US 2004/0110805 A1 · Aromatic sulfone hydroxamic acids and their use as protease inhibitors · patentgrep

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Abstract

This invention is directed to aromatic sulfone hydroxamates (also known as “aromatic sulfone hydroxamic acids”) and salts thereof that, inter alia, inhibit matrix metalloproteinase (also known as “matrix metalloprotease” or “MMP”) activity and/or aggrecanase activity. This invention also is directed to a prevention or treatment method that comprises administering such a compound or salt in an MMP-inhibiting and/or aggrecanase-inhibiting effective amount to an animal, particularly a mammal having (or disposed to having) a pathological condition associated with MMP and/or aggrecanase activity.

Claims393

Dependent claims

A compound or salt thereof, wherein:

the compound corresponds in structure to Formula 1-1:
910
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—, —(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
E2 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)—, —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.

32 more elements

A compound or salt thereof, wherein:

the compound corresponds in structure to Formula 122-1:
977
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.

20 more elements

A compound or salt thereof, wherein:

the compound corresponds in structure to Formula 225-1:
1065
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═N—OH, and —C═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.

19 more elements

A compound or salt thereof, wherein:

the compound corresponds in structure to Formula 235-1:
1073
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.

16 more elements

A compound or salt thereof, wherein:

the compound corresponds in structure to Formula 250-1:
1079
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.

14 more elements

A compound or salt thereof, wherein:

the compound corresponds in structure to Formula 260-1:
1085
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.

16 more elements

A compound or salt thereof, wherein:

the compound corresponds in structure to Formula 267-1:
1089
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 3 carbon atoms between E1 and E5;
and
E5 is selected from the group consisting of optionally-substituted heterocyclyl, optionally-substituted fused-ring carbocyclyl, and substituted single-ring carbocyclyl;
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.

14 more elements

A compound or salt thereof, wherein:

the compound corresponds in structure to Formula 296-1:
1104
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
R1 and R2 are independently selected from the group consisting of —H and alkyl, wherein the alkyl optionally is substituted;
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 4 carbon atoms between E1 and E5;
and
E5 is selected from the group consisting of —OH and optionally-substituted carbocyclyl;
and
neither R1 nor R2 forms a ring structure with E5.

14 more elements

A compound or salt thereof, wherein:

the compound corresponds in structure to Formula 303-1:
1108
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 —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, 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, E4, or E5

14 more elements

A compound or salt thereof, wherein:

the compound corresponds in structure to Formula 308-1:
1111
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.

16 more elements

A compound or salt thereof, wherein:

the compound corresponds in structure to Formula 322-1:
1119
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
an atom in E2 optionally is bound to an atom in E5 to form a ring.

24 more elements

A compound or salt thereof, wherein:

the compound corresponds in structure to Formula 335-1:
1125
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 —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, 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, E4, or E5

14 more elements

A compound or salt thereof, wherein:

the compound corresponds in structure to Formula 337-1:
1126
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 alkyl and alkenyl, wherein the alkyl or alkenyl optionally is substituted;
and
E5 is selected from the group consisting of —H, alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl, and heterocyclyl, wherein any member of such group optionally is substituted.

8 more elements

A compound or salt thereof, wherein:

the compound corresponds in structure to Formula 344-1:
1130
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 contains less than 5 carbon atoms;
and
E5 is selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyalkyl, carbocyclyl, and heterocyclyl, wherein any member of such group optionally is substituted.

8 more elements

A compound or salt thereof, wherein:

the compound corresponds in structure to Formula 354-1:
1135
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
E5 is selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyalkyl, saturated carbocyclyl, partially saturated carbocyclyl, and heterocyclyl, wherein any member of such group optionally is substituted.

6 more elements

A compound or salt thereof, wherein:

the compound corresponds in structure to Formula 359-1:
1138
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 —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, 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, E4, or E5.

14 more elements

A compound or salt thereof, wherein:

the compound corresponds in structure to Formula 361-1:
1139
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
A2and 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:
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.

18 more elements

A compound or salt thereof, wherein:

the compound corresponds in structure to Formula 368-1:
1142
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
E5 is substituted heterocyclyl;
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.

12 more elements

A compound or salt thereof, wherein:

the compound corresponds in structure to Formula 372-1:
1145
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 comprises at least two carbon atoms;
and
E5 is optionally-substituted heterocyclyl;
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.

14 more elements

A compound or salt thereof, wherein:

the compound corresponds in structure to Formula 376-1:
1148
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—R14, —N(R14)(R15), 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, E3, E4, or E5.

36 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/657,034Filed 5 Sep 2003
Priority: 11 May 2001
Published: 10 Jun 2004
Term ends: Not estimatedThe source records don’t support an estimate.

Classification52 codes

C07D 401/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61K 31/351
Having six-membered rings with one oxygen as the only ring hetero atom: not condensed with another ring
A61K 31/41
Having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins: having five-membered rings with two or more ring hetero atoms, at least…
A61K 31/453
Containing further heterocyclic ring systems: containing a six-membered ring with oxygen as a ring hetero atom

Family

Application60/290,375Us provisional application · filed 11 May 2001
Application10/142,737Division · filed 10 May 2002
Application10/657,034Division · filed 5 Sep 2003
US 2004/0010019 A1Published application
US 6,689,794 B2Related patent
US 6,890,928 B2Related patent
US 2004/0110805 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Citations

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