U.S. patent application number 14/534909 was filed with the patent office on 2015-05-14 for novel 3,5-disubstituted-3h-imidazo[4,5-b]pyridine and 3,5-disubstituted -3h-[1,2,3]triazolo[4,5-b] pyridine compounds as modulators of protein kinases.
The applicant listed for this patent is Incozen Therapeutics Pvt. Ltd., Rhizen Pharmaceuticals SA. Invention is credited to Govindarajulu Babu, Meyyappan MUTHUPPALANIAPPAN, Swaroop K. Vakkalanka, Srikant Viswanadha.
Application Number | 20150133449 14/534909 |
Document ID | / |
Family ID | 44315015 |
Filed Date | 2015-05-14 |
United States Patent
Application |
20150133449 |
Kind Code |
A1 |
MUTHUPPALANIAPPAN; Meyyappan ;
et al. |
May 14, 2015 |
NOVEL 3,5-DISUBSTITUTED-3H-IMIDAZO[4,5-B]PYRIDINE AND
3,5-DISUBSTITUTED -3H-[1,2,3]TRIAZOLO[4,5-B] PYRIDINE COMPOUNDS AS
MODULATORS OF PROTEIN KINASES
Abstract
The present invention provides, inter alia, compounds of formula
I as protein kinase modulators, methods of preparing them,
pharmaceutical compositions containing them and methods of
treatment, prevention and/or amelioration of kinase mediated
diseases or disorders with them.
Inventors: |
MUTHUPPALANIAPPAN; Meyyappan;
(Hyderabad, IN) ; Viswanadha; Srikant; (Hyderabad,
IN) ; Babu; Govindarajulu; (Hyderabad, IN) ;
Vakkalanka; Swaroop K.; (La Chaux-de- Fonds, CH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Incozen Therapeutics Pvt. Ltd.
Rhizen Pharmaceuticals SA |
Hyderabad
La Chaux-de-Fonds |
|
IN
CH |
|
|
Family ID: |
44315015 |
Appl. No.: |
14/534909 |
Filed: |
November 6, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13891961 |
May 10, 2013 |
8912331 |
|
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14534909 |
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13108642 |
May 16, 2011 |
8481739 |
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13891961 |
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Current U.S.
Class: |
514/234.2 ;
435/375; 514/253.06; 514/274; 514/300; 514/303; 544/128; 544/315;
544/363; 546/117; 546/118 |
Current CPC
Class: |
A61P 9/10 20180101; A61P
43/00 20180101; A61P 35/00 20180101; A61P 37/08 20180101; A61K
31/4709 20130101; A61K 31/496 20130101; G01N 33/5011 20130101; A61K
31/5377 20130101; A61P 17/06 20180101; A61P 37/00 20180101; A61P
35/02 20180101; C07D 471/04 20130101; A61K 31/506 20130101; A61P
9/00 20180101; Y02A 50/30 20180101; A61K 31/437 20130101; A61P
29/00 20180101; A61P 35/04 20180101; A61P 1/16 20180101; A61P 13/12
20180101; A61P 27/02 20180101; G01N 2500/10 20130101; A61P 37/02
20180101; A61P 37/06 20180101; A61K 45/06 20130101 |
Class at
Publication: |
514/234.2 ;
546/117; 514/300; 544/363; 514/253.06; 544/128; 546/118; 514/303;
544/315; 514/274; 435/375 |
International
Class: |
C07D 471/04 20060101
C07D471/04; A61K 31/506 20060101 A61K031/506; A61K 31/496 20060101
A61K031/496; A61K 31/5377 20060101 A61K031/5377; A61K 31/437
20060101 A61K031/437; A61K 45/06 20060101 A61K045/06 |
Foreign Application Data
Date |
Code |
Application Number |
May 17, 2010 |
IN |
1377/CHE/2010 |
Claims
1. A compound of the formula ##STR00314## or a tautomer,
stereoisomer, enantiomer, diastereomer, salt, prodrug, or N-oxide
thereof, wherein R.sup.2 is hydrogen, nitro, hydroxy, cyano,
halogen, --OR.sup.a, --S(.dbd.O).sub.q--R.sup.a, --NR.sup.aR.sup.b,
--C(.dbd.O)--R.sup.a, or --C(.dbd.O)--R.sup.a, wherein R.sup.a and
R.sup.b in the R.sup.2 group are independently hydrogen, hydroxy,
or substituted or unsubstituted C.sub.1-6 alkyl; X is CR.sup.1 or
N; Cy.sup.1 and Cy.sup.2 may be same or different and are
independently selected from substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclic group,
substituted or unsubstituted aryl, and substituted or unsubstituted
heteroaryl; wherein (i) when X is N, then Cy.sup.1 is other than
phenyl substituted with one to five substituents selected from
halogen, substituted or unsubstituted alkyl, and CONR.sup.xR.sup.y;
and (ii) when X is CR.sup.1 or N, then L.sub.2-Cy.sup.2 is other
than ##STR00315## wherein Z is selected from CR.sup.c, S, O,
NR.sup.c, R.sup.cC.dbd.CR.sup.c, --N.dbd.CR.sup.c-, and
--R.sup.cC.dbd.N--; and Z.sub.1 is selected from N, NR.sup.c and
CR.sup.c; L.sub.2 is selected from --O--, --S(.dbd.O).sub.q--,
--NR.sup.a--, --(CR.sup.aR.sup.b).sub.n--, --C(.dbd.Y)--,
--C(.dbd.Y)--C(.dbd.Y)--,
--CR.sup.aR.sup.b--C(.dbd.Y)--CR.sup.aR.sup.b--,
--CR.sup.aR.sup.b--Y--CR.sup.aR.sup.b, --C(.dbd.Y)--NR.sup.a,
--NR.sup.a--C(.dbd.Y)--NR.sup.a, --S(.dbd.O).sub.q--NR.sup.a,
--NR.sup.a--S(.dbd.O).sub.q--NR.sup.a, --NR.sup.a--NR.sup.a--,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted cycloalkyl, and substituted or unsubstituted
heterocyclyl; R.sup.1 is selected from hydrogen, nitro, hydroxy,
cyano, halogen, --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--, 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; 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 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; each occurrence of n
independently represents 0, 1, 2, 3 or 4; and each occurrence of q
independently represents 0, 1 or 2.
2. A compound of claim 1, wherein Cy.sup.1 is substituted or
unsubstituted aryl or substituted or unsubstituted heteroaryl.
3. A compound of claim 1, wherein Cy.sup.1 is selected from
##STR00316## ##STR00317## ##STR00318## ##STR00319## ##STR00320##
##STR00321## ##STR00322## ##STR00323## ##STR00324## ##STR00325##
##STR00326## ##STR00327## ##STR00328## ##STR00329## ##STR00330##
##STR00331## ##STR00332## ##STR00333## ##STR00334## ##STR00335##
##STR00336## ##STR00337## ##STR00338## ##STR00339## ##STR00340##
##STR00341## ##STR00342## ##STR00343## ##STR00344##
4. A compound of claim 1, wherein the compound has the formula
##STR00345## or a tautomer, stereoisomer, enantiomer, diastereomer,
salt, prodrug, or N-oxide thereof, wherein D is substituted or
unsubstituted monocyclic aryl or substituted or unsubstituted
monocyclic heteroaryl; each occurrence of R.sup.2 is independently
hydrogen, nitro, hydroxy, cyano, halogen, --OR.sup.a,
--S(.dbd.O).sub.q--R.sup.a, --NR.sup.aR.sup.b,
--C(.dbd.O)--R.sup.a, --C(.dbd.O)--R.sup.a, wherein R.sup.a and
R.sup.b in the R.sup.2 group are independently hydrogen, hydroxy,
or substituted or unsubstituted C.sub.1-6 alkyl; L.sub.2 is
--CR.sup.aR.sup.b--; and X, Cy.sup.2, R.sup.a, R.sup.b, and q are
as defined in claim 1.
5. A compound of claim 4, wherein, D is substituted with one to
five substituents selected from halogen, substituted or
unsubstituted alkyl, substituted or unsubstituted alkoxy,
--COR.sup.x, --CONR.sup.xR.sup.y, --S(O).sub.qNR.sup.xR.sup.y or
--NR.sup.xR.sup.y, wherein each occurrence of R.sup.x and R.sup.y
is independently 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 heterocycyl, substituted or
unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
heteroarylalkyl, --COOR.sup.z, --C(O)R.sup.z, --C(S)R.sup.z,
--C(O)NR.sup.zR, --C(O)ONR.sup.zR.sup.z, --NR.sup.zR.sup.z,
--NR.sup.zCONR.sup.zR.sup.z, --N(R.sup.z)SOR.sup.z,
--N(R.sup.z)SO.sub.2R.sup.z, --(.dbd.N--N(R.sup.z)R.sup.z),
--NR.sup.zC(O)OR.sup.z, --NR.sup.zC(O)R.sup.z--,
--NR.sup.zC(S)R.sup.y--NR.sup.zC(S)NR.sup.zR.sup.z,
--SONR.sup.zR.sup.z--, --SO.sub.2NR.sup.zR.sup.z--, --OR.sup.z,
--OR.sup.zC(O)NR.sup.zR.sup.z, --OR.sup.zC(O)OR.sup.z--,
--OC(O)R.sup.z, --OC(O)NR.sup.zR.sup.z,
--R.sup.zNR.sup.zC(O)R.sup.z, --R.sup.zOR.sup.z,
--R.sup.zC(O)OR.sup.z, --R.sup.zC(O)NR.sup.zR.sup.z,
--R.sup.zC(O)R.sup.z, --R.sup.zC(O)R.sup.z, --SR.sup.z,
--SOR.sup.z, --SO.sub.2R.sup.z, and --ONO.sub.2, or any two of
R.sup.x and R.sup.y 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.sup.z or S, or (ii) an oxo (.dbd.O), thio
(.dbd.S) or imino (.dbd.NR.sup.z); each occurrence of R.sup.z 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 heterocycyl, 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.z 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.sup.z); and q in the group D is 0, 1 or 2.
6. A compound of claim 4, wherein D is selected from ##STR00346##
##STR00347## ##STR00348## ##STR00349## ##STR00350## ##STR00351##
##STR00352## ##STR00353## ##STR00354## ##STR00355## ##STR00356##
##STR00357## ##STR00358## ##STR00359## ##STR00360## ##STR00361##
##STR00362## ##STR00363## ##STR00364## ##STR00365## ##STR00366##
##STR00367## ##STR00368## ##STR00369## ##STR00370## ##STR00371##
##STR00372## ##STR00373## ##STR00374## ##STR00375##
7. A compound of the formula ##STR00376## or a tautomer,
stereoisomer, enantiomer, diastereomer, salt, prodrug, or N-oxide
thereof, wherein X is CR.sup.1 or N; Cy.sup.2 is selected from
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocyclic group, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl; L.sub.2 is
selected from --(CR.sup.aR.sup.b).sub.n--, --O--,
--S(.dbd.O).sub.q--, --NR.sup.a--, --(CR.sup.aR.sup.b).sub.n--,
--C(.dbd.Y)--, --C(.dbd.Y)--C(.dbd.Y)--,
--CR.sup.aR.sup.b--C(.dbd.Y)--CR.sup.aR.sup.b--,
--CR.sup.aR.sup.b--Y--CR.sup.aR.sup.b--, --C(.dbd.Y)--NR.sup.a,
--NR.sup.a--C(.dbd.Y)--NR.sup.a--, --S(.dbd.O).sub.q--NR.sup.a--,
--NR.sup.a--S(.dbd.O).sub.q--NR.sup.a--, --NR.sup.a--NR.sup.a--,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted cycloalkyl, and substituted or unsubstituted
heterocyclyl; wherein L.sub.2-Cy.sup.2 is other than ##STR00377##
wherein Z is selected from CR.sup.c, S, O, NR.sup.c,
R.sup.cC.dbd.CR.sup.c, --N.dbd.CR.sup.c--, --R.sup.cC.dbd.N--; and
Z.sub.1 is selected from N, NR.sup.c and CR.sup.c wherein R.sup.c
is absent or selected from hydrogen, hydroxy and halogen; each
occurrence of R.sup.1 and R.sup.2 may be same or different and is
independently selected from hydrogen, nitro, hydroxy, cyano,
halogen, --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--, 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.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 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 (where each occurrence of R.sup.c here
independently refers to 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); R.sup.c
and R.sup.d together with the nitrogen to which they are attached
form 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.e or
S; R.sup.e 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 cycloalkylalkyl, substituted or unsubstituted
cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl,
substituted or unsubstituted heterocyclic ring, substituted or
unsubstitituted heterocycylalkyl ring, substituted or unsubstituted
aryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
heteroarylalkyl, substituted or unsubstituted guanidine,
--COOR.sup.x, --C(O)R.sup.x, --C(S)R.sup.x, --C(O)NR.sup.xR.sup.y,
--C(O)ONR.sup.xR.sup.y, NR.sup.yR.sup.z,
--NR.sup.xCONR.sup.yR.sup.z, --N(R.sup.x)SOR.sup.y,
--N(R.sup.x)SO.sub.2R.sup.y, --(.dbd.N--N(R.sup.x)R.sup.y),
--NR.sup.xC(O)OR.sup.y, --NR.sup.xR.sup.y, --NR.sup.xC(O)R.sup.y--,
--NR.sup.xC(S)R.sup.y, --NR.sup.xC(S)NR.sup.yR.sup.z,
--SONR.sup.xR.sup.y--, --SO.sub.2NR.sup.xR.sup.y--, --OR.sup.x,
--OR.sup.xC(O)NR.sup.yR.sup.z, --OR.sup.xC(O)OR.sup.y--,
--OC(O)R.sup.x, --OC(O)NR.sup.xR.sup.y,
--R.sup.xNR.sup.yC(O)R.sup.z, --R.sup.xOR.sup.y,
--R.sup.xC(O)OR.sup.y, --R.sup.xC(O)NR.sup.yR.sup.z,
--R.sup.xC(O)R.sup.x, --R.sup.xC(O)R.sup.y, --SR.sup.x,
--SOR.sup.x, --SO.sub.2R.sup.x, and --ONO.sub.2, wherein each
occurrence of R.sup.x, R.sup.y and R.sup.z is independently
hydrogen, substituted or unsubstituted amino, substituted or
unsubstituted alkyl, substituted or unsubstituted alkoxy,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkylalkyl, substituted or unsubstituted
cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl,
substituted or unsubstituted heterocyclic ring, substituted or
unsubstituted heterocyclylalkyl ring, substituted or unsubstituted
aryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, and substituted or unsubstituted
heteroarylalkyl, or any two of R.sup.x, R.sup.y and R.sup.z which
are directly bound to a common atom may be joined to form (i) an
oxo (C.dbd.O), thio (C.dbd.S) or imino (C.dbd.NR') group (where R'
is H or alkyl) or (ii) substituted or unsubstituted, saturated or
unsaturated 3-10 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; 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.
8. A compound of claim 7, wherein NR.sup.cR.sup.d is selected from
##STR00378## wherein each occurrence of R.sup.x and R.sup.y is
independently selected from hydrogen, substituted or unsubstituted
alkyl, substituted or unsubstituted alkoxy, or any two of R.sup.x
and R.sup.y which are directly bound to a common atom may be joined
to form an oxo (C.dbd.O), thio (C.dbd.S) or imino (C.dbd.NR') group
(where R' is H or alkyl), or any two of R.sup.x and R.sup.y may be
joined to form a substituted or unsubstituted, saturated or
unsaturated 3-6 membered ring, which may optionally include
heteroatoms which may be the same or different and are selected
from O, NR' (where R' is H or alkyl) or S.
9. A compound of claim 8, wherein NR.sup.cR.sup.d is selected from
##STR00379##
10. A compound of the formula ##STR00380## or a tautomer,
stereoisomer, enantiomer, diastereomer, salt, prodrug, or N-oxide
thereof, wherein X is CR.sup.1 or N; U and V are each independently
selected from CR.sup.3 or N; W is selected from O, S, or NR.sup.4;
each occurrence of R.sup.1 and R.sup.2 may be same or different and
is independently selected from hydrogen, nitro, hydroxy, cyano,
halogen, --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--, 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; R.sup.4 is selected from hydrogen, hydroxy,
carboxyl, cyano, 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 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.3 is independently hydrogen, halogen, cyano
(CN), --OR.sup.c, --S(.dbd.O).sub.q--R.sup.c, --NR.sup.cR.sup.d,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted C.sub.3-6 cycloalkyl, substituted or unsubstituted
C.sub.3-6 cycloalkylalkyl, or substituted or unsubstituted
C.sub.3-6 cycloalkenyl; 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 cycloalkylalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
heterocyclic ring, substituted or unsubstituted heterocyclylalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
arylalkyl, substituted or unsubstituted heteroaryl, substituted or
unsubstituted heteroarylalkyl, substituted or unsubstituted
guanidine, --COOR.sup.x, --C(O)R.sup.x, --C(S)R.sup.x,
--C(O)NR.sup.xR.sup.y, --C(O)ONR.sup.xR.sup.y, --NR.sup.xR.sup.y,
--NR.sup.xCONR.sup.yR.sup.z, --N(R.sup.x)SOR.sup.y,
--N(R.sup.x)SO.sub.2R.sup.y, --(.dbd.N--N(R.sup.x)R.sup.y),
--NR.sup.xC(O)OR.sup.y, --NR.sup.xC(O)R.sup.y--,
--NR.sup.xC(S)R.sup.y--NR.sup.xC(S)NR.sup.yR.sup.z,
--SONR.sup.xR.sup.y--, --SO.sub.2NR.sup.xR.sup.y--, --OR.sup.x,
--OC(O)OR.sup.y--, --OC(O)R.sup.x, --OC(O)NR.sup.xR.sup.y,
--R.sup.xNR.sup.yC(O)R.sup.z, --R.sup.xOR.sup.y,
--R.sup.xC(O)OR.sup.y, --R.sup.xC(O)NR.sup.yR.sup.z,
--R.sup.xC(O)R.sup.x, --R.sup.xOC(O)R.sup.y, --SR.sup.x,
--SOR.sup.x, --SO.sub.2R.sup.x, and --ONO.sub.2; or optionally when
W is NR.sup.4, R.sup.4 and R.sup.5 together with the nitrogen to
which they are attached form 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.e or S; Cy.sup.2 is selected from
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocyclic group, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl; L.sub.2 is
selected from --O--, --S(.dbd.O).sub.q--, --NR.sup.a--,
--(CR.sup.aR.sup.b).sub.n--, --C(.dbd.Y)--,
--C(.dbd.Y)--C(.dbd.Y)--,
--CR.sup.aR.sup.b--C(.dbd.Y)--CR.sup.aR.sup.b--,
--CR.sup.aR.sup.b--Y--CR.sup.aR.sup.b, --C(.dbd.Y)--NR.sup.a,
--NR.sup.a--C(.dbd.Y)--NR.sup.a, --S(.dbd.O).sub.q--NR.sup.a--,
--NR.sup.a--S(.dbd.O).sub.q--NR.sup.a--, --NR.sup.a--NR.sup.a--,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted cycloalkyl, and substituted or unsubstituted
heterocyclyl; wherein L.sub.2-Cy.sup.2 is other than ##STR00381##
wherein Z is selected from CR.sup.c, S, O, NR.sup.c,
R.sup.cC.dbd.CR.sup.c, --N.dbd.CR.sup.c--, --R.sup.cC.dbd.N--; and
Z.sub.1 is selected from N, NR.sup.c or CR.sup.c; 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 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, R.sup.d, and R.sup.e are independently 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 cycloalkylalkyl,
substituted or unsubstituted cycloalkenyl, substituted or
unsubstituted cycloalkenylalkyl, substituted or unsubstituted
heterocyclic ring, substituted or unsubstitituted heterocycylalkyl
ring, substituted or unsubstituted aryl, substituted or
unsubstituted arylalkyl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted heteroarylalkyl, substituted or
unsubstituted guanidine, --COOR.sup.x, --C(O)R.sup.x,
--C(S)R.sup.x, --C(O)NR.sup.xR.sup.y, --C(O)ONR.sup.xR.sup.y,
--NR.sup.yR.sup.z, --NR.sup.xCONR.sup.yR.sup.z,
--N(R.sup.x)SOR.sup.y, --N(R.sup.x)SO.sub.2R.sup.y,
--(.dbd.N--N(R.sup.x)R.sup.y), --NR.sup.xC(O)OR.sup.y,
--NR.sup.xR.sup.y, --NR.sup.xC(O)R.sup.y--, --NR.sup.xC(S)R.sup.y,
--NR.sup.xC(S)NR.sup.yR.sup.z, --SONR.sup.xR.sup.y--,
--SO.sub.2NR.sup.xR.sup.y--, --OR.sup.x, --OC(O)OR.sup.y,
--OC(O)R.sup.x, --OC(O)NR.sup.xR.sup.y,
--R.sup.xNR.sup.yC(O)R.sup.z, --R.sup.xOR.sup.y,
--R.sup.xC(O)OR.sup.y, --R.sup.xC(O)NR.sup.yR.sup.z,
--R.sup.xC(O)R.sup.x, --R.sup.xOC(O)R.sup.y, --SR.sup.x,
--SOR.sup.x, --SO.sub.2R.sup.x, and --ONO.sub.2; each occurrence of
R.sup.x, R.sup.y and R.sup.z is independently hydrogen, substituted
or unsubstituted amino, substituted or unsubstituted alkyl,
substituted or unsubstituted alkoxy, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
cycloalkylalkyl, substituted or unsubstituted cycloalkenyl,
substituted or unsubstituted cycloalkenylalkyl, substituted or
unsubstituted heterocyclic ring, substituted or unsubstituted
heterocyclylalkyl ring, substituted or unsubstituted aryl,
substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, and substituted or unsubstituted
heteroarylalkyl, or any two of R.sup.x, R.sup.y and R.sup.z which
are directly bound to a common atom may be joined to form (i) an
oxo (C.dbd.O), thio (C.dbd.S) or imino (C.dbd.NR') group (where R'
is H or alkyl) or (ii) substituted or unsubstituted, saturated or
unsaturated 3-10 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; each occurrence
of Y is independently selected from O, S, and NR.sup.a; each
occurrence of n independently represents 0, 1, 2, 3 or 4; and each
occurrence of q independently represents 0, 1 or 2.
11. A compound of claim 10, wherein U is CR.sup.3.
12. A compound of claim 10, wherein V is N.
13. A compound of claim 10, wherein W is O or NR.sup.4.
14. A compound of claim 10, wherein --U.dbd.V--W--R.sup.5 is
selected from ##STR00382##
15. A compound of claim 10, wherein the compound has the formula
##STR00383## wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5, X, L.sup.2
and Cy.sup.2 are as defined in claim 10.
16. A compound of claim 15, wherein --CR.sup.3.dbd.N--O--R.sup.5 is
selected from ##STR00384##
17. A compound of claim 15, wherein
--CR.sup.3.dbd.N--NR.sup.4R.sup.5 is selected from ##STR00385##
18. A compound of claim 1, wherein X is CR.sup.1.
19. A compound of claim 1, wherein X is N.
20. A compound of claim 1, wherein R.sup.1 is H.
21. A compound of claim 1, wherein each occurrence of R.sup.2 is
H.
22. A compound of claim 1, wherein L.sub.2 is
--CR.sup.aCR.sup.b--.
23. A compound of claim 22, wherein L.sub.2 is --CH.sub.2--,
--CH(OH)--, --CHF--, --CF.sub.2--, --CH(CH.sub.3)-- or
--C(CH.sub.3).sub.2--.
24. A compound of claim 22, wherein L.sub.2 is --CH.sub.2-- or
--CH(CH.sub.3)--.
25. A compound of claim 1, wherein Cy.sup.2 is substituted or
unsubstituted aryl or substituted or unsubstituted heteroaryl.
26. A compound of claim 25, wherein Cy.sup.2 is selected from
##STR00386## ##STR00387## ##STR00388## ##STR00389## ##STR00390##
##STR00391## ##STR00392## ##STR00393## ##STR00394## ##STR00395##
##STR00396##
27. A compound of claim 25, wherein Cy.sup.2 is selected from
##STR00397## ##STR00398## ##STR00399## ##STR00400##
28-66. (canceled)
67. A compound selected from
3-(4-Fluorobenzyl)-5-(1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridine,
3-(4-Fluorobenzyl)-5-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-
-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridine,
2-(4-(3-(4-Fluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-pyrazo-
l-1-yl) ethanol,
2-(4-(3-(2-Chloro-3,6-difluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5--
yl)-1H-pyrazol-1-yl) ethanol, tert-Butyl
4-(4-(3-(2-chloro-3,6-difluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5--
yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate,
3-(2-Chloro-3,6-difluorobenzyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-
-[1,2,3]triazolo[4,5-b]pyridine hydrochloride,
3-(2-Chloro-3,6-difluorobenzyl)-5-(1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,-
5-b]pyridine, and pharmaceutically acceptable salts thereof.
68. A compound selected from
3-(4-Fluorobenzyl)-5-(1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridine,
3-(4-Fluorobenzyl)-5-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-
-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridine,
2-(4-(3-(4-Fluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-pyrazo-
l-1-yl) ethanol,
2-(4-(3-(2-Chloro-3,6-difluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5--
yl)-1H-pyrazol-1-yl) ethanol, tert-Butyl
4-(4-(3-(2-chloro-3,6-difluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5--
yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate,
3-(2-Chloro-3,6-difluorobenzyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-
-[1,2,3]triazolo[4,5-b]pyridine hydrochloride,
3-(2-Chloro-3,6-difluorobenzyl)-5-(1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,-
5-b]pyridine,
2-Chloro-4-(3-(quinolin-6-ylmethyl)-3H-imidazo[4,5-b]pyridin-5-yl)benzami-
de, and pharmaceutically acceptable salts thereof.
69. A pharmaceutical composition, comprising a compound of claim 1
and a pharmaceutically acceptable carrier.
70. The pharmaceutical composition of claim 69, further comprising
one or more additional therapeutic agents and mixtures thereof.
71. The pharmaceutical composition of claim 70, wherein the one or
more additional therapeutic agent is an anti-cancer agent, an
anti-inflammatory agent, an immunosuppressive agent, a steroid, a
non-steroidal anti-inflammatory agent, an antihistamine, an
analgesic, or a mixture thereof.
72. A method of inhibiting the HGF/c-Met kinase signaling pathway
in a cell comprising contacting said cell with a compound of claim
1.
73. A method of inhibiting the proliferative activity of a cell
comprising contacting said cell with a compound of claim 1.
74. A method of inhibiting tumor growth in a patient comprising
administering to said patient a therapeutically effective amount of
a compound of claim 1.
75. A method of inhibiting tumor metastasis in a patient comprising
administering to said patient a therapeutically effective amount of
a compound of claim 1.
76. A method for the treatment of a c-Met associated disease or
disorder, comprising the step of administering to a subject in need
thereof an effective amount of compound of claim 1.
77. A method of claim 76, further comprising the step of
administering simultaneously or sequentially to a subject in need
thereof at least one other anti-cancer agent, anti-inflammatory
agent, immunosuppressive agent, steroid, non-steroidal
anti-inflammatory agent, antihistamine, analgesic, or a mixture
thereof.
78. A method of claim 76, wherein the c-Met associated disease,
disorder or condition is an immune system-related disease, a
disease or disorder involving inflammation, cancer or other
proliferative disease, a hepatic disease or disorder, or a renal
disease or disorder.
79. A method of treating a cancer in a patient comprising
administering to said patient a therapeutically effective amount of
a compound of claim 1.
80. The method of claim 79, wherein said cancer is a carcinoma,
musculoskeletal sarcoma, soft tissue sarcoma, or hematopoietic
malignancy.
81. The method of claim 80, wherein said cancer is carcinoma of the
bladder, carcinoma of the breast, carcinoma of the colon, carcinoma
of the kidney, carcinoma of the liver, carcinoma of the lung, small
cell lung cancer, esophageal cancer, gall bladder cancer, ovarian
cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid
cancer, prostate cancer, skin cancer, squamous cell carcinoma;
cholangiocarcinoma cancer, tumors of mesenchymal origin,
fibrosarcoma, rhabdomyosarcoma; tumors of the central and
peripheral nervous system, astrocytoma, neuroblastoma, glioma,
schwannoma; melanoma, seminoma, teratocarcinoma, osteosarcoma,
xenoderoma pigmento sum, keratoctanthoma, thyroid follicular cancer
and Kaposi's sarcoma, synovial sarcoma, rhabdomyosarcoma,
MFH/fibrosarcoma, leiomyosarcoma, multiple myeloma, lymphoma,
glioblastoma, astrocytoma, melanoma, mesothelioma, Wilm's tumor,
hematopoietic tumors of lymphoid lineage, leukemia, acute
lymphocytic leukemia, acute lymphoblastic leukemia, B-cell
lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkins
lymphoma, hairy cell lymphoma and Burkett's lymphoma; hematopoietic
tumors of myeloid lineage, acute myelogenous leukemias, chronic
myelogenous leukemias, myelodysplastic syndrome, or promyelocytic
leukemia.
82. A method of inhibiting the HGF/c-Met kinase signaling pathway
in a cell comprising contacting the cell with a compound of formula
##STR00401## or a tautomer, stereoisomer, enantiomer, diastereomer,
salt, prodrug, or N-oxide thereof, wherein X is N; Cy.sup.2 is
selected from substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclic group, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl; D is phenyl
substituted with one to five substituents selected from halogen,
substituted or unsubstituted alkyl, and --CONR.sup.xR.sup.y; each
occurrence of R.sup.x and R.sup.y 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 heterocyclylalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted arylalkyl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted heteroarylalkyl, --COOR.sup.z, --C(O)R.sup.z,
--C(S)R.sup.z, --C(O)NR.sup.zR.sup.z, --C(O)ONR.sup.zR.sup.z,
--R.sup.zR.sup.z, --NR.sup.zCONR.sup.zR.sup.z,
--N(R.sup.z)SOR.sup.z, --N(R.sup.z)SO.sub.2R.sup.z,
--(.dbd.N--N(R.sup.z)R.sup.z), --NR.sup.zC(O)OR.sup.z,
--NR.sup.zC(O)R.sup.z--, --NR.sup.zC(S)R.sup.z,
--NR.sup.zC(S)NR.sup.zR.sup.z, --SONR.sup.zR.sup.z--,
--SO.sub.2NR.sup.zR.sup.z--, --OR.sup.z,
--OR.sup.zC(O)NR.sup.zR.sup.z, --OR.sup.zC(O)OR.sup.z--,
--OC(O)R.sup.z, --OC(O)NR.sup.zR.sup.z,
--R.sup.zNR.sup.zC(O)R.sup.z, --R.sup.zOR.sup.y,
--R.sup.zC(O)OR.sup.z, --R.sup.zC(O)NR.sup.zR.sup.z,
--R.sup.zC(O)R.sup.z, --R.sup.zOC(O)R.sup.z, --SR.sup.z,
--SOR.sub.z, --SO.sub.2R.sup.z, and --ONO.sub.2 or any two of
R.sup.x and R.sup.y which are directly bound to a common atom may
be joined to form (i) 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.sup.z or S or (ii) an oxo (.dbd.O), thio
(.dbd.S) or imino (.dbd.NR.sup.z) group; each occurrence R.sup.z is
independently 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
unsubstitituted heterocycylalkyl, substituted or unsubstituted
aryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
heteroarylalkyl and ONO.sub.2, any two of R.sup.z which are
directly bound to a common atom may be joined to form (i)
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'
(wherein R' is H or alkyl) or S or (ii) an oxo (.dbd.O), thio
(.dbd.S) or imino (.dbd.NR.sup.z); each occurrence of R.sup.2 is
hydrogen; and L.sub.2 is substituted or unsubstituted alkyl.
83. The method of claim 82, wherein the cell is contacted with an
effective amount of a compound of formula (IA-1) to inhibit the
proliferative activity of the cell.
84. The method of claim 82, wherein the cell is contacted with an
effective amount of a compound of formula (IA-1) to inhibiting
tumor growth in the cell of a patient in need thereof.
85. The method of claim 82, wherein the cell is contacted with an
effective amount of a compound of formula (IA-1) to inhibiting
tumor metastasis in the cell of a patient in need thereof.
86. The method of claim 82, wherein the cell is contacted with an
effective amount of a compound of formula (IA-1) to treat a c-Met
associated disease or disorder in a subject in need thereof.
87. The method of claim 86, further comprising the step of
administering simultaneously or sequentially to the subject at
least one other anti-cancer agent, anti-inflammatory agent,
immunosuppressive agent, steroid, non-steroidal anti-inflammatory
agent, antihistamine, analgesic, or a mixture thereof.
88. The method of claim 86, wherein the c-Met associated disease,
disorder or condition is an immune system-related disease, a
disease or disorder involving inflammation, cancer or other
proliferative disease, a hepatic disease or disorder, or a renal
disease or disorder.
89. The method of claim 82, wherein the cell is contacted with an
effective amount of a compound of formula (IA-1) to treat cancer in
a subject in need thereof.
90. The method of claim 89, wherein said cancer is a carcinoma,
musculoskeletal sarcoma, soft tissue sarcoma, or hematopoietic
malignancy.
91. The method of claim 89, wherein said cancer is carcinoma of the
bladder, carcinoma of the breast, carcinoma of the colon, carcinoma
of the kidney, carcinoma of the liver, carcinoma of the lung, small
cell lung cancer, esophageal cancer, gall bladder cancer, ovarian
cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid
cancer, prostate cancer, skin cancer, squamous cell carcinoma;
cholangiocarcinoma cancer, tumors of mesenchymal origin,
fibrosarcoma, rhabdomyosarcoma; tumors of the central and
peripheral nervous system, astrocytoma, neuroblastoma, glioma,
schwannoma; melanoma, seminoma, teratocarcinoma, osteosarcoma,
xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer
and Kaposi's sarcoma, synovial sarcoma, rhabdomyosarcoma,
MFH/fibrosarcoma, leiomyosarcoma, multiple myeloma, lymphoma,
glioblastoma, astrocytoma, melanoma, mesothelioma, Wilm's tumor,
hematopoietic tumors of lymphoid lineage, leukemia, acute
lymphocytic leukemia, acute lymphoblastic leukemia, B-cell
lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkins
lymphoma, hairy cell lymphoma and Burkett's lymphoma; hematopoietic
tumors of myeloid lineage, acute myelogenous leukemias, chronic
myelogenous leukemias, myelodysplastic syndrome, or promyelocytic
leukemia.
92. The method of claim 89, wherein the compound is selected from
(3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)-
methanol,
(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-y-
l)phenyl)methanol,
N-Methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)benzamide,
2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)benzamide,
(2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-y-
l)phenyl) methanol,
N-(2-Hydroxyethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]py-
ridin-5-yl)benzamide,
4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamid-
e,
(4-Methylpiperazin-1-yl)(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[-
4,5-b]pyridin-5-yl)phenyl)methanone,
N-(2-(dimethylamino)ethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[-
4,5-b]pyridin-5-yl)benzamide,
4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(tetr-
ahydro-2H-pyran-4-yl)benzamide, tert-Butyl
4-(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benza-
mido)piperidine-1-carboxylate,
N-(Piperidin-4-yl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]py-
ridin-5-yl)benzamide hydrochloride
N-(2-(dimethylamino)ethyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]-
triazolo[4,5-b]pyridin-5-yl)benzamide,
(S)-(2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)(4-(3-(quinolin-6-ylmethyl)-
-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)methanone
hydrochloride,
(4-(2-hydroxyethyl)piperazin-1-yl)(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]t-
riazolo[4,5-b]pyridin-5-yl)phenyl)methanone,
(R)-(3-hydroxypyrrolidin-1-yl)(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triaz-
olo[4,5-b]pyridin-5-yl)phenyl)methanone hydrochloride,
N-(2-(piperidin-1-yl)ethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo-
[4,5-b]pyridin-5-yl)benzamide,
N-(2-morpholinoethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b-
]pyridin-5-yl)benzamide,
N-(2-(pyrrolidin-1-yl)ethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazol-
o[4,5-b]pyridin-5-yl)benzamide,
(4-(pyrrolidin-1-yl)piperidin-1-yl)(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]-
triazolo[4,5-b]pyridin-5-yl)phenyl)methanone,
N-(3-(dimethylamino)propyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo-
[4,5-b]pyridin-5-yl)benzamide,
N,N-Bis(2-methoxyethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-
-b]pyridin-5-yl)benzamide hydrochloride,
(2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-y-
l)phenyl)methanol hydrochloride,
6-((5-(3-Fluoro-4-(methoxymethyl)phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-
-3-yl)methyl)quinoline,
N-ethyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyri-
din-5-yl)benzamide,
2-Fluoro-N-(2-(pyrrolidin-1-yl)ethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,-
3]triazolo[4,5-b]pyridin-5-yl)benzamide,
N-cyclohexyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b-
]pyridin-5-yl)benzamide,
N-Cyclopropyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5--
b]pyridin-5-yl)benzamide,
2-Fluoro-N-(pyridin-4-yl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4-
,5-b]pyridin-5-yl)benzamide,
N-Benzyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyr-
idin-5-yl)benzamide,
2-Fluoro-N,N-dimethyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b-
]pyridin-5-yl)benzamide, Methyl
2-(2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-
-yl)benzamido)acetate,
2-(2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-
-yl)benzamido)acetic acid,
2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)-N-(1H-1,2,4-triazol-3-yl)benzamide,
N-Methyl-3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)benzamide,
6-((5-(3-Fluorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quino-
line,
2-Fluoro-N-methoxy-N-methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]tri-
azolo[4,5-b]pyridin-5-yl)benzamide hydrochloride,
N-tert-Butyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b-
]pyridin-5-yl)benzamide,
N-Allyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyri-
din-5-yl)benzamide,
2-Fluoro-N-methoxy-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]py-
ridin-5-yl)benzamide,
N-(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)pheny-
l) acetamide,
6-((5-(4-Fluorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quino-
line,
6-((5-(2-Fluorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)-
quinoline,
N-(3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin--
5-yl)phenyl) acetamide,
N-(3-(dimethylamino)propyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3-
]triazolo[4,5-b]pyridin-5-yl)benzamide,
N-Ethyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyri-
din-5-yl)benzamide hydrochloride,
2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)benzamide hydrochloride,
N-(3-(dimethylamino)-3-oxopropyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H--
[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide,
N-(2-(dimethylamino)-2-oxoethyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[-
1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide,
2-Fluoro-N-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-4-(3-(quinolin-6-ylmethyl)-3H-
-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide,
2-Fluoro-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyr-
idin-5-yl)benzamide,
2-Fluoro-N-propyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyr-
idin-5-yl)benzamide
6-((5-(4-(Cyclopropylcarbamoyl)-3-fluorophenyl)-3H-[1,2,3]triazolo[4,5-b]-
pyridin-3-yl)methyl)quinoline 1-oxide,
N-Cyclopropyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5--
b]pyridin-5-yl)benzamide hydrochloride,
N-(Cyclopropylmethyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triaz-
olo[4,5-b]pyridin-5-yl)benzamide,
N-Butyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyri-
din-5-yl)benzamide,
2-Fluoro-N-(furan-2-ylmethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazo-
lo[4,5-b]pyridin-5-yl)benzamide,
2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)-N-(2,2,2-trifluoroethyl)benzamide,
2-Fluoro-N-(2-methoxyethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo-
[4,5-b]pyridin-5-yl)benzamide,
2-Fluoro-N-isobutyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]p-
yridin-5-yl)benzamide,
N-Cyclopentyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5--
b]pyridin-5-yl)benzamide,
2-Fluoro-N-isopropyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]-
pyridin-5-yl)benzamide,
2-Chloro-N-propyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyr-
idin-5-yl)benzamide,
2-Fluoro-N-methyl-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[-
4,5-b]pyridin-5-yl)benzamide,
N-Cyclobutyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b-
]pyridin-5-yl)benzamide,
2-Fluoro-N-propyl-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[-
4,5-b]pyridin-5-yl)benzamide,
N-Cyclopropyl-2-fluoro-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]tria-
zolo[4,5-b]pyridin-5-yl)benzamide,
N-Ethyl-2-fluoro-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[4-
,5-b]pyridin-5-yl)benzamide,
2-Chloro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)benzamide,
2-Chloro-N-methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyr-
idin-5-yl)benzamide,
2-Fluoro-N-methoxy-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]py-
ridin-5-yl)benzamide hydrochloride,
2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)-N-(thiazol-2-yl)benzamide,
N-(3-Aminopropyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[-
4,5-b]pyridin-5-yl)benzamide,
2-Chloro-N-cyclopropyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5--
b]pyridin-5-yl)benzamide,
2-Fluoro-N-(3-oxo-3-(pyrrolidin-1-yl)propyl)-4-(3-(quinolin-6-ylmethyl)-3-
H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide,
2-Fluoro-N-hydroxy-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]py-
ridin-5-yl)benzamide,
N-Isopropyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-
-yl)benzamide,
2-Fluoro-N-(3-oxo-3-(piperidin-1-yl)propyl)-4-(3-(quinolin-6-ylmethyl)-3H-
-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide,
2-Chloro-N-ethyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyri-
din-5-yl)benzamide,
2-Fluoro-N-(3-morpholino-3-oxopropyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,-
3]triazolo[4,5-b]pyridin-5-yl)benzamide,
N-(3-(dimethylamino)propyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3-
]triazolo[4,5-b]pyridin-5-yl)benzamide dihydrochloride,
2-chloro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)-N-(1H-1,2,4-triazol-3-yl)benzamide,
2-Chloro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)benzamide hydrochloride,
2-Fluoro-N-(3-(piperidin-1-yl)propyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,-
3]triazolo[4,5-b]pyridin-5-yl)benzamide,
N-(3-Aminopropyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[-
4,5-b]pyridin-5-yl)benzamide dihydrochloride,
2-Chloro-N-(3-(dimethylamino)propyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3-
]triazolo[4,5-b]pyridin-5-yl)benzamide dihydrochloride,
2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)-N-(1H-1,2,4-triazol-3-yl)benzamide hydrochloride,
2,6-Difluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin--
5-yl)benzamide,
2-Chloro-N-ethyl-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[-
4,5-b]pyridin-5-yl)benzamide,
2-Chloro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]py-
ridin-5-yl)benzamide,
2-Fluoro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]py-
ridin-5-yl)benzamide,
3-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamid-
e,
2,6-Difluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridi-
n-5-yl)benzamide hydrochloride,
2-Chloro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]py-
ridin-5-yl)benzamide hydrochloride,
2-Fluoro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]py-
ridin-5-yl)benzamide hydrochloride,
2-Methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)benzamide,
2-Fluoro-5-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)benzamide,
2-Chloro-4-(3-((5,7-difluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5--
b]pyridin-5-yl)benzamide,
4-(3-(Benzo[d]thiazol-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)--
2-chloro benzamide,
2-(2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-
-yl)phenyl)propan-2-ol,
2-Chloro-5-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)benzamide,
2-Chloro-4-(3-(1-(quinolin-6-yl)ethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-
-yl)benzamide,
(-)-2-Chloro-4-(3-(1-(quinolin-6-yl)ethyl)-3H-[1,2,3]triazolo[4,5-b]pyrid-
in-5-yl)benzamide,
(+)-2-Chloro-4-(3-(1-(quinolin-6-yl)ethyl)-3H-[1,2,3]triazolo[4,5-b]pyrid-
in-5-yl)benzamide,
4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-2-(trif-
luoromethyl)benzamide,
6-((5-(4-carbamoyl-3-chlorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-
methyl)quinoline 1-oxide,
2-chloro-N-ethyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyri-
din-5-yl)benzamide hydrochloride,
6-((5-(4-carbamoyl-3-chlorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-
methyl)quinoline 1-oxide,
4-(3-(4-Fluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzaldehyde,
(4-(3-(4-Fluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)metha-
nol, Methyl
4-(3-(2-chloro-3,6-difluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-
-2-fluoro benzoate,
4-(3-(2-Chloro-3,6-difluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-
-2-fluoro benzoic acid,
4-(3-(2-Chloro-3,6-difluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-
-2-fluoro-N-methyl benzamide, and pharmaceutically acceptable salts
thereof.
93. A method of inhibiting the HGF/c-Met kinase signaling pathway
in a cell comprising contacting said cell with a compound of
formula ##STR00402## or a tautomer, stereoisomer, enantiomer,
diastereomer, salt, prodrug, or N-oxide thereof, wherein B is
Cy.sup.1; Cy.sup.1 is phenyl substituted with one to five
substituents selected from halogen, substituted or unsubstituted
alkyl, and --CONR.sup.xR.sup.y, with the proviso that at least one
substituent is --CONR.sup.xR.sup.y; each occurrence of R.sup.x and
R.sup.y is independently selected from hydrogen, hydroxy,
substituted or unsubstituted alkyl, and substituted or
unsubstituted alkoxy; X is N; R.sup.2 is hydrogen; each occurrence
of R.sup.a and R.sup.b may be same or different and are
independently selected from hydrogen, halogen, substituted or
unsubstituted (C.sub.1-6)alkyl, or both together with carbon atom
to which they are attached form a saturated 3 to 6 member cyclic
ring which may optionally include heteroatoms which may be same or
different and are selected from O, NR.sup.e or S; R.sup.e 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
cycloalkylalkyl, substituted or unsubstituted cycloalkenyl,
substituted or unsubstituted cycloalkenylalkyl, substituted or
unsubstituted heterocyclic ring, substituted or unsubstitituted
heterocycylalkyl ring, substituted or unsubstituted aryl,
substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
heteroarylalkyl, substituted or unsubstituted guanidine,
--COOR.sup.x, --C(O)R.sup.x, --C(S)R.sup.x, --C(O)NR.sup.xR.sup.y,
--C(O)ONR.sup.xR.sup.y, --NR.sup.yR.sup.z,
--NR.sup.xCONR.sup.yR.sup.z, --N(R.sup.x)SOR.sup.y,
--N(R.sup.x)SO.sub.2R.sup.y, --(.dbd.N--N(R.sup.x)R.sup.y),
--NR.sup.xC(O)OR.sup.y, --NR.sup.xR.sup.y, --NR.sup.xC(O)R.sup.y--,
--NR.sup.xC(S)R.sup.y, --OR.sup.x, --OR.sup.xC(O)NR.sup.yR.sup.z,
--OR.sup.xC(O)OR.sup.y--, --OC(O)R.sup.x, --OC(O)NR.sup.xR.sup.y,
--R.sup.xNR.sup.yC(O)R.sup.z, --R.sup.xOR.sup.y,
--R.sup.xC(O)OR.sup.y, --R.sup.xC(O)NR.sup.yR.sup.z,
--R.sup.xC(O)R.sup.x, --R.sup.xOC(O)R.sup.y, --SR.sup.x,
--SOR.sup.x, --SO.sub.2R.sup.x, and --ONO.sub.2; Z is selected from
CR.sup.c, S, O, NR.sup.c, R.sup.cC.dbd.CR.sup.c, --N.dbd.CR.sup.c-,
--R.sup.cC.dbd.N--; Z.sub.1 is selected from N, NR.sup.c or
CR.sup.c; and each occurrence of R.sup.c is independently absent,
hydrogen, hydroxyl or halogen.
94. The method of claim 93, wherein (i) each of R.sup.a and R.sup.b
is independently selected from hydrogen, methyl and methyl; (ii)
each of R.sup.a and R.sup.b is independently selected from hydrogen
and methyl; (iii) Z is CR.sup.c, N, S, O, HC.dbd.CH--, or
--N.dbd.CH--; (iv) Z.sub.1 is CH or N; (v) Z is --HC.dbd.CH--,
--S-- or --O-- and Z.sub.1 is CH; (vi) Z is --HC.dbd.CH-- and
Z.sub.1 is CH; (vii) Z is --S-- and Z.sub.1 is CH; or (viii) each
occurrence of R.sup.c is independently hydrogen or fluoro.
95. The method of claim 93, wherein the cell is contacted with an
effective amount of a compound of formula (IV) to inhibit the
proliferative activity of the cell.
96. The method of claim 93, wherein the cell is contacted with an
effective amount of a compound of formula (IV) to inhibiting tumor
growth in the cell of a patient in need thereof.
97. The method of claim 93, wherein the cell is contacted with an
effective amount of a compound of formula (IV) to inhibiting tumor
metastasis in the cell of a patient in need thereof.
98. The method of claim 93, wherein the cell is contacted with an
effective amount of a compound of formula (IV) to treat a c-Met
associated disease or disorder in a subject in need thereof.
99. The method of claim 98, further comprising the step of
administering simultaneously or sequentially to a subject in need
thereof at least one other anti-cancer agent, anti-inflammatory
agent, immunosuppressive agent, steroid, non-steroidal
anti-inflammatory agent, antihistamine, analgesic, or a mixture
thereof.
100. The method of claim 98, wherein the c-Met associated disease,
disorder or condition is an immune system-related disease, a
disease or disorder involving inflammation, cancer or other
proliferative disease, a hepatic disease or disorder, or a renal
disease or disorder.
101. The method of claim 93, wherein the cell is contacted with an
effective amount of a compound of formula (IV) to treat cancer in a
subject in need thereof.
102. The method of claim 101, wherein said cancer is a carcinoma,
musculoskeletal sarcoma, soft tissue sarcoma, or hematopoietic
malignancy.
103. The method of claim 102, wherein said cancer is carcinoma of
the bladder, carcinoma of the breast, carcinoma of the colon,
carcinoma of the kidney, carcinoma of the liver, carcinoma of the
lung, small cell lung cancer, esophageal cancer, gall bladder
cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical
cancer, thyroid cancer, prostate cancer, skin cancer, squamous cell
carcinoma; cholangiocarcinoma cancer, tumors of mesenchymal origin,
fibrosarcoma, rhabdomyosarcoma; tumors of the central and
peripheral nervous system, astrocytoma, neuroblastoma, glioma,
schwannoma; melanoma, seminoma, teratocarcinoma, osteosarcoma,
xenoderoma pigmento sum, keratoctanthoma, thyroid follicular cancer
and Kaposi's sarcoma, synovial sarcoma, rhabdomyosarcoma,
MFH/fibrosarcoma, leiomyosarcoma, multiple myeloma, lymphoma,
glioblastoma, astrocytoma, melanoma, mesothelioma, Wilm's tumor,
hematopoietic tumors of lymphoid lineage, leukemia, acute
lymphocytic leukemia, acute lymphoblastic leukemia, B-cell
lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkins
lymphoma, hairy cell lymphoma and Burkett's lymphoma; hematopoietic
tumors of myeloid lineage, acute myelogenous leukemias, chronic
myelogenous leukemias, myelodysplastic syndrome, or promyelocytic
leukemia.
104. The method of claim 101, wherein the compound is selected from
N-Methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)benzamide,
2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)benzamide,
N-(2-Hydroxyethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]py-
ridin-5-yl)benzamide,
4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamid-
e,
N-(2-(dimethylamino)ethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazol-
o[4,5-b]pyridin-5-yl)benzamide,
N-(2-(dimethylamino)ethyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]-
triazolo[4,5-b]pyridin-5-yl)benzamide,
N-(2-(piperidin-1-yl)ethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo-
[4,5-b]pyridin-5-yl)benzamide,
N-(2-morpholinoethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b-
]pyridin-5-yl)benzamide,
N-(2-(pyrrolidin-1-yl)ethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazol-
o[4,5-b]pyridin-5-yl)benzamide,
N-(3-(dimethylamino)propyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo-
[4,5-b]pyridin-5-yl)benzamide,
N,N-Bis(2-methoxyethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-
-b]pyridin-5-yl)benzamide hydrochloride,
N-ethyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyri-
din-5-yl)benzamide,
2-Fluoro-N-(2-(pyrrolidin-1-yl)ethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,-
3]triazolo[4,5-b]pyridin-5-yl)benzamide,
N-Benzyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyr-
idin-5-yl)benzamide,
2-Fluoro-N,N-dimethyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b-
]pyridin-5-yl)benzamide, Methyl
2-(2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-
-yl)benzamido)acetate,
2-(2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-
-yl)benzamido)acetic acid,
N-Methyl-3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)benzamide,
2-Fluoro-N-methoxy-N-methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo-
[4,5-b]pyridin-5-yl)benzamide hydrochloride,
N-tert-Butyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b-
]pyridin-5-yl)benzamide,
N-Allyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyri-
din-5-yl)benzamide,
2-Fluoro-N-methoxy-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]py-
ridin-5-yl)benzamide,
N-(3-(dimethylamino)propyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3-
]triazolo[4,5-b]pyridin-5-yl)benzamide,
N-Ethyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyri-
din-5-yl)benzamide hydrochloride,
2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)benzamide hydrochloride,
N-(3-(dimethylamino)-3-oxopropyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H--
[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide,
N-(2-(dimethylamino)-2-oxoethyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[-
1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide,
2-Fluoro-N-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-4-(3-(quinolin-6-ylmethyl)-3H-
-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide,
2-Fluoro-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyr-
idin-5-yl)benzamide,
2-Fluoro-N-propyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyr-
idin-5-yl)benzamide,
N-(Cyclopropylmethyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triaz-
olo[4,5-b]pyridin-5-yl)benzamide,
N-Butyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyri-
din-5-yl)benzamide,
2-Fluoro-N-(furan-2-ylmethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazo-
lo[4,5-b]pyridin-5-yl)benzamide,
2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)-N-(2,2,2-trifluoroethyl)benzamide,
2-Fluoro-N-(2-methoxyethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo-
[4,5-b]pyridin-5-yl)benzamide,
2-Fluoro-N-isobutyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]p-
yridin-5-yl)benzamide,
2-Fluoro-N-isopropyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]-
pyridin-5-yl)benzamide,
2-Chloro-N-propyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyr-
idin-5-yl)benzamide,
2-Fluoro-N-methyl-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[-
4,5-b]pyridin-5-yl)benzamide,
2-Fluoro-N-propyl-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[-
4,5-b]pyridin-5-yl)benzamide,
N-Ethyl-2-fluoro-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[4-
,5-b]pyridin-5-yl)benzamide,
2-Chloro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)benzamide,
2-Chloro-N-methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyr-
idin-5-yl)benzamide,
2-Fluoro-N-methoxy-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]py-
ridin-5-yl)benzamide hydrochloride,
N-(3-Aminopropyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[-
4,5-b]pyridin-5-yl)benzamide,
2-Fluoro-N-(3-oxo-3-(pyrrolidin-1-yl)propyl)-4-(3-(quinolin-6-ylmethyl)-3-
H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide,
2-Fluoro-N-hydroxy-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]py-
ridin-5-yl)benzamide,
N-Isopropyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-
-yl)benzamide,
2-Fluoro-N-(3-oxo-3-(piperidin-1-yl)propyl)-4-(3-(quinolin-6-ylmethyl)-3H-
-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide,
2-Chloro-N-ethyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyri-
din-5-yl)benzamide,
2-Fluoro-N-(3-morpholino-3-oxopropyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,-
3]triazolo[4,5-b]pyridin-5-yl)benzamide,
N-(3-(dimethylamino)propyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3-
]triazolo[4,5-b]pyridin-5-yl)benzamide dihydrochloride,
2-Chloro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)benzamide hydrochloride,
2-Fluoro-N-(3-(piperidin-1-yl)propyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,-
3]triazolo[4,5-b]pyridin-5-yl)benzamide,
N-(3-Aminopropyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[-
4,5-b]pyridin-5-yl)benzamide dihydrochloride,
2-Chloro-N-(3-(dimethylamino)propyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3-
]triazolo[4,5-b]pyridin-5-yl)benzamide dihydrochloride,
2,6-Difluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin--
5-yl)benzamide,
2-Chloro-N-ethyl-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[-
4,5-b]pyridin-5-yl)benzamide,
2-Chloro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]py-
ridin-5-yl)benzamide,
2-Fluoro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]py-
ridin-5-yl)benzamide,
3-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamid-
e,
2,6-Difluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridi-
n-5-yl)benzamide hydrochloride,
2-Chloro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]py-
ridin-5-yl)benzamide hydrochloride,
2-Fluoro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]py-
ridin-5-yl)benzamide hydrochloride,
2-Methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)benzamide,
2-Fluoro-5-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)benzamide,
2-Chloro-4-(3-((5,7-difluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5--
b]pyridin-5-yl)benzamide,
4-(3-(Benzo[d]thiazol-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)--
2-chloro benzamide,
2-Chloro-5-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)benzamide,
2-Chloro-4-(3-(1-(quinolin-6-yl)ethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-
-yl)benzamide,
(-)-2-Chloro-4-(3-(1-(quinolin-6-yl)ethyl)-3H-[1,2,3]triazolo[4,5-b]pyrid-
in-5-yl)benzamide,
(+)-2-Chloro-4-(3-(1-(quinolin-6-yl)ethyl)-3H-[1,2,3]triazolo[4,5-b]pyrid-
in-5-yl)benzamide,
4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-2-(trif-
luoromethyl)benzamide,
6-((5-(4-carbamoyl-3-chlorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-
methyl)quinoline 1-oxide,
2-chloro-N-ethyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyri-
din-5-yl)benzamide hydrochloride,
6-((5-(4-carbamoyl-3-chlorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-
methyl)quinoline 1-oxide, and pharmaceutically acceptable salts
thereof.
Description
[0001] This application claims the benefit of Indian Provisional
Patent Application No. 1377/CHE/2010 dated 17 May 2010 which is
hereby incorporated by reference.
FIELD OF THE INVENTION
[0002] The present invention provides, inter alia, compounds of
formula I as protein kinase modulators, methods of preparing them,
pharmaceutical compositions containing them and methods of
treatment, prevention and/or amelioration of kinase mediated
diseases or disorders with them.
BACKGROUND OF THE INVENTION
[0003] In the recent past immense research has been dedicated to
the discovery and understanding of the structure and functions of
enzymes and bio-molecules associated with various diseases. One
such important class of enzymes that has been the subject of
extensive research is Protein Kinase.
[0004] In general, protein kinases represent a set of structurally
related phosphoryl transferases, having conserved structures and
catalytic functions. These enzymes modify proteins by chemically
adding phosphate groups (phosphorylation). Phosphorylation involves
the removal of a phosphate group from ATP and covalently attaching
it to amino acids that have a free hydroxyl group such as serine,
threonine or tyrosine. Phosphorylation usually results in a
functional change of the target protein (substrate) by altering
enzyme activity, cellular localization or association with other
proteins. Up to 30% of all proteins may be modified by kinase
activity.
[0005] This class of proteins are classified into subsets depending
upon the substrate they act upon such as tyrosine kinase,
serine/theronine kinase, histidine kinase and the like. These
proteins can also be classified based on their localization into
receptor tyrosine kinases (RTKs) or non-receptor tyrosine
kinases.
[0006] Receptor tyrosine kinases (RTKs) have an extracellular
portion, a transmembrane domain, and an intracellular portion,
while non-receptor tyrosine kinases are entirely intracellular.
Receptor tyrosine kinase mediated signal transduction is typically
initiated by an extracellular interaction with a specific growth
factor (ligand), followed by receptor dimerization, stimulation of
the intrinsic protein tyrosine kinase activity, and phosphorylation
of amino acid residues. The ensuing conformational change leads to
the formation of complexes with a spectrum of cytoplasmic
signalling molecules and facilitates a myriad of responses such as
cell division, differentiation, metabolic effects, and changes in
the extracellular microenvironment.
[0007] At present, at least twenty (20) distinct RTK subfamilies
have been identified. One subfamily of the RTKs is designated as
the Met subfamily (c-Met, Ron and Sea). For a detailed discussion
of protein kinases, see, Plowman et al., DN&P 7(6): 334-339,
1994, Blume-Jensen, P. et al., Nature 2001, 411(6835):355-365 and
Manning, G. et al., Science. 2002, 298(5600): 1912-1934.
[0008] Kinases have also been classified either based on the
pathway or the diseases in which they are involved
(visit:www.reactionbiology.com/pages/kinase.htm). c-Met has been
identified as involved in oncogenesis.
[0009] Protein kinases exert their physiological functions through
phosphorylation of proteins (or substrates) thereby modulating the
cellular activities of the substrate in various biological
contexts. Protein kinases are known to control a wide variety of
biological processes such as cell growth, survival and
differentiation, organ formation and morphogenesis,
neovascularisation, tissue repair and regeneration. In addition to
their functions in normal tissues/organs, many protein kinases also
play specialized roles in a host of human diseases including
cancer. A subset of protein kinases (also referred to as oncogenic
protein kinases), when dysregulated, can cause tumor formation and
growth and contribute to tumor maintenance and progression
(Blume-Jensen P et al, Nature 2001, 411(6835):355-365). Thus far,
oncogenic protein kinases represent one of the largest and most
attractive groups of protein targets for therapeutic intervention
and drug development.
