U.S. patent application number 13/527018 was filed with the patent office on 2012-10-11 for inhibitors of e1 activating enzymes.
This patent application is currently assigned to Millennium Pharmaceuticals, Inc.. Invention is credited to Steven P. Langston, Edward J. Olhava, Stepan Vyskocil.
Application Number | 20120258977 13/527018 |
Document ID | / |
Family ID | 38180115 |
Filed Date | 2012-10-11 |
United States Patent
Application |
20120258977 |
Kind Code |
A1 |
Langston; Steven P. ; et
al. |
October 11, 2012 |
INHIBITORS OF E1 ACTIVATING ENZYMES
Abstract
This invention relates to compounds that inhibit E1 activating
enzymes, pharmaceutical compositions comprising the compounds, and
methods of using the compounds. The compounds are useful for
treating disorders, particularly cell proliferation disorders,
including cancers, inflammatory and neurodegenerative disorders;
and inflammation associated with infection and cachexia.
Inventors: |
Langston; Steven P.; (North
Andover, MA) ; Olhava; Edward J.; (Cambridge, MA)
; Vyskocil; Stepan; (Watertown, MA) |
Assignee: |
Millennium Pharmaceuticals,
Inc.
Cambridge
MA
|
Family ID: |
38180115 |
Appl. No.: |
13/527018 |
Filed: |
June 19, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11700614 |
Jan 31, 2007 |
8207177 |
|
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13527018 |
|
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60764487 |
Feb 2, 2006 |
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Current U.S.
Class: |
514/265.1 ;
544/280 |
Current CPC
Class: |
A61P 37/00 20180101;
A61P 29/00 20180101; A61K 31/519 20130101; A61P 9/14 20180101; A61P
43/00 20180101; C07D 487/04 20130101; A61K 31/52 20130101; A61P
25/28 20180101; C07D 473/34 20130101; C07D 403/04 20130101; A61P
35/00 20180101; C07D 519/00 20130101; A61P 37/02 20180101; C07D
471/04 20130101; A61P 9/00 20180101; A61P 31/00 20180101; A61P
35/02 20180101; C07D 405/14 20130101 |
Class at
Publication: |
514/265.1 ;
544/280 |
International
Class: |
C07D 487/04 20060101
C07D487/04; A61P 25/28 20060101 A61P025/28; A61P 29/00 20060101
A61P029/00; A61K 31/519 20060101 A61K031/519; A61P 35/00 20060101
A61P035/00 |
Claims
1. (canceled)
2. A compound of formula (I-A): ##STR00137## or a pharmaceutically
acceptable salt thereof, wherein: stereochemical configurations
depicted at asterisked positions indicate relative stereochemistry;
Ring A is selected from the group consisting of: ##STR00138##
wherein one ring nitrogen atom in Ring A optionally is oxidized; X
is --CH.sub.2--, --CHF--, --CF.sub.2--, --NH--, or --O--; Y is
--C(R.sup.m)(R.sup.n)--; R.sup.a is selected from the group
consisting of hydrogen, fluoro, --CN, --N.sub.3, --OR.sup.5,
--N(R.sup.4).sub.2, --NR.sup.4CO.sub.2R.sup.6,
--NR.sup.4C(O)R.sup.5, --C(O)N(R.sup.4).sub.2, --C(O)R.sup.5,
--OC(O)N(R.sup.4).sub.2, --OC(O)R.sup.5, --OCO.sub.2R.sup.6, or a
C.sub.1-4 aliphatic or C.sub.1-4 fluoroaliphatic optionally
substituted with one or two substituents independently selected
from the group consisting of --OR.sup.5x, --N(R.sup.4x)(R.sup.4y),
--CO.sub.2R.sup.5x, or --C(O)N(R.sup.4x)(R.sup.4y); or R.sup.a and
R.sup.c together form a bond; R.sup.b is selected from the group
consisting of hydrogen, fluoro, C.sub.1-4 aliphatic, and C.sub.1-4
fluoroaliphatic; R.sup.c is selected from the group consisting of
hydrogen, fluoro, --CN, --N.sub.3, --OR.sup.5, --N(R.sup.4).sub.2,
--NR.sup.4CO.sub.2R.sup.6, --NR.sup.4C(O)R.sup.5,
--C(O)N(R.sup.4).sub.2, --C(O)R.sup.5, --OC(O)N(R.sup.4).sub.2,
--OC(O)R.sup.5, --OCO.sub.2R.sup.6, or a C.sub.1-4 aliphatic or
C.sub.1-4 fluoroaliphatic optionally substituted with one or two
substituents independently selected from the group consisting of
--OR.sup.5x, --N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, or
--C(O)N(R.sup.4x)(R.sup.4y); or R.sup.a and R.sup.c together form a
bond; R.sup.d is selected from the group consisting of hydrogen,
fluoro, C.sub.1-4 aliphatic, and C.sub.1-4 fluoroaliphatic; R.sup.e
is hydrogen, or C.sub.1-4 aliphatic; or R.sup.e, taken together
with one R.sup.f and the intervening carbon atoms, forms a 3- to
6-membered spirocyclic ring; R.sup.e' is hydrogen or C.sub.1-4
aliphatic; each R.sup.f is independently hydrogen, fluoro,
C.sub.1-4 aliphatic, or C.sub.1-4 fluoroaliphatic, provided that if
X is --O-- or --NH--, then R.sup.f is not fluoro; or two R.sup.f
taken together form .dbd.O; or two R.sup.f, taken together with the
carbon atom to which they are attached, form a 3- to 6-membered
carbocyclic ring; or one R.sup.f, taken together with R.sup.e and
the intervening carbon atoms, forms a 3- to 6-membered spirocyclic
ring; R.sup.g is hydrogen, halo, --NO.sub.2, --CN,
--C(R.sup.5).dbd.C(R.sup.5).sub.2, --C.ident.C--R.sup.5,
--OR.sup.5, --SR.sup.6, --S(O)R.sup.6, --SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.4).sub.2, --N(R.sup.4).sub.2,
--NR.sup.4C(O)R.sup.5, --NR.sup.4C(O)N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--R.sup.6, --NR.sup.4CO.sub.2R.sup.6,
--N(R.sup.4)SO.sub.2R.sup.6, --N(R.sup.4)SO.sub.2N(R.sup.4).sub.2,
--O--C(O)R.sup.5, --OCO.sub.2R.sup.6, --OC(O)N(R.sup.4).sub.2,
--C(O)R.sup.5, --CO.sub.2R.sup.5, --C(O)N(R.sup.4).sub.2,
--C(O)N(R.sup.4)--OR.sup.5,
--C(O)N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4)--C(O)R.sup.5,
--C(.dbd.NR.sup.4)--N(R.sup.4).sub.2, --C(.dbd.NR.sup.4)--OR.sup.5,
--N(R.sup.4)--N(R.sup.4).sub.2, --N(R.sup.4)--OR.sup.5,
--C(.dbd.NR.sup.4)--N(R.sup.4)--OR.sup.5,
--C(R.sup.6).dbd.N--OR.sup.5, or an optionally substituted
aliphatic, aryl, heteroaryl, or heterocyclyl; each R.sup.h
independently is hydrogen, halo, --CN--, --N(R.sup.4).sub.2,
--SR.sup.6, or an optionally substituted C.sub.1-4 aliphatic group;
R.sup.j is hydrogen, --OR.sup.5, --SR.sup.6, --N(R.sup.4).sub.2, or
an optionally substituted aliphatic, aryl, or heteroaryl group;
R.sup.k is hydrogen, halo, --OR.sup.5, --SR.sup.6,
--N(R.sup.4).sub.2, or an optionally substituted C.sub.1-4
aliphatic group; R.sup.m is hydrogen, fluoro, --N(R.sup.4).sub.2,
or an optionally substituted C.sub.1-4 aliphatic group; and R.sup.n
is hydrogen, fluoro, or an optionally substituted C.sub.1-4
aliphatic group; or R.sup.m and R.sup.n together form .dbd.O or
.dbd.C(R.sup.5).sub.2; each R.sup.4 independently is hydrogen or an
optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl
group; or two R.sup.4 on the same nitrogen atom, taken together
with the nitrogen atom, form an optionally substituted 4- to
8-membered heterocyclyl ring having, in addition to the nitrogen
atom, 0-2 ring heteroatoms independently selected from N, O, and S;
R.sup.4x is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 fluoroalkyl, or
C.sub.6-10 ar(C.sub.1-4)alkyl, the aryl portion of which may be
optionally substituted; R.sup.4y is hydrogen, C.sub.1-4 alkyl,
C.sub.1-4 fluoroalkyl, C.sub.6-10 ar(C.sub.1-4)alkyl, the aryl
portion of which may be optionally substituted, or an optionally
substituted 5- or 6-membered aryl, heteroaryl, or heterocyclyl
ring; or R.sup.4x and R.sup.4y, taken together with the nitrogen
atom to which they are attached, form an optionally substituted 4-
to 8-membered heterocyclyl ring having, in addition to the nitrogen
atom, 0-2 ring heteroatoms independently selected from N, O, and S;
and each R.sup.5 independently is hydrogen or an optionally
substituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
each R.sup.5x independently is hydrogen, C.sub.1-4 alkyl, C.sub.1-4
fluoroalkyl, or an optionally substituted C.sub.6-10 aryl or
C.sub.6-10 ar(C.sub.1-4)alkyl; each R.sup.6 independently is an
optionally substituted aliphatic, aryl, or heteroaryl group; and m
is 1, 2, or 3.
3. The compound of claim 2, wherein: R.sup.g is hydrogen, C.sub.1-6
aliphatic, C.sub.1-6 fluoroaliphatic, halo, --R.sup.1g, --R.sup.2g,
-T.sup.1-R.sup.1g, -T.sup.1-R.sup.2g, --V.sup.1-T.sup.1-R.sup.1g,
and --V.sup.1-T.sup.1-R.sup.2g; T.sup.1 is a C.sub.1-6 alkylene
chain substituted with 0-2 independently selected R.sup.3a or
R.sup.3b, wherein the alkylene chain optionally is interrupted by
--C(R.sup.5).dbd.C(R.sup.5)--, --C.ident.C--, --O--, --S--,
--S(O)--, --S(O).sub.2--, --SO.sub.2N(R.sup.4)--, --N(R.sup.4)--,
--N(R.sup.4)C(O)--, --NR.sup.4C(O)N(R.sup.4)--,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4)--,
--N(R.sup.4)--C(.dbd.NR.sup.4)--, --N(R.sup.4)CO.sub.2--,
--N(R.sup.4)SO.sub.2--, --N(R.sup.4)SO.sub.2N(R.sup.4)--,
--OC(O)--, --OC(O)N(R.sup.4)--, --C(O)--, --CO.sub.2--,
--C(O)N(R.sup.4)--, --C(.dbd.NR.sup.4)--N(R.sup.4)--,
--C(NR.sup.4).dbd.N(R.sup.4)--, --C(.dbd.NR.sup.4)--O--, or
--C(R.sup.6).dbd.N--O--, and wherein T.sup.1 or a portion thereof
optionally forms part of a 3-7 membered ring; V.sup.1 is
--C(R.sup.5).dbd.C(R.sup.5)--, --C.ident.C--, --O--, --S--,
--S(O)--, --S(O).sub.2--, --SO.sub.2N(R.sup.4)--, --N(R.sup.4)--,
--N(R.sup.4)C(O)--, --NR.sup.4C(O)N(R.sup.4)--,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4)--,
--N(R.sup.4)C(.dbd.NR.sup.4)--, --N(R.sup.4)CO.sub.2--,
--N(R.sup.4)SO.sub.2--, --N(R.sup.4)SO.sub.2N(R.sup.4)--,
--OC(O)--, --OC(O)N(R.sup.4)--, --C(O)--, --CO.sub.2--,
--C(O)N(R.sup.4)--, --C(O)N(R.sup.4)--O--,
--C(O)N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4)--,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4)--C(O)--,
--C(.dbd.NR.sup.4)--N(R.sup.4)--, --C(NR.sup.4).dbd.N(R.sup.4)--,
--C(.dbd.NR.sup.4)--O--, or --C(R.sup.6).dbd.N--O--; each R.sup.1g
independently is an optionally substituted aryl, heteroaryl,
heterocyclyl, or cycloaliphatic ring; each R.sup.2g independently
is --NO.sub.2, --CN, --C(R.sup.5).dbd.C(R.sup.5).sub.2,
--C.ident.C--R.sup.5, --OR.sup.5, --SR.sup.6, --S(O)R.sup.6,
--SO.sub.2R.sup.6, --SO.sub.2N(R.sup.4).sub.2, --N(R.sup.4).sub.2,
--NR.sup.4C(O)R.sup.5, --NR.sup.4C(O)N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--R.sup.6, --NR.sup.4CO.sub.2R.sup.6,
--N(R.sup.4)SO.sub.2R.sup.6, --N(R.sup.4)SO.sub.2N(R.sup.4).sub.2,
--O--C(O)R.sup.5, --OCO.sub.2R.sup.6, --OC(O)N(R.sup.4).sub.2,
--C(O)R.sup.5, --CO.sub.2R.sup.5, --C(O)N(R.sup.4).sub.2,
--C(O)N(R.sup.4)--OR.sup.5,
--C(O)N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4)--C(O)R.sup.5,
--C(.dbd.NR.sup.4)--N(R.sup.4).sub.2, --C(.dbd.NR.sup.4)--OR.sup.5,
--N(R.sup.4)--N(R.sup.4).sub.2, --N(R.sup.4)--OR.sup.5,
--C(.dbd.NR.sup.4)--N(R.sup.4)--OR.sup.5, or
--C(R.sup.6).dbd.N--OR.sup.5; each R.sup.3a independently is
selected from the group consisting of --F, --OH, --O(C.sub.1-4
alkyl), --CN, --N(R.sup.4).sub.2, --C(O)(C.sub.1-4 alkyl),
--CO.sub.2H, --CO.sub.2(C.sub.1-4 alkyl), --C(O)NH.sub.2, and
--C(O)NH(C.sub.1-4 alkyl); each R.sup.3b independently is a
C.sub.1-3 aliphatic optionally substituted with R.sup.3a or
R.sup.7, or two substituents R.sup.3b on the same carbon atom,
taken together with the carbon atom to which they are attached,
form a 3- to 6-membered cycloaliphatic ring; and each R.sup.7
independently is an optionally substituted aryl or heteroaryl
ring.
4. The compound of claim 2, characterized by one or more of the
following features: (a) X is --O--; (b) Y is --CH.sub.2--; (c)
R.sup.a is --OH; (d) R.sup.b and R.sup.d are each independently
hydrogen, fluoro, or C.sub.1-4 aliphatic; (e) R.sup.c is hydrogen,
fluoro, or --OR.sup.5; (f) R.sup.e and R.sup.e' are each hydrogen;
(g) each R.sup.f is hydrogen; (h) each R.sup.h is hydrogen; (i)
R.sup.j is hydrogen or C.sub.1-4 aliphatic; (j) R.sup.k is
hydrogen, halo, or C.sub.1-4 aliphatic; (k) m is 1; and (l)
stereochemical configurations depicted at asterisked positions
indicate absolute stereochemistry.
5. The compound of claim 4, characterized by formula (III):
##STR00139## or a pharmaceutically acceptable salt thereof, wherein
Q is .dbd.N-- or .dbd.C(R.sup.k)--.
6. The compound of claim 5, wherein: R.sup.g is
--V.sup.1-T.sup.1-R.sup.1g, --V.sup.1--R.sup.1g, -T.sup.1-R.sup.1g
or -T.sup.1-V.sup.1--R.sup.1g; V.sup.1 is
--C(R.sup.5).dbd.C(R.sup.5), --C.ident.C--, --O--, --S--, or
--N(R.sup.4)--; T.sup.1 is a C.sub.1-4 alkylene chain optionally
substituted with one or two groups independently selected from
fluoro or a C.sub.1-4 aliphatic or C.sub.1-4 fluoroaliphatic
optionally substituted with one or two substituents independently
selected from the group consisting of --OR.sup.5x,
--N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, and
--C(O)N(R.sup.4x)(R.sup.4y)(O); and R.sup.1g is an optionally
substituted mono- or bicyclic aryl, heteroaryl, heterocyclyl, or
cycloaliphatic group.
7. The compound of claim 6, characterized by formula (V):
##STR00140## or a pharmaceutically acceptable salt thereof,
wherein: V.sup.1 is --N(R.sup.8)--, --O--, or --S--; R.sup.8 is
hydrogen or C.sub.1-4 aliphatic; T.sup.1 is a C.sub.1-4 alkylene
chain optionally substituted with one or two groups independently
selected from fluoro or a C.sub.1-4 aliphatic or C.sub.1-4
fluoroaliphatic optionally substituted with one or two substituents
independently selected from the group consisting of --OR.sup.5x,
--N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, and
--C(O)N(R.sup.4x)(R.sup.4y); and Ring C is a 3- to 8-membered
heterocyclyl or cycloaliphatic ring, or a 5- or 6-membered aryl or
heteroaryl ring, any of which rings is substituted with 0-2 R.sup.o
and 0-2 R.sup.8o; each R.sup.o independently is halo, --NO.sub.2,
--CN, --C(R.sup.5).dbd.C(R.sup.5).sub.2, --C.ident.C--R.sup.5,
--OR.sup.5, --SR.sup.6, --S(O)R.sup.6, --SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.4).sub.2, --N(R.sup.4).sub.2,
--NR.sup.4C(O)R.sup.5, --NR.sup.4C(O)N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--R.sup.6, --NR.sup.4CO.sub.2R.sup.6,
--N(R.sup.4)SO.sub.2R.sup.6, --N(R.sup.4)SO.sub.2N(R.sup.4).sub.2,
--O--C(O)R.sup.5, --OCO.sub.2R.sup.6, --OC(O)N(R.sup.4).sub.2,
--C(O)R.sup.5, --CO.sub.2R.sup.5, --C(O)N(R.sup.4).sub.2,
--C(O)N(R.sup.4)--OR.sup.5,
--C(O)N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4)--C(O)R.sup.5,
--C(.dbd.NR.sup.4)--N(R.sup.4).sub.2, --C(.dbd.NR.sup.4)--OR.sup.5,
--C(.dbd.NR.sup.4)--N(R.sup.4)--OR.sup.5,
--C(R.sup.6).dbd.N--OR.sup.5, or an optionally substituted
aliphatic, or an optionally substituted aryl, heterocyclyl, or
heteroaryl group; or two R.sup.o on the same saturated ring carbon
atom, taken together with the carbon atom, form an optionally
substituted 3- to 8-membered spirocyclic cycloaliphatic or
heterocyclyl ring; or two adjacent R.sup.o, taken together with the
intervening ring atoms, form an optionally substituted fused 4- to
8-membered aromatic or non-aromatic ring having 0-3 ring
heteroatoms selected from the group consisting of O, N, and S; each
R.sup.8o independently is selected from the group consisting of
C.sub.1-4 aliphatic, C.sub.1-4 fluoroaliphatic, halo, --OR.sup.5x,
--N(R.sup.4x)(R.sup.4y), or a C.sub.1-4 aliphatic or C.sub.1-4
fluoroaliphatic optionally substituted with --OR.sup.5x,
--N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, or
--C(O)N(R.sup.4x)(R.sup.4y); R.sup.4x is hydrogen, C.sub.1-4 alkyl,
C.sub.1-4 fluoroalkyl, or C.sub.6-10 ar(C.sub.1-4)alkyl, the aryl
portion of which may be optionally substituted; R.sup.4y is
hydrogen, C.sub.1-4 alkyl, C.sub.1-4 fluoroalkyl, C.sub.6-10
ar(C.sub.1-4)alkyl, the aryl portion of which may be optionally
substituted, or an optionally substituted 5- or 6-membered aryl,
heteroaryl, or heterocyclyl ring; or R.sup.4x and R.sup.4y, taken
together with the nitrogen atom to which they are attached, form an
optionally substituted 4- to 8-membered heterocyclyl ring having,
in addition to the nitrogen atom, 0-2 ring heteroatoms
independently selected from N, O, and S; and each R.sup.5x
independently is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 fluoroalkyl,
or an optionally substituted C.sub.6-10 aryl or C.sub.6-10
ar(C.sub.1-4)alkyl.
8. The compound of claim 7, wherein: T.sup.1 is a C.sub.1-2
alkylene chain optionally substituted with one or two groups
independently selected from fluoro or a C.sub.1-4 aliphatic or
C.sub.1-4 fluoroaliphatic optionally substituted with one or two
substituents independently selected from the group consisting of
--OR.sup.5x, --N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, and
--C(O)N(R.sup.4x)(R.sup.4y); and Ring C is a C.sub.3-6
cycloaliphatic, phenyl, oxazolyl, or isoxazolyl ring, any of which
is substituted with 0-2 R.sup.8o and optionally is fused to an
optionally substituted benzene, dioxolane, or dioxane ring.
9. The compound of claim 5, characterized by formula (VI):
##STR00141## or a pharmaceutically acceptable salt thereof,
wherein: T.sup.1 is a C.sub.1-4 alkylene chain optionally
substituted with one or two groups independently selected from
fluoro or a C.sub.1-4 aliphatic or C.sub.1-4 fluoroaliphatic
optionally substituted with one or two substituents independently
selected from the group consisting of --OR.sup.5x,
--N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, and
--C(O)N(R.sup.4x)(R.sup.4y); and Ring C is a 3- to 8-membered
heterocyclyl or cycloaliphatic ring, or a 5- or 6-membered aryl or
heteroaryl ring, any of which rings is substituted with 0-2 R.sup.o
and 0-2 R.sup.8o; each R.sup.o independently is halo, --NO.sub.2,
--CN, --C(R.sup.5).dbd.C(R.sup.5).sub.2, --C.ident.C--R.sup.5,
--OR.sup.5, --SR.sup.6, --S(O)R.sup.6, --SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.4).sub.2, --N(R.sup.4).sub.2,
--NR.sup.4C(O)R.sup.5, --NR.sup.4C(O)N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--R.sup.6, --NR.sup.4CO.sub.2R.sup.6,
--N(R.sup.4)SO.sub.2R.sup.6, --N(R.sup.4)SO.sub.2N(R.sup.4).sub.2,
--O--C(O)R.sup.5, --OCO.sub.2R.sup.6, --OC(O)N(R.sup.4).sub.2,
--C(O)R.sup.5, --CO.sub.2R.sup.5, --C(O)N(R.sup.4).sub.2,
--C(O)N(R.sup.4)--OR.sup.5,
--C(O)N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4)--C(O)R.sup.5,
--C(.dbd.NR.sup.4)--N(R.sup.4).sub.2, --C(.dbd.NR.sup.4)--OR.sup.5,
--C(.dbd.NR.sup.4)--N(R.sup.4)--OR.sup.5,
--C(R.sup.6).dbd.N--OR.sup.5, or an optionally substituted
aliphatic, or an optionally substituted aryl, heterocyclyl, or
heteroaryl group; or two R.sup.o on the same saturated ring carbon
atom, taken together with the carbon atom, form an optionally
substituted 3- to 8-membered spirocyclic cycloaliphatic or
heterocyclyl ring; or two adjacent R.sup.o, taken together with the
intervening ring atoms, form an optionally substituted fused 4- to
8-membered aromatic or non-aromatic ring having 0-3 ring
heteroatoms selected from the group consisting of O, N, and S; each
R.sup.8o independently is selected from the group consisting of
C.sub.1-4 aliphatic, C.sub.1-4 fluoroaliphatic, halo, --OR.sup.5x,
--N(R.sup.4x)(R.sup.4y), or a C.sub.1-4 aliphatic or C.sub.1-4
fluoroaliphatic optionally substituted with --OR.sup.5x,
--N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, or
--C(O)N(R.sup.4x)(R.sup.4y); R.sup.4x is hydrogen, C.sub.1-4 alkyl,
C.sub.1-4 fluoroalkyl, or C.sub.6-10 ar(C.sub.1-4)alkyl, the aryl
portion of which may be optionally substituted; R.sup.4y is
hydrogen, C.sub.1-4 alkyl, C.sub.1-4 fluoroalkyl, C.sub.6-10
ar(C.sub.1-4)alkyl, the aryl portion of which may be optionally
substituted, or an optionally substituted 5- or 6-membered aryl,
heteroaryl, or heterocyclyl ring; or R.sup.4x and R.sup.4y, taken
together with the nitrogen atom to which they are attached, form an
optionally substituted 4- to 8-membered heterocyclyl ring having,
in addition to the nitrogen atom, 0-2 ring heteroatoms
independently selected from N, O, and S; and each R.sup.5x
independently is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 fluoroalkyl,
or an optionally substituted C.sub.6-10 aryl or C.sub.6-10
ar(C.sub.1-4)alkyl.
10. The compound of claim 9, wherein: T.sup.1 is a C.sub.1-2
alkylene chain optionally substituted with one or two groups
independently selected from fluoro or a C.sub.1-4 aliphatic or
C.sub.1-4 fluoroaliphatic optionally substituted with one or two
substituents independently selected from the group consisting of
--OR.sup.5x, --N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, and
--C(O)N(R.sup.4x)(R.sup.4y); and Ring C is phenyl, which is
substituted with 0-2 R.sup.8o and optionally is fused to an
optionally substituted benzene, dioxolane, or dioxane ring.
11. The compound of claim 5, characterized by formula (VII):
##STR00142## or a pharmaceutically acceptable salt thereof,
wherein: V.sup.2 is --N(R.sup.8)--, --O--, or --S--; R.sup.8 is
hydrogen or C.sub.1-4 aliphatic; and Ring D is an optionally
substituted mono-, bi-, or tricyclic ring system.
12. The compound of claim 11, wherein Ring D is selected from the
group consisting of furanyl, thienyl, pyrrolyl, oxazolyl,
thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,
oxadiazolyl, triazolyl, thiadiazolyl, phenyl, naphthyl, pyranyl,
pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,
indolizinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl,
benzthiazolyl, benzothienyl, benzofuranyl, purinyl, quinolyl,
isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,
naphthyridinyl, pteridinyl, tetrahydrofuranyl, tetrahydrothienyl,
pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl,
tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl,
oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl,
oxazepinyl, thiazepinyl, morpholinyl, quinuclidinyl,
tetrahydroquinolinyl, tetrahydroisoquinolinyl, indanyl,
phenanthridinyl, tetrahydronaphthyl, indolinyl, benzodioxanyl,
benzodioxolyl, chromanyl, cyclopropyl, cyclobutyl, cyclopentyl,
cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl,
cycloheptenyl, cyclooctyl, cyclooctenyl, cyclooctadienyl,
bicycloheptanyl and bicyclooctanyl.
13. The compound of claim 12, wherein: each substitutable saturated
ring carbon atom in Ring D is unsubstituted or substituted with
.dbd.O, .dbd.S, .dbd.C(R.sup.5).sub.2, .dbd.N--N(R.sup.4).sub.2,
.dbd.N--OR.sup.5, .dbd.N--NHC(O)R.sup.5, .dbd.N--NHCO.sub.2R.sup.6,
.dbd.N--NHSO.sub.2R.sup.6, .dbd.N--R.sup.5 or --R.sup.p; each
substitutable unsaturated ring carbon atom in Ring D is
unsubstituted or substituted with --R.sup.p; each substitutable
ring nitrogen atom in Ring D is unsubstituted or substituted with
--R.sup.9p; each R.sup.p independently is halo, --NO.sub.2, --CN,
--C(R.sup.5).dbd.C(R.sup.5).sub.2, --SR.sup.6, --S(O)R.sup.6,
--SO.sub.2R.sup.6, --SO.sub.2N(R.sup.4).sub.2, --N(R.sup.4).sub.2,
--NR.sup.4C(O)R.sup.5, --NR.sup.4C(O)N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--R.sup.6, --NR.sup.4CO.sub.2R.sup.6,
--N(R.sup.4)SO.sub.2R.sup.6, --N(R.sup.4)SO.sub.2N(R.sup.4).sub.2,
--O--C(O)R.sup.5, --OCO.sub.2R.sup.6, --OC(O)N(R.sup.4).sub.2,
--C(O)R.sup.5, --CO.sub.2R.sup.5, --C(O)N(R.sup.4).sub.2,
--C(O)N(R.sup.4)--OR.sup.5,
--C(O)N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4)--C(O)R.sup.5,
--C(.dbd.NR.sup.4)--N(R.sup.4).sub.2, --C(.dbd.NR.sup.4)--OR.sup.5,
--C(.dbd.NR.sup.4)--N(R.sup.4)--OR.sup.5,
--C(R.sup.6).dbd.N--OR.sup.5, or an optionally substituted
aliphatic, or an optionally substituted aryl, heterocyclyl, or
heteroaryl group; or two R.sup.p on the same saturated carbon atom,
taken together with the carbon atom to which they are attached,
form an optionally substituted 3- to 6-membered spirocyclic
cycloaliphatic ring; and each R.sup.9p independently is
--C(O)R.sup.5, --C(O)N(R.sup.4).sub.2, --CO.sub.2R.sup.6,
--SO.sub.2R.sup.6, --SO.sub.2N(R.sup.4).sub.2, or a C.sub.1-4
aliphatic optionally substituted with R.sup.3 or R.sup.7.
14. The compound of claim 12, wherein: each R.sup.p independently
is selected from the group consisting of halo, C.sub.1-6 aliphatic,
C.sub.1-6 fluoroaliphatic, --R.sup.1p, --R.sup.2p,
-T.sup.2-R.sup.1p, and -T.sup.2-R.sup.2p; or two R.sup.p on the
same saturated carbon atom, taken together with the carbon atom to
which they are attached, form an optionally substituted 3- to
6-membered spirocyclic cycloaliphatic ring; T.sup.2 is a C.sub.1-6
alkylene chain optionally substituted with R.sup.3a or R.sup.3b;
each R.sup.1p independently is an optionally substituted aryl,
heteroaryl, or heterocyclyl group; and each R.sup.2p independently
is --NO.sub.2, --CN, --C(R.sup.5).dbd.C(R.sup.5).sub.2,
--C.ident.C--R.sup.5, --OR.sup.5, --SR.sup.6, --S(O)R.sup.6,
--SO.sub.2R.sup.6, --SO.sub.2N(R.sup.4).sub.2, --N(R.sup.4).sub.2,
--NR.sup.4C(O)R.sup.5, --NR.sup.4C(O)N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--R.sup.6, --NR.sup.4CO.sub.2R.sup.6,
--N(R.sup.4)SO.sub.2R.sup.6, --N(R.sup.4)SO.sub.2N(R.sup.4).sub.2,
--O--C(O)R.sup.5, --OCO.sub.2R.sup.6, --OC(O)N(R.sup.4).sub.2,
--C(O)R.sup.5, --CO.sub.2R.sup.5, --C(O)N(R.sup.4).sub.2,
--C(O)N(R.sup.4)--OR.sup.5,
--C(O)N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4)--C(O)R.sup.5,
--C(.dbd.NR.sup.4)--N(R.sup.4).sub.2, --C(.dbd.NR.sup.4)--OR.sup.5,
--C(.dbd.NR.sup.4)--N(R.sup.4)--OR.sup.5, or
--C(R.sup.6).dbd.N--OR.sup.5.
15. The compound of claim 14, wherein Ring D is an optionally
substituted indanyl, tetrahydronaphthyl, or chromanyl.
16. The compound of claim 15, wherein: V.sup.1 is --N(R.sup.8)--;
Ring D is selected from the group consisting of: ##STR00143## each
R.sup.p independently is selected from the group consisting of
halo, --OR.sup.5x, --N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, or
--C(O)N(R.sup.4x)(R.sup.4y), or a C.sub.1-4 aliphatic or C.sub.1-4
fluoroaliphatic optionally substituted with --OR.sup.5x,
--N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, or
--C(O)N(R.sup.4x)(R.sup.4y); each R.sup.8p independently is
selected from the group consisting of fluoro, --OR.sup.5x,
--N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, or
--C(O)N(R.sup.4x)(R.sup.4y), or a C.sub.1-4 aliphatic or C.sub.1-4
fluoroaliphatic optionally substituted with --OR.sup.5x,
--N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, or
--C(O)N(R.sup.4x)(R.sup.4y), provided that R.sup.8p is other than
--OR.sup.5x or --N(R.sup.4x)(R.sup.4y) when located at a position
adjacent to a ring oxygen atom, and further provided that when two
R.sup.8p are attached to the same carbon atom, one must be selected
from the group consisting of fluoro, --CO.sub.2R.sup.5x,
--C(O)N(R.sup.4x)(R.sup.4y), and C.sub.1-4 aliphatic or C.sub.1-4
fluoroaliphatic optionally substituted with --OR.sup.5x,
--N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, or
--C(O)N(R.sup.4x)(R.sup.4y); or two R.sup.8p on the same carbon
atom together form .dbd.O or .dbd.C(R.sup.5x).sub.2; or two
R.sup.8p on the same carbon atom are taken together with the carbon
atom to which they are attached to form a 3- to 6-membered
spirocyclic ring; s is 0, 1, 2, 3, or 4; t is 0, 1, or 2.
17. The compound of claim 5, characterized by formula (VIII):
##STR00144## or a pharmaceutically acceptable salt thereof, wherein
stereochemical configurations depicted at asterisked positions
indicate absolute stereochemistry.
18. The compound of claim 17, characterized by formula (VIIIa):
##STR00145## or a pharmaceutically acceptable salt thereof,
wherein: R.sup.a is --OH; R.sup.b and R.sup.d are each
independently hydrogen, fluoro, or C.sub.1-4 aliphatic; R.sup.c is
hydrogen, fluoro, or --OR.sup.5x; R.sup.8 is hydrogen or C.sub.1-4
aliphatic; each R.sup.p independently is selected from the group
consisting of fluoro, --OR.sup.5x, --N(R.sup.4x)(R.sup.4y),
--CO.sub.2R.sup.5x, or --C(O)N(R.sup.4x)(R.sup.4y), or a C.sub.1-4
aliphatic or C.sub.1-4 fluoroaliphatic optionally substituted with
--OR.sup.5x, --N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, or
--C(O)N(R.sup.4x)(R.sup.4y); each R.sup.8p independently is
selected from the group consisting of fluoro, --OR.sup.5x,
--N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, or
--C(O)N(R.sup.4x)(R.sup.4y), or a C.sub.1-4 aliphatic or C.sub.1-4
fluoroaliphatic optionally substituted with --OR.sup.5x,
--N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, or
--C(O)N(R.sup.4x)(R.sup.4y), provided that R.sup.8p is other than
--OR.sup.5x or --N(R.sup.4x)(R.sup.4y) when located at a position
adjacent to a ring oxygen atom, and further provided that when two
R.sup.8p are attached to the same carbon atom, one must be selected
from the group consisting of fluoro, --CO.sub.2R.sup.5x,
--C(O)N(R.sup.4x)(R.sup.4y), and C.sub.1-4 aliphatic or C.sub.1-4
fluoroaliphatic optionally substituted with --OR.sup.5x,
--N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, or
--C(O)N(R.sup.4x)(R.sup.4y); or two R.sup.8p on the same carbon
atom together form .dbd.O or .dbd.C(R.sup.5x).sub.2; R.sup.4x is
hydrogen, C.sub.1-4 alkyl, C.sub.1-4 fluoroalkyl, or C.sub.6-10
ar(C.sub.1-4)alkyl, the aryl portion of which may be optionally
substituted; R.sup.4y is hydrogen, C.sub.1-4 alkyl, C.sub.1-4
fluoroalkyl, C.sub.6-10 ar(C.sub.1-4)alkyl, the aryl portion of
which may be optionally substituted, or an optionally substituted
5- or 6-membered aryl, heteroaryl, or heterocyclyl ring; or
R.sup.4x and R.sup.4y, taken together with the nitrogen atom to
which they are attached, form an optionally substituted 4- to
8-membered heterocyclyl ring having, in addition to the nitrogen
atom, 0-2 ring heteroatoms independently selected from N, O, and S;
each R.sup.5x independently is hydrogen, C.sub.1-4 alkyl, C.sub.1-4
fluoroalkyl, or an optionally substituted C.sub.6-10 aryl or
C.sub.6-10 ar(C.sub.1-4)alkyl; s is 0, 1, or 2; and t is 0, 1, or
2.
19. (canceled)
20. (canceled)
21. (canceled)
22. (canceled)
23. (canceled)
24. (canceled)
25. (canceled)
26. (canceled)
27. (canceled)
28. (canceled)
29. A pharmaceutical composition, comprising a compound of formula
(I-A): ##STR00146## or a pharmaceutically acceptable salt thereof,
wherein: stereochemical configurations depicted at asterisked
positions indicate relative stereochemistry; Ring A is selected
from the group consisting of: ##STR00147## wherein one ring
nitrogen atom in Ring A optionally is oxidized; X is --CH.sub.2--,
--CHF--, --CF.sub.2--, --NH--, or --O--; Y is
--C(R.sup.m)(R.sup.n)--; R.sup.a is selected from the group
consisting of hydrogen, fluoro, --CN, --N.sub.3, --OR.sup.5,
--N(R.sup.4).sub.2, --NR.sup.4CO.sub.2R.sup.6,
--NR.sup.4C(O)R.sup.5, --C(O)N(R.sup.4).sub.2, --C(O)R.sup.5,
--OC(O)N(R.sup.4).sub.2, --OC(O)R.sup.5, --OCO.sub.2R.sup.6, or a
C.sub.1-4 aliphatic or C.sub.1-4 fluoroaliphatic optionally
substituted with one or two substituents independently selected
from the group consisting of --OR.sup.5x, --N(R.sup.4x)(R.sup.4y),
--CO.sub.2R.sup.5x, or --C(O)N(R.sup.4x)(R.sup.4y); or R.sup.a and
R.sup.c together form a bond; R.sup.b is selected from the group
consisting of hydrogen, fluoro, C.sub.1-4 aliphatic, and C.sub.1-4
fluoroaliphatic; R.sup.c is selected from the group consisting of
hydrogen, fluoro, --CN, --N.sub.3, --OR.sup.5, --N(R.sup.4).sub.2,
--NR.sup.4CO.sub.2R.sup.6, --NR.sup.4C(O)R.sup.5,
--C(O)N(R.sup.4).sub.2, --C(O)R.sup.5, --OC(O)N(R.sup.4).sub.2,
--OC(O)R.sup.5, --OCO.sub.2R.sup.6, or a C.sub.1-4 aliphatic or
C.sub.1-4 fluoroaliphatic optionally substituted with one or two
substituents independently selected from the group consisting of
--OR.sup.5x, --N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, or
--C(O)N(R.sup.4x)(R.sup.4y); or R.sup.a and R.sup.c form a bond;
R.sup.d is selected from the group consisting of hydrogen, fluoro,
C.sub.1-4 aliphatic, and C.sub.1-4 fluoroaliphatic; R.sup.e is
hydrogen, or C.sub.1-4 aliphatic; or R.sup.e, taken together with
one R.sup.f and the intervening carbon atoms, forms a 3- to
6-membered spirocyclic ring; R.sup.e' is hydrogen or C.sub.1-4
aliphatic; each R.sup.f is independently hydrogen, fluoro,
C.sub.1-4 aliphatic, or C.sub.1-4 fluoroaliphatic, provided that if
X is --O-- or --NH--, then R.sup.f is not fluoro; or two R.sup.f
taken together form .dbd.O; or two R.sup.f, taken together with the
carbon atom to which they are attached, form a 3- to 6-membered
carbocyclic ring; or one R.sup.f, taken together with R.sup.e and
the intervening carbon atoms, forms a 3- to 6-membered spirocyclic
ring; R.sup.g is hydrogen, halo, --NO.sub.2, --CN,
--C(R.sup.5).dbd.C(R.sup.5).sub.2, --C.ident.C--R.sup.5,
--OR.sup.5, --SR.sup.6, --S(O)R.sup.6, --SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.4).sub.2, --N(R.sup.4).sub.2,
--NR.sup.4C(O)R.sup.5, --NR.sup.4C(O)N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--R.sup.6, --NR.sup.4CO.sub.2R.sup.6,
--N(R.sup.4)SO.sub.2R.sup.6, --N(R.sup.4)SO.sub.2N(R.sup.4).sub.2,
--O--C(O)R.sup.5, --OCO.sub.2R.sup.6, --OC(O)N(R.sup.4).sub.2,
--C(O)R.sup.5, --CO.sub.2R.sup.5, --C(O)N(R.sup.4).sub.2,
--C(O)N(R.sup.4)--OR.sup.5,
--C(O)N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4)--C(O)R.sup.5,
--C(.dbd.NR.sup.4)--N(R.sup.4).sub.2, --C(.dbd.NR.sup.4)--OR.sup.5,
--N(R.sup.4)--N(R.sup.4).sub.2, --N(R.sup.4)--OR.sup.5,
--C(.dbd.NR.sup.4)--N(R.sup.4)--OR.sup.5,
--C(R.sup.6).dbd.N--OR.sup.5, or an optionally substituted
aliphatic, aryl, heteroaryl, or heterocyclyl; each R.sup.h
independently is hydrogen, halo, --CN--, --N(R.sup.4).sub.2,
--SR.sup.6, or an optionally substituted C.sub.1-4 aliphatic group;
R.sup.j is hydrogen, --OR.sup.5, --SR.sup.6, --N(R.sup.4).sub.2, or
an optionally substituted aliphatic, aryl, or heteroaryl group;
R.sup.k is hydrogen, halo, --OR.sup.5, --SR.sup.6,
--N(R.sup.4).sub.2, or an optionally substituted C.sub.1-4
aliphatic group; R.sup.m is hydrogen, fluoro, --N(R.sup.4).sub.2,
or an optionally substituted C.sub.1-4 aliphatic group; and R.sup.n
is hydrogen, fluoro, or an optionally substituted C.sub.1-4
aliphatic group; or R.sup.m and R together form .dbd.O or
.dbd.C(R.sup.5).sub.2; each R.sup.4 independently is hydrogen or an
optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl
group; or two R.sup.4 on the same nitrogen atom, taken together
with the nitrogen atom, form an optionally substituted 4- to
8-membered heterocyclyl ring having, in addition to the nitrogen
atom, 0-2 ring heteroatoms independently selected from N, O, and S;
R.sup.4x is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 fluoroalkyl, or
C.sub.6-10 ar(C.sub.1-4)alkyl, the aryl portion of which may be
optionally substituted; R.sup.4y is hydrogen, C.sub.1-4 alkyl,
C.sub.1-4 fluoroalkyl, C.sub.6-10 ar(C.sub.1-4)alkyl, the aryl
portion of which may be optionally substituted, or an optionally
substituted 5- or 6-membered aryl, heteroaryl, or heterocyclyl
ring; or R.sup.4x and R.sup.4y, taken together with the nitrogen
atom to which they are attached, form an optionally substituted 4-
to 8-membered heterocyclyl ring having, in addition to the nitrogen
atom, 0-2 ring heteroatoms independently selected from N, O, and S;
and each R.sup.5 independently is hydrogen or an optionally
substituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
each R.sup.5x independently is hydrogen, C.sub.1-4 alkyl, C.sub.1-4
fluoroalkyl, or an optionally substituted C.sub.6-10 aryl or
C.sub.6-10 ar(C.sub.1-4)alkyl; each R.sup.6 independently is an
optionally substituted aliphatic, aryl, or heteroaryl group; and m
is 1, 2, or 3; and a pharmaceutically acceptable carrier.
30. The pharmaceutical composition of claim 29, formulated for
administration to a human patient.
31. (canceled)
32. (canceled)
33. (canceled)
34. (canceled)
35. (canceled)
36. (canceled)
Description
[0001] The present application is a continuation of U.S. Ser. No.
11/700,614, filed Jan. 31, 2007, which claims priority under 35
U.S.C. .sctn.119(e) to U.S. Provisional Application No. 60/764,487,
filed Feb. 2, 2006, the entire contents of which are hereby
incorporated by reference.
FIELD OF THE INVENTION
[0002] This invention relates to compounds, compositions and
methods for the treatment of various disorders, particularly
disorders of cell proliferation, including cancers, and
inflammatory disorders. In particular, the invention provides
compounds which inhibit the activity of E1 type activating
enzymes.
BACKGROUND OF THE INVENTION
[0003] The post-translational modification of proteins by
ubiquitin-like molecules (ubls) is an important regulatory process
within cells, playing key roles in controlling many biological
processes including cell division, cell signaling and the immune
response. Ubls are small proteins that are covalently attached to a
lysine on a target protein via an isopeptide linkage with a
C-terminal glycine of the ubl. The ubiquitin-like molecule alters
the molecular surface of the target protein and can affect such
properties as protein-protein interactions, enzymatic activity,
stability and cellular localization of the target.
[0004] Ubiquitin and other ubls are activated by a specific E1
enzyme which catalyzes the formation of an acyl-adenylate
intermediate with the C-terminal glycine of the ubl. The activated
ubl molecule is then transferred to the catalytic cysteine residue
within the E1 enzyme through formation of a thioester bond
intermediate. The E1-ubl intermediate and an E2 associate,
resulting in a thioester exchange wherein the ubl is transferred to
the active site cysteine of the E2. The ubl is then conjugated to
the target protein, either directly or in conjunction with an E3
ligase, through isopeptide bond formation with the amino group of a
lysine side chain in the target protein.
[0005] The biological consequence of ubl modification depends on
the target in question. Ubiquitin is the best characterized of the
ubls and a consequence of modification by ubiquitination is the
degradation of poly-ubiquitinated proteins by the 26S proteasome.
Ubiquitin is conjugated to its target proteins through an enzymatic
cascade involving its specific E1 activating enzyme, Uba1
(ubiquitin activating enzyme, UAE), a conjugating enzyme from the
family of E2s, and a ubiquitin ligase from either the RING or HECT
classes of E3s. See, Huang et al., Oncogene. 23:1958-71 (2004).
Target specificity is controlled by the particular combination of
E2 and E3 protein, with >40 E2s and >100 E3s being known at
present. In addition to ubiquitin, there are at least 10
ubiquitin-like proteins, each believed to be activated by a
specific E1 activating enzyme and processed through similar but
distinct downstream conjugation pathways. Other ubls for which E1
activating enzymes have been identified include Nedd8
(APPBP1-Uba3), ISG15 (UBE1L) and the SUMO family (Aos1-Uba2).
[0006] The ubl Nedd8 is activated by the heterodimer
Nedd8-activating enzyme (APPBP1-Uba3) (NAE) and is transferred to a
single E2 (Ubc12), ultimately resulting in ligation to cullin
proteins. The function of neddylation is the activation of
cullin-based ubiquitin ligases involved in the ubiquitination and
hence turnover of many cell cycle and cell signaling proteins,
including p27 and I-.kappa.B. See Pan et al., Oncogene. 23:1985-97,
(2004). The ubl SUMO is activated by the heterodimer sumo
activating enzyme (Aos1-Uba2) (SAE) and is transferred to a single
E2 (Ubc9), followed by coordination with multiple E3 ligases,
ultimately resulting in sumoylation of target proteins. Sumo
modification can affect the cellular localization of target
proteins and proteins modified by SUMO family members are involved
in nuclear transport, signal transduction and the stress response.
See Seeler and Dejean, Nat Rev Mol Cell Biol. 4:690-9, (2003). The
function of sumoylation includes activation of cell signaling
pathways (e.g., cytokine, WNT, growth factor, and steroid hormone
signaling) involved in transcription regulation; as well as
pathways involved in control of genomic integrity (e.g., DNA
replication, response to DNA damage, recombination and repair). See
Muller et al, Oncogene. 23:1998-2006, (2004). There are other ubls
(e.g., ISG15, FAT10, Apg12p) for which the biological functions are
still under investigation.
[0007] A particular pathway of importance which is regulated via E1
activating enzyme activities is the ubiquitin-proteasome pathway
(UPP). As discussed above, the enzymes UAE and NAE regulate the UPP
at two different steps in the ubiquitination cascade. UAE activates
ubiquitin in the first step of the cascade, while NAE, via
activation of Nedd8, is responsible for the activation of the
cullin based ligases, which in turn are required for the final
transfer of ubiquitin to certain target proteins A functional UPP
pathway is required for normal cell maintenance. The UPP plays a
central role in the turnover of many key regulatory proteins
involved in transcription, cell cycle progression and apoptosis,
all of which are important in disease states, including tumor
cells. See, e.g., King et al., Science 274: 1652-1659 (1996);
Vorhees et al., Clin. Cancer Res., 9: 6316-6325 (2003); and Adams
et al., Nat. Rev. Cancer, 4: 349-360 (2004). Proliferating cells
are particularly sensitive to inhibition of the UPP. See, Drexler,
Proc. Natl. Acad. Sci., USA 94: 855-860 (1977). The role of the UPP
pathway in oncogenesis has led to the investigation of proteasome
inhibition as a potential anticancer therapy. For example,
modulation of the UPP pathway by inhibition of the 26S proteasome
by VELCADE.RTM. (bortezomib) has proven to be an effective
treatment in certain cancers and is approved for the treatment of
relapsed and refractory multiple myeloma. Examples of proteins
whose levels are controlled by cullin-based ubiquitin ligases which
are downstream of NAE and UAE activity include the CDK inhibitor
p27.sup.Kip1 and the inhibitor of NF.kappa.B, I.kappa.B. See,
Podust et al., Proc. Natl. Acad. Sci., 97: 4579-4584, (2000), and
Read et al., Mol. Cell Biol., 20: 2326-2333, (2000). Inhibition of
the degradation of p27 is expected to block the progression of
cells through the G1 and S phases of the cell cycle. Interfering
with the degradation of I.kappa.B should prevent the nuclear
localization of NF-.kappa.B, transcription of various
NF-.kappa.B-dependent genes associated with the malignant
phenotype, and resistance to standard cytotoxic therapies.
Additionally, NF-.kappa.B plays a key role in the expression of a
number of pro-inflammatory mediators, implicating a role for such
inhibitors in inflammatory diseases. Furthermore, inhibition of UPP
has been implicated as a useful target for additional therapeutics,
such as inflammatory disorders, including, e.g., rheumatoid
arthritis, asthma, multiple sclerosis, psoriasis and reperfusion
injury; neurodegenerative disorders, including e.g., Parkinson's
disease, Alzheimer's disease, triplet repeat disorders; neuropathic
pain; ischemic disorders, e.g., stroke, infarction, kidney
disorders; and cachexia. See, e.g., Elliott and Ross, Am J Clin
Pathol. 116:637-46 (2001); Elliott et al., J Mol Med. 81:235-45
(2003); Tarlac and Storey, J. Neurosci. Res. 74: 406-416 (2003);
Mori et al., Neuropath. Appl. Neurobiol., 31: 53-61 (2005);
Manning, Curr Pain Headache Rep. 8: 192-8 (2004); Dawson and
Dawson, Science 302: 819-822 (2003); Kukan, J Physiol Pharmacol.
55: 3-15 (2004); Wojcik and DiNapoli, Stroke. 35:1506-18 (2004);
Lazarus et al., Am J Physiol. 27:E332-41 (1999).
