U.S. patent application number 14/245770 was filed with the patent office on 2014-10-09 for compounds and methods for kinase modulation, and indications therefor.
The applicant listed for this patent is Plexxikon Inc.. Invention is credited to Prabha N. Ibrahim, Songyuan Shi, Wayne Spevak, James Tsai, Guoxian Wu, Chao Zhang, Jiazhong Zhang.
Application Number | 20140303187 14/245770 |
Document ID | / |
Family ID | 39745045 |
Filed Date | 2014-10-09 |
United States Patent
Application |
20140303187 |
Kind Code |
A1 |
Wu; Guoxian ; et
al. |
October 9, 2014 |
COMPOUNDS AND METHODS FOR KINASE MODULATION, AND INDICATIONS
THEREFOR
Abstract
Compounds active on protein kinases are described, as well as
methods of using such compounds to treat diseases and conditions
associated with aberrant activity of protein kinases.
Inventors: |
Wu; Guoxian; (Foster City,
CA) ; Zhang; Jiazhong; (Foster City, CA) ;
Zhang; Chao; (Moraga, CA) ; Ibrahim; Prabha N.;
(Mountain View, CA) ; Shi; Songyuan; (Fremont,
CA) ; Spevak; Wayne; (Berkeley, CA) ; Tsai;
James; (Vallejo, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Plexxikon Inc. |
Berkeley |
CA |
US |
|
|
Family ID: |
39745045 |
Appl. No.: |
14/245770 |
Filed: |
April 4, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13866353 |
Apr 19, 2013 |
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14245770 |
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12669450 |
Jan 15, 2010 |
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PCT/US08/70124 |
Jul 16, 2008 |
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13866353 |
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60959907 |
Jul 17, 2007 |
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Current U.S.
Class: |
514/256 ;
544/333 |
Current CPC
Class: |
A61P 37/00 20180101;
C07D 213/76 20130101; C07D 213/82 20130101; C07D 285/135 20130101;
A61P 3/06 20180101; A61P 17/14 20180101; A61P 25/06 20180101; A61P
35/02 20180101; A61P 1/16 20180101; A61P 5/14 20180101; C07D 285/16
20130101; C07D 405/12 20130101; A61P 17/00 20180101; A61P 19/08
20180101; A61P 31/04 20180101; A61P 31/12 20180101; A61P 35/04
20180101; A61P 3/10 20180101; A61P 11/02 20180101; A61P 13/08
20180101; A61P 1/18 20180101; A61P 9/08 20180101; A61P 9/10
20180101; A61P 25/14 20180101; A61P 29/00 20180101; A61P 25/16
20180101; A61P 37/08 20180101; A61P 25/04 20180101; A61K 31/42
20130101; A61K 31/4439 20130101; A61P 11/06 20180101; A61K 31/415
20130101; A61P 21/00 20180101; C07D 213/75 20130101; A61P 19/00
20180101; A61P 21/04 20180101; A61P 25/02 20180101; C07D 215/38
20130101; A61K 31/549 20130101; A61P 17/06 20180101; A61P 19/02
20180101; A61P 27/02 20180101; A61P 31/16 20180101; C07D 215/14
20130101; C07D 401/12 20130101; A61P 3/04 20180101; A61P 7/02
20180101; A61P 19/10 20180101; A61P 35/00 20180101; A61P 13/12
20180101; C07D 239/48 20130101; A61P 5/00 20180101; A61P 11/00
20180101; C07D 215/12 20130101; C07D 261/14 20130101; A61K 31/4545
20130101; A61P 25/28 20180101; A61P 37/06 20180101; A61P 43/00
20180101; C07D 417/04 20130101; A61K 45/06 20130101; A61P 17/02
20180101; C07D 213/74 20130101; C07D 239/49 20130101; A61P 31/14
20180101; C07D 471/04 20130101; A61P 1/04 20180101; A61P 15/10
20180101; C07D 409/12 20130101; A61K 31/4436 20130101; A61P 17/04
20180101; A61P 15/00 20180101; A61P 31/20 20180101; C07D 215/20
20130101; A61P 7/00 20180101; C07D 231/40 20130101; A61K 31/437
20130101; A61K 31/505 20130101; A61P 25/00 20180101; A61K 31/506
20130101; C07D 263/48 20130101; C07D 417/12 20130101; A61K 31/44
20130101; A61P 3/00 20180101; A61P 9/00 20180101; A61K 31/444
20130101; A61P 9/04 20180101; A61K 31/433 20130101; A61K 31/47
20130101; A61K 31/5377 20130101; A61K 31/4427 20130101; A61K
2300/00 20130101 |
Class at
Publication: |
514/256 ;
544/333 |
International
Class: |
C07D 417/04 20060101
C07D417/04; A61K 31/506 20060101 A61K031/506 |
Claims
1. A compound of formula (Ic): ##STR00307## or a pharmaceutically
acceptable salt thereof, wherein: each R.sup.1 is independently
selected from optionally substituted lower alkyl or optionally
substituted heteroaryl; R.sup.2 is hydrogen or halogen; R.sup.3 is
optionally substituted aryl; R.sup.4 is hydrogen; the subscript m
is 2; and Ar is optionally substituted heteroaryl, with the proviso
that Ar is other than ##STR00308## wherein ##STR00309## indicates
the point of the attachment to the phenyl moiety in formula
(Ic).
2. The compound of claim 1, wherein R.sup.2 is hydrogen.
3. The compound of claim 2, wherein R.sup.2 is halogen.
4. The compound of claim 2, wherein R.sup.3 is optionally
substituted phenyl.
5. The compound of claim 2, wherein R.sup.3 is phenyl optionally
substituted with one or more halogen substituents.
6. The compound of claim 1, wherein R.sup.3 is phenyl optionally
substituted with one or more fluoro substituents.
7. The compound of claim 6, wherein R.sup.3 is phenyl substituted
with two fluoro substituents.
8. The compound of claim 1, wherein each R.sup.1 is independently
optionally substituted lower alkyl or optionally substituted
heteroaryl.
9. The compound of claim 8, wherein one R.sup.1 is lower alkyl and
the other R.sup.1 is heteroaryl substituted with one or more
NH.sub.2 groups.
10. The compound of claim 8, wherein one R.sup.1 is lower alkyl and
the other R.sup.1 is pyrimidinyl substituted with one or more
NH.sub.2 groups.
11. The compound of claim 10, wherein one R.sup.1 is t-butyl and
the other R.sup.1 is pyrimidinyl substituted with NH.sub.2.
12. The compound of claim 1, wherein Ar is: ##STR00310## wherein
each X is independently N or CH; and Y is S.
13. The compound of claim 12, wherein Ar is thiazolyl.
14. The compound of claim 12, wherein Ar is 4-thiazolyl.
15. A compound of formula (Ic): ##STR00311## or a pharmaceutically
acceptable salt thereof, wherein: each R.sup.1 is independently
selected from t-butyl or pyrimidinyl substituted with NH.sub.2;
R.sup.2 is H; R.sup.3 is phenyl substituted with two fluoro groups;
R.sup.4 is hydrogen; the subscript m is 2; and Ar is
4-thiazolyl.
16. A pharmaceutical composition comprising: a compound of claim 1
and a pharmaceutically acceptable carrier or excipient.
17. A pharmaceutical composition comprising: a compound of claim 15
and a pharmaceutically acceptable carrier or excipient.
18. A pharmaceutical composition comprising a compound of claim 1
and another therapeutic agent.
19. A method for treating a subject suffering from melanoma,
thyroid cancer or colorectal cancer, said method comprising:
administering to the subject an effective amount of a compound of
claim 15.
20. The method of claim 19, wherein the melanoma is melanoma having
a mutation encoding a V600E amino acid substitution.
Description
[0001] This application is a continuation application of U.S.
application Ser. No. 12/669,450, filed Jan. 15, 2010, which
application is a National Phase application under 35 U.S.C.
.sctn.371 of PCT/US2008/070124, filed Jul. 16, 2008, which claims
the benefit under 35 U.S.C. .sctn.119(e) from U.S. Application No.
60/959,907, filed Jul. 17, 2007, which applications are hereby
incorporated by reference in their entirety.
FIELD OF THE INVENTION
Background of the Invention
[0002] The present invention relates to kinases and compounds which
modulate kinases, and uses therefor. Particular embodiments
contemplate disease indications which are amenable to treatment by
modulation of kinase activity by the compounds of the present
invention.
SUMMARY OF THE INVENTION
[0003] Compounds are contemplated that are active on protein
kinases in general, including, but not limited to, Abl, Akt1, Akt2,
Akt3, ALK, Alk5, A-Raf, B-Raf, Brk, Btk, Cdk2, CDK4, CDK5, CDK6,
CHK1, c-Raf-1, Csk, EGFR, EphA1, EphA2, EphB2, EphB4, Erk2, Fak,
FGFR1, FGFR2, FGFR3, FGFR4, Flt1, Flt3, Flt4, Fms, Frk, Fyn,
Gsk3.alpha.c, Gsk3.beta., HCK, Her2/Erbb2, Her4/Erbb4, IGF1R, IKK
beta, Irak4, Itk, Jak1, Jak2, Jak3, Jnk1, Jnk2, Jnk3, Kdr, Kit,
Lck, Lyn, MAP2K1, MAP2K2, MAP4K4, MAPKAPK2, Met, Mnk1, MLK1, p38,
PDGFRA, PDGFRB, PDPK1, Pim1, Pim2, Pim3, PKC alpha, PKC beta, PKC
theta, Plk1, Pyk2, Ret, ROCK1, ROCK2, Ron, Src, Stk6, Syk, TEC,
Tie2, TrkA, TrkB, Yes, and/or Zap70, including any mutations of
these kinases. In some aspects, the compounds are active on Raf
protein kinases including A-Raf, B-Raf and/or c-Raf-1, including
any mutations thereof. In some aspects, compounds are of Formula I
as described below.
[0004] Also contemplated in accordance with the present invention
are methods for the use of the above-described compounds in
treating diseases and conditions associated with regulation of the
activity of the above-described kinases. Thus, the use of compounds
for therapeutic methods involving modulation of protein kinases are
provided, as well as compounds that can be used for therapeutic
methods involving modulation of protein kinases.
[0005] In some embodiments, compounds have the structure according
to the following Formula I:
##STR00001##
or a salt, a prodrug, a tautomer or an isomer thereof, wherein:
[0006] Ar is optionally substituted heteroaryl; [0007] R.sup.1 at
each occurrence is independently selected from the group consisting
of halogen, optionally substituted lower alkyl, optionally
substituted lower alkenyl, optionally substituted lower alkynyl,
optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, optionally
substituted heteroaryl, --NO.sub.2, --CN, --O--R.sup.5,
--N(R.sup.5)--R.sup.6, --C(X)--N(R.sup.5)--R.sup.6,
--C(X)--R.sup.7, --S(O).sub.2--N(R.sup.5)--R.sup.6,
--S(O).sub.n--R.sup.7, --O--C(X)--R.sup.7, --C(X)--O--R.sup.5,
--C(NH)--N(R.sup.8)--R.sup.9, --N(R.sup.5)--C(X)--R.sup.7,
--N(R.sup.5)--S(O).sub.2--R.sup.7,
--N(R.sup.5)--C(X)--N(R.sup.5)--R.sup.6, and
--N(R.sup.5)--S(O).sub.2--N(R.sup.5)--R.sup.6; [0008] m is 0, 1, 2,
3, 4 or 5; [0009] n is 0, 1 or 2; [0010] R.sup.2 is hydrogen, lower
alkyl or halogen; [0011] L.sub.2 is selected from the group
consisting of --S(O).sub.2--, --C(X)--, --C(X)--N(R.sup.10)--, and
--S(O).sub.2--N(R.sup.10)--; [0012] R.sup.3 is optionally
substituted lower alkyl, optionally substituted C.sub.3-6
cycloalkyl, optionally substituted heterocycloalkyl, optionally
substituted aryl or optionally substituted heteroaryl; [0013]
L.sub.1 is selected from the group consisting of a bond,
--N(R.sup.11)--, --O--, --S--, --C(X)--,
--C(R.sup.12R.sup.13)--X--, --X--C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)--N(R)--,
--N(R.sup.11)--C(R.sup.12R.sup.13)--, --O--C(X)--, --C(X)--O--,
--C(X)--N(R.sup.11)--, --N(R.sup.11)--C(X)--, --S(O)--,
--S(O).sub.2--, --S(O).sub.2--N(R.sup.11)--,
--N(R.sup.11)--S(O).sub.2--, --C(NH)--N(R.sup.11)--,
--N(R.sup.11)--C(NH)--, --N(R.sup.11)--C(X)--N(R.sup.11)--, and
--N(R.sup.11)--S(O).sub.2--N(R.sup.11)--; [0014] X is O or S;
[0015] R.sup.4, R.sup.10 and each R.sup.11 are independently
hydrogen or lower alkyl, wherein lower alkyl is optionally
substituted with one or more substituents selected from the group
consisting of fluoro, --OH, --NH.sub.2, lower alkoxy, fluoro
substituted lower alkoxy, lower alkylthio, fluoro substituted lower
alkylthio, mono-alkylamino, fluoro substituted mono-alkylamino,
di-alkylamino, fluoro substituted di-alkylamino, and
--NR.sup.14R.sup.15; [0016] R.sup.5, R.sup.6, R.sup.8, and R.sup.9
at each occurrence are independently selected from the group
consisting of hydrogen, optionally substituted lower alkyl,
optionally substituted C.sub.3-6 alkenyl, optionally substituted
C.sub.3-6 alkynyl, optionally substituted cycloalkyl, optionally
substituted heterocycloalkyl, optionally substituted aryl, and
optionally substituted heteroaryl, or [0017] R.sup.8 and R.sup.9
combine with the nitrogen to which they are attached to form a 5-7
membered optionally substituted nitrogen containing
heterocycloalkyl or a 5 or 7 membered optionally substituted
nitrogen containing heteroaryl; [0018] R.sup.7 at each occurrence
is independently selected from the group consisting of optionally
substituted lower alkyl, optionally substituted C.sub.3-6 alkenyl,
optionally substituted C.sub.3-6 alkynyl, optionally substituted
cycloalkyl, optionally substituted heterocycloalkyl, optionally
substituted aryl, and optionally substituted heteroaryl; [0019]
R.sup.12 and R.sup.13 are independently selected from the group
consisting of hydrogen, fluoro, --OH, --NH.sub.2, lower alkyl,
lower alkoxy, lower alklylthio, mono-alkylamino, di-alkylamino, and
--NR.sup.14R.sup.15, wherein the alkyl chain(s) of lower alkyl,
lower alkoxy, lower alkylthio, mono-alkylamino, or di-alkylamino
are optionally substituted with one or more substituents selected
from the group consisting of fluoro, --OH, --NH.sub.2, lower
alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro
substituted lower alkylthio, mono-alkylamino, di-alkylamino, and
cycloalkylamino; or [0020] R.sup.12 and R.sup.13 combine with the
carbon to which they are attached to form a 3-7 membered monocyclic
cycloalkyl or 5-7 membered monocyclic heterocycloalkyl, wherein the
monocyclic cycloalkyl or monocyclic heterocycloalkyl are optionally
substituted with one or more substituents selected from the group
consisting of halogen, --OH, --NH.sub.2, lower alkyl, fluoro
substituted lower alkyl, lower alkoxy, fluoro substituted lower
alkoxy, lower alkylthio, fluoro substituted lower alkylthio,
mono-alkylamino, di-alkylamino, and cycloalkylamino; and [0021]
R.sup.14 and R.sup.15 at each occurrence independently combine with
the nitrogen to which they are attached to form a 5-7 membered
heterocycloalkyl or 5-7 membered heterocycloalkyl substituted with
one or more substituents selected from the group consisting of
fluoro, --OH, --NH.sub.2, lower alkyl, fluoro substituted lower
alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower
alkylthio, and fluoro substituted lower alkylthio, provided,
however, that when L.sub.1 is a bond, --NR.sup.11--, --O--, --S--,
--C(X)--, --S(O)--, or --S(O).sub.2--, Ar is not
1H-pyrrolo[2,3-b]pyridine-3-yl, 1H-pyrazolo[3,4-b]pyridine-3-yl,
5H-pyrrolo[2,3-b]pyrazine-7-yl, 7H-pyrrolo[2,3-d]pyrimidine-5-yl,
or 7H-pyrrolo[2,3-c]pyridazine-5-yl, i.e. is not
##STR00002##
[0021] wherein
##STR00003##
indicates the attachment point to L.sub.1.
[0022] In some embodiments, the compound of Formula I has a
structure according to the following sub-generic structure Formula
Ia:
##STR00004##
or a salt, a prodrug, a tautomer or an isomer thereof, wherein m,
Ar, R.sup.1, R.sup.2, R.sup.3, R.sup.4, and L.sub.1 are as defined
for Formula I.
[0023] In some embodiments of compounds of Formula I or Ia, L.sub.1
is a bond, --N(R.sup.11)--, --N(R.sup.11)--C(X)--,
--N(R.sup.11)--S(O).sub.2--, --N(R.sup.11)--C(NH)--,
--N(R.sup.11)--C(X)--N(R.sup.11)--, or
--N(R.sup.11)--S(O).sub.2--N(R.sup.11)--, also --N(R.sup.11)--,
--N(R.sup.11)--C(X)--, or --N(R.sup.11)--S(O).sub.2--, also
--N(R.sup.11)--C(O)--, wherein the left side (i.e. --N(R.sup.11)--)
of L.sub.1 is attached to Ar and the right side of L.sub.1 is
attached to the phenyl ring of Formula I or Ia. In some
embodiments, L.sub.1 is a bond, --N(R.sup.11)--,
--N(R.sup.11)--C(X)--, --N(R.sup.11)--S(O).sub.2--,
--N(R.sup.11)--C(NH)--, --N(R.sup.11)--C(X)--N(R.sup.11)--, or
--N(R.sup.11)--S(O).sub.2--N(R.sup.11)--, also --N(R.sup.11)--,
--N(R.sup.11)--C(X)--, or --N(R.sup.11)--S(O).sub.2--, also
--N(R.sup.11)--C(O)--, and each R.sup.11 and R.sup.4 are
independently hydrogen or lower alkyl, wherein lower alkyl is
optionally substituted with one or more substituents selected from
the group consisting of fluoro, lower alkoxy, fluoro substituted
lower alkoxy, lower alkylthio, and fluoro substituted lower
alkylthio, preferably each R.sup.11 and R.sup.4 are H.
[0024] In some embodiments of compounds of Formula I or Ia, L.sub.1
is --C(X)--N(R.sup.11)--, --C(R.sup.12R.sup.13)--X--,
--X--C(R.sup.12R.sup.13)--, --C(R.sup.12R.sup.13)--N(R.sup.11)--,
or --N(R.sup.11)--C(R.sup.12R.sup.13)--, wherein the left side of
L.sub.1 is attached to Ar and the right side of L.sub.1 is attached
to the phenyl ring of Formula I or Ia. In some embodiments, L.sub.1
is --C(X)--N(R.sup.11)--, --C(R.sup.12R.sup.13)--X--,
--X--C(R.sup.12R.sup.13)--, --C(R.sup.12R.sup.13)--N(R.sup.11)--,
or --N(R.sup.11)--C(R.sup.12R.sup.13)--, and each R.sup.11 and
R.sup.4 are independently hydrogen or lower alkyl, wherein lower
alkyl is optionally substituted with one or more substituents
selected from the group consisting of fluoro, lower alkoxy, fluoro
substituted lower alkoxy, lower alkylthio, and fluoro substituted
lower alkylthio, preferably each R.sup.11 and R.sup.4 are H.
[0025] In some embodiments of compounds of Formula I or Ia, R.sup.2
is hydrogen, fluoro or chloro, preferably fluoro or chloro. In some
embodiments, R.sup.2 is hydrogen, fluoro or chloro, each R.sup.11
and R.sup.4 are independently hydrogen or lower alkyl, wherein
lower alkyl is optionally substituted with one or more substituents
selected from the group consisting of fluoro, lower alkoxy, fluoro
substituted lower alkoxy, lower alkylthio, and fluoro substituted
lower alkylthio, preferably R.sup.2 is fluoro or chloro and each
R.sup.11 and R.sup.4 are H. In some embodiments, R.sup.2 is
hydrogen, fluoro or chloro, preferably fluoro or chloro, and
L.sub.1 is a bond, --N(R.sup.11)--, --N(R.sup.11)--C(X)--,
--N(R.sup.11)--S(O).sub.2--, --N(R.sup.11)--C(NH)--,
--N(R.sup.11)--C(X)--N(R.sup.11)--, or
--N(R.sup.11)--S(O).sub.2--N(R.sup.11)--, also --N(R.sup.11)--,
--N(R.sup.11)--C(X)--, or --N(R.sup.11)--S(O).sub.2--, also
--N(R.sup.11)--C(O)--, wherein the left side (i.e. --N(R.sup.11)--)
of L.sub.1 is attached to Ar and the right side of L.sub.1 is
attached to the phenyl ring of Formula I or Ia. In some
embodiments, R.sup.2 is hydrogen, fluoro or chloro, preferably
fluoro or chloro; L.sub.1 is a bond, --N(R.sup.11)--,
--N(R.sup.11)--C(X)--, --N(R.sup.11)--S(O).sub.2--,
--N(R.sup.11)--C(NH)--, --N(R.sup.11)--C(X)--N(R.sup.11)--, or
--N(R.sup.11)--S(O).sub.2--N(R.sup.11)--, also --N(R.sup.11)--,
--N(R.sup.11)--C(X)--, or --N(R.sup.11)--S(O).sub.2--, also
--N(R.sup.11)--C(O)--; and each R.sup.11 and R.sup.4 are
independently hydrogen or lower alkyl, wherein lower alkyl is
optionally substituted with one or more substituents selected from
the group consisting of fluoro, lower alkoxy, fluoro substituted
lower alkoxy, lower alkylthio, and fluoro substituted lower
alkylthio, preferably each R.sup.11 and R.sup.4 are H.
[0026] In some embodiments of compounds of Formula I or Ia, R.sup.2
is hydrogen, fluoro or chloro, preferably fluoro or chloro. In some
embodiments, R.sup.2 is hydrogen, fluoro or chloro, each R.sup.11
and R.sup.4 are independently hydrogen or lower alkyl, wherein
lower alkyl is optionally substituted with one or more substituents
selected from the group consisting of fluoro, lower alkoxy, fluoro
substituted lower alkoxy, lower alkylthio, and fluoro substituted
lower alkylthio, preferably R.sup.2 is fluoro or chloro and each
R.sup.11 and R.sup.4 are H. In some embodiments, R.sup.2 is
hydrogen, fluoro or chloro, preferably fluoro or chloro, and
L.sub.1 is --C(X)--N(R.sup.11)--, --C(R.sup.12R.sup.13)--X--,
--X--C(R.sup.12R.sup.13)--, --C(R.sup.12R.sup.13)--N(R.sup.11)--,
or --N(R.sup.11)--C(R.sup.12R.sup.13)--, wherein the left side of
L.sub.1 is attached to Ar and the right side of L.sub.1 is attached
to the phenyl ring of Formula I or Ia. In some embodiments, R.sup.2
is hydrogen, fluoro or chloro, preferably fluoro or chloro; L.sub.1
is --C(X)--N(R.sup.11)--, --C(R.sup.12R.sup.13)--X--,
--X--C(R.sup.12R.sup.13)--, --C(R.sup.12R.sup.13)--N(R.sup.11)--,
or --N(R.sup.11)--C(R.sup.12R.sup.13)--; and each R.sup.11 and
R.sup.4 are independently hydrogen or lower alkyl, wherein lower
alkyl is optionally substituted with one or more substituents
selected from the group consisting of fluoro, lower alkoxy, fluoro
substituted lower alkoxy, lower alkylthio, and fluoro substituted
lower alkylthio, preferably each R.sup.11 and R.sup.4 are H.
[0027] In some embodiments, the compound of Formula I has a
structure according to the following sub-generic structure Formula
Ib:
##STR00005##
or a salt, a prodrug, a tautomer or an isomer thereof, wherein A is
--C(O)-- or --C(R.sup.12R.sup.13)--; and m, Ar, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.11, R.sup.12 and R.sup.13 are as defined
for Formula I.
[0028] In some embodiments of compounds of Formula Ib, R.sup.4,
R.sup.11, R.sup.12 and R.sup.13 are independently hydrogen or lower
alkyl, wherein lower alkyl is optionally substituted with one or
more substituents selected from the group consisting of fluoro,
lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and
fluoro substituted lower alkylthio, preferably R.sup.4, R.sup.11,
R.sup.12 and R.sup.13 are H. In some embodiments, R.sup.2 is
hydrogen, fluoro or chloro, preferably fluoro or chloro. In some
embodiments, R.sup.2 is hydrogen, fluoro or chloro, and R.sup.4,
R.sup.11, R.sup.12 and R.sup.13 are independently hydrogen or lower
alkyl, wherein lower alkyl is optionally substituted with one or
more substituents selected from the group consisting of fluoro,
lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and
fluoro substituted lower alkylthio, preferably R.sup.2 is fluoro or
chloro and R.sup.4, R.sup.11, R.sup.12 and R.sup.13 are H.
[0029] In some embodiments of compounds of Formula Ib, A is
--C(O)--, and R.sup.4 and R.sup.11 are independently hydrogen or
lower alkyl, wherein lower alkyl is optionally substituted with one
or more substituents selected from the group consisting of fluoro,
lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and
fluoro substituted lower alkylthio, preferably R.sup.4 and R.sup.11
are H. In some embodiments, A is --C(O)--, and R.sup.2 is hydrogen,
fluoro or chloro, preferably fluoro or chloro. In some embodiments,
A is --C(O)--, R.sup.2 is hydrogen, fluoro or chloro, preferably
fluoro or chloro; and R.sup.4 and R.sup.11 are independently
hydrogen or lower alkyl, wherein lower alkyl is optionally
substituted with one or more substituents selected from the group
consisting of fluoro, lower alkoxy, fluoro substituted lower
alkoxy, lower alkylthio, and fluoro substituted lower alkylthio,
preferably R.sup.4 and R.sup.11 are H.
[0030] In some embodiments of compounds of Formula Ib, A is
--C(R.sup.12R.sup.13)--, and R.sup.4, R.sup.11, R.sup.12 and
R.sup.13 are independently hydrogen or lower alkyl, wherein lower
alkyl is optionally substituted with one or more substituents
selected from the group consisting of fluoro, lower alkoxy, fluoro
substituted lower alkoxy, lower alkylthio, and fluoro substituted
lower alkylthio, preferably R.sup.4, R.sup.11, R.sup.12 and
R.sup.13 are H. In some embodiments, A is --C(R.sup.12R.sup.13)--,
R.sup.12 and R.sup.13 are independently hydrogen or lower alkyl,
wherein lower alkyl is optionally substituted with one or more
substituents selected from the group consisting of fluoro, lower
alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and
fluoro substituted lower alkylthio, preferably R.sup.12 and
R.sup.13 are H, and R.sup.2 is hydrogen, fluoro or chloro,
preferably fluoro or chloro. In some embodiments, A is
--C(R.sup.12R.sup.13)--; R.sup.2 is hydrogen, fluoro or chloro,
preferably fluoro or chloro; and R.sup.4, R.sup.11, R.sup.12 and
R.sup.13 are independently hydrogen or lower alkyl, wherein lower
alkyl is optionally substituted with one or more substituents
selected from the group consisting of fluoro, lower alkoxy, fluoro
substituted lower alkoxy, lower alkylthio, and fluoro substituted
lower alkylthio, preferably R.sup.4, R.sup.11, R.sup.12 and
R.sup.13 are H.
[0031] In some embodiments, the compound of Formula I has a
structure according to the following sub-generic structure Formula
Ic:
##STR00006##
or a salt, a prodrug, a tautomer or an isomer thereof, wherein m,
Ar, R.sup.1, R.sup.2, R.sup.3, and R.sup.4, are as defined for
Formula I.
[0032] In some embodiments of compounds of Formula Ic, R.sup.4 is
hydrogen or lower alkyl, wherein lower alkyl is optionally
substituted with one or more substituents selected from the group
consisting of fluoro, lower alkoxy, fluoro substituted lower
alkoxy, lower alkylthio, and fluoro substituted lower alkylthio,
preferably R.sup.4 is H. In some embodiments, R.sup.2 is hydrogen,
fluoro or chloro, preferably fluoro or chloro. In some embodiments,
R.sup.2 is hydrogen, fluoro or chloro and R.sup.4 is hydrogen or
lower alkyl, wherein lower alkyl is optionally substituted with one
or more substituents selected from the group consisting of fluoro,
lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and
fluoro substituted lower alkylthio, preferably R.sup.2 is fluoro or
chloro and R.sup.4 is H.
[0033] In some embodiments, the compound of Formula I has a
structure according to the following sub-generic structure Formula
Id:
##STR00007##
or a salt, a prodrug, a tautomer or an isomer thereof, wherein A is
--C(O)-- or --C(R.sup.12R.sup.13)--; and m, Ar, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.11, R.sup.12, R.sup.13 and L.sub.2 are as
defined for Formula I.
[0034] In some embodiments of compounds of Formula Id, R.sup.4,
R.sup.11, R.sup.12 and R.sup.13 are independently hydrogen or lower
alkyl, wherein lower alkyl is optionally substituted with one or
more substituents selected from the group consisting of fluoro,
lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and
fluoro substituted lower alkylthio, preferably R.sup.4, R.sup.11,
R.sup.12 and R.sup.13 are H. In some embodiments, R.sup.2 is
hydrogen, fluoro or chloro, preferably fluoro or chloro. In some
embodiments, R.sup.2 is hydrogen, fluoro or chloro, and R.sup.4,
R.sup.11, R.sup.12 and R.sup.13 are independently hydrogen or lower
alkyl, wherein lower alkyl is optionally substituted with one or
more substituents selected from the group consisting of fluoro,
lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and
fluoro substituted lower alkylthio, preferably R.sup.2 is fluoro or
chloro and R.sup.4, R.sup.11, R.sup.12 and R.sup.13 are H.
[0035] In some embodiments of compounds of Formula Id, A is
--C(O)--, and R.sup.4 and R.sup.11 are independently hydrogen or
lower alkyl, wherein lower alkyl is optionally substituted with one
or more substituents selected from the group consisting of fluoro,
lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and
fluoro substituted lower alkylthio, preferably R.sup.4 and R.sup.11
are H. In some embodiments, A is --C(O)--, and R.sup.2 is hydrogen,
fluoro or chloro, preferably fluoro or chloro. In some embodiments,
A is --C(O)--, R.sup.2 is hydrogen, fluoro or chloro, preferably
fluoro or chloro; and R.sup.4 and R.sup.11 are hydrogen or lower
alkyl, wherein lower alkyl is optionally substituted with one or
more substituents selected from the group consisting of fluoro,
lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and
fluoro substituted lower alkylthio, preferably R.sup.4 and R.sup.11
are H.
[0036] In some embodiments of compounds of Formula Id, A is
--C(R.sup.12R.sup.13)--, and R.sup.4, R.sup.11, R.sup.12 and
R.sup.13 are independently hydrogen or lower alkyl, wherein lower
alkyl is optionally substituted with one or more substituents
selected from the group consisting of fluoro, lower alkoxy, fluoro
substituted lower alkoxy, lower alkylthio, and fluoro substituted
lower alkylthio, preferably R.sup.4, R.sup.11, R.sup.12 and
R.sup.13 are H. In some embodiments, A is --C(R.sup.12R.sup.13)--,
R.sup.12 and R.sup.13 are independently hydrogen or lower alkyl,
wherein lower alkyl is optionally substituted with one or more
substituents selected from the group consisting of fluoro, lower
alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and
fluoro substituted lower alkylthio, preferably R.sup.12 and
R.sup.13 are H, and R.sup.2 is hydrogen, fluoro or chloro,
preferably fluoro or chloro. In some embodiments, A is
--C(R.sup.12R.sup.13)--; R.sup.2 is hydrogen, fluoro or chloro,
preferably fluoro or chloro; and R.sup.4, R.sup.11, R.sup.12 and
R.sup.13 are independently hydrogen or lower alkyl, wherein lower
alkyl is optionally substituted with one or more substituents
selected from the group consisting of fluoro, lower alkoxy, fluoro
substituted lower alkoxy, lower alkylthio, and fluoro substituted
lower alkylthio, preferably R.sup.4, R.sup.11, R.sup.12 and
R.sup.13 are H.
[0037] In some embodiments, the compound of Formula I has a
structure according to the following sub-generic structure Formula
Ie:
##STR00008##
or a salt, a prodrug, a tautomer or an isomer thereof, wherein m,
Ar, R.sup.1, R.sup.2, R.sup.3, R.sup.4, and L.sub.2 are as defined
for Formula I.
[0038] In some embodiments of compounds of Formula Ie, R.sup.4 is
hydrogen or lower alkyl, wherein lower alkyl is optionally
substituted with one or more substituents selected from the group
consisting of fluoro, lower alkoxy, fluoro substituted lower
alkoxy, lower alkylthio, and fluoro substituted lower alkylthio,
preferably R.sup.4 is H. In some embodiments, R.sup.2 is hydrogen,
fluoro or chloro, preferably fluoro or chloro. In some embodiments,
R.sup.2 is hydrogen, fluoro or chloro and R.sup.4 is hydrogen or
lower alkyl, wherein lower alkyl is optionally substituted with one
or more substituents selected from the group consisting of fluoro,
lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and
fluoro substituted lower alkylthio, preferably R.sup.2 is fluoro or
chloro and R.sup.4 is H.
[0039] In some embodiments, the compound of Formula I has a
structure according to the following sub-generic structure Formula
If:
##STR00009##
or a salt, a prodrug, a tautomer or an isomer thereof,
[0040] wherein:
L.sub.3 is --C(X)--N(R.sup.11)--, --C(R.sup.12R.sup.13)--X--,
--X--C(R.sup.12R.sup.13)--, --C(R.sup.12R.sup.13)--N(R.sup.11)--,
or --N(R.sup.11)--C(R.sup.12R.sup.13)--; and m, Ar, R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.11, R.sup.12, R.sup.13, and X are
as defined for Formula I.
[0041] In some embodiments of compounds of Formula If, L.sub.3 is
--C(O)--N(R.sup.11)--, --C(R.sup.12R.sup.13)--O--,
--O--C(R.sup.12R.sup.13)--, --C(R.sup.12R.sup.31)--N(R.sup.11)--,
or --N(R.sup.11)--C(R.sup.12R.sup.13)--, wherein the left side of
L.sub.3 is attached to Ar and the right side of L.sub.3 is attached
to the phenyl ring of Formula If. In some embodiments, L.sub.3 is
--C(O)--N(R.sup.11)--, --C(R.sup.12R.sup.13)--O--,
--O--C(R.sup.12R.sup.13)--, --C(R.sup.12R.sup.13)--N(R.sup.11)--,
or --N(R.sup.11)--C(R.sup.12R.sup.13)--, and R.sup.4, R.sup.11,
R.sup.12 and R.sup.13 are independently hydrogen or lower alkyl,
wherein lower alkyl is optionally substituted with one or more
substituents selected from the group consisting of fluoro, lower
alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and
fluoro substituted lower alkylthio, preferably R.sup.4, R.sup.11,
R.sup.12 and R.sup.13 are H.
[0042] In some embodiments, the compound of Formula I has a
structure according to the following sub-generic structure Formula
Ig:
##STR00010##
or a salt, a prodrug, a tautomer or an isomer thereof,
[0043] wherein:
L.sub.3 is --C(X)--N(R.sup.11)--, --C(R.sup.12R.sup.13)--X--,
--X--C(R.sup.12R.sup.13)--, --C(R.sup.12R.sup.13)--N(R.sup.11)--,
or --N(R.sup.11)--C(R.sup.12R.sup.13)--; and m, Ar, R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.11, R.sup.12, R.sup.13, X and
L.sub.2 are as defined for Formula I.
[0044] In some embodiments of compounds of Formula Ig, L.sub.3 is
--C(O)--N(R.sup.11)--, --C(R.sup.12R.sup.13)--O--,
--O--C(R.sup.12R.sup.13)--, --C(R.sup.12R.sup.13)--N(R.sup.11)--,
or --N(R.sup.11)--C(R.sup.12R.sup.13)--, wherein the left side of
L.sub.3 is attached to Ar and the right side of L.sub.3 is attached
to the phenyl ring of Formula Ig. In some embodiments, L.sub.3 is
--C(O)--N(R.sup.11)--, --C(R.sup.12R.sup.13)--O--,
--O--C(R.sup.12R.sup.13)--, --C(R.sup.12R.sup.13)--N(R.sup.11)--,
or --N(R.sup.11)--C(R.sup.12R.sup.13)--, and R.sup.4, R.sup.11,
R.sup.12 and R.sup.13 are independently hydrogen or lower alkyl,
wherein lower alkyl is optionally substituted with one or more
substituents selected from the group consisting of fluoro, lower
alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and
fluoro substituted lower alkylthio, preferably R.sup.4, R.sup.11,
R.sup.12 and R.sup.13 are H.
[0045] In some embodiments, the compound of Formula I has a
structure according to the following sub-generic structure Formula
Ih:
##STR00011##
or a salt, a prodrug, a tautomer or an isomer thereof, wherein A is
--C(O)-- or --C(R.sup.12R.sup.13)--; and m, Ar, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.11, R.sup.12 and R.sup.13 are as defined
for Formula I.
[0046] In some embodiments of compounds of Formula Ih, R.sup.4,
R.sup.11, R.sup.12 and R.sup.13 are independently hydrogen or lower
alkyl, wherein lower alkyl is optionally substituted with one or
more substituents selected from the group consisting of fluoro,
lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and
fluoro substituted lower alkylthio, preferably R.sup.4, R.sup.11,
R.sup.12 and R.sup.13 are H. In some embodiments, R.sup.2 is
hydrogen, fluoro or chloro, preferably fluoro or chloro. In some
embodiments, R.sup.2 is hydrogen, fluoro or chloro, and R.sup.4,
R.sup.11, R.sup.12 and R.sup.13 are independently hydrogen or lower
alkyl, wherein lower alkyl is optionally substituted with one or
more substituents selected from the group consisting of fluoro,
lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and
fluoro substituted lower alkylthio, preferably R.sup.2 is fluoro or
chloro and R.sup.4, R.sup.11, R.sup.12 and R.sup.13 are H.
[0047] In some embodiments of compounds of Formula Ih, A is
--C(O)--, and R.sup.4 and R.sup.11 are independently hydrogen or
lower alkyl, wherein lower alkyl is optionally substituted with one
or more substituents selected from the group consisting of fluoro,
lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and
fluoro substituted lower alkylthio, preferably R.sup.4 and R.sup.11
are H. In some embodiments, A is --C(O)--, and R.sup.2 is hydrogen,
fluoro or chloro, preferably fluoro or chloro. In some embodiments,
A is --C(O)--, R.sup.2 is hydrogen, fluoro or chloro, preferably
fluoro or chloro; and R.sup.4 and R.sup.11 are independently
hydrogen or lower alkyl, wherein lower alkyl is optionally
substituted with one or more substituents selected from the group
consisting of fluoro, lower alkoxy, fluoro substituted lower
alkoxy, lower alkylthio, and fluoro substituted lower alkylthio,
preferably R.sup.4 and R.sup.11 are H.
[0048] In some embodiments of compounds of Formula Ih, A is
--C(R.sup.12R.sup.13)--, and R.sup.4, R.sup.11, R.sup.12 and
R.sup.13 are independently hydrogen or lower alkyl, wherein lower
alkyl is optionally substituted with one or more substituents
selected from the group consisting of fluoro, lower alkoxy, fluoro
substituted lower alkoxy, lower alkylthio, and fluoro substituted
lower alkylthio, preferably R.sup.4, R.sup.11, R.sup.12 and
R.sup.13 are H. In some embodiments, A is --C(R.sup.12R.sup.13)--,
R.sup.12 and R.sup.13 are independently hydrogen or lower alkyl,
wherein lower alkyl is optionally substituted with one or more
substituents selected from the group consisting of fluoro, lower
alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and
fluoro substituted lower alkylthio, preferably R.sup.12 and
R.sup.13 are H, and R.sup.2 is hydrogen, fluoro or chloro,
preferably fluoro or chloro. In some embodiments, A is
--C(R.sup.12R.sup.13)--; R.sup.2 is hydrogen, fluoro or chloro,
preferably fluoro or chloro; and R.sup.4, R.sup.11, R.sup.12 and
R.sup.13 are independently hydrogen or lower alkyl, wherein lower
alkyl is optionally substituted with one or more substituents
selected from the group consisting of fluoro, lower alkoxy, fluoro
substituted lower alkoxy, lower alkylthio, and fluoro substituted
lower alkylthio, preferably R.sup.4, R.sup.11, R.sup.12 and
R.sup.13 are H.
[0049] In some embodiments, the compound of Formula I has a
structure according to the following sub-generic structure Formula
Ii:
##STR00012##
or a salt, a prodrug, a tautomer or an isomer thereof, wherein A is
--C(O)-- or --C(R.sup.12R.sup.13)--; and m, Ar, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.11, R.sup.12, R.sup.13 and L.sub.2 are as
defined for Formula I.
[0050] In some embodiments of compounds of Formula Ii, R.sup.4,
R.sup.11, R.sup.12 and R.sup.13 are independently hydrogen or lower
alkyl, wherein lower alkyl is optionally substituted with one or
more substituents selected from the group consisting of fluoro,
lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and
fluoro substituted lower alkylthio, preferably R.sup.4, R.sup.11,
R.sup.12 and R.sup.13 are H. In some embodiments, R.sup.2 is
hydrogen, fluoro or chloro, preferably fluoro or chloro. In some
embodiments, R.sup.2 is hydrogen, fluoro or chloro, and R.sup.4,
R.sup.11, R.sup.12 and R.sup.13 are independently hydrogen or lower
alkyl, wherein lower alkyl is optionally substituted with one or
more substituents selected from the group consisting of fluoro,
lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and
fluoro substituted lower alkylthio, preferably R.sup.2 is fluoro or
chloro and R.sup.4, R.sup.11, R.sup.12 and R.sup.13 are H.
