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US 2026/0199293 A1Published application
2-Arylbenzimidazole Compounds for the Treatment of Hemoglobinopathies
AssigneeTranquis Therapeutics, Inc.
InventorsSanjay Kumar Kakkar, Jonas O'Gara Hannestad
Life of this patent
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Abstract
The present disclosure provides 2-arylbenzimidazole compounds and pharmaceutical compositions or formulations thereof for the treatment of hemoglobinopathies in a subject. In some embodiments, the hemoglobinopathy is a sickle cell disease (SCD). The present disclosure also provides 2-arylbenzimidazole compounds and pharmaceutical compositions or formulations thereof for increasing fetal hemoglobin (HbF) production in a subject.
Claims39
A method of treating a hemoglobinopathy in a subject, comprising administering to a subject suffering from a hemoglobinopathy an effective amount of a compound of formula (I):
- or a pharmaceutically acceptable salt, solvate, deuterated derivative, or prodrug thereof, wherein:
- Ar is
- W1 is chosen from O, S, and N—R1, or, when W9 is N, W1 may additionally be C—R50;
- W2 is N or C—R2;
- W3 is N or C—R3;
- W4 is N or C—R4;
- W5 is N or C—R5;
- W6 is N or C—R6;
- W7 is N or C—R7;
- W8 is N or C—R8;
- W9 is C, or, when W1 is C—R50;
- W9 may be N;
- wherein:
- R1 is chosen from H, (C1-C3)alkyl, —CH2OC(═O)R30;
- —CH2OP(═O)OR40OR41, —C(═O)OR42, and —C(═O)R43;
- wherein:
- R30 is chosen from (C1-C10)hydrocarbyl, (C1-C10)hydrocarbyl substituted with amino, (C1-C10)hydrocarbyl substituted with (C1-C4)alkoxycarbonyl, (C1-C10)hydrocarbyl substituted with carboxyl, carboxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonylamino, methylthio, heterocyclyl, (C1-C10)oxaalkyl, CHR44NHR45, and guanidino;
- wherein:
- R44 is chosen from any naturally occurring amino acid sidechain;
- R45 is chosen from H, methyl, and (C1-C4)alkoxycarbonyl;
- R40 and R41 are chosen independently from hydrogen and (C1-C6)hydrocarbyl;
- R42 is (C1-C5)alkyl;
- R43 is (C1-C3)alkyl;
- and
- R50 is H or (C1-C3)alkyl;
- R2, R3, R4 and R5 are chosen independently from hydrogen, deuterium, halogen, perfluoro(C1-C4)alkyl, (C1-C4)alkyl, (C1-C4)alkoxy, perfluoro(C1-C4)alkoxy, (C1-C4)acyl, (C1-C4)alkoxy(C1-C4)alkyl, hydroxy(C1-C4)alkyl, hydroxy, carboxy, (C1-C4)alkoxycarbonylamino[—HNC(═O)O-alkyl], carboxamido[—C(═O)NH2], (C1-C4)alkylaminocarbonyl [—C(═O)NH-alkyl], cyano, acetoxy, nitro, amino, (C1-C4)alkylamino, di(C1-C4)alkylamino, mercapto, (C1-C4)alkylthio, aminosulfonyl, (C1-C4)alkylsulfonyl, and (C1-C4)acylamino;
- R6 and R10 are chosen independently from hydrogen, deuterium, halo, (C1-C3)alkyl, perfluoro(C1-C3)alkyl, hydroxy, (C1-C3)alkoxy, perfluoro(C1-C3)alkoxy, and amino;
- R7 and R9 are chosen independently from hydrogen, deuterium, hydroxy, cyano, amino, halogen, halo(C1-C4)alkyl, (C1-C4)alkyl, (C1-C4)alkoxy, and halo(C1-C4)alkoxy,
- and
- R8 is chosen from hydrogen, deuterium, halogen, halo(C1-C4)alkyl, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano, phenyl, phenoxy, benzyloxy, and amino,
- with the proviso that:
- i) when Ar is
- R8 is not (C1-C4)alkyl when:
- (a) W1 is N—R1;
- (b) R1 is hydrogen;
- (c) W2, W3, W4, W5, W6, and W7 are C—H;
- (d) W8 is C—R8;
- (e) W9 is C;
- and
- (f) R9 and R10 are hydrogen.
