JP2008534472A - Pyrazolyl-pyrimidine and its medical use as potassium channel modulators - Google Patents

Abstract

  The present invention relates to a novel potassium channel modulator of formula I having the definitions of R1-R4, X, Y and n as defined in claim 1 and its use in the preparation of pharmaceutical compositions. The invention further relates to diseases or disorders associated with the activity of potassium channels, in particular respiratory diseases, epilepsy, convulsions, vasospasm, coronary spasm, renal dysfunction, polycystic kidneys, bladder spasms, urinary incontinence, bladder outflow disorders Irritable bowel syndrome, gastrointestinal disorders, secretory diarrhea, ischemia, cerebral ischemia, ischemic heart disease, angina, coronary heart disease, traumatic brain injury, psychosis, schizophrenia, anxiety, Depression, dementia, memory impairment and attention deficit, Alzheimer's disease, dysmenorrhea, narcolepsy, Raynaud's disease, intermittent claudication, Sjogren's syndrome, migraine, arrhythmia, hypertension, absence seizure, myotonic muscle dystrophy, It is aimed at a pharmaceutical composition useful for treating or alleviating xerostomia, type II diabetes, hyperinsulinemia, premature labor, baldness, cancer, immunosuppression or pain.

Description

  The present invention relates to novel potassium channel modulators and their use in the preparation of pharmaceutical compositions.

  The invention further includes diseases or disorders associated with the activity of potassium channels, particularly respiratory diseases, epilepsy, seizures, seizures, absence seizures, vasospasm, coronary spasm, renal dysfunction, polycystic kidneys, bladder spasms, Urinary incontinence, bladder outflow disorder, erectile dysfunction, gastrointestinal disorder, secretory diarrhea, ischemia, cerebral ischemia, ischemic heart disease, angina pectoris, coronary heart disease, ataxia, traumatic brain injury, Parkinson's disease, Bipolar disorder, psychosis, schizophrenia, anxiety, depression, mood disorder, dementia, memory impairment and attention deficit, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dysmenorrhea, narcolepsy, Raynaud Disease, intermittent claudication, Sjogren's syndrome, arrhythmia, hypertension, myotonic muscular dystrophy, spasticity, xerostomia, type II diabetes, hyperinsulinemia, premature labor, baldness, cancer, irritable bowel disease Group, immunosuppression, for the purpose of pharmaceutical compositions useful for the treatment or alleviation of migraine or pain.

  Ion channels are transmembrane proteins that catalyze the transport of inorganic ions across cell membranes. Ion channels are involved in various processes such as action potential generation and timing, synaptic transmission, hormone secretion, muscle contraction and the like.

All mammalian cells express potassium (K ⁺ ) channels in their cell membranes, which channels play a major role in regulating membrane potential. They regulate the frequency and form of action potentials, neurotransmitter release, and the degree of bronchial and vascular dilation in nerve and muscle cells.

From a molecular point of view, the K ⁺ channel represents the largest and most diverse group of ion channels. Overall, these can be divided into five large subfamilies. Voltage-activated K ⁺ channel (K _v ), K ⁺ channel associated with long QT (KvLQT), inward rectification (K _IR ), two-pore K ⁺ channel (K _TP ) and calcium activity The K ⁺ channel (K _ca ).

The latter group, Ca ²⁺ activated K ⁺ channel, consists of three distinct subtypes: SK channel, IK channel and BK channel. SK, IK and BK refer to single channel conductance (small, medium and large conductance K channels). SK, IK and BK channels show differences in, for example, voltage and calcium sensitivity, pharmacology, distribution and function.

  The SK channel is present in many central neurons and ganglia, where its primary function is to follow one or more action potentials in order to prevent long-lasting epileptiogenic activity. Is hyperpolarized. SK channels are also present in several peripheral cells including skeletal muscle, glandular cells, hepatocytes and T-lymphocytes. The importance of SK channels in normal skeletal muscle is not clear, but the number increases significantly in paralyzed muscles, and the number of SK channels in the muscles of patients with myotonic muscular dystrophy is high. Suggests a role in the development of the disease.

Studies have shown that K ⁺ channels are found in asthma, cystic fibrosis, chronic obstructive pulmonary disease and rhinorrhea, convulsions, vasospasm, coronary spasm, renal dysfunction, polycystic kidneys, bladder spasms, urinary incontinence, bladder Outflow disorder, irritable bowel syndrome, gastrointestinal disorder, secretory diarrhea, ischemia, cerebral ischemia, ischemic heart disease, angina, coronary heart disease, traumatic brain injury, psychosis, anxiety, depression , Dementia, memory impairment and attention deficit, Alzheimer's disease, dysmenorrhea, narcolepsy, Raynaud's disease, intermittent claudication, Sjogren's syndrome, migraine, arrhythmia, hypertension, absence seizures, myotonic muscle dystrophy, dry mouth It has been shown to be a therapeutic target in the treatment of a number of diseases including diabetes, type II diabetes, hyperinsulinemia, premature labor, baldness, cancer and immunosuppression.

  US Pat. No. 6,559,307 describes an improved method for preparing substituted pyrimidines. However, the pyrazolyl-pyrimidine derivatives of the present invention are not disclosed and their activity as potassium channel modulators is not proposed at all.

  WO 97/19065 describes substituted 2-anilinopyrimidines useful as protein kinase inhibitors. However, the pyrazolyl-pyrimidine derivatives of the present invention are not disclosed and their activity as potassium channel modulators is not proposed at all.

  WO2001 / 29009 describes 4,5-substituted anilinopyrimidines useful as protein kinase inhibitors. However, the pyrazolyl-pyrimidine derivatives of the present invention are not disclosed and their activity as potassium channel modulators is not proposed at all.

  WO2003 / 075828 describes various compounds useful for the treatment of cancer, including compounds of formula VI, VII and XI. However, the pyrazolyl-pyrimidine derivatives of the present invention are not disclosed and their activity as potassium channel modulators is not proposed at all.

  An object of the present invention is to provide a novel compound capable of selectively modulating a SK channel or a subtype of the SK channel.

  Furthermore, the present invention relates to respiratory diseases, epilepsy, seizures, seizures, absence seizures, vasospasm, coronary spasm, renal dysfunction, polycystic kidneys, bladder spasms, urinary incontinence, bladder outflow disorders, erectile dysfunction, gastrointestinal disorders , Secretory diarrhea, ischemia, cerebral ischemia, ischemic heart disease, angina, coronary heart disease, ataxia, traumatic brain injury, Parkinson's disease, bipolar disorder, psychosis, schizophrenia, anxiety , Depression, mood disorders, dementia, memory impairment and attention deficit, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dysmenorrhea, narcolepsy, Raynaud's disease, intermittent claudication, Sjogren's syndrome, arrhythmia, hypertension Diseases such as dystrophy, myotonic dystrophy, spasticity, xerostomia, type II diabetes, hyperinsulinemia, premature labor, baldness, cancer, irritable bowel syndrome, immunosuppression, migraine or pain or State No, for the purpose of pharmaceutical compositions useful for the treatment or alleviation of diseases or disorders associated with the activity of potassium channels.

（式中、
ｎは０、１、２又は３であり、
ＸはＯ、Ｓ又はＮＲ’を表し、但し、Ｒ’は水素、アルキル、シクロアルキル又はシクロアルキル−アルキルを表すか、又は、ｎが０でありＸがＮＲ’である場合、Ｒ’は、Ｙ及びそれらが結合している窒素と一緒になって複素環を形成しており、その複素環は、アルキル及びフェニルからなる群から選択される１つ若しくは２つの置換基で任意選択で置換されており、
Ｙはアルキル、シクロアルキル、アルキル−シクロアルキル、アミノ−アルキル、アルキル−アミノ、アルキル−アミノ−アルキル、ヒドロキシ−アルキル、アルコキシ−アルキル、アルケニル、フェニル、ベンジル、ナフチル、１，２，３，４−テトラヒドロ−ナフチル、インデニル、１，２−ジヒドロ−インデニル、フラニル、チエニル、ピラニル、テトラヒドロ−ピラン−４−イル、ピリジニル、インドリニル又はキノリニルを表し、そのフェニル、ベンジル、ナフチル、１，２，３，４−テトラヒドロ−ナフチル、インデニル、１，２−ジヒドロ−インデニル、フラニル、チエニル、ピラニル、２，３，５，６−テトラヒドロ−４Ｈ−ピラン−４−イル、ピリジニル、インドリニル及びキノリニル基は、アルキル、アミノ−アルキル、アルキル−アミノ、アルキル−アミノ−アルキル、ヒドロキシ−アルキル、アルコキシ−アルキル、シクロアルキル、シクロアルキル−アルキル、アルケニル、ハロ、ハロアルキル、ヒドロキシ、アルコキシ、メチレンジオキシ、ハロアルコキシ、シアノ、ニトロ、アミノ、フェニル及びモルホリニルからなる群から選択される１つ若しくは複数の置換基で任意選択で置換されていてよいか、又は、ｎが０でありＸがＮＲ’である場合、Ｙは、Ｒ’及びそれらが結合している窒素と一緒になって複素環を形成しており、その複素環は、アルキル及びフェニルからなる群から選択される１つ若しくは２つの置換基で任意選択で置換されており、
Ｒ^１、Ｒ^２、Ｒ^３及びＲ^４は互いに独立に、水素、アルキル、シクロアルキル、シクロアルキル−アルキル、シクロアルキル、シクロアルキル−アルキル、ハロ、ハロアルキル、ヒドロキシ、アルコキシ、アルコキシ−カルボニル、ハロアルコキシ、シアノ、ニトロ及び／又はアミノを表す） Accordingly, in its first aspect, the present invention provides novel pyrazolyl-pyrimidine derivatives of formula I, isomers or mixtures of isomers thereof, N-oxides thereof, prodrugs thereof or pharmaceutically acceptable salts thereof. .

