JP2008524294A - Compounds that interact with ion channels, especially Kv family ion channels - Google Patents

Abstract

The present invention relates to compounds that interact with ion channels.
In particular, the invention relates to structural formula (I), (II), (III) or (IV), stereoisomers, tautomers, racemates, prodrugs, metabolites thereof, or pharmaceutically acceptable And / or a compound having a solvate thereof.
Formula (I), (II), (III), (IV):

Wherein X ¹ , X ² , Y, Z, W, R ¹ , R ⁸ , R ⁹ , R ¹⁰ , L, A, z, and n have the meanings defined in claim 1.
The invention also relates to methods for producing the compounds, pharmaceutical compositions comprising the compounds, and the use of said compounds in methods for treating the human and animal body.

Description

  The present invention relates to compounds that interact with ion channels.

  In particular, the present invention relates to compounds that interact with ion channels of the Kv family, in particular the Kv4 subfamily.

  The invention also provides a method for producing the compound, a pharmaceutical composition comprising the compound, and the use of the compound in a method for treating the human and animal body, and / or for producing the pharmaceutical composition. It relates to the use of the compounds.

  The compounds of the present invention can be used, for example, for the prevention and / or treatment of symptoms or diseases associated with ion channels, specifically, for the prevention and / or treatment of symptoms and diseases associated with ion channel Kv family. More specifically, it can be used for the prevention and / or treatment of symptoms and diseases associated with the ion channel Kv4 family.

  Other aspects, embodiments, uses and advantages of the present invention will become apparent from the following more detailed description.

  The Kv4 channel has been described in the art accordingly for its coding sequence, biological function / activity, and disease association, for example, Bahring et al., J. Biol. Chem., Vol. 276, no. 26, 233888-23894 (2001); Baldwin et al., Neuron 7: 471-483 (1991); Dixon et al., Circ. Res. 79: 659-688 (1996); Dilks et al., J. Neurophysiol. 81: 1974 -1977 (1999); Kuo et al., Cell, Vol. 107, 801-813 (2001); Pak et al., Proc. Natl. Acad. Sci USA 88, 4386-4390 (1991); Ohya et al., FEBS Lett. 47-53 (1997); Roberts and Tamkun, Proc. Natl. Acad. Sci USA 88, 1798-1802; Rudy et al., Mol. Cell. Neurosci. 2, 89-102 (1991); Serodio et al., J. Neurophysiol 75 : 2174-2179 (1996); Serodio and Rudy, J. Neurophysiol. 79: 1081-1091 (1998); and Takimoto et al., Circ. Res. 81: 553-539 (1997), and cited therein, and more. See detailed references.

  In general, because Kv4 channels are voltage-gated potassium channels, they are involved, inter alia, in the events of membrane depolarization and repolarization, eg as part of and / or following neuronal firing and / or muscle Involved as part of the contraction / relaxation cycle.

  Specifically, as described in the above references, the Kv4 channel is a wild type generated by various types of primary cultured cells (Dilks et al., Supra), particularly primary cultured cells in muscle and nerve cells. It is believed to be involved in type A current. Kv4.2 and Kv4.3 transcripts are found in most neurons, especially CNS neurons (see Serodi and Rudy above, discussing the distribution of Kv4 channels in rat brain), as well as myocardium (Dixon et al. See, and by Serodio et al., Both noted above, which discuss the abundance and distribution of Kv4 transcripts in rat, dog, and human hearts). Compared to other family Kv-type channels, such as Kv1-type channels, it has also been found that Kv4 channels are activated, inactivated at subthreshold potentials, and inactivated by time constants, which are voltage As a function of (even at extreme negative potentials) with little change and very quickly recovering from inactivation (see Rudy and Serodio above).

  In neurons, particularly brain neurons, Kv4 channels are particularly important for firing rate modulation, action potential initiation, burst pattern formation, and integration of post-synaptic signals (Dilks et al. And Bahring et al. Above) And is believed to be involved in physiological conditions / diseases resulting from such activity (Serodio and Rudy, supra).

In the heart, Kv4 channels are thought to play an important role, especially in the myocardium (“transient outward current” or l _to ), especially in calcium-independent type A currents in ventricular muscles, and thus early reactivation. It is believed to be involved in polarization and thus in the overall duration of action potentials and the length of the refractory period (Serodio and Rudy, supra). For this reason, Kv4 channels are thought to be involved in heart disease (susceptibility to), such as arrhythmias and other types of heart failure (Kuo et al., Supra).

  So far, three mammalian Kv4 genes have been named Kv4.1 (also known as mSha1), Kv4.2 (also known as RK5) and Kv4.3, respectively, ie rat and dog (Dixon et al., Serodio et al., Ohya et al., And Takimoto et al., All described above) and from humans (Dilks et al., And Bahring et al., Supra, eg, WO 98/42833 and US Publication No. 6,395, 477), and has been cloned and characterized.

  Gene sequences encoding mammalian Kv4 channels can also be obtained from publicly available databases such as GenBank / NCBI, eg, mouse-derived Kv4.1 (accession numbers NP_032449 and A38372), human-derived Kv4 .1 (accession numbers BAA96454, AAF65617, and AF65516), mouse-derived Kv4.2 (accession numbers NP_062671 and AAD16972), rat-derived Kv4.2 (accession number NP_113918); human-derived Kv4.2 (accession number AAD22053) And CAB56841), mouse-derived Kv4.3 (accession numbers NM_019931 and AF384170), rat-derived Kv4.3 (accession number U 42975) and human-derived Kv4.3 (accession number XM — 052127) are available.

  The above references also show that additional channels from the Kv4 family may be identified and cloned in the future, eg, Kv4.1, Kv4, although brain neurons show Kv4-like subthreshold A channel. .2 and / or does not show abundant expression of the Kv4.3 transcript (see Serodio and Rudy above) or similarly in other suitable tissues / cells.

  As noted above, the mammalian Kv4 channel also has a high degree of sequence homology (> 70%) with the Shal-like gene product encoding the Drosophila potassium channel and is therefore considered to be closely related. (See Baldwin et al., WO 01/58952, above).

  In WO 03/097682, the applicant gives the Kv channel of a compound using a genetically engineered strain of C. elegans that expresses a heterologous Kv channel, such as a human Kv4.3 channel. An assay for quantifying the effect is described. Other assays and techniques for quantifying the effects of test compounds on common ion channels, particularly on Kv channels, will be apparent to those skilled in the art, for example, the FLIPR method and the use of oocytes. It is also described in 03/097682. Such assays can be used to determine whether a compound “interacts” with such ion channels. Such compounds, as described below and for the purposes of the present description and appended claims, act as antagonists of the ion channel and / or biological functions and / or pathways associated with the ion channel. In particular, a compound “interacts” with an ion channel of an ion channel of the Kv family, in particular the Kv4 subfamily, if such a compound can completely or partially “inhibit” such an ion channel. I think that.

  In view of the biological functions and disease relevance described above, compounds that interact with ion channels are pharmaceutically useful, particularly in the prevention and / or treatment of diseases and conditions associated with ion channels with which the compound interacts. It can serve as an active formulation. By way of non-limiting example, a compound that interacts with an ion channel of the Kv4 subfamily, in particular the Kv4.3 ion channel (eg, a compound described in further detail hereinbelow) for the prevention and / or treatment of the following diseases: Can be used (manufacture of pharmaceutical compositions), for example, heart disease such as arrhythmia, hypertension-induced heart disease such as hypertension-induced cardiac hypertrophy (eg ventricular hypertrophy), and epilepsy, stroke, traumatic brain injury Nervous system diseases such as anxiety, insomnia, spinal cord injury, encephalomyelitis, multiple sclerosis, demyelinating disease, Alzheimer's disease and Parkinson's syndrome.

  Some major drawbacks of the known compounds are that the drug does not act selectively, ie the drug does not select different ion channel differences. For example, many of these compounds also inhibit the potassium channel referred to as the potassium channel of the human delayed rectifier potassium ion channel gene (hERG). Compounds that inhibit this channel with high potency can cause lethal reactions. This undesirable blockade can cause acquired QT prolongation syndrome, a disease that puts patients at risk of life-threatening arrhythmias. According to the American Heart Association, cardiac arrhythmia is the leading cause of sudden death in the United States. Currently, the FDA requires any drug assay prior to approval to inhibit hERG. Even drugs that appear to be beneficial to the majority of patients have not been marketed or retrieved from the market if the drug inhibits hERG.

  Thus, in addition to being able to modulate specific Kv channels, it is desirable to find compounds that are selective for Kv channels when compared to hERG channels. That is, it is necessary to find compounds that modulate the Kv channel but do not inhibit the hERG channel.

There remains an urgent need in the art to find new compounds that overcome the above disadvantages.
Bahring et al., J. Biol. Chem., Vol. 276, no. 26, 233888-23894 (2001) Baldwin et al., Neuron 7: 471-483 (1991) Dixon et al., Circ. Res. 79: 659-688 (1996) Dilks et al., J. Neurophysiol. 81: 1974-1977 (1999) Kuo et al., Cell, Vol. 107, 801-813 (2001) Pak et al., Proc. Natl. Acad. Sci USA 88, 4386-4390 (1991) Ohya et al., FEBS Lett. 420: 47-53 (1997) Roberts and Tamkun, Proc. Natl. Acad. Sci USA 88, 1798-1802 Rudy et al., Mol. Cell. Neurosci. 2, 89-102 (1991) Serodio et al., J. Neurophysiol 75: 2174-2179 (1996) Serodio and Rudy, J. Neurophysiol. 79: 1081-1091 (1998) Takimoto et al., Circ. Res. 81: 553-539 (1997) International Publication No. 98/42833 US Open No. 6,395,477 International Publication No. 01/58952 International Application Publication No. 03/097682 International Publication No. 03/097682 The Pharmacological Basis of Therapeutics, 8th edition, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", p 13-15 International Publication No. 99/33795 International Publication No. 99/33815 International Publication No. 99/33793 International Publication No. 99/33792 Protective groups in organic synthesis, 3rd edition, Wiley and Sons, 1999 US Pat. No. 6,372,778 US Pat. No. 6,369,086 US Pat. No. 6,369,087 US Pat. No. 6,372,733 European Patent Application No. 721,331 US Pat. No. 6,372,733

  Accordingly, it is an object of the present invention to provide compounds that interact with ion channels, preferably Kv family ion channels, more specifically Kv4 subfamily ion channels, and particularly preferably Kv4. 3 channels, which are in particular vertebrate, more particularly warm-blooded animals, more particularly mammalian, particularly preferably human ion channels. Yet another object of the present invention is to provide compounds that interact with ion channels, particularly Kv ion channels, and are selective for Kv ion channels when compared to hERG channels.

In a first aspect, the present invention includes a compound of formula I, II, III or IV, or a stereoisomer, tautomer, racemate, prodrug, metabolite thereof, or pharmaceutical thereof An acceptable salt and / or solvate,
Wherein X ¹ is a heteroatom and is selected from —O—, —S—, —N═, or —N (R ³ ) —, wherein R ³ is selected from alkyl, aralkyl or alkylcarbonyl;
X ² is selected from = C, = CH or -CH _2-
n is an integer of 0 or 1,
Y is selected from C, -C (R ⁵ )-or N, wherein R ⁵ is a hydrogen atom, amino, alkyl, hydroxyl group, alkylamino, heteroaryl, alkylcarbonyloxy, alkylamidyl or alkylaminocarbonylamino Selected from
Z is selected from -C (= O), -CH ₂ -or -NH-
W is -C (= O), -N (R ² )-, -N (R ² )-NH-, -C (= O) -NH-, -CH =, -O- or-in formula 1. CH _2-
And W is selected from N or CH in formula 2, 3 or 4;
R ¹ is a hydrogen atom, halogen, hydroxyl group, nitro group, amino group, azide, cyano, or alkyl, cycloalkyl, alkylamino, alkoxy, alkylaminocarbonyl, alkylcarbonyl, heterocyclyl-alkyl, heteroarylalkyl, alkoxy Carbonyl, aminocarbonyl, alkylamino (substituted with alkyl) alkyl, alkylcarbonylaminoalkyl or alkylthio, each of which may be substituted with one or more substituents, where z Is an integer selected from 1, 2, 3 or 4;
R ² is selected from a hydrogen atom, alkyl, cycloalkyl, cyanoalkyl, alkenyl, aryl, aminocarbonyl, haloalkyl, aralkyl, acyl or alkynyl;
A is selected from aryl, cycloalkyl, heterocyclyl and heteroaryl, which are optionally halogen, hydroxyl, nitro, azide, hydrazino, cyano, alkyl, aryl,
Heteroarylalkyl, cycloalkyl, acyl, alkylamino, alkylaminocarbonyl, —SO ₂ R ¹⁵ , alkylcarbonyloxy, fused heterocyclyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxy, Acylamino, alkyl ester, carbamate, thioamide, alkylcarbonyl, urea, or sulphonamide, wherein R ¹⁵ is alkyl, alkylamino or cycloalkyl;
L is a single bond, the formula -R ⁸ -R ⁹ - groups, Arukirin, Arukeniriru, ^{cycloalkylene, -NH- (C (R 4)} (R 4)) q -, - (C (R 4) (R ⁴ )) _q -,-(C (R ⁴ ) (R ⁴ )) _v -O- (C (R ⁴ ) (R ⁴ )) _w -,-(C (R ⁴ ) (R ⁴ )) _v- N- (C (R ⁴ ) (R ⁴ )) _w -,-(C (R ⁴ ) (R ⁴ )) _V- (C (R ⁴ )) _W =,-(C (R ⁴ ) (R ⁴ )) _q- (C = O)-, or a linking group selected from cycloalkyleneoxyalkylene, wherein-(C (R ⁴ ) (R ⁴ )) _q- , (C (R ⁴ ) (R ⁴ )) _W and-(C (R ⁴ ) (R ⁴ )) _v -are each independently aliphatic or form a cycloalkyl, wherein each R ⁴ is independently a hydrogen atom, hydroxyl group, alkyl, carboxy , Hydroxyalkyl, alkoxyalkyl, alkylamino, or alkyloxycarbonyl, q is an integer selected from 0, 1, 2, 3, 4, 5 or 6, and v is 0, 1, 2, From 3, 4, 5 or 6 Is an integer selected, and w is an integer selected from 0, 1, 2, 3, 4, 5 or 6.
R ⁸ is alkylin,-(C (R ⁴ ) (R ⁴ )) _P -C (R ¹⁴ ) or-(C (R ⁴ ) (R ⁴ )) _P -C (R ⁴ ) = C ,
R ⁹ is selected from a single bond,-(C (R ⁴ ) (R ⁴ )) _q- , or C (= O)-, wherein R ¹⁴ is selected from a hydrogen atom, a hydroxyl group or an alkyl, wherein p is an integer selected from 0, 1, 2 or 3, and
R ¹⁰ is-(C (R ⁴ ) (R ⁴ )) _m -,-(C (R ⁴ ) (R ⁴ )) _m -C (= O) O- (C (R ⁴ ) (R ⁴ ) ) _q- , _or- (C (R ⁴ ) (R ⁴ )) _m -N (R ¹² )-(C (R ⁴ ) (R ⁴ )) _q- , where m is 1, 2, An integer selected from 3, 4, 5 or 6, wherein R ¹² is selected from a hydrogen atom, alkyl, aryl, arylalkyl or alkylcarbonyl.

In a second aspect, the invention relates to a method for the synthesis of a compound having structural formula I, II, III or IV, a compound of formula LXIV:
And a compound of formula LXV, LXVI, LXVII or LXVIII:
And a compound of formula I, II, III, or IV:
Wherein R ¹ , z, X ¹ , X ² , W, Y, Z, n, L, A, R ⁸ , R ⁹ and R ¹⁰ have the same meaning as previously defined herein. It is a method including the process of obtaining.

  Surprisingly, the compounds of the present invention interact with ion channels, in particular the Kv family ion channels, and more specifically the Kv4 subfamily ion channels, and in particular the Kv4, as shown in the examples below. It was found to interact with 3 channels. The Kv4.3 ion channel is associated with various symptoms or diseases. In another aspect of the invention, there is provided a compound of formula I, II, III, or IV for use as a medicament.

  The compounds of the present invention are particularly useful for the manufacture of a medicament in the prevention and / or treatment of conditions or diseases associated with Kv4 family ion channels. Non-limiting examples of symptoms or diseases associated with the Kv4 family ion channel include heart diseases including arrhythmias, hypertension-induced heart diseases including hypertension-induced cardiac hypertrophy, and epilepsy, stroke, traumatic brain injury, anxiety, insomnia, It can be selected from the group comprising spinal cord injury, encephalomyelitis, multiple sclerosis, demyelinating disease, Alzheimer's disease and nervous system diseases and neurological diseases including Parkinson's syndrome. In an embodiment, the present invention provides the use of a compound of the present invention for the manufacture of a medicament for the treatment of heart disease. In another embodiment, the present invention provides the use of a compound of the present invention for the manufacture of a medicament for the treatment of nervous system diseases.

  In yet another aspect, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound according to the present invention. Such compositions are particularly useful for the prevention and / or treatment of conditions or diseases associated with Kv4 family ion channels, such as those cited herein. The composition is particularly suitable for the treatment of eg heart and nervous system diseases.

  Surprisingly, it has also been found that the compounds according to the invention interact with ion channels of the Kv1 subfamily, in particular with the Kv1.5 channel.

  The present invention also provides a method for treating heart disease comprising means for administering the pharmaceutical composition of the present invention to an individual in need of such treatment. In another embodiment, the present invention provides a method for treating a nervous system disease comprising means for administering a pharmaceutical composition of the present invention to an individual in need of such treatment.

(Detailed description of the invention)
Accordingly, in a first aspect, the invention provides a compound of formula I, II, III, or IV,
Alternatively, the present invention relates to stereoisomers, tautomers, racemates, prodrugs, metabolites thereof, or pharmaceutically acceptable salts and / or solvates thereof.

As used herein, X ¹ is a heteroatom and is selected from —O—, —S—, —N═, or —N (R ³ ) —, wherein R ³ is selected from alkyl, aralkyl, or alkylcarbonyl. X ² is selected from ═C, ═CH or —CH ₂ —, and n is an integer of 0 or 1. In another embodiment, X1 is an oxygen atom and n is 0. In still other embodiments, X ¹ is —N (R ³ ) —, n is 0, and R ³ has the same meaning as defined above. In yet another embodiment, X ¹ is —N═, and X ² is ═CH— or C, and n is 1. In yet another embodiment, Y is N and X ¹ is —N (R ¹³ ) —, wherein R ¹³ is selected from a hydrogen atom, alkyl, aralkyl or alkylcarbonyl.
Z is selected from -C (= O), -CH ₂ -or -NH-, and W is -C (= O), -N (R ² )-, -N (R ² ) in formula 1. —NH—, —C (═O) —NH—, —CH═, —O— or —CH ₂ —, and W is selected from N or CH in formula II, III or IV.

R ¹ is a hydrogen atom, halogen, hydroxyl group, nitro group, amino group, azide, cyano, or alkyl, cycloalkyl, alkylamino, alkoxy, alkylaminocarbonyl, alkylcarbonyl, heterocyclyl-alkyl, heteroarylalkyl, alkoxy Selected from carbonyl, aminocarbonyl, alkylamino (substituted with alkyl) alkyl, alkylcarbonylaminoalkyl or alkylthio, each of which has one or more substituents, eg 1, 2, or 3 substitutions A group, wherein the substituent may be present as described, such as “substituted alkyl”. According to the present invention, z is an integer selected from 1, 2, 3 or 4, for example, z is 1, 2 or 3.

R ² is selected from a hydrogen atom, alkyl, cycloalkyl, cyanoalkyl, alkenyl, aryl, aminocarbonyl, haloalkyl, aralkyl, acyl or alkynyl, which are selected from the following groups, 1, 2, or 3 respectively: The group optionally having a substituent is alkyl, aryl, halogen, haloalkyl, haloalkoxy. For example, R ² is a hydrogen atom, aryl, aralkyl, alkyl cyanoalkyl or cycloalkyl group. In one aspect, R ² is a hydrogen atom, phenyl, benzyl, C ₁ -C ₆ cyanoalkyl or C ₁ -C ₆ alkyl group, for example, a hydrogen atom, phenyl, benzyl, one C ₁ -C ₄ Cyanoalkyl or one C ₁ -C ₄ alkyl group.

A may be substituted or polysubstituted aryl, cycloalkyl, heterocyclyl and heteroaryl. A is unsubstituted or has 1, 2, 3, 4 or 5 substituents, preferably 1, 2 or 3, more preferably 1 or 2. Suitable substituents for A are not limited, but include halogen, hydroxyl, nitro, azide, hydrazino, cyano, alkyl, aryl,
Heteroarylalkyl, cycloalkyl, acyl, alkylamino, alkylaminocarbonyl, heterocyclyl alkylcarbonyloxy, to condensation, -SO ₂ R ^15, haloalkyl, alkylcarbonyl, aryloxy, alkyloxycarbonyl, arylcarbonyl, haloalkoxy, alkoxy, Thiol, alkylthio, carboxy, acylamino, alkyl ester, carbamate, thioamide, urea, or sulfonamide, where R ¹⁵ is alkyl, alkylamino, or cycloalkyl.

L is a single bond, the formula -R ⁸ -R ⁹ - groups, Arukirin, Arukeniriru, ^{cycloalkylene, -NH- (C (R 4)} (R 4)) q -, - (C (R 4) (R ⁴ )) _q -,-(C (R ⁴ ) (R ⁴ )) _v -O- (C (R ⁴ ) (R ⁴ )) _w -,-(C (R ⁴ ) (R ⁴ )) _V- (C (R ⁴ )) _W =,-(C (R ⁴ ) (R ⁴ )) _v -N- (C (R ⁴ ) (R ⁴ )) _w -,-(C (R ⁴ ) (R ⁴ )) _q- (C = O)-, or a linking group selected from cycloalkyleneoxyalkylene, wherein-(C (R ⁴ ) (R ⁴ )) _q- , (C (R ⁴ ) (R ⁴ )) _W and-(C (R ⁴ ) (R ⁴ )) _v -are each independently aliphatic or form a cycloalkyl, wherein each R ⁴ is independently a hydrogen atom, hydroxyl group, alkyl, carboxy , Hydroxyalkyl, alkylaminoalkyl, alkoxyalkyl, alkylamino, or alkyloxycarbonyl, q is an integer selected from 0, 1, 2, 3, 4, 5 or 6, and v is 0, 1, 2 Is an integer selected from 3, 4, 5 or 6, and w is an integer selected from 0, 1, 2, 3, 4, 5 or 6. R ⁸ is alkylin,-(C ( R ⁴ ) (R ⁴ )) _P -C (R ¹⁴ ) or-(C (R ⁴ ) (R ⁴ )) _P -C (R ⁴ ) = C, R ⁹ is a single bond,-(C (R ⁴ ) (R ⁴ )) _q- , or C (= O)-, wherein R ₁₄ is selected from a hydrogen atom, a hydroxyl group, or alkyl, where p is from 0, 1, 2, or 3 An integer chosen.

R ^{10 in} structural formulas II, III and IV is-(C (R ⁴ ) (R ⁴ )) _m -,-(C (R ⁴ ) (R ⁴ )) _m -C (= O) O- (C (R ⁴ ) (R ⁴ )) _q- , _or- (C (R ⁴ ) (R ⁴ )) _m -N (R ¹² )-(C (R ⁴ ) (R ⁴ )) _q- M is an integer selected from 1, 2, 3, 4, 5 or 6, wherein R ¹² is selected from a hydrogen atom, alkyl, aryl, arylalkyl or alkylcarbonyl.

  When describing the compounds of the invention, the terms used are to be interpreted according to the following definitions unless otherwise indicated.

The term “alkyl” by itself or as part of another substituent is connected by a single carbon-carbon bond and is 1 to 10 carbon atoms, eg 1 to 8 carbon atoms, eg A straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. In this specification, when a subscript is used after a carbon atom, the subscript refers to the number of carbon atoms that the group of the name can contain. Thus, for example, C _1-4 alkyl means an alkyl of 1 to 4 carbon atoms. Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 2-methylbutyl, pentyliso-amyl and its isomers, hexyl and its isomers, heptyl and its isomers, And octyl and its isomers.

  The term “optionally substituted alkyl” is optionally substituted with one or more substituents (eg, 1 to 4 substituents or 1 to 2 substituents) at any available point of attachment. Refers to a substituted alkyl group. Examples of such substituents include, but are not limited to, halogen, hydroxyl, oxo, nitro, amino, oxime, imine, azide, hydrazine, cyano, alkyl, aryl, heteroaryl, cycloalkyl, acyl, alkyl Amino, alkoxy, thiol, alkylthio, carboxylic acid, acylamino, alkyl ester, carbamate, thioamide, urea, sulfonamide and the like are included.

