CN101516873A

CN101516873A - Indazolyl derivatives useful as potassium channel modulating agents

Info

Publication number: CN101516873A
Application number: CNA2007800341682A
Authority: CN
Inventors: B·L·埃里克森; U·S·瑟伦森; C·霍高; L·托伊贝尔; D·彼得斯; P·克里斯托弗森; T·H·约翰森
Original assignee: Neurosearch AS
Current assignee: NTG Nordic Transport Group AS
Priority date: 2006-10-03
Filing date: 2007-10-03
Publication date: 2009-08-26

Abstract

The invention relates to novel indazolyl derivatives of formula (Ia) and (Ib) useful as potassium channel modulating agents, and their use in the preparation of pharmaceutical compositions. Moreover the invention is directed to pharmaceutical compositions useful for the treatment or alleviation of diseases or disorders associated with the activity of potassium-channels, in particular respiratory diseases, epilepsy, convulsions, seizures, absence seizures, vascular spasms, coronary artery spasms, renal disorders, polycystic kidney disease, bladder spasms, urinary incontinence, bladder outflow obstruction, erectile dysfunction, gastrointestinal dysfunction, secretory diarrhoea, ischaemia, cerebral ischaemia, ischaemic heart, disease, angina pectoris, coronary heart disease, autism, ataxia, traumatic brain injury, Parkinson's disease, bipolar disorder, psychosis, schizophrenia, anxiety, depression, mania, mood disorders, dementia, memory and attention deficits, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dysmenorrhea,narcolepsy, Reynaud's disease, intermittent claudication, Sjorgren's syndrome, arrhythmia, hypertension, myotonic muscle' dystrophia, spasticity, xerostomi, diabetes type II, hypehnsulinemia, premature labour, baldness, cancer, irritable bowel syndrome, immune suppression, migraine and pain.

Description

Indazolyl derivative as potassium channel modulating agents

Technical field

The present invention relates to new indazolyl derivative and the purposes in pharmaceutical compositions thereof as potassium channel modulating agents.

The invention still further relates to and be used for the treatment of or the disease that alleviation is relevant with activity of potassium channels or the pharmaceutical composition of illness, described disease or illness be respiratory disease particularly, epilepsy, faint from fear epileptic seizures, petit mal, vascular spasm, coronary vasospasm, kidney disorders, POLYCYSTIC KIDNEY DISEASE, cystospasm, the urinary incontinence, the bladder outflow obstruction, erective dysfunction, gastrointestinal dysfunction, secretory diarrhea, local asphyxia, cerebral ischemia, ischemic heart disease, stenocardia, coronary heart disease, autism, ataxia, traumatic brain injury, Parkinson's disease, bipolar affective disorder, psychosis, schizophrenia, anxiety, dysthymia disorders, manic, emotional handicap, dementia, memory and attention deficit, alzheimer's disease, amyotrophic lateral sclerosis (ALS), dysmenorrhoea, hypnolepsy, raynaud's disease, intermittent claudication, this Jaeger logical sequence syndrome, irregular pulse, hypertension, myotonic muscular dystrophy, spasticity, xerostomia disease (xerostomi), type ii diabetes, the superelevation insulinemia, premature labor, alopecia, cancer, irritable bowel syndrome, immunosuppression, migraine and pain.

Background technology

Ionic channel is a transmembrane protein, their catalysis mineral ions transhipment passing through cytolemma.Ionic channel is participated in action potential, cynapse conduction, hormone secretion, various processes such as Muscle contraction generation and timing.

All mammalian cells are all expressed the potassium (K in its cytolemma ⁺) passage and these passages play a leading role in regulating membrane potential.In the N﹠M born of the same parents, they regulate action potential frequency and form, neurotransmitter release and segmental bronchus and vasorelaxation degree.

From molecule viewpoint, K ⁺Passage is represented maximum and major part ionic channel not of the same clan.Generally, they can be divided into 5 big subtribes: the K of voltage activated ⁺Passage (K _v), the long QT K that is correlated with ⁺Passage (KvLQT), inward rectifier (K _IR), diplopore K ⁺Passage (K _TP) and calcium activation K ⁺Passage (K _Ca).

The family of back, i.e. Ca ²⁺-activation K ⁺Passage is made up of three kinds of hypotypes of fully determining: SK passage, IK passage and BK passage.SK, IK and BK intention single passage electricity are led (little, medium and big electricity is led the K passage).SK, IK and BK passage are in for example voltage-and calcium-susceptibility, and pharmacology distributes and function aspects shows difference.

The SK passage is present in many nervus centralis and the neuroganglion, and wherein its major function is neurocyte in one or several action potential after hyperpolarization, causes the active generation of epilepsy so that prevent long string.The SK passage also is present in several peripheral cells, comprises skeletal muscle, glandular cell, liver cell and T-lymphocyte.The difference of SK in normal bone flesh is not obvious, and its quantity significantly increases in denervated muscle, and has the effect of a large amount of SK promptings in disease incidence mechanism in patient's muscle of myotonic muscular dystrophy.

Studies show that K ⁺Passage can comprise asthma, cystic fibrosis, chronic obstructive pulmonary disease and rhinorrhea for the treatment target of treatment numerous disease, faint from fear vascular spasm, coronary vasospasm, kidney disorders, POLYCYSTIC KIDNEY DISEASE, cystospasm, the urinary incontinence, bladder outflow obstruction, irritable bowel syndrome, gastrointestinal dysfunction, secretory diarrhea, local asphyxia, cerebral ischemia, ischemic heart disease, stenocardia, coronary heart disease, traumatic brain injury, psychosis, anxiety, dysthymia disorders, dementia, memory and attention deficit, alzheimer's disease, dysmenorrhoea, hypnolepsy, raynaud's disease, intermittent claudication, this Jaeger logical sequence syndrome, migraine, irregular pulse, hypertension, petit mal, myotonic muscular dystrophy, xerostomia disease, type ii diabetes, superelevation insulinemia, premature labor, alopecia, cancer and immunosuppression.

Summary of the invention

The present invention relates to prepare and selectivity to regulate the new indazolyl derivative of SK passage or SK passage hypotype.

The invention still further relates to and be used for the treatment of or disease or illness that alleviation is relevant with activity of potassium channels, comprise the pharmaceutical composition of disease or illness, as respiratory disease, epilepsy is fainted from fear epileptic seizures, petit mal, vascular spasm, coronary vasospasm, kidney disorders, POLYCYSTIC KIDNEY DISEASE, cystospasm, the urinary incontinence, bladder outflow obstruction, erective dysfunction, gastrointestinal dysfunction, secretory diarrhea, local asphyxia, cerebral ischemia, ischemic heart disease, stenocardia, coronary heart disease, autism, ataxia, traumatic brain injury, Parkinson's disease, bipolar affective disorder, psychosis, schizophrenia, anxiety, dysthymia disorders, manic, emotional handicap, dementia, memory and attention deficit, alzheimer's disease, amyotrophic lateral sclerosis (ALS), dysmenorrhoea, hypnolepsy, raynaud's disease, intermittent claudication, this Jaeger logical sequence syndrome, irregular pulse, hypertension, myotonic muscular dystrophy, spasticity, xerostomia disease, type ii diabetes, superelevation insulinemia, premature labor, alopecia, cancer, irritable bowel syndrome, immunosuppression, migraine or pain.

Therefore, the present invention provides the new indazolyl derivative of formula Ia or Ib in aspect its first

The mixture of its enantiomer or its enantiomer, its N-oxide compound or its pharmacy acceptable salt, wherein

N is 0,1,2 or 3;

X represents O, S or NR '; Wherein R ' represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl;

Y represents alkyl, alkyl-cycloalkyl, cycloalkyl, cycloalkyl-alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, thiazolinyl, or phenyl, described phenyl can randomly selectedly replace one or many from following substituting group: alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogeno-group (halo), haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, cyano group, nitro and amino;

A ' expression N or CR ², R wherein ²The following definition; And

A " expression N or CH;

But, condition is A ' and A " in only have one the expression N; And

R ¹, R ², R ³And R ⁴Represent hydrogen independently of one another, alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, alkyl-carbonyl-amino, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogeno-group, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, alkoxyl group-carbonyl, cyano group, nitro and amino; Or R ¹And R ²Constitute benzo-fused ring with the heteroaromatic rings that connects them; And R ³And R ⁴Represent hydrogen independently of one another, alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, alkyl-carbonyl-amino, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogeno-group, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, alkoxyl group-carbonyl, cyano group, nitro and amino.

The present invention provides the pharmaceutical composition that comprises the indazolyl derivative of the present invention for the treatment of significant quantity in one aspect of the method.

