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US 2024/0190831 A1Published application
Transthyretin stabilizing compounds
AssigneeProtego Biopharma, Inc.
InventorsRichard F. Labaudiniere, Bradley Dean Tait, Hank Michael James Petrassi
Life of this patent
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Abstract
Provided herein are compounds having activity against TTR related conditions, and pharmaceutically accepted salts and solvates thereof. Also provided are methods of using the compounds for inhibiting and preventing TTR aggregation and/or amyloid formation in the peripheral nerves, kidney, cardiac tissue, eye and CNS, and of treating a subject with peripheral TTR amyloidosis.
Claims149
A compound of Formula I:
- or a pharmaceutically acceptable salt or solvate thereof, wherein:
- A is
- X1 is O or NR5;
- X2 is H, halo, heteroaryl, CN, OR6 or NR7R8;
- n is an integer from 1-2;
- p is an integer from 0-3;
- Ar1 is aryl or heteroaryl, optionally substituted with halo, OR9, CN, COOH, CONR7R8, alkyl, haloalkyl, —(CR10R11)qOR9, —(CR10R11)qNR7R8 or —(CR10R11)qSH;
- q is an integer from 0-6;
- R1-R8 are selected from (i)-(viii):
- (i) R1, R2, R3 and R4 are each independently H, halo, haloalkyl, alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl (all optionally substituted);
- and R5, R6, R7 and R8 are each independently H, haloalkyl, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl (all optionally substituted) or —(CH2)mOR9;
- where m is an integer from 1-3;
- or
- (ii) R1 and R3 together with the atoms to which they are attached form a 3-6 membered ring, and R2 and R4-R8 are selected as above;
- or
- (iii) R1 and R5 together with the atoms to which they are attached form a 3-6 membered ring, and R2-R4 and R6-R8 are selected as above;
- or
- (iv) R1 and R7 together with the atoms to which they are attached form a 3-6 membered ring, and R2-R6 and R8 are selected as above;
- or
- (v) R1 and R6 together with the atoms to which they are attached form a 3-6 membered ring, and R2-R5 and R7-R8 are selected as above;
- or
- (vi) R3 and R5 together with the atoms to which they are attached form a 3-6 membered ring, and R1-R2, R4 and R6-R8 are selected as above;
- or
- (vii) R3 and R8 together with the atoms to which they are attached form a 3-6 membered ring, and R1-R2 and R4-R7 are selected as above;
- or
- (viii) R5 and R7 together with the atoms to which they are attached form a 3-6 membered ring, and R1-R4, R6 and R8 are selected as above;
- R9 is H, haloalkyl, alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl (all optionally substituted);
- and
- R10 and R11 are each independently H, halogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroaralkyl (all optionally substituted) or OR9.
26 more elements
A compound of Formula II:
- or a pharmaceutically acceptable salt or solvate thereof, wherein:
- A is
- X11 is O or NR26;
- X12 is N or C;
- X13 is N or C;
- X14 is CR29, N, ═CR29—CR35R36—, ═N—CR35R36— or ═CR29—NR27—;
- X15 is N or CR28;
- X16 is NR26 or CR25;
- t is an integer from 1-3 and y is an integer from 0-2, wherein t+y≥2;
- Ar11 is aryl or heteroaryl, optionally substituted with halo, OR30, CN, COOH, CONR31R32, alkyl, haloalkyl, —(CR33R34)qOR30, —(CR33R34)qNR31R32 or —(CR33R34)qSH or CF3;
- q is an integer from 0-6;
- R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R35 and R36 are each independently H, alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl (all optionally substituted);
- and
- R33 and R34 are independently H, alkyl, haloalkyl, cycloakyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroaralkyl (all optionally substituted) or OR30.
11 more elements
A compound selected from:
- Compound #
- Structure
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125 more elements
Dependencies are inferred from the claim text.