U.S. patent application number 15/073324 was filed with the patent office on 2018-04-12 for process for preparation of optically pure and optionally substituted 2-(1-hydroxy-alkyl)-chromen-4-one derivatives and their use in preparing pharmaceuticals.
The applicant listed for this patent is Rhizen Pharmaceuticals SA. Invention is credited to Swaroop K. VAKKALANKA, Jayaraman VENKAT RAMAN.
Application Number | 20180098994 15/073324 |
Document ID | / |
Family ID | 59855128 |
Filed Date | 2018-04-12 |
United States Patent
Application |
20180098994 |
Kind Code |
A9 |
VENKAT RAMAN; Jayaraman ; et
al. |
April 12, 2018 |
PROCESS FOR PREPARATION OF OPTICALLY PURE AND OPTIONALLY
SUBSTITUTED 2-(1-HYDROXY-ALKYL)-CHROMEN-4-ONE DERIVATIVES AND THEIR
USE IN PREPARING PHARMACEUTICALS
Abstract
The present invention relates to compounds useful as
pharmaceutical intermediates, to processes for preparing the
intermediates, to intermediates used in the processes, and to the
use of the intermediates in the preparation of pharmaceuticals. In
particular, the present invention concerns enantiomerically pure
optionally substituted 2-(1-hydroxy-alkyl)-chromen-4-one
derivatives represented by formula (IA) and (IB), processes for
preparing the alcohol derivatives and their use in preparing
pharmaceuticals.
Inventors: |
VENKAT RAMAN; Jayaraman;
(Gujarat, IN) ; VAKKALANKA; Swaroop K.; (La Chaux
de Fonds, CH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Rhizen Pharmaceuticals SA |
La Chaux-de-Fonds |
|
CH |
|
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20170266196 A1 |
September 21, 2017 |
|
|
Family ID: |
59855128 |
Appl. No.: |
15/073324 |
Filed: |
March 17, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14398902 |
Nov 4, 2014 |
9309216 |
|
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PCT/IB2013/053544 |
May 3, 2013 |
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15073324 |
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61671956 |
Jul 16, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 311/36 20130101;
A61K 31/5377 20130101; C07D 311/58 20130101; C07B 55/00 20130101;
C07D 473/34 20130101; C07D 487/04 20130101; A61K 31/352 20130101;
C07B 2200/07 20130101; C07D 487/14 20130101; A61K 31/52
20130101 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; C07B 55/00 20060101 C07B055/00; C07D 311/58 20060101
C07D311/58; A61K 31/352 20060101 A61K031/352; C07D 487/14 20060101
C07D487/14; C07D 473/34 20060101 C07D473/34; A61K 31/52 20060101
A61K031/52 |
Foreign Application Data
Date |
Code |
Application Number |
May 4, 2012 |
IN |
1737/CHE/2012 |
Claims
1-14. (canceled)
15. A process for preparing a PI3K inhibitor of formula (I)
##STR00097## or a tautomer thereof, N-oxide thereof,
pharmaceutically acceptable ester thereof, prodrug thereof, or
pharmaceutically acceptable salt thereof, wherein each occurrence
of R is independently selected from hydrogen, hydroxy, halogen,
carboxyl, cyano, nitro, substituted or unsubstituted alkyl,
substituted or unsubstituted alkoxy, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
cycloalkenyl, substituted or unsubstituted cycloalkylalkyl,
substituted or unsubstituted cycloalkenylalkyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted
heterocyclylalkyl, substituted or unsubstituted aryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted heteroarylalkyl,
--COOR.sup.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.xR.sup.y, --N(R.sup.x)SOR.sup.x,
--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.xR.sup.y,
--SONR.sup.xR.sup.y, --SO.sub.2NR.sup.xR.sup.y, --OR.sup.x,
--OR.sup.xC(O)NR.sup.xR.sup.y, --OR.sup.xC(O)OR.sup.x,
--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.xR.sup.y,
--R.sup.xC(O)R.sup.y, --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 is independently
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkoxy, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
aryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
heteroarylalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkylalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
heterocyclic ring, substituted or unsubstituted heterocyclylalkyl
ring, or substituted or unsubstituted amino, or (i) any two of
R.sup.x and R.sup.y, when bound to a common atom, are joined to
form a substituted or unsubstituted, saturated or unsaturated 3-14
membered ring, which may optionally include heteroatoms which may
be the same or different and are selected from O, NR.sup.z or S, or
(ii) any two of R.sup.x and R.sup.y, when bound to a common atom,
are joined to form an oxo (.dbd.O), thio (.dbd.S) or imino
(.dbd.NR.sup.f) (wherein R.sup.f is hydrogen or substituted or
unsubstituted alkyl); R.sup.1 is substituted or unsubstituted
C.sub.1-6 alkyl; Cy.sup.1 is a monocyclic or bicyclic group
selected from substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclic group, substituted or unsubstituted
aryl and substituted or unsubstituted heteroaryl; n is an integer
selected from 0, 1, 2, 3 or 4; Cy.sup.2 is selected from a
substituted or unsubstituted heterocyclic group, substituted or
unsubstituted aryl and substituted or unsubstituted heteroaryl;
L.sub.1 is absent, --(CR.sup.aR.sup.b).sub.q--, --O--,
--S(.dbd.O).sub.q--, --NR.sup.a-- or --C(.dbd.Y)--; each occurrence
of R.sup.a and R.sup.b may be the same or different and are
independently selected from hydrogen, halogen, hydroxy, cyano,
substituted or unsubstituted (C.sub.1-6)alkyl, --NR.sup.cR.sup.d
(wherein R.sup.c and R.sup.d are independently hydrogen, halogen,
hydroxy, cyano, substituted or unsubstituted (C.sub.1-6)alkyl, or
(C.sub.1-6)alkoxy) and --OR.sup.c (wherein R.sup.c is substituted
or unsubstituted (C.sub.1-6)alkyl) or when R.sup.a and R.sup.b are
directly bound to a common atom, they may be joined to form an oxo
group (.dbd.O) or form a substituted or unsubstituted, saturated or
unsaturated 3-10 member ring (including the common atom to which
R.sup.a and R.sup.b are directly bound), which may optionally
include one or more heteroatoms which may be the same or different
and are selected from O, NR.sup.d (wherein R.sup.d is hydrogen or
substituted or unsubstituted (C.sub.1-6)alkyl) or S; Y is selected
from O, S, and NR.sup.a; and q is 0, 1 or 2, the process comprising
(a) treating the compound of formula (IA) with Cy.sup.2-H to obtain
the compound of formula (I) or a tautomer thereof; and (b)
optionally converting the compound of formula (I) to an N-oxide
thereof, a pharmaceutically acceptable ester thereof, a prodrug
thereof, or a pharmaceutically acceptable salt thereof.
16. A process for preparing a PI3K inhibitor of formula (I)
##STR00098## or a tautomer thereof, N-oxide thereof,
pharmaceutically acceptable ester thereof, prodrug thereof, or
pharmaceutically acceptable salt thereof, wherein each occurrence
of R is independently selected from hydrogen, hydroxy, halogen,
carboxyl, cyano, nitro, substituted or unsubstituted alkyl,
substituted or unsubstituted alkoxy, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
cycloalkenyl, substituted or unsubstituted cycloalkylalkyl,
substituted or unsubstituted cycloalkenylalkyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted
heterocyclylalkyl, substituted or unsubstituted aryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted heteroarylalkyl,
--COOR.sup.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.xR.sup.y, --N(R.sup.x)SOR.sup.x,
--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.xR.sup.y,
--SONR.sup.xR.sup.y, --SO.sub.2NR.sup.xR.sup.y, --OR.sup.x,
--OR.sup.xC(O)NR.sup.xR.sup.y, --OR.sup.xC(O)OR.sup.x,
--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.xR.sup.y,
--R.sup.xC(O)R.sup.y, --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 is independently
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkoxy, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
aryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
heteroarylalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkylalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
heterocyclic ring, substituted or unsubstituted heterocyclylalkyl
ring, or substituted or unsubstituted amino, or (i) any two of
R.sup.x and R.sup.y, when bound to a common atom, are joined to
form a substituted or unsubstituted, saturated or unsaturated 3-14
membered ring, which may optionally include heteroatoms which may
be the same or different and are selected from O, NR.sup.z or S, or
(ii) any two of R.sup.x and R.sup.y, when bound to a common atom,
are joined to form an oxo (.dbd.O), thio (.dbd.S) or imino
(.dbd.NR.sup.f) (wherein R.sup.f is hydrogen or substituted or
unsubstituted alkyl); R.sup.1 is substituted or unsubstituted
C.sub.1-6 alkyl; Cy.sup.1 is a monocyclic or bicyclic group
selected from substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclic group, substituted or unsubstituted
aryl and substituted or unsubstituted heteroaryl; n is an integer
selected from 0, 1, 2, 3 or 4; Cy.sup.2 is selected from a
substituted or unsubstituted heterocyclic group, substituted or
unsubstituted aryl and substituted or unsubstituted heteroaryl;
L.sub.1 is absent, --(CR.sup.aR.sup.b).sub.q--, --O--,
--S(.dbd.O).sub.q--, --NR.sup.a-- or --C(.dbd.Y)--; each occurrence
of R.sup.a and R.sup.b may be the same or different and are
independently selected from hydrogen, halogen, hydroxy, cyano,
substituted or unsubstituted (C.sub.1-6)alkyl, --NR.sup.cR.sup.d
(wherein R.sup.c and R.sup.d are independently hydrogen, halogen,
hydroxy, cyano, substituted or unsubstituted (C.sub.1-6)alkyl, or
(C.sub.1-6)alkoxy) and --OR.sup.c (wherein R.sup.c is substituted
or unsubstituted (C.sub.1-6)alkyl) or when R.sup.a and R.sup.b are
directly bound to a common atom, they may be joined to form an oxo
group (.dbd.O) or form a substituted or unsubstituted, saturated or
unsaturated 3-10 member ring (including the common atom to which
R.sup.a and R.sup.b are directly bound), which may optionally
include one or more heteroatoms which may be the same or different
and are selected from O, NR.sup.d (wherein R.sup.d is hydrogen or
substituted or unsubstituted (C.sub.1-6)alkyl) or S; Y is selected
from O, S, and NR.sup.a; and q is 0, 1 or 2, the process comprising
(a) reacting a compound of formula (IA) ##STR00099## with a
phosphorus halide or mesyl halide in the presence of a base to
obtain a compound of formula (8a) ##STR00100## wherein X.sup.1 is
halogen or --O-Mesyl; (b) reacting the compound of formula (8a)
with Cy.sup.2-H in the presence of a base to give the desired
compound of formula (I) or a tautomer thereof; and (c) optionally
converting the compound of formula (I) to an N-oxide thereof, a
pharmaceutically acceptable ester thereof, a prodrug thereof, or a
pharmaceutically acceptable salt thereof.
17. (canceled)
18. A process for preparing a PI3K inhibitor of formula (II)
##STR00101## or a tautomer thereof, N-oxide thereof,
pharmaceutically acceptable ester thereof, prodrug thereof, or
pharmaceutically acceptable salt thereof, wherein each occurrence
of R is independently selected from hydrogen, hydroxy, halogen,
carboxyl, cyano, nitro, substituted or unsubstituted alkyl,
substituted or unsubstituted alkoxy, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
cycloalkenyl, substituted or unsubstituted cycloalkylalkyl,
substituted or unsubstituted cycloalkenylalkyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted
heterocyclylalkyl, substituted or unsubstituted aryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted heteroarylalkyl,
--COOR.sup.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.xR.sup.y, --N(R.sup.x)SOR.sup.x,
--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.xR.sup.y,
--SONR.sup.xR.sup.y, --SO.sub.2NR.sup.xR.sup.y, --OR.sup.x,
--OR.sup.xC(O)NR.sup.xR.sup.y, --OR.sup.xC(O)OR.sup.x,
--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.xR.sup.y,
--R.sup.xC(O)R.sup.y, --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 is independently
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkoxy, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
aryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
heteroarylalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkylalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
heterocyclic ring, substituted or unsubstituted heterocyclylalkyl
ring, or substituted or unsubstituted amino, or (i) any two of
R.sup.x and R.sup.y, when bound to a common atom, are joined to
form a substituted or unsubstituted, saturated or unsaturated 3-14
membered ring, which may optionally include heteroatoms which may
be the same or different and are selected from O, NR.sup.z or S, or
(ii) any two of R.sup.x and R.sup.y, when bound to a common atom,
are joined to form an oxo (.dbd.O), thio (.dbd.S) or imino
(.dbd.NR.sup.f) (wherein R.sup.f is hydrogen or substituted or
unsubstituted alkyl); R.sup.1 is substituted or unsubstituted
C.sub.1-6 alkyl; Cy.sup.1 is a monocyclic or bicyclic group
selected from substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclic group, substituted or unsubstituted
aryl and substituted or unsubstituted heteroaryl; n is an integer
selected from 0, 1, 2, 3 or 4; Cy.sup.2 is selected from a
substituted or unsubstituted heterocyclic group, substituted or
unsubstituted aryl and substituted or unsubstituted heteroaryl; and
L.sub.1 is NH; the process comprising (a) treating a compound of
formula (IA) ##STR00102## with a phosphorus halide or mesyl halide
in the presence of a base to give a compound of formula (8a)
##STR00103## wherein X.sup.1 is halogen or --O-Mesyl; (b)
converting the compound of formula (8a) to obtain a compound of
formula (9a) ##STR00104## (c) converting the compound of formula
(9a) to obtain a compound of formula (10a) ##STR00105## (d)
coupling the compound of formula (10a) with a compound of formula
Cy.sup.2-Lg, wherein Lg is a leaving group, in the presence of a
base to give the desired compound of formula (II) or a tautomer
thereof; and (e) optionally converting the compound of formula (II)
to an N-oxide thereof, a pharmaceutically acceptable ester thereof,
a prodrug thereof, or a pharmaceutically acceptable salt
thereof.
