U.S. patent application number 15/674376 was filed with the patent office on 2017-11-30 for novel compounds as modulators of gpr-119.
The applicant listed for this patent is Rhizen Pharmaceuticals SA. Invention is credited to Gayatri S. Merikapudi, Dhanapalan Nagarathnam, Swaroop K. Vakkalanka, Srikant Viswanadha.
Application Number | 20170342089 15/674376 |
Document ID | / |
Family ID | 47296484 |
Filed Date | 2017-11-30 |
United States Patent
Application |
20170342089 |
Kind Code |
A1 |
Nagarathnam; Dhanapalan ; et
al. |
November 30, 2017 |
NOVEL COMPOUNDS AS MODULATORS OF GPR-119
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.
Inventors: |
Nagarathnam; Dhanapalan; (La
Chaux-de-Fonds, CH) ; Vakkalanka; Swaroop K.; (La
Chaux-de-Fonds, CH) ; Viswanadha; Srikant;
(Hyderabad, IN) ; Merikapudi; Gayatri S.;
(Hyderabad, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Rhizen Pharmaceuticals SA |
La Chaux-de-Fonds |
|
CH |
|
|
Family ID: |
47296484 |
Appl. No.: |
15/674376 |
Filed: |
August 10, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14832349 |
Aug 21, 2015 |
9777018 |
|
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15674376 |
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|
13492309 |
Jun 8, 2012 |
9181214 |
|
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14832349 |
|
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61543152 |
Oct 4, 2011 |
|
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61543157 |
Oct 4, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 9/12 20180101; C07D
498/04 20130101; A61P 19/08 20180101; A61P 27/12 20180101; C07D
413/04 20130101; A61P 3/00 20180101; C07D 405/04 20130101; A61P
3/10 20180101; A61P 3/06 20180101; A61P 43/00 20180101; A61P 25/28
20180101; C07D 401/14 20130101; A61P 17/02 20180101; A61P 13/12
20180101; A61P 25/00 20180101; C07D 401/04 20130101; A61P 25/02
20180101; C07D 413/14 20130101; A61P 25/08 20180101; A61P 9/10
20180101; A61P 5/48 20180101; A61P 27/02 20180101; A61P 1/18
20180101; C07D 417/14 20130101; A61P 25/16 20180101; A61P 29/00
20180101; A61P 9/00 20180101; C07D 417/04 20130101; A61P 1/00
20180101; A61P 27/06 20180101; A61P 3/04 20180101; A61P 25/14
20180101; A61P 9/04 20180101 |
International
Class: |
C07D 498/04 20060101
C07D498/04; C07D 417/04 20060101 C07D417/04; C07D 413/04 20060101
C07D413/04; C07D 401/04 20060101 C07D401/04; C07D 405/04 20060101
C07D405/04; C07D 401/14 20060101 C07D401/14; C07D 417/14 20060101
C07D417/14; C07D 413/14 20060101 C07D413/14 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 9, 2011 |
IN |
1958/CHE/2011 |
Jul 11, 2011 |
IN |
2352/CHE/2011 |
Oct 7, 2011 |
IN |
3462/CHE/2011 |
Oct 7, 2011 |
IN |
3463/CHE/2011 |
Jan 9, 2012 |
IN |
82/CHE/2012 |
Claims
1-33. (canceled)
34. A compound of formula (A-I), (A-II), (B-I), (B-II), (B-III) and
(B-IV): ##STR00193## 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.sup.1; X.sup.1 is CR.sup.1 or N; X.sup.2 is
CR.sup.2 or N; X.sup.3 is CR.sup.3 or N; and X.sup.4 is CR.sup.4 or
N; X is CR or N; Z is NR; Cy.sup.1 is selected from substituted or
unsubstituted cycloalkyl or substituted or unsubstituted
heterocyclic group; each occurrence of R, R.sup.2, and R.sup.3 may
be same or different and is independently selected from hydrogen,
nitro, hydroxy, cyano, halogen, substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl,
substituted or unsubstituted C.sub.2-6 alkynyl, substituted or
unsubstituted C.sub.3-6 cycloalkyl, substituted or unsubstituted
C.sub.3-6 cycloalkylalkyl, substituted or unsubstituted C.sub.3-6
cycloalkenyl, --OR.sup.a, --S(.dbd.O).sub.q--R.sup.a,
--NR.sup.aR.sup.b, C(.dbd.Y)--R.sup.a,
--CR.sup.aR.sup.b--C(.dbd.Y)--R.sup.a,
--CR.sup.aR.sup.b--Y--CR.sup.aR.sup.b--,
--C(.dbd.Y)--NR.sup.aR.sup.b--,
--NR.sup.a--C(.dbd.Y)--NR.sup.aR.sup.b--,
--S(.dbd.O).sub.q--NR.sup.aR.sup.b--,
--NR.sup.a--S(.dbd.O).sub.q--NR.sup.aR.sup.b--, and
--NR.sup.a--NR.sup.aR.sup.b--; each occurrence of R.sup.1 and
R.sup.4 may be same or different and is independently selected from
hydrogen, nitro, hydroxy, halogen, substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl,
substituted or unsubstituted C.sub.2-6 alkynyl, substituted or
unsubstituted C.sub.3-6 cycloalkyl, substituted or unsubstituted
C.sub.3-6 cycloalkylalkyl, substituted or unsubstituted C.sub.3-6
cycloalkenyl, --OR.sup.a, --S(.dbd.O).sub.q--R.sup.a,
--NR.sup.aR.sup.b, C(.dbd.Y)--R.sup.a,
--CR.sup.aR.sup.b--C(.dbd.Y)--R.sup.a,
--CR.sup.aR.sup.b--Y--CR.sup.aR.sup.b--,
--C(.dbd.Y)--NR.sup.aR.sup.b--,
--NR.sup.a--C(.dbd.Y)--NR.sup.aR.sup.b--,
--S(.dbd.O).sub.q--NR.sup.aR.sup.b--,
--NR.sup.a--S(.dbd.O).sub.q--NR.sup.aR.sup.b--, and
--NR.sup.a--NR.sup.aR.sup.b; each occurrence of R.sup.a and R.sup.b
may be same or different and are independently selected from
hydrogen, nitro, hydroxy, cyano, halogen, substituted or
unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl,
substituted or unsubstituted C.sub.3-6 cycloalkyl, substituted or
unsubstituted C.sub.3-6 cycloalkylalkyl, and substituted or
unsubstituted C.sub.3-6 cycloalkenyl, or when two R.sup.a and/or
R.sup.b substituents are directly bound to a common atom, they may
be joined to form (i) an oxo (.dbd.O), thio (.dbd.S) or imino
(.dbd.NR.sup.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.sup.c or S; each occurrence of R.sup.c is independently
selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted
or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl,
substituted or unsubstituted C.sub.3-6 cycloalkyl, substituted or
unsubstituted C.sub.3-6 cycloalkylalkyl, and substituted or
unsubstituted C.sub.3-6 cycloalkenyl; each occurrence of Y is
independently selected from O, S, and NR.sup.a; and each occurrence
of q independently represents 0, 1 or 2; D and E are independently
selected from CH or N; R.sup.5 is selected from hydrogen, hydroxy,
halogen, carboxyl, cyano, nitro, oxo (.dbd.O), thio (.dbd.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.sup.a, --C(O)R.sup.a,
--C(S)R.sup.a, --C(O)NR.sup.aR.sup.b, --C(O)ONR.sup.aR.sup.b,
--NR.sup.aR.sup.b, --NR.sup.aCONR.sup.aR.sup.b,
--N(R.sup.a)SOR.sup.b, --N(R.sup.a)SO.sub.2R.sup.b,
-(.dbd.N--N(R.sup.a)R.sup.b), --NR.sup.aC(O)OR.sup.b,
--NR.sup.aC(O)R.sup.b--, --NR.sup.aC(S)R.sup.b
NR.sup.aC(S)NR.sup.aR.sup.b, --SONR.sup.aR.sup.b--, --OR.sup.a,
--OR.sup.aC(O)NR.sup.aR.sup.b, --OR.sup.aC(O)OR.sup.b--,
--OC(O)R.sup.a, --OC(O)NR.sup.aR.sup.b,
--R.sup.aNR.sup.bC(O)R.sup.a, --R.sup.aOR.sup.b,
--R.sup.aC(O)OR.sup.b, --R.sup.aC(O)NR.sup.aR.sup.b,
--R.sup.aC(O)R.sup.b, --R.sup.aOC(O)R.sup.b, --SR.sup.a,
--SOR.sup.a, --SO.sub.2R.sup.a, and --ONO.sub.2; with the proviso
that when R.sup.5 is --SO.sub.2R.sup.a, then R.sup.a is not
unsubstituted alkyl; each occurrence of R.sup.d is independently
hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (.dbd.O),
thio (.dbd.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.sub.2, or any two of
R.sup.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 (.dbd.O),
thio (.dbd.S) or imino (.dbd.NR'); and each occurrence of R.sup.e,
R.sup.f, R.sup.g, R.sup.h, R.sup.i, R.sup.j, R.sup.k and R.sup.l is
independently selected from hydrogen, nitro, hydroxy, cyano,
halogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted
or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6
cycloalkyl, substituted or unsubstituted C.sub.3-6 cycloalkylalkyl,
and substituted or unsubstituted C.sub.3-6 cycloalkenyl; or any two
of R.sup.e, R.sup.f, R.sup.g, R.sup.h, R.sup.i, R.sup.j, R.sup.k,
and R.sup.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 (.dbd.O), thio (.dbd.S) or imino
(.dbd.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): ##STR00194## 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.sup.1; X.sup.1
is CR.sup.1 or N; X.sup.2 is CR.sup.2 or N; X.sup.3 is CR.sup.3 or
N; and X.sup.4 is CR.sup.4 or N; X is CR or N; Z is NR; Cy.sup.1 is
selected from substituted or unsubstituted cycloalkyl or
substituted or unsubstituted heterocyclic group; each occurrence of
R, R.sup.2, and R.sup.3 may be same or different and is
independently selected from hydrogen, nitro, hydroxy, cyano,
halogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted
or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6
cycloalkyl, substituted or unsubstituted C.sub.3-6 cycloalkylalkyl,
substituted or unsubstituted C.sub.3-6 cycloalkenyl, --OR.sup.a,
--S(.dbd.O).sub.q--R.sup.a, --NR.sup.aR.sup.b, C(.dbd.Y)--R.sup.a,
--CR.sup.aR.sup.b--C(.dbd.Y)--R.sup.a,
--CR.sup.aR.sup.b--Y--CR.sup.aR.sup.b--,
--C(.dbd.Y)--NR.sup.aR.sup.b--,
--NR.sup.a--C(.dbd.Y)--NR.sup.aR.sup.b--,
--S(.dbd.O).sub.q--NR.sup.aR.sup.b--,
--NR.sup.a--S(.dbd.O).sub.q--NR.sup.aR.sup.b--, and
--NR.sup.a--NR.sup.aR.sup.b--; each occurrence of R.sup.1 and
R.sup.4 may be same or different and is independently selected from
hydrogen, nitro, hydroxy, halogen, substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl,
substituted or unsubstituted C.sub.2-6 alkynyl, substituted or
unsubstituted C.sub.3-6 cycloalkyl, substituted or unsubstituted
C.sub.3-6 cycloalkylalkyl, substituted or unsubstituted C.sub.3-6
cycloalkenyl, --OR.sup.a, --S(.dbd.O).sub.q--R.sup.a,
--NR.sup.aR.sup.b, C(.dbd.Y)--R.sup.a,
--CR.sup.aR.sup.b--C(.dbd.Y)--R.sup.a,
--CR.sup.aR.sup.b--Y--CR.sup.aR.sup.b--,
--C(.dbd.Y)--NR.sup.aR.sup.b--,
--NR.sup.a--C(.dbd.Y)--NR.sup.aR.sup.b--,
--S(.dbd.O).sub.q--NR.sup.aR.sup.b--,
--NR.sup.a--S(.dbd.O).sub.q--NR.sup.aR.sup.b--, and
--NR.sup.a--NR.sup.aR.sup.b--; each occurrence of R.sup.a and
R.sup.b may be same or different and are independently selected
from hydrogen, nitro, hydroxy, cyano, halogen, substituted or
unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl,
substituted or unsubstituted C.sub.3-6 cycloalkyl, substituted or
unsubstituted C.sub.3-6 cycloalkylalkyl, and substituted or
unsubstituted C.sub.3-6 cycloalkenyl, or when two R.sup.a and/or
R.sup.b substituents are directly bound to a common atom, they may
be joined to form (i) an oxo (.dbd.O), thio (.dbd.S) or imino
(.dbd.NR.sup.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.sup.c or S; each occurrence of R.sup.c is independently
selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted
or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl,
substituted or unsubstituted C.sub.3-6 cycloalkyl, substituted or
unsubstituted C.sub.3-6 cycloalkylalkyl, and substituted or
unsubstituted C.sub.3-6 cycloalkenyl; each occurrence of Y is
independently selected from O, S, and NR.sup.a; and each occurrence
of q independently represents 0, 1 or 2; D and E are independently
selected from CH or N; R.sup.5 is selected from hydrogen, hydroxy,
halogen, carboxyl, cyano, nitro, oxo (.dbd.O), thio (.dbd.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.sup.a, --C(O)R.sup.a,
--C(S)R.sup.a, --C(O)NR.sup.aR.sup.b, --C(O)ONR.sup.aR.sup.b,
--NR.sup.aR.sup.b, --NR.sup.aCONR.sup.aR.sup.b,
--N(R.sup.a)SOR.sup.b, --N(R.sup.a)SO.sub.2R.sup.b,
-(.dbd.N--N(R.sup.a)R.sup.b), --NR.sup.aC(O)OR.sup.b,
--NR.sup.aC(O)R.sup.b--, --NR.sup.aC(S)R.sup.b
NR.sup.aC(S)NR.sup.aR.sup.b, --SONR.sup.aR.sup.b--,
--SO.sub.2NR.sup.aR.sup.b--, --OR.sup.a,
--OR.sup.aC(O)NR.sup.aR.sup.b, --OR.sup.aC(O)OR.sup.b--,
--OC(O)R.sup.a, --OC(O)NR.sup.aR.sup.b,
--R.sup.aNR.sup.bC(O)R.sup.a, --R.sup.aOR.sup.b,
--R.sup.aC(O)OR.sup.b, --R.sup.aC(O)NR.sup.aR.sup.b,
--R.sup.aC(O)R.sup.b, --R.sup.aOC(O)R.sup.b, --SR.sup.a,
--SOR.sup.a--SO.sub.2R.sup.a, and --ONO.sub.2, each occurrence of
R.sup.d is independently hydrogen, hydroxy, halogen, carboxyl,
cyano, nitro, oxo (.dbd.O), thio (.dbd.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.sub.2, or any two of R.sup.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 (.dbd.O), thio
(.dbd.S) or imino (.dbd.NR'); and each occurrence of R.sup.e,
R.sup.f, R.sup.g, R.sup.h, R.sup.i, R.sup.j, R.sup.k and R.sup.l is
independently selected from hydrogen, nitro, hydroxy, cyano,
halogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted
or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6
cycloalkyl, substituted or unsubstituted C.sub.3-6 cycloalkylalkyl,
and substituted or unsubstituted C.sub.3-6 cycloalkenyl; or any two
of R.sup.e, R.sup.f, R.sup.g, R.sup.h, R.sup.i, R.sup.j, R.sup.k,
and R.sup.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 (.dbd.O), thio (.dbd.S) or imino
(.dbd.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.noteq.0,
36. A compound of claim 34, wherein Ar is selected from
##STR00195## ##STR00196## ##STR00197## ##STR00198##
##STR00199##
37. A compound of claim 34, wherein Z is NH or N--CH.sub.3.
38. A compound of claim 34, wherein Cy.sup.1 is selected from
##STR00200## ##STR00201## ##STR00202## ##STR00203## ##STR00204##
##STR00205## ##STR00206## ##STR00207##
39. A compound of claim 34, wherein R.sup.5 is selected from
##STR00208## ##STR00209##
40. A compound of claim 34, wherein R.sup.5 is
--C(O)OC(CH.sub.3).sub.3 or --C(O)OCH(CH.sub.3).sub.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}piperid-
ine-1-carboxylate; Tert-butyl
4-{5-[2-fluoro-4-(methylsulfonyl)phenyl]-1-methyl-1H-benzo[d]imidazol-2-y-
l}piperidine-1-carboxylate; Tert-butyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]-1H-benzo[d]imidazol-5-yl}-5,6-di-
hydropyridine-1(2H)-carboxylate; Tert-butyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]-1H-benzo[d]imidazol-5-yl}piperid-
ine-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.
Description
[0001] This application claims the benefit of Indian Provisional
Patent Application Nos. 1958/CHE/2011 dated 9 Jun. 2011,
2352/CHE/2011 dated 11 Jul. 2011, 3462/CHE/2011 dated 7 Oct. 2011,
3463/CHE/2011 dated 7 Oct. 2011, 82/CHE/2012 dated 9 Jan. 2012, and
US Provisional Patent Application Nos. 61/543,152 dated 4 Oct. 2011
and 61/543,157 dated 4 Oct. 2011, each of which is hereby
incorporated by reference.
FIELD OF THE INVENTION
[0002] 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.
BACKGROUND OF THE INVENTION
[0003] Metabolic disorders in general and in particular, obesity
and diabetes are the most common human health problems in the
developed world. Its estimated that in developed countries around a
third of the population is at least 20% overweight. In the United
States, the percentage of obese people has increased from 25% at
the end of the 1970's, to 33% at the beginning the 1990's. Obesity
is one of the most important risk factors for NIDDM
(noninsulin-dependent diabetes mellitus) which is the result of an
imbalance between caloric intake and energy expenditure, and is
highly correlated with insulin resistance and diabetes in
experimental animals and humans.
[0004] Obesity is a medical condition in which excess body fat has
accumulated to the extent that it may have an adverse effect on
health, leading to reduced life expectancy and/or increased health
problems. Body mass index (BMI), a measurement which compares
weight and height, defines people as overweight (pre-obese) if
their BMI is between 25 and 30 kg/m.sup.2, and obese when it is
greater than 30 kg/m.sup.2. (see Haslam D W, James W P (2005),
"Obesity", Lancet 366 (9492): 1197-209; World Health Organization
Obesity pg 6 & 9, 2000). Obesity increases the likelihood of
various diseases, particularly heart disease, type 2 diabetes,
breathing difficulties during sleep, certain types of cancer, and
osteoarthritis. Obesity is most commonly caused by a combination of
excessive food energy intake, lack of physical activity, and
genetic susceptibility, although a few cases are caused primarily
by genes, endocrine disorders, medications or psychiatric illness.
Evidence to support the view that some obese people eat little yet
gain weight due to a slow metabolism is limited; on average obese
people have a greater energy expenditure than their thin
counterparts due to the energy required to maintain an increased
body mass. (http://en.wikipedia.org/wiki/Obesity)
[0005] Dieting and physical exercise are the mainstays of treatment
for obesity. Moreover, it is important to improve diet quality by
reducing the consumption of energy-dense foods such as those high
in fat and sugars, and by increasing the intake of dietary fiber.
To supplement this, or in case of failure, anti-obesity drugs may
be taken to reduce appetite or inhibit fat absorption. In severe
cases, surgery is performed or an intragastric balloon is placed to
reduce stomach volume and/or bowel length, leading to earlier
satiation and reduced ability to absorb nutrients from food.
[0006] Obesity is a leading preventable cause of death worldwide,
with increasing prevalence in adults and children, and authorities
view it as one of the most serious public health problems of the
21st century (see Barness L A et. al., "Obesity: genetic,
molecular, and environmental aspects". Am. J. Med. Genet. A 143A
(24): 3016-34, 2007). Obesity is stigmatized in much of the modern
world (particularly in the Western world), though it was widely
perceived as a symbol of wealth and fertility at other times in
history, the low- and middle income people suffer from
obsesity.
[0007] Obesity considerably increases the risk of developing
cardiovascular diseases as well. Coronary insufficiency,
atheromatous disease, and cardiac insufficiency are at the
forefront of the cardiovascular complication induced by obesity. It
is estimated that if the entire population had an ideal weight, the
risk of coronary insufficiency would decrease by 25% and the risk
of cardiac insufficiency and of cerebral vascular accidents by 35%.
The incidence of coronary diseases is doubled in subjects less than
50 years of age who are 30% overweight.
[0008] Diabetes is one of the major causes of premature illness and
death worldwide. Developing countries are on the radar with huge
population especially the low- and middle income people being
suffering from the said disease. The reason being, lack of
sufficient diagnosis and treatment, being made available to the
patients. This is reflected from the number of deaths attributable
to diabetes in 2010 which shows a 5.5% increase over the estimates
for the year 2007. Although 80% of type 2 diabetes is preventable
by changing diet, increasing physical activity and improving the
living environment. Yet, without effective prevention and control
programmes, the incidence of diabetes is likely to continue rising
globally.
[0009] Currently it's estimated that 285 million people,
corresponding to 6.4% of the worlds adult population, is living
with diabetes. The number is expected to grow to 438 million by
2030, corresponding to 7.8% of the adult population. The largest
age group currently affected by diabetes is between 40-59 years. By
2030 this "record" is expected to move to the 60-79 age groups with
some 196 million cases. With an estimated 50.8 million people
living with diabetes, India has the world's largest diabetes
population, followed by China with 43.2 million. Unless addressed,
the mortality and disease burden from diabetes and other NCDs will
continue to increase. WHO projects that globally, deaths caused by
these health problems will increase by 17% over the next decade,
with the greatest increase in low- and middle-income countries,
mainly in the African (27%) and Eastern Mediterranean (25%)
regions. (see: IDF, Diabetes Atlas, 4th edition)
[0010] Diabetes is a chronic disease that occurs when the pancreas
does not produce enough insulin, or when the body cannot
effectively use the insulin it produces. Hyperglycemia, or raised
blood sugar, is a common effect of uncontrolled diabetes and over
time leads to serious damage to many of the body's systems. It
implicated in the development of kidney disease, eye diseases and
nervous system problems. Diabetes causes about 5% of all deaths
globally each year and is likely to increase by >50% in the next
10 years. Thus the pharmaceutical industry has been on a quest to
characterize more promising molecular targets to satisfy stringent
new criteria for anti-hyperglycaemic agents.
[0011] Type 1 diabetes, also known as insulin-dependent diabetes
mellitus (IDDM), is caused by the autoimmune destruction of the
insulin producing pancreatic beta-cells, and requires regular
administration of exogenous insulin. Type 1 diabetes usually starts
in childhood or young adulthood manifesting sudden symptoms of high
blood sugar (hyperglycemia).
[0012] Type 2 diabetes, also known as non-insulin-dependent
diabetes mellitus (NIDDM), manifests with an inability to
adequately regulate blood-glucose levels. NIDDM may be
characterized by a defect in insulin secretion or by insulin
resistance. NIDDM is a genetically heterogeneous disease caused by
various reasons such as genetic susceptibility to other
environmental factors contributing to NIDDM, such as obesity,
sedentary lifestyle, smoking, and certain drugs. NIDDM is a chronic
disease resulting from defects in both insulin secretion and
sensitivity. In NIDDM patients, the gradual loss of pancreatic
.beta.-cell function is a characteristic feature of disease
progression that is associated with sustained hyperglycemia and
poor outcome. Strategies for promoting normoglycemia have focused
on enhancing glucose stimulated insulin secretion (GSIS) through
the targeting of G protein-coupled receptors (GPCRs), such as the
glucagon-like peptidel (GLP-1) receptor, which have been shown to
mediate this effect. In clinical therapy for NIDDM, metformin,
.alpha.-glucosidase inhibitors, thiazolidines (TZDs), and
sulfonylurea (SU) derivatives (SUs) are widely used as
hypoglycaemic agents; however, the side effects of these compounds
include hypoglycaemic episodes, weight-gain, gastrointestianal
problems, and loss of therapy responsiveness.
[0013] Along with GLP-1 receptor as a major targets for the
treatment of diabetes, GPR119 agonists have also been recognised as
a major targets for the treatment of diabetes was discussed
recently at the American Chemical Society 239.sup.th National
Meeting (2010, San Francisco).
[0014] Further glucagon-like peptide 1 receptor agonists have shown
promising therapeutic benefit over the existing therapy by way of
body weight loss in type 2 diabetics, however these being
injectables (Exenatide, marketed as Byetta) lack patient compliance
there by limiting their usage. Other glucagon-like peptide 1
receptor agonists such as Liraglutide (Victoza), Albiglutide and
Taspoglutide are also injectables.
[0015] GPR119 agonists have potential to achieve blood glucose
control together with body weight loss in type 2 diabetics, similar
to that of glucagon-like peptide 1 receptor agonists by way of oral
route. Accordingly, oral GPR119 agonist would prove to a preferred
choice of drug therapy for diabetics.
[0016] GPR119, a class-A (rhodopsin-like) G protein-coupled
receptor, expressed primarily in the human pancreas and
gastrointestinal tract, has attracted considerable interest as a
drug target for NIDDM. The activation of GPR119 increases the
intracellular accumulation of cAMP, leading to enhanced
glucose-dependent insulin secretion and increased levels of the
incretion hormones GLP-1 (glucagon-like peptide 1) and GIP
(glucose-dependent insulinotropic peptide). (Overton H A et al.
Cell Metab, 2006, 3, 167-175). In rodent models, orally available
GPR119-specific agonists have been shown to attenuate blood glucose
levels with a simultaneous body weight loss. (Shah U. see Curr Opin
Drug Discov Devel. 2009 July; 12(4):519-32.).
[0017] In various animal models of type 2 diabetes and obesity,
orally available, potent, selective, synthetic GPR119 agonists: i)
lowers blood glucose without hypoglycaemia; ii) slow diabetes
progression; and iii) reduce food intake and body weight.
[0018] GPR119 was first described by Fredriksson et al. (see
Fredriksson R, et. al. FEBS Lett. 2003; 554:381-388) as a class 1
(rhodopsin-type) orphan G-protein-coupled receptor having no close
primary sequence relative in the human genome. Independently,
GPR119 has been studied and described in the literature under
various synonyms including SNORF25 (see: Bonini et al., U.S. Pat.
No. 6,221,660, U.S. Pat. No. 6,468,756), RUP3 (Jones et al., WO
2004/065380.), GPCR2 (Takeda et al., FEBS Lett. 2002; 520:97-101
2002), 19AJ (see Davey et. al., Expert Opin Ther Targets. 2004;
8:165-170.2004), OSGPR116 (see. U.S. Pat. No. 7,083,933) and
glucose-dependent insulinotropic receptor (Chu et al., Keystone
Symposium. Diabetes: Molecular Genetics, Signalling Pathways and
Integrated Physiology, Keystone, Colo., USA, 14-19 Jan. 2007,
abstract 117 and abstract 230).
[0019] Early signs of GPR119 as an attractive target were
established by the teachings of Hilary Overton and colleagues from
(OSI) Prosidion, who found that the naturally occurring
lipid-signalling agent oleoylethanolamide, was capable of reducing
the food intake and weight gain in rats, and can exert its effects
through the G protein-coupled receptor (GPCR) GPR119. Found
predominantly in the pancreas and digestive tract in humans and
mice, as well as in the rodent brain, the mysterious/unknown
function of GPR119 was solved.
[0020] The demonstration that GPR119 agonists stimulate the release
of GLP-1 lends further credence to these agents having an effect on
body weight, since GLP-1 is known to cause gastric deceleration and
increase satiety, phenomena that lead to reduced caloric intake and
weight loss in both animal models and human subjects (Meier et al.,
Eur J Pharmacol.; 440:269-279, 2002; Zander et al., 2002; Lancet.;
359:824-830. 2002 and Nielsen L L Drug Discov Today. 10,703-710,
2005). Possibly as a result of their effects on GLP-1 secretion,
selective small-molecule GPR119 agonists inhibit gastric emptying
and suppress food intake upon acute dosing to rats, with no
indication of drug-induced malaise or conditioned taste aversion
(Fyfe et al., Diabetes. 55 Suppl 1:346-P, 2006; Diabetes; 56 Suppl
1:532-P, 2007; Overton et. al., Cell Metab. 3,167-175, 2006). The
hypophagic actions of GPR119 agonists lead to reduced weight gain,
fat pad masses and plasma leptin/triglyceride levels when
administered sub-chronically in rodent models of obesity (Fyfe et
al., Diabetes. 55 Suppl 1:346-P, 2006; Diabetes; 56 Suppl 1:532-P,
2007; Overton et. al., Cell Metab. 3,167-175, 2006). The testing of
potent, selective agonists for food intake and body weight effects
in GPR119-deficient mouse models has not been reported so far.
[0021] There are suggesting evidence about the isoforms of GPR119
been identified in a number of mammalian species, including rats,
mice, hamsters, chimpanzees, rhesus monkeys, cattle and dogs. For
example see. Fredriksson et al. FEBS Lett.; 554:381-388,2003; U.S.
Pat. No. 6,221,660; U.S. Pat. No. 6,468,756 and EP 1338651-A1.
[0022] GPR 119 is thus an attractive target from a clinical
perspective mainly because of GPR119 agonists are capable of
lowering blood glucose without hypoglycaemia; slowing of diabetes
progression; and most improtantaly helping in reduction of food
intake and body weight.
[0023] More recently Unmesh shah et. al., in Chapter-16 Vitamins
& Harmones, Volume 84, pg 415-448 (2010), and Chapter-7. Annual
reports in Med Chem 44 pg 149-170 (2009) have provided additional
insight about GRP119
[0024] Patent literature belonging to some of these applicants
include the following patents and/or patent applications:
WO2011005929A1, WO2009126245A1, WO2008005576A1, WO2008005569A2,
WO2007120702A2, WO2007120689A2, WO2007035355A2, WO06127595A1,
WO06083491A2, WO06076455A2, WO2006 076243A1, WO05121121A2,
WO05007658A2, WO05007647A1, WO04076413A2, WO2004065380;
WO2010009183A1, WO2009012277A1, WO2008137436A1, WO2008 137435A1;
WO2011041154A1, WO2010008739A2, WO2009014910A2, WO2009 123992A1,
WO2008083238A2; WO2010103335A1, WO2010103334A1, WO2010 103333A1,
WO2010004348A1, WO2010004347A1, WO2010001166A1, WO2009 050523A1,
WO2009050522A1, WO2009034388A1, WO2008081208A1, WO2008081207 A1,
WO2008081206A1, WO2008081205A1, WO2008081204A1, WO2007116230A1,
WO2007116229A1, WO2007003964A1, WO2007003962A2, WO2007003961A2,
WO2007 003960A1, WO05061489A1; WO2011061679A1, WO2011036576A1,
WO2010 140092A1, WO2010128425A1, WO2010128414A1, WO2010106457A2;
WO2011 062889A1, WO2011 062885A1, WO2011053688A1, WO2010114958A1,
WO2010 114957A1, WO2010 075273A1, WO2010075271A1, WO2010075269A1,
WO2010 009208A1, WO2010 009207A1, WO2010009195A1, WO2009143049A1,
WO2009 055331A2, WO2008 130615A1, WO2008130584A1, WO2008130581A1,
WO2008033465A1, WO2008 033464A2, WO2008033460A2, WO2008033456A1,
WO2008033431A1, WO2011030139A1, WO2011019538A1, WO2011014520A2,
WO2011008663A1, WO2011044001A1, WO2011055770A1, WO2011066137A1,
WO2011078306A1, WO2011093501A1, WO2011127051A1, WO2011127106A1,
WO2011128394A1, WO2011128395A1, WO2011138427A2, WO2011140160A1,
WO2011140161A1, WO2011147951A1, WO2011159657A1, WO2011146335A1,
WO2011145718A1, WO2011148922A1, WO2012006955A1, WO2012011707A2,
WO2012025811A1, WO2012037393A1, WO2012040279A1, WO2012046249A1,
WO2012045363A1, WO2012066077A1, WO2012069948A1, WO2012069917A1.
[0025] Further review and literature disclosure on GPR119 molecules
have been given by Sempl, G et al., (See; Bio org. Med. Chem. Lett.
(2011), doi: 10.1016/j. bmcl. 2011.03.007), Szewczyk, J. W. Et al.,
(See; Bio org. Med. Chem. Lett. (2011), doi:10.1016/j.bmcl.
2010.12.086), Vincent Mascitti et al., (See; Bioorganic &
Medicinal Chemistry Letters 21 (2011) 1306-1309), Shigeru Yoshida
et al., (See; Biochemical and Biophysical Research Communications
400 (2010) 745-751), Yulin Wu et. al., (See; Bioorganic &
Medicinal Chemistry Letters 20 (2010) 2577-2581), Chu et al., (See;
Endocrinology 2008 149:2038-2047), Y Ning et al., (see; British
Journal of Pharmacology (2008) 155, 1056-1065), HA Overton et al.,
(See; British Journal of Pharmacology (2008)153, S76-S81), Carolyn
Root et al., (See; Journal of Lipid Research, Volume 43, 2002, Pg
1320-1330). All of these patents and/or patent applications and
literature disclosures are incorporated herein as reference in
their entirety for all purposes.
[0026] Despite the advances made in the treatment of metabolic
disorders and in particular in the treatment of diabetes and
obesity, challenges remain in terms of the complexities of the
diseases involved, and most importantly the safety concerns
expected from any treatment. Accordingly, there is a need in the
art for additional GPR 119 modulators with improved efficacy and
safety profiles. The compounds, compositions, and pharmaceutical
methods provided herein are aimed at meeting these needs.
SUMMARY OF THE INVENTION
[0027] The present invention relates to novel compounds useful as
GPR-119 modulators and in particular GPR-119 agonists.
[0028] In one embodiment, the compound of the present invention has
the formula (A) and (B)
##STR00001##
or a tautomer, stereoisomer, enantiomer, diastereomer, salt (e.g.,
pharmaceutically acceptable salt), prodrug (e.g., ester), or
N-oxide thereof, wherein Ar is selected from substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl or
Cy.sup.1; L.sub.1 is absent or is selected from NR.sup.a, O,
S(O).sub.q or CR.sup.aR.sup.b; L.sub.2 is absent or is selected
from NR.sup.a, O, S(O).sub.q or CR.sup.aR.sup.b; X.sup.1 is
CR.sup.1 or N; X.sup.2 is CR.sup.2 or N; X.sup.3 is CR.sup.3 or N
and X.sup.4 is CR.sup.4 or N;
X is CR or N;
Z is NR, CO, O or S(O).sub.q;
[0029] Cy is selected from substituted or unsubstituted cycloalkyl
or substituted or unsubstituted heterocyclic group; Cy.sup.1 is
selected from substituted or unsubstituted cycloalkyl or
substituted or unsubstituted heterocyclic group; each occurrence of
R, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 may be same or different
and is independently selected from hydrogen, nitro, hydroxy, cyano,
halogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted
or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-6
cycloalkyl, substituted or unsubstituted C.sub.3-6 cycloalkylalkyl,
and substituted or unsubstituted C.sub.3-6 cycloalkenyl,
--OR.sup.a, --S(.dbd.O).sub.q--R.sup.a, --NR.sup.aR.sup.b,
C(.dbd.Y)--R.sup.a, --CR.sup.aR.sup.b--C(.dbd.Y)--R.sup.a,
--CR.sup.aR.sup.b--Y--CR.sup.aR.sup.b--,
--C(.dbd.Y)--NR.sup.aR.sup.b--,
--NR.sup.aR.sup.b--C(.dbd.Y)--NR.sup.aR.sup.b--,
--S(.dbd.O).sub.q--NR.sup.aR.sup.b--,
--NR.sup.aR.sup.b--S(.dbd.O).sub.q--NR.sup.aR.sup.b--,
--NR.sup.aR.sup.b--NR.sup.aR.sup.b--; each occurrence of R.sup.a
and R.sup.b may be same or different and are independently selected
from hydrogen, nitro, hydroxy, cyano, halogen, substituted or
unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl,
substituted or unsubstituted C.sub.3-6 cycloalkyl, substituted or
unsubstituted C.sub.3-6 cycloalkylalkyl, and substituted or
unsubstituted C.sub.3-6 cycloalkenyl, or when two R.sup.a and/or
R.sup.b substituents are directly bound to a common atom, they may
be joined to form (i) an oxo (.dbd.O), thio (.dbd.S) or imino
(.dbd.NR.sup.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.sup.c or S; each occurrence of R.sup.c is independently
selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted
or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl,
substituted or unsubstituted C.sub.3-6 cycloalkyl, substituted or
unsubstituted C.sub.3-6 cycloalkylalkyl, and substituted or
unsubstituted C.sub.3-6 cycloalkenyl; each occurrence of R.sup.d is
independently hydrogen, hydroxy, halogen, carboxyl, cyano, nitro,
oxo (.dbd.O), thio (.dbd.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.sub.2; each occurrence of Y is independently selected from O,
S, and NR.sup.a; and each occurrence of q independently represents
0, 1 or 2.
