Fused azole-pyrimidine derivatives
View Patent ↗The present invention relates to hovel fused azolepyrimidine derivatives, processes for preparing them and pharmaceutical preparations containing them. The fused azolepyrimidine derivatives of the present invention exhibit enhanced potency for phosphotidylinositol-3-kinase (PI3K) inhibition, especially for PI3K-γ inhibition and can be used for the prophylaxis and treatment of diseases associated with PI3K and particularly with PI3K-γ activity. More specifically, the azole derivatives of the present invention are useful for treatment and prophylaxis of diseases as follows: inflammatory and immunoregulatory disorders, such as asthma, atopic dermatitis, rhinitis, allergic diseases, chronic obstructive pulmonary disease (COPD), septic shock, joint diseases, autoixnmune pathologies such as rheumatoid arthritis, and Graves' disease, cancer, myocardial contractility disorders, heart failure, thromboembolism, ischemia, and atherosclerosis. The compounds of the present invention are also useful for pulmonary hypertension, renal failure, cardiac hypertrophy, as well as neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, diabetes and focal ischemia, since the diseases also relate to PI3K activity in a human or animal subject.
1. A fused azolepyrimidine derivative of the formula (I), its tautomeric or stereoisomeric form, or a salt thereof:
wherein
X represents CR 5 R 6 or NH;
Y 1 represents CR 3 or N;
Chemical bond between Y 2 ═Y 3 represents a single bond or double bond, with the proviso that when the Y 2 ═Y 3 represents a double bond, Y 2 and Y 3 independently represent CR 4 or N, and
when Y 2 ═Y 3 represents a single bond, Y 2 and Y 3 independently represent CR 3 R 4 or NR 4 ;
Z 1 , Z 2 , Z 3 and Z 4 independently represent CH, CR 2 or N;
R 1 represents aryl optionally having 1 to 3 substituents selected from R 11 ,
C 3-8 cycloalkyl optionally having 1 to 3 substituents selected from R 11 ,
C 1-6 alkyl optionally substituted by aryl, heteroaryl, C 1-6 alkoxyaryl, aryloxy, heteroaryloxy or one or more halogen,
C 1-6 alkoxy optionally substituted by carboxy, aryl, heteroaryl, C 1-6 alkoxyaryl, aryloxy, heteroaryloxy or one or more halogen,
or
a 3 to 15 membered mono- or bi-cyclic heterocyclic ring that is saturated or unsaturated, optionally having 1 to 3 substituents selected from R 11 , and contains 1 to 3 heteroatoms selected from the group consisting of N, O and S,
wherein
R 11 represents
halogen, nitro, hydroxy, cyano, carboxy, amino, N—(C 1-6 alkyl)amino, N-(hydroxyC 1-6 alkyl)amino, N,N-di(C 1-6 alkyl)amino, N—(C 1-6 acyl)amino, N-(formyl)-N—(C 1-6 alkyl)amino, N—(C 1-6 alkanesulfonyl) amino, N-(carboxyC 1-6 -alkyl)-N—(C 1-6 alkyl)amino, N—(C 1-6 alkoxycabonyl)amino, N—[N,N-di(C 1-6 alkyl)amino methylene]amino, N—[N,N-di(C 1-6 alkyl)amino (C 1-6 alkyl)methylene]amino, N—[N,N-di(C 1-6 alkyl)amino C 2-6 alkenyl]amino, aminocarbonyl, N—(C 1-6 alkyl)aminocarbonyl, N,N-di(C 1-6 alkyl)aminocarbonyl, C 3-8 cycloalkyl, C 1-6 alkylthio, C 1-6 alkanesulfonyl, sulfamoyl, C 1-6 alkoxycarbonyl,
N-arylamino wherein said aryl moiety is optionally having 1 to 3 substituents selected from R 101 , N-(aryl C 1-6 alkyl)amino wherein said aryl moiety is optionally having 1 to 3 substituents selected from R 101 , aryl C 1-6 alkoxycarbonyl wherein said aryl moiety is optionally having 1 to 3 substituents selected from R 101 ,
C 1-6 alkyl optionally substituted by mono-, di- or tri-halogen, amino, N—(C 1-6 alkyl)amino or N,N-di(C 1-6 alkyl)amino,
