U.S. patent application number 12/564156 was filed with the patent office on 2010-06-24 for compounds useful as inhibitors of janus kinases.
This patent application is currently assigned to Vertex Pharmaceuticals Incorporated. Invention is credited to Alex Aronov, Randy Bethiel, Luc Farmer, Emilie Porter Huck, Mark Ledeboer, Brian Ledford, Gabriel Martinez-Botella, Albert Pierce, Francesco Salituro, Jian Wang, Tiansheng Wang, Marion W. Wannamaker.
Application Number | 20100160287 12/564156 |
Document ID | / |
Family ID | 39730636 |
Filed Date | 2010-06-24 |
United States Patent
Application |
20100160287 |
Kind Code |
A1 |
Wannamaker; Marion W. ; et
al. |
June 24, 2010 |
COMPOUNDS USEFUL AS INHIBITORS OF JANUS KINASES
Abstract
The present invention relates to compounds useful as inhibitors
of protein kinases, particularly of JAK family kinases. The
invention also provides pharmaceutically acceptable compositions
comprising said compounds and methods of using the compositions in
the treatment of various disease, conditions, or disorders.
Inventors: |
Wannamaker; Marion W.;
(Bolton, MA) ; Salituro; Francesco; (Marlborough,
MA) ; Pierce; Albert; (Cambridge, MA) ;
Aronov; Alex; (Newton, MA) ; Martinez-Botella;
Gabriel; (Wayland, MA) ; Wang; Jian; (Newton,
MA) ; Farmer; Luc; (Foxboro, MA) ; Ledeboer;
Mark; (Acton, MA) ; Wang; Tiansheng; (Concord,
MA) ; Bethiel; Randy; (Lexington, MA) ;
Ledford; Brian; (Attleboro, MA) ; Huck; Emilie
Porter; (Sudbury, MA) |
Correspondence
Address: |
VERTEX PHARMACEUTICALS INC.
130 WAVERLY STREET
CAMBRIDGE
MA
02139-4242
US
|
Assignee: |
Vertex Pharmaceuticals
Incorporated
Cambridge
MA
|
Family ID: |
39730636 |
Appl. No.: |
12/564156 |
Filed: |
September 22, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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PCT/US08/57797 |
Mar 21, 2008 |
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12564156 |
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60919469 |
Mar 22, 2007 |
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Current U.S.
Class: |
514/210.18 ;
435/375; 514/249; 514/256; 514/275; 544/295; 544/324; 544/327;
544/328 |
Current CPC
Class: |
A61P 9/00 20180101; A61P
37/00 20180101; C07D 401/14 20130101; C07D 401/04 20130101; A61P
35/02 20180101; C07D 471/04 20130101; A61P 25/18 20180101; C07D
213/74 20130101; C07D 403/12 20130101; A61P 35/00 20180101; A61P
37/06 20180101; A61P 37/08 20180101; C07D 417/14 20130101; A61P
7/00 20180101; A61P 37/04 20180101; C07D 403/04 20130101; C07D
403/14 20130101; A61P 31/12 20180101; A61P 1/16 20180101; A61P
19/02 20180101; A61P 25/14 20180101; C07D 417/04 20130101; A61P
9/10 20180101; A61P 21/02 20180101; C07D 405/04 20130101; A61P 9/04
20180101; A61P 25/28 20180101; A61P 3/10 20180101; A61P 25/00
20180101; A61P 25/16 20180101; A61P 19/08 20180101; A61P 31/18
20180101; C07D 417/12 20130101; A61P 11/06 20180101; A61P 17/06
20180101; A61P 29/00 20180101; A61P 43/00 20180101; C07D 239/42
20130101; A61P 17/14 20180101; A61P 37/02 20180101 |
Class at
Publication: |
514/210.18 ;
544/328; 514/256; 544/324; 514/275; 544/327; 544/295; 514/249;
435/375 |
International
Class: |
A61K 31/506 20060101
A61K031/506; C07D 401/04 20060101 C07D401/04; C07D 403/04 20060101
C07D403/04; C07D 417/10 20060101 C07D417/10; C07D 403/10 20060101
C07D403/10; C07D 405/10 20060101 C07D405/10; A61P 35/00 20060101
A61P035/00; A61P 9/00 20060101 A61P009/00; A61P 19/08 20060101
A61P019/08; A61P 37/06 20060101 A61P037/06; A61P 29/00 20060101
A61P029/00; A61P 37/00 20060101 A61P037/00; A61P 31/12 20060101
A61P031/12; C12N 5/00 20060101 C12N005/00 |
Claims
1. A compound of formula (I): ##STR00205## or a pharmaceutically
acceptable salt thereof, wherein: X.sup.1 is N or CR.sup.1; X.sup.2
is N or CR.sup.2; wherein no more than one of X.sup.1 or X.sup.2 is
N; X.sup.3 is N or CR.sup.23; X.sup.4 is N or CR.sup.24; wherein at
least one of X.sup.3 and X.sup.4 is N; R.sup.1 is H, halo, R', OH,
OR', COR', COOH, COOR', CONH.sub.2, CONHR', CON(R').sub.2, or CN;
R.sup.2 is H, halo, R', OH, OR', COR', COOH, COOR', CONH.sub.2,
CONHR', CON(R').sub.2, or CN; or R.sup.1 and R.sup.2, taken
together, form a 5-7 membered aryl or heteroaryl ring optionally
substituted with 1-4 occurrences of R.sup.9; each R.sup.9 is
independently selected from halogen, OCH.sub.3, OH, NO.sub.2,
NH.sub.2, SH, SCH.sub.3, NCH.sub.3, CN or unsubstituted
C.sub.1-2aliphatic; R.sup.23 is H, halo, R', OH, OR', COR', COOH,
COOR', CONH.sub.2, CONHR', CON(R').sub.2, or CN; R.sup.24 is H,
halo, R', OH, OR', COR', COOH, COOR', CONH.sub.2, CONHR',
CON(R').sub.2, or CN; R' is a C.sub.1-3 aliphatic optionally
substituted with 1-4 occurrences of R.sup.10; each R.sup.10 is
independently selected from halogen, CF.sub.3, OCH.sub.3, OH, SH,
NO.sub.2, NH.sub.2, SCH.sub.3, NCH.sub.3, CN or unsubstituted
C.sub.1-2 aliphatic, or two R.sup.10 groups, together with the
carbon to which they are attached, form a cyclopropyl ring or
C.dbd.O; R.sup.3 is selected from ##STR00206## ##STR00207##
##STR00208## ##STR00209## ##STR00210## ##STR00211## ##STR00212##
##STR00213## ##STR00214## R.sup.19 is selected from H; a C.sub.3-7
cycloaliphatic optionally substituted with 1-4 occurrences of
halogen, OH, NO.sub.2, NH.sub.2, SH or CN; or a C.sub.1-6
aliphatic, wherein up to two methylene units of said C.sub.1-6
aliphatic are optionally and independently replaced by G.sup.R and
wherein said C.sub.1-6 aliphatic is optionally substituted with 1-4
R.sup.20; G.sup.R is --NH--, --NR.sup.21--, --O--, --O--,
--CO.sub.2--, --OC(O)--, --C(O)CO--, --C(O)--, --C(O)NH--,
--C(O)NR.sup.21--, --NC(.dbd.N--CN)N--, --NHCO--, --NR.sup.21CO--,
--NHC(O)O--, --NR.sup.21C(O)O--, --SO.sub.2NH--,
--SO.sub.2NR.sup.21--, --NHSO.sub.2--, --NR.sup.21SO.sub.2--,
--NHC(O)NH--, --NR.sup.21C(O)NH--, --NHC(O)NR.sup.21--,
--NR.sup.21C(O)NR.sup.21, --OC(O)NH--, --OC(O)NR.sup.21--,
--NHSO.sub.2NH--, --NR.sup.21SO.sub.2NH--, --NHSO.sub.2NR.sup.21--,
--NR.sup.21SO.sub.2NR.sup.21--, --SO--, or --SO.sub.2--; R.sup.21
is C.sub.1-6 aliphatic or C.sub.3-7 cycloaliphatic optionally
substituted with 1-6 occurrences of halogen, N(R.sup.X).sub.2,
R.sup.X, --OR.sup.X, --SR.sup.X, --NO.sub.2, --CF.sub.3, --CN,
--CO.sub.2R.sup.X, --COR.sup.X, OCOR.sup.X, CONHR.sup.X, or
NHCOR.sup.X; each R.sup.X is independently selected from H or an
unsubstituted C.sub.1-6 aliphatic; each R.sup.20 is independently
selected from halogen, OH, OR.sup.22, NO.sub.2, NH.sub.2,
NHR.sup.22, N(R.sup.22).sub.2, SH, SR.sup.22, CN, or R.sup.22; or
two R.sup.20, together with the carbon(s) to which they are
attached, form a cyclopropyl ring or C.dbd.O; each R.sup.22 is
independently selected from a C.sub.1-6 aliphatic or C.sub.3-7
cycloaliphatic optionally substituted with 1-6 occurrences of
halogen, OH, NO.sub.2, NH.sub.2, SH or CN; R.sup.25 is
--(U).sub.m--Y; U is a C.sub.1-6 aliphatic, wherein up to two
methylene units are optionally and independently replaced by
G.sup.U and wherein U is optionally substituted with 1-4 J.sup.U;
G.sup.U is --NH--, --NR.sup.26--, --O--, --O--, --CO.sub.2--,
--OC(O)--, --C(O)CO--, --C(O)--, --C(O)NH--, --C(O)NR.sup.26--,
--NC(.dbd.N--CN)N--, --NHCO--, --NR.sup.26CO--, --NHC(O)O--,
--NR.sup.26C(O)O--, --SO.sub.2NH--, --SO.sub.2NR.sup.26--,
--NHSO.sub.2--, --NR.sup.26SO.sub.2--, --NHC(O)NH--,
--NR.sup.26C(O)NH--, --NHC(O)NR.sup.26--, --NR.sup.26C(O)NR.sup.26,
--OC(O)NH--, --OC(O)NR.sup.26--, --NHSO.sub.2NH--,
--NR.sup.26SO.sub.2NH--, --NHSO.sub.2NR.sup.26--,
--NR.sup.26SO.sub.2NR.sup.26--, --SO--, or --SO.sub.2--; R.sup.26
is a C.sub.1-6 aliphatic, C.sub.3-10 cycloaliphatic, C.sub.6-10
aryl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl;
wherein said aliphatic, cycloaliphatic, aryl, heteroaryl or
heterocyclyl is optionally substituted with halogen, R.sup.X,
--OR.sup.X, --SR.sup.X, --NO.sub.2, --CF.sub.3, --CN,
--CO.sub.2R.sup.X, --COR.sup.X, OCOR.sup.X, CONHR.sup.X, or
NHCOR.sup.X; each J.sup.U is independently selected from halogen,
L, -(L.sub.n)-R', -(L.sub.n)-N(R').sub.2, -(L.sub.n)-SR',
-(L.sub.n)-OR', -(L.sub.n)-(C.sub.3-10 cycloaliphatic),
-(L.sub.n)-(C.sub.6-10 aryl), -(L.sub.n)-(5-10 membered
heteroaryl), -(L.sub.n)-(5-10 membered heterocyclyl), oxo,
C.sub.1-4haloalkoxy, C.sub.1-4haloalkyl, -(L.sub.n)-NO.sub.2,
-(L.sub.n)-CN, -(L.sub.n)-OH, -(L.sub.n)-CF.sub.3, --CO.sub.2R',
--CO.sub.2H, --COR', --COH, --OC(O)R', --C(O)NHR', C(O)N(R').sub.2,
--NHC(O)R', or NR'C(O)R'; or two J.sup.U groups, on the same
substituent or different substituents, together with the atom(s) to
which each J.sup.U group is bound, form a 5-7 membered saturated,
unsaturated, or partially saturated ring; m is 0 or 1; Y is H,
halogen, CN, NO.sub.2, NH.sub.2, NHR, N(R).sub.2, or a group
selected from a C.sub.1-6 aliphatic, a C.sub.3-10 cycloaliphatic, a
C.sub.6-10 aryl, a 5-10 membered heteroaryl, or a 5-10 membered
heterocyclyl, wherein said group is optionally substituted with 1-8
occurrences of J.sup.Y; each J.sup.Y is independently selected from
halogen, L, -(L.sub.n)-R.sup.26, -(L.sub.n)-N(R.sup.26).sub.2,
-(L.sub.n)-SR.sup.26, -(L.sub.n)-OR.sup.26, -(L.sub.n)-(C.sub.3-10
cycloaliphatic), -(L.sub.n)-(C.sub.6-10 aryl), -(L.sub.n)-(5-10
membered heteroaryl), -(L.sub.n)-(5-10 membered heterocyclyl), oxo,
C.sub.1-4haloalkoxy, C.sub.1-4haloalkyl, -(L.sub.n)-NO.sub.2,
-(L.sub.n)-CN, -(L)-OH, -(L.sub.n)-CF.sub.3, --CO.sub.2R.sup.26,
--CO.sub.2H, --COR.sup.26, --COH, --OC(O)R.sup.26,
--C(O)NHR.sup.26, C(O)N(R.sup.26).sub.2, --NHC(O)R.sup.26, or
NR.sup.26C(O)R.sup.26; or two J.sup.Y groups, on the same
substituent or different substituents, together with the atom(s) to
which each J.sup.Y group is bound, form a 5-7 membered saturated,
unsaturated, or partially saturated ring; each L is independently a
C.sub.1-6 aliphatic wherein up to three methylene units are
replaced by --NH--, --NR.sup.L--, --O--, --O--, --CO.sub.2--,
--OC(O)--, --C(O)CO--, --C(O)--, --C(O)NH--, --C(O)NR.sup.L--,
--NC(.dbd.N--CN)N, --NHCO--, --NR.sup.LCO--, --NHC(O)O--,
--NR.sup.LC(O)O--, --SO.sub.2NH--, --SO.sub.2NR.sup.L--,
--NHSO.sub.2--, --NR.sup.LSO.sub.2--, --NHC(O)NH--,
--NR.sup.LC(O)NH--, --NHC(O)NR.sup.L--, --NR.sup.LC(O)NR.sup.L,
--OC(O)NH--, --OC(O)NR.sup.L--, --NHSO.sub.2NH--,
--NR.sup.LSO.sub.2NH--, --NHSO.sub.2NR.sup.L--,
--NR.sup.LSO.sub.2NR.sup.L--, --SO--, or --SO.sub.2--; each n is
independently 0 or 1; R.sup.L is selected from C.sub.1-6 aliphatic,
C.sub.3-10 cycloaliphatic, C.sub.6-10 aryl, 5-10 membered
heteroaryl, or 5-10 membered heterocyclyl; or two R.sup.L groups,
on the same substituent or different substituents, together with
the atom(s) to which each R.sup.L group is bound, form a 3-8
membered heterocyclyl; each R is independently selected from a
C.sub.1-6 aliphatic or a C.sub.3-6 cycloaliphatic optionally
substituted with 1-6 occurrences of halogen, OH, NO.sub.2,
NH.sub.2, SH or CN, or two R groups, together with the atom to
which the R groups are bound, form a 5-7 membered saturated,
unsaturated, or partially saturated ring; wherein each
substitutable carbon of an R.sup.3 ring is optionally and
independently substituted with halogen; --R.degree.; --OR.degree.;
--SR.degree.; 1,2-methylenedioxy; 1,2-ethylenedioxy; phenyl (Ph)
optionally substituted with R.degree.; --O(Ph) optionally
substituted with R.degree.; --(CH.sub.2).sub.1-2(Ph), optionally
substituted with R.degree.; --CH.dbd.CH(Ph), optionally substituted
with R.degree.; --NO.sub.2; --CN; --N(R.degree.).sub.2;
--NR.degree.C(O)R.degree.; --NR.degree.C(S)R.degree.;
--NR.degree.C(O)N(R.degree.).sub.2;
--NR.degree.C(S)N(R.degree.).sub.2; --NR.degree.CO.sub.2R.degree.;
--NR.degree.NR.degree.C(O)R.degree.;
--NR.degree.NR.degree.C(O)N(R.degree.).sub.2;
--NR.degree.NR.degree.CO.sub.2R.degree.; --C(O)C(O)R.degree.;
--C(O)CH.sub.2C(O)R.degree.; --CO.sub.2R.degree.; --C(O)R.degree.;
--C(S)R.degree.; --C(O)N(R.degree.).sub.2;
--C(S)N(R.degree.).sub.2; --OC(O)N(R.degree.).sub.2;
--OC(O)R.degree.; --C(O)N(OR.degree.)R.degree.;
--C(NOR.degree.)R.degree.; --S(O).sub.2R.degree.;
--S(O).sub.3R.degree.; --SO.sub.2N(R.degree.).sub.2;
--S(O)R.degree.; --NR.degree.SO.sub.2N(R.degree.).sub.2;
--NR.degree.SO.sub.2R.degree.; --N(OR.degree.)R.degree.;
--C(.dbd.NH)--N(R.degree.).sub.2; or
--(CH.sub.2).sub.0-2NHC(O)R.degree.; wherein each independent
occurrence of R.degree. is selected from hydrogen, optionally
substituted C.sub.1-6 aliphatic, an unsubstituted 5-6 membered
heteroaryl or heterocyclic ring, phenyl, --O(Ph), or
--CH.sub.2(Ph), or, two independent occurrences of R.degree., on
the same substituent or different substituents, taken together with
the atom(s) to which each R.degree. group is bound, form a
5-8-membered heterocyclyl, aryl, or heteroaryl ring or a
3-8-membered cycloalkyl ring, wherein said heteroaryl or
heterocyclyl ring has 1-3 heteroatoms independently selected from
nitrogen, oxygen, or sulfur; and wherein each of said optional
substituents on the aliphatic group of R.degree. is independently
selected from NH.sub.2, NH(C.sub.1-4aliphatic),
N(C.sub.1-4aliphatic).sub.2, halogen, C.sub.1-4aliphatic, OH,
O(C.sub.1-4aliphatic), NO.sub.2, CN, CO.sub.2H,
CO.sub.2(C.sub.1-4aliphatic), O(haloC.sub.1-4 aliphatic), or
haloC.sub.1-4aliphatic, wherein each of the foregoing
C.sub.1-4aliphatic groups of R.degree. is unsubstituted; wherein
each substitutable nitrogen of a non-aromatic heterocyclic ring of
R.sup.3 is optionally and independently substituted with --R.sup.+,
--N(R.sup.+).sub.2, --C(O)R.sup.+, --CO.sub.2R.sup.+,
--C(O)C(O)R.sup.+, --C(O)CH.sub.2C(O)R.sup.+, --SO.sub.2R.sup.+,
--SO.sub.2N(R.sup.+).sub.2, --C(.dbd.S)N(R.sup.+).sub.2,
--C(.dbd.NH)--N(R.sup.+).sub.2, or --NR.sup.+SO.sub.2R.sup.+;
wherein R.sup.+ is hydrogen, an optionally substituted C.sub.1-6
aliphatic, optionally substituted phenyl, optionally substituted
--O(Ph), optionally substituted --CH.sub.2(Ph), optionally
substituted --(CH.sub.2).sub.1-2(Ph); optionally substituted
--CH.dbd.CH(Ph); or an unsubstituted 5-6 membered heteroaryl or
heterocyclic ring having one to four heteroatoms independently
selected from oxygen, nitrogen, or sulfur, or, two independent
occurrences of R.sup.+, on the same substituent or different
substituents, taken together with the atom(s) to which each R.sup.+
group is bound, form a 5-8-membered heterocyclyl, aryl, or
heteroaryl ring or a 3-8-membered cycloalkyl ring, wherein said
heteroaryl or heterocyclyl ring has 1-3 heteroatoms independently
selected from nitrogen, oxygen, or sulfur; wherein each of said
optional substituents on the aliphatic group or the phenyl ring of
R.sup.+ is independently selected from NH.sub.2, NH(C.sub.1-4
aliphatic), N(C.sub.1-4 aliphatic).sub.2, halogen, C.sub.1-4
aliphatic, OH, O(C.sub.1-4 aliphatic), NO.sub.2, CN, CO.sub.2H,
CO.sub.2(C.sub.1-4 aliphatic), O(halo C.sub.1-4 aliphatic), or
halo(C.sub.1-4aliphatic), wherein each of the foregoing
C.sub.1-4aliphatic groups of R.sup.+ is unsubstituted; R.sup.4 is H
or is a --C.sub.1-2 aliphatic optionally substituted with 1-3
occurrences of R.sup.11; each R.sup.11 is independently selected
from halogen, CF.sub.3, OCH.sub.3, OH, SH, NO.sub.2, NH.sub.2,
SCH.sub.3, NCH.sub.3, CN, CON(R.sup.15).sub.2 or unsubstituted
C.sub.1-2 aliphatic, or two R.sup.11 groups, together with the
carbon to which they are attached, form a cyclopropyl ring or
C.dbd.O; R.sup.15 is H or unsubstituted C.sub.1-2 alkyl; R.sup.5 is
H or a C.sub.1-6 aliphatic optionally substituted with 1-5
occurrences of R.sup.12; R.sup.6 is H or a C.sub.1-6 aliphatic
optionally substituted with 1-5 occurrences of R.sup.13; each
R.sup.12 is independently selected from halogen, OCH.sub.3, OH,
NO.sub.2, NH.sub.2, SH, SCH.sub.3, NCH.sub.3, CN or unsubstituted
C.sub.1-2aliphatic, or two R.sup.12 groups, together with the
carbon to which they are attached, form a cyclopropyl ring; each
R.sup.13 is independently selected from halogen, OCH.sub.3, OH,
NO.sub.2, NH.sub.2, SH, SCH.sub.3, NCH.sub.3, CN or unsubstituted
C.sub.1-2aliphatic, or two R.sup.13 groups, together with the
carbon to which they are attached, form a cyclopropyl ring; or
R.sup.5 and R.sup.6 are taken together to form a 3-7 membered
carbocyclic or heterocyclic saturated ring optionally substituted
with 1-5 occurrences of R.sup.12; or R.sup.4 and R.sup.6, taken
together with the nitrogen to which R.sup.4 is attached, form a 3-8
membered saturated, partially saturated or aromatic
nitrogen-containing ring comprising up to two additional
heteroatoms selected from N, O or S and optionally substituted with
1-4 occurrences of R.sup.14; or R.sup.1 and R.sup.4, taken together
with the nitrogen to which R.sup.4 is attached, form a 3-8 membered
saturated, partially saturated or aromatic nitrogen-containing ring
comprising up to two additional heteroatoms selected from N, O or S
and optionally substituted with 1-4 occurrences of R.sup.14; or
each R.sup.14 is independently selected from halogen, R'',
NH.sub.2, NHR'', N(R'').sub.2, SH, SR'', OH, OR'', NO.sub.2, CN,
CF.sub.3, COOR'', COOH, COR'', OC(O)R'' or NC(O)R''; or any two
R.sup.14 groups, on the same substituent or different substituents,
together with the atom(s) to which each R.sup.14 group is bound,
form a 3-7 membered saturated, unsaturated, or partially saturated
carbocyclic or heterocyclic ring optionally substituted with 1-3
occurrences of R.sup.16; R'' is a C.sub.1-3 aliphatic optionally
substituted with 1-4 occurrences of R.sup.10; each R.sup.16 is
independently selected from halogen, CF.sub.3, OCH.sub.3, OH, SH,
NO.sub.2, NH.sub.2, SCH.sub.3, NCH.sub.3, CN, CON(R.sup.15).sub.2
or unsubstituted C.sub.1-2 aliphatic, or two R.sup.16 groups,
together with the carbon to which they are attached, form a
cyclopropyl ring or C.dbd.O; R.sup.7 is H or C.sub.1-4 aliphatic
optionally substituted with 1-3 occurrences of R.sup.17; each
R.sup.17 is independently selected from halogen, CF.sub.3,
OCH.sub.3, OH, SH, NO.sub.2, NH.sub.2, SCH.sub.3, NCH.sub.3, CN,
CON(R.sup.15).sub.2 or unsubstituted C.sub.1-2 aliphatic, or two
R.sup.17 groups, together with the carbon to which they are
attached, form a cyclopropyl ring or C.dbd.O; R.sup.8 is C.sub.1-4
aliphatic optionally substituted with 1-6 occurrences of R.sup.18;
and each R.sup.18 is independently selected from halogen, CF.sub.3,
OCH.sub.3, OH, SH, NO.sub.2, NH.sub.2, SCH.sub.3, NCH.sub.3, CN,
CON(R.sup.15).sub.2 or unsubstituted C.sub.1-2 aliphatic, or two
R.sup.18 groups, together with the carbon to which they are
attached, form a cyclopropyl ring or C.dbd.O.
2. The compound according to claim 1, wherein said compound is
selected from one of formulae I-a to I-i: ##STR00215##
##STR00216##
3. The compound according to claim 2, wherein said compound is
selected from one of formulae I-a, I-b, I-c or I-d.
4. The compound according to claim 3, wherein said compound is
selected from one of formulae I-c or I-d.
5. The compound according to claim 2, wherein said compound is
selected from one of formulae I-a, I-b, I-c, I-f, I-g or I-i and
R.sup.1 is H, Cl, F, R', OH or OR'.
6. The compound according to claim 5, wherein R.sup.1 is H,
CH.sub.3, Cl or F.
7. The compound according to claim 2, wherein said compound is
selected from one of formulae I-a, I-b, I-c, I-d, I-e or I-h, and
R.sup.2 is H, Cl, F, R', OH or OR'.
8. The compound according to claim 7, wherein R.sup.2 is H,
CH.sub.3, Cl or F.
9. The compound according to claim 2, wherein said compound is of
formula I-c, and R.sup.1 is H, Cl or F and R.sup.2 is H.
10-16. (canceled)
17. The compound according to claim 1, wherein R.sup.4 is H,
CH.sub.3, CH.sub.2CH.sub.3 or CH(CH.sub.3).sub.2.
18. The compound according to claim 17, wherein R.sup.4 is H or
CH.sub.3.
19. The compound according to claim 18, wherein R.sup.4 is H.
20. (canceled)
21. The compound according to claim 1, wherein R.sup.5 is H or a
C.sub.1-2 alkyl optionally substituted with up to 3 occurrences of
R.sup.12.
22. The compound according to claim 21, wherein R.sup.5 is H or a
C.sub.1-2 alkyl.
23. The compound according to claim 1, wherein R.sup.6 is a
C.sub.1-4 aliphatic optionally substituted with 1-5 occurrences of
R.sup.13.
24-31. (canceled)
32. The compound according to claim 1, wherein R.sup.4 and R.sup.6,
taken together with the nitrogen to which R.sup.4 is attached, form
a 3-8 membered saturated, partially saturated or aromatic
nitrogen-containing ring comprising up to two additional
heteroatoms selected from N, O or S and optionally substituted with
1-4 occurrences of R.sup.14.
33-40. (canceled)
41. The compound according to claim 1, wherein R.sup.7 is H or
C.sub.1-2 alkyl optionally substituted with 1-3 occurrences of
R.sup.17.
42. (canceled)
43. The compound according to claim 1, wherein R.sup.8 is a
C.sub.1-4 aliphatic or cycloaliphatic optionally substituted with
up to 6 occurrences of R.sup.18.
44-48. (canceled)
49. The compound according to claim 1, wherein R.sup.3 is selected
from (1-a), (1-c), (1-k), (2-d), (2-e), (2-k), (2-w), (2-x), (3-d),
(3-e), (3-g), (3-h), (3-i) and (3-j).
50. The compound according to claim 49, wherein R.sup.3 is selected
from (1-a), (1-c), (1-k), (2-d), (2-e), (2-n), (2-o), (2-u), (2-x)
and (2-z).
51. The compound according to claim 50, wherein R.sup.3 is selected
from (1-a), (1-c), (2-d), (2-e), (2-n), (2-o), (2-u) and (2-x).
52. The compound according to claim 51, wherein R.sup.3 is selected
from (1-c), (2-d), (2-n) and (2-o).
53. The compound according to claim 1, wherein R.sup.3 is
unsubstituted.
54. The compound according to claim 1, wherein up to two
substitutable carbons and up to one substitutable nitrogens of a
non-aromatic heterocyclic ring of the R.sup.3 ring are
substituted.
55. The compound according to claim 54, wherein one substitutable
carbon and up to one substitutable nitrogens of a non-aromatic
heterocyclic ring of the R.sup.3 ring are substituted.
56. The compound according to claim 55, wherein one substitutable
carbon of the R.sup.3 ring is substituted.
57. The compound according to claim 52, wherein R.sup.3 is (2-n)
and R.sup.25 is C(O)NR.sub.2.
58. The compound according to claim 52, wherein R.sup.3 is (2-o)
and R.sup.25 is an optionally substituted aryl or heteroaryl.
59. The compound according to claim 58, wherein R.sup.25 is an
optionally substituted phenyl.
60. The compound according to claim 52, wherein R.sup.3 is (1-c) or
(2-d) and R.sup.3 is unsubstituted.
61. The compound according to claim 1, wherein said compound is
selected from Table 1.
62. A pharmaceutical composition comprising a compound according to
claim 1 and a pharmaceutically acceptable carrier, adjuvant, or
vehicle.
63. The composition according to claim 62, additionally comprising
a therapeutic agent selected from a chemotherapeutic or
anti-proliferative agent, an anti-inflammatory agent, an
immunomodulatory or immunosuppressive agent, a neurotrophic factor,
an agent for treating cardiovascular disease, an agent for treating
destructive bone disorders, an agent for treating liver disease, an
anti-viral agent, an agent for treating blood disorders, an agent
for treating diabetes, or an agent for treating immunodeficiency
disorders.
64. A method of inhibiting JAK kinase activity in a biological
sample, comprising contacting said biological sample with a
compound according to claim 1.
65. A method of inhibiting JAK kinase activity in a patient,
comprising administering to said patient a compound according to
claim 1.
66. A method of treating or lessening the severity of a disease of
condition selected from a proliferative disorder, a cardiac
disorder, a neurodegenerative disorder, an autoimmune disorder, a
condition associated with organ transplantation, an inflammatory
disorder, or an immunologically mediated disorder in a patient,
comprising the step of administering to said patient a compound
according to claim 1.
67-72. (canceled)
Description
TECHNICAL FIELD OF THE INVENTION
[0001] The present invention relates to compounds useful as
inhibitors of Janus kinases (JAK). The invention also provides
pharmaceutically acceptable compositions comprising the compounds
of the invention and methods of using the compositions in the
treatment of various disorders.
BACKGROUND OF THE INVENTION
[0002] The Janus kinases (JAK) are a family of tyrosine kinases
consisting of JAK1, JAK2, JAK3 and TYK2. The JAKs play a critical
role in cytokine signaling. The down-stream substrates of the JAK
family of kinases include the signal transducer and activator of
transcription (STAT) proteins. JAK/STAT signaling has been
implicated in the mediation of many abnormal immune responses such
as allergies, asthma, autoimmune diseases such as transplant
rejection, rheumatoid arthritis, psoriasis, amyotrophic lateral
sclerosis and multiple sclerosis as well as in solid and
hematologic malignancies such as leukemias and lymphomas. JAK2 has
also been implicated in myeloproliferative disorders, which include
polycythemia vera, essential thrombocythemia, chronic idiopathic
myelofibrosis, myeloid metaplasia with myelofibrosis, chronic
myeloid leukemia, chronic myelomonocytic leukemia, chronic
eosinophilic leukemia, hypereosinophilic syndrome and systematic
mast cell disease.
[0003] Accordingly, there is a great need to develop compounds
useful as inhibitors of protein kinases. In particular, it would be
desirable to develop compounds that are useful as inhibitors of JAK
family kinases.
SUMMARY OF THE INVENTION
[0004] It has now been found that compounds of this invention, and
pharmaceutically acceptable compositions thereof, are effective as
inhibitors of protein kinases, particularly the JAK family kinases.
These compounds have the general formula I:
##STR00001##
or a pharmaceutically acceptable salt thereof, wherein X.sup.1,
X.sup.2, X.sup.3, X.sup.4, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are as defined herein.
[0005] These compounds, and pharmaceutically acceptable
compositions thereof, are useful for treating or lessening the
severity of a variety of disorders, including proliferative
disorders, cardiac disorders, neurodegenerative disorders,
autoimmune disorders, conditions associated with organ
transplantation, inflammatory disorders, or immunologically
mediated disorders in a patient.
[0006] The compounds and compositions provided by this invention
are also useful for the study of JAK kinases in biological and
pathological phenomena; the study of intracellular signal
transduction pathways mediated by such kinases; and the comparative
evaluation of new kinase inhibitors.
DETAILED DESCRIPTION OF THE INVENTION
Definitions and General Terminology
[0007] As used herein, the following definitions shall apply unless
otherwise indicated. For purposes of this invention, the chemical
elements are identified in accordance with the Periodic Table of
the Elements, CAS version, and the Handbook of Chemistry and
Physics, 75.sup.th Ed. 1994. Additionally, general principles of
organic chemistry are described in "Organic Chemistry", Thomas
Sorrell, University Science Books, Sausalito: 1999, and "March's
Advanced Organic Chemistry", 5.sup.th Ed., Smith, M. B. and March,
J., eds. John Wiley & Sons, New York: 2001, the entire contents
of which are hereby incorporated by reference.
[0008] As described herein, compounds of the invention may
optionally be substituted with one or more substituents, such as
are illustrated generally above, or as exemplified by particular
classes, subclasses, and species of the invention. It will be
appreciated that the phrase "optionally substituted" is used
interchangeably with the phrase "substituted or unsubstituted." In
general, the term "substituted", whether preceded by the term
"optionally" or not, refers to the replacement of one or more
hydrogen radicals in a given structure with the radical of a
specified substituent. Unless otherwise indicated, an optionally
substituted group may have a substituent at each substitutable
position of the group. When more than one position in a given
structure can be substituted with more than one substituent
selected from a specified group, the substituent may be either the
same or different at each position.
[0009] As described herein, when the term "optionally substituted"
precedes a list, said term refers to all of the subsequent
substitutable groups in that list. If a substituent radical or
structure is not identified or defined as "optionally substituted",
the substituent radical or structure is unsubstituted. For example,
if X is halogen; optionally substituted C.sub.1-3alkyl or phenyl; X
may be either optionally substituted alkyl or optionally
substituted phenyl. Likewise, if the term "optionally substituted"
follows a list, said term also refers to all of the substitutable
groups in the prior list unless otherwise indicated. For example:
if X is halogen, C.sub.1-3alkyl or phenyl wherein X is optionally
substituted by J.sup.X, then both C.sub.1-3alkyl and phenyl may be
optionally substituted by J.sup.X. As is apparent to one having
ordinary skill in the art, groups such as H, halogen, NO.sub.2, CN,
NH.sub.2, OH, or OCF.sub.3 would not be included because they are
not substitutable groups.
[0010] Combinations of substituents envisioned by this invention
are preferably those that result in the formation of stable or
chemically feasible compounds. The term "stable", as used herein,
refers to compounds that are not substantially altered when
subjected to conditions to allow for their production, detection,
and, preferably, their recovery, purification, and use for one or
more of the purposes disclosed herein. In some embodiments, a
stable compound or chemically feasible compound is one that is not
substantially altered when kept at a temperature of 40.degree. C.
or less, in the absence of moisture or other chemically reactive
conditions, for at least a week.
[0011] The term "aliphatic" or "aliphatic group", as used herein,
means a straight-chain (i.e., unbranched) or branched, substituted
or unsubstituted hydrocarbon chain that is completely saturated or
that contains one or more units of unsaturation. Unless otherwise
specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In
some embodiments, aliphatic groups contain 1-10 aliphatic carbon
atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic
carbon atoms. In still other embodiments, aliphatic groups contain
1-6 aliphatic carbon atoms, and In yet other embodiments, aliphatic
groups contain 1-4 aliphatic carbon atoms. Suitable aliphatic
groups include, but are not limited to, linear or branched,
substituted or unsubstituted alkyl, alkenyl, or alkynyl groups.
Further examples of aliphatic groups include methyl, ethyl, propyl,
butyl, isopropyl, isobutyl, vinyl, and sec-butyl.
[0012] The term "cycloaliphatic" (or "carbocycle" or "cycloalkyl")
refers to a hydrocarbon that is completely saturated or that
contains one or more units of unsaturation, but which is not
aromatic, that has a single point of attachment to the rest of the
molecule, and wherein any individual ring in said bicyclic ring
system has 3-7 members. Unless otherwise specified, the term
"cycloaliphatic" refers to a monocyclic C.sub.3-C.sub.8 hydrocarbon
or bicyclic C.sub.8-C.sub.12 hydrocarbon. Suitable cycloaliphatic
groups include, but are not limited to, cycloalkyl, cycloalkenyl,
and cycloalkynyl. Further examples of aliphatic groups include
cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,
cyclohexenyl, cycloheptyl, and cycloheptenyl.
[0013] The term "heterocycle", "heterocyclyl" or "heterocyclic" as
used herein refers to a monocyclic, bicyclic, or tricyclic ring
system in which one or more ring members are an independently
selected heteroatom and that is completely saturated or that
contains one or more units of unsaturation, but which is not
aromatic, that has a single point of attachment to the rest of the
molecule. In some embodiments, the "heterocycle", "heterocyclyl" or
"heterocyclic" group has three to fourteen ring members in which
one or more ring members is a heteroatom independently selected
from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the
system contains 3 to 7 ring members.
[0014] Examples of heterocyclic rings include, but are not limited
to, the following monocycles: 2-tetrahydrofuranyl,
3-tetrahydrofuranyl, 2-tetrahydrothiophenyl,
3-tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino,
2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino,
1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl,
1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl,
3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl,
3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl,
5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl,
4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl,
1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl,
5-imidazolidinyl; and the following bicycles:
3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one, indolinyl,
tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolane,
benzodithiane, and 1,3-dihydro-imidazol-2-one.
[0015] The term "heteroatom" means one or more of oxygen, sulfur,
nitrogen, phosphorus, or silicon, including any oxidized form of
nitrogen, sulfur, phosphorus, or silicon, the quaternized form of
any basic nitrogen, or a substitutable nitrogen of a heterocyclic
ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in
pyrrolidinyl) or NR.sup.+ (as in N-substituted pyrrolidinyl).
[0016] The term "unsaturated", as used herein, means that a moiety
has one or more units of unsaturation.
[0017] The term "aryl" used alone or as part of a larger moiety as
in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic,
bicyclic, and tricyclic carbocyclic ring systems having a total of
six to fourteen ring members, wherein at least one ring in the
system is aromatic, wherein each ring in the system contains 3 to 7
ring members and that has a single point of attachment to the rest
of the molecule. The term "aryl" may be used interchangeably with
the term "aryl ring". Examples of aryl rings would include phenyl,
naphthyl, and anthracene.
[0018] The term "heteroaryl", used alone or as part of a larger
moiety as in "heteroaralkyl" or "heteroarylalkoxy", refers to
monocyclic, bicyclic, and tricyclic ring systems having a total of
five to fourteen ring members, wherein at least one ring in the
system is aromatic, at least one ring in the system contains one or
more heteroatoms, wherein each ring in the system contains 3 to 7
ring members and that has a single point of attachment to the rest
of the molecule. The term "heteroaryl" may be used interchangeably
with the term "heteroaryl ring" or the term "heteroaromatic".
[0019] Further examples of heteroaryl rings include the following
monocycles: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl,
4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl,
5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl,
2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g.,
3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl
(e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and
5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl),
isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl,
1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl,
and the following bicycles: benzimidazolyl, benzofuryl,
benzothiophenyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl
(e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl
(e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl).
[0020] In some embodiments, an aryl (including aralkyl, aralkoxy,
aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl
and heteroarylalkoxy and the like) group may contain one or more
substituents. Suitable substituents on the unsaturated carbon atom
of an aryl or heteroaryl group are selected from those listed in
the definitions of R.sup.2 and R.sup.4 below. Other suitable
substituents include: halogen; --R.degree.; --OR.degree.;
--SR.degree.; 1,2-methylenedioxy; 1,2-ethylenedioxy; phenyl (Ph)
optionally substituted with R.degree.; --O(Ph) optionally
substituted with R.degree.; --(CH.sub.2).sub.1-2(Ph), optionally
substituted with R.degree.; --CH.dbd.CH(Ph), optionally substituted
with R.degree.; --NO.sub.2; --CN; --N(R.degree.).sub.2;
--NR.degree.C(O)R.degree.; --NR.degree.C(S)R.degree.;
--NR.degree.C(O)N(R.degree.).sub.2;
--NR.degree.C(S)N(R.degree.).sub.2; --NR.degree.CO.sub.2R.degree.;
--NR.degree.NR.degree.C(O)R.degree.;
--NR.degree.NR.degree.C(O)N(R.degree.).sub.2;
--NR.degree.NR.degree.CO.sub.2R.degree.; --C(O)C(O)R.degree.;
--C(O)CH.sub.2C(O)R.degree.; --CO.sub.2R.degree.; --C(O)R.degree.;
--C(S)R.degree.; --C(O)N(R.degree.).sub.2;
--C(S)N(R.degree.).sub.2; --OC(O)N(R.degree.).sub.2;
--OC(O)R.degree.; --C(O)N(OR.degree.) R.degree.;
--C(NOR.degree.)R.degree.; --S(O).sub.2R.degree.;
--S(O).sub.3R.degree.; --SO.sub.2N(R.degree.).sub.2;
--S(O)R.degree.; --NR.degree.SO.sub.2N(R.degree.).sub.2;
--NR.degree.SO.sub.2R.degree.; --N(OR.degree.)R.degree.;
--C(.dbd.NH)--N(R.degree.).sub.2; or
--(CH.sub.2).sub.0-2NHC(O)R.degree.; wherein each independent
occurrence of R.degree. is selected from hydrogen, optionally
substituted C.sub.1-6 aliphatic, an unsubstituted 5-6 membered
heteroaryl or heterocyclic ring, phenyl, --O(Ph), or
--CH.sub.2(Ph), or, two independent occurrences of R.degree., on
the same substituent or different substituents, taken together with
the atom(s) to which each R.degree. group is bound, form a
5-8-membered heterocyclyl, aryl, or heteroaryl ring or a
3-8-membered cycloalkyl ring, wherein said heteroaryl or
heterocyclyl ring has 1-3 heteroatoms independently selected from
nitrogen, oxygen, or sulfur. Optional substituents on the aliphatic
group of R.degree. are selected from NH.sub.2,
NH(C.sub.1-4aliphatic), N(C.sub.1-4aliphatic).sub.2, halogen,
C.sub.1-4aliphatic, OH, O(C.sub.1-4aliphatic), NO.sub.2, CN,
CO.sub.2H, CO.sub.2(C.sub.1-4aliphatic), O(haloC.sub.1-4
aliphatic), or haloC.sub.1-4aliphatic, wherein each of the
foregoing C.sub.1-4aliphatic groups of R.degree. is
unsubstituted.
[0021] In some embodiments, an aliphatic or heteroaliphatic group,
or a non-aromatic heterocyclic ring may contain one or more
substituents. Suitable substituents on the saturated carbon of an
aliphatic or heteroaliphatic group, or of a non-aromatic
heterocyclic ring are selected from those listed above for the
unsaturated carbon of an aryl or heteroaryl group and additionally
include the following: .dbd.O, .dbd.S, .dbd.NNHR*,
.dbd.NN(R*).sub.2, .dbd.NNHC(O)R*, .dbd.NNHCO.sub.2(alkyl),
.dbd.NNHSO.sub.2(alkyl), or .dbd.NR*, where each R* is
independently selected from hydrogen or an optionally substituted
C.sub.1-6 aliphatic. Optional substituents on the aliphatic group
of R* are selected from NH.sub.2, NH(C.sub.1-4 aliphatic),
N(C.sub.1-4 aliphatic).sub.2, halogen, C.sub.1-4 aliphatic, OH,
O(C.sub.1-4 aliphatic), NO.sub.2, CN, CO.sub.2H, CO.sub.2(C.sub.1-4
aliphatic), O(halo C.sub.1-4 aliphatic), or halo(C.sub.1-4
aliphatic), wherein each of the foregoing C.sub.1-4aliphatic groups
of R* is unsubstituted.
[0022] In some embodiments, optional substituents on the nitrogen
of a non-aromatic heterocyclic ring include --R.sup.+,
--N(R.sup.+).sub.2, --C(O)R.sup.+, --CO.sub.2R.sup.+,
--C(O)C(O)R.sup.+, --C(O)CH.sub.2C(O)R.sup.+, --SO.sub.2R.sup.+,
--SO.sub.2N(R.sup.+).sub.2, --C(.dbd.S)N(R.sup.+).sub.2,
--C(.dbd.NH)--N(R.sup.+).sub.2, or --NR.sup.+SO.sub.2R.sup.+;
wherein R.sup.+ is hydrogen, an optionally substituted C.sub.1-6
aliphatic, optionally substituted phenyl, optionally substituted
--O(Ph), optionally substituted --CH.sub.2(Ph), optionally
substituted --(CH.sub.2).sub.1-2(Ph); optionally substituted
--CH.dbd.CH(Ph); or an unsubstituted 5-6 membered heteroaryl or
heterocyclic ring having one to four heteroatoms independently
selected from oxygen, nitrogen, or sulfur, or, two independent
occurrences of R.sup.+, on the same substituent or different
substituents, taken together with the atom(s) to which each R.sup.+
group is bound, form a 5-8-membered heterocyclyl, aryl, or
heteroaryl ring or a 3-8-membered cycloalkyl ring, wherein said
heteroaryl or heterocyclyl ring has 1-3 heteroatoms independently
selected from nitrogen, oxygen, or sulfur. Optional substituents on
the aliphatic group or the phenyl ring of R.sup.+ are selected from
NH.sub.2, NH(C.sub.1-4 aliphatic), N(C.sub.1-4 aliphatic).sub.2,
halogen, C.sub.1-4 aliphatic, OH, O(C.sub.1-4 aliphatic), NO.sub.2,
CN, CO.sub.2H, CO.sub.2(C.sub.1-4 aliphatic), O(halo C.sub.1-4
aliphatic), or halo(C.sub.1-4 aliphatic), wherein each of the
foregoing C.sub.1-4aliphatic groups of R.sup.+ is
unsubstituted.
[0023] As detailed above, in some embodiments, two independent
occurrences of R.degree. (or R.sup.+, or any other variable
similarly defined herein), may be taken together with the atom(s)
to which each variable is bound to form a 5-8-membered
heterocyclyl, aryl, or heteroaryl ring or a 3-8-membered cycloalkyl
ring. Exemplary rings that are formed when two independent
occurrences of R.degree. (or R.sup.+, or any other variable
similarly defined herein) are taken together with the atom(s) to
which each variable is bound include, but are not limited to the
following: a) two independent occurrences of R.degree. (or R.sup.+,
or any other variable similarly defined herein) that are bound to
the same atom and are taken together with that atom to form a ring,
for example, N(R.degree.).sub.2, where both occurrences of
R.degree. are taken together with the nitrogen atom to form a
piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl group; and b) two
independent occurrences of R.degree. (or R.sup.+, or any other
variable similarly defined herein) that are bound to different
atoms and are taken together with both of those atoms to form a
ring, for example where a phenyl group is substituted with two
occurrences of OR.degree.
##STR00002##
these two occurrences of R.degree. are taken together with the
oxygen atoms to which they are bound to form a fused 6-membered
oxygen containing ring:
##STR00003##
It will be appreciated that a variety of other rings can be formed
when two independent occurrences of R.degree. (or R.sup.+, or any
other variable similarly defined herein) are taken together with
the atom(s) to which each variable is bound and that the examples
detailed above are not intended to be limiting.
[0024] In some embodiments, an alkyl or aliphatic chain can be
optionally interrupted with another atom or group. This means that
a methylene unit of the alkyl or aliphatic chain is optionally
replaced with said other atom or group. Examples of such atoms or
groups would include, but are not limited to, --NR--, --O--, --S--,
--CO.sub.2--, --OC(O)--, --C(O)CO--, --C(O)--, --C(O)NR--,
--C(.dbd.N--CN), --NRCO--, --NRC(O)O--, --SO.sub.2NR--,
--NRSO.sub.2--, --NRC(O)NR--, --OC(O)NR--, --NRSO.sub.2NR--,
--SO--, or --SO.sub.2--, wherein R is defined herein. Unless
otherwise specified, the optional replacements form a chemically
stable compound. Optional interruptions can occur both within the
chain and at either end of the chain; i.e. both at the point of
attachment and/or also at the terminal end. Two optional
replacements can also be adjacent to each other within a chain so
long as it results in a chemically stable compound. Unless
otherwise specified, if the replacement or interruption occurs at
the terminal end, the replacement atom is bound to an H on the
terminal end. For example, if --CH.sub.2CH.sub.2CH.sub.3 were
optionally interrupted with --O--, the resulting compound could be
--OCH.sub.2CH.sub.3, --CH.sub.2OCH.sub.3, or
--CH.sub.2CH.sub.2OH.
[0025] As described herein, a bond drawn from a substituent to the
center of one ring within a multiple-ring system (as shown below),
represents substitution of the substituent at any substitutable
position in any of the rings within the multiple ring system. For
example, Figure a represents possible substitution in any of the
positions shown in Figure b.
##STR00004##
[0026] This also applies to multiple ring systems fused to optional
ring systems (which would be represented by dotted lines). For
example, in Figure c, X is an optional substituent both for ring A
and ring B.
##STR00005##
[0027] If, however, two rings in a multiple ring system each have
different substituents drawn from the center of each ring, then,
unless otherwise specified, each substituent only represents
substitution on the ring to which it is attached. For example, in
Figure d, Y is an optionally substituent for ring A only, and X is
an optional substituent for ring B only.
##STR00006##
[0028] Unless otherwise stated, structures depicted herein are also
meant to include all isomeric (e.g., enantiomeric, diastereomeric,
and geometric (or conformational)) forms of the structure; for
example, the R and S configurations for each asymmetric center, (Z)
and (E) double bond isomers, and (Z) and (E) conformational
isomers. Therefore, single stereochemical isomers as well as
enantiomeric, diastereomeric, and geometric (or conformational)
mixtures of the present compounds are within the scope of the
invention.
[0029] Unless otherwise stated, all tautomeric forms of the
compounds of the invention are within the scope of the invention.
Additionally, unless otherwise stated, structures depicted herein
are also meant to include compounds that differ only in the
presence of one or more isotopically enriched atoms. For example,
compounds having the present structures except for the replacement
of hydrogen by deuterium or tritium, or the replacement of a carbon
by a .sup.13C- or .sup.14C-enriched carbon are within the scope of
this invention. Such compounds are useful, for example, as
analytical tools, probes in biological assays, or as JAK inhibitors
with improved therapeutic profile.
Description of Compounds of the Invention
[0030] The present invention relates to a compound of formula
I:
##STR00007## [0031] or a pharmaceutically acceptable salt thereof,
wherein: [0032] X.sup.1 is N or CR.sup.1; [0033] X.sup.2 is N or
CR.sup.2; wherein no more than one of X.sup.1 or X.sup.2 is N;
[0034] X.sup.3 is N or CR.sup.23; [0035] X.sup.4 is N or CR.sup.24;
wherein at least one of X.sup.3 and X.sup.4 is N; [0036] R.sup.1 is
H, halo, R', OH, OR', COR', COOH, COOR', CONH.sub.2, CONHR',
CON(R').sub.2, or CN; [0037] R.sup.2 is H, halo, R', OH, OR', COR',
COOH, COOR', CONH.sub.2, CONHR', CON(R').sub.2, or CN; [0038] or
R.sup.1 and R.sup.2, taken together, form a 5-7 membered aryl or
heteroaryl ring optionally substituted with 1-4 occurrences of
R.sup.9; [0039] each R.sup.9 is independently selected from
halogen, OCH.sub.3, OH, NO.sub.2, NH.sub.2, SH, SCH.sub.3,
NCH.sub.3, CN or unsubstituted C.sub.1-2aliphatic; [0040] R.sup.23
is H, halo, R', OH, OR', COR', COOH, COOR', CONH.sub.2, CONHR',
CON(R').sub.2, or CN; [0041] R.sup.24 is H, halo, R', OH, OR',
COR', COOH, COOR', CONH.sub.2, CONHR', CON(R').sub.2, or CN; [0042]
R' is a C.sub.1-3 aliphatic optionally substituted with 1-4
occurrences of R.sup.10; [0043] each R.sup.10 is independently
selected from halogen, CF.sub.3, OCH.sub.3, OH, SH, NO.sub.2,
NH.sub.2, SCH.sub.3, NCH.sub.3, CN or unsubstituted C.sub.1-2
aliphatic, or two R.sup.10 groups, together with the carbon to
which they are attached, form a cyclopropyl ring or C.dbd.O; [0044]
R.sup.3 is selected from
[0044] ##STR00008## ##STR00009## ##STR00010## ##STR00011##
##STR00012## ##STR00013## ##STR00014## ##STR00015## ##STR00016##
[0045] R.sup.19 is selected from H; a C.sub.3-7 cycloaliphatic
optionally substituted with 1-4 occurrences of halogen, OH,
NO.sub.2, NH.sub.2, SH or CN; or a C.sub.1-6 aliphatic, wherein up
to two methylene units of said C.sub.1-6 aliphatic are optionally
and independently replaced by G.sup.R and wherein said C.sub.1-6
aliphatic is optionally substituted with 1-4 R.sup.20; [0046]
G.sup.R is --NH--, --NR.sup.21--, --O--, --S--, --CO.sub.2--,
--OC(O)--, --C(O)CO--, --C(O)--, --C(O)NH--, --C(O)NR.sup.21--,
--NC(.dbd.N--CN)N--, --NHCO--, --NR.sup.21CO--, --NHC(O)O--,
--NR.sup.21C(O)O--, --SO.sub.2NH--, --SO.sub.2NR.sup.21--,
--NHSO.sub.2--, --NR.sup.21SO.sub.2--, --NHC(O)NH--,
--NR.sup.21C(O)NH--, --NHC(O)NR.sup.21--, --NR.sup.21C(O)NR.sup.21,
--OC(O)NH--, --OC(O)NR.sup.21--, --NHSO.sub.2NH--,
--NR.sup.21SO.sub.2NH--, --NHSO.sub.2NR.sup.21--,
--NR.sup.21SO.sub.2NR.sup.21--, --SO--, or --SO.sub.2--; [0047]
R.sup.21 is C.sub.1-6 aliphatic or C.sub.3-7 cycloaliphatic
optionally substituted with 1-6 occurrences of halogen,
N(R.sup.X).sub.2, R.sup.X, --OR.sup.X, --SR.sup.X, --NO.sub.2,
--CF.sub.3, --CN, --CO.sub.2R.sup.X, --COR.sup.X, OCOR.sup.X,
CONHR.sup.X, or NHCOR.sup.X; [0048] each R.sup.X is independently
selected from H or an unsubstituted C.sub.1-6 aliphatic; [0049]
each R.sup.20 is independently selected from halogen, OH,
OR.sup.22, NO.sub.2, NH.sub.2, NHR.sup.22, N(R.sup.22).sub.2, SH,
SR.sup.22, CN, or R.sup.22; or two R.sup.20, together with the
carbon(s) to which they are attached, form a cyclopropyl ring or
C.dbd.O; [0050] each R.sup.22 is independently selected from a
C.sub.1-6 aliphatic or C.sub.3-7 cycloaliphatic optionally
substituted with 1-6 occurrences of halogen, OH, NO.sub.2,
NH.sub.2, SH or CN; [0051] R.sup.25 is --(U).sub.m--Y; [0052] U is
a C.sub.1-6 aliphatic, wherein up to two methylene units are
optionally and independently replaced by G.sup.U and wherein U is
optionally substituted with 1-4 J.sup.U; [0053] G.sup.U is --NH--,
--NR.sup.26--, --O--, --S--, --CO.sub.2--, --OC(O)--, --C(O)CO--,
--C(O)--, --C(O)NH--, --C(O)NR.sup.26--, --NC(.dbd.N--CN)N--,
--NHCO--, --NR.sup.26CO--, --NHC(O)O--, --NR.sup.26C(O)O--,
--SO.sub.2NH--, --SO.sub.2NR.sup.26--, --NHSO.sub.2--,
--NR.sup.26SO.sub.2--, --NHC(O)NH--, --NR.sup.26C(O)NH--,
--NHC(O)NR.sup.26--, --NR.sup.26C(O)NR.sup.26, --OC(O)NH--,
--OC(O)NR.sup.26--, --NHSO.sub.2NH--, --NR.sup.26SO.sub.2NH--,
--NHSO.sub.2NR.sup.26--, --NR.sup.26SO.sub.2NR.sup.26--, --SO--, or
--SO.sub.2--; [0054] R.sup.26 is a C.sub.1-6 aliphatic, C.sub.3-10
cycloaliphatic, C.sub.6-10 aryl, 5-10 membered heteroaryl, or 5-10
membered heterocyclyl; wherein said aliphatic, cycloaliphatic,
aryl, heteroaryl or heterocyclyl is optionally substituted with
halogen, R.sup.X, --OR.sup.X, --SR.sup.X, --NO.sub.2, --CF.sub.3,
--CN, --CO.sub.2R.sup.X, --COR.sup.X, OCOR.sup.X, CONHR.sup.X, or
NHCOR.sup.X; [0055] each J.sup.U is independently selected from
halogen, L, -(L.sub.n)-R', -(L.sub.n)-N(R').sub.2, -(L.sub.n)-SR',
-(L.sub.n)-OR', -(L.sub.n)-(C.sub.3-10 cycloaliphatic),
-(L.sub.n)-(C.sub.6-10 aryl), -(L.sub.n)-(5-10 membered
heteroaryl), -(L.sub.n)-(5-10 membered heterocyclyl), oxo,
C.sub.1-4haloalkoxy, C.sub.1-4haloalkyl, -(L.sub.n)-NO.sub.2,
-(L.sub.n)-CN, -(L.sub.n)-OH, -(L.sub.n)-CF.sub.3, --CO.sub.2R',
--CO.sub.2H, --COR', --COH, --OC(O)R', --C(O)NHR', C(O)N(R').sub.2,
--NHC(O)R', or NR'C(O)R'; or two J.sup.U groups, on the same
substituent or different substituents, together with the atom(s) to
which each J.sup.U group is bound, form a 5-7 membered saturated,
unsaturated, or partially saturated ring; [0056] m is 0 or 1;
[0057] Y is H, halogen, CN, NO.sub.2, NH.sub.2, NHR, N(R).sub.2, or
a group selected from a C.sub.1-6 aliphatic, a C.sub.3-10
cycloaliphatic, a C.sub.6-10 aryl, a 5-10 membered heteroaryl, or a
5-10 membered heterocyclyl, wherein said group is optionally
substituted with 1-8 occurrences of J.sup.Y; [0058] each J.sup.Y is
independently selected from halogen, L, -(L.sub.n)-R.sup.26,
-(L.sub.n)-N(R.sup.26).sub.2, -(L.sub.n)-SR.sup.26,
-(L.sub.n)-OR.sup.26, -(L.sub.n)-(C.sub.3-10 cycloaliphatic),
-(L.sub.n)-(C.sub.6-10 aryl), -(L.sub.n)-(5-10 membered
heteroaryl), -(L.sub.n)-(5-10 membered heterocyclyl), oxo,
C.sub.1-4haloalkoxy, C.sub.1-4haloalkyl, -(L.sub.n)-NO.sub.2,
-(L.sub.n)-CN, -(L.sub.n)-OH, -(L.sub.n)-CF.sub.3,
--CO.sub.2R.sup.26, --CO.sub.2H, --COR.sup.26, --COH,
--OC(O)R.sup.26, --C(O)NHR.sup.26, C(O)N(R.sup.26).sub.2,
--NHC(O)R.sup.26, or NR.sup.26C(O)R.sup.26; or two J.sup.Y groups,
on the same substituent or different substituents, together with
the atom(s) to which each J.sup.Y group is bound, form a 5-7
membered saturated, unsaturated, or partially saturated ring;
[0059] each L is independently a C.sub.1-6 aliphatic wherein up to
three methylene units are replaced by --NH--, --NR.sup.L--, --O--,
--O--, --CO.sub.2--, --OC(O)--, --C(O)CO--, --C(O)--, --C(O)NH--,
--C(O)NR.sup.L--, --NC(.dbd.N--CN)N, --NHCO--, --NR.sup.LCO--,
--NHC(O)O--, --NR.sup.LC(O)O--, --SO.sub.2NH--,
--SO.sub.2NR.sup.L--, --NHSO.sub.2--, --NR.sup.LSO.sub.2--,
--NHC(O)NH--, --NR.sup.LC(O)NH--, --NHC(O)NR.sup.L--,
--NR.sup.LC(O)NR.sup.L, --OC(O)NH--, --OC(O)NR.sup.L--,
--NHSO.sub.2NH--, --NR.sup.LSO.sub.2NH--, --NHSO.sub.2NR.sup.L--,
--NR.sup.LSO.sub.2NR.sup.L--, --SO--, or --SO.sub.2--; [0060] each
n is independently 0 or 1; [0061] R.sup.L is selected from
C.sub.1-6 aliphatic, C.sub.3-10 cycloaliphatic, C.sub.6-40 aryl,
5-10 membered heteroaryl, or 5-10 membered heterocyclyl; or two
R.sup.L groups, on the same substituent or different substituents,
together with the atom(s) to which each R.sup.L group is bound,
form a 3-8 membered heterocyclyl; [0062] each R is independently
selected from a C.sub.1-6 aliphatic or a C.sub.3-6 cycloaliphatic
optionally substituted with 1-6 occurrences of halogen, OH,
NO.sub.2, NH.sub.2, SH or CN, or two R groups, together with the
atom to which the R groups are bound, form a 5-7 membered
saturated, unsaturated, or partially saturated ring; [0063] wherein
each substitutable carbon of an R.sup.3 ring is optionally and
independently substituted with halogen; --R.degree.; --OR.degree.;
--SR.degree.; 1,2-methylenedioxy; 1,2-ethylenedioxy; phenyl (Ph)
optionally substituted with R.degree.; --O(Ph) optionally
substituted with R.degree.; --(CH.sub.2).sub.1-2(Ph), optionally
substituted with R.degree.; --CH.dbd.CH(Ph), optionally substituted
with R.degree.; --NO.sub.2; --CN; --N(R.degree.).sub.2;
--NR.degree.C(O)R.degree.; --NR.degree.C(S)R.degree.;
--NR.degree.C(O)N(R.degree.).sub.2;
--NR.degree.C(S)N(R.degree.).sub.2; --NR.degree.CO.sub.2R.degree.;
--NR.degree.NR.degree.C(O)R.degree.;
--NR.degree.NR.degree.C(O)N(R.degree.).sub.2;
--NR.degree.NR.degree.CO.sub.2R.degree.; --C(O)C(O)R.degree.;
--C(O)CH.sub.2C(O)R.degree.; --CO.sub.2R.degree.; --C(O)R.degree.;
--C(S)R.degree.; --C(O)N(R.degree.).sub.2;
--C(S)N(R.degree.).sub.2; --OC(O)N(R.degree.).sub.2;
--OC(O)R.degree.; --C(O)N(OR.degree.)R.degree.;
--C(NOR.degree.)R.degree.; --S(O).sub.2R.degree.;
--S(O).sub.3R.degree.; --SO.sub.2N(R.degree.).sub.2;
--S(O)R.degree.; --NR.degree.SO.sub.2N(R.degree.).sub.2;
--NR.degree.SO.sub.2R.degree.; --N(OR.degree.)R.degree.;
--C(.dbd.NH)--N(R.degree.).sub.2; or
--(CH.sub.2).sub.0-2NHC(O)R.degree.; wherein each independent
occurrence of R.degree. is selected from hydrogen, optionally
substituted C.sub.1-6 aliphatic, an unsubstituted 5-6 membered
heteroaryl or heterocyclic ring, phenyl, --O(Ph), or
--CH.sub.2(Ph), or, two independent occurrences of R.degree., on
the same substituent or different substituents, taken together with
the atom(s) to which each R.degree. group is bound, form a
5-8-membered heterocyclyl, aryl, or heteroaryl ring or a
3-8-membered cycloalkyl ring, wherein said heteroaryl or
heterocyclyl ring has 1-3 heteroatoms independently selected from
nitrogen, oxygen, or sulfur; and wherein each of said optional
substituents on the aliphatic group of R.degree. is independently
selected from NH.sub.2, NH(C.sub.1-4aliphatic),
N(C.sub.1-4aliphatic).sub.2, halogen, C.sub.1-4aliphatic, OH,
O(C.sub.1-4aliphatic), NO.sub.2, CN, CO.sub.2H,
CO.sub.2(C.sub.1-4aliphatic), O(haloC.sub.1-4 aliphatic), or
haloC.sub.1-4aliphatic, wherein each of the foregoing
C.sub.1-4aliphatic groups of R.degree. is unsubstituted; [0064]
wherein each substitutable nitrogen of a non-aromatic heterocyclic
ring of R.sup.3 is optionally and independently substituted with
--R.sup.+, --N(R.sup.+).sub.2, --C(O)R.sup.+, --CO.sub.2R.sup.+,
--C(O)C(O)R.sup.+, --C(O)CH.sub.2C(O)R.sup.+, --SO.sub.2R.sup.+,
--SO.sub.2N(R.sup.+).sub.2, --C(.dbd.S)N(R.sup.+).sub.2,
--C(.dbd.NH)--N(R.sup.+).sub.2, or --NR.sup.+SO.sub.2R.sup.+;
wherein R.sup.+ is hydrogen, an optionally substituted C.sub.1-6
aliphatic, optionally substituted phenyl, optionally substituted
--O(Ph), optionally substituted --CH.sub.2(Ph), optionally
substituted --(CH.sub.2).sub.1-2(Ph); optionally substituted
--CH.dbd.CH(Ph); or an unsubstituted 5-6 membered heteroaryl or
heterocyclic ring having one to four heteroatoms independently
selected from oxygen, nitrogen, or sulfur, or, two independent
occurrences of R.sup.+, on the same substituent or different
substituents, taken together with the atom(s) to which each R.sup.+
group is bound, form a 5-8-membered heterocyclyl, aryl, or
heteroaryl ring or a 3-8-membered cycloalkyl ring, wherein said
heteroaryl or heterocyclyl ring has 1-3 heteroatoms independently
selected from nitrogen, oxygen, or sulfur; wherein each of said
optional substituents on the aliphatic group or the phenyl ring of
R.sup.+ is independently selected from NH.sub.2, NH(C.sub.1-4
aliphatic), N(C.sub.1-4 aliphatic).sub.2, halogen, C.sub.1-4
aliphatic, OH, O(C.sub.1-4 aliphatic), NO.sub.2, CN, CO.sub.2H,
CO.sub.2(C.sub.1-4 aliphatic), O(halo C.sub.1-4 aliphatic), or
halo(C.sub.1-4 aliphatic), wherein each of the foregoing
C.sub.1-4aliphatic groups of R.sup.+ is unsubstituted; [0065]
R.sup.4 is H or is a --C.sub.1-2 aliphatic optionally substituted
with 1-3 occurrences of R.sup.11; [0066] each R.sup.11 is
independently selected from halogen, CF.sub.3, OCH.sub.3, OH, SH,
NO.sub.2, NH.sub.2, SCH.sub.3, NCH.sub.3, CN, CON(R.sup.15).sub.2
or unsubstituted C.sub.1-2 aliphatic, or two R.sup.11 groups,
together with the carbon to which they are attached, form a
cyclopropyl ring or C.dbd.O; [0067] R.sup.15 is H or unsubstituted
C.sub.1-2 alkyl; [0068] R.sup.5 is H or a C.sub.1-6 aliphatic
optionally substituted with 1-5 occurrences of R.sup.12; [0069]
R.sup.6 is H or a C.sub.1-6 aliphatic optionally substituted with
1-5 occurrences of R.sup.13; [0070] each R.sup.12 is independently
selected from halogen, OCH.sub.3, OH, NO.sub.2, NH.sub.2, SH,
SCH.sub.3, NCH.sub.3, CN or unsubstituted C.sub.1-2aliphatic, or
two R.sup.12 groups, together with the carbon to which they are
attached, form a cyclopropyl ring; [0071] each R.sup.13 is
independently selected from halogen, OCH.sub.3, OH, NO.sub.2,
NH.sub.2, SH, SCH.sub.3, NCH.sub.3, CN or unsubstituted
C.sub.1-2aliphatic, or two R.sup.13 groups, together with the
carbon to which they are attached, form a cyclopropyl ring; or
[0072] R.sup.5 and R.sup.6 are taken together to form a 3-7
membered carbocyclic or heterocyclic saturated ring optionally
substituted with 1-5 occurrences of R.sup.12; or [0073] R.sup.4 and
R.sup.6, taken together with the nitrogen to which R.sup.4 is
attached, form a 3-8 membered saturated, partially saturated or
aromatic nitrogen-containing ring comprising up to two additional
heteroatoms selected from N, O or S and optionally substituted with
1-4 occurrences of R.sup.14; or [0074] R.sup.1 and R.sup.4, taken
together with the nitrogen to which R.sup.4 is attached, form a 3-8
membered saturated, partially saturated or aromatic
nitrogen-containing ring comprising up to two additional
heteroatoms selected from N, O or S and optionally substituted with
1-4 occurrences of R.sup.14; or [0075] each R.sup.14 is
independently selected from halogen, R'', NH.sub.2, NHR'',
N(R'').sub.2, SH, SR'', OH, OR'', NO.sub.2, CN, CF.sub.3, COOR'',
COOH, COR'', OC(O)R'' or NC(O)R''; or any two R.sup.13 groups, on
the same substituent or different substituents, together with the
atom(s) to which each R.sup.14 group is bound, form a 3-7 membered
saturated, unsaturated, or partially saturated carbocyclic or
heterocyclic ring optionally substituted with 1-3 occurrences of
R.sup.16; [0076] R'' is a C.sub.1-3 aliphatic optionally
substituted with 1-4 occurrences of R.sup.10; [0077] each R.sup.16
is independently selected from halogen, CF.sub.3, OCH.sub.3, OH,
SH, NO.sub.2, NH.sub.2, SCH.sub.3, NCH.sub.3, CN,
CON(R.sup.15).sub.2 or unsubstituted C.sub.1-2 aliphatic, or two
R.sup.16 groups, together with the carbon to which they are
attached, form a cyclopropyl ring or C.dbd.O; [0078] R.sup.7 is H
or C.sub.1-4 aliphatic optionally substituted with 1-3 occurrences
of R.sup.17; [0079] each R.sup.17 is independently selected from
halogen, CF.sub.3, OCH.sub.3, OH, SH, NO.sub.2, NH.sub.2,
SCH.sub.3, NCH.sub.3, CN, CON(R.sup.15).sub.2 or unsubstituted
C.sub.1-2 aliphatic, or two R.sup.17 groups, together with the
carbon to which they are attached, form a cyclopropyl ring or
C.dbd.O; [0080] R.sup.8 is C.sub.1-4 aliphatic optionally
substituted with 1-6 occurrences of R.sup.18; and [0081] each
R.sup.18 is independently selected from halogen, CF.sub.3,
OCH.sub.3, OH, SH, NO.sub.2, NH.sub.2, SCH.sub.3, NCH.sub.3, CN,
CON(R.sup.15).sub.2 or unsubstituted C.sub.1-2 aliphatic, or two
R.sup.18 groups, together with the carbon to which they are
attached, form a cyclopropyl ring or C.dbd.O. [0082] In one
embodiment, a compound of the invention has one of formulae I-A,
I-B, I-C, I-D, I-E, I-F, I-G, I-H or I-i:
##STR00017## ##STR00018##
[0083] In one embodiment, said compound is selected from one of
formulae I-A, I-B, I-C or I-D. In a further embodiment, said
compound is selected from one of formulae I-C or I-D. In yet a
further embodiment, said compound has formula I-D.
[0084] In another embodiment, said compound is selected from one of
formulae I-A, I-B, I-C, I-F, I-G or I-I and R.sup.1 is H, Cl, F,
R', OH or OR'. In a further embodiment, R.sup.1 is H, CH.sub.3, Cl
or F.
[0085] In another embodiment, said compound is selected from one of
formulae I-A, I-B, I-C, I-D, I-E or I-H, and R.sup.2 is H, Cl, F,
R', OH or OR'. In a further embodiment, R.sup.2 is H, CH.sub.3, Cl
or F. In yet another embodiment, said compound is of formula I-C,
and R.sup.1 is H, Cl or F and R.sup.2 is H.
[0086] In another embodiment, said compound is selected from one of
formulae I-A, I-E or I-G, and R.sup.23 is H, Cl, F, R', OH or OR'.
In a further embodiment, R.sup.23 is H, CH.sub.3, Cl or F. In yet a
further embodiment, R.sup.23 is H.
[0087] In another embodiment, said compound is selected from one of
formulae I-B, I-D or I-F, and R.sup.24 is H, Cl, F, R', OH or OR'.
In a further embodiment, R.sup.24 is H, CH.sub.3, Cl or F. In yet
another embodiment, said compound is of formula I-D, and R.sup.2
and R.sup.24 are both H.
[0088] In another embodiment, X.sup.1 is CR.sup.1 and X.sup.2 is
CR.sup.2, and R.sup.1 and R.sup.2, taken together, form a 5-7
membered aryl or heteroaryl ring optionally substituted with 1-4
occurrences of R.sup.9.
[0089] In another embodiment of any of the above-disclosed
embodiments, R.sup.4 is H, CH.sub.3, CH.sub.2CH.sub.3 or
CH(CH.sub.3).sub.2. In a further embodiment, R.sup.4 is H or
CH.sub.3. In yet a further embodiment, R.sup.4 is H.
[0090] In an alternative embodiment, R.sup.1 and R.sup.4, taken
together with the nitrogen to which R.sup.4 is attached, form a 3-8
membered saturated, partially saturated or aromatic
nitrogen-containing ring comprising up to two additional
heteroatoms selected from N, O or S and optionally substituted with
1-4 occurrences of R.sup.14.
[0091] In another embodiment of any of the above-disclosed
embodiments, R.sup.5 is H or a C.sub.1-2 alkyl optionally
substituted with up to 3 occurrences of R.sup.12. In a further
embodiment, R.sup.5 is H or an unsubstituted C.sub.1-2 alkyl.
[0092] In another embodiment of any of the above-disclosed
embodiments, R.sup.6 is a C.sub.1-4 aliphatic optionally
substituted with 1-5 occurrences of R.sup.13. In a further
embodiment, R5 is H and R.sup.6 is selected from
##STR00019## ##STR00020##
[0093] In a further embodiment, R.sup.6 is selected from
##STR00021##
[0094] In yet a further embodiment, R.sup.6 is selected from
##STR00022##
[0095] In a still further embodiment, R.sup.6 is selected from
##STR00023##
[0096] In another embodiment, R.sup.5 and R.sup.6 are taken
together to form a ring selected from
##STR00024##
wherein one or more carbon atoms in of said ring are optionally and
independently replaced by N, O or S.
[0097] In another embodiment, R.sup.5 and R.sup.6 are
##STR00025##
[0098] In a further embodiment, R.sup.5 and R.sup.6 are
##STR00026##
[0099] In yet a further embodiment, R.sup.5 and R.sup.6 are
##STR00027##
[0100] In another embodiment, R.sup.4 and R.sup.6, taken together
with the nitrogen to which R.sup.4 is attached, form a 3-8 membered
saturated, partially saturated or aromatic nitrogen-containing ring
comprising up to two additional heteroatoms selected from N, O or S
and optionally substituted with 1-4 occurrences of R.sup.14. In a
further embodiment, R.sup.4 and R.sup.6 taken together is selected
from
##STR00028##
and R.sup.14, is H or R.sup.14.
[0101] In a further embodiment, R.sup.4 and R.sup.6 taken together
is
##STR00029##
[0102] In yet a further embodiment, R.sup.4 and R.sup.6 taken
together is
##STR00030##
[0103] In a further embodiment, the ring formed by R.sup.4 and
R.sup.6 is unsubstituted. In another embodiment, the ring formed by
R.sup.4 and R.sup.6 is substituted with one occurrence of R.sup.14.
In a further embodiment, R.sup.14 is OH, CH.sub.3, F, OR' or NHR'.
In yet a further embodiment, R' is C.sub.1-2 alkyl or C.sub.2-3
alkenyl. In a still further embodiment, R.sup.14 is OH.
[0104] In another embodiment of any of the above-disclosed
embodiments, R.sup.7 is H or C.sub.1-2 alkyl optionally substituted
with 1-3 occurrences of R.sup.17. In a further embodiment, R.sup.7
is H or unsubstituted C.sub.1-2 alkyl.
[0105] In another embodiment of any of the above-disclosed
embodiments, R.sup.8 is a C.sub.1-4 aliphatic or cycloaliphatic
optionally substituted with up to 6 occurrences of R.sup.18. In a
further embodiment, R.sup.8 is a C.sub.2-3 aliphatic or
cycloaliphatic optionally substituted with up to 6 occurrences of
R.sup.18. In a further embodiment, R.sup.18 is F. In yet a further
embodiment, R.sup.8 is CH.sub.2CH.sub.3, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F, CH.sub.2CH.sub.2CH.sub.3,
CH.sub.2CH.sub.2CF.sub.3, CH.sub.2CH.sub.2CH.sub.2F or
CH.sub.2CH.sub.2CHF.sub.2. In a still further embodiment, R.sup.8
is CH.sub.2CH.sub.3, CH.sub.2CF.sub.3, CH.sub.2CH.sub.2CH.sub.3 or
CH.sub.2CH.sub.2CF.sub.3. In yet a further embodiment, R.sup.8 is
CH.sub.2CF.sub.3.
[0106] In another embodiment of any of the above-disclosed
embodiments, R.sup.3 is selected from (1-a), (1-c), (1-k), (2-d),
(2-e), (2-f), (2-n), (2-o), (2-u), (2-v), (2-x), (2-y), (2-z) and
(3-a). In a further embodiment, R.sup.3 is selected from (1-a),
(1-c), (1-k), (2-d), (2-e), (2-n), (2-o), (2-u), (2-x) and (2-z).
In yet a further embodiment, R.sup.3 is selected from (1-a), (1-c),
(2-d), (2-e), (2-n), (2-o), (2-u) and (2-x). In a still further
embodiment, R.sup.3 is selected from (1-c), (2-d), (2-n) and
(2-o).
[0107] In another embodiment, R.sup.3 is unsubstituted. In an
alternative embodiment, up to two substitutable carbons and up to
one substitutable nitrogens of a non-aromatic heterocyclic ring of
the R.sup.3 ring are substituted. In a further embodiment, one
substitutable carbon and up to one substitutable nitrogens of a
non-aromatic heterocyclic ring of the R.sup.3 ring are substituted.
In yet a further embodiment, one substitutable carbon of the
R.sup.3 ring is substituted.
[0108] In another embodiment, R.sup.3 is (2-n) and R.sup.25 is
C(O)NR.sub.2. In another embodiment, R.sup.3 is (2-o) and R.sup.25
is an optionally substituted aryl or heteroaryl. In a further
embodiment, R.sup.25 is an optionally substituted phenyl. In
another embodiment, R.sup.3 is (1-c) or (2-d) and R.sup.3 is
unsubstituted.
[0109] In another embodiment, the invention provides a compound of
Table 1:
TABLE-US-00001 TABLE 1 1 ##STR00031## 2 ##STR00032## 3 ##STR00033##
4 ##STR00034## 5 ##STR00035## 6 ##STR00036## 7 ##STR00037## 8
##STR00038## 9 ##STR00039## 10 ##STR00040## 11 ##STR00041## 12
##STR00042## 13 ##STR00043## 14 ##STR00044## 15 ##STR00045## 16
##STR00046## 17 ##STR00047## 18 ##STR00048## 19 ##STR00049## 20
##STR00050## 21 ##STR00051## 22 ##STR00052## 23 ##STR00053## 24
##STR00054## 25 ##STR00055## 26 ##STR00056## 27 ##STR00057## 28
##STR00058## 29 ##STR00059## 30 ##STR00060## 31 ##STR00061## 32
##STR00062## 33 ##STR00063## 34 ##STR00064## 35 ##STR00065## 36
##STR00066## 37 ##STR00067## 38 ##STR00068## 39 ##STR00069## 40
##STR00070## 41 ##STR00071## 42 ##STR00072## 43 ##STR00073## 44
##STR00074## 45 ##STR00075## 46 ##STR00076## 47 ##STR00077## 48
##STR00078## 49 ##STR00079## 50 ##STR00080## 51 ##STR00081## 52
##STR00082## 53 ##STR00083## 54 ##STR00084## 55 ##STR00085## 56
##STR00086## 57 ##STR00087## 58 ##STR00088## 59 ##STR00089## 60
##STR00090## 61 ##STR00091## 62 ##STR00092## 63 ##STR00093## 64
##STR00094## 65 ##STR00095## 66 ##STR00096## 67 ##STR00097## 68
##STR00098## 69 ##STR00099## 70 ##STR00100## 71 ##STR00101## 72
##STR00102## 73 ##STR00103## 74 ##STR00104## 75 ##STR00105## 76
##STR00106## 77 ##STR00107## 78 ##STR00108## 79 ##STR00109## 80
##STR00110## 81 ##STR00111## 82 ##STR00112## 83 ##STR00113## 84
##STR00114## 85 ##STR00115## 86 ##STR00116## 87 ##STR00117## 88
##STR00118## 89 ##STR00119## 90 ##STR00120## 91 ##STR00121## 92
##STR00122## 93 ##STR00123## 94 ##STR00124## 95 ##STR00125## 96
##STR00126## 97 ##STR00127## 98 ##STR00128## 99 ##STR00129## 100
##STR00130## 101 ##STR00131## 102 ##STR00132## 103 ##STR00133## 104
##STR00134## 105 ##STR00135## 106 ##STR00136## 107 ##STR00137## 108
##STR00138## 109 ##STR00139## 110 ##STR00140## 111 ##STR00141## 112
##STR00142## 113 ##STR00143## 114 ##STR00144## 115 ##STR00145## 116
##STR00146## 117 ##STR00147## 118 ##STR00148## 119 ##STR00149## 120
##STR00150## 121 ##STR00151## 122 ##STR00152## 123 ##STR00153## 124
##STR00154##
125 ##STR00155## 126 ##STR00156## 127 ##STR00157## 128 ##STR00158##
129 ##STR00159## 130 ##STR00160## 131 ##STR00161## 132 ##STR00162##
133 ##STR00163## 134 ##STR00164## 135 ##STR00165## 136 ##STR00166##
137 ##STR00167## 138 ##STR00168## 139 ##STR00169## 140 ##STR00170##
141 ##STR00171## 142 ##STR00172## 143 ##STR00173## 144 ##STR00174##
145 ##STR00175## 146 ##STR00176## 147 ##STR00177## 148 ##STR00178##
149 ##STR00179## 150 ##STR00180## 151 ##STR00181## 152 ##STR00182##
153 ##STR00183## 154 ##STR00184## 155 ##STR00185## 156 ##STR00186##
157 ##STR00187## 158 ##STR00188## 159 ##STR00189## 160 ##STR00190##
161 ##STR00191## 162 ##STR00192## 163 ##STR00193## 164 ##STR00194##
165 ##STR00195## 166 ##STR00196## 167 ##STR00197## 168
##STR00198##
Uses, Formulation and Administration
Pharmaceutically Acceptable Compositions
[0110] In another embodiment, the invention provides a
pharmaceutical composition comprising a compound of formula I.
[0111] In a further embodiment, the composition additionally
comprising a therapeutic agent selected from a chemotherapeutic or
anti-proliferative agent, an anti-inflammatory agent, an
immunomodulatory or immunosuppressive agent, a neurotrophic factor,
an agent for treating cardiovascular disease, an agent for treating
destructive bone disorders, an agent for treating liver disease, an
anti-viral agent, an agent for treating blood disorders, an agent
for treating diabetes, or an agent for treating immunodeficiency
disorders.
[0112] According to another embodiment, the invention provides a
composition comprising a compound of this invention or a
pharmaceutically acceptable derivative thereof and a
pharmaceutically acceptable carrier, adjuvant, or vehicle. The
amount of compound in the compositions of this invention is such
that is effective to measurably inhibit a protein kinase,
particularly a JAK family kinase, in a biological sample or in a
patient. Preferably the composition of this invention is formulated
for administration to a patient in need of such composition. Most
preferably, the composition of this invention is formulated for
oral administration to a patient.
[0113] The term "patient", as used herein, means an animal,
preferably a mammal, and most preferably a human.
[0114] Accordingly, in another aspect of the present invention,
pharmaceutically acceptable compositions are provided, wherein
these compositions comprise any of the compounds as described
herein, and optionally comprise a pharmaceutically acceptable
carrier, adjuvant or vehicle. In certain embodiments, these
compositions optionally further comprise one or more additional
therapeutic agents.
[0115] It will also be appreciated that certain of the compounds of
present invention can exist in free form for treatment, or where
appropriate, as a pharmaceutically acceptable derivative thereof.
According to the present invention, a pharmaceutically acceptable
derivative includes, but is not limited to, pharmaceutically
acceptable prodrugs, salts, esters, salts of such esters, or any
other adduct or derivative which upon administration to a patient
in need is capable of providing, directly or indirectly, a compound
as otherwise described herein, or a metabolite or residue thereof.
As used herein, the term "inhibitorily active metabolite or residue
thereof" means that a metabolite or residue thereof is also an
inhibitor of a JAK family kinase.
[0116] As used herein, the term "pharmaceutically acceptable salt"
refers to those salts which are, within the scope of sound medical
judgement, suitable for use in contact with the tissues of humans
and lower animals without undue toxicity, irritation, allergic
response and the like.
[0117] Pharmaceutically acceptable salts are well known in the art.
For example, S. M. Berge et al., describe pharmaceutically
acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66,
1-19, incorporated herein by reference. Pharmaceutically acceptable
salts of the compounds of this invention include those derived from
suitable inorganic and organic acids and bases. Examples of
pharmaceutically acceptable, nontoxic acid addition salts are salts
of an amino group formed with inorganic acids such as hydrochloric
acid, hydrobromic acid, phosphoric acid, sulfuric acid and
perchloric acid or with organic acids such as acetic acid, oxalic
acid, maleic acid, tartaric acid, citric acid, succinic acid or
malonic acid or by using other methods used in the art such as ion
exchange. Other pharmaceutically acceptable salts include adipate,
alginate, ascorbate, aspartate, benzenesulfonate, benzoate,
bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptonate,
glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate,
hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate,
laurate, lauryl sulfate, malate, maleate, malonate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oleate, oxalate, palmitate, pamoate, pectinate, persulfate,
3-phenylpropionate, phosphate, picrate, pivalate, propionate,
stearate, succinate, sulfate, tartrate, thiocyanate,
p-toluenesulfonate, undecanoate, valerate salts, and the like.
Salts derived from appropriate bases include alkali metal, alkaline
earth metal, ammonium and N.sup.+(C.sub.1-4alkyl).sub.4 salts. This
invention also envisions the quaternization of any basic
nitrogen-containing groups of the compounds disclosed herein. Water
or oil-soluble or dispersable products may be obtained by such
quaternization. Representative alkali or alkaline earth metal salts
include sodium, lithium, potassium, calcium, magnesium, and the
like. Further pharmaceutically acceptable salts include, when
appropriate, nontoxic ammonium, quaternary ammonium, and amine
cations formed using counterions such as halide, hydroxide,
carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and
aryl sulfonate.
[0118] As described above, the pharmaceutically acceptable
compositions of the present invention additionally comprise a
pharmaceutically acceptable carrier, adjuvant, or vehicle, which,
as used herein, includes any and all solvents, diluents, or other
liquid vehicle, dispersion or suspension aids, surface active
agents, isotonic agents, thickening or emulsifying agents,
preservatives, solid binders, lubricants and the like, as suited to
the particular dosage form desired. Remington's Pharmaceutical
Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co.,
Easton, Pa., 1980) discloses various carriers used in formulating
pharmaceutically acceptable compositions and known techniques for
the preparation thereof. Except insofar as any conventional carrier
medium is incompatible with the compounds of the invention, such as
by producing any undesirable biological effect or otherwise
interacting in a deleterious manner with any other component(s) of
the pharmaceutically acceptable composition, its use is
contemplated to be within the scope of this invention.
[0119] Some examples of materials which can serve as
pharmaceutically acceptable carriers include, but are not limited
to, ion exchangers, alumina, aluminum stearate, lecithin, serum
proteins, such as human serum albumin, buffer substances such as
phosphates, glycine, sorbic acid, or 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, polyacrylates, waxes,
polyethylene-polyoxypropylene-block polymers, wool fat, sugars such
as lactose, glucose and sucrose; starches such as corn starch and
potato starch; cellulose and its derivatives such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate;
powdered tragacanth; malt; gelatin; talc; excipients such as cocoa
butter and suppository waxes; oils such as peanut oil, cottonseed
oil; safflower oil; sesame oil; olive oil; corn oil and soybean
oil; glycols; such a propylene glycol or polyethylene glycol;
esters such as ethyl oleate and ethyl laurate; agar; buffering
agents such as magnesium hydroxide and aluminum hydroxide; alginic
acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl
alcohol, and phosphate buffer solutions, as well as other non-toxic
compatible lubricants such as sodium lauryl sulfate and magnesium
stearate, as well as coloring agents, releasing agents, coating
agents, sweetening, flavoring and perfuming agents, preservatives
and antioxidants can also be present in the composition, according
to the judgment of the formulator.
[0120] The term "measurably inhibit", as used herein means a
measurable change in kinase activity, particularly JAK kinase
activity, between a sample comprising a compound of this invention
and a JAK kinase and an equivalent sample comprising JAK kinase in
the absence of said compound.
[0121] The 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, intramuscular, intra-articular,
intra-synovial, intrasternal, intrathecal, intraocular,
intrahepatic, intralesional and intracranial injection or infusion
techniques. Preferably, the compositions are administered orally,
intraperitoneally or intravenously. 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.
[0122] 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 that 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.
[0123] The pharmaceutically acceptable 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. In the case of tablets for oral
use, carriers commonly used include lactose and corn starch.
Lubricating agents, such as magnesium stearate, are also typically
added. For oral administration in a capsule form, useful diluents
include lactose and dried cornstarch. 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.
[0124] Alternatively, the pharmaceutically acceptable compositions
of this invention may be administered in the form of suppositories
for rectal administration. These can be prepared by mixing the
agent with a suitable non-irritating excipient that 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.
[0125] The pharmaceutically acceptable 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.
[0126] Topical application for the lower intestinal tract can be
effected in a rectal suppository formulation (see above) or in a
suitable enema formulation. Topically-transdermal patches may also
be used.
[0127] For topical applications, the pharmaceutically acceptable
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 pharmaceutically acceptable compositions can 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.
[0128] For ophthalmic use, the pharmaceutically acceptable
compositions may be formulated, e.g., as micronized suspensions in
isotonic, pH adjusted sterile saline or other aqueous solution, or,
preferably, as solutions in isotonic, pH adjusted sterile saline or
other aqueous solution, either with or without a preservative such
as benzylalkonium chloride. Alternatively, for ophthalmic uses, the
pharmaceutically acceptable compositions may be formulated in an
ointment such as petrolatum. The pharmaceutically acceptable
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.
[0129] Most preferably, the pharmaceutically acceptable
compositions of this invention are formulated for oral
administration.
[0130] Liquid dosage forms for oral administration include, but are
not limited to, pharmaceutically acceptable emulsions,
microemulsions, solutions, suspensions, syrups and elixirs. In
addition to the active compounds, the liquid dosage forms may
contain inert diluents commonly used in the art such as, for
example, water or other solvents, solubilizing agents and
emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor, and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include
adjuvants such as wetting agents, emulsifying and suspending
agents, sweetening, flavoring, and perfuming agents.
[0131] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions may be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution, suspension or emulsion in a nontoxic
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, U.S.P.
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 can be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid are used in the preparation of injectables.
[0132] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium prior to use.
[0133] In order to prolong the effect of a compound of the present
invention, it is often desirable to slow the absorption of the
compound from subcutaneous or intramuscular injection. This may be
accomplished by the use of a liquid suspension of crystalline or
amorphous material with poor water solubility. The rate of
absorption of the compound then depends upon its rate of
dissolution that, in turn, may depend upon crystal size and
crystalline form. Alternatively, delayed absorption of a
parenterally administered compound form is accomplished by
dissolving or suspending the compound in an oil vehicle. Injectable
depot forms are made by forming microencapsule matrices of the
compound in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of compound to
polymer and the nature of the particular polymer employed, the rate
of compound release can be controlled. Examples of other
biodegradable polymers include poly(orthoesters) and
poly(anhydrides). Depot injectable formulations are also prepared
by entrapping the compound in liposomes or microemulsions that are
compatible with body tissues.
[0134] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating excipients
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at ambient temperature but liquid
at body temperature and therefore melt in the rectum or vaginal
cavity and release the active compound.
[0135] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
b) binders such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants
such as glycerol, d) disintegrating agents such as agar--agar,
calcium carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such
as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, for example, cetyl alcohol
and glycerol monostearate, h) absorbents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof. In the case of capsules, tablets and
pills, the dosage form may also comprise buffering agents.
[0136] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like. The solid dosage forms of
tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings and other
coatings well known in the pharmaceutical formulating art. They may
optionally contain opacifying agents and can also be of a
composition that they release the active ingredient(s) only, or
preferentially, in a certain part of the intestinal tract,
optionally, in a delayed manner. Examples of embedding compositions
that can be used include polymeric substances and waxes. Solid
compositions of a similar type may also be employed as fillers in
soft and hard-filled gelatin capsules using such excipients as
lactose or milk sugar as well as high molecular weight polethylene
glycols and the like.
[0137] The active compounds can also be in micro-encapsulated form
with one or more excipients as noted above. The solid dosage forms
of tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings, release
controlling coatings and other coatings well known in the
pharmaceutical formulating art. In such solid dosage forms the
active compound may be admixed with at least one inert diluent such
as sucrose, lactose or starch. Such dosage forms may also comprise,
as is normal practice, additional substances other than inert
diluents, e.g., tableting lubricants and other tableting aids such
a magnesium stearate and microcrystalline cellulose. In the case of
capsules, tablets and pills, the dosage forms may also comprise
buffering agents. They may optionally contain opacifying agents and
can also be of a composition that they release the active
ingredient(s) only, or preferentially, in a certain part of the
intestinal tract, optionally, in a delayed manner. Examples of
embedding compositions that can be used include polymeric
substances and waxes.
[0138] Dosage forms for topical or transdermal administration of a
compound of this invention include ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants or patches.
The active component is admixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives or
buffers as may be required. Ophthalmic formulation, ear drops, and
eye drops are also contemplated as being within the scope of this
invention. Additionally, the present invention contemplates the use
of transdermal patches, which have the added advantage of providing
controlled delivery of a compound to the body. Such dosage forms
can be made by dissolving or dispensing the compound in the proper
medium. Absorption enhancers can also be used to increase the flux
of the compound across the skin. The rate can be controlled by
either providing a rate controlling membrane or by dispersing the
compound in a polymer matrix or gel.
[0139] The compounds of the invention are preferably formulated in
dosage unit form for ease of administration and uniformity of
dosage. The expression "dosage unit form" as used herein refers to
a physically discrete unit of agent appropriate for the patient to
be treated. It will be understood, however, that the total daily
usage of the compounds and compositions of the present invention
will be decided by the attending physician within the scope of
sound medical judgment. The specific effective dose level for any
particular patient or organism will depend upon a variety of
factors including the disorder being treated and the severity of
the disorder; the activity of the specific compound employed; the
specific composition employed; the age, body weight, general
health, sex and diet of the patient; the time of administration,
route of administration, and rate of excretion of the specific
compound employed; the duration of the treatment; drugs used in
combination or coincidental with the specific compound employed,
and like factors well known in the medical arts.
[0140] The amount of the compounds of the present invention that
may be combined with the carrier materials to produce a composition
in a single dosage form will vary depending upon the host treated,
the particular mode of administration. Preferably, the compositions
should be formulated so that a dosage of between 0.01-100 mg/kg
body weight/day of the inhibitor can be administered to a patient
receiving these compositions.
[0141] Depending upon the particular condition, or disease, to be
treated or prevented, additional therapeutic agents, which are
normally administered to treat or prevent that condition, may also
be present in the compositions of this invention. As used herein,
additional therapeutic agents that are normally administered to
treat or prevent a particular disease, or condition, are known as
"appropriate for the disease, or condition, being treated".
[0142] For example, chemotherapeutic agents or other
anti-proliferative agents may be combined with the compounds of
this invention to treat proliferative diseases and cancer. Examples
of known chemotherapeutic agents include, but are not limited to,
Gleevec.TM., adriamycin, dexamethasone, vincristine,
cyclophosphamide, fluorouracil, topotecan, taxol, interferons, and
platinum derivatives.
[0143] Other examples of agents the inhibitors of this invention
may also be combined with include, without limitation: treatments
for Alzheimer's Disease such as Aricept.RTM. and Excelon.RTM.;
treatments for Parkinson's Disease such as L-DOPA/carbidopa,
entacapone, ropinrole, pramipexole, bromocriptine, pergolide,
trihexephendyl, and amantadine; agents for treating Multiple
Sclerosis (MS) such as beta interferon (e.g., Avonex.RTM. and
Rebif.RTM.), Copaxone.RTM., and mitoxantrone; treatments for asthma
such as albuterol and Singulair.RTM.; agents for treating
schizophrenia such as zyprexa, risperdal, seroquel, and
haloperidol; anti-inflammatory agents such as corticosteroids, TNF
blockers, IL-1 RA, azathioprine, cyclophosphamide, and
sulfasalazine; immunomodulatory and immunosuppressive agents such
as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil,
interferons, corticosteroids, cyclophophamide, azathioprine, and
sulfasalazine; neurotrophic factors such as acetylcholinesterase
inhibitors, MAO inhibitors, interferons, anti-convulsants, ion
channel blockers, riluzole, and anti-Parkinsonian agents; agents
for treating cardiovascular disease such as beta-blockers, ACE
inhibitors, diuretics, nitrates, calcium channel blockers, and
statins; agents for treating liver disease such as corticosteroids,
cholestyramine, interferons, and anti-viral agents; agents for
treating blood disorders such as corticosteroids, anti-leukemic
agents, and growth factors; and agents for treating
immunodeficiency disorders such as gamma globulin.
[0144] Therapeutic agents that may be used in combination with a
compound of the invention include one or more agents for treating
rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing
spondylitis, reactive arthritis, arthritis associated with Crohn's
disease and arthritis associated with ulcerative colitis. Agents
that may be used for treating arthritis (e.g., rheumatoid
arthritis, psoriatic arthritis, reactive arthritis, or arthritis
associated with Crohn's disease or ulcerative colitis) include,
without limitation, non-steroidal anti-inflammatory drugs (NSAIDS;
e.g., aspirin, ibuprofen, naproxen, ketoprofen, indomethacin,
tolmetin, sulindac, piroxicam, diclofenac and celecoxib), local
injection and/or oral administration of anti-inflammatory steroids
(e.g., cortisone or prednisone), methotrexate, oral administration
and/or intramuscular injections of gold compounds, antimalarials
(e.g., hydroxychloroquine), cyclosporin, leflunomide, azathioprine,
sulfasalazine, d-penicillamine, cyclophosphamide, mycophenolate, a
p38 antagonist (e.g., VX-702), a biological agent, or combinations
thereof. Biological agents include, without limitation, tumor
necrosis factor .alpha. (TNF.alpha.) antagonists,
interleukin-1.alpha. (IL-1.alpha.) antagonists, CD28 antagonists
and CD20 antagonists. In a further embodiment, biological agents
include etanercept (ENBREL.TM.), adalimumab (HUMIRA.TM.),
infliximab (REMICADE.TM.), anakinra (KINERET.TM.), abatacept
(ORENCIA.TM.), rituximab (RITUXAN.TM.) and certolizumab pegol
(CIMZIA.TM.). Therapies that may be used to treat psoriasis
include, without limitation, topical agents such as
corticosteroids, calcipotriene, coal tar, anthralin and salicylic
acid; phototherapy in association with coal tar or psoralen; and
systemic agents such as methotrexate, retinoids (e.g., etretinate
and isotretinoin), hydroxyurea and biological agents such as
etanercept, infliximab, adalimumab, alafacept (AMEVIVE.TM.) and
efalizumab (RAPTIVA.TM.).
[0145] The amount of additional therapeutic agent present in the
compositions of this invention 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 in the presently disclosed
compositions will range from about 50% to 100% of the amount
normally present in a composition comprising that agent as the only
therapeutically active agent.
Uses of the Compounds and Compositions
[0146] In one embodiment, the invention provides a method of
inhibiting JAK kinase activity in a patient, comprising
administering to said patient a compound or composition of the
invention.
[0147] In another embodiment, the invention comprises a method of
treating or lessening the severity of a JAK-mediated condition or
disease in a patient. The term "JAK-mediated disease", as used
herein means any disease or other deleterious condition in which a
JAK family kinase, in particular JAK2 or JAK3, is known to play a
role. In a further embodiment, the invention comprises a method of
treating a JAK3-mediated disease. Such conditions include, without
limitation, immune responses such as allergic or type I
hypersensitivity reactions, asthma, autoimmune diseases such as
transplant rejection, graft versus host disease, rheumatoid
arthritis, amyotrophic lateral sclerosis, and multiple sclerosis,
neurodegenerative disorders such as familial amyotrophic lateral
sclerosis (FALS), as well as in solid and hematologic malignancies
such as leukemias and lymphomas.
[0148] In another embodiment, the invention provides a method of
treating or lessening the severity of a disease of condition
selected from a proliferative disorder, a cardiac disorder, a
neurodegenerative disorder, an autoimmune disorder, a condition
associated with organ transplant, an inflammatory disorder, an
immune disorder or an immunologically mediated disorder, comprising
administering to said patient a compound or composition of the
invention.
[0149] In a further embodiment, the method comprises the additional
step of administering to said patient an additional therapeutic
agent selected from a chemotherapeutic or anti-proliferative agent,
an anti-inflammatory agent, an immunomodulatory or
immunosuppressive agent, a neurotrophic factor, an agent for
treating cardiovascular disease, an agent for treating diabetes, or
an agent for treating immunodeficiency disorders, wherein said
additional therapeutic agent is appropriate for the disease being
treated and said additional therapeutic agent is administered
together with said composition as a single dosage form or
separately from said composition as part of a multiple dosage
form.
[0150] In one embodiment, the disease or disorder is allergic or
type I hypersensitivity reactions, asthma, diabetes, Alzheimer's
disease, Huntington's disease, Parkinson's disease, AIDS-associated
dementia, amyotrophic lateral sclerosis (ALS, Lou Gehrig's
disease), multiple sclerosis (MS), schizophrenia, cardiomyocyte
hypertrophy, reperfusion/ischemia, stroke, baldness, transplant
rejection, graft versus host disease, rheumatoid arthritis,
amyotrophic lateral sclerosis, and multiple sclerosis, and solid
and hematologic malignancies such as leukemias and lymphomas. In a
further embodiment, said disease or disorder is asthma. In another
embodiment, said disease or disorder is transplant rejection. In
another embodiment, said disease or disorder is rheumatoid
arthritis.
[0151] In another embodiment, a compound or composition of this
invention may be used to treat a myeloproliferative disorder. In
one embodiment, the myeloproliferative disorder is polycythemia
vera, essential thrombocythemia, or chronic idiopathic
myelofibrosis. In another embodiment, the myeloproliferative
disorder is myeloid metaplasia with myelofibrosis, chronic myeloid
leukemia (CML), chronic myelomonocytic leukemia, chronic
eosinophilic leukemia, hypereosinophilic syndrome, systematic mast
cell disease, atypical CML or juvenile myelomonocytic leukemia.
[0152] In another embodiment, the invention provides for the use of
a compound of formula I to treat a JAK-mediated disease. In a
further embodiment, the invention provides for the use of said
compound to treat any of the diseases discussed above. In another
embodiment, the invention provides for the use of a compound of
formula I for the manufacture of a medicament for treating a
JAK-mediated disease. In a further embodiment, the invention
provides for the use of said compound for the manufacture of a
medicament for treating any of the diseases discussed above.
[0153] In another embodiment, the invention provides a method of
inhibiting JAK kinase activity in a biological sample, comprising
contacting said biological sample with a compound or composition of
the invention.
[0154] The term "biological sample", as used herein, means an ex
vivo sample, and includes, without limitation, cell cultures or
extracts thereof tissue or organ samples or extracts thereof
biopsied material obtained from a mammal or extracts thereof and
blood, saliva, urine, feces, semen, tears, or other body fluids or
extracts thereof.
[0155] Inhibition of kinase activity, particularly JAK kinase
activity, in a biological sample is useful for a variety of
purposes that are known to one of skill in the art. Examples of
such purposes include, but are not limited to, blood transfusion,
organ-transplantation, biological specimen storage, and biological
assays.
[0156] In certain embodiments of the present invention an
"effective amount" of the compound or pharmaceutically acceptable
composition is that amount effective for treating or lessening the
severity of one or more of the aforementioned disorders. The
compounds and compositions, according to the method of the present
invention, may be administered using any amount and any route of
administration effective for treating or lessening the severity of
the disorder or disease. The exact amount required will vary from
subject to subject, depending on the species, age, and general
condition of the subject, the severity of the infection, the
particular agent, its mode of administration, and the like.
[0157] In an alternate embodiment, the methods of this invention
comprise the additional step of separately administering to said
patient an additional therapeutic agent. When these additional
therapeutic agents are administered separately they may be
administered to the patient prior to, sequentially with or
following administration of the compositions of this invention.
[0158] The compounds of this invention or pharmaceutical
compositions thereof may also be used for coating an implantable
medical device, such as prostheses, artificial valves, vascular
grafts, stents and catheters. Vascular stents, for example, have
been used to overcome restenosis (re-narrowing of the vessel wall
after injury). However, patients using stents or other implantable
devices risk clot formation or platelet activation. These unwanted
effects may be prevented or mitigated by pre-coating the device
with a pharmaceutically acceptable composition comprising a
compound of this invention.
[0159] Suitable coatings and the general preparation of coated
implantable devices are described in U.S. Pat. Nos. 6,099,562;
5,886,026; and 5,304,121. The coatings are typically biocompatible
polymeric materials such as a hydrogel polymer,
polymethyldisiloxane, polycaprolactone, polyethylene glycol,
polylactic acid, ethylene vinyl acetate, and mixtures thereof. The
coatings may optionally be further covered by a suitable topcoat of
fluorosilicone, polysaccarides, polyethylene glycol, phospholipids
or combinations thereof to impart controlled release
characteristics in the composition. Implantable devices coated with
a compound of this invention are another embodiment of the present
invention. The compounds may also be coated on implantable medical
devices, such as beads, or co-formulated with a polymer or other
molecule, to provide a "drug depot", thus permitting the drug to be
released over a longer time period than administration of an
aqueous solution of the drug.
Methodology for Synthesis and Characterization of Compounds
[0160] The compounds of this invention may be prepared in general
by methods known to those skilled in the art for analogous
compounds or by those methods depicted in the Examples below. See,
e.g., the examples described in WO 2005/095400, which is herein
incorporated by reference in its entirety.
[0161] All references provided in the Examples are herein
incorporated by reference. As used herein, all abbreviations,
symbols and conventions are consistent with those used in the
contemporary scientific literature. See, e.g., Janet S. Dodd, ed.,
The ACS Style Guide: A Manual for Authors and Editors, 2nd Ed.,
Washington, D.C.: American Chemical Society, 1997, herein
incorporated in its entirety by reference.
EXAMPLES
Example 1
Preparation of Compounds of the Invention
General Synthetic Schemes
##STR00199##
[0163] Compounds of formula F may be prepared as outlined in Scheme
I using methods previously described in WO2005/095400.
[0164] Specifically, compounds of formulae A and C as well as
R.sup.7R.sup.8NH--HCl may be obtained commercially or prepared by
one having ordinary skill in the art. Compounds of formula E and/or
R.sup.3--B(OR.sup.27).sub.2 may be obtained commercially or
prepared by one having ordinary skill in the art, such as described
in the cited references in Table 2. Further derivatives of R.sup.3
or other substituents may be made using known methods.
TABLE-US-00002 TABLE 2 R.sup.3 Reference 1-b WO 2004056369; WO
2004050659; Mobinikhaledi et al., N. Asian J. Chem. 2003, 15,
455-458; Van den Haak et al., J. Org. Chem. 1982, 47, 1673-7 1-d WO
2001053262 1-e DiMauro et al. J. Med. Chem. 2006, 49, 5671; PCT WO
2006039718 1-f Sako, Science of Synthesis 2004, 16, 1155-1267;
Pomorski et al., Roczniki Chemii 1973, 47, 549-52 1-h Sugimoto et
al. Helv. Chim. Acta 2001, 84, 1112-1118. 1-i WO 2006105289; WO
2006032466 1-j Wozniak, Zeszyty Naukowe Uniwersytetu
Jagiellonskiego, Prace Chemiczne 1978, 23, 55-66; Wozniak, Ibid.
1978, 23, 43-53 1-l Gallou et al. Synlett. 2005, 2400-2402; Kelly
et al. J. Med. Chem. 1997, 40, 2430-2433 1-m Kelly et al. J. Med.
Chem. 1997, 40, 2430-2433; Ciriano et al. J. Organomet. Chem. 1993,
445, 273-81; Yakhontov et al. Tetrahedron Lett. 1969, 1909-12 1-n
Kelly et al. J. Med. Chem. 1997, 40, 2430-2433; Yakhontov et al.
Tetrahedron Lett. 1969, 1909-12 1-o WO 2006015124 1-r FR 2867778
A1; US 2005090529; Prokopov, A. A.; Yakhontov, L. N. Khimiya
Geterotsiklicheskikh Soedinenii 1979, 86-8 1-s WO 2006050006; US
2005009876; US 2004127536; WO 2003053344; US 2002099208; WO
2002010137; Welch et al. Synthesis 1992, 937-9 1-t WO 2006058120
1-u FR 2845388 A1; WO 2003053344; US 2002099208; Milhavet et al.
Arch. Pharmazie 1989, 322, 885-7; Chapman et al. J. Chem. Soc.
Perkin Trans. 1 1980, 2398-2404 1-v WO 2003101968 1-w WO 2003101968
1-x US 2002156081; WO 2002080926; WO 2001019829; WO 9816184 1-y WO
2006058120 1-z WO 2006046031; WO 2006046040 2-a WO 2006077319 2-b
WO 2005110410 2-c Duca et al. Biopolymers 2005, 80, 312-318 2-g
Zhang et al. J. Org. Chem. 2002, 67, 2345-2347 2-h JP 2005289921
2-i Bilodeau et al. Bioorg. Med. Chem. Lett. 2003, 13, 2485-8; U.S.
Pat. No. 6,465,484; U.S. Pat. No. 6,162,804; WO 2000012089; Wang et
al. Tetrahedron Lett. 2003, 44, 8967-8969 2-j EP 1122254 2-k Dudash
et al. Bioorg. Med. Chem. Lett. 15 (2005) 4790 2-l Scheme II 2-m
Scheme II 2-o WO2004/046120; WO 2006/034116; WO2005/095400 2-p US
2006106218; US 2005256130; WO 2005056015; US 2004162282; WO
2003105853; Tavares et al. J. Med. Chem. 2004, 47, 588-599; WO
2003026650; WO 2002069901; Fraley et al. Bioorg. Med. Chem. Lett.
2002, 12, 2767-2770; WO 9928317; WO 9854093; U.S. Pat. No.
5,846,990; WO 9729748; WO 9506034; JP 06056792; JP 01271751;
Springer et al. J. Med. Chem. 1982, 25, 235-242; U.S. Pat. No.
4,281,000 2-q Lebedev et al. Vestnik Moskovskogo Universiteta,
Seriya 2: Khimiya 1988, 29, 506-510; Kolobov et al. Khimiya
Geterotsiklicheskikh Soedinenii 1987, 1503-8 2-r J. Org. Chem.
2005, 70, 3997; Heterocycles 2005, 65, 2721 2-s Heterocycles 1987,
26, 3153; Talanta 1993, 40, 577 2-t Eur. J. Chem. 2000, 13, 2449
3-a Durrant et al. Heterocycles 2006, 70, 509 3-c Fraley et al.
Bioorg. Med. Chem. Lett. 2002, 12, 3537-3541; US 2002041880; U.S.
Pat. No. 7,087,755; US 2006084650; WO 2004081008 3-d Cheung et al.
J. Org. Chem. 2005, 70, 3741-3744 3-f Matulenko et al., Bioorg.
Med. Chem. 2007, 15, 1586-1605; Hirayama et al., Chem. Pharm. 1976,
24, 26-36 3-h Scheme III 3-o Scheme IV 3-p J. Heterocyclic Chem.
1986, 23, 541 3-q Scheme V
[0165] Compounds 1-32 and 59-168 were prepared according to Scheme
I.
##STR00200##
[0166] II-l and II-m were prepared according to the method
described in Tetrahedron 1976, 32 341-348. The resulting mixture
was separated and the compounds reacted as shown in Scheme II to
give the corresponding boronates.
##STR00201##
[0167] Compounds of formula I wherein R.sup.3 is 3-h may be
prepared according to Scheme III.
##STR00202##
##STR00203##
[0168] Compounds of formula I wherein R.sup.3 is 3-o or 3-q may be
prepared according to Scheme IV or Scheme V, respectively.
##STR00204##
[0169] Compounds of formulae G and H may be prepared using methods
previously described in WO2004/046120, WO 2006/034116 and
WO2005/095400.
[0170] Compounds 33-58 were prepared according to Scheme VI.
Example 2
Analytical Results
[0171] Table 2 below depicts exemplary .sup.1H-NMR data (NMR) and
liquid chromatographic mass spectral data, reported as mass plus
proton (M+H), as determined by electrospray, and retention time
(RT) for certain compounds of the present invention, wherein
compound numbers in Table 2 corresponds to the compounds depicted
in Table 1 (empty cells indicate that the test was not
performed):
TABLE-US-00003 TABLE 3 Cmpd # M + H RT NMR 1 362.3 2.4 H NMR (500
MHz, DMSO-d6) d 9.02 (d, J = 2.3 Hz, 1H), 8.76 (t, J = 6.3 Hz, 1H),
8.67 (dt, J = 11.9, 4.2 Hz, 1H), 8.32 (d, J = 3.7 Hz, 1H), 8.03 (d,
J = 6.3 Hz, 1H), 7.25 (dd, J = 8.6, 2.6 Hz, 1H), 4.63 (m, 1H),
3.93-3.86 (m, 2H), 1.44 (d, J = 7.2 Hz, 3H) 2 378.3 2.6 3 344.2 1.3
H NMR (500 MHz, DMSO-d6) d 8.79-8.76 (m, 3H), 8.40 (d, J = 3.6 Hz,
1H), 8.26 (d, J = 6.1 Hz, 2H), 8.14 (d, J = 6.2 Hz, 1H), 4.63 (m,
1H), 3.93-3.86 (m, 2H), 1.44 (d, J = 7.2 Hz, 3H) 4 344.2 1.4 H NMR
(500 MHz, DMSO-d6) d 9.39 (d, J = 1.7 Hz, 1H), 8.76 (t, J = 6.3 Hz,
1H), 8.70 (dd, J = 4.9, 1.6 Hz, 1H), 8.63 (d, J = 8.0 Hz, 1H), 8.35
(d, J = 3.7 Hz, 1H), 8.05 (d, J = 6.3 Hz, 1H), 7.58 (dd, J = 7.9,
5.0 Hz, 1H), 4.63 (m, 1H), 3.93-3.86 (m, 2H), 1.44 (d, J = 7.2 Hz,
3H) 5 378.3 2.1 6 359.3 1.4 H NMR (500 MHz, DMSO-d6) d 8.70 (t, J =
6.3 Hz, 1H), 8.58 (d, J = 1.7 Hz, 1H), 8.54 (dd, J = 9.3, 1.8 Hz,
1H), 8.28 (d, J = 3.6 Hz, 1H), 8.08 (d, J = 6.0 Hz, 3H), 6.99 (d, J
= 9.3 Hz, 1H), 4.63 (m, 1H), 3.93-3.86 (m, 2H), 1.44 (d, J = 7.2
Hz, 3H) 7 376.0 1.6 H NMR (500 MHz, DMSO-d6) 12.28 (s, 1H), 8.79
(d, J = 6.3 Hz, 1H), 8.5 (bs, 1H) 8.33 (d, J = 4.1 Hz, 1H), 7.65
(s, 1H), 7.32 (s, 1H), 4.73 (t, J = 7.0 Hz, 1H), 3.97-3.83 (m, 2H),
1.44 (d, J = 7.2 Hz, 3H) 8 348.3 1.8 9 348.3 2.1 10 360.4 1.9 11
330.3 1.3 12 362.4 1.7 13 362.4 2.1 14 374.4 1.8 15 344.3 1.5 16
333.3 0.7 17 362.4 1.9 18 374.4 2.0 19 362.4 2.3 20 344.3 1.4 21
388.4 2.0 22 388.4 2.4 23 370.4 1.7 24 388.4 2.0 25 388.4 2.4 26
370.4 1.6 27 359.1 2.0 H NMR (500 MHz, DMSO-d6) 8.86 (d, J = 7.8
Hz, 1H), 8.79 (t, J = 6.3 Hz, 1H), 8.36 (d, J = 3.5 Hz, 1H), 8.29
(d, J = 5.8 Hz, 1H), 8.14 (dd, J = 1.7, 5.9 Hz, 1H), 6.96-6.94 (m,
1H), 4.58 (t, J = 6.8 Hz, 1H), 3.93-3.86 (m, 2H) 1.45 (d, J = 7.2
Hz, 3H) 28 369.4 1.7 29 345.1 1.5 30 359.1 1.6 31 355.1 1.5 32
371.3 1.8 33 440.4 2.4 34 454.4 2.5 35 440.4 2.1 36 426.4 2.2 37
466.4 2.5 38 466.4 2.0 39 496.4 2.3 40 510.4 2.3 41 500.3 2.6 42
480.4 2.1 43 498.4 2.5 44 484.1 2.7 45 458.1 2.5 46 467.1 1.5 47
472.3 2.3 48 486.4 2.5 49 633.2 1.7 50 470.5 2.3 51 466.1 2.6 52
430.1 1.9 53 432.1 1.9 54 432.1 2.0 55 474.1 1.9 56 481.1 1.6 57
481.1 1.6 58 456.1 2.0 59 395.2 1.7 60 402.2 2.3 61 423.2 2.1 62
382.3 2.4 63 465.3 1.6 64 471.0 2.4 H NMR (300 MHz, DMSO) 12.42 (s,
1H), 8.70 (d, J = 1.5 Hz, 1H), 8.36-8.25 (m, 3H), 7.74 (d, J = 8.5
Hz, 1H), 7.65 (s, 1H), 3.82-3.70 (m, 2H), 2.22 (s, 3H), 1.57 (s,
6H). 65 467.1 2.4 66 429.1 2.2 67 401.2 2.8 H NMR (300 MHz, DMSO)
8.29 (t, J = 6.4 Hz, 1H), 8.24 (d, J = 3.9 Hz, 1H), 7.78 (dd, J =
1.7, 8.2 Hz, 1H), 7.63 (br, 2H), 6.95 (d, J = 8.2 Hz, 1H), 6.07 (s,
2H), 3.79-3.68 (m, 2H), 1.53 (s, 6H). 68 408.3 2.4 69 388.2 2.6 H
NMR (300 MHz, DMSO) 8.91 (d, J = 2.0 Hz, 1H), 8.37-8.26 (m, 3H),
7.68 (s, 1H), 6.86 (dd, J = 0.6, 8.7 Hz, 1H), 3.80-3.68 (m, 2H),
1.54 (s, 6H). 70 384.3 2.6 71 397.3 2.7 72 404.3 2.5 73 425.2 2.3 H
NMR (300 MHz, DMSO) 9.22-9.11 (m, 1H), 9.05-9.01 (m, 1H), 8.56 (d,
J = 1.8 Hz, 1H), 8.21-7.99 (m, 4H), 7.49 (d, J = 8.6 Hz, 1H), 6.85
(d, J = 6.8 Hz, 1H), 4.76-4.71 (m, 1H), 4.13-3.76 (m, 2H),
2.19-2.10 (m, 1H), 1.00 (d, J = 6.7 Hz, 6H). 74 383.2 2.3 H NMR
(300 MHz, DMSO) 8.87 (br, 1H), 8.41 (t, J = 6.2 Hz, 1H), 8.18 (d, J
= 6.7 Hz, 1H), 7.80 (dd, J = 1.8, 8.3 Hz, 1H), 7.65 (d, J = 1.7 Hz,
1H), 7.10 (d, J = 8.3 Hz, 1H), 6.66 (d, J = 6.6 Hz, 1H), 6.14 (d, J
= 7.6 Hz, 2H), 3.84-3.72 (m, 2H), 1.54 (s, 6H). 75 390.2 2.2 76
415.3 3.0 77 422.2 2.7 H NMR (300 MHz, DMSO) 9.01 (dd, J = 1.6, 4.4
Hz, 1H), 8.96-8.91 (m, 2H), 8.72 (dd, J = 1.9, 8.9 Hz, 1H), 8.63
(d, J = 7.9 Hz, 1H), 8.37 (d, J = 3.7 Hz, 1H), 8.11 (d, J = 8.9 Hz,
1H), 7.73-7.67 (m, 2H), 4.53-4.48 (m, 1H), 4.06-3.85 (m, 2H),
2.31-2.19 (m, 1H), 1.05 (d, J = 6.7 Hz, 3H), 1.03 (d, J = 6.7 Hz,
3H). 78 443.1 2.5 79 410.9 1.3 80 370.2 1.7 81 402.1 2.3 82 453.1
1.6 83 368.1 1.7 84 374.1 1.7 85 370.1 1.9 86 356.1 1.6 87 388.1
2.0 88 413.1 2.8 89 420.2 2.6 90 441.1 2.4 91 400.2 2.7 92 483.1
2.5 93 417.3 2.0 H NMR (300 MHz, DMSO) 11.62 (br, 1H), 8.29-8.25
(m, 1H), 8.20 (m, 1H), 8.11 (m, 1H), 7.33 (s, 1H), 7.24 (s, 1H),
3.80-3.68 (m, 2H), 3.29-3.20 (m, 2H), 1.53 (s, 6H), 1.10 (t, J =
7.1 Hz, 3H). 94 429.2 2.1 H NMR (300 MHz, DMSO) 11.78 (br, 1H),
8.27-8.09 (m, 3H), 7.32 (s, 1H), 7.24 (s, 1H), 3.85-3.68 (m, 2H),
2.54 (m, 1H), 1.53 (s, 6H), 0.68-0.59 (m, 2H), 0.55-0.50 (m, 2H).
95 2.4 96 431.3 2.2 H NMR (300 MHz, DMSO) 11.70 (br, 1H), 8.28-8.17
(m, 2H), 7.86 (d, J = 8.7 Hz, 1H), 7.30 (d, J = 2.4 Hz, 2H),
4.41-3.50 (m, 3H, obscured by water), 1.53 (s, 6H), 1.14 (d, J =
6.6 Hz, 6H). 97 443.3 2.1 H NMR (300 MHz, DMSO) 11.93 (br, 1H),
8.36-8.31 (m, 3H), 7.46 (s, 1H), 7.17 (s, 1H), 3.77-3.68 (m, 4H),
3.50 (br, 2H), 2.03-1.97 (m, 4H), 1.53 (s, 6H). 98 411.3 1.9 99
461.1 2.4 100 413.3 2.0 101 425.3 2.0 102 423.3 2.0 103 417.2 2.2 H
NMR (300 MHz, DMSO) 11.92 (br, 1H), 8.84-8.80 (m, 1H), 8.23 (br,
1H), 7.63 (s, 1H), 7.29 (s, 1H), 4.53 (t, J = 7.9 Hz, 1H),
4.10-3.93 (m, 1H), 3.88-3.78 (m, 1H), 2.76 (d, J = 4.5 Hz, 3H),
2.42-2.15 (m, 1H), 0.98 (d, J = 6.6 Hz, 3H), 0.97 (d, J = 6.6 Hz,
3H). 104 493.2 2.7 H NMR (300 MHz, DMSO) 11.99 (br, 1H), 8.84-8.80
(m, 1H), 8.68 (t, J = 6.0 Hz, 1H), 8.24 (d, J = 3.9 Hz, 1H), 7.67
(s, 1H), 7.33 (d, J = 1.8 Hz, 1H), 7.32-7.21 (m, 5H), 4.52 (t, J =
7.9 Hz, 1H), 4.46 (d, J = 6.2 Hz, 2H), 4.07-3.93 (m, 1H), 3.87-3.73
(m, 1H), 2.28-2.15 (m, 1H), 0.98 (d, J = 6.6 Hz, 3H), 0.97 (d, J =
6.6 Hz, 3H). 105 445.3 2.4 H NMR (300 MHz, DMSO) 11.84 (br, 1H),
8.85-8.81 (m, 1H), 8.21 (s, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.61 (s,
1H), 7.36 (d, J = 1.6 Hz, 1H), 4.50 (t, J = 7.7 Hz, 1H), 4.11-3.78
(m, obscured by water), 2.24-2.14 (m, 1H), 1.15 (d, J = 6.6 Hz,
3H), 1.15 (d, J = 6.6 Hz, 3H), 0.98 (d, J = 6.6 Hz, 3H), 0.97 (d, J
= 6.6 Hz, 3H). 106 457.3 2.5 107 457.3 2.4 H NMR (300 MHz, DMSO)
12.01 (br, 1H), 8.88 (s, 1H), 8.29 (s, 1H), 7.72 (s, 1H), 7.20 (s,
1H), 4.48 (t, J = 7.8 Hz, 1H), 4.06-3.74 (m, obscured by water),
1.99-1.87 (m, 4H), 1.00-0.96 (m, 6H). 108 455.2 2.4 H NMR (300 MHz,
DMSO) 12.13 (br, 1H), 8.92-8.88 (m, 1H), 8.32 (d, J = 4.2 Hz, 1H),
7.78 (s, 1H), 7.28 (s, 1H), 6.01 (s, 2H), 4.51 (br, 2H), 4.50 (t, J
= 7.7 Hz, 1H), 4.32 (br, 2H), 4.11-3.97 (m, 1H), 3.89-3.71 (m, 1H),
2.28-2.16 (m, 1H), 1.00 (d, J = 6.6 Hz, 3H), 0.98 (d, J = 6.6 Hz,
3H). 109 399.2 2.0 110 475.2 2.5 111 427.3 2.2 112 439.3 2.3 113
439.3 2.2 114 437.3 2.2 115 415.2 2.0 116 491.3 2.5 117 443.2 2.3
118 455.3 2.4 119 455.3 2.3 120 453.2 2.3 121 473.2 2.4 122 425.3
2.1 123 373.2 2.3 H NMR (300 MHz, DMSO) 9.86 (br, 1H), 8.31-8.24
(m, 2H), 8.00 (d, J = 8.7 Hz, 2H), 7.69 (s, 1H), 6.78 (d, J = 8.8
Hz, 2H), 3.80-3.68 (m, 2H), 1.54 (s, 6H). 124 387.2 2.8 H NMR (300
MHz, DMSO) 8.31-8.24 (m, 2H), 8.13-8.09 (m, 2H), 7.64 (s, 1H),
7.00-6.95 (m, 2H), 3.81 (s, 3H), 3.77-3.68 (m, 2H), 1.54 (s, 6H).
125 415.2 2.7 H NMR (300 MHz, DMSO) 8.30-8.23 (m, 2H), 7.69-7.62
(m, 3H), 6.87 (d, J = 8.3 Hz, 1H), 4.27 (s, 4H), 3.80-3.68 (m, 2H),
1.53 (s, 6H). 126 443.3 2.3 H NMR (300 MHz, DMSO) 11.89 (br, 1H),
8.83-8.79 (m, 1H), 8.19 (d, J = 4.3 Hz, 1H), 8.10 (d, J = 3.5 Hz,
1H), 7.59 (s, 1H), 7.31 (s, 1H), 4.50 (t, J = 7.7 Hz, 1H),
4.19-3.52 (m, obscured by water), 2.83-2.76 (m, 1H), 2.23-2.16 (m,
1H), 0.97 (dd, J = 4.5, 6.6 Hz, 6H), 0.69-0.65 (m, 2H), 0.56-0.51
(m, 2H). 127 402.0 1.6 128 372.2 1.5 129 429.1 1.6 130 437.3 2.0
131 403.1 1.7 H NMR (300 MHz, DMSO) 12.40 (br, 1H), 11.97 (br, 1H),
8.82 (t, J = 6.3 Hz, 1H), 8.11 (d, J = 3.8 Hz, 1H), 7.55 (m, 1H),
7.23 (dd, J = 1.6, 2.5 Hz, 1H), 4.48 (t, J = 7.8 Hz, 1H), 4.08-3.94
(m, 1H), 3.87-3.73 (m, 1H), 2.22-2.07 (m, 1H), 0.98 (d, J = 6.6 Hz,
3H), 0.96 (d, J = 6.6 Hz, 3H). 132 399.1 1.5 H NMR (300 MHz, DMSO)
11.67-11.56 (m, 1H), 8.13 (m, 2H), 8.03 (d, J = 5.9 Hz, 1H), 7.39
(s, 1H), 7.04 (s, 1H), 6.30 (m, 1H), 3.79-3.67 (m, 2H), 3.14 (br,
6H), 1.45 (s, 6H). 133 390.0 1.4 134 386.1 1.7 135 385.2 1.5 H NMR
(300 MHz, DMSO) 11.63 (d, J = 4.5 Hz, 1H), 8.73-8.69 (m, 1H), 8.04
(d, J = 5.9 Hz, 1H), 7.62 (d, J = 3.7 Hz, 1H), 7.37 (m, 2H), 6.48
(m, 1H), 5.03 (br, 2H), 4.40 (br, 1H), 4.09-3.95 (m, 1H), 3.92-3.79
(m, 1H), 2.13-2.01 (m, 1H), 0.97 (d, J = 6.3 Hz, 3H), 0.95 (d, J =
6.3 Hz, 3H). 136 371.1 1.3 H NMR (300 MHz, DMSO) 11.55 (d, J = 5.6
Hz, 1H), 8.13 (m, 1H), 8.07 (d, J = 5.9 Hz, 1H), 7.50 (d, J = 3.7
Hz, 1H), 7.44 (s, 1H), 7.33 (d, J = 2.2 Hz, 1H), 6.35 (d, J = 5.8
Hz, 1H), 5.00 (s, 2H), 3.82-3.71 (m, 2H), 1.45 (s, 6H). 137 403.1
1.6 138 401.2 1.4 139 435.2 2.1 140 414.0 2.5 141 426.0 2.7 142
387.4 2.5 H NMR (300 MHz, DMSO) 9.86 (br, 1H), 8.81 (t, J = 6.4 Hz,
1H), 8.24 (d, J = 4.0 Hz, 1H), 8.12 (dd, J = 1.9, 6.9 Hz, 2H), 7.61
(m, 1H), 6.83-6.79 (m, 2H), 4.50 (t, J = 7.7 Hz, 1H), 4.07-3.74 (m,
2H), 2.28-2.14 (m, 1H), 0.99 (d, J = 6.6 Hz, 3H), 0.98
(d, J = 6.6 Hz, 3H). 143 383.2 2.7 H NMR (300 MHz, DMSO) 8.97 (m,
2H), 8.23 (d, J = 9.0 Hz, 2H), 8.16 (d, J = 6.7 Hz, 1H), 7.13 (d, J
= 8.9 Hz, 2H), 6.82 (d, J = 6.6 Hz, 1H), 4.74 (m, 1H), 4.10-3.69
(m, 5H), 2.19-2.07 (m, 1H), 0.98 (d, J = 6.8 Hz, 6H). 144 355.0 2.0
145 401.2 3.0 H NMR (300 MHz, DMSO) 8.82 (t, J = 6.2 Hz, 1H),
8.26-8.21 (m, 3H), 7.65-7.52 (m, 1H), 7.00 (d, J = 9.0 Hz, 2H),
4.49 (t, J = 7.6 Hz, 1H), 4.05-3.85 (m, 2H), 3.82 (s, 3H),
2.38-2.12 (m, 1H), 1.00 (d, J = 6.6 Hz, 3H), 0.98 (d, J = 6.3 Hz,
3H). 146 411.3 2.7 H NMR (300 MHz, DMSO) 9.08 (m, 2H), 8.14 (d, J =
6.7 Hz, 1H), 7.80-7.77 (m, 2H), 7.05 (d, J = 8.4 Hz, 1H), 6.82 (m,
1H), 4.77 (m, 1H), 4.34 (d, J = 4.7 Hz, 4H), 4.16-3.78 (m, 2H),
2.16-2.05 (m, 1H), 0.97 (d, J = 6.8 Hz, 6H). 147 367.1 2.2 H NMR
(300 MHz, DMSO) 10.39 (br, 1H), 8.93 (m, 1H), 8.29 (d, J = 6.9 Hz,
1H), 8.08 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 6.78 (d, J
= 7.4 Hz, 1H), 4.80 (m, 1H), 4.03-3.89 (m, 2H), 3.74-3.63 (m, 2H),
2.44-2.31 (m, 1H), 2.07-1.97 (m, 3H). 148 409.8 2.6 149 369.2 2.5 H
NMR (300 MHz, DMSO) 8.39 (m, 1H), 8.18-8.13 (m, 3H), 7.11 (d, J =
8.9 Hz, 2H), 6.65 (m, 1H), 3.86 (s, 3H), 3.81-3.62 (m, 2H), 1.54
(s, 6H). 150 381.2 2.6 H NMR (300 MHz, DMSO) 8.92 (t, J = 6.3 Hz,
1H), 8.32 (d, J = 6.7 Hz, 1H), 8.18 (d, J = 8.7 Hz, 2H), 7.09 (d, J
= 8.5 Hz, 2H), 6.78 (d, J = 7.1 Hz, 1H), 4.79 (m, 1H), 4.00-3.91
(m, 2H), 3.86 (s, 3H), 3.72-3.55 (m, 2H), 2.38-2.26 (m, 1H),
2.07-2.04 (m, 3H). 151 385.1 2.4 H NMR (300 MHz, DMSO) 9.78 (br,
1H), 8.75 (m, 1H), 8.25 (d, J = 5.8 Hz, 1H), 8.07 (d, J = 8.4 Hz,
2H), 6.79 (d, J = 8.6 Hz, 2H), 4.71 (m, 1H), 4.23-3.58 (m, obscured
by water), 2.32-2.07 (m, 1H), 2.02 (m, 3H). 152 399.2 2.9 H NMR
(300 MHz, DMSO) 8.78-8.74 (m, 1H), 8.28 (d, J = 5.9 Hz, 1H), 8.17
(d, J = 8.7 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 4.73-4.70 (m, 1H),
3.96-3.79 (m, 7H), 2.27 (m, 1H), 1.97 (m, 3H). 153 427.2 2.8 H NMR
(300 MHz, DMSO) 8.77-8.73 (m, 1H), 8.25 (d, J = 5.8 Hz, 1H), 7.72
(m, 2H), 6.88 (d, J = 8.5 Hz, H)1, 4.77-4.65 (m, 1H), 4.28 (s, 4H),
4.02-3.51 (m, obscured by water), 2.27 (m, 1H), 1.96 (m, 3H). 154
395.7 2.3 155 408.0 2.4 156 430.0 3.0 157 442.0 3.0 158 412.0 2.7 H
NMR (300 MHz, DMSO) 12.38 (br, 1H), 8.58-8.23 (m, 2H), 8.14 (d, J =
6.5 Hz, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H),
6.64-6.58 (m, 1H), 3.87-3.75 (m, 2H), 1.63 (s, 6H). 159 424.0 2.8
160 444.0 3.2 H NMR (300 MHz, DMSO) 11.83 (s, 1H), 8.81 (t, J = 6.4
Hz, 1H), 8.43 (d, J = 2.1 Hz, 1H), 8.29 (d, J = 4.1 Hz, 1H), 8.22
(d, J = 2.8 Hz, 1H), 7.66-7.57 (m, 1H), 7.47 (d, J = 8.6 Hz, 1H),
7.18 (dd, J = 2.2, 8.6 Hz, 1H), 4.56 (t, J = 7.8 Hz, 1H), 4.22-3.82
(m, obscured by water), 2.31-2.18 (m, 1H), 1.03 (d, J = 6.9 Hz,
3H), 1.00 (d, J = 7.1 Hz, 3H). 161 426.0 2.9 H NMR (300 MHz, DMSO)
12.47 (br, 1H), 9.20-8.95 (m, 1H), 8.50 (s, 1H), 8.34 (s, 1H), 8.13
(d, J = 6.3 Hz, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.30 (d, J = 8.3 Hz,
1H), 6.81 (br, 1H), 4.83 (m, 1H), 4.16-3.85 (m, 2H), 2.33-2.27 (m,
1H), 1.05 (d, J = 6.9 Hz, 3H), 1.02 (d, J = 6.7 Hz, 3H). 162 409.2
2.4 H NMR (300 MHz, DMSO) 8.98 (dd, J = 1.8, 8.8 Hz, 2H), 8.86 (d,
J = 1.7 Hz, 1H), 8.64 (dd, J = 1.9, 8.9 Hz, 1H), 8.41-8.35 (m, 2H),
8.13 (d, J = 8.8 Hz, 1H), 7.77 (s, 1H), 3.83-3.72 (m, 2H), 1.60 (s,
6H). 163 391.3 2.1 H NMR (300 MHz, DMSO) 9.01 (d, J = 5.3 Hz, 2H),
8.94 (s, 1H), 8.64 (d, J = 9.0 Hz, 1H), 8.36-8.31 (m, 3H), 8.18 (d,
J = 9.0 Hz, 1H), 6.68 (m, 1H), 3.82-3.74 (m, obscured by water),
1.57 (s, 6H). 164 405.2 2.4 165 421.2 2.5 H NMR (300 MHz, DMSO)
9.04-8.91 (m, 4H), 8.70 (d, J = 7.8 Hz, 1H), 8.42 (d, J = 5.6 Hz,
1H), 8.15 (d, J = 8.7 Hz, 1H), 4.79 (m, 1H), 4.09-3.82 (m, 4H),
2.40-2.27 (m, 1H), 2.15-2.01 (m, 3H). 166 429.2 2.1 H NMR (300 MHz,
DMSO) 8.82 (t, J = 6.3 Hz, 1H), 8.22 (d, J = 3.7 Hz, 1H), 7.80-7.75
(m, 2H), 7.34 (d, J = 7.7 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 4.50
(t, J = 7.6 Hz, 1H), 4.28 (s, 4H), 4.10-3.74 (m, 2H), 2.28-2.13 (m,
1H), 0.99 (d, J = 6.6 Hz, 3H), 0.97 (d, J = 6.6 Hz, 3H). 167 368.8
1.7 H NMR (300 MHz, DMSO) 9.75 (s, 1H), 8.75 (t, J = 6.4 Hz, 1H),
8.19-8.08 (m, 3H), 7.44-7.36 (m, 1H), 6.80 (d, J = 8.8 Hz, 2H),
6.52 (d, J = 5.5 Hz, 1H), 4.67-4.57 (m, 1H), 4.07-3.76 (m, 2H),
2.14-2.01 (m, 1H), 0.97 (d, J = 6.8 Hz, 3H), 0.96 (d, J = 6.8 Hz,
3H). 168 423.3 2.4 H NMR (300 MHz, DMSO) 9.01-8.95 (m, 4H), 8.76
(dd, J = 1.9, 8.8 Hz, 1H), 8.40 (d, J = 3.7 Hz, 1H), 8.16 (d, J =
8.8 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 4.59 (t, J = 7.6 Hz, 1H),
4.13-3.81 (m, 2H), 2.30-2.19 (m, 1H), 1.04 (d, J = 6.6 Hz, 3H),
1.02 (d, J = 6.6 Hz, 3H).
Example 3
JAK3 Inhibition Assay
[0172] Compounds were screened for their ability to inhibit JAK3
using the assay shown below. Reactions were carried out in a kinase
buffer containing 100 mM HEPES (pH 7.4), 1 mM DTT, 10 mM
MgCl.sub.2, 25 mM NaCl, and 0.01% BSA. Substrate concentrations in
the assay were 5 .mu.M ATP (200 uCi/.mu.mole ATP) and 1 .mu.M
poly(Glu).sub.4Tyr. Reactions were carried out at 25.degree. C. and
1 nM JAK3.
[0173] To each well of a 96 well polycarbonate plate was added 1.5
.mu.l of a candidate JAK3 inhibitor along with 50 .mu.l of kinase
buffer containing 2 .mu.M poly(Glu).sub.4Tyr and 10 .mu.M ATP. This
was then mixed and 50 .mu.l of kinase buffer containing 2 nM JAK3
enzyme was added to start the reaction. After 20 minutes at room
temperature (25.degree. C.), the reaction was stopped with 50 .mu.l
of 20% trichloroacetic acid (TCA) that also contained 0.4 mM ATP.
The entire contents of each well were then transferred to a 96 well
glass fiber filter plate using a TomTek Cell Harvester. After
washing, 60 .mu.l of scintillation fluid was added and .sup.33P
incorporation detected on a Perkin Elmer TopCount.
[0174] The following compounds inhibited JAK3 with a Ki of less
than or equal to 1.0 .mu.M: 29, 33, 34, 35, 36, 37, 42, 56, 68, 74,
75, 97, 101, 102, 108, 114, 120, 123, 132, 139, 140, 144, 148, 154,
155, 162 and 163. The following compounds inhibited JAK3 with a Ki
of greater than 1.0 .mu.M and less than or equal to 10 .mu.M: 4,
11, 26, 27, 28, 30, 31, 32, 38, 39, 43, 44, 45, 49, 50, 51, 57, 58,
59, 60, 61, 64, 65, 66, 67, 72, 73, 77, 78, 79, 82, 86, 93, 94, 98,
104, 107, 109, 110, 112, 113, 119, 121, 130, 133, 136, 141, 147,
156, 158, 164, 167 and 168. The following compounds inhibited JAK3
with a Ki of greater than 10 .mu.M and less than or equal to 50
.mu.M: 2, 6, 8, 15, 20, 63, 71, 76, 80, 83, 84, 85, 88, 89, 96, 99,
100, 103, 106, 115, 116, 118, 126, 129, 135, 137, 142, 151, 159,
161 and 165. The following compounds did not inhibit JAK3 at
concentrations of 50 .mu.M: 1, 3, 5, 7, 9, 10, 12, 13, 14, 16, 17,
18, 19, 21, 22, 23, 24, 25, 62, 69, 70, 81, 87, 90, 91, 92, 95,
105, 111, 117, 122, 124, 125, 127, 128, 131, 134, 138, 143, 145,
146, 149, 150, 152, 153, 157, 160 and 166. The following compounds
did not inhibit JAK3 at concentrations of 5.0 .mu.M: 40, 41, 46,
47, 48, 52, 53, 54 and 55.
[0175] While we have described a number of embodiments of this
invention, it is apparent that our basic examples may be altered to
provide other embodiments which utilize the compounds and methods
of this invention. Therefore, it will be appreciated that the scope
of this invention is to be defined by the appended claims rather
than by the specific embodiments that have been represented by way
of example above.
* * * * *