US 2004/0024024 A1 · Aromatic sulfone hydroxamates and their use as protease inhibitors

A method for treating a pathological condition of the central nervous system associated with nitrosative or oxidative stress in a mammal, wherein:

the method comprises administering a compound or a pharmaceutically-acceptable salt thereof to the mammal in an amount that is therapeutically effective to treat the condition;
and
the compound corresponds in structure to Formula 1-1:
954
A1 is selected from the group consisting of —H, alkylcarbonyl, alkoxycarbonyl, carbocyclylcarbonyl, carbocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclylalkylcarbonyl, carbocyclyloxycarbonyl, carbocyclylalkoxycarbonyl, aminoalkylcarbonyl, alkyl(thiocarbonyl), alkoxy(thiocarbonyl), carbocyclyl(thiocarbonyl), carbocyclylalkyl(thiocarbonyl), heterocyclyl(thiocarbonyl), heterocyclylalkyl(thiocarbonyl), carbocyclyloxy(thiocarbonyl), carbocyclylalkoxy(thiocarbonyl), and aminoalkyl(thiocarbonyl), wherein any member (except —H) of such group optionally is substituted;
and
A2 and A3, together with the carbon atom to which they are both attached, form an optionally-substituted heterocyclyl containing from 5 to 8 ring members;
and
E1 is selected from the group consisting of —O—, —S(O)2—, —S(O)—, —S—, —N(R1)—, —C(O)—N(R1)—, —N(R1)—C(O)—, and —C(R1)(R2)—;
and
E is selected from the group consisting of alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, and alkylcycloalkylalkyl, wherein any member of such group optionally is substituted;
and
E forms a link of at least 2 carbon atoms between E1 and E3;
and
E3 is selected from the group consisting of —C(O)—, —O—(CO)—, —C(O)—O—, —C(NR3)—, —N(R4)—, —N(R4)—C(NR3)—, —C(NR3)—N(R4)—, —C(O)—N(R4)—, —N(R4)—C(O)—, —N(R4)—C(O)—N(R5)—, —S—, —S(O)—, —N(R4)—S(O)2—, —S(O)2—N(R4)—, —C(O)—N(R4)—N(R5)—C(O)_, —C(R4)(R6)—C(O)—, and —C(R7)(R8)—;
and
E4 is selected from the group consisting of a bond, alkyl, and alkenyl, wherein the alkyl or alkenyl optionally is substituted;
and
E5 is selected from the group consisting of —H, —OH, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, and heterocyclyl, wherein any member (except —H or, —OH) of such group optionally is substituted;
and
R1 and R2 are independently selected from the group consisting of —H and alkyl, wherein the alkyl optionally is substituted;
and
R3 is selected from the group consisting of —H and —OH;
and
R4 and R5 are independently selected from the group consisting of —H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl, wherein any member (except —H) of such group optionally is substituted;
and
R6 is selected from the group consisting of —CN and —OH;
and
R7 is selected from the group consisting of —H, halogen, —OH, alkyl, alkoxy, and alkoxyalkyl, wherein the alkyl, alkoxy, or alkoxyalkyl optionally is substituted;
and
R8 is selected from the group consisting of —OH and alkoxy, wherein the alkoxy optionally is substituted;
and
neither R1 nor R2 forms a ring structure with E2, E3, E4, or E5;
and
neither R4 nor R5 forms a ring structure with E2, E4, or E5;
and
E5 is not —H when both E3 is —C(R7)(R8)— and E4 is a bond.

