NOVEL COMPOUNDS AS MODULATORS OF GPR-119
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.
1 - 33 . (canceled)
34 . 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 NR;
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;
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 —, —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 ; with the proviso that when R 5 is —SO 2 R a , then R a is not unsubstituted alkyl;
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 i , 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 i , R j , R k , and 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.
35 . 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 NR;
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;
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 , —SOR 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 heterocyclcyalkyl, 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 i , 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 i , R j , R k , and R 1 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,
36 . A compound of claim 34 , wherein Ar is selected from
37 . A compound of claim 34 , wherein Z is NH or N—CH 3 .
38 . A compound of claim 34 , wherein Cy 1 is selected from
39 . A compound of claim 34 , wherein R 5 is selected from
40 . A compound of claim 34 , wherein R 5 is —C(O)OC(CH 3 ) 3 or —C(O)OCH(CH 3 ) 2 .
41 . 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;
Tert-butyl 4-{5-[2-fluoro-4-(methylsulfonyl)phenyl]-1-methyl-1H-benzo[d]imidazol-2-yl}piperidine-1-carboxylate;
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;
and pharmaceutically acceptable salts thereof.
42 . A pharmaceutical composition comprising a compound of claim 34 and a pharmaceutically acceptable carrier.
43 . The pharmaceutical composition of claim 34 , further comprising one or more additional therapeutic agents and mixtures thereof.