Substituted 1, 4-thiazepine and analogs as activators of caspases and inducers of apoptosis and the use thereof

1. A compound of Formula I:

in which:

the dashed lines indicate optional unsaturation without violating valency rules;

R 1 is hydrogen, (C 1-6 )alkyl or —C(O)R 6 , wherein R 6 is as defined below, or R 1 is absent when a double bond exists between the nitrogen atom to which R 1 is attached and an adjacent ring atom;

X 1 is —S(O) n —, wherein n is 0, 1, or 2;

A 1 is a monocyclic or fused polycyclic ring system selected from aryl containing a total of 6 to 14 ring atoms, heteroaryl containing a total of 5 to 14 ring atoms and unsaturated, partially unsaturated or saturated carbocycloalkyl or heterocycloalkyl each containing a total of 3 to 14 ring atoms, wherein A 1 may be substituted with a group selected from —X 2 R 3 , —X 2 OR 3 , —X 2 C(O)R 3 , —X 2 OC(O)R 3 , —X 2 C(O)OR 3 , —X 2 SR 3 , —X 2 S(O)R 3 , —X 2 S(O) 2 R 3 , —X 2 NR 3 R 4 , —X 2 NR 4 C(O)R 3 , —X 2 NR 4 C(O)OR 3 , —X 2 C(O)NR 3 R 4 , —X 2 NR 4 C(O)NR 3 R 4 , —X 2 NR 4 C(NR 4 )NR 3 R 4 , —X 2 NR 4 S(O) 2 R 3 and —X 2 S(O) 2 NR 3 R 4 , wherein X 2 is a bond or (C 1-6 )alkylene, R 3 is —X 2 R 5 wherein X 2 is as defined above and R 5 is aryl containing a total of 6 to 10 ring atoms, heteroaryl containing a total of 5 to 10 ring atoms or unsaturated, partially unsaturated or saturated carbocycloalkyl or heterocycloalkyl each containing a total of 3 to 10 ring atoms, and R 4 at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-6 )alkyl, wherein each ring within A 1 and R 5 contains from 3 to 8 ring atoms and may be substituted with 1 to 3 groups independently selected from (C 1-6 )alkyl, cyano, halo, nitro, halo-substituted (C 1-6 )alkyl, —X 2 OR 4 , —X 2 C(O)R 6 , —X 2 OC(O)R 6 , —X 2 C(O)OR 4 , —X 2 SR 4 , —X 2 S(O)R 6 , —X 2 S(O) 2 R 6 , —X 2 NR 4 R 4 , —X 2 NR 4 C(O)R 6 , —X 2 NR 4 C(O)OR 4 , —X 2 C(O)NR 4 R 4 , —X 2 NR 4 C(O)NR 4 R 4 , —X 2 NR 4 C(NR 4 )NR 4 R 4 , —X 2 NR 4 S(O) 2 R 6 and —X 2 S(O) 2 NR 4 R 4 , wherein X 2 and R 4 are as defined above and R 6 is (C 1-6 )alkyl or halo-substituted (C 1-6 )alkyl, and wherein any said carbocycloalkyl and heterocycloalkyl rings within A 1 and R 5 may be substituted further with 1 to 2 groups independently selected from (C 1-6 )alkylidene, oxo, imino and thioxo, with the proviso that only one of A 1 and R 5 is a fused polycyclic ring system;

A 2 is a monocyclic ring selected from heteroarylene or unsaturated, partially unsaturated or saturated heterocycloalkylene containing a total of 7 ring atoms, wherein A 2 may be substituted with a group selected from —X 2 R 8 , —X 2 OR 8 , —X 2 C(O)R 8 , —X 2 OC(O)R 8 , —X 2 C(O)OR 8 , —X 2 SR 8 , —X 2 S(O)R 8 , —X 2 S(O) 2 R 8 , —X 2 NR 4 R 8 , —X 2 NR 4 C(O)R 8 , —X 2 NR 4 C(O)OR 8 , —X 2 C(O)NR 4 R 8 , —X 2 NR 4 C(O)NR 4 R 8 , —X 2 NR 4 C(NR 4 )NR 4 R 8 , —X 2 NR 4 S(O) 2 R 8 and —X 2 S(O) 2 NR 4 R 8 , wherein X 2 is a bond or (C 1-6 )alkylene, R 8 is —X 2 R 9 wherein X 2 is as defined above and R 9 is aryl containing a total of 6 to 10 ring atoms, heteroaryl containing a total of 5 to 10 ring atoms or unsaturated, partially unsaturated or saturated carbocycloalkyl or heterocycloalkyl each containing a total of 3 to 10 ring atoms, and R 4 at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-6 )alkyl, wherein each ring within A 2 and R 8 contains from 3 to 8 ring atoms and may be substituted with 1 to 3 groups independently selected from (C 1-6 )alkyl, cyano, halo, nitro, halo-substituted (C 1-6 )alkyl, —X 2 OR 4 , —X 2 C(O)R 6 , —X 2 OC(O)R 6 , —X 2 C(O)OR 4 , —X 2 SR 4 , —X 2 S(O)R 6 , —X 2 S(O) 2 R 6 , —X 2 NR 4 R 4 , —X 2 NR 4 C(O)R 6 , —X 2 NR 4 C(O)OR 4 , —X 2 C(O)NR 4 R 4 , —X 2 NR 4 C(O)NR 4 R 4 , —X 2 NR 4 C(NR 4 )NR 4 R 4 , —X 2 C(O)NR 4 X 2 C(O)OR 4 , —X 2 NR 2 S(O) 2 R 6 and —X 2 S(O) 2 NR 4 R 4 , wherein X 2 and R 4 are as defined above and R 6 is (C 1-6 )alkyl or halo-substituted (C 1-6 )alkyl, and wherein any said heterocycloalkylene, carbocycloalkyl and heterocycloalkyl rings within A 2 and R 8 may be substituted further with 1 to 2 groups independently selected from (C 1-6 )alkylidene, oxo, imino and thioxo; and

