Ligands for aggregated tau molecules
View Patent ↗Provided are certain benzothiazole, imidazothiazole, imidazopyrimidine and imidazopyridine compounds, including, for example: formula (I) and pharmaceutically and physiologically acceptable salts, hydrates, and solvates thereof. Such compounds can be used as diagnostic ligands or labels of tau protein and PHF.
1. A compound having the formula:
wherein
—R— is independently selected from:
wherein (T) indicates the point of attachment to -T;
and (Q) indicates the point of attachment to -Q-;
-Q- is independently selected from:
—N═N—;
—CH═CH—; —CR 1 ═CH—; —CH═CR 1 —; —CR 1 ═CR 1 —;
each —R 1 is independently unsubstituted saturated aliphatic C 1-4 -alkyl;
—P is independently selected from:
where the asterisk indicates the point of attachment;
-T is independently selected from:
where the asterisk indicates the point of attachment;
and X is independently CH;
—W 1 is independently —W A ;
—W 2 is independently —H or —W A ;
—W 3 is independently —H or —W A ;
—W 4 is independently —H or —W A ;
—W 5 is independently —H or —W A ;
—W 6 is independently —H or —W A ;
with the proviso that at least one of —W 4 , —W 5 and —W 6 is —W A ;
where —W A is independently selected from:
—F, —Cl, —Br, —I,
—OH, —W A1 , —O—W A1 ,
—NH 2 , —NHW A1 , and —N(W A1 ) 2 ;
and —W A1 is independently selected from:
unsubstituted saturated aliphatic C 1-4 -alkyl,
—CF 3 ,
—CH 2 CH 2 OH, and
—CH 2 CH 2 N(Me) 2 ;
-G 1 is independently —H or -G A ;
-G 2 is independently —H or -G A ;
where -G A is independently selected from:
—F, —Cl, —Br, —I,
—CF 3 , —OCF 3 ,
—OH, —OR 2 ;
—[O—CH 2 CH 2 ] n —R B2 , where n is 2 to 6;
-G 3 is independently —H or -G B ;
-G 4 is independently —H or -G B
where -G B is independently selected from:
—F, —Cl, —Br, —I,
—CF 3 , —OCF 3 ,
—OH, —OR 2 ;
—[O—CH 2 CH 2 ] n —R B2 , where n is 2 to 6;
wherein:
—P 1 is independently —H or —P A ;
—P 2 is independently —H or —P B ;
—P 3 is independently —H or —P C ;
—P 4 is independently —H or —P B ;
—P 5 is independently —H or —P A ;
and wherein:
each —P A , each —P B , and each —P C is independently:
—F, —Cl, —Br, —I,
—R 2 ,
—CF 3 , —OCF 3 ,
—OH, -L 1 -OH,
—OR 2 , -L 1 -OR 2 , —O-L 1 -OR 2 ,
—SH, —SR 2 ,
—CN,
—NO 2 ,
—NH 2 , —NHR 2 , —NR 2 2 , —NR 3 R 4 ,
—NHOH,
-L 1 -NH 2 , -L 1 -NHR 2 , -L 1 -NR 2 2 , -L 1 -NR 3 R 4 ,
—O-L 1 -NH 2 , —O-L 1 -NHR 2 , —O-L 1 -NR 2 2 , —O-L 1 -NR 3 R 4 ,
—C(═O)OH, —C(═O)OR 2 ,
—OC(═O)R 2 ,
—C(═O)NH 2 , —C(═O)NHR 2 , —C(═O)NR 2 2 , —C(═O)NR 3 R 4 ,
—NHC(═O)R 2 , —NR 2 C(═O)R 2 ,
—C(═O)NHOR 2 , —C(═O)NR 2 OR 2 ,
—NHC(═O)OR 2 , —NR 2 C(═O)OR 2 ,
—OC(═O)NH 2 , —OC(═O)NHR 2 , —OC(═O)NR 2 2 , —OC(═O)NR 3 R 4 ,
—C(═O)R 2 ,
—NHC(═O)NH 2 , —NHC(═O)NHR 2 ,
—NHC(═O)NR 2 2 , —NHC(═O)NR 3 R 4 ,
—NR 2 C(═O)NH 2 , —NR 2 C(═O)NHR 2 ,
