IP Library › Granted Patent US 9,181,214

Granted Patent B2

US 9,181,214 · App. 13/492,309 · Granted Nov 10, 2015

Bicyclic compounds as modulators of GPR-119

Inventors: Dhanapalan Nagarathnam (La Chaux-de-Fonds, CH); Swaroop Kumar V. S. Vakkalanka (La Chaux-de-Fonds, CH); Srikant Viswanadha (Hyderabad, IN); Gayatri S. Merikapudi (Hyderabad, IN)

Assignee: RHIZEN PHARMACEUTICALS SA

C07D401/04 C07D401/14 C07D405/04 C07D413/04 C07D413/14 C07D417/04 C07D417/14 C07D498/04

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Quick Facts

Patent No.: US 9,181,214
App. No.: 13/492,309
Granted: Nov 10, 2015
Kind: B2

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Abstract

The present invention relates to novel compounds of formula (A) and (B) as modulators of GPR-119, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of GPR-119 mediated diseases or disorders with them.

Claims (312)

1. A compound of formula (A-I), (A-II), (B-I), (B-II), (B-III) and (B-IV):

or a tautomer, stereoisomer, enantiomer, diastereomer, salt, or N-oxide thereof, wherein

Ar is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or Cy 1 ;

X 1 is CR 1 or N; X 2 is CR 2 or N; X 3 is CR 3 or N; and X 4 is CR 4 or N;

X is CR or N;

Z is CO, O or S(O) q ;

Cy 1 is selected from substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclic group;

each occurrence of R, R 2 , and R 3 may be same or different and is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 3-6 cycloalkylalkyl, substituted or unsubstituted C 3-6 cycloalkenyl, —OR a , —S(═O) q —R a , —NR a R b , —C(═Y)—R a , —CR a R b —C(═Y)—R a , —CR a R b —Y—CR a R b -, —C(═Y)—NR a R b -, —NR a —C(═Y)—NR a R b -, —S(═O) q —NR a R b -, —NR a —S(═O) q —NR a R b -, and —NR a —NR a R b -;

each occurrence of R 1 and R 4 may be same or different and is independently selected from hydrogen, nitro, hydroxy, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 3-6 cycloalkylalkyl, substituted or unsubstituted C 3-6 cycloalkenyl, —OR a , —S(═O) q —R a , —NR a R b , —C(═Y)—R a , —CR a R b —C(═Y)—R a , —CR a R b —Y—CR a R b -, —C(═Y)—NR a R b -, —NR a —C(═Y)—NR a R b -, —S(═O) q —NR a R b -, —NR a —S(═O) q —NR a R b -, and —NR a —NR a R b ;

each occurrence of R a and R b may be same or different and are independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 3-6 cycloalkylalkyl, and substituted or unsubstituted C 3-6 cycloalkenyl, or when two R a and/or R b substituents are directly bound to a common atom, they may be joined to form (i) an oxo (═O), thio (═S) or imino (═NR d ), or (ii) a substituted or unsubstituted, saturated or unsaturated 3-10 member ring, which may optionally include one or more heteroatoms which may be same or different and are selected from O, NR c or S;

each occurrence of R c is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 3-6 cycloalkylalkyl, and substituted or unsubstituted C 3-6 cycloalkenyl;

each occurrence of Y is independently selected from O, S, and NR a ; and

each occurrence of q independently represents 0, 1 or 2;

D and E are independently selected from CH or N;

each occurrence of R d is independently hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (═O), thio (═S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocycicyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, and —ONO 2 , or any two of R d which are directly bound to a common atom may be joined to form (i) a substituted or unsubstituted, saturated or unsaturated 3-14 membered ring, which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NR′ (where R′ is H or alkyl) or S, or (ii) an oxo (═O), thio (═S) or imino (═NR′); and

each occurrence of R e , R f , R g , R h , R j , R k and R l is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 3-6 cycloalkylalkyl, and substituted or unsubstituted C 3-6 cycloalkenyl; or any two of R e , R f , R g , R h , R j , R k , R l may be joined to form (i) a substituted or unsubstituted, saturated or unsaturated 3-14 membered ring, which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NR′ (where R′ is H or alkyl) or S, or (ii) an oxo (═O), thio (═S) or imino (═NR′) (where R′ is H or alkyl); and

each of r, s, t and u is 0, 1 or 2 with the proviso that r+s+t+u≠0.