  Where the term “alkyl” is used as a suffix after another term, such as “hydroxyalkyl”, this is a 1 or 2 selected from other specifically named groups as also defined herein. It shall refer to an alkyl group as defined above which is substituted with one (preferably one) substituent. “Alkoxyalkyl” refers to an alkyl group substituted with one or two OR ′, where R ′ is alkoxy as shown below. For example, “aralkyl” or “(allyl) alkyl” refers to an alkyl group substituted as indicated above, wherein at least one alkyl substituent is as shown below, such as allyl, eg, benzyl Is.

The term “hydroxyalkyl” refers to the group —R ^a —OH, where R ^a is alkylene as defined herein. For example, “hydroxyalkyl” includes 2-hydroxyethyl, 1- (hydroxymethyl) -2methylpropyl, 3,4-dihydroxybutyl, and the like.

  The term “cycloalkyl” by itself or as part of another substituent includes 1 to 3 rings containing a monocyclic, bicyclic, or polycyclic alkyl group, all saturated, or Partially saturated hydrocarbon groups (including 1 or 2 double bonds) are included, where each cyclic moiety contains 3 to 8 carbon atoms, such as 3 to 7 carbon atoms, such as 3 to 6 carbon atoms, for example 3 to 5 carbon atoms. The further rings of the polycyclic cycloalkyl can be fused, bridged and / or linked by one or more spiro atoms. Examples of monocyclic cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Examples of polycyclic cycloalkyl radicals include decahydronaphthyl, bicyclo [5.4.0] undecyl, adamantyl and the like. “Optionally substituted cycloalkyl” refers to one or more substituents selected from the substituents defined above for substituted alkyl (eg, 1 to 3 substituents, or 1 to 2 substituents). Refers to cycloalkyl optionally containing When the suffix “ene” is used in conjunction with a cyclic group, this shall mean two cyclic bonds as defined herein, with two single bonds as the point of attachment to the other group.

  The term “alkenyl” by itself or as part of another substituent contains at least one unsaturation in the form of a single carbon-carbon double bond and contains 2 to 10 carbon atoms, for example 2 to Refers to a straight or branched alkyl chain having 8 carbon atoms, preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms. Examples of alkenyl groups include ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2-heptenyl and its isomers, 2-octenyl and its Isomers, 2,4-pentadienyl and the like. Optionally substituted alkenyl optionally represents one or more substituents selected from the substituents defined above for substituted alkyl (eg, 1 to 3 substituents, or 1 to 2 substituents). Including alkenyl.

  The term “alkynyl” by itself or as part of another substituent contains at least one unsaturation in the form of a single carbon-carbon triple bond and contains 2 to 10 carbon atoms, eg 2-8 A straight or branched alkyl chain having 1 carbon atom, preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms. Examples of alkynyl groups include ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and its isomer, 2-hexynyl and its isomer, 2-heptynyl and its isomer, 2-octynyl and its There are isomers and the like. An optionally substituted alkynyl optionally has one or more substituents selected from the substituents defined above for substituted alkyl (eg, 1-4 substituents, or 1-2 substituents). Contains alkynyl.

  When an alkyl group as defined is divalent, ie, contains two single bonds for bonding to two other groups, those groups are referred to as “alkylene” groups. Non-limiting examples of these alkylene groups include methylene, ethylene, methylmethylene, trimethylene, propylene, tetramethylene, ethylethylene, 1,2-dimethylethylene, pentamethylene and hexamethylene. Similarly, when an alkenyl group as defined above and an alkynyl group as defined above are each a divalent radical containing a single bond for bonding to two other groups, then those groups Are referred to as “alkenylene” and “alkynylene”, respectively.

When an alkyl group as defined is trivalent, i.e. contains three single bonds for bonding to three other groups, those groups are referred to as "alkylin" or "alkylin" groups. . Non-limiting examples of these alkylin groups include methine, 1,1,2-ethylin, and the like.
When an alkenyl group as defined is trivalent, that is, if it contains three single bonds for bonding to three other groups, those groups are referred to as “alkenylin” or “alkenylin” groups. .

  As used herein or as part of another group, the term “aryl” as used herein includes, but is not limited to, a monocyclic of 5-14 carbon atom homocycles (ie, hydrocarbons), Bicyclic or tricyclic aromatic rings, or typically 1 to 4 rings containing 5 to 8 atoms, fused or covalently bonded together, at least one of which is aromatic A ring system that is a family. An aromatic ring can optionally include the step of condensing 1-3 additional rings (cycloalkyl, heterocyclyl, or heteroaryl) with the ring.

  Non-limiting examples of these include phenyl, biphenylyl, biphenylenyl, 5- or 6-tetralinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-azurenyl, 1- or 2-naphthyl, 1-, 2- or 3-indenyl, 1-, 2- or 9-anthryl, 1-, 2-, 3-, 4- or 5-acenaphthylenyl, 3-, 4- or 5-acenaphthenyl, 1-, 2-, 3-, 4- or 10-phenanthryl, 1- or 2-pentalenyl, 1-, 2-, 3- or 4-fluorenyl, 4- or 5-indanyl, 5-, 6-, 7- or 8-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, dibenzo [a, d] silcoheptenyl, 1-, 2-, 3-, - or it includes a 5-pyrenyl.

The aryl ring can be optionally substituted with one or more aromatic substituents. “Optionally substituted aryl” optionally includes one or more substituents (eg, 1 to 5 substituents, or 1 to 2 substituents) at any available point of attachment. Point to aryl. Although not limited to such substituents, examples include halogen, hydroxyl, oxo, nitro, amino, azide, hydrazino, cyano, alkyl, aryl, heteroaryl,
Heteroarylalkyl, cycloalkyl, acyl, alkylamino, alkylaminocarbonyl, —SO ₂ R ¹⁵ , alkylcarbonyloxy, fused heterocyclyl, haloalkyl, alkylcarbonyl, alkyloxycarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, thiol , Alkylthio, haloaryl, carboxy, acylamino, alkyl ester, carbamate, thioamide, urea, sulfonamide, and the like, wherein R ¹⁵ is alkyl or cycloalkyl.

  The term “aryloxy” as used herein refers to the group —O-aryl, where aryl is as defined above.

  The term “aroyl” as used herein refers to the group —C (O) -aryl, where aryl is as defined above.

  As used herein or as part of another group, the term “heteroaryl” as used herein includes, but is not limited to, 5-12 carbon atom aromatic rings, or typically 5-8. Refers to a ring system containing 1, 2, or 3 rings containing one atom and fused or covalently bonded together, wherein at least one of the rings is aromatic, wherein One or more carbon atoms in one or more rings can be replaced with oxygen, nitrogen, or sulfur atoms, where the nitrogen and sulfur heteroatoms can be optionally oxidized, and the nitrogen heteroatoms can optionally It may be quaternized. Such rings can be fused with aryl, cycloalkyl, heteroaryl, or heterocyclyl rings. “Optionally substituted heteroaryl” refers to one or more substituents selected from the substituents defined above for substituted aryl (eg, 1, 2, 3 or 4 substituents, or 1, 2 or Heteroaryl optionally containing 3 substituents).

  Without being limited to these heteroaryls, examples include 2- or 3-furyl, 2- or 3-thienyl (thiophen-yl), 1-, 2- or 3-pyrrolyl, 1-, 2- , 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isothiazolyl , 2-, 4- or 5-thiazolyl, 1,2,3-triazol-1-,-2-,-4- or -5-yl, 1,2,4-triazole-1-,-3- -4- or -5-yl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,2,5 -Oxadiazolyl, 1,3,4-oxadiazolyl, 1,2 , 3-thiadiazol-4- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,5-thiadiazol-3- or -4-yl, 1,3,4 -Thiadiazolyl, 1- or 5-tetrazolyl, 2-, 3- or 4-pyridyl, 3- or 4-pyridazinyl, 2-, 4-, 5- or 6-pyrimidinyl, 2-, 3-, 4-, 5 -6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 1-, 3-, 4- or 5-iso Benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 3-, 4- or 5-isobenzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2- or 3-pyrazinyl, 1, -Oxazin-2- or -3-yl, 1,4-dioxin-2- or -3-yl, 1,4-thiazin-2- or -3-yl, 1,2,3-triazinyl, 1,2 , 4-Triazinyl, 1,3,5-triazin-2-, -4- or -6-yl, thieno [2,3-b] furan-2-, -3-, -4-, or -5 Yl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 3-, 4-, 5-, 6- or 7-benz Isoxazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzoisothiazolyl, 2-, 4-, 5 -, 6- or 7-benzothiazolyl, 1-, 2-thiantrenyl, 3-, 4- or 5-isobenzoph Nyl, 1-, 2-, 3-, 4- or 9-xanthenyl, 1-, 2-, 3- or 4-phenoxathiinyl, 2-, 3-pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-indolidinyl, 2-, 3-, 4- or 5-isoindolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indazolyl 2-, 6-, 7- or 8-purinyl, 4-, 5- or 6-phthalazinyl, 2-, 3- or 4-naphthyridinyl, 2-, 5- or 6-quinoxalinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 1-, 2-, 3- or 4-quinolidinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl (quinolyl) ), 2-, 4-, 5-, 6-, 7- or 8-quinazolyl, 1-, 3-, 4-, 5-, 6 -, 7- or 8-isoquinolinyl (isoquinolyl), 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 6- or 7-pteridinyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-carbolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-phenanthridinyl, 1-, 2-, 3- or 4-acridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-perimidinyl, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10- (1,7) phenanthrolinyl, 1 -Or 2-phenazinyl, 1-, 2-, 3-, 4-, or 10-phenothiazinyl, 3- or 4-furanyl, 1-, 2-, 3-, -, or 10 phenoxazinyl, azepinyl, diazepinyl, dibenzo [b, f] azepinyl, dioxanyl, thietanyl, oxazolyl dibenzo [a, d] be a Shirukoheputeniru, or may be further substituted derivatives thereof.

  As used herein or as part of another group, the term “heterocyclyl” or “heterocyclo” as used herein includes a non-aromatic complete group containing at least one heteroatom in a ring containing at least one carbon atom. A saturated or partially unsaturated cyclic group (e.g. 3 to 13 membered monocyclic, 7 to 17 membered bicyclic, or 10 to 20 membered tricyclic ring system, or a total of 3 to 10 ring atoms Containing cyclic groups). Each ring of the heterocyclic group containing one heteroatom may contain 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen and / or sulfur atoms, wherein nitrogen and sulfur heteroatoms The atoms can be optionally oxidized and the nitrogen heteroatoms can optionally be quaternized. The heterocyclic group may be bonded to any heteroatom or carbon atom of the ring or ring system depending on the valence. Polycyclic heterocyclic rings may be fused, bridged, and / or linked by one or more spiro atoms. “Optionally substituted heterocyclyl” refers to one or more substituents selected from the substituents defined above for substituted aryl (eg, 1, 2, 3, or 4 substituents, or 1 to 2 substituents). Or a heterocyclyl optionally containing a substituent.

  Representative heterocyclic groups include piperidinyl, azetidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidyl, succinimidyl, 3H-indolyl, indolinyl, isoindolinyl, chromenyl , Isochromanyl, xanthenyl, 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 4H-quinolidinyl, 4aH-carbazolyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, Pyranyl, dihydro-2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, triazinyl, cinnolinyl, phthalazinyl, azepinyl, oxetanyl Thietanyl, 3-dioxolanyl, 1,4-dioxanyl, 2,5-dioxyimidazolidinyl, 2,2,4-piperidonyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, indolinyl, Tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolanyl, 1,4-oxathianyl, 1,4-dithianyl, 1,3,5-trioxanyl, 6H-1,2,5-thiadiazinyl, 2H-1,5,2-dithiazinyl, 2H-oxosinyl, 1H-pyrrolidinyl, tetrahydro-1,1-dioxo Thienyl, N-formylpipera Dinyl, 2,3-dihydrobenzo [1,4] dioxin-2-yl, 2,3-dihydrobenzo [1,4] dioxin-6-yl, and morpholinyl are included.

  The term “aralkyl” by itself or as part of another substituent refers to a group containing the aforementioned alkyl bonded as an alkyl moiety to one of the aforementioned aryl rings. Examples of aralkyl radicals include benzyl, phenethyl, dibenzylmethyl, methylphenylmethyl, 3- (2-naphthyl) -butyl and the like.

  The term “cycloalkylalkyl” by itself or as part of another substituent refers to a group comprising one of the aforementioned cycloalkyl groups attached to one of the aforementioned alkyl chains. Examples of such cycloalkylalkyl radicals include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1-cyclopentylethyl, 1-cyclohexylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, cyclobutylpropyl, Cyclopentylpropyl, 3-cyclopentylbutyl, cyclohexylbutyl and the like are included.

The term “heterocyclyl-alkyl” by itself or as part of another substituent refers to a group containing one of the aforementioned heterocyclyl groups attached to one of the aforementioned alkyl groups, ie, a group R ^b —R ^c [formula Wherein R ^b is alkylene or alkylene substituted with an alkyl group, and R ^c is a heterocyclyl group].

The term “acyl” by itself or as part of another substituent refers to an alkanoyl group having 2 to 6 carbon atoms or a phenylalkanoyl group whose alkanoyl moiety contains 1 to 4 carbon atoms. That is, but not limited to, alkyl, aryl, and more specifically the group —COR ¹¹ , wherein R ¹¹ is selected from alkyl, aryl, substituted alkyl, or substituted aryl as defined herein. A carbonyl group linked to a radical such as Thus, the term “acyl” includes the group alkylcarbonyl (—COR ¹¹ ), wherein R ¹¹ is alkyl. Said acyl can be exemplified by acetyl, propionyl, butyryl, valeryl and pivaloyl, benzoyl, phenylacetyl, phenylpropionyl and phenylbutytyl.

The term “alkylamino” by itself or as part of another substituent refers to an amino linked to one or two independently selected and optionally substituted alkyl, cycloalkyl, arylalkyl or cycloalkylalkyl groups. N (R ⁶ ) (R ⁷ ), wherein R ⁶ and R ⁷ are each independently selected from a hydrogen atom, cycloalkyl, arylalkyl, cycloalkylalkyl or alkyl ] Alkylamino group, but are not limited those here, examples include methylamino (NHCH _3), ethylamino _{(NHCH 2} CH 3), n- propylamino, isopropylamino, n- butylamino, isobutylamino, sec- butyl Amino, tert-butylamino, n-hexylamino and the like are included.

  As used herein, the term “keto” refers to the group ═O.

The term “amino” refers to the group NH ₂ .

  The term “aminocarbonyl” refers to the group — (C═O) —NH 2.

The term “aminoalkyl” refers to the group —R ^b —NR ^d R ^{e where} R ^b is alkylene or substituted alkylene, R ^d is hydrogen, or alkyl or substituted alkyl as defined herein, R ^e is hydrogen or alkyl as defined herein].
The term “cyanoalkyl” refers to the group —R ^b —CN, wherein R ^b is alkylene or substituted alkylene, and the substituents defined herein are the same as described above for substituted alkyl.

The term “alkylaminocarbonyl” refers to the group — (C═O) —NR ^d R ^e , where Rd is a hydrogen atom, or alkyl or substituted alkyl as defined herein, and R ^e is as defined herein. Or the substituted alkyl is the same as described above for the substituted alkyl].

The term “alkylaminocarbonylamino” refers to the group —NH (C═O) —NR ^d R ^e or —NR ′ (C═O) —NR ^d R ^e , wherein R ^d is a hydrogen atom, or And R ^e is alkyl or substituted alkyl as defined herein, wherein R ′ is alkyl or substituted alkyl, and the substituent is the same as described above for substituted alkyl. Point to].

The term “carboxy” refers to the group —CO ₂ H. Thus, carboxyalkyl is an alkyl group as defined above containing at least one substituent that is —CO ₂ H.

The term “alkoxycarbonyl” refers to a carboxy group linked to an alkyl radical, ie, C (═O) OR ¹¹ , wherein R ¹¹ is as previously defined for acyl.

The term “alkylcarbonyloxy” refers to O—C (═O) R ¹¹ , wherein R ¹¹ is as defined above for acyl.

  The term “alkylamidyl” or “alkylamide” refers to the formula —NH (C═O) R or —NR ′ (C═O) R, wherein R and R ′ are each independently alkyl or substituted alkyl. Wherein the substituent is the same as described above for the substituted alkyl].

The term “alkylcarbonylaminoalkyl” refers to the group —R ^b —NR ^d —C (═O) —R ^e , where R ^b is alkylene or alkylene substituted with alkyl, and R ^d is hydrogen or Is alkyl as defined herein, and R ^e is alkyl as defined herein, and the substituents are the same as those described above for substituted alkyl].

The term “alkylamino (alkyl-substituted) alkyl” refers to the group —R ^f —NR ^d R ^e , where R ^f is alkylene substituted by alkyl and R ^d is a hydrogen atom or alkyl as defined herein. Or substituted alkyl, and R ^e is alkyl or substituted alkyl as defined herein, and the substituents are the same as described above for substituted alkyl.

  The term “alkoxy” by itself or as part of another substituent is attached to one optionally substituted linear or branched alkyl group, cycloalkyl group, arylalkyl or cycloalkylalkyl group. A group consisting of oxygen atoms, each group is optionally substituted with one or two substituents, the substituents being the same as described above for substituted alkyl. Although not limited solely by examples herein, examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, hexanoxy and the like It is.

The term “alkylthio by itself or as part of another substituent” refers to a group consisting of a sulfur atom bonded to one optionally substituted alkyl, cycloalkyl, arylalkyl or cycloalkylalkyl group. Each group is optionally substituted with one or two substituents, and the substituents are the same as described above for substituted alkyl. Although not limited in these examples, examples of alkylthio groups include methylthio (SCH ₃ ), ethylthio (SCH ₂ CH ₃ ), n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio. , N-hexylthio and the like.

  The term “acylamino” by itself or as part of another substituent refers to a group consisting of one or two independently selected amino groups attached to an acyl group as described above. When two acyl groups of a dicarboxylic acid are bonded to an amino group, these represent imides such as phthalimide and maleimide, and are included in the meaning of the term acylamino.

  The term “halo” or “halogen” as a group or part of a group is the generic name for fluoro, chloro, bromo, or iodo.

  The term “haloalkyl”, alone or in combination, refers to an alkyl radical having the previously defined meaning, wherein one or more hydrogen atoms are replaced with halogen as defined herein. Although not limited in these examples, examples of haloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and the like.

  The term “haloaryl”, alone or in combination, refers to an aryl radical having the previously defined meaning, wherein one or more hydrogen atoms are replaced with halogen as defined above.

The term “haloalkoxy”, alone or in combination, refers to a group of formula —O-alkyl, where the alkyl group is substituted by 1, 2 or 3 halogen atoms. For example, “haloalkoxy” includes —OCF ₃ and —OCHF ₂ .

The term “sulfonamide”, alone or in combination, refers to the formula SO ₂ —NR ^d R ^e , where R ^d is hydrogen, or alkyl or substituted alkyl as defined herein, and R ^e is a hydrogen atom or The alkyl is as defined in the specification, and the substituent is the same as described above for the substituted alkyl. ].

  As used herein, the term “optionally substituted alkyl, cycloalkyl, alkenyl or alkynyl” or “optionally substituted with alkyl, cycloalkyl, alkenyl or alkynyl” means that each group is Means optionally substituted, i.e. means "optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, or optionally substituted alkynyl" Where the substituents are the same as those described above for the substituted alkyl.

  Whenever the term "substituted" is used in the present invention, one or more hydrogen atoms on the atom indicated in the expression using "substituted" are in the group indicated. Indicates substituted with a selectable group, but does not exceed the normal valence of the indicated atom, and the substitution isolates a chemically stable compound, i.e., a useful degree of purity from the reaction mixture. And that it results in compounds that are sufficiently stable to withstand formulation into therapeutic agents.

  As used herein, the term “compounds of the invention” or similar terms is intended to include compounds of general formula I, II, III, or IV, and any subgroups (subgroups) thereof. The term also includes compounds shown in Table 12 and derivatives thereof, N-oxides, salts, solvates, hydrates, stereoisomers, racemic mixtures, tautomers, optical isomers, analogs, prodrugs, Refers to esters, and metabolites, and also refers to these quaternized nitrogen analogs. The N-oxide form of the compound is meant to include a compound in which one or several nitrogen atoms are oxidized to a so-called N-oxide.

  As used in the specification and the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. By way of example, “a compound” means one compound or more than one compound.

  The asterisk (*) is used herein to denote the point at which the indicated monovalent, divalent, or trivalent radical is connected to the structure involved and the structure that the radical forms part of. used.

  As used herein, the term “prodrug” refers to pharmacologically acceptable derivatives, such as esters, amides, and phosphates, where the in vivo biotransformation product of the resulting derivative is the active drug. means. References to Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8th edition, McGraw-Hill, Int. Ed. 1992, “Biotransformation of Drugs”, p 13-15), which generally describes prodrugs, Prodrugs are described and incorporated. Prodrugs of the compounds of the present invention can be prepared by modifying functional groups present in the components such that the modification is cleaved in the normal procedure or in vivo to the parent component. Typical examples of prodrugs are described, for example, in WO 99/33795, WO 99/33815, WO 99/33793, and WO 99/33792, all Are incorporated herein by reference. Prodrugs are characterized by high bioavailability and are readily metabolized in vivo to active inhibitors.

In certain embodiments, the present invention provides a compound of formula I, II, III, or IV, wherein X ¹ is —N (R ³ ) —, n is 0, and R ³ is as defined above. Has the same meaning as the definition. In another embodiment, the present invention provides a compound of formula I, II, III or IV, wherein X ¹ is n is O is 0. In yet another embodiment, the invention provides compounds of formula I, II, III, or IV, wherein X ¹ is S and n is 0. In yet another embodiment, the invention provides compounds of formula I, II, III, or IV, wherein X ¹ is —N═, and X ² is ═CH—, and n is 1. In a further embodiment, the present invention provides a compound of formula I, II, III or IV, wherein Y is N and X ¹ is —N (R ¹³ ) —, wherein R ¹³ is hydrogen Selected from atoms, alkyl, aralkyl or alkylcarbonyl.
In a specific embodiment, the invention provides a compound of formula V, VI, VII, VIII, IX or X;
Here, R ¹ , z, X ¹ , X ² , W, Y, Z, n, L, A, R ⁸ , R ⁹ and R ¹⁰ have the same meaning as defined above.

In other specific embodiments, the invention provides compounds of formula XI, XII, XIII, XIV, or XV;
Here, R ¹ , z, X ¹ , X ² , Y, Z, n, L, A, R ⁸ , R ⁹ , R ¹⁰ and R ² have the same meaning as defined above.
Preferably, the present invention provides compounds of formula XVI to XXXI
Where R ⁵ is selected from a hydrogen atom, alkyl, or aralkyl, and R ¹ , z, Z, W, L, A, R ⁸ , R ⁹ , R ¹⁰ and R ³ have the same meaning as previously defined. Has meaning.
In an embodiment, the present invention provides compounds of formula XXXII to LXIII,
Here, R ¹ , z, R ⁵ , R ² , R ³ , R ⁸ , R ⁹ , R ¹⁰ , L and A have the same meaning as previously defined.