[0030] Another embodiment is a compound of the formula (A-I),
(A-II), (A-III), (A-IV), (B-I), (B-II), (B-III) or (B-IV):
##STR00002##
or a tautomer, stereoisomer, enantiomer, diastereomer, salt (e.g.,
pharmaceutically acceptable salt), prodrug (e.g., ester), or
N-oxide thereof, wherein Z is NR, CO, O or S(O).sub.q; wherein R
and q is as defined above for compound of formula (A) or (B); D and
E are independently selected from CH or N; R.sup.5 is selected from
hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (.dbd.O),
thio (.dbd.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.sup.a, --C(O)R.sup.a,
--C(S)R.sup.a, --C(O)NR.sup.aR.sup.b, --C(O)ONR.sup.aR.sup.b,
--NR.sup.aR.sup.b, --NR.sup.aCONR.sup.aR.sup.b,
--N(R.sup.a)SOR.sup.b, --N(R.sup.a)SO.sub.2R.sup.b,
-(.dbd.N--N(R.sup.a)R.sup.b), --NR.sup.aC(O)OR.sup.b,
--NR.sup.aC(O)R.sup.b--,
--NR.sup.aC(S)R.sup.b--NR.sup.aC(S)NR.sup.aR.sup.b,
--SONR.sup.aR.sup.b--, --SO.sub.2NR.sup.aR.sup.b--, --OR.sup.a,
--OR.sup.aC(O)NR.sup.aR.sup.b, --OR.sup.aC(O)OR.sup.a--,
--OC(O)R.sup.a, --OC(O)NR.sup.aR.sup.b,
--R.sup.aNR.sup.bC(O)R.sup.a, --R.sup.aOR.sup.b,
--R.sup.aC(O)OR.sup.b, --R.sup.aC(O)NR.sup.aR.sup.b,
--R.sup.aC(O)R.sup.b, --R.sup.aOC(O)R.sup.b, --SR.sup.a,
--SOR.sup.a--SO.sub.2R.sup.a, and --ONO.sub.2, wherein R.sup.a and
R.sup.b are as defined in formula (A) or (B); each occurrence of
R.sup.e, R.sup.f, R.sup.g, R.sup.h, R.sup.i, R.sup.j, R.sup.k and
R.sup.l is independently selected from hydrogen, nitro, hydroxy,
cyano, halogen, substituted or unsubstituted C.sub.1-6 alkyl,
substituted or unsubstituted C.sub.2-6 alkenyl, substituted or
unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted
C.sub.3-6 cycloalkyl, substituted or unsubstituted C.sub.3-6
cycloalkylalkyl, and substituted or unsubstituted C.sub.3-6
cycloalkenyl; or any two of R.sup.e, R.sup.f, R.sup.g, R.sup.h,
R.sup.i, R.sup.j, R.sup.k, R.sup.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 (.dbd.O), thio
(.dbd.S) or imino (.dbd.NR') (where R' is H or alkyl); each of r,
s, t and u is 0, 1 or 2 with the proviso that r+s+t+u.noteq.0; and
and all the other variables are the same as described above for the
compound of formula (A) and (B), with the proviso
[0031] 1. that for compound of formula (A-III), wherein Z is O or S
and X.sub.4 is N or CR.sup.4 then Ar cannot be
##STR00003##
[0032] 2. that for compound of formula (A-IV) wherein Z is O or S
and X.sub.1 is N or CR.sup.1 then Ar cannot be
##STR00004##
wherein R.sup.1 and R.sup.4 is as defined above for compound of
formula (A) W is S(.dbd.O).sub.2--R.sub.1,
S(.dbd.O).sub.2--NR.sub.1aR.sub.1, --C(.dbd.O)--R.sub.1,
--C(.dbd.O)--O--R.sub.1, --C(.dbd.O)--NR.sub.1aR.sub.1,
--NR.sub.1a--S(.dbd.O).sub.2--R.sub.1, halo, or a 4 to 10-membered
optionally substituted heteroaryl, which contains 1-4 heteroatoms
selected from N, O, and S; R.sub.1a, at each occurrence, is
independently hydrogen or (C.sub.1-C.sub.8)alkyl; and R.sub.1 is
optionally substituted (C.sub.1-C.sub.6)-alkyl, optionally
substituted (C.sub.2-C.sub.6)-alkenyl, optionally substituted
(C.sub.2-C.sub.6)-alkynyl, optionally substituted
(C.sub.3-C.sub.12)-cycloalkyl, optionally substituted
(C.sub.6-C.sub.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.
[0033] Further preferred is a compound of formula (A), (A-I),
(A-II), (A-III), (A-IV), (B), (B-I), (B-II), (B-III) or (B-IV)
wherein Ar is selected from
##STR00005## ##STR00006## ##STR00007## ##STR00008##
[0034] Further preferred is a compound of formula (A), (A-I),
(A-II), (A-III), (A-IV), (B), (B-I), (B-II), (B-III) or (B-IV)
wherein Ar is Cy.sup.1.
[0035] Further preferred is a compound of formula (A), (A-I),
(A-II), (A-III), (A-IV), (B), (B-I), (B-II), (B-III) or (B-IV)
wherein Cy.sup.1 is selected from
##STR00009##
[0036] Further preferred is a compound of formula (A) or (B)
wherein L.sub.1 is absent.
[0037] Further preferred is a compound of formula (A) or (B)
wherein L.sub.2 is absent.
[0038] Further preferred is a compound of formula (A), (A-I),
(A-II), (A-III), (A-IV), (B), (B-I), (B-II), (B-III) or (B-IV)
wherein Z is NH or N--CH.sub.3.
[0039] Further preferred is a compound of formula (A), (A-I),
(A-II), (A-III), (A-IV), (B), (B-I), (B-II), (B-III) or (B-IV)
wherein Z is O.
[0040] Further preferred is a compound of formula (A), (A-I),
(A-II), (A-III), (A-IV), (B), (B-I), (B-II), (B-III) or (B-IV)
wherein Z is S.
[0041] Further preferred is a compound of formula (A), (A-I),
(A-II), (A-III), (A-IV), (B), (B-I), (B-II), (B-III) or (B-IV)
wherein X.sup.1 is CR.sup.1 or N, wherein R.sup.1 is H or
Halogen.
[0042] Further preferred is a compound of formula (A), (A-II),
(A-IV), (B), (B-II) or (B-IV) wherein X.sup.2 is CH.
[0043] Further preferred is a compound of formula (A), (A-II),
(A-IV), (B), (B-II) or (B-IV) wherein X.sup.3 is CH.
[0044] Further preferred is a compound of formula (A), (A-I),
(A-II), (A-III), (A-IV), (B), (B-I), (B-II), (B-III) or (B-IV)
wherein X.sup.4 is CR.sup.4 or N, wherein R.sup.4 is H or
Halogen.
[0045] Further preferred is a compound of formula (A), (A-I),
(A-II), (A-III), (A-IV), (B), (B-I), (B-II), (B-III) or (B-IV)
wherein X is CR or N, wherein R is H, hydrogen, cyano, halogen,
substituted or unsubstituted C.sub.1-6 alkyl, substituted or
unsubstituted C.sub.3-6 cycloalkyl, and substituted or
unsubstituted C.sub.3-6 cycloalkenyl, --OR.sup.a, --NR.sup.aR.sup.b
or C(.dbd.Y)--R.sup.a and R.sup.a, R.sup.b, and Y are as defined
above for compound of formula (A) or (B);
[0046] Further preferred is a compound of formula (A), (A-I),
(A-II), (A-III), (A-IV), (B), (B-I), (B-II), (B-III) or (B-IV):
wherein Cy is selected from
##STR00010## ##STR00011## ##STR00012## ##STR00013## ##STR00014##
##STR00015## ##STR00016## ##STR00017##
[0047] Yet another embodiment is a compound of formula (A-IA),
(A-IIA), (B-IA), (B-IIA), (B-IIIA) or (B-IVA):
##STR00018##
or a tautomer, stereoisomer, enantiomer, diastereomer, salt (e.g.,
pharmaceutically acceptable salt), prodrug (e.g., ester), or
N-oxide thereof, wherein
Ar is
##STR00019##
[0048] G is independently selected from
##STR00020##
R is substituted or unsubstituted alkyl, substituted or
unsubstituted alkoxy, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl or substituted or
unsubstituted cycloalkyl. R.sup.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.sup.a, --C(O)R.sup.a, --C(S)R.sup.a,
--C(O)NR.sup.aR.sup.b, --C(O)ONR.sup.aR.sup.b, --NR.sup.aR.sup.b,
--NR.sup.aCONR.sup.aR.sup.b, --N(R.sup.a)SOR.sup.b,
--N(R.sup.a)SO.sub.2R.sup.b, -(.dbd.N--N(R.sup.a)R.sup.b),
--NR.sup.aC(O)OR.sup.b, --NR.sup.aC(O)R.sup.b--,
--NR.sup.aC(S)R.sup.b--NR.sup.aC(S)NR.sup.aR.sup.b,
--SONR.sup.aR.sup.b--, --SO.sub.2NR.sup.aR.sup.b--, --OR.sup.a,
--OR.sup.aC(O)NR.sup.aR.sup.b, --OR.sup.aC(O)OR.sup.b--,
--OC(O)R.sup.a, --OC(O)NR.sup.aR.sup.b,
--R.sup.aNR.sup.bC(O)R.sup.a, --R.sup.aOR.sup.b,
--R.sup.aC(O)OR.sup.b, --R.sup.aC(O)NR.sup.aR.sup.b,
--R.sup.aC(O)R.sup.b, --R.sup.aOC(O)R.sup.b, --SR.sup.a,
--SOR.sup.a--SO.sub.2R.sup.a, and --ONO.sub.2; each occurrence of
R.sup.a and R.sup.b may be same or different and are independently
selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted
or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl,
substituted or unsubstituted C.sub.3-6 cycloalkyl, substituted or
unsubstituted C.sub.3-6 cycloalkylalkyl, and substituted or
unsubstituted C.sub.3-6 cycloalkenyl, or when two R.sup.a and/or
R.sup.b substituents are directly bound to a common atom, they may
be joined to form (i) an oxo (.dbd.O), thio (.dbd.S) or imino
(.dbd.NR.sup.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.sup.d or S; each occurrence of R.sup.d is independently
hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (.dbd.O),
thio (.dbd.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.sub.2, p is 0, 1, 2, 3 or
4; and all the other variables (X.sub.1-X.sub.4, X, and R.sup.5)
are the same as described above for compound of formula (A), (B),
(A-I), (B-I), (A-II) or (B-II).
[0049] Yet another embodiment is a compound of formula (A-IIIA) and
(A-IVA)
##STR00021##
wherein the variables Ar, G, R.sup.6, and p are defined as above
with respect to formulas (A-MA) or (A-IVA), and all the other
variables (X.sub.1-X.sub.4, X, and R.sup.5) are the same as
described above for compound of formula (A), (B), (A-I), (B-I),
(A-II) or (B-II) with the proviso
[0050] 1. that for compound of formula (A-IIIA), wherein Z is O or
S and X.sub.4 is N or CR.sup.4 then Ar-G cannot be
##STR00022##
[0051] 2. that for compound of formula (A-IVA) wherein Z is O or S
and X.sub.1 is N or CR.sup.1 then Ar-G cannot be
##STR00023##
wherein R.sup.1 and R.sup.4 is as defined above for compound of
formula (A) W is S(.dbd.O).sub.2--R.sub.1,
S(.dbd.O).sub.2--NR.sub.1aR.sub.1, --C(.dbd.O)--R.sub.1,
--C(.dbd.O)--O--R.sub.1, --C(.dbd.O)--NR.sub.1aR.sub.1,
--NR.sub.1a--S(.dbd.O).sub.2--R.sub.1, halo, or a 4- to 10-membered
optionally substituted heteroaryl, which contains 1-4 heteroatoms
selected from N, O, and S; R.sub.1a, at each occurrence, is
independently hydrogen or (C.sub.1-C.sub.8)alkyl; R.sub.1 is
optionally substituted (C.sub.1-C.sub.6)-alkyl, optionally
substituted (C.sub.2-C.sub.6)-alkenyl, optionally substituted
(C.sub.2-C.sub.6)-alkynyl, optionally substituted
(C.sub.3-C.sub.12)-cycloalkyl, optionally substituted
(C.sub.6-C.sub.10)aryl, a 4-10-membered optionally substituted
heteroaryl, which contains 1-4 heteroatoms selected from N, O, and
S; or a 4- to 10-membered heterocyclo, which contains 1-4
heteroatoms selected from N, O, and S;
[0052] Further preferred is a compound of formula (A-IA), (A-IIA),
(A-IIIA), (A-IVA), (B-IA), (B-IIA), (B-IIIA) or (B-IVA) wherein Ar
is selected from.
##STR00024##
[0053] Further preferred is a compound of formula (A-IA), (A-IIA),
(A-IIIA), (A-IVA), (B-IA), (B-IIA), (B-IIIA) or (B-IVA) wherein G
is selected from.
##STR00025##
[0054] Further preferred is a compound of formula (A-IA), (A-IIA),
(A-IIIA), (A-IVA), (B-IA), (B-IIA), (B-IIIA) or (B-IVA) wherein
X.sup.1 is CR.sup.1 or N, wherein R.sup.1 is H or Halogen.
[0055] Further preferred is a compound of formula (A-IIA), (A-IVA),
(B-IIA) or (B-IVA) wherein X.sup.2 is CH.
[0056] Further preferred is a compound of formula (A-IA), (A-IIIA),
(B-IA) or (B-IIIA) wherein X.sup.3 is CH.
[0057] Further preferred is a compound of formula (A-IA), (A-IIA),
(A-IIIA), (A-IVA), (B-IA), (B-IIA), (B-IIIA) or (B-IVA) wherein
X.sup.4 is CR.sup.4 or N, wherein R.sup.1 is H or Halogen.
[0058] Further preferred is a compound of formula (A-IA), (A-IIA),
(A-IIIA), (A-IVA), (B-IA), (B-IIA), (B-IIIA) or (B-IVA) wherein X
is CH or N.
[0059] Further preferred is a compound of formula (A-IA), (A-IIA),
(A-IIIA) or (A-IVA) (B-IA), (B-IIA), (B-IIIA) or (B-IVA) wherein
R.sup.5 is selected from
##STR00026## ##STR00027##
[0060] Further preferred is a compound of formula (A-IA), (A-IIA),
(A-IIIA), (A-IVA), (B-IA), (B-IIA), (B-IIIA) or (B-IVA) wherein
R.sup.5 is BOC (--C(O)OC(CH.sub.3).sub.3).
[0061] Further preferred is a compound of formula (A-IA), (A-IIA),
(A-IIIA), (A-IVA) (B-IA), (B-IIA), (B-IIIA) or (B-IVA) wherein
R.sup.5 is --C(O)OCH(CH.sub.3).sub.2.
[0062] Further preferred is a compound of formula (A-IIA) or
(B-IIA) wherein X.sup.1 is CH or CF.
[0063] In one preferred embodiment, X is N.
[0064] In one preferred embodiment, X is CH.
[0065] In one preferred embodiment, Z is S
[0066] In one preferred embodiment, Z is O.
[0067] Further preferred is a compound of formula (A-IA), (A-IIA),
(A-IIIA), (A-IVA), (B-IA), (B-IIA), (B-IIIA) or (B-IVA) wherein p
is 0 or 1.
[0068] Further preferred is a compound of formula (A-IA), (A-IIA),
(A-IIIA), (A-IVA), (B-IA), (B-IIA), (B-IIIA) or (B-IVA) wherein
R.sup.6 is halogen, substituted or unsubstituted alkyl or
--OR.sup.a; wherein R.sup.a is substituted or unsubstituted
alkyl.
[0069] Further preferred is a compound of formula ((A-IA), (A-IIA),
(A-IIIA), (A-IVA), (B-IA), (B-IIA), (B-IIIA) or (B-IVA) wherein
R.sup.6 is --F, --CH.sub.3, --CF.sub.3 or --OCH.sub.3.
[0070] Yet another embodiment is a compound of formula (A-IB) and
(A-IIB):
##STR00028##
or a tautomer, stereoisomer, enantiomer, diastereomer, salt (e.g.,
pharmaceutically acceptable salt), prodrug (e.g., ester), or
N-oxide thereof, wherein
Z is O or S
Ar1-G is
##STR00029##
[0071] p is 0, 1-7 or 8 and all the variables (R.sup.6,
X.sub.1-X.sub.4, X, and R.sup.5) are the same as described
above
[0072] Yet another embodiment is a compound of formula (A-IIIB) and
(A-IVB):
##STR00030##
or a tautomer, stereoisomer, enantiomer, diastereomer, salt (e.g.,
pharmaceutically acceptable salt), prodrug (e.g., ester), or
N-oxide thereof, wherein
Z is O or S
Ar1-G is
##STR00031##
[0073] p is 0, 1-7 or 8 and all the variables (R.sup.6,
X.sub.1-X.sub.4, X, and R.sup.5) are the same as described
above.
[0074] 1. that for compound of formula (A-IIIB), wherein Z is O or
S and X.sub.4 is N or CR.sup.4 then Ar1-G cannot be
##STR00032##
[0075] 2. that for compound of formula (A-IVB) wherein Z is O or S
and X.sub.1 is N or CR.sup.1 then Ar1-G cannot be
##STR00033##
wherein R.sup.1 and R.sup.4 is as defined above for compound of
formula (A) W is S(.dbd.O).sub.2--R.sub.1,
S(.dbd.O).sub.2--NR.sub.1aR.sub.1, --C(.dbd.O)--R.sub.1,
--C(.dbd.O)--O--R.sub.1, --C(.dbd.O)--NR.sub.1aR.sub.1,
--NR.sub.1a--S(.dbd.O).sub.2--R.sub.1, halo, or a 4 to 10-membered
optionally substituted heteroaryl, which contains 1-4 heteroatoms
selected from N, O, and S; R.sub.1a, at each occurrence, is
independently hydrogen or (C.sub.1-C.sub.8)alkyl; and R.sub.1 is
optionally substituted (C.sub.1-C.sub.6)-alkyl, optionally
substituted (C.sub.2-C.sub.6)-alkenyl, optionally substituted
(C.sub.2-C.sub.6)-alkynyl, optionally substituted
(C.sub.3-C.sub.12)-cycloalkyl, optionally substituted
(C.sub.6-C.sub.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 heterocyclo, which contains 1-4
heteroatoms selected from N, O, and S.
[0076] Yet another embodiment is a compound of formula (A-V):
##STR00034##
or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is
hydrogen or F; R.sup.5 is as defined above; G is selected from
--SO.sub.2R.sup.a, --C(O)R.sup.aR.sup.b, C.sub.1-C.sub.4 alkyl
substituted with one or more halogens, and a tetrazole of the
formula
##STR00035##
each occurrence of R.sup.6 is independently halogen; each
occurrence of R.sup.a and R.sup.b is independently hydrogen or
unsubstituted or substituted C.sub.1-C.sub.6 alkyl; and p is 0, 1,
2 or 3.
[0077] In one preferred embodiment of the compound of formula
(A-V), R.sup.5 is selected from --COO--R.sup.a and
--SO.sub.2--R.sup.a (wherein R.sup.a is an unsubstituted
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkyl with one or more
halogens, or C.sub.3-C.sub.6 cycloalkyl).
[0078] In a preferred embodiment of the compound of formula (A-V),
G is selected from --SO.sub.2R.sup.a (where R.sup.a is an
unsubstituted C.sub.1-C.sub.4 alkyl), --C(O)R.sup.aR.sup.b (where
R.sup.a and R.sup.b are independently selected from hydrogen and a
C.sub.1-C.sub.4 alkyl optionally substituted with one or more
halogen), a C.sub.1-C.sub.2 alkyl substituted with one or more
halogens, and a tetrazole of the formula above.
[0079] Yet another embodiment is a compound of formula (B-V):
##STR00036##
or a pharmaceutically acceptable salt thereof, wherein R.sup.5 is
as defined above; G is selected from --SO.sub.2R.sup.a; each
occurrence of R.sup.6 is independently halogen; each occurrence of
R.sup.a is independently hydrogen or unsubstituted or substituted
C.sub.1-C.sub.6 alkyl; and p is 0, 1, 2 or 3.
[0080] In one preferred embodiment of the compound of formula
(B-V), R.sup.5 is --COO--R.sup.a where R.sup.a is an unsubstituted
or substituted C.sub.1-C.sub.6 alkyl. More preferably, R.sup.a is
an unsubstituted C.sub.1-C.sub.6 alkyl, such as an unsubstituted
C.sub.1-C.sub.4 alkyl.
[0081] In a preferred embodiment of the compound of formula (B-V),
G is selected from --SO.sub.2R.sup.a where R.sup.a is an
unsubstituted C.sub.1-C.sub.4 alkyl, such as methyl.
[0082] In a preferred embodiment of the compound of formula (B-V),
p is 1 and R.sup.6 is fluorine. More preferably, the fluorine is at
a position ortho the benzo[d]oxazole group.
[0083] Representative compounds of the present invention include
those specified below (including Table 1 and Table 2) and
pharmaceutically acceptable salts thereof. The present invention
should not be construed to be limited to them. [0084] 1.
2-[1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl]-5-[2-fluoro-4-(methylsulfonyl-
)phenyl]-1H-benzo[d]imidazole: [0085] 2. Tert-butyl
4-{5-[2-fluoro-4-(methylsulfonyl)phenyl]-1H-benzo[d]imidazol-2-yl}piperid-
ine-1-carboxylate: [0086] 3.
2-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]-5-[2-fluoro-4-(methylsulfonyl-
)phenyl]benzo[d]oxazole: [0087] 4. Tert-butyl
4-{5-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1--
carboxylate: [0088] 5. Tert-butyl
4-{5-[2-fluoro-4-(methylsulfonyl)phenyl]-1-methyl-1H-benzo[d]imidazol-2-y-
l}piperidine-1-carboxylate: [0089] 6. Tert-butyl
4-{6-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1--
carboxylate: [0090] 7. Isopropyl
4-{5-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1--
carboxylate: [0091] 8. Tert-butyl
4-{7-fluoro-5-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-2-yl}pipe-
ridine-1-carboxylate: [0092] 9. Tert-butyl
4-[5-(4-cyanophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate:
[0093] 10. Tert-butyl
4-{5-[3-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1--
carboxylate: [0094] 11. Tert-butyl
4-{5-[4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxy-
late: [0095] 12. Tert-butyl
4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine--
1-carboxylate: [0096] 13. Tert-butyl
4-{5-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxyl-
ate: [0097] 14. Isopropyl
4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine--
1-carboxylate: [0098] 15. Tert-butyl
4-{5-[3-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine--
1-carboxylate: [0099] 16.
2-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]-5-[2-fluoro-4-(1H-tetrazol-1--
yl)phenyl]benzo[d]oxazole: [0100] 17. Tert-butyl
4-[5-(4-cyano-3-fluorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate-
: [0101] 18. Isopropyl
4-{5-[3-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine--
1-carboxylate: [0102] 19. Tert-butyl
4-{5-[3-fluoro-4-(1H-tetrazol-5-yl)phenyl]benzo[d]oxazol-2-yl}piperidine--
1-carboxylate: [0103] 20. Tert-butyl
4-[5-(4-carbamoyl-3-chlorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxy-
late: [0104] 21. Tert-butyl
4-[5-(4-carbamoyl-3-fluorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxy-
late: [0105] 22. Tert-butyl
4-[5-(3-fluoro-4-isopropoxyphenyl)benzo[d]oxazol-2-yl]piperidine-1-carbox-
ylate: [0106] 23. Cyclobutyl
4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine--
1-carboxylate: [0107] 24. Sec-butyl
4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine--
1-carboxylate: [0108] 25. Pentan-3-yl
4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine--
1-carboxylate: [0109] 26.
5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole-
: [0110] 27. Isopropyl
4-{5-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxyl-
ate: [0111] 28. Isopropyl
4-{5-(4-formylphenyl)benzo[d]oxazol-2-yl}piperidine-1-carboxylate:
[0112] 29. Isopropyl
4-{5-[4-(difluoromethyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxyla-
te: [0113] 30. Isopropyl
4-[5-(4-carbamoyl-3-chlorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxy-
late: [0114] 31. Isopropyl
4-[5-(4-carbamoyl-3-fluorohenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxyl-
ate: [0115] 32.
1-{4-[5-(2-fluoro-4-(1H-tetrazol-1-yl)phenyl)benzo[d]oxazol-2-yl]piperidi-
n-1-yl}-2-methylpropan-1-one: [0116] 33. Isopropyl
4-{6-[4-(difluoromethyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxyla-
te: [0117] 34.
6-{2-[1-(isopropoxycarbonyl)piperidin-4-yl]benzo[d]oxazol-5-yl}nicotinic
acid: [0118] 35.
5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-[1-(methylsulfonyl)piperidin-4--
yl]benzo[d]oxazole: [0119] 36. Isopropyl
4-[5-(5-carbamoylpyridin-2-yl)benzo[d]oxazol-2-yl]piperidine-1-carboxylat-
e: [0120] 37. Isopropyl
4-[5-(4-carbamoyl-2-fluorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxy-
late: [0121] 38. Isopropyl
4-[5-(4-carbamoyl-2-chlorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxy-
late: [0122] 39.
2-Fluoro-4-{2-[1-(3-methylbutanoyl)piperidin-4-yl]benzo[d]oxazol-5-yl}ben-
zamide: [0123] 40.
1-{4-[5-(2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl]piperidi-
n-1-yl}-3-methylbutan-1-one: [0124] 41.
5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-[1-(2-methoxyethyl)piperidin-4--
yl]benzo[d]oxazole: [0125] 42. Isopropyl
4-{5-[3-fluoro-4-(methylcarbamoyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-
-carboxylate: [0126] 43.
2-Fluoro-4-[2-(1-isobutyrylpiperidin-4-yl)benzo[d]oxazol-5-yl]benzamide:
[0127] 44. Isopropyl
4-[6-(4-carbamoyl-3-fluorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxy-
late: [0128] 45. Isopropyl
4-{5-[3-fluoro-4-(2-hydroxyethylcarbamoyl)phenyl]benzo[d]oxazol-2-yl}pipe-
ridine-1-carboxylate: [0129] 46. Isopropyl
4-{5-[3-fluoro-4-(isopropylcarbamoyl)phenyl]benzo[d]oxazol-2-yl}piperidin-
e-1-carboxylate: [0130] 47. Isopropyl
4-{5-[4-(N-methylsulfamoyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carbox-
ylate: [0131] 48. Isopropyl
4-{5-[6-(methylcarbamoyl)pyridin-3-yl]benzo[d]oxazol-2-yl}piperidine-1-ca-
rboxylate: [0132] 49. Isopropyl
4-{5-[3-methyl-4-(methylcarbamoyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-
-carboxylate: [0133] 50. Isopropyl
4-{5-[4-(cyclopropylcarbamoyl)-3-fluorophenyl]benzo[d]oxazol-2-yl}piperid-
ine-1-carboxylate: [0134] 51.
2-Fluoro-4-{2-[1-(5-fluoropyrimidin-2-yl)piperidin-4-yl]benzo[d]oxazol-5--
yl}benzamide: [0135] 52. Tert-butyl
4-[5-(4-carbamoyl-3-fluorophenyl)benzofuran-2-yl]-5,6-dihydropyridine-1(2-
H)-carboxylate: [0136] 53.
2-fluoro-4-{2-[1-(propylsulfonyl)piperidin-4-yl]benzo[d]oxazol-5-yl}benza-
mide: [0137] 56. Tert-butyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]-1H-benzo[d]imidazol-5-yl}-5,6-di-
hydropyridine-1(2H)-carboxylate; [0138] 57. Tert-butyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]-1H-benzo[d]imidazol-5-yl}piperid-
ine-1-carboxylate; [0139] 58.
5-[1(5-ethylpyrimidin-2-yl)piperidin-4-yl]-2-[2-fluoro-4-(methylsulfonyl)-
phenyl]-1H-benzo[d]imidazole; [0140] 59. Tert-butyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}-5,6-dihydrop-
yridine-1(2H)-carboxylate; [0141] 60. Tert-butyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}piperidine-1--
carboxylate; [0142] 61.
2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(piperidin-4-yl)benzo[d]oxazole
2,2,2-trifluoro acetate; [0143] 62.
5-[1(5-ethylpyrimidin-2-yl)piperidin-4-yl]-2-[2-fluoro-4-(methylsulfonyl)-
phenyl]benzo[d]oxazole. [0144] 63. Tert-butyl
4-{7-fluoro-2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}pipe-
ridine-1-carboxylate: [0145] 64. Isopropyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}piperidine-1--
carboxylate: [0146] 65. Tert-butyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]thiazol-6-yl}-5,6-dihydro-
pyridine-1(2H)-carboxylate: [0147] 66. Tert-butyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]thiazol-5-yl}-5,6-dihydro-
pyridine-1(2H)-carboxylate: [0148] 67. Tert-butyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-6-yl}piperidine-1--
carboxylate: [0149] 68. Tert-butyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]thiazol-5-yl}piperidine-1-
-carboxylate: [0150] 69. Ethyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}piperidine-1--
carboxylate: [0151] 70. Tert-butyl
4-{2-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-5-yl}piperidine-1-carboxyl-
ate: [0152] 71. Isopropyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-6-yl}piperidine-1--
carboxylate: [0153] 72. Ethyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-6-yl}piperidine-1--
carboxylate: [0154] 73. Ethyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-6-yl}piperidine-1--
carboxylate: [0155] 74. Benzyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}piperidine-1--
carboxylate: [0156] 75. Isobutyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}piperidine-1--
carboxylate: [0157] 76. Isopropyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]thiazol-6-yl}piperidine-1-
-carboxylate: [0158] 77. Isopropyl
4-{2-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-5-yl}piperidine-1-carboxyl-
ate: [0159] 78. Isopropyl
4-(2-p-tolylbenzo[d]oxazol-6-yl)piperidine-1-carboxylate: [0160]
79.
3-{4-[2-(2-fluoro-4-(methylsulfonyl)phenyl)benzo[d]oxazol-5-yl]-5,6-dihyd-
ropyridin-1(2H)-ylsulfonyl}propan-1-ol: [0161] 80.
3-{4-[2-(2-fluoro-4-(methylsulfonyl)phenyl)benzo[d]oxazol-5-yl]piperidin--
1-ylsulfonyl}propan-1-ol: [0162] 81.
3-{4-[2-(2-fluoro-4-(methylsulfonyl)phenyl)benzo[d]oxazol-5-yl]piperidin--
1-ylsulfonyl}propan-1-ol: [0163] 82. Tert-butyl
4-[2-(4-carbamoyl-3-fluorophenyl)benzo[d]oxazol-5-yl]piperidine-1-carboxy-
late: [0164] 83.
2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(3-isopropyl-1,2,4-oxadiazol-5-
-yl)piperidin-1-yl]benzo[d]oxazole: [0165] 84. Tert-butyl
4-{2-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-6-yl}piperidine-1-carboxyl-
ate [0166] 85. Isopropyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}piperazine-1--
carboxylate: [0167] 86. Tert-butyl
4-{2-[4-(trifluoromethyl)phenyl]oxazolo[5,4-b]pyridin-6-yl}-5,6-dihydropy-
ridine-1(2H)-carboxylate: [0168] 87. Tert-butyl
4-{2-[4-(trifluoromethyl)phenyl]oxazolo[5,4-b]pyridin-6-yl}piperidine-1-c-
arboxylate:
TABLE-US-00001 [0168] TABLE 1 Example Structure 1 ##STR00037## 2
##STR00038## 3 ##STR00039## 4 ##STR00040## 5 ##STR00041## 6
##STR00042## 7 ##STR00043## 8 ##STR00044## 9 ##STR00045## 10
##STR00046## 11 ##STR00047## 12 ##STR00048## 13 ##STR00049## 14
##STR00050## 15 ##STR00051## 16 ##STR00052## 17 ##STR00053## 18
##STR00054## 19 ##STR00055## 20 ##STR00056## 21 ##STR00057## 22
##STR00058## 23 ##STR00059## 24 ##STR00060## 25 ##STR00061## 26
##STR00062## 27 ##STR00063## 28 ##STR00064## 29 ##STR00065## 30
##STR00066## 31 ##STR00067## 32 ##STR00068## 33 ##STR00069## 34
##STR00070## 35 ##STR00071## 36 ##STR00072## 37 ##STR00073## 38
##STR00074## 39 ##STR00075## 40 ##STR00076## 41 ##STR00077## 42
##STR00078## 43 ##STR00079## 44 ##STR00080## 45 ##STR00081## 46
##STR00082## 47 ##STR00083## 48 ##STR00084## 49 ##STR00085## 50
##STR00086## 51 ##STR00087## 52 ##STR00088## 53 ##STR00089##
TABLE-US-00002 TABLE 2 56 ##STR00090## 57 ##STR00091## 58
##STR00092## 59 ##STR00093## 60 ##STR00094## 61 ##STR00095## 62
##STR00096## 63 ##STR00097## 64 ##STR00098## 65 ##STR00099## 66
##STR00100## 67 ##STR00101## 68 ##STR00102## 69 ##STR00103## 70
##STR00104## 71 ##STR00105## 72 ##STR00106## 73 ##STR00107## 74
##STR00108## 75 ##STR00109## 76 ##STR00110## 77 ##STR00111## 78
##STR00112## 79 ##STR00113## 80 ##STR00114## 81 ##STR00115## 82
##STR00116## 83 ##STR00117## 84 ##STR00118## 85 ##STR00119## 86
##STR00120## 87 ##STR00121##
[0169] Yet another embodiment of the present invention is a method
for treating a GPR119 receptor related disorder by administering to
a subject in need of such treatment an effective amount of at least
one compound of the present invention, such as a compound of
formula (A), (A-I), (A-II), (A-III), (A-IV), (A-IA), (A-IIA),
(A-IIIA), (A-IVA), (A-IB), (A-IIB), (A-IIIB), (A-IVB), (A-V), (B),
(B-I), (B-II), (B-III), (B-IV), (B-IA), (B-IIA), (B-IIIA), (B-IVA),
(B-IB) (B-IIB), (B-IIIB), (B-IVB), or (B-V) as defined above.
[0170] Yet another embodiment of the present invention is a method
for treating a GPR119 receptor related disorder by administering to
a subject in need of such treatment an effective amount of at least
one compound of the present invention, such as a compound of
formula (A), (A-I), (A-II), (A-III), (A-IV), (A-IA), (A-IIA),
(A-IIIA), (A-IVA), (A-IB), (A-IIB), (A-IIIB), (A-IVB), (A-V), (B),
(B-I), (B-II), (B-III), (B-IV), (B-IA), (B-IIA), (B-IIIA), (B-IVA),
(B-IB), (B-IIB), (B-IIIB), (B-IVB), or (B-V) as defined above, in
combination (simultaneously or sequentially) with at least one
other therapeutic agent. In a preferred embodiment, the GPR119
receptor related disorder is a metabolic disorder and in particular
the metabolic disorder is diabetes and/or obesity.
[0171] More particularly, the compounds of formula (A), (A-I),
(A-II), (A-III), (A-IV), (A-IA), (A-IIA), (A-IIIA), (A-IVA),
(A-IB), (A-IIB), (A-IIIB), (A-IVB), (A-V), (B), (B-I), (B-II),
(B-III), (B-IV), (B-IA), (B-IIA), (B-IIIA), (B-IVA), (B-IB),
(B-IIB), (B-IIIB), (B-IVB), and (B-V) as defined above can be
administered for the treatment, prevention and/or amelioration of
GPR119 receptor associated diseases or disorders including, but not
limited to, diabetes and other metabolic disorders or diseases.
[0172] Yet another embodiment of the present invention pertains to
the use of a compound of the present invention, such as a compound
of formula (A), (A-I), (A-II), (A-M), (A-IV), (A-IA), (A-IIA),
(A-IIIA), (A-IVA), (A-IB), (A-IIB), (A-IIIB), (A-IVB), (A-V), (B),
(B-I), (B-II), (B-III), (B-IV), (B-IA), (B-IIA), (B-IIIA), (B-IVA),
(B-IB), (B-IIB), (B-IIIB), (B-IVB), or (B-V) as defined above, or a
composition thereof in the manufacture of a medicament for
modulating the activity of a GPR 119 receptor.
[0173] More particularly, the present invention pertains to the use
of a compound of the present invention, such as a compound of
formula (A), (A-I), (A-II), (A-III), (A-IV), (A-IA), (A-IIA),
(A-IIIA), (A-IVA), (A-IB), (A-IIB), (A-IIIB), (A-IVB), (A-V), (B),
(B-I), (B-II), (B-III), (B-IV), (B-IA), (B-IIA), (B-IIIA), (B-IVA),
(B-IB), (B-IIB), (B-IIIB), (B-IVB), or (B-V) as defined above, or a
composition thereof in the manufacture of a medicament for
agonizing a GPR 119 receptor
[0174] The compounds of the present invention, such as the
compounds of formula (A), (A-I), (A-II), (A-III), (A-IV), (A-IA),
(A-IIA), (A-IIIA), (A-IVA), (A-IB) (A-IIB), (A-IIIB), (A-IVB),
(A-V), (B), (B-I), (B-II), (B-III), (B-IV), (B-IA), (B-IIA),
(B-IIIA), (B-IVA), (B-IB), (B-IIB), (B-IIIB). (B-IVB), and (B-V) as
defined above are useful in the treatment of a variety of metabolic
disorders including, but not limited to, diabetes mellitus, type 1
diabetes, type 2 diabetes, inadequate glucose tolerance, impaired
glucose tolerance, insulin resistance, hyperglycemia,
hyperlipidemia, hypertriglyceridemi a, hypercholesterolemia,
dyslipidemia, atherosclerosis, stroke, syndrome X, hypertension,
pancreatic beta-cell insufficiency, enteroendocrine cell
insufficiency, glucosuria, metabolic acidosis, cataracts, diabetic
nephropathy, diabetic neuropathy, peripheral neuropathy, diabetic
coronary artery disease, diabetic cerebrovascular disease, diabetic
peripheral vascular disease, diabetic retinopathy, metabolic
syndrome, a condition related to diabetes mellitus, myocardial
infarction, learning impairment, memory impairment, a
neurodegenerative disorder, a condition ameliorated by increasing a
blood GLP-1 level in an individual with a neurodegenerative
disorder, excitotoxic brain damage caused by severe epileptic
seizures, Alzheimer's disease, Parkinson's disease, Huntington's
disease, prion-associated disease, stroke, motor-neuron disease,
traumatic brain injury, spinal cord injury, obesity, delayed wound
healing, abnormal heart function, myocardial ischemia, low HDL,
high LDL, non-cardiac ischemia, vascular restenosis, pancreatitis,
neurodegenerative disease, lipid disorders, cognitive impairment
and dementia, bone disease, HIV protease associated lipodystrophy
and glaucoma.