Find out that from another aspect of the present invention it relates to the purposes and relate to of indazolyl derivative of the present invention in the medicine of preparation is used for the treatment of or alleviation is relevant with activity of potassium channels disease or illness and treats or alleviate and to regulating potassium channel the illness of replying or the method for illness are arranged.

The present invention provides treatment in one aspect of the method, the disease of prevention or alleviation moving object (comprising the people) or the method for illness or illness, described disease, illness or illness are replied regulating potassium channel, and described method comprises the indazolyl derivative of the present invention of this class moving object (comprising the people) that these needs are arranged being treated significant quantity.

Detailed disclosure content of the present invention

Potassium channel modulating agents

The present invention provides new 1-or the 2-indazolyl derivative of formula Ia or Ib in aspect its first:

N is 0,1,2 or 3;

Y represents alkyl, alkyl-cycloalkyl, cycloalkyl, cycloalkyl-alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, thiazolinyl, or phenyl, described phenyl can randomly selectedly replace one or many from following substituting group: alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogeno-group, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, cyano group, nitro and amino;

A ' expression N or CR ², R wherein ²The following definition; And

A " expression N or CH;

But, condition is A ' and A " in only have one the expression N; And

In a preferred embodiment, indazolyl derivative of the present invention 1-indazolyl derivative that is formula Ia or the 2-indazolyl derivative of formula Ib.

In a preferred embodiment, the 1-indazolyl derivative that indazolyl derivative of the present invention is formula Ia.

In another preferred embodiment, the 2-indazolyl derivative that indazolyl derivative of the present invention is formula Ib.

In another preferred embodiment, the indazolyl derivative that indazolyl derivative of the present invention is formula Ia or Ib, wherein n is 0,1,2 or 3.

In a preferred embodiment, n is 0,1 or 2.

In a preferred embodiment, n is 0 or 1.

In a preferred embodiment, n is 0.

In another preferred embodiment, n is 1.

In the 3rd embodiment preferred, the indazolyl derivative that indazolyl derivative of the present invention is formula Ia or Ib, wherein X represents O, S or NR '; Wherein R ' represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl.

In a preferred embodiment, X represents NR '; Wherein R ' represents hydrogen or alkyl.

In a preferred embodiment, X represents NH.

In the 4th embodiment preferred, the indazolyl derivative that indazolyl derivative of the present invention is formula Ia or Ib, wherein Y represents alkyl, alkyl-cycloalkyl, cycloalkyl, cycloalkyl-alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, thiazolinyl, or phenyl, described phenyl can randomly selectedly replace one or many from following substituting group: alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogeno-group, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, cyano group, nitro and amino.

In a preferred embodiment, Y represents alkyl, alkyl-cycloalkyl, cycloalkyl, or phenyl, described phenyl can randomly selectedly replace one or many from following substituting group: alkyl, cycloalkyl, halogeno-group, haloalkyl, halogenated alkoxy, cyano group, nitro and amino.

In a preferred embodiment, Y represents alkyl-cycloalkyl, cycloalkyl, or phenyl, described phenyl can randomly selectedly replace one or many from following substituting group: halogeno-group, fluoro base particularly, chloro base, bromo base or iodo base, trifluoromethyl, trifluoromethoxy, cyano group, nitro and amino.

In a preferred embodiment, Y representative ring alkyl, cyclopentyl particularly, cyclohexyl or suberyl, or phenyl, described phenyl can randomly selectedly replace one or many from following substituting group: halogeno-group, fluoro base particularly, chloro base, bromo base or iodo base, trifluoromethyl and trifluoromethoxy.

In a preferred embodiment, Y representative ring alkyl, particularly cyclopentyl, cyclohexyl or suberyl.

In the most preferred embodiment, Y representative ring hexyl.

In another preferred embodiment, Y represents phenyl, and described phenyl can be randomly by halogeno-group, fluoro base particularly, and the chloro base, bromo base or iodo base, or trifluoromethyl replaces.

In another preferred embodiment, Y represents phenyl, and it is randomly by halogeno-group, fluoro base particularly, and the chloro base, bromo base or iodo base replace.

In the 5th embodiment preferred, the indazolyl derivative that indazolyl derivative of the present invention is formula Ia or Ib, wherein A ' expression N or CR ², R wherein ²The following definition; And A " expression N or CH; But, condition is A ' and A " in only have one the expression N.

In a preferred embodiment, A ' represents N; And A " expression CH.

In another preferred embodiment, A ' represents CR ², R wherein ²Expression hydrogen, alkyl, particularly methyl, ethyl, propyl group or sec.-propyl, or cycloalkyl; And A " expression N.

In the 3rd preferred embodiment, A ' represents CR ², R wherein ²Expression hydrogen or methyl; And A " expression N.

In the 4th preferred embodiment, A ' represents CR ², R wherein ²Be hydrogen, alkyl, particularly methyl, ethyl, propyl group or sec.-propyl, or cycloalkyl; And A " expression CH.

In the 5th preferred embodiment, A ' represents CR ², R wherein ²Be hydrogen or methyl; And A " expression CH.

In the 6th embodiment preferred, the indazolyl derivative that indazolyl derivative of the present invention is formula Ia or Ib, wherein R ¹, R ², R ³And R ⁴Represent hydrogen independently of one another, alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, alkyl-carbonyl-amino, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogeno-group, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, alkoxyl group-carbonyl, cyano group, nitro and amino; Or R ¹And R ²Constitute benzo-fused ring with the heteroaromatic rings that connects them; And R ³And R ⁴Represent hydrogen independently of one another, alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogeno-group, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, alkoxyl group-carbonyl, cyano group, nitro and amino.

In a preferred embodiment, R ¹, R ², R ³And R ⁴Represent hydrogen independently of one another, alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogeno-group, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, alkoxyl group-carbonyl, cyano group, nitro and amino; Or R ¹And R ²The heteroaromatic rings that connects them constitutes benzo-fused ring together; And R ³And R ⁴Represent hydrogen independently of one another, alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogeno-group, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, alkoxyl group-carbonyl, cyano group, nitro and amino.

In one even preferred embodiment, R ¹, R ², R ³And R ⁴Represent hydrogen independently of one another, alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, alkyl-carbonyl-amino, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogeno-group, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, alkoxyl group-carbonyl, cyano group, nitro and amino.

In a still preferred embodiment, R ¹, R ², R ³And R ⁴Represent hydrogen independently of one another, alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogeno-group, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, alkoxyl group-carbonyl, cyano group, nitro and amino.

In another preferred embodiment, R ¹And R ²Represent hydrogen independently of one another, alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogeno-group, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, alkoxyl group-carbonyl, cyano group, nitro and amino; And R ³And R ⁴Represent hydrogen independently of one another, alkyl-carbonyl-amino, nitro or amino.

In one even preferred embodiment, R ¹And R ²Represent hydrogen independently of one another, alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogeno-group, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, alkoxyl group-carbonyl, cyano group, nitro and amino; And R ³And R ⁴All represent hydrogen.

In a still preferred embodiment, R ¹And R ²Represent hydrogen independently of one another, alkyl, and methyl particularly, cycloalkyl or amino; And R ³And R ⁴Represent hydrogen independently of one another, alkyl-carbonyl-amino, and particularly methyl-carbonyl-amino, nitro or amino.

In a still preferred embodiment, R ¹And R ²One of the expression hydrogen; And R ¹And R ²In another expression alkyl, and methyl particularly, or amino.

In another preferred embodiment, R ³And R ⁴One of the expression hydrogen; And R ³And R ⁴In another expression alkyl-carbonyl-amino, and particularly methyl-carbonyl-amino, nitro or amino.

In another still preferred embodiment, R ¹And R ²Represent hydrogen independently of one another, alkyl, and methyl particularly, or cycloalkyl; And R ³And R ⁴All represent hydrogen.

In the 3rd preferred embodiment, R ¹Expression hydrogen or amino; And R ²Expression hydrogen, alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogeno-group, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, alkoxyl group-carbonyl, cyano group, nitro and amino; And R ³And R ⁴Represent hydrogen independently of one another, alkyl-carbonyl-amino, nitro or amino.

In one even preferred embodiment, R ¹Expression hydrogen or amino; R ²Expression hydrogen or alkyl, and methyl particularly; And R ³And R ⁴Represent hydrogen independently of one another, alkyl-carbonyl-amino, and particularly methyl-carbonyl-amino, nitro or amino.

In a still preferred embodiment, R ²Expression hydrogen, alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogeno-group, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, alkoxyl group-carbonyl, cyano group, nitro and amino; And R ¹, R ³And R ⁴All represent hydrogen.

In a still preferred embodiment, R ¹Expression is amino; R ²Expression hydrogen, alkyl and particularly methyl; And R ³And R ⁴All represent hydrogen.

In another preferred embodiment, R ²Expression hydrogen, alkyl, and methyl particularly, or cycloalkyl; And R ¹, R ³And R ⁴All represent hydrogen.