37 more elements
35-38. (canceled)
A method of increasing fetal hemoglobin (HbF) production, the method comprising administering to the subject in need of increased HbF production an effective amount of a compound of formula I:
- or a pharmaceutically acceptable salt, solvate, deuterated derivative, or prodrug thereof,
- wherein:
- Ar is
- W1 is chosen from O, S, and N—R1, or, when W9 is N, W1 may additionally be C—R50;
- W2 is N or C—R2;
- W3 is N or C—R3;
- W4 is N or C—R4;
- W5 is N or C—R5;
- W6 is N or C—R6;
- W7 is N or C—R7;
- W8 is N or C—R8;
- W9 is C, or, when W1 is C—R50;
- W9 may be N;
- wherein:
- R1 is chosen from H, (C1-C3)alkyl, —CH2OC(═O)R30;
- —CH2OP(═O)OR40OR41, —C(═O)OR42, and —C(═O)R43;
- wherein:
- R30 is chosen from (C1-C10)hydrocarbyl, (C1-C10)hydrocarbyl substituted with amino, (C1-C10)hydrocarbyl substituted with (C1-C4)alkoxycarbonyl, (C1-C10)hydrocarbyl substituted with carboxyl, carboxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonylamino, methylthio, heterocyclyl, (C1-C10)oxaalkyl, CHR44NHR45, and guanidino;
- wherein:
- R44 is chosen from any naturally occurring amino acid sidechain;
- R45 is chosen from H, methyl, and (C1-C4)alkoxycarbonyl;
- R40 and R41 are chosen independently from hydrogen and (C1-C6)hydrocarbyl;
- R42 is (C1-C5)alkyl;
- R43 is (C1-C3)alkyl;
- and
- R50 is H or (C1-C3)alkyl;
- R2, R3, R4 and R5 are chosen independently from hydrogen, deuterium, halogen, perfluoro(C1-C4)alkyl, (C1-C4)alkyl, (C1-C4)alkoxy, perfluoro(C1-C4)alkoxy, (C1-C4)acyl, (C1-C4)alkoxy(C1-C4)alkyl, hydroxy(C1-C4)alkyl, hydroxy, carboxy, (C1-C4)alkoxycarbonylamino[—HNC(═O)O-alkyl], carboxamido[—C(═O)NH2], (C1-C4)alkylaminocarbonyl [—C(═O)NH-alkyl], cyano, acetoxy, nitro, amino, (C1-C4)alkylamino, di(C1-C4)alkylamino, mercapto, (C1-C4)alkylthio, aminosulfonyl, (C1-C4)alkylsulfonyl, and (C1-C4)acylamino;
- R6 and R10 are chosen independently from hydrogen, deuterium, halo, (C1-C3)alkyl, perfluoro(C1-C3)alkyl, hydroxy, (C1-C3)alkoxy, perfluoro(C1-C3)alkoxy, and amino;
- R7 and R9 are chosen independently from hydrogen, deuterium, hydroxy, cyano, amino, halogen, halo(C1-C4)alkyl, (C1-C4)alkyl, (C1-C4)alkoxy, and halo(C1-C4)alkoxy,
- R8 is chosen from hydrogen, deuterium, halogen, halo(C1-C4)alkyl, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano, phenyl, phenoxy, benzyloxy, and amino,
- with the proviso that:
- i) when Ar is
- R8 is not (C1-C4)alkyl when:
- (a) W1 is N—R1;
- (b) R1 is hydrogen;
- (c) W2, W3, W4, W5, W6, and W7 are C—H;
- (d) W1 is C—R8;
- (e) W9 is C;
- and
- (f) R9 and R10 are hydrogen.
37 more elements
A method of treating a hemoglobinopathy, comprising:
- administering to a subject suffering from a hemoglobinopathy an effective amount of a pharmaceutical composition comprising an amorphous solid dispersion of 2-(4-tert-butylphenyl)-1H-benzimidazole (TQS-168) or a pharmaceutically acceptable salt, solvate, deuterated derivative, or prodrug thereof;
- and a pharmaceutically acceptable carrier matrix.
41-111. (canceled)
A method of increasing fetal hemoglobin (HbF) production, the method comprising:
- administering to a subject in need of increased HbF production an effective amount of a pharmaceutical composition comprising an amorphous solid dispersion of 2-(4-tert-butylphenyl)-1H-benzimidazole (TQS-168) or a pharmaceutically acceptable salt, solvate, deuterated derivative or prodrug thereof, and
- a pharmaceutically acceptable carrier matrix.
Dependencies are inferred from the claim text.