—NR 2 C(═O)NR 2 2 , —NR 2 C(═O)NR 3 R 4 ,
—NHS(═O) 2 R 2 , —NR 2 S(═O) 2 R 2 ,
—S(═O) 2 NH 2 , —S(═O) 2 NHR 2 , —S(═O) 2 NR 2 2 , —S(═O) 2 NR 3 R 4 ,
—S(═O)R 2 , —S(═O) 2 R 2 , —OS(═O) 2 R 2 , or —S(═O) 2 OR 2
wherein:
each -L 1 - is independently saturated aliphatic C 1-5 alkylene;
in each group —NR 3 R 4 , —R 3 and —R 4 , taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N, O, or S;
each —R 2 is independently:
—R A1 , —R A2 , —R A3 , —R A4 , —R A5 , —R A6 , —R A7 , —R A8 ,
L A -R A4 , -L A -R A5 , -L A -R A6 , -L A -R A7 , or -L A -R A8 ;
wherein:
each —R A1 is independently saturated aliphatic C 1-6 alkyl;
each —R A2 is independently aliphatic C 2-6 alkenyl;
each —R A3 is independently aliphatic C 2-6 alkynyl;
each —R A4 is independently saturated C 3-6 cycloalkyl;
each —R A5 is independently C 3-6 cycloalkenyl;
each —R A6 is independently non-aromatic C 3-7 heterocyclyl;
each —R A7 is independently C 6-10 -carboaryl;
each —R A8 is independently C 5-10 heteroaryl;
each -L A - is independently saturated aliphatic C 1-3 alkylene;
and wherein:
each —R A4 , —R A5 , —R A6 , —R A7 , and —R A8 is optionally substituted, for example, with one or more substituents —R B1 and/or one or more substituents —R B2 , and
each —R A1 , —R A2 , —R A3 , and -L A - is optionally substituted, for example, with one or more substituents —R B2 ,
wherein:
each —R B1 is independently saturated aliphatic C 1-4 -alkyl, phenyl, or benzyl;
each —R B2 is independently:
—F, —Cl, —Br, —I,
—CF 3 , —OCF 3 ,
—OH, -L C -OH, —O-L C -OH,
—OR C1 , -L C -OR C1 , —O-L C -OR C1 ,
—SH, —SR C1 ,
—CN,
—NO 2 ,
—NH 2 , —NHR C1 , —NR C1 2 , —NR C2 R C3 ,
-L C -NH 2 , -L C -NHR C1 , -L C -NR C1 2 , or -L C -NR C2 R C3 ,
—O-L C -NH 2 , —O-L C -NHR C1 , —O-L C -NR C1 2 , —O-L C -NR C2 R C3 ,
—C(═O)OH, —C(═O)OR C1 ,
—OC(═O)R C1 ,
—C(═O)R C1 ,
—C(═O)NH 2 , —C(═O)NHR C1 , —C(═O)NR C1 2 , —C(═O)NR C2 R C3 ,
—NHC(═O)R C1 , —NR C1 C(═O)R C1 ,
—NHS(═O) 2 R C1 , —NR C1 S(═O) 2 R C1 ,
—S(═O) 2 NH 2 , —S(═O) 2 NHR C1 , —S(═O) 2 NR C1 2 , —S(═O) 2 NR C2 R C3 , or
—S(═O) 2 R C1 ;
wherein:
each —R C1 is independently unsubstituted saturated aliphatic C 1-4 -alkyl, phenyl, or benzyl;
each -L C - is independently unsubstituted saturated aliphatic C 1-5 alkylene; and
in each group —NR C2 R C3 , —R C2 and —R C3 , taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N, O, or S,
and pharmaceutically and physiologically acceptable salts thereof,
with the proviso that the compound is not a compound:
(a) P-002 through P-015; and
(b) where -T is:
—R— is:
and —P is:
and —W 4 is —H, -Q- is —CH═CH—, -G 1 , -G 2 , -G 3 , and -G 4 are all —H, and
(i) —P 1 , —P 2 , —P 4 and —P 5 are all —H, and —P 3 is —R A1 ; or
(ii) one of —P 1 , —P 2 , —P 3 , P 4 and —P 5 is —R A7 , and the others of —P 1 , —P 2 , —P 3 , P 4 and —P 5 are —H.