34 more elements

A method for treating a pathological condition of the central nervous system associated with nitrosative or oxidative stress in a mammal, wherein:

the method comprises administering a compound or a pharmaceutically-acceptable salt thereof to the mammal in an amount that is therapeutically effective to treat the condition;
and
the compound corresponds in structure to Formula 8-1:
955
A1 is selected from the group consisting of —H, alkylcarbonyl, alkoxycarbonyl, carbocyclylcarbonyl, carbocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclylalkylcarbonyl, carbocyclyloxycarbonyl, carbocyclylalkoxycarbonyl, aminoalkylcarbonyl, alkyl(thiocarbonyl), alkoxy(thiocarbonyl), carbocyclyl(thiocarbonyl), carbocyclylalkyl(thiocarbonyl), heterocyclyl(thiocarbonyl), heterocyclylalkyl(thiocarbonyl), carbocyclyloxy(thiocarbonyl), carbocyclylalkoxy(thiocarbonyl), and aminoalkyl(thiocarbonyl), wherein any member (except —H) of such group optionally is substituted;
and
A2 and A3, together with the carbon atom to which they are both attached, form an optionally-substituted heterocyclyl containing from 5 to 8 ring members;
and
E1 is selected from the group consisting of —O—, —S(O)2—, —S(O)—, —N(R1)—, —C(O)—N(R1)—, —N(R1)—C(O)—, and —C(R1)(R2)—;
and
E2 is selected from the group consisting of alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, and alkylcycloalkylalkyl, wherein any member of such group optionally is substituted;
and
E2 forms a link of at least 2 carbon atoms between E1 and E3;
and
E3 is selected from the group consisting of carbocyclyl and heterocyclyl, wherein the carbocyclyl or heterocyclyl has 5 or 6 ring members and optionally is substituted;
and
E4 is selected from the group consisting of a bond, alkyl, alkenyl, —O—, and, —N(R3)—, wherein the alkyl or alkenyl optionally is substituted;
and
E5 is selected from the group consisting of carbocyclyl and heterocyclyl, wherein the carbocyclyl or heterocyclyl optionally is substituted;
and
R1 and R2 are independently selected from the group consisting of —H and alkyl, wherein the alkyl optionally is substituted;
and
R3 is selected from the group consisting of —H and alkyl, wherein the alkyl optionally is substituted;
and
neither R1 nor R2 forms a ring structure with E2, E3, E4, or E5.

22 more elements

A method for treating a pathological condition of the central nervous system associated with nitrosative or oxidative stress in a mammal, wherein:

the method comprises administering a compound or a pharmaceutically-acceptable salt thereof to the mammal in an amount that is therapeutically effective to treat the condition;
and
the compound corresponds in structure to Formula 9-1:
956
A1 is selected from the group consisting of —H, alkylcarbonyl, alkoxycarbonyl, carbocyclylcarbonyl, carbocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclylalkylcarbonyl, carbocyclyloxycarbonyl, carbocyclylalkoxycarbonyl, aminoalkylcarbonyl, alkyl(thiocarbonyl), alkoxy(thiocarbonyl), carbocyclyl(thiocarbonyl), carbocyclylalkyl(thiocarbonyl), heterocyclyl(thiocarbonyl), heterocyclylalkyl(thiocarbonyl), carbocyclyloxy(thiocarbonyl), carbocyclylalkoxy(thiocarbonyl), and aminoalkyl(thiocarbonyl), wherein any member (except —H) of such group optionally is substituted;
and
A2 and A3, together with the carbon atom to which they are both attached, form an optionally-substituted heterocyclyl containing from 5 to 8 ring members;
and
E1 is selected from the group consisting of —O—, —S(O)2—, —S(O)—, —N(R1)—, —C(O)—N(R1)—, —N(R1)—C(O)—, and —C(R1)(R2)—;
and
E2 is selected from the group consisting of alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, and alkylcycloalkylalkyl, wherein any member of such group optionally is substituted;
and
E4 is selected from the group consisting of a bond and alkyl, wherein the alkyl optionally is substituted;
and
E5 is selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, and heterocyclyl, wherein any member of such group optionally is substituted;
and
E6 is selected from the group consisting of —H, halogen, and alkyl, wherein the alkyl optionally is substituted;
E7 is selected from the group consisting of —H, alkyl, alkenyl, alkynyl, —S(O)2—R3, —NO2, —C(O)—N(R3)(R4), —(C)(OR3), carbocyclyl, carbocyclylalkyl, alkoxycarbocyclyl, —CN, —C(H)(NOH)—, and —C(H)(NH)—, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, carbocyclylalkyl, or alkoxycarbocyclyl optionally is substituted;
and
R1 and R2 are independently selected from the group consisting of —H and alkyl, wherein the alkyl optionally is substituted;
and
R3 and R4 are independently selected from the group consisting of —H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, heterocyclylalkyl, wherein any member (except —H) of such group optionally is substituted;
and
neither R1 nor R2 forms a ring structure with E2, E4, E5, E6, or E7.