In an embodiment, the present invention provides a compound of formula I to LXIII,
Where A is 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- Or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isothizolyl, 2-, 4- or 5-thiazolyl, 1-, 2- , 3-Triazol-1, -2, -4 or -5-yl, 1,2,4-triazol-1-,-3-,-4- or -5-yl, 1,2,3-oxadi Azol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 1,2,4- Thiadiazol-3- or -5-yl, 1,2,5-thiadiazol-3- or -4-yl, 1- or 5-tetrazolyl, phenyl, biphenyl, 2-, 3- or 4-pyridyl, pyridinyl, anthracenyl , Azulenyl, indenyl, 3- or 4-pyridazinyl, 2-, 4-, 5- or 6-pyrimidinyl, 2-, 3-, 4-, 5-6-2H-thiopyranyl, 2-, 3- or 4- Four H-thiopyranyl, furyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuranyl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2- , 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzpyrazolyl , 3-, 4-, 5-, 6-, or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisothiazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 1,3-benzodioxolyl, 1- or 2-naphthyl, 2-, 3-, 4- , 5-, 6-, 7-, 8-quinolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolyl, 1-, 3-, 4-, 5-, 6-, 7- , 8-isoquinolinyl, or 1-, 2-, 3-, 4- or 9-carbazolyl, 5,6,7,8, -tetrahydronaphthyl, thienyl, benzothienyl, dibenzo [b, f] azepinyl, dibenzo [a , d] silcoheptenyl, pyrrololyl, dioxanyl, thietanyl, oxazolyl, piperidinyl, imida Linyl, isoxazolinyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 2-oxopiperazinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, oxetanyl, azepinyl, 4-piperidonyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 5- (2,3-dihydro) benzofuranyl, 2-oxoazepinyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, tetrahydro-1, I-dioxo Thienyl, piperazinyl or morpholyl, optionally substituted with 1, 2, 3 or 4 substituents, the substituents being selected from the following groups: halogen, hydroxyl, nitro, azide, hydrazino, cyano Alkyl, aryl, cycloalkyl, acyl, a Killamino, alkylaminocarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, fused heterocyclyl, haloalkyl, alkylcarbonyl, heteroarylalkyl, aryloxy, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, thiol, alkylthio, carboxy, acylamino, alkyl ester , Carbamate, thioamide, urea, —SO ₂ R ¹⁵ , or sulfonamide, wherein R ¹⁵ is alkylamino, alkyl or cycloalkyl, and L is a single bond, of formula —R ⁸ —R ⁹ — Group, alkyne, alkenyl, cycloalkylene, -NH- (C (R ⁴ ) (R ⁴ )) _q -,-(C (R ⁴ ) (R ⁴ )) _v -N- (C (R ⁴ ) ( R ⁴ )) _w -,-(C (R ⁴ ) (R ⁴ )) _q -,-(C (R ⁴ ) (R ⁴ )) _v -O- (C (R ⁴ ) (R ⁴ )) _w -,-(C (R ⁴ ) (R ⁴ )) _V- (C (R ⁴ )) _W =,-(C (R ⁴ ) (R ⁴ )) _q- (C = O)-, Or a linking group selected from cycloalkyleneoxyalkylene, wherein-(C (R ⁴ ) (R ⁴ )) _q- , (C (R ⁴ ) (R ⁴ )) _W and-(C (R ⁴ ) (R ⁴ )) _v -are each independently aliphatic or form a cycloalkyl, wherein each R ⁴ is independently a hydrogen atom, alkylaminoalkyl, hydroxyl, alkyl, carboxy, hydroxyalkyl, alkoxyalkyl. , Alkylamino, or alkyloxycarbonyl, q is an integer selected from 0, 1, 2, 3 or 4, v is an integer selected from 0, 1, 2, 3 or 4; And w is an integer selected from 0, 1, 2, 3 or 4, and R ⁸ is alkylin,-(C (R ⁴ ) (R ⁴ )) _P -C (R ¹⁴ ) or-(C (R ⁴ ) (R ⁴ )) _P -C (R ⁴ ) = C, where R ⁹ is a single bond,-(C (R ⁴ ) (R ⁴ )) _q- , or C (= O)-, wherein R ¹⁴ is selected from a hydrogen atom, a hydroxyl group or an alkyl, wherein p is an integer selected from 0, 1, 2 or 3, and R ¹⁰ is-(C (R ⁴ ) (R ⁴ )) _m -,-(C (R ⁴ ) (R ⁴ )) _m -C (= O) O- (C (R ⁴ ) (R ⁴ )) _q- , _or- ( C (R ⁴ ) (R ⁴ )) _m -N (R ¹² )-(C (R ⁴ ) (R ⁴ )) _q- , where m is 1, 2, 3, 4, 5 or 6 R ¹² is selected from a hydrogen atom, alkyl, aryl, arylalkyl or alkylcarbonyl, and R ² is a hydrogen atom, CH ₃ −, —CH ₂ —CH ₃ , — (CH _{2) 2 -CH 3, - (} CH 2) 2 -CN, phenyl, benzyl or CH ₃ -C (= O).

In another embodiment, this invention provides compounds of formulas XVI to XXII and XXXII to LI;
Where A is phenyl, 3-indolyl, 5- (2,3-dihydro) benzofuranyl, 6-indolyl, 4-pyridinyl, 1.3-benzodioxolyl, 2-thienyl, 2-naphthyl, dibenzo [b, f ] Azepinyl, or dibenzo [a, d] cycloheptenyl, and optional substitution with the respective 1,2,3, or 4 substituents is -OCH ₃ , -NO ₂ , -CO ₂ H, -C (= O ) -N (CH ₃ ) ₂ , -OC (= O) -CH ₃ , -CH ₃ , -CH ₂ -CH ₃ , phenyl, -SO ₂ -CH ₃ , F, Cl, Br, -CF ₃ ,- S-CH ₃ , -OCF ₃ , -C (= O) -CH ₃ , -OC (= O) -CH ₃ , -C (= O) O-CH ₃ , -C (= O) N (CH ₃ ) ₂ , -N (CH ₃ ) ₂ , -SO ₂ -N (CH ₃ ) ₂ ,
, N-morpholino, phenoxyl, benzoyl, -C (CH ₃ ) ₃ , -O- (CH ₂ ) ₂ -CH ₃ , -OH or -CN;
Where L is a single bond, -CH ₂ -,-(CH ₂ ) ₂ -,-(CH ₂ ) _3- , -CH (CH ₂ OH)-, -CH (CH ₂ -O-CH ₃ )- , -CH (CH ₃ )-, -CH (CH ₂ -CH ₃ )-, -CH (CO ₂ H)-, -CH (CO ₂ CH ₃ )-,-(CH ₂ ) ₂ -O-CH ₂ -, -CH (CH ₂ -N (CH ₃ ) ₂ )-,-(CH ₂ ) ₂ -CH =, or
Or where -LA is selected from
Or
Wherein R ¹ is a hydrogen atom, Cl, Br, F, -CF ₃ , -OCH ₃ , CH ₃ -C (= O)-, (CH ₃ ) ₂ N-CH (CH ₃ )- , -CO ₂ H, (CH ₃ ) ₂ NC (= O)-,
CH ₃ -C (= O) O-, CH ₃ -OC (= O)-, CH ₃ -NH-C (= O)-, CH ₃ -C (= O) -NH-CH (CH ₃ )- , HO—CH ₂ —, CH ₃ —CH ₂ —, CH ₃ —O—CH ₂ —, wherein z is 1 or 2, and R ⁵ is H, —NH ₂ , CH ₃ — NH-C (= O) -NH-, CH ₃ -C (= O) -NH-, CH ₃ -C (= O) O-, -OH, -CH ₃ , CH ₃ -CH _2- , (CH ₃ ) ₂ N- or
Wherein R ² is a hydrogen atom, CH _3- , phenyl, CH _3- , -CH ₂ -CH ₃ -,-(CH ₂ ) ₂ -CH ₃ ,-(CH ₂ ) ₂ -CN, Selected from benzyl or CH ₃ —C (═O).

In another embodiment, this invention provides compounds of formula XXIII to XXXI and LII to LXIII,
Where
Is
Selected from here
Is
Selected from here
Is
Selected from
Where A is phenyl, 3-indolyl, 5- (2,3-dihydro) benzofuranyl, 6-indolyl, 4-pyridinyl, 2-thienyl, 2-naphthyl, 1,3-benzodioxolyl, dibenzo [ b, f] azepinyl, dibenzo [a, d] cycloheptenyl, and optional substitution with the respective 1,2,3 or 4 substituents includes —OCH ₃ , —NO ₂ , —CO ₂ H, —C ( = O) -N (CH ₃ ) ₂ , -OC (= O) -CH ₃ , -CH ₃ , -CH ₂ -CH ₃ , phenyl, -SO ₂ -CH ₃ , F, Cl, Br, -CF ₃ , -S-CH ₃ , -OCF ₃ , -C (= O) -CH ₃ , -OC (= O) -CH ₃ , -C (= O) O-CH ₃ , -C (= O) N ( _{CH 3) 2, -N (CH} 3) 2, -SO 2 -N (CH 3) 2,
, N-morpholino, phenoxyl, benzoyl, —C (CH ₃ ) ₃ , —O— (CH ₂ ) ₂ —CH ₃ , —OH or —CN, wherein R ¹² is a hydrogen atom, CH ₃ -C (= O)-, CH ₃ -or benzyl, and R ¹ is a hydrogen atom, Cl, Br, F, -CF ₃ , -OCH ₃ , CH ₃ -C (= O)- , -CO ₂ H, (CH ₃ ) ₂ NC (= O)-,
, CH ₃ -C (= O) O-, CH ₃ -OC (= O)-, CH ₃ -NH-C (= O)-, CH ₃ -C (= O) -NH-CH (CH ₃ ) -, HO-CH _2- , CH ₃ -CH _2- , CH ₃ -O-CH _2- , wherein z is 1 or 2, wherein R ⁵ is H, CH ₃ -NH -C (= O) -NH-, CH ₃ -C (= O) -NH-, CH ₃ -C (= O) O-, -OH, -CH ₃ , CH ₃ -CH _2- , (CH ₃ ) ₂ N-, or
Wherein R ² is a hydrogen atom, CH _3- , CH _3- , -CH ₂ -CH ₃ -,-(CH ₂ ) ₂ -CH ₃ ,-(CH ₂ ) ₂ -CN, phenyl, Selected from benzyl or CH ₃ —C (═O).

In a specific embodiment, the invention provides a compound described herein, wherein R ⁵ is a hydrogen atom, —CH ₃ , —NH ₂ , CH ₃ —C (═O) —NH—, Or
Wherein R ² is a hydrogen atom, CH _3- , phenyl, CH _3- , -CH ₂ -CH ₃ -,-(CH ₂ ) ₂ -CH ₃ or-(CH ₂ ) ₂ -CN Wherein R ¹ is selected from H, Cl, F, Br, -OCH ₃ , -C (= O) CH ₃ , z is an integer selected from 1, 2 or 3; A is phenyl, 3-indolyl, 5- (2,3-dihydro) benzofuranyl, 6-indolyl, 4-pyridinyl, 2-thienyl, 1,3-benzodioxolyl, 2-naphthyl, dibenzo [ b, f] azepinyl, dibenzo [a, d] cycloheptenyl, and optional substitution with the respective 1,2 or 3 substituents includes -OCH ₃ , -NO ₂ , -CO ₂ H, -C (= O ) -N (CH ₃ ) ₂ , -OC (= O) -CH ₃ , -CH ₃ , -CH ₂ -CH ₃ , phenyl, -SO ₂ -CH ₃ , F, Cl, Br, -CF ₃ ,- S-CH ₃ , -OCF ₃ , -C (= O) -CH ₃ , -OC (= O) -CH ₃ , -C (= O) O-CH ₃ , -C (= O) N (CH ₃ ) ₂ , -N (CH ₃ ) ₂ , -SO ₂ -N (CH ₃ ) ₂ ,
, N-morpholino, phenoxyl, benzoyl, -C (CH ₃ ) ₃ , -O- (CH ₂ ) ₂ -CH ₃ , -OH or -CN;
Here, L is a single bond, the formula -R ⁸ -R ⁹ - groups, Arukirin, Arukeniriru, ^{cycloalkylene, -NH- (C (R 4)} (R 4)) q -, - (C (R 4) (R ⁴ )) _q -,-(C (R ⁴ ) (R ⁴ )) _v -O- (C (R ⁴ ) (R ⁴ )) _W -,-(C (R ⁴ ) (R ⁴ )) _v -N- (C (R ⁴ ) (R ⁴ )) _W -,-(C (R ⁴ ) (R ⁴ )) _V- (C (R ⁴ )) _W =,-(C (R ⁴ ) ( R ⁴ )) _q- (C = O)-, or a linking group selected from cycloalkyleneoxyalkylene, wherein-(C (R ⁴ ) (R ⁴ )) _q- , (C (R ⁴ ) (R ⁴ )) _W and-(C (R ⁴ ) (R ⁴ )) _v are each independently aliphatic or form a cycloalkyl, where each R ⁴ is independently hydrogen, alkyl, hydroxyl, Selected from carboxy, hydroxyalkyl, alkoxyalkyl, alkylamino, alkylaminoalkyl or alkyloxycarbonyl, q is an integer selected from 0, 1, 2, 3, 4, 5 or 6 and v is 0, 1, 2, 3, 4, 5 or Is an integer selected from 6, and w is an integer selected from 0, 1, 2, 3, 4, 5 or 6, wherein R ⁸ is an alkyline,-(C (R ⁴ ) (R ⁴ ) ) _P -C (R ¹⁴ ) or-(C (R ⁴ ) (R ⁴ )) _P -C (R ⁴ ) = C, where R ⁹ is a single bond,-(C (R ⁴ ) ( R ⁴ )) _q- , or C (= O)-, wherein R ¹⁴ is selected from a hydrogen atom, a hydroxyl group or alkyl, where p is an integer selected from 0, 1, 2 or 3; R ¹⁰ is-(C (R ⁴ ) (R ⁴ )) _m -,-(C (R ⁴ ) (R ⁴ )) _m -C (= O) O- (C (R ⁴ ) (R ⁴ )) _q- , _or- (C (R ⁴ ) (R ⁴ )) _m -N (R ¹² )-(C (R ⁴ ) (R ⁴ )) _q- , where m is 1, 2 , 3, 4, 5 or 6, wherein R ¹² is selected from a hydrogen atom, alkyl, aryl, arylalkyl or alkylcarbonyl. The present invention includes all compounds having a structure selected from the group consisting of compounds of structural formulas I to LXIII shown above, wherein R ¹ , z, X ¹ , X ² , W, Y, Z, n, L, A, R ² , R ³ , R ⁸ , R ⁹ and R ¹⁰ have the same meaning as previously defined.

In embodiments, the present invention provides compounds of structural formulas I to LXIII, wherein X ¹ is a heteroatom and selected from —O—, —S—, —N═, or —N (R ³ ) —. Wherein R ³ is selected from alkyl, aralkyl or alkylcarbonyl, wherein X ² is selected from C, ═CH or —CH ₂ —, wherein n is an integer of 0 or 1 Wherein Y is selected from C, -C (R ⁵ )-or N, wherein R ⁵ is a hydrogen atom, amino, alkyl, hydroxyl group, alkylamino, heteroaryl, alkylcarbonyloxy, alkylamidyl or alkyl is selected from aminocarbonylamino, wherein Z, -C (= O), - CH 2 - or is selected from -NH-, wherein W is, -C in the formula I (= O), - N (R2 )-, -N (R2)-NH-, -C (= O) -NH-, -CH =, -O- or -CH _2- , and its subformula, and W Is of formula II, III or IV And in the subformula thereof, selected from N or CH,
Where A is phenyl, 3-indolyl, 5- (2,3-dihydro) benzofuranyl, 6-indolyl, 4-pyridinyl, 1,3-benzodioxolyl, 2-thienyl, 2-naphthyl, dibenzo [ b, f] azepinyl, or dibenzo [a, d] cycloheptenyl, and optional substitution with the respective 1,2,3 or 4 substituents includes —OCH ₃ , —NO ₂ , —CO ₂ H, —C (= O) -N (CH ₃ ) ₂ , -OC (= O) -CH ₃ , -CH ₃ , -CH ₂ -CH ₃ , phenyl, -SO ₂ -CH ₃ , F, Cl, Br, -CF ₃ , -S-CH ₃ , -OCF ₃ , -C (= O) -CH ₃ , -OC (= O) -CH ₃ , -C (= O) O-CH ₃ , -C (= O) N (CH ₃ ) ₂ , -N (CH ₃ ) ₂ , -SO ₂ -N (CH ₃ ) ₂ ,
, N-morpholino, phenoxyl, benzoyl, -C (CH ₃ ) ₃ , -O- (CH ₂ ) ₂ -CH ₃ , -OH or -CN;
Where L is a single bond, -CH ₂ -,-(CH ₂ ) ₂ -,-(CH ₂ ) _3- , -CH (CH ₂ OH)-, -CH (CH ₂ -O-CH ₃ )- , -CH (CH ₃ )-, -CH (CH ₂ -CH ₃ )-, -CH (CO ₂ H)-, -CH (CO ₂ CH ₃ )-,-(CH ₂ ) ₂ -O-CH ₂ -, -CH (CH ₂ -N (CH ₃ ) ₂ )-,-(CH ₂ ) ₂ -CH =, or
Or where -LA is selected from
Or
Or selected from
Is
Selected from
Where
Is
Selected from here
Is
Selected from
Here, R ¹ is a hydrogen atom, Cl, Br, F, -CF ₃ , -OCH ₃ , CH ₃ -C (= O)-, (CH ₃ ) ₂ N-CH (CH ₃ )-, -CO ₂ H, (CH ₃ ) ₂ NC (= O)-,
, CH ₃ -C (= O) O-, CH ₃ -OC (= O)-, CH ₃ -NH-C (= O)-, CH ₃ -C (= O) -NH-CH (CH ₃ ) -, HO-CH _2- , CH ₃ -CH _2- , CH ₃ -O-CH _2-
Where z is 1 or 2,
Where R ⁵ is H, —NH ₂ , CH ₃ —NH—C (═O) —NH—, CH ₃ —C (═O) —NH—, CH ₃ —C (═O) O—, — _{OH, -CH 3, CH3-CH} 2 -, (CH 3) 2 N- or
And wherein R ² is a hydrogen atom, CH _3- , phenyl, CH _3- , -CH ₂ -CH ₃ -,-(CH ₂ ) ₂ -CH ₃ ,-(CH ₂ ) ₂ -CN , Benzyl or CH ₃ —C (═O).

In specific embodiments, the present invention provides compounds of formula XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, XL, XLI, XLII, XLIII, XLIV, XLV, XLVI, XLVII, XLVIII, XLIX, L or LI. A compound of
Where A is phenyl,
, Substituents or -OCH ₃ of each _{1,2, -NO 2, -CH 3,} Cl, Br, -N (CH 3) 2, -OC (= O) -CH 3,
, F, -CF ₃ , -S-CH ₃ , -C (= O) O-CH ₃ , -C (= O) N (CH ₃ ) ₂ , -SO ₂ -N (CH ₃ ) ₂ , phenoxyl , -C (CH ₃ ) ₃ , phenyl, -C (= O) -CH ₃ , -SO ₂ -CH ₃ , -CN, -OCF ₃ ,
Or -OH, optionally substituted with a substituent selected from
Here, L is a single bond, -CH ₂ -,-(CH ₂ ) ₂ -,-(CH ₂ ) _3- , -CH (CH ₂ OH)-, -CH (CH ₂ -O-CH ₃ )- , -CH (CH ₃ )-, -CH (CH ₂ -CH ₃ )-, -CH (CO ₂ H)-, -CH (CO ₂ CH ₃ )-,-(CH ₂ ) ₂ -O-CH ₂ -, -CH (CH ₂ -N (CH ₃ ) ₂ )-,-(CH ₂ ) ₂ -CH =, or
Or where -LA is selected from
Or
Where A is optionally -OCH ₃ , -NO ₂ , -CH ₃ , Cl, Br, -N (CH ₃ ) ₂ , -OC (= O) -CH ₃ ,
F, -CF ₃ , -S-CH ₃ , -C (= O) O-CH ₃ , -C (= O) N (CH ₃ ) ₂ , -SO ₂ -N (CH ₃ ) ₂ , phenoxyl, -C (CH ₃ ) ₃ , phenyl, -C (= O) -CH ₃ , -SO ₂ -CH ₃ , -CN, -OCF ₃ ,
Or having 1, 2, or 3 substituents substituted with a substituent selected from:
Where R ¹ is selected from H, Cl, Br, F, -CF ₃ , -OCH ₃ , CH ₃ -C (= O)-,
Where z is 1 or 2,
Where R ⁵ is H, —CH ₃ ,
, —NH ₂ , CH ₃ —C (═O) —NH—, or CH ₃ —NH—C (═O) —NH—, and wherein R ² is H, CH ₃ —, — ( CH _{2) 2} -CH _{3, phenyl, CH 3 -, - CH 2} -CH 3 -, - (CH 2) 2 -CH 3, - (CH 2) 2 -CN, benzyl or CH ₃ -C (= O ) Is selected.

In specific embodiments, the invention provides compounds of formula LII, LIII, LIV, LV, LVI, LVII, LVIII, LIX, LX, LXI, LXII, or LXIII,
Where
Is
Selected from
Where
Is
Selected from
Where
Is
Selected from
Where A is phenyl,
, Substituents or -OCH ₃ of each _{1,2, -NO 2, -CH 3,} Cl, Br, -N (CH 3) 2, -OC (= O) -CH 3,
, F, -CF ₃ , -S-CH ₃ , -C (= O) O-CH ₃ , -C (= O) N (CH ₃ ) ₂ , -SO ₂ -N (CH ₃ ) ₂ , phenoxyl , -C (CH ₃ ) ₃ , phenyl, -C (= O) -CH ₃ , -SO ₂ -CH ₃ , -CN, -OCF ₃ ,
Or optionally substituted with a substituent selected from -OH,
Where R ¹ is selected from H, Cl, Br, F, -CF ₃ , -OCH ₃ , CH ₃ -C (= O)-,
Where z is 1 or 2,
Where R ⁵ is H, —CH ₃ ,
, —NH ₂ , CH ₃ —C (═O) —NH—, or CH ₃ —NH—C (═O) —NH—, and wherein R ² is H, CH ₃ —, — ( CH ₂ ) ₂ —CH ₃ , phenyl, CH ₃ —, —CH ₂ —CH ₃ —, — (CH ₂ ) ₂ —CN, benzyl or CH ₃ —C (═O).

In a specific embodiment of the invention, the compound has a structure represented by structural formula LXIX,
Wherein X ¹ is selected from O, S or —N—CH ₃ , wherein R ⁵ is selected from a hydrogen atom, methyl or pyrylyl, wherein R ¹⁸ is —OCH ₃ , F, Cl , Me, -OCF ₃ , or -CF ₃ , and z is an integer selected from 1 or 2, and in a specific embodiment, X ¹ is O or S, and z is 2 , And R ¹⁸ are —OCH ₃ and R ⁵ is H or CH ₃ .

In a specific embodiment of the invention, the compound has a structure represented by structural formula LXX,
Wherein X ¹ is selected from O, S or —N—CH ₃ , wherein R ⁵ is selected from a hydrogen atom, methyl, or pyrylyl; in a specific embodiment, X ¹ is O, or S, preferably S and R ⁵ are H or —CH ₃ , preferably —CH ₃ .

  The invention also relates to a process for producing the compounds according to the invention, for example using structurally related compounds. In an embodiment of the invention, the compounds of the invention can be prepared in the Examples using methods described below but not limited thereto.

In an embodiment, a method of making a compound of the invention comprises a compound of formula LXIV:
And a compound of formula LXV, LXVI, LXVII or LXVIII:
And a compound of formula I, II, III or IV:
[Wherein R ¹ , z, X ¹ , X ² , W, Y, Z, n, L, A, R ⁸ , R ⁹ and R ¹⁰ have the same meaning as previously defined herein. ]
The process of obtaining.

  For example, the condensation can be carried out by forming an acyl chloride of an acid of a compound of formula LXIV and then coupling said acyl chloride with a compound of formula LXV, LXVI, LXVII or ¥ LXVIII, where W is N. In another embodiment, the condensation can be performed by use of a suitable coupling agent in the presence of a suitable base in a suitable solvent.

In a specific embodiment, the method of producing a compound of the invention is a method comprising, for example, condensing an acid of a compound of formula LXIIIa with an amine of a compound of formula LXIVa, LXVa, LXVIa, or LXVIIa,
Wherein R ¹ and z have the same meaning as previously defined herein, and X is X ¹ as defined above. ]
[Wherein, A, L, R ¹⁰ and R ² have the same meaning as defined above. ]

This reaction can be performed by a general method of condensing a compound of the structural formula LXIIIa with a compound of the structural formula LXIVa, LXVa, LXVIa, or LXVIIa.
This condensation can be carried out in the course of the formation of the acid, acyl chloride of the compound of structural formula LXIIIa, and then the acyl chloride is coupled to the amine of the compound of structural formula LXIVa, LXVa, LXVIa, or LXVIIa. by. In other embodiments, the condensation can be performed in the presence of a suitable coupling agent, a suitable solvent, and a suitable base. Suitable coupling agents include dicyclo-hexylcarbodiimide, hydroxybenzotriazole, o-benzotriazol-1-yl-N, N, N ′, N-4-tetramethyluronium hexafluorophosphate, and the like, and mixtures thereof. A group can be selected. Suitable solvents can be selected from the group comprising dichloromethane, dimethylformamide and the like, or mixtures thereof. Although not limited to this example, examples of suitable bases include potassium carbonate, diisopropylethylamine, triethylamine, triisopropylamine, and the like.

As described above, the condensation can be accomplished by formation of the corresponding acyl chloride followed by coupling with the desired amine. In another embodiment, the condensation is carried out with a suitable coupling agent such as hydroxybenzotriazole (HOBT), o-benzotriazol-1-yl-N, N, N ′, N-4-tetramethyluronium hydroxybenzo A suitable solvent or mixed solvent, for example dichloromethane, using triazole hexafluorophosphate (TBTU) etc. in a suitable molar ratio, for example a molar ratio between 1: 1 and 1: 3 with respect to the acid derivative. (DCM) or dimethylformamide (DMF), etc., at a suitable temperature, usually between 0 ° C. and the boiling point of the solvent used, for a suitable time, usually 0.25 to 48 hours, suitable organic base, for example In the presence of an organic base such as potassium carbonate (K ₂ CO ₃ ), diisopropylethylamine (DIEA), triethylamine (TEA), triisopropylamine, etc. It can be carried out in an amount of 1 to 5.0 equivalents.