In another still preferred embodiment, R ²Expression hydrogen or methyl; And R ¹, R ³And R ⁴All represent hydrogen.

In the 4th preferred embodiment, R ¹And R ²All represent hydrogen; And R ³And R ⁴Represent hydrogen independently of one another, alkyl-carbonyl-amino, and particularly methyl-carbonyl-amino, nitro or amino.

In one even preferred embodiment, R ¹, R ², R ³And R ⁴All represent hydrogen.

In the 5th preferred embodiment, R ¹And R ²Constitute benzo-fused ring with the heteroaromatic rings that connects them; And R ³And R ⁴Represent hydrogen independently of one another, alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, alkyl-carbonyl-amino, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogeno-group, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, alkoxyl group-carbonyl, cyano group, nitro and amino.

In one even preferred embodiment, R ¹And R ²Constitute benzo-fused ring with the heteroaromatic rings that connects them; And R ³And R ⁴Represent hydrogen independently of one another, alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogeno-group, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, alkoxyl group-carbonyl, cyano group, nitro and amino.

In a still preferred embodiment, R ¹And R ²Constitute benzo-fused ring with the heteroaromatic rings that connects them; And R ³And R ⁴Represent hydrogen independently of one another, alkyl, cycloalkyl, alkyl-carbonyl-amino, nitro or amino.

In a still preferred embodiment, R ¹And R ²Constitute benzo-fused ring with the heteroaromatic rings that connects them; And R ³And R ⁴Represent hydrogen independently of one another, alkyl or cycloalkyl.

In another preferred embodiment, R ¹And R ²Constitute benzo-fused ring with the heteroaromatic rings that connects them; And R ³And R ⁴All represent hydrogen.

In the most preferred embodiment, indazolyl derivative of the present invention is:

(4-chloro-phenyl)-(2-indazole-2-base-6-methyl-pyrimidine-4-yl)-amine;

(4-chloro-phenyl)-(2-indazole-1-base-6-methyl-pyrimidine-4-yl)-amine;

Cyclohexyl-(2-indazole-1-base-quinazoline-4-yl)-amine;

Cyclohexyl-(2-indazole-1-base-pyrimidine-4-yl)-amine;

Cyclohexyl-(2-indazole-1-base-6-methyl-pyrimidine-4-yl)-amine;

(4-chloro-benzyl)-(2-indazole-2-base-pyrimidine-4-yl)-amine;

(4-chloro-benzyl)-(2-indazole-1-base-pyrimidine-4-yl)-amine;

(4-chloro-phenyl)-[2-(6-nitro-indazole-2-yl)-pyrimidine-4-yl]-amine;

(4-chloro-phenyl)-[2-(5-nitro-indazole-2-yl)-pyrimidine-4-yl]-amine;

(4-chloro-phenyl)-(2-indazole-2-base-6-methyl-pyrimidine-4-yl)-amine;

(4-chloro-phenyl)-(6-indazole-1-base-pyridine-2-yl)-amine;

[6-(3-chloro-indazole-1-yl)-pyridine-2-yl]-(4-chloro-phenyl)-amine;

(4-chloro-phenyl)-(6-indazole-2-base-pyrazine-2-yl)-amine;

(4-chloro-phenyl)-(6-indazole-1-base-pyrazine-2-yl)-amine;

N-(4-chloro-phenyl)-2-indazole-2-base-pyrimidine-4, the 5-diamines;

2-[4-(4-chloro-phenyl amino)-pyrimidine-2-base]-2H-indazole-6-base amine;

N-{2-[4-(4-chloro-phenyl amino)-pyrimidine-2-base]-2H-indazole-6-yl }-ethanamide; Or

N-{2-[4-(4-chloro-phenyl amino)-pyrimidine-2-base]-2H-indazole-5-yl }-ethanamide;

Or its pharmacy acceptable salt.

Two or more arbitrary composition in the embodiment described herein all is regarded as belonging to scope of the present invention.

The substituting group definition

In the context of the present invention, halogeno-group is represented the fluoro base, chloro base, bromo base or iodo base.Therefore, trihalomethyl group represents, trifluoromethyl for example, the methyl of trichloromethyl and similar three halogeno-group-replacements.

In the context of the present invention, haloalkyl is represented alkyl as herein defined, and described alkyl is replaced one or many by halogeno-group.The preferred haloalkyl of the present invention comprises trihalomethyl group, preferred trifluoromethyl.

In the context of the invention, alkyl is represented unit price hydrocarbon chain saturated, straight or branched.Described hydrocarbon chain preferably comprises 1-18 carbon atom (C _1-18-alkyl), more preferably 1-6 carbon atom (C _1-6-alkyl; Low alkyl group), comprise amyl group, isopentyl, neo-pentyl, tert-pentyl, hexyl and isohexyl.In a preferred embodiment, alkyl is represented C _1-4-alkyl comprises butyl, isobutyl-, sec-butyl and the tertiary butyl.In another embodiment preferred of the present invention, alkyl is represented C _1-3-alkyl, it can be methyl, ethyl, propyl group or sec.-propyl especially.

In the context of the present invention, thiazolinyl represents to comprise the carbochain of one or more pairs of keys, comprises two-alkene class, three-alkene class and polyalkenes.In a preferred embodiment, thiazolinyl of the present invention comprises the thiazolinyl (C of 2-8 carbon atom _2-8-thiazolinyl), more preferably 2-6 carbon atom (C _2-6-thiazolinyl), comprise a two key at least.In a most preferred embodiment, chain base of the present invention is a vinyl; 1-or 2-propenyl; 1-, 2-or 3-butenyl or 1,3-butenyl; 1-, 2-, 3-, 4-or 5-hexenyl or 1,3-hexenyl; Or 1,3, the 5-hexenyl; 1-, 2-, 3-, 4-, 5-, 6-or 7-octenyl or 1,3-octenyl or 1,3,5-octenyl or 1,3,5,7-octenyl.

In the context of the present invention, cycloalkyl is represented cyclic alkyl, preferably comprises 3-10 carbon atom (C _3-10-cycloalkyl), preferred 3-8 carbon atom (C _3-8-cycloalkyl), comprise cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group.

In the context of the present invention, cycloalkyl-alkyl is represented the cycloalkyl that defines as mentioned, and described cycloalkyl is being substituted on alkyl of definition as mentioned also.The example of the preferred cycloalkyl-alkyl of the present invention comprises cyclopropyl methyl and cyclopropyl ethyl.

In the context of the present invention, alkoxyl group intention " alkyl-O-", wherein alkyl is as hereinbefore defined.

In the context of the present invention, haloalkoxy basis representation alkoxyl group as defined herein, described alkoxyl group is replaced one or many by halogeno-group.The preferred halogenated alkoxy of the present invention comprises three halogenated methoxies, preferred trifluoromethoxy.

In the context of the present invention, amino-alkyl is represented " NH-alkyl-", i.e. secondary amino group, and wherein alkyl is as hereinbefore defined.The example of the preferred amino-alkyl of the present invention comprises amino methyl and amino-ethyl.

In the context of the present invention, alkyl-amino-alkyl is represented " alkyl-NH-alkyl-", and wherein alkyl as hereinbefore defined.The example of the preferred alkyl-amino of the present invention-alkyl comprises methyl-amino-methyl, ethyl-amino-methyl, methyl-amino-ethyl and ethyl-amino-ethyl.

In the context of the present invention, alkyl-carbonyl-amino expression " alkyl-CO-NH-", wherein alkyl is as hereinbefore defined.Preferred alkyl-the carbonyl of the present invention-amino comprises kharophen.

In the context of the present invention, hydroxyl-alkyl is represented the alkyl that defines as mentioned, and described hydroxyl-alkyl is replaced by one or more hydroxyls.The example of the preferred hydroxyl-alkyl of the present invention comprises 2-hydroxyl-ethyl, 3-hydroxyl-propyl group, 4-hydroxyl-butyl, 5-hydroxyl-amyl group and 6-hydroxyl-hexyl.

In the context of the present invention, alkoxyl group-alkyl is represented " alkyl-O-alkyl-", and wherein alkyl as hereinbefore defined.The example of the preferred alkoxyl group-alkyl of the present invention comprises methoxyl group-methyl, methoxyl group-ethyl, oxyethyl group-methyl and oxyethyl group-ethyl.

Steric isomer

It will be understood by those skilled in the art that indazolyl derivative of the present invention can (+) and (-) form and racemic form exist, the racemoid of these isomer and each isomer self all belong to scope of the present invention.

Can racemic form be split into enantiomers by known method and technology.A kind of mode of separation of racemic isomer salt is to use optically-active acid and passes through to discharge the optically active amine compound with alkaline purification.The another kind of method that racemate resolution is become enantiomers is based on the chromatography of using optically-active matrix.Thus, for example can be by for example d-or l-(tartrate, mandelate or camsilate) salt classification crystallization are split into its enantiomers with racemic compound of the present invention.

