CETP inhibitors derived from benzoxazole arylamides

1. A compound having Formula I, or a pharmaceutically acceptable salt thereof, wherein

Q is O;

A is a difunctional cyclic group selected from 1,4-phenylene, 2,5-pyridinylene, and 2,5-pyrimidinylene, wherein A is optionally substituted with 1-3 substituent groups R 1 ;

Each R 1 is independently selected from the group consisting of halogen, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, and —OC 1 -C 3 alkyl, wherein each alkyl, alkenyl, and alkynyl substituent is optionally substituted with 1-5 halogens;

Each R 2 is independently selected from the group consisting of H, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, and C 2 -C 3 alkynyl, wherein each alkyl, alkenyl, and alkynyl substituent is optionally substituted with 1-5 halogens;

R W is selected from the group consisting of (a) C 1 -C 5 alkyl which is optionally substituted with 1-5 halogens, (b) C 2-5 alkenyl which is optionally substituted with 1-5 halogens; (c) —OC 1 -C 5 alkyl which is optionally substituted with 1-5 halogens, (d)-SC 1 -C 5 alkyl which is optionally substituted with 1-5 halogens, (e) —OC 2-5 alkenyl which is optionally substituted with 1-5 halogens, (f) C 3 -C 6 cycloalkyl, (g) phenyl, (h) a 5-6 membered saturated or partly unsaturated heterocyclic group having 1-3 heteroatoms independently selected from N, S and O, (i) a 5-7 membered heteroaromatic group having 1-3 heteroatoms independently selected from N, S, and O, (j) —C(═O)OC 1-3 alkyl which is optionally substituted with 1-5 halogens, and (k) —C(═O)OH, wherein said C 3 -C 6 cycloalkyl, phenyl, 5-6 membered saturated or partly unsaturated heterocyclic group, and 5-7 membered heteroaromatic group are optionally substituted with 1-3 substituents independently selected from halogen, CH 3 , CF 3 , —OCH 3 , and —OCF 3 ;

R Y is selected from the group consisting of halogen, CH 3 , CF 3 , —OCH 3 , —OCF 3 , —CN, phenyl, and a 6-membered heteroaroaromatic group having 1-2 N, wherein phenyl and the 6-membered heteroaroaromatic group are optionally substituted with 1-3 substituents independently selected from halogen, CH 3 , CF 3 , —OCH 3 , and —OCF 3 ;

R X and R Z are each selected from the group consisting of H, halogen, CH 3 , CF 3 , —OCH 3 , and —OCF 3 ;

B is selected from the group consisting of:

(a) —C(═O)N(R 3 )(CR 4 R 5 ) x (CR 6 R 7 ) y D 2 , and

(b) —C(═O)N(R 3 )(CR 4 R 5 )D 5 ;

R 3 is selected from the group consisting of H and C 1 -C 3 alkyl;

R 4 is selected from the group consisting of H, C 1 -C 3 alkyl, CF 3 , —C(═O)OH, and —C(═O)OC 1 -C 3 alkyl;

R 5 is selected from the group consisting of H, C 1 -C 3 alkyl, and CF 3 ;

R 6 is selected from the group consisting of H, C 1 -C 3 alkyl, CF 3 , —C(═O)OH, and —C(═O)OC 1 -C 3 alkyl;

R 7 is selected from the group consisting of H, C 1 -C 3 alkyl, CF 3 , and phenyl, which is optionally substituted with 1-3 groups independently selected from halogen, CH 3 , CF 3 , —OCH 3 , and —OCF 3 ;

x is 0 or 1;

y is 0, 1, or 2;

D 2 is a cyclic group selected from the group consisting of

(a) C 3 -C 8 Cycloalkyl which optionally comprises 1-2 double bonds and is optionally fused to a phenyl ring,