[0010] Both receptor and non-receptor protein kinases have been
found to be attractive targets for small molecule drug discovery
due to their impact on cell physiology and signalling.
Dysregulation of protein kinase activity thus leads to altered
cellular responses including uncontrolled cell growth associated
with cancer. In addition to oncological indications, altered kinase
signalling is implicated in numerous other pathological diseases.
These include, but are not limited to immunological disorders,
cardiovascular diseases, inflammatory diseases, and degenerative
diseases.
[0011] A significant number of tyrosine kinases (both receptor and
nonreceptor) are associated with cancer (see Madhusudan S, Ganesan
T S. Tyrosine kinase inhibitors in cancer therapy. Clin. Biochem.
2004, 37(7):618-35). Clinical studies suggest that over expression
or dysregulation of tyrosine kinases may also be of prognostic
value. For example, members of the HER family of RTKs have been
implicated in breast, colorectal, head and neck and lung cancer.
Mutation of c-Kit tyrosine kinase is associated with decreased
survival in gastrointestinal stromal tumors (GIST). In acute
myelogenous leukemia, Flt-3 mutation predicts shorter disease free
survival. VEGFR expression, which is important for tumor
angiogenesis, is associated with a lower survival rate in lung
cancer. Tie-1 kinase expression is inversely correlated to survival
in gastric cancer. BCR-AbI expression is an important predictor of
response in chronic myelogenous leukemia while Src tyrosine kinase
expression is co-related to the stage of colorectal cancer.
[0012] Modulation (particularly inhibition) of cell proliferation
and angiogenesis, the two key cellular processes needed for tumor
growth and survival is an attractive goal for development of
small-molecule drugs (Matter A. Drug Disc Technol 2001, 6,
1005-1024). Anti-angiogenic therapy represents a potentially
important approach for the treatment of solid tumors and other
diseases associated with dysregulated vascularisation including
ischemic coronary artery disease, diabetic retinopathy, psoriasis
and rheumatoid arthritis. Similarly, cell antiproliferative agents
are desirable to slow or inhibit the growth of tumors.
[0013] Some of the kinases implicated in cancer are c-Met, RON
(recepteur d'origine nantais) receptor, Vascular Endothelial Growth
Factor (VEGF) receptor, Epidermal growth factor receptor kinase
(EGF-R kinase), Eph receptors, c-Kit, and Flt-3.
[0014] A number of small molecule kinase modulators have found
their way into the clinic which either act selectively on either
one or multiple kinases. These include Gefitinib (AstraZeneca), a
EGFR kinase inhibitor; Gleevec (Novartis), a dual c-Kit and AbI
kinase inhibitor approved for the treatment of Chronic Myeloid
Leukemia (CML) and gastrointestinal stroma cancers; Dasatinib
(BMS), a dual BCR/ABL and Src family tyrosine kinases inhibitor,
and Sunitinib (Pfizer) a multi kinase inhibitor targeting
PDGF-R,VEGF-R, RET, KIT(CD117), CSF-1R and flt-3.
[0015] The kinase, c-Met, is the prototypic member of a subfamily
of heterodimeric receptor tyrosine kinases (RTKs) which include
Met, Ron and Sea (see Birchmeier, C. et al., Nat. Rev. Mol. Cell
Biol. 2003, 4(12):915-925; Christensen, J. G. et al., Cancer Lett.
2005, 225(1): 1-26). Expression of c-Met occurs in a wide variety
of cell types including epithelial, endothelial and mesenchymal
cells where activation of the receptor induces cell migration,
invasion, proliferation and other biological activities associated
with "invasive cell growth." As such, signal transduction through
c-Met receptor activation is responsible for many of the
characteristics of tumor cells.
[0016] The only high affinity endogenous ligand for c-Met is the
hepatocyte growth factor (HGF), also known as scatter factor (SF).
Binding of HGF to c-Met induces activation of the receptor via
autophosphorylation resulting in an increase of receptor dependent
signalling, which promotes cell growth and invasion. Both c-Met and
HGF are widely expressed in a variety of organs, but their
expression is normally confined to cells of epithelial and
mesenchymal origin. Anti-HGF antibodies or HGF antagonists have
been shown to inhibit tumor metastasis in vivo (See: Maulik et al
Cytokine & Growth Factor Reviews 2002, 13, 41-59). The
biological functions of c-Met (or c-Met signalling pathway) in
normal tissues and human malignancies such as cancer have been well
documented (Christensen, J. G. et al., Cancer Lett. 2005, 225(1):
1-26; Corso, S. et al., Trends in MoI. Med. 2005, 11
(6):284-292).
[0017] Tumor growth progression involves the recruitment of new
blood vessels into the tumor as well as invasion, adhesion and
proliferation of malignant cells. c-Met over expression has been
demonstrated on a wide variety of tumor types including breast,
colon, renal, lung, squamous cell myeloid leukemia, hemangiomas,
melanomas, astrocytomas, and glioblastomas. Additionally activating
mutations in the kinase domain of c-Met have been identified in
hereditary and sporadic renal papilloma and squamous cell
carcinoma. See Maulik et al Cytokine & growth Factor reviews
2002, 13, 41-59; Longati et al Curr Drug Targets 2001, 2, 41-55;
Funakoshi et al Clinica Chimica Acta 2003 1-23. Thus modulation of
c-Met offers an attractive opportunity to target key oncogenic
processes thus limiting cell proliferation, survival and
metastasis.
[0018] Dysregulated c-Met pathway is linked to tumor formation,
growth, maintenance and progression (Birchmeier, C. et al., Nat.
Rev. MoI. Cell. Biol. 2003, 4(12):915-925; Boccaccio, C. et al.,
Nat. Rev. Cancer 2006, 6(8):637-645; Christensen, J. G. et al.,
Cancer Lett. 2005, 225(1): 1-26). HGF and/or c-Met are over
expressed in significant portions of most human cancers, and are
often associated with poor clinical outcomes such as more
aggressive disease, disease progression, tumor metastasis and
shortened patient survival. Further, patients with high levels of
HGF/c-Met proteins are more resistant to chemotherapy and
radiotherapy. In addition to abnormal HGF/c-Met expression, the
c-Met receptor can also be activated in cancer patients through
genetic mutations (both germline and somatic) and gene
amplification. Although gene amplification and mutations are the
most common genetic alterations that have been reported in
patients, the receptor can also be activated by deletions,
truncations, and gene rearrangement, as well as abnormal receptor
processing and defective negative regulatory mechanisms.
[0019] The various cancers in which c-Met is implicated include but
are not limited to carcinomas (e.g., bladder, breast, cervical,
cholangiocarcinoma, colorectal, esophageal, gastric, head and neck,
kidney, liver, lung, nasopharygeal, ovarian, pancreas, prostate,
thyroid); musculo skeletal sarcomas (e.g., osteosarcaoma, synovial
sarcoma, rhabdomyosarcoma); soft tissue sarcomas (e.g.,
MFH/fibrosarcoma, leiomyosarcoma, Kaposi's sarcoma); hematopoietic
malignancies (e.g., multiple myeloma, lymphomas, adult T cell
leukemia, acute myelogenous leukemia, chronic myeloid leukemia);
and other neoplasms (e.g., glioblastomas, astrocytomas, melanoma,
mesothelioma and Wilm's tumor (www.vai.org/met/; Christensen, J. G.
et al., Cancer Lett. 2005, 225(1): 1-26). c-Met inhibitors may also
be useful in preventative and adjuvant therapy settings. In
addition, certain cancers (e.g., papillary renal cell carcinoma,
and some gastric and lung cancers) may be treated with c-Met
inhibitors as they are believed to be driven by c-Met
mutation/genetic alteration and dependent on c-Met for growth and
survival. These cancers are expected to be sensitive to
treatment.
[0020] The notion that activated c-Met contributes to tumor
formation and progression and could therefore be a potential target
for effective cancer intervention has been further validated by
numerous preclinical studies (Birchmeier, C. et al., Nat. Rev. MoI.
Cell Biol. 2003, 4(12):915-925; Christensen, J. G. et al., Cancer
Lett. 2005, 225(1): 1-26; Corso, S. et al., Trends in MoI. Med.
2005, 11(6):284-292). For example, studies have demonstrated that
the tpr-met fusion gene, over expression of c-Met, and activated
c-Met mutations caused oncogenic transformation of various model
cell lines and resulted in tumor formation and metastasis in mice.
Conversely, significant anti-tumor and anti-metastasis activities
have been demonstrated in vitro and in vivo with agents that
specifically impair and/or block HGF/c-Met signalling. Those agents
include anti-HGF and anti-c-Met antibodies, HGF peptide
antagonists, decoy c-Met receptor, c-Met peptide antagonists,
dominant negative c-Met mutations, c-Met specific antisense
oligonucleotides and ribozymes, and selective small molecule c-Met
kinase inhibitors (Christensen, J. G. et al., Cancer Lett. 2005,
225(1): 1-26). In addition to its established role in cancer,
abnormal HGF/c-Met signalling is also implicated in
atherosclerosis, lung fibrosis, renal fibrosis and regeneration,
liver diseases, allergic disorders, inflammatory and autoimmune
disorders, cerebrovascular diseases, cardiovascular diseases, and
conditions associated with organ transplantation. See Ma, H. et
al., Atherosclerosis. 2002, 164(1):79-87; Crestani, B. et al., Lab.
Invest. 2002, 82(8): 1015-1022; Sequra-Flores, A. A. et al., Rev.
Gastroenterol. Mex. 2004, 69(4)243-250; Morishita, R. et al., Curr.
Gene Ther. 2004, 4(2)199-206; Morishita, R. et al., Endocr. J.
2002, 49(3)273-284; Liu, Y., Curr. Opin. Nephrol. Hypertens. 2002,
11 (1):23-30; Matsumoto, K. et al., Kidney Int. 2001,
59(6):2023-2038; Balkovetz, D. F. et al., Int. Rev. Cytol. 1999,
186:225-250; Miyazawa, T. et al., J. Cereb. Blood Flow Metab. 1998,
18(4)345-348; Koch, A. E. et al., Arthritis Rheum. 1996,
39(9):1566-1575; Futamatsu, H. et al., Circ. Res. 2005,
96(8)823-830; Eguchi, S. et al., Clin. Transplant. 1999,
13(6)536-544.
[0021] c-Met is thus an attractive target from a clinical
perspective mainly because of its upstream localisation which aids
in early detection and limiting metastasis and implications in the
growth and metastases of most types of cancers. These observations
suggest that c-Met kinase inhibitors would be an effective
treatment for tumors driven by c-Met, and also would prevent
disseminated micrometastases from further progression.
[0022] A family of novel compounds have been discovered which
exhibit c-Met modulating ability and have an ameliorating effect
against disorders related to abnormal c-Met activity such as
Johnson & Johnson's JNJ-38877605, Amgen's AMG-458, Eisai's
E-7050 and Pfizer's PF-04217903. However, to date, none of them
have been used in a clinical study.
##STR00001##
[0023] More recently Dussault et. al., Anti-Cancer Agents in
Medicinal Chemistry, 2009, 9(2), 221-229, have provided additional
insight about a receptor tyrosine kinase namely, RON (recepteur
d'origine nantais) which is closely related to c-Met. Both c-MET
and RON receptors upon activation can induce cell migration,
invasion, proliferation and survival. Moreover, both possess
oncogenic activity in vitro and in vivo and are often dysregulated
in human cancers.
[0024] While c-Met is now a well-accepted target for anti-cancer
treatment, less is known about the role of RON in cancer. Despite
their common attributes, c-Met and RON are activated by different
mechanisms in cancer cells. Due to a significant homology between
the two RTKs, some small molecule kinase inhibitors of c-Met have
inhibitory activity on RON suggesting that both receptors might be
involved in cancer progression. The review (Dussault et al., supra)
discusses the relevance of both c-Met and RON deregulation in human
cancers and the progress made in identifying small molecule kinase
inhibitors that can block the activity of these targets in vitro
and in animal models. One of the compounds discussed in the review,
AMG-458, inhibited c-Met and RON with IC.sub.50s of 4 and 9 nM
respectively.
[0025] Various research groups around the world such as Amgen,
Arquel, AstraZeneca, Bristol-Myers Squibb, Exelixis, Eisai, Incyte,
MethylGene, Pfizer, SGX Pharma, SmithKline Beecham, Schering,
Vertex, Xcovery, Novartis and others have been working on targeting
either single, dual or multiple kinase targets.
[0026] Patent literature belonging to some of these applicants
include the following patents and/or patent applications: U.S. Pat.
No. 7,446,199; U.S. Pat. No. 7,470,693; U.S. Pat. No. 7,459,562;
U.S. Pat. No. 7,439,246; U.S. Pat. No. 7,432,373; U.S. Pat. No.
7,348,325; U.S. Pat. No. 7,173,031; U.S. Pat. No. 7,314,885; U.S.
Pat. No. 7,169,800; US 20100105656, US20090012076; US20080312232;
US20080161305; US20070244116; US20070225307; US20070054928;
US20070179130; US20070254868; US20070191369; US20060173055;
US20060135537; U520050148574; US20050137201; US20050101650;
WO2009002806; WO2008088881; WO2008051805; WO2008102870;
WO2008078085; WO2008060866; WO200854702; WO2008036272;
WO2007111904; WO2007064797; WO2006052913; WO2006021881;
WO2006021886; WO2006021884; WO2006108059; WO2006014325;
WO2006052913; WO200507891; WO2005030140; WO2005040345;
WO2005028475; WO2005016920.
[0027] Recent PCT patent applications viz., WO2009058728,
WO2009058729, WO2009058730 and WO2009058739 all assigned to
Schering corporation disclose a series of thiazole carboxamide
compounds as protein kinase inhibitors and more specifically to be
inhibiting Aurora, MEK1 and/or CDK2 kinases.
[0028] Further review and literature disclosure on protein kinase
molecules have been given by Isabelle Dussault et. al., (see;
Anti-Cancer Agents in Medicinal Chemistry, 2009, 9, 221-229), Ted
L. Underiner et. al., (see; Anti-Cancer Agents in Medicinal
Chemistry, 2010, 10, 7-27) and Stephen Claridge et. al (see;
Bioorganic & Medicinal Chemistry Letters 18 (2008) 2793-2798).
All of these patents and/or patent applications and literature
disclosures are incorporated herein as reference in their entirety
for all purposes.
[0029] Despite the advances made in the area of kinases and in
particular the role that c-met, RON, EGFR or KDR pathway plays in
human diseases, challenges remain in term of the complexities of
the target involved, the protein structure of the kinases,
specificity issues for various kinase inhibitors, side effects and
desired clinical benefits expected form the small molecule
inhibitors. Accordingly, there still remains an unmet and dire need
for small molecule compounds having specificity towards either one,
two or multiple kinase inhibitors in order to regulate and/or
modulate transduction of kinases, particularly c-Met, RON, EGFR or
KDR for the treatment of diseases and disorders associated with
kinases-mediated events.
[0030] The c-Met pathway plays an important role in the above
described human diseases including cancer. There are no c-Met
inhibitors or antagonists that are currently available for treating
these human disorders that are characterized by abnormal HGF/c-Met
signaling. Therefore, there is a clear unmet medical need for
compounds which inhibit c-Met and other kinases. The compounds,
compositions, and pharmaceutical methods provided herein help meet
this need.
SUMMARY OF THE INVENTION
[0031] The present invention is directed to compounds useful as
protein kinase modulators and in particular as inhibitors of
c-Met.
[0032] In one embodiment, the compound of the present invention has
the formula I:
##STR00002##
or a tautomer, stereoisomer, enantiomer, diastereomer, salt (e.g.,
pharmaceutically acceptable salt), prodrug (e.g., ester), or
N-oxide thereof, wherein
X is CR.sup.1 or N;
[0033] Cy.sup.1 and Cy.sup.2 may be same or different and are
independently selected from substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclic group,
substituted or unsubstituted aryl, and substituted or unsubstituted
heteroaryl;
[0034] L.sub.1 is absent or selected from --O--,
--S(.dbd.O).sub.q--, --NR.sup.a--, --(CR.sup.aR.sup.b).sub.n--,
--C(.dbd.Y)--, --C(.dbd.Y)--C(.dbd.Y)--,
--CR.sup.aR.sup.b--C(.dbd.Y)--CR.sup.aR.sup.b--,
--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--, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, and
substituted or unsubstituted heterocyclyl;
L.sub.2 is selected from --O--, --S(.dbd.O).sub.q--, --NR.sup.a--,
--(CR.sup.aR.sup.b).sub.n--, --C(.dbd.Y)--, C(.dbd.Y)--C(.dbd.Y)--,
--CR.sup.aR.sup.b--C(.dbd.Y)--CR.sup.aR.sup.b--,
--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--, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, and
substituted or unsubstituted heterocyclyl; each occurrence of
R.sup.1 and R.sup.2 may be same or different and is independently
selected from hydrogen, nitro, hydroxy, cyano, halogen, --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--, 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.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 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; each occurrence of
n independently represents 0, 1, 2, 3 or 4; and each occurrence of
q independently represents 0, 1 or 2.
[0035] Another embodiment is a compound of formula (IA):
##STR00003##
or a tautomer, stereoisomer, enantiomer, diastereomer, salt (e.g.,
pharmaceutically acceptable salt), prodrug (e.g., ester), or
N-oxide thereof, wherein each occurrence of R.sup.2 is
independently hydrogen, nitro, hydroxy, cyano, halogen, --OR.sup.a,
--S(.dbd.O).sub.q--R.sup.a, --NR.sup.aR.sup.b, C(.dbd.O)--R.sup.a,
or C(.dbd.O)--R.sup.a, wherein R.sup.a and R.sup.b in the R.sup.2
group are independently hydrogen, hydroxy, or substituted or
unsubstituted C.sub.1-6 alkyl; and all the other variables are the
same as described above for compound of formula (I).
[0036] Further preferred is a compound of formula (I) and (IA)
wherein Cy.sup.1 is selected from: (The squiggly lines () in the
structures below represent the point of attachment of the structure
to the rest of the compound.)
##STR00004## ##STR00005## ##STR00006## ##STR00007## ##STR00008##
##STR00009## ##STR00010## ##STR00011## ##STR00012## ##STR00013##
##STR00014## ##STR00015## ##STR00016## ##STR00017## ##STR00018##
##STR00019## ##STR00020## ##STR00021## ##STR00022## ##STR00023##
##STR00024## ##STR00025## ##STR00026## ##STR00027## ##STR00028##
##STR00029## ##STR00030##
[0037] Yet another embodiment is a compound of formula (IA-I):
##STR00031##
or a tautomer, stereoisomer, enantiomer, diastereomer, salt (e.g.,
pharmaceutically acceptable salt), prodrug (e.g., ester), or
N-oxide thereof, wherein D is substituted or unsubstituted
monocyclic aryl or substituted or unsubstituted monocyclic
heteroaryl; each occurrence of R.sup.2 is independently hydrogen,
nitro, hydroxy, cyano, halogen, --OR.sup.a,
--S(.dbd.O).sub.q--R.sup.a, --NR.sup.aR.sup.b, C(.dbd.O)--R.sup.a,
C(.dbd.O)--R.sup.a, wherein each occurrence of R.sup.a and R.sup.b
in group R.sup.2 is independently hydrogen, hydroxy, or substituted
or unsubstituted C.sub.1-6 alkyl; and all other variables are the
same as described herein above.
[0038] Further preferred is a compound of formula (IA-1) wherein
L.sub.2 is --CR.sup.aR.sup.b--.
[0039] Further preferred is a compound of formula (IA-1) wherein D
is substituted with one to five substituents selected from halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkoxy, --COR.sup.x, --CONR.sup.xR.sup.y,
--S(O).sub.qNR.sup.xR.sup.y or --NR.sup.xR.sup.y;
wherein each occurrence of R.sup.x and R.sup.y is independently
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 heterocycyl, substituted or unsubstituted
heterocyclylalkyl, substituted or unsubstituted aryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted heteroarylalkyl,
--COOR.sup.z, --C(O)R.sup.z, --C(S)R.sup.z, --C(O)NR.sup.zR.sup.z,
--C(O)ONR.sup.zR.sup.z, --NR.sup.zR.sup.z,
--NR.sup.zCONR.sup.zR.sup.z, --N(R.sup.z)SOR.sup.z,
--N(R.sup.z)SO.sub.2R.sup.z, --(.dbd.N--N(R.sup.z)R.sup.z),
--NR.sup.zC(O)OR.sup.z--, --NR.sup.zC(O)R.sup.z--,
--NR.sup.xC(S)R.sup.y--NR.sup.zC(S)NR.sup.zR.sup.z,
--SONR.sup.zR.sup.z--, --SO.sub.2NR.sup.zR.sup.z--, --OR.sup.z,
--OR.sup.zC(O)NR.sup.zR.sup.z, --OR.sup.zC(O)OR.sup.z--,
--OC(O)R.sup.z, --OC(O)NR.sup.zR.sup.z,
--R.sup.zNR.sup.zC(O)R.sup.z, --R.sup.zOR.sup.z,
--R.sup.zC(O)OR.sup.z, --R.sup.zC(O)NR.sup.zR.sup.z,
--R.sup.zC(O)R.sup.z, --R.sup.zOC(O)R.sup.z, --SR.sup.z,
--SOR.sup.z, --SO.sub.2R.sup.z, and --ONO.sub.2, or any two of
R.sup.x and R.sup.y 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.sup.z or S, or (ii) an oxo (.dbd.O), thio
(.dbd.S) or imino (.dbd.NR.sup.z), wherein each occurrence of
R.sup.z 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 heterocycyl, 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.z 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.sup.z); and q in the group D is 0, 1 or
2.
[0040] Further preferred is a compound of formula (IA-1) wherein D
is selected from
##STR00032## ##STR00033## ##STR00034## ##STR00035## ##STR00036##
##STR00037## ##STR00038## ##STR00039## ##STR00040## ##STR00041##
##STR00042## ##STR00043## ##STR00044## ##STR00045## ##STR00046##
##STR00047## ##STR00048## ##STR00049## ##STR00050## ##STR00051##
##STR00052## ##STR00053## ##STR00054## ##STR00055## ##STR00056##
##STR00057## ##STR00058## ##STR00059## ##STR00060##
##STR00061##
[0041] Yet another embodiment is a compound of formula (II):
##STR00062##
or a tautomer, stereoisomer, enantiomer, diastereomer, salt (e.g.,
pharmaceutically acceptable salt), prodrug (e.g., ester), or
N-oxide thereof, wherein A is selected from halogen, --OR.sup.c,
--S(.dbd.O).sub.q--R.sup.c, --NR.sup.cR.sup.d,
--(CR.sup.cR.sup.d).sub.n--R.sup.e, --C(.dbd.Y)--R.sup.c,
--C(.dbd.Y)----C(.dbd.Y)--R.sup.c,
--CR.sup.cR.sup.d--C(.dbd.Y)--CR.sup.cR.sup.d--R.sup.e,
--CR.sup.cR.sup.d--Y--CR.sup.cR.sup.d--R.sup.e,
--C(.dbd.Y)--NR.sup.cR.sup.d,
--NR.sup.c--C(.dbd.Y)--NR.sup.cR.sup.d,
--S(.dbd.O).sub.q--NR.sup.cR.sup.d,
--NR.sup.c--S(.dbd.O).sub.q--NR.sup.cR.sup.d,
--NR.sup.c--NR.sup.cR.sup.d, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted C.sub.3-6 cycloalkyl, and
substituted or unsubstituted C.sub.3-6 cycloalkenyl; or when two
R.sup.c and R.sup.d substituents are directly bound to a common
atom, they may be joined to form 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.e or S;
[0042] each occurrence of R.sup.c, R.sup.d, and R.sup.e are
independently 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 cycloalkylalkyl, substituted or unsubstituted
cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl,
substituted or unsubstituted heterocyclic ring, substituted or
unsubstitituted heterocycylalkyl ring, substituted or unsubstituted
aryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
heteroarylalkyl, substituted or unsubstituted guanidine,
--COOR.sup.x, --C(O)R.sup.x, --C(S)R.sup.x, --C(O)NR.sup.xR.sup.y,
--C(O)ONR.sup.xR.sup.y, --NR.sup.yR.sup.z,
--NR.sup.xCONR.sup.yR.sup.z, --N(R.sup.x)SOR.sup.y,
--N(R.sup.x)SO.sub.2R.sup.y, --(.dbd.N--N(R.sup.x)R.sup.y),
--NR.sup.xC(O)OR.sup.y, --NR.sup.xR.sup.y, --NR.sup.xC(O)R.sup.y--,
--NR.sup.xC(S)R.sup.y, --NR.sup.xC(S)NR.sup.yR.sup.z,
--SONR.sup.xR.sup.y--, --SO.sub.2NR.sup.xR.sup.y--, --OR.sup.x,
--OR.sup.xC(O)NR.sup.yR.sup.z, --OR.sup.xC(O)OR.sup.y--,
--OC(O)R.sup.x, --OC(O)NR.sup.xR.sup.y,
--R.sup.xNR.sup.yC(O)R.sup.z, --R.sup.xOR.sup.y,
--R.sup.xC(O)OR.sup.y, --R.sup.xC(O)NR.sup.yR.sup.z,
--R.sup.xC(O)R.sup.x, --R.sup.xOC(O)R.sup.y, --SR.sup.x,
--SOR.sup.x, --SO.sub.2R.sup.x, and --ONO.sub.2, wherein each
occurrence of R.sup.x, R.sup.y and R.sup.z in each of the above
groups is independently hydrogen, substituted or unsubstituted
amino, substituted or unsubstituted alkyl, substituted or
unsubstituted alkoxy, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloalkylalkyl,
substituted or unsubstituted cycloalkenyl, substituted or
unsubstituted cycloalkenylalkyl, substituted or unsubstituted
heterocyclic ring, substituted or unsubstituted heterocyclylalkyl
ring, substituted or unsubstituted aryl, substituted or
unsubstituted arylalkyl, substituted or unsubstituted heteroaryl,
and substituted or unsubstituted heteroarylalkyl, or any two of
R.sup.x, R.sup.y and R.sup.z which are directly bound to a common
atom may be joined to form (i) an oxo (C.dbd.O), thio (C.dbd.S) or
imino (C.dbd.NR') group (where R' is H or alkyl) or (ii)
substituted or unsubstituted, saturated or unsaturated 3-10
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; and all other variables are the same
as described above for compound of formula (I).
[0043] Yet another embodiment is a compound of formula (IIA):
##STR00063##
or a tautomer, stereoisomer, enantiomer, diastereomer, salt (e.g.,
pharmaceutically acceptable salt), prodrug (e.g., ester), or
N-oxide thereof, wherein R.sup.c and R.sup.d together with the
nitrogen to which they are attached form 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.e or S; and all other
variables are the same as described above for compound of formula
(II).
[0044] Further preferred is a compound of formula (IIA) wherein
NR.sup.cR.sup.d is selected from
##STR00064##
wherein each occurrence of R.sup.x and R.sup.y is independently
selected from hydrogen, substituted or unsubstituted alkyl, and
substituted or unsubstituted alkoxy, or any two of R.sup.x and
R.sup.y which are directly bound to a common atom may be joined to
form an oxo (C.dbd.O), thio (C.dbd.S) or imino (C.dbd.NR') group
(where R' is H or alkyl) or, any two of R.sup.x and R.sup.y may be
joined to form a substituted or unsubstituted, saturated or
unsaturated 3-6 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.
[0045] Further preferred is a compound of formula (IIA) wherein
NR.sup.cR.sup.d is selected from
##STR00065##
[0046] Yet another embodiment is a compound of formula (III):
##STR00066##
or a tautomer, stereoisomer, enantiomer, diastereomer, salt (e.g.,
pharmaceutically acceptable salt), prodrug (e.g., ester), or
N-oxide thereof, wherein U and V are each independently selected
from CR.sup.3 or N; W is selected from O, S, or NR.sup.4; each
occurrence of R.sup.3 is independently hydrogen, halogen, cyano
(CN), --OR.sup.c, --S(.dbd.O).sub.q--R.sup.c, --NR.sup.cR.sup.d,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted C.sub.3-6 cycloalkyl, substituted or unsubstituted
C.sub.3-6 cycloalkylalkyl, or substituted or unsubstituted
C.sub.3-6 cycloalkenyl; R.sup.4 is selected from hydrogen, hydroxy,
carboxyl, cyano, 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 C.sub.3-6 cycloalkyl,
substituted or unsubstituted C.sub.3-6 cycloalkylalkyl, and
substituted or unsubstituted C.sub.3-6 cycloalkenyl; 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
cycloalkylalkyl, substituted or unsubstituted cycloalkenyl,
substituted or unsubstituted heterocyclic ring, substituted or
unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
heteroarylalkyl, substituted or unsubstituted guanidine,
--COOR.sup.x, --C(O)R.sup.x, --C(S)R.sup.x, --C(O)NR.sup.xR.sup.y,
--C(O)ONR.sup.xR.sup.y, --NR.sup.xR.sup.z,
--NR.sup.xCONR.sup.yR.sup.z, --N(R.sup.x)SOR.sup.y,
--N(R.sup.x)SO.sub.2R.sup.y, --(.dbd.N--N(R.sup.x)R.sup.y),
--NR.sup.xC(O)OR.sup.y, --NR.sup.xC(O)R.sup.y--,
--NR.sup.xC(S)R.sup.y, --NR.sup.xC(S)NR.sup.yR.sup.z,
--SONR.sup.xR.sup.y--, --SO.sub.2NR.sup.xR.sup.y--, --OR.sup.x,
--OR.sup.xC(O)NR.sup.yR.sup.z, --OR.sup.xC(O)OR.sup.y--,
--OC(O)R.sup.x, --OC(O)NR.sup.xR.sup.y,
--R.sup.xNR.sup.yC(O)R.sup.z, --R.sup.xOR.sup.y,
--R.sup.xC(O)OR.sup.y, --R.sup.xC(O)NR.sup.yR.sup.z,
--R.sup.xC(O)R.sup.x, --R.sup.xOC(O)R.sup.y, --SR.sup.x,
--SOR.sup.x, --SO.sub.2R.sup.x, and --ONO.sub.2, wherein R.sup.x,
R.sup.y and R.sup.z in each of the above groups can be hydrogen,
substituted or unsubstituted amino, substituted or unsubstituted
alkyl, substituted or unsubstituted alkoxy, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkylalkyl, substituted or unsubstituted
cycloalkenyl, substituted or unsubstituted heterocyclic ring,
substituted or unsubstituted heterocyclylalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted arylalkyl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted heteroarylalkyl, or any two of R.sup.x, R.sup.y and
R.sup.z which are directly bound to a common atom may be joined to
form an oxo (C.dbd.O), thio (C.dbd.S) or imino (C.dbd.NR') group
(where R' is H or alkyl) or substituted or unsubstituted, saturated
or unsaturated 3-10 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 when W is
NR.sup.4, R.sup.4 and R.sup.5 together with the nitrogen to which
they are attached form 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.e or S; and all the other variables are the same as
described above for compound of formula (I).
[0047] Further preferred is a compound of formula (III) wherein U
is CR.sup.3.
[0048] Further preferred is a compound of formula (III) wherein V
is N.
[0049] Further preferred is a compound of formula (III) wherein W
is O or NR.sup.4.
[0050] Further preferred is a compound of formula (III) wherein
--U.dbd.V--W--R.sup.5 is
##STR00067##
[0051] Yet another embodiment is compound of formula (MA) or
(IIIB):
##STR00068##
or a tautomer, stereoisomer, enantiomer, diastereomer, salt (e.g.,
pharmaceutically acceptable salt), prodrug (e.g., ester), or
N-oxide thereof, wherein all the variables are the same as
described above for compound of formula (III).
[0052] Further preferred is a compound of formula (IIIA) wherein
--CR.sup.3.dbd.N--O--R.sup.5 is selected from
##STR00069##
[0053] Further preferred is a compound of formula (IIIA) wherein
--CR.sup.3.dbd.N--NR.sup.4R.sup.5 is selected from
##STR00070##
[0054] Further preferred is a compound of formula (I), (IA),
(IA-1), (II), (IIA), (III), (IIIA) or (IIIB) wherein X is
CR.sup.1.
[0055] Further preferred is a compound of formula (I), (IA),
(IA-1), (II), (IIA), (III), (IIIA) or (IIIB) wherein X is N.
[0056] Further preferred is a compound of formula (I), (IA),
(IA-1), (II), (IIA), (III), (IIIA) or (IIIB) wherein R.sup.1 is
H.
[0057] Further preferred is a compound of formula (I), (IA),
(IA-1), (II), (IIA), (III), (IIIA) or (IIIB) wherein each of
R.sup.2 is H;
[0058] Further preferred is a compound of formula (I), (IA),
(IA-1), (II), (IIA), (III), (IIIA) or (IIIB) wherein L.sub.2 is
--CR.sup.aCR.sup.b--.
[0059] Further preferred is a compound of formula (I), (IA),
(IA-1), (II), (IIA), (III), (IIIA) or (IIIB) wherein L.sub.2 is
CH.sub.2--, --CH(OH)--, --CHF--, --CF.sub.2--, --CH(CH.sub.3)-- or
--C(CH.sub.3).sub.2--.
[0060] Further preferred is a compound of formula (I), (IA),
(IA-1), (II), (IIA), (III), (IIIA) or (IIIB) wherein L.sub.2 is
CH.sub.2-- or --CH(CH.sub.3)--.
[0061] Further preferred is a compound of formula (I), (IA),
(IA-1), (II), (IIA), (III), (IIIA) or (IIIB) wherein Cy.sup.2 is
substituted or unsubstituted aryl or substituted or unsubstituted
heteroaryl.
[0062] Further preferred is a compound of formula (I), (IA),
(IA-1), (II), (IIA), (III), (IIIA) or (IIIB) wherein Cy.sup.2 is
selected from
##STR00071## ##STR00072## ##STR00073##
[0063] Further preferred is a compound of formula (I), (IA),
(IA-1), (II), (IIA), (III), (IIIA) or (IIIB) wherein Cy.sup.2 is
selected from
##STR00074##
[0064] Yet another embodiment is a compound of formula (IV):
##STR00075##
or a tautomer, stereoisomer, enantiomer, diastereomer, salt (e.g.,
pharmaceutically acceptable salt), prodrug (e.g., ester), or
N-oxide thereof, wherein B is selected from L.sub.1-Cy.sub.1,
Cy.sub.1, D, A, NR.sup.cR.sup.d and --U.dbd.V--W--R.sup.5 (e.g.,
Cy.sup.1, D, NR.sup.cR.sup.d or --U.dbd.V--W--R.sup.5); R.sup.a and
R.sup.b, located between the two bicyclic groups, are independently
selected from hydrogen, halogen, and substituted or unsubstituted
(C.sub.1-6)alkyl, or both together with the carbon atom to which
they are attached form a saturated 3 to 6 member cyclic ring which
may optionally include one or more heteroatoms which may be same or
different and are selected from O, NR.sup.e and S; Z is selected
from CR.sup.c, S, O, NR.sup.c, R.sup.cC.dbd.CR.sup.c,
--N.dbd.CR.sup.c--, and --R.sup.cC.dbd.N--; Z.sub.1 is selected
from N, NR.sup.c and CR.sup.c; R.sup.c is absent or selected from
hydrogen, hydroxy and halogen; and all other variables are the same
as described herein above.
[0065] Further preferred is a compound of formula (IV) wherein X is
N.
[0066] Further preferred is a compound of formula (IV) wherein each
occurrence of R.sup.2 is H.
[0067] Further preferred is a compound of formula (IV) wherein each
of R.sup.a and R.sup.b is hydrogen.
[0068] Further preferred is a compound of formula (IV) wherein
R.sup.a methyl and R.sup.b is hydrogen.
[0069] Further preferred is a compound of formula (IV) wherein
R.sup.a is fluoro and R.sup.b is hydrogen.
[0070] Further preferred is a compound of formula (IV) wherein
R.sup.a and R.sup.b both are fluoro.
[0071] Further preferred is a compound of formula (IV) wherein
R.sup.a and R.sup.b both are methyl.
[0072] Further preferred is a compound of formula (IV) wherein Z is
CR.sup.c, N, S, O, HC.dbd.CH--, or --N.dbd.CH--.
[0073] Further preferred is a compound of formula (IV) wherein
Z.sub.1 is CH or N.
[0074] Further preferred is a compound of formula (IV) wherein Z is
--HC.dbd.CH--, --S-- or --O-- and Z.sub.1 is CH.
[0075] Further preferred is a compound of formula (IV) wherein Z is
--HC.dbd.CH-- and Z.sub.1 is CH.
[0076] Further preferred is a compound of formula (IV) wherein Z is
--S-- and Z.sub.1 is CH.
[0077] Further preferred is a compound of formula (IV) wherein Z is
--O-- and Z.sub.1 is CH.
[0078] Further preferred is a compound of formula (IV) wherein Z is
--CH-- and Z.sub.1 is NH.
[0079] Further preferred is a compound of formula (IV), wherein
each occurrence of R.sup.c is hydrogen or fluoro.
[0080] Further preferred is a compound of formula (IV) wherein B is
L.sub.1-Cy.sup.1, wherein L.sub.1-Cy.sup.1 is as described above
for the compound of formula (I).
[0081] Further preferred is a compound of formula (IV) wherein B is
Cy.sup.1, wherein Cy.sup.1 is as described above for the compound
of formula (IA).
[0082] Further preferred is a compound of formula (IV) wherein D is
as described above for the compound of formula (IA-1).
[0083] Further preferred is a compound of formula (IV) wherein A is
as described above for the compound of formula (II).
[0084] Further preferred is a compound of formula (IV) wherein B is
NR.sup.cR.sup.d, wherein NR.sup.cR.sup.d is as described above for
the compound of formula (IIA).
[0085] Further preferred is a compound of formula (IV) wherein B is
--U.dbd.V--W--R.sup.5, wherein U.dbd.V--W--R.sup.5 is as described
above for the compound of formula (III).
[0086] Further preferred is a compound of formula (IV) wherein
U.dbd.V--W--R.sup.5 is CR.sup.3.dbd.N--O--R.sup.5, wherein
--CR.sup.3.dbd.N--O--R.sup.5 is as described above for the compound
of formula (IIIA).
[0087] Further preferred is a compound of formula (IV) wherein
U.dbd.V--W--R.sup.5 is CR.sup.3.dbd.N--NR.sup.4R.sup.5, wherein
--CR.sup.3.dbd.N--NR.sup.4R.sup.5 is as described above for the
compound of formula (IIIB).
[0088] In one embodiment, in the compound of formula (IV), (a) the
bicyclic ring containing ring atoms Z and Z.sub.1 is quinoline,
benzo[d]thiazol-6-yl, or an N-oxide thereof, which is optionally
substituted with one or two halogen (e.g., F), (b) R.sup.a,
R.sup.b, and each R.sup.c are hydrogen, (c) each R.sup.2 is
hydrogen, and (d) B is substituted phenyl, substituted thiophenyl,
--CR.sup.3.dbd.N--O--R.sup.5 or --CR.sup.3.dbd.N--NR.sup.4R.sup.5
(where R.sup.3, R.sup.4, and R.sup.5 are as described above for the
compounds of formulas (IIIA) and (IIIB)). For example, B may be
4-amidophenyl (i.e., 4-NH.sub.2C(O)--Ph) or 4-(R'--NHC(O))-phenyl
(where R' is (C.sub.1-C.sub.4)alkyl), where the phenyl group may
optionally be further substituted by one, two, or three
substituents selected from halogens (e.g., F or Cl) and fluorinated
methyl (e.g., --CF.sub.3). In another embodiment, B is thiophenyl
substituted with hydroxymethyl, or B is a pyrazolyl group
optionally substituted with (C.sub.1-C.sub.6)alkyl or hydroxy
(C.sub.1-C.sub.6)alkyl.
[0089] Yet another embodiment is a compound of formula (IVA) or
(IVB):
##STR00076##
or a tautomer, stereoisomer, enantiomer, diastereomer, salt (e.g.,
pharmaceutically acceptable salt), prodrug (e.g., ester), or
N-oxide thereof, wherein R.sup.a is halogen or substituted or
unsubstituted (C.sub.1-6)alkyl (e.g., methyl); and all other
variables are the same as described herein above.
[0090] In one embodiment, the bicyclic ring containing ring atoms Z
and Z.sub.1 in the compound of formula (IVA) is quinoline or an
N-oxide thereof, which is optionally substituted with one or two
halogen (e.g., F).
[0091] In one embodiment, the bicyclic ring containing ring atoms Z
and Z.sub.1 in the compound of formula (IVB) is quinoline or an
N-oxide thereof, which is optionally substituted with one or two
halogen (e.g., F).
[0092] In one embodiment, the bicyclic ring containing ring atoms Z
and Z.sub.1 in the compound of formula (IVA) is
benzo[d]thiazol-6-yl or an N-oxide thereof, which is optionally
substituted with one or two halogen (e.g., F).
[0093] In one embodiment, the bicyclic ring containing ring atoms Z
and Z.sub.1 in the compound of formula (IVB) is
benzo[d]thiazol-6-yl or an N-oxide thereof, which is optionally
substituted with one or two halogen (e.g., F).
[0094] In a preferred embodiment, B in compound (IVA) or (IVB) is
substituted phenyl, substituted thiophenyl,
--CR.sup.3.dbd.N--O--R.sup.5 or --CR.sup.3.dbd.N--NR.sup.4R.sup.5
(where R.sup.3, R.sup.4, and R.sup.5 are as described above for the
compounds of formulas (IIIA) and (IIIB)). For example, B may be
4-amidophenyl (i.e., 4-NH.sub.2C(O)-phenyl) or
4-(R'--NHC(O))-phenyl (where R' is (C.sub.1-C.sub.4) alkyl), where
the phenyl group may optionally be further substituted by one, two,
or three substituents selected from halogens (e.g., F or Cl) and
fluorinated methyl (e.g., --CF.sub.3). In another embodiment, B is
thiophenyl substituted with hydroxymethyl, or B is a pyrazolyl
group optionally substituted with (C.sub.1-C.sub.6)alkyl or hydroxy
(C.sub.1-C.sub.6)alkyl.
[0095] In a preferred embodiment, each R.sup.2 is hydrogen.
[0096] Representative compounds of the present invention include
those specified below and pharmaceutically acceptable salts
thereof. The present invention should not be construed to be
limited to them. [0097] 1.
6-((5-(4-Methoxyphenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)q-
uinoline [0098] 2.
6-((5-(3-Methoxyphenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quin-
oline [0099] 3.
3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzalde-
hyde [0100] 4.
(3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)-
methanol [0101] 5.
4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzalde-
hyde [0102] 6.
(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)-
methanol [0103] 7. Methyl
4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoate
[0104] 8.
4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-y-
l)benzoic acid [0105] 9.
N-Methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)benzamide [0106] 10.
4-(3-(4-Fluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzaldehyde
[0107] 11.
(4-(3-(4-Fluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)metha-
nol [0108] 12. Methyl
2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)benzoate [0109] 13.
2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)benzoic acid [0110] 14.
2-Fluoro-N-methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyr-
idin-5-yl)benzamide [0111] 15.
2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)benzamide [0112] 16.
(2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-y-
l)phenyl) methanol [0113] 17. Methyl
4-(3-(2-chloro-3,6-difluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-
-2-fluoro benzoate [0114] 18.
4-(3-(2-Chloro-3,6-difluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-
-2-fluoro benzoic acid [0115] 19.
4-(3-(2-Chloro-3,6-difluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-
-2-fluoro-N-methyl benzamide [0116] 20.
N-(2-Hydroxyethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]py-
ridin-5-yl)benzamide [0117] 21.
4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamid-
e [0118] 22. Lithium
4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoate
[0119] 23.
6-((5-(3-(trifluoromethoxy)phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-
methyl)quinoline [0120] 24.
3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenol
[0121] 25.
6-((5-(3-(difluoromethoxy)phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)m-
ethyl) quinoline [0122] 26.
(4-Methylpiperazin-1-yl)(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,-
5-b]pyridin-5-yl)phenyl)methanone [0123] 27.
N-(2-(dimethylamino)ethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[-
4,5-b]pyridin-5-yl)benzamide [0124] 28.
4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(tetr-
ahydro-2H-pyran-4-yl)benzamide [0125] 29. tert-Butyl
4-(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benza-
mido)piperidine-1-carboxylate [0126] 30.
N-(Piperidin-4-yl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]py-
ridin-5-yl)benzamide hydrochloride [0127] 31.
N-(2-(dimethylamino)ethyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]-
triazolo[4,5-b]pyridin-5-yl)benzamide [0128] 32.
(S)-(2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)(4-(3-(quinolin-6-ylmethyl)-
-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)methanone
hydrochloride [0129] 33.
(4-(2-hydroxyethyl)piperazin-1-yl)(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]t-
riazolo[4,5-b]pyridin-5-yl)phenyl)methanone [0130] 34.
(R)-(3-hydroxypyrrolidin-1-yl)(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triaz-
olo[4,5-b]pyridin-5-yl)phenyl)methanone hydrochloride [0131] 35.
N-(2-(piperidin-1-yl)ethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo-
[4,5-b]pyridin-5-yl)benzamide [0132] 36.
N-(2-morpholinoethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b-
]pyridin-5-yl)benzamide [0133] 37.
N-(2-(pyrrolidin-1-yl)ethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazol-
o[4,5-b]pyridin-5-yl)benzamide [0134] 38.
(4-(pyrrolidin-1-yl)piperidin-1-yl)(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]-
triazolo[4,5-b]pyridin-5-yl)phenyl)methanone [0135] 39.
N-(3-(dimethylamino)propyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo-
[4,5-b]pyridin-5-yl)benzamide [0136] 40.
N,N-Bis(2-methoxyethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-
-b]pyridin-5-yl)benzamide hydrochloride [0137] 41.
(2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-y-
l)phenyl)methanol hydrochloride [0138] 42.
6-((5-(3-Fluoro-4-(methoxymethyl)phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-
-3-yl)methyl)quinoline [0139] 43.
N-ethyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyri-
din-5-yl)benzamide [0140] 44.
2-Fluoro-N-(2-(pyrrolidin-1-yl)ethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,-
3]triazolo[4,5-b]pyridin-5-yl)benzamide [0141] 45.
N-cyclohexyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b-
]pyridin-5-yl)benzamide [0142] 46.
N-Cyclopropyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5--
b]pyridin-5-yl)benzamide [0143] 47.
2-Fluoro-N-(pyridin-4-yl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4-
,5-b]pyridin-5-yl)benzamide [0144] 48.
N-Benzyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyr-
idin-5-yl)benzamide [0145] 49.
2-Fluoro-N,N-dimethyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b-
]pyridin-5-yl)benzamide [0146] 50. Methyl
2-(2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-
-yl)benzamido)acetate. [0147] 51.
2-(2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-
-yl)benzamido)acetic acid [0148] 52.
2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)-N-(1H-1,2,4-triazol-3-yl)benzamide [0149] 53. Methyl
3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoate
[0150] 54.
3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoic
acid [0151] 55.
N-Methyl-3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)benzamide [0152] 56.
6-((5-(3-Fluorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quino-
line [0153] 57. Methyl
3-(2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-
-yl) phenyl amino) propanoate [0154] 58.
3-(2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-
-yl)phenylamino)propanoic acid [0155] 59.
2-Fluoro-N-methoxy-N-methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo-
[4,5-b]pyridin-5-yl)benzamide hydrochloride [0156] 60.
N-tert-Butyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b-
]pyridin-5-yl)benzamide [0157] 61.
N-Allyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyri-
din-5-yl)benzamide [0158] 62.
2-Fluoro-N-methoxy-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]py-
ridin-5-yl)benzamide [0159] 63.
N-(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)pheny-
l) acetamide [0160] 64.
4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)aniline
[0161] 65.
6-((5-(3,4-Dimethoxyphenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)-
quinoline [0162] 66.
6-((5-(3-Fluoro-4-methoxyphenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)me-
thyl) quinoline [0163] 67.
6-((5-(4-Fluorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quino-
line [0164] 68.
6-((5-(2-Fluorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quino-
line [0165] 69.
N-(3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)pheny-
l) acetamide [0166] 70.
6-((5-(3-(2,2,2-Trifluoroethoxyl)phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-
-3-yl)methyl) quinoline [0167] 71.
3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)aniline
[0168] 72.
N-(3-(dimethylamino)propyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3-
]triazolo[4,5-b]pyridin-5-yl)benzamide [0169] 73.
N-Ethyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyri-
din-5-yl)benzamide hydrochloride [0170] 74.
2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)benzamide hydrochloride [0171] 75.
6-((5-(3-Fluoro-4-isopropoxyphenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl-
)methyl) quinoline [0172] 76.
N-(3-(dimethylamino)-3-oxopropyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H--
[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide [0173] 77.
N-(2-(dimethylamino)-2-oxoethyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[-
1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide [0174] 78.
2-Fluoro-N-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-4-(3-(quinolin-6-ylmethyl)-3H-
-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide [0175] 79.
6-((5-(4-(Cyclopropylmethoxy)-3-fluorophenyl)-3H-[1,2,3]triazolo[4,5-b]py-
ridin-3-yl)methyl) quinoline [0176] 80.
6-((5-(3-Fluoro-4-isobutoxyphenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-
methyl)quinoline [0177] 81.
3-(2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-
-yl) phenoxy)-N,N-dimethylpropan-1-amine [0178] 82. Methyl
2-fluoro-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyr-
idin-5-yl)benzoate [0179] 83.
2-Fluoro-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyr-
idin-5-yl)benzoic acid [0180] 84.
2-Fluoro-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyr-
idin-5-yl)benzamide [0181] 85.
6-((5-(3-Fluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl)-3H-[1,2,3]triazolo-
[4,5-b]pyridin-3-yl)methyl)quinoline [0182] 86.
6-((5-(3-Fluoro-4-(2-methoxyethoxyl)phenyl)-3H-[1,2,3]triazolo[4,5-b]pyri-
din-3-yl)methyl)quinoline [0183] 87.
2-Fluoro-N-propyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyr-
idin-5-yl)benzamide [0184] 88.
6-((5-(4-(Cyclopropylcarbamoyl)-3-fluorophenyl)-3H-[1,2,3]triazolo[4,5-b]-
pyridin-3-yl)methyl)quinoline 1-oxide [0185] 89.
N-Cyclopropyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5--
b]pyridin-5-yl)benzamide hydrochloride [0186] 90.
N-(Cyclopropylmethyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triaz-
olo[4,5-b]pyridin-5-yl)benzamide [0187] 91.
N-Butyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyri-
din-5-yl)benzamide [0188] 92.
2-Fluoro-N-(furan-2-ylmethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazo-
lo[4,5-b]pyridin-5-yl)benzamide [0189] 93.
2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)-N-(2,2,2-trifluoroethyl)benzamide [0190] 94.
2-Fluoro-N-(2-methoxyethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo-
[4,5-b]pyridin-5-yl)benzamide [0191] 95.
N-Isopropyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-
-yl)benzenesulfonamide [0192] 96.
N,N-Dimethyl-3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin--
5-yl) aniline [0193] 97.
2-Fluoro-N-isobutyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]p-
yridin-5-yl)benzamide [0194] 98.
N-Cyclopentyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5--
b]pyridin-5-yl)benzamide [0195] 99.
2-Fluoro-N-isopropyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]-
pyridin-5-yl)benzamide [0196] 100. Methyl
2-chloro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)benzoate [0197] 101.
2-Chloro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)benzoic acid [0198] 102.
2-Chloro-N-propyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyr-
idin-5-yl)benzamide [0199] 103.
2-Fluoro-N-methyl-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[-
4,5-b]pyridin-5-yl)benzamide [0200] 104.
N-Cyclobutyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b-
]pyridin-5-yl)benzamide [0201] 105.
2-Fluoro-N-propyl-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[-
4,5-b]pyridin-5-yl)benzamide [0202] 106.
N-Cyclopropyl-2-fluoro-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]tria-
zolo[4,5-b]pyridin-5-yl)benzamide [0203] 107.
N-Ethyl-2-fluoro-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[4-
,5-b]pyridin-5-yl)benzamide [0204] 108.
2-Chloro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)benzamide: [0205] 109.
2-Chloro-N-methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyr-
idin-5-yl)benzamide [0206] 110.
2-Fluoro-N-methoxy-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]py-
ridin-5-yl)benzamide hydrochloride [0207] 111.
2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)-N-(thiazol-2-yl)benzamide [0208] 112.
N-(3-Aminopropyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[-
4,5-b]pyridin-5-yl)benzamide [0209] 113.
2-Chloro-N-cyclopropyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5--
b]pyridin-5-yl)benzamide [0210] 114.
2-Fluoro-N-(3-oxo-3-(pyrrolidin-1-yl)propyl)-4-(3-(quinolin-6-ylmethyl)-3-
H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide [0211] 115.
2-Fluoro-N-hydroxy-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]py-
ridin-5-yl)benzamide [0212] 116.
N-Isopropyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-
-yl)benzamide [0213] 117.
2-Fluoro-N-(3-oxo-3-(piperidin-1-yl)propyl)-4-(3-(quinolin-6-ylmethyl)-3H-
-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide [0214] 118.
1-Ethyl-3-(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5--
yl)phenyl) urea [0215] 119.
2-Chloro-N-ethyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyri-
din-5-yl)benzamide [0216] 120.
2-Fluoro-N-(3-morpholino-3-oxopropyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,-
3]triazolo[4,5-b]pyridin-5-yl)benzamide [0217] 121.
N-(3-(dimethylamino)propyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3-
]triazolo[4,5-b]pyridin-5-yl)benzamide dihydrochloride [0218] 122.
2-chloro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)-N-(1H-1,2,4-triazol-3-yl)benzamide [0219] 123.
2-Chloro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)benzamide hydrochloride [0220] 124.
2-Fluoro-N-(3-(piperidin-1-yl)propyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,-
3]triazolo[4,5-b]pyridin-5-yl)benzamide [0221] 125.
N-(3-Aminopropyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[-
4,5-b]pyridin-5-yl)benzamide dihydrochloride [0222] 126.
2-Chloro-N-(3-(dimethylamino)propyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3-
]triazolo[4,5-b]pyridin-5-yl)benzamide dihydrochloride [0223] 127.
2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)-N-(1H-1,2,4-triazol-3-yl)benzamide hydrochloride [0224] 128.
Methyl
2,6-difluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin--
5-yl)benzoate [0225] 129.
2,6-Difluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin--
5-yl)benzoic acid [0226] 130.
2,6-Difluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin--
5-yl)benzamide [0227] 131. Methyl
2-chloro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]py-
ridin-5-yl)benzoate [0228] 132.
2-Chloro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]py-
ridin-5-yl)benzoic acid [0229] 133.
2-Chloro-N-ethyl-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[-
4,5-b]pyridin-5-yl)benzamide [0230] 134.
2-Chloro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]py-
ridin-5-yl)benzamide [0231] 135. Methyl
2-fluoro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]py-
ridin-5-yl)benzoate [0232] 136.
2-Fluoro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]py-
ridin-5-yl)benzoic acid
[0233] 137.
2-Fluoro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]py-
ridin-5-yl)benzamide [0234] 138.
3-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamid-
e [0235] 139.
2,6-Difluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin--
5-yl)benzamide hydrochloride [0236] 140.
2-Chloro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]py-
ridin-5-yl)benzamide hydrochloride [0237] 141.
2-Fluoro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]py-
ridin-5-yl)benzamide hydrochloride [0238] 142.
2-Methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)benzamide [0239] 143.
6-((5-(1H-Pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quin-
oline [0240] 144.
6-((5-(1-Methyl-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)me-
thyl)quinoline [0241] 145.
6-((5-(1-(2-(Tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)-3H-triaz-
olo[4,5-b]pyridin-3-yl)methyl)quinoline [0242] 146.
2-(4-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-p-
yrazol-1-yl) ethanol [0243] 147.
6-((5-(1H-Pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)quinoline
[0244] 148.
6-((5-(1-Methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)qui-
noline [0245] 149.
6-((5-(1-(2-(Tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)-3H-imida-
zo[4,5-b]pyridin-3-yl)methyl)quinoline [0246] 150.
2-(4-(3-(Quinolin-6-ylmethyl)-3H-imidazo[4,5-b]pyridin-5-yl)-1H-pyrazol-1-
-yl) ethanol [0247] 151.
2-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-ylamino)eth-
anol [0248] 152.
6-((5-(1H-Imidazol-1-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)qui-
noline [0249] 153.
6-((5-(1-Propyl-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)me-
thyl) quinoline [0250] 154. Ethyl
2-(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-p-
yrazol-1-yl)acetate [0251] 155.
2-(4-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-p-
yrazol-1-yl) acetic acid [0252] 156. tert-Butyl
4-(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-p-
yrazol-1-yl)piperidine-1-carboxylate [0253] 157.
6-((5-(1-(Piperidin-4-yl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyrid-
in-3-yl)methyl) quinoline [0254] 158.
(R)-1-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)pyrr-
olidin-3-ol [0255] 159.
3-(4-Fluorobenzyl)-5-(1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridine
[0256] 160.
3-(4-Fluorobenzyl)-5-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-
-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridine [0257] 161.
2-(4-(3-(4-Fluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-pyrazo-
l-1-yl) ethanol [0258] 162.
6-(1-(5-(1H-Pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)ethyl)qui-
noline [0259] 163.
6-(1-(5-(1-(2-(Tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)-3H-[1,-
2,3]triazolo[4,5-b]pyridin-3-yl)ethyl)quinoline [0260] 164.
2-(4-(3-(1-(Quinolin-6-yl)ethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1-
H-pyrazol-1-yl)ethanol [0261] 165.
2-(4-(3-(2-Chloro-3,6-difluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5--
yl)-1H-pyrazol-1-yl)ethanol [0262] 166. tert-Butyl
4-(4-(3-(2-chloro-3,6-difluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5--
yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate [0263] 167.
3-(2-Chloro-3,6-difluorobenzyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-
-[1,2,3]triazolo[4,5-b]pyridine hydrochloride [0264] 168.
6-((5-(3-Methyl-1H-indazol-6-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)me-
thyl) quinoline [0265] 169.
6-((5-(1H-Indol-5-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinol-
ine [0266] 170.
6-((5-(1H-Indol-6-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinol-
ine [0267] 171.
6-((5-(2-Chloropyridin-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl-
) quinoline [0268] 172.
6-((5-(3-Methyl-1H-indazol-5-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)me-
thyl) quinoline [0269] 173.
6-((5-(Pyridin-3-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoli-
ne [0270] 174.
(S)-6-((5-(1-(Pyrrolidin-3-yl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]-
pyridin-3-yl)methyl)quinoline [0271] 175.
(S)-6-((5-(1-(Pyrrolidin-3-yl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]-
pyridin-3-yl)methyl)quinoline hydrochloride [0272] 176.
4-(2-(4-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1-
H-pyrazol-1-yl)ethyl)morpholine hydrochloride [0273] 177.
6-((5-(1-(Tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4-
,5-b]pyridin-3-yl)methyl)quinoline [0274] 178.
6-((5-(1-(2-Hydroxyethyl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyrid-
in-3-yl)methyl)quinoline 1-oxide [0275] 179.
6-((5-(1,3-Dimethyl-1H-indazol-6-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-y-
l)methyl) quinoline [0276] 180.
5-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)pyrimidi-
n-2-amine [0277] 181. tert-Butyl
3-ethyl-6-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-
-1H-indazole-1-carboxylate [0278] 182.
4-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)thiophen-
e-2-carbaldehyde [0279] 183.
6-((5-(2-Methoxypyrimidin-5-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)met-
hyl) quinoline [0280] 184.
6((5-(Benzo[d][1,3]dioxol-5-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)met-
hyl) quinoline [0281] 185.
6-((5-(2,3-Dihydrobenzofuran-5-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-
methyl) quinoline [0282] 186.
5-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)pyridin--
2-amine [0283] 187.
6-((5-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridi-
n-3-yl)methyl) quinoline [0284] 188.
(4-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)thiophe-
n-2-yl) methanol [0285] 189.
6-(2-(5-(1-(2-(Tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)-3H-[1,-
2,3]triazolo[4,5-b]pyridin-3-yl)propan-2-yl)quinoline [0286] 190.