2. A compound of formula (A-III) and (A-IV):

or a tautomer, stereoisomer, enantiomer, diastereomer, salt, or N-oxide thereof, wherein

Ar is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or Cy 1 ;

X 1 is CR 1 or N; X 2 is CR 2 or N; X 3 is CR 3 or N; and X 4 is CR 4 or N;

X is CR or N;

Z is CO, O or S(O) q ;

Cy 1 is selected from substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclic group;

each occurrence of R, R 2 , and R 3 may be same or different and is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 3-6 cycloalkylalkyl, substituted or unsubstituted C 3-6 cycloalkenyl, OR a , —S(═O) q —R a , —NR a R b , —C(═Y)—R a , —CR a R b —C(═Y)—R a , —CR a R b —Y—CR a R b -, —C(═Y)—NR a R b -, —NR a —C(═Y)—NR a R b -, —S(═O) q —NR a R b -, —NR a —S(═O) q —NR a R b -, and —NR a —NR a R b -;

each occurrence of R 1 and R 4 may be same or different and is independently selected from hydrogen, nitro, hydroxy, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 3-6 cycloalkylalkyl, substituted or unsubstituted C 3-6 cycloalkenyl, OR a , —S(═O) q —R a , —NR a R b , —C(═Y)—R a , —CR a R b —C(═Y)—R a , —CR a R b —Y—CR a R b -, —C(═Y)—NR a R b -, —NR a —C(═Y)—NR a R b -, —S(═O) q —NR a R b -, —NR a —S(═O) q —NR a R b -, and —NR a —NR a R b -;

each occurrence of Y is independently selected from O, S, and NR a ; and

each occurrence of q independently represents 0, 1 or 2;

D and E are independently selected from CH or N;

each of r, s, t and u is 0, 1 or 2 with the proviso that r+s+t+u≠0,

a) that for compound of formula (A-III), wherein Z is O or S and X 4 is N or CR 4 then Ar cannot be

b) that for compound of formula (A-IV) wherein Z is O or S and X 1 is N or CR 1 then Ar cannot be

wherein

R 1 and R 4 is as defined above for compound of formula (A);

W is S(═O) 2 —R 1 , S(═O) 2 —NR 1a R 1 , —C(═O)—R 1 , —C(═O)—O—R 1 , —C(═O)—NR 1a R 1 , —NR 1a —S(═O) 2 —R 1 , halo, or a 4 to 10-membered optionally substituted heteroaryl, which contains 1-4 heteroatoms selected from N, O, and S;

R 1a , at each occurrence, is independently hydrogen or (C 1 -C 8 )alkyl; and

R 1 is optionally substituted (C 1 -C 6 )-alkyl, optionally substituted (C 2 -C 6 )-alkenyl, optionally substituted (C 2 -C 6 )-alkynyl, optionally substituted (C 3 -C 12 )-cycloalkyl, optionally substituted (C 1 -C 10 )aryl, a 4 to 10-membered optionally substituted heteroaryl, which contains 1-4 heteroatoms selected from N, O, and S; or a 4 to 10-membered heterocyclyl, which contains 1-4 heteroatoms selected from N, O, and S.

3. A compound of formula (A-I), (A-II), (B-I), (B-II), (B-III) and (B-IV):

or a tautomer, stereoisomer, enantiomer, diastereomer, salt, or N-oxide thereof, wherein Ar is selected from

X 1 is CR 1 or N; X 2 is CR 2 or N; X 3 is CR 3 or N; and X 4 is CR 4 or N;

X is CR or N;

Z is CO, O or S(O) q ;

Cy 1 is selected from substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclic group;

each occurrence of Y is independently selected from O, S, and NR a ; and

each occurrence of q independently represents 0, 1 or 2;

D and E are independently selected from CH or N;

each of r, s, t and u is 0, 1 or 2 with the proviso that r+s+t+u≠0.