2. A compound of formula:
wherein
—R— is independently selected from:
wherein (T) indicates the point of attachment to -T;
and (Q) indicates the point of attachment to -Q-;
-Q- is independently selected from:
—NHC(O)—; —NR 1 C(O)—;
each —R 1 is independently unsubstituted saturated aliphatic C 1-4 -alkyl;
—P is independently selected from:
where the asterisk indicates the point of attachment;
-T is independently selected from:
where the asterisk indicates the point of attachment;
and X is independently CH;
—W 1 is independently —W A ;
—W 2 is independently —H or —W A ;
—W 3 is independently —H or —W A ;
where —W A is independently selected from:
—F, —Cl, —Br, —I,
—OH, —W A1 , —O—W A1 ,
—NH 2 , —NHW A1 , and —N(W A1 ) 2 ;
and —W A1 is independently selected from:
unsubstituted saturated aliphatic C 1-4 -alkyl,
—CF 3 ,
—CH 2 CH 2 OH, and
—CH 2 CH 2 N(Me) 2 ;
-G 1 is independently —H or -G A ;
-G 2 is independently —H or -G A ;
where -G A is independently selected from:
—F, —Cl, —Br, —I,
—CF 3 , —OCF 3 ,
—OH, —OR 2 ;
—[O—CH 2 CH 2 ] n —R B2 , where n is 2 to 6;
-G 3 is independently —H or -G B ;
-G 4 is independently —H or -G B
where -G B is independently selected from:
—F, —Cl, —Br, —I,
—CF 3 , —OCF 3 ,
—OH, —OR 2 ;
—[O—CH 2 CH 2 ] n —R B2 , where n is 2 to 6;
wherein:
—P 1 is independently —H or —P A ;
—P 2 is independently —H or —P B ;
—P 3 is independently —H or —P C ;
—P 4 is independently —H or —P B ;
—P 5 is independently —H or —P A ;
and wherein:
each —P A , each —P B , and each —P C is independently:
—F, —Cl, —Br, —I,
—R 2 ,
—CF 3 , —OCF 3 ,
—OH, -L 1 -OH,
—OR 2 , -L 1 -OR 2 , —O-L 1 -OR 2 ,
—SH, —SR 2 ,
—CN,
—NO 2 ,
—NH 2 , —NHR 2 , —NR 2 2 , —NR 3 R 4 ,
—NHOH,
-L 1 -NH 2 , -L 1 -NHR 2 , -L 1 -NR 2 2 , -L 1 -NR 3 R 4 ,
—O-L 1 -NH 2 , —O-L 1 -NHR 2 , —O-L 1 -NR 2 2 , —O-L 1 -NR 3 R 4 ,
—C(═O)OH, —C(═O)OR 2 ,
—OC(═O)R 2 ,
—C(═O)NH 2 , —C(═O)NHR 2 , —C(═O)NR 2 2 , —C(═O)NR 3 R 4 ,
—NHC(═O)R 2 , —NR 2 C(═O)R 2 ,
—C(═O)NHOR 2 , —C(═O)NR 2 OR 2 ,
—NHC(═O)OR 2 , —NR 2 C(═O)OR 2 ,
—OC(═O)NH 2 , —OC(═O)NHR 2 , —OC(═O)NR 2 2 , —OC(═O)NR 3 R 4 ,
—C(═O)R 2 ,
—NHC(═O)NH 2 , —NHC(═O)NHR 2 ,
—NHC(═O)NR 2 2 , —NHC(═O)NR 3 R 4 ,
—NR 2 C(═O)NH 2 , —NR 2 C(═O)NHR 2 ,
—NR 2 C(═O)NR 2 2 , —NR 2 C(═O)NR 3 R 4 ,
—NHS(═O) 2 R 2 , —NR 2 S(═O) 2 R 2 ,
—S(═O) 2 NH 2 , —S(═O) 2 NHR 2 , —S(═O) 2 NR 2 2 , —S(═O) 2 NR 3 R 4 ,
—S(═O)R 2 , —S(═O) 2 R 2 , —OS(═O) 2 R 2 , or —S(═O) 2 OR 2
wherein:
each -L 1 - is independently saturated aliphatic C 1-5 alkylene;
in each group —NR 3 R 4 , —R 3 and —R 4 , taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N, O, or S;
each —R 2 is independently:
—R A1 , —R A2 , —R A3 , —R A4 , —R A5 , —R A6 , —R A7 , —R A8 ,
-L A -R A4 , -L A -R A5 -L A -R A6 , L A -R A7 , or -L A -R A8 ;
wherein:
each —R A1 is independently saturated aliphatic C 1-6 alkyl;