C 1-6 alkoxy optionally substituted by mono-, di- or tri-halogen, N—(C 1-6 alkyl)sulfonamide, or N-(aryl)sulfonamide,
or
a 5 to 7 membered saturated or unsaturated ring having 1 to 3 heteroatoms selected from the group consisting of O, S and N, and optionally having 1 to 3 substituents selected from R 101
wherein
R 101 represents halogen, carboxy, amino, N—(C 1-6 alkyl)amino, N,N-di(C 1-6 alkyl)amino, aminocarbonyl, N—(C 1-6 alkyl)aminocarbonyl, N,N-di(C 1-6 alkyl)aminocarbonyl, pyridyl,
C 1-6 alkyl optionally substituted by cyano or mono- di- or tri-halogen,
and
C 1-6 alkoxy optionally substituted by cyano, carboxy, amino, N—(C 1-6 alkyl)amino, N,N-di(C 1-6 alkyl)amino, aminocarbonyl, N—(C 1-6 alkyl)aminocarbonyl, N,N-di(C 1-6 alkyl)amino carbonyl or mono-, di- or tri-halogen;
R 2 represents hydroxy, halogen, nitro, cyano, amino, N—(C 1-6 alkyl)amino, N,N-di(C 1-6 alkyl)amino, N-(hydroxyC 1-6 alkyl)amino, N-(hydroxyC 1-6 alkyl)-N—(C 1-6 alkyl)amino, C 1-6 acyloxy, aminoC 1-6 acyloxy, C 2-6 alkenyl, aryl,
a 5-7 membered saturated or unsaturated heterocyclic ring having 1 to 3 heteroatoms selected from the group consisting O, S and N, and optionally substituted by
hydroxy, C 1-6 alkyl, C 1-6 alkoxy, oxo, amino, amino C 1-6 alkyl, N—(C 1-6 alkyl)amino, N,N-di(C 1-6 alkyl)amino, N—(C 1-6 acyl)amino, N—(C 1-6 alkyl)carbonylamino, phenyl, phenyl C 1-6 alkyl, carboxy, C 1-6 alkoxycarbonyl, aminocarbonyl, N-(C 1-6 alkyl)aminocarbonyl, or N,N-di(C 1-6 alkyl)amino, —C(O)—R 20
wherein
R 20 represents C 1-6 alkyl, C 1-6 alkoxy, amino, N—(C 1-6 alkyl)amino, N,N-di(C 1-6 alkyl)amino, N—(C 1-6 acyl)amino, or a 5-7 membered saturated or unsaturated heterocyclic ring having 1 to 3 heteroatoms selected from the group consisting O, S and N, and optionally substituted by C 1-6 alkyl, C 1-6 alkoxy, oxo, amino, N—(C 1-6 alkyl)amino, N,N-di(C 1-6 alkyl)amino, N—(C 1-6 acyl)amino, phenyl, or benzyl,
C 1-6 alkyl optionally substituted by R 21 ,
or
C 1-6 alkoxy optionally substituted by R 21 ,
wherein
R 21 represents cyano, mono-, di or tri-halogen, hydroxy, amino, N—(C 1-6 alkyl)amino, N,N-di(C 1-6 alkyl)amino, N-(hydroxyC 1-6 alkyl) amino, N-(halophenylC 1-6 alkyl) amino, amino C 2-6 alkylenyl, C 1-6 alkoxy, hydroxyC 1-6 alkoxy, —C(O)—R 201 , —NHC(O)—R 201 , C 3-8 cycloalkyl, isoindolino, phthalimidyl, 2-oxo-1,3-oxazolidinyl, aryl or a 5 or 6 membered saturated or unsaturated heterocyclic ring having 1 to 4 heteroatoms selected from the group consisting O, S and N, and optionally substituted by hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, hydroxyC 1-6 alkoxy, oxo, amino, aminoC 1-6 alkyl, N—(C 1-6 alkyl)amino, N,N-di(C 1-6 alkyl)amino, N—(C 1-6 acyl)amino, or benzyl,
wherein
R 201 represents hydroxy, amino, N—(C 1-6 alkyl)amino, N,N-di(C 1-6 alkyl)amino, N-(halophenylC 1-6 alkyl) amino, C 1-6 alkyl, aminoC 1-6 alkyl, aminoC 2-6 alkylenyl, C 1-6 alkoxy, a 5 or 6 membered saturated or unsaturated heterocyclic ring having 1 to 4 heteroatoms selected from the group consisting O, S and N, and optionally substituted by hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, hydroxyC 1-6 alkoxy, oxo, amino, N—(C 1-6 alkyl)amino, N,N-di(C 1-6 alkyl)amino, N—(C 1-6 acyl)amino or benzyl;
R 3 represents hydrogen, halogen, aminocarbonyl, or C 1-6 alkyl optionally substituted by aryl C 1-6 alkoxy or mono-, di- or tri-halogen;
R 4 represents hydrogen or C 1-6 alkyl;
R 5 represents hydrogen or C 1-6 alkyl; and
R 6 represents halogen, hydrogen or C 1-6 alkyl.