The starting materials for this reaction can be purchased or prepared by methods known per se.
The compounds of the invention are then isolated from the reaction mixture, optionally further known per se techniques such as solvent evaporation, washing, grinding, recrystallization from a suitable solvent or mixed solvent, and column chromatography, for example Purification can be accomplished using silica gel or C18 as the solid phase, or using chromatographic methods such as preparative thin layer chromatography.

  As used herein, the term “stereoisomer” can be composed of the same atoms that are linked by the same binding sequence but have different incompatible three-dimensional structures that the compounds of the invention may have. Defined as all such compounds. It will be apparent to those skilled in the art that some of the compounds of the present invention may contain one or more asymmetric carbon atoms, and this asymmetric carbon atom, which functions as an asymmetric center, can be a variety of optical entities (eg, enantiomers). (Enantiomers) or diastereoisomers). Unless otherwise stated or indicated, the chemical names of the compounds herein are the names of all such optical isomers that take all possible configurations and all possible stereochemical isomeric forms that the compounds may have. Includes mixtures. The mixture may contain all diastereomers and / or enantiomers of the basic molecular structure of the compound. All stereochemically isomeric forms of the compounds of the invention which are in pure form or mixed with each other are within the scope of the invention.

  More generally, it will be apparent to those skilled in the art from the above that, although not limited thereto, several isomeric forms of the present invention may exist in various isomeric and / or tautomeric forms. In the presence of geometric, conformational, and stereochemical isomers (ie enantiomers and diastereoisomers) and the same substituents on different positions of the ring present in the compounds of the invention. Corresponding isomers are included. All such possible isomers, tautomers and mixtures thereof are included within the scope of the present invention.

  In addition, when the desired compound of the present invention and / or the starting materials, precursors and / or intermediates used in the production thereof contain functional groups that are sensitive to the reaction conditions used in the production of the compound of the present invention ( That is, if the functional group is not properly protected, it is likely that an undesired reaction will occur under those conditions), during the reaction it can be protected with one or more suitable protecting groups, and then the reaction It will also be apparent that the protecting group can be suitably removed after completion and / or later or after the final step in the preparation of the compounds of the invention. Protected forms of the compounds of the invention are included within the scope of the invention. Appropriate protecting groups, as well as methods and conditions for inserting and removing protecting groups will be apparent to those skilled in the art, and standard handbooks of organic chemistry, such as Greene and Wuts, Protective groups in organic synthesis, 3rd edition. Wiley and Sons, 1999, etc., which are incorporated herein by reference in their entirety. It will also be apparent to those skilled in the art that compounds of the present invention in which one or more functional groups are protected with appropriate functional groups may serve as intermediates in the production and / or synthesis of the compounds of the present invention, This in itself forms another aspect of the present invention.

  The invention further encompasses compounds obtainable by the method according to the invention.

  Surprisingly, the compounds of the present invention interact with ion channels, as shown in the examples below, in particular ion channels from the Kv family, and more specifically ion channels from the Kv4 subfamily, In particular, it was found to interact with the Kv4.3 channel.

  “Interact” means that a compound of the invention acts as an antagonist of said ion channels and / or the biological functions and / or pathways with which these channels are associated, A compound can fully or partially “inhibit” the channel. It is preferred that the compounds of the present invention interact with an ion channel from an animal, preferably a vertebrate, more preferably a warm-blooded animal, even more preferably a mammal, and most preferably a human ion channel.

  In an embodiment of the invention, the compounds of the invention act as an antagonist of said ion channel and / or the biological function or pathway associated therewith. The compound of the present invention preferably inhibits the ion channel.

In another embodiment, the compounds of the invention act as antagonists of the Kv family of ion channels and / or biological functions or pathways associated therewith. Furthermore, the compounds of the present invention preferably inhibit ion channels derived from the Kv family. In the present invention, specific choices are given for compounds of structural formula I, II, III or IV above, there are specific activities for Kv4.3 and Kv1.5 ion channels, and as a value of IC ₅₀ , Less than 100 μM, preferably less than 50 μM, more preferably less than 10 μM, preferably less than 5 μM, more preferably less than 1 μM, this value can be determined by a suitable assay, as in the examples below. Will be shown.

  In the present invention, specific choices are given for compounds of structural formula I, II, III or IV as described above and have specific activity for Kv4.3 ion channel and Kv1.5 ion channel, where residual after application of the compound Is currently measured and determined by the appropriate assay used in the examples below and is less than or equal to 90%, preferably less than 85%, more preferably less than 80%, preferably less than the control. Less than 70%.

According to yet another embodiment, the compounds of the invention act as antagonists of ion channels from the Kv4 subfamily and / or biological functions or pathways associated therewith. Furthermore, preferably the compounds of the invention inhibit ion channels from the Kv4 subfamily.

  According to yet another embodiment, the compounds of the invention act as antagonists of the Kv4.3 ion channels and / or biological functions or pathways associated therewith. Also most preferably, the compounds of the invention inhibit the Kv4.3 ion channel.

  According to a further aspect, the compounds of the invention that inhibit the Kv4.3 ion channel also inhibit Kv1 subfamily ion channels, in particular the Kv1.5 ion channel.

  Whether a compound of the invention interacts with an ion channel can be determined using an appropriate technique or assay, such as the assay described in the Examples.

  Thus, in general, the compounds of the present invention have (1) ion channel and / or as an antagonist of the biological function or pathway associated therewith, ie, in vitro, in vivo or therapeutic settings, (2) ion channel inhibition Production of a pharmaceutical composition as an agent, ie in vitro, in vivo or in a therapeutic setting, and / or as a pharmaceutically active agent, in particular for the prevention and / or treatment of symptoms or diseases associated with said ion channels ) Can be used.

  In particular, the compounds of the invention that interact with ion channels from the Kv family are (1) antagonists of the ion channels from the Kv family, and / or their associated biological functions or pathways, ie in vitro, in vivo or In a therapeutic setting, (2) as an ion channel inhibitor from the Kv family, ie in vitro, in vivo or in a therapeutic setting, and / or as a pharmaceutically active agent, in particular a condition associated with an ion channel from the Kv family Or it can be used in disease symptoms and / or treatment (manufacture of pharmaceutical compositions for).

  More specifically, compounds of the present invention that interact with ion channels derived from the Kv4 subfamily are (1) as antagonists of the ion channels derived from the Kv4 subfamily and / or biological functions or pathways associated therewith. In particular, in an in vitro, in vivo or therapeutic setting, (2) as an ion channel inhibitor from the Kv4 subfamily, ie in an in vitro, in vivo or therapeutic setting, and / or (3) as a pharmaceutically active agent, in particular the Kv4 subfamily It can be used in the prevention and / or treatment (manufacture of a pharmaceutical composition) for a condition or disease associated with an ion channel derived from.

  Even more specifically, the compounds of the present invention that interact with Kv4.3 ion channels from the Kv4 subfamily include in particular (1) Kv4.3 ion channels and / or biological functions or pathways associated therewith. As an antagonist of, i.e. in vitro, in vivo or therapeutic setting, (2) as a Kv4.3 ion channel inhibitor, i.e. in vitro, in vivo or therapeutic setting, and / or (3) as a pharmaceutically active agent, in particular Kv4. It can be used in the prevention and / or treatment (manufacture of a pharmaceutical composition) for a condition or disease associated with a three ion channel.

  According to a further embodiment, the compounds of the present invention that interact with ion channels from the Kv1 subfamily include: (1) an ion channel from the Kv1 subfamily, and / or an antagonist of a biological function or pathway associated therewith As an ion channel inhibitor from the Kv1 subfamily (ie in vitro, in vivo or therapeutic setting) and / or (3) as a pharmaceutically active agent, in particular, in an in vitro, in vivo or therapeutic setting. It can be used in the prevention and / or treatment (manufacture of a pharmaceutical composition) for a condition or disease associated with a family-derived ion channel.

  More specifically, the compounds of the present invention that interact with Kv1.5 ion channels from the Kv1 subfamily include in particular (1) Kv1.5 ion channels and / or biological functions or pathways associated therewith. As an antagonist of i.e. in vitro, in vivo or therapeutic setting, (2) as a Kv1.5 ion channel inhibitor, i.e. in vitro, in vivo or therapeutic setting and / or (3) as a pharmaceutically active agent, in particular Kv1. It can be used in the prevention and / or treatment (manufacture of pharmaceutical compositions for) of symptoms or diseases associated with 5 ion channels.

  In another aspect, the present invention provides a compound of formula I, II, III or IV for use as a medicament. Furthermore, the present invention provides a compound of formula I, II, III or IV for use as an ion channel inhibitor. Furthermore, the present invention provides a compound of formula I, II, III or IV for use as an ion channel inhibitor of the Kv4 ion channel family. In particular, the present invention provides a compound of formula I, II, III or IV for use as an ion channel inhibitor of the Kv4.3 ion channel family. Furthermore, the present invention provides a compound of formula I, II, III or IV for use as an ion channel inhibitor of the Kv1 ion channel family. In particular, the present invention provides compounds of formula I, II, III or IV for use as ion channel inhibitors of the Kv1.5 ion channel family.

  The present invention further provides the use of a compound according to the present invention for the manufacture of a medicament for the prevention and / or treatment of symptoms or diseases associated with Kv4 and / or Kv1 family ion channels.

  Such diseases and conditions will be apparent to those skilled in the art. For example, symptoms and disorders associated with the Kv4.3 ion channel, particularly in humans, include heart diseases such as arrhythmias, hypertension-induced heart diseases such as hypertension-induced cardiac hypertrophy (eg ventricular hypertrophy), and nervous system diseases Examples include but are not limited to epilepsy, stroke, traumatic brain injury, anxiety, insomnia, Alzheimer's disease, spinal cord injury, encephalomyelitis, multiple sclerosis, demyelinating disease and Parkinson's syndrome, The compounds of the invention that interact with Kv4.3 ion channels can be used for the prevention and / or treatment of such conditions and diseases.

  Similar symptoms and diseases are associated with the Kv1.5 ion channel and can be used for the prevention and / or treatment of such symptoms and diseases. For example, class III antiarrhythmic drugs exert their effects by blocking cardiac potassium channels, thereby prolonging repolarization and refractory properties. 1 (Kur), an ultrafast delayed rectifier current was identified in human atrial tissue, but not in ventricular tissue.

  Thus, the current causes repolarization of the action potential only in the atria. The Kv1.5 protein is presumed to be an important cardiac voltage-gated potassium channel that forms l (Kur). Compounds that inhibit Kv1.5 delay the repolarization of action potentials in the atrium and consequently prolong the atrial refractory period. Given the high selectivity of Kv1.5 inhibitors for hERG, such inhibitors should not interfere with ventricular repolarization associated with pro-arrhythmias (arrhythmic promoting effects) such as ventricular arrhythmias (torsades de pointes) It is. Thus, Kv1.5 inhibitors are particularly important for the treatment of atrial paroxysmal tachycardia such as atrial fibrillation. Thus, according to another embodiment, the present invention also interacts with Kv1.5 ion channel to prevent and / or treat the above conditions and diseases and is associated with Kv4.3 ion channel related diseases. It relates to the use of compounds. Preferred compounds for use in the treatment of these conditions or diseases are compounds that are active on Kv4.3 and Kv1.5 ion channels. For example, the compounds are suitable for the treatment and / or prevention of various diseases: supraventricular arrhythmia, atrial arrhythmia, atrial fibrillation, atrial flutter, cardiac ischemic complications. In addition, the compounds may be used to stop current atrial fibrillation or flutter, for example, to restore sinus rhythm (heart version). Furthermore, this substance can reduce the sensitivity to the formation of new microfibrotic events (maintenance of sinus rhythm, prevention).

  The compounds according to the invention are used as heart rate regulators, including angina including release of Prinzmetal symptoms, vasospastic symptoms and deformities; reflux esophagitis, functional dyspepsia, motor disorders (including constipation and diarrhea) And gastrointestinal disorders including irritable bowel syndrome; asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, peripheral vascular disease (including intermittent claudication), venous insufficiency, impotence, cerebral and coronary spasm, and white wax disease Vascular and visceral smooth muscle diseases including; inflammatory bowel disease, rheumatoid arthritis, graft rejection, asthma, chronic obstructive pulmonary disease, cystic fibrosis and atherosclerosis; Cell proliferative diseases including restenosis and cancer (including leukemia); auditory vision system diseases including macular degeneration and cataracts; sugars including diabetic retinopathy, diabetic nephropathy and diabetic neuropathy Diseases; muscle tone and wasting, peripheral neuropathy, cognitive impairment, migraine, memory loss including Alzheimer's type and dementia, CNS-mediated motor impairment including Parkinson's disease, and muscle disorders including ataxia; epilepsy, and other It can also be used for ion channel mediated diseases.

  As inhibitors of the K1 subfamily of voltage-gated K + channels, the compounds according to the invention are useful in the treatment of various diseases including: tolerance by organ or tissue transplantation, graft-versus-host disease caused by bone marrow transplantation, Rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, juvenile or recently onset diabetes, posterior uveitis, allergic encephalomyelitis, Glomerulonephritis, infections caused by pathogenic microorganisms, inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczema dermatitis, seborrheic dermatitis, lichen planus, pemphigus , Bullous pemphigoid, epidermolysis bullosa, hives, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, spring Catar, Behcet's disease-associated uveitis, keratitis, herpetic keratitis, keratoconus, dystrophic epithelial cornea, corneal vitiligo, pemphigus, Mohren's ulcer, scleritis, Graves' eye disease, Vogt-Koyanagi- Harada syndrome, sarcoidosis, pollen allergy, reversible obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or refractory asthma, late-onset asthma and airway hypersensitivity, Bronchitis, gastric ulcer, vascular injury caused by ischemic disease and thrombosis, ischemic bowel disease, inflammatory bowel disease, necrotizing enterocolitis, burns and leukotriene B4 mediated disease associated bowel lesions, coriaz disease, proctitis, eosinic acid Gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Goodpasture syndrome, hemolytic uremic syndrome, diabetic nephropathy, Onset myositis, Guillain-Barre syndrome, Meniere's disease, polyneuritis, polyneuritis, mononeuritis, radiculopathy, hyperthyroidism, Graves' disease, erythroblastoma, aplastic anemia, hypoplastic anemia , Idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, erythropoiesis, osteoporosis, sarcoidosis, pulmonary fibrosis, idiopathic interstitial Pneumonia, dermatomyositis, vitiligo vulgaris, ichthyosis vulgaris, photoallergic hypersensitivity, cutaneous T-cell lymphoma, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, cardiomyopathy, scleroderma , Wegener's granulomatosis, Sjogren's syndrome, steatosis, eosinophil fasciitis, gingival lesions, periodontal tissue, alveolar bone, dental cementum, glomerulonephritis, hair loss prevention or hair growth supply and / or hair growth promotion and Male type with hair growth promotion or Senile alopecia, muscular dystrophy, pyoderma and Sézary syndrome, Addison's disease, preservation, transplantation or organ ischemia-reperfusion injury caused by ischemic disease, endotoxin shock, pseudomembranous colitis, colon caused by drug or irradiation Inflammation, ischemic acute renal dysfunction, chronic renal failure, pulmonary oxygen or drug-induced poisoning, lung cancer, emphysema, cataract, iron deposition, retinitis, pigmentation, senile macular degeneration, vitreous scar, Corneal alkali burn, polymorphic erythematous dermatitis, linear IgA bullous dermatitis and cement dermatitis, gingivitis, periodontal disease, sepsis, pancreatitis, diseases caused by environmental pollution, aging, carcinogenesis, carcinoma metastasis and Takayama Disease, disease caused by release of histamine or leukotriene C4, Behcet's disease, autoimmune hepatitis, primary biliary cirrhosis sclerosing cholangitis, partial hepatectomy, Acute liver necrosis; necrosis caused by toxins, viral hepatitis, shock, or anoxia; B viral hepatitis, non-A / non-B hepatitis, cirrhosis, alcoholic cirrhosis, liver failure, fulminant liver failure, Delayed liver failure, “chronic acute” liver failure, increased chemotherapeutic action, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile dementia, trauma, and chronic bacterial infection.

  The compounds of the present invention are antiarrhythmic agents that are useful for the prevention and treatment (including partial alleviation or cure) of arrhythmias. As inhibitors of Kv1.5, compounds within the scope of the present invention are particularly useful for the selective prevention and treatment of supraventricular arrhythmias such as atrial fibrillation and atrial flutter.

  Whether a compound of the present invention interacts with an ion channel, eg, a Kv family ion channel, eg, a Kv4 or Kv1 subfamily ion channel, eg, a Kv4.3 or Kv1.5 ion channel, respectively, is a suitable technique. Alternatively, assays can be determined using, for example, the assays and techniques described herein, or other suitable assays or techniques known in the art.

  For pharmaceutical use, the compounds of the present invention may be used as free acids or free bases and / or pharmaceutically acceptable acid and / or base addition salts (eg, non-toxic organic or inorganic acids or bases). In the form of hydrates, solvates and / or complexes, and / or in the form of prodrugs or predrugs such as esters. As used herein and unless otherwise specified, the term “solvate” includes any suitable inorganic solvent (eg, hydrate) or organic solvent, such as, but not limited to, alcohols, ketones, esters And any combination that can be formed by a compound of the present invention. Such salts, hydrates, solvates and the like, and their preparation will be apparent to those skilled in the art, for example, US Pat. No. 6,372,778, US Pat. No. 6,369,086, US Pat. See the salts, hydrates, solvates and the like described in US Pat. No. 6,369,087 and US Pat. No. 6,372,733.

  The pharmaceutically acceptable salts of the compounds according to the invention, ie in the form of water-soluble, oil-soluble or dispersible products, are formed from conventional non-toxic salts or, for example, from inorganic or organic acids or bases. Quaternary ammonium salts are included. Examples of such acid addition salts include: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citric acid Salt, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate , Hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalene-sulfonate, nicotinic acid Salt, oxalate, pamoate, pectate, persulfate, 3-phenylpropionic acid, picrate, pivalate, propionate, succinate, liquor Salt, thiocyanate, tosylate, and undecanoate. Base salts include the following: ammonium salts; alkali metal salts such as sodium and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; salts with organic bases such as dicyclohexylamine salts , N-methyl-D-glucamine; and salts with amino acids such as arginine, lysine and the like. In addition, basic nitrogen-containing groups can be quaternized with agents such as: lower alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromide and iodide; dimethyl, diethyl, dibutyl and the like Dialkyl sulfates; and diamyl sulfate, long chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides and iodides; aralkyl halides such as benzyl and phenethyl bromide and others. Other pharmaceutically acceptable salts include sulfate ethanol adduct and sulfate.

  In another embodiment, the invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutic amount of a compound according to the invention.

  As used herein, the term “therapeutically effective amount” means the amount of an active compound or ingredient or pharmaceutical agent that elicits a biological or pharmaceutical response in a tissue, system, animal, or human, the response being a study Including alleviation of the disease symptoms being sought by an investigator, veterinarian, medical doctor, or other clinician.

  This pharmaceutical composition can be produced by a method known per se to those skilled in the art. For this purpose, a suitable combination of at least one compound having the formula I, II, III or IV and one or more solid or liquid pharmaceutical excipients, optionally with other pharmaceutically active compounds, is suitable. The dosage form or dosage form can then be used as a medicament in human or veterinary medicine.

  In general, for pharmaceutical use, the compounds of the invention comprise at least one compound of the invention and at least one pharmaceutically acceptable carrier, diluent or excipient and / or adjuvant, and optionally Can further be formulated as a pharmaceutical product containing one or more pharmaceutically active compounds. By way of example and not limitation, such formulations are for oral administration, for parenteral administration (eg, by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for local administration, for inhalation administration. , Forms suitable for administration by skin patches, implants, suppositories and the like. Such suitable dosage forms—which may be solid, semi-solid or liquid depending on the mode of administration—and methods, and carriers, diluents and excipients for use in the production thereof will be apparent to those skilled in the art. For example, US Pat. No. 6,372,778, US Pat. No. 6,369,086, US Pat. No. 6,369,087 and US Pat. No. 6,372,733, and Remington, Pharmaceutical Sciences Please refer to the standard handbook again, such as the latest edition of

Some preferred, but not limited to examples herein, examples of such preparations include tablets, pills, powders, troches, (medicine packaging) sachets, capsules, elixirs, suspensions, Sterile injections and sterilization (usually reconstituted before use) for emulsions, solutions, syrups, aerosols, ointments, creams, lotions, soft and hard gelatin capsules, suppositories, for rapid and / or continuous administration Powders are included, which are carriers, excipients and diluents that are suitable per se for such formulations, such as lactose, glucose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, Alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) , Methylcellulose, methyl - can be formulated by and propyl hydroxybenzoate, talc, magnesium stearate, edible oils, vegetable oils and mineral oils or suitable mixtures thereof. This formulation contains other pharmaceutically active substances (which may or may not be synergistic with the compounds of the present invention) and other substances commonly used in pharmaceutical preparations such as lubricants , Wetting agents, emulsifying and suspending agents, dispersing agents, disintegrating agents, bulking agents, injecting agents, preservatives, sweetening agents, flavoring agents, flow control agents, releasing agents and the like. The composition may also be formulated using, for example, natural gels or synthetic polymer-based liposomes or hydrophilic polymer matrices to provide rapid, sustained, or delayed release of the active compound contained therein.
In order to enhance the solubility and / or stability of the compounds of the pharmaceutical composition according to the invention, it may be advantageous to use [α]-, [β]-, or [γ] -cyclodextrin or derivatives thereof. Absent. Furthermore, the solubility and / or stability of the compound may be improved by a co-solvent such as an alcohol. In the manufacture of aqueous compositions, it may be more appropriate to add salts of the compounds of the present invention due to their high water solubility.

  Suitable cyclodextrins are [α]-, [β]-, or [γ] -cyclodextrin (CD) or ethers and mixed ethers thereof, wherein one or more of the hydroxyl groups of the anhydroglucose unit of the cyclodextrin is Substituted with: alkyl, especially methyl, ethyl or isopropyl, for example [β] -CD randomly methylated; hydroxyalkyl, especially hydroxyethyl, hydroxypropyl, or hydroxybutyl; carboxyalkyl, especially Carboxymethyl or carboxyethyl; alkylcarbonyl, especially acetyl; alkoxycarbonylalkyl or carboxyalkoxyalkyl, especially carboxymethoxypropyl or carboxyethoxypropyl; alkylcarbonyloxyalkyl, especially 2- Cetyl propyl. Of particular note as complexing agents and / or solubilizers are [β] -CD, randomly methylated [β] -CD, 2,6-dimethyl- [β] -CD, 2-hydroxyethyl -[Β] -CD, 2-hydroxyethyl- [γ] -CD, 2-hydroxypropyl- [γ] -CD and (2-carboxymethoxy) propyl- [β] -CD, in particular 2-hydroxypropyl- [ β] -CD (2-HP- [β] -CD). The term mixed ether refers to a cyclodextrin derivative, wherein the hydroxyl groups of at least two cyclodextrins are etherified with different groups such as hydroxypropyl and hydroxyethyl. An interesting way of formulating this compound in combination with cyclodextrin or its derivatives is described in European Patent Application No. 721,331. The formulations described therein are used with antifungal active ingredients, but they are equally interesting as the formulations of this compound. The formulation may also be made more palatable by adding pharmaceutically acceptable sweeteners and / or flavors. In particular, the invention encompasses pharmaceutical compositions comprising an effective amount of a compound according to the invention and a pharmaceutically acceptable cyclodextrin. The invention also encompasses a cyclodextrin complex consisting of a compound according to the invention and a cyclodextrin.

  More specifically, the composition is formulated into a pharmaceutical formulation comprising a therapeutically effective amount of particles comprising a solid dispersion of a compound of the invention and one or more pharmaceutically acceptable water-soluble polymers. Can do.

  The term “solid dispersion” is defined as a solid-state system comprising at least two components (as opposed to a liquid or gaseous state), where one component is the whole of the other component or components. Distributed more or less evenly. If the dispersion of components is such that the system is chemically and physically homogeneous or homogeneous throughout, or consists of a single phase as defined by thermodynamics, such a solid dispersion is referred to as “ This is referred to as “solid solution”. Solid solution is the preferred physical system. This is because the organism to which the solid solution is administered can usually readily utilize the components therein. The term “solid dispersion” also includes dispersions that are less homogeneous than solid solutions throughout. Such dispersions are not chemically and physically uniform throughout or comprise more than one phase.