19-20. (canceled)
21. A process for preparing a PI3K inhibitor of formula (III)
##STR00106## or a tautomer thereof, N-oxide thereof,
pharmaceutically acceptable ester thereof, prodrug thereof, or
pharmaceutically acceptable salt thereof, wherein each occurrence
of R is independently selected from hydrogen, hydroxy, halogen,
carboxyl, cyano, nitro, substituted or unsubstituted alkyl,
substituted or unsubstituted alkoxy, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
cycloalkenyl, substituted or unsubstituted cycloalkylalkyl,
substituted or unsubstituted cycloalkenylalkyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted
heterocyclylalkyl, substituted or unsubstituted aryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted heteroarylalkyl,
--COOR.sup.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.xR.sup.y, --N(R.sup.x)SOR.sup.x,
--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.xR.sup.y,
--SONR.sup.xR.sup.y, --SO.sub.2NR.sup.xR.sup.y, --OR.sup.x,
--OR.sup.xC(O)NR.sup.xR.sup.y, --OR.sup.xC(O)OR.sup.x,
--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.xR.sup.y,
--R.sup.xC(O)R.sup.y, --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 is independently
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkoxy, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
aryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
heteroarylalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkylalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
heterocyclic ring, substituted or unsubstituted heterocyclylalkyl
ring, or substituted or unsubstituted amino, or (i) any two of
R.sup.x and R.sup.y, when bound to a common atom, are joined to
form a substituted or unsubstituted, saturated or unsaturated 3-14
membered ring, which may optionally include heteroatoms which may
be the same or different and are selected from O, NR.sup.z or S, or
(ii) any two of R.sup.x and R.sup.y, when bound to a common atom,
are joined to form an oxo (.dbd.O), thio (.dbd.S) or imino
(.dbd.NR.sup.f) (wherein R.sup.f is hydrogen or substituted or
unsubstituted alkyl); R.sup.1 is substituted or unsubstituted
C.sub.1-6 alkyl; Cy.sup.1 is a monocyclic or bicyclic group
selected from substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclic group, substituted or unsubstituted
aryl and substituted or unsubstituted heteroaryl; n is an integer
selected from 0, 1, 2, 3 or 4; Cy.sup.2 is selected from a
substituted or unsubstituted heterocyclic group, substituted or
unsubstituted aryl and substituted or unsubstituted heteroaryl;
L.sub.1 is absent, --(CR.sup.aR.sup.b).sub.q--, --O--,
--S(.dbd.O).sub.q--, --NR.sup.a-- or --C(.dbd.Y)--; each occurrence
of R.sup.a and R.sup.b may be the same or different and are
independently selected from hydrogen, halogen, hydroxy, cyano,
substituted or unsubstituted (C.sub.1-6)alkyl, --NR.sup.cR.sup.d
(wherein R.sup.c and R.sup.d are independently hydrogen, halogen,
hydroxy, cyano, substituted or unsubstituted (C.sub.1-6)alkyl, or
(C.sub.1-6)alkoxy) and --OR.sup.c (wherein W is substituted or
unsubstituted (C.sub.1-6)alkyl) or when R.sup.a and R.sup.b are
directly bound to a common atom, they may be joined to form an oxo
group (.dbd.O) or form a substituted or unsubstituted, saturated or
unsaturated 3-10 member ring (including the common atom to which
R.sup.a and R.sup.b are directly bound), which may optionally
include one or more heteroatoms which may be the same or different
and are selected from O, NR.sup.d (wherein R.sup.d is hydrogen or
substituted or unsubstituted (C.sub.1-6)alkyl) or S; Y is selected
from O, S, and NR.sup.a; and q is 0, 1 or 2, the process comprising
(a) reacting a compound of formula (IB) ##STR00107## with
Cy.sup.2-H to obtain the compound of formula (III) or a tautomer
thereof; and (b) optionally converting the compound of formula
(III) to an N-oxide thereof, a pharmaceutically acceptable ester
thereof, a prodrug thereof, or a pharmaceutically acceptable salt
thereof.
22. A process for preparing a PI3K inhibitor of formula (III)
##STR00108## or a tautomer thereof, N-oxide thereof,
pharmaceutically acceptable ester thereof, prodrug thereof, or
pharmaceutically acceptable salt thereof, wherein each occurrence
of R is independently selected from hydrogen, hydroxy, halogen,
carboxyl, cyano, nitro, substituted or unsubstituted alkyl,
substituted or unsubstituted alkoxy, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
cycloalkenyl, substituted or unsubstituted cycloalkylalkyl,
substituted or unsubstituted cycloalkenylalkyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted
heterocyclylalkyl, substituted or unsubstituted aryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted heteroarylalkyl,
--COOR.sup.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.xR.sup.y, --N(R.sup.x)SOR.sup.x,
--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.xR.sup.y,
--SONR.sup.xR.sup.y, --SO.sub.2NR.sup.xR.sup.y, --OR.sup.x,
--OR.sup.xC(O)NR.sup.xR.sup.y, --OR.sup.xC(O)OR.sup.x,
--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.xR.sup.y,
--R.sup.xC(O)R.sup.y, --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 is independently
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkoxy, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
aryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
heteroarylalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkylalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
heterocyclic ring, substituted or unsubstituted heterocyclylalkyl
ring, or substituted or unsubstituted amino, or (i) any two of
R.sup.x and R.sup.y, when bound to a common atom, are joined to
form a substituted or unsubstituted, saturated or unsaturated 3-14
membered ring, which may optionally include heteroatoms which may
be the same or different and are selected from O, NR.sup.z or S, or
(ii) any two of R.sup.x and R.sup.y, when bound to a common atom,
are joined to form an oxo (.dbd.O), thio (.dbd.S) or imino
(.dbd.NR.sup.f) (wherein R.sup.f is hydrogen or substituted or
unsubstituted alkyl); R.sup.1 is substituted or unsubstituted
C.sub.1-6 alkyl; Cy.sup.1 is a monocyclic or bicyclic group
selected from substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclic group, substituted or unsubstituted
aryl and substituted or unsubstituted heteroaryl; n is an integer
selected from 0, 1, 2, 3 or 4; Cy.sup.2 is selected from a
substituted or unsubstituted heterocyclic group, substituted or
unsubstituted aryl and substituted or unsubstituted heteroaryl;
L.sub.1 is absent, --(CR.sup.aR.sup.b).sub.q--, --O--,
--S(.dbd.O).sub.q--, --NR.sup.a-- or --C(.dbd.Y)--; each occurrence
of R.sup.a and R.sup.b may be the same or different and are
independently selected from hydrogen, halogen, hydroxy, cyano,
substituted or unsubstituted (C.sub.1-6)alkyl, --NR.sup.cR.sup.d
(wherein R.sup.c and R.sup.d are independently hydrogen, halogen,
hydroxy, cyano, substituted or unsubstituted (C.sub.1-6)alkyl, or
(C.sub.1-6)alkoxy) and --OR.sup.c (wherein R.sup.c is substituted
or unsubstituted (C.sub.1-6)alkyl) or when R.sup.a and R.sup.b are
directly bound to a common atom, they may be joined to form an oxo
group (.dbd.O) or form a substituted or unsubstituted, saturated or
unsaturated 3-10 member ring (including the common atom to which
R.sup.a and R.sup.b are directly bound), which may optionally
include one or more heteroatoms which may be the same or different
and are selected from O, NR.sup.d (wherein R.sup.d is hydrogen or
substituted or unsubstituted (C.sub.1-6)alkyl) or S; Y is selected
from O, S, and NR.sup.a; and q is 0, 1 or 2, the process comprising
(a) treating a compound of formula (IB) ##STR00109## with a
phosphorus halide or mesyl halide in the presence of a base to
obtain a compound of formula (8b) ##STR00110## wherein X.sup.1 is
halogen or --O-Mesyl; (b) reacting the compound of formula (8b)
with Cy.sup.2-H in the presence of a base to obtain the compound of
formula (III) or a tautomer thereof; and (h) optionally converting
the compound of formula (III) to N-oxide thereof, a
pharmaceutically acceptable ester thereof, a prodrug thereof or a
pharmaceutically acceptable salt thereof.
23. (canceled)
24. A process for preparing a PI3K inhibitor of formula (IV)
##STR00111## or a tautomer thereof, N-oxide thereof,
pharmaceutically acceptable ester thereof, prodrug thereof, or
pharmaceutically acceptable salt thereof, wherein each occurrence
of R is independently selected from hydrogen, hydroxy, halogen,
carboxyl, cyano, nitro, substituted or unsubstituted alkyl,
substituted or unsubstituted alkoxy, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
cycloalkenyl, substituted or unsubstituted cycloalkylalkyl,
substituted or unsubstituted cycloalkenylalkyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted
heterocyclylalkyl, substituted or unsubstituted aryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted heteroarylalkyl,
--COOR.sup.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.xR.sup.y, --N(R.sup.x)SOR.sup.x,
--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.xR.sup.y,
--SONR.sup.xR.sup.y, --SO.sub.2NR.sup.xR.sup.y, --OR.sup.x,
--OR.sup.xC(O)NR.sup.xR.sup.y, --OR.sup.xC(O)OR.sup.x,
--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.xR.sup.y,
--R.sup.xC(O)R.sup.y, --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 is independently
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkoxy, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
aryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
heteroarylalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkylalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
heterocyclic ring, substituted or unsubstituted heterocyclylalkyl
ring, or substituted or unsubstituted amino, or (i) any two of
R.sup.x and R.sup.y, when bound to a common atom, are joined to
form a substituted or unsubstituted, saturated or unsaturated 3-14
membered ring, which may optionally include heteroatoms which may
be the same or different and are selected from O, NR.sup.z or S, or
(ii) any two of R.sup.x and R.sup.y, when bound to a common atom,
are joined to form an oxo (.dbd.O), thio (.dbd.S) or imino
(.dbd.NR.sup.f) (wherein R.sup.f is hydrogen or substituted or
unsubstituted alkyl); R.sup.1 is substituted or unsubstituted
C.sub.1-6 alkyl; Cy.sup.1 is a monocyclic or bicyclic group
selected from substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclic group, substituted or unsubstituted
aryl and substituted or unsubstituted heteroaryl; n is an integer
selected from 0, 1, 2, 3 or 4; Cy.sup.2 is selected from a
substituted or unsubstituted heterocyclic group, substituted or
unsubstituted aryl and substituted or unsubstituted heteroaryl; and
Li is NH; the process comprising (a) reacting a compound of formula
(IB) ##STR00112## with a phosphorus halide or mesyl halide in the
presence of a base to obtain a compound of formula (8b)
##STR00113## wherein X.sup.1 is halogen or --O-Mesyl; (b)
converting the compound of formula (8b) to obtain a compound of
formula (9b) ##STR00114## (c) converting the compound of formula
(9b) to obtain a compound of formula (10b) ##STR00115## (d)
coupling the compound of formula (10b) with a compound of formula
Cy.sup.2-Lg, wherein Lg is a leaving group, in the presence of a
base to obtain the compound of formula (IV) or a tautomer thereof;
and (e) optionally converting the compound of formula (IV) to an
N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug
thereof, or pharmaceutically acceptable salt thereof.
