U.S. patent application number 15/227395 was filed with the patent office on 2017-06-29 for derivatives of n-(arylamino) sulfonamides as inhibitors of mek.
This patent application is currently assigned to ARDEA BIOSCIENCES, INC.. The applicant listed for this patent is ARDEA BIOSCIENCES, INC.. Invention is credited to Dinesh Barawkar, Varaprasad Chamakura, Hassan El Abdellaoul, Zhi Hong, Andreas Maderna, Jean-Michel Vernier.
Application Number | 20170183333 15/227395 |
Document ID | / |
Family ID | 39152584 |
Filed Date | 2017-06-29 |
United States Patent
Application |
20170183333 |
Kind Code |
A1 |
Maderna; Andreas ; et
al. |
June 29, 2017 |
DERIVATIVES OF N-(ARYLAMINO) SULFONAMIDES AS INHIBITORS OF MEK
Abstract
This invention concerns N-(2-arylamino) aryl sulfonamides, which
are inhibitors of MEK and are useful in treatment of cancer and
other hyperproliferative diseases.
Inventors: |
Maderna; Andreas; (Stony
Point, NY) ; Vernier; Jean-Michel; (Laguna Niguel,
CA) ; Barawkar; Dinesh; (Foothill Ranch, CA) ;
Chamakura; Varaprasad; (Irvine, CA) ; El Abdellaoul;
Hassan; (High-Point, NC) ; Hong; Zhi; (Irvine,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ARDEA BIOSCIENCES, INC. |
San Diego |
CA |
US |
|
|
Assignee: |
ARDEA BIOSCIENCES, INC.
San Diego
CA
|
Family ID: |
39152584 |
Appl. No.: |
15/227395 |
Filed: |
August 3, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14478467 |
Sep 5, 2014 |
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15227395 |
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13243368 |
Sep 23, 2011 |
8829052 |
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14478467 |
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11830733 |
Jul 30, 2007 |
8101799 |
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13243368 |
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PCT/US2006/028326 |
Jul 21, 2006 |
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11830733 |
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60833886 |
Jul 28, 2006 |
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60731633 |
Oct 28, 2005 |
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60706719 |
Aug 8, 2005 |
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60701814 |
Jul 21, 2005 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/381 20130101;
C07C 311/29 20130101; C07D 213/38 20130101; C07D 333/34 20130101;
A61K 31/415 20130101; A61P 9/10 20180101; A61P 35/02 20180101; C07B
2200/07 20130101; A61P 3/00 20180101; A61K 31/18 20130101; A61P
29/00 20180101; A61K 31/4164 20130101; C07D 417/04 20130101; C07D
231/18 20130101; A61K 31/496 20130101; C07D 231/12 20130101; A61K
31/495 20130101; C07D 277/36 20130101; A61P 19/02 20180101; C07D
285/04 20130101; C07D 295/13 20130101; A61K 31/4406 20130101; A61K
31/426 20130101; C07C 2601/08 20170501; C07C 2601/14 20170501; A61P
35/00 20180101; A61K 31/433 20130101; C07C 2601/04 20170501; C07D
295/088 20130101; C07C 2601/02 20170501; A61P 17/06 20180101; C07C
311/21 20130101; A61K 31/4409 20130101; A61K 31/42 20130101; A61K
31/34 20130101; C07D 307/64 20130101; C07C 311/10 20130101; C07D
233/84 20130101; A61K 31/40 20130101; C07C 311/28 20130101; A61K
45/06 20130101; A61P 31/00 20180101; C07C 311/14 20130101; C07D
277/54 20130101; A61P 25/00 20180101; C07C 311/09 20130101; A61P
9/00 20180101; C07D 211/54 20130101; C07D 213/42 20130101; C07C
311/08 20130101; A61P 37/00 20180101; C07D 261/10 20130101; C07C
311/32 20130101; C07D 207/36 20130101 |
International
Class: |
C07D 417/04 20060101
C07D417/04; C07C 311/10 20060101 C07C311/10; C07C 311/09 20060101
C07C311/09; C07C 311/14 20060101 C07C311/14; C07C 311/28 20060101
C07C311/28; C07D 307/64 20060101 C07D307/64; C07D 277/54 20060101
C07D277/54; C07D 261/10 20060101 C07D261/10; C07D 231/18 20060101
C07D231/18; C07D 277/36 20060101 C07D277/36; C07D 233/84 20060101
C07D233/84; C07D 333/34 20060101 C07D333/34; C07D 207/36 20060101
C07D207/36; C07C 311/21 20060101 C07C311/21; C07D 231/12 20060101
C07D231/12; C07D 213/38 20060101 C07D213/38; C07C 311/32 20060101
C07C311/32; C07D 295/088 20060101 C07D295/088; C07C 311/08 20060101
C07C311/08 |
Claims
1. A compound of formula I or a pharmaceutically acceptable salt,
solvate, polymorph, ester, tautomer or prodrug thereof ##STR00411##
wherein Z is H or F; X is F, Cl, CH.sub.3, CH.sub.2OH, CH.sub.2F,
CHF.sub.2, or CF.sub.3; Y is I, Br, Cl, CF.sub.3, C.sub.1-C.sub.3
alkyl, C.sub.2-C.sub.3 alkenyl, C.sub.2-C.sub.3 alkynyl,
cyclopropyl, OMe, OEt, SMe, phenyl or Het, where Het is a 5- to
10-membered mono- or bicyclic heterocyclic group, which group is
saturated, olefinic, or aromatic, containing 1-5 ring heteroatoms
selected independently from N, O, and S; where all said phenyl or
Het groups are optionally substituted with F, Cl, Br, I, acetyl,
methyl, CN, NO.sub.2, CO.sub.2H, C.sub.1-C.sub.3 alkyl,
C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 alkyl-C(.dbd.O)--,
C.sub.1-C.sub.3 alkyl-C(.dbd.S)--, C.sub.1-C.sub.3
alkoxy-C(.dbd.S)--, C.sub.1-C.sub.3 alkyl-C(.dbd.O)O--,
C.sub.1-C.sub.3 alkyl-O--(C.dbd.O)--, C.sub.1-C.sub.3
alkyl-C(.dbd.O)NH--, C.sub.1-C.sub.3 alkyl-C(.dbd.NH)NH--,
C.sub.1-C.sub.3 alkyl-NH--(C.dbd.O)--, di-C.sub.1-C.sub.3
alkyl-N--(C.dbd.O)--, C.sub.1-C.sub.3
alkyl-C(.dbd.O)N(C.sub.1-C.sub.3 alkyl)-, C.sub.1-C.sub.3
alkyl-S(.dbd.O).sub.2NH-- or trifluoromethyl; all said methyl,
ethyl, C.sub.1-C.sub.3 alkyl, and cyclopropyl groups are optionally
substituted with OH; all said methyl groups are optionally
substituted with one, two, or three F atoms; R.sup.0 is H, F, Cl,
Br, I, CH.sub.3NH--, (CH.sub.3).sub.2N--, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.3-C.sub.6 cycloalkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, phenyl, monosubstituted phenyl,
O(C.sub.1-C.sub.4 alkyl), O--C(.dbd.O)(C.sub.1-C.sub.4 alkyl) or
C(.dbd.O)O(C.sub.1-C.sub.4 alkyl); where said alkyl, alkoxy,
cycloalkyl, alkenyl, alkynyl and phenyl groups are optionally
substituted with 1-3 substituents selected independently from F,
Cl, Br, I, OH, CN, cyanomethyl, nitro, phenyl and trifluoromethyl;
said C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.4 alkoxy groups also
optionally substituted with OCH.sub.3 or OCH.sub.2CH.sub.3; G is
G.sub.1, G.sub.2, R.sub.1a, R.sub.1b, R.sub.1c, R.sub.1d, R.sub.1e,
Ar.sub.1, Ar.sub.2 or Ar.sub.3; where G.sub.1 is C.sub.1-C.sub.6
alkyl optionally substituted with one amino, C.sub.1-C.sub.3
alkylamino, or dialkylamino group, said dialkylamino group
comprising two C.sub.1-C.sub.4 alkyl groups which may be identical
or non-identical; or G.sub.1 is a C.sub.3-C.sub.8 diamino alkyl
group; G.sub.2 is a 5- or 6-membered ring, which is saturated,
unsaturated, or aromatic, containing 1-3 ring heteroatoms selected
independently from N, O, and S, optionally substituted with 1-3
substituents selected independently from F, Cl, OH,
O(C.sub.1-C.sub.3 alkyl), OCH.sub.3, OCH.sub.2CH.sub.3,
CH.sub.3C(.dbd.O)NH, CH.sub.3C(.dbd.O)O, CN, CF.sub.3, and a
5-membered aromatic heterocyclic group containing 1-4 ring
heteroatoms selected independently from N, O, and S; R.sub.1a is
methyl, optionally substituted with 1-3 fluorine atoms or 1-3
chlorine atoms, or with OH, cyclopropoxy, or C.sub.1-C.sub.3
alkoxy, where said cyclopropoxy group or the C.sub.1-C.sub.3 alkyl
moieties of said C.sub.1-C.sub.3 alkoxy groups are optionally
substituted with one hydroxy or methoxy group, and where all
C.sub.3-alkyl groups within said C.sub.1-C.sub.4 alkoxy are
optionally further substituted with a second OH group; R.sub.1b is
CH(CH.sub.3)--C.sub.1-3 alkyl or C.sub.3-C.sub.6 cycloalkyl, said
alkyl and cycloalkyl groups optionally substituted with 1-3
substituents selected independently from F, Cl, Br, I, OH,
OCH.sub.3, and CN; R.sub.1c is (CH.sub.2).sub.nO.sub.mR'; where m
is 0 or 1; and where when m is 0, n is 1 or 2; when m is 1, n is 2
or 3; R' is C.sub.1-C.sub.6 alkyl, optionally substituted with 1-3
substituents selected independently from F, Cl, OH, OCH.sub.3,
OCH.sub.2CH.sub.3, and C.sub.3-C.sub.6 cycloalkyl; R.sub.1d is
C(A)(A')(B)--; where B is H or C.sub.1-4 alkyl, optionally
substituted with one or two OH groups; A and A' are independently H
or C.sub.1-4 alkyl, optionally substituted with one or two OH
groups; or A and A', together with the carbon atom to which they
are attached, form a 3- to 6-member saturated ring; R.sub.1e is
##STR00412## where q is 1 or 2; R.sub.2 and R.sub.3 are each
independently, H, F, Cl, Br, CH.sub.3, CH.sub.2F, CHF.sub.2,
CF.sub.3 OCH.sub.3, OCH.sub.2F, OCHF.sub.2, OCF.sub.3, ethyl,
n-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl
or methylsulfonyl; R.sub.4 is H, F, Cl, Br, CH.sub.3, CH.sub.2F,
CHF.sub.2, CF.sub.3 OCH.sub.3, OCH.sub.2F, OCHF.sub.2, OCF.sub.3,
ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl,
tert-butyl, methylsulfonyl, nitro, acetamido, amidinyl, cyano,
carbamoyl, methylcarbamoyl, dimethylcarbamoyl,
1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazol, 1,3,4-thiadiazol,
5-methyl-1,3,4-thiadiazol 1H-tetrazolyl, N-morpholyl carbonyl
amino, N-morpholylsulfonyl and N-pyrrolidinylcarbonylamino; R.sub.5
is H, F, Cl or methyl; R.sub.6 is H, F, Cl or methyl; Ar.sub.1 is
##STR00413## where U and V are, independently, N, CR.sub.2 or
CR.sub.3; R.sub.2, R.sub.3 and R.sub.4 are, independently, H, F,
Cl, Br, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3 OCH.sub.3,
OCH.sub.2F, OCHF.sub.2, OCF.sub.3, ethyl, n-propyl, isopropyl,
cyclopropyl, isobutyl, sec-butyl, tert-butyl, acetamido, amidinyl,
cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoyl,
1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazolyl,
1,3,4-thiadiazolyl, 5-methyl-1,3,4-thiadiazolyl, 1H-tetrazolyl,
N-morpholylcarbonylamino, N-morpholylsulfonyl,
N-pyrrolidinylcarbonylamino, and methylsulfonyl; R.sub.5 and
R.sub.6 are, independently, H, F, Cl or methyl; Ar.sub.2 is
##STR00414## where the dashed line represents alternative formal
locations for the second ring double bond; U is --S--, --O-- or
--N.dbd., and where when U is --O-- or --S--, V is --CH.dbd.,
--CCl.dbd. or --N.dbd.; when U is --N.dbd., V is --CH.dbd.,
--CCl.dbd., or --N.dbd.; R.sub.7 is H or methyl; R.sub.8 is H,
acetamido, methyl, F or Cl; Ar.sub.3 is ##STR00415## where U is
--NH--, --NCH.sub.3-- or --O--; R.sub.7 and R.sub.8 are,
independently, H, F, Cl, or methyl.
2. The compound of claim 1, or its pharmaceutically acceptable
salt.
3-68. (canceled)
69. A method for inhibiting MEK enzymes comprising contacting said
MEK enzyme with a composition comprising a compound of formula I or
a polymorph, solvate, ester, tautomer, pharmaceutically acceptable
salt or prodrug thereof, sufficient to inhibit said enzyme, wherein
said enzyme is inhibited ##STR00416## wherein Z is H or F; X is F,
Cl, CH.sub.3, CH.sub.2OH, CH.sub.2F, CHF.sub.2, or CF; Y is I, Br,
Cl, CF.sub.3, C.sub.1-C.sub.3 alkyl, C.sub.2-C.sub.3 alkenyl,
C.sub.2-C.sub.3 alkynyl, cyclopropyl, OMe, OEt, SMe, phenyl or Het,
where Het is a 5- to 10-membered mono- or bicyclic heterocyclic
group, which group is saturated, olefinic, or aromatic, containing
1-5 ring heteroatoms selected independently from N, 0, and S; where
all said phenyl or Het groups are optionally substituted with F,
Cl, Br, I, acetyl, methyl, CN, NO.sub.2, CO.sub.2H, C.sub.1-C.sub.3
alkyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 alkyl-C(.dbd.O)--,
C.sub.1-C.sub.3 alkyl-C(.dbd.S)--, C.sub.1-C.sub.3
alkoxy-C(.dbd.S)--, C.sub.1-C.sub.3 alkyl-C(.dbd.O)O--,
C.sub.1-C.sub.3 alkyl-O--(C.dbd.O)--, C.sub.1-C.sub.3
alkyl-C(.dbd.O)NH--, C.sub.1-C.sub.3 alkyl-C(.dbd.NH)NH--,
C.sub.1-C.sub.3 alkyl-NH--(C.dbd.O)--, di-C.sub.1-C.sub.3
alkyl-N--(C.dbd.O)--, C.sub.1-C.sub.3
alkyl-C(.dbd.O)N(C.sub.1-C.sub.3 alkyl)-, C.sub.1-C.sub.3
alkyl-S(.dbd.O).sub.2NH-- or trifluoromethyl; all said methyl,
ethyl, C.sub.1-C.sub.3 alkyl, and cyclopropyl groups are optionally
substituted with OH, all said methyl groups are optionally
substituted with one, two, or three F atoms; R.sup.0 is H, F, Cl,
Br, I, CH.sub.3NH--, (CH.sub.3).sub.2N--, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.3-C.sub.6 cycloalkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, phenyl, monosubstituted phenyl,
O(C.sub.1-C.sub.4 alkyl), O--C(.dbd.O)(C.sub.1-C.sub.4 alkyl) or
C(.dbd.O)O(C.sub.1-C.sub.4 alkyl); where said alkyl, alkoxy,
cycloalkyl, alkenyl, alkynyl and phenyl groups are optionally
substituted with 1-3 substituents selected independently from F,
Cl, Br, I, OH, CN, cyanomethyl, nitro, phenyl and trifluoromethyl;
said C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.4 alkoxy groups also
optionally substituted with OCH.sub.3 or OCH.sub.2CH.sub.3; G is
G.sub.1, G.sub.2, R.sub.1a, R.sub.1b, R.sub.1c, R.sub.1d, R.sub.1e,
Ar.sub.1, Ar.sub.2 or Ar.sub.3; where G.sub.1 is C.sub.1-C.sub.6
alkyl optionally substituted with one amino, C.sub.1-C.sub.3
alkylamino, or dialkylamino group, said dialkylamino group
comprising two C.sub.1-C.sub.4 alkyl groups which may be identical
or non-identical; or G.sub.1 is a C.sub.3-C.sub.8 diamino alkyl
group; G.sub.2 is a 5- or 6-membered ring, which is saturated,
unsaturated, or aromatic, containing 1-3 ring heteroatoms selected
independently from N, O, and S, optionally substituted with 1-3
substituents selected independently from F, Cl, OH,
O(C.sub.1-C.sub.3 alkyl), OCH.sub.3, OCH.sub.2CH.sub.3,
CH.sub.3C(.dbd.O)NH, CH.sub.3C(.dbd.O)O, CN, CF.sub.3, and a
5-membered aromatic heterocyclic group containing 1-4 ring
heteroatoms selected independently from N, O, and S; R.sub.1a is
methyl, optionally substituted with 1-3 fluorine atoms or 1-3
chlorine atoms, or with OH, cyclopropoxy, or C.sub.1-C.sub.3
alkoxy, where said cyclopropoxy group or the C.sub.1-C.sub.3 alkyl
moieties of said C.sub.1-C.sub.3 alkoxy groups are optionally
substituted with one hydroxy or methoxy group, and where all
C.sub.3-alkyl groups within said C.sub.1-C.sub.4 alkoxy are
optionally further substituted with a second OH group; R.sub.1b is
CH(CH.sub.3)--C.sub.1-3 alkyl or C.sub.3-C.sub.6 cycloalkyl, said
alkyl and cycloalkyl groups optionally substituted with 1-3
substituents selected independently from F, Cl, Br, I, OH,
OCH.sub.3, and CN; R.sub.1c is (CH.sub.2).sub.nO.sub.mR'; where m
is 0 or 1; and where when m is 0, n is 1 or 2: when m is 1, n is 2
or 3: R' is C.sub.1-C.sub.6 alkyl, optionally substituted with 1-3
substituents selected independently from F, Cl, OH, OCH.sub.3,
OCH.sub.2CH.sub.3, and C.sub.3-C.sub.6 cycloalkyl; R.sub.1d is
C(A)(A')(B)--; where B is H or C.sub.1-4 alkyl, optionally
substituted with one or two OH groups; A and A' are independently H
or C.sub.1-4 alkyl, optionally substituted with one or two OH
groups; or A and A', together with the carbon atom to which they
are attached, form a 3- to 6-member saturated ring; R.sub.1e is
##STR00417## where q is 1 or 2; R.sub.2 and R.sub.3 are each
independently, H, F, Cl, Br, CH.sub.3, CH.sub.2F, CHF.sub.2,
CF.sub.3 OCH.sub.3, OCH.sub.2F, OCHF.sub.2, OCF.sub.3, ethyl,
n-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl
or methylsulfonyl; R.sub.4 is H, F, Cl, Br, CH.sub.3, CH.sub.2F,
CHF.sub.2, CF.sub.3 OCH.sub.3, OCH.sub.2F, OCHF.sub.2, OCF.sub.3,
ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl,
tert-butyl, methylsulfonyl, nitro, acetamido, amidinyl, cyano,
carbamoyl, methylcarbamoyl, dimethylcarbamoyl,
1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazol, 1,3,4-thiadiazol,
5-methyl-1,3,4-thiadiazol 1H-tetrazolyl, N-morpholyl carbonyl
amino, N-morpholylsulfonyl and N-pyrrolidinylcarbonylamino; R.sub.5
is H, F, Cl or methyl: R.sub.6 is H, F, Cl or methyl; A.sub.1 is
##STR00418## where U and V are, independently, N, CR.sub.2 or
CR.sub.3; R.sub.2, R.sub.3 and R.sub.4 are, independently, H, F,
Cl, Br, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3 OCH.sub.3,
OCH.sub.2F, OCHF.sub.2, OCF.sub.3, ethyl, n-propyl, isopropyl,
cyclopropyl, isobutyl, sec-butyl, tert-butyl, acetamido, amidinyl,
cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoyl,
1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazolyl,
1,3,4-thiadiazolyl, 5-methyl-1,3,4-thiadiazolyl, 1H-tetrazolyl,
N-morpholylcarbonylamino, N-morpholylsulfonyl,
N-pyrrolidinylcarbonylamino, and methylsulfonyl; R.sub.5 and
R.sub.6 are, independently, H, F, Cl or methyl; Ar.sub.2 is
##STR00419## where the dashed line represents alternative formal
locations for the second ring double bond; U is --S--, --O-- or
--N.dbd., and where when U is --O-- or --S--, V is --CH.dbd.,
--CCl.dbd. or --N.dbd.; when U is --N.dbd., V is --CH.dbd.,
--CCl.dbd., or --N.dbd.; R.sub.7 is H or methyl: R.sub.8 is H,
acetamido, methyl, F or Cl; Ar.sub.3 is ##STR00420## where U is
--NH--, --NCH.sub.3-- or --O--; R.sub.7 and R.sub.8 are,
independently, H, F, Cl, or methyl.
70-101. (canceled)
102. A method for the treatment of an oncologic disease, a
proliferative disease or an inflammatory disease in an individual
or a method for inhibiting tumor size increase, reducing the size
of a tumor, or reducing tumor proliferation in an individual,
comprising administering to said individual an effective amount of
a compound of formula I or a pharmaceutically acceptable salt,
ester, or tautomer thereof: ##STR00421## wherein Z is H or F; X is
F, Cl, CH.sub.3, CH.sub.2OH, CH.sub.2F, CHF.sub.2, or CF.sub.3; Y
is I, Br, Cl, CF.sub.3, C.sub.1-C.sub.3 alkyl, C.sub.2-C.sub.3
alkenyl, C.sub.2-C.sub.3 alkynyl, cyclopropyl, O-Methyl, O-Ethyl,
S-Methyl or phenyl; where said phenyl group is optionally
substituted with F, Cl, Br, I, acetyl, methyl, CN, NO.sub.2,
CO.sub.2H, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy,
C.sub.1-C.sub.3 alkyl-C(.dbd.O)--, C.sub.1-C.sub.3
alkyl-C(.dbd.S)--, C.sub.1-C.sub.3 alkoxy-C(.dbd.S)--,
C.sub.1-C.sub.3 alkyl-C(.dbd.O)O--, C.sub.1-C.sub.3
alkyl-O--(C.dbd.O)--, C.sub.1-C.sub.3 alkyl-C(.dbd.O)NH--,
C.sub.1-C.sub.3 alkyl-C(.dbd.NH)NH--, C.sub.1-C.sub.3
alkyl-NH--(C.dbd.O)--, di-C.sub.1-C.sub.3 alkyl-N--(C.dbd.O)--,
C.sub.1-C.sub.3 alkyl-C(.dbd.O)N(C.sub.1-C.sub.3 alkyl)-,
C.sub.1-C.sub.3 alkyl-S(.dbd.O).sub.2NH-- or trifluoromethyl; all
said methyl, ethyl, C.sub.1-C.sub.3 alkyl, and cyclopropyl groups
are optionally substituted with OH; all said methyl groups are
optionally substituted with one, two, or three F atoms; R.sup.0 is
H, F, Cl, Br, I, CH.sub.3NH--, (CH.sub.3).sub.2N--, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.3-C.sub.6 cycloalkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, phenyl,
monosubstituted phenyl, O(C.sub.1-C.sub.4 alkyl),
O--C(.dbd.O)(C.sub.1-C.sub.4 alkyl) or C(.dbd.O)O(C.sub.1-C.sub.4
alkyl); where said alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl and
phenyl groups are optionally substituted with 1-3 substituents
independently selected from the group consisting of F, Cl, Br, I,
OH, CN, cyanomethyl, nitro, phenyl and trifluoromethyl; said
C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.4 alkoxy groups are also
optionally substituted with OCH.sub.3 or OCH.sub.2CH.sub.3; G is
G.sub.1, G.sub.2, R.sub.1a, R.sub.1b, R.sub.1c, R.sub.1d, R.sub.1e,
Ar.sub.1, Ar.sub.2 or Ar.sub.3; where G.sub.1 is C.sub.1-C.sub.6
alkyl optionally substituted with one amino, or is a
C.sub.3-C.sub.8 diamino alkyl group; G.sub.2 is a 5- or 6-membered
ring, which is saturated, unsaturated, or aromatic, containing 1-3
ring heteroatoms independently selected from the group consisting
of O, and S, optionally substituted with 1-3 substituents
independently selected from the group consisting of F, Cl, OH,
O(C.sub.1-C.sub.3 alkyl), OCH.sub.3, OCH.sub.2CH.sub.3,
CH.sub.3C(.dbd.O)NH, CH.sub.3C(.dbd.O)O, CN, CF.sub.3, and a
5-membered aromatic heterocyclic group containing 1-4 ring
heteroatoms independently selected from the group consisting of N,
O, and S; R.sub.1a is methyl, optionally substituted with 1-3
fluorine atoms or 1-3 chlorine atoms, or with OH, cyclopropoxy, or
C.sub.1-C.sub.3 alkoxy, where said cyclopropoxy group or the
C.sub.1-C.sub.3 alkyl moieties of said C.sub.1-C.sub.3 alkoxy
groups are optionally substituted with one hydroxy or methoxy
group, and where all C.sub.3-alkyl groups within said
C.sub.1-C.sub.3 alkoxy are optionally further substituted with a
second OH group; R.sub.1b is CH(CH.sub.3)--C.sub.1-3 alkyl or
C.sub.3-C.sub.6 cycloalkyl, said alkyl and cycloalkyl groups
optionally substituted with 1-3 substituents independently selected
from the group consisting of F, Cl, Br, I, OH, OCH.sub.3, and CN;
R.sub.1c is (CH.sub.2).sub.nO.sub.mR'; where m is 0 or 1; and where
when m is 0, n is 1 or 2; when m is 1, n is 2 or 3; R' is
C.sub.1-C.sub.6 alkyl, optionally substituted with 1-3 substituents
independently selected from the group consisting of F, Cl, OH,
OCH.sub.3, OCH.sub.2CH.sub.3, and C.sub.3-C.sub.6 cycloalkyl;
R.sub.1d is C(A)(A')(B)--; where B is H or C.sub.1-4 alkyl,
optionally substituted with one or two OH groups; A and A' are
independently H or C.sub.1-4 alkyl, optionally substituted with one
or two OH groups; or A and A', together with the carbon atom to
which they are attached, form a 3- to 6-member saturated ring;
R.sub.1e is ##STR00422## where q is 1 or 2; R.sub.2 and R.sub.3 are
each independently, H, F, Cl, Br, CH.sub.3, CH.sub.2F, CHF.sub.2,
CF.sub.3 OCH.sub.3, OCH.sub.2F, OCHF.sub.2, OCF.sub.3, ethyl,
n-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl
or methylsulfonyl; R.sub.4 is H, F, Cl, Br, CH.sub.3, CH.sub.2F,
CHF.sub.2, CF.sub.3 OCH.sub.3, OCH.sub.2F, OCHF.sub.2, OCF.sub.3,
ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl,
tert-butyl, methylsulfonyl, nitro, acetamido, amidinyl, cyano,
carbamoyl, methylcarbamoyl, dimethylcarbamoyl,
1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazol, 1,3,4-thiadiazol,
5-methyl-1,3,4-thiadiazol 1H-tetrazolyl, N-morpholyl carbonyl
amino, N-morpholylsulfonyl or N-pyrrolidinylcarbonylamino; R.sub.5
is H, F, Cl or methyl; R.sub.6 is H, F, Cl or methyl; Ar.sub.1 is
##STR00423## where U and V are, independently, N, CR.sub.2 or
CR.sub.3; R.sub.2, R.sub.3 and R.sub.4 are, independently, H, F,
Cl, Br, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3 OCH.sub.3,
OCH.sub.2F, OCHF.sub.2, OCF.sub.3, ethyl, n-propyl, isopropyl,
cyclopropyl, isobutyl, sec-butyl, tert-butyl, acetamido, amidinyl,
cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoyl,
1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazolyl,
1,3,4-thiadiazolyl, 5-methyl-1,3,4-thiadiazolyl, 1H-tetrazolyl,
N-morpholylcarbonylamino, N-morpholylsulfonyl,
N-pyrrolidinylcarbonylamino, or methylsulfonyl; R.sub.5 and R.sub.6
are, independently, H, F, Cl or methyl; Ar.sub.2 is ##STR00424##
where the dashed line represents alternative formal locations for
the second ring double bond; U is --S--, --O-- or --N.dbd., and
where when U is --O-- or --S--, V is --CH.dbd., --CCl.dbd. or
--N.dbd.; when U is --N.dbd., V is --CH.dbd., --CCl.dbd., or
--N.dbd.; R.sub.7 is H or methyl; R.sub.8 is H, acetamido, methyl,
F or Cl; Ar.sub.3 is ##STR00425## where U is --NH--, --NCH.sub.3--
or --O--; and R.sub.7 and R.sub.8 are, independently, H, F, Cl, or
methyl.