each —R A2 is independently aliphatic C 2-6 alkenyl;
each —R A3 is independently aliphatic C 2-6 alkynyl;
each —R A4 is independently saturated C 3-6 cycloalkyl;
each —R A5 is independently C 3-6 cycloalkenyl;
each —R A6 is independently non-aromatic C 3-7 heterocyclyl;
each —R A7 is independently C 6-10 -carboaryl;
each —R A8 is independently C 5-10 heteroaryl;
each -L A - is independently saturated aliphatic C 1-3 alkylene;
and wherein:
each —R A4 , —R A5 , —R A6 , —R A7 , and —R A8 is optionally substituted, for example, with one or more substituents —R B1 and/or one or more substituents —R B2 , and
each —R A1 , —R A2 , —R A3 , and -L A - is optionally substituted, for example, with one or more substituents —R B2 ,
wherein:
each —R B1 is independently saturated aliphatic C 1-4 -alkyl, phenyl, or benzyl;
each —R B2 is independently:
—F, —Cl, —Br, —I,
—CF 3 , —OCF 3 ,
—OH, -L C -OH, —O-L C -OH,
—OR C1 , -L C -OR C1 , —O-L C -OR C1 ,
—SH, —SR C1 ,
—CN,
—NO 2 ,
—NH 2 , —NHR C1 , —NR C1 2 , —NR C2 R C3 ,
-L C -NH 2 , -L C -NHR C1 , -L C -NR C1 2 , or -L C -NR C2 R C3 ,
—O-L C -NH 2 , —O-L C -NHR C1 , —O-L C -NR C1 2 , —O-L C -NR C2 R C3 ,
—C(═O)OH, —C(═O)OR C1 ,
—OC(═O)R C1 ,
—C(═O)R C1 ,
—C(═O)NH 2 , —C(═O)NHR C1 , —C(═O)NR C1 2 , —C(═O)NR C2 R C3 ,
—NHC(═O)R C1 , —NR C1 C(═O)R C1 ,
—NHS(═O) 2 R C1 , —NR C1 S(═O) 2 R C1 ,
—S(═O) 2 NH 2 , —S(═O) 2 NHR C1 , —S(═O) 2 NR C1 2 , —S(═O) 2 NR C2 R C3 , or
—S(═O) 2 R C1 ;
wherein:
each —R C1 is independently unsubstituted saturated aliphatic C 1-4 -alkyl, phenyl, or benzyl;
each -L C - is independently unsubstituted saturated aliphatic C 1-5 alkylene; and
in each group —NR C2 R C3 , —R C2 and —R C3 , taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N, O, or S,
and pharmaceutically and physiologically acceptable salts thereof.
3. A compound of formula:
wherein
—R— is independently selected from:
wherein (T) indicates the point of attachment to -T;
and (Q) indicates the point of attachment to -Q-;
-Q- is independently selected from:
—NHC(O)—; —NR 1 C(O)—;
each —R 1 is independently unsubstituted saturated aliphatic C 1-4 -alkyl;
—P is independently selected from:
where the asterisk indicates the point of attachment;
-T is independently selected from:
where the asterisk indicates the point of attachment;
—W 4 is independently —H or —W A ;
—W 5 is independently —H or —W A ;
—W 6 is independently —H or —W A ;
with the proviso that at least one of —W 4 , —W 5 and —W 6 is —W A ;
where —W A is independently selected from:
—F, —Cl, —Br, —I,
—OH, —W A1 , —O—W A1 ,
—NH 2 , —NHW A1 , and —N(W A1 ) 2 ;
and —W A1 is independently selected from:
unsubstituted saturated aliphatic C 1-4 -alkyl,
—CF 3 ,
—CH 2 CH 2 OH, and
—CH 2 CH 2 N(Me) 2 ;
-G 1 is independently —H or -G A ;
-G 2 is independently —H or -G A ;