(Where
n is 0, 1, 2 or 3;
X represents O, S or NR ′, where R ′ represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl, or when n is 0 and X is NR ′, R ′ is Together with Y and the nitrogen to which they are attached form a heterocycle, which is optionally substituted with one or two substituents selected from the group consisting of alkyl and phenyl. And
Y is alkyl, cycloalkyl, alkyl-cycloalkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxy-alkyl, alkoxy-alkyl, alkenyl, phenyl, benzyl, naphthyl, 1,2,3,4- Represents tetrahydro-naphthyl, indenyl, 1,2-dihydro-indenyl, furanyl, thienyl, pyranyl, tetrahydro-pyran-4-yl, pyridinyl, indolinyl or quinolinyl, phenyl, benzyl, naphthyl, 1,2,3,4 -Tetrahydro-naphthyl, indenyl, 1,2-dihydro-indenyl, furanyl, thienyl, pyranyl, 2,3,5,6-tetrahydro-4H-pyran-4-yl, pyridinyl, indolinyl and quinolinyl groups are alkyl, amino -Alkyl Alkyl-amino, alkyl-amino-alkyl, hydroxy-alkyl, alkoxy-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, halo, haloalkyl, hydroxy, alkoxy, methylenedioxy, haloalkoxy, cyano, nitro, amino, phenyl And optionally substituted with one or more substituents selected from the group consisting of morpholinyl, or when n is 0 and X is NR ′, Y is R ′ and they are Together with the nitrogen to which it is attached forms a heterocycle, which is optionally substituted with one or two substituents selected from the group consisting of alkyl and phenyl;
R ¹ , R ² , R ³ and R ⁴ are independently of one another hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, cycloalkyl, cycloalkyl-alkyl, halo, haloalkyl, hydroxy, alkoxy, alkoxy-carbonyl, haloalkoxy Represents cyano, nitro and / or amino)

  In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of the present invention.

  In another aspect, the invention relates to the use of a compound of the invention for the manufacture of a medicament for the treatment or alleviation of a disease or disorder associated with the activity of potassium channels, and disorders that respond to modulation of potassium channels Or relates to a method of treatment or alleviation of a condition.

（式中、
ｎは０、１、２又は３であり、
ＸはＯ、Ｓ又はＮＲ’を表し、但し、Ｒ’は水素、アルキル、シクロアルキル又はシクロアルキル−アルキルを表すか、又は、ｎが０でありＸがＮＲ’である場合、Ｒ’は、Ｙ及びそれらが結合している窒素と一緒になって複素環を形成しており、その複素環は、アルキル及びフェニルからなる群から選択される１つ若しくは２つの置換基で任意選択で置換されており、
Ｙはアルキル、シクロアルキル、アルキル−シクロアルキル、アミノ−アルキル、アルキル−アミノ、アルキル−アミノ−アルキル、ヒドロキシ−アルキル、アルコキシ−アルキル、アルケニル、フェニル、ベンジル、ナフチル、１，２，３，４−テトラヒドロ−ナフチル、インデニル、１，２−ジヒドロ−インデニル、フラニル、チエニル、ピラニル、テトラヒドロピラン−４−イル、ピリジニル、インドリニル又はキノリニルを表し、そのフェニル、ベンジル、ナフチル、１，２，３，４−テトラヒドロ−ナフチル、インデニル、１，２−ジヒドロ−インデニル、フラニル、チエニル、ピラニル、２，３，５，６−テトラヒドロ−４Ｈ−ピラン−４−イル、ピリジニル、インドリニル及びキノリニル基は、アルキル、アミノ−アルキル、アルキル−アミノ、アルキル−アミノ−アルキル、ヒドロキシ−アルキル、アルコキシ−アルキル、シクロアルキル、シクロアルキル−アルキル、アルケニル、ハロ、ハロアルキル、ヒドロキシ、アルコキシ、メチレンジオキシ、ハロアルコキシ、シアノ、ニトロ、アミノ、フェニル及びモルホリニルからなる群から選択される１つ若しくは複数の置換基で任意選択で置換されていてよいか、又は、ｎが０でありＸがＮＲ’である場合、Ｙは、Ｒ’及びそれらが結合している窒素と一緒になって複素環を形成しており、その複素環は、アルキル及びフェニルからなる群から選択される１つ若しくは２つの置換基で任意選択で置換されており、
Ｒ^１、Ｒ^２、Ｒ^３及びＲ^４は互いに独立に、水素、アルキル、シクロアルキル、シクロアルキル−アルキル、シクロアルキル、シクロアルキル−アルキル、ハロ、ハロアルキル、ヒドロキシ、アルコキシ、アルコキシ−カルボニル、ハロアルコキシ、シアノ、ニトロ及び／又はアミノを表し、
但し、ピラゾリル−ピリミジン誘導体は
メチル−［２−（３，５−ジメチル−ピラゾール−１−イル）−６−メチル−ピリミジン−４−イル］−アミン；
シクロヘキシル−［２−（３，５−ジメチル−ピラゾール−１−イル）−６−メチル−ピリミジン−４−イル］−アミン；
フェニル−［２−（３，５−ジメチル−ピラゾール−１−イル）−６−メチル−ピリミジン−４−イル］−アミン；
［２−（３，５−ジメチル−ピラゾール−１−イル）−６−メチル−ピリミジン−４−イル］−（４−クロロ−フェニル）−アミン；
［２−（３，５−ジメチル−ピラゾール−１−イル）−６−メチル−ピリミジン−４−イル］−（４−メチル−フェニル）−アミン；
［２−（３，５−ジメチル−ピラゾール−１−イル）−６−メチル−ピリミジン−４−イル］−（４−ｎ−ブチル−フェニル）−アミン；
［２−（３，５−ジメチル−ピラゾール−１−イル）−５−エチル−６−メチル−ピリミジン−４−イル］−（４−ｎ−ブチル−フェニル）−アミン；
［２−（３，５−ジメチル−ピラゾール−１−イル）−６−メチル−ピリミジン−４−イル］−（４−メトキシ−フェニル）−アミン；
［２−（３，５−ジメチル−ピラゾール−１−イル）−６−メチル−ピリミジン−４−イル］−（４−エトキシ−フェニル）−アミン；
［２−（３，５−ジメチル−ピラゾール−１−イル）−６−メチル−ピリミジン−４−イル］−（２−トリフルオロメチル−フェニル）−アミン；
［２−（３，５−ジメチル−ピラゾール−１−イル）−６−メチル−ピリミジン−４−イル］−（３−トリフルオロメチル−フェニル）−アミン；
［２−（３，５−ジメチル−ピラゾール−１−イル）−６−メチル−ピリミジン−４−イル］−（４−エトキシ−フェニル）−アミン；
［２−（３，５−ジメチル−ピラゾール−１−イル）−６−メチル−ピリミジン−４−イル］−（３−トリフルオロメチル−フェニル）−アミン；
フェニル−［２−（３，５−ジメチル−ピラゾール−１−イル）−５−エチル−６−メチル−ピリミジン−４−イル］−アミン；
２−［２−（３，５−ジメチル−ピラゾール−１−イル）−６−メチル−ピリミジン−４−イル−アミノ］−エタノール；
４−シクロヘキシルアミノ−２−（３，５−ジメチル−ピラゾール−１−イル）−ピリミジン−５−カルボン酸エチルエステル；
２−（３，５−ジメチル−ピラゾール−１−イル）−４−メチル−６−（４−メチル−ピペラジン−１−イル）−ピリミジン；
２−（３，５−ジメチル−ピラゾール−１−イル）−４−メチル−６−（４−フェニル−ピペラジン−１−イル）−ピリミジン；
４−［２−（３，５−ジメチル−ピラゾール−１−イル）−６−メチル−ピリミジン−４−イル］−モルホリン；又は
２，４−ビス−（３，５−ジメチル−ピラゾール−１−イル）−６−メチル−ピリミジン
ではない。 Potassium Channel Modulator In its first aspect, the present invention provides a novel pyrazolyl-pyrimidine derivative of formula I, an isomer or a mixture of isomers thereof, an N-oxide thereof, a prodrug thereof or a pharmaceutically acceptable salt thereof. I will provide a.

(Where
n is 0, 1, 2 or 3;
X represents O, S or NR ′, where R ′ represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl, or when n is 0 and X is NR ′, R ′ is Together with Y and the nitrogen to which they are attached form a heterocycle, which is optionally substituted with one or two substituents selected from the group consisting of alkyl and phenyl. And
Y is alkyl, cycloalkyl, alkyl-cycloalkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxy-alkyl, alkoxy-alkyl, alkenyl, phenyl, benzyl, naphthyl, 1,2,3,4- Represents tetrahydro-naphthyl, indenyl, 1,2-dihydro-indenyl, furanyl, thienyl, pyranyl, tetrahydropyran-4-yl, pyridinyl, indolinyl or quinolinyl, phenyl, benzyl, naphthyl, 1,2,3,4- Tetrahydro-naphthyl, indenyl, 1,2-dihydro-indenyl, furanyl, thienyl, pyranyl, 2,3,5,6-tetrahydro-4H-pyran-4-yl, pyridinyl, indolinyl and quinolinyl groups are alkyl, amino- Alkyl, Alkyl-amino, alkyl-amino-alkyl, hydroxy-alkyl, alkoxy-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, halo, haloalkyl, hydroxy, alkoxy, methylenedioxy, haloalkoxy, cyano, nitro, amino, phenyl And optionally substituted with one or more substituents selected from the group consisting of: and morpholinyl, or when n is 0 and X is NR ′, Y is R ′ and they are Together with the attached nitrogen form a heterocycle, which is optionally substituted with one or two substituents selected from the group consisting of alkyl and phenyl;
R ¹ , R ² , R ³ and R ⁴ are independently of one another hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, cycloalkyl, cycloalkyl-alkyl, halo, haloalkyl, hydroxy, alkoxy, alkoxy-carbonyl, haloalkoxy Represents cyano, nitro and / or amino,
Provided that the pyrazolyl-pyrimidine derivative is methyl- [2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -amine;
Cyclohexyl- [2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -amine;
Phenyl- [2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl]-(4-chloro-phenyl) -amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl]-(4-methyl-phenyl) -amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl]-(4-n-butyl-phenyl) -amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -5-ethyl-6-methyl-pyrimidin-4-yl]-(4-n-butyl-phenyl) -amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl]-(4-methoxy-phenyl) -amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl]-(4-ethoxy-phenyl) -amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl]-(2-trifluoromethyl-phenyl) -amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl]-(3-trifluoromethyl-phenyl) -amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl]-(4-ethoxy-phenyl) -amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl]-(3-trifluoromethyl-phenyl) -amine;
Phenyl- [2- (3,5-dimethyl-pyrazol-1-yl) -5-ethyl-6-methyl-pyrimidin-4-yl] -amine;
2- [2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl-amino] -ethanol;
4-cyclohexylamino-2- (3,5-dimethyl-pyrazol-1-yl) -pyrimidine-5-carboxylic acid ethyl ester;
2- (3,5-dimethyl-pyrazol-1-yl) -4-methyl-6- (4-methyl-piperazin-1-yl) -pyrimidine;
2- (3,5-dimethyl-pyrazol-1-yl) -4-methyl-6- (4-phenyl-piperazin-1-yl) -pyrimidine;
4- [2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -morpholine; or 2,4-bis- (3,5-dimethyl-pyrazol-1- Yl) -6-methyl-pyrimidine.