2. The fused azolepyrimidine derivative of the formula (I), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 1 ,
wherein
X represents CR 5 R 6 or NH;
Y 1 represents N;
Y 2 and Y 3 represent CR 3 R 4 ;
Chemical bond between Y 2 ═Y 3 represents a single bond;
Z 4 represents CH;
Z 1 , Z 2 and Z 3 independently represent CH, CR 2 or N;
R 1 represents
C 1-6 alkyl optionally substituted by mono-, di- or tri-halogen, phenyl, methoxyphenyl, phenoxy, or thienyl,
C 1-6 alkoxy optionally substituted by phenyl phenoxy, thienyl or mono-, di- or tri-halogen,
or
one of the following carbocyclic and heterocyclic rings selected from the group consisting of cyclopropyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, isoimidazolyl, pyrazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1-benzothiophenyl, benzothiazolyl, benzimidazolyl, 3H-imidazo [4,5-b]pyridinyl, benzotriazolyl, indolyl, indazolyl, imidazo[1,2-a]pyridinyl, quino linyl, and 1,8-naphthyridinyl,
wherein
said carbocyclic and heterocyclic rings optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, carboxy, amino, N—(C 1-6 alkyl)amino, N-(hydroxyC 1-6 alkyl)amino, N,N-di (C 1-6 alkyl)amino, N—(C 1-6 acyl)amino, N—(C 1-6 alkoxycarbonyl)amino, N-(formyl)-N—(C 1-6 alkyl)amino, N,N-di(C 1-6 alkyl) amino (C 2-6 alkenyl) amino, N—(C 1-6 alkane)sulfonyl amino, N[N,N-di(C 1-6 alkyl)amino methylene]amino, C 1-6 alkylthio, C 1-6 alkanesulfonyl, sulfamoyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, pyrrolyl, imidazolyl, pyrazolyl, pyrrolidinyl, pyridyl, phenyl C 1-6 alkoxycarbonyl, thiazolyl optionally substituted by pyridyl, piperazinyl optionally substituted by C 1-6 alkyl or C 1-6 alkoxy and C 1-6 alkyl optionally substituted by mono-, di- or tri-halogen;
R 2 represents halogen, hydroxy, nitro, cyano, amino, N—(C 1-6 alkyl)amino, N,N-di(C 1-6 alkyl)amino, N-(hydroxyC 1-6 alkyl)-N—(C 1-6 alkyl)amino, (C 2-6 )alkenyl, C 1-6 alkoxycarbonyl, aminocarbonyl, furyl, piperidino, morpholino, phenyl, pyrrolidinyl optionally substituted by N—(C 1-6 acyl)amino, or N—(C 1-6 alkyl)carbonylamino, piperidino optionally substituted by hydroxy, piperazinyl optionally substituted by C 1-6 alkyl, phenylC 1-6 alkyl, C 1-6 alkoxycarbonyl, or aminocarbonyl;
C 1-6 alkyl optionally substituted by amino, cyano, C 1-6 alkoxycarbonyl, morpholino, or mono-, di- or tri-halogen,
or
C 1-6 alkoxy optionally substituted by hydroxy, cyano, carboxy, C 1-6 alkoxy, C 1-6 acyl, C 1-6 alkoxycarbonyl, amino, N—(C 1-6 alkyl)amino, N—(C 1-6 alkyl)aminocarbonyl, N,N-di(C 1-6 alkyl)amino, N,N-di(C 1-6 alkyl)aminocarbonyl, aminocarbonyl, aminoC 1-6 alkylcarbonyl, N-(halobenzyl)aminocarbonyl, hydroxyC 1-6 alkoxy, C 3-6 cycloalkyl, morpholino, morpholinocarbonyl, pyrrolidinyl, pyrrolyl, piperidino, phthalimidyl,
or
piperazinyl optionally substituted by benzyl;
R 3 represents hydrogen;
R 4 represents hydrogen;
R 5 represents hydrogen; and
R 6 represents hydrogen.