A 3 is a monocyclic or fused polycyclic ring system selected from aryl containing a total of 6 to 14 ring atoms, heteroaryl containing a total of 5 to 14 ring atoms and unsaturated, partially unsaturated or saturated carbocycloalkyl or heterocycloalkyl each containing a total of 3 to 14 ring atoms, wherein A 3 may be substituted with a group selected from —X 2 R 9′ , —X 2 OR 9′ , —X 2 C(O)R 9′ , —X 2 OC(O)R 9′ , —X 2 C(O)OR 9′ , —X 2 SR 9′ , —X 2 S(O)R 9′ , —X 2 S(O) 2 R 9′ , —X 2 NR 4 R 9′ , —X 2 NR 4 C(O)R 9′ , —X 2 NR 4 C(O)OR 9′ , —X 2 C(O)NR 4 R 9′ , —X 2 NR 4 C(O)NR 4 R 9′ , —X 2 NR 4 C(NR 4 )NR 4 R 9′ , —X 2 NR 4 S(O) 2 R 9′ and —X 2 S(O) 2 NR 4 R 9′ , wherein X 2 is a bond or (C 1-6 )alkylene, R 9′ is —X 2 R 10 wherein X 2 is as defined above and R 10 is aryl containing a total of 6 to 10 ring atoms, heteroaryl containing a total of 5 to 10 ring atoms or unsaturated, partially unsaturated or saturated carbocycloalkyl or heterocycloalkyl each containing a total of 3 to 10 ring atoms, and R 4 at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-6 )alkyl, wherein each ring within A 3 and R 10 contains from 3 to 8 ring atoms and may be substituted with 1 to 3 groups independently selected from (C 1-6 )alkyl, cyano, halo, nitro, halo-substituted (C 1-6 )alkyl, —X 2 OR 4 , —X 2 C(O)R 6 , —X 2 OC(O)R 6 , —X 2 C(O)OR 4 , —X 2 SR 4 , —X 2 S(O)R 6 , —X 2 S(O) 2 R 6 , —X 2 NR 4 R 4 , —X 2 NR 4 C(O)R 6 , —X 2 NR 4 C(O)OR 4 , —C(O)NR 4 R 4 , —X 2 NR 4 C(O)NR 4 R 4 , —X 2 NR 4 C(NR 4 )NR 4 R 4 , —X 2 NR 4 S(O) 2 R 6 and —X 2 S(O) 2 NR 4 R 4 , wherein X 2 and R 4 are as defined above and R 6 is (C 1-6 )alkyl or halo-substituted (C 1-6 )alkyl, and wherein any said carbocycloalkyl and heterocycloalkyl rings within A 3 and R 10 may be substituted further with 1 to 2 groups independently selected from (C 1-6 )alkylidene, oxo, imino and thioxo, with the proviso that only one of A 3 and R 10 is a fused polycyclic ring system; and the individual stereoisomers and mixtures of stereoisomers; and the pharmaceutically acceptable salts thereof; with the proviso that when said compound is Formulae II(a):

then A 3 is other than:

unsubstituted pyridyl;

unsubstituted thienyl;

unsubstituted indolyl;

unsubstituted phenyl;

benzo[1,3]dioxolyl;

2,3-dihydro-benzo[1,4]dioxinyl;

phenyl which is mono-substituted by fluoro, bromo, iodo, nitro, methyl, isopropyl, ethoxy or methylsulfanyl; and

phenyl which is substituted by at least one of chloro, hydroxy or methoxy.