25. A process for inverting a compound of formula (IA) to obtain a
compound of formula (IB) ##STR00116## the process comprising (a)
reacting the compound of formula (IA) with R'-COOH (wherein R' is
selected from substituted or unsubstituted alkyl and substituted or
unsubstituted aryl) to obtain a compound of formula IA-2
##STR00117## and (b) converting the compound of formula (IA-2) to
obtain a compound of formula (IB), wherein each occurrence of R is
independently selected from hydrogen, hydroxy, halogen, carboxyl,
cyano, nitro, substituted or unsubstituted alkyl, substituted or
unsubstituted alkoxy, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted
or unsubstituted cycloalkylalkyl, substituted or unsubstituted
cycloalkenylalkyl, substituted or unsubstituted heterocyclyl,
substituted or unsubstituted heterocyclylalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted arylalkyl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted heteroarylalkyl, --COOR.sup.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.xR.sup.y,
--N(R.sup.x)SOR.sup.x, --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.xR.sup.y,
--SONR.sup.xR.sup.y, --SO.sub.2NR.sup.xR.sup.y, --OR.sup.x,
--OR.sup.xC(O)NR.sup.xR.sup.y, --OR.sup.xC(O)OR.sup.x,
--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.xR.sup.y,
--R.sup.xC(O)R.sup.y, --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 is independently
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkoxy, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
aryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
heteroarylalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkylalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
heterocyclic ring, substituted or unsubstituted heterocyclylalkyl
ring, or substituted or unsubstituted amino, or (i) any two of
R.sup.x and R.sup.y, when bound to a common atom, are joined to
form a substituted or unsubstituted, saturated or unsaturated 3-14
membered ring, which may optionally include heteroatoms which may
be the same or different and are selected from O, NR.sup.z or S, or
(ii) any two of R.sup.x and R.sup.y, when bound to a common atom,
are joined to form an oxo (.dbd.O), thio (.dbd.S) or imino
(.dbd.NR.sup.f) (wherein R.sup.f is hydrogen or substituted or
unsubstituted alkyl); R.sup.1 is substituted or unsubstituted
C.sub.1-6 alkyl; Cy.sup.1 is a monocyclic or bicyclic group
selected from substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclic group, substituted or unsubstituted
aryl and substituted or unsubstituted heteroaryl; and n is an
integer selected from 0, 1, 2, 3 or 4.
26. A process for inverting a compound of formula (IB) to obtain a
compound of formula (IA) ##STR00118## the process comprising (a)
reacting the compound of formula (IB) with R'-COOH (wherein R' is
selected from substituted or unsubstituted alkyl and substituted or
unsubstituted aryl) to obtain a compound of formula IB-2
##STR00119## and (b) converting the compound of formula (IB-2) to
obtain a compound of formula (IA), wherein each occurrence of R is
independently selected from hydrogen, hydroxy, halogen, carboxyl,
cyano, nitro, substituted or unsubstituted alkyl, substituted or
unsubstituted alkoxy, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted
or unsubstituted cycloalkylalkyl, substituted or unsubstituted
cycloalkenylalkyl, substituted or unsubstituted heterocyclyl,
substituted or unsubstituted heterocyclylalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted arylalkyl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted heteroarylalkyl, --COOR.sup.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.xR.sup.y,
--N(R.sup.x)SOR.sup.x, --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.xR.sup.y,
--SONR.sup.xR.sup.y, --SO.sub.2NR.sup.xR.sup.y, --OR.sup.x,
--OR.sup.xC(O)NR.sup.xR.sup.y, --OR.sup.xC(O)OR.sup.x,
--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.xR.sup.y,
--R.sup.xC(O)R.sup.y, --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 is independently
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkoxy, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
aryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
heteroarylalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkylalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
heterocyclic ring, substituted or unsubstituted heterocyclylalkyl
ring, or substituted or unsubstituted amino, or (i) any two of
R.sup.x and R.sup.y, when bound to a common atom, are joined to
form a substituted or unsubstituted, saturated or unsaturated 3-14
membered ring, which may optionally include heteroatoms which may
be the same or different and are selected from O, NR.sup.z or S, or
(ii) any two of R.sup.x and R.sup.y, when bound to a common atom,
are joined to form an oxo (.dbd.O), thio (.dbd.S) or imino
(.dbd.NR.sup.f) (wherein R.sup.f is hydrogen or substituted or
unsubstituted alkyl); R.sup.1 is substituted or unsubstituted
C.sub.1-6 alkyl; Cy.sup.1 is a monocyclic or bicyclic group
selected from substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclic group, substituted or unsubstituted
aryl and substituted or unsubstituted heteroaryl; and n is an
integer selected from 0, 1, 2, 3 or 4.
27. The process of claim 25, wherein R' is 4-chlorophenyl.
28. A compound of formula (IA) or (IB) ##STR00120## or a salt
thereof, wherein each occurrence of R is independently selected
from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkoxy, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, substituted or
unsubstituted cycloalkylalkyl, substituted or unsubstituted
cycloalkenylalkyl, substituted or unsubstituted heterocyclyl,
substituted or unsubstituted heterocyclylalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted arylalkyl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted heteroarylalkyl, --COOR.sup.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.xR.sup.y, --N(R.sup.x)S
OR.sup.x, --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.xR.sup.y,
--SONR.sup.xR.sup.y, --SO.sub.2NR.sup.xR.sup.y, --OR.sup.x,
--OR.sup.xC(O)NR.sup.xR.sup.y, --OR.sup.xC(O)OR.sup.x,
--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.xR.sup.y,
--R.sup.xC(O)R.sup.y, --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 is independently
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkoxy, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
aryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
heteroarylalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkylalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
heterocyclic ring, substituted or unsubstituted heterocyclylalkyl
ring, or substituted or unsubstituted amino, or (i) any two of
R.sup.x and R.sup.y, when bound to a common atom, are joined to
form a substituted or unsubstituted, saturated or unsaturated 3-14
membered ring, which may optionally include heteroatoms which may
be the same or different and are selected from O, NR.sup.z or S, or
(ii) any two of R.sup.x and R.sup.y, when bound to a common atom,
are joined to form an oxo (.dbd.O), thio (.dbd.S) or imino
(.dbd.NR.sup.f) (wherein R.sup.f is hydrogen or substituted or
unsubstituted alkyl); R.sup.1 is substituted or unsubstituted
C.sub.1-6 alkyl; Cy.sup.1 is a group selected from substituted or
unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic
group, substituted or unsubstituted aryl and substituted or
unsubstituted heteroaryl; and n is an integer selected from 0, 1,
2, 3 or 4, wherein the compound is not selected from ##STR00121##
or a salt thereof.
29. The compound of claim 28, wherein R is alkyl or halogen;
Cy.sup.1 is a monocyclic group selected from substituted or
unsubstituted aryl; and n is 1.
30. A compound of claim 28, wherein R is chloro, fluoro or methyl;
Cy.sup.1 is ##STR00122## and R.sup.1 is methyl or ethyl.
31-32. (canceled)
33. A compound of claim 28, wherein R.sup.1 is methyl or ethyl.
34. A compound of claim 28, wherein n is 1.
35. A compound of claim 28, wherein the compound has an
enantiomeric excess of at least 75%, 90%, 95%, 97%, or 98%.
36. A compound selected from
(R)-6-fluoro-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one;
(R)-2-(1-hydroxyethyl)-5-methyl-3-phenyl-4H-chromen-4-one;
(R)-6-fluoro-2-(1-hydroxyethyl)-3-phenyl-4H-chromen-4-one;
(R)-2-(1-hydroxyethyl)-3-phenyl-4H-chromen-4-one;
(R)-3-(3-fluorophenyl)-2-(1-hydroxypropyl)-4H-chromen-4-one;
(R)-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one;
(S)-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one; and
salts thereof.
37. A composition comprising (i) (a) a compound of formula (IA) or
(IB) ##STR00123## or a salt thereof, and (b) a PI3K inhibitor of
formula (I) ##STR00124## or a tautomer thereof, N-oxide thereof,
pharmaceutically acceptable ester thereof, prodrug thereof, or
pharmaceutically acceptable salt thereof, or (ii) (a) a compound of
formula (IA) or (IB) ##STR00125## or a salt thereof, and (b) a PI3K
inhibitor of formula (III) ##STR00126## or a tautomer thereof,
N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug
thereof, or pharmaceutically acceptable salt thereof; wherein each
occurrence of R is independently selected from hydrogen, hydroxy,
halogen, carboxyl, cyano, nitro, substituted or unsubstituted
alkyl, substituted or unsubstituted alkoxy, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
heteroarylalkyl, --COOR.sup.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.xR.sup.y, --N(R.sup.x)SOR.sup.x,
--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.xR.sup.y,
--SONR.sup.xR.sup.y, --SO.sub.2NR.sup.xR.sup.y, --OR.sup.x,
--OR.sup.xC(O)NR.sup.xR.sup.y, --OR.sup.xC(O)OR.sup.x,
--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.xR.sup.y,
--R.sup.xC(O)R.sup.y, --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 is independently
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkoxy, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
aryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
heteroarylalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkylalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
heterocyclic ring, substituted or unsubstituted heterocyclylalkyl
ring, or substituted or unsubstituted amino, or (i) any two of
R.sup.x and R.sup.y, when bound to a common atom, are joined to
form a substituted or unsubstituted, saturated or unsaturated 3-14
membered ring, which may optionally include heteroatoms which may
be the same or different and are selected from O, NR.sup.z or S, or
(ii) any two of R.sup.x and R.sup.y, when bound to a common atom,
are joined to form an oxo (.dbd.O), thio (.dbd.S) or imino
(.dbd.NR.sup.f) (wherein R.sup.f is hydrogen or substituted or
unsubstituted alkyl); R.sup.1 is substituted or unsubstituted
C.sub.1-6 alkyl; Cy.sup.1 is a monocyclic or bicyclic group
selected from substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclic group, substituted or unsubstituted
aryl and substituted or unsubstituted heteroaryl; n is an integer
selected from 0, 1, 2, 3 or 4; Cy.sup.2 is selected from a
substituted or unsubstituted heterocyclic group, substituted or
unsubstituted aryl and substituted or unsubstituted heteroaryl;
L.sub.1 is absent, --(CR.sup.aR.sup.b).sub.q--, --O--,
--S(.dbd.O).sub.q--, --NR.sup.a-- or --C(.dbd.Y)--; each occurrence
of R.sup.a and R.sup.b may be the same or different and are
independently selected from hydrogen, halogen, hydroxy, cyano,
substituted or unsubstituted (C.sub.1-6)alkyl, --NR.sup.cR.sup.d
(wherein R.sup.c and R.sup.d are independently hydrogen, halogen,
hydroxy, cyano, substituted or unsubstituted (C.sub.1-6)alkyl, or
(C.sub.1-6)alkoxy) and --OR.sup.c (wherein R.sup.c is substituted
or unsubstituted (C.sub.1-6)alkyl) or when R.sup.a and R.sup.b are
directly bound to a common atom, they may be joined to form an oxo
group (.dbd.O) or form a substituted or unsubstituted, saturated or
unsaturated 3-10 member ring (including the common atom to which
R.sup.a and R.sup.b are directly bound), which may optionally
include one or more heteroatoms which may be the same or different
and are selected from O, NR.sup.d (wherein R.sup.d is hydrogen or
substituted or unsubstituted (C.sub.1-6)alkyl) or S; Y is selected
from O, S, and NR.sup.a; and q is 0, 1 or 2, wherein the compound
of formula (IA) or (IB) is present in the composition in an amount
up to 0.5% by weight, based upon the total of components (a) and
(b) in the composition.
38. (canceled)
39. The composition of claim 37, wherein the compound of formula
(IA) or (IB) is present in the composition in an amount up to 0.2%
by weight, based upon the total of components (a) and (b) in the
composition.
40. A process for preparing a compound of formula (I): ##STR00127##
or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable
ester thereof, prodrug thereof, or pharmaceutically acceptable salt
thereof; the process comprising (a) converting a compound of
formula (IA) or (IB) ##STR00128## to a compound of formula (I), or
a tautomer thereof; and (b) optionally converting the compound of
formula (I) to an N-oxide thereof, a pharmaceutically acceptable
ester thereof, a prodrug thereof, or a pharmaceutically acceptable
salt thereof; wherein (i) n is 1, R is 6-fluoro, Cy.sup.1 is
3-fluorophenyl and R.sup.1 is methyl; (ii) n is 1, R is 5-methyl,
Cy.sup.1 is phenyl and R.sup.1 is methyl; (iii) n is 1, R is
6-fluoro, Cy.sup.1 is phenyl and R.sup.1 is methyl; (iv) n is 1, R
is hydrogen, Cy.sup.1 is phenyl and R.sup.1 is methyl; (v) n is 1,
R is hydrogen, Cy.sup.1 is 3-fluorophenyl and R.sup.1 is ethyl; or
(vi) n is 1, R is hydrogen, Cy.sup.1 is 3-fluorophenyl and R.sup.1
is methyl; and L.sup.1 is, in each case, independently, absent or
NR.sup.a, wherein R.sup.a is, in each case, independently selected
from hydrogen, halogen, hydroxy, cyano, substituted or
unsubstituted (C.sub.1-6)alkyl, --NR.sup.cR.sup.d (wherein R.sup.c
and R.sup.d are independently hydrogen, halogen, hydroxy, cyano,
substituted or unsubstituted (C.sub.1-6)alkyl, or
(C.sub.1-6)alkoxy) and --OR.sup.c (wherein R.sup.c is substituted
or unsubstituted (C.sub.1-6)alkyl); and Cy.sup.2 is, in each case,
independently selected from a substituted or unsubstituted
heterocyclic group, substituted or unsubstituted aryl and
substituted or unsubstituted heteroaryl.