[0175] More particularly, the compounds of the present invention,
such as the compounds of formula (A), (A-I), (A-II), (A-III),
(A-IV), (A-IA), (A-IIA), (A-IIIA), (A-IVA), (A-IB), (A-IIB),
(A-IIIB), (A-IVB), (A-V), (B), (B-I), (B-II), (B-III), (B-IV),
(B-IA), (B-IIA), (B-IIIA), (B-IVA), (B-IB) (B-IIB), (B-IIIB),
(B-IVB), and (B-V) as defined above can be administered for the
treatment of metabolic-related disorder selected from the group
consisting of type 2 diabetes, hyperglycemia, hyperinsulinemia,
hyperlipidemia, hypertriglyceridemia, insulin resistance, type 1
diabetes, idiopathic type 1 diabetes (type Ib), latent autoimmune
diabetes in adults (LADA), early-onset type 2 diabetes (EOD),
youth-onset atypical diabetes (YOAD), maturity onset diabetes of
the young (MODY), malnutrition-related diabetes, gestational
diabetes, coronary heart disease, vascular restenosis, restenosis,
restenosis after angioplasty, peripheral vascular disease,
claudication, intermittent claudication, cell death associated with
myocardial infarction (e.g. necrosis and apoptosis), dyslipidemia,
post-prandial lipemia, conditions of impaired glucose tolerance
(IGT), impaired glucose metabolism, conditions of impaired glucose
metabolism, conditions of impaired fasting plasma glucose,
metabolic acidosis, ketosis, arthritis, obesity, osteoporosis,
hypertension, congestive heart failure, left ventricular
hypertrophy, peripheral arterial disease, diabetic retinopathy,
macular degeneration, cataract, diabetic nephropathy,
glomerulosclerosis, chronic renal failure, diabetic neuropathy,
metabolic syndrome, syndrome X, premenstrual syndrome, angina
pectoris, thrombosis, atherosclerosis, ischemic stroke, transient
ischemic attacks, stroke, erectile dysfunction, skin and connective
tissue disorders, foot ulcerations, ulcerative colitis, endothelial
dysfunction, and impaired vascular compliance.
[0176] More particularly, the compounds of the present invention,
such as the compounds of formula (A), (A-I), (A-II), (A-III),
(A-IV), (A-IA), (A-IIA), (A-IIIA), (A-IVA), (A-IB) (A-IIB),
(A-IIIB), (A-IVB), (A-V), (B), (B-I), (B-II), (B-III), (B-IV),
(B-IA), (B-IIA), (B-IIIA), (B-IVA), (B-IB), (B-IIB), (B-IIIB),
(B-IVB), and (B-V) as defined above can be administered for the
treatment of type 2 diabetes, hyperglycemia, hyperlipidemia,
hypertriglyceridemia, type 1 diabetes, dyslipidemia, and syndrome
X.
[0177] The invention further provides a pharmaceutical composition
comprising one or more compounds of the present invention together
with a pharmaceutically acceptable carrier. The pharmaceutical
composition may further comprise one or more of the active
ingredients identified above, such as other anti-cancer agents. In
one embodiment, the pharmaceutical composition includes a
therapeutically effective amount of one or more compounds of the
present invention, such as at least one compound of formula (A),
(A-I), (A-II), (A-III), (A-IV), (A-IA), (A-IIA), (A-IIIA), (A-IVA),
(A-IB) (A-IIB), (A-IIIB), (A-IVB), (A-V), (B), (B-I), (B-II),
(B-III), (B-IV), (B-IA), (B-IIA), (B-IIIA), (B-IVA), (B-IB),
(B-IIB), (B-IIIB), (B-IVB), or (B-V) as defined above.
[0178] Yet another embodiment is a method of treating metabolic
disorder in a subject in need thereof by administering a
therapeutically effective amount of a compound of the present
invention. For example, the compounds of the present invention are
effective for treating diabetes (e.g., type II diabetes) and/or
obesity.
BRIEF DESCRIPTION OF THE FIGURES
[0179] FIG. 1 is a graph of blood glucose over time in C57BI/6J
mice according to the oral glucose tolerance test (Biological Assay
Procedure E) before and after oral administration of vehicle
(control), compound A (Example 64 @ 30 mg/kg), or sitagliptin (10
mg/kg @ 10 mg/kg).
[0180] FIG. 2 is a graph of blood glucose over time in C57BI/6J
mice according to the oral glucose tolerance test (Biological Assay
Procedure E) before and after oral administration of vehicle
(control), compound A (Example 42 @ 10 mg/kg), or sitagliptin (10
mg/kg @ 10 mg/kg).
DETAILED DESCRIPTION
[0181] It is appreciated that certain features of the invention,
which are, for clarity, described in the context of separate
embodiments, may also be provided in combination in a single
embodiment. Conversely, various features of the invention, which
are, for brevity, described in the context of a single embodiment,
may also be provided separately or in any suitable subcombination.
Accordingly, all combinations of uses and medical indications
described herein specifically embraced by the present invention
just as if each and every subcombination of uses and medical
indications was individually and explicitly recited herein.
[0182] As used herein the following definition shall apply unless
otherwise indicated. Further many of the groups defined herein can
be optionally substituted. The listing of substituents in the
definition is exemplary and is not to be construed to limit the
substituents defined elsewhere in the specification.
[0183] The term `alkyl` refers to a straight or branched
hydrocarbon chain radical consisting solely of carbon and hydrogen
atoms, containing no unsaturation, having, unless otherwise
indicated, from one to eight carbon atoms, and which is attached to
the rest of the molecule by a single bond, e.g., methyl, ethyl,
n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and
1,1-dimethylethyl (t-butyl).
[0184] The term substituted or unsubstituted (C.sub.1-4)alkyl
refers to an alkyl group as defined above having up to 4 carbon
atoms, and the term substituted or unsubstituted (C.sub.1-6)alkyl
refers to an alkyl group as defined above having up to 6 carbon
atoms.
[0185] The term "alkenyl" refers to an aliphatic hydrocarbon group
containing a carbon-carbon double bond and which may be a straight
or branched or branched chain having, unless otherwise indicated, 2
to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl
(allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, and
2-butenyl.
[0186] The term substituted or unsubstituted (C.sub.2-6) alkenyl
refers to an alkenyl group as defined above having up to 6 carbon
atoms.
[0187] The term "alkynyl" refers to a straight or branched chain
hydrocarbyl radicals having at least one carbon-carbon triple bond,
and having, unless otherwise indicated, in the range of 2 up to 12
carbon atoms (with radicals having in the range of about 2 up to 10
carbon atoms presently being preferred) e.g., ethynyl, propynyl,
and butnyl.
[0188] The term substituted or unsubstituted (C.sub.2-6) alkynyl
refers to an alkynyl group as defined above having up to 6 carbon
atoms.
[0189] The term "alkoxy" denotes an alkyl group as defined above
attached via an oxygen linkage to the rest of the molecule.
Representative examples of these groups are OCH.sub.3 and
--OC.sub.2H.sub.5. The term "substituted alkoxy" refers to an
alkoxy group where the alkyl constituent is substituted (i.e.,
--O-(substituted alkyl) wherein the term "substituted alkyl" is the
same as defined above for "alkyl". For example "alkoxy" refers to
the group --O-alkyl, including, unless otherwise indicated, from 1
to 8 carbon atoms of a straight, branched, cyclic configuration and
combinations thereof attached to the parent structure through
oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy,
cyclopropyloxy, and cyclohexyloxy.
[0190] The term "cycloalkyl" denotes a non-aromatic mono or
multicyclic ring system of, unless otherwise indicated, 3 to about
12 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, and
cyclohexyl. Examples of multicyclic cycloalkyl groups include
perhydronapththyl, adamantyl and norbomyl groups, bridged cyclic
groups, and sprirobicyclic groups, e.g., sprio (4,4) non-2-yl.
[0191] The term "C.sub.3-8 cycloalkyl" refers to a cycloalkyl group
as defined above having up to 8 atoms.
[0192] The term "cycloalkylalkyl" refers to a cyclic
ring-containing radical containing, unless otherwise indicated, in
the range of 3 up to about 8 carbon atoms directly attached to an
alkyl group which are then attached to the main structure at any
carbon from alkyl group that results in the creation of a stable
structure such as cyclopropylmethyl, cyclobuyylethyl, and
cyclopentylethyl.
[0193] The term "C.sub.3-6 cycloalkylalkyl" refers to a
cycloalkylalkyl group as defined above having up to 6 atoms.
[0194] The term "cycloalkenyl" refers to cyclic ring-containing
radicals containing, unless otherwise indicated, in the range of 3
up to about 8 carbon atoms with at least one carbon-carbon double
bond such as cyclopropenyl, cyclobutenyl, and cyclopentenyl. The
term "cycloalkenylalkyl" refers to a cycloalkenyl group directly
attached to an alkyl group which are then attached to the main
structure at any carbon from alkyl group that results in the
creation of a stable structure
[0195] The term "C.sub.3-6 cycloalkenyl" refers to a cycloalkenyl
group as defined above having up to 6 atoms.
[0196] The term "aryl" refers to aromatic radicals having, unless
otherwise indicated, in the range of 6 up to 20 carbon atoms such
as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.
[0197] The term "arylalkyl" refers to an aryl group as defined
above directly bonded to an alkyl group as defined above. e.g.,
--CH.sub.2C.sub.6H.sub.5 and --C.sub.2H.sub.5C.sub.6H.sub.5.
[0198] The term "heterocyclic ring" refers to a non-aromatic 3 to
15 member ring radical which, consists of carbon atoms and at least
one heteroatom selected from the group consisting of nitrogen,
phosphorus, oxygen and sulfur. For purposes of this invention, the
heterocyclic ring radical may be a mono-, bi-, tri- or tetracyclic
ring system, which may include fused, bridged or spiro ring
systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur
atoms in the heterocyclic ring radical may be optionally oxidized
to various oxidation states. In addition, the nitrogen atom may be
optionally quaternized. The heterocyclic ring radical may be
attached to the main structure at any heteroatom or carbon atom
that results in the creation of a stable structure.
[0199] The term "heterocyclyl" refers to a heterocylic ring radical
as defined above. The heterocylcyl ring radical may be attached to
the main structure at any heteroatom or carbon atom that results in
the creation of a stable structure.
[0200] The term "heterocyclylalkyl" refers to a heterocylic ring
radical as defined above directly bonded to an alkyl group. The
heterocyclylalkyl radical may be attached to the main structure at
carbon atom in the alkyl group that results in the creation of a
stable structure. Examples of such heterocycloalkyl radicals
include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl,
decahydroisoquinolyl, imidazolinyl, imidazolidinyl,
isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl,
octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl,
2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl,
4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,
thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,
thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and
1,1-dioxo-thiomorpholinyl.
[0201] The term "heteroaryl" refers to an optionally substituted 5
to 14 member aromatic ring having one or more heteroatoms selected
from N, O, and S as ring atoms. The heteroaryl may be a mono-, bi-
or tricyclic ring system. Examples of such "heterocyclic ring" or
"heteroaryl" radicals include, but are not limited to, oxazolyl,
thiazolyl, imidazolyl, pyrrolyl, furanyl, pyridinyl, pyrimidinyl,
pyrazinyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl,
carbazolyl, quinolyl, isoquinolyl, azetidinyl, acridinyl,
benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl,
dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl,
phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,
purinyl, quinazolinyl, quinoxalinyl, tetrazoyl,
tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,
2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl,
4-piperidonyl, pyrrolidinyl, pyridazinyl, oxazolinyl, oxazolidinyl,
triazolyl, indanyl, isoxazolyl, isoxazolidinyl, morpholinyl,
thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl,
isothiazolidinyl, isoindolyl, indolinyl, isoindolinyl,
octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl,
benzimidazolyl, thiadiazolyl, benzopyranyl, tetrahydrofuryl,
tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl,
thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,
dioxaphospholanyl, oxadiazolyl, chromanyl, and isochromanyl. The
heteroaryl ring radical may be attached to the main structure at
any heteroatom or carbon atom that results in the creation of a
stable structure. The term "substituted heteroaryl" also includes
ring systems substituted with one or more oxide (--O--)
substituents, such as pyridinyl N-oxides.
[0202] The term "heteroarylalkyl" refers to heteroaryl ring radical
as defined above directly bonded to an alkyl group. The
heteroarylalkyl radical may be attached to the main structure at
any carbon atom from alkyl group that results in the creation of a
stable structure.
[0203] The term "heterocyclylalkyl" refers to a heterocylic ring
radical as defined above directly bonded to an alkyl group. The
heterocyclylalkyl radical may be attached to the main structure at
carbon atom in the alkyl group that results in the creation of a
stable structure.
[0204] The term "cyclic ring" refers to a cyclic ring containing,
unless otherwise indicated, 3 to 10 carbon atoms.
[0205] The term "substituted" unless otherwise specified, refers to
substitution with any one or any combination of the following
substituents and may be the same or different which one or more are
selected from the groups such as hydrogen, hydroxy, halogen,
carboxyl, cyano, nitro, oxo (.dbd.O), thio (.dbd.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 heterocycyl, substituted or
unsubstituted heterocycicyalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
heteroarylalkyl, --COOR', --C(O)R', --C(S)R', --C(O)NR'R'',
--C(O)ONR'R'', --NR'R'', --NR'CONR'R'', --N(R')SOR'',
--N(R')SO.sub.2R'', -(.dbd.N--N(R') R''), --NR'C(O)OR'', --NR'R'',
--NR'C(O)R''--, --NR'C(S)R''--NR'C(S)NR''R''', --SONR'R''--,
--SO.sub.2NR'R''--, --OR', --OR'C(O)NR''R''', --OR'C(O)OR''--,
--OC(O)R', --OC(O)NR'R'', --R'NR''C(O)R''', --R'OR'', --R'C(O)OR'',
--R'C(O)NR''R''', --R'C(O)R'', --R'OC(O)R'', --SR', --SOR',
--SO.sub.2R', --ONO.sub.2 wherein R', R'' and R''' in each of the
above groups can independently be hydrogen, hydrogen, hydroxy,
halogen, carboxyl, cyano, nitro, oxo (.dbd.O), thio (.dbd.S), imino
(.dbd.NR'), 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 heterocycyl,
substituted or unsubstituted heterocycicyalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted arylalkyl,
substituted or unsubstituted heteroaryl, or substituted or
unsubstituted heteroarylalkyl, or any two of R', R'' and R'' may be
joined to form a substituted or unsubstituted saturated or
unsaturated 3-10 membered ring, which may optionally include
heteroatoms which may be the same or different and are selected
from O, NR.sup.X or S or form oxo (.dbd.O), thio (.dbd.S) or imino
(.dbd.NR', where R' is defined above). The substituents in the
aforementioned "substituted" groups cannot be further substituted.
For example, when the substituent on "substituted alkyl" is
"substituted aryl", the substituent on "substituted aryl" cannot be
"substituted alkenyl". Substitution or the combinations of
substituents envisioned by this invention are preferably those that
result in the formation of a stable or chemically feasible
compound. The term stable as used herein refers to the compounds or
the structure that are not substantially altered when subjected to
conditions to allow for their isolation, production, detection and
preferably their recovery, purification and incorporation into a
pharmaceutical composition.
[0206] The term "halo", "halide", or, alternatively, "halogen"
means fluoro, chloro, bromo or iodo. The terms "haloalkyl,"
"haloalkenyl," "haloalkynyl" and "haloalkoxy" include alkyl,
alkenyl, alkynyl and alkoxy structures that are substituted with
one or more halo groups or with combinations thereof. For example,
the terms "fluoroalkyl" and "fluoroalkoxy" refer to haloalkyl and
haloalkoxy groups, respectively, in which the halo is fluorine.
[0207] The term "protecting group" or "PG" refers to a substituent
that is employed to block or protect a particular functionality.
Other functional groups on the compound may remain reactive. For
example, an "amino-protecting group" is a substituent attached to
an amino group that blocks or protects the amino functionality in
the compound. Suitable amino-protecting groups include, but are not
limited to, acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC),
benzyloxycarbonyl (CBz) and 9-fluorenylmethylenoxycarbonyl (Fmoc).
Similarly, a "hydroxy-protecting group" refers to a substituent of
a hydroxy group that blocks or protects the hydroxy functionality.
Suitable hydroxy-protecting groups include, but are not limited to,
acetyl and silyl. A "carboxy-protecting group" refers to a
substituent of the carboxy group that blocks or protects the
carboxy functionality. Suitable carboxy-protecting groups include,
but are not limited to, --CH.sub.2CH.sub.2SO.sub.2Ph, cyanoethyl,
2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl,
-2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl,
2-(diphenylphosphino)-ethyl, and nitroethyl. For a general
description of protecting groups and their use, see T. W. Greene,
Protective Groups in Organic Synthesis, John Wiley & Sons, New
York, 1991.
[0208] The term "stereoisomer" refers to compounds, which have
identical chemical composition, but differ with regard to
arrangement of the atoms and the groups in space. These include
enantiomers, diastereomers, geometrical isomers, atropisomer or
conformational isomers.
[0209] All the stereoisomers of compounds described herein are
within the scope of this invention. Racemic mixtures are also
encompassed within the scope of this invention. Therefore, single
stereochemical isomers as well enantiomeric, diastereoisomeric and
geometric (or conformational) mixtures of the present compounds
fall within the scope of the invention.
[0210] Certain of the compounds described herein contain one or
more asymmetric centers and can thus give rise to enantiomers,
diastereomers, and other stereoisomeric forms that can be defined,
in terms of absolute stereochemistry, as (R)- or (S)-. The present
chemical entities, pharmaceutical compositions and methods are
meant to include all such possible isomers, including racemic
mixtures, optically pure forms and intermediate mixtures. For the
instance the non-limiting example of intermediate mixutures include
a mixture of isomers in a ratio of 10:90, 13:87, 17:83, 20:80, or
22:78. Optically active (R)- and (S)-isomers can be prepared using
chiral synthons or chiral reagents, or resolved using conventional
techniques. When the compounds described herein contain olefinic
double bonds or other centers of geometric asymmetry, and unless
specified otherwise, it is intended that the compounds include both
E and Z geometric isomers.
[0211] The term "tautomers" refers to compounds, which are
characterized by relatively easy interconversion of isomeric forms
in equilibrium. These isomers are intended to be covered by this
invention. "Tautomers" are structurally distinct isomers that
interconvert by tautomerization. "Tautomerization" is a form of
isomerization and includes prototropic or proton-shift
tautomerization, which is considered a subset of acid-base
chemistry. "Prototropic tautomerization" or "proton-shift
tautomerization" involves the migration of a proton accompanied by
changes in bond order, often the interchange of a single bond with
an adjacent double bond. Where tautomerization is possible (e.g. in
solution), a chemical equilibrium of tautomers can be reached. An
example of tautomerization is keto-enol tautomerization. A specific
example of keto-enol tautomerization is the interconversion of
pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another
example of tautomerization is phenol-keto tautomerization. A
specific example of phenol-keto tautomerization is the
interconversion of pyridin-4-ol and pyridin-4(1H)-one
tautomers.
[0212] A "leaving group or atom" is any group or atom that will,
under the reaction conditions, cleave from the starting material,
thus promoting reaction at a specified site. Suitable examples of
such groups unless otherwise specified are halogen atoms and
mesyloxy, p-nitrobenzensulphonyloxy and tosyloxy groups.
[0213] The term "prodrug" refers to a compound, which is an
inactive precursor of a compound, converted into its active form in
the body by normal metabolic processes. Prodrug design is discussed
generally in Hardma, et al. (Eds.), Goodman and Gilman's The
Pharmacological Basis of Therapeutics, 9th ed., pp. 11-16 (1996). A
thorough discussion is provided in Higuchi, et al., Prodrugs as
Novel Delivery Systems, Vol. 14, ASCD Symposium Series, and in
Roche (ed.), Bioreversible Carriers in Drug Design, American
Pharmaceutical Association and Pergamon Press (1987). To
illustrate, prodrugs can be converted into a pharmacologically
active form through hydrolysis of, for example, an ester or amide
linkage, thereby introducing or exposing a functional group on the
resultant product. The prodrugs can be designed to react with an
endogenous compound to form a water-soluble conjugate that further
enhances the pharmacological properties of the compound, for
example, increased circulatory half-life. Alternatively, prodrugs
can be designed to undergo covalent modification on a functional
group with, for example, glucuronic acid, sulfate, glutathione,
amino acids, or acetate. The resulting conjugate can be inactivated
and excreted in the urine, or rendered more potent than the parent
compound. High molecular weight conjugates also can be excreted
into the bile, subjected to enzymatic cleavage, and released back
into the circulation, thereby effectively increasing the biological
half-life of the originally administered compound.
[0214] The term "ester" refers to a compound, which is formed by
reaction between an acid and an alcohol with elimination of water.
An ester can be represented by the general formula RCOOR'.
[0215] These prodrugs and esters are intended to be covered within
the scope of this invention.
[0216] Additionally the instant invention also includes the
compounds which differ only in the presence of one or more
isotopically enriched atoms for example replacement of hydrogen
with deuterium or tritium, or the replacement of a carbon by
.sup.13C- or .sup.14C-enriched carbon.
[0217] The compounds of the present invention may also contain
unnatural proportions of atomic isotopes at one or more of atoms
that constitute such compounds. For example, the compounds may be
radiolabeled with radioactive isotopes, such as for example tritium
(.sup.3H), iodine-125 (.sup.125I) or carbon-14 (.sup.14C). All
isotopic variations of the compounds of the present invention,
whether radioactive or not, are encompassed within the scope of the
present invention.
[0218] Pharmaceutically acceptable salts forming part of this
invention include salts derived from inorganic bases such as Li,
Na, K, Ca, Mg, Fe, Cu, Zn, and Mn; salts of organic bases such as
N,N'-diacetylethylenediamine, glucamine, triethylamine, choline,
hydroxide, dicyclohexylamine, metformin, benzylamine,
trialkylamine, and thiamine; chiral bases such as alkylphenylamine,
glycinol, and phenyl glycinol; salts of natural amino acids such as
glycine, alanine, valine, leucine, isoleucine, norleucine,
tyrosine, cystine, cysteine, methionine, proline, hydroxy proline,
histidine, omithine, lysine, arginine, and serine; quaternary
ammonium salts of the compounds of invention with alkyl halides,
alkyl sulphates such as MeI and (Me).sub.2SO.sub.4; non-natural
amino acids such as D-isomers or substituted amino acids;
guanidine; and substituted guanidine wherein the substituents are
selected from nitro, amino, alkyl, alkenyl, alkynyl, ammonium or
substituted ammonium salts and aluminum salts. Salts may include
acid addition salts where appropriate which are sulphates,
nitrates, phosphates, perchlorates, borates, hydrohalides,
acetates, tartrates, maleates, citrates, fumarates, succinates,
palmoates, methanesulphonates, benzoates, salicylates,
benzenesulfonates, ascorbates, glycerophosphates, and
ketoglutarates.
[0219] When ranges are used herein for physical properties, such as
molecular weight, or chemical properties, such as chemical
formulae, all combinations and subcombinations of ranges and
specific embodiments therein are intended to be included. The term
"about" when referring to a number or a numerical range means that
the number or numerical range referred to is an approximation
within experimental variability (or within statistical experimental
error), and thus the number or numerical range may vary from, for
example, between 1% and 15% of the stated number or numerical
range. The term "comprising" (and related terms such as "comprise"
or "comprises" or "having" or "including") includes those
embodiments, for example, an embodiment of any composition of
matter, composition, method, or process, or the like, that "consist
of" or "consist essentially of" the described features.
[0220] The term "agonist" generally refers to a moiety that
interacts and activates a receptor, such as, the GPR119 receptor
and initiates a physiological or pharmacological response
characteristic of that receptor. For example, when moieties
activate the intracellular response upon binding to the receptor,
or enhance GTP binding to membranes.
[0221] The term "contact or contacting" refers to bringing the
indicated moieties together, whether in an in vitro system or an in
vivo system. Thus, "contacting" a GPR 119 receptor with a compound
of the invention includes the administration of a compound of the
present invention to an individual, preferably a human, having a
GPR 119 receptor, as well as, for example, introducing a compound
of the invention into a sample containing a cellular or more
purified preparation containing a GPR 119 receptor.
[0222] The term "hydrate" as used herein means a compound of the
invention or a salt thereof, that further includes a stoichiometric
or non-stoichiometric amount of water bound by non-covalent
intermolecular forces.
[0223] The terms "in need of treatment" and "in need thereof," when
referring to treatment are used interchangeably to refer to a
judgment made by a caregiver (e.g. physician, nurse, or nurse
practitioner in the case of humans; veterinarian in the case of
animals, including non-human mammals) that an individual or animal
requires or will benefit from treatment. This judgment is made
based on a variety of factors that are in the realm of a
caregiver's expertise, but that includes the knowledge that the
individual or animal is ill, or will become ill, as the result of a
disease, condition or disorder that is treatable by the compounds
of the invention. Accordingly, the compounds of the invention can
be used in a protective or preventive manner; or compounds of the
invention can be used to alleviate, inhibit or ameliorate the
disease, condition or disorder.
[0224] The term "modulate or modulating" refers to an increase or
decrease in the amount, quality, response or effect of a particular
activity, function or molecule.
[0225] The term "pharmaceutical composition" refers to a
composition comprising at least one active ingredient, including
but not limited to, salts, solvates, and hydrates of compounds of
the present inventionm whereby the composition is amenable to
investigation for a specified, efficacious outcome in a mammal (for
example, without limitation, a human). Those of ordinary skill in
the art will understand and appreciate the techniques appropriate
for determining whether an active ingredient has a desired
efficacious outcome based upon the needs of the artisan.
[0226] The term "solvate" as used herein means a compound of the
invention or a salt, thereof, that further includes a
stoichiometric or non-stoichiometric amount of a solvent bound by
non-covalent intermolecular forces. Preferred solvents are
volatile, non-toxic, and/or acceptable for administration to humans
in trace amounts.
[0227] Abbreviations, unless otherwise indicated, used herein have
their conventional meaning within the chemical and biological
arts.
[0228] The term "co-administration," "administered in combination
with," and their grammatical equivalents, as used herein,
encompasses administration of two or more agents to an animal so
that both agents and/or their metabolites are present in the animal
at the same time. Co-administration includes simultaneous
administration in separate compositions, administration at
different times in separate compositions, or administration in a
composition in which both agents are present.
[0229] The term "effective amount" or "therapeutically effective
amount" refers to that amount of a compound described herein that
is sufficient to effect the intended application including, but not
limited to, disease treatment, as defined below. The
therapeutically effective amount may vary depending upon the
intended application (in vitro or in vivo), or the subject and
disease condition being treated, e.g., the weight and age of the
subject, the severity of the disease condition, the manner of
administration and the like, which can readily be determined by one
of ordinary skill in the art. The term also applies to a dose that
will induce a particular response in target cells, e.g. reduction
of platelet adhesion and/or cell migration. The specific dose will
vary depending on the particular compounds chosen, the dosing
regimen to be followed, whether it is administered in combination
with other compounds, timing of administration, the tissue to which
it is administered, and the physical delivery system in which it is
carried.
[0230] As used herein, "treatment," "treating," or "ameliorating"
are used interchangeably. These terms refers to an approach for
obtaining beneficial or desired results including but not limited
to therapeutic benefit and/or a prophylactic benefit. By
therapeutic benefit is meant eradication or amelioration of the
underlying disorder being treated. Also, a therapeutic benefit is
achieved with the eradication or amelioration of one or more of the
physiological symptoms associated with the underlying disorder such
that an improvement is observed in the subject, notwithstanding
that the subject may still be afflicted with the underlying
disorder. For prophylactic benefit, the compositions may be
administered to a subject at risk of developing a particular
disease, or to a subject reporting one or more of the physiological
symptoms of a disease, even though a diagnosis of this disease may
not have been made.
[0231] A "therapeutic effect," as that term is used herein,
encompasses a therapeutic benefit and/or a prophylactic benefit as
described above. A prophylactic effect includes delaying or
eliminating the appearance of a disease or condition, delaying or
eliminating the onset of symptoms of a disease or condition,
slowing, halting, or reversing the progression of a disease or
condition, or any combination thereof.
[0232] The term "subject" or "individual" or "subject" is intended
to mean any animal, including mammals, preferably mice, rats, other
rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or
primates and most preferably humans. In another embodiment, the
individual is a human and in certain embodiments, the human is an
infant, child, adolescent or adult. In one embodiment, the
individual is at risk for developing a GPR119-related disorder. In
one embodiment, the individual is at risk for developing a
metabolic-related disease or disorder. Individuals who are at risk
include, but are not limited to, those with hereditary history of a
metabolic-related disease or disorder, or those in a state of
physical health which puts them at risk for a metabolic-related
disease or disorder. In another embodiment, the individual has been
determined, by the care-giver or someone acting under the guidance
of the care-giver, to have a metabolic-related disease or disorder,
11381 The term "pharmaceutically acceptable carrier" or
"pharmaceutically acceptable excipient" includes, but is not
limited to, any and all solvents, dispersion media, coatings,
antibacterial and antifungal agents, isotonic and absorption
delaying agents, one or more suitable diluents, fillers, salts,
disintegrants, binders, lubricants, glidants, wetting agents,
controlled release matrices, colorants/flavoring, carriers,
excipients, buffers, stabilizers, solubilizers, and combinations
thereof. Except insofar as any conventional media or agent is
incompatible with the active ingredient, its use in the therapeutic
compositions of the invention is contemplated. Supplementary active
ingredients can also be incorporated into the compositions.
Method of Treatment
[0233] In addition to the foregoing beneficial uses for compounds
of the present invention as disclosed herein, compounds of the
invention are useful in the treatment of additional diseases.
Without limitation, these include the following.
[0234] The most significant pathologies in type 2 diabetes are
impaired insulin signaling at its target tissues ("insulin
resistance") and failure of the insulin-producing cells of the
pancreas to secrete an appropriate degree of insulin in response to
a hyperglycemic signal. Current therapies to treat the latter
include inhibitors of the .beta.-cell ATP-sensitive potassium
channel to trigger the release of endogenous insulin stores, or
administration of exogenous insulin. Neither of these achieves
accurate normalization of blood glucose levels and both carry the
risk of inducing hypoglycemia. For these reasons, there has been
intense interest in the development of pharmaceuticals that
function in a glucose-dependent action, i.e. potentiators of
glucose signaling.
[0235] Physiological signaling systems which function in this
manner are well-characterized and include the gut peptides GLP1,
GIP and PACAP. These hormones act via their cognate G-protein
coupled receptor to stimulate the production of cAMP in pancreatic
3-cells. The increased cAMP does not appear to result in
stimulation of insulin release during the fasting or preprandial
state. However, a series of biochemical targets of cAMP signaling,
including the ATP-sensitive potassium channel, voltage-sensitive
potassium channels and the exocytotic machinery, are modified in
such a way that the insulin secretory response to a postprandial
glucose stimulus is markedly enhanced. Accordingly, agonists of
novel, similarly functioning, .beta.-cell GPCRs, including GPRl 19,
would also stimulate the release of endogenous insulin and
consequently promote normoglycemia in type 2 diabetes.
[0236] It is also established that increased cAMP, for example as a
result of GLP-1 stimulation, promotes .beta.-cell proliferation,
inhibits .beta.-cell death and thus improves islet mass. This
positive effect on .beta.-cell mass is expected to be beneficial in
both type 2 diabetes, where insufficient insulin is produced, and
type 1 diabetes, where .beta.-cells are destroyed by an
inappropriate autoimmune response.
[0237] Some .beta.-cell GPCRs, including GPRl 19, are also present
in the hypothalamus where they modulate hunger, satiety, decrease
food intake, controlling or decreasing weight and energy
expenditure. Hence, given their function within the hypothalamic
circuitry, agonists or inverse agonists of these receptors mitigate
hunger, promote satiety and therefore modulate weight.
[0238] It is also well-established that metabolic diseases exert a
negative influence on other physiological systems. Thus, there is
often the co-development of multiple disease states (e.g. type 1
diabetes, type 2 diabetes, inadequate glucose tolerance, insulin
resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia,
hypercholesterolemia, dyslipidemia, obesity or cardiovascular
disease in "syndrome X") or diseases which clearly occur secondary
to diabetes mellitus (e.g. kidney disease, peripheral neuropathy).
Thus, it is expected that effective treatment of the diabetic
condition will in turn be of benefit to such interconnected disease
states.
[0239] In some embodiments of the present invention the
metabolic-related disorder is selected from type 2 diabetes,
hyperglycemia, hyperinsulinemia, hyperlipidemia,
hypertriglyceridemia, insulin resistance, type 1 diabetes,
idiopathic type 1 diabetes (type Ib), latent autoimmune diabetes in
adults (LADA), early-onset type 2 diabetes (EOD), youth-onset
atypical diabetes (YOAD), maturity onset diabetes of the young
(MODY), malnutrition-related diabetes, gestational diabetes,
cardiovascular disease, coronary heart disease, vascular
restenosis, restenosis, restenosis after angioplasty, peripheral
vascular disease, claudication, intermittent claudication, cell
death associated with myocardial infarction (e.g. necrosis and
apoptosis), dyslipidemia, post-prandial lipemia, conditions of
impaired glucose tolerance (IGT), impaired glucose metabolism,
conditions of impaired glucose metabolism, conditions of impaired
fasting plasma glucose, metabolic acidosis, ketosis, arthritis,
obesity, osteoporosis, hypertension, congestive heart failure, left
ventricular hypertrophy, peripheral arterial disease, diabetic
retinopathy, macular degeneration, cataract, diabetic nephropathy,
glomerulosclerosis, chronic renal failure, diabetic neuropathy,
metabolic syndrome, syndrome X, premenstrual syndrome, angina
pectoris, thrombosis, atherosclerosis, ischemic stroke, transient
ischemic attacks, stroke, erectile dysfunction, skin and connective
tissue disorders, foot ulcerations, ulcerative colitis, endothelial
dysfunction, and impaired vascular compliance.
[0240] It will be appreciated that the treatment methods of the
invention are useful in the fields of human medicine and veterinary
medicine. Thus, the individual to be treated may be a mammal,
preferably human, or other animals. For veterinary purposes,
individuals include but are not limited to farm animals including
cows, sheep, pigs, horses, and goats; companion animals such as
dogs and cats; exotic and/or zoo animals; laboratory animals
including mice, rats, rabbits, guinea pigs, and hamsters; and
poultry such as chickens, turkeys, ducks, and geese.
[0241] The invention also relates to a method of treating diabetes
in a mammal that comprises administering to said mammal a
therapeutically effective amount of a compound of the present
invention.
[0242] In addition, the compounds described herein may be used for
the treatment of arteriosclerosis, including atherosclerosis.
Arteriosclerosis is a general term describing any hardening of
medium or large arteries. Atherosclerosis is a hardening of an
artery specifically due to an atheromatous plaque.
[0243] Further the compounds described herein may be used for the
treatment of glomerulonephritis. Glomerulonephritis is a primary or
secondary autoimmune renal disease characterized by inflammation of
the glomeruli. It may be asymptomatic, or present with hematuria
and/or proteinuria. There are many recognized types, divided in
acute, subacute or chronic glomerulonephritis. Causes are
infectious (bacterial, viral or parasitic pathogens), autoimmune or
paraneoplastic.
[0244] Additionally, the compounds described herein may be used for
the treatment of bursitis, lupus, acute disseminated
encephalomyelitis (ADEM), addison's disease, antiphospholipid
antibody syndrome (APS), aplastic anemia, autoimmune hepatitis,
coeliac disease, Crohn's disease, diabetes mellitus (type 1),
goodpasture's syndrome, graves' disease, guillain-barre syndrome
(GBS), hashimoto's disease, inflammatory bowel disease, lupus
erythematosus, myasthenia gravis, opsoclonus myoclonus syndrome
(OMS), optic neuritis, ord's thyroiditis, Ostheoarthritis,
uveoretinitis, pemphigus, polyarthritis, primary biliary cirrhosis,
reiter's syndrome, takayasu's arteritis, temporal arteritis, warm
autoimmune hemolytic anemia, Wegener's granulomatosis, alopecia
universalis, chagas.sup.1 disease, chronic fatigue syndrome,
dysautonomia, endometriosis, hidradenitis suppurativa, interstitial
cystitis, neuromyotonia, sarcoidosis, scleroderma, ulcerative
colitis, vitiligo, vulvodynia, appendicitis, arteritis, arthritis,
blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis,
cholecystitis, chorioamnionitis, colitis, conjunctivitis, cystitis,
dacryoadenitis, dermatomyositis, endocarditis, endometritis,
enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis,
fibrositis, gastritis, gastroenteritis, gingivitis, hepatitis,
hidradenitis, ileitis, iritis, laryngitis, mastitis, meningitis,
myelitis, myocarditis, myositis, nephritis, omphalitis, oophoritis,
orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis,
peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis,
proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis,
sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis,
vaginitis, vasculitis, or vulvitis.