4. A compound of claim 1 , wherein Z is, O or S.

5. A compound of claim 1 , wherein X 1 is CR 1 or N, and R 1 is H or Halogen.

6. A compound of claim 1 , wherein X 2 in compound of formula (A), (A-II), (A-IV), (B), (B-II) or (B-IV) is CH.

7. A compound of claim 1 , wherein X 3 in compound of formula (A), (A-II), (A-IV), (B), (B-II) or (B-IV) is CH.

8. A compound of claim 1 , wherein X 4 is CR 4 or N, and R 4 is H or Halogen.

9. A compound of claim 1 , wherein X is CR or N.

10. A compound of formula (A-I), (A-II), (B-I), (B-II), (B-M) and (B-IV):

(B-II) (B-IV)

or a tautomer, stereoisomer, enantiomer, diastereomer, salt, or N-oxide thereof, wherein

Ar is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or Cy 1 ;

X 1 is CR 1 or N; X 2 is CR 2 or N; X 3 is CR 3 or N; and X 4 is CR 4 or N;

X is CR or N;

Z is CO, O or S(O) q ;

Cy 1 is selected from

each occurrence of R 1 and R 4 may be same or different and is independently selected from hydrogen, nitro, hydroxy, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 3-6 cycloalkylalkyl, substituted or unsubstituted C 3-6 cycloalkenyl, OR a , —S(═O) q —R a , —NR a R b , —C(═Y)—R a , —CR a R b —C(═Y)—R a , —CR a R b —Y—CR a R b -, —C(═Y)—NR a R b -, —NR a —C(═Y)—NR a R b -, —S(═O) q —NR a R b -, —NR a —S(═O) q —NR a R b -, and —NR a —NR a R b ;

each occurrence of Y is independently selected from O, S, and NR a ; and

each occurrence of q independently represents 0, 1 or 2;

D and E are independently selected from CH or N;

each of r, s, t and u is 0, 1 or 2 with the proviso that r+s+t+u≠0.

11. A compound of formula (A-IA), (A-IIA), (B-IA), (B-IIA), (B-IIIA) or (B-IVA):

or a tautomer, stereoisomer, enantiomer, diastereomer, salt, or N-oxide thereof,

wherein

Ar is

G is independently selected from

R′ is substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsubstituted cycloalkyl;

X 1 is CR 1 or N; X 2 is CR 2 or N; X 3 is CR 3 or N and X 4 is CR 4 or N;

X is CR or N;

each occurrence of R, R 1 , R 2 , R 3 and R 4 may be same or different and is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 3-6 cycloalkylalkyl, substituted or unsubstituted C 3-6 cycloalkenyl, —OR a , —S(═O) q —R a , —NR a R b , —C(═Y)—R a , —CR a R b —C(═Y)—R a , —CR a R b —Y—CR a R b -, —C(═Y)—NR a R b -, —NR a —C(═Y)—NR a R b -, —S(═O) q —NR a R b -, —NR a —S(═O) q —NR a R b -, and —NR a —NR a R b -;

each occurrence of Y is independently selected from O, S, and NR a ; and

each occurrence of q independently represents 0, 1 or 2;

R 5 is selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (═O), thio (═S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, —COOR a , —C(O)R a , —C(S)R a , —C(O)NR a R b , —C(O)ONR a R b , —NR a R b , —NR a CONR a R b , —N(R a )SOR b , —N(R a )SO 2 R b , -(═N—N(R a )R b ), —NR a C(O)OR b , —NR a C(O)R b -, —NR a C(S)R b —NR a C(S)NR a R b , —SONR a R b -, —SO 2 NR a R b -, —OR a , —OR a C(O)NR a R b , —OR a C(O) OR b -, —OC(O)R a , —OC(O)NR a R b , —R a NR b C(O)R a , —R a OR b , —R a C(O)OR b , —R a C(O)NR a R b , —R a C(O)R b , —R a OC(O)R b , —SR a , —SO 2 R a , and —ONO 2 ; each occurrence of R d is independently hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (═O), thio (═S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocycicyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, and —ONO 2 , or any two of R d which are directly bound to a common atom may be joined to form (i) a substituted or unsubstituted, saturated or unsaturated 3-14 membered ring, which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NR′ (where R′ is H or alkyl) or S, or (ii) an oxo (═O), thio (═S) or imino (═NR′); and

R 6 is selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, —COOR a , —C(O)R a , —C(S)R a , —C(O)NR a R b , —C(O)ONR a R b , —NR a R b , —NR a CONR a R b , —N(R a )SOR b , —N(R a )SO 2 R b , -(═N—N(R a )R b ), —NR a C(O)OR b , —NR a C(O)R b -, —NR a C(S)R b —NR a C(S)NR a R b , —SONR a R b -, —SO 2 NR a R b -, —OR a , —OR a C(O)NR a R b , —OR a C(O)OR b -, —OC(O)R a , —OC(O)NR a R b , —R a NR b C(O)R a , —R a OR b , —R a C(O)OR b , —R a C(O)NR a R b , —R a C(O)R b , —R a OC(O)R b , —SR a , —SOR a , —SO 2 R a , and —ONO 2 ;

p is 0, 1, 2, 3 or 4.

