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US 2025/0066349 A1Published application
Cyclic compounds and their use for the treatment of neurological disorders
AssigneeProthena Biosciences Limited
InventorStéphane DE LOMBAERT
Life of this patent
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Abstract
This disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, that inhibit Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A). These chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) DYRK1A activation contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., a neurological disorder) in a subject (e.g., a human). This disclosure also provides compositions containing the same as well as methods of using and making the same.
Claims61
A compound of Formula (I):
- or a pharmaceutically acceptable salt thereof, wherein:
- each dashed line represents a single bond or a double bond;
- X1 is CR1AR1B, NRA, S, or O;
- X2 is CR2AR2B, C(═O), or NRB;
- X3 is CR3AR3B, NRC, S, or O;
- X4 is CR4 or N;
- X5 is CR5 or N;
- X6 is CR6 or N;
- X7 is CH, CF, or N;
- R1A is hydrogen, C1-C6 alkyl, —C(═O)NRFRG, —(C0-C6 alkyl)-5-6 membered heteroaryl,
- —C(═O)-3-6 membered heterocyclyl optionally substituted with C1-C6 alkyl, a phenyl optionally substituted with halogen or —CO2H, a 3-6 membered heterocyclyl optionally substituted with C1-C6 alkyl or —S(O2)—C1-C6 alkyl, or a C3-C6 cycloalkyl optionally substituted with hydroxyl, —C(═O)NRFRG, —NRFRG, —CO2RH, or C1-C6 alkoxy;
- R1B is hydrogen or absent, wherein R1B is absent when x1x2 is a double bond;
- R2A is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 5-6 membered heteroaryl, a phenyl optionally substituted with —CO2H, or a 3-6 membered heterocyclyl optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or —(C0-C6 alkyl)-3-6 membered cycloalkyl optionally substituted with —CO2H;
- R2B is hydrogen or absent, wherein R2B is absent when either of x1x2 or x2x3 is a double bond;
- R3A is hydrogen;
- R3B is hydrogen, C1-C6 alkyl, or absent, wherein R3B is absent when x2x3 is a double bond;
- R4 is hydrogen, halogen, C1-C6 alkyl, or 3-6 membered heterocyclyl optionally substituted with C1-C6 alkyl;
- R5 is hydrogen, —CO2H, —C(═O)OCH3, C1-C6 alkyl optionally substituted with hydroxyl, or a 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl;
- R6 is hydrogen or a 5-6 membered heteroaryl optionally substituted with 1-2 substituents independently selected from RD, C1-C6 alkyl, and 4-6 membered heterocyclyl optionally substituted with hydroxyl;
- RA and RB are independently absent, hydrogen, C1-C6 alkyl optionally substituted with 3-6 membered heterocyclyl or 5-6 membered heteroaryl, or a C3-C6 cycloalkyl optionally substituted with hydroxyl or C1-C6 alkoxy;
- RC is absent, hydrogen, or methyl;
- RD is
- RE is a C1-C6 alkyl, phenyl, 5-6 membered heteroaryl, or 4-6 membered heterocyclyl;
- wherein the C1-C6 alkyl, phenyl, 5-6 membered heteroaryl, and 4-6 membered heterocyclyl are each optionally substituted with 1-2 independently selected R1;
- each RF and RG are independently selected from hydrogen and C1-C6 alkyl;
- or RF and RG together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl;
- RH is hydrogen or C1-C6 alkyl;
- each RI is independently C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, cyano, or trifluoromethyl.
25 more elements
A compound of Formula (II):
- or a pharmaceutically acceptable salt thereof, wherein:
- each dashed line represents a single bond or a double bond;
- Rings A and B are aromatic;
- Ring W is a 9 membered heteroaryl, a 9 membered heterocyclyl, or a 9 membered cycloalkyl;
- each RX is independently selected from C1-C6 alkyl, 3-6 membered heterocyclyl optionally substituted with C1-C6 alkyl, and C3-C6 cycloalkyl;
- X1 is CH, S, N, or NRA;
- X2 is N, CH, or CR2;
- X3 is N, NRB, O, CR3, or CH;
- X4 is CH or N;
- R2 is benzyl or
- R3 is C1-C6 alkyl;
- RA is C1-C6 alkyl or C3-C6 cycloalkyl;
- RB is hydrogen or C3-C6 cycloalkyl;
- RC is 3-6 membered heterocyclyl optionally substituted with C1-C6 alkyl;
- m is 0, 1, or 2;
- and
- n is 0 or 1.
14 more elements
A compound of Formula (III):
- or a pharmaceutically acceptable salt thereof, wherein:
- each dashed line represents a single bond or a double bond;
- Rings A and B are aromatic;
- Ring C is aromatic or partially saturated;
- X1 is C or N;
- X2 is CH, O, or S;
- X3 is CH or N;
- X4 is C or N;
- X5 is CH, C(═O), O, S, NH, or NRA;
- X6 is CH, N, or O;
- X7 is CH, CR7, CH2, CRBRC, or N;
- R1 is hydrogen or —XRD;
- R2 is hydrogen, —NHC(═O)-3-6 membered heterocyclyl optionally substituted with C1-C6 haloalkyl, or joins with the bond denoted with *;
- R7 is C1-C6 alkyl optionally substituted with a 3-6 membered heterocyclyl optionally substituted with C(═O)OH;
- RA is -(3-6 membered heterocyclyl)m-(C1-C6 alkyl)n;
- RB and RC are independently hydrogen or C1-C6 alkyl;
- X is ethynylene, —NHC(═O)—, or —NHC(═O)OCH2—;
- RD is 3-6 membered heterocyclyl optionally substituted with C1-C6 alkyl, 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, or C6-C10 aryl optionally substituted with C1-C6 alkyl;
- m is 0 or 1;
- and
- n is 0, 1, or 2;
- provided that when n is 2, m is 1.
19 more elements
A compound of Formula (IV):
- or a pharmaceutically acceptable salt thereof, wherein:
- Ring A is a 12-14 membered fused tricyclic heterocyclyl comprising 2-5 nitrogen atoms or a 12-14 membered fused tricyclic heteroaryl comprising 2-5 nitrogen atoms;
- R1 is cyano, C1-C6 alkyl, —NHC(═O)(C1-C6 alkylene)nRA, -Q-phenyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, and C1-C6 alkoxy;
- C3-C6 cycloalkyl optionally substituted with hydroxyl, —(C1-C6 alkylene)p-5-10 membered heteroaryl, or 5-10 membered heterocyclyl;
- R2 is hydrogen, cyano, C1-C6 alkyl, —C(═O)—C1-C6 alkyl, —(SO2)C1-C6 alkyl, —CO2RB, C1-C6 alkoxy optionally substituted with —NRCRD;
- RA is 4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl, or 5-10 membered heteroaryl optionally substituted with C1-C6 alkoxy or C1-C6 alkyl;
- RB, RC, and RD are independently hydrogen or C1-C6 alkyl;
- Q is a bond or O;
- m is 0 or 1;
- n is 0 or 1;
- and
- p is 0 or 1.
9 more elements
Dependencies are inferred from the claim text.