US 2022/0089613 A1Published application

Novel 3-amino-pyrrolo[3,4-c]pyrazole-5(1h, 4h,6h) carbaldehyde derivatives

AssigneePfizer Inc.

InventorsHui LI, Seiji NUKUI, Stephanie Anne SCALES, Min TENG, Chunfeng YIN

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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 disase pression, virus diseases, inflammatory disorders, or diseases in which the liver is a target organ.

Claims25

Dependent claims

A compound of Formula A,

wherein
X is C—R11 or N, wherein R11 is H, halo, OH, C1-C3alkyl, CF3, or CN;
A and B are independently C or N;
R1, 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, —(R)—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 R2 and R3 may together optionally cyclize to form a saturated or unsaturated 3-7 membered heterocyclyl fused to the 6-membered N-containing heteroaryl to which they are attached;
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 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;
R9 and R10 are each independently C1-C2 alkyl or can together cyclize to form a cyclopropyl or cyclobutyl;
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)-, —(C2-C5 alkenylene)-, or —(C2-C5 alkynylene)-;
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.

18 more elements

A compound of Formula B,

wherein
X is C—R11 or N, wherein R11 is H, halo, OH, C1-C3alkyl, CF3, or CN;
A and B are independently C or N;
R1 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(RO)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;
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;
wherein R2 and R3 may together optionally cyclize to form a saturated or unsaturated 3-7 membered heterocyclyl fused to the 6-membered N-containing heteroaryl to which they are attached;
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(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,
R8 is 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;
R9 and R10 are each independently C1-C2 alkyl or can together cyclize to form a cyclopropyl or cyclobutyl;
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)-, —(C2-C5 alkenylene)-, or —(C2-C5 alkynylene)-;
and each m is independently 0 or 1,
or a pharmaceutically acceptable salt thereof.

17 more elements

A compound selected from the group consisting of:

N4-(6,6-dimethyl-5-{[(2S)-2,4,5,5-tetramethylpiperazin-1-yl]carbonyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-N2-ethyl-5-fluoropyrimidine-2,4-diamine,
N4-(6,6-dimethyl-5-{[(2S)-2,4,5,5-tetramethylpiperazin-1-yl]carbonyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-5-fluoro-N2,N2-dimethylpyrimidine-2,4-diamine,
N2-cyclopropyl-N4-(6,6-dimethyl-5-{[(2S)-2,4,5,5-tetramethylpiperazin-1-yl]carbonyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-5-fluoropyrimidine-2,4-diamine
N4-(6,6-dimethyl-5-{[(2S)-2,4,5,5-tetramethylpiperazin-1-yl]carbonyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-5-fluoro-N2-methylpyrimidine-2,4-diamine,
N4-(6,6-dimethyl-5-{[(2S)-2,4,5,5-tetramethylpiperazin-1-yl]carbonyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-5-fluoro-N2-isopropylpyrimidine-2,4-diamine,
N4-(6,6-dimethyl-5-{[(2S)-2,4,5,5-tetramethylpiperazin-1-yl]carbonyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-N2-ethylpyrimidine-2,4-diamine,
N4-(6,6-dimethyl-5-{[(2S)-2,4,5,5-tetramethylpiperazin-1-yl]carbonyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-N2,N2-dimethylpyrimidine-2,4-diamine,
5-{[(8S)-6,8-dimethyl-6,9-diazaspiro[4.5]dec-9-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine,
N4-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-1-yl]carbonyl}-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-N2-ethyl-5-fluoropyrimidine-2,4-diamine,
N4-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl]carbonyl}-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-N2-ethyl-5-fluoropyrimidine-2,4-diamine,
N2-ethyl-5-fluoro-N4-(5-{[(2S,5R)-4-(3-methoxypropyl)-2,5-dimethylpiperazin-1-yl]carbonyl}-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)pyrimidine-2,4-diamine acetate salt,
N4-(6,6-dimethyl-5-{[(2S,5R)-2,4,5-trimethylpiperazin-1-yl]carbonyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-N2-ethyl-5-fluoropyrimidine-2,4-diamine,
4-[(6,6-dimethyl-5-{[(2S,5R)-2,4,5-trimethylpiperazin-1-yl]carbonyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)amino]pyrimidine-2-carbonitrile,
N-(2-ethyl-5-fluoropyrimidin-4-yl)-6,6-dimethyl-5-{[(2S)-2,4,5,5-tetramethylpiperazin-1-yl]carbonyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine,
N-(2-ethyl-5-fluoropyrimidin-4-yl)-5-{[(2S,5R)-4-(3-methoxypropyl)-2,5-dimethylpiperazin-1-yl]carbonyl}-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amin,
2-((5S)-4-{[3-[(2-ethyl-5-fluoropyrimidin-4-yl)amino]-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl]carbonyl}-1,5-dimethylpiperazin-2-yl)ethanol,
5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-1-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine,
N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-5-{[(2S)-2,4,5,5-tetramethylpiperazin-1-yl]carbonyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine,
N-(5-fluoro-2-propylpyrimidin-4-yl)-6,6-dimethyl-5-{[(2S)-2,4,5,5-tetramethylpiperazin-1-yl]carbonyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine,
N-(5-fluoro-2-isopropylpyrimidin-4-yl)-6,6-dimethyl-5-{[(2S)-2,4,5,5-tetramethylpiperazin-1-yl]carbonyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine,
N-(3-fluoro-6-methylpyridin-2-yl)-6,6-dimethyl-5-{[(2S,5R)-2,4,5-trimethylpiperazin-1-yl]carbonyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine,
5-{[(3S,8aS)-3,8a-dimethylhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]carbonyl}-N-(3-fluoro-6-methylpyridin-2-yl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine,
N-(3-fluoro-6-methylpyridin-2-yl)-6,6-dimethyl-5-{[(3S,8aS)-3-methylhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]carbonyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine,
N-(3-fluoro-6-methylpyridin-2-yl)-6,6-dimethyl-5-{[(2S)-2,4,5,5-tetramethylpiperazin-1-yl]carbonyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine,
N-[5-fluoro-2-(methoxymethyl)pyrimidin-4-yl]-6,6-dimethyl-5-{[(2S)-2,4,5,5-tetramethylpiperazin-1-yl]carbonyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine,
5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-1-yl]carbonyl}-N-(2-ethyl-5-fluoropyrimidin-4-yl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine,
5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl]carbonyl}-N-(4-methoxypyrimidin-2-yl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine,
5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl]carbonyl}-6,6-dimethyl-N-(4-methylpyrimidin-2-yl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine,
5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl]carbonyl}-6,6-dimethyl-N-[4-(trifluoromethyl)pyrimidin-2-yl]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine,
5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-1-yl]carbonyl}-6,6-dimethyl-N-(4-methylpyrimidin-2-yl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine,
N-(2-ethoxy-5-fluoropyrimidin-4-yl)-6,6-dimethyl-5-{[(2S,5R)-2,4,5-trimethylpiperazin-1-yl]carbonyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine,
N-(2-ethoxy-5-fluoropyrimidin-4-yl)-6,6-dimethyl-5-{[4-ethyl(2S,5R)-2,5-dimethylpiperazin-1-yl]carbonyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine,
N-(2-ethoxy-5-fluoropyrimidin-4-yl)-6,6-dimethyl-5-{[(2S)-2,4,5,5-tetramethylpiperazin-1-yl]carbonyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine,
N-(2-ethoxy-5-fluoropyrimidin-4-yl)-5-{[(2S,5R)-4-(2-methoxyethyl)-2,5-dimethylpiperazin-1-yl]carbonyl}-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine,
N-(2-ethoxy-5-fluoropyrimidin-4-yl)-5-{[(2S,5R)-4-(3-methoxypropyl)-2,5-dimethylpiperazin-1-yl]carbonyl}-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine,
N-[5-fluoro-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]-5-{[(2S,5R)-4-(3-methoxypropyl)-2,5-dimethylpiperazin-1-yl]carbonyl}-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine,
N-[5-fluoro-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]-6,6-dimethyl-5-{[(2S,5R)-2,4,5-trimethylpiperazin-1-yl]carbonyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine,
N-[5-fluoro-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]-6,6-dimethyl-5-{[(2S)-2,4,5,5-tetramethylpiperazin-1-yl]carbonyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine,
5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-1-yl]carbonyl}-N-(2-ethoxy-5-fluoropyrimidin-4-yl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine,
5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl]carbonyl}-N-(2-ethoxy-5-fluoropyrimidin-4-yl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine,
2-((5S)-4-{[3-[(2-ethoxy-5-fluoropyrimidin-4-yl)amino]-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl]carbonyl}-1,5-dimethylpiperazin-2-yl)ethanol,
2-((5S)-4-{[3-[(2-ethoxy-5-fluoropyrimidin-4-yl)amino]-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl]carbonyl}-1,5-dimethylpiperazin-2-yl)ethanol,
5-[(4-fluoro-1-methylpiperidin-4-yl)carbonyl]-N-[5-fluoro-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine,
5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-1-yl]carbonyl}-N-[5-fluoro-2-(methoxymethyl)pyrimidin-4-yl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine,
2-((5S)-4-{[3-{[5-fluoro-2-(methoxymethyl)pyrimidin-4-yl]amino}-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl]carbonyl}-1,5-dimethylpiperazin-2-yl)ethanol;
or a pharmaceutically acceptable salt thereof.

