C5-C6-oxacyclic fused iminothiazine dioxide compounds bearing an ether linker as BACE inhibitors, compositions, and their use

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:

ring C is selected from the group consisting of tetrahydrofuranyl and tetrahydropyranyl, wherein 1 or 2 of the ring carbon atoms having two available substitutable hydrogen atoms of said tetrahydrofuranyl and tetrahydropyranyl rings are optionally independently replaced with a —C(R C1 R C2 )— group,

wherein R C1 and R C2 are each independently selected from the group consisting of H, halogen, —CO 2 —(C 1 -C 6 -alkyl), alkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and -alkyl-heteroaryl,

wherein each said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of R C1 and R C2 are optionally substituted with one or more R 3 , and

wherein 1 to 2 non-adjacent, non-terminal carbon atoms in each said alkyl of R C1 and R C2 are optionally independently replaced with —O—, —NH—, —N(C 1 -C 6 -alkyl)-, —S—, —S(O)—, or —S(O) 2 —,

or, alternatively, wherein said R cl and R C2 of one said —C(R C1 R C2 )— group are taken together with the carbon to which they are attached form a spirocyclic ring consisting of from 3 to 6 carbon atoms,

wherein 1 of said carbon atoms may be replaced with —O—, —NH—, —N(C 1 -C 6 -alkyl)-, —N(C 1 -C 6 -haloalkyl)-, —S—, —S(O)—, or —S(O) 2 —, and

wherein 1 to 2 of the carbon atoms of said spirocyclic ring may be optionally and independently substituted with 1 to 2 fluorine, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, or —CH 2 O—(C 1 -C 6 -alkyl);

R 1 is selected from the group consisting of H, halogen, and alkyl,

wherein said alkyl is optionally substituted with one or more fluorine, and

wherein 1 to 2 non-adjacent, non-terminal carbon atoms in said alkyl are optionally independently replaced with —O—, —NH—, —N(alkyl)-, —S—, —S(O)—, or —S(O) 2 —;

R 2 and R 3 are each independently selected from the group consisting of H, halogen, alkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and alkyl-heteroaryl,

wherein each said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of R 2 and R 3 are optionally substituted with one or more R 4 , and

wherein 1 to 2 non-adjacent, non-terminal carbon atoms in each said alkyl of R 2 and R 3 are optionally independently replaced with —O—, —NH—, —N(C 1 -C 3 -alkyl)-, —S—, —S(O)—, or —S(O) 2 —,

or, alternatively, R 2 and R 3 are taken together with the carbon to which they are attached form a spirocyclic ring consisting of from 3 to 6 carbon atoms,

wherein 1 of said carbon atoms may be replaced with —O—, —NH—, —N(C 1 -C 3 -alkyl)-, —N(C 1 -C 3 -haloalkyl)-, —S—, —S(O)—, or —S(O) 2 —, and

wherein 1 to 2 of the carbon atoms of said spirocyclic ring may be optionally independently substituted with 1 to 2 fluorine, C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, or —CH 2 O—(C 1 -C 3 -alkyl);

ring A is selected from the group consisting of aryl and heteroaryl;

m is 0 or more, with the proviso that the value of m does not exceed the number of available substitutable hydrogen atoms on ring A;

each R A (when present) is independently selected from the group consisting of halogen, oxo, —OH, —CN, alkyl, —O-alkyl, and cycloalkyl,

wherein said alkyl, —O-alkyl, and cycloalkyl of R A are each optionally independently unsubstituted or substituted with one or more fluorine, and wherein 1 to 2 non-adjacent, non-terminal carbon atoms in said alkyl and —O-alkyl are optionally independently replaced with —O—, —NH—, —N(C 1 -C 3 -alkyl)-, —S—, —S(O)—, or —S(O) 2 —;

n is 1;

-L 1 represents a bond or a divalent moiety selected from the group consisting of —O—, —CH 2 O—, —CH(CH 3 )O—, —CH(CF 3 )O—, and —CH(CHF 2 )O—;

ring B is selected from the group consisting of aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, with the provision that when L 1 is —O— or —CH 2 O—, then ring B is other than cycloalkyl;

p is 0 or more, with the proviso that the value of p does not exceed the number of available substitutable hydrogen atoms on ring B; and

each R B (when present) is independently selected from the group consisting of halogen, oxo, —OH, —CN, —SF 5 , —OSF 5 , —OR B1 , —SR B1 , alkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, and heteroaryl,

wherein said each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of R B are each optionally independently unsubstituted or substituted with one or more groups independently selected from R 4 , and wherein 1 to 2 non-adjacent, non-terminal carbon atoms in said alkyl are optionally independently replaced with —O—, —NH—, —N(alkyl)-, —S—, —S(O)—, or —S(O) 2 —;