2-(4-(3-(2-(Quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-
-yl)-1H-pyrazol-1-yl)ethanol [0287] 191.
6-((5-(3-ethyl-1H-indazol-6-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)met-
hyl)quinoline [0288] 192.
6-(2-(5-(1H-Pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)propan-2--
yl) quinoline [0289] 193.
6-((5-(4-Methylthiophen-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methy-
l) quinoline [0290] 194.
6-((5-(5-Methylthiophen-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methy-
l) quinoline [0291] 195.
4-(5-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)pyrid-
in-2-yl) morpholine [0292] 196.
6-((5-(6-(Piperidin-1-yl)pyridin-3-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-
-yl)methyl) quinoline [0293] 197.
6-((5-(1-Ethyl-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)met-
hyl)quinoline [0294] 198.
6-((5-(1-Isopropyl-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl-
)methyl) quinoline [0295] 199.
6-((5-(1-Isobutyl-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-
methyl) quinoline [0296] 200.
1-(Pyrrolidin-1-yl)-2(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b-
]pyridin-5-yl)-1H-pyrazol-1-yl)ethanone [0297] 201.
6-((5-(1-(2-Methoxyethyl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyrid-
in-3-yl)methyl)quinoline [0298] 202.
N-Phenyl-3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine
[0299] 203.
6-((5-Phenoxy-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline
[0300] 204. Methyl
2-fluoro-5-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)benzoate [0301] 205.
2-Fluoro-5-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)benzoic acid [0302] 206.
2-Fluoro-5-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)benzamide [0303] 207.
2-Chloro-4-(3-((5,7-difluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5--
b]pyridin-5-yl)benzamide [0304] 208.
1-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)ethanone
[0305] 209.
2-(1-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)ethyl-
idene) hydrazinecarboxamide [0306] 210.
443-(Benzo[d]thiazol-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-2-
-chloro benzamide [0307] 211.
2-(2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-
-yl)phenyl)propan-2-ol [0308] 212.
2-Chloro-5-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)benzamide [0309] 213.
3-(2-Chloro-3,6-difluorobenzyl)-5-(1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,-
5-b]pyridine [0310] 214.
(.+-.)2-Chloro-4-(3-(1-(quinolin-6-yl)ethyl)-3H-[1,2,3]triazolo[4,5-b]pyr-
idin-5-yl)benzamide [0311] 215.
2-Chloro-4-(3-(quinolin-6-ylmethyl)-3H-imidazo[4,5-b]pyridin-5-yl)benzami-
de [0312] 216.
1-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)ethanone
oxime [0313] 217.
1-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)ethanone-
O-methyl oxime [0314] 218.
N'-(1-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)ethy-
lidene) acetohydrazide [0315] 219.
6-((5-(4-Methylpiperazin-1-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)meth-
yl) quinoline [0316] 220.
N'-(1-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)ethy-
lidene) isonicotinohydrazide [0317] 221. (-)
2-Chloro-4-(3-(1-(quinolin-6-yl)ethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-
-yl)benzamide [0318] 222. (+)
2-Chloro-4-(3-(1-(quinolin-6-yl)ethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-
-yl)benzamide [0319] 223.
4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-2-(trif-
luoromethyl)benzamide [0320] 224.
6-((5-(4-carbamoyl-3-chlorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-
methyl) quinoline 1-oxide [0321] 225.
2-chloro-N-ethyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyri-
din-5-yl)benzamide hydrochloride [0322] 226.
6-((5-(4-carbamoyl-3-chlorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-
methyl) quinoline 1-oxide [0323] 227.
6-((5-(3-methyl-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)me-
thyl)quinoline
TABLE-US-00001 [0323] TABLE 1 Compound Structure Ex 1 ##STR00077##
Ex 2 ##STR00078## Ex 3 ##STR00079## Ex 4 ##STR00080## Ex 5
##STR00081## Ex 6 ##STR00082## Ex 7 ##STR00083## Ex 8 ##STR00084##
Ex 9 ##STR00085## Ex 10 ##STR00086## Ex 11 ##STR00087## Ex 12
##STR00088## Ex 13 ##STR00089## Ex 14 ##STR00090## Ex 15
##STR00091## Ex 16 ##STR00092## Ex 17 ##STR00093## Ex 18
##STR00094## Ex 19 ##STR00095## Ex 20 ##STR00096## Ex 21
##STR00097## Ex 22 ##STR00098## Ex 23 ##STR00099## Ex 24
##STR00100## Ex 25 ##STR00101## Ex 26 ##STR00102## Ex 27
##STR00103## Ex 28 ##STR00104## Ex 29 ##STR00105## Ex 30
##STR00106## Ex 31 ##STR00107## Ex 32 ##STR00108## Ex 33
##STR00109## Ex 34 ##STR00110## Ex 35 ##STR00111## Ex 36
##STR00112## Ex 37 ##STR00113## Ex 38 ##STR00114## Ex 39
##STR00115## Ex 40 ##STR00116## Ex 41 ##STR00117## Ex 42
##STR00118## Ex 43 ##STR00119## Ex 44 ##STR00120## Ex 45
##STR00121## Ex 46 ##STR00122## Ex 47 ##STR00123## Ex 48
##STR00124## Ex 49 ##STR00125## Ex 50 ##STR00126## Ex 51
##STR00127## Ex 52 ##STR00128## Ex 53 ##STR00129## Ex 54
##STR00130## Ex 55 ##STR00131## Ex 56 ##STR00132## Ex 57
##STR00133## Ex 58 ##STR00134## Ex 59 ##STR00135## Ex 60
##STR00136## Ex 61 ##STR00137## Ex 62 ##STR00138## Ex 63
##STR00139## Ex 64 ##STR00140## Ex 65 ##STR00141## Ex 66
##STR00142## Ex 67 ##STR00143## Ex 68 ##STR00144## Ex 69
##STR00145## Ex 70 ##STR00146## Ex 71 ##STR00147## Ex 72
##STR00148## Ex 73 ##STR00149## Ex 74 ##STR00150## Ex 75
##STR00151## Ex 76 ##STR00152## Ex 77 ##STR00153## Ex 78
##STR00154## Ex 79 ##STR00155## Ex 80 ##STR00156## Ex 81
##STR00157## Ex 82 ##STR00158## Ex 83 ##STR00159## Ex 84
##STR00160## Ex 85 ##STR00161## Ex 86 ##STR00162## Ex 87
##STR00163## Ex 88 ##STR00164## Ex 89 ##STR00165## Ex 90
##STR00166## Ex 91 ##STR00167## Ex 92 ##STR00168## Ex 93
##STR00169## Ex 94 ##STR00170## Ex 95 ##STR00171## Ex 96
##STR00172## Ex 97 ##STR00173## Ex 98 ##STR00174## Ex 99
##STR00175## Ex 100 ##STR00176## Ex 101 ##STR00177## Ex 102
##STR00178## Ex 103 ##STR00179## Ex 104 ##STR00180## Ex 105
##STR00181## Ex 106 ##STR00182## Ex 107 ##STR00183## Ex 108
##STR00184## Ex 109 ##STR00185## Ex 110 ##STR00186## Ex 111
##STR00187## Ex 112 ##STR00188## Ex 113 ##STR00189## Ex 114
##STR00190## Ex 115 ##STR00191## Ex 116 ##STR00192## Ex 117
##STR00193## Ex 118 ##STR00194## Ex 119 ##STR00195## Ex 120
##STR00196## Ex 121 ##STR00197## Ex 122 ##STR00198## Ex 123
##STR00199##
Ex 124 ##STR00200## Ex 125 ##STR00201## Ex 126 ##STR00202## Ex 127
##STR00203## Ex 128 ##STR00204## Ex 129 ##STR00205## Ex 130
##STR00206## Ex 131 ##STR00207## Ex 132 ##STR00208## Ex 133
##STR00209## Ex 134 ##STR00210## Ex 135 ##STR00211## Ex 136
##STR00212## Ex 137 ##STR00213## Ex 138 ##STR00214## Ex 139
##STR00215## Ex 140 ##STR00216## Ex 141 ##STR00217## Ex 142
##STR00218## Ex 143 ##STR00219## Ex 144 ##STR00220## Ex 145
##STR00221## Ex 146 ##STR00222## Ex 147 ##STR00223## Ex 148
##STR00224## Ex 149 ##STR00225## Ex 150 ##STR00226## Ex 151
##STR00227## Ex 152 ##STR00228## Ex 153 ##STR00229## Ex 154
##STR00230## Ex 155 ##STR00231## Ex 156 ##STR00232## Ex 157
##STR00233## Ex 158 ##STR00234## Ex 159 ##STR00235## Ex 160
##STR00236## Ex 161 ##STR00237## Ex 162 ##STR00238## Ex 163
##STR00239## Ex 164 ##STR00240## Ex 165 ##STR00241## Ex 166
##STR00242## Ex 167 ##STR00243## Ex 168 ##STR00244## Ex 169
##STR00245## Ex 170 ##STR00246## Ex 171 ##STR00247## Ex 172
##STR00248## Ex 173 ##STR00249## Ex 174 ##STR00250## Ex 175
##STR00251## Ex 176 ##STR00252## Ex 177 ##STR00253## Ex 178
##STR00254## Ex 179 ##STR00255## Ex 180 ##STR00256## Ex 181
##STR00257## Ex182 ##STR00258## Ex183 ##STR00259## Ex184
##STR00260## Ex185 ##STR00261## Ex186 ##STR00262## Ex187
##STR00263## Ex188 ##STR00264## Ex189 ##STR00265## Ex190
##STR00266## Ex 191 ##STR00267## Ex 192 ##STR00268## Ex 193
##STR00269## Ex 194 ##STR00270## Ex 195 ##STR00271## Ex 196
##STR00272## Ex 197 ##STR00273## Ex 198 ##STR00274## Ex 199
##STR00275## Ex 200 ##STR00276## Ex 201 ##STR00277## Ex 202
##STR00278## Ex 203 ##STR00279## Ex 204 ##STR00280## Ex 205
##STR00281## Ex 206 ##STR00282## Ex 207 ##STR00283## Ex 208
##STR00284## Ex 209 ##STR00285## Ex 210 ##STR00286## Ex 211
##STR00287## Ex 212 ##STR00288## Ex 213 ##STR00289## Ex 214
##STR00290## Ex 215 ##STR00291## Ex 216 ##STR00292## Ex 217
##STR00293## Ex 218 ##STR00294## Ex 219 ##STR00295## Ex 220
##STR00296## Ex221 ##STR00297## Ex 222 ##STR00298## Ex 223
##STR00299## Ex 224 ##STR00300## Ex 225 ##STR00301## Ex 226
##STR00302## Ex 227 ##STR00303##
[0324] Yet another embodiment of the present invention is a method
for treating a proliferative disease via modulation of a protein
kinase (such as c-Met) by administering to a patient in need of
such treatment an effective amount of at least one compound of
formula (I), (I-A), (IA-1), (II), (II-A), (III), (IIIA), (IIIB),
(IV), (IVA) or (IVB) as defined above.
[0325] Yet another embodiment of the present invention is a method
for treating a proliferative disease via modulation of a protein
kinase (such as c-Met) by administering to a patient in need of
such treatment an effective amount of at least one compound of
formula (I), (I-A), (IA-1), (II), (II-A), (III), (IIIA), (IIIB),
(IV), (IVA) or (IVB) as defined above, in combination
(simultaneously or sequentially) with at least one other
anti-cancer agent. In a preferred embodiment, the proliferative
disease is cancer.
[0326] More particularly, the compounds of formula (I), (I-A),
(IA-1), (II), (II-A), (III), (IIIA), (IIIB), (IV), (IVA) or (IVB)
and pharmaceutically acceptable esters or salts thereof can be
administered for the treatment, prevention and/or amelioration of
c-Met, RON, EGFR or KDR kinase associated diseases or disorders,
including but not limited to, cancer and other proliferative
diseases or disorders.
[0327] The compounds of formula (I), (I-A), (IA-1), (II), (II-A),
(III), (IIIA), (IIIB), (IV), (IVA) or (IVB) are useful in the
treatment of a variety of cancers, including, but not limited to,
the following: [0328] carcinoma, including that of the bladder,
breast, colon, kidney, liver, lung, including small cell lung
cancer, esophagus, gall bladder, ovary, pancreas, stomach, cervix,
thyroid, prostate, and skin, including squamous cell carcinoma;
[0329] hematopoietic tumors of lymphoid lineage, including
leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia,
B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkins
lymphoma, hairy cell lymphoma and Burkett's lymphoma; [0330]
hematopoietic tumors of myeloid lineage, including acute and
chronic myelogenous leukemias, myelodysplastic syndrome and
promyelocytic leukemia; [0331] tumors of mesenchymal origin,
including fibrosarcoma and rhabdomyosarcoma; [0332] tumors of the
central and peripheral nervous system, including astrocytoma,
neuroblastoma, glioma and schwannomas; and [0333] other tumors,
including melanoma, seminoma, teratocarcinoma, osteosarcoma,
xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer
and Kaposi's sarcoma.
[0334] Due to the key role of protein kinases in the regulation of
cellular proliferation in general, inhibitors could act as
reversible cytostatic agents which may be useful in the treatment
of any disease process which features abnormal cellular
proliferation, e.g., benign prostatic hyperplasia, familial
adenomatosis polyposis, neuro-fibromatosis, atherosclerosis,
pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis,
restenosis following angioplasty or vascular surgery, hypertrophic
scar formation, inflammatory bowel disease, transplantation
rejection, endotoxic shock, and fungal infections.
[0335] The compounds of the present invention as modulators of
apoptosis, are useful in the treatment of cancer (including but not
limited to those types mentioned herein above), viral infections
(including but not limited to herpevirus, poxvirus,
Epstein-Barr-virus, Sindbis virus and adenovirus), prevention of
AIDS development in HIV-infected individuals, autoimmune diseases
(including but not limited to systemic lupus, erythematosus,
autoimmune mediated glomerulonephritis, rheumatoid arthritis,
psoriasis, inflammatory bowel disease, and autoimmune diabetes
mellitus), neurodegenerative disorders (including but not limited
to Alzheimer's disease, AIDS-related dementia, Parkinson's disease,
amyotrophic lateral sclerosis, retinitis pigmentosa, spinal
muscular atrophy and cerebellar degeneration), myelodysplastic
syndromes, aplastic anemia, ischemic injury associated with
myocardial infarctions, stroke and reperfusion injury, arrhythmia,
atherosclerosis, toxin-induced or alcohol related liver diseases,
hematological diseases (including but not limited to chronic anemia
and aplastic anemia), degenerative diseases of the musculoskeletal
system (including but not limited to osteoporosis and arthritis)
aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple
sclerosis, kidney diseases and cancer pain.
[0336] The compounds of present invention can modulate the level of
cellular RNA and DNA synthesis. These agents are therefore useful
in the treatment of viral infections (including but not limited to
HIV, human papilloma virus, herpesvirus, poxvirus, Epstein-Barr
virus, Sindbis virus and adenovirus).
[0337] The compounds of the present invention are useful in the
chemoprevention of cancer. Chemoprevention is defined as inhibiting
the development of invasive cancer by either blocking the
initiating mutagenic event or by blocking the progression of
pre-malignant cells that have already suffered an insult or
inhibiting tumor relapse. The compounds are also useful in
inhibiting tumor angiogenesis and metastasis. One embodiment of the
invention is a method of inhibiting tumor angiogenesis or
metastasis in a patient in need thereof by administering an
effective amount of one or more compounds of the present
invention.
[0338] Another embodiment of the present invention is a method of
treating an immune system-related disease (e.g., an autoimmune
disease), a disease or disorder involving inflammation (e.g.,
asthma, chronic obstructive pulmonary disease, rheumatoid
arthritis, inflammatory bowel disease, glomerulonephritis,
neuroinflammatory diseases, multiple sclerosis, uveitis and
disorders of the immune system), cancer or other proliferative
disease, a hepatic disease or disorder, a renal disease or
disorder. The method includes administering an effective amount of
one or more compounds of the present invention.
[0339] Examples of immune disorders include psoriasis, rheumatoid
arthritis, vasculitis, inflammatory bowel disease, dermatitis,
osteoarthritis, asthma, inflammatory muscle disease, allergic
rhinitis, vaginitis, interstitial cystitis, scleroderma,
osteoporosis, eczema, allogeneic or xenogeneic transplantation
(organ, bone marrow, stem cells and other cells and tissues) graft
rejection, graft-versus-host disease, lupus erythematosus,
inflammatory disease, type I diabetes, pulmonary fibrosis,
dermatomyositis, Sjogren's syndrome, thyroiditis (e.g., Hashimoto's
and autoimmune thyroiditis), myasthenia gravis, autoimmune
hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic
relapsing hepatitis, primary biliary cirrhosis, allergic
conjunctivitis and atopic dermatitis.
[0340] In one embodiment, the compounds described herein are used
as immunosuppresants to prevent transplant graft rejections,
allogeneic or xenogeneic transplantation rejection (organ, bone
marrow, stem cells, other cells and tissues), and graft-versus-host
disease. In other embodiments, transplant graft rejections result
from tissue or organ transplants. In further embodiments,
graft-versus-host disease results from bone marrow or stem cell
transplantation. One embodiment is a method of preventing or
decreasing the risk of transplant graft rejection, allogeneic or
xenogeneic transplantation rejection (organ, bone marrow, stem
cells, other cells and tissues), or graft-versus-host disease by
administering an effective amount of one or more compounds of the
present invention.
[0341] The compounds of the present invention are also useful in
combination (administered together or sequentially) with known
anti-cancer treatments such as radiation therapy or with cytostatic
or cytotoxic or anticancer agents, such as for example, but not
limited to, DNA interactive agents, such as cisplatin or
doxorubicin; topoisomerase II inhibitors, such as etoposide;
topoisomerase I inhibitors such as CPT-11 or topotecan; tubulin
interacting agents, such as paclitaxel, docetaxel or the
epothilones (for example ixabepilone), either naturally occurring
or synthetic; hormonal agents, such as tamoxifen; thymidilate
synthase inhibitors, such as 5-fluorouracil; and anti-metabolites,
such as methotrexate, other tyrosine kinase inhibitors such as
Iressa and OSI-774; angiogenesis inhibitors; EGF inhibitors; VEGF
inhibitors; CDK inhibitors; SRC inhibitors; c-Kit inhibitors;
Her1/2 inhibitors and monoclonal antibodies directed against growth
factor receptors such as erbitux (EGF) and herceptin (Her2) and
other protein kinase modulators as well.
[0342] RON The compounds of the present invention are also useful
in combination (administered together or sequentially) with one or
more steroidal anti-inflammatory drugs, non-steroidal
anti-inflammatory drugs (NSAIDs) or Immune Selective
Anti-Inflammatory Derivatives (ImSAIDs).
[0343] The invention further provides a pharmaceutical composition
comprising one or more compounds of the present invention (such as
a compound having formula (I), (I-A), (IA-1), (II), (II-A), (III),
(IIIA), (IIIB), (IV), (IVA) or (IVB)) 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
formula (I), (I-A), (IA-1), (II), (II-A), (III), (IIIA), (IIIB),
(IV), (IVA) or (IVB).
[0344] Yet another embodiment is a method of treating leukemia in a
patient 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 carcinoma of the bladder, carcinoma of the breast,
carcinoma of the colon, carcinoma of the kidney, carcinoma of the
liver, carcinoma of the lung, small cell lung cancer, esophageal
cancer, gall bladder cancer, ovarian cancer, pancreatic cancer,
stomach cancer, cervical cancer, thyroid cancer, prostate cancer,
skin cancer, squamous cell carcinoma; cholangiocarcinoma cancer,
tumors of mesenchymal origin, fibrosarcoma, rhabdomyosarcoma;
tumors of the central and peripheral nervous system, astrocytoma,
neuroblastoma, glioma, schwannoma; melanoma, seminoma,
teratocarcinoma, osteosarcoma, xenoderoma pigmentosum,
keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma,
synovial sarcoma, rhabdomyosarcoma, MFH/fibrosarcoma,
leiomyosarcoma, multiple myeloma, lymphoma, glioblastoma,
astrocytoma, melanoma, mesothelioma, Wilm's tumor, hematopoietic
tumors of lymphoid lineage, leukemia, acute lymphocytic leukemia,
acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma,
Hodgkin's lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma and
Burkett's lymphoma; hematopoietic tumors of myeloid lineage, acute
myelogenous leukemias, chronic myelogenous leukemias,
myelodysplastic syndrome, promyelocytic leukemia.
[0345] Yet another embodiment is a pharmaceutical composition
comprising one or more compounds having formula (I), (I-A), (IA-1),
(II), (II-A), (III), (IIIA), (IIIB), (IV), (IVA) or (IVB) together
with a pharmaceutically acceptable carrier.
DETAIL DESCRIPTION
[0346] 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.
[0347] The term `alkyl` refers to a straight or branched
hydrocarbon chain radical consisting solely of carbon and hydrogen
atoms, containing no unsaturation, having 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).
[0348] 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.
[0349] 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 about 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.
[0350] The term substituted or unsubstituted (C.sub.1-6)alkenyl
refers to an alkenyl group as defined above having up to 4 carbon
atoms.
[0351] The term "alkynyl" refers to a straight or branched chain
hydrocarbyl radicals having at least one carbon-carbon triple bond,
and having in the range of about 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.
[0352] The term substituted or unsubstituted (C.sub.1-6)alkynyl
refers to an alkynyl group as defined above having up to 4 carbon
atoms.
[0353] 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 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.
[0354] The term "cycloalkyl" denotes a non-aromatic mono or
multicyclic ring system of about 3 to 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.
[0355] The term "C.sub.3-8 cycloalkyl" refers to an cycloalkyl
group as defined above having up to 6 atoms.
[0356] The term "cycloalkylalkyl" refers to a cyclic
ring-containing radical containing in the range of about 3 up to 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.
[0357] The term "C.sub.3-6 cycloalkylalkyl" refers to an
cycloalkylalkyl group as defined above having up to 6 atoms.
[0358] The term "cycloalkenyl" refers to cyclic ring-containing
radicals containing in the range of about 3 up to 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
[0359] The term "C.sub.3-6 cycloalkenyl" refers to an cycloalkenyl
group as defined above having up to 6 atoms.
[0360] The term "aryl" refers to aromatic radicals having in the
range of 6 up to 20 carbon atoms such as phenyl, naphthyl,
tetrahydronapthyl, indanyl, and biphenyl.
[0361] 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.
[0362] 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.
[0363] 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.
[0364] 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.
[0365] 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.
[0366] 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.
[0367] 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.
[0368] The term "cyclic ring" refers to a cyclic ring containing
3-10 carbon atoms.
[0369] 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 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 heterocyclcyalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted arylalkyl,
substituted or unsubstituted heteroaryl, 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'). 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.
[0370] 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" include haloalkyl and
haloalkoxy groups, respectively, in which the halo is fluorine.
[0371] 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, --CH2CH2SO2Ph, 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.
[0372] 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.
[0373] 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.
[0374] 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 mixtures 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.
[0375] 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.
[0376] 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.
[0377] 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.
[0378] 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'.
[0379] These prodrugs and esters are intended to be covered within
the scope of this invention.
[0380] 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.
[0381] 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.
[0382] 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.
[0383] 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.
[0384] The following abbreviations and terms have the indicated
meanings throughout: HGFR is hepatocyte growth factor receptor;
AIDS=Acquired Immuno Deficiency Syndrome; HIV=Human
Immunodeficiency Virus; MeI=Methyl Iodide; POCI.sub.3=Phosphorous
Oxychloride; KCNS=Potassium IsoThiocyanate; TLC=Thin Layer
Chromatography; MeOH=Methanol; and CHCI.sub.3=Chloroform.
[0385] Abbreviations used herein have their conventional meaning
within the chemical and biological arts.
[0386] The term "cell proliferation" refers to a phenomenon by
which the cell number has changed as a result of division. This
term also encompasses cell growth by which the cell morphology has
changed (e.g., increased in size) consistent with a proliferative
signal.
[0387] 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.
[0388] 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.
[0389] 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 patient, notwithstanding
that the patient may still be afflicted with the underlying
disorder. For prophylactic benefit, the compositions may be
administered to a patient at risk of developing a particular
disease, or to a patient reporting one or more of the physiological
symptoms of a disease, even though a diagnosis of this disease may
not have been made.
[0390] 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.
[0391] The term "subject" or "patient" refers to an animal, such as
a mammal, for example a human. The methods described herein can be
useful in both human therapeutics and veterinary applications. In
some embodiments, the patient is a mammal, and in some embodiments,
the patient is human.
[0392] "Radiation therapy" means exposing a patient, using routine
methods and compositions known to the practitioner, to radiation
emitters such as alpha-particle emitting radionuclides (e.g.,
actinium and thorium radionuclides), low linear energy transfer
(LET) radiation emitters (i.e. beta emitters), conversion electron
emitters (e.g. strontium-89 and samarium-153-EDTMP, or high-energy
radiation, including without limitation x-rays, gamma rays, and
neutrons.
[0393] "Signal transduction" is a process during which stimulatory
or inhibitory signals are transmitted into and within a cell to
elicit an intracellular response. A modulator of a signal
transduction pathway refers to a compound which modulates the
activity of one or more cellular proteins mapped to the same
specific signal transduction pathway. A modulator may augment
(agonist) or suppress (antagonist) the activity of a signaling
molecule.
[0394] The term "selective inhibition" or "selectively inhibit" as
applied to a biologically active agent refers to the agent's
ability to selectively reduce the target signaling activity as
compared to off-target signaling activity, via direct or indirect
interaction with the target.
[0395] 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.
[0396] Inhibition of c-met kinase may be of therapeutic benefit in
treatment of various conditions, e.g., conditions characterized by
an inflammatory response including but not limited to autoimmune
diseases, allergic diseases, and arthritic diseases.
[0397] "Inflammatory response" as used herein is characterized by
redness, heat, swelling and pain (i.e., inflammation) and typically
involves tissue injury or destruction. An inflammatory response is
usually a localized, protective response elicited by injury or
destruction of tissues, which serves to destroy, dilute or wall off
(sequester) both the injurious agent and the injured tissue.
Inflammatory responses are notably associated with the influx of
leukocytes and/or leukocyte (e.g., neutrophil) chemotaxis.
Inflammatory responses may result from infection with pathogenic
organisms and viruses, noninfectious means such as trauma or
reperfusion following myocardial infarction or stroke, immune
responses to foreign antigens, and autoimmune diseases.
Inflammatory responses amenable to treatment with the methods and
compounds according to the invention encompass conditions
associated with reactions of the specific defense system as well as
conditions associated with reactions of the non-specific defense
system.
[0398] The therapeutic methods of the invention include methods for
the amelioration of conditions associated with inflammatory cell
activation. "Inflammatory cell activation" refers to the induction
by a stimulus (including but not limited to, cytokines, antigens or
auto-antibodies) of a proliferative cellular response, the
production of soluble mediators (including but not limited to
cytokines, oxygen radicals, enzymes, prostanoids, or vasoactive
amines), or cell surface expression of new or increased numbers of
mediators (including but not limited to, major histocompatibility
antigens or cell adhesion molecules) in inflammatory cells
(including but not limited to monocytes, macrophages, T
lymphocytes, B lymphocytes, granulocytes (polymorphonuclear
leukocytes including neutrophils, basophils, and eosinophils) mast
cells, dendritic cells, Langerhans cells, and endothelial cells).
It will be appreciated by persons skilled in the art that the
activation of one or a combination of these phenotypes in these
cells can contribute to the initiation, perpetuation, or
exacerbation of an inflammatory condition.
[0399] "Autoimmune disease" as used herein refers to any group of
disorders in which tissue injury is associated with humoral or
cell-mediated responses to the body's own constituents. "Transplant
rejection" as used herein refers-to any immune response directed
against grafted tissue (including organs or cells (e.g., bone
marrow), characterized by a loss of function of the grafted and
surrounding tissues, pain, swelling, leukocytosis, and
thrombocytopenia). "Allergic disease" as used herein refers to any
symptoms, tissue damage, or loss of tissue function resulting from
allergy. "Arthritic disease" as used herein refers to any disease
that is characterized by inflammatory lesions of the joints
attributable to a variety of etiologies. "Dermatitis" as used
herein refers to any of a large family of diseases of the skin that
are characterized by inflammation of the skin attributable to a
variety of etiologies.
[0400] The relative efficacies of compounds as inhibitors of an
enzyme activity (or other biological activity) can be established
by determining the concentrations at which each compound inhibits
the activity to a predefined extent and then comparing the results.
Typically, the preferred determination is the concentration that
inhibits 50% of the activity in a biochemical assay, i.e., the 50%
inhibitory concentration or "IC50". IC50 determinations can be
accomplished using conventional techniques known in the art. In
general, an IC50 can be determined by measuring the activity of a
given enzyme in the presence of a range of concentrations of the
inhibitor under study. The experimentally obtained values of enzyme
activity then are plotted against the inhibitor concentrations
used. The concentration of the inhibitor that shows 50% enzyme
activity (as compared to the activity in the absence of any
inhibitor) is taken as the IC50 value. Analogously, other
inhibitory concentrations can be defined through appropriate
determinations of activity. For example, in some settings it can be
desirable to establish a 90% inhibitory concentration, i.e., IC90,
etc.
[0401] Accordingly, a c-met selective inhibitor alternatively can
be understood to refer to a compound that exhibits a 50% inhibitory
concentration (IC50) with respect to c-met kinase, that is at least
10-fold, in another aspect at least 20-fold, and in another aspect
at least 30-fold, lower than the IC50 value with respect to any or
all of the other class receptor tyrosine kinase (RTK) family
members. In an alternative embodiment of the invention, the term
c-met kinase selective inhibitor can be understood to refer to a
compound that exhibits an IC50 with respect to c-met kinase that is
at least 50-fold, in another aspect at least 100-fold, in an
additional aspect at least 200-fold, and in yet another aspect at
least 500-fold, lower than the IC50 with respect to any or all of
the other RTK family members. A c-met kinase selective inhibitor is
typically administered in an amount such that it selectively
inhibits c-met activity, as described above.
[0402] The methods of the invention may be applied to cell
populations in vivo or ex vivo. "In vivo" means within a living
individual, as within an animal or human or in a subject's body. In
this context, the methods of the invention may be used
therapeutically or prophylactically in an individual. "Ex vivo" or
"In vitro" means outside of a living individual. Examples of ex
vivo cell populations include in vitro cell cultures and biological
samples including but not limited to fluid or tissue samples
obtained from individuals. Such samples may be obtained by methods
known in the art. Exemplary biological fluid samples include blood,
cerebrospinal fluid, urine, and saliva. Exemplary tissue samples
include tumors and biopsies thereof. In this context, the invention
may be used for a variety of purposes, including therapeutic and
experimental purposes. For example, the invention may be used ex
vivo or in vitro to determine the optimal schedule and/or dosing of
administration of a c-met kinase selective inhibitor for a given
indication, cell type, individual, and other parameters.
Information gleaned from such use may be used for experimental or
diagnostic purposes or in the clinic to set protocols for in vivo
treatment. Other ex vivo uses for which the invention may be suited
are described below or will become apparent to those skilled in the
art.
Pharmaceutical Compositions
[0403] The invention provides a pharmaceutical composition
comprising one or more compounds of the present invention. The
pharmaceutical composition may include one or more additional
active ingredients as described herein. The pharmaceutical
composition may be administered for any of the disorders described
herein
[0404] In some embodiments, the invention provides pharmaceutical
compositions for treating diseases or conditions related to an
undesirable, over-active, harmful or deleterious immune response in
a mammal Such undesirable immune response can be associated with or
result in, e.g., asthma, emphysema, bronchitis, psoriasis, allergy,
anaphylaxsis, auto-immune diseases, rhuematoid arthritis, graft
versus host disease, and lupus erythematosus. The pharmaceutical
compositions of the present invention can be used to treat other
respiratory diseases including but not limited to diseases
affecting the lobes of lung, pleural cavity, bronchial tubes,
trachea, upper respiratory tract, or the nerves and muscle for
breathing.
[0405] In some embodiments, the invention provides pharmaceutical
compositions for the treatment of disorders such as
hyperproliferative disorder including but not limited to cancer
such as acute myeloid leukemia, thymus, brain, lung, squamous cell,
skin, eye, retinoblastoma, intraocular melanoma, oral cavity and
oropharyngeal, bladder, gastric, stomach, pancreatic, bladder,
breast, cervical, head, neck, renal, kidney, liver, ovarian,
prostate, colorectal, esophageal, testicular, gynecological,
thyroid, CNS, PNS, AIDS related (e.g. Lymphoma and Kaposi's
Sarcoma) or Viral-Induced cancer. In some embodiments, the
pharmaceutical composition is for the treatment of a non-cancerous
hyperproliferative disorder such as benign hyperplasia of the skin
(e. g., psoriasis), restenosis, or prostate (e. g., benign
prostatic hypertrophy (BPH)).
[0406] The invention also relates to a composition for treating a
disease related to vasculogenesis or angiogenesis in a mammal which
can manifest as tumor angiogenesis, chronic inflammatory disease
such as rheumatoid arthritis, inflammatory bowel disease,
atherosclerosis, skin diseases such as psoriasis, eczema, and
scleroderma, diabetes, diabetic retinopathy, retinopathy of
prematurity, age-related macular degeneration, hemangioma, glioma,
melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic,
prostate, colon and epidermoid cancer.
[0407] The invention also provides compositions for the treatment
of liver diseases (including diabetes), pancreatitis or kidney
disease (including proliferative glomerulonephritis and
diabetes-induced renal disease) or pain in a mammal.
[0408] The invention further provides a composition for the
prevention of blastocyte implantation in a mammal.
[0409] The subject pharmaceutical compositions are typically
formulated to provide a therapeutically effective amount of a
compound of the present invention as the active ingredient, or a
pharmaceutically acceptable salt, ester, or prodrug thereof. Where
desired, the pharmaceutical compositions contain a compound of the
present invention as the active ingredient or a pharmaceutically
acceptable salt and/or coordination complex thereof, and one or
more pharmaceutically acceptable excipients, carriers, such as
inert solid diluents and fillers, diluents, including sterile
aqueous solution and various organic solvents, permeation
enhancers, solubilizers and adjuvants.
[0410] The subject pharmaceutical compositions can be administered
alone or in combination with one or more other agents, which are
also typically administered in the form of pharmaceutical
compositions. Where desired, the subject compounds and other
agent(s) may be mixed into a preparation or both components may be
formulated into separate preparations to use them in combination
separately or at the same time.
[0411] Methods include administration of an inhibitor by itself, or
in combination as described herein, and in each case optionally
including 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.
[0412] Preparations of various pharmaceutical compositions are
known in the art. See, e.g., Anderson, Philip O.; Knoben, James E.;
Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth
Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of
Drug Action, Third Edition, Churchill Livingston, N.Y., 1990;
Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition,
McGraw Hill, 2003; Goodman and Gilman, eds., The Pharmacological
Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons
Pharmaceutical Sciences, 20th Ed., Lippincott Williams &
Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second
Edition (The Pharmaceutical Press, London, 1999), all of which are
incorporated by reference herein in their entirety.
[0413] The compounds or pharmaceutical composition of the present
invention can be administered by any route that enables delivery of
the compounds to the site of action, such asoral routes,
intraduodenal routes, parenteral injection (including intravenous,
intraarterial, subcutaneous, intramuscular, intravascular,
intraperitoneal or infusion), topical administration (e.g.
transdermal application), rectal administration, via local delivery
by catheter or stent or through inhalation. The compounds can also
be administered intraadiposally or intrathecally.
[0414] The compositions can be administered in solid, semi-solid,
liquid or gaseous form, or may be in dried powder, such as
lyophilized form. The pharmaceutical compositions can be packaged
in forms convenient for delivery, including, for example, solid
dosage forms such as capsules, sachets, cachets, gelatins, papers,
tablets, capsules, suppositories, pellets, pills, troches, and
lozenges. The type of packaging will generally depend on the
desired route of administration. Implantable sustained release
formulations are also contemplated, as are transdermal
formulations.
Routes of Administration
[0415] In the methods according to the invention, the inhibitor
compounds may be administered by various routes. For example,
pharmaceutical compositions may be for injection, or for oral,
nasal, transdermal or other forms of administration, including,
e.g., by intravenous, intradermal, intramuscular, intramammary,
intraperitoneal, intrathecal, intraocular, retrobulbar,
intrapulmonary (e.g., aerosolized drugs) or subcutaneous injection
(including depot administration for long term release e.g.,
embedded-under the-splenic capsule, brain, or in the cornea); by
sublingual, anal, or vaginal administration, or by surgical
implantation, e.g., embedded under the splenic capsule, brain, or
in the cornea. The treatment may consist of a single dose or a
plurality of doses over a period of time. In general, the methods
of the invention involve administering effective amounts of a
modulator of the invention together with one or more
pharmaceutically acceptable diluents, preservatives, solubilizers,
emulsifiers, adjuvants and/or carriers, as described above.
[0416] The subject pharmaceutical composition may, for example, be
in a form suitable for oral administration as a tablet, capsule,
pill, powder, sustained release formulations, solution, suspension,
for parenteral injection as a sterile solution, suspension or
emulsion, for topical administration as an ointment or cream or for
rectal administration as a suppository. The pharmaceutical
composition may be in unit dosage forms suitable for single
administration of precise dosages. The pharmaceutical composition
will include a conventional pharmaceutical carrier or excipient and
a compound according to the invention as an active ingredient. In
addition, it may include other medicinal or pharmaceutical agents,
carriers, and adjuvants.
[0417] In one aspect, the invention provides methods for oral
administration of a pharmaceutical composition of the invention.
Oral solid dosage forms are described generally in Remington's
Pharmaceutical Sciences, supra at Chapter 89. Solid dosage forms
include tablets, capsules, pills, troches or lozenges, and cachets
or pellets. Also, liposomal or proteinoid encapsulation may be used
to formulate the compositions (as, for example, proteinoid
microspheres reported in U.S. Pat. No. 4,925,673). Liposomal
encapsulation may include liposomes that are derivatized with
various polymers (e.g., U.S. Pat. No. 5,013,556). The formulation
may include a compound of the invention and inert ingredients which
protect against degradation in the stomach and which permit release
of the biologically active material in the intestine.
[0418] Toxicity and therapeutic efficacy of the met kinase
compounds can be determined by standard pharmaceutical procedures
in cell cultures or experimental animals, e.g., for determining the
LD50 (the dose lethal to 50% of the population) and the ED50 (the
dose therapeutically effective in 50% of the population).
Additionally, this information can be determined in cell cultures
or experimental animals additionally treated with other therapies
including but not limited to radiation, chemotherapeutic agents,
photodynamic therapies, radiofrequency ablation, anti-angiogenic
agents, and combinations thereof.
[0419] The amount of the compound administered will be dependent on
the mammal being treated, the severity of the disorder or
condition, the rate of administration, the disposition of the
compound and the discretion of the prescribing physician. However,
an effective dosage is in the range of about 0.001 to about 100 mg
per kg body weight per day, preferably about 1 to about 35
mg/kg/day, in single or divided doses. For a 70 kg human, this
would amount to about 0.05 to 7 g/day, preferably about 0.05 to
about 2.5 g/day. In some instances, dosage levels below the lower
limit of the aforesaid range may be more than adequate, while in
other cases still larger doses may be employed without causing any
harmful side effect, e.g. by dividing such larger doses into
several small doses for administration throughout the day.
[0420] In some embodiments, a compound of the invention is
administered in a single dose. Typically, such administration will
be by injection, e.g., intravenous injection, in order to introduce
the agent quickly. However, other routes may be used as
appropriate. A single dose of a compound of the invention may also
be used for treatment of an acute condition.
[0421] In practice of the methods of the invention, the
pharmaceutical compositions are generally provided in doses ranging
from 1 pg compound/kg body weight to 1000 mg/kg, 0.1 mg/kg to 100
mg/kg, 0.1 mg/kg to 50 mg/kg, and 1 to 20 mg/kg, given in daily
doses or in equivalent doses at longer or shorter intervals, e.g.,
every other day, twice weekly, weekly, or twice or three times
daily. The inhibitor compositions may be administered by an initial
bolus followed by a continuous infusion to maintain therapeutic
circulating levels of drug product. Those of ordinary skill in the
art will readily optimize effective dosages and administration
regimens as determined by good medical practice and the clinical
condition of the individual to be treated. The frequency of dosing
will depend on the pharmacokinetic parameters of the agents and the
route of administration. The optimal pharmaceutical formulation
will be determined by one skilled in the art depending upon the
route of administration and desired dosage [see, for example,
Remington's Pharmaceutical Sciences, pp. 1435-1712, the disclosure
of which is hereby incorporated by reference]. Such formulations
may influence the physical state, stability, rate of in vivo
release, and rate of in vivo clearance of the administered agents.
Depending on the route of administration, a suitable dose may be
calculated according to body weight, body surface area or organ
size. Further refinement of the calculations necessary to determine
the appropriate dosage for treatment involving each of the above
mentioned formulations is routinely made by those of ordinary skill
in the art without undue experimentation, especially in light of
the dosage information and assays disclosed herein, as well as the
pharmacokinetic data observed in human clinical trials. Appropriate
dosages may be ascertained by using established assays for
determining blood level dosages in conjunction with an appropriate
physician considering various factors which modify the action of
drugs, e.g., the drug's specific activity, the severity of the
indication, and the responsiveness of the individual, the age,
condition, body weight, sex and diet of the individual, the time of
administration and other clinical factors. As studies are
conducted, further information will emerge regarding the
appropriate dosage levels and duration of treatment for various
diseases and conditions capable of being treated with the methods
of the invention.
[0422] In some embodiments, a compound of the invention is
administered in multiple doses. Dosing may be about once, twice,
three times, four times, five times, six times, or more than six
times per day. Dosing may be about once a month, once every two
weeks, once a week, or once every other day. In another embodiment
a compound of the invention and another agent are administered
together about once per day to about 6 times per day. In another
embodiment the administration of a compound of the invention and an
agent continues for less than about 7 days. In yet another
embodiment the administration continues for more than about 6, 10,
14, 28 days, two months, six months, or one year. In some cases,
continuous dosing is achieved and maintained as long as
necessary.
[0423] Administration of the agents of the invention may continue
as long as necessary. In some embodiments, an agent of the
invention is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or
28 days. In some embodiments, an agent of the invention is
administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In
some embodiments, an agent of the invention is administered
chronically on an ongoing basis, e.g., for the treatment of chronic
effects.
[0424] An effective amount of a compound of the invention may be
administered in either single or multiple doses by any of the
accepted modes of administration of agents having similar
utilities, including rectal, buccal, intranasal and transdermal
routes, by intra-arterial injection, intravenously,
intraperitoneally, parenterally, intramuscularly, subcutaneously,
orally, topically, or as an inhalant.
[0425] The compounds of the invention may be administered in
dosages. It is known in the art that due to intersubject
variability in compound pharmacokinetics, individualization of
dosing regimen is necessary for optimal therapy. Dosing for a
compound of the invention may be found by routine experimentation
in light of the instant disclosure.
[0426] When a compound of the invention, is administered in a
composition that comprises one or more agents, and the agent has a
shorter half-life than the compound of the invention unit dose
forms of the agent and the compound of the invention may be
adjusted accordingly.
[0427] The inhibitors of the invention may be covalently or
noncovalently associated with a carrier molecule including but not
limited to a linear polymer (e.g., polyethylene glycol, polylysine,
dextran, etc.), a branched-chain polymer (see U.S. Pat. Nos.
4,289,872 and 5,229,490; PCT Publication No. WO 93/21259), a lipid,
a cholesterol group (such as a steroid), or a carbohydrate or
oligosaccharide. Specific examples of carriers for use in the
pharmaceutical compositions of the invention include
carbohydrate-based polymers such as trehalose, mannitol, xylitol,
sucrose, lactose, sorbitol, dextrans such as cyclodextran,
cellulose, and cellulose derivatives. Also, the use of liposomes,
microcapsules or microspheres, inclusion complexes, or other types
of carriers is contemplated.
[0428] Other carriers include one or more water soluble polymer
attachments such as polyoxyethylene glycol, or polypropylene glycol
as described U.S. Pat. Nos. 4,640,835, 4,496,689, 4,301,144,
4,670,417, 4,791,192 and 4,179,337. Still other useful carrier
polymers known in the art include monomethoxy-polyethylene glycol,
poly-(N-vinyl pyrrolidone)-polyethylene glycol, propylene glycol
homopolymers, a polypropylene oxidelethylene oxide co-polymer,
polyoxyethylated polyols (e.g., glycerol) and polyvinyl alcohol, as
well as mixtures of these polymers.
[0429] Derivitization with bifunctional agents is useful for
cross-linking a compound of the invention to a support matrix or to
a carrier. One such carrier is polyethylene glycol (PEG). The PEG
group may be of any convenient molecular weight and may be straight
chain or branched. The average molecular weight of the PEG can
range from about 2 kDa to about 100 kDa, in another aspect from
about 5 kDa to about 50 kDa, and in a further aspect from about 5
kDa to about 10 kDa. The PEG groups will generally be attached to
the compounds of the invention via acylation, reductive alkylation,
Michael addition, thiol alkylation or other chemoselective
conjugation/ligation methods through a reactive group on the PEG
moiety (e.g., an aldehyde, amino, ester, thiol, ci-haloacetyl,
maleimido or hydrazino group) to a reactive group on the target
inhibitor compound (e.g., an aldehyde, amino, ester, thiol,
a-haloacetyl, maleimido or hydrazino group). Cross-linking agents
can include, e.g., esters with 4-azidosalicylic acid,
homobifunctional imidoesters, including disuccinimidyl esters such
as 3,3'-dithiobis (succinimidylpropionate), and bifunctional
maleimides such as bis-N-maleimido-1,8-octane. Derivatizing agents
such as methyl-3-Rp-azidophenyl)dithiolpropioimidate yield
photoactivatable intermediates that are capable of forming
crosslinks in the presence of light. Alternatively, reactive
water-insoluble matrices such as cyanogen bromide-activated
carbohydrates and the reactive substrates described in U.S. Pat.
Nos. 3,969,287; 3,691,016; 4,195,128; 4,247,642; 4,229,537; and
4,330,440 may be employed for inhibitor immobilization.
Method of Treatment
[0430] The invention also provides methods of using the compounds
or pharmaceutical compositions of the present invention to treat
disease conditions, including but not limited to diseases
associated with malfunctioning of c-met kinase and family.
[0431] The treatment methods provided herein comprise administering
to the subject a therapeutically effective amount of a compound of
the invention. In one embodiment, the present invention provides a
method of treating an inflammation disorder, including autoimmune
diseases in a mammal. The method comprises administering to said
mammal a therapeutically effective amount of a compound of the
present invention.
[0432] The disorders, diseases, or conditions treatable with a
compound provided herein, include, but are not limited to, [0433]
inflammatory or allergic diseases, including systemic anaphylaxis
and hypersensitivity disorders, atopic dermatitis, urticaria, drug
allergies, insect sting allergies, food allergies (including celiac
disease and the like), anaphylaxis, serum sickness, drug reactions,
insect venom allergies, hypersensitivity pneumonitis, angioedema,
erythema multiforme, Stevens-Johnson syndrome, atopic
keratoconjunctivitis, venereal keratoconjunctivitis, giant
papillary conjunctivitis, and mastocytosis; [0434] inflammatory
bowel diseases, including Crohn's disease, ulcerative colitis,
ileitis, enteritis, and necrotizing enterocolitis; [0435]
vasculitis, and Behcet's syndrome; [0436] psoriasis and
inflammatory dermatoses, including dermatitis, eczema, allergic
contact dermatitis, viral cutaneous pathologies including those
derived from human papillomavirus, HIV or RLV infection, bacterial,
flugal, and other parasital cutaneous pathologies, and cutaneous
lupus erythematosus; [0437] asthma and respiratory allergic
diseases, including allergic asthma, exercise induced asthma,
allergic rhinitis, otitis media, hypersensitivity lung diseases,
chronic obstructive pulmonary disease and other respiratory
problems; [0438] autoimmune diseases and inflammatory conditions,
including but are not limited to 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), Reynaud's syndrome, Hashimoto's disease, lupus
erythematosus, systemic lupus erythematosus (SLE), multiple
sclerosis, myasthenia gravis, opsoclonus myoclonus syndrome (OMS),
optic neuritis, Ord's thyroiditis, oemphigus, polyarthritis,
primary biliary cirrhosis, psoriasis, rheumatoid arthritis,
psoriatic arthritis, gouty arthritis, spondylitis, reactive
arthritis, chronic or acute glomerulonephritis, lupus nephritis,
Reiter's syndrome, Takayasu's arteritis, temporal arteritis (also
known as "giant cell arteritis"), warm autoimmune hemolytic anemia,
Wegener's granulomatosis, alopecia universalis, Chagas' disease,
chronic fatigue syndrome, dysautonomia, endometriosis, hidradenitis
suppurativa, interstitial cystitis, neuromyotonia, sarcoidosis,
scleroderma, ulcerative colitis, connective tissue disease,
autoimmune pulmonary inflammation, autoimmune thyroiditis,
autoimmune inflammatory eye disease, vitiligo, and vulvodynia.
Other disorders include bone-resorption disorders and thromobsis;
[0439] tissue or organ transplant rejection disorders including but
not limited to graft rejection (including allograft rejection and
graft-v-host disease (GVHD)), e.g., skin graft rejection, solid
organ transplant rejection, bone marrow transplant rejection;
[0440] fever; [0441] cardiovascular disorders, including acute
heart failure, hypotension, hypertension, angina pectoris,
myocardial infarction, cardiomyopathy, congestive heart failure,
atherosclerosis, coronary artery disease, restenosis, and vascular
stenosis; [0442] cerebrovascular disorders, including traumatic
brain injury, stroke, ischemic reperfusion injury and aneurysm;
[0443] cancers of the breast, skin, prostate, cervix, uterus,
ovary, testes, bladder, lung, liver, larynx, oral cavity, colon and
gastrointestinal tract (e.g., esophagus, stomach, pancreas), brain,
thyroid, blood, and lymphatic system; [0444] fibrosis, connective
tissue disease, and sarcoidosis; [0445] genital and reproductive
conditions, including erectile dysfunction; [0446] gastrointestinal
disorders, including gastritis, ulcers, nausea, pancreatitis, and
vomiting; [0447] neurologic disorders, including Alzheimer's
disease;
[0448] sleep disorders, including insomnia, narcolepsy, sleep apnea
syndrome, and Pickwick Syndrome; [0449] pain, myalgias due to
infection; [0450] renal disorders; [0451] ocular disorders,
including glaucoma; [0452] infectious diseases, including HIV;
[0453] sepsis; septic shock; endotoxic shock; gram negative sepsis;
gram positive sepsis; toxic shock syndrome; multiple organ injury
syndrome secondary to septicemia, trauma, or hemorrhage; [0454]
pulmonary or respiratory conditions including but not limited to
asthma, chronic bronchitis, allergic rhinitis, adult respiratory
distress syndrome (ARDS), severe acute respiratory syndrome (SARS),
chronic pulmonary inflammatory diseases (e.g., chronic obstructive
pulmonary disease), silicosis, pulmonary sarcoidosis, pleurisy,
alveolitis, vasculitis, pneumonia, bronchiectasis, hereditary
emphysema, and pulmonary oxygen toxicity; [0455]
ischemic-reperfusion injury, e.g., of the myocardium, brain, or
extremities; [0456] fibrosis including but not limited to cystic
fibrosis; keloid formation or scar tissue formation; [0457] central
or peripheral nervous system inflammatory conditions including but
not limited to meningitis (e.g., acute purulent meningitis),
encephalitis, and brain or spinal cord injury due to minor trauma;
[0458] Sjorgren's syndrome; diseases involving leukocyte
diapedesis; alcoholic hepatitis; bacterial pneumonia; community
acquired pneumonia (CAP); Pneumocystis carinii pneumonia (PCP);
antigen-antibody complex mediated diseases; hypovolemic shock;
acute and delayed hypersensitivity; disease states due to leukocyte
dyscrasia and metastasis; thermal injury; granulocyte transfusion
associated syndromes; cytokine-induced toxicity; stroke;
pancreatitis; myocardial infarction, respiratory syncytial virus
(RSV) infection; and spinal cord injury.
[0459] In certain embodiments, the cancer or cancers treatable with
the methods provided herein includes, but is or are not limited to,
[0460] leukemias, including, but not limited to, acute leukemia,
acute lymphocytic leukemia, acute myelocytic leukemias such as
myeloblasts, promyelocyte, myelomonocytic, monocytic,
erythroleukemia leukemias and myelodysplastic syndrome or a symptom
thereof (such as anemia, thrombocytopenia, neutropenia, bicytopenia
or pancytopenia), refractory anemia (RA), RA with ringed
sideroblasts (RARS), RA with excess blasts (RAEB), RAEB in
transformation (RAEB-T), preleukemia, and chronic myelomonocytic
leukemia (CMML); [0461] chronic leukemias, including, but not
limited to, chronic myelocytic (granulocytic) leukemia, chronic
lymphocytic leukemia, and hairy cell leukemia; [0462] polycythemia
vera; [0463] lymphomas, including, but not limited to, Hodgkin's
disease and non-Hodgkin's disease; [0464] multiple myelomas,
including, but not limited to, smoldering multiple myeloma,
nonsecretory myeloma, osteosclerotic myeloma, plasma cell leukemia,
solitary plasmacytoma, and extramedullary plasmacytoma; [0465]
Waldenstrom's macroglobulinemia; monoclonal gammopathy of
undetermined significance; benign monoclonal gammopathy; [0466]
heavy chain disease; [0467] bone and connective tissue sarcomas,
including, but not limited to, bone sarcoma, osteosarcoma,
chondrosarcoma, Ewing's sarcoma, malignant giant cell tumor,
fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissue
sarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi's
sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, metastatic
cancers, neurilemmoma, rhabdomyosarcoma, and synovial sarcoma;
[0468] brain tumors, including, but not limited to, glioma,
astrocytoma, brain stem glioma, ependymoma, oligodendroglioma,
nonglial tumor, acoustic neurinoma, craniopharyngioma,
medulloblastoma, meningioma, pineocytoma, pineoblastoma, and
primary brain lymphoma; [0469] breast cancer, including, but not
limited to, adenocarcinoma, lobular (small cell) carcinoma,
intraductal carcinoma, medullary breast cancer, mucinous breast
cancer, tubular breast cancer, papillary breast cancer, primary
cancers, Paget's disease, and inflammatory breast cancer; [0470]
adrenal cancer, including, but not limited to, pheochromocytom and
adrenocortical carcinoma; [0471] thyroid cancer, including, but not
limited to, papillary or follicular thyroid cancer, medullary
thyroid cancer, and anaplastic thyroid cancer; [0472] pancreatic
cancer, including, but not limited to,insulinoma, gastrinoma,
glucagonoma, vipoma, somatostatin-secreting tumor, and carcinoid or
islet cell tumor; [0473] pituitary cancer, including, but limited
to, Cushing's disease, prolactin-secreting tumor, acromegaly, and
diabetes insipidus; [0474] eye cancer, including, but not limited,
to ocular melanoma such as iris melanoma, choroidal melanoma, and
cilliary body melanoma, and retinoblastoma; [0475] vaginal cancer,
including, but not limited to, squamous cell carcinoma,
adenocarcinoma, and melanoma; [0476] vulvar cancer, including, but
not limited to, squamous cell carcinoma, melanoma, adenocarcinoma,
basal cell carcinoma, sarcoma, and Paget's disease; [0477] cervical
cancers, including, but not limited to, squamous cell carcinoma,
and adenocarcinoma; [0478] uterine cancer, including, but not
limited to, endometrial carcinoma and uterine sarcoma; [0479]
ovarian cancer, including, but not limited to, ovarian epithelial
carcinoma, borderline tumor, germ cell tumor, and stromal tumor;
[0480] esophageal cancer, including, but not limited to, squamous
cancer, adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid
carcinoma, adenosquamous carcinoma, sarcoma, melanoma,
plasmacytoma, verrucous carcinoma, and oat cell (small cell)
carcinoma; [0481] stomach cancer, including, but not limited to,
adenocarcinoma, fungating (polypoid), ulcerating, superficial
spreading, diffusely spreading, malignant lymphoma, liposarcoma,
fibrosarcoma, and carcinosarcoma; [0482] colon cancer; [0483]
rectal cancer; [0484] liver cancer, including, but not limited to,
hepatocellular carcinoma and hepatoblastoma; [0485] gallbladder
cancer, including, but not limited to, adenocarcinoma; [0486]
cholangiocarcinomas, including, but not limited to, pappillary,
nodular, and diffuse; [0487] lung cancer, including, but not
limited to, non-small cell lung cancer, squamous cell carcinoma
(epidermoid carcinoma), adenocarcinoma, large-cell carcinoma, and
small-cell lung cancer; [0488] testicular cancer, including, but
not limited to, germinal tumor, seminoma, anaplastic, classic
(typical), spermatocytic, nonseminoma, embryonal carcinoma,
teratoma carcinoma, and choriocarcinoma (yolk-sac tumor); [0489]
prostate cancer, including, but not limited to, adenocarcinoma,
leiomyosarcoma, and rhabdomyosarcoma; [0490] penal cancer; [0491]
oral cancer, including, but not limited to, squamous cell
carcinoma; [0492] bas al cancer; [0493] salivary gland cancer,
including, but not limited to, adenocarcinoma, mucoepidermoid
carcinoma, and adenoidcystic carcinoma; [0494] pharynx cancer,
including, but not limited to, squamous cell cancer and verrucous;
[0495] skin cancer, including, but not limited to, basal cell
carcinoma, squamous cell carcinoma and melanoma, superficial
spreading melanoma, nodular melanoma, lentigo malignant melanoma,
and acral lentiginous melanoma; [0496] kidney cancer, including,
but not limited to, renal cell cancer, adenocarcinoma, [0497]
hypernephroma, fibrosarcoma, and transitional cell cancer (renal
pelvis and/or uterer); [0498] Wilms' tumor; [0499] bladder cancer,
including, but not limited to, transitional cell carcinoma,
squamous cell cancer, adenocarcinoma, and carcinosarcoma; and other
cancer, including, not limited to, myxosarcoma, osteogenic sarcoma,
endotheliosarcoma, lymphangio-endotheliosarcoma, mesothelioma,
synovioma, hemangioblastoma, epithelial carcinoma,
cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma,
sebaceous gland carcinoma, papillary carcinoma, and papillary
adenocarcinomas See Fishman et al., 1985, Medicine, 2d Ed., J.B.
Lippincott Co., Philadelphia and Murphy et al., 1997, Informed
Decisions: The Complete Book of Cancer Diagnosis, Treatment, and
Recovery, Viking Penguin, Penguin Books U.S.A., Inc., United States
of America.
[0500] 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.
[0501] In another embodiment, the compounds described herein are
used for the treatment of cancer such as acute myeloid leukemia,
thymus, brain, lung, squamous cell, skin, eye, retinoblastoma,
intraocular melanoma, oral cavity and oropharyngeal, bladder,
gastric, stomach, pancreatic, bladder, breast, cervical, head,
neck, renal, kidney, liver, ovarian, prostate, colorectal,
esophageal, testicular, gynecological, thyroid, CNS, PNS,
AIDS-related (e.g. Lymphoma and Kaposi's Sarcoma) or viral-induced
cancer. In some embodiments, said method relates to the treatment
of a non-cancerous hyperproliferative disorder such as benign
hyperplasia of the skin (e. g., psoriasis), restenosis, or prostate
(e.g., benign prostatic hypertrophy (BPH)).
[0502] The invention also relates to a method of treating diseases
related to vasculogenesis or angiogenesis in a mammal that
comprises administering to said mammal a therapeutically effective
amount of a compound of the present invention. In some embodiments,
said method is for treating a disease selected from the group
consisting of tumor angiogenesis, chronic inflammatory disease such
as rheumatoid arthritis, atherosclerosis, inflammatory bowel
disease, skin diseases such as psoriasis, eczema, and scleroderma,
diabetes, diabetic retinopathy, retinopathy of prematurity,
age-related macular degeneration, hemangioma, glioma, melanoma,
Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate,
colon and epidermoid cancer.
