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US 12,636,385 B2Granted
Selective ligands for tau aggregates
AssigneeSentonix, Inc.
InventorDaniel Dungan Sohn
Life of this patent
Estimating the term…
Abstract
The invention provides a compound of formula (I): or a pharmaceutically acceptable salt, ester, amide or carbamate thereof, or a salt of such an ester, amide or carbamate. The invention further provides uses of the compounds of formula (I) and compositions comprising compounds of formula (I), including the use of such compounds for the detection of tau deposits, and the use of such compounds and compositions as diagnostic agents in the diagnosis or monitoring of the progression of a disease or disorder such as Alzheimer's disease, corticobasal degeneration and progressive supranuclear palsy, or for the prevention or treatment of a disease or disorder such as Alzheimer's disease, corticobasal degeneration and progressive supranuclear palsy.
Claims19
A compound of formula (I), or a pharmaceutically acceptable salt thereof,
- wherein
- A is
- and
- A1 and A4 are independently selected from the group consisting of N and CH;
- A2 is selected from the group consisting of N, CR2 and CH, and A3 is selected from the group consisting of N and CH, wherein at least two of A1, A2, A3, and A4 are CH, or wherein A2 is CR2 and at least one of A1, A3 and A4 is CH;
- or
- A2 is selected from the group consisting of N and CH, and A3 is selected from the group consisting of N, CR2 and CH, wherein at least two of A1, A2, A3, and A4 are CH, or wherein A3 is CR2 and at least one of A1, A2 and A4 is CH;
- provided at least one of A2 and A3 is CR2;
- W is selected from the group consisting of O, S and NH;
- X is selected from the group consisting of N and CH, with a proviso that if W is NH then X is CH;
- and with a proviso that if W is S, X is N;
- or A is
- and
- A2 is selected from the group consisting of N, CR2 and CH and A3 is selected from the group consisting of N and CH, or A2 is selected from the group consisting of N and CH and A3 is selected from the group consisting of N, CR2 and CH;
- provided at least one of A2 and A3 is CR2;
- B1, B2, and B3, are each independently selected from the group consisting of N, CH and CR3, wherein at least one of B1, B2, and B3 is CH or CR3;
- R1 is selected from the group consisting of halogen;
- —OH;
- —CN;
- —C1-6alkyl optionally substituted with 1, 2 or 3 halogen or OH groups;
- —O—C1-6alkyl optionally substituted with 1, 2 or 3 halogen or OH groups;
- C1-3alkyl-O—C1-6alkyl optionally substituted with 1, 2 or 3 halogen or OH groups;
- —C1-6alkyl-O—S(O)2-C1-3alkyl optionally substituted with 1, 2 or 3 halogen or OH groups;
- —C1-6alkyl-S(O)2—O—C1-3alkyl optionally substituted with 1, 2 or 3 halogen or OH groups;
- —C1-6alkyl-O—S(O)2-phenyl wherein said phenyl is optionally substituted with 1 C1-3alkyl group and said C1-3alkyl is optionally substituted with 1, 2 or 3 halogen;
- —C1-6alkyl-S(O)2—O-phenyl wherein said phenyl is optionally substituted with 1 C1-3alkyl group and said C1-3alkyl is optionally substituted with 1, 2 or 3 halogen;
- —C1-6alkyl-O—S(halogen)2N(Rb)2;
- —N(Rc)2;
- —C1-6alkylN(Rc)2;
- —C(O)—N(R4)2;
- N(R4)C(O)H;