[0051] In some embodiments of compounds of Formula Ii, A is
--C(O)--, and R.sup.4 and R.sup.11 are independently hydrogen or
lower alkyl, wherein lower alkyl is optionally substituted with one
or more substituents selected from the group consisting of fluoro,
lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and
fluoro substituted lower alkylthio, preferably R.sup.4 and R.sup.11
are H. In some embodiments, A is --C(O)--, and R.sup.2 is hydrogen,
fluoro or chloro, preferably fluoro or chloro. In some embodiments,
A is --C(O)--, R.sup.2 is hydrogen, fluoro or chloro, preferably
fluoro or chloro; and R.sup.4 and R.sup.11 are hydrogen or lower
alkyl, wherein lower alkyl is optionally substituted with one or
more substituents selected from the group consisting of fluoro,
lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and
fluoro substituted lower alkylthio, preferably R.sup.4 and R.sup.11
are H.
[0052] In some embodiments of compounds of Formula Ii, A is
--C(R.sup.12R.sup.13)--, and R.sup.4, R.sup.11, R.sup.12 and
R.sup.13 are independently hydrogen or lower alkyl, wherein lower
alkyl is optionally substituted with one or more substituents
selected from the group consisting of fluoro, lower alkoxy, fluoro
substituted lower alkoxy, lower alkylthio, and fluoro substituted
lower alkylthio, preferably R.sup.4, R.sup.11, R.sup.12 and
R.sup.13 are H. In some embodiments, A is --C(R.sup.12R.sup.13)--,
R.sup.12 and R.sup.13 are independently hydrogen or lower alkyl,
wherein lower alkyl is optionally substituted with one or more
substituents selected from the group consisting of fluoro, lower
alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and
fluoro substituted lower alkylthio, preferably R.sup.12 and
R.sup.13 are H, and R.sup.2 is hydrogen, fluoro or chloro,
preferably fluoro or chloro. In some embodiments, A is
--C(R.sup.12R.sup.13)--; R.sup.2 is hydrogen, fluoro or chloro,
preferably fluoro or chloro; and R.sup.4, R.sup.11, R.sup.12 and
R.sup.13 are independently hydrogen or lower alkyl, wherein lower
alkyl is optionally substituted with one or more substituents
selected from the group consisting of fluoro, lower alkoxy, fluoro
substituted lower alkoxy, lower alkylthio, and fluoro substituted
lower alkylthio, preferably R.sup.4, R.sup.11, R.sup.12 and
R.sup.13 are H.
[0053] In some embodiments, the compound of Formula I has a
structure according to the following sub-generic structure Formula
Ij:
##STR00013##
or a salt, a prodrug, a tautomer or an isomer thereof, wherein:
[0054] m, Ar, R.sup.1, R.sup.2, R.sup.4, and L.sub.1 are as defined
for Formula I; and [0055] R.sup.22 is selected from the group
consisting of mono-alkylamino, di-alkylamino, optionally
substituted lower alkyl, optionally substituted cycloalkyl,
optionally substituted heterocycloalkyl, optionally substituted
aryl and optionally substituted heteroaryl, wherein the alkyl
chain(s) of mono-alkylamino or di-alkylamino are independently
optionally substituted with one or more substituents selected from
the group consisting of fluoro, --OH, --NH.sub.2, lower alkoxy,
fluoro substituted lower alkoxy, lower alkylthio, fluoro
substituted lower alkylthio, mono-alkylamino, di-alkylamino and
cycloalkylamino.
[0056] In some embodiments of compounds of Formula Ij, L.sub.1 is a
bond, --N(R.sup.11)--, --N(R.sup.11)--C(X)--,
--N(R.sup.11)--S(O).sub.2--, --N(R.sup.11)--C(NH)--,
--N(R.sup.11)--C(X)--N(R.sup.11)--, or
--N(R.sup.11)--S(O).sub.2--N(R.sup.11)--, also --N(R.sup.11)--,
--N(R.sup.11)--C(X)--, or --N(R.sup.11)--S(O).sub.2--, also
--N(R.sup.11)--C(O)--, wherein the left side (i.e. --N(R.sup.11)--)
of L.sub.1 is attached to Ar and the right side of L.sub.1 is
attached to the phenyl ring of Formula Ij. In some embodiments,
L.sub.1 is a bond, --N(R.sup.11)--, --N(R.sup.11)--C(X)--,
--N(R.sup.11)--S(O).sub.2--, --N(R.sup.11)--C(NH)--,
--N(R.sup.11)--C(X)--N(R.sup.11)--, or
--N(R.sup.11)--S(O).sub.2--N(R.sup.11)--, also --N(R.sup.11)--,
--N(R.sup.11)--C(X)--, or --N(R.sup.11)--S(O).sub.2--, also
--N(R.sup.11)--C(O)--, and each R.sup.11 and R.sup.4 are
independently hydrogen or lower alkyl, wherein lower alkyl is
optionally substituted with one or more substituents selected from
the group consisting of fluoro, lower alkoxy, fluoro substituted
lower alkoxy, lower alkylthio, and fluoro substituted lower
alkylthio, preferably each R.sup.11 and R.sup.4 are H.
[0057] In some embodiments of compounds of Formula Ij, L.sub.1 is
--C(X)--N(R.sup.11)--, --C(R.sup.12R.sup.13)--X--,
--X--C(R.sup.12R.sup.13)--, --C(R.sup.12R.sup.13)--N(R.sup.11)--,
or --N(R.sup.11)--C(R.sup.12R.sup.13)--, wherein the left side of
L.sub.1 is attached to Ar and the right side of L.sub.1 is attached
to the phenyl ring of Formula Ij. In some embodiments, L.sub.1 is
--C(X)--N(R.sup.11)--, --C(R.sup.12R.sup.13)--X--,
--X--C(R.sup.12R.sup.13)--, --C(R.sup.12R.sup.13)--N(R.sup.11)--,
or --N(R.sup.11)--C(R.sup.12R.sup.13)--, and each R.sup.11 and
R.sup.4 are independently hydrogen or lower alkyl, wherein lower
alkyl is optionally substituted with one or more substituents
selected from the group consisting of fluoro, lower alkoxy, fluoro
substituted lower alkoxy, lower alkylthio, and fluoro substituted
lower alkylthio, preferably each R.sup.11 and R.sup.4 are H.
[0058] In some embodiments of compounds of Formula Ij, R.sup.2 is
hydrogen, fluoro or chloro, preferably fluoro or chloro. In some
embodiments, R.sup.2 is hydrogen, fluoro or chloro, each R.sup.11
and R.sup.4 are independently hydrogen or lower alkyl, wherein
lower alkyl is optionally substituted with one or more substituents
selected from the group consisting of fluoro, lower alkoxy, fluoro
substituted lower alkoxy, lower alkylthio, and fluoro substituted
lower alkylthio, preferably R.sup.2 is fluoro or chloro and each
R.sup.11 and R.sup.4 are H. In some embodiments, R.sup.2 is
hydrogen, fluoro or chloro, preferably fluoro or chloro, and
L.sub.1 is a bond, --N(R.sup.11)--, --N(R.sup.11)--C(X)--,
--N(R.sup.11)--S(O).sub.2--, --N(R.sup.11)--C(NH)--,
--N(R.sup.11)--C(X)--N(R.sup.11)--, or
--N(R.sup.11)--S(O).sub.2--N(R.sup.11)--, also --N(R.sup.11)--,
--N(R.sup.11)--C(X)--, or --N(R.sup.11)--S(O).sub.2--, also
--N(R.sup.11)--C(O)--, wherein the left side (i.e. --N(R.sup.11)--)
of L.sub.1 is attached to Ar and the right side of L.sub.1 is
attached to the phenyl ring of Formula Ij. In some embodiments,
R.sup.2 is hydrogen, fluoro or chloro, preferably fluoro or chloro;
L.sub.1 is a bond, --N(R.sup.11)--, --N(R.sup.11)--C(X)--,
--N(R.sup.11)--S(O).sub.2--, --N(R.sup.11)--C(NH)--,
--N(R.sup.11)--C(X)--N(R.sup.11)--, or
--N(R.sup.11)--S(O).sub.2--N(R.sup.11)--, also --N(R.sup.11)--,
--N(R.sup.11)--C(X)--, or --N(R.sup.11)--S(O).sub.2--, also
--N(R.sup.11)--C(O)--; and each R.sup.11 and R.sup.4 are
independently hydrogen or lower alkyl, wherein lower alkyl is
optionally substituted with one or more substituents selected from
the group consisting of fluoro, lower alkoxy, fluoro substituted
lower alkoxy, lower alkylthio, and fluoro substituted lower
alkylthio, preferably each R.sup.11 and R.sup.4 are H.
[0059] In some embodiments of compounds of Formula Ij, R.sup.2 is
hydrogen, fluoro or chloro, preferably fluoro or chloro. In some
embodiments, R.sup.2 is hydrogen, fluoro or chloro, each R.sup.11
and R.sup.4 are independently hydrogen or lower alkyl, wherein
lower alkyl is optionally substituted with one or more substituents
selected from the group consisting of fluoro, lower alkoxy, fluoro
substituted lower alkoxy, lower alkylthio, and fluoro substituted
lower alkylthio, preferably R.sup.2 is fluoro or chloro and each
R.sup.11 and R.sup.4 are H. In some embodiments, R.sup.2 is
hydrogen, fluoro or chloro, preferably fluoro or chloro, and
L.sub.1 is --C(X)--N(R.sup.11)--, --C(R.sup.12R.sup.13)--X--,
--X--C(R.sup.12R.sup.13)--, --C(R.sup.12R.sup.13)--N(R.sup.11)--,
or --N(R.sup.11)--C(R.sup.12R.sup.13)--, wherein the left side of
L.sub.1 is attached to Ar and the right side of L.sub.1 is attached
to the phenyl ring of Formula Ij. In some embodiments, R.sup.2 is
hydrogen, fluoro or chloro, preferably fluoro or chloro; L.sub.1 is
--C(X)--N(R.sup.11)--, --C(R.sup.12R.sup.13)--X--,
--X--C(R.sup.12R.sup.13)--, --C(R.sup.12R.sup.13)--N(R.sup.11)--,
or --N(R.sup.11)--C(R.sup.12R.sup.13)--; and each R.sup.11 and
R.sup.4 are independently hydrogen or lower alkyl, wherein lower
alkyl is optionally substituted with one or more substituents
selected from the group consisting of fluoro, lower alkoxy, fluoro
substituted lower alkoxy, lower alkylthio, and fluoro substituted
lower alkylthio, preferably each R.sup.11 and R.sup.4 are H.
[0060] In some embodiments of compounds of Formula Ij, further to
any of the above embodiments of Formula Ij, R.sup.22 is
mono-alkylamino, di-alkylamino, or optionally substituted
heterocycloalkyl, preferably wherein heterocycloalkyl is a 5 or 6
membered nitrogen containing heterocycloalkyl, wherein a nitrogen
of the heterocycloalkyl is bound to the S(O).sub.2 of Formula Ij.
In some embodiments, R.sup.22 is mono-alkylamino, di-alkylamino or
5 or 6 membered nitrogen containing heterocycloalkyl, wherein the
heterocycloalkyl is substituted with one or more substituents
selected from the group consisting of fluoro, --OH, --NH.sub.2,
lower alkyl, lower alkoxy, lower alkylthio, mono-alkylamino,
di-alkylamino, and cycloalkylamino, wherein lower alkyl or the
alkyl chain(s) of lower alkoxy, lower alkylthio, mono-alkylamino,
or di-alkylamino are optionally substituted with one or more
substituents selected from the group consisting of fluoro, --OH,
--NH.sub.2, lower alkoxy, fluoro substituted lower alkoxy, lower
alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,
di-alkylamino and cycloalkylamino, preferably wherein the 5 or 6
membered nitrogen containing heterocycloalkyl is optionally
substituted with one or more substituents selected from the group
consisting of fluoro, lower alkyl, fluoro substituted lower alkyl,
lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and
fluoro substituted lower alkylthio.
[0061] In some embodiments of compounds of Formula I, Ia, Ib, Ic,
Id, Ie, If, Ig, Ih, Ii, or Ij, further to any of the above
embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii or Ij,
Ar is monocyclic or bicyclic nitrogen containing heteroaryl. In
some embodiments, Ar is selected from the group consisting of
##STR00014##
wherein
##STR00015##
indicates the attachment point of the Ar ring to L.sub.1 in Formula
I, Ia or Ij, to L.sub.3 in Formula If or Ig, to the nitrogen of
Ar--N-- in Formula Ib or Id, to A of Formula Ih or Ii, or to the
phenyl ring of Formula Ic or Ie, and wherein: [0062] T, U, X, and Z
at each occurrence are independently N or CH, provided, however,
that at least one, and no more than 2 of X in any ring is N, no
more than 2 of U in any ring is N, at least one T is N and no more
than two of T within any six-membered ring is N, and at least one Z
is N and no more than 2 of Z within any bicyclic ring is N; [0063]
Y is NH, O, or S; [0064] W at each occurrence is independently N or
CH; [0065] V is O, S, or NH, provided, however, that when V is O or
S, at least one of U in any ring or [0066] W in any ring is N; and
[0067] any R.sup.1 is bound to Ar at any available NH or CH,
preferably any R.sup.1 is independently R.sup.16, wherein R.sup.16
at each occurrence is independently selected from the group
consisting of --OH, --NH.sub.2, --CN, --NO.sub.2, --C(O)--OH,
--S(O).sub.2--NH.sub.2, --C(O)--NH.sub.2, --O--R.sup.17,
--S--R.sup.17, --N(R.sup.19)--R.sup.17,
--N(R.sup.19)--C(O)--R.sup.17, --N(R.sup.19)--S(O).sub.2--R.sup.17,
--S(O).sub.2--R.sup.17, --C(O)--R.sup.17, --C(O)--O--R.sup.17,
--C(O)--N(R.sup.19)--R.sup.17, --S(O).sub.2--N(R.sup.19)--R.sup.17,
halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and
heteroaryl, wherein lower alkyl is optionally substituted with one
or more substituents selected from the group consisting of fluoro,
lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio,
fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino,
cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein
cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R.sup.16, or
as substituents of lower alkyl, are optionally substituted with one
or more substituents selected from the group consisting of --OH,
--NH.sub.2, --CN, --NO.sub.2, --C(O)--OH, --S(O).sub.2--NH.sub.2,
--C(O)--NH.sub.2, --O--R.sup.18, --S--R.sup.18,
--N(R.sup.19)--R.sup.18, --N(R.sup.19)--C(O)--R.sup.18,
--N(R.sup.19)--S(O).sub.2--R.sup.18, --S(O).sub.2--R.sup.18,
--C(O)--R.sup.18, --C(O)--O--R.sup.18,
--C(O)--N(R.sup.19)--R.sup.18, --S(O).sub.2--N(R.sup.19)--R.sup.18,
halogen, lower alkyl, fluoro substituted lower alkyl, and
cycloalkylamino; [0068] R.sup.17 at each occurrence is
independently selected from the group consisting of lower alkyl,
cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower
alkyl is optionally substituted with one or more substituents
selected from the group consisting of fluoro, lower alkoxy, fluoro
substituted lower alkoxy, lower alkylthio, fluoro substituted lower
alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl,
heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl,
heterocycloalkyl, aryl, and heteroaryl as R.sup.17 or as
substituents of lower alkyl are optionally substituted with one or
more substituents selected from the group consisting of --OH,
--NH.sub.2, --CN, --NO.sub.2, --C(O)--OH, --S(O).sub.2--NH.sub.2,
--C(O)--NH.sub.2, --O--R.sup.18, --S--R.sup.18,
--N(R.sup.19)--R.sup.18, --N(R.sup.19)--C(O)--R.sup.18,
--N(R.sup.19)--S(O).sub.2--R.sup.18, --S(O).sub.2--R.sup.18,
--C(O)--R.sup.18, --C(O)--O--R.sup.18,
--C(O)--N(R.sup.19)--R.sup.18, --S(O).sub.2--N(R.sup.19)--R.sup.18,
halogen, lower alkyl, fluoro substituted lower alkyl, and
cycloalkylamino; [0069] R.sup.18 at each occurrence is
independently selected from the group consisting of lower alkyl,
heterocycloalkyl and heteroaryl, wherein lower alkyl is optionally
substituted with one or more substituents selected from the group
consisting of fluoro, lower alkoxy, fluoro substituted lower
alkoxy, lower alkylthio, fluoro substituted lower alkylthio,
mono-alkylamino, di-alkylamino, and cycloalkylamino; and [0070]
R.sup.19 at each occurrence is independently hydrogen or lower
alkyl, wherein lower alkyl is optionally substituted with one or
more substituents selected from the group consisting of fluoro,
lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and
fluoro substituted lower alkylthio.
[0071] In some embodiments of compounds of Formula I, Ia, Ib, Id,
If, Ig, Ih, Ii, or Ij, further to any of the above embodiments of
Formula I, Ia, Ib, Id, If, Ig, Ih, Ii, or Ij, when L.sub.1 is other
than a bond, Ar is selected from the group consisting of
##STR00016##
wherein
##STR00017##
indicates the attachment point of the Ar ring to L.sub.1 in Formula
I, Ia or Ij, to L.sub.3 in Formula If or Ig, to the nitrogen of
Ar--N-- in Formula Ib or Id, or to A of Formula Ih or Ii, and
wherein: [0072] T.sub.1, U.sub.1, W.sub.1, X.sub.1, and Z.sub.1 at
each occurrence are independently N or CH, provided, however, that
at most 1 of T.sub.1, Ui, Xi, and Zi is N; [0073] T.sub.2 at each
occurrence is independently N or CH, provided, however, that at
most 2 of T.sub.2 are N; [0074] Y and V.sub.1 are O, S, or NH;
[0075] any R.sup.1 is bound to Ar at any available NH or CH,
preferably any R.sup.1 is independently R.sup.16, as defined in
paragraph [0041], preferably wherein R.sup.16 at each occurrence is
independently selected from the group consisting of halogen, --OH,
--NH.sub.2, --CN, lower alkyl, lower alkoxy, lower alkylthio,
mono-alkylamino, di-alkylamino, and --NR.sup.20R.sup.21, wherein
lower alkyl and the alkyl chain(s) of lower alkoxy, lower
alkylthio, mono-alkylamino or di-alkylamino are optionally
substituted with one or more, preferably 1, 2, or 3 substituents
selected from the group consisting of fluoro, --OH, --NH.sub.2,
lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio,
fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino,
or cycloalkylamino; and [0076] R.sup.20 and R.sup.21 at each
occurrence independently combine with the nitrogen to which they
are attached to form a 5-7 membered heterocycloalkyl or 5-7
membered heterocycloalkyl substituted with one or more substituents
selected from the group consisting of fluoro, --OH, --NH.sub.2,
lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro
substituted lower alkoxy, lower alkylthio, and fluoro substituted
lower alkylthio.
[0077] In some embodiments of compounds of Formula I, Ia, Ib, Id,
If, Ig, Ih, Ii, or Ij, further to any of the above embodiments of
Formula I, Ia, Ib, Id, If, Ig, Ih, Ii, or Ij, when L.sub.1 is other
than a bond, Ar is selected from the group consisting of
##STR00018##
wherein
##STR00019##
indicates the attachment point of the Ar ring to L.sub.1 in Formula
I, Ia or Ij, to L.sub.3 in Formula If or Ig, to the nitrogen of
Ar--N-- in Formula Ib or Id, or to A of Formula Ih or Ii, and
wherein: [0078] W.sub.1 at each occurrence is independently N or
CH; [0079] Y and V.sub.1 are O, S, or NH; [0080] p is 0, 1, 2 or 3;
and [0081] R.sup.16, substituting at any available CH or NH, is as
defined in paragraph [0041], preferably wherein R.sup.16 at each
occurrence is independently selected from the group consisting of
halogen, --OH, --NH.sub.2, --CN, lower alkyl, lower alkoxy, lower
alkylthio, mono-alkylamino, di-alkylamino, and --NR.sup.20R.sup.21,
wherein lower alkyl and the alkyl chain(s) of lower alkoxy, lower
alkylthio, mono-alkylamino or di-alkylamino are optionally
substituted with one or more, preferably 1, 2, or 3 substituents
selected from the group consisting of fluoro, --OH, --NH.sub.2,
lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio,
fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino,
or cycloalkylamino, wherein R.sup.20 and R.sup.21 are as defined in
paragraph [0042].
[0082] In some embodiments of compounds of Formula I, Ia, Ib, Id,
If, Ig, Ih, Ii, or Ij, further to any of the above embodiments of
Formula I, Ia, Ib, Id, If, Ig, Ih, Ii, or Ij, when L.sub.1 is other
than a bond, Ar is selected from the group consisting of
##STR00020##
wherein
##STR00021##
indicates the attachment point of the Ar ring to L.sub.1 in Formula
I, Ia or Ij, to L.sub.3 in Formula If or Ig, to the nitrogen of
Ar--N-- in Formula Ib or Id, or to A of Formula Ih or Ii, and
wherein:
[0083] p is 0, 1, 2 or 3; and
[0084] R.sup.16, substituting at any available CH or NH, is as
defined in paragraph [0041].
[0085] In some embodiments of compounds of Formula Ic or Ie,
further to any of the above embodiments of Formula Ic or Ie, Ar is
selected from the group consisting of
##STR00022##
wherein
##STR00023##
indicates the attachment point of the Ar ring to the phenyl ring of
Formula Ic or Ie, and wherein: [0086] T.sub.1, U.sub.1, W.sub.1 and
Z.sub.1 at each occurrence is independently N or CH, provided,
however, that at most 1 of T.sub.1, U.sub.1, and Z.sub.1 is N;
[0087] T.sub.2 is N or CH, provided, however, that no more than 2
of T.sub.2 are N; [0088] V.sub.1 is O, S, or NH; and [0089] any
R.sup.1 is bound to Ar at any available NH or CH, preferably any
R.sup.1 is independently R.sup.16, as defined in paragraph [0041],
preferably wherein R.sup.16 at each occurrence is independently
selected from the group consisting of halogen, --OH, --NH.sub.2,
--CN, lower alkyl, lower alkoxy, lower alkylthio, mono-alkylamino,
di-alkylamino, and --NR.sup.20R.sup.21, wherein lower alkyl and the
alkyl chain(s) of lower alkoxy, lower alkylthio, mono-alkylamino or
di-alkylamino are optionally substituted with one or more,
preferably 1, 2, or 3 substituents selected from the group
consisting of fluoro, --OH, --NH.sub.2, lower alkoxy, fluoro
substituted lower alkoxy, lower alkylthio, fluoro substituted lower
alkylthio, mono-alkylamino, di-alkylamino, or cycloalkylamino,
wherein R.sup.20 and R.sup.21 are as defined in paragraph
[0042].
[0090] In some embodiments of compounds of Formula Ic or Ie,
further to any of the above embodiments of Formula Ic or Ie,
R.sup.1 is selected from the group consisting of
##STR00024##
wherein
##STR00025##
indicates the attachment point of the Ar ring to the phenyl ring of
Formula Ic or Ie, and wherein: [0091] W.sub.1 is N or CH; [0092]
V.sub.1 is O, S, or NH; [0093] p is 0, 1, 2 or 3; and [0094]
R.sup.16, substituting at any available CH or NH, is as defined in
paragraph [0041], preferably wherein R.sup.16 at each occurrence is
independently selected from the group consisting of halogen, --OH,
--NH.sub.2, --CN, lower alkyl, lower alkoxy, lower alkylthio,
mono-alkylamino, di-alkylamino, and --NR.sup.20R.sup.21, wherein
lower alkyl and the alkyl chain(s) of lower alkoxy, lower
alkylthio, mono-alkylamino or di-alkylamino are optionally
substituted with one or more, preferably 1, 2, or 3 substituents
selected from the group consisting of fluoro, --OH, --NH.sub.2,
lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio,
fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino,
or cycloalkylamino, wherein R.sup.20 and R.sup.21 are as defined in
paragraph [0042].
[0095] In some embodiments of compounds of Formula I, Ia, Ib, Ic,
Id, Ie, If, Ig, Ih, or Ii, further to any of the above embodiments
of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, or Ii, R.sup.3 is
optionally substituted lower alkyl or optionally substituted
C.sub.3-6 cycloalkyl. In some embodiments, R.sup.3 is lower alkyl
or C.sub.3-6 cycloalkyl, wherein lower alkyl is optionally
substituted with one or more substituents selected from the group
consisting of fluoro, --OH, --NH.sub.2, lower alkoxy, fluoro
substituted lower alkoxy, lower alkylthio, fluoro substituted lower
alkylthio, mono-alkylamino, fluoro substituted mono-alkylamino,
di-alkylamino, fluoro substituted di-alkylamino, cycloalkylamino,
and C.sub.3-5 cycloalkyl, and wherein C.sub.3-6 cycloalkyl is
optionally substituted with one or more substituents selected from
the group consisting of fluoro, --OH, --NH.sub.2, lower alkoxy,
fluoro substituted lower alkoxy, lower alkylthio, fluoro
substituted lower alkylthio, mono-alkylamino, fluoro substituted
mono-alkylamino, di-alkylamino, and fluoro substituted
di-alkylamino. In some embodiments, R.sup.3 is lower alkyl or
C.sub.3-6 cycloalkyl, wherein lower alkyl or C.sub.3-6 cycloalkyl
are optionally substituted with one or more substituents selected
from the group consisting of fluoro, lower alkoxy, fluoro
substituted lower alkoxy, lower alkylthio, and fluoro substituted
lower alkylthio. In some embodiments, R.sup.3 is optionally fluoro
substituted lower alkyl or optionally fluoro substituted C.sub.3-6
cycloalkyl. In some embodiments, R.sup.3 is lower alkyl, wherein
lower alkyl is optionally substituted with one or more substituents
selected from the group consisting of fluoro, --OH, --NH.sub.2,
lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio,
fluoro substituted lower alkylthio, mono-alkylamino, fluoro
substituted mono-alkylamino, di-alkylamino, fluoro substituted
di-alkylamino, cycloalkylamino, also one or more substituents
selected from the group consisting of fluoro, --OH, --NH.sub.2,
lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio,
fluoro substituted lower alkylthio, mono-alkylamino, fluoro
substituted mono-alkylamino, di-alkylamino, and fluoro substituted
di-alkylamino, also one or more substituents selected from the
group consisting of fluoro, lower alkoxy, fluoro substituted lower
alkoxy, lower alkylthio, and fluoro substituted lower alkylthio. In
some embodiments, R.sup.3 is optionally fluoro substituted lower
alkyl.
[0096] In some embodiments of compounds of Formula I, Ia, Ib, Ic,
Id, Ie, If, Ig, Ih, or Ii, further to any of the above embodiments
of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, or Ii, R.sup.3 is
optionally substituted phenyl, also phenyl mono-substituted at the
para position, also phenyl mono-substituted at the meta position.
In some embodiments, R.sup.3 is phenyl optionally substituted with
one or more substituents selected from the group consisting of
halogen, --CN, --NO.sub.2, --OH, --NH.sub.2, lower alkyl, lower
alkoxy, lower alkylthio, mono-alkylamino, di-alkylamino, and
cycloalkylamino, wherein lower alkyl or the alkyl chain(s) of lower
alkoxy, lower alkylthio, mono-alkylamino, or di-alkylamino are
optionally substituted with one or more substituents selected from
the group consisting of fluoro, --OH, --NH.sub.2, lower alkoxy,
fluoro substituted lower alkoxy, lower alkylthio, fluoro
substituted lower alkylthio, mono-alkylamino, di-alkylamino and
cycloalkylamino, preferably wherein the phenyl is mono-substituted
at either the para or meta position. In some embodiments, R.sup.3
is phenyl optionally substituted with one or more substituents
selected from the group consisting of fluoro, lower alkyl, fluoro
substituted lower alkyl, lower alkoxy, fluoro substituted lower
alkoxy, lower alkylthio, and fluoro substituted lower alkylthio,
preferably wherein the phenyl is mono-substituted at either the
para or meta position.
[0097] In one embodiment of compounds of Formula I, the compound is
selected from the group consisting of: [0098]
6-Chloro-2-fluoro-3-(propane-1-sulfonylamino)-N-pyridin-3-yl-benzamide
(P-0001), [0099]
N-(6-Acetylamino-pyridin-3-yl)-6-chloro-2-fluoro-3-(propane-1-sulfonylami-
no)-benzamide (P-0002),
6-Chloro-2-fluoro-N-(6-methoxy-pyridin-3-yl)-3-(propane-1-sulfonylamino)--
benzamide (P-0003), [0100]
N-(2-Acetylamino-pyrimidin-5-yl)-6-chloro-2-fluoro-3-(propane-1-sulfonyla-
mino)-benzamide (P-0004), [0101]
6-Chloro-2-fluoro-N-(6-isopropylamino-pyridin-3-yl)-3-(propane-1-sulfonyl-
amino)-benzamide (P-0005), [0102] Pyrrolidine-1-carboxylic acid
{5-[6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoylamino]-pyridin-2-
-yl}-amide (P-0006), [0103]
6-Chloro-N-(3,5-dimethyl-isoxazol-4-yl)-2-fluoro-3-(propane-1-sulfonylami-
no)-benzamide (P-0007), [0104]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(propane-1-sulfonylamino)-b-
enzamide (P-0008), [0105]
6-Chloro-N-(6-cyclopentylamino-pyridin-3-yl)-2-fluoro-3-(propane-1-sulfon-
ylamino)-benzamide (P-0009), [0106]
6-Chloro-N-[5-(4-chloro-phenyl)-2H-pyrazol-3-yl]-2-fluoro-3-(propane-1-su-
lfonylamino)-benzamide (P-0010), [0107]
6-Chloro-2-fluoro-N-[6-(5-methyl-thiazol-2-ylamino)-pyridin-3-yl]-3-(prop-
ane-1-sulfonylamino)-benzamide (P-0011), [0108]
6-Chloro-N-[5-(4-chloro-benzyl)-[1,3,4]thiadiazol-2-yl]-2-fluoro-3-(propa-
ne-1-sulfonylamino)-benzamide (P-0012), [0109]
6-Chloro-2-fluoro-3-(propane-1-sulfonylamino)-N-quinolin-3-yl-benzamide
(P-0013), [0110]
[2-[6-Chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoylamino]-4H-[1,3,4-
]thiadiazin-(5E)-ylidene]-acetic acid ethyl ester (P-0014), [0111]
6-Chloro-N-(6-cyclopropylamino-pyridin-3-yl)-2-fluoro-3-(propane-1-sulfon-
ylamino)-benzamide (P-0015), [0112]
6-Chloro-2-fluoro-3-(propane-1-sulfonylamino)-N-{6-[(thiophen-2-ylmethyl)-
-amino]-pyridin-3-yl}-benzamide (P-0016), [0113]
N-(6-Benzylamino-pyridin-3-yl)-6-chloro-2-fluoro-3-(propane-1-sulfonylami-
no)-benzamide (P-0017), [0114]
6-Chloro-2-fluoro-N-imidazo[1,2-a]pyridin-3-yl-3-(propane-1-sulfonylamino-
)-benzamide (P-0018), [0115] Propane-1-sulfonic acid
{2,4-difluoro-3-[(5-methyl-isoxazol-3-ylamino)-methyl]-phenyl}-amide
(P-0019), [0116]
N-{5-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzylamino]-pyridin-2-yl}-
-acetamide (P-0020), [0117] Propane-1-sulfonic acid
[2,4-difluoro-3-(quinolin-3-ylaminomethyl)-phenyl]-amide (P-0021),
[0118] Propane-1-sulfonic acid
{3-[(6-chloro-pyridin-3-ylamino)-methyl]-2,4-difluoro-phenyl}-amide
(P-0022), [0119] Propane-1-sulfonic acid
{2,4-difluoro-3-[(6-methoxy-pyridin-3-ylamino)-methyl]-phenyl}-amide
(P-0023), [0120] Quinoline-3-carboxylic acid
[2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-amide (P-0024),
[0121] Propane-1-sulfonic acid
{2,4-difluoro-3-[(quinolin-3-ylmethyl)-amino]-phenyl}-amide
(P-0025), [0122] Propane-1-sulfonic acid
[2,4-difluoro-3-(quinolin-3-yloxymethyl)-phenyl]-amide (P-0026),
[0123]
2,6-Difluoro-3-(propane-1-sulfonylamino)-N-quinolin-3-yl-benzamide
(P-0027), [0124]
6-Acetylamino-N-[2,6-difluoro-3-(2-fluoro-benzenesulfonylamino)-phenyl]-n-
icotinamide (P-0028), [0125]
6-Acetylamino-N-[2,6-difluoro-3-(3-fluoro-benzenesulfonylamino)-phenyl]-n-
icotinamide (P-0029), [0126]
6-Acetylamino-N-[3-(2,6-difluoro-benzenesulfonylamino)-2,6-difluoro-pheny-
l]-nicotinamide (P-0030), [0127]
6-Acetylamino-N-[3-(2,4-difluoro-benzenesulfonylamino)-2,6-difluoro-pheny-
l]-nicotinamide (P-0031), [0128]
6-Acetylamino-N-[3-(2,5-difluoro-benzenesulfonylamino)-2,6-difluoro-pheny-
l]-nicotinamide (P-0032), [0129]
6-Acetylamino-N-[2,6-difluoro-3-(3-fluoro-4-methoxy-benzenesulfonylamino)-
-phenyl]-nicotinamide (P-0033), [0130]
6-Acetylamino-N-[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)--
phenyl]-nicotinamide (P-0034), [0131]
6-Acetylamino-N-[3-(4-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro--
phenyl]-nicotinamide (P-0035), [0132]
6-Acetylamino-N-[3-(3-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro--
phenyl]-nicotinamide (P-0036), [0133]
6-Acetylamino-N-[2,6-difluoro-3-(4-isopropyl-benzenesulfonylamino)-phenyl-
]-nicotinamide (P-0037), [0134]
6-Acetylamino-N-[3-(4-tert-butyl-benzenesulfonylamino)-2,6-difluoro-pheny-
l]-nicotinamide (P-0038), [0135]
6-Acetylamino-N-[2,6-difluoro-3-(4-propyl-benzenesulfonylamino)-phenyl]-n-
icotinamide (P-0039), [0136]
6-Acetylamino-N-[2,6-difluoro-3-(pyridine-2-sulfonylamino)-phenyl]-nicoti-
namide (P-0040), [0137]
6-Acetylamino-N-[2,6-difluoro-3-(pyridine-3-sulfonylamino)-phenyl]-nicoti-
namide (P-0041), [0138]
6-Acetylamino-N-[2,6-difluoro-3-(dimethylaminosulfonylamino)-phenyl]-nico-
tinamide (P-0042), [0139]
6-Acetylamino-N-[2,6-difluoro-3-(piperidine-1-sulfonylamino)-phenyl]-nico-
tinamide (P-0043), [0140]
6-Acetylamino-N-[2,6-difluoro-3-(morpholine-4-sulfonylamino)-phenyl]-nico-
tinamide (P-0044), [0141]
6-Acetylamino-N-[2,6-difluoro-3-(tetrahydro-pyran-4-sulfonylamino)-phenyl-
]-nicotinamide (P-0045), [0142]
6-Acetylamino-N-(3-cyclopentanesulfonylamino-2,6-difluoro-phenyl)-nicotin-
amide (P-0046), [0143]
6-Acetylamino-N-[2,6-difluoro-3-(pyrrolidine-1-sulfonylamino)-phenyl]-nic-
otinamide (P-0047), [0144]
6-Acetylamino-N-[2,6-difluoro-3-(3,3,3-trifluoro-propane-1-sulfonylamino)-
-phenyl]-nicotinamide (P-0048), [0145]
1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(2-fluoro-benzenesulfonylamino)-phenyl]-amide
(P-0049), [0146] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(3-fluoro-benzenesulfonylamino)-phenyl]-amide
(P-0050), [0147] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[3-(2,6-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide
(P-0051), [0148] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[3-(2,4-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide
(P-0052), [0149] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[3-(2,5-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide
(P-0053), [0150] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(3-fluoro-4-methoxy-benzenesulfonylamino)-phenyl]-amide
(P-0054), [0151] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-phenyl]-amide
(P-0055), [0152] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[3-(4-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide
(P-0056), [0153] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[3-(3-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide
(P-0057), [0154] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(4-isopropyl-benzenesulfonylamino)-phenyl]-amide
(P-0058), [0155] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[3-(4-tert-butyl-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide
(P-0059), [0156] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(4-propyl-benzenesulfonylamino)-phenyl]-amide
(P-0060), [0157] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(pyridine-2-sulfonylamino)-phenyl]-amide (P-0061),
[0158] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(pyridine-3-sulfonylamino)-phenyl]-amide (P-0062),
[0159] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(dimethylaminosulfonylamino)-phenyl]-amide
(P-0063), [0160] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(piperidine-1-sulfonylamino)-phenyl]-amide
(P-0064), [0161] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(morpholine-4-sulfonylamino)-phenyl]-amide
(P-0065), [0162] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(tetrahydro-pyran-4-sulfonylamino)-phenyl]-amide
(P-0066), [0163] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
(3-cyclopentanesulfonylamino-2,6-difluoro-phenyl)-amide (P-0067),
[0164] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(pyrrolidine-1-sulfonylamino)-phenyl]-amide
(P-0068), [0165] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(3,3,3-trifluoro-propane-1-sulfonylamino)-phenyl]-amide
(P-0069), [0166] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(2-fluoro-benzenesulfonylamino)-phenyl]-amide
(P-0070), [0167] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(3-fluoro-benzenesulfonylamino)-phenyl]-amide
(P-0071), [0168] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[3-(2,6-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide
(P-0072), [0169] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[3-(2,4-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide
(P-0073), [0170] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[3-(2,5-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide
(P-0074), [0171] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(3-fluoro-4-methoxy-benzenesulfonylamino)-phenyl]-amide
(P-0075), [0172] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-phenyl]-amide
(P-0076), 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[3-(4-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide
(P-0077), [0173] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[3-(3-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide
(P-0078), [0174] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(4-isopropyl-benzenesulfonylamino)-phenyl]-amide
(P-0079), [0175] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[3-(4-tert-butyl-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide
(P-0080), [0176] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(4-propyl-benzenesulfonylamino)-phenyl]-amide
(P-0081), [0177] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(pyridine-2-sulfonylamino)-phenyl]-amide (P-0082),
[0178] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(pyridine-3-sulfonylamino)-phenyl]-amide (P-0083),
[0179] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(dimethylaminosulfonylamino)-phenyl]-amide
(P-0084), [0180] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(piperidine-1-sulfonylamino)-phenyl]-amide
(P-0085), [0181] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(morpholine-4-sulfonylamino)-phenyl]-amide
(P-0086), [0182] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(tetrahydro-pyran-4-sulfonylamino)-phenyl]-amide
(P-0087), [0183] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
(3-cyclopentanesulfonylamino-2,6-difluoro-phenyl)-amide (P-0088),
[0184] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(pyrrolidine-1-sulfonylamino)-phenyl]-amide
(P-0089), [0185] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(3,3,3-trifluoro-propane-1-sulfonylamino)-phenyl]-amide
(P-0090), [0186]
N-{5-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzyloxy]-pyridin-2-yl}-a-
cetamide (P-0091), Propane-1-sulfonic acid
[3-(2-amino-pyridin-3-yloxymethyl)-2,4-difluoro-phenyl]-amide
(P-0092), [0187] Propane-1-sulfonic acid
[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridin-5-yloxymethyl)-phenyl]-amide
(P-0093), [0188]
N-{5-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzyloxy]--
pyridin-2-yl}-acetamide (P-0094), [0189]
N-[3-(2-Amino-pyridin-3-yloxymethyl)-2,4-difluoro-phenyl]-4-trifluorometh-
yl-benzenesulfonamide (P-0095), [0190]
N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridin-5-yloxymethyl)-phenyl]-4-trif-
luoromethyl-benzenesulfonamide (P-0096), [0191]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(2-fluoro-benzenesulfonylam-
ino)-benzamide (P-0097), [0192]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(3-fluoro-benzenesulfonylam-
ino)-benzamide (P-0098), [0193]
N-(6-Acetylamino-pyridin-3-yl)-3-(2,6-difluoro-benzenesulfonylamino)-2,6--
difluoro-benzamide (P-0099), [0194]
N-(6-Acetylamino-pyridin-3-yl)-3-(2,4-difluoro-benzenesulfonylamino)-2,6--
difluoro-benzamide (P-0100), [0195]
N-(6-Acetylamino-pyridin-3-yl)-3-(2,5-difluoro-benzenesulfonylamino)-2,6--
difluoro-benzamide (P-0101), [0196]
6-Acetylamino-N-[2,6-difluoro-3-(3-fluoro-4-methoxy-benzenesulfonylamino)-
-phenyl]-nicotinamide (P-0102), [0197]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(4-trifluoromethyl-benzenes-
ulfonylamino)-benzamide (P-0103), [0198]
N-(6-Acetylamino-pyridin-3-yl)-3-(4-difluoromethoxy-benzenesulfonylamino)-
-2,6-difluoro-benzamide (P-0104), [0199]
N-(6-Acetylamino-pyridin-3-yl)-3-(3-difluoromethoxy-benzenesulfonylamino)-
-2,6-difluoro-benzamide (P-0105), [0200]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(4-isopropyl-benzenesulfony-
lamino)-benzamide (P-0106), [0201]
N-(6-Acetylamino-pyridin-3-yl)-3-(4-tert-butyl-benzenesulfonylamino)-2,6--
difluoro-benzamide (P-0107), [0202]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(4-propyl-benzenesulfonylam-
ino)-benzamide (P-0108), [0203]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(pyridine-2-sulfonylamino)--
benzamide (P-0109), [0204]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(pyridine-3-sulfonylamino)--
benzamide (P-0110), [0205]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(dimethylaminosulfonylamino-
)-benzamide (P-0111), [0206]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(piperidine-1-sulfonylamino-
)-benzamide (P-0112), [0207]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(morpholine-4-sulfonylamino-
)-benzamide (P-0113), [0208]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(tetrahydro-pyran-4-sulfony-
lamino)-benzamide (P-0114), [0209]
N-(6-Acetylamino-pyridin-3-yl)-3-cyclopentanesulfonylamino-2,6-difluoro-b-
enzamide (P-0115), [0210]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(pyrrolidine-1-sulfonylamin-
o)-benzamide (P-0116), [0211]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(3,3,3-trifluoro-propane-1--
sulfonylamino)-benzamide (P-0117), [0212]
6-Acetylamino-N-[2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-nicotin-
amide (P-0118), 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-amide (P-0119),
[0213] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-amide (P-0120),
and any salt, prodrug, tautomer, or isomer thereof.
