C2-carbocyclic iminothiazine dioxides as BACE inhibitors, compositions, and their use
In its many embodiments, the present invention provides certain C2-carbocyclic iminothiazine dioxide compounds, including compounds Formula (I); or a tautomers thereof, and pharmaceutically acceptable salts of said compounds and said tautomers, wherein R 1 , R 2 , ring A, R A , m, ring B, RB, n, ring C, R C and p are as defined herein. The novel compounds of the invention are useful as BACE inhibitors and/or for the treatment and prevention of various pathologies related thereto. Pharmaceutical compositions comprising one or more such compounds (alone and in combination with one or more other active agents), and methods for their preparation and use, including for the possible treatment of Alzheimer's disease, are also disclosed.
1. A compound, or a pharmaceutically acceptable salt thereof, said compound having the structural Formula (I):
or a tautomer thereof having the structural Formula (I′):
or pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of H, halogen, lower alkyl, and lower heteroalkyl, wherein said lower alkyl and said lower heteroalkyl is optionally substituted with one or more halogen;
R 2 is selected from the group consisting of H, lower alkyl, lower cycloalkyl, and lower heteroalkyl, wherein said lower alkyl, lower cycloalkyl, and said lower heteroalkyl are optionally substituted with one or more halogen;
ring A is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl;
m is 0, 1, 2, or 3;
each R A (when present) is independently selected from the group consisting of halogen, —CN, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , cyclopropyl, —CH 2 OCH 3 , —CF 3 , —CHF 2 , —CH 2 F, —OCH 3 , —O-cyclopropyl, —O—CH 2 -cyclopropyl, —OCF 3 , —OCHF 2 , and —OCH 2 F;
ring B is heteroaryl;
n is 0, 1, 2, or 3;
each R B (when present) is independently selected from the group consisting of halogen, —CN, —OH, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , cyclopropyl, —CH 2 -cyclopropyl, —CH 2 OCH 3 , —C≡CH, —C≡C—CH 3 , —CF 3 , —CHF 2 , —CH 2 F, —OCH 3 , —OCH 2 CH 3 , —O-cyclopropyl, —O—CH 2 -cyclopropyl, —OCH 2 —C≡C—H, —OCH 2 —C≡C—CH 3 , —OCF 3 , —OCHF 2 , —OCH 2 F, and —OCH 2 CH 2 F;
ring C is selected from the group consisting of cyclopropyl and cyclobutyl;
p is 0, 1, or 2; and
each R C (when present) is independently selected from the group consisting of: halogen, —OH, —CN, lower alkyl, and lower alkoxy, where said lower alkyl and said lower alkoxy are each optionally substituted with 1 to 3 fluorine.
2. A compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
R 1 is selected from the group consisting of —CH 3 and —CH 2 F;
ring C is cyclopropyl;
p is 0; and
R 2 is —CH 3 .
3. A compound of claim 2 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
ring A is selected from the group consisting of phenyl, pyridinyl, and pyrimidinyl;
m is 1; and
each R A is independently selected from the group consisting of fluoro.
4. A compound of claim 3 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
n is 0 or 1;
ring B, R B , and n form a moiety selected from the group consisting of:
and
R B (when present) is selected from the group consisting of fluoro, chloro, bromo, —OH, —CN, —OCH 3 , and —OCH 2 —C≡C—CH 3 .
5. A compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, said compound selected from the group consisting of:
6. A compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, said compound selected from the group consisting of:
7. A pharmaceutical composition comprising a compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable carrier or diluent.
8. A method of treating a disease or pathology, wherein said disease or pathology is Alzheimer's disease, olfactory impairment associated with Alzheimer's disease, Down's syndrome, olfactory impairment associated with Down's syndrome, Parkinson's disease, olfactory impairment associated with Parkinson's disease, stroke, microgliosis brain inflammation, pre-senile dementia, senile dementia, progressive supranuclear palsy, cortical basal degeneration, β-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, mild cognitive impairment, glaucoma, amyloidosis, type II diabetes, diabetes-associated amyloidogenesis, scrapie, bovine spongiform encephalitis, traumatic brain injury, or Creutzfeld-Jakob disease, said method comprising administering a compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, to a patient in need thereof in an amount effective to treat said disease or pathology.
9. The method of claim 8 , wherein disease or pathology is Alzheimer's disease.