Can also be by making indazolyl derivative of the present invention and activity optically active carboxylic acid, such as derived from (+) or (-) phenylalanine (+) or (-) phenylglycocoll, the carboxylic acid reaction of (+) or (-) dextrocamphoric acid forms the diastereomer amides or by making reactions formation diastereomer amino formates such as indazolyl derivative of the present invention and optically-active chloro-formic ester split indazolyl derivative of the present invention.

The additional method that splits optically active isomer is well known in the art.These class methods comprise the J by Jaques, Collet A ， ﹠amp; Wilen S is at Enantiomers, Racemates, andResolutions ", those methods of describing among the John Wiley and Sons, New York (1981).

Pharmacy acceptable salt

Indazolyl derivative of the present invention can provide with the form of any suitable expection administration.The form that is fit to comprises that the pharmacy (being physiology) of indazolyl derivative of the present invention goes up acceptable salt and prodrug (predrug) or prodrug (prodrug) form.

The example of pharmaceutically acceptable addition salt class includes but not limited to the inorganic and organic acid addition salt class of nontoxicity, such as hydrochloride derived from hydrochloric acid, derived from hydrobromic hydrobromate, nitrate derived from nitric acid, perchlorate derived from perchloric acid, phosphoric acid salt derived from phosphoric acid, derived from vitriolic vitriol, formate derived from formic acid, acetate derived from acetate, aconitate derived from equisetic acid, ascorbate salt derived from xitix, benzene sulfonate derived from Phenylsulfonic acid, derived from benzoic benzoate, cinnamate derived from styracin, Citrate trianion derived from citric acid, embonate derived from pamoic acid, derived from the enanthate of enanthic acid, derived from the fumarate of fumaric acid, derived from the glutaminate of L-glutamic acid, oxyacetate derived from hydroxyethanoic acid, derived from the lactic acid salt of lactic acid, derived from the maleate of toxilic acid, derived from the malonate of propanedioic acid, mandelate derived from amygdalic acid, derived from the mesylate of methylsulfonic acid, derived from the naphthalene-2-sulfonic acid salt of naphthalene-2-sulfonic acid, derived from the phthalate of phthalandione, derived from salicylic salicylate, derived from the sorbate of Sorbic Acid, derived from stearic stearate, derived from the succinate of succsinic acid, derived from tartaric tartrate, derived from tosilate of tosic acid etc.This class salt can operation steps well-known by this area and that describe form.

Be not considered as pharmaceutically acceptable other acid, can be used to prepare the salt of the intermediate that is used as the salt that obtains indazolyl derivative of the present invention and pharmaceutically acceptable sour addition thereof such as oxalic acid.

The metal-salt of indazolyl derivative of the present invention comprises an alkali metal salt, such as the sodium salt of carboxylic indazolyl derivative of the present invention.

In the context of the invention, " salt " that contains the N compound also is considered to pharmacy acceptable salt.Preferably " salt " comprises alkyl-salt, cycloalkyl-salt and cycloalkylalkyl-salt.

Indazolyl derivative of the present invention and pharmaceutically acceptable solvent can be made solubility or insoluble form such as water, ethanol etc.Soluble form can also comprise hydrated form, such as monohydrate, and dihydrate, semihydrate, trihydrate, tetrahydrate etc.Generally with regard to purpose of the present invention, soluble form is regarded as and insoluble form equivalence.

The preparation method

Can be by the ordinary method of chemosynthesis, for example those methods of describing in preparation embodiment prepare indazolyl derivative of the present invention.The raw material that is used for method described in the application is known or is easy to by ordinary method by being purchased chemical production.

Can pass through routine techniques, for example separate reacting final product as herein described by extraction, crystallization, distillation, chromatogram etc.

Biological activity

Indazolyl derivative of the present invention has carried out experiment in vitro and discovery and has been particularly useful as potassium channel modulating agents.More particularly, compound of the present invention can selectivity be regulated SK1, SK2 and/or SK3 passage.

Therefore, the present invention relates to the purposes of indazolyl derivative of the present invention in the preparation medicine in one aspect of the method, and described medicine can be used for the treatment of or alleviation and potassium channel, particularly the SK passage, the SK1 that more specifically says so, disease or illness that SK2 and/or SK3 channel activity are relevant.

In one embodiment, disease relevant with activity of potassium channels or illness are respiratory disease, and epilepsy is fainted from fear, epileptic seizures, petit mal, vascular spasm, coronary vasospasm, kidney disorders, POLYCYSTIC KIDNEY DISEASE, cystospasm, the urinary incontinence, the bladder outflow obstruction, erective dysfunction, gastrointestinal dysfunction, secretory diarrhea, local asphyxia, cerebral ischemia, ischemic heart disease, stenocardia, coronary heart disease, autism, ataxia, traumatic brain injury, Parkinson's disease, bipolar affective disorder, psychosis, schizophrenia, anxiety, dysthymia disorders, manic, emotional handicap, dementia, memory and attention deficit, alzheimer's disease, amyotrophic lateral sclerosis (ALS), dysmenorrhoea, hypnolepsy, raynaud's disease, intermittent claudication, this Jaeger logical sequence syndrome, irregular pulse, hypertension, myotonic muscular dystrophy, spasticity, xerostomia disease, type ii diabetes, superelevation insulinemia, premature labor, alopecia, cancer, irritable bowel syndrome, immunosuppression, migraine or pain.

In a preferred embodiment, disease relevant with activity of potassium channels or illness are respiratory disease, the urinary incontinence, erective dysfunction, anxiety, epilepsy, psychosis, schizophrenia, amyotrophic lateral sclerosis (ALS) or pain.

In another preferred embodiment, disease relevant with activity of potassium channels or illness are respiratory disease, particularly asthma, cystic fibrosis, chronic obstructive pulmonary disease (COPD) or rhinorrhea.

In the 3rd embodiment preferred, disease relevant with activity of potassium channels or illness are the urinary incontinence.

In the 4th embodiment preferred, disease relevant with activity of potassium channels or illness are epilepsy, epileptic seizures, petit mal or convulsions.

In the 5th embodiment preferred, disease relevant with activity of potassium channels or illness are respiratory disease, particularly asthma, cystic fibrosis, chronic obstructive pulmonary disease (COPD) or rhinorrhea.

The compound of being tested all shows biological activity micromole and sub-micro molar range, promptly is lower than 1 to being higher than 100 μ M.The preferred compound of the present invention shows the biological chemistry of mensuration as described herein at sub-micro mole and micro-molar range, promptly is lower than 0.1 to about 10 μ M.

Pharmaceutical composition

In one aspect of the method, the invention provides the novel pharmaceutical combination thing, it comprises the indazolyl derivative of the present invention for the treatment of significant quantity.

Can be although be used for the indazolyl derivative of the present invention of therapy with the form administration of raw material indazolyl derivative, but preferably with active ingredient, randomly with the form of physiologically acceptable salt, introducing with one or more adjuvants, vehicle, carrier and/or thinner becomes pharmaceutical composition.

In preferred embodiments, the invention provides pharmaceutical composition, it comprises indazolyl derivative of the present invention or its pharmacy acceptable salt or derivative and one or more pharmaceutically acceptable carriers and therapeutic and/or preventative component randomly known in the art with other and that use.Described carrier must be " acceptable ", promptly with preparation in other component compatibility and can be harmful to its recipient.

Pharmaceutical composition of the present invention can be those pharmaceutical compositions that are suitable for oral, rectum, segmental bronchus, nose, lung, part (comprising in the cheek and the hypogloeeis), transdermal, vagina or parenteral (comprise in skin, subcutaneous, intramuscular, intraperitoneal, intravenously, intra-arterial, the brain, intraocular injection or infusion) administration, or those are adapted to pass through the forms that suck or be blown into administration, comprise powder and liquid aerosol drug delivery or the pharmaceutical composition by the slow-released system administration.The example of suitable slow-released system comprises the semi-permeable matrix of the solid hydrophobic polymkeric substance that contains The compounds of this invention, and described matrix can be the formed article form, for example film or micro-capsule.

Therefore indazolyl derivative of the present invention can be made the form of pharmaceutical composition and unitary dose thereof with adjuvant, carrier or the thinner of routine.Such form comprises solid, and the especially form and the liquid of tablet, filled capsules, powder and pill, especially the capsule of the aqueous solution or non-aqueous solution, suspension, emulsion, elixir and the above-mentioned form of filling, the suppository that all these forms all is used for is oral, be used for rectal administration and be used for the sterile injectable solution that parenteral uses.Such pharmaceutical composition and unit dosage thereof can comprise conventional ratio conventional component, contain or do not contain other active compound or composition, and such unit dosage can contain the active ingredient of any suitable effective amount suitable with expection application dose scope every day.

