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HK1084393B - Fused azole-pyrimidine derivatives - Google Patents

Fused azole-pyrimidine derivatives Download PDF

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Publication number
HK1084393B
HK1084393B HK06104675.8A HK06104675A HK1084393B HK 1084393 B HK1084393 B HK 1084393B HK 06104675 A HK06104675 A HK 06104675A HK 1084393 B HK1084393 B HK 1084393B
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HK
Hong Kong
Prior art keywords
alkyl
amino
optionally substituted
hydroxy
quinazolin
Prior art date
Application number
HK06104675.8A
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Chinese (zh)
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HK1084393A1 (en
Inventor
Mitsuyuki Shimada
Toshiki Murata
Kinji Fuchikami
Hideki Tsujishita
Naoki Omori
Issei Kato
Mami Miura
Klaus Urbahns
Florian Gantner
Kevin Bacon
Original Assignee
Bayer Intellectual Property Gmbh
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Application filed by Bayer Intellectual Property Gmbh filed Critical Bayer Intellectual Property Gmbh
Priority claimed from PCT/EP2003/010377 external-priority patent/WO2004029055A1/en
Publication of HK1084393A1 publication Critical patent/HK1084393A1/en
Publication of HK1084393B publication Critical patent/HK1084393B/en

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Description

Fused pyrrole-pyrimidine derivatives
Detailed Description
Technical Field
The present invention relates to novel fused pyrrolopyrimidine derivatives, processes for preparing them and pharmaceutical compositions containing them. The fused pyrrolopyrimidine derivatives of the present invention show improved phosphatidylinositol-3-kinase (PI3K) inhibition, especially PI3K- γ inhibition, and are useful for the prevention and treatment of diseases associated with PI3K, especially PI3K- γ activity.
More specifically, the fused pyrrolopyrimidine derivatives of the present invention are useful for the treatment and prevention of the following diseases: inflammatory and immunoregulatory diseases such as asthma, atopic dermatitis, rhinitis, allergic diseases, Chronic Obstructive Pulmonary Disease (COPD), septic shock, joint diseases, autoimmune pathologies such as rheumatoid arthritis, and Graves' disease, cancer, myocardial contractile disease, heart failure, thromboembolism, ischemia and atherosclerosis.
The compounds of the invention are also useful in pulmonary hypertension, renal failure, cardiac hypertrophy, and neurodegenerative diseases such as parkinson's disease, alzheimer's disease, diabetes and focal ischemia, as these diseases are also associated with PI3K activity in human or animal patients.
Background
The signal transduction pathway derived from the chemoattractant factor, whose activation of the heterotrimeric G-protein is thought to be an important target for controlling leukocyte activity in inflammatory diseases, leukocyte trafficking is controlled by the chemoattractant factorReceptors (GPCRs) are coupled, triggering complex downstream intracellular events. Signal transduction in one of the pathways leads to intracellular free Ca2+Mobilization, cytoskeletal reorganization and directed mobilization, signal transduction is dependent on lipid-derived second messengers [1, 2] produced by phosphoinositide 3-kinase (PI3K) activity]。
PI3K phosphorylated membrane phospholipid inositol phosphate-4, 5-diphosphate (PtdIns (4, 5) P2) The D3-hydroxy position of (A) to give inositol phosphate-3, 4, 5-triphosphate (PtdIns (3, 4, 5) P3). The PI3K family contains three classes [4-6 ] based on membrane specificity and protein structure]. Of particular interest in leukocyte trafficking are IPI-like 3Ks, both of which are involved in receptor-induced inflammatory cell responses and are further divided into subclasses IA (p110 α, β, δ) and IB (p110 γ).
Class IA enzymes (p110 α, β, δ) are associated with a p85 linker subunit containing two SH2 domains, forming a heterodimeric complex capable of recognizing the phosphotyrosine YxxM motif, leading to association with receptor tyrosine kinases, followed by activation of the enzyme by the receptor tyrosine kinases [1, 2 ]. The class IA subtype is thought to be associated with cell proliferation and carcinogenesis, and binds to the activated rat oncogene found in many cancers to express its enzymatic activation. P110 α and β have also been found to play important roles in human cancer growth [3 ].
The class IB (p110 γ) enzyme, whose expression is mainly restricted to leukocytes, is activated by the G protein β γ complex, running the downward flow of 7 transmembrane chemoattractant receptors [7-9 ]. A p101 linker protein that does not share similarities with any other known protein is essential for the G protein β γ response of p110 γ (PI3K γ) [10-12 ].
Recent studies of functionally deficient PI3K γ (PI3K γ -/-mice) that are capable of survival, reproduction and exhibiting normal lifespan in conventional mouse laboratories have shown that neutrophils are unable to produce PtdIns (3, 4, 5) P when stimulated with GPCR agonists such as fMLP, C5a or IL-83. This indicates that PI3K γ is the only PI3K [13-16 ] coupled to these GPCRs in these cells]. Furthermore, therePtdIns (3, 4, 5) P of Protein Kinase B (PKB) does not exist in some neutrophils3Dependent activation, while PKB can still be activated by either GM-CSF or IgG/C3 b-coated zymosan via p110 α, β or δ. At the same time, in response to G-protein transmission, PLC β activation was intact and PI3K γ -/-mice showed impaired thymocyte development and increased neutrophil, monocyte and eosinophil populations [14]]. In addition, neutrophils and macrophages isolated from PI3K γ -/-mice show severe defects in locomotion and paroxysmal breathing in response to GPCR agonists and tropisms [14, 16]. Expression of PI3K γ was also examined in transgenic mice expressing Green Fluorescent Protein (GFP) under the control of an endogenous PI3K γ promoter. GFP was detected in spleen and bone marrow cells and neutrophils, suggesting that expression of PI3K γ was restricted to hematopoietic cells [15]]. Taken together, the class IB phosphoinositide 3-kinase PI3K γ appears to be critical in controlling leukocyte trafficking, and therefore, the development of isoform-selective inhibitors of PI3K γ should be an attractive anti-inflammatory strategy.
The hypertrophic response can be triggered by the PI3K signaling pathway, and recent studies published to date have established a role for the PTEN-PI3K γ pathway in modulating myocardial contractility, however, PI3K α mediates the cell size changes observed during cardiac hypertrophy to heart failure, and PI3K γ acts as a negative regulator of cardiac contractility.
PTEN is a dual specific protein phosphatase contained in cell growth signals as phosphoinositide phosphatase, and the tumor suppressor TPEN shows dephosphorylation of phosphoinositide 3, 4, 5-triphosphate (PIP3), PIP3 is an important second messenger specifically produced by PI3K action. PTEN reduces PIP3 content in cells, fighting the cellular signals transmitted by PI 3K. It has also been reported that the expression of dominant negative PTEN in rat cardiomyocytes (cardioblastocytes) in tissue culture causes hypertrophy.
PI3K gamma modulates baseline cAMP levels, controlling contractility of cells, and this study also shows that changes in baseline cAMP levels contribute to increased contractility in mutant mice [17 ].
Thus, the results of this study show that PI3K γ is involved in myocardial contractility, and thus the inhibitor would be effective in the treatment of congestive heart failure, ischemia, pulmonary hypertension, renal failure, cardiac hypertrophy, arteriosclerosis, thromboembolism, and diabetes.
PI3K inhibitors that are predicted to block signal transduction by GPCRs and activation of various immune cells should have a broad anti-inflammatory spectrum and be effective in the treatment of inflammatory and immunoregulatory diseases [2] including asthma, atopic dermatitis, rhinitis, allergic diseases, Chronic Obstructive Pulmonary Disease (COPD), septic shock, joint diseases, autoimmune pathologies such as rheumatoid arthritis, and Graves' disease, diabetes, cancer, myocardial contractile disease, thromboembolism [18] and atherosclerosis.
Certain PI3-kinase inhibitors have been identified: wortmannin, isolated as a mycotoxin by penicillium wortmannii [19], the most relevant, but not well characterized demethoxy-viridomycin and LY294002, morpholino derivatives of the broad spectrum kinase inhibitor quercetin [20 ].
US 3644354 discloses 5-substituted 2, 3 dihydroimidazo [1, 2-c ] quinazolines of the general formula:
wherein R and R0Respectively H, lower alkyl, lower alkenyl; r 'and R' are independently H, halogen, lower alkyl, lower alkoxy
Or
However, no reference discloses fused pyrrolopyrimidines with PI3K inhibitory activity as wellPyridines, such as, but not limited to, pyrrole-quinazoline, pyrrole-pyridopyrimidine, pyrrole-pyrimidopyrimidine, pyrrole-pyrimidopyridazine, pyrrole-pyrimidotriazine, pyrrole-pteridine, pyrrole-pyrimidotetrazine and fused pyrrolopyrimidine having an acylated amine or-CR attached at the 5 or 6 position5R6-C(O)-(R5Is H or C1-6Alkyl and R6Is halogen, H or C1-6Alkyl) other derivatives.
There remains a need to develop compounds for the treatment and prevention of inflammation, cancer and/or myocardial contractile disease associated with PI3K activity.
Summary of The Invention
As a result of extensive studies on chemical modification of fused pyrrolopyrimidine derivatives, the present inventors found that compounds of novel chemical structures related to the present invention have PI3K inhibitory activity, particularly PI3K γ inhibitory activity, and based on this finding, completed the present invention.
The present invention provides novel fused pyrrolopyrimidine derivatives of formula (I), their tautomeric and stereoisomeric forms and their salts:
wherein
X represents CR5R6Or NH;
Y1represents CR3Or N;
in thatThe chemical bond therebetween represents a single bond or a double bond,
the premise is that,
when in useWhen representing a double bond, Y2And Y3Respectively represent CR4Or N, and
when in useWhen represents a single bond, Y2And Y3Respectively represent CR3R4Or NR4；
Z1、Z2、Z3And Z4Respectively represent CH and CR2Or N;
R1represents optionally having 1-3 substituents selected from R11Aryl of the substituent(s), optionally bearing 1-3 substituents selected from R11C of a substituent of (3)3-8A cycloalkyl group, a,
Optionally substituted by aryl, heteroaryl, C1-6Alkoxyaryl, aryloxy, heteroaryloxy or C substituted by one or more halogens1-6Alkyl, aryl, heteroaryl, and heteroaryl,
Optionally substituted by carboxyl, aryl, heteroaryl, C1-6Alkoxyaryl, aryloxy, heteroaryloxy or C substituted by one or more halogens1-6Alkoxy radical, or
3-15 membered mono-or bicyclic heterocycle, saturated or unsaturated, containing 1-3 heteroatoms selected from N, O and S and optionally carrying 1-3 heteroatoms selected from R11The substituent(s) of (a),
wherein
R11Represents halogen, nitro, hydroxy, cyano, carboxyl, amino, N- (C)1-6Alkyl) amino, N- (hydroxy C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, N- (C)1-6Acyl) amino, N- (formyl) -N- (C)1-6Alkyl) amino, N- (C)1-6Alkylsulfonyl) amino, N- (carboxy-C)1-6Alkyl) -N- (C1-6Alkyl) amino, N- (C)1-6Alkoxycarbonyl) amino, N- [ N, N-Two (C)1-6Alkyl) aminomethylene]Amino, N- [ N, N-di (C)1-6Alkyl) amino (C)1-6Alkyl) methylene]Amino, N- [ N, N-di (C)1-6Alkyl) amino C2-6Alkenyl radical]Amino, aminocarbonyl, N- (C)1-6Alkyl) aminocarbonyl, N-di (C)1-6Alkyl) aminocarbonyl, C3-8Cycloalkyl radical, C1-6Alkylthio radical, C1-6Alkylsulfonyl, aminosulfonyl, C1-6An alkoxycarbonyl group,
N-arylamino, wherein the aryl moiety optionally bears 1-3 substituents selected from R101A substituent of (A),
N- (aryl C)1-6Alkyl) amino, wherein the aryl moiety optionally bears 1-3 substituents selected from R101Substituent of (1), aryl C1-6Alkoxycarbonyl wherein the aryl moiety optionally bears 1 to 3 substituents selected from R101A substituent of (A),
Optionally mono-, di-or tri-halogen, amino, N- (C)1-6Alkyl) amino or N, N-di (C)1-6Alkyl) amino-substituted C1-6Alkyl, aryl, heteroaryl, and heteroaryl,
Optionally mono-, di-or tri-halogen, amino, N- (C)1-6Alkyl) sulfonamides or N- (aryl) sulfonamides substituted C1-6Alkoxy radical, or
5-7 membered saturated or unsaturated ring containing 1-3 heteroatoms selected from O, S and N and optionally carrying 1-3 heteroatoms selected from R101The substituent(s) of (a),
wherein
R101Represents halogen, carboxyl, amino, N- (C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, aminocarbonyl, N- (C)1-6Alkyl) aminocarbonyl, N-di (C)1-6Alkyl) aminocarbonyl, pyridinyl, C optionally substituted by cyano or mono-, di-or tri-halogen1-6Alkyl, or optionally cyano, carboxyl, amino, N- (C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, aminocarbonyl, N- (C)1-6Alkyl) aminocarbonyl, N-di (C)1-6Alkyl) aminocarbonyl or mono-, di-or tri-halogen substituted C1-6An alkoxy group;
R2represents hydroxy, halogen, nitro, cyano, amino, N- (C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, N- (hydroxy C)1-6Alkyl) amino, N- (hydroxy C)1-6Alkyl) -N- (C1-6Alkyl) amino, C1-6Acyloxy, amino C1-6Acyloxy, C2-6Alkenyl, aryl, 5-7 membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms selected from O, S and N, optionally substituted by hydroxy, C1-6Alkyl radical, C1-6Alkoxy, oxo, amino C1-6Alkyl, N- (C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, N- (C)1-6Acyl) amino, N- (C)1-6Alkyl) carbonylamino, phenyl C1-6Alkyl, carboxyl, C1-6Alkoxycarbonyl, aminocarbonyl, N- (C)1-6Alkyl) aminocarbonyl or N, N-di (C)1-6Alkyl) amino substitution, -C (O) -R20
Wherein
R20Is represented by C1-6Alkyl radical, C1-6Alkoxy, amino, N- (C)1-6Alkyl) amino, N-di (C)1- 6Alkyl) amino, N- (C)1-6Acyl) cyano, or a 5-to 7-membered saturated or unsaturated heterocyclic ring containing 1 to 3 heteroatoms selected from O, S and N, optionally substituted by C1-6Alkyl radical, C1-6Alkoxy, oxo, amino, N- (C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, N- (C)1-6Acyl) amino, phenyl or benzyl,
by R21Optionally substituted C1-6Alkyl, aryl, heteroaryl, and heteroaryl,
Or
By R21Optionally substituted C1-6An alkoxy group,
wherein
R21Represents cyano, mono-, di-or tri-halogen, hydroxy, amino, N- (C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, N- (hydroxy C)1-6Alkyl) amino, N- (halophenyl C1-6Alkyl) amino, amino C2-6Alkenyl radical, C1-6Alkoxy, hydroxy C1-6Alkoxy, -C (O) -R201、-NHC(O)-R201、C3-8Cycloalkyl, isoindolyl, phthalimidyl, 2-oxo-1, 3-oxazolidinyl, aryl, or a 5-or 6-membered saturated or unsaturated heterocyclic ring containing 1 to 4 heteroatoms selected from O, S and N, optionally substituted by hydroxy, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkoxycarbonyl, hydroxy C1-6Alkoxy, oxo, amino C1-6Alkyl, N- (C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, N- (C)1-6Acyl) cyano or benzyl, in which
R201Represents a hydroxyl group, an amino group, N- (C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, N- (halophenyl C1-6Alkyl) amino, C1-6Alkyl, amino C1-6Alkyl, amino C2-6Alkenyl radical, C1-6Alkoxy, or a 5-or 6-membered saturated or unsaturated heterocycle containing 1 to 4 heteroatoms selected from O, S and N, optionally substituted by hydroxy, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkoxycarbonyl, hydroxy C1-6Alkoxy, oxo, amino, N- (C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, N- (C)1-6Acyl) cyano or benzyl group or a pharmaceutically acceptable salt thereof,
R3represents H, halogen, aminocarbonyl or arylC1-6Alkoxy or mono-, di-or tri-halogen optionally substituted C1-6An alkyl group;
R4represents H or C1-6An alkyl group;
R5represents H or C1-6An alkyl group; and
R6represents halogen, H or C1-6An alkyl group.
The compounds of the present invention show PI3K inhibitory activity and PI3K γ inhibitory activity and are therefore suitable for the manufacture of medicaments and pharmaceutical compositions which are useful for the treatment and prevention of PI3K and/or PI3K γ associated diseases, such as inflammatory and immunoregulatory diseases, e.g. asthma, atopic dermatitis, rhinitis, allergic diseases, Chronic Obstructive Pulmonary Disease (COPD), septic shock, joint diseases, autoimmune pathologies, such as rheumatoid arthritis, and Graves' disease, myocardial contractile disease, heart failure, thromboembolism, ischemia, cardiac hypertrophy, arteriosclerosis and cancers, such as skin cancer, bladder cancer, breast cancer, uterine cancer, ovarian cancer, prostate cancer, lung cancer, colon cancer, pancreatic cancer, kidney cancer, stomach cancer, brain tumors, leukemias and the like.
The compounds of the invention are also useful in the treatment of pulmonary hypertension, renal failure, Huntington's disease and cardiac hypertrophy, as well as neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, diabetes and focal ischemia, as these diseases are also associated with PI3K activity in human or animal patients.
The invention also relates to a method for the treatment or prevention of symptoms or diseases associated with PI3K activity, in particular PI3K γ activity, in a human or animal patient, comprising administering to said patient a therapeutically effective amount of a fused pyrrolopyrimidine derivative represented by formula (I), a tautomeric or stereoisomeric form thereof or a physiologically acceptable salt thereof.
Furthermore, the present invention provides the use of fused pyrrolopyrimidine derivatives represented by formula (I), their tautomeric or stereoisomeric forms or their physiologically acceptable salts for the preparation of a medicament.