2. The compound of claim 1 , and the individual stereoisomers and mixtures of stereoisomers; and the pharmaceutically acceptable salts of said compound, with the further proviso that A 3 is other than:

unsubstituted pyridyl;

unsubstituted thienyl;

unsubstituted indolyl;

unsubstituted phenyl;

benzo[1,3]dioxolyl;

2,3-dihydro-benzo[1,4]dioxinyl; and

phenyl which is substituted by at least one of halogen, nitro, hydroxy, (C 13 )alkyl, methoxy, ethoxy and methylsulfanyl.

3. The compound of claim 1 , and the individual stereoisomers and mixtures of stereoisomers; and the pharmaceutically acceptable salts of said compound, with the further proviso that A 1 is not 4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl.

4. The compound of claim 1 in which said compound is of Formula I(A):

in which R 1 , A 1 , A 2 and A 3 are as defined in claim 1 ; and the individual stereoisomers and mixtures of stercoisomers; and the pharmaceutically acceptable salts thereof.

5. The compound of claim 4 in which said compound is of Formula I(B):

and the individual stereoisomers and mixtures of stereoisomers; and the pharmaceutically acceptable salts thereof.

6. The compound of claim 5 in which said A 2 is 2,3,6,7-tetrahydro-[1,4]thiazepin-5,7-ylene, that is the compound of Formula I(C):

in which said 2,3,6,7-tetrahydro-[1,4]thiazepin-5,7-ylene may be substituted with 1 to 3 groups independently selected from (C 1-6 )alkyl, cyano, halo, nitro, halo-substituted (C 1-6 )alkyl, —X 2 OR 4 , —X 2 C(O)R 6 , —X 2 OC(O)R 6 , —X 2 C(O)OR 4 , —X 2 SR 4 , —X 2 S(O)R 6 , —X 2 S(O) 2 R 6 , —X 2 NR 4 R 4 , —X 2 NR 4 C(O)R 6 , —X 2 NR 4 C(O)OR 4 , —X 2 C(O)NR 4 R 4 , —X 2 NR 4 C(O)NR 4 R 4 , —X 2 NR 4 C(NR 4 )NR 4 R 4 , —X 2 C(O)NR 4 X 2 C(O)OR 4 , —X 2 NR 4 S(O) 2 R 6 and —X 2 S(O) 2 NR 4 R 4 , wherein X 2 is a bond or (C 1-6 )alkylene, R 4 at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-6 )alkyl, and R 6 is (C 1-6 )alkyl or halo-substituted (C 1-6 )alkyl; and the individual stereoisomers and mixtures of stereoisomers; and the pharmaceutically acceptable salts thereof.

7. The compound of claim 6 in which A 1 is 4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl or 4-methoxy-6-methyl-2-oxo-2H-pyran-3-yl; and the individual stereoisomers and mixtures of stereoisomers; and the pharmaceutically acceptable salts thereof.

8. The compound of claim 7 in which said compound is selected from the group consisting of:

4-hydroxy-6-methyl-3-[7-(3-phenyl-1H-pyrazol-4-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;

3-[7-(5-ethyl-thien-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;

3-[7-(1-benzyl-1H-indol-3-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;

4-hydroxy-6-methyl-3[7-(2-trifluoromethylsulfanyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;

4-hydroxy-6-methyl-3[7-(3-trifluoromethylsulfanyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;

4-hydroxy-6-methyl-3[7-(4-trifluoromethylsulfanyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;

4-hydroxy-6-methyl-3-[7-[3-(3-trifluoromethyl-phenoxy)-phenyl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;

3-[7-[3-(3,4-dichloro-phenoxy)-phenyl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;

3-[7-[3-(3,5-dichloro-phenoxy)-phenyl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;

4-hydroxy-6-methyl-3-{7-[5-(3-trifluoromethyl-phenyl)-furan-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-pyran-2-one;

3-{7-[5-(2-chloro-phenyl)-furan-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-4-hydroxy-6-methyl-pyran-2-one;

3-{7-[5-(3-chloro-phenyl)-furan-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-4-hydroxy-6-methyl-pyran-2-one;

3-{7-[5-(4-chloro-phenyl)-furan-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-4-hydroxy-6-methyl-pyran-2-one;

4-hydroxy-6-methyl-3-{7-[5-(2-chloro-5-trifluoromethyl-phenyl)-furan-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-pyran-2-one;

3-[7-(4-bromo-thien-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;

3-[7-(5-bromo-thien-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;

3-[7-(1-benzenesulfonyl-1H-pyrrol-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;

4-hydroxy-6-methyl-3-[7-(3-methyl-thien-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;

4-hydroxy-6-methyl-3-[7-(5-methyl-thien-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;

4-hydroxy-6-methyl-3-[7-(1-methyl-1H-indol-3-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;

3-[7-(3-chloro-2-methyl-5-trifluoromethyl-1H-pyrazol-4-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;

3-{7-[1-(2,4-difluoro-benzenesulfonyl)-1H-pyrrol-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-4-hydroxy-6-methyl-pyran-2-one;