(b) Bicyclic C 6 -C 12 Cycloalkyl optionally comprising 1-2 double bonds,

(c) A 4-8 membered saturated or partly unsaturated heterocyclic ring comprising 1-3 ring members independently selected from —O— and —S—, optionally one carbonyl group, and optionally 1-2 double bonds, said heterocyclic ring being connected to the remainder of the structure represented by Formula I through a carbon atom of the heterocyclic ring, wherein said heterocyclic ring is optionally fused to a phenyl ring or to a C 5 -C 7 Cycloalkyl,

(d) A spirocyclic group having two rings joined by a spirocyclic linkage through a carbon atom wherein each ring is a 5-7-membered ring, wherein D 2 optionally comprises in either ring of the spirocyclic group (i) optionally 1-2 ring members independently selected from —O— and —S—, (ii) optionally one carbonyl group, and (iii) optionally 1-2 double bonds, wherein either ring of the spirocylic group D 2 is optionally fused to a phenyl ring or to a C 5 -C 7 Cycloalkyl,

(e) An aromatic ring selected from phenyl and naphthyl, and

(f) A 5-7 membered heteroaromatic ring having 1-3 heteroatoms independently selected from N, S, and O, and optionally having one —C(═O)— group as a ring member, said heteroaromatic ring being connected to the right side of the structure represented by Formula I through a carbon atom of the heteroaromatic ring, wherein said heteroromatic ring is optionally fused to a phenyl ring;

Wherein said cyclic groups D 2 defined in (a)-(f), including optional fused rings, are optionally substituted with 1-5 substitutents independently selected from halogen, —CN, —NO 2 , —OH, —N(R 3 ) 2 —, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, CF 3 , —OC 1 -C 5 alkyl, —C 1 -C 5 alkylene-OC 1 -C 5 alkyl, —OCF 3 , —C(═O)C 1 -C 5 alkyl, —C(═O)OC 1 -C 5 alkyl, —C(═O)OH, and —NR 3 C(═O)C 1 -C 5 alkyl, and are optionally substituted with one substituent selected from the group consisting of 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl and a cyclic group D 4 , wherein C 1 -C 7 alkyl, C 2 -C 7 alkenyl, and OC 1 -C 5 alkyl in all uses are optionally substituted with 1-9 halogens, wherein D 4 is connected directly to D 2 or is connected to D 2 through a linking group L 4 ,

Wherein D 4 is selected from the group consisting of (a) phenyl, (b) naphthyl, (c) C 3 -C 8 cycloalkyl optionally having 1-2 double bonds, (d) a saturated or partially unsaturated monocyclic or bicyclic 4-10 membered heterocycle having 1-3 heteroatoms independently selected from N, O, and S and optionally one —C(═O)— group, said heterocycle optionally having 1-2 double bonds, and (e) a monocyclic or bicyclic 5-12 membered heteroaromatic group having 1-3 heteroatoms independently selected from N, S, and O and optionally having one —C(═O)— group, and

L 4 is selected from the group consisting of —C(═O)—, —S—, —S(O) 2 —, —O—, —N(R 3 )C(═O)—, —CH 2 N(R 3 )C(═O)—, —CH 2 C(═O)N(R 3 )—, —N(R 3 )S(O) 2 —, —CH 2 N(R 3 )S(O) 2 —, —CH 2 S(O) 2 N(R 3 )—, —C 2 -C 5 alkenylene-, and —C 1 -C 5 alkylene-which optionally comprises one heteroatom or a difunctional group selected from O, S, —S(O) 2 —, —NR 3 —, —N(R 3 )C(═O)—, and —N(R 3 )S(O) 2 — between 2 adjacent carbons of the —C 1 -C 5 alkylene-group, wherein D 4 is optionally substituted with 1-3 substituents independently selected from halogen, —CN, —NO 2 , —N(R 3 ) 2 —, —OH, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, CF 3 , —OC 1 -C 5 alkyl, —C 1 -C 5 alkylene-OC 1 -C 5 alkyl, CO 2 H, CO 2 C 1 -C 5 alkyl, and —OCF 3 , and is optionally substituted with one cyclic group D 6 bonded directly to D 4 or connected to D 4 through a linking group L 6 , wherein D 6 has the same selections as D 4 , and L 6 has the same selections as L 4 , and D 6 is optionally substituted with 1-3 substituents independently selected from halogen, —CN, —NO 2 , —N(R 3 ) 2 —, —OH, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, CF 3 , —OC 1 -C 5 alkyl, —C 1 -C 5 alkylene-OC 1 -C 5 alkyl, and —OCF 3 , wherein the C 1 -C 7 alkyl, C 2 -C 7 alkenyl, and —OC 1 -C 5 alkyl groups in all uses in substituents on D4 and D6 are optionally substituted with 1-5 halogens; and