[0214] In reference to compounds herein, unless clearly indicated
to the contrary, specification of a compound or group of compounds
includes pharmaceutically acceptable salts of such compound(s),
pharmaceutically acceptable formulations of such compound(s),
prodrug(s), and all stereoisomers thereof. In reference to
compositions, kits, methods of use, etc. of compounds of Formula I
described herein, it is understood (unless indicated otherwise)
that a compound of Formula I includes all sub-embodiments thereof
(e.g. including Formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, and Ij
and all embodiments as described above).
[0215] In one aspect, methods are provided for treating a protein
kinase mediated disease or condition in an animal subject, wherein
the method involves administering to the subject an effective
amount of one or more compound(s) of Formula I. The terms "treat,"
"therapy," and like terms refer to the administration of material,
e.g., one or more compound(s) of Formula I, in an amount effective
to prevent, alleviate, or ameliorate one or more symptoms of a
disease or condition, i.e., indication, and/or to prolong the
survival of the subject being treated. The term "protein kinase
mediated disease or condition" refers to a disease or condition in
which the biological function of a protein kinase affects the
development, and/or course, and/or symptoms of the disease or
condition, and/or in which modulation of the protein kinase alters
the development, course, and/or symptoms of the disease or
condition. A protein kinase mediated disease or condition includes
a disease or condition for which modulation provides a therapeutic
benefit, e.g. wherein treatment with protein kinase modulators,
including compounds described herein, provides a therapeutic
benefit to the subject suffering from or at risk of the disease or
condition. In one aspect, the protein kinase modulator is an
inhibitor of the protein kinase. In one aspect, the method involves
administering to the subject an effective amount of one or more
compound(s) of Formula I in combination with one or more other
therapies for the disease or condition.
[0216] In one aspect, methods are provided for treating a protein
kinase mediated disease or condition in an animal subject, wherein
the method involves administering to the subject an effective
amount of any one or more compound(s) of Formula I.
[0217] In one aspect, the invention provides methods for treating a
Raf protein kinase mediated disease or condition in an animal
subject, wherein the method involves administering to the subject
an effective amount of one or more compound(s) of Formula I. The
terms "Raf protein kinase mediated disease or condition," "Raf
mediated disease or condition," and the like refer to a disease or
condition in which the biological function of a Raf kinase,
including any mutations thereof, affects the development, course,
and/or symptoms of the disease or condition, and/or in which
modulation of the Raf protein kinase alters the development,
course, and/or symptoms of the disease or condition. The Raf
protein kinase includes, but is not limited to, A-Raf, mutations of
A-Raf, B-Raf, mutations of B-Raf, c-Raf-1 and mutations of c-Raf-1.
In some embodiments, the Raf protein kinase is B-Raf mutation
V600E. In some embodiments, the Raf protein kinase is B-Raf
mutation V600E/T529I. In some embodiments, the disease or condition
is a cancer that is amenable to treatment by an inhibitor of the
V600E mutant B-Raf. In some embodiments, the disease or condition
is a cancer that is amenable to treatment by an inhibitor of the
V600E/T529I mutant B-Raf. The Raf protein kinase mediated disease
or condition includes a disease or condition for which Raf
modulation provides a therapeutic benefit, e.g. wherein treatment
with Raf modulators, including compounds described herein, provides
a therapeutic benefit to the subject suffering from or at risk of
the disease or condition. In one aspect, the Raf modulator is a Raf
inhibitor. In one aspect, the method involves administering to the
subject an effective amount of a compound of Formula I in
combination with one or more other therapies for the disease or
condition. Similarly, the terms "A-Raf, B-Raf or c-Raf-1 protein
kinase mediated disease or condition," "A-Raf, B-Raf or c-Raf-1
mediated disease or condition," and the like refer to a disease or
condition in which the biological function of an A-Raf, B-Raf or
c-Raf-1 kinase, respectively, including any mutations thereof,
affects the development, course, and/or symptoms of the disease or
condition, and/or in which modulation of the A-Raf, B-Raf or
c-Raf-1 protein kinase, respectively, alters the development,
course, and/or symptoms of the disease or condition.
[0218] In some embodiments, a compound of Formula I will have an
IC.sub.50 of less than 500 nm, less than 100 nM, less than 50 nM,
less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM
as determined in a generally accepted kinase activity assay. In
some embodiments, a compound of Formula I will have an IC.sub.50 of
less than 500 nm, less than 100 nM, less than 50 nM, less than 20
nM, less than 10 nM, less than 5 nM, or less than 1 nM with respect
to at least one kinase selected from the group consisting of Abl,
Akt1, Akt2, Akt3, ALK, Alk5, A-Raf, B-Raf, Brk, Btk, Cdk2, CDK4,
CDK5, CDK6, CHK1, c-Raf-1, Csk, EGFR, EphA1, EphA2, EphB2, EphB4,
Erk2, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Flt1, Flt3, Flt4, Fms, Frk,
Fyn, Gsk3.alpha., Gsk3.beta., HCK, Her2/Erbb2, Her4/Erbb4, IGF1R,
IKK beta, Irak4, Itk, Jak1, Jak2, Jak3, Jnk1, Jnk2, Jnk3, Kdr, Kit,
Lck, Lyn, MAP2K1, MAP2K2, MAP4K4, MAPKAPK2, Met, Mnk1, MLK1, p38,
PDGFRA, PDGFRB, PDPK1, Pim1, Pim2, Pim3, PKC alpha, PKC beta, PKC
theta, Plk1, Pyk2, Ret, ROCK1, ROCK2, Ron, Src, Stk6, Syk, TEC,
Tie2, TrkA, TrkB, Yes, and Zap70, including any mutations
thereof.
[0219] In some embodiments, a compound of Formula I will have an
IC.sub.50 of less than 500 nm, less than 100 nM, less than 50 nM,
less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM
with respect to at least one kinase selected from the group
consisting of Abl, Akt1, Akt2, Akt3, ALK, Alk5, A-Raf, B-Raf, Btk,
Cdk2, CDK4, CDK5, CDK6, CHK1, c-Raf-1, Csk, EGFR, EphA1, EphA2,
EphB2, EphB4, Erk2, Fak, Fms, Fyn, Gsk3.alpha., Gsk3.beta., HCK,
Her2/Erbb2, Her4/Erbb4, IGF1R, IKK beta, Irak4, Itk, Jak1, Jak2,
Jak3, Jnk1, Jnk2, Jnk3, Kit, Lck, Lyn, MAP2K1, MAP2K2, MAP4K4,
MAPKAPK2, Met, Mnk1, MLK1, p38, PDPK1, Pim1, Pim2, Pim3, PKC alpha,
PKC beta, PKC theta, Plk1, Pyk2, Ron, Src, Stk6, Syk, TEC, Tie2,
TrkA, TrkB, Yes, and Zap70, including any mutations thereof.
[0220] In some embodiments, a compound of Formula I will have an
IC.sub.50 of less than 500 nm, less than 100 nM, less than 50 nM,
less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM
with respect to at least one kinase selected from the group
consisting of Abl, A-Raf, B-Raf, Btk, c-Raf-1, EGFR, EphB2, Erk2,
Fak, FGFR1, Flt1, Flt3, Flt4, Fms, Irak4, Jnk1, Jnk2, Jnk3, Kdr,
Kit, Lck, Lyn, MAP2K1, MAP4K4, MAPKAPK2, Met, p38, PDGFRB, Pim1,
PKC theta, Pyk2, Ret, Src, Stk6, TrkA, TrkB, Yes, and Zap70,
including any mutations thereof.
[0221] In some embodiments, a compound of Formula I will have an
IC.sub.50 of less than 500 nm, less than 100 nM, less than 50 nM,
less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM
with respect to at least one kinase selected from the group
consisting of Abl, A-Raf, B-Raf, Btk, c-Raf-1, EGFR, EphB2, Erk2,
Fak, Fms, Irak4, Jnk1, Jnk2, Jnk3, Kit, Lck, Lyn, MAP2K1, MAP4K4,
MAPKAPK2, Met, p38, Pim1, PKC theta, Pyk2, Src, Stk6, TrkA, TrkB,
Yes, and Zap70, including any mutations thereof.
[0222] In some embodiments, a compound of Formula I will have an
IC.sub.50 of less than 500 nm, less than 100 nM, less than 50 nM,
less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM
with respect to at least one kinase selected from the group
consisting of A-Raf, B-Raf, B-Raf V600E mutant, B-Raf V600E/T529I
mutant, c-Raf-1, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Jnk1, Jnk2, Jnk3,
Lck, Lyn, Met, Pim1, Pim2, Pim3, Pyk2, Kdr, Src and Ret, including
any mutations thereof.
[0223] In some embodiments, a compound of Formula I is an inhibitor
of a Raf kinase and has an IC.sub.50 of less than 500 nm, less than
100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less
than 5 nM, or less than 1 nM as determined in a generally accepted
Raf kinase activity assay. In some embodiments, a compound of
Formula I will have an IC.sub.50 of less than 500 nm, less than 100
nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5
nM, or less than 1 nM with respect to A-Raf, B-Raf, c-Raf-1, B-Raf
V600E mutant, or B-Raf V600E/T529I mutant. In some embodiments, a
compound of Formula I will selectively inhibit one Raf kinase
relative to one or more other Raf kinases. In some embodiments, the
compound of Formula I will selectively inhibit a mutation of the
Raf kinase relative to the wild type kinase, for example B-RafV600E
mutant relative to wild type B-Raf.
[0224] Further to any of the above mentioned embodiments, a
compound of Formula I will also inhibit the effects of a mutation
of the kinase, including, but not limited to, a mutation that is
related to a disease state, such as a cancer. For example,
B-RafV600E mutant is present in a high percentage of some cancers,
such as melanoma, and compounds will inhibit the kinase activity of
this mutant.
[0225] Further to any of the above embodiments, a compound of
Formula I may selectively inhibit one kinase relative to one or
more other kinases, where preferably inhibition is selective with
respect to any of the other kinases, whether a kinase discussed
herein, or other kinases. In some embodiments, the compound may
selectively inhibit the effects of a mutation of the kinase
relative to the wild type kinase, for example B-Raf V600E mutant
relative to wild type B-Raf. Selective inhibition of one kinase
relative to another is such that the IC.sub.50 for the one kinase
may be at least about 2-fold, also 5-fold, also 10-fold, also
20-fold, also 50-fold, or at least about 100-fold less than the
IC.sub.50 for any of the other kinases as determined in a generally
accepted kinase activity assay.
[0226] In another aspect, compositions are provided that include a
therapeutically effective amount of one or more compound(s) of
Formula I and at least one pharmaceutically acceptable carrier,
excipient, and/or diluent, including combinations of any two or
more compounds of Formula I. The composition can further include a
plurality of different pharmacologically active compounds, which
can include a plurality of compounds of Formula I. In another
aspect, the composition can include one or more compounds of
Formula I along with one or more compounds that are therapeutically
effective for the same disease indication. In one aspect, the
composition includes one or more compounds of Formula I along with
one or more compounds that are therapeutically effective for the
same disease indication, wherein the compounds have a synergistic
effect on the disease indication. In one aspect, the composition
includes one or more compounds of Formula I effective in treating a
cancer and one or more other compounds that are effective in
treating the cancer, further wherein the compounds are
synergistically effective in treating the cancer.
[0227] In another aspect, methods are provided for modulating the
activity of a protein kinase selected from the group consisting of
Abl, Akt1, Akt2, Akt3, ALK, Alk5, A-Raf, B-Raf, Brk, Btk, Cdk2,
CDK4, CDK5, CDK6, CHK1, c-Raf-1, Csk, EGFR, EphA1, EphA2, EphB2,
EphB4, Erk2, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Flt1, Flt3, Flt4,
Fms, Frk, Fyn, Gsk3.alpha., Gsk3.beta., HCK, Her2/Erbb2,
Her4/Erbb4, IGF1R, IKK beta, Irak4, Itk, Jak1, Jak2, Jak3, Jnk1,
Jnk2, Jnk3, Kdr, Kit, Lck, Lyn, MAP2K1, MAP2K2, MAP4K4, MAPKAPK2,
Met, Mnk1, MLK1, p38, PDGFRA, PDGFRB, PDPK1, Pim1, Pim2, Pim3, PKC
alpha, PKC beta, PKC theta, Plk1, Pyk2, Ret, ROCK1, ROCK2, Ron,
Src, Stk6, Syk, TEC, Tie2, TrkA, TrkB, Yes, and Zap70, including
any mutations thereof, by contacting the protein kinase with an
effective amount of one or more compound(s) of Formula I.
[0228] In another aspect, methods are provided for treating a
protein kinase mediated disease or condition in an animal subject,
wherein the method involves administering to the subject an
effective amount of a composition including one or more compound(s)
of Formula I.
[0229] In one aspect, methods are provided for treating a disease
or condition mediated by a protein kinase selected from the group
consisting of Abl, Akt1, Akt2, Akt3, ALK, Alk5, A-Raf, B-Raf, Brk,
Btk, Cdk2, CDK4, CDK5, CDK6, CHK1, c-Raf-1, Csk, EGFR, EphA1,
EphA2, EphB2, EphB4, Erk2, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Flt1,
Flt3, Flt4, Fms, Frk, Fyn, Gsk3.alpha., Gsk3.beta., HCK,
Her2/Erbb2, Her4/Erbb4, IGF1R, IKK beta, Irak4, Itk, Jak1, Jak2,
Jak3, Jnk1, Jnk2, Jnk3, Kdr, Kit, Lck, Lyn, MAP2K1, MAP2K2, MAP4K4,
MAPKAPK2, Met, Mnk1, MLK1, p38, PDGFRA, PDGFRB, PDPK1, Pim1, Pim2,
Pim3, PKC alpha, PKC beta, PKC theta, Plk1, Pyk2, ROCK1, ROCK2,
Ron, Src, Stk6, Syk, TEC, Tie2, TrkA, TrkB, Yes, and Zap70,
including any mutations thereof, by administering to the subject an
effective amount of a composition including one or more compound(s)
of Formula I.
[0230] In one aspect, the invention provides methods for treating a
disease or condition mediated by a protein kinase selected from the
group consisting of Abl, Akt1, Akt2, Akt3, ALK, Alk5, A-Raf, B-Raf,
Btk, Cdk2, CDK4, CDK5, CDK6, CHK1, c-Raf-1, Csk, EGFR, EphA1,
EphA2, EphB2, EphB4, Erk2, Fak, Fms, Fyn, Gsk3.alpha., Gsk3.beta.,
HCK, Her2/Erbb2, Her4/Erbb4, IGF1R, IKK beta, Irak4, Itk, Jak1,
Jak2, Jak3, Jnk1, Jnk2, Jnk3, Kit, Lck, Lyn, MAP2K1, MAP2K2,
MAP4K4, MAPKAPK2, Met, Mnk1, MLK1, p38, PDPK1, Pim1, Pim2, Pim3,
PKC alpha, PKC beta, PKC theta, Plk1, Pyk2, Ron, Src, Stk6, Syk,
TEC, Tie2, TrkA, TrkB, Yes, and Zap70, including any mutations
thereof, by administering to the subject an effective amount of a
composition including one or more compound(s) of Formula I.
[0231] In one aspect, the invention provides methods for treating a
disease or condition mediated by a protein kinase selected from the
group consisting of Abl, A-Raf, B-Raf, Btk, c-Raf-1, EGFR, EphB2,
Erk2, Fak, FGFR1, Flt1, Flt3, Flt4, Fms, Irak4, Jnk1, Jnk2, Jnk3,
Kdr, Kit, Lck, Lyn, MAP2K1, MAP4K4, MAPKAPK2, Met, p38, PDGFRB,
Pim1, PKC theta, Pyk2, Ret, Src, Stk6, TrkA, TrkB, Yes, and Zap70,
including any mutations thereof, by administering to the subject an
effective amount of a composition including one or more compound(s)
of Formula I.
[0232] In one aspect, the invention provides methods for treating a
disease or condition mediated by a protein kinase selected from the
group consisting of Abl, A-Raf, B-Raf, Btk, c-Raf-1, EGFR, EphB2,
Erk2, Fak, Fms, Irak4, Jnk1, Jnk2, Jnk3, Kit, Lck, Lyn, MAP2K1,
MAP4K4, MAPKAPK2, Met, p38, Pim1, PKC theta, Pyk2, Src, Stk6, TrkA,
TrkB, Yes, and Zap70, including any mutations thereof, by
administering to the subject an effective amount of a composition
including one or more compound(s) of Formula I.
[0233] In one aspect, the invention provides methods for treating a
disease or condition mediated by a protein kinase selected from the
group consisting of A-Raf, B-Raf, B-RafV600E mutant, B-Raf
V600E/T529I mutant, c-Raf-1, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Jnk1,
Jnk2, Jnk3, Lck, Lyn, Met, Pim1, Pim2, Pim3, Pyk2, Kdr, Src and
Ret, including any mutations thereof, by administering to the
subject an effective amount of a composition including one or more
compound(s) of Formula I.
[0234] In one aspect, the invention provides methods for treating a
disease or condition mediated by A-Raf, B-Raf, c-Raf-1, B-Raf V600E
mutant, or B-Raf V600E/T529I mutant by administering to the subject
an effective amount of a composition including one or more
compound(s) of Formula I. In one aspect, the invention provides
methods for treating a disease or condition mediated by A-Raf,
B-Raf, c-Raf-1, B-RafV600E mutant, or B-RafV600E/T529I mutant by
administering to the subject an effective amount of a composition
including one or more compound(s) of Formula I in combination with
one or more other suitable therapies for treating the disease. In
one aspect, the invention provides methods for treating a cancer
mediated by B-RafV600E mutant or B-RafV600E/T529I mutant by
administering to the subject an effective amount of a composition
including one or more compound(s) of Formula I in combination with
one or more suitable anticancer therapies, such as one or more
chemotherapeutic drugs.
[0235] In one aspect, the invention provides a method of treating a
cancer by administering to the subject an effective amount of a
composition including one or more compound(s) of Formula I, in
combination with one or more other therapies or medical procedures
effective in treating the cancer. Other therapies or medical
procedures include suitable anticancer therapy (e.g. drug therapy,
vaccine therapy, gene therapy, photodynamic therapy) or medical
procedure (e.g. surgery, radiation treatment, hyperthermia heating,
bone marrow or stem cell transplant). In one aspect, the one or
more suitable anticancer therapies or medical procedures is
selected from treatment with a chemotherapeutic agent (e.g.
chemotherapeutic drug), radiation treatment (e.g. x-ray, -ray, or
electron, proton, neutron, or particle beam), hyperthermia heating
(e.g. microwave, ultrasound, radiofrequency ablation), Vaccine
therapy (e.g. AFP gene hepatocellular carcinoma vaccine, AFP
adenoviral vector vaccine, AG-858, allogeneic GM-CSF-secretion
breast cancer vaccine, dendritic cell peptide vaccines), gene
therapy (e.g. Ad5CMV-p53 vector, adenovector encoding MDA7,
adenovirus 5-tumor necrosis factor alpha), photodynamic therapy
(e.g. aminolevulinic acid, motexafin lutetium), surgery, and bone
marrow and stem cell transplantation.
[0236] In a preferred embodiment, the invention provides a method
of treating a cancer by administering to the subject an effective
amount of a composition including one or more compound(s) of
Formula I in combination with one or more suitable chemotherapeutic
agents. In one aspect, the one or more suitable chemotherapeutic
agents is selected from an alkylating agent, including, but not
limited to, adozelesin, altretamine, bizelesin, busulfan,
carboplatin, carboquone, carmustine, chlorambucil, cisplatin,
cyclophosphamide, dacarbazine, estramustine, fotemustine,
hepsulfam, ifosfamide, improsulfan, irofulven, lomustine,
mechlorethamine, melphalan, oxaliplatin, piposulfan, semustine,
streptozocin, temozolomide, thiotepa, and treosulfan; an
antibiotic, including, but not limited to, bleomycin, dactinomycin,
daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril,
mitomycin, mitoxantrone, neocarzinostatin, pentostatin, and
plicamycin; an antimetabolite, including, but not limited to,
azacitidine, capecitabine, cladribine, clofarabine, cytarabine,
decitabine, floxuridine, fludarabine, 5-fluorouracil, ftorafur,
gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine,
pemetrexed, raltitrexed, thioguanine, and trimetrexate; an
immunotherapy, including, but not limited to, alemtuzumab,
bevacizumab, cetuximab, galiximab, gemtuzumab, panitumumab,
pertuzumab, rituximab, tositumomab, trastuzumab, and 90 Y
ibritumomab tiuxetan; a hormone or hormone antagonist, including,
but not limited to, anastrozole, androgens, buserelin,
diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin,
idoxifene, letrozole, leuprolide, magestrol, raloxifene, tamoxifen,
and toremifene; a taxane, including, but not limited to, DJ-927,
docetaxel, TPI 287, paclitaxel and DHA-paclitaxel; a retinoid,
including, but not limited to, alitretinoin, bexarotene,
fenretinide, isotretinoin, and tretinoin; an alkaloid, including,
but not limited to, etoposide, homoharringtonine, teniposide,
vinblastine, vincristine, vindesine, and vinorelbine; an
antiangiogenic agent, including, but not limited to, AE-941
(GW786034, Neovastat), ABT-510, 2-methoxyestradiol, lenalidomide,
and thalidomide; a topoisomerase inhibitor, including, but not
limited to, amsacrine, edotecarin, exatecan, irinotecan (also
active metabolite SN-38 (7-ethyl-10-hydroxy-camptothecin)),
rubitecan, topotecan, and 9-aminocamptothecin; a kinase inhibitor,
including, but not limited to, erlotinib, gefitinib, flavopiridol,
imatinib mesylate, lapatinib, sorafenib, sunitinib malate, AEE-788,
AG-013736, AMG 706, AMN107, BMS-354825, BMS-599626, UCN-01
(7-hydroxy-staurosporine), and vatalanib; a targeted signal
transduction inhibitor including, but not limited to bortezomib,
geldanamycin, and rapamycin; a biological response modifier,
including, but not limited to, imiquimod, interferon-, and
interleukin-2; and other chemotherapeutics, including, but not
limited to 3-AP (3-amino-2-carboxyaldehyde thiosemicarbazone),
aminoglutethimide, asparaginase, bryostatin-1, cilengitide, E7389,
ixabepilone, procarbazine, sulindac, temsirolimus, tipifamib.
Preferably, the method of treating a cancer involves administering
to the subject an effective amount of a composition including one
or more compound(s) of Formula I in combination with a
chemotherapeutic agent selected from 5-fluorouracil, carboplatin,
dacarbazine, gefitinib, oxaliplatin, paclitaxel, SN-38,
temozolomide, vinblastine, bevacizumab, cetuximab, or
erlotinib.
[0237] In another aspect, the invention provides a method of
treating or prophylaxis of a disease or condition in a mammal, by
administering to the mammal a therapeutically effective amount of
one or more compound(s) of Formula I, a prodrug of such compound, a
pharmaceutically acceptable salt of such compound or prodrug, or a
pharmaceutically acceptable formulation of such compound or
prodrug. The compound can be alone or can be part of a composition.
In another aspect, the invention provides a method of treating or
prophylaxis of a disease or condition in a mammal, by administering
to the mammal a therapeutically effective amount of one or more
compound(s) of Formula I, a prodrug of such compound, a
pharmaceutically acceptable salt of such compound or prodrug, or a
pharmaceutically acceptable formulation of such compound or prodrug
in combination with one or more other suitable therapies for the
disease or condition.
[0238] In a related aspect, the invention provides kits that
include a composition as described herein. In some embodiments, the
composition is packaged, e.g., in a vial, bottle, flask, which may
be further packaged, e.g., within a box, envelope, or bag; the
composition is approved by the U.S. Food and Drug Administration or
similar regulatory agency for administration to a mammal, e.g., a
human; the composition is approved for administration to a mammal,
e.g., a human, for a protein kinase mediated disease or condition;
the invention kit includes written instructions for use and/or
other indication that the composition is suitable or approved for
administration to a mammal, e.g., a human, for a protein
kinase-mediated disease or condition; and the composition is
packaged in unit dose or single dose form, e.g., single dose pills,
capsules, or the like.
[0239] In aspects involving treatment or prophylaxis of a disease
or condition with the compounds of Formula I, the disease or
condition is, for example without limitation, neurologic diseases,
including, but not limited to, cerebrovascular ischemia,
multi-infarct dementia, head injury, spinal cord injury,
Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral
sclerosis, dementia, senile chorea, and Huntington's disease;
neoplastic diseases and associated complications, including, but
not limited to, chemotherapy-induced hypoxia, gastrointestinal
stromal tumors (GISTs), prostate tumors, mast cell tumors
(including canine mast cell tumors), acute myeloid leukemia, acute
lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic
leukemia, multiple myeloma, melanoma, mastocytosis, gliomas,
glioblastoma, astrocytoma, neuroblastoma, sarcomas (e.g. sarcomas
of neuroectodermal origin, leiomyosarcoma), carcinomas (e.g. lung,
breast, pancreatic, colon, hepatocellular, renal, female genital
tract, squamous cell, carcinoma in situ), lymphoma (e.g.
histiocytic lymphoma, non-Hodgkin's lymphoma), MEN2 syndromes,
neurofibromatosis (including Schwann cell neoplasia),
myelodysplastic syndrome, leukemia, tumor angiogenesis, cancers of
the thyroid, liver, bone, skin, brain, central nervous system,
pancreas, lung (e.g. small cell lung cancer, non small cell lung
cancer), breast, colon, bladder, prostate, gastrointestinal tract,
endometrium, fallopian tube, testes and ovary, and metastasis of
tumors to other tissues; pain of neuropathic or inflammatory
origin, including, but not limited to, acute pain, chronic pain,
bone pain, cancer-related pain and migraine; cardiovascular
diseases, including, but not limited to, heart failure, ischemic
stroke, cardiac hypertrophy, thrombosis (e.g. thrombotic
microangiopathy syndromes), atherosclerosis, reperfusion injury and
ischemia (e.g. cerebrovascular ischemia, liver ischemia);
inflammation including, but not limited to, age-related macular
degeneration, rheumatoid arthritis, allergic rhinitis, inflammatory
bowel disease (e.g. ulcerative colitis, Crohn's disease), systemic
lupus erythematosis, Sjogren's Syndrome, Wegener's granulomatosis,
psoriasis, scleroderma, chronic thyroiditis, Grave's disease,
myasthenia gravis, multiple sclerosis, osteoarthritis,
endometriosis, scarring (e.g. dermal, tissue), vascular restenosis,
fibrotic disorders, hypereosinophilia, CNS inflammation,
pancreatitis, nephritis, atopic dermatitis, and hepatitis;
immunodeficiency diseases, including, but not limited to, severe
combined immunodeficiency (SCID), organ transplant rejection, and
graft versus host disease; renal or prostatic diseases, including,
but not limited to, diabetic nephropathy, polycystic kidney
disease, nephrosclerosis, glomerulonephritis, interstitial
nephritis, Lupus nephritis, prostate hyperplasia, chronic renal
failure, tubular necrosis, diabetes-associated renal complications,
and hypertrophy; metabolic diseases, including, but not limited to,
type 1 diabetes, type 2 diabetes, metabolic syndrome, obesity,
hepatic steatosis, insulin resistance, hyperglycemia, lipolysis and
obesity; infection, including, but not limited to, Helicobacter
pylori, Hepatitis and Influenza viruses, fever, and sepsis;
pulmonary diseases, including, but not limited to, chronic
obstructive pulmonary disease (COPD), acute respiratory distress
syndrome (ARDS), asthma, allergy, bronchitis, emphysema, and
pulmonary fibrosis; genetic developmental diseases, including, but
not limited to, Noonan's syndrome, Crouzon syndrome,
acrocephalo-syndactyly type I, Pfeiffer's syndrome, Jackson-Weiss
syndrome, Costello syndrome, (faciocutaneoskeletal syndrome),
LEOPARD syndrome, cardio-faciocutaneous syndrome (CFC) and neural
crest syndrome abnormalities causing cardiovascular, skeletal,
intestinal, skin, hair and endocrine diseases; disorders of bone
structure, mineralization and bone reformation and resorption,
including, but not limited to, osteoporosis, increased risk of
fracture, Paget's disease, hypercalcemia, and metastatis of cancer
to bone; Grave's disease; Hirschsprung's disease; lymphoedema;
selective T-cell defect (STD); X-linked agammaglobulinemia;
diabetic retinopathy; alopecia; erectile dysfunction; tuberous
sclerosis, and diseases associated with muscle regeneration or
degeneration, including, but not limited to, sarcopenia, muscular
dystrophies (including, but not limited to, Duchenne, Becker,
Emery-Dreifuss, Limb-Girdle, Facioscapulohumeral, Myotonic,
Oculopharyngeal, Distal and Congenital Muscular Dystrophies), motor
neuron diseases (including, but not limited to, amyotrophic lateral
sclerosis, infantile progressive spinal muscular atrophy,
intermediate spinal muscular atrophy, juvenile spinal muscular
atrophy, spinal bulbar muscular atrophy, and adult spinal muscular
atrophy), inflammatory myopathies (including, but not limited to,
dermatomyositis, polymyositis, and inclusion body myositis),
diseases of the neuromuscular junction (including, but not limited
to, myasthenia gravis, Lambert-Eaton syndrome, and congenital
myasthenic syndrome), myopathies due to endocrine abnormalities
(including, but not limited to, hyperthyroid myopathy and
hypothyroid myopathy) diseases of peripheral nerve (including, but
not limited to, Charcot-Marie-Tooth disease, Dejerine-Sottas
disease, and Friedreich's ataxia), other myopathies (including, but
not limited to, myotonia congenita, paramyotonia congenita, central
core disease, nemaline myopathy, myotubular myopathy, and periodic
paralysis), and metabolic diseases of muscle (including, but not
limited to, phosphorylase deficiency, acid maltase deficiency,
phosphofructokinase deficiency, debrancher enzyme deficiency,
mitochondrial myopathy, carnitine deficiency, carnitine palmatyl
transferase deficiency, phosphoglycerate kinase deficiency,
phosphoglycerate mutase deficiency, lactate dehydrogenase
deficiency, and myoadenylate deaminase deficiency).
[0240] In some aspects, compounds of Formula I can be used in the
preparation of a medicament for the treatment of a disease or
condition is, for example without limitation, neurologic diseases,
including, but not limited to, cerebrovascular ischemia,
multi-infarct dementia, head injury, spinal cord injury,
Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral
sclerosis, dementia, senile chorea, and Huntington's disease;
neoplastic diseases and associated complications, including, but
not limited to, chemotherapy-induced hypoxia, gastrointestinal
stromal tumors (GISTs), prostate tumors, mast cell tumors
(including canine mast cell tumors), acute myeloid leukemia, acute
lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic
leukemia, multiple myeloma, melanoma, mastocytosis, gliomas,
glioblastoma, astrocytoma, neuroblastoma, sarcomas (e.g. sarcomas
of neuroectodermal origin, leiomyosarcoma), carcinomas (e.g. lung,
breast, pancreatic, colon, hepatocellular, renal, female genital
tract, squamous cell, carcinoma in situ), lymphoma (e.g.
histiocytic lymphoma, non-Hodgkin's lymphoma), MEN2 syndromes,
neurofibromatosis (including Schwann cell neoplasia),
myelodysplastic syndrome, leukemia, tumor angiogenesis, cancers of
the thyroid, liver, bone, skin, brain, central nervous system,
pancreas, lung (e.g. small cell lung cancer, non small cell lung
cancer), breast, colon, bladder, prostate, gastrointestinal tract,
endometrium, fallopian tube, testes and ovary, and metastasis of
tumors to other tissues; pain of neuropathic or inflammatory
origin, including, but not limited to, acute pain, chronic pain,
bone pain, cancer-related pain and migraine; cardiovascular
diseases, including, but not limited to, heart failure, ischemic
stroke, cardiac hypertrophy, thrombosis (e.g. thrombotic
microangiopathy syndromes), atherosclerosis, reperfusion injury and
ischemia (e.g. cerebrovascular ischemia, liver ischemia);
inflammation including, but not limited to, age-related macular
degeneration, rheumatoid arthritis, allergic rhinitis, inflammatory
bowel disease (e.g. ulcerative colitis, Crohn's disease), systemic
lupus erythematosis, Sjogren's Syndrome, Wegener's granulomatosis,
psoriasis, scleroderma, chronic thyroiditis, Grave's disease,
myasthenia gravis, multiple sclerosis, osteoarthritis,
endometriosis, scarring (e.g. dermal, tissue), vascular restenosis,
fibrotic disorders, hypereosinophilia, CNS inflammation,
pancreatitis, nephritis, atopic dermatitis, and hepatitis;
immunodeficiency diseases, including, but not limited to, severe
combined immunodeficiency (SCID), organ transplant rejection, and
graft versus host disease; renal or prostatic diseases, including,
but not limited to, diabetic nephropathy, polycystic kidney
disease, nephrosclerosis, glomerulonephritis, interstitial
nephritis, Lupus nephritis, prostate hyperplasia, chronic renal
failure, tubular necrosis, diabetes-associated renal complications,
and hypertrophy; metabolic diseases, including, but not limited to,
type 1 diabetes, type 2 diabetes, metabolic syndrome, obesity,
hepatic steatosis, insulin resistance, hyperglycemia, lipolysis and
obesity; infection, including, but not limited to, Helicobacter
pylori, Hepatitis and Influenza viruses, fever, and sepsis;
pulmonary diseases, including, but not limited to, chronic
obstructive pulmonary disease (COPD), acute respiratory distress
syndrome (ARDS), asthma, allergy, bronchitis, emphysema, and
pulmonary fibrosis; genetic developmental diseases, including, but
not limited to, Noonan's syndrome, Crouzon syndrome,
acrocephalo-syndactyly type I, Pfeiffer's syndrome, Jackson-Weiss
syndrome, Costello syndrome, (faciocutaneoskeletal syndrome),
LEOPARD syndrome, cardio-faciocutaneous syndrome (CFC) and neural
crest syndrome abnormalities causing cardiovascular, skeletal,
intestinal, skin, hair and endocrine diseases; disorders of bone
structure, mineralization and bone reformation and resorption,
including, but not limited to, osteoporosis, increased risk of
fracture, Paget's disease, hypercalcemia, and metastatis of cancer
to bone; Grave's disease; Hirschsprung's disease; lymphoedema;
selective T-cell defect (STD); X-linked agammaglobulinemia;
diabetic retinopathy; alopecia; erectile dysfunction; tuberous
sclerosis, and diseases associated with muscle regeneration or
degeneration, including, but not limited to, sarcopenia, muscular
dystrophies (including, but not limited to, Duchenne, Becker,
Emery-Dreifuss, Limb-Girdle, Facioscapulohumeral, Myotonic,
Oculopharyngeal, Distal and Congenital Muscular Dystrophies), motor
neuron diseases (including, but not limited to, amyotrophic lateral
sclerosis, infantile progressive spinal muscular atrophy,
intermediate spinal muscular atrophy, juvenile spinal muscular
atrophy, spinal bulbar muscular atrophy, and adult spinal muscular
atrophy), inflammatory myopathies (including, but not limited to,
dermatomyositis, polymyositis, and inclusion body myositis),
diseases of the neuromuscular junction (including, but not limited
to, myasthenia gravis, Lambert-Eaton syndrome, and congenital
myasthenic syndrome), myopathies due to endocrine abnormalities
(including, but not limited to, hyperthyroid myopathy and
hypothyroid myopathy) diseases of peripheral nerve (including, but
not limited to, Charcot-Marie-Tooth disease, Dejerine-Sottas
disease, and Friedreich's ataxia), other myopathies (including, but
not limited to, myotonia congenita, paramyotonia congenita, central
core disease, nemaline myopathy, myotubular myopathy, and periodic
paralysis), and metabolic diseases of muscle (including, but not
limited to, phosphorylase deficiency, acid maltase deficiency,
phosphofructokinase deficiency, debrancher enzyme deficiency,
mitochondrial myopathy, carnitine deficiency, carnitine palmatyl
transferase deficiency, phosphoglycerate kinase deficiency,
phosphoglycerate mutase deficiency, lactate dehydrogenase
deficiency, and myoadenylate deaminase deficiency).
[0241] In aspects involving treatment or prophylaxis of a disease
or condition with the compounds of Formula I, the invention
provides methods for treating an A-Raf-mediated, B-Raf-mediated
and/or c-Raf-1-mediated disease or condition in an animal subject
(e.g. a mammal such as a human, other primates, sports animals,
animals of commercial interest such as cattle, farm animals such as
horses, or pets such as dogs and cats), e.g., a disease or
condition characterized by abnormal A-Raf, B-Raf, and/or c-Raf-1
activity (e.g. kinase activity). Invention methods involve
administering to the subject suffering from or at risk of an
A-Raf-mediated, B-Raf-mediated and/or c-Raf-1-mediated disease or
condition an effective amount of compound of Formula I. In one
embodiment, the A-Raf-mediated, B-Raf-mediated, and/or
c-Raf-1-mediated disease is selected from the group consisting of
neurologic diseases, including, but not limited to, multi-infarct
dementia, head injury, spinal cord injury, Alzheimer's disease
(AD), Parkinson's disease; neoplastic diseases including, but not
limited to, melanoma, glioma, sarcoma, carcinoma (e.g. colorectal,
lung, breast, pancreatic, thyroid, renal, ovarian), lymphoma (e.g.
histiocytic lymphoma) neurofibromatosis, acute myeloid leukemia,
myelodysplastic syndrome, leukemia, tumor angiogenesis,
neuroendocrine tumors such as medullary thyroid cancer, carcinoid,
small cell lung cancer and pheochromocytoma; pain of neuropathic or
inflammatory origin, including, but not limited to, acute pain,
chronic pain, cancer-related pain, and migraine; cardiovascular
diseases including, but not limited to, heart failure, ischemic
stroke, cardiac hypertrophy, thrombosis (e.g. thrombotic
microangiopathy syndromes), atherosclerosis, and reperfusion
injury; inflammation including, but not limited to, psoriasis,
arthritis and autoimmune diseases and conditions, osteoarthritis,
endometriosis, scarring, vascular restenosis, fibrotic disorders,
rheumatoid arthritis, inflammatory bowel disease; immunodeficiency
diseases, including, but not limited to, organ transplant
rejection, graft versus host disease; renal or prostatic diseases,
including, but not limited to, diabetic nephropathy, polycystic
kidney disease, nephrosclerosis, glomerulonephritis, prostate
hyperplasia; metabolic disorders, including, but not limited to,
obesity; infection, including, but not limited to Helicobacter
pylori, Hepatitis and Influenza viruses, fever, and sepsis;
pulmonary diseases including, but not limited to, chronic
obstructive pulmonary disease (COPD) and acute respiratory distress
syndrome (ARDS); genetic developmental diseases, including, but not
limited to, Noonan's syndrome, Costello syndrome,
(faciocutaneoskeletal syndrome), LEOPARD syndrome,
cardio-faciocutaneous syndrome (CFC), and neural crest syndrome
abnormalities causing cardiovascular, skeletal, intestinal, skin,
hair and endocrine diseases; and diseases associated with muscle
regeneration or degeneration, including, but not limited to,
sarcopenia, muscular dystrophies (including, but not limited to,
Duchenne, Becker, Emery-Dreifuss, Limb-Girdle, Facioscapulohumeral,
Myotonic, Oculopharyngeal, Distal and Congenital Muscular
Dystrophies), motor neuron diseases (including, but not limited to,
amyotrophic lateral sclerosis, infantile progressive spinal
muscular atrophy, intermediate spinal muscular atrophy, juvenile
spinal muscular atrophy, spinal bulbar muscular atrophy, and adult
spinal muscular atrophy), inflammatory myopathies (including, but
not limited to, dermatomyositis, polymyositis, and inclusion body
myositis), diseases of the neuromuscular junction (including, but
not limited to, myasthenia gravis, Lambert-Eaton syndrome, and
congenital myasthenic syndrome), myopathies due to endocrine
abnormalities (including, but not limited to, hyperthyroid myopathy
and hypothyroid myopathy) diseases of peripheral nerve (including,
but not limited to, Charcot-Marie-Tooth disease, Dejerine-Sottas
disease, and Friedreich's ataxia), other myopathies (including, but
not limited to, myotonia congenita, paramyotonia congenita, central
core disease, nemaline myopathy, myotubular myopathy, and periodic
paralysis), and metabolic diseases of muscle (including, but not
limited to, phosphorylase deficiency, acid maltase deficiency,
phosphofructokinase deficiency, debrancher enzyme deficiency,
mitochondrial myopathy, carnitine deficiency, carnitine palmatyl
transferase deficiency, phosphoglycerate kinase deficiency,
phosphoglycerate mutase deficiency, lactate dehydrogenase
deficiency, and myoadenylate deaminase deficiency).
