4-aminoquinazoline antagonists of selective sodium and calcium ion channels

FIELD: chemistry.

SUBSTANCE: present invention relates to a quinazoline compound of formula or its pharmaceutically acceptable salts, used as inhibitors of potential-dependant sodium and calcium channels, where R1, R2, R3, R5a, R5, y and x are defined in the formula of invention. The invention also relates to a pharmaceutical composition containing the disclosed compound and to methods of inhibiting one or more of NaV1.2, NaV1.3, NaV1.8, or CaV2.2.

EFFECT: 4-aminoquinazoline antagonists of selective sodium and calcium ion channels.

17 cl, 3 tbl, 1 ex

 

Information about priority

In this application claims priority under 35 U.S.. § 119 on the basis of the provisional application U.S. No. 60/451458, filed on March 3, 2003, entitled "Compositions Useful as Inhibitors of Voltage-Gated Sodium Channels", and 60/463797, filed on April 18, 2003, entitled "Compositions Useful as Inhibitors of Voltage-Gated Sodium Channels", and the entire contents of each of these applications is included in the present description for details.

Technical field of invention

The present invention relates to compounds useful as inhibitors of ion channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention, and methods of using the compositions in the treatment of various disorders.

Background of the invention

Sodium channels are Central in relation to the generation of action potentials in all excitable cells such as neurons and myocytes. They play a key role in excitable tissues, including the brain, smooth muscle of the gastrointestinal tract, skeletal muscle, peripheral nervous system, spinal cord and air routes. As such, they play a key role in a wide variety of painful conditions such as epilepsy (see Moulard, B. and D. Bertrand (2002), "Epilepsy and sodium channel blockers" Expert Opin. Ther. Patents 12(1): 85-91)), pain (see Waxman, S. G., S. Dib-Hajj et al. (1999) “Sodium channels and pain”Proc Natl Acad Sci U S A96J Rehabil Res Dev37(5): 517-28), myotonia (see Meola, G. and V. Sansone (2000), “Therapy in myotonic disordrs and in muscle channelopathies”Neurol Sci21(5): S953-61 and Mankodi, A. and C. A. Thornton (2002) “Myotonic syndromes”Curr Opin Neurol15(5): 545-52), ataxia (see eisler, M. H., J. A. Kearney et al. (2002) “Mutations of volage-gated sodium channels in movement disorders and epilepsy”Novartis Found Symp241: 72-81), multiple sclerosis (see Black, J. A., S. Dib-Hajj et al. (2000) “Sensory neuron " secific sodium channel SNS is abnormally expressed in the brains of mice with experimental allergic encephalomyelitis and humans with multiple sclerosis”Proc Natl Acad Sci U S A97(21): 11598-602, and Renganathan, M., M. Gelderblom et al. (2003) “Expression of Na(v)1.8 sodium channels perturbs the firing patterns of cerebellar purkinje cells”Brain Res959(2): 235-42), irritable or painful sensitive intestines (see Su, X., R. E. Wahtel et al. (1999) “Capsaicin sensitivity and voltage-gated sodium currents in colon sensory neurons from rat dorsal root ganglia”Am J Physiol277(6 Pt 1): G1180-8, and Laird, J. M., V. Souslova et al. (2002) “Deficits in visceral pain and referred hyperlgesia in Navl.8 (SNS/PN3)- null mice”J Neurosci22(19): 8352-6), incontinence, visceral pain (see Yoshimura, N.,S. Seki, et al. (2001) “The involvement of the tetrodotoxin-resistant sodium channel Na(v)l.8 (PN3/SNS) in a rat model of visceral pain”J Neurosci21(21): 8690-6), as well as many mental disorders, such as anxiety and depression (see Hurley, S. C. (2002) “Lamotrigine update and its ise in mood disorders” Ann Pharmacother 36(5): 860-73).

Potentialization sodium channels comprise a family of genes consisting of 9 different subtypes (NaV1.1-NaV1.9). As pok is shown in table 1, these subtypes show specific to the tissue localization and functional differences (see Goldin, A. L. (2001) “the Resurgence of sodium channel research”Annu Rev Physiol63: 871-94). Three members of this gene family (NaV1.8, 1.9, 1.5) are resistant to blocking a well-known blocker of Na channel TTX, demonstrating the specificity of subtype within this gene family. Mutational analysis identified glutamate 387 as a critical residue for TTX binding (see Noda, M., H. Suzuki et al. (1989) “A single point mutation confers tetrodotoxin and saxitoxin insensitivity on the sodium channl II”FEBS Lett259(1): 213-6).

Table 1 (abbreviations CNS=Central nervous system, PNS=peripheral nervous system, DRG=dorsal root ganglion, TG=trigeminal ganglion):

Na
isoform
ClothTTX IC50Signs
NV1.1CNS, PNS soma of neurons10 nmPain, epilepsy, neurodegeneration
NV1.2CNS, axons
(in high concentrations)
10 nmThe neurodegeneration, epilepsy
NV1.3CNS,fetal, damaged nerves15 nmPain
NV1.4Skeletal muscles25 nmMyotonia
NV1.5Heart2 µmArrhythmia, long QT
NV1.6CNS, widely distributed, most abundant6 nmPain, movement disorder
NV1.7PNS, DRG, neuroendocrine terminals25 nmPain, neuroendocrine disorders
NV1.8PNS, small neurons in DRG and TG>50 micronsPain
NV1.9PNS, small neurons in DRG and TG1 micronPain

In General, potentialization sodium channels (NaVs) are responsible for initiating quick jump increasing the action potentials in the irritable tissue in the nervous system that transmits electricity is practical signals, soothing and encode normal and aberrant or different from the norm pain. Antagonists NaV channels can ease pain data signals and are useful for the treatment of a wide variety of pain conditions including, but not limited to, acute, chronic, inflammatory and neuropathic pain. It has been shown that known NaV antagonists, such as TTX, lidocaine (see Mao, J. and L. L. Chen (2000) “Systemic lidocaine for neuropathic pain relief”Pain87(1): 7-17), bupivacaine, phenytoin (see Jensen, T. S. (2002) “nticonvulsants in neuropathic pain: rationale and clinical evidence”Eur J Pain6(Suppl A): 61-8), lamotrigine (see Rozen, T. D. (2001) “Antiepileptic drugs in the management of cluster headache and trigeminal neuralgia”Headache41 Suppl 1: S25-32 and Jensen, T. S. (2002) “Anticonvulsants in neurpathic pain: rationale and clinical evidence”Eur J Pain6(Suppl A): 61-8), and carbamazepine (see Backonja, M. M. (2002) “Use of anticonvulsants for treatment of neuropathic pain”Neurology59(5 Suppl 2): S14-7), are useful for the relief of pain in humans and animal models.

Hyperalgesia (extreme sensitivity to anything that hurts) develops in the presence of tissue damage or inflammatory reflex, at least partially, the increase in excitability vysokorakovyh primary afferent neurons that Innervate the site of damage. Activation is sensitive to the voltage of the sodium channels is critical for the generation and dissemination is anemia potentials of neural activity. There is a growing body of evidence indicates that modulation of NaV flows is an endogenous mechanism used to regulate neuronal excitability (see Goldin, A. L. (2001) “the Resurgence of sodium channel research”Annu Rev Physiol63: 871-94). Several kinetically and pharmacologically excellent potentialization sodium channels found in the neurons of the dorsal root ganglion (DRG). Resistant to TTX flow is not sensitive to micromolar concentrations of tetrodotoxin and shows slow activation and inactivation kinetics and a more depolarized activation threshold compared to other potentsialzavisimye sodium channels. TTX-resistant sodium flows primarily limited to the subpopulation of sensory neurons, likely involved in nociception (pain reception). In particular, TTX-resistant sodium flows are expressed almost exclusively in neurons, which have a small diameter cells, and cause a slowly conducting axons of small diameter, and they respond to capsaicin. A huge mass of experimental evidence shows that TTX-resistant sodium channels expressed in C-fibers and are important in the transmission nociceptive information to the spinal cord.

Intrathecal antisense oligo-deoxynucleotides aimed at UNIKOM the optimum region TTX-resistant sodium channel NaV1.8, has resulted in a significant decrease in PGE2induced hyperalgesia (see Khasar, S. G., M. S. Gold et al. (1998) “A tetrodotoxin-resistant sodium current mediates inflammatory pain in the rat”Neur-Sci Lett256(1): 17-20). Recently Wood with colleagues generated knocked out mouse line, which lacks functional NaV1.8. Mutation gives analgesic effect in experiments on the assessment of the response of animals to inflammatory agent carrageenan (see Akopian, A.N., V. Souslova et al. (1999) “The tetrdtoxin-resistant sodium channel SNS has a specialized function in pain pathways”Nat Neurosci2(6): 541-8). In addition to the above, these animals were deficient as mechano-and thermoreceptive. Analgesia shown NaV1.8 knock-out mutants, consistent with observations regarding the role of TTX-resistant threads in nociception.

Immunohistochemical experiments, experiments in city hybridization and in vitro electrophysiology - all showed that sodium channel NaV1.8 is selectively localized to small sensory neurons of the dorsal root ganglion and trigeminal ganglion (see Akopian, A. N., L. Sivilotti et al. (1996) "A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons"Nature379(6562): 257-62). The primary role of these neurons is the detection and transmission of nociceptive stimuli. Antisense and immunohistochemical evidence also speaks about the role of NaV1.8 in neuropathic pain (with whom. Lai, J., M. S. Gold et al. (2002) "Inhibition of neuropthic rap by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8"Pain95(1-2): 143-52, and Lai, J., J. C. Hunter et al. (2000) "Blockade of neuropathic pain by antisense targeting of tetrodotoxin-resistant sodium channels in sensory neurons"Mthods Enzymol314: 201-13.). NaV1.8 protein is positively regulated intact C-fibers adjacent to the nerve damage. Antisense treatment prevents the redistribution of NaV1.8 nerves and reverses neuropathic pain. Taken together, gene knock-out and antisense data confirm the role of NaV1.8 in detection and transmission of inflammatory and neuropathic pain.

Under conditions of neuropathic pain occurs remodeling distribution and subtypes of sodium channels. In the damaged nerve expression of NaV1.8 and NaV1.9 is significantly reduced, whereas the expression of TTX-sensitive of polyadenine NaV1.3 5-10-fold increases (see Dib-Hajj, S. D., J. Fjell et al. (1999) “Plasticity of sodium channel expression in DRG neurons in the chronic constrition injury model of neuropathic pain.”Pain83(3): 591-600). The time course of the increase in NaV1.3 corresponds to the appearance of allodynia in animal models due to nerve damage. Biophysics NaV1.3 channel is characterized by the fact that it shows a very rapid recovery readiness after inactivation following the action potential. It gives a continuing high rate of excitation, as is often seen in damaged ner is e (see Cummins. T. R., F. Aglieco et al. (2001) “NaV1.3 sodium channels: rapid repriming and slow closed-state inactivation display quantitative differences after expression in a mammalian cell line and in spinal sensory neurons”J. Neurosci21(16): 5952-61). NaV1.3 is expressed in Central and peripheral systems. NaV1.9 is similar to NaV1.8, as it selectively localizes with small sensory neurons of the dorsal root ganglion and trigeminal ganglion (see Fang, X., L. Djouhri et al. (2002). “The presence and role of the tetrodotoxin-resistant sodium channel Na(v)1,9 (NaN) in nociceptive primary afferent neurons.”J Neurosci22(17): 7425-33). It has a slow rate of inactivation and shifted to the left an activation dependency on voltage (see Dib-Hajj, S., J. A. Black et al. (2002) “NaN/NaV1.9: a sodium channel with unique properties”Trends Neurosci25(5): 253-9). These two biophysical properties allow NaV1.9 to play a role in setting remains unchanged membrane potential nociceptive neurons. Remaining unchanged membrane potential NaV1.9 expressing cells is in the range of -55 to -50 mV compared to-65mv to most other peripheral and Central neurons. This persistent depolarization is in large part a consequence of weak low-level activation of NaV1.9 channels. This depolarization allows the neurons to more easily reach the threshold potential of the exciting action in response to nociceptive stimuli. Compounds that block the NaV1.9 channel, which may play an important role in establishing the starting point of the detection of painful stimuli. In chronic pain States nerves and nerve endings can become swollen and hypersensitive, showing the initiation of the action potential high frequency under the influence of weak stimulation or no stimulation. Data abnormal swelling of nerves called narimani, and primary Na channels expressed in them are NaV1.8 and NaV1.7 (see Kretschmer, T., L. T. Happel et al. (2002) “Accumulation of PN1 and PN3 sodium channels in painfull human neuroma - evidence from immunocytochemistry”Acta Neurochir (Wien)144(8): 803-10; discussion 810). NaV1.6 and NaV1.7 are also expressed in neurons of the dorsal root ganglion and promote small TTX-sensitive component, prominent in these cells. NaV1.7, in particular, may therefore be a potential pain target in addition to its role in neuroendocrine excitability (see Klugbauer, N., L. Lacinova et al. (1995) Structure and functional expression of a new member of the tetrodotoxin - sensitive voltage-activated sodium channel family from human neuroendocrine cells"Embo J14(6): 1084-90).

NaV1.1 (see Sugawara, T., E. Mazaki-Miyazaki et al. (2001) “Nav1.1 mutations cause febrile seizures associated with afebrile partial seizures.”Neurology57(4): 703-5) and NaV1.2 (see Sugawara, T., Y. Tsurubuchi, et al. (2001) A missense mutation of the Na+ channel alpha II subunit gene Na(v)1.2 in a patient with febrile and afebrile seizures causes channel dysfunction”Proc Natl Acad Sci U S A98(11): 6384-9) associated with conditions of epilepsy, including bouts of fever. There are more than 9 genetic mutations of NaV1.1 associated with bouts of fever (see Meisler, M. H. J. A. Kearney, et al. (2002) “Mutations of voltage-gated sodium channels in movement disorders and epilepsy”Novartis Found Symp241: 72-81).

For the treatment of cardiac arrhythmias have been developed and are antagonists of NaV1.5. Genetic defect in NaV1.5, which produces larger mainactivity component to the current, is associated with long QT in humans, and to treat this condition is used orally available local anesthetic of mexiletine (see Wang, D. W., K. Yazawa et al. (1997) “Pharmacological targeting of long QT mutant sodium channels.”J Clin Invest99(7): 1714-20).

Currently, several blockers of Na channels are being used or tested in the clinic for the treatment of epilepsy (see Moulard, B. and D. Bertrand (2002) “Epilepsy and sodium channel blockers”Expert Opin. Ther. Patents12(1): 85-91);acute (see Wiffen, P., S. Collins, et al. (2000) “Anticonvulsant drugs for acute and chronic pain”Cochrane Database Syst Rev3), chronic (see Wiffen, P., S. Collins, et al. (2000) “Anticonvulsant drugs for acute and chronic pain”Cochrane Database Syst Rev3, and Guay, D. R. (2001) “Ajuncive agents in the management of chronic pain”Pharmacotherapy21(9): 1070-81), inflammatory (see Gold, M. S. (1999) “Tetrodotoxin-resistant Na+ currents and inflammatory hyperalgesia.”Proc Natl Acad Sci U S A96(14): 7645-9) and neuropathic pain (see Strichartz, G. R., Z. Zhou, et al. (2002) “Therapeutic concentrations of local anaethetics unveil the potential role of sodium channels in neuropathic pain”Novartis Found Symp241: 189-201, and Sandner-Kiesling, A., G. Rumpold Seitlinger, et al. (2002) “Lamotrigine monotherapy for control of neuralgia after nerve section”Acta Anaesthesiol Scand46(10): 1261-4); cardiac arrhythmia (see An, R. H., R. Bangalore, et al (1996) “Lidocane block of LQT-3 mutant human Na+ channels” Circ Res79(1): 103-8, and Wang, D. W., K. Yazawa, et al. (1997) “Pharmacological targeting of long QT mutant sodium channels"J Clin Invest99(7): 1714-20); neurotoxity (see Taylor, C. P. and L. S. Narasimhan (1997) ”Sodium channels and therapy of central nervous system diseases”Adv Pharmacol39: 47-98) and as anesthetics (see Strichartz, G. R., Z. Zhou, et al. (2002) “Therapeutic concentrations of local anaesthetics unveil the potential role of sodium channels in neuropathic pain.”Novartis Found Symp241: 189-201).

Calcium channels are membrane-spanning, multi-subunit proteins, which provide the output Sa from the outer environment and the simultaneous depolarization potential of the cell membrane. Traditionally, the calcium channels are classified based on their functional characteristics, such as nizkovoltnaya or vysokovoltnoye activation, and their kinetics (L,T,N,P,Q). The ability to clone and Express subunit of calcium channels leads to improved understanding of the composition of the channels, which gives the data of the functional response. There are three major types of subunits, which form calcium channels - α1, α2δ and β. α1 is the subunit that contains the channel pore and the sensor voltage, α2 is mainly extracellular and represents the disulfide associated with the transmembrane δ subunit, β is deglycosylation subunit, was found associated with the cytoplasmic region of the α1 subunit of the CA channel. In toadie time consider that different subtypes of calcium channels are composed of the following characteristic subunits:

• L-type, including subunit α1Cα1Dα1For α1Sα2δ and β3A

• N-type, including the subunit α1B, α2δ, β1b

• R-type, including the subunit α1A, α2δ, β4A

• Q-type, including the subunit α1A(splice variant) α2δ, β4A

• R-type, including the subunit α1, α2δ, β1b

• T-type, including the subunit α1Gα1Hor α1I

Calcium channels play a Central role in the release of neurotransmitter. The influx of calcium in the presynaptic terminal nerve process associated with the cascade and produces a cascade of protein-protein interactions (syntaxin 1A, SNAP-25 and synaptotagmin), which eventually ends with the fusion of synaptic bubble and release of neurotransmitter package. Blockade of presynaptic calcium channels reduces the influx of CA and gives the cubic X3the decrease in the release of neurotransmitter.

Calcium channel N-type (CaV2.2) highly expressed in presynaptic nerve endings dorsal root ganglion, as it forms a synapse with neurons in the dorsal horn in the layer I and II. These neurons, in turn, have a large number of CA channels N type in their presnap the practical terminals, because they are in contact with the neurons of the second and third order. This path is very important in the transmission of pain information to the brain.

The pain can be roughly divided into three different types: acute, inflammatory and neuropathic. Acute pain serves an important protective function in keeping the body safe from stimuli that can cause tissue damage. Strong thermal, mechanical or chemical effects have the potential to cause severe damage to the body if left unattended. Acute pain serves for the rapid removal of the individual from causing harm to the environment. Acute pain, by its nature, is usually long lasting and intense. Inflammatory pain, on the other hand, can last for longer periods of time, and its intensity varies more gradually. Inflammation can occur for many reasons, including tissue damage, autoimmune response and pathogenic invasion. Inflammatory pain is mediated by “inflammatory soup”, which consists of substance P, histamines, acids, prostaglandin, bradykinin, CGRP, cytokines, ATP, and the release of neurotransmitter. The third class of pain is neuropathic pain and includes nerve damage which results in financial p is brought to the reorganization of neural proteins and makes the cycle, which gives pathological “increased sensitivity” state, which can give chronic pain that has lasted for many years. This type of pain does not provide any adaptive benefit, and it is particularly difficult to treat with existing therapies.

Pain, especially neuropathic pain is difficult to treat, in great measure is unresolved medical problem. Millions of individuals suffer from severe pain, which is not regulated by existing therapies. Modern medicines used to treat pain include NSAIDs, COX2 inhibitors, opioids, tricyclic antidepressants and anticonvulsive means. Neuropathic pain is particularly difficult to treat, as she is not responsible enough to opioids until then, until you have achieved a high dose. Gabapentin is currently a therapeutic tool, which is preferred for the treatment of neuropathic pain, although it works only in 60% of patients, in which case it detects a reasonable efficiency. This medication is however a very safe and side effects are usually tolerated, although relief is achieved at higher doses.

Sa a N channel type the person was employed by intrathecal injections of toxin ziconotide for l is ing untreatable pain, cancer pain resistant to opioids, pain, and neuropathic pain. This toxin has an 85% degree of success for the treatment of pain in people with greater potency than morphine. Orally available antagonist Sa N channel type would be a much larger market share of the funds from the pain. Ziconotide causes mast cell degranulation and gives a dose-dependent Central side effects. They include dizziness, nystagmus, excitement and dysmetria. Some patients at high doses is also orthostatic hypotension. The main risk to this target includes side effects in the Central nervous system observed with ziconotide at high dosage. They include dizziness, nystagmus, excitement and dysmetria. Some patients at high doses is also orthostatic hypotension. It is believed that this may be a consequence caused by ziconotide degranulation of mast cells and/or its action on the sympathetic ganglia, and spinal ganglia also expresses Sa N channel type. Depending on the use of compounds that block is preferably in the higher frequency range >10 Hz, should be useful in minimizing possible side effects. The degree of excitation of people sympathetic efferents is 0.3 Hz interval. The neurons of the CNS can exist p and higher frequencies, but this usually occurs only during short bursts of action potentials. Even with selectivity attached depending on use with internal inherent selectivity against calcium channel L-type calcium channel is still needed, as they are involved in the contraction of the heart and vascular smooth muscle.

Unfortunately, as described above, the effectiveness of currently used blockers of sodium channels and calcium channel blockers against the disease conditions described above, to a great extent limited side effects. These side effects include CNS disorders such as blurred vision, dizziness, nausea and sedation, as well as more possible life-threatening heart arrhythmia and heart failure. Accordingly, there remains a need to develop additional antagonists Na channels and calcium channels, preferably antagonists higher strength and with fewer side effects.

Summary of invention

It was found that the compounds of this invention and their pharmaceutically acceptable compositions are useful as inhibitors potentialization sodium channels and calcium channels. These compounds have the General formula I:

or p is establet their pharmaceutically acceptable derivatives, where R1, X, R3, x and ring A have the meanings defined below.

These compounds and pharmaceutically acceptable compositions are useful for treating or reducing the severity of a wide range of diseases, disorders or conditions, including but not limited to them, acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, trigeminal neuralgia, herpetic neuralgia, General neuralgia, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritus pain, post herpetic neuralgia, diabetic neuropathy, radicular pain, ischialgia, spinal pain, headache and neck pain, severe or enduring pain, nociceptive pain, pain during breaks fabrics, surgical pain, or cancer pain.

Detailed description of the invention

I. General description of the compounds of the invention:

The present invention relates to compounds of the formulaIuseful as inhibitors potentialization sodium channels and calcium channels:

or their pharmaceutically acceptable with the NML,

where X represents O or NR2; R1and R2are each independently optionally substituted group selected from hydrogen, C1-6aliphatic group or su1where su1represents a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms selected independently from nitrogen, oxygen, or sulfur, or represents a 3-12-membered saturated or partially unsaturated monocyclic or bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, in which su1linked directly to the nitrogen atom, or linked via optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by a group-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, -SO2NR - or-NRSO2-; or R1and R2taken together with the nitrogen atom to which they are attached, form an optionally substituted 3-12-membered monocyclic or bicyclic saturated, partially unsaturated or fully unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur or oxygen; R1and R2or the ring formed by R1and

R2taken together, each optionally and independently Zam is disposed at one or more substitutable carbon atoms, nitrogen or sulphur, z is the number of independent substituents R4where z is 0-5;

ring a is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms selected independently from nitrogen, oxygen, or sulfur, or represents a 3-12-membered monocyclic or bicyclic saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, where the ring And optionally substituted with independent substituents R5where y is 0-5, and is additionally optionally substituted by the number q of independent cases R5Awhere q is 0-2;

x is 0-4;

each of R3, R4and R5is independently Q-RXwhere Q represents a bond or represents C1-C6alkylidene chain, where up to two non-adjacent methylene units of Q optionally and independently substituted by a group-NR-, -S-, -O-, -CS-CO2-, -OCO-, -CO-, -COCO-, -CONR-, -NRCO-, -NRCO2, -SO2NR-, -NRSO2-, -CONRNR-, -NRCONR-, -OCONR-, -NRNR-, -NRSO2NR-, -SO-, -SO2-, -PO-, -PO2-, -OP(O)(OR) -, or-POR-;

each of RXindependently selected from-R', =O, =NR', - halogen, -NO2, -CN, -OR', -SR', -N(R')2, -NR'r COR', -NR'r CON(R')2, -NR'r CO2R', -COR', -CO2R', -OCOR', -CON(R')2, -OCON(R')2, -SOR', -SO2R', -SO2 N(R')2, -NR'r SO2R', -NR'r SO2N(R')2, -COCOR', -COCH2COR', -OP(O)(OR')2, -P(O)(OR')2-OP(O)2OR', -P(O)2OR', -PO(R')2or-OPO(R')2

each of R5ais independently optionally substituted C1-C6aliphatic group, halogen, -OR', -SR', -N(R')2, -NR'r COR', -NR'r CON(R')2, -NR'r CO2R', -COR', -CO2R', -OCOR', -CON(R')2, -OCON(R')2, -SOR', -SO2R', -SO2N(R')2, -NR'r SO2R', -NR'r SO2N(R')2, -COCOR', -COCH2COR', -OP(O)(OR')2, -P(O)(OR')2, -OP(O)2OR', -P(O)2OR', -PO(R')2or-OPO(R')2and

each R is independently hydrogen or optionally substituted C1-6aliphatic group and each R' is independently hydrogen or optionally substituted C1-6aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R and R', two of R, or two of R' taken together with the atom(s)to which they are attached, form a optionally saturated 3-12-membered saturated, partially unsaturated or fully nenas the seal monocyclic or bicyclic ring, having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

In some embodiments of compounds directly above:

i) when x is 1 and R3is optionally substituted 6-phenyl or 6-pyridyl, and R1is hydrogen, then R2is not Cy1and

ii) monohydrochloride 1-(4-amino-6,7-dimethoxy-2-hintline)-4-(2-fornicator)piperazine and 1-(4-amino-6,7-dimethoxy-2-hintline)-4-[(2,3-dihydro-1,4-benzodioxin-2-yl)carbonyl]piperazine are excluded.

2. Connections and definitions:

The compounds of this invention include compounds described in General above, and further illustrated by the classes, subclasses, and species disclosed herein. In the sense used here should apply the following definitions, unless otherwise specified. For the purposes of this invention, the chemical elements are identified in accordance with the Periodic table of elements in the CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, General principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire content of which is included in this description by reference.

As described herein, compounds of the invention can be optionally substituted by one the or more substituents, such as illustrated above, or shown by examples classes, subclasses and species of the invention. It should be understood that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted". In General, the term "substituted", precedes him, the term "optionally" or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise specified, optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted by more than one Deputy, selected from a specified group, the Deputy may be either the same or different in each position. Combinations of substituents, provided by this invention are preferably those which result in the formation of a stable or chemically possible connections. The term “stable”, as used here, refers to compounds, which essentially do not change when exposed to conditions enabling them to receive, identify, and preferably their separation, purification, and use for one or more purposes described here. According to some embodiments stable compound or chemically POS of the important connection is the which essentially does not change when stored at a temperature of about 40aboutC or lower, in the absence of moisture or other chemically reactive conditions, for at least a week.

The term “aliphatic” or “aliphatic group”, as used here, denotes unbranched (i.e., a normal chain or branched, saturated or unsaturated hydrocarbon chain that is completely saturated or which contains one or more unsaturated chains, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more unsaturated chains, but which is not aromatic (referred to here as “carbocycle”, “cycloaliphatic” or “cycloalkyl”), which has one position to join the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. According to some embodiments of the aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments aliphatic groups contain 1-8 aliphatic carbon atoms. In the following embodiments of the aliphatic groups contain 1-6 aliphatic carbon atoms and in the following embodiments of the aliphatic groups contain 1-4 aliphatic carbon atoms. In some the x incarnations “cycloaliphatic traveler” (or “carbocycle” or “cycloalkyl”refers to monocyclic 3-C8the hydrocarbon or bicyclic8-C12the hydrocarbon that is completely saturated or that contains one or more links with desaturation, but which is not aromatic, that has a single attachment point to the rest of the molecule, where any individual ring in the specified bicyclic system has 3-7 members. Suitable aliphatic groups include, but are not limited to these, linear or branched, saturated or unsaturated alkyl, alkeline, alkyline groups and their hybrids, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term “heteroaromatics(s)”used here denotes an aliphatic group in which one or two carbon atoms independently substituted by one or more atoms of oxygen, sulfur, nitrogen, phosphorus or silicon. Heteroaromatics groups can be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and include a heterocycle(practical)”, “heterocyclyl(inou)”, “heterocyclizations” or “heterocyclic” group.

The term “heterocycle”, “heterocyclyl”, “geterotsiklicheskikh traveler” or “heterocyclic(s)” used herein means non-aromatic, monocyclic, bicyclic or articlecheck ring system, in which one or more ring members are an independently selected heteroatom. In some embodiments, the “heterocycle(practical)”, “heterocyclyl(other)”, “heterocyclizations” or “heterocyclic” group is of three to fourteen ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen or phosphorus and each ring in the system contains 3-7 ring members.

The term “heteroatom” means one or more atoms of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus or silicon; quaternion the form of any basic nitrogen or a substituted nitrogen heterocyclic ring, for example N - (3,4-dihydro-2H-pyrrolyl), NH (as pyrrolidinyl) or NR+(in the form of N-substituted pyrrolidinyl)).

The term "unsaturated"as used here, indicates that the fragment has one or more links with desaturation.

The term "alkoxy" or "thioalkyl", as used here, refers to an alkyl group as previously defined, attached to the main carbon chain through an oxygen atom ("alkoxy") or sulfur ("thioalkyl").

The term "halogenated", "halogenoalkanes and halogenoalkane" denotes alkyl, alkenyl or alkoxy, and this radical may be substituted by one or more at the Mami halogen. The term "halogen" means F, Cl, Br or I.

The term "aryl"used alone or as part of a larger fragment, as in the case of "aralkyl", "arakaki" or "aryloxyalkyl", refers to monocyclic, bicyclic and tricyclic ring systems having a total of five to fourteen ring members, where at least one ring in the system is aromatic and where each ring in the system contains 3-7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring". The term "aryl" refers to heteroaryl ring systems as defined here below.

The term "heteroaryl"used by itself or as part of a larger fragment, as in the case of "heteroalkyl" or "heteroaromatics", refers to monocyclic, bicyclic and tricyclic ring systems having a total of five to fourteen ring members, where at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and where each ring in the system contains 3-7 ring members. The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic".

Aryl (including aralkyl, Alcoxy, aryloxyalkyl and EN is logical) or heteroaryl (including heteroalkyl, heteroaromatics and the like) group may contain one or more substituents, and thus, it may be "optionally substituted". Unless otherwise defined above and herein suitable substituents at the unsaturated carbon atoms of aryl or heteroaryl groups are selected from halogen; -Ro; -ORo; -SRo; phenyl (Ph)optionally substituted by the radical Ro; -O(Ph), optionally substituted Ro; -(CH2)1-2(Ph), optionally substituted Ro; -CH=CH(Ph), optionally substituted Ro; -NO2; -CN; -N(Ro)2; -NRoC(O)Ro; -NRoC(S)Ro; -NRoC(O)N(Ro)2; -NRoC(S)N(Ro)2; -NRoCO2Ro; -NRoNRoC(O)Ro; -NRoNRoC(O)N(Ro)2; -NRoNRoCO2Ro; -C(O)C(O)Ro; -C(O)CH2C(O)Ro; -CO2Ro; -C(O)Ro; -C(S)Rabout; -C(O)N(Ro)2; -C(S)N(Ro)2; -OC(O)N(Ro)2; -OC(O)Ro; -C(O)N(ORoRo; -C(NORoRo; -S(O)2Ro; -S(O)3Ro; -SO2N(Ro)2; -S(O)Ro; -NRoSO2N(Ro)2; -NRoSO2Ro; -N(ORoRo; -C(=NH)-N(Ro)2; -P(O)2Ro; -PO(Ro)2; -OPO(Ro)2; -(CH2)0-2NHC(O)Ro; phenyl (Ph)optionally substituted by the radical Ro; -O(Ph), optionally substituted Ro; -(CH2 )1-2(Ph), optionally substituted Ro; or-CH=CH(Ph), optionally substituted Rowhere each of Roindependently selected from hydrogen, optionally substituted C1-6aliphatic, unsaturated 5-6-membered heteroaryl or heterocyclic ring, phenyl, -O(Ph), or CH2(Ph), or, notwithstanding the definition above, two independent case of Roat the same substituent or different substituents, taken together with the atom(s)attached to each Rothe group, forming an optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

Optional substituents of the aliphatic groups of Roselected from NH2, NH(C1-4aliphatic) groups, NH(C1-4aliphatic)2group, halogen, C1-4aliphatic group, HE, (C1-4aliphatic) groups, NR2Joint VENTURE, CO2N

CO2(C1-4aliphatic) groups, (Halogens1-4aliphatic) groups or Halogens1-4aliphatic group, where each of the previous With the1-4aliphatic groups group Rois unsubstituted.

Aliphatic or heteroaromatics group or nonaromatic of heteros licence ring may contain one or more substituents, and thus, it can be “optionally substituted”. Unless otherwise defined above and herein suitable substituents at the saturated carbon of an aliphatic or heteroaromatics group or non-aromatic heterocyclic ring are selected from the substituents listed above for the unsaturated carbon aryl or heteroaryl group and additionally include the following =O, =S, =NNHR*, =NN(R*)2, =NNHC(O)R*, =NNHCO2(alkyl), =NNHSO2(alkyl), or =NR*, where each R* is independently selected from hydrogen or optionally substituted C1-6aliphatic group.

Unless otherwise defined above and herein, optional substituents in non-aromatic nitrogen heterocyclic rings are usually chosen from-R+,

-N(R+)2, -C(O)R+, -CO2R+, -C(O)C(O)R+, -C(O)CH2C(O)R+, -SO2R+, -SO2N(R+)2, -C(=S)N(R+1)2, -C(=NH)-N(R+)2or-NR+SO2R+where R+represents hydrogen, optionally substituted C1-6aliphatic group, optionally substituted phenyl, optionally substituted-O(PH), optionally substituted-CH2(PH), optionally substituted -(CH2)1-2(PH), optionally substituted-CH=CH(PH) or unsubstituted 5-6 membered heteroaryl or heterocyclic number of the TSO, having 1-4 heteroatoms independently selected oxygen, nitrogen or sulfur, or, notwithstanding the definition above, two independent case of R+at the same substituent or different substituents, taken together with the atom(s)attached to each R+group, form a optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

Optional substituents of the aliphatic group or the phenyl ring of the group R+selected from-NH2, -NH(C1-4aliphatic) groups, -N(C1-4aliphatic)2group, halogen, C1-4aliphatic group, -OH, -O(C1-4aliphatic) groups, -NR2, -CN, -CO2H, -CO2(C1-4aliphatic) groups, -O(Halogens1-4aliphatic) groups or halogen(C1-4aliphatic) groups, where each of the previous With the1-4aliphatic groups group R+is unsubstituted.

The term “alkylidene chain” refers to a straight or branched carbon chain, which may be fully saturated or have one or more links with desaturation and has two points of connection to the rest of the molecule.

As discussed at length is use, in some embodiments, two independent Deputy of Rabout(or R+, R, R' or any other variable defined similarly above), taken together with the atom(s)to which they are attached, form an optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

Examples of rings that are formed when two independent Deputy of Rabout(or R+, R, R' or any other variable defined similarly above) taken together with the atom(s)attached to each variable, include, but are not limited to, the following: a) two independent Deputy of Rabout(or R+, R, R' or any other variable defined similarly to the above)that are attached to the same atom and are taken together with the atom forming a ring, for example, N(Rabout)2when both of the substituent Rabouttaken together with the nitrogen atom, form a piperidine-1-ilen, piperazine-1-ilen, or morpholine-4-ilen group and b) two independent Deputy of Rabout(or R+, R, R' or any other variable defined similarly to the above)that are attached to different atoms and are taken together with both of these atoms forming a ring, for example, is when the phenyl group is substituted by two substituents from OR othe two Deputy Rabouttaken together with the oxygen atoms to which they are attached, form a fused 6-membered oxygen-containing ring.You should understand that you can produce many other rings, when two independent Deputy of Rabout(or R+, R, R' or any other variable defined similarly above) taken together with the atom or atoms, which are attached to each of the variables, and examples detailed above are not intended to limit them.

Unless otherwise stated, there is also aware that the structure shown here include all isomeric (e.g., enantiomeric, diastereomeric and geometric (or conformational)) forms of the structure, such as R and S configurations for each asymmetric center, (Z) and (E) isomers with double bonds and (Z) and (E) conformational isomers. Therefore, the scope of the invention covered by the single stereochemical isomers as well as enantiomeric, diastereomeric and geometric (or conformational) mixtures of these compounds. Unless otherwise specified, the scope of the invention covers all tautomeric forms of the compounds of the invention. In addition, unless otherwise stated, we mean that the structure shown here, include compounds that are about lechyutsya only the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of carbon13With or14C-enriched carbon are covered by the scope of the invention. Such compounds are useful, for example, as analytical tools or probes or probes in biological assays.

3. Description typical connections:

As described in General above for compounds of the invention X is O or NR2. Accordingly, in some embodiments X is NR2and compounds have the structure formulaI-A:

In other embodiments X is O, and compounds have the structure formulaI-B:

In some embodiments of the compounds of the formulaI-Aone of R1or R2represents hydrogen and the other of R1and R2selected from optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by a group-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, -SO2NR-, or-NRSO2or is Cy1where Cy1represents a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms selected independently from nitrogen, oxygen, or sulfur, or pre who is 3-12-membered saturated or partially unsaturated monocyclic or bicyclic ring, having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, where Cy1linked directly to the nitrogen atom, or linked via optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by a group-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, -SO2NR - or-NRSO2-.

In still other embodiments, R1and R2each independently selected from Cy1where Cy1represents a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms selected independently from nitrogen, oxygen, or sulfur, or represents a 3-12-membered saturated or partially unsaturated monocyclic or bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, where Cy1linked directly to the nitrogen atom, or linked via optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by a group-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, -SO2NR-, or-NRSO2-; or optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by a group-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, -SO2NR - or-NRSO 2-.

In other embodiments of the compounds of the formulaI-Aone of R1or R2represents hydrogen and the other of R1or R2represents optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by a group-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, -SO2NR - or-NRSO2-. According to other embodiments optionally substituted C1-4aliphatic group substituted by a group Cy1where Cy1represents a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms selected independently from nitrogen, oxygen, or sulfur, or represents a 3-12-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, where Cy1optionally substituted by 0 to 5 independent substituents-R5. According to further embodiments, one of R1or

R2represents hydrogen or C1-C4alkyl and the other of R1and R2represents-CH2-Su1.

In some additional embodiments of the compounds of the formulaI-InR1represents optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4al the factual group optionally substituted by a group-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, -SO2NR - or-NRSO2-.