- N(R4)C(O)C1-6alkyl optionally substituted with 1, 2 or 3 halogen;
- —C1-6alkyl-C(O)—N(Rd)2;
- —O—C1-6alkyl-C(O)—N(R4)2;
- —C(O)—O—C1-6alkyl optionally substituted with 1, 2 or 3 halogen;
- —O—C(O)C1-6alkyl optionally substituted with 1, 2 or 3 halogen;
- —C1-6alkyl-C(O)—O—C1-6alkyl optionally substituted with 1, 2 or 3 halogen;
- C1-6alkyl-O—C(O)C1-6alkyl optionally substituted with 1, 2 or 3 halogen;
- —(CH2CH2O)p—Re;
- —(CH2CH2O)p—CH2CH2—Rf;
- and —(OCH2CH2)p—Rf;
- each R2 is independently selected from the group consisting of halogen;
- OH;
- CN;
- C1-6alkyl optionally substituted with 1, 2 or 3 halogen or OH groups;
- O—C1-6alkyl optionally substituted with 1, 2 or 3 halogen or OH groups;
- C2-6alkenyl;
- C2-6alkynyl;
- C(O)C1-6alkyl optionally substituted with 1, 2 or 3 halogen;
- C(O)—O—C1-6alkyl optionally substituted with 1, 2 or 3 halogen;
- —O—Si(C1-6alkyl)3 optionally substituted with 1, 2 or 3 halogen;
- C1-6alkylS;
- C1-6alkylS═O;
- C1-6alkylSO2;
- NO2;
- —N(Ra)2;
- C1-6alkylN(Ra)2;
- —N(Ra)C(O)H;
- —N(Ra)C(O)C1-6alkyl optionally substituted with 1, 2 or 3 halogen;
- C(O)N(Rg)2;
- and —C1-6alkylC(O)N(Rg)2;
- R3 is selected from the group consisting of halogen;
- OH;
- C1-6alkyl optionally substituted with 1, 2 or 3 halogen;
- and —OC1-6alkyl optionally substituted with 1, 2 or 3 halogen;
- Ra, Rb, Rc and Rd are each independently selected from the group consisting of H and C1-6alkyl optionally substituted with 1, 2 or 3 halogen;
- Re is selected from the group consisting of H and C1-6alkyl optionally substituted with 1, 2 or 3 halogens;
- Rf is selected from the group consisting of H;
- halogen;
- —CH2(halogen), —CH(halogen)2, C(halogen)3, and OH;
- each Rg is independently selected from the group consisting of H;
- C1-6alkyl;
- C1-6alkyl substituted with 1, 2 or 3 halogen;
- C1-6alkyl substituted with 1, 2 or 3 OH group;
- C1-6alkyl substituted with 1, 2 or 3 —OC1-3alkyl groups;
- C1-6alkyl substituted with a —OS(O)2CH3 group;
- and C1-6alkyl substituted with a —S(O)2OCH3 group;
- and
- p is 2, 3, 4, 5, 6, 7 or 8.
76 more elements
A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof,
- wherein
- A is
- and
- A1 and A4 are independently selected from the group consisting of N and CH;
- A2 is selected from the group consisting of N, CR2 and CH, and A3 is selected from the group consisting of N and CH, wherein at least two of A1, A2, A3, and A4 are CH, or wherein A2 is CR2 and at least one of A1, A3 and A4 is CH;
- or
- A2 is selected from the group consisting of N and CH, and A3 is selected from the group consisting of N, CR2 and CH, wherein at least two of A1, A2, A3, and A4 are CH, or wherein A3 is CR2 and at least one of A1, A2 and A4 is CH;
- provided at least one of A2 and A3 is CR2;
- W is selected from the group consisting of O, S and NH;
- X is selected from the group consisting of N and CH, with a proviso that if W is NH then X is CH;
- and with a proviso that if W is S, X is N;
- or A is
- and
- A2 is selected from the group consisting of N, CR2 and CH and A3 is selected from the group consisting of N and CH, or A2 is selected from the group consisting of N and CH and A3 is selected from the group consisting of N, CR2 and CH;
- provided at least one of A2 and A3 is CR2;
