HK1110584A

HK1110584A - 2, 5 and 2, 6-disubstituted benzazole analogues useful as protein kinase inhibitors

Info

Publication number: HK1110584A
Application number: HK08101421.9A
Authority: HK
Inventors: Thomas Herz; Rolf Krauss; Michael Kubbutat; Martin Lang; Christoph SCHÄCHTELE; Stefan Tasler; Frank Totzke
Original assignee: 4Sc Ag
Priority date: 2004-12-27
Filing date: 2005-12-22
Publication date: 2008-07-18

Description

2, 5 and 2, 6 disubstituted benzazole analogs useful as protein kinase inhibitors

Technical Field

The present invention relates to benzazoles of general formula (I) or salts or physiologically functional derivatives or stereoisomers thereof for use as a medicament. The compounds of the present invention are useful for the treatment of diseases associated with abnormal and excessive proliferation of cells in mammals, especially humans. In particular, they are useful in the treatment of all forms of cancer.

In addition, a method for preparing the indolizine derivative is also disclosed.

Background

Protein kinases play an important role in regulating cellular function. It includes processes such as cell growth and division, cell differentiation and cell death, as well as many other cellular activities. Protein kinases catalyze the transfer of phosphate residues from ATP to target proteins, which alter their three-dimensional structure and thus their physiological function as a result of phosphorylation mediated by such protein kinases. These enzymes are divided into two classes, so-called serine/threonine protein kinases and tyrosine protein kinases, according to the amino acids phosphorylated by the protein kinases.

Based on human genetic engineering, it is known that 518 DNA sequences encoding protein kinase-like protein sequences exist in humans. In the last 20 years or so, for some of the 518 proteins, it was known that changes in their associated gene sequences (e.g., point mutations, deletions or gene amplifications) led to pathological changes in the cellular activity of the corresponding protein kinases. This is particularly true for protein kinases involved in cell proliferation and cell cycle control, in cell survival and cell death, in tumor angiogenesis, and in the formation of tumor metastases.

Several so-called oncogenes are pathologically modified genes which, in their proto-oncogene form, encode protein kinases involved in the regulation of normal, physiological cell growth and division.

Since protein kinases are key regulators of cellular function, and since they may exhibit deregulated enzyme activity in cells, they are promising targets for the development of therapeutic agents. There are many ongoing drug discovery challenges in the pharmaceutical industry, the target of which is to recognize protein kinase modulators. The main focus has generally been on protein kinases involved in inflammation and cancer, but in addition to this, protein kinases have also been widely discussed as promising targets in almost every disease area.

In the field of oncology, the first protein kinase inhibitor (Gleevec, Iressa) has been marketed. In addition, a number of protein kinase inhibitors are currently in different stages of clinical development. In most cases, these compounds are either targeted to the EGF (epidermal growth factor) receptor subtype or to the VEGF (vascular endothelial growth factor) receptor subtype. All these compounds have been developed with targets that specifically inhibit a specific protein kinase, evidence of which is that they interfere with one or four major molecular processes of tumor progression. The four processes are: (1) cell proliferation/cell cycle control, (2) modulation of programmed cell death (apoptosis) and cell survival, (3) tumor angiogenesis and (4) tumor metastasis.

The present invention relates to indolizine derivatives which are useful for inhibiting protein kinases involved in diseases other than cancer, but which are particularly useful as anti-tumour agents. This includes monospecific protein kinase inhibitors which preferentially inhibit one protein kinase which is causally involved in tumor progression, but also so-called multi-target protein kinase inhibitors which inhibit at least two different protein kinases which act with different molecular mechanisms of two or more tumor progression. For example, such compounds may be inhibitors of tumor angiogenesis and, in addition, stimulators of apoptosis.

The concept of multi-target protein kinase inhibitors is a new approach, although the concept of developing "multi-protein kinase inhibitors" has been described by J.Adams et al, Current Opinion in chemical biology 6, 486-. Compounds are described which inhibit several protein kinases simultaneously, however all of these compounds are involved in one molecular mechanism of tumor progression, namely tumor angiogenesis.

Benzazole is described as a kinase inhibitor in WO 2004085425. 2-aminobenzothiazoles are described in WO 9924035. These compounds have been disclosed in Das et al, bioorg. med. chem. lett 13, 2003, 2587-. In WO 2000061580, benzimidazolyl and benzoxazolyl acetylaminopyridyl butyrates are described as integrin antagonists. Five-membered benzofused heterocycles are described in WO 9940072 for use as anticoagulants.

The object of the invention is solved by the teaching of the independent claims. Further advantageous features, aspects and details of the invention emerge from the dependent claims, the description, the figures and the embodiments of the application. Given the current lack of available therapeutic options for the majority of disease conditions associated with protein kinases such as ABL1, ACV-R1, AKT1, AKT2, AKT3, ARK5, Aurora-A, Aurora-B, Aurora-B, Aurora-RAF, BRK, CDC42BPB, CDK B, Aurora, CHK B, Aurora, CK B, Aurora, COT, CSK, DAPK B, Aurora, EGF-B, Aurora, EPHA B, Aurora, EPHB B, Aurora, ERBB B, Aurora, FAK, FGF-R B, Aurora, FGF-36r B, Aurora, FGR 72, FGR β, flk-B, Aurora, IGF-B, Aurora, nkk B, Aurora, k B, Aurora, PAK4, PBK, PCTAIRE1, PDGFR-alpha, PDGFR-beta, PDK1, PIM1, PIM2, PKC-alpha, PKC-beta 1, PKC-beta 2, PKC-delta, PKC-epsilon, PKC-eta, PKC-gamma, PKC-iota, PKC-mu, PKC-theta, PKC-zeta, PLK1, PRK1, RET, ROCK2, S6K, SAK, SGK1, SGK3, SNK, SRC, SRPK2, SYK, TGFB-R1, TIE2, TSF1, K2, TTK, VEGF-R1, VEGF-R2, VEGF-R3, VRK 3, VEE 3, YES, P3, especially related protein kinases such as EGF-R (cell proliferation), ERBB (cell proliferation), PDGFR-R3), VEGF-production control of cells (IGF-R), and apoptosis (IGF) 3), and angiogenesis control of cells (VEGF-growth cycle 3), and angiogenesis (IGF) growth control of cells (VEGF-R3), and angiogenesis (IGF) and angiogenesis control cell production of cells (VEGF-3), and angiogenesis (IGF) and angiogenesis (VEGF-R) and angiogenesis control cell proliferation of cells (VEGF-3), and angiogenesis (VEGF-3, TIE2 (angiogenesis), EPHB4 (angiogenesis), FAK (metastasis) and SRC kinase (metastasis).

The benzazole derivatives described herein are a new class of protein kinase inhibitors that exhibit inhibition of different protein kinases, each of which can be attributed to one of four molecular mechanisms of tumor development.

The invention relates to compounds of general formula (I) or salts thereof + or physiologically functional derivatives or stereoisomers thereof,

formula (I)

Wherein

substituent-Y-R¹Attached to the 5-or 6-position of the benzazole;

x independently represents S, O, SO or SO₂；

Y independently represents S, O, NR²SO or SO₂；

A independently represents ← CO-,. No. CS-,. No. SO₂-、←CO₂-、←CONR⁸-、←NR⁸CO-、←NR⁸CONR⁹-、←NR⁸COO-、←NR⁸NR⁹CO-、←NR⁸OCO-、←ONR⁸CO-or ← NR⁸SO₂-, where ← value is linked to R³A point of (a);

R²independently represents H, alkyl, cycloalkyl, -COR⁶、-SOR⁶、-SO₂R⁶-CN, hydroxyalkyl, haloalkyl or haloalkoxy;

R³independently represents H, alkyl, cycloalkyl, aryl or heteroaryl;

R⁴independently represent H, -COR⁶、-CO₂R⁶、-SOR⁶、-SO₂R⁶、-SO₃R⁶、-NO₂、-CN、-CF₃、-OCH₃、-OCF₃Alkyl, cycloalkyl, alkoxy, -NH₂Alkylamino, -NR⁷COR⁶Halogen, -OH, -SH, alkylthio, haloalkyl, haloalkoxy, aryl or heteroaryl;

R⁵independently represents H, alkyl, cycloalkyl, -COR⁶、-SOR⁶、-SO₂R⁶-CN, hydroxyalkyl, haloalkyl, haloalkoxy, aryl or heteroaryl;

R^6aindependently represent H, alkyl, cycloalkaneRadical, -NR⁸NR²R⁹、-ONR⁸R⁹、-NR⁸OR⁹Aryl or heteroaryl;

R⁶independently represents H, alkyl, cycloalkyl, -NR⁸R⁹、-NR⁸NR²R⁹、-ONR⁸R⁹、-NR⁸OR⁹Aryl or heteroaryl;

R⁷independently represents H, alkyl, cycloalkyl or alkoxy;

R⁸independently represents H, alkyl, cycloalkyl, -COR⁶、-SOR⁶、-SO₂R⁶Haloalkyl, haloalkoxy, aryl or heteroaryl;

R⁹independently represents H, alkyl, cycloalkyl, -COR⁶、-SOR⁶、-SO₂R⁶Haloalkyl, haloalkoxy, aryl or heteroaryl;

R¹independently represents one of the following groups:

wherein^*Points representing connections;

z independently represents O, NR⁸Or S;

R¹²independently represents H, halogen, nitro, trifluoromethyl, alkyl, aryl, heteroaryl, -NR^8aR^9aor-X²R¹⁶；

R^8aIndependently represents H, alkyl, cycloalkyl, -COR^6a、-SOR⁶、-SO₂R⁶Haloalkyl, haloalkoxy, aryl or heteroaryl;

R^9aindependently represents H, alkyl, cycloalkyl, -COR^6a、-SOR⁶、-SO₂R⁶Haloalkyl, haloalkoxy, aryl or heteroaryl;

R¹³independently represents H, halogen, nitro, trifluoromethyl, alkyl, aryl, heteroaryl, -NR^8aR^9aor-X²R¹⁶；

R¹⁴Independently represents H, halogen, nitro, trifluoromethyl, alkyl, aryl, heteroaryl, -NR^8aR^9aor-X²R¹⁶；

R¹⁵Independently represents H, halogen, nitro, trifluoromethyl, alkyl, aryl, heteroaryl, -NR^8aR^9aor-X²R¹⁶；

R¹⁷Independently represents H, halogen, nitro, trifluoromethyl, alkyl, aryl, heteroaryl, -NR^8aR^9aor-X²R¹⁶；

X²Independently represents a direct bond, -O-, -CH₂-, -OCO-, carbonyl, -S-, -SO-, -SO₂-、-NR⁸CO-、-CONR⁸-、-SO₂NR⁸-、-NR⁸SO₂-or-NR^8a-；

R¹⁶Independently represents H, alkyl, cycloalkyl, -SOR⁶、-SO₂R⁶、-OCH₃Hydroxyalkyl, haloalkyl, haloalkoxy or one of the following groups:

wherein^*Points representing connections;

m independently represents an integer of 1 to 3;

l is absent or represents a divalent linking group selected from alkylene, cycloalkylene, heterocyclylene, arylene or heteroarylene, wherein one or more (-CH)₂-) groups may be substituted by oxygen or NR⁸And wherein one or more carbon atoms may be independently substituted with one or two substituents selected from halogen, hydroxy, alkoxy, haloalkoxy, phosphonooxy (phosphonooxy) or phosphonooxyalkyl (phosphonooxyalkylyl);

X³independently represent-COOH, -COOalkyl, -OH, -SH, -SO₃H or-SO₂NR⁸R⁹；

R¹⁸Independently represents H, phosphonooxy or phosphonooxyalkyl;

R¹⁹independently represents H, alkyl, cycloalkyl, alkylamino or alkoxy;

with the proviso that the following compounds are excluded:

n- [6- (6, 7-dimethoxy-quinolin-4-yloxy) -5-fluoro-benzothiazol-2-yl ] -2-phenyl-acetamide, N- [6- (6, 7-dimethoxy-quinolin-4-yloxy) -5-fluoro-benzothiazol-2-yl ] -3-phenyl-propionamide, N- [6- (6, 7-dimethoxy-quinolin-4-yloxy) -5-fluoro-benzothiazol-2-yl ] -2- (3 -trifluoromethyl-phenyl) -acetamide, 2- (3, 5-bis-trifluoromethyl-phenyl) -N- [6- (6, 7-dimethoxy-quinolin-4-yloxy) -5-fluoro-benzothiazol-2-yl ] -acetamide, 2- (2-chloro-5-trifluoromethyl-phenyl) -N- [6- (6, 7-dimethoxy-quinolin-4-yl-oxy) -5-fluoro-benzothiazol-2-yl ] -acetamide;

alkyl, if not otherwise stated, denotes straight-chain or branched C₁-C₆-alkyl, preferablyStraight or branched chain of one to five carbon atoms, straight or branched C₂-C₆Alkenyl, or straight or branched C₂-C₆-alkynyl, which may be substituted by one or more substituents R';

said C is₁-C₆Alkyl radical, C₂-C₆-alkenyl, C₂-C₆-the alkynyl residue may be selected from the group consisting of:

-CH₃，-C₂H₅，-CH＝CH₂，-C≡CH，-C₃H₇，-CH(CH₃)₂，-CH₂-CH＝CH₂，-C(CH₃)＝CH₂，-CH＝CH-CH₃，-C≡C-CH₃，-CH₂-C≡CH，-C₄H₉，-CH₂-CH(CH₃)₂，-CH(CH₃)-C₂H₅，-C(CH₃)₃，-C₅H₁₁，-C₆H₁₃，-C(R`)₃，-C₂(R`)₅，-CH₂-C(R`)₃，-C₃(R`)₇，-C₂H₄-C(R`)₃，-C₂H₄-CH＝CH₂，-CH＝CH-C₂H₅，-CH＝C(CH₃)₂，-CH₂-CH＝CH-CH₃，-CH＝CH-CH＝CH₂，-C₂H₄-C≡CH，-C≡C-C₂H₅，-CH₂-C≡C-CH₃，-C≡C-CH＝CH₂，-CH＝CH-C≡CH，-C≡C-C≡CH，-C₂H₄-CH(CH₃)₂，-CH(CH₃)-C₃H₇，-CH₂-CH(CH₃)-C₂H₅，-CH(CH₃)-CH(CH₃)₂，-C(CH₃)₂-C₂H₅，-CH₂-C(CH₃)₃，-C₃H₆-CH＝CH₂，-CH＝CH-C₃H₇，-C₂H₄-CH＝CH-CH₃，-CH₂-CH＝CH-C₂H₅，-CH₂-CH＝CH-CH＝CH₂，-CH＝CH-CH＝CH-CH₃，-CH＝CH-CH₂-CH＝CH₂，-C(CH₃)＝CH-CH＝CH₂，-CH＝C(CH₃)-CH＝CH₂，-CH＝CH-C(CH₃)＝CH₂，-CH₂-CH＝C(CH₃)₂，C(CH₃)＝C(CH₃)₂，-C₃H₆-C≡CH，-C≡C-C₃H₇，-C₂H₄-C≡C-CH₃，-CH₂-C≡C-C₂H₅，-CH₂-C≡C-CH＝CH₂，-CH₂-CH＝CH-C≡CH，-CH₂-C≡C-C≡CH，-C≡C-CH＝CH-CH₃，-CH＝CH-C≡C-CH₃，-C≡C-C≡C-CH₃，-C-≡C-CH₂-CH＝CH₂，-CH＝CH-CH₂-C≡CH，-C≡C-CH₂-C≡CH，-C(CH₃)＝CH-CH＝CH₂，-CH＝C(CH₃)-CH＝CH₂，-CH＝CH-C(CH₃)＝CH₂，-C(CH₃)＝CH-C≡CH，-CH＝C(CH₃)-C≡CH，-C≡C-C(CH₃)＝CH₂，-C₃H₆-CH(CH₃)₂，-C₂H₄-CH(CH₃)-C₂H₅，-CH(CH₃)-C₄H₉，-CH₂-CH(CH₃)-C₃H₇，-CH(CH₃)-CH₂-CH(CH₃)₂，-CH(CH₃)-CH(CH₃)-C₂H₅，-CH₂-CH(CH₃)-CH(CH₃)₂，-CH₂-C(CH₃)₂-C₂H₅，-C(CH₃)₂-C₃H₇，-C(CH₃)₂-CH(CH₃)₂，-C₂H₄-C(CH₃)₃，-CH(CH₃)-C(CH₃)₃，-C₄H₈-CH＝CH₂，-CH＝CH-C₄H₉，-C₃H₆-CH＝CH-CH₃，-CH₂-CH＝CH-C₃H₇，-C₂H₄-CH＝CH-C₂H₅，-CH₂-C(CH₃)＝C(CH₃)₂，-C₂H₄-CH＝C(CH₃)₂，-C₄H₈-C≡CH，-C≡C-C₄H₉，-C₃H₆-C≡C-CH₃，-CH₂-C≡C-C₃H₇，-C₂H₄-C≡C-C₂H₅；

r' independently represents H, -CO₂R″、-CONHR″、-CR″O、-SO₂NR ', -NR' -CO-haloalkyl, -NO₂、-NR″-SO₂-haloalkyl, -NR' -SO₂-alkyl, -SO₂-alkyl, -NR "-CO-alkyl, -CN, alkyl, cycloalkyl, aminoalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkoxy, aryl, arylalkyl or heteroaryl;

r' independently represents H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, heteroaryl or aminoalkyl;

alkylene means divalent straight or branched chain C₁-C₆Alkylene, preferably linear or branched, C having from one to five carbon atoms₂-C₆Alkenylene radicals, or C being straight-chain or branched₂-C₆-alkynylene, which may be substituted with one or more substituents R';

cycloalkylene refers to a divalent non-aromatic ring system comprising three to eight carbon atoms, preferably four to eight carbon atoms, wherein one or more carbon atoms in the ring may be substituted by a group E, E being O, S, SO₂N or NR ', R' is as defined above;

heterocyclylene means a 3-to 8-membered divalent heterocyclic non-aromatic group comprising at least one heteroatom selected from O, N and S, wherein the heterocyclylene group may be fused to another non-aromatic ring and may be substituted with one or more substituents R ', wherein R' is as defined above;

arylene means an aromatic divalent radical having five to fifteen carbon atoms which may be substituted with one or more substituents R 'and may be fused to another aromatic ring, wherein R' is as defined above;

heteroarylene means a divalent 5-or 6-membered heterocyclic group comprising at least one heteroatom selected from O, N and S, wherein the heterocyclylene group may be fused to another aromatic ring and may be substituted with one or more substituents R ', wherein R' is as defined above;

cycloalkyl refers to a non-aromatic ring system comprising three to eight carbon atoms, preferably four to eight carbon atoms, wherein one or more carbon atoms in the ring may be substituted by a group E, E being O, S, SO₂N or NR ', R' is as defined above; said C is₃-C₈The cycloalkyl residue may be selected from-ring-C₃H₅-Ring-C₄H₇-Ring-C₅H₉-Ring-C₆H₁₁-Ring-C₇H₁₃-Ring-C₈H₁₅Morpholin-4-yl, piperazinyl, 1-alkylpiperazin-4-yl;

alkoxy means O-alkyl, said alkyl being as defined above; the alkoxy group is preferably methoxy, ethoxy, isopropoxy, tert-butoxy or pentyloxy;

alkylthio refers to S-alkyl, said alkyl being as defined above;

haloalkyl refers to an alkyl group substituted with one to five halogen atoms, said alkyl group being as defined above; the haloalkyl is preferably-C (R)¹⁰)₃、-CR¹⁰(R¹⁰′)₂、-CR¹⁰(R¹⁰′)R¹⁰″、-C₂(R¹⁰)₅、-CH₂-C(R¹⁰)₃、-CH₂-CR¹⁰(R¹⁰′)₂、-CH₂-CR¹⁰(R¹⁰′)R¹⁰″、-C₃(R¹⁰)₇or-C₂H₄-C(R¹⁰)₃Wherein R is¹⁰、R¹⁰′、R¹⁰"denotes F, Cl, Br or I, preferably F;

hydroxyalkyl refers to a "HO-alkyl" group, the alkyl being as defined above;

haloalkoxy means alkoxy substituted by one to five halogen atoms, said alkyl being as defined above; the haloalkoxy group is preferably-OC (R)¹⁰)₃、-OCR¹⁰(R¹⁰′)₂、-OCR¹⁰(R¹⁰′)R¹⁰″、-OC₂(R¹⁰)₅、-OCH₂-C(R¹⁰)₃、-OCH₂-CR¹⁰(R¹⁰′)₂、-OCH₂-CR¹⁰(R¹⁰′)R¹⁰″、-OC₃(R¹⁰)₇or-OC₂H₄-C(R¹⁰)³Wherein R is¹⁰、R¹⁰′、R¹⁰"denotes F, Cl, Br or I, preferably F;

hydroxyalkylamino refers to "(HO-alkyl)₂-an N- "group or a" HO-alkyl-NH- "group, the alkyl group being as defined above;

alkylamino refers to an "NH-alkyl" or "N-dialkyl" group, the alkyl being as defined above;

the halogen group is fluorine, chlorine, bromine or iodine;

aryl means an aromatic group having five to fifteen carbon atoms, which may be substituted with one or more substituents R ', wherein R' is as defined above; the aryl group is preferably phenyl, -o-C₆H₄-R', -m-C₆H₄-R', -p-C₆H₄-R', 1-naphthyl, 2-naphthyl, 1-anthryl or 2-anthryl;

heteroaryl refers to a 5 or 6 membered heterocyclic group containing at least one heteroatom such as O, N, S. The heterocyclic group may be fused to another aromatic ring. For example, the group may be selected from thiadiazoles, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, 1, 2, 4-oxadiazol-3-yl, 1, 2, 4-oxadiazol-5-yl, 1, 2, 5-oxadiazol-3-yl, 1, 2, 5-oxadiazol-4-yl, 1, 2, 4-thiadiazol-3-yl, 1, 2, 4-thiadiazol-5-yl, thiadiazol-3-yl, isothiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isoxazol-4-yl, isoxazol-, Isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1, 2, 5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, 1, 2, 5-thiadiazol-4-yl, 4-imidazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyranyl, 3-pyranyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-5-yl, pyridin-6-yl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1, 2, 3-triazol-4-yl, 1, 2, 3-triazol-5-yl, 1, 2, 4-triazol-3-yl, 1, 2, 4-triazol-5-yl, 1H-tetrazol-2-yl, 1H-tetrazol-3-yl, tetrazolyl, acridinyl, phenazinyl, carbazolyl, phenoxazinyl, indolizinyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-isoindolyl, 3-isoindolyl, 4-isoindolyl, 5-isoindolyl, 6-isoindolyl, 7-isoindolyl, 2-indolinyl, 3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl, benzo [ b ] furanyl, benzofurazan, benzothiofurazan, benzotriazol-1-yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzotriazol-7-yl, benzotriazine, benzo [ b ] thiophenyl, benzimidazolyl, benzothiazolyl, quinazolinyl (quinoxalinyl), cinnoline, quinolyl, tetrahydroquinolyl, isoquinolyl, or tetrahydroisoquinolyl, Purine, 2, 3-naphthyridine, pteridine, thiatetrazine, thiatriazene, isothiazolopyrazine, isothiazolopyrimidine, pyrazolotriazine, pyrazolopyrimidine, imidazopyridazine, imidazopyrimidine, imidazopyridine, imidazotriazine, triazolotriazine, triazolopyridine, triazolopyrazine, triazolopyrimidine, triazolopyridazine groups. These heterocyclic groups may be substituted with one or more substituents R ', wherein R' is as defined above;

phosphonooxy is-O-P (═ O) (OH)₂Or a salt thereof;

phosphonooxyalkyl means-alkyl-O-P (═ O) (OH)₂Or a salt thereof, alkyl being as defined above.

The invention also relates to compounds of general formula (Ia) or salts or physiologically functional derivatives or stereoisomers thereof,

formula (Ia)

Wherein

substituent-Y^a-R^1aAttached to the 5-or 6-position of the benzazole;

X^aindependently S, O, SO or SO₂；

Y^aIndependently represent S, NR²SO or SO₂；

A^aIndependently represent ← CO-, ° CS-, ° SO₂-、←CO₂-、←CONR⁸-、←NR⁸CO-、←NR⁸CONR⁹-、←NR⁸COO-、←NR⁸NR⁹CO-、←NR⁸OCO-、←ONR⁸CO-or ← NR⁸SO₂-，

Wherein ← refers to the term "connected to R³A point of (a);

R^1aindependently represents one of the following groups:

wherein^*Points representing connections;

R¹¹independently represent H, -NHR^8aOr one of the following groups:

or

Wherein^*Points representing connections;

R^13aindependently represent H, halogen, nitro, trifluoromethyl, alkyl, -NR^8aR^9aor-X²R¹⁶；

R²、R³、R⁴、R⁵、R⁶、R^6a、R⁷、R⁸、R^8a、R⁹、R^9a、R¹²、R¹³、R¹⁶Or X²Is as defined above;

alkyl, if not otherwise stated, denotes straight-chain or branched C₁-C₆Alkyl, preferably a linear or branched, linear or branched C of one to five carbon atoms₂-C₆Alkenyl, or straight or branched C₂-C₆-alkynyl, which may be substituted by one or more substituents R';

-CH₃，-C₂H₅，-CH＝CH₂，-C≡CH，-C₃H₇，-CH(CH₃)₂，-CH₂-CH＝CH₂，-C(CH₃)＝CH₂，-CH＝CH-CH₃，-C≡C-CH₃，-CH₂-C≡CH，-C₄H₉，-CH₂-CH(CH₃)₂，-CH(CH₃)-C₂H₅，-C(CH₃)₃，-C₅H₁₁，-C₆H₁₃，-C(R`)₃，-C₂(R`)₅，-CH₂-C(R`)₃，-C₃(R`)₇，-C₂H₄-C(R`)₃，-C₂H₄-CH＝CH₂，-CH＝CH-C₂H₅，-CH＝C(CH₃)₂，-CH₂-CH＝CH-CH₃，-CH＝CH-CH＝CH₂，-C₂H₄-C≡CH，-C≡C-C₂H₅，-CH₂-C≡C-CH₃，-C≡C-CH＝CH₂，-CH＝CH-C≡CH，-C≡C-C≡CH，-C₂H₄-CH(CH₃)₂，-CH(CH₃)-C₃H₇，-CH₂-CH(CH₃)-C₂H₅，-CH(CH₃)-CH(CH₃)₂，-C(CH₃)₂-C₂H₅，-CH₂-C(CH₃)₃，-C₃H₆-CH＝CH₂，-CH＝CH-C₃H₇，-C₂H₄-CH＝CH-CH₃，-CH₂-CH＝CH-C₂H₅，-CH₂-CH＝CH-CH＝CH₂，-CH＝CH-CH＝CH-CH₃，-CH＝CH-CH₂-CH＝CH₂，-C(CH₃)＝CH-CH＝CH₂，-CH＝C(CH₃)-CH＝CH₂，-CH＝CH-C(CH₃)＝CH₂，-CH₂-CH＝C(CH₃)₂，C(CH₃)＝C(CH₃)₂，-C₃H₆-C≡CH，-C≡C-C₃H₇，-C₂H₄-C≡C-CH₃，-CH₂-C≡C-C₂H₅，-CH₂-C≡C-CH＝CH₂，-CH₂-CH＝CH-C≡CH，-CH₂-C≡C-C≡CH，-C≡C-CH＝CH-CH₃，-CH＝CH-C≡C-CH₃，-C≡C-C≡C-CH₃，-C≡C-CH₂-CH＝CH₂，-CH＝CH-CH₂-C≡CH，-C≡C-CH₂-C≡CH，-C(CH₃)＝CH-CH＝CH₂，-CH＝C(CH₃)-CH＝CH₂，-CH＝CH-C(CH₃)＝CH₂，-C(CH₃)＝CH-C≡CH，-CH＝C(CH₃)-C≡CH，-C≡C-C(CH₃)＝CH₂，-C₃H₆-CH(CH₃)₂，-C₂H₄-CH(CH₃)-C₂H₅，-CH(CH₃)-C₄H₉，-CH₂-CH(CH₃)-C₃H₇，-CH(CH₃)-CH₂-CH(CH₃)₂，-CH(CH₃)-CH(CH₃)-C₂H₅，-CH₂-CH(CH₃)-CH(CH₃)₂，-CH₂-C(CH₃)₂-C₂H₅，-C(CH₃)₂-C₃H₇，-C(CH₃)₂-CH(CH₃)₂，-C₂H₄-C(CH₃)₃，-CH(CH₃)-C(CH₃)₃，-C₄H₈-CH＝CH₂，-CH＝CH-C₄H₉，-C₃H₆-CH＝CH-CH₃，-CH₂-CH＝CH-C₃H₇，-C₂H₄-CH＝CH-C₂H₅，-CH₂-C(CH₃)＝C(CH₃)₂，-C₂H₄-CH＝C(CH₃)₂，-C₄H₈-C≡CH，-C≡C-C₄H₉，-C₃H₆-C≡C-CH₃，-CH₂-C≡C-C₃H₇，-C₂H₄-C≡C-C₂H₅；

alkylene means divalent straight or branched chain C₁-C₆Alkylene, preferably linear or branched, C having from one to five carbon atoms₂-C₆Alkenylene, or C, linear or branched₂-C₆-alkynylene, which may be substituted with one or more substituents R';