12. A compound of formula (A-IIIA) or (A-IVA)

wherein

Ar is

G is independently selected from

R′ is substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsubstituted cycloalkyl.

X 1 is CR 1 or N; X 2 is CR 2 or N; X 3 is CR 3 or N and X 4 is CR 4 or N;

X is CR or N;

each occurrence of Y is independently selected from O, S, and NR a ; and

each occurrence of q independently represents 0, 1 or 2;

p is 0, 1, 2, 3 or 4,

with the proviso

a) that for compound of formula (A-IIIA), wherein Z is O or S and X 4 is N or CR 4 then Ar-G cannot be

b) that for compound of formula (A-IVA) wherein Z is O or S and X 1 is N or CR 1 then Ar-G cannot be

wherein

R 1 and R 4 is as defined above for compound of formula (A)

W is S(═O) 2 —R 1 , S(═O) 2 —NR 1a R 1 , —C(═O)—R 1 , —C(═O)—O—R 1 , —C(═O)-NR 1a R 1 , —NR 1a —S(═O) 2 —R 1 , halo, or a 4 to 10-membered optionally substituted heteroaryl, which contains 1-4 heteroatoms selected from N, O, and S;

R 1a , at each occurrence, is independently hydrogen or (C 1 -C 8 )alkyl;

13. A compound of claim 11 wherein X 1 is CR 1 or N and R 1 is H or Halogen.

14. A compound of claim 11 , wherein X 2 in compound of formula (A-IIA), (A-IVA), (B-IIA) or (B-IVA) is CH.

15. A compound of claim 11 , wherein X 3 in compound of formula (A-IA), (A-IIIA), (B-IA) or (B-IIIA) is CH.

16. A compound of claim 11 , wherein X 4 is CR 4 or N, and R 4 is H or Halogen.

17. A compound of claim 11 , wherein X is CR or N.

18. A compound of claim 11 , wherein R 5 is selected from

19. A compound of claim 18 , wherein R 5 is —C(O)OC(CH 3 ) 3 or —C(O)OCH(CH 3 ) 2 .

20. A compound of claim 11 , wherein p is 0 or 1.

21. A compound of claim 11 , wherein R 6 is halogen, substituted or unsubstituted alkyl or —OR a ; wherein R a is substituted or unsubstituted alkyl.

22. A compound of claim 21 , wherein R 6 is —F, —CH 3 , —CF 3 or —OCH 3 .

23. A compound of claim 11 , wherein Ar-G is selected from

24. A compound of claim 23 , wherein G is independently selected from

25. A compound of claim 23 , wherein X 1 is CH or CF; X is N or CH and Z is S or O.

26. A compound of claim 25 wherein X 1 is CH or CF; X is N or CH and Z is O.

27. A compound of formula (A-IB) and (A-IIB)

or a tautomer, stereoisomer, enantiomer, diastereomer, salt, or N-oxide thereof,

wherein

Z is O or S;

Ar1-G is

p is 0, 1-7 or 8;

G is selected from

R′ is substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsubstituted cycloalkyl;

X 1 is CR 1 or N; X 2 is CR 2 or N; X 3 is CR 3 or N and X 4 is CR 4 or N;

X is CR or N;

each occurrence of Y is independently selected from O, S, and NR a ;

each occurrence of q independently represents 0, 1 or 2;

28. A compound of formula (A-IIIB) and (A-IVB)

or a tautomer, stereoisomer, enantiomer, diastereomer, salt, or N-oxide thereof,

wherein

Z is O or S;

Ar1-G is

p is 0, 1-7 or 8;

G is selected from

R′ is substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsubstituted cycloalkyl;