41. The process of claim 40, wherein step (a) comprises (i)
reacting the compound of formula (IA) or (IB) with a phosphorus
halide or mesyl halide in the presence of a base to obtain a
compound of formula (8a) or (8b) ##STR00129## wherein X.sup.1 is
halogen or --O-Mesyl; and (ii) reacting the compound of formula
(8a) or (8b) with Cy.sup.2-H in the presence of a base to give the
desired compound of formula (I) in which L.sup.1 is absent.
Description
PRIORITY
[0001] This application claims the benefit of Indian Provisional
Patent Application No. 1737/CHE/2012 dated 4 May 2012 and U.S.
Provisional Patent Application No. 61/671,956 dated 16 Jul. 2012;
each of which is hereby incorporated by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to compounds useful as
pharmaceutical intermediates, to processes for preparing the
intermediates, to intermediates used in the processes, and to the
use of the intermediates in the preparation of pharmaceuticals. In
particular, the present invention concerns enantiomerically pure
optionally substituted 2-(1-hydroxy-alkyl)-chromen-4-one
derivatives, processes for preparing the alcohol derivatives and
their use in preparing pharmaceuticals.
BACKGROUND OF THE INVENTION
[0003] International Publication No. WO 2011/055215, International
Publication No. WO2012151525A1, U.S. Publication No. 2011/0118257,
U.S. Publication No. 2012/0289496, Indian Provisional Patent
Application Nos. 1542/CHE/2011 dated 4 May 2011 and 81/CHE/2012
dated 9 Jan. 2012 (all of which are incorporated herein by
reference in their entirety for all purposes) generally disclose
2,3 disubstituted-4H-chromen-4-one compounds as PI3K inhibitors
useful for the treatment, prevention and/or amelioration of kinase
mediated diseases or disorders.
SUMMARY OF THE INVENTION
[0004] The present inventors have developed an improved process for
preparing optionally substituted 2-(1-hydroxy-alkyl)-chromen-4-one
derivatives (including 2-(1-hydroxy-alkyl), 6-substituted
4H-chromen-4-one compounds), which may be used in the preparation
of 2,3 disubstituted-4H-chromen-4-one compounds. The process is
particularly useful for preparing enantiomerically pure optionally
substituted 2-(1-hydroxy-alkyl)-chromen-4-one derivatives. The
process is enantioselective and suitable for large scale
production, has high yield, uses non-hazardous reagents and results
in less waste.
[0005] The present invention provides processes for preparing a
compound of formula (IA)
##STR00001##
wherein
[0006] each occurrence of R is independently selected from
hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, substituted or
unsubstituted alkyl, substituted or unsubstituted alkoxy,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
heteroarylalkyl, --COOR.sup.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.xR.sup.y, --N(R.sup.x)SOR.sup.x,
--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.xR.sup.y,
--SONR.sup.xR.sup.y, --SO.sub.2NR.sup.xR.sup.y, --OR.sup.x,
--OR.sup.xC(O)NR.sup.xR.sup.y, --OR.sup.xC(O)OR.sup.x,
--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.xR.sup.y,
--R.sup.xC(O)R.sup.y, --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 is independently
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkoxy, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
aryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
heteroarylalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkylalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
heterocyclic ring, substituted or unsubstituted heterocyclylalkyl
ring, or substituted or unsubstituted amino, or (i) any two of
R.sup.x and R.sup.y, when bound to a common atom, are joined to
form a substituted or unsubstituted, saturated or unsaturated 3-14
membered ring, which may optionally include heteroatoms which may
be the same or different and are selected from O, NR.sup.z or S, or
(ii) any two of R.sup.x and R.sup.y, when bound to a common atom,
are joined to form an oxo (.dbd.O), thio (.dbd.S) or imino
(.dbd.NR.sup.f) (wherein R.sup.f is hydrogen or substituted or
unsubstituted alkyl); [0007] R.sup.1 is substituted or
unsubstituted C.sub.1-6 alkyl; [0008] Cy.sup.1 is a group (e.g., a
monocyclic or bicyclic group) selected from substituted or
unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic
group, substituted or unsubstituted aryl and substituted or
unsubstituted heteroaryl; and [0009] n is an integer selected from
0, 1, 2, 3 or 4.
[0010] In one embodiment, the compound is not selected from
##STR00002##
or a salt thereof.
[0011] Further preferred is a compound of formula (IA) wherein R is
alkyl (e.g., C.sub.1-C.sub.4 alkyl, such as methyl or ethyl) or
halogen.
[0012] Further preferred is a compound of formula (IA) wherein R is
chloro, fluoro or methyl.
[0013] Further preferred is a compound of formula (IA) wherein
Cy.sup.1 is a monocyclic group selected from substituted or
unsubstituted aryl.
[0014] Further preferred is a compound of formula (IA) wherein
Cy.sup.1 is selected from
##STR00003##
[0015] Further preferred is a compound of formula (IA) wherein
R.sup.1 is methyl or ethyl.
[0016] Further preferred is a compound of formula (IA) wherein n is
1.
[0017] In yet another embodiment is a compound selected from [0018]
1.
(R)-6-fluoro-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one
[0019] 2. (R)-2-(1-hydroxyethyl)-5-methyl-3-phenyl-4H-chromen-4-one
[0020] 3. (R)-6-fluoro-2-(1-hydroxyethyl)-3-phenyl-4H-chromen-4-one
[0021] 4. (R)-2-(1-hydroxyethyl)-3-phenyl-4H-chromen-4-one [0022]
5. (R)-3-(3-fluorophenyl)-2-(1-hydroxypropyl)-4H-chromen-4-one
[0023] 6.
(R)-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one [0024]
7. (S)-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one;
TABLE-US-00001 [0024] TABLE 1 ##STR00004## Example-1 ##STR00005##
Example-2 ##STR00006## Example-3 ##STR00007## Example-4
##STR00008## Example-5 ##STR00009## Example-6 ##STR00010##
Example-7
[0025] One embodiment is a process of preparing a compound of
formula (IA) which includes [0026] (a) treating a compound of
formula (6) wherein R, n and Cy.sup.1 are as defined above with a
compound of formula (A) wherein R.sup.1 is as defined above and Pg
is a protecting group (such as benzyl)
[0026] ##STR00011## [0027] and [0028] (b) deprotecting the compound
formed in step (a) to obtain a compound of formula (IA), and
optionally converting it to its salt.
[0029] In yet another embodiment, the reaction of compound of
formula (6) with compound of formula A is performed in presence of
a suitable coupling reagent such as HATU
((2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate), HBTU
(O-Benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro-phosphate),
TBTU (O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyl uronium
tetrafluoroborate), COMU (Morpholinium,
4-[[[(1-cyano-2-ethoxy-2-oxoethylidene)amino] oxayl] (dimethyl
amino) methylene]-hexafluorophosphate), TOTU ((O-[(Ethoxy
carbonyl)cyanomethylenamino]-N,N,N',N'-tetra methyl uronium
tetrafluoroborate), HCTU
((2-(6-Chloro-1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium
hexafluorophosphate), TCTU
(O-(6-Chloro-1-hydrocibenzotriazol-1-yl)-1,1,3,3-tetramethyl
uronium tetra fluoroborate), TATU
(O-(7-Azabenzotriazole-1-yl)-N,N,N',N'-tetramethyl uronium tetra
fluoroborate), TSTU (O-(N-Succinimidyl)-1,1,3,3-tetramethyl uranium
tetrafluoroborate), TDBTU
(N,N,N',N'-Tetramethyl-O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)
uranium tetrafluoroborate), any other suitable coupling reagents,
or any combination of any of the foregoing.
[0030] Further preferred is where the reaction of compound of
formula (6) with compound of formula A is performed in presence of
HATU, HBTU, TBTU or COMU.
[0031] Further preferred is where the reaction of compound of
formula (6) with compound of formula A is performed in presence of
HATU.
[0032] Another embodiment is a process for preparing a compound of
formula (IB)
##STR00012##
wherein all the variables are as defined above, the method includes
the steps of [0033] (a) treating a compound of formula (6), wherein
R, n and Cy.sup.1 are as defined above, with a compound of formula
(B) wherein R.sup.1 is as defined above and Pg is a protecting
group (such as benzyl)
##STR00013##
[0033] and [0034] (b) deprotecting the compound formed in step (a)
to obtain a compound of Formula (IB).
[0035] In one embodiment, the compound is not selected from
##STR00014##
or a salt thereof.
[0036] Further preferred is a compound of formula (IB) wherein R is
alkyl (e.g., C.sub.1-C.sub.4 alkyl, such as methyl or ethyl) or
halogen.
[0037] Further preferred is a compound of formula (IB) wherein R is
chloro, fluoro or methyl.
[0038] Further preferred is a compound of formula (IB) wherein
Cy.sup.1 is a monocyclic group selected from substituted or
unsubstituted aryl.
[0039] Further preferred is a compound of formula (IB) wherein
Cy.sup.1 is selected from
##STR00015##
[0040] Further preferred is a compound of formula (IB) wherein
R.sup.1 is methyl or ethyl.
[0041] Further preferred is a compound of formula (IB) wherein n is
1.
[0042] Yet another embodiment is a process for preparing a compound
of formula (IA)
##STR00016##
wherein all the variables are as defined above, the method includes
the steps of [0043] (a) converting a compound of formula (1)
[0043] ##STR00017## [0044] wherein R and n are as defined above and
Pg is a protecting group, to a compound of formula (2)
[0044] ##STR00018## [0045] (b) converting the compound of formula
(2) to a compound of formula (3)
[0045] ##STR00019## [0046] (c) converting the compound of formula
(3) to a compound of formula (5)
[0046] ##STR00020## [0047] wherein R, n, Cy.sup.1 and Pg are as
described above; [0048] (d) deprotection of the compound of formula
(5) to give a compound of formula (6)
[0048] ##STR00021## [0049] (e) reacting the compound of formula (6)
with a compound of formula (A)
[0049] ##STR00022## [0050] to give a compound of formula (7a)
[0050] ##STR00023## [0051] (f) deprotection of the compound of
formula (7a) to give the desired compound of formula (IA); and
[0052] (g) optionally, converting the compound of formula (IA) to a
salt of the compound.
[0053] The compound of Formula (1) may be converted to a compound
of Formula (2) by treating the compound of formula (1) with
hydroxyl amine or a salt thereof (such as NH.sub.2OH.HCl) in
presence of a base. The compound of Formula (3) may be obtained by
treating the compound of formula (2) with N,N'-carbonyldiimidazole
(CDI). The compound of Formula (3) may be converted to a compound
of Formula (5) by treating the compound of formula (3) with a
Grignard reagent of formula (4a)
Cy.sup.1-CH.sub.2--MgX 4a
wherein X is halogen and Cy.sup.1 is as defined above.
[0054] Yet another embodiment is a process for preparing a compound
of formula (IB)
##STR00024##
wherein all the variables are as defined above, the process
includes the steps of [0055] (a) converting a compound of formula
(1)
##STR00025##
[0055] to a compound of formula (2)
##STR00026##
wherein R and n are as defined above and Pg is a protecting group
(for example by reacting the compound of formula (1) with
hydroxylamine or a salt thereof (such as NH.sub.2OH.HCl) in
presence of a base); [0056] (b) converting the compound of formula
(2) to a compound of formula (3)
##STR00027##
[0056] (for example, by treating the compound of formula (2) with
N,N'-carbonyldiimidazole (CDI)); [0057] (c) converting the compound
of formula (3) to a compound of formula (5)
##STR00028##
[0057] wherein R, n, Cy.sup.1 and Pg are as described above (for
example by treating the compound of formula (3) with a Grignard
reagent of formula (4a)
Cy.sup.1-CH.sub.2--MgX 4a
wherein X is halogen and Cy.sup.1 is as defined above); [0058] (d)
deprotection of the compound of formula (5) to give a compound of
formula (6)
[0058] ##STR00029## [0059] (e) reacting the compound of formula (6)
with a compound of formula (B)
##STR00030##
[0059] to give a compound of formula (7b)
##STR00031## [0060] (f) deprotection of the compound of formula
(7b) to give the desired compound of formula (IB) wherein all the
variables (R, R.sup.1, n and Cy.sup.1) are as described above in
relation to Formula (IA); and [0061] (g) optionally, converting the
compound of formula (IB) to a salt of the compound.
[0062] In yet another embodiment, the reaction of compound of
formula (6) with compound of formula B is performed in presence of
a suitable coupling reagent such as HATU
((2-(7-Ara-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate), HBTU
(O-Benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro-phosphate),
TBTU (O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyl uronium
tetrafluoroborate), COMU (Morpholinium,
4-[[[(1-cyano-2-ethoxy-2-oxoethylidene)amino] oxayl] (dimethyl
amino) methylene]-hexafluorophosphate), TOTU ((O-[(Ethoxy carbonyl)
cyanomethylenamino]-N,N,N',N'-tetra methyl uronium
tetrafluoroborate), HCTU
((2-(6-Chloro-1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium
hexafluorophosphate), TCTU
(O-(6-Chloro-1-hydrocibenzotriazol-1-yl)-1,1,3,3-tetramethyl
uronium tetra fluoroborate), TATU
(O-(7-Azabenzotriazole-1-yl)-N,N,N',N'-tetramethyl uronium tetra
fluoroborate), TSTU (O-(N-Succinimidyl)-1,1,3,3-tetramethyl uranium
tetrafluoroborate), TDBTU
(N,N,N',N'-Tetramethyl-O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)
uranium tetrafluoroborate), any other suitable coupling reagents,
or any combination of any of the foregoing.