In a preferred embodiment, the pyrazolyl-pyrimidine derivative of the present invention is
n is 0, 1, 2 or 3,
X represents O, S or NR ′, wherein R ′ represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl, or when n is 0, R ′ is Y and they are bonded. Together with nitrogen to form a heterocycle,
Y represents alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxy-alkyl, alkoxy-alkyl, alkenyl or a monocyclic or polycyclic carbocyclic or heterocyclic group, and the carbocyclic or heterocyclic ring The groups are alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxy-alkyl, alkoxy-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, Optionally substituted with one or more substituents selected from the group consisting of nitro and amino, or when n is 0, Y is R ′ and the nitrogen to which they are attached. Together with it to form a heterocycle,
R ¹ , R ² and R ³ are independently of each other hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, nitro and A compound of formula I representing amino, wherein R ⁴ represents hydrogen.

  In other preferred embodiments, the pyrazolyl-pyrimidine derivatives of the present invention are compounds of formula I, wherein n is 0, 1, 2, or 3.

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

  In a further preferred embodiment, n is 0.

  In a third preferred embodiment, the pyrazolyl-pyrimidine derivatives of the present invention are such that X represents O, S or NR ′, wherein R ′ represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl, or When n is 0 and X is NR ′, R ′ is taken together with Y and the nitrogen to which they are attached to form a heterocycle, the heterocycle comprising the group consisting of alkyl and phenyl A compound of formula I optionally substituted with one or two substituents selected from

  In a more preferred embodiment, X represents O, S or NR ′, wherein R ′ represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl, or n is 0 and X is NR ′. In some cases, R ′ is taken together with Y and the nitrogen to which they are attached to form a heterocycle.

In a fourth preferred embodiment, the pyrazolyl-pyrimidine derivative of the present invention is
Compounds of formula I in which X represents O, S or NR ′, wherein R ′ represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl.

  In a more preferred embodiment, X represents NR ', where R' represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl.

  In a further preferred embodiment, X represents NR ', where R' represents hydrogen or alkyl, in particular methyl or ethyl.

  In a further preferred embodiment, X represents NR ', where R' represents hydrogen, methyl or ethyl.

  In a further preferred embodiment, X represents NR 'where R' represents hydrogen.

  In a further preferred embodiment, X represents NR 'where R' represents methyl or ethyl.

In a fifth preferred embodiment, the pyrazolyl-pyrimidine derivative of the present invention is
n is 0,
X is NR ′, wherein R ′ together with Y and the nitrogen to which they are attached form a heterocycle, in particular pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or pyrazolyl, which heterocycle is A compound of formula I optionally substituted with one or two substituents selected from the group consisting of alkyl and phenyl.

In a more preferred embodiment,
n is 0,
X represents NR ', provided that R' together with Y and the nitrogen to which they are attached form a pyrrolidinyl or piperidinyl ring.

In a further preferred embodiment,
n is 0,
X is NR ′, wherein R ′, together with Y and the nitrogen to which they are attached, forms a piperidinyl, piperazinyl or pyrazolyl ring, the heterocyclic ring being a group consisting of alkyl and phenyl Optionally substituted with one or two substituents selected from

In a further preferred embodiment,
n is 0,
X is NR ′, where R ′ together with Y and the nitrogen to which they are attached piperidinyl, 4-methyl-piperidinyl, piperazinyl, 4-phenylpiperazinyl, pyrazolyl or 3,5- A dimethyl-pyrazolyl ring is formed.

In a further preferred embodiment,
n is 0,
X is NR ′, wherein R ′, together with Y and the nitrogen to which they are attached, forms a 4-methyl-piperidinyl, 4-phenyl-piperazinyl or 3,5-dimethylpyrazolyl ring. Yes.

In a sixth preferred embodiment, the pyrazolyl-pyrimidine derivative of the present invention is
Y is alkyl, cycloalkyl, alkylcycloalkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxy-alkyl, alkoxy-alkyl, alkenyl, phenyl, benzyl, naphthyl, 1,2,3,4 tetrahydro- Represents naphthyl, indenyl, 1,2-dihydroindenyl, furanyl, thienyl, pyranyl, tetrahydro-pyran-4-yl, pyridinyl, indolinyl or quinolinyl, its phenyl, benzyl, naphthyl, 1,2,3,4-tetrahydro -Naphthyl, indenyl, 1,2-dihydroindenyl, furanyl, thienyl, pyranyl, 2,3,5,6 tetrahydro-4H-pyran-4-yl, pyridinyl, indolinyl and quinolinyl groups are alkyl, amino-alkyl, Alkyl From amino, alkylamino-alkyl, hydroxy-alkyl, alkoxy-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, halo, haloalkyl, hydroxy, alkoxy, methylenedioxy, haloalkoxy, cyano, nitro, amino, phenyl and morpholinyl A compound of formula I which is optionally substituted with one or more substituents selected from the group consisting of:

In a seventh preferred embodiment, the pyrazolyl-pyrimidine derivative of the present invention is
Y represents alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxy-alkyl, alkoxy-alkyl, alkenyl, or a monocyclic or polycyclic carbocyclic or heterocyclic group, and the carbocyclic or heterocyclic ring The groups are alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxy-alkyl, alkoxy-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, Optionally substituted with one or more substituents selected from the group consisting of nitro and amino, or when n is 0 and X is NR ′, Y is R ′ and Together with the nitrogen to which they are attached forms a heterocyclic ring It is a compound of I.

  In a more preferred embodiment Y is alkyl, especially methyl, ethyl, propyl, butyl or pentyl; cycloalkyl, especially cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; alkyl-cycloalkyl, especially methyl-cyclohexyl or t- Butyl-cyclohexyl; hydroxy-alkyl, in particular hydroxyl-methyl, 2-hydroxy-ethyl or 3-hydroxy-propyl; alkenyl, in particular propenyl; phenyl, benzyl or naphthyl, the phenyl, benzyl and naphthyl groups being alkyl, One or two substituents selected from the group consisting of in particular methyl; halo, in particular fluoro, chloro, bromo or iodo; haloalkyl, in particular trifluoromethyl; and alkoxy, in particular methoxy. It may optionally be substituted.

  In more preferred embodiments, Y is methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methylcyclohexyl, t-butyl-cyclohexyl, hydroxyl-methyl, 2-hydroxy-ethyl, Represents 3-hydroxy-propyl, phenyl, benzyl or naphthyl, wherein the phenyl, benzyl and naphthyl groups are optionally one or two substituents selected from the group consisting of methyl, fluoro, chloro, trifluoromethyl and methoxy May be replaced by selection.

  In a further preferred embodiment Y represents alkyl, alkenyl or cycloalkyl.

  In a further preferred embodiment Y represents phenyl, benzyl or naphthyl, wherein the phenyl, benzyl and naphthyl groups are one or two substitutions selected from the group consisting of methyl, fluoro, chloro, trifluoromethyl and methoxy It may be optionally substituted with a group.

  In a further preferred embodiment Y represents phenyl or benzyl, wherein the phenyl and benzyl groups are optionally one or two substituents selected from the group consisting of methyl, fluoro, chloro, trifluoromethyl and methoxy. May be substituted.

  In a further preferred embodiment, Y represents naphthyl.

  In a further preferred embodiment, Y is a monocyclic or polycyclic carbocyclic group selected from phenyl, naphthyl or 1,2,3,4-tetrahydronaphthyl; a single group selected from pyrrolidinyl, piperidinyl, furanyl, thienyl and pyrrolyl. Represents a cyclic or polycyclic heterocyclic group, the phenyl, naphthyl, 1,2,3,4 tetrahydronaphthyl, pyrrolidinyl, piperidinyl, furanyl, thienyl and pyrrolyl groups are alkyl, amino-alkyl, alkyl-amino, alkyl- One or more selected from the group consisting of amino-alkyl, hydroxy-alkyl, alkoxy-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, nitro and amino Substituent It may optionally be substituted.

In an eighth preferred embodiment, the pyrazolyl-pyrimidine derivative of the present invention is
R ¹ , R ² , R ³ and R ⁴ are independently of each other hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, cycloalkyl, cycloalkylalkyl, halo, haloalkyl, hydroxy, alkoxy, alkoxy-carbonyl, haloalkoxy, Compounds of formula I representing cyano, nitro and / or amino.

In a more preferred embodiment,
R ¹ and R ² independently of one another represent hydrogen or alkyl, in particular methyl, ethyl or propyl,
R ³ and R ⁴ are independently of each other hydrogen; alkyl, in particular methyl, ethyl or propyl; halo, in particular fluoro, chloro, bromo or iodo; haloalkyl, in particular trifluoromethyl; alkoxy-carbonyl, in particular methoxy-carbonyl or ethoxy- Carbonyl; and / or cyano.

In a further preferred embodiment,
R ¹ and R ² independently of one another represent alkyl, in particular methyl, ethyl or propyl,
R ³ and R ⁴ are independently of each other hydrogen; alkyl, in particular methyl, ethyl or propyl; halo, in particular fluoro, chloro, bromo or iodo; haloalkyl, in particular trifluoromethyl; alkoxy-carbonyl, in particular methoxy-carbonyl or ethoxy- Represents carbonyl and / or cyano.

In a further preferred embodiment,
R ¹ and R ² independently of one another represent methyl, ethyl or propyl;
R ³ and R ⁴ are independently of each other hydrogen; alkyl, in particular methyl, ethyl or propyl; halo, in particular fluoro, chloro, bromo or iodo; haloalkyl, in particular trifluoromethyl; alkoxy-carbonyl, in particular methoxy-carbonyl or ethoxy- Represents carbonyl and / or cyano.

In a further preferred embodiment,
R ¹ and R ² represent methyl,
R ³ and R ⁴ are independently of each other hydrogen; alkyl, in particular methyl, ethyl or propyl; halo, in particular fluoro, chloro, bromo or iodo; haloalkyl, in particular trifluoromethyl; alkoxy-carbonyl, in particular methoxy-carbonyl or ethoxy- Carbonyl; and / or cyano.