- B1, B2, and B3, are each independently selected from the group consisting of N, CH and CR3, wherein at least one of B1, B2, and B3 is CH or CR3;
- R1 is selected from the group consisting of halogen;
- OH;
- —CN;
- —C1-6alkyl optionally substituted with 1, 2 or 3 halogen or OH groups;
- —O—C1-6alkyl optionally substituted with 1, 2 or 3 halogen or OH groups;
- C1-3alkyl-O—C1-6alkyl optionally substituted with 1, 2 or 3 halogen or OH groups;
- —C1-6alkyl-O—S(O)2—C1-3alkyl optionally substituted with 1, 2 or 3 halogen or OH groups;
- —C1-6alkyl-S(O)2—O—C1-3alkyl optionally substituted with 1, 2 or 3 halogen or OH groups;
- —C1-6alkyl-O—S(O)2-phenyl wherein said phenyl is optionally substituted with 1 C1-3alkyl group and said C1-3alkyl is optionally substituted with 1, 2 or 3 halogen;
- —C1-6alkyl-S(O)2—O-phenyl wherein said phenyl is optionally substituted with 1 C1-3alkyl group and said C1-3alkyl is optionally substituted with 1, 2 or 3 halogen;
- —C1-6alkyl-O—S(halogen)2N(Rb)2;
- —N(Rc)2;
- —C1-6alkylN(Rc)2;
- —C(O)—N(R4)2;
- N(R4)C(O)H;
- N(R4)C(O)C1-6alkyl optionally substituted with 1, 2 or 3 halogen;
- —C1-6alkyl-C(O)—N(R4)2;
- —O—C1-6alkyl-C(O)—N(R4)2;
- —C(O)—O—C1-6alkyl optionally substituted with 1, 2 or 3 halogen;
- —O—C(O)C1-6alkyl optionally substituted with 1, 2 or 3 halogen;
- —C1-6alkyl-C(O)—O—C1-6alkyl optionally substituted with 1, 2 or 3 halogen;
- C1-6alkyl-O—C(O)C1-6alkyl optionally substituted with 1, 2 or 3 halogen;
- —(CH2CH2O)p—Re;
- —(CH2CH2O)p—CH2CH2Rf;
- and —(OCH2CH2)p—Rf;
- each R2 is independently selected from the group consisting of halogen;
- OH;
- CN;
- C1-6alkyl optionally substituted with 1, 2 or 3 halogen or OH groups;
- O—C1-6alkyl optionally substituted with 1, 2 or 3 halogen or OH groups;
- C2-6alkenyl;
- C2-6alkynyl;
- C(O)C1-6alkyl optionally substituted with 1, 2 or 3 halogen;
- C(O)—O—C1-6alkyl optionally substituted with 1, 2 or 3 halogen;
- —O—Si(C1-6alkyl)3 optionally substituted with 1, 2 or 3 halogen;
- C1-6alkylS;
- C1-6alkylS═O;
- C1-6alkylSO2;
- NO2;
- —N(Ra)2;
- —C1-6alkylN(Ra)2;
- —N(Ra)C(O)H;
- —N(Ra)C(O)C1-6alkyl optionally substituted with 1, 2 or 3 halogen;
- C(O)N(Rg)2;
- and —C1-6alkylC(O)N(Rg)2;
- R3 is selected from the group consisting of halogen;
- OH;
- C1-6alkyl optionally substituted with 1, 2 or 3 halogen;
- and —OC1-6alkyl optionally substituted with 1, 2 or 3 halogen;
- Ra, Rb, Rc and Rd are each independently selected from the group consisting of H and C1-6alkyl optionally substituted with 1, 2 or 3 halogen;
- Re is selected from the group consisting of H or C1-6alkyl optionally substituted with 1, 2 or 3 halogens;
- Rf is selected from the group consisting of H;
- halogen;
- —CH2(halogen),
- —CH(halogen)2,
- —C(halogen)3, and OH;
- each Rg is independently selected from the group consisting of H;
- C1-6alkyl;
- C1-6alkyl substituted with 1, 2 or 3 halogen;
- C1-6alkyl substituted with 1, 2 or 3 OH group;
- C1-6alkyl substituted with 1, 2 or 3-OC1-3alkyl groups;
- C1-6alkyl substituted with a —OS(O)2CH3 group;
- and C1-6alkyl substituted with a —S(O)2OCH3 group;
- and
- p is 2, 3, 4, 5, 6, 7 or 8;
- together with a pharmaceutically suitable carrier.
79 more elements
Dependencies are inferred from the claim text.