2-spiro-substituted iminothiazines and their mono-and dioxides 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, or a pharmaceutically acceptable salt of said tautomer, said tautomer thereof having the structural Formula (I′):

wherein:

W is selected from the group consisting of S, S(O), and S(O) 2 ;

ring C is selected from the group consisting of:

ring A is selected from the group consisting of aryl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycloalkyl, monocyclic heterocycloalkenyl, and a multicyclic group;

ring B (when present) is independently selected from the group consisting of aryl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycloalkyl, monocyclic heterocycloalkenyl, and a multicyclic group;

-L 1 - (when present) independently represents a bond or a divalent moiety selected from the group consisting of -alkyl-, -haloalkyl-, -heteroalkyl-, -alkenyl-, -alkynyl-, —N(R 6 )—, —O—, —NHC(O)—, —C(O)NH—, NHS(O) 2 —, —S(O) 2 NH—, —O—CH 2 —, —CH 2 —O—, —NHCH 2 —, —CH 2 NH—, and —CH(CF 3 )NH—, —NHCH(CF 3 )—;

m, n, and p are each independently selected integers, wherein:

m is 0 or more;

n is 0 or 1; and

p is 0 or more,

wherein the maximum value of m is the maximum number of available substitutable hydrogen atoms on ring A, and wherein the maximum value of p is the maximum number of available substitutable hydrogen atoms on ring B;

each R 1 (when present) is independently selected from the group consisting of: H, halogen, —OH, alkyl, alkoxy, -alkyl-OH, haloalkyl, haloalkoxy, heteroalkyl, haloheteroalkyl, cycloalkyl, -alkyl-cycloalkyl, —O-cycloalkyl, —O-alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, —O-heterocycloalkyl, and —O-alkyl-heterocycloalkyl,

wherein said cycloalkyl, -alkyl-cycloalkyl, —O-cycloalkyl, —O-alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, —O-heterocycloalkyl, and —O-alkyl-heterocycloalkyl is optionally substituted with halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, heteroalkyl, haloheteroalkyl;

each R 1H is independently selected from the group consisting of: H, alkyl, -alkyl-OH, haloalkyl, heteroalkyl, haloheteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl,

wherein said cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl is optionally substituted with halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, heteroalkyl, haloheteroalkyl;

each R 2 (when present) is independently selected from the group consisting of: halogen, —OH, —CN, —SF 5 , —OSF 5 , —NO 2 , —Si(R 5 ) 3 , —P(O)(OR 5 ) 2 , —P(O)(OR 5 )(R 5 ), —N(R 6 ) 2 , —NR 7 C(O)R 6 , —NR 7 S(O) 2 R 6 , —NR 7 S(O) 2 N(R 6 ) 2 , —NR 7 C(O)N(R 6 ) 2 , —NR 7 C(O)OR 6 , —C(O)R 6 , —C(O) 2 R 6 , —C(O)N(R 6 ) 2 , —S(O)R 6 , —S(O) 2 R 6 , —S(O) 2 N(R 6 ) 2 , —OR 6 , —SR 6 , alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, aryl, -alkyl-aryl, heteroaryl, -alkyl-heteroaryl, heterocycloalkyl, and -alkyl-heterocycloalkyl,

wherein said alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, aryl, -alkyl-aryl, heteroaryl, -alkyl-heteroaryl, heterocycloalkyl, and -alkyl-heterocycloalkyl of R 2 are each optionally unsubstituted or substituted with one or more groups independently selected from R 8 ;

each R 3 (when present) is independently selected from the group consisting of: halogen, —OH, —CN, —SF 5 , —OSF 5 , —NO 2 , —Si(R 5 ) 3 , —P(O)(OR 5 ) 2 , —P(O)(OR 5 )(R 5 ), —N(R 6 ) 2 , —NR 7 C(O)R 6 , —NR 7 S(O) 2 R 6 , —NR 7 S(O) 2 N(R 6 ) 2 , —NR 7 C(O)N(R 6 ) 2 , —NR 7 C(O)OR 6 , —C(O)R 6 , —C(O) 2 R 6 , —C(O)N(R 6 ) 2 , —S(O)R 6 , —S(O) 2 R 6 , —S(O) 2 N(R 6 ) 2 , —OR 6 , —SR 6 , alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, aryl, -alkyl-aryl, heteroaryl, -alkyl-heteroaryl, heterocycloalkyl, and -alkyl-heterocycloalkyl,

wherein said alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, aryl, -alkyl-aryl, heteroaryl, -alkyl-heteroaryl, and heterocycloalkyl of R 3 are each optionally unsubstituted or substituted with one or more groups independently selected from R 8 ;