103. A method according to claim 102, which is for the treatment of
an oncologic disease.
104. A method according to claim 102, wherein the compound of
formula I is selected from the group consisting of: ##STR00426##
##STR00427##
105. A method according to claim 102, wherein said proliferative
disease is cancer, which is brain cancer, breast cancer, lung
cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal
cancer, colorectal cancer, leukemia, myeloid leukemia,
glioblastoma, follicular lymphona, pre-B acute leukemia, chronic
lymphocytic B-leukemia, mesothelioma, small cell line cancer,
non-small-cell lung cancer, melanoma, pancreatic cancer, thyroid
carcinoma, hepatocellular carcinoma, biliary carcinoma acute
myeloid leukemia or multiple myeloma.
106. A method according to claim 102, which is for inhibiting tumor
size increase, reducing the size of a tumor, or reducing tumor
proliferation in an individual, wherein said tumor occurs in the
brain, breast, lung, ovaries, pancreas, prostate, kidney, colon or
rectum.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part application of
International Application Ser. No PCT/US2006/028326 filed Jul. 21,
2006, which is incorporated herein by reference in its entirety and
to which application we claim priority under 35 USC .sctn.120,
which claims priority to U.S. Provisional Application Ser. No.
60/701,814, filed Jul. 21, 2005; to U.S. Provisional Application
Ser. No. 60/706,719, filed Aug. 8, 2005; and to U.S. Provisional
Application Ser. No. 60/731,633, filed Oct. 28, 2005 all of which
are hereby incorporated by reference herein in their entirety.
[0002] This application also claims the benefit of U.S. Provisional
Application No. 60/833,886 filed Jul. 28, 2006, which application
is incorporated herein by reference.
FIELD OF THE INVENTION
[0003] This invention concerns N-(2-arylamino) aryl sulfonamides,
which are inhibitors of MEK. Such compounds are useful in the
treatment of cancer and other hyperproliferative diseases.
BACKGROUND OF THE INVENTION
[0004] Oncogenes--genes that contribute to the production of
cancers--are generally mutated forms of certain normal cellular
genes ("proto-oncogenes"). Oncogenes often encode abnormal versions
of signal pathway components, such as receptor tyrosine kinases,
serine-threonine kinases, or downstream signaling molecules. The
central downstream signaling molecules are the Ras proteins, which
are anchored on the inner surfaces of cytoplasmic membranes, and
which hydrolyze bound guanosine triphosphate (GTP) to guanosine
diphosphate (GDP). When activated by a growth factor, growth factor
receptors initiate a chain of reactions that leads to the
activation of guanine nucleotide exchange activity on Ras. Ras
alternates between an active "on" state with a bound GTP (hereafter
"Ras.GTP") and an inactive "off state with a bound GDP. The active
"on" state, Ras.GTP, binds to and activates proteins that control
the growth and differentiation of cells.
[0005] For example, in the "mitogen-activated protein kinase (MAP
kinase) cascade," Ras.GTP leads to the activation of a cascade of
serine/threonine kinases. One of several groups of kinases known to
require a Ras.GTP for their own activation is the Raf family. The
Raf proteins activate "MEK1" and "MEK2," abbreviations for
mitogen-activated ERK-activating kinases (where ERK is
extracellular signal-regulated protein kinase, another designation
for MAPK). MEK1 and MEK2 are dual-function serine/threonine and
tyrosine protein kinases and are also known as MAP kinase kinases.
Thus, Ras.GTP activates Raf, which activates MEK1 and MEK2, which
activate MAP kinase (MAPK). Activation of MAP kinase by mitogens
appears to be essential for proliferation, and constitutive
activation of this kinase is sufficient to induce cellular
transformation. Blockade of downstream Ras signaling, as by use of
a dominant negative Raf-1 protein, can completely inhibit
mitogenesis, whether induced from cell surface receptors or from
oncogenic Ras mutants.
[0006] The interaction of Raf and Ras is a key regulatory step in
the control of cell proliferation. To date, no substrates of MEK
other than MAPK have been identified; however, recent reports
indicate that MEK may also be activated by other upstream signal
proteins such as MEK kinase or MEKK1 and PKC. Activated MAPK
translocates and accumulates in the nucleus, where it can
phosphorylate and activate transcription factors such as Elk-1 and
Sapla, leading to the enhanced expression of genes such as that for
c-fos.
[0007] Once activated, Raf and other kinases phosphorylate MEK on
two neighboring serine residues, S.sup.218 and S.sup.222 in the
case of MEK1. These phosphorylations are required for activation of
MEK as a kinase. In turn, MEK phosphorylates MAP kinase on two
residues separated by a single amino acid: a tyrosine, Y.sup.185
and a threonine, T.sup.183. MEK appears to associate strongly with
MAP kinase prior to phosphorylating it, suggesting that
phosphorylation of MAP kinase by MEK may require a prior strong
interaction between the two proteins. Two factors--MEK's unusual
specificity and its requirement for a strong interaction with MAP
kinase prior to phosphorylation--suggest that MEK's mechanism of
action may differ sufficiently from the mechanisms of other protein
kinases as to allow for selective inhibitors of MEK. Possibly, such
inhibitors would operate through allosteric mechanisms rather than
through the more usual mechanism involving blockage of an ATP
binding site.
[0008] Thus, MEK1 and MEK2 are validated and accepted targets for
anti-proliferative therapies, even when the oncogenic mutation does
not affect MEK structure or expression. See, e.g., U.S. Patent
Publications 2003/0149015 by Barrett et al. and 2004/0029898 by
Boyle et al.
[0009] Several examples of
1-substituted-2(p-substituted-phenylamino)-aryl inhibitors of MEK
have been reported. U.S. Pat. Nos. 6,440,966 and 6,750,217 and
corresponding publication WO 00/42003 described carboxylic and
hydroxamic acid esters and N-substituted amide derivatives of
sulfonamide-substituted-2(4-iodophenylamino)-benzoic acid esters
and N-substituted benzamides as functioning as MEK inhibitors. The
sulfonamide may also be N-substituted.
[0010] U.S. Pat. No. 6,545,030 and corresponding publication WO
00/42029 describe MEK inhibitors that are
1-heterocyclyl-2(4-iodophenylamino)-benzene, where the heterocycle
is a five-membered nitrogen-containing ring such as pyrazole,
triazole, oxazole, isoxazole, and isoxazolinone. The more recent
U.S. Patent Publication 2005/004186 describes related compounds in
which the 4-iodo substituent of the '030 patent is replaced by a
very broad genus of moieties including alkyl, alkoxy, acyloxy,
alkenyl, carbamoyl, carbamoylalkyl, carboxyl, carboxylalkyl,
N-acylsulfonamido, and others.
[0011] U.S. Pat. No. 6,469,004 and corresponding publication WO
00/42022 describe carboxylic and hydroxamic acid esters of a group
of heterocyclo-condensed phenylene compounds, i.e., benzimidazoles,
benzooxazoles, benzothiazoles, benzothiadiazoles, quinazolines,
etc. The heterocycles are 7-F-6-(4-iodo-phenylamino)-5-carboxylic
acid esters, carboxylic acid amides or hydroxamic acid esters. More
recent publication U.S. 2005/0026970 described similar compounds in
which the 4-iodo substituent was replaced by a very broad genus of
structures. Related compounds are described in patent publications
WO 03/077855, WO 03/77914 and US 2005/0554701. Further examples of
2-(4-iodophenylamino)-phenylhydroxamic acid esters which are
reported to be useful as MEK inhibitors can be found in WO
2005/028426.
[0012] Patent Publication WO 02/06213 and corresponding U.S.
application Ser. No. 10/333,399 (U.S. 2004/0054172) describe
hydroxy-substituted acid esters of 1-oxamic
acid-2(4-halophenylamino)-3,4-difluorobenzene. U.S. Pat. No.
6,891,066 and corresponding publication WO 03/62191 describe
similar compounds wherein the 4-halo substituent is replaced by a
very broad genus of structures. Among the substituents in the
4-position were methyl, ethyl, ethynyl, and 2-hydroxyethyl.
Specific related compounds are described in U.S. Pat. No.
6,770,778.
[0013] Patent Publication WO 04/083167, published Sep. 30, 2004,
(in Japanese) discloses more than two thousand--but provides NMR
data for only 400-1-(N-substituted sulfonyl
urea)-2(2,4-dihalophenylamino)-3,4-difluorobenzenes and asserts
that they useful as MEK inhibitors. Data indicating inhibition of
MEK were presented for a subgroup of just twelve. In addition to a
secondary or tertiary amine, these twelve compounds all contained
one of the following groups: an N, N-disubstituted sulfonyl urea,
N-piperazinesulfonamide, N-piperidinesulfonamide or
N-pyrrolidinesulfonamide.
[0014] The MEK cascade has also been implicated in inflammatory
diseases and disorders. U.S. Application Publication No.
2006/0030610 to Koch et al., U.S. Application Publication No.
2006/0140872 to Fume et al. This includes both acute and chronic
inflammation disorders. Examples of such disorders are allergic
contact dermatitis, rheumatoid arthritis, osteoarthritis,
inflammatory bowel diseases, chronic obstructive pulmonary
disorder, psoriasis, multiple sclerosis, asthma, diseases and
disorders related to diabetic complications, and inflammatory
complications of the cardiovascular system such as acute coronary
syndrome. Among inflammatory bowel diseases are Crohn's disease and
ulcerative colitis.
[0015] All cited references are incorporated herein by
reference.
SUMMARY OF THE INVENTION
[0016] This invention provides compounds of formula I, or
pharmaceutically acceptable salts, solvates, polymorphs, esters,
tautomers or prodrugs thereof:
##STR00001##
wherein
[0017] Z is H or F;
[0018] X is F, Cl, CH.sub.3, CH.sub.2OH, CH.sub.2F, CHF.sub.2, or
CF.sub.3;
[0019] Y is I, Br, Cl, CF.sub.3, C.sub.1-C.sub.3 alkyl,
C.sub.2-C.sub.3 alkenyl, C.sub.2-C.sub.3 alkynyl, cyclopropyl, OMe,
OEt, SMe, phenyl or Het, where Het is a 5- to 10-membered mono- or
bicyclic heterocyclic group, which group is saturated, olefinic, or
aromatic, containing 1-5 ring heteroatoms selected independently
from N, O, and S; where [0020] all said phenyl or Het groups are
optionally substituted with F, Cl, Br, I, acetyl, methyl, CN,
NO.sub.2, CO.sub.2H, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy,
C.sub.1-C.sub.3 alkyl-C(.dbd.O)--, C.sub.1-C.sub.3
alkyl-C(.dbd.S)--, C.sub.1-C.sub.3 alkoxy-C(.dbd.S)--,
C.sub.1-C.sub.3 alkyl-C(.dbd.O)O--, C.sub.1-C.sub.3
alkyl-0-(C.dbd.O)--, C.sub.1-C.sub.3 alkyl-C(.dbd.O)NH--,
C.sub.1-C.sub.3 alkyl-C(.dbd.NH)NH--, C.sub.1-C.sub.3
alkyl-NH--(C.dbd.O)--, di-C.sub.1-C.sub.3 alkyl-N--(C.dbd.O)--,
C.sub.1-C.sub.3 alkyl-C(--O)N(C.sub.1-C.sub.3 alkyl)-,
C.sub.1-C.sub.3 alkyl-S(--O).sub.2NH-- or trifluoromethyl; [0021]
all said methyl, ethyl, C.sub.1-C.sub.3 alkyl, and cyclopropyl
groups are optionally substituted with OH; [0022] all said methyl
groups are optionally substituted with one, two, or three F
atoms;
[0023] R.sup.0 is H, F, Cl, Br, I, CH.sub.3NH--,
(CH.sub.3).sub.2N--, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.3-C.sub.6 cycloalkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, phenyl, monosubstituted phenyl,
O(C.sub.1-C.sub.4 alkyl),
O--C(.dbd.O)(C.sub.1-C.sub.4 alkyl) or C(.dbd.O)O(C.sub.1-C.sub.4
alkyl); where [0024] said alkyl, alkoxy, cycloalkyl, alkenyl,
alkynyl and phenyl groups are optionally substituted with 1-3
substituents selected independently from F, Cl, Br, I, OH, CN,
cyanomethyl, nitro, phenyl and trifluoromethyl; [0025] said
C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.4 alkoxy groups also
optionally substituted with OCH.sub.3 or OCH.sub.2CH.sub.3;
[0026] G is G.sub.1, G.sub.2, R.sub.1a, R.sub.1b, R.sub.1c,
R.sub.1d, R.sub.1e, Ar.sub.1, Ar.sub.2 or Ar.sub.3; where [0027]
G.sub.1 is C.sub.1-C.sub.6 alkyl optionally substituted with one
amino, C.sub.1-C.sub.3 alkylamino, or dialkylamino group, said
dialkylamino group comprising two C.sub.1-C.sub.4 alkyl groups
which may be identical or non-identical; or [0028] G.sub.1 is a
C.sub.3-C.sub.8 diamino alkyl group; [0029] G.sub.2 is a 5- or
6-membered ring, which is saturated, unsaturated, or aromatic,
containing 1-3 ring heteroatoms selected independently from N, O,
and S, optionally substituted with 1-3 substituents selected
independently from F, Cl, OH, O(C.sub.1-C.sub.3 alkyl), OCH.sub.3,
OCH.sub.2CH.sub.3, CH.sub.3C(.dbd.O)NH, CH.sub.3C(.dbd.O)O, CN,
CF.sub.3, and a 5-membered aromatic heterocyclic group containing
1-4 ring heteroatoms selected independently from N, O, and S;
[0030] R.sub.1a is methyl, optionally substituted with 1-3 fluorine
atoms or 1-3 chlorine atoms, or with OH, cyclopropoxy, or
C.sub.1-C.sub.3 alkoxy, where said cyclopropoxy group or the
C.sub.1-C.sub.3 alkyl moieties of said C.sub.1-C.sub.3 alkoxy
groups are optionally substituted with one hydroxy or methoxy
group, and where all C.sub.3-alkyl groups within said
C.sub.1-C.sub.4 alkoxy are optionally further substituted with a
second OH group; [0031] R.sub.1b is CH(CH.sub.3)--C.sub.1-3 alkyl
or C.sub.3-C.sub.6 cycloalkyl, said alkyl and cycloalkyl groups
optionally substituted with 1-3 substituents selected independently
from F, Cl, Br, I, OH, OCH.sub.3, and CN; [0032] R.sub.1c is
(CH.sub.2).sub.nO.sub.mR'; where [0033] m is 0 or 1; and where
[0034] when m is 0, n is 1 or 2; [0035] when m is 1, n is 2 or 3;
[0036] R' is C.sub.1-C.sub.6 alkyl, optionally substituted with 1-3
substituents selected independently from F, Cl, OH, OCH.sub.3,
OCH.sub.2CH.sub.3, and C.sub.3-C.sub.6 cycloalkyl; [0037] R.sub.1d
is C(A)(A')(B)--; where [0038] B is H or C.sub.1-4 alkyl,
optionally substituted with one or two OH groups; [0039] A and A'
are independently H or C.sub.1-4 alkyl, optionally substituted with
one or two OH groups; or [0040] A and A', together with the carbon
atom to which they are attached, form a 3- to 6-member saturated
ring; [0041] R.sub.1e is
[0041] ##STR00002## [0042] where [0043] q is 1 or 2; [0044] R.sub.2
and R.sub.3 are each independently, H, F, Cl, Br, CH.sub.3,
CH.sub.2F, CHF.sub.2, CF.sub.3 OCH.sub.3, OCH.sub.2F, OCHF.sub.2,
OCF.sub.3, ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl,
sec-butyl, tert-butyl or methylsulfonyl; [0045] R.sub.4 is H, F,
Cl, Br, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3 OCH.sub.3,
OCH.sub.2F, OCHF.sub.2, OCF.sub.3, ethyl, n-propyl, isopropyl,
cyclopropyl, isobutyl, sec-butyl, tert-butyl, methylsulfonyl,
nitro, acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl,
dimethylcarbamoyl, 1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazol,
1,3,4-thiadiazol, 5-methyl-1,3,4-thiadiazol 1H-tetrazolyl,
N-morpholyl carbonyl amino, N-morpholylsulfonyl and
N-pyrrolidinylcarbonylamino; [0046] R.sub.5 is H, F, Cl or methyl;
[0047] R.sub.6 is H, F, Cl or methyl; [0048] Ar.sub.1 is
[0048] ##STR00003## [0049] where [0050] U and V are, independently,
N, CR.sub.2 or CR.sub.3; [0051] R.sub.2, R.sub.3 and R.sub.4 are,
independently, H, F, Cl, Br, CH.sub.3, CH.sub.2F, CHF.sub.2,
CF.sub.3 OCH.sub.3, OCH.sub.2F, OCHF.sub.2, OCF.sub.3, ethyl,
n-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl,
acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl,
dimethylcarbamoyl, 1,3,4-oxadiazol-2-yl,
5-methyl-1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl,
5-methyl-1,3,4-thiadiazolyl, 1H-tetrazolyl,
N-morpholylcarbonylamino, N-morpholylsulfonyl,
N-pyrrolidinylcarbonylamino, and methylsulfonyl; [0052] R.sub.5 and
R.sub.6 are, independently, H, F, Cl or methyl; [0053] Ar.sub.2
is
[0053] ##STR00004## [0054] where [0055] the dashed line represents
alternative formal locations for the second ring double bond;
[0056] U is --S--, --O-- or --N.dbd., and where [0057] when U is
--O-- or --S--, V is --CH.dbd., --CCl.dbd. or --N.dbd.; [0058] when
U is --N.dbd., V is --CH.dbd., --CCl.dbd., or --N.dbd.; [0059]
R.sub.7 is H or methyl; [0060] R.sub.8 is H, acetamido, methyl, F
or Cl; [0061] Ar.sub.3 is
[0061] ##STR00005## [0062] where [0063] U is --NH--, --NCH.sub.3--
or --O--; [0064] R.sub.7 and R.sub.8 are, independently, H, F, Cl,
or methyl.
[0065] In some embodiments, the invention provides a compound of
formula I, where G is G.sub.1 or G.sub.2. In other embodiments, G
is G.sub.1. In further or additional embodiments, G is G.sub.2.
[0066] In some embodiments, the invention provides a compound of
formula I, where G is R.sub.1a, R.sub.1b, R.sub.1c, R.sub.1d,
R.sub.1e, Ar.sub.1, Ar.sub.2 or Ar.sub.3. In further or additional
embodiments, G is R.sub.1a, R.sub.1b, R.sub.1c, R.sub.1d or
R.sub.1e. In further or additional embodiments, G is R.sub.1a. In
further or additional embodiments, G is R.sub.1b. In further or
additional embodiments, G is R.sub.1c. In further or additional
embodiments, G is R.sub.1d. In further or additional embodiments, G
is R.sub.1e. In further or additional embodiments, G is Ar.sub.1,
Ar.sub.2 or Ar.sub.3. In further or additional embodiments, G is
Ar.sub.1. In further or additional embodiments, G is Ar.sub.2. In
further or additional embodiments, G is Ar.sub.3
[0067] In some embodiments, the invention provides compounds of
formula I, or their pharmaceutically acceptable salts. In further
or additional embodiments, the invention provides compounds of
formula I, or their solvates. In further or additional embodiments,
the invention provides compounds of formula I, or their polymorphs.
In further or additional embodiments, the invention provides
compounds of formula I, or their tautomers. In further or
additional embodiments, the invention provides compounds of formula
I, or their prodrugs.
[0068] In some embodiments, Z is H. In some embodiments, Z is F. In
some embodiments, X is F. In some embodiments, X is Cl. In some
embodiments, X is CH.sub.3. In some embodiments, X is CH.sub.2OH.
In some embodiments, X is CH.sub.2F. In some embodiments, X is
CHF.sub.2. In some embodiments, X is CF.sub.3. In some embodiments,
X is F, Cl, or CH.sub.3.
[0069] In some embodiments, G is G.sub.1 or G.sub.2, X is F, Cl, or
CH.sub.3; Y is I, Br, Cl, CF.sub.3, C.sub.1-C.sub.3 alkyl, phenyl,
pyridyl, pyrrolyl, pyrazolyl, said phenyl, pyridyl, pyrrolyl, and
pyrazolyl groups optionally substituted with F, Cl, Br, I, acetyl,
methyl, CN, NO.sub.2, CO.sub.2H, C.sub.1-C.sub.3 alkyl,
C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 alkyl-C(.dbd.O)--,
C.sub.1-C.sub.3 alkyl-C(.dbd.S)--, C.sub.1-C.sub.3
alkoxy-C(.dbd.S)--, C.sub.1-C.sub.3 alkyl-C(.dbd.O)O--,
C.sub.1-C.sub.3 alkyl-O--(C.dbd.O)--, C.sub.1-C.sub.3
alkyl-C(.dbd.O)NH--, C.sub.1-C.sub.3 alkyl-C(.dbd.NH)NH--,
C.sub.1-C.sub.3 alkyl-NH--(C.dbd.O)--, di-C.sub.1-C.sub.3
alkyl-N--(C.dbd.O)--, C.sub.1-C.sub.3
alkyl-C(.dbd.O)N(C.sub.1-C.sub.3 alkyl)-, C.sub.1-C.sub.3
alkyl-S(.dbd.O).sub.2NH-- or trifluoromethyl; and Z is H or F. In
further or additional embodiments, G is G.sub.1 or G.sub.2, and
R.sup.0 is F, Cl, C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkoxy,
said C.sub.1-C.sub.4 alkyl group and the C.sub.1-C.sub.4 alkyl
moiety of said C.sub.1-C.sub.4 alkoxy group optionally substituted
with F, Cl, OCH.sub.3, or OCH.sub.2CH.sub.3. In further or
additional embodiments, G is G.sub.1 or G.sub.2, and R.sup.0 is H,
F, Cl, C.sub.1-C.sub.4 alkyl, methoxy, ethoxy, or
2-methoxy-ethoxy.
[0070] In some embodiments, G is N-methyl-2-aminoethyl. In further
or additional embodiments, G.sub.1 is
(CH.sub.3).sub.2N--CH.sub.2CH.sub.2--NH--(CH.sub.2).sub.n--, where
n is 1, 2, or 3. In further or additional embodiments, G.sub.1 is
(CH.sub.3).sub.2N--CH.sub.2CH--NH--(CH.sub.2)--, where n is 1, 2,
or 3, and X is F. In further or additional embodiments, G.sub.1 is
(CH.sub.3).sub.2N--CH.sub.2CH.sub.2--NH--(CH.sub.2).sub.n--, where
n is 1, 2, or 3, X is F and Z is F.