[0063] Further preferred is where the reaction of compound of
formula (6) with compound of formula B is performed in presence of
HATU, HBTU, TBTU or COMU.
[0064] Further preferred is where the reaction of compound of
formula (6) with compound of formula B is performed in presence of
HATU.
[0065] Yet another embodiment is a process for inverting a compound
of formula (IA) to yield a compound of formula (IB) comprising the
step of [0066] (a) reacting the compound of formula (IA) with
R'-COOH (wherein R.sup.1 is selected from substituted or
unsubstituted alkyl or substituted or unsubstituted aryl) to
provide a compound of formula IA-2
[0066] ##STR00032## [0067] (b) treating the compound of formula
(IA-2) with a suitable base in a polar solvent to yield a compound
of formula (IB).
[0068] Yet another embodiment is a process for inverting a compound
of formula (IB) to yield a compound of formula (IA) comprising the
step of [0069] (a) reacting the compound of formula (IB) with
R'-COOH (wherein R.sup.1 is selected from substituted or
unsubstituted alkyl or substituted or unsubstituted aryl) to
provide a compound of formula IB-2
[0069] ##STR00033## [0070] (b) treating the compound of formula
(IB-2) with a suitable base in a polar solvent to yield a compound
of formula (IA).
[0071] Further preferred is where R.sup.1 is 4-chloro phenyl.
[0072] Further preferred is where the base is selected from
inorganic bases, such as K.sub.2CO.sub.3 , Na.sub.2CO.sub.3 or
CsCO.sub.3 and the polar solvent used is a suitable alcohol
selected from methanol or ethanol.
[0073] Yet another embodiment is a process for preparing a compound
of formula (IA-I)
##STR00034##
wherein all the variables are as defined above, the method
comprising the steps of [0074] (a) converting a compound of formula
(1a)
##STR00035##
[0074] to a compound of formula (2a)
##STR00036##
wherein R and n are as defined above and Pg is a protecting group
(for example, reacting a compound of formula (1a) with
hydroxylamine or a salt thereof (such as NH.sub.2OH.HCl) in the
presence of a base); [0075] (b) converting a compound of formula
(2a) to a compound of formula (3a)
##STR00037##
[0075] (for example, by treating the compound of formula (2a) with
N,N'-carbonyldiimidazole (CDI)); [0076] (c) converting a compound
of formula (3a) to a compound of formula (5a)
##STR00038##
[0076] (for example, by treating the compound of formula (3a) with
a Grignard reagent of formula (4a)
Cy.sup.1-CH.sub.2--MgX 4a
wherein X is halogen and Cy.sup.1 is as described above); [0077]
(d) deprotection of the compound of formula (5a) to give a compound
of formula (6a)
[0077] ##STR00039## [0078] (e) reacting the compound of formula
(6a) with a compound of formula (A)
##STR00040##
[0078] to give a compound of formula (7aa)
##STR00041## [0079] (f) deprotection of the compound of formula
(7aa) to give the desired compound of formula (IA-I) wherein all
the variables (R, R.sup.1, n and Cy.sup.1) are as described above
in relation to Formula (IA); and [0080] (g) optionally, converting
the compound of formula (IA-I) to a salt of the compound.
[0081] Yet another embodiment is a process for preparing a compound
of formula (IA-II)
##STR00042##
wherein all the variables are as defined above, the methods
comprising the step of [0082] (a) converting a compound of formula
(1b)
##STR00043##
[0082] wherein R is as defined above and Pg is a protecting group,
to a compound of formula (2b)
##STR00044##
(for example, by treating a compound of formula (1a) with
hydroxylamine or a salt thereof (such as NH.sub.2OH.HCl) in the
presence of a base); [0083] (b) converting a compound of formula
(2b) to a compound of formula (3b)
##STR00045##
[0083] (for example, by treating the compound of formula (2b) with
N,N'-carbonyldiimidazole (CDI)); [0084] (c) converting the compound
of formula (3b) to a compound of formula (5b)
##STR00046##
[0084] (for example, treating a compound of formula (3b) with a
Grignard reagent of formula (4a)
Cy.sup.1-CH.sub.2--MgX 4a
wherein X is halogen and Cy.sup.1 is as described above); [0085]
(d) deprotection of the compound of formula (5b) to give a compound
of formula (6b)
[0085] ##STR00047## [0086] (e) reacting the compound of formula
(6b) with a compound of formula (A)
##STR00048##
[0086] to give a compound of formula (7ab)
##STR00049##
and [0087] (f) deprotection of the compound of formula (7ab) to
give the desired compound of formula (IA-II) wherein all the
variables (R, R.sup.1, n and Cy.sup.1) are as described above in
relation to Formula (IA); and [0088] (g) optionally, converting the
compound of formula (IA-II) to a salt of the compound.
[0089] Yet another embodiment is a process for inverting a compound
of formula (IA-I) to yield a compound of formula (IB-I) (shown
below) comprising the step of [0090] (a) reacting the compound of
formula (IA-I) with R'-COOH (wherein R.sup.1 is selected from
substituted or unsubstituted alkyl or substituted or unsubstituted
aryl) to provide a compound of formula (IA-I2)
[0090] ##STR00050## [0091] (b) treating the compound of formula
(IA-I2) with a suitable base in a polar solvent to yield a compound
of formula (IB-I).
[0092] Yet another embodiment is a process for inverting a compound
of formula (IB-I) to yield a compound of formula (IA-I) comprising
the step of [0093] (a) reacting the compound of formula (IB-I) with
R'-COOH (wherein R.sup.1 is selected from substituted or
unsubstituted alkyl or substituted or unsubstituted aryl) to
provide a compound of formula (IB-I2)
[0093] ##STR00051## [0094] (b) treating the compound of formula
(IB-I2) with a suitable base in a polar solvent to yield a compound
of formula (IA-I).
[0095] Yet another embodiment is a process for preparing a compound
of formula (IB-I)
##STR00052##
wherein all the variables are as defined above, the method
comprising the steps of [0096] (a) reacting the compound of formula
(6a) with a compound of formula (B)
##STR00053##
[0096] to give a compound of formula (7ba)
##STR00054## [0097] (b) deprotection of the compound of formula
(7ba) to give the desired compound of formula (IB-I) wherein all
the variables (R, R.sup.1, n and Cy.sup.1) are as described above
in relation to Formula (IA); and [0098] (c) optionally, converting
the compound of formula (IB-I) to a salt of the compound.
[0099] Yet another embodiment is a process for preparing a compound
of formula (IB-II)
##STR00055##
wherein all the variables are as defined above, the method
comprising the steps of [0100] (a) reacting the compound of formula
(6b) with a compound of formula (B)
##STR00056##
[0100] to give a compound of formula (7bb)
##STR00057## [0101] (b) deprotection of the compound of formula
(7bb) to give the desired compound of formula (IB-II) wherein all
the variables (R, R.sup.1, n and Cy.sup.1) are as described above
in relation to Formula (IA); and [0102] (c) optionally, converting
the compound of formula (IB-II) to a salt of the compound.
[0103] Yet another embodiment is a process for inverting a compound
of formula (IA-II) to yield a compound of formula (IB-II)
comprising the step of [0104] (a) reacting the compound of formula
(IA-II) with R'-COOH (wherein R.sup.1 is selected from substituted
or unsubstituted alkyl or substituted or unsubstituted aryl) to
provide a compound of formula IA-II2
[0104] ##STR00058## [0105] (b) treating the compound of formula
(IA-II2) with a suitable base in a polar solvent to yield a
compound of formula (IB-II).
[0106] Yet another embodiment is a process for inverting a compound
of formula (IB-II) to yield a compound of formula (IA-II)
comprising the step of [0107] (a) reacting the compound of formula
(IB-II) with R'-COOH (wherein R.sup.1 is selected from substituted
or unsubstituted alkyl or substituted or unsubstituted aryl) to
provide a compound of formula IB-II2
[0107] ##STR00059## [0108] (b) treating the compound of formula
(IB-II2) with a suitable base in a polar solvent to yield a
compound of formula (IA-II).
[0109] Yet another embodiment is a compound of formula (IA) or
(IB)
##STR00060##
or a salt thereof, wherein the variables R, n, Cy.sup.1, and
R.sup.1 are defined as above.
[0110] In one embodiment, the compound of formula (IA) or (IB) has
an enantiomeric excess (EE) of at least 75%, 90%, 95%, 97%, or
98%.
[0111] Yet another embodiment is the use of the compound of formula
(IA), or any other intermediate described herein, for preparation
of PI3K inhibitors of formula (I)
##STR00061##
or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable
ester thereof, prodrug thereof, or pharmaceutically acceptable salt
thereof, wherein [0112] the variables R, n, Cy.sup.1, and R.sup.1
are defined as above; [0113] Cy.sup.2 is selected from a
substituted or unsubstituted heterocyclic group, substituted or
unsubstituted aryl and substituted or unsubstituted heteroaryl;
[0114] L.sub.1 is absent or selected from
--(CR.sup.aR.sup.b).sub.q--, --O--, --S(.dbd.O).sub.q--,
--NR.sup.a-- or --C(.dbd.Y)--; [0115] each occurrence of R.sup.a
and R.sup.b may be the same or different and are independently
selected from hydrogen, halogen, hydroxy, cyano, substituted or
unsubstituted (C.sub.1-6)alkyl, --NR.sup.cR.sup.d (wherein R.sup.c
and R.sup.d are independently hydrogen, halogen, hydroxy, cyano,
substituted or unsubstituted (C.sub.1-6)alkyl, or
(C.sub.1-6)alkoxy) and --OR.sup.c (wherein R.sup.c is substituted
or unsubstituted (C.sub.1-6)alkyl) or when R.sup.a and R.sup.b are
directly bound to a common atom, they may be joined to form an oxo
group (.dbd.O) or form a substituted or unsubstituted, saturated or
unsaturated 3-10 member ring (including the common atom to which
R.sup.a and R.sup.b are directly bound), which may optionally
include one or more heteroatoms which may be the same or different
and are selected from O, NR.sup.d (wherein R.sup.d is hydrogen or
substituted or unsubstituted (C.sub.1-6)alkyl) or S; [0116] Y is
selected from O, S, and NR.sup.a; and [0117] q is 0, 1 or 2.
[0118] The compound of formula (I) may be prepared by [0119] (a)
treating the compound of formula (IA)
##STR00062##
[0119] with Cy.sup.2-H (for example, by a Mitsunobu reaction) to
give the desired compound of formula (I) or a tautomer thereof,
N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug
thereof, or pharmaceutically acceptable salt thereof, wherein
[0120] R, R.sup.1, n and Cy.sup.1 are as described above in
relation to Formula (IA). [0121] Cy.sup.2 is selected from a
substituted or unsubstituted heterocyclic group, substituted or
unsubstituted aryl and substituted or unsubstituted heteroaryl; and
[0122] L.sub.1 is absent; and [0123] (b) optionally converting the
compound of formula (I) to a salt of the compound.
[0124] The compound of formula (I) may also be prepared by [0125]
(a) treating the compound of formula (IA)
##STR00063##
[0125] with a phosphorus halide or mesyl chloride (or other mesyl
halide) in the presence of a base to give a compound of formula
(8a)
##STR00064##
wherein X.sup.1 is halogen or --O-Mesyl (i.e.,
--O--SO.sub.2CH.sub.3); and [0126] (b) reacting the compound of
formula (8a) with Cy.sup.2-H in the presence of a base to give the
desired compound of formula (I) or a tautomer thereof, N-oxide
thereof, pharmaceutically acceptable ester thereof, prodrug
thereof, wherein [0127] R, R.sup.1, n and Cy.sup.1 are as described
above in relation to Formula (IA); [0128] Cy.sup.2 is selected from
a substituted or unsubstituted heterocyclic group, substituted or
unsubstituted aryl and substituted or unsubstituted heteroaryl; and
[0129] L.sub.1 is absent; and [0130] (c) optionally, converting the
compound of formula (I) to a salt of the compound.
[0131] Yet another embodiment provided is the use of the compound
of formula (IA) for preparation of PI3K inhibitors of formula
(II)
##STR00065##
or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable
ester thereof, prodrug thereof, wherein [0132] R, R.sup.1, n and
Cy.sup.1 are as described above in relation to Formula (IA); [0133]
Cy.sup.2 is selected from a substituted or unsubstituted
heterocyclic group, substituted or unsubstituted aryl and
substituted or unsubstituted heteroaryl; and [0134] L.sub.1 is
NH.