R 4 is selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, aryl, -alkyl-aryl, heteroaryl, -alkyl-heteroaryl, cycloalkyl, -alkyl-cycloalkyl, cycloalkenyl, -alkyl-cycloalkenyl, heterocycloalkyl, -alkyl-heterocycloalkyl, heterocycloalkenyl, and -alkyl-heterocycloalkenyl,

wherein each of said alkyl, haloalkyl, heteroalkyl, aryl, -alkyl-aryl, heteroaryl, -alkyl-heteroaryl, cycloalkyl, -alkyl-cycloalkyl, cycloalkenyl, -alkyl-cycloalkenyl, heterocycloalkyl, -alkyl-heterocycloalkyl, heterocycloalkenyl, and -alkyl-heterocycloalkenyl of R 4 is unsubstituted or substituted with one or more independently selected R 11 groups;

each R 5 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, haloalkyl, cycloalkyl, -alkyl-cycloalkyl, aryl, -alkyl-aryl, heteroaryl, and -alkyl-heteroaryl,

wherein each said aryl, -alkyl-aryl, heteroaryl, and -alkyl-heteroaryl of R 5 is unsubstituted or substituted with one or more groups independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, haloalkyl, alkoxy, —O-heteroalkyl, and haloalkoxy;

each R 6 (when present) is independently selected from the group consisting of H, alkyl, -alkyl-OH, alkenyl, alkynyl, heteroalkyl, -heteroalkyl-OH, haloalkyl, -haloalkyl-OH, cycloalkyl, lower alkyl-substituted cycloalkyl, lower alkyl-substituted -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and -alkyl-heteroaryl,

wherein each said heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and said -alkyl-heteroaryl of R 6 is unsubstituted or substituted with one or more groups independently selected from halogen, —CN, alkyl, cycloalkyl, heteroalkyl, haloalkyl, alkoxy, —O-heteroalkyl, and haloalkoxy;

each R 7 (when present) is independently selected from the group consisting of H, alkyl, heteroalkyl, haloalkyl, cycloalkyl, -alkyl-cycloalkyl, aryl, -alkyl-aryl, heteroaryl, and -alkyl-heteroaryl,

wherein each said aryl, -alkyl-aryl, heteroaryl, and -alkyl-heteroaryl of R 7 is unsubstituted or substituted with one or more groups independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, haloalkyl, alkoxy, —O-heteroalkyl, and haloalkoxy;

each R 8 (when present) is independently selected from the group consisting of halogen, —OH, —CN, —SF 5 , —OSF 5 , alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, -alkyl-cycloalkyl, —O-cycloalkyl, —O-alkyl-cycloalkyl, heteroalkyl, —O-heteroalkyl, and -alkyl-OH;

R 9 and R 10 are each independently selected from the group consisting of H, halogen, —CN, —P(O)(OR 5 ) 2 , —P(O)(OR 5 )(R 5 ), —NR 7 C(O)R 6 , —NR 7 S(O) 2 R 6 , —NR 7 C(O)N(R 6 ) 2 , —NR 7 C(O)OR 6 , —C(O)R 6 , —C(O) 2 R 6 , —C(O)N(R 6 ) 2 , —S(O)R 6 , —S(O) 2 R 6 , —S(O) 2 N(R 6 ) 2 , —OR 6 , —SR 6 , alkyl, haloalkyl, heteroalkyl, alkenyl and alkynyl,

wherein each of said alkyl, haloalkyl, heteroalkyl, alkenyl and alkynyl of R 9 and R 10 is unsubstituted or substituted with one or more independently selected R 12 groups;