Indazolyl derivative of the present invention can various oral and parenteral dosage form administrations.Concerning the ability technician, it is evident that following formulation can comprise as the indazolyl derivative of the present invention of activeconstituents or the pharmacy acceptable salt of indazolyl derivative of the present invention.

For from indazolyl derivative pharmaceutical compositions of the present invention, pharmaceutically acceptable carrier can be solid or liquid.The preparation of solid form comprises powder, tablet, pill, capsule, cachet, suppository and dispersible granules agent.Solid carrier can be one or more materials that can also be used as thinner, seasonings, solubilizing agent, lubricant, suspension agent, tackiness agent, sanitas, tablet disintegrant or coating material.

In pulvis, carrier is a fine-grained solids, and it is mixed with the activeconstituents fine powder.

In tablet, activeconstituents mixed in the proper ratio with the carrier with necessary binding capacity and be compressed into required shape and size.

Pulvis and tablet preferably contain 5% or 10% to about 70% active compound.Suitable carriers is magnesiumcarbonate, Magnesium Stearate, talcum powder, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose gum, Xylo-Mucine, low melt wax, theobroma oil etc.Active compound and formulation as the coating material of carrier desired to comprise in term " preparation ", and described coating material provides capsule, wherein contains or carrier-free activeconstituents suppressed by vector surrounds, and carrier combines with active compound thus.Similarly, also comprise cachet and lozenge.Tablet, powder agent, capsule, pill, cachet and lozenge can be as the solid forms that is suitable for oral administration.

In order to prepare suppository, at first with low-melting wax, as the mixture melt of glycerin fatty acid ester or theobroma oil, and activeconstituents is evenly dispersed in wherein by stirring.With in the suitable big or small mould of the uniform mixture impouring of described fusing, make its cooling and curing thus then.

The composition that is suitable for vagina administration can exist with the form of vaginal suppository, tampon, ointment, gelifying agent, paste, foam or sprays, and they also contain suitable carriers known in the art except that containing active ingredient.

Liquid preparation comprises solution, suspension and emulsion.For example, the aqueous solution or water-propylene glycol solution.For example, the parenteral injection liquid preparation can be mixed with the solution of the solution form of moisture polyoxyethylene glycol.

Therefore, indazolyl derivative of the present invention can be mixed with and be used for administered parenterally (for example injection, as bolus injection or continuous infusion) preparation, and can provide with the unit dosage form of ampoule, pre-filled syringe, small volume transfusion or with multi-dose container with the sanitas that adds.Described composition can be taked the form of suspension, solution or the emulsion of oiliness or aqueous carrier, and can contain the preparation composition, as suspension agent, stablizer and/or dispersion agent.In addition, activeconstituents can be a powder type, and the aseptic separation by sterile solid or obtain by the solution freeze-drying is used for before use preparing with suitable carriers such as aseptic, pyrogen-free water.

The aqueous solution that is suitable for orally using can prepare by activeconstituents being dissolved in the water and adding suitable tinting material, seasonings, stablizer and thickening material as required.

The aqeous suspension that is suitable for orally using can by will segment active ingredient be dispersed in contain viscous substance, as natural or synthetic is gummy, prepare in the water of resin, methylcellulose gum, Xylo-Mucine or other known suspension agent.

Also comprise the solid form preparation of desiring before facing usefulness, to be converted into the liquid form preparation that is used for oral administration.Such liquid form comprises solution, suspension and emulsion.Except that active ingredient, such preparation can comprise tinting material, seasonings, stablizer, buffer reagent, artificial and natural sweeting agent, dispersion agent, thickening material, solubilizing agent etc.

In order to locally apply to epidermis, The compounds of this invention can be mixed with ointment, creme, or lotion, or transdermal patch.For example, ointment and creme can add suitable thickening and/or jelling agent is formulated with water-based or oleaginous base.Lotion can be formulated with water-based or oleaginous base, and also contain one or more emulsifying agents, stablizer, dispersion agent, suspension agent, thickening material or tinting material usually.

Be suitable for that topical drug delivery composition is included in flavoured base in the oral cavity, be generally the lozenge that comprises activeconstituents in sucrose and kordofan gum or the tragacanth gum; The pastille that comprises activeconstituents at inert base, as gelatin and glycerine or sucrose and kordofan gum; And the mouth wash shua that in suitable liquid vehicle, comprises activeconstituents.

Solution or suspension for example can be applied directly to nasal cavity with dropper, suction pipe or atomizer with ordinary method.Described composition can single dose or the form of multiple doses provide.Recently with regard to the situation of dropper or suction pipe, can give solution or suspension realization this purpose of suitable pre-determined volume by the patient.With regard to sprays, can for example realize this purpose by metering atomisation pump.

Respiratory tract administration also can be realized by aerosol, wherein active ingredient provides in pressurized package with suitable propelling agent, suitable propelling agent comprises chlorofluorocarbon (CFC) for example Refrigerant 12, trichlorofluoromethane or dichloro tetrafluoro ethane, carbonic acid gas or other suitable gas.Aerosol also can suitably contain tensio-active agent such as Yelkin TTS.The dosage of medicine can be by being equipped with metering valve control.

Perhaps, active ingredient can provide by dry powder form, for example the powdered mixture of compound in suitable powder matrix such as lactose, starch, starch derivative such as Vltra tears and polyvinylpyrrolidone (PVP).Aptly, powder carrier will form gel at nasal cavity.Powder composition can present by unit dosage form, for example with capsule or cartridge case (as the capsule or the cartridge case of gelatin) form, or can be by the sucker Blister Package form of administration therefrom with powder.

Comprise intranasal compositions at the composition of desiring to be used for respiratory tract administration, compound has little particle diameter usually, for example is 5 microns or the littler order of magnitude.Such particle diameter can be by methods known in the art, for example obtain by micronization.

When needing, can use the composition that is fit to provide the active ingredient slowly-releasing.

Pharmaceutical preparation is preferably unit dosage.In this class form, preparation is subdivided into the unitary dose that contains an amount of active ingredient.Unit dosage form can be the preparation of packing, and described packing contains the preparation of discrete amount, as tablet, the capsule of packing, and the powder in bottle or the ampoule.In addition, unit dosage can be capsule, tablet, cachet or a lozenge itself, maybe can be the packaged form that is fit to any of these formulation of quantity.

The tablet or the capsule that are used for oral administration are preferred compositions with the liquid and the continuous infusion liquid that are used for intravenously administrable.

About the more detailed data of preparation and medicine-feeding technology can (Maack Publishing Co., Easton find on PA) at the Remington ' of latest edition s Pharmaceutical Sciences.

The treatment effective dose refers to the amount of active ingredient, and it can improve symptom or symptom.Treatment effectiveness and toxicity, for example ED ₅₀And LD ₅₀Can in cell culture or laboratory animal, be measured by standard pharmacology program.But the dosage between result of treatment and the toxic action is than being therapeutic index and passing ratio LD ₅₀/ ED ₅₀Expression.Preferably show the pharmaceutical composition of big therapeutic index.

The dosage that gives certainly must be at age, body weight and the illness of the individuality of being treated, and route of administration, dosage form and dosage regimen, and the result of expectation and adjusting carefully, and definite dosage should be determined by the doctor certainly.

Actual dosage depends on the character and the severity of the disease for the treatment of, and within doctor's determination range, can be according to the present invention particular case the reaction of dosage is changed, to produce required result of treatment.Yet expection at present contains from about 0.1 to about 500mg, preferably from about 1 to about 100mg, more preferably the pharmaceutical composition from about active ingredient of 1 to about 10mg/single dosage is suitable for therapeutic treatment.

Active ingredient can every day one or several doses give.In some cases, can obtain gratifying result with the dosage that is low to moderate 0.1 μ g/kg (intravenously) and 1 μ g/kg (oral).Think that at present the upper limit of dosage range is about 10mg/kg (intravenously) and 100mg/kg (oral).Preferable range is from about 0.1 μ g/kg to about 10mg/kg/ day (intravenously), and from about 1 μ g/kg to about 100mg/kg/ day (oral).

Methods of treatment

Another aspect of the present invention provides treatment, prevention or has alleviated the disease of moving object (comprising the people) or the method for illness or illness, described disease or illness or illness are replied regulating potassium channel, and described method comprises the chemical compound of the present invention of this class moving object (comprising the people) that these needs are arranged being treated significant quantity.

The preferred indication that the present invention pays close attention to be aforesaid those.

Expection at present, suitable dosage range is that every day 0.1 is to 1000mg, every day 10-500mg, and particularly every day 30-100mg, depend on definite administering mode usually, form of medication, administration at indication, related experimenter and related experimenter's body weight, and further, be responsible for doctor or animal doctor's preference and experience.