alkylthio refers to S-alkyl, said alkyl being as defined above;

hydroxyalkyl refers to a "HO-alkyl" group, the alkyl being as defined above;

haloalkoxy means alkoxy substituted by one to five halogen atoms, said alkyl being as defined above; the haloalkoxy group is preferably-OC (R)¹⁰)₃、-OCR¹⁰(R¹⁰′)₂、-OCR¹⁰(R¹⁰′)R¹⁰″、-OC₂(R¹⁰)₅、-OCH₂-C(R¹⁰)₃、-OCH₂-CR¹⁰(R¹⁰′)₂、-OCH₂-CR¹⁰(R¹⁰′)R¹⁰″、-OC₃(R¹⁰)₇or-OC₂H₄-C(R¹⁰)₃Wherein R is¹⁰、R¹⁰′、R¹⁰"denotes F, Cl, Br or I, preferably F;

the halogen group is fluorine, chlorine, bromine or iodine;

heteroaryl refers to a 5 or 6 membered heterocyclic group containing at least one heteroatom such as O, N, S. The heterocyclic group may be fused to another aromatic ring. For example, the group may be selected from thiadiazoles, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, 1, 2, 4-oxadiazol-3-yl, 1, 2, 4-oxadiazol-5-yl, 1, 2, 5-oxadiazol-3-yl, 1, 2, 5-oxadiazol-4-yl, 1, 2, 4-thiadiazol-3-yl, 1, 2, 4-thiadiazol-5-yl, thiadiazol-3-yl, isothiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isoxazol-4-yl, isoxazol-, Isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1, 2, 5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, 1, 2, 5-thiadiazol-4-yl, 4-imidazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyranyl, 3-pyranyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-5-yl, pyridin-6-yl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1, 2, 3-triazol-4-yl, 1, 2, 3-triazol-5-yl, 1, 2, 4-triazol-3-yl, 1, 2, 4-triazol-5-yl, 1H-tetrazol-2-yl, 1H-tetrazol-3-yl, tetrazolyl, acridinyl, phenazinyl, carbazolyl, phenoxazinyl, indolizinyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-isoindolyl, 3-isoindolyl, 4-isoindolyl, 5-isoindolyl, 6-isoindolyl, 7-isoindolyl, 2-indolinyl, 3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl, benzo [ b ] furanyl, benzofurazan, benzothiofurazan, benzotriazol-1-yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzotriazol-7-yl, benzotriazine, benzo [ b ] thiophenyl, benzimidazolyl, benzothiazolyl, quinazolinyl, cinnolinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, or tetrahydroisoquinolinyl, purine, 2, 3-naphthyridine, pteridine, thiatetrazine, thiatriazene, isothiazolopyrazine, isothiazolopyrimidine, pyrazolotriazine, pyrazolopyrimidine, imidazopyridazine, imidazopyrimidine, imidazopyridine, imidazotriazine, triazolotriazine, triazolopyridine, triazolopyrazine, triazolopyrimidine, triazolopyridazine group. These heterocyclic groups may be substituted with one or more substituents R ', wherein R' is as defined above;

phosphonooxy is-O-P (═ O) (OH)₂Or a salt thereof;

The invention also relates to compounds of general formula (II) or salts or physiologically functional derivatives or stereoisomers thereof,

formula (II)

Wherein

substituent-Y^bAttached to the 5-or 6-position of the benzazole;

X^bindependently S, O, SO or SO₂；

Y^bIndependently represent S, NR²SO or SO₂；

A^bIndependently represent ← CO-, ° CS-, ° SO₂-、←CO₂-、←CONR⁸-、←NR⁸CO-、←NR⁸CONR⁹-、←NR⁸COO-、←NR⁸NR⁹CO-、←NR⁸OCO-、←ONR⁸CO-or ← NR⁸SO₂-, where ← value is linked to R³A point of (a);

R^4bindependently represent H, -SOR⁶、-SO₂R⁶、-SO₃R⁶、-NO₂、-CN、-CF₃、-OCH₃、-OCF₃Alkyl, cycloalkyl, alkoxy, -NH₂Alkylamino, -NR⁷COR⁶Halogen, -OH, -SH, alkylthio, haloalkyl, haloalkoxy, aryl or heteroaryl;

R²、R³、R⁵、R⁶、R^6a、R⁷、R⁸、R^8a、R⁹、R^9a、R¹¹、R¹²、R¹⁶、X²is as defined above;

alkyl, if not otherwise stated, denotes straight-chain or branched C₁-C₆-alkyl, preferablySelected from one to five carbon atoms, straight or branched, C₂-C₆Alkenyl, or straight or branched C₂-C₆-alkynyl, which may be substituted by one or more substituents R';

said C is₁-C₆Alkyl radical, C₂-C₆-alkenyl, C₂-C₆-alkynyl residues may be selected from the group comprising:

-CH₃，-C₂H₅，-CH＝CH₂，-C≡CH，-C₃H₇，-CH(CH₃)₂，-CH₂-CH＝CH₂，-C(CH₃)＝CH₂，-CH＝CH-CH₃，-C≡C-CH₃，-CH₂-C≡CH，-C₄H₉，-CH₂-CH(CH₃)₂，-CH(CH₃)-C₂H₅，-C(CH₃)₃，-C₅H₁₁，-C₆H₁₃，-C(R`)₃，-C₂(R`)₅，-CH₂-C(R`)₃，-C₃(R`)₇，-C₂H₄-C(R`)₃，-C₂H₄-CH＝CH₂，-CH＝CH-C₂H₅，-CH＝C(CH₃)₂，-CH₂-CH＝CH-CH₃，-CH＝CH-CH＝CH₂，-C₂H₄-C≡CH，-C≡C-C₂H₅，-CH₂-C≡C-CH₃，-C≡C-CH＝CH₂，-CH＝CH-C≡CH，-C≡C-C≡CH，-C₂H₄-CH(CH₃)₂，-CH(CH₃)-C₃H₇，-CH₂-CH(CH₃)-C₂H₅，-CH(CH₃)-CH(CH₃)₂，-C(CH₃)₂-C₂H₅，-CH₂-C(CH₃)₃，-C₃H₆-CH＝CH₂，-CH＝CH-C₃H₇，-C₂H₄-CH＝CH-CH₃，-CH₂-CH＝CH-C₂H₅，-CH₂-CH＝CH-CH＝CH₂，-CH＝CH-CH＝CH-CH₃，-CH＝CH-CH₂-CH＝CH₂，-C(CH₃)＝CH-CH＝CH₂，-CH＝C(CH₃)-CH＝CH₂，-CH＝CH-C(CH₃)＝CH₂，-CH₂-CH＝C(CH₃)₂，C(CH₃)＝C(CH₃)₂，-C₃H₆-C≡CH，-C≡C-C₃H₇，-C₂H₄-C≡C-CH₃，-CH₂-C≡C-C₂H₅，-CH₂-C≡C-CH＝CH₂，-CH₂-CH＝CH-C≡CH，-CH₂-C≡C-C≡CH，-C≡C-CH＝CH-CH₃，-CH＝CH-C≡C-CH₃，-C≡C-C≡C-CH₃，-C≡C-CH₂-CH＝CH₂，-CH＝CH-CH₂-C≡CH，-C≡C-CH₂-C≡CH，-C(CH₃)＝CH-CH＝CH₂，-CH＝C(CH₃)-CH＝CH₂，-CH＝CH-C(CH₃)＝CH₂，-C(CH₃)＝CH-C≡CH，-CH＝C(CH₃)-C≡CH，-C≡C-C(CH₃)＝CH₂，-C₃H₆-CH(CH₃)₂，-C₂H₄-CH(CH₃)-C₂H₅，-CH(CH₃)-C₄H₉，-CH₂-CH(CH₃)-C₃H₇，-CH(CH₃)-CH₂-CH(CH₃)₂，-CH(CH₃)-CH(CH₃)-C₂H₅，-CH₂-CH(CH₃)-CH(CH₃)₂，-CH₂-C(CH₃)₂-C₂H₅，-C(CH₃)₂-C₃H₇，-C(CH₃)₂-CH(CH₃)₂，-C₂H₄-C(CH₃)₃，-CH(CH₃)-C(CH₃)₃，-C₄H₈-CH＝CH₂，-CH＝CH-C₄H₉，-C₃H₆-CH＝CH-CH₃，-CH₂-CH＝CH-C₃H₇，-C₂H₄-CH＝CH-C₂H₅，-CH₂-C(CH₃)＝C(CH₃)₂，-C₂H₄-CH＝C(CH₃)₂，-C₄H₈-C≡CH，-C≡C-C₄H₉，-C₃H₆-C≡C-CH₃，-CH₂-C≡C-C₃H₇，-C₂H₄-C-≡C-C₂H₅；

alkylthio refers to S-alkyl, said alkyl being as defined above;

hydroxyalkyl refers to a "HO-alkyl" group, the alkyl being as defined above;

alkylamino refers to a "HN-alkyl" or "N-dialkyl" group, the alkyl being as defined above;

the halogen group is fluorine, chlorine, bromine or iodine;

phosphonooxy is-O-P (═ O) (OH)₂Or a salt thereof;

The invention also provides a pharmaceutical composition comprising a compound of formula (I), in free form or in pharmaceutically acceptable salt and physiologically functional derivative form, together with a pharmaceutically acceptable diluent or carrier therefor.

The term "physiologically functional derivative" as used herein refers to compounds which are not pharmaceutically active per se, but which are converted into their pharmaceutically active form in vivo, i.e. in the subject to which the compound is administered. Examples of physiologically functional derivatives are prodrugs, such as those described below in the present application.

Prodrugs of compounds of the present invention include, but are not limited to: conversion in vivo to the corresponding ester of the active alcohol, conversion in vivo to the corresponding ester of the active acid, conversion in vivo to the imine of the corresponding active amine, metabolism in vivo to the imine of the corresponding active carbonyl derivative (e.g., aldehyde or ketone), decarboxylation in vivo to the 1-carboxy-amine of the active amine, dephosphorylation in vivo by a phosphatase to the phosphoryloxy compound of the active alcohol, and metabolism in vivo to the corresponding amide of the active amine or acid, respectively.

The term "stereoisomer" as used herein refers to a compound having at least one stereogenic center, which may be in the R or S configuration. It must be understood that in compounds having more than one stereocenter, the stereocenters, independently of one another, may be of the R or S configuration. The term "stereoisomer" as used herein also refers to salts of the compounds described herein having an optically active acid or base.

In addition, the present invention provides a process for the preparation of the compounds of the invention, such as compounds of formula (I).

The compounds of formula (I), formula (Ia) and formula (II) may be obtained by a variety of methods. One possibility for the synthesis of compounds of formula (I) comprises the step of reacting a compound of formula (VII) wherein R is R with a compound of formula (VIII)³、R⁴、R⁵A, X and Y are as defined above in formula (I), formula (Ia) and formula (II), in formula (VIII) R¹Are as defined above and LG comprises a leaving group, such as Cl, Br and I. Nucleophilic substitution or palladium catalyzed crosslinking may be applied. If Y is NR²，R²Can be added with R¹Before or after.

Another method for synthesizing compounds of formula (I), (Ia) and (II) comprises adding R to a compound of formula (IX)⁵Wherein R is¹、R⁴X and Y are as defined above for formula (I), formula (Ia) and formula (II), followed by a step of reaction with an acid chloride, carboxylic acid, sulfonyl chloride or isocyanate, or vice versa.

The compound of formula (IX) may be synthesized by reacting a compound of formula (X) wherein R is R with a compound of formula (VIII)⁴X and Y are as defined above in formula (I), formula (Ia) and formula (II), in formula (VIII) R¹Is as defined above in formula (I), formula (Ia) and formula (II), and LG comprises a leaving group, such as Cl, Br and I. Nucleophilic substitution or palladium catalyzed crosslinking may be applied. Protection of the 2-amino group of the benzazole (e.g., Boc protection) may be necessary. If Y is NR²，R²Can be added with R¹Before or after.

A compound of formula (VII) wherein Y ═ NH, can be synthesized by reduction of a compound of formula (XI) wherein in formula (XI), R is³、R⁴、R⁵A and X are as defined above in formula (I), formula (Ia) and formula (II). Heterogeneous catalytic hydrogenation may be applied, for example.

The compound of formula (XI) can be prepared by adding R to the compound of formula (XII)⁵Wherein in the formula (XII), R⁴And X is as defined above, then reacted with an acid chloride, carboxylic acid, sulfonyl chloride, or isocyanate, or vice versa.

A preferred embodiment of the present invention are compounds of formula (III),

formula (III)

Wherein Y is attached to the 5 or 6 position of the benzazole;

A、X、Y、R³、R⁴、R⁵、R¹²、R¹³、R¹⁴、R¹⁵is as defined above in formula (I).

Another preferred embodiment of the inventionThe formula (III) wherein R¹²And R¹⁵Is H, and R¹³And R¹⁴Independently represents an O-alkyl group which may be substituted.

A more preferred embodiment of the invention are compounds of formula (III) wherein X independently represents S or O; y represents NH; a independently represents-CO-or ← NHCO-, wherein ← means linked to R³A point of (a); r³Is optionally substituted aryl or heteroaryl, R⁵、R¹²And R¹⁵Is H; r¹³And R¹⁴is-O-alkyl which may be substituted.

Another preferred embodiment of the present invention are compounds of formula (IV),

formula (IV)

Wherein Y is attached to the 5 or 6 position of the benzazole; A. x, Y, R³、R⁴、R⁵、R¹²、R¹³As defined above in formula (I).

Another preferred embodiment of the present invention are compounds of formula (V),

formula (V)

Wherein Y is attached to the 5 or 6 position of the benzazole; A. x, Y, R³、R⁴、R⁵、R¹²、R¹³、R¹⁴、R¹⁵As defined above in formula (I).

Another preferred embodiment of the present invention are compounds of formula (VI),

formula (VI)

Wherein Y is attached to the 5 or 6 position of the benzazole; A. x, Y, R³、R⁴、R⁵、R¹⁶As defined above in formula (I).

Another preferred embodiment of the invention are compounds of formula (I) wherein X represents S; y represents NH; a represents-CO-; r⁵Represents H.

Another preferred embodiment of the invention are compounds of formula (I) wherein X represents S; y represents NH; a denotes ← NHCO-, wherein ← denotes binding to R³A point of (a); r⁵Represents H.

Another preferred embodiment of the invention are compounds of formula (I) wherein X represents O; y represents NH; a represents-CO-; r⁵Represents H.

Another preferred embodiment of the invention are compounds of formula (I) wherein X represents O; y represents NH; a denotes ← NHCO-, wherein ← denotes binding to R³A point of (a); r⁵Represents H.