[0245] The invention also relates to a method of treating a
cardiovascular disease in a mammal that comprises administering to
said mammal a therapeutically effective amount of a compound of the
present invention. Examples of cardiovascular conditions include,
but are not limited to, atherosclerosis, restenosis, vascular
occlusion and carotid obstructive disease.
[0246] The invention further provides methods of modulating GPR119
activity by contacting a GPR119 receptor with an amount of a
compound of the invention sufficient to modulate the activity of
the GPR119. Modulate can be inhibiting or activating GPR119
activity. In some embodiments, the invention provides methods of
agonizing GPR119 activity by contacting a GRP119 receptor with an
amount of a compound of the invention sufficient to activate the
activity of the GPR119 receptor. In some embodiments, the invention
provides methods of agonising in a solution by contacting said
solution with an amount of a compound of the invention sufficient
to activate the activity of the GPR119 receptor in said solution.
In some embodiments, the invention provides methods of agonizing
GPR119 activity in a cell by contacting said cell with an amount of
a compound of the invention sufficient to activate the activity of
GPR119 receptor in said cell. In some embodiments, the invention
provides methods of agonizing GPR119 activity in a tissue by
contacting said tissue with an amount of a compound of the
invention sufficient to activate the activity of GPR119 receptor in
said tissue. In some embodiments, the invention provides methods of
agonizing GPR119 activity in a organism by contacting said organism
with an amount of a compound of the invention sufficient to
activate the activity of GPR119 receptor in said organism. In some
embodiments, the invention provides methods of agonizing
[0247] GPR119 activity in a animal by contacting said animal with
an amount of a compound of the invention sufficient to activate the
activity of GPR119 receptor in said animal. In some embodiments,
the invention provides methods of agonizing GPR119 activity in a
mammal by contacting said mammal with an amount of a compound of
the invention sufficient to activate the activity of GPR119
receptor in said mammal. In some embodiments, the invention
provides methods of agonizing GPR119 activity in a human by
contacting said human with an amount of a compound of the invention
sufficient to activate the activity of GPR119 receptor in said
human.
Combination Treatment
[0248] The present invention also provides methods for combination
therapies in which is an agent known to modulate other pathways, or
other components of the same pathway, or even overlapping sets of
target enzymes or receptors are used in combination with a compound
of the present invention. In one aspect, such therapy includes but
is not limited to the combination of the subject compound with
other agents such as known antidiabetic, anti-obesity agents or any
other agents use for the treatment of metabolic disorders to
provide a synergistic or additive therapeutic effect.
[0249] In the context of the present invention, a compound as
described herein or a pharmaceutical composition thereof can be
utilized for modulating the activity of GPR 119 receptor related
diseases, conditions and/or disorders as described herein. Examples
of modulating the activity of GPRl19 receptor related diseases
include the treatment of metabolic related disorders. Metabolic
related disorders include, but are not limited to, hyperlipidemia,
type 1 diabetes, type 2 diabetes, and conditions associated
therewith, such as, but not limited to coronary heart disease,
ischemic stroke, restenosis after angioplasty, peripheral vascular
disease, claudication, intermittent claudication, cell death
associated with myocardial infarction (e.g. necrosis and
apoptosis), dyslipidemia, post-prandial lipemia, conditions of
impaired glucose tolerance (IGT), conditions of impaired fasting
plasma glucose, metabolic acidosis, ketosis, arthritis, obesity,
osteoporosis, hypertension, congestive heart failure, left
ventricular hypertrophy, peripheral arterial disease, diabetic
retinopathy, macular degeneration, cataract, diabetic nephropathy,
glomerulosclerosis, chronic renal failure, diabetic neuropathy,
metabolic syndrome, syndrome X, premenstrual syndrome, coronary
heart disease, angina pectoris, thrombosis, atherosclerosis,
myocardial infarction, transient ischemic attacks, stroke, vascular
restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia,
hypertriglyceridemia, insulin resistance, impaired glucose
metabolism, conditions of impaired glucose tolerance, conditions of
impaired fasting plasma glucose, obesity, erectile dysfunction,
skin and connective tissue disorders, foot ulcerations, ulcerative
colitis, endothelial dysfunction and impaired vascular compliance.
In some embodiments, metabolic related disorders include type 1
diabetes, type 2 diabetes, inadequate glucose tolerance, insulin
resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia,
hypercholesterolemia, dyslipidemia and syndrome X. Other examples
of modulating the activity of GPRl 19 receptor related diseases
include the treatment of obesity and/or overweight by decreasing
food intake, inducing satiation (i.e., the feeling of fullness),
controlling weight gain, decreasing body weight and/or affecting
metabolism such that the recipient loses weight and/or maintains
weight.
[0250] While a compound of the invention can be administered as the
sole active pharmaceutical agent (i.e., mono-therapy), the compound
can also be used in combination with one or more pharmaceutical
agents (i.e., combination-therapy) either administered together or
separately for the treatment of the diseases/conditions/disorders
described herein. Therefore, another aspect of the present
invention includes methods of treatment of a metabolic related
disorder, including a weight related disorder, such as obesity,
comprising administering to an individual in need of prophylaxis
and/or treatment a therapeutically effective amount of a compound
of the present invention in combination with one or more additional
pharmaceutical agent as described herein.
[0251] Suitable pharmaceutical agents that can be used in
combination with the compounds of the present invention include
anti-obesity agents such as apolipoprotein-B secretion/microsomal
triglyceride transfer protein (apo-B/MTP) inhibitors, MCR-4
agonists, cholescystokinin-A (CCK-A) agonists, serotonin and
norepinephrine reuptake inhibitors (for example, sibutramine),
sympathomimetic agents, .beta.3 adrenergic receptor agonists,
dopamine agonists (for example, bromocriptine),
melanocyte-stimulating hormone receptor analogues, cannabinoid 1
receptor antagonists [for example, SR141716:
N-(piperidin-1-yi)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H--
pyrazole-3-carboxamide], melanin concentrating hormone antagonists,
leptons (the OB protein), leptin analogues, leptin receptor
agonists, galanin antagonists, lipase inhibitors (such as
tetrahydrolipstatin, i.e., Orlistat), anorectic agents (such as a
bombesin agonist), Neuropeptide-Y antagonists, thyromimetic agents,
dehydroepiandrosterone or an analogue thereof, glucocorticoid
receptor agonists or antagonists, orexin receptor antagonists,
urocortin binding protein antagonists, glucagon-like peptide-1
receptor agonists, ciliary neutrotrophic factors (such as
Axokine.TM. available from Regeneron Pharmaceuticals, Inc.,
Tarrytown, N.Y. and Procter & Gamble Company, Cincinnati,
Ohio), human agouti-related proteins (AGRP), ghrelin receptor
antagonists, histamine 3 receptor antagonists or reverse agonists,
neuromedin U receptor agonists, noradrenergic anorectic agents (for
example, phentermine, mazindol and the like) and appetite
suppressants (for example, bupropion).
[0252] Other anti-obesity agents, including the agents set forth
infra, are well known, or will be readily apparent in light of the
instant disclosure, to one of ordinary skill in the art.
[0253] It is understood that the scope of combination-therapy of
the compounds of the present invention with other anti-obesity
agents, anorectic agents, appetite suppressant and related agents
is not limited to those listed above, but includes in principle any
combination with any pharmaceutical agent or pharmaceutical
composition useful for the treatment of overweight and obese
individuals.
[0254] It is understood that the scope of combination-therapy of
the compounds of the present invention with other pharmaceutical
agents is not limited to those listed herein, supra or infra, but
includes in principle any combination with any pharmaceutical agent
or pharmaceutical composition useful for the treatment of diseases,
conditions or disorders that are linked to metabolic related
disorders.
[0255] Some embodiments of the present invention include methods of
treatment of a disease, disorder, condition or complication thereof
as described herein, comprising administering to an individual in
need of such treatment a therapeutically effective amount or dose
of a compound of the present invention in combination with at least
one pharmaceutical agent selected from the group consisting of:
sulfonylureas (for example, glyburide, glipizide, glimepiride and
other sulfonylureas known in the art), meglitinides (for example,
repaglinide, nateglinide and other meglitinides known in the art),
biguanides (for example, biguanides include phenformin, metformin,
buformin, and biguanides known in the art), .alpha.-glucosidase
inhibitors [for example, acarbose,
N-(1,3-dihydroxy-2-propyl)valiolamine (generic name; voglibose),
miglitol, and .alpha.-glucosidase inhibitors known in the art],
peroxisome proliferators-activated receptor-.gamma. (i.e.,
PPAR-.gamma.) agonists (for example, rosiglitazone, pioglitazone,
tesaglitazar, netoglitazone, GW-409544, GW-501516 and PPAR-.gamma.
agonists known in the art), insulin, insulin analogues, HMG-CoA
reductase inhibitors (for example, rosuvastatin, pravastatin and
its sodium salt, simvastatin, lovastatin, atorvastatin,
fluvastatin, cerivastatin, rosuvastatin, pitavastatin, BMS's
"superstatin", and HMG-CoA reductase inhibitors known in the art),
cholesterol-lowering drugs (for example, fibrates that include:
bezafibrate, beclobrate, binifibrate, ciplofibrate, clinofibrate,
clofibrate, clofibric acid, etofibrate, fenofibrate, gemfibrozil,
nicofibrate, pirifibrate, ronifibrate, simfibrate, theofibrate, and
fibrates known in the art; bile acid sequestrants which include:
cholestyramine, colestipol and the like; and niacin), antiplatelet
agents (for example, aspirin and adenosine diphosphate receptor
antagonists that include: clopidogrel, ticlopidine and the like),
angiotensin-converting enzyme inhibitors (for example, captopril,
enalapril, alacepril, delapril; ramipril, lisinopril, imidapril,
benazepril, ceronapril, cilazapril, enalaprilat, fosinopril,
moveltopril, perindopril, quinapril, spirapril, temocapril,
trandolapril, and angiotensin converting enzyme inhibitors known in
the art), angiotensin II receptor antagonists [for example,
losartan (and the potassium salt form)], angiotensin II receptor
antagonists known in the art, adiponectin, squalene synthesis
inhibitors (for example,
(S)-.alpha.-[bis[2,2-dimethyl-1-oxopropoxy)methoxy]
phosphinyl]-3-phenoxybenzenebutanesulfonic acid, mono potassium
salt (BMS-188494) and squalene synthesis inhibitors known in the
art), and the like. In some embodiments, compounds of the present
invention and the pharmaceutical agents are administered
separately. In further embodiments, compounds of the present
invention and the pharmaceutical agents are administered
together.
[0256] Suitable pharmaceutical agents that can be used in
conjunction with compounds of the present invention include, but
not limited to, amylin agonists (for example, pramlintide), insulin
secretagogues (for example, GLP-I agonists; exendin-4;
insulinotropin (NN2211); acyl CoA cholesterol acetyltransferase
inhibitors (for example, ezetimibe, eflucimibe, and like
compounds), cholesterol absorption inhibitors (for example,
ezetimibe, pamaqueside and like compounds), cholesterol ester
transfer protein inhibitors (for example, CP-529414, JTT-705,
CETi-I, and like compounds), microsomal triglyceride transfer
protein inhibitors (for example, implitapide, and like compounds),
cholesterol modulators (for example, NO-1886, and like compounds),
bile acid modulators (for example, GT103-279 and like compounds),
insulin signaling pathway modulators, like inhibitors of protein
tyrosine phosphatases (PTPases), non-small molecule mimetic
compounds and inhibitors of glutamine-fructose-6-phosphate
amidotransferase (GFAT), compounds influencing a dysregulated
hepatic glucose production, like inhibitors of
glucose-6-phosphatase (GOPase), inhibitors of
fructose-1,6-bisphosphatase (F-1,6-BPase), inhibitors of glycogen
phosphorylase (GP), glucagon receptor antagonists and inhibitors of
phosphoenolpyruvate carboxykinase (PEPCK), pyruvate dehydrogenase
kinase (PDHK) inhibitors, insulin sensitivity enhancers, insulin
secretion enhancers, inhibitors of gastric emptying,
.alpha..sub.2-adrenergic antagonists, retinoid X receptor (PvXR)
agonists, and dipeptidyl peptidase-4 (DPP-IV) inhibitors.
[0257] In accordance with the present invention, the combination
can be used by mixing the respective active components, a compound
of the present invention and pharmaceutical agent, either all
together or independently with a physiologically acceptable
carrier, excipient, binder, diluent, etc., as described herein
above, and administering the mixture or mixtures either orally or
non-orally as a pharmaceutical composition. When a compound or a
mixture of compounds of the present invention are administered as a
combination therapy with another active compound the therapeutic
agents can be formulated as separate pharmaceutical compositions
given at the same time or at different times; or the compound or a
mixture of compounds of the present invention and the therapeutic
agent(s) can be formulated together as a single unit dosage.
[0258] Further therapeutic agents that can be combined with a
subject compound may be found in Goodman and Gilman's "The
Pharmacological Basis of Therapeutics" Tenth Edition edited by
Hardman, Limbird and Gilman or the Physician's Desk Reference, both
of which are incorporated herein by reference in their
entirety.
[0259] The compounds described herein can be used in combination
with the agents disclosed herein or other suitable agents,
depending on the condition being treated. Hence, in some
embodiments the compounds of the invention will be co-administered
with other agents as described above. When used in combination
therapy, the compounds described herein may be administered with
the second agent simultaneously or separately. This administration
in combination can include simultaneous administration of the two
agents in the same dosage form, simultaneous administration in
separate dosage forms, and separate administration. That is, a
compound described herein and any of the agents described above can
be formulated together in the same dosage form and administered
simultaneously. Alternatively, a compound of the present invention
and any of the agents described above can be simultaneously
administered, wherein both the agents are present in separate
formulations. In another alternative, a compound of the present
invention can be administered just followed by and any of the
agents described above, or vice versa. In the separate
administration protocol, a compound of the present invention and
any of the agents described above may be administered a few minutes
apart, or a few hours apart, or a few days apart.
[0260] The methods in accordance with the invention may include
administering a GPR 119 agonist with one or more other agents that
either enhance the activity of the agonist or compliment its
activity or use in treatment. Such additional factors and/or agents
may produce an augmented or even synergistic effect when
administered with a GPR 119 agonist, or minimize side effects.
[0261] The following general methodology described herein provides
the manner and process of making and using the compound of the
present invention and are illustrative rather than limiting.
Further modification of provided methodology and additionally new
methods may also be devised in order to achieve and serve the
purpose of the invention. Accordingly, it should be understood that
there may be other embodiments which fall within the spirit and
scope of the invention as defined by the specification hereto.
[0262] Representative compounds of the present invention include
those specified above in Table 1 and pharmaceutically acceptable
salts thereof. The present invention also includes the intermediate
compounds discussed in the examples and elsewhere in the
specification as well as their salts. The present invention should
not be construed to be limited to them.
General Method of Preparation of Compounds of the Invention
[0263] The compounds of the present invention may be prepared by
the following processes. Unless otherwise indicated, the variables
(e.g. Z, X, X.sub.1, X.sub.2, X.sub.3, X.sub.4, Cy, L and Ar) when
used in the below formulae are to be understood to present those
groups described above in relation to formula (A) and (B).
[0264] Scheme 1:
[0265] This scheme provides a method for the preparation of a
compound of formula (A) wherein L.sub.2 is absent, NH or O, X is N,
Z is NR or O and other variables such as Cy, X.sub.1, X.sub.2,
X.sub.3, X.sub.4, and are the same as described above in relation
to formula (A). L.sub.2 is shown as L in the scheme below.
##STR00122##
[0266] A compound of formula (1) wherein Hal represent halogen and
Z is NH or O can be coupled with a compound of formula (2) in the
presence of a suitable poly phosphoric acid at a sufficiently high
temperature to give a compound of (3). The compound of formula (3)
can then be coupled with a compound of formula Ar--B(OH).sub.2 in
the presence of a catalyst, such as Palladium tetrakis
triphenylphosphine, and a suitable base, such as potassium
carbonate, to give the desired compounds of formula (A), i.e
wherein L is absent, X is N, Z is O or NR and other variables are
the same as described above in relation to formula (A).
[0267] Similarly, the corresponding compound of formula (3) can be
coupled with a compound of the formula Ar--NH.sub.2 or Ar--OH in
the presence of a suitable base, such as potassium carbonate, to
give the desired compounds of formula (A), wherein L is NH or O, X
is N, Z is O or NR and other variables are the same as described
above in relation to formula (A).
Illustration:
##STR00123##
[0269] Scheme 2:
[0270] This scheme provides a method for the preparation of a
compound of formula (A-I) wherein L.sub.1 and L.sub.2 are absent, X
is N, Z is O, D is CH, E is N and other variables such as
R.sup.e-1, X.sub.1, X.sub.3 and X.sub.4 are the same as described
above in relation to formula (A-I).
##STR00124##
[0271] A compound of formula (1a) wherein Hal represents halogen
can be coupled with a compound of formula (2a) in the presence of a
suitable poly phosphoric acid at a sufficiently high temperature to
give a compound of formula (3a). The compound of formula (3a) can
then be coupled with a compound of formula R.sup.5-Lg (where Lg
represents a leaving group) in the presence of a suitable base such
as diisoprpyl amine to give a compound of formula (4). The compound
of formula (4) can then be coupled with a compound of formula
Ar--B(OH).sub.2 in the presence of a catalyst, such as Palladium
tetrakis triphenylphosphine, and a suitable base, such as potassium
carbonate, to give the desired compounds of formula (A-I), where X
is N, Z is O, D is CH, E is N and other variables are the same as
described above in relation to formula (A-I).
Illustration:
##STR00125##
[0273] Scheme 3:
[0274] This scheme provides a method for the preparation of a
compound of formula (A-II) wherein L.sub.1 and L.sub.2 are absent,
X is N, Z is O, D is CH, E is N and other variables such as
R.sup.e-1, X.sub.1, X.sub.2 and X.sub.4 are the same as described
above in relation to formula (A-II)
##STR00126##
[0275] A compound of formula (1b) wherein Hal represent halogen and
Z is NH or O can be coupled with a compound of formula (2b) in the
presence of a suitable poly phosphoric acid at a sufficiently high
temperature to give a compound of formula (3b). The compound of
formula (3b) can then be coupled with a compound of formula
R.sup.5-Lg (where Lg is a leaving group) in the presence of a
suitable base such as diisoprpyl amine to give the compound of
formula (4a). The compound of formula (4a) can then be coupled with
a compound of formula Ar--B(OH).sub.2 in the presence of a
catalyst, such as Palladium tetrakis triphenylphosphine, and a
suitable base, such as potassium carbonate, to give the desired
compounds of formula (A-II), X is N, Z is O, D is CH, E is N and
other variables are the same as described above in relation to
formula (A-II).
[0276] Scheme 3A:
[0277] This scheme provides a method for the preparation of a
compound of formula (A-II) wherein L.sub.1 and L.sub.2 are absent,
X is CH, Z is O, D is CH, E is N and other variables such as
R.sup.e-1, X.sub.1, X.sub.2 and X.sub.4 are the same as described
above in relation to formula (A-II).
##STR00127##
[0278] A compound of formula (1d) can be coupled with a compound of
formula (2c) in the presence of catalyst, such as Palladium
tetrakis triphenylphosphine, and a suitable base, such as potassium
carbonate, to give a compound of (3c). The compound of formula (3c)
can then be lithiated followed by treatment with triisopropyl
borate to give the compound of formula (4b). The compound of
formula (4b) can then be coupled with a compound of formula (4c) to
give a compound of formula (5a) which can then be reduced using
suitable reducing agent to give the desired compounds of formula
(A-II) wherein X is C, Z is O, D is CH, E is N and all the other
variables are the same as described above in relation to formula
(A-II).
Illustration:
##STR00128##
[0280] Scheme 4:
[0281] This scheme provides a method for the preparation of
compound of formula (B) wherein L.sub.1 is absent, NH or O, X is N,
Z is NR or O, L.sub.2 is absent and other variables such as Ar, Cy,
X.sub.1, X.sub.2, X.sub.3 and X.sub.4 are the same as described
above in relation to formula (B).
##STR00129##
[0282] A compound of formula (1) wherein Hal represent halogen and
Z is NH or O can be coupled with a compound of formula (5) in the
presence of poly phosphoric acid at a sufficiently high temperature
to give a compound of formula (6). The compound of formula (6) can
then be coupled with a compound of formula Cy-NH.sub.2 or Cy-OH in
the presence of a suitable base, such as potassium carbonate, to
give the desired compounds of formula (B) wherein L.sub.1 is NH or
O, X is N, Z is O or NR and other variables are the same as
described above in relation to formula (B). Alternately, the
compound of formula (6) can be converted to compound of formula
(6a) using
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) under
Suzuki coupling conditions. The compound of formula (6a) can then
be coupled with a compound of formula Cy-Lg (wherein Lg is an
leaving group) in the presence of a catalyst, such as Palladium
tetrakis triphenylphosphine, and a suitable base, such as potassium
carbonate, to give the desired compounds of formula (B), i.e
wherein L.sub.1 is absent, X is N, Z is O or NR and other variables
are the same as described above in relation to formula (B).
Illustration:
##STR00130##
[0284] Scheme 5:
[0285] This scheme provides a method for the preparation of a
compound of formula (B-I) wherein L.sub.1 and L.sub.2 are absent, X
is N, D is CH, E is N, Z is O and other variables such as
R.sup.e-1, X.sub.1, X.sub.3 and X.sub.4 are the same as described
above in relation to formula (B-I).
##STR00131##
[0286] A compound of formula (1b) wherein Hal represents halogen
can be coupled with a compound of formula (5) in the presence of
poly phosphoric acid at a sufficiently high temperature to give a
compound of formula (6b). The compound of formula (6b) can then be
converted to a compound of formula (6c) using Suzuki coupling. The
compound of formula (6c) can then be coupled with a compound of
formula (7) (wherein Pg is a protecting group) using palladium
tetrakis triphenylphosphine and a suitable base, such as potassium
carbonate, to provide a compound of formula (8). The compound of
formula (8) can then be subjected to hydrogenation to give the
compound of formula (9). The compound of formula (9) can then be
de-protected followed by coupling with a compound of formula
R.sup.5-Lg wherein Lg is a leaving group to give the desired
compounds of formula (B-I).
Illustration:
##STR00132##
[0288] Scheme 6:
[0289] This scheme provides a method for the preparation of a
compound of formula (B-II) wherein L.sub.1 and L.sub.2 are absent,
X is N, D is CH, E is N, Z is O and other variables such as
R.sup.e-1, X.sub.1, X.sub.2 and X.sub.4 are the same as described
above in relation to formula (B-II).
##STR00133##
Illustration:
##STR00134##
[0291] A compound of formula (1c) wherein Hal represents halogen
can be coupled with a compound of formula (5) in the presence of a
suitable poly phosphoric acid at sufficiently high temperature to
give a compound of formula (6d). The compound of formula (6d) can
then be converted to compound of formula (6e) using Suzuki
coupling. The compound of formula (6e) can then be coupled with a
compound of formula (7) using palladium tetrakis triphenylphosphine
and a suitable base, such as potassium carbonate, to provide a
compound of formula (8a). The compound of formula (8a) can then be
subjected to hydrogenation to give the compound of formula (9a).
The compound of formula (9a) can then be de-protected followed by
coupling with a compound of formula R.sup.5-Lg wherein Lg is a
leaving group to give the desired compounds of formula (B-II).
[0292] Similar methodologies with certain modifications as known to
those skilled in the art can be used to synthesize compounds of
formula (A), (A-I), (A-II), (A-III), (A-IV), (A-IA), (A-IIA),
(A-IIIA), (A-IVA), (A-IB) (A-IIB), (A-IIIB), (A-IVB), (A-V), (B),
(B-I), (B-II), (B-III), (B-IV), (B-IA), (B-IIA), (B-IIIA), (B-IVA),
(B-IB) (B-IIB), (B-IIIB), (B-IVB), and (B-V) wherein all the
variables are to be understood to present those groups described
above in relation to formula (A) or (B) using suitable
intermediates and reagents.
EXPERIMENTAL
[0293] Unless otherwise mentioned, work-up refers to distribution
of a reaction mixture between the aqueous and organic phases
indicated within parenthesis, separation and drying over
Na.sub.2SO.sub.4 of the organic layer and evaporating the solvent
to give a residue. Unless otherwise stated, purification refers to
column chromatography using silica gel as the stationary phase and
a mixture of petroleum ether (boiling at 60-80.degree. C.) and
ethyl acetate or dichloromethane and methanol of suitable polarity
as the mobile phases. RT generally refers to ambient temperature
(25-28.degree. C.).
Intermediates
TABLE-US-00003 [0294] TABLE 3 ##STR00135## Intermediate 1
##STR00136## Intermediate 2 ##STR00137## Intermediate 3
##STR00138## Intermediate 4 ##STR00139## Intermediate 5
##STR00140## Intermediate 6 ##STR00141## Intermediate 7
##STR00142## Intermediate 8 ##STR00143## Intermediate 9
##STR00144## Intermediate 10 ##STR00145## Intermediate 11
##STR00146## Intermediate 12 ##STR00147## Intermediate 13
##STR00148## Intermediate 14 ##STR00149## Intermediate 15
##STR00150## Intermediate 16 ##STR00151## Intermediate 17
##STR00152## Intermediate 18 ##STR00153## Intermediate 19
##STR00154## Intermediate 20 ##STR00155## Intermediate 21
##STR00156## Intermediate 22 ##STR00157## Intermediate 23
##STR00158## Intermediate 24 ##STR00159## Intermediate 25
##STR00160## Intermediate 26 ##STR00161## Intermediate 27
##STR00162## Intermediate 28 ##STR00163## Intermediate 29
##STR00164## Intermediate 30 ##STR00165## Intermediate 31
##STR00166## Intermediate 32 ##STR00167## Intermediate 33
##STR00168## Intermediate 34 ##STR00169## Intermediate 35
##STR00170## Intermediate 36 ##STR00171## Intermediate 37
##STR00172## Intermediate 38 ##STR00173## Intermediate 39
##STR00174## Intermediate 40 ##STR00175## Intermediate 41
##STR00176## Intermediate 42 ##STR00177## Intermediate 43
##STR00178## Intermediate 44 ##STR00179## Intermediate 45
##STR00180## Intermediate 46 ##STR00181## Intermediate 47
##STR00182## Intermediate 48 ##STR00183## Intermediate 49
##STR00184## Intermediate 50 ##STR00185## Intermediate 51
##STR00186## Intermediate 52 ##STR00187## Intermediate 53
##STR00188## Intermediate 54 ##STR00189## Intermediate 55
##STR00190## Intermediate 56 ##STR00191## Intermediate 57
##STR00192## Intermediate 58
Intermediate 1: 5-Bromo-2-(piperidin-4-yl)-1H-benzo[d]imidazole
[0295] 4-bromobenzene-1,2-diamine (1.43 g, 7.64 mmol) and
piperidine-4-carboxylic acid (0.99 g, 7.64 mmol) were dissolved in
polyphosphoric acid (20 g). This mixture was heated at 190.degree.
C. for three and half hours. Reaction mixture cooled to rt and
diluted with water (100 ml). Aqueous layer basified with sodium
hydroxide pellets to pH 14. Solid was filtered, washed with
methanol and dried to obtain the title compound (1 g) as a dark
brown solid.
Intermediate 2:
5-Bromo-2-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-1H
-benzo[d]imidazole
[0296] Intermediate 1 (500 mg, 1.69 mmol) and
2-chloro-5-ethylpyrimidine (264 mg, 1.86 mmol) were dissolved in
propan-2-ol (25 ml). To this mixture N,N-Diisopropylethyl amine
(1.8 ml, 10.1 mmol) added and stirred at 90.degree. C. for 12 h.
After completion of the reaction, propan-2-ol was removed to obtain
the crude. Crude was purified by combiflash using a mixture of
AcOET and Petether (40:60) as eluent to afford the titled compound
(0.2 g) as a pale-yellow solid.
Intermediate 3:
2-[2-Fluoro-4-(methylsulfonyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lane
[0297] 1-bromo-2-fluoro-4-(methylsulfonyl)benzene (900 mg, 3.5
mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)
(1.15 g, 4.5 mmol) and potassium acetate (1.13 g, 11.48 mmol) were
dissolved in dioxane (30 ml) under N.sub.2 atmosphere. This mixture
was degassed with nitrogen for 30 mins and added
Pd(dppf).sub.2Cl.sub.2.CH.sub.2Cl.sub.2 (85 mg, 0.1 mmol). This
mixture stirred at 105.degree. C. for 12 h. Reaction mixture
diluted with water and work up (AcOEt/H.sub.2O) afforded the crude.
Crude was purified by combiflash using a mixture of AcOEt and
Petether (20:80) to afford the titled compound (900 mg) as a white
solid. .sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400 MHz): 7.97-7.92
(m, 1H), 7.70 (dd, J 1.4, 7.7, 1H), 7.60 (dd, J 1.2, 8.1, 1H), 3.05
(s, 3H), 1.37 (s, 12H).
Intermediate 4: Tert-butyl
4-(5-bromo-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate
[0298] Intermediate 1 (200 mg, 0.68 mmol) was dissolved in DCM (40
ml) and added TEA (0.2 ml, 0.68 mmol). Reaction mixture cooled to
0.degree. C. and added di-tert-butyl dicarbonate (0.2 ml, 0.68
mmol). Reaction mixture stirred at 0.degree. C. for 2 h. After
completion of the reaction, reaction mixture washed with water, DCM
layer dried over Na.sub.2SO.sub.4 and removal of DCM afforded the
crude. Crude was purified by combiflash using AcOEt and Petether
(35:65) as eluent to afford the titled compound (60 mg) as a brown
solid.
Intermediate 5: 5-Bromo-2-(piperidin-4-yl)benzo[d]oxazole
[0299] 2-amino-4-bromophenol (1.2 g, 5.8 mmol) and
piperidine-4-carboxylic acid (0.74 g, 5.8 mmol) were dissolved in
polyphosphoric acid (30 g). This mixture was heated at 190.degree.
C. for three and half hours. Reaction mixture cooled to rt and
diluted with water (100 ml). Aqueous layer basified with sodium
hydroxide pellets to pH 9. Work up (AcOEt/H.sub.2O) followed
removal of AcOEt afforded the titled compound (0.8 g) as a
pale-yellow gummy solid.
Intermediate 6:
5-Bromo-2-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]benzo[d]oxazole
[0300] Intermediate 5 (800 mg, 2.85 mmol) and
2-chloro-5-ethylpyrimidine (447 mg, 3.14 mmol) were dissolved in
propan-2-ol (25 ml). To this mixture N,N-Diisopropylethyl amine
(3.1 ml, 17.12 mmol) added and stirred at 90.degree. C. for 12 h.
After completion of the reaction, propan-2-ol was removed to obtain
the crude. Crude was purified by combiflash using a mixture of
AcOEt and Petether (8:92) as eluent to afford the titled compound
(80 mg) as a pale-yellow solid. .sup.1H-NMR (.delta. ppm,
CDCl.sub.3, 400 MHz): 8.19 (s, 2H), 7.81 (s, 1H), 7.41 (dd, J 1.6,
8.6, 1H), 7.35 (d, J 8.6, 1H), 4.72 (d, J 13.6, 2H), 3.27-3.11 (m,
3H), 2.47 (q, J 7.6, 2H), 2.21 (dd, J 2.6, 13.1, 2H), 2.02-1.90 (m,
2H), 1.19 (t, J 7.6, 3H).
Intermediate 7: Tert-butyl 4-(5-bromobenzo[d]oxazol-2-yl)
piperidine-1-carboxylate
[0301] Intermediate 5 (500 mg, 1.78 mmol) was dissolved in DCM (30
ml) and added TEA (180 mg, 1.78 mmol). Reaction mixture cooled to
0.degree. C. and added di-tert-butyl dicarbonate (388 mg, 1.78
mmol). Reaction mixture stirred at 0.degree. C. for 1 h. After
completion of the reaction, reaction mixture washed with water, DCM
layer dried over Na.sub.2SO.sub.4 and removal of DCM afforded the
crude. Crude was purified by combiflash using AcOEt and Petether
(8:92) as eluent to afford the titled compound (150 mg) as an
off-white solid.
Intermediate 8: tert-butyl
4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-yl)pip-
eridine-1-carboxylate
[0302] Intermediate 7 (1.8 g, 6.6 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.2 g,
8.6 mmol) and potassium acetate (2.1 g, 21.8 mmol) were dissolved
in dioxane (20 ml) under N.sub.2 atmosphere. This mixture was
degassed with nitrogen for 30 mins and added
Pd(dppf).sub.2Cl.sub.2.CH.sub.2Cl.sub.2 (210 mg, 0.26 mmol).
Reaction mixture was stirred at 105.degree. C. for 12 h. Reaction
mixture diluted with water and work up (AcOEt/H.sub.2O) afforded
the crude. Crude was purified by combiflash using a mixture of
AcOEt and Petether (10:90) as eluent to afford the titled compound
(1.3 g) as a brown solid.
Intermediate 9: 6-bromo-2-(piperidin-4-yl)benzo[d]oxazole
[0303] 2-amino-5-bromophenol (1.3 g, 6.9 mmol) and isonipecotic
acid (893 mg, 6.91 mmol) were dissolved in polyphosphoric acid (39
g). This mixture was heated to 190.degree. C. for 3 h. After 3 h,
reaction mixture cooled to rt and basified with 10% aqueous NaOH
solution to pH 8. Work up (EtOAc/H.sub.2O) followed by removal of
EtOAc afforded the title compound (500 mg) as a black solid. It was
used in the next step without further purification.
Intermediate 10: tert-butyl
4-(6-bromobenzo[d]oxazol-2-yl)piperidine-1-carboxylate
[0304] Intermediate 9 (500 mg, 1.77 mmol) was dissolved in DCM (20
mol), cooled to 0.degree. C. and added TEA (0.25 ml, 1.77 mmol). To
this mixture (Boc).sub.2O (0.4 ml, 1.77 mmol) was added and stirred
at rt for 3 h. At this stage, reaction mixture diluted with water
and extracted with DCM. DCM removed on rotavapour to obtain the
crude. Crude was purified by combiflash using EtOAc and Petether
(7.5%) as eluent to obtain the title compound (500 mg). .sup.1H-NMR
(.delta. ppm, CDCl.sub.3, 400 MHz): 7.65 (d, J 1.6, 1H), 7.53 (d, J
8.4, 1H), 7.43 (dd, J 1.7, 8.4, 1H), 4.13 (d, J 9.9, 2H), 3.17-3.05
(m, 1H), 2.97 (t, J 12.6, 2H), 2.20-2.08 (m, 2H), 1.96-1.82 (m,
2H), 1.47 (s, 9H).
Intermediate 11:
5-bromo-7-fluoro-2-(piperidin-4-yl)benzo[d]oxazole
[0305] 2-amino-4-bromo-6-fluorophenol (1.7 g, 8.24 mmol) and
isonipecotic acid (1.06 g, 8.24 mmol) were dissolved in
polyphosphoric acid (28 g). This mixture was heated to 195.degree.
C. for 3 h. After 3 h, reaction mixture cooled to rt and basified
with aqueous NaOH solution to pH 14. Solid that obtained was
filtered and dried to obtain the title compound (1.3 g) as a brown
solid.
Intermediate 12: Tert-butyl 4-(5-bromo-7-fluorobenzo[d]oxazol-2-yl)
piperidine-1-carboxylate
[0306] Intermediate 11 (1.3 g, 4.36 mmol) was dissolved in DCM (40
mol), cooled to 0.degree. C. and added TEA (1.2 ml, 8.72 mmol). To
this mixture (Boc).sub.2O (950 mg, 4.36 mmol) was added and stirred
at rt for 3 h. At this stage reaction mixture diluted with water
and extracted with DCM. DCM removed on rotavapour to obtain the
crude. Crude was purified by combiflash using EtOAc and Petether
(10:90) as eluent to obtain the title compound (200 mg) as a brick
brown solid.
Intermediate 13: Isopropyl
4-(5-bromobenzo[d]oxazol-2-yl)piperidine-1-carboxylate
[0307] Intermediate 5 (980 mg, 3.31 mmol) was dissolved in DCM (50
mol) and added TEA (0.45 ml, 3.31 mmol). Reaction mixture cooled to
0.degree. C., isopropylchloro formate (2.7 ml, 6.62 mmol) was added
and stirred the reaction mixture for 3 h at rt. Work up
(DCM/H.sub.2O) followed by column purification on 60-120 mesh
silica gel using EtOAc and Petether (15:85) as eluent afforded the
titled compound (500 mg) as a pale-red solid.
Intermediate 14: Isopropyl
4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-yl)pip-
eridine-1-carboxylate
[0308] Intermediate 7 (0.35 g, 0.95 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.31
g, 1.23 mmol) and potassium acetate (0.3 g, 3.14 mmol) were
dissolved in dioxane (20 ml) under N.sub.2 atmosphere. This mixture
was degassed with nitrogen for 30 mins and added
Pd(dppf).sub.2Cl.sub.2.CH.sub.2Cl.sub.2 (31 mg, 0.04 mmol).
Reaction mixture was stirred at 105.degree. C. for 12 h. Reaction
mixture diluted with water and work up (AcOEt/H.sub.2O) afforded
the crude. Crude was purified by combiflash using a gradient
mixture of AcOEt and Petether (20:80) as eluent to afford the
titled compound (0.3 g) as a pale-red solid.
Intermediate 15: Isopropyl
4-(6-bromobenzo[d]oxazol-2-yl)piperidine-1-carboxylate
[0309] Intermediate 9 (1.3 g, 4.4 mmol) was dissolved in DCM (50
mol) and added TEA (1.22 ml, 8.8 mmol). Reaction mixture cooled to
0.degree. C., isopropylchloro formate (2.6 ml, 6.6 mmol) was added
and stirred the reaction mixture for 3 h at rt. Work up
(DCM/H.sub.2O) followed by purification on combiflash using
gradient mixture of EtOAc and Petether (15:85) as eluent afforded
the titled compound (510 mg) as a brown viscous liquid.
Intermediate 16: Isopropyl
4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-yl)pip-
eridine-1-carboxylate
[0310] Intermediate 15 (0.51 g, 1.4 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.45
g, 1.8 mmol) and potassium acetate (0.4 g, 4.2 mmol) were dissolved
in dioxane (20 ml) under N.sub.2 atmosphere. This mixture was
degassed with nitrogen for 30 mins and added
Pd(dppf).sub.2Cl.sub.2.CH.sub.2Cl.sub.2 (45 mg, 0.05 mmol).
Reaction mixture was stirred at 105.degree. C. for 12 h. Reaction
mixture diluted with water and work up (AcOEt/H.sub.2O) afforded
the crude. Crude was purified by combiflash using a gradient
mixture of AcOEt and Petether (15:85) as eluent to afford the
titled compound (0.36 g) as a brown viscous liquid.
Intermediate 17: 5-(4-bromo-2-fluorophenyl)-1H-tetrazole
[0311] 2-Fluoro-4-bromobenzonitrile (300 mg, 1.5 mmol) dissolved in
EtOH, added sodium azide (320 mg, 4.9 mmol), Zinc chloride (240 mg,
1.8 mmol). This mixture was stirred refluxed for 38 h. Work up
(EtOAc/H.sub.2O) afforded the crude. Crude was washed with petether
to obtain the titled compound (120 mg) as a white solid.
.sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400 MHz): 7.89-7.79 (m,
1H), 7.59 (dd, J 1.6, 10.04, 1H), 7.45 (dd, J 1.8, 8.3, 1H).
Intermediate 18:
5-Bromo-2-[1-(5-fluoropyrimidin-2-yl)piperidin-4-yl]benzo[d]oxazole
[0312] Intermediate 5 (1 g, 3.4 mmol) and
2-Chloro-5-fluoropyrimidine was dissolved in isopropanol (20 ml)
and added N,N-diisopropylethyl amine (2.4 ml). This mixture was
stirred at 90.degree. C. for 90 mins. Isopropanol was removed on
rotavapour to obtain a residue. Work up (EtOAc/H2O) followed by
purification on combiflash using a gradient mixture of EtOAc and
Petether (7:93) as eluent afforded the titled compound as a pink
solid.
Intermediate 19:
2-[1-(5-Fluoropyrimidin-2-yl)piperidin-4-yl]-5-(4,4,5,5-tetramethyl-1,3,2-
-dioxaborolan-2-yl)benzo[d]oxazole
[0313] Intermediate 18 (0.28 g, 1.74 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.24
g, 1.0 mmol) and potassium acetate (0.22 g, 2.2 mmol) were
dissolved in dioxane (20 ml) under N.sub.2 atmosphere. This mixture
was degassed with nitrogen for 30 mins and added
Pd(dppO.sub.2Cl.sub.2.CH.sub.2Cl.sub.2 (24 mg, 0.03 mmol). Reaction
mixture was stirred at 105.degree. C. for 12 h. Reaction mixture
diluted with water and work up (AcOEt/H.sub.2O) afforded the crude.
Crude was purified by column chromatography on 60-120 mesh silica
gel using a gradient mixture of AcOEt and Petether (8:92) as eluent
to afford the titled compound (0.15 g) as a pink solid.
Intermediate 20: 4-(Benzofuran-5-yl)-2-fluorobenzamide
[0314] Following the general procedure-1 the titled compound (200
mg) was obtained from 5-Bromobenzofuran (200 mg, 1 mmol) and
2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide
(320 mg, 1.2 mmol) as a brown solid. .sup.1HNMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.05 (d, J 2.2, 2H), 8.02 (bs, 1H),
7.76-7.72 (m, 1H), 7.70-7.65 (m, 3H), 7.64-7.58 (m, 3H), 7.01 (d, J
1.9, 1H).
Intermediate 21:
5-(4-carbamoyl-3-fluorophenyl)benzofuran-2-ylboronic acid
[0315] Intermediate 20 (100 mg. 0.4 mmol) was dissolved in THF (10
ml) and this mixture was cooled to -78.degree. C. under N.sub.2
atmosphere. n-BuLi (0.5 ml, 1.3 mmol) was added to the above
mixture and stirred at same temperature for 20 mins Reaction
mixture warmed to 0.degree. C. and stirred for 2 hrs. After that
trisopropyl borate (88 mg, 0.47 mmol) was added and stirred the
reaction for 16 h at rt. Reaction mass quenched with 2N HCl worked
it up (EtOAC/H.sub.2O) to afford the titled compound (110 mg) as a
crude. It was used in the next step without further
purification.
Intermediate 22:
1-Benzyl-N-(5-bromo-2-hydroxyphenyl)piperidine-4-carboxamide
[0316] 1-Benzylpiperidine-4-carboxylic acid (29 g, 0.13 mol)
dissolved in DCM (300 ml), cooled to 0.degree. C. and added oxalyl
chloride (17.3 ml, 0.2 mol). Catalytic amount of DMF was added to
this mixture and strirred at rt for 2 h. After 2 h, DCM removed on
rotavapour and co-distilled the residue two times with DCM to
obtainl-benzylpiperidine-4-carbonyl chloride quantitatively.
2-Amino-4-bromophenol (23 g, 0.12 mol) dissolved in DCM and added
pyridine (11.5 g, 0.15 mol) under nitrogen atmosphere. This mixture
stirred at rt for 30 mins and added 1-benzylpiperidine-4-carbonyl
chloride (29 g, 0.12 mol) in DCM (100 ml). After continuing
stirring at rt for 2 h, DCM was removed on the rotavapour to obtain
the titled compound (47.6 g), which was used in the next step
without further purification.
Intermediate 23:
2-(1-Benzylpiperidin-4-yl)-5-bromobenzo[d]oxazole
[0317] Intermediate 22 (47.6 g, 0.122 mol) was dissolved in xylene
(500 ml) and added p-Toluenesulphonic acid (46 g, 0.24 mol). This
mixture was refluxed for 20 h under a dean-stark condenser. Xylene
was removed and pH of the residue was adjusted to 9 using aq
NaHCO.sub.3 solution. Work up (EtOAc/H2O) afforded the crude. Crude
was purified by column on 60-120 mesh silicagel using a gradient
mixture of EtOAc and Petether (10:90) as eluent to afford the
titled compound (11 g) as brown solid.
Intermediate 24:
4-(2-(1-benzylpiperidin-4-yl)benzo[d]oxazol-5-yl)-2-fluorobenzamide
[0318] Following the general procedure-3, the titled compound (4.8
g) was prepared from intermediate 23 (6 g, 16.2 mmol) and
2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide
(4.7 g, 17.8 mmol) as a brown solid.
Intermediate 25:
2-Fluoro-4-(2-(piperidin-4-yl)benzo[d]oxazol-5-yl)benzamide
[0319] Intermediate 24 (100 mg, 0.23 mmol) dissolved in MeOH (10
ml) and added Pd/C (100 mg). This mixture was stirred under 60 Psi
hydrogen atmosphere in an autoclave for 16. After 16 h, reaction
mass filtered through celite and celite was washed with MeOH. MeOH
was removed on rotavapour to obtain the titled compound (80 mg) as
an off-white solid.
Intermediate 26:
5-Bromo-2-[2-fluoro-4-(methylsulfonyl)phenyl]-1H-benzo[d]Imidazole
[0320] 4-bromobenzene-1,2-diamine (1.75 g, 9.39 mmol) and
2-fluoro-4-(methylsulfonyl)benzoic acid (2 g, 9.39 mmol) were
dissolved in polyphosphoric acid (70 g). This mixture was heated at
195.degree. C. for three and half hours. Reaction mixture cooled to
rt and diluted with ice water (100 ml). Aqueous layer basified with
sodium hydroxide pellets to pH 9. Work up (EtOAc/H.sub.2O) followed
by removal of EtOAc afforded the crude. Crude was purified on
combiflash with a gradient mixture of EtOAc and Petether (33:67) to
obtain the titled compound (1.5 g) as an off-white solid.
Intermediate 27:
2-[2-Fluoro-4-(methylsulfonyl)phenyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxab-
orolan-2-yl)-1H-benzo[d]imidazole
[0321] Intermediate 26 (1.5 g, 4.1 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.34
g, 5.3 mmol) and potassium acetate (1.32 g, 13.5 mmol) were
dissolved in dioxane (60 ml) under N.sub.2 atmosphere. This mixture
was degassed with nitrogen for 30 mins and added
Pd(dppf).sub.2Cl.sub.2.CH.sub.2Cl.sub.2 (133 mg, 0.16 mmol). This
mixture stirred at 105.degree. C. for 12 h. Reaction mixture
diluted with water and work up (AcOEt/H.sub.2O) afforded the crude.
Crude was purified by combiflash using a mixture of AcOEt and
Petether (33:67) to afford the titled compound (880 mg) as an
off-white solid.
Intermediate 28:
5-Bromo-2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazole
[0322] 2-Amino-4-bromophenol (1.77 g, 9.4 mmol) and
2-fluoro-4-(methylsulfonyl)benzoic acid (2 g, 9.4 mmol) were
dissolved in polyposphoric acid (60 g). This mixture was heated at
195.degree. C. for three and half hours. Reaction mixture cooled to
rt and diluted with ice water (100 ml). Aqueous layer basified with
sodium hydroxide pellets to pH 9. Work up (EtOAc/H.sub.2O) followed
by evaporation of EtOAc afforded the crude. Crude was purified on
combiflash with a gradient mixture of EtOAc and Petether (33:67) to
obtain the titled compound (2.8 g) as an off-white solid.
Intermediate 29:
2-[2-Fluoro-4-(methylsulfonyl)phenyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxab-
orolan-2-yl)benzo[d]oxazole
[0323] Intermediate 28 (2.8 g, 7.6 mmol)
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.5 g,
9.9 mmol) and potassium acetate (2.46 g, 25.08 mmol) were dissolved
in dioxane (150 ml) under N.sub.2 atmosphere. This mixture was
degassed with nitrogen for 30 mins and added
Pd(dppf).sub.2Cl.sub.2.CH.sub.2Cl.sub.2 (248 mg, 0.3 mmol). This
mixture stirred at 105.degree. C. for 12 h. Reaction mixture
diluted with water and work up (AcOEt/H.sub.2O) afforded the crude.
Crude was purified by combiflash using a gradient mixture of AcOEt
and Petether (33:67) to afford the titled compound (1 g) as an
off-white solid.
Intermediate 30:
5-Bromo-7-fluoro-2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazole
[0324] 2-Amino-4-bromo-6-fluorophenol (2.6 g, 9.7 mmol) and
2-fluoro-4-(methylsulfonyl)benzoic acid (2.1 g, 9.7 mmol) were
dissolved in polyposphoric acid (63.5 g). This mixture was heated
at 195.degree. C. for three and half hours. Reaction mixture cooled
to rt and diluted with ice water (100 ml). Aqueous layer basified
with sodium hydroxide pellets to pH 9. Work up (EtOAc/H.sub.2O)
followed by evaporation of EtOAc afforded the crude. Crude (3.1 g)
was used in the next step without further purification.
Intermediate 31:
7-Fluoro-2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(4,4,5,5-tetramethyl-1,3-
,2-dioxaborolan-2-yl)benzo[d]oxazole
[0325] Intermediate 30 (1.5 g, 3.87 mmol)
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.28
g, 5 mmol) and potassium acetate (1.25 g, 12.8 mmol) were dissolved
in dioxane (20 ml) under N.sub.2 atmosphere. This mixture was
degassed with nitrogen for 30 mins and added
Pd(dppf).sub.2Cl.sub.2.CH.sub.2Cl.sub.2 (126 mg, 0.15 mmol). This
mixture stirred at 105.degree. C. for 12 h. Reaction mixture
diluted with water and work up (AcOEt/H.sub.2O) afforded the crude.
Crude was purified by combiflash using a gradient mixture of AcOEt
and Petether (18:82) as eluent to afford the titled compound (620
mg) as an off-white solid.
Intermediate 32:
N-(4-Bromo-2-fluorophenyl)-2-fluoro-4-(methylsulfonyl)benzamide
[0326] 2-Fluoro-4-(methylsulfonyl)benzoic acid (2 g, 9.2 mmol)
dissolved in DCM (10 ml), cooled to 0.degree. C. and added oxalyl
chloride (1.2 ml, 13.8 mmol). Catalytic amount of DMF was added to
this mixture and strirred at rt for 30 mins After 30 mins, DCM
removed on rotavapour and co-distilled the residue two times with
DCM to obtain 2-fluoro-4-(methylsulfonyl)benzoyl chloride
quantitatively. 4-Bromo-2-fluoroaniline (1.4 g, 7.37 mmol)
dissolved in DCM and added Pyridine (0.7 g, 8.84 mmol) under
nitrogen atmosphere. This mixture stirred at rt for 30 mins and
added 2-fluoro-4-(methylsulfonyl)benzoyl chloride (2.08 g, 8.84
mmol). After continuing stifling at rt for 15 mins, reaction
mixture diluted with water and extracted with DCM. DCM layer washed
with aq. NaHCO.sub.3 and DCM removed on rotavapour to obtain the
solil. Solid was triturated with Et.sub.2O and Petether mixture
(4:1) to obtain the titled compound (1 g) as a brown solid.
Intermediate 33:
N-(4-Bromo-2-fluorophenyl)-2-fluoro-4-(methylsulfonyl)benzothioamide
[0327] Intermediate 32 (1 g, 2.56 mmol) dissolved in toluene (10
ml) and added P.sub.2S.sub.5 (0.57 g, 2.56 mmol). This mixture was
refluxed for 18 h. Toluene removed on rotavapour to obtain the
crude. Crude was purified by column chromatography on 60-120 mesh
silicagel using EtOAc and Petether (20:80) as eluent to afford the
title compound (500 mg) as a yellow solid. .sup.1H-NMR (.delta.
ppm, DMSO-d.sub.6, 400 MHz): 11.02 (s, 1H), 7.92-7.85 (m, 2H), 7.69
(dd, J 1.6, 8.1, 1H), 7.63 (dd, J 1.6, 9, 1H), 7.33-7.27 (m, 2H),
3.02 (s, 3H).
Intermediate 34:
6-Bromo-2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]thiazole
[0328] Intermediate 33 (600 mg, 1.47 mmol) dissolved in DMF (7 ml)
and added Na.sub.2CO.sub.3 (156 mg, 1.47 mmol). This mixture
stirred at 110.degree. C. for 17 h. Work up (EtOAc/H.sub.2O)
afforded the crude. Crude was triturated with Petether and dried to
obtain the titled compound (360 mg) as a white solid. .sup.1H-NMR
(.delta. ppm, CDCl.sub.3, 400 MHz): 8.71-8.65 (m, 1H), 8.13 (d, J
1.9, 1H), 8.01 (d, J 8.7, 1H), 7.91-7.83 (m, 2H), 7.66 (dd, J 1.9,
8.7, 1H), 3.12 (s, 3H).
Intermediate 35:
2-[2-Fluoro-4-(methylsulfonyl)phenyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxab-
orolan-2-yl)benzo[d]thiazole
[0329] Intermediate 34 (360 mg, 0.94 mmol)
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (300
mg, 1.2 mmol) and potassium acetate (300 mg, 1.2 mmol) were
dissolved in dioxane (10 ml) under N.sub.2 atmosphere. This mixture
was degassed with nitrogen for 30 mins and added
Pd(dppf).sub.2Cl.sub.2.CH.sub.2Cl.sub.2 (30 mg, 0.04 mmol). This
mixture stirred at 105.degree. C. for 12 h. Reaction mixture
diluted with water and work up (AcOEt/H.sub.2O) afforded the crude.
Crude was purified by combiflash using a mixture of AcOEt and
Petether (12:88) as eluent to afford the titled compound (300 mg)
as an off-white solid. .sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400
MHz): 8.74-8.69 (m, 1H), 8.46 (s, 1H), 8.14 (d, J 8.2, 1H), 7.97
(dd, J 1, 8.2, 1H), 7.91-7.83 (m, 2H), 3.12 (s, 3H), 1.38 (s,
12H).
Intermediate 36:
N-(2,5-Dibromophenyl)-2-fluoro-4-(methylsulfonyl)benzamide
[0330] 2-Fluoro-4-(methylsulfonyl)benzoic acid (1 g, 4.6 mmol)
dissolved in DCM (15 ml), cooled to 0.degree. C. and added oxalyl
chloride (0.6 ml, 6.9 mmol). Catalytic amount of DMF was added to
this mixture and strirred at rt for 30 mins After 30 mins, DCM
removed on rotavapour and co-distilled the residue two times with
DCM to obtain 2-fluoro-4-(methylsulfonyl)benzoyl chloride
quantitatively. 2,5-Dibromoaniline (0.9 g, 3.59 mmol) dissolved in
DCM (10 ml) and added Pyridine (0.34 g, 4.30 mmol) under nitrogen
atmosphere. This mixture stirred at rt for 30 mins and added
2-fluoro-4-(methylsulfonyl)benzoyl chloride (1.01 g, 3.59 mmol).
After continuing stirring at rt for 15 mins, reaction mass diluted
with water and extracted with DCM. DCM layer washed with aq.
NaHCO.sub.3 and DCM removed on rotavapour to obtain the solid.
Solid was triturated with Et.sub.2O and Petether mixture (4:1) to
obtain the titled compound (1.6 g) as a brown solid. .sup.1H-NMR (6
ppm, DMSO-d.sub.6, 400 MHz): 10.34 (s, 1H), 8.34-7.99 (m, 1H),
7.98-7.93 (m, 2H), 7.92-7.89 (m, 1H), 7.68 (d, J 8.6, 1H), 7.43
(dd, J 2.4, 8.6, 1H), 3.33 (s, 3H).
Intermediate 37:
N-(2,5-Dibromophenyl)-2-fluoro-4-(methylsulfonyl)benzothioamide
[0331] Intermediate 36 (1.5 g, 3.34 mmol) dissolved in toluene (20
ml) and added P.sub.2S.sub.5 (0.74 g, 3.34 mmol). This mixture was
refluxed for 18 h. Toluene removed on rotavapour to obtain the
crude. Crude was purified by column chromatography on 60-120 mesh
silicagel using EtOAc and Petether (20:80) as eluent to afford the
title compound (480 mg) as a yellow solid. .sup.1H-NMR (.delta.
ppm, DMSO-d.sub.6, 400 MHz): 12.26 (s, 1H), 7.94-7.83 (m, 3H),
7.78-7.72 (m, 2H), 7.55 (dd, J 2.3, 8.6, 1H), 3.32 (s, 3H).
Intermediate 38:
5-Bromo-2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]thiazole
[0332] Intermediate 37 (0.48 g, 1.03 mmol) dissolved in
N-Methylpyrrolidinone (0.97 ml) and added NaH (52 mg, 2.2 mmol).
This mixture was stirred at 140.degree. C. for 3 h. Reaction
mixture cooled to rt and diluted with water to obtain the solid.
Solid was filtered and dried to obtain the crude. Crude was
purified on column chromatography using 60-120 mesh silicagel and
DCM as eluent to afford the titled compound (260 mg) as a white
solid. .sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400 MHz): 8.71-8.66
(m, 1H), 8.32 (d, J 1.7, 1H), 7.92-7.83 (m, 3H), 7.59 (dd, J 1.8,
8.6, 1H), 3.13 (s, 3H).
Intermediate 39:
2-[2-Fluoro-4-(methylsulfonyl)phenyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxab-
orolan-2-yl)benzo[d]thiazole
[0333] Intermediate 38 (360 mg, 0.94 mmol)
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (220
mg, 0.88 mmol) and potassium acetate (220 mg, 2.2 mmol) were
dissolved in dioxane (10 ml) under N.sub.2 atmosphere. This mixture
was degassed with nitrogen for 30 mins and added
Pd(dppf).sub.2Cl.sub.2.CH.sub.2Cl.sub.2 (22 mg, 0.03 mmol). This
mixture stirred at 105.degree. C. for 12 h. Reaction mixture
diluted with water and work up (AcOEt/H.sub.2O) afforded the crude.
Crude was purified by combiflash using a mixture of AcOEt and
Petether (12:88) as eluent to afford the titled compound (230 mg)
as a yellow solid. .sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400 MHz):
8.73-8.67 (m, 1H), 8.62 (s, 1H), 7.98 (d, J 8, 1H), 7.90-7.81 (m,
3H), 3.12 (s, 3H), 1.39 (s, 12H).
Intermediate 40:
6-Bromo-2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazole
[0334] 2-amino-5-bromophenol (1.72 g, 9.2 mmol) and
2-fluoro-4-(methylsulfonyl)benzoic acid (2 g, 9.2 mmol) were
dissolved in polyposphoric acid (30 g). This mixture was heated at
195.degree. C. for three and half hours. Reaction mixture cooled to
rt and diluted with ice water (100 ml). Aqueous layer basified with
sodium hydroxide pellets to pH 9. Solid that formed was filtered
and dried to obtain the crude. Crude was purified by combiflash
using a gradient mixture of EtOAc and Petether (1:3) as eluent to
afford the titled compound (450 mg) as a dark brown solid.
Intermediate 41:
2-[2-fluoro-4-(methylsulfonyl)phenyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxab-
orolan-2-yl)benzo[d]oxazole
[0335] Intermediate 40 (1.5 g, 4.1 mmol)
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.35
g, 5.29 mmol) and potassium acetate (1.32 g, 13.45 mmol) were
dissolved in dioxane (10 ml) under N.sub.2 atmosphere. This mixture
was degassed with nitrogen for 30 mins and added
Pd(dppf).sub.2Cl.sub.2.CH.sub.2Cl.sub.2 (133 mg, 0.16 mmol). This
mixture stirred at 105.degree. C. for 12 h. Reaction mixture
diluted with water and work up (AcOEt/H.sub.2O) afforded the crude.
Crude was purified by combiflash using a gradient mixture of AcOEt
and Petether (1:3) as eluent to afford the titled compound (500 mg)
as a pink solid.
Intermediate 42: N-(5-Br omo-2-hy dr oxyphenyl)-4-(trifluor
omethyl)benzamide
[0336] 4-(Trifluoromethyl)benzoic acid (1 g, 5.3 mmol) dissolved in
DCM (10 ml), cooled to 0.degree. C. and added oxalyl chloride (0.7
ml, 7.9 mmol). Catalytic amount of DMF was added to this mixture
and strirred at rt for 30 mins. After 30 mins, DCM removed on
rotavapour and co-distilled the residue two times with DCM to
obtain 4-(trifluoromethyl)benzoyl chloride quantitatively.
2-Amino-4-bromophenol (0.8 g, 4.25 mmol) dissolved in DCM (20 ml)
and added Pyridine (0.4 ml, 5.1 mmol) under nitrogen atmosphere.
This mixture stirred at rt for 30 mins and added
4-(trifluoromethyl)benzoyl chloride (1.06 g, 5.1 mmol). After
continuing stirring at rt for 15 mins, reaction mass diluted with
water and extracted with DCM. DCM layer washed with aq. NaHCO.sub.3
and DCM removed on rotavapour to obtain the solid. Solid was
triturated with Et.sub.2O and Petether mixture (4:1) to obtain the
titled compound (1 g) as a brown solid. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 10.15 (bs, 1H), 9.75 (s, 1H), 8.13 (d, J
8.1, 2H), 7.92-7.87 (m, 3H), 7.20 (dd, J 2.5, 8.6, 1H), 6.88 (d, J
8.6, 1H).
Intermediate 43:
5-bromo-2-[4-(trifluoromethyl)phenyl]benzo[d]oxazole
[0337] Intermediate 42 (1 g, 2.77 mmol) was dissolved in
1,4-Dioxane and added Phosphorus oxychloride (0.76 ml, 8.3 mmol).
This mixture was refluxed for 2 h. 1,4-Dioxane removed on
rotavapour to obtain the residue. Residue was washed with water to
obtain solid. Solid was filtered and dried to obtain the titled
compound (630 mg) as an off-white solid. .sup.1H-NMR (6 ppm,
CDCl.sub.3, 400 MHz): 8.35 (d, J 8.2, 2H), 7.93 (d, J 1.5, 1H),
7.79 (d, J 8.3, 2H), 7.52-7.49 (m, 2H).
Intermediate 44:
5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(4-(trifluoromethyl)phe-
nyl)benzo[d]oxazole
[0338] Intermediate 43 (630 mg, 1.84 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (600
mg, 2.4 mmol) and potassium acetate (590 mg, 6.1 mmol) were
dissolved in 1,4-dioxane (10 ml) under N.sub.2 atmosphere. This
mixture was degassed with nitrogen for 30 mins and added
Pd(dppf).sub.2Cl.sub.2.CH.sub.2Cl.sub.2 (60 mg, 0.08 mmol). This
mixture stirred at 105.degree. C. for 12 h. Reaction mixture
diluted with water and work up (AcOEt/H.sub.2O) afforded the crude.
Crude was purified by combiflash using a mixture of AcOEt and
Petether (8:92) as eluent to afford the titled compound (400 mg) as
a yellow solid. .sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400 MHz):
8.38 (d, J 8.1, 2H), 8.25 (s, 1H), 7.86 (dd, J 1, 7.9, 1H), 7.78
(d, J 8.3, 2H), 7.59 (d, J 8.6, 1H), 1.38 (s, 12H).
Intermediate 45:
N-(4-Bromo-2-hydroxyphenyl)-4-(difluoromethyl)benzamide
[0339] 4-(difluoromethyl)benzoic acid (0.7 g, 4 mmol) dissolved in
DCM (20 ml), cooled to 0.degree. C. and added oxalyl chloride (0.8
g, 6.1 mmol). Catalytic amount of DMF was added to this mixture and
strirred at rt for 30 mins. After 30 mins, DCM removed on
rotavapour and co-distilled the residue two times with DCM to
obtain 4-(difluoromethyl)benzoyl chloride quantitatively.
2-Amino-5-bromophenol (0.64 g, 3.4 mmol) dissolved in DCM (20 ml)
and added Pyridine (0.32 ml, 4.1 mmol) under nitrogen atmosphere.
This mixture stirred at rt for 30 mins and added
4-(difluoromethyl)benzoyl chloride (0.77 g, 4.1 mmol). After
continuing stirring at rt for 15 mins, reaction mass diluted with
water and extracted with DCM. DCM layer washed with aq. NaHCO.sub.3
and DCM removed on rotavapour to obtain the solid. Solid was
triturated with Et.sub.2O and Petether mixture (4:1) to obtain the
titled compound (0.5 g) as a yellow solid. .sup.1H-NMR (.delta.
ppm, DMSO-d.sub.6, 400 MHz): 10.27 (s, 1H), 9.62 (s, 1H), 8.07 (d,
J 8.2, 2H), 7.71 (d, J 8.2, 2H), 7.61 (d, J 8.5, 1H), 7.12 (t, J
55.7, 1H), 7.07 (d, J 2.2, 1H), 7.03-6.94 (m, 1H).
Intermediate 46:
6-Bromo-2-[4-(difluoromethyl)phenyl]benzo[d]oxazole
[0340] N-(4-Bromo-2-hydroxyphenyl)-4-(difluoromethyl)benzamide (0.5
g, 1.5 mmol) was dissolved in 1,4-Dioxane (10 ml) and added
Phosphorus oxychloride (0.4 ml, 4.4 mmol). This mixture was
refluxed for 2 h. 1,4-Dioxane removed on rotavapour to obtain the
residue. Residue was washed with water to obtain solid. Solid was
purified by column on 60-120 mesh silica gel using DCM as eluent to
obtain the titled compound (130 mg) as an off-white solid.
.sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400 MHz): 8.28 (d, J 8.4,
2H), 7.74 (d, J 1.7, 1H), 7.65-7.58 (m, 3H), 7.46 (dd, J 1.8, 8.4,
1H), 6.68 (t, J 56.2, 1H).
Intermediate 47:
2-[4-(Difluoromethyl)phenyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl)benzo[d]oxazole
[0341] Intermediate 46 (130 mg, 0.4 mmol)
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (130
mg, 0.52 mmol) and potassium acetate (110 mg, 1.2 mmol) were
dissolved in 1,4-dioxane (15 ml) under N.sub.2 atmosphere. This
mixture was degassed with nitrogen for 30 mins and added
Pd(dppf).sub.2Cl.sub.2.CH.sub.2Cl.sub.2 (13 mg, 0.02 mmol). This
mixture stirred at 105.degree. C. for 4 h. Reaction mixture diluted
with water and work up (AcOEt/H.sub.2O) afforded the crude. Crude
was purified by combiflash using a mixture of AcOEt and Petether
(8:92) as eluent to afford the titled compound (100 mg) as a yellow
solid.
Intermediate 48: Tert-butyl
4-{2-[4-(difluoromethyl)phenyl]benzo[d]oxazol-6-yl}-5,6-dihydropyridine-1-
(2H)-carboxylate
[0342] Following the general procedure-2, the titled compound was
prepared from intermediate 47 (0.1 g, 0.27 mmol) and tert-butyl
4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate
(89 mg, 0.27 mmol) as an off-white solid. .sup.1H-NMR (.delta. ppm,
CDCl.sub.3, 400 MHz): 8.34 (d, J 8.4, 2H), 7.72 (d, J 8.4, 1H),
7.67 (d, J 8.2, 2H), 7.58 (d, J 1.4, 1H), 7.43 (dd, J 1.6, 8.4,
1H), 6.72 (t, J 56.2, 1H), 6.12 (bs, 1H), 4.12 (d, J 2.7, 2H), 3.68
(t, J 5.6, 2H), 2.60 (bs, 2H), 1.50 (s, 9H).
Intermediate 49: tert-butyl
4-(2-p-tolylbenzo[d]oxazol-6-yl)piperidine-1-carboxylate
[0343] Intermediate 48 (45 mg, 0.14 mmol) dissolved in MeOH (10 ml)
and added Pd/C (5%) (100 mg). This mixture was stirred under 60 Psi
hydrogen pressure for 15 h in an autoclave. After completion of the
reaction, reaction mixture filtered through a bed of celite and
celite was washed with MeOH. Combined MeOH layers were removed on
rotavapour to obtain the residue. Residue was triturated with
petether to obtain the titled compound (40 mg) as an off-white
solid. MS (m/z): 393.2 [M+f1].sup.+.
Intermediate 50: Tert-butyl
4-(2-aminobenzo[d]oxazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate
[0344] 5-Bromobenzo[d]oxazol-2-amine (824 mg, 3.9 mmol) and
tert-butyl 4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1
(2H)-carboxylate (1.8 g, 5.8 mmol), Potassium fluoride (674 mg,
11.61 mmol) were dissolved in DMF under N.sub.2 atmosphere. This
mixture was purged with N.sub.2 for 30 mins
Pd(dppf).sub.2Cl.sub.2.CH.sub.2Cl.sub.2 (252 mg, 0.3 mmol) was
added to the above mixture and again purged with N.sub.2 for 30
mins. The reaction mixture was stirred at 90.degree. C. for 12 h.
Work up (EtOAc/H2O) followed by column purification on combiflash
using a gradient mixture of EtOAc and Petether (1:1) as eluent
afforded the titled compound (550 mg) as an off-white solid.
.sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400 MHz): 7.38-7.36 (m,
2H), 7.26-7.22 (m, 2H), 7.02 (d, J 7.9, 1H), 6.05 (s, 1H),
4.01-3.90 (m, 2H), 3.49-3.55 (m, 2H), 2.50-2.40 (m, 2H), 1.50 (s,
9H).
Intermediate 51: Tert-butyl
4-(2-aminobenzo[d]oxazol-5-yl)piperidine-1-carboxylate
[0345] Intermediate 50 (550 mg, 0.14 mmol) dissolved in MeOH (25
ml) and added Pd/C (5%) (700 mg). This mixture was stirred under 80
Psi hydrogen pressure for 12 h in an autoclave. After completion of
the reaction, reaction mixture filtered through a bed of celite and
celite was washed with MeOH. MeOH was removed on rotavapour to
obtain the residue. Residue was triturated with petether to obtain
the titled compound (400 mg) as an off-white solid.
Intermediate 52: Tert-butyl
4-(2-bromobenzo[d]oxazol-5-yl)piperidine-1-carboxylate
[0346] Intermediate 51 (400 mg, 1.3 mmol) was dissolved in
acetonitrile (50 ml) and added CuBr.sub.2 (563 mg, 2.5 mmol). This
mixture stirred at rt for 15 mins Tert-Butyl nitrite (259 mg, 2.5
mmol) was added to the above mixture for 5 mins and stirred at
45.degree. C. for 2 h. Work up (DCM/H.sub.2O) followed by
purification on combiflash using a gradient mixture of EtOAc and
Petether (1:3) as eluent afforded the titled compound (130 mg) as
an off-white solid. .sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400 MHz):
8.28 (bs, 1H), 7.41 (s, 1H), 6.91 (s, 1H), 4.35-4.19 (m, 2H),
3.21-3.10 (m, 1H), 2.85 (t, J 11.3, 2H), 1.90-1.80 (m, 2H),
1.60-1.40 (m, 11H).
Intermediate 53:
N-(4-bromo-2-hydroxyphenyl)-4-(trifluoromethyl)benzamide
[0347] 4-(Trifluoromethyl)benzoic acid (0.8 g, 4.2 mmol) dissolved
in DCM (20 ml), cooled to 0.degree. C. and added oxalyl chloride
(0.8 g, 6.1 mmol). Catalytic amount of DMF was added to this
mixture and strirred at rt for 30 mins. After 30 mins, DCM removed
on rotavapour and co-distilled the residue two times with DCM to
obtain 4-(trifluoromethyl)benzoyl chloride quantitatively.
2-Amino-5-bromophenol (0.71 g, 3.8 mmol) dissolved in DCM (20 ml)
and added Pyridine (0.32 ml, 4.1 mmol) under nitrogen atmosphere.
This mixture stirred at rt for 30 mins and added
4-(trifluoromethyl)benzoyl chloride (0.88 g, 4.2 mmol). After
continuing stirring at rt for 15 mins, reaction mass diluted with
water and extracted with DCM. DCM layer washed with aq. NaHCO.sub.3
and DCM removed on rotavapour to obtain the solid. Solid was
triturated with Et.sub.2O and Petether mixture (4:1) to obtain the
titled compound (0.6 g) as a yellow solid.
Intermediate 54:
6-bromo-2-(4-(trifluoromethyl)phenyl)benzo[d]oxazole
[0348] Intermediate 53 (940 mg, 2.6 mmol) was dissolved in xylene
(25 ml) and added p-Toluenesulphonic acid (991 mg, 5.22 mmol). This
mixture was refluxed to 160.degree. C. for 12 h under a dean-stork
condenser. Xylene removed from the reaction mixture and basified
the residue with aq. NaHCO.sub.3 (30 ml). Work up (EtOAc/H.sub.2O)
followed by purification with combiflash using a gradient mixture
of EtOAc and Petether (5:95) as eluent to afford the titled
compound (650 mg) as an Off-White solid.
Intermediate 55:
6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[4-(trifluoromethyl)phe-
nyl]benzo[d]oxazole
[0349] Intermediate 54 (630 mg, 1.84 mmol)
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (600
mg, 2.4 mmol) and potassium acetate (590 mg, 3.3 mmol) were
dissolved in 1,4-dioxane (30 ml) under N.sub.2 atmosphere. This
mixture was degassed with nitrogen for 30 mins and added
Pd(dppf).sub.2Cl.sub.2.CH.sub.2Cl.sub.2 (60 mg, 0.074 mmol). This
mixture stirred at 105.degree. C. for 17 h. Reaction mixture
diluted with water and work up (AcOEt/H.sub.2O) afforded the crude.
Crude was purified by combiflash using a mixture of AcOEt and
Petether (20:80) as eluent to afford the titled compound (420 mg)
as an off-white solid. .sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400
MHz): 8.39 (d, J 8.1, 2H), 8.05 (s, 1H), 7.84 (dd, J 0.8, 8, 1H),
7.82-7.76 (m, 3H), 1.38 (s, 12H).
Intermediate 56:
N-(5-bromo-2-hydroxypyridin-3-yl)-4-(trifluoromethyl)benzamide
[0350] 4-(Trifluoromethyl)benzoic acid (2.45 g, 12.9 mmol)
dissolved in DCM (30 ml), cooled to 0.degree. C. and added oxalyl
chloride (3.4 ml, 38.6 mmol). Catalytic amount of DMF was added to
this mixture and strirred at rt for 30 mins After 30 mins, DCM
removed on rotavapour and co-distilled the residue two times with
DCM to obtain 4-(trifluoromethyl)benzoyl chloride quantitatively.
