Benzothiazole derivatives
AssigneeBASF Aktiengesellschaft Ludwigshafen, Germany
InventorsKevin P. Cusack, Barbara Scott, Lee D. Arnold, Anna M. Ericsson
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Abstract
The present invention is directed to a compound of formula (I), 1 racemic-diastereomeric mixtures thereof, optical isomers thereof, prodrugs thereof, isotopes thereof or pharmaceutically-acceptable salts of said compound, isomers, prodrugs and isotopes, wherein the variables are defined herein. The compounds of this invention are useful as inhibitors of serine/threonine and tyrosine kinases. In particular, compounds of this invention are useful as inhibitors of tyrosine kinases that are important in hyperproliferative diseases, especially in cancer and in the process of angiogenesis.
Claims60
A compound of formula (I),
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- racemic-diastereomeric mixtures thereof, optical isomers thereof, prodrugs thereof, isotopes thereof or pharmaceutically-acceptable salts of said compound, isomers, prodrugs and isotopes, wherein, Q is H or represents a bond which is taken together with X1 and the two nitrogen atoms to which Q and X1 are attached and the C═Y group to which the two nitrogen atoms are attached to form
- 265
- Q is (C1 -C6)alkyl;
- Y is O or S;
- W is H, Cl, Br, I, NO2, CN, SCN, OCF3, —Xq—(C(R10)2)a—Y1q—(C(R10)2)a-Z1q, or an optionally substituted group selected from the group consisting of alkyl, alkenyl, alkynyl, heterocyclyl-alkenyl, and heterocyclyl-alkynyl;
- Y1 and X are each independently selected from the group consisting of phenyl, heterocyclyl,
- NR10, O, S, SO, SO2CF2, CFR, C═O, (C═O)NR10, SONR10, SO2NR10, NR10(C═O), NR10SO,
- NR10SO2, NR10 SO2NR10, NR 10(C═O)NR10,
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- 267
- q for each occurrence is independently 0 or 1;
- a for each occurrence is independently 0 or an integer from 1 to 5;
- R10 for each occurrence is independently selected from the group consisting of H, optionally substituted aryl, optionally substituted heterocyclyl andan optionally substituted alkyl group optionally substituted with one or more of the following:
- a C1-6 alkyl group optionally substituted by one or more hydroxy, halo or optionally substituted amino;
- a C1-6 alkoxy group optionally substituted by one or more hydroxy, halo or optionally substituted amino;
- hydroxy;
- halo;
- or optionally substituted amino;
- Z1 is H, optionally substituted alkyl, optionally substituted aryl or optionally substituted heterocyclyl;
- X1 is hydrogen, alkyl, hydroxyalkyl or represents a bond which is taken together with R3 as described below or represents a bond which is taken together with Q as described above;
- R1 and R2 are each independently hydrogen, halogen, hydroxy, nitro, cyano, COOH, COOX3, SX3, SO2X3, SOX3, C(O)X3, NHC(O)X3, C(O)NHX3, NHSO2X3 or selected from an optionally substituted group consisting of alkyl, alkenyl, alkynyl, alkoxy, amino, NHX3, NX3X3, alkylamino, arylamino, heterocyclylamino, alkylthio, alkylsulfonato, aryl, aryloxy, arylalkyl, arylalkenyl, arylalkynyl, arylalkyloxy, heterocyclyl, heterocyclyloxy, heterocyclyl-alkyl, heterocyclyl-alkenyl, heterocyclyl-alkynyl, heterocyclyl-alkyloxy, heterocyclylthio, heterocyclylsulfinyl, heterocyclylsulfonyl, cycloalkyl, —(CH2)m—(CHX2)CN, —(CH2)m-(CHX2)COOH, -(CH2)m-(CHX2)COOX3, —(CH2)m—(CHX2)SO2X3, —(CH2)m—(CHX2)C(O)X3, —(CH2)m—(CHX2)C(O)NHX3 and —(CH2)m—(CHX2)NHSO2X3;
- where m is 0 to 4;
- X2 for each occurrence is independently H or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, alkynyl, carbonyl, S(O)palkyl, S(O)paryl, S(O)pheterocyclyl, amino, alkoxy, alkylthio, arylthio, perhaloalkyl, aryl, aryloxy, arylalkyl, arylalkyloxy, heterocyclyl and heterocyclyl-alkyl;
- p is 0, 1 or 2;