[0071] In some embodiments, G.sub.2 is 1-piperidyl, 2-piperidyl,
3-piperidyl, or 4-piperidyl. In further or additional embodiments,
G.sub.2 is morpholyl, 1-piperazyl, or 2-piperazyl.
[0072] In some embodiments, G is R.sub.1a, R.sub.1b, R.sub.1c,
R.sub.1d, R.sub.1e, Ar.sub.1, Ar.sub.2 or Ar.sub.3 and X is F, Cl,
or CH.sub.3. In further or additional embodiments, G is R.sub.1a,
R.sub.1b, R.sub.1c, R.sub.1d, R.sub.1e, Ar.sub.1, Ar.sub.2 or
Ar.sub.3, X is F, Cl, or CH.sub.3 and Y is I, Br, Cl, CF.sub.3, or
C.sub.1-C.sub.3 alkyl In further or additional embodiments, G is
R.sub.1a, R.sub.1b, R.sub.1c, R.sub.1d, R.sub.1e, Ar.sub.1,
Ar.sub.2 or Ar.sub.3, X is F, Cl, or CH.sub.3, Y is I, Br, Cl,
CF.sub.3, or C.sub.1-C.sub.3 alkyl and Z is H or F
[0073] In further or additional embodiments, G is R.sub.1a,
R.sub.1b, R.sub.1c, R.sub.1d, R.sub.1e, Ar.sub.1, Ar.sub.2 or
Ar.sub.3 and R.sup.0 is F, Cl, C.sub.1-C.sub.4 alkyl or
C.sub.1-C.sub.4 alkoxy, said C.sub.1-C.sub.4 alkyl group and the
C.sub.1-C.sub.4 alkyl moiety of said C.sub.1-C.sub.4 alkoxy group
optionally substituted with F, Cl, OCH.sub.3, or OCH.sub.2CH.sub.3.
In further or additional embodiments, G is R.sub.1a, R.sub.1b,
R.sub.1c, R.sub.1d, R.sub.1e, Ar.sub.1, Ar.sub.2 or Ar.sub.3 and
R.sup.0 is H, F, Cl, C.sub.1-C.sub.4 alkyl, methoxy, ethoxy, or
2-methoxy-ethoxy.
[0074] In some embodiments, G is R.sub.1a; and Z is F. In further
or additional embodiments, G is R.sub.1a where R.sub.1a is
CH.sub.3, R.sup.0 is H; and Y is Br, I, CF.sub.3, or CH.sub.3. In
some embodiments, G is R.sub.1b and Z is F. In further or
additional embodiments, G is R.sub.1b, Z is F, and R.sup.0 is H, F,
or OCH.sub.3. In further or additional embodiments, G is R.sub.1b,
Z is F, R.sup.0 is H, F, or OCH.sub.3, and X is F or CH.sub.3. In
further or additional embodiments, G is R.sub.1b, Z is F, R.sup.0
is H, F, or OCH.sub.3, X is F or CH.sub.3 and Y is Br, I or
CH.sub.3. In further or additional embodiments, G is R.sub.1b where
R.sub.1b is C.sub.3-C.sub.6 cycloalkyl. In further or additional
embodiments, G is R.sub.1b where R.sub.1b is substituted
C.sub.3-C.sub.6 cycloalkyl. In further or additional embodiments, G
is R.sub.1b where R.sub.1b is unsubstituted C.sub.3-C.sub.6
cycloalkyl. In further or additional embodiments, G is R.sub.1b
where R.sub.1b is unsubstituted C.sub.3-C.sub.6 cycloalkyl and
R.sup.0 is H. In further or additional embodiments, G is R.sub.1b
where R.sub.1b is isopropyl or cyclopropyl.
[0075] In some embodiments, G is R.sub.1c, and Y is I, Br,
CH.sub.3, or CF.sub.3. In further or additional embodiments, G is
R.sub.1c, Y is I, Br, CH.sub.3, or CF.sub.3, and Z is F. In further
or additional embodiments, G is R.sub.1c, Y is I, Br, CH.sub.3, or
CF.sub.3, Z is F and m is zero.
[0076] In some embodiments, G is R.sub.1d and R.sup.0 is fluoro,
chloro, methyl, ethyl, propyl, isopropyl, sec-butyl, iso-butyl,
tert-butyl, cyclopropyl, cyclobutyl, fluoromethyl, methoxy,
fluoromethoxy, methylamino or dimethylamino. In further of
additional embodiments, G is R.sub.1d, R.sup.0 is fluoro, chloro,
methyl, ethyl, propyl, isopropyl, sec-butyl, iso-butyl, tert-butyl,
cyclopropyl, cyclobutyl, fluoromethyl, methoxy, fluoromethoxy,
methylamino or dimethylamino and X is F, Cl, CH.sub.3, or mono-,
di- or tri-fluoromethyl. In further or additional embodiments, G is
R.sub.1d, R.sup.0 is fluoro, chloro, methyl, ethyl, propyl,
isopropyl, sec-butyl, iso-butyl, tert-butyl, cyclopropyl,
cyclobutyl, fluoromethyl, methoxy, fluoromethoxy, methylamino or
dimethylamino, X is F, Cl, CH.sub.3, or mono-, di- or
tri-fluoromethyl and Y is I, Br, Cl, or mono-, di- or
tri-fluoromethyl. In further or additional embodiments, G is
R.sub.1d, R.sup.0 is fluoro, chloro, methyl, ethyl, propyl,
isopropyl, sec-butyl, iso-butyl, tert-butyl, cyclopropyl,
cyclobutyl, fluoromethyl, methoxy, fluoromethoxy, methylamino or
dimethylamino, X is F, Cl, CH.sub.3, or mono-, di- or
tri-fluoromethyl, Y is I, Br, Cl, or mono-, di- or tri-fluoromethyl
and Z is H or F. In further or additional embodiments, G is
R.sub.1d and R.sup.0 is F, Cl, methyl, ethyl, methoxy, ethoxy, or
2-methoxy-ethoxy.
[0077] In further or additional embodiments, G is R.sub.1d, R.sup.0
is F, Cl, methyl, ethyl, methoxy, ethoxy, or 2-methoxy-ethoxy and X
is F, Cl, or CH.sub.3. In further or additional embodiments, G is
R.sub.1d, R.sup.0 is F, Cl, methyl, ethyl, methoxy, ethoxy, or
2-methoxy-ethoxy, X is F, Cl, or CH.sub.3 and Y is I, Br, Cl, or
mono-, di- or tri-fluoromethyl. In further or additional
embodiments, G is R.sub.1d, R.sup.0 is F, Cl, methyl, ethyl,
methoxy, ethoxy, or 2-methoxy-ethoxy, X is F, Cl, or CH.sub.3, Y is
I, Br, Cl, or mono-, di- or tri-fluoromethyl and Z is H or F. In
further or additional embodiments, G is R.sub.1d and R.sup.0 is H;
X is F, Cl, CH.sub.3, or mono-, di- or tri-fluoromethyl. In further
or additional embodiments, G is R.sub.1d, R.sup.0 is H; X is F, Cl,
CH.sub.3, or mono-, di- or tri-fluoromethyl and Y is I, Br, Cl, or
mono-, di- or tri-fluoromethyl. In further or additional
embodiments, G is R.sub.1d, R.sup.0 is H; X is F, Cl, CH.sub.3, or
mono-, di- or tri-fluoromethyl, Y is I, Br, Cl, or mono-, di- or
tri-fluoromethyl and Z is H or F.
[0078] In further or additional embodiments, G is R.sub.1d where
R.sub.1d is C(A)(A') is C.sub.1-C.sub.6 cycloalkyl. In further or
additional embodiments, G is R.sub.1d where R.sub.1d is C(A)(A') is
C.sub.1-C.sub.6 cycloalkyl and B is H. In further or additional
embodiments, G is R.sub.1d where R.sub.1d is C(A)(A') is
C.sub.1-C.sub.6 cycloalkyl and B is methyl, ethyl, 2-hydroxyethyl,
n-propyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 3,4-dihydroxybutyl,
isopropyl, 1-methyl-2-hydroxy ethyl, n-butyl, sec-butyl, isobutyl,
or 2-hydroxymethyl-3-hydroxy propyl.
[0079] In further or additional embodiments, G is R.sub.1d where
R.sub.1d is C(A)(A') is C.sub.1-C.sub.6 cycloalkyl and B is
2,3-dihydroxypropyl or 3,4-dihydroxybutyl. In further or additional
embodiments, G is R.sub.1d where R.sub.1d is C(A)(A') is
C.sub.1-C.sub.6 cycloalkyl and B is 2,3-dihydroxypropyl or
3,4-dihydroxybutyl, in which the chiral carbon in B is in the R
configuration. In further or additional embodiments, G is R.sub.1d
where R.sub.1d is C(A)(A') is C.sub.1-C.sub.6 cycloalkyl and B is
2,3-dihydroxypropyl or 3,4-dihydroxybutyl, in which the chiral
carbon in B is in the S configuration. In further or additional
embodiments, G is R.sub.1d where R.sub.1d is C(A)(A') is
C.sub.1-C.sub.6 cycloalkyl and B is methyl, optionally substituted
with one OH group, or C.sub.2-C.sub.4 alkyl, optionally substituted
with one or two OH groups. In further or additional embodiments, G
is R.sub.1d where R.sub.1d is C(A)(A') is C.sub.1-C.sub.6
cycloalkyl and R.sup.0 is fluoro, chloro, methyl, ethyl, propyl,
isopropyl, sec-butyl, iso-butyl, tert-butyl, cyclopropyl,
cyclobutyl, fluoromethyl, methoxy, fluoromethoxy, methylamino or
dimethylamino. In further or additional embodiments, G is R.sub.1d
where R.sub.1d is C(A)(A') is C.sub.1-C.sub.6 cycloalkyl and
R.sup.0 is F, Cl, methyl, ethyl, methoxy, ethoxy, or
2-methoxy-ethoxy. In further or additional embodiments, G is
R.sub.1d where R.sub.1d is C(A)(A') is C.sub.1-C.sub.6 cycloalkyl
and R.sup.0 is H; X is F, Cl, CH.sub.3, or mono-, di- or
tri-fluoromethyl.
[0080] In further or additional embodiments, the invention provides
a composition comprising a compound of formula I, where G is
R.sub.1d where R.sub.1d is C(A)(A') is C.sub.3-C.sub.6 cycloalkyl
and B is 2,3-dihydroxypropyl or 3,4-dihydroxybutyl, in which the
chiral carbon in B is in the R configuration, which is
substantially free of the S isomer. In further or additional
embodiments, the invention provides a composition comprising a
compound of formula I, where G is R.sub.1d where R.sub.1d is
C(A)(A') is C.sub.1-C.sub.6 cycloalkyl and B is
2,3-dihydroxypropyl, in which the chiral carbon in B is in the R
configuration, which is substantially free of the S isomer. In
further or additional embodiments, the invention provides a
composition comprising a compound of formula I, where G is R.sub.1d
where R.sub.1d is C(A)(A') is C.sub.1-C.sub.6 cycloalkyl and B is
3,4-dihydroxybutyl, in which the chiral carbon in B is in the R
configuration, which is substantially free of the S isomer. In
further or additional embodiments, the invention provides a
composition comprising a compound of formula I, where G is R.sub.1d
where R.sub.1d is C(A)(A') is C.sub.1-C.sub.6 cycloalkyl and B is
2,3-dihydroxypropyl or 3,4-dihydroxybutyl, in which the chiral
carbon in B is in the S configuration, which is substantially free
of the R isomer. In further or additional embodiments, the
invention provides a composition comprising a compound of formula
I, where G is R.sub.1d where R.sub.1d is C(A)(A') is
C.sub.1-C.sub.6 cycloalkyl and B is 2,3-dihydroxypropyl, in which
the chiral carbon in B is in the S configuration, which is
substantially free of the R isomer. In further or additional
embodiments, the invention provides a composition comprising a
compound of formula I, where G is R.sub.1d where R.sub.1d is
C(A)(A') is C.sub.1-C.sub.6 cycloalkyl and B is 3,4-dihydroxybutyl,
in which the chiral carbon in B is in the S configuration, which is
substantially free of the R isomer.
[0081] In further or additional embodiments, G is R.sub.1d where
R.sub.1d is C(A)(A') is cyclopropyl. In further or additional
embodiments, G is R.sub.1d where R.sub.1d is C(A)(A') is
cyclopropyl and B is H. In further or additional embodiments, G is
R.sub.1d where R.sub.1d is C(A)(A') is cyclopropyl and B is methyl,
ethyl, 2-hydroxyethyl, n-propyl, 3-hydroxypropyl,
2,3-dihydroxypropyl, 3,4-dihydroxybutyl, isopropyl,
l-methyl-2-hydroxy ethyl, n-butyl, sec-butyl, isobutyl, or
2-hydroxymethyl-3-hydroxy propyl. In further or additional
embodiments, G is R.sub.1d where R.sub.1d is C(A)(A') is
cyclopropyl and B is 2,3-dihydroxypropyl or 3,4-dihydroxybutyl. In
further or additional embodiments, G is R.sub.1d where R.sub.1d is
C(A)(A') is cyclopropyl and B is 2,3-dihydroxypropyl or
3,4-dihydroxybutyl, in which the chiral carbon in B is in the R
configuration. In further or additional embodiments, G is R.sub.1d
where R.sub.1d is C(A)(A') is cyclopropyl and B is
2,3-dihydroxypropyl or 3,4-dihydroxybutyl, in which the chiral
carbon in B is in the S configuration. In further or additional
embodiments, G is R.sub.1d where R.sub.1d is C(A)(A') is
cyclopropyl and B is methyl, optionally substituted with one OH
group, or C.sub.2-C.sub.4 alkyl, optionally substituted with one or
two OH groups. In further or additional embodiments, G is R.sub.1d
where R.sub.1d is C(A)(A') is cyclopropyl and R.sup.0 is fluoro,
chloro, methyl, ethyl, propyl, isopropyl, sec-butyl, iso-butyl,
tert-butyl, cyclopropyl, cyclobutyl, fluoromethyl, methoxy,
fluoromethoxy, methylamino or dimethylamino. In further or
additional embodiments, G is R.sub.1d where R.sub.1d is C(A)(A') is
cyclopropyl and R.sup.0 is F, Cl, methyl, ethyl, methoxy, ethoxy,
or 2-methoxy-ethoxy. In further or additional embodiments, G is
R.sub.1d where R.sub.1d is C(A)(A') is cyclopropyl and R.sup.0 is
H; X is F, Cl, CH.sub.3, or mono-, di- or tri-fluoromethyl.
[0082] In further or additional embodiments, the invention provides
a composition comprising a compound of formula I, where G is
R.sub.1d where R.sub.1d is C(A)(A') is cyclopropyl and B is
2,3-dihydroxypropyl or 3,4-dihydroxybutyl, in which the chiral
carbon in B is in the R configuration, which is substantially free
of the S isomer. In further or additional embodiments, the
invention provides a composition comprising a compound of formula
I, where G is R.sub.1d where R.sub.1d is C(A)(A') is cyclopropyl
and B is 2,3-dihydroxypropyl, in which the chiral carbon in B is in
the R configuration, which is substantially free of the S isomer.
In further or additional embodiments, the invention provides a
composition comprising a compound of formula I, where G is R.sub.1d
where R.sub.1d is C(A)(A') is cyclopropyl and B is
3,4-dihydroxybutyl, in which the chiral carbon in B is in the R
configuration; which is substantially free of the S isomer. In
further or additional embodiments, the invention provides a
composition comprising a compound of formula I, where G is R.sub.1d
where R.sub.1d is C(A)(A') is cyclopropyl and B is
2,3-dihydroxypropyl or 3,4-dihydroxybutyl, in which the chiral
carbon in B is in the S configuration, which is substantially free
of the R isomer. In further or additional embodiments, the
invention provides a composition comprising a compound of formula
I, where G is R.sub.1d where R.sub.1d is C(A)(A') is cyclopropyl
and B is 2,3-dihydroxypropyl, in which the chiral carbon in B is in
the S configuration, which is substantially free of the R isomer.
In further or additional embodiments, the invention provides a
composition comprising a compound of formula I, where G is R.sub.1d
where R.sub.1d is C(A)(A') is cyclopropyl and B is
3,4-dihydroxybutyl, in which the chiral carbon in B is in the S
configuration, which is substantially free of the R isomer.
[0083] In some embodiments, G is R.sub.1e and n is 1. In further or
additional embodiments, G is R.sub.1e, R.sup.0 is H, R.sub.4-6 are
H, R.sub.2 and R.sub.3 are, independently, H, F, Cl, Br, CH.sub.3,
CH.sub.2F, CHF.sub.2, CF.sub.3, O CH.sub.3, OCH.sub.2F, OCHF.sub.2,
OCF.sub.3, ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl,
sec-butyl, tert-butyl, and methylsulfonyl, X is F and Y is I.
[0084] In some embodiments, G is Ar.sub.1 where Ar.sub.1 is phenyl
optionally substituted with one group selected from acetamido,
amidinyl, cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoyl,
1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazolyl,
1,3,4-thiadiazolyl, 5-methyl-1,3,4-thiadiazolyl, 1H-tetrazolyl,
N-morpholylcarbonylamino, N-morpholylsulfonyl,
N-pyrrolidinylcarbonylamino, and methylsulfonyl, optionally
substituted with 1-3 substituents selected independently from F,
Cl, and CH.sub.3. In further or additional embodiments, G is
Ar.sub.1 where Ar.sub.1 is phenyl optionally substituted with one
group selected from acetamido, amidinyl, cyano, carbamoyl,
methylcarbamoyl, dimethylcarbamoyl, 1,3,4-oxadiazol-2-yl,
5-methyl-1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl,
5-methyl-1,3,4-thiadiazolyl, 1H-tetrazolyl,
N-morpholylcarbonylamaino, N-morpholylsulfonyl,
N-pyrrolidinylcarbonylamino, and methylsulfonyl, optionally
substituted with 1-3 substituents selected independently from F,
Cl, and CH.sub.3, R.sup.0 is H, X is F, Cl, or methyl and Y is Br,
I, CF.sub.3, C.sub.1-C.sub.3 alkyl, C.sub.2-C.sub.3 alkenyl,
C.sub.2-C.sub.3 alkynyl, cyclopropyl, O CH.sub.3, OCH.sub.2CH.sub.3
or SCH.sub.3. In some embodiments, G is Ar.sub.1 where Ar.sub.1
is
##STR00006##
and where R.sub.2 and R.sub.3 are, independently, H, F, Cl,
CH.sub.3, CF.sub.3, OCH.sub.3. In further or additional
embodiments, G is Ar.sub.1 where Ar.sub.1 is
##STR00007##
and where R.sub.2 and R.sub.3 are, independently, H, F, Cl,
CH.sub.3, CF.sub.3, OCH.sub.3, X is F or CH.sub.3, Y is I, Br, or
Cl; and Z is F. In further or additional embodiments, G is Ar.sub.1
where Ar.sub.1 is phenyl or mono-substituted phenyl. In further or
additional embodiments, G is Ar.sub.1 where Ar.sub.1 is phenyl or
mono-substituted phenyl, X is F or CH.sub.3, Y is I, Br, or CI, Z
is F; and R.sup.0 is F, methyl, ethyl, methoxy, or
2-methoxy-ethoxy. In further or additional embodiments, G is
Ar.sub.1 where U is N or CR.sub.2 and V is N. In further or
additional embodiments, G is Ar.sub.1 where U is N or CR.sub.2 and
V is CR. In further or additional embodiments, G is Ar.sub.1 where
U is N or CR.sub.2, V is CR, R.sup.0 is H, X is F, Cl, or methyl
and Y is Br, I, CF.sub.3, C.sub.1-C.sub.3 alkyl, C.sub.2-C.sub.3
alkenyl, C.sub.1-C.sub.3 alkynyl, cyclopropyl, OCH.sub.3,
OCH.sub.2CH.sub.3 or SCH.sub.3.
[0085] In some embodiments, G is Ar.sub.2 where Ar.sub.2 is
##STR00008##
where R.sub.7 is H or methyl and R.sub.8 is H, acetamido, methyl, F
or Cl. In further or additional embodiments, G is Ar.sub.2 where
Ar.sub.2 is
##STR00009##
where R.sub.7 is H or methyl, R.sub.8 is H, acetamido, methyl, F or
Cl, R.sup.0 is H, X is F, Cl, or methyl, Y is Br, I, CF.sub.3,
C.sub.1-C.sub.3 alkyl, C.sub.2-C.sub.3 alkenyl, C.sub.2-C.sub.3
alkynyl, cyclopropyl, OCH.sub.3, OCH.sub.2CH.sub.3 or SCH.sub.3,
and Z is F. In further or additional embodiments, G is Ar.sub.2
where Ar.sub.2 is
##STR00010##
where U is S or O, V is CH.dbd., and R.sub.8 is H or CH.sub.3,
R.sub.7 is H or methyl, R.sub.8 is H, acetamido, methyl, F or Cl,
R.sup.0 is H, X is F, Cl, or methyl, Y is Br, I, CF.sub.3,
C.sub.1-C.sub.3 alkyl, C.sub.2-C.sub.3 alkenyl, C.sub.2-C.sub.3
alkynyl, cyclopropyl, OCH.sub.3, OCH.sub.2CH.sub.3 or SCH.sub.3 and
Z is F. In further or additional embodiments, R.sup.0 is H. In
further or additional embodiments, R.sup.0 is H, X is F or Cl and Y
is Br, I, CH.sub.2CH or SCH.sub.3
[0086] In some embodiments, G is Ar.sub.3 where U is --O--.
[0087] In further or additional embodiments, G is R.sub.1a, where
R.sub.1a is defined as above. In further or additional embodiments,
G is R.sub.1a, and R.sup.0 is H, where R.sub.1a is defined as
above. In further or additional embodiments, G is R.sub.1a and
R.sup.0 is as defined above, other than H, and R.sub.1a is defined
as above. In further or additional embodiments, G is R.sub.1a where
R.sub.1a is methyl, monohalomethyl, C.sub.1-C.sub.3 alkoxymethyl,
or cyclopropoxymethyl. In further or additional embodiments, G is
R.sub.1a, where R.sub.1a is methyl, monohalomethyl, C.sub.1-C.sub.3
alkoxymethyl, or cyclopropoxy methyl and where R.sup.0 is F, Cl,
C.sub.1-C.sub.3 alkyl, monochloro C.sub.1-C.sub.3 alkyl,
C.sub.1-C.sub.3 alkoxy, trifluoro methoxy, or 2-methoxy-ethoxy.
[0088] In further or additional embodiments, G is R.sub.1b, where
R.sub.1b is defined as above. In further or additional embodiments,
G is R.sub.1b, and R.sup.0 is H, where R.sub.1b is defined as
above. In further or additional embodiments, G is R.sub.1b, R.sup.0
is H and Z is F, where R.sub.1b is defined as above. In further or
additional embodiments, G is R.sub.1b and R.sup.0 is as defined
above, other than H, and R.sub.1b is defined as above. In further
or additional embodiments, G is R.sub.1b, where R.sub.1b is
isopropyl, 2-butyl, 2-pentyl, cyclopropyl, cyclobutyl, cyclopentyl,
or cyclohexyl, all optionally substituted with 1 or 2 substituents
selected independently from F, Cl, OH, and OCH.sub.3; Y is Br, I,
methyl, or trifluoromethyl. In further or additional embodiments, G
is R.sub.1b, where R.sub.1b is isopropyl, 2-butyl, 2-pentyl,
cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, optionally
substituted with 1 or 2 substituents selected independently from F,
Cl, OH, and OCH.sub.3; Y is Br, I, methyl, or trifluoromethyl; and
R.sup.0 is F, Cl, C.sub.1-C.sub.3 alkyl, monochloro C.sub.1-C.sub.3
alkyl, C.sub.1-C.sub.3 alkoxy, trifluoromethoxy, or
2-methoxy-ethoxy. In further or additional embodiments, G is
R.sub.1b, where R.sub.1b is isopropyl, 2-butyl, 2-pentyl,
cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, all optionally
substituted with one CI or with 1 or 2 OH groups; and Y is Br, I,
methyl, or trifluoromethyl. In further or additional embodiments, G
is R, where R.sub.1b is isopropyl, 2-butyl, 2-pentyl, cyclopropyl,
cyclobutyl, cyclopentyl, or cyclohexyl, all optionally substituted
with one Cl or with 1 or 2 OH groups; Y is Br, I, methyl, or
trifluoromethyl; and R.sup.0 is F, Cl, C.sub.1-C.sub.3 alkyl,
monochloro C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy,
trifluoromethoxy, or 2-methoxy-ethoxy.
[0089] In further or additional embodiments, G is R.sub.1c, where
R.sub.1c is defined as above. In further or additional embodiments,
G is R.sub.1c, and R.sup.0 is H, where R.sub.1c is defined as
above. In further or additional embodiments, G is R.sub.1c and
R.sup.0 is as defined above, other than H, and R.sub.1c is defined
as above. In further or additional embodiments, G is R.sub.1c, and
R.sup.0 is H, where R.sub.1c is (CH.sub.2).sub.nO.sub.mR', where m
is 0 or 1, n is 2 or 3 when m is 1, and n is 1 or 2 when m is O,
and R' is C.sub.1-C.sub.6 alkyl, optionally substituted with 1-3
substituents selected independently from F, Cl, OH, OCH.sub.3,
OCH.sub.2CH.sub.3, and C.sub.3-C.sub.6 cycloalkyl. In another more
specific subgeneric embodiment, m is zero, n is 1 or 2, and R' is
C.sub.1-C.sub.4 alkyl, optionally substituted as described above.