Another preferred embodiment of the invention are compounds of formula (I) which are wherein X represents O; y represents NH; a represents-CO-, R³Represents an optionally substituted aryl or heteroaryl group; r⁵A compound represented by formula (H).

A more preferred embodiment of the present invention are compounds of formula (III) wherein-Y-R¹The substituent is attached to the 5-position of the benzazole, and X independently represents S or O; y represents NH; a independently represents-CO-or ← NHCO-, wherein ← means linked to R³A point of (A), R³Is optionally substituted aryl or heteroaryl, R⁵、R¹²And R¹⁵Is H; r¹³And R¹⁴is-O-alkyl which may be substituted.

A more preferred embodiment of the present invention are compounds of formula (III) wherein-Y-R¹The substituent being attached to the 6-position of the benzazoleX independently represents S or O; y represents NH; a independently represents-CO-or ← NHCO-, wherein ← means linked to R³A point of (A), R³Is optionally substituted aryl or heteroaryl, R⁵、R¹²And R¹⁵Is H; r¹³And R¹⁴is-O-alkyl which may be substituted.

A more preferred embodiment of the present invention are compounds of formula (III) wherein-Y-R¹The substituent is attached to the 5-position of the benzazole, and X independently represents S or O; y represents NH; a independently represents-CO-or ← NHCO-, wherein ← means linked to R³A point of (A), R³Is optionally substituted phenyl, R⁵、R¹²And R¹⁵Is H; r¹³And R¹⁴is-O-alkyl which may be substituted.

A more preferred embodiment of the present invention are compounds of formula (III) wherein-Y-R¹The substituent is connected to the 6-position of the benzazole, and X independently represents S or O; y represents NH; a independently represents-CO-or ← NHCO-, wherein ← means linked to R³A point of (A), R³Is optionally substituted phenylaryl or heteroaryl, R⁵、R¹²And R¹⁵Is H; r¹³And R¹⁴is-O-alkyl which may be substituted.

Another preferred embodiment of the present invention are compounds of formula (I), wherein R is³Is an optionally substituted aryl or heteroaryl group.

Another preferred embodiment of the present invention are compounds of formula (I), wherein R is³Is optionally substituted phenyl.

Another preferred embodiment of the present invention are compounds of formula (I) wherein-Y-R¹The substituent is attached to the 5-position of the benzazole.

Another preferred embodiment of the present invention are compounds of formula (I) wherein-Y-R¹The substituent is attached to the 6-position of the benzazole.

Another preferred embodiment of the present invention are compounds of formula (III), wherein R is³Is an optionally substituted arylA group or a heteroaryl group.

Another preferred embodiment of the present invention are compounds of formula (III), wherein R is³Is optionally substituted phenyl.

Another preferred embodiment of the present invention are compounds of formula (III) wherein-Y-R¹The substituent is attached to the 5-position of the benzazole.

Another preferred embodiment of the present invention are compounds of formula (III) wherein-Y-R¹The substituent is attached to the 6-position of the benzazole.

Another preferred embodiment of the invention are compounds of formula (III) wherein X represents S; y represents NH; a represents-CO-; r⁵Represents H.

Another preferred embodiment of the invention are compounds of formula (III) wherein X represents S; y represents NH; a denotes ← NHCO-, wherein ← denotes binding to R³A point of (a); r⁵Represents H.

Another preferred embodiment of the invention are compounds of formula (III) wherein X represents O; y represents NH; a represents-CO-; r⁵Represents H.

Another preferred embodiment of the invention are compounds of formula (III) wherein X represents O; y represents NH; a denotes ← NHCO-, wherein ← denotes binding to R³A point of (a); r⁵Represents H.

Another preferred embodiment of the invention are compounds of formula (III) which are wherein X represents O; y represents NH; a represents-CO-, R³Represents an optionally substituted aryl or heteroaryl group; r⁵A compound represented by formula (H).

Another preferred embodiment of the present invention are compounds of the formula (Ia), in which X^aRepresents S; y is^aRepresents NH; a. the^aRepresents CO-; r⁵Represents H.

Another preferred embodiment of the present invention are compounds of the formula (Ia), in which X^aRepresents S; y is^aRepresents NH; a. the^aRepresenting ← NHCO-, wherein ← refers to binding to R³A point of (a); r⁵Represents H.

Another preferred embodiment of the present invention are compounds of formula (Ia), wherein R is³Is an optionally substituted aryl or heteroaryl group.

Another preferred embodiment of the present invention are compounds of formula (Ia), wherein R is³Is optionally substituted phenyl.

Another preferred embodiment of the present invention are compounds of formula (Ia), wherein-Y^a-R^1aThe substituent is attached to the 5-position of the benzazole.

Another preferred embodiment of the present invention are compounds of formula (Ia), wherein-Y^a-R^1aThe substituent is attached to the 6-position of the benzazole.

Another preferred embodiment of the present invention are compounds of the formula (II) in which X^bRepresents S; y is^bRepresents NH; a. the^brepresents-CO-; r⁵Represents H.

Another preferred embodiment of the present invention are compounds of the formula (II) in which X^bRepresents S; y is^bRepresents NH; a. the^bRepresenting ← NHCO-, wherein ← refers to binding to R³A point of (a); r⁵Represents H.

Another preferred embodiment of the present invention are compounds of formula (II) wherein R is³Is an optionally substituted aryl or heteroaryl group.

Another preferred embodiment of the present invention are compounds of formula (II) wherein R is³Is optionally substituted phenyl.

Another preferred embodiment of the present invention are compounds of the formula (II) in which-Y^b-the substituent is attached to the 5-position of the benzazole.

Another preferred embodiment of the present invention are compounds of the formula (II) in which-Y^b-the substituent is attached to the 6-position of the benzazole.

Another preferred embodiment is a composition comprising one or more compounds of the present invention and a pharmaceutically acceptable carrier or diluent.

The compounds of the invention can form salts with inorganic or organic acids or inorganic bases or organic. Examples of pharmaceutically acceptable salts include, but are not limited to, non-toxic inorganic or organic salts, such as acetate from acetic acid, aconitate from aconitic acid, ascorbate from ascorbic acid, benzoate from benzoic acid, cinnamate from cinnamic acid, citrate from citric acid, embonate from embonic acid, heptanoate from heptanoic acid, formate from formic acid, fumarate from fumaric acid, glutamate from glutamic acid, glycolate from glycolic acid, hydrochloride from hydrochloric acid, hydrobromide from hydrobromic acid, lactate from lactic acid, maleate from maleic acid, malonate from malonic acid, mandelate from mandelic acid, methanesulfonate from methanesulfonic acid, naphthalene-2-sulfonate from naphthalene-2-sulfonic acid, nitrate from nitric acid, Perchlorates from perchloric acid, phosphates from phosphoric acid, phthalates from phthalic acid, salicylates from salicylic acid, sorbates from sorbic acid, stearates from stearic acid, succinates from succinic acid, sulfates from sulfuric acid, tartrates from tartaric acid, p-toluenesulfonic acid from p-toluenesulfonic acid, and the like.

Salts of phosphonooxy and phosphonooxyalkyl groups may be those formed with alkali metal ions, for example sodium or potassium, or with alkaline earth metal ions, for example calcium or magnesium, or with zinc ions.

These salts of the compounds of the present invention may be anhydrous or solvated. These salts can be prepared by methods known to those skilled in the art and described in the prior art.

Other salts, such as the oxalate salt from oxalic acid, which are not considered pharmaceutically acceptable, may also be suitable as intermediates in the preparation of the compounds of the invention or pharmaceutically acceptable salts thereof or physiologically functional derivatives or stereoisomers thereof.

The compounds of the invention and medicaments prepared therefrom are generally useful for treating cell proliferative disorders, for treating or preventing immune diseases and conditions (e.g., inflammatory diseases, neuroimmune diseases, autoimmune diseases, etc.).

The compounds of the invention are useful for the treatment of diseases caused by the proliferation of malignant cells, such as all forms of solid tumors, leukemias, and lymphomas. Thus, the compounds of the present invention and the agents prepared therewith are generally useful for modulating cell activity, cell proliferation, cell survival, cell differentiation, cell cycle, cell maturation and cell death, or for inducing systemic alterations in metabolism, such as alterations in carbohydrate, lipid or protein metabolism. They may also be used to support cell generation renewal (cell generation mechanisms) including blood cell growth and generation (proanthogenic effects) after the depletion and destruction of cells caused by, for example, toxic substances, radiation, immunotherapy, growth defects, malnutrition, malabsorption, immune disorders, anemia, and the like, or to provide therapeutic control of tissue generation and degradation, as well as the maintenance of cells and tissues and therapeutic alteration of blood cell homeostasis.

These diseases and conditions include, but are not limited to, cancers such as hematological (e.g., leukemia, myeloma), or lymphoma (e.g., hodgkin's and non-hodgkin's lymphomas), or solid tumors (e.g., tumors of the breast, prostate, liver, bladder, lung, esophagus, stomach, colorectal, genitourinary, gastrointestinal, skin, pancreas, brain, uterus, colon, head and neck, and ovary, melanoma, astrocytoma, small cell lung cancer, glioma, basal cell and squamous cell carcinomas, sarcomas, such as Kaposi's sarcoma and osteosarcoma).

Other aspects of the invention relate to indolizine derivatives as novel pharmaceutically active agents, in particular for the preparation of pharmaceutical compositions for the treatment of diseases that can be cured or alleviated by inhibition of one or several kinases or phosphatases.

In another more preferred embodiment of the invention, the compounds of the invention are useful for the treatment and/or prevention of diseases by inhibiting one or more kinases, such as: aurora A, Aurora B, EGF-R, ERBB2, IGF1-R, PDGFR, FLT3 VEGF-R2, VEGF-R3, EPHB4, Tie2, FAK and SRC.

If desired, the compounds of the invention or their pharmaceutically acceptable salts or physiologically functional derivatives or stereoisomers are used together with suitable adjuvants and additives for the preparation of a medicament for the treatment or prophylaxis of diseases which are characterized by hyperproliferation of keratinocytes and/or T cells, in particular inflammatory and immunological disorders, preferably selected from Addison's disease, alopecia areata, ankylosing spondylitis, hemolytic anemia (hemolytic anemia), pernicious anemia (pernicious anemia), aphtha, aphthous stomatitis, arthritis, arteriosclerotic disorders, osteoarthritis, rheumatoid arthritis, aspermienese, bronchial asthma, autoimmune hemolysis, Bechet's disease, Boeck's disease, inflammatory bowel disease, Burkitt's lymphoma, Crohn's disease, choroiditis, ulcerative colitis (colitica), Coeliac's disease, cryoglobulinemia, Dermatitis herpetiformis, dermatomyositis, insulin-dependent type I diabetes mellitus, childhood diabetes mellitus, idiopathic diabetes insipidus, insulin-dependent type diabetes mellisis, autoimmune demyelinating disease, Dupuytren's contracture, encephalomyelitis, allergic encephalomyelitis (encephalitoneal), crystalloid ophthalmia (endophthora phacoanaphylactica), allergic enteritis (enteritis algebra), autoimmune enteropathy syndrome, leprous erythema nodosum, idiopathic facial palsy, chronic fatigue syndrome, rheumatic fever (febris rhabdomatosis), glomerulonephritis, Goodture's syndrome, Graves 'disease, Harnma-Rich's disease, Hashimoto's thyroiditis, sudden otopathy, sensorineural deafness, chronic hepatitis (pahetitis), Hodgkin's disease, hypopyonic anemia (hemoglobinuria), polycythematopathy (inflammatory disease), leukopenia, Disseminated lupus erythematosus, systemic lupus erythematosus, cutaneous lupus erythematosus, malignant lymphogranulomatosis, infectious mononucleosis, myasthenia gravis, myelitis destructor, primary idiopathic myxoedema, nephropathy, ophthalmia symphatica (opthalmia symphatica), granulomatosis orchitis (orchitis grandinulatosa), pancreatitis, pemphigus vulgaris, polyarteritis nodosa, chronic primary polyarthritis (polyarthritis chronolytica), polymyositis, acute multiradiculitis (polyarticus acutus), psoriasis, purpura, pyoderma gangrenosum, Quervain thyroiditis, Reiter's syndrome, sarcoidosis, comorbidity sclerosis, progressive systemic sclerosis, scleritis, scleroderma, idiopathic disseminated sclerosis, acquired atrophy, thrombocytopenia due to antiastteratocarcinoma, thrombocytopenia, acute thrombocytopenia, purpura, infertility, idiopathic thrombocytopenia, purpura, idiopathic thrombocytopenia, thrombocytopenia due to antibody, thrombocytopenia due to autoimmune thrombocytopenia, uveitis, thrombocytopenia, purpura, uveitis, thrombocytopenia, and other diseases, Vitiligo, AIDS, HIV, SCID and Epstein-Barr Virus-associated diseases such as Sjorgren's syndrome, virus (AIDS or EBV) -associated B-cell lymphoma, parasitic diseases such as leishmaniasis, and immunosuppressive disease states such as viral infection following allograft transplantation, AIDS, cancer, chronic active hepatitis diabetes, toxic shock (toxic chock) syndrome and food poisoning.

Treatment according to the invention is intended to mean complete or partial restoration of a disease, prevention of a disease or alleviation of a disease or halting the progression of a given disease.

The compounds of the invention are further useful for diseases caused by protozoan infections in humans and animals.

The compounds of the invention can also be used for viral infections or other infections caused by, for example, Pneumocystis carinii (Pneumocystis carinii).

In addition, the present invention relates to a method for treating or preventing diseases, which comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a physiologically functional derivative or stereoisomer thereof.

The compounds of the invention and their pharmaceutically acceptable salts can be administered to animals, preferably to mammals, and in particular to humans as therapeutic agents per se, as a mixture with one another or in the form of pharmaceutical preparations which allow enteral or parenteral use and comprise, as active ingredient, an effective amount of at least one compound of the invention or a salt thereof, in addition to customary pharmaceutically non-toxic excipients and additives.

The preparation of the medicaments comprising the compounds of the invention and their use can be carried out according to known pharmaceutical methods

Although the compounds of the invention for use in therapy may be administered as the starting compound, it is preferred that the active ingredient is introduced with one or more adjuvants, excipients, carriers, buffers, diluents and/or other conventional pharmaceutical adjuvants, optionally in the form of physiologically acceptable salts in pharmaceutical compositions. These salts of the compounds may be anhydrous or solvated.

In a preferred embodiment, the present invention provides a medicament comprising a compound of the present invention, or a pharmaceutically acceptable salt or physiologically functional derivative or stereoisomer thereof, in combination with one or more pharmaceutically acceptable carriers thereof, and optionally, other therapeutic and/or prophylactic ingredients. The carrier or carriers must be "acceptable" in the sense of being compatible with the other ingredients of the preparation and not deleterious to the recipient thereof.