- X3 for each occurrence is independently H or an optionally substituted moiety selected from the group consisting of mono- or di-alkylamino, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl and heterocyclyl-alkyl;
- or when R1 is in the 7-position of the benzothiazole ring, R1 and W can be taken together with the carbon atoms to which they are attached to form an optionally substituted 5- or 6-membered heterocyclyl ring;
- R3 is hydrogen, or an optionally substituted moiety selected from the group consisting of carbonyl, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-alkyl, heterocyclyl-heterocyclyl, heterocyclyl-cycloalkyl, amino, alkylamino, arylamino, alkoxy, thioalkoxy and acyl;
- or R3 and X1 are taken together with the nitrogen atom to which they are attached to form
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- where Z for each occurrence is independently selected from the group consisting of oxo, or an optionally substituted moiety selected from the group consisting of —C(O)(C1-C6)alkyl, —C(O)aryl, —C(O)N(C1-C6)alkyl, —C(O)N-aryl, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, amino, mono- or di-(C1-C6)alkylamino, —COO(C1-C6)alkyl, pyridyl, phenyl, phenyl(C1-C6)alkyl and phenyl(C1-C6)alkenyl;
- where each of the optionally substituted moieties described hereinabove is optionally substituted by one or more substituents each independently selected from the group consisting of oxo, amino, nitro, mono- or bi-(C1-C6)alkylamino, hydroxy, nitrile, chloro, fluoro, bromo, iodo, CF3, (C1-C6)alkyl, —C(O)(C1-C6)alkyl, —COOH, —COO(C1-C6)alkyl, —S—(C1-C6)alkyl, —S-aryl, (C1-C6)alkoxy, SO2NH2, phenyl, phenyl(C1-C6)alkyl, —O—(C1-C6)alkyl-OH, —O—(C1-C6)alkyl-O—(C1-C6)alkyl, —O—(C2-C6)alkyl-N—((C1-C6)alkyl)n, —N—(C1-C6)alkyl-OH, —N—(C1-C6)alkyl-O—(C1-C6)alkyl, —C(O)NH2, —C(O)N((C1-C6)alkyl)n, , —S(O)n(C1-C6)alkyl, —S(O)naryl, —S(O)nheterocyclyl, and heterocyclyl, where the alkyl groups mentioned herein optionally have one or more unsaturated bonds in the alkyl portion;
- n is 0, 1 or 2;
- provided that
- 1) when Q is H;
- Y is O;
- R1 and R2 are each hydrogen, halogen, alkyl, alkoxy, alkylthio, carboxyalkyl or optionally substituted phenyl;
- and X1 is hydrogen or alkyl;
- then R3 is not alkyl, alkenyl, alkoxy, cycloalkyl or optionally substituted phenyl;
- 2) when Q is H;
- Y is O;
- R1 and R2 are each hydrogen, halogen, alkyl, alkoxy, alkylthio, carboxyalkyl or optionally substituted phenyl;
- then X1 and R3 are not taken together to form
- 269
- 3) when W is Cl, Br or I;
- Q is hydrogen;
- Y is O;
- X1 is H;
- then R3 is not
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- or phenyl optionally substituted by 1 to 3 substituents independently selected from the group consisting of amino, mono- or bi-(C1-C6)alkylamino, hydroxy, chloro, fluoro, bromo, iodo, (C1-C6)alkyl, (C1-C6)alkoxy and —SO2NH2;
- 4) when W is Cl, Br or I;
- Q is H;
- R1 is 7-Cl;
- R2 is H;
- and X1 is alkyl;
- then R3 is not alkyl, alkoxy or cycloalkyl;
- 5) when W is Cl, Br or I;
- Q is H;
- R1 is 7-Cl;
- R2 is H;
- and X1 is H;
- then R3 is not alkyl or cycloalkylamino;
- 6) when W is Cl, Br, I or NO2;
- Q is H;
- Y is O;
- X1 is H;
- R1 is OH;
- R2 is NO2, amino, alkyl, alkoxy, hydroxy lower alkyl or dialkylamino;
- then R3 is not H or alkyl;
- 7) when W is Cl, Br or I;
- Q is H;
- Y is O;
- R1 is CF3, CH2F, NO2, alkyl or alkoxy;
- R2 is H;
- X1 is H;
- then R3 is not naphthyl or phenyl optionally substituted with halo, CF3, alkyl or alkoxy;
- 8) when W is Cl, Br or I;
- Q is H;
- R1 is alkyl;
- R2 is H;
- X1 is H or alkyl;
- then R3 is not alkyl or alkoxy;
- 9) when W is Cl;
- Q is H;
- Y is S;
- R1 and R2 are each H;
- X1 is H;
- then R3 is not ethyl;
- 10) when W is Cl;
- Q is H;
- Y is O;
- R1 and R2 are each H;
- X1 is H;
- then R3 is not n-butyl;
- and
- 11) when W is H, then R1 and R2 are not H at the same time.
