Compounds for Treating Neurodegenerative Diseases

What is claimed is:

1. A compound selected from Formula α:

and stereoisomers, diastereomers, enantiomers, tautomers and pharmaceutically acceptable salts thereof, wherein:

W is a bond or CR10R11;

Y is O, S or NR1;

Z is CR12R13 or C(=O), provided when Z is C(=O) then Y is NR1;

X1, X2 and X3 are independently selected from CR9 and N, wherein only one of X1, X2 or X3 may be N;

R1 is selected from hydrogen, alkyl, aralkyl, heteroaryl or heteroaralkyl;

R2 is selected from hydroxy, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, sulfonyl, sulfinyl, sulfanyl, aryloxy, a carbocycle or a heterocycle wherein said alkyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, sulfonyl, sulfinyl, sulfanyl, aryloxy, carbocycle and heterocycle are optionally substituted with hydroxy, halogen, amino, cyano, nitro, oxo, optionally substituted alkyl, optionally substituted alkoxy, sulfanyl, acyl, alkoxycarbonyl, haloalkyl, optionally substituted carbocycle or heterocycle;

R3 and R4 are independently selected from hydrogen, halogen and alkyl, or

R3 and R4 together form an oxo group;

R5 and R6 are independently hydrogen, hydroxy, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, sulfonyl, sulfinyl, sulfanyl, a carbocycle or a heterocycle wherein said alkyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, sulfonyl, sulfinyl, sulfanyl, carbocycle and heterocycle are optionally substituted with hydroxy, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl, haloalkyl, an optionally substituted carbocycle and an optionally substituted heterocycle, or

R5 and R6 together form a 3 to 6 member carbocycle or heterocycle optionally substituted with hydroxy, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl and haloalkyl;

R7 and R8 are independently hydrogen, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, sulfonyl, sulfinyl, sulfanyl, a carbocycle or a heterocycle wherein said alkyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, sulfonyl, sulfinyl, sulfanyl, carbocycle and heterocycle are optionally substituted with hydroxy, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl, haloalkyl, a carbocycle and an optionally substituted heterocycle, or

R7 and R8 together form a 3 to 6 member carbocycle or heterocycle optionally substituted with hydroxy, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl and haloalkyl;

R9 is independently is hydrogen, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, sulfonyl, sulfinyl, sulfanyl, a carbocycle or a heterocycle wherein said alkyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, sulfonyl, sulfinyl, sulfanyl, carbocycle and heterocycle are optionally substituted with hydroxy, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl and haloalkyl,

or R5 and R7 together form a 3 to 4 member carbocycle or heterocycle optionally substituted with hydroxy, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl and haloalkyl;

each R9 is independently selected from hydrogen, halogen or methyl;

R10 and R11 are independently selected from hydrogen and alkyl, or

R10 and R11 together with the atom to which they are attached form a 3 to 6 membered carbocycle or heterocycle; and

R12 and R13 are independently selected from hydrogen, alkyl and a carbocycle.

2. A compound of Claim 1, wherein:

W is a bond or CR10R11;

Y is O, S or NR1;

Z is CR12R13 or C(=O), provided when Z is C(=O) then Y is NR1;

X1, X2 and X3 are independently selected from CR9 and N, wherein only one of X1, X2 or X3 may be N;

R1 is selected from hydrogen, benzyl or C1-C3 alkyl optionally substituted with Ra;

R2 is halogen, CN, C1-C8 alkyl optionally substituted with Rb, C1-C8 alkenyl optionally substituted with Rb, C1-C8 alkynyl optionally substituted with Rb, phenyl optionally substituted with Rc, a 5 to 6 membered heteroaryl optionally substituted with Rc, a 3 to 6 membered saturated or unsaturated heterocyclyl optionally substituted with Rd, a 3 to 6 membered saturated or unsaturated carbocyclyl optionally substituted with Rd, a 9 to 10 membered bicyclic heteroaryl optionally substituted with Rc, a 9 to 10 membered bicyclic heterocyclyl optionally substituted with Rc, phenylamino, phenoxy optionally substituted with Re, or –NHC(=O)Ro;