each R 11 (when present) is independently selected from the group consisting of halogen, —OH, —CN, —SF 5 , —OSF 5 , —P(O)(OR 5 ) 2 , —P(O)(OR 5 )(R 5 ), —N(R 6 ) 2 , —NR 7 C(O)R 6 , —NR 7 S(O) 2 R 6 , —NR 7 S(O) 2 N(R 6 ) 2 , —NR 7 C(O)N(R 6 ) 2 , —NR 7 C(O)OR 6 , —C(O)R 6 , —C(O) 2 R 6 , —C(O)N(R 6 ) 2 , —S(O)R 6 , —S(O) 2 R 6 , —S(O) 2 N(R 6 ) 2 , —OR 6 , —SR 6 , alkyl, haloalkyl, haloalkoxy, heteroalkyl, -alkyl-OH, cycloalkyl, -alkyl-cycloalkyl;

each R 12 (when present) is independently selected from the group consisting of halogen, —OH, —CN, —SF 5 , —OSF 5 , —P(O)(OR 13 ) 2 , —P(O)(OR 13 )(R 13 ), —N(R 14 ) 2 , —NR 14 C(O)R 14 , —NR 14 S(O) 2 R 14 , —NR 14 S(O) 2 N(R 14 ) 2 , —NR 14 C(O)N(R 14 ) 2 , —NR—C(O)R 14 , —C(O) 2 R 14 , —C(O)N(R 14 ) 2 , —S(O)R 14 , —S(O) 2 R 14 , —S(O) 2 N(R 14 ) 2 , —OR 14 , —SR 14 , alkyl, haloalkyl, haloalkoxy, heteroalkyl, -alkyl-OH;

each R 13 (when present) is independently selected from the group consisting of alkyl, -alkyl-OH, alkenyl, alkynyl, heteroalkyl, -heteroalkyl-OH, haloalkyl, -haloalkyl-OH; and

each R 14 (when present) is independently selected from the group consisting of H, alkyl, -alkyl-OH, alkenyl, alkynyl, heteroalkyl, -heteroalkyl-OH, haloalkyl, -haloalkyl-OH.

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

W is S(O) 2 .

3. The compound of claim 2 , or the tautomer thereof, or the pharmaceutically acceptable salt of said compound or said tautomer, wherein:

R 1 and R 1H (when present) are each independently selected from the group consisting of H and OH.

4. The compound of claim 3 , or the tautomer thereof, or the pharmaceutically acceptable salt of said compound or said tautomer, wherein:

R 4 is selected from the group consisting of lower alkyl and lower haloalkyl.

5. The compound of claim 4 , or the tautomer thereof, or the pharmaceutically acceptable salt of said compound or said tautomer, wherein:

one of R 9 and R 10 is H and the other is selected from the group consisting of H, halogen, lower alkyl, lower haloalkyl, and lower alkyl ether.

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

R 9 and R 10 are each H.

7. The compound of claim 6 , or the tautomer thereof, or the pharmaceutically acceptable salt of said compound or said tautomer, wherein:

n is 1 and the moiety

has the form:

-L 1 - is selected from the group consisting of -alkynyl-, —NHC(O)— and —C(O)NH—;

ring A is selected from the group consisting of phenyl, pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, quinazolinyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothienyl, naphthyl, quinolyl, isoquinolyl, indazolyl, indolyl, thienopyridyl, and thienopyrazolyl;

m is 0, 1, 2, or 3;

each R 2 (when present) is independently selected from the group consisting of halogen, —CN, —SF 5 , —OSF 5 , —NO 2 , —NH 2 , —N(alkyl) 2 , —NH(alkyl), —NHC(O)R 6 , —NHS(O) 2 R 6 , —NHC(O)N(R 6 ) 2 , —NHC(O)OR 6 , —C(O)R 6 , —C(O) 2 R 6 , —C(O)N(R 6 ) 2 , —S(O)R 6 , —S(O) 2 R 6 , —S(O) 2 N(R 6 ) 2 , —OR 6 , —SR 6 , lower alkyl, lower haloalkyl, lower heteroalkyl, lower alkenyl, lower alkynyl, phenyl, benzyl, lower cycloalkyl, —CH 2 -(lower cycloalkyl), monocyclic heteroaryl, and —CH 2 -(monocyclic heteroaryl),

