M(Si-Svalkyl)5O»-, C1-Svalkyl -M(H)ZO"-, HgM5O"- and a 3-b-membered heterocycle containing 1-2 heteroatoms selected from the group consisting of M, O and 5, where the 3-b-membered heterocycle is optionally substituted by one to four substituents selected from the group consisting of Si-Svalkyl, Se-Svalkenyl, Co-Svalkynyl or Si-Svalkyl- C(-O)-; an optionally substituted 5-6-membered ring system is a 5-6 membered ring system unsubstituted or substituted with 1-3 substituents selected from the group consisting of oxo, halogen, nitro, cyano, aryl, 5-10- one-membered heteroaryl containing 1-3 heteroatoms selected from M, O and 5, C-Svalkyl, Co-Svalkenyl, Co-Svalkynyl, K'ba(C(-0)-, B'aB5O"-, BOdI -, riaOS(-0)-, Vas -O)0-, (АЯХН)IMO(-О)-, (В'ОХ(Si-SvalkyluMS(-О0)-, Va с(-ОУМ(Н) -, (VYEDN)IM-, (V'O(S-Svalkil)um-, (VYAHNIMO(-А"M(NI- and (AOS -Svalkil)/MS(AM(H)-; 3 - 10-membered optionally substituted saturated/unsaturated heterocyclic ring system - 3- 10-membered saturated/unsaturated heterocyclic ring system, unsubstituted or substituted 1- With substituents selected from the group consisting of oxo, halogen, nitro, cyano . baBO"-, B'OdT-, d'sZo(-0)-, B'sas(-0)0-, (B'HN)IMO(-O0)-, (V'EGS- Svalkil)mMS(- 0)-, Vas -OH)-, (B' ЭХН)М-, (А'(C1-Svalkyl)m-, (А'ЭХН)ИМС(-АМ(Н)- ии (АХ(С- Svalkyl/uMS(-AZM(HO-); where K' is selected from hydrogen, C1-Salkyl, C2-Salkylenyl, C20-Salkylenyl, aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from M, O and 5, cycloalkyl or 4- 10-membered heterocyclyl containing 1-3 heteroatoms selected from M, O and 5; and C'ba is selected from the group consisting of C1-Salkyl, C2-Salkyl, C2-Salkyl, C1-Swiperhaloalkyl, aryl, 5-10 membered heteroaryl, which contains 1-3 heteroatoms selected from M, O and 5, cycloalkyl or 4-10 membered heterocyclyl containing 1-3 heteroatoms selected from M, O and WITH. 20. The method of claim 19, wherein the disorder or condition or disease is selected from the group consisting of Alzheimer's disease, mild cognitive impairment, senile dementia, vascular dementia, Parkinson's disease dementia, attention deficit disorder, attention deficit hyperactivity disorder, dementia, Lewy body-associated, AIU5-dementia complex, Pick's disease, dementia associated with Down syndrome, Huntington's disease, cognitive deficits associated with traumatic brain injury, stroke-associated cognitive decline, neuroprotective effect after stroke, cognitive deficits and sensorimotor filtering associated with schizophrenia, cognitive deficits associated with bipolar disorder, cognitive impairment associated with depression, acute pain, post-surgical or postoperative pain, chronic pain, inflammation, inflammatory pain, neuropathic pain, smoking cessation, angiogenesis associated with wound healing, angiogenesis associated with skin graft vascularization, and lack of circulation, arthritis, rheumatoid arthritis, psoriasis, Crohn's disease, ulcerative colitis, pouchitis, inflammatory bowel disease, celiac disease, periodontitis, sarcoidosis, pancreatitis, organ transplant rejection, acute immune disease associated with organ transplantation, chronic immune disease associated with organ transplantation, septic shock, toxic shock syndrome, septic syndrome, depression and rheumatoid spondylitis. 21. The method of claim 19, wherein the disease or disorder or condition is selected from the group classified or diagnosed as major or minor neurocognitive disorders or disorders resulting from neurodegeneration. 