[0242] In some aspects, compounds of Formula I can be used in the
preparation of a medicament for the treatment of an A-Raf-mediated,
B-Raf-mediated or c-Raf-1-mediated disease or condition selected
from the group consisting of neurologic diseases, including, but
not limited to, multi-infarct dementia, head injury, spinal cord
injury, Alzheimer's disease (AD), Parkinson's disease; neoplastic
diseases including, but not limited to, melanoma, glioma, sarcoma,
carcinoma (e.g. colorectal, lung, breast, pancreatic, thyroid,
renal, ovarian), lymphoma (e.g. histiocytic lymphoma)
neurofibromatosis, acute myeloid leukemia, myelodysplastic
syndrome, leukemia, tumor angiogenesis, neuroendocrine tumors such
as medullary thyroid cancer, carcinoid, small cell lung cancer and
pheochromocytoma; pain of neuropathic or inflammatory origin,
including, but not limited to, acute pain, chronic pain,
cancer-related pain, and migraine; cardiovascular diseases,
including, but not limited to, heart failure, ischemic stroke,
cardiac hypertrophy, thrombosis (e.g. thrombotic microangiopathy
syndromes), atherosclerosis, and reperfusion injury; inflammation
including, but not limited to, psoriasis, arthritis and autoimmune
diseases and conditions, osteoarthritis, endometriosis, scarring,
vascular restenosis, fibrotic disorders, rheumatoid arthritis,
inflammatory bowel disease; immunodeficiency diseases, including,
but not limited to, organ transplant rejection, graft versus host
disease; renal or prostatic diseases, including, but not limited
to, diabetic nephropathy, polycystic kidney disease,
nephrosclerosis, glomerulonephritis, prostate hyperplasia;
metabolic disorders, including, but not limited to, obesity;
infection, including, but not limited to, Helicobacter pylori,
Hepatitis and Influenza viruses, fever, and sepsis; pulmonary
diseases, including, but not limited to, chronic obstructive
pulmonary disease (COPD) and acute respiratory distress syndrome
(ARDS); genetic developmental diseases, including, but not limited
to, Noonan's syndrome, Costello syndrome, (faciocutaneoskeletal
syndrome), LEOPARD syndrome, cardio-faciocutaneous syndrome (CFC),
and neural crest syndrome abnormalities causing cardiovascular,
skeletal, intestinal, skin, hair and endocrine diseases; and
diseases associated with muscle regeneration or degeneration,
including, but not limited to, sarcopenia, muscular dystrophies
(including, but not limited to, Duchenne, Becker, Emery-Dreifuss,
Limb-Girdle, Facioscapulohumeral, Myotonic, Oculopharyngeal, Distal
and Congenital Muscular Dystrophies), motor neuron diseases
(including, but not limited to, amyotrophic lateral sclerosis,
infantile progressive spinal muscular atrophy, intermediate spinal
muscular atrophy, juvenile spinal muscular atrophy, spinal bulbar
muscular atrophy, and adult spinal muscular atrophy), inflammatory
myopathies (including, but not limited to, dermatomyositis,
polymyositis, and inclusion body myositis), diseases of the
neuromuscular junction (including, but not limited to, myasthenia
gravis, Lambert-Eaton syndrome, and congenital myasthenic
syndrome), myopathies due to endocrine abnormalities (including,
but not limited to, hyperthyroid myopathy and hypothyroid myopathy)
diseases of peripheral nerve (including, but not limited to,
Charcot-Marie-Tooth disease, Dejerine-Sottas disease, and
Friedreich's ataxia), other myopathies (including, but not limited
to, myotonia congenita, paramyotonia congenita, central core
disease, nemaline myopathy, myotubular myopathy, and periodic
paralysis), and metabolic diseases of muscle (including, but not
limited to, phosphorylase deficiency, acid maltase deficiency,
phosphofructokinase deficiency, debrancher enzyme deficiency,
mitochondrial myopathy, carnitine deficiency, carnitine palmatyl
transferase deficiency, phosphoglycerate kinase deficiency,
phosphoglycerate mutase deficiency, lactate dehydrogenase
deficiency, and myoadenylate deaminase deficiency).
[0243] The compounds of Formula I with kinase activity IC.sub.50
less than 10 M as determined in a standard assay described herein
can be used to treat protein kinase mediated diseases and
conditions related to the following protein kinases, including any
mutations thereof, for example without limitation: [0244] Abl,
related to chronic myeloid leukemia (CML), acute lymphoblastic
leukemia (ALL) and acute myelogenous leukemia (AML); [0245] Akt1,
related to gastric, prostate, colorectal, ovarian, pancreatic and
breast cancer, glioblastoma and leukemia, as well as schizophrenia
and bipolar disorders, and also use in combination with other
chemotherapeutic drugs; [0246] Akt2, related to hyperglycemia due
to peripheral insulin resistance and nonsuppressible hepatic
glucose production accompanied by inadequate compensatory
hyperinsulinemia, also related to pancreatic, ovarian and breast
cancer; [0247] Akt3, related to melanoma, prostate and breast
cancer; [0248] ALK, related to non-Hodgkin lymphomas such as
diffuse large B-cell lymphoma and anaplastic large cell lymphoma;
[0249] Alk5, related to pancreatic and biliary cancers, and
cutaneous T-cell lymphoma; [0250] A-Raf, related to neurologic
diseases such as multi-infarct dementia, head injury, spinal cord
injury, Alzheimer's disease (AD), Parkinson's disease; neoplastic
diseases including, but not limited to, melanoma, glioma, sarcoma,
carcinoma (e.g. colorectal, lung, breast, pancreatic, thyroid,
renal, ovarian), lymphoma (e.g. histiocytic lymphoma),
neurofibromatosis, myelodysplastic syndrome, leukemia, tumor
angiogenesis; pain of neuropathic or inflammatory origin, including
acute pain, chronic pain, cancer-related pain and migraine; and
diseases associated with muscle regeneration or degeneration,
including, but not limited to, vascular restenosis, sarcopenia,
muscular dystrophies (including, but not limited to, Duchenne,
Becker, Emery-Dreifuss, Limb-Girdle, Facioscapulohumeral, Myotonic,
Oculopharyngeal, Distal and Congenital Muscular Dystrophies), motor
neuron diseases (including, but not limited to, amyotrophic lateral
sclerosis, infantile progressive spinal muscular atrophy,
intermediate spinal muscular atrophy, juvenile spinal muscular
atrophy, spinal bulbar muscular atrophy, and adult spinal muscular
atrophy), inflammatory myopathies (including, but not limited to,
dermatomyositis, polymyositis, and inclusion body myositis),
diseases of the neuromuscular junction (including, but not limited
to, myasthenia gravis, Lambert-Eaton syndrome, and congenital
myasthenic syndrome), myopathies due to endocrine abnormalities
(including, but not limited to, hyperthyroid myopathy and
hypothyroid myopathy) diseases of peripheral nerve (including, but
not limited to, Charcot-Marie-Tooth disease, Dejerine-Sottas
disease, and Friedreich's ataxia), other myopathies (including, but
not limited to, myotonia congenita, paramyotonia congenita, central
core disease, nemaline myopathy, myotubular myopathy, and periodic
paralysis), and metabolic diseases of muscle (including, but not
limited to, phosphorylase deficiency, acid maltase deficiency,
phosphofructokinase deficiency, debrancher enzyme deficiency,
mitochondrial myopathy, carnitine deficiency, carnitine palmatyl
transferase deficiency, phosphoglycerate kinase deficiency,
phosphoglycerate mutase deficiency, lactate dehydrogenase
deficiency, and myoadenylate deaminase deficiency); [0251] B-Raf or
c-Raf-1, related to neurologic diseases, including, but not limited
to, as multi-infarct dementia, head injury, spinal cord injury,
Alzheimer's disease (AD), Parkinson's disease; neoplastic diseases
including, but not limited to, melanoma, glioma, sarcoma, carcinoma
(e.g. colorectal, lung, breast, pancreatic, thyroid, renal,
ovarian), lymphoma (e.g. histiocytic lymphoma) neurofibromatosis,
acute myeloid leukemia, myelodysplastic syndrome, leukemia, tumor
angiogenesis, neuroendocrine tumors such as medullary thyroid
cancer, carcinoid, small cell lung cancer and pheochromocytoma;
pain of neuropathic or inflammatory origin, including, but not
limited to, acute pain, chronic pain, cancer-related pain, and
migraine; cardiovascular diseases including, but not limited to,
heart failure, ischemic stroke, cardiac hypertrophy, thrombosis
(e.g. thrombotic microangiopathy syndromes), atherosclerosis,
reperfusion injury; inflammation including, but not limited to,
psoriasis, arthritis and autoimmune diseases and conditions,
osteoarthritis, endometriosis, scarring, vascular restenosis,
fibrotic disorders, rheumatoid arthritis, inflammatory bowel
disease; immunodeficiency diseases, including, but not limited to,
organ transplant rejection, graft versus host disease; renal or
prostatic diseases, including, but not limited to, diabetic
nephropathy, polycystic kidney disease, nephrosclerosis,
glomerulonephritis, prostate hyperplasia; metabolic disorders,
including, but not limited to, obesity; infection, including, but
not limited to, Helicobacter pylori, Hepatitis and Influenza
viruses, fever, and sepsis; pulmonary diseases including, but not
limited to, chronic obstructive pulmonary disease (COPD) and acute
respiratory distress syndrome (ARDS); genetic developmental
diseases, including, but not limited to, Noonan's syndrome,
Costello syndrome, (faciocutaneoskeletal syndrome), LEOPARD
syndrome, cardio-faciocutaneous syndrome (CFC), and neural crest
syndrome abnormalities causing cardiovascular, skeletal,
intestinal, skin, hair and endocrine diseases; [0252] Brk, related
to breast and colon cancer, and head and neck squamous cell
carcinoma; [0253] Btk, related to X-linked agammaglobulinemia,
acute lymphocytic leukemia, autoimmune diseases such as multiple
sclerosis, systemic lupus erythematosis, rheumatoid arthritis, and
Graves' disease, immune suppression in organ transplant, and drug
sensitivity of B-lineage cells; [0254] Cdk2, related to prostate,
breast, colorectal and ovarian cancer; [0255] Cdk4, related to
glioblastoma (e.g. glioblastoma multiforme), anaplastic
astrocytoma, and breast cancer; [0256] Cdk5, related to Alzheimer's
disease, amyotrophic lateral sclerosis and Lewy body disease;
[0257] Cdk6, related to glioblastoma multiforme, non-Hodgkin's
lymphoma, splenic marginal zone lymphoma, T-cell lymphoblastic
lymphoma (T-LBL) and T-cell acute lymphoblastic leukemia (T-ALL);
[0258] CHK1, related to DNA damage repair, sensitizes cells to
chemotherapeutic agents; [0259] Csk, related to colon and
pancreatic carcinomas and autoimmune pathology such as type 1
diabetes, rheumatoid arthritis and systemic lupus erythematosus;
[0260] EGFR, related to breast, colorectal, bladder, prostate and
non small cell lung cancer, squamous cell carcinomas of the head
and neck cancer, oral cavity, and esophagus, and glioblastoma
multiforme; [0261] EphA1, related to head and neck squamous cell
carcinoma, hepatoma and lung cancer; [0262] EphA2, related to
aberrant short-range contact-mediated axonal guidance, bladder,
breast, prostate, colon, skin, cervical, ovarian, pancreatic and
lung cancers, and metastatic melanoma; [0263] EphB2, related to
angiogenesis disorder (e.g. ocular angiogenesis disease such as
retinopathy), and cancer (e.g. glioblastoma, breast and liver
cancer); [0264] EphB4, related to colorectal cancer (CRC), head and
neck squamous cell carcinoma, and tumours of the prostate, breast,
endometrium, and bladder; [0265] Erk2, related to aberrant
proliferation, differentiation, transcription regulation and
development, and may be useful in treating inflammation, for
example inflammation associated with Lyme neuroborreliosis, and in
treating cancers, such as gastric cancer; [0266] Fak, related to
colon and breast tumors, and is also related to esophageal squamous
cell carcinoma, melanoma, anaplastic astrocytoma, glioblastoma,
ductal carcinoma in situ, prostate and hepatocellular carcinoma,
and tumor metastases, and may also provide synergistic effects when
used with other chemotherapeutic drugs; [0267] FGFR1, related to
8p11 myeloproliferative syndrome; [0268] FGFR2, related to Crouzon
Syndrome, Jackson-Weiss Syndrome, Apert Syndrome, craniosynostosis,
Pfeiffer Syndrome, acrocephalo syndactyly type V, and
Beare-Stevenson Cutis Gyrata Syndrome; [0269] FGFR3, related to
angiogenesis, wound healing, achondroplasia, Muenke
craniosynostosis, Crouzon syndrome, acanthosis nigricans,
thanatophoric dysplasia, bladder carcinomas, and multiple myeloma;
[0270] FGFR4, related to cancer of the breast, lung, colon,
medullary thyroid, pancreas, ovary, prostate, endometrium, and
fallopian tube, head and neck squamous cell carcinomas and
leiomyosarcoma; [0271] Flt1, related to non-small cell lung
carcinoma, prostate carcinoma, and colorectal cancer; [0272] Flt3,
related to acute myeloid leukemia, myelodysplastic syndrome, acute
lymphoblastic leukemia; [0273] Flt4, related to primary
lymphoedema; [0274] Fms, related to immune disorders, including
rheumatoid arthritis, systemic lupus erythematosis (SLE), and
transplant rejection, inflammatory diseases including inflammatory
bowel disease (e.g. ulcerative colitis, Crohn's disease), chronic
obstructive pulmonary disease (COPD), emphysema, and
atherosclerosis, metabolic disorders, including Type I diabetes,
Type II diabetes, insulin resistance, hyperglycemia, and lipolysis,
disorders of bone structure, mineralization and bone formation and
resorption, including osteoporosis, increased risk of fracture,
Paget's disease, hypercalcemia, and metastasis of cancer to bone,
kidney diseases, including nephritis (e.g. glomerulonephritis,
interstitial nephritis, Lupus nephritis), tubular necrosis,
diabetes-associated renal complications (e.g. diabetic
nephropathy), and hypertrophy, disorders of the central nervous
system, including multiple sclerosis, stroke, Alzheimer's disease
and Parkinson's disease; inflammatory and chronic pain, including
bone pain; and cancers, including multiple myeloma, acute myeloid
leukemia, chronic myeloid leukemia (CML), prostate cancer, breast
cancer, ovarian cancer, and metastasis of tumors to other tissues;
[0275] Frk, related to acute myeloid leukemia and type 1 diabetes;
[0276] Fyn, related to Alzheimer's disease, schizophrenia and
prevention of metastases, e.g. in melanoma and squamous cell
carcinoma; [0277] GSK3 (Gsk3.alpha. and/or Gsk3.beta.), related to
CNS disorders such as Alzheimer's disease, Parkinson's disease,
amyotrophic lateral sclerosis, diabetes type II, bipolar disorders,
stroke, cancer, chronic inflammatory disease, leucopenia,
schizophrenia, chronic pain, neuropathic pain, and traumatic head
injury; [0278] HCK, related to chronic myelogenous leukemia and
acute lymphocytic leukemia; [0279] Her2/Erbb2, related to prostate
and breast cancer; [0280] Her4/Erbb4, related to childhood
medulloblastoma; [0281] IGF1R, related to prostate cancer,
hepatocellular carcinoma; [0282] IKK beta, related to leukemia of
T-cells, necrosis, insulin resistance, and malignant neoplasms;
[0283] Irak4, related to bacterial infections, immunodeficiency
syndrome, inflammatory bowel disease (e.g. ulcerative colitis,
Crohn's disease), asthma, chronic bronchitis, cardio hypertrophy,
and kidney hypertension; [0284] Itk, related to allergic asthma;
[0285] Jak1, related to Hepatitis C virus infection; [0286] Jak2,
related to myeloproliferative disorders such as polycythaemia vera,
myelofibrosis, essential thrombocythemia, myeloid metaplasia and
leukemias, including acute lymphoblastic leukemia, chronic
neutrophilic leukemia, juvenile myelomonocytic leukemia, CMML,
Philadelphia chromosome-negative CML, megakaryocytic leukemia, and
acute erythroid leukemia; [0287] Jak3, related to X-linked severe
combined immunodeficiency, myeloproliferative disorders, transplant
rejection and autoimmune diseases such as rheumatoid arthritis,
inflammatory bowel disease (e.g. ulcerative colitis, Crohn's
disease), systemic lupus erythematosis, psoriasis and multiple
sclerosis; [0288] Jnk (Jnk1, Jnk2, Jnk3), related to metabolic
diseases including type 1 diabetes, type 2 diabetes, metabolic
syndrome, obesity, and hepatic steatosis; cardiovascular diseases
such as atherosclerosis, ischemia (e.g. cerebrovascular ischemia,
liver ischemia), reperfusion injury, cardiac hypertrophy; renal
diseases such as chronic renal failure; neoplastic diseases and
associated complications, including chemotherapy-induced hypoxia,
prostate tumors, myeloid leukemia and cancers of the liver, bone,
skin, brain, pancreas, lung breast, colon, prostate and ovary;
transplant rejection; pain of neuropathic or inflammatory origin
including acute and chronic pain; inflammatory and autoimmune
diseases including age-related macular degeneration, rheumatoid
arthritis, inflammatory bowel disease (e.g. ulcerative colitis,
Crohn's disease), systemic lupus erythematosis, Sjogren's Syndrome,
psoriasis, scleroderma, chronic thyroiditis, Grave's disease,
myasthenia gravis, and multiple sclerosis, and inflammation in
other organs including CNS inflammation, pancreatitis, nephritis,
atopic dermatitis, and hepatitis; airway inflammatory diseases such
as asthma, allergy, bronchitis, pulmonary fibrosis, chronic
obstructive pulmonary disease; neurologic diseases such as stroke,
cerebrovascular ischemia, neurodegenerative diseases such as
Parkinson's disease, Alzheimer's disease, amyotrophic lateral
sclerosis, dementia, senile chorea, head and spinal cord trauma,
and Huntington's disease. More particularly, Jnk1 is related to
type 1 diabetes, type 2 diabetes, metabolic syndrome, obesity and
hepatic steatosis, Jnk2 is related to atherosclerosis, and Jnk3 is
related to inflammatory diseases including autoimmune diseases such
as rheumatoid arthritis, inflammatory bowel disease (e.g.
ulcerative colitis, Crohn's disease), systemic lupus erythematosis,
Sjogren's Syndrome, psoriasis and multiple sclerosis, airway
inflammatory diseases such as asthma, allergy, pulmonary fibrosis,
and chronic obstructive pulmonary disease, and inflammation in
other organs, such as CNS inflammation, pancreatitis, nephritis,
and hepatitis; neurologic diseases such as stroke, cerebrovascular
ischemia, and neurodegenerative diseases such as Parkinson's
disease, Alzheimer's disease, and Huntington's disease; and
neoplastic diseases such as prostate tumors and myeloid leukemia;
[0289] Kdr, related to anti-angiogenesis for treating solid tumor
growth (e.g. ovarian, lung, breast, prancreatic, prostate, colon,
gastrointestinal stromal tumor, non small cell lung cancer, and
epidermoid cancer), metastasis, psoriasis, rheumatoid arthritis,
diabetic retinopathy and age related macular degeneration; [0290]
Kit, related to malignancies, including mast cell tumors, small
cell lung cancer, testicular cancer, gastrointestinal stromal
tumors (GISTs), glioblastoma, astrocytoma, neuroblastoma,
carcinomas of the female genital tract, sarcomas of neuroectodermal
origin, colorectal carcinoma, carcinoma in situ, Schwann cell
neoplasia associated with neurofibromatosis, acute myelocytic
leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia,
mastocytosis, melanoma, and canine mast cell tumors, and
inflammatory diseases, including asthma, rheumatoid arthritis,
allergic rhinitis, multiple sclerosis, inflammatory bowel disease
(e.g. ulcerative colitis, Crohn's disease), transplant rejection,
and hypereosinophilia;
[0291] Lck, related to acute lymphoblastic leukemia, T-cell
lymphoma, lymphopenia, renal carcinoma, colon carcinoma, severe
combined immunodeficiency, multiple sclerosis, inflammatory bowel
disease (e.g. ulcerative colitis, Crohn's disease) and type I
diabetes; [0292] Lyn, related to cancers such as glioblastoma.
[0293] MAP2K1, related to acute myeloid leukemia, breast, ovarian
and liver cancer; [0294] MAP2K2, related to cancer and
inflammation; [0295] MAP4K4, related to metabolic indications,
including re-sensitizing fat and muscle cells to insulin,
ameliorating the pathology in adipocytes, ameliorating the
pathology in muscle cells, metabolic syndrome, and type II
diabetes; a broad range of oncology indications, including blocking
the migration, invasion and metastasis in many different tumor
types; and T-cell mediated autoimmune diseases; [0296] MAPKAPK2,
cancer (e.g. prostate, breast), stroke, menengitis, and
inflammatory disorders; [0297] Met, related to kidney, breast,
bladder, non-small-cell lung, colorectal, and bladder cancers, and
hepatocellular carcinoma; [0298] Mnk1, related to conditions
associated with heat shock, nutrient deprivation, oxidative or
osmotic stress, and infection of mammalian cells (e.g. with viruses
such as adenovirus (Ad) or influenza virus), and autoimmune
diseases; [0299] MLK1, related to neurodegenerative diseases such
as Alzheimer's disease and Parkinson's disease, and inflammatory
disorders; [0300] p38, related to acute coronary syndrome, stroke,
atherosclerosis, and inflammatory autoimmune diseases such as
rheumatoid arthritis, and inflammatory bowel disease (e.g.
ulcerative colitis, Crohn's disease); [0301] PDGFR (PDGFRA,
PDGFRB), related to idiopathic hypereosinophilic syndrome, chronic
eosinophilic leukemia, glioma, gastrointestinal stromal tumors
(GISTs), juvenile myelomonocytic leukemia, metastatic
medulloblastoma, atherogenesis, and restenosis. More particularly,
PDGFRA related to idiopathic hypereosinophilic syndrome, chronic
eosinophilic leukemia, glioma, gastrointestinal stromal tumors
(GISTs), juvenile myelomonocytic leukemia, metastatic
medulloblastoma, atherogenesis, and restenosis, and PDGFRB related
to idiopathic hypereosinophilic syndrome, chronic eosinophilic
leukemia, juvenile myelomonocytic leukemia, and metastatic
medulloblastoma; [0302] PDPK1, related to cancer and diabetes;
[0303] Pim1, related to cancers such as hematopoietic (e.g. acute
myeloid and acute lymphoid leukemias) and prostate cancers, and
non-Hodgkin's lymphomas; [0304] Pim2, related to lymphomas; [0305]
Pim3, related to hepatocellular carcinoma; [0306] PKC alpha,
related to pituitary tumors and prefrontal cortical dysfunction
such as distractibility, impaired judgment, impulsivity, and
thought disorder, also may be used to sensitize chemotherapy in
breast, colon, and non small cell lung cancers; [0307] PKC beta,
related to diabetic retinopathy; [0308] PKC-theta, related to
insulin resistance, T-cell lymphoma; [0309] Plk1, related to
cancers (e.g. lymphoma of the thyroid, non-Hodgkin's lymphomas,
colorectal cancers, leukemias and melanoma), also useful as
sensitizer in chemotherapy; [0310] Pyk2, related to inflammation
(e.g. osteoporosis, polycystic kidney disease, rheumatoid arthritis
and inflammatory bowel disease), CNS disease (e.g. Parkinson's
disease and Alzheimer's disease), stroke and cancers (e.g. gliomas,
breast cancer, and pancreatic cancer); [0311] Ret, related to
cancer of the thyroid, neuroblastoma, familial medullary thyroid
carcinoma (FMTC), multiple endocrine neoplasia type IIA and IIB
(MEN2A, MEN2B), and neurodegenerative disorders (e.g.
Hirschsprung's disease, Parkinson's disease, Alzheimer's disease,
and amyotrophic lateral sclerosis); [0312] ROCK (ROCK-1, ROCK-2),
related to cancers (e.g. ovarian cancer, hepatocellular carcinoma,
pancreatic cancer), ocular disease (e.g. glaucoma), cardiac
hypertrophy, improved renal perfusion, transplant rejection, and
acute respiratory distress syndrome; [0313] Ron, related to cancer
and inflammation; [0314] Src, related to cancer and osteoporosis;
[0315] Stk6, related to gastric, bladder, breast, lung, CNS,
ovarian, kidney, colon, prostate, pancreas, and cervical cancers,
melanoma, leukemia, and neuroblastoma; [0316] Syk, related to
lymphomas (e.g. mantle cell lymphoma); [0317] TEC, related to
sepsis, septic shock, inflammation, rheumatoid arthritis, Crohn's
disease, irritable bowel disease (IBD) and ulcerative colitis;
[0318] Tie2 (TEK), related to cancer, arthritis (e.g. rheumatoid
arthritis), and atherosclerosis; [0319] TrkA, related to pain (e.g.
chronic pain, neuropathic pain), cancer (e.g. prostate cancer, lung
cancer, pancreatic cancer), allergic disorders (e.g. asthma),
arthritis, diabetic retinopathy, macular degeneration and
psoriasis; [0320] TrkB, related to obesity, hyperphagia,
developmental delays, cancer (e.g. prostate cancer, lung cancer,
Wilms tumors, neuroblastoma, pancreatic cancer), various
neuropathies (e.g. stroke, multiple sclerosis, transverse myelitis,
and encephalitis), and diabetes. [0321] Yes, related to various
cancers including esophageal squamous cell carcinoma; and [0322]
Zap70, related to AIDS, systemic lupus erythematosus, myasthenia
gravis, atherosclerosis, rejection of transplanted organs or
tissues, allograft rejection including acute and chronic allograft
rejection, graft versus host disease, rheumathoid arthritis,
psoriasis, systemic sclerosis, atopic dermatitis, eczematous
dermatitis, alopecia, and inflammation of the nasal mucus membrane,
including all forms of rhinitis.
[0323] Additional aspects and embodiments will be apparent from the
following Detailed Description of the Invention and from the
claims.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0324] As used herein the following definitions apply unless
clearly indicated otherwise: [0325] "Halogen" refer to all
halogens, that is, chloro (Cl), fluoro (F), bromo (Br), or iodo
(I). [0326] "Hydroxyl" or "hydroxy" refer to the group --OH. [0327]
"Thiol" refers to the group --SH.
[0328] "Lower alkyl" alone or in combination means an
alkane-derived radical containing from 1 to 6 carbon atoms (unless
specifically defined) that includes a straight chain alkyl or
branched alkyl. The straight chain or branched alkyl group is
chemically feasible and attached at any available point to produce
a stable compound. In many embodiments, a lower alkyl is a straight
or branched alkyl group containing from 1-6, 1-4, or 1-2, carbon
atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl,
and the like. An "optionally substituted lower alkyl" denotes lower
alkyl that is optionally independently substituted, unless
indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5,
also 1, 2, or 3 substituents, attached at any available atom to
produce a stable compound, wherein the substituents are selected
from the group consisting of --F, --OH, --NH.sub.2, --NO.sub.2,
--CN, --C(O)--OH, --C(S)--OH, --C(O)--NH.sub.2, --C(S)--NH.sub.2,
--S(O).sub.2--NH.sub.2, --N(H)--C(O)--NH.sub.2,
--N(H)--C(S)--NH.sub.2, --N(H)--S(O).sub.2--NH.sub.2,
--C(NH)--NH.sub.2, --O--R.sup.o, --S--R.sup.o, --O--C(O)--R.sup.o,
--O--C(S)--R.sup.o, --C(O)--R.sup.o, --C(S)--R.sup.o,
--C(O)--O--R.sup.o, --C(S)--O--R.sup.o, --S(O)--R.sup.o,
--S(O).sub.2--R.sup.o, --C(O)--N(H)--R.sup.o,
--C(S)--N(H)--R.sup.o, --C(O)--N(R.sup.o)--R.sup.o,
--C(S)--N(R.sup.o)--R.sup.o, --S(O).sub.2--N(H)--R.sup.o,
--S(O).sub.2--N(R.sup.o)--R.sup.o, --C(NH)--N(H)--R.sup.o,
--C(NH)--N(R.sup.p)--R.sup.c, --N(H)--C(O)--R.sup.o,
--N(H)--C(S)--R.sup.o, --N(R.sup.o)--C(O)--R.sup.o,
--N(R.sup.o)--C(S)--R.sup.o, --N(H)--S(O).sub.2--R.sup.o,
--N(R.sup.o)--S(O).sub.2--R.sup.o, --N(H)--C(O)--N(H)--R.sup.o,
--N(H)--C(S)--N(H)--R.sup.o, --N(R.sup.o)--C(O)--NH.sub.2,
--N(R.sup.o)--C(S)--NH.sub.2, --N(R.sup.o)--C(O)--N(H)--R.sup.o,
--N(R.sup.o)--C(S)--N(H)--R.sup.o,
--N(H)--C(O)--N(R.sup.o)--R.sup.o,
--N(H)--C(S)--N(R.sup.o)--R.sup.o,
--N(R.sup.o)--C(O)--N(R.sup.o)--R.sup.o,
--N(R.sup.o)--C(S)--N(R.sup.o)--R.sup.o,
--N(H)--S(O).sub.2--N(H)--R.sup.o,
--N(R.sup.o)--S(O).sub.2--NH.sub.2,
--N(R.sup.o)--S(O).sub.2--N(H)--R.sup.o,
--N(H)--S(O).sub.2--N(R.sup.o)--R.sup.o,
--N(R.sup.o)--S(O).sub.2--N(R.sup.o)--R.sup.o, --N(H)--R.sup.o,
--N(R.sup.o)--R.sup.o, --R.sup.e, --R.sup.f, and --R.sup.g.
Furthermore, possible substitutions include subsets of these
substitutions, such as are indicated herein, for example, in the
description of compounds of Formula I, attached at any available
atom to produce a stable compound. For example "fluoro substituted
lower alkyl" denotes a lower alkyl group substituted with one or
more fluoro atoms, such as perfluoroalkyl, where preferably the
lower alkyl is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also
1, 2, or 3 fluoro atoms. It is understood that substitutions are
chemically feasible and attached at any available atom to provide a
stable compound.
[0329] "Lower alkenyl" alone or in combination means a straight or
branched hydrocarbon containing 2-6 carbon atoms (unless
specifically defined) and at least one, preferably 1-3, more
preferably 1-2, most preferably one, carbon to carbon double bond.
Carbon to carbon double bonds may be either contained within a
straight chain or branched portion. The straight chain or branched
lower alkenyl group is chemically feasible and attached at any
available point to provide a stable compound. Examples of lower
alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, and
the like. An "optionally substituted lower alkenyl" denotes lower
alkenyl that is optionally independently substituted, unless
indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5,
also 1, 2, or 3 substituents, attached at any available atom to
produce a stable compound, wherein the substituents are selected
from the group consisting of --F, --OH, --NH.sub.2, --NO.sub.2,
--CN, --C(O)--OH, --C(S)--OH, --C(O)--NH.sub.2, --C(S)--NH.sub.2,
--S(O).sub.2--NH.sub.2, --N(H)--C(O)--NH.sub.2,
--N(H)--C(S)--NH.sub.2, --N(H)--S(O).sub.2--NH.sub.2,
--C(NH)--NH.sub.2, --O--R.sup.o, --S--R.sup.o, --O--C(O)--R.sup.o,
--O--C(S)--R.sup.o, --C(O)--R.sup.o, --C(S)--R.sup.o,
--C(O)--O--R.sup.o, --C(S)--O--R.sup.o, --S(O)--R.sup.o,
--S(O).sub.2--R.sup.o, --C(O)--N(H)--R.sup.o,
--C(S)--N(H)--R.sup.o, --C(O)--N(R.sup.o)--R.sup.o,
--C(S)--N(R.sup.o)--R.sup.o, --S(O).sub.2--N(H)--R.sup.o,
--S(O).sub.2--N(R.sup.o)--R.sup.o, --C(NH)--N(H)--R.sup.o,
--C(NH)--N(R.sup.p)--R.sup.c, --N(H)--C(O)--R.sup.o,
--N(H)--C(S)--R.sup.o, --N(R.sup.o)--C(O)--R.sup.o,
--N(R.sup.o)--C(S)--R.sup.o, --N(H)--S(O).sub.2--R.sup.o,
--N(R.sup.o)--S(O).sub.2--R.sup.o, --N(H)--C(O)--N(H)--R.sup.o,
--N(H)--C(S)--N(H)--R.sup.o, --N(R.sup.o)--C(O)--NH.sub.2,
--N(R.sup.o)--C(S)--NH.sub.2, --N(R.sup.o)--C(O)--N(H)--R.sup.o,
--N(R.sup.o)--C(S)--N(H)--R.sup.o,
--N(H)--C(O)--N(R.sup.o)--R.sup.o,
--N(H)--C(S)--N(R.sup.o)--R.sup.o,
--N(R.sup.o)--C(O)--N(R.sup.o)--R.sup.o,
--N(R.sup.o)--C(S)--N(R.sup.o)--R.sup.o,
--N(H)--S(O).sub.2--N(H)--R.sup.o,
--N(R.sup.o)--S(O).sub.2--NH.sub.2,
--N(R.sup.o)--S(O).sub.2--N(H)--R.sup.o,
--N(H)--S(O).sub.2--N(R.sup.o)--R.sup.o,
--N(R.sup.o)--S(O).sub.2--N(R.sup.o)--R.sup.o, --N(H)--R.sup.o,
--N(R.sup.o)--R.sup.o, --R.sup.d, --R.sup.f, and --R.sup.g.
Further, possible substitutions include subsets of these
substitutions, such as are indicated herein, for example, in the
description of compounds of Formula I, attached at any available
atom to produce a stable compound. For example "fluoro substituted
lower alkenyl" denotes a lower alkenyl group substituted with one
or more fluoro atoms, where preferably the lower alkenyl is
substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3
fluoro atoms. "C.sub.3-6 alkenyl" denotes lower alkenyl containing
3-6 carbon atoms. An "optionally substituted C.sub.3-6 alkenyl"
denotes optionally substituted lower alkenyl containing 3-6 carbon
atoms. It is understood that substitutions are chemically feasible
and attached at any available atom to provide a stable
compound.
[0330] "Lower alkynyl" alone or in combination means a straight or
branched hydrocarbon containing 2-6 carbon atoms (unless
specifically defined) containing at least one, preferably one,
carbon to carbon triple bond. The straight chain or branched lower
alkynyl group is chemically feasible and attached at any available
point to provide a stable compound. Examples of alkynyl groups
include ethynyl, propynyl, butynyl, and the like. An "optionally
substituted lower alkynyl" denotes lower alkynyl that is optionally
independently substituted, unless indicated otherwise, with one or
more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents,
attached at any available atom to produce a stable compound,
wherein the substituents are selected from the group consisting of
--F, --OH, --NH.sub.2, --NO.sub.2, --CN, --C(O)--OH, --C(S)--OH,
--C(O)--NH.sub.2, --C(S)--NH.sub.2, --S(O).sub.2--NH.sub.2,
--N(H)--C(O)--NH.sub.2, --N(H)--C(S)--NH.sub.2,
--N(H)--S(O).sub.2--NH.sub.2, --C(NH)--NH.sub.2, --O--R.sup.o,
--S--R.sup.o, --O--C(O)--R.sup.o, --O--C(S)--R.sup.o,
--C(O)--R.sup.o, --C(S)--R.sup.o, --C(O)--O--R.sup.o,
--C(S)--O--R.sup.o, --S(O)--R.sup.o, --S(O).sub.2--R.sup.o,
--C(O)--N(H)--R.sup.o, --C(S)--N(H)--R.sup.o,
--C(O)--N(R.sup.o)--R.sup.o, --C(S)--N(R.sup.o)--R.sup.o,
--S(O).sub.2--N(H)--R.sup.o, --S(O).sub.2--N(R.sup.o)--R.sup.o,
--C(NH)--N(H)--R.sup.o, --C(NH)--N(R.sup.p)--R.sup.c,
--N(H)--C(O)--R.sup.o, --N(H)--C(S)--R.sup.o,
--N(R.sup.o)--C(O)--R.sup.o, --N(R.sup.o)--C(S)--R.sup.o,
--N(H)--S(O).sub.2--R.sup.o, --N(R.sup.o)--S(O).sub.2--R.sup.o,
--N(H)--C(O)--N(H)--R.sup.o, --N(H)--C(S)--N(H)--R.sup.o,
--N(R.sup.o)--C(O)--NH.sub.2, --N(R.sup.o)--C(S)--NH.sub.2,
--N(R.sup.o)--C(O)--N(H)--R.sup.o,
--N(R.sup.o)--C(S)--N(H)--R.sup.o,
--N(H)--C(O)--N(R.sup.o)--R.sup.o,
--N(H)--C(S)--N(R.sup.o)--R.sup.o,
--N(R.sup.o)--C(O)--N(R.sup.o)--R.sup.o,
--N(R.sup.o)--C(S)--N(R.sup.o)--R.sup.o,
--N(H)--S(O).sub.2--N(H)--R.sup.o,
--N(R.sup.o)--S(O).sub.2--NH.sub.2,
--N(R.sup.o)--S(O).sub.2--N(H)--R.sup.o,
--N(H)--S(O).sub.2--N(R.sup.o)--R.sup.o,
--N(R.sup.o)--S(O).sub.2--N(R.sup.o)--R.sup.o, --N(H)--R.sup.o,
--N(R.sup.o)--R.sup.o, --R.sup.d, --R.sup.e, and --R.sup.g.
Further, possible substitutions include subsets of these
substitutions, such as are indicated herein, for example, in the
description of compounds of Formula I, attached at any available
atom to produce a stable compound. For example "fluoro substituted
lower alkynyl" denotes a lower alkynyl group substituted with one
or more fluoro atoms, where preferably the lower alkynyl is
substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3
fluoro atoms. "C.sub.3-6 alkynyl" denotes lower alkynyl containing
3-6 carbon atoms. An "optionally substituted C.sub.3-6 alkynyl"
denotes optionally substituted lower alkynyl containing 3-6 carbon
atoms. It is understood that substitutions are chemically feasible
and attached at any available atom to provide a stable
compound.
[0331] "Cycloalkyl" refers to saturated or unsaturated,
non-aromatic monocyclic, bicyclic or tricyclic carbon ring systems
of 3-10, also 3-8, more preferably 3-6, ring members per ring, such
as cyclopropyl, cyclopentyl, cyclohexyl, adamantyl, and the like.
An "optionally substituted cycloalkyl" is a cycloalkyl that is
optionally independently substituted, unless indicated otherwise,
with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3
substituents, attached at any available atom to produce a stable
compound, wherein the substituents are selected from the group
consisting of halogen, --OH, --NH.sub.2, --NO.sub.2, --CN,
--C(O)--OH, --C(S)--OH, --C(O)--NH.sub.2, --C(S)--NH.sub.2,
--S(O).sub.2--NH.sub.2, --N(H)--C(O)--NH.sub.2,
--N(H)--C(S)--NH.sub.2, --N(H)--S(O).sub.2--NH.sub.2,
--C(NH)--NH.sub.2, --O--R.sup.o, --S--R.sup.o, --O--C(O)--R.sup.o,
--O--C(S)--R.sup.o, --C(O)--R.sup.o, --C(S)--R.sup.o,
--C(O)--O--R.sup.o, --C(S)--O--R.sup.o, --S(O)--R.sup.o,
--S(O).sub.2--R.sup.o, --C(O)--N(H)--R.sup.o,
--C(S)--N(H)--R.sup.o, --C(O)--N(R.sup.o)--R.sup.o,
--C(S)--N(R.sup.o)--R.sup.o, --S(O).sub.2--N(H)--R.sup.o,
--S(O).sub.2--N(R.sup.o)--R.sup.o, --C(NH)--N(H)--R.sup.o,
--C(NH)--N(R.sup.p)--R.sup.c, --N(H)--C(O)--R.sup.o,
--N(H)--C(S)--R.sup.o, --N(R.sup.o)--C(O)--R.sup.o,
--N(R.sup.o)--C(S)--R.sup.o, --N(H)--S(O).sub.2--R.sup.o,
--N(R.sup.o)--S(O).sub.2--R.sup.o, --N(H)--C(O)--N(H)--R.sup.o,
--N(H)--C(S)--N(H)--R.sup.o, --N(R.sup.o)--C(O)--NH.sub.2,
--N(R.sup.o)--C(S)--NH.sub.2, --N(R.sup.o)--C(O)--N(H)--R.sup.o,
--N(R.sup.o)--C(S)--N(H)--R.sup.o,
--N(H)--C(O)--N(R.sup.o)--R.sup.o,
--N(H)--C(S)--N(R.sup.o)--R.sup.o,
--N(R.sup.o)--C(O)--N(R.sup.o)--R.sup.o,
--N(R.sup.o)--C(S)--N(R.sup.o)--R.sup.o,
--N(H)--S(O).sub.2--N(H)--R.sup.o,
--N(R.sup.o)--S(O).sub.2--NH.sub.2,
--N(R.sup.o)--S(O).sub.2--N(H)--R.sup.o,
--N(H)--S(O).sub.2--N(R.sup.o)--R.sup.o,
--N(R.sup.o)--S(O).sub.2--N(R.sup.o)--R.sup.o, --N(H)--R.sup.o,
--N(R.sup.o)--R.sup.o, --R.sup.d, --R.sup.e, --R.sup.f, and
--R.sup.g. "C.sub.3-6 cycloalkyl" denotes cycloalkyl containing 3-6
carbon atoms. "C.sub.3-5 cycloalkyl" denotes cycloalkyl containing
3-5 carbon atoms. It is understood that substitutions are
chemically feasible and attached at any available atom to provide a
stable compound.