A compound of formula (IA),
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- racemic-diastereomeric mixtures thereof, optical isomers thereof, prodrugs thereof, isotopes thereof or pharmaceutically-acceptable salts of said compound, isomers, prodrugs and isotopes, wherein
- W is NO2 or CN;
- Y is O or S;
- R1 is in the 7-position and is hydrogen, methyl, ethyl, allyl, phenyl, benzyl, —CH2—C(O)—CH3, —CH2-CO2-t-Bu, —CH2—SO2-aryl, -alkyl-CN, or -alkyl(CN)(CH2-aryl);
- X1 is hydrogen, alkyl or hydroxyalkyl;
- R3 is selected from the group consisting of ethyl, n-butyl, t-butyl, n-propyl, allyl, hydroxyalkyl, aminoalkyl, -alkyl-N H-alkyl-OH, -alkyl-O-alkyl-OH,di-hydroxyalkyl, alkoxyalkyl, (alkylthio)hydroxyalkyl, cycloalkyl, cycloalkylalkyl, hydroxycycloalkyl, (alkylthio)(alkylester)alkyl, alkylesteralkyl, 2,4-dimethoxyphenyl, 3,5-trifluoromethylphenyl, 3-chlorophenyl, 4-chlorophenyl 2,6-dichlorophenyl, 2-methylphenyl, 3-methylphenyl, (substituted phenyl)alkyl, phenylalkyl, heterocyclylalkyl, N-alkylaminoalkyl, N,N-dialkylaminoalkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl.
A compound of the formula
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- racemic-diastereomeric mixtures thereof, optical isomers thereof, prodrugs thereof, isotopes thereof or pharmaceutically- acceptable salts of said compound, isomers, prodrugs and isotopes, wherein R3 is ethyl, propyl, t-butyl, 2,4,6-trichlorophenyl or 2,4-dimethoxyphenyl.
A compound of the formula
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- racemic-diastereomeric mixtures thereof, optical isomers thereof, prodrugs thereof, isotopes thereof or pharmaceutically-acceptable salts of said compound, isomers, prodrugs and isotopes, wherein R1 is methyl, methoxy or isopropoxy.
A method of inhibiting protein kinase activity, which comprises administering to a patient a compound of formula (IB) as defined hereinabove, racemic-diastereomeric mixtures thereof, optical isomers thereof, prodrugs thereof, isotopes thereof or pharmaceutically-acceptable salts of said compound, isomers, prodrugs and isotopes.