where -G A is independently selected from:
—F, —Cl, —Br, —I,
—CF 3 , —OCF 3 ,
—OH, —OR 2 ;
—[O—CH 2 CH 2 ] n —R B2 , where n is 2 to 6;
-G 3 is independently —H or -G B ;
-G 4 is independently —H or -G B
where -G B is independently selected from:
—F, —Cl, —Br, —I,
—CF 3 , —OCF 3 ,
—OH, —OR 2 ;
—[O—CH 2 CH 2 ] n —R B2 , where n is 2 to 6;
wherein:
—P 1 is independently —H or —P A ;
—P 2 is independently —H or —P B ;
—P 3 is independently —H or —P C ;
—P 4 is independently —H or —P B ;
—P 5 is independently —H or —P A ;
and wherein:
each —P A , each —P B , and each —P C is independently:
—F, —Cl, —Br, —I,
—R 2 ,
—CF 3 , —OCF 3 ,
—OH, -L 1 -OH,
—OR 2 , -L 1 -OR 2 , —O-L 1 -OR 2 ,
—SH, —SR 2 ,
—CN,
—NO 2 ,
—NH 2 , —NHR 2 , —NR 2 2 , —NR 3 R 4 ,
—NHOH,
-L 1 -NH 2 , -L 1 -NHR 2 , -L 1 -NR 2 2 , -L 1 -NR 3 R 4 ,
—O-L 1 -NH 2 , —O-L 1 -NHR 2 , —O-L 1 -NR 2 2 , —O-L 1 -NR 3 R 4 ,
—C(═O)OH, —C(═O)OR 2 ,
—OC(═O)R 2 ,
—C(═O)NH 2 , —C(═O)NHR 2 , —C(═O)NR 2 2 , —C(═O)NR 3 R 4 ,
—NHC(═O)R 2 , —NR 2 C(═O)R 2 ,
—C(═O)NHOR 2 , —C(═O)NR 2 OR 2 ,
—NHC(═O)OR 2 , —NR 2 C(═O)OR 2 ,
—OC(═O)NH 2 , —OC(═O)NHR 2 , —OC(═O)NR 2 2 , —OC(═O)NR 3 R 4 ,
—C(═O)R 2 ,
—NHC(═O)NH 2 , —NHC(═O)NHR 2 ,
—NHC(═O)NR 2 2 , —NHC(═O)NR 3 R 4 ,
—NR 2 C(═O)NH 2 , —NR 2 C(═O)NHR 2 ,
—NR 2 C(═O)NR 2 2 , —NR 2 C(═O)NR 3 R 4 ,
—NHS(═O) 2 R 2 , —NR 2 S(═O) 2 R 2 ,
—S(═O) 2 NH 2 , —S(═O) 2 NHR 2 , —S(═O) 2 NR 2 2 , —S(═O) 2 NR 3 R 4 ,
—S(═O)R 2 , —S(═O) 2 R 2 , —OS(═O) 2 R 2 , or —S(═O) 2 OR 2
wherein:
each -L 1 - is independently saturated aliphatic C 1-5 alkylene;
in each group —NR 3 R 4 , —R 3 and —R 4 , taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N, O, or S;
each —R 2 is independently:
—R A1 , —R A2 , —R A3 , —R A4 , —R A5 , —R A6 , —R A7 , —R A8 ,
-L A -R A4 , -L A -R A5 , -L A -R A6 , -L A -R A7 , or -L A -R A8 ;
wherein:
each —R A1 is independently saturated aliphatic C 1-6 alkyl;
each —R A2 is independently aliphatic C 2-6 alkenyl;
each —R A3 is independently aliphatic C 2-6 alkynyl;
each —R A4 is independently saturated C 3-6 cycloalkyl;
each —R A5 is independently C 3-6 cycloalkenyl;
each —R A6 is independently non-aromatic C 3-7 heterocyclyl;
each —R A7 is independently C 6-10 -carboaryl;
each —R A8 is independently C 5-10 heteroaryl;
each -L A - is independently saturated aliphatic C 1-3 alkylene;
and wherein:
each —R A4 , —R A5 , —R A6 , —R A7 , and —R A8 is optionally substituted, for example, with one or more substituents —R B1 and/or one or more substituents —R B2 , and
each —R A1 , —R A2 , —R A3 , and -L A - is optionally substituted, for example, with one or more substituents —R B2 ,
wherein:
each —R B1 is independently saturated aliphatic C 1-4 -alkyl, phenyl, or benzyl;
each —R B2 is independently:
—F, —Cl, —Br, —I,
—CF 3 , —OCF 3 ,
—OH, -L C -OH, —O-L C -OH,