In some cases, obtain gratifying result with the dosage that is low to moderate 0.005mg/kg (intravenously) and 0.01mg/kg (oral).The upper limit of described dosage range is about 10mg/kg (intravenously) and 100mg/kg (oral).Preferred range is about about 1mg/kg of 0.001-(intravenously) and the about 10mg/kg of about 0.1-(oral).

Embodiment

With further reference to the present invention of the following example illustration, but these embodiment are used for limiting the scope of the invention of asking for protection as claim never in any form.

Embodiment 1

Preparation embodiment

Method A

(2-chloro-6-methyl-pyrimidine-4-yl)-(4-chloro-phenyl)-amine (midbody compound)

With 2, (10g, 61.3mmol) (7.83g 61.3mmol) is dissolved in acetonitrile (100mL) to 4-two chloro-6-methylpyrimidines with the 4-chloroaniline.Add diisopropylethylamine (21.37mL, 122.7mmol) and be heated to 90 ℃ following 4 days.Concentrate described reaction mixture in a vacuum and, be white solid by using ethyl acetate-hexane to obtain (2-chloro-6-methyl-pyrimidine-4-yl)-(4-chloro-phenyl)-amine (1.5g, 10%) as the purified by flash chromatography crude product of eluent.

(4-chloro-phenyl)-(2-indazole-2-base-6-methyl-pyrimidine-4-yl)-amine (compd A 1); With (4-chloro-phenyl)-(2-indazole-1-base-6-methyl-pyrimidine-4-yl)-amine (compd A 2)

With (2-chloro-6-methyl-pyrimidine-4-yl)-(4-chloro-phenyl)-amine (300mg 1.18mmol) is dissolved in acetonitrile (4mL), add indazole (150mg, 1.3mmol) and will heat 30 minutes in the microwave oven of described mixture 160 ℃ under.Remove in a vacuum and desolvate and with alkalize remaining resistates and use chloroform extraction of sodium bicarbonate aqueous solution.With the organic phase that dried over sodium sulfate merges, filter and evaporation.By using ethyl acetate-hexane to obtain (4-chloro-phenyl)-(2-indazole-2-base-6-methyl-pyrimidine-4-yl)-amine (56mg as the column chromatography purifying crude product of eluent, 14%, mp=224.7-226.7 ℃) ([M+H]+LC-ESI-HRMS show 336.1019Da.Calculated value 336.101598Da, deviation 0.9ppm), for white solid and (4-chloro-phenyl)-(2-indazole-1-base-6-methyl-pyrimidine-4-yl)-amine (21mg, 5.3%, mp=166.7-168.7 ℃) ([M+H]+LC-ESI-HRMS show 336.1007Da.Calculated value 336.101598Da, deviation-2.7ppm), be white solid.

Cyclohexyl-(2-indazole-1-base-quinazoline-4-yl)-amine (compound A-13)

According to method A by 2,4-two chloro-quinazolines, the preparation of cyclo-hexylamine and indazole.Mp=278.1-281.4 ℃ [M+H]+LC-ESI-HRMS show 344.1879Da.Calculated value 344.18752Da, deviation 1.1ppm.

Cyclohexyl-(2-indazole-1-base-pyrimidine-4-yl)-amine (compd A 4)

According to method A by 2,4-dichloro pyrimidine, the preparation of cyclo-hexylamine and indazole.[M+H]+LC-ESI-HRMS show 294.173Da.Calculated value 294.17187Da, deviation 3.8ppm.

Cyclohexyl-(2-indazole-1-base-6-methyl-pyrimidine-4-yl)-amine (compound A-45)

According to method A by 2,4-two chloro-6-methylpyrimidines, the preparation of cyclo-hexylamine and indazole.[M+H]+LC-ESI-HRMS show 308.1859Da.Calculated value 308.18752Da, deviation-5.3ppm.

(4-chloro-benzyl)-(2-indazole-2-base-pyrimidine-4-yl)-amine (compd A 6); With (4-chloro-benzyl)-(2-indazole-1-base-pyrimidine-4-yl)-amine (compd A 7)

According to method A by 2,4-dichloro pyrimidine, the preparation of 4-benzyl chloride base amine and indazole.Compd A 6[M+H]+LC-ESI-HRMS show 336.1001Da.Calculated value 336.101598Da, deviation-4.5ppm.Compd A 7[M+H]+LC-ESI-HRMS show 336.1006Da.Calculated value 336.101598Da, deviation-3ppm.

(4-chloro-phenyl)-[2-(6-nitro-indazole-2-yl)-pyrimidine-4-yl]-amine (compound A-28)

According to method A by 2,4-dichloro pyrimidine, the preparation of 4-chloroaniline and 6-nitro indazole.[M+H]+LC-ESI-HRMS show 367.0717Da.Calculated value 367.071027Da, deviation 1.8ppm.

(4-chloro-phenyl)-[2-(5-nitro-indazole-2-yl)-pyrimidine-4-yl]-amine (compd A 9)

According to method A by 2,4-dichloro pyrimidine, the preparation of 4-chloroaniline and 5-nitro indazole.[M+H]+LC-ESI-HRMS show 367.0692Da.Calculated value 367.071027Da, deviation-5ppm.

(4-chloro-phenyl)-(2-indazole-2-base-5-nitro-pyrimidine-4-yl)-amine (midbody compound)

According to method A by 2,4-two chloro-5-nitro-pyrimidines, the preparation of 4-chloroaniline and indazole.

Method B

Acetate N '-benzyl-hydrazides (midbody compound)

(1.78g 24mmol) is dissolved in ethanol (20mL) and be cooled to 0 ℃ with acetic acid hydrazides.(2g, 8mmol) solution in ethanol (10mL) and stirring are at room temperature spent the night slowly to add the 2-bromo benzyl bromo.Under reduced pressure concentrate described reaction mixture and, be white solid by using ethyl acetate-hexane to obtain acetate N '-benzyl-hydrazides (1.7g, 87%) as the column chromatography purifying crude product of eluent.

Acetate N '-(2-bromo-benzyl)-N '-[4-(4-chloro-phenyl amino)-6-methyl-pyrimidine-2-base]-acyl Hydrazine (midbody compound)

(1.6g, 6.58mmol) (0.84g 3.29mmol) is dissolved in acetonitrile (10mL) with (2-chloro-6-methyl-pyrimidine-4-yl)-(4-chloro-phenyl)-amine with acetate N '-benzyl-hydrazides in sealed vessel.Described reaction mixture was heated 4 days in the sand bath under 100 ℃.Filter out the gained solid, with chloroform washing and concentrate in a vacuum and obtain acetate N '-(2-bromo-benzyl)-N '-[4-(4-chloro-phenyl amino)-6-methyl-pyrimidine-2-base]-hydrazides (0.5g, 33%), be white solid.

2-[N-(2-bromo-benzyl)-diazanyl]-6-methyl-pyrimidine-4-yl }-(4-chloro-phenyl)-amine (centre The body compound)

With acetate N '-(2-bromo-benzyl)-N '-[4-(4-chloro-phenyl amino)-6-methyl-pyrimidine-2-base]-hydrazides (0.4g, 0.87mmol) be suspended in aqueous hydrochloric acid (6M, 50mL) in and be heated to 100 ℃ following 3 days.Dilute described reaction mixture with (50mL) water, extract with the solid sodium bicarbonate alkalization and with chloroform (3x50mL).With the organic phase that the salt water washing merges, use dried over sodium sulfate, filter and be evaporated to and obtain 2-[N-(2-bromo-benzyl)-diazanyl]-6-methyl-pyrimidine-4-yl }-(4-chloro-phenyl)-amine (0.3g, 82%), be brown solid.

(4-chloro-phenyl)-(2-indazole-2-base-6-methyl-pyrimidine-4-yl)-amine (compound B-11; Identical with compd A 1, but obtain by selectable route of synthesis)

Will 2-[N-(2-bromo-benzyl)-diazanyl]-6-methyl-pyrimidine-4-yl }-(4-chloro-phenyl)-amine (0.3,0.72mmol), 1,1 '-two (diphenylphosphino) ferrocene 30mg, 0.054mmol) and potassium tert.-butoxide (127mg 1.07mmol) is suspended in the toluene and outgases twice.Add acid chloride (II) (8mg, 0.035mmol) and with described reaction mixture be heated to 90 ℃ following 48 hours.

Filter described reaction mixture by C salt pad, with chloroform washing and concentrated in a vacuum.By using ethyl acetate-hexane to obtain (4-chloro-phenyl)-(2-indazole-2-base-6-methyl-pyrimidine-4-yl)-amine (50mg, 20%), be white solid as the column chromatography purifying crude product of eluent.