21 more elements

A method for treating a pathological condition of the central nervous system associated with nitrosative or oxidative stress in a mammal, wherein:

the method comprises administering a compound or a pharmaceutically-acceptable salt thereof to the mammal in an amount that is therapeutically effective to treat the condition;
and
the compound corresponds in structure to Formula 10-1:
957
A1 is selected from the group consisting of —H, alkylcarbonyl, alkoxycarbonyl, carbocyclylcarbonyl, carbocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclylalkylcarbonyl, carbocyclyloxycarbonyl, carbocyclylalkoxycarbonyl, aminoalkylcarbonyl, alkyl(thiocarbonyl), alkoxy(thiocarbonyl), carbocyclyl(thiocarbonyl), carbocyclylalkyl(thiocarbonyl), heterocyclyl(thiocarbonyl), heterocyclylalkyl(thiocarbonyl), carbocyclyloxy(thiocarbonyl), carbocyclylalkoxy(thiocarbonyl), and aminoalkyl(thiocarbonyl), wherein any member (except —H) of such group optionally is substituted;
and
A2 and A3, together with the carbon atom to which they are both attached, form an optionally-substituted heterocyclyl containing from 5 to 8 ring members;
and
E1 is selected from the group consisting of —O—, —S(O)2—, —S(O)—, —N(R3)—, —C(O)—N(R3)—, —N(R3)—C(O)—, and —C(R1)(R2)—;
and
E2 is selected from the group consisting of a bond, alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, and alkylcycloalkylalkyl, wherein any member (except for the bond) of such group optionally is substituted;
and
E3 is carbonylpyrrollidinyl, wherein the carbonylpyrrollidinyl optionally is substituted;
and
E4 is selected from the group consisting of a bond, alkyl, and alkenyl, wherein the alkyl or alkenyl optionally is substituted;
and
E5 is selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, and heterocyclyl, wherein any member of such group optionally is substituted;
and
R1 and R2 are independently selected from the group consisting of —H and alkyl, wherein the alkyl optionally is substituted;
and
neither R1 nor R2 forms a ring structure with E2, E3, E4, or E5.

18 more elements

A method for treating a pathological condition of the central nervous system associated with nitrosative or oxidative stress in a mammal, wherein:

the method comprises administering a compound or a pharmaceutically-acceptable salt thereof to the mammal in an amount that is therapeutically effective to treat the condition;
and
the compound corresponds in structure to Formula 11-1:
958
A1 is selected from the group consisting of —H, alkylcarbonyl, alkoxycarbonyl, carbocyclylcarbonyl, carbocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclylalkylcarbonyl, carbocyclyloxycarbonyl, carbocyclylalkoxycarbonyl, aminoalkylcarbonyl, alkyl(thiocarbonyl), alkoxy(thiocarbonyl), carbocyclyl(thiocarbonyl), carbocyclylalkyl(thiocarbonyl), heterocyclyl(thiocarbonyl), heterocyclylalkyl(thiocarbonyl), carbocyclyloxy(thiocarbonyl), carbocyclylalkoxy(thiocarbonyl), and aminoalkyl(thiocarbonyl), wherein any member (except —H) of such group optionally is substituted;
and
A2 and A3, together with the carbon atom to which they are both attached, form an optionally-substituted heterocyclyl containing from 5 to 8 ring members;
and
E1 is selected from the group consisting of —O—, —S(O)2—, —S(O)—, —N(R1)—, —C(O)—N(R1)—, —N(R1)—C(O)—, and —C(R1)(R2)—;
and
E2 is selected from the group consisting of alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, and alkylcycloalkylalkyl, wherein any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, and haloalkyl;
and
E5 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, and cyclohexadienyl, wherein
the alkyl, alkenyl, or alkynyl (a) contains at least 4 carbon atoms, and (b) optionally is substituted with one or more substituents selected from the group consisting of —OH, —NO2, —CN, and halogen, and
the cycloalkyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, or cyclohexadienyl optionally is substituted;
and
R1 and R2 are independently selected from the group consisting of —H and alkyl, wherein the alkyl optionally is substituted;
and
neither R1 nor R2 forms a ring structure with E5.