In another more specific subgeneric embodiment, m is 1, n is 2 or
3, and R' is C.sub.1-C.sub.4 alkyl, optionally substituted as
described above. In a still more specific subgeneric embodiment, m
is zero, n is 1 or 2, and R' is C.sub.1-C.sub.4 alkyl, optionally
substituted with 1-3 groups selected from OH, OCH.sub.3, Cl, and
cyclopropyl.
[0090] In further or additional embodiments, G is R.sub.1d, where
R.sub.1d is defined as above. In further or additional embodiments,
G is R.sub.1d, and R.sup.0 is H, where R.sub.1d is defined as
above. In further or additional embodiments, G is R.sub.1d and
R.sup.0 is as defined above, other than H, and R.sub.1d is defined
as above. In further or additional embodiments, G is R.sub.1d, and
R.sup.0 is H, where R.sub.1d is C(A)(A')(B)-- where B, A, and A'
are, independently, H or C.sub.1-4 alkyl, optionally substituted
with one or two OH groups or halogen atoms, or A and A', together
with the carbon atom to which they are attached, form a 3- to
6-member saturated ring, said ring optionally containing one or two
heteroatoms selected, independently, from O, N, and S and
optionally substituted with one or two groups selected
independently from methyl, ethyl, fluoro, chloro, bromo and
iodo.
[0091] In further or additional embodiments, G is R.sub.1e, where
R.sub.1e is defined as above. In further or additional embodiments,
G is R.sub.1e, and R.sup.0 is H, where R.sub.1e is defined as
above. In further or additional embodiments, G is R.sub.1e and
R.sup.0 is as defined above, other than H, and R.sub.1e is defined
as above.
[0092] In further or additional embodiments, G is Ar.sub.1, where
Ar.sub.1 is defined as above. In further or additional embodiments,
G is Ar.sub.1, and R.sup.0 is H, where Ar.sub.1 is defined as
above. In further or additional embodiments, G is Ar.sub.1 and
R.sup.0 is as defined above, other than H, and Ar.sub.1 is defined
as above.
[0093] In further or additional embodiments, G is Ar.sub.2, where
Ar.sub.2 is defined as above. In further or additional embodiments,
G is Ar.sub.2, and R.sup.0 is H, where Ar.sub.2 defined as above.
In further or additional embodiments, G is Ar.sub.2 and R.sup.0 is
as defined above, other than H, and Ar.sub.2 is defined as
above.
[0094] In further or additional embodiments, X is F, Cl, or
CH.sub.3; Y is I, Br, Cl, CF.sub.3 or C.sub.1-C.sub.3 alkyl, and Z
is H or F. In further or additional embodiments, X is F, Cl, or
CH.sub.3: Y is I, Br, Cl, CF.sub.3, or C.sub.1-C.sub.3 alkyl, Z is
H or F, and R.sup.0 is halogen, C.sub.1-C.sub.6 alkyl, monohalo
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, phenyl, monosubstituted phenyl,
OR.sub.3, O--C(.dbd.O)R.sub.4, or C(.dbd.O)OR.sub.5. In further or
additional embodiments, X is F, Cl, or CH.sub.3: Y is I, Br, Cl,
CF.sub.3, or C.sub.1-C.sub.3 alkyl, Z is H or F, and R.sup.0 is
furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,
pyrrolyl, or pyrazolyl. In further or additional embodiments, X is
F, Cl, or CH.sub.3: Y is I, Br, Cl, CF.sub.3, or C.sub.1-C.sub.3
alkyl, Z is H or F, and R.sup.0 is F, Cl, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.3 alkoxy, trifluoromethoxy, or 2-methoxy-ethoxy.
[0095] In another more specific subgeneric embodiment, R.sub.1d is
cycloalkyl or 1-alkyl-cycloalkyl, in which the 1-alkyl group is
optionally substituted with one or two OH groups or with one or two
halogen atoms.
[0096] In another more specific subgeneric embodiment, R.sup.0 is
halogen, C.sub.1-C.sub.6 alkyl, monohalo C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.6 cycloalkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, phenyl, monosubstituted phenyl, OR.sub.3,
O--C(.dbd.O)R.sub.4, or C(.dbd.O)OR.sub.5; and R.sub.1d is
cycloalkyl or 1-alkyl-cycloalkyl, in which the 1-alkyl group is
optionally substituted with one or two OH groups or with one or two
halogen atoms.
[0097] In another more specific subgeneric embodiment, R.sup.0 is
furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,
pyrrolyl, or pyrazolyl; and R.sub.1d is cycloalkyl or
1-alkyl-cycloalkyl, in which the 1-alkyl group is optionally
substituted with one or two OH groups or one or two halogen
atoms.
[0098] In another more specific subgeneric embodiment, R.sub.1d is
cycloalkyl or 1-alkyl-cycloalkyl, in which the 1-alkyl group is
optionally substituted with one or two OH groups, and where Y is
Br, I, methyl, or trifluoromethyl. In another more specific
subgeneric embodiment, R.sub.1d is cycloalkyl or
1-alkyl-cycloalkyl, in which the 1-alkyl group is optionally
substituted with one or two fluorine or chlorine atoms, and where Y
is Br, I, methyl, or trifluoromethyl. In another more specific
subgeneric embodiment, R.sub.1d is cycloalkyl or (1-alley
1)-cycloalkyl, in which the 1-alkyl group is optionally substituted
with one or two OH groups, and where R.sup.0' is F, Cl,
C.sub.1-C.sub.3 alkyl, monochloro C.sub.1-C.sub.3 alkyl,
C.sub.1-C.sub.3 alkoxy, trifluoromethoxy, or 2-methoxy-ethoxy. In
another more specific subgeneric embodiment, R.sub.1d is
tetrahydrofuryl, tetrahydrothienyl, pyrrolidyl, piperidyl,
piperazinyl, or morpholyl, each optionally substituted as described
above, and where Y is Br, I, methyl, or trifluoromethyl. In another
more specific subgeneric embodiment, R.sub.1d is oxazolidinyl,
thiazolidinyl, isoxazolidinyl, isothiazolidinyl, tetrahydrofuryl,
tetrahydrothienyl, pyrrolidyl, piperidyl, piperazinyl, or
morpholyl, each optionally substituted as described above, and
where Y is Br, I, methyl, or trifluoromethyl. In another more
specific subgeneric embodiment, R.sub.1d is cyclopropyl or
1-alkyl-cyclopropyl, in which the 1-alkyl group is optionally
substituted with one or two OH groups, and where R.sup.0' is F, Cl,
methyl, ethyl, chloromethyl, C.sub.1-C.sub.2 alkoxy,
trifluoromethoxy, or 2-methoxy-ethoxy. In an even more specific
embodiment, R.sub.1d is 1-(monohydroxyalkyl) cycloalkyl. In another
more specific embodiment, R.sub.1d is 1-(monohydroxyalkyl)
cycloalkyl, where R.sup.0' is F, Cl, methyl, ethyl, chloromethyl,
C.sub.1-C.sub.2 alkoxy, trifluoromethoxy, or 2-methoxy-ethoxy. In
an even more specific embodiment, R.sub.1d is 1-(dihydroxyalkyl)
cycloalkyl. In another more specific embodiment, R.sub.1d is
1-(dihydroxyalkyl) cycloalkyl, where R.sup.0' is F, Cl, methyl,
ethyl, chloromethyl, C.sub.1-C.sub.2 alkoxy, trifluoromethoxy, or
2-methoxy-ethoxy.
[0099] In a more specific subgeneric embodiment U is CR.sub.2 and V
is N. In another more specific, subgeneric embodiment, U and V are
both N. In a more specific, subgeneric embodiment, U is CR.sub.2
and V is CR.sub.3.
[0100] In a still more specific subgeneric embodiment, this
invention provides a compound of formula I, where G is Ar.sub.1 and
Ar.sub.1 is phenyl or monosubstituted phenyl, R.sup.0 is F, methyl,
ethyl, C.sub.1-C.sub.3 alkoxy, trifluoromethoxy, or
2-methoxy-ethoxy; X is F, Cl, or CH.sub.3; Y is I; and Z is F. In
another subgeneric embodiment, this invention provides a compound
of formula I, where G is Ar.sub.1, where Ar.sub.1 is phenyl or
monosubstituted phenyl, R.sup.0 is halogen, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.6 cycloalkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.1-C.sub.6 alkynyl, all such alkyl, cycloalkyl, alkenyl, and
alkynyl groups optionally substituted with 1-3 substituents
selected independently from halogen, OH, CN, cyanomethyl, nitro,
phenyl, and trifluoromethyl; or R.sup.0 is phenyl, OR.sub.3, furyl,
thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl,
or pyrazolyl. In a more specific subgeneric embodiment, this
invention provides a compound of formula I, where A is Ar.sub.1,
where Ar.sub.1 is phenyl or monosubstituted phenyl, R.sup.0 is F,
Cl, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy, 2-methoxyethoxy,
C.sub.2-C.sub.3 alkenyl, C.sub.2-C.sub.3 alkynyl, trifluoromethyl,
phenyl, furyl, or thienyl, thiazolyl, isothiazolyl, oxazolyl,
isoxazolyl, pyrrolyl, or pyrazolyl; X is F, Cl, or methyl; Y is I,
Br, Cl, CF.sub.3, or C.sub.1-C.sub.3 alkyl; and Z is F.
[0101] In another still more specific subgeneric embodiment, this
invention provides a compound of formula I, where G is Ar.sub.1,
where Ar.sub.1 is phenyl or monosubstituted phenyl, R.sup.0 is H; X
is F, Cl, or CH.sub.3; Y is Br or I; and Z is F.
[0102] In another subgeneric embodiment his invention provides a
compound of formula I, where G is Ar.sub.2, where Ar.sub.2 is
2-thienyl, 2-furyl, 3-thienyl, 3-furyl, 2-pyrrolyl, or 3-pyrrolyl,
all optionally substituted with methoxycarbonyl, methylcarbamoyl,
acetamido, acetyl, methyl, ethyl, trifluoromethyl, or halogen. In a
more specific subgeneric embodiment his invention provides a
compound of formula I, where G is Ar.sub.2, where Ar.sub.2 is
2-thienyl, 2-furyl, 3-thienyl, 3-furyl, 2-pyrrolyl, or 3-pyrrolyl,
all optionally substituted with methoxycarbonyl, methylcarbamoyl,
acetamido, acetyl, methyl, ethyl, trifluoromethyl, or halogen;
R.sup.0 is other than H; X is F, Cl, or CH.sub.3: Y is I, Br, Cl,
CF.sub.3, or C.sub.1-C.sub.3 alkyl, and Z is H or F. In another
subgeneric embodiment this invention provides a compound of formula
I, where G is Ar.sub.2, where Ar.sub.2 is 2-thienyl, 2-furyl,
3-thienyl, 3-furyl, 2-pyrrolyl, or 3-pyrrolyl, all optionally
substituted with methoxycarbonyl, methylcarbamoyl, acetamido,
acetyl, methyl, ethyl, trifluoromethyl, or halogen; R.sup.0 is F,
Cl, C.sub.1-C.sub.3 alkyl, monochloro C.sub.1-C.sub.3 alkyl,
C.sub.1-C.sub.3 alkoxy, trifluoromethoxy, methyloxy-methoxy, or
2-methoxy-ethoxy; X is F, Cl, or CH.sub.3: Y is I, Br, Cl,
CF.sub.3, or C.sub.1-C.sub.3 alkyl, and Z is H or F. In another
subgeneric embodiment his invention provides a compound of formula
I, where G is Ar.sub.2, where Ar.sub.2 is 2-thienyl, 2-furyl,
3-thienyl, 3-furyl, 2-pyrrolyl, or 3-pyrrolyl, all optionally
substituted with methoxycarbonyl, methylcarbamoyl, acetamido,
acetyl, methyl, ethyl, trifluoromethyl, or halogen; R.sup.0 is H; X
is F, Cl, or CH.sub.3: Y is I, Br, Cl, CF.sub.3, or C.sub.1-C.sub.3
alkyl, and Z is H or F. In another subgeneric embodiment his
invention provides a compound of formula I, where G is Ar.sub.2,
where Ar.sub.2 is thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,
pyrrolyl, or pyrazolyl, all optionally substituted with
methoxycarbonyl, methylcarbamoyl, acetamido, acetyl, methyl, ethyl,
trifluoromethyl, or halogen; R.sup.0 is H or methoxy; X is F, Cl,
or CH.sub.3: Y is I, Br, Cl, CF.sub.3, or C.sub.1-C.sub.3 alkyl,
and Z is H or F.
[0103] In some embodiments, the invention provides a compound of
formula I, selected from the compounds below:
##STR00011## ##STR00012##
[0104] In some embodiments, the invention provides a compound of
formula I, selected from:
##STR00013##
where the 2-OH carbon is in the R configuration.
[0105] In some embodiments, the invention provides a compound of
formula I, selected from:
##STR00014##
where the 2-OH carbon is in the S configuration.
[0106] In some embodiments, the invention provides a composition
comprising a compound of formula I, selected from those shown
below, where the 2-OH carbon is in the R configuration,
substantially free of the S-isomer.
##STR00015##
[0107] In some embodiments, the invention provides a composition
comprising a compound of formula I, selected from those shown
below, where the 2-OH carbon is in the S configuration,
substantially free of the R-isomer.
##STR00016##
[0108] In some embodiments, this invention provides a compound of
formula I, where Y is phenyl, pyridyl, or pyrazolyl. In another
subgeneric embodiment, this invention provides a compound of
formula I, where Y is substituted phenyl, pyridyl, or pyrazolyl. In
yet another subgeneric embodiment, this invention provides a
compound of formula I, where Y is Br or I. In one subgeneric
embodiment, this invention provides a compound of formula I, where
G is 1-piperidyl, 2-piperidyl, 3-piperidyl, or 4-piperidyl. In
another subgeneric embodiment, this invention provides a compound
of formula I, where G is 1-piperazyl or 2-piperazyl. In another
subgeneric embodiment, this invention provides a compound of
formula I, where G is morpholyl. In another subgeneric embodiment,
this invention provides a compound of formula I, where G is
N-methyl-2-aminoethyl. In one subgeneric embodiment, this invention
provides a compound of formula I, where G is
N-methyl-3-amino-n-propyl. In another subgeneric embodiment, this
invention provides a compound of formula I, where G is
(CH.sub.3).sub.2N--CH.sub.2CH.sub.2--NH--(CH.sub.2).sub.n--, where
n is 1, 2, or 3. In another subgeneric embodiment, this invention
provides a compound of formula I, where G is
(CH.sub.3CH.sub.2).sub.2N--CH.sub.2CH.sub.2--NH--(CH.sub.2)--,
where n is 1 or 2. In a more specific subgeneric embodiment, this
invention provides a compound of formula I, where G is 1-piperidyl,
2-piperidyl, 3-piperidyl, or 4-piperidyl; R.sup.o is H, halo, or
methoxy; X is F; and Y is I. In another more specific subgeneric
embodiment, this invention provides a compound of formula I, where
G is 1-piperazyl or 2-piperazyl; R.sup.o is H, halo, or methoxy; X
is F; and Y is I In another more specific subgeneric embodiment,
this invention provides a compound of formula I, where G is
morpholyl; R.sup.o is H, halo, or methoxy; X is F; and Y is I. In
another more specific subgeneric embodiment, this invention
provides a compound of formula I, where G is N-methyl-2-aminoethyl;
R.sup.o is H, halo, or methoxy; X is F; and Y is I In another more
specific subgeneric embodiment, this invention provides a compound
of formula I, where G is N-methyl-3-amino-n-propyl; R.sup.o is H,
halo, or methoxy; X is F; and Y is I. In another more specific
subgeneric embodiment, this invention provides a compound of
formula I, where G is
(CH.sub.3).sub.2N--CH.sub.2CH.sub.2--NH--(CH.sub.2).sub.n--, where
n is 1, 2, or 3; R.sup.o is H, halo, or methoxy; X is F; and Y is
I. In another more specific subgeneric embodiment, this invention
provides a compound of formula I, where G is
(CH.sub.3CH.sub.2).sub.2N--CH.sub.2CH.sub.2--NH--(CH.sub.2).sub.n--,
where n is 1 or 2; R.sup.o is H, halo, or methoxy; X is F; and Y is
I.
[0109] In some embodiments, the invention provides a pharmaceutical
composition comprising a compound of formula I or a
pharmaceutically acceptable salt, solvate, polymorph, ester,
tautomer or prodrug thereof. In some embodiments the pharmaceutical
composition further comprises at least one pharmaceutically
acceptable carrier.
[0110] In some embodiments, the invention provides a pharmaceutical
composition comprising a compound of a compound selected from:
##STR00017##
or a pharmaceutically acceptable salt, solvate, polymorph, ester,
tautomer or prodrug thereof. In some embodiments, the
pharmaceutical composition further comprises at least one
pharmaceutically acceptable carrier. In some embodiments, the
compound is in the R configuration. In some embodiments, the
compound is in the R configuration, substantially free of the
S-isomer. In some embodiments, the compound is in the S
configuration. In some embodiments, the compound is in the S
configuration, substantially free of the R-isomer. In some
embodiments, the compound is:
##STR00018##
In some embodiments, the compound is:
##STR00019##
[0111] In other aspects, the present invention is directed to
pharmaceutical compositions comprising effective amounts of a
compound of formula I or a pharmaceutically acceptable salt,
solvate, polymorph, ester, tautomer or prodrug thereof. In some
embodiments, the pharmaceutical compositions further comprise a
pharmaceutically acceptable carrier. Such compositions may contain
adjuvants, excipients, and preservatives, agents for delaying
absorption, fillers, binders, adsorbents, buffers, disintegrating
agents, solubilizing agents, other carriers, and other inert
ingredients. Methods of formulation of such compositions are
well-known in the art.
[0112] In some aspects, the present invention is directed to a
method of treating a disease in an individual suffering from said
disease comprising administering to said individual an effective
amount of a composition comprising a compound of formula I or a
pharmaceutically acceptable salt, solvate, polymorph, ester,
tautomer or prodrug thereof.
[0113] In other aspects, the present invention is directed to a
method of treating a disorder in a mammal, comprising administering
to said mammal a therapeutically effective amount of the compound
of formula I or a pharmaceutically acceptable salt, solvate,
polymorph, ester, tautomer or prodrug thereof
[0114] In other aspects, the present invention is directed to a
method of treating a disorder in a human, comprising administering
to said mammal a therapeutically effective amount of the compound
of formula I or a pharmaceutically acceptable salt, solvate,
polymorph, ester, tautomer or prodrug thereof
[0115] In other aspects, the present invention is directed to a
method of treating a hyperproliferative disorder in a mammal,
including a human, comprising administering to said mammal a
therapeutically effective amount of the compound of formula I or a
pharmaceutically acceptable salt, solvate, polymorph, ester,
tautomer or prodrug thereof
[0116] In other aspects, the present invention is directed to a
method of treating an inflammatory disease, condition, or disorder
in a mammal, including a human, comprising administering to said
mammal a therapeutically effective amount of the compound of
formula I, or a pharmaceutically acceptable salt, ester, prodrug,
solvate, hydrate or derivative thereof.
[0117] In other aspects, the present invention is directed to a
method of treating a disorder or condition which is modulated by
the MEK cascade in a mammal, including a human, comprising
administering to said mammal an amount of the compound of formula
I, or a pharmaceutically acceptable salt, ester, prodrug, solvate,
hydrate or derivative thereof, effective to modulate said cascade.
The appropriate dosage for a particular patient can be determined,
according to known methods, by those skilled in the art.
[0118] In other aspects, the present invention is directed to a
pharmaceutical composition comprising a compound of formula I or a
pharmaceutically acceptable salt, solvate, polymorph, ester,
tautomer or prodrug thereof. In some embodiments, the
pharmaceutical composition is in a form suitable for oral
administration. In further or additional embodiments, the
pharmaceutical composition is in the form of a tablet, capsule,
pill, powder, sustained release formulation, solution, suspension,
for parenteral injection as a sterile solution, suspension or
emulsion, for topical administration as an ointment or cream or for
rectal administration as a suppository. In further or additional
embodiments, the pharmaceutical composition is in unit dosage forms
suitable for single administration of precise dosages. In further
or additional embodiments the amount of compound of formula I is in
the range of about 0.001 to about 1000 mg/kg body weight/day. In
further or additional embodiments the amount of compound of formula
I is in the range of about 0.5 to about 50 mg/kg/day. In further or
additional embodiments the amount of compound of formula I is about
0.001 to about 7 g/day. In further or additional embodiments the
amount of compound of formula I is about 0.002 to about 6 g/day. In
further or additional embodiments the amount of compound of formula
I is about 0.005 to about 5 g/day. In further or additional
embodiments the amount of compound of formula I is about 0.01 to
about 5 g/day. In further or additional embodiments the amount of
compound of formula I is about 0.02 to about 5 g/day. In further or
additional embodiments the amount of compound of formula I is about
0.05 to about 2.5 g/day. In further or additional embodiments the
amount of compound of formula I is about 0.1 to about 1 g/day. In
further or additional embodiments, dosage levels below the lower
limit of the aforesaid range may be more than adequate. In further
or additional embodiments, dosage levels above the upper limit of
the aforesaid range may be required. In further or additional
embodiments the compound of formula I is administered in a single
dose, once daily. In further or additional embodiments the compound
of formula I is administered in multiple doses, more than once per
day. In further or additional embodiments the compound of formula I
is administered twice daily. In further or additional embodiments
the compound of formula I is administered three times per day. In
further or additional embodiments the compound of formula I is
administered four times per day. In further or additional
embodiments the compound of formula I is administered more than
four times per day. In some embodiments, the pharmaceutical
composition is for administration to a mammal. In further or
additional embodiments, the mammal is human. In further or
additional embodiments, the pharmaceutical composition further
comprises a pharmaceutical carrier, excipient and/or adjuvant. In
further or additional embodiments, the pharmaceutical composition
further comprises at least one therapeutic agent In further or
additional embodiments, the therapeutic agent is selected from the
group of cytotoxic agents, anti-angiogenesis agents and
anti-neoplastic agents. In further or additional embodiments, the
anti-neoplastic agent is selected from the group of consisting of
alkylating agents, anti-metabolites, epidophyllotoxins;
antineoplastic enzymes, topoisomerase inhibitors, procarbazines,
mitoxantrones, platinum coordination complexes, biological response
modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic
agents, and haematopoietic growth factors. In further or additional
embodiments, the therapeutic agent is taxol, bortezomib or both. In
further or additional embodiments, the pharmaceutical composition
is administered in combination with an additional therapy. In
further or additional embodiments, the additional therapy is
radiation therapy, chemotherapy or a combination of both. In
further or additional embodiments, the pharmaceutical composition
comprises a pharmaceutically acceptable salt of a compound of
formula I.
[0119] In other aspects, the present invention is directed to a
method for inhibiting a MEK enzyme. In some embodiments, the method
comprises contacting said MEK enzyme with an amount of a
composition comprising a compound of formula I or a
pharmaceutically acceptable salt, solvate, polymorph, ester,
tautomer or prodrug thereof, sufficient to inhibit said enzyme,
wherein said enzyme is inhibited. In further or additional
embodiments the enzyme is at least about 1% inhibited. In further
or additional embodiments the enzyme is at least about 2%
inhibited. In further or additional embodiments the enzyme is at
least about 3% inhibited. In further or additional embodiments the
enzyme is at least about 4% inhibited. In further or additional
embodiments the enzyme is at least about 5% inhibited. In further
or additional embodiments the enzyme is at least about 10%
inhibited. In further or additional embodiments the enzyme is at
least about 20% inhibited. In further or additional embodiments the
enzyme is at least about 25% inhibited. In further or additional
embodiments the enzyme is at least about 30% inhibited. In further
or additional embodiments the enzyme is at least about 40%
inhibited. In further or additional embodiments the enzyme is at
least about 50% inhibited. In further or additional embodiments the
enzyme is at least about 60% inhibited. In further or additional
embodiments the enzyme is at least about 70% inhibited. In further
or additional embodiments the enzyme is at least about 75%
inhibited. In further or additional embodiments the enzyme is at
least about 80% inhibited. In further or additional embodiments the
enzyme is at least about 90% inhibited. In further or additional
embodiments the enzyme is essentially completely inhibited. In
further or additional embodiments the MEK enzyme is MEK kinase. In
further or additional embodiments the MEK enzyme is MEK1. In
further or additional embodiments the MEK enzyme is MEK2. In
further or additional embodiments the contacting occurs within a
cell. In further or additional embodiments the cell is a mammalian
cell. In further or additional embodiments the mammalian cell is a
human cell. In further or additional embodiments, the MEK enzyme is
inhibited with a composition comprising a pharmaceutically
acceptable salt of a compound of formula I.
[0120] In other aspects, the present invention is directed to a
method of treatment of a MEK mediated disorder in an individual
suffering from said disorder comprising administering to said
individual an effective amount of a composition comprising a
compound of formula I or a pharmaceutically acceptable salt,
solvate, polymorph, ester, tautomer or prodrug thereof. In some
embodiments, the composition comprising a compound of formula I is
administered orally, intraduodenally, parenterally (including
intravenous, subcutaneous, intramuscular, intravascular or by
infusion), topically or rectally. In some embodiments, the
pharmaceutical composition is in a form suitable for oral
administration. In further or additional embodiments, the
pharmaceutical composition is in the form of a tablet, capsule,
pill, powder, sustained release formulations, solution, suspension,
for parenteral injection as a sterile solution, suspension or
emulsion, for topical administration as an ointment or cream or for
rectal administration as a suppository. In further or additional
embodiments, the pharmaceutical composition is in unit dosage forms
suitable for single administration of precise dosages. In further
or additional embodiments, the pharmaceutical composition further
comprises a pharmaceutical carrier, excipient and/or adjuvant. In
further or additional embodiments the amount of compound of formula
I is in the range of about 0.001 to about 1000 mg/kg body
weight/day. In further or additional embodiments the amount of
compound, of formula I is in the range of about 0.5 to about 50
mg/kg/day. In further or additional embodiments the amount of
compound of formula I is about 0.001 to about 7 g/day. In further
or additional embodiments the amount of compound of formula I is
about 0.01 to about 7 g/day. In further or additional embodiments
the amount of compound of formula I is about 0.02 to about 5 g/day.