R3 and R4 are independently selected from hydrogen, halogen and C1-C6 alkyl, or

R3 and R4 together form an oxo group;

R5 and R6 are independently selected from hydrogen, a 3 to 6 membered saturated or unsaturated carbocyclyl, or C1-C6 alkyl optionally substituted with Rf, or

R5 and R6 together with the atom to which they are attached form a 3 to 6 membered carbocyclyl or heterocyclyl;

R7 and R8 are independently selected from hydrogen, halogen or C1-C6 alkyl optionally substituted with Rf, or

R7 and R8 together with the atom to which they are attached form a 3 to 6 membered carbocyclyl or heterocyclyl, or

R5 and R7 together with the atoms to which they are attached form a 3 to 4 membered carbocyclyl or heterocyclyl, wherein only one of the pairs of R5 and R6, R7 and R8 or R5 and R7 may together form a ring;

each R9 is independently selected from hydrogen, halogen or methyl;

R10 and R11 are independently selected from hydrogen and C1-C3 alkyl, or

R10 and R11 together with the atom to which they are attached form a 3 to 6 membered carbocycle or heterocycle;

R12 and R13 are independently selected from hydrogen, C1-C6 alkyl and C3-C6 carbocyclyl;

each Ra is independently selected from OH, OCH3, halogen, a 5 to 6 membered heteroaryl, and a 3-6 membered heterocyclyl optionally substituted with C1-C3 alkyl optionally substituted with oxo;

each Rb is independently selected from halogen, CN, OH, OCH3, cyclopropyl and phenyl optionally substituted with halogen, OH or OCH3;

each Rc is independently selected from halogen, CN, a 3 to 6 membered carbocyclyl, a 5 to 6 membered heteroaryl, a 3 to 6 membered heterocyclyl, phenyl, ORg, SRh, NRiRj, C1-C8 alkyl optionally substituted with Rk, C1-C8 alkynyl optionally substituted with Rk;

each Rd is independently selected from halogen, oxo, C1-C6 alkyl, and C1-C6 alkoxycarbonyl;

each Re is independently selected from halogen and benzyl;

each Rf is independently selected from halogen, oxo, OH, NRmRn, –O(C1-C6 alkyl) optionally substituted with halogen, phenyl, a 3 to 6 membered carbocyclyl, a 5 to 6 membered heteroaryl, and a 4 to 6 membered heterocyclyl, wherein the phenyl, carbocyclyl, heteroaryl and heterocyclyl are optionally substituted with halogen, C1-C6 alkyl optionally substituted with halogen, –O(C1-C6 alkyl) optionally substituted with halogen, phenyl or a 5 to 6 membered heteroaryl;

each Rg is independently selected from hydrogen and C1-C6 alkyl optionally substituted with halogen or phenyl;

each Rh is C1-C6 alkyl;

each Ri and Rj are independently selected from hydrogen and C1-C6 alkyl;

each Rk is independently selected from halogen, OH, OCH3, phenyl and a 3 to 6 membered carbocyclyl;

each Rm and Rn are independently selected from hydrogen and C1-C6 alkyl; and

Ro is C1-C6 alkyl, C3-C6 cycloalkyl, a 4 to 6 membered heterocyclyl, phenyl or a 5 to 6 membered heteroaryl, wherein the alkyl, cycloalkyl, phenyl and heteroaryl are optionally substituted with halogen, C1-C3 alkyl, and C1-C3 alkoxyl.

3. A compound of any one of Claims 1 or 2, wherein:

W is a bond or CR10R11;

Y is O, S or NR1;

Z is CR12R13 or C(=O), provided when Z is C(=O) then Y is NR1;

X1 and X2 are selected from CR9 and N, and X3 is CR9, wherein only one of X1 or X2 may be N;

R1 is C1-C3 alkyl optionally substituted with Ra;