[0332] "Heterocycloalkyl" refers to a saturated or unsaturated
non-aromatic cycloalkyl group having from 5 to 10 atoms in which
from 1 to 3 carbon atoms in the ring are replaced by heteroatoms of
O, S or N, and are optionally fused with benzo or heteroaryl of 5-6
ring members. Heterocycloalkyl is also intended to include oxidized
S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring
nitrogen. Heterocycloalkyl is also intended to include compounds in
which a ring carbon may be oxo substituted, i.e. the ring carbon is
a carbonyl group, such as lactones and lactams. The point of
attachment of the heterocycloalkyl ring is at a carbon or nitrogen
atom such that a stable ring is retained. Examples of
heterocycloalkyl groups include, but are not limited to,
morpholino, tetrahydrofuranyl, dihydropyridinyl, piperidinyl,
pyrrolidinyl, pyrrolidonyl, piperazinyl, dihydrobenzofuryl, and
dihydroindolyl. "Nitrogen containing heterocycloalkyl" refers to
heterocycloalkyl wherein at least one heteroatom is N. An
"optionally substituted heterocycloalkyl" is a heterocycloalkyl
that is optionally independently substituted, unless indicated
otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2,
or 3 substituents, attached at any available atom to produce a
stable compound, wherein the substituents are selected from the
group consisting of halogen, --OH, --NH.sub.2, --NO.sub.2, --CN,
--C(O)--OH, --C(S)--OH, --C(O)--NH.sub.2, --C(S)--NH.sub.2,
--S(O).sub.2--NH.sub.2, --N(H)--C(O)--NH.sub.2,
--N(H)--C(S)--NH.sub.2, --N(H)--S(O).sub.2--NH.sub.2,
--C(NH)--NH.sub.2, --O--R.sup.o, --S--R.sup.o, --O--C(O)--R.sup.o,
--O--C(S)--R.sup.o, --C(O)--R.sup.o, --C(S)--R.sup.o,
--C(O)--O--R.sup.o, --C(S)--O--R.sup.o, --S(O)--R.sup.o,
--S(O).sub.2--R.sup.o, --C(O)--N(H)--R.sup.o,
--C(S)--N(H)--R.sup.o, --C(O)--N(R.sup.o)--R.sup.o,
--C(S)--N(R.sup.o)--R.sup.o, --S(O).sub.2--N(H)--R.sup.o,
--S(O).sub.2--N(R.sup.o)--R.sup.o, --C(NH)--N(H)--R.sup.o,
--C(NH)--N(R.sup.p)--R.sup.c, --N(H)--C(O)--R.sup.o,
--N(H)--C(S)--R.sup.o, --N(R.sup.o)--C(O)--R.sup.o,
--N(R.sup.o)--C(S)--R.sup.o, --N(H)--S(O).sub.2--R.sup.o,
--N(R.sup.o)--S(O).sub.2--R.sup.o, --N(H)--C(O)--N(H)--R.sup.o,
--N(H)--C(S)--N(H)--R.sup.o, --N(R.sup.o)--C(O)--NH.sub.2,
--N(R.sup.o)--C(S)--NH.sub.2, --N(R.sup.o)--C(O)--N(H)--R.sup.o,
--N(R.sup.o)--C(S)--N(H)--R.sup.o,
--N(H)--C(O)--N(R.sup.o)--R.sup.o,
--N(H)--C(S)--N(R.sup.o)--R.sup.o,
--N(R.sup.o)--C(O)--N(R.sup.o)--R.sup.o,
--N(R.sup.o)--C(S)--N(R.sup.o)--R.sup.o,
--N(H)--S(O).sub.2--N(H)--R.sup.o,
--N(R.sup.o)--S(O).sub.2--NH.sub.2,
--N(R.sup.o)--S(O).sub.2--N(H)--R.sup.o,
--N(H)--S(O).sub.2--N(R.sup.o)--R.sup.o,
--N(R.sup.o)--S(O).sub.2--N(R.sup.o)--R.sup.o, --N(H)--R.sup.o,
--N(R.sup.o)--R.sup.o, --R.sup.d, --R.sup.e, --R.sup.f, and
--R.sup.g. It is understood that substitutions are chemically
feasible and attached at any available atom to provide a stable
compound.
[0333] "Aryl" alone or in combination refers to a monocyclic or
bicyclic ring system containing aromatic hydrocarbons such as
phenyl or naphthyl, which may be optionally fused with a cycloalkyl
of preferably 5-7, more preferably 5-6, ring members. An
"optionally substituted aryl" is an aryl that is optionally
independently substituted, unless indicated otherwise, with one or
more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents,
attached at any available atom to produce a stable compound,
wherein the substituents are selected from the group consisting of
halogen, --OH, --NH.sub.2, --NO.sub.2, --CN, --C(O)--OH,
--C(S)--OH, --C(O)--NH.sub.2, --C(S)--NH.sub.2,
--S(O).sub.2--NH.sub.2, --N(H)--C(O)--NH.sub.2,
--N(H)--C(S)--NH.sub.2, --N(H)--S(O).sub.2--NH.sub.2,
--C(NH)--NH.sub.2, --O--R.sup.o, --S--R.sup.o, --O--C(O)--R.sup.o,
--O--C(S)--R.sup.o, --C(O)--R.sup.o, --C(S)--R.sup.o,
--C(O)--O--R.sup.o, --C(S)--O--R.sup.o, --S(O)--R.sup.o,
--S(O).sub.2--R.sup.o, --C(O)--N(H)--R.sup.o,
--C(S)--N(H)--R.sup.o, --C(O)--N(R.sup.o)--R.sup.o,
--C(S)--N(R.sup.o)--R.sup.o, --S(O).sub.2--N(H)--R.sup.o,
--S(O).sub.2--N(R.sup.o)--R.sup.o, --C(NH)--N(H)--R.sup.o,
--C(NH)--N(R.sup.p)--R.sup.c, --N(H)--C(O)--R.sup.o,
--N(H)--C(S)--R.sup.o, --N(R.sup.o)--C(O)--R.sup.o,
--N(R.sup.o)--C(S)--R.sup.o, --N(H)--S(O).sub.2--R.sup.o,
--N(R.sup.o)--S(O).sub.2--R.sup.o, --N(H)--C(O)--N(H)--R.sup.o,
--N(H)--C(S)--N(H)--R.sup.o, --N(R.sup.o)--C(O)--NH.sub.2,
--N(R.sup.o)--C(S)--NH.sub.2, --N(R.sup.o)--C(O)--N(H)--R.sup.o,
--N(R.sup.o)--C(S)--N(H)--R.sup.o,
--N(H)--C(O)--N(R.sup.o)--R.sup.o,
--N(H)--C(S)--N(R.sup.o)--R.sup.o,
--N(R.sup.o)--C(O)--N(R.sup.o)--R.sup.o,
--N(R.sup.o)--C(S)--N(R.sup.o)--R.sup.o,
--N(H)--S(O).sub.2--N(H)--R.sup.o,
--N(R.sup.o)--S(O).sub.2--NH.sub.2,
--N(R.sup.o)--S(O).sub.2--N(H)--R.sup.o,
--N(H)--S(O).sub.2--N(R.sup.o)--R.sup.o,
--N(R.sup.o)--S(O).sub.2--N(R.sup.o)--R.sup.o, --N(H)--R.sup.o,
--N(R.sup.o)--R.sup.o, --R.sup.d, --R.sup.e, --R.sup.f, and
--R.sup.g. It is understood that substitutions are chemically
feasible and attached at any available atom to provide a stable
compound.
[0334] "Heteroaryl" alone or in combination refers to a monocyclic
aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic
aromatic group having 8 to 10 atoms, containing one or more,
preferably 1-4, more preferably 1-3, even more preferably 1-2,
heteroatoms independently selected from the group consisting of O,
S, and N. Heteroaryl is also intended to include oxidized S or N,
such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen.
A carbon or nitrogen atom is the point of attachment of the
heteroaryl ring structure such that a stable compound is produced.
Examples of heteroaryl groups include, but are not limited to,
pyridinyl, pyridazinyl, pyrazinyl, quinaoxalyl, indolizinyl,
benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl,
pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, thienyl,
isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl,
triazolyl, furanyl, benzofuryl, and indolyl. "Nitrogen containing
heteroaryl" refers to heteroaryl wherein at least one heteroatom is
N. In some instances, for example when R groups of a nitrogen
combine with the nitrogen to form a 5 or 7 membered nitrogen
containing heteroaryl, any heteroatoms in such 5 or 7 membered
heteroaryl are N. An "optionally substituted heteroaryl" is a
heteroaryl that is optionally independently substituted, unless
indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5,
also 1, 2, or 3 substituents, attached at any available atom to
produce a stable compound, wherein the substituents are selected
from the group consisting of halogen, --OH, --NH.sub.2, --NO.sub.2,
--CN, --C(O)--OH, --C(S)--OH, --C(O)--NH.sub.2, --C(S)--NH.sub.2,
--S(O).sub.2--NH.sub.2, --N(H)--C(O)--NH.sub.2,
--N(H)--C(S)--NH.sub.2, --N(H)--S(O).sub.2--NH.sub.2,
--C(NH)--NH.sub.2, --O--R.sup.o, --S--R.sup.o, --O--C(O)--R.sup.o,
--O--C(S)--R.sup.o, --C(O)--R.sup.o, --C(S)--R.sup.o,
--C(O)--O--R.sup.o, --C(S)--O--R.sup.o, --S(O)--R.sup.o,
--S(O).sub.2--R.sup.o, --C(O)--N(H)--R.sup.o,
--C(S)--N(H)--R.sup.o, --C(O)--N(R.sup.o)--R.sup.o,
--C(S)--N(R.sup.o)--R.sup.o, --S(O).sub.2--N(H)--R.sup.o,
--S(O).sub.2--N(R.sup.o)--R.sup.o, --C(NH)--N(H)--R.sup.o,
--C(NH)--N(R.sup.p)--R.sup.c, --N(H)--C(O)--R.sup.o,
--N(H)--C(S)--R.sup.o, --N(R.sup.o)--C(O)--R.sup.o,
--N(R.sup.o)--C(S)--R.sup.o, --N(H)--S(O).sub.2--R.sup.o,
--N(R.sup.o)--S(O).sub.2--R.sup.o, --N(H)--C(O)--N(H)--R.sup.o,
--N(H)--C(S)--N(H)--R.sup.o, --N(R.sup.o)--C(O)--NH.sub.2,
--N(R.sup.o)--C(S)--NH.sub.2, --N(R.sup.o)--C(O)--N(H)--R.sup.o,
--N(R.sup.o)--C(S)--N(H)--R.sup.o,
--N(H)--C(O)--N(R.sup.o)--R.sup.o,
--N(H)--C(S)--N(R.sup.o)--R.sup.o,
--N(R.sup.o)--C(O)--N(R.sup.o)--R.sup.o,
--N(R.sup.o)--C(S)--N(R.sup.o)--R.sup.o,
--N(H)--S(O).sub.2--N(H)--R.sup.o,
--N(R.sup.o)--S(O).sub.2--NH.sub.2,
--N(R.sup.o)--S(O).sub.2--N(H)--R.sup.o,
--N(H)--S(O).sub.2--N(R.sup.o)--R.sup.o,
--N(R.sup.o)--S(O).sub.2--N(R.sup.o)--R.sup.o, --N(H)--R.sup.o,
--N(R.sup.o)--R.sup.o, --R.sup.d, --R.sup.e, --R.sup.f, and
--R.sup.g. It is understood that substitutions are chemically
feasible and attached at any available atom to provide a stable
compound.
[0335] The variables R.sup.o, R.sup.p, R.sup.c, R.sup.d, R.sup.e,
R.sup.f and R.sup.g as used in the description of optional
substituents for alkyl, alkenyl, alkynyl, cycloalkyl,
heterocycloalkyl, aryl and heteroaryl are defined as follows:
[0336] each R.sup.o, R.sup.P, and R.sup.c are independently
selected from the group consisting of R.sup.d, R.sup.e, R.sup.f,
and R.sup.g, or R.sup.P and R.sup.c combine with the nitrogen to
which they are attached to form a 5-7 membered heterocycloalkyl or
a 5 or 7 membered nitrogen containing heteroaryl, wherein the 5-7
membered heterocycloalkyl or 5 or 7 membered nitrogen containing
heteroaryl are optionally substituted with one or more, preferably
1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the
group consisting of halogen, --NO.sub.2, --CN, --OH, --NH.sub.2,
--O--R.sup.u, --S--R.sup.u, --N(H)--R.sup.u, --N(R.sup.u)--R.sup.u,
--R.sup.x, and --R.sup.y; [0337] each R.sup.d is independently
lower alkyl, wherein lower alkyl is optionally substituted with one
or more, preferably 1, 2, 3, 4 or 5, also 1, 2 or 3 substituents
selected from the group consisting of fluoro, --OH, --NH.sub.2,
--NO.sub.2, --CN, --C(O)--OH, --C(S)--OH, --C(O)--NH.sub.2,
--C(S)--NH.sub.2, --S(O).sub.2--NH.sub.2, --N(H)--C(O)--NH.sub.2,
--N(H)--C(S)--NH.sub.2, --N(H)--S(O).sub.2--NH.sub.2,
--C(NH)--NH.sub.2, --O--R.sup.k, --S--R.sup.k, --O--C(O)--R.sup.k,
--O--C(S)--R.sup.k, --C(O)--R.sup.k, --C(S)--R.sup.k,
--C(O)--O--R.sup.k, --C(S)--O--R.sup.k, --S(O)--R.sup.k,
--S(O).sub.2--R.sup.k, --C(O)--N(H)--R.sup.k,
--C(S)--N(H)--R.sup.k, --C(O)--N(R.sup.k)--R.sup.k,
--C(S)--N(R.sup.k)--R.sup.k, --S(O).sub.2--N(H)--R.sup.k,
--S(O).sub.2--N(R.sup.k)--R.sup.k, --C(NH)--N(H)--R.sup.k,
--C(NH)--N(R.sup.m)--R.sup.n, --N(H)--C(O)--R.sup.k,
--N(H)--C(S)--R.sup.k, --N(R.sup.k)--C(O)--R.sup.k,
--N(R.sup.k)--C(S)--R.sup.k, --N(H)--S(O).sub.2--R.sup.k,
--N(R.sup.k)--S(O).sub.2--R.sup.k, --N(H)--C(O)--N(H)--R.sup.k,
--N(H)--C(S)--N(H)--R.sup.k, --N(R.sup.k)--C(O)--NH.sub.2,
--N(R.sup.k)--C(S)--NH.sub.2, --N(R.sup.k)--C(O)--N(H)--R.sup.k,
--N(R.sup.k)--C(S)--N(H)--R.sup.k,
--N(H)--C(O)--N(R.sup.k)--R.sup.k,
--N(H)--C(S)--N(R.sup.k)--R.sup.k,
--N(R.sup.k)--(O)--N(R.sup.k)--R.sup.k,
--N(R.sup.k)--C(S)--N(R.sup.k)--R.sup.k,
--N(H)--S(O).sub.2--N(H)--R.sup.k,
--N(R.sup.k)--S(O).sub.2--NH.sub.2,
--N(R.sup.k)--S(O).sub.2--N(H)--R.sup.k,
--N(H)--S(O).sub.2--N(R.sup.k)--R.sup.k,
--N(R.sup.k)--S(O).sub.2--N(R.sup.k)--R.sup.k, --N(H)--R.sup.k,
--N(R.sup.k)--R.sup.k, --R.sup.i, and --R; [0338] each R.sup.e is
independently lower alkenyl, wherein lower alkenyl is optionally
substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2
or 3 substituents selected from the group consisting of fluoro,
--OH, --NH.sub.2, --NO.sub.2, --CN, --C(O)--OH, --C(S)--OH,
--C(O)--NH.sub.2, --C(S)--NH.sub.2, --S(O).sub.2--NH.sub.2,
--N(H)--C(O)--NH.sub.2, --N(H)--C(S)--NH.sub.2,
--N(H)--S(O).sub.2--NH.sub.2, --C(NH)--NH.sub.2, --O--R.sup.k,
--S--R.sup.k, --O--C(O)--R.sup.k, --O--C(S)--R.sup.k,
--C(O)--R.sup.k, --C(S)--R.sup.k, --C(O)--O--R.sup.k,
--C(S)--O--R.sup.k, --S(O)--R.sup.k, --S(O).sub.2--R.sup.k,
--C(O)--N(H)--R.sup.k, --C(S)--N(H)--R.sup.k,
--C(O)--N(R.sup.k)--R.sup.k, --C(S)--N(R.sup.k)--R.sup.k,
--S(O).sub.2--N(H)--R.sup.k, --S(O).sub.2--N(R.sup.k)--R.sup.k,
--C(NH)--N(H)--R.sup.k, --C(NH)--N(R.sup.m)--R.sup.n,
--N(H)--C(O)--R.sup.k, --N(H)--C(S)--R.sup.k,
--N(R.sup.k)--C(O)--R.sup.k, --N(R.sup.k)--C(S)--R.sup.k,
--N(H)--S(O).sub.2--R.sup.k, --N(R.sup.k)--S(O).sub.2--R.sup.k,
--N(H)--C(O)--N(H)--R.sup.k, --N(H)--C(S)--N(H)--R.sup.k,
--N(R.sup.k)--C(O)--NH.sub.2, --N(R.sup.k)--C(S)--NH.sub.2,
--N(R.sup.k)--C(O)--N(H)--R.sup.k,
--N(R.sup.k)--C(S)--N(H)--R.sup.k,
--N(H)--C(O)--N(R.sup.k)--R.sup.k,
--N(H)--C(S)--N(R.sup.k)--R.sup.k,
--N(R.sup.k)--(O)--N(R.sup.k)--R.sup.k,
--N(R.sup.k)--C(S)--N(R.sup.k)--R.sup.k,
--N(H)--S(O).sub.2--N(H)--R.sup.k,
--N(R.sup.k)--S(O).sub.2--NH.sub.2,
--N(R.sup.k)--S(O).sub.2--N(H)--R.sup.k,
--N(H)--S(O).sub.2--N(R.sup.k)--R.sup.k,
--N(R.sup.k)--S(O).sub.2--N(R.sup.k)--R.sup.k, --N(H)--R.sup.k,
--N(R.sup.k)--R.sup.k, --R.sup.h, and --R.sup.j; [0339] each
R.sup.f is independently lower alkynyl, wherein lower alkynyl is
optionally substituted with one or more, preferably 1, 2, 3, 4 or
5, also 1, 2 or 3 substituents selected from the group consisting
of fluoro, --OH, --NH.sub.2, --NO.sub.2, --CN, --C(O)--OH,
--C(S)--OH, --C(O)--NH.sub.2, --C(S)--NH.sub.2,
--S(O).sub.2--NH.sub.2, --N(H)--C(O)--NH.sub.2,
--N(H)--C(S)--NH.sub.2, --N(H)--S(O).sub.2--NH.sub.2,
--C(NH)--NH.sub.2, --O--R.sup.k, --S--R.sup.k, --O--C(O)--R.sup.k,
--O--C(S)--R.sup.k, --C(O)--R.sup.k, --C(S)--R.sup.k,
--C(O)--O--R.sup.k, --C(S)--O--R.sup.k, --S(O)--R.sup.k,
--S(O).sub.2--R.sup.k, --C(O)--N(H)--R.sup.k,
--C(S)--N(H)--R.sup.k, --C(O)--N(R.sup.k)--R.sup.k,
--C(S)--N(R.sup.k)--R.sup.k, --S(O).sub.2--N(H)--R.sup.k,
--S(O).sub.2--N(R.sup.k)--R.sup.k, --C(NH)--N(H)--R.sup.k,
--C(NH)--N(R.sup.m)--R.sup.n, --N(H)--C(O)--R.sup.k,
--N(H)--C(S)--R.sup.k, --N(R.sup.k)--C(O)--R.sup.k,
--N(R.sup.k)--C(S)--R.sup.k, --N(H)--S(O).sub.2--R.sup.k,
--N(R.sup.k)--S(O).sub.2--R.sup.k, --N(H)--C(O)--N(H)--R.sup.k,
--N(H)--C(S)--N(H)--R.sup.k, --N(R.sup.k)--C(O)--NH.sub.2,
--N(R.sup.k)--C(S)--NH.sub.2, --N(R.sup.k)--C(O)--N(H)--R.sup.k,
--N(R.sup.k)--C(S)--N(H)--R.sup.k,
--N(H)--C(O)--N(R.sup.k)--R.sup.k,
--N(H)--C(S)--N(R.sup.k)--R.sup.k,
--N(R.sup.k)--(O)--N(R.sup.k)--R.sup.k,
--N(R.sup.k)--C(S)--N(R.sup.k)--R.sup.k,
--N(H)--S(O).sub.2--N(H)--R.sup.k,
--N(R.sup.k)--S(O).sub.2--NH.sub.2,
--N(R.sup.k)--S(O).sub.2--N(H)--R.sup.k,
--N(H)--S(O).sub.2--N(R.sup.k)--R.sup.k,
--N(R.sup.k)--S(O).sub.2--N(R.sup.k)--R.sup.k, --N(H)--R.sup.k,
--N(R.sup.k)--R.sup.k, --R.sup.h, and --R.sup.j; [0340] each
R.sup.g is independently selected from the group consisting of
cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein
cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally
substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2
or 3 substituents selected from the group consisting of halogen,
--OH, --NH.sub.2, --NO.sub.2, --CN, --C(O)--OH, --C(S)--OH,
--C(O)--NH.sub.2, --C(S)--NH.sub.2, --S(O).sub.2--NH.sub.2,
--N(H)--C(O)--NH.sub.2, --N(H)--C(S)--NH.sub.2,
--N(H)--S(O).sub.2--NH.sub.2, --C(NH)--NH.sub.2, --O--R.sup.k,
--S--R.sup.k, --O--C(O)--R.sup.k, --O--C(S)--R.sup.k,
--C(O)--R.sup.k, --C(S)--R.sup.k, --C(O)--O--R.sup.k,
--C(S)--O--R.sup.k, --S(O)--R.sup.k, --S(O).sub.2--R.sup.k,
--C(O)--N(H)--R.sup.k, --C(S)--N(H)--R.sup.k,
--C(O)--N(R.sup.k)--R.sup.k, --C(S)--N(R.sup.k)--R.sup.k,
--S(O).sub.2--N(H)--R.sup.k, --S(O).sub.2--N(R.sup.k)--R.sup.k,
--C(NH)--N(H)--R.sup.k, --C(NH)--N(R.sup.m)--R.sup.n,
--N(H)--C(O)--R.sup.k, --N(H)--C(S)--R.sup.k,
--N(R.sup.k)--C(O)--R.sup.k, --N(R.sup.k)--C(S)--R.sup.k,
--N(H)--S(O).sub.2--R.sup.k, --N(R.sup.k)--S(O).sub.2--R.sup.k,
--N(H)--C(O)--N(H)--R.sup.k, --N(H)--C(S)--N(H)--R.sup.k,
--N(R.sup.k)--C(O)--NH.sub.2, --N(R.sup.k)--C(S)--NH.sub.2,
--N(R.sup.k)--C(O)--N(H)--R.sup.k,
--N(R.sup.k)--C(S)--N(H)--R.sup.k,
--N(H)--C(O)--N(R.sup.k)--R.sup.k,
--N(H)--C(S)--N(R.sup.k)--R.sup.k,
--N(R.sup.k)--C(O)--N(R.sup.k)--R.sup.k,
--N(R.sup.k)--C(S)--N(R.sup.k)--R.sup.k,
--N(H)--S(O).sub.2--N(H)--R.sup.k,
--N(R.sup.k)--S(O).sub.2--NH.sub.2,
--N(R.sup.k)--S(O).sub.2--N(H)--R.sup.k,
--N(H)--S(O).sub.2--N(R.sup.k)--R.sup.k,
--N(R.sup.k)--S(O).sub.2--N(R.sup.k)--R.sup.k, --N(H)--R.sup.k,
--N(R.sup.k)--R.sup.k, --R.sup.h, --R.sup.i, and --R.sup.j; [0341]
wherein R.sup.k, R.sup.m, and R.sup.n at each occurrence are
independently selected from the group consisting of R.sup.h,
R.sup.i, and R.sup.j, or R.sup.m and R.sup.n combine with the
nitrogen to which they are attached to form a 5-7 membered
heterocycloalkyl or a 5 or 7 membered nitrogen containing
heteroaryl, wherein the 5-7 membered heterocycloalkyl or 5 or 7
membered nitrogen containing heteroaryl are optionally substituted
with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3
substituents selected from the group consisting of halogen,
--NO.sub.2, --CN, --OH, --NH.sub.2, O--R.sup.u, --S--R.sup.u,
--N(H)--R.sup.u, --NR.sup.UR.sup.u, --R.sup.x, and --R.sup.Y;
[0342] wherein each R.sup.h is independently lower alkyl optionally
substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1,
2, or 3 substituents selected from the group consisting of fluoro,
--OH, --NH.sub.2, --NO.sub.2, --CN, --C(O)--OH, --C(S)--OH,
--C(O)--NH.sub.2, --C(S)--NH.sub.2, --S(O).sub.2--NH.sub.2,
--N(H)--C(O)--NH.sub.2, --N(H)--C(S)--NH.sub.2,
--N(H)--S(O).sub.2--NH.sub.2, --C(NH)--NH.sub.2, --O--R.sup.r,
--S--R.sup.r, --O--C(O)--R.sup.r, --O--C(S)--R.sup.r,
--C(O)--R.sub.r, --C(S)--R, --C(O)--O--R.sub.r, --C(S)--O--R.sub.r,
--S(O)--R.sup.r, --S(O).sub.2--R.sup.r, --C(O)--N(H)--R.sup.r,
--C(S)--N(H)--R.sup.r, --C(O)--N(R.sup.r)--R.sup.r,
--C(S)--N(R.sup.r)--R.sup.r, --S(O).sub.2--N(H)--R.sup.r,
--S(O).sub.2--N(R.sup.r)--R.sup.r, --C(NH)--N(H)--R.sup.r,
--C(NH)--N(R.sup.s)--R.sup.t, --N(H)--C(O)--R.sup.r,
--N(H)--C(S)--R.sup.r, --N(R.sup.r)--C(O)--R.sup.r,
--N(R.sup.r)--C(S)--R.sup.r, --N(H)--S(O).sub.2--R.sup.r,
--N(R.sup.r)--S(O).sub.2--R.sup.r, --N(H)--C(O)--N(H)--R.sup.r,
--N(H)--C(S)--N(H)--R.sup.r, --N(R.sup.r)--C(O)--NH.sub.2,
--N(R.sup.r)--C(S)--NH.sub.2, --N(R.sup.r)--C(O)--N(H)--R.sup.r,
--N(R.sup.r)--C(S)--N(H)--R.sup.r,
--N(H)--C(O)--N(R.sup.r)--R.sup.r,
--N(H)--C(S)--N(R.sup.r)--R.sup.r,
--N(R.sup.r)--C(O)--N(R.sup.r)--R.sub.r,
--N(R.sup.r)--C(S)--N(R.sup.r)--R.sup.r,
--N(H)--S(O).sub.2--N(H)--R.sup.r,
--N(R.sup.r)--S(O).sub.2--NH.sub.2,
--N(R.sup.r)--S(O).sub.2--N(H)--R.sup.r,
--N(H)--S(O).sub.2--N(R.sup.r)--R.sup.r,
--N(R.sup.r)--S(O).sub.2--N(R.sup.r)--R.sup.r, --N(H)--R.sup.r,
--N(R.sup.r)--R.sup.r, --R.sup.i, and --R.sup.j; [0343] wherein
each R.sup.i is independently selected from the group consisting of
lower alkenyl and lower alkynyl, wherein lower alkenyl or lower
alkynyl are optionally substituted with one or more, preferably 1,
2, 3, 4 or 5, also 1, 2 or 3 substituents selected from the group
consisting of fluoro, --OH, --NH.sub.2, --NO.sub.2, --CN,
--C(O)--OH, --C(S)--OH, --C(O)--NH.sub.2, --C(S)--NH.sub.2,
--S(O).sub.2--NH.sub.2, --N(H)--C(O)--NH.sub.2,
--N(H)--C(S)--NH.sub.2, --N(H)--S(O).sub.2--NH.sub.2,
--C(NH)--NH.sub.2, --O--R.sup.r, --S--R.sup.r, --O--C(O)--R.sup.r,
--O--C(S)--R.sup.r, --C(O)--R.sup.r, --C(S)--R.sup.r,
--C(O)--O--R.sup.r, --C(S)--O--R.sup.r, --S(O)--R.sup.r,
--S(O).sub.2--R.sup.r, --C(O)--N(H)--R.sup.r,
--C(S)--N(H)--R.sup.r, --C(O)--N(R.sup.r)--R.sup.r,
--C(S)--N(R.sup.r)--R.sup.r, --S(O).sub.2--N(H)--R.sup.r,
--S(O).sub.2--N(R.sup.r)--R.sup.r, --C(NH)--N(H)--R.sup.r,
--C(NH)--N(R.sup.S)--R.sup.r, --N(H)--C(O)--R.sup.r,
--N(H)--C(S)--R.sup.r, --N(R.sup.r)--C(O)--R.sup.r,
--N(R.sup.r)--C(S)--R.sup.r, --N(H)--S(O).sub.2--R.sup.r,
--N(R.sup.r)--S(O).sub.2--R.sup.r, --N(H)--C(O)--N(H)--R.sup.r,
--N(H)--C(S)--N(H)--R.sup.r, --N(R.sup.r)--C(O)--NH.sub.2,
--N(R.sup.r)--C(S)--NH.sub.2, --N(R.sup.r)--C(O)--N(H)--R.sup.r,
--N(R.sup.r)--C(S)--N(H)--R.sup.r,
--N(H)--C(O)--N(R.sup.r)--R.sup.r,
--N(H)--C(S)--N(R.sup.r)--R.sup.r,
--N(R.sup.r)--C(O)--N(R.sup.r)--R.sup.r,
--N(R.sup.r)--C(S)--N(R.sup.r)--R.sup.r,
--N(H)--S(O).sub.2--N(H)--R.sup.r,
--N(R.sup.r)--S(O).sub.2--NH.sub.2,
--N(R.sup.r)--S(O).sub.2--N(H)--R.sup.r,
--N(H)--S(O).sub.2--N(R.sup.r)--R.sup.r,
--N(R.sup.r)--S(O).sub.2--N(R.sup.r)--R.sup.r, --N(H)--R.sup.r,
--N(R.sup.r)--R.sup.r, and --R; [0344] wherein each R.sup.j is
independently selected from the group consisting of cycloalkyl,
heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl,
heterocycloalkyl, aryl, and heteroaryl are optionally substituted
with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2 or 3
substituents selected from the group consisting of halogen, --OH,
--NH.sub.2, --NO.sub.2, --CN, --C(O)--OH, --C(S)--OH,
--C(O)--NH.sub.2, --C(S)--NH.sub.2, --S(O).sub.2--NH.sub.2,
--N(H)--C(O)--NH.sub.2, --N(H)--C(S)--NH.sub.2,
--N(H)--S(O).sub.2--NH.sub.2, --C(NH)--NH.sub.2, --O--R.sup.r,
--S--R.sup.r, --O--C(O)--R.sup.r, --O--C(S)--R.sup.r,
--C(O)--R.sup.r, --C(S)--R.sup.r, --C(O)--O--R.sup.r,
--C(S)--O--R.sup.r, --S(O)--R.sup.r, --S(O).sub.2--R.sup.r,
--C(O)--N(H)--R.sup.r, --C(S)--N(H)--R.sup.r,
--C(O)--N(R.sup.r)--R.sup.r, --C(S)--N(R.sup.r)--R.sup.r,
--S(O).sub.2--N(H)--R.sup.r, --S(O).sub.2--N(R.sup.r)--R.sup.r,
C(NH)--N(H)--R.sup.r, --C(NH)--N(R.sup.s)--R.sup.t,
--N(H)--C(O)--R.sup.r, --N(H)--C(S)--R.sup.r,
--N(R.sup.r)--C(O)--R.sup.r, --N(R.sup.r)--C(S)--R.sup.r,
--N(H)--S(O).sub.2--R.sup.r, --N(R.sup.r)--S(O).sub.2--R.sup.r,
--N(H)--C(O)--N(H)--R.sup.r, --N(H)--C(S)--N(H)--R.sup.r,
--N(R.sup.r)--C(O)--NH.sub.2, --N(R.sup.r)--C(S)--NH.sub.2,
--N(R.sup.r)--C(O)--N(H)--R.sup.r,
--N(R.sup.r)--C(S)--N(H)--R.sup.r,
--N(H)--C(O)--N(R.sup.r)--R.sup.r,
--N(H)--C(S)--N(R.sup.r)--R.sup.r,
--N(R.sup.r)--C(O)--N(R.sup.r)--R.sup.r,
--N(R.sup.r)--C(S)--N(R.sup.r)--R.sup.r,
--N(H)--S(O).sub.2--N(H)--R.sup.r,
--N(R.sup.r)--S(O).sub.2--NH.sub.2,
--N(R.sup.r)--S(O).sub.2--N(H)--R.sup.r,
--N(H)--S(O).sub.2--N(R.sup.r)--R.sup.r,
--N(R.sup.r)--S(O).sub.2--N(R.sup.r)--R.sup.r, --N(H)--R.sup.r,
--N(R.sup.r)--R.sup.r, cycloalkylamino, and --R.sup.X; [0345]
wherein each R.sup.r, R.sup.s, and R.sup.t at each occurrence are
independently selected from the group consisting of lower alkyl,
C.sub.3-6 alkenyl, C.sub.3-6 alkynyl, cycloalkyl, heterocycloalkyl,
aryl and heteroaryl, wherein lower alkyl is optionally substituted
with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3
substituents selected from the group consisting of --R.sup.y,
fluoro, --OH, --NH.sub.2, lower alkoxy, fluoro substituted lower
alkoxy, lower alkylthio, fluoro substituted lower alkylthio,
mono-alkylamino, di-alkylamino, and cycloalkylamino, and wherein
C.sub.3-6 alkenyl or C.sub.3-6 alkynyl are optionally substituted
with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3
substituents selected from the group consisting of --R.sup.y,
fluoro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy,
fluoro substituted lower alkoxy, lower alkylthio, fluoro
substituted lower alkylthio, mono-alkylamino, di-alkylamino, and
cycloalkylamino, and wherein cycloalkyl, heterocycloalkyl, aryl,
and heteroaryl are optionally substituted with one or more,
preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected
from the group consisting of halogen, --OH, --NH.sub.2, --NO.sub.2,
--CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy,
fluoro substituted lower alkoxy, lower alkylthio, fluoro
substituted lower alkylthio, mono-alkylamino, di-alkylamino, and
cycloalkylamino, or R.sup.s and R.sup.t combine with the nitrogen
to which they are attached to form a 5-7 membered heterocycloalkyl
or a 5 or 7 membered nitrogen containing heteroaryl, wherein the
5-7 membered heterocycloalkyl or 5 or 7 membered nitrogen
containing heteroaryl are optionally substituted with one or more,
preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected
from the group consisting of halogen,
--NO.sub.2, --CN, --OH, --NH.sub.2, O--R.sup.u, --S--R.sup.u,
--N(H)--R.sup.u, --N(R.sup.U)--R.sup.u, --R.sup.x, and --R.sup.Y;
[0346] wherein each R.sup.u is independently selected from the
group consisting of lower alkyl, C.sub.3-6 alkenyl, C.sub.3-6
alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,
wherein lower alkyl is optionally substituted with one or more,
preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected
from the group consisting of --R.sup.y, fluoro, --OH, --NH.sub.2,
lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio,
fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino,
and cycloalkylamino, and wherein C.sub.3-6 alkenyl or C.sub.3-6
alkynyl are optionally substituted with one or more, preferably 1,
2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group
consisting of --R.sup.y, fluoro, --OH, --NH.sub.2, lower alkyl,
fluoro substituted lower alkyl, lower alkoxy, fluoro substituted
lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio,
mono-alkylamino, di-alkylamino, and cycloalkylamino, and wherein
cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally
substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1,
2, or 3 substituents selected from the group consisting of halogen,
--OH, --NH.sub.2, --NO.sub.2, --CN, lower alkyl, fluoro substituted
lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower
alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,
di-alkylamino, and cycloalkylamino; [0347] wherein each R.sup.x is
selected from the group consisting of lower alkyl, lower alkenyl
and lower alkynyl, wherein lower alkyl is optionally substituted
with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3
substituents selected from the group consisting of --R.sup.y,
fluoro, --OH, --NH.sub.2, lower alkoxy, fluoro substituted lower
alkoxy, lower alkylthio, fluoro substituted lower alkylthio,
mono-alkylamino, di-alkylamino, and cycloalkylamino, and wherein
lower alkenyl or lower alkynyl are optionally substituted with one
or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents
selected from the group consisting of --R.sup.y, fluoro, --OH,
--NH.sub.2, lower alkyl, fluoro substituted lower alkyl, lower
alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro
substituted lower alkylthio, mono-alkylamino, di-alkylamino, and
cycloalkylamino; [0348] wherein each R.sup.y is selected from the
group consisting of cycloalkyl, heterocycloalkyl, aryl, and
heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and
heteroaryl are optionally substituted with one or more, preferably
1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the
group consisting of halogen, --OH, --NH.sub.2, --NO.sub.2, --CN,
lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro
substituted lower alkoxy, lower alkylthio, fluoro substituted lower
alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino.
[0349] In some embodiments, all occurrences of optionally
substituted lower alkyl, optionally substituted lower alkenyl,
optionally substituted C.sub.3-6 alkenyl, optionally substituted
lower alkynyl, or optionally substituted C.sub.3-6 alkynyl are
optionally substituted with one or more, also 1, 2 or 3 groups or
substituents selected from the group consisting of fluoro,
--NO.sub.2, --CN, --O--R.sup.1a, --S--R.sup.1a,
--N(R.sup.1a)--R.sup.1a, --O--C(O)--R.sup.1a, --O--C(S)--R.sup.1a,
--C(O)--R.sup.1a, --C(S)--R.sup.1a, --C(O)--O--R.sup.1a,
--C(S)--O--R.sup.1a, --C(O)--N(R.sup.1a)--R.sup.1a,
--C(S)--N(R.sup.1a)--R.sup.1a, --S(O).sub.2--N(R.sup.1a)--R.sup.1a,
--C(NH)--N(R.sup.1a)--R.sup.1a, --N(R.sup.1a)--C(O)--R.sup.1a,
--N(R.sup.1a)--C(S)--R.sup.1a, --N(R.sup.1a)--S(O).sub.2--R.sup.1a,
--N(R.sup.1a)--C(O)--N(R.sup.1a)--R.sup.1a,
--N(R.sup.1a)--C(S)--N(R.sup.1a)--R.sup.1a,
--N(R.sup.1a)--S(O).sub.2--N(R.sup.1a)--R.sup.1a, --S(O)--R.sup.1a,
--S(O).sub.2--R.sup.1a, cycloalkyl, heterocycloalkyl, aryl and
heteroaryl; wherein cycloalkyl, heterocycloalkyl, aryl and
heteroaryl are optionally substituted with one or more, also 1, 2
or 3 groups or substituents selected from the group consisting of
halogen, --NO.sub.2, --CN, --O--R.sup.1a, --S--R.sup.1a,
--N(R.sup.1a)--R.sup.1a, --O--C(O)--R.sup.1a, --O--C(S)--R.sup.11,
--C(O)--R.sup.1a, --C(S)--R.sup.1a, --C(O)--O--R.sup.1a,
--C(S)--O--R.sup.1a, --C(O)--N(R.sup.1a)--R.sup.1a,
--C(S)--N(R.sup.1a)--R.sup.1a, --S(O).sub.2--N(R.sup.1a)--R.sup.1a,
--C(NH)--N(R.sup.1a)--R.sup.1a, --N(R.sup.1a)--C(O)--R.sup.1a,
--N(R.sup.1a)--C(S)--R.sup.1a, --N(R.sup.1a)--S(O).sub.2--R.sup.1a,
--N(R.sup.1a)--C(O)--N(R.sup.1a)--R.sup.1a,
--N(R.sup.1a)--C(S)--N(R.sup.1a)--R.sup.1a,
--N(R.sup.1a)--S(O).sub.2--N(R.sup.1a)--R.sup.1a, --S(O)--R.sup.1a,
--S(O).sub.2--R.sup.1a, --R.sup.1b, and lower alkyl optionally
substituted with one or more, also 1, 2 or 3 groups or substituents
selected from the group consisting of fluoro, --OH, --NH.sub.2,
lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio,
fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino,
and --R.sup.1b; and all occurrences of optionally substituted
cycloalkyl, optionally substituted heterocycloalkyl, optionally
substituted 5-7 membered heterocycloalkyl, optionally substituted
aryl, optionally substituted heteroaryl, or optionally substituted
5 or 7 membered nitrogen containing heteroaryl are optionally
substituted with one or more, also 1, 2, or 3 groups or
substituents selected from the group consisting of halogen,
--NO.sub.2, --CN, --O--R.sup.1a, --S--R.sup.1a,
--N(R.sup.1a)--R.sup.1a, --O--C(O)--R.sup.1a, --O--C(S)--R.sup.1a,
--C(O)--R.sup.1a, --C(S)--R.sup.1a, --C(O)--O--R.sup.1a,
--C(S)--O--R.sup.1a, --C(O)--N(R.sup.1a)--R.sup.1a,
--C(S)--N(R.sup.1a)--R.sup.1a, --S(O).sub.2--N(R.sup.1a)--R.sup.1a,
--C(NH)--N(R.sup.1a)--R.sup.1a, --N(R.sup.1a)--C(O)--R.sup.1a,
--N(R.sup.1a)--C(S)--R.sup.1a, --N(R.sup.1a)--S(O).sub.2--R.sup.1a,
--N(R.sup.1a)--C(O)--N(R.sup.1a)--R.sup.1a,
--N(R.sup.1a)--C(S)--N(R.sup.1a)--R.sup.1a,
--N(R.sup.1a)--S(O).sub.2--N(R.sup.1a)--R.sup.1a, --S(O)--R.sup.1a,
--S(O).sub.2--R.sup.1a, --R.sup.1b, and lower alkyl optionally
substituted with one or more, also 1, 2 or 3 groups or substituents
selected from the group consisting of fluoro, --OH, --NH.sub.2,
lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio,
fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino,
and --R.sup.1b; wherein R.sup.1a is selected from the group
consisting of hydrogen, --R.sup.1b, and lower alkyl optionally
substituted with one or more, also 1, 2 or 3 groups or substituents
selected from the group consisting of fluoro, --OH, --NH.sub.2,
lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio,
fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino,
and --R.sup.1b, and wherein --R.sup.1b is selected from the group
consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl,
wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are
optionally substituted with one or more, also 1, 2 or 3 groups or
substituents selected from the group consisting of halogen, --CN,
--OH, --NH.sub.2, lower alkoxy, fluoro substituted lower alkoxy,
lower alkylthio, fluoro substituted lower alkylthio,
mono-alkylamino, di-alkylamino, and cycloalkylamino.