According to other embodiments of the compounds of the formulaI-Aneither R1or R2is not hydrogen, and R1and R2each independently selected from Cy1where Cy1represents a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms selected independently from nitrogen, oxygen, or sulfur, or represents a 3-12-membered saturated or partially unsaturated monocyclic or bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, where Cy1linked directly to the nitrogen atom, or linked via optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by a group-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, -SO2NR-, or-NRSO2-; or optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by a group-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, -SO2NR - or-NRSO2-. According to other embodiments, and R1and R2are optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by g is oppoi-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, -SO2NR - or-NRSO2-.

According to some embodiments of the compounds of the formulaI,I-AorI-InCy1chosen from:

where R4matter previously defined, and z is 0-4. Other examples of the rings include rings, shown below in table 2.

According to other embodiments of the compounds of the formulaI,I-AorI-Inexamples of groups R1and R2are optionally substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)co2CH3, (CH2)2Och3CH2(CO)co2CH3CH2(CO)co3,

CH(CH3)CH2CH3or n-butyl. Other examples R1and R2groups include the groups shown below in table 2.

According to still other embodiments for compounds of the formulaI-AR1and R2taken together with the nitrogen atom to which they are attached, form an optionally substituted 3-12-membered heterocyclyl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur. According to some preferred embodiments, R1and R2taken together with the nitrogen atom to which they are attached, form a group selected from:

where the ring formed by R1and R2taken together, optionally substituted at one or more substitutable carbon atoms, nitrogen or sulfur number z are independent substituents R4and z is 0-5.

According to other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted, azetidin-1-yl (jj), pyrrolidin-1-yl (ff)piperidine-1-yl (dd), piperazine-1-yl (ccor morpholine-4-yl (ee). According to other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted, azetidin-1-yl (jj), pyrrolidin-1-yl (ff)piperidine-1-yl (dd) or piperazine-1-yl (SS). According to still other embodiments for compounds of the formulaI-AR1and R2taken together, represent an optionally substituted, azetidin-1-yl (jj). According to still other embodiments for compounds of the formulaI-AR1and R2taken together, represent optionally substituted pyrrolidin-1-yl (ff). According to other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperidine-1-yl (dd). According to still other embodiments for compounds of the formulaI-AR1and R2taken together, represent optionally substituted Pieper is Zin-1-yl ( cc).

According to some embodiments z is 0-2. According to other embodiments, z is 0 and the ring is unsubstituted. Preferred

R4groups, when they are present, each independently represents halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -COOR', -NRCOR', -CON(R')2, -OCON(R')2, COR', -NHCOOR', -SO2R', -SO2N(R')2or an optionally substituted group selected from C1-C6aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocyclizations group, arils1-C6of alkyl, heteroaryl1-C6of alkyl, cycloaliphatic1-C6the alkyl or geterotsiklicheskikh1-C6the alkyl. Other examples R4groups are Cl, Br, F, CF3CH3, -CH2CH3CN, -COOH, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -CH2OH, -NHCOCH3, -SO2NH2, -SO2(CH2)3CH3, -SO2CH(CH3)2, -SO2N(CH3)2, -SO2CH2CH3, -C(O)och2CH(CH3)2, -C(O)NHCH2CH(CH3)2, -NHCOOCH3, -C(O)C(CH3)3, -COO - (CH2)2CH3-C(O)NHCH(CH3)2, -C(O)CH2CH3or an optionally substituted group, select the bedroom from piperidinyl, the piperazinil, morpholino,1-4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CH2of cyclohexyl, pyridyl, -CH2pyridyl or-CH2thiazolyl. Still other examples R4groups include the groups shown below in table 2.

According to some embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted, azetidin-1-yl (jj), where z is 1 or 2 and at least one of R4is-NRSO2R', -NRCOOR', -NRCOR'. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted, azetidin-1-yl (jj), where z is 1 and R4is-NRSO2R'. According to other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted, azetidin-1-yl (jj), where z is 1 and R4is-NRCOOR'. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted, azetidin-1-yl (jj), where z is 1 and R4is-NRCOR'. According to still other embodiments for compounds of the formulaI-AR1and R2taken together, represent optionally substituted pyrrolidin-1-yl (ff), where z, not only is no 1 or 2 and R 4represents Cl, Br, F, CF3CH3, -CH2CH3, -OR' or-CH2'OR'. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperidine-1-yl (dd), where z is 1 or 2 and at least one of the substituents R4represents Cl, Br, F, CF3CH3, -CH2CH3, -OR', or CH2OR', -NRCO2R', -NRCOOR', or -- OCON(R')2. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperidine-1-yl (dd), where z is 1 and R4is F, CF3CH3, -CH2CH3, -OR' or-CH2'OR'. According to other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperidine-1-yl (dd), where z is 1 and R4is-NRSO2R'. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperidine-1-yl (dd), where z is 1, and

R4is-NRCOOR'. According to still other embodiments for compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperazine-1-yl (SS), where z submitted is 1 or 2, and at least one of the substituents R4is-SOR', -CON(R')2, -SO2N(R')2, -COR' or-COOR'. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperazine-1-yl (SS), where z is 1 and R4is-SOR'. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperazine-1-yl (SS), where z is 1 and R4is-OR'. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperazine-1-yl (SS), where z is 1 and R4is-SOP(R')2. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperazine-1-yl (SS), where z is 1 and R4is-SO2N(R')2. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperazine-1-yl (SS), where z is 1 and R4is-COR'.

As described in General above for compounds of the formulaI,I-AorI-Inhintline collomore to be replaced by independent substituents R 3up to four. In some embodiments x is 0-2. In other embodiments x is 1 or 2. In still other embodiments, x is 1 and R3is substituted in the 6 position 7 chineselanguage rings. When hintline ring is replaced by (x is 1-4), R3groups are halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -COOR', -NRCOR', -CON(R')2, -OCON(R')2, -COR', -NHCOOR', -SO2R', -SO2N(R')2or an optionally substituted group selected from C1-C6aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocyclizations group, arils1-C6of alkyl, heteroaryl1-C6of alkyl, cycloaliphatic1-C6the alkyl or geterotsiklicheskikh1-C6the alkyl. According to still other embodiments, each substituent R3is independently Cl, Br, F, CF3, -OCF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -NHCOCH(CH3)2, -SO2NH2, -CONH(cyclopropyl), -CONHCH3, -CNHCH2CH3or an optionally substituted group selected from piperidinyl, piperazinil, morpholino, f the Nile, phenyloxy, benzyl, or benzyloxy. According to other embodiments x is 1 or 2 and each R3the group is independently halogen, CN, optionally substituted C1-C6alkyl, OR', N(R')2, CON(R')2or NRCOR'. According to other embodiments x is 1 or 2 and each R3the group represents-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3,

-NH2, -OCH2CH3or-CN. According to the following embodiments x is 1 and R3is in position 6 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3or-CN. According to the following embodiments x is 1 and R3is in position 7 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3or-CN. In accordance with the following further embodiments x is 1 and R3is in position 6 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3or-OCH2CH3. In accordance with the following further embodiments x is 1 and R3náchod is raised in position 7 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3or-OCH2CH3. According to other embodiments x is 1 and R3is in position 6 chineselanguage ring and is-CON(R')2or NRCOR'. According to other embodiments x is 1 and R3is in position 7 chineselanguage ring and is-CON(R')2NRCOR'. Other examples R3groups include the groups shown below in table 2.

As described in General above for compounds of the formulaI,I-AorI-Inring a is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms selected independently from nitrogen, oxygen, or sulfur, or represents a 3-12-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, where the ring And optionally substituted with independent substituents R5where y is 0-5, and is additionally optionally substituted by the number q of independent substituents R5Awhere q is 0-2.

According to some embodiments ring a is selected from:

According to some embodiments of the ring And selected from the optional samemanner is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or pyrrol-1-yl.

According to some embodiments y is 0-5, q is 0-2, R5and R5Agroups, when they are present, are each independently halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -NRCOR', -CON(R')2, -S(O)2N(R')2, -OCOR', -COR', -CO2R', -OCON(R')2, -NR'r SO2R', -OP(O)(OR')2, -P(O)(OR')2, -OP(O)2OR', -P(O)2OR', -PO(R')2, -OPO(R')2or an optionally substituted group selected from C1-C6aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocyclizations group, arils1-C6of alkyl, heteroaryl1-C6of alkyl, cycloaliphatic1-C6the alkyl or geterotsiklicheskikh1-C6the alkyl.

According to other embodiments y is 0-5, q is 1 or 2 and each R5Ais independently Cl, Br, F, CF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -SO2NH2, -SO2NHC(CH3)2, -OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-piperazine-1-yl, OCOCH(CH3)2, OCO(cyclopentyl), -COC 3not necessarily replaced phenoxy or optionally substituted benzyloxy.

According to the following embodiments is 0, q is 1 and R5ais F. According to another embodiments is 0, q is 1 and R5ais OR'. According to another embodiments is 0, q is 1 and R5ais HE. According to another embodiments is 0, q is 2 and one of the substituents R5arepresents OR', and the other of the substituents R5ais F. According to another embodiments is 0, q is 2 and one of the substituents R5ais HE, and the other of the substituents R5ais F.

In accordance with the following further embodiments ring a is phenyl, y is 0, q is 1 and R5ais F, substituted in position 2 of the phenyl ring. According to another embodiments ring a is phenyl, y is 0, q is 1 and R5arepresents OR', substituted in position 2 of the phenyl ring. According to another embodiments ring a is phenyl, y is 0, q is 1 and R5aHE is substituted in position 2 of the phenyl ring. According to another embodiments ring a is phenyl, y is 0, q is 2 and one R5arepresents OR', and is another of R 5ais F, where'OR' is substituted in position 2 of the phenyl ring and F is substituted in the 6 position of the phenyl ring. According to another embodiments ring a is phenyl, y is 0, q is 2 and one R5ais HE, and the other of R5ais F, where IT is substituted in position 2 of the phenyl ring and F is substituted in the 6 position of the phenyl ring.

Other examples R5and R5Agroups include the groups shown below in table 2.

As for the compounds described in General in this section above, it is noted that the compounds are useful as inhibitors of ion channels, preferably potentialization sodium channel and calcium channel N-type. In some examples of embodiments of the compounds of the invention are useful as inhibitors of NaV1.8. According to other embodiments of the compounds of the invention are useful as inhibitors of NaV1.8 and CaV2.2. In still other embodiments of the compounds of the invention are useful as inhibitors of CaV2.2. According to still other embodiments of the compounds of the invention are useful as dual inhibitors of NaV1.8 and TTX-sensitive ion channels, such as NaV1.3 or NaV1.7.

Some additional embodiments of the compounds, in General, described above, are described in more detail below.

I. Soy is inane formula IA:

or their pharmaceutically acceptable salts, where

R1and R2taken together with the nitrogen atom to which they are attached, form an optionally substituted 3-12-membered monocyclic or bicyclic saturated, partially unsaturated or fully unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur or oxygen, where the ring formed by R1and R2taken together, is optionally substituted at one or more substitutable carbon atoms, nitrogen or sulphur, z is the number of independent deputies-R4where z is 0-5;

ring a is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms selected independently from nitrogen, oxygen, or sulfur, or represents a 3-12-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, where the ring And optionally substituted with independent substituents R5where y is 0-5, and is additionally optionally substituted by q is independent of the substituents R5Awhere q is 0-2;

x is 0-4;

each Deputy of R3, R4and R5is independently Q-RXg is e Q represents a bond or represents C 1-C6alkylidene chain, where up to two non-adjacent methylene units of Q are not necessarily and independently replaced by a group-NR-, -S-, -O-, -CS-CO2-, -OCO-, -CO-, -COCO-, -CONR-, -NRCO-, -NRCO2, -SO2NR-, -NRSO2-, -CONRNR-, -NRCONR-, -OCONR-, -NRNR-, -NRSO2NR-, -SO- -SO2-, -PO-, -PO2-, -OP(O)(OR) -, or-POR-; and each of RXindependently selected from R', halogen, =O, =NR', -NO2, -CN, -OR', -SR', -N(R')2, -NR'r COR', -NR'r CON(R')2, -NR'r CO2R', -COR', -CO2R', -OCOR', -CON(R')2, -OCON(R')2, -SOR', -SO2R', -SO2N(R')2, -NR'r SO2R', -NR'r SO2N(R')2, -COCOR', -COCH2COR', -OP(O)(OR')2, -P(O)(OR')2, -OP(O)2OR', -P(O)2OR', -PO(R')2or-OPO(R')2;

each of R5ais independently optionally substituted C1-C6aliphatic group, halogen, -OR', -SR', -N(R')2, -NR'r COR', -NR'r CON(R')2, -NR'r CO2R', -COR', -CO2R', -OCOR', -CON(R')2, -OCON(R')2, -SOR', -SO2R', -SO2N(R')2, -NR'r SO2R', -NR'r SO2N(R')2, -COCOR', -COCH2COR', -OP(O)(OR')2, -P(O)(OR')2, -OP(O)2OR', -P(O)2OR', -PO(R')2or-OPO(R')2and

each R is independently hydrogen or optionally substituted C1-6aliphatic group and each R' is independently hydrogen or optionally substituted C1-6aliphatic group 3-8-membered saturated, partially unsaturated or fully replaced yennoe monocyclic ring, having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R and R', two of R, or two of R' taken together with the atom(s)to which they are attached, form a optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

In some embodiments of the compounds described directly above:

A. when R1and R2taken together with the nitrogen atom to which they are attached, form an optionally substituted 4-membered monocyclic saturated or partially unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur or oxygen, then (4S)-3-[(3R,4R)-2-oxo-1-(2-phenyl-4-hintline)-4-[2-(3-pyridinyl)ethynyl]-3-azetidinol]-4-phenyl-2-oxazolidinone is excluded;

b. when R1and R2taken together with the nitrogen atom to which they are attached, form an optionally substituted 5-membered monocyclic saturated or partially unsaturated ring having 0-3 additional heteroatoms, independently selected from the PTA, sulfur or oxygen, then:

i. the ring And is optionally substituted, hexahydro-1H-1,4-diazepin-1-yl and

ii. (R)-2-methoxy-5-[2-[[1-(2-phenyl-4-hintline)-3-pyrrolidinyl]amino]ethyl-]benzosulfimide, bis(triptorelin) and (S)-2-methoxy-5-[2-[[1-(2-phenyl-4-hintline)-3-pyrrolidinyl]amino]ethyl]benzosulfimide, bis(triptorelin) are excluded;

iii. 1-(2-phenyl-4-hintline)-3-pyrrolidinone and (S)-1-(2-phenyl-4-hintline)-, (R)-3-pyrrolidinone excluded;

iv. when R1and R2taken together, represent an unsubstituted pyrrolidin-1-yl, ring a is unsubstituted phenyl, and x is equal to 1, then R3is 6-OMe, or 6-HE;

v. when R1and R2taken together, represent an unsubstituted pyrrolidin-1-yl, ring a is unsubstituted phenyl, and x is equal to 2, then two R3the groups are 6-OMe 7-OMe;

vi. when R1and R2taken together, represent an unsubstituted pyrrolidin-1-yl, then ring a is not unsubstituted pyrrolidin-1-yl, optionally substituted piperazine-1-yl, unsubstituted morpholine-1-yl or unsubstituted piperidine-1-yl;

vii. when R1and R2taken together, represent pyrrolidin-1-yl, x is 0 and ring a is unsubstituted phenyl, then pyrrolidin-1-ilen group is not substituted in position 3 by a group HE or 2-methoxy-phenoxy;

viii. when R1and R2taken together, represent an unsubstituted pyrrolidin-1-yl, and x is equal to 0, then ring a is not 2,3-xilion, 3-were, unsubstituted phenyl, 4-Bromphenol, 4-chlorophenyl, 3-nitrophenyl, unsubstituted of pyrid-3-yl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 4-propoxyphenyl, 3-were, 3,4,5-trimethoxyphenyl, 2-chlorophenyl, unsubstituted of pyrid-4-yl, 2-hydroxyphenyl or 4-(1,1-dimethylethyl)phenyl;

C. when R1and R2taken together with the nitrogen atom to which they are attached, form an optionally substituted 6-membered monocyclic or bicyclic saturated or partially unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur or oxygen, then:

i. when R1and R2taken together, form an unsubstituted morpholino ring and ring a is unsubstituted phenyl, then x is not 0, or if x is equal to 1 or 2, then R3not is 6-fluoro, 6,7-dimethoxy, 6-nitro, 6-AcHN-, 6-methoxy, 6-NH2A 6-OCHN-, 6-OH, -6-AcMeN-, -6-TsHN-, 6-Me2N-, -7-OH, 6-aminothiazol-2-yl, 6-NHCOCOOEt or 6-(4-phenylimidazol-2-yl);

ii. when R1and R2taken together, form an unsubstituted morpholino ring and ring a is unsubstituted cyclohexyl, unsubstituted of pyrid-3-yl, unsubstituted 2-furyl, 2-forfinal, 3-thienyl, benzofuran, pyridazine, Anil, substituted in one or more of 3, 4 or 5-positions of the phenyl ring, and x is 1 or 2, then R3is not 6-NH2A 6-OHCHN-, 6-OH, 7-OH, 6-MsHN-, 6-N-, 6-fluoro or 6-OMe;

iii. when R1and R2taken together, constitute piperid-4-one, piperid-4-ol or thiomorpholine, or dimethylsilane morpholino ring, ring a is unsubstituted phenyl and x is equal to 1, then R3is not 6-HE;

iv. when x is 0 and a is unsubstituted phenyl, 3,4,5-trimethoxyphenyl or 3,4-acid, then R1and R2taken together, are optionally substituted by piperidinyl or optionally substituted piperazinil;

v. when x is 2 or 3 and R3represents 6,7-diome or 6,7,8-trione, then R1and R2taken together, are optionally substituted piperidine-1-yl, piperazine-1-yl or morpholine-1-yl;

vi. when x is 0 and ring a is unsubstituted phenyl, then R1and R2taken together, are optionally substituted or condensed with piperazinil;

vii when x is 0 and ring a is phenyl, optionally substituted in one or more of the 3-, 4 - or 5-positions of the phenyl ring, then R1and R2taken together, are optionally substituted piperazine-1-yl or morpholine-1-yl;

viii. when x is 0 and ring And represent the screens 2-F-phenyl, then R1and R2taken together, are not 4-(2-Cl-phenyl)-piperazine-1-yl, 4-(3-Cl-phenyl)piperazine-1-yl or unsubstituted morpholine-1-yl;

ix. when x is 0 and ring a is 2-Cl-phenyl, then R1and R2taken together are unsubstituted morpholine-1-yl, 4-Me-piperazine-1-yl, 4-Et-piperazine-1-yl, 4-phenylpiperazin-1-yl or 4-CH2Ph2-piperazine-1-yl;

x. when x is 0 and ring a is 2-OH-phenyl, then R1and R2taken together are unsubstituted morpholine-1-yl, 4-(2-OMe-phenyl)piperazine-1-yl, 4-CH2Ph-piperazine-1-yl, 4-Et-piperazine-1-yl or 4-Me-piperazine-1-yl;

xi. when x is 0, x is 1 and R3is 6-Br, or x is 2 and R3represents 6,7-diome and ring a is optionally substituted 2 - or 3-tanila, then R1and R2taken together, are not 4-Phenyl-piperazine-1-yl, 4-(3-CF3-phenyl)piperazine-1-yl, 4-(2-Et-phenyl)piperazine-1-yl, 4-Me-piperazinil or unsubstituted morpholine-1-yl;

xii. when x is 0 and ring a is unsubstituted of pyrid-3-yl or pyrid-4-yl, then R1and R2taken together, are optionally substituted morpholine-1-yl or optionally substituted piperazine-1-yl;

xiii. when x is 0 and ring a is optionally substituted 1H-imidazol-2-yl or 1H-imidazol-1-yl, is when R 1and R2taken together, are not, unsubstituted morpholine-1-yl, 4-Me-piperazine-1-yl or 4-CH2CH2HE-piperazine-1-yl;

xiv. when x is 0 and ring a is 5-NO2-thiazol-2-yl, then R1and R2taken together, are not 4-Me-piperazine-1-yl;

xv. when x is 0 and ring a is 5-NO2-2-furanyl, then R1and R2taken together, there are 4-CH2CH2HE-piperazine-1-yl, 4-Me-piperazine-1-yl or unsubstituted morpholine-1-yl;

xvi when x is 1, R3is 6-HE and the ring a is unsubstituted phenyl, then R1and R2taken together are unsubstituted morpholine-1-yl or 4-Me-piperazine-1-yl;

xvii. when x is 0 and R1and R2taken together, represent an unsubstituted piperidinyl, then the ring is not 2-OH-phenyl, 4-OMe-phenyl, 4-forfinal, 4-NO2-phenyl, pyrid-3-yl, pyrid-4-yl, 2-chlorophenyl, 4-OnPr-phenyl, 3,4-dichlorophenyl, 2-F-phenyl, 4-Br-phenyl, 4-Cl-phenyl, 3-NO2-phenyl or 2,4-dichlorophenyl;

xviii. when x is 0, ring a is 4-Br-phenyl, 2-F-phenyl, 2-Cl-phenyl, 4-Cl-phenyl, 4-OnPr-phenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 4-Me-phenyl, 3-Me-phenyl, pyrid-3-yl, pyrid-4-yl, 2-OH-phenyl, 4-NO2-phenyl, 4-tBu-phenyl, then R1and R2taken together, there are 2-IU-piperidine-1-yl, 4-CH2-Ph-piperidine-1-yl, 4-ethylpiperazin-1-yl, 3-COOEt-piperidine-1-yl, 4-COOEt-piperidine-1-yl, 2-Et-piperidine-1-yl, 3-Me-piperidine-1-yl, 3,5-dimethylpiperidin-1-yl, 4-N2-piperidine-1-yl, (4-piperidinyl, 4-carboxamido)piperidine-1-yl, 1,4-dioxa-8 azaspiro[4,5]decane, 3,4-dihydro-2(1H)-izokhinolinom or piperidine-4-one;

xix. when x is 1, R3is 6-Br, 6-Cl, 6-OH, 6-OMe or 6 IU and ring a represents a 4-bromophenyl, 4-CH2P(O)(OH)(t)phenyl or unsubstituted phenyl, then R1and R2taken together, are optionally substituted by piperidinyl;

xx. when x is 2, R3is 6,7-dimethoxy, and a is unsubstituted phenyl, then R1and R2taken together, are not 1,4-dioxa-8 azaspiro[4,5]decane or 3,4-dihydro-2(1H)-izokhinolinom;

xxi. when x is 3, three Deputy of R3present 5-SLA, 6-SLA and 8-piperidinyl and ring a is unsubstituted phenyl, then R1and R2taken together are unsubstituted piperidinyl ring;

xxii. when x is 3, three of R3are 6-Me, 7-t and 8-Me, ring a is 2-chlorophenyl, then R1and R2taken together, there are 4-phenylpiperidine-1-yl, 4-(4-chlorophenyl)-piperazine-1-yl, unsubstituted piperazine-1-yl, 4-CH2Ph-piperazine-1-yl, 4-(2-chlorophenyl)piperazine-1-yl or 4-t-piperazine-1-yl;

C. when R1and R2in atie together with the nitrogen atom, to which they are attached, form an optionally substituted 7-membered monocyclic or bicyclic saturated or partially unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur or oxygen, then:

i. benzosulfimide, 2-methoxy-5-[2-[5-(2-phenyl-4-hintline)-2,5-diazabicyclo[2,2,1]hept-2-yl]ethyl] -, and bis(triptorelin) 2,5 - diazabicyclo[2,2,1]heptane, 2-(2-phenyl-4-hintline)- are excluded;

ii. when x is equal to 2, both Deputy of R3are the OMe and the ring a is 4-chlorophenyl, then R1and R2taken together are unsubstituted, hexahydro-1H-azepin-1-yl;

iii. when x is 0 and R1and R2taken together, represent unsubstituted, hexahydro-1H-azepin-1-yl, then ring a is not unsubstituted phenyl, 4-florfenicol, 4-nitrophenyl, pyrid-4-yl, 3,4-dichlorophenyl, 2-chlorophenyl, 2,4-dichlorophenyl, 2,4-dichlorophenyl, 3-nitrophenyl, 4-chlorophenyl, 4-OnPr-phenyl, 3-Me-phenyl, 3,4-ome-phenyl, 3,4,5-ome-phenyl, pyrid-3-yl or 2-HE-phenyl;

d. when R1and R2taken together with the nitrogen atom to which they are attached, form an optionally substituted 8-membered monocyclic or bicyclic saturated or partially unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur sludge is oxygen, then

i. 2-methoxy-5-[2-[8-(2-phenyl-4-hintline)-3,8-diazabicyclo[3.2.1]Oct-3-yl]ethyl]benzosulfimide, bis(triptorelin), 3-(phenylmethyl)-8-(2-phenyl-4-hintline)- 3,8-diazabicyclo[3.2.1]octane, 8-(2-phenyl-4-hintline)-3,8-diazabicyclo[3.2.1]octane; monohydrochloride 2-(3-were)-4-(1,3 .3m-trimethyl-6-azabicyclo[3.2.1]Oct-6-yl)hintline; monohydrochloride 2-(4-nitrophenyl)-4-(1,3 .3m-trimethyl-6-azabicyclo[3.2.1]Oct-6-yl)hintline; 2-(3-were)-4-(1,3 .3m-trimethyl-6-azabicyclo[3.2.1]Oct-6-yl)hinzelin; 2-(4-were)-4-(1,3 .3m-trimethyl-6-azabicyclo[3.2.1]Oct-6-Il)hinzelin and 2-(4-nitrophenyl)-4-(1,3 .3m-trimethyl-6-azabicyclo[3.2.1]Oct-6-yl)-hinzelin excluded, and

that is, when R1and R2taken together with the nitrogen atom to which they are attached, form an optionally substituted 9-membered monocyclic or bicyclic saturated or partially unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur or oxygen, then

1-[4-(1,3-dihydro-1,3-dioxo-2H-isoindole-2-yl)-6,7-dimethoxy-2-hintline]-4-(2-fornicator)piperazine are excluded.

According to other embodiments for compounds described directly above, the ring formed by R1and R2taken together, is selected from:

where the ring formed by R1and R2taken together, I which is optionally substituted at one or more substitutable carbon atoms, nitrogen or sulfur number z are independent substituents R4and z is equal to 0-5.

According to other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted, azetidin-1-yl (jj), pyrrolidin-1-yl (ff)piperidine-1-yl (dd), piperazine-1-yl (ccor morpholine-4-yl (ee). According to other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted, azetidin-1-yl (jj), pyrrolidin-1-yl (ff)piperidine-1-yl (dd) or piperazine-1-yl (SS). According to still other embodiments for compounds of the formulaI-AR1and R2taken together, represent an optionally substituted, azetidin-1-yl (jj). According to still other embodiments for compounds of the formulaI-AR1and R2taken together, represent optionally substituted pyrrolidin-1-yl (ff). According to still other embodiments for compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperidine-1-yl (dd). According to still other embodiments for compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperazine-1-yl (cc).

For compounds described directly above, z is 0-5 and R4groups, when they are present, each before the hat is independently halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -COOR', -NRCOR', -CON(R')2, -OCON(R')2, COR', -NHCOOR', -SO2R', -SO2N(R')2or an optionally substituted group selected from C1-C6aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocyclizations group, arils1-C6of alkyl, heteroaryl1-C6of alkyl, cycloaliphatic1-C6the alkyl or geterotsiklicheskikh1-C6the alkyl.

According to other embodiments z is 0-5 and R4groups are each independently Cl, Br, F, CF3CH3, -CH2CH3CN, -COOH, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -CH2OH, -NHCOCH3, -SO2NH2, -SO2(CH2)3CH3, -SO2CH(CH3)2, -SO2N(CH3)2, -SO2CH2CH3, -C(O)och2CH(CH3)2, -C(O)NHCH2CH(CH3)2, -NHCOOCH3, -C(O)C(CH3)3,

-COO(CH2)2CH3-C(O)NHCH(CH3)2, -C(O)CH2CH3or an optionally substituted group selected from piperidinyl, piperazinil, morpholino,1-4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CH2of cyclohexyl, pyridyl, -CH2pyridyl or-H 2thiazolyl.

According to some embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted, azetidin-1-yl (jj), where z is 1 or 2 and at least one Deputy from R4is-NRSO2R', -NRCOOR', or-NRCOR'. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted, azetidin-1-yl (jj), where z is 1 and R4is-NRSO2R'. According to other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted, azetidin-1-yl (jj), where z is 1 and R4is - NRCOOR'. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted, azetidin-1-yl (jj), where z is 1 and R4is-NRCOR'. According to still other embodiments for compounds of the formulaI-AR1and R2taken together, represent optionally substituted pyrrolidin-1-yl (ff), where z is 1 or 2 and R4represents Cl, Br, F, CF3CH3, -CH2CH3, -OR' or-CH2'OR'. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, depict ablaut optionally substituted piperidine-1-yl ( dd), where z is 1 or 2, and at least one Deputy from R4represents Cl, Br, F, CF3CH3, -CH2CH3, -OR', -CH2OR', -NRSO2R', -NRCOOR', or -- OCON(R')2. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperidine-1-yl (dd), where z is 1, and R4is F, CF3CH3, -CH2CH3, -OR', or CH2'OR'. According to other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperidine-1-yl (dd), where z is 1, and R4is-NRSO2R'. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperidine-1-yl (dd), where z is 1, and R4is-NRCOOR'. According to still other embodiments for compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperazine-1-yl (SS), where z is 1 or 2 and at least one Deputy from R4is-SOR', -CON(R')2, -SO2N(R')2, -COR' or-COOR'. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent neobyazatelnostyu piperazine-1-yl ( SS), where z is 1, and R4is-SOR'. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperazine-1-yl (SS), where z is 1 and R4is-OR'. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperazine-1-yl (SS), where z is 1 and R4is-SOP(R')2. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperazine-1-yl (SS), where z is 1 and R4is-SO2N(R')2. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperazine-1-yl (SS), where z is 1 and R4is-COR'.

For compounds described directly above, according to some embodiments x is 0-4, and R3groups, when they are present, each independently represents halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -COOR', -NRCOR', -CON(R')2, -OCON(R')2, -COR', -NHCOOR', -SO2R', -SO2N(R')2or optionally substituted g is the SCP, selected from C1-C6aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocyclizations group, aryl With1-C6of alkyl, heteroaryl1-C6of alkyl, cycloaliphatic1-C6the alkyl or geterotsiklicheskikh1-C6the alkyl.

According to other embodiments x is 1 or 2 and each R3is independently Cl, Br, F, CF3, -OCF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -NHCOCH(CH3)2, -SO2NH2, -CONH(cyclopropyl), -CONHCH3, -CNHCH2CH3or an optionally substituted group selected from piperidinyl, piperazinil, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.

According to the following embodiments x is 1 or 2 and each R3the group is independently halogen, CN, optionally substituted C1-C6alkyl, OR', N(R')2, CON(R')2or NRCOR'.

According to the following embodiments x is 1 or 2 and each R3the group represents-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3or-CN.

The following is opladener x is 1 and R 3is in position 6 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3or-CN.

In accordance with the following further embodiments x is 1 and R3is in position 7 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3or-CN.

According to further embodiments x is 1 and R3is in position 6 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3or-OCH2CH3.

According to further embodiments x is 1 and R3is in position 7 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3or-OCH2CH3.

According to another embodiments x is 1 and R3is in position 6 chineselanguage ring and is-CON(R')2or NRCOR'.

According to another embodiments x is 1 and R3is in position 7 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3or-OCH2CH3.

To connect the s, described directly above, according to some embodiments of the ring And represents a group chosen from:

According to other embodiments of the ring And is optionally substituted phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, or pyrrol-1-yl.

For compounds described directly above, according to some embodiments y is 0-5, q is 0-2, R5and R5Agroups, when they are present, are each independently halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -NRCOR', -CON(R')2, -S(O)2N(R')2, -OCOR', -COR', -CO2R', -OCON(R')2, -NR'r SO2R', -OP(O)(OR')2, -P(O)(OR')2, -OP(O)2OR', -P(O)2OR', -PO(R')2, -OPO(R')2or an optionally substituted group selected from C1-C6aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocyclizations group, arils1-C6of alkyl, heteroaryl1-C6of alkyl, cycloaliphatic1-C6the alkyl or geterotsiklicheskikh1-C6the alkyl.

According to other embodiments y is 0-5, q is 1 or 2 and each R5Ais independently Cl, Br, F, CF3, Me, t, CN, -COOH, -NH2, -N(CH3)2,

-N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -SO2NH2, -SO2NHC(CH3)2, -OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-piperazine-1-yl, OCOCH(CH3)2, OCO(cyclopentyl), -COCH3not necessarily replaced phenoxy or optionally substituted benzyloxy.

According to the following embodiments is 0, q is 1 and R5ais F. According to another embodiments is 0, q is 1 and R5ais OR'. According to another embodiments is 0, q is 1 and R5ais HE. According to another embodiments is 0, q is 2 and one R5arepresents OR', and the other of R5ais F. According to another embodiments is 0, q is 2 and one R5ais HE, and the other of R5ais F.

According to other embodiments of the ring And is optionally substituted phenyl, and compounds have the structureIA-i:

where y is 0-5;

q is 0-2, and

each Deputy of R5ais independently optionally substituted C1/sub> -C6aliphatic group, halogen, -OR', -SR', -N(R')2, -NR'r COR', -NR'r CON(R')2, -NR'r CO2R', -COR', -CO2R', -OCOR', -CON(R')2, -OCON(R')2, -SOR', -SO2R', -SO2N(R')2, -NR'r SO2R', -NR'r SO2N(R')2, -COCOR', -COCH2COR', -OP(O)(OR')2, -P(O)(OR')2, -OP(O)2OR', -P(O)2OR', -PO(R')2or-OPO(R')2.

According to some example embodiments, the ring formed by R1and R2taken together, is selected from:

where the ring formed by R1and R2taken together, is optionally substituted at one or more substitutable carbon atoms, nitrogen or sulfur number z are independent substituents R4and z is equal to 0-5.

According to other embodiments of the compounds of the formulaIA-iR1and R2taken together, represent an optionally substituted, azetidin-1-yl (jj), pyrrolidin-1-yl (ff)piperidine-1-yl (dd), piperazine-1-yl (ccor morpholine-4-yl (ee). According to other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted, azetidin-1-yl (jj), pyrrolidin-1-yl (ff)piperidine-1-yl (dd) or piperazine-1-yl (SS). According to still other embodiments for compounds of formula

IA-iR1and R2taken together, represent optionally substituted assetid the n-1-yl ( jj). According to still other embodiments for compounds of the formulaIA-iR1and R2taken together, represent optionally substituted pyrrolidin-1-yl (ff). According to still other embodiments for compounds of the formulaIA-iR1and R2taken together, represent an optionally substituted piperidine-1-yl (dd). According to further embodiments of the compounds of the formulaIA-iR1and R2taken together, represent an optionally substituted piperazine-1-yl (cc).

For compounds of the formulaIA-iz is 0-5 and R4groups, when they are present, each independently represents halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -COOR', -NRCOR', -CON(R')2, -OCON(R')2, COR', -NHCOOR', -SO2R', -SO2N(R')2or an optionally substituted group selected from C1-C6aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocyclizations group, arils1-C6of alkyl, heteroaryl1-C6of alkyl, cycloaliphatic1-C6the alkyl or geterotsiklicheskikh1-C6the alkyl. According to other embodiments z is 0-5 and R4groups are each independently Cl, Br, F, CF3CH3,

-CH2CH3CN, -COOH, -N(CH3)2, -N(Et)2, -N(iPr)2-O(CH 2)2OCH3, -CONH2, -COOCH3, -OH, -CH2OH, -NHCOCH3, -SO2NH2, -SO2(CH2)3CH3, -SO2CH(CH3)2, -SO2N(CH3)2, -SO2CH2CH3, -C(O)och2CH(CH3)2, -C(O)NHCH2CH(CH3)2, -NHCOOCH3, -C(O)C(CH3)3, -COO - (CH2)2CH3-C(O)NHCH(CH3)2, -C(O)CH2CH3or an optionally substituted group selected from piperidinyl, piperazinil, morpholino,1-4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CH2of cyclohexyl, pyridyl, -CH2pyridyl, or-CH2thiazolyl.

According to some embodiments of the compounds of the formulaIA-iR1and R2taken together, represent an optionally substituted, azetidin-1-yl (jj), where z is 1 or 2 and at least one of R4is-NRSO2R', -NRCOOR', or-NRCOR'. According to some other embodiments of the compounds of the formulaIA-iR1and R2taken together, represent an optionally substituted, azetidin-1-yl (jj), where z is 1 and R4is-NRSO2R'. According to other embodiments of the compounds of the formulaIA-iR1and R2taken together, represent an optionally substituted, azetidin-1-yl (jj), where z is 1 and R4is-NRCOOR'. Solasmonocolores other embodiments for compounds of the formula IA-iR1and R2taken together, represent an optionally substituted, azetidin-1-yl (jj), where z is 1 and R4is-NRCOR'. According to still other embodiments for compounds of the formulaIA-iR1and R2taken together, represent optionally substituted pyrrolidin-1-yl (ff), where z is 1 or 2 and R4represents Cl, Br, F, CF3CH3, -CH2CH3, -OR', or-CH2'OR'. According to another embodiments of the compounds of the formulaIA-iR1and R2taken together, represent an optionally substituted piperidine-1-yl (dd), where z is 1 or 2 and at least one of R4represents Cl, Br, F, CF3CH3, -CH2CH3, -OR' or-CH2OR', -NRSO2R', -NRCOOR', or -- OCON(R')2. According to some other embodiments of the compounds of the formulaIA-iR1and R2taken together, represent an optionally substituted piperidine-1-yl (dd), where z is 1 and R4is F, CF3CH3, -CH2CH3, -OR' or-CH2'OR'. According to other embodiments of the compounds of the formulaIA-iR1and R2taken together, represent an optionally substituted piperidine-1-yl (dd), where z is 1 and R4is-NRSO2R'. According to some other embodiments of the compounds of the formulaIA-iR1 and R2taken together, represent an optionally substituted piperidine-1-yl (dd), where z is 1 and R4is-NRCOOR'. According to still other embodiments for compounds of the formulaIA-iR1and R2taken together, represent an optionally substituted piperazine-1-yl (SS), where z is 1 or 2 and at least one of R4is-SOR', -CON(R')2, -SO2N(R')2, -COR' or-COR'. According to some other embodiments of the compounds of the formulaIA-iR1and R2taken together, represent an optionally substituted piperazine-1-yl (SS), where z is 1 and R4is-SOR'. According to some other embodiments of the compounds of the formulaIA-iR1and R2taken together, represent an optionally substituted piperazine-1-yl (SS), where z is 1 and R4is-OR'. According to some other embodiments of the compounds of the formulaIA-iR1and R2taken together, represent an optionally substituted piperazine-1-yl (SS), where z is 1 and R4is-SOP(R')2. According to some other embodiments of the compounds of the formulaIA-iR1and R2taken together, represent an optionally substituted piperazine-1-yl (SS), where z is 1 and R4is-SO2N(R')2. who according to some other embodiments of the compounds of the formula IA-iR1and R2taken together, represent an optionally substituted piperazine-1-yl (SS), where z is 1 and R4is-COR'.