The agents of the invention may be those suitable for oral, rectal, bronchial, nasal, topical, buccal, sublingual, transdermal, vaginal or parenteral (including cutaneous, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, intraocular injection or infusion) administration, or those suitable for administration by inhalation or insufflation, including powder and liquid aerosol administration, or by sustained release systems. Suitable examples of sustained release systems include semipermeable matrices of solid hydrophobic polymers containing the compound of the invention, which matrices may be in the form of shaped articles, e.g. films, or microcapsules.

For the preparation of a medicament from a compound of the invention, and a pharmaceutically acceptable carrier may be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances that act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid, which is a mixture with a finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "article of manufacture" is intended to encompass a formulation of the active compound with encapsulating material as a carrier, such as providing a capsule in which the active ingredient is surrounded by a carrier, with or without the carrier, and which is thus associated therewith. Similarly, flat capsules and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.

To prepare suppositories, a low melting wax, such as a fatty acid glyceride or cocoa butter, is first melted and the active ingredient is dispersed homogeneously therein, for example by stirring. The molten homogeneous mixture is then poured into a suitably sized mould, allowed to cool and thus solidify. Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate. Liquid preparations include solvents, suspensions and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solutions.

The compounds of the invention may thus be formulated for parenteral administration (e.g. by e.g. bolus injection or continuous infusion) as a preparation and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusions or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by sterile isolation of a sterile solid or by lyophilization from solution, which is to be reconstituted with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable coloring, flavoring, stabilizing and thickening agents as desired. Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active component in water together with a viscous material such as a natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose or other known suspending agents.

Also included are solid form preparations which are to be converted, immediately prior to use, to liquid form preparations for oral administration. These liquid forms include solutions, suspensions and emulsions. These preparations may include, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

In a particularly preferred embodiment of the invention, the agent is administered topically. This reduces possible side effects and limits the necessary treatment to those areas affected.

Preferably, the medicament is prepared in the form of an ointment, gel, paste, emulsion, lotion, foam, cream of mixed phase or amphiphilic emulsion system (oil/water-water/oil mixed phase), liposome, carrier, paste or powder.

Ointments and creams may, for example, be formulated with an aqueous or oily base by the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents or colouring agents.

Compositions suitable for topical administration in the oral cavity include lozenges comprising the active agent in a flavored basis, usually sucrose and acacia or tragacanth; lozenges comprising the active ingredient in an inert base such as gelatin and glycerol or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

The solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or nebulizer. The compositions may be provided in single or multiple dose form. In the latter case of a dropper or pipette, this may be accomplished by the patient administering an appropriate predetermined volume of solution or suspension. In the case of a nebulizer, this can be done, for example, by means of a metered nebulization spray pump.

Administration to the respiratory tract may also be accomplished by means of an aerosol formulation in which the active ingredient is provided in a pressurized pack with a suitable propellant material such as a chlorofluorocarbon (CFC), for example dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gas. The aerosol may also conveniently comprise a surfactant, such as lecithin. The dosage of the medicament may be controlled by providing a metering valve.

Alternatively the active ingredient may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). The powder carrier will conveniently form a gel in the nasal cavity. The powder compositions may be presented in unit dosage form, for example in capsules or cartridges of, for example, gelatin, or in blister packs, from which the powder may be administered by means of an inhaler.

In compositions intended for administration to the respiratory tract, including intranasal compositions, the compounds will typically have a small particle size, for example on the order of 5 microns or less. Such particle sizes may be obtained by methods known in the art, for example by micronisation methods.

If desired, compositions suitable for providing sustained release of the active ingredient may be employed.

The pharmaceutical product is preferably in unit dose form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage forms can be packaged as articles of manufacture containing discrete quantities of the article of manufacture, such as packeted tablets, capsules, and powders in vials or ampoules. Likewise, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate amount of any of these in a packaged form. Tablets and capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.

Additional details regarding formulation and administration can be found in the latest version of Remington's pharmaceutical Sciences (Maack Publishing co.

The pharmaceutical composition may also comprise two or more compounds of the invention or pharmaceutically acceptable salts thereof and other therapeutically active substances.

The compounds of the invention can therefore be used in the form of one compound alone or in combination with other active compounds, for example with agents known for the treatment of the abovementioned diseases, so that in the latter case an advantageously increased, amplified effect is observed.

For the preparation of the pharmaceutical preparations, pharmaceutically inert inorganic or organic excipients may be used. For the preparation of pills, tablets, coated tablets and hard gelatin capsules, use may be made of, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like. Excipients for soft gelatine capsules and suppositories are, for example, fats and oils, waxes, semi-solid or solid polyols, natural or hardened oils and the like. Suitable excipients for the preparation of solutions and syrups are, for example, water, sucrose, invert sugar, glucose, polyols and the like. Suitable excipients for the preparation of injectable solutions are, for example, water, alcohols, glycerol, polyols or vegetable oils.

The dosage can vary within wide limits and be adapted to the individual conditions in each individual case. For the above applications, the appropriate dosage will vary depending upon the mode of administration, the particular condition to be treated and the desired effect, however, in general, satisfactory results can be obtained at dosage rates of about 1 to 100mg/kg animal body weight, preferably 1 to 50 mg/kg. Suitable dosage rates for larger mammals, for example humans, are of the order of about 10mg to 3 g/day, conveniently administered once a day, 2 to 4 times a day separately, or in a sustained release form.

The following examples and figures are included to illustrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in these examples, which follow, represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, it should be apparent to those skilled in the art from this disclosure that many changes can be made in the specific embodiments disclosed without departing from the spirit and scope of the invention, which is set forth in the appended claims. All cited references are incorporated herein by reference.

Examples

Abbreviations: min, min; h, hours; r.t., room temperature; rt, retention time; Ψ, false; s, singleness; t, triple; quint, quintuple, br, wide; j, coupling constant; pTLC, preparative thin layer chromatography; DAMP, 4-dimethylaminopyridine, IM, intermediate.

NMR spectra: bruker Avance 300 MHz.¹H NMR Spectroscopy at 300MHz utilizing residual solvent peaks (CDCl) as internal standard₃，δ_H7.26) was recorded.

Analytical LC/ESI-MS: 2 × Waters 600 multiple solvent delivery system. 50 μ l sample loop. Column, Chromolith Speed ROD RP18e (Merck, Darmstadt), 50X 4.6mm with a2 μm prefilter (Merck). Eluent A, H₂O+0.1％HCO₂H; eluent B, MeCN. Gradient, 5% B to 100% B within 5 min; flow rate, 3 ml/min. Waters LCZ single quadrupole mass spectrometry with electrospray source. MS method, MS8 minPM-80-800-20V; scanning in positive/negative ion mode, wherein m/z is 80-800 in 1 second; capillary voltage, 3.5 kV; cone voltage, 20V; amplified voltage, 400V; the probe and desolventizing gas temperatures were 120 ℃ and 350 ℃, respectively. Waters 2487 double lambda absorption detector set at 254 nm.

Preparative HPLC-MS: waters 600 multi-solvent delivery system with prepared pump head. 2000. mu.l or 5000. mu.l sample loop. Column, Waters X-Terra RP18, 7 μm, 19X 150mm, with X-Terra RP18 guard column 7 μm, 19X 10 mm; used at A flow rate of 20ml/min, or YMC ODS-A,40X 150mm with a 7 μm protective column of X-Terra RP18, 19X 10 mm; the flow rate was 50 ml/min. Make-up solvent: MeCN-H2O-HCO2H 80: 20: 0.05 (v: v). Eluent A, H₂O+O.1％HCO₂H; eluent B, MeCN. The method is suitable for samples with different linear gradients, namely 5-100% of eluent B. Injection volume: depending on the sample, 500. mu.l to 2000. mu.l. Waters ZQ Single quadrupole Mass Spectrometry with electrospray Source. Positive or negative ion mode scan, m/z 80-800 in 1 second; capillary voltage, 3.5kV or 3.0 kV; cone voltage, 20V; amplified voltage, 400V; the probe and desolventizing gas temperatures were 120 ℃ and 350 ℃, respectively. Waters FractionCollector II, with quality triggered fractionation. Waters 996 photodiode array detector.

And (5) synthesizing an intermediate.

Intermediate 1: n- (6-aminobenzoxazol-2-yl) benzamide.

Step 1. cyanogen bromide (3.50g, 33 mmol; caution: extreme toxicity! waste treatment A solution of cyanogen bromide in tetrahydrofuran (3mL) was added to an aqueous alkaline solution of cyanogen bromide with excess NaOCl to a solution of 2-amino-5-nitrophenol (4.62g, 30mmol) in tetrahydrofuran (20 mL). After stirring at room temperature for 1 day, a precipitate formed, which was dissolved by addition of water (5 mL). Stir at room temperature for an additional 3 days, add water (10mL) and add NaOH until the mixture becomes basic. The tetrahydrofuran was removed under vacuum and the precipitate formed in the remaining aqueous phase was isolated by filtration, washed with water and recrystallized from methanol (100 mL). When the mother liquor was additionally fractionated crystallized, a total of 3.80g (21.2mmol, 71%) of 2-amino-6-nitrobenzoxazole was obtained as a brown solid. LC/ESI-MS: m/z 180[ M + H ]]⁺；m/z＝178[M-H]^-；R_t＝2.52min。

Step 2 benzoyl chloride (1.17mL, 10.0mmol) was added to a suspension of 2-amino-6 nitrobenzoxazole (1.50g, 8.37mmol) in pyridine (10 mL). After stirring at 80 ℃ for 24 hours, the solution was poured into water (250 mL). The mixture was stirred at room temperature overnight and the precipitate formed was isolated by filtration. Thus N- (6-nitrobenzoxazol-2-yl) benzamide (2.08g, 7.32mmol, 88%) was obtained as a yellow solid. LC/ESI-MS: 284[ M + H ] M/z]⁺；m/z＝282[M-H]^-；R_t＝3.13min。

Step 3. to a solution of N- (6-nitrobenzoxazol-2-yl) benzamide (2.03g, 7.17mmol) in dimethylformamide (60mL), palladium on carbon catalyst (1.52g, 10% Pd, 1.43mmol Pd) was added and the air was replaced with hydrogen (1 bar). The mixture was stirred at 60 ℃ for 2 hours and then at room temperature overnight. The palladium was removed by filtration through a pad of Celite (Celite). After concentration to 20ml, water was added and the precipitate formed was isolated by filtration to give N- (6-aminobenzoxazol-2-yl) benzamide (0.823g, 3.25mmol, 45%) as a brown solid. LC/ESI-MS: 254[ M + H ] M/z]⁺；m/z＝252[M-H]^-；R_t＝1.92min。

Intermediate 2: n- (6-aminobenzothiazol-2-yl) benzamide.

Step 1 to a suspension of 2-amino-6-nitrobenzothiazole (Sigma Aldrich, 2.93g, 15mmol) in pyridine (20mL) was added benzoyl chloride (1.74mL, 15 mmol). After stirring at room temperature overnight, additional benzoyl chloride (1.74ml, 15mmol) was added and the mixture was stirred at 60 ℃. After completion of the reaction, the mixture was poured into water (250mL) and stirred at room temperature overnight. The precipitate formed was isolated to give N- (6-nitrobenzothiazol-2-yl) benzamide (3.87g, 12.9mmol, 86%) as a yellow solid. LC/ESI-MS: 300[ M + H ] M/z]⁺；m/z＝298[M-H]^-；R_t＝3.93min。

Step 2. A mixture of N- (6-nitrobenzothiazol-2-yl) benzamide (3.77g, 12.6mmol), palladium on charcoal catalyst (2g, 10% Pd, 1.88mmol Pd), dimethylformamide (80mL) and ethyl acetate (20mL) was hydrogenated at 60 deg.C (1 bar) for 2 hours. The palladium was removed by filtration through a celite pad. After concentration to 20ml, water was added and the precipitate formed was isolated by filtration to give N- (6-aminobenzothiazol-2-yl) benzamide (3.15g, 11.7mmol, 93%) as a grey solid. LC/ESI-MS: 270[ M + H ] M/z]⁺；m/z＝268[M-H]^-；R_t＝2.27min。

Intermediate 3: n- (6-aminobenzothiazol-2-yl) isonicotinamide.

Step 1 to a mixture of 2-amino-6-nitrobenzothiazole (Sigma Aldrich, 1.95g, 10mmol) and pyridine (40mL) was added benzoyl chloride (2.1mL, 18 mmol). After stirring at 80 ℃ for 5 hours, water (10ml) was added. The mixture was stirred at room temperature for 0.5 h, then methanol (30mL) and water (50mL) were added. The precipitated N- (6-nitrobenzothiazol-2-yl) isonicotinamide was isolated by filtration. The crude product was dissolved in dimethylformamide and reprecipitated by addition of methanol and water (2.53g, 8.42mmol, 84%). LC/ESI-MS: 301[ M + H ] M/z]⁺；m/z＝299[M-H]^-；R_t＝3.48min。

Step 2N- (6-nitrobenzothiazol-2-yl) isonicotinamide (2.42g, 8.04mmol) was suspended in acetic acidEthyl ester (150mL) and dimethylformamide was added until dissolution occurred. After addition of palladium on charcoal catalyst (4.25g, 10% Pd, 4mmol Pd), the mixture was hydrogenated (1 bar) at 60 ℃ until the reaction was complete. The palladium was removed by filtration through a celite pad and the solvent was evaporated. The residue was dissolved in a small amount of methanol and precipitated by adding water to obtain N- (6-aminobenzothiazol-2-yl) isonicotinamide (1.73g, 6.4mmol, 80%). LC/ESI-MS: m/z 271[ M + H ]]⁺；m/z＝269[M-H]^-；R_t＝1.43min。

Intermediate 4: n- (6-aminobenzothiazol-2-yl) nicotinamide.

Step 1. A mixture of 2-amino-6-nitrothiazole (0.976g, 5mmol), nicotinoyl chloride hydrochloride (1.07g, 6mmol), triethylamine (1.9mL, 13.8mmol), DMAP (catalytic amount) and dioxane (50mL) was heated to reflux for 7 hours. After addition of nicotinoyl chloride hydrochloride (0.89g, 5mmol) and triethylamine (1.8ml, 12.5mmol), heating was continued for 5 hours. After cooling to room temperature, the precipitate was separated by filtration. The solid was treated with boiling methanol (25mL) to remove soluble impurities. Thus, N- (6-nitrobenzothiazol-2-yl) nicotinamide (1.36g, 4.53mmol, 91%) was obtained. LC/ESI-MS: 301[ M + H ] M/z]⁺；m/z＝299[M-H]^-；R_t＝3.54min。

Step 2N- (6-nitrobenzothiazol-2-yl) nicotinamide (0.50g, 1.67mmol) was dissolved in dimethyl sulfoxide (50mL) with warming. After addition of palladium on charcoal catalyst (0.089g, 10% Pd, 0.08mmol Pd), the mixture was hydrogenated at 80 ℃ for 5.5 h. The palladium was removed by hot filtration through a silica pad. After removal of the solvent, N- (6-aminobenzothiazol-2-yl) nicotinamide (0.45g, 1.67mmol, 100%) LC/ESI-MS was obtained as a brown solid: m/z 271[ M + H ]]⁺；m/z＝269[M-H]^-；R_t＝1.67min。

Intermediate 5: n- (5-aminobenzothiazol-2-yl) benzamide.