In further or additional embodiments the amount of compound of
formula I is about 0.05 to about 2.5 g/day. In further or
additional embodiments the amount of compound of formula I is about
0.1 to about 1 g/day. In further or additional embodiments, dosage
levels below the lower limit of the aforesaid range may be more
than adequate. In further or additional embodiments, dosage levels
above the upper limit of the aforesaid range may be required. In
further or additional embodiments the compound of formula I is
administered in a single dose, once daily. In further or additional
embodiments the compound of formula I is administered in multiple
doses, more than once per day. In further or additional embodiments
the compound of formula I is administered twice daily. In further
or additional embodiments the compound of formula I is administered
three times per day. In further or additional embodiments the
compound of formula I is administered four times per day. In
further or additional embodiments the compound of formula I is
administered more than four times per day. In some embodiments, the
individual suffering from the MEK mediated disorder is a mammal. In
further or additional embodiments, the individual is a human. In
some embodiments, the composition comprising a compound of formula
I is administered in combination with an additional therapy. In
further or additional embodiments, the additional therapy is
radiation therapy, chemotherapy or a combination of both. In
further or additional embodiments, the composition comprising a
compound of formula I is administered in combination with at least
one therapeutic agent. In further or additional embodiments, the
therapeutic agent is selected from the group of cytotoxic agents,
anti-angiogenesis agents and anti-neoplastic agents. In further or
additional embodiments, the anti-neoplastic agent is selected from
the group of consisting of alkylating agents, anti-metabolites,
epidophyllotoxins; antineoplastic enzymes, topoisomerase
inhibitors, procarbazines, mitoxantrones, platinum coordination
complexes, biological response modifiers and growth inhibitors,
hormonal/anti-hormonal therapeutic agents, and haematopoietic
growth factors. In further or additional embodiments, the
therapeutic agent is selected from taxol, bortezomib or both. In
some embodiments, the MEK mediated disorder is selected from the
group consisting of inflammatory diseases, infections, autoimmune
disorders, stroke, ischemia, cardiac disorder, neurological
disorders, fibrogenetic disorders, proliferative disorders,
hyperproliferative disorders, non-cancer hyperproliferative
disorders, tumors, leukemias, neoplasms, cancers, carcinomas,
metabolic diseases, malignant disease, vascular restenosis,
psoriasis, atherosclerosis, rheumatoid arthritis, osteoarthritis,
heart failure, chronic pain, neuropathic pain, dry eye, closed
angle glaucoma and wide angle glaucoma. In further or additional
embodiments, the MEK mediated disorder is an inflammatory disease.
In further or additional embodiments, the MEK mediated disorder is
a hyperproliferative disease. In further or additional embodiments,
the MEK mediated disorder is selected from the group consisting of
tumors, leukemias, neoplasms, cancers, carcinomas and malignant
disease. In further or additional embodiments, the cancer is brain
cancer, breast cancer, lung cancer, ovarian cancer, pancreatic
cancer, prostate cancer, renal cancer, colorectal cancer or
leukemia. In further or additional embodiments, the fibrogenetic
disorder is scleroderma, polymyositis, systemic lupus, rheumatoid
arthritis, liver cirrhosis, keloid formation,
interstitial-nephritis or pulmonary fibrosis. In further or
additional embodiments, an effective amount of a composition
comprising a pharmaceutically acceptable salt of a compound of
formula I is administered.
[0121] In other aspects, the present invention is directed to a
method for degrading, inhibiting the growth of or killing a cancer
cell comprising contacting said cell with an amount of a
composition effective to degrade, inhibit the growth of or to kill
said cell, the composition comprising a compound of formula I or a
pharmaceutically acceptable salt, solvate, polymorph, ester,
tautomer or prodrug thereof. In some embodiments, the cancer cells
comprise brain, breast, lung, ovarian, pancreatic, prostate, renal,
or colorectal cancer cells. In further or additional embodiments,
the composition is administered with at least one therapeutic
agent. In further or additional embodiments, the therapeutic agent
is taxol, bortezomib or both. In further or additional embodiments,
the therapeutic agent is selected from the group consisting of
cytotoxic agents, anti-angiogenesis agents and anti-neoplastic
agents. In further or additional embodiments, the anti-neoplastic
agents selected from the group of consisting of alkylating agents,
anti-metabolites, epidophyllotoxins; antineoplastic enzymes,
topoisomerase inhibitors, procarbazines, mitoxantrones, platinum
coordination complexes, biological response modifiers and growth
inhibitors, hormonal/anti-hormonal therapeutic agents, and
haematopoietic growth factors. In some embodiments, the cancer
cells are degraded. In further or additional embodiments, 1% of the
cancer cells are degraded. In further or additional embodiments, 2%
of the cancer cells are degraded. In further or additional
embodiments, 3% of the cancer cells are degraded. In further or
additional embodiments, 4% of the cancer cells are degraded. In
further or additional embodiments, 5% of the cancer cells are
degraded. In further or additional embodiments, 10% of the cancer
cells are degraded. In further or additional embodiments, 20% of
the cancer cells are degraded. In further or additional
embodiments, 25% of the cancer cells are degraded. In further or
additional embodiments, 30% of the cancer cells are degraded. In
further or additional embodiments, 40% of the cancer cells are
degraded. In further or additional embodiments, 50% of the cancer
cells are degraded. In further or additional embodiments, 60% of
the cancer cells are degraded. In further or additional
embodiments, 70% of the cancer cells are degraded. In further or
additional embodiments, 75% of the cancer cells are degraded. In
further or additional embodiments, 80% of the cancer cells are
degraded. In further or additional embodiments, 90% of the cancer
cells are degraded. In further or additional embodiments, 100% of
the cancer cells are degraded. In further or additional
embodiments, essentially all of the cancer cells are degraded. In
some embodiments, the cancer cells are killed. In further or
additional embodiments, 1% of the cancer cells are killed. In
further or additional embodiments, 2% of the cancer cells are
killed. In further or additional embodiments, 3% of the cancer
cells are killed. In further or additional embodiments, 4% of the
cancer cells are killed. In further or additional embodiments, 5%
of the cancer cells are killed. In further or additional
embodiments, 10% of the cancer cells are killed. In further or
additional embodiments, 20% of the cancer cells are killed. In
further or additional embodiments, 25% of the cancer cells are
killed. In further or additional embodiments, 30% of the cancer
cells are killed. In further or additional embodiments, 40% of the
cancer cells are killed. In further or additional embodiments, 50%
of the cancer cells are killed. In further or additional
embodiments, 60% of the cancer cells are killed. In further or
additional embodiments, 70% of the cancer cells are killed. In
further or additional embodiments, 75% of the cancer cells are
killed. In further or additional embodiments, 80% of the cancer
cells are killed. In further or additional embodiments, 90% of the
cancer cells are killed. In further or additional embodiments, 100%
of the cancer cells are killed. In further or additional
embodiments, essentially all of the cancer cells are killed. In
further or additional embodiments, the growth of the cancer cells
is inhibited. In further or additional embodiments, the growth of
the cancer cells is about 1% inhibited. In further or additional
embodiments, the growth of the cancer cells is about 2% inhibited.
In further or additional embodiments, the growth of the cancer
cells is about 3% inhibited. In further or additional embodiments,
the growth of the cancer cells is about 4% inhibited. In further or
additional embodiments, the growth of the cancer cells is about 5%
inhibited. In further or additional embodiments, the growth of the
cancer cells is about 10% inhibited. In further or additional
embodiments, the growth of the cancer cells is about 20% inhibited.
In further or additional embodiments, the growth of the cancer
cells is about 25% inhibited. In further or additional embodiments,
the growth of the cancer cells is about 30% inhibited. In further
or additional embodiments, the growth of the cancer cells is about
40% inhibited. In further or additional embodiments, the growth of
the cancer cells is about 50% inhibited. In further or additional
embodiments, the growth of the cancer cells is about 60% inhibited.
In further or additional embodiments, the growth of the cancer
cells is about 70% inhibited. In further or additional embodiments,
the growth of the cancer cells is about 75% inhibited. In further
or additional embodiments, the growth of the cancer cells is about
80% inhibited. In further or additional embodiments, the growth of
the cancer cells is about 90% inhibited. In further or additional
embodiments, the growth of the cancer cells is about 100%
inhibited. In further or additional embodiments, a composition
comprising a pharmaceutically acceptable salt of a compound of
formula I is used.
[0122] In other aspects, the present invention is directed to a
method for the treatment or prophylaxis of a proliferative disease
in an individual comprising administering to said individual an
effective amount of a composition comprising a compound of formula
I or a pharmaceutically acceptable salt, solvate, polymorph, ester,
tautomer or prodrug thereof. In some embodiments, the proliferative
disease is cancer, psoriasis, restenosis, autoimmune disease, or
atherosclerosis. In further or additional embodiments, the
proliferative disease is a hyperproliferative disease. In further
or additional embodiments, the proliferative disease is selected
from the group consisting of tumors, leukemias, neoplasms, cancers,
carcinomas and malignant disease. In further or additional
embodiments, the cancer is brain cancer, breast cancer, lung
cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal
cancer, colorectal cancer or leukemia. In further or additional
embodiments, the fibrogenetic disorder is scleroderma,
polymyositis, systemic lupus, rheumatoid arthritis, liver
cirrhosis, keloid formation, interstitial nephritis or pulmonary
fibrosis. In further or additional embodiments, the cancer is brain
cancer, breast cancer, lung cancer, ovarian cancer, pancreatic
cancer, prostate cancer, renal cancer, colorectal cancer or
leukemia. In further or additional embodiments, the cancer is brain
cancer or adrenocortical carcinoma. In further or additional
embodiments, the cancer is breast cancer. In further or additional
embodiments, the cancer is ovarian cancer. In further or additional
embodiments, the cancer is pancreatic cancer. In further or
additional embodiments, the cancer is prostate cancer. In further
or additional embodiments, the cancer is renal cancer. In further
or additional embodiments, the cancer is colorectal cancer. In
further or additional embodiments, the cancer is myeloid leukemia.
In further or additional embodiments, the cancer is glioblastoma.
In further or additional embodiments, the cancer is follicular
lymphona. In further or additional embodiments, the cancer is pre-B
acute leukemia. In further or additional embodiments, the cancer is
chronic lymphocytic B-leukemia. In further or additional
embodiments, the cancer is mesothelioma. In further or additional
embodiments, the cancer is small cell line cancer. In some
embodiments, the composition comprising a compound of formula I is
administered in combination with an additional therapy. In further
or additional embodiments, the additional therapy is radiation
therapy, chemotherapy or a combination of both. In further or
additional embodiments, the composition comprising a compound of
formula I is administered in combination with at least one
therapeutic agent. In further or additional embodiments, the
therapeutic agent is selected from the group of cytotoxic agents,
anti-angiogenesis agents and anti-neoplastic agents. In further or
additional embodiments, the anti-neoplastic agent is selected from
the group of consisting of alkylating agents, anti-metabolites,
epidophyllotoxins; antineoplastic enzymes, topoisomerase
inhibitors, procarbazines, mitoxantrones, platinum coordination
complexes, biological response modifiers and growth inhibitors,
hormonal/anti-hormonal therapeutic agents, and haematopoietic
growth factors. In further or additional embodiments, the
therapeutic agent is selected from taxol, bortezomib or both. In
some embodiments, the composition is administered orally,
intraduodenally, parenterally (including intravenous, subcutaneous,
intramuscular, intravascular or by infusion), topically or
rectally. In further or additional embodiments the amount of
compound of formula I is in the range of about 0.001 to about 1000
mg/kg body weight/day. In further or additional embodiments the
amount of compound of formula I is in the range of about 0.5 to
about 50 mg/kg/day. In further or additional embodiments the amount
of compound of formula I is about 0.001 to about 7 g/day. In
further or additional embodiments the amount of compound of formula
I is about 0.01 to about 7 g/day. In further or additional
embodiments the amount of compound of formula I is about 0.02 to
about 5 g/day. In further or additional embodiments the amount of
compound of formula I is about 0.05 to about 2.5 g/day. In further
or additional embodiments the amount of compound of formula I is
about 0.1 to about 1 g/day. In further or additional embodiments,
dosage levels below the lower limit of the aforesaid range may be
more than adequate. In further or additional embodiments, dosage
levels above the upper limit of the aforesaid range may be
required. In further or additional embodiments the compound of
formula I is administered in a single dose, once daily. In further
or additional embodiments the compound of formula I is administered
in multiple doses, more than once per day. In further or additional
embodiments the compound of formula I is administered twice daily.
In further or additional embodiments the compound of formula I is
administered three times per day. In further or additional
embodiments the compound of formula I is administered four times
per day. In further or additional embodiments the compound of
formula I is administered more than four times per day. In some
embodiments, the individual suffering from the proliferative
disease is a mammal. In further or additional embodiments, the
individual is a human. In further or additional embodiments, an
effective amount of a composition comprising a pharmaceutically
acceptable salt of a compound of formula I is administered.
[0123] In other aspects, the present invention is directed to a
method for the treatment or prophylaxis of an inflammatory disease
in an individual comprising administering to said individual an
effective amount of a composition comprising a compound of formula
I or a pharmaceutically acceptable salt, solvate, polymorph, ester,
tautomer or prodrug thereof. In further or additional embodiments,
the inflammatory disease is selected from chronic inflammatory
diseases, rheumatoid arthritis, rheumatoid arthritis,
spondyloarthropathies, gouty arthritis, osteoarthritis, juvenile
arthritis, acute rheumatic arthritis, enteropathic arthritis,
neuropathic arthritis, psoriatic arthritis, pyogenic arthritis,
atherosclerosis, systemic lupus erythematosus, inflammatory bowel
disease, irritable bowel syndrome, ulcerative colitis, reflux
esophagitis, Crohn's disease, gastritis, asthma, allergies,
respiratory distress syndrome, pancreatitis, chronic obstructive
pulmonary disease, pulmonary fibrosis, psoriasis, eczema or
scleroderma. In some embodiments, the composition comprising a
compound of formula I is administered in combination with an
additional therapy. In further or additional embodiments, the
composition comprising a compound of formula I is administered in
combination with at least one therapeutic agent. In some
embodiments, the composition is administered orally,
intraduodenally, parenterally (including intravenous, subcutaneous,
intramuscular, intravascular or by infusion), topically or
rectally. In further or additional embodiments the amount of
compound of formula I is in the range of about 0.001 to about 1000
mg/kg body weight/day. In further or additional embodiments the
amount of compound of formula I is in the range of about 0.5 to
about 50 mg/kg/day. In further or additional embodiments the amount
of compound of formula I is about 0.001 to about 7 g/day. In
further or additional embodiments the amount of compound of formula
I is about 0.01 to about 7 g/day. In further or additional
embodiments the amount of compound of formula I is about 0.02 to
about 5 g/day. In further or additional embodiments the amount of
compound of formula I is about 0.05 to about 2.5 g/day. In further
or additional embodiments the amount of compound of formula I is
about 0.1 to about 1 g/day. In further or additional embodiments,
dosage levels below the lower limit of the aforesaid range may be
more than adequate. In further or additional embodiments, dosage
levels above the upper limit of the aforesaid range may be
required. In further or additional embodiments the compound of
formula I is administered in a single dose, once daily. In further
or additional embodiments the compound of formula I is administered
in multiple doses, more than once per day. In further or additional
embodiments the compound of formula I is administered twice daily.
In further or additional embodiments the compound of formula I is
administered three times per day. In further or additional
embodiments the compound of formula I is administered four times
per day. In further or additional embodiments the compound of
formula I is administered more than four times per day. In some
embodiments, the individual suffering from the inflammatory disease
is a mammal. In further or additional embodiments, the individual
is a human. In further or additional embodiments, an effective
amount of a composition comprising a pharmaceutically acceptable
salt of a compound of formula I is administered.
[0124] In other aspects, the present invention is directed to a
method for the treatment or prophylaxis of cancer in an individual
comprising administering to said individual an effective amount of
a composition comprising a compound of formula I or a
pharmaceutically acceptable salt, solvate, polymorph, ester,
tautomer or prodrug thereof. In further or additional embodiments,
the cancer is brain cancer, breast cancer, lung cancer, ovarian
cancer, pancreatic cancer, prostate cancer, renal cancer,
colorectal cancer or leukemia. In further or additional
embodiments, the fibrogenetic disorder is scleroderma,
polymyositis, systemic lupus, rheumatoid arthritis, liver
cirrhosis, keloid formation, interstitial nephritis or pulmonary
fibrosis. In further or additional embodiments, the cancer is brain
cancer, breast cancer, lung cancer, ovarian cancer, pancreatic
cancer, prostate cancer, renal cancer, colorectal cancer or
leukemia. In further or additional embodiments, the cancer is brain
cancer or adrenocortical carcinoma. In further or additional
embodiments, the cancer is breast cancer. In further or additional
embodiments, the cancer is ovarian cancer. In further or additional
embodiments, the cancer is pancreatic cancer. In further or
additional embodiments, the cancer is prostate cancer. In further
or additional embodiments, the cancer is renal cancer. In further
or additional embodiments, the cancer is colorectal cancer. In
further or additional embodiments, the cancer is myeloid leukemia.
In further or additional embodiments, the cancer is glioblastoma.
In further or additional embodiments, the cancer is follicular
lymphona. In further or additional embodiments, the cancer is pre-B
acute leukemia. In further or additional embodiments, the cancer is
chronic lymphocytic B-leukemia. In further or additional
embodiments, the cancer is mesothelioma. In further or additional
embodiments, the cancer is small cell line cancer. In some
embodiments, the composition comprising a compound of formula I is
administered in combination with an additional therapy. In further
or additional embodiments, the additional therapy is radiation
therapy, chemotherapy or a combination of both. In further or
additional embodiments, the composition comprising a compound of
formula I is administered in combination with at least one
therapeutic agent. In further or additional embodiments, the
therapeutic agent is selected from the group of cytotoxic agents,
anti-angiogenesis agents and anti-neoplastic agents. In further or
additional embodiments, the anti-neoplastic agent is selected from
the group of consisting of alkylating agents, anti-metabolites,
epidophyllotoxins; antineoplastic enzymes, topoisomerase
inhibitors, procarbazines, mitoxantrones, platinum coordination
complexes, biological response modifiers and growth inhibitors,
hormonal/anti-hormonal therapeutic agents, and haematopoietic
growth factors. In further or additional embodiments, the
therapeutic agent is selected from taxol, bortezomib or both. In
some embodiments, the composition is administered orally,
intraduodenally, parenterally (including intravenous, subcutaneous,
intramuscular, intravascular or by infusion), topically or
rectally. In further or additional embodiments the amount of
compound of formula I is in the range of about 0.001 to about 1000
mg/kg body weight/day. In further or additional embodiments the
amount of compound of formula I is in the range of about 0.5 to
about 50 mg/kg/day. In further or additional embodiments the amount
of compound of formula I is about 0.001 to about 7 g/day. In
further or additional embodiments the amount of compound of formula
I is about 0.01 to about 7 g/day. In further or additional
embodiments the amount of compound of formula I is about 0.02 to
about 5 g/day. In further or additional embodiments the amount of
compound of formula I is about 0.05 to about 2.5 g/day. In further
or additional embodiments the amount of compound of formula I is
about 0.1 to about 1 g/day. In further or additional embodiments,
dosage levels below the lower limit of the aforesaid range may be
more than adequate. In further or additional embodiments, dosage
levels above the upper limit of the aforesaid range may be
required. In further or additional embodiments the compound of
formula I is administered in a single dose, once daily. In further
or additional embodiments the compound of formula I is administered
in multiple doses, more than once per day. In further or additional
embodiments the compound of formula I is administered twice daily.
In further or additional embodiments the compound of formula I is
administered three times per day. In further or additional
embodiments the compound of formula I is administered four times
per day. In further or additional embodiments the compound of
formula I is administered more than four times per day. In some
embodiments, the individual suffering from cancer is a mammal. In
further or additional embodiments, the individual is a human. In
further or additional embodiments, an effective amount of a
composition comprising a pharmaceutically acceptable salt of a
compound of formula I is administered.
[0125] In other aspects, the present invention is directed to a
method of reducing the size of a tumor, inhibiting tumor size
increase, reducing tumor proliferation or preventing tumor
proliferation in an individual, comprising administering to said
individual an effective amount of a composition comprising a
compound of formula I or a pharmaceutically acceptable salt,
solvate, polymorph, ester, tautomer or prodrug thereof. In some
embodiments, the size of a tumor is reduced. In further or
additional embodiments, the size of a tumor is reduced by at least
1%. In further or additional embodiments, the size of a tumor is
reduced by at least 2%. In further or additional embodiments, the
size of a tumor is reduced by at least 3%. In further or additional
embodiments, the size of a tumor is reduced by at least 4%. In
further or additional embodiments, the size of a tumor is reduced
by at least 5%. In further or additional embodiments, the size of a
tumor is reduced by at least 10%. In further or additional
embodiments, the size of a tumor is reduced by at least 20%. In
further or additional embodiments, the size of a tumor is reduced
by at least 25%. In further or additional embodiments, the size of
a tumor is reduced by at least 30%. In further or additional
embodiments, the size of a tumor is reduced by at least 40%. In
further or additional embodiments, the size of a tumor is reduced
by at least 50%. In further or additional embodiments, the size of
a tumor is reduced by at least 60%. In further or additional
embodiments, the size of a tumor is reduced by at least 70%. In
further or additional embodiments, the size of a tumor is reduced
by at least 75%. In further or additional embodiments, the size of
a tumor is reduced by at least 80%. In further or additional
embodiments, the size of a tumor is reduced by at least 85%. In
further or additional embodiments, the size of a tumor is reduced
by at least 90%. In further or additional embodiments, the size of
a tumor is reduced by at least 95%. In further or additional
embodiments, the tumor is eradicated. In some embodiments, the size
of a tumor does not increase. In some embodiments, tumor
proliferation is reduced. In some embodiments, tumor proliferation
is reduced by at least 1%. In some embodiments, tumor proliferation
is reduced by at least 2%. In some embodiments, tumor proliferation
is reduced by at least 3%. In some embodiments, tumor proliferation
is reduced by at least 4%. In some embodiments, tumor proliferation
is reduced by at least 5%. In some embodiments, tumor proliferation
is reduced by at least 10%. In some embodiments, tumor
proliferation is reduced by at least 20%. In some embodiments,
tumor proliferation is reduced by at least 25%. In some
embodiments, tumor proliferation is reduced by at least 30%. In
some embodiments, tumor proliferation is reduced by at least 40%.
In some embodiments, tumor proliferation is reduced by at least
50%. In some embodiments, tumor proliferation is reduced by at
least 60%. In some embodiments, tumor proliferation is reduced by
at least 70%. In some embodiments, tumor proliferation is reduced
by at least 75%. In some embodiments, tumor proliferation is
reduced by at least 75%. In some embodiments, tumor proliferation
is reduced by at least 80%. In some embodiments, tumor
proliferation is reduced by at least 90%. In some embodiments,
tumor proliferation is reduced by at least 95%. In some
embodiments, tumor proliferation is prevented. In some embodiments,
the composition comprising a compound of formula I is administered
in combination with an additional therapy. In further or additional
embodiments, the additional therapy is radiation therapy,
chemotherapy or a combination of both. In further or additional
embodiments, the composition comprising a compound of formula I is
administered in combination with at least one therapeutic agent. In
further or additional embodiments, the therapeutic agent is
selected from the group of cytotoxic agents, anti-angiogenesis
agents and anti-neoplastic agents. In further or additional
embodiments, the anti-neoplastic agent is selected from the group
of consisting of alkylating agents, anti-metabolites,
epidophyllotoxins; antineoplastic enzymes, topoisomerase
inhibitors, procarbazines, mitoxantrones, platinum coordination
complexes, biological response modifiers and growth inhibitors,
hormonal/anti-hormonal therapeutic agents, and haematopoietic
growth factors. In further or additional embodiments, the
therapeutic agent is selected from taxol, bortezomib or both. In
some embodiments, the composition is administered orally,
intraduodenally, parenterally (including intravenous, subcutaneous,
intramuscular, intravascular or by infusion), topically or
rectally. In further or additional embodiments the amount of
compound of formula I is in the range of about 0.001 to about 1000
mg/kg body weight/day. In further or additional embodiments the
amount of compound of formula I is in the range of about 0.5 to
about 50 mg/kg/day. In further or additional embodiments the amount
of compound of formula I is about 0.001 to about 7 g/day. In
further or additional embodiments the amount of compound of formula
I is about 0.01 to about 7 g/day. In further or additional
embodiments the amount of compound of formula I is about 0.02 to
about 5 g/day. In further or additional embodiments the amount of
compound of formula I is about 0.05 to about 2.5 g/day. In further
or additional embodiments the amount of compound of formula I is
about 0.1 to about 1 g/day. In further or additional embodiments,
dosage levels below the lower limit of the aforesaid range may be
more than adequate. In further or additional embodiments, dosage
levels above the upper limit of the aforesaid range may be
required. In further or additional embodiments the compound of
formula I is administered in a single dose, once daily. In further
or additional embodiments the compound of formula I is administered
in multiple doses, more than once per day. In further or additional
embodiments the compound of formula I is administered twice daily.