In one embodiment, the present invention provides fused pyrrolopyrimidine derivatives of formula (I), tautomeric or stereoisomeric forms thereof, or salts thereof;
wherein
X represents CR5R6Or NH;
Y1represents CR3Or N;
in thatThe chemical bond between them represents a single or double bond, with the proviso that,
when in useWhen representing a double bond, Y2And Y3Respectively represent CR4Or N, and
when in useWhen represents a single bond, Y2And Y3Respectively represent CR3R4Or NR4；
Z1、Z2、Z3And Z4Respectively represent CH and CR2Or N;
R1to represent
C optionally substituted by mono-, di-or tri-halogen, phenyl, methoxyphenyl, phenoxy or thienyl1-6Alkyl, aryl, heteroaryl, and heteroaryl,
C optionally substituted by mono-, di-or tri-halogen, phenyl, methoxyphenyl, phenoxy or thienyl1-6An alkoxy group,
or
One of the following carbocyclic and heterocyclic rings selected from cyclopropyl, cyclohexyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, furanyl, 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, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1-benzothienyl, Benzothiazolyl, benzimidazolyl, 3H-imidazo [4, 5-b ] pyridyl, benzotriazolyl, indolyl, indazolyl, imidazo [1, 2-b ] pyridyl, quinolinyl, and 1, 8-naphthyridinyl,
wherein
The carbocycle and heterocycle are optionally substituted with 1-3 substituents selected from hydroxy, halo, nitro, cyano, carboxy, amino, N- (C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, N- (C)1-6Acyl) amino, N- (C)1-6Alkoxycarbonyl) amino, N- (formyl) -N- (C)1-6Alkyl) amino, N- [ N, N-di (C)1-6Alkyl) aminomethylene]Amino, N- [ N, N-di (C)1-6Alkyl) amino (C)1-6Alkylene) methylene]Amino, N- [ N, N-di (C)1-6Alkyl) amino C1-6Alkenyl radical]Amino group, C1-6Alkylthio radical, C1-6Alkylsulfonyl, aminosulfonyl, C1-6Alkoxy radical, C1-6Alkoxycarbonyl, pyrrolyl, imidazolyl, pyrazinyl, pyrrolidinyl, pyridyl, phenyl C1-6Alkoxycarbonyl, thiazolyl optionally substituted by pyridyl, by C1-6Alkyl or C1-6Alkoxy-optionally substituted piperazinyl and C optionally substituted by mono-, di-or tri-halogen1-6An alkyl group;
R2represents hydroxy, halogen, nitro, cyano, carboxyl, amino, N- (C)1-6Alkyl) amino, N- (hydroxy C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, N- (hydroxy C)1-6Alkyl) -N- (C1-6Alkyl) amino, C2-6Alkenyl radical, C1-6Alkoxycarbonyl, aminocarbonyl, C1-6Acyloxy, amino C1-6Acyloxy, furyl, morpholino, phenyl, piperidino, aryl, or C1-6Pyrrolidinyl optionally substituted with amido, by hydroxy, C1-6Alkyl, carboxyl, aminoCarbonyl group, N- (C)1-6Alkyl) aminocarbonyl or N, N-di (C)1-6Alkyl) aminocarbonyl optionally substituted piperidino, by C1-6Piperazinyl optionally substituted with alkyl, cyano, mono-, di-or tri-halo, hydroxy, amino, N- (C)1-6Alkyl) amino, N- (hydroxy C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, C3-6Cycloalkyl, tetrazolyl, tetrahydropyranyl, morpholino, phthalimido, 2-oxo-1, 3-oxazolidinyl, phenyl optionally substituted C1-6Alkyl, -C (O) -R201Quilt C1-6Pyrrolidinyl optionally substituted with amido, by hydroxy, C1-6Alkyl, carboxyl, aminocarbonyl, N- (C)1-6Alkyl) aminocarbonyl or N, N-di (C)1-6Alkyl) aminocarbonyl optionally substituted piperidino or by C1-6A piperazinyl group optionally substituted with an alkyl group,
wherein
R201Represents a hydroxyl group, an amino group, N- (C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, N- (halobenzyl) amino, C1-6Alkyl radical, C1-6Alkoxy, tetrazolyl, tetrahydropyranyl, morpholino, comononyl1-6Pyrrolidinyl optionally substituted with amido, by hydroxy, C1-6Alkyl, carboxyl, aminocarbonyl, N- (C)1-6Alkyl) aminocarbonyl or N, N-di (C)1-6Alkyl) aminocarbonyl optionally substituted piperidino, or by C1-6Piperazinyl optionally substituted with alkyl, cyano, mono-, di-or tri-halogen, hydroxy, C1-6Alkoxy, hydroxy C1-6Alkoxy, amino, N- (C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, pyrrolyl, tetrazolyl, tetrahydropyranyl, morpholino, phthalimido, 2-oxo-1, 3-oxazolidinyl, phenyl, -C (O) -R201Optionally substituted C1-6Alkoxy radical, C1-6Pyrrolidinyl optionally substituted with amido, by hydroxy, C1-6Alkyl, carboxyl, aminocarbonyl, N- (C)1-6Alkyl) aminocarbonyl or N, N-di (C)1-6Alkyl) aminocarbonyl optionally substitutedPiperidino or piperidino of C1-6A piperazinyl group optionally substituted with an alkyl group,
wherein
R201Represents a hydroxyl group, an amino group, N- (C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, N- (halobenzyl) amino, C1-6Alkyl radical, C1-6Alkoxy, amino C2-6Alkenyl, tetrazolyl, tetrahydropyranyl, morpholino, comorbid1-6Pyrrolidinyl optionally substituted with amido, by hydroxy, C1-6Alkyl, carboxyl, aminocarbonyl, N- (C)1-6Alkyl) aminocarbonyl or N, N-di (C)1-6Alkyl) aminocarbonyl optionally substituted piperidino, or by C1-6Piperazinyl optionally substituted with alkyl,
R3Represents H, halogen, aminocarbonyl, aryl C1-6Alkoxy or mono-, di-or tri-halogen optionally substituted C1-6An alkyl group;
R4represents H or C1-6An alkyl group;
R5represents H or C1-6An alkyl group; and
R6represents halogen, H or C1-6An alkyl group.
In another embodiment, the invention provides fused pyrrolopyrimidine derivatives of formula (I), tautomeric or stereoisomeric forms thereof or salts thereof:
wherein
X represents CR5R6Or NH;
Y1represents N;
Y2and Y3Represents CR3R4；
In thatThe chemical bond in between represents a single bond,
Z4represents CH;
Z1、Z2and Z3Respectively represent N, CH or CR2；
R1Represents cyclopropyl, cyclopentyl, cyclohexyl, 2-furyl, 3-furyl, imidazolyl, pyrimidinyl, pyridazinyl, piperazinyl, 1, 2, 3-thiadiazolyl, 1, 3-benzothiazolyl, quinolinyl, 3H-imidazo [4, 5-b ]]Pyridyl radical, quilt C1-61H-pyrrol-2-yl optionally substituted by alkyl, by C1-61H-pyrrol-3-yl optionally substituted by alkyl, by 1 or 2C1-6Pyrazolyl optionally substituted by alkyl, 1 or 2C1-6Isoxazolyl optionally substituted with alkyl, by chlorine, nitro, cyano or C1-62-thienyl optionally substituted by alkyl, by chlorine, nitro, cyano or C1-63-thienyl optionally substituted by alkyl, by C1-6Piperidinyl optionally substituted with alkoxycarbonyl or benzyloxycarbonyl, phenyl optionally substituted with 1 to 3 substituents selected from: fluorine, chlorine, hydroxyl, nitro, cyano, carboxyl, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkoxycarbonyl, amino, N- (C)1-6Alkyl) amino, N- (C)1-6Acyl) amino, N- (C)1-6Alkoxycarbonyl) amino, N-di (C)1-6Alkyl) amino, N- (formyl) -N-C1-6Alkylamino radical, C1-6Alkylthio radical, C1-6Alkylsulfonyl, sulfamoyl, pyrrolyl, imidazolyl, pyrazolyl and C1-6Piperazinyl optionally substituted with alkyl, pyridyl optionally substituted with 1 or 2 substituents selected from: chlorine, hydroxy, carboxyl, C1-6Alkoxy radical, C1-6Alkylthio, amino, N- (C)1-6Alkyl) amino, N- (hydroxy C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, N- (C)1-6Acyl) amino, N- (C)1-6Alkyl) sulfonylamino, N- [ N, N-di (C)1-6Alkyl) aminomethylene]Amino and C optionally substituted by three halogens1-6Alkyl radical, C1-6Piperazinyl optionally substituted with alkyl, 1 or 2 substituents selected from C1-6Alkyl, pyridyl and N- (C)1-6Alkoxycarbonyl) amino-substituted 1, 3-thiazolyl, optionally substituted by C1-6Indolyl optionally substituted by alkyl, by C1-6Alkyl or trihalo C1-6Benzimidazolyl optionally substituted by alkyl, by C1-6Alkyl-optionally substituted 1, 2, 3-benzotriazolyl, C optionally substituted with trihalo1-61, 8-naphthyridinyl optionally substituted by alkyl, C optionally substituted by trihalo, phenyl, phenoxy or thienyl1-6Alkyl, or C optionally substituted by phenyl, phenoxy or thienyl1-6An alkoxy group;
R2represents fluorine, chlorine, bromine, hydroxyl, nitro, vinyl, cyano, amino, aminoacetoxy, N- (C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, N- (hydroxy C)1-6Alkyl) -N- (C1-6Alkyl) amino, 2-furyl, piperidino, morpholino, phenyl, pyrrolidinyl optionally substituted with acetylamino, piperidino optionally substituted with hydroxy, methyl, benzyl, C1-6Piperazinyl optionally substituted by alkoxycarbonyl or aminocarbonyl, C optionally substituted by cyano, trifluoro, carboxyl, methoxycarbonyl, aminocarbonyl, tert-butoxycarbonyl, tetrahydropyranyl or morpholino1-6Alkyl, by hydroxy, cyano, methoxy, methoxycarbonyl, tert-butoxycarbonyl, carboxy, aminoacetyl, dimethylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, isopropylaminocarbonyl, fluoro-benzylcarbamoyl, cyclopropyl, pyrrolidinyl, piperidino, tetrahydropyranyl, morpholino, morpholinocarbonyl, 2-oxo-1, 3-oxazolidinyl, phthalimido-N-yl or hydroxy C1-6Alkenyloxy optionally substituted C1-6An alkoxy group,
R3represents H;
R4represents H;
R5represents H; and
R6represents H.
In another embodiment, the invention provides fused pyrrolopyrimidine derivatives of formula (I), tautomeric or stereoisomeric forms thereof or salts thereof:
wherein
X represents CR5R6Or NH;
Y1represents N;
Y2and Y3Represents CR3R4；
In thatThe chemical bond in between represents a single bond,
Z3and Z4Represents CH;
Z1and Z2Respectively represent CH or CR2；
R1Represents 3H-imidazo [4, 5-b ] optionally substituted by hydroxy, amino, acetylamino, methoxybenzyloxy or methylsulfonylamino]Pyridyl, benzimidazolyl, pyridyl, or1, 3-thiazolyl optionally substituted with 1 or 2 methyl groups;
R2represents fluorine, chlorine, bromine, morpholino, piperazinyl, methylpiperazinyl, methyl, trifluoromethyl, or C optionally substituted by hydroxy, cyano, carboxy, dimethylaminocarbonyl, tetrahydropyranyl, morpholino, morpholinocarbonyl, tetrazolyl or phthalimido-N-yl1-6An alkoxy group;
R3represents H;
R4represents H;
R5represents H; and
R6represents H.
In another embodiment, the invention provides fused pyrrolopyrimidine derivatives of formula (I), tautomeric or stereoisomeric forms thereof or salts thereof:
wherein
X represents CR5R6Or NH;
Y1represents N;
Y2and Y3Represents CR3R4；
In thatThe chemical bond in between represents a single bond,
Z3and Z4Represents CH;
Z1and Z2Respectively represent CH or CR2；
In another embodiment, the invention provides fused pyrrolopyrimidine derivatives of formula (I), tautomeric or stereoisomeric forms thereof or salts thereof:
wherein
X represents CR5R6Or NH;
Y1represents N;
Y2and Y3Represents CR3R4；
In thatThe chemical bond in between represents a single bond,
Z1and Z4Represents CH;
Z2and Z3Respectively represent CH or CR2；
In another embodiment, the invention provides fused pyrrolopyrimidine derivatives of formula (I), tautomeric or stereoisomeric forms thereof or salts thereof:
wherein
X represents CR5R6Or NH;
Y1represents N;
Y2and Y3Represents CR3R4；
In thatThe chemical bond in between represents a single bond,
Z1、Z3and Z4Represents CH;
Z2represents CR2；
Preferred compounds of the invention are as follows:
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-yl vinyl alcohol;
n- (7, 8-dimethoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) -1H-benzimidazole-5-carboxamide;
6- (acetylamino) -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-hydroxyethenyl ] pyridin-2-yl } acetamide;
2- ({5- [ 2-hydroxy-2-pyridin-3-ylvinyl ] -7-methoxy-2, 3-dihydroimidazo [1, 2-c ] 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-yl vinyl alcohol;
2- [8- (2-hydroxyethoxy) -7-methoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl ] -1-pyridin-3-yl vinyl alcohol;
({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) butyric 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-yl vinyl alcohol;
2- [ 7-methoxy-8- (4-morpholin-4-yl-4-oxobutoxy) -2, 3-dihydroimidazo [1, 2c ] quinazolin-5-yl ] -1-pyridin-3-yl vinyl alcohol;
5- [ 1-hydroxy-2- (8-morpholin-4-yl-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) ethenyl ] pyridin-3-ol;
n- (2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) -5-hydroxynicotinamide;
6- (acetylamino) -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-benzoimidazol-5-yl) -2- (8, 9-dimethoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) vinyl alcohol;
2- (8, 9-dimethoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) -1- (2, 4-dimethyl-1, 3-thiazol-5-yl) vinyl alcohol;
n- (9-methoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) -1H-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- (acetylamino) -N- (8-morpholin-4-yl-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) nicotinamide;
1- (1H-benzoimidazol-5-yl) -2- (8-morpholin-4-yl-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) vinyl alcohol;
n- {5- [ 1-hydroxy-2- (8-morpholin-4-yl-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) vinyl ] pyridin-2-yl } acetamide;
6-methyl-N- (8-morpholin-4-yl-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) nicotinamide;
1- (1H-benzimidazol-5-yl) -2- [8- (4-methylpiperazin-1-yl) -2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl ] vinyl alcohol;
n- (2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) -3H-imidazo [4, 5-b ] pyridine-6-carboxamide;
n- (7, 8-dimethoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) -3H-imidazo [4, 5-b ] pyridine-6-carboxamide;
n- [7- (trifluoromethyl) -2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl ] -1H-benzimidazole-5-carboxamide;
n- (7, 9-dimethoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) -1H-benzimidazole-5-carboxamide;
n- {5- [2- (7, 9-dimethoxy-8-methyl-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) -1-hydroxyethenyl ] pyridin-2-yl } acetamide;
n- {5- [2- (7-bromo-9-methyl-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) -1-hydroxyethenyl ] pyridin-2-yl } acetamide; and
2- (8, 9-dimethoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) -1-pyridin-3-yl vinyl alcohol;
and tautomeric or stereoisomeric forms, pharmaceutically acceptable salts thereof.
Furthermore, the present invention provides a medicament comprising one of the above compounds and optionally a pharmaceutically acceptable excipient.
Alkyl as such and "alkyl" in alkanes, alkoxy, alkanoyl, alkylamino, alkylaminocarbonyl and alkylaminosulfonyl, alkoxycarbonyl, alkoxycarbonylamino and alkanoylamino denotes straight-chain or branched alkyl groups, which usually contain 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms, and denotes by way of example and preferably methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, sec-butyl, pentyl, n-hexyl and the like.
Alkylene represents a divalent straight or branched saturated hydrocarbon group consisting of only carbon and hydrogen atoms, usually containing 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms, and exemplifies and preferably represents methylene, ethylene, 2-methylpropylene, butylene, 2-ethylbutylene, and the like.
Alkoxy represents, by way of example and by way of preference, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy, n-hexoxy and the like.
Alkylamino represents alkylamino having one or two (independently selected) alkyl substituents, and specifically and preferably represents methylamino, ethylamino, N-propylamino, isopropylamino, tert-butylamino, N-pentylamino, N-hexylamino, N-dimethylamino, N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino, N-isopropyl-N-propylamino, N-tert-butyl-N-methylamino, N-ethyl-N-pentylamino, N-hexyl-N-methylamino, etc.
Alkylaminocarbonyl represents a group having one or two (independently selected) alkyl substituents, and specifically and preferably represents methylaminocarbonyl, ethylaminocarbonyl, N-propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, N-pentylaminocarbonyl, N-hexylaminocarbonyl, N-dimethylaminocarbonyl, N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-N-propylaminocarbonyl, N-isopropyl-N-propylaminocarbonyl, N-tert-butyl-N-methylaminocarbonyl, N-ethyl-N-pentylaminocarbonyl, N-hexyl-N-methylaminocarbonyl, and the like.
Alkylaminosulfonyl denotes alkylaminosulfonyl with one or two (independently selected) alkyl substituents, with the list and preference denoting methylaminosulfonyl, ethylaminosulfonyl, N-propylaminosulfonyl, isopropylaminosulfonyl, tert-butylaminosulfonyl, N-pentylaminosulfonyl, N-hexylaminosulfonyl, N-dimethylaminosulfonyl, N, n-diethylaminosulfonyl, N-ethyl-N-methylaminosulfonyl, N-methyl-N-N-propylaminosulfonyl, N-isopropyl-N-N-propylaminosulfonyl, N-tert-butyl-N-methylaminosulfonyl, N-ethyl-N-N-pentylaminosulfonyl, N-N-hexyl-N-methylaminosulfonyl, and the like.
Alkylsulfonyl represents, by way of example and preferably, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, n-hexylsulfonyl and the like.
The alkoxycarbonyl group includes, but is not limited to, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl and the like.
The alkoxycarbonylamino group is exemplified by and preferably represents a methoxycarbonylamino group, an ethoxycarbonylamino group, a n-propoxycarbonylamino group, an isopropoxycarbonylamino group, a tert-butoxycarbonylamino group, a n-pentyloxycarbonylamino group, a n-hexyloxycarbonylamino group and the like.
The alkanoylamino group is exemplified by and preferably means acetylamino, ethylcarbonylamino and the like.
Cycloalkyl represents cycloalkyl on its own and in cycloalkylamino and cycloalkylcarbonyl, generally containing from 3 to 8, preferably from 5 to 7, carbon atoms, and lists and preferably represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
Aryl itself and "aryl" in arylamino, alkoxyaryl represent mono-to tricyclic aromatic carbocyclic groups, generally containing 6 to 14 carbon atoms, and are exemplified and preferred by phenyl, naphthyl, phenanthryl and the like.