According to some embodiments of the compounds of the formulaIA-ix is 0-4, and R3groups, when they are present, each independently represents halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -COOR', -NRCOR', -CON(R')2, OCON(R')2, COR', -NHCOOR', -SO2R', -SO2N(R')2or an optionally substituted group selected from C1-C6aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocyclizations group, arils1-C6of alkyl, heteroaryl1-C6of alkyl, cycloaliphatic1-C6the alkyl or geterotsiklicheskikh1-C6the alkyl.

According to some other embodiments x is 1 or 2 and each R3is independently Cl, Br, F, CF3, -OCF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -NHCOCH(CH3)2, -SO2NH2, -CONH(cyclopropyl), -CONHCH3, -CNHCH2CH3or an optionally substituted group selected from piperidinyl, piperazinil, morpholino, Fe the sludge, phenyloxy, benzyl, or benzyloxy.

According to the following embodiments x is 1 or 2 and each R3the group is independently halogen, CN, optionally substituted C1-C6alkyl, OR', N(R')2, CON(R')2or NRCOR'.

According to the following embodiments x is 1 or 2 and each R3the group represents-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3or-CN.

In accordance with the following further embodiments x is 1 and R3is in position 6 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3or-CN.

In accordance with the following further embodiments x is 1 and R3is in position 7 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3or-CN.

According to another embodiments x is 1 and R3is in position 6 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3or-OCH2CH3.

According to another embodiments of the x pre is is 1 and R 3is in position 7 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3or-OCH2CH3.

According to other embodiments x is 1 and R3is in position 6 chineselanguage ring and is-CON(R')2or NRCOR'.

According to another embodiments x is 1 and R3is in position 7 chineselanguage ring and is-CON(R')2or NRCOR'.

According to some embodiments of the compounds of the formulaIA-iy is 0-5, q is 0-2, and R5and R5Agroups, when they are present, are each independently halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -NRCOR', -CON(R')2, -S(O)2N(R')2, -OCOR', -COR', -CO2R', -OCON(R')2, -NR'r SO2R', -OP(O)(OR')2, -P(O)(OR')2, -OP(O)2OR', -P(O)2OR', -PO(R')2, -OPO(R')2or an optionally substituted group selected from C1-C6aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocyclizations group, arils1-C6of alkyl, heteroaryl1-C6of alkyl, cycloaliphatic1-C6the alkyl or geterotsiklicheskikh1-C6the alkyl.

According to other embodiments y is 0-5, q is 1 or 2 and each of Rsup> 5Ais independently Cl, Br, F, CF3, Me, Et, CN, -COOH, -NH2,

-N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -SO2NH2, -SO2NHC(CH3)2, -OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-piperazine-1-yl, OCOCH(CH3)2, OCO(cyclopentyl), -COCH3not necessarily replaced phenoxy or optionally substituted benzyloxy.

According to the following embodiments, when ring a is phenyl, y is 0, q is 1 and R5ais fluorine substituted in position 2 of the phenyl ring. According to another embodiments, when ring a is phenyl, y is 0, q is 1 and R5ais OR', substituted in position 2 of the phenyl ring. According to another embodiments, when ring a is phenyl, y is 0, q is 1 and R5aHE is substituted in position 2 of the phenyl ring. According to another embodiments, when ring a is phenyl, y is 0, q is 2 and one R5arepresents OR', and the other of R5ais F, where'OR' is substituted in position 2 of the phenyl ring and F is substituted in the 6 position of the phenyl ring. According to the SNO another embodiments, when ring a is phenyl, y is 0, q is 2 and one R5ais HE, and the other of R5ais F, where IT is substituted in position 2 of the phenyl ring and F is substituted in the 6 position of the phenyl ring.

According to other embodiments of the compounds of the formulaIA-iq is 1 and R5ais in position 2 of the phenyl ring, and compounds have the structureIA-ii:

where

a) the ring formed by R1and R2taken together, is selected from:

where the ring formed by R1and R2taken together, is optionally substituted at one or more substitutable carbon atoms, nitrogen or sulfur number z are independent substituents R4and z is equal to 0-5;

b) where z is 0-5 and R4groups, when they are present, each independently represents halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -COOR', -NRCOR', -CON(R')2, -OCON(R')2, COR', -NHCOOR', -SO2R', -SO2N(R')2or an optionally substituted group selected from C1-C6aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocyclizations group, arils1-C6of alkyl, heteroaryl1-C6 of alkyl, cycloaliphatic1-C6the alkyl or geterotsiklicheskikh1-C6the alkyl.

(C) where x is 0-4, and R3groups, when they are present, each independently represents halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -COOR', -NRCOR', -CON(R')2, -OCON(R')2, COR', -NHCOOR', -SO2R', -SO2N(R')2or optionally substituted group selected from C1-C6aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocyclizations group, arils1-C6of alkyl, heteroaryl1-C6of alkyl, cycloaliphatic1-C6the alkyl or geterotsiklicheskikh1-C6the alkyl.

d) where y is 0-5 and R5groups, when they are present, are each independently halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -NRCOR', -CON(R')2, -S(O)2N(R')2, -OCOR', -COR', -CO2R', -OCON(R')2, -NR'r SO2R', -OP(O)(OR')2, -P(O)(OR')2, -OP(O)2OR', -P(O)2OR', -PO(R')2, -OPO(R')2or an optionally substituted group selected from C1-C6aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocyclizations group, arils1-C6of alkyl, heteroaryl1-C6alkyl is, cycloaliphatic1-C6the alkyl, or geterotsiklicheskikh1-C6of alkyl, and

e) R5Arepresents Cl, Br, F, CF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -SO2NH2, -SO2NHC(CH3)2, -OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-piperazine-1-yl, OCOCH(CH3)2, OCO(cyclopentyl), -COCH3not necessarily replaced phenoxy or optionally substituted benzyloxy.

According to other embodiments of the compounds of the formulaIA-iiq is 1 and R5ais in position 2 of the phenyl ring, and compounds have the structureIA-ii:

where

a) R1and R2taken together, represent an optionally substituted ring selected from azetidin-1-yl (jj), pyrrolidin-1-yl (ff)piperidine-1-yl (dd) or piperazine-1-Il (cc);

b) z is 0-5 and R4groups are each independently Cl, Br, F, CF3CH3, -CH2CH3CN, -COOH, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -CH2OH, -NHCOCH3, -SO2NH2, -SO2(CH2)3The h 3, -SO2CH(CH3)2,

-SO2N(CH3)2, -SO2CH2CH3, -C(O)och2CH(CH3)2, -C(O)NHCH2CH(CH3)2, -NHCOOCH3, -C(O)C(CH3)3, -COO - (CH2)2CH3-C(O)NHCH(CH3)2, -C(O)CH2CH3or an optionally substituted group selected from piperidinyl, piperazinil, morpholino,1-4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CH2of cyclohexyl, pyridyl, -CH2pyridyl, or-CH2thiazolyl;

C) x is 1 or 2 and each R3is independently Cl, Br, F, CF3, -OCF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -NHCOCH(CH3)2, -SO2NH2, CONH(cyclopropyl), -CONHCH3, -CNHCH2CH3or an optionally substituted group selected from piperidinyl, piperazinil, morpholino, phenyl, phenyloxy, benzyl or benzyloxy;

d) where y is 0-4, and R5groups, when they are present, are each independently Cl, Br, F, CF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -SO2NH2, -SO2 NHC(CH3)2, -OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-piperazine-1-yl, -OCOCH(CH3)2, OCO(cyclopentyl), -COCH3not necessarily replaced phenoxy or optionally substituted benzyloxy and

e) R5Arepresents Cl, F, CF3, Me, Et, -OH, -OCH3, -OCH2CH3, -CH2OH, -SO2NH2, -SO2NHC(CH3)2, -OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-piperazine-1-yl, OCOCH(CH3)2, OCO(cyclopentyl) or-COCH3.

According to other embodiments of the compounds of the formulaIA-iix is 1 and R3is in position 6 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3or-CN. According to the following embodiments x is 1 and R3is in position 7 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl),

-OCH3, -NH2, -OCH2CH3or-CN. According to another embodiments x is 1 and R3is in position 6 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF , -OCF3, -OCH3or-OCH2CH3. According to another embodiments x is 1 and R3is in position 7 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3or-OCH2CH3. According to other embodiments x is 1 and R3is in position 6 chineselanguage ring and is-CON(R')2or NRCOR'.

According to other embodiments x is 1 and R3is in position 7 chineselanguage ring and is-CON(R')2or NRCOR'.

According to further embodiments, R5Arepresents Cl, F, CF3, Me, Et, OR', -OH, -OCH3, -OCH2CH3.

In accordance with the following further embodiments, R5Ais OR'. According to another embodiments, R5Ais F.

According to other example embodiments compounds have the formulaIA-ii:

where

a) R1and R2taken together, represent an optionally substituted ring selected from azetidin-1-yl (jj), pyrrolidin-1-yl (ff)piperidine-1-yl (dd) or piperazine-1-Il (cc);

b) z is 0-5 and R4groups are each independently Cl, Br, F, CF3CH3, -CH2CH3CN, -COOH, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, OH, -CH2OH, -NHCOCH3,

-SO2NH2, -SO2(CH2)3CH3, -SO2CH(CH3)2, -SO2N(CH3)2, -SO2CH2CH3, -C(O)och2CH(CH3)2, -C(O)NHCH2CH(CH3)2, -NHCOOCH3, -C(O)C(CH3)3, -COO - (CH2)2CH3-C(O)NHCH(CH3)2, -C(O)CH2CH3or an optionally substituted group selected from piperidinyl, piperazinil, morpholino,1-4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CH2of cyclohexyl, pyridyl, -CH2pyridyl or-CH2thiazolyl;

C) x is 1 and each of R3is independently Cl, Br, F, CF3, -OCF3, Me, Et, CN, -COOH, -OH or-OCH3;

d) y is 0 or 1 and R5groups, when they are present, are each independently Cl, Br, F, CF3Me, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -SO2NH2, -SO2NHC(CH3)2and

e) R5Ais F, -OR', or NHSO2R'.

According to other embodiments for compounds described directly above, x is 1 and R3is in position 6 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3or-CN. According to another GP is oseney x is 1, and R3is in position 7 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3or-CN. According to the following embodiments x is 1 and R3is in position 6 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3or-OCH2CH3. According to the following embodiments x is 1 and R3is in position 7 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3or-OCH2CH3. In accordance with the following further embodiments x is 1 and R3is in position 6 chineselanguage ring and is-CON(R')2or NRCOR'. In accordance with the following further embodiments x is 1 and R3is in position 7 chineselanguage ring and is-CON(R')2or NRCOR'.

According to another embodiments, R5Arepresents OR', x is 1 and R3is in position 6 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3or-OCH2CH3. According to another embodiments, R5Arepresents OR', x is 1 and R3is in position 7 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3or-OCH2CH3.

According to other embodiments, R5Ais HE, x is 1 and R3is in position 6 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3or-OCH2CH3. According to other embodiments, R5Ais HE, x is 1, and R3is in position 7 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3or-OCH2CH3.

According to another embodiments, R5Ais F, x is 1 and R3is in position 6 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3or-OCH2CH3. According to another embodiments, R5Ais F, x is 1 and R3is in position 7 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3or-OCH2CH3.

According to further embodiments of the compounds of the formulaIA-iiR1and R2taken together, represent an optionally substituted, azetidin-1-yl (jj). According to other embodiments of the compounds of the formulaIA-iiR1and R2taken together, represents the t optionally substituted pyrrolidin-1-yl ( ff). According to other embodiments of the compounds of the formulaIA-iiR1and R2taken together, represent an optionally substituted piperidine-1-yl (dd). According to other embodiments of the compounds of the formulaIA-iiR1and R2taken together, represent an optionally substituted piperazine-1-yl (cc).

According to other embodiments of the compounds of the formulaIA-iiR1and R2taken together, represent an optionally substituted, azetidin-1-yl (jj), where z is 1 or 2 and at least one R4is-NRSO2R', -NRCOOR', or-NRCOR'. According to other embodiments of the compounds of the formulaIA-iiR1and R2taken together, represent an optionally substituted, azetidin-1-yl (jj), where z is 1 and R4is-NRSO2R'. According to further embodiments of the compounds of the formulaIA-iiR1and R2taken together, represent an optionally substituted, azetidin-1-yl (jj), where z is 1 and R4is-NRCOOR'. According to further embodiments of the compounds of the formulaIA-iiR1and R2taken together, represent an optionally substituted, azetidin-1-yl (jj), where z is 1 and R4is-NRCOR'. In accordance with the following further embodiments of the compounds of the formulaIA-iiR1and R2taken together, before the order is optional substituted pyrrolidin-1-yl ( ff), where z is 1 or 2 and R4represents Cl, Br, F, CF3CH3, -CH2CH3, -OR', or CH2'OR'. In accordance with the following further embodiments of the compounds of the formulaIA-iiR1and R2taken together, represent an optionally substituted piperidine-1-yl (dd), where z is 1 or 2 and at least one R4represents Cl, Br, F, CF3CH3, -CH2CH3, -OR', or CH2OR', -NRSO2R', -NRCOOR', or -- OCON(R')2. According to another embodiments of the compounds of the formulaIA-iiR1and R2taken together, represent an optionally substituted piperidine-1-yl (dd), where z is 1 and R4is F, CF3CH3, -CH2CH3, -OR', or CH2'OR'. According to another embodiments of the compounds of the formulaIA-iiR1and R2taken together, represent an optionally substituted piperidine-1-yl (dd), where z is 1 and R4is-NRSO2R'. According to other embodiments of the compounds of the formulaIA-iiR1and R2taken together, represent an optionally substituted piperidine-1-yl (dd), where z is 1 and R4is-NRCOOR'. According to other embodiments of the compounds of the formulaIA-iiR1and R2taken together, represent an optionally substituted piperazine-1-yl (cc), where z is 1 is 2, and at least one of R4is-SOR', -CON(R')2, -SO2N(R')2, -CR' or COOR'. According to other embodiments of the compounds of the formulaIA-iiR1and R2taken together, represent an optionally substituted piperazine-1-yl (SS), where z is 1 and R4is-SOR'. According to further embodiments of the compounds of the formulaIA-iiR1and R2taken together, represent an optionally substituted piperazine-1-yl (SS), where z is 1 and R4is-COR'. According to further embodiments of the compounds of the formulaIA-iiR1and R2taken together, represent an optionally substituted piperazine-1-yl (SS), where z is 1 and R4is-SOP(R')2. In accordance with the following further embodiments of the compounds of the formulaIA-iiR1and R2taken together, represent an optionally substituted piperazine-1-yl (SS), where z is 1 and R4is - SO2N(R')2. According to some other embodiments of the compounds of the formulaIA-iiR1and R2taken together, represent an optionally substituted piperazine-1-yl (SS), where z is 1 and R4is-CR'.

In relation to the connections described in this section in General above, it is noted that the compounds are useful as inhibitor is s ion channels, preferably potentialization sodium channel and calcium channel N-type. In some examples of embodiments of the compounds of the invention are useful as inhibitors of NaV1.8. In other embodiments of the compounds of the invention are useful as inhibitors of NaV1.8 and CaV2.2. In still other embodiments of the compounds of the invention are useful as inhibitors of CaV2.2. In still other embodiments of the compounds of the invention are useful as dual inhibitors of NaV1.8 and TTX-sensitive ion channels, such as NaV1.3 or NaV1.7.

II. The compounds of formula IA-ii:

where R1and R2are each independently optionally substituted group selected from C1-6aliphatic group, Cy1where Cy1represents a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms selected independently from nitrogen, oxygen, or sulfur, or represents a 3-12-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, where Cy1linked directly to the nitrogen atom, or linked via optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by a group-NR-, -O-COO -, -OCO-,

-NRCO-, -CONR-, SO2NR - or-NRSO2-where R1and R2are each optionally and independently substituted at one or more substitutable carbon atoms, nitrogen or sulfur number z are independent substituents R4where z is 0-5;

x is 0-4;

is 0-4;

each of R3, R4and R5is independently Q-RXwhere Q represents a bond or represents C1-C6alkylidene chain, where up to two non-adjacent methylene units of the group Q are optionally and independently replaced by a group-NR-, -S-, -O-, -CS-CO2-, -OCO-, -CO-, -COCO-, -CONR-, -NRCO-, -NRCO2, -SO2NR-, -NRSO2-, -CONRNR-, -NRCONR-, -OCONR-, -NRNR-, -NRSO2NR-, -SO-, -SO2-, -PO-, -PO2-, -OP(O)(OR) -, or-POR-; and each of RXindependently selected from-R', =O, =NR', - halogen, -NO2, -CN, -OR', -SR', -N(R')2, -NR'r COR', -NR'r CON(R')2, -NR'r CO2R', -COR', -CO2R', -OCOR', -CON(R')2, -OCON(R')2, -SOR', -SO2R', -SO2N(R')2, -NR'r SO2R', -NR'r SO2N(R')2, -COCOR', -COCH2COR', -OP(O)(OR')2, -P(O)(OR')2, -OP(O)2OR', -P(O)2OR', -PO(R')2or-OPO(R')2;

R5arepresents optionally substituted C1-C6aliphatic group, halogen, -OR', -SR', -N(R')2, -NR'r COR', -NR'r CON(R')2, -NR'r CO2R', -COR', -CO2R', -OCOR', -CON(R')2, -OCON(R')2, -SOR', -SO2R', -SO2N(R')2, -NR'r SO2R', -NR'r SO 2N(R')2, -COCOR', -COCH2COR', -OP(O)(OR')2, -P(O)(OR')2, -OP(O)2OR', -P(O)2OR', -PO(R')2or-OPO(R')2and

each R is independently hydrogen or optionally substituted C1-6aliphatic group and each R' is independently hydrogen or optionally substituted C1-6aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or R and R', two of R, or two of R', taken together with the atom(s)to which they are attached, form a optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

In some embodiments for compounds directly above,

A. when x is 0, R1is hydrogen and R5ais Cl, Me, CF3, Br or F, then R2is not a group -(CH2)2-4-Cy1, -SO2CH2Cy1or-CH2SO2Cy1, where is Cy 1represents a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms selected independently from nitrogen, oxygen, or sulfur, or represents a 3-8-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

b. when x is 0 and R5ais Cl, Me, NO2or OH, then:

i. when R1is hydrogen, R2is not group Me iBu, nBu, -COCH3, -CH2COOEt, -CH2COOMe, -CH2CH2OH, iPr, -CH2-pyridyl, -CH2Ph -(CH2)3NH2, -(CH2)2-morpholinyl or-CH2CH2Ph;

ii. R1and R2are not both Et, or Me and

iii. when R1is Et, then R2is not group 4-Me-phenyl, 4-OMe-phenyl or 2-Me-phenyl;

c. when x is 1 and R3is 6-Cl, 7-F, or x is 0 and R5ais-Orgenor Cl, when R1is hydrogen, R2is not a group -(CH2)2-morpholino, -CH2(benzofuran) and

d. when x is 2 and one R3is 6-OMe, and the other R3is 7-OMe and R5ais F, when R1is hydrogen, R2is not a group -(CH2)3N(CH3)2.

In some the ryh other embodiments for compounds directly above,

a) one of R1or R2represents hydrogen and the other of R1and R2chosen from:

i. Cy1where Cy1linked directly to the nitrogen atom, or linked via optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by groups-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, -SO2NR - or-NRSO2-or

ii. optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by groups-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, -SO2NR - or-NRSO2-or

b) R1and R2each independently selected from Cy1where Cy1linked directly to the nitrogen atom, or linked via optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by groups-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, -SO2NR - or-NRSO2-, or optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by groups-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, -SO2NR - or-NRSO2-.

In other embodiments Cy1is:

In some embodiments for compounds directly above, R1represents hydrogen or optionally substituted C1-4aliphatic group, and R2is-CHR-Cy1where R is hydrogen or C1-4alkyl, and Cy1is:

In other embodiments, R1and R2are each independently optionally substituted C1-4aliphatic group and each is independently selected from optionally substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)co2CH3, (CH2)2Och3CH2(CO)co2CH3CH2(CO)co3,

CH(CH3)CH2CH3or n-butyl.

For compounds described directly above, z is 0-5 and R4groups, when they are present, each independently represents halogen, CN, NO2, -N(R')2CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -COOR', -NRCOR', -CON(R')2, -OCON(R')2, COR', -NHCOOR', -SO2R', -SO2N(R')2or an optionally substituted group selected from C1-C6aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocyclizations group, arils1-C6of alkyl, heteroaryl1-C6the alkyl cycloaliphatic 1-C6the alkyl or geterotsiklicheskikh1-C6the alkyl.

According to other embodiments z is 0-5 and R4groups are each independently Cl, Br, F, CF3CH3, -CH2CH3CN, -COOH, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -CH2OH, -NHCOCH3, -SO2NH2, -SO2(CH2)3CH3, -SO2CH(CH3)2, -SO2N(CH3)2, -SO2CH2CH3, -C(O)och2CH(CH3)2, -C(O)NHCH2CH(CH3)2, -NHCOOCH3, -C(O)C(CH3)3, -COO - (CH2)2CH3-C(O)NHCH(CH3)2, -C(O)CH2CH3or an optionally substituted group selected from piperidinyl, piperazinil, morpholino,1-4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CH2of cyclohexyl, pyridyl, -CH2pyridyl or-CH2thiazolyl.

According to another embodiments for compounds directly above, x is 0-4, and R3groups, when they are present, are each independently halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -COOR', -NRCOR', -CON(R')2, -OCON(R')2, COR', -NHCOOR', -SO2R', -SO2N(R')2or an optionally substituted group selected from C1-C6aligations the th group, aryl, heteroaryl, cycloaliphatic groups, heterocyclizations group, arils1-C6of alkyl, heteroaryl1-C6of alkyl, cycloaliphatic1-C6the alkyl or geterotsiklicheskikh1-C6the alkyl.

According to the following embodiments for compounds directly above, x is 1 or 2 and each R3is independently Cl, Br, F, CF3, -OCF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -NHCOCH(CH3)2, -SO2NH2, -CONH(cyclopropyl), -CONHCH3, -CNHCH2CH3or an optionally substituted group selected from piperidinyl, piperazinil, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.

According to the following embodiments x is 1 or 2 and each R3the group is independently halogen, CN, optionally substituted C1-C6alkyl, OR', N(R')2, CON(R')2or NRCOR'.

According to the following embodiments x is 1 or 2 and each R3the group represents-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3or-CN.

In accordance with the following Yes is its incarnations x is 1 and R 3is in position 6 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3or-CN.

In accordance with the following further embodiments x is 1 and R3is in position 7 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3or-CN.

According to another embodiments x is 1 and R3is in position 6 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3or-OCH2CH3.

According to another embodiments x is 1 and R3is in position 7 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3or-OCH2CH3.

According to other embodiments, R3is in position 6 chineselanguage ring and is-CON(R')2or NRCOR'.

According to other embodiments x is 1 and R3is in position 7 chineselanguage ring and is-CON(R')2or NRCOR'.

For compounds described directly above, y is 0-4, q is 0-2, and R5and R5Athe group to which they are present, are each independently halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -NRCOR', -CON(R')2, -S(O)2N(R')2, -OCOR', -COR', -CO2R', -OCON(R')2, -NR'r SO2R', -OP(O)(OR')2, -P(O)(OR')2, -OP(O)2OR', -P(O)2OR', -PO(R')2, -OPO(R')2or an optionally substituted group selected from C1-C6aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocyclizations group, arils1-C6of alkyl, heteroaryl1-C6the alkyl cycloaliphatic1-C6the alkyl or geterotsiklicheskikh1-C6the alkyl.

According to other embodiments y is 0-4, q is 1 or 2 and each R5Ais independently Cl, Br, F, CF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2,

-N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -SO2NH2, -SO2NHC(CH3)2, OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-piperazine-1-yl, OCOCH(CH3)2, OCO(cyclopentyl), -COCH3not necessarily replaced phenoxy or optionally substituted benzyloxy.

According to the following embodiments is 0 and R5ais F. Coz the ACLs another of the embodiments is 0, q is 1 and R5ais OR'. According to another embodiments is 0, q is 1 and R5ais HE. According to another embodiments is 1, R5arepresents OR', and R5is F, where'OR' is substituted in position 2 of the phenyl ring, and F is substituted in the 6 position of the phenyl ring. According to another embodiments is 1, R5ais HE and R5is F, where IT is substituted in position 2 of the phenyl ring, and F is substituted in the 6 position of the phenyl ring.

According to further embodiments of the compounds of the formulaIA-iidirectly above,

a) one of R1or R2represents hydrogen and the other of R1and R2selected from Cy1,

where Cy1linked directly to the nitrogen atom, or linked via optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group are optionally replaced by groups-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, -SO2NR - or-NRSO2-, or optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group are optionally replaced by groups-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, -SO2NR - or-NRSO2-; or R1 and R2each independently selected from optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by groups-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, -SO2NR - or-NRSO2-; or Cy1where Cy1linked directly to the nitrogen atom, or linked via optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by groups-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, -SO2NR - or-NRSO2-;

b) z is 0-5 and R4groups are each independently Cl, Br, F, CF3CH3, -CH2CH3CN, -COOH, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -CH2OH, -NHCOCH3, -SO2NH2, -SO2(CH2)3CH3, -SO2CH(CH3)2,

-SO2N(CH3)2, -SO2CH2CH3, -C(O)och2CH(CH3)2,

-C(O)NHCH2CH(CH3)2, -NHCOOCH3, -C(O)C(CH3)3, -COO - (CH2)2CH3-C(O)NHCH(CH3)2, -C(O)CH2CH3or an optionally substituted group selected from piperidinyl, piperazinil, morpholino,1-4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CH2of cyclohexyl, pyridyl, -CH2is iridia, or-CH2thiazolyl;

C) x is 0, 1 or 2 and each R3is independently Cl, Br, F, CF3, -OCF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -NHCOCH(CH3)2, -SO2NH2, CONH(cyclopropyl), -CONHCH3, -CNHCH2CH3or an optionally substituted group selected from piperidinyl, piperazinil, morpholino, phenyl, phenyloxy, benzyl or benzyloxy;

d) where is equal to 0-4, and R5groups, when they are present, are each independently Cl, Br, F, CF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3,

-SO2NH2, -SO2NHC(CH3)2, -OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-piperazine-1-yl, OCOCH(CH3)2, OCO(cyclopentyl), -COCH3not necessarily replaced phenoxy or optionally substituted benzyloxy and

e) R5Arepresents Cl, F, CF3, Me, Et, -OH, -OCH3, -OCH2CH3, -CH2OH, -SO2NH2, -SO2NHC(CH3)2, -OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2 N(CH3)2, 4-CH3-piperazine-1-yl, OCOCH(CH3)2, OCO(cyclopentyl) or-COCH3.

According to other embodiments for compounds directly above, x is 1 and R3is in position 6 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3or-CN. According to another embodiments x is 1, and R3is in position 7 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3or-CN. According to another embodiments x is 1 and R3is in position 6 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3or-OCH2CH3. According to another embodiments x is 1 and R3is in position 7 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3or-OCH2CH3. According to the following embodiments x is 1 and R3is in position 6 chineselanguage ring and is-CON(R')2or NRCOR'.

According to other embodiments x is equal to 1, and R3nah who is in position 7 chineselanguage ring and is-CON(R') 2or NRCOR'.

According to other embodiments, R5Arepresents Cl, F, CF3, Me, Et, -OH, -OCH3, -OCH2CH3.

According to other embodiments y is 0 and R5ais F. According to the following embodiments y is 0, q is 1 and R5ais OR'. According to the following embodiments is 0, q is 1 and R5ais HE. According to other embodiments y is 1, R5arepresents OR', and R5is F, where'OR' is substituted in position 2 of the phenyl ring and F is substituted in the 6 position of the phenyl ring. According to other embodiments y is 1, R5ais HE and R5is F, where IT is substituted in position 2 of the phenyl ring and F is substituted in the 6 position of the phenyl ring.

According to other embodiments of the compounds of the formulaIA-iidirectly above,

a) one of R1or R2represents hydrogen and the other of R1and R2selected from Cy1,

where Cy1linked directly to the nitrogen atom, or linked via optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by groups-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, -SO2NR - or-NRSO2-or long is Ino substituted C 1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by groups-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, -SO2NR - or-NRSO2-; or R1and R2each independently selected from optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by groups-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, -SO2NR - or-NRSO2-; or Cy1where Cy1linked directly to the nitrogen atom, or linked via optionally substituted C1-4aliphatic group, where one or more methylene units in

With1-4the aliphatic group is optionally replaced by groups-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, -SO2NR - or-NRSO2-; and Cy1chosen from:

or R1and R2are each independently optionally substituted C1-4aliphatic group and each is independently selected from optionally substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)co2CH3, (CH2)2Och3CH2(CO)co2CH3CH2(CO)co3CH(CH3)CH2CH3or n-butyl;

b) z is 0-5 and R4groups are each independently Cl, Br, F, CF3CH3, -CH2H 3CN, -COOH, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -CH2OH, -NHCOCH3, -SO2NH2, -SO2(CH2)3CH3, -SO2CH(CH3)2, -SO2N(CH3)2, -SO2CH2CH3, -C(O)och2CH(CH3)2, -C(O)NHCH2CH(CH3)2, -NHCOOCH3, -C(O)C(CH3)3, -COO - (CH2)2CH3-C(O)NHCH(CH3)2, -C(O)CH2CH3or an optionally substituted group selected from piperidinyl, piperazinil, morpholino,1-4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CH2of cyclohexyl, pyridyl, -CH2pyridyl or-CH2thiazolyl;

C) x is 0, 1 or 2 and each R3is independently Cl, Br, F, CF3, -OCF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -NHCOCH(CH3)2, -SO2NH2, -CONH(cyclopropyl), -CONHCH3, -CNHCH2CH3or an optionally substituted group selected from piperidinyl, piperazinil, morpholino, phenyl, phenyloxy, benzyl or benzyloxy;

d) where is equal to 0-4, and R5groups, when they are present, are each independently Cl, Br, F, CF3, Me, Et, CN, -COOH, -NH2, -N(CH 3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -SO2NH2, -SO2NHC(CH3)2, OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-piperazine-1-yl, OCOCH(CH3)2, OCO(cyclopentyl), -COCH3not necessarily replaced phenoxy or optionally substituted benzyloxy and

e) R5Arepresents Cl, F, CF3, Me, Et, -OH, -OCH3, -OCH2CH3, -CH2OH, -SO2NH2, -SO2NHC(CH3)2, -OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-piperazine-1-yl, OCOCH(CH3)2, OCO(cyclopentyl) or-COCH3.

According to another embodiments for compounds directly above, x is 1 and R3is in position 6 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl) -OCH3, -NH2, -OCH2CH3or-CN. According to another embodiments x is 1 and R3is in position 7 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH , -OCH2CH3or-CN. According to another embodiments x is 1 and R3is in position 6 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3or-OCH2CH3. According to the following embodiments x is 1 and R3is in position 7 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3or-OCH2CH3. According to the following embodiments x is 1, and R3is in position 6 chineselanguage ring and is-CON(R')2or NRCOR'. According to the following embodiments x is equal to 1, and R3is in position 7 chineselanguage ring and is-CON(R')2or NRCOR'. According to another embodiments, R5Arepresents Cl, F, CF3, Me, Et, -OH, -OCH3, -OCH2CH3.

According to other embodiments y is 0 and R5ais F. According to other embodiments y is 0, q is 1 and R5ais OR'. According to other embodiments y is 0, q is 1 and R5ais HE. According to another embodiments is 1, R5arepresents OR', and R5is F, where'OR' is substituted in position 2 of the phenyl ring and F is substituted in the 6 position of the phenyl ring. According to a further about what these embodiments is 1, R5ais HE and R5is F, where IT is substituted in position 2 of the phenyl ring and F is substituted in the 6 position of the phenyl ring.

For compounds that are described in General in this section above, it is noted that the compounds are useful as inhibitors of ion channels, preferably potentialization sodium channel and calcium channel N-type. In some examples of embodiments of the compounds of the invention are useful as inhibitors of NaV1.8. According to other embodiments of the compounds of the invention are useful as inhibitors of NaV1.8 and CaV2.2. In still other embodiments of the compounds of the invention are useful as inhibitors of CaV2.2. According to still other embodiments of the compounds of the invention are useful as dual inhibitors of NaV1.8 and TTX-sensitive ion channels, such as NaV1.3 or NaV1.7.

III. The compounds of formula IA-i:

or their pharmaceutically acceptable salt,

where R1and R2are each independently optionally substituted group selected from C1-6aliphatic group, Cy1where Cy1represents a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms selected independently from nitrogen, oxygen, or sulfur, or represents 3-12-the Lenna saturated or partially unsaturated monocyclic ring, having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, where Cy1linked directly to the nitrogen atom, or linked via optionally substituted C1-4aliphatic group, where one or more methylene units in

With1-4the aliphatic group is optionally replaced by a group-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, -SO2NR - or-NRSO2-; where R1and R2are each optionally and independently substituted at one or more substitutable carbon atoms, nitrogen or sulfur number z are independent substituents R4where z is 0-5;

x is 1 and R3is substituted or 6 or position 7 of the quinoline ring;

is 0-4;

q represents 0, 1 or 2;

each of R3, R4and R5is independently Q-RXwhere Q represents a bond or represents C1-C6alkylidene chain, where up to two non-adjacent methylene units of the group Q are optionally and independently replaced by groups-NR-, -S-, -O-, -CS-CO2-, -OCO-, -CO-, -COCO-, -CONR-, -NRCO-, -NRCO2, -SO2NR-, -NRSO2-, -CONRNR-, -NRCONR-, -OCONR-, -NRNR-, -NRSO2NR-, -SO-, -SO2-, -PO-, -PO2-, -OP(O)(OR)-, or-POR-; and each of RXindependently selected from-R', =O, =NR', - halogen, -NO2, -CN, -OR', -SR', -N(R')2, -NR'r COR', -NR'r CON(R')2, -NR'r CO2R', -COR', -CO2R', -OCOR', -CON(R')2, -OCON(R')2, -SOR', -SO22N(R')2, -NR'r SO2R', -NR'r SO2N(R')2, -COCOR', -COCH2COR', -OP(O)(OR')2, -P(O)(OR')2, -OP(O)2OR', -P(O)2OR', -PO(R')2or-OPO(R')2

each of R5ais independently optionally substituted C1-C6aliphatic group, halogen, -OR', -SR', -N(R')2, -NR'r COR', -NR'r CON(R')2, -NR'r CO2R', -COR', -CO2R', -OCOR', -CON(R')2, -OCON(R')2, -SOR', -SO2R', -SO2N(R')2, -NR'r SO2R', -NR'r SO2N(R')2, -COCOR', -COCH2COR', -OP(O)(OR')2, -P(O)(OR')2, -OP(O)2OR', -P(O)2OR', -PO(R')2or-OPO(R')2and

each R is independently hydrogen or optionally substituted C1-6aliphatic group and each R' is independently hydrogen or optionally substituted C1-6aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or R and R', two of R, or two of R', taken together with the atom(s)to which they are attached, form a optionally substituted 3-12-membered saturated, partially unsaturated or fully is part of an unsaturated monocyclic or bicyclic ring, having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

In some embodiments for compounds directly above,

a) when R3is in position 7 chineselanguage ring, then

i) when R3is Cl or Me, ring A is unsubstituted naphthyl, and R1is hydrogen, then R2is not a group -(CH2)3NMe2;

ii) when R3is Cl, the sum of q and y is 1 and the phenyl ring substituted at the 4-position Br, and R1is hydrogen, then R2is not Cy1where Cy1linked to the nitrogen atom through an optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by a group-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, -SO2NR - or-NRSO2-;

iii) when R3represents Cl or OMe, the sum of q and y is 1 and the phenyl ring substituted at the 4-position by a group or OMe or Cl and R1is hydrogen, then R2is not a group-CH(CH3)(CH2)3N(Et)2;

iv) when R3is Me, OMe or NO2, q and y are 0, then R1and R2both are not metelli;

v) when R3is OMe, q and y are 0 and R1is hydrogen, then R2is not-SO2(4-Me-phenyl);

vi) to the Yes R 3is F, the sum of q and y is equal to 1, the phenyl ring is substituted in position 2 is Cl and R1is hydrogen, then R2is not a group (-CH2)morpholino, and

b) when R3is in position 6 chineselanguage rings, then:

i) when R3represents NH2, Me, Cl, Br, -NHAc, the sum of q and y is equal to 1, the phenyl ring substituted at the 4-position with F, or ring a is naphthyl and R1is hydrogen, then R2is not a group (-CH3)3-4N(R')2;

ii) when R3represents-OCH2Ph or OH and q and y are 0, when R1is hydrogen, R2is not group Me, nBu, or -(CH2)morpholino or R1and R2at the same time are not Me or Et;

iii) when R3is Me or Cl, and the sum of q and y is 1, then the phenyl ring is not substituted at the 4-position with bromine;

iv) when R3is Cl, q and y are 0 and R1is hydrogen, then R2is not a group-SO2(4-Me-phenyl);

v) when R3is OMe, q and y are 0 and R1is hydrogen, then R2is not a group-CH2CH2HE or-CH2CH2pyrrolidinyl;

vi) when R3represents Cl or Br, the sum of q and y is 1 and the phenyl ring substituted at the 4-position the group-CH2RO(or SIG')2then R1is not the water is Odom, when R2is is Me or R1and R2at the same time are not Me or Et;

vii) when R3is HE and q and y are 0, then R1and R2at the same time are not-CH2CH2OMe;

viii) when R3is Cl, the sum of q and y is equal to 1 phenyl ring substituted in position 2 by a group of OnPr and R1is hydrogen, then R2is not-CH2(1,3-benzodioxole);

ix) when R3is OMe, IT, Br, Cl, NO2, Me and q and y are 0, when R1is hydrogen, R2is not IU, -CH2CH2The sooma, -CH2The sooma or -(CH2)3CH3or R1and R2are not both IU; and

x) when R3is Cl, the sum of q and y is 1 and the phenyl ring substituted at the 4-position with Cl, then R1and R2are not simultaneously Me or iPr.

In some other embodiments for compounds directly above:

a) one of R1or R2represents hydrogen and the other of R1and R2chosen from:

i) Cy1where Cy1linked directly to the nitrogen atom, or linked via optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by a group-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, -SO2 NR - or-NRSO2or

ii) optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by a group-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, -SO2NR - or-NRSO2-; or

b) R1and R2each independently selected from Cy1where Cy1linked directly to the nitrogen atom, or linked via optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by a group-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, -SO2NR-, or-NRSO2or optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by a group-NR-, -O-, -COO-, -OCO-, -NRCO-, -CONR-, -SO2NR - or-NRSO2-.