[0350] In some embodiments, all occurrences of optionally
substituted lower alkyl, optionally substituted lower alkenyl,
optionally substituted C.sub.3-6 alkenyl, optionally substituted
lower alkynyl, or optionally substituted C.sub.3-6 alkynyl are
optionally substituted with one or more, also 1, 2 or 3 groups or
substituents selected from the group consisting of fluoro, --CN,
--O--R.sup.1a, --S--R.sup.1a, --N(R.sup.1a)--R.sup.1a,
--C(O)--R.sup.1a, --C(S)--R.sup.1a, --C(O)--O--R.sup.1a,
--C(O)--N(R.sup.1a)--R.sup.1a, --C(S)--N(R.sup.1a)--R.sup.1a,
--S(O).sub.2--N(R.sup.1a)--R.sup.1a, --N(R.sup.1a)--C(O)--R.sup.1a,
--N(R.sup.1a)--C(S)--R.sup.1a, --N(R.sup.1a)--S(O).sub.2--R.sup.1a,
--S(O)--R.sup.1a, --S(O).sub.2--R.sup.1a, cycloalkyl,
heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl,
heterocycloalkyl, aryl and heteroaryl are optionally substituted
with one or more, also 1, 2 or 3 groups or substituents selected
from the group consisting of halogen, --CN, --O--R.sup.1a,
--S--R.sup.1a, --N(R.sup.1a)--R.sup.1a, --C(O)--R.sup.1a,
--C(S)--R.sup.1a, --C(O)--O--R.sup.1a,
--C(O)--N(R.sup.1a)--R.sup.1a, --C(S)--N(R.sup.1a)--R.sup.1a,
--S(O).sub.2--N(R.sup.1a)--R.sup.1a, --N(R.sup.1a)--C(O)--R.sup.1a,
--N(R.sup.1a)--C(S)--R.sup.1a, --N(R.sup.1a)--S(O).sub.2--R.sup.1a,
--S(O)--R.sup.1a, --S(O).sub.2--R.sup.1a, --R.sup.1b, and lower
alkyl optionally substituted with one or more, also 1, 2 or 3
groups or substituents selected from the group consisting of
fluoro, --OH, --NH.sub.2, lower alkoxy, fluoro substituted lower
alkoxy, lower alkylthio, fluoro substituted lower alkylthio,
mono-alkylamino, di-alkylamino, and --R.sup.1b; and all occurrences
of optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted 5-7 membered
heterocycloalkyl, optionally substituted aryl, optionally
substituted heteroaryl, or optionally substituted 5 or 7 membered
nitrogen containing heteroaryl are optionally substituted with one
or more, also 1, 2, or 3 groups or substituents selected from the
group consisting of halogen, --CN, --O--R.sup.1a, --S--R.sup.1a,
--N(R.sup.1a)--R.sup.1a, --C(O)--R.sup.1a, --C(S)--R.sup.1a,
--C(O)--O--R.sup.1a, --C(O)--N(R.sup.1a)--R.sup.1a,
--C(S)--N(R.sup.1a)--R.sup.1a, --S(O).sub.2--N(R.sup.1a)--R.sup.1a,
--N(R.sup.1a)--C(O)--R.sup.1a, --N(R.sup.1a)--C(S)--R.sup.1a,
--N(R.sup.1a)--S(O).sub.2--R.sup.1a, --S(O)--R.sup.1a,
--S(O).sub.2--R.sup.1a, --R.sup.1b, and lower alkyl optionally
substituted with one or more, also 1, 2 or 3 groups or substituents
selected from the group consisting of fluoro, --OH, --NH.sub.2,
lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio,
fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino,
and --R.sup.1b; wherein R.sup.1a is selected from the group
consisting of hydrogen, --R.sup.1b, and lower alkyl optionally
substituted with one or more, also 1, 2 or 3 groups or substituents
selected from the group consisting of fluoro, --OH, --NH.sub.2,
lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio,
fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino,
and --R.sup.1b, and wherein --R.sup.1b is selected from the group
consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl,
wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are
optionally substituted with one or more, also 1, 2 or 3 groups or
substituents selected from the group consisting of halogen, --CN,
--OH, --NH.sub.2, lower alkoxy, fluoro substituted lower alkoxy,
lower alkylthio, fluoro substituted lower alkylthio,
mono-alkylamino, di-alkylamino, and cycloalkylamino.
[0351] "Lower alkoxy" denotes the group --OR.sup.z, where R.sup.z
is lower alkyl. "Substituted lower alkoxy" denotes lower alkoxy in
which R.sup.z is lower alkyl substituted with one or more
substituents as indicated herein, for example, in the description
of compounds of Formula I, including descriptions of substituted
cycloalkyl, heterocycloalkyl, aryl and heteroaryl, attached at any
available atom to provide a stable compound. Preferably,
substitution of lower alkoxy is with 1, 2, 3, 4, or 5 substituents,
also 1, 2, or 3 substituents. For example "fluoro substituted lower
alkoxy" denotes lower alkoxy in which the lower alkyl is
substituted with one or more fluoro atoms, where preferably the
lower alkoxy is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also
1, 2, or 3 fluoro atoms. It is understood that substitutions on
alkoxy are chemically feasible and attached at any available atom
to provide a stable compound.
[0352] "Lower alkylthio" denotes the group --SR.sup.aa, where
R.sup.aa is lower alkyl. "Substituted lower alkylthio" denotes
lower alkylthio in which R.sup.aa is lower alkyl substituted with
one or more substituents as indicated herein, for example, in the
description of compounds of Formula I, including descriptions of
substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl,
attached at any available atom to provide a stable compound.
Preferably, substitution of lower alkylthio is with 1, 2, 3, 4, or
5 substituents, also 1, 2, or 3 substituents. For example "fluoro
substituted lower alkylthio" denotes lower alkylthio in which the
lower alkyl is substituted with one or more fluoro atoms, where
preferably the lower alkylthio is substituted with 1, 2, 3, 4 or 5
fluoro atoms, also 1, 2, or 3 fluoro atoms. It is understood that
substitutions on alkylthio are chemically feasible and attached at
any available atom to provide a stable compound.
[0353] "Amino" or "amine" denotes the group --NH.sub.2.
"Mono-alkylamino" denotes the group --NHR.sup.bb where R.sup.bb is
lower alkyl. "Di-alkylamino" denotes the group --NR.sup.bbR.sup.cc,
where R.sup.bb and Rec are independently lower alkyl.
"Cycloalkylamino" denotes the group --NR.sup.ddR.sup.ee, where
R.sup.dd and R.sup.ee combine with the nitrogen to form a 5-7
membered heterocycloalkyl, where the heterocycloalkyl may contain
an additional heteroatom within the ring, such as O, N, or S, and
may also be further substituted with lower alkyl. Examples of 5-7
membered heterocycloalkyl include, but are not limited to,
piperidine, piperazine, 4-methylpiperazine, morpholine, and
thiomorpholine. It is understood that when mono-alkylamino,
di-alkylamino, or cycloalkylamino are substituents on other
moieties, these are chemically feasible and attached at any
available atom to provide a stable compound.
[0354] As used herein, the term "composition" refers to a
formulation suitable for administration to an intended animal
subject for therapeutic purposes that contains at least one
pharmaceutically active compound and at least one pharmaceutically
acceptable carrier or excipient.
[0355] The term "pharmaceutically acceptable" indicates that the
indicated material does not have properties that would cause a
reasonably prudent medical practitioner to avoid administration of
the material to a patient, taking into consideration the disease or
conditions to be treated and the respective route of
administration. For example, it is commonly required that such a
material be essentially sterile, e.g., for injectibles.
[0356] In the present context, the term "therapeutically effective"
or "effective amount" indicates that the materials or amount of
material is effective to prevent, alleviate, or ameliorate one or
more symptoms of a disease or medical condition, and/or to prolong
the survival of the subject being treated.
[0357] In the present context, the terms "synergistically
effective" or "synergistic effect" indicate that two or more
compounds that are therapeutically effective, when used in
combination, provide improved therapeutic effects greater than the
additive effect that would be expected based on the effect of each
compound used by itself.
[0358] As used herein, the terms "ligand" and "modulator" are used
equivalently to refer to a compound that changes (i.e., increases
or decreases) the activity of a target biomolecule, e.g., an enzyme
such as a kinase. The term "inhibitor" refers to a modulator that
decreases the activity of the target biomolecule. Generally a
ligand or modulator will be a small molecule, where "small molecule
refers to a compound with a molecular weight of 1500 daltons or
less, or preferably 1000 daltons or less, 800 daltons or less, or
600 daltons or less.
[0359] In the context of compounds binding to a target, the terms
"greater affinity" and "selective" indicates that the compound
binds more tightly than a reference compound, or than the same
compound in a reference condition, i.e., with a lower dissociation
constant. In some embodiments, the greater affinity (i.e.
selectivity) is at least 2, 3, 4, 5, 8, 10, 50, 100, 200, 400, 500,
1000, or 10,000-fold greater affinity.
[0360] As used herein in connection with compounds of the
invention, the term "synthesizing" and like terms means chemical
synthesis from one or more precursor materials.
[0361] By "assaying" is meant the creation of experimental
conditions and the gathering of data regarding a particular result
of the experimental conditions. For example, enzymes can be assayed
based on their ability to act upon a detectable substrate. A
compound or ligand can be assayed based on its ability to bind to a
particular target molecule or molecules.
[0362] As used herein, the term "modulating" or "modulate" refers
to an effect of altering a biological activity, especially a
biological activity associated with a particular biomolecule such
as a protein kinase. For example, an agonist or antagonist of a
particular biomolecule modulates the activity of that biomolecule,
e.g., an enzyme, by either increasing (e.g. agonist, activator), or
decreasing (e.g. antagonist, inhibitor) the activity of the
biomolecule, such as an enzyme. Such activity is typically
indicated in terms of an inhibitory concentration (IC.sub.50) or
excitation concentration (EC.sub.50) of the compound for an
inhibitor or activator, respectively, with respect to, for example,
an enzyme.
[0363] In the context of the use, testing, or screening of
compounds that are or may be modulators, the term "contacting"
means that the compound(s) are caused to be in sufficient proximity
to a particular molecule, complex, cell, tissue, organism, or other
specified material that potential binding interactions and/or
chemical reaction between the compound and other specified material
can occur.
[0364] As used herein in connection with amino acid or nucleic acid
sequence, the term "isolate" indicates that the sequence is
separated from at least a portion of the amino acid and/or nucleic
acid sequences with which it would normally be associated.
[0365] In connection with amino acid or nucleic sequences, the term
"purified" indicates that the subject molecule constitutes a
significantly greater proportion of the biomolecules in a
composition than the proportion observed in a prior composition,
e.g., in a cell culture. The greater proportion can be 2-fold,
5-fold, 10-fold, or more than 10-fold, with respect to the
proportion found in the prior composition.
[0366] The present invention concerns compounds of Formula I, and
all sub-generic formulae, that are modulators of protein kinases,
for example without limitation, the compounds are modulators of at
least one of the kinases selected from the group consisting of Abl,
Akt1, Akt2, Akt3, ALK, Alk5, A-Raf, B-Raf, Brk, Btk, Cdk2, CDK4,
CDK5, CDK6, CHK1, c-Raf-1, Csk, EGFR, EphA1, EphA2, EphB2, EphB4,
Erk2, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Flt1, Flt3, Flt4, Fms, Frk,
Fyn, Gsk3.alpha., Gsk3.beta., HCK, Her2/Erbb2, Her4/Erbb4, IGF1R,
IKK beta, Irak4, Itk, Jak1, Jak2, Jak3, Jnk1, Jnk2, Jnk3, Kdr, Kit,
Lck, Lyn, MAP2K1, MAP2K2, MAP4K4, MAPKAPK2, Met, Mnk1, MLK1, p38,
PDGFRA, PDGFRB, PDPK1, Pim1, Pim2, Pim3, PKC alpha, PKC beta, PKC
theta, Plk1, Pyk2, Ret, ROCK1, ROCK2, Ron, Src, Stk6, Syk, TEC,
Tie2, TrkA, TrkB, Yes, and Zap70, and any mutations thereof, and
the use of such compounds in the treatment of diseases or
conditions.
Kinase Targets and Indications of the Invention
[0367] Protein kinases play key roles in propagating biochemical
signals in diverse biological pathways. More than 500 kinases have
been described, and specific kinases have been implicated in a wide
range of diseases or conditions (i.e., indications), including for
example without limitation, cancer, cardiovascular disease,
inflammatory disease, neurological disease, and other diseases. As
such, kinases represent important control points for small molecule
therapeutic intervention. Specific target protein kinases
contemplated by the present invention are described in the art,
including, without limitation, protein kinases as described in U.S.
patent application Ser. No. 11/473,347 (see also, PCT publication
WO2007002433), the disclosure of which is hereby incorporated by
reference in its entirety, including all specifications, figures,
and tables, and for all purposes, as well as the following:
[0368] A-Raf: Target kinase A-Raf (i.e., v-raf murine sarcoma 3611
viral oncogene homolog 1) is a 67.6 kDa serine/threonine kinase
encoded by chromosome Xp 11.4-p11.2 (symbol: ARAF). The mature
protein comprises RBD (i.e., Ras binding domain) and
phorbol-ester/DAG-type zinc finger domain and is involved in the
transduction of mitogenic signals from the cell membrane to the
nucleus. A-Raf inhibitors may be useful in treating neurologic
diseases such as multi-infarct dementia, head injury, spinal cord
injury, Alzheimer's disease (AD), Parkinson's disease; neoplastic
diseases including, but not limited to, melanoma, glioma, sarcoma,
carcinoma (e.g. colorectal, lung, breast, pancreatic, thyroid,
renal, ovarian), lymphoma (e.g. histiocytic lymphoma),
neurofibromatosis, myelodysplastic syndrome, leukemia, tumor
angiogenesis; pain of neuropathic or inflammatory origin, including
acute pain, chronic pain, cancer-related pain and migraine; and
diseases associated with muscle regeneration or degeneration,
including, but not limited to, vascular restenosis, sarcopenia,
muscular dystrophies (including, but not limited to, Duchenne,
Becker, Emery-Dreifuss, Limb-Girdle, Facioscapulohumeral, Myotonic,
Oculopharyngeal, Distal and Congenital Muscular Dystrophies), motor
neuron diseases (including, but not limited to, amyotrophic lateral
sclerosis, infantile progressive spinal muscular atrophy,
intermediate spinal muscular atrophy, juvenile spinal muscular
atrophy, spinal bulbar muscular atrophy, and adult spinal muscular
atrophy), inflammatory myopathies (including, but not limited to,
dermatomyositis, polymyositis, and inclusion body myositis),
diseases of the neuromuscular junction (including, but not limited
to, myasthenia gravis, Lambert-Eaton syndrome, and congenital
myasthenic syndrome), myopathies due to endocrine abnormalities
(including, but not limited to, hyperthyroid myopathy and
hypothyroid myopathy) diseases of peripheral nerve (including, but
not limited to, Charcot-Marie-Tooth disease, Dejerine-Sottas
disease, and Friedreich's ataxia), other myopathies (including, but
not limited to, myotonia congenita, paramyotonia congenita, central
core disease, nemaline myopathy, myotubular myopathy, and periodic
paralysis), and metabolic diseases of muscle (including, but not
limited to, phosphorylase deficiency, acid maltase deficiency,
phosphofructokinase deficiency, debrancher enzyme deficiency,
mitochondrial myopathy, carnitine deficiency, carnitine palmatyl
transferase deficiency, phosphoglycerate kinase deficiency,
phosphoglycerate mutase deficiency, lactate dehydrogenase
deficiency, and myoadenylate deaminase deficiency).
[0369] B-Raf: Target kinase B-Raf (i.e., v-raf murine sarcoma viral
oncogene homolog B1) is a 84.4 kDa serine/threonine kinase encoded
by chromosome 7q34 (symbol: BRAF). The mature protein comprises RBD
(i.e., Ras binding domain), Cl (i.e., protein kinase C conserved
region 1) and STK (i.e., serine/threonine kinase) domains.
[0370] Target kinase B-Raf is involved in the transduction of
mitogenic signals from the cell membrane to the nucleus and may
play a role in the postsynaptic responses of hippocampal neurons.
As such, genes of the RAF family encode kinases that are regulated
by Ras and mediate cellular responses to growth signals. Indeed,
B-Rafkinase is a key component of the
RAS->Raf->MEK->ERK/MAP kinase signaling pathway, which
plays a fundamental role in the regulation of cell growth, division
and proliferation, and, when constitutively activated, causes
tumorigenesis. Among several isoforms of Raf kinase, the B-type, or
B-Raf, is the strongest activator of the downstream MAP kinase
signaling.
[0371] The BRAF gene is frequently mutated in a variety of human
tumors, especially in malignant melanoma and colon carcinoma. The
most common reported mutation was a missense thymine (T) to adenine
(A) transversion at nucleotide 1796 (Ti 796A; amino acid change in
the B-Raf protein is Val<600> to Glu<600>) observed in
80% of malignant melanoma tumors. Functional analysis reveals that
this transversion is the only detected mutation that causes
constitutive activation of B-Raf kinase activity, independent of
RAS activation, by converting B-Raf into a dominant transforming
protein. Based on precedents, human tumors develop resistance to
kinase inhibitors by mutating a specific amino acid in the
catalytic domain as the "gatekeeper". (Balak, et. al., Clin Cancer
Res. 2006, 12:6494-501). Mutation of Thr-529 in BRAF to Ile is thus
anticipated as a mechanism of resistance to BRAF inhibitors, and
this can be envisioned as a transition in codon 529 from ACC to
ATC.
[0372] Niihori et al., report that in 43 individuals with
cardio-facio-cutaneous (CFC) syndrome, they identified two
heterozygous KRAS mutations in three individuals and eight BRAF
mutations in 16 individuals, suggesting that dysregulation of the
RAS-RAF-ERK pathway is a common molecular basis for the three
related disorders (Niihori et al., Nat. Genet. 2006,
38(3):294-6).
[0373] c-Raf-1: Target kinase c-Raf-1 (i.e., v-raf murine sarcoma
viral oncogene homolog 1) is a 73.0 kDa STK encoded by chromosome
3p25 (symbol: RAF1). c-Raf-1 can be targeted to to the mitochondria
by BCL2 (i.e., oncogene B-cell leukemia 2) which is a regulator of
apoptotic cell death. Active c-Raf-1 improves BCL2-mediated
resistance to apoptosis, and c-Raf-1 phosphorylates BAD (i.e.,
BCL2-binding protein). c-Raf-1 is implicated in carcinomas,
including colorectal, ovarian, lung and renal cell carcinoma.
C-Raf-1 is also implicated as an important mediator of tumor
angiogenesis (Hood, J. D. et al., 2002, Science 296, 2404). C-Raf-1
inhibitors may also be useful for the treatment of acute myeloid
leukemia and myelodysplastic syndromes (Crump, Curr Pharm Des 2002,
8(25):2243-8). Raf-1 activators may be useful as treatment for
neuroendocrine tumors, such as medullary thyroid cancer, carcinoid,
small cell lung cancer and pheochromocytoma (Kunnimalaiyaan et al.,
Anticancer Drugs 2006, 17(2):139-42).
[0374] Raf inhibitors (A-Raf and/or B-Raf and/or c-Raf-1) may be
useful in treating A-Raf-mediated, B-Raf-mediated or
c-Raf-1-mediated disease or condition selected from the group
consisting of neurologic diseases, including, but not limited to,
multi-infarct dementia, head injury, spinal cord injury,
Alzheimer's disease (AD), Parkinson's disease; neoplastic diseases
including, but not limited to, melanoma, glioma, sarcoma, carcinoma
(e.g. colorectal, lung, breast, pancreatic, thyroid, renal,
ovarian), lymphoma (e.g. histiocytic lymphoma) neurofibromatosis,
acute myeloid leukemia, myelodysplastic syndrome, leukemia, tumor
angiogenesis, neuroendocrine tumors such as medullary thyroid
cancer, carcinoid, small cell lung cancer and pheochromocytoma;
pain of neuropathic or inflammatory origin, including, but not
limited to, acute pain, chronic pain, cancer-related pain, and
migraine; cardiovascular diseases, including, but not limited to,
heart failure, ischemic stroke, cardiac hypertrophy, thrombosis
(e.g. thrombotic microangiopathy syndromes), atherosclerosis, and
reperfusion injury; inflammation including, but not limited to,
psoriasis, arthritis and autoimmune diseases and conditions,
osteoarthritis, endometriosis, scarring, vascular restenosis,
fibrotic disorders, rheumatoid arthritis, inflammatory bowel
disease (IBD); immunodeficiency diseases, including, but not
limited to, organ transplant rejection, graft versus host disease;
renal or prostatic diseases, including, but not limited to,
diabetic nephropathy, polycystic kidney disease, nephrosclerosis,
glomerulonephritis, prostate hyperplasia; metabolic disorders,
including, but not limited to, obesity; infection, including, but
not limited to, Helicobacter pylori, Hepatitis and Influenza
viruses, fever, and sepsis; pulmonary diseases, including, but not
limited to, chronic obstructive pulmonary disease (COPD) and acute
respiratory distress syndrome (ARDS); genetic developmental
diseases, including, but not limited to, Noonan's syndrome,
Costello syndrome, (faciocutaneoskeletal syndrome), LEOPARD
syndrome, cardio-faciocutaneous syndrome (CFC), and neural crest
syndrome abnormalities causing cardiovascular, skeletal,
intestinal, skin, hair and endocrine diseases.
Kinase Activity Assays
[0375] A number of different assays for kinase activity can be
utilized for assaying for active modulators and/or determining
specificity of a modulator for a particular kinase or group or
kinases. In addition to the assay mentioned in the Examples below,
one of ordinary skill in the art will know of other assays that can
be utilized and can modify an assay for a particular application.
For example, numerous papers concerning kinases describe assays
that can be used.
[0376] Additional alternative assays can employ binding
determinations. For example, this sort of assay can be formatted
either in a fluorescence resonance energy transfer (FRET) format,
or using an AlphaScreen (amplified luminescent proximity
homogeneous assay) format by varying the donor and acceptor
reagents that are attached to streptavidin or the phosphor-specific
antibody.
[0377] Organic Synthetic Techniques
[0378] A wide array of organic synthetic techniques exist in the
art to facilitate the construction of potential modulators. Many of
these organic synthetic methods are described in detail in standard
reference sources utilized by those skilled in the art. One example
of such a reference is March, 1994, Advanced Organic Chemistry;
Reactions, Mechanisms and Structures, New York, McGraw Hill. Thus,
the techniques useful to synthesize a potential modulator of kinase
function are readily available to those skilled in the art of
organic chemical synthesis.
Alternative Compound Forms or Derivatives
[0379] Compounds contemplated herein are described with reference
to both generic formulae and specific compounds. In addition,
invention compounds may exist in a number of different forms or
derivatives, all within the scope of the present invention.
Alternative forms or derivatives, include, for example, (a)
prodrugs, and active metabolites (b) tautomers, isomers (including
stereoisomers and regioisomers), and racemic mixtures (c)
pharmaceutically acceptable salts and formulations and (d) solid
forms, including different crystal forms, polymorphic or amorphous
solids, including hydrates and solvates thereof, and other
forms.
(a) Prodrugs and Metabolites
[0380] In addition to the present formulae and compounds described
herein, the invention also includes prodrugs (generally
pharmaceutically acceptable prodrugs), active metabolic derivatives
(active metabolites), and their pharmaceutically acceptable
salts.
[0381] Prodrugs are compounds or pharmaceutically acceptable salts
thereof which, when metabolized under physiological conditions or
when converted by solvolysis, yield the desired active compound.
Prodrugs include, without limitation, esters, amides, carbamates,
carbonates, ureides, solvates, or hydrates of the active compound.
Typically, the prodrug is inactive, or less active than the active
compound, but may provide one or more advantageous handling,
administration, and/or metabolic properties. For example, some
prodrugs are esters of the active compound; during metabolysis, the
ester group is cleaved to yield the active drug. Esters include,
for example, esters of a carboxylic acid group, or S-acyl or O-acyl
derivatives of thiol, alcohol, or phenol groups. In this context, a
common example is an alkyl ester of a carboxylic acid. Some
prodrugs are activated enzymatically to yield the active compound,
or a compound which, upon further chemical reaction, yields the
active compound. Prodrugs may proceed from prodrug form to active
form in a single step or may have one or more intermediate forms
which may themselves have activity or may be inactive.
[0382] As described in The Practice of Medicinal Chemistry, Ch.
31-32 (Ed. Wermuth, Academic Press, San Diego, Calif., 2001),
prodrugs can be conceptually divided into two non-exclusive
categories, bioprecursor prodrugs and carrier prodrugs. Generally,
bioprecursor prodrugs are compounds that are inactive or have low
activity compared to the corresponding active drug compound, that
contain one or more protective groups and are converted to an
active form by metabolism or solvolysis. Both the active drug form
and any released metabolic products should have acceptably low
toxicity. Typically, the formation of active drug compound involves
a metabolic process or reaction that is one of the follow
types:
[0383] Oxidative Reactions:
[0384] Oxidative reactions are exemplified without limitation to
reactions such as oxidation of alcohol, carbonyl, and acid
functionalities, hydroxylation of aliphatic carbons, hydroxylation
of alicyclic carbon atoms, oxidation of aromatic carbon atoms,
oxidation of carbon-carbon double bonds, oxidation of
nitrogen-containing functional groups, oxidation of silicon,
phosphorus, arsenic, and sulfur, oxidative N-dealkylation,
oxidative O- and S-dealkylation, oxidative deamination, as well as
other oxidative reactions.
[0385] Reductive Reactions:
[0386] Reductive reactions are exemplified without limitation to
reactions such as reduction of carbonyl functionalitites, reduction
of alcohol functionalities and carbon-carbon double bonds,
reduction of nitrogen-containing functional groups, and other
reduction reactions.
[0387] Reactions without Change in the Oxidation State:
[0388] Reactions without change in the state of oxidation are
exemplified without limitation to reactions such as hydrolysis of
esters and ethers, hydrolytic cleavage of carbon-nitrogen single
bonds, hydrolytic cleavage of non-aromatic heterocycles, hydration
and dehydration at multiple bonds, new atomic linkages resulting
from dehydration reactions, hydrolytic dehalogenation, removal of
hydrogen halide molecule, and other such reactions.
[0389] Carrier prodrugs are drug compounds that contain a transport
moiety, e.g., that improves uptake and/or localized delivery to a
site(s) of action. Desirably for such a carrier prodrug, the
linkage between the drug moiety and the transport moiety is a
covalent bond, the prodrug is inactive or less active than the drug
compound, the prodrug and any release transport moiety are
acceptably non-toxic. For prodrugs where the transport moiety is
intended to enhance uptake, typically the release of the transport
moiety should be rapid. In other cases, it is desirable to utilize
a moiety that provides slow release, e.g., certain polymers or
other moieties, such as cyclodextrins. (See, e.g., Cheng et al.,
U.S. Patent Publ. No. 20040077595, application Ser. No. 10/656,838,
incorporated herein by reference.) Such carrier prodrugs are often
advantageous for orally administered drugs. In some instances, the
transport moiety provides targeted delivery of the drug, for
example the drug maybe conjugated to an antibody or antibody
fragment. Carrier prodrugs can, for example, be used to improve one
or more of the following properties: increased lipophilicity,
increased duration of pharmacological effects, increased
site-specificity, decreased toxicity and adverse reactions, and/or
improvement in drug formulation (e.g., stability, water solubility,
suppression of an undesirable organoleptic or physiochemical
property). For example, lipophilicity can be increased by
esterification of hydroxyl groups with lipophilic carboxylic acids,
or of carboxylic acid groups with alcohols, e.g., aliphatic
alcohols. Wermuth, supra.
[0390] Metabolites, e.g., active metabolites, overlap with prodrugs
as described above, e.g., bioprecursor prodrugs. Thus, such
metabolites are pharmacologically active compounds or compounds
that further metabolize to pharmacologically active compounds that
are derivatives resulting from metabolic processes in the body of a
subject. Of these, active metabolites are such pharmacologically
active derivative compounds. For prodrugs, the prodrug compound is
generally inactive or of lower activity than the metabolic product.
For active metabolites, the parent compound may be either an active
compound or may be an inactive prodrug. For example, in some
compounds, one or more alkoxy groups can be metabolized to hydroxyl
groups while retaining pharmacologic activity and/or carboxyl
groups can be esterified, e.g., glucuronidation. In some cases,
there can be more than one metabolite, where an intermediate
metabolite(s) is further metabolized to provide an active
metabolite. For example, in some cases a derivative compound
resulting from metabolic glucuronidation may be inactive or of low
activity, and can be further metabolized to provide an active
metabolite.
[0391] Metabolites of a compound may be identified using routine
techniques known in the art, and their activities determined using
tests such as those described herein. See, e.g., Bertolini et al.,
1997, J. Med. Chem., 40:2011-2016; Shan et al., 1997, J Pharm Sci
86(7):756-757; Bagshawe, 1995, Drug Dev. Res., 34:220-230; Wermuth,
supra.
[0392] (b) Tautomers, Stereoisomers, and Regioisomers
[0393] It is understood that some compounds may exhibit
tautomerism. In such cases, the formulae provided herein expressly
depict only one of the possible tautomeric forms. It is therefore
to be understood that the formulae provided herein are intended to
represent any tautomeric form of the depicted compounds and are not
to be limited merely to the specific tautomeric form depicted by
the drawings of the formulae.
[0394] Likewise, some of the compounds according to the present
invention may exist as stereoisomers, i.e. having the same atomic
connectivity of covalently bonded atoms yet differing in the
spatial orientation of the atoms. For example, compounds may be
optical stereoisomers, which contain one or more chiral centers,
and therefore, may exist in two or more stereoisomeric forms (e.g.
enantiomers or diastereomers). Thus, such compounds may be present
as single stereoisomers (i.e., essentially free of other
stereoisomers), racemates, and/or mixtures of enantiomers and/or
diastereomers. As another example, stereoisomers include geometric
isomers, such as cis- or trans-orientation of substituents on
adjacent carbons of a double bond. All such single stereoisomers,
racemates and mixtures thereof are intended to be within the scope
of the present invention. Unless specified to the contrary, all
such steroisomeric forms are included within the formulae provided
herein.
[0395] In some embodiments, a chiral compound of the present
invention is in a form that contains at least 80% of a single
isomer (60% enantiomeric excess ("e.e.") or diastereomeric excess
("d.e.")), or at least 85% (70% e.e. or d.e.), 90% (80% e.e. or
d.e.), 95% (90% e.e. or d.e.), 97.5% (95% e.e. or d.e.), or 99%
(98% e.e. or d.e.). As generally understood by those skilled in the
art, an optically pure compound having one chiral center is one
that consists essentially of one of the two possible enantiomers
(i.e., is enantiomerically pure), and an optically pure compound
having more than one chiral center is one that is both
diastereomerically pure and enantiomerically pure. In some
embodiments, the compound is present in optically pure form, such
optically pure form being prepared and/or isolated by methods known
in the art (e.g. by recrystallization techniques, chiral synthetic
techniques (including synthesis from optically pure starting
materials), and chromatographic separation using a chiral
column.
[0396] (c) Pharmaceutically Acceptable Salts and Formulations
[0397] Unless specified to the contrary, specification of a
compound herein includes pharmaceutically acceptable salts of such
compound. Thus, compounds of Formula I can be in the form of
pharmaceutically acceptable salts, or can be formulated as
pharmaceutically acceptable salts. Contemplated pharmaceutically
acceptable salt forms include, without limitation, mono, bis, tris,
tetrakis, and so on. Pharmaceutically acceptable salts are
non-toxic in the amounts and concentrations at which they are
administered. The preparation of such salts can facilitate the
pharmacological use by altering the physical characteristics of a
compound without preventing it from exerting its physiological
effect. Useful alterations in physical properties include lowering
the melting point to facilitate transmucosal administration and
increasing the solubility to facilitate administering higher
concentrations of the drug. A compound of the invention may possess
a sufficiently acidic, a sufficiently basic, or both functional
groups, and accordingly react with any of a number of inorganic or
organic bases, and inorganic and organic acids, to form a
pharmaceutically acceptable salt.
[0398] Pharmaceutically acceptable salts include acid addition
salts such as those containing chloride, bromide, iodide,
hydrochloride, acetate, phenylacetate, acrylate, ascorbate,
aspartate, benzoate, 2-phenoxybenzoate, 2-acetoxybenzoate,
dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate,
bicarbonate, butyne-1,4 dioate, hexyne-1,6-dioate, caproate,
caprylate, chlorobenzoate, cinnamate, citrate, decanoate, formate,
fumarate, glycolate, gluconate, glucarate, glucuronate,
glucose-6-phosphate, glutamate, heptanoate, hexanoate, isethionate,
isobutyrate, gamma-hydroxybutyrate, phenylbutyrate, lactate,
malate, maleate, hydroxymaleate, methylmaleate, malonate,
mandelate, nicotinate, nitrate, isonicotinate, octanoate, oleate,
oxalate, pamoate, phosphate, monohydrogenphosphate,
dihydrogenphosphate, orthophosphate, metaphosphate, pyrophosphate,
2-phosphoglycerate, 3-phosphoglycerate, phthalate, propionate,
phenylpropionate, propiolate, pyruvate, quinate, salicylate,
4-aminosalicylate, sebacate, stearate, suberate, succinate,
sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, sulfamate,
sulfonate, benzenesulfonate (i.e. besylate), ethanesulfonate (i.e.
esylate), ethane-1,2-disulfonate, 2-hydroxyethanesulfonate (i.e.
isethionate), methanesulfonate (i.e. mesylate),
naphthalene-1-sulfonate, naphthalene-2-sulfonate (i.e. napsylate),
propanesulfonate, p-toluenesulfonate (i.e. tosylate),
xylenesulfonates, cyclohexylsulfamate, tartrate, and
trifluoroacetate. These pharmaceutically acceptable acid addition
salts can be prepared using the appropriate corresponding acid.
[0399] When acidic functional groups, such as carboxylic acid or
phenol are present, pharmaceutically acceptable salts also include
basic addition salts such as those containing benzathine,
chloroprocaine, choline, ethanolamine, diethanolamine,
triethanolamine, t-butylamine, dicyclohexylamine, ethylenediamine,
N,N'-dibenzylethylenediamine, meglumine, hydroxyethylpyrrolidine,
piperidine, morpholine, piperazine, procaine, aluminum, calcium,
copper, iron, lithium, magnesium, manganese, potassium, sodium,
zinc, ammonium, and mono-, di-, or tri-alkylamines, or salts
derived from amino acids such as L-histidine, L-glycine, L-lysine,
and L-arginine. For example, see Remington's Pharmaceutical
Sciences, 19.sup.th ed., Mack Publishing Co., Easton, Pa., Vol. 2,
p. 1457, 1995. These pharmaceutically acceptable base addition
salts can be prepared using the appropriate corresponding base.
[0400] Pharmaceutically acceptable salts can be prepared by
standard techniques. For example, the free-base form of a compound
can be dissolved in a suitable solvent, such as an aqueous or
aqueous-alcohol solution containing the appropriate acid and then
isolated by evaporating the solution. In another example, a salt
can be prepared by reacting the free base and acid in an organic
solvent. If the particular compound is an acid, the desired
pharmaceutically acceptable salt may be prepared by any suitable
method, for example, treatment of the free acid with an appropriate
inorganic or organic base.
[0401] The pharmaceutically acceptable salt of the different
compounds may be present as a complex. Examples of complexes
include 8-chlorotheophylline complex (analogous to, e.g.,
dimenhydrinate: diphenhydramine 8-chlorotheophylline (1:1) complex;
Dramamine) and various cyclodextrin inclusion complexes.
[0402] (d) Other Compound Forms
[0403] In the case of agents that are solids, it is understood by
those skilled in the art that the compounds and salts may exist in
different crystal or polymorphic forms, or may be formulated as
co-crystals, or may be in an amorphous form, or may be any
combination thereof (e.g. partially crystalline, partially
amorphous, or mixtures of polymorphs) all of which are intended to
be within the scope of the present invention and specified
formulae. Whereas salts are formed by acid/base addition, i.e. a
free base or free acid of the compound of interest forms an
acid/base reaction with a corresponding addition base or addition
acid, respectively, resulting in an ionic charge interaction,
co-crystals are a new chemical species that is formed between
neutral compounds, resulting in the compound and an additional
molecular species in the same crystal structure.
[0404] Additionally, the formulae are intended to cover hydrated or
solvated as well as unhydrated or unsolvated forms of the
identified structures. For example, the indicated structures
include both hydrated and non-hydrated forms. Other examples of
solvates include the structures in combination with a suitable
solvent, such as isopropanol, ethanol, methanol, dimethylsulfoxide,
ethyl acetate, acetic acid, or ethanolamine.
Administration
[0405] The methods and compounds will typically be used in therapy
for human subjects. However, they may also be used to treat similar
or identical indications in other animal subjects. Compounds of
Formula I can be administered by different routes, including
injection (i.e. parenteral, including intravenous, intraperitoneal,
subcutaneous, and intramuscular), oral, transdermal, transmucosal,
rectal, or inhalant. Such dosage forms should allow the compound to
reach target cells. Other factors are well known in the art, and
include considerations such as toxicity and dosage forms that
retard the compound or composition from exerting its effects.
Techniques and formulations generally may be found in Remington:
The Science and Practice of Pharmacy, 21.sup.st edition,
Lippincott, Williams and Wilkins, Philadelphia, Pa., 2005 (hereby
incorporated by reference herein).
[0406] In some embodiments, compositions will comprise carriers or
excipients, which may be chosen to facilitate administration of the
compound by a particular route. Examples of carriers include
calcium carbonate, calcium phosphate, various sugars such as
lactose, glucose, or sucrose, types of starch, cellulose
derivatives, gelatin, lipids, liposomes, nanoparticles, and the
like. Carriers also include physiologically compatible liquids as
solvents or for suspensions, including, for example, sterile
solutions of water for injection (WFI), saline solution, dextrose
solution, Hank's solution, Ringer's solution, vegetable oils,
mineral oils, animal oils, polyethylene glycols, liquid paraffin,
and the like.
[0407] In some embodiments, oral administration may be used.
Pharmaceutical preparations for oral use can be formulated into
conventional oral dosage forms such as capsules, tablets, and
liquid preparations such as syrups, elixirs, and concentrated
drops. Compounds of Formula I may be combined with solid
excipients, optionally grinding a resulting mixture, and processing
the mixture of granules, after adding suitable auxiliaries, if
desired, to obtain, for example, tablets, coated tablets, hard
capsules, soft capsules, solutions (e.g. aqueous, alcoholic, or
oily solutions) and the like. Suitable excipients are, in
particular, fillers such as sugars, including lactose, glucose,
sucrose, mannitol, or sorbitol; cellulose preparations, for
example, corn starch, wheat starch, rice starch, potato starch,
gelatin, gum tragacanth, methyl cellulose,
hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose (CMC),
and/or polyvinylpyrrolidone (PVP: povidone); oily excipients,
including vegetable and animal oils, such as sunflower oil, olive
oil, or codliver oil. The oral dosage formulations may also contain
disintegrating agents, such as the cross-linked
polyvinylpyrrolidone, agar, or alginic acid, or a salt thereof such
as sodium alginate; a lubricant, such as talc or magnesium
stearate; a plasticizer, such as glycerol or sorbitol; a sweetening
such as sucrose, fructose, lactose, or aspartame; a natural or
artificial flavoring agent, such as peppermint, oil of wintergreen,
or cherry flavoring; or dye-stuffs or pigments, which may be used
for identification or characterization of different doses or
combinations. Also provided are dragee cores with suitable
coatings. For this purpose, concentrated sugar solutions may be
used, which may optionally contain, for example, gum arabic, talc,
poly-vinylpyrrolidone, carbopol gel, polyethylene glycol, and/or
titanium dioxide, lacquer solutions, and suitable organic solvents
or solvent mixtures.
[0408] Pharmaceutical preparations that can be used orally include
push-fit capsules made of gelatin ("gelcaps"), as well as soft,
sealed capsules made of gelatin, and a plasticizer, such as
glycerol or sorbitol. The push-fit capsules can contain the active
ingredients in admixture with filler such as lactose, binders such
as starches, and/or lubricants such as talc or magnesium stearate
and, optionally, stabilizers. In soft capsules, the active
compounds may be dissolved or suspended in suitable liquids, such
as fatty oils, liquid paraffin, or liquid polyethylene glycols.
[0409] In some embodiments, injection (parenteral administration)
may be used, e.g., intramuscular, intravenous, intraperitoneal,
and/or subcutaneous. Compounds of Formula I for injection may be
formulated in sterile liquid solutions, preferably in
physiologically compatible buffers or solutions, such as saline
solution, Hank's solution, or Ringer's solution. Dispersions may
also be prepared in non-aqueous solutions, such as glycerol,
propylene glycol, ethanol, liquid polyethylene glycols, triacetin,
and vegetable oils. Solutions may also contain a preservative, such
as methylparaben, propylparaben, chlorobutanol, phenol, sorbic
acid, thimerosal, and the like. In addition, the compounds may be
formulated in solid form, including, for example, lyophilized
forms, and redissolved or suspended prior to use.
[0410] In some embodiments, transmucosal, topical or transdermal
administration may be used. In such formulations of compounds of
Formula I, penetrants appropriate to the barrier to be permeated
are used. Such penetrants are generally known in the art, and
include, for example, for transmucosal administration, bile salts
and fusidic acid derivatives. In addition, detergents may be used
to facilitate permeation. Transmucosal administration, for example,
may be through nasal sprays or suppositories (rectal or vaginal).
Compositions of compounds of Formula I for topical administration
may be formulated as oils, creams, lotions, ointments, and the like
by choice of appropriate carriers known in the art. Suitable
carriers include vegetable or mineral oils, white petrolatum (white
soft paraffin), branched chain fats or oils, animal fats and high
molecular weight alcohol (greater than C.sub.12). In some
embodiments, carriers are selected such that the active ingredient
is soluble. Emulsifiers, stabilizers, humectants and antioxidants
may also be included as well as agents imparting color or
fragrance, if desired. Creams for topical application are
preferably formulated from a mixture of mineral oil,
self-emulsifying beeswax and water in which mixture the active
ingredient, dissolved in a small amount of solvent (e.g., an oil),
is admixed. Additionally, administration by transdermal means may
comprise a transdermal patch or dressing such as a bandage
impregnated with an active ingredient and optionally one or more
carriers or diluents known in the art. To be administered in the
form of a transdermal delivery system, the dosage administration
will be continuous rather than intermittent throughout the dosage
regimen.
[0411] In some embodiments, compounds are administered as
inhalants. Compounds of Formula I may be formulated as dry powder
or a suitable solution, suspension, or aerosol. Powders and
solutions may be formulated with suitable additives known in the
art. For example, powders may include a suitable powder base such
as lactose or starch, and solutions may comprise propylene glycol,
sterile water, ethanol, sodium chloride and other additives, such
as acid, alkali and buffer salts. Such solutions or suspensions may
be administered by inhaling via spray, pump, atomizer, or
nebulizer, and the like. The compounds of Formula I may also be
used in combination with other inhaled therapies, for example
corticosteroids such as fluticasone proprionate, beclomethasone
dipropionate, triamcinolone acetonide, budesonide, and mometasone
furoate; beta agonists such as albuterol, salmeterol, and
formoterol; anticholinergic agents such as ipratroprium bromide or
tiotropium; vasodilators such as treprostinal and iloprost; enzymes
such as DNAase; therapeutic proteins; immunoglobulin antibodies; an
oligonucleotide, such as single or double stranded DNA or RNA,
siRNA; antibiotics such as tobramycin; muscarinic receptor
antagonists; leukotriene antagonists; cytokine antagonists;
protease inhibitors; cromolyn sodium; nedocril sodium; and sodium
cromoglycate.