[0503] Patients that can be treated with compounds of the present
invention, according to the methods of this invention include, for
example, patients that have been diagnosed as having psoriasis;
restenosis; atherosclerosis; BPH; breast cancer such as a ductal
carcinoma in duct tissue in a mammary gland, medullary carcinomas,
colloid carcinomas, tubular carcinomas, and inflammatory breast
cancer; ovarian cancer, including epithelial ovarian tumors such as
adenocarcinoma in the ovary and an adenocarcinoma that has migrated
from the ovary into the abdominal cavity; uterine cancer; cervical
cancer such as adenocarcinoma in the cervix epithelial including
squamous cell carcinoma and adenocarcinomas; prostate cancer, such
as a prostate cancer selected from the following: an adenocarcinoma
or an adenocarinoma that has migrated to the bone; pancreatic
cancer such as epitheliod carcinoma in the pancreatic duct tissue
and an adenocarcinoma in a pancreatic duct; bladder cancer such as
a transitional cell carcinoma in urinary bladder, urothelial
carcinomas (transitional cell carcinomas), tumors in the urothelial
cells that line the bladder, squamous cell carcinomas,
adenocarcinomas, and small cell cancers; leukemia such as acute
myeloid leukemia (AML), acute lymphocytic leukemia, chronic
lymphocytic leukemia, chronic myeloid leukemia, hairy cell
leukemia, myelodysplasia, myeloproliferative disorders, acute
myelogenous leukemia (AML), chronic myelogenous leukemia (CML),
mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma
(MM), and myelodysplastic syndrome (MDS); bone cancer; lung cancer
such as non-small cell lung cancer (NSCLC), which is divided into
squamous cell carcinomas, adenocarcinomas, and large cell
undifferentiated carcinomas, and small cell lung cancer; skin
cancer such as basal cell carcinoma, melanoma, squamous cell
carcinoma and actinic keratosis, which is a skin condition that
sometimes develops into squamous cell carcinoma; eye
retinoblastoma; cutaneous or intraocular (eye) melanoma; primary
liver cancer (cancer that begins in the liver); kidney cancer;
thyroid cancer such as papillary, follicular, medullary and
anaplastic; AIDS-related lymphoma such as diffuse large B-cell
lymphoma, B-cell immunoblastic lymphoma and small non-cleaved cell
lymphoma; Kaposi's Sarcoma; viral-induced cancers including
hepatitis B virus (HBV), hepatitis C virus (HCV), and
hepatocellular carcinoma; human lymphotropic virus-type 1 (HTLV-I)
and adult T-cell leukemia/lymphoma; and human papilloma virus (HPV)
and cervical cancer; central nervous system cancers (CNS) such as
primary brain tumor, which includes gliomas (astrocytoma,
anaplastic astrocytoma, or glioblastoma multiforme),
Oligodendroglioma, Ependymoma, Meningioma, Lymphoma, Schwannoma,
and Medulloblastoma; peripheral nervous system (PNS) cancers such
as acoustic neuromas and malignant peripheral nerve sheath tumor
(MPNST) including neurofibromas and schwannomas, malignant fibrous
cytoma, malignant fibrous histiocytoma, malignant meningioma,
malignant mesothelioma, and malignant mixed Miillerian tumor; oral
cavity and oropharyngeal cancer such as, hypopharyngeal cancer,
laryngeal cancer, nasopharyngeal cancer, and oropharyngeal cancer;
stomach cancer such as lymphomas, gastric stromal tumors, and
carcinoid tumors; testicular cancer such as germ cell tumors
(GCTs), which include seminomas and nonseminomas, and gonadal
stromal tumors, which include Leydig cell tumors and Sertoli cell
tumors; thymus cancer such as to thymomas, thymic carcinomas,
Hodgkin disease, non-Hodgkin lymphomas carcinoids or carcinoid
tumors; rectal cancer; and colon cancer.
[0504] 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.
[0505] In addition, the compounds described herein may be used to
treat acne.
[0506] 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.
[0507] 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.
[0508] 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 thyroiditiSjOstheoarthritis,
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.
[0509] 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.
[0510] In another aspect, the present invention provides methods of
disrupting the function of a leukocyte or disrupting a function of
an osteoclast. The method includes contacting the leukocyte or the
osteoclast with a function disrupting amount of a compound of the
invention.
[0511] In another aspect of the present invention, methods are
provided for treating ophthalmic disease by administering one or
more of the subject compounds or pharmaceutical compositions to the
eye of a subject.
[0512] The invention further provides methods of modulating kinase
activity by contacting a kinase with an amount of a compound of the
invention sufficient to modulate the activity of the kinase.
Modulate can be inhibiting or activating kinase activity. In some
embodiments, the invention provides methods of inhibiting kinase
activity by contacting a kinase with an amount of a compound of the
invention sufficient to inhibit the activity of the kinase. In some
embodiments, the invention provides methods of inhibiting kinase
activity in a solution by contacting said solution with an amount
of a compound of the invention sufficient to inhibit the activity
of the kinase in said solution. In some embodiments, the invention
provides methods of inhibiting kinase activity in a cell by
contacting said cell with an amount of a compound of the invention
sufficient to inhibit the activity of the kinase in said cell. In
some embodiments, the invention provides methods of inhibiting
kinase activity in a tissue by contacting said tissue with an
amount of a compound of the invention sufficient to inhibit the
activity of the kinase in said tissue. In some embodiments, the
invention provides methods of inhibiting kinase activity in an
organism by contacting said organism with an amount of a compound
of the invention sufficient to inhibit the activity of the kinase
in said organism. In some embodiments, the invention provides
methods of inhibiting kinase activity in an animal by contacting
said animal with an amount of a compound of the invention
sufficient to inhibit the activity of the kinase in said animal. In
some embodiments, the invention provides methods of inhibiting
kinase activity in a mammal by contacting said mammal with an
amount of a compound of the invention sufficient to inhibit the
activity of the kinase in said mammal. In some embodiments, the
invention provides methods of inhibiting kinase activity in a human
by contacting said human with an amount of a compound of the
invention sufficient to inhibit the activity of the kinase in said
human. In some embodiments, the % of kinase activity after
contacting a kinase with a compound of the invention is less than
1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or 99% of the kinase
activity in the absence of said contacting step.
[0513] In some embodiments, the kinase is a protein kinase, more
particularly a non-receptor or receptor tyrosine protein kinase. In
some embodiments, the kinase is selected from the group consisting
of C-met including mutants if any; AbI, VEGFR, Ephrin receptor B4
(EphB4); TEK receptor tyrosine kinase (HE2); FMS-related tyrosine
kinase 3 (FLT-3); Platelet derived growth factor receptor (PDGFR);
RET; ATM; ATR; hSmg-1; Hck; Src; Epidermal growth factor receptor
(EGFR); KIT; Inulsin Receptor (IR) and IGFR.
[0514] The invention further provides methods of modulating c-met
kinase activity by contacting a c-met kinase with an amount of a
compound of the invention sufficient to modulate the activity of
the c-met kinase. Modulate can be inhibiting or activating c-met
kinase activity. In some embodiments, the invention provides
methods of inhibiting c-met kinase activity by contacting a c-met
kinase with an amount of a compound of the invention sufficient to
inhibit the activity of the c-met kinase. In some embodiments, the
invention provides methods of inhibiting c-met kinase activity.
Such inhibition can take place in solution, in a cell expressing
one or more c-met kinase, in a tissue comprising a cell expressing
one or more c-met kinases, or in an organism expressing one or more
c-met kinase. In some embodiments, the invention provides methods
of inhibiting c-met kinase activity in an animal (including mammal
such as humans) by contacting said animal with an amount of a
compound of the invention sufficient to inhibit the activity of the
c-met kinase in said animal.
Combination Treatment
[0515] The present invention also provides methods for combination
therapies in which an agent known to modulate other pathways, or
other components of the same pathway, or even overlapping sets of
target enzymes 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
chemotherapeutic agents, therapeutic antibodies, and radiation
treatment, to provide a synergistic or additive therapeutic
effect.
[0516] For treatment of autoimmune diseases, the subject compounds
or pharmaceutical compositions can be used in combination with
commonly prescribed drugs including but not limited to Enbrel.RTM.,
Remicade.RTM., Humira.RTM., Avonex.RTM., and Rebif.RTM.. For
treatment of respiratory diseases, the subject compounds or
pharmaceutical compositions can be administered in combination with
commonly prescribed drugs including but not limited to Xolair.RTM.,
Advair.RTM., Singulair.RTM., and Spiriva.RTM..
[0517] The compounds of the invention may be formulated or
administered in conjunction with other agents that act to relieve
the symptoms of inflammatory conditions such as encephalomyelitis,
asthma, and the other diseases described herein. These agents
include non-steroidal anti-inflammatory drugs (NSAIDs), e.g.
acetylsalicylic acid; ibuprofen; naproxen; indomethacin;
nabumetone; tolmetin; etc. Corticosteroids are used to reduce
inflammation and suppress activity of the immune system. The most
commonly prescribed drug of this type is Prednisone. Chloroquine
(Aralen) or hydroxychloroquine (Plaquenil) may also be very useful
in some individuals with lupus. They are most often prescribed for
skin and joint symptoms of lupus. Azathioprine (Imuran) and
cyclophosphamide (Cytoxan) suppress inflammation and tend to
suppress the immune system. Other agents, e.g. methotrexate and
cyclosporin are used to control the symptoms of lupus.
Anticoagulants are employed to prevent blood from clotting rapidly.
They range from aspirin at very low dose which prevents platelets
from sticking, to heparin/coumadin.
[0518] In another one aspect, this invention also relates to a
pharmaceutical composition for inhibiting abnormal cell growth in a
mammal which comprises an amount of a compound of the present
invention, in combination with an amount of an anti-cancer agent
(e.g. a chemotherapeutic agent). Many chemotherapeutics are
presently known in the art and can be used in combination with the
compounds of the invention.
[0519] In some embodiments, the chemotherapeutic is selected from
the group consisting of mitotic inhibitors, alkylating agents,
anti-metabolites, intercalating antibiotics, growth factor
inhibitors, cell cycle inhibitors, enzymes, topoisomerase
inhibitors, biological response modifiers, anti-hormones,
angiogenesis inhibitors, and anti-androgens. Non-limiting examples
are chemotherapeutic agents, cytotoxic agents, and non-peptide
small molecules such as Gleevec (Imatinib Mesylate), Velcade
(bortezomib), Iressa (gefitinib), Sprycel (Dasatinib), and
Adriamycin as well as a host of chemotherapeutic agents.
Non-limiting examples of chemotherapeutic agents include alkylating
agents such as thiotepa and cyclosphosphamide (CYTOXAN.TM.); alkyl
sulfonates such as busulfan, improsulfan and piposulfan; aziridines
such as benzodopa, carboquone, meturedopa, and uredopa;
ethylenimines and methylamelamines including altretamine,
triethylenemelamine, trietylenephosphoramide,
triethylenethiophosphaoramide and trimethylolomelamine; nitrogen
mustards such as chlorambucil, chlornaphazine, cholophosphamide,
estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide
hydrochloride, melphalan, novembichin, phenesterine, prednimustine,
trofosfamide, uracil mustard; nitrosureas such as carmustine,
chlorozotocin, fotemustine, lomustine, nimustine, ranimustine;
antibiotics such as aclacinomysins, actinomycin, authramycin,
azaserine, bleomycins, cactinomycin, calicheamicin, carabicin,
carminomycin, carzinophilin, Casodex.TM., chromomycins,
dactinomycin, daunorubicin, detorubicin,
6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin,
idarubicin, marcellomycin, mitomycins, mycophenolic acid,
nogalamycin, olivomycins, peplomycin, p.kappa.)tfiromycin,
puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin,
tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such
as methotrexate and 5-fluorouracil (5-FU); folic acid analogues
such as denopterin, methotrexate, pteropterin, trimetrexate; purine
analogs such as fludarabine, 6-mercaptopurine, thiamiprine,
thioguanine; pyrimidine analogs such as ancitabine, azacitidine,
6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine,
enocitabine, floxuridine, androgens such as calusterone,
dromostanolone propionate, epitiostanol, mepitiostane,
testolactone; anti-adrenals such as aminoglutethimide, mitotane,
trilostane; folic acid replenisher such as frolinic acid;
aceglatone; aldophosphamide glycoside; aminolevulinic acid;
amsacrine; bestrabucil; bisantrene; edatraxate; defofamine;
demecolcine; diaziquone; elfomithine; elliptinium acetate;
etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine;
mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin;
phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide;
procarbazine; PSK.R.TM.-; razoxane; sizofiran; spirogermanium;
tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine;
urethan; vindesine; dacarbazine; mannomustine; mitobronitol;
mitolactol; pipobroman; gacyto sine; arabinoside ("Ara-C");
cyclophosphamide; thiotepa; taxanes, e.g. paclitaxel (TAXOL.TM.,
Bristol-Myers Squibb Oncology, Princeton, N.J.) and docetaxel
(TAXOTERE.TM., Rhone-Poulenc Rorer, Antony, France); retinoic acid;
esperamicins; capecitabine; and pharmaceutically acceptable salts,
acids or derivatives of any of the above. Also included as suitable
chemotherapeutic cell conditioners are anti-hormonal agents that
act to regulate or inhibit hormone action on tumors such as
anti-estrogens including for example tamoxifen (Nolvadex.TM.),
raloxifene, aromatase inhibiting 4(5)-imidazoles,
4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone,
and toremifene (Fareston); and anti-androgens such as flutamide,
nilutamide, bicalutamide (Casodex), leuprolide, and goserelin
(Zoladex); chlorambucil; gemcitabine; 6-thioguanine;
mercaptopurine; methotrexate; platinum analogs such as cisplatin
and carboplatin; vinblastine; platinum; etoposide (VP-16);
ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine;
navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda;
ibandronate; camptothecin-11 (CPT-11); topoisomerase inhibitor RFS
2000; difluoromethylornithine (DMFO), 17a-Ethinylestradiol,
Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone,
Megestrolacetate, Methylprednisolone, Methyl-testosterone,
Prednisolone, Triamcinolone, chlorotrianisene, Hydroxyprogesterone,
Aminoglutethimide, Medroxyprogesteroneacetate, matrix
metalloproteinase inhibitors, EGFR inhibitors, Pan Her inhibitors,
VEGF inhibitors, including as anti-VEGF antibodies such as Avastin,
and small molecules such as ZD6474 and SU6668, vatalanib,
BAY-43-9006, SU11248, CP-547632, and CEP-7055. Anti-Her2 antibodies
(such as Herceptin from Genentech) may also be utilized. Suitable
EGFR inhibitors include gefitinib, erlotinib, and cetuximab. Pan
Her inhibitors include canertinib, EKB-569, and GW-572016. Further
suitable anticancer agents include, but are not limited to, Src
inhibitors, MEK-1 kinase inhibitors, MAPK kinase inhibitors, PI3
kinase inhibitors, and PDGF inhibitors, such as imatinib. Also
included are anti-angiogenic and antivascular agents which, by
interrupting blood flow to solid tumors, render cancer cells
quiescent by depriving them of nutrition. Castration which also
renders androgen dependent carcinomas non-proliferative, may also
be utilized. Also included are IGF1R inhibitors, inhibitors of
non-receptor and receptor tyrosine kinases, and inhibitors of
integrin signalling. Additional anticancer agents include
microtubule-stabilizing agents 7-O-methylthiomethylpaclitaxel
(disclosed in U.S. Pat. No. 5,646,176),
4-desacetyl-4-methylcarbonatepaclitaxel,
3'-tert-butyl-3'-N-tert-butyloxycarbonyl-4-desacetyl-3'-dephenyl-3'-N-deb-
enzoyl-4-O-methoxycarbonyl-paclitaxel (disclosed in U.S. Ser. No.
09/712,352 filed on Nov. 14, 2000), C-4 methyl carbonate
paclitaxel, epothilone A, epothilone B, epothilone C, epothilone D,
desoxyepothilone A, desoxyepothilone B,
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7-11-dihydroxy-8,8,10,12,16-pen-
tamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17
oxabicyclo[14.1.0]heptadecane-5,9-dione (disclosed in WO 99/02514),
[1S-[1R*,3R* (E),
7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(aminomethyl)-4-thiazolyl]-1-methyl
ethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4-17-dioxabicyclo[14.1.0-
]-heptadecane-5,9-dione (as disclosed in U.S. Pat. No. 6,262,094)
and derivatives thereof; and microtubule-disruptor agents. Also
suitable are CDK inhibitors, an antiproliferative cell cycle
inhibitor, epidophyllotoxin; an antineoplastic enzyme; biological
response modifiers; growth inhibitors; antihormonal therapeutic
agents; leucovorin; tegafur; and haematopoietic growth factors.
[0520] Additional cytotoxic agents include, hexamethyl melamine,
idatrexate, L-asparaginase, camptothecin, topotecan,
pyridobenzoindole derivatives, interferons, and interleukins. Where
desired, the compounds or pharmaceutical composition of the present
invention can be used in combination with commonly prescribed
anti-cancer drugs such as Herceptin.RTM., Avastin.RTM.,
Erbitux.RTM., Rituxan.RTM., Taxol.RTM., Arimidex.RTM.,
Taxotere.RTM., and Velcade.RTM.
[0521] This invention further relates to a method for using the
compounds or pharmaceutical composition in combination with
radiation therapy in inhibiting abnormal cell growth or treating
the hyperproliferative disorder in the mammal. Techniques for
administering radiation therapy are known in the art, and these
techniques can be used in the combination therapy described herein.
The administration of the compound of the invention in this
combination therapy can be determined as described herein.
[0522] Radiation therapy can be administered through one of several
methods, or a combination of methods, including without limitation
external-beam therapy, internal radiation therapy, implant
radiation, stereotactic radiosurgery, systemic radiation therapy,
radiotherapy and permanent or temporary interstitial brachytherapy.
The term "brachytherapy," as used herein, refers to radiation
therapy delivered by a spatially confined radioactive material
inserted into the body at or near a tumor or other proliferative
tissue disease site. The term is intended without limitation to
include exposure to radioactive isotopes (e.g. At-211, 1-131,
1-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioactive
isotopes of Lu). Suitable radiation sources for use as a cell
conditioner of the present invention include both solids and
liquids. By way of non-limiting example, the radiation source can
be a radionuclide, such as 1-125, 1-131, Yb-169, Ir-192 as a solid
source, 1-125 as a solid source, or other radionuclides that emit
photons, beta particles, gamma radiation, or other therapeutic
rays. The radioactive material can also be a fluid made from any 5
solution of radionuclides), e.g., a solution of 1-125 or 1-131, or
a radioactive fluid can be produced using a slurry of a suitable
fluid containing small particles of solid radionuclides, such as
Au-198, Y-90. Moreover, the radionuclide(s) can be embodied in a
gel or radioactive micro spheres.
[0523] Without being limited by any theory, the compounds of the
present invention can render abnormal cells more sensitive to
treatment with radiation for purposes of killing and/or inhibiting
the growth of such cells. Accordingly, this invention further
relates to a method for sensitizing abnormal cells in a mammal to
treatment with radiation which comprises administering to the
mammal an amount of a compound of the present invention, which
amount is effective is sensitizing abnormal cells to treatment with
radiation.
[0524] The compounds or pharmaceutical compositions of the present
invention can be used in combination with an amount of one or more
substances selected from anti-angiogenesis agents, signal
transduction inhibitors, and antiproliferative agents.
[0525] Anti-angiogenesis agents, such as MMP-2
(matrix-metalloprotienase 2) inhibitors, MMP-9
(matrix-metalloprotienase 9) inhibitors, and COX--H (cyclooxygenase
11) inhibitors, can be used in conjunction with a compound of the
present invention and pharmaceutical compositions described herein.
Examples of useful COX-II inhibitors include CELEBREX.TM.
(alecoxib), valdecoxib, and rofecoxib. Examples of useful matrix
metalloproteinase inhibitors are described in WO 96/33172
(published Oct. 24, 1996), WO 96/27583 (published Mar. 7, 1996),
European Patent Application No. 97304971.1 (filed Jul. 8, 1997),
European Patent Application No. 99308617.2 (filed Oct. 29, 1999),
WO 98/07697 (published Feb. 26, 1998), WO 98/03516 (published Jan.
29, 1998), WO 98/34918 (published Aug. 13, 1998), WO 98/34915
(published Aug. 13, 1998), WO 98/33768 (published Aug. 6, 1998), WO
98/30566 (published Jul. 16, 1998), European Patent Publication
606,046 (published Jul. 13, 1994), European Patent Publication 931,
788 (published Jul. 28, 1999), WO 90/05719 (published May 31,
1990), WO 99/52910 (published Oct. 21, 1999), WO 99/52889
(published Oct. 21, 1999), WO 99/29667 (published Jun. 17, 1999),
PCT International Application No. PCT/IB98/01113 (filed Jul. 21,
1998), European Patent Application No. 99302232.1 (filed Mar. 25,
1999), Great Britain Patent Application No. 9912961.1 (filed Jun.
3, 1999), U.S. Provisional Application No. 60/148,464 (filed Aug.
12, 1999), U.S. Pat. No. 5,863,949 (issued Jan. 26, 1999), U.S.
Pat. No. 5,861,510 (issued Jan. 19, 1999), and European Patent
Publication 780,386 (published Jun. 25, 1997), all of which are
incorporated herein in their entireties by reference. Preferred
MMP-2 and MMP-9 inhibitors are those that have little or no
activity inhibiting MMP-I. More preferred, are those that
selectively inhibit MMP-2 and/or AMP-9 relative to the other
matrix-metalloproteinases (i. e., MAP-1, MMP-3, MMP-4, MMP-5,
MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some
specific examples of MMP inhibitors useful in the present invention
are AG-3340, RO 32-3555, and RS 13-0830.
[0526] The invention also relates to a method of and to a
pharmaceutical composition of treating a cardiovascular disease in
a mammal which comprises an amount of a compound of the present
invention, or an isotopically-labeled derivative thereof, and an
amount of one or more therapeutic agents use for the treatment of
cardiovascular diseases.
[0527] Examples for use in cardiovascular disease applications are
anti-thrombotic agents, e.g., prostacyclin and salicylates,
thrombolytic agents, e.g., streptokinase, urokinase, tissue
plasminogen activator (TPA) and anisoylated
plasminogen-streptokinase activator complex (APSAC), anti-platelets
agents, e.g., acetyl-salicylic acid (ASA) and clopidrogel,
vasodilating agents, e.g., nitrates, calcium channel blocking
drugs, antiproliferative agents, e.g., colchicine and alkylating
agents, intercalating agents, growth modulating factors such as
interleukins, transformation growth factor-beta and congeners of
platelet derived growth factor, monoclonal antibodies directed
against growth factors, anti-inflammatory agents, both steroidal
and non-steroidal, and other agents that can modulate vessel tone,
function, arteriosclerosis, and the healing response to vessel or
organ injury post intervention. Antibiotics can also be included in
combinations or coatings comprised by the invention. Moreover, a
coating can be used to effect therapeutic delivery focally within
the vessel wall. By incorporation of the active agent in a
swellable polymer, the active agent will be released upon swelling
of the polymer.
[0528] Other exemplary therapeutic agents useful for a combination
therapy include but are not limited to agents as described above,
radiation therapy, hormone antagonists, hormones and their
releasing factors, thyroid and antithyroid drugs, estrogens and
progestins, androgens, adrenocorticotropic hormone; adrenocortical
steroids and their synthetic analogs; inhibitors of the synthesis
and actions of adrenocortical hormones, insulin, oral hypoglycemic
agents, and the pharmacology of the endocrine pancreas, agents
affecting calcification and bone turnover: calcium, phosphate,
parathyroid hormone, vitamin D, calcitonin, vitamins such as
water-soluble vitamins, vitamin B complex, ascorbic acid,
fat-soluble vitamins, vitamins A, K, and E, growth factors,
cytokines, chemokines, muscarinic receptor agonists and
antagonists; anticholinesterase agents; agents acting at the
neuromuscular junction and/or autonomic ganglia; catecholamines,
sympathomimetic drugs, and adrenergic receptor agonists or
antagonists; and 5-hydroxytryptamine (5-HT, serotonin) receptor
agonists and antagonists.
[0529] Therapeutic agents can also include agents for pain and
inflammation such as histamine and histamine antagonists,
bradykinin and bradykinin antagonists, 5-hydroxytryptamine
(serotonin), lipid substances that are generated by
biotransformation of the products of the selective hydrolysis of
membrane phospholipids, eicosanoids, prostaglandins, thromboxanes,
leukotrienes, aspirin, nonsteroidal anti-inflammatory agents,
analgesic-antipyretic agents, agents that inhibit the synthesis of
prostaglandins and thromboxanes, selective inhibitors of the
inducible cyclooxygenase, selective inhibitors of the inducible
cyclooxygenase-2, autacoids, paracrine hormones, somatostatin,
gastrin, cytokines that mediate interactions involved in humoral
and cellular immune responses, lipid-derived autacoids,
eicosanoids, .beta.-adrenergic agonists, ipratropium,
glucocorticoids, methylxanthines, sodium channel blockers, opioid
receptor agonists, calcium channel blockers, membrane stabilizers
and leukotriene inhibitors.
[0530] Additional therapeutic agents contemplated herein include
diuretics, vasopressin, agents affecting the renal conservation of
water, rennin, angiotensin, agents useful in the treatment of
myocardial ischemia, anti-hypertensive agents, angiotensin
converting enzyme inhibitors, .beta.-adrenergic receptor
antagonists, agents for the treatment of hypercholesterolemia, and
agents for the treatment of dyslipidemia.
[0531] Other therapeutic agents contemplated include drugs used for
control of gastric acidity, agents for the treatment of peptic
ulcers, agents for the treatment of gastroesophageal reflux
disease, prokinetic agents, antiemetics, agents used in irritable
bowel syndrome, agents used for diarrhea, agents used for
constipation, agents used for inflammatory bowel disease, agents
used for biliary disease, agents used for pancreatic disease.
Therapeutic agents used to treat protozoan infections, drugs used
to treat Malaria, Amebiasis, Giardiasis, Trichomoniasis,
Trypanosomiasis, and/or Leishmaniasis, and/or drugs used in the
chemotherapy of helminthiasis. Other therapeutic agents include
antimicrobial agents, sulfonamides, trimethoprim-sulfamethoxazole
quinolones, and agents for urinary tract infections, penicillins,
cephalosporins, and other, .beta.-Lactam antibiotics, an agent
comprising an aminoglycoside, protein synthesis inhibitors, drugs
used in the chemotherapy of tuberculosis, mycobacterium avium
complex disease, and leprosy, antifungal agents, antiviral agents
including nonretroviral agents and antiretroviral agents.
[0532] Examples of therapeutic antibodies that can be combined with
a subject compound include but are not limited to anti-receptor
tyrosine kinase antibodies (cetuximab, panitumumab, trastuzumab),
anti CD20 antibodies (rituximab, tositumomab), and other antibodies
such as alemtuzumab, bevacizumab, and gemtuzumab.
[0533] Moreover, therapeutic agents used for immunomodulation, such
as immunomodulators, immunosuppressive agents, tolerogens, and
immunostimulants are contemplated by the methods herein. In
addition, therapeutic agents acting on the blood and the
blood-forming organs, hematopoietic agents, growth factors,
minerals, and vitamins, anticoagulant, thrombolytic, and
antiplatelet drugs.
[0534] 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.
[0535] 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.
[0536] The methods in accordance with the invention may include
administering a c-met kinase selective inhibitor with one or more
other agents that either enhance the activity of the inhibitor 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 c-met kinase selective inhibitor,
or minimize side effects.
[0537] In one embodiment, the methods of the invention may include
administering formulations comprising a c-met kinase selective
inhibitor of the invention with a particular cytokine, lymphokine,
other hematopoietic factor, thrombolytic or anti-thrombotic factor,
or anti-inflammatory agent before, during, or after administration
of the c-met kinase inhibitor. One of ordinary skill can easily
determine if a particular cytokine, lymphokine, hematopoietic
factor, thrombolytic of anti-thrombotic factor, and/or
anti-inflammatory agent enhances or compliments the activity or use
of the c-met kinase inhibitors in treatment.
[0538] More specifically, and without limitation, the methods of
the invention may comprise administering a c-met kinase selective
inhibitor with one or more of TNF, IL-1, IL-2, IL-3, IL4, IL-5,
IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15,
IL-16, IL-17, IL-18, IFN, G-CSF, Meg-CSF, GM-CSF, thrombopoietin,
stem cell factor, and erythropoietin. Compositions in accordance
with the invention may also include other known angiopoietins such
as Ang-2, Ang4, and Ang-Y, growth factors such as bone morphogenic
protein-1, bone morphogenic protein-2, bone morphogenic protein-3,
bone morphogenic protein-4, bone morphogenic protein-5, bone
morphogenic protein-6, bone morphogenic protein-7, bone morphogenic
protein-8, bone morphogenic protein-9, bone morphogenic protein-10,
bone morphogenic protein-11, bone morphogenic protein-12, bone
morphogenic protein-13, bone morphogenic protein-14, bone
morphogenic protein-15, bone morphogenic protein receptor IA, bone
morphogenic protein receptor IB, brain derived neurotrophic factor,
ciliary neutrophic factor, ciliary neutrophic factor receptor a,
cytokine-induced neutrophil chemotactic factor 1, cytokine-induced
neutrophil chemotactic factor 2 alpha, cytokine-induced neutrophil
chemotactic factor 2 beta, beta endothelial cell growth factor,
endothelin 1, epidermal growth factor, epithelial-derived
neutrophil attractant, fibroblast growth factor 4, fibroblast
growth factor 5, fibroblast growth factor 6, fibroblast growth
factor 7, fibroblast growth factor 8, fibroblast growth factor 8b,
fibroblast growth factor 8c, fibroblast growth factor 9, fibroblast
growth factor 10, fibroblast growth factor acidic, fibroblast
growth factor basic, glial cell line-derived neutrophic factor
receptor al, glial cell line-derived neutrophic factor receptor a2,
growth related protein, growth related protein a, growth related
protein .beta., growth related protein .gamma., heparin binding
epidermal growth factor, hepatocyte growth factor, hepatocyte
growth factor receptor, insulin-like growth factor I, insulin-like
growth factor receptor, insulin-like growth factor II, insulin-like
growth factor binding protein, keratinocyte growth factor, leukemia
inhibitory factor, leukemia inhibitory factor receptor alpha, nerve
growth factor, nerve growth factor receptor, neurotrophin-3,
neurptrophin-4, placenta growth factor, placenta growth factor 2,
platelet derived endothelial cell growth factor, platelet derived
growth factor, platelet derived growth factor A chain, platelet
derived growth factor AA, platelet derived growth factor AB,
platelet derived growth factor B chain, platelet derived growth
factor BB, platelet derived growth factor receptor a, platelet
derived growth factor receptor beta, pre-B cell growth stimulating
factor, stem cell factor, stem cell factor receptor, transforming
growth factor alpha, transforming growth factor beta, transforming
growth factor beta 1, transforming growth factor beta 1.2,
transforming growth factor beta 2, transforming growth factor beta
3, transforming growth factor beta 5, latent transforming growth
factor beta 1, transforming growth factor beta binding protein I,
transforming growth factor beta binding protein II, transforming
growth factor beta binding protein III, tumor necrosis factor
receptor type I, tumor necrosis factor receptor type II,
urokinase-type plasminogen activator receptor, and chimeric
proteins and biologically or immunologically active fragments
thereof.
[0539] 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.
[0540] 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
[0541] The compounds of the present invention may be prepared by
the following processes. Unless otherwise indicated, the variables
(e.g. Cy', R.sup.2, L.sub.2, X, and Cy.sup.2) when used in the
below formulae are to be understood to present those groups
described above in relation to formula (I).
[0542] Scheme 1: This scheme provides a method for the preparation
of the compound of formula (IA) wherein L.sub.2 is
--CR.sup.aR.sup.b--, X is CR.sup.1 or N and the other variables
such as Cy.sup.1, R.sup.2, and Cy.sup.2 are the same as described
above in relation to formula (I).
##STR00304##
[0543] The compound of formula (1) wherein Hal represents a halogen
and R.sup.2 is the same as described above in relation to formula
(I) can be coupled with a compound of formula
Cy.sup.2-L.sub.2-NH.sub.2 in the presence of a suitable base, such
as sodium or potassium carbonate, to give a compound of formula (2)
wherein L.sub.2 is --CR.sup.aR.sup.b--. The compound of formula (2)
can then be converted to a compound of formula (3) by reducing with
a metal such as iron, or a metal halide such as stannous chloride
and an acid (such as acetic acid, hydrochloric acid or ammonium
chloride). The compound of formula (3) can then be cyclised to a
compound of formula (4) wherein X=N using nitrous acid, generated
in situ by reacting an alkali metal nitrite such as sodium nitrite
with an acid such as acetic acid or hydrochloric acid. The compound
of formula (3) can also be cyclised to form a compound of formula
(4) wherein X=CR.sup.1, by heating or irradiating with microwaves
in the presence of R.sup.1COOH wherein R.sup.1 is H or a
C.sub.1-C.sub.4 alkyl group. The compound of formula (4) can be
coupled with a boronic acid of formula Cy.sup.1-B(OR).sub.2
(wherein R=H) or its ester (wherein R=alkyl) in the presence of a
transition metal catalyst such as
tetrakis(triphenylphosphine)palladium(0) and a suitable base such
as potassium carbonate to give the desired compounds of formula
(IA) wherein L.sub.2 is CR.sup.aR.sup.b--, X is CR.sup.1 or N and
the other variables such as Cy.sup.1, R.sup.2 and Cy.sup.2 are the
same as described above in relation to formula (I)
[0544] Alternatively, the compound of formula (2) may be coupled
with a boronic acid of formula Cy.sup.1-B(OR).sub.2 (wherein R=H)
or its ester (wherein R=alkyl) in the presence of a catalyst such
as tetrakis(triphenylphosphine)palladium(0) and a suitable base
such as potassium carbonate to give a compound of formula (5). The
compound of formula (5) can then be converted to a compound of
formula (6) by reducing with a metal such as iron, or a metal
halide such as stannous chloride and an acid such as acetic acid,
hydrochloric acid or ammonium chloride. The compound of formula (6)
can then be cyclised to a compound of formula (IA) wherein X=N
using nitrous acid, generated in situ by reacting an alkali metal
nitrite such as sodium nitrite with an acid such as acetic acid or
hydrochloric acid. The compound of formula (6) can also be cyclised
to a compound of formula (IA) wherein X=CR.sup.1, by heating or
irradiating with microwaves in the presence of R'COOH wherein
R.sup.1 is H or a C.sub.1-C.sub.4 alkyl group.
[0545] Scheme 2: This scheme provides a method for the preparation
of a compound of formula (IA-1) wherein D is substituted or
unsubstituted monocyclic aryl or substituted or unsubstituted
monocyclic heteroaryl and the other variables such as L.sub.2,
R.sup.2, X, and Cy.sup.2 are the same as described above in
relation to formula (IA-1):
##STR00305##
[0546] A compound of formula (4) can be coupled with a boronic acid
of formula 7 (wherein R=H) or its ester (wherein R=alkyl) in the
presence of a transition metal catalyst such as
tetrakis(triphenylphosphine)palladium(0) and a suitable base such
as potassium carbonate to give compound of formula (IA-1).
[0547] Schemes 2A and 2B provide a non-limiting specific
illustration covering some of the embodiments of the compound of
formula (IA-1).
[0548] Scheme 2A: This scheme provides a method for the preparation
of a compound of formula (IA-1) wherein D is a substituted phenyl.
In particular the phenyl ring is substituted with a group of
formula COOR.sup.x (refered to as a compound of fomrnla (IA-1a)) or
CONR.sup.xR.sup.y (refered to as a compound of formula (IA-1b))
wherein R.sup.x and R.sup.y are the same as decribed herein.
Optionally the phenyl ring is further substituted with one or more
R' wherein each R' is independently hydrogen, halogen or
substituted or unsubstituted alkyl.
##STR00306##
[0549] The compound of formula (4) can be coupled with a boronic
acid of formula 8 (wherein R=H) or its ester (wherein R=alkyl) in
the presence of a transition metal catalyst such as
tetrakis(triphenylphosphine)palladium(0) and a suitable base such
as potassium carbonate to give the compound of formula (9). The
compound of formula (9) can be hydrolysed in the presence of an
alkali metal hydroxide such as lithium hydroxide to give the
compound of formula (1A-1a). The compound of formula (IA-1a) can be
converted into a compound of formula (IA-1b) by reacting it with an
amine of the formula R.sup.xR.sup.yNH in the presence of an amide
coupling reagent such as
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
(EDC.HCl), (benzotriazol-lyl)oxytris(dimethylamino)phosphonium
hexafluorophosphate (BOP) or any other amide coupling reagent known
in the art. Alternatively the conversion can be effected by
reacting the compound of formula (IA-la) with with a halogenating
agent such as thionyl chloride and subsequently reacting the
resultant acid halide with an amine of the formula R.sup.xR.sup.yNH
in the presence of a suitable base such as a trialkylamine. The
compounds of formula (IA-1b) can also be obtained by reacting the
compound of formula 4 with a boronic acid of formula 10 (wherein
R=H) or its ester (wherein R=alkyl).
Illustrative Examples for Scheme 2A
##STR00307##
[0551] Scheme 2B: This scheme provides a method for the preparation
of compound of formula (IA-1) wherein D is a pyrazole (refered to
as compound of formula (IA-1c)) or substituted Pyrazole reffered to
as compound of formula (IA-1d). In particular the pyrazole ring is
substituted with substituted or unsubstituted alkyl. Optionally the
said pyrazole ring is further substitueted with one or more of R';
wherein R' is hydrogen, halogen or substituted or unsubstituted
alkyl.
##STR00308##
[0552] The compound of formula (4) can be coupled with a boronic
acid of formula 11 (wherein R=H) or its ester (wherein R=alkyl) in
the presence of a transition metal catalyst such as
tetrakis(triphenylphosphine)palladium(0) and a suitable base such
as potassium carbonate to give compound of formula (IA-1c). The
compound of formula (IA-1c) can be alkylated with an alkyl halide
of formula R'X wherein R' is substituted or unsubstituted alkyl in
the presence of a suitable base such as a metal hydride to give the
compound of formula (IA-1d).
Illustrative Examples for Scheme 2B
##STR00309##
[0554] Scheme 3: This scheme provides a method for the preparation
of the compound of formula (II) and (IIA) wherein A is --OR.sup.c
or R.sup.cR-N--, L.sub.2 is --CR.sup.aR.sup.b, X is CR.sup.1 or N
and the other variables such as R.sup.2, and Cy.sup.2 are the same
as described above in relation to formula (II) and (IIA).
##STR00310##
[0555] The compound of formula (4) can be reacted with a
nucleophilic compound of formula AH wherein A is --OR.sup.c or
R.sup.cR--N, in the presence of a base such as an alkali metal
fluoride, alkali metal carbonate or an alkali metal alkoxide to
give a compound of formula (II). Optionally this reaction may be
carried out in the presence of a transition metal catalyst such as
palladium acetate and a phosphine ligand such as triphenyl
phosphine.
Illustrative Examples for Scheme 3
##STR00311##
[0557] Scheme 4: This scheme provides a method for the preparation
of a compound of formula (III) wherein L.sub.2 is
--CR.sup.aR.sup.b--, X is CR.sup.1 or N, U is C-CR.sup.3, V is N, W
is O or NR.sup.4 and the other variables such as R.sup.5, R.sup.2,
and Cy.sup.2 are the same as described above in relation to formula
(III).
##STR00312##
[0558] The compound of formula (4) can be reacted with a tin
compound of formula 12 wherein R.sup.a and R.sup.b are (optionally
R.sup.a and R.sup.b can also be alkyl or aryl) in the presence of a
transition metal catalyst such as
tris(dibenzylidineacetone)palladium(0) and optionally in the
presence of a ligand such as triphenylphosphine to give the
compound of formula (4a). The compound of formula (4a) can be
reacted with the compound of formula R.sup.5--W--NH.sub.2 or
R.sup.5.sub.2NCO wherein R.sup.5 is as defined herein above and W
is O, S or NR.sup.4 to give the desired compound of formula
(III).
Illustrative Examples for Scheme 4
##STR00313##
[0560] Similar methodologies with certain modifications as known to
those skilled in the art can be used to synthesize compounds of
formula (I), (IA), (IA-1) (II), (IIA), (III), (IRA), (IIIB) and
(IV) wherein all the variables are to be understood to present
those groups described above in relation to formula (I), (IA),
(IA-1) (II), (IIA), (III), (IIIA), (IIIB) and (IV) using suitable
intermediates and reagents.
Experimental
[0561] Unless otherwise mentioned, work-up implies distribution of
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 implies 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 implies ambient temperature (25-28.degree. C.).
Intermediate 1: Quinolin-6-ylmethanamine
Step 1: Quinoline-6-carboxylic acid
[0562] To a mixture of 4-aminobenzoic acid (175 g, 1.28 mol),
4-nitrophenol (88.75 g, 0.64 mol) and sulphuric acid (1.2 lit.),
glycerol (234.8 g, 2.55 mol) was added dropwise at 135.degree. C.
After 48 h, the reaction mixture was cooled to 0.degree. C. and the
pH adjusted to 3-5 with 10% sodium hydroxide solution. The
resulting precipitate was collected by filtration and washed with
water and dried under vacuum to afford the title compound as a
black solid (125 g, 56%).
Step 2: Methyl quinoline-6-carboxylate
[0563] To a solution of quinoline-6-carboxylic acid (183 g, 1.06
mol) in methanol (1 lit.), thionyl chloride (150.7 g, 1.2 mol) was
added dropwise at 0.degree. C. and then stirred at 65.degree. C.
for 12 h. The reaction mixture was concentrated and to the residue
dichloromethane and aqueous sodium carbonate solutions were added.
The organic layer was dried with sodium sulphate and concentrated
to afford the title compound as a brown solid (150 g, 75%).
Step 3: Quinoline-6-carboxamide
[0564] To a solution of methyl quinoline-6-carboxylate (148 g, 0.79
mol) in methanol (600 ml.), aqueous ammonia (800 ml) was added and
then stirred at 45.degree. C. for 12 h. The reaction mixture was
concentrated to afford the title compound as a dark red solid (120
g, 88%).
Step 4: Quinoline-6-carbonitrile
[0565] To a solution of quinoline-6-carboxamide (177 g, 1.03 mol)
in chloroform (1.5 lit.) and triethylamine (520.15 g, 5.15 mol),
trifluoroacetic anhydride (540.34 g, 2.57 mol) was added dropwise
below 10.degree. C. After 1.5 h, the pH was adjusted to 7 with
sodium bicarbonate solution and extracted with dichloromethane. The
organic layer was dried with sodium sulphate and concentrated to
afford the title compound as a brown solid (96 g, 59%).
Step 5: Quinolin-6-ylmethanamine
[0566] To a solution of quinoline-6-carbonitrile (96 g, 0.62 mol)
in saturated ammonia in methanol (1 lit.), Raney-Ni (10 g) was
added and the mixture was stirred at 1 atm of H.sub.2 at RT for 16
h. The reaction mixture was filtered and the filtrate was
concentrated under vacuum to afford the title compound as a brown
oil (80 g, 82%). .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400 MHz):
.delta. 8.83 (dd, J=4.2, 1.7 Hz, 1H), 8.29 (d, J=8.3 Hz, 1H), 7.95
(d, J=8.6 Hz, 1H), 7.85 (s, 1H), 7.75 (dd J=8.7, 1.8 Hz, 1H), 7.49
(dd, J=8.2, 4.2 Hz, 1H), 3.90 (s, 2H).
Intermediate 2: 2-(quinolin-6-yl)propan-2-amine
Step 1: 2-(quinolin-6-yl)propan-2-ol
[0567] To an ice-cold solution of methylmagnesium iodide prepared
from magnesium (0.454 g, 18.69 mmol) and methyliodide (1.16 ml,
18.69 mmol) in diethyl ether (15 ml), methyl
quinoline-6-carboxylate (0.50 g, 2.67 mmol) in diethyl ether (5 ml)
was added and warmed to room temperature. After 12 h, the reaction
mixture was cooled to 0.degree. C., quenched with dil. 6N HCl and
extracted with ethyl acetate. The organic layer was dried over
sodium sulphate and concentrated under reduced pressure and column
chromatographed with ethyl acetate: petroleum ether to afford the
title compound as a yellow liquid (0.42 g, 84%). .sup.1H-NMR
(.delta. ppm, DMSO-d.sub.6, 400 MHz): 8.83 (dd J=4.2, 1.7 Hz, 1H),
8.34 (dd, J=8.2, 1.1 Hz, 1H), 8.00 (d, J=1.9 Hz, 1H), 7.95 (d,
J=8.8 Hz, 1H), 7.88 (dd, J=8.9, 2.0 Hz, 1H), 7.50 (q, J=4.1 Hz,
1H), 5.23 (s, 1H), 1.51 (s, 6H).
Step 2: 6-(2-azidopropan-2-yl)quinoline
[0568] 2-(Quinolin-6-yl)propan-2-ol (0.50 g, 2.67 mmol) and sodium
azide (1.73 g, 26.70 mmol) were added successively to ice-cold
trifluoroacetic acid (20 ml) and warmed to room temperature. After
12 h, the reaction mixture was cooled to 0.degree. C., quenched
with water and basified with sodium hydroxide solution and
extracted with ethyl acetate. The organic layer was dried over
sodium sulphate and concentrated under reduced pressure to afford
the title compound as brown liquid (0.340 g, 60%). .sup.1H-NMR
(.delta. ppm, DMSO-d.sub.6, 400 MHz): .delta. 8.90 (dd J=4.1, 1.6
Hz, 1H), 8.41 (d, J=7.6 Hz, 1H), 8.06 (d, J=2.1 Hz, 1H), 8.04 (d,
J=9.0 Hz, 1H), 7.88 (dd, J=8.1, 2.2 Hz, 1H), 7.56 (q, J=4.2 Hz,
1H), 1.71 (s, 6H).
Step 3: 2-(quinolin-6-yl)propan-2-amine
[0569] To 6-(2-azidopropan-2-yl)quinoline (0.100 g, 2.67 mmol) in
ethanol (3 ml), palladium on carbon (10 mg, 10% w/w) was added and
stirred under a hydrogen atmosphere using hydrogen filled balloon.
After 6 h, the reaction mass was filtered through celite, washed
with methanol and concentrated to afford the title compound as
brown liquid (0.079 g, 90%). .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): .delta. 8.82 (dd J=4.2, 1.6 Hz, 1H), 8.31
(d, J=8.9 Hz, 1H), 8.02 (d, J=1.9 Hz, 1H), 7.99 (dd, J=8.9, 2.1 Hz,
1H), 7.93 (d, J=8.9 Hz, 1H), 7.49 (q, J=4.2 Hz, 1H), 2.06 (s, 2H),
1.46 (s, 6H).
Intermediate 3: (7-fluoroquinolin-6-yl)methanamine
Step 1: 6-Bromo-7-fluoroquinoline
[0570] To a mixture of 4-bromo-2-fluoroaniline (10 g, 52.62 mmol),
ferrous sulphate (3.33 g, 11.97 mmol) and glycerol (15.78 ml), con.
sulphuric acid (9.15 ml) was added slowly and the reaction mixture
was heated to 140.degree. C. After 12 h, the reaction mixture was
cooled to 0.degree. C. and the pH adjusted to 10-12 with 10% sodium
hydroxide solution. The reaction mixture was filtered through
celite, washed with ethyl acetate and layers were separated. The
organic layer was washed with brine solution, dried over sodium
sulphate and concentrated. The crude product was purified by column
chromatography with ethyl acetate: petroleum ether to afford the
title compound as a white solid (4.9 g, 44%). .sup.1H-NMR (.delta.
ppm, CDCl.sub.3, 400 MHz): 8.96 (dd, J=4.3, 2.7 Hz, 1H), 8.15 (m,
2H), 7.81 (d, J=9.5 Hz, 1H), 7.42 (dd, J=8.3, 4.3 Hz, 1H).
Step 2: 7-Fluoroquinoline-6-carbonitrile
[0571] To a solution of 6-bromo-7-fluoroquinoline (4.90 g, 22.12
mmol) in dimethylacetamide (38 ml), potassium ferrocyanide (2.65 g,
4.86 mmol) and sodium carbonate (2.34 g, 22.12 mmol). The system
was purged with nitrogen for 15 min Palladium acetate (0.248 g,
1.10 mmol) was added under nitrogen and heated to 120.degree. C.
After 3 h, the reaction mixture was filtered through celite, washed
with ethyl acetate. The organic layer was washed with brine
solution, dried over sodium sulphate and concentrated. The crude
product was purified by column chromatography with ethyl acetate:
petroleum ether to afford the title compound as a white solid (3.2
g, 86%). .sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400 MHz): 9.05 (dd,
J=4.1, 2.9 Hz, 1H), 8.25 (m, 2H), 7.90 (d, J=10.0 Hz, 1H), 7.53
(dd, J=8.3, 4.3 Hz, 1H).
Step 3: (7-Fluoroquinolin-6-yl) methanamine
[0572] To 7-fluoroquinoline-6-carbonitrile (1.00 g, 5.813 mmol),
methanol saturated with ammonia (13.5 ml) and Raney-Ni (1.27 g)
were added and hydrogenated at 50-60 psi for 4 h. The reaction
mixture was filtered and concentrated to afford the title compound
as a brown oil (0.80 g, 78%). .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.85 (d, J=2.3 Hz, 1H), 8.35 (d, J=8.0 Hz,
1H), 8.06 (d, J=9.5 Hz, 1H), 7.68 (d, J=11.8 Hz, 1H), 7.49 (t,
J=3.8 Hz, 1H), 3.92 (s, 2H), 1.90 (br s, 2H).
Intermediate 4:
6-Chloro-3-nitro-N-(quinolin-6-ylmethyl)pyridin-2-amine
[0573] To a solution of 2,6-Dichloro-3-nitropyridine (1.62 g, 8.42
mmol) in ethanol (30 ml), sodium carbonate (2.34 g, 22.12 mmol) was
added at RT and cooled to 0.degree. C. followed by the addition of
intermediate 1 (2 g, 12.64 mmol) in ethanol (20 ml) the mixture was
stirred at RT for 12 h. The reaction mixture was poured into 25 ml
of water and extracted with ethyl acetate, washed with brine
solution, dried over sodium sulphate and concentrated. The crude
product was purified by column chromatography with
dichloromethane:methanol to afford the title compound as a yellow
solid (2.0 g, 50%). .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400
MHz): .delta. 9.35 (t, J=6.0 Hz, 1H), 8.85 (dd, J=4.0, 1.4 Hz, 1H),
8.46 (d, J=8.5 Hz, 1H), 8.31 (d, J=7.8 Hz, 1H), 7.98 (d J=8.7 Hz,
1H), 7.88 (s, 1H), 7.79 (dd, J=8.7, 1.6 Hz, 1H), 7.50 (dd, J=8.3,
4.2 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 4.92 (d, J=6.1 Hz, 2H).
Intermediate 5:
6-chloro-N-(4-fluorobenzyl)-3-nitropyridin-2-amine
[0574] The title compound was obtained as a yellow solid (2.1 g,
70%) by using a procedure that is similar to the one described for
intermediate 4 from 2,6-Dichloro-3-nitropyridine (2.05 g, 10.65
mmol), 4-Fluorobenzylamine (2.0 g, 15.98 mmol), ethanol (50 ml) and
sodium carbonate (2.94 g, 27.80 mmol). .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): .delta. 9.21 (t, J=5.9 Hz, 1H), 8.43 (d,
J=8.6 Hz, 1H), 7.43 (m, 2H), 7.15 (m, 2H), 6.79 (d, J=8.6 Hz, 1H),
4.68 (d, J=6.1 Hz, 2H).
Intermediate 6:
6-chloro-N-(2-chloro-3,6-difluorobenzyl)-3-nitropyridin-2-amine
[0575] The title compound was obtained as a yellow solid (1.14 g,
61%) by using a procedure that is similar to the one described for
intermediate 4 from 2,6-Dichloro-3-nitropyridine (0.724 g, 3.75
mmol), 2-chloro-3,6-difluorobenzylamine (1.0 g, 5.63 mmol), ethanol
(25 ml) and sodium carbonate (2.94 g, 27.80 mmol). .sup.1H-NMR
(.delta. ppm, DMSO-d.sub.6, 400 MHz): .delta. 8.94 (t, J=5.5 Hz,
1H), 8.41 (d, J=8.6 Hz, 1H), 7.44 (dt, J=9.0, 4.7 Hz, 1H), 7.34
(dt, J=9.3, 4.3 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 4.86 (d, J=5.5 Hz,
2H).
Intermediate 7:
6-chloro-3-nitro-N-(2-(quinolin-6-yl)propan-2-yl)pyridin-2-amine
[0576] The title compound was obtained as a yellow solid (0.860 g,
47%) by using a procedure that is similar to the one described for
intermediate 4 from 2,6-Dichloro-3-nitropyridine (1.55 g, 8.05
mmol), Intermediate 2 (1.0 g, 5.36 mmol), ethanol (35 ml) and
sodium carbonate (2.34 g, 22.12 mmol). .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): .delta. 8.84 (dd, J=4.2, 1.7 Hz, 1H), 8.76
(s, 1H), 8.42 (d, J=8.6 Hz, 1H), 8.33 (d, J=7.3 Hz, 1H), 8.00 (d,
J=1.9 Hz, 1H), 7.91 (d, J=8.9 Hz, 1H), 7.85 (dd, J=8.9, 2.1 Hz,
1H), 7.49 (q, J=4.2 Hz, 1H), 6.70 (d, J=8.6 Hz, 1H), 1.89 (s,
6H).
Intermediate 8:
6-Chloro-N-((7-fluoroquinolin-6-yl)methyl)-3-nitropyridin-2-amine
[0577] The title compound was obtained as a yellow solid (0.750 g,
50%) by using a procedure that is similar to the one described for
intermediate 4 from 2,6-dichloro-3-nitropyridine (1.31 g, 6.81
mmol), Intermediate 3 (0.80 g, 4.54 mmol), ethanol (15 ml) and
sodium carbonate (0.838 g, 7.90 mmol). .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 9.27 (t, J=5.7 Hz, 1H), 8.87 (d, J=2.8 Hz,
1H), 8.49 (d, J=8.5 Hz, 1H), 8.34 (d, J=8.0 Hz, 1H), 7.96 (d, J=8.4
Hz, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.49 (dd, J=8.3, 4.2 Hz, 1H), 6.83
(d, J=8.6 Hz, 1H), 4.95 (d, J=5.9 Hz, 2H).
Intermediate 9: 6-chloro-N2-(quinolin-6-ylmethyl)
pyridine-2,3-diamine
[0578] Stannous chloride (0.258 g, 1.143 mmol) and conc. HCl (3 ml)
were added to intermediate 4 (0.180 g, 0.571 mmol) at RT and
stirred for 1 h. After 1 h stannous chloride (0.258 g, 1.143 mmol)
and conc. HCl (2 ml) were added and maintained for 1 h. The
reaction mixture was poured into ice water and the pH was adjusted
to ca. (approx) 8 with sodium bicarbonate solution, extracted with
ethyl acetate, washed with brine, dried over anhydrous sodium
sulphate and concentrated to afford the title compound as a yellow
solid (0.150 g, 92%). .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400
MHz): .delta. 8.85 (dd, J=4.2, 1.6 Hz, 1H), 8.32 (d, J=7.9 Hz, 1H),
7.98 (d, J=8.7 Hz, 1H), 7.86 (s, 1H), 7.76 (dd, J=8.7, 1.8 Hz, 1H),
7.51 (dd, J=8.3, 4.2 Hz, 1H), 6.73 (d, J=7.8 Hz, 1H), 6.59 (t,
J=5.6 Hz, 1H), 6.38 (d, J=7.7 Hz, 1H), 4.92 (s, 2H), 4.70 (s,
2H).
Intermediate 10:
6-chloro-N2-(4-fluorobenzyl)pyridine-2,3-diamine
[0579] The title compound was obtained as a yellow solid (1.3 g,
99%) by using a procedure that is similar to the one described for
intermediate 9 from intermediate 5 (1.5 g, 5.33 mmol), stannous
chloride (4.09 g, 18.13 mmol) and conc. HCl (11.5 ml). .sup.1H-NMR
(.delta. ppm, DMSO-d.sub.6, 400 MHz): .delta. 7.38 (m, 2H), 7.15
(m, 2H), 6.71 (d, J=7.8 Hz, 1H), 6.43 (t, J=5.9 Hz, 1H), 6.37 (d,
J=7.8 Hz, 1H), 4.87 (s, 2H), 4.47 (d, J=5.6 Hz, 2H).
Intermediate 11:
6-chloro-N2-(2-chloro-3,6-difluorobenzyl)pyridine-2,3-diamine
[0580] Iron powder (2.0 g, 35.81 mmol) was added to a solution of
the intermediate 6 (1.0 g, 2.99 mmol) in methanol (10 ml) and conc.
HCl (1.5 ml) were added at RT and refluxed for 5 h. The reaction
mixture was filtered through celite and concentrated. Ice water was
added to the residue and the pH was adjusted to ca. 8 with sodium
bicarbonate solution, extracted with ethyl acetate, washed with
brine, dried over anhydrous sodium sulphate and concentrated to
afford the title compound as a yellow solid (0.67 g, 74%).
.sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400 MHz): .delta. 7.47 (dt,
J=9.0, 4.8 Hz, 1H), 7.34 (dt, J=9.1, 4.3 Hz, 1H), 6.69 (d, J=7.7
Hz, 1H), 6.40 (d, J=7.7 Hz, 1H), 6.13 (t, J=4.4 Hz, 1H), 4.89 (s,
2H), 4.55 (d J=3.5 Hz, 2H).
Intermediate 12:
6-chloro-N2-(2-(quinolin-6-yl)propan-2-yl)pyridine-2,3-diamine
[0581] Acetic acid (30 ml) was added at RT to a mixture of
intermediate 7 (2.0 g, 5.83 mmol) and iron powder (1.6 g, 29.17
mmol) and stirred for 12 h. The reaction mixture was basified with
sodium bicarbonate solution, extracted with ethyl acetate, washed
with brine, dried over anhydrous sodium sulphate and concentrated
to afford the title compound as a brown solid (1.42 g, 77%).
.sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400 MHz): .delta. 8.80 (d,
J=2.7 Hz, 1H), 8.30 (d, J=8.0 Hz, 1H), 7.92 (s, 1H), 7.89 (d, J=8.0
Hz, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.46 (q, J=4.2 Hz, 1H), 6.66 (d,
J=7.7 Hz, 1H), 6.20 (d, J=7.7 Hz, 1H), 6.04 (s, 1H), 5.02 (s, 2H),
1.79 (s, 6H).
Intermediate 13:
6-Chloro-N2-((7-fluoroquinolin-6-yl)methyl)pyridine-2,3-diamine
[0582] The title compound was obtained as a yellow solid (0.550 g,
74%) by using a procedure that is similar to the one described for
intermediate 9 from intermediate 8 (0.750 g, 2.25 mmol), stannous
chloride (2.28 g, 10.14 mmol) and conc. HCl (13 ml). .sup.1H-NMR
(.delta. ppm, DMSO-d.sub.6, 400 MHz): .delta. 8.87 (d, J=3.0 Hz,
1H), 8.36 (d, J=8.2 Hz, 1H), 7.97 (d, J=8.3 Hz, 1H), 7.77 (d,
J=11.6 Hz, 1H), 7.50 (dd, J=8.2, 4.1 Hz, 1H), 6.74 (d, J=8.5 Hz,
1H), 6.54 (t, J=5.0 Hz, 1H), 6.39 (d, J=7.8 Hz, 1H), 4.94 (s, 2H),
4.72 (d, J=5.3 Hz, 2H).
Intermediate 14:
6-((5-chloro-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline
[0583] Intermediate 9 (0.220 g, 0.772 mmol) was dissolved in acetic
acid (1.3 ml) and cooled to 5.degree. C. Sodium nitrite (0.063 g,
0.927 mmol) in 0.35 ml water was added slowly followed by sulphuric
acid (0.09 ml). The reaction mixture was warmed to RT and stirred
for 30 min. The reaction mixture was poured into ice water and pH
adjusted to ca. 8 with sodium bicarbonate solution, extracted with
ethyl acetate, washed with brine, dried over sodium sulphate and
concentrated to afford the title compound as a brown solid (0.220
g, 96%). .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400 MHz): .delta.
8.88 (s, 1H), 8.69 (d, J=8.6 Hz, 1H), 8.35 (d, J=8.1 Hz, 1H), 8.01
(d, J=8.6 Hz, 1H), 7.90 (s, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.61 (d,
J=8.5 Hz, 1H), 7.53 (dd, J=8.0, 4.0 Hz, 1H), 6.12 (s, 2H).