16 more elements

A method for treating a pathological condition of the central nervous system associated with nitrosative or oxidative stress in a mammal, wherein:

the method comprises administering a compound or a pharmaceutically-acceptable salt thereof to the mammal in an amount that is therapeutically effective to treat the condition;
and
the compound corresponds in structure to Formula 12-1:
959
A1 is selected from the group consisting of —H, alkylcarbonyl, alkoxycarbonyl, carbocyclylcarbonyl, carbocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclylalkylcarbonyl, carbocyclyloxycarbonyl, carbocyclylalkoxycarbonyl, aminoalkylcarbonyl, alkyl(thiocarbonyl), alkoxy(thiocarbonyl), carbocyclyl(thiocarbonyl), carbocyclylalkyl(thiocarbonyl), heterocyclyl(thiocarbonyl), heterocyclylalkyl(thiocarbonyl), carbocyclyloxy(thiocarbonyl), carbocyclylalkoxy(thiocarbonyl), and aminoalkyl(thiocarbonyl), wherein any member (except —H) of such group optionally is substituted;
and
A2 and A3, together with the carbon atom to which they are both attached, form an optionally-substituted heterocyclyl containing from 5 to 8 ring members;
and
E1 is selected from the group consisting of —O—, —S(O)2—, —S(O)—, —N(R1)—, —C(O)—N(R1)—, —N(R1)—C(O)—, and —C(R1)(R2)—;
and
E2 is selected from the group consisting of alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, and alkylcycloalkylalkyl, wherein any member of such group optionally is substituted;
and
E3 is carbonylpiperidinyl, wherein the carbonylpiperidinyl optionally is substituted;
and
E4 is selected from the group consisting of a bond, alkyl, and alkenyl, wherein the alkyl or alkenyl optionally is substituted;
and
E5 is selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, and heterocyclyl, wherein any member of such group optionally is substituted;
and
R1 and R2 are independently selected from the group consisting of —H and alkyl, wherein the alkyl optionally is substituted;
and
neither R1 nor R2 forms a ring structure with E2, E3, E4, or E5.

18 more elements

A method for treating a pathological condition of the central nervous system associated with nitrosative or oxidative stress in a mammal, wherein:

the method comprises administering a compound or a pharmaceutically-acceptable salt thereof to the mammal in an amount that is therapeutically effective to treat the condition;
and
the compound corresponds in structure to Formula 16-1:
963
A1 is selected from the group consisting of —H, alkylcarbonyl, alkoxycarbonyl, carbocyclylcarbonyl, carbocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclylalkylcarbonyl, carbocyclyloxycarbonyl, carbocyclylalkoxycarbonyl, aminoalkylcarbonyl, alkyl(thiocarbonyl), alkoxy(thiocarbonyl), carbocyclyl(thiocarbonyl), carbocyclylalkyl(thiocarbonyl), heterocyclyl(thiocarbonyl), heterocyclylalkyl(thiocarbonyl), carbocyclyloxy(thiocarbonyl), carbocyclylalkoxy(thiocarbonyl), and aminoalkyl(thiocarbonyl), wherein any member (except —H) of such group optionally is substituted;
and
A2 and A3, together with the carbon atom to which they are both attached, form an optionally-substituted heterocyclyl containing from 5 to 8 ring members;
and
E2 is selected from the group consisting of alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, and alkylcycloalkylalkyl, wherein any member of such group optionally is substituted;
and
E2 comprises at least 3 carbon atoms;
and
E5 is selected from the group consisting of —H, alkyl, alkenyl, alkynyl, alkoxyalkyl, carbocyclyl, carbocyclylalkoxyalkyl, heterocyclyl, heterocyclylalkyl, and heterocyclylalkoxyalkyl, wherein:
the alkyl, alkenyl, alkynyl, or alkoxyalkyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO2, and —CN, and
the carbocyclyl, carbocyclylalkoxyalkyl, heterocyclyl, heterocyclylalkyl, or heterocyclylalkoxyalkyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO2, —CN, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, halogen-substituted alkoxyalkyl, —N(R3)(R4), —C(O)(R5), —S—R3, —S(O)2—R3, carbocyclyl, halocarbocyclyl, carbocyclylalkyl, and halogen-substituted carbocyclylalkyl;
and
R1 and R2 are independently selected from the group consisting of —H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl, wherein any member (except —H) of such group optionally is substituted with one or more halogen;
and
R3 is selected from the group consisting of —H, alkyl, —O—R4, —N(R4)(R5), carbocyclylalkyl, and heterocyclylalkyl, wherein the alkyl, carbocyclylalkyl, or heterocyclylalkyl optionally is substituted with one or more halogen;
and
R4 and R5 are independently selected from the group consisting of —H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl, wherein any member (except —H) of such group optionally is substituted with one or more halogen.