In a further preferred embodiment,
R ¹ and R ² represent methyl,
R ³ represents hydrogen or alkyl, in particular methyl, ethyl or propyl,
R ⁴ represents hydrogen; alkyl, in particular methyl, ethyl or propyl; halo, in particular fluoro, chloro, bromo or iodo; alkoxy-carbonyl, in particular methoxy-carbonyl or ethoxy-carbonyl; and / or cyano.

In a further preferred embodiment,
R ¹ and R ² represent methyl,
R ³ represents hydrogen, methyl, ethyl or propyl;
R ⁴ represents hydrogen, methyl, ethyl, propyl, chloro, bromo, ethoxycarbonyl and / or cyano.

In a ninth preferred embodiment, the pyrazolyl-pyrimidine derivative of the present invention is
R ¹ , R ² and R ³ are independently of each other hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, nitro and A compound of formula I representing amino, wherein R ⁴ represents hydrogen.

In a more preferred embodiment, R ¹ , R ² and R ³ independently of one another represent alkyl, cycloalkyl or cycloalkyl-alkyl and R ⁴ represents hydrogen.

In a tenth preferred embodiment, the pyrazolyl-pyrimidine derivative of the present invention comprises
n is 0,
X is NH,
Y is alkyl, especially methyl, ethyl, propyl, butyl or pentyl; cycloalkyl, especially cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; alkyl-cycloalkyl, especially methyl-cyclohexyl or t-butyl-cyclohexyl; hydroxy- Alkyl, in particular hydroxyl-methyl, 2-hydroxy-ethyl or 3-hydroxy-propyl; represents phenyl, benzyl or naphthyl;
R ¹ and R ² represent methyl,
R ³ represents hydrogen, methyl, ethyl or propyl;
Compounds of formula I wherein R ⁴ represents hydrogen, methyl, ethyl, propyl, chloro, bromo, ethoxycarbonyl and / or cyano.

In an eleventh preferred embodiment, the pyrazolyl-pyrimidine derivative of the present invention is
n is 0,
X represents NR ′, wherein R ′ is hydrogen, methyl, ethyl or propyl;
Y represents alkyl, cycloalkyl, cycloalkyl-alkyl, or alkenyl, piperidinyl or phenyl, which phenyl may be optionally substituted with one or two of halo or trifluoromethyl;
Compounds of formula I wherein R ¹ , R ² and R ³ independently of one another represent methyl, ethyl or propyl and R ⁴ represents hydrogen.

In a twelfth preferred embodiment, the pyrazolyl-pyrimidine derivative of the present invention is
n is 0,
X represents NR ′, wherein R ′, together with Y and the nitrogen to which they are attached, forms a pyrrolidinyl or piperidinyl ring;
Compounds of formula I wherein R ¹ , R ² and R ³ independently of one another represent methyl, ethyl or propyl and R ⁴ represents hydrogen.

In a thirteenth preferred embodiment, the pyrazolyl-pyrimidine derivative of the present invention is
n is 1,
X represents NR ′, wherein R ′ is hydrogen, methyl, ethyl or propyl;
Y represents furanyl, thienyl or phenyl, which phenyl is optionally substituted with one or two of halo or trifluoromethyl;
Compounds of formula I wherein R ¹ , R ² and R ³ independently of one another represent methyl, ethyl or propyl and R ⁴ represents hydrogen.

In a fourteenth preferred embodiment, the pyrazolyl-pyrimidine derivative of the present invention is
n is 0,
X is NH,
Y represents phenyl or benzyl, the phenyl and benzyl groups being selected from the group consisting of alkyl, in particular methyl; halo, in particular fluoro, chloro, bromo or iodo; haloalkyl, in particular trifluoromethyl and alkoxy, in particular methoxy. Optionally substituted with one or two substituents,
R ¹ and R ² represent methyl,
R ³ represents hydrogen, methyl, ethyl or propyl;
Compounds of formula I in which R ⁴ represents hydrogen, methyl, ethyl, propyl, chloro, bromo, ethoxycarbonyl or cyano.

In a more preferred embodiment,
n is 0,
X is NH,
Y represents phenyl or benzyl, wherein the phenyl and benzyl groups may be optionally substituted with one or two substituents selected from the group consisting of methyl, chloro, trifluoromethyl and methoxy;
R ¹ and R ² represent methyl, R ³ represents hydrogen, methyl, ethyl or propyl,
R ⁴ represents hydrogen, methyl, ethyl, propyl, chloro, bromo, ethoxycarbonyl or cyano.

In a most preferred embodiment, the pyrazolyl-pyrimidine derivative of the present invention is
Benzyl- [2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -amine;
Cyclopentyl- [2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -diethyl-amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -phenyl-amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -p-tolyl-amine;
(3,4-dichloro-phenyl)-[2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -naphthalen-2-yl-amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -pyrimidin-4-yl]-(3-trifluoromethyl-phenyl) -amine;
Cyclohexyl- [2- (3,5-dimethyl-pyrazol-1-yl) -pyrimidin-4-yl] -amine;
[5-chloro-2- (3,5-dimethyl-pyrazol-1-yl) -pyrimidin-4-yl] -cyclohexyl-amine;
(4-chloro-phenyl)-[2- (3,5-dimethyl-pyrazol-1-yl) -pyrimidin-4-yl] -amine;
[5-bromo-2- (3,5-dimethyl-pyrazol-1-yl) -pyrimidin-4-yl]-(4-chloro-phenyl) -amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -pyrimidin-4-yl] -p-tolyl-amine;
(4-chloro-phenyl)-[2- (3,5-dimethyl-pyrazol-1-yl) -5-methyl-pyrimidin-4-yl] -amine;
[5-bromo-2- (3,5-dimethyl-pyrazol-1-yl) -pyrimidin-4-yl] -cyclohexyl-amine; or [5-chloro-2- (3,5-dimethyl-pyrazole-1 -Yl) -pyrimidin-4-yl]-(4-chloro-phenyl) -amine;
Or a pharmaceutically acceptable salt thereof.

  Any combination of two or more of the embodiments described herein is intended to be within the scope of the present invention.

Definition of Substituents In the context of this invention halo represents fluoro, chloro, bromo or iodo. Thus, a trihalomethyl group represents, for example, a trifluoromethyl group, a trichloromethyl group, and similar trihalo-substituted methyl groups.

  In the context of this invention a haloalkyl group represents an alkyl group as defined herein, which alkyl group is substituted with one or more halo. Preferred haloalkyl groups of the present invention include trihalomethyl, preferably trifluoromethyl.

In the context of the present invention, an alkyl group represents a monovalent saturated linear or branched monovalent hydrocarbon chain. The hydrocarbon chain preferably comprises 1 to 18 carbon atoms (C _1-18 -alkyl), more preferably 5 to 6 carbon atoms (including pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl and isohexyl). C _1-6 -alkyl; lower alkyl). In a preferred embodiment, alkyl represents a C _1-4 -alkyl group including butyl, isobutyl, sec-butyl and tert-butyl. In a preferred embodiment of the invention, alkyl represents a C _1-3 -alkyl group and may specifically be methyl, ethyl, propyl or isopropyl.

  In the context of the present invention, a hydroxy-alkyl group represents an alkyl group as defined above, which hydroxy-alkyl group is substituted with one or more hydroxy groups. Examples of preferred hydroxy-alkyl groups of the present invention include 2-hydroxy-ethyl, 3-hydroxy-propyl, 4-hydroxy-butyl, 5-hydroxy-pentyl and 6-hydroxyhexyl.

In the context of this invention an alkenyl group represents a carbon chain containing one or more double bonds including di-enes, tri-enes and poly-enes. In a preferred embodiment, the alkenyl groups of the present invention have 2 to 8 carbon atoms (C _2-8 -alkenyl), more preferably 2 to 6 carbon atoms (C ₂ -C), containing at least one double bond _{. 6} -alkenyl). In the most preferred embodiments, the alkenyl groups of the present invention are ethenyl; 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 1,3,5-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 groups are 3 to 10 carbon atoms (C _3-10 -cycloalkyl) including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, preferably 3-8. Represents a cyclic alkyl group preferably containing 1 carbon atom (C _3-8 -cycloalkyl).

  In the context of the present invention, a cycloalkyl-alkyl group represents a cycloalkyl group as defined above, which cycloalkyl group is substituted on an alkyl group as also defined above. Examples of preferred cycloalkyl-alkyl groups of the present invention include cyclopropylmethyl and cyclopropylethyl.

  In the context of this invention an alkoxy group designates an “alkyl-O—” group, wherein alkyl is as defined above.

  In the context of this invention a haloalkoxy group represents an alkoxy group as defined herein, which alkoxy group is substituted with one or more halo. Preferred haloalkoxy groups of the present invention include trihalomethoxy, preferably trifluoromethoxy.

In the context of the present invention, the amino group may be a primary (—NH ₂ ), secondary (—NH-alkyl), or tertiary (—N (alkyl) ₂ ) amino group, ie one or It may be substituted with two alkyl groups as defined above.

  In the context of the present invention, a monocyclic or polycyclic carbocyclic group represents a monocyclic or polycyclic hydrocarbon group, which is specifically an aromatic hydrocarbon group, ie a monocyclic or polycyclic hydrocarbon group. It may be an aryl group, or a saturated or partially saturated hydrocarbon group. Preferred polycarbocyclic groups are bicyclic carbocyclic groups.

  In the context of the present invention, a monocyclic or polycyclic carbocyclic group represents a monocyclic or polycyclic hydrocarbon group. Examples of preferred carbocyclic groups of the present invention include cycloalkyl, phenyl, naphthyl, indenyl, azulenyl, anthracenyl and fluorenyl. The most preferred carbocyclic groups of the present invention include phenyl, naphthyl and 1,2,3,4 tetrahydro-naphthyl.

  In the context of this invention a monocyclic or polycyclic heterocyclic group represents a monocyclic or polycyclic group in which the group carries one or more heteroatoms in the ring structure. Preferred heteroatoms include nitrogen (N), oxygen (O) and sulfur (S). One or more of the ring structures are in particular aromatic (ie heteroaryl) and may be saturated or partially saturated. Preferred heteromonocyclic groups of the present invention include 5- and 6-membered heteromonocyclic groups. Preferred polyheterocyclic groups of the present invention are bicyclic heterocyclic groups.