3. The fused azolepyrimidine derivative of the formula (I), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 1 ,
wherein
X represents CR 5 R 6 or NH;
Y 1 represents N;
Y 2 and Y 3 represent CR 3 R 4 ;
Chemical bond between Y 2 ═Y 3 represents a single bond
Z 4 represents CH;
Z 1 , Z 2 and Z 3 independently represent N, CH CR 2 ;
R 1 represents cyclopropyl, cyclopentyl, cyclohexyl, 2-furyl, 3-furyl, imidazolyl, pyrimidinyl, pyridazinyl, piperazinyl, 1,2,3-thiadiazolyl, 1,3-benzothiazolyl, quinolyl, 3H-imidazo[4,5-b]pyridinyl,
1H-pyrrol-2-yl optionally substituted by C 1-6 alkyl,
1H-pyrrol-3-yl optionally substituted by C 1-6 alkyl,
pyrazolyl optionally substituted by 1 or 2 C 1-6 alkyl,
isoxazolyl optionally substituted by 1 or 2 C 1-6 alkyl,
2-thienyl optionally substituted by chloro, nitro, cyano, or C 1-6 alkyl,
3-thienyl optionally substituted by chloro, nitro, cyano, or C 1-6 alkyl, piperidinyl optionally substituted by C 1-6 alkoxycarbonyl, or benzyloxycarbonyl, phenyl optionally substituted by 1 to 3 substituents selected from the group consisting of fluoro, chloro, hydroxy, nitro, cyano, carboxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, amino, N—(C 1-6 alkyl)amino, N—(C 1-6 acyl)amino, N—(C 1-6 alkoxycabonyl)amino, N,N-di(C 1-6 alkyl)amino, N-(formyl)-N—C 1-6 alkylamino, C 1-6 alkylthio, C 1-6 alkanesulfonyl, sulfamoyl, pyrrolyl, imidazolyl, pyrazolyl, and piperazinyl optionally substituted by C 1-6 alkyl,
pyridyl optionally substituted by 1 or 2 substituents selected from the group consisting of chloro, hydroxy, carboxy, C 1-6 alkoxy, C 1-6 alkylthio, amino, N—(C 1-6 alkyl)amino, N-(hydroxyC 1-6 alkyl)amino, N,N-di(C 1-6 alkyl)amino, N—(C 1-6 acyl)amino, N—(C 1-6 alkane)sulfonyl amino, N[N,N-di(C 1-6 alkyl)amino methylene]amino, and C 1-6 alkyl optionally substituted by tri halogen,
pyrazinyl optionally substituted by C 1-6 alkyl, 1,3-thiazolyl optionally substituted by 1 or 2 substituents selected from the group consisting of C 1-6 alkyl, pyridyl and N—(C 1-6 alkoxycrbonyl)amino, indolyl optionally substituted by C 1-6 alkyl,
benzimidazolyl optionally substituted by C 1-6 alkyl or tri-halo C 1-6 alkyl,
1,2,3-benzotriazolyl optionally substituted by C 1-6 alkyl,
1,8-naphthyridinyl optionally substituted by C 1-6 alkyl optionally substituted by tri halogen,
C 1-6 alkyl optionally substituted by tri-halogen, phenyl, phenoxy, or thienyl,
or
C 1-6 alkoxy optionally substituted by phenyl, phenoxy, or thienyl;
R 2 represents fluoro, chloro, bromo, hydroxy, nitro, vinyl, cyano, amino, aminoacetoxy, N—(C 1-6 alkyl)amino, N,N-di(C 1-6 alkyl)amino, N-(hydroxyC 1-6 alkyl)-N—(C 1-6 alkyl)amino, 2-furyl, piperidino, morpholino, phenyl, pyrrolidinyl optionally substituted by acetamido, piperidino optionally substituted by hydroxy, piperazinyl optionally substituted by methyl, benzyl, C 1-6 alkoxycarbonyl, or aminocarbonyl,
C 1-6 alkyl optionally substituted by cyano, tri-fluoro, carboxy, methoxycarbonyl, aminocarbonyl, tert-butoxycarbonyl, tetrahydropyranyl, or morpholino,
C 1-6 alkoxy optionally substituted by hydroxy, cyano, methoxy, methoxycarbonyl, tert-butoxycarbonyl, carboxy, aminoacetyl, dimethylamino, aminocarbonyl, methylaminocarbonyl, dimethylamino carbonyl, isopropylaminocarbonyl, fluorobenzylaminocarbonyl, cyclopropyl, pyrrolidinyl, piperidino, tetrahydropyranyl, morpholino, morpholinocarbonyl, 2-oxo-1,3-oxazolidin-4-yl, phthalimid-N-yl, or hydroxy C 1-6 alkyleneoxy,
R 3 represents hydrogen;
R 4 represents hydrogen;
R 5 represents hydrogen; and
R 6 represents hydrogen.
