US 6,713,474 B2 · Pyrrolopyrimidines as therapeutic agents

Abstract

Chemical compounds having structural formula I and physiologically acceptable salts and metabolites thereof, are inhibitors of serine/threonine and tyrosine kinase activity. Several of the kinases, whose activity is inhibited by these chemical compounds, are involved in immunologic, hyperproliferative, or angiogenic processes. Thus, these chemical compounds can ameliorate disease states where angiogenesis or endothelial cell hyperproliferation is a factor. These compounds can be used to treat cancer and hyper proliferative disorders, rheumatiod arthritis, disorders of the immune system, trasplant rejections and imflammatory disorders.

A compound represented by the following structural formula:

and pharmaceutically acceptable salts thereof, wherein:
Ring A is a six membered aromatic ring or a five or six membered heteroaromatic ring which is optionally substituted with one or more substituents selected from the group consisting of a substituted or unsubstituted aliphatic group, a halogen, a substituted or unsubstituted aromatic group, substituted or unsubstituted heteroaromatic group, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, cyano, nitro, —NR4R5, —C(O)2H, —OH, a substituted or unsubstituted alkoxycarbonyl, —C(O)2-haloalkyl, a substituted or unsubstituted alkylthio ether, a substituted or unsubstituted alkylsulfoxide, a substituted or unsubstituted alkylsulfone, a substituted or unsubstituted arylthio ether, a substituted or unsubstituted arylsulfoxide, a substituted or unsubstituted arylsulfone, a substituted or unsubstituted alkyl carbonyl, —C(O)-haloalkyl, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, carboxamido, tetrazolyl, trifluoromethylsulphonamido, trifluoromethylcarbonylamino, a substituted or unsubstituted alkynyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkyl amido, a substituted or unsubstituted aryl amido, —NR95C(O)R95, a substituted or unsubstituted styryl and a substituted or unsubstituted aralkyl amido, wherein R95 is an aliphatic group or an aromatic group;
L is —O—;
—S—;
—S(O)—;
—S(O)2—;
—N(R)—;
—N(C(O)OR)—;
—N(C(O)R)—;
—N(SO2R);
—CH2O—;
—CH2S—;
—CH2N(R)—;
—C(NR)—;
—CH2N(C(O)R))—;
—CH2N(C(O)OR)—;
—CH2N(SO2R)—;
—CH(NHR)—;
—CH(NHC(O)R)—;
—CH(NHSO2R);
—CH(NHC(O)OR)—;
—CH(OC(O)R)—;
—CH(OC(O)NHR)—;
—CH═CH—;
—C(═NOR)—;
—C(O)—;
—CH(OR)—;
—C(O)N(R)—;
N(R)C(O)—;
—N(R)S(O)—;
—N(R)S(O)2—;
—OC(O)N(R)—;
—N(R)C(O)N(R)—;
—NRC(O)O—;
—S(O)N(R)—;
—S(O)2N(R)—;
N(C(O)R)S(O)—;
N(C(O)R)S(O)2—;
—N(R)S(O)N(R);
—N(R)S(O)2N(R);
—C(O)N(R)C(O)—;
—S(O)N(R)C(O)—;
—S(O)2N(R)C(O)—;
—OS(O)N(R)—;
—OS(O)2N(R)—;
—N(R)S(O)O—;
—N(R)S(O)2O—;
—N(R)S(O)C(O)—;
—NR)S(O)2C(O)—;
—SON(C(O)R)—;
—SO2N(C(O)R)—;
—N(R)SON(R)—;
—N(R)SO2N(R);
—C(O)O—;
CHR)S(O)—;
—CH(R)S(O)2—;
—CH(R)N(C(O)OR)—;
—CH(R)N(C(O)R)—;
—CH(R)N(SO2R);
—CH(R)O—;
—CH(R)S—;
—CH(R)N(R)—;
—CH(R)N(C(O)R))—;
—CH(R)N(C(O)OR)—;
—CH(R)N(SO2R)—;
—CH(R)C(═NOR)—;
—CH(R)C(O)—;
—CH(R)CH(OR)—;
—CH(R)C(O)N(R)—;
—CH(R)N(R)C(O)—;
—CH(R)N(R)S(O)—;
—CH(R)N(R)S(O)2—;
—CH(R)OC(O)N(R)—;
—CH(R)N(R)C(O)N(R)—;
—CH(R)N(R)C(O)O—;
—CH(R)S(O)N(R)—;
—CH(R)S(O)2N(R)—;
—CH(R)N(C(O)R)S(O)—;
—CH(R)N(C(O)R)S(O)2—;
—CH(R)N(R)S(O)N(R)—;
—CH(R)N(R)S(O)2N(R)—;
—CH(R)C(O)N(R)C(O)—;
—CH(R)S(O)N(R)C(O)—;
—CH(R)S(O)2N(R)C(O)—;
—CH(R)OS(O)N(R)—;
—CH(R)OS(O)2N(R)—;
—CH(R)N(R)S(O)O—;
—CH(R)N(R)S(O)2O—;
—CH(R)N(R)S(O)C(O)—;
—CH(R)N(R)S(O)2C(O)—;
—CH(R)SON(C(O)R)—;
—CH(R)S(O)2N(C(O)R)—;
—CH(R)N(R)SON(R)—;
—CH(R)N(R)S(O)2N(R)—;
or —CH(R)C(O)O—, wherein each R and R′ is, independently, —H, an acyl group, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted heteroaromatic group, or a substituted or unsubstituted cycloalkyl group or a substituted or unsubstituted arylalkyl group;
or
L is —RbN(R)S(O)2— wherein Rb is an alkylene group which when taken together with the sulphonamide group to which it is bound forms a five or six membered ring fused to ring A;
G is a direct bond;
—(CH2)j—, wherein j is 1 to 6;
a C2-C6-alkenylene group, a C3-C8-cycloalkylene group or a C1-C6-oxaalkylene group;