Intermediate 15:
5-chloro-3-(4-fluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridine
[0584] The title compound was obtained as a brown solid (1.0 g,
76%) by using a procedure that is similar to the one described for
intermediate 14 from intermediate 10 (1.3 g, 5.17 mmol), acetic
acid (9 ml), sodium nitrite (0.428 g, 6.20 mmol), water (2.4 ml)
and sulphuric acid (0.58 ml). .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): .delta. 8.66 (d, J=8.7 Hz, 1H), 7.60 (d,
J=8.6 Hz, 1H), 7.43 (m, 2H), 7.20 (m, 2H), 5.90 (s, 2H).
Intermediate 16:
5-chloro-3-(2-chloro-3,6-difluorobenzyl)-3H-triazolo[4,5-b]pyridine
[0585] The title compound was obtained as a brown solid (0.66 g,
98%) by using a procedure that is similar to the one described for
intermediate 14 from intermediate 11 (0.65 g, 2.13 mmol), acetic
acid (4 ml), sodium nitrite (0.177 g, 2.56 mmol), water (0.93 ml)
and sulphuric acid (0.58 ml). .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): .delta. 8.66 (d, J=8.7 Hz, 1H), 7.61 (d,
J=8.8 Hz, 1H), 7.60 (dt, J=9.0, 4.9 Hz, 1H), 7.45 (dt, J=9.2, 4.2
Hz, 1H), 5.98 (s, 2H).
Intermediate 17:
6-(2-(5-chloro-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)propan-2-yl)quinolin-
e
[0586] The title compound was obtained as a brown solid (1.1 g,
91%) by using a procedure that is similar to the one described for
intermediate 14 from intermediate 12 (1.20 g, 3.83 mmol), acetic
acid (7.2 ml), sodium nitrite (0.317 g, 4.604 mmol), water (2.8 ml)
and sulphuric acid (0.5 ml). .sup.1H-NMR (.delta. ppm, CDCl.sub.3,
400 MHz): .delta. 8.88 (dd, J=4.2, 1.5 Hz, 1H), 8.29 (d, J=8.6 Hz,
1H), 8.12 (d, J=7.8 Hz, 1H), 8.10 (d, J=8.9 Hz, 1H), 7.70 (d, J=2.1
Hz, 1H), 7.48 (dd, J=8.9, 2.2 Hz, 1H), 7.41 (q, J=4.2 Hz, 1H), 7.25
(m, 1H), 2.44 (s, 6H). Mass: 323.76 (M.sup.+).
Intermediate 18:
6-((5-Chloro-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)-7-fluoroquinol-
ine
[0587] The title compound was obtained as a brown solid (0.345 g,
62%) by using a procedure that is similar to the one described for
intermediate 14 from intermediate 13 (0.540 g, 1.78 mmol), acetic
acid (3.1 ml), sodium nitrite (0.148 g, 2.13 mmol), water (0.8 ml)
and sulphuric acid (0.2 ml). .sup.1H-NMR (.delta. ppm, CDCl.sub.3,
400 MHz): .delta. 8.91 (d, J=2.9 Hz, 1H), 8.36 (d, J=8.6 Hz, 1H),
8.08 (d, J=8.1 Hz, 1H), 7.80 (d, J=11.0 Hz, 1H), 7.70 (d, J=7.8 Hz,
1H), 7.40 (m, 2H), 6.11 (s, 2H).
Intermediate 19:
2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)
propan-2-ol
Step 1: 1-(4-bromo-2-fluorophenyl)ethanol
[0588] A solution of 4-bromo-2-fluorobenzaldehyde (5 g, 24.62 mmol)
in diethyl ether (10 ml) was added to an ice-cold solution of
methylmagnesium iodide prepared from magnesium (1.7 g, 73.88 mmol)
and methyliodide (4.58 ml, 73.88 mmol) in diethyl ether (50 ml).
The mixture was warmed stirred at RT. for 12 h, and cooled to
0.degree. C., quenched with dil. 6N HCl and extracted with ethyl
acetate. The organic layer was dried over sodium sulphate and
concentrated under reduced pressure to afford the title compound as
red colour liquid (5 g, 94%). .sup.1H-NMR (.delta. ppm, CDCl.sub.3,
400 MHz): .delta. 7.40 (t, J=8.2 Hz, 1H), 7.30 (dd, J=8.3, 1.7 Hz,
1H), 7.21 (dd, J=9.9, 1.9 Hz, 1H), 5.17 (q, J=6.4 Hz, 1H), 1.49 (d,
J=6.5 Hz, 3H).
Step 2: 1-(4-bromo-2-fluorophenyl)ethanone
[0589] To a solution of intermediate 19 (step 1) (5.0 g, 22.82
mmol) in DMF (25 ml), pyridinium dichromate (12.8 g, 34.23 mmol)
was added at room temperature. After 12 h, the reaction mixture was
quenched with water, diluted with ethyl acetate and filtered
through celite. The organic layer was washed with brine solution
and dried over sodium sulphate and concentrated under reduced
pressure to afford the title compound as a red colour liquid (4.1
g, 84%). .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400 MHz): .delta.
7.76 (t, J=8.3 Hz, 1H), 7.73 (dd, J=10.8, 1.8 Hz, 1H), 7.55 (dd,
J=5.2, 1.8 Hz, 1H), 2.55 (s, 3H).
Step 3: 2-(4-bromo-2-fluorophenyl)propan-2-ol
[0590] A procedure similar to the one described in step 1 was
followed to get the crude product from magnesium (0.33 g, 73.88
mmol), methyliodide (0.856 ml, 13.69 mmol), diethyl ether (10 ml)
and the intermediate from step 2 (1 g, 4.56 mmol) in diethyl ether
(10 ml). Purification by column chromatography with ethyl acetate:
petroleum ether gave the title compound as a yellow liquid (0.5 g,
47% yield). .sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400 MHz): .delta.
7.48 (t, J=8.6 Hz, 1H), 7.27 (m, 1H), 7.21 (dd, J=11.3, 1.9 Hz,
1H), 2.04 (s, 1H), 1.60 (s, 6H).
Step 4:
2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)
propan-2-ol
[0591] Potassium acetate (0.404 g, 4.11 mmol) and
bis(pinacolato)diboron (0.575 g, 2.26 mmol) were added to a
solution of the intermediate from step 3 (0.4800 g, 2.05 mmol) in
dioxane (16 ml), and the solution was degassed for 30 min [1,1'-bis
(diphenylphosphino) ferrocene]dichloro palladium(II).
CH.sub.2Cl.sub.2 (0.084 g, 0.102 mmol) was added under nitrogen
atmosphere and heated to 80.degree. C. After 12 h, the reaction
mixture was filtered through celite and concentrated. The crude
product was purified by column chromatography with ethyl acetate:
petroleum ether to afford the title compound as a colourless oil
(0.450 g, 61%). .sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400 MHz):
.delta. 7.55 (s, 1H), 7.54 (d, J=4.8 Hz, 1H), 7.46 (d, J=12.6 Hz,
1H), 2.13 (d, J=3.5 Hz, 1H), 1.63 (d, J=5.5 Hz, 6H), 1.33 (s,
12H).
Intermediate 20:
2-(3-fluoro-4-isopropoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
Step 1: 4-bromo-2-fluoro-1-isopropoxybenzene
[0592] To a solution of 4-bromo-3-fluorophenol (10 g, 52.35 mmol)
in THF (100 ml), isopropyl alcohol (4.8 ml, 62.62 mmol) and
triphenylphosphine (20.6 g, 78.52 mmol) were added and heated to
45'C followed by diisopropylazodicarboxylate (15.4 ml, 78.52 mmol).
The mixture was refluxed for 1 h, concentrated and the residue was
purified by column chromatography with ethyl acetate: petroleum
ether to afford the title compound as a colourless liquid (13.1 g,
99%) which was used without purification in the next step.
Step 2:
2-(3-fluoro-4-isopropoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxabor-
olane
[0593] The title compound was obtained as a yellow oil (13.9 g,
99%) by using the procedure described in step 4 for intermediate 19
from the product of step 1 (12.5 g g, 53.60 mmol),
bis(pinacolato)diboron (15 g, 58.96 mmol), potassium acetate (10.52
g, 107 2 mmol), dioxane (125 ml) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloro palladium(II).
CH.sub.2Cl.sub.2 (4.4 g, 5.36 mmol) which was used without
purification in the next step.
Intermediate 21:
2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide
[0594] The title compound was obtained as a brown solid (0.600 g,
70%) by using the procedure described in step 4 for intermediate 19
from 4-bromo-2-methylbenzamide (0.700 g, 3.27 mmol),
bis(pinacolato)diboron (0.913 g, 3.59 mmol), potassium acetate
(0.96 g, 9.81 mmol), dioxane (12 ml) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloro palladium(II).
CH.sub.2Cl.sub.2 (0.080 g, 0.098 mmol) which was used without
characterisation in the next step.
Intermediate 22:
2-Chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide
[0595] The title compound was obtained as a brown solid (0.75 g,
69%) by using the procedure described in step 4 for intermediate 19
from 5-bromo-2-chlorobenzamide (0.800 g, 3.83 mmol),
bis(pinacolato)diboron (1.07 g, 4.21 mmol), potassium acetate (1.12
g, 11.49 mmol), dioxane (10.5 ml) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloro palladium(II).
CH.sub.2Cl.sub.2 (0.083 g, 0.102 mmol) which was used without
characterisation in the next step.
Intermediate 23: 3-amino-N,N-dimethylpropanamide
trifluoroacetate
[0596] To a solution of N-boc-3-aminopropanoic acid (0.150 g, 0.793
mmol) in DMF (1.5 ml), N-Ethyldiisopropylamine (0.205 g, 1.58 mmol)
and HATU (0.301 g, 0.793 mmol) were added and stirred for 5 min
Dimethylamine hydrochloride (0.065 g, 0.793 mmol) was added at RT
and the reaction mixture was stirred for 12 h. Water was added to
the reaction mixture and extracted with ethyl acetate, dried over
sodium sulphate and concentrated under reduced pressure. The crude
product was purified by column chromatography with methanol:
dichloromethane to afford tert-butyl
3-(dimethylamino)-3-oxopropylcarbamate. Trifluoroacetic acid (1 ml)
was added to the product obtained, stirred for 2 h and concentrated
to afford title compound as the trifluoroacetate salt (0.090 g,
40%).
Intermediate 24: 2-amino-N,N-dimethylacetamide trifluoroacetate
[0597] Tert-butyl 2-(dimethylamino)-2-oxoethylcarbamate (0.120 g,
69%) was obtained by using the procedure described under
intermediate 23 from N-boc-glycine (0.150 g, 0.856 mmol), DMF (1.5
ml), N-Ethyldiisopropylamine (0.221 g, 1.70 mmol), HATU (0.325 g,
0.856 mmol) and dimethylamine hydrochloride (0.069 g, 0.856 mmol).
The product was dissolved in dichloromethane (1 ml),
trifluoroacetic acid (0.5 ml) was added, stirred for 2 h and
concentrated to give the title compound as the trifluoroacetate
salt (0.100 g, 46%).
Intermediate 25: 2-amino-1-(pyrrolidin-1-yl)ethanone
trifluoroacetate
[0598] Tert-butyl 2-oxo-2-(pyrrolidin-1-yl)ethylcarbamate (0.120 g,
61%) was prepared by using the procedure described under
intermediate 23 from N-boc-glycine (0.150 g, 0.856 mmol), DMF (1.5
ml), N-Ethyldiisopropylamine (0.110 g, 0.856 mmol), HATU (0.325 g,
0.856 mmol) and pyrrolidine (0.061 g, 0.856 mmol). The product was
dissolved in dichloromethane (1 ml), trifluoroacetic acid (0.5 ml)
was added, stirred for 2 h and concentrated to give the title
compound as the trifluoroacetate salt (0.100 g, 41%).
Intermediate 26: 3-amino-1-(pyrrolidin-1-yl)propan-1-one
trifluoroacetate
[0599] Tert-butyl 2-oxo-2-(pyrrolidin-1-yl)propylcarbamate (0.080
g, 40%) was prepared by using the procedure described under
intermediate 23 from N-boc-3-aminopropionic acid (0.150 g, 0.793
mmol), DMF (1.5 ml), N-Ethyldiisopropylamine (0.205 g, 1.58 mmol),
HATU (0.301 g, 0.793 mmol) and pyrrolidine (0.056 g, 0.793 mmol).
Trifluoroacetic acid (1 ml) was added to the product, stirred for 2
h and concentrated to give the title compound as the
trifluoroacetate salt (0.080 g, 40%).
Intermediate 27: 3-amino-1-(piperidin-1-yl)propan-1-one
trifluoroacetate
[0600] Tert-butyl 2-oxo-2-(piperidin-1-yl)propylcarbamate was
prepared by using the procedure described under intermediate 23
from N-boc-3-aminopropionic acid (0.250 g, 1.32 mmol), DMF (2.5
ml), N-Ethyldiisopropylamine (0.171 g, 1.32 mmol), HATU (0.503 g,
1.32 mmol) and piperidine (0.225 g, 2.64 mmol). Trifluoroacetic
acid (1 ml) was added to the product, stirred for 2 h and
concentrated to give the title compound as the trifluoroacetate
salt (0.120 g, 34%).
Intermediate 28: 3-amino-1-morpholinopropan-1-one
trifluoroacetate
[0601] Tert-butyl 3-morpholino-3-oxopropylcarbamate was prepared by
using the procedure described under intermediate 23 from
N-boc-3-aminopropionic acid (0.250 g, 1.32 mmol), DMF (2.5 ml),
N-Ethyldiisopropylamine (0.171 g, 1.32 mmol) and HATU (0.503 g,
1.32 mmol) and morpholine (0.230 g, 2.64 mmol). Trifluoroacetic
acid (1 ml) was added to the product, stirred for 2 h and
concentrated to give the title compound as the trifluoroacetate
salt (0.120 g, 33%).
Intermediate 29:
6-((5-chloro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)quinoline
[0602] Intermediate 9 (0.200 g, 0.702 mmol) was dissolved in formic
acid (1.0 ml) and heated to 100.degree. C. and stirred for 12 h.
The reaction mixture was poured into ice water and pH adjusted to
7-8 with sodium bicarbonate solution, extracted with ethyl acetate,
washed with brine, dried over sodium sulphate and concentrated to
afford the title compound as yellowish brown solid (0.200 g, 97%
yield). .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400 MHz): .delta.
8.88 (dd, J=4.0, 1.3 Hz, 1H), 8.70 (s, 1H), 8.33 (d, J=8.2 Hz, 1H),
8.19 (d, J=8.3 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.81 (s, 1H), 7.73
(dd, J=8.7, 1.7 Hz, 1H), 7.52 (dd, J=8.3, 2.2 Hz, 1H), 7.37 (d,
J=8.4 Hz, 1H), 5.69 (s, 2H).
Intermediate 30:
6-chloro-3-nitro-N-(1-(quinolin-6-yl)ethyl)pyridin-2-amine
[0603] The title compound was obtained as a yellow solid (0.785 g,
50%) by using a procedure that is similar to the one described for
intermediate 4 from 2,6-Dichloro-3-nitropyridine (0.924 g, 4.78
mmol), 1-(quinolin-6-yl)ethanamine (1.25. g, 7.25 mmol), ethanol (7
ml) and sodium carbonate (1.32 g, 12.54 mmol). .sup.1H-NMR (.delta.
ppm, DMSO-d.sub.6, 400 MHz): .delta. 8.86 (dd, J=4.2, 1.7 Hz, 1H),
8.78 (d, J=7.5 Hz, 1H), 8.44 (d, J=8.6 Hz, 1H), 8.33 (dd, J=8.3,
1.0 Hz, 1H), 7.99 (m, 2H), 7.89 (dd, J=8.8, 1.9 Hz, 1H), 7.51 (q,
J=4.2 Hz, 1H), 6.80 (d, J=7.5 Hz, 1H), 5.57 (quintet, J=7.1 Hz,
1H). 1.69 (d, J=7.0 Hz, 3H).
Intermediate 31:
6-(1H-pyrazol-4-yl)-N2-(1-(quinolin-6-yl)ethyl)pyridine-2,3-diamine
[0604] To a solution of intermediate 30 (0.20 g, 0.608 mmol) and
1-tert-butoxycarbonyl-1H-pyrazole-4-boronic acid pinacol ester
(0.229 g, 0.778 mmol) in dioxane (4 ml), potassium carbonate (0.279
g, 2.02 mmol) and water (0.8 ml) were added and degassed for 30 min
Tetrakis(triphenylphosphine)palladium(0) (0.055 g, 0.047 mmol) was
added under nitrogen at RT and the reaction mixture was refluxed
for 12 h. The solvent was evaporated completely and to the residue
water was added and extracted with ethyl acetate, dried over sodium
sulphate and concentrated under reduced pressure to afford the
crude pyrazole compound as a yellow solid (0.219 g). To a solution
of this intermediate in conc. HCl (3 ml), stannous chloride (0.750
g, 18.13 mmol) was added at RT and stirred for 5 h. The reaction
mixture was poured into ice water and pH adjusted to 7-8 with
sodium bicarbonate solution, extracted with ethyl acetate, washed
with brine, dried over anhydrous sodium sulphate and concentrated
to afford the title compound as yellow solid (0.194 g, 97%) which
was used as such for the next step.
Intermediate 32:
6-chloro-N-((5,7-difluoroquinolin-6-yl)methyl)-3-nitropyridin-2-amine
Step 1: 2-(5,7-difluoroquinolin-6-yl)acetic acid
[0605] A mixture of 4-amino-2,6-difluorophenylacetic acid (3.2 g,
17.1 mmol), ferrous sulphate (1.04 g, 3.76 mmol), nitrobenzene
(1.05 ml, 10.26 mmol) and conc. H.sub.2SO.sub.4 in glycerol (5.2
ml) was heated at 150.degree. C. for 16 h. The mixture was cooled
to RT, methanol (28 ml) was added followed by aq. 6N NaOH (28 ml)
and heated at 110.degree. C. for 3 h. After cooling to RT, the
mixture was acidified with conc. HCl to pH 3.0. The precipitate
formed was filtered, washed with water and dried under vacuum. The
precipitate was refluxed with methanol, filtered under hot
conditions and the filtrate was evaporated to give the title
compound (1 g, 25%) as a brown solid. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): .delta. 12.72 (bs, 1H), 8.98 (d, J=3.1 Hz,
1H); 8.47 (d, J=8.4, 1H); 7.71 (d, J=9.7, 1H); 7.62 (dd, J=8.4,
4.1, 2H); 3.85 (s, 2H).
Step 2: (5,7-difluoroquinolin-6-yl)methanamine
[0606] Diphenyl phosphoryl azide (0.5 ml, 2.32 mmol), triethylamine
(0.34 ml, 2.43 mmol) and tert-butanol (1.3 ml, 13.78 mmol) were
added to a solution of the product from step 1 (0.5 g, 2.24 mmol)
in dioxan (6.5 ml) and heated at 110.degree. C. for 4 h. The
mixture was cooled to RT and distributed between ethyl acetate and
aq. 10% citric acid. The organic layer was separated, dried over
Na.sub.2SO.sub.4 and concentrated to leave a brown residue which
was dissolved in dioxane (5 ml) and dichloromethane (1.5 ml) and
treated with ether saturated with HCl (10 ml) and stirred at RT
overnight. After removing the solvents completely, aq. NaHCO.sub.3
was added to the residue and extracted into ethyl acetate, the
organic layer dried over Na.sub.2SO.sub.4 and the solvent was
removed. Purification of the residue by column chromatography gave
the title compound as a mixture containing ca. 35 mol % of
1,3-bis((5,7-difluoroquinolin-6-yl)methyl)urea, which was used as
such in the next step. .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400
MHz): .delta. 8.95 (d, J=3.8 Hz, 2H); 8.45 (dd, J=7.5, 5.2, 2H);
7.65 (d, J=10.9, 2H); 7.59 (dd, J=8.29, 4.2, 2H); 6.50 (t, J=5.6,
1H), 4.44 (d, J=5.6, 2H); 3.90 (s, 2H).
Step 3:
6-chloro-N-((5,7-difluoroquinolin-6-yl)methyl)-3-nitropyridin-2-am-
ine
[0607] The title compound was obtained as a yellow solid (0.050 g,
5%) by using a procedure that is similar to the one described for
intermediate 4 from 2,6-Dichloro-3-nitropyridine (1.40 g, 7.73
mmol), (5,7-difluoroquinolin-6-yl)methanamine (1.00 g, 5.15 mmol),
ethanol (10 ml) and sodium carbonate (0.97 g, 9.22 mmol).
.sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400 MHz): .delta. 9.09 (t,
J=5.1 Hz, 1H), 8.96 (d, J=3.7 Hz, 1H), 8.49 (d, J=8.4 Hz, 1H), 8.41
(d, J=8.5 Hz, 1H), 7.68 (d, J=11.0 Hz, 1H), 7.61 (dd, J=8.4, 4.2
Hz, 1H), 6.79 (d, J=8.5 Hz, 1H), 4.97 (d, J=5.5 Hz, 2H).
Intermediate 33:
6-chloro-N2-((5,7-difluoroquinolin-6-yl)methyl)pyridine-2,3-diamine
[0608] The title compound was obtained as a brown solid (0.080 g,
73%) by using a procedure that is similar to the one described for
intermediate 9 from intermediate 32 (0.12 g, 0.342 mmol), stannous
chloride (0.347 g, 1.54 mmol) and conc. HCl (2 ml) which was used
as such for the next step.
Intermediate 34:
6-((5-chloro-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)-5,7-difluoroqu-
inoline
[0609] The title compound was obtained as a brown solid (0.068 g,
83%) by using a procedure that is similar to the one described for
intermediate 14 from intermediate 33 (0.080 g, 0.249 mmol), acetic
acid (0.4 ml), sodium nitrite (0.020 g, 0.299 mmol), water (0.2 ml)
and sulphuric acid (0.1 ml). .sup.1H-NMR (.delta. ppm, CDCl.sub.3,
400 MHz): .delta. 8.98 (d, J=2.7 Hz, 1H), 8.43 (d, J=8.2 Hz, 1H),
8.32 (d, J=8.6 Hz, 1H), 7.65 (d, J=10.4 Hz, 1H), 7.48 (dd, J=8.5,
4.3 Hz, 1H), 6.10 (s, 2H), 7.39 (d, J=8.6 Hz, 1H).
Intermediate 35:
2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide
[0610] The title compound was obtained as a brown solid (0.75 g,
69%) by using the procedure described in step 4 for intermediate 19
from 4-bromo-2-chlorobenzamide (0.500 g, 2.13 mmol),
bis(pinacolato)diboron (0.595 g, 2.34 mmol), potassium acetate
(0.627 g, 6.39 mmol), dioxane (3.6 ml) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloro palladium(II).
CH.sub.2Cl.sub.2 (0.052 g, 0.063 mmol). .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): .delta. 7.91 (s, 1H), 7.89 (m, 1H), 7.61
(m, 2H), 7.44 (d, J=7.6 Hz, 1H), 1.14 (s, 12H).
Intermediate 36:
N-(benzo[d]thiazol-6-ylmethyl)-6-chloro-3-nitropyridin-2-amine
[0611] The title compound was obtained as a yellow solid (0.460 g,
9%) by using a procedure that is similar to the one described for
intermediate 4 from 2,6-Dichloro-3-nitropyridine (4.75 g, 24.66
mmol), benzo[d]thiazol-6-ylmethanamine (2.70 g, 16.44 mmol),
ethanol (50 ml) and sodium carbonate (3.03 g, 28.60 mmol) which was
used as such for the next step.
Intermediate 37:
N2-(benzo[d]thiazol-6-ylmethyl)-6-chloropyridine-2,3-diamine
[0612] The title compound was obtained as a yellow solid (0.360 g,
88%) by using a procedure that is similar to the one described for
intermediate 9 from intermediate 36 (0.450 g, 1.40 mmol), stannous
chloride (1.42 g, 6.31 mmol) and conc. HCl (7.5 ml) which was used
as such for the next step.
Intermediate 38:
6-((5-chloro-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-
e
[0613] The title compound was obtained as a brown solid (0.068 g,
83%) by using a procedure that is similar to the one described for
intermediate 14 from intermediate 37 (0.350 g, 0.249 mmol), acetic
acid (1.75 ml), sodium nitrite (0.099 g, 1.44 mmol), water (0.8 ml)
and sulphuric acid (0.4 ml). .sup.1H-NMR (.delta. ppm, CDCl.sub.3,
400 MHz): .delta. 8.99 (s, 1H), 8.32 (d, J=8.5 Hz, 1H), 8.11 (d,
J=8.4 Hz, 1H), 8.07 (s, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.36 (d, J=8.5
Hz, 1H), 6.00 (s, 2H).
Intermediate 39:
6-chloro-N2-(1-(quinolin-6-yl)ethyl)pyridine-2,3-diamine
[0614] The title compound was obtained as a pale brown solid (0.600
g, 74%) by using a procedure that is similar to the one described
for intermediate 9 from intermediate 30 (0.900 g, 2.72 mmol),
stannous chloride (2.77 g, 12.28 mmol) and conc. HCl (1.5 ml) which
is used without purification for next step.
Intermediate 40:
6-(1-(5-chloro-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)ethyl)quinoline
[0615] The title compound was obtained as a brown solid (0.500 g,
84%) by using a procedure that is similar to the one described for
intermediate 14 from intermediate 39 (0.575 g, 1.91 mmol), acetic
acid (3.5 ml), sodium nitrite (0.159 g, 2.30 mmol), water (1 ml)
and sulphuric acid (0.3 ml). .sup.1H-NMR (.delta. ppm, CDCl.sub.3,
400 MHz): .delta. 8.90 (dd, J=4.0, 2.7 Hz, 1H), 8.31 (d, J=8.6 Hz,
1H), 8.15 (d, J=8.2 Hz, 1H), 8.09 (d, J=8.8 Hz, 1H), 7.93 (s,
1H),), 7.89 (dd, J=8.8, 1.9 Hz, 1H), 7.42 (dd, J=8.3, 4.1 Hz, 1H),
7.34 (d, J=8.6 Hz, 1H), 6.50 (q, J=7.1 Hz, 1H), 2.29 (d, J=7.2 Hz,
3H).
Intermediate 41: 4-bromo-2-(trifluoromethyl)benzamide
[0616] Thionyl chloride (10 ml) was added to
4-bromo-3-(trifluoromethyl)benzoic acid (1.0 g, 3.71 mmol, prepared
as described by Hattori et. al. in Bioorg. Med. Chem. 2007, 15,
2198) and refluxed for 3 h. Excess thionyl chloride was removed
under reduced pressure and the residue was cooled to 0.degree. C.
Aqueous 25% ammonia (7 ml) was added and stirred for 15 min. The
precipitate formed was washed with sodium bicarbonate solution and
vacuum dried to afford title compound as a brown solid (0.500 g,
50%) which is used as such for next step.
Intermediate 42:
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)benzam-
ide
[0617] The title compound was obtained as a brown solid (0.30 g,
50%) by using the procedure described in step 4 for intermediate 19
from intermediate 41 (0.500 g, 1.86 mmol), bis(pinacolato)diboron
(0.705 g, 2.77 mmol), potassium acetate (0.743 g, 7.57 mmol),
dioxane (4.6 ml) and [1,1'-bis(diphenylphosphino)ferrocene]dichloro
palladium(II). CH.sub.2Cl.sub.2 (0.061 g, 0.067 mmol) which was
used without purification for the next step.
EXAMPLES
Example 1
6-((5-(4-Methoxyphenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quino-
line
[0618] To a solution of intermediate 14 (0.120 g, 0.405 mmol) and
4-methoxyphenylboronic acid (0.078 g, 0.519 mmol) in dioxane (2.4
ml), potassium carbonate (0.186 g, 1.35 mmol) and water (0.5 ml)
were added and degassed for 30 min tetrakis(triphenylphosphine)
palladium(0) (0.037 g, 0.032 mmol) was added under nitrogen at RT
and the reaction mixture was refluxed for 12 h. The solvent was
evaporated completely and water was added to the residue and
extracted with ethyl acetate, dried over sodium sulphate and
concentrated under reduced pressure. The crude product was purified
by column chromatography with methanol: dichloromethane to afford
the title compound as a yellow solid (0.084 g, 56%). M.P.:
144-146.degree. C. .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400
MHz): 8.88 (d, J=2.6 Hz, 1H), 8.58 (d, J=8.7 Hz, 1H), 8.37 (d,
J=8.1 Hz, 1H), 8.22 (d, J=8.9 Hz, 2H), 8.06 (d, J=8.7 Hz, 1H), 8.02
(m, 2H), 7.83 (dd, J=8.8, 1.5 Hz, 1H), 7.55 (dd, J=8.4, 4.2 Hz,
1H), 7.10 (d, J=8.8 Hz, 2H), 6.18 (s, 2H), 3.83 (s, 3H). MS (m/z):
367.95 (M.sup.+).
Example 2
6-((5-(3-Methoxyphenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quino-
line
[0619] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.120 g, 0.405
mmol), 3-methoxyphenylboronic acid (0.078 g, 0.519 mmol), potassium
carbonate (0.186 g, 1.35 mmol), dioxane (2.4 ml), water (0.5 ml)
and tetrakis(triphenylphosphine)palladium(0) (0.037 g, 0.032 mmol).
Yellow solid (0.080 g, 53%). M.P.: 133-135.degree. C. .sup.1H-NMR
(.delta. ppm, DMSO-d.sub.6, 400 MHz): 8.88 (dd, J=4.0, 1.1 Hz, 1H),
8.64 (d, J=8.9 Hz, 1H), 8.36 (d, J=8.4 Hz, 1H), 8.13 (d, J=8.7 Hz,
1H), 8.02 (s, 1H), 7.99 (d, J=10.2 Hz, 1H), 7.83 (m, 2H), 7.74 (s,
1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 7.47 (t, J=8.0 Hz, 1H), 7.10
(dd, J=8.2, 2.4 Hz, 1H), 6.21 (s, 2H), 3.83 (s, 3H). MS (m/z):
368.02 (M.sup.+).
Example 3
3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzaldeh-
yde
[0620] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.140 g, 0.473
mmol), 3-formylphenylboronic acid (0.098 g, 0.605 mmol), potassium
carbonate (0.217 g, 1.57 mmol), dioxane (2.8 ml), water (0.6 ml)
and Tetrakis(triphenylphosphine)palladium(0) (0.043 g, 0.032 mmol)
to give the title compound quantitatively.
Example 4
(3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)m-
ethanol
[0621] Sodium borohydride (0.018 g, 0.493 mmol) was added to a
solution of example 3 (0.180 g, 0.493 mmol) in methanol (4 ml),
cooled to 0.degree. C., and stirred for 1 h. Ice-cold water was
added to the mixture, extracted with ethyl acetate, washed with
brine, dried over sodium sulphate and concentrated. The crude
product was purified by column chromatography with methanol:
dichloromethane to afford the title compound as a yellow solid
(0.044 g, 24%). M.P. 191-193.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.88 (dd, J=4.2, 1.7 Hz, 1H), 8.63 (d,
J=8.7 Hz, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.21 (d, J=8.3 Hz, 2H), 8.12
(d, J=8.8 Hz, 1H), 8.02 (s, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.83 (dd,
J=8.7, 2.0 Hz, 1H), 7.53 (m, 3H), 6.20 (s, 2H), 5.30 (t, J=5.7 Hz,
1H), 4.58 (d, J=5.4 Hz, 2H). MS (m/z): 368.37 (M.sup.++1).
Example 5
4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzaldeh-
yde
[0622] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.140 g, 0.473
mmol), 4-formylphenylboronic acid (0.098 g, 0.605 mmol), potassium
carbonate (0.217 g, 1.57 mmol), dioxane (2.8 ml), water (0.5 ml)
and tetrakis(triphenylphosphine)palladium(0) (0.043 g, 0.037 mmol).
Brown solid (0.100 g, 58%). .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6,
400 MHz): 10.10 (s, 1H), 8.88 (dd, J=4.2, 1.7 Hz, 1H), 8.74 (d,
J=8.7 Hz, 1H), 8.48 (d, J=8.3 Hz, 2H), 8.39 (dd, J=8.4, 1.0 Hz,
1H), 8.25 (d, J=8.7 Hz, 1H), 8.08 (d, J=8.5 Hz, 2H), 8.04 (d, J=1.7
Hz, 1H), 8.02 (d, J=8.7 Hz, 1H), 7.84 (dd, J=8.7, 2.0 Hz, 1H), 7.51
(q, J=4.3 Hz, 1H), 6.23 (s, 2H).
Example 6
(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)m-
ethanol
[0623] To a solution of example 5 (0.180 g, 0.493 mmol) in methanol
(4 ml) cooled to 0.degree. C., sodium borohydride (0.018 g, 0.493
mmol) was added and stirred for 1 h. The reaction was quenched by
the addition of ice-cold water, extracted with ethyl acetate,
washed with brine, dried over sodium sulphate and concentrated. The
crude product was purified by column chromatography with methanol:
dichloromethane to afford the title compound as a yellow solid
(0.070 g, 39%). M.P.: 187-189.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.88 (dd, J=4.2, 1.7 Hz, 1H), 8.63 (d,
J=8.7 Hz, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.22 (d, J=8.3 Hz, 2H), 8.12
(d, J=8.7 Hz, 1H), 8.02 (s, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.83 (dd,
J=8.7, 2.0 Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 7.49 (d, J=8.4
Hz, 2H), 6.20 (s, 2H), 5.32 (t, J=5.7 Hz, 1H), 4.58 (d, J=5.7 Hz,
2H). MS (m/z): 367.88 (M.sup.+).
Example 7
Methyl
4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)be-
nzoate
[0624] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.130 g, 0.439
mmol), 4-methoxycarbonylphenylboronic acid (0.100 g, 0.562 mmol),
potassium carbonate (0.202 g, 1.46 mmol), dioxane (2.6 ml), water
(0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.040 g,
0.035 mmol). Off-white solid (0.100 g, 57%). .sup.1H-NMR (.delta.
ppm, DMSO-d.sub.6, 400 MHz): 8.88 (dd, J=4.2, 1.8 Hz, 1H), 8.72 (d,
J=8.7 Hz, 1H), 8.39 (m, 3H), 8.21 (d, J=8.8 Hz, 1H), 8.12 (d, J=8.6
Hz, 2H), 8.02 (s, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.84 (dd, J=8.6, 2.0
Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.23 (s, 2H), 3.89 (s,
3H).
Example 8
4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoic
acid
[0625] To a solution of Example 7 (0.095 g, 0.240 mmol) in methanol
(1.4 ml), lithium hydroxide (0.028 g, 1.20 mmol) in water (0.36 ml)
was added and stirred at RT. After 12 h, the pH was adjusted to
(approx) 7.5 using 0.5N HCl and the solid precipitated was
filtered, washed with ethyl acetate and petroleum ether and dried
under vacuum to afford the title compound as an off-white solid
(0.070 g, 76%). M.P.: 245-247.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 13.18 (s, 1H), 8.88 (dd, J=4.1, 1.7 Hz,
1H), 8.71 (d, J=8.7 Hz, 1H), 8.39 (d, J=1.1 Hz, 1H), 8.36 (d, J=8.5
Hz, 2H), 8.21 (d, J=8.7 Hz, 1H), 8.10 (d, J=8.5 Hz, 2H), 8.03 (d,
J=9.2 Hz, 2H), 7.84 (dd, J=8.7, 2.0 Hz, 1H), 7.53 (dd, J=8.4, 4.2
Hz, 1H), 6.22 (s, 2H). MS (m/z): 381.88 (M.sup.+).
Example 9
N-Methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-
benzamide
[0626] To Example 8 (0.050 g, 0.131 mmol) was refluxed with thionyl
chloride (2 ml) for 3 h. Thionyl chloride was evaporated and the
residue was cooled to 0.degree. C. and an ethanolic 50% methylamine
(1 ml) was added and stirred for 15 min. The precipitate formed was
dissolved in dichloromethane, washed with sodium bicarbonate
solution dried over sodium sulphate and concentrated to afford the
title compound as an off-white solid (0.020 g, 39%).
M.P.:220-222.degree. C. .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400
MHz): 8.88 (dd, J=4.2, 1.7 Hz, 1H), 8.69 (d, J=8.7 Hz, 1H), 8.57
(q, J=4.5 Hz, 1H), 8.38 (d, J=1.6 Hz, 2H), 8.33 (d, J=8.5 Hz, 2H),
8.20 (d, J=8.8 Hz, 1H), 8.03 (m, 4H), 7.84 (dd, J=8.7, 1.6 Hz, 1H),
7.53 (dd, J=8.3, 4.1 Hz, 1H), 6.22 (s, 2H), 2.81 (d, J=4.5 Hz, 3H).
MS (m/z): 394.97 (M.sup.+).
Example 10
4-(3-(4-Fluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzaldehyde
[0627] The title compound was prepared by following the procedure
described for example 1 using intermediate 15 (0.100 g, 0.380
mmol), 4-formylphenylboronic acid (0.073 g, 0.487 mmol), potassium
carbonate (0.175 g, 1.26 mmol), dioxane (2.3 ml), water (0.5 ml)
and Tetrakis (triphenylphosphine)palladium(0) (0.035 g, 0.030
mmol). Brown solid (0.095 g, 68%). .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz):10.11 (s, 1H), 8.72 (d, J=8.7 Hz, 1H), 8.48
(d, J=8.3 Hz, 2H), 8.24 (d, J=8.7 Hz, 1H), 8.10 (d, J=8.4 Hz, 2H),
7.55 (m, 2H), 7.22 (m, 2H), 6.01 (s, 2H).
Example 11
(4-(3-(4-Fluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)methan-
ol
[0628] To a solution of example 10 (0.095 g, 0.259 mmol) in
methanol (2 ml) cooled to 0.degree. C., sodium borohydride (0.010
g, 0.259 mmol) was added and stirred for 1 h. The reaction was
quenched by the addition of ice-cold water, extracted with ethyl
acetate, washed with brine, dried over sodium sulphate and
concentrated. The crude product was purified by column
chromatography with methanol: dichloromethane to afford the title
compound as an off-white solid (0.040 g, 46%). M.P.:
210-213.degree. C. .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400
MHz): 8.61 (d, J=8.7 Hz, 1H), 8.22 (d, J=8.3 Hz, 2H), 8.11 (d,
J=8.8 Hz, 1H), 7.53 (m, 4H), 7.21 (m, 2H), 5.98 (s, 2H), 5.32 (t,
J=5.8 Hz, 1H), 4.59 (d, J=5.7 Hz, 2H). MS (m/z): 335.05
(M.sup.++1).
Example 12
Methyl
2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridi-
n-5-yl)benzoate
[0629] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.300 g, 1.01 mmol),
3-fluoro-4-methoxycarbonylphenylboronic acid (0.257 g, 1.29 mmol),
potassium carbonate (0.466 g, 13.37 mmol), dioxane (6 ml), water
(1.2 ml) and tetrakis(triphenylphosphine)palladium(0) (0.093 g,
0.081 mmol). Brown colour solid (0.300 g, 71%). .sup.1H-NMR
(.delta. ppm, DMSO-d.sub.6, 400 MHz): 8.88 (dd, J=4.2, 1.8 Hz, 1H),
8.74 (d, J=8.7 Hz, 1H), 8.38 (dd, J=8.4, 1.0 Hz, 1H), 8.27 (d,
J=8.8 Hz, 1H), 8.24 (s, 1H), 8.22 (m, 1H), 8.07-8.00 (m, 3H), 7.83
(dd, J=8.7, 2.0 Hz, 1H), 7.63 (m, 1H), 6.24 (s, 2H), 3.89 (s,
3H).
Example 13
2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-
benzoic acid
[0630] To a solution of Example 12 (0.230 g, 0.556 mmol) in
methanol (3.5 ml), lithium hydroxide (0.132 g, 5.56 mmol) in water
(0.9 ml) was added and stirred at RT. After 12 h, the pH was
adjusted to 7-7.5 using 0.5N HCl and the solid precipitated was
filtered, washed with ethyl acetate and petroleum ether and dried
under vacuum to afford the title compound as pale brown solid
(0.130 g, 61%). M.P.: 254-257.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 13.43 (s, 1H), 8.88 (dd, J=4.2, 1.7 Hz,
1H), 8.73 (d, J=8.8 Hz, 1H), 8.38 (d, J=7.5 Hz, 1H), 8.25 (d, J=8.8
Hz, 1H), 8.19 (m, 2H), 8.04 (m, 3H), 7.83 (dd, J=8.8, 2.0 Hz, 1H),
7.53 (dd, J=8.4, 4.2 Hz, 1H), 6.23 (s, 2H). MS (m/z): 400.01
(M.sup.++1).
Example 14
2-Fluoro-N-methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyri-
din-5-yl)benzamide
[0631] To Example 13 (0.045 g, 0.112 mmol), thionyl chloride (3 ml)
was added and refluxed for 3 h. The excess thionyl chloride was
removed under reduced pressure and the residue was cooled to
0.degree. C. Methylamine in ethanol (50% solution, 3 ml) was added
and stirred for 15 min. The precipitate formed was dissolved in
dichloromethane, washed with sodium bicarbonate solution dried over
sodium sulphate and concentrated to afford title compound as pale
brown solid (0.015 g, 32%). M.P.: 212-214.degree. C. .sup.1H-NMR
(.delta. ppm, DMSO-d.sub.6, 400 MHz): 8.88 (dd, J=4.2, 1.7 Hz, 1H),
8.72 (d, J=8.7 Hz, 1H), 8.37 (m, 2H), 8.23 (d, J=8.8 Hz, 1H), 8.18
(m, 2H), 8.04 (d, J=1.7 Hz, 1H), 8.02 (d, J=8.7 Hz, 1H), 7.83 (dd,
J=8.8, 2.0 Hz, 1H), 7.80 (t, J=8.1 Hz, 1H), 7.53 (dd, J=8.3, 4.1
Hz, 1H), 6.23 (s, 2H), 2.80 (d, J=4.6 Hz, 3H). MS (m/z): 412.96
(M.sup.+).
Example 15
2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-
benzamide
[0632] To Example 13 (0.045 g, 0.112 mmol), thionyl chloride (3 ml)
was added and refluxed for 3 h. The excess thionyl chloride was
removed under reduced pressure and the residue was cooled to
0.degree. C. Aqueous ammonia (25% solution, 3 ml) was added and
stirred for 15 min. The precipitate formed was dissolved in
dichloromethane, washed with sodium bicarbonate solution dried over
sodium sulphate and concentrated to afford title compound as
off-white solid (0.025 g, 56%). M.P.: 198-200.degree. C.
.sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400 MHz): 8.88 (dd, J=4.2,
1.7 Hz, 1H), 8.72 (d, J=8.7 Hz, 1H), 8.38 (dd, J=8.5, 1.0 Hz, 1H),
8.23 (d, J=8.7 Hz, 1H), 8.17 (m, 2H), 8.04 (d, J=1.6 Hz, 1H), 8.02
(d, J=8.7 Hz, 1H), 7.84 (m, 3H), 7.74 (br s, 1H), 7.54 (dd, J=8.3,
4.2 Hz, 1H), 6.23 (s, 2H). MS (m/z): 398.89 (M.sup.+).
Example 16
(2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)phenyl)methanol
[0633] To a solution of Example 12 (0.130 g, 0.314 mmol) in THF
(1.3 ml) cooled to 0.degree. C., DIBAL-H (25% in toluene, 0.84 ml,
1.25 mmol) was added stirred at RT for 3 h. The reaction mixture
was poured in ice-cold water and extracted with ethyl acetate,
washed with brine, dried over sodium sulphate and concentrated. The
crude product was purified by column chromatography with methanol:
dichloromethane to afford the title compound as pale yellow solid
(0.030 g, 25%). M.P.: 202-204.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.88 (dd, J=4.1, 1.6 Hz, 1H), 8.67 (d,
J=8.7 Hz, 1H), 8.38 (d, J=8.4 Hz, 1H), 8.18 (d, J=8.7 Hz, 1H), 8.12
(dd, J=8.0, 1.5 Hz, 1H), 8.04 (m, 3H), 7.83 (dd, J=8.7, 1.9 Hz,
1H), 7.65 (t, J=7.9 Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.22 (s,
2H), 5.41 (t, J=5.8 Hz, 1H), 4.62 (d, J=5.6 Hz, 2H). MS (m/z):
386.01 (M.sup.++1).
Example 17
Methyl
4-(3-(2-chloro-3,6-difluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-
-5-yl)-2-fluorobenzoate
[0634] The title compound was prepared by following the procedure
described for example 1 using intermediate 16 (0.300 g, 0.951
mmol), 3-fluoro-4-methoxycarbonyl phenylboronic acid (0.241 g, 1.21
mmol), potassium phosphate (0.606 g, 2.856 mmol), toluene (10 ml),
and Tetrakis (triphenylphosphine) palladium(0) (0.088 g, 0.076
mmol). Brown colour solid (0.380 g, 92%). .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.71 (d, J=8.7 Hz, 1H), 8.25 (d, J=8.7 Hz,
1H), 8.17 (s, 1H), 8.15 (d, J=7.2 Hz, 1H), 8.06 (t, J=8.0 Hz, 1H),
7.53 (dt, J=8.9, 5.2 Hz, 1H), 7.46 (dt, J=9.1, 4.2 Hz, 1H), 6.13
(s, 2H), 3.89 (s, 3H).
Example 18
4-(3-(2-Chloro-3,6-difluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)--
2-fluorobenzoic acid
[0635] To a solution of Example 17 (0.300 g, 0.725 mmol) in
methanol (1 ml), THF (2 ml), sodium hydroxide (0.150 g, 3.75 mmol)
in water (1 ml) was added and stirred at RT. After 12 h, the pH was
adjusted to 7-7.5 using 0.5N HCl and the solid precipitated was
filtered, washed with ethyl acetate and petroleum ether and dried
under vacuum to afford the title compound as a pale brown solid
(0.120 g, 41%). M.P.: 211-213.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.65 (d, J=8.8 Hz, 1H), 8.18 (d, J=8.8 Hz,
1H), 8.02 (m, 2H), 7.83 (t, J=7.4 Hz, 1H), 7.60 (dt, J=9.1, 4.8 Hz,
1H), 7.46 (dt, J=9.0, 4.0 Hz, 1H), 6.11 (s, 2H). MS (m/z): 418.70
(M.sup.+).
Example 19
4-(3-(2-Chloro-3,6-difluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)--
2-fluoro-N-methylbenzamide
[0636] To Example 18 (0.100 g, 0.250 mmol), thionyl chloride (2 ml)
was added and refluxed for 3 h. The excess thionyl chloride was
removed under reduced pressure and the residue was cooled to
0.degree. C. Methylamine in ethanol (50% solution, 3 ml) was added
and stirred for 15 min. The precipitate formed was filtered and
washed with petroleum ether and to afford title compound as pale
brown solid (0.030 g, 27%). M.P.: 213-215.degree. C. .sup.1H-NMR
(.delta. ppm, DMSO-d.sub.6, 400 MHz): 8.69 (d, J=8.8 Hz, 1H), 8.36
(br s, 1H), 8.22 (d, J=8.8 Hz, 1H), 8.12 (d, J=7.4 Hz, 1H), 8.10
(d, J=11.2 Hz, 1H), 7.80 (t, J=7.8 Hz, 1H), 7.61 (dt, J=8.8, 4.7
Hz, 1H), 7.45 (dt, J=9.2, 4.3 Hz, 1H), 6.13 (s, 2H), 2.80 (d, J=4.3
Hz, 3H). MS (m/z): 431.80 (M.sup.+).
Example 20
N-(2-Hydroxyethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyr-
idin-5-yl)benzamide
[0637] To Example 8 (0.090 g, 0.235 mmol), thionyl chloride (3 ml)
was added and refluxed for 3 h. The excess thionyl chloride was
removed under reduced pressure and the residue was cooled to
0.degree. C. Ethanolamine (5 ml) was added and stirred for 1 h. The
precipitate formed was filtered and washed with petroleum ether and
to afford title compound as an off-white solid (0.022 g, 22%).
M.P.: >260.degree. C. .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6,
400 MHz): 8.88 (d, J=2.9 Hz, 1H), 8.69 (d, J=8.8 Hz, 1H), 8.57 (t,
J=5.4 Hz, 1H), 8.38 (d, J=8.7 Hz, 1H), 8.34 (d, J=8.3 Hz, 2H), 8.21
(d, J=8.7 Hz, 1H), 8.03 (m, 4H), 7.84 (d, J=8.8 Hz, 1H), 7.53 (dd,
J=8.3, 4.2 Hz, 1H), 6.22 (s, 2H), 4.76 (t, J=5.3 Hz, 1H), 3.53 (q,
J=6.0 Hz, 2H), 3.36 (t, J=6.04.3 Hz, 2H).
Example 21
4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide
[0638] To Example 8 (0.050 g, 0.131 mmol), thionyl chloride (1 ml)
was added and refluxed for 3 h. The excess thionyl chloride was
removed under reduced pressure and the residue was cooled to
0.degree. C. Aqueous ammonia (25% solution, 3 ml) was added and
stirred for 15 min. The precipitate formed was filtered, washed
with petroleum ether and dried to afford title compound as a yellow
solid (0.020 g, 40%). M.P.: 229-231.degree. C. .sup.1H-NMR (.delta.
ppm, DMSO-d.sub.6, 400 MHz): 8.88 (dd, J=4.1, 1.5 Hz, 1H), 8.69 (d,
J=8.7 Hz, 1H), 8.38 (dd, J=7.4 Hz, 1H), 8.33 (d, J=8.3 Hz, 2H),
8.21 (d, J=8.9 Hz, 1H), 8.09 (s, 1H), 8.04-8.00 (m, 4H), 7.84 (dd,
J=8.8, 1.9 Hz, 1H), 7.53 (dd, J=8.4, 4.2 Hz, 1H), 7.48 (s, 1H),
6.22 (s, 2H). MS (m/z): 380.90 (M.sup.++1).
Example 22
Lithium
4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)b-
enzoate
[0639] To Example 8 (0.010 g, 0.026 mmol), in methanol, lithium
hydroxide (1.09 m g) was and stirred at RT for 12 h. The reaction
mixture was concentrated completely to afford title compound as a
yellow solid (0.010 g, 98%). M.P.: >280.degree. C. .sup.1H-NMR
(.delta. ppm, DMSO-d.sub.6, 400 MHz): 8.88 (d, J=2.7 Hz, 1H), 8.61
(d, J=8.7 Hz, 1H), 8.38 (d, J=8.1 Hz, 1H), 8.13 (m, 3H), 8.03 (s,
1H), 8.02 (d, J=8.9 Hz, 1H), 7.97 (d, J=8.1 Hz, 2H), 7.83 (d, J=7.3
Hz, 1H), 7.53 (dd, J=8.2, 4.1 Hz, 1H), 6.20 (s, 2H).
Example 23
6-05-(3-(trifluoromethoxy)phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)me-
thyl)quinoline
[0640] To a solution of intermediate 14 (0.120 g, 0.405 mmol) and
3-trifluoromethoxyphenyl boronic acid (0.107 g, 0.519 mmol) in
dioxane (2.4 ml), potassium carbonate (0.186 g, 1.35 mmol) and
water (0.5 ml) were added and degassed for 30 min. Tetrakis
triphenylphosphine palladium (0) (0.037 g, 0.032 mmol) was added
under nitrogen at RT and the reaction mixture was refluxed for 12
h. The solvent was evaporated completely and to the residue water
was added and extracted with ethyl acetate, dried over sodium
sulphate and concentrated under reduced pressure. The crude product
was purified by column chromatography with methanol:
dichloromethane to afford the title compound as grey solid (0.090
g, 53%). M.P.: 140-142.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.88 (dd, J=4.1, 1.6 Hz, 1H), 8.71 (d,
J=8.7 Hz, 1H), 8.35 (d, J=7.9 Hz, 1H), 8.29 (d, J=8.0 Hz, 1H), 8.21
(d, J=8.8 Hz, 1H), 8.19 (s, 1H), 8.03 (s, 1H), 8.01 (d, J=8.7 Hz,
1H), 7.83 (dd, J=8.7, 1.9 Hz, 1H), 7.71 (t, J=8.1 Hz, 1H), 7.53
(dd, J=8.3, 4.1 Hz, 2H), 6.22 (s, 2H). MS (m/z): 421.92
(M.sup.+).
Example 24
3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenol
[0641] To a solution of example 2 (0.110 g, 0.299 mmol) in
dichloromethane (1 ml), BBr.sub.3 (1M in dichloromethane, 0.82 ml)
was added at 0.degree. C. and the reaction mixture was warmed to RT
and stirred for 1 h. The reaction mixture was quenched with 1.5N
HCl solution and extracted with dichloromethane. The organic layer
was dried over sodium sulphate and concentrated. The crude product
was purified by column chromatography with methanol:
dichloromethane to afford the title compound as an off-white solid
(0.030 g, 28%). M.P.: 255-257.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 9.70 (s, 1H), 8.88 (dd, J=4.1, 2.6 Hz, 1H),
8.62 (d, J=8.7 Hz, 1H), 8.37 (d, J=8.0 Hz, 1H), 8.04 (m, 3H), 7.83
(dd, J=8.7, 1.8 Hz, 1H), 7.64 (s, 1H), 7.64 (d, J=8.6 Hz, 1H), 7.53
(dd, J=8.3, 4.2 Hz, 1H), 7.35 (t, J=7.9 Hz, 1H), 6.92 (dd, J=7.9,
1.4 Hz, 1H), 6.19 (s, 2H). MS (m/z): 354.02 (M.sup.+).
Example 25
6-((5-(3-(difluoromethoxy)phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)me-
thyl) quinoline
[0642] To a solution of intermediate 14 (0.100 g, 0.405 mmol) and
3-difluoromethoxyphenyl boronic acid (0.081 g, 0.438 mmol) in
dioxane (3 ml), potassium carbonate (0.155 g, 1.12 mmol) and water
(0.5 ml) were added and degassed for 30 min Tetrakis
triphenylphosphine palladium (0) (0.031 g, 0.032 mmol) was added
under nitrogen at RT and the reaction mixture was refluxed for 12
h. The solvent was evaporated completely and to the residue water
was added and extracted with ethyl acetate, dried over sodium
sulphate and concentrated under reduced pressure. The crude product
was purified by column chromatography with methanol:
dichloromethane to afford the title compound as an off-white solid
(0.046 g, 29%). M.P.: 122-125.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.88 (dd, J=4.1, 1.6 Hz, 1H), 8.69 (d,
J=8.7 Hz, 1H), 8.36 (d, J=8.5 Hz, 1H), 8.18 (d, J=8.8 Hz, 1H), 8.13
(d, J=7.9 Hz, 1H), 8.03 (m, 3H), 7.84 (dd, J=8.7, 1.5 Hz, 1H), 7.63
(t, J=8.0 Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 7.36 (s, 1H), 7.34
(dd, J=8.1, 2.2 Hz, 1H), 6.22 (s, 2H). MS (m/z): 403.79
(M.sup.+).
Example 26
(4-Methylpiperazin-1-yl)(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-
-b]pyridin-5-yl)phenyl)methanone
[0643] To a solution of example 8 (0.100 g, 0.262 mmol) in DMF (1
ml) HOBT (0.042 g, 0.314 mmol), EDC-HCl (0.125 g, 0.655 mmol) and
triethylamine (0.1 ml, 0.786 mmol) were added and stirred for 5 min
4-Methylpiperazine (0.023 g, 0.235 mmol) was added at RT and the
reaction mixture was stirred for 12 h. To the reaction mixture
water was added and extracted with ethyl acetate, dried over sodium
sulphate and concentrated under reduced pressure. The crude product
was purified by column chromatography with methanol:
dichloromethane to afford the title compound as a yellow solid
(0.020 g, 17%). M.P.: 156-158.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.88 (dd, J=4.1, 1.6 Hz, 1H), 8.69 (d,
J=8.8 Hz, 1H), 8.36 (d, J=7.6 Hz, 1H), 8.31 (d, J=8.3 Hz, 2H), 8.17
(d, J=8.7 Hz, 1H), 8.02 (dd, J=5.1, 3.6 Hz, 2H), 7.83 (dd, J=8.8,
1.8 Hz, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.52 (dd, J=8.2, 4.1 Hz, 1H),
6.21 (s, 2H), 3.63 (s, 2H), 3.30 (s, 2H), 2.36 (s, 4H), 2.19 (s,
3H).
Example 27
N-(2-(dimethylamino)ethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4-
,5-b]pyridin-5-yl)benzamide
[0644] To a solution of example 8 (0.200 g, 0.524 mmol) in DMF (1
ml), HOBT (0.084 g, 0.629 mmol), EDC-HCl (0.250 g, 1.31 mmol) and
triethylamine (0.2 ml, 1.57 mmol) were added and stirred for 5 min
2-N,N-Dimethylethylamine (0.046 g, 0.524 mmol) was added at RT and
the reaction mixture was stirred for 12 h. To the reaction mixture
water was added and extracted with ethyl acetate, dried over sodium
sulphate and concentrated under reduced pressure. The crude product
was purified by column chromatography with methanol:
dichloromethane to afford the title compound as a yellow solid
(0.100 g, 42%). M.P.: 122-125.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.88 (dd, J=4.1, 1.5 Hz, 1H), 8.69 (d,
J=8.8 Hz, 1H), 8.54 (t, J=5.4 Hz, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.33
(d, J=8.3 Hz, 2H), 8.20 (d, J=8.7 Hz, 1H), 8.03-7.98 (m, 4H), 7.84
(dd, J=8.7, 1.7 Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.22 (s,
2H), 3.41 (q, J=6.6 Hz, 2H), 2.47 (m, 2H), 2.20 (s, 6H).
Example 28
4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(tetra-
hydro-2H-pyran-4-yl)benzamide
[0645] To a solution of example 8 (0.200 g, 0.524 mmol) in DMF(1
ml) HOBT (0.084 g, 0.629 mmol), EDC-HCl (0.250 g, 1.31 mmol) and
triethylamine (0.2 ml, 1.57 mmol) were added and stirred for 5 min
4-Aminotetrahydropyran (0.106 g, 1.04 mmol) was added at RT and the
reaction mixture was stirred for 12 h. To the reaction mixture
water was added and extracted with ethyl acetate, dried over sodium
sulphate and concentrated under reduced pressure. The crude product
was purified by column chromatography with methanol:
dichloromethane to afford the title compound as an off-white solid
(0.050 g, 20%). M.P.: 202-205.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.88 (dd, J=4.1, 1.6 Hz, 1H), 8.69 (d,
J=8.8 Hz, 1H), 8.44 (d, J=7.5 Hz, 1H), 8.38 (d, J=7.7 Hz, 1H), 8.33
(d, J=8.5 Hz, 2H), 8.20 (d, J=8.8 Hz, 1H), 8.03-7.99 (m, 4H), 7.85
(dd, J=8.7, 1.9 Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.22 (s,
2H), 4.04 (m, 1H), 3.89 (d, J=9.7 Hz, 2H), 3.39 (t, J=10.0 Hz, 2H),
1.78 (d, J=10.5 Hz, 2H), 1.63 (m, 2H).
Example 29
tert-Butyl
4-(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin--
5-yl)benzamido)piperidine-1-carboxylate
[0646] To a solution of example 8 (0.200 g, 0.524 mmol) in DMF (1
ml), HOBT (0.084 g, 0.629 mmol), EDC-HCl (0.250 g, 1.31 mmol) and
triethylamine (0.2 ml, 1.57 mmol) were added and stirred for 5 min
1-Boc-4-aminopiperidine (0.210 g, 1.04 mmol) was added at RT and
the reaction mixture was stirred for 12 h. To the reaction mixture
water was added and extracted with ethyl acetate, dried over sodium
sulphate and concentrated under reduced pressure. The crude product
was purified by column chromatography with methanol:
dichloromethane to afford the title compound as an off-white solid
(0.125 g, 42%). .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400 MHz):
8.88 (dd, J=4.1, 1.6 Hz, 1H), 8.69 (d, J=8.7 Hz, 1H), 8.40 (d,
J=7.8 Hz, 1H), 8.38 (d, J=8.5 Hz, 1H), 8.33 (d, J=8.5 Hz, 2H), 8.20
(d, J=8.7 Hz, 1H), 8.03-7.99 (m, 4H), 7.84 (dd, J=8.7, 1.8 Hz, 1H),
7.53 (dd, J=8.3, 4.1 Hz, 1H), 6.22 (s, 2H), 3.99 (m, 3H), 2.87 (m,
2H), (d, J=9.9 Hz, 2H), 1.45-1.37 (m, 11H).