22. The method according to claim 19, including the steps in which the compound of formula I is administered in combination with or as an adjunct to drugs used in the treatment of attention deficit hyperactivity disorder, schizophrenia, cognitive disorders such as Alzheimer's disease, dementia in Parkinson's disease, vascular dementia or dementia associated with Lewy bodies, or traumatic brain injury. 23. The method according to claim 19, which additionally includes the steps of administering a compound of formula I in combination with acetylcholinesterase inhibitors, disease-modifying drugs, or biological drugs for neurodegenerative disorders, dopaminergic drugs, antidepressants, or a typical or atypical antipsychotic, or as a supplement to them. 24. Use of a compound according to claim 1 in the preparation of a medicinal preparation for the prevention or treatment of a disease or its symptoms or a disorder partially or completely mediated by nicotinic acetylcholine receptors, where the disease or disorder is selected from Alzheimer's disease, moderate cognitive impairment, senile dementia, vascular dementia, dementia in Parkinson's disease, attention deficit disorder, attention deficit hyperactivity disorder, dementia associated with Lewy bodies, AIJO5-dementia complex, Pick's disease, dementia associated with Down syndrome, Huntington's disease, cognitive deficits associated with traumatic brain injury, reduction in cognitive functions associated with a stroke, neuroprotective action after a stroke, deficits in cognitive and sensorimotor filtering associated with schizophrenia, deficits in cognitive functions associated with bipolar disorder, cognitive impairment associated with depression, acute pain, after surgical or postoperative pain, chronic pain, inflammation, inflammatory pain, neuropathic pain, smoking cessation, need for new blood vessel growth associated with wound healing, need for new blood vessel growth associated with skin graft vascularization, and lack of blood circulation, arthritis , rheumatoid arthritis, psoriasis, Crohn's disease, ulcerative colitis, pouchitis, inflammatory bowel disease, celiac disease, periodontitis, sarcoidosis, pancreatitis, organ transplant rejection, acute immune disease associated with organ transplantation, chronic immune disease associated with organ transplantation, septic shock , toxic shock syndrome, septic syndrome, depression and rheumatoid spondylitis. 25. Use of a compound of formula I!, its tautomeric forms, its stereoisomers or its pharmaceutically acceptable salts in the preparation of a medicinal product for the treatment of a disease or disorder, or condition M, 7 k КИ и: ;() where in the compound of formula I 2 is selected from the group including -5-, -O- and -M(B2)-; B is selected from the group consisting of hydrogen, optionally substituted C1-Salkyl, optionally substituted C1-Salkyl, optionally substituted C1-Salkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted 5-10-membered heteroaryl, which contains 1-3 heteroatoms selected from M, O and 5, and optionally substituted 4-10 membered heterocyclyl which contains 1-3 heteroatoms selected from M, O and 5; B' is selected from the group consisting of optionally substituted aryl, optionally substituted 5- to 10-membered heteroaryl containing 1-3 heteroatoms selected from M, O, and 5, optionally substituted cycloalkyl, and optionally optionally substituted 4-10-membered heterocyclyl containing 1-3 heteroatoms selected from M, O and 5; IN? selected from the group consisting of hydrogen, optionally substituted C:-Swalkyl, optionally substituted C0-Swalkenyl, optionally substituted C2-Swalquinyl, halogen, C1-Swperhaloalkyl, optionally substituted