Granted Patent B2

US 9,527,875 · App. 14/418,147 · Granted Dec 27, 2016

Abstract

Claims (227)

1. A compound of structural formula I:

wherein

n is 1;

X is oxygen;

T is CH;

U is N;

V is CH;

A is selected from the group consisting of: phenyl and pyridine, wherein A is unsubstituted or substituted with one to five substituents selected from R a ;

B is selected from the group consisting of: phenyl, pyridine, pyrimidine, thiazole, benzimidazole, benzthiazole, benzoxazole, and benzisoxazole, wherein B is unsubstituted or substituted with one to five substituents selected from R b ;

R 1 , R 2 , R 5 and R 6 are hydrogen;

R 3 and R 4 are selected from the group consisting of: hydrogen, halogen, and —C 1-6 alkyl, wherein each C 1-6 alkyl is unsubstituted or substituted with one to three substituents selected from R L ;

R a is selected from the group consisting of:

(1) halogen,

(2) —OR e ,

(3) —NR c S(O) m R e ,

(4) —S(O) m R e ,

(5) —S(O) m NR c R d ,

(6) —NR c R d ,

(7) —C(O)R e ,

(8) —OC(O)R e ,

(9) —CO 2 R e ,

(10) —CN,

(11) —C(O)NR c R d ,

(12) —NR c C(O)R e ,

(13) —NR c C(O)OR e ,

(14) —NR c C(O)NR c R d ,

(15) —CF 3 ,

(16) —OCF 3 , and,

(17) —OCHF 2 ;

R b is independently selected from the group consisting of:

(1) —C 1-10 alkyl,

(2) halogen,

(3) —OH,

(4) —OC 1-10 alkyl,

(5) —O(CH 2 )pOC 1-10 alkyl,

(6) —O(CH 2 ) P C 3-6 cycloalkyl,

(7) —O(CH 2 )pC 2-10 cycloheteroalkyl,

(8) —O(CH 2 )pO-C 3-6 cycloalkyl,

(9) —O(CH 2 )pO-C 2-10 cycloheteroalkyl,

(10) —CF 3 ,

(11) —OCF 3 ,

(12) —OCHF 2 ,

(13) —(CH 2 )p-C 2-10 cycloheteroalkyl, and

(14) —S(O) 2 C 1-10 alkyl,

wherein each R b is unsubstituted or substituted with one to five substituents selected from R k ;

R c and R d are each independently selected from the group consisting of:

(1) hydrogen,

(2) —C 1-10 alkyl, and

(3) —C 2-10 alkenyl,

wherein each R c and R d is unsubstituted or substituted with one to three substituents independently selected from R f ;

each R e is independently selected from the group consisting of:

(1) hydrogen, and

(2) —C 1-10 alkyl,

wherein each R e is unsubstituted or substituted with one to three substituents selected from R h ;

each R f is selected from the group consisting of:

(1) halogen,

(2) C 1-10 alkyl,

(3) —OH,

(4) —O—C 1-4 alkyl,

(5) —S(O) m —C 1-4 alkyl,

(6) —CN,

(7) —CF 3 ,

(8) —OCHF 2 , and

(9) —OCF 3 ,

wherein each C 1-10 alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, halogen, cyano, and —S(O) 2 CH 3 ;

each R g is selected from the group consisting of:

(1) hydrogen,

(2) —C(O)R e , and

(3) —C 1-10 alkyl,

wherein —C 1-10 alkyl is unsubstituted or substituted with one to five fluorines;

each R h is selected from the group consisting of:

(1) halogen,

(2) C 1-10 alkyl,

(3) —OH,

(4) —O—C 1-4 alkyl,

(5) —S(O) m —C 1-4 alkyl,

(6) —CN,

(7) —CF 3 ,

(8) —OCHF 2 , and

(9) —OCF 3 ,

wherein each C 1-10 alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, halogen, cyano, and —S(O) 2 CH 3 ;

each R k is independently selected from the group consisting of:

(1) halogen,

(2) —C 1-10 alkyl,

(3) —OH,

(4) oxo,

(5) halogen,

(6) —O—C 1-4 alkyl,

(7) —SO 2 —C 1-6 alkyl,

(8) —C 1-6 alkyl-SO 2 C 1-6 alkyl,

(9) —CN,

(10) —CF 3 ,

(11) —OCHF 2 ,

(12) —OCF 3 ,

(13) —NH 2 ,

(14) —NHSO 2 C 1-6 alkyl,

(15) —NHCOC 1-6 alkyl,

(16) ═N(OCH 3 ),

(17) —P(O)(OH) 2 , and

(18) —P(O)(OC 1-6 alkyl) 2 ,

wherein each C 1-10 alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, —OC 1-6 alkyl, halogen, cyano, and —S(O) 2 C 1-6 alkyl;

R L is selected from the group consisting of:

(1) —C 1-6 alkyl,

(2) halogen,

(3) —OR e ,

(4) —NR c R d ,

(5) —C(O)R e ,

(6) —OC(O)R e ,

(7) —CO 2 R e ,

(8) —CN,

(9) —CF 3 ,

(10) —OCF 3 , and

(11) —OCHF 2 ;

each m is independently selected from: 0, 1 or 2; and

each p is independently selected from: 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

or a pharmaceutically acceptable salt thereof.