D 5 is selected from the group consisting of −OC 1 -C 7 alkyl, —CH 2 S(O) 2 C 1 -C 7 alkyl, C 1 -C 15 alkyl, C 2 -C 15 alkenyl, C 2 -C 15 alkynyl, —NR 3 C 1 -C 7 alkyl, —NR 3 C(═O)OC 1 -C 7 alkyl, and —OC(═O)OC 1 -C 7 alkyl, wherein the C 1 -C 15 alkyl, C 2 -C 15 alkenyl, C 2 -C 15 alkynyl, and C 1 -C 7 alkyl groups of D 5 are optionally substituted with 1-9 halogens and are optionally substituted with one group selected from —N(R 3 ) 2 , —N(R 3 )C(═O)OC 1 -C 7 alkyl, —N(R 3 )C(═O)C 1 -C 7 alkyl, and —OH, wherein the C 1 -C 7 alkyl groups of the —N(R 3 )C(═O)OC 1 -C 7 alkyl and —N(R 3 )C(═O)C 1 -C 7 alkyl substituents on D 5 are optionally substituted with 1-9 halogens.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

Q is O;

A is a difunctional cyclic group selected from 1,4-phenylene, 2,5-pyridinylene, and 2,5-pyrimidinylene, wherein A is optionally substituted with 1-3 substituent groups R 1 ;

Each R 1 is independently selected from the group consisting of halogen, CH 3 , CF 3 , —OCH 3 , and —OCF 3 ;

R W is selected from the group consisting of (a) C 1 C 5 alkyl which is optionally substituted with 1-5 F, (b) C 2-3 alkenyl which is optionally substituted with 1-3 F, (c) —OC 1 -C 3 alkyl which is optionally substituted with 1-3 F, (d)-SC 1 -C 3 alkyl which is optionally substituted with 1-3 F, (e) —OC 2-3 alkenyl which is optionally substituted with 1-3 F, (f) C 3 -C 6 cycloalkyl, (g) phenyl, (h) pyridyl, (i) —C(═O)OC 1-3 alkyl which is optionally substituted with 1-3 F, and (k) —C(═O)OH, wherein said C 3 -C 6 cycloalkyl, phenyl, and pyridinyl substituents are optionally substituted with 1-3 substituents independently selected from halogen, CH 3 , CF 3 , —OCH 3 , and —OCF 3 ;

R Y is selected from the group consisting of halogen, CH 3 , CF 3 , —OCH 3 , —OCF 3 , and —CN; and

R X and R Z are each selected from the group consisting of H, halogen, CH 3 , CF 3 , —OCH 3 , and —OCF 3 .

3. The compound of claim 1 having Formula Ia, or a pharmaceutically acceptable salt thereof:

wherein R W is selected from the group consisting of C 1 -C 4 alkyl which is optionally substituted with 1-3 F, C 2-3 alkenyl, —OCH 3 , —OCF 3 , —SCH 3 , —SCF 3 , cyclopropyl, —C(═O)OC 1-3 alkyl, and phenyl which is optionally substituted with 1-3 substituents independently selected from halogen, CH 3 , CF 3 , —OCH 3 , and —OCF 3 ;

R 3 is selected from the group consisting of H and CH 3 ;

R 4 is selected from the group consisting of H, —C(═O)OH, and —C(═O)OC 1 -C 3 alkyl;

R 5 is selected from the group consisting of H and CH 3 ;

R 6 and R 7 are H;

x is 0or 1; and

y is 0, 1, or 2.