—OR C1 , -L C -OR C1 , —O-L C -OR C1 ,
—SH, —SR C1 ,
—CN,
—NO 2 ,
—NH 2 , —NHR C1 , —NR C1 2 , —NR C2 R C3 ,
-L C -NH 2 , -L C -NHR C1 , -L C -NR C1 2 , or -L C -NR C2 R C3 ,
—O-L C -NH 2 , —O-L C -NHR C1 , —O-L C -NR C1 2 , —O-L C -NR C2 R C3 ,
—C(═O)OH, —C(═O)OR C1 ,
—OC(═O)R C1 ,
—C(═O)R C1 ,
—C(═O)NH 2 , —C(═O)NHR C1 , —C(═O)NR C1 2 , —C(═O)NR C2 R C3 ,
—NHC(═O)R C1 , —NR C1 C(═O)R C1 ,
—NHS(═O) 2 R C1 , —NR C1 S(═O) 2 R C1 ,
—S(═O) 2 NH 2 , —S(═O) 2 NHR C1 , —S(═O) 2 NR C1 2 , —S(═O) 2 NR C2 R C3 , or
—S(═O) 2 R C1 ;
wherein:
each —R C1 is independently unsubstituted saturated aliphatic C 1-4 -alkyl, phenyl, or benzyl;
each -L C - is independently unsubstituted saturated aliphatic C 1-5 alkylene; and
in each group —NR C2 R C3 , —R C2 and —R C3 , taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N, O, or S;
wherein the compound contains a —F group;
and pharmaceutically and physiologically acceptable salts thereof;
with the proviso that the compound is not compound P-001.
4. A compound of formula:
wherein
—R— is independently selected from:
wherein (T) indicates the point of attachment to -T;
and (Q) indicates the point of attachment to -Q-;
-Q- is independently selected from:
—NHC(O)—; —NR 1 C(O)—;
—N═N—;
—CH═CH—; —CR 1 ═CH—; —CH═CR 1 —; —CR 1 ═CR 1 —;
each —R 1 is independently unsubstituted saturated aliphatic C 1-4 -alkyl;
—P is independently selected from:
where the asterisk indicates the point of attachment;
-T is independently selected from:
where the asterisk indicates the point of attachment;
and X is independently N;
—W 1 is independently H or —W A ;
where —W A is independently selected from:
—F, —Cl, —Br, —I,
—OH, —W A1 , —O—W A1 ,
—NH 2 , —NHW A1 , and —N(W A1 ) 2 ;
and —W A1 is independently selected from:
unsubstituted saturated aliphatic C 1-4 -alkyl,
—CF 3 ,
—CH 2 CH 2 OH, and
—CH 2 CH 2 N(Me) 2 ;
-G 1 is independently —H or -G A ;
-G 2 is independently —H or -G A ;
where -G A is independently selected from:
—F, —Cl, —Br, —I,
—CF 3 , —OCF 3 ,
—OH, —OR 2 ;
—[O—CH 2 CH 2 ] n —R B2 , where n is 2 to 6;
-G 3 is independently —H or -G B ;
-G 4 is independently —H or -G B
where -G B is independently selected from:
—F, —Cl, —Br, —I,
—CF 3 , —OCF 3 ,
—OH, —OR 2 ;
—[O—CH 2 CH 2 ] n —R B2 , where n is 2 to 6;
wherein:
—P 1 is independently —H or —P A ;
—P 2 is independently —H or —P B ;
—P 3 is independently —H or —P C ;
—P 4 is independently —H or —P B ;
—P 5 is independently —H or —P A ;
and wherein:
each —P A , each —P B , and each —P C is independently:
—F, —Cl, —Br, —I,
—R 2 ,
—CF 3 , —OCF 3 ,
—OH, -L 1 -OH,
—OR 2 , -L 1 -OR 2 , —O-L 1 -OR 2 ,
—SH, —SR 2 ,
—CN,
—NO 2 ,
—NH 2 , —NHR 2 , —NR 2 2 , —NR 3 R 4 ,
—NHOH,
-L 1 -NH 2 , -L 1 -NHR 2 , -L 1 -NR 2 2 , -L 1 -NR 3 R 4 ,
—O-L 1 -NH 2 , —O-L 1 -NHR 2 , —O-L 1 -NR 2 2 , —O-L 1 -NR 3 R 4 ,