2. A compound of structural formula I:

wherein:

n is 1;

X is oxygen;

T is CH;

U is N;

V is CH;

A is selected from the group consisting of: phenyl and pyridine, wherein A is unsubstituted or substituted with one to five substituents selected from R a ;

B is selected from the group consisting of: phenyl, pyridine, pyrimidine, thiazole, benzimidazole, benzthiazole, benzoxazole, and benzisoxazole, wherein B is unsubstituted or substituted with one to five substituents selected from R b ;

R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are hydrogen;

R a is selected from the group consisting of: —C 1-6 alkyl, halogen, and —CF 3 ;

R b is independently selected from the group consisting of:

(1) —C 1-10 alkyl,

(2) halogen,

(3) —OH,

(4) —OC 1-10 alkyl,

(5) —O(CH 2 )pOC 1-10 alkyl,

(6) —O(CH 2 )pC 3-6 cycloalkyl,

(7) —O(CH 2 )pC 2-10 cycloheteroalkyl,

(8) —O(CH 2 )pO-C 3-6 cycloalkyl,

(9) —O(CH 2 )pO-C 2-10 cycloheteroalkyl,

(10) —CF 3 ,

(11) —OCF 3 ,

(12) —OCHF 2 ,

(13) —(CH 2 )p-C 2-10 cycloheteroalkyl, and

(14) —S(O) 2 C 2-10 alkyl,

wherein each R b is unsubstituted or substituted with one to five substituents selected from R k ; and

each R k is independently selected from the group consisting of:

(1) —C 1-10 alkyl,

(2) —O—C 1-4 alkyl,

(3) —OH,

(4) halogen,

(5) —SO 2 —C 1-6 alkyl,

(6) —C 1-6 alkyl-SO 2 C 1-6 alkyl,

(7) —CN,

(8) —NHSO 2 C 1-6 alkyl,

(9) ═N(OCH 3 ), and

(10) —P(O)(OC 1-6 alkyl) 2 ,

wherein each C 1-10 alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, —OC 1-6 alkyl, halogen, cyano, and —S(O) 2 C 1-6 alkyl; and

each p is independently selected from: 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

or a pharmaceutically acceptable salt thereof.

3. A compound of structural formula I:

wherein:

n is 1;

X is oxygen;

T is CH;

U is N;

V is CH;

A is phenyl, wherein phenyl is unsubstituted or substituted with one to five substituents selected from R a ;

B is selected from the group consisting of: phenyl and pyridine, wherein B is unsubstituted or substituted with one to five substituents selected from R b ;

R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are hydrogen;

R a is selected from the group consisting of: —C 1-6 alkyl, halogen, and —CF 3 ;

R b is independently selected from the group consisting of:

(1) —C 1-10 alkyl,

(2) halogen,

(3) —OH,

(4) —OC 1-10 alkyl,

(5) —O(CH 2 )pC 2-10 cycloheteroalkyl,

(6) —CF 3 , and

(7) —(CH 2 )p-C 2-10 cycloheteroalkyl,

wherein each R b is unsubstituted or substituted with one to five substituents selected from R k ; and

each R k is independently selected from the group consisting of:

(1) —C 1-10 alkyl,

(2) —OH,

(3) halogen,

(4) —SO 2 —C 1-6 alkyl,

(5) —C 1-6 alkyl-SO 2 C 1-6 alkyl, and

(6) —CN,

wherein each C 1-10 alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, —OC 1-6 alkyl, halogen, cyano, and —S(O) 2 C 1-6 alkyl; and

each p is independently selected from: 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

or a pharmaceutically acceptable salt thereof.

4. A compound selected from:

or a pharmaceutically acceptable salt thereof.

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

6. A pharmaceutical composition comprising

(1) a compound of claim 1 or a pharmaceutically acceptable salt thereof;

(2) one or more compounds selected from the group consisting of:

(a) PPAR gamma agonists and partial agonists;

(b) biguanides;

(c) protein tyrosine phosphatase-1B (PTP-1B) inhibitors;

(d) dipeptidyl peptidase IV (DP-IV) inhibitors;

(e) insulin or an insulin mimetic;

(f) sulfonylureas;

(g) α-glucosidase inhibitors;

(h) agents which improve a patient's lipid profile, said agents being selected from the group consisting of (i) HMG-CoA reductase inhibitors, (ii) bile acid sequestrants, (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPARα agonists, (v) cholesterol absorption inhibitors, (vi) acyl CoA: cholesterol acyltransferase (ACAT) inhibitors, (vii) CETP inhibitors, and (viii) phenolic anti-oxidants;

(i) PPARα/γ dual agonists,

(j) PPARδ agonists,

(k) antiobesity compounds,

(l) ileal bile acid transporter inhibitors;

(m) anti-inflammatory agents;

(n) glucagon receptor antagonists;

(o) GLP-1;

(p) GIP-1;

(q) GLP-1 analogs;

(r) HSD-1 inhibitors;

(s) SGLT 1 inhibitors; and

(t) SGLT 2 inhibitors; and

(3) a pharmaceutically acceptable carrier.

7. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a compound selected from simvastatin, ezetimibe and sitagliptin; and a pharmaceutically acceptable carrier.

8. The compound according to claim 4 selected from:

or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 4 selected from:

or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 4 selected from:

or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 4 selected from:

or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 4 selected from:

or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 4 selected from:

or a pharmaceutically acceptable salt thereof.

Assignments (8)