Arylamino represents arylamino having one or two (independently selected) aryl substituents, and specifically and preferably represents phenylamino, diphenylamino, naphthylamino and the like.
Heteroaryl by itself and "heteroaryl" in heteroarylamino and heteroarylcarbonyl denotes an aromatic mono-or bicyclic group, usually containing 5 to 15, preferably 5 or 6 ring atoms, up to 5, preferably up to 4 heteroatoms selected from S, O and N, and lists and preferably denotes thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, thiazolyl, pyrazinyl, pyridyl, pyrimidinyl, pyridazinyl, thienyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, quinolinyl, isoquinolinyl, 1, 3 benzodioxole, benzofuranyl, benzofuran-2, 5-diyl, benzofuran-3, 5-diyl and the like.
Heterocycle itself and denotes a mono-or polycyclic, preferably mono-or bicyclic, non-aromatic heterocyclic group, usually containing from 4 to 10, preferably from 5 to 8, ring atoms, up to 3, preferably up to 2, heteroatoms or hetero groups selected from N, O, S, SO and SO 2. The heterocyclyl group may be saturated or partially unsaturated, preferably a 5-8 membered monocyclic saturated heterocyclic group carrying up to two heteroatoms selected from O, N and S, listing and preferably being tetrahydrofuran-2-yl, pyrrolidin-3-yl, pyrrolinyl, piperidinyl, morpholino, perhydroazepinyl.
Heterocyclylcarbonyl represents, by way of example and by preference, tetrahydrofuran-2-ylcarbonyl, pyrrolidinyl-2-carbonyl, pyrrolidinyl-3-carbonyl, pyrrolidinocarbonyl, piperidinocarbonyl, morpholinocarbonyl, perhydroazepinocarbonyl.
Halogen and halo represent fluorine, chlorine, bromine and/or iodine.
Furthermore, the present invention provides a medicament comprising one of the compounds as described above and optionally a pharmaceutically acceptable excipient.
Embodiments of the invention
The compounds of formula (I) of the present invention may be prepared, but are not limited to, by the reactions described below. In certain embodiments, one or more substituents of the compounds used as starting materials or intermediates, such as amino, carboxyl, and hydroxyl Groups, may advantageously be protected by protecting Groups known in the art, examples of which are described in "Protective Groups in organic Synthesis (third edition) by Greene and Wuts.
The compound of formula (I) of the present invention can be prepared, but is not limited to, by the following methods [ A ] and [ B ].
A compound of formula (I-a):
(wherein R is1、R5、R6、Y1、Y2、Y3、Z1、Z2、Z3And Z4Same as defined above) can be prepared, but is not limited to, by the following method a.
Method [ A ]
The compounds of formula (I-a) can be prepared, for example, by reacting a compound of formula (II) (wherein Y is1、Y2、Y3、Z1、Z2、Z3And Z4As described above) with a compound of formula (III) (wherein R is1、R5And R6L represents C as described above1-6Alkyl) reaction.
The reaction may be carried out without solvent or in a solvent including, for example, ethers such as diethyl ether, isopropyl ether, dioxane and Tetrahydrofuran (THF) and 1, 2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; amides such as N, N-Dimethylformamide (DMF), N-dimethylacetamide and N-methylpyrrolidone; sulfoxides, such as dimethyl sulfoxide (DMSO); alcohols such as methanol, ethanol, 1-propanol, isopropanol and tert-butanol; water, and the like. Optionally, two or more solvents selected from the above may be used in admixture.
The reaction temperature can be optionally set according to the compounds to be reacted, and the reaction temperature is by no means limited to, about 10 ℃ to 200 ℃, preferably about 50 ℃ to 160 ℃, and the reaction can be generally carried out for 10 minutes to 48 hours, preferably 30 minutes to 24 hours.
Preparation of intermediates
A compound of formula (II') (wherein Y1、Z1、Z2、Z3And Z4As defined above, Y2And Y3Respectively represent CR3R4Or NR4Connected by a single bond) and compounds of the formula (II') (in which Y is1、Z1、Z2、Z3And Z4As defined above, Y2And Y3Respectively represent CH or N, linked by a double bond) may be, but is not limited to, by the following method [ A-i]Preparation of
Method [ A-i ]
In step 1, a compound of formula (II') (wherein Y1、Z1、Z2、Z3And Z4As defined above, Y2And Y3Respectively represent CR3R4Or NR4Connected by a single bond) can be prepared, for example, by compounds of the formula (VI) in which Z is1、Z2、Z3And Z4As defined above) with a diaminoalkane derivative, such as ethylenediamine.
The reaction may advantageously be carried out using a suitable dehydrating agent, such as SOCl2In situ formation of POCl3、P2O5、P2S5、CS2And the like.
The reaction may be carried out without solvent or in a solvent including, for example, ethers such as diethyl ether, isopropyl ether, dioxane and Tetrahydrofuran (THF) and 1, 2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene, xylene, and the like. Optionally, two or more solvents selected from the above may be used in admixture.
The reaction temperature is usually, but not limited to, about 10 to 200 c, preferably about 50 to 200 c, and the reaction may be carried out for 10 minutes to 48 hours, preferably 30 minutes to 24 hours.
In step 2, a compound of formula (II') (wherein Y1、Z1、Z2、Z3And Z4As defined above, Y2And Y3Each represents CH or N, linked by a double bond) may be represented, for example, by a compound of formula (II') (wherein Y is1、Z1、Z2、Z3And Z4As defined above, Y2And Y3Respectively represent CR3R4Or NR4By single bond) by using reagents, e.g. MnO2、KMnO4Etc. or by dehydrogenation using palladium on carbon.
The reaction may be carried out in a solvent including, for example, ethers such as diethyl ether, isopropyl ether, dioxane, and Tetrahydrofuran (THF) and 1, 2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; dimethylformamide (DMF), Dimethylacetamide (DMAC), 1, 3-dimethyl-3, 4, 5, 6-tetrahydro-2 (1H) -pyrimidinone (DMPU), 1, 3-dimethyl-2-pyrimidinone (DMI), N-methylpyrrolidone (NMP), and the like. Optionally, two or more solvents selected from the above may be used in admixture.
The reaction temperature is generally, but not limited to, about 0 ℃ to 200 ℃, preferably about 50 ℃ to 160 ℃, and the reaction may be generally carried out for 30 minutes to 48 hours, preferably 2 hours to 24 hours.
The compounds of formula (VI) are commercially available or may be synthesized by conventional methods.
The compound of the formula (III) can be produced, for example, by the following method [ A-ii ].
Method [ A-ii ]
A compound of formula (III) (wherein L, R1、R5And R6As defined above) can be obtained by reacting a compound of formula (VII) wherein R is1、R5And R6The same as defined above) with a compound of formula (VIII) wherein L is the same as defined above, in the presence of a base such as potassium hydride, potassium hexamethyldisilazide (potassium hexa methyl diliazide), and the like.
The reaction may be carried out in a solvent including, for example, ethers such as diethyl ether, isopropyl ether, dioxane, and Tetrahydrofuran (THF) and 1, 2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; dimethylformamide (DMF), Dimethylacetamide (DMAC), 1, 3-dimethyl-3, 4, 5, 6-tetrahydro-2 (1H) -pyrimidinone (DMPU), 1, 3-dimethyl-2-pyrimidinone (DMI), N-methylpyrrolidone (NMP), and the like. Optionally, two or more solvents selected from the above may be used in admixture.
The reaction temperature is generally, but not limited to, about-100 ℃ to 100 ℃ and the reaction may be carried out for generally 30 minutes to 48 hours, preferably 2 hours to 24 hours.
Alternatively, the compound of formula (III) can be prepared, for example, by the following method [ A-III ].
Method [ A-iii ]
A compound of formula (III) (wherein L, R1、R5And R6As defined above) can be prepared by reacting a compound of formula (IX) wherein R is1L' is a leaving group, e.g. a halogen atom, e.g. a chlorine or bromine atom or an imidazole, as defined above, with a compound of formula (X) wherein L, R5And R6The same as defined above) or a salt thereof, for example, a potassium salt.
The reaction may be carried out in the presence of a lewis acid, including magnesium salts such as magnesium bromide, magnesium chloride, magnesium iodide, magnesium acetate, and the like, or in the presence of a base such as n-butyllithium, sec-butyllithium, and the like. The reaction may be carried out in a solvent including ethers such as diethyl ether, isopropyl ether, dioxane and Tetrahydrofuran (THF) and 1, 2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene, xylene, and the like. Optionally, two or more solvents selected from the above may be mixed and used.
Preparation of the Compound of formula (I-b):
(wherein R is1、R5、R6、Y1、Y2、Y3、Z1、Z2、Z3And Z4Same as defined above) can be prepared, but is not limited to, by the following method B.
Method [ B ]
Compounds of formula (I-b) can be prepared, for example, by reacting a compound of formula (IV) (wherein Y is1、Y2、Y3、Z1、Z2、Z3And Z4As defined above) and a compound of formula (V) (wherein R is1As defined above, L "is a leaving group, e.g. hydroxy; a halogen atom, such as a chlorine, bromine or iodine atom; imidazole orWherein R is1The same as defined above). In case L "is a hydroxyl group, the reaction is advantageously carried out by using coupling reagents such as benzotriazol-1-yl-oxy-tripyrrolidonium-hexafluorophosphate (PyBOP), 1 '-carbonylbis (1, 3-imidazole) (CDI), 1' -carbonylbis (1, 2, 4-triazole) (CDT) and the like.
In which L' is a halogen atom, imidazole orIn the case of (b), the reaction may advantageously be carried out in the presence of a base including, for example, pyridine, triethylamine and N, N-diisopropylethylamine, diethylaniline, etc.
The reaction may be carried out without solvent or in a solvent including, for example, ethers such as diethyl ether, isopropyl ether, dioxane and Tetrahydrofuran (THF) and 1, 2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles, such as ethylamine; amides such as N, N-Dimethylformamide (DMF), N-Dimethylacetamide (DMAC), and N-methylpyrrolidone (NMP); ureas, such as 1, 3-dimethyl-2-imidazolidinone (DMI); sulfoxides such as dimethyl sulfoxide (DMSO), and the like. Optionally, two or more solvents selected from the above may be used in admixture.
The reaction temperature is generally, but not limited to, about 40 ℃ to 200 ℃, preferably about 20 ℃ to 180 ℃, and the reaction may be generally carried out for 30 minutes to 48 hours, preferably 2 hours to 12 hours.
Preparation of intermediates
The compound of formula (IV) can be prepared, but is not limited to, by the following method [ B-i ]:
method [ B-i ]
A compound of formula (IV) (wherein Y1、Y2、Y3、Z1、Z2、Z3And Z4As defined above) can be prepared by reacting a compound of formula (II) (wherein Y is1、Y2、Y3、Z1、Z2、Z3And Z4As defined above) with a cyanogen halide, such as cyanogen bromide.
The reaction may be carried out in a solvent including, for example, ethers such as diethyl ether, isopropyl ether, dioxane, and Tetrahydrofuran (THF) and 1, 2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; amides such as N, N-Dimethylformamide (DMF), N-dimethylacetamide and N-methylpyrrolidone; alcohols such as methanol, ethanol, 1-propanol, isopropanol, tert-butanol, and the like. Optionally, two or more solvents selected from the above may be used in admixture.
The reaction temperature is generally, but not limited to, about-10 ℃ to 200 ℃ and the reaction may be carried out for generally 30 minutes to 48 hours, preferably 1 hour to 24 hours.
A compound of formula (II) (wherein Y1、Y2、Y3、Z1、Z2、Z3And Z4Same as defined above) can be performed [ A-i ]]Obtained by the same method as described in (1).
The compounds of formulae (VII), (VIII), (IX) and (X) are commercially available or can be synthesized by conventional methods.
When the compound represented by the formula (I) or a salt thereof has an asymmetric carbon in the structure, optically active compounds and racemic mixtures thereof are also included in the scope of the present invention.
Typical salts of the compounds of formula (I) include salts prepared by reacting a compound of the present invention with an inorganic or organic acid, or an organic or inorganic base, which are referred to as acid addition salts and base addition salts, respectively.
The acid addition salt-forming acids include inorganic acids such as, but not limited to, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, and the like, and organic acids such as, but not limited to, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, acetic acid, and the like.
Base addition salts include those formed from inorganic bases such as, but not limited to, ammonium hydroxide, non-metallic hydroxides, alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, and organic bases such as, but not limited to, ethanolamine, triethylamine, tris (hydroxymethyl) aminomethane, and the like. Examples of the inorganic base include sodium hydroxide, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, calcium hydroxide, calcium carbonate and the like.
Depending on the substituents, the compounds of the invention or their salts may be modified to form lower alkyl esters or other esters as are known; and/or hydrates or other solvates, which esters, hydrates and solvates are included within the scope of the present invention.
The compounds of the invention may be administered in oral forms such as, but not limited to, normal and enteric coated tablets, capsules, pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups, solid and liquid aerosols and emulsions. They may also be administered in parenteral forms known to those skilled in the art of pharmacy, such as, but not limited to, intravenous, intraperitoneal, subcutaneous, intramuscular, and the like. The compounds of the present invention may be administered topically via suitable intranasal vehicles, in intranasal form, or using transdermal delivery systems known to those skilled in the art.
The dosage regimen for using the compounds of the present invention will be selected by one of ordinary skill in the art based on a variety of factors including, but not limited to, the age, weight, sex, and clinical condition of the patient, the severity of the condition being treated, the route of administration, the level of metabolic and secretory functions of the patient, the dosage form used, the particular compound used, and salts thereof.
The compounds of the invention are preferably formulated for administration with one or more pharmaceutically acceptable excipients. Excipients are inert substances such as, but not limited to, carriers, diluents, flavoring agents, sweeteners, lubricants, solubilizers, suspending agents, binders, tablet disintegrating agents, and encapsulating materials.
Another embodiment of the invention is a pharmaceutical formulation comprising a compound of the invention and one or more pharmaceutically acceptable excipients that are compatible with the other ingredients of the formulation and not deleterious to the patient. The pharmaceutical formulations of the present invention are prepared by mixing a therapeutically effective amount of a compound of the present invention with one or more pharmaceutically acceptable excipients. In preparing the compositions of the present invention, the active ingredient may be mixed with a diluent or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. The carrier may act as a diluent and may be a solid, semi-solid, or liquid material used as an excipient, or may be in the form of tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments containing, for example, up to 10% by weight of the active ingredient, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
For oral administration, the active ingredient may be combined with an oral and non-toxic pharmaceutically acceptable carrier such as, but not limited to, lactose, starch, sucrose, glucose, sodium carbonate, mannitol, sorbitol, calcium carbonate, calcium phosphate, calcium sulfate, methyl cellulose, and the like, and optionally a disintegrant such as, but not limited to, corn starch, methyl cellulose, agar, bentonite, xanthan gum, alginic acid, and the like; optional binders such as, but not limited to, capsules, natural sugar, beta-lactose, corn sweetener, natural and synthetic gums, gum arabic, gum tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like; optional lubricants such as, but not limited to, magnesium stearate, sodium stearate, stearic acid, sodium oleate, sodium benzoate, sodium acetate, sodium chloride, talc, and the like.
In powder form, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. The active ingredient may be mixed with a carrier having binding properties in suitable proportions and compressed in the shape and size desired to produce tablets. Powders and tablets preferably contain from about 1 to about 99% by weight of the active ingredient which is the novel composition of the invention, suitable solid carriers being magnesium carboxymethylcellulose, low melting waxes and cocoa butter.
Sterile liquid preparations include suspensions, emulsions, syrups and elixirs, the active ingredient may be dissolved or suspended in a pharmaceutically acceptable carrier, for example sterile water, a sterile organic solvent, or a mixture of sterile water and a sterile organic solvent.
The active ingredient may also be dissolved in a suitable organic solvent, such as aqueous propylene glycol. Other compositions may be prepared by dispersing the finely divided active ingredient in an aqueous starch or sodium carboxymethyl cellulose solution or in a suitable oil.
The formulations may be presented in unit dosage form, which is a physically discrete unit containing a unit dose, suitable for administration to a human or other mammal. The unit dosage form can be a capsule or tablet or a plurality of capsules or tablets, and a "unit dose" is a predetermined quantity of an active compound of the invention admixed with one or more excipients calculated to produce the desired therapeutic effect. The amount of active ingredient in a unit dose can vary or be adjusted from about 0.1 to about 1000mg depending on the particular treatment involved.
When used for the indicated effects, a typical oral dosage of the invention will be from about 0.01 mg/kg/day to about 100 mg/kg/day, preferably from 0.1 mg/kg/day to 30 mg/kg/day, most preferably from about 0.5 mg/kg/day to about 10 mg/kg/day. In the case of parenteral administration, it has generally proven advantageous to administer about 0.001 to 100 mg/kg/day, preferably 0.01 to 1 mg/kg/day. The compounds of the invention may be administered in a single daily dose, or the total daily dose may be divided doses administered 2, 3 or more times per day. Where delivery is transdermal, administration is, of course, continuous.
Examples
The present invention will be described in detail below in the form of examples, but they should not be construed as constituting the boundary and scope of the present invention.
In the following examples, all quantitative data, if not otherwise stated, refer to weight percentages.
1H NMR spectra were recorded using either a Bruker DRX-300(300MHz for1H) spectrometer or a Brucker500 UltraShield TM (500MHz for1H), with chemical shifts reported in parts per million (ppm) using 0ppm Tetramethylsilane (TMS) as an internal standard. Coupling constants are in hertz and the abbreviations s, d, t, q, m and br refer to singlet, doublet, triplet, quartet, multiplet and broad, respectively. The mass measurement was carried out with MAT95(Finnigan MAT).
Liquid chromatography-Mass Spectrometry (LC-MS) data were obtained by using a Shimadzu Phenomenex ODS column (4.6 mm)X 30mm) were recorded on a Micromass Platform LC rinsed with a mixture of 1 ml/flow acetonitrile-water (9: 1-1: 9). Mass spectra were obtained by Electron Spray (ES) ion technique (Micromass Platform LC), TLC was performed on pre-coated silica gel plates (Mercksilicagel 60F-254), and silica gel (WAKO-gel C-200(75-150 μm)) was used for all column chromatograms. All chemicals were reagent grade, purchased from Sigma-Aldrich, Wako pure Chemical industries, Ltd., Tokyo kasei kogyo co., Ltd., Nacalaitesque, inc., Watanabe Chemical ind.