R1 is a substituted aliphatic group, a substituted cycloalkyl, a substituted bicycloalkyl, a substituted cycloalkenyl, an optionally substituted aromatic group, an optionally substituted heteroaromatic group, an optionally substituted heteroaralkyl, an optionally substituted heterocycloalkyl, an optionally substituted heterobicycloalkyl, an optionally substituted alkylamido, and optionally substituted arylamido, an optionally substituted —S(O)2-alkyl or optionally substituted —S(O)2-cycloalkyl, a —C(O)-alkyl or an optionally substituted —(O)-alkyl, provided that when R1 is an aliphatic group or cycloalkyl group, R1 is not exclusively substituted with one or more substitutents selected from the group consisting of hydroxyl and lower alkyl ethers, provided that the heterocycloalkyl is not 2-phenyl-1,3-dioxan-5-yl and provided that an aliphatic group is not substituted exclusively with one or more aliphatic groups;
wherein one or more substituents are selected from the group consisting of a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic, a substituted or unsubstituted aralkyl, a substituted or unsubstituted heteroaralkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aromatic ether, a substituted or unsubstituted aliphatic ether, a substituted or unsubstituted alkoxycarbonyl, a substituted or unsubstituted alkylcarbonyl, a substituted or unsubstituted arylcarbonyl, a substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted aryloxycarbonyl, —OH, a substituted or unsubstituted aminocarbonyl, an oxime, a substituted or unsubstituted azabicycloalkyl, heterocycloalkyl, oxo, aldehyde, a substituted or unsubstituted alkyl sulfonamido group, a substituted or unsubstituted aryl sulfonamido group, a substituted or unsubstituted bicycloalkyl, a substituted or unsubstituted heterobicycloalkyl, cyano, —NH2, an alkylamino, ureido, thioureido;
or
R1 is —B—E, wherein
B is a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aromatic, a substituted or unsubstituted heteroaromatic, an alkylene, an aminoalkyl, an alkylenecarbnonyl, or an aminoalkylcarbonyl;
and
E is a substituted or unsubstituted azacycloalkyl, a substituted or unsubstituted azacycloalkylcarbonyl, a substituted or unsubstituted azacycloalkylsulfonyl, a substituted or unsubstituted azacycloalkylalkyl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heteroarylcarbonyl, a substituted or unsubstituted heteroarylsulfonyl, a substituted or unsubstituted heteroaralkyl, a substituted or unsubstituted alkyl sulfonamido, a substituted or unsubstituted aryl sulfonamido, a substituted or unsubstituted bicycloalkyl, a substituted or unsubstituted ureido, a substituted or unsubstituted thioureido or a substituted or unsubstituted aryl;
R2 is —H, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted cycloalkyl, a halogen, —OH, cyano, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted heteroaralkyl, —(CH2)0-3NR4R5, or —(CH2)0-3C(O)NR4R5;
R3 is an unsubstituted aliphatic group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, or a substituted or unsubstituted heterocycloalkyl;
provided that L is —SN(R)—, —S(O)N(R)—, —S(O)2N(R)—, —N(R)S—, —N(R)S(O)—, —N(R)S(O)2—, —N(R)SN(R′)—, —N(R)S(O)N(R′)—, or —N(R)S(O)2N(R′)13 when R3 is an unsubstituted aliphatic group, a substituted or unsubstituted alkenyl group;
provided that when L is —O—, —CH2NR—, —C(O)NR— or —NRC(O)— and R3 is azacycloalkyl or azaheteroaryl, G is a direct bond;
a C2-C6-alkenylene group, a C3-C8-cycloalkylene group or a C1-C6-oxaalkylene;
and
provided that when L is —O— and R3 is phenyl, G is a direct bond;
a C2-C6-alkenylene group, a C3-C8-cycloalkylene group or a C1-C6-oxaalkylene;
R4, R5 and the nitrogen atom together form a 3, 4, 5, 6 or 7-membered, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterobicycloalkyl or a substituted or unsubstituted heteroaromatic;
or
R4 and R5 are each, independently, —H, azabicycloalkyl, heterocycloalkyl, a substituted or unsubstituted alkyl group or Y—Z;
Y is selected from the group consisting of —C(O)—, —CH2)p—, —S(O)2—, —C(O)O—, —SO2NH—, —CONH—, —(CH2)pO—, —(CH2)pNH—, —(CH2)pS—, —(CH2)pS(O)—, and —(CH2)pS(O)2—;
p is an integer from 0 to 6;
and
Z is —H, a substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl group.

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Pyrrolopyrimidines as therapeutic agents

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Pyrrolopyrimidines as therapeutic agents

Life of this patent

Abstract

Claims70