cycloalkyl, cyano, nitro, ( XA) M-, v'ee(-OM(A-, (A7(VUIMS(-AM(AU)-, B"2OS(-O)MAU-, Na5OM(VVZ)-, B'A"- and K /a(-0)-; BZ is selected from the group consisting of optionally substituted C1-Salkyl, optionally substituted C0-Salkyl, optionally substituted C1-Salkyl, optionally substituted cycloalkyl, optionally substituted 4-10-membered heterocyclyl containing 1-3 heteroatoms selected from M, O and 5, wherein each of said optionally substituted cycloalkyl and optionally substituted heterocyclyl is optionally annelated or optionally with connected by a bridging bond, (К7)(АЗ)М-, (В"ЛМЖ(ОНВ)- and ВА"-; IVUt is a repeated "t" times group "B", and each EC" is independently selected from the group, including halogen, cyano, optionally substituted C.i.-Svalkyl, optionally substituted Cg2 - Svalkenyl, optionally substituted Co2-Svalkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted 4-10-membered heterocyclyl, which contains 1-3 heteroatoms selected from M, O and 5 , H/"ab(-0)-, H"ab5O»2-, B'A-, (B"a)C(-O)M(AU)-, (AL(vB)M-, (A7( AZIMS(-A")M(AU)-; where t-0-3; or two K" groups and the carbon atoms to which they are attached together form an optionally substituted 5-6-membered ring system which optionally contains 1-4 heteroatoms/groups selected from the group consisting of -M- , -5-, -O-, -C(-0)- and 250 -b(-5)-; Vo and 29 are independently selected from the group consisting of hydrogen, K/2C(-0)-, optionally substituted Ci-Svalkyl, optionally substituted Co-Svalkenyl, optionally substituted Cg2-Svalkynyl, optionally substituted cycloalkyl, optionally substituted 4-10-membered heterocyclyl containing 1-3 heteroatoms selected from M . attached, form a 3-10 membered optionally substituted saturated/unsaturated heterocyclic ring system containing from one to three heteroatoms/groups selected from the group consisting of -5-, -M-, -O-, -C( -0)- and -C(-5)-; where is K", B8 and KE? independently selected from the group consisting of hydrogen, optionally substituted C1-Swalkyl, optionally substituted Co-Swalkenyl, optionally substituted C2-Swalkynyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted 5 -10-membered heteroaryl containing 1-3 heteroatoms selected from M, O and 5, optionally substituted cycloalkyl and optionally substituted 4-10-membered heterocyclyl containing 1-3 heteroatoms selected from M, O and 5; AND! selected from the group consisting of c and 5; B is selected from the group consisting of optionally substituted C:-Svalkyl, optionally substituted Co-Svalkenyl, optionally substituted C2-Svalkynyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted 5 -10-membered heteroaryl containing 1-3 heteroatoms selected from M, O and 5, optionally substituted cycloalkyl and optionally substituted 4-10-membered heterocyclyl containing 1-3 heteroatoms selected from M, O and 5; where optionally substituted C1-Salkyl is a C1-Salkyl group unsubstituted or substituted with 1-6 substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, aryl, 5-10 membered heteroaryl, which contains 1-3 heteroatoms selected from M, O and 5, cycloalkyl, "a5(O"-, BOA!-, rab c(-0)-, B'basI-O)0-, (B'(H) IMOS(-0)-, (V'GS-Svalkil)mMS(-0)-, Vsasi-O)M(H)-, (АЕХН)М-, (ВЭХС:-Svalkil) M -, (ВХХ)ИМС(-АМН)- and (ХХ(С1- Svalkyl)MS(-AM(NI-); optionally substituted C2o-Svalkenyl is a C2o-Svalkenyl group, unsubstituted or substituted by 1-6 substituents , independently selected from the group consisting of oxo, halogen, nitro, cyano, aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from M, O and 5, cycloalkyl, 'ba5O'-, ВТОдТ-, V'baOS(-0)-, vas(-0)0-, (BA'(NIMS(-O)-, (V'KS- Svalkil/MS(-0)-, Vas -OM(H)-, (А'ЕХН)М-, (В'Х(C1-Svalkyl)Mm-, (ВІХНИМС(-AZM(Н)- and (Х(Сч1-Svalkyl/uMS(-AZM(HO-); optionally substituted Co-Svalkynyl is a Co-Svalkynyl group unsubstituted or substituted with 1-6 substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, aryl, 5-10 membered heteroaryl, which contains 1-3 heteroatoms selected from M, O and 5, cycloalkyl, "a5(O"-, VOA!