A method of treating a condition, disorder or disease, which comprises administering to a patient a compound of formula (IB) as defined hereinabove, racemic-diastereomeric mixtures thereof, optical isomers thereof, prodrugs thereof, isotopes thereof or pharmaceutically-acceptable salts of said compound, isomers, prodrugs and isotopes;
- where said condition, disorder or disease is selected from the group consisting of hyperproliferative disorders, an ulcer, Lyme disease, sepsis, von Hippel Lindau disease, pemphigoid, psoriasis, psoriasis arthropathy, paraneoplastic syndrome, turbid effusions, collagenosis, Lupus erythermatosus, poly-myositis, dermato-myositis, systemic sclerodermia, mixed collagenosis, postinfectious arthritis, seronegative spondylarthritis, spondylitis ankylosans, vasculitis, sarcoidosis, arthrosis, pain, Paget's disease, polycystic kidney disease, fibrosis, sarcoidosis, cirrhosis, thyroiditis, hyperviscosity syndrome, Osler-Weber-Rendu disease, chronic occlusive pulmonary disease, ovarian hyperstimulation syndrome, preeclampsia, menometrorrhagia, endometriosis, chronic inflammation, systemic lupus, glomerulonephritis, synovitis, inflammatory bowel disease, Crohn's disease, glomerulonephritis, rheumatoid arthritis, juvenile arthritis, osteoarthritis, multiple sclerosis, graft rejection, sickle cell anaemia, an ocular condition, a cardiovascular condition, atherosclerosis, restenosis, ischemia/reperfusion injury, vascular occlusion, carotid obstructive disease, cancer, Crow-Fukase (POEMS) syndrome, a diabetic condition, anemia, ischemia, infarct, transplant rejection, a wound, gangrene, necrosis, asthma or edema following bums, trauma, radiation, stroke, hypoxia or ischemia, and infection by Herpes simplex, Herpes Zoster, human immunodeficiency virus, parapoxyirus, protozoa or toxoplasmosis.
A method of decreasing fertility in a patient, which comprises administering to a patient an effective amount of a compound of formula (IB) as defined hereinabove, racemic-diastereomeric mixtures thereof, optical isomers thereof, prodrugs thereof, isotopes thereof or pharmaceutically-acceptable salts of said compound, isomers, prodrugs and isotopes.
A method of promoting angiogenesis or vasculogenesis, which comprises administering to a patient a compound of formula (IB) as defined hereinabove, racemic-diastereomeric mixtures thereof, optical isomers thereof, prodrugs thereof, isotopes thereof or pharmaceutically-acceptable salts of said compound, isomers, prodrugs and isotopes.
A method of treating a patient having a condition which is mediated by protein kinase activity, said method comprising the step of administering to the patient a therapeutically effective amount of a compound of formula (IB) as defined hereinabove, racemic-diastereomeric mixtures thereof, optical isomers thereof, prodrugs thereof, isotopes thereof or pharmaceutically-acceptable salts of said compound, isomers, prodrugs and isotopes.
A pharmaceutical composition for inhibiting a protein kinase, which composition comprises a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of formula (IB) as defined hereinabove, racemic-diastereomeric mixtures thereof, optical isomers thereof, prodrugs thereof, isotopes thereof or pharmaceutically-acceptable salts of said compound, isomers, prodrugs and isotopes.
A compound of the formula
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- wherein W is H, —OCF3, —O-Et, F, CH3, —OCH3, —SO2—Me, NH2, —NH—C(O)—Me, —NH—CH2-phenyl, —NH—S(O)2-2-thienyl, —NH—S(O)2-(3,5-dimethylisoxazol-4-yl), —NH—S(O)2-Me, —NH—S(O)2—CH2-phenyl, —NH—C(O)—O—CH2-CCl3, —NH—C(O)—O—CH2-Ph, —NH—C(O)—O—Me or NO2;
- R1 is H, F or —CH2—S(O)2-phenyl;
- and
- R2 is H, 4-Cl, 4-methyl, 5-methyl, 5-Cl, 5-F or 5-OCH3.
A method of using a compound of formula (IB) or a pharmaceutically acceptable salt thereof as a replacement therapy for anti-inflammatory glucocorticosteroid therapy in a patient undergoing anti-inflammatory glucocorticosteroid therapy comprising the step of replacing a glucocorticosteroid with a compound of formula (IB) or a pharmaceutically acceptable salt thereof.
A method of using a compound of formula (IB) or a pharmaceutically acceptable salt thereof in conjunction with glucocorticosteroid therapy in a patient undergoing glucocorticosteroid therapy comprising the step of replacing a portion of the amount of glucocorticosteroid administered to said patient.
Dependencies are inferred from the claim text.