18 more elements

A method for treating a pathological condition of the central nervous system associated with nitrosative or oxidative stress in a mammal, wherein:

the method comprises administering a compound or a pharmaceutically-acceptable salt thereof to the mammal in an amount that is therapeutically effective to treat the condition;
and
the compound corresponds in structure to Formula 17-1:
964
A1 is selected from the group consisting of —H, alkylcarbonyl, alkoxycarbonyl, carbocyclylcarbonyl, carbocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclylalkylcarbonyl, carbocyclyloxycarbonyl, carbocyclylalkoxycarbonyl, aminoalkylcarbonyl, alkyl(thiocarbonyl), alkoxy(thiocarbonyl), carbocyclyl(thiocarbonyl), carbocyclylalkyl(thiocarbonyl), heterocyclyl(thiocarbonyl), heterocyclylalkyl(thiocarbonyl), carbocyclyloxy(thiocarbonyl), carbocyclylalkoxy(thiocarbonyl), and aminoalkyl(thiocarbonyl), wherein any member (except —H) of such group optionally is substituted;
and
A2 and A3, together with the carbon atom to which they are both attached, form an optionally-substituted heterocyclyl containing from 5 to 8 ring members;
and
E2 is selected from the group consisting of alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, and alkylcycloalkylalkyl, wherein any member of such group optionally is substituted;
and
E4 is selected from the group consisting of a bond, alkyl, and alkenyl, wherein the alkyl or alkenyl optionally is substituted;
and
E5 is selected from the group consisting of:
optionally-substituted alkenyl, and
optionally-substituted alkynyl, and
optionally-substituted alkoxy, and
optionally-substituted alkoxyalkyl, and
single-ring carbocyclyl substituted with one or more substituents independently selected from the group consisting of —OH, —NO2, —CN, —N(R5)(R6), —C(O)(R7), —S—R5, —S(O)2—R5, carbocyclyl, halocarbocyclyl, carbocyclylalkyl, halogen-substituted carbocyclylalkyl, heterocyclyl, haloheterocyclyl, heterocyclylalkyl, and halogen-substituted heterocyclylalkyl, and
single-ring carbocyclyl having multiple substitutions, and
optionally-substituted fused-ring carbocyclyl, and
optionally-substituted heterocyclyl;
and
R1 and R2 are independently selected from the group consisting of —H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl, wherein any member (except —H) of such group optionally is substituted with one or more halogen;
and
R3 is selected from the group consisting of —H, alkyl, —O—R4, —N(R4)(R5), carbocyclylalkyl, and heterocyclylalkyl, wherein the alkyl, carbocyclylalkyl, or heterocyclylalkyl optionally is substituted with one or more halogen;
and
R4 and R5 are independently selected from the group consisting of —H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl, wherein any member (except —H) of such group optionally is substituted with one or more halogen;
and
R6 and R7 are independently selected from the group consisting of —H, alkyl, alkoxycarbonyl, alkylcarbonyl, carbocyclylalkyl, and carbocyclylalkoxycarbonyl, wherein any member (except —H) of such group optionally is substituted with one or more halogen;
and
an atom in E2 optionally is bound to an atom in E5 to form a ring.