4. The fused azolepyrimidine derivative of the formula (I), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 1 ,
wherein
X represents CR 5 R 6 or NH;
Y 1 represents N;
Y 2 and Y 3 represent CR 3 R 4 ;
Chemical bond between Y 2 ═Y 3 represents a single bond;
Z 3 and Z 4 represent CH;
Z 1 and Z 2 independently represent CH or CR 2 ;
R 1 represents cyclopropyl, cyclopentyl, cyclohexyl, 2-furyl, 3-furyl, imidazolyl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl, pyrimidinyl, pyridazinyl, piperazinyl, 1,2,3-thiadiazolyl, 1,3-benzothiazolyl, quinolyl, 3H-imidazo [4,5-b]pyridinyl,
pyrrolyl optionally substituted by C 1-6 alkyl, pyrazolyl optionally substituted by 1 or 2 C 1-6 alkyl, isoxazolyl optionally substituted by 1 or 2 C 1-6 alkyl, 2-thienyl optionally substituted by chioro, nitro, cyano, or C 1-6 alkyl, 3-thienyl optionally substituted by chloro, nitro, cyano, or C 1-6 alkyl,
piperidinyl optionally substituted by C 1-6 alkoxycarbonyl, or benzyloxycarbonyl,
phenyl optionally substituted by 1 to 3 substituents selected from the group consisting of fluoro, chloro, hydroxy, nitro, cyano, carboxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, amino, N—(C 1-6 alkyl)amino, N—(C 1-6 acyl)amino, N—(C 1-6 alkoxycabonyl)amino, N,N-di(C 1-6 alkyl)amino, N-(formyl)-N—C 1-6 alkylamino, C 1-6 alkylthio, C 1-6 alkanesulfonyl, sulfamoyl, pyrrolyl, imidazolyl, pyrazolyl, and piperazinyl optionally substituted by C 1-6 alkyl,
pyridyl optionally substituted by 1 or 2 substituents selected from the group consisting of chloro, hydroxy, carboxy, C 1-6 alkoxy, C 1-6 alkylthio, amino, N—(C 1-6 alkyl)amino, N-(hydroxyC 1-6 alkyl)amino, N,N-di(C 1-6 alkyl)amino, N—(C 1-6 acyl)amino, N—(C 1-6 alkane)sulfonyl amino, N[N,N-di(C 1-6 alkyl)amino methylene]amino, and C 1-6 alkyl optionally substituted by tri halogen,
pyrazinyl optionally substituted by C 1-6 alkyl, 1,3-thiazolyl optionally substituted by
1 or 2 substituents selected from the group consisting of C 1-6 alkyl, pyridyl and N—(C 1-6 alkoxycrbonyl)amino, indolyl optionally substituted by C 1-6 alkyl, benzimidazolyl optionally substituted by C 1-6 alkyl or tri-halo C 1-6 alkyl,
1,2,3-benzotriazolyl optionally substituted by C 1-6 alkyl, 1,8-naphthyridinyl optionally substituted by C 1-6 alkyl optionally substituted by tri halogen,
C 1-6 alkyl optionally substituted by tri-halogen, phenyl, phenoxy, or thienyl,
or
C 1-6 alkoxy substituted by phenyl, phenoxy, or thienyl;
R 2 represents fluoro, chioro, bromo, hydroxy, nitro, vinyl, cyano, amino, aminoacetoxy, N—(C 1-6 alkyl)amino, N,N-di(C 1-6 alkyl)amino, N-(hydroxyC 1-6 alkyl)-N—(C 1-6 alkyl)amino, 2-furyl, piperidino, morpho lino, phenyl,
pyrrolidinyl optionally substituted by acetamido,
piperidino optionally substituted by hydroxy, piperazinyl optionally substituted by methyl, benzyl, C 1-6 alkoxycarbonyl, or aminocarbonyl,
C 1-6 alkyl optionally substituted by cyano tri-fluoro, carboxy, methoxycarbonyl, aminocarbonyl, tert-butoxycarbonyl, tetrahydropyranyl, or morpholino,
or
C 1-6 alkoxy optionally substituted by hydroxy, cyano, methoxy, methoxycarbonyl, tert-butoxycarbonyl, carboxy, aminoacetyl, dimethylamino, aminocarbonyl, methylaminocarbonyl, dimethylamino carbonyl, isopropylamino carbonyl, fluorobenzylaminocarbonyl, cyclopropyl, pyrrolidinyl, piperidino, tetrahydropyranyl, morpholino, morpholinocarbonyl, 2-oxo- 1,3-oxazolidin-4-yl, phthalimid-N-yl, or hydroxy C 1-6 alkyleneoxy;
R 3 represents hydrogen;
R 4 represents hydrogen;
R 5 represents hydrogen; and
R 6 represents hydrogen.
5. The fused azolepyrimidine derivative of the formula (I), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 1 ,
wherein
X represents CR 5 R 6 or NH;
Y 1 represents N;
Y 2 and Y 3 represent CR 3 R 4 ;
Chemical bond between Y 2 ═Y 3 represents a single bond;
Z 1 and Z 4 represent CH;
Z 2 and Z 3 independently represent CH or CR 2 ;
R 1 represents cyclopropyl, cyclopentyl, cyclohexyl, 2-furyl, 3-furyl, imidazolyl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl, pyrimidinyl, piperazinyl, pyridazinyl, 1,2,3-thiadiazolyl, 1,3-benzothiazolyl, quinolyl, 3H-imidazo [4,5-b]pyridinyl,
pyrrolyl optionally substituted by C 1-6 alkyl,
pyrazolyl optionally substituted by 1 or 2 C 1-6 alkyl,
isoxazolyl optionally substituted by 1 or 2 C 1-6 alkyl,
2-thienyl optionally substituted by chloro, nitro, cyano, or C 1-6 alkyl,
3-thienyl optionally substituted by chloro, nitro, cyano, or C 1-6 alkyl,
piperidinyl optionally substituted by C 1-6 alkoxycarbonyl, or benzyloxycarbonyl,
phenyl optionally substituted by 1 to 3 substituents selected from the group consisting of fluoro, chloro, hydroxy, nitro, cyano, carboxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, amino, N—(C 1-6 alkyl)amino, N—(C 1-6 acyl)amino, N—(C 1-6 alkoxycabonyl)amino, N,N-di(C 1-6 alkyl)amino, N-(formyl)-N—C 1-6 alkyl-amino, C 1-6 alkylthio, C 1-6 alkanesulfonyl, sulfamoyl, pyrrolyl, imidazolyl, pyrazolyl, and piperazinyl optionally substituted by C 1-6 alkyl,
pyridyl optionally substituted by 1 or 2 substituents selected from the group consisting of chloro, hydroxy, carboxy, C 1-6 alkoxy, C 1-6 alkylthio, amino, N—(C 1-6 alkyl)amino, N-(hydroxyC 1-6 alkyl)amino, N,N-di(C 1-6 alkyl)amino, N—(C 1-6 acyl)amino, N—(C 1-6 alkane)sulfonyl amino, N[N,N-di(C 1-6 alkyl)amino-methylene]amino, C 1-6 alkoxyphenylC 1-6 alkoxy, and C 1-6 alkyl optionally substituted by tri halogen,
pyrazinyl optionally substituted by C 1-6 alkyl,
1,3-thiazolyl optionally substituted by 1 or 2 substituents selected from the group consisting of C 1-6 alkyl, pyridyl and N—(C 1-6 alkoxycrbonyl)amino, indolyl optionally substituted by C 1-6 alkyl, benzimidazolyl optionally substituted by C 1-6 alkyl or tri-halo C 1-6 alkyl,
1,2,3-benzotriazolyl optionally substituted by C 1-6 alkyl, 1,8-naphthyridinyl optionally substituted by C 1-6 alkyl optionally substituted by tri halogen,
C 1-6 alkyl optionally substituted by tri-halogen, phenyl, phenoxy, or thienyl,
or
C 1-6 alkoxy substituted by phenyl, phenoxy, or thienyl;
R 2 represents fluoro, chloro, bromo, hydroxy, nitro, vinyl, cyano, amino, aminoacetoxy, N—(C 1-6 alkyl)amino, N,N-di(C 1-6 alkyl)amino, N-(hydroxyC 1-6 alkyl)-N—(C 1-6 alkyl)amino, 2-furyl, piperidino, morpho lino, phenyl,
pyrrolidinyl optionally substituted by acetamido, piperidino optionally substituted by hydroxy, piperazinyl optionally substituted by methyl, benzyl, C 1-6 alkoxycarbonyl, or aminocarbonyl,
C 1-6 alkyl optionally substituted by cyano, tri-fluoro, carboxy, methoxycarbonyl, aminocarbonyl, tert-butoxycarbonyl, tetrahydropyranyl, or morpholino,
or
C 1-6 alkoxy optionally substituted by hydroxy, cyano, methoxy, methoxycarbonyl, tert-butoxycarbonyl, carboxy, aminoacetyl, dimethylamino, aminocarbonyl, methylaminocarbonyl, dimethylamino carbonyl, isopropylamino carbonyl, fluorobenzylamino carbonyl, cyclopropyl, pyrrolidinyl, piperidino, tetrahydropyranyl, morpho lino, morpho linocarbonyl, tetrazolyl, 2-oxo-1,3-oxazolidin-4yl, phthalimid-N-yl, or hydroxy C 1-6 alkyleneoxy;
R 3 represents hydrogen;
R 4 represents hydrogen;
R 5 represents hydrogen; and
R 6 represents hydrogen.
6. The fused azolepyrimidine derivative of the formula (I), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 1 ,
X represents CR 5 R 6 or NH;
Y 1 represents N;
Y 2 and Y 3 represent CR 3 R 4 ;
Chemical bond between Y 2 ═Y 3 represents a single bond;
Z 3 and Z 4 represent CH;
Z 1 and Z 2 independently represent CH or CR 2 ;
R 1 represents 3H-imidazo [4,5-b]pyridinyl, benzimidazolyl
pyridyl optionally substituted by hydroxy, amino, acetamido, methoxybenzyloxy or methylsulfonylamino,
or
1,3-thiazolyl optionally substituted by 1 or 2 methyl;
R 2 represents fluoro, chloro, bromo, morpholino, piperazinyl, methylpiperazinyl, methyl, tri-fluoro methyl, or C 1-6 alkoxy optionally substituted by hydroxy, cyano, carboxy, dimethylaminocarbonyl, tetrahydropyranyl, morpholino, morpholinocarbonyl, tetrazolyl, or phthalimid-N-yl;
R 3 represents hydrogen;
R 4 represents hydrogen;
R 5 represents hydrogen; and
R 6 represents hydrogen.
7. The fused azolepyrimidine derivative of the formula (I), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 1 ,
X represents CR 5 R 6 or NH;
Y 1 represents N;
Y 2 and Y 3 represent CR 3 R 4 ;
Chemical bond between Y 2 ═Y 3 represents a single bond;
Z 1 , Z 3 and Z 4 represent CH;
Z 2 represents CR 2 ;
R 1 represents 3H-imidazo [4,5-b]pyridinyl, benzimidazolyl pyridyl optionally substituted by hydroxy, amino, acetamido, methoxybenzyloxy or methylsulfonylamino,
or
1,3-thiazolyl optionally substituted by 1 or 2 methyl,
R 2 represents fluoro, chloro, bromo, morpholino, piperazinyl, methylpiperazinyl, methyl, tri-fluoro methyl, C 1-6 alkoxy optionally substituted by hydroxy, cyano, carboxy, dimethylaminocarbonyl, tetrahydropyranyl, morpholino, morpholinocarbonyl, tetrazolyl, or phthalimid-N-yl;
R 3 represents hydrogen;
R 4 represents hydrogen;
R 5 represents hydrogen; and
R 6 represents hydrogen.
8. The fused azolepyrimidine derivative of the formula (I), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 1 , wherein said derivative is selected from the group consisting of the following compounds:
N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;
2-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-pyridin-3-ylethyleno;
N-(7,8-dimethoxy-2,3-dihydroimidazol[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;
6-(acetamido)-N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;
N-{5-[2-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-hydroxyvinyl]pyridin-2-yl}acetamide;
2-({5-[2-hydroxy-2-pyridin-3-ylvinyl]-7-methoxy-2,3-dihydroimidazo[1,2-]quinazolin-8-yl}oxy)-N,N-dimethylacetamide;
2-[7-methoxy-8-(tetrahydro-2H-pyran-2-ylmethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-pyridin-3-ylethylenol;
2-[8-(2-hydroxyethoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-pyridin-3-ylethylenol1;
({5-[2-hydroxy-2-pyridin-3-ylvinyl]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl}oxy)acetic acid;
4-({5-[2-hydroxy-2-pyridin-3-ylvinyl]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl}oxy)butanoic acid;
({5-[2-hydroxy-2-pyridin-3-ylvinyl]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl}oxy)acetonitrile;
2-[7-methoxy-8-(2H-tetrazol-5-ylmethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-pyridin-3-ylethyleno1;
2-[7-methoxy-8-(4-morpholin-4-yl-4-oxobutoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-pyridin-3-ylethylenol;
5-[1-hydroxy-2-(8-morpholin-4-yl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)vinyl]pyridin-3-ol;
N-(2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-5-hydroxynicotinamide;
6-(acetamido)-N-(7,9-dimethoxy-8-methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;
N-(8,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-5-hydroxynicotinamide;
5-hydroxy-N-(7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;
N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-5-[(4-methoxybenzyl)oxy]nicotinamide;
N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-5-hydroxynicotinamide;
5-hydroxy-N-[8-(trifluoromethyl)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;
N-{8-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;
N-(7-bromo-8-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;
6-amino-N-(8-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;
1-(1H-benzimidazol-5-yl)-2-(8,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)ethylenol;
2-(8,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-(2,4-dimethyl-1,3-thiazol1-5-yl)ethylenol;
N-(9-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-l H-benzimidazole-5-carboxamide;
N-(8-bromo-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;
N-(8-bromo-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;
N-(8-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;
N-(8-methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;
N-[8-(trifluoromethyl)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1H-benzimidazole-5-carboxamide;
N-(7-fluoro-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;
N-(7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;
N-(8-chloro-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;
6-(acetamido)-N-(8-morpholin-4-yl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;
1-(1H-benzimidazol-5-yl)-2-(8-morpholin-4-yl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)ethylenol;
N-{5-[1-hydroxy-2-(8-morpholin-4-yl-2,3-dihydroimidazol[1,2-c]quinazolin-5-yl)vinyl]pyridin-2-yl}acetamide;
6-methyl-N-(8-morpholin-4-y-2,3-dihydroimidazol[1,2-c]quinazolin-5-yl)nicotinamide;
1-(1H-benzimidazol-5-yl)-2-[8-(4-methylpiperazin-1-yl)-2,3-dihydroimidazol[1,2-c]quinazolin-5-yl]ethylenol;
N-(2,3-dihydroimidazol[1,2-c]quinazolin-5-yl)-3H-imidazo[4,5-b]pyridine-6-carboxamide;
N-(7,8-dimethoxy-2,3-dihydroimidazol[1,2-c]quinazolin-5-yl)-3H-imidazo[4,5-b]pyridine-6-carboxamide;
N-[7-(trifluoromethyl)-2,3-dihydroimidazol[1,2-c]quinazolin-5-yl]-1H-benzimidazole-5-carboxamide;
N-(7,9-dimethoxy-2,3-dihydroimidazol[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;
N-{5-[2-(7,9-dimethoxy-8-methyl-2,3-dihydroimidazol[1,2-c]quinazolin-5-yl)-1-hydroxyvinyl]pyridin-2-yl}acetamide;
N-{5-[2-(7-bromo-9-methyl-2,3-dihydroimidazol[1,2-c]quinazolin-5-yl)-1-hydroxyvinyl]pyridin-2-yl}acetamide; and
2-(8,9-dimethoxy-2,3-dihydroimidazol[1,2-c]quinazolin-5-yl)-1-pyridin-3-ylethylenol.
9. A medicament comprising the fused azolepyrimidine derivative, its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof as claimed in claim 1 as an active ingredient.
10. The medicament as claimed in claim 9 , further comprising one or more pharmaceutically acceptable excipients.
11. The medicament as claimed in claim 9 , wherein the fused azolepyrimidine derivative, its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof is a PI3K inhibitor.
12. The medicament as claimed in claim 9 , wherein the fused azolepyrimidine derivative, its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof is a PI3K-γ inhibitor.