In the following embodiments Cy1is:

In other embodiments, R1represents hydrogen or optionally substituted C1-C4aliphatic group, and R2is-CHR-Cy1where R is hydrogen or C1-C4alkyl and su1is:

In other embodiments, R1and R 2group each nezavisimo represent optionally substituted C1-C4aliphatic group and each is independently selected from optionally substituted methyl, ethyl, cyclopropane, n-through propenyloxy, cyclobutyl, (CO)co2CH3, (CH2)2Och3CH2(CO)co2CH3CH2(CO)co3CH(CH3)CH2CH3or n-butilkoi group.

In the following embodiments for compounds described directly above, z is 0-5 and R4groups, when they are present, each independently represents halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -COOR', -NRCOR', -CON(R')2, -OCON(R')2, COR', -NHCOOR', -SO2R', -SO2N(R')2or an optionally substituted group selected from C1-C6aliphatic group, aryl, heteroaryl, cycloaliphatic, heterocyclizations group, arils1-C6of alkyl, heteroaryl1-C6of alkyl, cycloaliphatic1-C6the alkyl, or geterotsiklicheskikh1-C6the alkyl.

In the following embodiments z is 0-5 and R4group each independently represents Cl, Br, F, CF3CH3, -CH2CH3CN, -COOH, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -ONH 2, -COOCH3, -OH, -CH2OH, -NHCOCH3, -SO2NH2, -SO2(CH2)3CH3, -SO2CH(CH3)2, -SO2N(CH3)2, -SO2CH2CH3, -C(O)och2CH(CH3)2, -C(O)NHCH2CH(CH3)2, -NHCOOCH3, -C(O)C(CH3)3, -COO - (CH2)2CH3-C(O)NHCH(CH3)2, -C(O)CH2CH3or optionally substituted group selected from piperidinyl, piperazinil, morpholino,1-4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CH2of cyclohexyl, pyridyl, -CH2pyridyl or-CH2thiazolyl.

In the following embodiments, for compounds described directly above, R3the group is halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -COOR', -NRCOR', -CON(R')2, -OCON(R')2, COR', -NHCOOR', -SO2R', -SO2N(R')2or an optionally substituted group selected from C1-C6aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocyclizations group, arils1-C6of alkyl, heteroaryl1-C6of alkyl, cycloaliphatic1-C6the alkyl or geterotsiklicheskikh1-C6the alkyl.

In other embodiments, R3represents Cl, Br, F, CF3, -OCF3, Me, Et, CN, -COOH, -NH2, -N(CH3) , -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -NHCOCH(CH3)2, -SO2NH2, CONH(cyclopropyl), -CONHCH3, -CNHCH2CH3or an optionally substituted group selected from piperidinyl, piperazinil, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.

In the following embodiments, R3the group is halogen, CN, optionally substituted C1-C6alkyl, OR', N(R')2, CON(R')2or NRCOR'. In the following embodiments, R3is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3,

-NH2, -OCH2CH3or-CN. In the following embodiments, R3is in position 6 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl),

-OCH3, -NH2, -OCH2CH3or-CN. In the following embodiments, R3is in position 7 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3or-CN. In other embodiments, R3is in position 6 chineselanguage number of the CA and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3or-OCH2CH3. In other embodiments, R3is in position 7 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3or-OCH2CH3. In other embodiments, R3is in position 6 chineselanguage ring and is-CON(R')2NRCOR'. In other embodiments, R3is in position 7 chineselanguage ring and is-CON(R')2or NRCOR'.

In other embodiments for compounds described directly above, y is 0-5, q is 0-2, and R5and R5Agroups, when they are present, are each independently halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -NRCOR', -CON(R')2, S(O)2N(R')2, -OCOR', -COR', -CO2R', -OCON(R')2, -NR'r SO2R', -OP(O)(OR')2, -P(O)(OR')2, -OP(O)2OR', -P(O)2OR', -PO(R')2, -OPO(R')2or an optionally substituted group selected from C1-C6aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocyclizations group, arils1-C6of alkyl, heteroaryl1-C6of alkyl, cycloaliphatic1-C6the alkyl or geterotsiklicheskikh1-C6the alkyl.

In other embodiments from before the hat 0-5, q represents 1 or 2 and each R5Ais independently Cl, Br, F, CF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -SO2NH2, -SO2NHC(CH3)2, -OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-piperazine-1-yl, OCOCH(CH3)2, OCO(cyclopentyl), -COCH3not necessarily replaced phenoxy or optionally substituted benzyloxy.

In other embodiments y is 0 and R5ais F. in another embodiment y is 0, q is 1 and R5ais OR'. In other embodiments y is 0, q is 1 and R5ais HE. In another embodiment y represents 1, R5arepresents OR', and R5is F, where'OR' is substituted in position 2 of the phenyl ring and F is substituted in the 6 position of the phenyl ring. In another embodiment y represents 1, R5ais HE and R5is F, where IT is substituted in position 2 of the phenyl ring and F is substituted in the 6 position of the phenyl ring.

In the following embodiments, R3is substituted in position 6 chineselanguage rings, q is 1 and y is 0, the compounds have the formula III:

In some embodiments of the compounds described above:

a) R1and R2each independently represent optionally substituted group selected from C1-6aliphatic group, Cy1where Cy1represents a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected ie nitrogen, oxygen or sulphur, or represents a 3-12-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, where Cy1attached directly to the nitrogen atom, or linked via optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by a group-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, SO2NR - or-NRSO2-where R1and R2each optionally and independently is optionally substituted at one or more substitutable carbon atoms, nitrogen or sulfur number z are independent substituents R4where z is equal to 0-5;

b) z is 0-5 and R4groups are each independently Cl, Br, F, CF3CH3, -CH2CH3CN, -COOH, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, COOCH 3, -OH, -CH2OH, -NHCOCH3, -SO2NH2, -SO2(CH2)3CH3, -SO2CH(CH3)2, -SO2N(CH3)2, -SO2CH2CH3, -C(O)och2CH(CH3)2, -C(O)NHCH2CH(CH3)2, -NHCOOCH3, -C(O)C(CH3)3, -COO - (CH2)2CH3-C(O)NHCH(CH3)2, -C(O)CH2CH3or an optionally substituted group selected from piperidinyl, piperazinil, morpholino,1-4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CH2of cyclohexyl, pyridyl, -CH2pyridyl or-CH2thiazolyl;

(C) R3represents Cl, Br, F, CF3, -OCF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -NHCOCH(CH3)2, -SO2NH2, -CONH(cyclopropyl), -CONHCH3, -CONHCH2CH3or an optionally substituted group selected from piperidinyl, piperazinil, morpholino, phenyl, phenyloxy, benzyl or benzyloxy;

d) R5Arepresents Cl, F, CF3, Me, Et, -OH, -OCH3, -OCH2CH3, -CH2OH, -SO2NH2, -SO2NHC(CH3)2, -OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-piperazine-1-yl, OCOCH(CH3)2, OCO(cyclo is Intel) or-COCH 3.

In some other embodiments for compounds described directly above, R3is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3or-CN. More other embodiments, R3is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3or-OCH2CH3. In other embodiments, R3is-CON(R')2or NRCOR'. In other embodiments, R5arepresents Cl, F, CF3, Me, Et, -OH, -OCH3, -OCH2CH3.

In some embodiments, y is 0, and R5ais F. In some embodiments y is 0, q is 1 and R5ais OR'. In the following embodiments, y is 0, q is 1 and R5arepresents OH.

In some other embodiments for compounds directly above:

a) su1is:

or R1and R2are each independently optionally substituted C1-4aliphatic group and each is independently selected from optionally substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)co2CH3, (CH2)2Och32(CO)co2CH3CH2(CO)co3CH(CH3)CH2CH3or n-butyl;

b) z is 0-5 and R4groups are each independently Cl, Br, F, CF3CH3, -CH2CH3CN, -COOH, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -CH2OH, -NHCOCH3, -SO2NH2, -SO2(CH2)3CH3, -SO2CH(CH3)2, -SO2N(CH3)2, -SO2CH2CH3, -C(O)och2CH(CH3)2, -C(O)NHCH2CH(CH3)2, -NHCOOCH3, -C(O)C(CH3)3, -COO - (CH2)2CH3-C(O)NHCH(CH3)2, -C(O)CH2CH3or an optionally substituted group selected from piperidinyl, piperazinil, morpholino,1-4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CH2of cyclohexyl, pyridyl, -CH2pyridyl or-CH2thiazolyl;

(C) R3represents Cl, Br, F, CF3, -OCF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -NHCOCH(CH3)2, -SO2NH2, -CONH(cyclopropyl), -CONHCH3, -CNHCH2CH3or an optionally substituted group selected from piperidinyl, piperazinil, morpholino, FeNi is a, phenyloxy, benzyl or benzyloxy, and

d) R5arepresents Cl, F, CF3, Me, Et, -OH, -OCH3, -OCH2CH3, -CH2OH, -SO2NH2, -SO2NHC(CH3)2, -OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-piperazine-1-yl, OCOCH(CH3)2, OCO(cyclopentyl) or-COCH3.

In some embodiments for compounds described directly above, R3is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3or-CN. In other embodiments, R3is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3or-OCH2CH3. In other embodiments, R3is-CON(R')2or NRCOR'. In some embodiments, R5arepresents Cl, F, CF3, Me, Et, -OH, -OCH3, -OCH2CH3. In some embodiments, y is 0, and R5ais F. In the following embodiments y is 0, q is 1 and R5ais OR'. In the following embodiments, y is 0, q is 1 and R5arepresents OH.

In other embodiments, R3is substituted in position 7 chineselanguage rings, q is 1 and y is 0, and the compound has the formulaIV:

(a) where R1and R2are each independently optionally substituted group selected from C1-6aliphatic group, Cy1where Cy1represents a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms selected independently from nitrogen, oxygen, or sulfur, or represents a 3-12-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, where Cy1linked directly to the nitrogen atom, or linked via optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by a group-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, -SO2NR - or-NRSO2-where R1and R2are each optionally and independently substituted at one or more substitutable carbon atoms, nitrogen or sulfur number z are independent substituents R4where z is 0-5;

b) z is 0-5 and R4groups are each independently Cl, Br, F, CF3CH3, -CH2CH3CN, -COOH, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -CH2OH, -NHCOCH3, -SO2NH2, -SO2(CH2)3CH3, -SO2CH(CH 3)2, -SO2N(CH3)2, -SO2CH2CH3, -C(O)och2CH(CH3)2, -C(O)NHCH2CH(CH3)2, -NHCOOCH3, -C(O)C(CH3)3, -COO - (CH2)2CH3-C(O)NHCH(CH3)2, -C(O)CH2CH3or an optionally substituted group selected from piperidinyl, piperazinil, morpholino,1-4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CH2of cyclohexyl, pyridyl, -CH2pyridyl or-CH2thiazolyl;

(C) R3represents Cl, Br, F, CF3, -OCF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -NHCOCH(CH3)2, -SO2NH2, -CONH(cyclopropyl), -CONHCH3, -CNHCH2CH3or an optionally substituted group selected from piperidinyl, piperazinil, morpholino, phenyl, phenyloxy, benzyl or benzyloxy, and

d) R5Arepresents Cl, F, CF3, Me, Et, -OH, -OCH3, -OCH2CH3, -CH2OH, -SO2NH2, -SO2NHC(CH3)2, -OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-piperazine-1-yl, OCOCH(CH3)2, OCO(cyclopentyl) or-COCH3.

In some embodiments for compounds directly above, R 3is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3-NH2, -OCH2CH3or-CN. In other embodiments, R3is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3or-OCH2CH3. In some embodiments, R3is-CON(R')2or NRCOR'. In some embodiments, R5arepresents Cl, F, CF3, Me, Et, -OH, -OCH3, -OCH2CH3. In the following embodiments, y is 0, and R5ais F. In the following embodiments y is 0, q is 1 and R5ais OR'. In the following embodiments, y is 0, q is 1 and R5arepresents OH.

In some other embodiments for compounds directly above:

a) su1is:

or R1or R2are each independently optionally substituted C1-4aliphatic group and each is independently selected from optionally substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)co2CH3, (CH2)2Och3CH2(CO)co2CH3CH2(CO)co3CH(CH3)CH2CH3or n-butyl;

b) z is 0-5 and R4the group made the presentations each independently Cl, Br, F, CF3CH3, -CH2CH3CN, -COOH, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -CH2OH, -NHCOCH3, -SO2NH2, -SO2(CH2)3CH3, -SO2CH(CH3)2, -SO2N(CH3)2, -SO2CH2CH3, -C(O)och2CH(CH3)2, -C(O)NHCH2CH(CH3)2, -NHCOOCH3, -C(O)C(CH3)3, -COO - (CH2)2CH3-C(O)NHCH(CH3)2, -C(O)CH2CH3or optionally substituted group selected from piperidinyl, piperazinil, morpholino,1-4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CH2of cyclohexyl, pyridyl, -CH2pyridyl or-CH2thiazolyl;

(C) R3represents Cl, Br, F, CF3, -OCF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -NHCOCH(CH3)2, -SO2NH2, -CONH(cyclopropyl), -CONHCH3, -CNHCH2CH3or an optionally substituted group selected from piperidinyl, piperazinil, morpholino, phenyl, phenyloxy, benzyl or benzyloxy, and

d) R5Arepresents Cl, F, CF3, Me, Et, -OH, -OCH3, -OCH2CH3, -CH2OH, -SO2NH2, -SO2NHC(CH3)2, -COC(CH 3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-piperazine-1-yl, OCOCH(CH3)2, OCO(cyclopentyl) or-COCH3.

In some other embodiments for compounds directly above, R3is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3or-CN. In other embodiments, R3is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3or-OCH2CH3. In other embodiments, R3is-CON(R')2or NRCOR'. In even more other embodiments, R5arepresents Cl, F, CF3, Me, Et, -OH, -OCH3or-OCH2CH3. In other embodiments y is 0, and R5ais F. in other embodiments y is 0, q is 1 and R5ais OR'. In other embodiments y is 0, q is 1 and R5arepresents OH.

For compounds that are described in General in this section above, it is noted that the compounds are useful as inhibitors of ion channels, preferably potentialization sodium channel and calcium channel N-type. In some examples of embodiments of the compounds of the invention are useful as inhibitors of NaV1.8. According to other embodiments with the organisations of the invention are useful as inhibitors of NaV1.8 and CaV2.2. In still other embodiments of the compounds of the invention are useful as inhibitors of CaV2.2. According to still other embodiments of the compounds of the invention are useful as dual inhibitors of NaV1.8 and TTX-sensitive ion channels, such as NaV1.3 or NaV1.7.

IV. The compounds of formula V:

where R1and R2are each independently optionally substituted group selected from C1-6aliphatic group, Cy1where Cy1represents a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms selected independently from nitrogen, oxygen, or sulfur, or represents a 3-12-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, where Cy1linked directly to the nitrogen atom, or linked via optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by a group-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, SO2NR - or-NRSO2-, or R1and R2taken together with the nitrogen atom to which they are attached, form an optionally substituted 3-12-membered saturated or partially unsaturated monocyclic or bicyclic number of the TSO, having 0-3 additional heteroatoms independently selected from nitrogen, sulfur or oxygen, where R1and R2or the ring formed by R1and R2taken together, are each optionally and independently substituted at one or more substitutable carbon atoms, nitrogen or sulfur number z are independent substituents R4where z is 0-5;

x is 0-4;

is 0-2;

each of R3, R4and R5is independently Q-RXwhere Q represents a bond or represents C1-C6alkylidene chain, where up to two non-adjacent methylene units of the group Q are optionally and independently replaced by groups-NR-, -S-, -O-, -CS-CO2-, -OCO-, -CO-, -COCO-, -CONR-, -NRCO-, -NRCO2, -SO2NR-, -NRSO2-, -CONRNR-, -NRCONR-, -OCONR-, -NRNR-, -NRSO2NR-, -SO-, -SO2-, -PO-, -PO2-, -OP(O)(OR)-, or-POR-; and each of RXindependently selected from-R', =O, =NR', - halogen, -NO2, -CN, -OR', -SR', -N(R')2, -NR'r COR', -NR'r CON(R')2, -NR'r CO2R', -COR', -CO2R', -OCOR', -CON(R')2, -OCON(R')2, -SOR', -SO2R', -SO2N(R')2, -NR'r SO2R', -NR'r SO2N(R')2, -COCOR', -COCH2COR', -OP(O)(OR')2, -P(O)(OR')2, -OP(O)2OR', -P(O)2OR', -PO(R')2or-OPO(R')2;

R5arepresents optionally substituted C1-C6aliphatic group, halogen, -OR', -SR', -N(R')2, -NR'r COR', -NR'r CON(R')2, -NR'r CO 2R', -COR', -CO2R', -OCOR', -CON(R')2, -OCON(R')2, -SOR', -SO2R', -SO2N(R')2, -NR'r SO2R', -NR'r SO2N(R')2, -COCOR', -COCH2COR', -OP(O)(OR')2, -P(O)(OR')2, -OP(O)2OR', -P(O)2OR', -PO(R')2or-OPO(R')2and

each R is independently hydrogen or optionally substituted C1-6aliphatic group and each R' is independently hydrogen or optionally substituted C1-6aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or R and R', two of R, or two of R', taken together with the atom(s)to which they are attached, form a optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

In some embodiments for compounds directly above, when x is 1 and R3is 6-OMe, R1is hydrogen and y and q both represent 0, then R 2is not-CH2CH2OCH2CH2OH group or monoethanolamine salt.

In some other embodiments for compounds directly above:

a) one of R1or R2represents hydrogen and the other of R1and R2chosen from:

i) Cy1where Cy1linked directly to the nitrogen atom, or linked via optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by a group-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, -SO2NR - or-NRSO2-or

ii) optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by a group-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, -SO2NR - or-NRSO2-or

b) R1and R2each independently selected from Cy1where Cy1linked directly to the nitrogen atom, or linked via optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by a group-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, -SO2NR-, or-NRSO2-, or optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4aliphatic group optionally C is replaced by a group-NR-, -O-, -COO-, -OCO-, -NRCO-, -CONR-, -SO2NR - or-NRSO2-.

In other embodiments su1is:

In other embodiments, R1represents hydrogen or optionally substituted C1-C4aliphatic group, and R2is-CHR-Cy1where R is hydrogen or C1-C4alkyl, and su1is:

In other embodiments, R1and R2group each nezavisimo represent optionally substituted C1-C4aliphatic group and each is independently selected from optionally substituted methyl, ethyl, cyclopropane, n-through propenyloxy, cyclobutyl, (CO)co2CH3, (CH2)2Och3CH2(CO)co2CH3CH2(CO)co3CH(CH3)CH2CH3or n-butilkoi group.

In the following embodiments for compounds described directly above, the group R1and R2taken together with the nitrogen atom to which they are attached, form an optionally substituted 3-12-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen or oxygen, and form a 3-12-membered heterocyclic is some ring, chosen from:

where the ring formed by R1and R2taken together, is optionally substituted at one or more substitutable carbon atoms, nitrogen or sulfur number z are independent substituents R4and z is equal to 0-5.

According to other embodiments of the compounds of the formulaI-And, R1and R2taken together, represent an optionally substituted, azetidin-1-yl (jj), pyrrolidin-1-yl (ff)piperidine-1-yl (dd), piperazine-1-yl (ccor morpholine-4-yl (ee). According to other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted, azetidin-1-yl (jj), pyrrolidin-1-yl (ff)piperidine-1-yl (dd) or piperazine-1-yl (SS). According to other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted, azetidin-1-yl (jj). According to another embodiments of the compounds of the formulaI-AR1and R2taken together, represent optionally substituted pyrrolidin-1-yl (ff). According to another embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperidine-1-yl (dd). According to further embodiments of the compounds of the formulaI-A R 1and R2taken together, represent an optionally substituted piperazine-1-yl (cc).

For compounds described directly above, z is 0-5 and R4groups, when they are present, each independently represents halogen, CN, NO2, -N(R')2CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -COOR', -NRCOR', -CON(R')2, -OCON(R')2, -COR', -NHCOOR', -SO2R', -SO2N(R')2or an optionally substituted group selected from C1-C6aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocyclizations group, arils1-C6of alkyl, heteroaryl1-C6of alkyl, cycloaliphatic1-C6the alkyl or geterotsiklicheskikh1-C6the alkyl.

According to other embodiments z is 0-5 and R4groups are each independently Cl, Br, F, CF3CH3, -CH2CH3CN, -COOH, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -CH2OH, -NHCOCH3, -SO2NH2, -SO2(CH2)3CH3, -SO2CH(CH3)2, -SO2N(CH3)2, -SO2CH2CH3, -C(O)och2CH(CH3)2, -C(O)NHCH2CH(CH3)2, -NHCOOCH3, -C(O)C(CH3)3, -COO - (CH2)2CH3-C(O)NHCH(CH 3)2, -C(O)CH2CH3or an optionally substituted group selected from piperidinyl, piperazinil, morpholino,1-4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CH2of cyclohexyl, pyridyl, -CH2pyridyl or-CH2thiazolyl.

According to some embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted, azetidin-1-yl (jj), where z is 1 or 2 and at least one of R4is-NRSO2R', -NRCOOR', or-NRCOR'. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted, azetidin-1-yl (jj), where z is 1 and R4is-NRSO2R'. According to other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted, azetidin-1-yl (jj), where z is 1 and R4is-NRCOOR'. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted, azetidin-1-yl (jj), where z is 1 and R4is-NRCOR'. According to another embodiments of the compounds of the formulaI-AR1and R2taken together, represent optionally substituted pyrrolidin-1-yl (<> ff), where z is 1 or 2 and R4represents Cl, Br, F, CF3CH3, -CH2CH3, -OR' or-CH2'OR'. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperidine-1-yl (dd), where z is 1 or 2 and at least one of R4represents Cl, Br, F, CF3CH3, -CH2CH3, -OR', -CH2OR', -NRSO2R', -NRCOOR', or -- OCON(R')2. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperidine-1-yl (dd), where z is 1 and R4is F, CF3CH3, -CH2CH3, -OR' or-CH2'OR'. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperidine-1-yl (dd), where z is 1 and R4is-NRSO2R'. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperidine-1-yl (dd), where z is 1 and R4is-NRCOOR'. According to another embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperazine-1-yl (with the ), where z is 1 or 2 and at least one of R4is-SOR', -CON(R')2, -SO2N(R')2, -COR' or-COOR'. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperazine-1-yl (SS), where z is 1 and R4is-SOR'. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperazine-1-yl (SS), where z is 1, and

R4is-OR'. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperazine-1-yl (SS), where z is 1 and R4is-SOP(R')2. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperazine-1-yl (SS), where z is 1 and R4is-SO2N(R')2. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperazine-1-yl (SS), where z is 1 and R4is-COR'.

According to other embodiments x is 0-4, and R3group, when they PR who are present, each independently represent halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -COOR', -NRCOR', -CON(R')2, -OCON(R')2, -COR', -NHCOOR', -SO2R', -SO2N(R')2or an optionally substituted group selected from C1-C6aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocyclizations group, arils1-C6of alkyl, heteroaryl1-C6of alkyl, cycloaliphatic1-C6the alkyl or geterotsiklicheskikh1-C6the alkyl. According to still other embodiments x is 1 or 2 and each R3is independently Cl, Br, F, CF3, -OCF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -NHCOCH(CH3)2, -SO2NH2, CONH(cyclopropyl), -CONHCH3, -CNHCH2CH3or an optionally substituted group selected from piperidinyl, piperazinil, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.

According to another embodiments x is 1 or 2 and each R3the group is independently halogen, CN, optionally substituted C1-C6alkyl, OR', N(R')2, CON(R')2or NRCOR'. According to another embodiments's submitted is 1 or 2, and each R3the group represents-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3or-CN. According to another embodiments x is 1 and R3is in position 6 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3or-CN. According to the following embodiments x is 1, R3is in position 7 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3or-CN. According to the following embodiments x is 1, and R3is in position 6 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3or-OCH2CH3. According to the following embodiments x is 1 and R3is in position 7 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3or-OCH2CH3. In accordance with the following further embodiments x is 1, R3is in position 6 chineselanguage ring and is-CON(R')2or NRCOR'. According what about the following further embodiments x is 1, R3is in position 7 chineselanguage ring and is-CON(R')2or NRCOR'.

For compounds described directly above, according to another embodiments is 0-2, q is 0-2, R5and R5Agroups, when they are present, are each independently halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -NRCOR', -CON(R')2, S(O)2N(R')2, -OCOR', -COR', -CO2R', -OCON(R')2, -NR'r SO2R', -OP(O)(OR')2, -P(O)(OR')2, -OP(O)2OR', -P(O)2OR', -PO(R')2, -OPO(R')2or an optionally substituted group selected from C1-C6aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocyclizations group, arils1-C6of alkyl, heteroaryl1-C6of alkyl, cycloaliphatic1-C6the alkyl or geterotsiklicheskikh1-C6the alkyl.

According to other embodiments y is 0-2, q is 1 or 2 and each R5Ais independently Cl, Br, F, CF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -SO2NH2, -SO2NHC(CH3)2, OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2) 2N(CH3)2, 4-CH3-piperazine-1-yl, OCOCH(CH3)2, OCO(cyclopentyl), -COCH3not necessarily replaced phenoxy or optionally substituted benzyloxy.

According to other embodiments y is 0, q is 1 and R5ais F. According to another embodiments is 0, q is 1 and R5ais OR'. According to other embodiments y is 0, q is 1 and R5ais HE. According to another embodiments is 0, q is 2 and one R5arepresents OR', and the other of R5ais F. According to another embodiments is 0, q is 2 and one R5ais HE, and the other of R5ais F.

According to other embodiments:

a) R1and R2taken together, represent an optionally substituted ring selected from azetidin-1-yl (jj), pyrrolidin-1-yl (ff)piperidine-1-yl (dd) or piperazine-1-Il (cc); one of R1or R2represents hydrogen and the other of R1and R2selected from Cy1where Cy1linked directly to the nitrogen atom, or linked via optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by groups-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, -SO NR - or-NRSO2-, or optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by groups-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, -SO2NR - or-NRSO2-; or R1and R2each independently selected from optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by groups-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, -SO2NR - or-NRSO2-; or Cy1where Cy1linked directly to the nitrogen atom, or linked via optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by groups-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, -SO2NR - or-NRSO2-;

b) z is 0-5 and R4groups are each independently Cl, Br, F, CF3CH3, -CH2CH3CN, -COOH, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -CH2OH, -NHCOCH3, -SO2NH2, -SO2(CH2)3CH3, -SO2CH(CH3)2, -SO2N(CH3)2, -SO2CH2CH3, -C(O)och2CH(CH3)2, -C(O)NHCH2CH(CH3)2, -NHCOOCH3, -C(O)C(CH3)3, -COO - (CH2)2CH3 -C(O)NHCH(CH3)2, -C(O)CH2CH3or an optionally substituted group selected from piperidinyl, piperazinil, morpholino,1-4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CH2of cyclohexyl, pyridyl, -CH2pyridyl or-CH2thiazolyl;

C) x is 0, 1 or 2 and each R3is independently Cl, Br, F, CF3, -OCF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -NHCOCH(CH3)2, -SO2NH2, -CONH(cyclopropyl), -CONHCH3, -CNHCH2CH3or an optionally substituted group selected from piperidinyl, piperazinil, morpholino, phenyl, phenyloxy, benzyl or benzyloxy;

d) where is equal to 0-2, and R5groups, when they are present, are each independently Cl, Br, F, CF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -SO2NH2, -SO2NHC(CH3)2, -OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-piperazine-1-yl, OCOCH(CH3)2, OCO(cyclopentyl) -COCH3not necessarily replaced phenoxy or neoba is consequently substituted benzyloxy and

e) R5Arepresents Cl, F, CF3, Me, Et, -OH, -OCH3, -OCH2CH3, -CH2OH, -SO2NH2, -SO2NHC(CH3)2, -OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-piperazine-1-yl, OCOCH(CH3)2, OCO(cyclopentyl) or-COCH3.

According to other embodiments of the compounds of the formulaI-AndR1and R2taken together, represent an optionally substituted, azetidin-1-yl (jj). According to another embodiments of the compounds of the formulaI-AR1and R2taken together, represent optionally substituted pyrrolidin-1-yl (ff). According to another embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperidine-1-yl (dd). According to further embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperazine-1-yl (cc).

According to some embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted, azetidin-1-yl (jj), where z is 1 or 2 and at least one of R4is-NRSO2R', -NRCOOR', or-NRCOR'. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, the pre is not necessarily constitute substituted azetidin-1-yl ( jj), where z is 1 and R4is-NRSO2R'. According to other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted, azetidin-1-yl (jj), where z is 1 and R4is-NRCOOR'. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted, azetidin-1-yl (jj), where z is 1 and R4is-NRCOR'. According to another embodiments of the compounds of the formulaI-AR1and R2taken together, represent optionally substituted pyrrolidin-1-yl (ff), where z is 1 or 2 and R4represents Cl, Br, F, CF3CH3, -CH2CH3, -OR', or CH2'OR'. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperidine-1-yl (dd), where z is 1 or 2 and at least one of R4represents Cl, Br, F, CF3CH3, -CH2CH3, -OR', -CH2OR', -NRSO2R', -NRCOOR', or -- OCON(R')2. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperidine-1-yl (dd), where z is 1 and R4is F, CF3CH3 , -CH2CH3, -OR' or-CH2'OR'. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperidine-1-yl (dd), where z is 1 and R4is-NRSO2R'. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperidine-1-yl (dd), where z is 1 and R4is-NRCOOR'. According to another embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperazine-1-yl (SS), where z is 1 or 2 and at least one of R4is-SOR', -CON(R')2, -SO2N(R')2, -COR' or-COOR'. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperazine-1-yl (SS), where z is 1, and

R4is-SOR'. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperazine-1-yl (SS), where z is 1 and R4is-OR'. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent obazatelno substituted piperazine-1-yl ( SS), where z is 1 and R4is-SOP(R')2. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperazine-1-yl (SS), where z is 1 and R4is-SO2N(R')2. According to some other embodiments of the compounds of the formulaI-AR1and R2taken together, represent an optionally substituted piperazine-1-yl (SS), where z is 1 and R4is-COR'.

According to another embodiments x is 1 and R3is in position 6 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3or-CN. According to the following embodiments x is 1 and R3is in position 7 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3or-CN. According to another embodiments x is 1 and R3is in position 6 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3or-OCH2CH3. According to the following embodiments x is a small town which defaults to 1 and R 3is in position 7 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3or-OCH2CH3. According to other embodiments x is 1 and R3is in position 6 chineselanguage ring and is-CON(R')2or NRCOR'. According to other embodiments x is 1 and R3is in position 7 chineselanguage ring and is-CON(R')2or NRCOR'. According to other embodiments, R5Arepresents Cl, F, CF3, Me, Et, -OH, -OCH3, -OCH2CH3. According to other embodiments y is 0, q is 1 and R5ais F. According to another embodiments is 0, q is 1 and R5ais OR'. According to the following embodiments is 0, q is 1 and R5ais HE. According to other embodiments y is 0, q is 2 and one R5arepresents OR', and the other of R5ais F. According to the following embodiments y is 0, q is 2 and one R5ais HE, and the other of R5ais F.

In some embodiments for compounds directly above:

a) su1is:

or R1and R2represent each Nezavisimosti substituted C 1-4aliphatic group and each is independently selected from optionally substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)co2CH3, (CH2)2Och3CH2(CO)co2CH3CH2(CO)co3CH(CH3)CH2CH3or n-butyl;

b) z is 0-5 and R4groups are each independently Cl, Br, F, CF3CH3, -CH2CH3CN, -COOH, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -CH2OH, -NHCOCH3, -SO2NH2, -SO2(CH2)3CH3, -SO2CH(CH3)2, -SO2N(CH3)2, -SO2CH2CH3, -C(O)och2CH(CH3)2, -C(O)NHCH2CH(CH3)2, -NHCOOCH3, -C(O)C(CH3)3, -COO - (CH2)2CH3-C(O)NHCH(CH3)2, -C(O)CH2CH3or an optionally substituted group selected from piperidinyl, piperazinil, morpholino,1-4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CH2of cyclohexyl, pyridyl, -CH2pyridyl or-CH2thiazolyl;

C) x is 0, 1 or 2, and each R3is independently Cl, Br, F, CF3, -OCF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2N(iPr)2, -O(CH2)2OCH3, -CONH2, COOCH 3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -NHCOCH(CH3)2, -SO2NH2, -CONH(cyclopropyl), -CONHCH3, -CNHCH2CH3or an optionally substituted group selected from piperidinyl, piperazinil, morpholino, phenyl, phenyloxy, benzyl or benzyloxy;

d) y is 0-5, R5groups, when they are present, each independently represents Cl, Br, F, CF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -SO2NH2, -SO2NHC(CH3)2, -OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-piperazine-1-yl, OCOCH(CH3)2, OCO(cyclopentyl), -COCH3not necessarily replaced phenoxy or optionally substituted benzyloxy and

e) R5arepresents Cl, F, CF3, Me, Et, -OH, -OCH3, -OCH2CH3, -CH2OH, -SO2NH2, -SO2NHC(CH3)2, OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-piperazine-1-yl, OCOCH(CH3)2, OCO(cyclopentyl) or-COCH3.

According to other embodiments for compounds directly above, x is 1 and R3is in position 6 chinasol the new ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3or-CN. According to other embodiments x is 1 and R3is in position 7 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3or-CN. According to another embodiments x is 1 and R3is in position 6 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3or-OCH2CH3. According to another embodiments x is 1 and R3is in position 7 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3or-OCH2CH3. According to the following embodiments x is 1 and R3is in position 6 chineselanguage ring and is-CON(R')2or NRCOR'. According to the following embodiments x is 1 and R3is in position 7 chineselanguage ring and is-CON(R')2or NRCOR'. According to other embodiments, R5Arepresents Cl, F, CF3, Me, Et, -OH, -OCH3, -OCH2CH3. According to other embodiments y is 0, q is 1, and R5arepresents the t F. According to other embodiments y is 0, q is 1 and R5ais OR'. According to other embodiments y is 0, q is 1 and R5ais HE. According to another embodiments is 0, q is 2 and one R5arepresents OR', and the other of R5ais F. According to another embodiments is 0, q is 2 and one R5ais HE, and the other of R5ais F.

For compounds that are described in General in this section above, it is noted that the compounds are useful as inhibitors of ion channels, preferably potentialization sodium channel and calcium channel N-type. In some examples of embodiments of the compounds of the invention are useful as inhibitors of NaV1.8. According to other embodiments of the compounds of the invention are useful as inhibitors of NaV1.8 and CaV2.2. In other embodiments of the compounds of the invention are useful as inhibitors of CaV2.2. According to another embodiments of the compounds of the invention are useful as dual inhibitors of NaV1.8 and TTX-sensitive ion channels, such as NaV1.3 or NaV1.7.

V. the compounds of formula I-B-i:

or their pharmaceutically acceptable salt,

where the group R1selected from C1-6aliphatic group, Cy1where Cysup> 1represents a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms selected independently from nitrogen, oxygen, or sulfur, or represents a 3-12-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, where Cy1linked directly to the nitrogen atom, or linked via optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by a group-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, -SO2NR - or-NRSO2-; where R1is optionally substituted at one or more substitutable carbon atoms, nitrogen or sulfur number z are independent substituents R4where z is 0-5;

x is 0-4;

is 0-4;

each of R3, R4and R5is independently Q-RXwhere Q represents a bond or represents C1-C6alkylidene chain, where up to two non-adjacent methylene units of the group Q are optionally and independently replaced by groups-NR-, -S-, -O-, -CS-CO2-, -OCO-, -CO-, -COCO-, -CONR-, -NRCO-, -NRCO2, -SO2NR-, -NRSO2-, -CONRNR-, -NRCONR-, -OCONR-, -NRNR-, -NRSO2NR-, -SO-, -SO2-, -PO-, -PO2-, -OP(O)(OR)-, or-POR-, and each of RXindependently selected from-R' =O, =NR', - halogen, -NO2, -CN, -OR', -SR', -N(R')2, -NR'r COR', -NR'r CON(R')2, -NR'r CO2R', -COR', -CO2R', -OCOR', -CON(R')2, -OCON(R')2, -SOR', -SO2R', -SO2N(R')2, -NR'r SO2R', -NR'r SO2N(R')2, -COCOR', -COCH2COR', -OP(O)(OR')2, -P(O)(OR')2, -OP(O)2OR', -P(O)2OR', -PO(R')2or-OPO(R')2;

each of R5ais independently optionally substituted C1-C6aliphatic group, halogen, -OR', -SR', -N(R')2, -NR'r COR', -NR'r CON(R')2, -NR'r CO2R', -COR', -CO2R', -OCOR', -CON(R')2, -OCON(R')2, -SOR', -SO2R', -SO2N(R')2, -NR'r SO2R', -NR'r SO2N(R')2, -COCOR', -COCH2COR', -OP(O)(OR')2, -P(O)(OR')2, -OP(O)2OR', -P(O)2OR', -PO(R')2or-OPO(R')2and

each R is independently hydrogen or optionally substituted C1-6aliphatic group and each R' is independently hydrogen or optionally substituted C1-6aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or R and R', two of R, or two of R'taken the place with the atom(s), to which they are attached, form a optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

For connections, directly above, in some embodiments:

a) when R5ais Me, Cl, or OMe, and x is 0, then R1is not Et, or Me;

b) when R5ais Cl, x is 3 and three position R3are 6-Me, 7-t and 8 IU, then R1does not represent -(CH2)2piperidine-1-yl;

(C) when R5ais Me, x is 1 and R3is NO2then R1is not Et;

d) when R5ais OH, NHMe or N(NO)IU and x is 0, then R1is not Et or IU or-CH2CH=CH2;

e) when R5arepresents NH2and x is 0, then R1not is-COCH3;

f) when R5ais Cl or Me and u represents 0 or 1 and y is 1, R5is 4-Cl and x is 0, then R1is not 4-CN-phenyl, 4-Me-phenyl, 4-OMe-phenyl, 4-Cl-phenyl, 4-NO2-phenyl, -CH2CH2NHMe, Et, Me, 4-COOMe-phenyl, -CH2Ph, iPr, 2-Me-phenyl, 4-phenyl-phenyl or-CH2CH=CH2.

In kotoryj other embodiments for compounds directly above:

a) R1chosen from:

i) Cy1where Cy1linked directly to the nitrogen atom, or linked via optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by a group-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, SO2NR - or-NRSO2-; or

ii) optionally substituted C1-4aliphatic group, where one or more methylene units in the C1-4the aliphatic group is optionally replaced by a group-NR-, -O-, -COO -,- OCO-, -NRCO-, -CONR-, SO2NR - or-NRSO2-.

In some embodiments for compounds directly above, su1is:

In other embodiments, R1is-CHR-Cy1where R represents hydrogen or

With1-C4alkyl and su1is:

In still some other embodiments, R1is optionally substituted

With1-C4aliphatic group and each is independently selected from optionally substituted methyl, ethyl, cyclopropane, n-through propenyloxy, cyclobutyl, (CO)co2CH3, (CH2)2Och3CH2(CO)co2CH3CH2(CO)co3 CH(CH3)CH2CH3or n-butilkoi group.

In other embodiments z is 0-5 and R4groups, when they are present, each independently represents halogen, CN, NO2, -N(R')2CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -COOR', -NRCOR', -CON(R')2, -OCON(R')2, -COR', -NHCOOR', -SO2R', -SO2N(R')2or an optionally substituted group selected from C1-C6aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocyclizations group, arils1-C6of alkyl, heteroaryl1-C6of alkyl, cycloaliphatic1-C6the alkyl or geterotsiklicheskikh1-C6the alkyl.

In some embodiments z is 0-5 and R4groups, each independently represents Cl, Br, F, CF3CH3, -CH2CH3CN, -COOH, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -CH2OH, -NHCOCH3, -SO2NH2, -SO2(CH2)3CH3, -SO2CH(CH3)2, -SO2N(CH3)2, -SO2CH2CH3, -C(O)och2CH(CH3)2, -C(O)NHCH2CH(CH3)2, -NHCOOCH3, -C(O)C(CH3)3, -COO - (CH2)2CH3-C(O)NHCH(CH3)2, -C(O)CH2CH3or an optionally substituted group of wybrand the Yu from piperidinyl, the piperazinil, morpholino,1-4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, CH2of cyclohexyl, pyridyl, -CH2pyridyl or-CH2thiazolyl.

In other embodiments, R3the group is halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -COOR', -NRCOR', -CON(R')2, -OCON(R')2, -COR', -NHCOOR', -SO2R', -SO2N(R')2or an optionally substituted group selected from C1-C6aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocyclizations group, arils1-C6of alkyl, heteroaryl1-C6of alkyl, cycloaliphatic1-C6the alkyl or geterotsiklicheskikh1-C6the alkyl.

In some embodiments, R3represents Cl, Br, F, CF3, -OCF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -NHCOCH(CH3)2, -SO2NH2, CONH(cyclopropyl), -CONHCH3, -CNHCH2CH3or an optionally substituted group selected from piperidinyl, piperazinil, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.

In the following embodiments, R3the group is halogen, CN, optionally substituted C1-C6al the sludge, OR', N(R')2, CON(R')2or NRCOR'. In the following embodiments, R3is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3or-CN. In the following embodiments, R3is in position 6 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3or-CN. In the following embodiments, R3is in position 7 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3or-CN. In the following embodiments, R3is in position 6 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3or-OCH2CH3. In other embodiments, R3is in position 7 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3or-OCH2CH3. In other embodiments, R3is in position 6 chineselanguage ring and is-CON(R')2or NRCOR'. In other embodiments, R3is in position 7 chineselanguage rings and depict the defaults-CON(R') 2or NRCOR'.

In some embodiments for compounds described directly above, y is 0-5, q is 0-2, and R5and R5Agroups, when they are present, are each independently halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -NRCOR', -CON(R')2, S(O)2N(R')2, -OCOR', -COR', -CO2R', -OCON(R')2, -NR'r SO2R', -OP(O)(OR')2, -P(O)(OR')2, -OP(O)2OR', -P(O)2OR', -PO(R')2, -OPO(R')2or an optionally substituted group selected from C1-C6aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocyclizations group, arils1-C6of alkyl, heteroaryl1-C6of alkyl, cycloaliphatic1-C6the alkyl or geterotsiklicheskikh1-C6the alkyl.

In some embodiments y is 0-5, q is 1 or 2 and each R5Ais independently Cl, Br, F, CF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -SO2NH2, -SO2NHC(CH3)2, -OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-piperazine-1-yl, OCOCH(CH3)2, OCO(Cyclops is ncil), -COCH3not necessarily replaced phenoxy or optionally substituted benzyloxy.

In the following embodiments is 0, R5ais F. In other embodiments y is 0, q is 1 and R5ais OR'. In still some other embodiments y is 0, q is 1 and R5ais HE. In some embodiments y is 1, R5arepresents OR', and R5is F, where'OR' is substituted in position 2 of the phenyl ring and F is substituted in the 6 position of the phenyl ring. In some embodiments y is 0, q is 1, R5ais HE and R5is F, where IT is substituted in position 2 of the phenyl ring and F is substituted in the 6 position of the phenyl ring.

For compounds that are described in General in this section above, it is noted that the compounds are useful as inhibitors of ion channels, preferably potentialization sodium channel and calcium channel N-type. In some examples of embodiments of the compounds of the invention are useful as inhibitors of NaV1.8. According to other embodiments of the compounds of the invention are useful as inhibitors of NaV1.8 and CaV2.2. In still other embodiments of the compounds of the invention are useful as inhibitors of CaV2.2. According to another embodiments of the soybean is inane of the invention are useful as dual inhibitors of NaV1.8 and TTX-sensitive ion channels, such as NaV1.3 or NaV1.7.

Typical examples of the compounds as described herein and above set forth below in table 2 (see end of description).

4. General methodology for the synthesis of:

The compounds of this invention can be obtained mainly by methods known in this area for similar compounds, as shown in the outline below and the preparative examples that follow.

The diagram below shows the General conditions for the synthesis of compounds of the formulaIAwhere X represents NR2. Basically, a useful intermediate compound iii may be obtained by condensation of benzoyl chloride with anthranilamide.

Scheme A:

The reaction of compounds i and ii (stage a) using K2CO3and simple ether boiling under reflux and subsequent treatment with 5% aqueous NaOH at boiling under reflux gives the intermediate compound iii. Reaction of intermediate iii with POCl3to obtain 4-chlorinated and subsequent interaction with (i) N,N-dimethylaniline in benzene at boiling under reflux; (ii) BBr3CH2Cl2at-78ºC and (iii) R1R2NH in a mixture of THF/CH2Cl2at room temperature gives the desired productIA.

Scheme:

The scheme shows an alternative synthesis of DL the compounds of the formula IA:

The reaction of compounds i and ii (stage a) using triethylamine and 1,4-dioxane in the environment gives the intermediate compound iii. The reaction mixture of intermediate compound iii (stage b) with 0.5m solution of ammonia in 1,4-dioxane, triethylamine, and a reagent THIEF stirred at ambient temperature for 16 hours, giving an intermediate compound iv. Processing the intermediate iv 5% aqueous NaOH at boiling under reflux gives intermediate compound v. Processing the intermediate v POCl3to obtain 4-chlorinated and subsequent interaction with (i) N,N-dimethylaniline in benzene at boiling under reflux; (ii) BBr3CH2Cl2at-78ºC and (iii) R1R2NH in a mixture of THF/CH2Cl2at room temperature gives the desired productIA.

Scheme:

The reaction of compounds i and ii (stage a) using pyridine gives the intermediate compound iii. Treatment of the intermediate compound iii 5% aqueous NaOH at boiling under reflux gives the intermediate compound iv. The reaction of the intermediate compound iv with POCl3to obtain 4-chlorinated and subsequent interaction with (i) N,N-dimethylaniline in benzene PR is boiling under reflux; ii) BBr3CH2Cl2at-78ºC and (iii) R1R2NH in a mixture of THF/CH2Cl2at room temperature gives the desired productIA.

Schemes D and E below show the synthesis of a variety of useful anthranilamide.

Scheme D:

The reaction of compound i (stage a) chloralhydrate in the presence of hydroxylamine hydrochloride gives the isatin ii. Treatment of compound ii basic hydrogen peroxide gives compound iii (stage b), as shown in scheme D.

Scheme E:

The reaction of compound i (stage a) with BOC anhydride gives compound ii. Subsequent substitution of the metal hydrogen attached to the carbon atom of the compound (ii), using utility at low temperature, and interaction with CO2gives the N-protected Anthranilic acid (stage b). Removal of BOC using TFA (triperoxonane acid) gives Anthranilic acid iii as shown in scheme E.

Scheme F:

The reaction Satinover anhydride i (stage a) with an aqueous ammonium hydroxide gives compound ii, as shown in scheme F.

Scheme G:

Stage A.

i) treating compound i Asón and N in aqueous medium at a temperature from 0 ° C to room temperature for 24 hours and posledowatel with ii) NaOH, followed by acidification with hydrochloric acid gives the intermediate compound ii (stage b). Treatment of compound ii POCl3and triethylamine in boiling under reflux gives the intermediate compound iii (stage C). Treatment of compound iii Mr1R2NH in a mixture of THF/CH2Cl2at a temperature from 0 ° C to room temperature to give the intermediate compound iv.

Scheme H:

Reaction of intermediate compound i (stage a) with POCl3gives 2,4-dichloropropane ii. Reaction of the intermediate compound ii (stage b) with R1-NH-R2and Et3N in CH2Cl2gives the amine iii. Reaction of the intermediate compound iii (stage C) with the NH - containing heterocycle, NaH and THF leads to compound iv. Reaction of the intermediate compound iii (stage d) with LiHMDS, Pd2(dba)3, 2-(DICYCLOHEXYL)fosinoprilat and THF gives the diamine v. The reaction of the intermediate compound v (stage e) with substituted 2,5-dimethoxytetrahydrofuran in Asón gives compound vi. The reaction of the intermediate compound v (stage f) with lCO-CH2-(CH2)n-CH2-Cl, Et3N and p-dioxane gives compound vii. Reaction of the intermediate compound iii (stage g) with a cyclic anhydride and p-dioxane leads to the compound viii.

Scheme I:

Reaction of intermediate compound i (stage a) with POCl3and the subsequent processing BBr3CH2Cl2PR is-78º gives 4-chlorinated ii. Reaction of the intermediate compound ii (stage b) with R'-NH-R2-X(R')H and Et3N in CH2Cl2gives compound iii. The reaction of the intermediate compound iii (stage C) with R N(R")X-SO2Cl and Et3N in CH2Cl2produces compound iv. Reaction of the intermediate compound iii (stage d) with R'-SO2Cl and Et3N in CH2Cl2network connection v. Reaction of the intermediate compound iii (stage e) with R'-CO2Cl and Et3N in CH2Cl2or with phosgene, and R'(R")XH forms a connection vi. Reaction of the intermediate compound iii (stage f) with R COCl and Et3N in CH2Cl2gives compound vii. Reaction of the intermediate compound iii (stage g) with electrophiles in the presence of Et3N (organic halide of the electrophiles) or NaBH(OAc)3(aldehyde or ketone electrophiles) gives compound viii.

Scheme J:

The interaction of compounds i and ii in dichloromethane under microwave irradiation at 150 º C gives the product iii.

Scheme K:

Conditions: (a) for M=Li: sec-BuLi, TMEDA, THF, -78º; for M=ZnX: i. sec-BuLi, TMEDA, THF, -78º; ii. ZnCl2; for M=MgX: Mg, THF, boiling under reflux. (b) i. RSSR; ii. H2O2(n=1) or KMnO4(n=2). (c) R1R2C=O, THF,- 78º to room temperature. (d) CO2, THF,- 78º to room temperature.(e) for R 1=H: R2NCO; other: R1R2COCl, THF. (f) i. H2C=O; ii. PBr3iii. R1R2NH. (g) Het-OTf, Ni(acac)2, PPh3, MeMgBr, THF, room temperature. (h) i. B(OMe)3; ii. ArX (X=halogen), Pd(PPh3)4, NaOEt, toluene, 80. (i) i. SOCl2CH2Cl2; ii. R1Sn(R)3Pd(PPh3)4, toluene; iii. R1MgX, THF. (j) i. SOCl2CH2Cl2; ii. R1R2NH, THF. (k) LiAlH4, THF.

Scheme L:

Conditions: (a) for M=Li: sec-BuLi, TMEDA, THF, -78º; for M=ZnX: i. sec-BuLi, TMEDA, THF, -78º; ii. ZnCl2; for M=MgX: Mg, THF, boiling under reflux. (b) i. RSSR; ii. H2O2(n=1) or KMnO4(n=2). (c) R1R2C=O, THF,- 78º to room temperature. (d) CO2, THF,- 78º to room temperature. (e) For R1=H: R2NCO; other: R1R2COCl, THF. (f) i. H2C=O; ii. PBr3iii. R1R2NH. (g) Het-OTf, Ni(acac)2, PPh3, MeMgBr, THF, room temperature. (h) For R1=aryl:

i. B(OMe)3; ii. ArX (X=halogen), Pd(PPh3)4, NaOEt, toluene, 80. For R1=alkyl R1I, THF,- 78º to room temperature. (i) i. SOCl2CH2Cl2; ii. R1Sn(R)3Pd(PPh3)4, toluene; iii. R2MgX, THF. (j) i. SOCl2CH2Cl2; ii. R1R2NH, THF. (k) LiAlH4, THF. (l) ArXB(OR)2Pd(PPh3)4, NaOEt, toluene, 80.

Scheme M:

Treatment of compound i with compound ii using catalytic palladium (stage a)

Pd(dppf)Cl2, KOAc in DMSO or DMF at 84º within 2-6 hours gives the intermediate compound iii. Reaction of the intermediate compound iii to compound iv using conditions catalyzed by palladium cross-combinations (stage b) Pd(dppf)Cl2or (Ph3P)4Pd, K2CO3, DMF:H2O (4:1) under microwave irradiation at 170º within 6 minutes gives compound v.

Scheme N:

Treatment of compound i of tert-butyllithium at 78º followed by the addition of solid CO2and heated to room temperature to give carboxylate compound ii. The carboxylate in the compound ii can be saved or used for the characteristic reactions of functional groups.

Scheme O:

Catalyzed by palladium cross-combination of compound i with an appropriate amine in toluene (80 ° C) gives compound ii.

Scheme P:

a) Dienzenhofer, DMAP, DIEA, CCl4CH3CN, from 0 ° C to room temperature; (b) TMSBr, CH2Cl2at room temperature; (c) H2Pd/C, MeOH; (d) NaOMe, MeOH, at room temperature.

Conditions: (a) R4COCl, pyridine, CH2Cl2, 0ºC, then at room temperature.

Scheme Q:

The reaction of compound i with compound IIA or iib (stage a), treatment with triethylamine in a mixture of THF/CH2Cl2at room temperature gives compound iii and v, respectively. Treatment of compound iii (stage b) (i) NaH in THF at 0OC, then interaction with electrophiles at from 0 ° C to room temperature gives compound iv.

Although some embodiment examples shown and described herein above, it should be noted that the compounds of the invention can be obtained in accordance with the methods described generally above using appropriate starting compounds, and in accordance with methods known in this field. For example, in some embodiments, the compounds as described herein, in which R1is hydrogen and R2is pyrazolyl, procedures, examples, and connections can be found in WO 02/22607, WO 02/22604, WO 02/066461, WO 02/22601, WO 02/22603, WO 02/22608, WO 02/22605 or WO 02/22602.

5. Application-ready form and introduction

Pharmaceutically acceptable composition

As described above, the present invention provides compounds that are inhibitors potentialization sodium ion channels and/or calcium to the channels, and thus the present compounds are useful for treating diseases, disorders and conditions, including, not limited to the above, acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, trigeminal neuralgia, neuralgia when shingles, General neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, and incontinence. Accordingly, according to another aspect of the present invention provides pharmaceutically acceptable compositions, and these compositions include any of the compounds described herein, and optionally include a pharmaceutically acceptable carrier, adjuvant or the migration tool. According to some embodiments of these compositions optionally further comprise one or more additional therapeutic agents.

Obviously, it is also clear that some of the compounds of the present invention can exist in free form for treatment, or where appropriate, in the form of their pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable manufacturers the data include, but not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative which, after administration to a patient who needs it, is able to give, directly or indirectly, a compound described herein otherwise, or a metabolite or residue.

Used here, the term “pharmaceutically acceptable salt” refers to those salts which are, according to medical recognition, are suitable for use in contact with the tissues of humans or lower animals without undue toxicity, irritation, allergic response, and similar reactions and commensurate with a reasonable benefit ratio or risk-to-benefit. “Pharmaceutically acceptable salt” means any non-toxic salt or salt of ester compounds of the present invention, which after administration to the recipient is able to give, either directly or indirectly, a compound of this invention or inhibitore active metabolite or residue. Used herein, the term “inhibitore active metabolite or residue” means that a metabolite or residue also is an inhibitor potentialization channels ions of sodium or calcium channels.

Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe in detail the FA is matemticas acceptable salt in J. Pharmaceutical Sciences,1977, 66, 1-19, introduced here for information. Pharmaceutically acceptable salts of the compounds of this invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid additive salts are salts of an amino group derived from inorganic acids such as hydrochloric acid, Hydrobromic, phosphoric, sulfuric, Perlina acid, or with organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, bansilalpet, benzoate, bisulfate, borate, butyrate, comfort, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulphate, aconsultant, formate, fumarate, glucoheptonate, glycerol, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonic, lactobionate, lactate, laurate, lauryl, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, sulfate,tartrate, thiocyanate, p-toluensulfonate, undecanoate, welaratna salt and similar. Salts, derivatives of the respective bases include salts of alkali metals, alkaline earth metals, ammonium and

N+(C1-4alkyl)4the salt. This invention also covers the quaternization of any containing basic nitrogen groups of compounds described herein. This quaternization can be obtained water - or oil-soluble or dispersible products. Typical representatives of salts of alkali and alkaline earth metals include sodium, lithium, potassium, calcium, magnesium and similar. Further pharmaceutically acceptable salts include, when it meets, non-toxic ammonium, Quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate and arylsulfonate.

As described above, the pharmaceutically acceptable compositions of the present invention optionally include a pharmaceutically acceptable carrier, adjuvant or vehicle, which, as it is used herein, includes any and all solvents, diluents, or other liquid funds auxiliary dispersion or suspension agents, surface-active agents, isotonic agents, thickening or among the dominant agents preservative agents, solid binders, lubricating agents and similar that are appropriate for your desired dosing form. In Remington''s Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co, Easton, Pa., 1980) discloses various carriers used in the preparation of pharmaceutically acceptable compositions and known techniques for getting them. Except when any of the media environment is incompatible with the compounds of the invention, such as obtaining undesirable biological effect or otherwise interacting deleterious manner with any other component(s) of pharmaceutically acceptable compositions, it is understood that its use is covered by the scope of the invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, or alumina, aluminum stearate, lecithin, serum proteins, such as albumin human serum, buffer substances such as phosphates, glycine, sorbic acid or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as preteenslut, sour centripetal, acid potassium phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidon is he, the polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches, such as corn and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragakant; malt; gelatin; talc; excipients, such as cocoa butter and suppozitornyj waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols, such as propylene glycol or polyethylene glycol; esters, such as etiloleat and tillaart; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; free from pyrogens water; isotonic saline; ringer's solution; ethyl alcohol and phosphate buffer solutions, as well as other non-toxic compatible lubricants agents, such as sodium lauryl sulfate and magnesium stearate, as well as tinted agents, agents that promote the release, coating agents, sweetening, flavoring and aromatic agents, preserving agents, and antioxidants can also be present in compositions according to the judgment of a pharmacist.

The use of compounds and pharmaceutically acceptable compositions

According to the school one aspect is provided a method of treating or reducing the severity of acute, chronic, neuropathic, or inflammatory pain, arthritis, migraines, trigeminal neuralgia, herpetic neuralgia, General neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, post herpetic neuralgia, diabetic neuropathy, root pain, ishialgii, back pain, head or neck pain, severe or resistant pain, nociceptive pain, pain in the tearing of the tissues, surgical pain, or cancer pain, including the introduction of an effective amount of a compound or pharmaceutically acceptable composition comprising the compound, to a subject in need of it. In some embodiments seems to be a method of treating or reducing the severity of acute, chronic or inflammatory pain, comprising introducing an effective amount of a compound or pharmaceutically acceptable composition to a subject in need of it. In some other embodiments presented a method of treating or reducing the severity of root pain, ishialgii, spinal pain, headaches or neck pain, including the introduction of effective the active amount of the compound or pharmaceutically acceptable composition to a subject, who needs this. In still some other embodiments presented a method of treating or reducing the severity severe or intractable pain, acute pain, surgical pain, back pain, or cancer pain, comprising introducing an effective amount of a compound or pharmaceutically acceptable composition to a subject in need of it.

According to some embodiments of the present invention an “effective amount” of a compound or pharmaceutically acceptable composition is that amount effective for treating or reducing the severity of one or more of acute, chronic, neuropathic, or inflammatory pain, arthritis, migraines, trigeminal neuralgia, herpetic neuralgia, General neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, post herpetic neuralgia, diabetic neuropathy, root pain, ishialgii, back pain, head or neck pain, severe or resistant pain, nociceptive pain, pain in the tearing of the tissues, surgical pain, or cancer pain.

Connected to the I and the compositions according to the method of the present invention may be administered using any amount and any route of administration effective for treating or reducing the severity of one or more acute chronic, neuropathic, or inflammatory pain, arthritis, migraines, trigeminal neuralgia, herpetic neuralgia, General neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, post herpetic neuralgia, diabetic neuropathy, root pain, ishialgii, back pain, head or neck pain, severe or resistant pain, nociceptive pain, pain in the tearing of the tissues, surgical pain, or cancer pain. The exact quantity required will vary from subject to subject, depending on the species, age and General condition of the subject, the severity of the disease, the particular agent, its mode of administration and similar factors. Compounds of the invention preferably are formed in the form of dosage units or single doses for ease of administration and uniformity of dosage. The expression “dosage form units or unit dose”as used here, refers to a physically discrete unit agent, suitable for being treated patient. It should be clear, however, that the total daily until the and use of the compounds and compositions of the present invention is established by the attending physician taking into account the well-known judgment of physicians. The specific effective dose for any particular patient or organism depends on a wide variety of factors, including being treated with the disorder, the severity of the disorder, specifically applied active connection; used concrete composition; the age, body weight, General health, sex and diet of the patient; the time of administration, route of administration and the degree of excretion specifically applied composition; the duration of the treatment; drugs used in combination or simultaneously with specifically used by the connection, and similar factors well known in medicine. The term “patient”as used here, means an animal, preferably a mammal, and most preferably human.

Pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intrawaginalno, intraperitoneally, topically (e.g., using powders, ointments or drops), buccal, in the form of an oral or nasal sprays or similar, depending on the severity of the exposed treatment of infection. According to some embodiments of the compounds of the invention can be administered orally or parenterally at dosage levels of about 0.01 mg/kg to 50 mg/kg and preferably from about 1 mg/kg to 25 mg/kg weight of the body of the subject per day, one or more times a day, to obtain the desired therapeutic effect.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, ground nut, maize, butter germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, glycols and sorbitane esters of fatty acids, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspendresume agents, sweeteners, flavoring and aromatic agents.

Injectable preparations, for example sterile injectable aqueous or oily suspensions may prigotavlivaetsya in accordance with known methods using suitable dispersing or wetting agent and suspendida agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example in the form of a solution in 1,3-butanediol. Among the eligible funds transfer and solvents that can be used are water, ringer's solution, U.S.. and isotonic sodium chloride solution. In addition, as a solvent or suspendida environment usually apply sterile, fixed oils. For this purpose you can use any fresh fixed oils, including synthetic mono - or diglycerides. In addition, in the preparation of injectable compositions use fatty acids such as oleic acid.

Injectable forms that can be sterilized, for example, by filtration through a bacteriostatic filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can before use to dissolve or dispergirujutsja in sterile water or other sterile injectable medium.

In order to extend the action of the compounds of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with PLO the Oh water. The speed of absorption of connection depends then on its degree of solubility, which, in turn, may depend upon crystal size and crystalline form. Alternative delayed absorption form input parenteral connection is achieved by dissolving or suspendirovanie compounds in the oil medium. Injectable forms are made by forming microencapsulating matrix compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of the compounds and polymers and the nature of the applied specifically to the polymer may be regulated by the rate of release of connection. Examples of other biodegradable polymers include complex poly(orthoevra) and poly(anhydrides). Injectable forms ready to store prepared also by capturing the connection liposomes or microemulsions that are compatible with body tissues.

Compositions for rectal or vaginal injection are preferably suppositories which can be obtained by mixing the compounds of this invention with suitable non-irritating with excipients or carriers such as cocoa butter, polyethylene glycol or suppozitornyj wax, which are solid at ambient temperature but liquid at body temperature and therefore melt in the nternet the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia, c) humectants such as glycerol, d) dezinfeciruyuhimi agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) agents, retarding dissolution such as paraffin, f) absorption accelerators such as Quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite compounds, preventing clay, and i) lubricating agents such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills dosage form may also include buferiruemoi agents.

Solid compositions of a similar tipout also be used as fillers in soft and hard filled gelatin capsules using such excipients, as lactose or milk sugar, as well as polyethylene glycols of high molecular weight and similar. Solid dosage forms of tablets, pills, capsules, pills and granules can be prepared with coatings and shells, such as enterococci coatings and other coatings well known in the field of machinery manufacture of finished pharmaceutical forms. They may not necessarily contain fogging agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, it is not necessarily slow. Examples of embedding compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar, as well as polyethylene glycols of high molecular weight and similar.

The active compounds can also be in microencapsulating form with one or more excipients as noted above. Solid dosage forms of tablets, pills, capsules, pills and granules can be prepared with coatings and shells, such as enterococci cover, cover, control release, and other coating is, well-known in the field of machinery manufacture of finished pharmaceutical forms. In such solid dosage forms the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms can also include, as a normal practice, additional substances other than inert diluents, for example tabletiruemye lubricating agents and other tabletiruemye vspomogatelnymi tools such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills dosage forms may also include buferiruemoi agents. They may not necessarily contain fogging agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, it is not necessarily slow. Examples of embedding compositions which can be used include polymeric substances and waxes.

Dosage forms for local or transdermal injection of the compounds of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants funds or bandages. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed conservera the relevant agents or buffers, if you may need. The ophthalmic form of ear drops and eye drops are also provided in the scope of this invention. In addition to described the present invention encompasses the use of transdermal bandages, which have the added advantage of providing controlled delivery of the compound into the body. Such dosage forms are prepared by dissolving or dispersing the compound in an appropriate environment. Can also be used amplifiers absorption to increase the flow connection on the skin. The degree can be adjusted or the provision regulating the speed of the membrane or by dispersing the compound in a polymer matrix or gel.

As described in General above, the compounds of the invention are useful as inhibitors potentialization sodium ion channels or calcium channels, preferably calcium channel N-type. According to one embodiment of the compounds and compositions of the invention are inhibitors of one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or V2.2 and, thus, without regard to any particular theory, the compounds and compositions are particularly useful for treating or reducing the severity of the disease, condition or disorder, when in the disease, condition or disorder involved the Jena activation or hyperactivity of one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or aV2.2. When a specific disease, condition, or disorder implicated activation or hyperactivity of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or aV2.2, the disease, condition, or disorder may also be referred to as “NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, or NaV1.9-mediated disease, condition or disorder” or “V2.2-mediated disease, condition or disorder”. Accordingly, according to another aspect of the present invention provides a method of treating or reducing the severity of the disease, condition or disorder, when in this state of the disease involved the activation or hyperactivity of one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or aV2.2.

The potency of the compound used in this invention as an inhibitor of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or aV2.2, can be estimated in accordance with the methods described in General here in the examples, or in accordance with the methods available to the average person skilled in the field.

According to some examples of embodiments of the compounds of the invention are useful as inhibitors of NaV1.8. According to other embodiments of the compounds of the invention are useful as inhibitors of NaV1.8 and aV2.2. According to other embodiments of the compounds from which retene are useful as inhibitors aV2.2. According to another embodiments of the compounds of the invention are useful as dual inhibitors of NaV1.8 and TTX-sensitive ion channels, such as NaV1.3 and NaV1.7.

Obviously it is also clear that the compounds and pharmaceutically acceptable kompoziziii of the present invention can be used in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be administered concurrently, before or after one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutic agents or procedures) in combination mode, you should consider taking into account compatibility of the desired therapeutics and/or procedures and achieved the desired therapeutic effect. Obviously it is also clear that the methods used for therapy can achieve desired effect for the same disorder (for example, the compound of the invention can be administered concurrently with another agent for treatment of the same disorder), or they may achieve different effects (e.g., control of any adverse action). As they are used herein, additional therapeutic agents, which typically are administered to treat, cure or prevent any specific disease or condition, known as “suitable or appropriate on the I being treated disease or condition”. For example, examples of additional therapeutic agents include, but are not limited to, non-opioids (indoles, such as etodolac, indomethacin, sulindac, tolmetin; naphtylamine, such as nabumeton; oxicam such as piroxicam; para-aminophenol derivatives such as acetaminophen; propionic acids such as fenoprofen, flurbiprofen, ibuprofen, Ketoprofen, naproxen, naproxen sodium, oxaprozin; the salicylates, such as aspirin, choline-magnesium-trisalicylate, diflunisal; fenamate, such as meclofenamic acid, mefenamovaya acid; pyrazoles such as phenylbutazone) or opioid (narcotic) agonists (such as codeine, fentanyl, hydromorphone, Levorphanol, meperidine, methadone, morphine, oxycodone, Oxymorphone, propoksifen, buprenorphine, butorphanol, dezocine, nalbuphine and pentazocine). Additionally, in conjunction with the introduction of one or more compounds of the invention can be used non-drug pain relief techniques. For example, can also be used anesthetic (intraspinal infusion, neural blockade), neurosurgical (neurosis CNS ways), neurostimulatory (transcutaneous nerve stimulation, stimulation of the dorsal column), physiotherapy (physical therapy, orthopedic devices, diathermy) or psychological intervention (cognitive method is - hypnosis, biofeedback or behavioral methods). Additional relevant therapeutic agents or approaches described in General in The Merck Manual, the seventeenth Edition, Ed. Mark H. Beers and Robert Berkow, Merck Research Laboratories, 1999, and Food and Drug Administration website,www.fda.govthe entire content of which is included in the description for details.

The amount of additional therapeutic agent present in the compositions of the present invention is not more than the number, which is usually introduced to the composition that include therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent described are compositions will comprise from about 50% to 100% of the amount normally present in a composition comprising the agent as the sole therapeutically active agent.

The compounds of this invention or their pharmaceutically acceptable compositions can also be incorporated into compositions for coating implantable medical devices such as prostheses, artificial valves, vascular grafts, stents and catheters. Accordingly, according to another aspect of the present invention includes a composition for coating an implantable funds, including the connection of the present invention, described in General wisei in classes and subclasses herein, and a carrier suitable for coating specified implantable means. According to another aspect of the present invention includes implantable tool coated with a composition comprising the compound of the present invention, described in General above and in classes and subclasses herein, and a carrier suitable for coating specified implantable means. Suitable coatings and the General manufacture of implantable funds from the coating disclosed in U.S. patent 6099562; 5886026 and 5304121. Coatings typically are biocompatible polymeric materials, such hydrohalide polymers, polymethylsiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate and mixtures thereof. The coating can be optionally additionally coated with a suitable top coating Versiliana, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart the characteristics of a controlled release composition.

Another aspect of the invention relates to the inhibition of the activity of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or aV2.2 in a biological sample or in a patient, the method includes the introduction of the patient or for introduction to the contact specified biological sample with a compound of formula I or a composition comprising the specified connection. The term “biological clicks the set of technical documents”, used herein, includes, without limitation, cell cultures or extracts; biopsy material obtained from a mammal or extracts and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts.

The inhibition activity of one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or aV2.2 in a biological sample is useful for a wide variety of purposes known to the experts in this field. Examples of such purposes include, but are not limited to, the study of the sodium ion channels in biological and pathological phenomena and comparative evaluation of new inhibitors of sodium ion channels.

In order for the invention described herein can be more fully understood, the following examples. It should be understood that these examples are presented for illustrative purposes only and should not in any way be considered as limiting the invention.

EXAMPLES

The SYNTHESIS of COMPOUNDS of the EXAMPLES of the INVENTION

Example 1:

A 2-liter three-neck round-bottom flask, equipped with a top stirrer and reflux condenser, in 1 liter of anhydrous ether suspended anthranilamide1(20,0 g, 147 mmol) and potassium carbonate (28.4 g, 206 mmol) and was heated to boiling under reflux. It heated the reflux mixture is slowly added chloride o-anisoyl (32,5 g, 191 mmol). After 3 hours boiling under reflux the reaction mixture was allowed to cool to room temperature, ether was removed under reduced pressure, the obtained residue was filtered and washed with water. The obtained solid is then suspended in 600 ml of 5% aqueous NaOH and boiled for 1 hour. The reaction mixture was allowed to cool to room temperature, then neutralized with acetic acid, after which hintline2was deposited. The product2was filtered, washed with water and dried overnight in a vacuum, getting 27 g (73%) of pure compound2.

LC/MS (10-99%) M/Z 253,0 retention time 3,22 min;1H-NMR (DMSO)3,86 (c, 3H), to 7.09 (t, 1H), 7,18 (d, 1H), 7,53 (m, 2H), of 7.70 (m, 2H), 7,80 (m, 1H), 8,14 (d, 1H), 12,11 (c, 1H);13C-NMR (DMSO)55,75, 111,86, 120,89, 120,97, 122,74, 125,75, 126,45, 127,26, 130,41, 132,13, 134,32, 148,97, 152,48, 157,12, 161,35.

Hintline2(20,0 g, 79.3 mmol) suspended in 500 ml of anhydrous benzene in a 1-liter round-bottom flask, equipped with reflux condenser. Was added N,N-dimethylaniline (14.4 g, 119 mmol) and the reaction mixture was heated under reflux for 30 minutes in a nitrogen atmosphere. After cooling to room temperature was added oxochloride phosphorus (12.2 g, 79.3 mmol) and then the reaction mixture was heated with reverse holo is rinicom for an additional 3 hours in a nitrogen atmosphere. The mixture was cooled to room temperature, poured into ice and neutralized with saturated aqueous sodium bicarbonate solution. The solution was then extracted 4 times with toluene and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to a reddish-brown solid. The obtained 4-chlorination3was purified flash chromatography (40% hexane, 60% dichloromethane), yielding 20 g (93%)3in the form of a yellow solid.

LC/MS (40-99%) M/Z 271,4 retention time 2,49 min;

1H-NMR (CDCl3)3,89 (c, 3H), 7,06 (d, 1H), to 7.09 (d, 1H), 7,45 (m, 1H), 7,71 (m, 1H), 7,80 (m, 1H), 7,95 (m, 1H), 8,17 (d, 1H), 8.30 to (d, 1H);13C-NMR (CDCl3)56,3 (d), 112,15 (d), to 121.0 (c), 122,29 (c), 125,97 (c), 126,76 (c), 127,25 (d), 128,71 (d), 132,10 (m), 135,26 (c), 151,16 (c), 158,19 (c), 161,02 (c), 162,58 (c).

In a 500-ml dvuhgolosy round bottom flask equipped with addition funnel, under nitrogen atmosphere was loaded 4-chlorination3(5,00 g, 18.5 mmol) and 80 ml of anhydrous dichloromethane. The mixture was cooled to-78º and through the addition funnel dropwise added 92 ml of 1M trichromate boron in dichloromethane. The cooling bath was removed and the reaction mixture was left to stir for 3 hours at room temperature. Then the mixture was cooled to 0 ° C and slowly neutralized with a saturated aqueous solution of bicarbonate is the atrium, 3 times was extracted with dichloromethane, the combined organic solutions were dried over magnesium sulfate, filtered and concentrated in vacuum, obtaining a yellow solid. The residue was immediately dissolved in 30 ml of a mixture of 2:1 anhydrous THF/CH2Cl2, then was treated with a 2M solution of dimethylamine in THF (46,3 ml of 92.5 mmol). After 30 minutes the solvent was removed under reduced pressure, the residue was distributed between dichloromethane and water, the aqueous solution was extracted 4 times with dichloromethane. The combined organic solutions were dried over magnesium sulfate, filtered and concentrated in vacuo to an orange solid. Recrystallization from ethanol gave 2,61 g (53%) of yellow crystalline substance,4.

LC/MS (10-99%) M/Z 266,0 retention time at 2.59 min;1H-NMR (DMSO)3,32 (c), 3,45 (c, 6H), 6,93 (m, 2H), 7,35 (m, 1H), 7,46 (m, 1H), 7,78 (m, 2H), 8,21 (d, 1H), 8,43 (d, 1H);13C-NMR (DMSO)41,62, 113,77, 117,18, 118,25, 118,97, 124,75, 126,15, 126,51, 128,96, 132,36, 133,11, 149,09, 159,22, 160,74, 161,69.

The HCl salt:

In a 250 ml round bottom flask was loaded hinzelin4(1.0 g, 3.8 mmol), 100 ml of anhydrous ether, 11 ml of anhydrous methanol, and then the flask was closed by a membrane and placed in an ultrasonic installation with bath temperature 43º. After complete dissolution of the connection4added essential rest the p HCl (1.9 ml, 3.8 mmol), causing immediate precipitation of the connection5. The solvent was removed in vacuum, salt twice resuspendable in anhydrous ether, concentrated and dried in vacuum. After drying in vacuum over night received 1.13 g (98%) of compound5in the form of a pale yellow solid.

M/Z 266,0 retention time at 2.59 min;1H-NMR (DMSO)3,59 (c, 6H), 7,02 (m, 1H), 7,19 (d, 1H), 7,49 (m, 1H), to 7.64 (m, 1H), of 7.96 (m, 1H), with 8.05 (d, 1H), to 8.20 (d, 1H), 8,35 (d, 1H);13C-NMR (DMSO)42,37, 112,07, 117,19, 119,23, 121,09, 126,15, 127,48, 130,45, 134,01, 134,67, 155,37, 158,61, 160,97.

Example 2: Synthesis of 2-(2-methoxyphenyl)-7-trifluoromethyl-3H-hinzelin-4-it

2-(2-Methoxybenzylamine)-4-triftorperasin acid

2-Amino-4-triptoreline acid (3,84 g, 18,73 mmol) was dissolved in 30 ml of anhydrous 1,4-dioxane, followed by slow addition of chloride on anisole (3,3 ml, 24,35 mmol), then triethylamine (a 7.85 ml, 56,19 mmol) and stirred under nitrogen atmosphere at room temperature for 2 hours. The solvent was removed under reduced pressure and the organic layer was distributed between water and EtOAc, and the pH was brought to 3 with hydrochloric acid. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated to obtain not quite white solid. Allocated to 6.35 g, 100% yield. LC/MS (10-99%) M/Z 339,9, time which I hold to 3.58 min

2-(2-Methoxybenzylamine)-4-cryptomelane

2-(2-Methoxybenzylamine)-4-triftorperasin acid (? 7.04 baby mortality g, 20,77 mmol) suspended in 0.5m solution of ammonia in 1,4-dioxane (125 ml, 62,31 mmol) followed by the addition of triethylamine (5,78 ml, 41,54 mmol) and then the THIEF reagent (12 g, of 27.0 mmol), the mixture was stirred at room temperature for 16 hours. The product was isolated by vacuum filtration and washed with water. The desired product was dried in liofilizadora within 24 hours. Allocated 3.8 g in the form of a white solid. LC/MS (10-99%) M/Z 339,1, retention time of 2.93 min

2-(2-Methoxyphenyl)-7-trifluoromethyl-3H-hinzelin-4-one

2-(2-Methoxybenzylamine)-4-cryptomelane (3.8 g, 11,24 mmol) suspended in 145 ml of 5% aqueous NaOH solution, then the mixture was heated under reflux for 3 hours at 120 ºC. The reaction mixture was cooled to room temperature and the pH was brought to 4, the desired product precipitated from solution. The solid was isolated by vacuum filtration as a white solid and dried on liofilizadora within 24 hours. White solid 2.7 g, 75% yield. LC/MS (10-99%) M/Z 321,1, retention time of 3.25 minutes

Synthesis of 2-(2-Methoxyphenyl)-7-methyl-3H-hinzelin-4-it

N-(2-Qi is but-5-were)-2-methoxybenzamide

2-Amino-4-methylanthranilic (50.0 g, 378,3 mmol) was dissolved in 1 l of anhydrous pyridine and cooled to 0OC. Within 40 min was added dropwise chloride o-anisoyl (63,0 ml, 453,96 mmol), the reaction mixture was left to warm to room temperature and was stirred in nitrogen atmosphere for 16 hours. The reaction mixture was poured into 2 l of ice and the product formed precipitates. The product was isolated by vacuum filtration and dried for 3 days, was obtained the desired product in the form of flakes reddish-brown solid. Allocated 92.0 g, 91% yield. LC/MS (10-99%) M/Z 267,2, retention time 3,34 minutes

2-(2-Methoxyphenyl)-7-methyl-3H-hinzelin-4-one

N-(2-Cyano-5-were)-2-methoxybenzamide (47,0 g, 176,5 mmol) suspended in 1 l of ethanol followed by the addition of 6M aqueous NaOH (326 ml) and then 30% solution of N2About2(100 ml). The reaction mixture was heated under reflux for 3 hours, cooled to room temperature and poured into an equal volume of ice. the solution pH was brought to 3.5, and the product was precipitated from the solution. The desired product was isolated by vacuum filtration and dried in liofilizadora within 24 hours. Was allocated 22.4 g, 48% yield. LC/MS (10-99%) M/Z 267,0, retention time of 2.54 minutes

5-fluoro-4-methylaminophenol acid

2-Amino-5-fluoro-4-methylbenzoic acid

Chloral hydrate (6 g) was dissolved in 1 l of water and then added to 1 kg of Na 2SO4, 94,1 g H2NOH·HCl and 51.3 g of 4-fluoro-3-methylaniline in 250 ml of 5% aqueous HCl. The suspension was heated to boiling and kept boiling for 1 minute. After cooling to room temperature, the solid was filtered and washed twice with warm water (40ºC). The yield after drying overnight at 60 ° C in vacuum was 275 g of the substance, which was used without further purification and drying. 275 g of crude product was slowly poured into 500 ml of concentrated H2SO4at 50 º C so that the temperature remained below 75º. When you are finished adding dark purple solution was heated to 85 º C for 15 minutes. After cooling to room temperature the solution was poured into 2 l of ice water and left to stand for half an hour. The red solid was filtered and washed twice with cold water. Next, the solid was dried in vacuum at 70 º C. The output of 69.9 g (quantitatively from 4-fluoro-3-methylaniline) a mixture of two regioisomers: 5-fluoro - and 3-fluoro-3-methylisatin in a ratio of about 55:45. A mixture of satinov (69,4 g) was dissolved in 1 l of 1N. aqueous NaOH and then dropwise added to 100 ml of 30% aqueous H2About2while maintaining the temperature below 30ºC. After complete addition, the mixture was heated to 45 º C until until gas evolution ceased. The solution was cooled to room temperature, filtered and acidified ledan the th acetic acid. Formed precipitate, which was filtered, washed twice with water and dried in air at 45 º C. The output of 29.4 g of 5-fluoro-4-methylaminoethanol acid iii.

2-Amino-5-triftorperasin acid

4-(Trifluoromethyl)aniline (25 g, 0.15 mol) was dissolved in THF (275 ml), then was treated with BOC anhydride (41 g, to 0.19 mol), ET3N (19 g, to 0.19 mol) and 4-(dimethylamino)pyridine (0.1 g, 0.8 mmol). The mixture was heated under reflux for 3 hours, the solvent was removed in vacuum, the organic residue was dissolved in ethyl acetate, washed with 1M NaOH, then 1M HCl, and then dried and concentrated. The resulting product was recrystallized from heptane, receiving 39 g of the final product as a white solid. Solid (0.15 mol) was dissolved in THF (350 ml) and cooled to-78º in nitrogen atmosphere, then was treated dropwise BuLi (1.6 m in hexane, 282 ml, 0.45 mol). After 1 hour the solution was heated to 0 ° C and kept for 1.5 hours. The mixture was poured into an excess of solid CO2and was stirred over night at room temperature. After distribution against 1M HCl THF layer is evaporated and the residue was dissolved in ethyl acetate, washed with 1M HCl, then dried and concentrated. The solid product was washed with hexane, obtaining the final product in the form of a white solid (15,8 g). LC/MS retention time of 2.0 min, M/Z (obs, M-N)=304,1. Finally Vos, anthranilate (11.3 g) was dissolved in CH2Cl2(26 ml) and was treated with TFA (21 ml). After stirring at room temperature for 2 hours the solution was dried in vacuum, the resulting residue was dissolved in toluene (100 ml), concentrated to dryness and the process of dissolution/drying was repeated twice more, getting the desired product as a white solid (10.8 g). LC/MS retention time of 1.2 min, M/Z (obs, M-N)=204,0.

2-Amino-5-bromobenzoic

Satinay anhydride (15 g, 0,062 mol) was combined with 1M aqueous NH4OH (340 ml) and was stirred for 2 days at room temperature. The solid product was filtered and dried in vacuum (6.6 g). LC/MS retention time 2,47 min, M/Z obs=215,2.

To a suspension of benzoylferrocene1(10.0 g, of 61.7 mmol) and oxochloride phosphorus (20 ml), stirred in a 500-ml three-neck round-bottom flask, equipped with magnetic stirrer and reflux condenser, at one time was added N,N-dimethylaniline (7,80 ml of 61.7 mmol). The suspension was heated at the boil under reflux for 3 hours and slowly formed a light red solution. The solution was concentrated under reduced pressure and the residue poured into ice (100 g). The solution was podslushivaet to a pH of 9.0 with concentrated aqueous sodium bicarbonate solution. CME is ü distributed between CH 2Cl2and H2O. the Organic portion was dried (MgSO4) and evaporated to dryness under reduced pressure. The residue was dissolved in anhydrous THF (75 ml) and cooled to 0OC. For 30 min under stirring was added dropwise dimethylaniline (67,7 ml, 135 mmol, 2.0m in THF). The solution is then stirred at 0OC for 1 hour. The solution was concentrated under reduced pressure and the residue was purified by chromatography on silica gel using a mixture (70% hexane, 30% ethyl acetate)to give compound2(of 7.90 g, 38,1 mmol, 62% yield) as a white solid.

1H-NMR (CDCl3)3,43 (c, 6H), 7,40 (t, 1H), 7,69 (t, 1H), 7,78 (d, 1H), 8,02 (d, 1H); M+1 (obc)=208,0; Rt=of 2.26.

A 5-ml microwave reaction vessel were loaded mixture of compounds2(100 mg, 0.48 mmol), 2-methoxyphenylacetic acid (96 mg, 0,63 mmol), tetrakis(triphenylphosphine)palladium(0) (55 mg, 0,048 mmol), sodium carbonate (1.20 ml, 0.48 mmol, 0,40 M aqueous solution) and acetonitrile (1.20 ml). The corked vessel and heated with stirring at 170º for 10 minutes using microwave radiation. The organic portion was concentrated under reduced pressure and the residue was purified by chromatography on silica gel using a mixture (80% hexane, 20% ethyl acetate)to give compound3(120 mg, 0.43 mmol, 89% yield) as a white solid.

1H-NMR (CDCl3)3,32 (c, 6H), 3,81 (c, 3H), 6.89 in-7,02 (m, 2H), 7,28-7,34 (m, 2H), a 7.62 (t, 1H), of 7.75 (d, 1H), 7,89 (d, 1H), 7,95 (d, 1H); M+1 (obc)=280,2; Rt=2,46.

Methyl ester 2-chloro-4-dimethylaminobenzoyl-7-carboxylic acid

A suspension of methyl ester 2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-carboxylic acid (12.2 g, a 55.4 mmol), N,N-dimethylaniline (14,0 ml and 110.8 mmol) and POCl3(25 ml), under stirring in nitrogen atmosphere, was heated at 100ºC for 15 minutes. The solution is evaporated to dryness under reduced pressure and the residual oil was poured into a mixture of ice-water (800 ml). The mixture was made strongly alkaline by addition of 50% aqueous NaOH solution at 0OC. The mixture was distributed between CH2Cl2and H2Oh and an organic part evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel using a mixture of 70% hexane/30% ethyl acetate, receiving the intermediate chloride as a white solid (5.1 g, to 19.8 mmol). The obtained intermediate compound was dissolved in CH2Cl2(100 ml). The solution was cooled to 0 ° C followed by addition of Et3N (5.5 ml, to 39.6 mmol) and dimethylamine hydrochloride (1.6 g, to 19.8 mmol). The mixture was then stirred at 0OC for 30 minutes. The mixture is evaporated to dryness and the obtained residue was purified by chromatography on silica gel using a mixture of 70% Huck is Ana/30% ethyl acetate, giving the desired amine as a white solid (3.3 g, 12.4 mmol, 11% yield). LC/MS (10-99%) M/Z 268,0, retention time 2,85 minutes

6-Fluoro-N4,N4-dimethylthiazole-2,4-diamine

A mixture of (2-chloro-6-florinopolis-4-yl)amine (50 mg, 0.22 mmol), bis(trimethylsilyl)amide lithium (260 μl, 0.26 mmol, 1.0m in hexane), Pd2(dba)3(20 mg, of 0.022 mmol), 2-(DICYCLOHEXYL)fosinopril (19 mg, 0,053 mmol) and THF (1.0 ml) with stirring, they were heated in a sealed tube via microwave radiation at 65 º C for 1.5 hours. Added 1,0N. an aqueous solution of HCl (3.0 ml) and the mixture was stirred at room temperature for 30 minutes. The mixture was distributed between H2O and EtOAc. Organic fraction is evaporated to dryness under reduced pressure. The obtained residue was purified by chromatography on silica gel using a mixture of 95% CH2Cl2/5% Meon, getting the desired amine as a tan solid (40 mg, and 19.4 mmol, 88% yield). LC/MS (10-99%) M/Z 206,9, retention time 1,18 minutes

1-(4-Dimethylamino-6-florinopolis-2-yl)pyrrolidin-2,5-dione

A mixture of 6-fluoro-N4,N4-dimethylthiazole-2,4-diamine (30.0 mg, 0.13 mmol), succinic anhydride (12 mg, 0.12 mmol) and p-dioxane (500 μl) with stirring, they were heated in a sealed tube via microwave radiation at 170º for 20 the minutes. The mixture was purified by HPLC, obtaining the desired succinate in the form of the TFA salt (40 mg, 0.10 mmol, 76% yield). LC/MS(10-99%) M/Z 289,3, retention time 2,01 minutes

1-(6-Fluoro-4-pyrrolidin-1-imaginaton-2-yl)pyrrolidin-2-he

A mixture of 6-fluoro-4-pyrrolidin-1-imaginaton-2-ylamine (30.0 mg, 0.14 mmol), 4-chlorobutyronitrile (17 μl, 0.15 mmol), Et3N (42 μl, 0.30 mmol) and p-dioxane (500 μl) with stirring, they were heated in a sealed tube via microwave radiation at 170º for 20 minutes. The mixture was purified by HPLC, obtaining the desired lactam as TFA salt (45 mg, 0.11 mmol, 81% yield). LC/MS (10-99%) M/Z 301,2, retention time of 2.24 minutes

1-(4-Dimethylamino-6-florinopolis-2-yl)-1H-pyrrole-3-carbaldehyde

A mixture of 6-fluoro-N4,N4-dimethylthiazole-2,4-diamine (20.0 mg, 0.10 mmol), 2,5-dimethoxy-3-tetrahydrobenzaldehyde (43 μl, 0.30 mmol) and Asón (500 μl) with stirring, they were heated at 90ºC for 30 minutes. The mixture is evaporated to dryness and the obtained residue was purified by chromatography on silica gel using a mixture of 70% hexane/30% ethyl acetate, obtaining the desired aldehyde as a white solid (15 mg, 0.05 mmol, 50% yield). LC/MS (10-99%) M/Z 285,1, retention time 3,23 minutes

(6-Methoxy-2-pyrrol-1-imaginaton-4-yl)dimethylamine

To a solution of pyrrole (310 mg, 4.6 mmol) and DMF (dimethylformamide) (5,ml) under stirring in nitrogen atmosphere was added NaH (170 mg, 4.2 mmol, 60% in mineral oil). The mixture was stirred at room temperature for 10 minutes. To this solution was added (2-chloro-6-methoxyquinazoline-4-yl)dimethylamine (1.0 g, 4.2 mmol). The mixture was heated in a sealed tube via microwave radiation at 220º for 20 minutes. The mixture is evaporated to dryness and the obtained residue was purified by chromatography on silica gel using a mixture of 70% hexane/30% ethyl acetate, obtaining the desired aldehyde as a white solid (15 mg, 0.05 mmol, 50% yield). LC/MS (10-99%) M/Z 269,0, retention time 2,39 minutes

[2-(2-Habitrol-1-yl)-6-methoxyquinazoline-4-yl]dimethylamine

With stirring to a solution of (6-methoxy-2-pyrrol-1-imaginaton-4-yl)amine (25 mg, 0.09 mmol) and THF (2.0 ml) under nitrogen atmosphere was added N-chlorosuccinimide (13 mg, 0.09 mmol). The solution was stirred at room temperature for 17 hours. The mixture was purified by HPLC, obtaining the required habitrol as TFA salt (23 mg, 0.06 mmol, 62% yield). LC/MS (10-99%) M/Z 303,0, retention time 2,71 minutes.

2-[4-(4-Aminopiperidin-1-yl)-7-methylisatin-2-yl]phenol

With stirring to a solution of 2-(4-chloro-7-methylisatin-2-yl)phenol (100 mg, 0.35 mmol), Et3N (72 μl, 0.52 mmol) and CH2Cl2(300 μl) under nitrogen atmosphere was added 4-aminopiperidin (54 μl, 0.52 mmol). A mixture of TRANS who massively at room temperature for 2 hours. The mixture is evaporated to dryness under reduced pressure. The obtained residue was purified by chromatography on silica gel using a mixture of 98% CH2Cl2/2% Meon, getting the desired amine as a white solid (11 mg, 0.31 mmol, 89% yield). LC/MS (10-99%) M/Z 349,3, retention time 2,22 minutes

{1-[2-(2-Hydroxyphenyl)-7-methylpyrazole-4-yl]piperidine-4-yl}amide econsultancy acid

With stirring to a solution of 2-[4-(4-aminopiperidin-1-yl)-7-methylisatin-2-yl]phenol (30 mg, 0.09 mmol), Et3N (25 μl, 0.18 mmol) and CH2Cl2(500 μl) under nitrogen atmosphere was added acanaloniidae (10 μl, 0.09 mmol). The mixture was stirred at room temperature for 3 hours. The mixture was purified by HPLC, obtaining the desired sulfonamide as TFA salt (33 mg, 0.06 mmol, 68% yield). LC/MS (10-99%) M/Z 427,3, retention time 2,80 minutes

3-{1-[2-(2-Hydroxyphenyl)-7-methylpyrazole-4-yl]piperidine-4-yl}-1,1-dimethylanthracene

With stirring to a solution of 2-[4-(4-aminopiperidin-1-yl)-7-methylisatin-2-yl]phenol (35 mg, 0.11 mmol), Et3N (30 μl, 0.22 mmol) and CH2Cl2(300 μl) under nitrogen atmosphere was added dimethylsulphamoyl (12 μl, 0.11 mmol). The mixture was stirred at room temperature for 17 hours. The mixture was purified by HPLC, obtaining the desired sulfanilate the inu as TFA salt (44 mg, 0.08 mmol, 71% yield). LC/MS (10-99%) M/Z 442,4, retention time 2,84 minutes

Isobutyl ether {1-[2-(2-hydroxyphenyl)-7-methylpyrazole-4-yl]piperidine-4-yl}carbamino acid

With stirring to a solution of 2-[4-(4-aminopiperidin-1-yl)-7-methylisatin-2-yl]phenol (30 mg, 0.09 mmol), Et3N (25 μl, 0.18 mmol) and CH2Cl2(300 μl) under nitrogen atmosphere was added isobutylparaben (12 μl, 0.09 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was purified by HPLC, obtaining the desired carbamate as TFA salt (27 mg, 0.05 mmol, 58% yield). LC/MS (10-99%) M/Z 435,2, retention time 3,21 minutes

1-[2-(2-Hydroxyphenyl)-7-methylpyrazole-4-yl]piperidine-4-ilen ether isobutylamino acid

With stirring to a solution of 1-[2-(2-methoxyphenyl)-7-methylpyrazole-4-yl]piperidine-4-ol (100 mg, 0.30 mmol) and THF (500 μl) under nitrogen atmosphere was added phosgene (317 μl, of 0.60 mmol, 20% in toluene). The mixture was stirred at room temperature for 15 minutes. Within 2 min was added dropwise to isobutylamine (300 μl, 3.0 mmol) followed by stirring at room temperature for 1 hour. The mixture is evaporated to dryness and the obtained residue was purified by chromatography on silica gel using a mixture of 97% CH2Cl2/3% Meon, getting the desired intermediate carb is foul compound as a clear oil (90 mg, 0.20 mmol). With stirring to a solution of intermediate urethane compound (90 mg, 0.20 mmol) and CH2Cl2(15 ml) in a nitrogen atmosphere at-78º within a 2 minute period was added dropwise VVG3(60 ml of 0.60 mmol 1.0m in CH2Cl2). The mixture then was allowed to warm to room temperature and then was heated at 50 º C for 15 minutes. The mixture was poured into a saturated aqueous solution of NaHCO3(80 ml) and the organic fraction is evaporated to dryness. The residue was purified by HPLC, obtaining the desired carbamate as TFA salt (66 mg, 0.12 mmol, 39% yield). LC/MS (10-99%) M/Z 435,3, retention time is 3.08 min

N-{1-[2-(2-Hydroxyphenyl)-7-methylpyrazole-4-yl]piperidine-4-yl}-3-methylbutyrate

With stirring to a solution of 2-[4-(4-aminopiperidin-1-yl)-7-methylisatin-2-yl]phenol (35 mg, 0.11 mmol), Et3N (30 μl, 0.22 mmol) and CH2Cl2(300 μl) under nitrogen atmosphere was added isovaleraldehyde (14 μl, 0.11 mmol). The mixture was stirred at room temperature for 17 hours. The mixture was purified by HPLC, obtaining the desired sulfonamide as TFA salt (37 mg, 0.07 mmol, 59% yield). LC/MS(10-99%) M/Z 419,3, retention time 2,77 minutes

Synthesis of 2-(4-Ethoxyquinoline-2-yl)phenol

2-(4-Ethoxyquinoline-2-yl)phenol

2-(4-Chlorination-2-yl)phenol (50 mg, 0,196 mmol) were placed the microwave tube, equipped with a stirrer, and dissolved in 0.5 ml of anhydrous dichloromethane followed by the addition of 2 ml of anhydrous ethanol. The tube was corked tube and was heated at a temperature of from 160º up to 200ºC for 1 hour in a microwave oven SEM. The solvent was removed under reduced pressure, the organic layer resuspendable in DMSO and purified by HPLC on Gilson. The desired compound was concentrated to a white solid as TFA salt. LC/MS (10-99%) M/Z 267,2, retention time to 2.57 minutes

Synthesis of 2-(4-dimethylaminobenzoyl-2-yl)-6-METHYLPHENOL

[2-(2-Methoxy-3-were)hinzelin-4-yl]dimethylamine

With stirring to a solution of [2-(2-methoxyphenyl)hinzelin-4-yl]amine (200 mg, to 0.72 mmol) in anhydrous THF in an argon atmosphere at-78º was added dropwise 1.6 m solution of n-BuLi in hexano (0,671 ml, 1,074 mmol). After 10 minutes, was added MeI (0,076 ml, 1,22 mmol) and the reaction mixture was left to warm to room temperature. After 10 minutes at room temperature, the reaction mixture was extinguished saturated aqueous NH4Cl and distributed between water and ethyl acetate. The organic phase was separated, dried over magnesium sulfate, filtered and concentrated to a yellow oil. Was purified flash chromatography with a mixture of 10% ethyl acetate/90% hexane, getting the product in the form of a white solid was Isolated 146 mg, 50% output. LC/MS (10-99%) M/Z 294,0, retention time 3,23 minutes

2-(4-Dimethylaminobenzoyl-2-yl)-6-METHYLPHENOL

With stirring to a solution of [2-(2-methoxyphenyl)hinzelin-4-yl]amine (54 mg, 0,184 mmol) in CH2Cl2when-78º in nitrogen atmosphere, was added VVG3(0,92 ml of 0.92 mmol). The reaction mixture was left to warm to room temperature and then was heated at 45 º C for 4 hours. The reaction mixture was left to cool to room temperature and then extinguished in an aqueous solution of NaHCO3to pH 8. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated to a yellow solid. Was purified by HPLC on Gilson and the desired product was isolated as TFA salt. LC/MS (10-99%) M/Z 280,2, retention time of 2.55 minutes

Synthesis of 2-(4-dimethylaminobenzoyl-2-yl)-4-morpholine-4-kilfenora

[2-(2-Methoxy-5-morpholine-4-ylphenyl)hinzelin-4-yl]dimethylamine

In the tube, equipped with a stirrer, was loaded Pd2(dba)3(of 51.1 mg, 0,0558 mmol), biphenyl-2-yldi-tert-butylphosphine (67 mg, 0,223 mmol), NaOtBu (80 mg, 0,837 mmol) in 2 ml of anhydrous toluene, was added 4-bromo-2-(4-dimethylaminobenzoyl-2-yl)phenol (200 mg, 0,558 mmol) and morpholine (0,073 ml, 0,837 mmol). The reaction tube was corked screw cap and heated at 100ºC for oil ban is for 16 hours. The mixture was purified flash chromatography with a mixture of 30%-60% ethyl acetate/hexane, giving the product as a white solid. Allocated 100 mg, 49% yield. LC/MS (10-99%) M/Z 365,0, retention time 2,07 minutes

2-(4-Dimethylaminobenzoyl-2-yl)-4-morpholine-4-infenal

With stirring to a solution of [2-(2-methoxy-5-morpholine-4-ylphenyl)hinzelin-4-yl]amine (109 mg, 0,299 mmol) in CH2Cl2when-78º in nitrogen atmosphere, was added VVG3(1.5 ml, 1.5 mmol). The reaction mixture was left to warm to room temperature and then was heated at 40 ºC for 2 hours. The reaction mixture was extinguished in an aqueous solution of NaHCO3to pH 8. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated to a yellow solid. Was purified by HPLC on Gilson and the desired product was separated in the form of the TFA salt. LC/MS (10-99%) M/Z 351,4, retention time 1,89 minutes

Synthesis of 2-(4-dimethylaminobenzoyl-2-yl)-4-METHYLPHENOL

[2-(2-Methoxy-5-were)hinzelin-4-yl]dimethylamine

With stirring to a solution of [2-(5-bromo-2-methoxyphenyl)hinzelin-4-yl]amine (200 mg, 0,558 mmol) in anhydrous THF in an argon atmosphere at-78º was added dropwise 1.6 m solution of n-BuLi in hexane (0,76 ml of 1.23 mmol). After 10 minutes, was added MeI (0,054 ml of 1.23 mmol) and the reaction mixture is left is to agrevate to room temperature. After 10 minutes at room temperature, the reaction mixture was extinguished saturated aqueous NH4Cl and distributed between water and ethyl acetate. The organic phase was separated, dried over magnesium sulfate, filtered and concentrated to a yellow oil. Was purified flash chromatography with a mixture of 30% ethyl acetate/70% hexane, receiving the product as a white solid. Distinguished 146 mg, 89% yield. LC/MS (10-99%) M/Z 294,4, retention time of 2.64 minutes

2-(4-Dimethylaminobenzoyl-2-yl)-4-METHYLPHENOL

With stirring to a solution of [2-(2-methoxy-5-were)hinzelin-4-yl]amine (146 mg, 0,498 mmol) in CH2Cl2at 78º in an atmosphere of nitrogen was added VVG3(2,49 ml, 2.49 mmol). The reaction mixture was left to warm to room temperature for 2 hours. The reaction mixture was extinguished in an aqueous solution of NaHCO3to pH 8. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated to a yellow solid. Was purified by HPLC on Gilson and the desired product was isolated as TFA salt. LC/MS (10-99%) M/Z 280,2, retention time 2,65 minutes

Synthesis of 2-(2'-methylsulfinylphenyl)-4-dimethylaminobenzene

2-(2'-Methylsulfinylphenyl)-4-dimethylaminobenzoyl

In 2-ml reaction vessel Personal Chemistry Microwave, equipped with MERALCO is, download 2-(2'-bromophenyl)-4-dimethylaminobenzoyl (0,020 g, 61 mmol), copper iodide(I) (0,017 g, 91 mmol), methanesulfonate sodium (0,010 g, 97 mmol) and 0.5 ml of DMF. This mixture was subjected to microwave irradiation at 180ºC for 10 minutes. After cooling, was added water and ether and was carried out by extraction. The ether layer was then filtered through celite and then again once were extracted using approximately 20% of NH4OH to remove additional copper. After concentration the product was again dissolved in 50/50 solution of DMSO/Meon. Purification was performed using LC/MS, receiving TFA salt. LC/MS (10-99%) M/Z 328,3, retention time 3,03 minutes

Synthesis of 2-(2'-aniline)-4-dimethylaminobenzene

2-(2'-Aniline)-4-dimethylaminobenzoyl

Powder zinc (1.18 g, 18.0 mmol) was added to a solution of 2-(2'-nitrophenyl)-4-dimethylaminobenzene (0,530 g of 1.80 mmol) in acetic acid (10.9 ml, 190 mmol) at 0OC. The reaction mixture was hardened, but the mixing was resumed after removal of the ice bath. The reaction mixture was stirred for 3 hours at room temperature. Then was added deionized water (approximately 10 ml), and formed a solution with subsequent sediment. This solution was slightly podslushivaet aqueous NaHCO3. The product was extracted three times with ethyl acetate, dried sulfate m is fester, was filtered and concentrated. Approximately 20 mg of the product was re-dissolved in 50/50 solution of DMSO/Meon and purified using LC/MS, receiving salt of bis-triperoxonane acid. LC/MS (10-99%) M/Z 265,0, retention time 2,81 minutes

Synthesis of 2-(2'-ethylsulfanyl)-4-dimethylaminobenzene

2-(2'-Ethylsulfanyl)-4-dimethylaminobenzoyl

Potassium carbonate (0,052 g, 0,374 mmol) and ethanthiol (by 0.055 ml, 0,748 mmol) was added to a solution of 2-(2'-forfinal)-4-dimethylaminobenzene (0,020 g, 0,0748 mmol) in N,N-dimethylformamide (1 ml) in a microwave reaction vessel with stirrer. This mixture was irradiated in a microwave reactor at 135º for 1.5 hours. The resulting mixture was filtered and then purified using LC/MS, receiving salt triperoxonane acid. LC/MS (10-99%) M/Z 310,2, retention time of 3.27 min

Synthesis of 2-(2'-cyanophenyl)-4-dimethylaminobenzene

2-(2'-Cyanophenyl)-4-dimethylaminobenzoyl

In a round bottom flask was loaded with 2-(2'-bromophenyl)-4-dimethylaminobenzoyl (0,010 g, 0,0305 mmol), potassium cyanide (0,0040 g, 0,0609 mmol), tetrakis(triphenylphosphine)palladium(0) (0,0018 g, 0,00152 mmol), copper iodide(I) (0,00058 g, 0,00305 mmol) and acetonitrile (0,50 ml) and was heated to boiling under reflux overnight. After cooling to room temperature was added ethyl acetate and the mixture is filtered through celite. Then extraction was performed using ammonium hydroxide (approximately 20%) to remove additional copper. After concentration the product was again dissolved in 50/50 solution of DMSO/Meon and purified using LC/MS, receiving TFA salt. LC/MS (10-99%) M/Z 275,2, retention time 2,85 minutes

Synthesis of 2-(2'-isopropylphenyl)-4-dimethylaminobenzene

2-(2'-Isopropylphenyl)-4-dimethylaminobenzoyl

0.5m solution of isopropylacrylamide (0,898 ml, 0,449 mmol) was added to a solution of 2-(2'-forfinal)-4-dimethylaminobenzene (0,040 g, 0,150 mmol) in dimethyl ether of ethylene glycol (1 ml) in a microwave vessel equipped with a mixer. The sample was irradiated in a microwave reactor for 5 minutes at 170º. Then was added deionized water (approximately 2 ml). Extraction was performed with ether. After concentration, the product was re-dissolved in 50/50 solution of DMSO/Meon and purified using LC/MS, giving the TFA salt. LC/MS (10-99%) M/Z 289,8, retention time 3,23 minutes

Synthesis of 2-(2'-hydroxyphenyl)-4-dimethylamino-6-methoxyquinazoline

2-(2'-Hydroxyphenyl)-4-dimethylamino-6-methoxyquinazoline

In the reaction vessel for a microwave reactor equipped with a stirrer, was loaded with 2-(2'-acetoxyphenyl)-4-dimethylamino-6-bromination (0,100 g, 0,259 mmol), copper iodide(I) (0,0245 g, 0,129 m is ol), N,N-dimethylformamide (0,90 ml) and 0.5m solution of sodium methoxide (1,04 ml, 0,518 mmol) in methanol. The sample was irradiated in a microwave reactor for 20 minutes at 150 º C. After cooling, the sample was diluted with ether and then filtered through celite. Further extraction was performed using ammonium hydroxide (approximately 20%) to remove additional copper. After concentration the product was again dissolved in 50/50 solution of DMSO/Meon and purified using LC/MS (20-99%), receiving TFA salt. The approximate yield of 60% (by LC/MS). LC/MS (10-99%) M/Z usd296.4, retention time 2,31 minutes

Synthesis of methyl ester of 4-fluoro-3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzoic acid

Methyl ester of 3-bromo-4-fermenting acid

3-Bromo-4-fermenting acid (2.5 g, 11,42 mmol) were placed in 100-ml round-bottom flask equipped with a stirrer, which was clogging the membrane and in nitrogen atmosphere was dissolved in 9 ml of anhydrous THF and 3 ml of anhydrous Meon. To the acid solution under stirring was added dropwise 2.0m solution TMS in ether (6,28 ml, 12,56 mmol). The conversion of acid to ester was completed after 20 minutes, according to the analysis of LC/MS. The solvent was removed under reduced pressure and the product was used without further purification. Allocated transparent oil (2.66 g, 100% yield) LC/MS (10-99%) M/Z 234, time is of ariania 3,09 minutes

Methyl ester of 4-fluoro-3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzoic acid

In a round bottom flask equipped with a stirrer, was added methyl ether 3-bromo-4-fermenting acid (1.66 g, 7,12 mmol), bis(pinacolato)LIBOR (2.2 g, 8.5 mmol), potassium acetate (2.1 g, is 21.3 mmol) and the complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.35 g, 0.43 mmol) with dichloromethane (1:1). The reaction flask was corked tube was pumped out the air and provided an atmosphere of nitrogen, followed by adding 20 ml of anhydrous DMSO. The reaction mixture was heated at 80 ° C in oil bath for 2 hours. The reaction mixture was left to cool to room temperature and distributed between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted two more times. All organics were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure to black oil. The product was purified flash chromatography using a gradient of ethyl acetate/hexane 0-60%, obtaining the desired product as a white solid (1.48 g, 74% yield). LC/MS (10-99%) M/Z 281,4, retention time 2,73 minutes

Hinzelin1(1.5 g, 3.0 mmol) was dissolved in THF (150 ml). After cooling to-78º was added dropwise tert-utility (1.7m in heptane, to 1.76 ml). After PE is emiliania for 10 minutes at-78º to the solution was added WITH 2(crushed) and the solution was heated to room temperature and was stirred for 30 minutes. The reaction mixture was extinguished with water (100 ml), diluted with ethyl acetate (100 ml). The organic layer was dried, concentrated, and purified flash chromatography (1%-10% Meon/DCM)to give compound2(600 mg, 43% yield).

Synthesis of 2-(2'-hydroxyphenyl)-4-dimethylamino-6-morpholinopropan

2-(2'-Hydroxyphenyl)-4-dimethylamino-6-morpholinopropan

In a dry reaction tube with a screw cap in the nitrogen atmosphere was loaded Tris(dibenzylideneacetone)dipalladium(0) (0,012 g, 13,0 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0,024 g, to 38.8 mmol), cesium carbonate (0,097 g, 298 mmol), toluene (0.25 ml), 2-(2'-acetoxyphenyl)-4-dimethylamino-6-bromination (0,050 g, 129 mmol) and morpholine (23 μl, 259 mmol) in that order. This mixture then was heated to 80ºC for 24 hours. After cooling, the mixture was diluted with ether, filtered through celite and silica gel and concentrated. The product was re-dissolved in 50/50 solution of DMSO/Meon and purified using LC/MS, receiving salt of bis-TFA. LC/MS (10-99%) M/Z 351,0, retention time min 2,75

Hinzelin1(0.2 g, of 0.62 mmol) was dissolved in CH3CN (5 ml). After cooling to -10 º C (ice/NaCl) was added to CCl4, DIEA and DMAP. After stirring for 10 minutes to a mixture of slow is about, within 10 minutes, the solution was added dibenzylamine

CH3CN (2 ml). Stirring was carried out at -10 º C for 2 hours, then at room temperature for 24 hours. The mixture was suppressed by the addition of 0.5m K2HPO4, was diluted with water (15 ml), was extracted with dichloromethane (30 ml), dried, concentrated, and purified flash chromatography (100% DCM)to give compound2(168 mg, 47% yield) as a colorless oil. LC/MS (10-99%) M/Z 586,0, retention time of 2.54 minutes

To a solution of hintline2(has 0.168 g, 0.29 mmol) in DCM (dichloromethane) (1.5 ml) was added TMSBr (0,079 ml, 0.61 mmol) at 0OC. The reaction mixture was stirred for 1 hour at 0 ° C and then for 1 hour at room temperature. The reaction mixture was extinguished with water (3 ml) and stirred 15 minutes. The aqueous layer was washed with ethyl acetate (5 ml) and dried in liofilizadora during the night, getting the desired product3in the form of a white foam (0.14 g, 100% yield). LC/MS (10-99%) M/Z 406,0, retention time of 3.32 min

To a solution of hintline3(0.14 g, 0.36 mmol) in Meon (3 ml) was added NaOMe (of 1.44 ml, to 0.72 mmol) at room temperature. The reaction mixture was stirred over night at room temperature. The reaction mixture was concentrated using a rotary evaporator (25), then the residue was dissolved in water (75 ml) and washed with ethyl what Etat (3×50 ml). The aqueous phase was dried by lyophilization, getting the final product4(0.14 g, 98% yield) as a solid. LC/MS (10-99%) M/Z 406,0, retention time of 3.32 min

2-{7-Methyl-4-[methyl-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)amino]hinzelin-2-yl}phenol

[2-(2-Methoxyphenyl)-7-methylpyrazole-4-yl]-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)Amin

4-Chloro-2-(2-methoxyphenyl)-7-methylisatin (400 mg, 1.48 mmol) was dissolved in 10 ml of anhydrous DMF followed by the addition of s-(5-methyl[1,3,4]oxadiazol-2-yl)methylamidosulphate (234 mg, 1.48 mmol), then triethylamine (413 μl, 2,96 mmol). After 6 hours the reaction was completed, the mixture was distributed between ethyl acetate and water. The organic phase was separated, dried with magnesium sulfate, filtered and concentrated to obtain oil. Was purified flash chromatography 60% ethyl acetate/40% hexane, obtaining the desired product as a white solid. Allocated 290 mg, 56% yield. LC/MS (10-99%) M/Z 348,4, retention time 2,17 minutes

[2-(2-Methoxyphenyl)-7-methylpyrazole-4-yl]methyl-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)Amin

Under stirring in nitrogen atmosphere at 0 ° C to a suspension sieprath of sodium hydride (42 mg, 1.04 mmol) in anhydrous DMF was added [2-(2-methoxyphenyl)-7-methylpyrazole-4-yl]-(5-methyl[1,3,4]oxadiazol-2-ylmethyl)amine (180 mg, 0,518 mmol, in 5 ml of DMF). After 30 minutes at 0 the C was added MeI (74 μl, 1,19 mmol) and the reaction mixture was left to warm to room temperature. After 1 hour the reaction mixture was extinguished with water and was extracted 3 times with ethyl acetate. Organic substances were combined, dried over magnesium sulfate, filtered and concentrated to a yellow oil. Was purified flash chromatography 50/50 ethyl acetate/hexane, obtaining the desired product as a clear oil. Allocated 128 mg, 66% yield. LC/MS (10-99%) M/Z 376,1, retention time of 2.06 minutes

2-{7-Methyl-4-[methyl-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)amino]hinzelin-2-yl}phenol

Under stirring in nitrogen atmosphere at-78º to a solution of [2-(2-methoxyphenyl)-7-methylpyrazole-4-yl]methyl-(5-methyl[1,3,4]oxadiazol-2-ylmethyl)amine (128 mg, 0,341 mmol) in anhydrous CH2Cl2was added dropwise BBr3(1,71 ml, 1,71 mmol). The reaction mixture was left to warm to room temperature and after 3 hours the mixture was suppressed saturated aqueous NaHCO3to pH 8. Organic matter was separated, dried over magnesium sulfate, filtered and concentrated to a light yellow oil. Was purified by HPLC on Gilson and the compound was isolated as TFA salt. LC/MS (10-99%) M/Z 362,3, retention time 2,12 minutes

To a solution of hintline (187 mg, 0,63 mmol) in CH2Cl2(5 ml) was added pyridine (0,11 ml of 1.36 mmol) at on the th temperature. After cooling to 0 ° C was added a solution of acetylchloride (50 μl, 0.70 mmol) in CH2Cl2(5 ml), stirring was continued for 45 minutes at room temperature and the solvent was removed in vacuum. Chromatography on silica gel (hexane/ethyl acetate/been certified with qi net3,2:1:0,05) gave compound1in the form of a white solid (90 mg, 42%). Connection1: LC/MS (10-99%) M/Z=338 [M+H]+the retention time of 3.28 min

Other compounds of General formulaIwere obtained using methods that are basically similar to those described above. Research data of these compounds are shown in table 3 below, and the numbers of the compounds correspond to the compounds shown in table 2.

td align="center"> 589td align="center"> 790 1113
Table 3
Research data samples for compounds of the formulaI
Conn.No.LC_MASS_LUS
15308,40
16306,00
164320,00
194389,20
195404,20
198302,00, 302,20, 302,00
202328,20, 328,20, 328,00
241268,30
250346,00
252310,00
253344,00
254319,00
255333,00
256348,00
257319,00
258289,80
259249,80, 250,40
260386,20
261357,00
262275,20
263358,00
264325,00
265296,60, 296,40, 296,40
266345,20
267310,20, 310,00
268351,00
269310,00
270340,10
271298,10
272314,00
273328,20
274284,00
275300,10
276328,10
277286,90
278306,00
279280,20
280380,00
281334,00, 334,00
282336,00
283351,00
284336,00, 336,00
285322,00, 322,00, 322,00, 322,00
286307,00
287378,00
288 405,00
289349,00
290292,00
291322,00
292342,00
293294,00
294358,20
295374,00
296382,40
297256,80
298239,00
299339,80
300279,00
301386,00
302307,20
303318,00
304296,20
305278,00
306291,80
307239,00
30889,00
309270,00
310402,20
311342,00
312342,00
313320,20
314309,00
315399,00
316318,00
317332,00
318332,00
319315,00
320329,00
321343,00
322357,00
323342,00
324342,00
325368,00, 368,10
326352,00
327369,80
32845620
329381,80
330384,00
331395,80
332322,00, 322,20
333284,00
334334,00
335280,00
336296,00
337306,00
338286,80
339286,80
340329,40
341356,20
342329,40
343463,20
344491,60
345353,20
346315,80
347359,00
34840220
349341,80
350359,80
351384,80
352371,80
353369,60
354343,00
355441,00
356353,80
357314,00
358320,00
359323,00
360289,00
361322,20
362400,00
363386,00
364390,00
365306,00
366385,80
367370,00
368374,00
369320,00
370320,00
371322,00
372320,00
373308,00, 308,00
374340,00
375356,00
376280,20, 280,00
377300,40, 300,00
378282,00
379326,20
380351,20
381338,20
382336,20
383309,20
384407,40
385334,20
386323,40
387380,20
388 294,00
389350,00
390345,00
391326,00
392352,80
393323,00
394286,00
395344,00
396340,00
397326,00
398314,00
399312,00
400343,20
401354,00
402340,00
403282,00
404285,00
405283,20
406292,00
407464,00
408for 98.00
409273,00
410326,20
411326,20
412356,00
413359,20
414355,00
415338,00
416370,00
417328,00
418298,20
419279,80
420281,80
421340,90
422269,30, 269,20
423303,00
424372,80
425272,80
426307,00
427322,20
42832420
429284,00, 285,00
430286,00
431429,00
432439,00
433443,00
434456,00
435486,00
436326,20
437328,00
438253,00
439257,00
440299,20
441273,00
442414,40
443286,00
444302,20
445330,00
446328,20
447355,40
44841200
449286,00
450338,20, 338,00
451352,20
452267,00
453326,20
454284,20
455309,20
456399,20
457312,00
458340,20
459302,00
460316,00
461344,00
462328,00
463378,00
464316,00
465327,80
466371,80, 371,60
467355,60
468 356,80
469359,00
470435,20
471368,00
472344,00
473282,20
474281,20
475355,00
476302,20
477316,20
478344,20
479328,20
480378,00
481316,20
482282,00
483286,00
484328,00
485324,20
486353,80
487377,80
48865,00
489339,80
490267,00
491281,00
492310,20
493352,20
494342,00
495328,00
496402,20, 402,40
497439,20
498421,00
499367,00
500397,20
501365,00
502270,00
508290,90
516403,40
517403,40
518403,60
519403,40
52040840
521409,20
522432,40
523432,20
524431,40
525432,40
526432,40
527437,40
528437,40
529446,40
530452,40
531463,00
532370,00
533382,20
534384,20
535398,20
536437,40
537439,40
538439,40
539439,20
540377,40
541384,00
542386,00
543391,20
544391,20
545397,40
546397,40
547397,40
548411,40
549368,20
550420,20
551441,40
552446,00
553449,40
554394,00
555450,20
556330,00
557332,20
558334,00
559346,00
560348,00
561372,00
562383,20
563383,20
564383,20
565383,20
566387,80
567388,80
568403,40
569412,00
570412,00
571412,00
572349,20
573361,00
574375,20
575389,20
576411,20
577411,20
586281,00
587342,40
588356,00
358,20
590365,20, 365,20
591369,20, 369,20
592370,00
593372,40
594383,20, 383,20, 383,20, 383,20
595384,00
596391,20
597397,40
598337,80
599350,00
600352,00
601376,00
602387,20
603391,80
604393,00
605416,00
606416,20
607416,00
608353,00
609415,20
610415,20
611416,20
612421,00
613430,20
614431,20
615436,20
616447,00
617459,20
618493,00
619353,80
620353,80
621365,80
622367,80
623367,80
624367,80
625383,00
626409,40
627421,00
628423,20
29 423,20
630423,20
631429,20, 429,00
632430.00 the
633435,20
634437,00
635437,40
636479,20
637361,00
638362,20
639364,80
640366,00
641366,00
642367,20
643367,80
644368,00
645370,00
646375,20
647375,20
648375,20
49 375,20
650375,20
651381,00
652381,00
653381,20
654381,20
655381,20
656388,20
657395,00
658395,20
659418,00
660352,00
661365,80
662365,80
663385,80
664404,20
665404,00
666406,00
667425,20
668430,20
669 430,20
670446,00
671429,40
672433,20
673457,20
674430.00 the
675418,20
676436,20
677378,00
678269,80
679411,20
680427,20
681399,80
682420,20
683420,00
684434,20
685454,20
686399,80
687414,20
688420,00
68932,00
690367,80, 367,80
691323,00
692324,00
693326,00
694326,00
695326,00
696338,00
697340,00
698342,00
699342,00
700349,00
701353,20
702353,00
703353,00
704353,20
705353,20
706354,00
707354,00
708356,00
70935580
710355,80
711367,00
712367,20
713367,20
714367,20
715368,00
716367,80
717371,80, 373,10
718375,00
719381,00
720382,00
721382,20
722383,20
723385,00
724389,20
725390,00
726393,20
727393,20
728397,20
72940020
730403,40
731404,20
732407,40
733411,20
734413,20
735415,40
736416,20
737419,00
738419,20
739421,00
740423,20
741428,20
742429,40
743430,20
744431,40
745431,20
746441,40
747446,00
748450,20
749432,00
750470,20
751352,00
752352,00
753352,00
754374,00
755373,80
756374,00
757378,00
758378,00
759378,00
760416,20
761429,20
762432,00
763441,40
764470,20
765477,00
766326,00
767366,00
768365,80
769388,20
770326,00
771352,20
772364,20
773380,80
774397,20
775407,40
776413,20
777415,20
778421,00
779429,20
780350,00
781283,80
782294,00
783296,00
784298,00
785312,00
786314,00
787314,00
788324,00
789328,00
340,00
791343,80
792310,00
793347,00
794347,00
795351,00
796373,80
797326,00
798326,00
799326,20
800338,00
801372,00
802372,00
803381,80
804377,20
805377,20
806377,20
807384,00
808391,00
809391,20
10 414,40
811348,00
812362,00
813362,00
814381,80
815399,80
816399,80
817402,00
818425,80
819426,00
820442,00
821474,20
822425,20
823425,20
824429,20
825453,00
826426,00
827373,80
828407,40
829413,00
830 423,20
831395,80
832416,00
833416,00
834430.00 the
835395,80
836410,00
837409,80
838416,00
839364,00, 364,00
840439,20
841319,00
842319,80
843321,80
844321,80
845322,00
846334,00
847336,20
848337,80
849337,80
850 344,80
851349,20, 349,00
852349,20
853349,20
854350,00
855350,00
856352,20
857353,00
858352,00
859352,00
860363,00
861363,00
862363,00
863363,20
864363,80, 364,00
865364,00
866363,80
867370,80
868373,20
869377,00
870 378,00
871379,20
872385,20
873385,80
874385,80
875389,20
876389,20
877392,80, 393,20, 393,30
878396,20
879398,20, 398,20
880399,00
881284,30
882412,20
883417,40
884417,20
885432,20
886417,40
887419,20
888357,00
889364,40
890 371,00
891348,00, 348,20
892360,20
893386,20
894393,20
895409,00
896417,40
897425,00
898346,00
899412,40
900426,20
901427,40
902443,20
903455,20
904489,20
905350,20
906350,20
907362,00
908364,00
909364,00
910 364,00
911378,60
912405,60
913419,40
914419,20
915425,00
916431,40
917433,40
918433,40
919475,20
920358,20
921361,00
922362,00
923362,00
924363,20
925364,00
926366,00
927371,20
928371,40
929371,20
93077,20
931377,20
932368,00, 368,00
933400,20
934400,00
935403,40
936407,60
937409,20
938411,20
939412,00
940415,20
941417,00
942419,20
943424,40
944425,20
945426,00
946427,00
947427,60
948437,20
949442,20
95044600
951348,00
952348,00
953348,00
954370,00
955370,00
956370,00
957374,00
958374,20
959374,00
960412,40
961425,00, 425,00
962430.00 the
963437,60
964440,00
965466,40
966473,00
967364,20, 364,00
968290,20
969292,00
970 306,20
971308,60
972310,00
973324,20
974336,00
975340,00
976306,60
977343,00
978347,00
979370,00
980322,20
981322,40, 322,00
982356,00
983368,40
984368,00
985378,20
986405,60
987409,40
988416,20
989420,00
990 423,40
991427,40
992429,20
993431,40
994435,40
995439,20
996445,20
997447,00
998466,40
999432,40
1000369,00
1001381,00
1002409,20
1003431,60
1004432,40
1005509,40
1006384,00
1007384,00
1008425,40
1009445,20
1010 451,20
1011452,40
1012495,40
1013381,00
1014382,00
1015411,20
1016444,40
1017457,40
1018384,00
1019352,40
1020368,00
1021391,20
1022391,20
1023328,40
1024434,40
1025382,00
1026358,20
1027369,20
1028369,20
1029383,20
1030 340,20
1031409,40
1032420,40
1033368,00
1034445,20
1035330,40
1036340,00
1037356,00
1038359,80
1039363,20
1040367,00
1041390,00
1042342,00
1043342,60
1044388,40
1045343,80
1048455,00
1049338,00
1050324,20
1051433,60
1052 427,00
1053443,20
1054398,20
1055435,20
1056415,20
1057417,40
1058393,00
1059361,00
1060422,00
1065385,20
1066353,10
1067354,10
1068367,10
1069380,90
1070388,30
1071353,10
1072368,10
1073410,00
1074383,90
1075429,10
1083 352,00, 351,90, 352,30, 352,20, 352,30, 352,30, 352,00
1084350,00
1085363,00
1086377,00
1087384,00, 384,00
1088380,00
1089362,00
1090410,00
1091426,00
1092370,00
1101293,00
1102307,00
1103334,00
1106374,10, 374,00
1107379,30
1108421,10, 421,00, 421,00
1109435,50
1110407,50
1111399,30
1112413,30
427,30
1114391,30
1115405,50
1116377,30
1117441,50, 441,00
1118410,90
1119335,90
1120355,80, 355,90
1121394,90
1122407,50
1123343,00, 341,90
1124427,10
1125396,00
1127461,30
1128393,80
1133443,00
1134419,80
1135453,00
1136378,00
1137463,00, 463,00
1138457,00
1141504,00
1142420,20
1143422,20
1144436,00
1145448,20
1146370,10
1147457,50
1148463,10, 463,10
1151435,80
1152450,00
1153407,60
1155518,10
1156482,00
1157485,50
1158432,20
1159473,10
1160432,20
1161468,50
1162 393,80
1163444,00
1164450,00
1165511,00
1166467,00
1167363,30
1168463,00
1169482,00
1170415,00
1171467,00
1172511,00
1173491,00
1174495,00
1175365,90
1176380,30
1179321,80
1180560,00
1181337,20
1182280,00
1183259,20
1184 500,20, 500,20, 500,20
1185353,00
1186526,80
1190350,20
1191392,00
1192376,00
1193404,20
1194462,20
1195427,20
1196407,40
1197391,10

Methods:

(A) 4-channel LC/MS Micromass MUC LCT, pump Waters 60F, automatic sampler Gilson 215 4, the injection module Gilson 849, volumetric flow rate of 1.5 ml/min/column, gradient 10-99% CH3CN (or 0.035% TFA)/H2O (0.05% of TFA), column Phenomenex Luna 5 μm C18 (50×4,60 mm), UV detector Waters MUX UV-2488, detectors Cedex 75 ELSD.

(B) PESciex API-150-EX LC/MS, the pump Shimadzu LC-8A, automatic sampler Gilson 215, injection module Gilson 819, volumetric flow rate of 3.0 ml/min, gradient 10-99% CH3CN (or 0.035% TFA)/H2O (0.05% of TFA), column Phenomenex Luna 5 μm C18 (50×4,60 mm), detector Shimadzu SPD-10A UV/Vis detector Cedex 75 ELSD.

(C) PESciex API-150-EX LC/MS, the pump Shimadzu LC-8A, automatic probe sampler Gilson 215, injection the th module Gilson 819, volumetric flow rate of 3.0 ml/min, gradient 40-99% CH3CN (or 0.035% TFA)/H2O (0.05% of TFA), column Phenomenex Luna 5 μm C18 (50×4,60 mm), detector Shimadzu SPD-10A UV/Vis detector Cedex 75 ELSD.

TESTS AND measurements of the properties of COMPOUNDS to INHIBIT NaV

(A)Optical methods for the evaluation of the inhibitory properties of compounds in relation to NaV

Compounds of the invention are useful as antagonists potentialization sodium ion channels. Antagonistic properties of the tested compounds was evaluated as follows. Cells expressing NV of interest was placed on microtiter plates. After the incubation period, cells were stained with fluorescent dyes that are sensitive to the transmembrane potential. In microtiter tablets were added compound. Cells stimulated or chemical or electrical means, to cause a change in NaV dependent membrane potential from non-blocked channels, which were identified and measured using transmembrane potentialcustomers dyes. Antagonists were detected on the lower membrane potential in response to a stimulus. For optical analysis of the membrane potential used potentialcustomers FRET sensors described by Gonzalez and Tsien (see Gonzalez, J. E. and R. Y. Tsien (1995) “Voltage snsing by fluorescence resonance energy transfr in single cells” Biophys J69(4): 1272-80, and Gonzalez, J. E. and R. Y. Tsien (1997) “Improved indicators of cell membrane potential that use fluorescence resonance energy transfer”Chem Biol4(4): 269-77) in combination with a measuring device for measuring fluorescence changes such as the Voltage/Ion Probe Reader (VIPR®(see Gonzalez, J. E., K. Oades, et al. (1999) “Cell-based assays and instrumentaion for screening ion-channel targets”Drug Discov Today4(9): 431-439).

(C) Method VIPR®optical analysis of the membrane potential with chemical stimulation

Processing of cells and loading dye

24 hours before analysis on VIPR Cho cells, expressing endogenous potentsialzavisimye NaV type NaV1.2, were sown in 96-well coated polylysine tablets in the amount of 60,000 cells per well. Other subtypes were performed similarly on a cell line expressing NaV.

1) on the day of analysis, the medium was drained by suction and the cells were washed twice with 225 ál of wash solution #2 (BS#2).

2) was used to 15 μm CC2-DMPE solution by mixing 5 mm coumarin base solution with 10% pluronic 127, 1:1 and then dissolving the mixture in an appropriate volume of BS#2.

3) After the wash solution was removed from the 96-well plates, the cells were immersed in 80 ál of CC2-DMPE solution. The plates were incubated in the dark for 30 minutes at room temperature.

4) While the cells were stained with coumarin, a sentence is alibali 15 μl of the solution Okolona BS#2. In addition DiSBAC2(3), this solution should contain 0.75 mm ABSCl and 30 ál veratridine (obtained from 10 mm base EtOH, Sigma #V-5754).

5) After 30 minutes CC2-DMPE was removed and cells were washed twice with 225 µl of BS#2. As before, the residual volume should be 40 mm.

6) After removal of the wash bath, the cells were immersed in 80 μl of solution DiSBAC2(3)to achieve the desired concentration in the experience of each well of the tablet was added to the test compound, dissolved in DMSO, with the addition of drugs and thoroughly mixed. The volume of the hole should be roughly 121 μl. Cells then were incubated for 20-30 minutes.

7) After the incubation was completed, the cells are ready for analysis on VIPR®Protocol after adding sodium. Added 120 μl of wash solution #1 to stimulate NaV dependent depolarization. As a positive control antagonist to block NaV channels used 200 μl of tetracaine.

Data analysis VIPR®

Data were analyzed and resulted in a normalized ratios of emission intensities with background subtraction, measured at 460 nm and 580 nm channels. The intensity of the background is then subtracted from each of the analyzed channel. The intensity of the background is obtained by measuring the emission intensities in the same time periods from identically treated analytic is UNOC, with no cells. Response as a function of time is then reproduced in the form of ratios obtained using the following formula:

The data is then converted by calculating the ratio of the initial (Riand Rf) reactions. These ratios represent average ratios for part or all prestimulation period and the time points of sampling during the stimulation period. Then we can calculate the response to the stimulus R=Rf/Ri. For time Windows of analysis after addition of Na+the base line is 2-7 sec, and the selection of the final response is made through 15-24 sec.

The control response obtained using the analysis in the presence of compounds with desired properties (positive control), such as tetracaine, and in the absence of pharmacological agents (negative control). The answer is negative (N) and positive (P) controls are computed as above. Activity And connection antagonist is defined as follows:where R is proportional to the response of the test compounds.

Solutions [mm]

Wash solution #1: NaCl 160, KCl 4.5 Is, CaCl22, MgCl21, HEPES 10, pH of 7.4, with NaOH.

Wash solution #2: TMA-Cl 160, CaCl 20,1, MgCl21, HEPES 10, pH to 7.4 with KOH (final concentration To≈5 mm).

CC2-DMPE: prepared as a 5 mm basic solution in DMSO and stored at -20aboutC.

DiSBAC2(3): prepared in the form of 12 mm base solution in DMSO and stored at -20aboutC.

ABSCl: prepared in 200 mm base solution in distilled water and stored at room temperature.

Cell culture

Cho cells are grown in DMEM (Wednesday Needle, modified by Dulbecco; GibcoBRL #10569-010) supplemented with 10% FBS (fetal bovine serum, diluted; GibcoBRL #16140-071) and 1% Pen-Strep (penicillin-streptomycin; GibcoBRL#15140-122). Cells are grown in containers with vented lids with 90% humidity and 10% CO2up to 100% confluence. They are usually separated using trypsinization 1:10 or 1:20, depending on the planned needs and grown for 2-3 days before the next division.

C) Method VIPR® optical analysis of membrane potential with electric stimulation

The following is an example of how the measured activity inhibition NaV1.3 using optical membrane potential #2. Other subtypes are performed similarly on the line of interest of cells expressing NaV.

Cells NEC expressing NaV1.3, placed in 96-well microtiter plates. After suitable for the subsequent incubation period, cells are stained potentialcustomers dyes CC2-DMPE/DiSBA 2(3) as follows.

Reagents:

100 mg/ml pluronic F-127 (Sigma #P2443) in anhydrous DMSO

10 mm DiSBA2(3) (Aurora #00-100-010) in anhydrous DMSO

10 mm CC2-DMPE (Aurora #00-100-008) in anhydrous DMSO

200 mm ABSCl in water

Balanced salt solution Hank (Hyclone #SH30268.02) supplemented with 10 mm HEPES (Gibco #15630-080)

The Protocol dip:

2 CC2-DMPE=20 μm CC2-DMPE:10 mm CC2-DMPE is mixed with an equivalent volume of 10% pluronic, followed by stirring the required amount of HBSS containing 10 mm HEPES. Each tablet with cells requires 5 ml of 2 CC2-DMPE. In wells containing washed cells, is added 50 μl of 2 CC2-DMPE, resulting in a 10 μm final concentration staining. Cells stained for 30 minutes in the dark at room temperature.

2X DISBAC2(3) with ABSCl=6 μm DISBAC2(3) and 1 mm ABSCl: The quantity required 10 mm DISBAC2(3) add 50 ml conical tube and mixed with 1 ál of 10% pluronic for each ml of solution for joint preparation and mixing. Then add HBSS/HEPES to get 2 solution. Finally add ABSCl.

For solutionone connection on the tablet can be used 2X DiSBAC2(3) solution. It should be noted that the tablets with get connection with a 2X concentration of the drug. Coated tablets are again washed, leaving a residual volume of 50 µl. We use the t 50 ál/well of 2X DiSBAC 2(3) w/ABSCl. Stained for 30 minutes in the dark at room temperature.

Device for electrical stimulation and methods of use described in ION Channel Assay Methods PCT/US01/21652, is shown here for information. The device includes a pointing device for microtiter plates, the optical system for the excitation of coumarin dye with simultaneous registration of emission of coumarin and oxonol, generator, waveform, power adjustable current or voltage and device for inserting electrodes into the hole. Under integrated or combined by computer control of the instrument passes the user-programmed protocols electrical stimulus in relation to the cells within the wells of microtiter plate.

Reagents

Analytical buffer #1

140 mm NaCl, 4.5 mm KCl, 2 mm CaCl2, 1 mm MgCl2, 10 mm HEPES, 10 mm glucose, pH 7,40, 330 mOsm

Source pluronic (1000X): 100 mg/ml pluronic 127 in anhydrous DMSO

Source oxonol (H): 10 mm DiSBAC2(3) in anhydrous DMSO

Source coumarin (1000X): 10 mm CC2-DMPE in anhydrous DMSO

Source ABSCl (400X): 200 mm ABSCl in water

Protocol analysis

1. To enter or use eletrode in each of the analyzed well.

2. To use the adjustable amplifier of current for supplying a stimulation wave pulses within 3 seconds. Conducted two-second performance, muscina registration for unstimulated intensities. Is second poststimulation registration for the evaluation of relaxation to a state of peace.

Data analysis

The data is analyzed and presented as normalized ratios of emission intensities with background subtraction, measured at 460 nm and 580 nm channels. The intensity of the background is then subtracted from each of the analyzed channel. The intensity of the background is obtained by measuring the emission intensities in the same time periods from identically treated analytic wells with no cells. Response as a function of time is then reproduced in the form of ratios obtained using the following formula:

The data is then converted by calculating the ratio of the initial (Riand Rf) reactions. These ratios represent average ratios for part or all prestimulation period and the time points of sampling during the stimulation period. Then we can calculate the response to the stimulus R=Rf/Ri.

The control response is obtained by analysis in the presence of compounds with desired properties (positive control), such as tetracaine, and in the absence of pharmacological agents (negative control). The answer is negative (N) and positive (P) counter is evaluated whether, as the above. Activity And connection antagonist is defined as follows:where R is proportional to the response of the test compounds.

ELECTROPHYSIOLOGICAL ANALYSES ON NaV ACTIVITY AND INHIBITORY EFFECT of the tested COMPOUNDS

To assess the effectiveness and selectivity of blockers of sodium channels in neurons of the dorsal root ganglion was used electrophysiology of fixed potential. The neurons of rats was isolated from dorsal root ganglia and were kept in culture for 2-10 days in the presence of NGF (50 ng/ml) culture medium consisted of NeurobasalA with the addition of B27, glutamine and antibiotics). The small diameter neurons (nociceptors, 8-12 µm in diameter) were visually identified and probed tonkokostnye glass electrodes connected to the amplifier (Axon Instruments). To estimate IC50 (IC50) of compounds within the cells at -60 mV was used the method of “fixing potential.” In addition to testing the effectiveness of compounds in blocking action on the generating capacity in response to current injections were applied way “live clip”. The results of these experiments contribute to the determination of the efficacy of the compounds.

Analysis of FIXATION POTENTIAL in DRG neurons

Register T Is X-stable sodium flows from somata DRG (dorsal root ganglion) using whole cell types of the method of fixation potential. Registration was carried out at room temperature (approximately 22about(C) with thick electrodes of borosilicate glass (WPI; the resistance of 3-4 MΩ) using amplifier Axopatch 200 (Axon Instruments). After establishing the configuration of whole cells before registration was given approximately 15 minutes to balance pipetochnoe solution in the cells. Currents were filtered at slow passage between 2-5 kHz and sampled at 10 kHz. During the experiment, the serial resistance was compensated by 60-70% and continuously monitored. Potential connections liquid (-7 mV) between intracellular pipetochnoe solution and the external recording solution was not taken into account for data analysis. The tested solutions were applied to the cells driven by the force of gravity rapid perfusion (SF-77; Warner Instruments).

The interdependence of the dose-response was determined by the method of fixation potential (voltage) with repeated depolarization of cells from the experimental unit capacity holding up to the experimental potential of +10 mV every 60 seconds. Before proceeding to the next experimental concentration of the blocking effects were superimposed on the plane.

Solutions

Intracellular solution (in mm): Cs-F (130), NaCl (10), MgCl2(1), EGTA (1,5), CaCl2(0,1), HEPES (10), glucose (2), pH=7,42, 290 mOsm.

Valeto the hydrated solution (in mm): NaCl (138), CaCl2(1,26), KCl (5,33), KH2PO4(0.44)and MgCl2(0,5), MgSO4(0,41), NaHCO3(4), Na2HPO4(0,3), glucose (5,6), HEPES (10), CdCl2(0,4), NiCl2(0,1), TTX (0,25×10-3).

Analysis of CONDUCTIVE CLIP on the activity of compounds on the inhibition of NaV channel

The cells were closed current conductive clip in the whole cell configuration using amplifier Multiplamp A (Axon Inst). Borosilicate pipettes (4-5 ohm) were filled with (in mm): 150 K-gluconate, 10 NaCl, 0.1 EGTA, 10 Hepes, 2 MgCl2(buffered to pH 7,34 with KOH). Cells were washed in (in mm): 140 NaCl, 3 KCl, 1 MgCl, 1 CaCl2and 10 Hepes. Before plugging pipetochnoe potential brought to zero; during the process, the potentials of the connection fluid was not adjusted. Registration was made at room temperature.

After these procedures were found to be typical representatives of the compounds of the present invention possess the desired activity and selectivity for potentialization sodium channel.

ANALYSES of DEFINING AND MEASURING properties of COMPOUNDS ON the INHIBITION V

A) Optical methods of analysis V inhibitory properties of compounds

Compounds of the invention are useful as antagonists potentialization calcium ion channels. Antagonistic properties of the tested compounds was assessed with edusim way. Cells expressing V of interest were placed in microtiter plates. After the incubation period the cells were stained with a fluorescent dye sensitive to the transmembrane potential. In microtiter tablets were added compound. Cells were stimulates electrical means to cause a change aV dependent membrane potential from non-blocked channels, which is detected and measured using transmembrane potentialcustomers dyes. Antagonists detected as the response with reduced membrane potential to the stimulus. For optical analysis of the membrane potential was used potentialcustomers FRET sensors described by the authors Gonzalez and Tsien (see Gonzalez, J. E. and R. Y. Tsien (1995) “Voltage snsing by fluorescence resonsnce energy transfer in single cells”Biophys J69(4): 1272-80, and Gonzalez, J. E. and R. Y. Tsien (1997) “Improved indicators of cell membrane potential that use fluorescence resonance energy transfer”Chem Biol4(4): 269-77)in combination with a measuring instrument for measuring fluorescence changes such as the Voltage/Ion Probe Reader (VIPR®(see Gonzalez, J. E., K. Oades, et al. (1999) “Cell-based assays and instrumentation for screening ion-channel targets”Drug Discov Today4(9): 431-439).

Method VIPR®optical analysis of the membrane potential with electric stimulation

The following one is by example as measured by the activity of inhibiting aV2.2 using optical membrane potential. Other subtypes are performed similarly on the line of interest of cells expressing aV.

Cells NECK, stably expressing aV2.2, placed in 96-well microtiter plates. After an appropriate incubation period, the cells are stained potentialcustomers dyes CC2-DMPE/DiSBAC2(3) as follows.

Reagents:

100 mg/ml Pluronic F-127 (Sigma #P2443) in anhydrous DMSO

10 mm DiSB6(3) (Aurora #00-100-010) in anhydrous DMSO

10 mm CC2-DMPE (Aurora #00-100-008) in anhydrous DMSO

200 mm of Acid Yellow 17 (Aurora #VABSC) in water

370 mm barium chloride (Sigma Cat# B6394) in water

The solution X

160 mm NaCl (Sigma Cat# S-9888)

4.5 mm KCl (Sigma Cat# P-5405)

1 mm MgCl2(Fluka Cat# 63064)

10 mm HEPES (Sigma Cat# H-4034)

pH 7.4 using NaOH

The Protocol immersion

2 CC2-DMPE=20 μm CC2-DMPE:10 mm CC2-DMPE is subjected to a rotation with an equivalent volume of 10% pluronic with subsequent rotation in the desired amount of HBSS containing 10 mm HEPES. Each plate with cells requires 5 ml of 2 CC2-DMPE. In wells containing washed cells, is added 50 μl of 2 CC2 - DMPE, resulting in a 10 μm final concentration staining. Cells are stained for 30 minutes in the dark at room temperature.

2X 2DME & DISBAC6(3)=8 μm 2DMPE & 2.5 μm DISBAC6(3): Are rotating along both dye with an equivalent volume of 10% pluronic (in DMSO). Produce rotation in the desired volume of Solution X with beta-cyclodextrin. Each 96-well plate with cells requires 5 ml 2XCC2DMPE. Washed tablet ELx405 with Solution X, leaving a residual volume of 50 µl/well. Add 50 ál 2X2DMPE & DISBAC6(3) in each well. Stained for 30 minutes in the dark at room temperature.

1.5X AY17=750 μm AY17 with 15 mm BaCl2:Add Acid Yellow 17 in the vessel containing the Solution X. Well mixed. Allow the solution to stand for 10 minutes. Slowly mixed with 370 mm VAS2. This solution can be used to solutionone connection on the tablet. Note that the tablets with the connection made with 1,5X concentration of the drug, not the usual 2. Washed painted CC2 tablet again, leaving a residual volume of 50 µl. Add 100 µl/well of a solution AY17. Stained for 15 minutes in the dark at room temperature. Work with plansyou optical reading device.

Device for electrical stimulation and methods of use described in ION Channel Assay Methods PCT/US01/21652, is shown here for information. The device includes a pointing device for microtiter plates, the optical system DL the excitation of the coumarin dye with simultaneous registration of emission of coumarin and oxonol, generator waveform, power adjustable current or voltage and device for inserting electrodes into the hole. Under integrated or combined by computer control of the instrument passes the user-programmed protocols electrical stimulus in relation to the cells within the wells microtiter plates.

Protocol analysis

To enter or use the electrodes in each of the analyzed well.

Use the adjustable amplifier of current for supplying a stimulation wave pulses within 3-5 sec. Is second prestimulation registration for unstimulated intensities. Is second poststimulation registration for the evaluation of relaxation to a state of peace.

Data analysis

The data is analyzed and presented as normalized ratios of emission intensities with background subtraction, measured at 460 nm and 580 nm channels. The intensity of the background is then subtracted from each of the analyzed channel. The intensity of the background is obtained by measuring the emission intensities in the same time periods from identically treated analytic wells with no cells. Response as a function of time is then reproduced in the form of ratios obtained using the following formula:

The data is then converted by calculating the ratio of the initial (Riand Rf) reactions. These ratios represent average ratios for part or all prestimulation period and the time points of sampling during the stimulation period. Then we can calculate the response to the stimulus R=Rf/Ri.

The control response is obtained by analysis in the presence of compounds with desired properties (positive control), such as mibefradil, and in the absence of pharmacological agents (negative control). The answer is negative (N) and positive (P) controls are computed as above. Activity And connection antagonist is defined as follows:where R is proportional to the response of the test compounds.

ELECTROPHYSIOLOGICAL ANALYSES ON aV ACTIVITY AND INHIBITORY EFFECT of the tested COMPOUNDS

To assess the effectiveness and selectivity of calcium channel blockers, expressed in NC cells were used electrophysiology of fixed potential. Cells NEC expressing V2.2, identified visually and probed tonkokostnye glass electrodes connected to the amplifier (Axon Instruments). To estimate IC50 (IC50) is connected to the th, contained in the cells, at -100 mV was used the method of “fixing potential.” The results of these experiments contribute to the determination of the efficacy of the compounds.

Analysis of FIXATION POTENTIAL in NECK cells expressing V2.2

Recorded flows V2.2 of NECK cells using whole cell types receive a fixed potential. Registration was carried out at room temperature (approximately 22about(C) with thick electrodes of borosilicate glass (WPI; the resistance of 3-4 MΩ) using amplifier Axopatch 200 (Axon Instruments). After establishing the configuration of whole cells before registration was given approximately 15 minutes to balance pipetochnoe solution in the cells. Flows were filtered with a slow passage between 2-5 kHz and samples at 10 kHz. During the experiment, the serial resistance was compensated by 60-70% and continuously monitored. Potential connections liquid (-7 mV) between intracellular pipetochnoe solution and the external recording solution was not taken into account for data analysis. The tested solutions were applied to the cells driven by the force of gravity rapid perfusion (SF-77; Warner Instruments).

The interdependence of the dose-response was determined by the method of fixation potential (voltage is placed at a repeated depolarization of cells from the experimental unit capacity holding up to the experimental potential of +20 mV for 50 min at frequencies of 0.1, 1,5, 10, 15 and 20 Hz. Before proceeding to the next experimental concentration of the blocking effects were superimposed on the plane.

Solutions

Intracellular solution (in mm): Cs-F (130), NaCl (10),

MgCl2(1), EGTA (1,5), CaCl2(0,1), HEPES (10), glucose (2), pH=7,42, 290 mOsm.

The extracellular solution (in mm): NaCl (138), aCl2(10), KCl (5,33), KH2PO4(0.44)and MgCl2(0,5), MgSO4(0,41), NaHCO3(4), Na2HPO4(0,3), glucose (5,6), HEPES (10).

After these techniques were found to be typical representatives of the compounds of the present invention possess the desired activity and selectivity in relation to modulation of calcium channel N-type.

1. The compound of formula IA-ii:

or its pharmaceutically acceptable salt,
where (a) the ring formed by R1and R2taken together, selected from




and the ring formed by R1and R2taken together, is optionally substituted at one or more substitutable carbon atoms, nitrogen or sulfur z independent substituents R 4and z is equal 0-2;
b) where z is 0-2, and R4groups, when they are present, each independently represents a halogen, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -COOR', -NR'r COR', -CON(R')2, -OCON(R')2, COR', -NHCOOR', -SO2R', -SO2N(R')2or optionally substituted group selected from C1-C6aliphatic group, phenyl, phenyl C1-C6of alkyl, 5-6-membered heteroaryl ring containing 1-2 heteroatoms selected from nitrogen, sulfur or oxygen, 5-6 membered heteroaryl1-C6of alkyl containing 1-2 heteroatoms selected from nitrogen or sulfur, 5-9-membered monocyclic or bicyclic heterocyclic ring containing 1-3 heteroatom selected from nitrogen, oxygen or sulfur, With6-cycloaliphatic group, a 5-7 membered heterocyclizations group containing 1-3 heteroatoms selected from nitrogen or oxygen, C6-cycloaliphatic C1-C6the alkyl or C5-6-geterotsiklicheskikh C1-C6of alkyl containing 1 nitrogen atom and where each substituent R' represents independently hydrogen or C1-C6aliphatic group, optionally substituted by 1-3 halogen atoms, a 5-6-membered saturated, or fully unsaturated monocyclic ring having 0-2 heteroatoms independently selected from nitrogen, Ki is the oxygen or sulfur, optionally substituted With 1-21-C2alkyl, C1-C2alkoxy, halogeno, triptoreline, ethoxycarbonyl, cyano, oxo or hydroxyl groups; or 9-membered fully unsaturated bicyclic ring system, or two groups R', taken together with the atom(s)to which they are attached, form an optionally substituted 9-membered fully unsaturated monocyclic or bicyclic ring having 0-4 nitrogen atom;
(C) where x is equal to 1, and R3represents halogen, CN, NO2, -OR', -NR'r COR', -CON(R')2or C1-C6aliphatic group, optionally substituted by 1-3 halogen atoms, where each substituent R' represents independently hydrogen, C1-C6aliphatic group or a C1-C6aliphatic group, substituted by 1 to 3 halogen atoms;
d) where y is 0-3, and R5groups, when they are present, are each independently R', halogen, CN, NO2, -N(R')2, -OR', -NR'r COR', -CON(R')2, -S(O)2N(R')2, -OCOR', -OCON(R')2, -NR'r SO2R', or-OP(O)(OR')2where each substituent R' represents independently hydrogen or C1-C6aliphatic group, 3-6-membered saturated, or fully unsaturated monocyclic ring;
e) R5arepresents Cl, Br, F, Me, Et, CN, -OH, -och3, -NHCOCH3, -SO2NH , -SO2NHC(CH3)3, EA(CH3)3-OSON2C(CH3)3-OSEN(CH3)2, CCA(cyclopentyl) or the PINES3;
provided that:
when R1and R2taken together, form an unsubstituted morpholine ring, and the phenyl ring is replaced with an R5aand (R5y represents a 2-forfinal, then R3does not represent a 6-NH2A 6-OHCHN-, 6 HE, 7 HE, 6-MsHN-, 6-AcHN-, 6-fluoro or 6-OMe.

2. The compound according to claim 1,
where (a) R1and R2taken together, represent an optionally substituted ring selected from azetidin-1-yl (jj), pyrrolidin-1-yl (ff), piperidine-1-yl (dd) or piperazine-1-yl (CC);
b) z is 0-2, and R4group, if present, represent, each independently, Cl, Br, F, CF3CH3, -CH2CH3, -COOH, -N(CH3)2, -N(Et)2, -N(iPr)2, -CONH2-SOON3, -OH, -CH2OH, -NHCOCH3, -SO2NH2, -SO2(CH2)3CH3, -SO2CH(CH3)2, -SO2N(CH3)2, -SO2CH2CH3-C(O)och2CH(CH3)2-C(O)NHCH2CH(CH3)2, -NHCOOCH3-C(O)C(CH3)3, -COO(CH2)2CH3, -C(O)NHCH(CH3)2-C(O)CH2CH3or an optionally substituted group selected from piperidinyl, piperazinil, morpholino,1-4/sub> alkoxy, phenyl, phenyloxy, benzyl, -CH2of cyclohexyl, pyridyl, -CH2pyridyl or-CH2thiazolyl;
c) x is 1, and R3represents Cl, Br, F, CF3, -OCF3, Me, Et, CN, -CONH2-HE,- NHCOCH3, -NHCOCH(CH3)2, -CONH(cyclopropyl), -CONHCH3or-CONHCH2CH3;
d) where y is 0-3, and R5groups, when they are present, are each independently Cl, Br, F, Me, Et, CN, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -CONH2, -OH, -och3, -Och2CH3, -NHCOCH3, -SO2NH2, -SO2NHC(CH3)3-EA(CH3)3or-OSON2C(CH3)3;
e) R5arepresents Cl, F, Me, Et, -OH, -och3, -SO2NH2, -SO2NHC(CH3)3-EA(CH3)3-OSON2C(CH3)3OSON(CH3)2, CCA(cyclopentyl) or the PINES3.

3. The compound according to claim 2, where R3is in position 6 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -co3, -Och2CH3or-CN.

4. The compound according to claim 2, where R3is in position 7 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(qi is sapropel), -Och3, -Och2CH3or-CN.