28 more elements

A method for treating a pathological condition of the central nervous system associated with nitrosative or oxidative stress in a mammal, wherein:

the method comprises administering a compound or a pharmaceutically-acceptable salt thereof to the mammal in an amount that is therapeutically effective to treat the condition;
and
the compound corresponds in structure to Formula 21-1:
968
A1 is selected from the group consisting of —H, alkylcarbonyl, alkoxycarbonyl, carbocyclylcarbonyl, carbocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclylalkylcarbonyl, carbocyclyloxycarbonyl, carbocyclylalkoxycarbonyl, aminoalkylcarbonyl, alkyl(thiocarbonyl), alkoxy(thiocarbonyl), carbocyclyl(thiocarbonyl), carbocyclylalkyl(thiocarbonyl), heterocyclyl(thiocarbonyl), heterocyclylalkyl(thiocarbonyl), carbocyclyloxy(thiocarbonyl), carbocyclylalkoxy(thiocarbonyl), and aminoalkyl(thiocarbonyl), wherein any member (except —H) of such group optionally is substituted;
and
A2 and A3, together with the carbon atom to which they are both attached, form an optionally-substituted heterocyclyl containing from 5 to 8 ring members;
and
E2 is selected from the group consisting of a bond, alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, and alkylcycloalkylalkyl, wherein any member of such group optionally is substituted;
and
E4 is selected from the group consisting of a bond, alkyl, and alkenyl, wherein the alkyl or alkenyl optionally is substituted;
and
E5 is selected from the group consisting of substituted carbocyclyl and optionally-substituted heterocyclyl, wherein:
the carbocyclyl is substituted with:
2 or more substituents independently selected from the group consisting of halogen, —OH, —NO2, —CN, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, halogen-substituted alkoxyalkyl, —N(R3)(R4), —C(O)(R5), —S—R3, —S(O)2—R3, carbocyclyl, halocarbocyclyl, carbocyclylalkyl, and halogen-substituted carbocyclylalkyl, or
a substituent selected from the group consisting of halogen, —OH, —NO2, —CN, —C(O)—O—R3, —S—R3, —S(O)2—R3, carbocyclyl, halocarbocyclyl, carbocyclylalkyl, and halogen-substituted carbocyclylalkyl, and
the heterocyclyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO2, —CN, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, halogen-substituted alkoxyalkyl, —N(R3)(R4), —C(O)(R5), —S—R3, —S(O)2—R3, carbocyclyl, halocarbocyclyl, carbocyclylalkyl, and halogen-substituted carbocyclylalkyl;
and
R3 and R4 are independently selected from the group consisting of —H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl, wherein any member (except —H) of such group optionally is substituted with one or more halogen;
and
R5 is selected from the group consisting of —H, alkyl, —O—R6, —N(R6)(R7), carbocyclylalkyl, and heterocyclylalkyl, wherein the alkyl, carbocyclylalkyl, or heterocyclylalkyl optionally is substituted with one or more halogen;
and
R6 and R7 are independently selected from the group consisting of —H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl, wherein any member (except —H) of such group optionally is substituted with one or more halogen.

20 more elements

A method for treating a pathological condition of the central nervous system associated with nitrosative or oxidative stress in a mammal, wherein:

the method comprises administering a compound or a pharmaceutically-acceptable salt thereof to the mammal in an amount that is therapeutically effective to treat the condition;
and
the compound corresponds in structure to Formula 24-1:
971
A1 is selected from the group consisting of —H, alkylcarbonyl, alkoxycarbonyl, carbocyclylcarbonyl, carbocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclylalkylcarbonyl, carbocyclyloxycarbonyl, carbocyclylalkoxycarbonyl, aminoalkylcarbonyl, alkyl(thiocarbonyl), alkoxy(thiocarbonyl), carbocyclyl(thiocarbonyl), carbocyclylalkyl(thiocarbonyl), heterocyclyl(thiocarbonyl), heterocyclylalkyl(thiocarbonyl), carbocyclyloxy(thiocarbonyl), carbocyclylalkoxy(thiocarbonyl), and aminoalkyl(thiocarbonyl), wherein any member (except —H) of such group optionally is substituted;
and
A2 and A3, together with the carbon atom to which they are both attached, form an optionally-substituted heterocyclyl containing from 5 to 8 ring members;
and
E1 is selected from the group consisting of —O—, —S(O)2—, —S(O)—, —S—, —N(R1)—, —C(O)—N(R1)—, —N(R1)—C(O)—, and —C(R1)(R2)—;
and
E2 is selected from the group consisting of alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, and alkylcycloalkylalkyl, wherein any member of such group optionally is substituted;
and
E3 is selected from the group consisting of —C(O)—, —O—(CO)—, —C(O)—O—, —C(NR3)—, —N(R4)—, —N(R4)—C(NR3)—, —C(NR3)—N(R4)—, —C(O)—N(R4)—, —N(R4)—C(O)—, —N(R4)—C(O)—N(R5)—, —S—, —S(O)—, —N(R4)—S(O)2—, —S(O)2—N(R4)—, —C(O)—N(R4)—N(R5)—C(O)—, —C(R4)(R6)—C(O)—, and —C(R7)(R8)—;
and
E4 is selected from the group consisting of a bond, alkyl, and alkenyl, wherein the alkyl or alkenyl optionally is substituted;
and
E5 is selected from the group consisting of carbocyclyl and heterocyclyl, wherein the carbocyclyl and heterocyclyl are:
substituted with a substituent selected from the group consisting of optionally-substituted carbocyclyl, optionally-substituted carbocyclylalkyl, optionally-substituted heterocyclyl, and optionally-substituted heterocyclylalkyl, and
optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO2, —CN, alkyl, alkoxy, alkoxyalkyl, —N(R11)(R12), —C(O)(R13), —S—R11, —S(O)2—R11, carbocyclyl, carbocyclylalkyl, haloalkyl, haloalkoxy, halogen-substituted alkoxyalkyl, halocarbocyclyl, halogen-substituted carbocyclylalkyl, hydroxycarbocyclyl, and heteroaryl;
and
R1 and R2 are independently selected from the group consisting of —H and alkyl, wherein the alkyl optionally is substituted;
and
R3 is selected from the group consisting of —H and —OH;
and
R4 and R5 are independently selected from the group consisting of —H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl, wherein any member (except —H) of such group optionally is substituted;
and
R6 is selected from the group consisting of —CN and —OH;
and
R7 is selected from the group consisting of —H, halogen, —OH, alkyl, alkoxy, and alkoxyalkyl, wherein the alkyl, alkoxy, or alkoxyalkyl optionally is substituted;
and
R8 is selected from the group consisting of —OH and alkoxy, wherein the alkoxy optionally is substituted;
and
R11 and R12 are independently selected from the group consisting of —H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl, wherein any member (except —H) of such group optionally is substituted with one or more halogen;
and
R13 is selected from the group consisting of —H, C1-C8-alkyl, —O—N(R14)(R5), carbocyclyl-C1-C8-alkyl, heterocyclyl-C1-C8-alkyl, halo-C1-C8-alkyl, halogen-substituted carbocyclyl-C1-C8-alkyl, and halogen-substituted heterocyclyl-C1-C8-alkyl;
and
R14 and R15 are independently selected from the group consisting of —H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl, wherein any member (except —H) of such group optionally is substituted with one or more halogen;
and
neither R1 nor R2 forms a ring structure with E2, E3, E4, or E5;
and
neither R4 nor R5 forms a ring structure with E2, E4, or E5.

38 more elements

Aromatic sulfone hydroxamates and their use as protease inhibitors

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Aromatic sulfone hydroxamates and their use as protease inhibitors

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Abstract

Claims26