In further or additional embodiments the compound of formula I is
administered three times per day. In further or additional
embodiments the compound of formula I is administered four times
per day. In further or additional embodiments the compound of
formula I is administered more than four times per day. In some
embodiments, the individual suffering from cancer is a mammal. In
further or additional embodiments, the individual is a human. In
further or additional embodiments, an effective amount of a
composition comprising a pharmaceutically acceptable salt of a
compound of formula I is administered.
[0126] In other aspects, the present invention is directed to a
method for achieving an effect in a patient comprising the
administration of an effective amount of a composition comprising a
compound of formula I or a pharmaceutically acceptable salt,
solvate, polymorph, ester, tautomer or prodrug thereof, to a
patient, wherein the effect is selected from the group consisting
of inhibition of various cancers, immunological diseases, and
inflammatory diseases. In some embodiments, the effect is
inhibition of various cancers. In further or additional
embodiments, the effect is inhibition of immunological diseases. In
further or additional embodiments, the effect is inhibition
inflammatory diseases. In some embodiments, the composition
comprising a compound of formula I is administered in combination
with an additional therapy. In further or additional embodiments,
the additional therapy is radiation therapy, chemotherapy or a
combination of both. In further or additional embodiments, the
composition comprising a compound of formula I is administered in
combination with at least one therapeutic agent. In some
embodiments, the composition is administered orally,
intraduodenally, parenterally (including intravenous, subcutaneous,
intramuscular, intravascular or by infusion), topically or
rectally. In further or additional embodiments the amount of
compound of formula I is in the range of about 0.001 to about 1000
mg/kg body weight/day. In further or additional embodiments the
amount of compound of formula I is in the range of about 0.5 to
about 50 mg/kg/day. In further or additional embodiments the amount
of compound of formula I is about 0.001 to about 7 g/day. In
further or additional embodiments the amount of compound of formula
I is about 0.01 to about 7 g/day. In further or additional
embodiments the amount of compound of formula I is about 0.02 to
about 5 g/day. In further or additional embodiments the amount of
compound of formula I is about 0.05 to about 2.5 g/day. In further
or additional embodiments the amount of compound of formula I is
about 0.1 to about 1 g/day. In further or additional embodiments,
dosage levels below the lower limit of the aforesaid range may be
more than adequate. In further or additional embodiments, dosage
levels above the upper limit of the aforesaid range may be
required. In further or additional embodiments the compound of
formula I is administered in a single dose, once daily. In further
or additional embodiments the compound of formula I is administered
in multiple doses, more than once per day. In further or additional
embodiments the compound of formula I is administered twice daily.
In further or additional embodiments the compound of formula I is
administered three times per day. In further or additional
embodiments the compound of formula I is administered four times
per day. In further or additional embodiments the compound of
formula I is administered more than four times per day. In some
embodiments, the individual suffering from cancer is a mammal. In
further or additional embodiments, the individual is a human. In
further or additional embodiments, an effective amount of a
composition comprising a pharmaceutically acceptable salt of a
compound of formula I is administered.
INCORPORATION BY REFERENCE
[0127] All publications and patent applications mentioned in this
specification are herein incorporated by reference to the same
extent as if each individual publication or patent application was
specifically and individually indicated to be incorporated by
reference.
DETAILED DESCRIPTION OF THE INVENTION
[0128] The novel features of the invention are set forth with
particularity in the appended claims. A better understanding of the
features and advantages of the present invention will be obtained
by reference to the following detailed description that sets forth
illustrative embodiments, in which the principles of the invention
are utilized.
[0129] While preferred embodiments of the present invention have
been shown and described herein, it will be obvious to those
skilled in the art that such embodiments are provided by way of
example only. Numerous variations, changes, and substitutions will
now occur to those skilled in the art without departing from the
invention. It should be understood that various alternatives to the
embodiments of the invention described herein may be employed in
practicing the invention. It is intended that the following claims
define the scope of the invention and that methods and structures
within the scope of these claims and their equivalents be covered
thereby.
[0130] The section headings used herein are for organizational
purposes only and are not to be construed as limiting the subject
matter described. All documents, or portions of documents, cited in
the application including, without limitation, patents, patent
applications, articles, books, manuals, and treatises are hereby
expressly incorporated by reference in their entirety for any
purpose.
Certain Chemical Terminology
[0131] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as is commonly understood by one
of skill in the art to which the claimed subject matter belongs.
All patents, patent applications, published materials referred to
throughout the entire disclosure herein, unless noted otherwise,
are incorporated by reference in their entirety. In the event that
there is a plurality of definitions for terms herein, those in this
section prevail. Where reference is made to a URL or other such
identifier or address, it is understood that such identifiers can
change and particular information on the internet can come and go,
but equivalent information can be found by searching the internet
or other appropriate reference source. Reference thereto evidences
the availability and public dissemination of such information.
[0132] It is to be understood that the foregoing general
description and the following detailed description are exemplary
and explanatory only and are not restrictive of any subject matter
claimed. In this application, the use of the singular includes the
plural unless specifically stated otherwise. It must be noted that,
as used in the specification and the appended claims, the singular
forms "a", "an" and "the" include plural referents unless the
context clearly dictates otherwise. It should also be noted that
use of "or" means "and/or" unless stated otherwise. Furthermore,
use of the term "including" as well as other forms, such as
"include", "includes", and "included" is not limiting.
[0133] Definition of standard chemistry terms may be found in
reference works, including Carey and Sundberg "ADVANCED ORGANIC
CHEMISTRY 4.sup.TH ED." Vols. A (2000) and B (2001), Plenum Press,
New York. Unless otherwise indicated, conventional methods of mass
spectroscopy, NMR, HPLC, IR and UV/Vis spectroscopy and
pharmacology, within the skill of the art are employed. Unless
specific definitions are provided, the nomenclature employed in
connection with, and the laboratory procedures and techniques of,
analytical chemistry, synthetic organic chemistry, and medicinal
and pharmaceutical chemistry described herein are those known in
the art. Standard techniques can be used for chemical syntheses,
chemical analyses, pharmaceutical preparation, formulation, and
delivery, and treatment of patients. Reactions and purification
techniques can be performed e.g., using kits of manufacturer's
specifications or as commonly accomplished in the art or as
described herein. The foregoing techniques and procedures can be
generally performed of conventional methods well known in the art
and as described in various general and more specific references
that are cited and discussed throughout the present specification.
Throughout the specification, groups and substituents thereof can
be chosen by one skilled in the field to provide stable moieties
and compounds.
[0134] Where substituent groups are specified by their conventional
chemical formulas, written from left to right, they equally
encompass the chemically identical substituents that would result
from writing the structure from right to left. As a non-limiting
example, --CH.sub.2O-- is equivalent to --OCH.sub.2--.
[0135] Unless otherwise noted, the use of general chemical terms,
such as though not limited to "alkyl," "amine," "aryl," are
equivalent to their optionally substituted forms. For example,
"alkyl," as used herein, includes optionally substituted alkyl.
[0136] The compounds presented herein may possess one or more
stereocenters and each center may exist in the R or S
configuration, or combinations thereof. Likewise, the compounds
presented herein may possess one or more double bonds and each may
exist in the E (trans) or Z (cis) configuration, or combinations
thereof. Presentation of one particular stereoisomer, regioisomer,
diastereomer, enantiomer or epimer should be understood to include
all possible stereoisomers, regioisomers, diastereomers,
enantiomers or epimers and mixtures thereof. Thus, the compounds
presented herein include all separate configurational
stereoisomeric, regioisomeric, diastereomeric, enantiomeric, and
epimeric forms as well as the corresponding mixtures thereof.
Presentation of one particular chemical structure or chemical name
for a compound which contains one or more chiral centers, but which
does not designate a particular stereochemistry, should be
understood to include all possible stereoisomers, including
mixtures of all possible stereoisomers, pure forms or substantially
pure forms of one particular stereoisomer and pure forms or
substantially pure forms of the alternate stereoisomer. Techniques
for inverting or leaving unchanged a particular stereocenter, and
those for resolving mixtures of stereoisomers are well known in the
art and it is well within the ability of one of skill in the art to
choose an appropriate method for a particular situation. See, for
example, Furniss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL
ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical
Ltd., Essex, 1991, 809-816; and Heller, Ace. Chem. Res. 1990, 23,
128.
[0137] The terms "moiety", "chemical moiety", "group" and "chemical
group", as used herein refer to a specific segment or functional
group of a molecule. Chemical moieties are often recognized
chemical entities embedded in or appended to a molecule.
[0138] The term "bond" or "single bond" refers to a chemical bond
between two atoms, or two moieties when the atoms joined by the
bond are considered to be part of larger substructure.
[0139] The term "optional" or "optionally" means that the
subsequently described event or circumstance may or may not occur,
and that the description includes instances where said event or
circumstance occurs and instances in which it does not. For
example, "optionally substituted alkyl" means either "alkyl" or
"substituted alkyl" as defined below. Further, an optionally
substituted group may be un-substituted (e.g., --CH.sub.2CH.sub.3),
fully substituted (e.g., --CF.sub.2CF.sub.3), mono-substituted
(e.g., --CH.sub.2CH.sub.2F) or substituted at a level anywhere
in-between fully substituted and mono-substituted (e.g.,
--CH.sub.2CHF.sub.2, --CH.sub.2CF.sub.3, --CF.sub.2CH.sub.3,
--CFHCHF.sub.2, etc). It will be understood by those skilled in the
art with respect to any group containing one or more substituents
that such groups are not intended to introduce any substitution or
substitution patterns (e.g., substituted alkyl includes optionally
substituted cycloalkyl groups, which in turn are defined as
including optionally substituted alkyl groups, potentially ad
infinitum) that are sterically impractical and/or synthetically
non-feasible. Thus, any substituents described should generally be
understood as having a maximum molecular weight of about 1,000
daltons, and more typically, up to about 500 daltons (except in
those instances where macromolecular substituents are clearly
intended, e.g., polypeptides, polysaccharides, polyethylene
glycols, DNA, RNA and the like).
[0140] As used herein, C.sub.1-C.sub.x includes C.sub.1-C.sub.2,
C.sub.1-C.sub.3 . . . C.sub.1-C.sub.x. By way of example only, a
group designated as "C.sub.1-C.sub.4" indicates that there are one
to four carbon atoms in the moiety, i.e. groups containing 1 carbon
atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms, as well as
the ranges C.sub.1-C.sub.2 and C.sub.1-C.sub.3. Thus, by way of
example only, "C.sub.1-C.sub.4 alkyl" indicates that there are one
to four carbon atoms in the alkyl group, i.e., the alkyl group is
selected from among methyl, ethyl, propyl, iso-propyl, n-butyl,
iso-butyl, sec-butyl, and t-butyl. Whenever it appears herein, a
numerical range such as "1 to 10" refers to each integer in the
given range; e.g., "1 to 10 carbon atoms" means that the group may
have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms,
5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9
carbon atoms, or 10 carbon atoms.
[0141] The term "A and A', together with the carbon atom to which
they are attached, form a 3- to 6-member saturated ring", as used
herein, refers to the following structures for compounds of formula
I:
##STR00020##
[0142] The terms "heteroatom" or "hetero" as used herein, alone or
in combination, refer to an atom other than carbon or hydrogen.
Heteroatoms are may be independently selected from among oxygen,
nitrogen, sulfur, phosphorous, silicon, selenium and tin but are
not limited to these atoms. In embodiments in which two or more
heteroatoms are present, the two or more heteroatoms can be the
same as each another, or some or all of the two or more heteroatoms
can each be different from the others.
[0143] The term "alkyl" as used herein, alone or in combination,
refers to an optionally substituted straight-chain, or optionally
substituted branched-chain saturated hydrocarbon monoradical having
from one to about ten carbon atoms, more preferably one to six
carbon atoms. Examples include, but are not limited to methyl,
ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl,
2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl,
2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,
4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,
4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,
2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl,
isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups,
such as heptyl, octyl and the like. Whenever it appears herein, a
numerical range such as "C.sub.1-C.sub.6 alkyl" or "C.sub.1-6
alkyl", means that the alkyl group may consist of 1 carbon atom, 2
carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6
carbon atoms, although the present definition also covers the
occurrence of the term "alkyl" where no numerical range is
designated.
[0144] The term "alkenyl" as used herein, alone or in combination,
refers to an optionally substituted straight-chain, or optionally
substituted branched-chain hydrocarbon monoradical having one or
more carbon-carbon double-bonds and having from two to about ten
carbon atoms, more preferably two to about six carbon atoms. The
group may be in either the cis or trans conformation about the
double bond(s), and should be understood to include both isomers.
Examples include, but are not limited to ethenyl
(--CH.dbd.CH.sub.2), 1-propenyl (--CH.sub.2CH.dbd.CH.sub.2),
isopropenyl [--C(CH.sub.3).dbd.CH)], butenyl, 1,3-butadienyl and
the like. Whenever it appears herein, a numerical range such as
"C.sub.2-C.sub.6 alkenyl" or "C.sub.2-6 alkenyl", means that the
alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4
carbon atoms, 5 carbon atoms or 6 carbon atoms, although the
present definition also covers the occurrence of the term "alkenyl"
where no numerical range is designated.
[0145] The term "alkynyl" as used herein, alone or in combination,
refers to an optionally substituted straight-chain or optionally
substituted branched-chain hydrocarbon monoradical having one or
more carbon-carbon triple-bonds and having from two to about ten
carbon atoms, more preferably from two to about six carbon atoms.
Examples include, but are not limited to ethynyl, 2-propynyl,
2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein,
a numerical range such as "C.sub.2-C.sub.6 alkynyl" or "C.sub.2-6
alkynyl", means that the alkynyl group may consist of 2 carbon
atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon
atoms, although the present definition also covers the occurrence
of the term "alkynyl" where no numerical range is designated.
[0146] The terms "heteroalkyl", "heteroalkenyl" and "heteroalkynyl"
as used herein, alone or in combination, refer to optionally
substituted alkyl, alkenyl and alkynyl structures respectively, as
described above, in which one or more of the skeletal chain carbon
atoms (and any associated hydrogen atoms, as appropriate) are each
independently replaced with a heteroatom (i.e. an atom other than
carbon, such as though not limited to oxygen, nitrogen, sulfur,
silicon, phosphorous, tin or combinations thereof), or heteroatomic
group such as though not limited to --O--O--, --S--S--, --O--S--,
--S--O--, .dbd.N--N.dbd., --N.dbd.N--, --N.dbd.N--NH--,
--P(O).sub.2--, --O--P(O).sub.2--, --P(O).sub.2--O--, --S(O)--,
--S(O).sub.2--, --SnH.sub.2-- and the like.
[0147] The terms "haloalkyl", "haloalkenyl" and "haloalkynyl" as
used herein, alone or in combination, refer to optionally
substituted alkyl, alkenyl and alkynyl groups respectively, as
defined above, in which one or more hydrogen atoms is replaced by
fluorine, chlorine, bromine or iodine atoms, or combinations
thereof. In some embodiments two or more hydrogen atoms may be
replaced with halogen atoms that are the same as each another (e.g.
difluoromethyl); in other embodiments two or more hydrogen atoms
may be replaced with halogen atoms that are not all the same as
each other (e.g. 1-chloro-1-fluoro-1-iodoethyl). Non-limiting
examples of haloalkyl groups are fluoromethyl and bromoethyl. A
non-limiting example of a haloalkenyl group is bromoethenyl. A
non-limiting example of a haloalkynyl group is chloroethynyl.
[0148] The term "carbon chain" as used herein, alone or in
combination, refers to any alkyl, alkenyl, alkynyl, heteroalkyl,
heteroalkenyl or heteroalkynyl group, which is linear, cyclic, or
any combination thereof. If the chain is part of a linker and that
linker comprises one or more rings as part of the core backbone,
for purposes of calculating chain length, the "chain" only includes
those carbon atoms that compose the bottom or top of a given ring
and not both, and where the top and bottom of the ring(s) are not
equivalent in length, the shorter distance shall be used in
determining the chain length. If the chain contains heteroatoms as
part of the backbone, those atoms are not calculated as part of the
carbon chain length.
[0149] The terms "cycle", "cyclic", "ring" and "membered ring" as
used herein, alone or in combination, refer to any covalently
closed structure, including alicyclic, heterocyclic, aromatic,
heteroaromatic and polycyclic fused or non-fused ring systems as
described herein. Rings can be optionally substituted. Rings can
form part of a fused ring system. The term "membered" is meant to
denote the number of skeletal atoms that constitute the ring. Thus,
by way of example only, cyclohexane, pyridine, pyran and pyrimidine
are six-membered rings and cyclopentane, pyrrole, tetrahydrofuran
and thiophene are five-membered rings.
[0150] The term "fused" as used herein, alone or in combination,
refers to cyclic structures in which two or more rings share one or
more bonds.
[0151] The term "cycloalkyl" as used herein, alone or in
combination, refers to an optionally substituted, saturated,
hydrocarbon monoradical ring, containing from three to about
fifteen ring carbon atoms or from three to about ten ring carbon
atoms, though may include additional, non-ring carbon atoms as
substituents (e.g. methylcyclopropyl). Whenever it appears herein,
a numerical range such as "C.sub.3-C.sub.6 cycloalkyl" or
"C.sub.3-6 cycloalkyl", means that the cycloalkyl group may consist
of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon
atoms, i.e., is cyclopropyl, cyclobutyl, cyclopentyl or cyclohepty,
although the present definition also covers the occurrence of the
term "cycloalkyl" where no numerical range is designated. The term
includes fused, non-fused, bridged and spiro radicals. A fused
cycloalkyl may contain from two to four fused rings where the ring
of attachment is a cycloalkyl ring, and the other individual rings
may be alicyclic, heterocyclic, aromatic, heteroaromatic or any
combination thereof. Examples include, but are not limited to
cyclopropyl, cyclopentyl, cyclohexyl, decalinyl, and bicyclo
[2.2.1] heptyl and adamantyl ring systems. Illustrative examples
include, but are not limited to the following moieties:
##STR00021##
and the like.
[0152] The terms "non-aromatic heterocyclyl" and "heteroalicyclyl"
as used herein, alone or in combination, refer to optionally
substituted, saturated, partially unsaturated, or fully unsaturated
nonaromatic ring monoradicals containing from three to about twenty
ring atoms, where one or more of the ring atoms are an atom other
than carbon, independently selected from among oxygen, nitrogen,
sulfur, phosphorous, silicon, selenium and tin but are not limited
to these atoms. In embodiments in which two or more heteroatoms are
present in the ring, the two or more heteroatoms can be the same as
each another, or some or all of the two or more heteroatoms can
each be different from the others. The terms include fused,
non-fused, bridged and spiro radicals. A fused non-aromatic
heterocyclic radical may contain from two to four fused rings where
the attaching ring is a non-aromatic heterocycle, and the other
individual rings may be alicyclic, heterocyclic, aromatic,
heteroaromatic or any combination thereof. Fused ring systems may
be fused across a single bond or a double bond, as well as across
bonds that are carbon-carbon, carbon-hetero atom or hetero
atom-hetero atom. The terms also include radicals having from three
to about twelve skeletal ring atoms, as well as those having from
three to about ten skeletal ring atoms. Attachment of a
non-aromatic heterocyclic subunit to its parent molecule can be via
a heteroatom or a carbon atom. Likewise, additional substitution
can be via a heteroatom or a carbon atom. As a non-limiting
example, an imidazolidine non-aromatic heterocycle may be attached
to a parent molecule via either of its N atoms (imidazolidin-1-yl
or imidazolidin-3-yl) or any of its carbon atoms
(imidazolidin-2-yl, imidazolidin-4-yl or imidazolidin-5-yl). In
certain embodiments, non-aromatic heterocycles contain one or more
carbonyl or thiocarbonyl groups such as, for example, oxo- and
thio-containing groups. Examples include, but are not limited to
pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl,
tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl,
piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl,
azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl,
thiepanyl, oxazepinyl, diazepinyl, thiazepinyl,
1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl,
2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl,
dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,
dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,
3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl
and quinolizinyl. Illustrative examples of heterocycloalkyl groups,
also referred to as non-aromatic heterocycles, include:
##STR00022##
and the like. The terms also include all ring forms of the
carbohydrates, including but not limited to the monosaccharides,
the disaccharides and the oligosaccharides.
[0153] The term "aromatic" as used herein, refers to a planar,
cyclic or polycyclic, ring moiety having a delocalized
.pi.-electron system containing 4n+2 .pi. electrons, where n is an
integer. Aromatic rings can be formed by five, six, seven, eight,
nine, or more than nine atoms. Aromatics can be optionally
substituted and can be monocyclic or fused-ring polycyclic. The
term aromatic encompasses both all carbon containing rings (e.g.,
phenyl) and those rings containing one or more heteroatoms (e.g.,
pyridine).
[0154] The term "aryl" as used herein, alone or in combination,
refers to an optionally substituted aromatic hydrocarbon radical of
six to about twenty ring carbon atoms, and includes fused and
non-fused aryl rings. A fused aryl ring radical contains from two
to four fused rings where the ring of attachment is an aryl ring,
and the other individual rings may be alicyclic, heterocyclic,
aromatic, heteroaromatic or any combination thereof. Further, the
term aryl includes fused and non-fused rings containing from six to
about twelve ring carbon atoms, as well as those containing from
six to about ten ring carbon atoms. A non-limiting example of a
single ring aryl group includes phenyl; a fused ring aryl group
includes naphthyl, phenanthrenyl, anthracenyl, azulenyl; and a
non-fused bi-aryl group includes biphenyl.
[0155] The term "heteroaryl" as used herein, alone or in
combination, refers to optionally substituted aromatic monoradicals
containing from about five to about twenty skeletal ring atoms,
where one or more of the ring atoms is a heteroatom independently
selected from among oxygen, nitrogen, sulfur, phosphorous, silicon,
selenium and tin but not limited to these atoms and with the
proviso that the ring of said group does not contain two adjacent O
or S atoms. In embodiments in which two or more heteroatoms are
present in the ring, the two or more heteroatoms can be the same as
each another, or some or all of the two or more heteroatoms can
each be different from the others. The term heteroaryl includes
optionally substituted fused and non-fused heteroaryl radicals
having at least one heteroatom. The term heteroaryl also includes
fused and non-fused heteroaryls having from five to about twelve
skeletal ring atoms, as well as those having from five to about ten
skeletal ring atoms. Bonding to a heteroaryl group can be via a
carbon atom or a heteroatom. Thus, as a non-limiting example, an
imidazole group may be attached to a parent molecule via any of its
carbon atoms (imidazol-2-yl, imidazol-4-yl or imidazol-5-yl), or
its nitrogen atoms (imidazol-1-yl or imidazol-3-yl). Likewise, a
heteroaryl group may be further substituted via any or all of its
carbon atoms, and/or any or all of its heteroatoms. A fused
heteroaryl radical may contain from two to four fused rings where
the ring of attachment is a heteroaromatic ring and the other
individual rings may be alicyclic, heterocyclic, aromatic,
heteroaromatic or any combination thereof. A non-limiting example
of a single ring heteroaryl group includes pyridyl; fused ring
heteroaryl groups include benzimidazolyl, quinolinyl, acridinyl;
and a non-fused bi-heteroaryl group includes bipyridinyl. Further
examples of heteroaryls include, without limitation, furanyl,
thienyl, oxazolyl, acridinyl, phenazinyl, benzimidazolyl,
benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,
benzothiophenyl, benzoxadiazolyl, benzotriazolyl, imidazolyl,
indolyl, isoxazolyl, isoquinolinyl, indolizinyl, isothiazolyl,
isoindolyloxadiazolyl, indazolyl, pyridyl, pyridazyl, pyrimidyl,
pyrazinyl, pyrrolyl, pyrazinyl, pyrazolyl, purinyl, phthalazinyl,
pteridinyl, quinolinyl, quinazolinyl, quinoxalinyl, triazolyl,
tetrazolyl, thiazolyl, triazinyl, thiadiazolyl and the like, and
their oxides, such as for example pyridyl-N-oxide. Illustrative
examples of heteroaryl groups include the following moieties:
##STR00023##
and the like.
[0156] The term "heterocyclyl" as used herein, alone or in
combination, refers collectively to heteroalicyclyl and heteroaryl
groups. Herein, whenever the number of carbon atoms in a
heterocycle is indicated (e.g., C.sub.1-C.sub.6 heterocycle), at
least one non-carbon atom (the heteroatom) must be present in the
ring. Designations such as "C.sub.1-C.sub.6 heterocycle" refer only
to the number of carbon atoms in the ring and do not refer to the
total number of atoms in the ring. Designations such as "4-6
membered heterocycle" refer to the total number of atoms that are
contained in the ring (i.e., a four, five, or six membered ring, in
which at least one atom is a carbon atom, at least one atom is a
heteroatom and the remaining two to four atoms are either carbon
atoms or heteroatoms). For heterocycles having two or more
heteroatoms, those two or more heteroatoms can be the same or
different from one another. Heterocycles can be optionally
substituted. Non-aromatic heterocyclic groups include groups having
only three atoms in the ring, while aromatic heterocyclic groups
must have at least five atoms in the ring. Bonding (i.e. attachment
to a parent molecule or further substitution) to a heterocycle can
be via a heteroatom or a carbon atom.
[0157] The terms "halogen", "halo" or "halide" as used herein,
alone or in combination refer to fluoro, chloro, bromo and/or
iodo.
[0158] The term "amino" as used herein, alone or in combination,
refers to the monoradical --NH.sub.2.
[0159] The term "alkylamino" as used herein, alone or in
combination, refers to the monoradical --NH(alkyl) where alkyl is
as defined herein.
[0160] The term "dialkylamino" as used herein, alone or in
combination, refers to the monoradical --N(alkyl)(alkyl) where each
alkyl may be identical or non-identical and is as defined
herein.
[0161] The term "diamino alkyl" as used herein, alone or in
combination, refers to an alkyl group containing two amine groups,
wherein said amine groups may be substituents on the alkyl group
which may be amino, alkylamino, or dialkylamino groups, or wherein
one or both of said amine groups may form part of an alkyl chain to
form -alkylene-N(H or alkyl)-alkylene-N(H or alkyl or alkylene-N(H
or alkyl or alkylene-).