R2 is halogen, C1-C8 alkyl optionally substituted with Rb, C1-C8 alkenyl optionally substituted with Rb, C1-C8 alkynyl optionally substituted with Rb, phenyl optionally substituted with Rc, a 5 to 6 membered heteroaryl optionally substituted with Rc, a 3 to 6 membered saturated or unsaturated carbocyclyl optionally substituted with Rd, a 9 to 10 membered bicyclic heterocyclyl, or –NHC(=O)Ro;

R3 and R4 are independently selected from hydrogen and C1-C6 alkyl, or

R3 and R4 together form an oxo group;

R5 and R6 are independently selected from hydrogen or C1-C6 alkyl optionally substituted with Rf, or

R5 and R6 together with the atom to which they are attached form a 3 to 6 membered carbocyclyl or heterocyclyl;

R7 and R8 are independently selected from hydrogen, halogen or C1-C6 alkyl optionally substituted with Rf, or

R7 and R8 together with the atom to which they are attached form a 3 to 6 membered heterocyclyl, or

each R9 is hydrogen;

R10 and R11 are hydrogen;

R12 and R13 are independently selected from hydrogen and C1-C6 alkyl;

each Ra is halogen;

each Rb is independently selected from CN and cyclopropyl;

each Rc is independently selected from halogen, CN, ORg, SRh, C1-C8 alkyl and a 5 to 6 membered heteroaryl;

each Rf is independently selected from halogen, OH, phenyl, a 5 to 6 membered heteroaryl and a 4 to 6 membered heterocyclyl, wherein the phenyl, heteroaryl and heterocyclyl are optionally substituted with halogen, C1-C6 alkyl optionally substituted with halogen, or a 5 to 6 membered heteroaryl;

Rg is C1-C6 alkyl optionally substituted with halogen;

Rh is C1-C6 alkyl; and

Ro is phenyl or a 5 to 6 membered heteroaryl, wherein the phenyl and heteroaryl are optionally substituted with halogen, C1-C3 alkyl, and C1-C3 alkoxyl.

4. A compound of any one of Claims 1 to 3, having the structure of Formula I:

5. A compound of any one of Claims 1 to 3, having the structure of Formula II:

6. A compound of any one of Claims 1 to 3, having the structure of Formula III:

III

7. A compound of any one of Claims 1 to 3, having the structure of Formula IV:

8. A compound of any one of Claims 1 to 3, having the structure of Formula V:

9. A compound of any one of Claims 1 to 3, having the structure of Formula VI:

10. A compound of any one of Claims 1 to 9, wherein X1, X2 and X3 are CR9.

11. A compound of any one of Claims 1 to 9, wherein X1 is N and X2 and X3 are CR9.

12. A compound of any one of Claims 1 to 9, wherein X2 is N and X1 and X3 are CR9.

13. A compound of any one of Claims 1 to 12, wherein each R9 is hydrogen.

14. A compound of any one of Claims 1 to 13, wherein R2 is Br, 4-(butanenitrile), isopentyl, cyclopropylvinyl, 3,3-dimethylbut-1-enyl, cyclopropylethynyl, 6-(hex-5-ynenitrile), 3-chlorophenyl, 3-methoxyphenyl, 3-chloro-5-fluorophenyl, 3-(difluoromethoxy)phenyl, 3-cyanophenyl (3-benzonitrile), 3-fluoro-5-methoxyphenyl, 3-chloro-2-fluorophenyl, 3-(trifluoromethoxy)phenyl, 3-methylphenyl, 3-(methylthio)phenyl, 2,5-dichlorophenyl, 5-chloro-2-fluorophenyl, pyridin-3-yl, 5-chloropyridin-3-yl, 5-methoxypyridin-3-yl, 2-fluoropyridin-3-yl, 5-nicotinonitrile (5-cyanopyridin-3-yl), 5-fluoropyridin-3-yl, 5-methylpyridin-3-yl, 5-trifluoromethylpyridin-3-yl, 2-fluoro-5-methylpyridin-3-yl, 2-(5-pyridin-3-yloxy)acetonitrile (5-cyanomethoxypyridin-3-yl), 2-(1H-pyrazol-1-yl)pyridin-3-yl, 4-methoxypyridin-2-yl, 2-isonicotinonitrile (4-cyanopyridin-2-yl), 4-trifluoromethylpyridin-2-yl, 4-methylpyridin-2-yl, 4-chloropyridin-2-yl, pyrimidin-5-yl, cyclohexyl, benzo[d][1,3]dioxol-5-yl, N-5-bromopicolinamide, N-5-chloropicolinamide, N-2-methyloxazole-4-carboxamide, N-2,5-dimethylfuran-3-carboxamide, N-5-methylpyrazine-2-carboxamide, N-pyrazine-2-carboxamide, N-benzamide, N-5-methoxypyrazine-2-carboxamide, N-4-methyloxazole-5-carboxamide and N-pivalamide.