[0412] The amounts of various compounds to be administered can be
determined by standard procedures taking into account factors such
as the compound activity (in vitro, e.g. the compound IC.sub.s5 vs.
target, or in vivo activity in animal efficacy models),
pharmacokinetic results in animal models (e.g. biological half-life
or bioavailability), the age, size, and weight of the subject, and
the disorder associated with the subject. The importance of these
and other factors are well known to those of ordinary skill in the
art. Generally, a dose will be in the range of about 0.01 to 50
mg/kg, also about 0.1 to 20 mg/kg of the subject being treated.
Multiple doses may be used.
[0413] The compounds of Formula I may also be used in combination
with other therapies for treating the same disease. Such
combination use includes administration of the compounds and one or
more other therapeutics at different times, or co-administration of
the compound and one or more other therapies. In some embodiments,
dosage may be modified for one or more of the compounds of the
invention or other therapeutics used in combination, e.g.,
reduction in the amount dosed relative to a compound or therapy
used alone, by methods well known to those of ordinary skill in the
art.
[0414] It is understood that use in combination includes use with
other therapies, drugs, medical procedures etc., where the other
therapy or procedure may be administered at different times (e.g.
within a short time, such as within hours (e.g. 1, 2, 3, 4-24
hours), or within a longer time (e.g. 1-2 days, 2-4 days, 4-7 days,
1-4 weeks)) than a compound of Formula I, or at the same time as a
compound of Formula I. Use in combination also includes use with a
therapy or medical procedure that is administered once or
infrequently, such as surgery, along with a compound of Formula I
administered within a short time or longer time before or after the
other therapy or procedure. In some embodiments, the present
invention provides for delivery of a compound of Formula I and one
or more other drug therapeutics delivered by a different route of
administration or by the same route of administration. The use in
combination for any route of administration includes delivery of a
compound of Formula I and one or more other drug therapeutics
delivered by the same route of administration together in any
formulation, including formulations where the two compounds are
chemically linked in such a way that they maintain their
therapeutic activity when administered. In one aspect, the other
drug therapy may be co-administered with a compound of Formula I.
Use in combination by co-administration includes administration of
co-formulations or formulations of chemically joined compounds, or
administration of two or more compounds in separate formulations
within a short time of each other (e.g. within an hour, 2 hours, 3
hours, up to 24 hours), administered by the same or different
routes. Co-administration of separate formulations includes
co-administration by delivery via one device, for example the same
inhalant device, the same syringe, etc., or administration from
separate devices within a short time of each other. Co-formulations
of a compound of Formula I and one or more additional drug
therapies delivered by the same route includes preparation of the
materials together such that they can be administered by one
device, including the separate compounds combined in one
formulation, or compounds that are modified such that they are
chemically joined, yet still maintain their biological activity.
Such chemically joined compounds may have a linkage that is
substantially maintained in vivo, or the linkage may break down in
vivo, separating the two active components.
EXAMPLES
[0415] Examples related to the present invention are described
below. In most cases, alternative techniques can be used. The
examples are intended to be illustrative and are not limiting or
restrictive to the scope of the invention. In some examples, the
mass spectrometry result indicated for a compound may have more
than one value due to the isotope distribution of an atom in the
molecule, such as a compound having a bromo or chloro
substituent.
[0416] Unless specifically indicated otherwise, the Formula
enumeration and R group enumeration used in the following examples
is not related to such enumeration in other sections of this
application. The reagents and solvents used in these examples can
be readily substituted with appropriate alternatives as are known
in the art and isolation of products is readily achieved by methods
known in the art, including, but not limited to, extraction,
crystallization, and chromatographic methods.
Example 1
Synthesis of compound of Formula Ib or Id wherein A is --C(O)--
[0417] Compounds of Formula Ib or Id, as defined in paragraphs
[0010] and [0016], respectively, wherein A is --C(O)--, can be
prepared in five steps as described in Scheme 1.
##STR00026##
Step 1--Synthesis of Compound 2
[0418] Compound 1 (R.sup.2 and R.sup.4 as defined in paragraph
[0004]) is dissolved in an anhydrous solvent (e.g. tetrahydrofuran)
under nitrogen atmosphere. The solution is cooled down with the aid
of a dry ice and acetone bath. To this solution is added a base
(e.g. n-butyllithium), followed by
1,2-bis(chlorodimethylsilyl)ethane at low temperature (typically
below -70.degree. C.). The resulting mixture is stirred at low
temperature for 1-2 hours. To this solution is added a base (e.g.
n-butyllithium), followed by ethyl chloroformate. The resulting
mixture is allowed to warm to room temperature and then stirred at
room temperature for 1-3 days. The reaction mixture is quenched by
an acid solution, stirred at room temperature for a couple of
hours, and then basified. The mixture is extracted with an organic
solvent (e.g. dichloromethane or ethyl acetate). The desired
compound 2 is purified by chromatography.
Step 2--Synthesis of Compound 3
[0419] To compound 2 in an organic solvent (e.g. dichloromethane)
is added pyridine, followed by an appropriate acylating agent,
isocyanate, or sulfonyl chloride such as
propane-1-sulfonylchloride. The reaction mixture is stirred at room
temperature for over 12 hours and the mixture is then poured into
water. The organic layer is separated and the aqueous layer is
extracted with an appropriate organic solvent (e.g.
dichloromethane). The desired compound 3 (L.sub.2 and R.sup.3 as
defined in paragraph [0005], or L.sub.2 is S(O).sub.2 for Formula
Ib) is purified by chromatography.
Step 3--Synthesis of Compound 4
[0420] To compound 3 in a solvent mixture (e.g. tetrahydrofuran and
water) is added a base (e.g. lithium hydroxide or sodium
hydroxide). The resulting suspension is stirred in a heated oil
bath for over 10 hours. The reaction mixture is cooled down to room
temperature and then acidified with an acid solution such as
concentrated hydrochloric acid. The aqueous layer is separated and
extracted with an appropriate organic solvent (e.g. ethyl acetate).
The desired compound 4 is purified by chromatography.
Step 4--Synthesis of Compound 5
[0421] To a suspension of compound 4 in an anhydrous solvent (e.g.
dichloromethane), cooled with an ice and water bath, oxalyl
chloride is added slowly, followed by dimethylformamide. The
reaction mixture is stirred at room temperature for a few hours.
After removal of the solvent and excess oxalyl chloride, the
residue is used in the next step without further purification.
Step 5--Synthesis of Compound of Formula Ib or Id
[0422] To an appropriate amine 6 (Ar, m, R.sup.1 and R.sup.11 as
defined in paragraph [0005]) in an anhydrous solvent (e.g.
tetrahydrofuran) is added a base (e.g. triethylamine). To this
mixture, cooled with an ice and salt bath, a solution of compound 5
in an anhydrous solvent (e.g. tetrahydrofuran) is added slowly. The
resulting mixture was stirred at room temperature for over 12
hours. The desired compound of Formula Ib (L.sub.2 is S(O).sub.2)
or Id is purified by chromatography.
Example 2
Synthesis of Compound of Formula Ic or Ie
[0423] Compounds of Formula Ic or Ie, as defined in paragraphs
[0015] and [0021], respectively, can be prepared in four steps as
described in Scheme 2.
##STR00027##
Step 1--Synthesis of Compound 8
[0424] Compound 7 (R.sup.2 as defined in paragraph [0005]) is
dissolved in an appropriate solvent (e.g. methanol). To this
solution is added catalyst (e.g. palladium on carbon). The
suspension is then placed under a hydrogen atmosphere and shaken at
room temperature for over 12 hours. The catalyst is removed by
filtration on a pad of celite and washed with an appropriate
solvent (e.g. methanol). The filtrate is concentrated under reduced
pressure to give compound 8, which is used in the next step without
further purification.
Step 2--Synthesis of Compound 9
[0425] To compound 8 in an organic solvent (e.g. dichloromethane)
is added a base (e.g. pyridine) followed by an appropriate
acylating agent, isocyanate, or sulfonyl chloride. The reaction
mixture is stirred at room temperature for over 12 hours. The
reaction mixture is then poured into water. The organic layer is
collected and the aqueous layer is extracted with an appropriate
organic solvent (e.g. dichloromethane). The organic solvents are
then combined. The desired compound 9 (L.sub.2 and R.sup.3 as
defined in paragraph [0005], or L.sub.2 is S(O).sub.2 for Formula
Ic) is purified by chromatography.
Step 3--Synthesis of Compound 10
[0426] To compound 9 in an organic solvent (e.g. tetrahydrofuran or
dichloromethane) is added a base (e.g. sodium hydride) at low
temperature, followed by an appropriate alkylating agent (e.g.
halide). The reaction mixture is stirred at room temperature or
heated in an oil bath as necessary, for a few hours. The reaction
mixture is then poured into water. The organic layer is collected
and the aqueous layer is extracted with an appropriate organic
solvent (e.g. ethyl acetate or dichloromethane). The organic
solvents are then combined. The desired compound 10 (R.sup.4 as
defined in paragraph [0005]) is purified by chromatography.
Step 4--Synthesis of Compound of Formula Ic or Ie
[0427] A mixture of compound 10, an appropriate boronic acid 11
(Ar, m and R.sup.1 as defined in paragraph [0004]), and a catalyst
(e.g. tetrakis(triphenylphosphine)palladium) in a mixture of base
(e.g. aqueous solution of potassium carbonate) and an appropriate
organic solvent (e.g. acetonitrile) is heated in an oil bath or is
irradiated in a microwave system at over 100.degree. C. for an
appropriate time depending on starting materials. The reaction
mixture is poured into water and then extracted with an appropriate
organic solvent (e.g. dichloromethane or ethyl acetate). The
organic solvents are then combined. The desired compound of Formula
Ic (L.sub.2 is S(O).sub.2) or Id is purified by chromatography.
Example 3
Synthesis of Compound of Formula I where L.sub.1 is
--CH.sub.2NR.sup.11--
[0428] Compounds of Formula I, as defined in paragraph [0005] where
L.sub.1 is --CH.sub.2NR.sup.11--, can be prepared in three steps as
described in Scheme 3--Method A, or one step as described in Scheme
3--Method B.
##STR00028##
Step 1--Synthesis of Compound 12
[0429] Compound 4 (prepared as described in Scheme 1, Step 3 in
Example 1) is dissolved in an appropriate solvent (e.g.
tetrahydrofuran). To this solution is added an appropriate reducing
agent (e.g. lithium tetrahydroaluminate) at low temperature
(typically below -30.degree. C.). The reaction mixture is then
stirred at room temperature for 2-24 hours. Sodium sulfate is added
and the mixture is stirred at room temperature for 30 minutes. The
mixture is filtered through a pad of celite and washed with an
appropriate solvent (e.g. ethyl acetate). The filtrate is
concentrated under reduced pressure to give compound 12, which is
used in the next step without further purification.
Step 2--Synthesis of Compound 13
[0430] Compound 13 (LG is a suitable leaving group) is prepared by
converting compound 12 into a mesylate or triflate by reacting with
the corresponding sulfonyl chloride in an appropriate organic
solvent. It can also be converted into the corresponding bromide by
reacting with an appropriate agent (e.g. phosphorous tribromide) in
the presence of an appropriate base (e.g. pyridine).
Step 3--Synthesis of Compound of Formula I where L.sub.1 is
--CH.sub.2NR.sup.11--
[0431] To a mixture of compound 13 and a base (e.g. cesium
carbonate) in an appropriate organic solvent (e.g. acetonitrile),
amine 6 is added. The reaction mixture is stirred at room
temperature, or heated in an oil bath if necessary, for 2-24 hours.
The reaction mixture is poured into water and then extracted with
an appropriate organic solvent (e.g. dichloromethane or ethyl
acetate). The organic solvents are then combined. The desired
compound of Formula I is purified by chromatography.
##STR00029##
Step 1--Preparation of Compound 63
[0432] To substituted phenylamine 1 (R.sup.2 and R.sup.4 as defined
in paragraph [0005]) in an appropriate solvent (e.g.
tetrahydrofuran) are added a base (e.g. triethylamine) and acid
halide (e.g. acid chloride or sulfonyl chloride) in an appropriate
organic solvent under an atmosphere of nitrogen. The reaction is
stirred at room temperature for 2-24 hours. The reaction mixture is
then poured into an acid solution and extracted with an appropriate
organic solvent (e.g. dichloromethane or ethyl acetate). The
organic layers are combined. The desired compound 63 (L.sub.2 and
R.sup.3 as defined in paragraph [0004]) is purified by
crystallization or chromatography.
Step 2--Preparation of Compound 64
[0433] Compound 63 in an appropriate solvent (e.g. tetrahydrofuran)
under an atmosphere of nitrogen is cooled in an acetone/dry ice
bath. To this solution is added a base (e.g. lithium
diisopropylamide) and then an appropriate reagent (e.g.
N,N-dimethyl-formamide). The reaction mixture is stirred for 0.5 to
3 hours at low temperature (<50.degree. C.) and then allowed to
warm to room temperature. The reaction mixture is poured into water
and extracted with an appropriate organic solvent (e.g.
dichloromethane or ethyl acetate). The desired compound 64 is
purified by chromatography.
Step 3--Synthesis of Compound of Formula I where L.sub.1 is
--CH.sub.2NR.sup.11--
[0434] To a mixture of compound 64 in an appropriate organic
solvent (e.g. acetonitrile) is added amine 6 (Ar, m, R.sup.1 and
R.sup.11 as defined in paragraph [0005]), and reducing agent (e.g.
triethylsilane and trifluoroacetic acid). The reaction mixture is
heated in an oil bath for 2-24 hours. The reaction mixture is
concentrated, poured into water and then extracted with an
appropriate organic solvent (e.g. dichloromethane or ethyl
acetate). The organic layers are then combined. The desired
compound of Formula I is purified by chromatography.
[0435] Alternatively, compounds of Formula I where L.sub.1 is
--CH.sub.2NR.sup.11-- may be prepared by reduction of compounds of
Formula Ib or Id wherein A is --C(O)-- (e.g. prepared as described
in Example 1) with an appropriate reducing agent (e.g. borane or
diisobutylaluminum hydride).
Example 4
Synthesis of
6-chloro-2-fluoro-N-[6-(5-methyl-thiazol-2-ylamino)-pyridin-3-yl]-3-(prop-
ane-1-sulfonylamino)-benzamide P-0011
[0436]
6-Chloro-2-fluoro-N-[6-(5-methyl-thiazol-2-ylamino)-pyridin-3-yl]-3-
-(propane-1-sulfonylamino)-benzamide P-0011 was synthesized in six
steps from 4-chloro-2-fluoroaniline 14 as shown in Scheme 4.
##STR00030## ##STR00031##
Step 1--Preparation 3-amino-6-chloro-2-fluorobenzoic acid ethyl
ester (15)
[0437] 4-Chloro-2-fluoroaniline (14, 12 mL) was dissolved in 200 mL
of anhydrous tetrahydrofuran under a nitrogen atmosphere in a 1 L
3-neck round bottom flask. The mixture was cooled to -78.degree. C.
(dry ice/acetone bath) and n-butyllithium (2.5 M, 45 mL) was slowly
added dropwise, maintaining the temperature below -70.degree. C.
The mixture was stirred at -70.degree. C. for 30 minutes.
1,2-Bis(chlorodimethylsilyl)ethane (24.80 g) was dissolved in 80 mL
of anhydrous tetrahydrofuran and slowly added dropwise to the
reaction mixture while maintaining the temperature below
-70.degree. C. The resulting mixture was stirred at -78.degree. C.
for 1 hour, then n-butyllithium (2.5 M, 45 mL) was slowly added
dropwise maintaining the temperature below -70.degree. C. The
mixture was then stirred for 30 minutes at -78.degree. C., then
warmed up to 15.degree. C. over 1 hour. The reaction mixture was
cooled down to -78.degree. C. and n-butyllithium (2.5 M, 50 mL) was
slowly added dropwise maintaining the temperature below -70.degree.
C. The mixture was stirred at -70.degree. C. for 90 minutes, then
13.40 mL of ethylchloroformate was slowly added dropwise
maintaining the temperature below -70.degree. C. The reaction
mixture was slowly warmed to room temperature and stirred at room
temperature for 64 hours. The reaction was quenched by careful
addition of a solution of 50 mL of concentrated hydrochloric acid
in 160 mL of water while cooling with an ice/water bath. The
mixture was stirred at room temperature for 2 hours, then made
basic by addition of potassium carbonate. The mixture was extracted
with 3.times.100 mL of ethyl acetate and the combined organic
extracts were washed with 50 mL of brine and dried with magnesium
sulfate. After removal of the solvent, the residue was purified
with silica gel column chromatography eluting with ethyl acetate in
hexane to provide the desired compound (15, 17 g, 72%).
Step 2--Preparation
6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid ethyl
ester (17)
[0438] 3-Amino-6-chloro-2-fluorobenzoic acid ethyl ester (15, 17 g)
was dissolved in 785 mL of dichloromethane, to which 13.2 mL of
pyridine was added, followed by propane-1-sulfonylchloride (16,
12.8 g). The reaction mixture was stirred at room temperature for
18 hours, then poured into 400 mL of water. The organic layer was
separated and the aqueous layer was extracted with 200 mL of
dicholormethane. The combined organic extracts were dried over
magnesium sulfate to give an orange oil (41 g). Trituration in 150
mL of diethylether removed the pyridine salt as a white solid. The
ether filtrate was concentrated to give orange oil, which was
purified with silica gel column chromatography eluting with ethyl
acetate in hexane to provide the desired compound as a pale yellow
solid (17, 20 g, 57%).
Step 3--Preparation
6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid (18)
[0439] 6-Chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid
ethyl ester (17, 20 g) was dissolved in a mixture of 500 mL
tetrahydrofuran and 150 mL water. Lithium hydroxide (12.95 g) was
added and the resulting suspension was stirred at 90.degree. C. for
17 hours. The mixture was cooled down to room temperature, then
brought to pH=1 with concentrated hydrochloric acid (.about.36 mL).
The aqueous layer was separated and extracted with 3.times.400 mL
of ethyl acetate. The combined organic extracts were dried over
magnesium sulfate and concentrated to give a beige solid (25 g).
The solid was triturated in 100 mL of diethyl ether for 30 minutes,
filtered, washed with 50 mL of diethyl ether and dried to provide
the desired compound as a white solid (18, 16 g, 87%).
Step 4--Preparation
6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoyl chloride
(19)
[0440] 6-Chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid
18 was suspended in anhydrous dichloromethane (30 mL/g).
Dimethylformamide (2 drops) was added and the suspension cooled in
an ice/water bath. Oxalyl chloride (5 eq) was slowly added
dropwise. The bath was then removed and the reaction mixture
stirred at room temperature for 2 to 3 hours and the solids slowly
disappeared. Dichloromethane and excess oxalyl chloride were
removed under reduced pressure and the residue was used without
further purification in the next step.
Step 5--Preparation of
N-(6-bromo-pyridin-3-yl)-6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-be-
nzamide (21)
[0441] 6-Bromo-pyridin-3-ylamine (20, 3.16 g, 18.26 mmol) was
dissolved in 55 mL of anhydrous tetrahydrofuran. Triethylamine
(1.85 g, 2.55 mL, 18.26 mmol) was added and the mixture cooled in
an ice/salt bath. A solution of
6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoyl chloride (19,
3.8 g, 12.17 mmol) in 55 mL of anhydrous tetrahydrofuran was slowly
added dropwise to the reaction mixture. The resulting mixture was
stirred at room temperature for 18 hours, then diluted with 180 mL
of ethyl acetate, washed 2.times.70 mL with water and once with 110
mL brine, dried over magnesium sulfate and concentrated to give a
brown residue. The residue was purified by silica gel flash
chromatography, eluting with 1% methanol, to provide the desired
compound as a yellow solid (21, 6.9 g, 66%).
Step 6--Preparation
6-chloro-2-fluoro-N-[6-(5-methyl-thiazol-2-ylamino)-pyridin-3-yl]-3-(prop-
ane-1-sulfonylamino)-benzamide (P-0011)
[0442]
N-(6-bromo-pyridin-3-yl)-6-chloro-2-fluoro-3-(propane-1-sulfonylami-
no)-benzamide (21, 250 mg, 0.555 mmol) was placed in a microwave
vial along with palladium acetate (12.5 mg, 0.055 mmol), BINAP (69
mg, 0.111 mmol), potassium tert-butoxide (124 mg, 1.11 mmol) and
2-amino-5-methyl-thiazole (22, 190 mg, 1.66 mmol).
Dimethylformamide (2.5 mL) was added and the vial sealed. The
mixture was then heated at 150.degree. C. in a microwave for 3
hours. The black mixture was diluted with 50 mL of ethyl acetate
and washed with 15 mL of water, then 15 mL of 0.67 M hydrochloric
acid solution, 15 mL of water and finally 15 mL of brine. The
organic phase was dried over magnesium sulfate. After removal of
the solvent, the residue was purified by preparative TLC and then
HPLC to provide the desired compound as a white solid (P-0011, 10
mg). MS (ESI) [M+H.sup.+].sup.+=483.8.
Example 5
Synthesis of
6-chloro-2-fluoro-N-(6-isopropylamino-pyridin-3-yl)-3-(propane-1-sulfonyl-
amino)-benzamide P-0005
[0443]
6-Chloro-2-fluoro-N-(6-isopropylamino-pyridin-3-yl)-3-(propane-1-su-
lfonylamino)-benzamide P-0005 was synthesized in three steps from
2-bromo-5-nitro-pyridine 23 as shown in Scheme 5.
##STR00032##
Step 1--Preparation of 6-isopropylamino-3-nitro pyridine (25)
[0444] 2-Bromo-5-nitro-pyridine (23, 400 mg) was placed in a
microwave vial. Isopropylamine (24, 3 mL) was added and the vial
sealed. The mixture was then heated at 120.degree. C. for 30
minutes using a Biotage Initiator EXP microwave. The crude mixture
was then absorbed on a column and purified by silica gel
chromatography. The fractions containing the desired compound were
combined and concentrated to provide the desired compound as a
yellow solid.
Step 2--Preparation of N*2*-isopropyl-pyridine-2,5-diamine (26)
[0445] The 6-isopropylamino-3-nitro pyridine 25 was dissolved in
methanol (35 mL/g). Palladium on carbon catalyst (10%, wet,
.about.100 mg) was added and the suspension was placed under a
hydrogen atmosphere at room temperature overnight (.about.18
hours). The catalyst was removed by filtration on a pad of celite
and washed with 2.times.10 mL of methanol. The filtrate was
concentrated under reduced pressure to provide the desired
compound, which was used without further purification in the next
step.
Step 3--Preparation of
6-chloro-2-fluoro-N-(6-isopropylamino-pyridin-3-yl)-3-(propane-1-sulfonyl-
amino)-benzamide (P-0005)
[0446] N*2*-isopropyl-pyridine-2,5-diamine (26, 155 mg, 1.01 mmol)
was dissolved in 4 mL of anhydrous tetrahydrofuran. Triethylamine
(103 mg, 142 .mu.L, 1.01 mmol) was added and the mixture cooled in
an ice/salt bath.
6-Chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoyl chloride (19,
200 mg, 0.68 mmol) in 4 mL of anhydrous tetrahydrofuran was then
slowly added dropwise. The resulting mixture was stirred at room
temperature for 20 hours, then diluted with 30 mL of ethyl acetate,
washed with 3.times.10 mL of water and 15 mL of brine. After
removal of the solvent, the residue was purified by silica gel
chromatography to provide the desired compound as a white solid
(P-0005, 35 mg). MS (ESI) [M+H.sup.+].sup.+=429.0.
[0447]
6-Chloro-N-(6-cyclopentylamino-pyridin-3-yl)-2-fluoro-3-(propane-1--
sulfonylamino)-benzamide P-0009,
6-Chloro-N-(6-cyclopropylamino-pyridin-3-yl)-2-fluoro-3-(propane-1-sulfon-
ylamino)-benzamide P-0015,
6-Chloro-2-fluoro-3-(propane-1-sulfonylamino)-N-{6-[(thiophen-2-ylmethyl)-
-amino]-pyridin-3-yl}-benzamide P-0016, and
N-(6-Benzylamino-pyridin-3-yl)-6-chloro-2-fluoro-3-(propane-1-sulfonylami-
no)-benzamide P-0017,
##STR00033##
were prepared following the protocol of Scheme 5, replacing
isopropylamine 24 with cyclopentylamine, cyclopropylamine,
thiophen-2-yl-methylamine and benzylamine, respectively, in Step 1.
MS (ESI) [M+H.sup.+].sup.+ P-0009=455.2, P-0015=427.0, P-0016=483.2
and P-0017=477.2.
Example 6
Synthesis of
N-(2-acetylamino-pyrimidin-5-yl)-6-chloro-2-fluoro-3-(propane-1-sulfonyla-
mino)-benzamide P-0004
[0448]
N-(2-Acetylamino-pyrimidin-5-yl)-6-chloro-2-fluoro-3-(propane-1-sul-
fonylamino)-benzamide P-0004 was synthesized in three steps from
2-amino-5-nitropyrimidine 27 as shown in Scheme 6.
##STR00034##
Step 1--Preparation of N-(5-nitro-pyrimidin-2-yl)-acetamide
(28)
[0449] 2-Amino-5-nitropyrimidine (27, 500 mg) was suspended in 5 mL
of acetic anhydride. The mixture was heated at 160.degree. C. for
two hours, then cooled to room temperature. The solids were
filtered and washed with 5 mL of water, then suspended in 10 mL of
water and the pH was brought to 8-9 by addition of 25% ammonium
hydroxide solution. The solids were filtered, washed with
2.times.10 mL cold water and recrystallized from ethyl acetate to
provide the desired compound as beige needles (28, 382 mg,
58%).
Step 2--Preparation of N-(5-amino-pyrimidin-2-yl)-acetamide
(29)
[0450] N-(5-Nitro-pyrimidin-2-yl)-acetamide (28, 620 mg) was
suspended in 31 mL of methanol. Palladium on carbon catalyst (10%,
wet, 60 mg) was added and the suspension was placed under hydrogen
atmosphere for 17 hours. The catalyst was filtered off on a pad of
celite and washed with 2.times.30 mL of methanol. The filtrate was
concentrated under reduced pressure to provide the desired compound
as pale yellow needles (29, 520 mg, 100%).
Step 3--Preparation of
N-(2-acetylamino-pyrimidin-5-yl)-6-chloro-2-fluoro-3-(propane-1-sulfonyla-
mino)-benzamide P-0004
[0451] N-(5-amino-pyrimidin-2-yl)-acetamide (29, 154 mg, 1.01 mmol)
was dissolved in 3 mL of anhydrous tetrahydrofuran. Triethylamine
(103 mg, 142 .mu.L, 1.01 mmol) was added and the mixture cooled in
an ice/salt bath.
6-Chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoyl chloride (19,
200 mg, 0.68 mmol) in 3 mL of anhydrous tetrahydrofuran was then
slowly added dropwise. The resulting mixture was stirred at room
temperature for 18 hours, then diluted with 20 mL of ethyl acetate,
washed with 2.times.10 mL of water and 10 mL of brine. The organic
layer was dried over magnesium sulfate. After removal of the
solvent, the residue was purified by silica gel chromatography to
provide the desired compound as a white solid (P-0004, 55 mg, 19%).
MS (ESI) [M+H.sup.+].sup.+=430.2.
Example 7
Synthesis of
N-(6-acetylamino-pyridin-3-yl)-2,6-difluoro-3-(propane-1-sulfonylamino)-b-
enzamide P-0008
[0452]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(propane-1-sulfonylam-
ino)-benzamide P-0008 was synthesized in three steps from
2,6-difluoro-3-nitro-benzoic acid 30 and
N-(5-amino-pyridin-2-yl)-acetamide 31 as shown in Scheme 7.
##STR00035##
Step 1--Preparation of
N-(6-acetylamino-pyridin-3-yl)-2,6-difluoro-3-nitro-benzamide
(32)
[0453] 2,6-difluoro-3-nitro-benzoic acid (30, 500 mg) was dissolved
in 15 mL of anhydrous dichloromethane. N,N-Dimethylformamide (1
drop) was then added and the mixture cooled to 5.degree. C. in an
ice/water bath. Oxalyl chloride (1.1 mL, 5 eq) was slowly added
dropwise. The reaction mixture was stirred at room temperature for
two hours, then concentrated under reduced pressure to give a
yellow solid residue, which was dissolved in 5 mL of anhydrous
tetrahydrofuran and slowly added dropwise to a solution of
N-(5-amino-pyridin-2-yl)-acetamide (31, 558 mg, 1.5 eq) and
triethylamine (0.52 mL) in 10 mL of anhydrous tetrahydrofuran. The
resulting suspension was stirred at room temperature overnight. The
mixture was diluted with 50 mL of ethyl acetate, washed with
2.times.25 mL of water, then 25 mL brine, dried over magnesium
sulfate and concentrated to provide the crude desired compound as a
brown solid (32, 980 mg, 84%), which was used in the next step
without further purification.
Step 2-Preparation of
N-(6-acetylamino-pyridin-3-yl)-3-amino-2,6-difluoro-benzamide
(33)
[0454]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-nitro-benzamide (32,
950 mg) was suspended in 15 mL of methanol. Palladium on carbon
catalyst (10%, wet, 100 mg) was added and the suspension was placed
under hydrogen atmosphere for 17 hours. The catalyst was filtered
off on a pad of celite and washed with 2.times.20 mL of methanol.
The filtrate was concentrated under reduced pressure to provide the
desired compound as a black solid (33, 750 mg, 86%).
Step 3--Preparation of
N-(6-acetylamino-pyridin-3-yl)-2,6-difluoro-3-(propane-1-sulfonylamino)-b-
enzamide (P-0008)
[0455]
N-(6-Acetylamino-pyridin-3-yl)-3-amino-2,6-difluoro-benzamide (33,
700 mg) was dissolved in 35 mL of pyridine.
4-dimethyl-amino-pyridine (1 eq) was added followed by
propane-1-sulfonyl chloride (16, 0.80 g, 2.3 eq). The resulting
mixture was stirred at room temperature for 3 days, then at
70.degree. C. for 18 hours. The pyridine was removed under reduced
pressure and the residue purified by silica gel column
chromatography eluting with ethyl acetate in hexanes to provide the
desired compound as a yellow solid (P-0008, 10 mg, 1%). MS (ESI)
[M+H.sup.+].sup.+=412.9.
[0456] Additional compounds may be prepared following the protocol
of Scheme 7, replacing propane-1-sulfonyl chloride 16 with a
suitable sulfonyl chloride in Step 3. The following compounds may
be prepared by this method: [0457]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(2-fluoro-benzenesulfonylam-
ino)-benzamide (P-0097), [0458]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(3-fluoro-benzenesulfonylam-
ino)-benzamide (P-0098), [0459]
N-(6-Acetylamino-pyridin-3-yl)-3-(2,6-difluoro-benzenesulfonylamino)-2,6--
difluoro-benzamide (P-0099), [0460]
N-(6-Acetylamino-pyridin-3-yl)-3-(2,4-difluoro-benzenesulfonylamino)-2,6--
difluoro-benzamide (P-0100), [0461]
N-(6-Acetylamino-pyridin-3-yl)-3-(2,5-difluoro-benzenesulfonylamino)-2,6--
difluoro-benzamide (P-0101), [0462]
6-Acetylamino-N-[2,6-difluoro-3-(3-fluoro-4-methoxy-benzenesulfonylamino)-
-phenyl]-nicotinamide (P-0102), [0463]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(4-trifluoromethyl-benzenes-
ulfonylamino)-benzamide (P-0103), [0464]
N-(6-Acetylamino-pyridin-3-yl)-3-(4-difluoromethoxy-benzenesulfonylamino)-
-2,6-difluoro-benzamide (P-0104), [0465]
N-(6-Acetylamino-pyridin-3-yl)-3-(3-difluoromethoxy-benzenesulfonylamino)-
-2,6-difluoro-benzamide (P-0105), [0466]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(4-isopropyl-benzenesulfony-
lamino)-benzamide (P-0106), [0467]
N-(6-Acetylamino-pyridin-3-yl)-3-(4-tert-butyl-benzenesulfonylamino)-2,6--
difluoro-benzamide (P-0107), [0468]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(4-propyl-benzenesulfonylam-
ino)-benzamide (P-0108), [0469]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(pyridine-2-sulfonylamino)--
benzamide (P-0109), [0470]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(pyridine-3-sulfonylamino)--
benzamide (P-0110), [0471]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(dimethylaminosulfonylamino-
)-benzamide (P-0111), [0472]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(piperidine-1-sulfonylamino-
)-benzamide (P-0112), [0473]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(morpholine-4-sulfonylamino-
)-benzamide (P-0113), [0474]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(tetrahydro-pyran-4-sulfony-
lamino)-benzamide (P-0114), [0475]
N-(6-Acetylamino-pyridin-3-yl)-3-cyclopentanesulfonylamino-2,6-difluoro-b-
enzamide (P-0115), [0476]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(pyrrolidine-1-sulfonylamin-
o)-benzamide (P-0116), and [0477]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(3,3,3-trifluoro-propane-1--
sulfonylamino)-benzamide (P-0117). The following table indicates
the compound number in Column 1, the sulfonyl chloride used in Step
3 in Column 2, and the resulting compound in Column 3:
TABLE-US-00001 [0477] Compound Sulfonyl Chloride in number Step 3
Compound P-0097 ##STR00036## ##STR00037## P-0098 ##STR00038##
##STR00039## P-0099 ##STR00040## ##STR00041## P-0100 ##STR00042##
##STR00043## P-0101 ##STR00044## ##STR00045## P-0102 ##STR00046##
##STR00047## P-0103 ##STR00048## ##STR00049## P-0104 ##STR00050##
##STR00051## P-0105 ##STR00052## ##STR00053## P-0106 ##STR00054##
##STR00055## P-0107 ##STR00056## ##STR00057## P-0108 ##STR00058##
##STR00059## P-0109 ##STR00060## ##STR00061## P-0110 ##STR00062##
##STR00063## P-0111 ##STR00064## ##STR00065## P-0112 ##STR00066##
##STR00067## P-0113 ##STR00068## ##STR00069## P-0114 ##STR00070##
##STR00071## P-0115 ##STR00072## ##STR00073## P-0116 ##STR00074##
##STR00075## P-0117 ##STR00076## ##STR00077##
Example 8
Synthesis of pyrrolidine-1-carboxylic acid
{5-[6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoylamino]-pyridin-2-
-yl}-amide P-0006
[0478] Pyrrolidine-1-carboxylic acid
{5-[6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoylamino]-pyridin-2-
-yl}-amide P-0006 was synthesized in four steps from
2-amino-5-nitro-pyridine 34 as shown in Scheme 8.
##STR00078##
Step 1--Preparation (5-nitro-pyridin-2-yl)-carbamic acid
isopropenyl ester (35)
[0479] 2-Amino-5-nitro-pyridine (34, 500 mg) was dissolved in 5 mL
of anhydrous tetrahydrofuran. N-Methyl morpholine (436 mg, 1.2 eq)
was added and the mixture cooled to -10.degree. C. in an ice/salt
acetone bath. A solution of isopropenyl chloroformate (520 mg) in 5
mL of tetrahydrofuran was then slowly added dropwise while
maintaining the temperature below -10.degree. C. The reaction
mixture was stirred at room temperature overnight, then diluted
with 25 mL of ethyl acetate and 20 mL of water. The aqueous layer
was separated and extracted with 2.times.25 mL of ethyl acetate.
The combined organic extracts were washed with 25 mL of half
saturated brine and dried over magnesium sulfate. After removal of
the solvent, the residue was purified with silica gel column
chromatography eluting with ethyl acetate in hexane to provide the
desired compound as a white solid (35, 0.52 g, 65%).
Step 2--Preparation of pyrrolidine-1-carboxylic acid
(5-nitro-pyridin-2-yl)-amide (37)
[0480] (5-Nitro-pyridin-2-yl)-carbamic acid isopropenyl ester (35,
160 mg) was dissolved in 2 mL of anhydrous tetrahydrofuran.
N-Methylpyrrolidine (6 mg, 0.1 eq) was added, followed by
pyrrolidine (36, 51 mg, 1 eq). The mixture was stirred at room
temperature overnight, forming a precipitate. The precipitate was
filtered off, washed with 1 mL of tetrahydrofuran and dried to give
a white solid. Additional compound was obtained by concentration of
the filtrate under reduced pressure and trituration of the residue
in diethyl ether (-5 mL) to provide the desired compound as a beige
solid (37, 0.12 g, 71%).
Step 3--Preparation of pyrrolidine-1-carboxylic acid
(5-amino-pyridin-2-yl)-amide (38)
[0481] Pyrrolidine-1-carboxylic acid (5-nitro-pyridin-2-yl)-amide
(37, 115 mg) was dissolved in 10 mL of methanol. Palladium on
carbon catalyst was added and the suspension placed under a
hydrogen atmosphere for 64 hours. The catalyst was filtered over a
pad of celite and washed with 2.times.10 mL of methanol. The
filtrate was concentrated under reduced pressure to provide the
desired compound as a grey solid (38, 0.1 g, 100%).
Step 4--Preparation of pyrrolidine-1-carboxylic acid
{5-[6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoylamino]-pyridin-2-
-yl}-amide (P-0006)
[0482] Pyrrolidine-1-carboxylic acid (5-amino-pyridin-2-yl)-amide
(38, 100 mg, 0.48 mmol) was dissolved in 2 mL of anhydrous
tetrahydrofuran. Triethylamine (49 mg, 67 .mu.L, 0.48 mmol) was
added and the mixture cooled in an ice/salt bath.
6-Chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoyl chloride (19,
100 mg, 0.34 mmol) in 1 mL of anhydrous tetrahydrofuran was then
slowly added dropwise. The resulting mixture was stirred at room
temperature for 60 hours, then diluted with 20 mL of ethyl acetate,
washed with 2.times.10 mL of water and 10 mL of brine. The organic
layer was dried over magnesium sulfate. After removal of solvent,
the residue was purified by silica gel column chromatography
eluting with ethyl acetate in hexanes to provide the desired
compound as a white solid (P-0006, 5 mg, 3%). MS (ESI)
[M+H.sup.+].sup.+=484.0.
Example 9
Synthesis of
6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-N-quinolin-3-yl-benzamide
P-0013
[0483]
6-Chloro-2-fluoro-3-(propane-1-sulfonylamino)-N-quinolin-3-yl-benza-
mide P-0013 was synthesized in one step from 3-aminoquinoline 39 as
shown in Scheme 9.
##STR00079##
Step 1--Preparation of
6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-N-quinolin-3-yl-benzamide
(P-0013)
[0484] 3-Aminoquinoline (39, 172 mg, 1.19 mmol) was dissolved in 5
mL of anhydrous tetrahydrofuran. Triethylamine (120 mg, 170 L, 1.19
mmol) was added and the mixture cooled in an ice/salt bath.
6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoyl chloride (19,
250 mg, 0.80 mmol) in 5 mL of anhydrous tetrahydrofuran was slowly
added dropwise. The resulting mixture was stirred at room
temperature for 20 hours, then diluted with 30 mL of ethyl acetate,
washed with 3.times.10 mL of water and 15 mL of brine. The organic
layer was dried over magnesium sulfate and concentrated to give a
pale yellow residue (400 mg), which was further triturated in ethyl
acetate to provide the desired compound as a white solid (P-0013,
110 mg, 32%). MS (ESI) [M+H.sup.+].sup.+=421.9.
[0485]
N-(6-Acetylamino-pyridin-3-yl)-6-chloro-2-fluoro-3-(propane-1-sulfo-
nylamino)-benzamide P-0002,
6-Chloro-2-fluoro-N-(6-methoxy-pyridin-3-yl)-3-(propane-1-sulfonylamino)--
benzamide P-0003,
6-Chloro-N-(3,5-dimethyl-isoxazol-4-yl)-2-fluoro-3-(propane-1-sulfonylami-
no)-benzamide P-0007,
6-chloro-N-[5-(4-chloro-phenyl)-2H-pyrazol-3-yl]-2-fluoro-3-(propane-1-su-
lfonylamino)-benzamide P-0010,
6-chloro-N-[5-(4-chloro-benzyl)-[1,3,4]thiadiazol-2-yl]-2-fluoro-3-(propa-
ne-1-sulfonylamino)-benzamide P-0012,
[2-[6-Chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoylamino]-4H-[1,3,4-
]thiadiazin-(5E)-ylidene]-acetic acid ethyl ester P-0014, and
6-Chloro-2-fluoro-N-imidazo[1,2-a]pyridin-3-yl-3-(propane-1-sulfonylamino-
)-benzamide P-0018,
##STR00080## ##STR00081##
were prepared following the protocol of Scheme 9, replacing
3-aminoquinoline 39 with N-(5-amino-pyridin-2-yl)-acetamide;
6-methoxy-pyridin-3-ylamine; 3,5-dimethyl-isoxazol-4-ylamine;
[0486] 5-(4-chloro-phenyl)-2H-pyrazol-3-ylamine;
5-(4-chloro-benzyl)-[1,3,4]thiadiazol-2-ylamine;
[2-amino-4H-[1,3,4]thiadiazin-(5E)-ylidene]-acetic acid ethyl
ester; and imidazo[1,2-a]pyridin-3-ylamine, respectively. MS (ESI)
[M+H.sup.+].sup.+ P-0002=429.2, P-0003=402.2, P-0007=389.9,
P-0010=471.2, P-0012=503.0, P-0014=478.9 and P-0018=411.0.
Example 10
Synthesis of
6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-N-pyridin-3-yl-benzamide
P-0001
[0487]
6-Chloro-2-fluoro-3-(propane-1-sulfonylamino)-N-pyridin-3-yl-benzam-
ide P-0001 was synthesized in two steps from
6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid 18 as
shown in Scheme 10.
##STR00082##
Step 1--Preparation of
6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoyl chloride
(19)
[0488] To 6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoic
acid (18, 502 mg, 1.70 mmol, prepared as in Step 3 of Scheme 4,
Example 4) in 35 mL of dichloromethane, oxalyl chloride (5 mL, 2.0
M in dichloromethane) and N,N-dimethylformamide (100 L, 0.001 mol)
were added. The reaction mixture was stirred at room temperature
for 2 hours. The reaction was concentrated to give compound 19,
used without further purification.