  The water-soluble polymer conveniently has an apparent viscosity of 1 to 100 mPa.s when dissolved in a 2% aqueous solution at 20 ° C. s polymer. A preferred water-soluble polymer is hydroxypropyl methylcellulose or HPMC. HPMC with a methoxy substitution degree of about 0.8 to about 2.5 and a hydroxypropyl molar substitution of about 0.05 to about 3.0 are generally water soluble. The degree of methoxy substitution refers to the average number of methyl ether groups present per anhydroglucose unit of the cellulose molecule. Hydroxy-propyl molar substitution refers to the molar average number of propylene oxide reacted with each anhydroglucose unit of the cellulose molecule.

  It would be further convenient to formulate the compound in the form of nanoparticles. The nanoparticles have a surface conditioning material adsorbed on the surface in an amount sufficient to maintain an effective average particle size of less than 1000 nm. Suitable surface modifiers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products, and surfactants. Preferred surface modifiers include nonionic and anionic surfactants.

  Yet another interesting method of formulating a compound according to the invention involves a pharmaceutical composition whereby the compound is incorporated into a hydrophilic polymer and this mixture is applied as a coating film to many small beads, thereby producing a good biological A composition having availability is obtained, the composition can be conveniently produced and is suitable for the production of a pharmaceutical dosage form for oral administration. The beads include (a) a central round or spherical core, (b) a coating film of a hydrophilic polymer and an antiretroviral drug, and (c) a seal coating polymer layer. There are a number of materials suitable for use as the core in the beads, provided that the materials are pharmaceutically acceptable and have the appropriate dimensions and stiffness. Examples of such materials include polymers, inorganic materials, organic materials, and sugars, and derivatives thereof.

  The above preparation can be produced by a method known per se, and usually the method comprises mixing the active substance to be used with one or more pharmaceutically acceptable carriers under the necessary aseptic conditions. Including. U.S. Pat. No. 6,372,778, U.S. Pat. No. 6,369,086, U.S. Pat. No. 6,369,087 and U.S. Pat. No. 6,372,733, as well as the above prior art and Remington Pharmaceutical Please refer to the standard handbook again, such as the latest edition of Science.

  The pharmaceutical product of the present invention is preferably in unit dosage form, such as a box, blister, vial, bottle, sachet, ampoule, or any other suitable single dose or multiple dose holder or container (preferably Can optionally be packaged with one or more leaflets, optionally containing product information and / or instructions for use. In general, such unit dosages comprise 1-1000 mg, usually 5-500 mg of at least one compound of the invention, eg about 10, 25, 50, 100, 200, 300 or 400 mg per unit dosage. It is.

  The compound can be variously routed, including oral, rectal, transdermal, transdermal, intravenous, intramuscular or intranasal, depending on the particular preparation used and the condition or prophylaxis to be treated. Oral and intravenous administration are usually preferred.

  In general, the compounds of this invention are administered in an effective amount, which is sufficient to obtain the desired therapeutic or prophylactic effect in the individual administered by appropriate administration. Usually, depending on the condition to be prevented or treated, and the route of administration, such an effective amount is usually 0.01 to 1000 mg per kg patient body weight per day, more often 0.1 to 500 mg, for example, 0.1 to 250 mg, for example, about 0.1, 1, 5, 10, 20, 50, 100, 150, 200 or 250 mg. It may be administered in divided doses or basically continuously, for example using instillation. The amount to be administered, the route of administration and the further treatment plan will be determined by the clinician's treatment depending on factors such as age, gender and general condition of the patient, and the nature and severity of the disease / symptom being treated can do. U.S. Pat. No. 6,372,778, U.S. Pat. No. 6,369,086, U.S. Pat. No. 6,369,087 and U.S. Pat. No. 6,372,733, as well as the above prior art and Remington Pharmaceutical Please refer to the standard handbook again, such as the latest edition of Science. However, the particular dose level and frequency of administration for any particular patient may vary, and the activity of the particular compound used, the metabolic stability and duration of the compound, age, weight, general health, sex, diet It will be understood that it will depend on a variety of factors, including mode of administration and time, excretion rate, drug combination, severity of the particular condition.

  Accordingly, in another aspect, the invention provides a composition, particularly a composition intended for pharmaceutical use, comprising at least one compound of the invention and at least one suitable carrier (ie a carrier suitable for pharmaceutical use). Related to things. The invention also relates to the use of the compounds of the invention in the manufacture of such compositions.

  In accordance with the method of the present invention, the pharmaceutical compositions can be administered separately in divided or single combination forms at different times or simultaneously in the course of treatment. Accordingly, the present invention is to be understood as encompassing all such modes of simultaneous or alternating treatment, and the term “administering” is to be interpreted accordingly.

  For oral dosage forms, the compositions of the invention are mixed with suitable additives such as excipients, stabilizers or inert diluents, and appropriate dosage forms such as tablets, coated tablets are prepared by conventional methods. , Hard capsules, aqueous solutions, alcohol solutions, or oily solutions. Examples of suitable inert carriers are gum arabic, magnesium oxide, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch. In this case, the production can be performed with dry granules and wet granules. Suitable oily excipients or solvents are vegetable or animal oils such as sunflower oil or cod liver oil. Suitable solvents for aqueous or alcohol solutions are water, ethanol, sugar solution, or mixtures thereof. Polyethylene glycol and polypropylene glycol are also useful as other auxiliaries for other dosage forms. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose, and / or other excipients, binders, bulking agents, disintegrations known in the art. Agents, diluents and lubricants can be included.

  When administered by nasal aerosol or inhalation, these compositions are prepared according to techniques known in the art of this pharmaceutical formulation, and benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability , Fluorocarbons, and / or other solubilizers or dispersants known in the art can be used to make the saline solution. Pharmaceutical formulations suitable for administration in the form of an aerosol or spray are, for example, compounds of the invention or their physiology in pharmaceutically acceptable solvents such as ethanol or water, or mixtures of such solvents. Solution, suspension or emulsion containing a chemically acceptable salt. If necessary, the formulation can additionally include other pharmaceutical auxiliaries and propellants such as surfactants, emulsifiers, and stabilizers.

  For subcutaneous or intravenous administration, the compounds according to the invention are suitably made into solutions, suspensions or emulsions by means of customary substances, for example solubilizers, emulsifiers or further auxiliaries. The compounds of the invention can also be lyophilized, and the resulting lyophilizate is used, for example, to produce an injection or infusion preparation. Suitable solvents are, for example, water, saline solutions or alcohols such as ethanol, propanol, glycerol and sugar solutions such as glucose or mannitol solutions, or alternatively various solvent mixtures described. Injection solutions or suspensions may be prepared according to the known art using suitable non-toxic parenterally acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersions Formulations may be made using humectants or wetting agents and suspending agents such as fixed oils, including sterile, palatable synthetic mono- or diglycerides, and fatty acids including oleic acid.

  When administered rectally in the form of suppositories, these preparations can be prepared by mixing the compounds according to the invention with a suitable nonirritating excipient such as cocoa butter, a synthetic glyceride ester or polyethylene glycol. The excipient is solid at room temperature but liquefies and / or dissolves in the rectal cavity to release the drug.

  The compounds according to the invention have been found to act as antagonists of ion channels of the Kv family, more specifically from the Kv4 subfamily, and / or biological functions or pathways associated therewith. It has also been found that the compounds according to the invention act as antagonists of ion channels from the Kv1 subfamily and / or their associated biological functions or pathways.

  Accordingly, the compounds of the present invention are (1) as antagonists of ion channels and / or biological functions or pathways associated therewith, ie in vitro, in vivo or therapeutic settings, (2) as ion channel inhibitors, ie In vitro, in vivo or therapeutic setting and / or (3) as a pharmaceutically active agent, in particular in the prevention and / or treatment (manufacture of a pharmaceutical composition) for a condition or disease associated with said ion channel. Can do. In addition, the compounds according to the invention show very low activity or inactivity with respect to the hERG channel and are therefore selective.

  As mentioned above, by inhibiting the activity on the ion channels mentioned above, the compounds according to the invention are particularly useful for the prevention and / or treatment of symptoms or diseases associated with ion channels derived from the Kv family. Such diseases and conditions will be apparent to those skilled in the art. For example, symptoms and disorders associated with the Kv4.3 ion channel can cause heart disease such as arrhythmia, hypertension-induced heart disease such as hypertension-induced cardiac hypertrophy (eg ventricular hypertrophy), and nervous system diseases such as epilepsy, particularly in humans. , Stroke, traumatic brain injury, anxiety, insomnia, spinal cord injury, encephalomyelitis, multiple sclerosis, demyelinating diseases Alzheimer's disease and Parkinson's syndrome. The compounds according to the invention interact with the Kv4.3 ion channel and can be used for the prevention and / or treatment of such conditions and diseases. In addition, particularly in humans, conditions and diseases associated with the Kv1.5 ion channel include the same diseases and conditions as described above for the Kv4.3 ion channel. The compounds according to the invention that interact with the Kv1.5 ion channel are particularly useful for the prevention and / or treatment of atrial paroxysmal tachycardia such as atrial fibrillation.

  Thus, in another embodiment, the invention also provides for heart disease such as arrhythmia, hypertension-induced heart disease such as hypertension-induced cardiac hypertrophy (eg ventricular hypertrophy), and nervous system diseases such as epilepsy, stroke, traumatic brain. It also relates to the use of a compound according to the invention in the treatment of disorders, anxiety, insomnia, spinal cord injury, encephalomyelitis, multiple sclerosis, demyelinating disease, Alzheimer's disease and Parkinson's syndrome, or a pharmaceutical composition comprising said compound . In another embodiment, the invention also relates to the use of a compound according to the invention in the treatment of a heart disease such as arrhythmia or a pharmaceutical composition comprising said compound. In yet another embodiment, the invention also relates to the use of a compound according to the invention in the treatment of nervous system diseases or a pharmaceutical composition comprising said compound.

  A method for treating heart disease comprises administering to an individual in need of this treatment a pharmaceutical composition comprising a compound according to the invention. A method of treating a nervous system disorder comprises administering to an individual in need of this treatment a pharmaceutical composition comprising a compound according to the invention.

  It is also envisioned that the compounds and compositions are useful in the veterinary field, and for purposes of this specification, these include not only the prevention and / or treatment of animal diseases, but also- For example, for cattle, pigs, sheep, chickens, fish, etc.-including increasing the growth and / or weight of animals and / or the quantity and / or quality of meat or other products obtained from animals. Accordingly, in another aspect, the invention provides at least one compound of the invention (ie, a compound identified, discovered, and / or developed using a nematode or method described herein), And a composition for veterinary use comprising at least one suitable carrier (ie a carrier suitable for veterinary use). The invention also relates to the use of the compounds of the invention in the manufacture of such compositions. It is envisioned that the compounds and compositions may also be useful as insecticides.

  The invention will now be illustrated by the following synthetic and biological examples, which in no way limit the scope of the invention.

Production of the Compounds of the Present Invention In the practice of the present invention, conventional techniques belonging to the art such as synthetic organic chemistry, biological tests, etc. are used unless otherwise stated. The description of these techniques is well documented in the literature. Unless otherwise stated, the purity of the compounds was confirmed by liquid chromatography / mass spectrometry (LC / MS) according to method A or method B below.

Method A:
HPLC: Waters Alliance 2690 and photodiode array detector Waters 996. Mass spectrometer: Micromass Platform ZMD LC. Ionization: Electrospray (polarity: negative and positive).

Method:
Phase: Tosohaas TSK-gel Super ODS (100Å, 2 μm), column: 4.6 × 50 mm; solvent A: water and formic acid (26.5 mM); solvent B: acetonitrile and formic acid (17 mM); flow rate: 2.75 ml / min; 5 Minute gradient: 100% A & 0% B to 20% A & 80% B for 3 minutes, 80% B constant concentration for 1 minute, 80% B & 20% A to 0% B & 100% A 0.5 minute, 100% A constant concentration For 0.5 minutes
NMR spectra were measured by Varian Mercury 300 MHz NMR using the specified solvent as an internal standard.
Melting points are measured with Buchi B-540 and are uncorrected. All reagents used are commercially available or can be prepared by methods known per se.

Methods of Preparation Compounds of structural formula I, II, III or IV may be prepared according to the following procedures and schemes and the knowledge of one skilled in the art.
Protocol A:
The acid derivative (0.5 mmol) was dissolved in a mixture of DMF (0.5 ml) and DIEA (1.5 mmol). A solution of TBTU (0.5 mmol) and HOBt (0.1 mmol) in DMF (0.5 ml) was added and the mixture was stirred for 30 minutes at room temperature. Amine (0.5 mmol) was added and the reaction was stirred at room temperature for 3 to 24 hours. DMF was removed under reduced pressure. The residue (0.5 mmol) is dissolved in EtOAc (5 ml) or DCM (5 ml), 0.5N HCl (2 × 5 ml), 0.5N NaOH (2 × 5 ml) and water (2 × 5 ml), or 1N NaHCO ₃ (2 × 5 ml) and water (2 × 5 ml) Washed with. The organic layer was dried over MgSO ₄ and the solvent removed in vacuo. The residue was purified by flash chromatography, semi-prep HPLC or recrystallization.

Illustrative examples, 5-chlorobenzofuran-2-carboxylic acid (R)-(4-nitrophen-1-yl) ethylamide (Compound 1)
In a round bottom flask, 5-chlorobenzofuran-2-carboxylic acid (98 mg; 0.5 mmol) was dissolved in a solution of DIEA (261 μl; 1.5 mmol) in DMF (0.5 ml). TBTU (160 mg; 0.5 mmol) and a solution of HOBT (14 mg; 0.1 mmol) in DMF (0.5 ml) were added and the reaction was stirred at room temperature for 30 minutes. (R)-(4-Nitrophen-1-yl) ethylamine (76 mg; 0.5 mmoles) was added (if the amine was stored as the hydrochloride, another equivalent of DIEA is required). After stirring at room temperature for 2 hours, a solution of TBTU (112 mg; 0.35 mmoles) and HOBT (14 mg; 0.1 mmol) in DMF (0.35 ml) was added. Stirring was continued for 4 hours at room temperature. DMF was removed under vacuum. The residue was dissolved in ethyl acetate (5 ml). The organic layer was washed with HCl 0.5N (2 × 5 ml), NaOH 0.5N (2 × 5 ml), and water (2 × 5 ml). The organic layer was dried (magnesium sulfate) and removed under vacuum. The residue was purified by preparative HPLC.

Protocol B:
SOCl ₂ (5 ml) and DMF (2 drops) were added to carboxylic acid (3.08 mmol) and the mixture was stirred for 30 minutes at 45 ° C. Excess SOCl ₂ was removed under reduced pressure. Traces of SOCl ₂ were removed by distillation from DCM ( ₂ × 5 ml). Acyl chloride was dissolved in DCM (5 ml), and a stirred mixture of amine (3.08 mmol) and Et ₃ N (18,5 mmol) or DIEA (18.5 mmol) in DCM (5 ml) was added under nitrogen atmosphere. Added at 0C. The mixture was stirred at 0 ° C. for 30 minutes and then warmed to room temperature. The reaction was stirred at room temperature for 30 minutes to 24 hours. The mixture was poured into water (100 ml) and extracted with DCM (3 × 100 ml). The combined organic layer was dried over MgSO ₄ and the solvent was removed under reduced pressure. The residue was purified by flash chromatography, semi-preparative HPLC or recrystallization.

Protocol C:
The ester (1.7 mmol) was dissolved in ethanol (5 ml) and 2N NaOH (10 ml) was added. The reaction was stirred at 45 ° C. for 30 minutes. The reaction solution was cooled to room temperature, and ethanol was removed under reduced pressure. The residue was diluted with water (10 ml), cooled to 0 ° C. and acidified to pH = 1 with 6N HCl. The precipitate was filtered, washed with water (3 × 10 ml) and dried under reduced pressure.

Protocol D:
5-Chloroindole-2-carboxylic acid (2.5 mmol) was dissolved in CH ₃ CN (20 ml). DBU (6.5 mmol) and Mel (5.6 mmol) were added. The mixture was stirred at 65 ° C. for 8 hours. The solvent was removed under reduced pressure.
The residue (2.5 mmol) was dissolved in dry 1,4-dioxane (20 ml) and the solution was cooled to 0 ° C. NaH (8.1 mmol) was added and the mixture was stirred at 0 ° C. for 15 minutes. Mel (10 mmol) was added and the mixture was stirred for 1 hour at 0 ° C. and for another 2 days at room temperature. The reaction mixture was poured into water (150 ml). The aqueous layer was extracted with Et ₂ O (3 × 100 ml). The combined organic layers were washed with 1N HCl (3 × 200 ml), dried over MgSO ₂ and the solvent removed under reduced pressure. The residue was purified by flash chromatography.

Protocol E:
To a solution of benzofuran-2-carboxylic acid (39.1 mmol) in dry dry 1,4-dioxane (250 ml) was added Et ₂ O (58.7 mmol) and diphenylphosphoryl azide (50.8 mmol). The reaction was stirred at room temperature overnight under a nitrogen atmosphere. EtOH (50 ml) was added and the reaction was heated to 100 ° C. overnight. The solvent was removed under reduced pressure and toluene was azeotropically distilled. The residue was crystallized from a toluene / EtOAc mixture.

Protocol F:
NaH (8.1 mmol) was added to (4-{[(5-chloro-benzofuran-2-carbonyl) -amino] -methyl} -phenyl) -carbamic acid ethyl ester (2.4) in dry dry 1,4-dioxane (20 ml). mmol) was added to the solution. The reaction was stirred for 2 hours at room temperature. A solution of (2,4-dimethoxy-phenyl) acetyl chloride (3.66 mmol) in dry dry 1,4-dioxane (10 ml) was added slowly. The reaction was stirred at room temperature overnight under a nitrogen atmosphere. The reaction was quenched by dilution with NaOH solution (100 ml) and extracted with Et ₂ O (3 × 100 ml). The combined organic layers were washed with water (3x100ml) and dried over MgSO2. The solvent was removed under reduced pressure and the residue was purified by flash chromatography.

Protocol G:
20 ml of 1.0 M Mg (OMe) ₂ -methanol solution was added to (4-{[(5-chloro-benzofuran-2-carbonyl) -amino] -methyl} -phenyl)-[2- (2,4-dimethoxy-phenyl) ) -Acetyl] carbamic acid ethyl ester (1.12 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 20% aqueous CH ₃ COOH (50 ml) and extracted with chloroform (3 × 100 ml). The combined organic layers were washed with aqueous NaOH (3 × 100 ml) and water (3 × 100 ml). The organic layer was dried over MgSO ₄ and the solvent was removed under reduced pressure. The residue was purified by flash chromatography.

Protocol H:
A solution of benzofuran (29.6 mmol) in dry THF (20 ml) was cooled to −80 ° C. under a nitrogen atmosphere. A solution of n-BuLi in 2.5M hexane (32.5 mmol) was added and the mixture was stirred for 1 h at −80 ° C. A solution of (2,4-dimethoxyphenyl) acetic acid (12.7 mmol) in dry THF (20 ml) was added slowly and then the mixture was slowly warmed to room temperature. After 4.5 hours, the reaction mixture was quenched with water (100 ml) and then extracted with EtOAc (5 × 100 ml). The combined organic layers were washed with brine (3 × 300 ml), dried over MgSO ₄ and then the solvent was removed under reduced pressure. The residue was purified by flash chromatography.

Protocol I:
Boron tribromide (5.0 mmol) was added to 5-chloro-benzofuran-2-carboxylic acid 4-methoxy-benzylamide (0.83 mmol) in DCM (5 ml). The solution was stirred for 1 hour and 20 minutes at −50 ° C. and then for 2 hours at room temperature. The reaction mixture was quenched with water (5 ml) and then extracted with EtOAc (3 × 100 ml). The combined organic layers were dried over MgSO ₄ and then the solvent was removed under reduced pressure. The residue was purified by recrystallization.

Protocol J:
DIEA (0.44 mmol) and acetyl chloride (0.44 mmol) were added to 5-chloro-benzofuran-2-carboxylic acid 4-hydroxy-benzylamide (0.44 mmol) in DCM (3 ml). The solution was stirred for 40 minutes at room temperature. The reaction mixture was diluted with DCM (20 ml) and washed with 1M Na ₂ CO ₃ solution. The organic layer was dried over MgSO ₄ and the solvent was removed under reduced pressure. The residue was purified by recrystallization.

Protocol K:
The ester (0.77 mmol) was dissolved in ethanol (3 ml) and then LiOH (0.77 mmol) was added. The mixture was stirred at 50 ° C. for 1 hour. The pH was adjusted to 2 with 1N HCl or poured into 20% KHSO ₄ aqueous solution. The precipitate was filtered, washed with water (2x20ml) and dried under reduced pressure.

Protocol L:
5-Chloro-benzofuran-2-carboxylic acid (0.5 mmol) and benzyl chloride (0.5 mmol) are dissolved in DMF (5 ml). K ₂ CO ₃ (0.6 mmol) is added and the mixture is stirred for 17 hours at 65 ° C. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was washed with MeOH (2 × 20 ml) and the filtrate's solvent was removed under reduced pressure. The residue was purified by flash chromatography.

Protocol M:
(4-Dimethylsulfamoyl-benzyl) -carbamic acid tert-butyl ester (0.65 mmol) was dissolved in a mixture of CH ₃ CN (2 ml) and 2N HCl (2 ml). The mixture was stirred at 50 ° C. overnight. After cooling to room temperature, the solvent was removed under reduced pressure.

Protocol N:
3-Amino-5-chlorobenzofuran-2 carboxylic acid methyl ester (0.89 mmol) was dissolved in DCM (2 ml). DIEA (2.2 mmol) and acetic anhydride (1.8 mmol) were added. The mixture was stirred for 48 hours at room temperature. The solvent was removed under reduced pressure.

  The present invention further includes compounds numbered 1 to 120 shown in Table 12, and stereoisomers, tautomers, racemates, prodrugs, metabolites thereof, or pharmaceutically acceptable salts and / or solvents thereof. Includes Japanese products.

  The present invention also includes 11 to 19 synthetic intermediate products.

  Compounds 1, 2, 3, 4, 5, 6, 7, 8, 24, 25, 26, 27, 28, 34, 36, 38, 39, 41, 44, 45, 49, 57, 58, 59, 60 61, 62, 63, 64, 65, 66, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 79, 80, 81, 82, 83, 84, 85, 87, 88 89, 90, 91, 92, 93, 94, 95, 98, 99, 101, 102, 103, 104, 105, 108, 109, 113, 114, 118 and 119 are 5-chloro-benzofuran-2- Synthesized from carboxylic acid. Compounds 9, 10, and 11 were synthesized from 7-methoxy-benzofuran-2-carboxylic acid.

Compound 13 was synthesized from 4-acetyl-7-methoxy-benzofuran-2-carboxylic acid.
Compounds 16 and 106 were synthesized from 5-chloro-3-methyl-benzofuran-2-carboxylic acid.
Compound 18 was synthesized from 3-pyrrol-1-yl-benzofuran-2-carboxylic acid.
Compound 19 was synthesized from 5-chloro-1H-indole-2-carboxylic acid according to Scheme 1.
Compounds 21, 107, 110 and 117 were synthesized from 5-chloro-3-methyl-benzo [b] thiophene-2-carboxylic acid.

Compound 22 was synthesized from benzofuran-2-carboxylic acid according to Scheme 2.

  Compounds 23 and 50 were synthesized from benzofuran-2-carboxylic acid. Compound 31 was synthesized from benzo [b] thiophene-2-carboxylic acid. Compound 33 was synthesized from intermediates 14 and 15. Compound 42 was synthesized from quinoline-3-carboxylic acid. Compound 43 was synthesized from 3-methyl-benzofuran-2-carboxylic acid. Compound 67 was synthesized from 5-chloro-benzofuran-2-carboxylic acid and intermediate 16. Compound 96 was synthesized from 1-benzyl-1H-indole-3-carboxylic acid. Compound 111 was synthesized from 5-chloro-1H-indole-2-carboxylic acid. Compound 112 was synthesized from quinoline-2-carboxylic acid.

Compound 115 was synthesized from 3-amino-5-chloro-benzofuran-2-carboxylic acid according to Scheme 3.

Compound 116 was synthesized from 3-amino-5-chloro-benzofuran-2-carboxylic acid.
Compound 120 was synthesized from 5-chloro-benzoxazole-2-carboxylic acid.