Step 1. ammonium thiocyanate (8.55g, 112.5mmol) was dissolved in acetone (80mL) and acetyl chloride (8.83g, 112.5mmol) was added dropwise. After stirring at room temperature for 1 hourThe solids were filtered off and the filtrate was added to a solution of 2-fluoro-5-nitroaniline in acetone (45 mL). The mixture was refluxed for 6 hours, then the solution was concentrated and left overnight at room temperature. The precipitated 1-acetyl-3- (2-fluoro-5-nitrophenyl) thiourea was filtered off, washed with acetone and dried. The mother liquor was concentrated and recrystallized from acetone to obtain another crop of product. A total of 12.55g (48.8mmol, 43%) of a grey solid were obtained. LC/ESI-MS: 258[ M + H ] M/z]⁺；R_t＝3.42min。

Step 2. A solution of 1-acetyl-3- (2-fluoro-5-nitrophenyl) thiourea (9.63g, 37.4mmol) in methanol (400mL) was poured quickly into a solution of sodium methoxide (concentration, 0.5mol/L) in methanol (100 mL). The solution was left overnight without stirring. The precipitated 2-amino-5-nitrobenzothiazole was filtered off, washed with methanol and dried (yellow crystals, 6.87g, 35.2mmol, 94%). LC/ESI-MS: 196[ M + H ] M/z]⁺；m/z＝194[M-H]^-；R_t＝2.71min。

Step 3. A mixture of 2-amino-5-nitrobenzothiazole (1.52g, 7.8mmol), benzoyl chloride (1.36mL, 11.7mmol) and pyridine (15mL) was heated to 60 ℃ for 24 h. The mixture was poured into water (250mL) and the precipitate formed was isolated by filtration to give N- (5-nitrobenzothiazol-2-yl) benzamide (1.83g, 6.12mmol, 78%) as a yellow solid.

Step 4. A mixture of N- (5-nitrobenzothiazol-2-yl) benzamide (1.79g, 6.00mmol) and palladium on carbon catalyst (0.95g, 10% Pd, 0.9mmol Pd) in dimethylformamide (40mL) was hydrogenated at 100 ℃ for 2 hours. The palladium was removed by filtration through a celite pad and the filtrate was concentrated to a small volume. Water (200mL) was added and the precipitate formed was isolated by filtration. Thus N- (5-aminobenzothiazol-2-yl) benzamide (1.39g, 5.14mmol, 86%) was obtained as a grey solid. LC/ESI-MS: 300[ M + H ] M/z]⁺；m/z＝298[M-H]^-；R_t＝4.2min。

Intermediate 7: 4-chloro-6-methoxy-7- [3- (4-methylpiperazin-1-yl) propoxy ] quinazoline.

Step 1 to a solution of methyl vanileate (7.29g, 40mmol) in dimethylformamide (25mL) was added potassium carbonate (8.29g, 60mmol) and benzyl bromide (5.26mL, 44 mmol). The mixture was heated to 100 ℃ for 3 hours. After cooling to room temperature, water was added and the product was extracted several times with ethyl acetate. The combined organic phases were washed with water and brine. Through Na₂SO₄After drying, the solvent was removed to give methyl 4-benzyloxy-3-methoxybenzoate (10.8g, 39.7mmol, 99%) as a grey solid which was used without further purification. LC/ESI-MS: 273[ M + H ] M/z]⁺；R_t＝3.82min。

Step 2 methyl 4-benzyloxy-3-methoxybenzoate (10.9g, 40.0mmol) was converted to methyl 4-benzyloxy-5-methoxy-2-nitrobenzoate (11.6g, 36.6mmol, 91%) as described in US 02/0026052A 1, page 51, reference example 15. LC/ESI-MS: m/z 318[ M + H ]]⁺；R_t＝3.85min。

Step 3. in a1 liter Schlenk flask filled with argon, methyl 4-benzyloxy-5-methoxy-2-nitrobenzoate (11.60g, 36.6mmol) and palladium on charcoal catalyst were combined and tetrahydrofuran (250mL) was added. Argon was replaced with hydrogen (1 bar) and the mixture was stirred vigorously at room temperature until the reaction was complete. The palladium was isolated by filtration through a pad of celite and the solvent was removed to give methyl 2-amino-4-hydroxy-5-methoxy-benzoate (6.56g, 36.0mmol, 98%) which was used without further purification. LC/ESI-MS: m/z is 166[ M-CH ]₄O+H]⁺；R_t＝2.17min。

Step 4 formamide (29mL), ammonium formate (3.41g, 54mmol) and methyl 2-amino-4-hydroxy-5-methoxy-benzoate (6.56g, 36.0mmol) were heated to 140 ℃ for 4 h. After cooling to room temperature, water (75mL) was added. After stirring for 1 hour, the precipitated 7-hydroxy-6-methoxy-3, 4-dihydroquinazolin-4-one was filtered off, washed with water and dried (grey solid, 5.86g, 30.5mmol, 85%). LC/ESI-MS: m/z 193[ M + H ]]⁺；m/z＝191[M-H]^-；R_t＝1.53min。

Step 5. reacting 7-hydroxyA mixture of-6-methoxy-3, 4-dihydroquinazolin-4-one (5.86g, 30.5mmol) and acetic anhydride (21.5ml, 229mmol) in pyridine (4.9ml, 61mmol) was heated to 100 ℃ for 4 hours. After cooling to room temperature, ice water (200mL) was added and the mixture was stirred vigorously for 1 hour. The precipitated 7-acetoxy-6-methoxy-3, 4-dihydroquinazolin-4-one was filtered off, washed with water and dried (grey solid, 6.64g, 28.3mmol, 93%). LC/ESI-MS: 235[ M + H ] M/z]⁺；m/z＝233[M-H]^-；R_t2.88 min. See also WO 04/043472, page 32.

Step 6. 7-acetoxy-6-methoxy-3, 4-dihydroquinazolin-4-one (2.34g, 10.0mmol) was converted to 4-chloro-7-hydroxy-6-methoxyquinazoline (1.22g, 5.79mmol, 58%) as described in WO 04/043472, page 32. LC/ESI-MS: 211[ M (M) ((M))³⁵Cl)+H]⁺；m/z＝209[M(³⁵Cl)-H]^-；R_t＝2.45min。

Step 7. di-tert-butyl azodicarboxylate (0.478g, 2.08mmol) was added dropwise at room temperature to a mixture of 4-chloro-7-hydroxy-6-methoxyquinazoline (0.350g, 1.66mmol), 3- (4-methyl-piperazin-1-yl) -propan-1-ol (intermediate 9, 0.276g, 1.74mmol) and triphenylphosphine (0.544g, 2.08mmol) in dichloromethane (20 mL). If necessary, further alcohol is added. After stirring for 2 hours, the solution was concentrated to 10ml, placed on silica and chromatographed (gradient dichloromethane to dichloromethane: methanol 3: 2 over 1 hour) to give 4-chloro-6-methoxy-7- [3- (4-methylpiperazin-1-yl) propoxy]Quinazoline (brown solid, 0.431g, 1.23mmol, 74%). LC/ESI-MS: m/z 351[ M (M) ((M))³⁵Cl)+H]⁺；R_t1.88 min. See also WO 04/043472, page 32.

Intermediate 8: 4-chloro-7-methoxy-6- [3- (4-methylpiperazin-1-yl) propoxy ] quinazoline.

Step 1 methyl isovanillate (2.73g, 15mmol) was converted to methyl 3-benzyloxy-4-methoxybenzoate (3.91g, 14.4mmol, 96%) analogously to step 1 in the preparation of intermediate 7. LC/ESI-MS: m/z ═273[M+H]⁺；R_t＝3.90min。

Step 2 methyl 3-benzyloxy-4-methoxybenzoate (2.83g, 10.4mmol) was converted to methyl 5-benzyloxy-4-methoxy-2-nitrobenzoate (3.08g, 9.71mmol, 94%) as in step 2 of the preparation of intermediate 7. LC/ESI-MS: m/z 318[ M + H ]]⁺；R_t＝4.00min。

Step 3 methyl 5-benzyloxy-4-methoxy-2-nitrobenzoate (4.11g, 13.0mmol) was converted to methyl 2-amino-5-hydroxy-4-methoxybenzoate (2.56g, 13.0mmol, 100%) in analogy to step 3 in the preparation of intermediate 7. LC/ESI-MS: m/z is 166[ M-CH ]₄O+H]⁺；R_t＝1.95min。

Step 4 methyl 2-amino-5-hydroxy-4-methoxybenzoate (2.56g, 13.0mmol) was converted to 6-hydroxy-7-methoxy-3, 4-dihydroquinazolin-4-one (1.91g, 9.94mmol, 76%) analogously to step 4 in the preparation of intermediate 7. LC/ESI-MS: m/z 193[ M + H ]]⁺；m/z＝191[M-H]^-；R_t＝1.77min。

Step 5 6-hydroxy-7-methoxy-3, 4-dihydroquinazolin-4-one (1.90g, 9.86mmol) was converted to 6-acetoxy-7-methoxy-3, 4-dihydroquinazolin-4-one (2.22g, 9.48mmol, 96%) similar to step 5 in the preparation of intermediate 7. LC/ESI-MS: 235[ M + H ] M/z]⁺；m/z＝233[M-H]^-；R_t＝2.20min。

Step 6-acetoxy-7-methoxy-3, 4-dihydroquinazolin-4-one (0.468g, 2.00mmol) was converted to 4-chloro-6-hydroxy-7-methoxyquinazoline (0.398g, 1.89mmol, 95%) analogously to step 6 in the preparation of intermediate 7. LC/ESI-MS: 211[ M (M) ((M))³⁵Cl)+H]⁺；m/z＝209[M(³⁵Cl)-H]^-；R_t＝2.40min。

Step 7. conversion of 4-chloro-6-hydroxy-7-methoxyquinazoline (0.373g, 1.77mmol) to 4-chloro-7-methoxy-6- [3- (4-methylpiperazin-1-yl) propoxy similar to step 7 in the preparation of intermediate 7Base of]Quinazoline (0.451g, 1.29mmol, 73%). LC/ESI-MS: m/z 351[ M (M) ((M))³⁵Cl)+H]⁺；R_t＝1.82min。

Intermediate 9: 3- (4-methylpiperazin-1-yl) propan-1-ol.

1-methylpiperazine (6.99mL, 63mol) was dissolved in toluene (30 mL). 3-Bromopropanol (2.62ml, 30mmol) was added slowly and the mixture was stirred at room temperature overnight. After heating to 80 ℃ for 2 hours and cooling to room temperature, the mixture was filtered and the filter cake was washed thoroughly with toluene. After removal of the solvent, the residue was distilled (boiling point 180 ℃/2 mbar) to give a colourless oil (4.08g, 25.8mmol, 86%).¹H NMR(CDCl₃)：δ＝1.70(Ψ-quint，J≈5.8Hz，2H)，2.26(s，3H)，2.35-2.6(m，8H)，2.60(Ψ-t，J＝5.8Hz，2H)，3.77(Ψ-t，J＝5.3Hz，2H)，4.09(s，br.，1H)。

Intermediate 10: 2-chloro-4- (methylpiperazin-1-yl) pyrimidine.

A mixture of 2, 4-dichloropyrimidine (0.967g, 6.49mmol), 1-methylpiperazine (0.65g, 6.40mmol) and ethyldiisopropylamine (2.8mL, 16.22mmol) in ethanol (13mL) was stirred at-10 ℃ for 2 hours and then at room temperature overnight. The mixture was partitioned between H2O/brine (3: 1; 100mL) and chloroform (3X 70 mL). The combined organic phases were washed once with brine (50mL) and over MgSO₄And (5) drying. Removal of the solvent gave a light brown solid, which was washed with ethyl acetate/sonication to give the desired product as a colorless powder, which was further treated with Et₂And O washing. Fractional crystallization of the wash solution yields more product. A total of 0.741g (3.48mmol, 54%) of 2-chloro-4- (methylpiperazin-1-yl) pyrimidine were obtained. LC/ESI-MS: 213[ M (M) ((M))³⁵Cl)+H]⁺；R_t＝0.5min。

Intermediate 11: (2-chloropyrimidin-4-yl) - (5-methylpyrazol-3-yl) amine.

2, 4-dichloropyrimidine (0.967g, 6.49mmol), 3-amino-5-methylpyrazole (0.63g, 6.40mmol) and ethyldiisopropylamine (2.8ml, 16.22mmol) were added to ethyl acetateThe mixture in alcohol (13mL) was stirred at-10 ℃ for 2 hours, then at room temperature overnight, and finally at 50 ℃ for 3.5 hours. The mixture was concentrated to a total volume of about 10 mL. When the addition of diethyl ether was repeated, (2-chloropyrimidin-4-yl) - (5-methylpyrazol-3-yl) amine (0.258g, 1.23mmol, 19%) was obtained as colorless crystals. LC/ESI-MS: 210[ M/z ] (M ═ M: (M³⁵Cl)+H]⁺；m/z＝208[M(³⁵Cl)-H]^-；R_t＝2.30min。

Intermediate 12: n is a radical of⁶- { 6-methoxy-7- [3- (4-methyl-piperazin-1-yl) -propoxy]-quinazolin-4-yl } -benzothiazole-2, 6-diamine hydrochloride

Intermediate 7(0.285mmol) and thiazole-2, 6-diamine (47mg, 0.285mmol) were dissolved in butanol (5 mL). A solution of HCl in dioxane (0.214ml, 4M solution) was added. The reaction was completed after 6 hours at 100 ℃. The precipitate formed was filtered, washed with dichloromethane and dried under vacuum (97% yield). LC/ESI-MS: m/z 480[ M + H ]]⁺。

Intermediate 13: n is a radical of⁵- { 6-methoxy-7- [3- (4-methyl-piperazin-1-yl) -propoxy]-quinazolin-4-yl } -benzothiazole-2, 5-diamine hydrochloride

Intermediate 7(0.285mmol) and thiazole-2, 5-diamine (47mg, 0.285mmol) were dissolved in butanol (5 mL). A solution of HCl in dioxane (0.214ml, 4M solution) was added. The reaction was completed after 6 hours at 100 ℃. The precipitate formed was filtered, washed with dichloromethane and dried under vacuum (97% yield). LC/ESI-MS: m/z 480[ M + H ]]⁺。

Intermediate 14: 1- [6- (6-chloro-pyrimidin-4-ylamino) -benzothiazol-2-yl ] -3- (2-methoxy-5-methyl-phenyl) -urea.