Step 2--Preparation of
6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-N-pyridin-3-yl-benzamide
(P-0001)
[0489] To 6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoyl
chloride (19, 0.200 g, 0.64 mmol) in 10.0 mL of dichloromethane,
pyridin-3-ylamine (40, 0.126 g, 1.34 mmol) and
4-dimethylaminopyridine (7.8 mg, 0.064 mmol) were added. The
reaction was stirred at room temperature overnight. The reaction
mixture was poured into water and extracted with ethyl acetate. The
organic layer was washed with brine, dried over anhydrous sodium
sulfate and filtered. The filtrate was concentrated and purified
with silica gel column chromatography eluting 5% methanol in
dichloromethane to provide the desired compound (P-0001, 0.15 g,
63%). MS (ESI) [M+H.sup.+].sup.+=371.1.
Example 11
Synthesis of propane-1-sulfonic acid
{2,4-difluoro-3-[(5-methyl-isoxazol-3-ylamino)-methyl]-phenyl}-amide
P-0019
[0490] Propane-1-sulfonic acid
{2,4-difluoro-3-[(5-methyl-isoxazol-3-ylamino)-methyl]-phenyl}-amide
P-0019 was synthesized in three steps from 2,4-difluoro-phenylamine
41 as shown in Scheme 11.
##STR00083##
Step 1--Preparation of propane-1-sulfonic acid
(2,4-difluoro-phenyl)-amide (42)
[0491] To 2,4-difluoro-phenylamine (41, 3.0 mL, 29.8 mmol) in 50 mL
of tetrahydrofuran, triethylamine (9.13 mL, 65.5 mmol) and
propane-1-sulfonyl chloride (16, 2.90 mL, 25.8 mmol) were added
under an atmosphere of nitrogen. The reaction was stirred at room
temperature overnight. The reaction was poured into 1 M HCl and
extracted with ethyl acetate. The organic layer was washed with
brine, dried over anhydrous sodium sulfate and filtered. The
filtrate was concentrated to provide the desired compound (42, 2.0
g, 28%), which was used without further purification in the next
step.
Step 2--Preparation of propane-1-sulfonic acid
(2,4-difluoro-3-formyl-phenyl)-amide (43)
[0492] To propane-1-sulfonic acid (2,4-difluoro-phenyl)-amide (42,
1.5 g, 6.38 mmol) in 10 mL of tetrahydrofuran under an atmosphere
of nitrogen, cooled in a -78.degree. C. acetone/dry ice bath,
lithium diisopropylamide (0.80 M in tetrahydrofuran, 24 mL, freshly
prepared from n-butyllithium and diisopropylamine) was added. After
30 minutes, N,N-dimethyl-formamide (542 L, 7.018 mmol) was added
dropwise to the reaction. The reaction was stirred for 30 minutes
at -78.degree. C. and then allowed to warm to room temperature for
40 minutes. The reaction was poured into water and extracted with
ethyl acetate. The organic layer was washed with brine, dried over
anhydrous sodium sulfate and filtered. The filtrate was
concentrated and purified by silica gel column chromatography
eluting with 5% ethyl acetate in hexane to give a light yellow
solid (43, 300 mg, 18%). MS (ESI)[M-H.sup.+].sup.-=262.3.
Step 3--Preparation of propane-1-sulfonic acid
{2,4-difluoro-3-[(5-methyl-isoxazol-3-ylamino)-methyl]-phenyl}-amide
(P-0019)
[0493] To 5-methyl-isoxazol-3-ylamine (44, 0.13 g, 1.3 mmol) in 20
mL of acetonitrile, propane-1-sulfonic acid
(2,4-difluoro-3-formyl-phenyl)-amide (43, 0.35 g, 1.3 mmol),
triethylsilane (1 mL, 7 mmol) and trifluoroacetic acid (0.5 mL, 7
mmol) were added. The reaction mixture was stirred at 80.degree. C.
overnight. The reaction mixture was concentrated, then poured into
aqueous potassium carbonate and extracted with ethyl acetate. The
organic layer was dried over anhydrous sodium sulfate. After
removal of drying agent and then solvent, the residue was purified
by silica gel column chromatography to provide the desired compound
as a white solid (P-0019, 0.22 g, 48%). MS (ESI) [M-H+]=346.95.
[0494]
N-{5-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzylamino]-pyridin-
-2-yl}-acetamide P-0020, propane-1-sulfonic acid
[2,4-difluoro-3-(quinolin-3-ylaminomethyl)-phenyl]-amide P-0021,
propane-1-sulfonic acid
{3-[(6-chloro-pyridin-3-ylamino)-methyl]-2,4-difluoro-phenyl}-amide
P-0022, and propane-1-sulfonic acid
{2,4-difluoro-3-[(6-methoxy-pyridin-3-ylamino)-methyl]-phenyl}-amide
P-0023,
##STR00084##
were prepared following the protocol of Scheme 11, replacing
5-methyl-isoxazol-3-ylamine 44 with
N-(5-amino-pyridin-2-yl)-acetamide, quinolin-3-ylamine,
6-chloro-pyridin-3-ylamine, and 6-methoxy-pyridin-3-ylamine,
respectively. MS (ESI) [M+H.sup.+].sup.+ P-0020=399.35,
P-0021=392.40, P-0022=376.95, and P-0023=372.55.
Example 12
Synthesis of quinoline-3-carboxylic acid
[2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-amide P-0024 and
propane-1-sulfonic acid
{2,4-difluoro-3-[(quinolin-3-ylmethyl)-amino]-phenyl}-amide
P-0025
[0495] Quinoline-3-carboxylic acid
[2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-amide P-0024 and
propane-1-sulfonic acid
{2,4-difluoro-3-[(quinolin-3-ylmethyl)-amino]-phenyl}-amide P-0025
were synthesized in three steps from propane-1-sulfonic acid
(2,4-difluoro-3-formyl-phenyl)-amide 43 as shown in Scheme 12.
##STR00085## ##STR00086##
Step 1--Preparation of
2,6-difluoro-3-(propane-1-sulfonylamino)-benzoic acid (45)
[0496] To a reaction flask, propane-1-sulfonic acid
(2,4-difluoro-3-formyl-phenyl)-amide (43, 3.00 g, 11.4 mmol) and
oxone (9.10 g, 14.8 mmol) and 30 mL of anhydrous
N,N-dimethylformamide were added under nitrogen. The mixture was
stirred at room temperature overnight, then quenched with 250 mL of
1 M hydrochloric acid solution and extracted with 250 mL of ethyl
acetate. The organic layers were washed with 3.times.100 mL of 1M
hydrochloric acid solution and dried over magnesium sulfate. After
removal of drying agent and solvent, the residue was dried in vacuo
to provide the desired compound (45, 2.9 g, 91%).
Step 2--Preparation of propane-1-sulfonic acid
(3-amino-2,4-difluoro-phenyl)-amide (46)
[0497] To a reaction flask,
2,6-difluoro-3-(propane-1-sulfonylamino)-benzoic acid (45, 2.88 g,
10.3 mmol), triethylamine (2.09 g, 20.6 mmol) and
diphenylphosphoryl azide (3.21 g, 11.7 mmol) and 84 mL of anhydrous
tert-butanol were added under nitrogen. The reaction mixture was
heated in an oil bath at 105.degree. C. overnight, then cooled to
room temperature and diluted with ethyl acetate. The organic layer
was washed with 3.times.250 mL of water, 250 mL of brine, dried
over magnesium sulfate, filtered and concentrated in vacuo to
provide 4.1 g of crude Boc-protected amine, which was purified by
silica gel column chromatography using hexane:ethyl acetate as
eluant to provide 3.3 g of the Boc-protected amine. This was
dissolved in 50 mL of dichloromethane and 16 mL of trifluoroacetic
acid was added and the reaction stirred at room temperature until
there was no starting material by TLC. The reaction was neutralized
by pouring into a cooled saturated solution of sodium bicarbonate
and extracted into 3.times.150 mL of dichloromethane. The combined
organic extracts were washed with 50 mL of brine, dried over
magnesium sulfate, filtered and concentrated in vacuo to provide
the desired compound (46, 1.94 g, 75%).
Step 3a --Preparation of quinoline-3-carboxylic acid
[2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-amide
(P-0024)
[0498] To a reaction vessel, 3-quinoline carboxylic acid (47, 39.1
mg, 0.23 mmol), 1.5 mL of anhydrous tetrahydrofuran, 1 drop of
anhydrous N,N-dimethylformamide and oxalyl chloride (86 mg, 0.68
mmol) were added under nitrogen. The reaction was stirred at room
temperature for 1.5 hours, then concentrated to dryness and the
residue was diluted with 2 mL of anhydrous tetrahydrofuran. To this
solution, triethylamine (15.8 mg, 0.16 mmol) and propane-1-sulfonic
acid (3-amino-2,4-difluoro-phenyl)-amide (46, 100 mg, 0.40 mmol)
were added and the reaction was stirred at room temperature over
weekend. The reaction mixture was diluted with 5 mL of water and
extracted into 3.times.10 mL of ethyl acetate. The organic extracts
were dried over magnesium sulfate, filtered and concentrated in
vacuo, then purified by silica gel column chromatography
(hexane:ethyl acetate gradient) to provide the desired compound
(P-0024, 33 mg, 36%). MS (ESI) [M+H].sup.+=406.1.
Step 3b --Preparation of propane-1-sulfonic acid
{2,4-difluoro-3-[(quinolin-3-ylmethyl)-amino]-phenyl}-amide
(P-0025)
[0499] To a reaction vessel, propane-1-sulfonic acid
(3-amino-2,4-difluoro-phenyl)-amide (46, 155 mg, 0.62 mmol), 2 mL
of anhydrous acetonitrile, 3-quinoline carboxaldehyde (48, 100 mg,
0.64 mmol), trifluoroacetic acid (431 mg, 3.78 mmol) and
triethylsilane (425 mg, 3.65 mmol) were added under nitrogen. The
reaction was heated at 80.degree. C. overnight, then cooled to room
temperature and concentrated in vacuo, to which 10 mL of an aqueous
solution of 10% potassium carbonate was added. This was extracted
into 3.times.15 mL of ethyl acetate. The combined organic extracts
were washed with 15 mL of brine, dried over magnesium sulfate,
filtered and concentrated in vacuo. The residue was purified by
silica gel column chromatography (hexane:ethyl acetate gradient) to
provide the desired compound (P-0025, 70 mg, 29%). MS (ESI)
[M+H.sup.+].sup.+=392.0.
Example 13
Synthesis of propane-1-sulfonic acid
[2,4-difluoro-3-(quinolin-3-yloxymethyl)-phenyl]-amide P-0026
[0500] Propane-1-sulfonic acid
[2,4-difluoro-3-(quinolin-3-yloxymethyl)-phenyl]-amide P-0026 was
synthesized in three steps from propane-1-sulfonic acid
(2,4-difluoro-3-formyl-phenyl)-amide 43 as shown in Scheme 13.
##STR00087##
Step 1--Preparation of propane-1-sulfonic acid
(2,4-difluoro-3-hydroxymethyl-phenyl)-amide 49)
[0501] To a reaction vessel, propane-1-sulfonic acid
(2,4-difluoro-3-formyl-phenyl)-amide (43, 1.00 g, 3.80 mmol), 20 mL
of methanol, and sodium borohydride (0.29 g, 7.60 mmol) were added
under nitrogen. The reaction was stirred at room temperature for 1
hour, then poured onto 50 mL of aqueous 10% sodium
dihydrogenphosphate. The mixture was extracted with 3.times.50 mL
of dichloromethane and the combined organic extracts were dried
over magnesium sulfate, filtered and concentrated in vacuo to
provide the desired compound (49, 0.97 g, 96%), used in the next
step without further purification.
Step 2--Preparation of propane-1-sulfonic acid
(3-bromomethyl-2,4-difluoro-phenyl)-amide (50)
[0502] To a reaction vessel under nitrogen containing
polymer-supported triphenylphosphine (2.45 g, 4.41 mmol) in 5 mL of
acetonitrile, bromine (0.70 g, 4.41 mmol) was added, followed by a
solution of propane-1-sulfonic acid
(2,4-difluoro-3-hydroxymethyl-phenyl)-amide (49, 0.97 g, 3.67 mmol)
in 5 mL of acetonitrile. The reaction mixture was stirred at
60.degree. C. for approximately 3 hours. The reaction mixture was
filtered and the polymer washed with 5 mL of ethyl acetate. The
filtrate and wash were concentrated in vacuo to provide the desired
compound (50, 0.91 g, 76%), used in the next step without further
purification.
Step 3--Preparation of propane-1-sulfonic acid
[2,4-difluoro-3-(quinolin-3-yloxymethyl)-phenyl]-amide (P-0026)
[0503] To reaction vessel, 3-hydroxyquinoline (51, 442 mg, 3.05
mmol) and 5 mL of anhydrous N,N-dimethylformamide were added under
nitrogen. Sodium hydride (60% dispersion in mineral oil, 183 mg,
4.57 mmol) was added in portions. The reaction was stirred at room
temperature for 30 minutes, then propane-1-sulfonic acid
(3-bromomethyl-2,4-difluoro-phenyl)-amide (50, 500 mg, 1.52 mmol)
was added and the reaction stirred at room temperature overnight.
The reaction mixture was neutralized with acetic acid and extracted
into 3.times.20 mL of ethyl acetate. The combined organic extracts
were dried over magnesium sulfate, filtered and concentrated in
vacuo. The residue was purified by silica gel column chromatography
(hexane:ethyl acetate gradient), followed by second purification by
silica gel column chromatography to provide the desired compound
(P-0026, 50 mg, 8%). MS (ESI) [M+H.sup.+].sup.+=393.0.
[0504] Additional compounds may be prepared following the protocol
of Scheme 13, optionally replacing propane-1-sulfonic acid
(2,4-difluoro-3-formyl-phenyl)-amide 43 with
N-(2,4-difluoro-3-formyl-phenyl)-4-trifluoromethyl-benzenesulfonamide
(prepared following the protocol of Scheme 11, Example 11, steps 1
and 2 using 4-trifluoromethyl-benzenesulfonyl chloride in Step 1 in
place of propane-1-sulfonyl chloride 16) in Step 1 and
3-hydroxyquinoline 51 with a suitable alcohol in Step 3. The
following compounds may be prepared by this method: [0505]
N-{5-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzyloxy]-pyridin-2-yl}-a-
cetamide (P-0091), Propane-1-sulfonic acid
[3-(2-amino-pyridin-3-yloxymethyl)-2,4-difluoro-phenyl]-amide
(P-0092), [0506] Propane-1-sulfonic acid
[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridin-5-yloxymethyl)-phenyl]-amide
(P-0093), [0507]
N-{5-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzyloxy]--
pyridin-2-yl}-acetamide (P-0094), [0508]
N-[3-(2-Amino-pyridin-3-yloxymethyl)-2,4-difluoro-phenyl]-4-trifluorometh-
yl-benzenesulfonamide (P-0095), and [0509]
N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridin-5-yloxymethyl)-phenyl]-4-trif-
luoromethyl-benzenesulfonamide (P-0096). The following table
indicates the compound number in Column 1, the aldehyde used in
Step 1 in Column 2, the alcohol used in Step 3 in Column 3, and the
resulting compound in Column 4:
TABLE-US-00002 [0509] Compound Aldehyde in Alcohol in number Step 1
Step 3 Compound P-0091 ##STR00088## ##STR00089## ##STR00090##
P-0092 ##STR00091## ##STR00092## ##STR00093## P-0093 ##STR00094##
##STR00095## ##STR00096## P-0094 ##STR00097## ##STR00098##
##STR00099## P-0095 ##STR00100## ##STR00101## ##STR00102## P-0096
##STR00103## ##STR00104## ##STR00105##
Example 14
Synthesis of
2,6-difluoro-3-(propane-1-sulfonylamino)-N-quinolin-3-yl-benzamide
P-0027
[0510]
2,6-Difluoro-3-(propane-1-sulfonylamino)-N-quinolin-3-yl-benzamide
P-0027 was synthesized in one step from
2,6-difluoro-3-(propane-1-sulfonylamino)-benzoic acid 45 as shown
in Scheme 14.
##STR00106##
Step 1--Preparation of
2,6-difluoro-3-(propane-1-sulfonylamino)-N-quinolin-3-yl-benzamide
(P-0027)
[0511] To reaction vessel,
2,6-difluoro-3-(propane-1-sulfonylamino)-benzoic acid (45, 250 mg,
0.90 mmol), 5 mL of anhydrous dichloromethane and anhydrous
N,N-dimethylformamide (6.54 mg, 0.09 mmol) were added under
nitrogen. The reaction mixture was cooled to 0.degree. C. and
oxalyl chloride (568 mg, 4.48 mmol) was added dropwise. This was
stirred at room temperature for 3 hours, then concentrated in
vacuo. The residue was diluted with 5 mL of anhydrous
tetrahydrofuran and triethylamine (136 mg, 1.34 mmol) and
3-aminoquinoline (39, 194 mg, 1.34 mmol) were added. The reaction
mixture was stirred at room temperature over the weekend, then
concentrated in vacuo. The residue was purified by silica gel
column chromatography (hexane:ethyl acetate gradient) to provide
the desired compound (P-0027, 163 mg, 45%). MS (ESI)
[M+H.sup.+].sup.+=406.1.
Example 15
Synthesis of Additional Compounds
[0512] Additional compounds may be synthesized in six steps
according to the following Scheme 15 or in four steps according the
following Scheme 16.
##STR00107##
Step 1--Preparation of (2,4-difluoro-phenyl)-carbamic acid methyl
ester (52)
[0513] To 2,4-difluoroaniline 41, potassium carbonate, and water,
methyl chloroformate 51 is added slowly dropwise. The reaction is
stirred at 0.degree. C. and then allowed to come to room
temperature. The reaction mixture is extracted with ethyl acetate
and washed with diluted HCl (pH=2), twice with saturated sodium
bicarbonate, twice with brine, and dried with magnesium sulfate.
Removal of solvent provides the desired compound as a crude
solid.
Step 2--Preparation of 2,6-difluoro-3-methoxycarbonylamino-benzoic
acid (53)
[0514] To (2,4-difluoro-phenyl)-carbamic acid methyl ester 52 in
tetrahydrofuran at -78.degree. C., 2.5 eq. of lithium
diisopropylamide is added. After 15 minutes, solid carbon dioxide
is added and the reaction is allowed to warm to room temperature.
The reaction mixture is extracted with ethyl acetate and washed
with diluted HCl (pH=2). The desired compound is isolated by silica
gel column chromatography.
Step 3--Preparation of (3-amino-2,4-difluoro-phenyl)-carbamic acid
methyl ester (54)
[0515] To 2,6-difluoro-3-methoxycarbonylamino-benzoic acid 53,
anhydrous tert-butanol, and triethylamine, diphenylphosphoryl azide
is added. The action is heated in an oil bath at 105.degree. C.
overnight. The reaction is cooled to room temperature and diluted
with ethyl acetate. The organic layer is washed 3.times. with
water, then 1.times. with brine, dried over magnesium sulfate and
filtered and concentrated in vacuo to provide crude Boc-protected
amine, which is purified by silica gel column chromatography. The
purified Boc-protected amine is dissolved in dichloromethane,
trifluoroacetic acid is added and the reaction stirred at room
temperature, monitoring by TLC for the disappearance of starting
material. The completed reaction is neutralised by pouring into a
cooled saturated solution of sodium hydrogen carbonate and then
extracted 3.times. into dichloromethane. The combined organic
extracts are washed with brine, dried over magnesium sulfate,
filtered and concentrated in vacuo to provide the desired
compound.
Step 4--Preparation of Compound 56
[0516] To a reaction vessel, carboxylic acid 55 (R.sup.a is
optionally substituted heteroaryl), anhydrous tetrahydrofuran, 1
drop anhydrous dimethylformamide, and oxalyl chloride are added
under nitrogen. The reaction mixture is allowed to stir at room
temperature for 1.5 hours, then concentrated to dryness. The
resulting residue is diluted with anhydrous tetrahydrofuran, then
triethylamine and (3-amino-2,4-difluoro-phenyl)-carbamic acid
methyl ester 54 are added and allowed to stir at room temperature
overnight. The reaction is diluted with water extracted 3.times.
into ethyl acetate. The organic extracts are dried over magnesium
sulfate, filtered and concentrated in vacuo to provide the desired
compound as a crude solid, which is purified by silica gel column
chromatography (hexane:ethyl acetate gradient).
Step 5--Preparation of compound 57
[0517] To compound 56 in dioxane, an equal volume of 1 N lithium
hydroxide is added. The reaction is allowed to stir at 60.degree.
C. and monitored by TLC. When complete, reaction is extracted with
1N aqueous HCl and ethyl acetate. The organic layer is dried over
anhydrous magnesium sulfate, filtered and volatile solvents removed
to provide the desired compound as a crude solid.
Step 6--Preparation of compound 59
[0518] To compound 57, tetrahydrofuran is added, followed by
addition of compound 58 (R.sup.b is di-alkylamino, optionally
substituted lower alkyl, optionally substituted cycloalkyl,
optionally substituted heterocycloalkyl, optionally substituted
aryl or optionally substituted heteroaryl) as a solution in
tetrahydrofuran, then adding pyridine. The reaction vial is allowed
to stir at room temperature. After 23 hours, the reaction is poured
into water and 1N aqueous HCl and extracted with ethyl acetate. The
organic layer is washed with brine, dried over anhydrous magnesium
sulfate and filtered. The filtrate is concentrated and purified by
silica gel column chromatography (hexane:ethyl acetate gradient) to
provide the desired compound.
##STR00108##
Step 1--Preparation of 2,6-difluoro-3-nitro-phenylamine (61)
[0519] 2,6-Difluoro-3-nitrobenzoic acid 60 is converted to
2,6-difluoro-3-nitro-phenylamine 61 following the methods described
in Scheme 15, Step 3.
Step 2--Preparation of Compound 62
[0520] 2,6-Difluoro-3-nitro-phenylamine 61 is reacted with compound
55 following the methods described in Scheme 15, Step 4 to provide
the desired compound 62.
Step 3--Preparation of Compound 57
[0521] To compound 62 in ethanol and tetrahydrofuran, .about.3 cc
of raney nickle slurry in water is added. The reaction is placed in
a parr hydrogenator under hydrogen at 35 psi and monitored by TLC
until all starting material is consumed. The reaction is filtered
and all volatile solvents are removed to provide the desired
compound as a crude solid.
Step 4--Preparation of Compound 59
[0522] Compound 57 is reacted with compound 58 following the
methods described in Scheme 15, Step 6 to provide the desired
compound 59.
[0523] The following compounds may be made following the protocol
of either Scheme 15 or Scheme 16: [0524]
6-Acetylamino-N-[2,6-difluoro-3-(2-fluoro-benzenesulfonylamino)-phenyl]-n-
icotinamide (P-0028), [0525]
6-Acetylamino-N-[2,6-difluoro-3-(3-fluoro-benzenesulfonylamino)-phenyl]-n-
icotinamide (P-0029), [0526]
6-Acetylamino-N-[3-(2,6-difluoro-benzenesulfonylamino)-2,6-difluoro-pheny-
l]-nicotinamide (P-0030), [0527]
6-Acetylamino-N-[3-(2,4-difluoro-benzenesulfonylamino)-2,6-difluoro-pheny-
l]-nicotinamide (P-0031), [0528]
6-Acetylamino-N-[3-(2,5-difluoro-benzenesulfonylamino)-2,6-difluoro-pheny-
l]-nicotinamide (P-0032), [0529]
6-Acetylamino-N-[2,6-difluoro-3-(3-fluoro-4-methoxy-benzenesulfonylamino)-
-phenyl]nicotinamide (P-0033), [0530]
6-Acetylamino-N-[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)--
phenyl]-nicotinamide (P-0034), [0531]
6-Acetylamino-N-[3-(4-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro--
phenyl]-nicotinamide (P-0035), [0532]
6-Acetylamino-N-[3-(3-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro--
phenyl]-nicotinamide (P-0036), [0533]
6-Acetylamino-N-[2,6-difluoro-3-(4-isopropyl-benzenesulfonylamino)-phenyl-
]-nicotinamide (P-0037), [0534]
6-Acetylamino-N-[3-(4-tert-butyl-benzenesulfonylamino)-2,6-difluoro-pheny-
l]-nicotinamide (P-0038), [0535]
6-Acetylamino-N-[2,6-difluoro-3-(4-propyl-benzenesulfonylamino)-phenyl]-n-
icotinamide (P-0039), [0536]
6-Acetylamino-N-[2,6-difluoro-3-(pyridine-2-sulfonylamino)-phenyl]-nicoti-
namide (P-0040), [0537]
6-Acetylamino-N-[2,6-difluoro-3-(pyridine-3-sulfonylamino)-phenyl]-nicoti-
namide (P-0041), [0538]
6-Acetylamino-N-[2,6-difluoro-3-(dimethylaminosulfonylamino)-phenyl]-nico-
tinamide (P-0042), [0539]
6-Acetylamino-N-[2,6-difluoro-3-(piperidine-1-sulfonylamino)-phenyl]-nico-
tinamide (P-0043), [0540]
6-Acetylamino-N-[2,6-difluoro-3-(morpholine-4-sulfonylamino)-phenyl]-nico-
tinamide (P-0044), [0541]
6-Acetylamino-N-[2,6-difluoro-3-(tetrahydro-pyran-4-sulfonylamino)-phenyl-
]-nicotinamide (P-0045), [0542]
6-Acetylamino-N-(3-cyclopentanesulfonylamino-2,6-difluoro-phenyl)-nicotin-
amide (P-0046), [0543]
6-Acetylamino-N-[2,6-difluoro-3-(pyrrolidine-1-sulfonylamino)-phenyl]-nic-
otinamide (P-0047), [0544]
6-Acetylamino-N-[2,6-difluoro-3-(3,3,3-trifluoro-propane-1-sulfonylamino)-
-phenyl]-nicotinamide (P-0048), [0545]
1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(2-fluoro-benzenesulfonylamino)-phenyl]-amide
(P-0049), [0546] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(3-fluoro-benzenesulfonylamino)-phenyl]-amide
(P-0050), [0547] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[3-(2,6-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide
(P-0051), [0548] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[3-(2,4-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide
(P-0052), [0549] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[3-(2,5-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide
(P-0053), [0550] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(3-fluoro-4-methoxy-benzenesulfonylamino)-phenyl]-amide
(P-0054), [0551] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-phenyl]-amide
(P-0055), [0552] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[3-(4-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide
(P-0056), [0553] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[3-(3-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide
(P-0057), [0554] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(4-isopropyl-benzenesulfonylamino)-phenyl]-amide
(P-0058), [0555] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[3-(4-tert-butyl-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide
(P-0059), [0556] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(4-propyl-benzenesulfonylamino)-phenyl]-amide
(P-0060), [0557] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(pyridine-2-sulfonylamino)-phenyl]-amide (P-0061),
[0558] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(pyridine-3-sulfonylamino)-phenyl]-amide (P-0062),
[0559] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(dimethylaminosulfonylamino)-phenyl]-amide
(P-0063), [0560] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(piperidine-1-sulfonylamino)-phenyl]-amide
(P-0064), [0561] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(morpholine-4-sulfonylamino)-phenyl]-amide
(P-0065), [0562] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(tetrahydro-pyran-4-sulfonylamino)-phenyl]-amide
(P-0066), [0563] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
(3-cyclopentanesulfonylamino-2,6-difluoro-phenyl)-amide (P-0067),
[0564] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(pyrrolidine-1-sulfonylamino)-phenyl]-amide
(P-0068), [0565] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(3,3,3-trifluoro-propane-1-sulfonylamino)-phenyl]-amide
(P-0069), [0566] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(2-fluoro-benzenesulfonylamino)-phenyl]-amide
(P-0070), [0567] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(3-fluoro-benzenesulfonylamino)-phenyl]-amide
(P-0071), [0568] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[3-(2,6-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide
(P-0072), [0569] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[3-(2,4-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide
(P-0073), [0570] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[3-(2,5-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide
(P-0074), [0571] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(3-fluoro-4-methoxy-benzenesulfonylamino)-phenyl]-amide
(P-0075), [0572] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-phenyl]-amide
(P-0076), [0573] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[3-(4-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide
(P-0077), [0574] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[3-(3-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide
(P-0078), [0575] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(4-isopropyl-benzenesulfonylamino)-phenyl]-amide
(P-0079), [0576] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[3-(4-tert-butyl-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide
(P-0080), [0577] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(4-propyl-benzenesulfonylamino)-phenyl]-amide
(P-0081), [0578] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(pyridine-2-sulfonylamino)-phenyl]-amide (P-0082),
[0579] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(pyridine-3-sulfonylamino)-phenyl]-amide (P-0083),
[0580] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(dimethylaminosulfonylamino)-phenyl]-amide
(P-0084), [0581] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(piperidine-1-sulfonylamino)-phenyl]-amide
(P-0085), [0582] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(morpholine-4-sulfonylamino)-phenyl]-amide
(P-0086), [0583] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(tetrahydro-pyran-4-sulfonylamino)-phenyl]-amide
(P-0087), [0584] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
(3-cyclopentanesulfonylamino-2,6-difluoro-phenyl)-amide (P-0088),
[0585] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(pyrrolidine-1-sulfonylamino)-phenyl]-amide
(P-0089), [0586] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(3,3,3-trifluoro-propane-1-sulfonylamino)-phenyl]-amide
(P-0090), [0587]
6-Acetylamino-N-[2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-nicotin-
amide (P-0118), [0588] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-amide (P-0119),
and [0589] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-amide
(P-0120).
[0590] These compounds are shown in the following table, where
column 1 provides the compound number, column 2 the carboxylic acid
compound 55 used in either Step 4 of Scheme 15 or Step 2 of Scheme
16, column 3 the sulfonyl chloride compound 58 used in either Step
6 of Scheme 15 or Step 4 of Scheme 16, and column 4 the resulting
compound 59.
TABLE-US-00003 Compound number Compound 55 Compound 58 Resulting
Compound 59 P-0028 ##STR00109## ##STR00110## ##STR00111## P-0029
##STR00112## ##STR00113## ##STR00114## P-0030 ##STR00115##
##STR00116## ##STR00117## P-0031 ##STR00118## ##STR00119##
##STR00120## P-0032 ##STR00121## ##STR00122## ##STR00123## P-0033
##STR00124## ##STR00125## ##STR00126## P-0034 ##STR00127##
##STR00128## ##STR00129## P-0035 ##STR00130## ##STR00131##
##STR00132## P-0036 ##STR00133## ##STR00134## ##STR00135## P-0037
##STR00136## ##STR00137## ##STR00138## P-0038 ##STR00139##
##STR00140## ##STR00141## P-0039 ##STR00142## ##STR00143##
##STR00144## P-0040 ##STR00145## ##STR00146## ##STR00147## P-0041
##STR00148## ##STR00149## ##STR00150## P-0042 ##STR00151##
##STR00152## ##STR00153## P-0043 ##STR00154## ##STR00155##
##STR00156## P-0044 ##STR00157## ##STR00158## ##STR00159## P-0045
##STR00160## ##STR00161## ##STR00162## P-0046 ##STR00163##
##STR00164## ##STR00165## P-0047 ##STR00166## ##STR00167##
##STR00168## P-0048 ##STR00169## ##STR00170## ##STR00171## P-0118
##STR00172## ##STR00173## ##STR00174## P-0049 ##STR00175##
##STR00176## ##STR00177## P-0050 ##STR00178## ##STR00179##
##STR00180## P-0051 ##STR00181## ##STR00182## ##STR00183## P-0052
##STR00184## ##STR00185## ##STR00186## P-0053 ##STR00187##
##STR00188## ##STR00189## P-0054 ##STR00190## ##STR00191##
##STR00192## P-0055 ##STR00193## ##STR00194## ##STR00195## P-0056
##STR00196## ##STR00197## ##STR00198## P-0057 ##STR00199##
##STR00200## ##STR00201## P-0058 ##STR00202## ##STR00203##
##STR00204## P-0059 ##STR00205## ##STR00206## ##STR00207## P-0060
##STR00208## ##STR00209## ##STR00210## P-0061 ##STR00211##
##STR00212## ##STR00213## P-0062 ##STR00214## ##STR00215##
##STR00216## P-0063 ##STR00217## ##STR00218## ##STR00219## P-0064
##STR00220## ##STR00221## ##STR00222## P-0065 ##STR00223##
##STR00224## ##STR00225## P-0066 ##STR00226## ##STR00227##
##STR00228## P-0067 ##STR00229## ##STR00230## ##STR00231## P-0068
##STR00232## ##STR00233## ##STR00234## P-0069 ##STR00235##
##STR00236## ##STR00237## P-0119 ##STR00238## ##STR00239##
##STR00240## P-0070 ##STR00241## ##STR00242## ##STR00243## P-0071
##STR00244## ##STR00245## ##STR00246## P-0072 ##STR00247##
##STR00248## ##STR00249## P-0073 ##STR00250## ##STR00251##
##STR00252## P-0074 ##STR00253## ##STR00254## ##STR00255## P-0075
##STR00256## ##STR00257## ##STR00258## P-0076 ##STR00259##
##STR00260## ##STR00261## P-0077 ##STR00262## ##STR00263##
##STR00264## P-0078 ##STR00265## ##STR00266## ##STR00267## P-0079
##STR00268## ##STR00269## ##STR00270## P-0080 ##STR00271##
##STR00272## ##STR00273## P-0081 ##STR00274## ##STR00275##
##STR00276## P-0082 ##STR00277## ##STR00278## ##STR00279## P-0083
##STR00280## ##STR00281## ##STR00282## P-0084 ##STR00283##
##STR00284## ##STR00285## P-0085 ##STR00286## ##STR00287##
##STR00288## P-0086 ##STR00289## ##STR00290## ##STR00291## P-0087
##STR00292## ##STR00293## ##STR00294## P-0088 ##STR00295##
##STR00296## ##STR00297## P-0089 ##STR00298## ##STR00299##
##STR00300## P-0090 ##STR00301## ##STR00302## ##STR00303## P-0120
##STR00304## ##STR00305## ##STR00306##
Example 12
Kinase Activity Assays
[0591] Assays for the activity of kinases, including, but not
limited to, Fins, Kit, B-Raf, B-Raf V600E, B-Raf V600E/T5291 and
c-Raf-1 are known in the art, for example as described in US Patent
Publication Number US20070032519 and U.S. patent application Ser.
No. 11/473,347 (see also, PCT publication WO2007002433), the
disclosures of which are hereby incorporated by reference in their
entireties including all specifications, figures, and tables, and
for all purposes.
[0592] Representative compounds screened by at least one of the
methods described above, or by similar methods, having IC.sub.50 of
less than 10 .mu.M under the test conditions employed are shown in
tables 2a (A-Raf), 2b (B-Raf), 2c (B-Raf V600E), 2d (c-Raf-1), 2e
(Brk), 2f (Btk), 2g (Csk), 2h (Fak), 2i (Fms), 2j (Kdr), 2k (Kit),
2l (Lck), 2m (Lyn), 2n (Src), 2o (TrkA), and 2p (Yes).
TABLE-US-00004 TABLE 2a Representative compounds with activity
toward kinase A-Raf with IC.sub.50 .ltoreq.10 .mu.M under the test
conditions employed. A-Raf P-0001, P-0002, P-0004, P-0005, P-0006,
P-0008, P-0009, P-0010, P-0011, P-0012, P-0013, P-0015, P-0016,
P-0017, P-0020, P-0021, P-0025, P-0026, P-0027
TABLE-US-00005 TABLE 2b Representative compounds with activity
toward kinase B-Raf with IC.sub.50 .ltoreq.10 .mu.M under the test
conditions employed. B-Raf P-0002, P-0004, P-0008, P-0011, P-0013,
P-0015, P-0016, P-0017, P-0018, P-0027
TABLE-US-00006 TABLE 2c Representative compounds with activity
toward kinase B-Raf V600E with IC.sub.50 .ltoreq.10 .mu.M under the
test conditions employed. B-Raf P-0001, P-0002, P-0004, P-0005,
P-0008, P-0011, V600E P-0013, P-0015, P-0016, P-0017, P-0018,
P-0020, P-0021, P-0025, P-0026, P-0027
TABLE-US-00007 TABLE 2d Representative compounds with activity
toward kinase c-Raf-1 with IC.sub.50 .ltoreq.10 .mu.M under the
test conditions employed. c-Raf-1: P-0001, P-0002, P-0004, P-0008,
P-0009, P-0011, P-0013, P-0015, P-0016, P-0017, P-0020, P-0021,
P-0027
TABLE-US-00008 TABLE 2e Representative compounds with activity
toward kinase Brk with IC.sub.50 .ltoreq.10 .mu.M under the test
conditions employed. Brk: P-0002
TABLE-US-00009 TABLE 2f Representative compounds with activity
toward kinase Btk with IC.sub.50 .ltoreq.10 .mu.M under the test
conditions employed. Btk: P-0011
TABLE-US-00010 TABLE 2g Representative compounds with activity
toward kinase Csk with IC.sub.50 .ltoreq.10 .mu.M under the test
conditions employed. Csk: P-0002
TABLE-US-00011 TABLE 2h Representative compounds with activity
toward kinase Fak with IC.sub.50 .ltoreq.10 .mu.M under the test
conditions employed. Fak: P-0002
TABLE-US-00012 TABLE 2i Representative compounds with activity
toward kinase Fms with IC.sub.50 .ltoreq.10 .mu.M under the test
conditions employed. Fms: P-0010, P-0026
TABLE-US-00013 TABLE 2j Representative compounds with activity
toward kinase Kdr with IC.sub.50 .ltoreq.10 .mu.M under the test
conditions employed. Kdr: P-0011
TABLE-US-00014 TABLE 2k Representative compounds with activity
toward kinase Kit with IC.sub.50 .ltoreq.10 .mu.M under the test
conditions employed. Kit: P-0011
TABLE-US-00015 TABLE 2l Representative compounds with activity
toward kinase Lck with IC.sub.50 .ltoreq.10 .mu.M under the test
conditions employed. Lck: P-0002
TABLE-US-00016 TABLE 2m Representative compounds with activity
toward kinase Lyn with IC.sub.50 .ltoreq.10 .mu.M under the test
conditions employed. Lyn: P-0002
TABLE-US-00017 TABLE 2n Representative compounds with activity
toward kinase Src with IC.sub.50 .ltoreq.10 .mu.M under the test
conditions employed. Src: P-0002, P-0011
TABLE-US-00018 TABLE 2o Representative compounds with activity
toward kinase TrkA with IC.sub.50 .ltoreq.10 .mu.M under the test
conditions employed. TrkA: P-0002, P-0011
TABLE-US-00019 TABLE 2p Representative compounds with activity
toward kinase Yes with IC.sub.50 .ltoreq.10 .mu.M under the test
conditions employed. Yes: P-0002
Example 13
Efficacy of Compounds in Combination with Standard-of-Care
Chemotherapeutic Agents in Four Human Cancer Cell Lines
[0593] Compounds of the invention, such as compounds of Formula I,
in combination with a standard chemotherapeutic agent, such as
5-fluorouracil, carboplatin, dacarbazine, gefitinib, oxaliplatin,
paclitaxel, SN-38, temozolomide, or vinblastine, can be assessed
for their effectiveness in killing human tumor cells. Such assays
are known in the art, for example, as described in U.S. patent
application Ser. No. 11/473,347.
[0594] Additional examples of certain methods contemplated by the
present invention may be found in the following applications: U.S.
Patent Publ. No. 2006/058339; U.S. Patent Publ. No. 2006/058340;
U.S. Patent Publ. No. 2007/0032519; and U.S. patent application
Ser. No. 11/473,347, filed Jun. 21, 2006 (Equivalent to PCT
published as WO 2007/002433), each of which are hereby incorporated
by reference herein in their entireties including all
specifications, figures, and tables, and for all purposes.
[0595] All patents and other references cited in the specification
are indicative of the level of skill of those skilled in the art to
which the invention pertains, and are incorporated by reference in
their entireties, including any tables and figures, to the same
extent as if each reference had been incorporated by reference in
its entirety individually.
[0596] One skilled in the art would readily appreciate that the
present invention is well adapted to obtain the ends and advantages
mentioned, as well as those inherent therein. The methods,
variances, and compositions described herein as presently
representative of preferred embodiments are exemplary and are not
intended as limitations on the scope of the invention. Changes
therein and other uses will occur to those skilled in the art,
which are encompassed within the spirit of the invention, are
defined by the scope of the claims.
[0597] The invention illustratively described herein suitably may
be practiced in the absence of any element or elements, limitation
or limitations which is not specifically disclosed herein. Thus,
for example, in each instance herein any of the terms "comprising",
"consisting essentially of" and "consisting of" may be replaced
with either of the other two terms. Thus, for an embodiment of the
invention using one of the terms, the invention also includes
another embodiment wherein one of these terms is replaced with
another of these terms. In each embodiment, the terms have their
established meaning. Thus, for example, one embodiment may
encompass a method "comprising" a series of steps, another
embodiment would encompass a method "consisting essentially of" the
same steps, and a third embodiment would encompass a method
"consisting of" the same steps. The terms and expressions which
have been employed are used as terms of description and not of
limitation, and there is no intention that in the use of such terms
and expressions of excluding any equivalents of the features shown
and described or portions thereof, but it is recognized that
various modifications are possible within the scope of the
invention claimed. Thus, it should be understood that although the
present invention has been specifically disclosed by preferred
embodiments and optional features, modification and variation of
the concepts herein disclosed may be resorted to by those skilled
in the art, and that such modifications and variations are
considered to be within the scope of this invention as defined by
the appended claims.
[0598] In addition, where features or aspects of the invention are
described in terms of Markush groups or other grouping of
alternatives, those skilled in the art will recognize that the
invention is also thereby described in terms of any individual
member or subgroup of members of the Markush group or other
group.
[0599] Also, unless indicated to the contrary, where various
numerical values are provided for embodiments, additional
embodiments are described by taking any 2 different values as the
endpoints of a range. Such ranges are also within the scope of the
described invention.
[0600] Thus, additional embodiments are within the scope of the
invention and within the following claims.
* * * * *