-, rab c(-0)-, B'basI-O)0-, (B'(H)IMOS(-0)-, (B'GS- Svalkyl/ uMC(0)-, Vas -OH)-, (V'EKHN)M-, (B')(C1-Svalkyl)m-, (V'EKHNIMS(-AM(H)I- and (K'9X( Ch1- Svalkil)MS(-AM(NI-; optionally substituted heteroalkyl is a heteroalkyl group unsubstituted or substituted by 1-6 substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, aryl, 5-10-membered heteroaryl, which contains 1-3 heteroatoms selected from M, O and 5, and cycloalkyl; optionally substituted cycloalkyl is a cycloalkyl group unsubstituted or substituted with 1-6 substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, aryl, 5-10-membered heteroaryl containing 1-3 heteroatoms , selected from M, O and 5, C-Svalkyl, Co-Svalkenyl, Co-Svalkinyl, K'ba(C(-0)-, V'aB5O»-, BOdI-, riaOS(-0)-, Vas - O)0-, (А"(H)MO(-0)-, (В'ХС1-Svalkil/MS(-0)-, V'bas(-О)М(Н)-, (В'Н)М-, (А (C:-Svalkyl)M-, (A'Z(NMS(-AZMN)O- and (K2)3(C1-Svalkyl/MS(A )M(NI-); optionally substituted aryl is (i ) an aryl group, unsubstituted or substituted by 1-3 substituents, independently selected from the group consisting of halogen, nitro, cyano, hydroxy, C1-Salkyl, Co-Salkyl, C1-Salkyl, C3-C8cycloalkyl, C1-Swperhaloalkyl, C1-Salkyl -Oh- So- Svalkenyl-O-, C2o-Svalkynyl-O-, C-Swperhaloalkyl-O-, C-Svalkyl-M(C1i-Svalkyl)-, C-Svalkyl- M(HO-, NeM-, C:-Svalkyl-5O» , C-Sweperhaloalkyl-5O2, C:-Svalkyl-C(O)M(C-Svalkyl)-, C-Svalkyl-C(-O)M(H)-, C-Svalkyl-M(C1-Svalkyl)/ C(-0)-, Si-Svalkyl-M(H)C(-0)-, NaMS(-0)-, C- Svalkyl-M(C1-Svalkyl)ZO»-, Si-Svalkyl-M(H )ZO»-, NagM5O»-, 3-6--lene heterocycle containing 1-2 heteroatoms selected from the group including M, O and 5, where the indicated 3-be--lene heterocycle is optionally substituted with Si -Svalkyl, Co-Svalkenyl, Co-Svalkynyl or C:i-Svalkyl-C(:0O)-, or (iii) the specified substituted or unsubstituted aryl ring, optionally fused with a cycloalkane ring or 3-b--lene heterocyclic ring a ring containing 1-3 heteroatoms selected from 5, 0, M, through a bond where the indicated cycloalkane ring or 3-6-membered heterocyclic ring is optionally substituted with oxo, Si-Svalkyl, Co-Svalkenyl, C2- With Svalkinil or Si-Svalkil-C(-0O)-; an optionally substituted 4-10-membered heterocyclyl containing 1-3 heteroatoms selected from M, O and 5 is (ii) a 4-10-membered heterocyclyl group containing 1-3 heteroatoms selected from M, O and 5, unsubstituted or substituted on ring carbons 1-6 with substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from M, O and 5, S:i-Svalkil, So-Svalkenil, Sgo-Svalkinil, K'OD"-, в'аОосС(-О)-, вя -О)0-, (ВЭХН)IMO(- О)-, (В'Е(С1-Svalkyl)МС(О)-, Vasi -О)М(Н)-, (А'(Н)М-, (В'ЕС-SvalkyluMm-, (В'ХН )IMS(-AM(H)А- ой (KOS -Svalkyl/MS(-А"М(Н)-; (ii) a 4-10-membered heterocyclyl group containing 1-3 heteroatoms selected from M, O and 5 optionally substituted on the ring nitrogen(s) with one or more substituents selected from the group consisting of 5- A 10-membered heteroaryl containing 1-3 heteroatoms selected from M, O and 5, C:i-Svalkyl, Co-Svalkenyl, Cg2-Svalkynyl, C'basb(-O)-, B'aBO"-, in 'aOS(-O0)-, (B'(H)MS(-0)-, (B'(C- Svalkyl/MS(-O)- and aryl, unsubstituted or substituted by 1-3 substituents independently selected from halogen , Si-Svalkyl, Co-Svalkenyl, Co-Svalkynyl, cyano or nitro; an optionally substituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from