each R B1 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and alkyl-heterocycloalkyl,

wherein each said alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl, of R B1 is unsubstituted or optionally substituted with one or more fluorine, and

wherein 1 to 2 non-adjacent, non-terminal carbon atoms in said alkyl are optionally independently replaced with —O—, —NH—, —N(C 1 -C 6 -alkyl)-, —S—, —S(O)—, or —S(O) 2 —;

each R 4 (when present) is independently selected from the group consisting of halogen, —OH, —CN, C 1 -C 6 -alkyl, —(C 1 -C 6 -alkyl)-OH, —O—(C 1 -C 6 -alkyl), cycloalkyl, —(C 1 -C 6 -alkyl)-cycloalkyl, —O-cycloalkyl, —O—(C 1 -C 6 -alkyl)-cycloalkyl, heterocycloalkyl, —(C 1 -C 6 -alkyl)-heterocycloalkyl, —O-heterocycloalkyl and —O—(C 1 -C 6 -alkyl)-heterocycloalkyl,

wherein each said C 1 -C 6 -alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more halogen,

and wherein 1 to 2 non-adjacent, non-terminal carbon atoms in each said C 1 -C 6 -alkyl is optionally independently replaced with —O—, —NH—, —N(C 1 -C 3 -alkyl)-, —S—, —S(O)—, or —S(O) 2 —.

2. A compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:

ring C is selected from the group consisting of:

3. A compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:

ring C is.

4. A compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:

R 2 and R 3 are each independently selected from the group consisting of methyl, —CHF 2 , and —CH 2 F, cyclopropyl, phenyl, pyridyl, and tetrahydropyranyl,

wherein each said cyclopropyl, phenyl, pyridyl, tetrahydropyranyl of R 2 and R 3 are unsubstituted or substituted with one or two groups independently selected from the group consisting of fluorine, methyl, ethyl, cyclopropyl, and —OCH 3 ,

wherein each said methyl, ethyl, cyclopropyl, and —OCH 3 is each optionally substituted with from 1 to 3 fluoro groups.

5. A compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:

R 2 and R 3 are methyl.

6. A compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:

n=1;

-L1- is —O—;

ring A is selected from the group consisting of phenyl and pyridinyl;

m is 0, 1, 2, or 3;

each R A (when present) is fluoro;

ring B is selected from the group consisting of phenyl, piperidinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl;

p is 0, 1, 2, or 3, with the proviso that the value of p does not exceed the number of available substitutable hydrogen atoms on ring B; and

each R B group (when present) is independently selected from the group consisting of fluoro, chloro, —CN, —OCH 3 , —O—CH 2 -cyclopropyl, —O—CH 2 —C≡, —O—CH 2 —C≡C—CH 3 , methyl, ethyl, cyclopropyl, —CH 2 -cyclopropyl, —CH 2 OCH 3 —C≡CH, —C≡C—CH 3 , —CF 3 , —CHF 2 , —OCF 3 , —OCHF 2 , oxadiazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, and triazolyl,

wherein each said oxadiazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, and triazolyl, is optionally substituted with one substituent from the group consisting of fluoro and methyl.

7. A compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:

n is 1;

-L 1 - is —CH 2 O—;

ring A is selected from the group consisting of phenyl and pyridinyl;

m is 0, 1, 2, or 3;

each R A (when present) is fluoro;

ring B is selected from the group consisting of oxazolyl, phenyl, pyrazinyl, pyridinyl, pyrimidinyl, tetrahydropyranyl, and thiazolyl;

p is 0, 1, 2, or 3, with the proviso that the value of p does not exceed the number of available substitutable hydrogen atoms on ring B; and

each R B group (when present) is independently selected from the group consisting of fluoro, chloro, —CN, —OCH 3 , O—CH 2 —C≡CH, —O—CH 2 —C≡C—CH 3 , methyl, cyclopropyl, —CH 2 OCH 3 , —C≡CH, —C≡C—CH 3 , —CF 3 , —CHF 2 , —OCF 3 , and —OCHF 2 .

8. A compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:

n=1;

-L 1 - is a bond;

ring A is selected from the group consisting of phenyl, pyridinyl, and thienyl;

m is 0, 1, 2, or 3;

each R A (when present) is independently selected from the group consisting of fluoro, chloro, methyl, and —CHF 2 ;

ring B is selected from the group consisting of phenyl, pyridinyl, and pyrimidinyl;

p is 0, 1, or 2; and

each R B group (when present) is independently selected from the group consisting of fluoro, chloro, methyl, —CN, —OMe, —C≡CH, —C≡C—CH 3 , and —CHF 2 .

9. 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:

10. A pharmaceutical composition comprising: (i) a compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and (ii) a pharmaceutically acceptable carrier or diluent.