Method C

N-(4-chloro-phenyl)-methane amide (midbody compound)

(10g 78.4mmol) is heated to backflow 30 minutes with formic acid with the 4-chloroaniline.Concentrate described reaction mixture in a vacuum.Add entry and with yellow soda ash alkalization and use ethyl acetate extraction.With the organic phase that dried over mgso merges, filter and be evaporated to and obtain N-(4-chloro-phenyl)-methane amide (10.7g, 88%).

(4-chloro-phenyl)-(6-fluoro-pyridine-2-yl)-amine (midbody compound)

(1.2g, (4g is 25.7mmol) at N, in the solution in the dinethylformamide (40mL) and stirred 15 minutes 30.9mmol) to join N-(4-chloro-phenyl)-methane amide with sodium hydride.Add 2, and the 6-difluoro pyridine (2.96g, 25.7mmol), with described reaction mixture ice-aqueous solution that stirring is spent the night and impouring is stirred under 70 ℃.Filter out gained precipitation and drying and obtain (4-chloro-phenyl)-(6-fluoro-pyridine-2-yl)-amine (5.95g), be crude product.With crude product without being further purified use.

(4-chloro-phenyl)-(6-indazole-1-base-pyridine-2-yl)-amine (Compound C 1)

(325mg, (800mg is 6.77mmol) at N, in the solution in the dinethylformamide (10mL) and stirred 30 minutes 8.12mmol) to join indazole with sodium hydride.(1.55g 6.77mmol) and with the stirring under 80 ℃ of described reaction mixture spends the night to add (4-chloro-phenyl)-(6-fluoro-pyridine-2-yl)-amine.Ice-aqueous solution that described mixture impouring is stirred and use ethyl acetate extraction.With the organic phase that dried over mgso merges, filter and concentrate in a vacuum.By using ethyl acetate-hexane to obtain (4-chloro-phenyl)-(6-indazole-1-base-pyridine-2-yl)-amine (230mg, 11%), be yellow solid as the column chromatography purifying crude product of eluent.[M+H]+LC-ESI-HRMS show 321.0901Da.Calculated value 321.090699Da, deviation-1.9ppm.

[6-(3-chloro-indazole-1-yl)-pyridine-2-yl]-(4-chloro-phenyl)-amine (Compound C 2)

According to method C by 2,6-difluoro pyridine, the preparation of 3-chlorine indazole and 4-chloroaniline.[M+H]+LC-ESI-HRMS show 355.0528Da.Calculated value 355.051727Da, deviation 3ppm.

Method D

N-(4-chloro-phenyl)-N-(6-chloro-pyrazine-2-yl)-2,2-dimethyl-propionic acid amide (midbody compound)

With 2, (10g, 67.12mmol), (7.78g, mixture 79.33mmol) are dissolved in toluene (250mL) and use argon-degassed 30min the 6-dichloropyrazine for 4-chloroaniline (61.02mmol) and sodium tert-butoxide.Add (±)-2,2 '-two (diphenylphosphino)-1,1 '-dinaphthalene ((±)-BINAP) (2.51g, 4.03mmol) and acid chloride (II) (452mg, 2.01mmol).Described mixture outgased 15 minutes again and stir down and spend the night at 105 ℃.Water makes described reaction cancellation and separates each phase.With ethyl acetate extraction water and the organic phase that merges with dried over sodium sulfate, filter and concentrate in a vacuum and obtain the 21.48g crude product, be dark oily matter.Described oil is dissolved in tetrahydrofuran (THF) (250mL), add tert-Butyl dicarbonate (40.36g, 183.1mmol) and 4-dimethylaminopyridine (1.5g 12.2mmol) and with described reaction mixture is heated to backflow 1 hour.Add saturated aqueous ammonium chloride and with ethyl acetate (4x50mL) aqueous phase extracted.With the organic phase that dried over sodium sulfate merges, filter and concentrate in a vacuum.By using ethyl acetate-heptane to obtain N-(4-chloro-phenyl)-N-(6-chloro-pyrazine-2-yl)-2 as the purified by flash chromatography crude product of eluent, 2-dimethyl-propionic acid amide (7.2g, 34%) is yellow solid.

(4-chloro-phenyl)-(6-indazole-2-base-pyrazine-2-yl)-amine (Compound D 1); With (4-chloro-phenyl)-(6-indazole-1-base-pyrazine-2-yl)-amine (Compound D 2)

(180mg, (543mg 4.40mmol) at N, stirred 20 minutes down at 50 ℃ in the suspension in the dinethylformamide (5mL) and with described reaction mixture 4.50mmol) to join indazole with sodium hydride.Add N-(4-chloro-phenyl)-N-(6-chloro-pyrazine-2-yl)-2 in described suspension, (300mg's 2-dimethyl-propionic acid amide 0.88mmol) and 100 ℃ of following stirrings spends the night.Make described reaction mixture cancellation and extract with salt solution with ethyl acetate (4x15mL).Organic phase with salt water washing merging, use dried over sodium sulfate, filter and evaporation, by using ethyl acetate-heptane to obtain (4-chloro-phenyl)-(6-indazole-2-base-pyrazine-2-yl)-amine (17mg as the column chromatography purifying crude product of eluent, 13%, Mp 249-252 ℃, [M+H]+LC-ESI-HRMS show 322.0864Da.Calculated value 322.085948Da, deviation 1.4ppm) be yellow solid and (4-chloro-phenyl)-(6-indazole-1-base-pyrazine-2-yl)-amine (19mg, 12%, Mp.204-207 ℃, [M+H]+LC-ESI-HRMS show 322.0876Da.Calculated value 322.085948Da, deviation 5.1 ppm), be brown solid.

Method E

N-(4-chloro-phenyl)-2-indazole-2-base-pyrimidine-4,5-diamines (compd E 1)

With (4-chloro-phenyl)-(2-indazole-2-base-5-nitro-pyrimidine-4-yl)-amine (600mg 1.64mmol) is dissolved in methyl alcohol (30mL), add palladium carbon (10%, 150mg) and with described reaction mixture at room temperature with in the hydrogen environment stir and spend the night.Filter and evaporation and obtain crude product, it is obtained N-(4-chloro-phenyl)-2-indazole-2-base-pyrimidine-4 by the preparation HPLC purifying, 5-diamines (27mg, 4.9%) is brown solid.[M+H]+LC-ESI-HRMS show 337.0955Da.Calculated value 337.096847Da, deviation-4ppm.

2-[4-(4-chloro-phenyl amino)-pyrimidine-2-base]-2H-indazole-6-base amine (compd E 2)

Prepare by (4-chloro-phenyl)-[2-(6-nitro-indazole-2-yl)-pyrimidine-4-yl]-amine according to method E.[M+H]+LC-ESI-HRMS show 337.0959Da.Calculated value 337.096847Da, deviation-2.8ppm.

Method F

N-{2-[4-(4-chloro-phenyl amino)-pyrimidine-2-base]-2H-indazole-6-yl }-ethanamide (compound F 17-hydroxy-corticosterone 1)

With (4-chloro-phenyl)-[2-(6-nitro-indazole-2-yl)-pyrimidine-4-yl]-amine (500mg, 1.36mmol) and iron powder (152mg 2.73mmol) is suspended in acetic anhydride (10mL) and the acetate (10mL).Described reaction mixture is heated to spends the night under 100 ℃ and concentrate in a vacuum.Add entry (30mL), use chloroform (3x30mL) extraction subsequently.Wash the organic layer that merges with salt solution with water, use anhydrous sodium sulfate drying, filter and concentrated in a vacuum and obtain crude product, be brown solid.Preparation HPLC obtains N-{2-[4-(4-chloro-phenyl amino)-pyrimidine-2-base]-2H-indazole-6-yl }-ethanamide (35.2mg, 6%), be the purple solid.[M+H]+LC-ESI-HRMS show 379.1073Da.Calculated value 379.107412Da, deviation-0.3ppm.

N-{2-[4-(4-chloro-phenyl amino)-pyrimidine-2-base]-2H-indazole-5-yl }-ethanamide (compound F 17-hydroxy-corticosterone 2)

Prepare by (4-chloro-phenyl)-[2-(5-nitro-indazole-2-yl)-pyrimidine-4-yl]-amine according to method F.[M+H]+LC-ESI-HRMS show 379.1088Da.Calculated value 379.107412Da, deviation 3.7ppm.

Embodiment 2

Biological activity

Present embodiment confirms the biological activity of the representational compound of the present invention (compd A 1).Use the full cell structure record in the patch clamp technique to lead Ca by little electricity ²⁺-activatory K ⁺The ion(ic)current of passage (SK passage, hypotype 3).

Make the HEK293 tissue culture cells of expressing the hSK3 passage be grown in 37 ℃ of following and 5%CO ₂In the DMEM that has replenished 10%FCS (foetal calf serum) (the improved Eagle substratum of Dulbecco) in.When 60-80% merges, by the trypsin treatment collecting cell and be seeded on the cover glass.