15. A compound of any one of Claims 1 to 14, wherein R3 and R4 are independently selected from hydrogen, F and methyl.

16. A compound of any one of Claims 1 to 15, wherein R5 and R6 are independently selected from hydrogen, methyl, CH2OH, benzyl, 4-bromobenzyl and 4-(pyrimidin-5-yl)benzyl.

17. A compound of any one of Claims 1 to 15, wherein R5 and R6 together with the atom to which they are attached form cyclobutyl or tetrahydropyran-4-yl.

18. A compound of any one of Claims 1 to 17, wherein R7 and R8 are independently selected from hydrogen, F, methyl, 1-(2,2-difluoroethyl)piperidin-4-yl)methyl, and pyridin-3-ylmethyl.

19. A compound of any one of Claims 1 to 16, R7 and R8 together with the atom to which they are attached form tetrahydropyran-4-yl.

20. A compound of any one of Claims 1 to 4 or 10 to 19, wherein R1 is selected from benzyl, methyl, ethyl, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2OCH3,
-CH2CH2CH2OCH3, -CH2CF3, pyridin-2-ylmethyl, pyridin-4-ylmethyl and (1-acetylpiperdin-4-yl)methyl.

21. A compound of Formula I as defined in any one of Claims 1 to 4 and named in any one of Examples 1 to 77 herein, or a stereoisomer, diastereomer, enantiomer, tautomer or pharmaceutically acceptable salt thereof.

22. A compound of Formula α as defined in any one of Claims 1 to 3 and named in any one of Examples 1 to 129 herein, or a stereoisomer, diastereomer, enantiomer, tautomer or pharmaceutically acceptable salt thereof.

23. A compound of Formula α as defined in any one of Claims 1 to 3 and named in any one of Examples 78 to 129 herein, or a stereoisomer, diastereomer, enantiomer, tautomer or pharmaceutically acceptable salt thereof.

24. A compound of Formula α as defined in any one of Claims 1 to 3 and named in any one of Examples 130 to 173 herein, or a stereoisomer, diastereomer, enantiomer, tautomer or pharmaceutically acceptable salt thereof.

25. A compound of Formula α as defined in any one of Claims 1 to 3 and named in any one of Examples 1 to 173 herein, or a stereoisomer, diastereomer, enantiomer, tautomer or pharmaceutically acceptable salt thereof.

26. A method of inhibiting cleavage of APP by β-secretase in a mammal comprising administering to said mammal an effective amount of a compound of any one of Claims 1 to 25.

27. A method for treating a disease or condition mediated by the cleavage of APP by β-secretase in a mammal, comprising administering to said mammal an effective amount of a compound of any one of Claims 1 to 25.

28. The method of Claim 27, wherein the disease is Alzheimer's disease.

29. A pharmaceutical compositions comprising a compound of any one of Claims 1 to 25 and a pharmaceutically acceptable carrier, diluent or excipient.

30. Use of a compound of any one of Claims 1 to 25 in the manufacture of a medicament for the treatment of a neurodegenerative disease.

31. The use of Claim 30, wherein the disease is Alzheimer's disease.

32. A compound of any one of Claims 1 to 25 for the treatment of a neurodegenerative disease.

33. The compound of Claim 32, wherein the disease is Alzheimer's disease.

34. A process for preparing a compound of Formula I, comprising:

(a) reacting a compound of Formula A:

with cyanopotassium and ammonium carbonate to provide a compound of Formula B: