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AssigneeAuckland Uniservices Limited
InventorsSwarnalatha Akuratiya GAMAGE, Peter Robin SHEPHERD, Jack Urquhart FLANAGAN, Gordon William REWCASTLE, Andrew James MARSHALL, Christina Maree BUCHANAN, Guo-Liang LU, Muriel BONNET, Stephen Michael Frazer JAMIESON, William Alexander DENNY
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Disclosed are tricyclic heterocyclic compounds having kinase inhibitory activity, pharmaceutical compositions and kits comprising the compounds, and use of the compounds in the treatment of or in medicaments for the treatment of various diseases and conditions. In particular, disclosed are tricyclic heterocyclic compounds of the formula (I) having CSF-1R (c-FMS kinase) inhibitory activity and their use in the treatment of various diseases and conditions, such as those mediated by CSF-1R, including proliferative or neoplastic diseases and conditions, including cancers, and bone, inflammatory, and autoimmune diseases and conditions.
A compound of formula (I):
The compound of any one of the preceding claims, wherein X is NR4, O, S, SO, or SO2.
The compound of any one of the preceding claims, wherein X is NR4, O, or S.
The compound of any one of the preceding claims, wherein X is O or S.
The compound of any one of the preceding claims wherein:
The compound of any one of the preceding claims wherein:
The compound of any one of the preceding claims, wherein:
The compound of any one of the preceding claims, wherein:
The compound of any one of the preceding claims, wherein R9a and R10a are each independently H or unsubstituted C1-6alkyl, for example CH3.
The compound of any one of the preceding claims, wherein Y is CH2, CO, CH2NR5, CH2O, CH2S, CH2SO2, CONR5, NR5, NR5CO, NR5SO2, O, OCH2, S, SO, SO2, SCH2, SO2CH2, or SO2NR5.
The compound of any one of the preceding claims, wherein Y is O, NR5, CH2, CO, S, SO, or SO2.
The compound of any one of the preceding claims, wherein Y is O, CH2, CO, or S.
The compound of any one of the preceding claims, wherein Y is O.
The compound of any one of the preceding claims, wherein W is an optionally substituted phenyl or an optionally substituted 5 or 6-membered heteroaryl.
The compound of any one of the preceding claims, wherein W is an optionally substituted phenyl or an optionally substituted 6-membered heteroaryl, for example an optionally substituted 6-membered heteroaryl comprising from one to three ring nitrogen atoms, one or two ring nitrogen atoms, or one ring nitrogen atom.
The compound of any one of the preceding claims, wherein R3 is H.
A pharmaceutical composition comprising a compound of the formula (I) according to any one of the preceding claims or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof;
A kit comprising a compound of the formula (I) according to any one of the preceding claims or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof;
A method of inhibiting CSF-1R in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the formula (I) according to any one of the preceding claims or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
A method of treating a disease or condition mediated by CSF-1R in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the formula (I) according to any one of the preceding claims or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
A method of treating a disease or condition selected from the group consisting of proliferative or neoplastic disease and conditions including cancers;
A compound of the formula (I) according to any one of the preceding claims or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof for use in inhibiting CSF-1R.
A compound of the formula (I) according to any one of the preceding claims or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof for use in treating a disease or condition mediated by CSF-1R.
A compound of the formula (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof for use in treating a disease or condition selected from the group consisting of proliferative or neoplastic disease and conditions including cancers;
Use of a compound of formula (I) according to any one of the preceding claims or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof in the manufacture of a medicament for inhibiting CSF-1R.
Use of a compound of formula (I) according to any one of the preceding claims or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof in the manufacture of a medicament for treating a disease or condition mediated by CSF-1R.
Use of a compound of formula (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof in the manufacture of a medicament for treating a disease or condition selected from the group consisting of proliferative or neoplastic disease and conditions including cancers;
Use of:
Use of:
Use of:
A method of inhibiting CSF-1R comprising contacting a cell and a compound of the formula (I) according to any one of the preceding claims or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof in an amount effective to inhibit CSF-1R.
The compound, pharmaceutical composition, kit, method, compound for use, or use according to any one of the preceding claims, wherein the compound of formula (I) has an IC50 value for the inhibition of CSF-1R of about 50 μM or less, for example 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, or 3 μM or less.
The compound, pharmaceutical composition, kit, method, compound for use, or use according to any one of the preceding claims, wherein the compound of formula (I) has an IC50 value for the inhibition of CSF-1R at least about 5 fold less, preferably 10, 15, 20, 25, 30, 40, 50, 75, or 100 fold less, than the IC50 value for the inhibition of VEGFR2.
Dependencies are inferred from the claim text.