A mixture of 4, 6-dichloropyrimidine (180mg, 1.21mmol), benzothiazole-2, 6-diamine (200mg, 1.21mmol), sodium iodide (216mg, 1.45mmol), ethyldiisopropylamine (0.25mL, 1.45mmol) and DMF (10mL) was heated at 85 ℃ for 3 hours. 2-methoxy-5-methylphenyl isocyanate (0.20ml, 1.33mmol) was added and the addition was continued at 85 deg.CThe heat was applied for 3 hours. The solvent was removed and the residue was washed with CH₂Cl₂And (6) processing. The precipitate was isolated (0.57g, 85%). LC/ESI-MS: m/z 441[ M + H ═ M/z]⁺；m/z＝439[M-H]^-；R_t＝3.64min。

Synthesis of examples

Example 1: n- [6- (6, 7-dimethoxyquinazolin-4-ylamino) benzooxazol-2-yl]The preparation of benzamide was carried out by heating a mixture of N- (6-aminobenzoxazol-2-yl) benzamide (IM 1, 30mg, 0.118mmol) and 4-chloro-6, 7-dimethoxyquinazoline (Fluorochem, 26.5mg, 0.118mmol) in ethanol (3mL) to 80 ℃ for 2 hours. The precipitate formed was isolated by filtration, washed with ethanol and dried (yellow solid, 38mg, 85 μmol, 72%). LC/ESI-MS: 442[ M + H ] M/z]⁺；m/z＝440[M-H]^-；R_t＝2.43min。

Example 2: n- [6- (6, 7-dimethoxyquinazolin-4-ylamino) benzothiazol-2-yl]The benzamide was prepared by heating a mixture of N- (6-aminobenzothiazol-2-yl) benzamide (IM2, 30mg, 0.111mmol) and 4-chloro-6, 7-dimethoxyquinazoline (Fluorochem, 25mg, 0.111mmol) in ethylene glycol (0.7mL) to 100 ℃ for 2 hours. Brine (25mL) and saturated sodium bicarbonate solution (25mL) were added and the product was extracted with chloroform (3X 40 mL). Through Na₂SO₄After drying, the solvent was removed and the residue was purified by pTLC (petroleum ether: dichloromethane: methanol: 12: 14: 3) to give a yellow solid (19mg, 41 μmol, 37%). LC/ESI-MS: 458[ M + H ] M/z]⁺；m/z＝456[M-H]^-；R_t＝2.88min。

Example 3: n- [6- (6, 7-dimethoxyquinazolin-4-ylamino) benzothiazol-2-yl]Preparation of isonicotinamide was performed by heating a mixture of N- (6-aminobenzothiazol-2-yl) isonicotinamide (intermediate 3, 50mg, 0.185mmol) and 4-chloro-6, 7-dimethoxyquinazoline (Fluorochem, 42mg, 0.185mmol) in ethanol (3mL) to 80 ℃ for 2 hours. The precipitate formed was isolated by filtration, washed with ethanol and dried (yellow solid, 82mg, 0.179 mmol)，97％)。LC/ESI-MS：m/z＝459[M+H]⁺；m/z＝457[M-H]^-；R_t＝2.65min。

Example 4: n- [6- (6, 7-dimethoxyquinazolin-4-ylamino) benzothiazol-2-yl]Nicotinamide was prepared by heating a mixture of N- (6-aminobenzothiazol-2-yl) nicotinamide (IM 4, 30mg, 0.111mmol) and 4-chloro-6, 7-dimethoxyquinazoline (Fluorochem, 25mg, 0.111mmol) in ethanol (3mL) to 80 ℃ for 2 hours. The precipitate formed was isolated by filtration, washed with ethanol and dried (yellow solid, 44mg, 96 μmol, 87%). LC/ESI-MS: m/z 459[ M + H ]]⁺；m/z＝457[M-H]^-；R_t＝2.60min。

Example 5: n- (6- { 6-methoxy-7- [3- (4-methylpiperazin-1-yl) propoxy group]Quinazolin-4-ylamino } benzothiazol-2-yl) benzamide was prepared by reacting N- (6-amino-benzothiazol-2-yl) benzamide (IM2, 30mg, 0.111mmol), 4-chloro-6-methoxy-7- [3- (4-methylpiperazin-1-yl) propoxy]A mixture of quinazoline (intermediate 7, 39mg, 0.111mmol), ethyldiisopropylamine (40 μ l, 0.222mmol) and HCl (84 μ l, 4M solution in dioxane, 0.333mmol) in n-butanol (3mL) was heated to 110 ℃ for 2 hours. Saturated sodium bicarbonate solution was added and the product was extracted with chloroform. Washing with water and passing through Na₂SO₄After drying, the solvent was removed. The residue was dissolved in a small amount of methanol and water was slowly added. After stirring the mixture overnight, a brown solid was obtained (38mg, 65 μmol, 59%). LC/ESI-MS: 584[ M + H ] M/z]⁺；m/z＝582[M-H]^-；R_t＝2.27min。

Example 6: n- (6- { 7-methoxy-6- [3- (4-methylpiperazin-1-yl) propoxy group]Quinazolin-4-ylamino } benzothiazol-2-yl) benzamides were prepared by reacting N- (6-amino-benzothiazol-2-yl) benzamide (IM2, 40mg, 0.148mmol), 4-chloro-7-methoxy-6- [3- (4-methylpiperazin-1-yl) propoxy]A mixture of quinazoline (IM 8, 52mg, 0.148mmol) and HCl (112 μ l, 4M solution in dioxane, 0.444mmol) in n-butanol (6mL) was heated to 110 ℃ for 5 hours. Adding saturated carbonSodium hydrogen carbonate solution and the product extracted with ethyl acetate. Washing with water and passing through Na₂SO₄After drying, the solvent was removed. The residue was dissolved in a small amount of methanol and water was slowly added. After stirring the mixture overnight, a grey solid was obtained (39mg, 66 μmol, 45%). LC/ESI-MS: 584[ M + H ] M/z]⁺；m/z＝582[M-H]^-；R_t＝2.26min。

Example 7: n- [6- (purin-6-ylamino) benzothiazol-2-yl]Benzamide was prepared by heating a mixture of N- (6-aminobenzothiazol-2-yl) benzamide (IM2, 50mg, 0.186mmol) and 6-chloropurine (29mg, 0.186mmol) in ethanol (3ml) to 80 ℃ for 4 hours. The precipitate formed was isolated by filtration and washed with ethanol (69mg, 0.178mmol, 96%). LC/ESI-MS: m/z 388[ M + H ]]⁺；m/z＝386[M-H]^-；R_t＝3.07min。

Example 8: n- {6- [4- (4-methylpiperazin-1-yl) pyrimidin-2-ylamino]The preparation of benzothiazol-2-yl } benzamide was carried out by heating a mixture of N- (6-aminobenzothiazol-2-yl) benzamide (IM2, 50mg, 0.186mmol) and 2-chloro-4- (4-methylpiperazin-1-yl) pyrimidine (IM 10, 40mg, 0.186mmol) in ethanol (3mL) to 80 ℃ for 4 days. After the precipitate was dissolved by adding dimethylformamide, pTLC (dichloromethane: methanol ═ 4: 1) was performed to obtain a solid (44mg, 0.100mmol, 54%). LC/ESI-MS: 446[ M + H ] M/z]⁺；m/z＝444[M-H]^-；R_t＝2.12min。

Example 9: n- {6- [4- (5-methylpyrazol-3-ylamino) pyrimidin-2-ylamino]The preparation of benzothiazol-2-yl } benzamide was carried out by heating a mixture of N- (6-aminobenzothiazol-2-yl) benzamide (IM2, 35mg, 0.13mmol) and (2-chloropyrimidin-4-yl) - (5-methylpyrazol-3-yl) amine (IM 11, 30mg, 0.143mmol) in ethanol (3mL) to 80 ℃ for 9 hours. The precipitate was isolated by filtration, washed with ethanol and dried (38mg, 85 μmol, 66%). LC/ESI-MS: 443[ M + H ] M/z]⁺；m/z＝441[M-H]^-；R_t＝2.80min。

Example 10: n- [5- (6, 7-dimethoxyquinazolin-4-ylamino) benzothiazol-2-yl]Benzamide was prepared by heating a mixture of N- (5-aminobenzothiazol-2-yl) benzamide (IM5, 30mg, 0.111mmol) and 4-chloro-6, 7-dimethoxyquinazoline (Fluorochem, 25mg, 0.111mmol) in ethylene glycol (0.7mL) to 100 ℃ for 2 hours. Brine (25mL) and saturated sodium bicarbonate solution (25mL) were added and the product was extracted with chloroform (3X 40 mL). In the presence of Na₂SO₄After drying, the solvent was removed and ethyl acetate and petroleum ether were added to the residue. Filtration gave a yellow solid (28mg, 60. mu. mol, 55%). LC/ESI-MS: 458[ M + H ] M/z]⁺；m/z＝456[M-H]^-；R_t＝3.20min。

Example 11: n- [5- (purin-6-ylamino) benzothiazol-2-yl]Benzamide was prepared by heating a mixture of N- (5-aminobenzothiazol-2-yl) benzamide (IM5, 50mg, 0.186mmol) and 6-chloropurine (29mg, 0.186mmol) in ethanol (3ml) to 80 ℃ for 4 hours. The precipitate formed was isolated by filtration and washed with ethanol (68mg, 0.174mmol, 94%). LC/ESI-MS: m/z 388[ M + H ]]⁺；m/z＝386[M-H]^-；R_t＝3.13min。

Example 12: n- {5- [4- (4-methylpiperazin-1-yl) pyrimidin-2-ylamino]Preparation of benzothiazol-2-yl } benzamide was performed by heating a mixture of N- (5-aminobenzothiazol-2-yl) benzamide (IM5, 50mg, 0.186mmol) and 2-chloro-4- (4-methylpiperazin-1-yl) pyrimidine (IM 10, 40mg, 0.186mmol) in ethanol (3mL) to 80 ℃ for 4 days. Brine (25mL) and saturated sodium bicarbonate solution (25mL) were added and the product was extracted with chloroform (3X 40mL) and ethyl acetate (40 mL). The combined organic phases are passed over Na₂SO₄Dried and the solvent removed. The residue was purified by performing pTLC (dichloromethane: methanol ═ 4: 1) to obtain a solid (44mg, 99 μmol, 53%). LC/ESI-MS: 446[ M + H ] M/z]⁺；m/z＝444[M-H]^-；R_t＝2.38min。

Example 13: n- {5- [4- (5-methylpyrazol-3-ylamino) pyrimidin-2-ylamino]Benzothiazol-2-yl } benzathinesThe amide was prepared by heating a mixture of N- (5-aminobenzothiazol-2-yl) benzamide (IM5, 35mg, 0.13mmol) and (2-chloropyrimidin-4-yl) - (5-methylpyrazol-3-yl) amine (IM 11, 30mg, 0.143mmol) in ethanol (3mL) to 80 ℃ for 9 hours. The precipitate was isolated by filtration, washed with ethanol and dried (32mg, 72 μmol, 56%). LC/ESI-MS: 443[ M + H ] M/z]⁺；m/z＝441[M-H]^-；R_t＝2.92min。

Example 15: n- (6- { 6-methoxy-7- [3- (4-methyl-piperazin-1-yl) -propoxy]Preparation of-quinazolin-4-ylamino } -benzooxazol-2-yl) -benzamide was carried out by reacting intermediate 1(0.138mM) with intermediate 7(0.138mM) in butanol (3mL) under acid catalysis (3.0eq., 0.105mL, 4M HCl in dioxane) at 110 ℃. The reaction was complete after 5 hours. After cooling, the reaction was quenched with saturated NaHCO₃Partitioned between aqueous and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic phases were washed with water to neutrality and Na2S0₄And (5) drying. After filtration and removal of the solvent under vacuum, the product was purified by preparative HPLC.

Example 16: n- (5- { 7-methoxy-6- [3- (4-methyl-piperazin-1-yl) -propoxy]Preparation of (E) -quinazolin-4-ylamino } -benzothiazol-2-yl) -benzamide N- (5-aminobenzothiazol-2-yl) benzamide (IM5, 35mg, 0.13mmol), 4-chloro-7-methoxy-6- [3- (4-methylpiperazin-1-yl) propoxy]A mixture of quinazoline (IM 8, 46mg, 0.13mmol) and HCl in 4M dioxane (0.09mL, 0.39mmol) in n-butanol (3mL) was heated to 110 ℃ for 5 hours. The HCl salt of the product precipitated out. Separation by filtration and use of CH₂Cl₂And washing twice. No further purification was required (65mg, 0.11mmol, 93%). LC/ESI-MS: 620[ M + H ] M/z]⁺；m/z＝618[M-H]^-；R_t＝2.43min。

Example 17: n- (5- { 6-methoxy-7- [3- (4-methyl-piperazin-1-yl) -propoxy ] -quinazolin-4-ylamino } -benzothiazol-2-yl) -benzamide was prepared from intermediate 5 and intermediate 7 according to the procedure described in example 15.

Example 18: 3-chloro-N- (6- { 6-methoxy-7- [3- (4-methyl-piperazin-1-yl) -propoxy]Preparation of-quinazolin-4-ylamino } -benzothiazol-2-yl) -benzamide intermediate 12(30mg, 58. mu. mol) was reacted with 3-chloro-benzoyl chloride (8. mu.l, 63. mu. mol) in a mixture of pyridine and DMF (1: 1, 4mL total) in the presence of triethylamine (100. mu.l, 0.71mmol) at 60 ℃. The reaction is constrained several times and further acid chloride is added if necessary. The reaction mixture was washed with saturated NaHCO₃Partition between aqueous solution and DCM. After extraction with dichloromethane, the combined organic phases are extracted with Na₂SO₄And (5) drying. After filtration the solvent was removed in vacuo and the product was purified by preparative HPLC (20mg, 55% yield).

Example 19: the preparation of 3-chloro-N- (5- { 6-methoxy-7- [3- (4-methyl-piperazin-1-yl) -propoxy ] -quinazolin-4-ylamino } -benzothiazol-2-yl) -benzamide starts from intermediate 13 with the procedure described in example 18.