[0008] Targeting E1 activating enzymes provides a unique
opportunity to interfere with a variety of biochemical pathways
important for maintaining the integrity of cell division and cell
signaling E1 activating enzymes function at the first step of ubl
conjugation pathways; thus, inhibition of an E1 activating enzyme
will specifically modulate the downstream biological consequences
of the ubl modification. As such, inhibition of these activating
enzymes, and the resultant inhibition of downstream effects of
ubl-conjugation, represents a method of interfering with the
integrity of cell division, cell signaling, and several aspects of
cellular physiology which are important for disease mechanisms.
Thus, E1 enzymes such as UAE, NAE, and SAE, as regulators of
diverse cellular functions, are potentially important therapeutic
targets for the identification of novel approaches to treatment of
diseases and disorders.
DESCRIPTION OF THE INVENTION
[0009] This invention provides compounds that are effective
inhibitors of E1 activating enzymes, particularly NAE. The
compounds are useful for inhibiting E1 activity in vitro and in
vivo, and are useful for the treatment of disorders of cell
proliferation, particularly cancers, and other disorders associated
with E1 activity. Compounds of the invention are of the general
formula (I):
##STR00001##
[0010] or a pharmaceutically acceptable salt thereof, wherein:
[0011] stereochemical configurations depicted at asterisked
positions indicate relative stereochemistry;
[0012] Ring A is selected from the group consisting of:
##STR00002##
[0013] wherein one ring nitrogen atom in Ring A optionally is
oxidized; [0014] X is --C(R.sup.f1).sub.2, --N(R.sup.f2)--, or
--O--; [0015] Y is --O--, --S--, or --C(R.sup.m)(R.sup.n)--; [0016]
R.sup.a is selected from the group consisting of hydrogen, fluoro,
--CN, --N.sub.3, --OR.sup.5, --N(R.sup.4).sub.2,
--NR.sup.4CO.sub.2R.sup.6, --NR.sup.4C(O)R.sup.5,
--C(O)N(R.sup.4).sub.2, --C(O)R.sup.5, --OC(O)N(R.sup.4).sub.2,
--OC(O)R.sup.5, --OCO.sub.2R.sup.6, or a C.sub.1-4 aliphatic or
C.sub.1-4 fluoroaliphatic optionally substituted with one or two
substituents independently selected from the group consisting of
--OR.sup.5x, --N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, or
--C(O)N(R.sup.4x)(R.sup.4y); or R.sup.a and R.sup.b together form
.dbd.O; or R.sup.a and R.sup.c together form a bond; [0017] R.sup.b
is selected from the group consisting of hydrogen, fluoro,
C.sub.1-4 aliphatic, and C.sub.1-4 fluoroaliphatic; or R.sup.b and
R.sup.a together form .dbd.O; or R.sup.b, taken together with
R.sup.d and the intervening carbon atoms, forms a fused
cyclopropane ring, which is optionally substituted with one or two
substituents independently selected from fluoro or C.sub.1-4
aliphatic; or R.sup.b, taken together with R.sup.e and the
intervening carbon atoms, forms a fused cyclopropane ring, which is
optionally substituted with one or two substituents independently
selected from fluoro or C.sub.1-4 aliphatic; [0018] R.sup.c is
selected from the group consisting of hydrogen, fluoro, --CN,
--N.sub.3, --OR.sup.5, --N(R.sup.4).sub.2,
--NR.sup.4CO.sub.2R.sup.6, --NR.sup.4C(O)R.sup.5,
--C(O)N(R.sup.4).sub.2, --C(O)R.sup.5, --OC(O)N(R.sup.4).sub.2,
--OC(O)R.sup.5, --OCO.sub.2R.sup.6, or a C.sub.1-4 aliphatic or
C.sub.1-4 fluoroaliphatic optionally substituted with one or two
substituents independently selected from the group consisting of
--OR.sup.5x, --N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, or
--C(O)N(R.sup.4x)(R.sup.4y); or R.sup.c and R.sup.a together form a
bond; or R.sup.c and R.sup.d together form .dbd.O;
[0019] R.sup.d is selected from the group consisting of hydrogen,
fluoro, C.sub.1-4 aliphatic, and C.sub.1-4 fluoroaliphatic; or
R.sup.d and R.sup.c together form .dbd.O; or R.sup.d, taken
together with R.sup.b and the intervening carbon atoms, forms a
fused cyclopropane ring, which is optionally substituted with one
or two substituents independently selected from fluoro or C.sub.1-4
aliphatic; or R.sup.d, taken together with R.sup.e' and the
intervening carbon atoms, forms a fused cyclopropane ring, which is
optionally substituted with one or two substituents independently
selected from fluoro or C.sub.1-4 aliphatic; [0020] R.sup.e is
hydrogen, or C.sub.1-4 aliphatic; or R.sup.e, taken together with
one R.sup.f and the intervening carbon atoms, forms a 3- to
6-membered spirocyclic ring, which is optionally substituted with
one or two substituents independently selected from fluoro or
C.sub.1-4 aliphatic; or R.sup.e, taken together with R.sup.m and
the intervening carbon atoms, forms a fused cyclopropane ring,
which is optionally substituted with one or two substituents
independently selected from fluoro or C.sub.1-4 aliphatic; or
R.sup.e, taken together with R.sup.b and the intervening carbon
atoms, forms a fused cyclopropane ring, which is optionally
substituted with one or two substituents independently selected
from fluoro or C.sub.1-4 aliphatic; [0021] R.sup.e' is hydrogen or
C.sub.1-4 aliphatic; or R.sup.e', taken together with R.sup.m and
the intervening carbon atoms, forms a fused cyclopropane ring,
which is optionally substituted with one or two substituents
independently selected from fluoro or C.sub.1-4 aliphatic; or
R.sup.e', taken together with R.sup.d and the intervening carbon
atoms, forms a fused cyclopropane ring, which is optionally
substituted with one or two substituents independently selected
from fluoro or C.sub.1-4 aliphatic; [0022] each R.sup.f is
independently hydrogen, fluoro, C.sub.1-4 aliphatic, or C.sub.1-4
fluoroaliphatic, provided that if X is --O-- or --NH--, then
R.sup.f is not fluoro; or two R.sup.f taken together form .dbd.O;
or two R.sup.f, taken together with the carbon atom to which they
are attached, form a 3- to 6-membered carbocyclic ring; or one
R.sup.f, taken together with R.sup.e and the intervening carbon
atoms, forms a 3- to 6-membered spirocyclic ring, which is
optionally substituted with one or two substituents independently
selected from fluoro or C.sub.1-4 aliphatic; or one R.sup.f, taken
together with an adjacent R.sup.f1 and the intervening carbon
atoms, forms a cyclopropyl ring, which is optionally substituted
with one or two substituents independently selected from fluoro or
C.sub.1-4 aliphatic; or one R.sup.f and one R.sup.f1 together form
a double bond; [0023] each R.sup.f1 is independently hydrogen or
fluoro; or one R.sup.f1, taken together with an adjacent R.sup.f
and the intervening carbon atoms forms a cyclopropyl ring, which is
optionally substituted with one or two substituents independently
selected from fluoro or C.sub.1-4 aliphatic; or one R.sup.f1 and
one R.sup.f together form a double bond; [0024] R.sup.f2 is
hydrogen, C.sub.1-4 aliphatic, and C.sub.1-4 fluoroaliphatic;
[0025] R.sup.g is hydrogen, halo, --NO.sub.2, --CN,
--C(R.sup.5).dbd.C(R.sup.5).sub.2, --C.ident.C--R.sup.5,
--OR.sup.5, --SR.sup.6, --S(O)R.sup.6, --SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.4).sub.2, --N(R.sup.4).sub.2,
--NR.sup.4C(O)R.sup.5, --NR.sup.4C(O)N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--R.sup.6, --NR.sup.4CO.sub.2R.sup.6,
--N(R.sup.4)SO.sub.2R.sup.6, --N(R.sup.4)SO.sub.2N(R.sup.4).sub.2,
--O--C(O)R.sup.5, --OCO.sub.2R.sup.6, --OC(O)N(R.sup.4).sub.2,
--C(O)R.sup.5, --CO.sub.2R.sup.5, --C(O)N(R.sup.4).sub.2,
--C(O)N(R.sup.4)--OR.sup.5,
--C(O)N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4)--C(O)R.sup.5,
--C(.dbd.NR.sup.4)--N(R.sup.4).sub.2, --C(.dbd.NR.sup.4)--OR.sup.5,
--N(R.sup.4)--N(R.sup.4).sub.2, --N(R.sup.4)--OR.sup.5,
--C(.dbd.NR.sup.4)--N(R.sup.4)--OR.sup.5,
--C(R.sup.6).dbd.N--OR.sup.5, or an optionally substituted
aliphatic, aryl, heteroaryl, or heterocyclyl; [0026] each R.sup.h
independently is hydrogen, halo, --CN--, --OR.sup.5,
--N(R.sup.4).sub.2, --SR.sup.6, or an optionally substituted
C.sub.1-4 aliphatic group; [0027] R.sup.j is hydrogen, --OR.sup.5,
--SR.sup.6, --N(R.sup.4).sub.2, or an optionally substituted
aliphatic, aryl, or heteroaryl group; [0028] R.sup.k is hydrogen,
halo, --OR.sup.5, --SR.sup.6, --N(R.sup.4).sub.2, or an optionally
substituted C.sub.1-4 aliphatic group; [0029] R.sup.m is hydrogen,
fluoro, --N(R.sup.4).sub.2, or an optionally substituted C.sub.1-4
aliphatic group; or R.sup.m and R.sup.n together form .dbd.O or
.dbd.C(R.sup.5).sub.2; or R.sup.m and R.sup.e, taken together with
the intervening carbon atoms, form a fused cyclopropane ring, which
is optionally substituted with one or two substituents
independently selected from fluoro or C.sub.1-4 aliphatic; or
R.sup.m and R.sup.e', taken together with the intervening carbon
atoms, form a fused cyclopropane ring, which is optionally
substituted with one or two substituents independently selected
from fluoro or C.sub.1-4 aliphatic; [0030] R.sup.n is hydrogen,
fluoro, or an optionally substituted C.sub.1-4 aliphatic group; or
R.sup.m and R.sup.n together form .dbd.O or .dbd.C(R.sup.5).sub.2;
[0031] each R.sup.4 independently is hydrogen or an optionally
substituted aliphatic, aryl, heteroaryl, or heterocyclyl group; or
two R.sup.4 on the same nitrogen atom, taken together with the
nitrogen atom, form an optionally substituted 4- to 8-membered
heterocyclyl ring having, in addition to the nitrogen atom, 0-2
ring heteroatoms independently selected from N, O, and S; [0032]
R.sup.4x is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 fluoroalkyl, or
C.sub.6-10 ar(C.sub.1-4)alkyl, the aryl portion of which may be
optionally substituted; [0033] R.sup.4y is hydrogen, C.sub.1-4
alkyl, C.sub.1-4 fluoroalkyl, C.sub.6-10 ar(C.sub.1-4)alkyl, the
aryl portion of which may be optionally substituted, or an
optionally substituted 5- or 6-membered aryl, heteroaryl, or
heterocyclyl ring; or [0034] R.sup.4x and R.sup.4y, taken together
with the nitrogen atom to which they are attached, form an
optionally substituted 4- to 8-membered heterocyclyl ring having,
in addition to the nitrogen atom, 0-2 ring heteroatoms
independently selected from N, O, and S; and [0035] each R.sup.5
independently is hydrogen or an optionally substituted aliphatic,
aryl, heteroaryl, or heterocyclyl group; [0036] each R.sup.5x
independently is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 fluoroalkyl,
or an optionally substituted C.sub.6-10 aryl or C.sub.6-10
ar(C.sub.1-4)alkyl; [0037] each R.sup.6 independently is an
optionally substituted aliphatic, aryl, or heteroaryl group; and
[0038] m is 0, 1, 2, or 3, provided that Y is
--C(R.sup.m)(R.sup.n)-- when m is 0.
[0039] In some embodiments, the invention relates to a compound of
formula (I), characterized by formula (I-A):
##STR00003##
[0040] or a pharmaceutically acceptable salt thereof, wherein:
[0041] stereochemical configurations depicted at asterisked
positions indicate relative stereochemistry;
[0042] Ring A is selected from the group consisting of:
##STR00004##
[0043] wherein one ring nitrogen atom in Ring A optionally is
oxidized; [0044] X is --CH.sub.2--, --CHF--, --CF.sub.2--, --NH--,
or --O--; [0045] Y is --O--, --S--, or --C(R.sup.m)(R.sup.n)--;
[0046] R.sup.a is selected from the group consisting of hydrogen,
fluoro, --CN, --N.sub.3, --OR.sup.5, --N(R.sup.4).sub.2,
--NR.sup.4CO.sub.2R.sup.6, --NR.sup.4C(O)R.sup.5,
--C(O)N(R.sup.4).sub.2, --C(O)R.sup.5, --OC(O)N(R.sup.4).sub.2,
--OC(O)R.sup.5, --OCO.sub.2R.sup.6, C.sub.1-4 fluoroaliphatic, or a
C.sub.1-4 aliphatic optionally substituted with one or two
substituents independently selected from the group consisting of
--OR.sup.5x, --N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, or
--C(O)N(R.sup.4x)(R.sup.4y); [0047] R.sup.b is selected from the
group consisting of hydrogen, fluoro, C.sub.1-4 aliphatic, and
C.sub.1-4 fluoroaliphatic; [0048] R.sup.c is selected from the
group consisting of hydrogen, fluoro, --CN, --N.sub.3, --OR.sup.5,
--N(R.sup.4).sub.2, --NR.sup.4CO.sub.2R.sup.6,
--NR.sup.4C(O)R.sup.5, --C(O)N(R.sup.4).sub.2, --C(O)R.sup.5,
--OC(O)N(R.sup.4).sub.2, --OC(O)R.sup.5, --OCO.sub.2R.sup.6,
C.sub.1-4 fluoroaliphatic, or a C.sub.1-4 aliphatic optionally
substituted with one or two substituents independently selected
from the group consisting of --OR.sup.5x, --N(R.sup.4x)(R.sup.4y),
--CO.sub.2R.sup.5x, or --C(O)N(R.sup.4x)(R.sup.4y); [0049] R.sup.d
is selected from the group consisting of hydrogen, fluoro,
C.sub.1-4 aliphatic, and C.sub.1-4 fluoroaliphatic; [0050] R.sup.e
is hydrogen, or C.sub.1-4 aliphatic; or R.sup.e, taken together
with one R.sup.f and the intervening carbon atoms, forms a 3- to
6-membered spirocyclic ring; [0051] R.sup.e' is hydrogen or
C.sub.1-4 aliphatic; [0052] each R.sup.f is independently hydrogen,
fluoro, C.sub.1-4 aliphatic, or C.sub.1-4 fluoroaliphatic, provided
that if X is --O-- or --NH--, then R.sup.f is not fluoro; or two
R.sup.f taken together form .dbd.O; or two R.sup.f, taken together
with the carbon atom to which they are attached, form a 3- to
6-membered carbocyclic ring; or one R.sup.f, taken together with
R.sup.e and the intervening carbon atoms, forms a 3- to 6-membered
spirocyclic ring; [0053] R.sup.g is hydrogen, halo, --NO.sub.2,
--CN, --C(R.sup.5).dbd.C(R.sup.5).sub.2, --C.ident.C--R.sup.5,
--OR.sup.5, --SR.sup.6, --S(O)R.sup.6, --SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.4).sub.2, --N(R.sup.4).sub.2,
--NR.sup.4C(O)R.sup.5, --NR.sup.4C(O)N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--R.sup.6, --NR.sup.4CO.sub.2R.sup.6,
--N(R.sup.4)SO.sub.2R.sup.6, --N(R.sup.4)SO.sub.2N(R.sup.4).sub.2,
--O--C(O)R.sup.5, --OCO.sub.2R.sup.6, --OC(O)N(R.sup.4).sub.2,
--C(O)R.sup.5, --CO.sub.2R.sup.5, --C(O)N(R.sup.4).sub.2,
--C(O)N(R.sup.4)--OR.sup.5,
--C(O)N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4)--C(O)R.sup.5,
--C(.dbd.NR.sup.4)--N(R.sup.4).sub.2, --C(.dbd.NR.sup.4)--OR.sup.5,
--N(R.sup.4)--N(R.sup.4).sub.2, --N(R.sup.4)--OR.sup.5,
--C(.dbd.NR.sup.4)--N(R.sup.4)--OR.sup.5,
--C(R.sup.6).dbd.N--OR.sup.5, or an optionally substituted
aliphatic, aryl, heteroaryl, or heterocyclyl; [0054] each R.sup.h
independently is hydrogen, halo, --CN--, --OR.sup.5,
--N(R.sup.4).sub.2, --SR.sup.6, or an optionally substituted
C.sub.1-4 aliphatic group; [0055] R.sup.j is hydrogen, --OR.sup.5,
--SR.sup.6, --N(R.sup.4).sub.2, or an optionally substituted
aliphatic, aryl, or heteroaryl group; [0056] R.sup.k is hydrogen,
halo, --OR.sup.5, --SR.sup.6, --N(R.sup.4).sub.2, or an optionally
substituted C.sub.1-4 aliphatic group; [0057] R.sup.m is hydrogen,
fluoro, --N(R.sup.4).sub.2, or an optionally substituted C.sub.1-4
aliphatic group; and [0058] R.sup.n is hydrogen, fluoro, or an
optionally substituted C.sub.1-4 aliphatic group; or [0059] R.sup.m
and R.sup.n together form .dbd.O or .dbd.C(R.sup.5).sub.2; [0060]
each R.sup.4 independently is hydrogen or an optionally substituted
aliphatic, aryl, heteroaryl, or heterocyclyl group; or two R.sup.4
on the same nitrogen atom, taken together with the nitrogen atom,
form an optionally substituted 4- to 8-membered heterocyclyl ring
having, in addition to the nitrogen atom, 0-2 ring heteroatoms
independently selected from N, O, and S; [0061] R.sup.4x is
hydrogen, C.sub.1-4 alkyl, C.sub.1-4 fluoroalkyl, or C.sub.6-10
ar(C.sub.1-4)alkyl, the aryl portion of which may be optionally
substituted; [0062] R.sup.4y is hydrogen, C.sub.1-4 alkyl,
C.sub.1-4 fluoroalkyl, C.sub.6-10 ar(C.sub.1-4)alkyl, the aryl
portion of which may be optionally substituted, or an optionally
substituted 5- or 6-membered aryl, heteroaryl, or heterocyclyl
ring; or [0063] R.sup.4x and R.sup.4y, taken together with the
nitrogen atom to which they are attached, form an optionally
substituted 4- to 8-membered heterocyclyl ring having, in addition
to the nitrogen atom, 0-2 ring heteroatoms independently selected
from N, O, and S; and [0064] each R.sup.5 independently is hydrogen
or an optionally substituted aliphatic, aryl, heteroaryl, or
heterocyclyl group; [0065] each R.sup.5x independently is hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 fluoroalkyl, or an optionally
substituted C.sub.6-10 aryl or C.sub.6-10 ar(C.sub.1-4)alkyl;
[0066] each R.sup.6 independently is an optionally substituted
aliphatic, aryl, or heteroaryl group; and [0067] m is 1, 2, or
3.
[0068] Compounds of the invention include those described generally
above, and are further defined and illustrated by the detailed
description and examples herein.
[0069] As used herein, the term "E1," "E1 enzyme," or "E1
activating enzyme" refers to any one of a family of related
ATP-dependent activating enzymes involved in activating or
promoting ubiquitin or ubiquitin-like (collectively "ubl")
conjugation to target molecules. E1 activating enzymes function
through an adenylation/thioester intermediate formation to transfer
the appropriate ubl to the respective E2 conjugating enzyme through
a transthiolation reaction. The resulting activated ubl-E2 promotes
ultimate conjugation of the ubl to a target protein. A variety of
cellular proteins that play a role in cell signaling, cell cycle,
and protein turnover are substrates for ubl conjugation which is
regulated through E1 activating enzymes (e.g., NAE, UAE, SAE).
Unless otherwise indicated by context, the term "E1 enzyme" is
meant to refer to any E1 activating enzyme protein, including,
without limitation, nedd8 activating enzyme (NAE (APPBP1/Uba3)),
ubiquitin activating enzyme (UAE (Uba1)), sumo activating enzyme
(SAE (Aos1/Uba2)), or ISG15 activating enzyme (Ube1L), preferably
human NAE, SAE or UAE, and more preferably NAE.
[0070] The term "E1 enzyme inhibitor" or "inhibitor of E1 enzyme"
is used to signify a compound having a structure as defined herein,
which is capable of interacting with an E1 enzyme and inhibiting
its enzymatic activity. Inhibiting E1 enzymatic activity means
reducing the ability of an E1 enzyme to activate ubiquitin like
(ubl) conjugation to a substrate peptide or protein (e.g.,
ubiquitination, neddylation, sumoylation). In various embodiments,
such reduction of E1 enzyme activity is at least about 50%, at
least about 75%, at least about 90%, at least about 95%, or at
least about 99%. In various embodiments, the concentration of E1
enzyme inhibitor required to reduce an E1 enzymatic activity is
less than about 1 .mu.M, less than about 500 nM, less than about
100 nM, less than about 50 nM, or less than about 10 nM.
[0071] In some embodiments, such inhibition is selective, i.e., the
E1 enzyme inhibitor reduces the ability of one or more E1 enzymes
(e.g., NAE, UAE, or SAE) to promote ubl conjugation to substrate
peptide or protein at a concentration that is lower than the
concentration of the inhibitor that is required to produce another,
unrelated biological effect. In some such embodiments, the E1
enzyme inhibitor reduces the activity of one E1 enzyme at a
concentration that is lower than the concentration of the inhibitor
that is required to reduce enzymatic activity of a different E1
enzyme. In other embodiments, the E1 enzyme inhibitor also reduces
the enzymatic activity of another E1 enzyme, preferably one that is
implicated in regulation of pathways involved in cancer (e.g., NAE
and UAE).
[0072] The term "about" is used herein to mean approximately, in
the region of, roughly, or around. When the term "about" is used in
conjunction with a numerical range, it modifies that range by
extending the boundaries above and below the numerical values set
forth. In general, the term "about" is used herein to modify a
numerical value above and below the stated value by a variance of
10%.
[0073] The term "aliphatic", as used herein, means straight-chain,
branched or cyclic C.sub.1-C.sub.12 hydrocarbons which are
completely saturated or which contain one or more units of
unsaturation, but which are not aromatic. For example, suitable
aliphatic groups include substituted or unsubstituted linear,
branched or cyclic alkyl, alkenyl, alkynyl groups and hybrids
thereof, such as cycloalkyl, (cycloalkyl)alkyl, (cycloalkenyl)alkyl
or (cycloalkyl)alkenyl. In various embodiments, the aliphatic group
has one to ten, one to eight, one to six, one to four, or one, two,
or three carbons.
[0074] The terms "alkyl", "alkenyl", and "alkynyl", used alone or
as part of a larger moiety, refer to a straight and branched chain
aliphatic group having from one to twelve carbon atoms. For
purposes of the present invention, the term "alkyl" will be used
when the carbon atom attaching the aliphatic group to the rest of
the molecule is a saturated carbon atom. However, an alkyl group
may include unsaturation at other carbon atoms. Thus, alkyl groups
include, without limitation, methyl, ethyl, propyl, allyl,
propargyl, butyl, pentyl, and hexyl. The term "alkoxy" refers to an
--O-alkyl radical.
[0075] For purposes of the present invention, the term "alkenyl"
will be used when the carbon atom attaching the aliphatic group to
the rest of the molecule forms part of a carbon-carbon double bond.
Alkenyl groups include, without limitation, vinyl, 1-propenyl,
1-butenyl, 1-pentenyl, and 1-hexenyl.
[0076] For purposes of the present invention, the term "alkynyl"
will be used when the carbon atom attaching the aliphatic group to
the rest of the molecule forms part of a carbon-carbon triple bond.
Alkynyl groups include, without limitation, ethynyl, 1-propynyl,
1-butynyl, 1-pentynyl, and 1-hexynyl.
[0077] The term "cycloaliphatic", used alone or as part of a larger
moiety, refers to a saturated or partially unsaturated cyclic
aliphatic ring system having from 3 to about 14 members, wherein
the aliphatic ring system is optionally substituted. In some
embodiments, the cycloaliphatic is a monocyclic hydrocarbon having
3-8 or 3-6 ring carbon atoms. Nonlimiting examples include
cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,
cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl,
and cyclooctadienyl. In some embodiments, the cycloaliphatic is a
bridged or fused bicyclic hydrocarbon having 6-12, 6-10, or 6-8
ring carbon atoms, wherein any individual ring in the bicyclic ring
system has 3-8 members.
[0078] In some embodiments, two adjacent substituents on a
cycloaliphatic ring, taken together with the intervening ring
atoms, form an optionally substituted fused 5- to 6-membered
aromatic or 3- to 8-membered non-aromatic ring having 0-3 ring
heteroatoms selected from the group consisting of O, N, and S.
Thus, the term "cycloaliphatic" includes aliphatic rings that are
fused to one or more aryl, heteroaryl, or heterocyclyl rings.
Nonlimiting examples include indanyl,
5,6,7,8-tetrahydroquinoxalinyl, decahydronaphthyl, or
tetrahydronaphthyl, where the radical or point of attachment is on
the aliphatic ring.
[0079] The terms "haloaliphatic", "haloalkyl", "haloalkenyl" and
"haloalkoxy" refer to an aliphatic, alkyl, alkenyl or alkoxy group,
as the case may be, which is substituted with one or more halogen
atoms. As used herein, the term "halogen" or "halo" means F, Cl,
Br, or I. The term "fluoroaliphatic" refers to a haloaliphatic
wherein the halogen is fluoro.
[0080] The terms "aryl" and "ar-", used alone or as part of a
larger moiety, e.g., "aralkyl", "aralkoxy", or "aryloxyalkyl",
refer to a C.sub.6 to C.sub.1-4 aromatic hydrocarbon, comprising
one to three rings, each of which is optionally substituted.
Preferably, the aryl group is a C.sub.6-10 aryl group. Aryl groups
include, without limitation, phenyl, naphthyl, and anthracenyl. In
some embodiments, two adjacent substituents on an aryl ring, taken
together with the intervening ring atoms, form an optionally
substituted fused 5- to 6-membered aromatic or 4- to 8-membered
non-aromatic ring having 0-3 ring heteroatoms selected from the
group consisting of O, N, and S. Thus, the term "aryl", as used
herein, includes groups in which an aromatic ring is fused to one
or more heteroaryl, cycloaliphatic, or heterocyclyl rings, where
the radical or point of attachment is on the aromatic ring.
Nonlimiting examples of such fused ring systems include indolyl,
isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl,
benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl,
phthalazinyl, quinazolinyl, quinoxalinyl, carbazolyl, acridinyl,
phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, fluorenyl, indanyl, phenanthridinyl,
tetrahydronaphthyl, indolinyl, phenoxazinyl, benzodioxanyl, and
benzodioxolyl. An aryl group may be mono-, bi-, tri-, or
polycyclic, preferably mono-, bi-, or tricyclic, more preferably
mono- or bicyclic. The term "aryl" may be used interchangeably with
the terms "aryl group", "aryl moiety", and "aryl ring".
[0081] An "aralkyl" or "arylalkyl" group comprises an aryl group
covalently attached to an alkyl group, either of which
independently is optionally substituted. Preferably, the aralkyl
group is C.sub.6-10 aryl(C.sub.1-6)alkyl, including, without
limitation, benzyl, phenethyl, and naphthylmethyl.
[0082] The terms "heteroaryl" and "heteroar-", used alone or as
part of a larger moiety, e.g., heteroaralkyl, or "heteroaralkoxy",
refer to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or
10 ring atoms; having 6, 10, or 14 n electrons shared in a cyclic
array; and having, in addition to carbon atoms, from one to four
heteroatoms. The term "heteroatom" refers to nitrogen, oxygen, or
sulfur, and includes any oxidized form of nitrogen or sulfur, and
any quaternized form of a basic nitrogen. Thus, when used in
reference to a ring atom of a heteroaryl, the term "nitrogen"
includes an oxidized nitrogen (as in pyridine N-oxide). Certain
nitrogen atoms of 5-membered heteroaryl groups also are
substitutable, as further defined below. Heteroaryl groups include,
without limitation, thienyl, furanyl, pyrrolyl, imidazolyl,
pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,
oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl,
naphthyridinyl, and pteridinyl.
[0083] In some embodiments, two adjacent substituents on a
heteroaryl ring, taken together with the intervening ring atoms,
form an optionally substituted fused 5- to 6-membered aromatic or
4- to 8-membered non-aromatic ring having 0-3 ring heteroatoms
selected from the group consisting of O, N, and S. Thus, the terms
"heteroaryl" and "heteroar-", as used herein, also include groups
in which a heteroaromatic ring is fused to one or more aryl,
cycloaliphatic, or heterocyclyl rings, where the radical or point
of attachment is on the heteroaromatic ring. Nonlimiting examples
include indolyl, isoindolyl, benzothienyl, benzofuranyl,
dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl,
isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,
4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl,
phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and
pyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group may be
mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or
tricyclic, more preferably mono- or bicyclic. The term "heteroaryl"
may be used interchangeably with the terms "heteroaryl ring", or
"heteroaryl group", any of which terms include rings that are
optionally substituted. The term "heteroaralkyl" refers to an alkyl
group substituted by a heteroaryl, wherein the alkyl and heteroaryl
portions independently are optionally substituted.
[0084] As used herein, the terms "aromatic ring" and "aromatic ring
system" refer to an optionally substituted mono-, bi-, or tricyclic
group having 0-6, preferably 0-4 ring heteroatoms, and having 6,
10, or 14.pi. electrons shared in a cyclic array. Thus, the terms
"aromatic ring" and "aromatic ring system" encompass both aryl and
heteroaryl groups.
[0085] As used herein, the terms "heterocycle", "heterocyclyl",
"heterocyclic radical", and "heterocyclic ring" are used
interchangeably and refer to a stable 3- to 7-membered monocyclic,
or to a fused 7- to 10-membered or bridged 6- to 10-membered
bicyclic heterocyclic moiety that is either saturated or partially
unsaturated, and having, in addition to carbon atoms, one or more,
preferably one to four, heteroatoms, as defined above. When used in
reference to a ring atom of a heterocycle, the term "nitrogen"
includes a substituted nitrogen. As an example, in a heterocyclyl
ring having 1-3 heteroatoms selected from oxygen, sulfur or
nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH
(as in pyrrolidinyl), or .sup.+NR (as in N-substituted
pyrrolidinyl). A heterocyclic ring can be attached to its pendant
group at any heteroatom or carbon atom that results in a stable
structure, and any of the ring atoms can be optionally substituted.
Examples of such saturated or partially unsaturated heterocyclic
radicals include, without limitation, tetrahydrofuranyl,
tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl,
pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,
decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl,
dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and
quinuclidinyl.
[0086] In some embodiments, two adjacent substituents on a
heterocyclic ring, taken together with the intervening ring atoms,
form an optionally substituted fused 5- to 6-membered aromatic or
3- to 8-membered non-aromatic ring having 0-3 ring heteroatoms
selected from the group consisting of O, N, and S. Thus, the terms
"heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic
group", "heterocyclic moiety", and "heterocyclic radical", are used
interchangeably herein, and include groups in which a heterocyclyl
ring is fused to one or more aryl, heteroaryl, or cycloaliphatic
rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl,
or tetrahydroquinolinyl, where the radical or point of attachment
is on the heterocyclyl ring. A heterocyclyl group may be mono-,
bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more
preferably mono- or bicyclic. The term "heterocyclylalkyl" refers
to an alkyl group substituted by a heterocyclyl, wherein the alkyl
and heterocyclyl portions independently are optionally
substituted.
[0087] As used herein, the term "partially unsaturated" refers to a
ring moiety that includes at least one double or triple bond
between ring atoms. The term "partially unsaturated" is intended to
encompass rings having multiple sites of unsaturation, but is not
intended to include aryl or heteroaryl moieties, as herein
defined.
[0088] The term "linker group" or "linker" means an organic moiety
that connects two parts of a compound. Linkers typically comprise
an atom such as oxygen or sulfur, a unit such as --NH--,
--CH.sub.2--, --C(O)--, --C(O)NH--, or a chain of atoms, such as an
alkylene chain. The molecular mass of a linker is typically in the
range of about 14 to 200, preferably in the range of 14 to 96 with
a length of up to about six atoms. In some embodiments, the linker
is a C.sub.1-6 alkylene chain which is optionally substituted.
[0089] The term "alkylene" refers to a bivalent alkyl group. An
"alkylene chain" is a polymethylene group, i.e.,
--(CH.sub.2).sub.n--, wherein n is a positive integer, preferably
from one to six, from one to four, from one to three, from one to
two, or from two to three. A substituted alkylene chain is a
polymethylene group in which one or more methylene hydrogen atoms
is replaced with a substituent. Suitable substituents include those
described below for a substituted aliphatic group. An alkylene
chain also may be substituted at one or more positions with an
aliphatic group or a substituted aliphatic group.
[0090] An alkylene chain also can be optionally interrupted by a
functional group. An alkylene chain is "interrupted" by a
functional group when an internal methylene unit is replaced with
the functional group. Examples of suitable "interrupting functional
groups" include --C(R*).dbd.C(R*)--, --C.ident.C--, --O--, --S--,
--S(O)--, --S(O).sub.2--, --S(O).sub.2N(R.sup.+)--, --N(R*)--,
--N(R.sup.+)CO--, --N(R.sup.+)C(O)N(R.sup.+)--,
--N(R.sup.+)CO.sub.2--, --C(O)N(R.sup.+)--, --C(O)--,
--C(O)--C(O)--, --CO.sub.2--, --OC(O)--, --OC(O)O--,
--OC(O)N(R.sup.+)--, --C(NR.sup.+).dbd.N, --C(OR*).dbd.N--,
--N(R.sup.+)--N(R.sup.+)--, or --N(R.sup.+)S(O).sub.2--. Each
R.sup.+, independently, is hydrogen or an optionally substituted
aliphatic, aryl, heteroaryl, or heterocyclyl group, or two R.sup.+
on the same nitrogen atom, taken together with the nitrogen atom,
form a five to eight membered aromatic or non-aromatic ring having,
in addition to the nitrogen atom, zero to two ring heteroatoms
selected from N, O, and S. Each R* independently is hydrogen or an
optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl
group.
[0091] Examples of C.sub.3-6 alkylene chains that have been
"interrupted" with --O-- include --CH.sub.2OCH.sub.2--,
--CH.sub.2O(CH.sub.2).sub.2--, --CH.sub.2O(CH.sub.2).sub.3--,
--CH.sub.2--O--(CH.sub.2).sub.4--, --(CH.sub.2).sub.2OCH.sub.2--,
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--,
--(CH.sub.2).sub.2O(CH.sub.2).sub.3--,
--(CH.sub.2).sub.3O(CH.sub.2)--,
--(CH.sub.2).sub.3O(CH.sub.2).sub.2--, and
--(CH.sub.2).sub.4O(CH.sub.2)--. Other examples of alkylene chains
that are "interrupted" with functional groups include
--CH.sub.2GCH.sub.2--, --CH.sub.2G(CH.sub.2).sub.2--,
--CH.sub.2G(CH.sub.2).sub.3--, --CH.sub.2G(CH.sub.2).sub.4--,
--(CH.sub.2).sub.2GCH.sub.2--,
--(CH.sub.2).sub.2G(CH.sub.2).sub.2--,
--(CH.sub.2).sub.2G(CH.sub.2).sub.3--,
--(CH.sub.2).sub.3G(CH.sub.2)--,
--(CH.sub.2).sub.3G(CH.sub.2).sub.2--, and
--(CH.sub.2).sub.4G(CH.sub.2)--, wherein G is one of the
"interrupting" functional groups listed above.
[0092] For purposes of clarity, all bivalent groups described
herein, including, e.g., the alkylene chain linkers described above
and the variables V.sup.1, V.sup.2, T.sup.1, T.sup.2, T.sup.3, and
T.sup.4, are intended to be read from left to right, with a
corresponding left-to-right reading of the formula or structure in
which the variable appears.
[0093] One of ordinary skill in the art will recognize that when an
alkylene chain having an interruption is attached to a functional
group, certain combinations are not sufficiently stable for
pharmaceutical use. Only stable or chemically feasible compounds
are within the scope of the present invention. A stable or
chemically feasible compound is one in which the chemical structure
is not substantially altered when kept at a temperature from about
-80.degree. C. to about +40.degree. C., preferably from about
-20.degree. C. to about +40.degree. C., in the absence of moisture
or other chemically reactive conditions, for at least a week, or a
compound which maintains its integrity long enough to be useful for
therapeutic or prophylactic administration to a patient.
[0094] The term "substituted", as used herein, means that a
hydrogen radical of the designated moiety is replaced with the
radical of a specified substituent, provided that the substitution
results in a stable or chemically feasible compound. The term
"substitutable", when used in reference to a designated atom, means
that attached to the atom is a hydrogen radical, which can be
replaced with the radical of a suitable substituent.
[0095] The phrase "one or more substituents", as used herein,
refers to a number of substituents that equals from one to the
maximum number of substituents possible based on the number of
available bonding sites, provided that the above conditions of
stability and chemical feasibility are met. Unless otherwise
indicated, an optionally substituted group may have a substituent
at each substitutable position of the group, and the substituents
may be either the same or different. As used herein, the term
"independently selected" means that the same or different values
may be selected for multiple instances of a given variable in a
single compound.
[0096] An aryl (including the aryl moiety in aralkyl, aralkoxy,
aryloxyalkyl and the like) or heteroaryl (including the heteroaryl
moiety in heteroaralkyl and heteroaralkoxy and the like) group may
contain one or more substituents. Examples of suitable substituents
on the unsaturated carbon atom of an aryl or heteroaryl group
include -halo, --NO.sub.2, --CN, --R*, --C(R*).dbd.C(R*).sub.2,
--C.ident.C--R*, --OR*, --SR.sup.o, --S(O)R.sup.o,
--SO.sub.2R.sup.o, --SO.sub.2N(R.sup.+).sub.2, --N(R.sup.+).sub.2,
--NR.sup.+C(O)R*, --NR.sup.+C(O)N(R.sup.+).sub.2,
--NR.sup.+CO.sub.2R.sup.o, --O--CO.sub.2R.sup.o,
--OC(O)N(R.sup.+).sub.2, --O--C(O)R*, --CO.sub.2R*, --C(O)--C(O)R*,
--C(O)R*, --C(O)N(R.sup.+).sub.2,
--C(.dbd.NR.sup.+)--N(R.sup.+).sub.2, --C(.dbd.NR.sup.+)--OR*,
--N(R.sup.+)--N(R.sup.+).sub.2,
--N(R.sup.+)C(.dbd.NR.sup.+)--N(R.sup.+).sub.2,
--NR.sup.+SO.sub.2R.sup.o, --NR.sup.+SO.sub.2N(R.sup.+).sub.2,
--P(O)(R*).sub.2, --P(O)(OR*).sub.2, --O--P(O)--OR*, and
--P(O)(NR.sup.+)--N(R.sup.+).sub.2, wherein R.sup.o is an
optionally substituted aliphatic or aryl group, and R.sup.+ and R*
are as defined above, or two adjacent substituents, taken together
with their intervening atoms, form a 5- to 6-membered unsaturated
or partially unsaturated ring having 0-3 ring atoms selected from
the group consisting of N, O, and S.
[0097] An aliphatic group or a non-aromatic heterocyclic ring may
be substituted with one or more substituents. Examples of suitable
substituents on the saturated carbon of an aliphatic group or of a
non-aromatic heterocyclic ring include, without limitation, those
listed above for the unsaturated carbon of an aryl or heteroaryl
group and the following: .dbd.O, .dbd.S, .dbd.C(R*).sub.2,
.dbd.N--N(R.sup.+).sub.2, .dbd.N--OR*, .dbd.N--NHC(O)R*,
.dbd.N--NHCO.sub.2R.sup.o, .dbd.N--NHSO.sub.2R.sup.o, or
.dbd.N--R*, where each R* and R.sup.o is as defined above. For the
purposes of clarity, the term "substituted aliphatic" refers to an
aliphatic group having at least one non-aliphatic substituent.
[0098] Suitable substituents on a substitutable nitrogen atom of a
heteroaryl or heterocyclic ring include --R*, --N(R*).sub.2,
--C(O)R*, --CO.sub.2R.sup.o, --C(O)--C(O)R*--C(O)CH.sub.2C(O)R*,
--SO.sub.2R.sup.o, --SO.sub.2N(R*).sub.2, --C(.dbd.S)N(R*).sub.2,
--C(.dbd.NH)--N(R*).sub.2, and --NR*SO.sub.2R.sup.o; wherein each
R* and R.sup.o is as defined above.
[0099] Unless otherwise stated, structures depicted herein are
meant to include compounds which differ only in the presence of one
or more isotopically enriched atoms. For example, compounds having
the present structure except for the replacement of a hydrogen atom
by a deuterium or tritium, or the replacement of a carbon atom by a
.sup.13C- or .sup.14C-enriched carbon are within the scope of the
invention.
[0100] It also will be apparent to one skilled in the art that
certain compounds of this invention may exist in tautomeric forms,
all such tautomeric forms of the compounds being within the scope
of the invention. Unless stereochemical configuration is expressly
defined, structures depicted herein are meant to include all
stereochemical forms of the structure; i.e., the R and S
configurations for each asymmetric center. Therefore, unless
otherwise indicated, single stereochemical isomers as well as
enantiomeric and diastereomeric mixtures of the present compounds
are within the scope of the invention. By way of example, the
compounds of formula (I) wherein R.sup.a is hydroxy can have R or S
configuration at the carbon atom bearing R.sup.a. Both the R and
the S stereochemical isomers, as well as all mixtures thereof, are
included within the scope of the invention.
[0101] Where stereochemical configuration at a given asymmetric
center is defined by structure, unless stated otherwise, the
depicted configuration indicates stereochemistry relative to other
asymmetric centers in the molecule. Where stereochemical
configuration is defined by chemical name, the designations (rel),
(R*), and (S*) indicate relative stereochemistry, while the
designations (R), (S), (+), (-), and (abs) indicate absolute
stereochemistry.
[0102] In the compounds of formula (I), stereochemical
configurations depicted at asterisked positions indicate relative
stereochemistry, unless expressly stated to indicate absolute
stereochemistry. Preferably, the diastereomeric purity of the
compound is at least 80%, more preferably at least 90%, still more
preferably at least 95%, and most preferably at least 99%. As used
herein, the term "diastereomeric purity" refers to the amount of a
compound having the depicted relative stereochemistry, expressed as
a percentage of the total amount of all diastereomers present.
[0103] In some embodiments, stereochemical configurations depicted
at asterisked positions indicate absolute as well as relative
stereochemistry. Preferably, the enantiomeric purity of the
compound is at least 80%, more preferably at least 90%, still more
preferably at least 95%, and most preferably at least 99%. As used
herein, the term "enantiomeric purity" refers to the amount of a
compound having the depicted absolute stereochemistry, expressed as
a percentage of the total amount of the depicted compound and its
enantiomer.
[0104] Methods for determining diastereomeric and enantiomeric
purity are well-known in the art. Diastereomeric purity can be
determined by any analytical method capable of quantitatively
distinguishing between a compound and its diastereomers. Examples
of suitable analytical methods include, without limitation, nuclear
magnetic resonance spectroscopy (NMR), gas chromatography (GC), and
high performance liquid chromatography (HPLC). Similarly,
enantiomeric purity can be determined by any analytical method
capable of quantitatively distinguishing between a compound and its
enantiomer. Examples of suitable analytical methods include,
without limitation, GC or HPLC, using a chiral column packing
material. Enantiomers may also be distinguishable by NMR if first
derivatized with an optically enriched derivatizing agent, e.g.,
Mosher's acid.
[0105] In the compounds of formula (I), X is --C(R.sup.f1).sub.2,
--N(R.sup.f2)--, or --O--. Each R.sup.f1 is independently hydrogen
or fluoro; or one R.sup.f1, taken together with an adjacent R.sup.f
and the intervening carbon atoms forms a cyclopropyl ring; or one
R.sup.f1 and one R.sup.f together form a double bond. R.sup.f2 is
hydrogen, C.sub.1-4 aliphatic, or C.sub.1-4 fluoroaliphatic. In
some embodiments, X is --CH.sub.2--, --CHF--, --CF.sub.2--, --NH--,
or --O--. In certain embodiments, X is --CH.sub.2--, --NH--, or
--O--. In certain particular embodiments, X is --O--.
[0106] In the compounds of formula (I), Y is --O--, --S--, or
--C(R.sup.m)(R.sup.n)--, where R.sup.m and R.sup.n are as described
above. In some embodiments, R.sup.m is hydrogen, fluoro,
--NH.sub.2, --NH(C.sub.1-4 aliphatic), --N(C.sub.1-4
aliphatic).sub.2, or C.sub.1-4 aliphatic, or R.sup.m and R.sup.n
together form .dbd.O. In some embodiments, Y is --O-- or
--CH.sub.2.
[0107] In the compounds of formula (I), m is 0, 1, 2, or 3,
provided that Y is --C(R.sup.m)(R.sup.n)-- when in is 0. In some
embodiments, m is 1, 2, or 3. In certain particular embodiments, m
is 1.
[0108] In the compounds of formula (I), R.sup.a is selected from
the group consisting of hydrogen, fluoro, --CN, --N3, --OR.sup.5,
--N(R.sup.4).sub.2, --NR.sup.4CO.sub.2R.sup.6,
--NR.sup.4C(O)R.sup.5, --C(O)N(R.sup.4).sub.2, --C(O)R.sup.5,
--OC(O)N(R.sup.4).sub.2, --OC(O)R.sup.5, --OCO.sub.2R.sup.6, or a
C.sub.1-4 aliphatic or C.sub.1-4 fluoroaliphatic optionally
substituted with one or two substituents independently selected
from the group consisting of --OR.sup.5x, --N(R.sup.4x)(R.sup.4y),
--CO.sub.2R.sup.5x, or --C(O)N(R.sup.4x)(R.sup.4y); or R.sup.a and
R.sup.b together form .dbd.O; or R.sup.a and R.sup.c together form
a bond. In some embodiments R.sup.a is selected from the group
consisting of hydrogen, fluoro, --CN, N.sub.3, C.sub.1-4 aliphatic,
C.sub.1-4 fluoroaliphatic, --OR.sup.5x, --NH(R.sup.4),
--N(H)CO.sub.2R.sup.5, --N(H)C(O)R.sup.5, --C(O)NHR.sup.4,
--C(O)R.sup.5, --OC(O)NHR.sup.4, --OC(O)R.sup.5, and
--OC(O)OR.sup.5. In some embodiments, R.sup.a is selected from the
group consisting of hydrogen, --OH, --OCH.sub.3, C.sub.1-4
aliphatic, C.sub.1-4 fluoroaliphatic, and fluoro. In certain
embodiments, R.sup.a is selected from the group consisting of
hydrogen, --OH, --OCH.sub.3, --CH.sub.3, and fluoro. In certain
particular embodiments, R.sup.a is --OH.
[0109] In the compounds of formula (I), R.sup.c is selected from
the group consisting of hydrogen, fluoro, --CN, --N.sub.3,
--OR.sup.5, --N(R.sup.4).sub.2, --NR.sup.4CO.sub.2R.sup.6,
--NR.sup.4C(O)R.sup.5, --C(O)N(R.sup.4).sub.2, --C(O)R.sup.5,
--OC(O)N(R.sup.4).sub.2, --OC(O)R.sup.5, --OCO.sub.2R.sup.6, or a
C.sub.1-4 aliphatic or C.sub.1-4 fluoroaliphatic optionally
substituted with one or two substituents independently selected
from the group consisting of --OR.sup.5x, --N(R.sup.4x)(R.sup.4y),
--CO.sub.2R.sup.5x, or --C(O)N(R.sup.4x)(R.sup.4y); or R.sup.c and
R.sup.a together form a bond; or R.sup.c and R.sup.d together from
.dbd.O. In some embodiments, R.sup.c is hydrogen, fluoro, --CN,
N.sub.3, C.sub.1-4 aliphatic, C.sub.1-4 fluoroaliphatic,
--OR.sup.5x, --NH(R.sup.4), --N(H)CO.sub.2R.sup.5,
--N(H)C(O)R.sup.5, --C(O)NHR.sup.4, --C(O)R.sup.5,
--OC(O)NHR.sup.4, --OC(O)R.sup.5, and --OC(O)OR.sup.5. In certain
embodiments, R.sup.c is hydrogen, --OH, --OCH.sub.3, or fluoro. In
certain particular embodiments, R.sup.c is hydrogen or --OH.
[0110] In the compounds of formula (I), R.sup.b is selected from
the group consisting of hydrogen, fluoro, C.sub.1-4 aliphatic, and
C.sub.1-4 fluoroaliphatic; or R.sup.b and R.sup.a together form
.dbd.O; or R.sup.b, taken together with R.sup.d and the intervening
carbon atoms, forms a fused cyclopropane ring, which is optionally
substituted with one or two substituents independently selected
from fluoro or C.sub.1-4 aliphatic; or R.sup.b, taken together with
R.sup.e and the intervening carbon atoms, forms a fused
cyclopropane ring, which is optionally substituted with one or two
substituents independently selected from fluoro or C.sub.1-4
aliphatic.
[0111] In the compounds of formula (I), R.sup.d is selected from
the group consisting of hydrogen, fluoro, C.sub.1-4 aliphatic, and
C.sub.1-4 fluoroaliphatic; or R.sup.d and R.sup.c together form
.dbd.O; or R.sup.d, taken together with R.sup.b and the intervening
carbon atoms, forms a fused cyclopropane ring, which is optionally
substituted with one or two substituents independently selected
from fluoro or C.sub.1-4 aliphatic; or R.sup.d, taken together with
R.sup.e' and the intervening carbon atoms, forms a fused
cyclopropane ring, which is optionally substituted with one or two
substituents independently selected from fluoro or C.sub.1-4
aliphatic.
[0112] In some embodiments, each of R.sup.b and R.sup.d
independently is selected from the group consisting of hydrogen,
fluoro, C.sub.1-4 aliphatic, and C.sub.1-4 fluoroaliphatic. In some
embodiments, one of R.sup.b and R.sup.d is C.sub.1-4 aliphatic and
the other is hydrogen. In some embodiments, R.sup.b and R.sup.d are
each hydrogen.
[0113] In one embodiment, R.sup.a and R.sup.c are each --OH, and
R.sup.b and R.sup.d are each hydrogen. In another embodiment,
R.sup.a is --OH, and each of R.sup.b, R.sup.c, and R.sup.d is
hydrogen. In another embodiment, R.sup.a is --OH, R.sup.c is fluoro
or --OCH.sub.3, and R.sup.b and R.sup.d are each hydrogen. In
another embodiment, R.sup.a is --OH, R.sup.b is --CH.sub.3, R.sup.c
is hydrogen or --OH, and R.sup.d is hydrogen. In another
embodiment, R.sup.a and R.sup.c together form a bond, and R.sup.b
and R.sup.d are each hydrogen.