[0135] The compound of formula (II) may be prepared by [0136] (a)
treating the compound of formula (IA)
##STR00066##
[0136] with a phosphorus halide or mesyl chloride (or other mesyl
halide) in the presence of a base to give a compound of formula
(8a)
##STR00067##
wherein X.sup.1 is halogen or --O-Mesyl; [0137] (b) converting the
compound of formula (8a) to give a compound of formula (9a)
##STR00068##
[0137] (for example, by treating the compound of formula (8a) with
sodium azide); [0138] (c) converting the compound of formula (9a)
to give a compound of formula (10a)
##STR00069##
[0138] (for example, by treating the compound of formula (8a) with
triphenyl phosphine); [0139] (d) coupling the compound of formula
(10a) with a compound of formula Cy.sup.2-Lg, wherein Lg is a
leaving group, in the presence of a base to give the desired
compound of formula (II); and [0140] (e) optionally, converting the
compound of formula (II) to a salt of the compound.
[0141] Yet another embodiment is the use of the compound of formula
(IB), or any other intermediate described herein, for preparation
of PI3K inhibitors of formula (III)
##STR00070##
or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable
ester thereof, prodrug thereof, or pharmaceutically acceptable salt
thereof, wherein [0142] the variables R, n, Cy.sup.1, and R.sup.1
are defined as above; [0143] Cy.sup.2 is selected from a
substituted or unsubstituted heterocyclic group, substituted or
unsubstituted aryl and substituted or unsubstituted heteroaryl;
[0144] L.sub.1 is absent or selected from
--(CR.sup.aR.sup.b).sub.q--, --O--, --S(.dbd.O).sub.q--,
--NR.sup.a-- or --C(.dbd.Y)--; [0145] each occurrence of R.sup.a
and R.sup.b may be the same or different and are independently
selected from hydrogen, halogen, hydroxy, cyano, substituted or
unsubstituted (C.sub.1-6)alkyl, --NR.sup.cR.sup.d (wherein R.sup.c
and R.sup.d are independently hydrogen, halogen, hydroxy, cyano,
substituted or unsubstituted (C.sub.1-6)alkyl, or
(C.sub.1-6)alkoxy) and --OR.sup.c (wherein R.sup.c is substituted
or unsubstituted (C.sub.1-6)alkyl) or when R.sup.a and R.sup.b are
directly bound to a common atom, they may be joined to form an oxo
group (.dbd.O) or form a substituted or unsubstituted, saturated or
unsaturated 3-10 member ring (including the common atom to which
R.sup.a and R.sup.b are directly bound), which may optionally
include one or more heteroatoms which may be the same or different
and are selected from O, NR.sup.d (wherein R.sup.d is hydrogen or
substituted or unsubstituted (C.sub.1-6)alkyl) or S; [0146] Y is
selected from O, S, and NR.sup.a; and [0147] q is 0, 1 or 2.
[0148] The compound of formula (III) may be prepared by [0149] (a)
treating the compound of formula (IB)
##STR00071##
[0149] with Cy.sup.2-H (for example, by a Mitsunobu reaction) to
give the desired compound of formula (III) or a tautomer thereof,
N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug
thereof, or pharmaceutically acceptable salt thereof, wherein
[0150] R, R.sup.1, n and Cy.sup.1 are as described above in
relation to Formula (IB); [0151] Cy.sup.2 is selected from a
substituted or unsubstituted heterocyclic group, substituted or
unsubstituted aryl and substituted or unsubstituted heteroaryl; and
[0152] L.sub.1 is absent; and [0153] (b) optionally converting the
compound of formula (III) to a salt of the compound.
[0154] The compound of formula (III) may also be prepared by [0155]
(a) treating the compound of formula (IB)
##STR00072##
[0155] with a phosphorus halide or mesyl chloride (or other mesyl
halide) in the presence of a base to give a compound of formula
(8b)
##STR00073##
wherein X.sup.1 is halogen or --O-Mesyl (i.e.,
--O--SO.sub.2CH.sub.3); and [0156] (b) reacting the compound of
formula (8b) with Cy.sup.2-H in the presence of a base to give the
desired compound of formula (III) or a tautomer thereof, N-oxide
thereof, pharmaceutically acceptable ester thereof, prodrug
thereof, or pharmaceutically acceptable salt thereof, wherein
[0157] R, R.sup.1, n and Cy.sup.1 are as described above in
relation to Formula (IB); [0158] Cy.sup.2 is selected from a
substituted or unsubstituted heterocyclic group, substituted or
unsubstituted aryl and substituted or unsubstituted heteroaryl; and
[0159] L.sub.1 is absent; and [0160] (c) optionally, converting the
compound of formula (III) to a salt of the compound.
[0161] Yet another embodiment provided is the use of the compound
of formula (IB) for preparation of PI3K inhibitors of formula
(IV)
##STR00074##
or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable
ester thereof, prodrug thereof, or pharmaceutically acceptable salt
thereof, wherein [0162] R, R.sup.1, n and Cy.sup.1 are as described
above in relation to Formula (IB); [0163] Cy.sup.2 is selected from
a substituted or unsubstituted heterocyclic group, substituted or
unsubstituted aryl and substituted or unsubstituted heteroaryl; and
[0164] L.sub.1 is NH.
[0165] The compound of formula (IV) may be prepared by [0166] (a)
treating the compound of formula (IB)
##STR00075##
[0166] with a phosphorus halide or mesyl chloride (or other mesyl
halide) in the presence of a base to give a compound of formula
(8b)
##STR00076##
wherein X.sup.1 is halogen or --O-Mesyl; [0167] (b) converting the
compound of formula (8b) to give a compound of formula (9b)
##STR00077##
[0167] (for example, by treating the compound of formula (8b) with
sodium azide); [0168] (c) converting the compound of formula (9b)
to give a compound of formula (10b)
##STR00078##
[0168] (for example, by treating the compound of formula (8b) with
triphenyl phosphine); [0169] (d) coupling the compound of formula
(10b) with a compound of formula Cy.sup.2-Lg, wherein Lg is a
leaving group, in the presence of a base to give the desired
compound of formula (IV); and [0170] (e) optionally, converting the
compound of formula (IV) to a salt of the compound.
[0171] In one preferred embodiment, the coupling reaction of the
compound of formula 6 with the compound of formula A or B is
performed in the presence of
N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-meth-
yl methanaminium hexafluorophosphate N-oxide (HATU).
[0172] The protecting groups, such as those on the compounds of
formulas 7a, 7b, 7aa, 7ab, 7ba, and 7bb may be removed using
suitable deprotecting agents, such as aluminium chloride, boron
tribromide, or any combination of the foregoing. Optionally the
deprotection may be performed using other suitable deprotecting
agents including use of hydrogenation for deprotection.
[0173] Yet another embodiment is a composition (e.g., a
pharmaceutical composition) comprising (a) a PI3K inhibitor of
formula (I) or (II) or a salt thereof, and (b) a compound of
formula (IA) or (IB) or a salt thereof. In one embodiment, the
composition comprises at least about 99.5% by weight of the PI3K
inhibitor, and the compound of formula (IA) or (IB) in an amount up
to 0.5% by weight, based upon the total of components (a) and (b).
In another embodiment, the composition includes the compound of
formula (IA) or (IB) in an amount up to 0.2% or 0.1% by weight. The
pharmaceutical composition can be, for example, a tablet or
capsule.
DETAIL DESCRIPTION OF THE INVENTION
[0174] As used herein the following definitions 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.
[0175] 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).
[0176] 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 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.
[0177] The term "alkynyl" refers to a straight or branched chain
hydrocarbyl radical having at least one carbon-carbon triple bond,
and having in the range of 2 to up to 12 carbon atoms (with
radicals having in the range of 2 to up to 10 carbon atoms
presently being preferred) e.g., ethynyl, propynyl, and butnyl.
[0178] The term "alkoxy" denotes an alkyl, cycloalkyl, or
cycloalkylalkyl group as defined above attached via an oxygen
linkage to the rest of the molecule. 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 a
oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy,
cyclopropyloxy, and cyclohexyloxy.
[0179] The term "cycloalkyl" denotes a non-aromatic mono or
multicyclic ring system of 3 to about 12 carbon atoms such as
cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of
multicyclic cycloalkyl groups include perhydronaphthyl, adamantyl
and norbornyl groups, bridged cyclic groups, and sprirobicyclic
groups, e.g., sprio (4,4) non-2-yl.
[0180] The term "cycloalkylalkyl" refers to a cyclic
ring-containing radical containing in the range of 3 up to about 8
carbon atoms directly attached to an alkyl group which are then
attached to the main structure at any carbon from the alkyl group
that results in the creation of a stable structure such as
cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.
[0181] The term "cycloalkenyl" refers to cyclic ring-containing
radicals containing in the range of 3 up to about 8 carbon atoms
with at least one carbon-carbon double bond such as cyclopropenyl,
cyclobutenyl, and cyclopentenyl. The term "cycloalkenylalkyl"
refers to a cycloalkenyl group directly attached to an alkyl group
which are then attached to the main structure at any carbon from
the alkyl group that results in the creation of a stable
structure.
[0182] The term "aryl" refers to aromatic radicals having in the
range of 6 up to 20 carbon atoms such as phenyl, naphthyl,
tetrahydronaphthyl, indanyl, and biphenyl.
[0183] 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.
[0184] 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 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.
[0185] 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.
[0186] 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, 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.
[0187] 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 oxidesubstituents, such
as pyridinyl N-oxides.
[0188] The term "heteroarylalkyl" refers to a 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.
[0189] The term "cyclic ring" refers to a cyclic ring containing 3
to 10 carbon atoms.
[0190] The term "substituted" unless otherwise specified, refers to
substitution with any one or any combination of the following
substituents which may be the same or different and 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 aryl, substituted or
unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkylalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
cycloalkenylalkyl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted heteroarylalkyl, substituted or
unsubstituted heterocyclic ring, substituted heterocyclylalkyl
ring, 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.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 R.sup.x,
R.sup.y and R.sup.z in each of the above groups can be hydrogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkoxy, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted aryl,
substituted or unsubstituted arylalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
cycloalkylalkyl, substituted or unsubstituted cycloalkenyl,
substituted or unsubstituted amino, substituted or unsubstituted
heteroaryl, substituted or unsubstituted heteroarylalkyl,
substituted or unsubstituted heterocyclic ring, or substituted
heterocyclylalkyl ring, or any two of R.sup.x, R.sup.y and R.sup.z
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 (e.g., R.sup.x can be hydrogen or C.sub.1-6 alkyl)
or S. 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 production, detection and preferably their recovery,
purification and incorporation into a pharmaceutical composition.
The substituents in the aforementioned "substituted" groups cannot
be further substituted. For example, when the substituent on
"substituted alkyl" is "substituted aryl", the substituent on
"substituted aryl" cannot be "substituted alkenyl".
[0191] 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. For example, the terms "fluoroalkyl" and
"fluoroalkoxy" include haloalkyl and haloalkoxy groups,
respectively, in which the halo is fluorine.
[0192] 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-fluorenylmethyloxycarbonyl (Fmoc).
Similarly, a "hydroxy-protecting group" refers to a substituent of
a hydroxy group that blocks or protects the hydroxy functionality.
Suitable hydroxy-protecting groups include, but are not limited to,
acetyl and silyl. A "carboxy-protecting group" refers to a
substituent of the carboxy group that blocks or protects the
carboxy functionality. Suitable carboxy-protecting groups include,
but are not limited to, --CH.sub.2CH.sub.2SO.sub.2Ph, cyanoethyl,
2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl,
-2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl,
2-(diphenylphosphino)-ethyl, and nitroethyl. For a general
description of protecting groups and their use, see T. W. Greene,
Protective Groups in Organic Synthesis, John Wiley & Sons, New
York, 1991.
[0193] 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
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.
[0194] 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.
[0195] 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.
[0196] The term "prodrug" refers to a compound, which is a
precursor (for example, 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.
[0197] 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'.
[0198] These prodrugs and esters are intended to be covered within
the scope of this invention.
[0199] 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.
[0200] 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.
[0201] 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.
[0202] Representative processes of the present invention include
those specified below. The present invention should not be
construed to be limited to them.
Experimental
[0203] The examples and preparations provided below further
illustrate and exemplify the methods of preparing compounds of the
invention. It is to be understood that the scope of the present
invention is not limited in any way by the scope of the following
examples and preparations. In the following examples molecules with
a single chiral center, unless otherwise noted, exist as a racemic
mixture. Those molecules with two or more chiral centers, unless
otherwise noted, exist as a racemic mixture of diastereomers.
Single enantiomers/diastereomers may be obtained by methods known
to those skilled in the art.