43 more elements

Dependencies are inferred from the claim text.

Facts

Application: 17/539,948Filed 1 Dec 2021
Priority: 7 Feb 2007
Published: 24 Mar 2022
Term ends: Not estimatedThe source records don’t support an estimate.

Classification18 codes

C07D 519/00
Heterocyclic compounds containing more than one system of two or more relevant
A61P 1/16
Drugs for disorders of the alimentary tract or the digestive system: for liver or gallbladder disorders, e.g. hepatoprotective agents,…
A61P 3/00
Drugs for disorders of the metabolism
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics

Family

Application60/888,749Us provisional application · filed 7 Feb 2007
Application60/989,086Us provisional application · filed 19 Nov 2007
Application61/020,965Us provisional application · filed 14 Jan 2008
Application12/523,965Continuation · filed 18 Dec 2009
Application13/450,388Continuation · filed 18 Apr 2012
Application14/506,470Continuation · filed 3 Oct 2014
Application15/376,279Continuation · filed 12 Dec 2016
Application16/387,369Continuation · filed 17 Apr 2019
Application17/539,948Continuation
US 10,316,045 B2Related patent
US 11,220,518 B2Related patent
US 11,780,853 B2Related patent
US 2010/0130501 A1Published application
US 2012/0202809 A1Published application
US 2015/0099743 A1Published application
US 2017/0217991 A1Published application
US 2020/0002359 A1Published application
US 8,183,255 B2Related patent
US 8,877,761 B2Related patent
US 9,518,060 B2Related patent
US 2022/0089613 A1This patent

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Abstract

A compound of Formula A,

wherein
X is C—R11 or N, wherein R11 is H, halo, OH, C1-C3alkyl, CF3, or CN;
A and B are independently C or N;
R1, 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, —(R)—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 R2 and R3 may together optionally cyclize to form a saturated or unsaturated 3-7 membered heterocyclyl fused to the 6-membered N-containing heteroaryl to which they are attached;
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 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;
R9 and R10 are each independently C1-C2 alkyl or can together cyclize to form a cyclopropyl or cyclobutyl;
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)-, —(C2-C5 alkenylene)-, or —(C2-C5 alkynylene)-;
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.

18 more elements

Facts

Application

17/539,948Filed 1 Dec 2021

Priority

7 Feb 2007

Published

24 Mar 2022

Term ends

Not estimatedThe source records don’t support an estimate.

Classification18 codes

C07D 519/00
Heterocyclic compounds containing more than one system of two or more relevant
A61P 1/16
Drugs for disorders of the alimentary tract or the digestive system: for liver or gallbladder disorders, e.g. hepatoprotective agents,…
A61P 3/00
Drugs for disorders of the metabolism
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics

Family

Application60/888,749Us provisional application · filed 7 Feb 2007

Application60/989,086Us provisional application · filed 19 Nov 2007

Application61/020,965Us provisional application · filed 14 Jan 2008

Application12/523,965Continuation · filed 18 Dec 2009

Application13/450,388Continuation · filed 18 Apr 2012

Application14/506,470Continuation · filed 3 Oct 2014

Application15/376,279Continuation · filed 12 Dec 2016

Application16/387,369Continuation · filed 17 Apr 2019

Application17/539,948Continuation

US 10,316,045 B2Related patent

US 11,220,518 B2Related patent