X 1 is CR 1 or N; X 2 is CR 2 or N; X 3 is CR 3 or N and X 4 is CR 4 or N;

X is CR or N;

each occurrence of R, R 1 , R 2 , and R 3 and R 4 may be same or different and is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 3-6 cycloalkylalkyl, substituted or unsubstituted C 3-6 cycloalkenyl, —OR a , —S(═O) q —R a , —NR a R b , —C(═Y)—R a , —CR a R b —C(═Y)—R a , —CR a R b —Y—CR a R b -, —C(═Y)—NR a R b -, —NR a —C(═Y)—NR a R b -, —S(═O) q —NR a R b -, —NR a —S(═O) q —NR a R b -, and —NR a —NR a R b -;

each occurrence of Y is independently selected from O, S, and NR a ;

each occurrence of q independently represents 0, 1 or 2;

with the proviso

a) that for compound of formula (A-IIIB), wherein Z is O or S and X 4 is N or CR 4 then Ar1-G cannot be

b) that for compound of formula (A-IVB) wherein Z is O or S and X 1 is N or CR 1 then Ar1-G cannot be

wherein

R 1 and R 4 is as defined above for compound of formula (A)

R 1a , at each occurrence, is independently hydrogen or (C 1 -C 8 )alkyl; and

R 1 is optionally substituted (C 1 -C 6 )-alkyl, optionally substituted (C 2 -C 6 )-alkenyl, optionally substituted (C 2 -C 6 )-alkynyl, optionally substituted (C 3 -C 12 )-cycloalkyl, optionally substituted (C 1 -C 10 )aryl, a 4- to 10-membered optionally substituted heteroaryl, which contains 1-4 heteroatoms selected from N, O, and S; or a 4 to 10-membered heterocyclyl, which contains 1-4 heteroatoms selected from N, O, and S.

29. A compound selected from

2-[1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl]-5-[2-fluoro-4-(methylsulfonyl)phenyl]-1H-benzo[d]imidazole;

Tert-butyl 4-{5-[2-fluoro-4-(methylsulfonyl)phenyl]-1H-benzo[d]imidazol-2-yl}piperidine-1-carboxylate;

2-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]-5-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazole;

Tert-butyl 4-{5-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate;

Tert-butyl 4-{5-[2-fluoro-4-(methylsulfonyl)phenyl]-1-methyl-1H-benzo[d]imidazol-2-yl}piperidine-1-carboxylate;

Tert-butyl 4-{6-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate;

Isopropyl 4-{5-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate;

Tert-butyl 4-{7-fluoro-5-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate;

Tert-butyl 4-[5-(4-cyanophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate;

Tert-butyl 4-{5-[3-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate;

Tert-butyl 4-{5-[4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate;

Tert-butyl 4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate;

Tert-butyl 4-{5-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate;

Isopropyl 4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate;

Tert-butyl 4-{5-[3-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate;

2-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]-5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazole;

Tert-butyl 4-[5-(4-cyano-3-fluorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate;

Isopropyl 4-{5-[3-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate;

Tert-butyl 4-{5-[3-fluoro-4-(1H-tetrazol-5-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate;

Tert-butyl 4-[5-(4-carbamoyl-3-chlorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate;

Tert-butyl 4-[5-(4-carbamoyl-3-fluorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate;

Tert-butyl 4-[5-(3-fluoro-4-isopropoxyphenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate;

Cyclobutyl 4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate;

Sec-butyl 4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate;

Pentan-3-yl 4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate;

5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole;

Isopropyl 4-{5-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate;

Isopropyl 4-[5-(4-formylphenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate;

Isopropyl 4-{5-[4-(difluoromethyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate;

Isopropyl 4-[5-(4-carbamoyl-3-chlorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate;

Isopropyl 4-[5-(4-carbamoyl-3-fluorohenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate;

1-{4-[5-(2-fluoro-4-(1H-tetrazol-1-yl)phenyl)benzo[d]oxazol-2-yl]piperidin-1-yl}-2-methylpropan-1-one;

Isopropyl 4-{6-[4-(difluoromethyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate;

6-{2-[1-(isopropoxycarbonyl)piperidin-4-yl]benzo[d]oxazol-5-yl}nicotinic acid;