2-Hydroxy-3-amino-5-bromopyridine (2.4 g, 11.1 mmol) dissolved in
DCM (15 ml) and added Pyridine (1.74 g, 22 mmol) under nitrogen
atmosphere. This mixture stirred at rt for 30 mins and added
4-(trifluoromethyl)benzoyl chloride (2.4 g, 13.3 mmol). After
continuing stirring at rt for 30 mins, reaction mass diluted with
water and extracted with DCM. DCM removed on rotavapour to obtain
the crude. Crude was purified on column using 60-120 mesh silica
gel and a gradient mixture of MeOH and DCM (2:98) as eluent to
afford the titled compound (2.1 g) as a brown solid. .sup.1H-NMR
(.delta. ppm, DMSO-d.sub.6, 400 MHz): 12.43 (bs, 1H), 9.58 (s, 1H),
8.37 (d, J 2.6, 1H), 8.09 (d, J 8.2, 2H), 7.91 (d, J 8.2, 2H), 7.48
(d, J 2.6, 1H).
Intermediate 57:
6-bromo-2-(4-(trifluoromethyl)phenyl)oxazolo[5,4-b]pyridine
[0351] Intermediate 56 (2.1 g, 5.4 mmol) was dissolved in Dioxane
(30 ml) and added POCl.sub.3 (1.5 ml). This mixture was refluxed
for 5 h. After 5 h, dioxane was removed on rotavapour to obtain the
residue. Work up (EtOAc/H.sub.2O) of the residue afforded the
crude. Crude was purified by column on 60-120 mesh silica gel using
DCM as eluent to afford the titled compound (1.2 g). .sup.1H-NMR
(.delta. ppm, CDCl.sub.3, 400 MHz): 8.46 (d, J 2.1, 1H), 8.41 (d, J
8.2, 2H), 8.24 (d, J 2.1, 1H), 7.83 (d, J 8.2, 2H).
Intermediate 58:
6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[4-(trifluoromethyl)phe-
nyl]oxazolo[5,4-b]pyridine
[0352] Intermediate 57 (1.2 g, 3.5 mmol)
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (973
mg, 3.8 mmol) and potassium acetate (1.03 g, 10.5 mmol) were
dissolved in 1,4-dioxane (40 ml) under N.sub.2 atmosphere. This
mixture was degassed with nitrogen for 30 mins and added
Pd(dppf).sub.2Cl.sub.2.CH.sub.2Cl.sub.2 (113 mg, 0.14 mmol). This
mixture stirred at 105.degree. C. for 15 h. Reaction mixture
diluted with water and work up (AcOEt/H.sub.2O) afforded the crude.
Crude was purified by combiflash using a gradient mixture of AcOEt
and Petether (5:95) as eluent to afford the titled compound (1.2 g)
as an off-white solid. .sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400
MHz): 8.77 (d, J 1.5, 1H), 8.46 (d, J 1.5, 1H), 8.41 (d, J 8.1,
2H), 7.80 (d, J 8.1, 2H), 1.38 (s, 12H).
[0353] General Procedure-1 for Suzuki Coupling:
[0354] Aryl bromide (1 eq.) was dissolved in Dioxane and water
(5:1) and added arylboronic acid (1.3 eq), Pd(PPh.sub.3).sub.4
(0.08 eq) and Na.sub.2CO.sub.3 (3.3 eq). Reaction mixture degassed
with N.sub.2 for 30 mins and refluxed until both the starting
materials disappeared. Work-up (H.sub.2O/AcOEt) and purification
gave the desired product.
[0355] General Procedure-2 for Suzuki Coupling:
[0356] Aryl bromide (1 eq), arylboronic acid (1 eq.), Sodium
carbonate (3 eq) dissolved in DMF and water (4:1) and degassed with
N.sub.2 for 15 mins. To this mixture
Pd(dppf).sub.2Cl.sub.2.CH.sub.2Cl.sub.2 (0.08 eq) was added and
degassed again with N.sub.2 for 15 mins. This mixture was
irradiated in micro wave for 105 mins, at 80.degree. C. Work-up
(H.sub.2O/AcOEt) and purification gave the desired product.
[0357] General Procedure-3 for Suzuki Coupling:
[0358] Same as General Procedure-2 except that KF was used instead
of Na.sub.2CO.sub.3
[0359] General Procedure-4 for Suzuki Coupling:
[0360] Same as General Procedure-2 except that Dioxane was used
instead of DMF.
Example 1
2-[1-(5-Ethylpyrimidin-2-yl)
piperidin-4-yl]-5-[2-fluoro-4-(methylsulfonyl)phenyl]-1H-benzo[d]imidazol-
e
[0361] Following the General Procedure-1, the titled compound (25
mg) was prepared from Intermediate 2 (80 mg, 0.199 mmol) and
Intermediate 3 (79 mg, 0.26 mmol) as a yellow solid. M.P.:
186.5-190.degree. C. .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400
MHz): 12.41 (d, J 4, 1H), 8.26 (s, 2H), 7.90-7.80 (m, 3H),
7.79-7.50 (m, 2H), 7.40-7.32 (m, 1H), 4.66 (d, J 13.1, 2H), 3.29
(s, 3H), 3.21 (t, J 8.3, 1H), 3.09 (t, J 11.7, 2H), 2.43 (q, J
7.73, 2H), 2.06 (d, J 12.5, 2H), 1.82-1.71 (m, 2H), 1.13 (t, J 7.5,
3H).
Example 2
Tert-butyl 4-{5-[2-fluoro-4-(methylsulfonyl)
phenyl]-1H-benzo[d]imidazol-2-yl}piperidine-1-carboxylate
[0362] Following the General Procedure-1, the titled compound (40
mg) was prepared from Intermediate 4 (100 mg, 0.25 mmol) and
Intermediate 3 (98 mg, 0.33 mmol) as a yellow solid. M.P.:
88-92.degree. C. .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400 MHz):
12.39 (s, 1H), 7.89-7.81 (m, 3H), 7.69-7.58 (m, 2H), 7.40-7.32 (m,
1H), 4.01 (d, J 12.5, 2H), 3.30 (s, 3H), 3.12-3.05 (m, 1H),
3.00-2.88 (m, 2H), 2.00 (d, J 11.8, 2H), 1.76-1.55 (m, 2H), 1.41
(s, 9H).
Example 3
2-[1-(5-ethylpyrimidin-2-yl)
piperidin-4-yl]-5-[2-fluoro-4-(methylsulfonyl)phenyl]
benzo[d]oxazole
[0363] Following the General Procedure-1, the titled compound (30
mg) was prepared from Intermediate 6 (80 mg, 0.21 mmol) and
Intermediate 3 (80 mg, 0.27 mmol) as an off-white solid. M.P.:
247-250.degree. C. .sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400 MHz):
8.20 (s, 2H), 7.86 (s, 1H), 7.80 (m, 1H), 7.79-7.74 (m, 1H), 7.66
(t, J 7.5, 1H), 7.59 (d, J 8.4, 1H), 7.50 (d, J 8.5, 1H), 4.75 (d,
J 13.4, 2H), 3.35-3.15 (m, 3H), 3.11 (s, 3H), 2.47 (q, J 7.6, 2H),
2.31-2.22 (m, 2H), 2.09-1.94 (m, 2H), 1.20 (t, J 7.6, 3H).
Example 4
tert-butyl
4-{5-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-2-yl}pip-
eridine-1-carboxylate
[0364] Following the General Procedure-1, the titled compound (40
mg) was prepared from Intermediate 7 (150 mg, 0.4 mmol) and
Intermediate 3 (154 mg, 0.51 mmol) as an off-white solid. M.P.:
144-147.degree. C. .sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400 MHz):
7.87 (s, 1H), 7.82 (d, J 8, 1H), 7.77 (dd, J 1.4, 9.4, 1H), 7.67
(t, J 7.5, 1H), 7.59 (d, J 8.4, 1H), 7.50 (d, J 8.5, 1H), 4.15 (d,
J 7.7, 2H), 3.22-3.10 (m, 4H), 3.00 (t, J 11.3, 2H), 2.21-2.12 (m,
2H), 2.00-1.88 (m, 2H), 1.48 (s, 9H).
Example 5
Tert-butyl
4-{5-[2-fluoro-4-(methylsulfonyl)phenyl]-1-methyl-1H-benzo[d]im-
idazol-2-yl}piperidine-1-carboxylate
[0365] Tert-butyl
4-{5-[2-fluoro-4-(methylsulfonyl)phenyl]-1H-benzo[d]imidazol-2-yl}piperid-
ine-1-carboxylate (85 mg, 0.17 mmol) dissolved in THF (15 ml) and
cooled to 0.degree. C. Sodium hydride (9 mg, 0.342 mmol) added to
the above mixture and stirred at the same temperature for 30 mins.
To this mixture methyl iodide (48 mg, 0.342 mmol) added at same
temperature and stirred the reaction mixture at rt for 3 h.
Reaction mixture diluted with ice and worked up (EtOAc/H.sub.2O).
Crude was purified by column chromatography on 60-120 mesh silica
gel using EtOAc: Petether (3:1) as eluent to afford the title
compound (50 mg) as an orange solid. M.P.: 85-88.degree. C.
.sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400 MHz): 7.85-7.75 (m, 2H),
7.73-7.64 (m, 2H), 7.56-7.51 (m, 1H), 7.50-7.45 (m, 1H), 4.39-4.21
(m, 2H), 3.82 (s, 3H), 3.11 (s, 3H), 3.10-3.00 (m, 2H), 3.00-2.88
(m, 2H), 2.05-1.93 (m, 3H), 1.48 (s, 9H).
Example 6
Tert-butyl
4-{6-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-2-yl}pip-
eridine-1-carboxylate
[0366] Following the General Procedure-1, the titled compound (21
mg) was prepared from Intermediate 10 (100 mg, 0.26 mmol) and
Intermediate 3 (102 mg, 0.34 mmol) as an off-white solid. M.P.:
174-178.3.degree. C. .sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400
MHz): 7.85-7.75 (m, 3H), 7.73-7.64 (m, 2H), 7.50 (d, J 8.2, 1H),
4.15 (d, J 12.4, 2H), 3.20-3.10 (m, 4H), 3.0 (t, J 12.5, 2H),
2.20-2.12 (m, 2H), 2.00-1.85 (m, 2H), 1.48 (s, 9H).
Example 7
Isopropyl
4-{5-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-2-yl}pipe-
ridine-1-carboxylate
[0367] Tert-butyl
4-{5-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1--
carboxylate (200 mg, 0.42 mmol) dissolved in DCM and added
Trifluoroacetic acid (0.75 ml). This mixture was stirred at rt for
2 h. DCM removed from the reaction mixture to obtain
5-(2-fluoro-4-(methylsulfonyl)phenyl)-2-(piperidin-4-yl)benzo[d]oxazole
2,2,2-trifluoroacetate (190 mg).
5-(2-fluoro-4-(methylsulfonyl)phenyl)-2-(piperidin-4-yl)benzo[d]oxazole
2,2,2-trifluoroacetate (190 mg, 0.39 mmol) was dissolved in DCM (20
ml) and added TEA (0.43 ml, 3.12 mmol). This mixture stirred at rt
for 30 mins and added isopropyl chloroformate in toluene (0.095 g,
0.78 mmol). After 1 h, reaction mass diluted with water and
extracted with DCM. Removal of DCM afforded crude. Crude was
purified by combiflash using a mixture of EtOAc and Petether
(35:65) as eluent to afford the titled compound (120 mg) as a
pale-yellow solid. M.P.: 96.5-101.2.degree. C. .sup.1H-NMR (.delta.
ppm, CDCl.sub.3, 400 MHz): 7.87 (s, 1H), 7.81 (dd, J 1.7, 8, 1H),
7.80-7.75 (m, 1H), 7.67 (t, J 7.5, 1H), 7.59 (d, J 8.4, 1H), 7.50
(d, J 8.5, 1H), 4.94 (septet, J 6.2, 1H), 4.19 (d, J 10.9, 2H),
3.22-3.13 (m, 1H), 3.12 (s, 3H), 3.04 (t, J 10.9, 2H), 2.22-2.14
(m, 2H), 2.00-1.88 (m, 2H), 1.26 (d, J 6.2, 6H).
Example 8
Tert-butyl
4-{7-fluoro-5-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-
-2-yl}piperidine-1-carboxylate
[0368] Following the General Procedure-1, the titled compound (50
mg) was prepared from Intermediate 12 (200 mg, 0.50 mmol) and
Intermediate 3 (151 mg, 0.50 mmol) as an off-white solid. M.P.:
155.3-158.4.degree. C. .sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400
MHz): 7.82 (dd, J 1.8, 8.1, 1H), 7.78 (dd, J 1.7, 9.4, 1H),
7.69-7.63 (m, 2H), 7.29 (td, 1.3, 10.6, 1H), 4.16 (d, J 11.2, 2 H),
3.22-3.16 (m, 1H), 3.11 (s, 3H), 3.00 (t, J 13.3, 2H), 2.21-2.14
(m, 2H), 2.00-1.88 (m, 2H), 1.48 (s, 9H).
Example 9
Tert-butyl
4-[5-(4-cyanophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylat-
e
[0369] Following the General Procedure-1, the titled compound (45
mg) was prepared from Intermediate 7 (140 mg, 0.37 mmol) and
4-Cyanophenylboronic acid (53 mg, 0.37 mmol) as an off-white solid.
M.P.: 137.3-141.2.degree. C. .sup.1H-NMR (.delta. ppm, CDCl.sub.3,
400 MHz): 7.88 (d, 1.4, 1H), 7.74 (dd, J 1.8, 8.5, 2H), 7.69 (dd, J
1.8, 8.5, 2H), 7.58 (d, J 8.5, 1H), 7.53 (dd, J 1.8, 8.5, 2H), 4.15
(d, J 10.4, 2H), 3.20-3.10 (m, 1H), 3.00 (t, J 11.2, 2H), 2.20-2.12
(m, 2H), 2.00-1.85 (m, 2H), 1.48 (s, 9H).
Example 10
Tert-butyl
4-{5-[3-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-2-yl}pip-
eridine-1-carboxylate
[0370] Following the General Procedure-1, the titled compound (30
mg) was prepared from Intermediate 8 (100 mg, 0.23 mmol) and
4-bromo-2-fluoro-1-(methylsulfonyl)benzene (70 mg, 0.37 mmol) as an
off-white solid. M.P.: 174.3-177.5.degree. C. .sup.1H-NMR (.delta.
ppm, CDCl.sub.3, 400 MHz): 8.03 (t, J 7.9, 1H), 7.88 (d, J 1.6,
1H), 7.61-7.51 (m, 3H), 7.46 (dd, J 1.6, 11.1, 1H), 4.15 (d, J
11.2, 2H), 3.26 (s, 3H), 3.20-3.11 (m, 1H), 3.00 (t, J 12.2, 2H),
2.20-2.12 (m, 2H), 1.98-1.84 (m, 2H), 1.48 (s, 9H).
Example 11
Tert-butyl
4-{5-[4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-
-1-carboxylate
[0371] Following the General Procedure-1, the titled compound (80
mg) was prepared from Intermediate 8 (200 mg, 0.47 mmol) and
1-(4-bromophenyl)-1H-tetrazole (100 mg, 0.44 mmol) as a brown
solid. M.P.: 207-211.degree. C. .sup.1H-NMR (.delta. ppm,
CDCl.sub.3, 400 MHz): 9.02 (s, 1H), 7.91 (d, J 1.2, 1H), 7.82-7.79
(m, 4H), 7.62-7.55 (m, 2H), 4.16 (d, J 10.6, 2H), 3.21-3.12 (m,
1H), 3.00 (t, J 12.3, 2H), 2.20-2.14 (m, 2H), 2.00-1.88 (m, 2H),
1.48 (s, 9H).
Example 12
Tert-butyl
4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}p-
iperidine-1-carboxylate
[0372] Following the General Procedure-1, the titled compound (10
mg) was prepared from Intermediate 8 (200 mg, 0.47 mmol) and
1-(4-bromo-3-fluorophenyl)-1H-tetrazole (110 mg, 0.45 mmol) as a
brown solid. M.P.: 203-207.degree. C. .sup.1H-NMR (.delta. ppm,
CDCl.sub.3, 400 MHz): 9.04 (s, 1H), 7.88 (s, 1H), 7.71-7.58 (m,
4H), 7.52 (td, 1.6, 8.4, 1H), 4.16 (d, J 10.8, 2H), 3.21-3.12 (m,
1H), 3.00 (t, J 12.2, 2H), 2.21-2.13 (m, 2H), 2.00-1.85 (m, 2H),
1.48 (s, 9H).
Example 13
Tert-butyl
4-{5-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-2-yl}piperidine--
1-carboxylate
[0373] Following the General Procedure-1, the titled compound (40
mg) was prepared from Intermediate 7 (150 mg, 0.4 mmol) and
4-(trifluoromethyl)phenylboronic acid (74 mg, 0.39 mmol) as an
off-white solid. M.P.: 166-169.degree. C. .sup.1H-NMR (.delta. ppm,
CDCl.sub.3, 400 MHz): 7.88 (d, J 1.2, 1H), 7.73-7.67 (m, 4H),
7.59-7.52 (m, 2H), 4.15 (d, J 10, 2H), 3.20-3.10 (m, 1H), 3.00 (t,
J 11.6, 2H), 2.21-2.12 (m, 2H), 1.99-1.86 (m, 2H), 1.48 (s,
9H).
Example 14
Isopropyl
4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}pi-
peridine-1-carboxylate
[0374] Tert-butyl
4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine--
1-carboxylate (120 mg, 0.26 mmol) dissolved in DCM and added
Trifluoroacetic acid (0.5 ml). This mixture was stirred at rt for 2
h. DCM removed from the reaction mixture to obtain
5-(2-fluoro-4-(1H-tetrazol-1-yl)phenyl)-2-(piperidin-4-yl)benzo[d]oxazole
2,2,2-trifluoro ac etate (150 mg).
5-(2-fluoro-4-(1H-tetrazol-1-yl)phenyl)-2-(piperidin-4-yl)benzo[d]oxazole
2,2,2-trifluoroacetate (70 mg, 0.17 mmol) was dissolved in DCM (15
ml) and added TEA (0.2 ml, 1.4 mmol). This mixture stirred at rt
for 30 mins and added isopropyl chloroformate in toluene (42 mg,
0.34 mmol). After 1 h, reaction mass diluted with water and
extracted with DCM. Removal of DCM afforded crude. Crude was
purified by combiflash using a mixture of EtOAc and Petether
(35:65) as eluent to afford the titled compound (30 mg) as an
off-white solid. M.P.: 168-171.degree. C. .sup.1H-NMR (.delta. ppm,
CDCl.sub.3, 400 MHz): 9.03 (s, 1H), 7.88 (s, 1H), 7.68 (t, J 8.2,
1H), 7.64-7.58 (m, 3H), 7.54-7.50 (m, 1H), 4.95 (septet, J 6.2,
1H), 4.20 (d, J 11.2, 2H), 3.22-3.14 (m, 1H), 3.04 (t, J 11.2, 2H),
2.22-2.15 (m, 2H), 2.00-1.88 (m, 2H), 1.26 (d, J 6.2, 6H).
Example 15
Tert-butyl
4-{5-[3-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}p-
iperidine-1-carboxylate
[0375] Following the General Procedure-3, the titled compound (22
mg) was prepared from Intermediate 8 (100 mg, 0.23 mmol) and
1-(4-bromo-2-fluorophenyl)-1H-tetrazole (56 mg, 0.23 mmol) as a
pale-yellow solid. M.P.: 154-159.degree. C. .sup.1H-NMR (.delta.
ppm, CDCl.sub.3, 400 MHz): 9.14 (d, J 2.5, 1H), 8.04 (t, J 7.8,
1H), 7.91 (d, J 3.9, 1H), 7.64-7.54 (m, 4H), 4.16 (d, J 10, 2H),
3.21-3.13 (m, 1H), 3.01 (t, J 11.9, 2H), 2.21-2.12 (m, 2H),
2.00-1.87 (m, 2H), 1.48 (s, 9H).
Example 16
2-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]-5-[2-fluoro-4-(1H-tetrazol-1-y-
l)phenyl]benzo[d]oxazole
[0376] Tert-butyl
4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine--
1-carboxylate (120 mg, 0.26 mmol) dissolved in DCM (15 ml) and
added Trifluoroacetic acid (0.5 ml). This mixture was stirred at rt
for 2 h. DCM removed from the reaction mixture to obtain
5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole
2,2,2-trifluoroacetate (150 mg).
5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole
2,2,2-trifluoroacetate (70 mg, 0.15 mmol) was dissolved in IPA (10
ml), added DiPEA (0.25 ml, 1.2 mmol) and stirred at rt for 30 mins
2-Chloro-5-ethyl piperidine was added to the above reaction mixture
and heated the reaction mixture to 90.degree. C. for overnight.
After completion of the reaction, work-up (EtOAc/H.sub.2O) followed
by purification on combiflash using the gradient mixture of ethyl
acetate and petether (1:1) as eluent afforded the titled compound
(20 mg) as an off-white solid. M.P.: 188-192.degree. C. .sup.1H-NMR
(.delta. ppm, CDCl.sub.3, 400 MHz): 9.03 (s, 1H), 8.20 (s, 2H),
7.88 (s, 1H), 7.68 (t, J 8.2, 1H), 7.65-7.58 (m, 3H), 7.54-7.49
((m, 1H), 4.80-4.70 (m, 2H), 3.33-3.23 (m, 1H), 3.22 (t, J 14, 2H),
2.48 (q, J 7.6, 2H), 2.30-2.22 (m, 2H), 2.07-1.95 (m, 2H), 1.20 (t,
J 7.6, 3H).
Example 17
Tert-butyl
4-[5-(4-cyano-3-fluorophenyl)benzo[d]oxazol-2-yl]piperidine-1-c-
arboxylate
[0377] Following the General Procedure-2, the titled compound (70
mg) was prepared from Intermediate 8 (150 mg, 0.35 mmol) and
4-bromo-2-fluorobenzonitrile (70 mg, 0.35 mmol) as a white solid.
M.P.: 138-142.degree. C. .sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400
MHz): 7.87 (d, J 1.6, 1H), 7.72-7.68 (m, 1H), 7.59 (d, J 8.5, 1H),
7.53-7.42 (m, 3H), 4.15 (d, J 10.6, 2H), 3.20-3.11 (m, 1H), 3.00
(t, J 11.8, 2H), 2.2-2.12 (m, 2H), 1.98-1.86 (m, 2H), 1.56 (S,
9H).
Example 18
Isopropyl
4-{5-[3-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}pi-
peridine-1-carboxylate
[0378] Tert-butyl
4-{5-[3-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine--
1-carboxylate (120 mg, 0.26 mmol) dissolved in DCM (15 ml) and
added Trifluoroacetic acid (0.5 ml). This mixture was stirred at rt
for 2 h. DCM removed from the reaction mixture to obtain
5-[3-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole
2,2,2-trifluoroacetate (120 mg).
5-[3-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole
2,2,2-trifluoroacetate (120 mg, 0.25 mmol) was dissolved in DCM (15
ml) and added TEA (0.27 ml, 2 mmol). This mixture stirred at rt for
30 mins and added isopropyl chloroformate in toluene (61 mg, 0.34
mmol). After 1 h, reaction mass diluted with water and extracted
with DCM. Removal of DCM afforded crude. Crude was purified by
combiflash using a mixture of EtOAc and Petether (35:65) as eluent
to afford the titled compound (20 mg) as an off-white solid. M.P.:
187-191.degree. C. .sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400 MHz):
9.14 (d, J 2.6, 1H), 8.02 (t, J 8.2, 1H), 7.90 (d, J 1.4, 1H),
7.63-7.55 (m, 4H), 4.95 (septet, J 6.2, 1H), 4.20 (d, J 11.2, 2H),
3.22-3.14 (m, 1H), 3.04 (t, J 11.4, 2H), 2.18 (d, J 10.8, 2H),
2.00-1.88 (m, 2H), 1.26 (d, J 6.2, 6H).
Example 19
Tert-butyl
4-{5-[3-fluoro-4-(1H-tetrazol-5-yl)phenyl]benzo[d]oxazol-2-yl}p-
iperidine-1-carboxylate
[0379] Following the General Procedure-2, the titled compound (6
mg) was prepared from Intermediate 8 (150 mg, 0.35 mmol) and
intermediate 17 (85 mg, 0.35 mmol) as a brown solid. M.P.:
163-167.degree. C. .sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400 MHz):
8.15 (s, 1H), 8.11 (t, J 8, 1H), 7.86 (d, J 12.2, 1H), 7.82-7.77
(m, 3H), 3.95 (d, J 13.4, 2H), 3.42-3.35 (m, 1H), 3.05-2.92 (m,
2H), 2.14-2.06 (m, 2H), 1.76-1.64 (m, 2H), 1.41 (s, 9H).
Example 20
Tert-butyl
4-[5-(4-carbamoyl-3-chlorophenyl)benzo[d]oxazol-2-yl]piperidine-
-1-carboxylate
[0380] Following the General Procedure-2, the titled compound (25
mg) was prepared from Intermediate 7 (150 mg, 0.4 mmol) and
2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide
(110 mg, 0.4 mmol) as a brown solid. M.P.: 169-171.degree. C.
.sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400 MHz): 8.03 (s, 1H),
7.87 (bs, 1H), 7.82-7.75 (m, 2H), 7.73-7.66 (m, 2H), 7.59 (bs, 1H),
7.52 (d, J 7.9, 1H), 3.94 (d, J 12.9, 2H), 3.30-3.22 (m, 1H),
3.08-2.92 (m, 2H), 2.09 (d, J 10.6, 2H), 1.75-1.63 (m, 2H), 1.40
(s, 9H).
Example 21
Tert-butyl
4-[5-(4-carbamoyl-3-fluorophenyl)benzo[d]oxazol-2-yl]piperidine-
-1-carboxylate
[0381] Following the General Procedure-3, the titled compound (25
mg) was prepared from Intermediate 8 (150 mg, 0.35 mmol) and
4-bromo-2-fluorobenzamide (77 mg, 0.35 mmol) as a white solid.
M.P.: 202-206.degree. C. .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6,
400 MHz): 8.22 (t, J 8.3, 1H), 7.89 (s, 1H), 7.59-7.49 (m, 3H),
7.37 (dd, J 1.6, 13.24, 1H), 6.71 (d, J 9.5, 1H), 5.85 (s, 1H),
4.15 (d, J 10.7, 2H), 3.20-3.10 (m, 1H), 3.00 (t, J 11.8, 2H),
2.20-2.12 (m, 2H), 1.99-1.85 (m, 2H), 1.48 (s, 9H).
Example 22
Tert-butyl
4-[5-(3-fluoro-4-isopropoxyphenyl)benzo[d]oxazol-2-yl]piperidin-
e-1-carboxylate
[0382] Following the General Procedure-3, the titled compound (25
mg) was prepared from Intermediate 8 (150 mg, 0.35 mmol) and
4-bromo-2-fluoro-1-isopropoxybenzene (81 mg, 0.35 mmol) as a white
solid. M.P.: 124-128.degree. C. .sup.1H-NMR (.delta. ppm,
CDCl.sub.3, 400 MHz): 7.81 (d, J 1.4, 1H), 7.53-7.45 (m, 2H),
7.35-7.27 (m, 2H), 7.05 (t, J 8.6, 1H), 4.58 (septet, J 6.1, 1H),
4.15 (d, J 10.4, 2H), 3.20-3.10 (m, 1H), 2.99 (t, J 11.7, 2H), 2.15
(dd, J 2.8, 13.4, 2H), 1.97-1.86 (m, 2H), 1.56 (s, 9H), 1.39 (d, J
6.1, 6H).
Example 23
Cyclobutyl
4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}p-
iperidine-1-carboxylate
[0383] Tert-butyl
4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine--
1-carboxylate (300 mg, 0.65 mmol) dissolved in DCM (15 ml) and
added Trifluoroacetic acid (1.5 ml). This mixture was stirred at rt
for 2 h. DCM removed from the reaction mixture to obtain
5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole
2,2,2-trifluoroacetate (300 mg).
5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole
2,2,2-trifluoroacetate (150 mg, 0.31 mmol) was dissolved in DMF
(2.6 ml) and added N,N-Carbonyl diimidazole (101 mg, 0.63 mmol) and
stirred at rt for 1 h. To this mixture added cyclobutanol (0.05 ml,
0.63 mmol) and TEA (0.13 ml, 0.94 mmol) and stirred at 60.degree.
C. for overnight. Work up (EtOAc/H.sub.2O) and purification of the
crude by combiflash with gradient mixture of ethyl acetate and
petether (1:1) as eluent afforded the titled compound (25 mg) as an
off-white solid. M.P.: 165-169.degree. C. .sup.1H-NMR (.delta. ppm,
CDCl.sub.3, 400 MHz): 9.04 (s, 1H), 7.88 (s, 1H), 7.72-7.58 (m,
4H), 7.55-7.50 (m, 1H), 4.96 (septet, J 7.8, 1H), 4.20 (d, J 12.4,
2H), 3.22-3.13 (m, 1H), 3.06 (t, J 9.8, 2H), 2.40-2.30 (m, 2H),
2.24-2.15 (m, 2H), 2.15-2.02 (m, 2H), 2.00-1.90 (m, 2H), 1.78 (q, J
10, 2H).
Example 24
Sec-butyl
4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}pi-
peridine-1-carboxylate
[0384] Tert-butyl
4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine--
1-carboxylate (250 mg, 0.54 mmol) dissolved in DCM (15 ml) and
added Trifluoroacetic acid (1 ml). This mixture was stirred at rt
for 2 h. DCM removed from the reaction mixture to obtain
5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole
2,2,2-trifluoro acetate (260 mg).
5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole
2,2,2-trifluoroacetate (150 mg, 0.31 mmol) was dissolved in DMF
(2.6 ml) and added N,N-Carbonyl diimidazole (101 mg, 0.63 mmol) and
stirred at rt for 1 h. To this mixture added 2-butanol (46 mg, 0.63
mmol) and TEA (0.13 ml, 0.94 mmol) and stirred at 60.degree. C. for
overnight. Work up (EtOAc/H.sub.2O) and purification of the crude
by combiflash with gradient mixture of ethyl acetate and petether
(1:1) as eluent afforded the titled compound (30 mg) as an
off-white solid. M.P.: 118-122.degree. C. .sup.1H-NMR (.delta. ppm,
CDCl.sub.3, 400 MHz): 9.03 (s, 1H), 7.88 (s, 1H), 7.72-7.58 (m,
4H), 7.55-7.50 (m, 1H), 4.82-4.73 (m, 1H), 4.21 (d, J 12.7, 2H),
3.24-3.13 (m, 1H), 3.06 (t, J 11.6, 2H), 2.19 (d, J 10.9, 2H),
2.00-1.88 (m, 2H), 1.69-1.50 (m, 2H), 1.24 (d, J 6.2, 3H), 0.92 (t,
J 7.4, 3H).
Example 25
Pentan-3-yl
4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine--
1-carboxylate
[0385] Tert-butyl
4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine--
1-carboxylate (250 mg, 0.54 mmol) dissolved in DCM (15 ml) and
added Trifluoroacetic acid (1 ml). This mixture was stirred at rt
for 2 h. DCM removed from the reaction mixture to obtain
5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole
2,2,2-trifluoroacetate (260 mg).
5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole
2,2,2-trifluoroacetate (150 mg, 0.31 mmol) was dissolved in DMF
(2.6 ml) and added N,N-Carbonyl diimidazole (101 mg, 0.63 mmol) and
stirred at rt for 1 h. To this mixture added 3-pentanol (46 mg,
0.63 mmol) and TEA (0.13 ml, 0.94 mmol) and stirred at 60.degree.
C. for overnight. Work up (EtOAc/H.sub.2O) and purification of the
crude by combiflash with gradient mixture of ethyl acetate and
petether (1:1) as eluent afforded the titled compound (20 mg) as an
off-white solid. M.P.: 114-117.degree. C. .sup.1H-NMR (.delta. ppm,
CDCl.sub.3, 400 MHz): 9.03 (s, 1H), 7.88 (s, 1H), 7.72-7.58 (m,
4H), 7.54-7.50 (m, 1H), 4.69 (quintet, J 6, 1H), 4.23 (d, J 13.5,
2H), 3.25-3.15 (m, 1H), 3.07 (t, J 11.9, 2H), 2.21-2.17 (m, 2H),
2.02-1.88 (m, 2H), 1.65-1.50 (m, 4H), 0.91 (t, J 7.4, 6H).
Example 26
5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole
[0386]
5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]o-
xazole 2,2,2-trifluoroacetate (50 mg) was dissolved in DCM (15 ml)
and added TEA (0.3 ml). This mixture stirred for 3 h at rt. Work up
(DCM/H.sub.2O) followed by purification of the crude by preparative
TLC using MeOH and DCM (1:5) as eluent afforded the titled compound
(15 mg) as an off-white solid. M.P.: 148-151.degree. C. .sup.1H-NMR
(.delta. ppm, DMSO-d.sub.6, 400 MHz): 10.17 (s, 1H), 8.03 (d, J
9.6, 1H), 7.95-7.79 (m, 4H), 7.58 (d, J 8.5, 1H), 3.22-3.13 (m,
1H), 3.07 (d, J 12.4, 2H), 2.70 (t, J 11.2, 2H), 2.06 (d, J 11.1,
2H), 1.82-1.70 (m, 2H).
Example 27
Isopropyl
4-{5-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-
-carboxylate
[0387] Following the General Procedure-1, the titled compound (100
mg) was prepared from Intermediate 13 (200 mg, 0.54 mmol) and
4-(trifluoromethyl)phenylboronic acid (124 mg, 0.65 mmol) as an
off-white solid. M.P.: 123-126.degree. C. .sup.1H-NMR (.delta. ppm,
CDCl.sub.3, 400 MHz): 7.88 (d, J 1, 1H), 7.72-7.68 (m, 4H),
7.60-7.53 (m, 2H), 4.95 (septet, J 6.3, 1H), 4.20 (d, J 13.3, 2H),
3.22-3.12 (m, 1H), 3.04 (t, J 11.3, 2H), 2.17 (dd, J 2.6, 13.2,
2H), 2.00-1.88 (m, 2H), 1.26 (d, J 6.2, 6H).
Example 28
Isopropyl
4-[5-(4-formylphenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylat-
e
[0388] Following the General Procedure-1, the titled compound (100
mg) was prepared from Intermediate 13 (270 mg, 0.73 mmol) and
4-formylphenylboronic acid (132 mg, 0.88 mmol) as an off-white
solid. M.P.: 167-170.degree. C. .sup.1H-NMR (.delta. ppm,
CDCl.sub.3, 400 MHz): 10.07 (S, 1H), 7.96 (dd, J 1.7, 6.6, 2H),
7.93 (s, 1H), 7.76 (d, J 8.2, 2H), 7.58 (s, 2H), 4.95 (septet, J
6.2, 1H), 4.20 (d, J 11.1, 2H), 3.22-3.13 (m, 1H), 3.04 (t, J 11.3,
2H), 2.18 (dd, J 2.8, 13.3, 2H).
Example 29
Isopropyl
4-{5-[4-(difluoromethyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1--
carboxylate
[0389] Isopropyl
4-[5-(4-formylphenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate
(100 mg, 0.25 mmol) dissolved in DCM and added DAST (123 mg, 0.76
mmol) and stirred the reaction mixture at 55.degree. C. Work up
(DCM/H.sub.2O) followed by purification on combiflash with a
gradient mixture of EtOAc and Petether (1:4) as eluent afforded the
titled compound (35 mg) as an off-white solid. M. P.:
151-154.degree. C. .sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400 MHz):
7.88 (s, 1H), 7.68 (d, J 8.2, 2H), 7.60 (d, J 8.2, 2H), 7.58-7.52
(m, 2H), 6.70 (t, J 56.5, 1H), 4.95 (septet, J 6.2, 1H), 4.19 (d, J
11.1, 2H), 3.21-3.13 (m, 1H), 3.04 (t, J 11.4, 2H), 2.17 (d, J
10.4, 2H), 2.00-1.88 (m, 2H), 1.26 (d, J 6.2, 6H).
Example 30
Isopropyl
4-[5-(4-carbamoyl-3-chlorophenyl)benzo[d]oxazol-2-yl]piperidine--
1-carboxylate
[0390] Following the General Procedure-2, the titled compound (30
mg) was prepared from Intermediate 13 (150 mg, 0.41 mmol) and
2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide
(110 mg, 0.41 mmol) as a pale-yellow solid. M.P.: 178-181.degree.
C. .sup.1H-NMR (6 ppm, DMSO-d.sub.6, 400 MHz): 8.04 (d, J 1.7, 1H),
7.88 (bs, 1H), 7.80 (d, J 1.7, 1H), 7.77 (d, J 8.5, 1H), 7.73-7.68
(m, 2H), 7.62-7.58 (m, 1H), 7.52 (d, J 8, 1H), 4.78 (septet, J 6.2,
1H), 3.97 (d, J 13.2, 2H), 3.34-3.24 (m, 1H), 3.10-3.00 (m, 2H),
2.15-2.05 (m, 2H), 1.75-1.65 (m, 2H), 1.19 (d, J 6.2, 6H).