[0162] The term "hydroxy" as used herein, alone or in combination,
refers to the monoradical --OH.
[0163] The term "cyano" as used herein, alone or in combination,
refers to the monoradical --CN.
[0164] The term "cyanomethyl" as used herein, alone or in
combination, refers to the motoradical --CH.sub.2CN.
[0165] The term "nitro" as used herein, alone or in combination,
refers to the monoradical --NO.sub.2.
[0166] The term "oxy" as used herein, alone or in combination,
refers to the diradical --O--.
[0167] The term "oxo" as used herein, alone or in combination,
refers to the diradical .dbd.O.
[0168] The term "carbonyl" as used herein, alone or in combination,
refers to the diradical --C(.dbd.O)--, which may also be written as
--C(O)--.
[0169] The terms "carboxy" or "carboxyl" as used herein, alone or
in combination, refer to the moiety --C(O)OH, which may also be
written as --COOH.
[0170] The term "alkoxy" as used herein, alone or in combination,
refers to an alkyl ether radical, --O-alkyl, including the groups
--O-aliphatic and --O-carbocyclyl, wherein the alkyl, aliphatic and
carbocyclyl groups may be optionally substituted, and wherein the
terms alkyl, aliphatic and carbocyclyl are as defined herein.
Non-limiting examples of alkoxy radicals include methoxy, ethoxy,
n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy,
tert-butoxy and the like.
[0171] The term "sulfinyl" as used herein, alone or in combination,
refers to the diradical --S(.dbd.O)--.
[0172] The term "sulfonyl" as used herein, alone or in combination,
refers to the diradical --S(.dbd.O)Z--.
[0173] The terms "sulfonamide", "sulfonamido" and "sulfonamidyl" as
used herein, alone or in combination, refer to the diradical groups
--S(.dbd.O).sub.2--NH-- and --NH--S(.dbd.O).sub.2--.
[0174] The terms "sulfamide", "sulfamido" and "sulfamidyl" as used
herein, alone or in combination, refer to the diradical group
--NH--S(.dbd.O).sub.2--NH--.
[0175] The term "reactant," as used herein, refers to a nucleophile
or electrophile used to create covalent linkages.
[0176] It is to be understood that in instances where two or more
radicals are used in succession to define a substituent attached to
a structure, the first named radical is considered to be terminal
and the last named radical is considered to be attached to the
structure in question. Thus, for example, the radical arylalkyl is
attached to the structure in question by the alkyl group.
Certain Pharmaceutical Terminology
[0177] The term "MEK inhibitor" as used herein refers to a compound
that exhibits an IC.sub.50 with respect to MEK activity, of no more
than about 100 .mu.M or not more than about 50 .mu.M, as measured
in the Mek1 kinase assay described generally herein. "IC.sub.50" is
that concentration of inhibitor which reduces the activity of an
enzyme (e.g., MEK) to half-maximal level. Compounds described
herein have been discovered to exhibit inhibition against MEK.
Compounds of the present invention preferably exhibit an IC.sub.50
with respect to MEK of no more than about 10 .mu.M, more
preferably, no more than about 5M, even more preferably not more
than about 1 .mu.M, and most preferably, not more than about 200
nM, as measured in the Mek1 kinase assay described herein.
[0178] The term "subject", "patient" or "individual" as used herein
in reference to individuals suffering from a disorder, and the
like, encompasses mammals and non-mammals. Examples of mammals
include, but are not limited to, any member of the Mammalian class:
humans, non-human primates such as chimpanzees, and other apes and
monkey species; farm animals such as cattle, horses, sheep, goats,
swine; domestic animals such as rabbits, dogs, and cats; laboratory
animals including rodents, such as rats, mice and guinea pigs, and
the like. Examples of non-mammals include, but are not limited to,
birds, fish and the like. In one embodiment of the methods and
compositions provided herein, the mammal is a human.
[0179] The terms "treat," "treating" or "treatment," and other
grammatical equivalents as used herein, include alleviating,
abating or ameliorating a disease or condition symptoms, preventing
additional symptoms, ameliorating or preventing the underlying
metabolic causes of symptoms, inhibiting the disease or condition,
e.g., arresting the development of the disease or condition,
relieving the disease or condition, causing regression of the
disease or condition, relieving a condition caused by the disease
or condition, or stopping the symptoms of the disease or condition,
and are intended to include prophylaxis. The terms further include
achieving a therapeutic benefit and/or a prophylactic benefit. By
therapeutic benefit is meant eradication or amelioration of the
underlying disorder being treated. Also, a therapeutic benefit is
achieved with the eradication or amelioration of one or more of the
physiological symptoms associated with the underlying disorder such
that an improvement is observed in the patient, notwithstanding
that the patient may still be afflicted with the underlying
disorder. For prophylactic benefit, the compositions may be
administered to a patient at risk of developing a particular
disease, or to a patient reporting one or more of the physiological
symptoms of a disease, even though a diagnosis of this disease may
not have been made.
[0180] The terms "effective amount", "therapeutically effective
amount" or "pharmaceutically effective amount" as used herein,
refer to a sufficient amount of at least one agent or compound
being administered which will relieve to some extent one or more of
the symptoms of the disease or condition being treated. The result
can be reduction and/or alleviation of the signs, symptoms, or
causes of a disease, or any other desired alteration of a
biological system. For example, an "effective amount" for
therapeutic uses is the amount of the composition comprising a
compound as disclosed herein required to provide a clinically
significant decrease in a disease. An appropriate "effective"
amount in any individual case may be determined using techniques,
such as a dose escalation study.
[0181] The terms "administer," "administering", "administration,"
and the like, as used herein, refer to the methods that may be used
to enable delivery of compounds or compositions to the desired site
of biological action. These methods include, but are not limited to
oral routes, intraduodenal routes, parenteral injection (including
intravenous, subcutaneous, intraperitoneal, intramuscular,
intravascular or infusion), topical and rectal administration.
Those of skill in the art are familiar with administration
techniques that can be employed with the compounds and methods
described herein, e.g., as discussed in Goodman and Gilman, The
Pharmacological Basis of Therapeutics, current ed.; Pergamon; and
Remington's, Pharmaceutical Sciences (current edition), Mack
Publishing Co., Easton, Pa. In preferred embodiments, the compounds
and compositions described herein are administered orally.
[0182] The term "acceptable" as used herein, with respect to a
formulation, composition or ingredient, means having no persistent
detrimental effect on the general health of the subject being
treated.
[0183] The term "pharmaceutically acceptable" as used herein,
refers to a material, such as a carrier or diluent, which does not
abrogate the biological activity or properties of the compounds
described herein, and is relatively nontoxic, i.e., the material
may be administered to an individual without causing undesirable
biological effects or interacting in a deleterious manner with any
of the components of the composition in which it is contained.
[0184] The term "pharmaceutical composition," as used herein,
refers to a biologically active compound, optionally mixed with at
least one pharmaceutically acceptable chemical component, such as,
though not limited to carriers, stabilizers, diluents, dispersing
agents, suspending agents, thickening agents, and/or
excipients.
[0185] The term "carrier" as used herein, refers to relatively
nontoxic chemical compounds or agents that facilitate the
incorporation of a compound into cells or tissues.
[0186] The term "agonist," as used herein, refers to a molecule
such as a compound, a drug, an enzyme activator or a hormone
modulator which enhances the activity of another molecule or the
activity of a receptor site.
[0187] The term "antagonist," as used herein, refers to a molecule
such as a compound, a drug, an enzyme inhibitor, or a hormone
modulator, which diminishes, or prevents the action of another
molecule or the activity of a receptor site.
[0188] The term "modulate," as used herein, means to interact with
a target either directly or indirectly so as to alter the activity
of the target, including, by way of example only, to enhance the
activity of the target, to inhibit the activity of the target, to
limit the activity of the target, or to extend the activity of the
target.
[0189] The term "modulator," as used herein, refers to a molecule
that interacts with a target either directly or indirectly. The
interactions include, but are not limited to, the interactions of
an agonist and an antagonist.
[0190] The term "pharmaceutically acceptable derivative or prodrug"
as used herein, refers to any pharmaceutically acceptable salt,
ester, salt of an ester or other derivative of a compound of
formula I or formula II, which, upon administration to a recipient,
is capable of providing, either directly or indirectly, a compound
of this invention or a pharmaceutically active metabolite or
residue thereof. Particularly favored derivatives or prodrugs are
those that increase the bioavailability of the compounds of this
invention when such compounds are administered to a patient (e.g.,
by allowing orally administered compound to be more readily
absorbed into blood) or which enhance delivery of the parent
compound to a biological compartment (e.g., the brain or lymphatic
system).
[0191] The term "pharmaceutically acceptable salt" as used herein,
includes salts that retain the biological effectiveness of the free
acids and bases of the specified compound and that are not
biologically or otherwise undesirable. Compounds described may
possess acidic or basic groups and therefore may react with any of
a number of inorganic or organic bases, and inorganic and organic
acids, to form a pharmaceutically acceptable salt. Examples of
pharmaceutically acceptable salts include those salts prepared by
reaction of the compounds described herein with a mineral or
organic acid or an inorganic base, such salts including, acetate,
acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate,
bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate,
camphorate, camphorsulfonate, caproate, caprylate, chlorides,
chlorobenzoate, chloride, citrate, cyclopentanepropionate,
decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate,
dodecylsulfate, ethanesulfonate, formate, fumarate,
glucoheptanoate, glycerophosphate, glycolate, hemisulfate,
heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate,
.gamma.-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide,
2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate,
malonate, methanesulfonate, mandelate metaphosphate,
methanesulfonate, methoxybenzoate, methylbenzoate,
monohydrogenphosphate, 1-napthalenesulfonate,
2-napthalenesulfonate, nicotinate, nitrate, oxalates, palmoate,
pectinate, persulfate, phenylacetates, phenylpropionates,
3-phenylpropionate, phosphate, picrate, pivalate, propionate,
pyrosulfate, pyrophosphate, propiolate, propionates, phthalate,
phenylbutyrate, propanesulfonate, pyrophosphates, salicylate,
succinate, sulfate, sulfite, succinate, suberate, sebacate,
sulfonate, tartrate, thiocyanate, tosylate undeconate and
xylenesulfonate. Other acids, such as oxalic, while not in
themselves pharmaceutically acceptable, may be employed in the
preparation of salts useful as intermediates in obtaining the
compounds of the invention and their pharmaceutically acceptable
acid addition salts. (See for example Berge et al., J. Pharm. Sci.
1977, 66, 1-19.) Further, those compounds described herein which
may comprise a free acid group may react with a suitable base, such
as the hydroxide, carbonate or bicarbonate of a pharmaceutically
acceptable metal cation, with ammonia, or with a pharmaceutically
acceptable organic primary, secondary or tertiary amine.
Representative alkali or alkaline earth salts include the lithium,
sodium, potassium, calcium, magnesium, and aluminum salts and the
like. Illustrative examples of bases include sodium hydroxide,
potassium hydroxide, choline hydroxide, sodium carbonate,
N.sup.+(C.sub.1-4 alkyl).sub.4, and the like. Representative
organic amines useful for the formation of base addition salts
include ethylamine, diethylamine, ethylenediamine, ethanolamine,
diethanolamine, piperazine and the like. It should be understood
that the compounds described herein also include the quaternization
of any basic nitrogen-containing groups they may contain. Water or
oil-soluble or dispersible products may be obtained by such
quaternization. See, for example, Berge et al, supra. These salts
can be prepared in situ during the final isolation and purification
of the compounds of the invention, or by separately reacting a
purified compound in its free base form with a suitable organic or
inorganic acid, and isolating the salt thus formed.
[0192] As used herein, a "prodrug" is a compound that may be
converted under physiological conditions or by solvolysis to the
specified compound or to a pharmaceutically acceptable salt of such
compound. Prodrugs include compounds wherein an amino acid residue,
or a polypeptide chain of two or more amino acid residues, is
covalently joined through an amide or ester bond to a free amino,
hydroxy, or carboxylic acid group of compounds of Formulas I. The
amino acid residues contemplated include but are not limited to the
20 naturally-occurring amino acids. Other suitable amino acids
include 4-hydroxyproline, hydroxylysine, demosine, isodemosine,
3-methyl histidine, norvaline, .beta.-alanine, .gamma.-aminobutyric
acid, cirtulline, homocysteine, homoserine, ornithine and
methionine sulfone. Additional types of prodrugs are well known in
the art.
[0193] Pharmaceutically acceptable prodrugs of the compounds
described herein include, but are not limited to, esters,
carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl
derivatives, quaternary derivatives of tertiary amines, N-Mannich
bases, Schiff bases, amino acid conjugates, phosphate esters, metal
salts and sulfonate esters. Various forms of prodrugs are well
known in the art. See for example Design of Prodrugs, Bundgaard, A.
Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al.,
Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard, H. "Design and
Application of Prodrugs" in A Textbook of Drug Design and
Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter
5, p. 113-191; and Bundgaard, H., Advanced Drug Delivery Review,
1992, 8, 1-38, each of which is incorporated herein by reference.
The prodrugs described herein include, but are not limited to, the
following groups and combinations of these groups; amine derived
prodrugs:
##STR00024##
Hydroxy prodrugs include, but are not limited to acyloxyalkyl
esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters
and disulfide containing esters.
[0194] The terms "enhance" or "enhancing," as used herein, means to
increase or prolong either in potency or duration a desired effect.
Thus, in regard to enhancing the effect of therapeutic agents, the
term "enhancing" refers to the ability to increase or prolong,
either in potency or duration, the effect of other therapeutic
agents on a system. An "enhancing-effective amount," as used
herein, refers to an amount adequate to enhance the effect of
another therapeutic agent in a desired system.
[0195] The terms "pharmaceutical combination", "administering an
additional therapy", "administering an additional therapeutic
agent" and the like, as used herein, refer to a pharmaceutical
therapy resulting from the mixing or combining of more than one
active ingredient and includes both fixed and non-fixed
combinations of the active ingredients. The term "fixed
combination" means that at least one of the compounds described
herein, and at least one co-agent, are both administered to a
patient simultaneously in the form of a single entity or dosage.
The term "non-fixed combination" means that at least one of the
compounds described herein, and at least one co-agent, are
administered to a patient as separate entities either
simultaneously, concurrently or sequentially with variable
intervening time limits, wherein such administration provides
effective levels of the two or more compounds in the body of the
patient. These also apply to cocktail therapies, e.g. the
administration of three or more active ingredients.
[0196] The terms "co-administration", "administered in combination
with" and their grammatical equivalents or the like, as used
herein, are meant to encompass administration of the selected
therapeutic agents to a single patient, and are intended to include
treatment regimens in which the agents are administered by the same
or different route of administration or at the same or different
times. In some embodiments the compounds described herein will be
co-administered with other agents. These terms encompass
administration of two or more agents to an animal so that both
agents and/or their metabolites are present in the animal at the
same time. They include simultaneous administration in separate
compositions, administration at different times in separate
compositions, and/or administration in a composition in which both
agents are present. Thus, in some embodiments, the compounds of the
invention and the other agent(s) are administered in a single
composition. In some embodiments, compounds of the invention and
the other agent(s) are admixed in the composition.
[0197] The term "metabolite," as used herein, refers to a
derivative of a compound which is formed when the compound is
metabolized.
[0198] The term "active metabolite," as used herein, refers to a
biologically active derivative of a compound that is formed when
the compound is metabolized.
[0199] The term "metabolized," as used herein, refers to the sum of
the processes (including, but not limited to, hydrolysis reactions
and reactions catalyzed by enzymes) by which a particular substance
is changed by an organism. Thus, enzymes may produce specific
structural alterations to a compound. For example, cytochrome P450
catalyzes a variety of oxidative and reductive reactions while
uridine diphosphate glucuronyltransferases catalyze the transfer of
an activated glucuronic-acid molecule to aromatic alcohols,
aliphatic alcohols, carboxylic acids, amines and free sulphydryl
groups. Further information on metabolism may be obtained from The
Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill
(1996).
Compounds
[0200] Described herein are compounds of formula I,
pharmaceutically acceptable salts, solvates, polymorphs, esters,
tautomers or prodrugs thereof,
##STR00025##
wherein
[0201] Z is H or F;
[0202] X is F, Cl, CH.sub.3, CH.sub.2OH, CH.sub.2F, CHF.sub.2, or
CF.sub.3;
[0203] Y is I, Br, Cl, CF.sub.3, C.sub.1-C.sub.3 alkyl,
C.sub.2-C.sub.3 alkenyl, C.sub.2-C.sub.3 alkynyl, cyclopropyl, OMe,
OEt, SMe, phenyl or Het, where Het is a 5- to 10-membered mono- or
bicyclic heterocyclic group, which group is saturated, olefinic, or
aromatic, containing 1-5 ring heteroatoms selected independently
from N, O, and S; where [0204] all said phenyl or Het groups are
optionally substituted with F, Cl, Br, I, acetyl, methyl, CN,
NO.sub.2, CO.sub.2H, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy,
C.sub.1-C.sub.3 alkyl-C(.dbd.O)--, C.sub.1-C.sub.3
alkyl-C(.dbd.S)--, C.sub.1-C.sub.3 alkoxy-C(.dbd.S)--,
C.sub.1-C.sub.3 alkyl-C(.dbd.O)O--, C.sub.1-C.sub.3
alkyl-O--(C.dbd.O)--, C.sub.1-C.sub.3 alkyl-C(.dbd.O)NH--,
C.sub.1-C.sub.3 alkyl-C(--NH)NH--, C.sub.1-C.sub.3
alkyl-NH--(C.dbd.O)--, di-C.sub.1-C.sub.3 alkyl-N--(C.dbd.O)--,
C.sub.1-C.sub.3 alkyl-C(.dbd.O)N(C.sub.1-C.sub.3 alkyl)-,
C.sub.1-C.sub.3 alkyl-S(.dbd.O).sub.2NH-- or trifluoromethyl;
[0205] all said methyl, ethyl, C.sub.1-C.sub.3 alkyl, and
cyclopropyl groups are optionally substituted with OH; [0206] all
said methyl groups are optionally substituted with one, two, or
three F atoms;
[0207] R.sup.0 is H, F, Cl, Br, I, CH.sub.3NH--,
(CH.sub.3).sub.2N--, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.3-C.sub.6 cycloalkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, phenyl, monosubstituted phenyl,
O(C.sub.1-C.sub.4 alkyl),
O--C(.dbd.O)(C.sub.1-C.sub.4 alkyl) or C(.dbd.O)O(C.sub.1-C.sub.4
alkyl); where [0208] said alkyl, alkoxy, cycloalkyl, alkenyl,
alkynyl and phenyl groups are optionally substituted with 1-3
substituents selected independently from F, Cl, Br, I, OH, CN,
cyanomethyl, nitro, phenyl and trifluoromethyl; [0209] said
C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.4 alkoxy groups also
optionally substituted with OCH.sub.3 or OCH.sub.2CH.sub.3; G is
G.sub.1, G.sub.2, R.sub.1a, R.sub.1b, R.sub.1c, R.sub.1d, R.sub.1e,
Ar.sub.1, Ar.sub.2 or Ar.sub.3; where [0210] G.sub.1 is
C.sub.1-C.sub.6 alkyl optionally substituted with one amino,
C.sub.1-C.sub.3 alkylamino, or dialkylamino group, said
dialkylamino group comprising two C.sub.1-C.sub.4 alkyl groups
which may be identical or non-identical; or [0211] G.sub.1 is a
C.sub.3-C.sub.8 diamino alkyl group; [0212] G.sub.2 is a 5- or
6-membered ring, which is saturated, unsaturated, or aromatic,
containing 1-3 ring heteroatoms selected independently from N, O,
and S, optionally substituted with 1-3 substituents selected
independently from F, Cl, OH, O(C.sub.1-C.sub.3 alkyl), OCH.sub.3,
OCH.sub.2CH.sub.3, CH.sub.3C(--O)NH, CH.sub.3C(O)O, CN, CF.sub.3,
and a 5-membered aromatic heterocyclic group containing 1-4 ring
heteroatoms selected independently from N, O, and S; [0213]
R.sub.1a is methyl, optionally substituted with 1-3 fluorine atoms
or 1-3 chlorine atoms, or with OH, cyclopropoxy, or C.sub.1-C.sub.3
alkoxy, where said cyclopropoxy group or the C.sub.1-C.sub.3 alkyl
moieties of said C.sub.1-C.sub.3 alkoxy groups are optionally
substituted with one hydroxy or methoxy group, and where all
C.sub.3-alkyl groups within said C.sub.1-C.sub.4 alkoxy are
optionally further substituted with a second OH group; [0214]
R.sub.1b is CH(CH.sub.3)--C.sub.1-3 alkyl or C.sub.3-C.sub.6
cycloalkyl, said alkyl and cycloalkyl groups optionally substituted
with 1-3 substituents selected independently from F, Cl, Br, I, OH,
OCH.sub.3, and CN; [0215] R.sub.1c is (CH.sub.2).sub.nO.sub.mR';
where [0216] m is 0 or 1; and where [0217] when m is 0, n is 1 or
2; [0218] when m is 1, n is 2 or 3; [0219] R' is C.sub.1-C.sub.6
alkyl, optionally substituted with 1-3 substituents selected
independently from F, Cl, OH, OCH.sub.3, OCH.sub.2CH.sub.3, and
C.sub.3-C.sub.6 cycloalkyl; [0220] R.sub.1d is C(A)(A')(B)--; where
[0221] B is H or C.sub.1-4 alkyl, optionally substituted with one
or two OH groups; [0222] A and A' are independently H or C.sub.1-4
alkyl, optionally substituted with one or two OH groups; or [0223]
A and A', together with the carbon atom to which they are attached,
form a 3- to 6-member saturated ring; [0224] R.sub.1e is
[0224] ##STR00026## [0225] where [0226] q is 1 or 2; [0227] R.sub.2
and R.sub.3 are each independently, H, F, Cl, Br, CH.sub.3,
CH.sub.2F, CHF.sub.2, CF.sub.3 OCH.sub.3, OCH.sub.2F, OCHF.sub.2,
OCF.sub.3, ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl,
sec-butyl, tert-butyl or methylsulfonyl; [0228] R.sub.4 is H, F,
Cl, Br, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3 OCH.sub.3,
OCH.sub.2F, OCHF.sub.2, OCF.sub.3, ethyl, n-propyl, isopropyl,
cyclopropyl, isobutyl, sec-butyl, tert-butyl, methylsulfonyl,
nitro, acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl,
dimethylcarbamoyl, 1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazol,
1,3,4-thiadiazol, 5-methyl-1,3,4-thiadiazol 1H-tetrazolyl,
N-morpholyl carbonyl amino, N-morpholylsulfonyl and
N-pyrrolidinylcarbonylamino; [0229] R.sub.5 is H, F, Cl or methyl;
[0230] R is H, F, Cl or methyl; [0231] Ar.sub.1 is
[0231] ##STR00027## [0232] where [0233] U and V are, independently,
N, CR.sub.2 or CR.sub.3; [0234] R.sub.2, R.sub.3 and R.sub.4 are,
independently, H, F, Cl, Br, CH.sub.3, CH.sub.2F, CHF.sub.2,
CF.sub.3 OCH.sub.3, OCH.sub.2F, OCHF.sub.2, OCF.sub.3, ethyl,
n-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl,
acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl,
dimethylcarbamoyl, 1,3,4-oxadiazol-2-yl,
5-methyl-1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl,
5-methyl-1,3,4-thiadiazolyl, 1H-tetrazolyl,
N-morpholylcarbonylamino, N-morpholylsulfonyl,
N-pyrrolidinylcarbonylamino, and methylsulfonyl; [0235] R.sub.5 and
R.sub.6 are, independently, H, F, Cl or methyl; [0236] Ar.sub.2
is
[0236] ##STR00028## [0237] where [0238] the dashed line represents
alternative formal locations for the second ring double bond;
[0239] U is --S--, --O-- or --N.dbd., and where [0240] when U is
--O-- or --S--, V is --CH.dbd., --CCl.dbd. or --N.dbd.; [0241] when
U is --N.dbd., V is --CH--, --CCl.dbd., or --N.dbd.; [0242] R.sub.7
is H or methyl; [0243] R.sub.8 is H, acetamido, methyl, F or Cl;
[0244] Ar.sub.3 is
[0244] ##STR00029## [0245] where [0246] U is --NH--, --NCH.sub.3--
or --O--; [0247] R.sub.7 and R.sub.8 are, independently, H, F, Cl,
or methyl.
[0248] In some embodiments, the invention provides for compounds of
formula I and their pharmaceutically acceptable salts. In further
or additional embodiments, the invention provides for compounds of
formula I and their pharmaceutically acceptable solvates. In
further or additional embodiments, the invention provides for
compounds of formula I and their pharmaceutically acceptable
hydrates. In further or additional embodiments, the invention
provides for compounds of formula I and their pharmaceutically
acceptable polymorphs. In further or additional embodiments, the
invention provides for compounds of formula I and their
pharmaceutically acceptable esters. In further or additional
embodiments, the invention provides for compounds of formula I and
their pharmaceutically acceptable tautomers. In further or
additional embodiments, the invention provides for compounds of
formula I and their pharmaceutically acceptable prodrugs.
[0249] In addition to the definitions given herein for the groups
G, R.sup.0, X, Y and Z additional substitutions which could be
contemplated by those of skill in the chemical and pharmaceutical
arts are included.
[0250] Compounds of formula I, pharmaceutically acceptable salts,
pharmaceutically active metabolites, pharmaceutically acceptable
prodrugs, and pharmaceutically acceptable solvates thereof, may
modulate the activity of MEK enzymes; and, as such, are useful for
treating diseases or conditions in which aberrant MEK enzyme
activity contributes to the pathology and/or symptoms of a disease
or condition.