The structural formula of the intermediate is listed in Table 1. The following ellipsis is used below. P: protocol, Rt: residence time, Pu: purity, ES +: molecular ion obtained by electrospraying in positive ion mode

This is an example of the compound of the present invention, but is not limited thereto.
The present invention includes compounds of Formulas I to LXVII, and stereoisomers, tautomers, racemates, prodrugs, metabolites, or pharmaceutically acceptable salts and / or solvates thereof.
Compound 1: 5-Chlorobenzofuran-2-carboxylic acid (R)-[(4-nitrophen-1-yl) ethyl] -amide This compound comprises 5-chlorobenzofuran-2-carboxylic acid and (R)-(4 Obtained by protocol A from -nitrophen-1-yl) ethylamine.
Compound 2: 5-chlorobenzofuran-2-carboxylic acid 3,5-dimethoxybenzyl-amide This compound was obtained from protocol A from 5-chlorobenzofuran-2-carboxylic acid and 3,5-dimethoxybenzylamine.
Compound 3: 5-chlorobenzofuran-2-carboxylic acid 2- (5-methylindol-3-yl) -ethyl-amide This compound comprises 5-chlorobenzofuran-2-carboxylic acid and 2- (5-methylindole- Obtained by protocol A from 3-yl) -ethylamine.
Compound 4: 5-chlorobenzofuran-2-carboxylic acid [3- (10,11-dihydro-dibenzo [b, f] azepin-5-yl) propyl] methyl-amide Protocol A was obtained from carboxylic acid and [3- (10,11-dihydro-dibenzo [b, f] azepin-5-yl) propyl] methyl-amine.
Compound 5: 5-chlorobenzofuran-2-carboxylic acid [3- (10,11-dihydro-dibenzo [a, d] cyclohepten-5-ylidene) ethyl] -methyl-amide This compound is 5-chlorobenzofuran-2 -Protocol A from carboxylic acid and [3- (10,11-dihydro-dibenzo [a, d] cyclohepten-5-ylidene) propyl] -methyl-amine.
Compound 6: 5-Chlorobenzofuran-2-carboxylic acid (4-nitrobenzyl) -propyl-amide This compound was prepared from Protocol A using 5-chlorobenzofuran-2-carboxylic acid and (4-nitrobenzyl) -propyl-amine. Was obtained.
Compound 7: 5-Chlorobenzofuran-2-yl- [4- (4-chlorobenzoyl) -piperidin-1-yl] -methanone This compound consists of 5-chlorobenzofuran-2-carboxylic acid and 4- (4-chloro It was obtained by protocol A from benzoyl) -piperidine.
Compound 8: 5-Chlorobenzofuran-2-carboxylic acid 4-dimethylamino-benzylamide This compound was obtained by protocol A from 5-chlorobenzofuran-2-carboxylic acid and 4-dimethylamino-benzylamine.
Compound 9: 7-methoxybenzofuran-2-carboxylic acid (R)-(4-nitrophen-1-yl) -ethyl-amide This compound is composed of 7-methoxybenzofuran-2-carboxylic acid and (R)-(4- Obtained by protocol A from nitrophen-1-yl) -ethyl-amine.
Compound 10: 7-Methoxybenzofuran-2-carboxylic acid (S)-(Naphtho-2-yl) -ethyl-amide This compound comprises 7-methoxybenzofuran-2-carboxylic acid and (S)-(naphth-2- Yl) -ethyl-amine.
Compound 11: 7-Methoxybenzofuran-2-carboxylic acid (1R, 2R) -2- (benzyloxycyclopent-1-yl) -amide This compound is 7-methoxybenzofuran-2-carboxylic acid (1R, 2R)- 2- (Benzyloxycyclopent-1-yl) -amide This compound is composed of 7-methoxybenzofuran-2-carboxylic acid and (1R, 2R) -2- (5-benzyloxycyclopent-1-yl) -amine. , Protocol A.

The compounds of the present invention are listed in Table 12. The present invention includes compounds 1 to 120, as well as stereoisomers, tautomers, racemates, prodrugs, metabolites, or pharmaceutically acceptable salts and / or solvates thereof.

Bioassay using screening by C. elegans
Establishing in vivo SAR (structure / activity relationship: effect of chemical structure on biological activity) for Kv4.3 of compounds of the present invention using C. elegans based on a high-throughput screen for Kv4.3 modulators did.

  This assay uses a stable transduced nematode strain that functionally expresses human Kv4.3 in the pharynx and a visible selection GFP marker in body wall muscle.

A method for describing the construction of a transduced nematode strain expressing human Kv4.3 is described in WO 03/097682. In brief, 5 ng / μl of plasmid pGV8 (human Kv4.3), 20 ng / μl of pDW2821 (GFP-marker) and 40 ng / ul of nematode genomic DNA were used to create the strain UG1755 to be used in practice. Is microinjected into the gonad of wild type strain N2. Transduced animals are isolated and subjected to integration of their extrachromosomal array into the nematode genome. A system that has transmitted 50% of the functionally expressed human Kv4.3 is mutated by gamma irradiation using a cobalt source. Select approximately 12,000 F2 animals and screen their offspring for a system that transmits 100% of the GFP marker. The GFP 100% transmission system is thought to be potentially integrated. These lines are further tested and crossed twice with the N2 strain. All resulting systems are tested for viability, GFP and human Kv4.3 expression. At the end of the selection process, UG1755 has been identified as the most suitable nematode for use in high-throughput screening (HTS). It has been confirmed by electropharyngeal (EPG) analysis that this stable strain expresses human Kv4.3. This method is described in WO 03/097682. That is, a pharynx dissected from a UG1755 nematode is prepared and recorded using an Axopatch-1D amplifier (Axon Instruments Inc.) with a pharyngeal electrogram (EPG). The pharynx is equilibrated in bath solution (saline containing Dent 0.5% DMSO) for approximately 2 minutes until a stable EPG record is seen. A compound solution (DMSO or 100 μM flecainide) is added to the bath solution. The numbers of ultrashort EPG (10-20 ms) and normal EPG (100-200 ms) are analyzed and expressed as a percentage. A decrease in the number of ultrashort EPGs indicates partial reversion to wild-type EPG, and thus inhibition of human Kv4.3, with 50-80% of EPGs being very short (Table 2). In UG1755, which can be modulated with flecainide, human Kv4.3 induces ultrashort EPG. In addition, the human Kv4.3 transgene was confirmed by standard qRT-PCR in UG1755, and the human Kv4.3 protein was detected with the human Kv4.3 antibody P0358 in the pharynx of UG1755 animals.

Assay background:
The pharynx is a nematode's vegetative organ and contracts rhythmically 3-4 times in 2 minutes. Pharyngeal contractions are controlled by the nervous system via action potentials similar to human muscle cells and can therefore be used in nematodes to study in vivo human ion channel physiology.

  In one characteristic form, the introduction of the human Kv4.3 channel into the nematode pharynx affects the action potential of the nematode. As the number of potassium channels further increases, potassium ion efflux increases and repolarization is promoted, thus reducing the action potential duration. The ultrashort action potential of human Kv4.3 transduced nematodes is restored to normal action potential by 4-aminopyridine, non-specific potassium channel blocker or flecanide, SCN5a, and Kv4.3 blocker. The nematode pharyngeal short action potential resulting from the expression of human Kv4.3 alters the pharyngeal contraction cycle and thus reduces pumping / phagocytosis in these transduced animals. This change in pumping is an endpoint that can be used for high-throughput screening techniques. The pumping endpoint can be technically translated for high throughput readout using a pre-fluorescent dye. Prefluorescent dyes are taken up by nematodes that depend on their own pumping activity and converted to fluorescent dyes by enzymes present in the intestine. After a certain incubation, the change in fluorescence intensity in the intestine can be measured with a plate reader.

  Screening of compounds according to the present invention is performed on a high-throughput screen using nematodes for the Kv4.3 modulator described above. In terms of its activity, the method for testing the human Kv4.3 activity of the compound of the present invention using a nematode strain expressing human Kv4.3 is the same as the method described in WO 03/097682. The method for testing compounds on wild type nematode strains that do not express human Kv4.3 is similar to the method described in WO 00/63427. In summary, UG1755 animals are housed in large numbers, and young adults (not in uterus or only a few eggs) are collected on the day of screening. Approximately 125 bodies in 80 μl buffer were dispensed into each well of a U-shaped 96 well plate. Compound plates were pre-loaded with compound material at a final concentration of 30 μM in 0.3% DMSO. After 1 hour of incubation, 10 μl of a fluorescent label, calcein AM (CAM) was added to bring the final concentration of CAM to 5 μM and the final concentration of DMSO to 0.8%. After further incubation at 20 ° C. for 4 hours, the nematode swallowing (or the reaction measured by CAM ingestion) is stopped by adding 60 μM ivermectin solution. The fluorescence intensity (measured in seconds) is measured at a wavelength of 535 nm (after excitation at 485 nm) with a Wallac plate reader 40 minutes after ivermectin addition.

The active compound has been identified and confirmed by dose response analysis. EC ₅₀ is calculated and the results are listed in Table 3 below. Dose response curves are determined at a concentration of 30 μM and the EC ₅₀ is calculated using the XLfit 2.09 software package.

These compounds have also been tested in a similar assay format using the nematode wild type strain N2 and the corresponding EC ₅₀ calculated. The EC ₅₀ ratio obtained for two strains (human Kv4.3 expression transduced and wild type) per compound is an indicator of whether the compound is active at human Kv4.3. Compound is a ratio of (EC ₅₀ about divided by EC ₅₀ for at Kv4.3 expressing strain N2) potentially cutoff value to determine that it is active in Kv4.3 1.8. The results of this ratio for the compounds of the present invention are listed in Table 3 below.
All compounds tested were active with respect to Kv4.3 even at fairly low concentrations. The compounds of the present invention were also active with respect to the Kv1.5 ion channel described further in Example 5.

Patch clamp assay cell culture:
In this experiment, a recombinant CHO-K1 cell line that stably expresses the human Kv4.3 / KChlP2.2 potassium channel was used. The cells used in this experiment were maintained in continuous culture under standard conditions (37 ° C., 7% CO ₂ air supply). CHO-K1 Kv4.3 / KChlP2.2 cells consist of 100 U / ml penicillin, 100 μg / ml streptomycin, 7% fetal calf serum (FCS), 2.5 μg / ml amphotericin, 400 μg / ml G418 and 400 μg / ml. Retained in Iscove's modified DMEM (Dulbecco's Modified Eagle Medium) medium (IMEM) supplemented with ml Zeocin®. Cells were subjected every 3-4 days after separation using trypsin solution. Cultured cell quality was assured by vigor and contamination tests. Cells were cultured as described in Protocol B below.

Protocol B: Cells were cultured in 94 mm culture dishes under 5% CO ₂ and 37 ° C. culture conditions. The medium was removed and the dishes were then rinsed with 8 ml PBS (phosphate buffered saline) and subcultures were performed every 3-4 days. PBS was removed and 1 ml trypsin / EDTA was added to the cells. Cells were incubated at 37 ° C. for about 2 minutes or at room temperature for 5 minutes, then the dish was tapped to separate and unify the cells. To incubate the enzyme, 9 ml of medium was added and the solution was pipetted up and down to break up cell clumps. A portion of the suspension was then transferred to a new 94 mm dish and medium added to a final volume of 8 ml. If necessary, cells were seeded in 35 mm or 94 mm dishes (2 ml medium for each 35 mm dish and 8 ml medium for each 94 mm dish). The medium was changed every 2-3 days. The used medium is a solution for culturing the above-mentioned cells. Antibiotics G418, hygromycin, blasticidin or zeocin were not added to stabilize the cells.

  The PBS used was Dulbecco's PBS (1x) and does not contain Ca or Mg. The 10x trypsin / EDTA solution contained 5 g / l trypsin, 2 g / l EDTA and 8.5 g / l NaCl. 450 ml PBS was added to 50 ml 10x trypsin / EDTA to prepare 1x trypsin / EDTA.

  At least 18 hours prior to electrophysiological experiments, cells were detached using frozen PBS or trypsin and re-plated on coverslips.

  For electrophysiological experiments, cells were prepared as described in Protocol C below.

  Protocol C: Transduced and stable cells were transferred from 35 mm cell culture dishes to coverslips using chilled PBS. : The medium was removed and 0.3 ml PBS (4-10 ° C) was added. Cells were incubated for 5 minutes at room temperature. The dish was tapped to separate and unify the cells. 1.7 ml of medium was added and the solution was pipetted up and down to break up cell clumps. Thereafter, a portion of the cell suspension was transferred to a 35 mm dish equipped with a coverslip and medium. Transduced and stable cells could also be transferred from 35 mm cell culture dishes to coverslips using trypsin. : The medium was removed and the dishes were then rinsed with 3 ml PBS. PBS was removed, 0.3 ml 1x trypsin / EDTA was added and the cells were incubated at room temperature for 5 minutes. The dish was tapped to separate and singulate the cells, 1.7 ml of medium was added, and the solution was pipetted up and down to break up cell clumps. Thereafter, a portion of the cell suspension was transferred to a 35 mm dish equipped with a coverslip and medium.

Solution preparation:
A 10 mM compound stock solution was prepared in DMSO. Compound solutions were prepared by diluting the stock solution in bath solution. If the desired stock volume was theoretically less than 1 μl, a bath solution containing a high concentration of compound was used for dilution. The highest DMSO concentration during the experiment was 0.1% (v / v).

  For patch clamp experiments, the following mineral-removed aqueous solutions were used as vehicles (numbers are concentration in mM).

Bath (external) solution: 4 KCl, 135 NaCl, 2 CaCl ₂ , 1 MgCl ₂ , 10 D (+)-glucose, 5 HEPES, pH 7.4 (NaOH)

Pipette (internal) solution: 130 KCl, 1 MgCl ₂ , 10 EGTA, 5 Na ₂ ATP, 5 HEPES, pH 7.4 (KOH)

Electrophysiological measurements:
The activity of human Kv4.3 / KChlP2.2 channel was investigated using patch clamp technique in whole cell mode. This means that the current required to clamp all cells expressing the K ⁺ channel was measured against a specific potential. The experiment was performed using a patch clamp equipment. The technical equipment necessary for cell manipulation was installed on a vibration isolation table and blocked by a Faraday box to minimize electrical noise. The amplifier and control system were installed on a stand outside the Faraday box. The system consists of an EPC9 or EPC10 patch clamp amplifier (HEKA, Lambrecht, Germany) and a perfusion system DADVC8 (ALA Scientific, New York, USA), which is a Pulse software package (HEKA, Lambrecht, Germany) installed on a personal computer. ) Controlled by. The pipette used for the patch clamp was made of borosilicate glass.

  The measurement was performed at room temperature (20-25 ° C). In each experiment (ie each cell), only one concentration of compound was investigated and not at a cumulative dose. Each cell acted to control itself. The effect of the compound on the Kv4.3 / KChlP2.2 mediated current was investigated in two replicates (c = 1, n = 2) at one concentration (2 μM).

Between voltage pulses, the cells were fixed at a holding potential of -80 mV (internal). The test protocol is represented in FIG. The test protocol shown in FIG. 1a was used to characterize the properties of the Kv4.3 / KChlP2.2 channel and to examine the quality (voltage control) of individual patch clamp experiments. The test protocol shown in FIG. 1b shows a standard test pulse for channel activity. Each trial protocol consisted of four segments. Segment durations and voltages are listed in Table 4.

  After setting the whole cell composition, a current-voltage curve (IV activation 1; FIG. 1a and Table 4a) was recorded under constant superfusion with bath solution, and Kv4.3 / KChlP2.2 expression and individual patches The quality of the clamp experiment (voltage control) was examined. Subsequently, 14 test pulses (System 1; FIG. 1b and Table 4b) were applied at 0.1 Hz under constant superfusion with the bath solution. The protocol was started by raising the voltage to 100 mV (400 ms) and completely inactivated. The Kv4.3 / KChlP2.2 channel was then transferred to the open upper body by depolarizing to +40 mV (activation) for 300 milliseconds. Only cells producing current amplitudes between 1 nA and 50 nA were used in the experimental procedure. There was very little or no rundown.

  Next, 36 test pulses (System 2) were applied at 0.1 Hz with constant overmelting with the compound dissolved in the bath solution. Finally, another current-voltage curve was recorded in the presence of the compound (IV activation 2).

  If the experimental parameters remained sufficient, the experiment was expanded to study compound efflux. To do so, the cells were again thawed with the bath solution, during which time up to 30 test pulses were applied at 0.1 Hz (system 3). Spill operations were not necessary for accurate data analysis.

  All data were corrected for leakage using a P / n protocol of n = 5. (See Data analysis).

All test protocols / systems and their use in data analysis are summarized in Table 5.

During the experiment, vehicle control was performed as a separate experiment, in which compound vehicle (DMSO) was used at its highest concentration (0.1%).

Data analysis Leaks were corrected using the classic P / n protocol. It is desirable that the leakage pulse does not reach the activation level of the channel and thus has been reduced to 1 / n of the original pulse amplitude. Here, n = 5 was used. The cell current response to the leak pulse was then multiplied by n to calculate the cell's theoretical passive response to the test sequence. The calculated curve was then subtracted from the actual sensitivity, leaving only the active part of the response.

  Three different analyzes were used: inhibition at peak current, inhibition of translocation charge and inhibition after 75 ms activation at +40 mV (sustained current). Peak current / charge / current after 75 ms was determined using an online analysis tool, HEKA Pulse Software Package. The cursor position was set so that the peak current was closed and activation of all segments (see Table 5) was selected, or was set at 75 milliseconds. The obtained current peak amplitude / dislocation charge / current amplitude at 75 milliseconds was written out as an ASCII data file.

  The resulting ASCII file was read into the software package Prism (Graphpad Software, San Diego, USA) and further analyzed as described below. A rundown fix was needed. The average value of the last five current peak amplitude / dislocation charge / current amplitude at 75 milliseconds before administration of the compound solution was calculated and used as the 100% activity value. The average value of the last five current peak amplitude / dislocation charge / current amplitude at 75 milliseconds in the presence of the compound solution was calculated to determine the inhibition value.

All data points were consistent with a Hill function with three individual parameters. Here, y _max is the maximum inhibition value in%, IC ₅₀ is the concentration at half the maximum inhibition value, and hill is the Hill coefficient.

The matching parameters y _max , IC ₅₀ and hill characterize the interaction of the test compound with the Kv4.3 / KChlP2.2 channel expressed in CHO-K1 cells. The error bar, ie the agreement of the curve obtained with the mean result with the standard error of the mean (SEM) is shown:

In order to compare the results, IC ₅₀ values were determined. Therefore, the Hill coefficient was fixed (hill = 1), the maximum inhibition value at a high concentration was fixed (y _max = 100), and the data were combined using the Hill equation.

The results of the patch clamp experiment are shown in Table 6.

  The compounds of the present invention have been found to be particularly active against the Kv4.3 ion channel.

  It was also important to measure possible side effects in order to maximize therapeutic utility. In addition to being able to regulate specific calcium channels, the compounds of the present invention were found to have a high selectivity ratio of Kv4.3 channel to hERG channel.

hERG experiment test system and test method test system:
In this experiment, HEK 293 T-REx HERG cells (# 23) were used. The cell line created by IonGate is characterized by inducible expression of the hERG gene. The T-REx ™ system (Invitrogen, Karlsruhe, Germany) is a tetracycline-controlled mammalian expression system that uses regulatory elements derived from the tetracycline (Tet) resistant operon encoded by E. coli Tn10. In the absence of Tet, expression is repressed. Tetracycline regulation in the T-REx ™ system is based on tetracycline binding to the Tet repressor and derepression of the promoter that controls the expression of the hERG gene. When Tet is added to the cell culture medium, the hERG potassium channel is expressed.

  To construct the HEK 293 T-REx HERG cell line, the hERG gene was ligated into the inducible expression vector pcDNA4 / TO (→ pc4TO-HERG) and transduced into HEK 293 T-Rex cells (this cell line It expresses a Tet inhibitor and was purchased from Invitrogen). Stable cell clones were isolated after selection with blasticidin (5 μg / ml) and Zeocin ™ (300 μg / ml). Clones were characterized electrophysiologically after induction with 1 μg / ml tetracycline. Clone # 23 showed the best expression of hERG potassium channel.

Test Method The experiment was conducted using a patch clamp equipment. The technical equipment necessary for cell manipulation was installed on a vibration isolation table and blocked by a Faraday box to minimize electrical noise. The amplifier and control system were installed on a stand outside the Faraday box. The system consists of an EPC9 or EPC10 patch clamp amplifier (HEKA, Lambrecht, Germany) and a perfusion system DADVC8 (ALA Scientific, New York, USA), which is a Pulse software package (HEKA, Lambrecht, Germany) installed on a personal computer. ) Controlled by.

Cell Culture Cells used in this experiment were maintained in continuous culture under standard conditions (37 ° C., 5% CO ₂ air supply). HEK 293 T-REx HERG cells were treated with 100 U / ml penicillin, 100 μg / ml streptomycin, 10% fetal calf serum (FCS), 1% nonessential amino acids (NEAA), 2.5 μg / ml amphotericin, 300 μg / ml. Maintained in basal medium (MEM) supplemented with ml Zeocin ™ and 5 μg / ml blasticidin. Cells were subjected every 3-4 days after separation using trypsin solution. Cultured cell quality was assured by vigor and contamination tests. Cells were cultured as described in protocol B above.

  At least 18 hours prior to electrophysiological experiments, cells were detached using frozen PBS (phosphate buffered saline) or trypsin and plated again on coverslips. 1 μg / ml tetracycline was added to the cells to induce hERG expression.

  For electrophysiological experiments, cells were prepared according to protocol E described above. The solution was prepared as described above below the paragraph preparation of the solution.

Electrophysiological measurements:
The activity of cardiac hERG channel was investigated using patch clamp technique in whole cell mode. This means that the current required to clamp all cells expressing the K + channel was measured against a specific potential. The pipette used for the patch clamp was made of borosilicate glass. The measurement was performed at room temperature (20-25 ° C.). In each experiment (ie each cell), only one concentration of compound was investigated and not at a cumulative dose. Each cell acted to control itself. The effect of compounds on hERG-mediated currents was investigated in two replicates (c = 1, n = 2) at one concentration (10 μM).

  Between voltage pulses, the cells were fixed at a holding potential of -80 mV (internal).

The test protocol for the electrophysiological investigation of hERG K + channels is presented in FIG. In Table 7 and FIG. 2, (a) is a standard test pulse for determination of channel activity. (b) and (c) were used to characterize the nature of the hERG channel and to examine the quality (voltage control) of individual patch clamp experiments. Each study protocol consisted of 6 segments. Segment durations and voltages are listed in Table 7.

  After setting the whole cell configuration, a series of pulses was applied to examine hERG expression and the amplifier settings were optimized. However, only the following measured values were used for data analysis. Fifteen test pulses (Fig. 2a and Table 7a) were applied at 0.1 Hz (system 1) under constant overmelting with the bath solution. The protocol was initiated by a leak test at -40 mV (50 ms). After returning the holding potential (-80 mV, 0.25 sec.), The hERG channel was shifted to the inactive state by depolarizing to +40 mV (activated) for 2.5 seconds. The maximum hERG tail current amplitude was measured at -40 mV (tail current test, 1.5 sec.). Only cells that generate tail current amplitudes between 300 pA and 10 nA were used in the experimental procedure.

  In FIG. 3, hERG channels mediated currents induced by the hERG channel test test protocol. FIG. 3a shows the channel activity test in the presence and absence of 10 μM compound 21 (upper line). Figures 5b and 5c are the current responses to Table 7b (IV activation) and Figure 7c (IV tail current) of the protocol.

Next, the current / voltage curve (IV curve) was investigated using two pulse systems under overmelting with the bath solution. With the pulse system “IV activation”, the potential of the activation pulse changes between each successive pulse of the system (−60 to +60 mV at 20 mV intervals, FIG. 2b and Table 6b). The tail current amplitude after activation at +60 mV had to be within ± 20% of the value seen at the +40 mV activation voltage. Due to the pulse system “IV tail current”, the potential of the tail current test pulse varies between each successive pulse of the system (−100 to +20 mV at 20 mV intervals, FIG. 2c and Table 6c). The maximum tail current amplitude (I _max ) had to be measured at 40 mV (± 10% I _max ). System "IV activation" and "IV tail current" test pulses were applied at 0.1 Hz.

  If the current characterization was successful, another 10 test pulses were applied at 0.1 Hz during which time the cells were superfused with the bath solution (System 2). Using systems 1 and 2, the mathematical function was matched to the tail current peak value to determine the signal amplitude rundown. An additional 30 test pulses (System 3) were applied, during which time the cells were overmelted with a solution containing the desired concentration of compound. If necessary, another test pulse was applied (system 4).

  When the experimental parameters were sufficient, the experiment was expanded to study compound efflux. For this purpose, the cells were again superfused with the bath solution, during which up to 20 test pulses were applied at 0.1 Hz (system 5). However, because the operations were matched to systems 1 and 2 to construct a baseline (rundown correction), spill operations were not necessary for the corrected data analysis.

All test protocols / systems and their use in electrophysiological data analysis are summarized in Table 8.

  During the experiment, vehicle control was performed as a separate experiment, in which compound vehicle (DMSO) was used at its highest concentration (0.1%).