3-(7-[2,2′]bithienyl-5-yl-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl)-4-hydroxy-6-methyl-pyran-2-one;

3-{7-[1-(3,5-dichloro-phenyl)-1H-pyrrol-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin -5-yl}-4-hydroxy-6-methyl-pyran-2-one;

3-{7-[1-(4-chloro-phenyl)-1H-pyrrol-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-4-hydroxy-6-methyl-pyran-2-one;

3-[7-(5-chloro-1H-indol-3-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;

4-hydroxy-6-methyl-3-[7-(6-p-tolylsulfanyl-imidazo[2,1-b]thiazol-5-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;

3-[7-(4,5-dibromo-thien-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;

4-hydroxy-6-methyl-3-[7-(5-methylsulfanyl-thien-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;

3-[7-(5-chloro-1-methyl-3-phenyl-1H-pyrazol-4-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;

3-[7-(4-dimethylamino-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;

4-hydroxy-6-methyl-3-[7-(4-trifluoromethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;

3-[7-(bis-trifluoromethyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;

4-hydroxy-3-[7-(4-methanesulfonyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-6-methyl-pyran-2-one; and

3-[7-(2,4-dimethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-methoxy-6-methyl-pyran-2-one; and the pharmaceutically acceptable salts thereof.

9. The compound of claim 6 in which A 1 is 4-hydroxy-6-methyl-2-oxo-5,6-dihydro-2H-pyran-3-yl or 4-methoxy-6-methyl-2-oxo-5,6-dihydro-2H-pyran-3-yl; and the individual stereoisomers and mixtures of stereoisomers; and the pharmaceutically acceptable salts thereof.

10. The compound of claim 9 in which said compound is selected from the group consisting of:

3-[7-(2,4-dimethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one;

3-[7-(2,4-diethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one;

3-[7-(4-dimethylamino-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one; and

3-[7-(2,3,4-trimethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one; and the pharmaceutically acceptable salts thereof.

11. The compound of claim 6 in which A 1 is 2-hydroxy-6-oxo-cyclohex-1-enyl or 2-methoxy-6-oxo-cyclohex-1-enyl; and the individual stereoisomers and mixtures of stereoisomers; and the pharmaceutically acceptable salts thereof.

12. The compound of claim 11 in which said compound is selected from the group consisting of:

2-[7-(2,4-dimethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-3-hydroxy -cyclohex-2-enone;

2-[7-(2,4-diethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-3-hydroxy -cyclohex-2-enone; and

3-hydroxy-2-[7-(2,3,4-trimethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-cyclohex-2-enone; and the pharmaceutically acceptable salts thereof.

13. The compound of claim 6 in which A 1 is a group of Formula (c):

in which R 7 is hydrogen or methyl, R 11 is hydrogen or (C 1-6 )alkyl and the free valence is attached to A 2 ; and the individual stereoisomers and mixtures of stereoisomers; and the pharmaceutically acceptable salts thereof.

14. The compound of claim 13 which is:

3-[7-2,4-dimethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-1H-quinolin-2-one;

and the pharmaceutically acceptable salts thereof.

15. The compound of claim 4 in which said A 2 is a group of Formula (k):

in which said group of Formula (k) may be substituted with 1 to 3 groups independently selected from (C 1-6 )alkyl, cyano, halo, nitro, halo-substituted (C 1-6 )alkyl, —X 2 OR 4 , —X 2 C(O)R 6 , —X 2 OC(O)R 6 , —X 2 C(O)OR 4 , —X 2 SR 4 , —X 2 S(O)R 6 , —X 2 S(O) 2 R 6 , —X 2 NR 4 R 4 , —X 2 NR 4 C(O)R 6 , —X 2 NR 4 C(O)OR 4 , —X 2 C(O)NR 4 R 4 , —X 2 NR 4 C(O)NR 4 R 4 , —X 2 NR 4 C(O)NR 4 R 4 , —X 2 NR 4 C(NR 4 )NR 4 R 4 , —X 2 C(O)NR 4 X 2 C(O)OR 4 , —X 2 NR 4 S(O) 2 R 6 and —X 2 S(O) 2 NR 4 R 4 , wherein X 2 is a bond or (C 1-6 )alkylene, R 4 at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-6 )alkyl, and R 6 is (C 1-6 )alkyl or halo-substituted (C 1-6 )alkyl; and the individual stereoisomers and mixtures of stereoisomers; and the pharmaceutically acceptable salts thereof.

16. The compound of claim 15 in which R 1 is hydrogen; and the individual stereoisomers and mixtures of stereoisomers; and the pharmaceutically acceptable salts thereof.

17. The compound of claim 15 in which A 1 is 4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl or 4-methoxy-6-methyl-2-oxo-2H-pyran-3-yl; and the individual stereoisomers and mixtures of stereoisomers; and the pharmaceutically acceptable salts thereof.

18. The compound of claim 17 in which said compound is selected from the group consisting of:

3-[4-acetyl-7-(2,4-dimethoxy-phenyl)-[1,4]thiazepan-5-yl]-4-hydroxy-6-methyl -pyran-2-one; and

3-[7-(2,4-dimethoxy-phenyl)-4-(2,2,2-trifluoro-ethanoyl)-[1,4]thiazepan-5-yl]-4-hydroxy-6-methyl-pyran-2-one;

and the pharmaceutically acceptable salts thereof.

19. The compound of claim 15 in which A 1 is optionally substituted phenyl.

20. The compound of claim 19 which is:

1-[7-(2,4-dimethoxy-phenyl)-5-(3-fluoro-4-methoxyphenyl)-[1,4]thiazepan-4-yl]-ethanone;

and the pharmaceutically acceptable salts thereof.

21. The compound of claim 4 in which said A 2 is 2,3-dihydro-[1,4]thiazepin-5,7-ylene that is the compound of Formula I(F):

in which said 2,3-dihydro-[1,4]thiazepin-5,7-ylene may be substituted with 1 to 3 groups independently selected from (C 1-6 )alkyl, cyano, halo, nitro, halo-substituted (C 1-6 )alkyl, —X 2 OR 4 , —X 2 C(O)R 6 , —X 2 OC(O)R 6 , —X 2 C(O)OR 4 , —X 2 SR 4 , —X 2 S(O)R 6 , —X 2 S(O) 2 R 6 , —X 2 NR 4 R 4 , —X 2 NR 4 C(O)R 6 , —X 2 NR 4 C(O)OR 4 , —X 2 C(O)NR 4 R 4 , —X 2 NR 4 C(O)NR 4 R 4 , —X 2 NR 4 C(NR 4 )NR 4 R 4 , —X 2 C(O)NR 4 X 2 C(O)OR 4 , —X 2 NR 4 S(O) 2 R 6 and —X 2 S(O) 2 NR 4 R 4 , wherein X 2 is a bond or (C 1-6 )alkylene, R 4 at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-6 )alkyl, and R 6 is (C 1-6 )alkyl or halo-substituted (C 1-6 )alkyl; and the individual stereoisomers and mixtures of stereoisomers; and the pharmaceutically acceptable salts thereof.

22. The compound of claim 21 in which A 1 is 4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl or 4-methoxy-6-methyl-2-oxo-2H-pyran-3-yl; and the individual stereoisomers and mixtures of stereoisomers; and the pharmaceutically acceptable salts thereof.

23. The compound of claim 22 in which said compound is selected from the group consisting of:

3-[7-(2,4-dimethoxy-phenyl)-2,3-dihydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;

3-[7-(2,4-diethoxy-phenyl)-2,3-dihydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl -pyran-2-one; and

3-(7-[2,2′]bithienyl-5-yl-2,3-dihydro-[1,4]thiazepin-5-yl)-4-hydroxy-6-methyl-pyran-2-one;

and the pharmaceutically acceptable salts thereof.

24. The compound of claim 21 in which A 1 is 4-hydroxy-6-methyl-2-oxo-5,6-dihydro-2H-pyran-3-yl or 4-methoxy-6-methyl-2-oxo-5,6-dihydro-2H-pyran-3-yl; and the individual stereoisomers and mixtures of stereoisomers; and the pharmaceutically acceptable salts thereof.

25. The compound of claim 24 which is:

3-[7-(2,4-diethoxy-phenyl)-2,3-dihydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl -5,6-dihydro-pyran-2-one;

and the pharmaceutically acceptable salts thereof.

26. The compound of claim 26 in which A 1 is 2-hydroxy-6-oxo-cyclohex-1-enyl or 2-methoxy-6-oxo-cyclohex-1-enyl; and the individual stereoisomers and mixtures of stereoisomers; and the pharmaceutically acceptable salts thereof.

27. The compound of claim 26 which is:

2-[7-(2,4-diethoxy-phenyl)-2,3-dihydro-[1,4]thiazepin-5-yl]-3-hydroxy-cyclohex-2-enone;

and the individual stereoisomers and mixtures of stereoisomers; and the pharmaceutically acceptable salts thereof.

28. The compound of claim 1 in which said compound is of Formula I(G):

in which n, R 1 , A 1 , A 2 and A 3 are defined as in claim 1 ; and the individual stereoisomers and mixtures of stereoisomers; and the pharmaceutically acceptable salts thereof.

29. The compound of claim 28 in which A 2 is a group of Formula (1):

in which said group of Formula (1) may be substituted with 1 to 3 groups independently selected from (C 1-6 )alkyl, cyano, halo, nitro, halo-substituted (C 1-6 )alkyl, —X 2 OR 4 , —X 2 C(O)R 6 , —X 2 OC(O)R 6 , —X 2 C(O)OR 4 , —X 2 SR 4 , —X 2 S(O)R 6 , —X 2 S(O) 2 R 6 , —X 2 NR 4 R 4 , —X 2 NR 4 C(O)R 6 , —X 2 NR 4 C(O)OR 4 , —X 2 C(O)NR 4 R 4 , —X 2 NR 4 C(O)NR 4 R 4 , —X 2 NR 4 C(NR 4 )NR 4 R 4 , —X 2 C(O)NR 4 X 2 C(O)OR 4 , —X 2 NR 4 S(O) 2 R 6 and —X 2 S(O) 2 NR 4 R 4 , wherein X 2 is a bond or (C 1-6 )alkylene, R 4 at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-6 )alkyl, and R 6 is (C 1-6 )alkyl or halo-substituted (C 1-6 )alkyl; and the individual stereoisomers and mixtures of stereoisomers; and the pharmaceutically acceptable salts thereof.

30. The compound of claim 29 in which n is 1 and A 1 is 4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl or 4-methoxy-6-methyl-2-oxo-2H-pyran-3-yl; and the individual stereoisomers and mixtures of stereoisomers; and the pharmaceutically acceptable salts thereof.

31. The compound of claim 30 which is:

3-[7-(2,4-dimethoxy-phenyl)-1-oxo-2,3,6,7-tetrahydro-1H-1λ 4 -[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;

and the pharmaceutically acceptable salts thereof.

32. The compound of claim 29 in which n is 2 and A 1 is 4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl or 4-methoxy-6-methyl-2-oxo-2H-pyran-3-yl; and the individual stereoisomers and mixtures of stereoisomers; and the pharmaceutically acceptable salts thereof.

33. The compound of claim 32 which is:

3-[7-(2,4-dimethoxy-phenyl)-1,1-dioxo-2,3,6,7-tetrahydro-1H-1λ 6 -[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;

and the individual stereoisomers and mixtures of stereoisomers; and the pharmaceutically acceptable salts thereof.

34. A compound selected from the group consisting of:

4-hydroxy-3-[7-(2-methoxy-4-methylsulfanyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-6-methyl-pyran-2-one;

3-[7-(2-chloro-5-trifluoromethyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;

3-[7-(4-dimethylamino-2-methoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;

4-hydroxy-3-[7-(4-chloro-2-methoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-6-methyl-pyran-2-one; and

4-hydroxy-3-[7-(2,4-diethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-6-methyl-pyran-2-one; or

an individual stereoisomer and mixtures of stereoisomers; or the pharmaceutically acceptable salt thereof.

35. A compound selected from the group consisting of:

7-(2,4-dimethoxy-phenyl)-5-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2,2-dimethyl-2,3,6,7-tetrahydro-[1,4]thiazepine-3-carboxylic acid; and

2-({1-[7-(2,4-dimethoxy-phenyl)-5-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2,2-dimethyl-2,3,6,7-tetrahydro-[1,4]thiazepin-3-yl]-methanoyl}-amino)-propionic acid tert-butyl ester;

and the pharmaceutically acceptable salts thereof.

36. The compound of claim 1 in which A 1 is a group selected from Formulae (b), (c), (d), (e) and (f):

in which R 7 is hydrogen or methyl, R 11 is hydrogen or (C 1-6 )alkyl and the free valance is attached to A 2 ; and