Example 30
N-(Piperidin-4-yl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyr-
idin-5-yl)benzamide hydrochloride
[0647] To a solution of example 29 (0.125 g, 0.222 mmol) in THF (1
ml), ether saturated with HCl (1.5 ml) was added at 0.degree. C.
and stirred for 15 min. The precipitate formed was washed with
ether and dried under vacuum to afford the title compound as light
yellow solid (0.105 g, 95%). M.P.: 220-224.degree. C. .sup.1H-NMR
(.delta. ppm, DMSO-d.sub.6, 400 MHz): 9.14 (d, J=3.6 Hz, 1H), 8.90
(m, 3H), 8.72 (d, J=8.7 Hz, 1H), 8.67 (d, J=7.4 Hz, 1H), 8.33 (d,
J=8.5 Hz, 2H), 8.28 (m, 3H), 8.11 (dd, J=8.7, 1.5 Hz, 1H), 8.05 (d,
J=8.5 Hz, 2H), 7.89 (dd, J=8.3, 4.8 Hz, 1H), 6.29 (s, 2H), 4.11 (m,
1H), 3.59 (m, 1H), 3.34 (m, 1H), 3.01 (m, 2H), 1.99 (m, 2H), 1.85
(m, 2H).
Example 31
N-(2-(dimethylamino)ethyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]t-
riazolo[4,5-b]pyridin-5-yl)benzamide
[0648] To a solution of example 13 (0.150 g, 0.375 mmol) in DMF
(1.5 ml), HOBT (0.068 g, 0.454 mmol), EDC-HCl (0.180 g, 0.941 mmol)
and triethylamine (0.15 ml, 1.09 mmol) were added and stirred for 5
min 2-N,N-Dimethylethylamine (0.123 g, 1.39 mmol) was added at RT
and the reaction mixture was stirred for 12 h. To the reaction
mixture water was added and extracted with ethyl acetate, dried
over sodium sulphate and concentrated under reduced pressure. The
crude product was purified by column chromatography with methanol:
dichloromethane to afford the title compound as a yellow solid
(0.029 g, 17%). M.P.: 122-125.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.88 (d, J=2.8 Hz, 1H), 8.72 (d, J=8.7 Hz,
1H), 8.37 (d, J=8.3 Hz, 1H), 8.29 (br s, 1H), 8.23 (d, J=8.8 Hz,
1H), 8.18 (m, 2H), 8.04 (s, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.84 (m,
2H), 7.53 (dd, J=8.3, 4.1 Hz, 1H), 6.23 (s, 2H), 3.39 (m, 4H), 2.49
(s, 6H).
Example 32
(S)-(2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)(4-(3-(quinolin-6-ylmethyl)--
3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)methanone
hydrochloride
[0649] To a solution of example 8 (0.100 g, 0.262 mmol) in DMF (1
ml), HOBT (0.042 g, 0.314 mmol), EDC-HCl (0.125 g, 0.655 mmol) and
triethylamine (0.3 ml, 2.35 mmol) were added and stirred for 5 min
(s)-1-(pyrrolidin-2-ylmethyl)pyrrolidine (0.120 g, 0.783 mmol) was
added at RT and the reaction mixture was stirred for 12 h. To the
reaction mixture water was added and extracted with ethyl acetate,
dried over sodium sulphate and concentrated under reduced pressure.
The crude product was purified by column chromatography with
methanol: dichloromethane to afford the free base as a yellow solid
(0.060 g). The free base was dissolved in THF (5 ml), ether
saturated with HCl (2 ml) was added at 0.degree. C. and stirred for
15 min. The precipitate formed was washed with ether and dried
under vacuum to afford the title compound as a light yellow solid
(0.040 g, 27%). M.P.: 120-122.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 10.00 (s, 1H), 9.09 (s, 1H), 8.77 (m, 1H),
8.72 (d, J=8.7 Hz, 1H), 8.33 (d, J=8.2 Hz, 2H), 8.22 (m, 3H), 8.04
(d, J=9.0 Hz, 1H), 7.80 (m, 1H), 7.74 (d, J=8.0 Hz, 2H), 6.28 (s,
2H), 3.75-3.30 (m, 9H), 2.18-1.90 (m, 8H).
Example 33
(4-(2-hydroxyethyl)piperazin-1-yl)(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]tr-
iazolo[4,5-b]pyridin-5-yl)phenyl)methanone
[0650] To a solution of example 8 (0.150 g, 0.393 mmol) in DMF (1
ml), HOBT (0.063 g, 0.471 mmol), EDC-HCl (0.187 g, 0.983 mmol) and
triethylamine (0.16 ml, 1.17 mmol) were added and stirred for 5 min
(2-(piperazin-1-yl)ethanol (0.046 g, 0.353 mmol) was added at RT
and the reaction mixture was stirred for 12 h. To the reaction
mixture water was added and extracted with ethyl acetate, dried
over sodium sulphate and concentrated under reduced pressure. The
crude product was purified by column chromatography with methanol:
dichloromethane to afford the title compound as a yellow solid
(0.025 g, 13%). M.P.: 158-160.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.88 (d, J=2.7 Hz, 1H), 8.67 (d, J=8.7 Hz,
1H), 8.38 (d, J=7.8 Hz, 1H), 8.31 (d, J=8.2 Hz, 2H), 8.17 (d, J=8.8
Hz, 1H), 8.02 (t, J=4.2 Hz, 2H), 7.83 (dd, J=8.7, 1.6 Hz, 1H), 7.56
(d, J=8.4 Hz, 2H), 7.52 (dd, J=8.3, 4.2 Hz, 1H), 6.21 (s, 2H), 4.44
(t, J=5.3 Hz, 1H), 3.62 (m, 2H), 3.51 (q, J=6.0 Hz, 2H), 2.42 (m,
8H).
Example 34
(R)-(3-hydroxypyrrolidin-1-yl)(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazo-
lo[4,5-b]pyridin-5-yl)phenyl)methanone hydrochloride
[0651] To a solution of example 8 (0.150 g, 0.393 mmol) in DMF (1
ml), HOBT (0.063 g, 0.471 mmol), EDC-HCl (0.187 g, 0.983 mmol) and
triethylamine (0.16 ml, 1.17 mmol) were added and stirred for 5 min
(R)-pyrrolidin-3-ol (0.030 g, 0.353 mmol) was added at RT and the
reaction mixture was stirred for 12 h. To the reaction mixture
water was added and extracted with ethyl acetate, dried over sodium
sulphate and concentrated under reduced pressure. The crude product
was purified by column chromatography with methanol:
dichloromethane to afford the amide as a yellow solid (0.015 g).
The amide was dissolved in THF (2 ml), ether saturated with HCl (2
ml) was added at 0.degree. C. and stirred for 15 min. The
precipitate formed was washed with ether and dried under vacuum to
afford the title compound as a yellow solid (0.017 g, 10%). M.P.:
120-122.degree. C. .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400
MHz): 8.87 (d, J=2.9 Hz, 1H), 8.68 (d, J=8.7 Hz, 1H), 8.38 (d,
J=8.2 Hz, 1H), 8.30 (d, J=8.2 Hz, 2H), 8.17 (d, J=8.8 Hz, 1H), 8.02
(d, J=8.3 Hz, 2H), 7.83 (d, J=8.7 Hz, 1H), 7.69 (m, 2H), 7.52 (dd,
J=8.2, 4.1 Hz, 1H), 6.21 (s, 2H), 3.61 (m, 3H), 3.44 (m, 1H),
1.95-1.80 (m, 4H).
Example 35
N-(2-(piperidin-1-yl)ethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[-
4,5-b]pyridin-5-yl)benzamide
[0652] To a solution of example 8 (0.120 g, 0.314 mmol) in DMF (0.7
ml), N-ethyldiisopropylamine (0.041 g, 0.314 mmol) and HATU (0.119
g, 0.314 mmol) were added and stirred for 5 min
(2-(piperidin-1-yl)ethanamine (0.040 g, 0.314 mmol) was added at RT
and the reaction mixture was stirred for 12 h. To the reaction
mixture water was added and extracted with ethyl acetate, dried
over sodium sulphate and concentrated under reduced pressure. The
crude product was purified by column chromatography with methanol:
dichloromethane to afford the title compound as a yellow solid
(0.080 g, 52%). M.P.: 104-107.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.88 (dd, J=4.1, 1.6 Hz, 1H), 8.70 (d,
J=8.7 Hz, 1H), 8.62 (bs, 1H), 8.38 (m, 3H), 8.21 (d, J=8.8 Hz, 1H),
8.03-7.98 (m, 4H), 7.84 (dd, J=8.7, 1.9 Hz, 1H), 7.53 (dd, J=8.3,
4.2 Hz, 1H), 6.22 (s, 2H), 3.48 (bs, 2H), 2.48 (m, 6H), 1.54 (m,
6H).
Example 36
N-(2-morpholinoethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]-
pyridin-5-yl)benzamide
[0653] The title compound was prepared by following the procedure
described for example 35 using 2-morpholinoethanamine (0.040 g,
0.314 mmol) instead of (2-(piperidin-1-yl)ethanamine Yellow solid
(0.070 g, 45%). M.P.: 146-149.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.88 (dd, J=4.2, 1.6 Hz, 1H), 8.70 (d,
J=8.7 Hz, 1H), 8.54 (t, J=4.5 Hz, 1H), 8.38 (d, J=8.5 Hz, 1H), 8.34
(d, J=8.5 Hz, 2H), 8.20 (d, J=8.8 Hz, 1H), 8.03-7.98 (m, 4H), 7.84
(dd, J=8.8, 2.0 Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.22 (s,
2H), 3.57 (t, J=4.4 Hz, 4H), 3.41 (m, 2H), 2.46 (m, 6H).
Example 37
N-(2-(pyrrolidin-1-yl)ethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo-
[4,5-b]pyridin-5-yl)benzamide
[0654] The title compound was prepared by following the procedure
described for example 35 using 2-(pyrrolidin-1-yl)ethanamine (0.036
g, 0.314 mmol) instead of (2-(piperidin-1-yl)ethanamine. Yellow
solid (0.065 g, 43%). M.P.: 135-137.degree. C. .sup.1H-NMR (.delta.
ppm, DMSO-d.sub.6, 400 MHz):8.88 (dd, J=4.2, 1.7 Hz, 1H), 8.70 (d,
J=8.7 Hz, 1H), 8.58 (m, 1H), 8.38 (d, J=7.5 Hz, 1H), 8.34 (d, J=8.4
Hz, 2H), 8.21 (d, J=8.8 Hz, 1H), 8.03 (d, J=3.5 Hz, 2H), 8.00 (d,
J=8.3 Hz, 2H), 7.84 (dd, J=8.7, 2.0 Hz, 1H), 7.53 (dd, J=8.3, 4.2
Hz, 1H), 6.22 (s, 2H), 3.41 (d, J=5.4 Hz, 2H), 2.49 (m, 6H), 1.68
(s, 4H).
Example 38
(4-(pyrrolidin-1-yl)piperidin-1-yl)(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]t-
riazolo[4,5-b]pyridin-5-yl)phenyl)methanone
[0655] To a solution of example 8 (0.100 g, 0.262 mmol) in 1:1
DMF/dichloromethane mixture (1.0 ml), BOP (0.121 g, 0.275 mmol) and
triethylamine (0.1 ml, 0.786 mmol) were added and stirred for 30
min 4-(pyrrolidin-1-yl)piperidine (0.044 g, 0.288 mmol) was added
at RT and the reaction mixture was stirred for 12 h. To the
reaction mixture water was added and extracted with ethyl acetate,
dried over sodium sulphate and concentrated under reduced pressure.
The crude product was purified by column chromatography with
methanol: dichloromethane to afford the title compound as a yellow
solid (0.017 g, 12%). M.P.: 125-127.degree. C. .sup.1H-NMR (.delta.
ppm, DMSO-d.sub.6, 400 MHz): 8.88 (dd, J=4.2, 1.6 Hz, 1H), 8.71 (d,
J=8.7 Hz, 1H), 8.38 (d, J=8.1 Hz, 1H), 8.33 (d, J=8.2 Hz, 2H), 8.19
(d, J=8.8 Hz, 1H), 8.03 (d, J=8.9 Hz, 1H), 8.00 (s, 1H), 7.83 (dd,
J=8.7, 1.9 Hz, 1H), 7.57 (d, J=8.2 Hz, 2H), 7.53 (dd, J=8.4, 4.2
Hz, 1H), 6.22 (s, 2H), 3.49-3.10 (m, 9H), 2.07-1.53 (m, 8H).
Example 39
N-(3-(dimethylamino)propyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[-
4,5-b]pyridin-5-yl)benzamide
[0656] The title compound was prepared by following the procedure
described for example 35 using 3-N,N-dimethylaminopropylamine
(0.026 g, 0.262 mmol) instead of (2-(piperidin-1-yl)ethanamine
Yellow solid (0.035 g, 29%). M.P.: 132-135.degree. C. .sup.1H-NMR
(.delta. ppm, DMSO-d.sub.6, 400 MHz): .delta. 8.88 (dd, J=4.1, 1.6
Hz, 1H), 8.70 (d, J=8.8 Hz, 1H), 8.66 (t, J=5.8 Hz, 1H), 8.38 (d,
J=8.3 Hz, 1H), 8.33 (d, J=8.4 Hz, 2H), 8.20 (d, J=8.8 Hz, 1H),
8.03-7.97 (m, 4H), 7.84 (dd, J=8.7, 1.9 Hz, 1H), 7.53 (dd, J=8.3,
4.2 Hz, 1H), 6.22 (s, 2H), 3.30 (m, 2H), 2. 30 (t, J=7.0 Hz, 2H),
2.14 (s, 6H), 1.68 (t, J=7.0 Hz, 2H).
Example 40
N,N-Bis(2-methoxyethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5--
b]pyridin-5-yl)benzamide hydrochloride
[0657] To a solution of example 8 (0.150 g, 0.393 mmol) in DMF (1
ml), HOBT (0.063 g, 0.471 mmol), EDC-HCl (0.187 g, 0.983 mmol) and
triethylamine (0.16 ml, 1.17 mmol) were added and stirred for 5 min
Bis(2-methoxyethyl)amine (0.104 g, 0.786 mmol) was added at RT and
the reaction mixture was stirred for 12 h. To the reaction mixture
water was added and extracted with ethyl acetate, dried over sodium
sulphate and concentrated under reduced pressure. The crude product
was purified by column chromatography with methanol:
dichloromethane to afford the amide as a yellow solid (0.04 g). The
amide was dissolved in THF (2 ml), ether saturated with HCl (2 ml)
was added at 0.degree. C. and stirred for 15 min. The precipitate
formed was washed with ether and dried under vacuum to afford the
title compound as a yellow solid (0.035 g, 17%). M.P.:
126-129.degree. C. .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400
MHz): 9.07 (m, 1H), 8.74 (m, 1H), 8.70 (d, J=8.7 Hz, 1H), 8.29 (d,
J=8.3 Hz, 2H), 8.19 (m, 3H), 8.02 (m, 1H), 7.78 (m, 1H), 7.53 (d,
J=8.2 Hz, 2H), 6.27 (s, 2H), 3.64 (bs, 2H), 3.58 (br.s, 2H), 3.41
(br.s, 4H), 3.30 (s, 3H), 3.16 (s, 3H).
Example 41
(2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl-
)phenyl)methanol hydrochloride
[0658] Example 16 (0.050 g. 0.129 mmol) was dissolved in THF (3 ml)
and methanol (3 ml), ether saturated with HCl (3 ml) was added at
0.degree. C. and stirred for 15 min. The precipitate formed was
washed with ether and dried under vacuum to afford the title
compound as an off-white solid (0.040 g, 74%). M.P.:
190-192.degree. C. .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400
MHz): 9.14 (d, J=3.6 Hz, 1H), 8.88 (d, J=8.1 Hz, 1H), 8.68 (d,
J=8.7 Hz, 1H), 8.24 (s, 1H), 8.24 (d, J=8.6 Hz, 1H), 8.18 (d, J=8.8
Hz, 1H), 8.11 (m, 2H), 8.03 (dd, J=11.7, 1.5 Hz, 1H), 7.87 (dd,
J=8.1, 4.8 Hz, 1H), 7.65 (t, J=7.9 Hz, 1H), 6.29 (s, 2H), 5.86 (s,
1H), 4.61 (s, 2H).
Example 42
6-((5-(3-Fluoro-4-(methoxymethyl)phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin--
3-yl)methyl)quinoline
[0659] Sodium hydride (0.010 g, 0.259 mmol) was added at 0.degree.
C. to a solution of example 16 (0.100 g, 0.259 mmol) in DMF (1 ml)
and stirred for 30 min Methyl iodide (0.073 g, 0.518 mmol) was
added and the reaction mixture was warmed to RT. After 12 h, the
reaction mixture was poured into ice-cold water and extracted with
ethyl acetate, washed with brine, dried over sodium sulphate and
concentrated. The crude product was purified by column
chromatography with methanol: dichloromethane to afford the title
compound as an off-white solid (0.033 g, 32%). M.P.:
200-201.degree. C. .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400
MHz): 8.88 (dd, J=4.2, 1.7 Hz, 1H), 8.68 (d, J=8.8 Hz, 1H), 8.37
(d, J=8.4 Hz, 1H), 8.18 (d, J=8.8 Hz, 1H), 8.11-8.00 (m, 4H), 7.83
(dd, J=8.7, 1.9 Hz, 1H), 7.61 (t, J=7.7 Hz, 1H), 7.53 (dd, J=8.4,
4.2 Hz, 1H), 6.22 (s, 2H), 4.53 (s, 2H), 3.33 (s, 3H).
Example 43
N-ethyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrid-
in-5-yl)benzamide
[0660] To a solution of example 13 (0.100 g, 0.250 mmol) in DMF
(0.7 ml), N-ethyldiisopropylamine (0.064 g, 0.50 mmol) and HATU
(0.095 g, 0.250 mmol) were added and stirred for 5 min Ethylamine
hydrochloride (0.020 g, 0.250 mmol) was added at RT and the
reaction mixture was stirred for 12 h. Water was added to the
reaction mixture and extracted with ethyl acetate, dried over
sodium sulphate and concentrated under reduced pressure. The crude
product was purified by column chromatography with methanol:
dichloromethane to afford the title compound as a yellow solid
(0.070 g, 66%). M.P.: 207-209.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.88 (dd, J=4.2, 1.7 Hz, 1H), 8.71 (d,
J=8.7 Hz, 1H), 8.41 (m, 1H), 8.37 (d, J=7.6 Hz, 1H), 8.23 (d, J=8.8
Hz, 1H), 8.17 (m, 2H), 8.04 (s, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.84
(dd, J=8.7, 1.9 Hz, 1H), 7.77 (t, J=7.9 Hz, 1H), 7.54 (dd, J=8.3,
4.1 Hz, 1H), 6.23 (s, 2H), 3.29 (m, 2H), 1.4 (t, J=7.2 Hz, 3H).
Example 44
2-Fluoro-N-(2-(pyrrolidin-1-yl)ethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3-
]triazolo[4,5-b]pyridin-5-yl)benzamide
[0661] The title compound was prepared by following the procedure
described for example 43 using (2-(piperidin-1-yl)ethanamine (0.028
g, 0.250 mmol) instead of ethylamine hydrochloride. Yellow solid
(0.015 g, 12%). M.P.: 183-186.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.89 (dd, J=4.0, 1.5 Hz, 1H), 8.74 (d,
J=8.7 Hz, 1H), 8.59 (m, 1H), 8.37 (d, J=7.7 Hz, 1H), 8.25-8.19 (m,
3H), 8.03 (s, 1H), 8.02 (d, J=8.7 Hz, 1H), 7.90 (t, J=8.0 Hz, 1H),
7.84 (dd, J=8.7, 1.8 Hz, 1H), 7.54 (dd, J=8.4, 4.2 Hz, 1H), 6.24
(s, 2H), 3.62 (m, 4H), 3.06-2.89 (m, 4H), 1.89-1.86 (m, 4H).
Example 45
N-cyclohexyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]-
pyridin-5-yl)benzamide
[0662] The title compound was prepared by following the procedure
described for example 43 using cyclohexylamine (0.025 g, 0.250
mmol) instead of ethylamine hydrochloride. Yellow solid (0.050 g,
41%). M.P.: 172-175.degree. C. MS (m/z): 481.21 (M.sup.++1).
Example 46
N-Cyclopropyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b-
]pyridin-5-yl)benzamide
[0663] The title compound was prepared by following the procedure
described for example 43 using cyclopropylamine (0.014 g, 0.250
mmol) instead of ethylamine hydrochloride. Off-white solid (0.015
g, 14%). M.P.: 193-195.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.88 (dd, J=4.1, 1.6 Hz, 1H), 8.71 (d,
J=8.7 Hz, 1H), 8.48 (d, J=3.8 Hz, 1H), 8.37 (d, J=7.3 Hz, 1H), 8.23
(d, J=8.8 Hz, 1H), 8.16 (m, 2H), 8.04 (s, 1H), 8.02 (d, J=8.7 Hz,
1H), 7.83 (dd, J=8.7, 2.0 Hz, 1H), 7.72 (t, J=8.0 Hz, 1H), 7.54
(dd, J=8.4, 4.2 Hz, 1H), 6.23 (s, 2H), 2.87 (m, 1H), 0.70 (m, 2H),
0.57 (m, 2H).
Example 47
2-Fluoro-N-(pyridin-4-yl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,-
5-b]pyridin-5-yl)benzamide
[0664] The title compound was prepared by following the procedure
described for example 43 using 4-aminopyridine (0.023 g, 0.250
mmol) instead of ethylamine hydrochloride. Yellow solid (0.050 g,
42%). M.P.: 217-219.degree. C. MS (m/z): 476.17 (M.sup.++1).
Example 48
N-Benzyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyri-
din-5-yl)benzamide
[0665] The title compound was prepared by following the procedure
described for example 43 using benzylamine (0.023 g, 0.250 mmol)
instead of ethylamine hydrochloride. Pale green solid (0.040 g,
32%). M.P.: 163-165.degree. C. MS (m/z): 489.19 (M.sup.++1).
Example 49
2-Fluoro-N,N-dimethyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]-
pyridin-5-yl)benzamide
[0666] The title compound was prepared by following the procedure
described for example 43 using dimethylamine hydrochloride (0.020
g, 0.250 mmol) instead of ethylamine hydrochloride. Pale brown
solid (0.020 g, 18%). M.P.: 163-165.degree. C. MS (m/z): 426.96
(M.sup.++1).
Example 50
Methyl
2-(2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyr-
idin-5-yl)benzamido)acetate
[0667] To glycine (0.100 g, 1.133 mmol) in methanol (4 ml), thionyl
chloride (0.9 ml) was added and refluxed for 1 h. The solvent was
removed and the residue was dissolved in DMF (2 ml). To this
solution example 13 (0.150 g, 0.375 mmol), N-ethyldiisopropylamine
(0.097 g, 0.751 mmol) and HATU (0.0142 g, 0.375 mmol) were added at
RT and the reaction mixture was stirred for 12 h. To the reaction
mixture water was added and extracted with ethyl acetate, dried
over sodium sulphate and concentrated under reduced pressure. The
crude product was purified by column chromatography with methanol:
dichloromethane to afford the title compound as a yellow solid
(0.055 g, 31%). .sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400 MHz):
.delta. 8.92 (dd, J=4.2, 1.6 Hz, 1H), 8.48 (d, J=8.6 Hz, 1H), 8.27
(t, J=8.4 Hz, 1H), 8.16 (d, J=8.8 Hz, 1H), 8.10 (d, J=8.7 Hz, 1H),
8.00 (m, 3H), 7.88 (m, 2H), 7.43 (dd, J=8.4, 4.2 Hz, 1H), 7.36 (m,
1H), 6.16 (s, 2H), 4.32 (d, J=4.7 Hz, 2H), 3.83 (s, 3H).
Example 51
2-(2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5--
yl)benzamido)acetic acid
[0668] To a solution of Example 50 (0.055 g, 0.113 mmol) in
methanol (0.5 ml), lithium hydroxide (0.045 g, 1.05 mmol) in water
(0.5 ml) was added and stirred at RT. After 12 h, pH was adjusted
to ca. 7 using 0.5N HCl and the solid precipitated was filtered,
washed with ethyl acetate and petroleum ether and dried under
vacuum to afford the title compound as a pale green solid (0.050 g,
96%). M.P.: 252-254.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 12.70 (s, 1H), 9.01 (d, J=3.9 Hz, 1H), 8.73
(d, J=8.7 Hz, 1H), 8.64 (m, 2H), 8.25 (d, J=8.8 Hz, 1H), 8.20 (m,
4H), 7.97 (d, J=8.9 Hz, 1H), 7.86 (t, J=8.1 Hz, 1H), 7.71 (dd,
J=7.8, 4.2 Hz, 1H), 6.27 (s, 2H), 3.96 (d, J=5.8 Hz, 2H). MS (m/z):
456.85 (M.sup.+).
Example 52
2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-
-N-(1H-1,2,4-triazol-3-yl)benzamide
[0669] The title compound was prepared by following the procedure
described for example 43 using 3-amino-1,2,4-triazole (0.021 g,
0.250 mmol) instead of ethylamine hydrochloride. Off-white solid
(0.010 g, 9%). M.P.: 265-267.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 13.70 (s, 1H), 12.10 (s, 1H), 8.87 (m, 1H),
8.74 (d, J=8.5 Hz, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.27-8.22 (m, 3H),
8.05 (m, 2H), 7.89-7.79 (m, 3H), 7.54 (q, J=4.2 Hz, 1H), 6.25 (s,
2H). MS (m/z): 465.95 (M.sup.+).
Example 53
Methyl
3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)be-
nzoate
[0670] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.250 g, 0.845
mmol), 3-methoxycarbonylphenylboronic acid (0.190 g, 1.056 mmol),
potassium acetate (0.276 g, 2.81 mmol), dioxane (5 ml) and
tetrakis(triphenylphosphine)palladium(0) (0.078 g, 0.067 mmol).
Brown solid (0.190 g, 56%).
Example 54
3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoic
acid
[0671] To a solution of example 53 (0.190 g, 0.480 mmol) in
methanol (2.7 ml), lithium hydroxide (0.201 g, 4.80 mmol) in water
(0.75 ml) was added and stirred at RT. After 12 h, the pH was
adjusted to 7-7.5 using 0.5N HCl and the solid precipitated was
filtered, washed with ethyl acetate and petroleum ether and dried
under vacuum to afford the title compound as brown solid (0.070 g,
38%). .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400 MHz): 13.39 (s,
1H), 8.87 (d, J=2.6 Hz, 1H), 8.77 (s, 1H), 8.68 (d, J=8.7 Hz, 1H),
8.39 (m, 2H), 8.16 (d, J=8.7 Hz, 1H), 8.07 (m, 3H), 7.85 (dd,
J=8.7, 1.5 Hz, 1H), 7.66 (t, J=7.8 Hz, 1H), 7.52 (dd, J=8.3, 4.1
Hz, 1H), 6.22 (s, 2H).
Example 55
N-Methyl-3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-
benzamide
[0672] To example 54 (0.070 g, 0.183 mmol), thionyl chloride (3 ml)
was added and refluxed for 3 h. The excess thionyl chloride was
removed under reduced pressure and the residue was cooled to
0.degree. C. Methylamine in ethanol (50% solution, 5 ml) was added
and stirred for 15 min. The precipitate formed was washed with
sodium bicarbonate solution and dried under vacuum to afford the
title compound as pale brown solid (0.050 g, 69%). M.P.:
215-217.degree. C. MS (m/z): 359.04 (M.sup.++1).
Example 56
6-((5-(3-Fluorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinol-
ine
[0673] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.100 g, 0.338
mmol), 3-fluorophenylboronic acid (0.059 g, 0.422 mmol), potassium
carbonate (0.156 g, 0.027 mmol), dioxane (2 ml), water (0.5 ml) and
tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.067 mmol) in
microwave oven (100 W, 100.degree. C.) for 20 min Yellow solid
(0.040 g, 30%. M.P.: 145-147.degree. C. MS (m/z): 356.05
(M.sup.++1).
Example 57
Methyl
3-(2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyr-
idin-5-yl)phenylamino)propanoate
[0674] To 2-aminopropionic acid (0.100 g, 1.122 mmol) in methanol
(4 ml), thionyl chloride (0.9 ml) was added and refluxed for 1 h.
Solvents were removed and residue was dissolved in DMF (2 ml). To
this solution example 13 (0.150 g, 0.375 mmol),
N-ethyldiisopropylamine (0.097 g, 0.751 mmol) and HATU (0.0142 g,
0.375 mmol) were added at RT and the reaction mixture was stirred
for 12 h. To the reaction mixture water was added and extracted
with ethyl acetate, dried over sodium sulphate and concentrated
under reduced pressure. The crude product was purified by column
chromatography with methanol: dichloromethane to afford the title
compound as a yellow solid (0.078 g, 44%).
Example 58
3-(2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5--
yl)phenylamino)propanoic acid
[0675] To a solution of example 57 (0.080 g, 0.165 mmol) in
methanol (0.8 ml), lithium hydroxide (0.064 g, 1.54 mmol) in water
(0.8 ml) was added and stirred at RT. After 12 h, pH was adjusted
to ca. 7.5 using 0.5N HCl and the solid precipitated was filtered,
washed with ethyl acetate and petroleum ether and dried under
vacuum to afford the title compound as pale green solid (0.075 g,
68%). M.P.: 132-135.degree. C.
Example 59
2-Fluoro-N-methoxy-N-methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[-
4,5-b]pyridin-5-yl)benzamide hydrochloride
[0676] The title compound was prepared by following the procedure
described for example 43 using N,O-dimethylhydroxylamine
hydrochloride (0.025 g, 0.250 mmol) instead of Ethylamine
hydrochloride. Yellow solid (0.055 g, 46%). M.P.: 201-202.degree.
C. MS (m/z): 443.20 (M.sup.++1-HCl).
Example 60
N-tert-Butyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]-
pyridin-5-yl)benzamide
[0677] The title compound was prepared by following the procedure
described for example 43 using tert-butylamine (0.018 g, 0.250
mmol) instead of ethylamine hydrochloride. Yellow solid (0.050 g,
44%). M.P.: 210-212.degree. C. MS (m/z): 455.10 (M.sup.++1).
Example 61
N-Allyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrid-
in-5-yl)benzamide
[0678] The title compound was prepared by following the procedure
described for example 43 using allylamine (0.018 g, 0.250 mmol)
instead of ethylamine hydrochloride. Yellow solid (0.033 g, 29%).
M.P.: 162-164.degree. C. MS (m/z): 438.93 (M.sup.+).
Example 62
2-Fluoro-N-methoxy-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyr-
idin-5-yl)benzamide
[0679] The title compound was prepared by following the procedure
described for example 43 using methoxylamine hydrochloride (0.0208
g, 0.250 mmol) instead of ethylamine hydrochloride. Yellow solid
(0.055 g, 51%). M.P.: 197-199.degree. C. MS (m/z): 429.06
(M.sup.+).
Example 63
N-(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl-
)acetamide
[0680] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.100 g, 0.338
mmol), 4-acetamidophenylboronic acid (0.076 g, 0.422 mmol),
potassium carbonate (0.156 g, 0.027 mmol), dioxane (2 ml), water
(0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.031 g,
0.067 mmol) in microwave oven (100 W, 100.degree. C.) for 20 min.
Brown solid (0.090 g, 67%). M.P.: 220-223.degree. C. MS (m/z):
394.83 (M.sup.+1).
Example 64
4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)aniline
[0681] To a solution of example 63 (0.060 g, 0.152 mmol) in ethanol
(1 ml) was added con. HCl (0.5 ml) and refluxed for 2 h. The
reaction mixture was cooled, basified with sodium bicarbonate
solution, extracted with ethyl acetate, dried over sodium sulphate
and concentrated under reduced pressure to afford the title
compound as a brown solid (0.030 g, 42%). M.P.: 190-193.degree. C.
MS (m/z): 353.18 (M.sup.++1).
Example 65
6-((5-(3,4-Dimethoxyphenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)q-
uinoline
[0682] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.100 g, 0.338
mmol), 3,4-dimethoxyphenylboronic acid (0.076 g, 0.422 mmol),
potassium carbonate (0.156 g, 0.027 mmol), dioxane (2 ml), water
(0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.031 g,
0.067 mmol) in microwave oven (100 W, 100.degree. C.) for 20 min
Brown solid (0.090 g, 67%). M.P.: 149-152.degree. C. MS (m/z):
397.77 (M.sup.+).
Example 66
6-((5-(3-Fluoro-4-methoxyphenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)met-
hyl)quinoline
[0683] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.100 g, 0.338
mmol), 3-fluoro-4-methoxyphenylboronic acid (0.074 g, 0.439 mmol),
potassium carbonate (0.156 g, 0.027 mmol), dioxane (2 ml), water
(0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.031 g,
0.067 mmol) in microwave oven (100 W, 100.degree. C.) for 20 min
Pale green solid (0.060 g, 46%). M.P.: 187-190.degree. C. MS (m/z):
385.873 (M.sup.+).
Example 67
6-((5-(4-Fluorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinol-
ine
[0684] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.100 g, 0.338
mmol), 4-fluorophenylboronic acid (0.059 g, 0.422 mmol), potassium
carbonate (0.156 g, 0.027 mmol), dioxane (2 ml), water (0.5 ml) and
tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.067 mmol) in
microwave oven (100 W, 100.degree. C.) for 20 min Yellow solid
(0.060 g, 50%). M.P.: 153-156.degree. C. MS (m/z): 355.98
(M.sup.+).
Example 68
6-((5-(2-Fluorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinol-
ine
[0685] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.100 g, 0.338
mmol), 2-fluorophenylboronic acid (0.059 g, 0.422 mmol), potassium
carbonate (0.156 g, 0.027 mmol), dioxane (2 ml), water (0.5 ml) and
tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.067 mmol) in
microwave oven (100 W, 100.degree. C.) for 20 min Yellow solid
(0.050 g, 41%). M.P.: 164-166.degree. C. MS (m/z): 355.84
(M.sup.+).
Example 69
N-(3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl-
)acetamide
[0686] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.100 g, 0.338
mmol), 4-acetamidophenylboronic acid (0.078 g, 0.439 mmol),
potassium carbonate (0.156 g, 0.027 mmol), dioxane (2 ml), water
(0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.031 g,
0.067 mmol) in microwave oven (100 W, 100.degree. C.) for 20 min
Pale green solid (0.065 g, 49%). M.P.: 198-201.degree. C. MS (m/z):
395.11 (M.sup.++1).
Example 70
6-((5-(3-(2,2,2-Trifluoroethoxyl)phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin--
3-yl)methyl)quinoline
[0687] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.100 g, 0.338
mmol), 3-trifluoroethoxyphenylboronic acid (0.096 g, 0.439 mmol),
potassium carbonate (0.156 g, 0.027 mmol), dioxane (2 ml), water
(0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.031 g,
0.067 mmol) in microwave oven (100 W, 100.degree. C.) for 20 min
Off-white solid (0.040 g, 42.7%). M.P.: 151-154.degree. C. MS
(m/z): 435.97 (M.sup.+).
Example 71
3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)aniline
[0688] To a solution of example 69 (0.045 g, 0.152 mmol) in ethanol
(1 ml), con. HCl (0.5 ml) was added and refluxed for 2 h. The
reaction mixture was cooled, basified with sodium bicarbonate
solution, extracted with ethyl acetate, dried over sodium sulphate
and concentrated under reduced pressure to afford the title
compound as brown solid (0.028 g, 70%). M.P.: 187-189.degree. C. MS
(m/z): 352.90 (M.sup.+).
Example 72
N-(3-(dimethylamino)propyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]-
triazolo[4,5-b]pyridin-5-yl)benzamide
[0689] The title compound was prepared by following the procedure
described for example 43 using 3-N,N-Dimethylaminopropylamine
(0.026 g, 0.262 mmol) instead of ethylamine hydrochloride.
Off-white solid (0.063 g, 54%). M.P.: 148-150.degree. C. MS (m/z):
483.92 (M.sup.+).
Example 73
N-Ethyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrid-
in-5-yl)benzamide hydrochloride
[0690] The example 43 (0.050 g, 0.117 mmol) was dissolved in THF (1
ml), ether saturated with HCl (1 ml) was added at 0.degree. C. and
stirred for 15 min. The precipitate formed was washed with ether
and dried under vacuum to afford the title compound as an off-white
solid (0.052 g, 95%). M.P.: 236-238.degree. C. .sup.1H-NMR (.delta.
ppm, DMSO-d.sub.6, 400 MHz): 9.07 (m, 1H), 8.73 (m, 2H), 8.41 (m,
1H), 8.24 (d, J=8.8 Hz, 1H), 8.19-8.13 (m, 4H), 8.02 (d, J=7.4 Hz,
1H), 7.80 (m, 2H), 6.29 (s, 2H), 3.23 (m, 2H), 1.14 (t, J=7.2 Hz,
3H).
Example 74
2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-
benzamide hydrochloride
[0691] The example 15 (0.040 g. 0.100 mmol) was dissolved in THF (1
ml), ether saturated with HCl (1 ml) was added at 0.degree. C. and
stirred for 15 min. The precipitate formed was washed with ether
and dried under vacuum to afford the title compound as an off-white
solid (0.043 g, 96%). M.P.: 165-1688.degree. C. .sup.1H-NMR
(.delta. ppm, DMSO-d.sub.6, 400 MHz): .delta. 9.10 (m, 1H), 8.79
(m, 1H), 8.73 (d, J=8.8 Hz, 1H), 8.24-8.13 (m, 4H), 8.05 (d, J=8.7
Hz, 1H), 7.83 (m, 3H), 7.74 (s, 1H), 6.29 (s, 2H).
Example 75
6-((5-(3-Fluoro-4-isopropoxyphenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-
methyl)quinoline
[0692] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.100 g, 0.338
mmol), 3-fluoro-4-isopropoxyphenylboronic acid pinacol ester (0.113
g, 0.439 mmol), potassium carbonate (0.156 g, 0.027 mmol), dioxane
(2 ml), water (0.5 ml) and tetrakis
(triphenylphosphine)palladium(0) (0.031 g, 0.067 mmol) in microwave
oven (100 W, 100.degree. C.) for 30 min Brown solid (0.095 g, 68%).
M.P.: 128-130.degree. C. MS (m/z): 413.92 (M.sup.+).
Example 76
N-(3-(dimethylamino)-3-oxopropyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[-
1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide
[0693] The title compound was prepared by following the procedure
described for example 43 using intermediate 23 (0.075 g, 0.326
mmol) instead of Ethylamine hydrochloride. Off-white solid (0.075
g, 60%). M.P.: 163-165.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.91 (dd, J=4.2, 1.6 Hz, 1H), 8.46 (d,
J=8.7 Hz, 1H), 8.21 (d, J=7.9 Hz, 1H), 8.17 (d, J=9.3 Hz, 1H), 8.10
(d, J=8.7 Hz, 1H), 7.97-7.83 (m, 5H), 7.78 (m, 1H), 7.43 (dd,
J=8.3, 4.2 Hz, 1H), 6.15 (s, 2H), 3.84 (q, J=5.4 Hz, 1H), 2.68 (t,
J=5.5 Hz, 2H), 3.01 (s, 3H), 2.98 (s, 3H).MS (m/z): 498.41
(M.sup.++1).
Example 77
N-(2-(dimethylamino)-2-oxoethyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1-
,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide
[0694] The title compound was prepared by following the procedure
described for example 43 using intermediate 24 (0.050 g, 0.280
mmol) instead of Ethylamine hydrochloride. Off-white solid (0.085
g, 70%). M.P.: 177-179.degree. C. MS (m/z): 483.85 (M.sup.+).
Example 78
2-Fluoro-N-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-4-(3-(quinolin-6-ylmethyl)-3H--
[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide
[0695] The title compound was prepared by following the procedure
described for example 43 using intermediate 25 (0.096 g, 0.396
mmol) instead of Ethylamine hydrochloride. Off-white solid (0.085
g, 66%). M.P.: 175-177.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.91 (dd, J=4.1, 1.5 Hz, 1H), 8.47 (d,
J=8.6 Hz, 1H), 8.22 (d, J=8.0 Hz, 1H), 8.17 (d, J=8.4 Hz, 1H), 8.10
(d, J=8.7 Hz, 1H), 7.98 (m, 4H), 7.87 (dd, J=8.7, 3.2 Hz, 2H), 7.43
(dd, J=8.3, 4.2 Hz, 1H), 6.15 (s, 2H), 4.25 (d, J=3.5 Hz, 2H), 3.58
(t, J=5.9 Hz, 2H), 3.48 (t, J=5.8 Hz, 2H), 2.06 (q, J=6.9 Hz, 2H),
1.94 (q, J=6.8 Hz, 2H). MS (m/z): 509.96 (M.sup.+).
Example 79
6-((5-(4-(Cyclopropylmethoxy)-3-fluorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyr-
idin-3-yl)methyl)quinoline
[0696] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.100 g, 0.338
mmol),
2-(4-(cyclopropylmethoxy)-3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxa-
borolane (0.123 g, 0.422 mmol), potassium carbonate (0.156 g, 0.027
mmol), dioxane (2 ml), water (0.5 ml) and tetrakis
(triphenylphosphine)palladium(0) (0.031 g, 0.067 mmol) in microwave
oven (100 W, 100.degree. C.) for 30 min Off-white solid (0.040 g,
28%). M.P.: 160-162.degree. C. MS (m/z): 425.89 (M.sup.+).
Example 80
6-((5-(3-Fluoro-4-isobutoxyphenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)m-
ethyl)quinoline
[0697] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.100 g, 0.338
mmol), 4-isobutyloxy-3-fluorophenyl boronic acid pinacol ester
(0.122 g, 0.422 mmol), potassium carbonate (0.156 g, 0.027 mmol),
dioxane (2 ml), water (0.5 ml) and tetrakis
(triphenylphosphine)palladium(0) (0.031 g, 0.067 mmol) in microwave
oven (100 W, 100.degree. C.) for 30 min. Pale brown solid (0.065 g,
45%). M.P.: 115-157.degree. C. MS (m/z): 428.13 (M.sup.++1).
Example 81
3-(2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5--
yl)phenoxy)-N,N-dimethylpropan-1-amine
[0698] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.100 g, 0.338
mmol),
3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-N,N-d-
imethylpropan-1-amine (0.137 g, 0.422 mmol), potassium carbonate
(0.156 g, 0.027 mmol), dioxane (2 ml), water (0.5 ml) and tetrakis
(triphenylphosphine)palladium(0) (0.031 g, 0.067 mmol) in microwave
oven (100 W, 100.degree. C.) for 30 min Pale brown solid (0.055 g,
45%). M.P.: 102-105.degree. C. MS (m/z): 457.18 (M.sup.++1).
Example 82
Methyl
2-fluoro-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[4,5-
-b]pyridin-5-yl)benzoate
[0699] The title compound was prepared by following the procedure
described for example 1 using intermediate 17 (0.600 g, 1.841
mmol), 3-fluoro-4-methoxycarbonyl phenylboronic acid (0.459 g, 2.30
mmol), potassium acetate (0.585 g, 5.965 mmol), dioxane (12 ml) and
tetrakis(triphenylphosphine)palladium(0) (0.170 g, 0.147 mmol).
Off-white solid (0.705 g, 87%). .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.90 (dd, J=4.2, 1.5 Hz, 1H), 8.44 (d,
J=8.7 Hz, 1H), 8.18 (d, J=7.8 Hz, 1H), 8.00 (d, J=9.0 Hz, 1H), 7.92
(m, 2H), 7.75 (d, J=8.7 Hz, 1H), 7.69-7.60 (m, 3H), 7.41 (m, 1H),
3.93 (s, 3H), 2.50 (s, 6H).
Example 83
2-Fluoro-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyri-
din-5-yl)benzoic acid
[0700] To a solution of Example 82 (0.700 g, 1.60 mmol) in methanol
(3.7 ml), lithium hydroxide (0.626 g, 14.94 mmol) in water (3.7 ml)
and THF (14 ml) were added and stirred at RT. After 12 h, the pH
was adjusted to 7-7.5 using 0.5N HCl and the solid precipitated was
filtered, washed with ethyl acetate and petroleum ether and dried
under vacuum to afford the title compound as an off-white solid
(0.485 g, 71%) MS (m/z): 472.99 (M.sup.+).
Example 84
2-Fluoro-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyri-
din-5-yl)benzamide
[0701] To Example 83 (0.050 g, 0.116 mmol), thionyl chloride (1 ml)
was added and refluxed for 3 h. The excess thionyl chloride was
removed under reduced pressure and the residue was cooled to
0.degree. C. Aqueous ammonia (25% solution, 3 ml) was added and
stirred for 15 min. The precipitate formed was washed with sodium
bicarbonate solution and vacuum dried to afford title compound as
brown solid (0.025 g, 50%). M.P.: 127-130.degree. C. .sup.1H-NMR
(.delta. ppm, DMSO-d.sub.6, 400 MHz): 8.87 (d, J=2.5 Hz, 1H), 8.67
(d, J=8.9 Hz, 1H), 8.42 (d, J=7.9 Hz, 1H), 8.11 (d, J=8.9 Hz, 1H),
8.09 (s, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.79 (d, J=8.3 Hz, 1H),
7.71-7.61 (m, 4H), 7.75 (m, 2H), 2.48 (s, 6H).
Example 85
6-((5-(3-Fluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl)-3H-[1,2,3]triazolo[-
4,5-b]pyridin-3-yl)methyl)quinoline
[0702] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.100 g, 0.338
mmol),
2-(3-fluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl)-4,4,5,5-tetramethyl-1,-
3,2-dioxaborolane (0.109 g, 0.422 mmol), potassium carbonate (0.156
g, 0.027 mmol), dioxane (2 ml), water (0.5 ml) and Tetrakis
(triphenylphosphine)palladium(0) (0.031 g, 0.067 mmol) in microwave
oven (100 W, 100.degree. C.) for 30 min Pale brown solid (0.055 g,
35%). M.P.: 165-167.degree. C. MS (m/z): 455.85 (M.sup.+).
Example 86
6-((5-(3-Fluoro-4-(2-methoxyethoxy)phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridi-
n-3-yl)methyl)quinoline
[0703] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.100 g, 0.338
mmol),
2-(3-fluoro-4-(2-methoxyethoxyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxabo-
rolane (0.125 g, 0.422 mmol), potassium carbonate (0.156 g, 0.027
mmol), dioxane (2 ml), water (0.5 ml) and
tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.067 mmol) in
microwave oven (100 W, 100.degree. C.) for 30 min Pale yellow solid
(0.060 g, 41%). M.P.: 122-124 C. MS (m/z): 430.02 (M.sup.++1).
Example 87
2-Fluoro-N-propyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyri-
din-5-yl)benzamide
[0704] The title compound was prepared by following the procedure
described for example 43 using propylamine (0.015 g, 0.250 mmol)
instead of ethylamine hydrochloride. Pale yellow solid (0.070 g,
63%). M.P.: 157-159.degree. C. MS (m/z): 440.87 (M.sup.+).
Example 88
6-((5-(4-(Cyclopropylcarbamoyl)-3-fluorophenyl)-3H-[1,2,3]triazolo[4,5-b]p-
yridin-3-yl)methyl)quinoline 1-oxide
[0705] To a solution of example 46 (0.080 g, 0.182 mmol) in
dichloromethane (1 ml), m-chloroperbenzoic acid (0.044 g, 0.255
mmol) was added and stirred at RT for 12 h. The reaction mixture
was quenched with sodium sulphite solution, washed with saturated
potassium carbonate solution and concentrated. The crude product
was chromatographed using methanol: dichloromethane to afford the
title compound as a pale yellow solid (0.025 g, 30%). M.P.:
89-92.degree. C. .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400 MHz):
8.88 (dd, J=4.1, 1.6 Hz, 1H), 8.75 (d, J=9.0 Hz, 1H), 8.51 (m, 2H),
8.28 (t, J=8.1 Hz, 1H), 7.98-7.86 (m, 5H), 7.71 (d, J=8.5 Hz, 1H),
7.32 (dd, J=8.5, 6.1 Hz, 1H), 6.89 (d, J=11.8 Hz, 1H), 6.15 (s,
2H), 2.99 (m, 1H), 0.94 (m, 2H), 0.69 (m, 2H).
Example 89
N-Cyclopropyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b-
]pyridin-5-yl)benzamide hydrochloride
[0706] The example 46 (0.045 g. 0.102 mmol) was dissolved in THF (1
ml), ether saturated with HCl (1 ml) was added at 0.degree. C. and
stirred for 15 min. The precipitate formed was washed with ether
and dried under vacuum to afford the title compound as an off-white
solid (0.046 g, 95%). M.P.: 105-107.degree. C. MS (m/z): 439.12
(M.sup.++1-HCl).
Example 90
N-(Cyclopropylmethyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazo-
lo[4,5-b]pyridin-5-yl)benzamide
[0707] The title compound was prepared by following the procedure
described for example 43 using cyclopropylmethylamine (0.018 g,
0.250 mmol) instead of ethylamine hydrochloride. Off-white solid
(0.085 g, 75%). M.P.: 120-122.degree. C. MS (m/z): 452.91
(M.sup.+).
Example 91
N-Butyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrid-
in-5-yl)benzamide
[0708] The title compound was prepared by following the procedure
described for example 43 using n-butylamine (0.019 g, 0.250 mmol)
instead of ethylamine hydrochloride. Off-white solid (0.064 g,
56%). M.P.: 100-102.degree. C. MS (m/z): 455.08 (M.sup.+).
Example 92
2-Fluoro-N-(furan-2-ylmethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazol-
o[4,5-b]pyridin-5-yl)benzamide
[0709] The title compound was prepared by following the procedure
described for example 43 using furfurylamine (0.024 g, 0.250 mmol)
instead of ethylamine hydrochloride. Brown solid (0.060 g, 50%).
M.P.: 144-147.degree. C. MS (m/z): 479.02 (M.sup.+).
Example 93
2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-
-N-(2,2,2-trifluoroethyl)benzamide
[0710] The title compound was prepared by following the procedure
described for example 43 using 2,2,2-trifluoroethylamine (0.024 g,
0.250 mmol) instead of ethylamine hydrochloride. Pale yellow solid
(0.060 g, 50%). M.P.: 194-196.degree. C. MS (m/z): 481.12
(M.sup.+).
Example 94
2-Fluoro-N-(2-methoxyethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[-
4,5-b]pyridin-5-yl)benzamide
[0711] The title compound was prepared by following the procedure
described for example 43 using 2-methoxyethylamine (0.019 g, 0.250
mmol) instead of ethylamine hydrochloride. Pale green solid (0.060
g, 52%). M.P.: 162-164.degree. C. MS (m/z): 456.83 (M.sup.+).
Example 95
N-Isopropyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5--
yl)benzenesulfonamide
[0712] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.102 g, 0.338
mmol), 4-(N-isopropylsulfamoyl)phenylboronic acid (0.102 g, 0.422
mmol), potassium carbonate (0.156 g, 0.027 mmol), dioxane (2 ml),
water (0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.031
g, 0.067 mmol) in microwave oven (100 W, t100.degree. C.) for 30
min Green solid (0.050 g, 30%). M.P.: 154-156.degree. C. MS (m/z):
458.79 (M.sup.+).
Example 96
N,N-Dimethyl-3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-
-yl)aniline
[0713] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.102 g, 0.338
mmol), 3-(dimethylamino)phenylboronic acid (0.072 g, 0.422 mmol),
potassium carbonate (0.156 g, 0.027 mmol), dioxane (2 ml), water
(0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.031 g,
0.067 mmol) in microwave oven (100 W, 100.degree. C.) for 30 min
Green solid (0.040 g, 31%). M.P.: 124-126.degree. C. MS (m/z):
380.88 (M.sup.+).
Example 97
2-Fluoro-N-isobutyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]py-
ridin-5-yl)benzamide
[0714] The title compound was prepared by following the procedure
described for example 43 using isobutylamine (0.018 g, 0.250 mmol)
instead of ethylamine hydrochloride. Off-white solid (0.050 g,
44%). M.P.: 158-160.degree. C. MS (m/z): 455.01 (M.sup.++1).
Example 98
N-Cyclopentyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b-
]pyridin-5-yl)benzamide
[0715] The title compound was prepared by following the procedure
described for example 43 using cyclopentylamine (0.021 g, 0.250
mmol) instead of ethylamine hydrochloride. Pale green solid (0.040
g, 34%). M.P.: 166-168.degree. C. MS (m/z): 467.12 (M.sup.++1).
Example 99
2-Fluoro-N-isopropyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]p-
yridin-5-yl)benzamide
[0716] The title compound was prepared by following the procedure
described for example 43 using isopropylamine (0.029 g, 0.500 mmol)
instead of ethylamine hydrochloride. Off-white solid (0.060 g,
54%). M.P.: 177-179.degree. C. MS (m/z): 440.87 (M.sup.+).
Example 100
Methyl
2-chloro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridi-
n-5-yl)benzoate
[0717] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (1.00 g, 3.07 mmol),
3-chloro-4-methoxycarbonylphenylboronic acid (0.825 g, 3.84 mmol),
potassium acetate (0.976 g, 9.945 mmol), dioxane (20 ml) and
tetrakis(triphenylphosphine)palladium(0) (0.284 g, 0.246 mmol).
Reddish brown solid (1.00 g, 71%). .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.92 (dd, J=4.2, 1.6 Hz, 1H), 8.48 (d,
J=8.6 Hz, 1H), 8.24 (d, J=1.3 Hz, 1H), 8.17 (d, J=8.3 Hz, 1H), 8.10
(d, J=11.8 Hz, 1H), 8.04 (m, 3H), 7.87 (m, 2H), 7.43 (q, J=4.2 Hz,
1H), 6.15 (s, 2H), 3.98 (s, 3H).
Example 101
2-Chloro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-
benzoic acid
[0718] To a solution of Example 100 (1.00 g, 2.18 mmol) in methanol
(5 ml), lithium hydroxide (0.856 g, 20.40 mmol) in water (5 ml) and
THF (19 ml) were added and stirred at RT. After 12 h, pH was
adjusted to 7-7.5 using 0.5N HCl and the solid precipitated was
filtered, washed with ethyl acetate and petroleum ether and dried
under vacuum to afford the title compound as an off-white solid
(0.900 g, 93%).
Example 102
2-Chloro-N-propyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyri-
din-5-yl)benzamide
[0719] The title compound was prepared by following the procedure
described for example 43 by replacing the example 13 with example
101 (0.100 g, 0.240 mmol) and using propylamine (0.028 g, 0.480
mmol) instead of ethylamine hydrochloride. Brown solid (0.043 g,
39%). M.P.: 128-130.degree. C. MS (m/z): 456.83 (M.sup.++1).
Example 103
2-Fluoro-N-methyl-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[4-
,5-b]pyridin-5-yl)benzamide
[0720] To Example 83 (0.100 g, 0.234 mmol), thionyl chloride (3 ml)
was added and refluxed for 3 h. The excess thionyl chloride was
removed under reduced pressure and the residue was cooled to
0.degree. C. Methylamine in ethanol (50% solution, 5 ml) was added
and stirred for 15 min. The precipitate formed was filtered, washed
with sodium bicarbonate solution, dried over sodium sulphate and
concentrated to afford title compound as a yellow solid (0.028 g,
27%). M.P.: 171-173.degree. C. MS (m/z): 440.94 (M.sup.+).
Example 104
N-Cyclobutyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]-
pyridin-5-yl)benzamide
[0721] The title compound was prepared by following the procedure
described for example 43 by using cyclobutylamine (0.035 g, 0.500
mmol) instead of ethylamine hydrochloride. Off-white solid (0.050
g, 44%). M.P.: 171-174.degree. C. MS (m/z): 452.91 (M.sup.+).
Example 105
2-Fluoro-N-propyl-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[4-
,5-b]pyridin-5-yl)benzamide
[0722] The title compound was prepared by following the procedure
described for example 43 by replacing the example 13 with example
83 (0.100 g, 0.234 mmol) and using propylamine (0.027 g, 0.468
mmol) instead of ethylamine hydrochloride. Pale green solid (0.050
g, 47%). M.P.: 162-164.degree. C. MS (m/z): 468.94 (M.sup.+).
Example 106
N-Cyclopropyl-2-fluoro-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triaz-
olo[4,5-b]pyridin-5-yl)benzamide
[0723] The title compound was prepared by following the procedure
described for example 43 by replacing the example 13 with example
83 (0.080 g, 0.187 mmol) and using cyclopropylamine (0.021 g, 0.374
mmol) instead of ethylamine hydrochloride. Pale green solid (0.015
g, 17%). M.P.: 156-159.degree. C. MS (m/z): 466.98 (M.sup.+).
Example 107
N-Ethyl-2-fluoro-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[4,-
5-b]pyridin-5-yl)benzamide
[0724] The title compound was prepared by following the procedure
described for example 43 by replacing the example 13 with example
83 (0.080 g, 0.187 mmol) and ethylamine hydrochloride (0.015 g,
0.187 mmol). Pale green solid (0.015 g, 17%). M.P.: 132-135.degree.
C. MS (m/z): 454.94 (M.sup.+).
Example 108
2-Chloro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-
benzamide
[0725] To Example 101 (0.100 g, 0.240 mmol), thionyl chloride (3
ml) was added and refluxed for 3 h. The excess thionyl chloride was
removed under reduced pressure and the residue was cooled to
0.degree. C. Aqueous 25% ammonia (4 ml) was added and stirred for
15 min. The precipitate formed was washed with sodium bicarbonate
solution and vacuum dried to afford title compound as a brown solid
(0.060 g, 60%). M.P.: 212-215.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.88 (dd, J=4.1, 2.6 Hz, 1H), 8.70 (d,
J=8.7 Hz, 1H), 8.37 (d, J=8.3 Hz, 1H), 8.31 (s, 1H), 8.24 (d, J=8.1
Hz, 1H), 8.21 (d, J=8.8 Hz, 1H), 8.04 (m, 3H), 7.83 (dd, J=8.7, 1.6
Hz, 1H), 7.69 (s, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.53 (dd, J=8.3, 4.2
Hz, 1H), 6.23 (s, 2H). MS (m/z): 415.11 (M.sup.+).
Example 109
2-Chloro-N-methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyri-
din-5-yl)benzamide
[0726] To Example 101 (0.100 g, 0.240 mmol), thionyl chloride (3
ml) was added and refluxed for 3 h. The excess thionyl chloride was
removed under reduced pressure and the residue was cooled to
0.degree. C. Methylamine in ethanol (50% solution, 4 ml) was added
and stirred for 15 min. The precipitate formed was filtered, washed
with sodium bicarbonate solution and diethyl ether and vacuum dried
to afford title compound as pale brown solid (0.060 g, 58%). M.P.:
227-230.degree. C. MS (m/z): 429.04 (M.sup.++1).
Example 110
2-Fluoro-N-methoxy-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyr-
idin-5-yl)benzamide hydrochloride
[0727] The example 62 (0.040 g. 0.093 mmol) was dissolved in THF (1
ml), ether saturated with HCl (1 ml) was added at 0.degree. C. and
stirred for 15 min. The precipitate formed was washed with ether
and dried under vacuum to afford the title compound as an off-white
solid (0.030 g, 69%). M.P.: 145-147.degree. C. MS (m/z): 429.46
(M.sup.++1-HCl).
Example 111
2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-
-N-(thiazol-2-yl)benzamide
[0728] The title compound was prepared by following the procedure
described for example 43 by using 2-aminothiazole (0.050 g, 0.500
mmol) instead of ethylamine hydrochloride. Pale brown solid (0.016
g, 13%). M.P.: 204-206.degree. C. MS (m/z): 481.89 (M.sup.+).
Example 112
N-(3-Aminopropyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4-
,5-b]pyridin-5-yl)benzamide
[0729] To a solution of example 13 (0.150 g, 0.375 mmol) in DMF (1
ml)N-ethyldiisopropylamine (0.048 g, 0.375 mmol) and HATU (0.143 g,
0.375 mmol) were added and stirred for 5 min
N-boc-1,3-diaminopropane (0.130 g, 0.751 mmol) was added at RT and
the reaction mixture was stirred for 12 h. To the reaction mixture
water was added and extracted with ethyl acetate, dried over sodium
sulphate and concentrated under reduced pressure. The crude product
was purified by column chromatography with methanol:
dichloromethane to afford N-boc-protected amide (0.200 g). The
amide was dissolved in dichlomethane (1 ml) and trifluoroacetic
acid (0.5 ml) was added and stirred at RT for 1 h. The reaction
mixture was quenched with sodium bicarbonate solution, extracted
with dicloromethane, dried over sodium sulphate and concentrated to
afford the title compound as a pale brown solid (0.160 g, 93%).