5. The compound according to claim 2, where R3is in position 6 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -Och3or-och2CH3.

6. The compound according to claim 2, where R3is in position 7 chineselanguage ring and is-Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -Och3or-och2CH3.

7. The compound according to claim 2, where R5arepresents Cl, F, Me, Et, -IT or-och3.

8. The compound according to claim 2, where R5ais HE.

9. The compound according to claim 2, where R5ais F.

10. The compound according to claim 2,
where (a) R1and R2taken together, represent an optionally substituted ring selected from azetidin-1-yl (jj), pyrrolidin-1-yl (ff), piperidine-1-yl (dd) or piperazine-1-yl (CC);
b) z is 0-2, and R4group, if present, represent, each independently, Cl, Br, F, CF3CH3, -CH2CH3, -COOH, -N(CH3)2, -N(Et)2, -N(iPr)2, -CONH2-SOON3, -OH, -CH2OH, -NHCOCH3, -SO2NH2, -SO2(CH2)3CH3, -SO2CH(CH3)2, -SO2N(CH3)2, -SO2CH2CH3With(O)och2CH(CH3)2, -C(O)NHCH2CH(CH3)2, -NHCOOCH3-C(O)C(CH3) , -COO(CH2)2CH3, -C(O)NHCH(CH3)2-C(O)CH2CH3or an optionally substituted group selected from piperidinyl, piperazinil, morpholino,1-4alkoxy, phenyl, phenyloxy, benzyl, -CH2of cyclohexyl, pyridyl, -CH2pyridyl or-CH2thiazolyl;
c) R3is independently Cl, Br, F, CF3, -OCF3, Me, Et, CN, -HE or-och3;
d) y is 0 or 1, and R5groups, when they are present, are each independently Cl, Br, F, Me, -OH, -och3, -OCH2CH3, -NHCOCH3, -SO2NH2, -SO2NHC(CH3)3;
e) R5ais F or IT.

11. The compound according to claim 1, where the specified connection choose from any of the following compounds: 200, 202-204, 206-209, 225, 312, 323-324, 349-355, 357, 361-363, 365-367, 415-416, 427-428, 436, 442, 447-448, 457-458, 465-468, 475, 484, 489, 496, 498-501, 510-523, 525-530, 532-539, 549-550, 552-553, 555, 557-572, 577, 581-582, 584-585, 588, 591-592, 594-595, 597-608, 610-615, 618-631, 633-636, 660-666, 668-672, 675, 676, 681-686, 689, 697, 701, 706-707, 711-713, 715-716, 719-720, 726-728, 730, 732, 733, 735-741, 743-745, 747-752, 764, 767-768, 811-824, 831-834, 837-838, 847, 851, 854-855, 860-862, 865-866, 869-870, 875-877, 880, 882-887, 899, 900-901, 904-919, 932, 935-943, 945-952, 963, 965, 987, 990-995, 997-998, 1000-1001, 1003-1012, 1016-1017, 1019-1020, 1025, 1027, 1031, 1033, 1045, 1054, 1056-1058, 1060-1063, 1065-1074, 1078-1081, 1083-1086, 1089-1091, 1103, 1105-1117, 1119-1125, 1127-1141, 1143-1145, 1150-1154, 1156-1160, 1167-1168, 1171, 1173-1174, 1176-1177, 1179, 1185, 1187 and 1190-1193, 1195, 1196, namely:




































































12. Pharmaceutical composition having antagonistic activity against potentialization sodium or calcium ion channels, comprising an effective amount of a compound according to any one of claims 1 to 11, and a pharmaceutically acceptable carrier, the migration tool or diluent.

13. A method of inhibiting one or more of the NaV1.2, NaV1.3, NaV1.8, or CaV2.2 activity in a biological sample, which includes introduction to the contact specified biological sample with a compound according to any one of claims 1 to 11.

14. The method according to item 13, including inhibition aV1.3 or NaV1.8 activity.

15. The method according to item 13, including inhibition of CaV2.2 activity.

16. The method according to item 13, including inhibition of NaV1.8, or CaV2.2 activity.

17. The method according to item 13, including inhibition NaVl.8 activity.



 

Same patents:

FIELD: pharmacology.

SUBSTANCE: present invention refers to compounds of formula (I) , to its N-oxides, salts, stereoisomer forms where n is equal 1, 2 or 3; R1 means cyano group; X means bivalent radical NR2 or O; R2 means hydrogen or C1-10alkyl, each Q1 independently stands for direct coupling, -CH2- or -CH2-CH2-; each R4 independently means hydrogen or C1-4alkyl; each R5a, R5b, R5c independently means hydrogen, C1-4alkyl or arylC1-4alkyl; each R5e, R5f independently means hydrogen, C1-4alkyl or arylC1-4alkyl, or R5e and R5f together can form bivalent alkandiyl radical of formula -CH2-CH2- or -CH2-CH2-CH2-; R11 means aryl, arylC1-4alkyl, C1-4alkylcarbonyl, arylcarbonyl, arylC1-4alkylcarbonyl, C1-4alkyloxycarbonyl, arylC1-4alkyloxycarbonyl, R5aR5bN-carbonyl, hydroxyC1-4alkyl, C1-4alkyloxyC1-4alkyl, arylC1-4alkyloxyC1-4alkyl, aryloxyC1-4alkyl, pyridyl; -a1=a2-a3=a4- means a bivalent radical of formula -CH=CH-CH=CH- (c-1); where one or two hydrogen atoms in (c-1) are substituted by radical C1-6alkyl, C1-4alkoxy, halogen, hydroxy group, (R5g)(R5h)N-(C1-4alkandiyl)-O-trifluoromethyl, cyano group, radical -COOR4, (R5a)(R5b)N-sulphonyl, pyrrolidinyl-sulphonyl, piperidinyl sulphonyl, radical N(R5a)(R5b), radical (a-1), (a-7), morpholinyl, (R5g)(R5h)N-(C1-4alkandiyl)-N(R5c)-, C1-6alkylcarbonylamino, C1-6alkyloxycarbonylamino, C1-6alkylsulphonylamino, (R5a)(R5b)N-C1-4alkyl; R20 means hydrogen, spiro (C2-4alkylenedioxy), spiro (diC1-4alkyoxy) or -NR5gR5h; each R5g or R5h independently means either hydrogen, or C1-4alkyl, or R5g and R5h together with nitrogen atom whereto attached form pyrrolidinyl, piperidinyl or morpholinyl; R3 means nitro group, cyano group, amino group, halogen, hydroxy group or C1-4alkoxy; aryl means phenyl optionally substituted with one or more substitutes chosen from the group consisting of C1-6alkyl, C1-4alkoxy, halogen, hydroxy, amino and trifluoromethyl. Besides it relates to the pharmaceutical composition with antiviral activity, and method for making said compounds.

EFFECT: there are prepared and described new compounds with antiviral activity.

9 cl, 15 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: present invention is related to new crystalline forms of salt of mesylate2,3-dimethyl-8-(2,6-dimethylbenzylamino)-N-hydroxyethyl-imidaso[1,2-a]pyridine-6-carboxamide and to their mixture. Besides the present invention is also related to methods of their preparation, application and pharmaceutical composition for inhibition of gastric acid secretion, which contains them. Production of new salt of 2,3-dimethyl-8-(2,6-dimethylbenzylamino)-N-hydroxyethyl-imidaso[1,2-a]pyridine-6-carboxamide and its crystalline forms for production of medicinal agent for use in treatment or prophylaxis of gastrointestinal disorders such as gastritis, gastric ulcer, duodenal ulcer, peptic ulcerous diseases, reflux-esophagitis, Zollinger-Ellison syndrome, ulcerogenic adenomas of pancreas, acute bleeding from upper compartments of gastrointestinal tract.

EFFECT: wider area of compounds application.

33 cl, 1 tbl, 12 dwg, 8 ex

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of aryl and heteroarylpiperidinecarboxylates, of formula (I): , where: type means integer numbers from 1 to 3, such that m+n is integer number from 2 to 5; p means integer number from 1 to 7; A means simple connection or is selected from one or several groups X, Y; X means -CH2-; Y means C2-alkynilene group; R1 means group R5, substituted with one or several groups R6 and/or R7; R2 means H, F, OH; R3 means H; R4 means H, C1-6-alkyl; R5 means group selected from phenyl, pyridinyl, pyrimidinyl, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, naphthyl, chinolynyl, tetrahydrochinolinyl, isochinolinyl, tetrahydroisochinolinyl, indolyl, indolinyl, isoindolyl, benzimidazolyl, benzoxazolyl, benzizoxazolyl, benzothiazolyl, benzithiazolyl, benzotriazolyl, benzoxadiazolyl, pyrrolopyridinyl; R6 means halogen, CN, C1-6-alkyl, C3-7-cycloalkyl, C1-6-alkoxy, OH, C1-6-fluoroalkyl, C1-6-fluoroalkoxy, or cycle selected from pyrrolidine and piperidine cycle, besides this cycle is unnecessarily substituted with C1-6-alkyl group; R7 means phenyl group, besides group or groups R7 may be substituted with one or several groups R6, identical or differing from each other, selected from halogen, C1-6-alkyl and C1-6-fluoroalkyl, C1-6-alkoxy, in the form of pharmaceutically acceptable base or acid-additive salt.

EFFECT: compounds are applicable as inhibitors of FAAH ferment.

10 cl, 1 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: invention is related to monohydrate of sodium salt S-tenatoprazol, which complies with the following formula: . Invention is also related to method for production of monohydrate of sodium salt of S-tenatoprazol, to application and pharmaceutical composition on its basis for treatment of gastrointestinal pathologies.

EFFECT: production of new compound and pharmaceutical composition on its basis, which may be used in medicine for production of medicinal agents for treatment of gastrointestinal pathologies, gastroesophageal reflux and gastrointestinal haemorrhages in patients, which are prescribed polymedicamental therapy.

19 cl, 9 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of hydantoin with common formula I , where R1 represents cyclobutyl or cyclopropyl; where mentioned group cyclopropyl may be additionally substituted with CH3; R2 represents C1-3alkyl or cyclopropyl; and A, A1 and B independently represent CH or N. Invention is also related to method for production of compounds of formula I, pharmaceutical composition on its basis, its use for making of medicinal agent and to method for inhibition of metal proteinases, based on use of compound of formula I.

EFFECT: new derivatives of hydantoin have activity of metal proteinase inhibitor.

11 cl, 1 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: there are described new isoindole derivatives of general formula (1), wherein A1, A2 and A4 stands for CH, and A3 means N or C-OH; n is equal to 2; R1 represents O; R2-stands for H; and a pharmaceutical composition containing thereof.

EFFECT: new compounds are inhibitors of chaperone protein Hsp90 activity and can be used in chemotherapy of cancerous diseases.

6 cl, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to substituted pyrazolopyridines representing compound of formula (I) , where: 1) Ar-L-A represents: where X2 is chosen from N and CH; 2) A represents phenyl optionally substituted with substitutes in number 1 to 3 chosen from (C1-C6)alkyl, halogenated (C1-C6)alkyl, halogen, OH, O-(C1-C6)alkyl, halogenated O-(C1-C6)alkyl, S-(C1-C6)alkyl, halogenated 8-(C1-C6)alkyl, COOH, N(R8)CO(R9) where R8 represents H or (C1-C6)alkyl, and R9 represents (C1-C6)alkyl; herewith if A is disubsituted, two substitutes A together with benzene ring form benzodioxol fragment; 3) L is chosen from the group composed of: NH-CO-NH, NH-SO2; 4) one of radicals X, Y and Z is chosen from N, and other two radicals Z, Y and X represent CH; or to their pharmaceutically acceptable salts. The offered compounds inhibit reactions catalysed by kinase chosen from FAK, KDR and Tie2. Besides the inventive subject matters are a medicinal agent and a pharmaceutical composition applied for inhibition of specified kinases, particularly application of offered compounds for making the medicinal agent intended for therapy of cancer. There are also offered intermediate compounds for making the compound of formula I.

EFFECT: higher efficiency of new agents.

17 cl, 1 tbl, 41 ex

FIELD: medicine.

SUBSTANCE: invention refers to new derivatives of pyrrolo[3,2-c]pyridine of general formula (I)

where R1 represents hydrogen; linear or branched C1-C6alkyl group optionally substituted with one or more substitutes chosen from the group consisting of C1-C5alkoxy, C3-C7cyclalkyl, 1,3-dioxolanyl, cyano, naphtyl, C2-C5alkenyloxy and 2,3-dihydrobenzo[1,4]dioxinyl; C2-C6alkenyl group; C2-C6alkinyl group; or benzyl group optionally substituted with one or more substitutes chosen from the group consisting of halogen, C1-C3alkyl, C1-C3alkoxy, cyano, C1-C3alkoxycarbonyl and trifluoru-C1-C3alkyl, R2 represents linear or branched C1-C6alkyl group, R3 represents hydrogen; linear or branched C1-C6alkyl group optionally substituted with hydroxyl or cyano, and R4 represents 1,2,3,4-tetrahydroisoquinolinic group optionally substituted with one or more halogens or C1-C5alkyls; benzyloxy-group optionally substituted with one or more halogens or C1-C5alkyls; or benzylamino group optionally substituted with halogen, and also to the method for making thereof and the pharmaceutical composition inhibiting proton pump.

EFFECT: there are produced and disclosed new compound with inhibitory action on the proton pump and ability to ensure reversible inhibitory effect of the proton pump.

7 cl, 45 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a new derivative of sulfonamide substituted imidazoquinolines, and specifically to N-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo-[4,5-c]-qunolin-1-yl]-1,1-dimethylethyl}-methanesulfonamide and its pharmaceutically acceptable salts, as well as to a pharmaceutical composition based on this compound.

EFFECT: invention also relates to a method of inducing biosynthesis of cytokines in an animal organism and methods of treating viral and oncological diseases in animals using said compound and pharmaceutical composition based on said compound.

5 cl, 1 tbl, 39 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 5-methoxy-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-6-methyl-3H-imidazo[4,5-b]pyridine or to its salt, as well as a pharmaceutical composition which inhibits secretion of gastric acid based on the said compound. Description is given of production of the new compound and a pharmaceutical composition based on the new compound, which can be used in medicine for treating such diseases as gastric ulcer, duodenal ulcer, stomal ulcer, gastroesophageal reflux, Zollinger-Ellison syndrome, symptomatic gastroesophageal reflux, endoscopy negative gastroesophageal reflux, gastroesophageal regurgitation, pharyngolaryngeal paresthesia, Barrett's esophagus, Non-steroidal anti-inflammatory drug (NSAID) induced ulcer, gastritis, gastric hemorrhage, gastrointestinal hemorrhage, peptic ulcer, bleeding ulcer, stress ulcer, gastric hyperchlorhydria, dyspepsia, gastroparesis, senile ulcer, intractable ulcer, heartburn, bruxism, stomach ache, heavy stomach or erosive gastritis.

EFFECT: increased effectiveness of composition and disease treatment.

7 cl, 6 tbl, 29 ex

FIELD: medicine.

SUBSTANCE: invention is related to compounds with common formulae I , III , IV and V , value of radicals such as given in formula of invention. Also suggested invention is related to pharmaceutical composition in the basis of above-mentioned compounds, to their use, and also to method of frequent urination treatment, enuresis and increased activity of urinary bladder.

EFFECT: increased efficiency of diseases treatment, in particular for treatment of frequent urination and enuresis, increased activity of urinary bladder and pain.

16 cl, 406 ex, 73 tbl

V:

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 1,3-diiminoisoindoline, and more specifically to N1,N3-bis(5-amino-3-pentyl-1,3,4-thiadiazol-2-ylidene)-2H-isoindole-1,3-diamine. This compound is soluble in organic solvents and can be used for colouring hydrocarbons, synthetic fibre, fats, wax, alcohols, polymers of plastics, rubber.

EFFECT: wider assortment of fat-soluble light tone dyes.

1 cl, 2 dwg, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), their enatiomers, racemates and pharmaceutically acceptable salts, as well as a pharmaceutical composition based on said inhibitors and method of treating, preventing or suppressing inflammation and other conditions which are mediated by activity of leukotriene A4-hydrolase. In general formula (II) , X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is O; Z is chosen from a group which consists of O and a bond; W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to the nitrogen atom which is bonded to the said W; R4 is chosen from a group which consists of H, OCH3 and Cl; R6 is H or F; and R2' and R3' are each independently chosen from a group which consists of: A) H, C1-7alkyl, C3-7cycloalkyl, C3-7cycloalkyl-C1-7alkyl, where each of substitutes (A) is independently substituted with 0 or 1 RQ, where each of said RQ is a carbon atom substitute, which is at least one carbon atom, separate from nitrogen atom; B) HetRa substitute; C) -C1-7alkyl-C(O)Rx; H) -C0-4alkyl-Ar5, where Ar5 is a 5-member heteroaryl, which has one heteroatom, chosen from a group >NRY, and 0 or 1 additional heteroatom -N=, and optionally contains two carbonyl groups, and optionally benzo-condensed; I) -C0-4alkyl-Ar5' , where Ar5' is a 5-member heteroaryl, which contains 3 or 4 nitrogen atoms; M) SO2C1-4alkyl; alternatively, R2' and R3', taken together with a nitrogen atom with which they are bonded, form a heterocyclic ring which contains at least one heteroatom, which is the said bonded nitrogen atom, where the said heterocyclic ring is chosen from a group which consists of i) 4-7-member heterocyclic ring HetRb, where the said 4-7-member heterocyclic ring HetRb has one heteroatom, which is the said bonded nitrogen atom, and is substituted with 0, 1 or 2 identical or different substitutes, where the said substitutes are chosen from a group which consists of -RY, -CN, -C(O)RY, -C0-4alkyl-CO2RY, -C0-4alkyl-C(O)CO2RY, -C0-4alkyl-ORY, -C0-4alkyl-C(O)NRYRZ-, -C0-4alkyl-NRYC(O)RZ-, -C(O)NRZORY, -C0-4alkyl-NRYCO2RY, -C0-4alkyl-NRYC(O)NRYRY, -C0-4alkyl-NRYC(S)NRYRZ, -NRYC(O)CO2RY, -C0-4alkyl-NRWSO2RY, 1,3-dihydrobenzoimidazol-2-on-1-yl, 1-RY-1H-tetrazol-5-yl, RY-triazolyl, 2-RY-2H-tetrazol- 5-yl, -C0-4alkyl-C(O)N(RY)(SO2RY), -C0-4alkyl-N(RY)(SO2)NRYRY, -C0-4alkyl-N(RY)(SO2)NRYCO2RY, halogen, , ,; ii) 5-7-member heterocyclic ring HetRC which has one additional heteroatom separated from the said bonded nitrogen atom by at least one carbon atom, where the said additional heteroatom is chosen from a group which consists of O, S(=O)2 and >NRM, where the said 5-7-member heterocyclic ring HetRC has 0 or 1 carbonyl group and is substituted with 0, 1 or 2 substitutes at identical or different substituted carbon atoms, where the said substitutes are chosen from a group which consists of -C(O)RY and RZ; iii) one of 1H-tetrazol-1-yl, where 1H-tetrazol-1-yl is substituted at the carbon atom by 0 or 1 substitute such as -C0-4alkyl-RZ, -C0-4alkyl-CO2RY; and iv) one of benzimidazol-1-yl, 2,8-diazospiro[4.5]decan-1-on-8-yl, 4-{[(2-tert-butoxycarbonylaminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 4-{[(2-aminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 9-yl-tert-butyl ether 3,9-diazaspiro[5.5]undecane-3-carboxylic acid, 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl, and where substitute HetRa is a 6-member heterocyclic ring, with a carbon atom at the bonding site and contains a >NRM group as a heteroatom, where the said heteroatom is separated from the said carbon atom at the bonding site with at least 1 additional carbon atom; Rk is chosen from a group which consists of H and -C1-4alkyl; RL is chosen from a group which consists of -CO2RS; RS is hydrogen; RM is chosen from a group which consists of RZ, -C(O)RY; RN is chosen from a group which consists of OCH3, CI, F, Br, I, OH, NH2, CN, CF3, CH3 and NO2; RQ is chosen from a group which consists of -CN, -C0-4alkyl-ORY, -C0-4alkyl-CO2RY, -C0-4alkyl-NRYRY, -C0-4alkyl-NRYCORY, -C0-4alkyl-NRYCONRYRZ, -C0-4alkyl-NRYSO2RY; RW is chosen from a group which consists of RY; RX is chosen from a group which consists of -ORY, -NRYRZ, -C1-4alkyl and -C1-4alkyl-RAr; RY is chosen from a group which consists of H, C1-4alkyl, -C0-4alkyl-RAr and -C0-4alkyl-RAr', each of which is substituted with 1 or 2 RN substitutes; RZ is chosen from a group which consists of RY, -C1-2alkyl-CO2RY ; RAr is a radical with a carbon atom at the bonding position, where the said radical is chosen from a group which consists of phenyl, pyridyl and pyrazinyl, where each carbon atom with permissible valence in each of the said groups is independently substituted with at least 0, 1 or 2 RN or 0 or 1 RL; RAr' is a 5-6-member ring which has 1 or 2 heteroatoms, chosen from a group which consists of O, S, N and >NRY, and has 0 or 2 unsaturated bonds and 0 or 1 carbonyl group, where each member with permissible valence in each of the said rings is independently substituted with 0 or 1 or 2 RK; Description is given of inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), a composition which contains these inhibitions, and their use for inhibiting activity of the LTA4H enzyme, as well as for treating, preventing or suppressing inflammation and/or conditions which are associated with such inflammation. In the said formula (I): X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is chosen from a group which consists of CH2 and O, W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to a nitrogen atom; R4 is chosen from a group which consist of H, OCH3, CI, F, Br, OH, NH2, CN, CF3 and CH3; R6 is H or F; and R2 and R3 are each independently chosen from different groups.

EFFECT: new compounds have useful biological activity.

43 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

SUBSTANCE: in new compounds with formula (I): (I) A is absent or represents (CH2)2; L is CH or N; M is NR1, O, S, S(O) or S(O)2; R1 is C1-6alkyl, substituted with phenyl {which itself is possibly substituted with halogen, C1-4alkyl, C1-4alkoxy, CF3}; phenyl {which is possibly substituted with halogen, C1-4alkyl, C1-4alkoxy, CF3, C1-4alkylthio}, S(O)2R, S(O)2NR6R7, C(O)R8; R2 is phenyl (which is possibly substituted with halogen, CN or C1-4halogenalkyl), thienyl or halogenthienyl; R3 is hydrogen or methyl; Rb is hydrogen or C1-3alkyl; R4 is a five- or six-member heterocycle, containing at least one carbon atom, one to four nitrogen atoms and, possibly, one oxygen or sulphur atom, where the carbon atom in the said heterocycle R4 is possibly substituted with oxo, C1-6alkyl [which is possibly substituted with halogen, OH, C1-4alkoxy, S(C1-4alkyl) group or piperidinyl {which it self is possibly substituted with benzene [which is possibly substituted with a S(O)2(C1-4alkyl) group], C(O)(C1-4alkoxy) group, C(O)NH2, C(O)NH(C1-4alkyl), C(O)N(C1-4alkyl)2 or S(O)2(C1-4alkyl) [where alkyl is possibly substituted with fluoro]}], C3-6cycloalkyl, CN, C(O)NH2, C(O)NH(phenylC1-2alkyl) group, phenyl [which is possibly substituted with a S(O)2(C1-4alkyl) group] or benzyl [which is possibly substituted with a S(O)2(C1-4alkyl) group]; if possible, the nitrogen atom in the said heterocycle R4 is substituted with C1-6alkyl [which is possibly substituted with C1-4alkoxy, S(O)(C1-4alkyl) group, S(O)2(C1-4alkyl), C(O)(C1-4alkoxy), CONH2, CONH(C1-4alkyl), CON(C1-4alkyl)2, phenyl{which is possibly substituted with C1-4alkyl, C1-4alkoxy, S(O)(C1-4alkyl) group or S(O)2(C1-4alkyl)}, piperidinyl {which is possibly substituted with a S(O)(C1-4alkyl) group or S(O)2(C1-4alkyl)}], C3-6cycloalkyl, CO(C1-4alkyl) group [which is possibly substituted with a halogen], S(O)2(C1-4alkyl) group [which is possibly substituted with fluorine], COO(C1-6alkyl) group, phenyl [which is possibly substituted with a S(O)(C1-4alkyl) or S(O)2(C1-4alkyl) group]; - under the condition that the nitrogen atom in the said heterocycle R4 is substituted with an alky group, the said alkyl does not have C1-4alkoxy, S(O)(C1-4alkyl) or S(O)2(C1-4alkyl) substitute on the carbon atom, bonded to the nitrogen atom in the said heterocycle R4; - five- or six-member heterocyle R4 is possibly condensed with cyclohexane, piperadine, benzole, pyridine, pyridazine, pyrimidine or pyrazine ring; ring carbon atoms in the said condensed cyclohexane, piperadine, benzole, pyridine, pyridazine, pyrimidine or pyrazine ring are possibly substituted with a halogen, C1-4alkyl, C1-4alkoxy, CF3, S(C1-4alkyl), S(O)(C1-4alkyl) or S(O)2(C1-4alkyl) group; and the nitrogen atom of the condensed piperidine ring is possibly substituted with C1-4alkyl [which is possibly substituted with oxo, halogen, OH, C1-4alkoxy, C(O)(C1-4alkoxy), C(O)NH2, C(O)NH(C1-4alkyl) group, C(O)N(C1-4alkyl)2 group, C(O)(C1-4alkyl)group [where alkyl is possibly substituted with C1-4alkoxy or halogen], benzene [which is possibly substituted with S(O)(C1-4alkyl) or S(O)2(C1-4alkyl)], C(O)(C1-4alkoxy), C(O)NH2, C(O)NH(C1-4alkyl), C(O)N(C1-4alkyl)2 or S(O)2(C1-4alkyl) group [where alkyl is possibly substituted with fluoro]; R5 is C1-6alkyl [which is possibly substituted with a halogen (for example fluoro), C1-4alkoxy, phenyl {which itself is possibly substituted with a halogen, C1-4alkyl, C1-4alkoxy}], C3-7cycloalkyl (which is possibly substituted with a halogen or C1-6alkyl), piranyl, phenyl {which is possibly substituted with halogen, C1-4alkyl, C1-4alkoxy}, or a 5- or 6-member saturated nitrogen-containing heterocyclic ring {which is possibly substituted with a S(O)2(C1-4alkyl) or C(O)(C1-4alkyl) group}; R8 is hydrogen, C1-4alkyl [which is possibly substituted with halogen (for example fluro), C1-4alkoxy, phenyl{which itself is possibly substituted with halogen, C1-4alkyl, C1-4alkoxy}], C3-7cycloalkyl (which is possibly substituted with halogen or C1-4alkyl), piranyl, phenyl {which is possibly substituted with halogen, C1-4alkyl, C1-4alkoxy}, or a 5- or 6-member saturated nitrogen-containing heterocyclic ring {which is possibly substituted with S(O)2(C1-4alkyl) or C(O)(C1-4alkyl) group}; R6 and R7 are bonded, forming a 5- or 6-member ring which is possibly substituted with C1-4alkyl; R9 and R10 independently represent hydrogen or C1-6alkyl; or to its pharmaceutically acceptable salts. The invention also relates to a method of obtaining compounds in paragraph 1, to a method of modulating activity of CCR5 receptor, as well as to a pharmaceutical composition.

EFFECT: obtaining new biologically active compounds with modulating effect towards CCR5 receptor.

15 cl, 29 ex, 12 tbl

FIELD: chemistry.

SUBSTANCE: invented compounds have inhibitory activity towards protein kinase. In formula 1a m lies between 0 and 1, R1 is chosen from a group which includes hydrogen, methyl, isopropyl, imidazolylpropyl, piperazinylpropyl, pyridinyl, diethylaminopropyl, hydroxyethyl, pyrimidinyl, morpholinopropyl, phenyl, cyclopropyl, morpholinoethyl, benzyl and morpholino, where any of pyridinyl, imidazolyl, piperazinyl or pyrimidinyl in R1 are optionally substituted with 1-3 radicals, independently chosen from a group, which includes methyl, methylamine, dimethylaminomethyl, cycloproylamine, hydroxyethylamine, diethylaminopropylamine, pyrrolydinylmethyl, morpholino, morpholinomethyl, piperazinylmethyl and piperazinyl, where any of morpholino and piperazinyl in R1 are optionally further substituted with a radical, chosen from a group which includes methyl, hydroxyethyl and ethyl, R2, R3 and R5 each represents hydrogen, R4 represents methyl, L is chosen from a group which includes -NR5C(O)- and -C(O)NR5-, R10 represents trifluoromethyl, and R11 is chosen from a group which includes halogen, morpholinomethyl, piperazinyl, optionally substituted with a methyl, ethyl or hydroxyethyl group; piperazinylmethyl, optionally substituted with a methyl or ethyl group, imidazolyl, optionally substituted with methyl, pyrrolidinylmethoxy and piperidinyl, optionally substituted with a hydroxy group.

EFFECT: more effective treatment.

4 cl, 1 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention covers thaizole derivatives of formula (I) and to their pharmaceutically acceptable salts. In formula I: X1 and X2 differ from each other and represent sulphur atom or carbon atom; R1 represents phenyl group; phenyl group substituted by 1-2 members chosen from the group including halogen atoms, alkoxygroup with 1-6 carbon atoms, hydroxygroup, phenylalkoxygroup with 7-12 carbon atoms; phenyl group fused with 5-7-membered heteroaromatic or nonaromatic ring with at least one heteroatom consisting of N, O and S; pyridyl group; R2 represents hydrogen atom, halogen atom, alkyl group with 1-6 carbon atoms, alkyl group with 1-6 carbon atoms substituted by 1-5 halogen atoms, alkoxygroup with 1-6 carbon atoms, or hydroxyalkyl group with 1-5 carbon atoms; A represents group which is presented by formula or . Also, the invention concerns ALK5 inhibitor containing compound of the invention as an active component, stimulators of hair follicles proliferation and hair growth, and also to thiazole derivative of formula where A1 represents .

EFFECT: higher efficiency.

12 cl, 2 tbl, 50 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: present invention refers to the aminopyridin compound of general formula (I) or its salt wherein X1, X2, X3, Z, Y1, Y2 are carbon or nitrogen atom, R, R1, R5, R6 are hydrogen atom, alkyl group, further see formula of the invention, and R7 is hydrogen or halogen atom, nitro or cyano group, -CpH2(p-1)(Ra1)(Ra2)-O-Ra3, -C(=O)-Rd1, 5-or 6-membered saturated heterocycle group, aromatic heterocycle group, -N(Rh1)(Rh2), further see formula of the invention. The invention refers also to the pharmaceutic composition thereof intended for treatment or prevention of allergic diseases, autoimmune diseases caused by malignant tumour, to the Syk inhibitor containing the compound of formula I and to the therapeutic and/or preventive agent.

EFFECT: compounds which not only possess high Syk inhibition activity but are selective Syk inhibitors are obtained and described.

24 cl, 24 ex, 2 tbl

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: chemistry; medicine.

SUBSTANCE: compounds of claimed invention possess properties of positive allosteric modulator mGluR5. In general formula I , W represents 6-member heterocycloalkyl ring with 1-2 heteroatoms, selected from N, O; R1 and R2 independently represent hydrogen, C1-C6-alkyl; P and Q each independently is selected from: , R3, R4, R5, R6 and R7 independently represent hydrogen; halogen; -CN; nitro; C1-C6-alkyl; C3-C6-cycloalkyl; halogen-C1-C6-alkyl; 5-6-member heteroaryl with 1-2 atoms N as heteroatoms; 6-member heterocycle with 2 heteroatoms representing N, O; phenyl, optionally substituted with halogen; naphtyl; -OR8; where optionally two substituents together with located between them atoms form 9-10-member bicyclic aryl or heteroaryl ring with 1-2 heteroatoms, selected from N, S; R8 represents hydrogen, C1-C6-alkyl; D, E, F, G and H independently represent -C(R3)=, -O-, -N=, -N(R3)- or -S-; A represents ethinyl, -C(=O)NR8- or group of formula . B represents -C(=O)-C0-C2-alkyl-, -C(=O)-C2-C6-alkenyl-. Invention also relates to pharmaceutical composition based on invention compounds.

EFFECT: novel compounds possess useful biological proprties.

20 cl, 3 dwg, 75 ex

FIELD: chemistry.

SUBSTANCE: invention is related to compounds of formula (II) as inhibitor of leukotriene A4-hydrolase (LTA4H) and their enantiomers, racemic compounds and pharmaceutically acceptable salts, and also to treatment methods, method inhibition and pharmaceutical composition on their basis. In general formula (II) , X is selected from group that consists of O and S; Y is selected from group that consists of CH2 and O; R4 represents H; R6 represents H or F; and R2' is determined as R2, and R3' is determined as R3, as follows: R2 and R3, each, is independently selected from group that consists of A) H, C1-7alkyl, C3-7cycloalkyl, where each of substitutes of A) is independently substituted with 0 or 1 RQ, and each of mentioned RQ is substitute at carbon, which is distanced from nitrogen at least by one carbon atom; alternatively, R2 and R3, taken together with nitrogen, to which they are connected, create heterocyclic ring, which contains at least one heteroatom, which is specified nitrogen of connection, and specified heterocyclic ring is selected from group that consists of i) (4-7)-member heterocyclic ring HetRb, where specified (4-7)-member heterocyclic ring HetRb has single heteroatom, which is specified nitrogen of connection, and 0, 1 or 2 are substituted by substitutes at the same or different substituted atoms, at that specified substitutes are selected from group that consists of -RY, -C(O)RY, -C0-4alkylCO2RY, -C0-4alkylC(O)NRYRZ, -C0-4alkylNRYC(O)Rz, -C0-4alkylNRYC(O)CH2ORY, -C0-4alkylNRYCO2RY, -C0-4alkylNRYC(O)NRYRz, -C0-4alkylNRyC(S)NRyRz, -NRyC(O)CO2Ry, -C0-4alkylNRwSO2RY, tetrazol-5-yl, -C0-4alkylN(RY)(SO2)NRYRY, -C0-4alkylN(RY)(SO2)NRYCO2RY, ii) (5-7)-member heterocyclic ring HetRc, where specified (5-7)-member heterocyclic ring has single additional heteroatom distanced from specified nitrogen of connection at least by one carbon atom, thereat the specified additional heteroatom is selected from group that consists of O, S(=O)0-2 and >NRM, and where mentioned (5-7)-member heterocyclic ring HetRc has 0 or 1 carbonyl group; iv) one of 2,8-diazaspyro[4.5]decan-1-on-8-yl, 4-{[(2-tret- butoxycarbonylaminocyclobutancarbonyl)amino]methyl}-piperidine-1-yl, 4-{[(2-aminocyclobutancarbonyl)amino]methyl}piperidine-1-yl, tret-butyl ether of 3,9-diazaspyro [5.5]undecan-3-carbonic acid-9-yl; where RK is selected from group that consists of H, -C1-4alkyl, each not necessarily substituted by 1 substitute RN; RM is selected from group that consists of -SO2RY, -C(O)RY, -C(O)C1-4alkylORY, each not necessarily substituted by 1 substitute RN; RN is selected from group that consists of OH, NH2, CF3; RQ is selected from group that consists of -C0-4alkylRAr', -C0-4alkylCO2RY, -C0-4alkylNRYRz, -C0-4alkylNRYCORY, -C0-4alkylNRyCONRyRz; Rw is selected from group that consists of RY and -C3-7cycloalkyl; RY is selected from group that consists of H, -C1-4alkyl, -C0-4alkylRAr and -C0-4alkylRAr', each not necessarily substituted by 1 substitute RN; Rz is selected from group that consists of RY, -C1-2alkylCO2RY; RAr represents fragment connected via carbon atom, and specified fragment is selected from phenyl, pyridyl; RAr' represents (5-6)-member cyclic ring, having 1 or 2 heteroatoms selected from group that consists of O, N and >NRY, having 0 unsaturated connections, having 0 or 1 carbonyl group, where each atom, when allows for valency, in every of mentioned cyclic rings is independently substituted by 0 or 1 RK; provided that (a) specified R2' and R3', moreover, satisfy the following requirements: (e1): specified R2' and R3', both, are not H, when Y represents O and X represents S; (e3): specified R2' and R3', taken together with nitrogen, with which they are connected, do not create piperazine group, when X represents O and Y is one of O and CH2; (e4): specified R2' and R3', taken together with nitrogen, with which they are connected, do not create piperidine group, which is mono-substituted by 6-member cyclic group, when X represents O and Y is one of O and CH2; and (e5): specified R2' and R3', taken together with nitrogen, with which they are connected, create neither substituted piperidine group or substituted piperazine group, where specified substituted piperidine group or specified substituted piperazine group is substituted in position 4 by substitute XG, at that specified XG has structure , where n=0, 1, and when ne=1, then XL represents C1-6alkyl, OSG represents O or S, and XR1 and XR2, taken together with nitrogen, with which they are connected, create one of piperidine group, piperazine group, morpholine group, thiomorpholine group and pyrrolidine group, or each of XR1 and XR2, taken independently, represent one of H, C1-6alkyl, aryl, aralkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-6alkyl, heteroalkyl, heteroaryl-C1-6alkyl, heterocycloalkyl and heterocycloalkyl-C1-6alkyl; where aryl, aralkyl, cycloalkyl, heteroaryl or heterocycloalkyl may be not necessarily substituted by one or several substitutes, independently selected from halogen, hydroxy, C1-6alkyl, C1-6alkoxy, halogenated C1-6alkyl, halogenated C1-6alkoxy, nitro, cyano, amino, C1-4alkylamino, di(C1-4alkyl)amino, heteroaryl or heterocycloalkyl; and (b) further provided that when X represents S and Y represents O, then one of R2' and R3' is not XCG, while the other represents C1-6alkyl, where XCG represents group , where HC16 represents one of H, C1-6alkyl, halogenC1-6alkyl, allyl and C1-6alcoxymethyl, and GO represents group connected to carbon atom, which has substitute =0, creating amido group with nitrogen, with which all mentioned GO group is connected.

EFFECT: compounds may find application for treatment and prevention of diseases mediated by LTA4H, for instance, asthma, chronic obstructive lung disease, atherosclerosis, rheumatoid arthritis, disseminated sclerosis, inflammatory disease of bowels and psoriasis.

39 cl, 8 tbl, 12 dwg, 484 ex

FIELD: pharmacology.

SUBSTANCE: invention refers to compounds of formula (I) as inhibitor of phosphotyrosinphosphotase 1B, and to application thereof for making a based medical product. In general formula (I) X represents C-R2; Y represents O, R1 represents phenyl, 5-merous heterocycle with one sulphur atom with phenyl residue, and heterocyclic residue being mono-, twice- or trisubstituted with halogen, CN, -OH, -CF3, -(C1-C6)alkyl, -COOH, -(CH2)-COOH, phenyl, -O-phenyl with phenyl ring being substituted with halogen; R2, R3, R4, R5, R6, R7 and R8 represent H.

EFFECT: compounds can find application in treating adipose and carbohydrate metabolic disorders, including for controlling blood glucose.

3 cl, 2 tbl, 8 ex

Up!