Example 31
Isopropyl
4-[5-(4-carbamoyl-3-fluorohenyl)benzo[d]oxazol-2-yl]piperidine-1-
-carboxylate
[0391] Following the General Procedure-2, the titled compound (30
mg) was prepared from Intermediate 14 (300 mg, 0.72 mmol) and
4-bromo-2-fluorobenzamide (157 mg, 0.72 mmol) as an off-white
solid. M.P.: 184-187.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.08 (d, J 1.4, 1H), 7.80-7.72 (m, 3H),
7.70-7.62 (m, 4H), 4.78 (septet, 6.2, 1H), 3.97 (d, J 13.4, 2H),
3.33-3.25 (m, 1H), 3.10-2.98 (m, 2H), 2.15-2.07 (m, 2H), 1.76-1.64
(m, 2H), 1.19 (d, J 6.2, 6H).
Example 32
1-{4-[5-(2-fluoro-4-(1H-tetrazol-1-yl)phenyl)benzo[d]oxazol-2-yl]piperidin-
-1-yl}-2-methylpropan-1-one
[0392] Tert-butyl
4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine--
1-carboxylate (100 mg, 0.22 mmol) dissolved in DCM (25 ml) and
added trifluoroacetic acid (0.4 ml). This mixture stirred at rt for
3 h. After completion of the reaction, DCM removed on rotavapour
and residue was co-distilled with ether to obtain
5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole
2,2,2-trifluoroacetate (100 mg).
5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole
2,2,2-trifluoroacetate (100 mg, 0.21 mmol) was dissolved in DMF (3
ml) and added isobutyric acid (202 mg, 0.23 mmol), EDC.HCl (99 mg,
0.52 mmol), HOBt (33 mg, 0.25 mmol) and TEA (0.23 ml, 1.7 mmol).
After completion of the reaction, work up (EtOAc/H.sub.2O) followed
by purification on combiflash using the gradient mixture of EtOAc
and Petether (65:35) as eluent afforded the titled compound (20 mg)
as a brown solid. M.P.: 190-194.degree. C. .sup.1H-NMR (.delta.
ppm, CDCl.sub.3, 400 MHz): 9.04 (s, 1H), 7.88 (s, 1H), 7.68 (t, J
8.2, 1H), 7.67-7.59 (m, 2H), 7.52 (td, J 1.6, 8.4, 1H), 4.58 (d, J
12.1, 1H), 4.04 (d, J 13.2, 1H), 3.35-3.22 (m, 2H), 2.96 (t, J 12,
1H), 2.85 (septet, J 6.8, 1H), 2.30-2.18 (m, 2H), 2.05-1.72 (m,
2H), 1.16 (d, J 6.8, 6H).
Example 33
Isopropyl
4-{6-[4-(difluoromethyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1--
carboxylate
[0393] Following the General Procedure-1, Isopropyl
4-[6-(4-formylphenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate
(140 mg) was prepared from Intermediate 15 (300 mg, 0.82 mmol) and
4-formylphenylboronic acid (146 mg, 0.98 mmol) as an off-white
solid. Isopropyl
4-[6-(4-formylphenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxyla- te
(100 mg, 0.25 mmol) was dissolved in DCM (5 ml) and added DAST (0.1
ml, 0.76 mmol). This mixture stirred at reflux for 2 h. Work up
(DCM/H.sub.2O) followed by the purification of the crude on
combiflash using gradient mixture of EtOAc and Petether (1:4) as
eluent afforded the titled compound (35 mg) as an off-white solid.
M. P.: 149-153.degree. C. MS (m/z): 415.1 [M+H].sup.+.
Example 34
6-{2-[1-(isopropoxycarbonyl)piperidin-4-yl]benzo[d]oxazol-5-yl}nicotinic
acid
[0394] Following the General Procedure-2, Methyl
6-{2-(1-(isopropoxycarbonyl)piperidin-4-yl)benzo[d]oxazol-5-yl]nicotinate
(50 mg) was prepared from Intermediate 14 (400 mg, 0.97 mmol) and
methyl 6-chloronicotinate (166 mg, 0.97 mmol) as a brown solid.
Methyl
6-{2-(1-(isopropoxycarbonyl)piperidin-4-yl)benzo[d]oxazol-5-yl]nicotinate
(35 mg, 0.08 mmol) was dissolved in MeOH (5 ml) and added
K.sub.2CO.sub.3 (22 mg, 0.17 mmol). This mixture was stirred at
reflux for overnight. MeOH removed on rotavapour and pH adjusted to
6 using acetic acid to obtain a solid. Solid was filtered and dried
to obtain the titled compound (20 mg) as a grey solid. M. P.:
239-242.degree. C. MS (m/z): 410.4 [M+H].sup.+
Example 35
5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-[1-(methylsulfonyl)piperidin-4-y-
l]benzo[d]oxazole
[0395]
5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]o-
xazole 2,2,2-trifluoroacetate (30 mg, 0.06 mmol) was dissolved in
DCM (5 ml) and added TEA (60 mg, 0.6 mmol) and stirred the mixture
at rt for 30 mins. To this mixture added methanesulphonyl chloride
(14 mg, 0.12 mmol) and stirred at rt for 2 h. Work up
(DCM/H.sub.2O) followed by purification on combiflash using a
gradient mixture of EtOAc and Petether (7:3) as eluent afforded the
titled compound (17 mg) as a brown solid. M. P.: 209-212.degree. C.
MS (m/z): 443.2 [M+H].sup.+.
Example 36
Isopropyl
4-[5-(5-carbamoylpyridin-2-yl)benzo[d]oxazol-2-yl]piperidine-1-c-
arboxylate
[0396] Following the General Procedure-3, the titled compound (40
mg) was prepared from Intermediate 14 (250 mg, 0.6 mmol) and
6-chloronicotinamide (94 mg, 0.6 mmol) as an off-white solid. M.P.:
227-230.degree. C. MS (m/z): 409.1 [M+H].sup.+.
Example 37
Isopropyl
4-[5-(4-carbamoyl-2-fluorophenyl)benzo[d]oxazol-2-yl]piperidine--
1-carboxylate
[0397] Following the General Procedure-3, the titled compound (80
mg) was prepared from Intermediate 14 (200 mg, 0.48 mmol) and
4-bromo-3-fluorobenzamide (105 mg, 0.48 mmol) as an off-white
solid. M.P.: 194-197.degree. C. MS (m/z): 426.0 [M+H].sup.+.
Example 38
Isopropyl
4-[5-(4-carbamoyl-2-chlorophenyl)benzo[d]oxazol-2-yl]piperidine--
1-carboxylate
[0398] Following the General Procedure-3, the titled compound (80
mg) was prepared from Intermediate 14 (200 mg, 0.48 mmol) and
4-bromo-3-chlorobenzamide (105 mg, 0.48 mmol) as a brown solid.
M.P.: 178-182.degree. C. MS (m/z): 442.0 [M+H].sup.+.
Example 39
2-Fluoro-4-{2-[1-(3-methylbutanoyl)piperidin-4-yl]benzo[d]oxazol-5-yl}benz-
amide
[0399] Tert-butyl
4-[5-(4-carbamoyl-3-fluorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxy-
late (140 mg, 0.32 mmol) dissolved in DCM (25 ml) and added
trifluoroacetic acid (1 ml). This mixture stirred at rt for 3 h.
After completion of the reaction, DCM removed on rotavapour and
residue was co-distilled with ether to obtain
2-fluoro-4-(2-(piperidin-4-yl)benzo[d]oxazol-5-yl)benzamide
2,2,2-trifluoroacetate (140 mg).
2-Fluoro-4-(2-(piperidin-4-yl)benzo[d]oxazol-5-yl)benzamide
2,2,2-trifluoroacetate (140 mg, 0.31 mmol) was dissolved in DMF (5
ml) and added isovaleric acid (34.6 mg, 0.34 mmol), EDC.HCl (147
mg, 0.77 mmol), HOBt (50 mg, 0.37 mmol) and TEA (0.4 ml, 2.47
mmol). After completion of the reaction, water added to the
reaction mixture to obtain solid. Solid was filtered and washed
with ether to obtain the titled compound (20 mg) as a brown solid.
M.P.: 186-190.degree. C. MS (m/z): 424.1 [M+H].sup.+.
Example 40
1-{4-[5-(2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl]piperidin-
-1-yl}-3-methylbutan-1-one
[0400]
5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]o-
xazole 2,2,2-trifluoroacetate (140 mg, 0.29 mmol) was dissolved in
DMF (4 ml) and added isovaleric acid (38 mg, 0.37 mmol), EDC.HCl
(147 mg, 0.73 mmol), HOBt (47 mg, 0.35 mmol) and TEA (88 mg, 0.88
mmol). After completion of the reaction, work up (EtOAc/H.sub.2O)
followed by purification of crude on combiflash using a gradient
mixture of EtOAc and Petether (7:3) as eluent afforded the titled
compound (100 mg) as a pale-yellow solid. M.P.: 168-172.degree. C.
MS (m/z): 449.1 [M+H].sup.+
Example 41
5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-[1-(2-methoxyethyl)piperidin-4-y-
l]benzo[d]oxazole
[0401]
5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]o-
xazole 2,2,2-trifluoroacetate (30 mg, 0.06 mmol) was dissolved in
DMF (2 ml) and added K.sub.2CO.sub.3 (40 mg, 0.29 mmol) and stirred
the mixture at rt for 15 mins. To this mixture added 2-methoxyethyl
methanesulfonate (45 mg, 0.29 mmol) and stirred at rt for 17 h.
Work up (EtOAc/H.sub.2O) followed by purification by column
chromatography on 60-120 mesh silicagel using a gradient mixture of
DCM and MeOH (98:2) as eluent afforded the titled compound (90 mg)
as a brown solid (15 mg). M.P.: 148-152.degree. C. MS (m/z): 423.3
[M+H].sup.+.
Example 42
Isopropyl
4-{5-[3-fluoro-4-(methylcarbamoyl)phenyl]benzo[d]oxazol-2-yl}pip-
eridine-1-carboxylate
[0402] Following the General Procedure-3, the titled compound (80
mg) was prepared from Intermediate 14 (200 mg, 0.54 mmol) and
4-bromo-2-fluoro-N-methylbenzamide (200 mg, 0.54 mmol) as a brown
solid. M.P.: 116-120.degree. C. MS (m/z): 440.3 [M+H].sup.+.
Example 43
2-Fluoro-4-[2-(1-isobutyrylpiperidin-4-yl)benzo[d]oxazol-5-yl]benzamide
[0403] Tert-butyl
4-[5-(4-carbamoyl-3-flurophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxyl-
ate (190 mg, 0.32 mmol) dissolved in DCM (40 ml) and added
trifluoroacetic acid (1.5 ml). This mixture stirred at rt for 3 h.
After completion of the reaction, DCM removed on rotavapour and
residue was co-distilled with ether to obtain
2-fluoro-4-(2-(piperidin-4-yl)benzo[d]oxazol-5-yl)benzamide
2,2,2-trifluoroacetate (190 mg).
2-Fluoro-4-(2-(piperidin-4-yl)benzo[d]oxazol-5-yl)benzamide
2,2,2-trifluoroacetate (190 mg, 0.42 mmol) was dissolved in DMF (7
ml) and added isobutyric acid (47 mg, 0.46 mmol), EDC.HCl (200 mg,
1.04 mmol), HOBt (70 mg, 0.5 mmol) and TEA (0.7 ml, 3.3 mmol).
After completion of the reaction, water added to the reaction
mixture to obtain solid. Solid was filtered and washed with ether
to obtain the titled compound (120 mg) as a brown solid. M.P.:
193-196.degree. C. MS (m/z): 410.2 [M+f1].sup.+
Example 44
Isopropyl
4-[6-(4-carbamoyl-3-fluorophenyl)benzo[d]oxazol-2-yl]piperidine--
1-carboxylate
[0404] Following the General Procedure-3, the titled compound (55
mg) was prepared from Intermediate 16 (360 mg, 0.87 mmol) and
4-bromo-2-fluorobenzamide (190 mg, 0.87 mmol) as an off-white
solid. M.P.: 178-181.degree. C. MS (m/z): 425.45 [M+H].sup.+.
Example 45
Isopropyl
4-{5-[3-fluoro-4-(2-hydroxyethylcarbamoyl)phenyl]benzo[d]oxazol--
2-yl}piperidine-1-carboxylate
[0405] Following the General Procedure-3, the titled compound (65
mg) was prepared from Intermediate 14 (200 mg, 0.54 mmol) and
4-bromo-2-fluoro-N-(2-hydroxyethyl)benzamide (110 mg, 0.43 mmol) as
a brown solid. M.P.: 145-147.degree. C. MS (m/z): 470.4
[M+H].sup.+.
Example 46
Isopropyl
4-{5-[3-fluoro-4-(isopropylcarbamoyl)phenyl]benzo[d]oxazol-2-yl}-
piperidine-1-carboxylate
[0406] Following the General Procedure-3, the titled compound (45
mg) was prepared from Intermediate 13 (200 mg, 0.54 mmol) and
3-fluoro-4-(isopropylcarbamoyl)phenylboronic acid (120 mg, 0.54
mmol) as a grey solid. M.P.: 147-150.degree. C. MS (m/z): 468.4
[M+H].sup.+.
Example 47
Isopropyl
4-{5-[4-(N-methylsulfamoyl)phenyl]benzo[d]oxazol-2-yl}piperidine-
-1-carboxylate
[0407] Following the General Procedure-3, the titled compound (35
mg) was prepared from Intermediate 13 (200 mg, 0.54 mmol) and
4-(N-methylsulfamoyl)phenylboronic acid (120 mg, 0.54 mmol) as a
white solid. M.P.: 179-181.degree. C. MS (m/z): 458.3
[M+H].sup.+
Example 48
Isopropyl
4-{5-[6-(methylcarbamoyl)pyridin-3-yl]benzo[d]oxazol-2-yl}piperi-
dine-1-carboxylate
[0408] Following the General Procedure-1, the titled compound (20
mg) was prepared from Intermediate 13 (300 mg, 0.82 mmol) and
N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide
(256 mg, 0.98 mmol) as a brown solid. M.P.: 158-161.degree. C. MS
(m/z): 423.5 [M+H].sup.+
Example 49
Isopropyl
4-{5-[3-methyl-4-(methylcarbamoyl)phenyl]benzo[d]oxazol-2-yl}pip-
eridine-1-carboxylate
[0409] Following the General Procedure-3, the titled compound (30
mg) was prepared from Intermediate 13 (250 mg, 0.68 mmol) and
N,2-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide
(187 mg, 0.68 mmol) as an off-white solid. M.P.: 151-154.degree. C.
MS (m/z): 436.5 [M+H].sup.+
Example 50
Isopropyl
4-{5-[4-(cyclopropylcarbamoyl)-3-fluorophenyl]benzo[d]oxazol-2-y-
l}piperidine-1-carboxylate
[0410] Following the General Procedure-3, the titled compound (20
mg) was prepared from Intermediate 14 (250 mg, 0.61 mmol) and
4-bromo-N-cyclopropyl-2-fluorobenzamide (156 mg, 0.61 mmol) as an
off-white solid. M.P.: 162-165.degree. C. MS (m/z): 466.3
[M+H].sup.+
Example 51
2-Fluoro-4-{2-[1-(5-fluoropyrimidin-2-yl)piperidin-4-yl]benzo[d]oxazol-5-y-
l}benzamide
[0411] Following general procedure-3 and using DMF as solvent
titled compound (40 mg) was obtained from intermediate 19 (150 mg,
0.35 mmol) and 4-bromo-2-fluorobenzamide (77 mg, 0.35 mmol) as a
brown solid. M.P.: 226-229.degree. C. MS (m/z): 436.5
[M+H].sup.+
Example 52
Tert-butyl
4-[5-(4-carbamoyl-3-fluorophenyl)benzofuran-2-yl]-5,6-dihydropy-
ridine-1(2H)-carboxylate
[0412] Following the general procedure-4, the titled compound (370
mg) was obtained from intermediate 21 (1.5 g, 5.02 mmol) and
tert-butyl
4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate
(1.99 g, 6 mmol) as a white solid. M.P.: 189-191.degree. C.
.sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400 MHz): 7.95 (s, 1H),
7.77-7.71 (m, 1H), 7.69-7.58 (m, 6H), 6.91 (s, 1H), 6.50 (s, 1H),
4.10-4.05 (m, 2H), 3.56 (t, J 5.5, 2H), 3.30-3.20 (m, 2H), 1.42 (s,
9H).
Example 53
2-fluoro-4-{2-[1-(propylsulfonyl)piperidin-4-yl]benzo[d]oxazol-5-yl}benzam-
ide
[0413] Intermediate 25 (80 mg, 0.24 mmol) was dissolved in DCM (10
ml) and added TEA (35 mg, 0.35 mmol). This mixture was stirred at
rt for 15 mins Reaction mixture cooled to 0.degree. C. and added
propane-1-sulphonylchloride (33 mg, 0.23 mmol). Reaction mixture
stirred at rt for 2 h. Work up (DCM/H.sub.2O) afforded the crude
product. Crude was purified by column chromatography on 60-120 mesh
silica gel using a gradient mixture of EtOAC and Petether (70:30)
as eluent to afford the titled compound (8 mg) as a white solid.
M.P.: 222-225.degree. C. .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6,
400 MHz): 8.09 (d, J 1.3, 1H), 7.82-7.72 (m, 3H), 7.71-7.61 (m,
4H), 3.67-3.58 (m, 2H), 3.30-3.22 (m, 2H), 3.09-2.99 (m, 2H),
2.25-2.16 (m, 2H), 1.92-1.79 (m, 2H), 1.69 (hextet, J 7.6, 2H),
0.98 (t, J 7.4, 3H).
Example 56
Tert-butyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]-1H-benzo[d]imidazol-5--
yl}-5,6-dihydropyridine-1(2H)-carboxylate
[0414] 2-[2-fluoro-4-(methyl
sulfonyl)phenyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxa
borolan-2-yl)-1H-benzo[d]imidazole (880 mg, 2.12 mmol), tert-butyl
4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate
(700 mg, 2.12 mmol) and sodium carbonate (1.13 g, 11.48 mmol) were
dissolved in DMF (20 ml) under N.sub.2 atmosphere. This mixture was
degassed with nitrogen for 30 mins and added
Pd(dppf).sub.2Cl.sub.2.CH.sub.2Cl.sub.2 (138 mg, 0.17 mmol). This
mixture stirred at 80.degree. C. for 90 mins in microwave. Reaction
mixture diluted with water and work up (AcOEt/H.sub.2O) afforded
the crude. Crude was purified by combiflash using a mixture of
AcOEt and Petether (35:65) to afford the titled compound (240 mg)
as an off-white solid. .sup.1H-NMR (6 ppm, DMSO-d.sub.6, 400 MHz):
12.80 (s, 1H), 8.49 (t, J 7.5, 1H), 8.02 (d, J 10.4, 1H), 7.92 (d,
J 8.2, 1H), 7.88-7.67 (m, 1H), 7.66-7.54 (m, 1H), 7.48-7.39 (m,
1H), 6.18 (bs, 1H), 4.02 (bs, 2H), 3.57 (bs, 2H), 3.34 (s, 3H),
2.60-2.55 (m, 2H), 1.43 (s, 9H).
Example 57
Tert-butyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]-1H-benzo[d]imidazol-5--
yl}piperidine-1-carboxylate
[0415] Example 56 (240 mg, 0.51 mmol) was dissolved in MeOH (25 ml)
and added 10% Pd/C (100 mg). This mixture was stirred in an auto
clave under hydrogen atmosphere at 55 psi for 14 h. After 14 h,
reaction mass filtered through a pad of celite and celite washed
thoroughly with methanol. Methanol removed on rotavapour to obtain
the titled compound (200 mg) as an off-white solid. M.P.:
208-211.5.degree. C. .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400
MHz): 12.71 (s, 1H), 8.47 (t, J 7.7, 1H), 8.01 (d, J 10.4, 1H),
7.91 (dd, J 1.4, 8.2, 1H), 7.65-7.40 (m, 2H), 7.30-7.24 (m, 1H),
4.08 (d, J 11.1, 2H), 3.33 (s, 3H), 2.92-2.74 (m, 3H), 1.81 (d, J
12.2, 2H), 1.54 (d, J 10.4, 2H), 1.42 (s, 9H).
Example 58
5-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]-2-[2-fluoro-4-(methylsulfonyl)-
phenyl]-1H-benzo[d]imidazole
[0416] Example 57 (150 mg, 0.3 mmol) dissolved in DCM (12 ml) and
added TFA (0.45 ml). This mixture stirred at rt for 3 h. After 3 h,
DCM removed on rotavapour and co-distilled with DCM to obtain
2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(piperidin-4-yl)-1H-benzo[d]imida-
zole 2,2,2-trifluoroacetate (150 mg).
2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(piperidin-4-yl)-1H-benzo[d]imida-
zole 2,2,2-trifluoroacetate (150 mg, 0.4 mmol) and
2-chloro-5-ethylpyrimidine (60 mg, 0.4 mmol) were dissolved in
propan-2-ol (10 ml) and added DiPEA (0.6 ml, 3.2 mmol). This
mixture was refluxed at 90.degree. C. for 12 h. After 12 h,
propan-2-ol removed on rotavapor to obtain the residue. Residue was
purified on combiflash using Ethyl acetate and Petether (1:1) as
eluent to afford the titled compound (50 mg) as a white solid.
M.P.: 220-223.5.degree. C. .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6,
400 MHz): 12.69 (d, J 12.8, 1H), 8.49-8.45 (m, 1H), 8.24 (s, 2H),
8.00 (dd, J 1.5, 10.4, 1H), 7.91 (d, J 8.3, 1H), 7.67-7.56 (m, 1H),
7.55-7.40 (m, 1H), 7.22-7.12 (m, 1H), 4.80 (d, J 12.6, 2H), 3.33
(s, 3H), 2.97-2.91 (m, 3H), 2.43 (q, J 7.5, 2H), 1.89 (d, J 12.4,
2H), 1.69-1.54 (m, 2H), 1.13 (t, J 7.6, 3H).
Example 59
Tert-butyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}-5,-
6-dihydropyridine-1(2H)-carboxylate
[0417]
2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(4,4,5,5-tetramethyl-1,3,2--
dioxa borolan-2-yl)benzo[d]oxazole (50 mg, 0.12 mmol), tert-butyl
4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate
(39 mg, 0.12 mmol) and sodium carbonate (38 mg, 0.36 mmol) were
dissolved in DMF (2 ml) under N.sub.2 atmosphere. This mixture was
degassed with nitrogen for 30 mins and added
Pd(dppf).sub.2Cl.sub.2.CH.sub.2Cl.sub.2 (10 mg, 0.009 mmol). This
mixture stirred at 80.degree. C. for 90 mins in microwave. Reaction
mixture diluted with water and work up (AcOEt/H.sub.2O) afforded
the crude. Crude was purified by combiflash using a mixture of
AcOEt and Petether (27:73) to afford the titled compound (25 mg) as
an off-white solid. M.P.: 149-151.degree. C. .sup.1H-NMR (.delta.
ppm, CDCl.sub.3, 400 MHz): 8.47 (t, J 7.4, 1H), 7.93-7.80 (m, 3H),
7.65-7.57 (m, 1H), 7.53-7.45 (m, 1H), 6.20-6.02 (m, 1H), 4.12 (bs,
2H), 3.68 (t, J 5.3, 2H), 3.13 (s, 3H), 2.65-2.55 (m, 2H), 1.50 (s,
9H).
Example 60
Tert-butyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}pip-
eridine-1-carboxylate
[0418] Example 59 (300 mg, 0.64 mmol) was dissolved in MeOH (25 ml)
and added 10% Pd/C (100 mg). This mixture was stirred in an auto
clave under hydrogen atmosphere at 55 psi for 14 h. After 14 h,
reaction mass filtered through a pad of celite and celite washed
thoroughly with methanol. Methanol removed on rotavapour to obtain
the titled compound (200 mg) as an off-white solid. M.P.:
168-171.degree. C. .sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400 MHz):
8.46 (t, J 7.1, 1H), 7.87 (t, J 7.6, 2H), 7.69 (s, 1H), 7.57 (d, J
8.4, 1H), 7.30 (d, J 7.7, 1H), 4.35-4.20 (m, 2H), 3.13 (s, 3H),
2.90-2.75 (m, 3H), 1.90 (d, J 12.6, 2H), 1.63-1.74 (m, 2H), 1.49
(s, 9H).
Example 61
2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(piperidin-4-yl)benzo[d]oxazole
2,2,2-trifluoroacetate
[0419] Example 60 (170 mg, 0.36 mmol) dissolved in DCM (15 ml) and
added TFA (0.6 ml). This mixture stirred at rt for 3 h. After 3 h,
DCM removed on rotavapour and co-distilled with DCM to obtain
2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(piperidin-4-yl)benzo[d]oxazole
2,2,2-trifluoroacetate (180 mg). M.P.: 223-227.degree. C.
.sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400 MHz): 8.61 (bs, 1H),
8.47 (t, J 7.6, 1H), 8.39 (bs, 1H), 8.07 (d, J 10, 1H), 7.98 (d, J
8.1, 1H), 7.83 (d, J 8.4, 1H), 7.74 (s, 1H), 7.39 (d, J 8.3, 1H),
3.45-3.33 (m, 5H), 3.10-2.98 (m, 3H), 2.02 (d, J 12.9, 2H),
1.93-1.80 (m, 2H).
Example 62
5-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]-2-[2-fluoro-4-(methylsulfonyl)-
phenyl]benzo[d]oxazole
[0420] Example 61 (150 mg, 0.31 mmol) and
2-chloro-5-ethylpyrimidine (48 mg, 0.34 mmol) were dissolved in
propan-2-ol (20 ml) and added DiPEA (0.4 ml, 2.45 mmol). This
mixture was refluxed at 90.degree. C. for 12 h. After 12 h,
propan-2-ol removed on rotavapor to obtain the residue. Residue was
purified on combiflash using Ethyl acetate and Petether (35:65) as
eluent to afford the titled compound (30 mg) as a white solid.
M.P.: 190-194.degree. C. .sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400
MHz): 8.49-8.43 (m, 1H), 8.20 (s, 2H), 7.90-7.84 (m, 2H), 7.71 (s,
1H), 7.57 (d, J 8.4, 1H), 7.33 (d, J 7.6, 1H), 4.91 (d, J 13.3,
2H), 3.13 (s, 3H), 3.05-2.90 (m, 3H), 2.48 (q, J 7.5, 2H), 2.00 (d,
J 13, 2H), 1.83-1.70 (m, 2H), 1.20 (t, J 7.6, 3H).
Example 63
Tert-butyl
4-{7-fluoro-2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-
-5-yl}piperidine-1-carboxylate
[0421] Following the general procedure-1 Tert-butyl
4-{7-fluoro-2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}-5,6-
-dihydropyridine-1(2H)-carboxylate (180 mg) obtained from
intermediate 31 (600 mg, 1.38 mmol) and tert-butyl
4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate
(456 mg, 1.38 mmol). Tert-butyl
4-{7-fluoro-2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}-5,6-
-dihydropyridine-1(2H)-carboxylate (150 mg, 0.30 mmol) dissolved in
MeOH and added Pd/C (71 mg). This mixture was stirred in an auto
clave in hydrogen atmosphere at 55 Psi for 12 h. Reaction mixture
filtered through celite and washed the cetile with MeOH. Methanol
was removed on rotavapour to obtain the titled compound (100 mg) as
a brown solid. M.P.: 188-192.4.degree. C. .sup.1H-NMR (.delta. ppm,
CDCl.sub.3, 400 MHz): 8.47 (t, J 7.12, 1H), 7.89 (t, J 7.6, 2H),
7.49 (s, 1H), 7.07 (d, J 11.2, 1H), 4.28 (bs, 2H), 3.13 (s, 3H),
2.90-2.72 (m, 3H), 1.95-1.85 (m, 2H), 1.72-1.56 (m, 2H). 1.49 (s,
9H).
Example 64
Isopropyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}pipe-
ridine-1-carboxylate
[0422] Example 61 (100 mg, 0.20 mmol) was dissolved in DCM (10 ml)
and added TEA (1.4 ml). This mixture was stirred at rt for 30 mins
Isopropyl chloroformate in toluene (50 mg, 0.41 mmol) added to the
above mixture and stirred at rt for 1 h. Reaction mixture diluted
with water and extracted with DCM. DCM removed on rotavapour to
obtain the crude. Crude was purified by combiflash with EA and
Petehter (35:65) as eluent to afford the title compound (50 mg) as
an off-white solid. M.P.: 151.4-156.5.degree. C. .sup.1H-NMR
(.delta. ppm DMSO-d.sub.6, 400 MHz): 8.47 (t, J 7.8, 1H), 8.05 (d,
J 10.3, 1H), 7.97 (dd, J 1.5, 8.2, 1H), 7.78-7.74 (m, 2H), 7.42 (d,
J 8.6, 1H), 4.79 (heptet, J 6.2, 1H), 4.12 (d, J 11.6, 2H), 3.29
(s, 3H), 2.95-2.80 (m, 3H), 1.86-1.77 (m, 2H), 1.65-1.55 (m, 2H),
1.20 (d, J 6.2, 6H).
Example 65
Tert-butyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]thiazol-6-yl}-5-
,6-dihydropyridine-1(2H)-carboxylate
[0423] Following the general procedure-1, the titled compound (140
mg) was obtained from intermediate 35 (300 mg, 0.69 mmol) and
tert-butyl
4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate
(230 mg, 0.69 mmol) as a brown solid. M.P.: 159.9-163.5.degree. C.
.sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400 MHz): 8.68 (t, J 6.9,
1H), 8.09 (d, J 8.6, 1H), 7.94 (d, J 1.3, 1H), 7.90-7.82 (m, 2H),
7.88 (d, J 1.7, 8.2, 1H), 6.18 (s, 1H), 4.13 (d, J 2.3, 2H), 3.69
(t, J 5.6, 2H), 3.12 (s, 3H), 2.62 (bs, 2H), 1.50 (s, 9H).
Example 66
Tert-butyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]thiazol-5-yl}-5-
,6-dihydropyridine-1(2H)-carboxylate
[0424] Following the general procedure-1, the titled compound (120
mg) was obtained from intermediate 39 (230 mg, 0.53 mmol) and
tert-butyl
4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate
(175 mg, 0.53 mmol) as an yellow solid. M.P.: 170-174.8.degree. C.
.sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400 MHz): 8.71-8.67 (m, 1H),
8.13 (d, J 1.3, 1H), 7.95-7.82 (m, 3H), 7.55 (dd, J 1.7, 8.5, 1H),
6.19 (s, 1H), 4.14 (d, J 2.6, 2H), 3.70 (t, J 5.6, 2H), 3.12 (s,
3H), 2.70-2.60 (m, 2H), 1.51 (s, 9H).
Example 67
Tert-butyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-6-yl}pip-
eridine-1-carboxylate
[0425] Following the general procedure-1 Tert-butyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-6-yl}-5,6-dihydrop-
yridine-1(2H)-carboxylate (35 mg) obtained from intermediate 41
(400 mg, 0.96 mmol) and tert-butyl
4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate
(318 mg, 0.961 mmol). Tert-butyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-6-yl}-5,6-dihydrop-
yridine-1(2H)-carboxylate (50 mg, 0.11 mmol) dissolved in MeOH and
added Pd/C (30 mg). This mixture was stirred in an auto clave under
hydrogen atmosphere at 55 Psi for 12 h. Reaction mixture filtered
through celite and washed the cetile with MeOH. Methanol was
removed on rotavapour to obtain the crude. Crude was purified by
combiflash using EtOAc and Petether (38:62) as eluent to obtain
titled compound (18 mg) as an off-white solid. M.P.:
166.2-169.3.degree. C. .sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400
MHz): 8.48-8.46 (m, 1H), 7.91-7.83 (m, 2H), 7.78 (d, J 8.3, 1H),
7.49 (s, 1H), 7.33-7.25 (m, 1H), 4.35-4.20 (m, 2H), 3.13 (s, 3H),
2.90-2.75 (m, 3H), 1.95-1.85 (m, 2H), 1.75-1.60 (m, 2H), 1.49 (s,
9H).
Example 68
{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]thiazol-5-yl}piperidine-1-ca-
rboxylate
[0426] Tert-butyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]thiazol-5-yl}piperidine-1-
-carboxylate (30 mg, 0.06 mmol) dissolved in MeOH and added Pd/C
(30 mg). This mixture was stirred in an auto clave under hydrogen
atmosphere at 55 Psi for 87 h. Reaction mixture filtered through
celite and washed the cetile with MeOH. Methanol was removed on
rotavapour to obtain the crude. Crude was purified by combiflash
using EtOAc and Petether (20:80) as eluent to obtain titled
compound (12 mg) as a pale-yellow solid. M.P.: 173.3-178.1.degree.
C. .sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400 MHz): 8.71-8.65 (m,
1H), 7.99 (s, 1H), 7.93-7.82 (m, 3H), 7.35 (dd, J 1.5, 8.3, 1H),
4.35-4.20 (m, 2H), 3.12 (s, 3H), 2.91-2.79 (m, 3H), 1.96-1.88 (m,
2H), 1.80-1.68 (m, 2H), 1.50 (s, 9H).
Example 69
Ethyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}piperidi-
ne-1-carboxylate
[0427]
2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(piperidin-4-yl)benzo[d]oxa-
zole 2,2,2-trifluoroacetate (80 mg, 0.16 mmol) dissolved in DCM (10
ml) and added TEA (0.12 ml, 0.8 mmol). This mixture was stirred at
rt for 30 mins Ethylchloro formate (35 mg, 0.33 mmol) was added to
the above mixture and stirred at rt for 30 mins Reaction mixture
extracted with DCM. DCM removed on rotavapour to obtain the crude.
Crude was purified by combiflash using EtOAc and Petether (38:62)
as eluent to afford the titled compound (20 mg) as an off-white
solid. M.P.: 145-148.degree. C. .sup.1H-NMR (.delta. ppm,
CDCl.sub.3, 400 MHz): 8.49-8.44 (m, 1H), 7.90-7.84 (m, 2H), 7.69
(d, J 1.2, 1H), 7.58 (d, J 8.5, 1H), 7.30 (dd, J 1.6, 8.5, 1H),
4.40-4.28 (m, 2H), 4.17 (q, J 7.1, 2H), 3.13 (s, 3H), 2.95-2.79 (m,
3H), 1.96-1.88 (m, 2H), 1.75-1.65 (m, 2H), 1.29 (t, J 7.1, 3H).
Example 70
Tert-butyl
4-{2-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-5-yl}piperidine--
1-carboxylate
[0428] Following the general procedure-1, Tert-butyl
4-{2-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-5-yl}-5,6-dihydropyridine--
1(2H)-carboxylate (90 mg) obtained from intermediate 44 (200 mg,
0.51 mmol) and Tert-butyl
4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate
(170 mg, 0.511 mmol). Tert-butyl
4-{2-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-5-yl}-5,6-dihydropyridine--
1(2H)-carboxylate (90 mg, 0.2 mmol) dissolved in MeOH (30 ml) and
added Pd/C (90 mg). This mixture was stirred in an auto clave in
hydrogen atmosphere at 55 Psi for 12 h. Reaction mixture filtered
through celite and washed the cetile with MeOH. Methanol was
removed on rotavapour to obtain the crude. Crude was triturated
with Petether and EtOAc (1:1) to obtain the titled compound (50 mg)
as an off-white solid. M.P.: 161-164.degree. C. .sup.1H-NMR
(.delta. ppm CDCl.sub.3, 400 MHz): 8.36 (d, J 8.2, 2H), 7.78 (d, J
8.4, 2H), 7.63 (d, J 1.5, 1H), 7.53 (d, J 8.4, 1H), 7.26-7.20 (m,
1H), 4.34-4.20 (m, 2H), 2.90-2.75 (m, 3H), 1.93-1.84 (m, 2H),
1.74-1.62 (m, 2H), 1.49 (s, 9H).
Example 71
Isopropyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-6-yl}pipe-
ridine-1-carboxylate
[0429] Tert-butyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-6-yl}piperidine-1--
carboxylate (270 mg, 5.7 mmol) dissolved in THF (5 ml) and added
Et.sub.2O.HCl (10 ml). Reaction mixture stirred at rt for 3 h.
Ether removed on rotavapour to obtain crude. Crude was triturated
with ether to obtain
2-[2-fluoro-4-(methylsulfonyl)phenyl]-6-(piperidin-4-yl)benzo[d]ox-
azole hydrochloride (225 mg).
2-[2-fluoro-4-(methylsulfonyl)phenyl]-6-(piperidin-4-yl)benzo[d]oxazole
hydrochloride (70 mg, 0.17 mmol) was dissolved in DCM (5 ml) and
added TEA (0.11 ml, 0.85 mmol). This mixture stirred at rt for 30
mins and added isopropylchloro formate in toluene (42 mg, 0.34
mmol). After 30 mins reaction mixture quenched with water and
extracted with DCM. DCM removed on rotavapour to obtain the crude.
Crude was purified by combiflash using EtOAC and Petether (1:3) as
eluent to afford the titled compound (30 mg) as a white solid.