The effect of the compounds of the present invention was examined by the following test.
[ determination of Compound IC50 values in PI 3K. gamma. kinase assay ]
Chemical substances and test materials
Inositol phosphates (PtdIns) and phosphatidylserine (PtdSer) were purchased from DOOSANSERDARY RESEARCH LABORATORIES (Toronto, Canada). Recombinant human PI3K γ (fusion His at C-terminus expressed in s.frugiperda 9 insect cells6Full length human PI3Kp110 γ) by ALEXIS biocemics (#201 and 055-C010; san Diego, CA). [ gamma ] gamma33P]ATP and unlabeled ATP were obtained from AMERSHAMPHARMACIA BIOTECH (Buckinghamshire, UK) and ROCHE DIAGNOSTICS (Mannheim, Germany), respectively. Scintillation cocktail and MicroScint PSTMPurchased from PACKARD (Meriden, CT), MaxisorpTMPlates were purchased from NALGE NUNC internationalk.k. (Tokyo, Japan) and gaseous other CHEMICALS not otherwise specified were from WAKO PURE CHEMICALS (Osaka, Japan).
Solid phase lipid kinase assay
To assess the inhibitory effect of compounds on PI3K gamma, Maxisorp was usedTMThe plate was coated with 50. mu.l/well of a solution containing 50. mu.l/ml PtdIns and 50. mu.g/ml PtdSer dissolved in chloroform: ethanol (3: 7). The plates were then air dried in a fume hood for at least 2 hours by mixing 25. mu.l/well assay buffer 2 × (100mM MPSO/NaOH, 0.2M NaCl, pH7.0, 8mM MgCl. sub.C.) in a lipid pre-coated plate22mg/ml BSA (no fatty acid)) and 50 ng/well PI3K γ, 10 test compounds in 2% DMSO were added. The reaction was performed by adding 20. mu.l/well ATP mix (final 10. mu.M ATP; 0.05. mu. Ci/well. gamma. [ gamma. ])33P]ATP). After 2 hours of RT incubation, the reaction was stopped by adding 50. mu.l/well stop solution (50mM EDTA, pH 8.0). The plate was then washed twice with Tris buffered saline (TBS, pH7.4) and MicroScintiPS added at 100. mu.l/wellTM(PACKARD) scintillation hydrate, using TopCountTM(PACKARD) scintillation counter counts radioactivity.
Percent inhibition was calculated at each compound concentration and IC50 values were determined from the inhibition curves.
[ Selectivity of the same enzyme in PI3K ]
{ determination of Compound IC50 values in the PI3K beta kinase assay }
Recombinant baculoviruses of PI3K β p110 β and GST-p85 α were obtained from Dr.Katada (University of Tokyo), and recombinant PI3K heterocomplexes of p110 β and GST-p85 α were co-expressed in insect cells according to the manufacturer's instructions (Pharmingen, San Diego, Calif.) and purified using a glutathione affinity column. The kinase assay for PI3K β was prepared in a similar manner as described in the section [ determination of compound IC50 values in PI3K γ kinase assay ].
[ test for Selectivity for other kinases ]
The kinase properties of the compounds are determined by using several kinase assays, such as the Syk kinase assay.
{ Syk tyrosine kinase inhibition assay for selectivity }
(1) Syk protein preparation
The cDNA fragments encoding the human Syk open reading frame were cloned by RT-PCR from total RNA of the human Burkitt's lymphoma B cell line, Raji (American Type CurtureCollection). The cDNA fragment was inserted into pAcG2T (Pharmingen, San Diego, Calif.) to constitute a non-baculovirus transfer factor. This factor was then used with linearized baculovirus (BaculoGoldTM, Pharmingen) to transfect Sf21 cells (Invitrogen, San Diego, CA).
The resulting recombinant baculovirus was cloned and amplified in Sf21 cells. Infection of Sf21 cells with this amplified high titer virus produced a chimeric protein of Syk kinase fused by glutathione-S-transferase (GST).
The GST-Syk obtained was purified on a glutathione column (Amersham pharmacia Biotech AB, Uppsala, Sweden) according to the manufacturer's instructions and the purity of the protein was more than 90% as confirmed by SDS-PAGE.
(2) Synthesis of peptides
Subsequently, a peptide fragment comprising 30 residues, including two tyrosine residues, KISDFGLSKALRADENYYKAQTHGKWPVKW, was synthesized using a peptide synthesizer, and the N-terminus of the fragment was subsequently biotinylated to obtain a biotin-labeled activated cyclic peptide (AL).
(3) Measurement of Syk tyrosine kinase Activity
All reagents were assayed in Syk kinase assay buffer (50mM Tris-HCl (pH8.0), 10mM MgCl2，0.1 mMNa3VO40.1% BSA, 1mM DTT). A mixture (35. mu.l) comprising 3.2. mu.g GST-Syk and 0.5. mu.g AL was first added to each well of a 96-well plate, followed by 5. mu.l test compound in the presence of 2.5% dimethyl sulfoxide (DMSO) in each well, to which mixture 300. mu.M ATP (10. mu.l) was added to initiate the kinase reaction, the final reaction mixture (50. mu.l) consisting of 0.65nM GST-Syk, 3. mu.M AL, 30. mu.M ATP, test compound, 0.25% DMSO and Syk kinase assay buffer.
The mixture was incubated at Room Temperature (RT) for1 hour, and the reaction was stopped by adding 120. mu.l of stop buffer (50mM Tris-HCl (pH8.0), 10mM EDTA, 500 mM NaCl, 0.1% BSA). The mixture was transferred to streptavidin-coated plates and incubated at room temperature for 30 minutes to bind biotin-AL to the plates. After washing 3 times with Tris-buffered saline (TBS) (50mM Tris-HCl (pH8.0), 138 mM NaCl, 2.7mM KCl) containing 0.05% Tween-20, 100. mu.l of an antibody solution consisting of 50mM Tris-HCl (pH8.0), 138 mM NaCl, 2.7mM KCl, 1% BSA, 60ng/ml anti-phosphotyrosine monoclonal antibody labeled with europium beforehand using Amersham Pharmacia's apparatus, 4G10(Upstate Biotechnology) was added, and incubated at room temperature for 60 minutes. After washing, 100. mu.l of enhancing solution (Amersham Pharmacia Biotech) was added, and time-resolved fluorescence was measured with a multi-label counter ARVO (Wallac Oy, Finland) at 340nm excitation and 615nm emission with a 400 microsecond delay and a 400 microsecond window.
[ measurement of Compound IC50 value in peroxide Generation from human peripheral mononuclear cells ]
Blood (100 ml/donor) was collected from healthy human volunteers by venipuncture using a 50ml syringe containing 50 units of heparin, and red blood cells were removed by incubation with 1% (w/v) dextran and 0.45% (w/v) glucose for 30 minutes at room temperature. After centrifugation at 350Xg for 10 minutes, the cell pellets were suspended in 10ml PBS and the cell suspension was gradually fractionated in 50ml tubes (#2335-050, Iwaki, Japan) in PBS on a gradient of 20ml of 60% and 20ml of 80% Percoll (Amersham Pharmacia Biotech, Sweden). Peripheral polymorphonuclear leukocytes (PMNs) were obtained from the 60% and 80% Percoll phase interface after centrifugation at 400Xg for 30 minutes at room temperature. After two washes in PBS, the PMN was washed at 107The cells/ml were suspended at density in Hank's Balanced Salt Solution (HBSS: Nissui, Japan) enhanced with 10mM Na-Hepes (pH7.6), 0.1% BSA and kept on ice until further use.
Test Compounds for inhibition of formyl-methionyl-leucyl-phenylalanine (fMLP) -induced peroxide Generation, PMN (2X 10)5Cells/well) were seeded in 96-well clear-bottomed blackboards (Cat #3904, Costar) in HBSS, 10mMNa-Hepes (ph7.6), 0.1% BSA, and 3-aminobenzenedihydrazide (1 μ g/well; sigma) and test compound were pretreated at 37 ℃ for 10 min. fMLP peptides (Cat. # 4066; Peptide Institute Inc, Japan) were prepared at 10. mu.M in the same buffer and prepared in polypropylene plates (Cat. #3365, Coster). Chemiluminescence (CL) was measured with FDSS-6000(Hamamatsu Photonics) 15 minutes after stimulation with 1. mu.M fMLP. Percent inhibition at each compound concentration was calculated based on the first peak of CL at about 1 minute after addition of the stimulus, and IC50 values were determined from the inhibition curves.
To condition zymosan (OZ) and phorbol 12-myristate 13-acetate (PMA) stimulation, zymosan A (Sigma) was suspended in HBSS at a concentration of 1mg/ml, incubated with human serum at a final concentration of 9-80% for 30 minutes at 37 ℃ to condition zymosan, followed by centrifugation at 500Xg for 10 minutes at 4 ℃. The sediment was then washed twice with HBSS and finally suspended in HBSS to a concentration of 1-10 mg/ml. ConditionedZymosan (OZ) was used at 5mg/ml for stimulation. Phorbol 12-myristate 13-acetate (PMA) was initially dissolved in DMSO at a concentration of 0.1mg/ml as a stock solution and stored frozen at-20 ℃. A PMA solution was prepared from the stock solution by further dilution in HBSS to a concentration of 100 ng/ml. PMN (2X 10)5Cells/well) were seeded in 96-well white plate (Packard) in HBSS, 10mM Na-Hepes (ph7.6), 0.1% BSA, and 3-aminobenzenedihydrazide (1 μ g/well; sigma) and test compound were pretreated at 37 ℃ for 10 min. CL was measured with an Arvo counter (Wallac) 30 minutes after stimulation with OZ or PMA. Percent inhibition was calculated at each compound concentration and IC50 values were determined from the inhibition curves.
[ measurement of Compound IC50 value in elastase Release from human peripheral mononuclear cells ]
To test the inhibition of elastase release by compounds, PMNs (5X 10)5Cells/well) were seeded in 96-well plates in HBSS enhanced with 10mM Na-Hepes (ph7.6), 0.1% BSA, cells were seeded with cytochalasin B (0.1 μ g/well; nakarai, Japan) and test compounds were pretreated at 90 μ l/well for 10 minutes at 37 ℃. Cells were stimulated with 1 μ M fMLP at 37 ℃ for 15 minutes, and the supernatant (40 μ l/well) was collected into a 384-well blackboard (Packard) to measure elastase activity. . The fluorescent-based elastase activity was initiated by adding 10. mu.l of 0.5mM Suc-Ala-Ala-Ala-MCA (Cat. #3133 v; Peptide I nstitute Inc, Japan) in 384-well plates at room temperature. Fluorescence emission was measured at 460nm (. lamda.ex, 360nm) for 120 min using a Wallac-Arvo counter (Perkin Elmer, Boston, Mass.) fluorescence plate reader. IC50 values for compounds were determined at the initial rate of the reaction.
[ determination of Compound IC50 value in chemotaxis assay Using human PMN ]
Freshly prepared PMN (1.1X 10)7Cells/ml) were cultured in a polypropylene 96-well plate (Cat. #3365, Coster) in HBSS enhanced with 10mM Na-Hepes (ph7.6), 0.1% BSA, together with the compounds. Cells (100. mu.l) were incubated with test compound or vehicle for 30 minutes, transferred to a Multiwell insert (Cat. # 351183; Falcon)24w plate, and placed in the lower chamber of the plateFMLP (10nM, 0.5ml) was added in CO2The incubator measures chemotaxis at 37 ℃ for1 hour. Migrated cells were counted in a FACScan (Becton Dickinson, Franklin Lakes, N.J.). Percent inhibition was calculated at each compound concentration and IC50 values were determined from the inhibition curves.
[ determination of Compound IC50 value in chemotaxis assay Using transfectants ]
(1) Cells
Human CCR 3-transformed L1.2 cells were used. Human CCR 3-expressing li.2 stable transformants reference j.exp.med.183: 2437-2448, 1996. Human CCR 3-transformed L1.2 cells were maintained in RPMI-1640 enhanced with 10% FCS, 100 units/ml penicillin G and 100. mu.g/ml streptomycin and 0.4mg/ml Geneticin. One day prior to chemotaxis assay, cells were plated in media (5X 10)5Cells/ml) for 20-24 hours to increase expression of CCR 3.
(2) Chemotaxis test
Butyrate-pretreated cells were suspended at a density of 1.1X 107cells/ml in chemotactic buffer (Hanks solution Cat. #05906 Nissui, 20mM HEPES pH7.6, 0.1% human serum albumin Cat. # A-1887 Sigma). A mixture of 90. mu.l of the cell suspension and 10. mu.l of a compound solution diluted with chemotaxis buffer (10-fold concentration of the final concentration) was preincubated at 37 ℃ for 10 minutes. The mixture of cells and compounds was added to a 24-well chemotaxis chamber (Transwell)TMCat. #3421, Costar, pore size; 5 μm) in the upper chamber. 0.5ml of 10nM human recombinant eotaxin (Cat. #23209, Genzyme Techne) diluted in chemotaxis buffer was added to the lower chamber of the chemotaxis plate. Then in CO2The incubator was subjected to chemotaxis at 37 ℃ for 4 hours, and after 4 hours of culture, migrated cells were counted using a FACScan (Becton Dickinson). Percent inhibition was calculated at each compound concentration and IC50 values were determined from the inhibition curves.
[ mouse fMLP-induced pleurisy model ]
7-week-old BALB/c female mice were divided into 3 groups, non-treated group, vehicle group and treated group. Mice in the treatment group were first injected intravenously with different doses of the compound of the invention, and mice in the vehicle group were injected with a vehicle containing 10% Cremophor EL (Nacalai Tesque) in saline. 3 minutes after treatment, 1 mg/mouse fMLP in 3.3% DMSO in PBS was administered intrapleurally to both the vehicle and treatment groups of mice. 4 hours after fMLP, mice were sacrificed and pleural fluid was collected by twice with 2ml PBS pleural cavity. Total cells per ml of pleural fluid were counted using a hemocytometer. Cellular differentiation of pleural fluid was determined by counting the smallest 200 cells by Giemsa's-stained cytospin slide preparation. Statistical analysis was performed using GraphPad PRISM for Windows, version 2.01 by analyzing the changes in paired data using Student's-test or Dunnett's Post test.
For practical reasons, the compounds are grouped into certain active classes as follows:
in vitro IC500.1 [ mu ] M < B (═ or <) 0.5 [ mu ] M < C (═ or <) 2 [ mu ] M < D
The compounds of the invention likewise exhibit strong activity in vivo tests.
The decomposition is indicated in the following table (dec.).
Example 1-1:
z) -2- (8, 9-dimethoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) -1- (3-pyridyl) ethanol
(1) 3-oxo-3- (3-pyridyl) propionic acid methyl ester
A0.5M solution of sodium hexamethyldisilazide in toluene (22ml, 11mmol) was mixed with tetrahydrofuran (5ml) and the mixture was cooled to-78 ℃. To the cooled (-78 ℃ C.) mixture was added dropwise a solution of 3-acetylpyridine (1.0g, 8.26mmol) in tetrahydrofuran (5 ml). The mixture was warmed to room temperature and stirred for 3 hours. The mixture was cooled to-78 ℃ and dimethyl carbonate (1.2ml, 14.3mmol) was then added dropwise. The resulting solution was allowed to warm to room temperature and stirred overnight. The reaction solution was quenched by addition of aqueous 1N hydrochloric acid solution and extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate, 1/1) to give methyl 3-oxo-3- (3-pyridyl) propionate (1.0g, 68% yield) as an oil.
(2)2- (4, 5-dihydro-1H-imidazol-2-yl) -4, 5-dimethoxyaniline:
2-amino-4, 5-dimethoxybenzonitrile (5.0g, 28mmol) was added to ethylenediamine (7.9g, 131mmol) at room temperature, the resulting solution was warmed to 40, and a catalytic amount of phosphorus pentasulfide (50mg) was added. The mixture was heated to 80-90 deg.C and stirring was continued overnight. The reaction mixture was diluted with water and the resulting precipitate was collected by filtration to give 2- (4, 5-dihydro-1H-imidazol-2-yl) -4, 5-dimethoxyaniline (5.1g, 82%) as a solid.
(3) (-2- (8, 9-dimethoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) -1- (3-pyridyl) ethenol
A mixture of 2- (4, 5-dihydro-1H-imidazol-2-yl) -4, 5-dimethoxyaniline (0.15g, 0.68mmol) and methyl-3-oxo-3 (3-pyridinyl) propionate (0.20g, 1.12mmol) was stirred at 155 for1 hour. The reaction mixture was purified by column chromatography on silica gel (dichloromethane/methanol, 25/1) to give (Z) -2- (8, 9 dimethoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) -1- (3-pyridyl) ethenol (66.9mg, 28%) as a yellow solid.
Melting point: 275 deg.C
Mass spectrum: 351
In vitro PI3K- β inhibitory activity: c
In vitro PI3K- γ inhibitory activity: a. the
1H-NMR(500MHz，DMSO-d6)：δ3.79(3H，s)，3.88(3H，s)，3.98-4.08(4H，m)，5.63(1H，s)，7.13(1H，s)，7.24(1H，s)，7.50(1H，dd，J＝4.7，7.8Hz)，8.27(1H，dt，J＝1.6，7.8Hz)，8.67(1H，dd，J＝1.6，4.7Hz)，9.13(1H，d，J＝1.6Hz)，13.9(1H，bs)。
Examples 1 to 2:
(Z) -2- (8, 9-dimethoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) -1- (3-pyridinyl) -vinyl alcohol hydrochloride
To a solution of (Z) -2- (8, 9-dimethoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) -1- (3-pyridyl) ethenol (16.8mg, 0.05mmol) in dioxane (15ml) was added a solution containing 6N HCl (0.05ml) at room temperature. After stirring for 30 minutes, the mixture was dried under reduced pressure to give (Z) -2- (8, 9-dimethoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) -1- (3-pyridyl) ethenol hydrochloride (18.5mg, quantitative) as a yellow solid.