4. The compound of claim 3 , wherein:

R W is —CH(CH 3 ) 2 ; and

R 3 is H.

5. The compound of claim 3 , wherein:

R W is —CH(CH 3 ) 2 ;

R 3 is H;

D 2 is a cyclic group selected from phenyl, indolyl, imidazolyl, cyclopropyl, C 4 -C 7 cycloalkyl which is optionally fused to a phenyl, C 5 -C 6 cycloalkenyl, and a 6-7-membered cyclic monoether or diether fused to a phenyl, wherein D 2 is optionally substituted with 1-3 substitutents independently selected from halogen, C 1 -C 3 alkyl, CF 3 , —OCH 3 , —OCF 3 , —CO 2 H, —CO 2 CH 3 , —NO 2 , —OH, and C 1 -C 2 alkylene-O—C 1 -C 4 alkyl optionally substituted with 1-9 F, and is optionally substituted with one substituent selected from 4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl and D 4 , wherein D 4 is connected directly to D 2 or is connected to D 2 through a linking group L 4 ;

D 4 is a cyclic group selected from phenyl, C 5 -C 6 cycloalkyl, C 5 -C 6 cycloalkenyl, pyrrolidinyl, piperidinyl, piperazinyl, thiazolyl, pyrazolyl, furanyl, pyridyl, indolyl, benzothiophenyl, benzofuranyl, and naphthyl, wherein D 4 is optionally substituted with 1-3 substituents independently selected from C 1 -C 5 alkyl, CF 3 , C 2 -C 6 alkenyl, —OC 1 —C 4 alkyl, —OCF 3 , halogen, —CO 2 H, —CO 2 C 1 -C 5 alkyl, —CN, and —OH, and is optionally substituted with one group D 6 , which is optionally connected directly to D 4 or is connected to D 4 through a linking group L 6 ;

D 6 is selected from the group consisting of phenyl, C 3 -C 6 cycloalkyl, pyridyl, morpholinyl, pyrrolidinyl, furanyl, 2-oxazolidinonyl and 2-azetidinonyl, wherein D 6 is optionally substituted with 1-2 substitutents independently selected from C 1 -C 3 alkyl, CF 3 , —OC 1 -C 3 alkyl, —OCF 3 , Cl, and F;

L 4 is selected from the group consisting of —CH 2 —, —O—, —C(═O)—, —CH 2 CH 2 NHCH 2 —, —CH 2 C(═O)NH— and C 2 -C 3 alkenylene;

L 6 is selected from —S(O) 2 — and C 2 -C 3 alkenylene; and

D 5 is selected from the group consisting of C 2 -C 3 alkynyl and C 1 -C 12 alkyl, wherein C 1 -C 12 alkyl is optionally substituted with 1-3F.

6. The compound of claim 1 , wherein D 2 is a cyclic group selected from phenyl, indolyl, imidazolyl, cyclopropyl, C 4 -C 7 cycloalkyl which is optionally fused to a phenyl, C 5 -C 6 cycloalkenyl, and a 6-7-membered cyclic monoether or diether fused to a phenyl, wherein D 2 is optionally substituted with 1-3 substitutents independently selected from halogen, C 1 -C 3 alkyl, CF 3 , —OCH 3 , —OCF 3 , —CO 2 H, —CO 2 CH 3 , —NO 2 , —OH, and C 1 -C 2 alkylene-O—C 1 -C 4 alkyl optionally substituted with 1-9 F, and is optionally substituted with one substituent selected from 4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl and D 4 , wherein D 4 is connected directly to D 2 or is connected to D 2 through a linking group L 4 .