Data analysis The basis of data analysis was tail current peak amplitude mediated by hERG K + channel at -40 mV after activation at +40 mV. The peak current was determined using an online analysis tool, HEKA pulse software package. The cursor was placed so that the peak current closed. The current at the leak test pulse (segment 2 in each test pulse) was set to zero. The obtained tail current peak amplitude was written out as an ASCII data file.

The resulting ASCII file was read into the software package Prism (Graphpad Software, San Diego, USA) and further analyzed as described below. Systems 1 and 2 were matched using the appropriate function (ie single or double exponential decay). Using the obtained function, rundown correction was performed on a set of data (systems 1 to 5) by partitioning. The last 5 tail current peak amplitudes prior to administration of the compound solution were averaged and used as the 100% activity value. The last five tail current peak amplitudes in the presence of the compound solution were averaged to determine the inhibition value. All data points were matched by a Hill function with three separate parameters. Here, y _max is the maximum inhibition value in%, IC ₅₀ is the concentration at half the maximum inhibition value, and hill is the Hill coefficient.

The matching parameters y _max , IC ₅₀ and hill characterize the interaction of the hERG K ⁺ channel expressed in HEK293 cells with the test compound. The resulting curves that are in agreement are shown in the graph (% inhibition value vs. log concentration) with error bars, ie, average results with standard error of the mean (SEM).

In order to compare the results, IC ₅₀ values were determined. Therefore, in using the Hill equation, the Hill coefficient was fixed (hill = 1), and the maximum inhibition value at a high concentration was fixed (y _max = 100), and the data was matched. The results of channel activity are shown in Table 9.

  Compounds with a Kv4.3 versus hERG selectivity (patch clamp test) of 5 or> 5 (ratio value) were considered highly selective for the Kv4.3 channel.

  Therefore, in addition to being active with respect to the Kv4.3 ion channel even at fairly low concentrations, the compounds of the present invention were found to be more selective for the Kv4.3 ion channel than the hERG channel.

  Table 12 also shows the effects of additional non-limiting compounds in the present invention on Kv4.3 and hERG. Unless otherwise specified, in a patch clamp assay according to the protocol described in Example 3, the compounds were tested for Kv4.3 mediated potassium channels at that one concentration (1 μM). The results are shown in Table 12. In Table 12, the Kv4.3 charge expressed in% means the residual current measured after addition of the compound, and is a relative value with no addition. The Kv4.3 peak in% means the height of the residual peak measured after compound addition, and is a relative value with no addition. As used herein, the term “ND” means not yet measured. Unless otherwise specified, the tests were conducted at a concentration of 1 μM for the Kv4.3 charge and peak. Unless otherwise specified, the effect of the patch clamp assay on the hERG channel was investigated at its 10 μm concentration for a non-limiting number of additional compounds of the invention.

Example 5: Patch clamp assay using Kv1.5 ion channel
A cDNA encoding Kv1.5 (GenBank Ace. No. M55513) was cloned into the pcDNA6 vector (Invitrogen, Leak, New Zealand). An AC terminal epitope tag was introduced by PCR. The plasmid was sequenced and subsequently introduced into the cells. A clonal cell line stably expressing the Kv1.5 channel was established. Protein expression was analyzed by immunofluorescence using an antibody against the epitope tag. The functional expression of ion channels was confirmed electrophysiologically.

Cell culture
Experiments were performed using CHO cells stably expressing the Kv1.5 potassium channel.
Cells 37 ° C., under 5% CO _2, 25 ml flasks (Greiner Bioone, Cellstar, Cat. No. 690160) at, 10% (v / v) heat-inactivated fetal bovine serum (Sigma, Cat. No. F9665), 1% (v / v) P / S / G solution (Sigma, Cat. No. G6784) and G-418 (750 μg / ml medium; Sigma, Germany, Cat. No. A1720; 50 mg / ml in water , Sigma, Germany, Cat. No. W3500) in 6 ml of MEM ALPHA medium (Sigma, Taufkirchen, Germany, Cat No M8042).

Electrophysiology
Kv1.5 mediated current stimulation protocol Cells were hyperpolarized from -60 mV HP to 70 mV for 100 milliseconds followed by depolarization for 50 milliseconds to +50 mV. The current amplitude at the end of the +50 mV test pulse was used for the analysis. The pulse period rate was 10 seconds (0.1 Hz).

Test item application protocol of Kv1.5 mediated current The application protocol of the test compound is shown in FIG. The first 14 stimuli were needed to stabilize the current amplitude. A non-specific current reduction rate was calculated and used to modify the operation during data analysis. After the 14th stimulation, test compounds began to be added through Teflon and silicone tubing (indicated by arrows) and were expected to reach the cells after 6 additional stimulations. Perfusion is adjusted with a defined drop rate of 10 drops / 10-12 seconds. Concentrations up to 3 were successfully applied to one cell and then washed for 5 minutes. The total number of stimuli was 140. For the first concentration, the effect of the test compound was analyzed between stimulus numbers 21-50 (5 minutes, long dashed line) and for another 5 minutes between stimulus numbers 51-80 (5 minutes, short dashed line). If the cells remained stable, they were subsequently washed. The start of test compound addition at a given concentration is indicated by an arrow. The number of each stimulation is shown in the protocol of FIG.

Negative control A vehicle (DMSO) control experiment was conducted under the same conditions throughout the study period to demonstrate the stability of the current over time and to evaluate the state of the cells.

Effect of test compounds on Kv1.5 mediated current
The effect of compounds on Kv1.5 mediated potassium channel was investigated at one concentration (2 μM or 1 μM). As a control, vehicle control experiments were performed with Kv1.5 mediated potassium channels. The results are shown in Table 10.

Example 6: Ex vivo organ test in rats and guinea pigs In isolated rat left atrium (Rat LA), the effect of compounds on contractile force and stimulation threshold and functional refractory period (FRP) were investigated. The rat left atrium functionally expresses the Kv4.3 ion channel and produces the action potential Ito current. In addition, the relative effects of the compounds were examined in isolated guinea pig right ventricular papillary muscle (GP pap. Muscle) that does not express Kv4.3. Guinea pig action potentials are dominated by ion channels like hERG for non-responsive currents. Therefore, the in vivo hERG channel activity is preferably in the GP pap specimen.

Method: Rat LA (similar method applies to GP pap. Muscle)
Assay Principle The left atrium is placed in two tanks containing 100 ml of buffer solution (mM indication: NaH ₂ PO ₄ 0.6, MgSO ₄ 0.6, KCl 4.7, NaHCO ₃ 25, glucose 4.5, NaCl 120, CaCl ₂ 2.4). Placed vertically in separate organ tanks. The solution was saturated and circulated with a gas mixture containing 95% O ₂ and 5% CO ₂ . The temperature was kept constant at 30 ° C. A preload of about 8 mN was set in the atria. A square pulse with a duration of 1.5 ms and a strength of 3.5x threshold was applied with 1 Hz electrical stimulation. The force of the specimen was measured with a force transducer connected to an amplifier, documented with a pen recorder and incorporated into a computer for evaluation. Twenty minutes after compound addition, contractile force (FC), threshold stimulation (TS) and functional refractory period (FRP) were measured at baseline (pre) and washed at the end of the experiment. A threshold stimulus representing the excitability of the tissue was measured by changing the voltage applied to the electrical stimulus. TS was defined as the lowest voltage that induced tissue contraction. The functional refractory period, which represents the time required for depolarization, was assessed by applying overstimulation at various time intervals from the preceding normal rate stimulation. FRP was defined as the shortest interval between normal and overstimulation, resulting in tissue contraction in response to overstimulation.

Compound Administration Compounds were tested by 5 cumulative doses at 20 minute intervals starting after at least 60 minutes equilibration. After measurement at the highest concentration of the compound, washing was performed twice at intervals.
The results are shown in FIGS. 5 and 6 and Table 11.

FIG. 5 shows the functional refractory period in isolated rat left atrium for compound 2. FIG. 6 shows the functional refractory period in isolated guinea pig ventricular papillary muscle for the same compound.

Example 7: In vivo test transmitter implantation of mice and ECG recording:
Male mice (NRMI) were anesthetized with a mixed gas of isoflurane, nitrous oxide and oxygen. A lead wire connected to a telemetry transmitter (TA10EA-F20, DSI, St. Paul, USA) was sutured and fixed to the xiphoid process and the ventral neck region. A telemetry transmitter was placed inside the back skin. The wound was closed in layers and the animals returned to normal over a minimum of one week.

  Female guinea pigs (Charles River species, CrLHA (BR) were anesthetized with halothane inhalation anesthesia. The negative biopotential lead of a telemetry transmitter (TA11 CTA-F40, DSI, St. Paul, USA) was applied to the muscle tissue in the right shoulder region. Fixed, the positive lead was fixed to the left sixth rib of the chest to mimic the standard lead II structure, a telemetry transmitter was placed in the abdominal cavity, fixed to the peritoneal muscle, and the incision was sutured in layers. After transmitter implantation, the animals returned to normal for a minimum of one week.

Experimental study design, intraperitoneal (ip) application On the day of the experiment, the vehicle was continuously administered intraperitoneally at 60 min intervals. ECG tracking (12 seconds duration) was recorded using the Data Sciences A. RT system. After the experiment was completed, the ECG was automatically analyzed by Data Sciences ECG software (DSI, St. Paul, USA). The interval between QT and QRS was measured manually in the stored ECG. QTc was calculated from the QT interval and the corresponding heart rate using the Bazett's equation. Heart rate was obtained from online analysis provided by DSI Labpro and DSI ART system (DSI, St. Paul, USA). Finally, the ECG interval was transferred to an Excel spreadsheet, examined for validity, and converted to an average value at 15 minutes.

Results in mice When the compound of the present invention was continuously administered, the QT and QTc intervals of mouse ECG were significant and dose-dependent, but an extension that delayed initiation was observed. The results for vehicle and compound 2 are shown in FIGS. 7 and 8, respectively. The highest extension of QT and QTc was achieved in the highest dose study (15 μmol / kg) and showed 12 ms / 33 ms, respectively. PQ and QRS showed no dose-dependent changes. The decrease in heart rate was small and not significant. Motor activity increased reproducibly after each successive infusion. As shown in FIG. 7, in transmitter-transplanted mice, the effects of vehicle and compound 2 (3-15 μmol / kg, intraperitoneal administration) on the QT interval were observed. Mean ± SD, n = 5. As shown in FIG. 8, in transmitter-transplanted mice, the effects of vehicle and compound 2 (3-15 μmol / kg, intraperitoneal administration) on the QTc interval were observed. Mean ± SD, n = 5.

Conclusion
In a dose-dependent prolongation of QT and QTc, mice were dependent on Kv4.2 and Kv4.3, and repolarization K + current was blocked because compound addition did not show any effect on PQ and QRS This is consistent with the fact that the compound is characterized as a Kv4.2 / Kv4.3 blocker. It should be noted that the highest dose tested in this experiment is 15 μmol / kg and that higher doses up to 30 μmol / kg may be tested in this model as well.

The test protocol shown in FIG. 1a was used to characterize the properties of the Kv4.3 / KChlP2.2 channel and to examine the quality (voltage control) of individual patch clamp experiments. The test protocol shown in FIG. 1b shows a standard test pulse for channel activity. Each trial protocol consisted of four segments. The test protocol for the electrophysiological investigation of the hERG K + channel is depicted in FIG. In FIG. 2, (a) is a standard test pulse for the determination of channel activity. (b) and (c) were used to characterize the nature of the hERG channel and to examine the quality (voltage control) of individual patch clamp experiments. Each study protocol consisted of 6 segments. FIG. 3a shows the channel activity test in the presence and absence of 10 μM compound 21 (upper line). Figures 3b and 3c are the current responses to Tables 7b (IV activation) and 7c (IV tail current) of the protocol. Kv1.5 mediated current test item application protocol. The application protocol of the test compound is shown in FIG. FIG. 5 shows the functional refractory period in isolated rat left atrium for compound 68. FIG. 6 shows the functional refractory period in isolated guinea pig ventricular papillary muscle for compound 68. When the compound of the present invention was continuously administered, the QT and QTc intervals of mouse ECG were significant and dose-dependent, but an extension that delayed initiation was observed. The results for vehicle and compound 68 are shown in FIGS. 7 and 8, respectively (vehicle and control injected intraperitoneally (3-15 μM / kg)). When the compound of the present invention was continuously administered, the QT and QTc intervals of mouse ECG were significant and dose-dependent, but an extension that delayed initiation was observed. The results for vehicle and compound 68 are shown in FIGS. 7 and 8, respectively (vehicle and control injected intraperitoneally (3-15 μM / kg)).

Claims (47)

Compounds having the structural formula I, II, III or IV, their stereoisomers, tautomers, racemates, prodrugs, metabolites, or pharmaceutically acceptable salts and / or solvates thereof:
Wherein X ¹ is a heteroatom and is selected from —O—, —S—, —N═, or —N (R ³ ) —, wherein R ³ is selected from alkyl, aralkyl or alkylcarbonyl;
X ² is selected from = C-, = CH- or -CH _2-
n is an integer of 0 or 1,
Y is selected from C, -C (R ⁵ )-or N, wherein R ⁵ is a hydrogen atom, amino, alkyl, hydroxyl group, alkylamino, heteroaryl, alkylcarbonyloxy, alkylamidyl or alkylaminocarbonylamino Selected from
Z is selected from -C (= O), -CH ₂ -or -NH-
W is -C (= O)-, -N (R ² )-, -N (R ² )-NH-, -C (= O) -NH-, -CH =, -O- or -CH _2-
And W is selected from N or CH in formula II, III or IV;
R ¹ is a hydrogen atom, halogen, hydroxyl group, nitro group, amino group, azide, cyano, or alkyl, cycloalkyl, alkylamino, alkoxy, carboxy, alkylaminocarbonyl, alkylcarbonyl, heterocyclyl-alkyl, heteroarylalkyl , Alkoxycarbonyl, aminocarbonyl, alkylamino (alkyl-substituted) alkyl, alkylcarbonylaminoalkyl or alkylthio, each of which may be substituted with one or more substituents, where z is An integer selected from 1, 2, 3 or 4;
R ² is selected from a hydrogen atom, alkyl, cycloalkyl, cyanoalkyl, alkenyl, aryl, aminocarbonyl, haloalkyl, aralkyl, cycloalkylalkyl, acyl or alkynyl,
A is selected from aryl, cycloalkyl, heterocyclyl and heteroaryl, which are optionally halogen, hydroxyl, nitro, azide, hydrazino, cyano, alkyl, aryl,
Heteroarylalkyl, cycloalkyl, acyl, alkylamino, heterocyclyl alkyl aminocarbonyl, -SO ₂ R ^15, alkylcarbonyloxy, to condensation, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxy, An acylamino, alkyl ester, carbamate, thioamide, alkyloxycarbonyl, urea, or sulphonamide, wherein R ¹⁵ is alkyl, alkylamino or cycloalkyl;
L is a single bond, the formula -R ⁸ -R ⁹ - groups, Arukirin, Arukeniriru, ^{cycloalkylene, -NH- (C (R 4)} (R 4)) q -, - (C (R 4) (R ⁴ )) _q -,-(C (R ⁴ ) (R ⁴ )) _v -O- (C (R ⁴ ) (R ⁴ )) _w -,-(C (R ⁴ ) (R ⁴ )) _v- N- (C (R ⁴ ) (R ⁴ )) _w -,-(C (R ⁴ ) (R ⁴ )) _V- (C (R ⁴ )) _W =,-(C (R ⁴ ) (R ⁴ )) _q- (C = O)-, or a linking group selected from cycloalkyleneoxyalkylene, wherein-(C (R ⁴ ) (R ⁴ )) _q- , (C (R ⁴ ) (R ⁴ )) _W and-(C (R ⁴ ) (R ⁴ )) _v -are each independently aliphatic or form a cycloalkyl, wherein each R ⁴ is independently a hydrogen atom, hydroxyl group, alkyl, carboxy , Hydroxyalkyl, alkoxyalkyl, alkylamino, alkylaminoalkyl or alkyloxycarbonyl, q is an integer selected from 0, 1, 2, 3, 4, 5 or 6 and v is 0, 1 2, An integer selected from 3, 4, 5 or 6 and w is an integer selected from 0, 1, 2, 3, 4, 5 or 6;
R ⁸ is alkylin,-(C (R ⁴ ) (R ⁴ )) _P -C (R ¹⁴ ) or-(C (R ⁴ ) (R ⁴ )) _P -C (R ⁴ ) = C ,
R ⁹ is selected from a single bond,-(C (R ⁴ ) (R ⁴ )) _q- , or C (= O)-, wherein R ¹⁴ is selected from a hydrogen atom, a hydroxyl group or an alkyl, wherein p is an integer selected from 0, 1, 2 or 3, and
R ¹⁰ is-(C (R ⁴ ) (R ⁴ )) _m -,-(C (R ⁴ ) (R ⁴ )) _m -C (= O) O- (C (R ⁴ ) (R ⁴ ) ) _q- , _or- (C (R ⁴ ) (R ⁴ )) _m -N (R ¹² )-(C (R ⁴ ) (R ⁴ )) _q- , where m is 1, 2, It is an integer selected from 3, 4, 5 or 6, wherein R ¹² represents a compound selected from a hydrogen atom, alkyl, aryl, arylalkyl or alkylcarbonyl. A compound according to claim ¹ , wherein X ¹ is -N (R ³ )-, n is 0, and R ³ has the same meaning as defined in claim 1. The compound according to claim ¹ , wherein X ¹ is O and n is 0. The compound of claim ¹ , wherein X ¹ is S and n is 0. The compound according to claim ¹ , wherein X ¹ is -N =, X ² is = CH- or C, and n is 1. The compound according to any one of claims 1 to 6, wherein the compound is represented by any one of structural formulas V, VI, VII, VIII, IX, or X.
Wherein R ¹ , z, X ¹ , X ² , W, Z, n, L, A, R ⁸ , R ⁹ , R ¹⁰ and R ² have the same meaning as defined in any of the preceding claims. Having a compound. The compound according to any one of claims 1 to 6, wherein the compound is represented by any one of structural formulas X, XI, XII, XIII, XIV or XV,
Wherein R ¹ , z, X ¹ , X ² , Y, Z, n, L, A, R ⁸ , R ⁹ , R ¹⁰ and R ² have the same meaning as defined in any of the preceding claims. Having a compound. The compound according to any one of claims 1 to 6, wherein the compound is represented by any one of structural formulas XVI to XXXI,
Wherein R ⁵ is selected from a hydrogen atom, alkyl, or aralkyl, and R ¹ , z, Z, W, L, A, R ⁸ , R ⁹ , R ¹⁰ and R ³ are any of the preceding claims. A compound having the same meaning as defined above. The compound according to any one of claims 1 to 8, wherein the compound is represented by any one of structural formulas XXXII to LVII.
A compound wherein R ¹ , z, R ⁵ , R ² , R ³ , R ⁸ , R ⁹ , R ¹⁰ , L and A have the same meaning as defined in any of the preceding claims. A compound according to any one of claims 1 to 9,
In which A is 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- Or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5 oxazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4- or 5-thiazolyl, 1, 2,3- Triazol-1-, -2-, -4- or -5-yl, 1,2,4-triazol-1-, -3-, -4- or -5-yl, 1,2,3-oxadi Azol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 1,2,4- Thiadiazol-3- or -5-yl, 1,2,5-thiadiazol-3- or -4-yl, 1- or 5-tetrazolyl, phenyl, biphenyl, 2-, 3- or 4-pyridyl, pyridinyl, anthracenyl , Azulenyl, indenyl, 3- or 4-pyridazinyl, 2-, 4-, 5- or 6-pyrimidinyl, 2-, 3-, 4-, 5-6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, furyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2 -, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisothiazolyl, 2-, 4-, 5-, 6- or 7 benzothiazolyl, 1,3-benzodioxolyl, 1- or 2-naphthyl, 2-, 3-, 4-, 5-, 6-, 7-, 8-quinolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-isoquinolinyl, or 1-, 2-, 3-, 4- or 9-carbazolyl, 5 -, 6-, 7-, 8-tetrahydronaphthyl, thienyl, benzothienyl, dibenzo [b, f] Zepinyl, dibenzo [a, d] silcoheptenyl, pyrrololyl, dioxanyl, thietanyl, oxazolyl, piperidinyl, imidazolinyl, isoxazolinyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 2-oxopipedinyl, pyrazinyl, triazinyl, cinrazinyl, phthalazinyl Azepinyl, 4-piperidonyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 5- (2,3-dihydro) benzofuranyl, 2-oxoazepinyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide, Thiamorpholinyl sulfone, 1,3-dioxolane, tetrahydro-1,1-dioxothienyl, piperazinyl or morpholinyl,
Optional substitution with each 1,2,3 or 4 substituent can be halogen, hydroxyl, nitro, amino, azide, hydrazino, cyano, alkyl, aryl, heteroarylalkyl, cycloalkyl, alkyloxycarbonyl, acyl, alkylamino , alkylaminocarbonyl, alkylcarbonyloxy, fused heterocyclyl, haloalkyl, -SO ₂ -R ^15, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, thiol, alkylthio, carboxy, acylamino, alkyl esters, carbamates, thioamides, Selected from urea, or sulfonamide, wherein R ¹⁵ is alkyl, alkylamino or cycloalkyl;
Wherein, L is a single bond, the formula -R ⁸ -R ⁹ - groups, Arukirin, Arukeniriru, ^{cycloalkylene, -NH- (C (R 4)} (R 4)) q -, - (C (R 4) (R ⁴ )) _q -,-(C (R ⁴ ) (R ⁴ )) _v -O- (C (R ⁴ ) (R ⁴ )) _W -,-(C (R ⁴ ) (R ⁴ )) _v -N- (C (R ⁴ ) (R ⁴ )) _W -,-(C (R ⁴ ) (R ⁴ )) _V- (C (R ⁴ )) _W =,-(C (R ⁴ ) ( R ⁴ )) _q- (C = O)-, or cycloalkyleneoxyalkylene, wherein-(C (R ⁴ ) (R ⁴ )) _q- , (C (R ⁴ ) (R ⁴ )) _W and-(C (R ⁴ ) (R ⁴ )) _v are each independently aliphatic or form a cycloalkyl, wherein each R ⁴ is independently hydrogen, alkyl, hydroxyl, carboxy, hydroxyalkyl, Selected from alkoxyalkyl, alkylamino, alkylaminoalkyl or alkyloxycarbonyl, q is an integer selected from 0, 1, 2, 3 or 4 and v is an integer selected from 0, 1, 2, 3 or 4 And w Is an integer selected from 0, 1, 2, 3 or 4;
Where R ⁸ is alkylin,-(C (R ⁴ ) (R ⁴ )) _P -C (R ¹⁴ ) or-(C (R ⁴ ) (R ⁴ )) _P -C (R ⁴ ) = C Yes,
Wherein R ⁹ is a single bond,-(C (R ⁴ ) (R ⁴ )) _q- , or C (= O)-, wherein R ¹⁴ is selected from a hydrogen atom, a hydroxyl group or an alkyl, wherein And p is an integer selected from 0, 1, 2 or 3, and
In the formula, R ¹⁰ is-(C (R ⁴ ) (R ⁴ )) _m -,-(C (R ⁴ ) (R ⁴ )) _m -C (= O) O- (C (R ⁴ ) (R ⁴ )) _q- , _or- (C (R ⁴ ) (R ⁴ )) _m -N (R ¹² )-(C (R ⁴ ) (R ⁴ )) _q- where m is 1, An integer selected from 2, 3 or 4, wherein R ¹² is selected from a hydrogen atom, alkyl, aryl, arylalkyl or alkylcarbonyl, and
In the formula, R ² is a hydrogen atom, CH _3- , -CH ₂ -CH ₃ ,-(CH ₂ ) ₂ -CH ₃ ,-(CH ₂ ) ₂ -CN, phenyl, benzyl or CH ₃ -C (= O) is selected. A compound according to any one of claims 1 to 10, having a structural formula selected from structural formulas XVI to XXII and XXXII to LI,
Where A is phenyl, 3-indolyl, 5- (2,3-dihydro) benzofuranyl, 6-indolyl, 4-pyridinyl, 1,3-benzodioxolyl, 2-thienyl, 2-naphthyl, dibenzo [b, f] azepinyl, dibenzo [a, d] cycloheptenyl is selected, and optional substitution with the respective 1,2,3 or 4 substituents includes —OCH ₃ , —NO ₂ , —CO ₂ H, —C (= O) -N (CH ₃ ) ₂ , -OC (= O) -CH ₃ , -CH ₃ , -CH ₂ -CH ₃ , phenyl, -SO ₂ -CH ₃ , F, Cl, Br, -CF ₃ , -S-CH ₃ , -OCF ₃ , -C (= O) -CH ₃ , -OC (= O) -CH ₃ , -C (= O) O-CH ₃ , -C (= O) N (CH ₃ ) ₂ , -N (CH ₃ ) ₂ , -SO ₂ -N (CH ₃ ) ₂ ,
, N-morpholino, phenoxyl, benzoyl, -C (CH ₃ ) ₃ , -O- (CH ₂ ) ₂ -CH ₃ , -OH or -CN;
In the formula, L is a single bond, -CH ₂ -,-(CH ₂ ) ₂ -,-(CH ₂ ) _3- , -CH (CH ₂ OH)-, -CH (CH ₂ -O-CH ₃ )- , -CH (CH ₃ )-, -CH (CH ₂ -CH ₃ )-, -CH (CO ₂ H)-, -CH (CO ₂ CH ₃ )-,-(CH ₂ ) ₂ -O-CH ₂ -, -CH (CH ₂ -N (CH ₃ ) ₂ )-,-(CH ₂ ) ₂ -CH =, or
Or where -LA is selected from
Or
Chosen from
In the formula, R ₁ is a hydrogen atom, Cl, Br, F, -CF ₃ , -OCH ₃ , CH ₃ -C (= O)-, -CO ₂ H, (CH ₃ ) ₂ NC (= O)-,
CH ₃ -C (= O) O-, CH ₃ -OC (= O)-, CH ₃ -NH-C (= O)-, CH ₃ -C (= O) -NH-CH (CH ₃ )- , HO—CH ₂ —, CH ₃ —CH ₂ —, CH ₃ —O—CH ₂ —, wherein z is 1 or 2;
In the formula, R ⁵ is H, —NH ₂ , CH ₃ —NH—C (═O) —NH—, CH ₃ —C (═O) —NH—, CH ₃ —C (═O) O—, — _{OH, -CH 3, CH 3 -CH} 2 -, (CH 3) 2 N -, (CH 3) 2 -N-CH (CH 3) -, or
Selected from
In the formula, R ² represents a hydrogen atom, CH _3- , CH _3- , -CH ₂ -CH ₃ -,-(CH ₂ ) ₂ -CH ₃ ,-(CH ₂ ) ₂ -CN, phenyl, benzyl or CH ₃ Selected from -C (= O). A compound according to any one of claims 1 to 10, having a structural formula selected from structural formulas XXIII to XXXI and LII to LXIII,
In the formula
Is
Selected from
In the formula
Is
Selected from
In the formula
Is
Selected from
In the formula, A is phenyl, 3-indolyl, 5- (2,3-dihydro) benzofuranyl, 6-indolyl, 4-pyridinyl, 2-thienyl, 1,3-benzodioxolyl, 2-naphthyl, dibenzo [b, f] azepinyl, dibenzo [a, d] cycloheptenyl is selected, and optional substitution with the respective 1,2,3 or 4 substituents includes —OCH ₃ , —NO ₂ , —CO ₂ H, —C (= O) -N (CH ₃ ) ₂ , -OC (= O) -CH ₃ , -CH ₃ , -CH ₂ -CH ₃ , phenyl, -SO ₂ -CH ₃ , F, Cl, Br, -CF ₃ , -S-CH ₃ , -OCF ₃ , -C (= O) -CH ₃ , -OC (= O) -CH ₃ , -C (= O) O-CH ₃ , -C (= O) N (CH ₃ ) ₂ , -N (CH ₃ ) ₂ , -SO ₂ -N (CH ₃ ) ₂ ,
, N-morpholino, phenoxyl, benzoyl, -C (CH ₃ ) ₃ , -O- (CH ₂ ) ₂ -CH ₃ , -OH or -CN;
Wherein R ¹² is selected from a hydrogen atom, CH ₃ —C (═O) —, CH ₃ — or benzyl,
In the formula, R ¹ is a hydrogen atom, Cl, Br, F, -CF ₃ , -OCH ₃ , CH ₃ -C (= O)-, -CO ₂ H, (CH ₃ ) ₂ NC (= O)-,
, CH ₃ -C (= O) O-, CH ₃ -OC (= O)-, CH ₃ -NH-C (= O)-, CH ₃ -C (= O) -NH-CH (CH ₃ ) -, HO-CH _2- , CH ₃ -CH _2- , CH ₃ -O-CH _2- , wherein z is 1 or 2;
Wherein R ⁵ is H, CH ₃ —NH—C (═O) —NH—, CH ₃ —C (═O) —NH—, CH ₃ —C (═O) O—, —OH, —CH ₃ , CH ₃ -CH _2- , (CH ₃ ) ₂ N-, or
Selected from
In the formula, R ² is a hydrogen atom, CH _3- , phenyl, CH _3- , -CH ₂ -CH ₃ -,-(CH ₂ ) ₂ -CH ₃ ,-(CH ₂ ) ₂ -CN, benzyl or CH ₃ Selected from -C (= O). A compound according to any one of claims 1 to 12,
In which R ⁵ represents a hydrogen atom, —CH ₃ , —NH ₂ , CH ₃ —C (═O) —NH—, or
Selected from
Wherein R ² is selected from a hydrogen atom, CH _3- , phenyl, CH _3- , -CH ₂ -CH ₃ -,-(CH ₂ ) ₂ -CH ₃ or-(CH ₂ ) ₂ -CN;
Wherein R ¹ is selected from H, Cl, F, Br, —OCH ₃ , —C (═O) CH ₃ , z is an integer selected from 1, 2 or 3;
Where A is phenyl, 3-indolyl, 5- (2,3-dihydro) benzofuranyl, 6-indolyl, 4-pyridinyl, 2-thienyl, 1,3-benzodioxolyl, 2-naphthyl, dibenzo [b, f] azepinyl, dibenzo [a, d] cycloheptenyl, and optional substitution with the respective 1,2 or 3 substituents includes —OCH ₃ , —NO ₂ , —CO ₂ H, —C (= O) -N (CH ₃ ) ₂ , -OC (= O) -CH ₃ , -CH ₃ , -CH ₂ -CH ₃ , phenyl, -SO ₂ -CH ₃ , F, Cl, Br, -CF ₃ , -S-CH ₃ , -OCF ₃ , -C (= O) -CH ₃ , -OC (= O) -CH ₃ , -C (= O) O-CH ₃ , -C (= O) N (CH _{3) 2, -N (CH 3} ) 2, -SO 2 -N (CH 3) 2,
, N-morpholino, phenoxyl, benzoyl, -C (CH ₃ ) ₃ , -O- (CH ₂ ) ₂ -CH ₃ , -OH or -CN;
Wherein, L is a single bond, the formula -R ⁸ -R ⁹ - groups, Arukirin, Arukeniriru, ^{cycloalkylene, -NH- (C (R 4)} (R 4)) q -, - (C (R 4) (R ⁴ )) _q -,-(C (R ⁴ ) (R ⁴ )) _v -O- (C (R ⁴ ) (R ⁴ )) _W -,-(C (R ⁴ ) (R ⁴ )) _v -N- (C (R ⁴ ) (R ⁴ )) _W -,-(C (R ⁴ ) (R ⁴ )) _V- (C (R ⁴ )) _W =,-(C (R ⁴ ) ( R ⁴ )) _q- (C = O)-, or a linking group selected from cycloalkyleneoxyalkylene, wherein-(C (R ⁴ ) (R ⁴ )) _q- , (C (R ⁴ ) (R ⁴ )) _W and-(C (R ⁴ ) (R ⁴ )) _v are each independently aliphatic or form a cycloalkyl, where each R ⁴ is independently hydrogen, alkyl, hydroxyl, Selected from carboxy, hydroxyalkyl, alkoxyalkyl, alkylamino, alkylaminoalkyl or alkyloxycarbonyl, q is an integer selected from 0, 1, 2, 3 or 4 and v is 0, 1, 2, 3 or An integer chosen from 4 And w is an integer selected from 0, 1, 2, 3 or 4;
Where R ⁸ is alkylin,-(C (R ⁴ ) (R ⁴ )) _P -C (R ¹⁴ ) or-(C (R ⁴ ) (R ⁴ )) _P -C (R ⁴ ) = C Yes,
Wherein R ⁹ is a single bond,-(C (R ⁴ ) (R ⁴ )) _q- , or C (= O)-, wherein R ¹⁴ is selected from a hydrogen atom, a hydroxyl group or an alkyl, And p is an integer selected from 0, 1, 2 or 3, and
In the formula, R ¹⁰ is-(C (R ⁴ ) (R ⁴ )) _m -,-(C (R ⁴ ) (R ⁴ )) _m -C (= O) O- (C (R ⁴ ) (R ⁴ )) _q- , _or- (C (R ⁴ ) (R ⁴ )) _m -N (R ¹² )-(C (R ⁴ ) (R ⁴ )) _q- where m is 1, It is an integer selected from 2, 3, 4, 5 or 6, wherein R ¹² is selected from a hydrogen atom, alkyl, aryl, arylalkyl or alkylcarbonyl. 14. The compound according to any one of claims 1 to 13, wherein the compound is selected from the following group:
5-chloro-benzofuran-2-carboxylic acid [(R) -1- (4-nitro-phenyl) -ethyl] -amide, 5-chloro-benzofuran-2-carboxylic acid 2,4-dimethoxy-benzylamide, 5 -Chloro-benzofuran-2-carboxylic acid [2- (5-methyl-1H-indol-3-yl) -ethyl] -amide, 5-chloro-benzofuran-2-carboxylic acid [3- (10,11-dihydro -Dibenzo [b, f] azepin-5-yl) -propyl] -methyl-amide, 5-chloro-benzofuran-2-carboxylic acid [3- (10,11-dihydro-dibenzo [a, d] cycloheptene-5 -Iridene) -propyl] -methyl-amide, 5-chloro-benzofuran-2-carboxylic acid (4-nitro-benzyl) -propyl-amide, (5-chloro-benzofuran-2-yl)-[4- (4 -Chloro-benzoyl) -piperidin-1-yl] -methanone, 5-chloro-benzofuran-2-carboxylic acid 4-dimethylamino-benzylamide, 7-methoxy-benzof Lan-2-carboxylic acid [(R) -1- (4-nitro-phenyl) -ethyl] -amide, 7-methoxy-benzofuran-2-carboxylic acid ((S) -1-naphthalen-2-yl-ethyl ) -Amide, 7-methoxy-benzofuran-2-carboxylic acid ((1R, 2R) -2-benzyloxy-cyclopent-1-yl) -amide, benzofuran-2-carboxylic acid 2,4-dimethoxy-benzylamide, 4-acetyl-7-methoxy-benzofuran-2-carboxylic acid 2,4-dimethoxy-benzylamide, 5-chloro-3-methyl-benzofuran-2-carboxylic acid 2,4-dimethoxy-benzylamide, 3-pyrrole- 1-yl-benzofuran-2-carboxylic acid 2,4-dimethoxy-benzylamide, 5-chloro-1-methyl-1H-indole-2-carboxylic acid 2,4-dimethoxy-benzylamide, 5-chloro-3- Methyl-benzo [b] thiophene-2-carboxylic acid 2,4-dimethoxy-benzylamide, N-benzofuran-2-yl-2- (2,4-dimethoxy-phene Nyl) -acetamide, 1-benzofuran-2-yl-2- (2,4-dimethoxy-phenyl) -ethanone, 5-chloro-benzofuran-2-carboxylic acid (2,4-dimethoxy-phenyl) -amide, 5 -Chloro-benzofuran-2-carboxylic acid indan-2-ylamide, (5-chloro-benzofuran-2-yl)-(1,3-dihydro-isoindol-2-yl) -methanone, (5-chloro-benzofuran -2-yl)-(3,4-dihydro-1H-isoquinolin-2-yl) -methanone, (2-benzyl-piperidin-1-yl)-(5-chloro-benzofuran-2-yl) -methanone, Benzo [b] thiophene-2-carboxylic acid 2,4-dimethoxy-benzylamide, acetic acid 4-{[(5-chloro-benzofuran-2-carbonyl) -amino] -methyl} -phenyl ester, 5-chloro-benzofuran 2-Carboxylic acid 4-thiophen-2-yl-benzylamide, 5-chloro-benzofuran-2-carboxylic acid 4- Tyl-benzylamide, (5-chloro-benzofuran-2-yl)-(4-phenyl-piperidin-1-yl) -methanone, 5-chloro-benzofuran-2-carboxylic acid 4- (thiophen-2-ylmethyl) -Amide, (S)-[(5-chloro-benzofuran-2-carbonyl) -amino] -phenyl-acetic acid, quinoline-3-carboxylic acid 2,4-dimethoxy-benzylamide, 3-methyl-benzofuran-2- Carboxylic acid 2,4-dimethoxy-benzylamide, 5-chloro-benzofuran-2-carboxylic acid benzyl ester, 5-chloro-benzofuran-2-carboxylic acid benzylamide, 5-chloro-benzofuran-2-carboxylic acid (2- Dimethylamino-1-phenyl-ethyl) -amide. 14. The compound according to any one of claims 1 to 13, wherein the compound is selected from the following group:
Benzofuran-2-carboxylic acid 4-fluoro-3-trifluoromethyl-benzylamide, 5-chloro-benzofuran-2-carboxylic acid (1-phenyl-ethyl) -amide, 5-chloro-benzofuran-2-carboxylic acid ( (R) -1-Phenyl-propyl) -amide, 5-chloro-benzofuran-2-carboxylic acid ((S) -1-phenyl-propyl) -amide, 2-chloro-benzofuran-2-carboxylic acid 2-methyl Sulfanyl-benzylamide, 5-chloro-benzofuran-2-carboxylic acid 4-methylsulfanyl-benzylamide, 5-chloro-benzofuran-2-carboxylic acid 2-chloro-6-methyl-benzylamide, 4-{[(5 -Chloro-benzofuran-2-carbonyl) -amino] -methyl} -benzoic acid methyl ester, 5-chloro-benzofuran-2-carboxylic acid 4-dimethylamino-benzylamide, 3-{[(5-chloro-benzofuran- 2-Carbonyl) -amino] -methyl L} -benzoic acid methyl ester, 5-chloro-benzofuran-2-carboxylic acid 3-dimethylcarbamoyl-benzylamide, 5-chloro-benzofuran-2-carboxylic acid 4-dimethylsulfamoyl-benzylamide, 5-chloro- Benzofuran-2-carboxylic acid 4-phenoxy-benzylamide, 5-chloro-benzofuran-2-carboxylic acid 2-methyl-benzylamide, 5-chloro-benzofuran-2-carboxylic acid 3-methyl-benzylamide, 5-chloro -Benzofuran-2-carboxylic acid 4-tert (tertiary) -butyl-benzylamide, 5-chloro-benzofuran-2-carboxylic acid (biphenyl-2-ylmethyl) -amide, 5-chloro-benzofuran-2-carboxylic acid (Biphenyl-3-ylmethyl) -amide, 5-chloro-benzofuran-2-carboxylic acid 3-acetyl-benzylamide, 5-chloro-benzofuran-2-carboxylic acid 2-bromo-benzylamide, 5- Loro-benzofuran-2-carboxylic acid 3-bromo-benzylamide, 5-chloro-benzofuran-2-carboxylic acid 4-bromo-benzylamide, 5-chloro-benzofuran-2-carboxylic acid 4-methanesulfonyl-benzylamide, 5-chloro-benzofuran-2-carboxylic acid 4-cyano-benzylamide, 5-chloro-benzofuran-2-carboxylic acid (pyridin-4-ylmethyl) -amide, 5-chloro-benzofuran-2-carboxylic acid ((S ) -2-Hydroxy-1-phenyl-ethyl) -amide, 5-chloro-benzofuran-2-carboxylic acid ((S) -2-methoxy-1-phenyl-ethyl) -amide, (R)-[(5 -Chloro-benzofuran-2-carbonyl) -amino] -phenyl-acetic acid methyl ester, (S)-[(5-chloro-benzofuran-2-carbonyl) -amino] -phenyl-acetic acid methyl ester, 5-chloro-benzofuran -2-Carboxylic acid 2-trifluoromethoxy - benzylamide, 5-chloro - benzofuran-2-carboxylic acid 3-trifluoromethoxy - benzyl amide, 5-chloro - benzofuran-2-carboxylic acid 4-trifluoromethoxy - benzyl amide. 14. The compound according to any one of claims 1 to 13, wherein the compound is selected from the following group:
5-chloro-benzofuran-2-carboxylic acid 2,5-dimethyl-benzylamide, 5-chloro-benzofuran-2-carboxylic acid 4- [1,2,3] thiadiazol-5-yl-benzylamide, 5-chloro -Benzofuran-2-carboxylic acid (benzo [1,3] dioxol-5-ylmethyl) -benzylamide, (5-chloro-benzofuran-2-yl)-[4- (4-fluoro-phenyl) -3,6 Dihydro-2H-pyridin-1-yl] -methanone, 5-chloro-benzofuran-2-carboxylic acid indan-1-ylamide, (5-chloro-benzofuran-2-yl)-[4- (2-methoxy-phenyl) ) -Piperidin-1-yl] -methanone, 1-benzyl-1H-indole-3-carboxylic acid 2,4-dimethoxy-benzylamide, (5-chloro-benzofuran-2-yl)-[4-p-tolyl -Piperidin-1-yl] -methanone, 5-chloro-benzofuran-2-carboxylic acid (4-morpholin-4-yl-phenyl) -amide, (4-benzi -Piperidin-1-yl)-(5-chloro-benzofuran-2-yl) -methanone, (5-chloro-benzofuran-2-yl)-[4- (4-fluoro-benzoyl) -piperidin-1-yl ] -Methanone, (5-chloro-benzofuran-2-yl)-(2-phenyl-pyrrolidin-1-yl) -methanone, (5-chloro-benzofuran-2-yl)-[2- (4-fluoro- Phenyl) -pyrrololidin-1-yl] -methanone, 5-chloro-benzofuran-2-carboxylic acid (4-pyrazol-1-ylmethyl-phenyl) -amide, (2-benzyl-piperidin-1-yl)-(5 -Chloro-3-methyl-benzofuran-2-yl) -methanone, 5-chloro-3-methyl-benzo [b] -thiophene-2-carboxylic acid 4-fluoro-3-trifluoromethyl-benzylamide, 5- Chloro-benzofuran-2-carboxylic acid 2-hydroxy-4-methoxy-benzylamide, 5-chloro-benzofuran-2-carboxylic acid benzyl- (2- Ano-ethyl) -amide, 5-chloro-3-methyl-benzo [b] -thiophene-2-carboxylic acid 2-chloro-6-methyl-benzylamide, 5-chloro-1H-indole-2-carboxylic acid 2 , 4-Dimethoxy-benzylamide, quinoline-2-carboxylic acid 2,4-dimethoxy-benzylamide, 5-chloro-benzofuran-2-carboxylic acid (2,3-dihydro-benzo [1,4] dioxin-2- Ylmethyl) -amide, (5-chloro-benzofuran-2-yl)-[4- (2,5-dimethoxy-benzyl) -piperazin-1-yl] -methanone, 3-acetylamino-5-chloro-benzofuran- 2-carboxylic acid 2,4-dimethoxy-benzylamide, 3-amino-5-chloro-benzofuran-2-carboxylic acid 2,4-dimethoxy-benzylamide, 5-chloro-3-methyl-benzo [b] thiophene- 2-carboxylic acid 4-fluoromethoxy-benzylamide, 5-chloro-benzofuran-2-carboxylic acid benzyl-phenyl- Amide, 5-chloro-benzofuran-2-carboxylic acid 2,4-dichloro-6-methyl-benzylamide, N- (5-chloro-benzoxazol-2-yl) -2-phenyl-acetamide. 14. The compound according to claim 1, wherein the compound is 5-chlorobenzofuran-2-carboxylic acid 3,5-dimethoxybenzyl-amide, or 5-chlorobenzofuran-2-carboxylic acid [3- ( 10,11-Dihydro-dibenzo [b, f] azepin-5-yl) propyl] methyl-amide or 5-chloro-3-methyl-benzo [b] thiophene-2-carboxylic acid 2,4-dimethoxy-benzyl Amide.   18. A compound according to any of claims 1 to 17, wherein the compound is 5-chlorobenzofuran-2-carboxylic acid 3,5-dimethoxybenzyl-amide or 5-chloro-3-methyl-benzo [b] thiophene -2-carboxylic acid 2,4-dimethoxy-benzylamide. A method for the synthesis of a compound having the structural formula I, II, III or IV, the compound of formula LXIV:
And the compound of formula LXV, LXVI, LXVII or LXVIII:
And a compound of formula I, II, III or IV:
In the formula, R ¹ , z, X ¹ , X ² , W, Y, Z, n, L, A, R ⁸ , R ⁹ and R ¹⁰ have the same meaning as defined in any one of claims 1 to 14. Have
A method comprising the step of obtaining   In performing the condensation, an acyl chloride of a compound of formula LXVI is made, and then this acyl chloride is coupled with formula LXV, LXVI, LXVII, or LXVIII (where W is N). The method described in 1.   21. The method of claim 20, wherein a suitable coupling agent is used in the presence of a suitable base in a suitable solvent for performing the condensation.   The coupling agent is selected from the group comprising hydroxybenzotriazole, o-benzotriazol-1-yl-N, N, N ′, N-4-tetramethyluronium hexafluorophosphate and the like. The method described in 1.   24. A process according to claim 21 or 23, wherein the solvent is selected from the group comprising dichloromethane, dimethylformamide and the like, or mixtures thereof.   24. A method according to any one of claims 21 to 23, wherein the base is selected from the group comprising potassium carbonate, diisopropylethylamine, triethylamine, triisopropylamine and the like.   25. A process according to any one of claims 21 to 24, wherein an amount of 0.1 to 5.0 equivalents of base is used.   The compound obtained by the method of any one of Claims 20-25.   27. A compound according to any one of claims 1 to 18 and 26 for use as a medicament.   28. Use of a compound according to any one of claims 1 to 18 and 27 as an ion channel inhibitor.   29. Use of a compound according to claim 28 as an ion channel inhibitor of the ion channel Kv4 family.   29. Use of a compound according to claim 28 as an ion channel inhibitor of the ion channel Kv1 family.   30. Use of a compound according to claim 28 or 29 as an ion channel inhibitor of the ion channel Kv4.3 family.   Use of a compound according to claim 28 or 30 as an ion channel inhibitor of the ion channel Kv1.5 family.   27. Use of a compound according to any one of claims 1 to 18 and 26 for the manufacture of a medicament for the prevention and / or treatment of symptoms or diseases associated with the ion channel Kv4 family.     Symptoms or diseases associated with ion channel Kv4 family, preferably Kv4.3 ion channel, include heart disease including arrhythmia, hypertension-induced heart disease including hypertension-induced cardiac hypertrophy, and epilepsy, stroke, traumatic brain injury, anxiety 34. Use according to claim 33, selected from the group of: sleeplessness, spinal cord injury, encephalomyelitis, multiple sclerosis, demyelinating disease Alzheimer's disease, nervous system diseases including Parkinson's syndrome.   27. Use of a compound according to any one of claims 1 to 18 and 26 for the manufacture of a medicament for the prevention and / or treatment of symptoms or diseases associated with the ion channel Kv4 family. Symptoms or diseases associated with the ion channel Kv1 family, preferably the Kv1.5 ion channel, include heart disease including arrhythmia, hypertension induced heart disease including hypertension-induced cardiac hypertrophy, and epilepsy, stroke, traumatic brain injury, anxiety 35. Use according to claim 32, selected from the group of: sleeplessness, spinal cord injury, encephalomyelitis, multiple sclerosis, demyelinating disease Alzheimer's disease, nervous system diseases including Parkinson's syndrome.   37. Use according to claim 33 or 36 for the manufacture of a medicament for the treatment of heart disease.   37. Use according to claim 33 or 36 for the manufacture of a medicament for the treatment of nervous system diseases. 27. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound according to any one of claims 1-18 and 26. 40. Use of a pharmaceutical composition according to claim 39 for the treatment of a condition or disease associated with the ion channel Kv4 family.   Symptoms or diseases related to the ion channel Kv4 family include heart disease including arrhythmia, hypertension-induced heart disease including hypertension-induced cardiac hypertrophy, and epilepsy, stroke, traumatic brain injury, anxiety, insomnia, spinal cord injury, cerebrospinal cord 41. Use according to claim 40, selected from the group of inflammation, multiple sclerosis, demyelinating disease Alzheimer's disease, nervous system diseases including Parkinson's syndrome.   40. Use of the pharmaceutical composition according to claim 39 for the treatment of a condition or disease associated with the ion channel Kv1 family, preferably the Kv1.5 ion channel.   40. Use of the pharmaceutical composition according to claim 39 for the treatment of heart disease, preferably arrhythmia.   40. Use of the pharmaceutical composition according to claim 39 for the treatment of heart disease.   40. Use of the pharmaceutical composition according to claim 39 for the treatment of nervous system diseases.   40. A method for treating heart disease, comprising administering the pharmaceutical composition of claim 39 to an individual in need thereof.   40. A method for treating a nervous system disease comprising administering the pharmaceutical composition according to claim 39 to an individual in need thereof.