M.P.: 170.3-174.3.degree. C. .sup.1H-NMR (.delta. ppm, CDCl.sub.3,
400 MHz): 8.47-8.44 (m, 1H), 7.90-7.83 (m, 2H), 7.78 (d, J 8.3,
1H), 7.49 (s, 1H), 7.28 (dd. J 1.5, 8.3, 1H), 4.96 (septet, J 6.2,
1H), 4.40-4.28 (m, 2H), 3.13 (s, 3H), 2.92-2.80 (m, 3H), 1.96-1.88
(m, 2H), 1.75-1.62 (m, 2H), 1.28 (d, J 6.2, 6H).
Example 72
Ethyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-6-yl}piperidi-
ne-1-carboxylate
[0430] 2-[2-fluoro-4-(methyl
sulfonyl)phenyl]-6-(piperidin-4-yl)benzo[d]oxazole hydrochloride
(70 mg, 0.17 mmol) from Example 71 was dissolved in DCM (10 ml) and
added TEA (0.12 ml, 0.83 mmol). This mixture stirred at rt for 30
mins and added Ethylchloro formate (35 mg, 0.34 mmol). After 30
mins reaction mixture quenched with water and extracted with DCM.
DCM removed on rotavapour to obtain the crude. Crude was purified
by combiflash using EtOAc and Petether (1:3) as eluent to afford
the titled compound (30 mg) as a white solid. M.P.:
153.5-157.5.degree. C. .sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400
MHz): 8.49-8.43 (m, 1H), 7.90-7.82 (m, 2H), 7.78 (d, J 8.3, 1H),
7.49 (s, 1H), 7.28 (dd, J 1.4, 8.3, 1H), 4.42-4.28 (m, 2H), 4.17
(q, J 7.1, 2H), 3.13 (s, 3H), 2.95-2.80 (m, 3H), 1.96-1.88 (m, 2H),
1.75-1.65 (m, 2H), 1.29 (t, J 7.1, 3H).
Example 73
Ethyl
4-{2-[2-fluoro-4-(methylsulfonyhenyl]benzo[d]oxazol-6-yl}piperidine--
1-carboxylate
[0431] Tert-butyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]thiazol-5-yl}piperidine-1-
-carboxylate (130 mg, 0.27 mmol) dissolved in DCM (5 ml) and added
TFA (0.5 ml). Reaction mixture stirred at rt for 3 h. DCM removed
on rotavapour to obtain crude. Crude was triturated with ether to
obtain
2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(piperidin-4-yl)benzo[d]thiazole
2,2,2-trifluoroacetate (150 mg). 2-[2-fluoro-4-(methylsulfonyl)
phenyl]-5-(piperidin-4-yl)benzo[d]thiazole 2,2,2-trifluoroacetate
(105 mg, 0.21 mmol) was dissolved in DCM (20 ml) and added TEA
(0.23 ml, 1.66 mmol). This mixture stirred at rt for 30 mins and
added isopropylchloro formate in toluene (51 mg, 0.42 mmol). After
30 mins reaction mixture quenched with water and extracted with
DCM. DCM removed on rotavapour to obtain the crude. Crude was
purified by combiflash using EtOAc and Petether (1:3) as eluent to
afford the titled compound (60 mg) as a grey solid. M.P.:
174-177.degree. C. .sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400 MHz):
8.71-8.65 (m, 1H), 8.00 (d, J 1.2, 1H), 7.93-7.81 (m, 3H), 7.35
(dd, J 1.6, 8.4, 1H), 4.96 (septet, J 6.2, 1H), 4.40-4.22 (m, 2H),
3.12 (s, 3H), 2.95-2.82 (m, 3H), 2.0-1.90 (m, 2H), 1.80-1.64 (m,
2H), 1.28 (d, J 6.3, 6 H).
Example 74
Benzyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}piperid-
ine-1-carboxylate
[0432]
2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(piperidin-4-yl)benzo[d]oxa-
zole 2,2,2-trifluoroacetate (Example 61) (70 mg, 0.14 mmol)
dissolved in DCM (10 ml) and added TEA (0.1 ml, 0.72 mmol). This
mixture stirred at rt for 30 mins and added benzyl
carbonochloridate in toluene (48 mg, 0.28 mmol). After 30 mins
reaction mixture quenched with water and extracted with DCM. DCM
removed on rotavapour to obtain the crude. Crude was purified by
combiflash using EtOAc and Petether (1:2) as eluent to afford the
titled compound (30 mg) as an off-white solid. M.P.:
172-175.degree. C. .sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400 MHz):
8.49-8.43 (m, 1H), 7.90-7.84 (m, 2H), 7.68 (d, J 1.4, 1H), 7.57 (d,
J 8.5, 1H), 7.42-7.22 (m, 6H), 5.17 (s, 2H), 4.42-4.25 (bs, 2H),
3.13 (s, 3H), 3.00-2.78 (m, 3H), 2.00-1.88 (m, 2H), 1.80-1.65 (m,
2H).
Example 75
Isobutyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}piper-
idine-1-carboxylate
[0433]
2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(piperidin-4-yl)benzo[d]oxa-
zole 2,2,2-trifluoroacetate (Example 61) (140 mg, 0.29 mmol),
isobutanol (42 mg, 0.58 mmol), N,N-Carbonyl diimidazole (82 mg,
0.50 mmol) and TEA (0.2 ml, 1.26 mmol) were dissolved in DMF (2.4
ml). Reaction mixture heated to 60.degree. C. for 18 h. Work up
(EtOAc/H.sub.2O) followed by purification of the crude by column
chromatography on 60-120 mesh silica gel using EtOAc and Petether
as eluent to afford the titled compound as a white solid. M.P.:
169-173.degree. C. .sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400 MHz):
8.49-8.43 (m, 1H), 7.83-7.90 (m, 2H), 7.69 (d, J 1.4, 1H), 7.58 (d,
J 8.5, 1H), 7.30 (dd, J 1.7, 8.5, 1H) 4.42-4.26 (m, 2H), 3.90 (d, J
6.7, 2H), 3.13 (s, 3H), 3.00-2.78 (m, 3H), 2.00-1.88 (m, 3H),
1.80-1.65 (m, 2H), 0.96 (d, J 6.7, 6H).
Example 76
Isopropyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]thiazol-6-yl}pip-
eridine-1-carboxylate
[0434] Tert-butyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]thiazol-5-yl}piperidine-1-
-carboxylate (190 mg, 0.38 mmol) dissolved in DCM, cooled to
0.degree. C., trifluoroacetic acid (0.8 ml) was added and stirred
the reaction mixture at rt for 3 h. DCM and trifluoroacetic acid
was removed on rotavapour to obtain the crude. Crude was washed
with petether to obtain
2-[2-fluoro-4-(methylsulfonyl)phenyl]-6-(piperidin-4-yl)benzo[d]thiazole
(190 mg) as an off-white solid.
2-[2-fluoro-4-(methylsulfonyl)phenyl]-6-(piperidin-4-yl)benzoldlthiazole
(190 mg, 0.38 mmol) dissolved in DCM (20 ml). To this mixture added
TEA (0.3 g, 3 mmol) and stirred the reaction mixture at rt for 30
mins Reaction mixture cooled to 0.degree. C. and added
isopropylchloro formate (92 mg, 0.75 mmol). This mixture was
stirred at rt for 30 mins Work up (DCM/H.sub.2O) followed by
evaporation of the DCM on rotavapour afforded crude. Crude was
triturated with diethyl ether and dried on high vacuum to afford
the titled compound (60 mg) as a white solid. M.P.: 163-166.degree.
C. .sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400 MHz):
Example 77
Isopropyl
4-{2-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-5-yl}piperidine-1-
-carboxylate
[0435] Tert-butyl
4-{2-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-5-yl}-5,6-dihydropyridine--
1(2H)-carboxylate (80 mg, 0.17 mmol) dissolved in DCM (15 ml),
cooled to 0.degree. C., trifluoroacetic acid (0.1 ml) was added and
stirred the reaction mixture at rt for 3 h. DCM and trifluoroacetic
acid was removed on rotavapour to obtain the crude. Crude was
washed with petether to obtain
5-(piperidin-4-yl)-2-(4-(trifluoromethyl)phenyl)benzo[d]oxazole
2,2,2-trifluoroacetate (90 mg) as an off-white solid.
5-(piperidin-4-yl)-2-(4-(trifluoromethyl)phenyl)benzo[d]oxazole
2,2,2-trifluoroacetate (90 mg, 0.19 mmol) dissolved in DCM (15 ml).
To this mixture added TEA (0.1 ml, 0.56 mmol) and stirred the
reaction mixture at rt for 30 mins. Reaction mixture cooled to
0.degree. C. and added isopropylchloro formate (46 mg, 0.38 mmol).
This mixture was stirred at rt for 30 mins Work up (DCM/H.sub.2O)
followed by evaporation of the DCM on rotavapour afforded crude.
Crude was purified with combiflash using a gradient mixture of
ethylacetate and petether (15:85) as eluent to afford the titled
compound (30 mg) as an off-white solid. M.P.: 145-148.degree. C.
.sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400 MHz): 8.36 (d, J 8.1,
2H), 7.78 (d, J 8.3, 2H), 7.62 (d, J 1.5, 1H), 7.54 (d, J 8.5, 1H),
7.29-7.21 (m, 1H), 4.96 (septet, 6.2, 1H), 4.31 (bs, 2H), 2.95-2.76
(m, 3H), 1.90 (d, J 12.7, 2H), 1.75-1.63 (m, 2H), 1.27 (d, J 6.2,
6H).
Example 78
Isopropyl
4-(2-p-tolylbenzobiloxazol-6-yl)piperidine-1-carboxylate
[0436] Intermediate 49 (40 mg, 0.14 mmol) was dissolved in DCM (10
ml) and added trifluooroacetic acid (0.15 ml) at 0.degree. C. This
mixture was stirred at rt for 3 h. After 3 h DCM was removed on
rotavapour and the residue that obtained was washed with diethyl
ether to obtain 6-(piperidin-4-yl)-2-p-tolylbenzo[d]oxazole
2,2,2-trifluoroacetate (40 mg).
6-(piperidin-4-yl)-2-p-tolylbenzo[d]oxazole 2,2,2-trifluoroacetate
(40 mg, 0.1 mmol) was dissolved in DCM (10 ml) and added TEA (0.1
ml, 0.79 mmol) at 0.degree. C. To the above mixture isopropylchloro
formate (24 mg, 0.2 mmol) was added and stirred at rt for 15 mins.
Workup (DCM/H.sub.2O) followed by column purification on 60-120
mesh silica gel using EtOAc and Petether (2:8) as eluent afforded
the titled compound (12 mg) as an off-white solid. .sup.1H-NMR
(.delta. ppm, CDCl.sub.3, 400 MHz): 8.12 (d, J 8.2, 2H), 7.66 (d, J
8.2, 1H), 7.40 (d, J 1.2, 1H), 7.32 (d, J 8, 2H), 7.19 (dd, J 1.4,
8.2, 1H), 4.96 (septet, J 6.2, 1H), 4.32 (bs, 2H), 2.93-2.75 (m,
3H), 2.44 (s, 3H), 1.90 (d, J 13.4, 2H), 1.75-1.65 (m, 2H), 1.27
(d, J 6.2, 6H).
Example 79
3-{4-[2-(2-fluoro-4-(methylsulfonyl)phenyl)benzo[d]oxazol-5-yl]-5,6-dihydr-
opyridin-1(2H)-ylsulfonyl}propan-1-ol
[0437] Example 59 (200 mg, 0.42 mmol) was dissolved in DCM (30 ml)
and added TFA (1.5 ml, 9.2 mmol). This mixture was stirred at rt
for 3 h and DCM was removed on rotavapour to obtain a residue.
Residue was co-distilled with diethyl ether to obtain
2-(2-fluoro-4-(methyl
sulfonyl)phenyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d]oxazole
2,2,2-trifluoroacetate (210 mg).
2-(2-fluoro-4-(methylsulfonyl)phenyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)b-
enzo[d]oxazole 2,2,2-trifluoroacetate (200 mg, 0.4 mmol) was
dissolved in DCM (10 ml) and added TEA (0.46 ml, 3.3 mmol). This
mixture was stirred at rt for 30 mins After 30 mins reaction
mixture cooled to 0.degree. C. and added ethyl
3-(chlorosulfonyl)propanoate (164 mg, 0.4 mmol). This reaction
continued for 30 mins at rt. Work up (H.sub.2O/DCM) followed by
column purification on combiflash using a gradient mixture of EtOAc
and Petether (45:55) as eluent afforded ethyl
2-{4-[2-(2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}-5,6-dihyd-
ropyridin-1(2H)-ylsulfonyl)acetate (120 mg). Ethyl
2-{4-[2-(2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}-5,6-dihyd-
ropyridin-1(2H)-ylsulfonyl)acetate (100 mg, 0.19 mmol) was
dissolved in THF (5 ml) and added Lithiumaluminium hydride (14 mg,
0.38 mmol) at 0.degree. C. This mixture was stirred at same
temperature for 90 mins After completion of the reaction, reaction
mass quenched with 1N HCl (7 ml). Work up (DCM/H.sub.2O) followed
by purification on combiflash using a gradient mixture of EtOAc and
Petether (80:20) as eluent afforded the titled compound (40 mg) as
a white solid. M.P.: 184-186.degree. C. .sup.1H-NMR (.delta. ppm,
CDCl.sub.3, 400 MHz): 8.48 (t, J 8.1, 1H), 8.06 (dd, J 1.6, 10.1,
1H), 8.00-7.94 (m, 2H), 7.84 (d, J 8.6, 1H), 7.63 (dd, J 1.8, 8.5,
1H), 6.29 (s, 1H), 4.64 (t, J 5.3, 1H), 3.94 (d, J 2.9, 2H),
3.50-3.42 (m, 4H), 3.36 (s, 3H), 3.18-3.10 (m, 2H), 2.70-2.62 (m,
2H), 1.88-1.80 (m, 2H).
Example 80
3-{4-[2-(2-fluoro-4-(methylsulfonyl)phenyl)benzo[d]oxazol-5-yl]piperidin-1-
-ylsulfonyl}propan-1-ol
[0438] Example 61 (0.2 g, 0.41 mmol) was dissolved in DCM and and
added TEA (0.33 g, 3.3 mmol). This mixture was stirred at rt for 30
mins After 30 mins reaction mixture cooled to 0.degree. C. and
added ethyl 3-(chlorosulfonyl)propanoate (245 mg, 1.2 mmol). This
reaction continued for 30 mins at rt. Work up (H.sub.2O/DCM)
followed by column purification on combiflash using a gradient
mixture of EtOAc and Petether (65:35) as eluent afforded ethyl
2-{4-[2-(2-fluoro-4-(methylsulfonyl)phenyl)benzo[d]oxazol-5-yl]piperidin--
1-ylsulfonyl}acetate. Ethyl
2-{4-[2-(2-fluoro-4-(methylsulfonyl)phenyl)benzo[d]oxazol-5-yl]piperidin--
1-ylsulfonyl}acetate (100 mg, 0.19 mmol) was dissolved in THF (5
ml) and added Lithiumaluminium hydride (14 mg, 0.37 mmol) at
0.degree. C. This mixture was stirred at same temperature for 90
mins After completion of the reaction, reaction mass quenched with
1N HCl (7 ml). Work up (DCM/H.sub.2O) followed by purification on
combiflash using a gradient mixture of EtOAc and Petether (65:35)
as eluent afforded the titled compound (120 mg) as an off-white
solid. M.P.: 204-206.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.47 (t, J 8.03, 1H), 8.06 (dd, J 1.6,
10.1, 1H), 7.97 (dd, J 1.6, 8.2, 1H), 7.82-7.75 (m, 2H), 7.43 (dd,
J 1.5, 8.6, 1H), 4.66 (t, J 5.3, 1H), 3.74 (d, J 12.1, 2H), 3.50
(q, J 6.1, 2H), 3.38 (s, 3H), 3.12-3.06 (m, 2H), 2.98-2.80 (m, 3H),
1.96-1.90 (m, 2H), 1.88-1.81 (m, 2H), 1.79-1.69 (m, 2H).
Example 81
3-{4-[2-(2-fluoro-4-(methylsulfonyl)phenyl)benzo[d]oxazol-5-yl]piperidin-1-
-ylsulfonyl}propan-1-ol
[0439] Example 61 (150 mg, and 0.31 mmol) and
2-Chloro-5-fluoropyrimidine (44 mg, 0.34 mmol) were dissolved in
isopropanol (20 ml). To this mixture DiPEA (0.45 ml) was added and
heated to 90.degree. C. for 12 h. Isopropanol was removed on
rotavapour to obtain a residue. Residue was purified by combiflash
using a gradient mixture of EtOAc and Petether (38:62) as eluent to
afford the titled compound (30 mg) as an off-white solid. M. P.:
220-222.degree. C. MS (m/z): 471.2 [M+H].sup.+
Example 82
Tert-butyl
4-[2-(4-carbamoyl-3-fluorophenyl)benzo[d]oxazol-5-yl]piperidine-
-1-carboxylate
[0440] Intermediate 52 (40 mg, 0.1 mmol),
2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide
(30 mg, 0.12 mmol) and KF (18 mg, 0.3 mmol) were dissolved in a
mixture of DMF (1 ml) and and water (0.4 ml). This mixture was
purged with N.sub.2 for 30 mins. Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2
was added to the above mixture and again purged with N.sub.2 for 30
mins. This reaction mixture was heated to 90.degree. C. for 12 h.
Work up (EtOAc and H.sub.2O) followed by purification on combiflash
using a gradient mixture of EtOAc and Petether (55:45) as eluent
afforded the titled compound (3 mg) as an Off-White solid. MS
(m/z): 439.5 [M+H].sup.+
Example 83
2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(3-isopropyl-1,2,4-oxadiazol-5--
yl)piperidin-1-yl]benzo[d]oxazole
[0441] Intermediate 28 (150 mg, 0.41 mmol),
3-isopropyl-5-(piperidin-4-yl)-1,2,4-oxadiazole hydrochloride (96
mg, 0.5 mmol), K.sub.2CO.sub.3 (59 mg, 0.43 mmol), CuCl (2 mg, 0.02
mmol), acetyl acetone (5 mg, 0.05 mmol) were dissolved in NMP (1
ml). This reaction mixture was stirred at 130.degree. C. for 16 h
under N.sub.2 atmposphere. Work up (EtOAc/H2O) followed by
purification on combiflash using a gradient mixture of EtOAc and
Petether (30:70) as eluent afforded the titled compound (25 mg) as
a pale-yellow solid. M. P.: 206-209.degree. C. .sup.1H-NMR (.delta.
ppm, CDCl.sub.3, 400 MHz): 8.26 (d, J 8.2, 1H), 7.97 (d, J 1.4,
1H), 7.69 (d, J 1.4, 1H), 7.63 (dd, J 1.5, 8.2, 1H), 7.56-7.48 (m,
2H), 3.49-3.39 (m, 2H), 3.15-3.04 (m, 5H), 3.03-2.93 (m, 2H),
2.25-2.16 (m, 4 h), 1.36 (d, J 7, 6H).
Example 84
Tert-butyl
4-{2-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-6-yl}piperidine--
1-carboxylate
[0442] Following the general procedure, tert-butyl
4-[2-(4-(trifluoromethyl)phenyl]benzo[d]oxazol-6-yl)-5,6-dihydropyridine--
1(2H)-carboxylate (260 mg) was prepared from intermediate 55 (420
mg, 1.08 mmol) and tert-butyl
4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate
(358 mg, 1.08 mmol). tert-butyl
4-[2-(4-(trifluoromethyl)phenyl]benzo[d]oxazol-6-yl)-5,6-dihydropyridine--
1(2H)-carboxylate (260 mg, 0.58 mmol) was dissolved in methanol (8
ml) and added Pd/C (5%) (520 mg). This mixture was stirred under
H.sub.2 pressure (6.5 kg) for 12 h. Combined methanol fractions
were evaporated on rotavapour to obtain the crude. Crude was
purified on combiflash using a gradient mixture of EtOAc and
Petether (1:9) as eluent to afford the titled compound (150 mg) as
a white solid. M. P.: 174-179.degree. C. MS (m/z): 446.46
[M+H].sup.+.
Example 85
Isopropyl
4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}pipe-
razine-1-carboxylate
[0443] Intermediate 28 (490 mg, 1.32 mmol), N-Benzylpiprazine (280
mg, 1.6 mmol), K.sub.2CO.sub.3 (190 mg, 1.4 mmol), CuCl (6.5 mg,
0.05 mmol), acetyl acetone (17 mg, 0.12 mmol) were dissolved in NMP
(2 ml). This reaction mixture was stirred at 130.degree. C. for 15
h under N.sub.2 atmposphere. Work up (EtOAc/H2O) followed by column
purification on 60-120 mesh silica gel using a gradient mixture of
EtOAc and Petether (1:1) as eluent afforded
5-(4-benzylpiperazin-1-yl)-2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]o-
xazole (250 mg) as a yellow solid.
5-(4-Benzylpiperazin-1-yl)-2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]o-
xazole (130 mg, 0.28 mmol) dissolved in DCM (15 ml) and added
isopropylchloro formate (102 mg, 0.84 mmol). This mixture was
stirred at reflux for 18 h. Work up (DCM/H.sub.2O) followed by
purification of the crude by column chromatography on 230-400 mesh
silica gel using a gradient mixture of EtOAc and Petether (30:70)
as eluent afforded the titled compound (25 mg) as a pale-yellow
solid. M.P.: 231-234.degree. C. .sup.1H-NMR (.delta. ppm,
CDCl.sub.3, 400 MHz): 8.28 (d, J 8.7, 1H), 7.96 (d, J 1.6, 1H),
7.68-7.64 (m, 2H), 7.57-7.47 (m, 2H), 4.95 (septet, J 6.2, 1H),
3.71-3.63 (m, 4H), 3.12-3.06 (m, 4H), 1.26 (d, J 6.2, 6H).
Example 86
Tert-butyl
4-{2-[4-(trifluoromethyl)phenyl]oxazolo[5,4-b]pyridin-6-yl}-5,6-
-dihydropyridine-1(2H)-carboxylate
[0444] Following the general procedure-1, the titled compound (230
mg) was obtained from intermediate 58 (500 mg, 1.28 mmol) and
tert-butyl
4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate
(467 mg, 1.4 mmol) as an off-white solid. M.P.: 207-212.degree. C.
.sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400 MHz): 8.44-8.38 (m, 3H),
8.04 (d, J 2.2, 1H), 7.82 (d, J 8.3, 2H), 6.13 (bs, 1H), 4.14 (d, J
2.6, 2H), 3.70 (t, J 5.6, 2H), 2.59 (bs, 2H), 1.50 (s, 9H).
Example 87
Tert-butyl
4-{2-[4-(trifluoromethyl)phenyl]oxazolo[5,4-b]pyridin-6-yl}pipe-
ridine-1-carboxylate
[0445] Tert-butyl
4-{2-[4-(trifluoromethyl)phenyl]oxazolo[5,4-b]pyridin-6-yl}-5,6-dihydropy-
ridine-1(2H)-carboxylate (170 mg, 0.38 mmol) was dissolved in
methanol (10 ml) and added Pd/C (5%) (283 mg). This mixture was
stirred under H.sub.2 pressure (6.5 kg) for 12 h. Combined methanol
fractions were evaporated on rotavapour to obtain the crude. Crude
was purified on combiflash using a gradient mixture of EtOAc and
Petether (1:9) as eluent to afford the titled compound (35 mg) as a
white solid. M. P.: 184-188.degree. C. .sup.1H-NMR (.delta. ppm,
CDCl.sub.3, 400 MHz): 8.40 (d, J 8.1, 2H), 8.27 (d, J 2, 1H), 7.93
(d, J 2, 1H), 7.81 (d, J 8.3, 2H), 4.31 (d, J 13.5, 2H), 2.91-2.81
(m, 3H), 1.91 (d, J 12.9, 2H), 1.78-1.62 (m, 2H), 1.50 (s, 9H).
Biological Assay
[0446] The biological properties of the compounds of this invention
may be confirmed by a number of biological assays. The biological
assays which can be been carried out with the compounds of the
invention are exemplified below.
A. In Vitro Cyclic AMP Assay:
[0447] cAMP measurements were done using a Cisbio dynamic 2 HTRF
kit (Cisbio, Bedford, Mass.) according to the manufacturer's
protocol. Briefly, HEK293 cells (0.2.times.10.sup.6/well) were
plated in a 24 well plate and incubated overnight at 37.degree. C.
Cells were transfected with either empty vector DNA or human GPR119
expression plasmid DNA using Lipofectamine 2000 (Invitrogen). After
24 h, transfected cells were harvested, counted and plated at 1000
cells/5 ul in a black 384 welled small volume plate. Cells were
treated with desired concentrations of compounds and incubated for
60 min at room temperature. Lysis buffer containing cAMP-d2 and
cryptate conjugate were added and incubated for 1 h. HRTF ratio was
measured on a microplate reader (BMG Labtech, Germany) at an
excitation wavelength of 337 nm and emission wavelengths of 665 and
620 nm with an integration time of 400 .mu.sec. Data were analyzed
using Graphpad Prism (Graphpad software; San Diego Calif.) for
EC.sub.50 determination.
Results:
[0448] The results are as given in Table I as % Induction@ 10 tiM,
Table II as % Induction@ 10 tiM and EC 50 in nM
B. In Vitro Mouse GPR 119 Cyclic AMP Assay:
[0449] cAMP measurements were done using a Cisbio dynamic 2 HTRF
kit (Cisbio, Bedford, Mass.) according to the manufacturer's
protocol. HEK293 Cells were stably transfected with Mouse GPR119
expression plasmid DNA using Lipofectamine 2000 (Invitrogen) and
maintained in culture. Cells were harvested, counted and plated at
1000 cells/5 ul in a black 384 welled small volume plate. Cells
were treated with desired concentrations of compounds and incubated
for 60 min at room temperature. Lysis buffer containing cAMP-d2 and
cryptate conjugate were added and incubated for 1 h. HRTF ratio was
measured on a microplate reader (BMG Labtech, Germany) at an
excitation wavelength of 337 nm and emission wavelengths of 665 and
615 nm with an integration time of 400 .mu.sec. Data were analyzed
using Graphpad Prism (Graphpad software; San Diego Calif.) for
EC.sub.50 determination. For example example 12 showed an EC 50 of
<25 nM
C. In Vitro HIT-T15 Cyclic AMP Assay:
[0450] cAMP measurements were done using a Cisbio dynamic 2 HTRF
kit (Cisbio, Bedford, Mass.) according to the manufacturer's
protocol. Briefly, HIT-T15 cells were harvested, counted and plated
at 4000 cells/5 ul PBS-BSA solution in a black 384 welled small
volume plate. Cells were treated with desired concentrations of
compounds and incubated for 60 min at room temperature. Lysis
buffer containing cAMP-d2 and cryptate conjugate were added and
incubated for 1 h. HRTF ratio was measured on a microplate reader
(BMG Labtech, Germany) at an excitation wavelength of 337 nm and
emission wavelengths of 665 and 615 nm with an integration time of
400 .mu.sec. Data were analyzed using Graphpad Prism (Graphpad
software; San Diego Calif.) for EC.sub.50 determination. For
instance example 12 showed an EC 50 of <25 nM
D. In Vitro HIT-T15 Insulin Assay:
[0451] Insulin measurements were done using a Ultra Sensitive
Insulin ELISA kit (Crystal Chem Inc, USA) according to the
manufacturer's protocol. Briefly, 2.5.times.10.sup.5 HIT-15
cells/well were plated in 24 well plate and incubator for 24 hours.
Next day, media was replaced with DMEM-3 mM Glucose with 10% Horse
Serum, 2.5% FBS, 1% pen-strep and further incubated for 24 h. Cells
were treated with desired concentrations of compounds and incubated
for 60 min at room temperature. Supernatant was collected,
centrifuged and soup added to the pre-coated strips followed by
ELISA. The absorbance was measured at 450 and 630 nM. Data were
analyzed using Granhnad Prism (Granhnad software; San Diego Calif.)
for EC.sub.50 determination.
TABLE-US-00004 TABLE I COMPOUND Induction EC50* EXAMPLE-1 55.35 ND
EXAMPLE-2 35.78 ND EXAMPLE-3 35.44 ND EXAMPLE-4 74.19 A EXAMPLE-5
40.98 ND EXAMPLE-6 73.22 A+ EXAMPLE-7 62.63 A EXAMPLE-8 66.72 A+
EXAMPLE-9 46.83 ND EXAMPLE-10 59.24 C EXAMPLE-11 70.09 ND
EXAMPLE-12 82.95 A++ EXAMPLE-13 68.17 B EXAMPLE-14 68.59 A+
EXAMPLE-15 77.69 B EXAMPLE-16 43.71 ND EXAMPLE-17 41.47 ND
EXAMPLE-18 36.44 ND EXAMPLE-19 37.17 ND EXAMPLE-20 73.88 A+
EXAMPLE-21 59.02 A EXAMPLE-22 64.55 ND EXAMPLE-23 69.56 A+
EXAMPLE-24 67.48 A++ EXAMPLE-25 63.39 ND EXAMPLE-26 73.99 ND
EXAMPLE-27 46.54 ND EXAMPLE-28 45.37 ND EXAMPLE-29 78.62 A+
EXAMPLE-30 62.20 C EXAMPLE-31 80.38 A++ EXAMPLE-32 63.93 A
EXAMPLE-33 10.61 ND EXAMPLE-34 -- ND EXAMPLE-35 0.28 ND EXAMPLE-36
4.83 ND EXAMPLE-37 6.56 ND EXAMPLE-38 16.59 ND EXAMPLE-39 27.49 ND
EXAMPLE-40 21.87 ND EXAMPLE-41 -- ND EXAMPLE-42 78.40 A+ EXAMPLE-43
48.77 ND EXAMPLE-44 64.79 A+ EXAMPLE-45 56.43 ND EXAMPLE-46 53.02
ND EXAMPLE-47 33.13 ND EXAMPLE-48 26.66 ND EXAMPLE-49 32.86 ND
EXAMPLE-50 38.68 ND EXAMPLE-51 38.73 ND EXAMPLE-52 68.36 B
EXAMPLE-53 39.87 ND ND: Not done; A++: .ltoreq.25 nM; A+: >25 to
.ltoreq.50 nM; A: >50 to .ltoreq.100 nM; B: >100 to
.ltoreq.500 nM; C: >500 to .ltoreq.1000 nM; *Emax varies between
65 to 80%.
TABLE-US-00005 TABLE II COMPOUND Induction EC50* EXAMPLE-56 38.53
ND EXAMPLE-57 47.05 ND EXAMPLE-58 32.25 ND EXAMPLE-59 63.76 ND
EXAMPLE-60 72.78 A+ EXAMPLE-61 29.77 ND EXAMPLE-62 59.34 B
EXAMPLE-63 56.57 ND EXAMPLE-64 75.03 A++ EXAMPLE-65 32.09 ND
EXAMPLE-66 18.89 ND EXAMPLE-67 73.03 A+ EXAMPLE-68 72.69 ND
EXAMPLE-69 71.83 A+ EXAMPLE-70 64.66 A++ EXAMPLE-71 76.63 A++
EXAMPLE-72 81.57 A++ EXAMPLE-73 46.02 C EXAMPLE-74 14.69 ND
EXAMPLE-75 57.49 ND EXAMPLE-76 74.90 A EXAMPLE-77 80.37 A
EXAMPLE-78 59.36 ND EXAMPLE-79 46.17 ND EXAMPLE-80 26.39 ND
EXAMPLE-81 42.96 ND EXAMPLE-82 ND ND EXAMPLE-83 57.64 ND EXAMPLE-84
13.17 ND EXAMPLE-85 ND ND EXAMPLE-86 ND ND EXAMPLE-87 47.29 ND ND:
Not done; ; A++: .ltoreq.25 nM; A+: >25 to .ltoreq.50 nM; A:
>50 & <250 nM; B: <500 nM; C: >500 to .ltoreq.1000
nM; *Emax varies between 65 to 80%.
E: Oral Glucose Tolerance Test (OGTT) in C57Bl/6J Mice:
[0452] Results of the OGTT not only diagnose diabetes but can
determine if a subject has impaired fasting glucose (IFG) or
impaired glucose tolerance (IGT). Having either of these conditions
indicates a significantly increased risk of developing diabetes in
the future.
[0453] After the quarantine period, 6 hr fasted animals were
randomized and divided into various groups depending on their blood
glucose levels. Test compounds or standard drug (sitagliptin) was
prepared as a suspension in a vehicle consisting of 0.5%
methylcellulose and Tween 80 as a suspending agent. The standard
drug, Compound A (example-64), Compound B (example-42) or vehicle
were administered by oral gavage in a volume of 10 mL/kg. 1 h after
the test compounds, standard drug and vehicle administration, blood
was sampled from the tail vein of mice at time 0 min (baseline) and
at 30, 60, 90 and 120 min after an oral glucose load of 2.0 g/kg of
body weight. Food, but not water, was withheld from the cages
during the course of experiment. The area under curve (AUC) of
experimental animals was compared with that of vehicle-treated
control group. The results are shown in FIGS. 1 and 2 and are
discussed below.
[0454] Results:
[0455] Compound A and Sitagliptin dosed as single agents lowered
AUC.sub.oucose by 24% and 59%, respectively, and Compound B and
sitagliptin dosed as single agents lowered AUC.sub.oucose by 22 and
50%, respectively.
F: Intraperitoneal Glucose Tolerance Test (IPGTT) in C57Bl/6J
Mice:
[0456] After the quarantine period, 6 hr fasted animals are to be
randomized and divided into various groups depending on their blood
glucose levels. Test compound or standard drug is to be prepared as
a suspension in a vehicle consisting of 0.5% methylcellulose in
which Tween 80 as a suspending agent. The compound or vehicle is to
be administered by oral gavage in a volume of 10 mL/kg. 1 h after
drug or vehicle administration, blood is to be sampled from the
tail vein of mice at time 0 min (baseline) and at 30, 60, 90 and
120 min after intraperitoneal administration of glucose solution of
2.0 g/kg of body weight. Food, but not water is to be withheld from
the cages during the course of experiment. The area under curve
(AUC) of experimental animals will be compared with that of
vehicle-treated control group.
G: Oral Glucose Tolerance Test (OGTT) in Streptozotocin &
Nicotinamide Induced Type 2 Diabetes in CD-1 Mice:
[0457] After the quarantine period, animals are to be randomized
and divided into various groups depending on their body weights and
animals are to be administered with nicotinamide (100 mg/kg) and
streptozotocin (150 mg/kg) by intraperitoneally to induce diabetes.
Sham control mice are to be intraperitoneally administered with
physiological saline. Two weeks later, the diabetic mice were
grouped to provide similar mean non-fasting blood glucose levels in
each group, 6 hr fasted animals are to be randomized and divided
into various groups depending on their blood glucose levels. Test
compound or standard drug is to be prepared as a suspension in a
vehicle consisting of 0.5% methylcellulose in which Tween 80 as a
suspending agent. The compound or vehicle is to be administered by
oral gavage in a volume of 10 mL/kg. 1 h after drug or vehicle
administration, blood is to be sampled from the tail vein of mice
at time 0 min (baseline) and at 30, 60, 90 and 120 min after an
oral glucose load of 2.0 g/kg of body weight. Food, but not water
is to be withheld from the cages during the course of experiment.
The area under curve (AUC) of experimental animals will be compared
with that of vehicle-treated control group.
H: Sub-Acute Treatment of Test Compound in Streptozotocin &
Nicotinamide Induced Type 2 Diabetes in CD-1 Mice:
[0458] After the quarantine period, animals are to be randomized
and divided into various groups depending on their body weights and
animals are to be administered with nicotinamide (100 mg/kg) and
streptozotocin (150 mg/kg) by intraperitoneally to induce diabetes.
Sham control mice are to be intraperitoneally administered with
physiological saline. Two weeks later, the diabetic mice are to be
grouped to provide similar mean non-fasting blood glucose levels in
each group, on day 0, fasted animals are to be randomized and
divided into various groups depending on their blood glucose
levels. Test compound or standard drug is to be prepared as a
suspension in a vehicle consisting of 0.5% methylcellulose in which
Tween 80 as a suspending agent. The compound or vehicle is to be
administered by oral gavage in a volume of 10 mL/kg. 1 h after drug
or vehicle administration, blood is to be sampled from the tail
vein of mice at time 0 min (baseline) and at 30, 60, 90 and 120 min
after an oral glucose load of 2.0 g/kg of body weight. Food, but
not water is to be withheld from the cages during the course of
experiment. The area under curve (AUC) of experimental animals will
be compared with that of vehicle-treated control group. After
conducting the OGTT on day 0, the treatment will be continued for
14 days, on day 14, 6 hr fasted animals will be used for the same
OGTT procedure. After conducting the OGTT, blood samples will be
collected from the animals and analysed for the lipid profile,
insulin, and GLP-1 levels.
[0459] Although the invention herein has been described with
reference to particular embodiments, it is to be understood that
these embodiments are merely illustrative of the principles and
applications of the present invention. It is therefore to be
understood that numerous modifications may be made to the
illustrative embodiments and that other arrangements may be devised
without departing from the spirit and scope of the present
invention as described above.
[0460] All publications and patent and/or patent applications cited
in this application are herein incorporated by reference to the
same extent as if each individual publication or patent application
was specifically and individually indicated to be incorporated
herein by reference.
* * * * *
References