7. The compound of claim 1 , wherein D 4 is a cyclic group selected from phenyl, C 5 -C 6 cycloalkyl, C 5 -C 6 cycloalkenyl, pyrrolidinyl, piperidinyl, piperazinyl, thiazolyl, pyrazolyl, furanyl, pyridyl, indolyl, benzothiophenyl, benzofuranyl, and naphthyl, wherein D 4 is optionally substituted with 1-3 substituents independently selected from C 1 -C 5 alkyl, CF 3 , C 2 -C 6 alkenyl, —OC 1 -C 4 alkyl, —OCF 3 , halogen, —CO 2 H, —CO 2 C 1 -C 5 alkyl, —CN, and —OH, and is optionally substituted with one group D 6 , which is optionally connected directly to D 4 or is connected to D 4 through a linking group L 6 .

8. The compound of claim 1 , wherein D 6 is selected from the group consisting of phenyl, C 3 -C 6 cycloalkyl, pyridyl, morpholinyl, pyrrolidinyl, furanyl, 2-oxazolidinonyl and 2-azetidinonyl, wherein D 6 is optionally substituted with 1-2 substitutents independently selected from C 1 -C 3 alkyl, CF 3 , —OC 1 -C 3 alkyl, —OCF 3 , Cl, and F.

9. The compound of claim 1 , wherein linking group L 4 is selected from the group consisting of —CH 2 —, —O—, —C(═O)—, —CH 2 CH 2 NHCH 2 —, —CH 2 C(═O)NH— and C 2 -C 3 alkenylene.

10. The compound of claim 1 , wherein linking group L 6 is selected from —S(O) 2 — and C 2 -C 3 alkenylene.

11. The compound of claim 1 , wherein D 5 is selected from the group consisting of C 2 -C 3 alkynyl and C 1 -C 12 alkyl, wherein C 1 -C 12 alkyl is optionally substituted with 1-3F.

12. The compound of claim 1 , which is selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt thereof:

Ex.

Structure

 1

 2

 3

 4

 5

 6

26

34

35

36

41

42

43

44

45

46

47

86

87

88

89

115  (a) 

115  (b) 

116 

117 

118

13. The compound of claim 1 , which is selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt thereof:

(a)

Example

wherein R is

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

(b)

Example

wherein R is

27

28

29

30

31

32

33

(c)

Example

wherein R is

37

38

39

40

(d)

Example

wherein R is

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

(e)

Example

wherein R is

90

91

92

93

94

95

96

97

98

99

(f)

Example

wherein R is

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

14. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and one or more active ingredients selected from the group consisting of:

(i) HMG-CoA reductase inhibitors;

(ii) bile acid sequestrants;

(iii) niacin and related compounds;

(iv) PPARα agonists;

(v) cholesterol absorption inhibitors;

(vi) acyl CoA:cholesterol acyltransferase (ACAT) inhibitors;

(vii) phenolic anti-oxidants;

(viii) microsomal triglyceride transfer protein (MTP)/ApoB secretion inhibitors;

(ix) anti-oxidant vitamins;

(x) thyromimetics;

(xi) LDL (low density lipoprotein) receptor inducers;

(xii) platelet aggregation inhibitors;

(xiii) vitamin B12 (also known as cyanocobalamin);

(xiv) folic acid or a pharmaceutically acceptable salt or ester thereof;

(xv) FXR and LXR ligands;

(xvi) agents that enhance ABCA1 gene expression; and

(xvii) ileal bile acid transporters.

15. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

16. A method of treating atherosclerosis in a patient in need of treatment comprising the administration of a therapeutically effective amount of the compound of claim 1 to said patient, or a pharmaceutically acceptable salt thereof.

17. A method of raising HDL-C in a patient in need of treatment comprising the administration of a therapeutically effective amount of the compound of claim 1 to said patient, or a pharmaceutically acceptable salt thereof.

18. A method of lowering LDL-C in a patient in need of treatment comprising the administration of a therapeutically effective amount of the compound of claim 1 to said patient, or a pharmaceutically acceptable salt thereof.