Example 20: preparation of 1- (4-chloro-3-trifluoromethyl-phenyl) -3- (6- { 6-methoxy-7- [3- (4-methyl-piperazin-1-yl) -propoxy ] -quinazolin-4-ylamino } -benzothiazol-2-yl) -urea was carried out by reacting intermediate 12(58 μmol, 30mg) with 1-chloro-4-isocyanato-2-trifluoromethyl-benzene (13mg, 58 μmol) in dichloromethane in the presence of triethylamine (5 drops). Purification by preparative HPLC (5mg, 15% yield).

Example 21: preparation of 1- (4-chloro-3-trifluoromethyl-phenyl) -3- (5- { 6-methoxy-7- [3- (4-methyl-piperazin-1-yl) -propoxy ] -quinazolin-4-ylamino } -benzothiazol-2-yl) -urea starts from intermediate 13 using the procedure described in example 20.

Example 22: preparation of 1- (2-methoxy-5-methyl-phenyl) -3- (6- { 6-methoxy-7- [3- (4-methyl-piperazin-1-yl) -propoxy ] -quinazolin-4-ylamino } -benzothiazol-2-yl) -urea starting from intermediate 12 and 2-isocyanato-1-methoxy-4-methyl-benzene according to the procedure described in example 20.

Example 23: preparation of 1- (6- { 6-methoxy-7- [3- (4-methyl-piperazin-1-yl) -propoxy ] -quinazolin-4-ylamino } -benzothiazol-2-yl) -3- (2-methoxy-phenyl) -urea starts from intermediate 12 and 1-isocyanato-2-methoxy-benzene according to the procedure described in example 20.

Example 24: preparation of 1- {6- [6- (2-hydroxy-ethylamino) -pyrimidin-4-ylamino ] -benzothiazol-2-yl } -3- (2-methoxy-5-methyl-phenyl) -urea was performed by heating a mixture of IM 14(100mg, 0.227mmol) and 3-aminoethanol (1mL) at 85 deg.C for 3 hours. The product was precipitated out by addition of water (47mg, 45%).

Example 25: preparation of 1- {6- [6- (3-hydroxy-propylamino) -pyrimidin-4-ylamino ] -benzothiazol-2-yl } -3- (2-methoxy-5-methyl-phenyl) -urea was carried out by heating a mixture of IM 14(100mg, 0.227mmol) and 3-aminopropanol (1mL) at 85 ℃ for 3 hours. The product was precipitated by addition of water (42mg, 39%).

Analytical data for the compounds of formula (I) according to the invention:

analytical data for the Compounds of formula (Ia) according to the invention

Analytical data for the compounds of the formula (II) according to the invention:

materials and methods

Protein kinase assay

The effect of the benzazole derivatives was tested on recombinant, human protein kinase. All protein kinases were expressed in Sf9 insect cells as human recombinant GST fusion proteins and as histidine-tagged proteins by means of a baculovirus expression system. Protein kinase was purified by affinity chromatography using GSH-agarose or Ni-NTH-agarose. The purity and identity of each was checked by SDS-PAGE/silver staining and Western blot analysis with specific antibodies.

Will have a proprietary protein kinase assay (³³PanQinase^_Activity assay) for measuring the activity of the kinase. All kinase assays were performed in 96-well Flashplates^TM50 μ l of the reactionThe process is repeated. The assay for all enzymes contained 60mM HEPES-NaOH, pH7.5, 3mM MgCl₂，3mM MnCl₂3 μ M Na-orthovanadate, 1.2mM DTT, 50 μ g/ml PEG₂₀₀₀₀And 1. mu.M [ gamma-³³P]-ATP (ca. 5X 10)⁵cpm/well).

The reaction mix was incubated at 30 ℃ for 80 minutes. With 50. mu.l of 2% (v/v) H₃PO₄The reaction was stopped and the plate was aspirated and washed 2 times with 200. mu.l of 0.9% (w/v) NaCl. Measurement with microplate scintillation counter³³P_iAnd (3) doping. All analyses were performed using a BeckmanCoulter/Sagian robotic system.

Cell receptor tyrosine kinase assays

The effects of thiazole derivatives were tested by determining the inhibition of different Receptor Tyrosine Kinases (RTKs) in various cell lines expressing the following growth factor receptors: EGF-R, PDGF-R, TIE2, IGF-IR, EPHB4, and VEGF-R2. Autophosphorylation of receptors is induced by specific ligands for each receptor. Stimulation of the cells resulted in maximal autophosphorylation in control cells without inhibitor (high control). The test compound is applied to the cells prior to stimulation. Cells were lysed using standard cell lysis buffer that retained the unique phosphoprotein levels. The amount of RTK-phosphorylation was determined by sandwich enzyme-linked immunoassay using a receptor-specific capture antibody and a phosphotyrosine antibody.

Generation of a Sigmoidal inhibitor curve based on relative inhibition compared to phosphorylation levels under high control conditions, which allows determination of the IC of each test compound₅₀The value is obtained.

Cellular Aurora-B kinase assay

The effect of thiazole derivatives was examined in cellular Aurora-B assays by measuring the effect of the test compounds on nuclear re-replication (endo) of genomic DNA. Nuclear re-replication in cells can be detected as a DNA content above 4 n. Propidium Iodide (PI) was used to quantify the DNA content using a Fluorescence Activated Cell Sorter (FACS).

In this experiment, HT29 colon cancer cells were treated with test compounds at different concentrations for 3 days. On day 5, cells were harvested and fixed in methanol. Rehydrating and incubating with ribonuclease A and PI on day 6. Incorporated PI was detected by FACS measurement of 650nm fluorescence emission under 488nm excitation. For the concentration of each compound, the percentage of the endo-population compared to the whole cell population was measured. To estimate IC of Aurora-B₅₀Values, the percent inhibition of the endo R-population is plotted against the concentration of compound.

Cellular Aurora-B kinase histone H3 phosphorylation assay

Effect of the Compounds the phosphorylation of Aurora B substrate protein histone H3(HisH3-pS10) at serine 10 was measured in the cellular Aurora-B assay and tested. Inhibition of Aurora B resulted in a decrease in HisH3-pS10, which was detected in a specific immunoassay.

In this assay, HT-29 colon cancer cells were seeded the first day and different concentrations of test compound were added the second day. Cells were incubated with test compounds for 1 hour. Subsequently, calyclin a was added for 30 minutes. For DELFIA _ -detection (PerkinElmer) of HisH3-pS10, the lysates were transferred to microtiter plates and incubated with detection antibody directed against HisH3-pS10 and a europium-labeled secondary anti-IgG-antibody. The emission at 615nm under excitation at 340nm was measured and the percent inhibition for each concentration of test compound was calculated relative to the control without inhibitor. The mean values of the percentages of HisH3-pS10 were plotted against compound concentration for IC calculation₅₀The value is obtained.

Results

The following examples show the IC for at least one kinase₅₀A value below 500nM, said kinase being selected from Aurora A, Aurora B, EGF-R, ERBB2, PDGFR, IGFl-R, VEGF-R2, VEGF-R3, EPHB4, Tie2 and SRC, or by having IC₅₀Values below 500 nM: inhibit at least two kinases and show a favorable activity profile: 1,2，5，6，9，11，15，17，18，20，21，22。

The compounds of the invention show IC in cellular receptor tyrosine kinase assays and/or cellular Aurora-B kinase assays₅₀Values below 10. mu.M.

Claims

1. A compound of the general formula (I) or a salt or physiologically functional derivative thereof,

formula (I)

Wherein

substituent-Y-R¹Attached to the 5-or 6-position of the benzazole;

x independently represents S, O, SO or SO₂；

Y independently represents S, O, NR²SO or SO₂；

A independently represents ← CO-,. No. CS-,. No. SO₂-、←CO₂-、←CONR⁸-、←NR⁸CO-、←NR⁸CONR⁹-、←NR⁸COO-、←NR⁸NR⁹CO-、←NR⁸OCO-、←ONR⁸CO-or ← NR⁸SO₂-，

Wherein ← refers to the term "connected to R³A point of (a);

R³independently represents H, alkyl, cycloalkyl, aryl or heteroaryl;

R^6aindependently represents H, alkyl, cycloalkyl, -NR⁸NR²R⁹、-ONR⁸R⁹、-NR⁸OR⁹Aryl or heteroaryl;

R⁷independently represents H, alkyl, cycloalkyl or alkoxy;

R¹independently represents one of the following groups:

wherein^*Points representing connections;

z independently represents O, NR⁸Or S;

wherein^*Points representing connections;

m independently represents an integer of 1 to 3;

l is absent or represents a divalent linking group selected from alkylene, cycloalkylene, heterocyclylene, arylene or heteroarylene, wherein one or more (-CH)₂-) groups may be substituted by oxygen or NR⁸And wherein one or more carbon atoms may be independently substituted with one or two substituents selected from halogen, hydroxy, alkoxy, haloalkoxy, phosphonooxy or phosphonooxyalkyl;

R¹⁸Independently represents H, phosphonooxy or phosphonooxyalkyl;

R¹⁹independently represents H, alkyl, cycloalkyl, alkylamino or alkoxy;

with the proviso that the following compounds are excluded:

wherein alkyl, if not otherwise stated, refers to straight or branched C₁-C₆Alkyl, preferably a linear or branched, linear or branched C of one to five carbon atoms₂-C₆Alkenyl, or straight or branched C₂-C₆-alkynyl, which may be substituted by one or more substituents R';

wherein R' independently represents H, -CO₂R″、-CONHR″、-CR″O、-SO₂NR ', -NR' -CO-haloalkyl, -NO₂、-NR″-SO₂-haloalkyl, -NR' -SO₂-alkyl, -SO₂-alkyl, -NR "-CO-alkyl, -CN, alkyl, cycloalkyl, aminoalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkoxy, aryl, arylalkyl or heteroaryl;

wherein R' independently represents H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, heteroaryl or aminoalkyl;

wherein cycloalkyl refers to a non-aromatic ring system comprising three to eight carbon atoms, preferably four to eight carbon atoms, wherein one or more carbon atoms in the ring may be substituted by a group E, E being O, S, SO₂N orNR ', R' is as defined above;

wherein alkoxy means O-alkyl, said alkyl being as defined above; the alkoxy group is preferably methoxy, ethoxy, isopropoxy, tert-butoxy or pentyloxy;

wherein alkylthio means S-alkyl, said alkyl being as defined above;

wherein haloalkyl refers to an alkyl group substituted with one to five halogen atoms, said alkyl group being as defined above;

wherein hydroxyalkyl refers to HO-alkyl, said alkyl being as defined above;

wherein haloalkoxy refers to alkoxy substituted with one to five halogen atoms, said alkyl being as defined above;

wherein hydroxyalkylamino means (HO-alkyl)₂-an N-group or an HO-alkyl-NH-group, the alkyl group being as defined above;

wherein alkylamino means NH-alkyl or N-dialkyl, said alkyl being as defined above;

wherein the halogen group is chlorine, bromine, fluorine or iodine;

wherein aryl means an aromatic group having five to fifteen carbon atoms, which may be substituted with one or more substituents R ', wherein R' is as defined above;

wherein heteroaryl refers to a 5-or 6-membered heterocyclic group comprising at least one heteroatom such as O, N, S, which heterocyclic group may be fused to another ring, which heterocyclic group may be substituted with one or more substituents R ', wherein R' is as defined above.

2. A compound of claim 1, wherein R is¹Is prepared from (a)^*Point of finger attachment):

3. the compound of claim 1 or a salt or physiologically functional derivative thereof, wherein XIndependently represent S or O; y represents NH; a represents-CO-; r⁵Represents H.

4. A compound according to claim 1, or a salt or physiologically functional derivative thereof, wherein X independently represents S or O; y represents NH; r5 represents H; a denotes ← NHCO-, wherein ← denotes binding to R³Point (2) of (c).

5. A compound according to any one of claims 1 to 4, or a salt or physiologically functional derivative thereof, wherein-Y-R¹The substituent is attached to the 6-position of the benzazole.

6. A compound of claim 5, wherein R is¹²And R¹⁵Is H, and R¹³And R¹⁴Independently represents an-O-alkyl group which may be substituted.

7. A compound of the general formula (Ia) or a salt or physiologically functional derivative thereof,

formula (Ia)

Wherein

substituent-Y^a-R^1aAttached to the 5-or 6-position of the benzazole;

X^aindependently S, O, SO or SO₂；

Y^aIndependently represent S, NR²SO or SO₂；

Wherein ← refers to the term "connected to R³A point of (a);

R^1aindependently represents one of the following groups:

wherein^*Points representing connections;

R¹¹independently represent H, -NHR^8aOr one of the following groups:

or

Wherein^*Points representing connections;

R²、R³、R⁴、R⁵、R⁶、R^6a、R⁷、R⁸、R^8a、R⁹、R^9a、R¹²、R¹³、R¹⁶Or X²As defined in claims 1-6.

8. A compound of the general formula (II) or a salt or physiologically functional derivative thereof,

formula (II)

Wherein

substituent-Y⁶Attached to the 5-or 6-position of the benzazole;

X^bindependently S, O, SO or SO₂；

Y^bIndependently represent S, NR²SO or SO₂；

A^bIndependently represent ← CO-, ° CS-, ° SO₂-、←CO₂-、←CONR⁸-、←NR⁸CO-、←NR⁸CONR⁹-、←NR⁸COO-、←NR⁸NR⁹CO-、←NR⁸OCO-、←ONR⁸CO-or ← NR⁸SO₂-，

Wherein ← refers to the term "connected to R³A point of (a);

R^4bindependently represent H, -SOR⁶、-SO₂R⁶、-SO₃R⁶、-NO₂、-CN、-CF₃、-OCH₃、-OCF₃Alkyl, cycloalkyl, alkoxy, oxyalkyl, alkoxyalkyl, -NH₂Alkylamines, aminoalkyl, alkylaminoalkyl, -NR⁷COR⁶Halogen, -OH, -SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkoxy, aryl or heteroaryl;

R²、R³、R⁵、R⁶、R^6a、R⁷、R⁸、R^8a、R⁹、R^9a、R¹¹、R¹²、R¹⁶、X²as defined in claims 1-6.

9. A compound according to any one of claims 1 to 8, or a salt or physiologically functional derivative thereof, for use as a medicament.

10. A compound according to any one of claims 1 to 8, or a salt or physiologically functional derivative thereof, for use in therapy.

11. A composition comprising a compound according to any one of claims 1 to 8 or a salt or physiologically functional derivative thereof.

12. The composition of claim 11, comprising an adjuvant and/or an additive.

13. Use of a compound according to any one of claims 1 to 10 or a salt or physiologically functional derivative thereof or a composition according to claim 11 or 12 for the preparation of a pharmaceutical composition for the treatment of a disease which can be cured or alleviated by inhibition of one or several kinases.

14. Use of a compound according to any one of claims 1 to 10 or a salt or physiologically functional derivative thereof or a composition according to claim 11 or 12 for the manufacture of a medicament for the treatment, alleviation and/or prevention of cancer.