M.P.: 292-294.degree. C. MS (m/z): 456.270 (M.sup.++1).
Example 113
2-Chloro-N-cyclopropyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b-
]pyridin-5-yl)benzamide
[0730] The title compound was prepared by following the procedure
described for example 43 by replacing the example 13 with example
101 (0.100 g, 0.240 mmol) and using cyclopropylamine (0.028 g,
0.480 mmol) instead of ethylamine hydrochloride. Off-white solid
(0.047 g, 43%). M.P.: 197-199.degree. C. MS (m/z): 455.08
(M.sup.++1).
Example 114
2-Fluoro-N-(3-oxo-3-(pyrrolidin-1-yl)propyl)-4-(3-(quinolin-6-ylmethyl)-3H-
-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide
[0731] The title compound was prepared by following the procedure
described for example 43 using intermediate 26 (0.080 g, 0.312
mmol) instead of ethylamine hydrochloride. Off-white solid (0.075
g, 57%). M.P.: 151-153.degree. C. MS (m/z): 524.24 (M.sup.++1).
Example 115
2-Fluoro-N-hydroxy-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyr-
idin-5-yl)benzamide
[0732] The title compound was prepared by following the procedure
described for example 43 by using hydroxylamine hydrochloride
(0.035 g, 0.500 mmol) instead of ethylamine hydrochloride.
Off-white solid (0.010 g, 9%). M.P.: 180-182.degree. C. MS (m/z):
415.31 (M.sup.++1).
Example 116
N-Isopropyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5--
yl)benzamide
[0733] The title compound was prepared by following the procedure
described for example 43 by using example 8 (0.100 g, 0.262 mmol)
and isopropylamine (0.031 g, 0.524 mmol) instead of ethylamine
hydrochloride. Off-white solid (0.080 g, 72%). M.P.:
181-183.degree. C. MS (m/z): 423.37 (M.sup.++1).
Example 117
2-Fluoro-N-(3-oxo-3-(piperidin-1-yl)propyl)-4-(3-(quinolin-6-ylmethyl)-3H--
[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide
[0734] The title compound was prepared by following the procedure
described for example 43 using intermediate 27 (0.135 g, 0.500
mmol) instead of ethylamine hydrochloride. Off-white solid (0.025
g, 19%). M.P.: 109-111.degree. C. MS (m/z): 538.03 (M.sup.+).
Example 118
1-Ethyl-3-(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-y-
l)phenyl)urea
[0735] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.102 g, 0.338
mmol), 4-(3-ethylureido)phenylboronic acid (0.123 g, 0.422 mmol),
potassium carbonate (0.156 g, 0.027 mmol), dioxane (2 ml), water
(0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.031 g,
0.067 mmol) in microwave oven (100 W, 100.degree. C.) for 30 min
Brown solid (0.060 g, 42%). M.P.: 193-196.degree. C. MS (m/z):
424.28 (M.sup.++1).
Example 119
2-Chloro-N-ethyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrid-
in-5-yl)benzamide
[0736] The title compound was prepared by following the procedure
described for example 43 by replacing the example 13 with example
101 (0.100 g, 0.240 mmol) and ethylamine hydrochloride. Off-white
solid (0.050 g, 47%). M.P.: 187-190.degree. C. .sup.1H-NMR (.delta.
ppm, DMSO-d.sub.6, 400 MHz): 8.88 (dd, J=4.1, 1.4 Hz, 1H), 8.70 (d,
J=8.7 Hz, 1H), 8.51 (d, J=5.4 Hz, 1H), 8.37 (d, J=8.3 Hz, 1H), 8.31
(s, 1H), 8.25 (d, J=8.0 Hz, 1H), 8.21 (d, J=8.0 Hz, 1H), 8.04 (s,
1H), 8.01 (d, J=8.7 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H), 7.58 (d, J=8.0
Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.23 (s, 2H), 3.30 (m, 2H),
1.14 (t, J=7.2 Hz, 3H). MS (m/z): 443.04 (M.sup.+).
Example 120
2-Fluoro-N-(3-morpholino-3-oxopropyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3-
]triazolo[4,5-b]pyridin-5-yl)benzamide
[0737] The title compound was prepared by following the procedure
described for example 43 using intermediate 28 (0.136 g, 0.500
mmol) instead of ethylamine hydrochloride. Pale yellow solid (0.025
g, 19%). M.P.: 212-215.degree. C. MS (m/z): 540.13 (M.sup.++1).
Example 121
N-(3-(dimethylamino)propyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]-
triazolo[4,5-b]pyridin-5-yl)benzamide dihydrochloride
[0738] Ether saturated with HCl (1 ml) was added at 0.degree. C. to
a solution of example 72 (0.040 g. 0.082 mmol) in THF (1 ml), and
stirred for 15 min. The precipitate formed was washed with ether
and dried under vacuum to afford the title compound as an off-white
solid (0.040 g, 88%). M.P.: 137-140.degree. C. MS (m/z): 483.54
(M.sup.+-2HCl).
Example 122
2-chloro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-
-N-(1H-1,2,4-triazol-3-yl)benzamide
[0739] The title compound was prepared by following the procedure
described for example 43 by replacing example 13 with example 101
(0.100 g, 0.240 mmol) and 3-amino-1,2,4-triazole (0.040 g, 0.480
mmol) instead of ethylamine hydrochloride. Pale green solid (0.015
g, 13%). M.P.: 286-288.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.88 (d, J=3.7 Hz, 1H), 8.74 (d, J=8.7 Hz,
1H), 8.40-8.32 (m, 3H), 8.26 (d, J=8.7 Hz, 1H), 8.05 (s, 1H), 8.02
(d, J=8.7 Hz, 1H), 7.87-7.82 (m, 4H), 7.54 (s, 1H), 7.53 (dd,
J=8.4, 4.2 Hz, 1H), 6.24 (s, 2H). MS (m/z): 482.03 (M.sup.+).
Example 123
2-Chloro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-
benzamide hydrochloride
[0740] Example 108 (0.150 g. 0.360 mmol) was dissolved in THF (1
ml), ether saturated with HCl (1 ml) was added at 0.degree. C. and
stirred for 15 min. The precipitate formed was washed with ether
and dried under vacuum to afford the title compound as an off-white
solid (0.060 g, 46%). M.P.: 273-275.degree. C.
Example 124
2-Fluoro-N-(3-(piperidin-1-yl)propyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3-
]triazolo[4,5-b]pyridin-5-yl)benzamide
[0741] The title compound was prepared by following the procedure
described for example 43 using 3-(piperidin-1-yl)propan-1-amine
(0.086 g, 0.500 mmol) instead of ethylamine hydrochloride.
Off-white solid (0.040 g, 30%). M.P.: 135-137.degree. C. MS (m/z):
524.52 (M.sup.++1).
Example 125
N-(3-Aminopropyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4-
,5-b]pyridin-5-yl)benzamide dihydrochloride
[0742] Example 112 (0.130 g. 0.287 mmol) was dissolved in THF (2
ml), ether saturated with HCl (1 ml) was added at 0.degree. C. and
stirred for 15 min. The precipitate formed was washed with ether
and dried under vacuum to afford the title compound as an off-white
solid (0.090 g, 64%). M.P.: 290-293.degree. C.
Example 126
2-Chloro-N-(3-(dimethylamino)propyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]-
triazolo[4,5-b]pyridin-5-yl)benzamide dihydrochloride
[0743] The title compound was prepared by following the procedure
described for example 43 by replacing example 13 with example 101
(0.150 g, 0.360 mmol) and 3-N,N-dimethylaminopropylamine (0.072 g,
0.720 mmol) instead of ethylamine hydrochloride and hydrochloride
salt formation with ether saturated with HCl (2 ml). Pale yellow
solid (0.045 g, 22%). M.P.: 185-187.degree. C. .sup.1H-NMR (.delta.
ppm, DMSO-d.sub.6, 400 MHz): 10.11 (br. s, 1H), 9.06 (d, J=4.4 Hz,
1H), 8.73 (d, J=8.8 Hz, 1H), 8.71 (m, 2H), 8.33 (s, 1H), 8.27 (m,
2H), 8.17 (m, 2H), 8.00 (d, J=8.7 Hz, 1H), 7.79 (dd, J=8.1, 4.1 Hz,
1H), 7.64 (d, J=8.0 Hz, 1H), 6.28 (s, 2H). 3.34 (q, J=6.5 Hz, 2H),
3.13 (m, 2H), 2.76 (s, 3H), 2.75 (s, 3H), 1.93 (m, 2H).
Example 127
2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-
-N-(1H-1,2,4-triazol-3-yl)benzamide hydrochloride
[0744] The example 52 (0.026 g. 0.055 mmol) was dissolved in THF (1
ml), ether saturated with HCl (0.5 ml) was added at 0.degree. C.
and stirred for 15 min. The precipitate formed was washed with
ether and dried under vacuum to afford the title compound as an
off-white solid (0.024 g, 87%). M.P.: 274-276.degree. C.
.sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400 MHz): .delta. 11.74 (br
s, 1H), 9.06 (d, J=4.1 Hz, 1H), 8.79 (m, 2H), 8.79 (m, 2H),
8.35-8.12 (m, 6H), 8.02 (m, 2H), 7.87 (m, 1H), 7.78 (dd, J=8.0, 4.7
Hz, 1H), 6.30 (s, 2H).
Example 128
Methyl
2,6-difluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]py-
ridin-5-yl)benzoate
[0745] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (1.15 g, 3.91 mmol),
3,5-difluoro-4-methoxycarbonyl phenylboronic acid (prepared
according to Krzysztof Durka et. al in Eur. J. Org. Chem. 2009,
4325-4332, 1.10 g, 5.09 mmol), potassium acetate (1.276 g, 13.03
mmol), dioxane (20) and tetrakis(triphenylphosphine)palladium(0)
(0.361 g, 0.31346 mmol). Brown solid (0.620 g, 37%). .sup.1H-NMR
(.delta. ppm, DMSO-d.sub.6, 400 MHz): 8.91 (d, J=2.9 Hz, 1H), 8.49
(d, J=8.6 Hz, 1H), 8.17 (d, J=8.2 Hz, 1H), 8.10 (d, J=8.7 Hz, 1H),
7.97 (s, 1H), 7.86 (dd, J=8.8, 1.4 Hz, 1H), 7.81 (d, J=8.6 Hz, 1H),
7.74 (d, J=9.1 Hz, 2H), 7.43 (dd, J=8.4, 4.2 Hz, 1H), 6.15 (s, 2H),
3.99 (s, 3H).
Example 129
2,6-Difluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-
-yl)benzoic acid
[0746] To a solution of Example 128 (0.70 g, 1.62 mmol) in methanol
(3.8 ml), lithium hydroxide (0.635 g, 15.13 mmol) in water (3.8 ml)
and THF (14.3 ml) were added and stirred at RT. After 12 h, pH was
adjusted to ca. 7 using 0.5N HCl and the solid precipitated was
filtered, washed with ethyl acetate and petroleum ether and dried
under vacuum to afford the title compound as pale brown solid (0.50
g, 74%).
Example 130
2,6-Difluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-
-yl)benzamide
[0747] The title compound was prepared by following the procedure
described for example 102 using Example 129 (0.500 g, 1.19 mmol),
thionyl chloride (10 ml) and aqueous 25% ammonia (7 ml). Off-white
solid (0.400 g, 81%). M.P.: 272-275.degree. C. .sup.1H-NMR (.delta.
ppm, DMSO-d.sub.6, 400 MHz): 8.88 (d, J=3.9 Hz, 1H), 8.74 (d, J=8.8
Hz, 1H), 8.37 (d, J=7.8 Hz, 1H), 8.25 (d, J=8.9 Hz, 1H), 8.20 (s,
1H), 8.07 (m, 3H), 8.01 (d, J=8.5 Hz, 1H), 7.93 (s, 1H), 7.83 (d,
J=6.8 Hz, 1H), 7.53 (dd, J=8.6, 4.4 Hz, 1H), 6.24 (s, 2H).
Example 131
Methyl
2-chloro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,-
5-b]pyridin-5-yl)benzoate
[0748] The title compound was prepared by following the procedure
described for example 1 using intermediate 18 (0.345 g, 1.091
mmol), 3-chloro-4-methoxycarbonylphenylboronic acid (0.295 g, 1.37
mmol), potassium acetate (0.359 g, 3.65 mmol), dioxane (8 ml) and
tetrakis(triphenylphosphine)palladium(0) (0.101 g, 0.087 mmol).
Off-white solid (0.277 g, 56%). .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.91 (d, J=3.3 Hz, 1H), 8.50 (d, J=8.6 Hz,
1H), 8.23 (s, 1H), 8.10 (d, J=8.2 Hz, 1H), 8.03 (d, J=6.9 Hz, 1H),
7.98 (d, J=8.1 Hz, 1H), 7.87 (m, 3H), 7.38 (dd, J=8.3, 4.2 Hz, 1H),
6.22 (s, 2H), 3.97 (s, 3H).
Example 132
2-Chloro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyr-
idin-5-yl)benzoic acid
[0749] To a solution of Example 131 (0.185 g, 0.412 mmol) in
methanol (2 ml), lithium hydroxide (0.161 g, 3.84 mmol) in water (2
ml), THF (4 ml) were added and stirred at RT. After 12 h, pH was
adjusted to ca.7 using 0.5N HCl and the solid precipitated was
filtered, washed with ethyl acetate and petroleum ether and dried
under vacuum to afford the title compound as a pale brown solid
(0.150 g, 84%).
Example 133
2-Chloro-N-ethyl-4-(3-((7-fluoro
quinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide
[0750] The title compound was prepared by following the procedure
described for example 43 replacing the example 13 with example 132
(0.100 g, 0.230 mmol) and ethylamine hydrochloride. Off-white solid
(0.020 g, 19%). M.P.: 197-199.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.92 (dd, J=4.2, 2.8 Hz, 1H), 8.70 (d,
J=8.7 Hz, 1H), 8.51 (t, J=5.4 Hz, 1H), 8.44 (d, J=8.0 Hz, 1H), 8.28
(d, J=1.4 Hz, 1H), 8.22 (m, 3H), 7.83 (d, J=11.4 Hz, 1H), 7.56 (m,
2H), 6.26 (s, 2H), 3.28 (m, 2H), 1.14 (t, J=7.2 Hz, 3H).
Example 134
2-Chloro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyr-
idin-5-yl)benzamide
[0751] The title compound was prepared by following the procedure
described for example 102 using Example 132 (0.050 g, 0.115 mmol),
thionyl chloride (2 ml) and aqueous 25% ammonia (2 ml). Brown solid
(0.015 g, 30%). M.P.: 202-204.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.92 (d, J=4.1 Hz, 1H), 8.70 (d, J=8.6 Hz,
1H), 8.44 (d, J=8.0 Hz, 1H), 8.27 (s, 1H), 8.22 (m, 3H), 7.96 (s,
1H), 7.83 (d, J=11.5 Hz, 1H), 7.68 (s, 1H), 7.60 (d, J=8.0 Hz, 1H),
7.55 (dd, J=8.4, 4.3 Hz, 1H), 6.26 (s, 2H).
Example 135
Methyl
2-fluoro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,-
5-b]pyridin-5-yl)benzoate
[0752] The title compound was prepared by following the procedure
described for example 1 using intermediate 18 (0.350 g, 1.15 mmol),
3-fluoro-4-methoxycarbonyl phenylboronic acid (0.276 g, 1.39 mmol),
potassium acetate (0.365 g, 3.71 mmol), dioxane (8 ml) and
tetrakis(triphenylphosphine)palladium(0) (0.103 g, 0.089 mmol).
Pale brown solid (0.350 g, 70%). M.P.: 213-215.degree. C.
Example 136
2-Fluoro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyr-
idin-5-yl)benzoic acid
[0753] To a solution of Example 135 (0.240 g, 0.605 mmol) in
methanol (3 ml), lithium hydroxide (0.237 g, 5.64 mmol) in water (3
ml), THF (6 ml) were added and stirred at RT. After 12 h, pH was
adjusted to ca 7 using 0.5N HCl and the solid precipitated was
filtered, washed with ethyl acetate and petroleum ether and dried
under vacuum to afford the title compound as pale brown solid
(0.110 g, 44%).
Example 137
2-Fluoro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyr-
idin-5-yl)benzamide
[0754] The title compound was prepared by following the procedure
described for example 102 using Example 136 (0.080 g, 0.191 mmol),
thionyl chloride (2 ml) and aqueous 25% ammonia (2 ml). Pale brown
solid (0.060 g, 75%). M.P.: 206-208.degree. C. .sup.1H-NMR (.delta.
ppm, DMSO-d.sub.6, 400 MHz): 8.92 (d, J=3.2 Hz, 1H), 8.71 (d, J=8.7
Hz, 1H), 8.44 (d, J=8.4 Hz, 1H), 8.23 (t, J=9.2 Hz, 2H), 8.19 (m,
2H), 7.83-7.73 (m, 4H), 7.54 (dd, J=8.2, 4.0 Hz, 1H), 6.26 (s,
2H).
Example 138
3-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide
[0755] The title compound was prepared by following the procedure
described for example 102 using Example 54 (0.100 g, 0.262 mmol),
thionyl chloride (4 ml) and aqueous 25% ammonia (4 ml). Brown solid
(0.040 g, 40%). M.P.: 263-265.degree. C.
Example 139
2,6-Difluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-
-yl)benzamide hydrochloride
[0756] Example 130 (0.040 g. 0.096 mmol) was dissolved in THF (1
ml), ether saturated with HCl (1 ml) was added at 0.degree. C. and
stirred for 15 min. The precipitate formed was washed with ether
and dried under vacuum to afford the title compound as a brown
solid (0.027 g, 43%). M.P.: 272-275.degree. C. .sup.1H-NMR (.delta.
ppm, DMSO-d.sub.6, 400 MHz): 9.02 (d, J=3.2 Hz, 1H), 8.74 (d, J=8.8
Hz, 1H), 8.63 (d, J=7.6 Hz, 1H), 8.26 (d, J=8.7 Hz, 1H), 8.20 (d,
J=13.6 Hz, 2H), 8.11 (m, 3H), 7.96 (m, 2H), 7.72 (dd, J=8.3, 4.6
Hz, 1H), 6.28 (s, 2H).
Example 140
2-Chloro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyr-
idin-5-yl)benzamide hydrochloride
[0757] The example 134 (0.035 g. 0.080 mmol) was dissolved in THF
(2 ml), ether saturated with HCl (2 ml) was added at 0.degree. C.
and stirred for 15 min. The precipitate formed was washed with
ether and dried under vacuum to afford the title compound as a pale
yellow solid (0.022 g, 59%). M.P.: 269-272.degree. C.
Example 141
2-Fluoro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyr-
idin-5-yl)benzamide hydrochloride
[0758] Example 137 (0.080 g. 0.192 mmol) was dissolved in THF (2
ml), ether saturated with HCl (2 ml) was added at 0.degree. C. and
stirred for 15 min. The precipitate formed was filtered, washed
with ether and dried under vacuum to afford the title compound as a
pale-brown solid (0.070 g, 80%). M.P.: 258-260.degree. C.
Example 142
2-Methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-
benzamide
[0759] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.100 g, 0.338
mmol), intermediate 21 (0.109 g, 0.422 mmol), potassium carbonate
(0.155 g, 1.12 mmol), DMF (8 ml), water (0.5 ml) and tetrakis
(triphenyl-phosphine) palladium(0) (0.031 g, 0.027 mmol). Pale
green solid (0.045 g, 34%). M.P.: 235-237.degree. C. .sup.1H-NMR
(.delta. ppm, DMSO-d.sub.6, 400 MHz): 8.88 (d, J=2.9 Hz, 1H), 8.66
(d, J=8.7 Hz, 1H), 8.38 (d, J=8.0 Hz, 1H), 8.15 (d, J=8.7 Hz, 1H),
8.07-8.00 (m, 4H), 7.83 (m, 2H), 7.54 (m, 2H), 7.45 (s, 1H), 6.21
(s, 2H), 2.46 (s, 3H).
Example 143
6-((5-(1H-Pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quino-
line
[0760] The title compound was obtained as a yellow solid (0.065 g,
29%) by following the procedure described for example 1 using
intermediate 14 (0.20 g, 0.676 mmol), tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate
(0.254 g, 0.856 mmol), potassium carbonate (0.310 g, 2.25 mmol),
dioxane (4 ml), water (0.8 ml) and tetrakis
(triphenylphosphine)palladium(0) (0.062 g, 0.054 mmol). .sup.1H-NMR
(.delta. ppm, DMSO-d.sub.6, 400 MHz): 13.25 (s, 1H), 8.88 (dd,
J=4.1, 1.4 Hz, 1H), 8.55 (s, 1H), 8.50 (d, J=8.7 Hz, 1H), 8.38 (d,
J=8.1, Hz, 1H), 8.23 (s, 1H), 8.01 (d, J=9.0, Hz, 2H), 7.85 (t,
J=8.6, 2H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.11 (s, 2H). MS (m/z):
328.12 (M.sup.++1).
Example 144
6-((5-(1-Methyl-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)met-
hyl)quinoline
[0761] Sodium hydride (0.014 g, 0.596 mmol) was added to a solution
of example 143 (0.130 g, 0.397 mmol) in DMF (3 ml) at 0.degree. C.
and stirred for 30 min To this solution methyl iodide (0.113 g,
0.794 mmol) was added and the reaction mixture was warmed to RT.
After 3 h, the reaction mixture was poured into ice water and
extracted with ethyl acetate, washed with brine, dried over sodium
sulphate and concentrated. The crude product was purified by column
chromatography with methanol: dichloromethane to afford the title
compound as an off-white solid (0.080 g, 59%). .sup.1H-NMR (.delta.
ppm, DMSO-d.sub.6, 400 MHz): 8.88 (d, J=2.8 Hz, 1H), 8.51 (s, 1H),
8.49 (s, 1H), 8.38 (d, J=7.9 Hz, 1H), 8.18 (s, 1H), 8.01 (d, J=8.8
Hz, 2H), 7.82 (t, J=9.6 Hz, 2H), 7.53 (dd, J=8.3, 4.1 Hz, 1H), 6.10
(s, 2H), 3.91 (s, 3H). MS (m/z):: 341.98 (M.sup.++1).
Example 145
6-((5-(1-(2-(Tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)-3H-[1,2,3-
]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline
[0762] To a solution of example 143 (0.250 g, 0.763 mmol) in DMF
(10 ml), cesium carbonate (0.496 g, 1.52 mmol) was added and
stirred for 15 min 2-(2-bromoethoxy)tetrahydro-2H-pyran (0.638 g,
3.04 mmol) and tetrabutylammonium iodide (0.20 g, 2.16 mmol) were
added and heated to 80-85.degree. C. for 12 h. The reaction was
quenched by the addition of water, extracted with ethyl acetate,
washed with brine, dried over sodium sulphate and concentrated. The
crude product was purified by column chromatography with methanol:
dichloromethane to afford the title compound as a yellow solid
(0.195 g, 56%). .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400 MHz):
8.88 (dd, J=4.1, 1.6 Hz, 1H), 8.52 (s, 1H), 8.51 (d, J=8.8 Hz, 1H),
8.37 (dd, J=8.4, 1.3 Hz, 1H), 8.22 (s, 1H), 8.01 (d, J=9.0 Hz, 2H),
7.82 (dd, J=8.7, 2.7 Hz, 2H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.11
(s, 2H), 4.54 (t, J=2.9 Hz, 1H), 4.37 (m, 2H), 3.99 (m, 1H), 3.73
(m, 1H), 3.55 (m, 1H), 1.63-1.30 (m, 6H).
Example 146
2-(4-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-py-
razol-1-yl)ethanol
[0763] To a solution of example 145 (0.190 g, 0.417 mmol) in
methanol (2 ml) and water (2 ml), camphor sulphonic acid (0.968 g,
4.17 mmol) was added and stirred for 1 h. The reaction was poured
into ice water and the pH was adjusted to ca 8 with sodium
bicarbonate solution, extracted with ethyl acetate, washed with
brine, dried over sodium sulphate and concentrated. The crude
product was purified by recrystallisation from isopropanol to
afford the title compound as a light yellow solid (0.059 g, 38%).
M.P.: 179-178.degree. C. .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6,
400 MHz): 8.88 (dd, J=4.2, 1.6 Hz, 1H), 8.51 (d, J=8.7 Hz, 1H),
8.49 (s, 1H), 8.38 (dd, J=8.3, 1.3 Hz, 1H), 8.20 (s, 1H), 8.01 (d,
J=8.0 Hz, 2H), 7.82 (dd, J=8.7, 1.7 Hz, 2H), 7.53 (dd, J=8.3, 4.1
Hz, 1H), 6.11 (s, 2H), 4.96 (t, J=5.3 Hz, 1H), 4.22 (t, J=5.5 Hz,
2H), 3.79 (dd, J=10.8, 5.4 Hz, 2H). MS (m/z):: 372.08
(M.sup.++1).
Example 147
6-((5-(1H-Pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)quinoline
[0764] The title compound was prepared as a yellow solid (0.110 g,
49%) by following the procedure described for example 1 using
intermediate 29 (0.20 g, 0.678 mmol), tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate
(0.255 g, 0.868 mmol), potassium carbonate (0.310 g, 2.24 mmol),
dioxane (4 ml), water (0.8 ml) and
tetrakis(triphenylphosphine)palladium(0) (0.062 g, 0.054 mmol).
M.P.: 214-216.degree. C. .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6,
400 MHz): 13.02 (s, 1H), 8.86 (dd, J=4.2, 1.7 Hz, 1H), 8.56 (s,
1H), 8.35 (dd, J=8.2, 1.1 Hz, 2H), 8.10 (s, 1H), 8.04-7.98 (m, 3H),
7.85 (dd, J=8.8, 1.9 Hz, 1H), 7.61 (d, J=8.3 Hz, 1H), 7.52 (dd,
J=8.3, 4.2 Hz, 1H), 5.69 (s, 2H). MS (m/z): 326.86 (M+).
Example 148
6-((5-(1-Methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)quin-
oline
[0765] The title compound was prepared as an off-white solid (0.022
g, 27%) by following the procedure described for example 144 using
example 147 (0.080 g, 0.245 mmol), sodium hydride (0.014 g, 0.367
mmol), methyl iodide (0.069 g, 0.49 mmol) and DMF (2 ml). M.P.:
150-152.degree. C. .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400
MHz): 8.86 (s, 1H), 8.56 (s, 1H), 8.35 (d, J=8.1 Hz, 1H), 8.29 (s,
1H), 8.04 (m, 4H), 7.84 (d, J=8.8 Hz, 1H), 7.56 (d, J=8.3 Hz, 1H),
7.52 (dd, J=7.8, 4.2 Hz, 1H), 5.69 (s, 2H), 3.88 (s, 3H). MS (m/z):
341.14 (M.sup.++1).
Example 149
6-((5-(1-(2-(Tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)-3H-imidaz-
o[4,5-b]pyridin-3-yl)methyl)quinoline
[0766] The title compound was prepared as a yellow solid (0.300 g,
86%) by following the procedure described for example 145 using
example 147 (0.250 g, 0.766
mmol),2-(2-bromoethoxy)tetrahydro-2H-pyran (0.640 g, 3.06 mmol),
cesium carbonate (0.746 g, 2.29 mmol), tetrabutylammonium iodide
(0.20 g, 0.54 mmol) and DMF (10 ml).
Example 150
2-(4-(3-(Quinolin-6-ylmethyl)-3H-imidazo[4,5-b]pyridin-5-yl)-1H-pyrazol-1--
yl)ethanol
[0767] The title compound was prepared by following the procedure
described for example 146 using example 149 (0.200 g, 0.44 mmol),
camphor sulphonic acid (1.02 g. 4.40 mmol), methanol (2 ml) and
water (2 ml). Yellow solid (0.09 g, 55%). M.P.: 160-163.degree. C.
.sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400 MHz): 8.86 (dd, J=4.0,
1.4 Hz, 1H), 8.55 (s, 1H), 8.35 (d, J=7.9 Hz, 1H), 8.30 (s, 1H),
8.05 (m, 4H), 7.84 (dd, J=8.7, 1.7 Hz, 1H), 7.57 (d, J=8.3 Hz, 1H),
7.52 (dd, J=8.4, 4.2 Hz, 1H), 5.69 (s, 2H), 4.94 (t, J=5.2 Hz, 1H),
4.19 (t, J=5.6 Hz, 2H), 3.77 (t, J=5.4 Hz, 2H). MS (m/z): 370.89
(M+).
Example 151
2-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-ylamino)etha-
nol
[0768] To a solution of intermediate 14 (0.100 g, 0.338 mmol) and
2-aminoethanol (0.041 g, 0.67 mmol) in ethanol (2.5 ml), sodium
carbonate (0.071 g, 0.676 mmol) was added and heated to reflux.
After 12 h, the reaction was quenched by the addition of ice water,
extracted with ethyl acetate, washed with brine, dried over sodium
sulphate and concentrated. The crude product was purified by column
chromatography with methanol: dichloromethane to afford the title
compound as a yellow solid (0.060 g, 55%). M.P.: 184-186.degree. C.
.sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400 MHz): 8.88 (dd, J=4.1,
1.6 Hz, 1H), 8.35 (dd, J=8.3, 0.9 Hz, 1H), 7.99 (d, J=8.7 Hz, 1H),
7.95 (d, J=8.9 Hz, 1H), 7.92 (s, 1H), 7.76 (dd, J=8.7, 2.0 Hz, 1H),
7.55 (t, J=4.5 Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.64 (d,
J=9.1 Hz, 1H), 5.82 (s, 2H), 4.73 (t, J=5.4 Hz, 1H), 3.58 (q, J=5.9
Hz, 2H), 3.45 (q, J=5.6 Hz, 2H). MS (m/z): 321.19 (M.sup.++1).
Example 152
6-((5-(1H-Imidazol-1-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quin-
oline
[0769] To a solution of intermediate 14 (0.100 g, 0.338 mmol) and
imidazole (0.100 g, 1.46 mmol) in DMF (3 ml), cesium fluoride
(0.056 g, 0.368 mmol) was added and heated to 130.degree. C. After
12 h, the reaction was quenched by the addition of ice water,
extracted with ethyl acetate, washed with brine, dried over sodium
sulphate and concentrated. The crude product was purified by column
chromatography with methanol: dichloromethane to afford the title
compound as light brown solid (0.023 g, 21%). M.P.: 227-230.degree.
C. .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400 MHz): 8.88 (dd,
J=4.2, 1.7 Hz, 1H), 8.80 (d, J=8.9 Hz, 1H), 8.76 (s, 1H), 8.39 (dd,
J=8.4, 0.9 Hz, 1H), 8.14 (s, 1H), 8.06 (d, J=1.6 Hz, 1H), 8.02 (d,
J=8.7 Hz, 1H), 7.98 (d, J=9.0 Hz, 1H), 7.84 (dd, J=8.7, 2.0 Hz,
1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 7.18 (s, 1H), 6.15 (s, 2H). MS
(m/z):: 327.91 (M+).
Example 153
6-((5-(1-Propyl-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)met-
hyl)quinoline
[0770] To a solution of Example 143 (0.100 g, 0.305 mmol) in DMF (4
ml), cesium carbonate (0.297 g, 0.913 mmol), tetrabutylammonium
iodide (0.078 g, 0.213 mmol) and 1-bromopropane (0.150 g, 1.22
mmol) were added and heated to 65.degree. C. After 12 h, the
reaction mixture was poured into ice water and extracted with ethyl
acetate, washed with brine, dried over sodium sulphate and
concentrated. The crude product was purified by column
chromatography with methanol: dichloromethane to afford the title
compound as a greenish-yellow solid (0.045 g, 40%). M.P.:
128-130.degree. C. .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400
MHz): 8.88 (dd, J=4.1, 1.6 Hz, 1H), 8.53 (s, 1H), 8.51 (d, J=8.8
Hz, 1H), 8.38 (dd, J=8.4, 1.8 Hz, 1H), 8.19 (s, 1H), 8.01 (d, J=8.3
Hz, 1H), 7.99 (s, 1H), 7.82 (m, 2H), 7.53 (q, J=4.2 Hz, 1H), 6.11
(s, 2H), 4.11 (t, J=6.9 Hz, 2H), 1.85 (m, 2H), 0.86 (t, J=7.3 Hz,
3H). MS (m/z): 370.33 (M.sup.++1).
Example 154
Ethyl
2-(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-
-1H-pyrazol-1-yl)acetate
[0771] To a solution of example 143 (0.250 g, 0.763 mmol) in DMF (3
ml) cooled to 0.degree. C., sodium hydride (0.0365 g, 0.916 mmol)
was added and stirred for 30 min, ethyl bromoacetate (0.153 g,
0.916 mmol) were added and warmed to RT. After 12 h, the reaction
mixture was poured into ice water and extracted with ethyl acetate,
washed with brine, dried over sodium sulphate and concentrated. The
crude product was purified by column chromatography with methanol:
dichloromethane to afford the title compound as a yellow solid
(0.225 g, 80%).
Example 155
2-(4-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-py-
razol-1-yl)acetic acid
[0772] To a solution of Example 154 (0.085 g, 0.218 mmol) in
methanol (1.4 ml), lithium hydroxide (0.026 g, 1.09 mmol) in water
(0.36 ml) was added and stirred at RT. After 12 h, the pH was
adjusted to 7-7.5 using 0.5N HCl and the solid precipitated was
filtered, washed with ethyl acetate and petroleum ether and dried
under to afford the title compound as a yellow solid (0.034 g,
38%). M.P.: >270.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.87 (d, J=2.7 Hz, 1H), 8.47 (d, J=8.7 Hz,
1H), 8.39 (m, 2H), 8.08 (s, 1H), 8.00 (s, 1H), 7.99 (d, J=7.1 Hz,
1H), 7.82 (t, J=8.9 Hz, 2H), 7.52 (q, J=4.1 Hz, 1H), 6.10 (s, 2H),
4.48 (s, 2H). MS (m/z): 385.87 (M+).
Example 156
tert-Butyl
4-(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin--
5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate
[0773] To a solution of example 143 (0.100 g, 0.305 mmol) in DMF (2
ml) was cooled to 0.degree. C., sodium hydride (0.0146 g, 0.366
mmol) was added and stirred for 30 min, tert-butyl
4-(methylsulfonyloxy)piperidine-1-carboxylate (0.093 g, 0.336 mmol)
were added and heated to 80.degree. C. After 12 h, the reaction
mixture was poured into ice water and extracted with ethyl acetate,
washed with brine, dried over sodium sulphate and concentrated. The
crude product was purified by column chromatography with methanol:
dichloromethane to afford the title compound as a yellow solid
(0.066 g, 42%). .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400 MHz):
8.88 (d, J=2.7 Hz, 1H), 8.60 (s, 1H), 8.52 (d, J=8.7 Hz, 1H), 8.30
(d, J=8.0 Hz, 1H), 8.21 (s, 1H), 8.01 (s, 1H), 8.01 (d, J=7.5 Hz,
1H), 7.82 (d, J=8.6 Hz, 2H), 7.53 (q, J=4.1 Hz, 1H), 6.11 (s, 2H),
4.46 (m, 1H), 4.12 (m, 2H), 2.91 (m, 2H), 2.06 (m, 2H), 1.87 (m,
2H), 1.41 (s, 9H).
Example 157
6-((5-(1-(Piperidin-4-yl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridi-
n-3-yl)methyl)quinoline
[0774] To a solution of example 156 (0.063 g, 0.123 mmol) in
dichloromethane (1 ml) was cooled to 0.degree. C., TFA (0.356 g,
2.47 mmol) was added and warmed to RT. After 12 h, the reaction
mixture was poured in ice water and pH was adjusted to 10-11 with
10% NaOH solution and extracted with ethyl acetate, washed with
brine, dried over sodium sulphate and concentrated to afford the
title compound as an off-white solid (0.021 g, 42%). M.P.:
188-191.degree. C. .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400
MHz): 8.88 (dd, J=4.2, 1.6 Hz, 1H), 8.55 (s, 1H), 8.51 (d, J=8.6
Hz, 1H), 8.38 (d, J=7.8 Hz, 1H), 8.20 (s, 1H), 8.01 (s, 1H), 8.01
(m, 2H), 7.82 (m, 2H), 7.53 (q, J=4.2 Hz, 1H), 6.11 (s, 2H), 4.29
(m, 1H), 3.07 (m, 2H), 2.63 (m, 2H), 1.99 (m, 2H), 1.86 (m, 2H). MS
(m/z): 411.28 (M.sup.++1).
Example 158
(R)-1-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)pyrro-
lidin-3-ol
[0775] The title compound was prepared by following the procedure
described for example 152 using intermediate 14 (0.100 g, 0.338
mmol), (R)-3-hydroxypyrrolidine (0.044 g, 0.507 mmol), cesium
fluoride (0.102 g, 0.676 mmoles) and DMF (3 ml). Brown solid (0.040
g, 34%). M.P.: 167-169.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.88 (dd, J=4.2, 1.7 Hz, 1H), 8.36 (dd,
J=8.4, 1.0 Hz, 1H), 8.11 (d, J=7.9 Hz, 1H), 7.99 (d, J=8.6 Hz, 1H),
7.93 (d, J=1.5 Hz, 1H), 7.77 (dd, J=8.7, 2.0 Hz, 1H), 7.53 (q,
J=4.2 Hz, 1H), 6.66 (d, J=9.2 Hz, 1H), 5.86 (s, 2H), 5.01 (s, 1H),
4.40 (s, 1H), 3.60 (m, 4H), 2.04-1.92 (m, 2H). MS (m/z): 346.95
(M+).
Example 159
3-(4-Fluorobenzyl)-5-(1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridine
[0776] The title compound was prepared by following the procedure
described for example 1 using intermediate 15 (0.500 g, 1.90 mmol),
tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate
(0.716 g, 2.43 mmol), potassium carbonate (0.874 g, 6.33 mmol),
dioxane (11 ml), water (2.2 ml) and
tetrakis(triphenylphosphine)palladium(0) (0.175 g, 0.152 mmol).
Yellow solid (0.270 g, 48%). .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 13.26 (s, 1H), 8.55 (s, 1H), 8.48 (d, J=8.7
Hz, 1H), 8.23 (s, 1H), 7.84 (d, J=8.7 Hz, 1H), 7.53 (dd, J=8.5, 6.4
Hz, 2H), 7.18 (t, J=8.9 Hz, 2H), 5.89 (s, 2H).
Example 160
3-(4-Fluorobenzyl)-5-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol--
4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridine
[0777] The title compound was prepared by following the procedure
described for example 145 using example 159 (0.270 g, 0.917 mmol),
2-(2-bromoethoxy) tetrahydro-2H-pyran (0.766 g, 3.66 mmol), cesium
carbonate (0.894 g, 2.75 mmol), tetrabutylammonium iodide (0.237 g,
0.624 mmol) and DMF (12 ml). Brown solid (0.150 g, 38%).
.sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400 MHz): 8.52 (s, 1H),
8.49 (d, J=8.6 Hz, 1H), 8.21 (s, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.50
(m, 2H), 7.20 (m, 2H), 5.89 (s, 2H), 4.56 (t, J=3.4 Hz, 1H), 4.38
(m, 2H), 3.98 (m, 1H), 3.80 (m, 1H), 3.57 (m, 1H), 3.38 (m, 1H),
1.66-1.05 (m, 6H).
Example 161
2-(4-(3-(4-Fluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-pyrazol-
-1-yl)ethanol
[0778] The title compound was prepared by following the procedure
described for example 145 using example 160 (0.150 g, 0.355 mmol),
camphor sulphonic acid (0.824 g. 3.55 mmol), methanol (2 ml) and
water (2 ml). Bbrown solid (0.070 g, 58%). M.P.: 204-206.degree. C.
.sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400 MHz): 8.49 (s, 1H),
8.49 (d, J=9.7 Hz, 1H), 8.20 (s, 1H), 7.80 (d, J=8.7 Hz, 1H), 7.51
(dd, J=8.7, 5.5 Hz, 2H), 7.20 (t, J=8.9 Hz, 2H), 5.89 (s, 2H), 4.96
(t, J=5.3 Hz, 1H), 4.23 (t, J=5.5 Hz, 2H), 3.80 (q, J=5.4 Hz, 2H).
MS (m/z): 339.25 (M.sup.++1).
Example 162
6-(1-(5-(1H-Pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)ethyl)quin-
oline
[0779] The title compound was prepared by following the procedure
described for intermediate 14 using intermediate 31 (0.290 g, 0.877
mmol), acetic acid (1.8 ml), sodium nitrite (0.072 g, 1.05 mmol)
and water (0.4 ml). Brown solid (0.250 g, 84%). .sup.1H-NMR
(.delta. ppm, DMSO-d.sub.6, 400 MHz): 13.25 (s, 1H), 8.87 (dd,
J=4.0, 1.4 Hz, 1H), 8.48 (d, J=8.7 Hz, 1H), 8.39 (d, J=7.6 Hz, 1H),
8.09 (d, J=1.5 Hz, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.88 (dd, J=8.8,
1.9 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H), 7.64-7.46 (m, 3H), 6.60 (q,
J=7.1 Hz, 1H), 2.22 (d, J=7.1 Hz, 3H).
Example 163
6-(1-(5-(1-(2-(Tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)-3H-[1,2-
,3]triazolo[4,5-b]pyridin-3-yl)ethyl)quinoline
[0780] The title compound was prepared by following the procedure
described for example 145 using example 162 (0.190 g, 0.556 mmol),
2-(2-bromoethoxy)tetrahydro-2H-pyran (0.465 g, 2.22 mmol), cesium
carbonate (0.550 g, 1.69 mmol), tetrabutylammonium iodide (0.143 g,
0.387 mmol) and DMF (7 ml). Yellow solid (0.138 g, 46%).
.sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400 MHz): 8.87 (dd, J=4.1,
1.6 Hz, 1H), 8.50 (s, 1H), 8.49 (d, J=8.7 Hz, 1H), 8.38 (d, J=8.1
Hz, 1H), 8.19 (s, 1H), 8.06 (s, 1H), 7.99 (d, J=8.7 Hz, 1H), 7.86
(d J=8.7 Hz, 1H), 7.78 (d, J=8.7 Hz, 1H), 7.52 (q, J=4.2 Hz, 1H),
6.59 (q, J=7.0 Hz, 1H), 4.53 (t, J=3.0 Hz, 1H), 4.48 (m, 2H), 3.99
(m, 1H), 3.78 (m, 1H), 3.56 (m, 1H), 2.23 (d, J=7.2 Hz, 3H),
1.59-1.20 (m, 7H).
Example 164
2-(4-(3-(1-(Quinolin-6-yl)ethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-
-pyrazol-1-yl)ethanol
[0781] The title compound was prepared by following the procedure
described for example 146 using example 163 (0.130 g, 0.276 mmol),
camphor sulphonic acid (0.643 g. 2.76 mmol), methanol (2 ml) and
water (2 ml). Yellow solid (0.030 g, 28%). M.P.: 188-191.degree. C.
.sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400 MHz): 8.87 (d, J=2.6
Hz, 1H), 8.48 (d, J=8.7 Hz, 1H), 8.47 (s, 1H), 8.39 (d, J=8.1 Hz,
1H), 8.18 (s, 1H), 8.08 (dd, J=0.7 Hz, 1H), 8.00 (d, J=8.7 Hz, 1H),
7.87 (dd, J=8.8, 1.9 Hz, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.52 (q,
J=4.2 Hz, 1H), 6.60 (q, J=6.8 Hz, 1H), 4.97 (t, J=5.4 Hz, 1H), 4.21
(t, J=5.4 Hz, 2H), 3.78 (q, J=5.4 Hz, 2H), 2.22 (d, J=7.2 Hz, 3H).
MS (m/z): 385.87 (M+).
Example 165
2-(4-(3-(2-Chloro-3,6-difluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-y-
l)-1H-pyrazol-1-yl)ethanol
[0782] To a solution of Example 213 (0.160 g, 0.461 mmol) in DMF (7
ml), cesium carbonate (0.449 g, 1.38 mmol) was added and stirred
for 15 min. 2-(2-bromoethoxy)tetrahydro-2H-pyran (0.385 g, 1.84
mmol) and tetrabutylammonium iodide (0.137 g, 0.368 mmol) were
added and heated to 80-85.degree. C. for 12 h. The reaction was
quenched by the addition of water, extracted with ethyl acetate,
washed with brine, dried over sodium sulphate and concentrated to
give the crude product (0.220 g). To a solution of above crude
product (0.210 g, 0.442 mmol) in methanol (2 ml) and water (2 ml),
camphor sulphonic acid (1.027 g. 4.42 mmol) was added and stirred
for 1 h. The reaction was poured into ice water and the pH was
adjusted to ca. 8 by sodium bicarbonate solution, extracted with
ethyl acetate, washed with brine, dried over sodium sulphate and
concentrated to afford the title compound as a yellow solid (0.045
g, 26%). M.P.: 143-145.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.47 (d, J=8.7 Hz, 1H), 8.43 (s, 1H), 8.11
(s, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.61 (dt, J=9.1, 4.8 Hz, 1H), 7.45
(dt, J=9.2, 4.3 Hz, 1H), 6.01 (s, 2H), 4.99 (t, J=5.2 Hz, 1H), 4.22
(t, J=5.3 Hz, 2H), 3.79 (q, J=5.2 Hz, 2H). MS (m/z):: 390.70
(M+).
Example 166
tert-Butyl
4-(4-(3-(2-chloro-3,6-difluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]-
pyridin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate
[0783] The title compound was prepared as a yellow solid (0.250 g,
41%) by following the procedure described for example 156 using
example 213 (0.400 g, 1.15 mmol), sodium hydride (0.060 g, 1.49
mmol), tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate
(0.400 g, 1.43 mmol) and DMF (2 ml).
Example 167
3-(2-Chloro-3,6-difluorobenzyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H--
[1,2,3]triazolo[4,5-b]pyridine hydrochloride
[0784] To a solution of Example 166 (0.240 g, 0.453 mmol) in
dichloromethane (3 ml) cooled to 0.degree. C., TFA (0.1 ml) was
added and warmed to RT. After 2 h, the reaction mixture was poured
in ice water and pH was adjusted to call with 10% NaOH solution and
extracted with ethyl acetate, washed with brine, dried over sodium
sulphate and concentrated. The residue was dissolved in THF (1 ml),
ether saturated with HCl (1 ml) was added at 0.degree. C. and
stirred for 15 min. The precipitate formed was filtered and washed
with ether and dried under vacuum to afford the title compound as
an off-white solid (0.090 g, 43%). M.P.: 85-87.degree. C.
.sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400 MHz): 8.48 (d, J=1.5
Hz, 1H), 8.45 (s, 1H), 8.09 (s, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.60
(dt, J=13.8, 4.8 Hz, 1H), 7.45 (dt, J=13.4, 4.2 Hz, 1H), 6.01 (s,
2H), 4.29 (m, 1H), 3.07 (d, J=12.4 Hz, 2H), 2.63 (m, 2H), 1.98 (m,
2H), 1.85 (m, 2H). MS (m/z):: 429.69 (H.sup.+-HCl).
Example 168
6-((5-(3-Methyl-1H-indazol-6-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)met-
hyl)quinoline
[0785] The title compound was prepared as a yellow solid (0.030 g,
15%) by Suzuki coupling of tert-butyl
3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-1-ca-
rboxylate (0.227 g, 0.634 mmol) with intermediate 14 (0.150 g,
0.507 mmol) following the procedure described for example 1 using
potassium carbonate (0.233 g, 1.68 mmol), dioxan (3 ml), water (0.6
ml) and tetrakis(triphenylphosphine)palladium(0) (0.046 g, 0.04052
mmol) followed by deprotection of the carbamate as described under
157. M.P.: 136-137.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 12.90 (s, 1H), 8.88 (d, J=3.1 Hz, 1H), 8.66
(d, J=8.8 Hz, 1H), 8.38 (d, J=8.5 Hz, 1H), 8.30 (s, 1H), 8.21 (d,
J=8.6 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H), 8.02 (s, 1H), 7.98 (d, J=8.4
Hz, 1H), 7.85 (d, J=8.5 Hz, 2H), 7.53 (q, J=4.2 Hz, 1H), 6.25 (s,
2H), 2.52 (s, 3H).
Example 169
6-((5-(1H-Indol-5-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoli-
ne
[0786] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.150 g, 0.507
mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole
(0.154 g, 0.634 mmol), potassium carbonate (0.233 g, 1.68 mmol),
dioxane (3 ml), water (0.6 ml) and
tetrakis(triphenylphosphine)palladium(0) (0.046 g, 0.04052 mmol).
Light green solid (0.025 g, 13%). M.P.: 120-122.degree. C.
.sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400 MHz): 11.30 (s, 1H),
8.88 (dd, J=4.2, 1.6 Hz, 1H), 8.56 (d, J=8.8 Hz, 1H), 8.45 (s, 1H),
8.39 (d, J=8.3 Hz, 1H), 8.13 (d, J=8.9 Hz, 1H), 8.04 (m, 3H), 7.84
(dd, J=8.8, 1.8 Hz, 1H), 7.53 (m, 2H), 7.42 (t, J=2.7 Hz, 1H), 6.56
(s, 1H), 6.20 (s, 2H).
Example 170
6-((5-(1H-Indol-6-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoli-
ne
[0787] The title compound was obtained as an off-white solid (0.015
g, 8%) by following the procedure described for example 1 using
intermediate 14 (0.150 g, 0.507 mmol), 1H-indole-6-yl boronic acid
(0.102 g, 0.634 mmol), potassium carbonate (0.233 g, 1.68 mmol),
dioxane (3 ml), water (0.6 ml) and
tetrakis(triphenylphosphine)palladium(0) (0.046 g, 0.04052 mmol).
M.P.: 143-145.degree. C. .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6,
400 MHz): 11.38 (s, 1H), 8.88 (dd, J=4.0, 1.5 Hz, 1H), 8.58 (d,
J=8.8 Hz, 1H), 8.38 (d, J=8.7 Hz, 1H), 8.31 (s, 1H), 8.13 (d, J=8.8
Hz, 1H), 8.04 (m, 2H), 7.92 (dd, J=8.4, 1.4 Hz, 1H), 7.86 (dd,
J=8.8, 1.9 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.54 (q, J=4.2 Hz, 1H),
7.49 (d, J=2.6 Hz, 1H), 6.49 (s, 1H), 6.20 (s, 2H).
Example 171
6-((5-(2-Chloropyridin-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)-
quinoline
[0788] The title compound was prepared as an off-white solid (0.020
g, 11%) by following the procedure described for example 1 using
intermediate 14 (0.150 g, 0.507 mmol), 2-chloropyridine-4-boronic
acid (0.099 g, 0.634 mmol), potassium carbonate (0.233 g, 1.68
mmol), dioxane (3 ml), water (0.6 ml) and
tetrakis(triphenylphosphine)palladium(0) (0.046 g, 0.04052 mmol).
M.P.: 197-199.degree. C. .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6,
400 MHz): 8.88 (dd, J=4.1, 1.5 Hz, 1H), 8.79 (d, J=8.7 Hz, 1H),
8.61 (d, J=5.2 Hz, 1H), 8.37 (d, J=8.4 Hz, 1H), 8.32 (d, J=8.8 Hz,
1H), 8.30 (s, 1H), 8.25 (dd, J=5.2, 1.5 Hz, 1H), 8.04 (s, 1H), 8.02
(d, J=8.7 Hz, 1H), 7.83 (dd, J=8.7, 1.9 Hz, 1H), 7.54 (q, J=4.2 Hz,
1H), 6.25 (s, 2H).
Example 172
6-((5-(3-Methyl-1H-indazol-5-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)met-
hyl)quinoline
[0789] The title compound was prepared as a yellow solid (0.050 g,
25%) by following the procedure described for example 1 using
intermediate 14 (0.150 g, 0.507 mmol), tert-butyl
3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-methyl-1H-inda-
zole-1-carboxylate (0.227 g, 0.634 mmol), potassium carbonate
(0.233 g, 1.68 mmol), dioxane (3 ml), water (0.6 ml) and
tetrakis(triphenylphosphine)palladium(0) (0.046 g, 0.04052 mmol)
followed by the procedure described in example 157. M.P.:
246-249.degree. C. .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400
MHz): 12.82 (s, 1H), 8.88 (d, J=2.6 Hz, 1H), 8.62 (d, J=8.8 Hz,
1H), 8.59 (s, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.30 (d, J=9.1 Hz, 1H),
8.23 (d, J=8.8 Hz, 1H), 8.03 (s, 1H), 8.01 (d, J=9.9 Hz, 1H), 7.84
(dd, J=8.6, 1.5 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.53 (q, J=4.2 Hz,
1H), 6.21 (s, 2H), 2.56 (s, 3H).
Example 173
6-((5-(Pyridin-3-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinolin-
e
[0790] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.150 g, 0.507
mmol), pyridine-3-boronic acid (0.079 g, 0.649 mmol), potassium
carbonate (0.233 g, 1.68 mmol), dioxane (3 ml), water (0.6 ml) and
tetrakis(triphenylphosphine)palladium(0) (0.046 g, 0.04052 mmol)
followed by the procedure described in example 157. Yellow solid
(0.040 g, 24%). M.P.: 208-210.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.88 (dd, J=4.1, 1.7 Hz, 1H), 8.77 (m, 3H),
8.38 (dd, J=8.4, 0.9 Hz, 1H), 8.26 (d, J=8.7 Hz, 1H), 8.21 (m, 2H),
8.04 (d, J=1.5 Hz, 1H), 8.02 (d, J=8.7 Hz, 1H), 7.85 (dd, J=8.7,
2.0 Hz, 1H), 7.53 (q, J=4.2 Hz, 1H), 6.24 (s, 2H).
Example 174
(S)-6-((5-(1-(Pyrrolidin-3-yl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]p-
yridin-3-yl)methyl)quinoline
[0791] The title compound was prepared by alkylation of example 143
(0.300 g, 0.916 mmol) with (R)-tert-butyl
3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (0.291 g, 1.09 mmol)
following the procedure described under example 156 using sodium
hydride (0.026 g, 1.09 mmol) and DMF (6 ml) followed by
deprotection of the carbamate using the procedure described for
157. Yellow solid (0.100 g, 44%). .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.88 (dd, J=4.1, 1.4 Hz, 1H), 8.59 (s, 1H),
8.52 (d, J=8.8 Hz, 1H), 8.37 (d, J=8.2 Hz, 1H), 8.22 (s, 1H), 8.01
(d, J=8.8 Hz, 1H), 7.99 (s, 1H), 7.82 (m, 2H), 7.53 (dd, J=8.3, 4.2
Hz, 1H), 6.11 (s, 2H), 4.98 (m, 1H), 3.26-2.96 (m, 5H), 2.28-2.11
(m, 2H).
Example 175
(S)-6-((5-(1-(Pyrrolidin-3-yl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]p-
yridin-3-yl)methyl)quinoline hydrochloride
[0792] Example 174 (0.100 g, 0.25 mmol), was dissolved in THF (1
ml), ether saturated with HCl (1 ml) was added at 0.degree. C. and
stirred for 15 min. The precipitate formed was washed with ether
and dried under vacuum to afford the title compound as a yellow
solid (0.070 g, 65%). M.P.: 117-121.degree. C. .sup.1H-NMR (.delta.
ppm, DMSO-d.sub.6, 400 MHz): 9.58 (s, 1H), 9.45 (s, 1H), 9.12 (d,
J=3.7 Hz, 1H), 8.87 (d, J=8.1 Hz, 1H), 8.73 (s, 1H), 8.56 (d, J=8.7
Hz, 1H), 8.30 (s, 1H), 8.25 (d, J=8.7 Hz, 1H), 8.21 (s, 1H), 8.07
(d, J=8.8 Hz, 1H), 7.85 (d, J=8.7 Hz, 2H), 6.18 (s, 2H), 5.27 (t,
J=3.3 Hz, 1H), 3.69-3.34 (m, 4H), 2.43-2.30 (s, 2H).
Example 176
4-(2-(4-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-
-pyrazol-1-yl)ethyl)morpholine hydrochloride
[0793] The title compound was prepared by following the procedure
described for example 156 using example 143 (0.150 g, 0.458 mmol),
sodium hydride (0.022 g, 0.55 mmol), (4-(2-chloroethyl)morpholine
(0.115 g, 1.00 mmol) and DMF (3 ml) followed by using the procedure
described for 175. Yellow solid (0.080 g, 36%). M.P.:
118-120.degree. C. .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400
MHz): 11.08 (s, 1H), 9.06 (d, J=3.7 Hz, 1H), 8.74 (d, J=8.3 Hz,
1H), 8.65 (s, 1H), 8.57 (d, J=8.6 Hz, 1H), 8.31 (s, 1H), 8.18 (d,
J=8.8 Hz, 1H), 8.13 (s, 1H), 7.99 (d, J=8.8 Hz, 1H), 7.85 (d, J=8.7
Hz, 1H), 7.78 (dd, J=7.7, 4.4 Hz, 1H), 6.16 (s, 2H), 4.72 (t, J=6.6
Hz, 1H), 3.97 (br.s, 2H), 3.77 (t, J=11.5 Hz, 2H), 3.65 (t, J=11.5
Hz, 2H), 3.42 (d, J=11.6 Hz, 2H), 3.17 (m, 2H).
Example 177
6-((5-(1-(Tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,-
5-b]pyridin-3-yl)methyl)quinoline
[0794] The title compound was prepared as a yellow solid (0.130 g,
52%) by following the procedure described for example 156 using
example 143 (0.200 g, 0.610 mmol), cesium carbonate (0.596 g, 1.83
mmol), tetrahydro-2H-pyran-4-yl methanesulfonate (0.220 g, 1.22
mmol) and DMF (6 ml). M.P.: 182-184.degree. C. .sup.1H-NMR (.delta.
ppm, DMSO-d.sub.6, 400 MHz): 8.88 (dd, J=4.2, 1.7 Hz, 1H), 8.59 (s,
1H), 8.51 (d, J=8.8 Hz, 1H), 8.38 (d, J=8.2 Hz, 1H), 8.21 (s, 1H),
8.01 (m, 2H), 7.82 (m, 2H), 7.53 (dd, J=8.3, 4.1 Hz, 1H), 6.11 (s,
2H), 4.52 (m, 1H), 3.99 (m, 2H), 3.51 (dt, J=11.2, 3.0 Hz, 2H),
2.02 (m, 4H).
Example 178
6-((5-(1-(2-Hydroxyethyl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridi-
n-3-yl)methyl)quinoline 1-oxide: T
[0795] To a solution of example 146 (0.100 g, 0.269 mmol) in acetic
acid (1 ml), hydrogen peroxide solution (50%, 1 ml) and heated to
100.degree. C. After 12 h, the mixture was concentrated, extracted
with chloroform, washed with brine, dried over sodium sulphate and
concentrated. The crude product was purified by column
chromatography using dichloromethane: methanol to afford the title
compound as an off-white solid (0.015 g, 14%). M.P.:
222-224.degree. C. .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400
MHz):8.58-8.48 (m, 4H), 8.19 (s, 1H), 8.08 (s, 1H), 7.93 (d, J=8.5
Hz, 1H), 7.85 (dd, J=9.0, 1.8 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.47
(dd, J=8.4, 6.0 Hz, 1H), 6.12 (s, 2H), 4.95 (t, J=5.2 Hz, 1H), 4.22
(t, J=5.5 Hz, 2H), 3.77 (q, J=5.5 Hz, 2H).
Example 179
6-((5-(1,3-dimethyl-1H-indazol-6-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl-
)methyl)quinoline
[0796] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.100 g, 0.338
mmol),
1,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole
(0.0117 g, 0.432 mmol), potassium carbonate (0.146 g, 1.05 mmol),
dioxane (3 ml), water (0.6 ml) and
tetrakis(triphenylphosphine)palladium(0). (0.061 g, 45%) Yellow
solid (0.061 g, 45%). M.P.: 159-163.degree. C. .sup.1H-NMR (.delta.
ppm, DMSO-d.sub.6, 400 MHz): 8.88 (dd, J=4.0, 1.6 Hz, 1H), 8.69 (d,
J=8.8 Hz, 1H), 8.41 (s, 1H), 8.38 (d, J=8.0 Hz, 1H), 8.30 (d, J=8.8
Hz, 1H), 8.05-8.01 (m, 3H), 7.85 (m, 2H), 7.54 (dd, J=8.3, 4.1 Hz,
1H), 6.24 (s, 2H).