5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-[1-(methylsulfonyl)piperidin-4-yl]benzo[d]oxazole;

Isopropyl 4-[5-(5-carbamoylpyridin-2-yl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate;

Isopropyl 4-[5-(4-carbamoyl-2-fluorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate;

Isopropyl 4-[5-(4-carbamoyl-2-chlorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate;

2-Fluoro-4-{2-[1-(3-methylbutanoyl)piperidin-4-yl]benzo[d]oxazol-5-yl}benzamide;

1-{4-[5-(2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl]piperidin-1-yl}-3-methylbutan-1-one;

5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-[1-(2-methoxyethyl)piperidin-4-yl]benzo[d]oxazole;

Isopropyl 4-{5-[3-fluoro-4-(methylcarbamoyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate;

2-Fluoro-4-[2-(1-isobutyrylpiperidin-4-yl)benzo[d]oxazol-5-yl]benzamide;

Isopropyl 4-[6-(4-carbamoyl-3-fluorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate;

Isopropyl 4-{5-[3-fluoro-4-(2-hydroxyethylcarbamoyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate;

Isopropyl 4-{5-[3-fluoro-4-(isopropylcarbamoyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate;

Isopropyl 4-{5-[4-(N-methylsulfamoyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate;

Isopropyl 4-{5-[6-(methylcarbamoyl)pyridin-3-yl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate;

Isopropyl 4-{5-[3-methyl-4-(methylcarbamoyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate;

Isopropyl 4-{5-[4-(cyclopropylcarbamoyl)-3-fluorophenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate;

2-Fluoro-4-{2-[1-(5-fluoropyrimidin-2-yl)piperidin-4-yl]benzo[d]oxazol-5-yl}benzamide;

Tert-butyl 4-[5-(4-carbamoyl-3-fluorophenyl)benzofuran-2-yl]-5,6-dihydropyridine-1(2H)-carboxylate;

2-fluoro-4-{2-[1-(propylsulfonyl)piperidin-4-yl]benzo[d]oxazol-5-yl}benzamide;

Tert-butyl 4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]-1H-benzo[d]imidazol-5-yl}-5,6-dihydropyridine-1(2H)-carboxylate;

Tert-butyl 4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]-1H-benzo[d]imidazol-5-yl}piperidine-1-carboxylate;

5-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]-2-[2-fluoro-4-(methylsulfonyl)phenyl]-1H-benzo[d]imidazole;

Tert-butyl 4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}-5,6-dihydropyridine-1(2H)-carboxylate;

Tert-butyl 4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}piperidine-1-carboxylate;

2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(piperidin-4-yl)benzo[d]oxazole 2,2,2-trifluoro acetate;

5-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]-2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazole;

Tert-butyl 4-{7-fluoro-2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}piperidine-1-carboxylate;

Isopropyl 4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}piperidine-1-carboxylate;

Tert-butyl 4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]thiazol-6-yl}-5,6-dihydropyridine-1(2H)-carboxylate;

Tert-butyl 4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]thiazol-5-yl}-5,6-dihydropyridine-1(2H)-carboxylate;

Tert-butyl 4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-6-yl}piperidine-1-carboxylate;

Tert-butyl 4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]thiazol-5-yl}piperidine-1-carboxylate;

Ethyl 4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}piperidine-1-carboxylate;

Tert-butyl 4-{2-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-5-yl}piperidine-1-carboxylate;

Isopropyl 4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-6-yl}piperidine-1-carboxylate;

Ethyl 4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-6-yl}piperidine-1-carboxylate;

Benzyl 4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}piperidine-1-carboxylate;

Isobutyl 4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}piperidine-1-carboxylate;

Isopropyl 4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]thiazol-6-yl}piperidine-1-carboxylate;

Isopropyl 4-{2-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-5-yl}piperidine-1-carboxylate;

Isopropyl 4-(2-p-tolylbenzo[d]oxazol-6-yl)piperidine-1-carboxylate;

3-{4-[2-(2-fluoro-4-(methylsulfonyl)phenyl)benzo[d]oxazol-5-yl]-5,6-dihydropyridin-1(2H)-ylsulfonyl}propan-1-ol;

3-{4-[2-(2-fluoro-4-(methylsulfonyl)phenyl)benzo[d]oxazol-5-yl]piperidin-1-ylsulfonyl}propan-1-ol;