  Examples of preferred heteromonocyclic groups of the invention include pyrrolidinyl, especially pyrrolidin-1-yl, pyrrolidin-2-yl and pyrrolidin-3-yl; piperidinyl, especially piperidin-1-yl, piperidin-2-yl, Piperidin-3-yl and piperidin-4-yl; furanyl, especially furan-2-yl and furan-3-yl; thienyl, especially thien-2-yl and thien-3-yl and pyrrolyl, especially pyrrol-1-yl Pyrrol-2-yl and pyrrol-3-yl.

Isomers One skilled in the art will appreciate that the compounds of the invention can exist in various stereoisomers, including enantiomers, diastereomers, and geometric isomers (cis-tothans isomers). The present invention includes all such isomers and any mixtures thereof including racemic mixtures.

  Racemates can be resolved into optical antipodes by known methods or techniques. One method for separating enantiomeric compounds (including enantiomeric intermediates) is to use an optically active amine and treat with acid to produce diastereomeric resolved salts. Another method of resolving racemates into optical enantiomers is by chromatography on an optically active matrix. Thus, the racemic compounds of the invention can be resolved into their optical enantiomers, for example by fractional crystallization of D- or L- (tartrate, mandelate or camphorsulfonate) salts.

  The compounds of the invention are optically derived from compounds of the invention and those derived from (+) or (−) phenylalanine, (+) or (−) phenylglycine, (+) or (−) camphanic acid. Resolution either by formation of diastereomeric amides by reaction of active activated carboxylic acids or by formation of diastereomeric amides by reaction of compounds of the invention with optically active chloroformates or analogues. Can do.

  Other methods for resolving optical isomers are well known in the art. Such methods are described in “Enantiomers, Racemates, and Resolutions” by Johns J, Collet A, & Wilen S, John Wiley and Sons, New York (1981). Etc. are included.

  Optical active compounds can also be prepared from optical active starting materials or intermediates.

Pharmaceutically acceptable salts The compounds of the invention can be provided in any form suitable for the desired administration. Suitable forms include pharmaceutically (ie physiologically) acceptable pre- or prodrugs of the compounds of the invention.

  Examples of pharmaceutically acceptable addition salts include, but are not limited to, hydrochloride derived from hydrochloric acid, hydrobromide derived from hydrogen bromide, nitrate derived from nitric acid, derived from perchloric acid. Perchlorate, phosphate derived from phosphoric acid, sulfate derived from sulfuric acid, formate derived from formic acid, acetate derived from acetic acid, aconitate derived from aconitic acid , Ascorbate derived from ascorbic acid, benzenesulfonate derived from benzenesulfonic acid, benzoate derived from benzoic acid, cinnamic acid derived from cinnamic acid, citric acid derived from citric acid Acid salt, embonate derived from embonic acid, enanthate derived from enanthic acid, fumarate derived from fumaric acid, glutamic acid derived from glutamic acid Tamates, glycolates derived from glycolic acid, lactates derived from lactic acid, maleates derived from maleic acid, malonates derived from malonic acid, mandelic acids derived from mandelic acid Salts, methanesulfonates derived from methanesulfonic acid, naphthalene-2-sulfonates derived from naphthalene-2-sulfonic acid, phthalates derived from phthalic acid, salicylates derived from salicylic acid, Sorbates derived from sorbic acid, stearates derived from stearic acid, succinates derived from succinic acid, tartaric acid derived from tartaric acid, salts derived from p-toluenesulfonic acid, etc. Non-toxic inorganic and organic acid addition salts are included. Such salts can be generated by the described procedures well known in the art.

  Other acids such as oxalic acid, which are considered pharmaceutically acceptable, are useful in the preparation of salts useful as intermediates to obtain the compounds of the invention and pharmaceutically acceptable acid addition salts thereof.

  The metal salt of the compound of the present invention includes an alkali metal salt such as a sodium salt of the compound of the present invention containing a carboxy group.

  In the context of the present invention, “onium salts” of N-containing compounds are also considered as pharmaceutically acceptable salts. Preferred “onium salts” include alkyl-onium salts, cycloalkyl-onium salts, and cycloalkylalkyl-onium salts.

  The compounds of the present invention can be provided in dissolved or undissolved form together with pharmaceutically acceptable solvents such as water, ethanol and the like. The dissolved forms also include hydrate forms such as monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate and the like. In general, for the purposes of the present invention, the dissolved form is considered equivalent to the undissolved form.

Methods of Preparation The compounds of the present invention can be prepared by conventional methods of chemical synthesis, such as those described in the Examples. The starting materials for the methods described in this application are either known or can be readily prepared by conventional methods of commercially available chemicals.

  The end product of the reactions described herein can be isolated by conventional techniques such as extraction, crystallization, distillation, chromatography, and the like.

Biological Activity The compounds of the present invention were subjected to in vitro experiments and found to be particularly useful as potassium channel modulators. More specifically, the compounds of the present invention can selectively modulate SK1, SK2 and / or SK3 channels.

  Accordingly, in another aspect, the invention relates to the use of a compound of the invention for the manufacture of a medicament, wherein the medicament comprises an activity such as a potassium channel, specifically a SK channel, more specifically SK1, SK2 and Useful for the treatment or alleviation of diseases or disorders associated with the activity of SK3 channels.

  In a preferred embodiment, the disease or disorder associated with potassium channel activity is respiratory disease, epilepsy, seizures, seizures, absence seizures, vasospasm, coronary spasm, renal dysfunction, polycystic kidneys, bladder spasms, Urinary incontinence, bladder outflow disorder, erectile dysfunction, gastrointestinal disorder, secretory diarrhea, ischemia, cerebral ischemia, ischemic heart disease, angina pectoris, coronary heart disease, ataxia, traumatic brain injury, Parkinson's disease, Bipolar disorder, psychosis, schizophrenia, anxiety, depression, mood disorder, dementia, memory impairment and attention deficit, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dysmenorrhea, narcolepsy, Raynaud Disease, intermittent claudication, Sjogren's syndrome, arrhythmia, hypertension, myotonic muscular dystrophy, spasticity, xerostomia, type II diabetes, hyperinsulinemia, premature labor, baldness, cancer, hypersensitivity Syndrome, immune suppression, migraine or pain.

  In a more preferred embodiment, the disease or disorder associated with the activity of potassium channels is respiratory disease, urinary incontinence, erectile dysfunction, anxiety, epilepsy, psychosis, schizophrenia, amyotrophic lateral sclerosis (ALS). ) Or pain.

  In another preferred embodiment, the disease or disorder associated with potassium channel activity is a respiratory disease, particularly asthma, cystic fibrosis, rhinorrhea such as chronic obstructive pulmonary disease (COPD).

  In a third preferred embodiment, the disease or disorder associated with potassium channel activity is urinary incontinence.

  In a fourth preferred embodiment, the disease or disorder associated with potassium channel activity is epilepsy, seizures, absence seizures or convulsions.

  In a fifth preferred embodiment, the disease or disorder associated with potassium channel activity is a respiratory disease, particularly asthma, cystic fibrosis, chronic obstructive pulmonary disease (COPD) or rhinorrhea.

  All tested compounds showed biological activity in the micromolar and sub-micromolar range, ie, less than 1 to about 100 μM. Preferred compounds of the present invention exhibit biological activity in the micromolar and sub-micromolar range, i.e., in the range of less than 1 to about 10 [mu] M, as measured herein.

Pharmaceutical Compositions In yet another aspect, the present invention provides novel pharmaceutical compositions comprising a therapeutically effective amount of a compound of the present invention, including the following compounds:
Benzyl- [2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -amine;
Cyclopentyl- [2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -diethyl-amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -phenyl-amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -p-tolyl-amine;
(3,4-dichloro-phenyl)-[2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -naphthalen-2-yl-amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -pyrimidin-4-yl]-(3-trifluoromethyl-phenyl) -amine;
Cyclohexyl- [2- (3,5-dimethyl-pyrazol-1-yl) -pyrimidin-4-yl] -amine;
[5-chloro-2- (3,5-dimethyl-pyrazol-1-yl) -pyrimidin-4-yl] -cyclohexyl-amine;
(4-chloro-phenyl)-[2- (3,5-dimethyl-pyrazol-1-yl) -pyrimidin-4-yl] -amine;
[5-bromo-2- (3,5-dimethyl-pyrazol-1-yl) -pyrimidin-4-yl]-(4-chloro-phenyl) -amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -pyrimidin-4-yl] -p-tolyl-amine;
(4-chloro-phenyl)-[2- (3,5-dimethyl-pyrazol-1-yl) -5-methyl-pyrimidin-4-yl] -amine;
[5-bromo-2- (3,5-dimethyl-pyrazol-1-yl) -pyrimidin-4-yl] -cyclohexyl-amine;
[5-chloro-2- (3,5-dimethyl-pyrazol-1-yl) -pyrimidin-4-yl]-(4-chloro-phenyl) -amine;
Methyl- [2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -amine;
Cyclohexyl- [2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -amine;
Phenyl- [2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl]-(4-chloro-phenyl) -amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl]-(4-methyl-phenyl) -amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl]-(4-n-butyl-phenyl) -amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -5-ethyl-6-methyl-pyrimidin-4-yl]-(4-n-butyl-phenyl) -amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl]-(4-methoxy-phenyl) -amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl]-(4-ethoxy-phenyl) -amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl]-(2-trifluoromethyl-phenyl) -amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl]-(3-trifluoromethyl-phenyl) -amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl]-(4-ethoxy-phenyl) -amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl]-(3-trifluoromethyl-phenyl) -amine;
Phenyl- [2- (3,5-dimethyl-pyrazol-1-yl) -5-ethyl-6-methyl-pyrimidin-4-yl] -amine;
2- [2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl-amino] -ethanol;
4-cyclohexylamino-2- (3,5-dimethyl-pyrazol-1-yl) -pyrimidine-5-carboxylic acid ethyl ester;
2- (3,5-dimethyl-pyrazol-1-yl) -4methyl-6- (4-methyl-piperidin-1-yl) -pyrimidine;
2- (3,5-dimethyl-pyrazol-1-yl) -4-methyl-6- (4-phenyl-piperazin-1-yl) -pyrimidine;
4- [2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -morpholine; and 2,4-bis- (3,5-dimethyl-pyrazol-1- Yl) -6-methyl-pyrimidine.

