US 9,518,060 B2 · Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors

Abstract

The present invention relates to compounds and pharmaceutically acceptable salts of Formulas A and B: wherein A, B, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are as defined above. The invention further relates to pharmaceutical compositions comprising the compounds and pharmaceutically acceptable salts and to methods of treating diabetes mellitus and its complications, cancer, ischemia, inflammation, central nervous system disorders, cardiovascular disease, Alzheimer's disease and dermatological disease pression, virus diseases, inflammatory disorders, or diseases in which the liver is a target organ.

A compound of Formula (A),

wherein
X is C—R11 or N, wherein R11 is H, halo, OH, C1-C3 alkyl, CF3, or CN;
A and B are independently C or N;
R1 is —Ra—O—Rb, C1-C8 alkyl, C2-C8 alkenyl, C2-C8alkynyl, —(Rd)m—(C3-C12 cycloalkyl), —(Rd)m-phenyl, —(Rd)m-(3-15 membered heterocyclyl), —(Rd)m—(C1-C6 perfluoroalkyl), —(Rd)m-halide, —(Rd)m—CN, —(Rd)m—C(O)Ra, —(Rd)m—C(O)ORa, —(Rd)m—C(O)NRaRb, —(Rd)m—ORa, —(Rd)m—OC(O)Ra, —(Rd)m—OC(O)NRaRb, —(Rd)m—O—S(O)Ra, —(Rd)m—OS(O)2Ra, —(Rd)m—OS(O)2NRaRb, —(Rd)m—OS(O)NRaRb, —(Rd)m—NO2, —(Rd)m—NRaRb, —(Rd)m—N(Ra)C(O)Rb, —(Rd)m—N(Ra)C(O)ORb, —(Rd)m—N(Rc)C(O)NRaRb, —(Rd)m—N(Ra)S(O)2Rb, —(Rd)m—N(Ra)S(O)Rb, —(Rd)m—SRa, —(Rd)m—S(O)Ra, —(Rd)m—S(O)2Ra, —(Rd)m—S(O)NRaRb, —(Rd)m—S(O)2NRaRb, —(Rd)m—O—(Re)m—NRaRb or —(Rd)m—NRa—(Re)—ORb;
wherein the said Ra, Rb, Rc, Rd, Re, C3-C12 cycloalkyl, aryl, the said 3-15 membered heterocyclyl, are independently optionally further substituted by 0-3 R12 groups;
R2 and R3 are each independently selected from H, —Ra—O—Rb, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(Rd)m—(C3-C12 cycloalkyl), —(Rd)m-phenyl, —(Rd)m-(3-15 membered heterocyclyl), —(Rd)m—(C1-C6 perfluoroalkyl), —(Rd)m-halide, —(Rd)m—CN, —(Rd)m—C(O)Ra, —(Rd)m—C(O)ORa, —(Rd)m—C(O)NRaRb, —(Rd)m—ORa, —(Rd)m—OC(O)Ra, —(Rd)m—OC(O)NRaRb, —(Rd)m—O—S(O)Ra, —(Rd)m—OS(O)2Ra, —(Rd)m—OS(O)2NRaRb, —(Rd)m—OS(O)NRaRb, —(Rd)m—NO2, —(Rd)m—NRaRb, —(Rd)m—N(Ra)C(O)Rb, —(Rd)m—N(Ra)C(O)ORb, —(Rd)m—N(Rc)C(O)NRaRb, —(Rd)m—N(Ra)S(O)2Rb, —(Rd)m—N(Ra)S(O)Rb, —(Rd)m—SRa, —(Rd)m—S(O)Ra, —(Rd)m—S(O)2Ra, —(Rd)m—S(O)NRaRb, —(Rd)m—S(O)2NRaRb, —(Rd)m—O—(Re)m—NRaRb or —(Rd)m—NRa—(Re)—ORb;
and wherein any of the said alkyl, alkenyl, alkynyl, Ra, Rb, Rc, Rd, Re, C3-C12 cycloalkyl, phenyl or 3-15 membered heterocyclyl, may independently be further optionally substituted by 0-3 R12 groups;