EXAMPLE 1
(R)-6-fluoro-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one
##STR00079##
[0205] Step 1: (R)-2-(1-(benzyloxy)
ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one: To
1-(5-fluoro-2-hydroxyphenyl)-2-(3-fluorophenyl) ethanone (11 g,
44.31 mmol), in Dichloromethane (110 ml), HATU (33.7 g, 88.63 mmol)
and (R)-Benzyloxypropionic acid (9.58 g, 53.17 mmol) were added and
stirred for .about.10 min Triethylamine (67 ml, 478 mmol) was added
dropwise and stirred at room temperature (RT) for 24 h. The
reaction mixture was quenched with water and extracted with
Dichloromethane (2.times.250 ml). The organic layer was dried with
sodium sulphate and concentrated under vacuum. The crude product
was purified by column chromatography with ethyl acetate: Petroleum
ether to afford the title compound as a off-white solid (10.9 g,
63%). .sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400 MHz): 7.85 (dd,
J=8.1, 3.0 Hz, 1H), 7.58 (dd, J=9.1, 4.1 Hz, 1H), 7.47-7.39 (m,
1H), 7.39-7.34 (m, 1H), 7.28-7.20 (m, 3H), 7.20-7.14 (m, 2H),
7.16-7.14 (m, 1H), 6.99-7.89 (m, 2H), 4.50-4.31 (m, 3H), 1.56 (d,
J=6.4 Hz, 3H). Mass: 392.9 (M.sup.+).
[0206] Step 2:
(R)-6-fluoro-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one:
To
(R)-2-(1-(benzyloxy)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one
(10.5 g, 26.69 mmol) in Dichloromethane (110 ml) cooled to
0.degree. C., anhydrous Aluminium chloride (5.35 g, 40.03 mmol) was
added portion wise and stirred for 1 h and then at RT for 2 h. The
reaction mixture was quenched with dilute aq. HCl (10 ml),
extracted with Dichloromethane (2.times.50 ml). The organic layer
was dried over sodium sulphate and concentrated under reduced
pressure. The crude product was purified by column chromatography
with ethyl acetate:petroleum ether to afford the title compound as
off-white solid (6.5 g, 81%). .sup.1H-NMR (.delta. ppm, CDCl.sub.3,
400 MHz): 7.86 (dd, J=8.3, 3.0 Hz, 1H), 7.56 (dd, J=9.2, 4.2 Hz,
1H), 7.45 (m, 2H), 7.12-6.99 (m, 3H), 4.76 (q, J=6.6 Hz, 1H), 1.55
(d, J=6.6 Hz, 3H). Mass: 303.2 (M.sup.++1). Purity: 99.78% .
[.alpha.].sup.25.sub.D 0.287 (c=1, CHCl.sub.3). Enantiomeric
excess: 97.74%, enriched in the late eluting isomer (retention
time: 10.93 min.) as determined by HPLC on a chiralpak AD-H
column.
EXAMPLE 2
(R)-2-(1-hydroxyethyl)-5-methyl-3-phenyl-4H-chromen-4-one
##STR00080##
[0208] Step 1:
(R)-2-(1-(benzyloxy)ethyl)-5-methyl-3-phenyl-4H-chromen-4-one: To
1-(2-hydroxy-6-methylphenyl)-2-phenylethanone (0.400 g, 1.76 mmol)
in dichloromethane (4 ml), R(+)-benzyloxypropionic acid (0.382 g,
2.12 mmol) and HATU (2.01 g, 5.30 mmol) were added followed by
triethylamine (2.6 ml, 19.08 mmol). After 20h at room temperature,
the reaction mixture was quenched with water, extracted with ethyl
acetate, dried over sodium sulphate and concentrated. The crude
product was column chromatographed with ethyl acetate:petroleum
ether to afford the title compound as off-white solid (0.080 g ,
12%). .sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400 MHz): 7.55 (t,
J=8.1 Hz, 1H), 7.43-7.13 (m, 12H), 4.47 (m, 2H), 4.30 (d, J=11.8
Hz, 1H), 2.84 (s, 3H), 1.54 (d, J=6.5 Hz, 3H). Mass: 370.9
(M.sup.+).
[0209] Step 2:
(R)-2-(1-hydroxyethyl)-5-methyl-3-phenyl-4H-chromen-4-one: To
(R)-2-(1-(benzyloxy)ethyl)-5-methyl-3-phenyl-4H-chromen-4-one
(0.850 g, 2.29 mmol) in dichloromethane (8.0 ml) at -78.degree. C.,
boron tribromide (0.78 ml, 1M in dichloromethane, 4.58 mmol) was
added slowly and maintained for 4 h. The reaction mass was quenched
at -78.degree. C. using 2N HCl (50 ml), extracted with ethyl
acetate, dried over sodium sulphate and concentrated. The crude
product was column chromatographed with ethyl acetate:petroleum
ether to afford the title compound as pale-yellow liquid (0.200 g,
31%). .sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400 MHz): 7.54 (t,
J=8.0 Hz, 1H), 7.46-7.26 (m, 6H), 7.13 (d, J=7.4 Hz, 1H), 4.71 (q,
J=6.6 Hz, 1H), 2.83 (s, 3H), 1.53 (d, J=6.6 Hz, 3H). Mass: 280.8
(M.sup.+).
EXAMPLE 3
(R)-6-fluoro-2-(1-hydroxyethyl)-3-phenyl-4H-chromen-4-one
##STR00081##
[0211] Step 1:
(R)-2-(1-(benzyloxy)ethyl)-6-fluoro-3-phenyl-4H-chromen-4-one: To
1-(5-fluoro-2-hydroxyphenyl)-2-phenylethanone (2.00 g, 8.68 mmol),
in dichloromethane (15 ml), HATU (6.60 g, 17.36 mmol), and
R-(+)2-benzyloxypropionic acid (1.87 g, 10.42 mmol) were added and
stirred for 10 min. Triethylamine (13.0 ml, 93.7 mmol) was added
dropwise and stirred at RT for 24 h. The reaction mixture was
quenched with water, extracted with dichloromethane, dried over
sodium sulphate and concentrated under reduced pressure. The crude
product was purified by column chromatography with ethyl
acetate:petroleum ether to afford the title compound as a yellow
solid (0.634 g, 19%). .sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400
MHz): 7.87 (dd, J=8.2, 3.1 Hz, 1H), 7.59 (dd, J=9.1, 4.1 Hz, 1H),
7.45-7.37 (m, 4H), 7.25-7.15 (m, 7H), 4.53 (q, J=6.5 Hz, 1H), 4.43
(d, J=11.8 Hz, 1H), 4.33 (d, J=11.7 Hz, 1H), 1.56 (d, J=6.5 Hz,
3H). Mass: 375.0 (M.sup.+).
[0212] Step 2:
(R)-6-fluoro-2-(1-hydroxyethyl)-3-phenyl-4H-chromen-4-one: To
(R)-2-(1-(benzyloxy)ethyl)-6-fluoro-3-phenyl-4H-chromen-4-one (0.63
g, 1.68 mmol) in dichloromethane (6 ml) cooled to 0.degree. C.,
aluminium chloride (0.330 g, 2.52 mmol) was added portion wise and
stirred at RT for 6 h. The reaction mixture was quenched with 2N
HCl solution, extracted with dichloromethane, dried over sodium
sulphate and concentrated under reduced pressure. The crude product
was purified by column chromatography with ethyl acetate:petroleum
ether to afford the title compound as yellow solid (0.348 g, 73%).
.sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400 MHz): 7.83 (m, 1H), 7.76
(m, 2H), 7.46 (m, 3H), 7.30 (m, 2H), 5.60 (d, J=4.9 Hz, 1H), 4.53
(m, 1H), 1.38 (d, J=6.5 Hz, 3H). Mass: 285.2 (M.sup.++1). Purity:
86.82%. [.alpha.].sup.25.sub.D-1.18 (c=1, CHCl.sub.3). Enantiomeric
excess: 97.8%, enriched in the late eluting isomer (retention time:
11.39 min.) as determined by HPLC on a chiralpak AD-H column.
EXAMPLE 4
(R)-2-(1-hydroxyethyl)-3-phenyl-4H-chromen-4-one
##STR00082##
[0214] Step 1:
(R)-2-(1-(benzyloxy)ethyl)-3-phenyl-4H-chromen-4-one: The title
compound was obtained as a yellow solid (1.50 g, 37%) by following
the procedure described for Step 1 of Example 3 from
1-(2-hydroxyphenyl)-2-phenylethanone (2.40 g, 11.30 mmol),
dichloromethane (30 ml), HATU (8.60 g, 22.60 mmol),
R-(+)2-benzyloxypropionic acid (2.44 g, 13.56 mmol) and
triethylamine (17.0 ml, 122.11 mmol) which was used as such in next
step.
[0215] Step 2: (R)-2-(1-hydroxyethyl)-3-phenyl-4H-chromen-4-one:
The title compound was obtained as a yellow solid (0.650 g, 58%) by
following the procedure described for Step 2 of Example 3 from
(R)-2-(1-(benzyloxy)ethyl)-3-phenyl-4H-chromen-4-one (1.50 g, 4.20
mmol) in dichloromethane (15 ml) cooled to 0.degree. C. and
aluminium chloride (0.843 g, 6.30 mmol). .sup.1H-NMR (.delta. ppm,
CDCl.sub.3, 400 MHz): 8.24 (dd, J=7.9, 1.5 Hz, 1H), 7.72 (m, 1H),
7.54 (d, J=8.0 Hz, 1H), 7.46-7.37 (m, 4H), 7.29 (m, 2H), 4.79 (q,
J=6.6 Hz, 1H), 1.55 (d, J=6.6 Hz, 3H). Mass: 267.0 (M.sup.+).
Purity: 98.28%. [.alpha.].sup.25.sub.D 6.53 (c=1, CHCl.sub.3).
Enantiomeric excess: 92.2%, enriched in the late eluting isomer
(retention time: 10.38 min.) as determined by HPLC on a chiralpak
AD-H column.
EXAMPLE 5
(R)-3-(3-fluorophenyl)-2-(1-hydroxypropyl)-4H-chromen-4-one
##STR00083##
[0217] Step 1:
(R)-2-(1-(benzyloxy)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one:
The title compound was obtained as a yellow solid (1.65 g, 45%) by
following the procedure described for Step 1 of Example 3 from
2-(3-fluorophenyl)-1-(2-hydroxyphenyl)ethanone (2.15 g, 9.36 mmol),
dichloromethane (20 ml), HATU (4.27 g, 11.23 mmol),
R-(+)2-benzyloxybutyric acid (2.00 g, 10.29 mmol) and triethylamine
(14.0 ml, 101.1 mmol). .sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400
MHz): 8.24 (dd, J=7.9, 1.5 Hz, 1H), 7.74 (dt, J=7.1, 1.7 Hz, 1H),
7.58 (dd, J=8.3, 0.4 Hz, 1H), 7.44-7.06 (m, 10H), 4.51 (d, J=7.8
Hz, 1H), 4.34 (d, J=7.8 Hz, 1H), 4.25 (dd, J=7.8, 6.2 Hz, 1H),
2.17-1.90 (m, 2H), 0.95 (t, J=7.5 Hz, 3H). Mass: 389.0
(M.sup.+).
[0218] Step 2:
(R)-3-(3-fluorophenyl)-2-(1-hydroxypropyl)-4H-chromen-4-one: The
title compound was obtained as a yellow solid (0.552 g, 48%) by
following the procedure described for Step 2 of Example 3 from
(R)-2-(1-(benzyloxy)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one
(1.50 g, 3.86 mmol) in dichloromethane (15 ml) cooled to 0.degree.
C. and aluminium chloride (1.00 g, 7.72 mmol). .sup.1H-NMR (.delta.
ppm, CDCl.sub.3, 400 MHz): 8.24 (dd, J=8.0, 1.6 Hz, 1H), 7.72 (m,
1H), 7.52 (dd, J=8.4, 0.5 Hz, 1H), 7.44 (m, 2H), 7.12-7.01 (m,3H),
4.49 (t, J=7.0 Hz, 1H), 1.94 (m, 2H), 0.93 (t, J=7.5 Hz, 3H). Mass:
(299.0 (M.sup.+). Purity: 96.93%. [.alpha.].sup.25.sub.D-14.73
(c=1, CHCl.sub.3). Enantiomeric excess: 85.92%, enriched in the
fast eluting isomer (retention time: 8.57 min) as determined by
HPLC on a chiralpak AS-3R column.
EXAMPLE 6
(R)-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one
##STR00084##
[0220] Step-1:
(R)-2-(1-(benzyloxy)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one: To
2-(3-fluorophenyl)-1-(2-hydroxyphenyl)ethanone (10.0 g, 43.43 mmol)
in dichloromethane (75 ml), HATU (33.0 g, 86.86 mmol) and
R-(+)2-benzyloxypropionic acid (9.39 g, 52.12 mmol) were added and
stirred for 10 min. Triethylamine (65.4 ml, 0.469 mol) was added
dropwise and stirred at RT for 24 h. The reaction mixture was
quenched with water, extracted with dichloromethane, dried over
sodium sulphate and concentrated under reduced pressure. The crude
product was purified by column chromatography with ethyl
acetate:petroleum ether to afford the title compound as a off-white
solid (9.0 g, 55%). .sup.1H-NMR (.delta. ppm, CDCl.sub.3, 400 MHz):
8.23 (dd, J=7.9, 1.2 Hz, 1H), 7.74-7.70 (m, 1H), 7.58 (d, J=8.3 Hz,
1H), 7.43 (t, J=7.2 Hz, 1H), 7.37 (q, J=7.2 Hz, 1H), 7.29-7.15 (m,
5H), 7.09 (dt, J=8.6, 1.7 Hz, 1H), 7.00-6.90 (m, 2H), 4.51-4.35 (m,
3H), 1.57 (d, J=6.4 Hz, 3H).