  In a preferred embodiment, the pharmaceutical composition of the invention comprises a therapeutically effective amount of the above pyrazolyl-pyrimidine derivative or a pharmaceutically acceptable addition salt thereof together with at least one pharmaceutically acceptable carrier or diluent. .

  The compounds of the present invention for use in therapy may be administered as is in the form of the compound, but may be optionally combined with one or more adjuvants, excipients, carriers and / or diluents in the pharmaceutical composition. It is preferred to introduce the active ingredient in the form of a physiologically acceptable salt, optionally in the form of a prodrug.

  Thus, in a preferred embodiment, the invention is acceptable as a compound or drug of the invention in combination with one or more pharmaceutically acceptable carriers and optionally other therapeutic and / or prophylactic ingredients. A pharmaceutical composition comprising the salt or derivative thereof. The carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the recipient thereof.

  The pharmaceutical composition of the present invention is oral, rectal, transbronchial, nasal, topical (including buccal and sublingual), transdermal, vaginal or parenteral (skin, subcutaneous, intramuscular, intraperitoneal, intravenous Suitable for administration (including internal, intraarterial, intracerebral, intraocular injection or infusion) or in a form suitable for administration by inhalation or gas infusion, including powder and liquid aerosol administration, or sustained release systems It may be. Suitable examples of sustained release systems include solid hydrophobic polymer semipermeable matrices containing the compounds of the present invention. The matrix may be in the form of a shaped article, for example a film or a microcapsule.

  Thus, the compounds of the present invention may be placed in pharmaceutical compositions and their unit doses together with conventional adjuvants, carriers or diluents. In such forms, these are all for oral use, but in the form of solids, especially tablets, filled capsules, powders and pellets, and liquids, especially aqueous or non-aqueous solutions, suspensions, emulsions, elixirs and the like. Capsules, suppositories for rectal administration, and sterile injectable solutions for parenteral use. Such pharmaceutical compositions and unit dosage forms thereof may contain the usual ingredients in the usual proportions with or without additional active compounds or components, the unit dosage form being Any suitable active ingredient corresponding to the daily dosage range can be included in an effective amount.

  The compounds of the present invention can be administered in a wide range of oral and parenteral dosage forms. It will be apparent to those skilled in the art that the following dosage forms may contain as an active ingredient a compound of the invention or a pharmaceutically acceptable salt of a compound of the invention.

  For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, dispersible granules. A solid carrier is one or more substances that can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablets, disintegrants or encapsulating materials. Good.

  In powders, the carrier is a finely divided solid, which is a mixture with the finely divided active component.

  In tablets, the active ingredient is mixed in a suitable proportion with a carrier having the necessary binding ability and compressed to the desired shape and size.

  Powders and tablets preferably contain 5 or 10% to 70% of active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxytylcellulose, a low melting wax, cocoa butter, and the like. The term “formulation” is intended to include the formulation of the active compound with the encapsulating material as a carrier to provide the capsule. Within the capsule, the active ingredient is surrounded by the carrier, with or without a carrier, so that the carrier will be used in combination with the active ingredient. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.

  For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, with stirring. The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and solidify.

  Compositions suitable for vaginal administration may be provided as pessaries, tampons, creams, gels, pastes, foams or sprays that contain, in addition to the active ingredient, carriers acceptable in the art. it can.

  Liquid preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.

  Thus, the compounds according to the invention can be formulated for parenteral administration (eg injection, eg bolus injection or continuous infusion) and can be ampoules, prefilled syringes, small volume infusions or multiple doses with preservatives It can be provided in unit dosage form in a container. The composition can take the form of a suspension, solution or emulsion in an oily or aqueous medium and can contain formulations such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient is obtained by aseptic isolation of sterile solids or by lyophilization from solution, powder for reconstitution with a suitable medium, such as sterile pyrogen-free water, before use It may be.

  Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired.

  Aqueous suspensions suitable for oral use can be refined using viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxytylcellulose, or other well-known suspending agents. The active ingredient can be prepared by dispersing in water.

  Also included are solid dosage forms for conversion to liquid dosage forms for oral administration immediately prior to use. Liquid forms include solutions, suspensions and emulsions. These preparations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers and the like.

  For topical administration to the epidermis the compounds according to the invention can be formulated as ointments, creams or lotions, or as a skin patch. Ointments and creams can be formulated, for example, using an aqueous or oily base with the addition of suitable thickening and / or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. .

  Compositions suitable for topical administration in the mouth include lozenges containing the active ingredient in flavored bases, generally sucrose and acacia or tragacanth; active ingredients in inert bases such as gelatin and glycerin or sucrose and acacia And gargles containing the active agent in a suitable liquid carrier.

  Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The composition can be provided in a single dose or multiple doses.

  For administration to the respiratory tract, the active ingredient is pressurized with a suitable propellant such as a chlorofluorocarbon (CFC) such as dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide or other suitable gas. It can also be carried out by means of an aerosol formulation provided in a pack. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of the drug can be controlled by providing a metering valve.

  Alternatively, the active ingredient can be provided in the form of a powder mix of the compound in a dry powder such as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose and a suitable powder base such as polyvinylpyrrolidone (PVP). Conveniently the powder carrier will form a gel in the nasal cavity. The powder composition can be provided in a unit dose form, for example in a capsule or cartridge made of gelatin, for example, or a blister pack from which the powder can be administered by inhaler.

  In compositions for administration to the respiratory tract, including nasal compositions, the compound typically has a small particle size, for example of the order of 5 microns or less. Such a particle size can be obtained by means well known in the art, for example by micronization.

  If desired, compositions adapted to provide sustained release of the active ingredient can be used.

  The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. A unit dosage form can be a packaged preparation, the package of which contains discrete quantities of formulation, such as packaged tablets, capsules and powders in vials or ampoules. The unit dosage form can be a capsule, tablet, cachet or lozenge itself, or any suitable number of these can be packaged.

  Tablets or capsules are preferred compositions for oral administration, and liquids are preferred for intravenous administration and continuous infusion.

  Further details of techniques for formulation and administration can be found in the latest edition of Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA).

A therapeutically effective dose refers to that amount of active ingredient that ameliorates the symptoms or condition. Therapeutic efficacy and toxicity, eg ED ₅₀ and LD ₅₀ , can be measured by standard pharmacological procedures in cell cultures or experimental animals. The dose ratio between therapeutic and toxic effects is the therapeutic index and may be expressed by the ratio _LD 50 / _{ED 50.} Pharmaceutical compositions that exhibit high therapeutic indices are preferred.

  The dose administered will, of course, be adjusted to the age, weight and condition of the individual being treated, as well as the route of administration, dosage form and regimen, and the desired result. The exact dressage should of course be determined by the physician.

  The actual dosage will depend on the nature and severity of the disease being treated and the route of administration, which is within the discretion of the physician and is tailored to the particular environment of the invention to provide the desired therapeutic effect. The dose can be gradually increased to change it. For therapeutic treatment, however, pharmaceutical compositions comprising from about 0.1 to about 500 mg, preferably from about 1 to about 100 mg, most preferably from about 1 to about 10 mg of active ingredient per individual dose are suitable for the present invention. It is thought that.

  The active ingredient can be administered at one or more doses per day. Satisfactory results may be obtained in some cases 0.1 μg / kg i.e. v. And 1 μg / kg p. o. It can be obtained even with only dorsage. The upper limit of the dosage range is about 10 mg / kg i. v. And 100 mg / kg p. o. it is conceivable that. A preferred range is from about 0.1 μg / kg to about 10 mg / kg / day i. v. And about 1 μg / kg to about 100 mg / kg / day p. o. It is.

Methods of treatment In another aspect, the invention provides for the prevention, treatment or alleviation of a disease, disorder or condition in an animal organism, including a human, wherein the disease, disorder or condition is responsive to modulation of potassium channels, particularly SK channels. Provide a method. The method comprises administering to such animal organisms, including humans in need thereof, a therapeutically effective amount of a compound of the invention.

  Preferred indications contemplated by the present invention are as described above.

  Appropriate dose ranges are defined according to the present invention as usual, the exact mode of administration, the form to be administered, the indications to be administered, the subject concerned, and the subject weight concerned, as well as the choice of the attending physician or veterinarian Depending on experience, it is considered to be 0.1-1000 mg per day, 10-500 mg per day, especially 30-100 mg per day.

  In some cases, 0.005 mg / kg i. v. And 0.01 mg / kg p. o. Satisfactory results can be obtained even with the only dressage. The upper limit of the dosage range is about 10 mg / kg i. v. And 100 mg / kg p. o. It is. A preferred range is from about 0.001 to about 1 mg / kg i.e. v. And about 0.1 to about 10 mg / kg p. o. It is.

  The invention will be further described with reference to the following examples. They are not intended to limit the scope of the claimed invention.

Example 1
Preliminary Example Method A
Benzyl- [2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -amine (Compound A1)
2,4-Dichloro-6-methylpyrimidine (528 mg; 3.24 mmol) was dissolved in acetonitrile (10 mL). Benzylamine (382 mg; 3.56 mmol) and triethylamine (2.26 mL; 16.2 mmol) were added. The mixture was stirred at room temperature overnight. This was filtered and evaporated to give a yellow oil. This was dissolved in dichloromethane and washed three times with water. Dehydration (MgSO ₄ ), filtration, evaporation followed by column chromatography with heptane / ethyl acetate 470 mg (61%) benzyl- (2-chloro-6-methyl-pyrimidin-4-yl) -amine Got.

Benzyl- (2-chloro-6-methyl-pyrimidin-4-yl) -amine (460 mg; 2.01 mmol) was dissolved in acetonitrile (5 mL) and 3,5-dimethylpyrazole (290 mg; 3.02 mmol). ) Was added. The mixture was heated in a microwave oven at 170 ° C. for 20 minutes. Evaporation followed by extraction with dichloromethane and sodium hydroxide 1M, dried (MgSO ₄ ), filtered and evaporated to give a yellow crystalline compound. Recrystallize in heptane / ethyl acetate to crystallize benzyl- [2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -amine (180 mg; 31%) Obtained as a functional compound. Mp. 135.9-137.3 ° C.

Cyclohexyl- [2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -amine (Compound A2)
Was prepared from 2,4-dichloro-6-methylpyrimidine, cyclohexylamine and 3,5-dimethylpyrazole according to Method A. Mp. 145.0-146.7 ° C.

Cyclopentyl- [2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -amine, hydrochloride (Compound A3)
Was prepared from 2,4-dichloro-6-methylpyrimidine, cyclopentylamine and 3,5-dimethylpyrazole according to Method A. However, instead of extraction, the product was precipitated and filtered as hydrochloride. Mp. 111.9-127.7 ° C.

[2- (3,5-Dimethylpyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -diethylamine, fumarate (Compound A4)
Was prepared from 2,4-dichloro-6-methylpyrimidine, diethylamine and 3,5-dimethylpyrazole according to Method A. However, instead of recrystallization, fumaric acid (0.0775 M in ether / methanol 9: 1) was added and the compound was isolated as a fumarate salt. Mp. 120.5 ° C.

Cyclohexyl- [2- (3,5-dimethyl-pyrazol-1-yl) -pyrimidin-4-yl] -amine (Compound A5)
Was prepared from 2,4-dichloropyrimidine, cyclohexylamine and 3,5-dimethylpyrazole according to Method A. Mp 144.5-146.7 ° C;

[5-Chloro-2- (3,5-dimethyl-pyrazol-1-yl) -pyrimidin-4-yl] -cyclohexyl-amine (Compound A6)
Was prepared from 2,4,5-trichloropyrimidine, cyclohexylamine and 3,5-dimethylpyrazole according to Method A. Mp 90.0-99.0 ° C;

[5-Bromo-2- (3.5-dimethyl-pyrazol-1-yl) -pyrimidin-4-yl] -cyclohexyl-amine (Compound A7)
Was prepared from 5-bromo 2,4-dichloropyrimidine, cyclohexylamine and 3,5-dimethylpyrazole according to Method A. LC-ESI-HRMS of [M + H] ⁺ was 350.0972 Da. Calc. 350.098033 Da. dev. -2.4 ppm.

Method B
[2- (3,5-Dimethylpyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -p-tolyl-amine (Compound B1)
2,4-Dichloro-6-methylpyrimidine (600 mg, 2.7 mmol) was dissolved in acetonitrile (4 mL). p-Toluidine (470 mg, 4.42 mmol) and triethylamine (0.65 mL, 5.52 mmol) were added. The mixture was shaken at 60 ° C. for 12 hours in a sealed vial on a sand bath. Evaporation followed by column chromatography (ethyl acetate: hexane) gave (2-chloro-6-methyl-pyrimidin-4-yl) -p-tolyl-amine (400 mg, 63%).

  (2-Chloro-6-methyl-pyrimidin-4-yl) p-tolyl-amine (400 mg, 1.7 mmol) was dissolved in acetonitrile (4 mL) and 3,5-dimethylpyrazole (181 mg, 1.88) was dissolved. Mmol) was added. The mixture was heated in a microwave at 130 ° C. for 30 minutes. The mixture was concentrated and the residue was basified with sodium bicarbonate, extracted with chloroform, dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography (ethyl acetate / hexane) to give [2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -p-tolyl-amine. (200 mg, 40%) Mp. 135.1-137.5 ° C was obtained.

The following compounds are prepared analogously:
[2- (3.5-Dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -phenyl-amine (Compound B2)
Was prepared from 2,4-dichloro-6-methylpyrimidine, aniline and 3,5-dimethylpyrazole according to Method B. Mp. 134.5-138.8 ° C.

(4-Chloro-phenyl)-[2- (3,5-dimethylpyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -amine (Compound B3)
Was prepared according to Method B from 2,4-dichloro-6-methylpyrimidine, 4-chloroaniline and 3,5-dimethylpyrazole. Mp. 181-183.2 ° C.

(3.4-Dichloro-phenyl)-[2- (3,5-dimethylpyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -amine (Compound B4)
Was prepared according to Method B from 2,4-dichloro-6-methylpyrimidine, 3,4-dichloroaniline and 3,5-dimethylpyrazole. Mp. 135.3-137.8 ° C.

[2- (3,5-Dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl]-(4-methoxy-phenyl) -amine (Compound B5)
Was prepared from 2,4-dichloro-6-methylpyrimidine, p-anisidine and 3,5-dimethylpyrazole according to Method B.

[2- (3,5-Dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl]-(3-trifluoromethyl-phenyl) -amine (Compound B6)
Was prepared from 2,4-dichloro-6-methylpyrimidine, 3-trifluoromethylaniline and 3,5-dimethylpyrazole according to Method B. Mp. 130.5-133.6 ° C.

[2- (3,5-Dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -naphthalen-2-yl-amine (Compound B7)
Was prepared from 2,4-dichloro-6-methylpyrimidine, 2-naphthylamine and 3,5-dimethylpyrazole according to Method B. LC-ESI-HRMS of [M + H] ⁺ was 330.1729 Da. Calc. 330.17187 Da, dev. 3.1 ppm is shown.

[2- (3,5-Dimethyl-pyrazol-1-yl) -pyrimidin-4-yl]-(3-trifluoromethyl-phenyl) -amine (Compound B8)
Was prepared from 2,4-dichloropyrimidine, 3-trifluoromethylaniline and 3,5-dimethylpyrazole according to Method B. Mp. 98.5-99.6 ° C.

(4-Chloro-phenyl)-[2- (3,5-dimethyl-pyrazol-1-yl) -pyrimidin-4-yl] -amine (Compound B9)
Was prepared from 2,4-dichloropyrimidine, 4-chloroaniline and 3,5-dimethylpyrazole according to Method B. Mp 135.5-140.0 ° C.

[5-Bromo-2- (3,5-dimethyl-pyrazol-1-yl) -pyrimidin-4-yl]-(4-chloro-phenyl) -amine (Compound B10)
Was prepared from 5-bromo 2,4-dichloropyrimidine, 4-chloroaniline and 3,5-dimethylpyrazole according to Method B. Mp. 144.5-154.0 ° C.

[2- (3,5-Dimethyl-pyrazol-1-yl) -pyrimidin-4-yl] -p-tolyl-amine (Compound B11)
Was prepared from 2,4-dichloropyrimidine, p-toluidine and 3,5-dimethylpyrazole according to Method B. Mp. 52-55.6 ° C.

(4-Chloro-phenyl)-[2- (3,5-dimethylpyrazol-1-yl) -5-methyl-pyrimidin-4-yl] -amine (Compound B12)
Was prepared according to Method B from 2,4-dichloro-5-methylpyrimidine, 4-chloroaniline and 3,5-dimethylpyrazole. Mp. 179.2-182.3 ° C.

[5-Chloro-2- (3,5-dimethyl-pyrazol-1-yl) -pyrimidin-4-yl]-(4-chloro-phenyl) -amine (Compound B13)
Was prepared from 2,4,5-trichloropyrimidine, 4-chloroaniline and 3,5-dimethylpyrazole according to Method B. LC-ESI-HRMS of [M + H] ⁺ was 334.064 Da. Calc. 336.062626 Da, dev. 4.1 ppm is indicated.

(Example 2)
Biological Activity This example demonstrates the biological activity of a representative compound of the invention (Compound A2). The ionic current flowing through the small conductance Ca ²⁺ activated K ⁺ channel (SK channel, subtype 3) was recorded using a whole cell structure by the patch clamp technique.

A small conductance Ca ²⁺ activated K ⁺ channel, subtype 3 (SK3) was cloned and stably expressed in HEK293 cells.

Stable expression of SK3 in HEK293 cells Human SK3 (hSK3) was subcloned into the expression vector pNS3n, a customized vector derived from pcDNA3 (InVitrogen), resulting in the plasmid construct pNS3_hSK3. HEK293 tissue culture cells were grown in DMEM (Dulbecco's Modified Eagle Medium) supplemented with 10% FCS (fetal calf serum) at 37 ° C. in 5% CO ₂ . Cells cultured to a culture density of 50% in T25 cell culture flasks were transfected with 2.5 μg pNS3_hSK3 using Lipofectamine (InVitrogen). Transfected cells were selected in medium supplemented with 0.25 mg / ml Zeocin. Single clones were picked and grown in selective media until enough cells were obtained to freeze. Thereafter, the cells were cultured in a normal medium without a selective agent. Functional hSK3 channel expression was verified by patch clamp.

Whole cell reading experiment was performed with one of several patch clamp devices. Cells plated on cover slips were placed in a 15 μl perfusion chamber (flow rate about 1 ml / min) mounted on an IMT-2 microscope. The microscope was placed on a vibration isolation table in a grounded Faraday box. All experiments are performed at room temperature (20-22 ° C). An EPC-9 patch clamp amplifier (HEKA-electronics, Lambrect, Germany) is connected to the Macintosh computer via the ITC16 interface. Data is stored directly on the hard disk and analyzed with IGOR software (Wavemetrics, Lake Oswega, OR, USA).

  Apply the whole cell structure of patch clamp technology. Schematically, a remote control device is used to gently place a borosilicate pipette tip (resistance 2-4 MΩ) on the cell membrane. When gently aspirated, a giga-seal (pipette resistance increases to> 1 GΩ) is formed, and then a stronger aspiration is applied to rupture the cell membrane under the pipette. The cell capacitance is electrically compensated and the resistance between the pipette and the cell interior (series resistance, Rs) is measured and compensated. Usually the cell capacitance is in the range of 5-20 pF (depending on cell size) and the series resistance is in the range of 3-6 MΩ. Update Rs as well as capacitance compensation during the experiment (before each stimulus). Exclude all experiments with drifting Rs values. Leak subtraction is not performed.

Solution The extracellular (bath) solution contains (in mM): 140 NaCl, 4 KCl, 0.1 CaCl ₂ , 3 MgCl ₂ , 10 HEPES (to pH = 7.4 with HCl). Test compounds are dissolved from concentrated stock solutions in DMSO to 1000-fold and then diluted in extracellular solution.

The intracellular (pipette) solution has the following composition (in mM): 105 KCl, 45 KOH, 10EGTA, 1.21 MgCl ₂ , 7.63 CaCl ₂ and 10 HEPES (to pH = 7.2 with HCl). The calculated free concentration of Ca ²⁺ in this solution is 300 nM and its Mg ²⁺ is 1 mM.

Quantification After building the whole cell structure, a voltage gradient (usually −120 to +30 mV) is applied to the cells every 5 seconds from a holding potential of −80 mV. A stable basal current is obtained within 100-500 seconds and then the compound is added by changing to an extracellular solution containing the test compound. Under these circumstances in native HEK293 cells, the endogenous current (<200 pA at 30 mV for 2-10 nA SK3 current) is hardly activated.

  The change in basal current at -20 mV is calculated to quantify the active compound. The current in the absence of compound is set to 100%. The activator has a value greater than 100, with a value of 200% indicating a double current. On the other hand, a value of 50% indicates that the compound reduced the basal current to half that value.

For the activator, the value of SC ₁₀₀ is estimated. The value of SC ₁₀₀ is defined as the stimulus concentration required to increase the basal current by 100%. The SC ₁₀₀ value measured for Compound A2 of the present invention was 0.1 μM. This shows its strong SK3 activation properties.

Claims (18)

A pyrazolyl-pyrimidine derivative of the formula I,

An isomer or a mixture of isomers thereof, an N-oxide thereof, a prodrug thereof or a pharmaceutically acceptable salt thereof, wherein
n is 0, 1, 2 or 3;
X represents O, S or NR ′, provided that
R ′ represents hydrogen, alkyl, in particular methyl or ethyl, cycloalkyl or cycloalkyl-alkyl,
Or when n is 0 and X is NR ′, R ′ is taken together with Y and the nitrogen to which they are attached to form a heterocyclic ring, said heterocyclic ring from alkyl and phenyl Optionally substituted with one or two substituents selected from the group consisting of:
Y is alkyl, cycloalkyl, alkyl-cycloalkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxy-alkyl, alkoxy-alkyl, alkenyl, phenyl, benzyl, naphthyl, 1,2,3,4- Represents tetrahydro-naphthyl, indenyl, 1,2-dihydro-indenyl, furanyl, thienyl, pyranyl, tetrahydro-pyran-4-yl, pyridinyl, indolinyl or quinolinyl, said phenyl, benzyl, naphthyl, 1,2,3,4 -Tetrahydro-naphthyl, indenyl, 1,2-dihydro-indenyl, furanyl, thienyl, pyranyl, 2,3,5,6-tetrahydro-4H-pyran-4-yl, pyridinyl, indolinyl and quinolinyl groups are alkyl, amino -Alkyl Alkyl-amino, alkyl-amino-alkyl, hydroxy-alkyl, alkoxy-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, halo, haloalkyl, hydroxy, alkoxy, methylenedioxy, haloalkoxy, cyano, nitro, amino, phenyl And optionally substituted with one or more substituents selected from the group consisting of morpholinyl,
Or when n is 0 and X is NR ′, Y is taken together with R ′ and the nitrogen to which they are attached to form a heterocycle, said heterocycle from alkyl and phenyl Optionally substituted with one or two substituents selected from the group consisting of:
R ¹ , R ² , R ³ and R ⁴ are independently of one another hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, cycloalkyl, cycloalkyl-alkyl, halo, haloalkyl, hydroxy, alkoxy, alkoxy-carbonyl, haloalkoxy Represents cyano, nitro and / or amino).   The pyrazolyl-pyrimidine derivative according to claim 1, wherein n is 0, 1, 2, or 3. X represents O, S or NR ′, provided that
R ′ represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl, or when n is 0 and X is NR ′, R ′ is taken together with Y and the nitrogen to which they are attached. A heterocycle is formed, wherein the heterocycle is optionally substituted with one or two substituents selected from the group consisting of alkyl and phenyl. Pyrimidine derivatives. X represents O, S or NR ′, provided that
The pyrazolyl-pyrimidine derivative according to claim 1 or 2, wherein R 'represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl. n is 0,
X is NR ′, provided that
R ′, together with Y and the nitrogen to which they are attached, forms a heterocycle, which is optionally substituted with one or two substituents selected from the group consisting of alkyl and phenyl 3. A pyrazolyl-pyrimidine derivative according to claim 1 or 2, optionally substituted.   Y is alkyl, cycloalkyl, alkyl-cycloalkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxy-alkyl, alkoxy-alkyl, alkenyl, phenyl, benzyl, naphthyl, 1,2,3,4- Represents tetrahydro-naphthyl, indenyl, 1,2-dihydro-indenyl, furanyl, thienyl, pyranyl, tetrahydropyran-4-yl, pyridinyl, indolinyl or quinolinyl, said phenyl, benzyl, naphthyl, 1,2,3,4- Tetrahydro-naphthyl, indenyl, 1,2-dihydro-indenyl, furanyl, thienyl, pyranyl, 2,3,5,6-tetrahydro-4H-pyran-4-yl, pyridinyl, indolinyl and quinolinyl groups are alkyl, amino- Alkyl, Alkyl-amino, alkyl-amino-alkyl, hydroxy-alkyl, alkoxy-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, halo, haloalkyl, hydroxy, alkoxy, methylenedioxy, haloalkoxy, cyano, nitro, amino, phenyl And a pyrazolyl-pyrimidine derivative according to any one of claims 1 to 5, optionally substituted with one or more substituents selected from the group consisting of morpholinyl.   Y represents alkyl, cycloalkyl, alkyl-cycloalkyl, hydroxy-alkyl, alkenyl, phenyl, benzyl or naphthyl, wherein the phenyl, benzyl and naphthyl groups are selected from the group consisting of alkyl, halo, haloalkyl and alkoxy 1 7. A pyrazolyl-pyrimidine derivative according to claim 6, optionally substituted with one or two substituents.   Y represents phenyl, benzyl or naphthyl, wherein the phenyl, benzyl and naphthyl groups are optionally substituted with one or two substituents selected from the group consisting of methyl, fluoro, chloro, trifluoromethyl and methoxy. The pyrazolyl-pyrimidine derivative according to claim 6, which may be R ¹ , R ² , R ³ and R ⁴ are independently of each other hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, cycloalkyl, cycloalkyl-alkyl, halo, haloalkyl, hydroxy, alkoxy, alkoxy-carbonyl, haloalkoxy A pyrazolyl-pyrimidine derivative according to any one of claims 1 to 8, which represents, cyano, nitro and / or amino. n is 0,
X is NH,
Y represents alkyl, cycloalkyl, alkyl-cycloalkyl, hydroxy-alkyl, phenyl, benzyl or naphthyl;
R ¹ and R ² represent methyl,
R ³ represents hydrogen, methyl, ethyl or propyl;
The pyrazolyl-pyrimidine derivative according to claim 1, wherein R ⁴ represents hydrogen, methyl, ethyl, propyl, chloro, bromo, ethoxycarbonyl and / or cyano. n is 0,
X is NH,
Y represents phenyl or benzyl, wherein the phenyl and benzyl groups may be optionally substituted with one or two substituents selected from the group consisting of alkyl, halo, haloalkyl and alkoxy;
R ¹ and R ² represent methyl,
R ³ represents hydrogen, methyl, ethyl or propyl;
The pyrazolyl-pyrimidine derivative according to claim 1, wherein R ⁴ represents hydrogen, methyl, ethyl, propyl, chloro, bromo, ethoxycarbonyl or cyano. Benzyl- [2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -amine;
Cyclopentyl- [2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -diethyl-amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -phenyl-amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -p-tolyl-amine;
(3,4-dichloro-phenyl)-[2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -6-methyl-pyrimidin-4-yl] -naphthalen-2-yl-amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -pyrimidin-4-yl]-(3-trifluoromethyl-phenyl) -amine;
Cyclohexyl- [2- (3,5-dimethyl-pyrazol-1-yl) -pyrimidin-4-yl] -amine;
[5-chloro-2- (3,5-dimethyl-pyrazol-1-yl) -pyrimidin-4-yl] -cyclohexyl-amine;
(4-chloro-phenyl)-[2- (3,5-dimethyl-pyrazol-1-yl) -pyrimidin-4-yl] -amine;
[5-bromo-2- (3,5-dimethyl-pyrazol-1-yl) -pyrimidin-4-yl]-(4-chloro-phenyl) -amine;
[2- (3,5-dimethyl-pyrazol-1-yl) -pyrimidin-4-yl] -p-tolyl-amine;
(4-chloro-phenyl)-[2- (3,5-dimethyl-pyrazol-1-yl) -5-methyl-pyrimidin-4-yl] -amine;
[5-bromo-2- (3,5-dimethyl-pyrazol-1-yl) -pyrimidin-4-yl] -cyclohexyl-amine; or [5-chloro-2- (3,5-dimethyl-pyrazole-1 -Yl) -pyrimidin-4-yl]-(4-chloro-phenyl) -amine;
Or a pyrazolyl-pyrimidine derivative according to claim 1, which is a pharmaceutically acceptable salt thereof.   The pyrazolyl-pyrimidine derivative according to any one of claims 1 to 12, or a pharmaceutically acceptable addition salt thereof, or a prodrug thereof together with at least one pharmaceutically acceptable carrier or diluent. A pharmaceutical composition comprising in an amount.   Use of a compound according to any of claims 1 to 12 for the manufacture of a medicament for treating, preventing or alleviating a disease, disorder or condition in mammals including humans, wherein said disease, disorder or condition Is associated with the activity of potassium channels.   The disease or disorder associated with the activity of potassium channel is respiratory disease, epilepsy, seizure, absence seizure, convulsions, vasospasm, coronary spasm, renal dysfunction, polycystic kidneys, bladder spasms, urinary incontinence, bladder Outflow disorder, irritable bowel syndrome, gastrointestinal disorder, secretory diarrhea, ischemia, cerebral ischemia, ischemic heart disease, angina, coronary heart disease, traumatic brain injury, psychosis, schizophrenia, anxiety , Depression, dementia, memory impairment and attention deficit, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dysmenorrhea, narcolepsy, Raynaud's disease, intermittent claudication, Sjogren's syndrome, migraine, arrhythmia, hypertension 15. Use according to claim 14, which is symptom, absence seizure, myotonic dystrophy, xerostomia, type II diabetes, hyperinsulinemia, premature labor, baldness, cancer, immunosuppression or pain.   The disease or disorder associated with potassium channel activity is respiratory disease, urinary incontinence, anxiety, epilepsy, psychosis, schizophrenia, amyotrophic lateral sclerosis (ALS) or pain. 14. Use according to 14.   15. Use according to claim 14, wherein the activity of the potassium channel is a respiratory disease, in particular asthma, cystic fibrosis, chronic obstructive pulmonary disease (COPD) or rhinorrhea.   A method for treating, preventing or alleviating a disease, disorder or condition in an animal including human, wherein the disease, disorder or condition responds to the regulation of potassium channels, and the animal includes a human in need of the method A method comprising administering to a living body a therapeutically effective amount of the pyrazolyl-pyrimidine derivative according to any one of claims 1 to 12.