A 2 is as defined in claim 1 or is a monocyclic ring from heteroarylene or unsaturated, partially unsaturated or saturated heterocycloalkylene containing a total of 7 ring atoms, wherein A 2 may be substituted with a group selected from —X 2 R 8 , —X 2 OR 8 , —X 2 C(O)R 8 , —X 2 OC(O)R 8 , —X 2 C(O)OR 8 , —X 2 SR 8 , —X 2 S(O)R 8 , —X 2 S(O) 2 R 8 , —X 2 NR 4 R 8 , —X 2 NR 4 C(O)R 8 , —X 2 NR 4 C(O)OR 8 , —X 2 C(O)NR 4 R 8 , —X 2 NR 4 C(O)NR 4 R 8 , —X 2 NR 4 C(NR 4 )NR 4 R 8 , —X 2 NR 4 S(O) 2 R 8 and —X 2 S(O) 2 NR 4 R 8 , wherein X 2 is a bond or (C 1-6 )alkylene, R 8 is —X 2 R 9 wherein X 2 is as defined above and R 9 is aryl containing a total of 6 to 10 ring atoms, heteroaryl containing a total of 5 to 10 ring atoms or unsaturated, partially unsaturated or saturated carbocycloalkyl or heterocycloalkyl each containing a total of 3 to 10 ring atoms, and R 4 at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-6 )alkyl, wherein each ring within A 2 and R 8 that contains from 3 to 8 ring atoms and may be substituted with 1 to 3 groups independently selected from (C 1-6 )alkyl, cyano, halo, nitro, halo-substituted (C 1-6 )alkyl, —X 2 OR 4 , —X 2 C(O)R 6 , —X 2 OC(O)R 6 , —X 2 C(O)OR 4 , —X 2 SR 4 , —X 2 S(O)R 6 , —X 2 S(O) 2 R 6 , —X 2 NR 4 R 4 , —X 2 NR 4 C(O)R 6 , —X 2 NR 4 C(O)OR 6 , —X 2 C(O)NR 4 R 4 , —X 2 NR 4 C(O)NR 4 R 4 , —X 2 NR 4 C(NR 4 )NR 4 R 4 , —X 2 C(O)NR 4 X 2 C(O)OR 4 , —X 2 NR 4 S(O) 2 R 6 and —X 2 S(O) 2 NR 4 R 4 , wherein X 2 and R 4 are as defined above and R 6 is (C 1-6 )alkyl or halo-substituted (C 1-6 )alkyl, and wherein any said heteroalkylene, carbocycloalkyl and heterocycloalkyl rings within A 2 and R 8 may be substituted further with 1 to 2 groups independently selected from (C 1-6 )alkylidene, oxo, imino and thioxo; and the individual stereoisomers and mixtures of stereoisomers; and the pharmaceutically acceptable salts thereof.

37. The compound of claim 36 in which A 2 is a group selected from Formulae (h), (i), (j), (k), (l) and (m):

in which n is 1 or 2 and R 1 is acetyl or trifluoroacetyl; and the individual stereoisomers and mixtures of stereoisomers; and the pharmaceutically acceptable salts thereof.

38. A compound of Formula II:

in which:

the dashed lines indicate optional unsaturation without violating valency rules;

R 1 is hydrogen, (C 1-6 )alkyl or —C(O)R 6 , wherein R 6 is as defined below, or R 1 is absent when a double bond exists between the nitrogen atom to which R 1 is attached and an adjacent ring atom;

R 7 is hydrogen;

X 1 is —S(O) n —, wherein n is 0, 1, or 2;

A 2 is a monocyclic ring selected from heteroarylene or unsaturated, partially unsaturated or saturated heterocycloalkylene containing a total of 7 ring atoms, wherein A 2 may be substituted with a group selected from —R 8 , —X 2 OR 8 , —X 2 C(O)R 8 , —X 2 OC(O)R 8 , —X 2 C(O)OR 8 , —X 2 SR 8 , —X 2 S(O)R 8 , —X 2 S(O) 2 R 8 , —X 2 NR 4 R 8 , —X 2 NR 4 C(O)R 8 , —X 2 NR 4 C(O)OR 8 ,—X 2 C(O)NR 4 R 8 , —X 2 NR 4 C(O)NR 4 R 8 , —X 2 NR 4 C(NR 4 )NR 4 R 8 , —X 2 NR 4 S(O) 2 R 8 and —X 2 S(O) 2 NR 4 R 8 , wherein X 2 is a bond or (C 1-6 )alkylene, R 8 is —X 2 R 9 wherein X 2 is as defined above and R 9 is aryl containing a total of 6 to 10 ring atoms, heteroaryl containing a total of 5 to 10 ring atoms or unsaturated, partially unsaturated or saturated carbocycloalkyl or heterocycloalkyl each containing a total of 3 to 10 ring atoms, and R 4 at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-6 )alkyl, wherein each ring within A 2 and R 8 contains from 3 to 8 ring atoms and may be substituted with 1 to 3 groups independently selected from (C 1-6 )alkyl, cyano, halo, nitro, halo-substituted (C 1-6 )alkyl, —X 2 OR 4 , —X 2 C(O)R 6 , —X 2 OC(O)R 6 , —X 2 C(O)OR 4 , —X 2 SR 4 , —X 2 S(O)R 6 , —X 2 S(O) 2 R 6 , —X 2 NR 4 R 4 , —X 2 NR 4 C(O)R 6 , —X 2 C(O)NR 4 R 4 , —X 2 NR 4 C(O)NR 4 R 4 , —X 2 NR 4 C(NR 4 )NR 4 R 4 , —X 2 C(O)NR 4 X 2 C(O)OR 4 , —X 2 NR 4 S(O) 2 R 6 and —X 2 S(O) 2 NR 4 R 4 , wherein X 2 and R 4 are as defined above and R 6 is (C 1-6 )alkyl or halo-substituted (C 1-6 )alkyl, and wherein any said heteroalkylene, carbocycloalkyl and heterocycloalkyl rings within A 2 and R 8 may be substituted further with 1 to 2 groups independently selected from (C 1-6 )alkylidene, oxo, imino and thioxo; and