wherein said phenyl, benzyl, lower cycloalkyl, —CH 2 -(lower cycloalkyl), monocyclic heteroaryl, and —CH 2 -(monocyclic heteroaryl) of R 2 is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, alkyl, heteroalkyl, haloalkyl, alkoxy, —O-cyclopropyl, —O-heteroalkyl, haloalkoxy, —CN, —SF 5 , and —OSF 5 ;

ring B is selected from the group consisting of benzimidazolyl, benzofuranyl, benzoisothiazole, benzoisoxazole, benzothiazole, benzothiophenyl, benzoxazole, furanyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl, imidazopyridyl, imidazothiazoyl, imidazothiadiazolyl, imidazolyl, indazolyl, indolyl, isothiazoyl, isoxazolopyridyl, isoxazolyl, morpholinoyl, oxadiazolyl, oxazolyl, oxetanyl, phenyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrazolopyridinyl, tetrahydrofuranyl, tetrahydropyranyl, thiadiazolyl, thiazolyl, thienyl, triazolyl;

p is 0, 1, 2, or 3; and

each R 3 (when present) is independently selected from the group consisting of halogen, —CN, —SF 5 , —OSF 5 , —NO 2 , —NH 2 , —N(alkyl) 2 , —NH(alkyl), —NHC(O)R 6 , —NHS(O) 2 R 6 , —NHC(O)N(R 6 ) 2 , —NHC(O)OR 6 , —C(O)R 6 , —C(O) 2 R 6 , —C(O)N(R 6 ) 2 , —S(O)R 6 , —S(O) 2 R 6 , —S(O) 2 N(R 6 ) 2 , —OR 6 , —SR 6 , lower alkyl, lower haloalkyl, lower heteroalkyl, lower alkenyl, lower alkynyl, phenyl, benzyl, lower cycloalkyl, —CH 2 -(lower cycloalkyl), monocyclic heteroaryl, and —CH 2 -(monocyclic heteroaryl),

wherein said phenyl, benzyl, lower cycloalkyl, —CH 2 -(lower cycloalkyl), monocyclic heteroaryl, and —CH 2 -(monocyclic heteroaryl) of R 3 is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, alkyl, heteroalkyl, haloalkyl, alkoxy, —O-cyclopropyl, —O-heteroalkyl, haloalkoxy, —CN, —SF 5 , and —OSF 5 .

8. The compound of claim 6 , or the tautomer thereof, or the pharmaceutically acceptable salt of said compound or said tautomer, wherein:

n is 1;

-L i - is a bond;

ring A is selected from the group consisting of phenyl, pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, quinazolinyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothienyl, naphthyl, quinolyl, isoquinolyl, indazolyl, indolyl, thienopyridyl, and thienopyrazolyl;

m is 0 or more;

each R 2 group (when present) is independently selected from the group consisting of halogen, —CN, —SF 5 , —NHCH 3 , —N(CH 3 ) 2 , —OCH 3 , —OCH 2 CH 3 , —O-cyclopropyl, —S(CH 3 ), methyl, ethyl, propyl, cyclopropyl, —CH 2 -cyclopropyl, —C≡C—CH 3 , CF 3 , —CHF 2 , —C(O)OH, —C(O)OCH 3 , —C(O)OCH 2 CH 3 , —OCF 3 , and —OCHF 2 ;

ring B is selected from the group consisting of phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, pyrimidinyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazinyl, thienyl, pyrazolyl, furanyl, thiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, isothiazolyl, indolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, morpholinoyl, benzofuranyl, oxetanyl, tetrahydrafuranyl, and tetrahydropyranyl;

p is 1; and R 3 is selected from the group consisting of cycloalkyl, -alkyl-cycloalkyl, aryl, -alkyl-aryl, heteroaryl, -alkyl-heteroaryl, heterocycloalkyl, and -alkyl-heterocycloalkyl,

wherein said cycloalkyl, -alkyl-cycloalkyl, aryl, -alkyl-aryl, heteroaryl, -alkyl-heteroaryl, heterocycloalkyl, -alkyl-heterocycloalkyl of R 3 are each optionally unsubstituted or substituted with one or more groups independently selected from R 8 .