[0114] In the compounds of formula (I), each R.sup.f independently
is independently hydrogen, fluoro, C.sub.1-4 aliphatic, or
C.sub.1-4 fluoroaliphatic, provided that if X is --O-- or --NH--,
then R.sup.f is not fluoro; or two R.sup.f taken together form
.dbd.O; or two R.sup.f, taken together with the carbon atom to
which they are attached, form a 3- to 6-membered carbocyclic ring;
or one R.sup.f, taken together with R.sup.e and the intervening
carbon atoms, forms a 3- to 6-membered spirocyclic ring, which is
optionally substituted with one or two substituents independently
selected from fluoro or C.sub.1-4 aliphatic; or one R.sup.f, taken
together with an adjacent R.sup.f1 and the intervening carbon atoms
forms a cyclopropyl ring, which is optionally substituted with one
or two substituents independently selected from fluoro or C.sub.1-4
aliphatic; or one R.sup.f and one R.sup.f1 together form a double
bond. In some embodiments, each R.sup.f independently is hydrogen
or C.sub.1-4 aliphatic. In some such embodiments, each R.sup.f
independently is hydrogen or --CH.sub.3. In certain embodiments,
one R.sup.f is hydrogen or --CH.sub.3, and the other R.sup.f is
hydrogen. In certain particular embodiments, each R.sup.f is
hydrogen.
[0115] In the compounds of formula (I), R.sup.e is hydrogen, or
C.sub.1-4 aliphatic; or R.sup.e, taken together with one R.sup.f
and the intervening carbon atoms, forms a 3- to 6-membered
spirocyclic ring, which is optionally substituted with one or two
substituents independently selected from fluoro or C.sub.1-4
aliphatic; or R.sup.e, taken together with R.sup.m and the
intervening carbon atoms, forms a fused cyclopropane ring, which is
optionally substituted with one or two substituents independently
selected from fluoro or C.sub.1-4 aliphatic; or R.sup.e, taken
together with R.sup.b and the intervening carbon atoms, forms a
fused cyclopropane ring, which is optionally substituted with one
or two substituents independently selected from fluoro or C.sub.1-4
aliphatic. In some embodiments, R.sup.e is hydrogen or C.sub.1-4
aliphatic. In some such embodiments, R.sup.e is hydrogen or
--CH.sub.3. In certain embodiments, R.sup.e is hydrogen.
[0116] In the compounds of formula (I), R.sup.e is hydrogen or
C.sub.1-4 aliphatic; or R.sup.e, taken together with R.sup.m and
the intervening carbon atoms, forms a fused cyclopropane ring,
which is optionally substituted with one or two substituents
independently selected from fluoro or C.sub.1-4 aliphatic; or
R.sup.e', taken together with R.sup.d and the intervening carbon
atoms, forms a fused cyclopropane ring, which is optionally
substituted with one or two substituents independently selected
from fluoro or C.sub.1-4 aliphatic. In some embodiments, R.sup.e'
is hydrogen or C.sub.1-4 aliphatic. In certain particular
embodiments, R.sup.e' is hydrogen.
[0117] In the compounds of formula (I), Ring A is selected from the
group consisting of:
##STR00005##
[0118] where R.sup.g, R.sup.h, R.sup.j and R.sup.k are as defined
above and as further defined below.
[0119] In the compounds of formula (I), each R.sup.h independently
is hydrogen, halo, --CN--, --OR.sup.5, --N(R.sup.4).sub.2,
--SR.sup.6, or an optionally substituted C.sub.1-4 aliphatic group.
In some embodiments, each R.sup.h independently is hydrogen, halo,
--CN, --OH, --O--(C.sub.1-4 aliphatic), --NH.sub.2,
--NH--(C.sub.1-4 aliphatic), --N(C.sub.1-4 aliphatic).sub.2, --SH,
--S--(C.sub.1-4 aliphatic), or an optionally substituted C.sub.1-4
aliphatic group. In certain embodiments, R.sup.h is hydrogen or
chloro. In certain particular embodiments, R.sup.h is hydrogen.
[0120] In the compounds of formula (I), each R.sup.j independently
is hydrogen, --OR.sup.5, --N(R.sup.4).sub.2, --SR.sup.6, or an
optionally substituted aliphatic, aryl, or heteroaryl group. In
some embodiments, each R.sup.j independently is hydrogen, --OH,
--O--(C.sub.1-4 aliphatic), --NH.sub.2, --NH--(C.sub.1-4
aliphatic), --N(C.sub.1-4 aliphatic).sub.2, --SH, --S--(C.sub.1-4
aliphatic), or an optionally substituted C.sub.1-4 aliphatic group.
In certain embodiments, R.sup.1 is hydrogen or C.sub.1-4 aliphatic.
In certain particular embodiments, R.sup.h is hydrogen.
[0121] In the compounds of formula (I), R.sup.k is hydrogen, halo,
--OR.sup.5, --N(R.sup.4).sub.2, --SR.sup.6, or an optionally
substituted C.sub.1-4 aliphatic group. In some embodiments, each
R.sup.k independently is hydrogen, halo, --OH, --O--(C.sub.1-4
aliphatic), --NH.sub.2, --NH--(C.sub.1-4 aliphatic), --N(C.sub.1-4
aliphatic).sub.2, --SH, --S--(C.sub.1-4 aliphatic), or an
optionally substituted C.sub.1-4 aliphatic group. In certain
embodiments, R.sup.k is hydrogen, halo, or C.sub.1-4 aliphatic. In
certain particular embodiments, R.sup.k is hydrogen.
[0122] In some embodiments, the compound of formula (I) is
characterized by at least one of the following features:
[0123] (a) X is --O--;
[0124] (b) Y is --O-- or --CH.sub.2--;
[0125] (c) R.sup.a is --OH;
[0126] (d) R.sup.b and R.sup.d are each independently hydrogen or
C.sub.1-4 aliphatic;
[0127] (e) R.sup.c is hydrogen, fluoro, or --OR.sup.5;
[0128] (f) R.sup.e and R.sup.e' are each hydrogen;
[0129] (g) each R.sup.f is hydrogen;
[0130] (h) each R.sup.h is hydrogen;
[0131] (i) R.sup.j is hydrogen or C.sub.1-4 aliphatic;
[0132] (j) R.sup.k is hydrogen, halo, or C.sub.1-4 aliphatic;
[0133] (k) m is 1; and
[0134] (l) stereochemical configurations depicted at asterisked
positions indicate absolute stereochemistry.
[0135] In the compounds of formula (I), R.sup.g is hydrogen, halo,
--NO.sub.2, --CN, --C(R.sup.5).dbd.C(R.sup.5).sub.2,
--C.ident.C--R.sup.5, --OR.sup.5, --SR.sup.6, --S(O)R.sup.6,
--SO.sub.2R.sup.6, --SO.sub.2N(R.sup.4).sub.2, --N(R.sup.4).sub.2,
--NR.sup.4C(O)R.sup.5, --NR.sup.4C(O)N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--R.sup.6, --NR.sup.4CO.sub.2R.sup.6,
--N(R.sup.4)SO.sub.2R.sup.6, --N(R.sup.4)SO.sub.2N(R.sup.4).sub.2,
--O--C(O)R.sup.5, --OCO.sub.2R.sup.6, --OC(O)N(R.sup.4).sub.2,
--C(O)R.sup.5, --CO.sub.2R.sup.5, --C(O)N(R.sup.4).sub.2,
--C(O)N(R.sup.4)--OR.sup.5,
--C(O)N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4)--C(O)R.sup.5,
--C(.dbd.NR.sup.4)--N(R.sup.4).sub.2, --C(.dbd.NR.sup.4)--OR.sup.5,
--N(R.sup.4)--N(R.sup.4).sub.2, --N(R.sup.4)--OR.sup.5,
--C(.dbd.NR.sup.4)--N(R.sup.4)--OR.sup.5,
--C(R.sup.6).dbd.N--OR.sup.5, or an optionally substituted
aliphatic, aryl, heteroaryl, or heterocyclyl.
[0136] In some embodiments, R.sup.g is hydrogen, C.sub.1-6
aliphatic, C.sub.1-6 fluoroaliphatic, halo, --R.sup.1g, --R.sup.2g,
-T.sup.1-R.sup.1g, -T.sup.1-R.sup.2g, --V.sup.1-T.sup.1-R.sup.2g,
and --V.sup.1-T.sup.1-R.sup.2g, where the variables R.sup.1g,
R.sup.2g, V.sup.1, and T.sup.1 have the values described below.
[0137] T.sup.1 is a C.sub.1-6 alkylene chain substituted with 0-2
independently selected R.sup.3a or R.sup.3b, wherein the alkylene
chain optionally is interrupted by --C(R.sup.5).dbd.C(R.sup.5)--,
--C.ident.C--, --O--, --S--, --S(O)--, --S(O).sub.2--,
--SO.sub.2N(R.sup.4)--, --N(R.sup.4)--, --N(R.sup.4)C(O)--,
--NR.sup.4C(O)N(R.sup.4)--,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4)--,
--N(R.sup.4)--C(.dbd.NR.sup.4)--, --N(R.sup.4)CO.sub.2--,
--N(R.sup.4)SO.sub.2--, --N(R.sup.4)SO.sub.2N(R.sup.4)--,
--OC(O)--, --OC(O)N(R.sup.4)--, --C(O)--, --CO.sub.2--,
--C(O)N(R.sup.4)--, --C(.dbd.NR.sup.4)--N(R.sup.4)--,
--C(NR.sup.4).dbd.N(R.sup.4)--, --C(.dbd.NR.sup.4)--O--, or
--C(R.sup.6).dbd.N--O--, and wherein T.sup.1 or a portion thereof
optionally forms part of a 3-7 membered ring.
[0138] In some embodiments, T.sup.1 is a C.sub.1-4 alkylene chain
optionally substituted with one or two groups independently
selected from fluoro or a C.sub.1-4 aliphatic or C.sub.1-4
fluoroaliphatic optionally substituted with one or two substituents
independently selected from the group consisting of --OR.sup.5x,
--N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, and
--C(O)N(R.sup.4x)(R.sup.4y).
[0139] In certain embodiments, T.sup.1 is a C.sub.1-4 alkylene
chain optionally substituted with one or two groups independently
selected from fluoro, C.sub.1-4 aliphatic, and C.sub.1-4
fluoroaliphatic.
[0140] Each R.sup.3a independently is selected from the group
consisting of --F, --OH, --O(C.sub.1-4 alkyl), --CN,
--N(R.sup.4).sub.2, --C(O)(C.sub.1-4 alkyl), --CO.sub.2H,
--CO.sub.2(C.sub.1-4 alkyl), --C(O)NH.sub.2, and --C(O)NH(C.sub.1-4
alkyl).
[0141] Each R.sup.3b independently is a C.sub.1-3 aliphatic
optionally substituted with R.sup.3a or R.sup.7, or two
substituents R.sup.3b on the same carbon atom, taken together with
the carbon atom to which they are attached, form a 3- to 6-membered
cycloaliphatic ring.
[0142] Each R.sup.7 independently is an optionally substituted aryl
or heteroaryl ring.
[0143] V.sup.1 is --C(R.sup.5).dbd.C(R.sup.5)--, --C.ident.C--,
--O--, --S--, --S(O)--, --S(O).sub.2--, --SO.sub.2N(R.sup.4)--,
--N(R.sup.4)--, --N(R.sup.4)C(O)--, --NR.sup.4C(O)N(R.sup.4)--,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4)--,
--N(R.sup.4)C(.dbd.NR.sup.4)--, --N(R.sup.4)CO.sub.2--,
--N(R.sup.4)SO.sub.2--, --N(R.sup.4)SO.sub.2N(R.sup.4)--,
--OC(O)--, --OC(O)N(R.sup.4)--, --C(O)--, --CO.sub.2--,
--C(O)N(R.sup.4)--, --C(O)N(R.sup.4)--O--,
--C(O)N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4)--,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4)--C(O)--,
--C(.dbd.NR.sup.4)--N(R.sup.4)--, --C(NR.sup.4).dbd.N(R.sup.4)--,
--C(.dbd.NR.sup.4)--O--, or --C(R.sup.6).dbd.N--O--. In some
embodiments, V.sup.1 is --N(R.sup.4)C(O)--,
--N(R.sup.4)C(O)N(R.sup.4)--, --N(R.sup.4)SO.sub.2--,
--N(R.sup.4)SO.sub.2N(R.sup.4)--, or --N(R.sup.4)CO.sub.2--. In
certain such embodiments, V.sup.1 is --N(R.sup.4)C(O)-- or
--N(R.sup.4)C(O)N(R.sup.4)--. In other embodiments, V.sup.1 is
--C(R.sup.5).dbd.C(R.sup.5), --C.ident.C--, --O--, --S--, or
--N(R.sup.4)--.
[0144] Each R.sup.1g independently is an optionally substituted
aryl, heteroaryl, heterocyclyl, or cycloaliphatic ring.
[0145] Each R.sup.2g independently is --NO.sub.2, --CN,
--C(R.sup.5).dbd.C(R.sup.5).sub.2, --C.ident.C--R.sup.5,
--OR.sup.5, --SR.sup.6, --S(O)R.sup.6, --SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.4).sup.2, --N(R.sup.4).sup.2,
--NR.sup.4C(O)R.sup.5, --NR.sup.4C(O)N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--R.sup.6, --NR.sup.4CO.sub.2R.sup.6,
--N(R.sup.4)SO.sub.2R.sup.6, --N(R.sup.4) SO.sub.2N(R.sup.4).sub.2,
--O--C(O)R.sup.5, --OCO.sub.2R.sup.6, --OC(O)N(R.sup.4).sub.2,
--C(O)R.sup.5, --CO.sub.2R.sup.5, --C(O)N(R.sup.4).sub.2,
--C(O)N(R.sup.4)--OR.sup.5,
--C(O)N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4)--C(O)R.sup.5,
--C(.dbd.NR.sup.4)--N(R.sup.4).sub.2, --C(.dbd.NR.sup.4)--OR.sup.5,
--N(R.sup.4)--N(R.sup.4).sub.2, --N(R.sup.4)--OR.sup.5,
--C(.dbd.NR.sup.4)--N(R.sup.4)--OR.sup.5, or
--C(R.sup.6).dbd.N--OR.sup.5.
[0146] The invention also relates to a subgenus of the compounds of
formula (I), characterized by formula (II):
##STR00006##
[0147] or a pharmaceutically acceptable salt thereof, wherein Ring
A and the variables X, Y, R.sup.a, R.sup.b, R.sup.c, R.sup.d,
R.sup.e, R.sup.e', R.sup.f, and m have the values and preferred
values described above for formula (I).
[0148] The invention also relates to a subgenus of the compounds of
formula (I), characterized by formula (III):
##STR00007##
[0149] or a pharmaceutically acceptable salt thereof, wherein Q is
.dbd.N-- or .dbd.C(R.sup.k)--, and the variables X, Y, R.sup.a,
R.sup.b, R.sup.c, R.sup.d, R.sup.e, R.sup.f, R.sup.g, R.sup.h,
R.sup.j, R.sup.k, and m have the values and preferred values
described above for formula (I).
[0150] Various particular embodiments of the invention relate to
subgenera of the compounds of formula (III), represented by
formulae (III-A), (III-B), (III-C), (III-D), and (III-F):
##STR00008##
[0151] or a pharmaceutically acceptable salt thereof, wherein the
variables Q, R.sup.a, R.sup.c, R.sup.g, R.sup.h and R.sup.j have
the values and preferred values described herein for formula
(I).
[0152] One embodiment of the invention relates to a compound of
formula (I), wherein R.sup.g is an optionally substituted aryl,
heteroaryl, or heterocyclyl group. In some such embodiments, the
invention relates to a subgenus of the compounds of formula (I),
characterized by formula (IV):
##STR00009##
[0153] or a pharmaceutically acceptable salt thereof, wherein:
[0154] Ring B is an optionally substituted 5- or 6-membered aryl or
heteroaryl ring having zero to three ring nitrogen atoms and
optionally one additional ring heteroatom selected from oxygen and
sulfur; and
[0155] the variables Q, X, Y, R.sup.a, R.sup.b, R.sup.c, R.sup.d,
R.sup.e, R.sup.f, R.sup.h, R.sup.j, and m have the values and
preferred values described above for formula (I).
[0156] In some embodiments, R.sup.g is an optionally substituted
furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,
pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,
thiadiazolyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,
or triazinyl, wherein one ring nitrogen atom in R.sup.g optionally
is oxidized. In certain particular embodiments, R.sup.g is an
optionally substituted phenyl, imidazolyl, or triazolyl.
[0157] Substitutable ring carbon atoms in Ring B preferably are
substituted with 0-3 substituents independently selected from the
group consisting of halo, --NO.sub.2, --CN,
--C(R.sup.5).dbd.C(R.sup.5).sub.2, --C.ident.C--R.sup.5,
--OR.sup.5, --SR.sup.6, --S(O)R.sup.6, --SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.4).sub.2, --N(R.sup.4).sub.2,
--NR.sup.4C(O)R.sup.5, --NR.sup.4C(O)N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--R.sup.6, --NR.sup.4CO.sub.2R.sup.6,
--N(R.sup.4)SO.sub.2R.sup.6, --N(R.sup.4)SO.sub.2N(R.sup.4).sub.2,
--O--C(O)R.sup.5, --OCO.sub.2R.sup.6, --OC(O)N(R.sup.4).sub.2,
--C(O)R.sup.5, --CO.sub.2R.sup.5, --C(O)N(R.sup.4).sub.2,
--C(O)N(R.sup.4)--OR.sup.5,
--C(O)N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4)--C(O)R.sup.5,
--C(.dbd.NR.sup.4)--N(R.sup.4).sub.2, --C(.dbd.NR.sup.4)--OR.sup.5,
--C(.dbd.NR.sup.4)--N(R.sup.4)--OR.sup.5,
--C(R.sup.6).dbd.N--OR.sup.5, or an optionally substituted
aliphatic, or an optionally substituted aryl, heterocyclyl, or
heteroaryl group; or two adjacent substituents, taken together with
the intervening ring atoms, form an optionally substituted fused 4-
to 8-membered aromatic or non-aromatic ring having 0-3 ring
heteroatoms selected from the group consisting of O, N, and S.
[0158] In some embodiments, Ring B is substituted with 0-2
substituents independently selected from the group consisting of
halo, --CN, --N(R.sup.4).sub.2, --NR.sup.4C(O)R.sup.5,
--NR.sup.4--C(O)N(R.sup.4).sub.2, --NR.sup.4CO.sub.2R.sup.6,
--C(O)N(R.sup.4).sub.2, --CO.sub.2R.sup.5, --OR.sup.5, or a
C.sub.1-4 aliphatic or C.sub.1-4 fluoroaliphatic optionally
substituted with --OR.sup.5>, --N(R.sup.4x)(R.sup.4y),
--CO.sub.2R.sup.5x, or --C(O)N(R.sup.4x)(R.sup.4y). The variables
R.sup.4, R.sup.5, R.sup.6, R.sup.4x, R.sup.4y, and R.sup.5x have
the values described above for formula (I).
[0159] Another embodiment of the invention relates to a compound of
formula (I), wherein R.sup.g is --V.sup.1-T.sup.1-R.sup.1g,
--V.sup.1--R.sup.1g, or -T.sup.1-V.sup.1--R.sup.1g. R.sup.1g is an
optionally substituted mono- or bicyclic aryl, heteroaryl,
heterocyclyl, or cycloaliphatic group. In some embodiments,
C.sub.1-4 alkylene chain optionally substituted with one or two
groups independently selected from fluoro or a C.sub.1-4 aliphatic
or C.sub.1-4 fluoroaliphatic optionally substituted with one or two
substituents independently selected from the group consisting of
--OR.sup.5x, --N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, and
--C(O)N(R.sup.4x)(R.sup.4y). In certain embodiments, T.sup.1 is a
C.sub.1-4 alkylene chain optionally substituted with one or two
groups independently selected from fluoro, C.sub.1-4 aliphatic, and
C.sub.1-4 fluoroaliphatic. In some embodiments, V.sup.1 is
--N(R.sup.4)C(O)--, --N(R.sup.4)C(O)N(R.sup.4)--,
--N(R.sup.4)SO.sub.2--, --N(R.sup.4)SO.sub.2N(R.sup.4)--, or
--N(R.sup.4)CO.sub.2--. In certain such embodiments, V.sup.1 is
--N(R.sup.4)C(O)-- or --N(R.sup.4)C(O)N(R.sup.4)--. In other
embodiments, V.sup.1 is --C(R.sup.5).dbd.C(R.sup.5), --C.ident.C--,
--O--, --S--, or --N(R.sup.4)--. In certain such embodiments,
V.sup.1 is --N(R.sup.4)--.
[0160] In some embodiments, the invention relates to a subgenus of
the compounds of formula (I), characterized by formula (V):
##STR00010##
[0161] or a pharmaceutically acceptable salt thereof, wherein:
[0162] V.sup.1 is --N(R.sup.8)--, --O--, or --S--; [0163] R.sup.8
is hydrogen or C.sub.1-4 aliphatic; [0164] T.sup.1 is a C.sub.1-4
alkylene chain optionally substituted with one or two groups
independently selected from fluoro or a C.sub.1-4 aliphatic or
C.sub.1-4 fluoroaliphatic optionally substituted with one or two
substituents independently selected from the group consisting of
--OR.sup.5x, --N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, and
--C(O)N(R.sup.4x)(R.sup.4y); [0165] Ring C is an optionally
substituted 3- to 8-membered heterocyclyl or cycloaliphatic ring,
or an optionally substituted 5- or 6-membered awl or heteroaryl
ring; and [0166] the variables Q, X, Y, R.sup.a, R.sup.b, R.sup.c,
R.sup.d, R.sup.e, R.sup.f, R.sup.h, R.sup.j, and m have the values
and preferred values described above for formula (I).
[0167] In some such embodiments, T.sup.1 is a C.sub.1-4 alkylene
chain optionally substituted with one or two groups independently
selected from fluoro, C.sub.1-4 aliphatic, and C.sub.1-4
fluoroaliphatic.
[0168] In some embodiments, Ring C is substituted with 0-2 R.sup.o
and 0-2 R.sup.8o, where: [0169] each R.sup.o independently is halo,
--NO.sub.2, --CN, --C(R.sup.5).dbd.C(R.sup.5).sub.2,
--C.ident.C--R.sup.5, --OR.sup.5, --SR.sup.6, --S(O)R.sup.6,
--SO.sub.2R.sup.6, --SO.sub.2N(R.sup.4).sub.2, --N(R.sup.4).sub.2,
--NR.sup.4C(O)R.sup.5, --NR.sup.4C(O)N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--R.sup.6, --NR.sup.4CO.sub.2R.sup.6,
--N(R.sup.4)SO.sub.2R.sup.6, --N(R.sup.4)SO.sub.2N(R.sup.4).sub.2,
--O--C(O)R.sup.5, --OCO.sub.2R.sup.6, --OC(O)N(R.sup.4).sub.2,
--C(O)R.sup.5, --CO.sub.2R.sup.5, --C(O)N(R.sup.4).sub.2,
--C(O)N(R.sup.4)--OR.sup.5,
--C(O)N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4)--C(O)R.sup.5,
--C(.dbd.NR.sup.4)--N(R.sup.4).sub.2, --C(.dbd.NR.sup.4)--OR.sup.5,
--C(.dbd.NR.sup.4)--N(R.sup.4)--OR.sup.5,
--C(R.sup.6).dbd.N--OR.sup.5, or an optionally substituted
aliphatic, or an optionally substituted aryl, heterocyclyl, or
heteroaryl group; or two R.sup.o on the same saturated ring carbon
atom, taken together with the carbon atom, form an optionally
substituted 3- to 8-membered spirocyclic cycloaliphatic or
heterocyclyl ring; or two adjacent R.sup.o, taken together with the
intervening ring atoms, form an optionally substituted fused 4- to
8-membered aromatic or non-aromatic ring having 0-3 ring
heteroatoms selected from the group consisting of O, N, and S;
[0170] each R.sup.8o independently is selected from the group
consisting of C.sub.1-4 aliphatic, C.sub.1-4 fluoroaliphatic, halo,
--OR.sup.5x, --N(R.sup.4x)(R.sup.4y), or a C.sub.1-4 aliphatic or
C.sub.1-4 fluoroaliphatic optionally substituted with --OR.sup.5x,
--N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, or
--C(O)N(R.sup.4x)(R.sup.4y); and [0171] the variables R.sup.4x,
R.sup.4y, and R.sup.5x have the values described above for formula
(I).
[0172] In some such embodiments, Ring C is a C.sub.3-6
cycloaliphatic, phenyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl,
isoxazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl,
oxadiazolyl, thiadiazolyl, pyrrolinyl, imidazolinyl, pyrazolinyl,
pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl,
morpholinyl, piperazinyl, pyridyl, pyridazinyl, pyrimidinyl,
pyrazinyl, or tetrahydropyrimidinyl ring, any of which is
substituted with 0-2 R.sup.o and 0-2 R.sup.8o.
[0173] In certain embodiments, T.sup.1 is a C.sub.1-2 alkylene
chain optionally substituted with one or two groups independently
selected from fluoro or a C.sub.1-4 aliphatic or C.sub.1-4
fluoroaliphatic optionally substituted with one or two substituents
independently selected from the group consisting of --OR.sup.5x,
--N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, and
--C(O)N(R.sup.4x)(R.sup.4y), and Ring C is a C.sub.3-6
cycloaliphatic, phenyl, oxazolyl, or isoxazolyl ring, any of which
is substituted with 0-2 R.sup.8o and optionally is fused to an
optionally substituted benzene, dioxolane, or dioxane ring.
[0174] Another embodiment of the invention relates to a subgenus of
the compounds of formula (I), characterized by formula (VI):
##STR00011##
[0175] or a pharmaceutically acceptable salt thereof, wherein:
[0176] T.sup.1 is a C.sub.1-4 alkylene chain optionally substituted
with one or two groups independently selected from fluoro or a
C.sub.1-4 aliphatic or C.sub.1-4 fluoroaliphatic optionally
substituted with one or two substituents independently selected
from the group consisting of --OR.sup.5x, --N(R.sup.4x)(R.sup.4y),
--CO.sub.2R.sup.5x, and --C(O)N(R.sup.4x)(R.sup.4y); [0177] Ring C
is a 3- to 8-membered heterocyclyl or cycloaliphatic ring, or a 5-
or 6-membered aryl or heteroaryl ring, any of which rings is
substituted with 0-2 R.sup.o and 0-2 R.sup.8o; and [0178] the
variables Q, X, Y, R.sup.a, R.sup.b, R.sup.c, R.sup.d, R.sup.e,
R.sup.f, R.sup.h, R.sup.j, R.sup.o, R.sup.8o, R.sup.4x, R.sup.4y,
R.sup.5x, and m have the values and preferred values described
above for formulae (I)-(V).
[0179] In a particular embodiment, the invention relates to a
compound of formula (VI) or a pharmaceutically acceptable salt
thereof, wherein: [0180] T.sup.1 is a C.sub.1-2 alkylene chain
optionally substituted with one or two groups independently
selected from fluoro or a C.sub.1-4 aliphatic or C.sub.1-4
fluoroaliphatic optionally substituted with one or two substituents
independently selected from the group consisting of --OR.sup.5x,
--N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, and
--C(O)N(R.sup.4x)(R.sup.4y); and [0181] Ring C is phenyl, which is
substituted with 0-2 R.sup.8o and optionally is fused to an
optionally substituted benzene, dioxolane, or dioxane ring.
[0182] Another embodiment of the invention relates to a subgenus of
the compounds of formula (I), characterized by formula (VII):
##STR00012##
[0183] or a pharmaceutically acceptable salt thereof, wherein:
[0184] V.sup.2 is --N(R.sup.8)--, --O--, or --S--; [0185] R.sup.8
is hydrogen or C.sub.1-4 aliphatic; [0186] Ring D is an optionally
substituted aryl, heteroaryl, heterocyclyl, or cycloaliphatic ring;
and [0187] the variables Q, X, Y, R.sup.a, R.sup.b, R.sup.e,
R.sup.d, R.sup.e, R.sup.f, R.sup.h, R.sup.j, and m have the values
and preferred values described above for formula (I).
[0188] In some embodiments, V.sup.2 is --N(R.sup.8)--. In certain
embodiments, V.sup.2 is --NH--.
[0189] In some embodiments, Ring D is a mono-, bi-, or ticyclic
ring system. In some embodiments, Ring D is a mono- or bicyclic
ring system. In some such embodiments, Ring D selected from the
group consisting of furanyl, thienyl, pyrrolyl, oxazolyl,
thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,
oxadiazolyl, triazolyl, thiadiazolyl, phenyl, naphthyl, pyranyl,
pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,
indolizinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl,
benzthiazolyl, benzothienyl, benzofuranyl, purinyl, quinolyl,
isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,
naphthyridinyl, pteridinyl, tetrahydrofuranyl, tetrahydrothienyl,
pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl,
tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl,
oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl,
oxazepinyl, thiazepinyl, morpholinyl, quinuclidinyl,
tetrahydroquinolinyl, tetrahydroisoquinolinyl, indanyl,
phenanthridinyl, tetrahydronaphthyl, indolinyl, benzodioxanyl,
benzodioxolyl, chromanyl, cyclopropyl, cyclobutyl, cyclopentyl,
cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl,
cycloheptenyl, cyclooctyl, cyclooctenyl, cyclooctadienyl,
bicycloheptanyl and bicyclooctanyl. In certain embodiments, Ring D
is an optionally substituted indanyl, tetrahydronaphthyl, or
chromanyl.
[0190] Ring D may be unsubstituted or may be substituted on either
or both of its component rings, and the substituents may be the
same or different. In particular, each substitutable saturated ring
carbon atom in Ring D is unsubstituted or substituted with .dbd.O,
.dbd.S, .dbd.C(R.sup.5).sub.2, .dbd.N--N(R.sup.4).sub.2,
.dbd.N--OR.sup.5, .dbd.N--NHC(O)R.sup.5, .dbd.N--NHCO.sub.2R.sup.6,
.dbd.N--NHSO.sub.2R.sup.6, .dbd.N--R.sup.5 or --R.sup.p. Each
substitutable unsaturated ring carbon atom in Ring D is
unsubstituted or substituted with --R.sup.p. Each substitutable
ring nitrogen atom in Ring D is unsubstituted or substituted with
--R.sup.9p. The variables R.sup.p and R.sup.9p have the values
described below.
[0191] Each R.sup.p independently is halo, --NO.sub.2, --CN,
--C(R.sup.5).dbd.C(R.sup.5).sub.2, --C.ident.C--R.sup.5,
--OR.sup.5, --SR.sup.6, --S(O)R.sup.6, --SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.4).sub.2, --N(R.sup.4).sub.2,
--NR.sup.4C(O)R.sup.5, --NR.sup.4C(O)N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--R.sup.6, --NR.sup.4CO.sub.2R.sup.6,
--N(R.sup.4)SO.sub.2R.sup.6, --N(R.sup.4)SO.sub.2N(R.sup.4).sub.2,
--O--C(O)R.sup.5, --OCO.sub.2R.sup.6, --OC(O)N(R.sup.4).sub.2,
--C(O)R.sup.5, --CO.sub.2R.sup.5, --C(O)N(R.sup.4).sub.2,
--C(O)N(R.sup.4)--OR.sup.5,
--C(O)N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sup.2,
--N(R.sup.4)--C(.dbd.NR.sup.4)--N(R.sup.4)--C(O)R.sup.5,
--C(.dbd.NR.sup.4)--N(R.sup.4).sub.2, --C(.dbd.NR.sup.4)--OR.sup.5,
--C(.dbd.NR.sup.4)--N(R.sup.4)--OR.sup.5,
--C(R.sup.6).dbd.N--OR.sup.5, or an optionally substituted
aliphatic, or an optionally substituted aryl, heterocyclyl, or
heteroaryl group; or two R.sup.p on the same saturated carbon atom,
taken together with the carbon atom to which they are attached,
form an optionally substituted 3- to 6-membered spirocyclic
cycloaliphatic ring.
[0192] Each R.sup.9p independently is --C(O)R.sup.5,
--C(O)N(R.sup.4).sub.2, --CO.sub.2R.sup.6, --SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.4).sub.2, or a C.sub.1-4 aliphatic optionally
substituted with R.sup.3 or R.sup.7.
[0193] In some embodiments, each R.sup.p independently is selected
from the group consisting of halo, C.sub.1-6 aliphatic, C.sub.1-6
fluoroaliphatic, --R.sup.1p, --R.sup.2p, -T.sup.2-R.sup.1p, and
-T.sup.2-R.sup.2p; or two R.sup.p on the same saturated carbon
atom, taken together with the carbon atom to which they are
attached, form an optionally substituted 3- to 6-membered
spirocyclic cycloaliphatic ring. The variables R.sup.1p, R.sup.2p,
and T.sup.2 have the values described below.
[0194] T.sup.2 is a C.sub.1-6 alkylene chain optionally substituted
with R.sup.3a or R.sup.3b.
[0195] Each R.sup.1p independently is an optionally substituted
aryl, heteroaryl, or heterocyclyl group.
[0196] Each R.sup.2p independently is --NO.sub.2, --CN,
--C(R.sup.5).dbd.C(R.sup.5).sub.2, --C.ident.C--R.sup.5,
--OR.sup.5, --SR.sup.6, --S(O)R.sup.6, --SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.4).sub.2, --N(R.sup.4).sub.2,
--NR.sup.4C(O)R.sup.5, --NR.sup.4C(O)N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--R.sup.6, --NR.sup.4CO.sub.2R.sup.6,
--N(R.sup.4)SO.sub.2R.sup.6, --N(R.sup.4)SO.sub.2N(R.sup.4).sub.2,
--O--C(O)R.sup.5, --OCO.sub.2R.sup.6, --OC(O)N(R.sup.4).sub.2,
--C(O)R.sup.5, --CO.sub.2R.sup.5, --C(O)N(R.sup.4).sub.2,
--C(O)N(R.sup.4)--OR.sup.5,
--C(O)N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4)--C(O)R.sup.5,
--C(.dbd.NR.sup.4)--N(R.sup.4).sub.2, --C(.dbd.NR.sup.4)--OR.sup.5,
--C(.dbd.NR.sup.4)--N(R.sup.4)--OR.sup.5, or
--C(R.sup.6).dbd.N--OR.sup.5.
[0197] In some embodiments, Ring D is selected from the group
consisting of:
##STR00013## [0198] each R.sup.p independently is selected from the
group consisting of fluoro, --OR.sup.5x, --N(R.sup.4x)(R.sup.4y),
--CO.sub.2R.sup.5x, or --C(O)N(R.sup.4x)(R.sup.4y), or a C.sub.1-4
aliphatic or C.sub.1-4 fluoroaliphatic optionally substituted with
--OR.sup.5x, --N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, or
--C(O)N(R.sup.4x)(R.sup.4y); [0199] each R.sup.8p independently is
selected from the group consisting of fluoro, --OR.sup.5x,
--N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, or
--C(O)N(R.sup.4x)(R.sup.4y), or a C.sub.1-4 aliphatic or C.sub.1-4
fluoroaliphatic optionally substituted with --OR.sup.5x,
--N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, or
--C(O)N(R.sup.4x)(R.sup.4y), provided that R.sup.8p is other than
--OR.sup.5x or --N(R.sup.4x)(R.sup.4y) when located at a position
adjacent to a ring oxygen atom, and further provided that when two
R.sup.8p are attached to the same carbon atom, one must be selected
from the group consisting of fluoro, --CO.sub.2R.sup.5x,
--C(O)N(R.sup.4x)(R.sup.4y), and C.sub.1-4 aliphatic or C.sub.1-4
fluoroaliphatic optionally substituted with --OR.sup.5x,
--N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, or
--C(O)N(R.sup.4x)(R.sup.4y); or two R.sup.8p on the same carbon
atom together form .dbd.O or .dbd.C(R.sup.5x).sub.2; or two
R.sup.8p on the same carbon atom are taken together with the carbon
atom to which they are attached to form a 3- to 6-membered
spirocyclic ring; [0200] s is 0, 1, 2, 3, or 4; [0201] t is 0, 1,
or 2; and [0202] the variables R.sup.4x, R.sup.4y, R.sup.5x have
the values described above for formula (I).
[0203] In some embodiments, each R.sup.8p independently is selected
from the group consisting of fluoro, --OR.sup.5x,
--N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, or
--C(O)N(R.sup.4x)(R.sup.4y), or a C.sub.1-4 aliphatic or C.sub.1-4
fluoroaliphatic optionally substituted with --OR.sup.5x,
--N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, or
--C(O)N(R.sup.4x)(R.sup.4y); or two R.sup.8p on the same carbon
atom are taken together with the carbon atom to which they are
attached to form a 3- to 6-membered spirocyclic ring; provided that
R.sup.8p is other than --OR.sup.5x or --N(R.sup.4x)(R.sup.4y) when
located at a position adjacent to a ring oxygen atom; and [0204] s
is 0, 1, or 2.
[0205] Another embodiment of the invention relates to a compound of
formula (I), wherein: [0206] R.sup.g is --N(R.sup.8)(R.sup.9);
[0207] R.sup.8 is hydrogen or C.sub.1-4 aliphatic; [0208] R.sup.9
is hydrogen, C.sub.1-4 aliphatic, -T.sup.3-R.sup.9a or
-T.sup.4-R.sup.9b; [0209] T.sup.3 is a C.sub.1-6 alkylene chain
substituted with 0-2 independently selected R.sup.1a or R.sup.3b;
[0210] T.sup.4 is a C.sub.2-6 alkylene chain substituted with 0-2
independently selected R.sup.1a or R.sup.3b; [0211] R.sup.9a is
--C(R.sup.5).dbd.C(R.sup.5).sub.2, --S(O)R.sup.6,
--SO.sub.2R.sup.6, --SO.sub.2--N(R.sup.4).sub.2,
--C(R.sup.5).dbd.N--OR.sup.5, --CO.sub.2R.sup.5,
--C(O)--C(O)R.sup.5, --C(O)R.sup.5, --C(O)N(R.sup.4).sub.2,
--C(.dbd.NR.sup.4)--N(R.sup.4).sub.2, or
--C(.dbd.NR.sup.4)--OR.sup.5; and [0212] R.sup.9b is halo,
--NO.sub.2, --CN, --OR.sup.5, --SR.sup.6, --N(R.sup.4).sub.2,
--N(R.sup.4)C(O)R.sup.5, --N(R.sup.4)C(O)N(R.sup.4).sub.2,
--N(R.sup.4)CO.sub.2R.sup.5, --O--CO.sub.2--R.sup.5,
--OC(O)N(R.sup.4).sub.2, --OC(O)R.sup.5,
--N(R.sup.4)--N(R.sup.4).sub.2, --N(R.sup.4)S(O).sub.2R.sup.6, or
--N(R.sup.4)SO.sub.2--N(R.sup.4).sub.2.
[0213] In some such embodiments, R.sup.9 is hydrogen or a C.sub.1-6
aliphatic or C.sub.1-6 fluoroaliphatic optionally substituted with
one or two substituents independently selected from the group
consisting of --OR.sup.5x, --N(R.sup.4x)(R.sup.4y),
--CO.sub.2R.sup.5x, --C(O)N(R.sup.4x)(R.sup.4y).
[0214] In a particular embodiment, the invention relates to a
subgenus of the compounds of formula (I), characterized by formula
(VIII):
##STR00014##
[0215] or a pharmaceutically acceptable salt thereof, wherein:
[0216] stereochemical configurations depicted at asterisked
positions indicate absolute stereochemistry; and
[0217] the variables Q, R.sup.a, R.sup.b, R.sup.c, R.sup.d,
R.sup.g, R.sup.h, and R.sup.j have the values and preferred values
described above for formulae (I)-(VII).
[0218] In some embodiments, the invention relates to a subgenus of
the compounds of formula (VIII), characterized by formula
(VIIIa):
##STR00015##
[0219] or a pharmaceutically acceptable salt thereof, wherein:
[0220] R.sup.a is --OH; [0221] R.sup.b and R.sup.d are each
independently hydrogen, fluoro, or C.sub.1-4 aliphatic; [0222]
R.sup.c is hydrogen, fluoro, or --OR.sup.5x; [0223] R.sup.8 is
hydrogen or C.sub.1-4 aliphatic; [0224] each R.sup.p independently
is selected from the group consisting of fluoro, --OR.sup.5x,
--N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, or
--C(O)N(R.sup.4x)(R.sup.4y), or a C.sub.1-4 aliphatic or C.sub.1-4
fluoroaliphatic optionally substituted with --OR.sup.5x,
--N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, or
--C(O)N(R.sup.4x)(R.sup.4y); [0225] each R.sup.8p independently is
selected from the group consisting of fluoro, --OR.sup.5x,
--N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, or
--C(O)N(R.sup.4x)(R.sup.4y), or a C.sub.1-4 aliphatic or C.sub.1-4
fluoroaliphatic optionally substituted with --OR.sup.5x,
--N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, or
--C(O)N(R.sup.4x)(R.sup.4y), provided that R.sup.8p is other than
--OR.sup.5x or --N(R.sup.4x)(R.sup.4y) when located at a position
adjacent to a ring oxygen atom, and further provided that when two
R.sup.8p are attached to the same carbon atom, one must be selected
from the group consisting of fluoro, --CO.sub.2R.sup.5x,
--C(O)N(R.sup.4x)(R.sup.4y), and C.sub.1-4 aliphatic or C.sub.1-4
fluoroaliphatic optionally substituted with --OR.sup.5x,
--N(R.sup.4x)(R.sup.4y), --CO.sub.2R.sup.5x, or
--C(O)N(R.sup.4x)(R.sup.4y); or two R.sup.8p on the same carbon
atom together form .dbd.O or .dbd.C(R.sup.5x).sub.2; [0226]
R.sup.4x is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 fluoroalkyl, or
C.sub.6-10 ar(C.sub.1-4)alkyl, the aryl portion of which may be
optionally substituted; [0227] R.sup.4y is hydrogen, C.sub.1-4
alkyl, C.sub.1-4 fluoroalkyl, C.sub.6-10 ar(C.sub.1-4)alkyl, the
aryl portion of which may be optionally substituted, or an
optionally substituted 5- or 6-membered aryl, heteroaryl, or
heterocyclyl ring; or [0228] R.sup.4x and R.sup.4y, taken together
with the nitrogen atom to which they are attached, form an
optionally substituted 4- to 8-membered heterocyclyl ring having,
in addition to the nitrogen atom, 0-2 ring heteroatoms
independently selected from N, O, and S; [0229] each R.sup.5x
independently is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 fluoroalkyl,
or an optionally substituted C.sub.6-10 aryl or C.sub.6-10
ar(C.sub.1-4)alkyl; [0230] s is 0, 1, 2, 3, or 4; and [0231] t is
0, 1, or 2.
[0232] Subgenus definitions for Ring A and variables X, Y, R.sup.a,
R.sup.b, R.sup.c, R.sup.d, R.sup.e, and R.sup.f described for
formula (I) also apply to formulae (II)-(VIII). Compounds embodying
any combination of the preferred values for the variables described
herein are within the scope of the present invention.
[0233] Representative examples of compounds of formula (I) are
shown in Table 1.
TABLE-US-00001 TABLE 1 E1 Activating Enzyme Inhibitors ##STR00016##
I-1 ##STR00017## I-2 ##STR00018## I-3 ##STR00019## I-4 ##STR00020##
I-5 ##STR00021## I-6 ##STR00022## I-7 ##STR00023## I-8 ##STR00024##
I-9 ##STR00025## I-10 ##STR00026## I-11 ##STR00027## I-12
##STR00028## I-13 ##STR00029## I-14 ##STR00030## I-15 ##STR00031##
I-16 ##STR00032## I-17 ##STR00033## I-18 ##STR00034## I-19
##STR00035## I-20 ##STR00036## I-21 ##STR00037## I-22 ##STR00038##
I-23 ##STR00039## I-24 ##STR00040## I-25 ##STR00041## I-26
##STR00042## I-27 ##STR00043## I-28 ##STR00044## I-29 ##STR00045##
I-30 ##STR00046## I-31 ##STR00047## I-32 ##STR00048## I-33
##STR00049## I-34 ##STR00050## I-35 ##STR00051## I-36 ##STR00052##
I-37 ##STR00053## I-38 ##STR00054## I-39 ##STR00055## I-40
##STR00056## I-41 ##STR00057## I-42 ##STR00058## I-43 ##STR00059##
I-44 ##STR00060## I-45 ##STR00061## I-46 ##STR00062## I-47
##STR00063## I-48 ##STR00064## I-49 ##STR00065## I-50 ##STR00066##
I-51 ##STR00067## I-52 ##STR00068## I-53 ##STR00069## I-54
##STR00070## I-55 ##STR00071## I-56 ##STR00072## I-57 ##STR00073##
I-58 ##STR00074## I-59 ##STR00075## I-60 ##STR00076## I-61
##STR00077## I-62 ##STR00078## I-63 ##STR00079## I-64 ##STR00080##
I-65 ##STR00081## I-66 ##STR00082## I-67 ##STR00083## I-68
##STR00084## I-69 ##STR00085## I-70 ##STR00086## I-71 ##STR00087##
I-72 ##STR00088## I-73 ##STR00089## I-74 ##STR00090## I-75
##STR00091## I-76 ##STR00092## I-77 ##STR00093## I-78 ##STR00094##
I-79 ##STR00095## I-80 ##STR00096## I-81 ##STR00097## I-82
##STR00098## I-83 ##STR00099## I-84 ##STR00100## I-85 ##STR00101##
I-86
[0234] The compounds in Table 1 above may also be identified by the
following chemical names:
TABLE-US-00002 Chemical Name I-1
((1S,2S,4R)-4-{4-[(2-chlorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7--
yl}-2- hydroxycyclopentyl)methyl sulfamate I-2
[(1S,2S,4R)-4-(4-{[2-(difluoromethoxy)benzyl]amino}-7H-pyrrolo[2,3-d]-
pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate I-3
[(1S,2S,4R)-2-hydroxy-4-(4-{methyl[(1S)-1-phenylethyl]amino}-7H-pyrrol-
o- [2,3-d]pyrimidin-7-yl)cyclopentyl]methyl sulfamate I-4
[(1S,2S,4R)-2-hydroxy-4-(4-{[(1S)-1-phenylethyl]amino}-7H-pyrrolo[2,3--
d]- pyrimidin-7-yl)cyclopentyl]methyl sulfamate I-5
((1S,2S,4R)-4-{4-[(4-chlorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7--
yl}-2- hydroxy-2-methylcyclopentyl)methyl sulfamate I-6
((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-yl(methyl)amino]-7H-pyrr-
olo- [2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate
I-7
[(1S,2S,4R)-2-hydroxy-4-(4-{[(1R)-1-phenylethyl]amino}-7H-pyrrolo[2,3--
d]- pyrimidin-7-yl)cyclopentyl]methyl sulfamate I-8
[(1S,2S,4R)-2-hydroxy-4-(4-{[4-(trifluoromethyl)benzyl]amino}-7H-pyrro-
lo- [2,3-d]pyrimidin-7-yl)cyclopentyl]methyl sulfamate I-9
{(1S,2S,4R)-4-[4-(acetylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-
hydroxycyclopentyl}methyl sulfamate I-10
((1S,2S,4R)-4-{4-[benzyl(methyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-y-
l}-2- hydroxycyclopentyl)methyl sulfamate I-11
((1S,3S)-3-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-
- pyrimidin-7-yl}cyclopentyl)methyl sulfamate I-12
((1S,2S,4R)-4-{4-[(4S)-3,4-dihydro-2H-chromen-4-ylamino]-7H-pyrrolo[2-
,3-d]- pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate I-13
((1S,2S,4R)-4-{4-[(1R)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-
-d]- pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate I-14
[(1S,2S,4R)-4-(4-{[(1S)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-
-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl
sulfamate I-15
((1S,2S,4R)-4-{4-[(2,6-difluorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimid-
in-7-yl}- 2-hydroxycyclopentyl)methyl sulfamate I-16
((1S,2S,4R)-4-{4-[(3,5-dichlorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimid-
in-7-yl}- 2-hydroxycyclopentyl)methyl sulfamate I-17
((1S,2R,3S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[-
2,3-d]- pyrimidin-7-yl}-2,3-dihydroxycyclopentyl)methyl sulfamate
I-18 [(1S,2S,4R)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-
hydroxycyclopentyl]methyl sulfamate I-19
((1S,2S,4R)-4-{4-[(2,4-dichlorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimid-
in-7-yl}- 2-hydroxycyclopentyl)methyl sulfamate I-20
((1R,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-
- pyrimidin-7-yl}cyclopent-2-en-1-yl)methyl sulfamate I-21
[(1S,2S,4R)-4-(4-{[(1R)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-
-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl
sulfamate I-22
((1S,2R,3S,4R)-4-{4-[(4-chlorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidi-
n-7-yl}- 2,3-dihydroxycyclopentyl)methyl sulfamate I-23
((1S,2S,4R)-4-{6-[(4-chlorobenzyl)amino]-9H-purin-9-yl}-2-
hydroxycyclopentyl)methyl sulfamate I-24
((1S,2S,4R)-4-{4-[(3,4-dichlorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimid-
in-7-yl}- 2-hydroxycyclopentyl)methyl sulfamate I-25
((1S,2S,4R)-4-{4-[(cyclopropylmethyl)amino]-7H-pyrrolo[2,3-d]pyrimidi-
n-7-yl}- 2-hydroxycyclopentyl)methyl sulfamate I-26
((1S,2S,4R)-4-{4-[(1,3-benzodioxol-5-ylmethyl)amino]-7H-pyrrolo[2,3-d-
]- pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate I-27
[(1S,2S,4R)-4-(4-{[(1S)-5-chloro-2,3-dihydro-1H-inden-1-yl]amino}-7H--
pyrrolo- [2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl
sulfamate I-28
{(1S,2S,4R)-2-hydroxy-4-[4-(2-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-
-7-yl]- cyclopentyl}methyl sulfamate I-29
((1S,2S,4R)-4-{4-[(cyclohexylmethyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-
-7-yl}-2- hydroxycyclopentyl)methyl sulfamate I-30
((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-
-d]- pyrimidin-7-yl}-2-hydroxy-2-methylcyclopentyl)methyl sulfamate
I-31
{(1S,2S,4R)-4-[4-(benzylamino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7--
yl]-2- hydroxycyclopentyl}methyl sulfamate I-32
{(1S,2S,4R)-4-[4-(benzylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-
hydroxycyclopentyl}methyl sulfamate I-33
[(1S,2S,4R)-4-(4-{[(1S)-5-bromo-2,3-dihydro-1H-inden-1-yl]amino}-7H-p-
yrrolo- [2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl
sulfamate I-34
((1S,2S,4R)-4-{4-[(4-chlorobenzyl)oxy]-7H-pyrrolo[2,3-d]pyrimidin-7-y-
l}-2- hydroxycyclopentyl)methyl sulfamate I-35
((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-
-d]- pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate I-36
[(1S,2S,4R)-4-(4-{[(1S)-5-fluoro-2,3-dihydro-1H-inden-1-yl]amino}-7H--
pyrrolo- [2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl
sulfamate I-37
((1S,2S,4R)-2-hydroxy-4-{4-[(1S)-1,2,3,4-tetrahydronaphthalen-1-ylami-
no]-7H- pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methyl sulfamate
I-38
((1S,2S,4R)-2-hydroxy-4-{4-[(1-naphthylmethyl)amino]-7H-pyrrolo[2,3-d-
]- pyrimidin-7-yl}cyclopentyl)methyl sulfamate I-39
[(1S,2S,4R)-4-(4-anilino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-
hydroxycyclopentyl]methyl sulfamate I-40
{(1S,2S,4R)-2-hydroxy-4-[4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-
-yl]- cyclopentyl}methyl sulfamate I-41
[(1S,2S,4R)-2-hydroxy-4-(4-{[(5-methylisoxazol-3-yl)methyl]amino}-7H--
pyrrolo- [2,3-d]pyrimidin-7-yl)cyclopentyl]methyl sulfamate I-42
[(1S,2S,4R)-4-(4-{[4-chloro-2-(trifluoromethyl)benzyl]amino}-7H-pyrro-
lo[2,3-d]- pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate
I-43
((1S,2S,4R)-2-hydroxy-4-{4-[(2-methoxybenzyl)amino]-7H-pyrrolo[2,3-d]-
- pyrimidin-7-yl}cyclopentyl)methyl sulfamate I-44
[(1S,2S,4R)-4-(5-ethynyl-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-
hydroxycyclopentyl]methyl sulfamate I-45
((1S,2S,4R)-4-{4-[(4-chlorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-
-yl}-2- hydroxycyclopentyl)methyl sulfamate I-46
[(1S,2S,4R)-2-hydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-
yl)cyclopentyl]methyl sulfamate I-47
[(1S,2S,4R)-2-hydroxy-4-(4-{[2-(trifluoromethyl)benzyl]amino}-7H-pyrr-
olo- [2,3-d]pyrimidin-7-yl)cyclopentyl]methyl sulfamate I-48
((1S,2S,4R)-4-{4-[(4-chloro-2-methylbenzyl)amino]-7H-pyrrolo[2,3-d]py-
rimidin- 7-yl}-2-hydroxycyclopentyl)methyl sulfamate I-49
{(1S,2S,4R)-4-[4-(benzylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-
hydroxycyclopentyl}methyl sulfamate I-50
{(1S,2S,4R)-2-hydroxy-4-[4-(2-methyl-2-phenylpropyl)-7H-pyrrolo[2,3-d-
]- pyrimidin-7-yl]cyclopentyl}methyl sulfamate I-51
((1S,2S,4R)-4-{4-[(3-chlorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-
-yl}-2- hydroxycyclopentyl)methyl sulfamate I-52
[(1S,2S,4R)-2-hydroxy-4-(4-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-
-yl]- amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methyl
sulfamate I-53
{(1S,2R,3S,4R)-2,3-dihydroxy-4-[4-(phenylsulfanyl)-7H-pyrrolo[2,3-d]-
pyrimidin-7-yl]cyclopentyl}methyl sulfamate I-54
[(1S,2S,4R)-2-hydroxy-4-(4-{[(1R,2S)-2-isopropoxy-2,3-dihydro-1H-inde-
n-1-yl]- amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methyl
sulfamate I-55
((2S,3S,5R)-5-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-
-d]- pyrimidin-7-yl}-3-hydroxytetrahydrofuran-2-yl)methyl sulfamate
I-56
N-[((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[-
2,3-d]- pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl]sulfamide I-57
{(2S,3S,5R)-5-[6-(benzylamino)-9H-purin-9-yl]-3-hydroxytetrahydrofura-
n-2-yl}- methyl sulfamate I-58
N-[((2S,3S,5R)-5-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[-
2,3-d]-
pyrimidin-7-yl}-3-hydroxytetrahydrofuran-2-yl)methyl]sulfamide I-59
2-((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2-
,3-d]- pyrimidin-7-yl}-2-hydroxycyclopentyl)ethanesulfonamide I-60
((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-
-d]- pyrimidin-7-yl}-2-hydroxy-1-methylcyclopentyl)methyl sulfamate
I-61
[(1S,2S,4R)-4-(4-{[(1S)-4-fluoro-2,3-dihydro-1H-inden-1-yl]amino}-7H-
pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate
I-62
[(1S,2S,4R)-4-(4-{[(1S)-4,7-difluoro-2,3-dihydro-1H-inden-1-yl]amino}-
-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl
sulfamate I-63
[(1S,2S,4R)-4-(4-{[(1R)-4-chloro-2,3-dihydro-1H-inden-1-yl]amino}-7H-
pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate
I-64
[(1S,2S,4R)-4-(4-{[(1S)-4-chloro-2,3-dihydro-1H-inden-1-yl]amino}-7H-
pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate
I-65
[(1S,2S,4R)-4-(4-{[(1S)-4-bromo-2,3-dihydro-1H-inden-1-yl]amino}-7H-
pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate
I-66
[(1S,2S,4R)-4-(4-{[(1S)-7-fluoro-2,3-dihydro-1H-inden-1-yl]amino}-7H-
pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate
I-67
[(1S,2S,4R)-4-(4-{[(1S)-5-chloro-3,3-dimethyl-2,3-dihydro-1H-inden-1-
yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl
sulfamate I-68
((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-5-fluoro-7H-
pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate
I-69
[(1S,2S,4R)-4-(5-fluoro-4-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-
yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl
sulfamate I-70
[(1S,2S,4R)-4-(4-{[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]amino}--
7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl
sulfamate I-71
[(1S,2S,4R)-2-hydroxy-4-(4-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-
- yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methyl
sulfamate I-72
[(1S,2S,4R)-2-hydroxy-4-(4-{[(1R,2R)-2-methoxy-2,3-dihydro-1H-inden-1-
- yl]amino}-7H-pyrrolo [2,3-d]pyrimidin-7-yl)cyclopentyl]methyl
sulfamate I-73
(E)-2-((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrro-
lo[2,3- d]pyrimidin-7-yl}-2-hydroxycyclopentyl)ethylenesulfonamide
I-74
N-{[(1S,2S,4R)-2-hydroxy-4-(4-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inde-
n-1-
yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methyl}sulfamide
I-75
N-[((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[-
2,3-
d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl]-N-methylsulfamide
I-76
2-((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2-
,3- d]pyrimidin-7-yl]-2-hydroxycyclopentyl)ethyl sulfamate I-77
(1S,2R,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-
d]pyrimidin-7-yl}-2-hydroxycyclopentyl sulfamate I-78
(1R,2S,4S)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-
d]pyrimidin-7-yl}-2-hydroxycyclopentyl sulfamate I-79
[(1S,2S,4R)-2-hydroxy-4-(4-{[(1R,2R)-2-(methoxymethyl)-2,3-dihydro-1H-
-inden-
1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methyl
sulfamate I-80
[(1S,2S,4R)-2-hydroxy-4-(4-{[(1S,2S)-2-(methoxymethyl)-2,3-dihydro-1H-
-inden-
1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methyl
sulfamate I-81
[(1S,2S,4R)-2-hydroxy-4-(4-{[(1R,2R)-2-methyl-2,3-dihydro-1H-inden-1-
yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methyl
sulfamate I-82
[(1S,2S,4R)-2-hydroxy-4-(4-{[(1S,2S)-2-methyl-2,3-dihydro-1H-inden-1-
yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methyl
sulfamate I-83
[(1S,2S,4R)-4-(4-{[(1R,2R)-2-ethyl-2,3-dihydro-1H-inden-1-yl]amino}-7-
H- pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl
sulfamate I-84
[(1S,2S,4R)-4-(4-{[(1S,2S)-2-ethyl-2,3-dihydro-1H-inden-1-yl]amino}-7-
H- pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl
sulfamate
I-85
[(1S,2S,4R)-2-hydroxy-4-(4-{[(1R,2S)-2-methoxy-1,2,3,4-tetrahydronaph-
thalen-
1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methyl
sulfamate I-86
((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-
- d]pyrimidin-7-yl}-2-methoxycyclopentyl)methyl sulfamate
General Synthetic Methodology
[0235] The compounds of the present invention can be prepared by
methods known to one of ordinary skill in the art and/or by
reference to the schemes shown below and the synthetic examples
that follow. Exemplary synthetic routes are set forth in Schemes
1-10 below, and in the Examples.
##STR00102## ##STR00103##
[0236] Scheme 1 above shows a general route for preparing compounds
of formula (I), wherein Ring A has formula A-ii. Those of ordinary
skill in the art will recognize that compounds of formula (I)
wherein Ring A is other than A-ii can be prepared by the same
general route, beginning with appropriate starting materials
analogous to i.
[0237] Methods for the synthesis of chloro-substituted
pyrrolopyrimidines such as formula i are known (P. Reigan et al.,
Bioorg. Med. Chem. Lett., 2004, 14, 5247-5250; J. Heterocyclic
Chem., 1988, 25, 1633-1639). As shown in Scheme 1, conversion of
compounds of formula i to substituted pyrrolopyrimidines is
accomplished by coupling with the appropriately substituted amines
or mercaptans (see Pathak, A. K.; Pathak, V.; Seitz, L. E.; Suling,
W. J.; Reynolds, R. C., J. Med. Chem. 2004, 47, 273-276) at
elevated temperature in protic solvents, such as butanol or
isopropanol, using an appropriate base, such as DIPEA or Et.sub.3N
(Method A). Alternatively, pyrrolopyrimidines i can be coupled with
an appropriately substituted alcohol in H.sub.2O in the presence of
a base, such as KOH, at refluxing temperatures (Method B).
Compounds of formula i can also be treated with Grignard reagents
in the presence of ferric acetylacetonate in THF (Method C) to
provide carbon-substituted pyrrolopyrimidines. Compounds Iv are
prepared from ii by the opening of epoxide iii with a suitable
base, such as NaH, LiHMDS, or cesium carbonate, at elevated
temperatures in DMF (Method D).
[0238] For preparation of compounds of formula (I), wherein R.sup.c
and R.sup.d are each hydrogen, deoxygenation can be effected at
this stage. Thus, alkylation of compounds of formula iv to provide
xanthates v is effected by treatment with
chlorophenylthionocarbonate and a suitable base, such as DMAP, in
DCM (Method E). Deoxygenation of compounds of formula v is achieved
by treatment with a radical source, such as Bu.sub.3SnH, and a
radical initiator, such as AIBN, in refluxing toluene (Method F).
Subsequent deprotection with an aqueous acid, such as AcOH (Method
G), provides compounds of formula vii.
[0239] The primary alcohol of the diols of formula vii is
selectively protected, e.g., with a bulky silyl protecting group
such as TBDMS. Subsequent treatment with acetic anhydride affords
the protected alcohols of formula viii (Method H). Selective
deprotection of the primary alcohol using a fluoride reagent, such
as pyridine hydrofluoride, in a basic solvent, such as pyridine,
provides compounds of formula ix (Method I). Further treatment with
freshly prepared chlorosulfonamide x affords the penultimate
sulfamates xi (Method J). Acetate removal by treatment with a base,
such as ammonia, in MeOH according to Method K yields compounds of
formula xii.
##STR00104##
[0240] Compounds of formula (I), wherein R.sup.g is
--N(R.sup.4).sub.2 may be prepared by an alternative procedure in
which a later stage intermediate incorporating a leaving group such
as a sulfone is directly displaced by a substituted amine. As shown
in Scheme 2, treatment of compounds of formula i with
benzylmercaptan under conditions described in Method B provides
benzylsulfanyl pyrrolopyrimidines of formula xiii. Subsequent
treatment with the conditions outlined in Methods D-F affords
compounds of formula xiv. Compounds xiv are reacted with an
oxidizing agent, such as m-CPBA, in DCM in the presence of a base,
such as sodium bicarbonate, to provide sulfones of formula xv
(Method L).
[0241] Compounds of formula xvi are then synthesized by treatment
of xv with an appropriately substituted amine using a base, such as
DIPEA, in a high-boiling protic solvent, such as EtOH, at elevated
temperatures (Method M) similar to literature procedures (Lin, X.;
Robins, M. J., Organic Lett. 2000, 2, 3497-3499). Removal of the
protecting group is accomplished in a manner analogous to that
depicted in Scheme 1, using the procedure described in Method G, to
give diols of formula xvii. Methods for the synthesis of tert-butyl
chlorosulfonylcarbamate xviii are known (Hirayama et al., Biorg.
Med. Chem., 2002, 10, 1509-1523), and this reagent is reacted
selectively with the primary alcohol using a hindered base, such as
2,6-di-tert-butyl-4-methylpyridine, in a solvent, such as AcCN, to
afford Boc sulfamates of formula xix (Method N). TFA-deprotection
according to Method O yields the compounds of formula xx. The
conversion of compounds xv to xvi has the potential advantage of
being amenable to solution phase library synthesis.
##STR00105##
[0242] Methods for the synthesis of the intermediate alkene diol
xxi are known (Nucleosides, Nucleotides & Nucleic Acids, 2002,
21, 65-72). Upon treatment with m-CPBA, diol xxi is converted to
epoxy diol xxvii. Subsequent protection of the diol using
p-anisaldehyde dimethyl acetal provides epoxide iii. Alternatively,
TBDPS-protection of the primary alcohol of xxi followed by PDC
oxidation gives the .alpha.,.beta.-unsaturated ketone xxii.
Addition of MeLi to the ketone in Et.sub.2O gives tertiary alcohol
xxiii, and treatment with TBAF in THF provides diol xxiv.
Epoxidation and diol protection affords the protected substituted
epoxide xxvi.
##STR00106##
[0243] The aminoindans used for the preparation of 4-aminoindanyl
compounds of formula xxx are either commercially available, or they
are prepared through the literature methods highlighted in Scheme
4. Appropriately substituted indanones of formula xxviii are
treated with (R)-2-amino-2-phenylethanol to provide the desired
intermediate imine. Subsequent reaction with an appropriate
reducing agent, such as sodium borohydride in the presence of AcOH,
gives amino alcohols of formula xxix (Method P). Treatment with
lead tetraacetate, followed by refluxing in HCl, gives aminoindans
of formula xxx (Method Q). One skilled in the art will recognize
that the use of (S)-2-amino-2-phenylethanol in Method P can be used
to afford the opposite enantiomer of indan xxx.
##STR00107##
[0244] Compounds of formula (I), wherein R.sup.c is --OR.sup.5 can
be prepared as outlined in Scheme 5. Thus, compounds of formula iv,
as prepared in Scheme 1, are directly converted to triols of
formula xxxi (Method G). Protection of the two secondary alcohols
with 2,2-dimethoxypropane and an acid catalyst, such as p-TSA
monohydrate, in acetone affords isopropylidenes xxxii (Method R).
Further reaction with chlorosulfonamide x by Method J, as described
in Scheme 1, affords sulfamates of formula xxxiii. Removal of the
isopropylidene using an acid, such as TFA, in the presence of water
yields compounds of formula xxxiv (II-C), according to Method S.
Alternatively, triol xxxi can be selectively sulfamoylated at the
primary hydroxyl and deprotected as described in Scheme 2, Methods
N--O to give compounds of formula xxxiv.
##STR00108##
[0245] Compounds of formula xxxv are prepared by the methods
described in Scheme 1. Treatment of benzylamines xxxv with an
aqueous acid, such as AcOH, affords amines xxxvi (Method G).
Selective protection of the primary alcohol using TBDMSCl and an
appropriate base, such as imidazole, in DMF gives compounds of
formula xxxvii (Method T). Bis-acylation is effected by treatment
with appropriately substituted acylating reagent of formula xxxviii
(X.dbd.Cl, OH, --OC(O)R.sup.5) and an appropriate base, such as
pyridine, to afford compounds of formula xxxix (Method U).
Subjecting compounds xxxix to the conditions described in Methods
I-K affords both the fully deprotected analogs xl as well as amides
xli.
##STR00109##
[0246] Compounds of formula (I) wherein R.sup.a and R.sup.c
together form a bond, and compounds of formula (I) wherein each of
R.sup.a-R.sup.d is hydrogen, can be prepared as outlined in Scheme
7. Triols of formula xlii are prepared following the procedure in
Scheme 5. The primary alcohol is selectively protected to give the
diols of formula xliii (Method T), which are then alkylated by
1,1'-thiocarbonyldiimidazole in a suitable solvent, such as DMF, to
yield dioxole-thiones xliv (Method U). Treatment with
1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine in an appropriate
solvent, such as THF, affords alkenes of formula xlv (Method V),
which are exposed to the conditions outlined in Methods I-J to
afford sulfamates xlvi. Hydrogenation under an atmosphere of
hydrogen in the presence of a catalyst, such as palladium on
carbon, in EtOAc gives saturated sulfamates of formula xlvii
(Method W).
##STR00110##
[0247] Compounds of formula (I) wherein R.sup.k is other than
hydrogen are prepared as outlined in Schemes 8-9. Conversion of i
to fluoro chloro pyrrolopyrimidine xlvii is effected by treatment
with Selectfluor.TM.
(1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane
bis(tetrafluoroborate)) and AcOH in AcCN. Compound xlviii is then
substituted with the appropriate substituents according to Methods
A-C and carried on to compounds of formula (I) according to Scheme
1.
##STR00111##
[0248] Compounds of formula xlix are prepared as shown in Scheme 1,
and are converted to iodide l by treatment with NIS (Method X).
Iodide 1 can be converted to compounds of formula li using a
variety of palladium-catalyzed coupling conditions, such as
Sonagashira coupling (CuI, PdCl.sub.2(PPh.sub.3).sub.2, DIPEA,
R.sup.iC.ident.CH, Method Y). Following the methods shown in Scheme
1, compounds of formula li are converted to final compounds of
formula (I).
##STR00112##
[0249] Compounds of formula (I) wherein Y is --O-- can be prepared
from compounds lviii. The synthesis of compounds of formula lviii
is reported in the literature (Ugarkar, B. G.; Castellino, A. J.;
DaRe, J. S.; Ramirez-Weinhouse, M.; Kopcho, J. J.; Rosengren, S.;
Erion, M. D., J. Med. Chem., 2003, 46, 4750-4760), and is outlined
in Scheme 10. Methods for the conversion of D-ribose to lii are
known (Inokawa, S.; Kitagawa, H.; Seo, K.; Yoshida, H.; Ogata, T.,
Carbohydr. Hydr. Res., 1973, 30, 127-132). Hydroboration-oxidation
using borane-THF complex affords lii, which is globally deprotected
using sulfuric acid. Tetraol liv is protected using
2,2-dimethoxypropane and subsequent protection of the primary
alcohol using TBDMS-Cl gives alcohol lvi. Selective chlorination
using CCl.sub.4 and HMPT in toluene affords the single enantiomer
lvii. Glycosylation using compounds of formula i gives
intermediates of formula lviii, which can be further elaborated as
described in Schemes 1, 2, and 6 above.
##STR00113## ##STR00114## ##STR00115##
[0250] Compounds of formula (I) wherein X is CH.sub.2 can be
prepared from compounds vii. As shown in Scheme 11, diol vii is
protected as a bis-TBDMS ether lix using TBDMS-Cl, suitable base,
such as triethylamine, and 4-DMAP (Method Z). Selective
deprotection of primary TBDMS group to lx is effected using aqueous
acetic acid at elevated temperature (Method AA). Aldehyde lxi is
obtained by oxidation of alcohol lx using TPAP and a suitable
oxidant, such as NMO (method AB). Treatment of aldehyde lxi with
(diethoxyphosphoryl)-methanesulfonic acid ethyl ester and n-BuLi
(Method AC) gives alkene lxii, which is in turn reduced to sulfonyl
ester lxiii using a suitable reducing agent, such as sodium
borohydride in ethanol (Method AD). Hydrolysis of the former ester
using TBAI under microwave conditions (Method AE) gives sulfonic
acid lxiv, which is transformed into protected sulfonamide lxv via
intermediate sulfonyl chloride (using thionyl chloride and then
ammonia in dioxane, Method AF). TBDMS deprotection using a suitable
reagent, such as TBAF in THF (Method AG) affords sulfonamide
lxvi.
##STR00116##
[0251] Compounds of formula (I) wherein X is --CH.dbd. can be
prepared from compounds lxi. As shown in Scheme 12,
tert-butyl{[(diphenylphosphoryl)methyl]sulfonyl}carbamate is
treated with n-BuLi and the formed reagent is mixed with aldehyde
lxi (Method AH) to give protected vinyl sulfonamide lxvi. The Boc
group is deprotected using a suitable Lewis acid, such as
ZnBr.sub.2 (Method AI) to afford lxvii. The final deprotection of a
TBDMS group is carried out using a suitable reagent, such as TBAF
in THF (Method AJ) to give lxviii.
##STR00117##
[0252] Compounds of formula (I) wherein X is NH can be prepared
from compounds lx. As shown in Scheme 13, alcohol lx is treated
with N-Boc-sulfonamide under Mitsunobu conditions, such as
triphenylphosphine and DEAD in ethyl acetate under elevated
temperature to afford protected sulfamide lxix (Method AK). The
TBDMS group is deprotected using a suitable acid, such as aqueous
HCl (Method AL) to afford lxx. The final deprotection of a Boc
group is carried out using a suitable reagent, such as TFA in
methylene chloride (Method AM) to give lxxi.
##STR00118##
[0253] Compounds of formula (I) wherein X is --N(CH.sub.3)-- can be
prepared from compounds lxix. As shown in Scheme 14, sulfamide lxix
is reduced with a suitable agent, such as LiAlH4 in THF under
elevated temperature to afford protected N-methyl sulfamide lxxii
(Method AN). The TBDMS group is deprotected using a suitable acid,
such as aqueous HCl (Method AL) to afford lxxiii.
##STR00119## ##STR00120##
[0254] Compounds of formula (I) wherein X is O and m=2 can be
prepared from compounds lx. As shown in Scheme 15, alcohol lx is
transformed to a suitable leaving group, such as mesylate lxxix,
using methanesulfonyl chloride and an appropriate base, such as
triethylamine in DCM (Method AO). The formed mesylate is displaced
with a nitrile group using a suitable nucleophile, such as sodium
cyanide in DMSO under elevated temperature (Method AP) to afford
nitrile lxxx, which is reduced to aldehyde lxxxi using a suitable
reducing agent, such as DIBAL in DCM (Method AQ). Further reduction
of lxxxi using a suitable reagent, such as sodium tetrahydroborate
in methanol affords alcohol lxxxii (Method AR). Treatment of lxxxii
with a sulfamating reagent, such as chlorosulfonamide in
acetonitrile in a presence of an appropriate base, such as
triethylamine affords protected sulfamate lxxxiii (Method J). TBDMS
removal by treatment with an acid, such as HF.pyridine, in
pyridine/THF according to Method AS yields compounds of formula
lxxxiv.
##STR00121##
[0255] Compounds of formula (I) wherein X is O and m=0 can be
prepared from 3-cyclopentene-1-ol (lxxxv). As shown in Scheme 16,
alcohol lxxxv is activated by transformation to a suitable leaving
group, such as mesylate lxxxvi using methanesulfonyl chloride and
an appropriate base, such as pyridine and DMAP in DCM (Method AT).
Treatment of mesylate lxxxvi with base lxxxvii in the presence of
cesium carbonate in DMF under elevated temperature (Method AU)
affords lxxxviii. Treatment of alkene lxxxviii with an appropriate
chiral dihydroxylation agent, such as AD-mix-.alpha.
(Sigma-Aldrich) in tert-butyl alcohol (Method AV) gives diol
lxxxix, which upon sulfamation with chlorosulfonamide as described
in Method J affords a diastereoisomeric mixture of sulfamates xc
and xci (Method AW).
[0256] The invention further provides synthetic intermediates
useful for the preparation of the compounds of formula (I). In one
embodiment, the invention provides a compound of formula (IX):
##STR00122## [0257] wherein:
[0258] depicted stereochemical configurations indicate absolute
stereochemistry;
[0259] R.sup.b is fluoro, C.sub.1-4 aliphatic, or C.sub.1-4
fluoroaliphatic; [0260] R.sup.aa and R.sup.bb are each
independently hydrogen or a hydroxyl protecting group, or R.sup.aa
and R.sup.bb together form a cyclic diol protecting group; and
[0261] the variables R.sup.d, R.sup.e, and R.sup.f have the values
and preferred values described above for formula (I).
[0262] As used herein, the term "hydroxyl protecting group" refers
to a chemical group that i) reacts with a hydroxyl functional group
of a substrate to form a protected substrate; ii) is stable to
reaction conditions to which the protected substrate will be
subjected; and iii) is removable from a protected substrate to
liberate the hydroxyl functional group under conditions that are
compatible with other functionality present in the substrate. The
hydroxyl groups of 1,2- and 1,3-diols may be individually protected
or may be jointly protected with a cyclic diol protecting group.
Examples of suitable hydroxyl protecting groups and diol protecting
groups may be found in T. W. Greene and P. G. M. Wuts, "Protective
Groups in Organic Synthesis", 3rd Ed., John Wiley & Sons Inc.,
NY (1999).
[0263] In a particular embodiment, the compound of formula (VIII)
is represented by the formula:
##STR00123##
[0264] The invention also provides a compound of formula (X):
##STR00124##
[0265] wherein:
[0266] depicted stereochemical configurations indicate absolute
stereochemistry;
[0267] R.sup.aa is hydrogen or a hydroxyl protecting group; and
[0268] R.sup.bb is hydrogen or a hydroxyl protecting group; or
[0269] R.sup.aa and R.sup.bb together form a cyclic diol protecting
group; and
[0270] the variables R.sup.b, R.sup.d, R.sup.e, and R.sup.f have
the values and preferred values described above for formula
(I).
[0271] In one embodiment, the compound of formula (X) is
characterized by formula (Xa):
##STR00125##
[0272] wherein Ar is an optionally substituted aryl group. In some
embodiments, Ar is an optionally substituted phenyl group. In
certain embodiments, Ar is para-methoxy-phenyl.
[0273] In certain particular embodiments, the compound of formula
(Xa) is selected from the group consisting of:
##STR00126##
[0274] wherein Ar is as described above for formula (Xa).
[0275] The invention also provides a compound of formula (XI) or
formula (XII):
##STR00127##
[0276] wherein:
[0277] depicted stereochemical configurations indicate absolute
stereochemistry;
[0278] R.sup.aa is hydrogen or a hydroxyl protecting group; and
[0279] R.sup.bb is hydrogen or a hydroxyl protecting group;
[0280] R.sup.cc is hydrogen or a hydroxyl protecting group; or
[0281] R.sup.aa and R.sup.bb together form a cyclic diol protecting
group; or
[0282] R.sup.aa and R.sup.cc together form a cyclic diol protecting
group; and
[0283] Ring A and the variables R.sup.b, R.sup.d, R.sup.e, and
R.sup.f have the values and preferred values described above for
formula (I).
[0284] In some embodiments, the compound is characterized by
formula (XIa) or (XIIa)
##STR00128##
[0285] In certain embodiments, the invention relates to a compound
selected from the group consisting of:
##STR00129##
[0286] In certain other embodiments, the invention relates to a
compound selected from the group consisting of:
##STR00130##
[0287] wherein R.sup.aa and R.sup.cc are each independently a
hydroxyl protecting group, or R.sup.aa and R.sup.cc together form a
cyclic diol protecting group.
[0288] In certain other embodiments, the invention relates to a
compound selected from the group consisting of:
##STR00131##
[0289] wherein R.sup.aa and R.sup.bb are each independently a
hydroxyl protecting group. In some embodiments, R.sup.aa and
R.sup.bb are selected so as to allow selective protection and
deprotection. In certain embodiments, R.sup.aa is an acyl
protecting group, and R.sup.bb is a silyl protecting group. In a
particular embodiment, R.sup.aa is acetyl or substituted acetyl,
and R.sup.bb is tert-butyl-dimethylsilyl or
tert-butyldiphenylsilyl.
Uses of Compounds of the Invention
[0290] The compounds of this invention are useful inhibitors of E1
enzyme activity. In particular, the compounds are designed to be
inhibitors of NAE, UAE, and/or SAE. Inhibitors are meant to include
compounds which reduce the promoting effects of E1 enzymes in ubl
conjugation to target proteins (e.g., reduction of ubiquitination,
neddylation, sumoylation), reduce intracellular signaling mediated
by ubl conjugation, and/or reduce proteolysis mediated by ubl
conjugation (e.g., inhibition of cullin-dependent ubiquitination
and proteolysis (e.g., the ubiquitin-proteasome pathway)). Thus,
the compounds of this invention may be assayed for their ability to
inhibit the E1 enzyme in vitro or in vivo, or in cells or animal
models according to methods provided in further detail herein, or
methods known in the art. The compounds may be assessed for their
ability to bind or mediate E1 enzyme activity directly.
Alternatively, the activity of compounds may be assessed through
indirect cellular assays, or assays of downstream effects of E1
activation to assess inhibition of downstream effects of E1
inhibition (e.g., inhibition of cullin-dependent ubiquitination and
proteolysis). For example, activity may be assessed by detection of
ubl-conjugated substrates (e.g., ubl-conjugated E2s, neddylated
cullins, ubiquitinated substrates, sumoylated substrates);
detection of downstream protein substrate stabilization (e.g.,
stabilization of p27, stabilization of I.kappa.B); detection of
inhibition of UPP activity; detection of downstream effects of
protein E1 inhibition and substrate stabilization (e.g., reporter
assays, e.g., NF.kappa.B reporter assays, p27 reporter assays).
Assays for assessing activities are described below in the
Experimental section and/or are known in the art.
[0291] One embodiment of this invention relates to a composition
comprising a compound of this invention or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable carrier.
It will be appreciated that the compounds of this invention may be
derivatized at functional groups to provide prodrug derivatives
which are capable of conversion back to the parent compounds in
vivo. Examples of such prodrugs include the physiologically
acceptable and metabolically labile ester derivatives, such as
methoxymethyl esters, methylthiomethyl esters, or pivaloyloxymethyl
esters derived from a hydroxyl group of the compound or a carbamoyl
moiety derived from an amino group of the compound. Additionally,
any physiologically acceptable equivalents of the present
compounds, similar to the metabolically labile esters or
carbamates, which are capable of producing the parent compounds
described herein in vivo, are within the scope of this
invention.
[0292] If pharmaceutically acceptable salts of the compounds of the
invention are utilized in these compositions, the salts preferably
are derived from inorganic or organic acids and bases. For reviews
of suitable salts, see, e.g., Berge et al, J. Pharm. Sci. 66:1-19
(1977) and Remington: The Science and Practice of Pharmacy, 20th
Ed., ed. A. Gennaro, Lippincott Williams & Wilkins, 2000.
[0293] Nonlimiting examples of suitable acid addition salts include
the following: acetate, adipate, alginate, aspartate, benzoate,
benzene sulfonate, bisulfate, butyrate, citrate, camphorate,
camphor sulfonate, cyclopentanepropionate, digluconate,
dodecylsulfate, ethanesulfonate, fumarate, lucoheptanoate,
glycerophosphate, hemisulfate, heptanoate, hexanoate,
hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate,
lactate, maleate, methanesulfonate, 2-naphthalenesulfonate,
nicotinate, oxalate, pamoate, pectinate, persulfate,
3-phenyl-propionate, picrate, pivalate, propionate, succinate,
tartrate, thiocyanate, tosylate and undecanoate.
[0294] Suitable base addition salts include, without limitation,
ammonium salts, alkali metal salts, such as sodium and potassium
salts, alkaline earth metal salts, such as calcium and magnesium
salts, salts with organic bases, such as dicyclohexylamine salts,
N-methyl-D-glucamine, and salts with amino acids such as arginine,
lysine, and so forth.
[0295] In some embodiments, the invention relates to an acid
addition salt of a compound of formula I formed by protonation of a
basic moiety in the molecule. In certain such embodiments, the
invention relates to a hydrochloride salt of a compound of formula
I.
[0296] In some other embodiments the invention relates to a base
addition salt of a compound of formula I formed by deprotonation of
the sulfamate (X.dbd.O) moiety, the sulfamide (X.dbd.NH) moiety, or
the sulfonamide (X.dbd.CH.sub.2) moiety, as applicable. In some
such embodiments, the invention relates to a sodium or potassium
salt of a compound of formula I.
[0297] Also, basic nitrogen-containing groups may be quaternized
with such agents as lower alkyl halides, such as methyl, ethyl,
propyl, and butyl chloride, bromides and iodides; dialkyl sulfates,
such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain
halides such as decyl, lauryl, myristyl and stearyl chlorides,
bromides and iodides, aralkyl halides, such as benzyl and phenethyl
bromides and others. Water or oil-soluble or dispersible products
are thereby obtained.
[0298] The term "pharmaceutically acceptable carrier" is used
herein to refer to a material that is compatible with a recipient
subject, preferably a mammal, more preferably a human, and is
suitable for delivering an active agent to the target site without
terminating the activity of the agent. The toxicity or adverse
effects, if any, associated with the carrier preferably are
commensurate with a reasonable risk/benefit ratio for the intended
use of the active agent.
[0299] The pharmaceutical compositions of the invention can be
manufactured by methods well known in the art such as conventional
granulating, mixing, dissolving, encapsulating, lyophilizing, or
emulsifying processes, among others. Compositions may be produced
in various forms, including granules, precipitates, or
particulates, powders, including freeze dried, rotary dried or
spray dried powders, amorphous powders, tablets, capsules, syrup,
suppositories, injections, emulsions, elixirs, suspensions or
solutions. Formulations may optionally contain stabilizers, pH
modifiers, surfactants, solubilizing agents, bioavailability
modifiers and combinations of these.
[0300] Pharmaceutically acceptable carriers that may be used in
these compositions include, but are not limited to, ion exchangers,
alumina, aluminum stearate, lecithin, serum proteins, such as human
serum albumin, buffer substances such as phosphates or carbonates,
glycine, sorbic acid, potassium sorbate, partial glyceride mixtures
of saturated vegetable fatty acids, water, salts or electrolytes,
such as protamine sulfate, disodium hydrogen phosphate, potassium
hydrogen phosphate, sodium chloride, zinc salts, colloidal silica,
magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based
substances, polyethylene glycol, sodium carboxymethylcellulose,
polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,
polyethylene glycol and wool fat.
[0301] According to a preferred embodiment, the compositions of
this invention are formulated for pharmaceutical administration to
a mammal, preferably a human being. Such pharmaceutical
compositions of the present invention may be administered orally,
parenterally, by inhalation spray, topically, rectally, nasally,
buccally, vaginally or via an implanted reservoir. The term
"parenteral" as used herein includes subcutaneous, intravenous,
intraperitoneal, intramuscular, intra-articular, intra-synovial,
intrasternal, intrathecal, intrahepatic, intralesional and
intracranial injection or infusion techniques. Preferably, the
compositions are administered orally, intravenously, or
subcutaneously. The formulations of the invention may be designed
to be short-acting, fast-releasing, or long-acting. Still further,
compounds can be administered in a local rather than systemic
means, such as administration (e.g., by injection) at a tumor
site.
[0302] Pharmaceutical formulations may be prepared as liquid
suspensions or solutions using a liquid, such as, but not limited
to, an oil, water, an alcohol, and combinations of these.
Solubilizing agents such as cyclodextrins may be included.
Pharmaceutically suitable surfactants, suspending agents, or
emulsifying agents, may be added for oral or parenteral
administration. Suspensions may include oils, such as but not
limited to, peanut oil, sesame oil, cottonseed oil, corn oil and
olive oil. Suspension preparation may also contain esters of fatty
acids such as ethyl oleate, isopropyl myristate, fatty acid
glycerides and acetylated fatty acid glycerides. Suspension
formulations may include alcohols, such as, but not limited to,
ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and
propylene glycol. Ethers, such as but not limited to,
poly(ethyleneglycol), petroleum hydrocarbons such as mineral oil
and petrolatum; and water may also be used in suspension
formulations.
[0303] Sterile injectable forms of the compositions of this
invention may be aqueous or oleaginous suspension. These
suspensions may be formulated according to techniques known in the
art using suitable dispersing or wetting agents and suspending
agents. The sterile injectable preparation may also be a sterile
injectable solution or suspension in a non-toxic parenterally
acceptable diluent or solvent, for example as a solution in
1,3-butanediol. Among the acceptable vehicles and solvents that may
be employed are water, Ringer's solution and isotonic sodium
chloride solution. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose, any bland fixed oil may be employed including synthetic
mono- or di-glycerides. Fatty acids, such as oleic acid and its
glyceride derivatives are useful in the preparation of injectables,
as are natural pharmaceutically-acceptable oils, such as olive oil
or castor oil, especially in their polyoxyethylated versions. These
oil solutions or suspensions may also contain a long-chain alcohol
diluent or dispersant, such as carboxymethyl cellulose or similar
dispersing agents which are commonly used in the formulation of
pharmaceutically acceptable dosage forms including emulsions and
suspensions. Other commonly used surfactants, such as Tweens, Spans
and other emulsifying agents or bioavailability enhancers which are
commonly used in the manufacture of pharmaceutically acceptable
solid, liquid, or other dosage forms may also be used for the
purposes of formulation. Compounds may be formulated for parenteral
administration by injection such as by bolus injection or
continuous infusion. A unit dosage form for injection may be in
ampoules or in multi-dose containers.
[0304] The pharmaceutical compositions of this invention may be
orally administered in any orally acceptable dosage form including,
but not limited to, capsules, tablets, aqueous suspensions or
solutions. When aqueous suspensions are required for oral use, the
active ingredient is combined with emulsifying and suspending
agents. If desired, certain sweetening, flavoring or coloring
agents may also be added. For oral administration in a capsule
form, useful diluents include lactose and dried cornstarch. In the
case of tablets for oral use, carriers that are commonly used
include lactose and corn starch. Lubricating agents, such as
magnesium stearate, are also typically added. Coatings may be used
for a variety of purposes; e.g., to mask taste, to affect the site
of dissolution or absorption, or to prolong drug action. Coatings
may be applied to a tablet or to granulated particles for use in a
capsule.
[0305] Alternatively, the pharmaceutical compositions of this
invention may be administered in the form of suppositories for
rectal administration. These may be prepared by mixing the agent
with a suitable non-irritating excipient which is solid at room
temperature but liquid at rectal temperature and therefore will
melt in the rectum to release the drug. Such materials include
cocoa butter, beeswax and polyethylene glycols.
[0306] The pharmaceutical compositions of this invention may also
be administered topically, especially when the target of treatment
includes areas or organs readily accessible by topical application,
including diseases of the eye, the skin, or the lower intestinal
tract. Suitable topical formulations are readily prepared for each
of these areas or organs.
[0307] Topical application for the lower intestinal tract may be
effected in a rectal suppository formulation (see above) or in a
suitable enema formulation. Topically-transdermal patches may also
be used. For topical applications, the pharmaceutical compositions
may be formulated in a suitable ointment containing the active
component suspended or dissolved in one or more carriers. Carriers
for topical administration of the compounds of this invention
include, but are not limited to, mineral oil, liquid petrolatum,
white petrolatum, propylene glycol, polyoxyethylene,
polyoxypropylene compound, emulsifying wax and water.
Alternatively, the pharmaceutical compositions may be formulated in
a suitable lotion or cream containing the active components
suspended or dissolved in one or more pharmaceutically acceptable
carriers. Suitable carriers include, but are not limited to,
mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters
wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and
water.
[0308] For ophthalmic use, the pharmaceutical compositions may be
formulated as micronized suspensions in isotonic, pH adjusted
sterile saline, or, preferably, as solutions in isotonic, pH
adjusted sterile saline, either with our without a preservative
such as benzylalkonium chloride. Alternatively, for ophthalmic
uses, the pharmaceutical compositions may be formulated in an
ointment such as petrolatum.
[0309] The pharmaceutical compositions of this invention may also
be administered by nasal aerosol or inhalation. Such compositions
are prepared according to techniques well known in the art of
pharmaceutical formulation and may be prepared as solutions in
saline, employing benzyl alcohol or other suitable preservatives,
absorption promoters to enhance bioavailability, fluorocarbons,
and/or other conventional solubilizing or dispersing agents.
[0310] The pharmaceutical compositions of this invention are
particularly useful in therapeutic applications relating to
disorders as described herein (e.g., proliferation disorders, e.g.,
cancers, inflammatory, neurodegenerative disorders). Preferably,
the composition is formulated for administration to a patient
having or at risk of developing or experiencing a recurrence of the
relevant disorder being treated. The term "patient", as used
herein, means an animal, preferably a mammal, more preferably a
human. Preferred pharmaceutical compositions of the invention are
those formulated for oral, intravenous, or subcutaneous
administration. However, any of the above dosage forms containing a
therapeutically effective amount of a compound of the invention are
well within the bounds of routine experimentation and therefore,
well within the scope of the instant invention. In certain
embodiments, the pharmaceutical composition of the invention may
further comprise another therapeutic agent. Preferably, such other
therapeutic agent is one normally administered to patients with the
disorder, disease or condition being treated.
[0311] By "therapeutically effective amount" is meant an amount of
compound or composition sufficient, upon single or multiple dose
administration, to cause a detectable decrease in E1 enzyme
activity and/or the severity of the disorder or disease state being
treated. "Therapeutically effective amount" is also intended to
include an amount sufficient to treat a cell, prolong or prevent
advancement of the disorder or disease state being treated (e.g.,
prevent additional tumor growth of a cancer, prevent additional
inflammatory response), ameliorate, alleviate, relieve, or improve
a subject's symptoms of the a disorder beyond that expected in the
absence of such treatment. The amount of E1 enzyme inhibitor
required will depend on the particular compound of the composition
given, the type of disorder being treated, the route of
administration, and the length of time required to treat the
disorder. It should also be understood that a specific dosage and
treatment regimen for any particular patient will depend upon a
variety of factors, including the activity of the specific compound
employed, the age, body weight, general health, sex, and diet of
the patient, time of administration, rate of excretion, drug
combinations, the judgment of the treating physician, and the
severity of the particular disease being treated. In certain
aspects where the inhibitor is administered in combination with
another agent, the amount of additional therapeutic agent present
in a composition of this invention typically will be no more than
the amount that would normally be administered in a composition
comprising that therapeutic agent as the only active agent.
Preferably, the amount of additional therapeutic agent will range
from about 50% to about 100% of the amount normally present in a
composition comprising that agent as the only therapeutically
active agent.
[0312] One embodiment of the invention relates to a method of
inhibiting or decreasing E1 enzyme activity in a sample comprising
contacting the sample with a compound of this invention, or
composition comprising a compound of the invention. The sample, as
used herein, includes, without limitation, sample comprising
purified or partially purified E1 enzyme, cultured cells or
extracts of cell cultures; biopsied cells or fluid obtained from a
mammal, or extracts thereof; and body fluid (e.g., blood, serum,
saliva, urine, feces, semen, tears) or extracts thereof. Inhibition
of E1 enzyme activity in a sample may be carried out in vitro or in
vivo, in cellulo, or in situ.
[0313] In another embodiment, the invention provides a method for
treating a patient having a disorder, a symptom of a disorder, at
risk of developing or experiencing a recurrence of a disorder,
comprises administering to the patient a compound or pharmaceutical
composition according to the invention. Treating can be to cure,
heal, alleviate, relieve, alter, remedy, ameliorate, palliate,
improve or affect the disorder, the symptoms of the disorder or the
predisposition toward the disorder. While not wishing to be bound
by theory, treating is believed to cause the inhibition of growth,
ablation, or killing of a cell or tissue in vitro or in vivo, or
otherwise reduce capacity of a cell or tissue (e.g., an aberrant
cell, a diseased tissue) to mediate a disorder, e.g., a disorder as
described herein (e.g., a proliferative disorder, e.g., a cancer,
inflammatory disorder). As used herein, "inhibiting the growth" or
"inhibition of growth" of a cell or tissue (e.g., a proliferative
cell, tumor tissue) refers to slowing, interrupting, arresting or
stopping its growth and metastases and does not necessarily
indicate a total elimination of growth.
[0314] Disease applications include those disorders in which
inhibition of E1 enzyme activity is detrimental to survival and/or
expansion of diseased cells or tissue (e.g., cells are sensitive to
E1 inhibition; inhibition of E1 activity disrupts disease
mechanisms; reduction of E1 activity stabilizes protein which are
inhibitors of disease mechanisms; reduction of E1 activity results
in inhibition of proteins which are activators of disease
mechanisms). Disease applications are also intended to include any
disorder, disease or condition which requires effective cullin
and/or ubiquitination activity, which activity can be regulated by
diminishing E1 enzyme activity (e.g., NAE, UAE activity).
[0315] For example, methods of the invention are useful in
treatment of disorders involving cellular proliferation, including,
but not limited to, disorders which require an effective
cullin-dependent ubiquitination and proteolysis pathway (e.g., the
ubiquitin proteasome pathway) for maintenance and/or progression of
the disease state. The methods of the invention are useful in
treatment of disorders mediated via proteins (e.g., NF.kappa.B
activation, p27.sup.Kip activation, p21.sup.WAF/CIP1 activation,
p53 activation) which are regulated by E1 activity (e.g., NAE
activity, UAE activity, SAE activity). Relevant disorders include
proliferative disorders, most notably cancers and inflammatory
disorders (e.g., rheumatoid arthritis, inflammatory bowel disease,
asthma, chronic obstructive pulmonary disease (COPD),
osteoarthritis, dermatosis (e.g., atopic dermatitis, psoriasis),
vascular proliferative disorders (e.g., atherosclerosis,
restenosis) autoimmune diseases (e.g., multiple sclerosis, tissue
and organ rejection)); as well as inflammation associated with
infection (e.g., immune responses), neurodegenerative disorders
(e.g., Alzheimer's disease, Parkinson's disease, motor neurone
disease, neuropathic pain, triplet repeat disorders, astrocytoma,
and neurodegeneration as result of alcoholic liver disease),
ischemic injury (e.g., stroke), and cachexia (e.g., accelerated
muscle protein breakdown that accompanies various physiological and
pathological states, (e.g., nerve injury, fasting, fever, acidosis,
HIV infection, cancer affliction, and certain
endocrinopathies)).
[0316] The compounds and pharmaceutical compositions of the
invention are particularly useful for the treatment of cancer. As
used herein, the term "cancer" refers to a cellular disorder
characterized by uncontrolled or disregulated cell proliferation,
decreased cellular differentiation, inappropriate ability to invade
surrounding tissue, and/or ability to establish new growth at
ectopic sites. The term "cancer" includes, but is not limited to,
solid tumors and bloodborne tumors. The term "cancer" encompasses
diseases of skin, tissues, organs, bone, cartilage, blood, and
vessels. The term "cancer" further encompasses primary and
metastatic cancers.
[0317] In some embodiments, the cancer is a solid tumor.
Non-limiting examples of solid tumors that can be treated by the
methods of the invention include pancreatic cancer; bladder cancer;
colorectal cancer; breast cancer, including metastatic breast
cancer; prostate cancer, including androgen-dependent and
androgen-independent prostate cancer; renal cancer, including,
e.g., metastatic renal cell carcinoma; hepatocellular cancer; lung
cancer, including, e.g., non-small cell lung cancer (NSCLC),
bronchioloalveolar carcinoma (BAC), and adenocarcinoma of the lung;
ovarian cancer, including, e.g., progressive epithelial or primary
peritoneal cancer; cervical cancer; gastric cancer; esophageal
cancer; head and neck cancer, including, e.g., squamous cell
carcinoma of the head and neck; melanoma; neuroendocrine cancer,
including metastatic neuroendocrine tumors; brain tumors,
including, e.g., glioma, anaplastic oligodendroglioma, adult
glioblastoma multiforme, and adult anaplastic astrocytoma; bone
cancer; and soft tissue sarcoma.
[0318] In some other embodiments, the cancer is a hematologic
malignancy. Non-limiting examples of hematologic malignancy include
acute myeloid leukemia (AML); chronic myelogenous leukemia (CML),
including accelerated CML and CML blast phase (CML-BP); acute
lymphoblastic leukemia (ALL); chronic lymphocytic leukemia (CLL);
Hodgkin's disease (HD); non-Hodgkin's lymphoma (NHL), including
follicular lymphoma and mantle cell lymphoma; B-cell lymphoma;
T-cell lymphoma; multiple myeloma (MM); Waldenstrom's
macroglobulinemia; myelodysplastic syndromes (MDS), including
refractory anemia (RA), refractory anemia with ringed siderblasts
(RARS), (refractory anemia with excess blasts (RAEB), and RAEB in
transformation (RAEB-T); and myeloproliferative syndromes.
[0319] In some embodiments, the compound or composition of the
invention is used to treat a patient having or at risk of
developing or experiencing a recurrence in a cancer selected from
the group consisting of colorectal cancer, ovarian cancer, lung
cancer, breast cancer, gastric cancer, prostate cancer, and
pancreatic cancer. In certain preferred embodiments, the cancer is
selected from the group consisting of lung cancer, colorectal
cancer, ovarian cancer and a hematologic cancer.
[0320] Depending on the particular disorder or condition to be
treated, in some embodiments, the E1 enzyme inhibitor of the
invention is administered in conjunction with additional
therapeutic agent or agents. In some embodiments, the additional
therapeutic agent(s) is one that is normally administered to
patients with the disorder or condition being treated. As used
herein, additional therapeutic agents that are normally
administered to treat a particular disorder or condition are known
as "appropriate for the disorder or condition being treated."
[0321] The E1 inhibitor of the invention may be administered with
the other therapeutic agent in a single dosage form or as a
separate dosage form. When administered as a separate dosage form,
the other therapeutic agent may be administered prior to, at the
same time as, or following administration of the E1 inhibitor of
the invention.
[0322] In some embodiments, the E1 enzyme inhibitor of the
invention is administered in conjunction with a therapeutic agent
selected from the group consisting of cytotoxic agents,
radiotherapy, and immunotherapy appropriate for treatment of
proliferative disorders and cancer. Non-limiting examples of
cytotoxic agents suitable for use in combination with the E1 enzyme
inhibitors of the invention include: antimetabolites, including,
e.g., capecitibine, gemcitabine, 5-fluorouracil or
5-fluorouracil/leucovorin, fludarabine, cytarabine, mercaptopurine,
thioguanine, pentostatin, and methotrexate; topoisomerase
inhibitors, including, e.g., etoposide, teniposide, camptothecin,
topotecan, irinotecan, doxorubicin, and daunorubicin; vinca
alkaloids, including, e.g., vincristine and vinblastin; taxanes,
including, e.g., paclitaxel and docetaxel; platinum agents,
including, e.g., cisplatin, carboplatin, and oxaliplatin;
antibiotics, including, e.g., actinomycin D, bleomycin, mitomycin
C, adriamycin, daunorubicin, idarubicin, doxorubicin and pegylated
liposomal doxorubicin; alkylating agents such as melphalan,
chlorambucil, busulfan, thiotepa, ifosfamide, carmustine,
lomustine, semustine, streptozocin, decarbazine, and
cyclophosphamide; including, e.g., CC-5013 and CC-4047; protein
tyrosine kinase inhibitors, including, e.g., imatinib mesylate and
gefitinib; proteasome inhibitors, including, e.g., bortezomib,
thalidomide and related analogs; antibodies, including, e.g.,
trastuzumab, rituximab, cetuximab, and bevacizumab; mitoxantrone;
dexamethasone; prednisone; and temozolomide.
[0323] Other examples of agents the inhibitors of the invention may
be combined with include anti-inflammatory agents such as
corticosteroids, TNF blockers, Il-1 RA, azathioprine,
cyclophosphamide, and sulfasalazine; immunomodulatory and
immunosuppressive agents such as cyclosporine, tacrolimus,
rapamycin, mycophenolate mofetil, interferons, corticosteroids,
cyclophosphamide, azathioprine, methotrexate, and sulfasalazine;
antibacterial and antiviral agents; and agents for Alzheimer's
treatment such as donepezil, galantamine, memantine and
rivastigmine.
[0324] In order that this invention be more fully understood, the
following preparative and testing examples are set forth. These
examples are for the purpose of illustration only and are not to be
construed as limiting the scope of the invention in any way.
EXAMPLES
Abbreviations
[0325] AA ammonium acetate [0326] AcOH acetic acid [0327] AcCN
acetonitrile [0328] AIBN 2,2'-azobisisobutyronitrile [0329] Boc
tert-butoxycarbonyl [0330] DCM dichloromethane [0331] DEAD diethyl
azodicarboxylate [0332] DIBAL diisobutylaluminum hydride [0333]
DIPEA N,N-diisopropylethylamine [0334] DMAP
N,N-dimethyl-4-aminopyridine [0335] DMF dimethylformamide [0336]
EtOAc ethyl acetate [0337] EtOH ethanol [0338] FA formic acid
[0339] h hours [0340] KO-t-Bu potassium tert-butoxide [0341] LC/MS
liquid chromatography mass spectrum [0342] LiHMDS lithium
bis(trimethylsilyl)amide [0343] m-CPBA meta-chloroperbenzoic acid
[0344] MeOH methanol [0345] MgSO.sub.4 magnesium sulfate [0346] min
minutes [0347] MS mass spectrum [0348] MWI microwave irradiation
[0349] NIS N-iodosuccinimide [0350] NMO N-methylmorpholine-N-oxide
[0351] rt room temperature [0352] TBAF tetra-n-butylammonium
fluoride [0353] TBAI tetra-n-butylammonium iodide [0354] TBDMS
tert-butyldimethylsilyl [0355] TFA trifluoroacetic acid [0356] THF
tetrahydrofuran [0357] TPAP tetrapropylammonium perruthenate
Analytical LC-MS Methods
[0358] Spectra were run on a Phenominex Luna 5 .mu.m C18
50.times.4.6 mm column on a Hewlett-Packard HP1100 at 2.5 mL/min
for a 3 minute run using the following gradients: [0359] Formic
Acid Standard (FA Standard): Acetonitrile containing zero to 100
percent 0.1% formic acid in water. [0360] Ammonium Acetate Standard
(AA Standard): Acetonitrile containing zero to 100 percent 10 mM AA
in water.
Example 1
((1S,2S,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-p-
yrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate (Compound
I-35)
Step a:
(1R,2R,3S,5S)-3-(Hydroxymethyl)-6-oxabicyclo[3.1.0]hexan-2-ol
[0361] (1S,5S)-5-(Hydroxymethyl)cyclopent-2-en-1-ol (3.19 g, 27.9
mmol) was dissolved in DCM (143 mL) and the solution was cooled to
0.degree. C. 3-Chloroperbenzoic acid (7.52 g, 33.5 mmol) was added
and the mixture was stirred at rt for 4 h. TLC indicated complete
conversion. Silica gel (20 g) was added, the mixture was
concentrated to dryness and was purified via silica gel
chromatography eluting with a gradient of 0 to 100% EtOAc in DCM to
afford the title compound (2.75 g, 76%). LC/MS: R.sub.t=0.37 min,
ES.sup.+ 131 (AA standard).
Step b:
(1aS,1bR,5aS,6aS)-3-(4-Methoxyphenyl)hexahydrooxireno[4,5]cyclopen-
ta[1,2-d]-[1,3]dioxine
[0362]
(1R,2R,3S,5S)-3-(Hydroxymethyl)-6-oxabicyclo[3.1.0]hexan-2-ol (3.65
g, 21.0 mol) was dissolved in DCM (121 mL) and the solution was
cooled to 0.degree. C. 1-(Dimethoxymethyl)-4-methoxybenzene (10.7
mL, 63.1 mmol) was added followed by pyridinium p-toluenesulfonate
(530. mg, 2.11 mmol). The mixture was stirred at rt overnight. TLC
indicated complete conversion. The reaction mixture was
concentrated in vacuo and the residue was purified via silica gel
chromatography eluting with a gradient of 0 to 50% EtOAc in hexanes
to afford the title compound (4.10 g, 78%). LC/MS: R.sub.t=1.68
min, ES.sup.+ 249 (AA standard).
Step c:
N-[(1S)-2,3-Dihydro-1H-inden-1-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-am-
ine
[0363] 4-Chloro-1H-pyrrolo[2,3-d]pyrimidine (2.10 g, 13.6 mmol) was
dissolved in 1-butanol (60.0 mL) and N,N-diisopropylethylamine
(3.57 mL, 20.5 mmol) was added followed by (S)-(+)-1-aminoindan
(1.93 mL, 15.0 mmol). The mixture was heated to reflux for 60 h,
cooled down to rt and the solvent was evaporated to dryness. The
residue was purified via silica gel chromatography eluting with a
gradient of 0 to 100% EtOAc in DCM to afford the title compound
(2.72 g, 80%). LC/MS: R.sub.t=1.42 min, ES.sup.+ 251 (AA
standard).
Step d:
(4aS,6R,7S,7aR)-6-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrr-
olo[2,3-d]-pyrimidin-7-yl}-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]d-
ioxin-7-ol
[0364]
N-[(1S)-2,3-Dihydro-1H-inden-1-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-ami-
ne (3.70 g, 14.8 mmol) was dissolved in DMF (49.4 mL) under an
atmosphere of nitrogen. Sodium hydride (546 mg, 13.6 mmol) was
added and the suspension was stirred at 70.degree. C. for 10 min to
give a clear solution.
(1aS,1bR,5aS,6aS)-3-(4-Methoxyphenyl)hexahydrooxireno[4,5]-cycl-
openta[1,2-c][1,3]dioxine (2.82 g, 11.4 mmol) dissolved in DMF
(35.3 mL) was added to the solution above and the reaction was
stirred at 110.degree. C. for 2 h. The reaction mixture was cooled
down, quenched with saturated aqueous sodium chloride solution (30
mL), extracted with EtOAc (3.times.50 mL), dried with MgSO.sub.4,
filtered, and evaporated under high vacuum. The residue was
purified via silica gel chromatography eluting with a gradient of
30 to 100% EtOAc in hexanes to afford the title compound (3.90 g,
69%). LC/MS: R.sub.t=1.86 min, ES.sup.+ 500. (AA standard).
Step e:
O-[(4aS,6R,7S,7aR)-6-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-p-
yrrolo-[2,3-d]pyrimidin-7-yl}-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,-
3]dioxin-7-yl]O-phenyl thiocarbonate
[0365]
(4aS,6R,7S,7aR)-6-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrro-
lo-[2,3-d]pyrimidin-7-yl}-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]di-
oxin-7-ol (4.00 g, 8.02 mmol) was dissolved in DCM (169 mL) under
an atmosphere of argon and 4-(dimethylamino)-pyridine (2.94 g, 24.1
mmol) was added followed by phenyl chlorothionocarbonate (2.22 mL,
16.0 mmol). The mixture was stirred at rt for 1 hour. The solvent
was concentrated in vacuo and purified via silica gel
chromatography eluting with a gradient of 20 to 100% EtOAc in
hexanes on a column pre-treated with 1% TEA in hexanes to afford
the title compound (5.00 g, 99%). LC/MS: R.sub.t=2.34 min, ES.sup.+
636 (AA standard).
Step f:
N-[(1S)-2,3-Dihydro-1H-inden-1-yl]-7-[(4aS,6R,7aS)-2-(4-methoxyphe-
nyl)-hexahydrocyclopenta[d][1,3]dioxin-6-yl]-7H-pyrrolo[2,3-d]pyrimidin-4--
amine
[0366]
O-[(4aS,6R,7S,7aR)-6-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-py-
rrolo-[2,3-d]pyrimidin-7-yl}-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3-
]dioxin-7-yl]O-phenyl thiocarbonate (5.00 g, 7.88 mmol) was
dissolved in toluene (150. mL) under an atmosphere of nitrogen and
tri-n-butyltin hydride (4.24 mL, 15.8 mmol) was added followed by
2,2'-azo-bis-isobutyronitrile (259 mg, 1.58 mmol). The solution was
heated to reflux for 30 min, the mixture was cooled down, the
solvent was concentrated to 30 mL and the residue was purified via
silica gel chromatography eluting with a gradient of 30 to 100%
EtOAc in hexanes to afford the title compound (3.00 g, 79%). LC/MS:
R.sub.t=2.12 min, ES.sup.+ 483 (AA standard).
Step g:
(1S,2S,4R)-4-{4[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,-
3-d]-pyrimidin-7-yl}-2-(hydroxymethyl)cyclopentanol
[0367]
N-[(1S)-2,3-Dihydro-1H-inden-1-yl]-7-[(4aS,6R,7aS)-2-(4-methoxyphen-
yl)-hexahydrocyclopenta[d][1,3]dioxin-6-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-a-
mine (3.00 g, 5.90 mmol) was dissolved in THF (11.6 mL), water
(11.6 mL) and AcOH (34.9 mL, 614 mmol) were added. The mixture was
stirred at rt under an atmosphere of argon for 60 h. The mixture
was concentrated under reduced pressure and the residue was
purified via silica gel chromatography eluting with a gradient of 0
to 10% MeOH in DCM to afford the title compound (2.10 g, 98%).
LC/MS: R.sub.t=1.46 min, ES.sup.+ 365 (AA standard).
Step h:
(1S,2S,4R)-2-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-4-{4-[(1S)-2-
,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl
acetate
[0368]
(1S,2S,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,-
3-d]-pyrimidin-7-yl}-2-(hydroxymethyl)cyclopentanol (3.00 g, 8.23
mmol), 1H-imidazole (1.68 g, 24.7 mmol) and
4-(dimethylamino)-pyridine (100 mg, 0.818 mmol) were dissolved in
DMF (90.0 mL) under an atmosphere of argon and the solution was
cooled to 0.degree. C. tert-Butyldimethylsilyl chloride (1.24 g,
8.23 mmol) was added and the mixture was stirred at rt for 2 h.
LC/MS indicated complete conversion. The reaction was quenched with
saturated aqueous sodium chloride solution (30 mL), extracted with
EtOAc (3.times.50 mL), dried with MgSO.sub.4, filtered, and
concentrated in vacuo. The remaining DMF was removed under high
vacuum. Crude
(1S,2S,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-{4-[(1S)-2,3-dihy-
dro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentanol
(3.94 g, 8.23 mmol) and 4-(dimethylamino)-pyridine (100. mg, 0.818
mol) were dissolved in pyridine (70.0 mL) and acetic anhydride
(4.66 mL, 49.4 mmol) was added. The mixture was stirred at rt
overnight. The solvent was evaporated and the remaining pyridine
was removed under high vacuum. The residue was purified via silica
gel chromatography eluting with a gradient of 10 to 66% EtOAc in
hexanes to afford the title compound (3.66 g, 86%). LC/MS:
R.sub.t=2.51 min, ES.sup.+ 521 (AA standard).
Step i:
(1S,2S,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2-
,3-d}-pyrimidin-7-yl]-2-(hydroxymethyl)cyclopentyl acetate
[0369]
(1S,2S,4R)-2-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-4-{4-[(1S)-2,-
3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl
acetate (3.66 g, 7.03 mmol) was dissolved in THF (31.3 mL) and
pyridine (31.3 mL, 387 mmol) in a polypropylene vial and the
solution was cooled to 0.degree. C. Pyridine hydrofluoride (8.61
mL, 95.6 mmol) was added dropwise and the mixture was stirred at rt
for 1 hour. The resulting solution was added dropwise into a
solution of saturated aqueous sodium bicarbonate (150 mL),
extracted with EtOAc (3.times.50 mL), dried with MgSO.sub.4,
filtered, and concentrated in vacuo. The residue was purified via
silica gel chromatography eluting with a gradient of 0 to 10% MeOH
in DCM to afford the title compound (2.30 g, 80%). LC/MS:
R.sub.t=1.64 min, ES.sup.+ 407 (AA standard).
Step j:
(1S,2S,4R)-2-{[(Aminosulfonyl)oxy]methyl}-4-{4-[(1S)-2,3-dihydro-1-
H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl
acetate
[0370] A 2.00 M solution of chlorosulfonamide in AcCN was prepared
as follows: FA (2.30 mL, 61.0 mmol) was added dropwise, with
stirring to chlorosulfonyl isocyanate (5.20 mL, 59.7 mmol) under
nitrogen at 0.degree. C. After the addition was complete and the
mixture had solidified, AcCN (22.5 mL) was added. The resulting
solution was left to stand under a vented source of nitrogen
overnight at rt.
[0371]
(1S,2S,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,-
3-d]-pyrimidin-7-yl}-2-(hydroxymethyl)cyclopentyl acetate (2.30 g,
5.38 mol) was dissolved in AcCN (108 mL) and TEA (3.75 mL, 26.9
mmol) was added. The solution was cooled to 0.degree. C. and a 2.00
M solution of chlorosulfonamide in AcCN (5.38 mL, 10.8 mmol, as
prepared above) was added. The mixture was stirred at rt for 45
min. TLC indicated 50% conversion. Additional 2.00 M
chlorosulfonamide in AcCN solution (5.38 mL, 10.8 mmol) was added
and the mixture was stirred at rt for 15 min. At this time, TLC
indicated complete conversion. The mixture was quenched with MeOH
(3.00 mL), and the solvent was removed in vacuo. The residue was
purified via silica gel chromatography eluting with a gradient of 0
to 10% MeOH in EtOAc to afford the title compound (2.45 g, 94%).
LC/MS: R.sub.t=1.68 min, ES.sup.+ 486 (AA standard).
Step k:
((1S,2S,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[-
2,3-d]-pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate
(Compound I-35)
[0372]
(1S,2S,4R)-2-{[(Aminosulfonyl)oxy]methyl}-4-{4-[(1S)-2,3-dihydro-1H-
-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl
acetate (2.45 g, 4.54 mmol) was dissolved in a 7.00 M solution of
ammonia in MeOH (108 mL) and the mixture was stirred at rt for 5
days. The solvent was removed in vacuo, re-dissolved in DCM and the
filtered residue was purified via silica gel chromatography eluting
with a gradient of 0 to 10% MeOH in DCM to afford the title
compound (1.80 g, 90%). .sup.1H NMR (CD.sub.3OD, 400 MHz, .delta.):
8.16 (s, 1H), 7.26-7.12 (m, 5H), 6.63 (d, J=3.6 Hz, 1H), 5.85 (dd,
J=7.6, 7.6 Hz, 1H), 5.46-5.40 (m, 1H), 4.50-4.47 (m, 1H), 4.37 (d,
J=7.6, 9.6 Hz, 1H), 4.19 (dd, J=7.4, 9.6 Hz, 1H), 3.08-3.02 (m,
1H), 2.96-2.87 (m, 1H), 2.85-2.75 (m, 1H), 2.67-2.59 (m, 1H),
2.37-2.20 (m, 3H), 2.07-1.97 (m, 2H) ppm. LC/MS: R.sub.t=1.54 min,
ES.sup.+ 444 (AA standard).
Step 1:
((1S,2S,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[-
2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate,
Potassium salt
[0373]
((1S,2S,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2-
,3-d]-pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate (2.64
g, 5.66 mmol) was dissolved in MeOH (43.0 mL) and a 1.002 M
solution of potassium hydroxide in water (5.64 mL, 5.65 mmol) was
added at rt and the mixture was stirred for 1 hour. The solvent was
removed in vacuo and the solid residue was dried under high vacuum
to afford the title compound (2.87 g, 100%). .sup.1H NMR
(CD.sub.3OD, 300 MHz, .delta.): 8.16 (s, 1H), 7.26-7.12 (m, 5H),
6.62 (d, J=3.9 Hz, 1H), 5.85 (dd, J=7.8, 7.8 Hz, 1H), 5.50-5.40 (m,
1H), 4.51-4.48 (m, 1H), 4.22 (dd, J=8.6, 10.0 Hz, 1H), 4.05 (dd,
J=6.6, 10.0 Hz, 1H), 3.10-3.00 (m, 1H), 2.96-2.85 (m, 1H),
2.81-2.71 (m, 1H), 2.68-2.58 (m, 1H), 2.37-2.13 (m, 3H), 2.07-1.94
(m, 2H) ppm. LC/MS: R.sub.t=1.54 min, ES.sup.+ 444 (AA
standard).
Example 2
((1S,2S,4R)-4-{4-[(1R)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-p-
yrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate (Compound
I-13)
Step a: 4-(Benzylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidine
[0374] To a round bottomed flask with a stir bar was added
4-chloro-1H-pyrrolo-[2,3-d]pyrimidine (5.07 g, 33.0 mmol), 1.00 M
of KO-t-Bu in THF (49.5 mL, 49.5 mmol), and benzenemethanethiol
(5.81 mL, 49.5 mmol) in isopropyl alcohol (350 mL). The reaction
mixture was heated to reflux at 85.degree. C. under an atmosphere
of nitrogen. After 48 h, the reaction mixture was cooled and
solvent was removed in vacuo. To the residue was added water (300
mL) and the solution was filtered to collect the resulting white
solid. The solid was washed with diethyl ether and MeOH and dried
under vacuum to afford the product as a white solid (6.29 g, 79%
yield). LC/MS: R.sub.t=1.68 min, ES.sup.+ 242 (FA standard).
Reference: Pathak, A. K., Pathak, V., Seitz, L. E., Suling, W. J.,
Reynolds, R. C. J. Med. Chem., 2004, 47, 273-276.
Step b:
(4aS,6R,7S,7aR)-6-[4-(Benzylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidin-7-
-yl]-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-7-ol
[0375] A round-bottomed flask under an atmosphere of argon was
charged with 4-(benzylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidine (194
mg, 0.804 mmol), and DMF (5.00 mL) followed by a 1.00 M solution of
lithium hexamethyldisilazide in THF (0.603 mL, 0.603 mmol). The
reaction mixture was heated to 60.degree. C. After 10 min,
(1aS,1bR,5aS,6aS)-3-(4-methoxyphenyl)hexahydrooxireno[4,5]cyclopenta[1,2--
d][1,3]dioxine (100. mg, 0.403 mmol, as prepared in Example 1a-b)
in DMF (2.00 mL) was added and the reaction was heated to
110.degree. C. After 6 h, the reaction mixture was cooled to rt and
saturated aqueous sodium chloride solution (50.0 mL) was added. The
aqueous layer was washed with EtOAc (2.times.50 mL). The combined
organic layers were washed with water (2.times.100 mL), dried over
MgSO.sub.4, filtered and concentrated in vacuo. Purification via
silica gel chromatography eluting with a gradient of 0 to 100%
EtOAc in hexanes afforded the title compound as a white solid (197
mg, 93%). LC/MS: R.sub.t=2.07 min, ES.sup.+ 490. (FA standard).
Step c:
O-[(4aS,6R,7S,7aR)-6-[4-(Benzylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidi-
n-7-yl]-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-7-yl]O-phenyl
thiocarbonate
[0376] To a solution of
(4aS,6R,7S,7aR)-6-[4-(benzylsulfanyl)-7H-pyrrolo[2,3-d]-pyrimidin-7-yl]-2-
-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-7-ol (990. mg,
2.02 mmol) in DCM (57.0 mL) was added 4-(dimethylamino)-pyridine
(748 mg, 6.07 mmol) and phenyl chlorothionocarbonate (0.565 mL,
4.04 mol) under an atmosphere of nitrogen and the yellow reaction
was stirred at rt. After 12 h, the dark yellow solution was
purified via silica gel chromatography eluting with 10% EtOAc in
hexanes, and then 10% MeOH in DCM on a column pre-treated with 1%
TEA in hexanes to afford the title compound as a yellow oil (1.77
g, 97%). LC/MS: R.sub.t=2.47 min, ES.sup.+ 626 (FA standard).
Step d:
4-(Benzylsulfanyl)-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)hexahydrocyc-
lopenta[d]-[1,3]dioxin-6-yl]-7H-pyrrolo[2,3-d]pyrimidine
[0377] To a solution of
O-[(4aS,6R,7S,7aR)-6-[4-(benzylsulfanyl)-7H-pyrrolo[2,3-d]-pyrimidin-7-yl-
]-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-7-yl]O-phenyl
thiocarbonate (1.77 g, 1.98 mmol) in toluene (91.0 mL) was added
2,2'-azo-bis-isobutyronitrile (67.7 mg, 0.404 mmol) and
tri-n-butyltin hydride (1.11 mL, 4.00 mmol) under an atmosphere of
nitrogen. The yellow solution was heated to reflux at 140.degree.
C. After 2 h, the reaction mixture was cooled, silica gel was
added, and the solvent was removed in vacuo. Silica gel
chromatography eluting with a gradient of 0 to 100% EtOAc in
hexanes afforded the title compound as a semi-solid (800 mg, 85%).
LC/MS: R.sub.t=2.38 min, ES.sup.+ 475 (FA standard).
Step e:
4-(Benzylsulfonyl)-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)hexahydrocyc-
lopenta[d]-[1,3]dioxin-6-yl]-7H-pyrrolo[2,3-d]pyrimidine
[0378] To a round bottomed flask with a stir bar was added
4-(benzylsulfanyl)-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)hexahydrocyclopenta-
[d][1,3]dioxin-6-yl]-7H-pyrrolo-[2,3-d]pyrimidine (693 mg, 1.32
mmol) and DCM (32.5 mL). Sodium bicarbonate (400 mg, 4.76 mmol) was
added followed by 3-chloroperbenzoic acid (754 mg, 3.36 mol) and
the reaction mixture was stirred for 12 h. The reaction mixture was
then treated with saturated aqueous sodium bicarbonate solution,
extracted with DCM and the combined organic layers were dried over
MgSO.sub.4, filtered and concentrated in vacuo. Silica gel
chromatography eluting with a gradient of 0 to 100% EtOAc in
hexanes afforded the product as a white solid (219 mg, 32%). LC/MS:
R.sub.t=1.94 min, ES.sup.+ 506 (FA standard).
Step f:
N-[(1R)-2,3-Dihydro-1H-inden-1-yl]-7-[(4aS,6R,7aS)-2-(4-methoxyphe-
nyl)-hexahydrocyclopenta[d][1,3]dioxin-6-yl]-7H-pyrrolo[2,3-d]pyrimidin-4--
amine
[0379] In a 0.5-2 mL microwave vial,
4-(benzylsulfonyl)-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)hexahydrocyclopenta-
[d][1,3]dioxin-6-yl]-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.198
mmol), (R)-(-)-1-aminoindan (0.127 mL, 0.989 mmol), and DIPEA
(0.172 mL, 0.989 mol) were dissolved in ethanol (1.22 mL). The vial
was sealed and heated to 110.degree. C. overnight. The solution was
then concentrated in vacuo and the resulting material was purified
via silica gel chromatography eluting with a gradient of 20 to 50%
EtOAc in hexanes to afford the product as an orange oil (70.0 mg,
73%). LC/MS: R.sub.t=1.42 min, ES.sup.+ 483 (FA standard).
Step g:
(1S,2S,4R)-4-{4-[(1R)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2-
,3-d]-pyrimidin-7-yl}-2-(hydroxymethyl)cyclopentanol
[0380]
N-[(1R)-2,3-Dihydro-1H-inden-1-yl]-7-[(4aS,6R,7aS)-2-(4-methoxyphen-
yl)-hexahydrocyclopenta[d][1,3]dioxin-6-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-a-
mine (70.0 mg, 0.145 mmol) was added to a solution of AcOH (0.742
mL, 13.0 mmol), THF (0.235 mL) and water (0.261 mL). The solution
was stirred at rt for 4 days before being concentrated in vacuo.
Silica gel chromatography eluting with a gradient of 0 to 10% MeOH
in DCM afforded the title compound (27.6 mg, 52%). LC/MS:
R.sub.t=0.94 min, ES.sup.+ 365 (FA standard).
Step h: tert-Butyl (chlorosulfonyl)carbamate
[0381] To a stirred solution of chlorosulfonyl isocyanate (3.20 mL,
36.0 mmol) in benzene (15.0 mL) in a water bath at rt was added
tert-butyl alcohol (3.50 mL, 36.2 mmol) dropwise via syringe under
an atmosphere of nitrogen. After 2 h, the mixture was diluted with
hexanes (30.0 mL) and the resulting white precipitate was filtered
and washed with hexanes (3.times.20 mL). The collected solid was
dried in a vacuum desiccator under house vacuum for 10 min to
afford the title compound as a white solid (5.08 g, 65%). The
product was stored under nitrogen in a freezer. .sup.1H NMR (300
MHz, CDCl.sub.3, .delta.): 8.44 (br s, 1H), 1.57 (s, 9H) ppm.
LC/MS: R.sub.t=0.939 min, ES.sup.+ 215 (AA standard). Reference: F.
Hirayama et al., Biorg. Med. Chem., 2002, 10, 1509-1523.
Step i: tert-Butyl
{[((1S,2S,4R)-4-{4-[(1R)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo-[2,3--
d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methoxy]sulfonyl}carbamate
[0382]
(1S,2S,4R)-4-{4-[(1R)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,-
3-d]-pyrimidin-7-yl}-2-(hydroxymethyl)cyclopentanol (27.6 mg, 0.117
mmol) and 2,6-di-tert-butyl-4-methylpyridine (48.5 mg, 0.236 mmol)
were suspended in AcCN (1.57 mL) and cooled to 0.degree. C.
tert-Butyl (chlorosulfonyl)carbamate was added and the mixture was
allowed to warm to rt overnight. The reaction was quenched via
addition of MeOH (1.00 mL) and concentrated in vacuo. Silica gel
chromatography eluting with a gradient of 0 to 10% MeOH in DCM
afforded the title compound (15.2 mg, 37%). LC/MS: R.sub.t=1.29
min, ES.sup.+ 544 (FA standard).
Step j:
((1S,2S,4R)-4-{4-[(1R)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[-
2,3-d]-pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate
(Compound I-13)
[0383] tert-Butyl
{[((1S,2S,4R)-4-{4-[(1R)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d-
]pyrimidin-7-yl}-2-hydroxycyclopentyl)methoxy]sulfonyl}carbamate
(31.0 mg, 0.0570 mmol) was dissolved in DCM (0.803 mL) and
trifluoroacetic acid (0.803 mL, 10.4 mmol) was added. The solution
was stirred at rt for 15 min before being concentrated in vacuo.
The residue was taken up in MeOH (5.00 mL), treated with solid
sodium bicarbonate (300 mg) and stirred for 10 min. Filtration and
silica gel chromatography eluting with a gradient of 0 to 10% MeOH
in DCM afforded the title compound (7.20 mg, 58%). .sup.1H NMR (400
MHz, CD.sub.3OD, .delta.): 8.17 (s, 1H), 7.27-7.14 (m, 5H), 6.64
(d, J=3.5 Hz, 1H), 5.86 (t, J=7.5 Hz, 1H), 5.49-5.42 (m, 1H),
4.51-4.48 (m, 1H), 4.38 (dd, J=7.5, 9.8 Hz, 1H), 4.21 (dd, J=7.3,
9.8 Hz, 1H), 3.10-3.03 (m, 1H), 2.97-2.88 (m, 1H), 2.86-2.76 (m,
1H), 2.68-2.60 (m, 1H), 2.37-2.21 (m, 3H), 2.08-1.97 (m, 2H) ppm.
LC/MS: R.sub.t=1.16 min, ES.sup.+ 444 (FA standard).
Example 3
{(1S,2R,3S,4R)-2,3-Dihydroxy-4-[4-(phenylsulfanyl)-7H-pyrrolo[2,3-d]-pyrim-
idin-7-yl]cyclopentyl}methyl sulfamate (Compound I-53)
Step a: 4-(Phenylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidine
[0384] To a solution of 4-chloro-1H-pyrrolo[2,3-d]pyrimidine (1.69
g, 11.0 mmol) and TEA (4.60 mL, 33.0 mmol) in 1-butanol (25.0 mL)
was added benzenethiol (3.39 mL, 33.0 mmol), and the mixture was
refluxed at 140.degree. C. overnight. The reaction was then cooled
to rt and concentrated in vacuo. The off-white solid was purified
by silica gel chromatography eluting with a gradient of 0 to 35%
EtOAc in DCM to afford the product (2.29 g, 92%). LC/MS:
R.sub.t=1.55 min, ES.sup.+ 228 (FA standard).
Step b:
(4aS,6R,7S,7aR)-2-(4-Methoxyphenyl)-6-[4-(phenylsulfanyl)-1H-pyrro-
lo[3,2-c]-pyridin-1-yl]hexahydrocyclopenta[d][1,3]dioxin-7-ol
[0385] A mixture of 4-(phenylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidine
(895 mg, 3.94 mmol) and NaH (148 mg, 3.69 mmol) in dry DMF (12.0
mL) was stirred at 60.degree. C. for 10 min. Then
(1aS,1bR,5aS,6aS)-3-(4-methoxyphenyl)hexahydrooxireno[4,5]cyclopenta[1,2--
d][1,3]-dioxine (611 mg, 2.46 mmol) was added and the mixture was
heated to 110.degree. C. for 5 h. The reaction mixture was then
cooled to rt, quenched with saturated aqueous sodium chloride
solution and the solution was extracted twice with EtOAc. The
combined organics were dried over sodium sulfate, filtered and
concentrated in vacuo. The crude product mixture was purified by
silica gel chromatography eluting with a gradient of 5 to 30% EtOAc
in DCM to afford the title compound (96.5 mg, 8.24%). LC/MS:
R.sub.t=1.95 min, ES.sup.+ 476 (FA standard).
Step c:
(1S,2R,3S,5R)-3-(Hydroxymethyl)-5-[4-(phenylsulfanyl)-7H-pyrrolo[2-
,3-d]-pyrimidin-7-yl]cyclopentane-1,2-diol
[0386] To a solution of AcOH (1.04 mL, 18.3 mmol), THF (0.330 mL),
and water (0.366 mL) was added
(4aS,6R,7S,7aR)-2-(4-methoxyphenyl)-6-[4-(phenylsulfanyl)-1H-pyrrolo[3,2--
c]pyridin-1-yl]hexahydrocyclopenta[d][1,3]dioxin-7-ol (96.7 mg,
0.203 mmol). The reaction solution was stirred at rt for 48 h then
concentrated in vacuo. The resulting oil was purified by silica gel
chromatography eluting with a gradient of 60 to 100% EtOAc in
hexanes to afford the title compound (32.0 mg, 44%). LC/MS:
R.sub.t=1.33 min, ES.sup.+ 358 (FA standard).
Step d:
{(3aR,4S,6R,6aS)-2,2-Dimethyl-6-[4-(phenylsulfanyl)-7H-pyrrolo[2,3-
-d]pyrimidin-7-yl]tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methanol
[0387]
(1S,2R,3S,5R)-3-(Hydroxymethyl)-5-[4-(phenylsulfanyl)-7H-pyrrolo[2,-
3-d]-pyrimidin-7-yl]cyclopentane-1,2-diol (320 mg, 0.0895 mmol),
2,2-dimethoxypropane (0.0549 mL, 0.446 mmol), and p-toluenesulfonic
acid monohydrate (17.0 mg, 0.0895 mmol) were dissolved in acetone
(2.20 mL) and stirred at rt overnight. Then the reaction was
quenched with saturated sodium bicarbonate solution and
approximately half the solvent was removed in vacuo. The resulting
residue was diluted with water and extracted with DCM (3.times.).
Combined organics were dried over sodium sulfate, filtered, and
concentrated in vacuo to afford the title compound as a white foam
(35.5 mg, 99%), which was used without further purification. LC/MS:
R.sub.t=1.72 min, ES.sup.+ 389 (FA standard).
Step e:
{(3aR,4R,6R,6aS)-2,2-Dimethyl-6-[4-(phenylsulfanyl)-7H-pyrrolo[2,3-
-d]pyrimidin-7-yl]tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methyl
sulfamate
[0388] A solution of
{(3aR,4S,6R,6aS)-2,2-dimethyl-6-[4-(phenylsulfanyl)-7H-pyrrolo-[2,3-d]pyr-
imidin-7-yl]tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methanol
(35.5 mg, 0.0893 mmol) and pyridine (0.0325 mL, 0.402 mmol) in dry
DCM (1.00 mL) was cooled with an ice bath. To this solution was
added a 2.00 M chlorosulfonamide solution in AcCN (0.178 mL, 0.356
mmol, as prepared in Example 1j) and the reaction was allowed to
warm to rt and stirred for 4 h. The mixture was diluted with DCM,
washed with water, and extracted with DCM (3.times.). Combined
organics were dried over sodium sulfate, filtered, and concentrated
in vacuo. The resulting oil was purified by silica gel
chromatography eluting with a gradient of 50 to 70% EtOAc in
hexanes to afford the title compound as a white solid (14.4 mg,
34%). LC/MS: R.sub.t=1.81 min, ES.sup.+ 477 (FA standard).
Step f:
{(1R,2R,3S,4R)-2,3-Dihydroxy-4-[4-(phenylsulfanyl)-7H-pyrrolo[2,3--
d]pyrimidin-7-yl]cyclopentyl}methyl sulfamate (Compound I-53)
[0389]
{(3aR,4R,6R,6aS)-2,2-Dimethyl-6-[4-(phenylsulfanyl)-7H-pyrrolo[2,3--
d]-pyrimidin-7-yl}tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methyl
sulfamate (14.4 mg, 30.2 mmol) was stirred in 1.00 mL of 90%
trifluoroacetic acid in water for 3 h at rt. The solvent was then
removed in vacuo and the resulting oil was purified by silica gel
chromatography eluting with a gradient of 60 to 100% EtOAc in
hexanes to afford the title compound (7.50 mg, 57%). .sup.1H NMR
(400 MHz, CD.sub.3OD, .delta.): 8.45 (s, 1H), 7.66-7.36 (m, 2H),
7.51-7.41 (m, 4H), 5.92 (d, J=3.8 Hz, 1H), 5.13-5.06 (m, 1H),
4.58-4.55 (dd, J=3.8, 9.0 Hz, 1H), 4.42-4.37 (dd, J=8.0, 9.8 Hz,
1H), 4.18-4.14 (m, 2H), 2.92-2.82 (m, 1H), 2.24-2.08 (m, 2H) ppm.
LC/MS: R.sub.t=1.38 min, ES.sup.+ 437 (FA standard).
Example 4
[(1S,2S,4R)-2-Hydroxy-4-(4-{[(1R)-1-phenylethyl]amino}-7H-pyrrolo[2,3-d]-p-
yrimidin-7-yl)cyclopentyl]methyl sulfamate (Compound I-7)
[0390] The title compound was prepared following the procedure
described in Example 1a-k using R-(+)-.alpha.-methylbenzylamine in
step c. .sup.1H NMR (400 MHz, CD.sub.3OD, .delta.): 8.05 (s, 1H),
7.41-7.38 (m, 2H), 7.31-7.26 (m, 2H), 7.21-7.16 (m, 2H), 6.71 (d,
J=3.5 Hz, 1H), 5.46-5.38 (m, 2H), 4.50-4.46 (m, 1H), 4.38-4.34 (dd,
J=7.5, 9.8 Hz, 1H), 4.21-4.17 (dd, J=7.3, 9.8 Hz, 1H), 2.84-2.74
(m, 1H), 2.35-2.15 (m, 3H), 2.06-1.98 (m, 1H), 1.59 (d, J=6.8 Hz,
3H) ppm. LC/MS: R.sub.t=1.16 min, ES.sup.+ 432 (FA standard).
Example 5
[(1S,2S,4R)-2-Hydroxy-4-(4-{methyl[(1S)-1-phenylethyl]amino}-7H-pyrrolo-[2-
,3-d]pyrimidin-7-yl)cyclopentyl]methyl sulfamate (Compound I-3)
[0391] The title compound was prepared following the procedure
described in Example 1a-k using
(S)-(-)-N,.alpha.-dimethylbenzylamine in step c. .sup.1H NMR
(CD.sub.3OD, 300 MHz, .delta.): 8.16 (s, 1H), 7.34-7.20 (m, 6H),
6.64 (d, J=3.6 Hz, 1H), 6.41-6.34 (m, 1H), 5.54-5.43 (m, 1H),
4.51-4.48 (m, 1H), 4.24 (dd, J=9.6, 9.6 Hz, 1H), 4.07 (dd, J=6.9,
9.6 Hz, 1H), 3.03 (s, 3H), 2.80-2.70 (m, 1H), 2.37-2.14 (m, 3H),
2.02-1.88 (m, 1H), 1.64 (d, J=7.2 Hz, 3H) ppm. LC/MS: R.sub.t=1.64
min, ES.sup.+ 446 (AA standard).
Example 6
((1S,2S,4R)-4-{4-[(4S)-3,4-Dihydro-2H-chromen-4-ylamino]-7H-pyrrolo[2,3-d]-
-pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate (Compound
I-12)
##STR00132##
[0393] The title compound was prepared following the procedure
described in Example 1a-k using (4S)-chroman-4-amine in step c.
.sup.1H NMR (CD.sub.3OD, 400 MHz, .delta.): 8.28 (s, 1H), 7.43 (d,
J=3.6 Hz, 1H), 7.27-7.20 (m, 2H), 6.94-6.85 (m, 3H), 5.56-5.48 (m,
1H), 5.34-5.30 (m, 1H), 4.54-4.49 (m, 1H), 4.38 (dd, J=7.4, 9.8 Hz,
1H), 4.33-4.29 (m, 2H), 4.21 (dd, J=7.6, 9.8 Hz, 1H), 2.90-2.80 (m,
1H), 2.39-2.05 (m, 6H) ppm. LC/MS: R.sub.t=1.51 min, ES.sup.+ 460
(AA standard).
Example 7
((1S,2S,4R)-4-{4-[(2,6-Difluorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7--
yl}-2-hydroxycyclopentyl)methyl sulfamate (Compound I-15)
[0394] The title compound was prepared following the procedure
described in Example 1a-k using (2,6-difluorophenyl)methanamine in
step c. .sup.1H NMR (CD.sub.3OD, 300 MHz, .delta.): 8.17 (s, 1H),
7.39-7.29 (m, 1H), 7.16 (d, J=3.6 Hz, 1H), 7.00-6.94 (m, 2H), 6.60
(d, J=3.6 Hz, 1H), 5.48-5.37 (m, 1H), 4.80 (s, 2H), 4.50-4.46 (m,
1H), 4.36 (dd, J=7.6, 9.6 Hz, 1H), 4.19 (dd, J=7.2, 9.6 Hz, 1H),
2.85-2.72 (m, 1H), 2.36-2.00 (m, 4H) ppm. LC/MS: R.sub.t=1.42 min,
ES.sup.+ 454 (AA standard).
Example 8
{(1S,2S,4R)-4-[4-(Benzylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-hydroxyc-
yclopentyl}methyl sulfamate (Compound I-49)
[0395] The title compound was prepared following the procedure
described in Example 1a-k using benzylamine in step c. .sup.1H NMR
(CD.sub.3OD, 400 MHz, .delta.): 8.12 (s, 1H), 7.36-7.20 (m, 6H),
6.62 (d, J=3.6 Hz, 1H), 5.49-5.40 (m, 1H), 4.76 (s, 2H), 4.50-4.48
(m, 1H), 4.37 (dd, J=7.6, 10.0 Hz, 1H), 4.20 (dd, J=7.6, 10.0 Hz,
1H), 2.85-2.76 (m, 1H), 2.36-2.19 (m, 3H), 2.08-2.00 (m, 1H) ppm.
LC/MS: R.sub.t=1.20 min, ES.sup.+ 418 (FA standard).
Example 9
[(1S,2S,4R)-2-Hydroxy-4-(4-{[(1S)-1-phenylethyl]amino}-7H-pyrrolo[2,3-d]-p-
yrimidin-7-yl)cyclopentyl]methyl sulfamate (Compound I-4)
[0396] The title compound was prepared following the procedure
described in Example 1a-k using (1S)-(-)-.alpha.-methylbenzylamine
in step c. .sup.1H NMR (400 MHz, CD.sub.3OD, .delta.): 8.05 (s,
1H), 7.41-7.39 (d, J=7.6 Hz, 2H), 7.31-7.27 (m, 2H), 7.22-7.17 (m,
2H), 6.72 (d, J=3.3 Hz, 1H), 5.46-5.38 (m, 2H), 4.48-4.47 (br s,
1H), 4.37 (dd, J=7.6, 9.6 Hz, 1H), 4.21-4.17 (m, 1H), 2.84-2.75 (m,
1H), 2.37-2.18 (m, 3H), 2.07-1.94 (m, 1H), 1.61-1.59 (d, J=7.0 Hz,
3H) ppm. LC/MS: R.sub.t=1.50 min, ES.sup.+ 432 (AA standard).
Example 10
((1S,2S,4R)-4-{4-[Benzyl(methyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2--
hydroxycyclopentyl)methyl sulfamate (Compound I-10)
[0397] The title compound was prepared following the procedure
described in Example 2a-j using N-methylbenzylamine in step f.
.sup.1H NMR (400 MHz, DMSO-d6, .delta.): 8.24 (s, 1H), 7.44-7.25
(m, 5H), 7.31-7.23 (m, 3H), 6.64 (br s, 1H), 5.49-5.37 (m, 1H),
5.04 (s, 2H), 4.37-4.30 (m, 1H), 4.23 (dd, J=7.0, 9.7 Hz, 1H), 4.04
(dd, J=8.0, 9.6 Hz, 1H), 3.35 (s, 3H), 2.77-2.64 (m, 1H), 2.22-1.87
(m, 4H) ppm. LC/MS: R.sub.t=1.51 min, ES.sup.+ 432 (AA
standard).
Example 11
((1S,2S,4R)-4-{4-[(2-Chlorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}--
2-hydroxycyclopentyl)methyl sulfamate (Compound I-1)
[0398] The title compound was prepared following the procedure
described in Example 2a-j using 2-chlorobenzylamine in step f.
.sup.1H NMR (400 MHz, DMSO-d6, .delta.): 8.10 (s, 1H), 8.03-7.94
(m, 1H), 7.48-7.42 (m, 1H), 7.38 (s, 1H), 7.36-7.24 (m, 4H), 6.65
(d, J=3.2 Hz, 1H), 5.36 (dt, J=8.9, 14.2 Hz, 1H), 4.89 (d, J=3.9
Hz, 1H), 4.76 (d, J=5.9 Hz, 2H), 4.36-4.30 (m, 1H), 4.24 (dd,
J=7.0, 9.7 Hz, 1H), 4.05 (dd, J=8.1, 9.5 Hz, 1H), 2.77-2.66 (m,
1H), 2.24-2.02 (m, 3H), 1.99-1.89 (m, 1H) ppm. LC/MS: R.sub.t=1.51
min, ES.sup.+ 452 (AA standard).
Example 12
{(1S,2S,4R)-2-Hydroxy-4-[4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]--
cyclopentyl}methyl sulfamate and
((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-yl(methyl)amino]-7H-pyrrolo-
[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate
(Compounds I-40 and I-6)
Step a: tert-Butyl (1S)-2,3-dihydro-1H-inden-1-ylcarbamate
[0399] To a solution of (S)-(+)-1-aminoindan (1.24 g, 9.22 mmol) in
THF (20.0 mL) was added TEA (1.42 mL, 10.1 mmol) followed by
di-tert-butyldicarbonate (2.07 g, 9.22 mmol) and the mixture was
stirred under an atmosphere of nitrogen for 24 h. The mixture was
concentrated in vacuo and purified via silica gel chromatography
eluting with a gradient of 0 to 20% EtOAc in hexanes to afford the
title compound as a white solid (2.02 g, 94%). LC/MS: R.sub.t=1.94
min, ES.sup.+ 234 (AA standard).
Step b: tert-Butyl
(1S)-2,3-dihydro-1H-inden-1-yl(methyl)carbamate
[0400] To a solution of tert-butyl
(1S)-2,3-dihydro-1H-inden-1-ylcarbamate (1.82 g, 7.80 mmol) in THF
(50.0 mL) under an atmosphere of argon at 0.degree. C. was added
60% sodium hydride in mineral oil (968 mg, 24.2 mmol) and the
suspension was allowed to warm to rt and stir for 30 min.
Iodomethane (1.52 mL, 24.2 mmol) was added and the mixture was
stirred overnight. The reaction was then quenched via addition of
saturated ammonium chloride solution (10.0 mL) and was concentrated
in vacuo. The mixture was then partitioned between water (20 mL)
and DCM (50 mL) and the aqueous layer was extracted with DCM
(3.times.50 mL). The combined organic layers were dried over
MgSO.sub.4, filtered, concentrated in vacuo and purified by silica
gel chromatography eluting with a gradient of 0 to 20% EtOAc in
hexanes to afford the title compound as a clear, colorless oil
(1.84 g, 95%). LC/MS: R.sub.t=2.21 min, ES.sup.+ 248 (AA
standard).
Step c: (1S)--N-Methylindan-1-amine, hydrochloride salt
[0401] To a solution of tert-butyl
(1S)-2,3-dihydro-1H-inden-1-yl(methyl)carbamate (1.84 g, 7.44 mmol)
in MeOH (50.0 mL) under an atmosphere of nitrogen was added
hydrochloric acid (6.00 mL, 72.4 mmol) and the mixture was stirred
overnight. The reaction was concentrated in vacuo to afford the
title compound as a white solid without further purification (1.35
g, 99%). LC/MS: R.sub.t=0.85 min, ES.sup.+ 148 (AA standard).
Step d: tert-Butyl
{[((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-yl(methyl)amino]-7H-pyrro-
lo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methoxy]sulfonyl}carbamate
[0402] The title compound was prepared following the procedure
described in Example 2a-i using (1S)--N-methylindan-1-amine,
hydrochloride salt in step f. LC/MS: R.sub.t=1.55 min, ES.sup.+ 558
(AA standard).
Step e:
{(1S,2S,4R)-2-Hydroxy-4-[4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidi-
n-7-yl]-cyclopentyl}methyl sulfamate and
((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-yl(methyl)amino]-7H-pyrrolo-
[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate
(Compounds I-40 and I-6)
[0403] To a solution of tert-butyl
{[((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-yl(methyl)amino]-7H-pyrro-
lo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methoxy]-sulfonyl}carbamate
(97.9 mg, 0.176 mmol) in DCM (5.00 mL) under an atmosphere of
nitrogen was added trifluoroacetic acid (5.00 mL, 64.9 mmol). LC/MS
after 10 min indicated the presence of both products, and the
mixture was concentrated in vacuo and purified via silica gel
chromatography eluting with a gradient of 0 to 10% MeOH in EtOAc to
afford both products as clear, colorless oils (9.70 mg, 10% and
30.6 mg, 51%, respectively). Analytical data for
{(1S,2S,4R)-2-Hydroxy-4-[4-(methylamino)-7H-pyrrolo[2,3-d]pyrimi-
din-7-yl]-cyclopentyl}methyl sulfamate (Compound I-40): .sup.1H NMR
(400 MHz, CD.sub.3OD, .delta.): 8.18 (s, 1H), 7.38 (d, J=3.6 Hz,
1H), 6.74 (d, J=3.1 Hz, 1H), 5.53-5.42 (m, 1H), 4.51-4.47 (m, 1H),
4.37 (dd, J=7.5, 9.8 Hz, 1H), 4.19 (dd, J=7.4, 9.7 Hz, 1H), 3.34
(s, 3H), 3.14 (br s, 3H), 2.90-2.75 (m, 1H), 2.37-2.18 (m, 3H),
2.12-1.96 (m, 1H) ppm. LC/MS: R.sub.t=1.03 min, ES.sup.+ 342 (AA
standard). Analytical data for
((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-yl(methyl)amino]-7H-pyrrolo-
[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate
(Compound I-6): .sup.1H NMR (400 MHz, CD.sub.3OD, .delta.): 8.28
(s, 1H), 7.54 (d, J=3.8 Hz, 1H), 7.39-7.21 (m, 4H), 7.02 (d, J=3.8
Hz, 1H), 6.26 (dd, J=7.5, 7.5 Hz, 1H), 5.58 (ddd, J=5.2, 8.9, 17.9
Hz, 1H), 5.47 (s, 1H), 4.51 (dd, J=3.3, 3.3 Hz, 1H), 4.38 (dd,
J=7.4, 9.8 Hz, 1H), 4.20 (dd, J=7.5, 9.7 Hz, 1H), 3.23-2.96 (m,
6H), 2.93-2.79 (m, 1H), 2.76-2.59 (m, 1H), 2.42-2.05 (m, 6H) ppm.
LC/MS: R.sub.t=1.89 min, ES.sup.+ 458 (AA standard).
Example 13
{(1S,2S,4R)-4-[4-(Benzylamino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-
-hydroxycyclopentyl}methyl sulfamate (Compound I-31)
Step a: 4-Chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine
[0404] To a stirred solution of
4-chloro-1H-pyrrolo[2,3-d]pyrimidine (3.00 g, 19.5 mmol) in AcCN
(148 mL) was added Selectfluor.TM.
(1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane
bis(tetrafluoroborate)), 10.4 g, 29.4 mmol) and AcOH (29.8 mL, 524
mmol), and then the mixture was allowed to stir for 26 hrs at
70.degree. C. under an atmosphere of nitrogen. After cooling to rt,
the mixture was concentrated in vacuo and the mixture was
co-evaporated with dry toluene (2.times.30 mL). The residue was
dissolved in a solution of 50% DCM in EtOAc and filtered through a
pad of silica gel which was thoroughly washed. The filtrate was
concentrated in vacuo, the residue was purified by silica gel
chromatography eluting with a gradient of 0 to 30% EtOAc in DCM to
afford the title compound as a light brown solid (1.22 g, 36%).
LC/MS: R.sub.t=1.51 min, ES.sup.+ 243 (AA standard).
Step b:
{(1S,2S,4R)-4-[4-(Benzylamino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-
-7-yl]-2-hydroxycyclopentyl}methyl sulfamate (Compound I-31)
[0405] The title compound was prepared following the procedure
described in Example 1a-k using benzylamine and
4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine in step c. .sup.1H
NMR (400 MHz, CD.sub.3OD, .delta.): 8.09 (s, 1H), 7.37-7.32 (m,
2H), 7.31-7.26 (m, 2H), 7.23-7.19 (m, 1H), 7.06 (d, J=2.0 Hz, 1H),
5.50-5.42 (m, 1H), 4.76 (br s, 2H), 4.47-4.43 (m, 1H), 4.34 (dd,
J=7.8, 9.8 Hz, 1H), 4.17 (dd, J=7.2, 9.8 Hz, 1H), 2.81-2.72 (m,
1H), 2.29 (ddd, J=1.5, 8.0 Hz, 14.0 Hz, 1H), 2.25-2.13 (m, 2H),
1.98 (ddd, J=5.0, 9.4, 14.0 Hz, 1H). LC/MS: R.sub.t=1.56 min,
ES.sup.+ 436 (AA standard).
Example 14
((1S,2S,4R)-4-{4-[(Cyclohexylmethyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl-
}-2-hydroxycyclopentyl)methyl sulfamate (Compound I-29)
[0406] The title compound was prepared following the procedure
described in Example 1a-k using cyclohexanemethylamine in step c.
.sup.1H NMR (300 MHz, CD.sub.3OD, .delta.): 8.08 (s, 1H), 7.17 (d,
J=3.6 Hz, 1H), 6.60 (d, J=3.6 Hz, 1H), 5.47-5.35 (m, 1H), 4.50-4.46
(m, 1H), 4.36 (dd, J=7.6, 9.8 Hz, 1H), 4.19 (dd, J=7.3, 9.8 Hz,
1H), 3.35 (br s, 1H), 3.34 (br s, 2H), 3.32 (br s, 1H), 2.85-2.72
(m, 1H), 2.36-2.15 (m, 3H), 2.01 (ddd, J=4.9, 9.2, 14.3 Hz, 1H),
1.88-1.60 (m, 6H), 1.36-1.15 (m, 3H), 1.06-0.91 (m, 2H). LC/MS:
R.sub.t=1.60 min, ES.sup.+ 424 (AA standard).
Example 15
((1S,2R,3S,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d-
]-pyrimidin-7-yl}-2,3-dihydroxycyclopentyl)methyl sulfamate
(Compound I-17)
Step a:
(1R,2S,3R,5S)-3-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrol-
o[2,3-d]-pyrimidin-7-yl}-5-(hydroxymethyl)cyclopentane-1,2-diol
[0407] To a solution of
(4aS,6R,7R,7aR)-6-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-
-d]pyrimidin-7-yl}-2-(4-methoxyphenyl)-7-methylhexahydrocyclopenta[d]-[1,3-
]dioxin-7-ol (312 mg, 0.594 mmol, as prepared following the
procedure in Example 1a-d, using (S)-(+)-1-aminoindan in step c) in
THF (1.17 mL) and water (1.17 mL) was added AcOH (3.51 mL, 61.7
mmol) under an atmosphere of nitrogen. The mixture was stirred at
rt overnight. The solvent was removed in vacuo and the residue was
purified by silica gel chromatography eluting with a gradient of 0
to 10% MeOH in DCM to afford the title compound as a white solid
(182 mg, 76%). LC/MS: R.sub.t=0.85 min, ES.sup.+ 381 (FA
standard).
Step b:
((3aR,4S,6R,6aS)-6-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyr-
rolo[2,3-d]-pyrimidin-7-yl}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]d-
ioxol-4-yl)methanol
[0408] To a suspension of
(1R,2S,3R,5S)-3-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d-
]pyrimidin-7-yl}-5-(hydroxymethyl)cyclopentane-1,2-diol (63.8 mg,
0.168 mmol) and 2,2-dimethoxypropane (0.103 mL, 0.838 mmol) in
acetone (2.10 mL) was added p-toluenesulfonic acid monohydrate
(31.9 mg, 0.168 mmol) with rapid stirring. The resulting solution
was stirred overnight. The reaction was quenched with saturated
aqueous sodium bicarbonate solution (1.00 mL) and the volume was
reduced in vacuo. The solution was diluted with water and extracted
with EtOAc. The combined organic layers were washed with saturated
aqueous sodium chloride solution, dried over sodium sulfate,
filtered and concentrated in vacuo. The residue was purified by
silica gel chromatography eluting with a gradient of 10 to 60%
EtOAc in hexanes to afford the title compound as a white solid
(49.6 mg, 70.%). LC/MS: R.sub.t=1.16 min, ES.sup.+ 421 (FA
standard).
Step c:
((1S,2R,3S,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrro-
lo[2,3-d]-pyrimidin-7-yl}-2,3-dihydroxycyclopentyl)methyl sulfamate
(Compound I-17)
[0409] To a suspension of
((3aR,4S,6R,6aS)-6-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,-
3-d]pyrimidin-7-yl}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]-dioxol-4-
-yl)methanol (45.9 mg, 0.109 mmol) and pyridine (0.0180 mL, 0.222
mmol) in AcCN (1.10 mL) and DCM (0.500 mL) at 0.degree. C. under an
atmosphere of nitrogen was added dropwise a 2.00 M solution of
chlorosulfonamide in AcCN (0.110 mL, 0.220 mmol, as prepared in
1j). The suspension was stirred for 2 h and more 2.00 M of
chlorosulfonamide in AcCN solution (0.150 mL, 3.00 mmol) was added.
After 5 min the reaction was quenched with MeOH (1.00 mL) and the
solvent was removed in vacuo. The residue was purified by silica
gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM
to afford the title compound as a white solid (23.1 mg, 46%).
.sup.1H NMR (400 MHz, CD.sub.3OD, .delta.): 8.36 (s, 1H), 7.62 (d,
J=3.1 Hz, 1H), 7.43-7.33 (m, 4H), 7.04 (d, J=3.0 Hz, 1H), 5.67 (br
s, 1H), 5.25-5.20 (m, 1H), 4.61 (dd, J=3.8, 9.3 Hz, 1H), 4.48 (dd,
J=2.0, 9.9 Hz, 1H), 4.27-4.22 (m, 2H), 3.74 (s, 1H), 3.27-3.20 (m,
1H), 3.13-3.05 (m, 1H), 3.02-2.90 (m, 1H), 2.87-2.77 (m, 1H),
2.35-2.19 (m, 3H) ppm. LC/MS: R.sub.t=0.94 min, ES.sup.+ 460. (FA
standard).
Example 16
((1R,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyri-
midin-7-yl}cyclopent-2-en-1-yl)methyl sulfamate and
((1S,3S)-3-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyri-
midin-7-yl}-cyclopentyl)methyl sulfamate (Compounds I-20 and
I-11)
Step a:
(1S,2R,3S,5R)-3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-5-{4-[(1S-
)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopen-
tane-1,2-diol
[0410] A solution of
(1R,2S,3R,5S)-3-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d-
]pyrimidin-7-yl}-5-(hydroxymethyl)cyclopentane-1,2-diol (166 mg,
0.436 mmol, as prepared in Example 15a), tert-butyldimethylsilyl
chloride (69.0 mg, 0.458 mmol), 1H-imidazole (44.6 mg, 0.654 mmol)
in DMF (2.00 mL) was stirred under an atmosphere of nitrogen. After
2 h additional tert-butyldimethylsilyl chloride (6.00 mg, 0.0365
mmol) was added and the solution was stirred for 1 hour. The
reaction was quenched with water and extracted with EtOAc. The
combined organics were washed with water and saturated aqueous
sodium chloride solution, dried over sodium sulfate, filtered, and
concentrated in vacuo. The residue filtered through a plug of
silica gel eluting with 60% EtOAc in hexanes to afford the title
compound as an off white solid (179 mg, 83%). LC/MS: R.sub.t=1.51
min, ES.sup.+ 495 (FA standard).
Step b:
(3aR,4S,6R,6aS)-4-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-6-{4-[(-
1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}tetrah-
ydro-3aH-cyclopenta[d][1,3]dioxole-2-thione
[0411] To a solution of
(1S,2R,3S,5R)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-{4-[(1S)-2,3-d-
ihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentane-1,-
2-diol (179 mg, 0.362 mmol) in DMF (2.00 mL) under an atmosphere of
nitrogen was added 1,1'-thiocarbonyldiimidazole (72.3 mg, 0.406
mmol) and the solution was heated to 80.degree. C. for 3 h. The
solvent was removed and the residue was purified by silica gel
chromatography eluting with a gradient of 0 to 50% EtOAc in hexanes
to afford the title compound (158 mg, 81%). LC/MS: R.sub.t=2.24
min, ES.sup.+ 538 (FA standard).
Step c:
7-[(1R,4R)-4-({[tert-Butyl(dimethyl)silyl]oxy}methyl)cyclopent-2-e-
n-1-yl]-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-am-
ine
[0412] To a solution of
(3aR,4S,6R,6aS)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-6-{4-[(1S)-2,3-
-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}tetrahydro-3
aH-cyclopenta[d][1,3]dioxole-2-thione (138 mg, 0.257 mmol) in THF
(0.860 mL) at 0.degree. C. under an atmosphere of nitrogen was
added 1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine (0.147 mL,
0.793 mmol) dropwise. The solution was stirred for 10 min at
0.degree. C. and then at rt for 5 h. The solvent was removed and
the residue was purified by silica gel chromatography eluting with
a gradient of 0 to 20% EtOAc in hexanes to afford the title
compound as a clear oil (.about.70% purity, 81.9 mg, 48%). LC/MS:
R.sub.t=2.10 min, ES.sup.+ 462 (FA standard).
Step d:
((1R,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-
-d]-pyrimidin-7-yl}cyclopent-2-en-1-yl)methanol
[0413] To a solution of
7-[(1R,4R)-4-({[tert-butyl(dimethyl)silyl]oxy}-methyl)cyclopent-2-en-1-yl-
]-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine
(81.9 mg, 0.178 mmol) in pyridine (0.800 mL) and THF (0.800 mL) at
0.degree. C. under an atmosphere of nitrogen was added dropwise
pyridine hydrofluoride (0.0500 mL, 0.555 mol). The solution was
warmed to rt and stirred overnight. The reaction was quenched with
saturated aqueous sodium bicarbonate solution and diluted with
EtOAc. The layers were separated and the aqueous layer was
extracted with EtOAc (3.times.20 mL). The combined organic layers
were dried over sodium sulfate, filtered and concentrated in vacuo.
The residue was purified by silica gel chromatography eluting with
a gradient of 0 to 5% MeOH in DCM to afford the title compound as a
white solid (.about.70% purity, 35.7 mg, 41%). LC/MS: R.sub.t=1.03
min, ES.sup.+ 347 (FA standard).
Step e:
((1R,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-
-d]-pyrimidin-7-yl}cyclopent-2-en-1-yl)methyl sulfamate (Compound
I-20)
[0414] To a solution of
((1R,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyri-
midin-7-yl}cyclopent-2-en-1-yl)methanol (35.7 mg, 0.103 mmol) and
pyridine (0.0417 mL, 0.515 mmol) in AcCN (1.00 mL) at 0.degree. C.
under an atmosphere of nitrogen was added dropwise a 2.00 M
solution of chlorosulfonamide in AcCN (0.260 mL, 0.520 mmol, as
prepared in 1j). The solution was stirred for 1 hour. The reaction
was quenched with saturated aqueous sodium bicarbonate solution and
partitioned between water and EtOAc. The layers were separated and
the aqueous layer was extracted with EtOAc (2.times.20 mL). The
combined organic layers were washed with saturated aqueous sodium
chloride solution, dried over sodium sulfate, filtered and
concentrated in vacuo. The residue was purified by silica gel
chromatography eluting with a gradient of 0 to 5% MeOH in DCM to
afford the title compound as a solid (28.9 mg, 66%). .sup.1H NMR
(400 MHz, CDCl.sub.3, .delta.): 8.36 (s, 1H), 7.35 (d, J=7.2 Hz,
1H), 7.30-7.18 (m, 3H), 6.89 (d, J=3.6 Hz, 1H), 6.32 (d, J=3.5 Hz,
1H), 6.14-6.12 (m, 1H), 6.04-5.97 (m, 2H), 5.89 (br s, 1H), 4.19
(dd, J=1.2, 6.0 Hz, 2H), 3.43-3.37 (m, 1H), 3.09-3.01 (m, 1H),
2.98-2.90 (m, 1H), 2.77-2.69 (m, 1H), 2.46-2.39 (m, 1H), 2.07-1.93
(m, 3H) ppm. LC/MS: R.sub.t=1.24 min, ES.sup.+ 426 (FA
standard).
Step f:
((1S,3S)-3-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-
-d]pyrimidin-7-yl}cyclopentyl)methyl sulfamate (Compound I-11)
[0415] A suspension of
((1R,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyri-
midin-7-yl}cyclopent-2-en-1-yl)methyl sulfamate (17.3 mg, 0.0406
mmol) and 10% palladium on carbon (8.60 mg) in EtOAc (0.500 mL) was
put under an atmosphere of hydrogen. After 3 h the flask was purged
with nitrogen and the suspension was filtered through Celite
eluting with EtOAc to afford the title compound as a white solid
(10.8 mg, 62%). .sup.1H NMR (400 MHz, CDCl.sub.3, .delta.): 8.36
(s, 1H), 7.36 (d, J=7.3 Hz, 1H), 7.29-7.15 (m, 3H), 7.00 (d, J=3.4
Hz, 1H), 6.33 (d, J=3.4 Hz, 1H), 5.91-5.87 (m, 1H), 5.41 (br s,
2H), 5.23-5.15 (m, 2H), 4.26 (dd, j=5.8, 9.8 Hz, 1H), 4.18 (dd,
J=6.2, 9.8 Hz, 1H), 3.09-3.02 (m, 1H), 2.99-2.90 (m, 1H), 2.36-2.27
(m, 2H), 2.21-2.12 (m, 2H), 2.09-1.93 (m, 3H), 1.66-1.57 (m, 1H)
ppm. LC/MS: R.sub.t=1.24 min, ES.sup.+ 428 (FA standard).
Example 17
[(1S,2S,4R)-2-Hydroxy-4-(4-{[(5-methylisoxazol-3-yl)methyl]amino}-1H-pyrro-
lo[2,3-d]pyridazin-1-yl)cyclopentyl]methyl sulfamate (Compound
I-41)
Step a:
N-[(5-Methylisoxazol-3-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ami-
ne
[0416] 4-Chloro-1H-pyrrolo[2,3-d]pyrimidine (1.14 g, 7.43 mmol),
(5-methyl-3-isoxazolyl)methylamine (1.00 g, 8.92 mmol) and DIPEA
(1.94 mL, 11.1 mmol) were added to 1-butanol (9.13 mL). The mixture
was heated at 190.degree. C. for 1600 seconds using MWI in three
batches. The combined reactions were concentrated in vacuo to give
a brown oil. The residue was purified by silica gel chromatography
eluting with EtOAc to afford the title compound as a yellow solid
(1.22 g, 72%). LC/MS: R.sub.t=0.63 min, ES.sup.+ 230. (FA
standard).
Step b:
[(1S,2S,4R)-2-Hydroxy-4-(4-{[(5-methylisoxazol-3-yl)methyl]amino}--
1H-pyrrolo-[2,3-d]pyridazin-1-yl)cyclopentyl]methyl sulfamate
(Compound I-41)
[0417] The title compound was prepared following the procedure
described in Example 1d-k using
N-[(5-methylisoxazol-3-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine
in step d. .sup.1H NMR (400 MHz, CD.sub.3OD, .delta.): 8.22 (s,
1H), 7.26 (d, J=3.6 Hz, 1H), 6.63 (d, J=3.6 Hz, 1H), 6.14 (s, 1H),
5.55-5.44 (m, 1H), 4.81 (s, 2H), 4.59 (br s, 1H), 4.42 (dd, J=7.6,
9.6 Hz, 1H), 4.25 (dd, J=7.4, 9.8 Hz, 1H), 2.91-2.79 (m, 1H), 2.41
(s, 3H), 2.40-2.22 (m, 3H), 2.15-2.04 (m, 1H) ppm.
[0418] LC/MS: R.sub.t=0.89 min, ES.sup.+ 423 (FA standard).
Example 18
[(1S,2S,4R)-4-(4-Anilino-1H-pyrrolo[2,3-d]pyridazin-1-yl)-2-hydroxycyclope-
ntyl]methyl sulfamate (Compound I-39)
[0419] The title compound was prepared following the procedure
described in Example 17a-b using aniline in step a. .sup.1H NMR
(400 MHz, CD.sub.3OD, .delta.): 8.18 (s, 1H), 7.62 (d, J=7.6 Hz,
2H), 7.31 (dd, J=7.5, 8.4 Hz, 2H), 7.23 (d, J=3.7 Hz, 1H), 7.06 (t,
J=7.4 Hz, 1H), 6.22 (d, J=3.7 Hz, 1H), 5.50-5.39 (m, 1H), 4.46 (br
s, 1H), 4.34 (dd, J=7.6, 7.6 Hz, 1H), 4.16 (dd, J=7.4, 7.4 Hz, 1H),
2.89-2.73 (m, 1H), 2.37-2.15 (m, 3H), 2.09-1.97 (m, 1H) ppm. LC/MS:
R.sub.t=1.03 min, ES.sup.+ 404 (FA standard).
Example 19
[(1S,2S,4R)-2-Hydroxy-4-(4-{[2-(trifluoromethyl)benzyl]amino}-4-1H-pyrrolo-
-[2,3-d]pyridazin-1-yl)cyclopentyl]methyl sulfamate (Compound
I-47)
[0420] The title compound was prepared following the procedure
described in Example 17a-b using 2-(trifluoromethyl)benzylamine in
step a. .sup.1H NMR (400 MHz, CD.sub.3OD, .delta.): 8.08 (s, 1H),
7.66 (d, J=7.7 Hz, 1H), 7.47 (d, J=4.0 Hz, 2H), 7.42-7.34 (m, 1H),
7.19 (d, J=3.7 Hz, 1H), 6.60 (d, J=3.2 Hz, 1H), 5.50-5.36 (m, 1H),
4.94 (s, 1H), 4.45 (br s, 1H), 4.34 (dd, J=7.5, 7.6 Hz, 1H), 4.16
(dd, J=7.4, 7.4 Hz, 1H), 3.27 (q, J=1.6, 3.3 Hz, 1H), 2.94-2.73 (m,
1H), 2.35-2.15 (m, 3H), 2.06-1.96 (m, 1H) ppm. LC/MS: R.sub.t=1.25
min, ES.sup.+ 486 (FA standard).
Example 20
((1S,2S,4R)-4-{4-[(Cyclopropylmethyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-y-
l}-2-hydroxycyclopentyl)methyl sulfamate (Compound I-25)
Step a:
(1S,2S,4R)-4-{4-[(Cyclopropylmethyl)amino]-7H-pyrrolo[2,3-d]pyrimi-
din-7-yl}-2-(hydroxymethyl)cyclopentanol
[0421] The title compound was prepared following the procedure
described in Example 1a-g using cyclopropylmethylamine in step c.
LC/MS: R.sub.t=0.90 min, ES.sup.+ 303 (FA standard).
Step b:
7-[(1R,3S,4S)-3-{[tert-Butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(d-
imethyl)silyl]oxy}-methyl)cyclopentyl]-N-(cyclopropylmethyl)-7H-pyrrolo[2,-
3-d]pyrimidin-4-amine
[0422]
(1S,2S,4R)-4-{4-[(Cyclopropylmethyl)amino]-7H-pyrrolo[2,3-d]pyrimid-
in-7-yl}-2-(hydroxymethyl)cyclopentanol (280. mg, 0.923 mmol) was
stirred in DMF (3.00 mL). tert-Butyldimethylsilyl chloride (698 mg,
4.63 mmol) was added followed by 1H-imidazole (142 mg, 2.08 mmol)
and 4-(dimethylamino)-pyridine (10.0 mg, 0.0818 mmol). The reaction
was stirred for 1 h then diluted with water and extracted with
EtOAc (3.times.15 mL). The organic layer was dried over MgSO.sub.4,
filtered and concentrated in vacuo. The resulting oil was dried
under high vacuum overnight. The residue was purified by silica gel
chromatography eluting with a gradient of 0 to 15% EtOAc in hexanes
to afford the title compound (203 mg, 41%). LC/MS: R.sub.t=2.16
min, ES.sup.+ 531 (FA standard).
Step c:
((1S,2S,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-{4-[(cyclopropylm-
ethyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methartol
[0423]
7-[(1R,3S,4S)-3-{[tert-Butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(di-
methyl)silyl]-oxy}methyl)cyclopentyl]-N-(cyclopropylmethyl)-7H-pyrrolo[2,3-
-d]pyrimidin-4-amine (100. mg, 0.188 mmol) was dissolved in THF
(0.900 mL) and pyridine (0.900 mL). Pyridine hydrofluoride (7
drops) was added and the reaction was stirred for 5 h. Additional
pyridine hydrofluoride (3 drops) was added and the reaction was
stirred for 2 h before being quenched with saturated aqueous sodium
bicarbonate solution. The aqueous layer was extracted using EtOAc
(3.times.10 mL), and the combined organic extracts were dried over
MgSO.sub.4, filtered, and concentrated in vacuo. The residue was
purified by silica gel chromatography eluting with a gradient of 0
to 50% EtOAc in hexanes to afford the title compound (47.0 mg,
50%). LC/MS: R.sub.t=1.53 min, ES.sup.+ 417 (FA standard).
Step d:
((1S,2S,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-{4-[(cyclopropylm-
ethyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methyl
sulfamate
[0424]
((1S,2S,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-{4-[(cyclopropylme-
thyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methanol
(74.0 mg, 0.178 mmol) was dissolved in AcCN (3.50 mL) and cooled to
0.degree. C. TEA (0.0500 mL, 0.355 mmol) was added followed by a
2.00 M solution of chlorosulfonamide in AcCN (0.178 mL, 0.356 mmol,
as prepared in 1j). The reaction was stirred for 2 h, quenched with
MeOH and concentrated in vacuo. The material was taken on to the
next step without further purification. LC/MS: R.sub.t=1.51 min,
ES.sup.+ 496 (FA standard).
Step e:
((1S,2S,4R)-4-{4-[(Cyclopropylmethyl)amino]-7H-pyrrolo[2,3-d]pyrim-
idin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate (Compound
I-25)
[0425]
((1S,2S,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-{4-[(cyclopropylme-
thyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methyl
sulfamate (88.0 mg, 0.178 mmol) was dissolved in THF (1.00 mL) and
pyridine (3.00 mL). Pyridine hydrofluoride (12 drops) was added and
the reaction was stirred for 3 h. The reaction was quenched using
saturated aqueous sodium bicarbonate solution. The aqueous layer
was extracted with EtOAc (3.times.10 mL), and the combined organic
extracts were dried over MgSO.sub.4, filtered, and concentrated in
vacuo. The residue was purified by silica gel chromatography
eluting with 5% MeOH in DCM. The compound was re-purified via
silica gel chromatography eluting with 10% MeOH in DCM to afford
the title compound (3.00 mg, 4.4%). .sup.1H NMR (400 MHz,
CD.sub.3OD, .delta.): 8.05 (s, 1H), 7.15 (d, J=3.6 Hz, 1H), 6.59
(d, J=3.6 Hz, 1H), 5.45-5.32 (m, 1H), 4.56 (br s, 1H), 4.45 (br s,
1H), 4.33 (dd, J=7.6, 7.6 Hz, 1H), 4.15 (dd, J=7.4, 7.4 Hz, 1H),
3.34 (d, J=6.9 Hz, 2H), 2.83-2.68 (m, 1H), 2.35-2.08 (m, 3H),
2.05-1.93 (m, 1H), 1.33-1.03 (m, 3H), 0.93-0.77 (m, 1H) ppm. LC/MS:
R.sub.t=0.85 min, ES.sup.+ 382 (FA standard).
Example 21
((1S,2S,4R)-4-{4-[(4-Chlorobenzyl)oxy]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2--
hydroxycyclopentyl)methyl sulfamate (Compound I-34)
##STR00133##
[0426] Step a:
4-[(4-Chlorobenzyl)oxy]-7H-pyrrolo[2,3-d]pyrimidine
[0427] To a 0.375 M solution of aqueous potassium hydroxide (26.2
mL, 9.83 mmol) was added (4-chlorophenyl)methanol (464 mg, 3.26
mmol) and the mixture was heated to 80.degree. C. for 30 min. Then
4-chloro-1H-pyrrolo[2,3-d]pyrimidine (500 mg, 3.26 mmol) was added
and the mixture was refluxed at 130.degree. C. After 6 h,
additional (4-chlorophenyl)methanol (100. g, 0.701 mmol) was added
and the solution was heated to 115.degree. C. overnight. The
reaction was cooled to rt and diluted with water. The solution was
then extracted with EtOAc (2.times.) and DCM (2.times.). The
combined organic layers were dried over sodium sulfate, filtered,
and concentrated in vacuo. The resulting crude oil was purified by
silica gel chromatography eluting with a gradient of 5 to 30% EtOAc
in DCM to afford the product as a white solid (210 mg, 25%). LC/MS:
R.sub.t=1.72 min, ES.sup.+ 260. (FA standard).
Step b:
((1S,2S,4R)-4-{4-[(4-Chlorobenzyl)oxy]-7H-pyrrolo[2,3-d]pyrimidin--
7-yl}-2-hydroxycyclopentyl)methyl sulfamate (Compound I-34)
[0428] The title compound was prepared following the procedure
described in Example 1d-g and then Example 2i-j, using
4-[(4-Chlorobenzyl)oxy]-7H-pyrrolo[2,3-d]-pyrimidine in step 1d.
.sup.1H NMR (400 MHz, CD.sub.3OD, .delta.): 8.35 (s, 1H), 7.51-7.34
(m, 5H), 6.56 (d, J=3.5 Hz, 1H), 5.55 (s, 2H), 5.54-5.46 (m, 1H),
4.52-4.48 (m, 1H), 4.37 (dd, J=7.8, 10.0 Hz, 1H), 4.20 (dd, J=7.3,
9.8 Hz, 1H), 2.90-2.80 (m, 1H), 2.34-2.20 (m, 3H), 2.11-2.03 (m,
1H) ppm. LC/MS: R.sub.t=1.81 min, ES.sup.+ 453 (FA standard).
Example 22
{(1S,2S,4R)-4-[4-(Benzylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydro-
xycyclopentyl]methyl sulfamate (Compound I-32)
[0429] The title compound was prepared following the procedure
described in Example 2a-d and g-j. .sup.1H NMR (400 MHz,
CD.sub.3OD, .delta.): 8.54 (s, 1H), 7.45-7.36 (m, 3H), 7.28-7.14
(m, 3H), 6.47 (d, J=3.6 Hz, 1H), 5.51-5.43 (m, 1H), 4.58 (s, 2H),
4.49-4.45 (m, 1H), 4.33 (dd, J=7.6, 9.7 Hz, 1H), 4.16 (dd, J=7.3,
9.7 Hz, 1H), 2.87-2.78 (m, 1H), 2.62 (s, 2H), 2.32-2.15 (m, 3H),
2.08-2.01 (m, 1H) ppm. LC/MS: R.sub.t=1.97 min, ES.sup.+ 435 (FA
standard).
Example 23
((1S,2S,4R)-4-{4-[(4-Chlorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}--
2-hydroxycyclopentyl)methyl sulfamate (Compound I-45)
[0430] The title compound was prepared following the procedure
described in Example 2a-j using 4-chlorobenzylamine in step f.
.sup.1H NMR (400 MHz, CD.sub.3OD, .delta.): 8.10 (s, 1H), 7.34-7.28
(m, 4H), 7.21 (d, J=3.6 Hz, 1H), 6.59 (d, J=3.6 Hz, 1H), 5.47-5.39
(m, 1H), 4.73 (s, 2H), 4.50-4.48 (m, 1H), 4.25 (dd, J=8.3, 9.9 Hz,
1H), 4.09 (dd, J=6.8, 10.0 Hz, 1H), 3.35-3.33 (m, 2H), 2.81-2.71
(m, 1H), 2.35-2.29 (m, 1H), 2.26-2.15 (m, 2H), 2.02-1.96 (m, 1H)
ppm. LC/MS: R.sub.t=5.39 min, ES.sup.+ 452 (FA standard, long
purity method)
Example 24
((1S,2S,4R)-4-{4-[(3-Chlorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}--
2-hydroxycyclopentyl)methyl sulfamate (Compound I-51)
[0431] The title compound was prepared following the procedure
described in Example 2a-j using 3-chlorobenzylamine in step f.
.sup.1H NMR (400 MHz, CD.sub.3OD, .delta.): 8.22 (s, 1H), 7.44-7.31
(m, 5H), 6.78 (d, J=3.6 Hz, 1H), 5.56-5.48 (m, 1H), 4.82 (s, 2H),
4.56-4.52 (m, 1H), 4.42 (dd, J=7.5, 9.8 Hz, 1H), 4.25 (dd, J=7.3,
9.8 Hz, 1H), 2.92-2.83 (m, 1H), 2.42-2.26 (m, 3H), 2.15-2.08 (m,
1H) ppm. LC/MS: R.sub.t=1.51 min, ES.sup.+ 452 (FA standard).
Example 25
((1S,2S,4R)-4-{4-[(4-Chloro-2-methylbenzyl)amino]-7H-pyrrolo[2,3-d]-pyrimi-
din-7-yl}-2-hydroxycyclopentyl)methyl sulfamate (Compound I-48)
[0432] The title compound was prepared following the procedure
described in Example 2a-j using 4-chloro-2-methylbenzylamine in
step f. .sup.1H NMR (400 MHz, CD.sub.3OD, .delta.): 8.12 (s, 1H),
7.26-7.21 (m, 3H), 7.14-7.11 (m, 1H), 6.66 (d, J=3.5 Hz, 1H),
5.49-5.41 (m, 1H), 4.69 (s, 2H), 4.50-4.47 (m, 1H), 4.36 (dd,
J=7.5, 9.8 Hz, 1H), 4.19 (dd, J=7.5, 9.8 Hz, 1H), 2.86-2.76 (m,
1H), 2.36 (s, 3H), 2.33-2.19 (m, 3H), 2.08-2.01 (m, 1H) ppm. LC/MS:
R.sub.t=1.11 min, ES.sup.+ 466 (FA standard).
Example 26
((1S,2S,4R)-2-Hydroxy-4-{4-[(2-methoxybenzyl)amino]-7H-pyrrolo[2,3-d]-pyri-
midin-7-yl}cyclopentyl)methyl sulfamate (Compound I-43)
[0433] The title compound was prepared following the procedure
described in Example 2a-j using 2-methoxybenzylamine in step f.
.sup.1H NMR (400 MHz, CD.sub.3OD, .delta.): 8.08 (s, 1H), 7.24-7.18
(m, 3H), 6.96 (d, J=7.8 Hz, 1H), 6.85 (dt, J=0.8, 7.3 Hz, 1H), 6.61
(d, J=3.5 Hz, 1H), 5.47-5.39 (m, 1H), 4.72 (s, 2H), 4.50-4.46 (m,
1H), 4.36 (dd, J=7.5, 9.8 Hz, 1H), 4.19 (dd, J=7.3, 9.8 Hz, 1H),
3.87 (s, 3H), 2.84-2.75 (m, 1H), 2.35-2.18 (m, 3H), 2.06-1.99 (m,
1H) ppm. LC/MS: R.sub.t=1.16 min, ES.sup.+ 448 (FA standard).
Example 27
((1S,2S,4R)-4-{4-[(3,4-Dichlorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7--
yl}-2-hydroxycyclopentyl)methyl sulfamate (Compound I-24)
[0434] The title compound was prepared following the procedure
described in Example 2a-j using 3,4-dichlorobenzylamine in step f.
.sup.1H NMR (400 MHz, CD.sub.3OD, .delta.): 8.15 (s, 1H), 7.51 (d,
J=2.0 Hz, 1H), 7.46 (d, J=8.3 Hz, 1H), 7.30-7.27 (m, 2H), 6.65 (d,
J=3.5 Hz, 1H), 5.48-5.41 (m, 1H), 4.74 (s, 2H), 4.49 (t, J=4.0 Hz,
1H), 4.37 (dd, J=7.5, 9.8 Hz, 1H), 4.20 (dd, J=7.5, 9.8 Hz, 1H),
2.86-2.77 (m, 1H), 2.36-2.20 (m, 3H), 2.08-2.01 (m, 1H) ppm. LC/MS:
R.sub.t=1.16 min, ES.sup.+ 486 (FA standard).
Example 28
((1S,2S,4R)-2-Hydroxy-4-{4-[(1S)-1,2,3,4-tetrahydronaphthalen-1-ylamino]-7-
H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methyl sulfamate
(Compound I-37)
[0435] The title compound was prepared following the procedure
described in Example 2a-j using
(S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine in step f. .sup.1H NMR
(400 MHz, CD.sub.3OD, .delta.): 8.16 (s, 1H), 7.26-7.07 (m, 5H),
6.63 (d, J=3.5 Hz, 1H), 5.56-5.50 (m, 1H), 5.49-5.41 (m, 1H), 4.50
(m, 1H), 4.38 (dd, J=7.5, 9.8 Hz, 1H), 4.20 (dd, J=7.3, 9.8 Hz,
1H), 2.93-2.76 (m, 3H), 2.37-2.20 (m, 3H), 2.17-1.82 (m, 5H) ppm.
LC/MS: R.sub.t=1.29 min, ES.sup.+ 458 (FA standard).
Example 29
((1S,2R,3S,4R)-4-{4-[(4-Chlorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-y-
l}-2,3-dihydroxycyclopentyl)methyl sulfamate (Compound I-22)
[0436] The title compound was prepared following the procedure
described in Example 2a-d and g-j using 4-chlorobenzylamine in step
f. .sup.1H NMR (300 MHz, CD.sub.3OD, .delta.): 8.11 (s, 1H),
7.34-7.21 (m, 5H), 6.60 (d, J=3.6 Hz, 1H), 5.06-4.97 (m, 1H), 4.74
(s, 2H), 4.51 (dd, J=3.6, 9.2 Hz, 1H), 4.40 (dd, J=8.0, 9.6 Hz,
1H), 4.18-4.14 (m, 2H), 2.88-2.78 (m, 1H), 2.23-2.02 (m, 2H) ppm.
LC/MS: R.sub.t=1.46 min, ES.sup.+ 468 (AA standard).
Example 30
((1S,2S,4R)-4-{6-[(4-Chlorobenzyl)amino]-9H-purin-9-yl}-2-hydroxycyclopent-
yl)methyl sulfamate (Compound I-23)
[0437] The title compound was prepared following the procedure
described in Example 1a-f and Example 2h-j, using
4-chlorobenzylamine and 6-chloro-9H-purine in step 1c. .sup.1H NMR
(300 MHz, CD.sub.3OD, .delta.): 8.23 (s, 1H), 8.14 (s, 1H),
7.35-7.25 (m, 4H), 5.31-5.22 (m, 1H), 4.79 (s, 2H), 4.51-4.49 (br
s, 1H), 4.37 (dd, J=7.5, 9.6 Hz, 1H), 4.23-4.17 (m, 1H), 2.93-2.87
(m, 1H), 2.47-2.30 (m, 2H), 2.28-2.10 (m, 2H) ppm. LC/MS:
R.sub.t=1.42 min, ES.sup.+ 453 (AA standard).
Example 31
[(1S,2S,4R)-2-Hydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopen-
tyl]methyl sulfamate (Compound I-46)
Step a: 4-Methyl-7H-pyrrolo[2,3-d]pyrimidine
[0438] A 3.00 M solution of magnesium chloride in THF (13.0 mL,
39.0 mmol) was added dropwise to a stirred solution of
4-chloro-1H-pyrrolo[2,3-d]pyrimidine (2.50 g, 16.3 mmol) and ferric
acetylacetonate (700. mg 1.98 mmol) in THF (30.0 mL) under an
atmosphere of argon. The resulting reaction mixture was stirred at
rt for 8 h. The mixture was poured onto a mixture of ice (100 mL)
and ammonium chloride (1.00 g) and the mixture was extracted with
chloroform. Volatiles were removed in vacuo, and C-18 column
chromatography eluting with a gradient of 0 to 60% AcCN in water
with 0.1% AA afforded the title compound (1.50 g, 69%). LC/MS:
R.sub.t=0.94 min, ES.sup.+ 134 (AA standard).
Step b:
[(1S,2S,4R)-2-Hydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-
cyclopentyl]-methyl sulfamate (Compound I-46)
[0439] The title compound was prepared following the procedure
described in Example 1a-k using
4-methyl-7H-pyrrolo[2,3-d]pyrimidine in step c. .sup.1H NMR
(CD.sub.3OD, 300 MHz, .delta.): 8.69 (s, 1H), 7.68 (d, J=3.6 Hz,
1H), 6.82 (d, J=3.6 Hz, 1H), 5.63-5.51 (m, 1H), 4.53-4.49 (m, 1H),
4.37 (dd, J=7.5, 9.9 Hz, 1H), 4.20 (dd, J=7.5, 9.9 Hz, 1H),
2.90-2.80 (m, 1H), 2.77 (s, 3H), 2.36-2.05 (m, 4H) ppm. LC/MS:
R.sub.t=0.50 min, ES.sup.+ 327 (FA standard).
Example 32
{(1S,2S,4R)-2-Hydroxy-4-[4-(2-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl-
]-cyclopentyl}methyl sulfamate (Compound I-28)
[0440] The title compound was prepared following the procedure
described in Example 31a-b using chloro(2-phenylethyl)magnesium in
step a. .sup.1H NMR (CD.sub.3OD, 300 MHz, .delta.): 8.62 (s, 1H),
7.48 (d, J=3.9 Hz, 1H), 7.19-7.09 (m, 5H), 6.57 (d, J=3.9 Hz, 1H),
5.55-5.46 (m, 1H), 4.49-4.46 (m, 1H), 4.35 (dd, J=7.8, 9.6 Hz, 1H),
4.18 (dd, J=7.5, 9.6 Hz, 1H), 3.28-3.24 (m, 2H), 3.10-3.04 (m, 2H),
2.88-2.80 (m, 1H), 2.31-2.01 (m, 4H) ppm. LC/MS: R.sub.t=1.56 min,
ES.sup.+ 417 (AA standard).
Example 33
{(1S,2S,4R)-2-Hydroxy-4-[4-(2-methyl-2-phenylpropyl)-7H-pyrrolo[2,3-d]-pyr-
imidin-7-yl]cyclopentyl}methyl sulfamate (Compound I-50)
[0441] The title compound was prepared following the procedure
described in Example 31a-b using
chloro(2-methyl-2-phenylpropyl)magnesium in step a. .sup.1H NMR
(400 MHz, CD.sub.3OD, .delta.): 8.62 (s, 1H), 7.37-7.34 (m, 2H),
7.25-7.21 (m, 2H), 7.16-7.12 (m, 1H), 6.15 (d, 1H), 5.56-5.47 (m,
1H), 4.49-4.48 (br s, 1H), 4.37 (dd, J=7.6, 9.6 Hz, 1H), 4.22-4.17
(m, 1H), 2.93-2.87 (m, 1H), 2.89-2.80 (m, 1H), 2.31-2.19 (m, 3H),
2.07-2.00 (m, 1H), 1.43 (s, 6H) ppm. LC/MS: R.sub.t=1.59 min,
ES.sup.+ 445 (AA standard).
Example 34
{(1S,2S,4R)-4-[4-(Acetylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-hydroxyc-
yclopentyl}methyl sulfamate and
[(1S,2S,4R)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopen-
tyl]methyl sulfamate (Compounds I-9 and I-18)
Step a:
(1S,2S,4R)-4-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxym-
ethyl)cyclopentanol
[0442] A solution of
N-(2,4-dimethoxybenzyl)-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)-hexahydrocycl-
openta[d][1,3]dioxin-6-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (123
mg, 0.238 mmol, prepared following the procedure described in
Example 1a-f using 2,4-dimethoxybenzylamine in step c) and AcOH
(1.00 mL, 17.6 mmol) in water (0.500 mL) and THF (0.500 mL) were
stirred at rt overnight. The reaction mixture was concentrated in
vacuo and purification by silica gel chromatography eluting with a
gradient of 0 to 10% MeOH in DCM afforded the title compound (43.0
mg, 73%). LC/MS: R.sub.t=0.15 min, ES.sup.+ 249 (FA standard).
Step b:
(1S,2S,4R)-4-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-({[tert-b-
utyl(dimethyl)silyl]oxy}methyl)cyclopentanol
[0443] To a solution of
(1S,2S,4R)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)c-
yclopentanol (43.0 mg, 0.173 mmol) and imidazole (25.0 mg, 0.367
mmol) in dry DMF (2.00 mL) at 0.degree. C. was added
tert-butyldimethylsilyl chloride (29.0 mg, 0.192 mmol). The
solution was stirred at rt for 2 h and concentrated in vacuo, the
residue was dissolved in water and extracted with EtOAc. The
combined organic extracts were dried over MgSO.sub.4, filtered and
concentrated in vacuo to afford the title compound (50.8 mg, 81%),
which was taken on without further purification. LC/MS:
R.sub.t=1.38 min, ES.sup.+ 364 (FA standard).
Step c:
(1S,2S,4R)-4-[4-(Acetylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-(-
{[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl acetate
[0444] To a solution of
(1S,2S,4R)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-({[tert-butyl(di-
methyl)silyl]oxy}methyl)cyclopentanol (125 mg, 0.345 mmol) in
pyridine (2.00 mL) at 0.degree. C. was added acetic anhydride
(0.380 mL, 4.03 mmol). The solution was stirred at rt overnight.
The reaction mixture was diluted with DCM and water. The layers
were separated and the aqueous layer was extracted with DCM. The
combined organic layers were dried over MgSO.sub.4, filtered and
concentrated in vacuo. The residue was purified by silica gel
chromatography eluting with a gradient of 0 to 50% EtOAc in hexanes
to afford the title compound (47.8 mg, 31%). LC/MS: R.sub.t=1.68
min, ES.sup.+ 447 (FA standard).
Step d:
(1S,2S,4R)-4-[4-(Acetylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-(-
hydroxymethyl)cyclopentyl acetate
[0445] To a solution of
(1S,2S,4R)-4-[4-(acetylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-({[tert--
butyl(dimethyl)silyl]oxy}methyl)cyclopentyl acetate (47.0 mg, 0.105
mmol) in a mixture of THF (2.00 mL) and pyridine (2.00 mL) was
added pyridine hydrofluoride (10 drops). After 2 h, additional
pyridine hydrofluoride (15 drops) was added and the solution
stirred for an additional 2 h. The reaction was quenched via
addition of saturated aqueous sodium bicarbonate solution and
extracted with EtOAc (2.times.50 mL). The combined organic extracts
were dried over MgSO.sub.4, filtered and concentrated in vacuo. The
residue was purified via silica gel chromatography eluting with a
gradient of 0 to 10% MeOH in DCM to afford the title compound (29.0
mg, 83%). LC/MS: R.sub.t=0.76 min, ES.sup.+ 333 (FA standard).
Step e:
(1S,2S,4R)-4-[4-(Acetylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-{-
[(aminosulfonyl)oxy]methyl}cyclopentyl acetate
[0446] A solution of
(1S,2S,4R)-4-[4-(acetylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-(hydroxy-
methyl)cyclopentyl acetate (63.0 mg, 0.190 mmol) and pyridine
(0.0800 mL, 0.989 mmol) in AcCN (5.00 mL) at 0.degree. C. was
stirred for 15 min. A 0.641 M solution chlorosulfonamide in AcCN
(0.640 mL, 0.410 mmol, as prepared in 1j) was then added slowly.
After 2 h another portion of the chlorosulfonamide solution (0.72
mL, 0.462 mmol) was added and the reaction was stirred for 1 hour.
The reaction was then concentrated in vacuo and the residue was
purified by silica gel chromatography eluting with a gradient of 0
to 10% MeOH in DCM to afford the title compound (78.0 mg, 100%).
LC/MS: R.sub.t=0.81 min, ES.sup.+ 412 (FA standard).
Step f:
{(1S,2S,4R)-4-[4-(Acetylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2--
hydroxycyclopentyl}methyl sulfamate and
[(1S,2S,4R)-4-(4-amino-7H-pyrrolo-[2,3-d]pyrimidin-7-yl)-2-hydroxycyclope-
ntyl]methyl sulfamate (Compounds I-9 and I-18)
[0447] To neat
(1S,2S,4R)-4-[4-(acetylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-{[(amino-
sulfonyl)oxy]methyl}cyclopentyl acetate (78.0 mg, 0.190 mmol) was
added a 7 M solution of ammonia in MeOH (5.00 mL) was stirred at rt
overnight. LC/MS showed partial conversion to the intermediate
mono-acetylated compound, the desired product and some starting
material remaining. The reaction mixture was concentrated in vacuo
and the residue was purified by reverse phase chromatography to
afford
{(1S,2S,4R)-4-[4-(acetylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-hydroxy-
cyclopentyl}methyl sulfamate (0.900 mg, 1.3%) and
[(1S,2S,4R)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopen-
tyl]methyl sulfamate (6.50 mg, 11%). Analytical data for
{(1S,2S,4R)-4-[4-(acetylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-hydroxy-
cyclopentyl}methyl sulfamate (Compound I-9): .sup.1H NMR (400 MHz,
CD.sub.3OD, .delta.): 8.48 (s, 1H), 7.47 (d, J=3.8 Hz, 1H), 6.82
(d, J=3.8, 1H), 5.65-5.48 (m, 1H), 4.60-4.45 (m, 1H), 4.40-4.27 (m,
1H), 4.24-4.11 (m, 1H), 2.98-2.80 (m, 1H), 2.42-2.13 (m, 6H),
2.18-1.93 (m, 1H) ppm. LC/MS: R.sub.t=0.98 min, ES.sup.+ 370. (FA
standard). Analytical data for
[(1S,2S,4R)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydrox-
ycyclopentyl]methyl sulfamate (Compound I-18): .sup.1H NMR (400
MHz, CD.sub.3OD, .delta.): 8.09 (s, 1H), 7.30 (d, J=3.8 Hz, 1H),
6.66 (d, J=3.5 Hz, 1H), 5.51-5.41 (m, 1H), 4.51-4.48 (m, 1H),
4.39-4.33 (m, 1H), 4.21-4.16 (m, 1H), 2.85-2.79 (m, 1H), 2.33-2.18
(m, 3H), 2.09-2.00 (m, 1H) ppm. LC/MS: R.sub.t=0.85 min, ES.sup.+
328 (FA standard).
Example 35
((1S,2S,4R)-4-{4-[(1,3-Benzodioxol-5-ylmethyl)amino]-7H-pyrrolo[2,3-d]-pyr-
imidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate Compound
(I-26)
[0448] The title compound was prepared following the procedure
described in Example 2a-j using 1-(1,3-benzodioxol-5-yl)methanamine
in step f. .sup.1H-NMR (400 MHz, CD.sub.3OD, .delta.): 8.09 (s,
1H), 7.15 (d, J=3.6 Hz, 1H), 6.81 (s, 1H), 6.79 (d, J=9.9 Hz, 1H),
6.70 (d, J=7.8 Hz, 1H), 6.56 (d, J=3.6 Hz, 1H), 5.85 (s, 2H),
5.45-5.35 (m, 1H), 4.62 (s, 2H), 4.49-4.42 (m, 1H), 4.33 (dd,
J=7.6, 7.6 Hz, 1H), 4.16 (dd, J=7.3, 7.3 Hz, 1H), 2.86-2.70 (m,
1H), 2.35-2.10 (m, 3H), 2.05-1.94 (m, 1H) ppm. LC/MS: R.sub.t=1.07
min, ES.sup.+ 462 (FA standard).
Example 36
((1S,2S,4R)-2-Hydroxy-4-{4-[(1-naphthylmethyl)amino]-7H-pyrrolo[2,3-d]-pyr-
imidin-7-yl}cyclopentyl)methyl sulfamate (Compound I-38)
[0449] The title compound was prepared following the procedure
described in Example 2a-j using 1-(1-naphthyl)methanamine in step
f. .sup.1H NMR (400 MHz, CD.sub.3OD, .delta.): 8.13 (s, 1H),
8.11-8.05 (m, 1H), 7.89-7.84 (m, 1H), 7.77 (d, J=8.2 Hz, 1H),
7.52-7.43 (m, 3H), 7.42-7.35 (m, 1H), 7.15 (d, J=3.6 Hz, 1H), 6.56
(d, J=3.3 Hz, 1H), 5.45-5.37 (m, 1H), 5.19 (s, 2H), 4.48-4.42 (m,
1H), 4.34 (dd, J=7.6, 7.6 Hz, 1H), 4.17 (dd, J=7.3, 7.4 Hz, 1H),
2.83-2.71 (m, 1H), 2.35-2.15 (m, 3H), 2.06-1.96 (m, 1H) ppm. LC/MS:
R.sub.t=1.24 min, 468 ES.sup.+ (FA standard).
Example 37
[(1S,2S,4R)-2-Hydroxy-4-(4-{[4-(trifluoromethyl)benzyl]amino}-7H-pyrrolo-[-
2,3-d]pyrimidin-7-yl)cyclopentyl]methyl sulfamate (Compound
I-8)
[0450] The title compound was prepared following the procedure
described in Example 2a-j using
1-[4-(trifluoromethyl)phenyl]methanamine in step f. .sup.1H NMR
(CD.sub.3OD, 400 MHz, .delta.): 8.08 (s, 1H), 7.56 (d, J=8.2 Hz,
2H), 7.48 (d, J=8.2 Hz, 2H), 7.18 (d, J=3.5 Hz, 1H), 6.58 (d, J=3.6
Hz, 1H), 5.43-5.34 (m, 1H), 4.80 (s, 2H), 4.45 (br s, 1H), 4.33
(dd, J=2.1, 7.6 Hz, 1H), 4.16 (dd, J=2.3, 7.4 Hz, 1H), 2.81-2.72
(m, 1H), 2.31-2.10 (m, 3H), 2.05-1.97 (m, 1H) ppm. LC/MS:
R.sub.t=1.33 min, ES.sup.+ 486 (FA standard).
Example 38
[(1S,2S,4R)-4-(4-([4-Chloro-2-(trifluoromethyl)benzyl]amino}-7H-pyrrolo-[2-
,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate
(Compound I-42)
[0451] The title compound was prepared following the procedure
described in Example 2a-j using
1-[4-chloro-2-(trifluoromethyl)phenyl]methanamine in step f.
.sup.1H NMR (CD.sub.3OD, 400 MHz, .delta.): 8.11 (s, 1H), 7.70 (s,
1H), 7.65-7.46 (m, 2H), 7.23 (d, J=3.6 Hz, 1H), 6.61 (d, J=3.4 Hz,
1H), 5.48-5.39 (m, 1H), 4.93 (s, 2H), 4.49 (br s, 1H), 4.36 (dd,
J=2.1, 7.6 Hz, 1H), 4.20 (dd, J=2.3, 7.4 Hz, 1H), 2.87-2.74 (m,
1H), 2.38-2.12 (m, 3H), 2.09-1.97 (m, 1H) ppm. LC/MS: R.sub.t=1.29
min, ES.sup.+ 520 (FA standard).
Example 39
((1S,2S,4R)-4-{4-[(2,4-Dichlorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7--
yl}-2-hydroxycyclopentyl)methyl sulfamate (Compound I-19)
[0452] The title compound was prepared following the procedure
described in Example 2a-j using 1-(2,4-dichlorophenyl)methanamine
in step f. .sup.1H NMR (CD.sub.3OD, 400 MHz, .delta.): 8.10 (s,
1H), 7.46 (s, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.29-7.20 (m, 2H), 6.61
(d, J=3.5 Hz, 1H), 5.54-5.37 (m, 1H), 4.92-4.74 (s, 2H), 4.49 (br
s, 1H), 4.37 (dd, J=2.1, 7.6 Hz, 1H), 4.19 (dd, J=2.4, 7.3 Hz, 1H),
2.88-2.72 (m, 1H), 2.40-2.17 (m, 3H), 2.11-1.98 (m, 1H) ppm. LC/MS:
R.sub.t=1.37 min, ES.sup.+ 488 (FA standard).
Example 40
((1S,2S,4R)-4-{4-[(3,5-Dichlorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7--
yl}-2-hydroxycyclopentyl)methyl sulfamate (Compound I-16)
[0453] The title compound was prepared following the procedure
described in Example 2a-j using 1-(3,5-dichlorophenyl)methanamine
in step f. .sup.1H NMR (CD.sub.3OD, 400 MHz, .delta.): 8.10 (s,
1H), 7.35-7.23 (m, 3H), 7.19 (d, J=3.6 Hz, 1H), 6.58 (d, J=3.6 Hz,
1H), 5.49-5.35 (m, 1H), 4.69 (s, 2H), 4.45 (br s, 1H), 4.33 (dd,
J=2.1, 7.6 Hz, 1H), 4.16 (dd, J=2.4, 7.3 Hz, 1H), 2.85-2.72 (m,
1H), 2.38-2.13 (m, 3H), 2.07-1.94 (m, 1H) ppm. LC/MS: R.sub.t=1.38
min, ES.sup.+ 488 (FA standard).
Example 41
[(1S,2S,4R)-2-Hydroxy-4-(4-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]--
amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methyl sulfamate
(Compound I-52)
Step a: tert-Butyl
[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]carbamate
[0454] (1R,2S)-1-Aminoindan-2-ol (1.83 g, 12.3 mmol) was dissolved
in DCM (70.0 mL) and TEA (3.42 mL, 24.5 mmol) was added.
Di-tert-butyldicarbonate (2.81 g, 12.9 mmol) was added at rt and
the reaction mixture was stirred for 5 h. The solution was
concentrated in vacuo and purified via silica gel chromatography
eluting with a gradient of 0 to 100% EtOAc in hexanes to afford the
title compound (3.12 g, 100%). LC/MS: R.sub.t=1.55 min, ES.sup.+
250. (AA standard).
Step b: tert-Butyl
[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]carbamate
[0455] A mixture of tert-butyl
[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-carbamate (680 mg,
2.73 mmol), DMF (21.1 mL), barium monoxide (5.02 g, 32.7 mmol),
barium hydroxide (2.80 g, 16.4 mmol) and iodomethane (1.70 mL, 27.3
mmol) was stirred overnight. LC/MS showed no starting material. The
reaction was quenched via addition of a saturated solution of
sodium bicarbonate and was extracted with DCM. The organic layer
was washed with water (3.times.), dried over sodium sulfate and
concentrated in vacuo. The residue was purified via silica gel
chromatography eluting with a gradient of 0 to 50% EtOAc in hexanes
to afford the title compound (178 mg, 25%). LC/MS: R.sub.t=1.24
min, ES.sup.+ 264 (AA standard).
Step c: (1R,2S)-2-Methoxyindan-1-amine
[0456] To tert-butyl
[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]carbamate (253 mg,
0.961 mmol) was added a 4.00 M solution of hydrochloric acid in
1,4-dioxane (5.00 mL) and the mixture was stirred for 10 min, after
which a white solid crashed out. The suspension was concentrated in
vacuo and co-evaporated with toluene to afford a white solid, which
was dissolved in water. The solution was adjusted to pH 10 via
addition of sodium carbonate. The mixture was then extracted with
diethyl ether (3.times.30 mL) and the organic extracts were
concentrated in vacuo to afford the title compound (150 mg, 99%).
LC/MS: R.sub.t=0.85 min, ES.sup.+ 164 (AA standard).
Step d:
[(1S,2S,4R)-2-Hydroxy-4-(4-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inde-
n-1-yl]-amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methyl
sulfamate (Compound I-52)
[0457] The title compound was prepared following the procedure
described in Example 2a-j using (1R,2S)-2-methoxyindan-1-amine in
step f. .sup.1H NMR (CD.sub.3OD, 400 MHz, .delta.): 8.20 (s, 1H),
7.27-7.14 (m, 5H), 6.67 (d, J=3.6 Hz, 1H), 5.90 (d, J=5.2 Hz, 1H),
4.49 (t, J=3.5 Hz, 1H), 4.37 (dd, J=7.6, 9.7 Hz, 1H), 4.31-4.28 (m,
1H), 4.20 (dd, J=7.3, 9.7 Hz, 1H), 3.31-3.29 (m, 4H) 3.19-3.05 (m,
2H), 2.85-2.77 (m, 1H), 2.37-2.20 (m, 3H), 2.08-2.00 (m, 1H) ppm.
LC/MS: R.sub.t=1.46 min, ES.sup.+ 474 (AA standard).
Example 42
[(1S,2S,4R)-4-(4-{[(1S)-3,3-Dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-7H-p-
yrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate
and
-[(1S,2S,4R)-4-(4-{[(1R)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-7H-
-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl
sulfamate (Compounds I-14 and I-21)
Step a: 3,3-Dimethylindan-1-one oxime
[0458] To a solution of 3,3-dimethylindan-1-one (1.16 g, 7.21 mmol)
and hydroxylamine hydrochloride (1.31 g, 18.8 mmol) in MeOH (20.0
mL) was added a solution of sodium hydroxide (765 mg, 19.1 mmol) in
water (10.0 mL). The mixture was heated to 80.degree. C. for 2 h.
The cooled reaction was concentrated in vacuo and partitioned
between DCM and water. The organic layer was separated and
concentrated in vacuo to afford the title compound as an oil (1.23
g, 97%). LC/MS: R.sub.t=1.61 min, ES.sup.+ 176 (AA standard).
Step b: 3,3-Dimethylindan-1-amine
[0459] 3,3-Dimethylindan-1-one oxime (1.22 g, 6.96 mmol) was
dissolved in MeOH (20.0 mL) and palladium (10 weight percent on
carbon, 50% water wet, 148 mg) was added. The reaction was placed
under an atmosphere of hydrogen and was stirred overnight. The
mixture was then filtered through Celite, washed through with MeOH
and the filtrates concentrated in vacuo to afford the product as a
grey oil (1.12 g, 100%). LC/MS: R.sub.t=1.04 min, ES.sup.+ 162 (AA
standard).
Step c:
[(1S,2S,4R)-4-(4-{[(1S)-3,3-Dimethyl-2,3-dihydro-1H-inden-1-yl]ami-
no}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl
sulfamate and
-[(1S,2S,4R)-4-(4-{[(1R)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino-
}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl
sulfamate (Compounds I-14 and I-21)
[0460] The title compounds were prepared following the procedure
described in Example 1a-g and then Example 2i-j using
3,3-dimethylindan-1-amine in step 1c. The mixture was separated
into its component diastereomers via chiral HPLC (Chiralpac -AS-RH,
20 mm ID.times.250 mm, 5 micron column eluting with 55% water in
AcCN with 0.1% AA at 6 mL/minute): Peak A--21.4 min,
[(1S,2S,4R)-4-(4-{[(1R)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino-
}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl
sulfamate, R-enantiomer (Compound I-21). Peak B--22.6 min,
[(1S,2S,4R)-4-(4-{[(1S)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-7H--
pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl
sulfamate, S-enantiomer (Compound I-14). .sup.1H NMR (CD.sub.3OD,
300 MHz, .delta.): 8.16 (s, 1H), 7.28-7.10 (m, 5H), 6.63 (d, J=3.6
Hz, 1H), 5.93 (t, J=8.1 Hz, 1H), 5.51-5.38 (m, 1H), 4.48 (br s,
1H), 4.37 (dd, J=7.6, 9.7 Hz, 1H), 4.20 (dd, J=7.4, 9.6 Hz, 1H),
2.88-2.72 (m, 1H), 2.47 (dd, J=7.3, 12.4 Hz, 1H), 2.37-2.19 (m,
3H), 2.03 (ddd, J=4.5, 9.2, 13.9 Hz, 1H), 1.93 (dd, J=9.1, 12.3 Hz,
1H), 1.42 (s, 3H), 1.27 (s, 3H) ppm. LC/MS: R.sub.t=1.66 min,
ES.sup.+ 472 (AA standard).
Example 43
[(1S,2S,4R)-4-(4-{[(1S)-3,3-Dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-7H-p-
yrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate
(Compound I-14), Chiral synthesis
Step a:
(2R)-2-{[(1S)-3,3-Dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-2-phen-
ylethanol
[0461] To a solution of 3,3-dimethylindan-1-one (925 mg, 5.77 mmol)
and (R)-(-)-2-phenylglycinol (893 mg, 6.51 mmol) in toluene (10.0
mL) was added p-toluenesulfonic acid monohydrate (62.5 mg, 0.328
mmol). The reaction was heated to reflux under an atmosphere of
nitrogen for 90 min. At this point, the mixture was cooled and
diluted with toluene (10.0 mL). The mixture was washed with
saturated aqueous sodium bicarbonate solution and water. The
organic layer was concentrated in vacuo and the residue was
dissolved in THF (10.0 mL) and cooled to 0.degree. C. Acetic acid
(1.13 mL, 19.9 mmol) was added, followed by sodium borohydride (251
mg, 6.64 mmol) and the reaction was allowed to warm to rt
overnight. The mixture was partitioned between DCM and saturated
aqueous sodium bicarbonate solution. The organic layer was
concentrated and silica gel chromatography eluting with a gradient
of 5 to 35% EtOAc in DCM afforded the title compound (1.49 g, 74%).
LC/MS: R.sub.t=1.92 min, ES.sup.+ 282 (AA standard).
Step b: (1S)-3,3-Dimethylindan-1-amine
[0462] A solution of
(2R)-2-{[(1S)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-2-phenylethan-
ol (1.44 g, 5.13 mmol) in MeOH (40.0 mL) was added to a stirred
solution of lead tetraacetate (3.75 g, 8.03 mmol) in MeOH (60.0 mL)
at 0.degree. C. dropwise over 20 min. After stirring for 45 min,
the reaction was quenched via addition of a 10% solution of sodium
carbonate in water (76.0 mL) and the mixture was stirred for 10
min. DCM (200 mL) was then added and the layers were separated. The
aqueous layer was extracted with DCM (50.0 mL). The combined
organic layers were concentrated in vacuo and the residue was
dissolved in ethanol (190 mL) and treated with a 10.4 M aqueous
solution of hydrochloric acid (5.70 mL, 59.3 mmol). The resulting
mixture was then heated to reflux for 16 h. The cooled reaction was
concentrated in vacuo and partitioned between water (150 mL) and
diethyl ether (50.0 mL). The aqueous layer was adjusted to pH 10
via addition of sodium carbonate and extracted with diethyl ether
(3.times.50.0 mL). The combined organic layers were concentrated in
vacuo and silica gel chromatography eluting with a gradient of 0 to
10% MeOH in DCM to afford the title compound as a pale yellow oil
(420 mg, 51%). .sup.1H NMR (CD.sub.3OD, 300 MHz, .delta.):
7.34-7.14 (m, 4H), 4.45-4.37 (m, 1H), 2.38 (dd, J=7.1, 12.4 Hz,
1H), 1.73 (br s, 2H), 1.60 (dd, J=8.7, 12.4 Hz, 1H), 1.39 (s, 3H),
1.19 (s, 3H) ppm.
Step c:
[(1S,2S,4R)-4-(4-{[(1S)-3,3-Dimethyl-2,3-dihydro-1H-inden-1-yl]ami-
no}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl
sulfamate (Compound I-14)
[0463] The title compound was prepared following the procedure
described in Example 1a-g and then Example 2i-j using
(1S)-3,3-dimethylindan-1-amine in step 1c. Chiral HPLC showed
co-elution with the compound synthesized in Example 42c, Peak B.
Analytical data identical to Example 42c.
Example 44
[(1S,2S,4R)-4-(4-{[(1S)-5-Chloro-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrro-
lo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate,
Potassium salt (Compound I-27)
[0464] The title compound was prepared following the procedure
described in Example 43a-b and then Example 2f-j using
5-chloroindan-1-one in step 43a and (1S)-5-chloroindan-1-amine in
step 2f. The potassium salt was formed following the procedure
described in Example 1l. .sup.1H NMR (CD.sub.3OD, 300 MHz,
.delta.): 8.17 (s, 1H), 7.28-7.10 (m, 4H), 6.62 (d, J=3.6 Hz, 1H),
5.82 (t, J=7.7 Hz, 1H), 5.44 (qd, J=4.6, 8.3 Hz, 1H), 4.48 (br s,
1H), 4.37 (dd, J=7.6, 9.7 Hz, 1H), 4.19 (dd, J=7.4, 9.7 Hz, 1H),
4.09 (q, J=7.1 Hz, 1H), 3.05 (ddd, J=3.3, 8.6, 15.9 Hz, 1H),
2.98-2.71 (m, 2H), 2.64 (dtd, J=3.5, 7.7, 11.2 Hz, 1H), 2.38-2.14
(m, 3H), 2.05 (dd, J=4.4, 8.6 Hz, 1H) ppm. LC/MS: R.sub.t=1.58 min,
ES.sup.+ 478 (AA standard).
Example 45
[(1S,2S,4R)-4-(4-{[(1S)-5-fluoro-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrro-
lo-[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate
(Compound I-36)
[0465] The title compound was prepared following the procedure
described in Example 44 using 5-fluoroindan-1-one. .sup.1H NMR
(CD.sub.3OD, 400 MHz, .delta.): 8.17 (s, 1H), 7.25-7.19 (m, 2H),
6.99-6.85 (m, 2H), 6.63 (d, J=3.6 Hz, 1H), 5.81 (t, J=7.5 Hz, 1H),
5.49-5.41 (m, 1H), 4.49 (t, J=3.6 Hz 1H), 4.37 (dd, J=7.6, 9.7 Hz,
1H), 4.20 (dd, J=7.4, 9.7 Hz, 1H), 3.12-3.02 (m, 1H), 2.95-2.87 (m,
1H), 2.84-2.75 (m, 1H), 2.69-2.61 (m, 1H), 2.36-2.19 (m, 3H),
2.10-1.97 (m, 2H) ppm. LC/MS: R.sub.t=1.56 min, ES.sup.+ 462 (AA
standard).
Example 46
[(1S,2S,4R)-4-(4-{[(1S)-5-bromo-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrol-
o[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate
(Compound I-33)
[0466] The title compound was prepared following the procedure
described in Example 44 using 5-bromoindan-1-one. .sup.1H NMR
(CD.sub.3OD, 400 MHz, .delta.): 8.17 (s, 1H), 7.42 (s, 1H), 7.29
(d, J=8.1 Hz, 1H), 7.19-7.14 (m, 2H), 6.63 (d, J=3.6 Hz, 1H), 5.82
(t, J=7.8 Hz, 1H), 5.49-5.41 (m, 1H), 4.49 (br s, 1H), 4.38 (dd,
J=7.6, 9.7 Hz, 1H), 4.20 (dd, J=7.4, 9.7 Hz, 1H), 3.08-3.01 (m,
1H), 2.96-2.88 (m, 1H), 2.85-2.75 (m, 1H), 2.67-2.59 (m, 1H),
2.36-2.20 (m, 3H), 2.08-1.99 (m, 2H) ppm. LC/MS: R.sub.t=1.64 min,
ES.sup.+ 524 (AA standard).
Example 47
((1S,2S,4R)-4-{4-[(4-Chlorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}--
2-hydroxy-2-methylcyclopentyl)methyl sulfamate (Compound I-5)
Step a:
(1S,5S)-5-({[tert-Butyl(diphenyl)silyl]oxy}methyl)cyclopent-2-en-1-
-ol
[0467] To a solution of
(1S,5S)-5-(hydroxymethyl)cyclopent-2-en-1-ol (1.14 g, 9.99 mmol) in
DCM (50.0 mL) was added TEA (4.18 mL, 30.0 mmol) and DMAP (60.0 mg,
0.491 mmol). The solution was cooled to 0.degree. C.,
tert-butylchlorodiphenylsilane (3.90 mL, 15.0 mol) was added and
the mixture was stirred at rt for 2 h. TLC indicated complete
conversion, and the reaction was quenched by addition of MeOH (1.00
mL). Concentration in vacuo and silica gel chromatography eluting
with a gradient of 0 to 100% EtOAc in hexanes afforded the title
compound (2.88 g, 86%). LC/MS: R.sub.t=2.51 min, ES.sup.+ 353 (AA
standard).
Step b:
(5S)-5-({[tert-Butyl(diphenyl)silyl]oxy}methyl)cyclopent-2-en-1-on-
e
[0468]
(1S,5S)-5-({[tert-Butyl(diphenyl)silyl]oxy}methyl)cyclopent-2-en-1--
ol (460. mg, 1.30 mmol) was dissolved in DCM (15.0 mL) and
pyridinium dichromate (1.47 g, 3.91 mmol) was added. The mixture
was stirred at rt overnight, at which point LC/MS indicated
complete conversion. The mixture was diluted with DCM (15.0 mL),
filtered and concentrated in vacuo. Silica gel chromatography
eluting with 0 to 50% EtOAc in hexanes afforded the title compound
(400. mg, 79%). LC/MS: R.sub.t=2.42 min, ES.sup.+ 351 (AA
standard).
Step c:
(1S,5S)-5-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-1-methylcyclope-
nt-2-en-1-ol
[0469] A solution of
(5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)cyclopent-2-en-1-one
(250. mg, 0.713 mmol) in diethyl ether (10.0 mL) under an
atmosphere of nitrogen was cooled to -40.degree. C. and a 1.60 M
solution of methyllithium in diethyl ether (0.579 mL, 0.926 mmol)
was added slowly and the mixture was stirred at -40.degree. C. for
3 h. TLC indicated complete conversion, and the reaction was
quenched via addition of saturated aqueous ammonium chloride (5.00
mL), extracted with EtOAc (3.times.10.0 mL), dried over MgSO.sub.4,
filtered, and concentrated in vacuo. Silica gel chromatography
eluting with a gradient of 0 to 50% EtOAc in hexanes afforded the
title compound (190 mg, 73%). Stereochemistry of the product was
confirmed using ROESY analysis. LC/MS: R.sub.t=2.55 min, ES.sup.+
367 (AA standard).
Step d: (1S,5S)-5-(Hydroxymethyl)-1-methylcyclopent-2-en-1-ol
[0470] To a solution of
(1S,5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-1-methylcyclopent-2-en-
-1-ol (560 mg, 1.53 mmol) in THF (29.5 mL) at 0.degree. C. was
added 1.00 M of tetra-n-butylammonium fluoride in THF (3.06 mL,
3.06 mmol). The mixture was stirred at rt for 2 h, at which point
the solvent was concentrated in vacuo and the residue was purified
by silica gel chromatography eluting with a gradient of 50 to 100%
EtOAc in hexanes to afford the title compound (181 mg, 92%). LC/MS:
R.sub.t=0.76 min, ES.sup.+ 129 (AA standard).
Step e:
(1S,2R,3S,5S)-3-(Hydroxymethyl)-2-methyl-6-oxabicyclo[3.1.0]hexan--
2-ol
[0471] To a solution of
(1S,5S)-5-(hydroxymethyl)-1-methylcyclopent-2-en-1-ol (0.181 g,
0.00141 mol) in DCM (18.0 mL) was added sodium bicarbonate (237 mg,
2.82 mmol) and the mixture was cooled to 0.degree. C. To this
mixture was added 3-chloroperbenzoic acid (380. mg, 1.69 mmol) and
the reaction was stirred at rt for 4 h. The solvent was removed in
vacuo and silica gel chromatography eluting with a gradient of 0 to
100% EtOAc in DCM afforded the title compound (200 mg, 98%). LC/MS:
R.sub.t=0.52 min, ES.sup.+ 145 (AA standard).
Step f:
(1aS,1bR,5aS,6aS)-3-(4-Methoxyphenyl)-1b-methylhexahydrooxireno[4,-
5]-cyclopenta[1,2-d][1,3]dioxine
[0472] To a solution of
(1S,2R,3S,5S)-3-(hydroxymethyl)-2-methyl-6-oxabicyclo[3.1.0]-hexan-2-ol
(200 mg, 1.39 mmol) in DCM (13.0 mL) at 0.degree. C. was added
dimethoxy(4-methoxyphenyl)methane (0.709 mL, 4.16 mmol) followed by
pyridinium p-toluenesulfonate (35.0 mg, 0.139 mmol) and the mixture
was stirred at rt overnight. TLC showed complete conversion. Silica
gel chromatography eluting with a gradient of 0 to 50% EtOAc in
hexanes afforded the title compound (215 mg, 59%). LC/MS:
R.sub.t=1.72 min, ES.sup.+ 263 (AA standard).
Step g:
((1S,2S,4R)-4-{4-[(4-Chlorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidi-
n-7-yl}-2-hydroxy-2-methylcyclopentyl)methyl sulfamate (Compound
I-5)
[0473] The title compound was prepared following the procedure
described in Example 1d-i using
(1aS,1bR,5aS,6aS)-3-(4-Methoxyphenyl)-1b-methylhexahydrooxireno-[4,5]cycl-
openta[1,2-d][1,3]dioxine and 4-chlorobenzylamine in step d.
.sup.1H NMR (CD.sub.3OD, 400 MHz, .delta.): 8.20 (s, 1H), 7.46 (d,
J=3.6 Hz, 1H), 7.37 (s, 4H), 6.82 (d, J=3.6 Hz, 1H), 5.48-5.40 (m,
1H), 4.78 (s, 2H), 4.41 (dd, J=6.0, 10.0 Hz, 1H), 4.14 (dd, J=8.2,
10.0 Hz, 1H), 2.69-2.64 (m, 1H), 2.39-2.16 (m, 4H), 1.47 (s, 3H)
ppm. LC/MS: R.sub.t=1.55 min, ES.sup.+ 466 (AA standard).
Example 48
(1S,2S,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-py-
rimidin-7-yl}-2-hydroxy-2-methylcyclopentyl)methyl sulfamate
(Compound I-30)
[0474] The title compound was prepared following the procedure
described in Example 47 using (S)-(+)-1-aminoindan in step g.
.sup.1H NMR (CD.sub.3OD, 400 MHz, .delta.): 8.25 (s, 1H), 7.48 (d,
J=3.6 Hz, 1H); 7.34-7.23 (m, 4H), 6.89 (d, J=3.6 Hz, 1H), 5.61-5.56
(m, 1H), 5.50-5.43 (m, 1H), 4.42 (dd, J=6.0, 10.0 Hz, 1H), 4.15
(dd, J=8.0, 10.0 Hz, 1H), 3.18-3.10 (m, 1H), 3.03-2.97 (m, 1H),
2.75-2.64 (m, 1H), 2.39-2.07 (m, 5H), 1.48 (s, 3H) ppm. LC/MS:
R.sub.t=1.57 min, ES.sup.+ 458 (AA standard).
Example 49
[(1S,2S,4R)-4-(4-{[2-(difluoromethoxy)benzyl]amino}-7H-pyrrolo[2,3-d]-pyri-
midin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate (Compound
I-2)
[0475] The title compound was prepared following the procedure
described in Example 2a-j, using 2-difluoromethoxybenzylamine in
step f. .sup.1H NMR (CD.sub.3OD, 400 MHz, .delta.): 8.10 (s, 1H),
7.35-7.26 (m, 2H), 7.22 (d, J=3.7 Hz, 1H), 7.17-7.13 (m, 2H), 6.87
(t, J=74.2 Hz, 1H), 6.62 (d, J=3.6 Hz, 1H), 545-5.20 (m, 1H), 4.80
(s, 2H), 4.49-4.47 (m, 1H), 4.36 (dd, J=7.6, 9.7 Hz, 1H), 4.19 (dd,
J=7.3, 9.7 Hz, 1H), 2.86-2.75 (m, 1H), 2.35-2.19 (m, 3H), 2.07-2.00
(m, 1H) ppm. LC/MS: R.sub.t=1.03 min, ES.sup.+ 484 (FA
standard).
Example 50
[(1S,2S,4R)-4-(5-ethynyl-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydro-
xycyclopentyl]methyl sulfamate (Compound I-44)
Step a:
5-iodo-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1-
,3]dioxin-6-yl]-4-methyl-7H-pyrrolo[2,3-d]pyrimidine
[0476] To a solution of
7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)hexahydrocyclopenta[d]-[1,3]dioxin-6-y-
l]-4-methyl-7H-pyrrolo[2,3-d]pyrimidine (363 mg, 0.995 mmol, as
prepared in Example 1a-f) in DCM (15.0 mL) was added
N-iodosuccinimide (256 mg, 1.14 mmol), and the mixture was stirred
at rt overnight. Silica gel chromatography eluting with a gradient
of 25 to 100% EtOAc in hexanes afforded the title compound (253 mg,
52%). LC/MS: R.sub.t=2.03 min, ES.sup.+ 492 (AA standard).
Step b:
7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]diox-
in-6-yl]-4-methyl-5-[(trimethylsilyl)ethynyl]-7H-pyrrolo[2,3-d]pyrimidine
[0477] To a suspension of
5-iodo-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)-hexahydrocyclopenta[d][1,3]dio-
xin-6-yl]-4-methyl-7H-pyrrolo[2,3-d]pyrimidine (337 mg, 0.685
mmol), copper(I) iodide (26.0 mg, 0.137 mmol),
dichlorobis(triphenylphosphine)-palladium(II) (48.0 mg, 0.0684
mmol) and DIPEA (0.240 mL, 1.38 mmol) in DMF (20.0 mL) was added
ethynyltrimethylsilane (188 mg, 1.91 mmol) and the mixture was
stirred at rt overnight. The reaction mixture was quenched via
addition of saturated aqueous sodium bicarbonate solution and
extracted with EtOAc. The combined organic layers were dried over
MgSO.sub.4, filtered, and concentrated in vacuo. Silica gel
chromatography eluting with a gradient of 0 to 75% EtOAc in hexanes
afforded the title compound (314 mg, 99%). LC/MS: R.sub.t=2.38 min,
ES.sup.+ 462 (AA standard).
Step c:
5-ethynyl-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)hexahydrocyclopenta[d-
][1,3]-dioxin-6-yl]-4-methyl-7H-pyrrolo[2,3-d]pyrimidine
[0478] Potassium carbonate (191 mg, 1.38 mmol) was added to a
solution of
7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-6-yl-
]-4-methyl-5-[(trimethylsilyl)ethynyl]-7H-pyrrolo[2,3-d]pyrimidine
(314 mg, 0.680 mmol) in MeOH (10.0, mL), and the mixture was
stirred at rt overnight. The reaction mixture was diluted with
EtOAc, washed with saturated aqueous sodium bicarbonate solution,
dried over MgSO.sub.4, filtered, and concentrated in vacuo to
afford the title compound as an oil (215 mg, 81%). LC/MS:
R.sub.t=1.94 min, ES.sup.+ 390 (AA standard).
Step d:
[(1S,2S,4R)-4-(5-ethynyl-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-
-2-hydroxycyclopentyl]methyl sulfamate (Compound I-44)
[0479] The title compound was prepared following the procedure
described in Example 1g-j, using
5-ethynyl-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)hexahydrocyclopenta[d]-[1,3]-
dioxin-6-yl]-4-methyl-7H-pyrrolo[2,3-d]pyrimidine in step g.
.sup.1H NMR (CD.sub.3OD, 400 MHz, .delta.): 8.63 (s, 1H), 7.87 (s,
1H), 5.47-5.58 (m, 1H) 4.51-4.47 (m, 1H), 4.36 (dd, J=7.5, 9.5 Hz,
1H), 4.19 (dd, J=7.5, 10.0 Hz, 1H), 3.65 (s, 1H), 3.48-3.46 (m,
1H), 3.13-3.11 (m, 1H), 2.90 (s, 3H), 2.33-2.20 (m, 2H), 2.00-2.12
(m, 1H) ppm. LC/MS: R.sub.t=1.16 min, ES.sup.+ 351 (AA
standard).
Example 51
[(1S,2S,4R)-4-(4-{[(1S)-4-fluoro-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrro-
lo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate
(Compound I-61)
[0480] The title compound was prepared following the procedure
described in Example 2a-j using
(R)-4-chloro-2,3-dihydro-1H-inden-1-yl amine in step f. .sup.1H NMR
(CD.sub.3OD, 400 MHz, .delta.): 8.27 (s, 1H), 7.44 (d, J=3.21 Hz,
1H) 7.30-7.24 (m, 1H), 7.15 (d, J=7.5, 1H), 7.02 (t, J=8.64, 8.64
Hz, 1H), 6.86 (d, J=2.93 Hz, 1H), 5.67 (t, J=6.99, 6.99 Hz, 1H),
5.56-5.48 (m, 1H), 4.52-4.48 (m, 1H), 4.37 (dd, J=9.76, 7.49 Hz,
1H), 4.19 (dd, J=9.75, 7.44 Hz, 1H), 3.22-3.14 (m, 1H), 3.02-2.93
(m, 1H), 2.90-2.70 (m, 2H), 2.38-2.04 (m, 5H), ppm. LC/MS: Rt=1.10
min, ES.sup.+ 462 (FA standard).
Example 52
[(1R,2R,4S)-4-(4-{[(1S)-4,7-difluoro-2,3-dihydro-1H-inden-1-yl]amino}-7H-p-
yrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate
(Compound I-62)
[0481] The title compound was prepared following the procedure
described in Example 2a-j using
(S)-4,7-difluoro-2,3-dihydro-1H-inden-1-yl amine in step f. .sup.1H
NMR (CD.sub.3OD, 400 MHz, .delta.): 8.17 (s, 1H), 7.17 (d, J=3.8
Hz, 1H), 6.99 (m, 1H), 6.89 (m, 1H), 6.60 (d, J=3.5 Hz, 1H), 6.05
(t, J=5.5 Hz, 1H), 5.48-5.41 (m, 1H), 4.48 (t, J=6.8 Hz, 1H), 4.36
(dd, J=7.5, 9.8 Hz, 1H), 4.19 (dd, J=7.3, 9.8 Hz, 1H), 3.20-3.11
(m, 1H), 2.98-2.89 (m, 1H), 2.84-2.75 (m, 1H), 2.70-2.60 (m, 1H),
2.35-2.20 (m, 3H), 2.19-2.09 (m, 1H), 2.07-1.99 (m, 1H). LC/MS:
R.sub.t=1.07 min, ES.sup.+ 480 (FA standard).
Example 53
[(1S,2S,4R)-4-(4-{[(1R)-4-chloro-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrro-
lo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate
(Compound I-63)
[0482] The title compound was prepared following the procedure
described in Example 2a-j using
(R)-4-chloro-2,3-dihydro-1H-inden-1-yl amine in step f. .sup.1H NMR
(CD.sub.3OD, 400 MHz, .delta.): 8.18 (s, 1H), 7.24-7.12 (m, 4H),
6.64 (d, J=3.6 Hz, 1H), 5.91 (t, J=8.1 Hz, 1H), 5.51-5.39 (m, 1H),
4.49 (t, J=7.2 Hz, 1H), 4.37 (dd, J=7.7, 9.8 Hz, 1H), 4.19 (dd,
J=7.3, 9.8 Hz, 1H), 3.18-3.07 (m, 1H), 2.98-2.85 (m, 1H), 2.84-2.74
(m, 1H), 2.72-2.60 (m, 1H), 2.38-2.17 (m, 3H), 2.11-1.98 (m, 2H).
LC/MS: R.sub.t=1.16 min, ES.sup.+ 478 (FA standard).
Example 54
((1S,2S,4R)-4-(4-((S)-4-chloro-2,3-dihydro-1H-inden-1-ylamino)-7H-pyrrolo[-
2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl)methyl sulfamate
(Compound I-64)
[0483] The title compound was prepared following the procedure
described in Example 2a-j using
(S)-4-chloro-2,3-dihydro-1H-inden-1-yl amine in step f. .sup.1H NMR
(CD.sub.3OD, 400 MHz, .delta.): 8.30 (s, 1H), 7.52 (br s, 1H),
7.38-7.23 (m, 3H), 6.93 (br s, 1H), 5.69-5.50 (m, 2H), 4.54-4.47
(m, 1H), 4.37 (dd, J=7.3, 9.8 Hz, 1H), 4.19 (dd, J=7.3, 9.5 Hz,
1H), 3.25-3.15 (m, 1H), 3.07-2.96 (m, 1H), 2.92-2.82 (m, 1H),
2.82-2.71 (m, 1H), 2.40-2.06 (m, 5H). LC/MS: R.sub.t=1.64 min,
ES.sup.+ 478 (AA standard).
Example 55
[(1S,2S,4R)-4-(4-{[(1R)-4-bromo-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrol-
o[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate
(Compound I-65)
[0484] The title compound was prepared following the procedure
described in Example 44 using 4-bromoindan-1-one. .sup.1H-NMR (400
MHz, MeOD, .delta.): 8.17 (s, 1H), 7.39 (d, J=7.9 Hz, 1H), 7.22 (d,
J=7.5 Hz, 1H), 7.19 (d, J=3.7 Hz, 1H), 7.08 (t, J=7.7 Hz, 1H), 6.62
(d, J=3.6 Hz, 1H), 5.96 (t, J=7.8 Hz, 1H), 5.44 (m, 1H), 4.48 (t,
J=3.5 Hz, 1H), 4.37 (dd, J=7.6 Hz, 9.7 Hz, 1H), 4.19 (dd, J=7.3 Hz,
9.7 Hz, 1H), 3.09 (ddd, J=3.2 Hz, 9.1 Hz, 16.3 Hz, 1H), 2.89 (td,
J=8.4 Hz, 16.6 Hz, 1H), 2.79 (m, 1H), 2.65 (dtd, J=3.3 Hz, 8.0 Hz,
12.7 Hz, 1H), 2.27 (m, 3H), 2.05 (m, 2H). LC/MS: R.sub.t=1.66 min,
ES.sup.+ 524 (AA standard).
Example 56
[(1R,2R,4S)-4-(4-{[(1S)-7-fluoro-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrro-
lo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate
(Compound I-66)
[0485] The title compound was prepared following the procedure
described in Example 44 using 7-fluoroindan-1-one. .sup.1H NMR
(CD.sub.3OD, 400 MHz, .delta.): 8.17 (s, 1H), 7.29-7.22 (m, 1H),
7.16 (d, J=3.5 Hz, 1H), 7.09 (d, J=7.5 Hz, 1H), 6.86 (t, J=9.0 Hz,
1H), 6.61 (d, J=3.8 Hz, 1H), 6.00 (t, J=7.5 Hz, 1H), 5.48-5.39 (m,
1H), 4.48 (t, J=6.8 Hz, 1H), 4.36 (dd, J=7.5, 9.8 Hz, 1H), 4.19
(dd, J=7.3, 9.8 Hz, 1H), 3.20-3.11 (m, 1H), 2.97-2.88 (m, 1H),
2.85-2.74 (m, 1H), 2.65-2.55 (m, 1H), 2.36-2.18 (m, 3H), 2.14-1.98
(m, 1H). LC/MS: R.sub.t=1.16 min, ES.sup.+ 462 (formic acid
standard).
Step a: 1-(4-chlorophenyl)-3-methylbutan-2-ol
[0486] Magnesium (5.02 g, 0.206 mol) was covered in dry ether (50
mL, 0.5 mol) under an atmosphere of nitrogen. Iodine (0.254 g,
0.001 mol) was added to the reaction, followed by approximately 1
mL of a solution of 1-chloro-4-(chloromethyl)-benzene (32.20 g,
0.200 mol) in ether (25.0 mL, 0.238 mol). An exotherm was noted and
the mixture reached reflux. The slow addition of solution was
continued over 90 minutes to maintain a gentle reflux. On
completion of the addition, the reaction was heated for 30 minutes
at 45.degree. C. The reaction was then cooled to 0.degree. C.
Isobutyraldehyde (25.19 mL, 0.2774 mol) in Ether (20 mL, 0.2 mol)
was then added slowly over 2 hours at 0.degree. C. On completion of
the addition the reaction was allowed to warm to room temperature
and stir overnight. The reaction was then quenched with ice (200 g)
and acidified with 2M HCl (100 mL). The organic phase was separated
and the aqueous was extracted twice with more ether. The combined
organic phase was evaporated and the residue was purified by silica
gel chromatography, eluting with 0 to 10% methanol in
dichloromethane to yield the product, 17.8 g (45%). .sup.1H NMR
(300 MHz, CDCl.sub.3, .delta.): 7.22 (m, 4H), 3.56 (m, 1H), 2.81
(dd, J=3.3 Hz, 13.7 Hz, 1H), 2.58 (dd, J=9.4 Hz, 13.7 Hz, 1H), 1.74
(dt, J=6.5 Hz, 12.9 Hz, 1H), 1.45 (s, 1H), 1.00 (s, 3H), 0.98 (s,
3H).
Step b: 6-chloro-1,1-dimethylindane
[0487] Concentrated sulfuric acid (45.0 mL) was added to water
(5.00 mL) carefully and allowed to cool down to room temperature.
1-(4-chlorophenyl)-3-methylbutan-2-ol (17.8 g, 0.0896 mol) was
added portionwise over 30 minutes. After the addition, the mixture
was left to stir at room temperature for 2 hours. The mixture was
then poured onto ice and the aqueous layer was extracted with
ether. The organic phase was washed water and then dried over
magnesium sulphate and concentrated to yield crude product. The
residue was purified by filtration through a plug of silica,
eluting with dichloromethane, to yield the product, 12.6 g (78%).
.sup.1H-NMR (400 MHz, CDCl.sub.3, .delta.): 7.10 (m, 3H), 2.85 (t,
J=7.2 Hz, 1H), 1.94 (t, J=7.2 Hz, 1H), 1.25 (s, 6H).
Step c: 5-chloro-3,3-dimethylindan-1-one
[0488] 6-chloro-1,1-dimethylindane (2.19 g, 0.0121 mol) was
dissolved in acetone (50 mL), and 1.41 M solution of magnesium
sulfate in water (9.02 mL) was added, followed by potassium
permanganate (3.83 g, 0.0242 mol). The mixture was stirred at room
temperature overnight. 1:1 water:isopropanol was then added to the
mixture and this was stirred for 1 hour. The mixture was then
evaporated to an aqueous residue and ethyl acetate was added. The
mixture was filtered, washing the collected solids with EtOAc, and
the filtrates were separated. The organic phase was concentrated,
and the residue was purified by silica gel chromatography, eluting
with 20 to 100% dichloromethane in hexanes to yield the product,
1.25 g (46%). .sup.1H-NMR (400 MHz, CDCl.sub.3, .delta.) 7.62 (d,
J=8.3 Hz, 1H), 7.47 (d, J=1.6 Hz, 1H), 7.34 (dd, j=1.8 Hz, 8.1 Hz,
1H), 2.60 (s, 2H), 1.42 (s, 6H).
Step d:
((1S,2S,4R)-4-(4-((S)-5-chloro-3,3-dimethyl-2,3-dihydro-1H-inden-1-
-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl)methyl
sulfamate (Compound I-67)
[0489] The title compound was prepared following the procedure
described in Example 44 using 5-chloro-3,3-dimethylindan-1-one.
.sup.1H NMR (CD.sub.3OD, 400 MHz, .delta.): 8.16 (bs, 1H); 7.22
(bs, 1H); 7.20 (d, j=3.77 Hz, 1H); 7.16-7.14 (m, 2H); 6.62 (d,
j=3.51 Hz, 1H); 5.91 (t, J=7.28 Hz, 1H); 5.50-5.40 (m, 1H); 4.49
(t, j=3.01 Hz, 1H); 4.33 (dd, j=7.78, 2.00 Hz); 4.16 (dd, j=7.28
Hz, 2.51 Hz); 2.85-2.74 (m, 1H); 2.53-2.45 (m, 1H); 2.37-2.18 (m,
3H); 2.08-1.94 (m, 2H); 1.43 (s, 3H); 1.28 (s, 3H). LC/MS:
R.sub.t=1.42 min, ES.sup.+ 506 (FA standard).
Example 57
((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-5-fluoro-7H-pyrrolo-
[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate
(Compound I-68)
[0490] The title compound was prepared following the procedure
described in Example 1a-g and then Example 2i-j using
(S)-1-aminoindane and 4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine
in step 1c. .sup.1H NMR (CD.sub.3OD, 400 MHz, .delta.): 8.18 (s,
1H), 7.30-7.14 (m, 5H), 5.82 (t, J=7.8, 7.8 Hz, 1H), 5.55-5.45 (m,
1H), 4.48-4.44 (m, 1H), 4.35 (dd, J=9.72, 7.37 Hz, 1H), 4.18 (dd,
J=9.72, 7.37 Hz, 1H), 3.11-3.02 (m, 1H), 2.98-2.88 (m, 1H),
2.88-2.73 (m, 1H), 2.71-2.63 (m, 1H), 2.34-2.16 (m, 3H), 2.10-1.96
(m, 2H) ppm. LC/MS: R.sub.t=1.50 min, ES.sup.+ 462 (FA
standard).
Example 58
[(1S,2S,4R)-4-(5-fluoro-4-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]am-
ino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl
sulfamate (Compound I-69)
[0491] The title compound was prepared following the procedure
described in Example 1a-g and then Example 2i-j using
(1R,2S)-2-methoxyindan-1-amine and
4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine in step 1c. .sup.1H
NMR (CD.sub.3OD, 400 MHz, .delta.): 8.20 (s, 1H), 7.27-7.13 (m,
4H), 7.10 (d, J=2.3 Hz, 1H), 5.88 (d, J=5.3 Hz, 1H), 5.49 (br s,
1H), 4.47 (t, J=7.3 Hz, 1H), 4.35 (dd, J=7.5, 9.8 Hz, 1H),
4.31-4.28 (m, 1H), 4.18 (dd, J=7.5, 9.8 Hz, 1H), 3.39 (s, 3H),
3.19-3.03 (m, 2H), 2.83-2.75 (m, 1H), 2.34-2.16 (m, 3H), 2.03-1.97
(m, 1H). LC/MS: R.sub.t=1.55 min, ES.sup.+ 492 (formic acid
standard).
Example 59
(1S,2S,4R)-2-hydroxy-4-(4-{[(1R,2S)-2-isopropoxy-2,3-dihydro-1H-inden-1-yl-
]-amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methyl
sulfamate (Compound I-70)
[0492] The title compound was prepared following the procedure
described in Example 41a-d, using ethyl iodide in step b. .sup.1H
NMR (CD.sub.3OD, 400 MHz, .delta.): 8.19 (s, 1H), 7.29-7.17 (m,
5H), 6.65 (d, J=3.6 Hz, 1H), 5.73 (d, J=5.1 Hz, 1H), 5.50-5.44 (m,
1H), 4.49-4.48 (m, 1H), 4.42-4.35 (m, 2H), 4.20 (dd, J=7.3, 9.8 Hz,
1H), 3.66-3.56 (m, 2H), 3.51-3.43 (m, 1H), 3.12 (d, J=3.8 Hz, 2H),
2.81 (m, 1H), 2.37-2.20 (m, 3H), 2.08-2.03 (m, 1H), 1.70-1.56 (m,
1H), 1.53-1.36 (m, 1H), 1.05 (t, J=7.0 Hz), 0.97-0.90 (m, 2H) ppm.
LC/MS: R.sub.t=1.59 min, ES.sup.+ 488 (AA standard).
Example 60
(1S,2S,4R)-2-hydroxy-4-(4-{[(1R,2S)-2-isopropoxy-2,3-dihydro-1H-inden-1-yl-
]-amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methyl
sulfamate (Compound I-54)
[0493] The title compound was prepared following the procedure
described in Example 41a-d, using isopropyl iodide in step b.
.sup.1H NMR (CD.sub.3OD, 400 MHz, .delta.): 8.20 (s, 1H), 7.31-7.18
(m, 5H), 6.67 (d, J=3.6 Hz, 1H), 5.82 (d, J=5.4 Hz, 1H), 5.51-5.44
(m, 1H), 4.53-4.48 (m, 2H), 4.37 (dd, J=7.6, 9.7 Hz, 1H), 4.20 (dd,
J=7.3, 9.7 Hz, 1H), 3.67-3.61 (m, 1H), 3.18-3.02 (m, 2H), 2.84-2.78
(m, 1H), 2.37-2.00 (m, 4H), 1.09 (d, J=6.1 Hz, 3H), 0.93 (d, J=6.1
Hz, 3H). LC/MS: R.sub.t=1.68 min, ES.sup.+ 502 (AA standard).
Example 61
[(1S,2S,4R)-2-hydroxy-4-(4-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]a-
mino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methyl sulfamate
(Compound I-71)
[0494] The title compound was prepared following the procedure
described in Example 2a-j using (1R,2S)-2-hydroxyindan-1-amine in
step f. .sup.1H NMR (CD.sub.3OD, 400 MHz, .delta.): 8.18 (s, 1H),
7.29-7.16 (m, 5H), 6.68 (d, J=3.8 Hz, 1H), 5.77 (d, J=4.5 Hz, 1H),
5.53-5.40 (m, 1H), 4.72-4.68 (m, 1H), 4.51-4.47 (m, 1H), 4.37 (dd,
J=7.5, 9.5 Hz, 1H), 4.21 (dd, J=7.5, 9.8 Hz, 1H), 3.24-3.18 (m,
1H), 3.02-2.95 (m, 1H), 2.87-2.78 (m, 1H), 2.39-2.19 (m, 3H),
2.09-2.00 (m, 1H). LC/MS: R.sub.t=0.90 min, ES.sup.+ 460 (formic
acid standard).
Example 62
[(1S,2S,4R)-2-hydroxy-4-(4-{[(1R,2R_-2-methoxy-2,3-dihydro-1H-inden-1-yl]a-
mino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methyl sulfamate
(Compound I-72)
##STR00134##
[0495] Step a:
2-[(1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-1H-isoindole-1,3(2H)-dion-
e
[0496] A suspension of (1R,2R)-1-aminoindan-2-ol (1.40 g, 0.00938
mol), phthalic anhydride (1.39 g, 0.00938 mol), and
N,N-diisopropylethylamine (1.63 mL, 0.00935 mol) in toluene (141
mL) in a 250 mL round bottom flask equipped with a Dean-Stark trap
and condenser was stirred at reflux under an atmosphere of nitrogen
18 h. The reaction mixture was cooled to rt. TLC showed complete
conversion of starting material to a higher R.sub.f spot. .sup.1H
NMR of an aliquot sample partitioned between EtOAc and water
confirmed that reaction was complete. The reaction mixture was
concentrated to a pale white and pale brown solid, redissolved in
EtOAc (25 mL), washed with 1N HCl (2.times.10 mL), aqueous
saturated NaHCO.sub.3 (1.times.10 mL), and brine (1.times.10 mL),
dried over Na.sub.2SO.sub.4, filtered, concentrated, and dried on
high vacuum to give the product as an off-white solid (2.53 g,
97%). .sup.1H NMR (CDCl.sub.3 400 MHz, .delta.): 7.86-7.84 (m, 2H),
7.74-7.72 (m, 2H), 7.26-7.25 (m, 2H), 7.20-7.14 (m, 1H), 7.01 (d,
J=7.5 Hz, 1H), 5.67 (d, J=6.3 Hz, 1H), 5.14 (m, 1H), 3.58 (dd,
J=7.5, 16.1 Hz, 1H), 2.97 (dd, J=6.8, 15.8 Hz, 1H), 2.12 (s, 1H)
ppm.
Step b:
2-[(1R,2R)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-1H-isoindole-1,3(2-
H)-dione
[0497] To a solution of
2-[(1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-1H-isoindole-1,3(2H)-dion-
e (0.860 g, 0.00308 mol) in THF (30 mL) at 0.degree. C. under an
atmosphere of nitrogen was added a 1.0 M solution of lithium
hexamethyldisilazide in THF (3.39 mL, 0.00339 mol). The reaction
mixture was stirred for 20 minutes, followed by the addition of
methyl iodide (0.575 mL, 0.00924 mol). The cold bath was removed,
and the reaction mixture was allowed to stir and warm to rt over 18
h. The reaction was monitored by .sup.1H NMR. The reaction mixture
was then re-cooled to 0.degree. C. To the reaction mixture was
added 1.0 M solution of lithium hexamethyldisilazide in THF (3.39
mL, 0.00339 mol). The reaction mixture was stirred for 15 minutes,
followed by addition of methyl iodide (0.575 mL, 0.00924 mol). The
cold bath was removed, and the reaction mixture was allowed to stir
at rt for 22 h. .sup.1H NMR indicated 80:20 product/starting
material. The reaction was quenched with aqueous 1N HCl solution
and then concentrated in vacuo. The residue was partitioned between
EtOAc and water. The organic phase was washed with saturated
NaHCO.sub.3 and brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The oil was purified by silica gel chromatography,
eluting with a gradient of hexanes to 10% EtOAc in hexanes) to
obtain product (4.18 g, 46%). LC/MS: R.sub.t=1.90 min, ES.sup.+ 294
(AA standard).
Step c: (1R,2R)-2-methoxyindan-1-amine
[0498] To a mixture of
2-[(1R,2R)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-1H-isoindole-1,3(2H)-dion-
e (4.13 g, 0.00141 mol) in ethanol (3.38 mL) under an atmosphere of
argon was added hydrazine (0.0442 mL, 0.0580 mol). The reaction
mixture was allowed to stir at rt overnight. White solid byproduct
crashed out of solution. TLC showed no starting material. The
reaction mixture was concentrated, and the residue was suspended in
DCM and filtered. The filtrate was concentrated in vacuo. .sup.1H
NMR showed that the reaction had not gone to completion. The yellow
oil was therefore stirred at reflux for 3 h. LCMS confirmed
reaction was complete. The reaction mixture was cooled to rt,
concentrated in vacuo, triturated with DCM, filtered, and the
filtrate was concentrated in vacuo to give product as a yellow oil
(0.154 g, 64%). LC/MS: R.sub.t=0.68 min, ES.sup.+ 164 (AA
standard).
Step d:
[(1S,2S,4R)-2-hydroxy-4-(4-{[(1R,2R_-2-methoxy-2,3-dihydro-1H-inde-
n-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methyl
sulfamate (Compound I-70)
[0499] The title compound was prepared following the procedure
described in Example 2a-j using (1R,2R)-2-methoxyindan-1-amine in
step f. .sup.1H NMR (CD.sub.3OD, 400 MHz, .delta.): 8.18 (s, 1H),
7.22-7.19 (m, 3H), 7.15-7.14 (m, 2H), 6.63 (d, J=3.4 Hz, 1H), 5.84
(d, J=5.9 Hz, 1H), 5.49-5.51 (m, 1H), 4.50-4.48 (m, 1H), 4.37 (dd,
J=7.5, 9.8 Hz, 1H), 4.25-4.18 (m, 2H), 3.47 (s, 3H), 3.37 (dd,
J=7.3, 15.8 Hz, 1H), 2.87 (dd, J=6.8, 15.7 Hz, 1H), 2.83-2.77 (m,
1H), 2.33-2.20 (m, 3H), 2.07-2.00 (m, 1H), 1.94 (s, 1H) ppm. LC/MS:
R.sub.t=1.51 min, ES.sup.+ 474 (AA standard).
Example 63
2-((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-
pyrimidin-7-yl}-2-hydroxycyclopentyl)ethanesulfonamide (Compound
I-59)
Step a: 7-[(1R,3S,4S)-3-[tert-butyl
(dimethyl)silyl]oxy-4-([tert-butyl
(dimethyl)silyl]oxymethyl)cyclopentyl]-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-
-7H-pyrrolo-2,3-d]pyrimidin-4-amine
[0500]
(1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,-
3-d]pyrimidin-7-yl}-2-(hydroxymethyl)cyclopentanol (0.787 g,
0.00216 mol), 1H-imidazole (0.588 g, 0.00864 mol) and
N,N-dimethylaminopyridine (0.022 g, 0.00018 mol) were dissolved in
N,N-dimethylformamide (24 mL) under an atmosphere of nitrogen.
After 2 hours, additional tert-butyldimethylsilyl chloride (0.500
g, 0.00332 mol) was added, and the mixture was stirred for a
further 1 hour. The mixture was quenched with brine and extracted
with ethyl acetate. The organic phase was evaporated and the
residue was purified by silica gel chromatography, eluting with 0
to 100% ethyl acetate in dichloromethane, to yield 1.17 g (92%) of
the title compound. .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.):
8.40 (s, 1H), 7.29 (m, 5H), 7.00 (d, J=3.6 Hz, 1H), 6.33 (d, J=3.3
Hz, 1H), 5.89 (dd, J=7.3 Hz, 15.3 Hz, 1H), 5.46 (ddd, J=4.3 Hz, 8.5
Hz, 18.1 Hz, 1H), 4.48 (t, J=3.1 Hz, 1H), 3.79 (dd, J=7.2 Hz, 9.9
Hz, 1H), 3.60 (dd, J=6.8 Hz, 9.9 Hz, 1H), 3.00 (m, 1H), 2.75 (dtd,
J=4.0 Hz, 7.6 Hz, 11.7 Hz, 1H), 2.45 (d, J=4.0 Hz, 1H), 2.22 (d,
J=4.0 Hz, 3H), 1.96 (d, J=4.0 Hz, 2H), 0.90 (s, 18H), 0.08 (s,
12H).
Step b:
((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihydr-
o-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methanol
[0501]
7-[(1R,3S,4S)-3-[tert-butyl(dimethyl)silyl]oxy-4-([tert-butyl(dimet-
hyl)silyl]-oxymethyl)cyclopentyl]-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-7H-py-
rrolo[2,3-d]pyrimidin-4-amine (1.66 g, 0.00280 mol) was dissolved
in a mixture of tetrahydrofuran (6.6 mL), water (6.6 mL, 0.36 mol),
and acetic acid (19 mL, 0.34 mol). The solution was then heated to
40.degree. C. overnight. The mixture was then cooled and
evaporated, azeotroped with toluene (2.times.50 mL) and the residue
was purified by silica gel chromatography eluting with 0 to 100%
ethyl acetate in dichloromethane to yield the product as a white
solid, 1.05 g (74%). LC/MS: R.sub.t=1.68 min, ES.sup.+ 479 (AA
standard).
Step c:
(1R,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihydro-
-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentanecarbaldeh-
yde
[0502]
((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihydro-
-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methanol
(257.0 mg, 0.0005369 mol) was dissolved in methylene chloride (10.0
mL) under argon. N-Methylmorpholine N-oxide (126 mg, 0.00107 mol),
and 4 .ANG. molecular sieves (250 mg, freshly flame dried) were
then added and the mixture was stirred for 10 minutes at room
temperature. Tetrapropylammonium perruthenateVII (18.9 mg,
0.0000537 mol) was then added, and the resulting dark green
solution was stirred for 1 h at room temperature. The reaction
mixture was filtered through a silica gel plug, eluting with DCM
(20 mL), followed by 50% ethyl acetate in DCM (150 mL). The eluate
was evaporated to provide the product as a clear light green oil.
The residue was carried on to the next reaction without further
purification.
Step d: Ethyl
(E)-2-((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{-4-[(1S)-2,3-dihydr-
o-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)ethylene-
sulfonate
[0503] To a stirred solution of
(diethoxy-phosphoryl)-methanesulfonic acid ethyl ester (285 mg,
0.00110 mol) in tetrahydrofuran (5.0 mL) was added, dropwise, 2.5 M
of n-butyllithium in hexane (440 pt, 0.00110 mol) at -78.degree. C.
under atmosphere of nitrogen. The mixture was then stirred for 30
minutes. To this solution was added, dropwise, a solution of
(1R,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihydro-1H-ind-
en-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentanecarbaldehyde
(212.0 mg, 0.0004447 mol) in tetrahydrofuran (5.0 mL) at
-78.degree. C. The resulting pink solution was stirred for 1.5 h at
-78.degree. C. The reaction mixture was warmed and quenched by
addition of saturated NH.sub.4Cl (30 mL). The resultant mixture was
extracted with DCM (3.times.30 mL). The combined organic layers
were dried over MgSO.sub.4, filtered, and concentrated in vacuo.
The residue was purified by silica gel chromatography with 30 to
50% ethyl acetate in hexane to yield the product as a colorless
oil, 132 mg (51%). LC/MS: R.sub.t=2.55 min, ES.sup.+ 583 (AA
standard).
Step e: Ethyl
2-((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihydro-1H--
inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)ethanesulfort-
ate
[0504]
Ethyl-2-((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-
-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)e-
thylenesulfonate (132.0 mg, 0.0002265 mol) was dissolved in ethanol
(8.0 mL) and sodium borohydride (42.8 mg, 0.00113 mol) was added.
The reaction mixture was stirred at room temperature overnight. The
mixture was quenched with NH.sub.4Cl solution, and the mixture was
concentrated to remove the ethanol. The aqueous residue was then
extracted with dichloromethane, and the organic phase was
concentrated. The residue was purified by silica gel chromatography
15% ethyl acetate in dichloromethane to yield the product, 92 mg
(69%). LC/MS: R.sub.t=2.51 min, ES.sup.+ 585 (AA standard).
Step f: N,N,N-tributylbutan-1-aminium
2-((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihydro-1H--
inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)ethanesulfona-
te
[0505] Ethyl
2-((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihydro-1H--
inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)ethanesulfona-
te (92 mg, 0.0001573 mol) and tetra-n-butylammonium iodide (62.0
mg, 0.000168 mol) were dissolved in acetone (2.5 mL, 0.034 mol) and
the mixture was heated using microwave irradiation at 140.degree.
C. for 70 seconds. The cooled reaction mixture was concentrated to
dryness to yield the crude product, 140 mg. LC/MS: R.sub.t=1.75
min, ES.sup.+ 557 (AA standard).
Step g:
2-((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihy-
dro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)ethane-
sulfonamide
[0506] N,N,N-tributylbutan-1-aminium
2-((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihydro-1H--
inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)ethanesulfona-
te (66.0 mg, 0.0000744 mol) was dissolved in methylene chloride
(2.0 mL, 0.031 mol) and N,N-dimethylformamide (5.50 .mu.L,
0.0000710 mol) was added. The mixture was cooled to 0.degree. C.
and thionyl chloride (50.0 .mu.L, 0.000685 mol) was added dropwise.
The reaction was allowed to stir at 0.degree. C. for 2.5 h. The
reaction mixture was diluted with toluene and concentrated to
dryness. The residue was again azeotroped with toluene. The residue
was eluted down a silica cartridge (.about.3 g) with 0 to 10%
THF/DCM to yield the acid chloride intermediate, 42 mg. The acid
chloride was taken up in a 0.500 M solution of ammonia in
1,4-dioxane (5.00 mL) and the resultant solution was stirred
overnight at room temperature under an atmosphere of nitrogen. The
mixture was then evaporated and the residue was partitioned between
DCM and water. The organic phase was evaporated to yield the crude
product, 35 mg (85%). LC/MS: R.sub.t=1.64 min, ES.sup.+ 556 (AA
standard).
Step h:
2-((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrol-
o[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)ethanesulfonamide
(Compound I-59)
[0507]
2-((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihyd-
ro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)ethanes-
ulfonamide (32 mg, 0.000057 mol) was dissolved in tetrahydrofuran
(1.0 mL, 0.012 mol) and a 1.00 M solution of tetra-n-butylammonium
fluoride in tetrahydrofuran (0.100 mL) was added. The mixture was
stirred at room temperature for 1 hour. The reaction mixture was
quenched with a little water and then concentrated. Purification of
the residue by silica gel chromatography, eluting with 0 to 100% of
(9:1 EtOAc:EtOH) in DCM, afforded the desired product, (9 mg, 40%).
.sup.1H-NMR (400 MHz, MeOD, .delta.): 8.16 (s, 1H), 7.19 (m, 5H),
6.62 (d, J=3.6 Hz, 1H), 5.85 (t, J=7.7 Hz, 1H), 5.43 (dddd, J=4.2
Hz, 8.4 Hz, 8.4 Hz, 8.4 Hz, 1H), 4.35 (t, J=3.7 Hz, 1H), 3.13 (m,
3H), 2.91 (m, 1H), 2.63 (m, 1H), 2.49 (m, 1H), 2.35 (ddd, J=1.2 Hz,
8.1 Hz, 13.8 Hz, 1H), 2.05 (m, 6H). LC/MS: R.sub.t=1.07 min,
ES.sup.+ 442 (AA standard).
Example 64
(E)-2-((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,-
3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)ethylenesulfonamide
(Compound I-73)
Step a: tert-Butyl
{[(E)-2-((1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-dih-
ydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)vinyl-
]sulfonyl}carbamate
[0508] tert-Butyl{[(diphenylphosphoryl)methyl]sulfonyl}carbamate
(602 mg, 1.45 mmol) was dissolved in THF (50.0 mL) under an
atmosphere of argon, a 1.60 M solution of n-butyllithium in hexane
(1.81 mL, 2.89 mmol) was added at -50.degree. C., and the resultant
mixture was stirred for 1 h. A solution of
(1R,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-dihydro-1H-i-
nden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentanecarbaldehyde
(300 mg, 0.60 mmol) in THF (8.0 mL) was added to the mixture, and
the resulting mixture was stirred for 30 min at room temperature.
After quenching by addition of water (200 mL), the mixture was
extracted with EtOAc (100 mL.times.3). The organic layer was dried
over MgSO.sub.4, filtered, and concentrated in vacuo. The residue
was purified via silica gel chromatography eluting with a gradient
of 10 to 60% EtOAc in hexane to afford the title compound (84.0 mg,
21%). LC/MS: R.sub.t=1.90 min, ES.sup.+ 654 (FA standard).
Step b:
(E)-2-((1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,-
3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)-
ethylenesulfonamide
[0509] tert-Butyl
{[(E)-2-((1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-dih-
ydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)vinyl-
]sulfonyl}-carbamate (120 mg, 0.17 mmol) was dissolved in DCM (10.0
mL) under an atmosphere of argon, and EtOH (0.05 mL, 8.72 mmol) was
added at room temperature. To this mixture was added ZnBr.sub.2
(0.10 mg, 0.44 mmol), and the resulting mixture was stirred for 4
h. After quenching by addition of water (20 mL), the mixture was
stirred for 1 h, and then was extracted with DCM (30 mL.times.3).
The organic layer was dried over MgSO.sub.4, filtered, and
concentrated in vacuo. The residue was purified via silica gel
chromatography, eluting with a gradient of 0 to 10% MeOH in DCM, to
afford the title compound (91.8 mg, 90%). LC/MS: R.sub.t=1.64 min,
ES.sup.+ 554 (FA standard).
Step c:
(E)-2-((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-py-
rrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)ethylenesulfonamide
(Compound I-73)
[0510]
(E)-2-((1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-
-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)e-
thylenesulfonamide (30 mg, 0.05 mmol) was dissolved in THF (2.00
mL). To this solution was added at room temperature a 1M solution
of tetra-n-butylammonium fluoride in THF (0.08 mL, 0.08 mmol), and
the resulting mixture was stirred for 1 h. The reaction mixture was
quenched by the addition of brine (20 mL) and extracted with EtOAc
(30 mL.times.3). The organic layer was dried over MgSO.sub.4,
filtered, and concentrated in vacuo. The residue was purified via
silica gel chromatography, eluting with a gradient of 5 to 15% MeOH
in DCM, to afford the title compound (21.3 mg, 81%). .sup.1H NMR
(CD.sub.3OD, 400 MHz, .delta.): 8.17 (s, 1H), 7.27-7.11 (m, 5H),
6.88 (dd, J=7.8, 15.1 Hz, 1H), 6.63 (d, J=3.5 Hz, 1H), 6.57 (dd,
J=1.0, 15.1 Hz, 1H), 5.85 (dd, J=7.7, 7.8 Hz, 1H), 5.47 (ddd,
J=4.6, 8.6, 18.1 Hz, 1H), 4.44-4.42 (m, 1H), 3.30-3.21 (m, 1H),
3.05 (ddd, J=3.4, 8.8, 15.8 Hz, 1H), 2.96-2.83 (m, 1H), 2.66-2.58
(m, 1H), 2.44 (dt, J=10.0, 13.8 Hz, 1H), 2.37 (ddd, J=1.8, 8.3,
13.8 Hz, 1H), 2.29 (ddd, J=4.6, 8.3, 13.8 Hz, 1H), 2.10-1.92 (m,
2H) ppm. LC/MS: R.sub.t=5.00 min, ES.sup.+ 440 (FA long
purity).
Example 65
N-[((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d-
]-pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl]sulfamide (Compound
I-56)
Step a: tert-butyl
(aminosulfonyl)[((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2-
,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl-
)methyl]carbamate
[0511]
((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihydro-
-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methanol
(700.0 mg, 0.001462 mol), N-Boc-sulfonamide (398 mg, 0.00203 mol)
and triphenylphosphine (575 mg, 0.00219 mol) were dissolved in
ethyl acetate (28 mL, 0.28 mol) at 50.degree. C. under an
atmosphere of nitrogen. Diethyl azodicarboxylate (350.0 .mu.L,
0.002223 mol) was added over 2-3 min and the mixture was stirred at
50.degree. C. for 30 minutes. The cooled mixture was evaporated and
the residue purified by silica gel chromatography, eluting with 10
to 100% ethyl acetate in hexanes, to yield the product as a white
solid, 636 mg (66%). LC/MS: R.sub.t=2.55 min, ES.sup.+ 657 (AA
standard).
Step b: tert-butyl
(aminosulfonyl)[((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-
-pyrrolo[2,3-d]pyrimidin-7-yl-2-hydroxycyclopentyl)methyl]carbamate
[0512] tert-Butyl
(aminosulfonyl)[((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-4-[(1S)-2,-
3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)-
-methyl]carbamate (457 mg, 0.000696 mol) was dissolved in
tetrahydrofuran (10.0 mL), 1.00 M aqueous hydrochloric acid (10.0
mL), and ethanol (10.0 mL). The mixture was stirred at room
temperature overnight. Sodium bicarbonate (842 mg, 0.0100 mol) was
added to the mixture, followed by water (10 mL). The mixture was
then concentrated to .about.20 mL volume, and this aqueous residue
was extracted with EtOAc (2.times.50 mL). The separated organics
were concentrated in vacuo and the residue was purified by silica
gel chromatography, eluting with 100% ethyl acetate to yield the
product, 362 mg (96%). LC/MS: R.sub.t=1.77 min, ES.sup.+ 543 (AA
standard).
Step c:
N-[((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrro-
lo[2,3-d]pyrimidin-7-yl}-2-hydroxycycloperityl)methyl]sulfamide
(Compound I-56)
[0513] tert-Butyl
(aminosulfonyl)[((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-
-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl]carbamate
(345 mg, 0.000636 mol) was dissolved in 2:1 methylene
chloride:trifluoroacetic acid (20 mL:10 mL) and left to stand for
15 minutes at room temperature. The mixture was diluted with
toluene (30 mL) and evaporated to dryness. The residue was then
re-subjected to the same conditions and azeotroped with toluene
after completion. The residue was purified by silica gel
chromatography, eluting with 5 to 10% Methanol in dichloromethane,
to yield the product, 135 mg (48%). .sup.1H-NMR (400 MHz, MeOD)
.delta. 8.16 (s, 1H), 7.19 (m, 5H), 6.62 (d, J=3.6 Hz, 1H), 5.85
(t, J=7.8 Hz, 1H) 5.43 (ddd, J=4.6 Hz, 8.5 Hz, 17.8 Hz, 1H), 4.46
(t, J=3.6 Hz, 1H), 3.15 (dd, J=7.1 Hz, 12.9 Hz, 1H), 3.05 (ddd,
J=3.3 Hz, 8.7 Hz, 15.4 Hz, 1H), 2.91 (m, 1H), 2.63 (m, 1H), 2.33
(ddd, J=1.5 Hz, 8.0 Hz, 13.8 Hz, 1H), 2.20 (m, 2H), 2.02 (m, 2H).
LC/MS: R.sub.t=1.45 min, ES.sup.+ 443 (AA standard).
Example 66
N-{[(1S,2S,4R)-4-(4-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}-7-
H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl}sulfamide
(Compound I-74)
[0514] The title compound was prepared following the procedures
described in Example 64a-b and Example 66a-c starting from
(1S,2S,4R)-4-{4-[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-ylamino]-7H-pyr-
rolo[2,3-d]pyrimidin-7-yl}-2-(hydroxymethyl)cyclopentanol (Example
41). .sup.1H-NMR (300 MHz, MeOD) .delta. 8.20 (s, 1H), 7.21 (m,
5H), 6.66 (d, j=3.6 Hz, 1H) 5.92 (d, j=5.3 Hz, 1H) 5.43 (m, 1H),
4.47 (t, J=3.5 Hz, 1H), 4.30 (dt, J=2.8 Hz, 5.2 Hz, 1H), 3.35 (s,
3H), 3.15 (m, 3H), 2.64 (m, 1H), 2.27 (m, 3H), 2.03 (ddd, J=4.7 Hz,
9.0 Hz, 13.6 Hz, 1H). LC/MS: R.sub.t=6.88 min, ES.sup.+ 473 (AA
purity).
Example 67
N-[((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d-
]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl]-N-methylsulfamide
(Compound I-75)
Step a:
N-[((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dih-
ydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methy-
l]-N-methylsulfamide
[0515] tert-Butyl
(aminosulfonyl)[((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2-
,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl-
)-methyl]carbamate (108 mg, 0.000164 mol) was dissolved in
tetrahydrofuran (2.0 mL) under an atmosphere of nitrogen. Lithium
tetrahydroaluminate (12.5 mg, 0.000329 mol) was added and the
mixture heated at 50.degree. C. for 80 minutes. The reaction was
then cooled, quenched with water and acidified to .about.pH 6 with
1M HCl. This mixture was then extracted with ethyl acetate, the
separated organic phase was evaporated, and the residue was
purified by silica gel chromatography, eluting with 10 to 100%
ethyl acetate in hexanes, to yield the product, 25 mg (27%). LC/MS:
R.sub.t=2.34 min, ES.sup.+ 571 (AA standard).
Step b:
N-[((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrro-
lo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl]-N-methylsulfamide
(Compound I-75)
[0516]
N-[((1S,2S,4R)-2-[tert-Butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihy-
dro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methyl-
]-N-methylsulfamide (25.0 mg, 0.0000438 mol) was dissolved in
tetrahydrofuran (2.0 mL), ethanol (2.0 mL) and 1.00 M of
hydrochloric acid in water (2.0 mL). The mixture was stirred
overnight at room temperature. The solution was evaporated to
dryness, and the residue was dissolved in methanol and treated with
a 7.00 M solution of ammonia in methanol (0.1 mL). Solvents were
again evaporated, and the residue was purified by silica gel
chromatography, eluting with 2 to 10% methanol in dichloromethane
to yield the product, 9.8 mg (49%). .sup.1H-NMR (400 MHz, MeOD)
.delta. 8.16 (s, 1H), 7.19 (m, 5H), 6.62 (d, 1H, J=3.6 Hz), 5.84
(t, J=7.7 Hz, 1H), 5.43 (ddd, J=4.5 Hz, 8.6 Hz, 12.8 Hz, 1H), 4.43
(t, J=3.7 Hz, 1H), 3.25 (dd, j=8.1 Hz, 13.7 Hz, 1H), 3.14 (dd,
J=7.2 Hz, 13.7 Hz, 1H), 3.05 (ddd, J=3.3 Hz, 8.8 Hz, 15.8 Hz, 1H),
2.91 (m, 1H), 2.74 (m, 1H), 2.63 (m, 1H), 2.34 (ddd, J=1.1 Hz, 7.8
Hz, 13.6 Hz, 1H), 2.20 (m, 2H), 1.99 (m, 2H). LC/MS: R.sub.t=1.51
min, ES.sup.+ 457 (AA standard).
Example 68
((1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-dihydro-1H-i-
nden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methyl
methanesulonate (Compound I-76)
Step a:
((1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-dihy-
dro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methyl
methanesulonate
[0517]
((1S,2S,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-dihyd-
ro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methano-
l (0.345 g, 0.721 mmol) was dissolved in methylene chloride (5.00
mL, 78.0 mmol) under an atmosphere of argon. Triethylamine (0.251
mL, 1.80 mmol) was added, and the solution was cooled to 0.degree.
C. Methanesulfonyl chloride (0.0669 mL, 0.865 mmol) was added in
one portion. The solution was stirred at 0.degree. C. under an
atmosphere of argon for 30 minutes. The solution was diluted with
EtOAc, washed with water and brine, dried over anhydrous sodium
sulfate, filtered, and concentrated in vacuo to give the title
compound (0.415 g, 89%). LC/MS: R.sub.t=2.45 min, ES.sup.+ 557 (AA
standard).
Step b:
((1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-dihy-
dro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)aceton-
itrile
[0518]
((1S,2S,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-dihyd-
ro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methyl
methanesulonate (0.415 g, 0.641 mmol) was dissolved in dimethyl
sulfoxide (7.00 mL, 98.6 mmol) under an atmosphere of argon. Sodium
cyanide (0.166 g, 3.28 mmol) was added, and the mixture was stirred
at 60.degree. C. for 24 h. The reaction mixture was heated for an
additional 24 h at 70.degree. C. The reaction mixture was cooled to
ambient temperature, diluted with EtOAc, washed with water and
brine, dried over anhydrous sodium sulfate, filtered, and
concentrated in vacuo. The residue was purified via silica gel
chromatography, eluting with a gradient of 0 to 40% EtOAc in
methylene chloride, to afford the title compound (0.306 g, 98%).
LC/MS: R.sub.t=1.85 min, ES.sup.+ 488. (FA standard).
Step c.
((1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-dihy-
dro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)acetal-
dehyde
[0519]
((1S,2S,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-dihyd-
ro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)acetoni-
trile (0.150 g, 0.308 mmol) was dissolved in methylene chloride
under an atmosphere of argon and cooled to -78.degree. C.
Diisobutylaluminum hydride (1.0M in methylene chloride, 0.340 mL,
0.340 mmol) was added to the solution and the reaction mixture was
stirred for 30 minutes at -78.degree. C. After a second addition of
diisobutylaluminum hydride (1.0M in methylene chloride, 0.340 mL,
0.340 mmol), the solution was stirred for an additional 30 minutes
at -78.degree. C. A third addition of diisobutylaluminum hydride
(1.0M in methylene chloride, 0.340 mL, 0.340 mmol) was made, and
the solution was stirred for another 30 minutes at -78.degree. C.
The reaction was quenched with a saturated solution of sodium
potassium tartrate tetrahydrate. EtOAc was added and the mixture
was stirred until the layers were clear. The layers were separated.
The aqueous layer was extracted with diethyl ether. The combined
organic extracts were washed with brine, dried over anhydrous
sodium sulfate, filtered and concentrated in vacuo to give the
title compound (0.160 g, 100%). LC/MS: R.sub.t=1.80 min, ES.sup.+
491 (FA standard).
Step d:
2-((1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-di-
hydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)etha-
nol
[0520]
((1S,2S,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-dihyd-
ro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)acetald-
ehyde (0.164 g, 0.314 mmol) was dissolved in methanol (5.00 mL, 123
mmol) under an atmosphere of argon and cooled to 0.degree. C.
Sodium tetrahydroborate (0.0291 g, 0.754 mmol) was added and the
reaction was stirred for 10 minutes. Additional sodium
tetrahydroborate (0.0143 g, 0.377 mmol) was added, and the reaction
mixture was stirred for another 30 minutes. The reaction was
quenched with water, extracted with EtOAc, dried over anhydrous
sodium sulfate, filtered, and concentrated in vacuo. The residue
was purified by silica gel chromatography, eluting with a gradient
of 0 to 100% EtOAc in methylene chloride, to afford the title
compound (0.0694 g, 45%). LC/MS: R.sub.t=1.65 min, ES.sup.+ 494 (FA
standard).
Step e:
2-((1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-di-
hydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)ethy-
l sulfamate
[0521]
((1S,2S,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-dihyd-
ro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)ethanol
(0.0694 g, 0.141 mmol) was dissolved in acetonitrile (3.00 mL, 57.4
mmol) and methylene chloride (2.00 mL, 31.2 mmol) under an
atmosphere of argon. Triethylamine (0.0589 mL, 0.422 mmol) was
added, and the solution was cooled to 0.degree. C.
Chlorosulfonamide (2.00M in acetonitrile, 0.141 mL) was added and
the solution was immediately warmed to room temperature. After 30
minutes, additional chlorosulfonamide (2.00M in acetonitrile, 0.141
mL) and triethylamine (0.0589 mL, 0.422 mmol) were added and the
reaction was stirred for 30 minutes. The reaction was quenched with
methanol and a 1:1 solution of saturated sodium bicarbonate and
water. The mixture was extracted with EtOAc. The combined organic
extracts were washed with brine, dried over anhydrous sodium
sulfate, filtered, and concentrated in vacuo. The residue was
purified by silica gel chromatography, eluting with 0 to 50% EtOAc
in methylene chloride, to give the title compound (0.0805 g, 55%).
LC/MS: R.sub.t=1.70 min, ES.sup.+ 573 (FA standard).
Step f:
2-((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrol-
o[2,3-d]-pyrimidin-7-yl}-2-hydroxycyclopenytl)ethyl sulfamate
(Compound I-76)
[0522]
2-((1S,2S,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-dih-
ydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)ethyl
sulfamate (0.0442 g, 0.0773 mmol) was dissolved in pyridine (0.344
mL, 4.25 mmol) and tetrahydrofuran (0.345 mL, 4.25 mmol). The
solution was cooled to 0.degree. C. Pyridine hydrofluoride (0.500
mL, 5.55 mmol) was added dropwise. The solution was warmed to room
temperature. After one hour, pyridine hydrofluoride (0.500 mL, 5.55
mmol) was added. After two hours, pyridine hydrofluoride (0.500 mL,
5.55 mmol) was added. The solution was stirred for 24 h. The
reaction was quenched with dropwise addition of saturated sodium
bicarbonate, and the mixture was extracted with EtOAc. The combined
organic extracts were dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuo. The residue was purified by
silica gel chromatography, eluting with 0 to 5% MeOH in EtOAc, to
give the title compound (0.005 g, 0.01 mmol). .sup.1H NMR
(CD.sub.3OD, 400 MHz, .delta.): 8.17 (s, 1H), 7.28-7.12 (m, 5H)
6.67 (d, J=3.61 Hz 1H) 5.58 (t, J=7.44, 7.44 Hz 1H), 5.48-5.40 (m,
1H), 4.40-4.35 (m, 1H), 4.28-4.17 (m, 2H), 3.10-3.02 (m, 1H),
2.98-2.88 (m, 1H), 2.68-2.47 (m, 1H), 2.57-2.47 (m, 1H), 2.38-1.98
(m, 5H), 1.89-1.80 (m, 1H) ppm. LC/MS: R.sub.t=1.25 min, ES.sup.+
458 (FA standard).
Example 70
Diastereoisomeric mixture of
(1S,2R,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]py-
rimidin-7-yl}-2-hydroxycyclopentyl sulfamate and
(1R,2S,4S)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3d]-py-
rimidin-7-yl}-2-hydroxycyclopentyl sulfamate (Compounds I-77 and
I-78)
##STR00135##
[0523] Step a: Cyclopent-3-en-1-yl methanesulfonate
[0524] 3-Cyclopentene-1-ol (0.500 g, 5.94 mmol) was stirred in DCM
(95 mL). Pyridine (2.40 mL), N,N-dimethylaminopyridine (0.10 g,
1.00 mmol) and methanesulfonyl chloride (0.690 mL, 8.92 mmol) were
added, and the reaction mixture was stirred at 35.degree. C. for 4
h. N,N-Dimethylaminopyridine (0.14 g, 1.2 mmol) and methanesulfonyl
chloride (0.69 mL, 8.92 mmol) were added, and the reaction was
stirred overnight. TLC indicated complete conversion. The reaction
mixture was cooled and concentrated. The residue was purified by
silica gel chromatography, eluting with DCM, to afford the title
compound as a clear oil (0.660 g, 68%).
Step b:
7-Cyclopent-3-en-1-yl-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-7H-pyrrol-
o[2,3-d]-pyrimidin-4-amine
[0525]
N-[(1S)-2,3-Dihydro-1H-inden-1-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-ami-
ne (1.32 g, 5.29 mmol) was azeotroped with toluene and placed under
high vacuum for 30 min. N,N-Dimethylformamide (17.7 mL) was added,
followed by cesium carbonate (1.99 g, 6.10 mmol). The mixture was
stirred at 70.degree. C. for 10 min. Cyclopent-3-en-1-yl
methanesulfonate (0.660 g, 4.07 mmol) in N,N-dimethylformamide
(12.6 mL) was added dropwise. The reaction mixture was heated to
110.degree. C. for 1 h. The reaction mixture was cooled, quenched
with brine and diluted with H.sub.2O. The aqueous layer was
extracted with EtOAc (3.times.), washed with H.sub.2O and brine,
dried (Na.sub.2SO.sub.4), filtered, and concentrated. The residue
was purified by via silica gel chromatography, eluting with a
gradient of 0 to 5% MeOH in DCM followed by 25 to 50% EtOAc in
hexanes, to afford the title compound as a pale brown solid (0.684
g, 53%). LC/MS: R.sub.t=1.38 min, ES.sup.+ 317 (FA standard).
Step c:
(1R,2S,4S)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2-
,3-d]pyrimidin-7-yl}cyclopentane-1,2-diol
[0526]
7-Cyclopent-3-en-1-yl-N-[(1S)-2,3-dihyrdo-1H-inden-1-yl]-7H-pyrrolo-
[2,3-d]pyrimidin-4-amine (0.312 g, 0.986 mmol) was stirred in
tert-butyl alcohol (4.9 mL) and H.sub.2O (4.9 mL). AD-mix-.alpha.
(Sigma-Aldrich, 1.4 g) was added, and the suspension was stirred at
rt overnight. TLC indicated complete conversion. The reaction was
quenched with sodium sulfite (1.48 g, 11.7 mmol), and the mixture
was stirred for 5 h. The reaction mixture was diluted with EtOAc
and H.sub.2O, and the aqueous layer was extracted with EtOAc
(2.times.). The organic layer was dried (Na.sub.2SO.sub.4),
filtered, and concentrated. The residue was purified via silica gel
chromatography, eluting with EtOAc, to afford the title compound as
a white solid (0.190 g, 55%).
Step d: Diastereoisomeric mixture of
(1S,2R,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]py-
rimidin-7-yl}-2-hydroxycyclopentyl sulfamate and
(1R,2S,4S)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]py-
rimidin-7-yl}-2-hydroxycyclopentyl sulfamate (Compounds I-77 and
I-78)
[0527]
(1R,2S,4S)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,-
3-d]pyrimidin-7-yl}cyclopentane-1,2-diol (0.080 g, 0.23 mmol) was
azeotroped with toluene and then was dissolved in anhydrous
acetonitrile (2.3 mL). Pyridine (0.0369 mL, 0.458 mmol) was added.
The reaction mixture was cooled to 0.degree. C., and a 2N solution
of chlorosulfonamide in acetonitrile (0.144 mL) was added dropwise.
The reaction was stirred for 1 h, and then additional 2N
chlorosulfonamide in acetonitrile (0.028 mL) was added. After 30
min, additional 2N chlorosulfonamide in acetonitrile (0.0342 mL)
was added, and the reaction mixture was stirred for 2 h. The
reaction was quenched with methanol, and the mixture was
concentrated in vacuo. The residue was purified by preparative thin
layer chromatography using DCM:AcCN:MeOH (50:45:5). The relevant
band was cut, washed with acetone, filtered, and concentrated to
give a mixture of diastereomers as a white solid. (11 mg, 11%).
.sup.1H NMR (CDCl.sub.3, 400 NMR, .delta.): 8.36-8.27 (m, 1H);
7.38-7.09 (m, 5H); 6.90-6.80 (m, 1H); 6.36-6.20 (m, 1H); 5.95-5.76
(m, 1H); 5.51-5.22 (m, 2H); 4.83-4.68 (m, 1H); 3.87-3.72 (m, 1H);
3.12-2.83 (m, 2H); 2.75-2.53 (m, 1H); 2.50-2.14 (m, 2H); 2.08-1.79
(m, 2H) ppm. LC/MS: R.sub.t=1.16 min, ES.sup.+ 430 (FA
standard).
[0528] The following additional compounds of formula (I) were also
prepared:
[(1R,2R,4S)-2-hydroxy-4-(4-{[(1R,2R)-2-(methoxymethyl)-2,3-dihydro-4H-inde-
n-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methylsulfamate
(Compound I-79)
[0529] .sup.1H NMR (CD.sub.3OD, 400 MHz, .delta.): 8.20 (s, 1H),
7.32-7.16 (m, 5H), 6.64 (d, J=3.6 Hz, 1H), 5.97 (d, J=7.0 Hz, 1H),
5.50-5.41 (m, 1H), 4.51-4.46 (m, 1H), 4.36 (dd, J=7.5, 9.8 Hz, 1H),
4.19 (dd, J=7.3, 9.8 Hz, 1H), 3.53-3.40 (m, 1H), 3.41-3.35 (m, 1H),
3.18 (s, 3H), 3.11-2.95 (m, 3H), 2.84-2.75 (m, 1H), 2.33 (ddd,
J=1.4, 7.7, 13.5 Hz, 1H), 2.29-2.19 (m, 2H), 2.04 (ddd, J=4.9, 9.5,
14.2 Hz, 1H) ppm. LC/MS: R.sub.t=11.24 min, ES.sup.+ 488 (FA long
purity).
[(1R,2R,4S)-2-hydroxy-4-(4-{[(1S,2S)-2-(methoxymethyl)-2,3-dihydro-1H-inde-
n-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methylsulfamate
(Compound I-80)
[0530] .sup.1H NMR (CD.sub.3OD, 400 MHz, .delta.): 8.20 (s, 1H),
7.32-7.16 (m, 5H), 6.64 (d, J=3.6 Hz, 1H), 5.97 (d, J=7.0 Hz, 1H),
5.50-5.41 (m, 1H), 4.51-4.46 (m, 1H), 4.36 (dd, J=7.5, 9.8 Hz, 1H),
4.19 (dd, J=7.3, 9.8 Hz, 1H), 3.53-3.40 (m, 1H), 3.41-3.35 (m, 1H),
3.18 (s, 3H), 3.11-2.95 (m, 3H), 2.84-2.75 (m, 1H), 2.33 (ddd,
J=1.4, 7.7, 13.5 Hz, 1H), 2.29-2.19 (m, 2H), 2.04 (ddd, J=4.9, 9.5,
14.2 Hz, 1H) ppm. LC/MS: R.sub.t=11.24 min, ES.sup.+ 488 (FA long
purity).
[(1R,2R,4S)-2-hydroxy-4-(4-{[(1R,2R)-2-methyl-2,3-dihydro-1H-inden-1-yl]am-
ino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methylsulfamate
(Compound I-81)
[0531] .sup.1H NMR (CD.sub.3OD, 400 MHz, .delta.): 8.17 (s, 1H),
7.32-7.16 (m, 5H), 6.69 (d, J=3.6 Hz, 1H), 5.86 (d, J=7.2 Hz, 1H),
5.50-5.41 (m, 1H), 4.51-4.47 (m, 1H), 4.38 (dd, J=9.7, 7.6 Hz, 1H),
4.20 (dd, J=7.4, 9.7 Hz, 1H), 3.14-3.08 (m, 1H), 2.95-2.88 (m, 1H),
2.83-2.72 (m, 2H), 2.37-2.20 (m, 3H), 2.09-2.00 (m, 1H), 0.98 (d,
J=7.1 Hz, 3H) ppm. LC/MS: R.sub.t=7.93 min, ES.sup.+ 458 (AA long
purity).
[(1R,2R,4S)-2-hydroxy-4-(4-{[(1S,2S)-2-methyl-2,3-dihydro-1H-inden-1-yl]am-
ino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methylsulfamate
(Compound I-82)
[0532] .sup.1H NMR (CD.sub.3OD, 400 MHz, .delta.): 8.17 (s, 1H),
7.32-7.16 (m, 5H), 6.69 (d, J=3.6 Hz, 1H), 5.86 (d, J=7.2 Hz, 1H),
5.50-5.41 (m, 1H), 4.51-4.47 (m, 1H), 4.38 (dd, J=9.7, 7.6 Hz, 1H),
4.20 (dd, J=7.4, 9.7 Hz, 1H), 3.14-3.08 (m, 1H), 2.95-2.88 (m, 1H),
2.83-2.72 (m, 2H), 2.37-2.20 (m, 3H), 2.09-2.00 (m, 1H), 0.98 (d,
J=7.1 Hz, 3H) ppm. LC/MS: R.sub.t=7.93 min, ES.sup.+ 458 (AA long
purity).
[(1R,2R,4S)-2-hydroxy-4-(4-{[(1R,2R)-2-ethyl-2,3-dihydro-1H-inden-1-yl]ami-
no}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methylsulfamate
(Compound I-83)
[0533] .sup.1H NMR (CD.sub.3OD, 400 MHz, .delta.): 8.17 (s, 1H),
7.31-7.15 (m, 5H), 6.66 (d, J=3.60 Hz, 1H), 5.94 (d, J=7.28 Hz,
1H), 5.48-5.41 (m, 1H), 4.48 (dd, J=3.98, 3.03 Hz, 1H), 4.36 (dd,
J=9.74, 7.58 Hz, 1H), 4.19 (dd, J=9.73, 7.33 Hz, 1H), 3.07-3.01 (m,
1H), 2.91-2.76 (m, 2H), 2.65-2.54 (m, 1H), 2.38-2.19 (m, 3H), 2.03
(ddd, J=13.95, 9.17, 4.93 Hz, 1H), 1.59 (ddd, J=13.33, 7.40, 5.81
Hz, 1H), 1.38-1.28 (m, 1H), 0.93 (t, J=7.41 Hz, 3H) ppm. LC/MS:
R.sub.t=8.36 min, ES.sup.+ 472 (AA long purity).
[(1R,2R,4S)-2-hydroxy-4-(4-{[(1S,2S)-2-ethyl-2,3-dihydro-1H-inden-1-yl]ami-
no}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methylsulfamate
(Compound I-84)
##STR00136##
[0535] .sup.1H NMR (CD.sub.3OD, 400 MHz, .delta.): 8.17 (s, 1H),
7.31-7.15 (m, 5H), 6.66 (d, J=3.60 Hz, 1H), 5.94 (d, J=7.28 Hz,
1H), 5.48-5.41 (m, 1H), 4.48 (dd, J=3.98, 3.03 Hz, 1H), 4.36 (dd,
J=9.74, 7.58 Hz, 1H), 4.19 (dd, J=9.73, 7.33 Hz, 1H), 3.07-3.01 (m,
1H), 2.91-2.76 (m, 2H), 2.65-2.54 (m, 1H), 2.38-2.19 (m, 3H), 2.03
(ddd, J=13.95, 9.17, 4.93 Hz, 1H), 1.59 (ddd, J=13.33, 7.40, 5.81
Hz, 1H), 1.38-1.28 (m, 1H), 0.93 (t, J=7.41 Hz, 3H) ppm. LC/MS:
R.sub.t=8.36 min, ES.sup.+ 472 (AA long purity).
((1S,2S,4R)-2-hydroxy-4-(4-((1R,2S)-2-methoxy-1,2,3,4-tetrahydronaphthalen-
-1-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)methyl
sulfamate (Compound I-85)
[0536] .sup.1H NMR (CD.sub.3OD, 400 MHz, .delta.): 8.17 (s, 1H),
7.25 (d, J=7.4, 1H), 7.20 (d, J=3.6 Hz, 1H), 7.15-7.06 (m, 3H),
6.66 (d, J=3.6 Hz, 1H), 5.81 (m, 1H), 5.50-5.40 (m, 1H), 4.49 (m,
1H), 4.37 (dd, J=3.3, 7.0 Hz, 1H), 4.20 (dd, J=7.3, 9.7 Hz, 1H),
3.85-3.82 (m, 1H), 3.42 (s, 3H), 3.06-2.96 (m, 1H), 2.84-2.73 (m,
2H), 2.38-2.18 (m, 4H), 2.08-2.18 (m, 2H) ppm. LC/MS: R.sub.t=1.51
min, ES.sup.+ 488 (AA standard).
((1S,2S,4R)-4-(4-((S)-2,3-dihydro-1H-inden-1-ylamino)-7H-pyrrolo[2,3-d]pyr-
imidin-7-yl)-2-methoxycyclopentyl)methyl sulfamate (Compound
I-86)
[0537] .sup.1H NMR (CD.sub.3OD, 400 MHz, .delta.): 8.13 (s, 1H),
7.23-7.08 (m, 5H), 6.60 (d, J=3.6 Hz, 1H), 5.81 (t, J=7.69, 15.4
Hz, 1H), 5.36-5.25 (m, 1H), 4.32 (dd, J=7.5, 9.6 Hz, 1H), 4.13 (dd,
J=7.3, 9.6 Hz, 1H), 4.02-4.00 (m, 1H), 3.32 (s, 3H), 3.06-2.98 (m,
1H), 2.94-2.77 (m, 2H), 2.63-2.54 (m, 1H), 2.54-2.48 (m, 1H),
2.18-2.08 (m, 2H) ppm. LC/MS: R.sub.t=8.10 min, ES.sup.+ 458 (AA
standard).
Example 69
Enzyme Preparation
[0538] All protein accession numbers provided herein refer to the
Entrez Protein database maintained by the National Center for
Biotechnology Information (NCBI), Bethesda, Md.
Generation of E1 Enzymes
[0539] Following manufacturer instructions, baculoviruses were
generated with the Bac-to-Bac Expression System (Invitrogen) for
the following proteins: untagged NAE.alpha. (APPBP1;
NP.sub.--003896.1), N-terminally His-tagged NAE.beta. (UBE1C;
NP.sub.--003959.3), untagged SAE.alpha. (SAE1; NP.sub.--005491.1),
N-terminally His-tagged SAE.beta. (UBA2; NP.sub.--005490.1),
N-terminally His-tagged murine UAE (UBE1X; NP.sub.--033483).
NAE.alpha./His-NAE.beta. and SAE.alpha./His-SAE.beta. complexes
were generated by co-infection of Sf9 cells, which were harvested
after 48 hours. His-mUAE was generated by single infection of Sf9
cells and harvested after 72 hours. Expressed proteins were
purified by affinity chromatography (Ni-NTA agarose, Qiagen) using
standard buffers.
Generation of E2 Enzymes
[0540] Ubc12 (UBE2M; NP.sub.--003960.1), Ubc9 (UBE2I;
NP.sub.--003336.1), Ubc2 (UBE2A; NP.sub.--003327.2) were subcloned
into pGEX (Pharmacia) and expressed as N-terminally GST tagged
fusion proteins in E. coli. Expressed proteins were purified by
conventional affinity chromatography using standard buffers.
Generation of Ubl Proteins
[0541] Nedd8 (NP.sub.--006147), Sumo-1 (NP.sub.--003343) and
Ubiquitin (with optimized codons) were subcloned into pFLAG-2
(Sigma) and expressed as N-terminally Flag tagged fusion proteins
in E. coli. Expressed proteins were purified by conventional
chromatography using standard buffers.
Example 70
E1 Enzyme Assays
Nedd8-Activating Enzyme (NAE) HTRF Assay.
[0542] The NAE enzymatic reaction totaled 50 .mu.L and contained 50
mM HEPES (pH 7.5), 0.05% BSA, 5 mM MgCl.sub.2, 20 .mu.M ATP, 250
.mu.M GSH, 0.01 .mu.M Ubc12-GST, 0.075 .mu.M Nedd8-Flag and 0.28 nM
recombinant human NAE enzyme. The enzymatic reaction mixture, with
and without compound inhibitor, was incubated at 24.degree. C. for
90 minutes in a 384-well plate before termination with 25 .mu.L of
Stop/Detection buffer (0.1M HEPES pH 7.5, 0.05% Tween20, 20 mM
EDTA, 410 mM KF, 0.53 nM Europium-Cryptate labeled monoclonal
anti-FLAG M2 antibody (CisBio International) and 8.125 .mu.g/mL
PHYCOLINK goat anti-GST allophycocyanin (XL-APC) antibody
(Prozyme)). After incubation for 3 hours at 24.degree. C.,
quantification of the FRET was performed on the Analyst.TM. HT
96.384 (Molecular Devices).
[0543] Compounds I-1 to I-54, I-56, I-59, I-61 to I-76, and I-79 to
I-85 exhibited IC.sub.50 values less than or equal to 10 .mu.M in
this assay. Compounds I-1, I-2, I-3, I-4, I-6, I-7, I-8, I-12,
I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-21, I-22, I-23, I-24,
I-25, I-26, I-27, I-28, I-29, I-30, I-31, I-32, I-33, I-34, I-35,
I-36, I-37, I-38, I-39, I-40, I-41, I-42, I-43, I-44, I-45, I-46,
I-47, I-48, I-49, I-50, I-51, I-52, I-54, I-56, I-59, I-61, I-62,
I-63, I-64, I-65, I-66, I-67, I-68, I-69, I-70, I-71, I-72, I-73,
I-74, I-76, I-78, I-79, I-80, I-81, I-82, I-83, I-84, and I-85
exhibited IC.sub.50 values less than or equal to 100 nM in this
assay.
Sumo-Activating Enzyme (SAE) HTRF Assay.
[0544] The SAE enzymatic reaction was conducted as outlined above
for NAE except that Ubc12-GST and Nedd8-Flag were replaced by 0.01
.mu.M Ubc9-GST and 0.125 .mu.M Sumo-Flag respectively and the
concentration of ATP was 0.5 .mu.M. Recombinant human SAE (0.11 nM)
was the source of enzyme.
Ubiquitin-Activating Enzyme (UAE) HTRF Assay.
[0545] The UAE enzymatic reaction was conducted as outlined above
for NAE except that Ubc12-GST and Nedd8-Flag were replaced by 0.005
.mu.M Ubc2-GST and 0.125 .mu.M Ubiquitin-Flag respectively and the
concentration of ATP was 0.1 .mu.M. Recombinant mouse UAE (0.3 nM)
was the source of enzyme.
Example 71
Cellular Assays
[0546] Selected compounds of formula (I) were tested in cellular
assays:
Anti-Proliferation Assay (WST)
[0547] Calu-6 (2400/well) or other tumor cells in 80 .mu.L of
appropriate cell culture medium (MEM for Calu6, Invitrogen)
supplemented with 10% fetal bovine serum (Invitrogen) was seeded in
wells of a 96-well cell culture plate and incubated for 24 hours in
a tissue culture incubator. Compound inhibitors were added in 20
.mu.L culture media to the wells and the plates was incubated for
72 hours at 37.degree. C. 10% final concentration of WST-1 reagent
(Roche) was added to each well and incubated for 3.5 hours (for
Calu6) at 37.degree. C. The optical density for each well was read
at 450 nm using a spectrophotometer (Molecular Devices). Percent
inhibition was calculated using the values from a DMSO control set
to 100% viability.
Anti-Proliferation Assay (ATPLite)
[0548] Calu-6 (1500 cells/well) or other tumor cells were seeded in
72 .mu.L of appropriate cell culture medium (MEM for Calu6,
Invitrogen) supplemented with 10% fetal bovine serum (Invitrogen)
in wells of a 384-well Poly-D-Lysine coated cell culture plate.
Compound inhibitors were added in 8 .mu.L 10% DMSO/PBS to the wells
and the plates were incubated for 72 hours at 37.degree. C. Cell
culture medium was aspirated, leaving 25 .mu.L in each well. 25
.mu.L of ATPlite 1step.TM. reagent (Perkin Elmer) was added to each
well. The luminescence for each well was read using the LeadSeeker
Microplate Reader (Molecular Devices). Percent inhibition was
calculated using the values from a DMSO control set to 100%
viability.
Example 72
In Vivo Assays
[0549] Selected compounds of formula (I) were tested in in vivo
assays.
In Vivo Tumor Efficacy Model
[0550] Calu6 (5.times.10.sup.6 cells), HCT116 (2.times.10.sup.6
cells) or other tumor cells in 100 .mu.L phosphate buffered saline
were aseptically injected into the subcutaneous space in the right
dorsal flank of female Ncr nude mice (age 5-8 weeks, Charles River)
using a 26-gauge needle. Beginning on day 7 after inoculation,
tumors were measured twice weekly using a vernier caliper. Tumor
volumes were calculated using standard procedures
(0.5.times.(length.times.width.sup.2)). When the tumors reached a
volume of approximately 200 mm.sup.3 mice were randomized into
groups and injected intravenously in the tail vein with compound
inhibitor (100 .mu.L) at various doses and schedules.
Alternatively, compound inhibitor may be delivered to mice by
intraperitoneal or subcutaneous injection or oral administration.
All control groups received vehicle alone. Tumor size and body
weight was measured twice a week and the study terminated when the
control tumors reached approximately 2000 mm.sup.3.
[0551] The patent and scientific literature referred to herein
establishes knowledge that is available to those with skill in the
art. Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. The
issued patents, applications, and references that are cited herein
are hereby incorporated by reference to the same extent as if each
was specifically and individually indicated to be incorporated by
reference. In the case of inconsistencies, the present disclosure,
including definitions, will control.
[0552] While a number of embodiments of this invention have been
described, it is apparent that the provided basic examples may be
altered to convey other embodiments, which utilize the compounds
and methods of this invention. It will thus be appreciated that the
scope of this invention has been represented herein by way of
example and is not intended to be limited by the specific
embodiments, rather is defined by the appended claims.
* * * * *