The use patch clamp experimentizes.Will be on cover glass the cell of bed board place 15 μ l perfusate chambers (in the flow velocity～1ml/min), on the inverted microscope on the chatter-free operation platform of described chamber in being placed on the ground connection faraday's cage.All experiments all at room temperature (20-22 ℃) are carried out.(HEKA-electronics, Lambrect Germany) are connected with macintosh computer by the ITC16 interface to make the EPC-9 patch clamp amplifier.Data directly are stored on the hard disk and (OR USA) analyzes for Wavemetrics, Lake Oswega by IGOR software.

Apply the full cell structure in the patch clamp technique.In brief: use remote control system that borosilicate pipette tip (resistance 2-4M Ω) slowly is placed on the cytolemma.Slight suction causes forming gigaseal (transfer pipet resistance increases to more than the 1G Ω) and makes membranolysis below the transfer pipet by strong pumping more then.With electric mode compensate cell capacitance and measure transfer pipet and cell interior between resistance (serial resistance, Rs) and compensate.Usually cell capacitance at 5-20pF scope (depending on the cell size) and serial resistance in 3-6M Ω scope.In experimentation, upgrade Rs-and capacitance compensation (before each the stimulation).Abandon the experiment that all have unsteady Rs-value.Do not carry out the seepage deduction.

Outer (bath) solution of born of the same parents comprises (by mM): 154mM KCl, 0.1 CaCl ₂, 3 MgCl ₂, 10 HEPES (pH=7.4 uses HCl).Test compounds is dissolved in DMSO and dilutes 1000 times in the solution then outside born of the same parents.

(transfer pipet) solution comprises in the born of the same parents: 154mM KCl, 10mM HEPES, 10mMEGTA.(Cambridge, UK) calculating need the required Ca of acquisition by EqCal software ²⁺Cf (0.3-0.4 μ M, Mg ²⁺Be always 1mM) CaCl ₂And MgCl ₂Concentration and interpolation.

After setting up full cellularstructure, from the 0mV sustaining voltage begin every 5 seconds with voltage sweep (normal for-80 to+80mV) put on the cell.Obtain stable base current in the time limit of second at 100-500, and add compound by changing over the outer solution of the born of the same parents that contain test compounds then.Base current during by calculating-75mV changes active compound is carried out quantitatively.With regard to activator, can estimate SC ₁₀₀Value.With SC ₁₀₀Value defined is for to increase to 100% required irritating concentration with base current.SC to The compounds of this invention A1 mensuration ₁₀₀Value is 0.08 μ M, is the indication of its strong SK3 activation characteristic.

Claims

1. the 1-of formula Ia or Ib or 2-indazolyl derivative:

N is 0,1,2 or 3;

X represents O, S or NR '; Wherein

R ' represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl;

A ' expression N or CR ², R wherein ²The following definition; And

A " expression N or CH;

But, condition is A ' and A " in only have one the expression N; And

R ¹, R ², R ³And R ⁴Represent hydrogen independently of one another, alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, alkyl-carbonyl-amino, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogeno-group, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, alkoxyl group-carbonyl, cyano group, nitro and amino; Or

R ¹And R ²Constitute benzo-fused ring with the heteroaromatic rings that connects them; And

R ³And R ⁴Represent hydrogen independently of one another, alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, alkyl-carbonyl-amino, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogeno-group, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, alkoxyl group-carbonyl, cyano group, nitro and amino.

2. the described indazolyl derivative of claim 1 is the 1-indazolyl derivative of formula Ia or the 2-indazolyl derivative of formula Ib, or its pharmacy acceptable salt.

3. each indazolyl derivative among the claim 1-2, or its pharmacy acceptable salt, wherein n is 0,1,2 or 3.

4. each described indazolyl derivative among the claim 1-3, or its pharmacy acceptable salt, wherein X represents O, S or NR '; Wherein R ' represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl.

5. each described indazolyl derivative among the claim 1-4, or its pharmacy acceptable salt, wherein Y represents alkyl, alkyl-cycloalkyl, cycloalkyl, cycloalkyl-alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, thiazolinyl, or phenyl, described phenyl can randomly selectedly replace one or many from following substituting group: alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogeno-group, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, cyano group, nitro and amino.

6. each described indazolyl derivative among the claim 1-5, or its pharmacy acceptable salt, wherein

A ' expression N or CR ², R wherein ²The following definition; And

A " expression N or CH;

But, condition is A ' and A " in only have one the expression N.

7. each described indazolyl derivative among the claim 1-6, or its pharmacy acceptable salt, wherein

R ³And R ⁴Represent hydrogen independently of one another, alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogeno-group, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, alkoxyl group-carbonyl, cyano group, nitro and amino.

8. the described indazolyl derivative of claim 1, it is:

(4-chloro-phenyl)-(2-indazole-2-base-6-methyl-pyrimidine-4-yl)-amine;

(4-chloro-phenyl)-(2-indazole-1-base-6-methyl-pyrimidine-4-yl)-amine;

Cyclohexyl-(2-indazole-1-base-quinazoline-4-yl)-amine;

Cyclohexyl-(2-indazole-1-base-pyrimidine-4-yl)-amine;

Cyclohexyl-(2-indazole-1-base-6-methyl-pyrimidine-4-yl)-amine;

(4-chloro-benzyl)-(2-indazole-2-base-pyrimidine-4-yl)-amine;

(4-chloro-benzyl)-(2-indazole-1-base-pyrimidine-4-yl)-amine;

(4-chloro-phenyl)-[2-(6-nitro-indazole-2-yl)-pyrimidine-4-yl]-amine;

(4-chloro-phenyl)-[2-(5-nitro-indazole-2-yl)-pyrimidine-4-yl]-amine;

(4-chloro-phenyl)-(2-indazole-2-base-6-methyl-pyrimidine-4-yl)-amine;

(4-chloro-phenyl)-(6-indazole-1-base-pyridine-2-yl)-amine;

[6-(3-chloro-indazole-1-yl)-pyridine-2-yl]-(4-chloro-phenyl)-amine;

(4-chloro-phenyl)-(6-indazole-2-base-pyrazine-2-yl)-amine;

(4-chloro-phenyl)-(6-indazole-1-base-pyrazine-2-yl)-amine;

N-(4-chloro-phenyl)-2-indazole-2-base-pyrimidine-4, the 5-diamines;

2-[4-(4-chloro-phenyl amino)-pyrimidine-2-base]-2H-indazole-6-base amine;

Or its pharmacy acceptable salt.

9. pharmaceutical composition, described pharmaceutical composition comprises each described indazolyl derivative or its pharmaceutically acceptable addition salt or its prodrug and at least a pharmaceutically acceptable carrier or thinner among the claim 1-8 that treats significant quantity.

10. each described indazolyl derivative is used for the treatment of in preparation among the claim 1-8, prevention alleviate the mammiferous disease comprise the people or the medicine of illness or illness in purposes, described disease, illness or illness are relevant with activity of potassium channels.

11. the described purposes of claim 10, wherein relevant with activity of potassium channels disease or illness are respiratory disease, and epilepsy is fainted from fear, epileptic seizures, petit mal, vascular spasm, coronary vasospasm, kidney disorders, POLYCYSTIC KIDNEY DISEASE, cystospasm, the urinary incontinence, the bladder outflow obstruction, erective dysfunction, gastrointestinal dysfunction, secretory diarrhea, local asphyxia, cerebral ischemia, ischemic heart disease, stenocardia, coronary heart disease, autism, ataxia, traumatic brain injury, Parkinson's disease, bipolar affective disorder, psychosis, schizophrenia, anxiety, dysthymia disorders, manic, emotional handicap, dementia, memory and attention deficit, alzheimer's disease, amyotrophic lateral sclerosis (ALS), dysmenorrhoea, hypnolepsy, raynaud's disease, intermittent claudication, this Jaeger logical sequence syndrome, irregular pulse, hypertension, myotonic muscular dystrophy, spasticity, xerostomia disease, type ii diabetes, superelevation insulinemia, premature labor, alopecia, cancer, irritable bowel syndrome, immunosuppression, migraine or pain.

12. each described indazolyl derivative among the claim 1-8 is as medicine.

13. each described indazolyl derivative is used for the treatment of among the claim 1-8, prevention or alleviation comprise the medicine of people's mammiferous disease or illness or illness, described disease, and illness or illness are relevant with activity of potassium channels.

14. treatment, prevention or alleviate the disease of the moving object comprise the people or the method for illness or illness, described disease, illness or illness are replied regulating potassium channel, and described method comprises the indazolyl derivative of this class moving object that comprises the people that these needs are arranged being treated among the claim 1-8 of significant quantity each.