9. The compound of claim 6 , or the tautomer thereof, or the pharmaceutically acceptable salt of said compound or said tautomer, wherein:

n is 0;

ring A is selected from the group consisting of phenyl, pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridazinyl, thiazolyl, and oxazolyl;

m is 0 to 5; and

each R 2 (when present) is independently selected from the group consisting of halogen, —OH, —CN, —SF 5 , —OSF 5 , —NO 2 , —N(R 6 ) 2 , —NR 7 C(O)R 6 , —NR 7 S(O) 2 R 6 , —NR 7 C(O)N(R 6 ) 2 , —NR 7 C(O)OR 6 , —C(O)R 6 , —C(O) 2 R 6 , —C(O)N(R 6 ) 2 , —S(O)R 6 , —S(O) 2 R 6 , —S(O) 2 N(R 6 ) 2 , —OR 6 , —SR 6 , lower alkyl, -(lower alkyl)-OH, lower haloalkyl, lower heteroalkyl, lower alkenyl, lower alkynyl, lower alkynyl substituted with 1 to 3 independently selected R 8 groups, phenyl, benzyl, lower cycloalkyl, —CH 2 -(lower cycloalkyl), monocyclic heteroaryl, and —CH 2 -(monocyclic heteroaryl),

wherein said phenyl, benzyl, lower cycloalkyl, —CH 2 -(lower cycloalkyl), monocyclic heteroaryl, and —CH 2 -(monocyclic heteroaryl) of R 2 is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, alkyl, heteroalkyl, haloalkyl, alkoxy, —O-cyclopropyl, —O-heteroalkyl, haloalkoxy, —CN, —SF 5 , and —OSF 5 .

10. The compound of claim 1 , or the tautomer thereof, or the pharmaceutically acceptable salt of said compound or said tautomer, said compound selected from the group consisting of:

Ex:

Compound

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

35a

35b

36

37

38

39

39a

39b

40

41

42

43

43a

44

45

46

47

47a

48

49

50

51

52

53

54

55

56

57

57a

58

59

60

61

61a

62

62a

62b

62c

62d

62e

62f

62g

62h

62i

62j

62k

62l

62m

62n

63

63a

63b

63c

63d

63e

63f

63g

63h

63i

63j

63k

63l

63m

63n

64

65

65a

66

67

68

69

70

71

72

73

74

75

76a

76b

77

77a

77b

77c

77d

78

79

79a

79b

79c

79d

80

80a

80b

80c

80d

80e

80f

80g

80h

80i

80j

80k

80l

80m

81

81a

81b

81c

81d

81e

81f

81g

81h

81i

81j

81k

81l

81m

81n

81o

81p

81q

81r

81s

81t

81u

81v

81w

81x

81y

81z

81aa

81ab

81ac

81ad

81ae

81af

81ag

11. The compound of claim 1 , or the tautomer thereof, or the pharmaceutically acceptable salt of said compound or said tautomer, said compound selected from the group consisting of:

Compound

6

7

11

12

16

17

21

22

26

27

31

35

38

41

44

14-4

14-5

14-7

14-8

15-3

12. 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.

13. A method of treating Alzheimer's disease, Down's syndrome, Parkinson's disease, stroke, microgliosis, brain inflammation, pre-senile dementia, senile dementia, progressive supranuclear palsy, cortical basal degeneration, olfactory impairment associated with Alzheimer's disease, olfactory impairment associated with Parkinson's disease, olfactory impairment associated with Down's syndrome, β-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, mild cognitive impairment, glaucoma, amyloidosis, type II diabetes, diabetes-associated amyloidogenesis, hemodialysis complications, scrapie, bovine spongiform encephalitis, traumatic brain injury, or Creutzfeld-Jakob disease, said method comprising administering a compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt thereof, to a patient in need of such treatment.

14. A method of treating Alzheimer's disease, Down's syndrome, pre-senile dementia, senile dementia, olfactory impairment associated with Alzheimer's disease, olfactory impairment associated with Down's syndrome, β-amyloid angiopathy, cerebral amyloid angiopathy, mild cognitive impairment, type II diabetes, or traumatic brain injury, said method comprising administering a compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt thereof, to a patient in need of such treatment.

15. A method of treating Alzheimer's disease comprising administering a compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt thereof, to a patient in need of such treatment.