Melting point: more than 300 DEG C
Mass spectrum: 351
In vitro PI3K- β inhibitory activity: c
In vitro PI3K- γ inhibitory activity: a. the
1H-NMR(500MHz，DMSO-d6)：δ3.88(3H，s)，4.00(3H，s)，4.22(2H，t，J＝9.1Hz)，4.55(2H，t，J＝9.1Hz)，6.21(1H，s)，7.60(1H，s)，7.66(1H，dd，J＝4.7，8.2Hz)，7.90(1H，s)，8.47(1H，d，J＝8.2Hz)，8.79(1H，d，J＝4.7Hz)，9.28(1H，s)，14.9(1H，bs)。
Examples 1 to 3:
2- [ 7-methoxy-8- (methoxymethyloxy) -2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl ] -1-pyridin-3-yl vinyl alcohol
(1) 4-formyl-2-methoxy-3-nitrophenyl acetate
Vanillin acetate 5.00g gives the title compound 4.54g as a yellow solid in 73.6% yield using the method described in US4287341 or j. chem. soc.376 (1948).
H-NMR(500MHz，DMSO-d6)δ：2.40(s 3H)，3.87(s 3H)，7.75(d1H J＝8.4Hz)，7.94(d 1H J＝8.4Hz)，9.90(s 1H)
(2) 4-hydroxy-3-methoxy-2-nitrobenzaldehyde
A mixture of 4.54g (19.0mmol) of 4-formyl-2-methoxy-3-nitrophenylacetate and 5.24g (37.9mmol) of potassium carbonate in 40mL of methanol was stirred at room temperature for 2 hours, the reaction mixture was poured into water, acidified with a 1N hydrochloric acid solution and extracted with AcOEt. The organic layer was washed with brine, over MgSO4Dry, filter and evaporate the solvent. The residue was washed with cyclohexane to give the title compound 3.60g as a white solidThe yield thereof was found to be 96.3%.
(3) 4-hydroxy-3-methoxy-2-nitrobenzonitrile
To a mixture of 14.5g (73.5mmol) of 4-hydroxy-3-methoxy-2-nitrobenzaldehyde in 150mL of 28% ammonia solution and 15mL of tetrahydrofuran was added 22.4g (88.2mmol) of iodine, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was acidified with 2N HCl solution and extracted with ether. The organic layer was washed with brine, over MgSO4Dry, filter and evaporate the solvent. The residue was washed with diisopropyl ether to give the title compound 12.1g as a brown solid. The yield thereof was found to be 84.5%.
(4) 3-methoxy-4- (methoxymethoxy) -2-nitrobenzonitrile
A mixture of 1.00g of 4-hydroxy-3-methoxy-2-nitrobenzonitrile, 0.47mL (6.18mmol) of chloromethyl methyl ether and 3.56g (25.8mmol) of potassium carbonate in 10mL of N, N-dimethylformamide was stirred at 50 ℃ for 2 hours. The reaction mixture was poured into water and extracted with ether. The organic layer was washed with brine, dried, filtered and the solvent evaporated. Chromatography on silica gel (cyclohexane/AcOEt ═ 4/1) gave 1.03g of the title compound as a colorless solid in 83.5% yield.
(5) 2-amino-3-methoxy-4- (methoxymethoxy) benzonitrile
To 6.00g of 5% palladium on activated carbon was added a solution of 6.00g (25.2mmol) of 3-methoxy-4- (methoxymethoxy) -2-nitrobenzonitrile in 50mL of ethanol under an argon atmosphere, and the mixture was stirred at room temperature for 8 hours under hydrogen. The reaction mixture was filtered, the filtrate was concentrated in vacuo, and the title compound was obtained by silica gel chromatography (cyclohexane/AcOEt ═ 4/1) as a white solid in a yield of 53.9%.
(6) [6- (4, 5-dihydro-1H-imidazol-2-yl) -2-methoxy-3- (methoxymethoxy) phenyl ] amine
A solution of 475mg (2.28mmol) of 2-amino-3-methoxy-4- (methoxymethoxy) benzonitrile and 25.4mg (0.11mmol) of phosphorus pentasulfide in 2.75g of ethylenediamine was stirred at 120 ℃ overnight. The reaction mixture was cooled to room temperature, poured into water, and the precipitate was collected and washed with water to give the title compound 293mg of a white solid in 51.1% yield.
(7) 3-oxo-3- (pyridin-3-yl) propionic acid ethyl ester
To a suspension of nicotinic acid (5.00g, 40.6mmol) in tetrahydrofuran (50mL) was added carbonyldiimidazole (9.76 g, 60.9mmol) at 5 ℃ and the mixture was stirred at room temperature for1 hour. In another flask, MgCl was stirred at 50 deg.C2A suspension of 4.64g (48.7mmol) and 10.37g (60.92mmol) of potassium ethyl malonate in 50mL of tetrahydrofuran was kept for 4 hours. To this suspension was added the above imidazole solution at room temperature and stirred for 12 hours. The reaction was quenched by addition of water and extracted with ethyl acetate. The organic layer was washed with brine, over MgSO4Dry, filter and evaporate the solvent. Chromatography on silica gel (cyclohexane/AcOEt ═ 2/1) gave the title compound 3.89g of a pale yellow oil in 49.5% yield.
(8)2- [ 7-methoxy-8- (methoxymethyloxy) -2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl ] -1-pyridin-3-yl vinyl alcohol
A solution of 1.31g (5.20mmol) of [6- (4, 5-dihydro-1H-imidazol-2-yl) -2-methoxy-3- (methoxymethoxy) phenyl ] amine and 1.00g (5.20mmol) of ethyl 3-oxo-3- (pyridin-3-yl) propionate in 30mL of toluene was refluxed overnight, the precipitate was collected and washed with diethyl ether to give the title compound 1.52g of a pale yellow solid in 76.9% yield.
Melting point: 215 ℃ 216 DEG C
Mass spectrum: 381
In vitro PI3K- β inhibitory activity:
in vitro PI3K- γ inhibitory activity: b is
H-NMR(500MHz，CDCl3)δ：3.54(s 3H)，3.95(t 2H J＝9.5Hz)，4.08(s 3H)，4.22(t 2H J＝9.5Hz)，5.30(s 2H)，5.38(s 1H)，6.98(d 1HJ＝8.8Hz)，7.37(dd 1H J＝8.0Hz，4.9Hz)，7.64(d 1H J＝8.8Hz)，8.21(dt 1HJ＝8.0Hz，1.7Hz)，8.67(dd 1H J＝4.9Hz，1.7Hz)，9.09(d1HJ＝1.7Hz)，13.75(s 1H)。
Examples 1 to 4:
5- (2-hydroxy-2-pyridin-3-ylvinyl) -7-methoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-8-ol hydrochloride
A suspension of 1.52g (4.00mmol) of 2- [ 7-methoxy-8- (methoxymethoxy) -2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl ] -1-pyridin-3-yl vinyl alcohol (example 1-3) in 4N HCl (Amersham pharmacia Biotech) in 30mL of 1, 4-dioxane and 0.3mL of water was stirred at room temperature overnight. The reaction mixture was diluted with ether and the precipitate was collected and washed with ether to give the title compound 1.23g of a yellow solid in 82.4% yield.
Melting point: 245 DEG C
Mass spectrum: 337
In vitro PI3K- β inhibitory activity: c
In vitro PI3K- γ inhibitory activity: a. the
H-NMR(500MHz，DMSO-d6)δ：3.97(s 3H)，4.22(dd 2H J＝12.3Hz，9.0Hz)，4.43(dd 2H J＝12.3Hz，J＝9.0Hz)，6.17(s 1H)，7.10(d 1HJ＝9.0Hz)，7.71(dd 1H J＝7.7Hz，4.7Hz)，7.98(d 1HJ＝9.0Hz)，8.57(brd 1H J＝7.7Hz)，8.82(dd 1H J＝4.7Hz，1.4Hz)，9.34(d1HJ＝1.4Hz)，11.79(s 1H)，14.60(s 1H)
Examples 1 to 5:
4- [5- (2-hydroxy-2-pyridin-3-ylvinyl) -7-methoxy-2, 3-dihydroimidazo [1, 2c ] quinazolin-8-yl ] oxy } butanoic acid methyl ester
Stirring 5- (2-hydroxy-2-pyridin-3-ylvinyl) -7-methoxy-2, 3-dihydroimidazo [1, 2-c ] at 120 deg.C]A mixture of 50.4mg (0.14mmol), methyl chlorobutyrate 22.2mg (0.16mmmol) and potassium carbonate 186.9mg (1.35mmmol) in N, N-dimethylformamide 1mL for 4 hours was quinazoline-8-ol hydrochloride (examples 1-4). The reaction mixture was poured into water and extracted with dichloroethane. The organic layer was washed with brine, over MgSO4Dry, filter and evaporate the solvent. The residue was washed with diethyl ether to give the title compound 35.0mg of a yellow solid in 59.3% yield.
Melting point: 199 + 200 deg.C
Mass spectrum: 437
In vitro PI3K- β inhibitory activity: c
In vitro PI3K- γ inhibitory activity: a. the
H-NMR(500MHz，CDCl3) δ: 2.20 (quintuple 2H J ═ 7.1Hz), 2.58(t 2HJ ═ 7.09Hz), 3.71(s 3H), 3.94(t 2H J ═ 9.5Hz), 4.06(s 3H), 4.15(t 2HJ ═ 7.1Hz), 4.21(t2H J ═ 9.5Hz), 5.38(s 1H), 6.76(d 1H J ═ 8.8Hz), 7.37(dd 1H J ═ 8.2Hz, 5.2Hz), 7.65(d 1H J ═ 8.8Hz), 8.21(dtJ ═ 8.2Hz, 2.1Hz), 8.67(d 1H J ═ 5.2Hz), 9.09(s 1H), 3613.70 (s1H), 1H)
Examples 1 to 6:
examples 3 to 4; 4- [5- (2-hydroxy-2-tiden-3-ylvinyl) -7-methoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-8-yl ] oxy } butanoic acid
A solution of methyl 4- { [5- (2-hydroxy-2-pyridin-3-ylvinyl) -7-methoxy-2, 3-dihydro-imidazo [1, 2-c ] quinazolin-8-yl ] oxy } butanoate (examples 1-5)20.0mg (0.05mmol) in 0.1mL of INLiOH solution and 1.0mL of ethanol was stirred at room temperature overnight. The reaction mixture was neutralized with 1N HCl solution, concentrated in vacuo, and the residue triturated with water and the precipitate collected to give the title compound as a white solid in 10.0mg, 51.7% yield.
Melting point: 257 ℃ and 258 DEG C
Mass spectrum: 423
In vitro PI3K- β inhibitory activity: b is
In vitro PI3K- γ inhibitory activity: a. the
H-NMR(500MHz，DMSO-d6) δ: 2.02 (quintet 2H J ═ 6.2Hz), 2.45(t 2HJ ═ 6.2Hz), 3.94(s 3H), 3.98(brt 2H) J＝8.5Hz)，4.06(brt 2HJ＝8.5Hz)，4.14(t 2H J＝6.2Hz)，5.67(s 1H)，6.97(d 1H J＝8.7Hz)，7.49(dd 1H J＝8.2Hz，4.4Hz)，7.57(d 1HJ＝8.7Hz)，8.29(d 1H J＝8.2Hz)，8.67(d 1H J＝4.4Hz)，9.14(s1H)，12.15(s1H)，13.76(s1H)
Examples 1 to 7:
hydrochloride salt of 4- [5- (2-hydroxy-2-pyridin-3-ylvinyl) -7-methoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-8-yl ] oxy } butyric acid
A mixture of 4- { [5- (2-hydroxy-2-pyridin-3-ylvinyl) -7-methoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-8-yl ] oxy } butyric acid (examples 1-6)4.0mg (9.5 μmol) in 1, 4-dioxane 2.0mL was stirred at room temperature for 2 hours, the reaction mixture was diluted with diethyl ether and the precipitate was collected to give the title compound 4.00mg of a yellow solid in 92.0% yield.
Melting point: 249 ℃ 251 ℃
Mass spectrum: 423
In vitro PI3K- β inhibitory activity: b is
In vitro PI3K- γ inhibitory activity: a. the
H-NMR(500MHz，DMSO-d6) δ: 2.06 (quintuple 2H J ═ 7.3Hz), 2.46(t 2HJ ═ 7.3Hz), 4.01(s 3H), 4.24(t 2HJ ═ 9.0Hz), 4.29(t 2H J ═ 7.3Hz), 4.45(t 2HJ ═ 9.0Hz), 6.18(s 1H), 7.36(d 1H J ═ 9.1Hz), 7.70(dd 1HJ ═ 7.9Hz, 5.0Hz), 8.14(d 1H J ═ 9.1Hz), 8.56(brd 1H J ═ 7.9Hz), 8.82(brd 1HJ ═ 5.0Hz), 9.34(s1H), 12.34(s1H), 14.57(s 1H)
Examples 1 to 8:
2- [ 7-methoxy-8- (4-morpholin-4-yl-4-oxobutoxy) -2, 3-dihydroimidazo [1, 2c ] quinazolin-5-yl ] -1-pyridin-3-yl vinyl alcohol
To a solution of 20.0mg (0.044mmol), 19.0mg (0.22mmol) of morpholine and 0.038mL (0.22mmol) of N, N-diisopropylethylamine (0.038 mL) in 2.0mL of N, N-dimethylformamide of 4- { [5- (2-hydroxy-2-pyridin-3-ylvinyl) -7-methoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-8-yl ] oxy } butyric acid (examples 1-6) was added 34.0mg (0.065mmol) of PyBOP (1H-1, 2, 3-benzotriazol-1-yloxy) (tripyrrolidin-1-yl) phosphonium hexafluorophosphate and stirred at 80 ℃ overnight. After cooling to room temperature, the reaction mixture was poured into water, and the precipitate was collected and washed with water to give the title compound 13.0mg of a white solid in a yield of 60.7%.
Melting point: 234 ℃ and 235 DEG C
Mass spectrum: 492
In vitro PI3K- β inhibitory activity: b is
In vitro PI3K- γ inhibitory activity: a. the
H-NMR(500MHz，DMSO-d6)δ：2.03(quint 2H J＝6.6Hz)，3.46(m4H)，3.56(m 4H)，3.96(s 3H)，3.99(brd 2H J＝8.2Hz)，4.05(br d 2HJ＝8.2Hz)，4.15(t 2H J＝6.6Hz)，5.66(s 1H)，6.98(d J＝8.8Hz)，7.50(dd 1H J＝7.7Hz，4.7Hz)，7.57(d 1H J＝8.8Hz)，8.29(brd 1HJ＝7.7Hz)，8.67(br d 1H J＝4.7Hz)，9.14(s 1H)，13.76(s 1H)
In a similar manner to that described above for examples 1-1 to 1-8, the compounds of examples 1-9 to 1-210 were synthesized.
TABLE 1
Example 2-1:
n- (2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) nicotinamide
(1)2- (4, 5-dihydro-IH-imidazol-2-yl) aniline
2-aminobenzonitrile (9.00g, 76.2mmol) was added to ethylenediamine (25.5ml, 381mmol) in small portions with stirring at 0 ℃. After addition of phosphorus pentasulfide (200mg, 0.900mmol), the mixture was stirred at 100 ℃ overnight. After cooling to 0 ℃, the reaction solution was diluted with water. The resulting white precipitate was collected by filtration, washed with water and diethyl ether, and dried under reduced pressure to give 2- (4, 5-dihydro-1H-imidazol-2-yl) aniline (10.0g, 81% yield).
(2)2, 3-Dihydroimidazo [1, 2-c ] quinazolin-5-ylamine hydrobromide
Cyanogen bromide (3.61g, 34.1mmol) was added portionwise to a suspension of 2- (4, 5-dihydro-1H-imidazol-2-yl) aniline (5.00g, 31.0mmol) in 85% methanol (60ml) at 0 ℃ and the mixture was stirred at room temperature overnight. After the mixture was concentrated under reduced pressure, the resulting precipitate was collected by filtration. The river green solid was washed with water, methanol and ether in sequence and dried under reduced pressure to give 2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-ylamine hydrobromide (4.94g, 60% yield).
(3) N- (2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) nicotinamide
To 2, 3-dihydroimidazo [1, 2-c ] at room temperature]To a suspension of quinazolin-5-ylamine hydrobromide (500mg, 1.87mmol) and nicotinic acid (346mg, 2.81mmol) in N, N-dimethylformamide (25ml) were added benzotriazol-1-yloxy-trispyrrolidine-phosphonium hexafluorophosphate (1.46g, 2.81mmol) and N, N-diisopropylethylamine (1.30ml, 7.49 mmol). The mixture was heated at 80 ℃ for 4 hours and after cooling to room temperature, the mixture was saturated with aqueous NaHCO3And (5) quenching the solution. Filtering to collect the obtained precipitate, washing with water and diethyl ether, and drying under reduced pressure to obtain N- (2, 3-dihydroimidazo [1, 2-c)]Quinazolin-5-yl) nicotinamide (450mg, 83% yield).
Melting point: 238℃ (decomposition)
Mass spectrum: 292
In vitro PI3K- β inhibitory activity: b is
In vitro PI3K- γ inhibitory activity: a. the
1H-NMR(300Hz，DMSO-d6)：δ4.00-4.11(2H，m)，4.11-4.21(2H，m)，7.29(1H，ddd，J＝3.0，5.3，7.9Hz)，7.52(1H，dd，J＝4.9，7.9Hz)，7.57-7.66(2H，m)，7.89(1H，d，J＝7.9Hz)，8.42-8.48(1H，m)，8.73(1H，dd，J＝1.9，4.9Hz)，9.32(1H，d，J＝1.1Hz)，12.36(1H，s)。
Example 2-2:
n- (2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) nicotinamide hydrochloride
To a suspension of N- (2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) nicotinamide (150mg, 0.515mmol) in tetrahydrofuran (4ml) at 0 ℃ was added a 4N solution of hydrochloric acid in 1, 4-dioxane (2ml, 8 mmol). The mixture was stirred at room temperature for1 hour and concentrated under reduced pressure. The resulting residue was triturated with ether, the resulting precipitate collected by filtration, washed with ether and dried under reduced pressure to give N- (2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) nicotinamide hydrochloride (192mg, quant.).
Melting point: 289 deg.C (decomposition)
Mass spectrum: 292
In vitro PI3K- β inhibitory activity: b is
In vitro PI3K- γ inhibitory activity: a. the
1H-NMR(300MHz，DMSO-d6)：δ4.18-4.30(2H，m)，4.54-4.65(2H，m)，7.56-7.65(1H，m)，7.88(1H，dd，J＝4.9，7.9Hz)，7.97-8.10(2H，m)，8.64(1H，d，J＝7.9Hz)，8.80(1H，d，J＝7.9Hz)，8.95(1H，dd，J＝1.5，5.3Hz)，9.43(1H，d，J＝1.1Hz)，12.7-13.3(1H，br)。
Examples 2 to 3:
6- (acetylamino) -N- [8- (morpholin-4-yl) -2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl ] nicotinamide
(1)4- (morpholin-4-yl) -2-nitrobenzonitrile
A mixture of 4.20g (21.75mmol) of 2, 4-dinitrobenzonitrile and 5.7mL (66.0mmol) of morpholine in 20mL of N, N-dimethylformamide was stirred at room temperature for 20 hours. The reaction mixture was poured into water and the precipitate was collected and washed with water to give the title compound 4.20g as an orange solid in 74.5% yield.
(2) 2-amino-4- (morpholin-4-yl) benzonitrile
To an ice-bath cooled mixture of 12.8g (56.7mmol) of tin (II) chloride dihydrate in 40mL of concentrated hydrochloric acid was added 4.20g (16.09mmol) of 4- (morpholin-4-yl) -2-nitrobenzonitrile, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into dilute NaOH solution and extracted with ethyl acetate. The organic layer was washed with water and brine, MgSO4Drying and evaporating the solvent. The crude product was washed with diethyl ether to give the title compound as 3.13g of an off-white solid in 95.0% yield.
(3) [2- (4, 5-dihydro-1H-imidazol-2-yl) -5- (morpholin-4-yl) phenyl ] amine
To a solution of 3.65g (18.0mmol) of 2-amino-4- (morpholin-4-yl) benzonitrile in 20mL of ethylenediamine was added 4.00mg (0.018mmol) of phosphorus pentasulfide, and the mixture was stirred at 140 ℃ for 16 hours. After cooling to room temperature, the solvent was evaporated. The residue was washed with water and diethyl ether to give the title compound 3.70g as an off-white solid in 83.5% yield.
(4)8- (morpholin-4-yl) -2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-amine hydrobromide
To a suspension of 3.60g (14.6mmol) of [2- (4, 5-dihydro-1H-imidazol-2-yl) -5- (morpholin-4-yl) phenyl ] amine in 20mL of 2-propanol was added in portions 2.32g (21.9mmol) of cyanogen bromide at 0 ℃ and stirred at 100 ℃ for 2 hours. After cooling to room temperature, the precipitate was collected and washed with diethyl ether to give the title compound 1.20g as a yellow solid in 77.5% yield.
(5)6- (acetylamino) nicotinic acid
A mixture of 5.00g (36.5mmol) of 6-aminonicotinic acid and 3.80mL (40.2mmol) of acetic anhydride in 30mL of pyridine was stirred at 140 ℃ for 24 hours, ethyl acetate was added to the reaction mixture, and the mixture was acidified to pH2 with dilute hydrochloric acid solution. The organic layer was washed with water and brine, MgSO4Dry, filter and evaporate the solvent. The residue was washed with diisopropyl ether to give the title compound 1.70g as an off-white solid in 26% yield.
(6)6- (acetylamino) -N- [8- (morpholin-4-yl) -2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl ] nicotinamide
To 8- (morpholin-4-yl) -2, 3-dihydroimidazo [1, 2-c)]To a mixture of 105.7mg (0.30mmol) of quinazoline-5-amine hydrobromide, 81.1mg (0.45mmol) of 6- (acetylamino) nicotinic acid and 0.26mL (1.50mmol) of N, N-diisopropylethylamine in 2mL of N, N-dimethylformamide was added 234.2mg (0.45mmol) of PyBOP ((1H-1, 2, 3-benzotriazol-1-yloxy) (trispyrrolidin-1-yl) phosphonium hexafluorophosphate) and the mixture was stirred at 90 ℃ for 16 hours. After cooling to room temperature, saturated NaHCO was added3And (3) solution. Collecting the precipitateWashing with water, methanol and ether gave the title compound 41.1mg of a yellow solid in 31.6% yield.
Melting point: 228 deg.C
Mass spectrum: 434
In vitro PI3K- β inhibitory activity: c
In vitro PI3K- γ inhibitory activity: a. the
H-NMR(500MHz，DMSO-d6)δ：3.22-3.30(m 4H)，3.74(s 3H)，3.86(m2H)，3.97(m 2H)，6.77(br s 1H)，7.60(m1H)，8.07(m 1H)，8.32(m1H)，8.95(br s1H)，10.60(s 1H)
Examples 2 to 4:
6- (acetylamino) -N- [8- (morpholin-4-yl) -2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl ] nicotinamide hydrochloride
To a mixture of 6- (acetylamino) -N- [8- (morpholin-4-yl) -2, 3-dihydroimidazo [1, 2-c ] -quinazolin-5-yl ] nicotinamide (example 2-3)20.0mg (0.046mmol) in 1.5mL 1, 4-dioxane was added 4N hydrochloric acid in 0.5mL 1, 4-dioxane and stirred at room temperature for 40 minutes. The precipitate was collected and washed with diethyl ether to give the title compound 17.0mg of a yellow solid, 78%.
Melting point: 237 deg.C
Mass spectrum: 434
In vitro PI3K- β inhibitory activity: b is
In vitro PI3K- γ inhibitory activity: a. the
H-NMR(500MHz，DMSO-d6)δ：3.41-3.76(m 7H)，3.86(m2H)，4.10(m2H)，7.20(m 1H)，7.39(m 1H)，8.19(mIH)，8.45(m 1H)，9.09(br s1H)，10.86(s 1H)
Examples 2 to 5:
n- (8-hydroxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) nicotinamide
A suspension of 3.50g (10.9mmol) of N- (8-methoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) nicotinamide (example 2-22) and 4.25g (54.5mmol) of sodium sulfide in 10mL of 1-methyl-2-pyrrolidone was heated to 160 ℃ for 4 hours (LC-MS showed complete consumption of starting material). The mixture was cooled to room temperature and the volatile by-products evaporated. The mixture was partitioned between chloroform and 0.5N NaOH solution, the aqueous layer was neutralized, and the precipitate formed was collected to give the title compound 2.34g as an off-white solid in 69.9% yield.
Melting point: 289 deg.C
Mass spectrum: 308
In vitro PI3K- β inhibitory activity: c
In vitro PI3K- γ inhibitory activity: b is
H-NMR(500MHz，DMSO-d6)δ：4.01(m 2H)，4.15(m 2H)，6.75(dd 1HJ＝8Hz，2Hz)，6.91(s 1H)，7.52(dd 1HJ＝8Hz，5Hz)，7.75(d 1H J＝8Hz)，8.44(d1H J＝8Hz)，8.73(dd 1HJ＝5Hz，2Hz)，9.31(s 1H)，10.61(br s1H)，12.24(br s 1H)
Examples 2 to 6:
n- {8- [2- (1-pyrrolyl) ethoxy ] -2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl } nicotinamide
In a sealed tube, N- (8-hydroxy-2, 3-dihydroimidazo [1, 2-cJ quinazolin-5-yl)]A suspension of 70.0mg (0.23mmol) of nicotinamide (example 2-1), 47.6mg (0.27mmol) of N- (2-bromoethyl) pyrrole and 126mg (0.91mmol) of potassium carbonate in 5mL of N, N-dimethylformamide is heated to 120 ℃ for 3 hours. The reaction mixture was concentrated, partitioned between dichloromethane and water, the organic layer washed with 0.1N NaOH solution and brine, and Na2SO4Drying and evaporation of the solvent gave 49.0mg of the title compound as an off-white solid in 54% yield.
Melting point: 209 deg.C
Mass spectrum: 401
In vitro PI3K- β inhibitory activity: b is
In vitro PI3K- γ inhibitory activity: b is
H-NMR(500MHz，DMSO-d6)δ：4.00(m 2H)，4.12(m2H)，4.30(s 4H)，6.00(m 2H)，6.84(m 2H)，6.85(dd 1H J＝6Hz，2Hz)，7.27(d 1H J＝2Hz)，7.52(dd 1H J＝6Hz)，7.76(d 1H J＝8Hz)，8.44(dd 1H J＝8Hz，2Hz)，8.72(dd 1H J＝5Hz，2Hz)，9.31(s 1H)，12.32(s 1H)。
The compounds in examples 2-7 to 2-368 were synthesized in a similar manner to that in examples 2-1 to 2-6 described above.
TABLE 2
Example 3-1:
(Z) -2-imidazo [1, 2-c1 quinazolin-5-yl-1- (2-thiophen) ethenol (1)2- (1H-imidazol-2-yl) aniline
A mixture of 2- (4, 5-dihydro-1H-imidazol-2-yl) aniline hydrobromide (50.0mg, 0.207mmol) and manganese dioxide (170mg, 1.96 mmol) in N, N' -dimethylpropylurea (2.0mL) was heated at 150 deg.C (bath temperature). After 1 hour, the reaction mixture was cooled to room temperature, a solution of hydroxylamine hydrochloride (0.5g) in water (50mL) was poured, and the resulting mixture was dissolved in ethyl acetateAnd (5) extracting with ethyl acetate. The separated organic layer was washed with brine, over MgSO4Drying, filtering, and concentrating under reduced pressure. The crude residue was triturated with isopropyl ether, the precipitate was removed by filtration, the filtrate was concentrated under reduced pressure and the residue was purified by preparative thin layer chromatography (silica gel, ethyl acetate as eluent) to give 2- (1H-imidazol-2-yl) aniline (20mg, 61% yield).
(2) 3-oxo-3- (2-thienyl) propionic acid ethyl ester
To a suspension of 2-thiophenecarboxylic acid (6.48g, 50.57mmol) in tetrahydrofuran (100ml) was added 1, 1' -carbonylbiimidazole (8.61g, 53.09mmol) portionwise at 5 ℃ and the mixture was allowed to warm to room temperature with constant stirring for1 hour. The reaction mixture was added to a suspension hydrate of magnesium chloride (4.86g, 51.07mmol) and 3-ethoxy-3-oxopropionate (12.91g, 75.85mmol) in tetrahydrofuran (50ml), and after stirring at 50 ℃ for 2 hours and at room temperature overnight, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, and MgSO4Drying, filtering and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane, 15/85) to give ethyl 3-oxo-3- (2-thienyl) propionate- (7.83g, 78% yield).
(3) (Z) -2-imidazo [1, 2-c ] quinazolin-5-yl-1- (2-thienyl) ethenol
A mixture of 2- (1H-imidazol-2-yl) aniline (60.0mg, 0.38mmol), ethyl 3-oxo-3- (2-thienyl) propionate (74.7mg, 0.38mmol) and p-toluenesulfonic acid monohydrate (36.1mg, 0.19mmol) in toluene (30ml) was heated at reflux for 2 hours. After cooling to room temperature, the reaction mixture was poured into saturated NaHCO3In the solution, the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and MgSO4Drying, filtering, and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane, 2/3-1/1) to give (Z) -2-imidazo [1, 2-c)]Quinazolin-5-yl-1- (2-thienyl) ethenol (37.0mg, 33% yield).
Melting point: 128 deg.C
Mass spectrum: 294
In vitro PI3K- β inhibitory activity:
in vitro PI3K- γ inhibitory activity: d
1H-NMR(300MHz，CDCl3)：δ6.11(1H，s)，7.16(1H，dd，J＝3.8，4.9Hz)，7.34-7.41(2H，m)，7.53-7.60(3H，m)，7.64(1H，d，J＝1.7Hz)，7.73(1H，dd，J＝1.1，3.8Hz)，8.34(1H，dd，J＝0.9，7.8Hz)，14.70(1H，bs)。
Examples 3 to 2
(Z) -2-imidazo [1, 2-c ] quinazolin-5-yl-1- (2-thienyl) ethenol hydrochloride
To a solution of (Z) -2-imidazo [1, 2-c ] quinazolin-5-yl-1- (2-thienyl) ethenol (0.06g, 0.07mmol) in chloroform (1.0ml) was added 4NHCl1, 4-dioxane solution (0.5 ml). The mixture was diluted with ether, the resulting precipitate was collected by filtration, washed with ether, and dried under reduced pressure to give (Z) -2-imidazo [1, 2-c ] quinazolin-5-yl-1- (2-thienyl) ethenol hydrochloride (0.07g, quantitative) as a yellow solid.
Melting point: 263 deg.C (decomposition)
Mass spectrum: 294
In vitro PI3K- β inhibitory activity:
in vitro PI3K- γ inhibitory activity: d
1H-NMR(300MHz，DMSO-d6)：δ6.79(1H，s)，7.28(1H，dd，J＝3.8，4.9Hz)，7.45(1H，t，J＝7.0Hz)，7.66-7.77(2H，m)，7.82(1H，d，1.7)，7.91(1H，dd，J＝1.1，5.0Hz)，8.17(1H，dd，J＝1.1，3.8Hz)，8.30(1H，dd，J＝1.0，8.0Hz)，8.62(1H，d，J 1.7Hz)，14.36(1H，br)。
Example 4-1:
n-imidazo [1, 2-c ] quinazolin-5-yl nicotinamide
(1) Imidazo [1, 2-c ] quinazolin-5-amines
To a solution of 2- (1H-imidazol-2-yl) aniline (0.06g.0.38mmol) in methanol (3ml) was added cyanogen bromide (0.05g, 0.45mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water and the resulting precipitate was collected by filtration, washed with acetone and dried under reduced pressure to give imidazo [1, 2-c ] quinazolin-5-amine hydrobromide (0.06g, 61% yield) as a white solid.
(2) N-imidazo [1, 2-c ] quinazolin-5-yl nicotinamide
To imidazo [1, 2-c)]To a mixture of quinazoline-5-amine hydrobromide (93mg, 0.35mmol) and nicotinic acid (124mg, 1.01mmol) and DMF (2.5ml) was added benzotriazol-1-yloxy-trispyrrolidinyl-phosphonium hexafluorophosphate (525mg, 1.01mmol) followed by N, N-diisopropylethylamine (0.264ml, 1.51mmol) and the mixture was stirred at 80 ℃ for 6 h. After having been cooled to room temperature, the mixture was cooled,the reaction mixture was poured into aqueous saturated NaHCO3In solution. Filtering and collecting the obtained precipitate, washing with acetone, and drying under reduced pressure to obtain N-imidazo [1, 2-c]Quinazolin-5-ylnicotinamide (40mg, 39% yield) was a white solid.
Melting point: 223 + 224 deg.C (decomposition)
Mass spectrum: 290
In vitro PI3K- β inhibitory activity:
in vitro PI3K- γ inhibitory activity: c
1H-NMR(300MHz，DMSO-d6)：δ7.53-7.62(3H，m)，7.70(1H，t，J＝7.34Hz)，8.00(1H，d，J＝8.10Hz)，8.30(1H，d，J＝7.91Hz)，8.44(1H，s)，8.63(1H，d，J＝7.72Hz)，8.81(1H，dd，J＝1.5，4.7Hz)，9.49(1H，s)，13.49(1H，br)。
Example 4 to 2
N-imidazo [1, 2-c ] quinazolin-5-yl nicotinamide hydrochloride
To a solution of N-imidazo [1, 2-c ] quinazolin-5-ylnicotinamide (40mg, 0.14mmol) in methanol (20ml) was added a 4N solution of hydrochloric acid in 1, 4-dioxane (0.5ml) and the mixture was concentrated under reduced pressure. The resulting solid was collected by filtration, washed with tetrahydrofuran, and dried under reduced pressure to give N-imidazo [1, 2-c ] quinazolin-5-ylnicotinamide hydrochloride (40mg, 89% yield) as a white solid.
Melting point: 228 deg.C (decomposition)
Mass spectrum: 290
In vitro PI3K- β inhibitory activity:
in vitro PI3K- γ inhibitory activity: c
1H-NMR(300MHz，DMSO-d6)：δ7.60(2H，br)，7.65(1H，t，J＝7.5Hz)，7.82(1H，dd，J＝7.3，8.1Hz)，7.92(1H，s)，8.02(1H，dd，J＝5.5，7.9Hz)，8.54(1H，d，J＝8.3Hz)，8.73(1H，s)，9.02(1H，dd，J＝1.3，5.3Hz)，9.07(1H，d，J＝7.53Hz)，9.67(1H，s)。
Reference to the literature
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[9] Stephens LR, Jackson TR, Hawkins PT: agonist-stimulated synthesis of inositol phosphate (3, 4, 5) -triphosphate: a new intracellular signaling system? (azonist-stimulated synthesis of phosphatyilinosol-triphosphate: a new intracellular signalling system; 1179: 27-75.
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[11] Stoyanov B, Volinia S, HanckT, RubioI, Loubtchenkov M, Malekd, Stoyanova S, Van-Haesebroeck B, Dhand R, Nurnberg B, GierschikP, Seedorf K, Hsuanan JJ, Waterfield MD, Wetzker R: cloning and characterization of G protein-activated human phosphoinositide-3 kinase (Cloning and characterization of G protein-activated human phosphoinositide-3 kinase.) Science 1995; 269: 690-693.
[12] Krugmann S, Hawkins PT, Pfyer N, Braselmann S: characterization of the interaction between two subunits of the p101/p110 gamma phosphoinositide 3-kinase and their role in G.beta.gamma.subunit activation of this enzyme (characterization of the interactions between the two subunits of the enzyme of the p101/p110 gamma phosphoinositide 3-kinase and the enzyme in the activation of enzyme by G.beta.gamma.subunits.) J.biol.chem.1999; 274: 17152-17158.
[13] Sasaki T, Suzuki A, Sasaki J, Penninger JM: phosphoinositide 3-kinase in immunity: training from stunning mice (Phosphoinositide 3-kinases immininity: mice from knockout mice.) j. biochem.2002; 131: 495-501.
[14] Sasaki T, Irie-Sasaki J, Jones RG, Oliveira-dos-SantoasAJ, Stanford.WL, Bolon B, Wakeham A, Itie A, BouchardD, Kozieradzki I, Joza N, Mak TW, Ohashi PS, Suzuki A, Penninger: the role of PI3K γ in thymocyte development, T cell activation and neutrophil migration (Function of PI3K γ in thymocyte degradation, Tcell activation, and neutrophile migration.) Science 2000; 287: 1040-1046.
[15] Li Z, Jiang H, Xie W, Zhang Z, Smrcka AV, Wu D: the role of PLC-. beta.2 and-. beta.3 and PI 3K. gamma.in signal transduction by chemoattractant delivery (PLC-Roles of PLC-beta2 and-beta3 and PI 3K. gamma. in chemoattractant-mediated signal transduction.) Science 2000; 287: 1046-1049.
[16] Hirsch E, Katanaev VL, Garlanda C, azzlino 0, pirola L, Silengo L, Sozzani S, Mantovani a, Altruda F, Wymann MP: the important role of G protein-coupled phosphoinositide 3-kinase in inflammation (Central role for G protein-coupled phosphoinositide 3-kinesey in inflammation.) Science 2000; 287: 1049-1053.
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Claims (18)

1. A fused pyrrolopyrimidine derivative of formula (I), a tautomer or stereoisomer thereof, or a salt thereof:
wherein
X represents CR5R6Or NH;
Y1represents N;
in thatThe chemical bond in between represents a single bond,
Y2and Y3Respectively represent CR3R4；
Z1、Z2、Z3And Z4Respectively represent CH or CR2；
R1Represents optionally having 1-3 substituents selected from R11Phenyl of the substituent(s),
Optionally with 1-3 substituents selected from R11C of a substituent of (3)3-8A cycloalkyl group, a,
C optionally substituted by one or more halogens1-6Alkyl or
3-15 membered mono-or bicyclic heterocycle, said ring being saturated or unsaturated, optionally carrying 1-3 substituents selected from R11And containing 1 to 3 heteroatoms selected from N, O and S,
wherein
R11Represents halogen, nitro, hydroxy, cyano, carboxyl, amino, N- (C)1-6Alkyl) amino, N- (hydroxy C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, N- (C)1-6Acyl) amino, N- (formyl) -N- (C)1-6Alkyl) amino, N- (C)1-6Alkylsulfonyl) amino, N- (carboxy-C)1-6Alkyl) -N- (C1-6Alkyl) amino, N- (C)1-6Alkoxycarbonyl) amino, N- [ N, N-di (C)1-6Alkyl) aminomethylene]Amino, N- [ N, N-di (C)1-6Alkyl) amino (C)1-6Alkyl) methylene]Amino, N- [ N, N-di (C)1-6Alkyl) amino C2-6Alkenyl radical]Amino, aminocarbonyl, N- (C)1-6Alkyl) aminocarbonyl, N-di (C)1-6Alkyl) aminocarbonyl, C3-8Cycloalkyl radical, C1-6Alkylthio radical, C1-6Alkylsulfonyl, aminosulfonyl, C1-6An alkoxycarbonyl group,
Wherein the phenyl moiety optionally bears 1-3 substituents selected from R101N-phenylamino group as a substituent of (a),
C optionally substituted by one, two or three halogen1-6Alkyl, aryl, heteroaryl, and heteroaryl,
C optionally substituted by one, two or three halogen1-6Alkoxy radical, or
5-7 membered saturated or unsaturated ring containing 1-3N atoms and optionally carrying 1-3 atoms selected from R101The substituent(s) of (a),
wherein
R101Represents halogen, carboxyl, amino, N- (C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, aminocarbonyl, N- (C)1-6Alkyl) aminocarbonyl, N-di (C)1-6Alkyl) aminocarbonyl or C1-6Alkyl or C1-6An alkoxy group;
R2represents hydroxy, halogen, nitro, cyano, amino, N- (C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, N- (hydroxy C)1-6Alkyl) amino, N- (hydroxy C)1-6Alkyl) -N- (C1-6Alkyl) amino, C1-6Acyloxy, amino C1-6Acyloxy, C2-6Alkenyl, phenyl,
5-7 membered saturated or unsaturated ring containing 1-2 heteroatoms selected from O and N, and optionally substituted by hydroxy, C1-6Alkyl, N- (C)1-6Acyl) amino, phenyl or phenyl C1-6Alkyl radical
Or by R21Optionally substituted C1-6Alkyl, or
By R21Optionally substituted C1-6An alkoxy group,
wherein
R21Represents cyano, mono-, di-or tri-halogen, hydroxy, amino, N- (C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, C1-6Alkoxy, hydroxy C1-6Alkoxy, -C (O) -R201、-NHC(O)-R201、C3-8Cycloalkyl, isoindolyl, phthalimidyl, 2-oxo-1, 3-oxazolidinyl, phenyl, or
5-or 6-membered saturated or unsaturated heterocyclic ring containing 1-4 heteroatoms selected from O and N, optionally substituted by hydroxy, C1-6Alkyl, N- (C)1-6Acyl) amino or benzyl group or a pharmaceutically acceptable salt thereof,
wherein
R201Represents a hydroxyl group, an amino group, N- (C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, N- (halophenyl C1-6Alkyl) amino, C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkoxy radical, or
A 5-or 6-membered saturated or unsaturated heterocyclic ring containing 1 to 2 heteroatoms selected from O and N,
R3represents H, halogen, aminocarbonyl or by phenyl, C1-6Alkoxy or mono-, di-or tri-halogen optionally substituted C1-6An alkyl group;
R4represents H or C1-6An alkyl group;
R5represents H or C1-6An alkyl group; and
R6represents halogen, H or C1-6An alkyl group.
2. A fused pyrrolopyrimidine derivative of the formula (I), its tautomer or stereoisomer, or a salt thereof, according to claim 1;
wherein
X represents CR5R6Or NH;
Y1represents N;
in thatThe chemical bond in between represents a single bond,
Y2and Y3Respectively represent CR3R4；
Z1、Z2、Z3And Z4Respectively represent CH or CR2；
R1To represent
C optionally substituted by mono-, di-or tri-halogen1-6Alkyl, aryl, heteroaryl, and heteroaryl,
Or
One of the following carbocyclic and heterocyclic rings selected from cyclopropyl, cyclohexyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, furanyl, 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, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1-benzothienyl, Benzothiazolyl, benzimidazolyl, 3H-imidazo [4, 5-b ] pyridyl, benzotriazolyl, indolyl, indazolyl, imidazo [1, 2-b ] pyridyl, quinolinyl, and 1, 8-naphthyridinyl,
wherein
The carbocycle and heterocycle are optionally substituted with 1-3 substituents selected from the group consisting of: hydroxy, halogen, nitro, cyano, carboxyl, amino, N- (C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, N- (C)1-6Acyl) amino, N- (C)1-6Alkoxycarbonyl) amino, N- (formyl) -N- (C)1-6Alkyl) amino, N- [ N, N-di (C)1-6Alkyl) aminomethylene]Amino, N- [ N, N-di (C)1-6Alkyl) amino (C)1-6Alkylene) methylene]Amino, N- [ N, N-di (C)1-6Alkyl) amino C2-6Alkenyl radical]Amino group, C1-6Alkylthio radical, C1-6Alkylsulfonyl, aminosulfonyl, C1-6Alkoxy radical, C1-6Alkoxycarbonyl, pyrrolyl, imidazolyl, pyrazinyl, pyrrolidinyl, pyridyl, phenyl C1-6An alkoxycarbonyl group,
Thiazolyl optionally substituted with pyridyl,
Quilt C1-6Alkyl or C1-6Alkoxy-optionally substituted piperazinyl and
c optionally substituted by mono-, di-or tri-halogen1-6An alkyl group;
R2represents hydroxy, halogen, nitro, cyano, carboxyl, amino, N- (C)1-6Alkyl) amino, N- (hydroxy C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, N- (hydroxy C)1-6Alkyl) -N- (C1-6Alkyl) amino, C2-6Alkenyl radical, C1-6Alkoxycarbonyl, aminocarbonylBase, C1-6Acyloxy, amino C1-6Acyloxy, furyl, morpholino, phenyl, piperidino, phenyl,
Quilt C1-6Pyrrolidinyl optionally substituted with amido,
By hydroxy, C1-6Alkyl, carboxyl, aminocarbonyl, N- (C)1-6Alkyl) aminocarbonyl or N, N-di (C)1-6Alkyl) aminocarbonyl optionally substituted piperidino,
Piperazinyl optionally substituted with:
C1-6alkyl, aryl, heteroaryl, and heteroaryl,
C optionally substituted by1-6Alkyl, said radical being selected from cyano, mono-, di-or tri-halogen, hydroxy, amino, N- (C)1-6Alkyl) amino, N- (hydroxy C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, C3-6Cycloalkyl, tetrazolyl, tetrahydropyranyl, morpholino, phthalimido, 2-oxo-1, 3-oxazolidinyl, phenyl, -C (O) -R201Quilt C1-6Pyrrolidinyl optionally substituted with amido,
By hydroxy, C1-6Alkyl, carboxyl, aminocarbonyl, N- (C)1-6Alkyl) aminocarbonyl or N, N-di (C)1-6Alkyl) aminocarbonyl optionally substituted piperidino or
Quilt C1-6A piperazinyl group optionally substituted with an alkyl group,
wherein
R201Represents a hydroxyl group, an amino group, N- (C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, N- (halobenzyl) amino, C1-6Alkyl radical, C1-6Alkoxy, tetrazolyl, tetrahydropyranyl, morpholino,
Quilt C1-6Pyrrolidinyl optionally substituted with amido,
By hydroxy, C1-6Alkyl, carboxyl, aminocarbonyl, N- (C)1-6Alkyl) aminocarbonyl or N, N-di (C)1-6Alkyl) aminocarbonyl optionally substituted piperidino,
Or
Quilt C1-6Piperazinyl optionally substituted with alkyl,
By cyano, mono-, di-or tri-halogen, hydroxy, C1-6Alkoxy, hydroxy C1-6Alkoxy, amino, N- (C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, pyrrolyl, tetrazolyl, tetrahydropyranyl, morpholino, phthalimido, 2-oxo-1, 3-oxazolidinyl, phenyl, -C (O) -R201Optionally substituted C1-6Alkoxy radical,
Quilt C1-6Pyrrolidinyl optionally substituted with amido,
By hydroxy, C1-6Alkyl, carboxyl, aminocarbonyl, N- (C)1-6Alkyl) aminocarbonyl or N, N-di (C)1-6Alkyl) aminocarbonyl optionally substituted piperidino or
Quilt C1-6A piperazinyl group optionally substituted with an alkyl group,
wherein
R201Represents a hydroxyl group, an amino group, N- (C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, N- (halobenzyl) amino, C1-6Alkyl radical, C1-6Alkoxy, amino C2-6Alkenyl, tetrazolyl, tetrahydropyranyl, morpholino, comorbid1-6Pyrrolidinyl optionally substituted with amido, by hydroxy, C1-6Alkyl, carboxyl, aminocarbonyl, N- (C)1-6Alkyl) aminocarbonyl or N, N-di (C)1-6Alkyl) aminocarbonyl optionally substituted piperidino,
Or by C1-6Piperazinyl optionally substituted with alkyl,
R3Represents H, halogen, aminocarbonyl, phenyl C1-6Alkoxy or mono-, di-or tri-halogen optionally substituted C1-6An alkyl group;
R4represents H or C1-6An alkyl group;
R5represents H or C1-6An alkyl group; and
R6represents halogen, H or C1-6An alkyl group.
3. A fused pyrrolopyrimidine derivative of the formula (I), its tautomer or stereoisomer, or a salt thereof, according to claim 1:
wherein
X represents CR5R6Or NH;
Y1represents N;
Y2and Y3Represents CR3R4；
Chemical bond(s)Represents a single bond, and is a hydrogen atom,
Z4represents CH;
Z1、Z2and Z3Respectively represent CH or CR2；
R1To represent
C optionally substituted by mono-, di-or tri-halogen1-6Alkyl, aryl, heteroaryl, and heteroaryl,
Or
One of the following carbocyclic and heterocyclic rings selected from cyclopropyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, furanyl, 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-benzothienyl, Benzothiazolyl, benzimidazolyl, 3H-imidazo [4, 5-b ] pyridyl, benzotriazolyl, indolyl, indazolyl, imidazo [1, 2-b ] pyridyl, quinolinyl, and 1, 8-naphthyridinyl,
wherein
The carbocycle and heterocycle are optionally substituted with 1-3 substituents selected from hydroxy, halo, nitro, cyano, carboxy, amino, N- (C)1-6Alkyl) amino, N- (hydroxy C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, N- (C)1-6Acyl) amino, N- (C)1-6Alkoxycarbonyl) amino, N- (formyl) -N- (C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino (C)2-6Alkenyl) amino, N- (C)1-6Alkyl) sulfonylamino, N- [ N, N-di (C)1-6Alkyl) aminomethylene]Amino group, C1-6Alkylthio radical, C1-6Alkylsulfonyl, aminosulfonyl, C1-6Alkoxy radical, C1-6Alkoxycarbonyl, pyrrolyl, imidazolyl, pyrazinyl, pyrrolidinyl, pyridyl, phenyl C1-6An alkoxycarbonyl group,
Thiazolyl optionally substituted by pyridyl, by C1-6Alkyl or C1-6Alkoxy-optionally substituted piperazinyl and
c optionally substituted by mono-, di-or tri-halogen1-6An alkyl group;
R2represents hydroxy, halogen, nitro, cyano, amino, N- (C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, N- (hydroxy C)1-6Alkyl) -N- (C1-6Alkyl) amino, (C)2-6) Alkenyl radical, C1-6Alkoxycarbonyl, aminocarbonyl, furanyl, piperidino, morpholino, phenyl,
Is N- (C)1-6Acyl) amino or N- (C)1-6Alkyl) carbonylamino optionally substituted pyrrolidinyl,
Piperidino optionally substituted with hydroxy,
Quilt C1-6Alkyl, phenyl C1-6Alkyl radical, C1-6Piperazinyl optionally substituted with alkoxycarbonyl or aminocarbonyl;
by amino, cyano, C1-6Alkoxycarbonyl, morpholino, or mono-, di-, or trihalo optionally substituted C1-6Alkyl, aryl, heteroaryl, and heteroaryl,
Or
By hydroxy, cyano, carboxy, C1-6Alkoxy radical, C1-6Acyl radical, C1-6Alkoxycarbonyl, amino, N- (C)1-6Alkyl) amino, N- (C)1-6Alkyl) aminocarbonyl, N-di (C)1-6Alkyl) amino, N-di (C)1-6Alkyl) aminocarbonyl, amino C1-6Alkylcarbonyl, N- (halobenzyl) aminocarbonyl, hydroxy C1-6Alkoxy radical, C3-6CycloalkanesOptionally substituted C with morpholino, morpholinocarbonyl, pyrrolidinyl, pyrrolyl, piperidino, phthalimido1-6An alkoxy group,
or
Piperazinyl optionally substituted with benzyl;
R3represents H;
R4represents H;
R5represents H; and
R6represents H.
4. A fused pyrrolopyrimidine derivative of the formula (I), its tautomer or stereoisomer, or a salt thereof, according to claim 1:
wherein
X represents CR5R6Or NH;
Y1represents N;
Y2and Y3Represents CR3R4；
In thatThe chemical bond in between represents a single bond,
Z4represents CH;
Z1、Z2and Z3Respectively represent CH or CR2；
R1Represents cyclopropyl, cyclopentyl, cyclohexyl, 2-furyl, 3-furyl, imidazolyl, pyrimidinyl, pyridazinyl, piperazinyl, 1, 2, 3-thiadiazolyl, 1, 3-benzothiazolyl, quinolinyl, 3H-imidazo [4, 5-b ]]A pyridyl group,
Quilt C1-61H-pyrrol-2-yl, optionally substituted by alkyl,
Quilt C1-61H-pyrrol-3-yl, optionally substituted by alkyl,
Is covered by 1 or 2C1-6Alkyl optionally substituted pyrazolyl,
Is covered by 1 or 2C1-6An alkyl-optionally substituted isoxazolyl group,
By chlorine, nitro, cyano, or C1-62-thienyl optionally substituted with alkyl,
By chlorine, nitro, cyano, or C1-63-thienyl optionally substituted with alkyl,
Quilt C1-6Piperidinyl optionally substituted with alkoxycarbonyl or benzyloxycarbonyl,
Phenyl optionally substituted with 1-3 substituents selected from: fluorine, chlorine, hydroxyl, nitro, cyano, carboxyl, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkoxycarbonyl, amino, N- (C)1-6Alkyl) amino, N- (C)1-6Acyl) amino, N- (C)1-6Alkoxycarbonyl) amino, N-di (C)1-6Alkyl) amino, N- (formyl) -N-C1-6Alkylamino radical, C1-6Alkylthio radical, C1-6Alkylsulfonyl, sulfamoyl, pyrrolyl, imidazolyl, pyrazolyl and C1-6Piperazinyl optionally substituted with alkyl,
Pyridyl optionally substituted with 1 or 2 substituents selected from: chlorine, hydroxy, carboxyl, C1-6Alkoxy radical, C1-6Alkylthio, amino, N- (C)1-6Alkyl) amino, N- (hydroxy C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, N- (C)1-6Acyl) amino, N- (C)1-6Alkyl) sulfonylamino, N- [ N, N-di (C)1-6Alkyl) aminomethylene]Amino and C optionally substituted by three halogens1-6Alkyl, aryl, heteroaryl, and heteroaryl,
Quilt C1-6Piperazinyl optionally substituted with alkyl,
Is 1 or 2 selected from C1-6Alkyl, pyridyl and N- (C)1-6Alkoxycarbonyl) amino, optionally substituted 1, 3-thiazolyl,
Quilt C1-6Indolyl optionally substituted by alkyl,
Quilt C1-6Alkyl or trihalo C1-6Benzimidazolyl optionally substituted with alkyl,
Quilt C1-61, 2, 3-benzotriazolyl optionally substituted by alkyl,
C optionally substituted by trihalo1-61, 8-naphthyridinyl optionally substituted with alkyl,
Optionally substituted by trihalo, phenyl, phenoxy or thienylC of (A)1-6Alkyl, aryl, heteroaryl, and heteroaryl,
Or
C optionally substituted by phenyl, phenoxy or thienyl1-6An alkoxy group;
R2represents fluorine, chlorine, bromine, hydroxyl, nitro, vinyl, cyano, amino, aminoacetoxy, N- (C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, N- (hydroxy C)1-6Alkyl) -N- (C1-6Alkyl) amino, 2-furyl, piperidino, morpholino, phenyl, methyl-, ethyl-, propyl-, or isopropyl-, or a pharmaceutically acceptable salt thereof,
Pyrrolidinyl optionally substituted with acetamido,
Piperidino optionally substituted with hydroxy,
By methyl, benzyl, C1-6Piperazinyl optionally substituted by alkoxycarbonyl or aminocarbonyl,
C optionally substituted by cyano, trifluoro, carboxy, methoxycarbonyl, aminocarbonyl, tert-butoxycarbonyl, tetrahydropyranyl or morpholino1-6Alkyl, aryl, heteroaryl, and heteroaryl,
By hydroxy, cyano, methoxy, methoxycarbonyl, tert-butoxycarbonyl, carboxy, aminoacetyl, dimethylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, isopropylaminocarbonyl, fluoro-benzylcarbamoyl, cyclopropyl, pyrrolidinyl, piperidino, tetrahydropyranyl, morpholino, morpholinocarbonyl, 2-oxo-1, 3-oxazolidin-4-yl, phthalimido-N-yl or hydroxy C1-6Alkenyloxy optionally substituted C1-6An alkoxy group,
R3represents H;
R4represents H;
R5represents H; and
R6represents H.
5. A fused pyrrolopyrimidine derivative of the formula (I), its tautomer or stereoisomer, or a salt thereof, according to claim 1:
wherein
X represents CR5R6Or NH;
Y1represents N;
Y2and Y3Represents CR3R4；
In thatThe chemical bond in between represents a single bond,
Z3and Z4Represents CH;
Z1and Z2Respectively represent CH or CR2；
R1Represents 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, quinolinyl, 3H-imidazo [4, 5-b ] or a salt thereof]A pyridyl group,
Quilt C1-6An alkyl-optionally substituted pyrrolyl group,
Is covered by 1 or 2C1-6Pyrazolyl optionally substituted by alkyl, 1 or 2C1-6An alkyl-optionally substituted isoxazolyl group,
By chlorine, nitro, cyano, or C1-62-thienyl optionally substituted with alkyl,
By chlorine, nitro, cyano, or C1-63-thienyl optionally substituted with alkyl,
Quilt C1-6Piperidinyl optionally substituted with alkoxycarbonyl or benzyloxycarbonyl,
Phenyl optionally substituted with 1-3 substituents selected from: fluorine, chlorine, hydroxyl, nitro, cyano, carboxyl, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkoxycarbonyl, amino, N- (C)1-6Alkyl) amino, N- (C)1-6Acyl) amino, N- (C)1-6Alkoxycarbonyl) amino, N-di (C)1-6Alkyl) amino, N- (formyl) -N-C1-6Alkylamino radical, C1-6Alkylthio radical, C1-6Alkylsulfonyl, sulfamoyl, pyrrolyl, imidazolyl, pyrazolyl andquilt C1-6Piperazinyl optionally substituted with alkyl,
Pyridyl optionally substituted with 1 or 2 substituents selected from: chlorine, hydroxy, carboxyl, C1-6Alkoxy radical, C1-6Alkylthio, amino, N- (C)1-6Alkyl) amino, N- (hydroxy C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, N- (C)1-6Acyl) amino, N- (C)1-6Alkyl) sulfonylamino, N- [ N, N-di (C)1-6Alkyl) aminomethylene]Amino and C optionally substituted by three halogens1-6Alkyl, aryl, heteroaryl, and heteroaryl,
Quilt C1-6Piperazinyl optionally substituted with alkyl,
Is 1 or 2 selected from C1-6Alkyl, pyridyl and N- (C)1-6Alkoxycarbonyl) amino, optionally substituted 1, 3-thiazolyl,
Quilt C1-6Indolyl optionally substituted by alkyl,
Quilt C1-6Alkyl or trihalo C1-6Benzimidazolyl optionally substituted with alkyl,
Quilt C1-61, 2, 3-benzotriazolyl optionally substituted by alkyl,
C optionally substituted by trihalo1-61, 8-naphthyridinyl optionally substituted with alkyl,
C optionally substituted by trihalo, phenyl, phenoxy or thienyl1-6Alkyl, aryl, heteroaryl, and heteroaryl,
Or
C optionally substituted by phenyl, phenoxy or thienyl1-6An alkoxy group;
R2represents fluorine, chlorine, bromine, hydroxyl, nitro, vinyl, cyano, amino, aminoacetoxy, N- (C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, N- (hydroxy C)1-6Alkyl) -N- (C1-6Alkyl) amino, 2-furyl, piperidino, morpholino, phenyl, methyl-, ethyl-, propyl-, or isopropyl-, or a pharmaceutically acceptable salt thereof,
Pyrrolidinyl optionally substituted with acetamido,
Piperidino optionally substituted with hydroxy,
By methyl, benzyl, C1-6Alkoxycarbonyl or aminocarbonyl optionallySubstituted piperazinyl groups,
C optionally substituted by cyano, trifluoro, carboxy, methoxycarbonyl, aminocarbonyl, tert-butoxycarbonyl, tetrahydropyranyl or morpholino1-6Alkyl, aryl, heteroaryl, and heteroaryl,
Or
By hydroxy, cyano, methoxy, methoxycarbonyl, tert-butoxycarbonyl, carboxy, aminoacetyl, dimethylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, isopropylaminocarbonyl, fluoro-benzylcarbamoyl, cyclopropyl, pyrrolidinyl, piperidino, tetrahydropyranyl, morpholino, morpholinocarbonyl, 2-oxo-1, 3-oxazolidin-4-yl, phthalimido-N-yl or hydroxy C1-6Alkenyloxy optionally substituted C1-6An alkoxy group,
R3represents H;
R4represents H;
R5represents H; and
R6represents H.
6. A fused pyrrolopyrimidine derivative of the formula (I), its tautomer or stereoisomer, or a salt thereof, according to claim 1:
wherein
X represents CR5R6Or NH;
Y1represents N;
Y2and Y3Represents CR3R4；
In thatThe chemical bond in between represents a single bond,
Z1and Z4Represents CH;
Z2and Z3Respectively represent CH or CR2；
R1Represents 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, quinolinyl, 3H-imidAzolo [4, 5-b ] s]A pyridyl group,
Quilt C1-6An alkyl-optionally substituted pyrrolyl group,
Is covered by 1 or 2C1-6Alkyl optionally substituted pyrazolyl,
Is covered by 1 or 2C1-6An alkyl-optionally substituted isoxazolyl group,
By chlorine, nitro, cyano, or C1-62-thienyl optionally substituted with alkyl,
By chlorine, nitro, cyano, or C1-63-thienyl optionally substituted with alkyl,
Quilt C1-6Piperidinyl optionally substituted with alkoxycarbonyl or benzyloxycarbonyl,
Phenyl optionally substituted with 1-3 substituents selected from: fluorine, chlorine, hydroxyl, nitro, cyano, carboxyl, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkoxycarbonyl, amino, N- (C)1-6Alkyl) amino, N- (C)1-6Acyl) amino, N- (C)1-6Alkoxycarbonyl) amino, N-di (C)1-6Alkyl) amino, N- (formyl) -N-C1-6Alkylamino radical, C1-6Alkylthio radical, C1-6Alkylsulfonyl, sulfamoyl, pyrrolyl, imidazolyl, pyrazolyl and C1-6Piperazinyl optionally substituted with alkyl,
Pyridyl optionally substituted with 1 or 2 substituents selected from: chlorine, hydroxy, carboxyl, C1-6Alkoxy radical, C1-6Alkylthio, amino, N- (C)1-6Alkyl) amino, N- (hydroxy C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, N- (C)1-6Acyl) amino, N- (C)1-6Alkyl) sulfonylamino, N- [ N, N-di (C)1-6Alkyl) aminomethylene]Amino group, C1-6Alkoxy phenyl radical C1-6Alkoxy and C optionally substituted with three halogens1-6Alkyl, aryl, heteroaryl, and heteroaryl,
Quilt C1-6Piperazinyl optionally substituted with alkyl,
Is 1 or 2 selected from C1-6Alkyl, pyridyl and N- (C)1-6Alkoxycarbonyl) amino, optionally substituted 1, 3-thiazolyl,
Quilt C1-6Indolyl optionally substituted by alkyl,
Quilt C1-6Alkyl or trihalo C1-6Benzimidazolyl optionally substituted with alkyl,
Quilt C1-61, 2, 3-benzotriazolyl optionally substituted by alkyl,
C optionally substituted by trihalo1-61, 8-naphthyridinyl optionally substituted with alkyl,
C optionally substituted by trihalo, phenyl, phenoxy or thienyl1-6Alkyl, aryl, heteroaryl, and heteroaryl,
Or
C optionally substituted by phenyl, phenoxy or thienyl1-6An alkoxy group;
R2represents fluorine, chlorine, bromine, hydroxyl, nitro, vinyl, cyano, amino, aminoacetoxy, N- (C)1-6Alkyl) amino, N-di (C)1-6Alkyl) amino, N- (hydroxy C)1-6Alkyl) -N- (C1-6Alkyl) amino, 2-furyl, piperidino, morpholino, phenyl, methyl-, ethyl-, propyl-, or isopropyl-, or a pharmaceutically acceptable salt thereof,
Pyrrolidinyl optionally substituted with acetamido,
Piperidino optionally substituted with hydroxy,
By methyl, benzyl, C1-6Piperazinyl optionally substituted by alkoxycarbonyl or aminocarbonyl,
C optionally substituted by cyano, trifluoro, carboxy, methoxycarbonyl, aminocarbonyl, tert-butoxycarbonyl, tetrahydropyranyl or morpholino1-6Alkyl, aryl, heteroaryl, and heteroaryl,
Or
By hydroxy, cyano, methoxy, methoxycarbonyl, tert-butoxycarbonyl, carboxy, aminoacetyl, dimethylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, isopropylaminocarbonyl, fluoro-benzylcarbamoyl, cyclopropyl, pyrrolidinyl, piperidino, tetrahydropyranyl, morpholino, morpholinocarbonyl, tetrazolyl, 2-oxo-1, 3-oxazolidin-4-yl, phthalimido-N-yl or hydroxy C1-6Alkenyloxy optionally substituted C1-6An alkoxy group,
R3represents H;
R4represents H;
R5represents H; and
R6represents H.
7. A fused pyrrolopyrimidine derivative of the formula (I), its tautomer or stereoisomer, or a salt thereof, according to claim 1:
wherein
X represents CR5R6Or NH;
Y1represents N;
Y2and Y3Represents CR3R4；
In thatThe chemical bond in between represents a single bond,
Z3and Z4Represents CH;
Z1and Z2Respectively represent CH or CR2；
R1Represents 3H-imidazo [4, 5-b ] optionally substituted by hydroxy, amino, acetylamino, methoxybenzyloxy or methylsulfonylamino]Pyridyl, benzimidazolyl, pyridyl,
Or
1, 3-thiazolyl optionally substituted with 1 or 2 methyl;
R2represents fluorine, chlorine, bromine, morpholino, piperazinyl, methylpiperazinyl, methyl, trifluoromethyl, or
C optionally substituted by hydroxy, cyano, carboxy, dimethylaminocarbonyl, tetrahydropyranyl, morpholino, morpholinocarbonyl, tetrazolyl or phthalimido-N-yl1-6An alkoxy group;
R3represents H;
R4represents H;
R5represents H; and
R6represents H.
8. A fused pyrrolopyrimidine derivative of the formula (I), its tautomer or stereoisomer, or a salt thereof, according to claim 1:
wherein
X represents CR5R6Or NH;
Y1represents N;
Y2and Y3Represents CR3R4；
In thatThe chemical bond in between represents a single bond,
Z1、Z3and Z4Represents CH;
Z2represents CR2；
R1Represents 3H-imidazo [4, 5-b ] optionally substituted by hydroxy, amino, acetylamino, methoxybenzyloxy or methylsulfonylamino]Pyridyl, benzimidazolyl, pyridyl,
Or
1, 3-thiazolyl optionally substituted with 1 or 2 methyl;
R2represents fluorine, chlorine, bromine, morpholino, piperazinyl, methylpiperazinyl, methyl, trifluoromethyl,
c optionally substituted by hydroxy, cyano, carboxy, dimethylaminocarbonyl, tetrahydropyranyl, morpholino, morpholinocarbonyl, tetrazolyl or phthalimido-N-yl1-6An alkoxy group;
R3represents H;
R4represents H;
R5represents H; and
R6represents H.
9. A fused pyrrolopyrimidine derivative of formula (I), a tautomer or stereoisomer thereof or a salt thereof according to claim 1, wherein the derivative is selected from the following compounds:
1) n- (7, 8-dimethoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) nicotinamide;
2)2- (7, 8-dimethoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) -1-pyridin-3-yl vinyl alcohol;
3) n- (7, 8-dimethoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) -1H-benzimidazole-5-carboxamide;
4)6- (acetylamino) -N- (7, 8-dimethoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) nicotinamide;
5) n- {5- [2- (7, 8-dimethoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) -1-hydroxyethenyl ] pyridin-2-yl } acetamide;
6)2- ({5- [ 2-hydroxy-2-pyridin-3-ylvinyl ] -7-methoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-8-yl } oxy) -N, N-dimethylacetamide;
7)2- [ 7-methoxy-8- (tetrahydro-2H-pyran-2-ylmethoxy) -2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl ] -1-pyridin-3-yl vinyl alcohol;
8)2- [8- (2-hydroxyethoxy) -7-methoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl ] -1-pyridin-3-yl vinyl alcohol;
9) ({5- [ 2-hydroxy-2-pyridin-3-ylvinyl ] -7-methoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-8-yl } oxy) acetic acid;
10)4- ({5- [ 2-hydroxy-2-pyridin-3-ylvinyl ] -7-methoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-8-yl } oxy) butyric acid;
11) ({5- [ 2-hydroxy-2-pyridin-3-ylvinyl ] -7-methoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-8-yl } oxy) acetonitrile;
12)2- [ 7-methoxy-8- (2H-tetrazol-5-ylmethoxy) -2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl ] -1-pyridin-3-yl vinyl alcohol;
13)2- [ 7-methoxy-8- (4-morpholin-4-yl-4-oxobutoxy) -2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl ] -1-pyridin-3-yl vinyl alcohol;
14)5- [ 1-hydroxy-2- (8-morpholin-4-yl-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) ethenyl ] pyridin-3-ol;
15) n- (2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) -5-hydroxynicotinamide;
16)6- (acetylamino) -N- (7, 9-dimethoxy-8-methyl-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) nicotinamide;
17) n- (8, 9-dimethoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) -5 hydroxynicotinamide;
18) 5-hydroxy-N- (7-methoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) nicotinamide;
19) n- (7, 8-dimethoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) -5-hydroxynicotinamide;
20) 5-hydroxy-N- [8- (trifluoromethyl) -2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl ] nicotinamide;
21) n- {8- [3- (1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl) propoxy ] -2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl } nicotinamide;
22) n- (7-bromo-8-methoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) nicotinamide;
23) 6-amino-N- (8-methoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) nicotinamide;
24)1- (1H-benzoimidazol-5-yl) -2- (8, 9-dimethoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) vinyl alcohol;
25)2- (8, 9-dimethoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) -1- (2, 4-dimethyl-1, 3-thiazol-5-yl) vinyl alcohol;
26) n- (9-methoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) -1H-benzimidazole-5-carboxamide;
27) n- (8-bromo-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) nicotinamide;
28) n- (8-bromo-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) -1H-benzimidazole-5-carboxamide;
29) n- (8-methoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) -1H-benzimidazole-5-carboxamide;
30) n- (8-methyl-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) -1H-benzoimidazole-5-carboxamide;
31) n- [8- (trifluoromethyl) -2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl ] -1H-benzimidazole-5-carboxamide;
32) n- (7-fluoro-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) -1H-benzoimidazole-5-carboxamide;
33) n- (7-methoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) nicotinamide;
34) n- (8-chloro-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) -1H-benzimidazole-5-carboxamide;
35)6- (acetylamino) -N- (8-morpholin-4-yl-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) nicotinamide;
36)1- (1H-benzoimidazol-5-yl) -2- (8-morpholin-4-yl-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) vinyl alcohol;
37) n- {5- [ 1-hydroxy-2- (8-morpholin-4-yl-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) vinyl ] pyridin-2-yl } acetamide;
38) 6-methyl-N- (8-morpholin-4-yl-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) nicotinamide;
39)1- (1H-benzimidazol-5-yl) -2- [8- (4-methylpiperazin-1-yl) -2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl ] vinyl alcohol;
40) n- (2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) -3H-imidazo [4, 5-b ] pyridine-6-carboxamide;
41) n- (7, 8-dimethoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) -3H-imidazo [4, 5-b ] pyridine-6-carboxamide;
42) 1H-benzoimidazole-5-carboxamide, N- [7- (trifluoromethyl) -2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl ] -amide;
43) n- (7, 9-dimethoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) -1H-benzimidazole-5-carboxamide;
44) n- {5- [2- (7, 9-dimethoxy-8-methyl-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) -1-hydroxyethenyl ] pyridin-2-yl } acetamide;
45) n- {5- [2- (7-bromo-9-methyl-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) -1-hydroxyethenyl ] pyridin-2-yl } acetamide; and
46)2- (8, 9-dimethoxy-2, 3-dihydroimidazo [1, 2-c ] quinazolin-5-yl) -1-pyridin-3-yl vinyl alcohol.
10. A medicament containing a fused pyrrolopyrimidine derivative, its tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient.
11. The medicament of claim 10, further comprising one or more pharmaceutically acceptable excipients.
12. The medicament of claim 10, wherein the fused pyrrolopyrimidine derivative, tautomer or stereoisomer thereof, or pharmaceutically acceptable salt thereof is a PI3K inhibitor.
13. The medicament of claim 10, wherein the fused pyrrolopyrimidine derivative, its tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof is a PI3K- γ inhibitor.
14. Use of a fused pyrrolopyrimidine derivative, its tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 1 for the production of a medicament for the prophylaxis and/or treatment of inflammatory diseases or conditions.
15. Use of a fused pyrrolopyrimidine derivative, its tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 1 for the production of a medicament for the prophylaxis and/or treatment of asthma, rhinitis, allergic diseases, or auto-immunopathology.
16. Use of a fused pyrrolopyrimidine derivative, its tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 1 for the production of a medicament for the prophylaxis and/or treatment of diabetes, cancer, myocardial contractile disease, heart failure, ischemia, pulmonary hypertension, renal failure, and cardiac hypertrophy.
17. Use of a fused pyrrolopyrimidine derivative according to claim 1, a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention and/or treatment of diseases or conditions associated with PI3K activity.
18. Use of a fused pyrrolopyrimidine derivative according to claim 1, a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prevention of diseases or conditions associated with PI3K- γ activity.
HK06104675.8A 2002-09-30 2003-09-18 Fused azole-pyrimidine derivatives HK1084393B (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP02021861 2002-09-30
EP02021861.6 2002-09-30
PCT/EP2003/010377 WO2004029055A1 (en) 2002-09-30 2003-09-18 Fused azole-pyrimidine derivatives

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HK1084393A1 HK1084393A1 (en) 2006-07-28
HK1084393B true HK1084393B (en) 2009-03-27

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