Tert-butyl 4-[2-(4-carbamoyl-3-fluorophenyl)benzo[d]oxazol-5-yl]piperidine-1-carboxylate;

2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl]benzo[d]oxazole;

Tert-butyl 4-{2-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-6-yl}piperidine-1-carboxylate

Isopropyl 4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}piperazine-1-carboxylate;

Tert-butyl 4-{2-[4-(trifluoromethyl)phenyl]oxazolo[5,4-b]pyridin-6-yl}-5,6-dihydropyridine-1(2H)-carboxylate;

Tert-butyl 4-{2-[4-(trifluoromethyl)phenyl]oxazolo[5,4-b]pyridin-6-yl}piperidine-1-carboxylate;

and pharmaceutically acceptable salts thereof.

30. A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

31. The pharmaceutical composition of claim 30 , further comprising one or more additional therapeutic agents and mixtures thereof.

32. A compound of formula (A-I), (A-II), (B-I), (B-II), (B-III) and (B-IV):

or a tautomer, stereoisomer, enantiomer, diastereomer, salt, or N-oxide thereof,

wherein

Ar is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or Cy 1 ;

X 1 is CR 1 or N; X 2 is CR 2 or N; X 3 is CR 3 or N; and X 4 is CR 4 or N;

X is N;

Z is CO, O or S(O) q ;

Cy 1 is selected from substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclic group;

each occurrence of R 1 and R 4 may be same or different and is independently selected from hydrogen, nitro, hydroxy, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 3-6 cycloalkylalkyl, substituted or unsubstituted C 3-6 cycloalkenyl, OR a, —S(═O) q —R a , —NR a R b , —C(═Y)—R a , —CR a R b —C(═Y)—R a , —CR a R b —Y—CR a R b -, —C(═Y)—NR a R b -, —NR a —C(═Y)—NR a R b -, —S(═O) q —NR a R b -, —NR a —S(═O) q —NR a R b -, and —NR a —NR a R b ;

each occurrence of Y is independently selected from O, S, and NR a ; and

each occurrence of q independently represents 0, 1 or 2;

D and E are independently selected from CH or N;

each of r, s, t and u is 0, 1 or 2 with the proviso that r+s+t+u≠0.

33. A compound of formula (A-I), (A-II), (B-I), (B-II), (B-III) and (B-IV):

or a tautomer, stereoisomer, enantiomer, diastereomer, salt, or N-oxide thereof,

wherein

Ar is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or Cy 1 ;

X 1 is CR 1 or N; X 2 is CR 2 or N; X 3 is CR 3 or N; and X 4 is CR 4 or N;

X is N;

Z is CO, O or S(O) q ;

Cy 1 is selected from

each occurrence of Y is independently selected from O, S, and NR a ; and

each occurrence of q independently represents 0, 1 or 2;

D and E are independently selected from CH or N;

each of r, s, t and u is 0, 1 or 2 with the proviso that r+s+t+u≠0.

Assignments (3)

CHANGE OF ADDRESS Recorded Oct 6, 2021

From: RHIZEN PHARMACEUTICALS AG

To: RHIZEN PHARMACEUTICALS AG

Reel/Frame 057836/0286 →

CHANGE OF ADDRESS Recorded Mar 22, 2021

From: RHIZEN PHARMACEUTICALS SA

To: RHIZEN PHARMACEUTICALS SA

Reel/Frame 056775/0375 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 26, 2012

From: NAGARATHNAM, DHANAPALAN; VAKKALANKA, SWAROOP KUMAR V.S.; VISWANADHA, SRIKANT; MERIKAPUDI, GAYATRI S

To: RHIZEN PHARMACEUTICALS SA

Reel/Frame 029198/0888 →

Priority Claims (5)

IN 1958/CHE/2011 · Jun 9, 2011 · national

IN 2352/CHE/2011 · Jul 11, 2011 · national

IN 3462/CHE2011 · Oct 7, 2011 · national

IN 3463/CHE/2011 · Oct 7, 2011 · national

IN 82/CHE/2012 · Jan 9, 2012 · national

Continuity (3)

Provisional Application 61543152 · Oct 4, 2011

Provisional Application 61543157 · Oct 4, 2011

Related Publication 20130045986A1 · Feb 21, 2013