[0221] Step 2:
(R)-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one: To
(R)-2-(1-(benzyloxy)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one (5.0
g, 13.35 mmol) in dichloromethane (50 ml) cooled to -78.degree. C.,
boron tribromide (1M in dichloromethane, 36.5 ml, 0.145 mmol) was
added dropwise and stirred for 1 h. The reaction mixture was
quenched with 2N HCl solution, extracted with dichloromethane,
dried over sodium sulphate and concentrated under reduced pressure.
The crude product was purified by column chromatography with ethyl
acetate:petroleum ether to afford
(R)-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one as an
off-white solid (3.05 g, 80%). .sup.1H-NMR (.delta. ppm,
CDCl.sub.3, 400 MHz): 8.24 (dd, J=7.9, 1.5 Hz, 1H), 7.73 (m, 1H),
7.54 (d, J=8.1 Hz, 1H), 7.44 (m, 2H), 7.13-7.01 (m, 3H), 4.71 (q,
J=6.6 Hz, 1H), 1.56 (d, J=6.5 Hz, 3H). Mass: 284.9 (M.sup.+).
Purity: 99.73%. [.alpha.].sup.25.sub.D-0.605 (c=1, CHCl.sub.3).
Enantiomeric excess: 95.2%, enriched in the late eluting isomer
(retention time: 10.19 min) as determined by HPLC on a chiralpak
AD-H column.
EXAMPLE 7
##STR00085##
[0223] Step-1:
(S)-1-(3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl
4-chlorobenzoate: To a solution of Example 6 (2.00 g, 7.03 mmol) in
THF (20 ml), 4-chlorobenzoic acid (1.10 g, 2.15 mmol) and
triphenylphosphine (2.70 g, 10.55 mmol) were added and heated to
45.degree. C. followed by and diisopropylazodicarboxylate (2.0 ml,
10.55 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 off-white
solid (2.35 g, 79%) which was used without purification in the next
step.
[0224] Step-2:
(S)-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one: To
(R)-11-(3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl
4-chlorobenzoate (2.35 g, 5.55 mmol) in methanol (20 ml), potassium
carbonate (0.384 g, 2.77 mmol) was added at 0.degree. C. After 30
min the methanol was concentrated, quenched with 2N HCl and
extracted with ethyl acetate. The organic layer was dried over
sodium sulphate and concentrated under reduced pressure. The crude
product was purified by column chromatography with ethyl
acetate:petroleum ether to
afford(S)-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one as
pale yellow solid (1.15 g, 73%). Enantiomeric excess: 95.2%,
enriched in the fast eluting isomer (retention time: 8.75 min.) as
determined by HPLC on a chiralpak AD-H column.
[0225] In order to fully understand and demonstrate the various
embodiment of the invention, provided herein below are certain
examples in detail as an illustration to enable the utility and/or
performance of the present invention.
Illustration 1
(R)-2-(1-(4-amino-3-(3-fluoro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]py-rim-
idin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one
[0226] This example is also described in Example 59 of WO
2012/151525. To a solution of
3-(3-fluoro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
(0.080 g, 0.254 mmol) in THF (2 ml), tris(4-methoxyphenyl)phosphine
(0.134 g, 0.381 mmol) and diisopropylazodicarboxylate (0.07 ml,
0.381 mmol) is added and stirred at room temperature (RT) for 10
minutes. To this mixture
(-)-5-fluoro-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one
(0.077 g, 0.254 mmol) is added and stirred for 12 h. The reaction
mixture is diluted with water and extracted with ethyl acetate. The
organic layer is dried over sodium sulphate and concentrated under
reduced pressure. The crude product is purified by column
chromatography with methanol: dichloromethane to afford the title
compound as an off-white solid. MP: 242-245.degree. C. Enantiomeric
excess: 96.21% Mass: 599.1 (M.sup.++1).
##STR00086##
[0227] This example is also described in Example 68 of WO
2012/151525. The title compound is obtained as an off-white solid
using a procedure that is similar to the one described for
Illustration 1 from tert-butyl 9-trityl-9H-purin-6-ylcarbamate
(0.235 g, 0.494 mmol),
(-)-5-fluoro-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one
(0.150 g, 0.494 mmol), triphenylphosphine (0.194 g, 0.741 mmol),
THF (8 ml) and diisopropylazodicarboxylate (0.15 ml, 0.749 mmol),
followed by the cleavage of the intermediate with trifluoroacetic
acid (1.8 ml) and dichloromethane (5 ml). MP: 194-197.degree. C.
Enantiomeric excess: 99.62%. [.alpha.].sup.25.sub.D 142.00 (c=1,
CHCl.sub.3). Mass: 420.1 (M.sup.++1).
##STR00087##
[0228] This example is also described in Example 114 of WO
2012/151525. The title compound is obtained as off-white solid
using a procedure that is similar to the one described for
Illustration 1 from
3-(4-isopropoxy-3-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
(0.150 g, 0.529 mmol),
(-)-5-fluoro-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one
(0.145 g, 0.481 mmol), tris-4-methoxytriphenylphosphine (0.254 g,
0.721 mmol), THF (3 ml) and diisopropylazodicarboxylate (0.14 ml,
0.721 mmol). MP: 217-220.degree. C. .sup.1H-NMR (.delta. ppm,
CDCl.sub.3, 400 MHz): .delta. 8.22 (s, 1H), 7.61 (dt, J=8.4, 5.4
Hz, 1H), 7.43 (m, 2H), 7.29 (m, 2H), 7.05-6.97 (m, 4H), 6.92 (d,
J=9.4 Hz, 1H), 6.07 (q, J=7.1 Hz, 1H), 5.42 (s, 2H), 4.63 (quintet,
J=6.0 Hz, 1H), 2.28 (s, 3H), 1.97 (d, J=7.1 Hz, 3H), 1.39 (d, J=6.0
Hz, 6H). Enantiomeric excess: 100% as determined by HPLC on a
chiralpak AD-H column, enriched in the fast eluting isomer
(retention time=9.36 min) [.alpha.].sup.25.sub.D 176.04 (c=1,
CHCl.sub.3).
##STR00088##
[0229] This example is also described in Example 115 of WO
2012/151525. The title compound is obtained as an off-white solid
using a procedure that is similar to the one described for
Illustration 1 from
3-(4-isopropoxy-3-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
(0.128 g, 0.453 mmol),
(+)-5-fluoro-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one
(0.125 g, 0.412 mmol), tris-4-methoxytriphenylphosphine (0.217 g,
0.618 mmol), THF (3 ml) and diisopropylazodicarboxylate (0.12 ml,
0.618 mmol). MP: 221-224.degree. C. .sup.1H-NMR (.delta. ppm,
CDCl.sub.3, 400 MHz): .delta. 8.22 (s, 1H), 7.61 (dt, J=8.4, 5.5
Hz, 1H), 7.43 (m, 2H), 7.29 (m, 2H), 7.05-6.95 (m, 4H), 6.92 (d,
J=9.5 Hz, 1H), 6.05 (q, J=7.1 Hz, 1H), 5.40 (s, 2H), 4.62 (quintet,
J=6.0 Hz, 1H), 2.28 (s, 3H), 1.99 (d, J=7.2 Hz, 3H), 1.39 (d, J=6.0
Hz, 6H). Enantiomeric excess: 99.6% as determined by HPLC on a
chiralpak AD-H column, enriched in the late eluting isomer
(retention time=11.43 min) [.alpha.].sup.25.sub.D-183.59 (c=1,
CHCl.sub.3).
##STR00089##
##STR00090##
[0230] This example is also described in Intermediate 141-143 of WO
2012/151525.
[0231] Step-1:
(S)/(R)-1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl
methanesulfonate: To a cooled solution of
(+)-5-fluoro-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one
(0.800 g, 2.63 mmol) in dichloromethane (16 ml) and triethylamine
(1.10 ml, 7.91 mmol), methanesulphonyl chloride (0.400 ml, 5.27
mmol) is added stirred at room temperature for 2 h. The reaction
mass is quenched with water, extracted with dichloromethane, dried
over sodium sulphate and concentrated to afford the title compound
as brown solid which is used as such in next step.
##STR00091##
[0232] Step-2:
(S)/(R)-2-(1-azidoethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:
To a solution of
(S)/(R)-1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl
methane sulfonate (0.900 g, 2.36 mmol) in DMF (18 ml), sodium azide
(0.306 g, 4.72 mmol) is added and heated to 60.degree. C. After 2
h, the reaction mass is quenched with water, extracted with
dichloromehane, dried over sodium sulphate and concentrated. The
crude product is column chromatographed with ethyl
acetate:petroleum ether to afford the title compound as a brown
liquid which is used as such in next step.
##STR00092##
[0233] Step-3:
(S)/(R)-2-(1-aminoethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:
To a solution of
(S)/(R)-2-(1-azidoethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one
(0.600 g, 1.82 mmol) in THF (2.4 ml) and water (1.2 ml),
triphenylphosphine (0.455 g, 1.73 mmol) is added and stirred at
room temperature for 14 h. The reaction mass is quenched with
water, extracted with ethyl acetate, dried over sodium sulphate and
concentrated. The crude product is column chromatographed with
methanol:dichloromethane to afford the title compound as a brown
liquid.
##STR00093##
[0234] This example is also described in Example 136 of WO
2012/151525. To a solution of
(S)/(R)-2-(1-aminoethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one
(0.22 g, 0.730 mmol), tert-butanol (1.5 ml)
N,N-diisopropylethylamine (0.25 ml, 1.46 mmol) and
6-chloro-2-fluoro-9H-purine (0.102 g, 0.663 mmol) are added and
heated to reflux for 248 h. The reaction mixture is concentrated,
quenched with water, extracted with ethyl acetate, dried with
sodium sulphate and concentrated. The crude product is purified by
column chromatography with methanol: ethyl acetate to afford the
title compound as a brown solid. MP: 183-186.degree. C. Mass: 437.9
(M.sup.+). Enantiomeric excess: 33% as determined by HPLC on a
chiralpak AD-H column, enriched in the fast eluting isomer
(retention time=7.21 min).
##STR00094##
[0235] This example is also described in Example 24 of WO
2011/055215. To a solution of
(S)-2-(1-aminoethyl)-6-bromo-3-phenyl-4H-chromen-4-one (0.20 g,
0.581 mmoles) in tert-butanol (6 ml), N,N-diisopropylethyl amine
(0.2 ml, 1.162 mmoles) and 6-bromopurine (0.087 g, 0.435 mmoles)
are added and refluxed for 24 h. The reaction mixture is
concentrated, diluted with water, extracted with ethyl acetate. The
organic layer is dried over sodium sulphate and concentrated under
reduced pressure. The crude product is purified by column
chromatography with methanol: ethyl acetate to afford the title
compound as yellow solid. MP: 151-154.degree. C. .sup.1H-NMR
(.delta. ppm, DMSO-D.sub.6, 400 MHz): .delta. 12.94 (s,1H), 8.09
(br s, 3H), 7.94 (d, J=7.9 Hz, 1H), 7.59 (d, J=8.7 Hz, 1H), 7.42
(m, 6H), 5.22 (br t,1H), 1.82 (d, J=6.4 Hz, 3H). Mass: 463.99
(M.sup.++1).
##STR00095##
[0236] This example is also described in Example 56 of WO
2011/055215. To a solution of
(R)-2-(1-Amino-ethyl)-3-(3-fluoro-phenyl)-chromen-4-one (0.41 g,
1.52 mmoles) in tert-butanol (7 ml), N,N-diisopropylethylamine
(0.53 ml, 3.04 mmoles) and 6-bromopurine (0.242 g, 1.21 mmoles) are
added and refluxed for 24 h. The reaction mixture is concentrated,
diluted with water, and extracted with ethyl acetate. The organic
layer is dried over sodium sulphate and concentrated under reduced
pressure. The crude product is purified by column chromatography
with methanol: ethyl acetate to afford the title compound as an
off-white solid. MP: 274-276.degree. C. .sup.1H-NMR (.delta. ppm,
DMSO-D.sub.6, 400 MHz): .delta. 12.96 (s, 1H), 8.14-8.01 (m, 4H),
8.11 (s, 1H), 7.81 (dt, J=8.5, 1.5 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H),
7.49 (m, 2H), 7.25-7.19 (m, 3H), 5.18 (br m, 1H), 1.56 (d, J=7.0
Hz, 3H). Mass: 402.04 (M.sup.++1).
##STR00096##
[0237] 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. It is intended that the appended
claims define the scope of the invention and that methods and
structures within the scope of these claims and their equivalents
be covered thereby.
[0238] All publications, patents and patent applications cited in
this application are herein incorporated by reference to the same
extent as if each individual publication, patent, or patent
application was specifically and individually indicated to be
incorporated herein by reference.
* * * * *