US 8,283,358 B2 · N-sulfonamido polycyclic pyrazolyl compounds

Abstract

The current invention provides compounds having a structure according to Formulae 1, 2, 3, and 4: wherein the A-ring, B-ring, C-ring, m, n, R25, R50, and R51 are as described in the specification. The invention also provides pharmaceutical compositions comprising compounds of Formulae 1, 2, 3, and 4, as well as methods of treating cognitive disorders, such as Alzheimer's disease. The invention further provides intermediates useful in preparing the compounds of Formulae 1, 2, 3, and 4.

A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein,
m and n are independently 0 or 1, provided that m+n is 0 or 1;
the A-ring is aryl, cycloalkyl, heteroaryl or heterocycloalkyl, where each ring is optionally substituted at a substitutable position with halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, CN, aryloxy, —S(O)0-2—(C1-C6 alkyl), —NR11R11, —C(O)NR11R11, —NR11C(O)R10, —NR11SO2R10, —O—C(O)NR11R11, NO2, CN, C2-C6 alkanoyl, C0-C3alkylCO2R11, heteroaryl, heterocycloalkyl, aryl, arylalkyl, —OCH2O—, —OCH2CH2O— or —SO2NR11R11;
the B-ring is pyrazolyl, dihydropyrazolyl, pyrazolonyl or pyrazolidinonyl, each of which is optionally substituted with C1-C6 alkyl, C3-C6 cycloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 alkoxy, amino, C1-C4 alkylamino, C1-C4 dialkylamino, hydroxy, hydroxyalkyl, halo, C1-C4 haloalkyl, C1-C4 haloalkoxy, —C(O)NR11R11, —NR11C(O)R10, —NR11SO2R10 or CN;
wherein the C-ring is aryl substituted with R30, R35, R40, and R45 or heteroaryl, optionally substituted with halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, CN, hydroxyl, C1-C6 alkoxy, —C1-C3 alkyl-OH, —C1-C3 alkyl-alkoxy, phenyloxy, —S(O2)R10, —SO2NR11R11, —C(O)NR11R11, —NR11C(O)R10, —NR11SO2R10, —O—C(O)NR11R11, C2-C6 alkanoyl, oxazolyl, pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, imidazolyl, indolyl, furanyl, thienyl, phenyl or phenyl C1-C4 alkyl, wherein the phenyl portions of the above are optionally substituted with one or more groups that are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C4 haloalky or halogen;
R30, R35, R40, and R45 are independently H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C8 haloalkenyl, C2-C8 haloalkynyl, —SO2NR11R11, arylalkyl, cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, CN, NO2, hydroxyl, C1-C6 alkoxy, —C1-C6 alkyl-OH, —C1-C6 alkyl-C1-C6 alkoxy, aryloxy, —S(O2)R10, —NR11R11, —C(O)NR11R11, —NR11C(O)R10, —NR11SO2R10, —O—C(O)NR11R11, C2-C6 alkanoyl, heteroarylalkyl, heteroaryl, wherein each heteroaryl group is optionally substituted with a C1-C6 alkyl group, heterocycloalkylalkyl, heterocycloalkyl, wherein each heterocycloalkyl group is optionally substituted with one or two groups that are independently C1-C6 alkyl, C1-C6 alkoxy or halogen, aryl, aryloxy or arylalkyl, where the aryl portions of the above are optionally substituted with one or more groups that are independently C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, C1-C4 haloalky or halogen;
and
wherein two adjacent substituents on the C-ring together with the carbons to which they are attached optionally form a heterocycloalkyl or a heteroaryl ring, each of which is optionally substituted with one or more groups that are independently alkyl, alkoxy, halogen or C2-C4 alkanoyl wherein the alkanoyl group is optionally further substituted with up to 3 halogen atoms;
or two adjacent carbons of the C-ring optionally form a benzo ring which is optionally substituted with 1 to 4 groups that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO2;
each R25 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, —C(O)OR11, —(C1-C6 alkyl)—C(O)OR11, C1-C6 alkoxy C1-C6 alkyl, —C(O)OR11, —CONR11R11, CN, C1-C6 alkyl-CN or hydroxy C1-C6 alkyl;
each R51 is independently absent, H, C1-C4 alkyl, halogen, CN, amino, mono alkylamino or dialkylamino, OH or C1-C4 haloalkyl;
further when there are two R51 groups on a carbon atom, the two R51 groups and the carbon to which they are attached may form a 3 to 6 membered cycloalkyl ring;
or when there are two R51 groups on a carbon, the two R51 groups may form an oxo group;
R10 and R11 at each occurrence are independently C1-C6 alkyl, heteroaryl that is selected from pyrazolyl, thiadiazolyl, triazolyl, isoxazolyl, isothiazolyl, imidazolyl, thiazolyl, oxadiazolyl, and pyridyl or aryl that is selected from phenyl and naphthyl, where the heteroaryl and aryl groups are optionally substituted with 1 to 3 groups that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO2;
and additionally R11 may be H;
or if two R11 groups are on a nitrogen, then the two R11 groups together with the nitrogen to which they are attached, may form a 3-8 membered ring optionally including an additional heteroatom such as NH, NR12, NR13, O or S;
R12 is H, C1-C6 alkyl, aryl or —SO2-aryl, where each aryl is optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO2;
and
R13 is H, aryl or C1-C6 alkyl optionally substituted with aryl, hydroxyl or halogen, where each aryl is optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO2.

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N-sulfonamido polycyclic pyrazolyl compounds

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N-sulfonamido polycyclic pyrazolyl compounds

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Abstract

Claims24