R4 and R5 are each independently selected from H, —Ra—O—Rb, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(Rd)m—(C3-C12 cycloalkyl), —(Rd)m-phenyl, —(Rd)m-(3-15 membered heterocyclyl), —(Rd)m—(C1-C6 perfluoroalkyl), —(Rd)m-halide, —(Rd)m—CN, —(Rd)m—C(O)Ra, —(Rd)m—C(O)ORa, —(Rd)m—C(O)NRaRb, —(Rd)m—ORa, —(Rd)m—OC(O)Ra, —(Rd)m—OC(O)NRaRb, —(Rd)m—O—S(O)Ra, —(Rd)m—OS(O)2Ra, —(Rd)m—OS(O)2NRaRb, —(Rd)m—OS(O)NRaRb, —(Rd)m—NO2, —(Rd)m—NRaRb, —(Rd)m—N(Ra)C(O)Rb, —(Rd)m—N(Ra)C(O)ORb, —(Rd)m—N(Rc)C(O)NRaRb, —(Rd)m—N(Ra)S(O)2Rb, —(Rd)m—N(Ra)S(O)Rb, —(Rd)m—SRa, —(Rd)m—S(O)Ra, —(Rd)m—S(O)2Ra, —(Rd)m—S(O)NRaRb, —(Rd)m—S(O)2NRaRb, —(Rd)m—O—(Re)m—NRaRb or —(Rd)m—NRa—(Re)—ORb;
wherein any of the said alkyl, alkenyl, alkynyl, Ra, Rb, Rc, Rd, Re, C3-C12 cycloalkyl, aryl or 3-15 membered heterocyclyl are independently optionally further substituted by 0-3 R12 groups;
R6 and R7 are each independently H, —Ra—O—Rb, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(Rd)m—(C3-C12 cycloalkyl), —(Rd)m-phenyl, —(Rd)m-(3-15 membered heterocyclyl), —(Rd)m—(C1-C6 perfluoroalkyl), —(Rd)m-halide, —(Rd)m—CN, —(Rd)m—C(O)Ra, —(Rd)m—C(O)ORa, —(Rd)m—C(O)NRaRb, —(Rd)m—ORa, —(Rd)m—OC(O)Ra, —(Rd)m—OC(O)NRaRb, —(Rd)m—O—S(O)Ra, —(Rd)m—OS(O)2Ra, —(Rd)m—OS(O)2NRaRb, —(Rd)m—OS(O)NRaRb, —(Rd)m—NO2, —(Rd)m—NRaRb, —(Rd)m—N(Ra)C(O)Rb, —(Rd)m—N(Ra)C(O)ORb, —(Rd)m—N(Rc)C(O)NRaRb, —(Rd)m—N(Ra)S(O)2Rb, —(Rd)m—N(Ra)S(O)Rb, —(Rd)m—SRa, —(Rd)m—S(O)Ra, —(Rd)m—S(O)2Ra, —(Rd)m—S(O)NRaRb, —(Rd)m—S(O)2NRaRb, —(Rd)m—O—(Re)m—NRaRb or —(Rd)m—NRa—(Re)—ORb;
wherein R6 and R7 may together optionally cyclize to form a C3-C7 cycloalkyl and wherein any of the said alkyl, alkenyl, alkynyl, Ra, Rb, Rc, Rd, Re, C3-C12 cycloalkyl, aryl or 3-15 membered heterocyclyl are independently optionally further substituted by 0-3 R12 groups;
R8 is —Ra—O—Rb, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(Rd)m—(C3-C12 cycloalkyl), —(Rd)m-phenyl, —(Rd)m-(3-15 membered heterocyclyl), —(Rd)m—(C1-C6 perfluoroalkyl), —(Rd)m-halide, —(Rd)m—CN, —(Rd)m—C(O)Ra, —(Rd)m—C(O)ORa, —(Rd)m—C(O)NRaRb, —(Rd)m—ORa, —(Rd)m—OC(O)Ra, —(Rd)m—OC(O)NRaRb, —(Rd)m—O—S(O)Ra, —(Rd)m—OS(O)2Ra, —(Rd)m—OS(O)2NRaRb, —(Rd)m—OS(O)NRaRb, —(Rd)m—NO2, —(Rd)m—NRaRb, —(Rd)m—N(Ra)C(O)Rb, —(Rd)m—N(Ra)C(O)ORb, —(Rd)m—N(Rc)C(O)NRaRb, —(Rd)m—N(Ra)S(O)2Rb, —(Rd)m—N(Ra)S(O)Rb, —(Rd)m—SRa, —(Rd)m—S(O)Ra, —(Rd)m—S(O)2Ra, —(Rd)m—S(O)NRaRb, —(Rd)m—S(O)2NRaRb, —(Rd)m—O—(Re)m—NRaRb or —(Rd)m—NRa—(Re)—ORb;