—C(═O)OH, —C(═O)OR 2 ,
—OC(═O)R 2 ,
—C(═O)NH 2 , —C(═O)NHR 2 , —C(═O)NR 2 2 , —C(═O)NR 3 R 4 ,
—NHC(═O)R 2 , —NR 2 C(═O)R 2 ,
—C(═O)NHOR 2 , —C(═O)NR 2 OR 2 ,
—NHC(═O)OR 2 , —NR 2 C(═O)OR 2 ,
—OC(═O)NH 2 , —OC(═O)NHR 2 , —OC(═O)NR 2 2 , —OC(═O)NR 3 R 4 ,
—C(═O)R 2 ,
—NHC(═O)NH 2 , —NHC(═O)NHR 2 ,
—NHC(═O)NR 2 2 , —NHC(═O)NR 3 R 4 ,
—NR 2 C(═O)NH 2 , —NR 2 C(═O)NHR 2 ,
—NR 2 C(═O)NR 2 2 , —NR 2 C(═O)NR 3 R 4 ,
—NHS(═O) 2 R 2 , —NR 2 S(═O) 2 R 2 ,
—S(═O) 2 NH 2 , —S(═O) 2 NHR 2 , —S(═O) 2 NR 2 2 , —S(═O) 2 NR 3 R 4 ,
—S(═O)R 2 , —S(═O) 2 R 2 , —OS(═O) 2 R 2 , or —S(═O) 2 OR 2
wherein:
each -L 1 - is independently saturated aliphatic C 1-5 alkylene;
in each group —NR 3 R 4 , —R 3 and —R 4 , taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N, O, or S;
each —R 2 is independently:
—R A1 , —R A2 , —R A3 , —R A4 , —R A5 , —R A6 , —R A7 , —R A8 ,
-L A -R A4 , -L A -R A5 , -L A -R A6 , -L A -R A7 , or -L A -R A8 ;
wherein:
each —R A1 is independently saturated aliphatic C 1-6 alkyl;
each —R A2 is independently aliphatic C 2-6 alkenyl;
each —R A3 is independently aliphatic C 2-6 alkynyl;
each —R A4 is independently saturated C 3-6 cycloalkyl;
each —R A5 is independently C 3-6 cycloalkenyl;
each —R A6 is independently non-aromatic C 3-7 heterocyclyl;
each —R A7 is independently C 6-10 -carboaryl;
each —R A8 is independently C 5-10 heteroaryl;
each -L A - is independently saturated aliphatic C 1-3 alkylene;
and wherein:
each —R A4 , —R A5 , —R A6 , —R A7 , and R A8 is optionally substituted, for example, with one or more substituents —R B1 and/or one or more substituents —R B2 , and
each —R A1 , —R A2 , —R A3 , and -L A - is optionally substituted, for example, with one or more substituents —R B2 ,
wherein:
each —R B1 is independently saturated aliphatic C 1-4 -alkyl, phenyl, or benzyl;
each —R B2 is independently:
—F, —Cl, —Br, —I,
—CF 3 , —OCF 3 ,
—OH, -L C -OH, —O-L C -OH,
—OR C1 , -L C -OR C1 , —O-L C -OR C1 ,
—SH, —SR C1 ,
—CN,
—NO 2 ,
—NH 2 , —NHR C1 , —NR C1 2 , —NR C2 R C3 ,
-L C -NH 2 , -L C -NHR C1 , -L C -NR C1 2 , or -L C -NR C2 R C3 ,
—O-L C -NH 2 , —O-L C -NHR C1 , —O-L C -NR C1 2 , —O-L C -NR C2 R C3 ,
—C(═O)OH, —C(═O)OR C1 ,
—OC(═O)R C1 ,
—C(═O)R C1 ,
—C(═O)NH 2 , —C(═O)NHR C1 , —C(═O)NR C1 2 , —C(═O)NR C2 R C3 ,
—NHC(═O)R C1 , —NR C1 C(═O)R C1 ,
—NHS(═O) 2 R C1 , —NR C1 S(═O) 2 R C1 ,
—S(═O) 2 NH 2 , —S(═O) 2 NHR C1 , —S(═O) 2 NR C1 2 , —S(═O) 2 NR C2 R C3 , or
—S(═O) 2 R C1 ;
wherein:
each —R C1 is independently unsubstituted saturated aliphatic C 1-4 -alkyl, phenyl, or benzyl; and
each -L C - is independently unsubstituted saturated aliphatic C 1-5 alkylene; and
in each group —NR C2 R C3 , —R C2 and —R C3 , taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N, O, or S,
and pharmaceutically and physiologically acceptable salts thereof.