A 3 is a monocyclic or fused polycyclic ring system selected from aryl containing a total of 6 to 14 ring atoms, heteroaryl containing a total of 5 to 14 ring atoms and unsaturated, partially unsaturated or saturated carbocycloalkyl or heterocycloalkyl each containing a total of 3 to 14 ring atoms, wherein A 3 may be substituted with a group selected from — 2 R 9′ , —X 2 OR 9′ , —X 2 C(O)R 9′ , —X 2 OC(O)R 9′ , —X 2 C(O)OR 9′ , —X 2 SR 9′ , —X 2 S(O)R 9′ , —X 2 S(O) 2 R 9′ , —X 2 NR 4 R 9′ , —X 2 NR 4 C(O)R 9′ , —X 2 NR 4 C(O)OR 9′ , —X 2 C(O)NR 4 R 9′ , —X 2 NR 4 C(O)NR 4 R 9′ , —X 2 NR 4 C(NR 4 )NR 4 R 9′ , —X 2 NR 4 S(O) 2 R 9 and —X 2 S(O) 2 NR 4 R 9 , wherein X 2 is a bond or (C 1-6 )alkylene, R 9′ is —X 2 R 10 wherein X 2 is as defined above and R 10 is aryl containing a total of 6 to 10 ring atoms, heteroaryl containing a total of 5 to 10 ring atoms or unsaturated, partially unsaturated or saturated carbocycloalkyl or heterocycloalkyl each containing a total of 3 to 10 ring atoms, and R 4 at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-6 )alkyl, wherein each ring within A 3 and R 10 contains from 3 to 8 ring atoms and may be substituted with 1 to 3 groups independently selected from (C 1-6 )alkyl, cyano, halo, nitro, halo-substituted (C 1-6 )alkyl, —X 2 OR 4 , —X 2 C(O)R 6 , —X 2 OC(O)R 6 , —X 2 C(O)OR 4 , —X 2 SR 4 , —X 2 S(O)R 6 , —X 2 S(O) 2 R 6 , —X 2 NR 4 R 4 , —X 2 NR 4 C(O)R 6 , —X 2 NR 4 C(O)OR 4 , —X 2 C(O)NR 4 R 4 , —X 2 NR 4 C(O)NR 4 R 4 , —X 2 NR 4 C(NR 4 )NR 4 R 4 , —X 2 NR 4 S(O) 2 R 6 and —X 2 S(O) 2 NR 4 R 4 , wherein X 2 and R 4 are as defined above and R 6 is (C 1-6 )alkyl or halo-substituted (C 1-6 )alkyl, and wherein any said carbocycloalkyl and heterocycloalkyl rings within A 3 and R 10 may be substituted further with 1 to 2 groups independently selected from (C 1-6 )alkylidene, oxo, imino and thioxo with the proviso that only one of A 3 and R 10 is a fused polycyclic ring system; and the individual stereoisomers and mixtures of stereoisomers; and the pharmaceutically acceptable salts thereof;

provided, however, Formula II does not represent a compound wherein A 2 is 2,3,6,7-tetrahydro-[1,4]thiazepinylene and A 3 is benzo[1,3]dioxolyl, indolyl, phenyl, pyridyl or thienyl, wherein said phenyl may be substituted with 1 to 3 groups independently selected from halo, nitro, hydroxy, (C 1-4 )alkyl, (C 1-4 )alkylsulfanyl and (C 1-4 )alkyloxy or any individual stereoisomer or mixture of stereoisomers, or pharmaceutically acceptable salt thereof.

39. The compound of claim 38 in which A 2 is a group selected from Formulae (h), (k), (l) and (m):

in which n is 1 or 2 and R 1 is acetyl or trifluoroacetyl; and the individual stereoisomers and mixtures of stereoisomers; and the pharmaceutically acceptable salts thereof.

40. The compound of claim 39 in which A 3 is phenyl or heteroaryl containing a total of 5 to 9 ring atoms, wherein A 3 may be substituted with a group selected from —R 9′ , —X 2 OR 9′ , —X 2 SR 9′ and —X 2 S(O) 2 R 9′ , wherein R 9′ is —X 2 R 10 , X 2 is a bond or (C 1-6 )alkylene and R 10 is phenyl or heteroaryl containing a total 5 to 6 ring atoms, wherein each ring within A 3 and R 10 may be substituted with 1 to 3 groups independently selected from (C 1-6 )alkyl, halo, halo-substituted (C 1-6 )alkyl, —X 2 OR 4 , —X 2 SR 4 , —X 2 S(O) 2 R 6 and —X 2 NR 4 R 4 , wherein R 4 at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-6 )alkyl and R 6 is (C 1-6 )alkyl or halo-substituted (C 1-6 )alkyl; and the individual stereoisomers and mixtures of stereoisomers; and the pharmaceutically acceptable salts thereof.