and wherein any of the said alkyl, alkenyl, alkynyl, Ra, Rb, Rc, Rd, Re, C3-C12 cycloalkyl, phenyl, or 3-15 membered heterocyclyl are independently optionally further substituted by 1-3 groups selected from —F, C1-C3 alkyl, C1-C3 perfluoroalkyl, hydroxyl, C1-C6alkoxyl, or oxo;
R9 and R10 are each independently C1-C2 alkyl;
each R12 is independently H, —Ra—O—Rb, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(Rd)m—(C3-C12 cycloalkyl), —(Rd)m-phenyl, —(Rd)m-(3-15 membered heterocyclyl), —(Rd)m—(C1-C6 perfluoroalkyl), —(Rd)m-halide, —(Rd)m—CN, —(Rd)m—C(O)Ra, —(Rd)m—C(O)ORa, —(Rd)m—C(O)NRaRb, —(Rd)m—ORa, —(Rd)m—OC(O)Ra, —(Rd)m—OC(O)NRaRb, —(Rd)m—O—S(O)Ra, —(Rd)m—OS(O)2Ra, —(Rd)m—OS(O)2NRaRb, —(Rd)m—OS(O)NRaRb, —(Rd)m—NO2, —(Rd)m—NRaRb, —(Rd)m—N(Ra)C(O)Rb, —(Rd)m—N(Ra)C(O)ORb, —(Rd)m—N(Rc)C(O)NRaRb, —(Rd)m—N(Ra)S(O)2Rb, —(Rd)m—N(Ra)S(O)Rb, —(Rd)m—SRa, —(Rd)m—S(O)Ra, —(Rd)m—S(O)2Ra, —(Rd)m—S(O)NRaRb, —(Rd)m—S(O)2NRaRb, —(Rd)m—O—(Re)m—NRaRb or —(Rd)m—NRa—(Re)—ORb;
and wherein any of the said alkyl, alkenyl, alkynyl, Ra, Rb, Rc, Rd, Re, C3-C12 cycloalkyl, phenyl, or 3-15 membered heterocyclyl, are independently optionally further substituted by 1-3 groups selected from —F, C1-C3 alkyl, C1-C3 perfluoroalkyl, hydroxyl, C1-C6alkoxyl or oxo;
each Ra, Rb and Rc is independently selected from H, C1-C8 alkyl, C2-C8 alkenyl, —(Rd)m—(C3-C8 cycloalkyl), —(Rd)m—(C3-C8 cycloalkenyl), C2-C8 alkynyl, —(Rd)m-phenyl, or —(Rd)m-(3-7 membered heterocyclyl), and each Ra, Rb and Rc is independently optionally further substituted by 1-3 groups selected from halide, hydroxyl, —CN, C1-C6 alkyl, C1-C6 perfluoroalkyl, C1-C6 alkoxyl and C1-C6 alkylamino;
or, when connected to the same nitrogen, Ra and Rb may together optionally form a 3-7 membered heterocyclyl, which may optionally be further substituted by 0-3 groups selected from halide, hydroxyl, —CN, C1-C6 alkyl, C1-C6 perfluoroalkyl, C1-C6 alkoxyl or C1-C6 alkylamino;
each Rd and Re is independently —(C1-C3 alkylene);
and
each m is independently 0 or 1;
with the proviso that when X is N, R6 and R7 are not both H, and that when X is C—R11, R6 and R7 are both H;
or a pharmaceutically acceptable salt thereof.

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Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors

Life of this patent

Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors

Life of this patent

Abstract

Claims10