Example 180
5-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)pyrimidin-
-2-amine
[0797] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.100 g, 0.338
mmol), 2-amino-5-pyrimidineboronic acid (0.058 g, 0.422 mmol),
potassium carbonate (0.156 g, 0.027 mmol), dioxane (2 ml), water
(0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.031 g,
0.067 mmol) under microwave irradiation (100 W, 100.degree. C.) for
20 min Yellow solid (0.020 g, 16%). M.P.: 244-246.degree. C. MS
(m/z): 354.72 (M+).
Example 181
tert-Butyl
3-ethyl-6-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyr-
idin-5-yl)-1H-indazole-1-carboxylate
[0798] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.100 g, 0.338
mmol), tert-butyl
3-ethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-1-car-
boxylate (0.157 g, 0.422 mmol), potassium carbonate (0.156 g, 0.027
mmol), dioxane (2 ml), water (0.5 ml) and
tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.067 mmol)
under microwave irradiation (100 W, 100.degree. C.) for 20 min
Off-white solid (0.070 g, 51%). M.P.: 185-188.degree. C.
.sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400 MHz): 8.93 (s, 1H),
8.91 (dd, J=4.2, 1.5 Hz, 1H), 8.47 (d, J=8.7 Hz, 1H), 8.20 (d,
J=8.3 Hz, 1H), 8.11 (m, 2H), 7.98 (s, 1H), 7.96 (d, J=8.7 Hz, 1H),
7.90 (dd, J=8.8, 1.8 Hz, 1H), 7.83 (d, J=8.3 Hz, 1H), 7.41 (dd,
J=8.3, 4.3 Hz, 1H), 6.16 (s, 2H), 3.10 (q, J=7.6 Hz, 2H), 1.74 (s,
9H), 1.48 (t, J=7.6 Hz, 3H).
Example 182
4-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)thiophene-
-2-carbaldehyde
[0799] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.100 g, 0.338
mmol), 2-formylthiophene-4-boronic acid (0.032 g, 0.422 mmol),
potassium carbonate (0.156 g, 0.027 mmol), dioxane (2 ml), water
(0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.031 g,
0.067 mmol) under microwave irradiation (100 W, 100.degree. C.) for
20 min Brown solid (0.060 g, 7%). M.P.: 195-197.degree. C. MS
(m/z): 372.08 (M+).
Example 183
6-((5-(2-Methoxypyrimidin-5-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)meth-
yl)quinoline
[0800] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.100 g, 0.338
mmol), 2-methoxypyrimidine-5-boronic acid (0.065 g, 0.422 mmol),
potassium carbonate (0.156 g, 0.027 mmol), dioxane (2 ml), water
(0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.031 g,
0.067 mmol) under microwave irradiation (100 W, 100.degree. C.) for
20 min Yellow solid (0.060 g, 48%). M.P.: 201-203.degree. C. MS
(m/z): 369.98 (M+).
Example 184
6-((5-(Benzo[d][1,3]dioxol-5-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)met-
hyl)quinoline
[0801] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.100 g, 0.338
mmol), benzo[d][1,3]dioxol-5-ylboronic acid (0.056 g, 0.422 mmol),
potassium carbonate (0.156 g, 0.027 mmol), dioxane (2 ml), water
(0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.031 g,
0.067 mmol) under microwave irradiation (100 W, 100.degree. C.) for
20 min Off-white solid (0.070 g, 54%). M.P.: 179-181.degree. C. MS
(m/z): 382.16 (M.sup.++1).
Example 185
6-((5-(2,3-Dihydrobenzofuran-5-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)m-
ethyl) quinoline
[0802] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.100 g, 0.338
mmol), 2,3-dihydrobenzofuran-5-ylboronic acid (0.055 g, 0.422
mmol), potassium carbonate (0.156 g, 0.027 mmol), dioxane (2 ml),
water (0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.031
g, 0.067 mmol) under microwave irradiation (100 W, 100.degree. C.)
for 20 min Pale brown solid (0.065 g, 50%). M.P.: 131-133.degree.
C. MS (m/z): 379.92 (M.sup.+).
Example 186
5-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)pyridin-2-
-amine
[0803] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.100 g, 0.338
mmol),
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine
(0.096 g, 0.439 mmol), potassium carbonate (0.156 g, 0.027 mmol),
dioxane (2 ml), water (0.5 ml) and
tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.067 mmol)
under microwave irradiation (100 W, 100.degree. C.) for 20 min.
Yellow solid (0.050 g, 42%). M.P.: 194-197.degree. C. MS (m/z):
353.95 (M.sup.+).
Example 187
6-((5-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-
-3-yl)methyl)quinoline
[0804] Methane sulphonyl chloride (0.069 g, 0.605 mmol) was added
at 0.degree. C. to a solution of example 146 (0.150 g, 0.403 mmol)
and triethylamine (0.122 g, 1.21 mmol) in dichloromethane (3 ml)
and warmed to RT. After 1 h, the mixture was diluted and washed
with sodium bicarbonate solution, washed with brine, dried over
sodium sulphate and concentrated. To the residue, cesium fluoride
(0.270 g, 1.77 mmol) and tert-butanol (2 ml) were added and heated
to 70.degree. C. for 12 h. The reaction mixture was poured in
water, extracted with ethyl acetate, washed with brine, dried over
sodium sulphate and concentrated. The crude product was purified by
column chromatography using dichloromethane: methanol to afford the
title compound as an off-white solid (0.015 g, 10%). M.P.:
168-170.degree. C. .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400
MHz): 8.88 (dd, J=4.2, 1.7 Hz, 1H), 8.57 (s, 1H), 8.53 (d, J=8.7
Hz, 1H), 8.37 (d, J=7.4 Hz, 1H), 8.26 (s, 1H), 8.01 (d, J=8.1 Hz,
1H), 7.99 (s, 1H), 7.83 (m, 2H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.11
(s, 2H), 4.88 (dt, J=47.1, 4.5 Hz, 2H), 4.56 (dt, J=27.7, 4.8 Hz,
2H) MS (m/z):: 374.1 (M.sup.++1).
Example 188
(4-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)thiophen-
-2-yl) methanol
[0805] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.100 g, 0.338
mmol),
(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)methanol
(0.066 g, 0.475 mmol), potassium carbonate (0.156 g, 0.027 mmol),
dioxane (2 ml), water (0.5 ml) and tetrakis(triphenylphosphine)
palladium(0) (0.031 g, 0.067 mmol) under microwave irradiation (100
W, 100.degree. C.) for 20 min Yellow solid (0.080 g, 63%). M.P.:
188-191.degree. C. MS (m/z): 373.95 (M+).
Example 189
6-(2-(5-(1-(2-(Tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)-3H-[1,2-
,3]triazolo[4,5-b]pyridin-3-yl)propan-2-yl)quinoline
[0806] The title compound was prepared by following the procedure
described for example 1 using intermediate 17 (0.100 g, 0.307
mmol),
1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dio-
xaborolan-2-yl)-1H-pyrazole (0.126 g, 0.394 mmol), potassium
carbonate (0.133 g, 0.963 mmol), dioxane (2.5 ml), water (0.5 ml)
and tetrakis(triphenylphosphine)palladium(0) (0.028 g, 0.024 mmol).
Yellow liquid (0.065 g, 44%). .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.85 (d, J=2.8 Hz, 1H), 8.47 (d, J=8.7 Hz,
1H), 8.37 (d, J=7.9 Hz, 1H), 8.22 (s, 1H), 7.95 (d, J=1.7 Hz, 1H),
7.90 (s, 1H), 7.88 (d, J=7.3 Hz, 1H), 7.69 (d, J=8.7 Hz, 1H), 7.53
(m, 1H), 4.46 (m, 1H), 4.27 (m, 2H), 3.88 (m, 1H), 3.69 (m, 1H),
3.47 (m, 1H), 3.26 (m, 1H), 1.63-1.30 (m, 6H).
Example 190
2-(4-(3-(2-(Quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5--
yl)-1H-pyrazol-1-yl)ethanol
[0807] The title compound was prepared by following the procedure
described for example 146 from example 189 (0.050 g, 0.104 mmol),
camphor sulphonic acid (0.121 g. 0.521 mmol), methanol (0.5 ml) and
water (0.5 ml). Brown solid (0.031 g, 74%). M.P.: 95-98.degree. C.
.sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400 MHz): 8.85 (d, J=2.8
Hz, 1H), 8.46 (d, J=8.7 Hz, 1H), 8.40 (d, J=7.9 Hz, 1H), 8.22 (s,
1H), 8.00 (d, J=1.8 Hz, 1H), 7.91 (d, J=8.9 Hz, 1H), 7.85 (s, 1H),
7.68 (d, J=8.7 Hz, 1H), 7.53 (m, 2H), 4.87 (t, J=5.3 Hz, 1H), 4.11
(t, J=5.4 Hz, 2H), 3.70 (q, J=5.4 Hz, 2H), 2.46 (s, 6H).
Example 191
6-((5-(3-ethyl-1H-indazol-6-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)meth-
yl)quinoline
[0808] To a solution of Example 181 (0.050 g, 0.099 mmol) in
dichloromethane (1 ml) cooled to 0.degree. C., TFA (0.5 ml) was
added and warmed to RT. After 2 h, the reaction mixture was poured
in ice water and pH was adjusted to ca. 11 with 10% NaOH solution
and extracted with ethyl acetate, washed with brine, dried over
sodium sulphate and concentrated to afford the title compound as a
yellow solid (0.023 g, 61%). M.P.: 211-213.degree. C. MS (m/z):
406.08 (M.sup.+).
Example 192
6-(2-(5-(1H-Pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)propan-2-y-
l)quinoline
[0809] The title compound was prepared by following the procedure
described for example 1 using intermediate 17 (0.20 g, 0.615 mmol),
tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate
(0.231 g, 0.788 mmol), potassium carbonate (0.266 g, 1.92 mmol),
dioxane (5 ml), water (1 ml) and
tetrakis(triphenylphosphine)palladium(0) (0.057 g, 0.049 mmol).
Yellow solid (0.075 g, 34%). M.P.: 218-220.degree. C. .sup.1H-NMR
(.delta. ppm, DMSO-d.sub.6, 400 MHz): 13.02 (s, 1H), 8.86 (dd,
J=4.2, 1.7 Hz, 1H), 8.56 (s, 1H), 8.35 (dd, J=8.2, 1.1 Hz, 2H),
8.10 (s, 1H), 8.04-7.98 (m, 3H), 7.85 (dd, J=8.8, 1.9 Hz, 1H), 7.61
(d, J=8.3 Hz, 1H), 7.52 (dd, J=8.3, 4.2 Hz, 1H), 5.69 (s, 2H). MS
(m/z): 359.89 (M.sup.+).
Example 193
6-((5-(4-Methylthiophen-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl-
)quinoline
[0810] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.100 g, 0.338
mmol), 4-methyl-2-thiopheneboronic acid (0.061 g, 0.432 mmol),
potassium carbonate (0.146 g, 1.058 mmol), dioxane (2.5 ml), water
(0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.031 g,
0.027 mmol) under microwave irradiation (100 W, 100.degree. C.) for
20 min Brown solid (0.048 g, 40%). M.P.: 153-156.degree. C. MS
(m/z): 357.85 (M+).
Example 194
6-((5-(5-Methylthiophen-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl-
)quinoline
[0811] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.100 g, 0.338
mmol), 5-methyl-2-thiopheneboronic acid (0.060 g, 0.422 mmol),
potassium carbonate (0.156 g, 1.12 mmol), dioxane (2.5 ml), water
(0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.031 g,
0.027 mmol) under microwave irradiation (100 W, 100.degree. C.) for
20 min Off-white solid (0.035 g, 29%). M.P.: 154-156.degree. C. MS
(m/z): 357.85 (M+).
Example 195
4-(5-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)pyridi-
n-2-yl)morpholine
[0812] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.100 g, 0.338
mmol), 6-morpholinopyridine-3-boronic acid (0.088 g, 0.422 mmol),
potassium carbonate (0.156 g, 1.12 mmol), dioxane (2.5 ml), water
(0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.031 g,
0.027 mmol) under microwave irradiation (100 W, 100.degree. C.) for
20 min Yellow solid (0.045 g, 31%). M.P.: 183-185.degree. C. MS
(m/z): 423.93 (M+).
Example 196
6-((5-(6-(Piperidin-1-yl)pyridin-3-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3--
yl)methyl)quinoline
[0813] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.100 g, 0.338
mmol),
2-(piperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-
e (0.122 g, 0.422 mmol), potassium carbonate (0.156 g, 1.12 mmol),
dioxane (2.5 ml), water (0.5 ml) and tetrakis
(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol) under
microwave irradiation (100 W, 100.degree. C.) for 20 min Brown
solid (0.090 g, 63%). M.P.: 133-135.degree. C. MS (m/z): 422.18
(M.sup.++1).
Example 197
6-((5-(1-Ethyl-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)meth-
yl)quinoline
[0814] The title compound was prepared by following the procedure
described for example 144 from example 143 (0.130 g, 0.397 mmol),
sodium hydride (0.014 g, 0.596 mmol), ethyl iodide (0.123 g, 0.794
mmol) and DMF (3 ml). Yellow solid (0.065 g, 46%). M.P.:
132-134.degree. C. MS (m/z): 356.03 (M.sup.++1).
Example 198
6-((5-(1-Isopropyl-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-
methyl)quinoline
[0815] The title compound was prepared by following the procedure
described for example 144 from example 143 (0.130 g, 0.397 mmol),
sodium hydride (0.014 g, 0.596 mmol), 2-bromopropane (0.097 g,
0.794 mmol) and DMF (3 ml). Off-white solid (0.050 g, 34%). M.P.:
126-128.degree. C. MS (m/z): 370.24 (M.sup.++1).
Example 199
6-((5-(1-Isobutyl-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)m-
ethyl)quinoline
[0816] The title compound was prepared by following the procedure
described for example 144 from example 143 (0.130 g, 0.397 mmol),
sodium hydride (0.014 g, 0.596 mmol), 1-bromo-2-methylpropane
(0.108 g, 0.794 mmol) and DMF (3 ml). Pale green solid (0.070 g,
46%). M.P.: 160-163.degree. C. MS (m/z): 384.10 (M.sup.++1).
Example 200
1-(Pyrrolidin-1-yl)-2-(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b-
]pyridin-5-yl)-1H-pyrazol-1-yl)ethanone
[0817] To a solution of example 155 (0.056 g, 0.145 mmol) in DMF
(0.5 ml)N-ethyldiisopropylamine (0.018 g, 0.145 mmol) and HATU
(0.055 g, 0.145 mmol) were added and stirred for 5 min Pyrrolidine
(0.020 g, 0.290 mmol) was added at RT and the reaction mixture was
stirred for 12 h. To the reaction mixture water was added and
extracted with ethyl acetate, dried over sodium sulphate and
concentrated under reduced pressure. The crude product was purified
by column chromatography with methanol: dichloromethane to afford
the title compound as a yellow solid (0.010 g, 16%). M.P.:
136-138.degree. C. .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400
MHz): 8.87 (dd, J=2.7 Hz, 1H), 8.52 (d, J=8.7 Hz, 1H), 8.45 (s,
1H), 8.37 (d, J=7.7 Hz, 1H), 8.20 (s, 1H), 8.01 (d, J=8.6 Hz, 1H),
7.99 (s, 1H), 7.83 (m, 2H), 7.52 (dd, J=8.3, 4.2 Hz, 1H), 6.11 (s,
2H), 5.11 (s, 2H), 3.52 (t, J=6.7 Hz, 2H), 3.33 (m, 2H), 1.93-1.77
(m, 4H).
Example 201
6-((5-(1-(2-Methoxyethyl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridi-
n-3-yl)methyl)quinoline
[0818] The title compound was prepared by following the procedure
described for example 144 from example 143 (0.130 g, 0.397 mmol),
sodium hydride (0.014 g, 0.596 mmol), 2-bromoethyl methyl ether
(0.110 g, 0.794 mmol) and DMF (3 ml). Pale yellow solid (0.050 g,
33%). M.P.: 162-164.degree. C. .sup.1H-NMR (.delta. ppm,
CDCl.sub.3, 400 MHz): 8.90 (d, J=3.5 Hz, 1H), 8.30 (d, J=8.6 Hz,
1H), 8.13 (m, 4H), 7.89 (s, 1H), 7.86 (d, J=8.9 Hz, 1H), 7.54 (d,
J=8.7 Hz, 1H), 7.41 (dd, J=8.3, 4.2 Hz, 1H), 6.07 (s, 2H), 4.38 (t,
J=5.0 Hz, 2H), 3.81 (t, J=5.1 Hz, 2H), 3.36 (s, 3H).
Example 202
N-Phenyl-3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine
[0819] To a solution of intermediate 14 (0.10 g, 0.338 mmol) and
aniline (0.047 g, 0.507 mmol) in o-xylene (0.8 ml), sodium
tert-butoxide (0.038 g, 0.405 mmol), triphenylphosphine (0.008 g,
0.033 mmol) and palladium acetate (0.003 g, 0.169 mmol) were added
and degassed for 30 min and the reaction mixture was heated to
120.degree. C. for 4 h. The reaction mixture was filtered through
celite and washed with ethyl acetate, dried over sodium sulphate
and concentrated under reduced pressure. The crude product was
purified by column chromatography with methanol: dichloromethane to
afford the title compound as a brown solid (0.030 g, 25%). M.P.:
237-239.degree. C. .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400
MHz): 9.72 (s, 1H), 8.87 (d, J=3.9 Hz, 1H), 8.36 (d, J=8.6 Hz, 1H),
8.19 (d, J=9.0 Hz, 1H), 8.00 (s, 1H), 7.98 (d, J=8.1 Hz, 1H), 7.73
(m, 3H), 7.53 (dd, J=8.0, 4.2 Hz, 1H), 7.26 (m, 2H), 6.96 (t, J=7.4
Hz, 1H), 6.90 (d, J=9.0 Hz, 1H), 5.98 (s, 2H).
Example 203
6-((5-Phenoxy-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline
[0820] To a solution of intermediate 14 (0.10 g, 0.338 mmol) and
phenol (0.031 g, 0.338 mmol) in N-methyl pyrrolidone (0.7 ml),
potassium tert-butoxide (0.045 g, 0.405 mmol) was added and the
reaction mixture was heated to 80.degree. C. for 12 h. The reaction
mixture was quenched with water, extracted with ethyl acetate,
dried over sodium sulphate and concentrated under reduced pressure.
The crude product was purified by column chromatography with
methanol: dichloromethane to afford the title compound as an
off-white solid (0.040 g, 33%). M.P.: 225-227.degree. C.
.sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400 MHz): 8.91 (d, J=2.9
Hz, 1H), 8.29 (d, J=8.8 Hz, 1H), 8.07 (d, J=8.1 Hz, 1H), 8.01 (d,
J=8.7 Hz, 1H), 7.76 (s, 1H), 7.67 (dd, J=8.6, 1.4 Hz, 1H), 7.47 (m,
3H), 7.33 (t, J=7.4 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 6.98 (d, J=8.9
Hz, 1H), 5.80 (s, 2H).
Example 204
Methyl
2-fluoro-5-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridi-
n-5-yl)benzoate
[0821] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.250 g, 0.845
mmol), 4-fluoro-3-methoxycarbonylphenylboronic acid pinacol ester
(0.294 g, 0.422 mmol), potassium acetate (0.276 g, 2.81 mmol),
dioxane (4 ml) and tetrakis(triphenylphosphine)palladium(0) (0.050
g, 0.042 mmol). Off-white solid (0.080 g, 23%).
Example 205
2-Fluoro-5-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-
benzoic acid
[0822] To a solution of Example 204 (0.080 g, 0.193 mmol) in
methanol (1 ml), lithium hydroxide (0.075 g, 1.80 mmol) in water (1
ml) and THF (2 ml) were added and stirred at RT. After 12 h, pH was
adjusted to ca. 7 using 0.5N HCl and the solid precipitated was
filtered, washed with ethyl acetate and petroleum ether and dried
under vacuum to afford the title compound as an off-white solid
(0.060 g, 78%). The acid was used without further purification in
the next step.
Example 206
2-Fluoro-5-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-
benzamide
[0823] To Example 205 (0.060 g, 0.149 mmol), thionyl chloride (0.8
ml) was added and refluxed for 3 h. The excess thionyl chloride was
removed; aqueous 25% ammonia (0.8 ml) was added to the residue at
0.degree. C. and stirred for 15 min. The precipitate formed was
washed with sodium bicarbonate solution and vacuum dried to afford
title compound as an off-white solid (0.020 g, 34%). M.P.:
262-264.degree. C. .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400
MHz): 8.87 (d, J=2.7 Hz, 1H), 8.68 (d, J=8.7 Hz, 1H), 8.50 (d,
J=6.7 Hz, 1H), 8.39 (d, J=8.1 Hz, 2H), 8.17 (d, J=8.7 Hz, 1H), 8.04
(s, 1H), 8.02 (d, J=8.6 Hz, 1H), 7.89 (s, 1H), 7.83 (d, J=8.7 Hz,
1H), 7.78 (s, 1H), 7.53 (dd, J=8.2, 3.9 Hz, 1H), 7.49 (d, J=9.7 Hz,
1H), 6.21 (s, 2H).
Example 207
2-Chloro-4-(3-((5,7-difluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b-
]pyridin-5-yl)benzamide
[0824] The title compound was prepared by following the procedure
described for example 1 using intermediate 34 (0.065 g, 0.196
mmol), intermediate 35 (0.070 g, 0.245 mmol), potassium carbonate
(0.090 g, 0.654 mmol), dioxane (2 ml), water (0.3 ml) and
tetrakis(triphenylphosphine)palladium(0) (0.018 g, 0.015 mmol)
under microwave irradiation (100 W, 100.degree. C.) for 30 min
Brown solid (0.020 g, 23%). M.P.: 216-219.degree. C. .sup.1H-NMR
(.delta. ppm, DMSO-d.sub.6, 400 MHz): 9.01 (d, J=2.9 Hz, 1H), 8.67
(d, J=8.7 Hz, 1H), 8.59 (d, J=8.5 Hz, 1H), 8.26 (s, 1H), 8.20 (d,
J=8.6 Hz, 1H), 8.18 (s, 1H), 7.96 (s, 1H), 7.77 (d, J=10.9 Hz, 1H),
7.69 (s, 1H), 7.67 (dd, J=8.6, 4.3 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H),
7.59 (d, J=8.0 Hz, 1H), 6.26 (s, 2H).
Example 208
1-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)ethanone
[0825] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.200 g, 0.676
mmol), 1-ethoxyvinyl tri(n-butyl)stannane (0.244 g, 0.676 mmol),
triphenylphosphine (0.0284 g, 0.054 mmol), toluene (3.8 ml) and
tris (dibenzilidineacetone) palladium(0) (0.028 g, 0.027 mmol)
followed by acid hydrolysis. Brown solid (0.080 g, 39%).
.sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400 MHz): 8.92 (d, J=3.0 Hz,
1H), 8.49 (d, J=8.5 Hz, 1H), 8.15 (m, 3H), 7.94 (s, 1H), 7.87 (d,
J=8.6 Hz, 1H), 7.43 (dd, J=8.3, 4.2 Hz, 1H), 6.15 (s, 2H), 2.82 (s,
3H).
Example 209
2-(1-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)ethyli-
dene) hydrazinecarboxamide
[0826] To a solution of example 208 (0.070 g, 0.230 mmol) in
ethanol (2 ml), sodium acetate (0.018 g, 0.230 mmol) and
semicarbazide hydrochloride (0.026 g, 0.230 mmol) were added and
stirred at RT for 12 h. The reaction mixture was concentrated and
the residue was washed with bicarbonate solution, dichloromethane
and dried under vacuum to afford the title compound as a yellow
solid (0.040 g, 48%). M.P.: 249-250.degree. C. .sup.1H-NMR (.delta.
ppm, DMSO-d.sub.6, 400 MHz): 9.70 (s, 1H), 8.88 (d, J=2.8 Hz, 1H),
8.54 (d, J=8.9 Hz, 1H), 8.45 (d, J=8.9 Hz, 1H), 8.37 (d, J=8.2 Hz,
1H), 8.01 (s, 1H), 7.99 (d, J=8.6 Hz, 1H), 7.81 (dd, J=8.6, 1.3 Hz,
1H), 7.53 (dd, J=8.2, 4.1 Hz, 1H), 6.78 (br s, 2H), 6.14 (s, 2H),
2.35 (s, 3H).
Example 210
4-(3-(Benzo[d]thiazol-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-2-
-chlorobenzamide
[0827] The title compound was prepared by following the procedure
described for example 1 using intermediate 38 (0.150 g, 0.496
mmol), intermediate 35 (0.174 g, 0.620 mmol), potassium carbonate
(0.228 g, 1.65 mmol), dioxane (3 ml), water (1 ml) and
tetrakis(triphenylphosphine)palladium(0) (0.045 g, 0.039 mmol)
under microwave irradiation (100 W, 100.degree. C.) for 30 min.
Yellow solid (0.090 g, 43%). M.P.: 238-240.degree. C. .sup.1H-NMR
(.delta. ppm, DMSO-d.sub.6, 400 MHz): 9.38 (s, 1H), 8.69 (d, J=8.7
Hz, 1H), 8.32 (s, 1H), 8.27 (s, 1H), 8.25 (d, J=8.2 Hz, 1H), 8.21
(d, J=8.8 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 7.97 (s, 1H), 7.69 (s,
1H), 7.64 (m, 2H), 6.18 (s, 2H).
Example 211
2-(2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5--
yl)phenyl)propan-2-ol
[0828] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.150 g, 0.507
mmol), intermediate 19 (0.177 g, 0.634 mmol), potassium carbonate
(0.233 g, 1.68 mmol), dioxane (3 ml), water (0.6 ml) and
tetrakis(triphenylphosphine)palladium(0) (0.047 g, 0.040 mmol).
Pale green solid (0.080 g, 38%). M.P.: 85-89.degree. C. .sup.1H-NMR
(.delta. ppm, DMSO-d.sub.6, 400 MHz): 9.59 (s, 1H), 8.88 (d, J=2.7
Hz, 1H), 8.67 (d, J=8.7 Hz, 1H), 8.37 (d, J=7.7 Hz, 1H), 8.15 (m,
4H), 7.83 (m, 2H), 7.53 (dd, J=8.1, 4.0 Hz, 1H), 6.21 (s, 2H), 5.38
(s, 1H), 1.51 (s, 6H).
Example 212
2-Chloro-5-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-
benzamide
[0829] The title compound was obtained as an off-white solid (0.065
g, 46%) by following the procedure described for example 1 using
intermediate 14 (0.100 g, 0.338 mmol), intermediate 22 (0.118 g,
0.422 mmol), potassium carbonate (0.155 g, 1.12 mmol), DMF (8 ml),
water (0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.031
g, 0.027 mmol). M.P.: 241-244.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.88 (dd, J=4.0, 2.6 Hz, 1H), 8.69 (d,
J=8.7 Hz, 1H), 8.36 (d, J=8.2 Hz, 1H), 8.29 (s, 1H), 8.26 (dd,
J=11.6, 1.5 Hz, 1H), 8.20 (d, J=8.8 Hz, 1H), 8.03 (m, 3H), 7.83
(dd, J=8.7, 1.6 Hz, 1H), 7.73 (s, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.53
(dd, J=8.3, 4.2 Hz, 1H), 6.22 (s, 2H).
Example 213
3-(2-Chloro-3,6-difluorobenzyl)-5-(1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-
-b]pyridine
[0830] The title compound was prepared by following the procedure
described for example 1 using intermediate 16 (0.180 g, 0.571
mmol), tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate
(0.215 g, 0.731 mmol), potassium carbonate (0.260 g, 1.88 mmol),
dioxane (3.5 ml), water (0.8 ml) and
tetrakis(triphenylphosphine)palladium(0) (0.052 g, 0.044 mmol).
Yellow solid (0.165 g, 83%). .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 13.22 (s, 1H), 8.48 (d, J=8.7 Hz, 1H), 8.18
(s, 1H), 7.82 (d, J=8.7 Hz, 1H), 7.63-7.51 (m, 2H), 7.45 (dt,
J=9.2, 4.2 Hz, 1H), 6.02 (s, 2H).
Example 214
2-Chloro-4-(3-(1-(quinolin-6-yl)ethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5--
yl)benzamide
[0831] The title compound was prepared by following the procedure
described for example 1 using intermediate 40 (0.450 g, 1.45 mmol),
intermediate 35 (0.511 g, 1.81 mmol), potassium carbonate (0.668 g,
3.33 mmol), dioxane (5 ml), water (1.5 ml) and
tetrakis(triphenylphosphine)palladium(0) (0.134 g, 0.116 mmol)
under microwave irradiation (100 W, 100.degree. C.) for 45 min
Off-white solid (0.250 g, 40%). M.P.: 140-143.degree. C.
.sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400 MHz): 8.87 (dd, J=3.8,
2.7 Hz, 1H), 8.68 (d, J=8.7 Hz, 1H), 8.39 (d, J=8.2 Hz, 1H), 8.25
(s, 1H), 8.20 (m, 2H), 8.11 (s, 1H), 8.00 (d, J=8.9 Hz, 1H), 7.94
(s, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.67 (s, 1H), 7.60 (d, J=8.0 Hz,
1H), 7.53 (dd, J=8.4, 4.2 Hz, 1H), 6.73 (q, J=6.7 Hz, 1H), 2.25 (d,
J=7.0 Hz, 3H).
Example 215
2-Chloro-4-(3-(quinolin-6-ylmethyl)-3H-imidazo[4,5-b]pyridin-5-yl)benzamid-
e
[0832] The title compound was prepared by following the procedure
described for example 1 using intermediate 29 (0.150 g, 0.508
mmol), intermediate 35 (0.179 g, 0.636 mmol), potassium carbonate
(0.234 g, 1.69 mmol), dioxan (3 ml), water (1 ml) and
tetrakis(triphenylphosphine) palladium(0) (0.047 g, 0.040 mmol) and
in microwave oven (100 W, 100.degree. C.) for 45 min Off-white
solid (0.095 g, 45%). M.P.: 212-214.degree. C. .sup.1H-NMR (.delta.
ppm, DMSO-d.sub.6, 400 MHz): 8.87 (dd, J=4.1, 2.8 Hz, 1H), 8.73 (s,
1H), 8.35 (d, J=8.5 Hz, 1H), 8.20 (s, 1H), 8.18 (d, J=7.6 Hz, 1H),
8.13 (d, J=8.1 Hz, 1H), 8.01 (m, 3H), 7.90 (s, 1H), 7.83 (d, J=8.7
Hz, 1H), 7.62 (s, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.53 (dd, J=8.6, 4.5
Hz, 1H), 5.78 (s, 2H).
Example 216
1-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)ethanone
oxime
[0833] To a solution of example 208 (0.060 g, 0.197 mmol) in
ethanol (1.3 ml), sodium acetate (0.016 g, 0.197 mmol) and
hydroxylamine hydrochloride (0.013 g, 0.197 mmol) were added and
stirred at RT for 12 h. The reaction mixture was concentrated and
the residue was washed with bicarbonate solution, dichloromethane
and dried under vacuum to afford the title compound as a ca. 9:1
mixture of two isomers. Off-white solid (0.030 g, 48%). M.P.:
259-261.degree. C. .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400
MHz): 11.95 (s, 0.9H), 11.28 (s, 0.1H), 8.88 (d, J=2.6 Hz, 1H),
8.74 (d, J=8.8 Hz, 0.1H), 8.61 (d, J=8.4 Hz, 0.1H), 8.52 (d, J=8.8
Hz, 0.9H), 8.36 (d, J=8.4 Hz, 0.9H), 8.00 (m, 3H), 7.81 (dd, J=8.4,
1.6 Hz, 1H), 7.53 (dd, J=8.3, 4.1 Hz, 1H), 6.24 (s, 0.2H), 6.15 (s,
1.8H), 2.74 (s, 0.3H), 2.30 (s, 2.7H).
Example 217
1-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)ethanone
O-methyl oxime
[0834] The title compound was prepared as a ca. 9.5:0.5 mixture of
two isomers by using a procedure similar to the one described for
example 216 from example 208 (0.070 g, 0.230 mmol), ethanol (1.5
ml), sodium acetate (0.018 g, 0.230 mmol) and methoxylamine
hydrochloride (0.019 g, 0.230 mmol). Off-white solid (0.020 g,
26%). M.P.: 155-157.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.88 (d, J=2.6 Hz, 1H), 8.61 (d, J=8.8 Hz,
0.05H), 8.55 (d, J=8.8 Hz, 0.95H), 8.36 (d, J=8.4 Hz, 1H), 8.02 (m,
3H), 7.81 (dd, J=8.8, 1.7 Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H),
6.16 (s, 2H), 4.01 (s, 2.85H), 3.79 (s, 0.15H), 2.32 (s, 2.85H),
2.24 (s, 0.15H).
Example 218
N'-(1-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)ethyl-
idene) acetohydrazide
[0835] To a solution of example 208 (0.070 g, 0.230 mmol) in
ethanol (1.3 ml), acetyl hydrazide (0.017 g, 0.230 mmol) was added
refluxed for 4 h. The reaction mixture was concentrated and the
residue was washed with water, ethyl acetate and dried under vacuum
to afford the title compound as a ca. 1:1 mixture of two isomers.
Pale yellow solid (0.035 g, 42%). M.P.: 249-251.degree. C.
.sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400 MHz): 10.79 (s, 0.5 H),
10.76 (s, 0.5H), 8.89 (d, J=2.9 Hz, 1H), 8.66 (d, J=8.7 Hz, 0.5H),
8.55 (d, J=8.8 Hz, 0.5H), 8.37 (m, 1.5H), 8.20 (d, J=9.0 Hz, 0.5H),
8.01 (m, 2H), 7.84 (dt, J=9.0, 1.8 Hz, 1H), 7.54 (dd, J=8.3, 4.2
Hz, 1H), 6.20 (s, 1H), 6.16 (s, 1H), 2.39 (s, 3H), 2.29 (s,
3H).
Example 219
6-((5-(4-Methylpiperazin-1-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methy-
l)quinoline
[0836] The title compound was prepared by following the procedure
described for example 152 using intermediate 14 (0.150 g, 0.507
mmol), N-methyl piperazine (0.076 g, 0.760 mmol), cesium fluoride
(0.154 g, 1.01 mmol) and DMF (4.5 ml). Brown solid (0.023 g, 13%).
M.P.: 131-133.degree. C. .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6,
400 MHz): 8.87 (d, J=2.6 Hz, 1H), 8.35 (d, J=8.1 Hz, 1H), 8.15 (d,
J=9.3 Hz, 1H), 7.99 (d, J=8.6 Hz, 1H), 7.93 (s, 1H), 7.74 (d, J=8.5
Hz, 1H), 7.53 (dd, J=8.0, 4.0 Hz, 1H), 7.05 (d, J=9.4 Hz, 1H), 5.89
(s, 2H), 3.68 (br. s, 4H), 2.42 (br.s, 4H), 2.22 (s, 3H).
Example 220
N'-(1-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)ethyl-
idene)iso-nicotinohydrazide
[0837] To a solution of example 208 (0.065 g, 0.214 mmol) in
ethanol (1.5 ml), isonicotinic hydrazide (0.050 g, 0.428 mmol) was
added refluxed for 12 h. The reaction mixture was concentrated and
the residue was washed with water, ethyl acetate and dried under
vacuum to afford the title compound as a single isomer and as a
pale yellow solid (0.070 g, 77%). M.P.: 239-241.degree. C.
.sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400 MHz): 11.24 (s, 1H),
8.88 (dd, J=4.1, 2.5 Hz, 1H), 8.77 (s, 2H), 8.60 (br s, 1H), 8.37
(d, J=8.0 Hz, 2H), 8.02 (d, J=8.8 Hz, 2H), 7.82 (d, J=7.1 Hz, 2H),
7.71 (m, 1H), 7.54 (dd, J=8.3, 4.2 Hz, 1H), 6.18 (s, 2H), 2.55 (s,
3H).
Example 221
(-)-2-chloro-4-(3-(1-(quinolin-6-yl)ethyl)-3H-[1,2,3]triazolo[4,5-b]pyridi-
n-5-yl)benzamide
[0838] The isomer was obtained through preparative SFC separation
of the racemic compound i.e.
(.+-.)-2-chloro-4-(3-(1-(quinolin-6-yl)ethyl)-3H-[1,2,3]triazolo[4,5-b]py-
ridin-5-yl)benzamide (0.24 g) on a CHIRALPAK IA column
(250.times.30 mm; 50 using ethanol:CO.sub.2 (35:65) as the mobile
phase at a flow rate of 70 g/min Off-white solid (0.095 g). e.e.
96.84%. Rt: 4.27 min (CHIRALPAK IA column (250.times.4.6 mm; 5.mu.)
using ethanol: CO.sub.2 (40:60) as the mobile phase at a flow rate
of 3.0 ml/min) MP: 202-203.degree. C. [a].sub.D.sup.23: -427.30
(c=1, CHCl.sub.3). .sup.1H-NMR (.delta. ppm,
CDCl.sub.3+DMSO-d.sub.6, 400 MHz): 8.88 (d, J=3.2 Hz, 1H), 8.43 (d,
J=8.6 Hz, 1H), 8.15 (d, J=6.1 Hz, 1H), 8.14 (s, 1H), 8.07 (d, J=8.7
Hz, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.98 (s, 1H), 7.91 (m, 2H), 7.79
(d, J=8.6 Hz, 1H), 7.40 (dd, J=8.2, 4.2 Hz, 1H), 6.62 (q, J=6.9 Hz,
1H), 6.54 (s, 1H), 6.12 (s, 1H), 2.34 (d, J=7.1 Hz, 3H).
Example 222
(+)-2-chloro-4-(3-(1-(quinolin-6-yl)ethyl)-3H-[1,2,3]triazolo[4,5-b]pyridi-
n-5-yl)benzamide
[0839] The isomers was obtained through preparative SFC separation
of the racemic compound i.e.
(.+-.)-2-chloro-4-(3-(1-(quinolin-6-yl)ethyl)-3H-[1,2,3]triazolo[4,5-b]py-
ridin-5-yl)benzamide (0.24 g) on a CHIRALPAK IA column
(250.times.30 mm; 5.mu.) using ethanol:CO.sub.2 (35:65) as the
mobile phase at a flow rate of 70 g/min Off-white solid (0.035 g).
e.e. 96.21%. Rt: 4.82 min (CHIRALPAK IA column (250.times.4.6 mm;
5.mu.) using ethanol:CO.sub.2 (40:60) as the mobile phase at a flow
rate of 3.0 ml/min) MP: 200-202.degree. C. .sup.1H-NMR (.delta.
ppm, CDCl.sub.3, 400 MHz): 8.90 (d, J=2.8 Hz, 1H), 8.46 (d, J=8.6
Hz, 1H), 8.16 (m, 2H), 8.10 (d, J=8.7 Hz, 1H), 8.13-7.95 (m, 3H),
7.92 (d, J=7.1 Hz, 1H), 7.81 (d, J=8.7 Hz, 1H), 7.42 (dd, J=8.2,
4.2 Hz, 1H), 6.64 (q, J=7.0 Hz, 1H), 6.43 (s, 1H), 5.87 (s, 1H),
2.36 (d, J=7.2 Hz, 3H).
Example 223
4-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-2-(trifl-
uoromethyl)benzamide
[0840] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.200 g, 0.676
mmol), intermediate 42 (0.277 g, 0.879 mmol), potassium carbonate
(0.311 g, 2.25 mmol), dioxane (4 ml), water (2 ml) and
tetrakis(triphenylphosphine)palladium(0) (0.062 g, 0.054 mmol) in a
microwave oven (100 W, 100.degree. C.) for 45 min Brown solid
(0.035 g, 12%). M.P.: 230-232.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.88 (d, J=2.9 Hz, 1H), 8.73 (d, J=8.7 Hz,
1H), 8.55 (d, J=5.5 Hz, 1H), 8.52 (s, 1H), 8.35 (d, J=8.1 Hz, 1H),
8.28 (d, J=8.8 Hz, 1H), 8.05 (m, 3H), 7.84 (dd, J=10.2, 1.4 Hz,
1H), 7.72 (d, J=8.6 Hz, 1H), 7.70 (s, 1H), 7.54 (dd, J=8.3, 4.3 Hz,
1H), 6.24 (s, 2H).
Example 224
6-((5-(4-carbamoyl-3-chlorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)m-
ethyl)quinoline 1-oxide
[0841] To a solution of example 108 (0.100 g, 0.241 mmol) in
acetone (0.6 ml), oxone (0.74 g, 1.20 mmol) in water (2 ml) was
added and heated under reflux for 20 h. The mixture was diluted
with aqueous 10% sodium bicarbonate solution and extracted with
dichloromethane, the organic layer dried over anhydrous sodium
sulphate and concentrated. The crude product was purified by column
chromatography with methanol:dichloromethane to afford the title
compound (0.030 g, 29%) as a pale brown solid. M.P.:
182-183.degree. C. .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400
MHz): 8.71 (d, J=8.8 Hz, 1H), 8.55 (d, J=6.1 Hz, 1H), 8.52 (d,
J=9.1 Hz, 1H), 8.29 (s, 1H), 8.23 (m, 2H), 8.12 (s, 1H), 7.95-7.83
(m, 3H), 7.67 (s, 1H), 7.61 (d, J=7.9 Hz, 1H), 7.47 (dd, J=8.4, 6.2
Hz, 1H), 6.24 (s, 2H).
Example 225
2-chloro-N-ethyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrid-
in-5-yl)benzamide hydrochloride
[0842] Ether saturated with HCl (1 ml) was added at 0.degree. C. to
a solution of example 119 (0.020 g. 0.045 mmol) in THF (1 ml), and
stirred for 15 min. The precipitate formed was filtered, washed
with ether and dried under vacuum to afford the title compound as
an off-white solid (0.012 g, 56%). M.P.: 151-153.degree. C.
Example 226
6-((5-(4-carbamoyl-3-chlorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)m-
ethyl)quinoline 1-oxide
[0843] To a solution of example 119 (0.060 g, 0.135 mmol) in
dichloromethane (1 ml), 3-chloroperbenzoic acid (0.46 g, 0.270
mmol) was added and stirred at RT for 12 h. The mixture was diluted
with water, extracted with dichloromethane, the organic layer dried
over sodium sulphate and concentrated. The crude product was
purified by column chromatography with methanol: dichloromethane as
the eluent to afford the title compound as a grey solid. (0.016 g,
26%). M.P.: 212-215.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-d.sub.6, 400 MHz): 8.71 (d, J=8.8 Hz, 1H), 8.68 (d, J=9.1 Hz,
1H), 8.56 (m, 2H), 8.30 (d, J=1.5 Hz, 1H), 8.24 (m, 2H), 8.12 (s,
1H), 7.93 (d, J=8.6 Hz, 1H), 7.86 (dd, J=9.1, 1.8 Hz, 1H), 7.57 (d,
J=8.0 Hz, 1H), 7.48 (dd, J=8.4, 6.0 Hz, 1H), 6.20 (s, 2H), 3.28 (m,
2H), 1.14 (t, J=7.3 Hz, 3H).
Example 227
6-((5-(1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quino-
line
[0844] The title compound was prepared by following the procedure
described for example 1 using intermediate 14 (0.100 g, 0.338
mmol), tert-butyl
3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-ca-
rboxylate (0.088 g, 0.422 mmol), potassium carbonate (0.155 g, 1.12
mmol), DMF (2 ml), water (0.5 ml) and tetrakis(triphenylphosphine)
palladium(0) (0.031 g, 0.027 mmol) under microwave irradiation (100
W, 100.degree. C.) for 45 min. Brown solid (0.025 g, 23%). M.P.:
215-218.degree. C. .sup.1H-NMR (.delta. ppm, DMSO-d.sub.6, 400
MHz): 12.94 (s, 1H), 8.88 (dd, J=4.1, 1.5 Hz, 1H), 8.47 (d, J=8.7
Hz, 1H), 8.36 (d, J=7.7 Hz, 1H), 8.13 (s, 1H), 8.00 (d, J=7.9 Hz,
1H), 8.00 (s, 1H), 7.79 (m, 2H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.11
(s, 2H), 2.56 (s, 3H).
Biological Assay
[0845] The pharmacological properties of the compounds of this
invention may be confirmed by a number of pharmacological assays.
The pharmacological assays which can be been carried out with the
compounds according to the invention and/or their pharmaceutically
acceptable salts are exemplified below.
1. MET Kinase Assay Protocol:
[0846] Colorimetric Determination of c-Met Kinase Activity
[0847] The receptor tyrosine kinase c-Met is a heterodimeric
transmembrane glycoprotein involved in several cellular processes
that aid in tumor progression. Phosphorylation of the tyrosine
residues in the c-Met kinase domain is critical for its activity
and the resulting down-stream effects. The colorimetric assay
allows detection of the phosphorylated form of a biotinylated
peptide upon activation of human recombinant Met kinase.
MET Kinase Assay Protocol:
[0848] c-Met Kinase activity shall be determined using an
HTScan.RTM. Met Kinase Assay Kit (Cell Signalling Technology,
Beverly, Mass.) with modifications. All incubations are carried out
at room temperature. Briefly, 12.5 .mu.l of a 4.times. reaction
cocktail (DTT/Kinase buffer containing appropriate quantity of
human Met kinase) is added to each well of a 96-well plate
containing 12.5 .mu.l pre-diluted compound of interest and
incubated for 5 minutes. After the initial incubation, 25
.mu.l/well of 2.times.ATP/biotinylated peptide is added and
incubated for an additional 30 minutes. The reaction is terminated
by the addition of 50 .mu.l/well stop buffer (50 mM EDTA, pH 8.0).
The reaction mixture (25 .mu.l/well) is then transferred to a
streptavidin coated plate (Perkin Elmer, Cat#4009-0010) containing
75 .mu.l dH.sub.2O and incubated for 60 minutes. The plate is
washed with 200 .mu.l/well wash buffer (1.times.PBS, 0.05%
Tween-20). After washing, 100 .mu.l/well phospho-tyrosine mAb
(1:1000 in wash buffer containing 1% BSA) is added and incubated
for 60 minutes. After another round of washes, 100 .mu.l/well
europium labelled anti-mouse IgG (1:500 in wash buffer containing
1% BSA) is added and incubated for an additional 30 minutes.
Following additional washes, 100 .mu.l/well Delfia.RTM. enhancement
solution (Perkin Elmer, Cat#1244-105) is added and incubated for 45
minutes. Florescence is measured on a microplate reader (BMG
Labtech., Germany) at 340 nm (excitation) and 615 nm (emission) for
calculating % inhibition. Data generated can be analyzed further
using Graphpad Prism (Graphpad software, San Diego Calif.) for
determination of IC.sub.50.
[0849] Results:
[0850] The results are as given below in Table 2 as % Inhibition of
c-Met at 1 .mu.M.
TABLE-US-00002 TABLE 2 Cpd. Inhibition IC 50 Ex 2 A +++ Ex 6 A +++
Ex 8 A +++ Ex 9 A +++ Ex 13 A +++ Ex 14 A ++ Ex 15 A +++ Ex 16 A
+++ Ex 21 B + Ex 52 A ++++ Ex 108 A ++++ Ex 119 A ++++ Ex 130 A
++++ Ex 134 A ++++ Ex 137 A ++++ Ex 221 A +++ Ex 222 B + A =
.gtoreq.75 to 100 and B = .gtoreq.50-<75%; ++++ = .ltoreq.50 nm;
+++ = >50 to .ltoreq.100 nM; ++ = >100-.ltoreq.250 and +=
>251-.ltoreq.1000 nM.
[0851] Inhibition of MKN-45 Proliferation:
[0852] Cell proliferation assays were carried out using the high
Met expressing human gastric adenocarcinoma cell line, MKN-45,
according to the following schedule:
[0853] Day 1: Cells were plated in 96-well plates in complete
growth medium.
[0854] Day 2: Compounds at desired concentrations were added.
[0855] Day 5: Cell viability was determined using the
3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT)
dye reduction test.
[0856] Results: The results are as given below as % Inhibition of
MKN-45 proliferation at 1 .mu.M in Table 3, at 0.1 .mu.M in Table
3A and as GI.sub.50 values in Table 4.
TABLE-US-00003 TABLE 3 % inhibition Cpd. @ 1 uM Ex 1 C Ex 18 D Ex
19 D Ex 22 D Ex 23 D Ex 24 D Ex 25 D Ex 47 B Ex 48 A Ex 49 C Ex 51
D Ex 56 D Ex 58 D Ex 59 B Ex 60 D Ex 61 A Ex 62 A Ex 63 B Ex 64 C
Ex 65 D Ex 66 C Ex 67 13.83 Ex 68 D Ex 69 D Ex 70 D Ex 71 C Ex 73 B
Ex 74 B Ex 75 D Ex 76 B Ex 77 B Ex 78 B Ex 79 B Ex 80 C Ex 81 A Ex
84 D Ex 85 A Ex 86 A Ex 87 D Ex 88 D Ex 89 D Ex 90 A Ex 91 B Ex 92
D Ex 93 C Ex 94 D Ex 95 B Ex 96 D Ex 97 C Ex 98 B Ex 99 B Ex 102 A
Ex 104 A Ex 105 D Ex 106 A Ex 110 B Ex 111 A Ex 114 B Ex 115 A Ex
116 A Ex 117 A Ex 118 A Ex 120 C Ex 121 D Ex 122 D Ex 124 B Ex 125
D Ex 127 A Ex 137 B Ex 138 A Ex 139 D Ex 140 A Ex 141 A Ex 147 D Ex
148 D Ex 150 D Ex 151 B Ex 167 C Ex 180 C Ex 181 A Ex 182 C Ex 184
D Ex 185 D Ex 186 D Ex 190 D Ex 191 C Ex 192 D Ex 193 B Ex 194 B Ex
195 B Ex 196 D Ex 212 C Ex 225 B Ex 226 D Ex 227 D D = <25%, C =
.gtoreq.25-<50%, B = .gtoreq.50-<75%, A = .gtoreq.75 to
100%
TABLE-US-00004 TABLE 3A Cpd Inhibition Ex 47 D Ex 48 D Ex 49 D Ex
51 D Ex 52 D Ex 55 D Ex 56 D Ex 58 D Ex 59 D Ex 60 D Ex 61 A Ex 62
A Ex 63 D Ex 64 D Ex 65 D Ex 66 D Ex 67 D Ex 68 D Ex 69 D Ex 70 D
Ex 71 D Ex 72 D Ex 73 A Ex 74 B Ex 75 D Ex 76 A Ex 77 B Ex 78 B Ex
79 D Ex 80 D Ex 81 B Ex 84 D Ex 85 D Ex 86 D Ex 87 A Ex 88 D Ex 89
A Ex 90 B Ex 91 C Ex 92 D Ex 93 C Ex 94 B Ex 95 D Ex 96 D Ex 97 C
Ex 98 C Ex 99 B Ex 102 B Ex 103 D Ex 104 B Ex 105 D Ex 106 D Ex 107
D Ex 108 B Ex 109 A Ex 110 B Ex 111 D Ex 113 A Ex 114 B Ex 115 D Ex
116 D Ex 117 B Ex 118 D Ex 119 A Ex 120 A Ex 121 A Ex 122 D Ex 123
B Ex 124 A Ex 125 D Ex 126 A Ex 127 A Ex 130 A Ex 133 A Ex 134 B Ex
135 D Ex 137 A Ex 138 C Ex 139 B Ex 140 A Ex 141 A Ex 142 A Ex 180
D Ex 181 D Ex 182 D Ex 183 D Ex 184 D Ex 185 D Ex 186 D Ex 187 A Ex
188 A Ex 190 D Ex 191 C Ex 192 D Ex 193 D Ex 194 D Ex 195 C Ex 196
D Ex 197 C Ex 198 D Ex 199 D Ex 200 D Ex 201 D Ex 202 D Ex 203 D Ex
212 A Ex 206 B Ex 207 A Ex 209 A Ex 210 A Ex 214 A Ex 215 D Ex 216
D Ex 217 B Ex 218 D Ex 219 D Ex 220 D Ex 221 B Ex 222 C Ex 223 A Ex
224 C Ex 225 A Ex 226 D Ex 227 C D = <25%, C =
.gtoreq.25-<50%, B = .gtoreq.50-<75%, A = .gtoreq.75 to
100%
TABLE-US-00005 TABLE 4 Cpd GI 50(nM) IC 50 (nM) Ex 2 E -- Ex 4 C --
Ex 6 C -- Ex 8 E -- Ex 9 B B' Ex 14 B B' Ex 15 B B' Ex 16 A A' Ex
21 C -- Ex 22 E -- Ex 26 D -- Ex 27 B -- Ex 28 C -- Ex 30 C -- Ex
31 C -- Ex 32 D -- Ex 33 C -- Ex 34 D -- Ex 35 B -- Ex 36 B -- Ex
37 A -- Ex 38 D -- Ex 39 B -- Ex 40 D -- Ex 41 B -- Ex 43 A B' Ex
44 B -- Ex 45 B -- Ex 46 A B' Ex 52 A A' Ex 55 B -- Ex 61 A -- Ex
62 A -- Ex 108 A A' Ex 119 A A' Ex 130 A A' Ex 133 A Ex 134 A A' Ex
137 A A' Ex 142 B -- Ex 143 B -- Ex 144 B -- Ex 146 B B' Ex 152 C
-- Ex 157 D -- Ex 164 B B' Ex 168 C -- Ex 169 D -- Ex 170 D -- Ex
171 C -- Ex 172 D -- Ex 173 D -- Ex 175 C -- Ex 176 D -- Ex 177 D
-- Ex 179 C -- Ex 187 A -- Ex 188 B -- Ex 207 A -- Ex 209 A -- Ex
210 A -- Ex 211 C -- Ex 214 A -- Ex 221 A -- Ex 222 C -- -- A = A'
= .ltoreq.50; B = B' = >50 to .ltoreq.150; C =
>150-.ltoreq.500; D = >500-.ltoreq.1000 & E = >1000 in
nM
[0857] Inhibition of c-Met Kinase Phosphorylation in MKN-45
Cells:
[0858] MKN45 cells are a prototype of "c-Met addicted" cells having
constitutively activated c-Met kinase similar to that observed in
sub-sects of gastric or hepatocellular cancer patients with
dysregulated c-Met kinase activity Inhibition of Met
phosphorylation was determined using a cell based ELISA assay
according to the following schedule:
[0859] Day 1: MKN-45 cells were plated in 96-well plates in
complete growth medium.
[0860] Day 2Inhibitors at the desired concentration were added to
the plates and incubated for 1 h and lysed subsequently.
[0861] Lysates were transferred to NUNC Maxisorp plates coated with
anti-cMet receptor antibody. Phopho-tyrosine mAb and HRP-lined
anti-mouse IgG were used as primary and secondary antibodies
respectively. Optical density was measured on a microplate reader
(BMG Labtech., Germany) at 450 nM Inhibition of c-Met
phosphorylation in this cell line indicates a therapeutic potential
for test compounds in patients diagnosed with cancers caused by
aberrant c-Met kinase signalling.
[0862] Results:
[0863] The results are provided above in Table 4 as IC50
values.
[0864] Inhibition of c-Met Kinase Phosphorylation in NCI-11441
Cells:
[0865] Inhibition of Met phosphorylation was determined using a
cell based ELISA assay according to the following schedule:
[0866] Day 1: NCI-H441 cells were plated in 96-well plates in
complete growth medium.
[0867] Day 2Inhibitors at the desired concentration were added to
the plates, incubated for 1 h and lysed subsequently. Lysates were
transferred to NUNC Maxisorp plates coated with anti-cMet receptor
antibody. Phopho-tyrosine mAb and HRP-lined anti-mouse IgG were
used as primary and secondary antibodies respectively. Optical
density was measured on a microplate reader (BMG Labtech., Germany)
at 450 nM. The compounds potently inhibited c-Met kinase
phosphorylation in NCI-H441, a non-small cell lung cancer derived
cell line indicating a therapeutic potential in lung cancer
patients with mutant kras.
[0868] Results:
[0869] The results are given below in Table 5 as IC50 values.
TABLE-US-00006 TABLE 5 Cpd IC 50 Ex 146 +++ Ex 14 ++ Ex 15 ++ Ex 52
+ Ex 108 + Ex 119 + Ex 139 + Ex 134 + Ex 137 + + = .ltoreq.10; ++'
= >10 to .ltoreq.50 +++ = >50-.ltoreq.100 in nM
[0870] Inhibition of Akt Phosphorylation in MKN-45 or NCI-11441
Cells:
[0871] Akt is a serine-threonine kinase and a downstream marker
regulated by c-Met kinase via the PI3K pathway. Once
phosphorylated, Akt regulates several end processes including cell
survival and growth. Cells were treated with 0-1000 nM of test
compounds, lysed, and the proteins separated on a 10% SDS-PAGE.
Following separation, proteins were transferred onto a
nitrocellulose membrane and detected by chemiluminescence after
incubation with pAkt S473 mAb (primary) and rabbit anti-mouse Ab
(secondary). Intensity of the bands was determined using ImageJ
1.42q (NIH, USA) and normalized to Actin (loading control).
Results: The results are provided below as IC50 values in Table
6.
TABLE-US-00007 TABLE 6 AKT PHOSPHORYLATION MKN-45 NCI-H441 Cpd
(IC50-nM) (IC50-nM) Ex 146 -- B Ex 15 D A Ex 52 C A Ex 108 A A Ex
119 A A Ex 130 C B Ex 134 A A A = .ltoreq.25; B = >25 to
.ltoreq.50, C = >50-.ltoreq.100, D = >100-.ltoreq.200 in
nM,
[0872] 6. Induction of Apoptosis in MKN-45 Cells:
[0873] Induction of Caspase 3 was measured fluorimetrically. Cells
were incubated with desired concentrations of the compound for 24
h. After incubation, cells were harvested and counted. An equal
number of viable cells per well (0.3.times.10.sup.6 cells) were
used for determination of caspase-3 activity. Increase in apoptosis
manifested by an elevation in caspase-3 levels was determined using
a Caspase-3 kit from Millipore. Data are expressed as a percent of
the maximum response (100%). Compounds of the invention
dose-dependently induced apoptosis in MKN-45 cells manifested by an
increase in caspase-3 activity.
[0874] Results:
[0875] The results are provided below as percentage induction @ 3
.mu.M in Table 7.
TABLE-US-00008 TABLE 7 Apoptosis in Cpd MKN-45 cells) Ex 15 A Ex 52
A Ex 108 A Ex 119 A Ex 130 B Ex 134 A B = .ltoreq.50, A = >50 to
100%
[0876] 7. Inhibition of HGF-Induced Met Phosphorylation in
MDA-MB-231 Cells:
[0877] MDA-MB-231 is a breast cancer cell line having a high level
of c-Met expression. Activation of Met kinase in these cells occurs
only after the addition of its natural ligand, Hepatocyte Growth
Factor (HGF). Upon binding to the extracellular domain of the
enzyme, it triggers phosphorylation of tyrosine residues and
regulates several downstream events such as cell proliferation.
Cell proliferation assays were carried out using the high Met
expressing cell line (MDA-MB-231) according to the following
schedule:
[0878] Day 1: Cells were plated in 96-well plates in complete
growth medium.
[0879] Day 2: Media was replaced with starvation medium containing
0.04% BSA.
[0880] Day 3: Inhibitors at the desired concentrations and HGF (50
ng/ml) were added.
[0881] Day 5: Cell viability was determined using the
3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT)
dye reduction test.
[0882] The compounds of the present invention tested potently
inhibited HGF-induced Met phosphorylation in MDA-MB-231 cells
thereby implicating their role in the modulation of the HGF/Met
axis in breast cancer.
[0883] Results:
[0884] The results are provided below in Table 8 as IC50
values.
TABLE-US-00009 TABLE 8 HGF stimulated Met Cpd phosphorylation Ex 15
+ Ex 108 + Ex 119 + Ex 130 + Ex 134 ++ + = .ltoreq.10; ++ = >10
to .ltoreq.50 nM
[0885] 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 and the claims.
[0886] 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.
* * * * *