M, O and 5, is a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from M, O and 5, unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of halogen, nitro, cyano, hydroxy, Ci-Svalkyl, C0-Svalkenyl, Co-Svalkynyl, C3-Svcycloalkyl, C1- Csperhaloalkyl, Cs-Svalkyl-O-, Co-Svalkenyl-O-, Co-Svalkynyl-O-, Cs-Svperhaloalkyl-O-, Si-Svalkyl-M(Si-Svalkyl)-, Si-Svalkyl-M(H)-, NeaM-, Si-Svalkyl-5O", Si-Superhaloalkyl-5O2-, C1-Swalkyl-C(-O)M(Si-Swalkyl)-, C-Swalkyl-C(O)M(H)-, C-Swalkyl-M(Si-Swalkyl)C(-0)-, C- Svalkyl-M(H)C(-0)-, NagMS(-0)-, C1-Svalkyl-M(Si-Svalkyl)5O"-, C1-Svalkyl-M(H)ZO"-, NgM5O"- and 3-b-membered heterocycle containing 1-2 heteroatoms selected from the group consisting of M, O and 5, where the 3-b-membered heterocycle is optionally substituted with one to four substituents selected from the group consisting of Si- Svalkyl, Se-Svalkenyl, Co-Svalkynyl or Si-Svalkyl-C(-O)-; an optionally substituted 5-6-membered ring system is a 5-6 membered ring system unsubstituted or substituted with 1-3 substituents selected from the group consisting of oxo, halogen, nitro, cyano, aryl, 5-10- one-membered heteroaryl containing 1-3 heteroatoms selected from M, O and 5, C-Svalkyl, Co-Svalkenyl, Co-Svalkynyl, K'ba(C(-0)-, B'aB5O"-, BOdI -, riaOS(-0)-, Vas -O)0-, (АЯХН)IMO(-О)-, (В'ОХ(Si-SvalkyluMS(-О0)-, Va с(-ОУМ(Н) -, (VYEDN)IM-, (V'O(S-Svalkil)um-, (510) (В'ХАН)ИМС(-АМ(Н)О- and (К'ОХ(С-Svalkyl)/MS(-АМ(Н)-); 3-10-membered optionally substituted saturated/unsaturated heterocyclic ring system - 3- 10-membered saturated/unsaturated heterocyclic ring system, unsubstituted or substituted 1- With substituents selected from the group consisting of oxo, halogen, nitro, cyano, aryl, 5-10-membered heteroaryl containing 1-3 heteroatoms selected from M, O and 5, Ci-Svalkyl, Co-Svalkenyl, Co-Svalkynyl, K'ba((-0)-, B' ba50O2-, V'OD-, V'saOO(-0)-, V'bas(-0)0-, (V'XHN)IMO(-0)-, (V'EGS- Svalkil)mMS(-0 )-, V'sasi-O)M(H)-, (АЭХН)M-, (ВЭХС:-Svalkil) M-, (ВЭХН)IMS(-АМН)- and (ХХ(С1 - Svalkyl)MS(-AM(NI-; where CO is selected from hydrogen, C-Svalkyl, Sco-Svalkenyl, Co-Svalkynyl, aryl, 5-10-membered heteroaryl, which contains 1-3 heteroatoms selected from M, O and 5, cycloalkyl or 4-10 membered heterocyclyl, which contains 1-3 heteroatoms selected from M, O and 5; and Ka is selected from the group consisting of C1-Salkyl, C0-Salkyl, C2-Salkyl, C1-Swperhaloalkyl , aryl, 5-10-membered heteroaryl containing 1-3 heteroatoms selected from M, O and 5, cycloalkyl or 4-10 membered heterocyclyl containing 1-3 heteroatoms selected from M, O and WITH. 26. The use of claim 25, wherein the disease or disorder or condition is selected from the group classified or diagnosed as major or minor neurocognitive disorders or disorders resulting from neurodegeneration. 27. Use according to claim 25 in combination with drugs used in the treatment of attention deficit hyperactivity disorder, schizophrenia, cognitive disorders, Alzheimer's disease, dementia in Parkinson's disease, vascular dementia or dementia associated with Lewy bodies, and traumatic brain injury, or as a supplement to them. 28. Use according to claim 25 in combination with, or in addition to, an acetylcholinesterase inhibitor, a disease-modifying drug, or a biological drug for a neurodegenerative disorder, a dopaminergic drug, an antidepressant, or a typical or atypical antipsychotic. 0 Computer keyboard. Matselod 00000000 State Intellectual Property Service of Ukraine, st. Vasylya Lypkivskoho, 45, Kyiv, SME, 03680, Ukraine SE "Ukrainian Institute of Intellectual Property", str. Glazunova, 1, Kyiv - 42, 01601