5. A compound according to any one of claims 1 to 4 , wherein -G A is independently selected from:
—F,
—CF 3 , —OCF 3 ,
—OH, and —OR 2 .
6. A compound according to any one of claims 1 to 4 , wherein -G B is independently selected from:
—F,
—CF 3 , —OCF 3 ,
—OH, —OR 2 ; and
—[O—CH 2 CH 2 ] n —R B2 , where n is 2 to 6.
7. A compound according to any one of claims 1 to 4 , wherein -G B is independently —OCH 2 CH 2 N(Me) 2 or [O—CH 2 CH 2 ] n —R B2 , where n is 2 to 6.
8. A compound according to any one of claims 1 to 4 , wherein —P is independently:
9. A compound according to claim 8 , wherein —P 1 and —P 5 are independently —H or —P A .
10. A compound according to claim 8 , wherein —P 2 and —P 4 are independently —H or —P B .
11. A compound according to claim 8 , wherein —P 3 is independently —H or —P C .
12. A compound according to claim 9 , wherein —P A is independently selected from:
—F,
—CF 3 , —OCF 3 ,
—OH,
—OR 2 ,
—NO 2 ,
—NH 2 , —NHR 2 , —NR 2 2 , and —NR 3 R 4 .
13. A compound according to claim 10 , wherein —P B is independently selected from:
—F,
—CF 3 , —OCF 3 ,
—NO 2 ,
—NH 2 , —NHR 2 , —NR 2 2 , and —NR 3 R 4 .
14. A compound according to claim 11 , wherein —P C is independently selected from:
—F, —Cl, —Br, —I,
—CF 3 , —OCF 3 ,
—OH, —OR 2 ,
—NO 2 ,
—NH 2 , —NHR 2 , —NR 2 2 , —NR 3 R 4 ,
—NHOH,
—OC(═O)R 2 , and
—NHC(═O)R 2 .
15. A compound according to claim 8 , wherein at least one of —P 1 , —P 2 , —P 3 , P 4 , and —P 5 is not —H.
16. A compound according to any one of claims 1 to 4 wherein —P is independently selected from:
17. A compound according to claim 16 , wherein —P 2 , —P 3 , and —P 4 are each independently —H.
18. A compound according to claim 1 or claim 3 , wherein —W 5 is independently —H.
19. A compound according to claim 18 , wherein —W 6 is independently —H.
20. A compound according to claim 18 , wherein —W 4 is independently —H or —W A .
21. A compound according to claim 20 wherein —W A is independently selected from —OH, —W A1 , and —O—W A1 .
22. A compound according to claim 21 , wherein —W A1 is independently -Me.
23. A compound according to claim 1 , claim 2 or claim 4 wherein —W 1 is independently —H or —W A .
24. A compound according to claim 23 , wherein —W A is independently —W A1 .
25. A compound according to claim 24 , wherein —W A1 is independently -Me.
26. A compound according to claim 1 or claim 2 wherein —W 2 is independently —H or —W A .
27. A compound according to claim 26 , wherein —W A is independently -Me.
28. A compound according to claim 1 or claim 2 , wherein —W 3 is independently —H or —W A .
29. A compound according to claim 28 , wherein —W A is independently -Me.
30. A compound according to any one of claims 1 to 4 , wherein the compound has a molecular weight of 500 or less.
31. A compound according to any one of claims 1 to 4 , wherein the compound has a miLog P of from 2.0 to 5.0.
32. A compound according to any one of claims 1 to 4 , wherein the compound has a Log D of from 2.0 to 5.0.
33. A compound according to any one of claims 1 to 4 , wherein the compound has a topological polar surface area of 90 Å 2 or less.
34. A compound according to any one of claims 1 to 4 , wherein the compound has 3 or less hydrogen bond donors.
35. A method of detecting and/or visualizing paired helical filaments (PHFs), the method comprising
(a) contacting the PHFs with a compound which binds to said PHFs; and
(b) detecting the presence of said compound;
wherein the compound which binds to said PHFs is a compound as defined in any one of claims 1 to 4 .
36. A method of detecting and/or visualizing aggregated tau molecules, the method comprising
(a) contacting the aggregated tau molecules with a compound which binds to said aggregated tau molecules; and
(b) detecting the presence of said compound;
wherein the compound which binds to said aggregated tau molecules is a compound as defined in any one of claims 1 to 4 .