[0251] The tables below show examples of individual compounds
provided or contemplated by this invention. These examples should
in no way be construed as limiting.
[0252] Table 1 shows embodiments of this invention which are
compounds of formula I, wherein G is R.sub.1, where R.sub.1a is as
defined in the table and X, Y and Z are defined in the table.
TABLE-US-00001 TABLE 1 R.sub.1a X Y Z CH.sub.3 F I F CH.sub.3 Cl I
F CH.sub.3 F Br F CH.sub.3 Cl Br F CH.sub.3 F CH.sub.3 F CH.sub.3
Cl CH.sub.3 F CH.sub.3 F CF.sub.3 F CH.sub.3 Cl CF.sub.3 F CH.sub.3
F C.ident.CH F CH.sub.3 Cl C.ident.CH F CH.sub.3 F SCH.sub.3 F
CH.sub.3 Cl SCH.sub.3 F CH.sub.3 F (CH.sub.2).sub.2CH.sub.3 F
CH.sub.3 Cl (CH.sub.2).sub.2CH.sub.3 F CH.sub.3 F CH.sub.2CH.sub.3
F CH.sub.3 Cl CH.sub.2CH.sub.3 F CH.sub.3 F CH.sub.2OH F CH.sub.3
Cl CH.sub.2OH F CH.sub.3 F F CH.sub.3 Cl F CH.sub.3 CH.sub.3
CH.dbd.CH.sub.2 F CH.sub.3 CH.sub.3 C.ident.CH F CH.sub.3 CH.sub.3
SCH.sub.3 F CH.sub.2F F I F CH.sub.2F Cl I F CH.sub.2F F Br F
CH.sub.2F Cl Br F CH.sub.2F F CH.sub.3 F CH.sub.2F Cl CH.sub.3 F
CH.sub.2F F CF.sub.3 F CH.sub.2F Cl CF.sub.3 F CF.sub.3 F I F
CF.sub.3 Cl I F CF.sub.3 F Br F CF.sub.3 Cl Br F CF.sub.3 F
CH.sub.3 F CF.sub.3 Cl CH.sub.3 F CF.sub.3 F CF.sub.3 F CF.sub.3 Cl
CF.sub.3 F CH.sub.2Cl F I F CH.sub.2Cl Cl I F CH.sub.2Cl F Br F
CH.sub.2Cl Cl Br F CH.sub.2Cl F CH.sub.3 F CH.sub.2Cl Cl CH.sub.3 F
CH.sub.2Cl F CF.sub.3 F CH.sub.2Cl Cl CF.sub.3 F CHCl.sub.2 F I F
CHCl.sub.2 Cl I F CHCl.sub.2 F Br F CHCl.sub.2 Cl Br F CHCl.sub.2 F
CH.sub.3 F CHCl.sub.2 Cl CH.sub.3 F CHCl.sub.2 F CF.sub.3 F
CHCl.sub.2 Cl CF.sub.3 F CCl.sub.3 F I F CCl.sub.3 Cl I F CCl.sub.3
F Br F CCl.sub.3 Cl Br F CCl.sub.3 F CH.sub.3 F CCl.sub.3 Cl
CH.sub.3 F CCl.sub.3 F CF.sub.3 F CCl.sub.3 Cl CF.sub.3 F
CH.sub.2OH F I F CH.sub.2OH Cl I F CH.sub.2OH F Br F CH.sub.2OH Cl
Br F CH.sub.2OH F CH.sub.3 F CH.sub.2OH Cl CH.sub.3 F CH.sub.2OH F
CF.sub.3 F CH.sub.2OH Cl CF.sub.3 F CH.sub.2OMe F I F CH.sub.2OMe
Cl I F CH.sub.2OMe F Br F CH.sub.2OMe Cl Br F CH.sub.2OMe F
CH.sub.3 F CH.sub.2OMe Cl CH.sub.3 F CH.sub.2OMe F CF.sub.3 F
CH.sub.2OMe Cl CF.sub.3 F CH.sub.2OMe F C.ident.CH F CH.sub.2OMe Cl
SCH.sub.3 F CH.sub.2OMe CH.sub.3 CF.sub.3 F CH.sub.2OMe CH.sub.3
C.ident.CH F CH.sub.2OEt F I F CH.sub.2OEt Cl I F CH.sub.2OEt F Br
F CH.sub.2OEt Cl Br F CH.sub.2OEt F CH.sub.3 F CH.sub.2OEt Cl
CH.sub.3 F CH.sub.2OEt F CF.sub.3 F CH.sub.2OEt Cl CF.sub.3 F
##STR00030## F I F ##STR00031## Cl I F ##STR00032## F Br F
##STR00033## Cl Br F ##STR00034## F CH.sub.3 F ##STR00035## Cl
CH.sub.3 F ##STR00036## F CF.sub.3 F ##STR00037## Cl CF.sub.3 F
##STR00038## F I F ##STR00039## Cl I F ##STR00040## F Br F
##STR00041## Cl Br F ##STR00042## F CH.sub.3 F ##STR00043## Cl
CH.sub.3 F ##STR00044## F CF.sub.3 F ##STR00045## Cl CF.sub.3 F
##STR00046## F I F ##STR00047## Cl I F ##STR00048## F Br F
##STR00049## Cl Br F ##STR00050## F CH.sub.3 F ##STR00051## Cl
CH.sub.3 F ##STR00052## F CF.sub.3 F ##STR00053## Cl CF.sub.3 F
##STR00054## F I F ##STR00055## Cl I F ##STR00056## F Br F
##STR00057## Cl Br F ##STR00058## F CH.sub.3 F ##STR00059## Cl
CH.sub.3 F ##STR00060## F CF.sub.3 F ##STR00061## Cl CF.sub.3 F
##STR00062## F I F ##STR00063## Cl I F ##STR00064## F Br F
##STR00065## Cl Br F ##STR00066## F CH.sub.3 F ##STR00067## Cl
CH.sub.3 F ##STR00068## F CF.sub.3 F ##STR00069## Cl CF.sub.3 F
CH.sub.3 F phenyl F CH.sub.3 Cl phenyl F CH.sub.3 CH.sub.3 phenyl
CH.sub.3 F 3-pyridyl F CH.sub.3 Cl 3-pyridyl F CH.sub.3 CH.sub.3
4-pyridyl CH.sub.3 F pyrazolyl F CH.sub.3 Cl pyrazolyl F CH.sub.3 F
4-pyridyl F CH.sub.3 Cl 4-pyridyl F CH.sub.3 CH.sub.3
2-(CH.sub.3--SO.sub.2--NH)- F phenyl CH.sub.3 CH.sub.3
3-(CH.sub.3--SO.sub.2--NH)- phenyl CH.sub.3 Cl
3-(CH.sub.3--SO.sub.2--NH)- F phenyl CH.sub.3 F
3-(CH.sub.3--SO.sub.2--NH)- F phenyl
[0253] Table 2 shows embodiments of this invention which are
compounds of formula I, wherein G is R.sub.1b where R.sub.1b is as
defined in the table and X, Y and Z are defined in the table.
TABLE-US-00002 TABLE 2 R.sub.1b X Y Z F I F Cl I F F Br F Cl Br F F
CH F Cl CH.sub.3 F F CF.sub.3 F Cl CF.sub.3 F F C.ident.CH F Cl
C.ident.CH F F SCH.sub.3 F Cl SCH.sub.3 F F CH.sub.2OH F Cl
CH.sub.2OH F F (CH.sub.2).sub.3OH F Cl (CH.sub.2).sub.3OH F F
(CH.sub.2).sub.2CH.sub.3 F Cl (CH.sub.2).sub.2CH.sub.3 F F
CH.sub.2CH.sub.3 F Cl CH.sub.2CH.sub.3 F F (CH.sub.2).sub.2CH.sub.3
F Cl (CH.sub.2).sub.2CH.sub.3 F CH I F CH Br F CH.sub.3 CH.sub.3 F
CH.sub.3 CF.sub.3 F CH.sub.3 CH.sub.2CH.sub.3 F CH.sub.3
(CH.sub.2).sub.2CH.sub.3 F CH.sub.3 CH F CH.sub.3 SCH.sub.3 F
##STR00070## CH.sub.3 (CH.sub.2).sub.2CH.sub.3 F ##STR00071##
CH.sub.3 I F F CH.dbd.CH.sub.2 F Cl CH.dbd.CH.sub.2 F CH.sub.3
CH.dbd.CH.sub.2 F F F F OCH.sub.3 F Cl (CH.sub.2).sub.2CH.sub.2OH F
##STR00072## F I F F ##STR00073## Cl I F ##STR00074## F Br F
##STR00075## Cl Br F ##STR00076## F CH.sub.3 F ##STR00077## Cl
CH.sub.3 F ##STR00078## F CF.sub.3 F ##STR00079## Cl CF.sub.3 F
##STR00080## Cl I F ##STR00081## Cl I F ##STR00082## F Br F
##STR00083## Cl Br F ##STR00084## F CH.sub.3 F ##STR00085## Cl
CH.sub.3 F ##STR00086## F CF.sub.3 F ##STR00087## Cl CF.sub.3 F
##STR00088## Cl F ##STR00089## F (CH.sub.2).sub.2CH.sub.3 F
##STR00090## Cl C.ident.CH F ##STR00091## CH.sub.3 SCH.sub.3 F
##STR00092## Cl CF.sub.3 F ##STR00093## CH.sub.3 CH.sub.3 F
##STR00094## F CH.sub.2OH F ##STR00095## Cl (CH.sub.2).sub.3OH F
##STR00096## F OCH.sub.2CH.sub.3 F ##STR00097## F I F ##STR00098##
Cl I F ##STR00099## F Br F ##STR00100## Cl Br F ##STR00101## F
CH.sub.3 F ##STR00102## Cl CH.sub.3 F ##STR00103## F CF.sub.3 F
##STR00104## Cl CF.sub.3 F F phenyl F Cl phenyl F F 3-pyridyl F Cl
3-pyridyl F F pyrazol-4-yl F Cl pyrazol-4-yl F F 4-pyridyl F Cl
4-pyridyl F F 1-methyl-pyrazol- F 4-yl Cl 1-methyl-pyrazol- F 4-yl
F pyrazol-3-yl F Cl pyrazol-3-yl F F 2-(CH.sub.3--SO.sub.2--NH)- F
phenyl Cl 2-(CH.sub.3--SO.sub.2--NH)- F phenyl F
3-(CH.sub.3--SO.sub.2--NH)- F phenyl Cl 3-(CH.sub.3--SO.sub.2--NH)-
F phenyl CH.sub.3 2-(CH.sub.3--SO.sub.2--NH)- F phenyl CH.sub.3
3-(CH.sub.3--SO.sub.2--NH)- F phenyl F 4-CF.sub.3O-phenyl F Cl
4-CF.sub.3O-phenyl F CH.sub.3 4-CF.sub.3O-phenyl F ##STR00105## Cl
2-(CH.sub.3--SO.sub.2--NH)- phenyl F ##STR00106## F phenyl F
##STR00107## phenyl ##STR00108## Cl 3-pyridyl F ##STR00109## F
3-pyridyl F ##STR00110## Cl pyrazol-4-yl F ##STR00111## F
pyrazol-4-yl F ##STR00112## Cl 4-pyridyl F ##STR00113## F 4-pyridyl
F ##STR00114## Cl 1-methyl-pyrazol-4-yl 4-yl F ##STR00115##
CH.sub.3 1-methyl-pyrazol- 4-yl F ##STR00116## F pyrazol-3-yl F
##STR00117## Cl pyrazol-3-yl F ##STR00118## F
2-(CH.sub.3--SO.sub.2--NH)- phenyl F ##STR00119## Cl
2-(CH.sub.3--SO.sub.2--NH)- phenyl F ##STR00120## Cl phenyl F
##STR00121## F 3-pyridyl F ##STR00122## Cl 3-pyridyl F ##STR00123##
Cl pyrazol-3-yl F
[0254] Table 3 shows embodiments of this invention which are
compounds of formula I, wherein G is R.sub.1c where R.sub.1c is as
defined in the table and X, Y and Z are defined in the table.
TABLE-US-00003 TABLE 3 R.sub.1c X Y Z CH.sub.2CH.sub.3 F I F
CH.sub.2CH.sub.3 Cl I F CH.sub.2CH.sub.3 F Br F CH.sub.2CH.sub.3 Cl
Br F CH.sub.2CH.sub.3 F CH.sub.3 F CH.sub.2CH.sub.3 Cl CH.sub.3 F
CH.sub.2CH.sub.3 F CF.sub.3 F CH.sub.2CH.sub.3 Cl CF.sub.3 F
CH.sub.2CH.sub.3 CH.sub.3 CH.sub.3 F CH.sub.2CH.sub.3 CH.sub.3
CH.sub.3 F CH.sub.2CH.sub.3 CH.sub.3 C.ident.CH F CH.sub.2CH.sub.3
CH.sub.3 SCH.sub.3 F CH.sub.2CH.sub.3 F C.ident.CH F
CH.sub.2CH.sub.3 Cl SCH.sub.3 F CH.sub.2CH.sub.3 F F
CH.sub.2CH.sub.3 Cl F CH.sub.2CH.sub.3 CH.sub.3 F
CH.sub.2(CH.sub.3).sub.2 F OCH.sub.3 F CH.sub.2(CH.sub.3).sub.2 Cl
OCH.sub.3 F CH.sub.2(CH.sub.3).sub.2 F I F CH.sub.2(CH.sub.3).sub.2
Cl I F CH.sub.2(CH.sub.3).sub.2 F Br F CH.sub.2(CH.sub.3).sub.2 Cl
Br F CH.sub.2(CH.sub.3).sub.2 F CH.sub.3 F CH.sub.2(CH.sub.3).sub.2
Cl CH.sub.3 F CH.sub.2(CH.sub.3).sub.2 F CH.sub.2CH.sub.3 F
CH(CH.sub.3).sub.2 Cl CH.sub.2CH.sub.3 F CH(CH.sub.3).sub.2
CH.sub.3 CH.sub.2CH.sub.3 F CH(CH.sub.3).sub.2 Cl CH.sub.2CH.sub.3
F CH(CH.sub.3).sub.2 Fl CH(CH.sub.3).sub.2 F CH(CH.sub.3).sub.2 Cl
CH(CH.sub.3).sub.2 F CH(CH.sub.3).sub.2 F CF.sub.3 F
CH(CH.sub.3).sub.2 Cl CH.sub.3 F CH(CH.sub.3).sub.2 CH.sub.3 Br F
CH(CH.sub.3).sub.2 CH.sub.3 CH F CH(CH.sub.3).sub.2 CH.sub.3
SCH.sub.3 F CH(CH.sub.3).sub.2 CH F CH(CH.sub.3).sub.2 F CH.sub.2OH
F CH(CH.sub.3).sub.2 Cl ##STR00124## F n-butyl F I F n-butyl Cl I F
n-butyl F Br F n-butyl Cl Br F n-butyl F CH.sub.3 F n-butyl Cl
CH.sub.3 F n-butyl F OCH.sub.3 F n-butyl Cl OCH.sub.3 F n-butyl
CH.sub.3 OCH.sub.3 F n-butyl Cl OCH.sub.2CH.sub.3 F n-butyl F
OCH.sub.2CH.sub.3 F n-butyl CH.sub.3 OCH.sub.2CH.sub.3 F n-butyl F
OCH.sub.2CH.sub.2OH F n-butyl F CF.sub.3 F n-butyl Cl CF.sub.3 F
sec-butyl F I F see-butyl Cl I F sec-butyl F Br F sec-butyl Cl Br F
sec-butyl F CH.sub.3 F sec-butyl Cl CH.sub.3 F sec-butyl F CF.sub.3
F sec-butyl Cl CF.sub.3 F CH.sub.2CF.sub.3 F I F CH.sub.2CF.sub.3
Cl I F CH.sub.2CF.sub.3 F Br F CH.sub.2CF.sub.3 Cl Br F
CH.sub.2CF.sub.3 F CH.sub.3 F CH.sub.2CF.sub.3 Cl CH.sub.3 F
CH.sub.2CF.sub.3 F CF.sub.3 F CH.sub.2CF.sub.3 Cl CF.sub.3 F
CH.sub.2CCl.sub.3 F I F CH.sub.2CCl.sub.3 Cl I F CH.sub.2CCl.sub.3
F Br F CH.sub.2CCl.sub.3 Cl Br F CH.sub.2CCl.sub.3 F CH.sub.3 F
CH.sub.2CCl.sub.3 Cl CH.sub.3 F CH.sub.2CCl.sub.3 F CF.sub.3 F
CH.sub.2CCl.sub.3 Cl CF.sub.3 F ##STR00125## F I F ##STR00126## Cl
I F ##STR00127## F Br F ##STR00128## Cl Br F ##STR00129## F
CH.sub.3 F ##STR00130## Cl CH.sub.3 F ##STR00131## F CF.sub.3 F
##STR00132## Cl CF.sub.3 F CH.sub.2CH.sub.2F F I F
CH.sub.2CH.sub.2F Cl I F CH.sub.2CH.sub.2F F Br F CH.sub.2CH.sub.2F
Cl Br F CH.sub.2CH.sub.2F F CH.sub.3 F CH.sub.2CH.sub.2F Cl
CH.sub.3 F CH.sub.2CH.sub.2F F CF.sub.3 F CH.sub.2CH.sub.2F Cl
CF.sub.3 F CH.sub.2CH.sub.2Cl F I F CH.sub.2CH.sub.2Cl Cl I F
CH.sub.2CH.sub.2Cl F Br F CH.sub.2CH.sub.2Cl Cl Br F
CH.sub.2CH.sub.2Cl F CH.sub.3 F CH.sub.2CH.sub.2Cl Cl CH.sub.3 F
CH.sub.2CH.sub.2Cl F CF.sub.3 F CH.sub.2CH.sub.2Cl Cl CF.sub.3 F
CH.sub.2CH.sub.2CH.sub.2Cl F I F CH.sub.2CH.sub.2CH.sub.2Cl Cl I F
CH.sub.2CH.sub.2CH.sub.2Cl F Br F CH.sub.2CH.sub.2CH.sub.2Cl Cl Br
F CH.sub.2CH.sub.2CH.sub.2Cl F CH.sub.3 F
CH.sub.2CH.sub.2CH.sub.2Cl Cl CH.sub.3 F CH.sub.2CH.sub.2CH.sub.2Cl
F CF.sub.3 F CH.sub.2CH.sub.2CH.sub.2Cl Cl CF.sub.3 F
CH.sub.2CH.sub.2OH F I F CH.sub.2CH.sub.2OH Cl I F
CH.sub.2CH.sub.2OH F Br F CH.sub.2CH.sub.2OH Cl Br F
CH.sub.2CH.sub.2OH F CH.sub.3 F CH.sub.2CH.sub.2OH Cl CH.sub.3 F
CH.sub.2CH.sub.2OH F CF.sub.3 F CH.sub.2CH.sub.2OH Cl CF.sub.3 F
CH.sub.2CH.sub.2CH.sub.2OH F I F CH.sub.2CH.sub.2CH.sub.2OH Cl I F
CH.sub.2CH.sub.2CH.sub.2OH F Br F CH.sub.2CH.sub.2CH.sub.2OH Cl Br
F CH.sub.2CH.sub.2CH.sub.2OH F CH.sub.3 F
CH.sub.2CH.sub.2CH.sub.2OH Cl CH.sub.3 F CH.sub.2CH.sub.2CH.sub.2OH
F CF.sub.3 F CH.sub.2CH.sub.2CH.sub.2OH Cl CF.sub.3 F
(CH.sub.2).sub.4OH F I F (CH.sub.2).sub.4OH Cl I F
(CH.sub.2).sub.4OH F Br F (CH.sub.2).sub.4OH Cl Br F
(CH.sub.2).sub.4OH F CH.sub.3 F (CH.sub.2).sub.4OH Cl CH.sub.3 F
(CH.sub.2).sub.4OH F CF.sub.3 F (CH.sub.2).sub.4OH Cl CF.sub.3 F
CH.sub.2CH.sub.2OCH.sub.3 F I F CH.sub.2CH.sub.2OCH.sub.3 Cl I F
CH.sub.2CH.sub.2OCH.sub.3 F Br F CH.sub.2CH.sub.2OCH.sub.3 Cl Br F
CH.sub.2CH.sub.2OCH.sub.3 F CH.sub.3 F CH.sub.2CH.sub.2OCH.sub.3 Cl
CH.sub.3 F CH.sub.2CH.sub.2OCH.sub.3 F CF.sub.3 F
CH.sub.2CH.sub.2OCH.sub.3 Cl CF.sub.3 F (CH.sub.2).sub.3OCH.sub.3 F
I F (CH.sub.2).sub.3OCH.sub.3 Cl I F (CH.sub.2).sub.3OCH.sub.3 F Br
F (CH.sub.2).sub.3OCH.sub.3 Cl Br F (CH.sub.2).sub.3OCH.sub.3 F
CH.sub.3 F (CH.sub.2).sub.3OCH.sub.3 Cl CH.sub.3 F
(CH.sub.2).sub.3OCH.sub.3 F CF.sub.3 F (CH.sub.2).sub.3OCH.sub.3 Cl
CF.sub.3 F CH.sub.2CH.sub.2OEt F I F CH.sub.2CH.sub.2OEt Cl I F
CH.sub.2CH.sub.2OEt F Br F CH.sub.2CH.sub.2OEt Cl Br F
CH.sub.2CH.sub.2OEt F CH.sub.3 F CH.sub.2CH.sub.2OEt Cl CH.sub.3 F
CH.sub.2CH.sub.2OEt F CF.sub.3 F CH.sub.2CH.sub.2OEt Cl CF.sub.3 F
##STR00133## F I F ##STR00134## Cl I F ##STR00135## F Br F
##STR00136## Cl Br F ##STR00137## F CH.sub.3 F ##STR00138## Cl
CH.sub.3 F ##STR00139## F CF.sub.3 F ##STR00140## Cl CF.sub.3 F
##STR00141## F I F ##STR00142## Cl I F ##STR00143## F Br F
##STR00144## Cl Br F ##STR00145## F CH.sub.3 F ##STR00146## Cl
CH.sub.3 F ##STR00147## F CF.sub.3 F ##STR00148## Cl CF.sub.3 F
CH.sub.2CH.sub.2CH.sub.2OEt F I F CH.sub.2CH.sub.2CH.sub.2OEt Cl I
F CH.sub.2CH.sub.2CH.sub.2OEt F Br F CH.sub.2CH.sub.2CH.sub.2OEt Cl
Br F CH.sub.2CH.sub.2CH.sub.2OEt F CH.sub.3 F
CH.sub.2CH.sub.2CH.sub.2OEt Cl CH.sub.3 F
CH.sub.2CH.sub.2CH.sub.2OEt F CF.sub.3 F
CH.sub.2CH.sub.2CH.sub.2OEt Cl CF.sub.3 F ##STR00149## F I F
##STR00150## Cl I F ##STR00151## F Br F ##STR00152## Cl Br F
##STR00153## F CH.sub.3 F ##STR00154## Cl CH.sub.3 F ##STR00155## F
CF.sub.3 F ##STR00156## Cl CF.sub.3 F ##STR00157## F I F
##STR00158## F I F ##STR00159## F Br F ##STR00160## Cl Br F
##STR00161## F CH.sub.3 F ##STR00162## Cl CH.sub.3 F ##STR00163## F
CF.sub.3 F ##STR00164## Cl CF.sub.3 F ##STR00165## F I F
##STR00166## Cl I F
##STR00167## F Br F ##STR00168## Cl Br F ##STR00169## F CH.sub.3 F
##STR00170## Cl CH.sub.3 F ##STR00171## F CF.sub.3 F ##STR00172##
Cl CF.sub.3 F ##STR00173## F I F ##STR00174## Cl I F ##STR00175## F
Br F ##STR00176## Cl Br F ##STR00177## F CH.sub.3 F ##STR00178## Cl
CH.sub.3 F ##STR00179## F CF.sub.3 F ##STR00180## Cl CF.sub.3 F
##STR00181## F I F ##STR00182## Cl I F ##STR00183## CH.sub.3 I F
##STR00184## F Br F ##STR00185## Cl Br F ##STR00186## CH.sub.3 Br F
##STR00187## F CH.sub.3 F ##STR00188## Cl CH.sub.3 F ##STR00189##
CH.sub.3 CH.sub.3 F ##STR00190## F C.ident.CH F ##STR00191## F
SCH.sub.3 F ##STR00192## F CH.sub.2CH.sub.2CH.sub.3 F ##STR00193##
Cl CH.sub.2CH(OH)CH.sub.3 F ##STR00194## F CH(CH.sub.3).sub.2 F
##STR00195## Cl CF.sub.3 F CH.sub.2CH.sub.3 F phenyl F
CH.sub.2CH.sub.3 Cl phenyl F CH.sub.2CH.sub.3 F phenyl F
CH.sub.2CH.sub.3 Cl 3-pyridyl F CH.sub.2CH.sub.3 F 3-pyridyl F
CH.sub.2CH.sub.3 Cl 4-pyridyl F CH.sub.2CH.sub.3 F pyrazolyl F
CH.sub.2CH.sub.3 Cl pyrazolyl F CH.sub.2CH.sub.3 CH.sub.3 4-pyridyl
F CH.sub.2CH.sub.3 CH.sub.3 4-pyridyl F CH.sub.2CH.sub.3 CH.sub.3
2-(CH.sub.3--SO.sub.2--NH)- F phenyl CH.sub.2CH.sub.3 CH.sub.3
3-(CH.sub.3--SO.sub.2--NH)- F phenyl CH.sub.2CH.sub.3 F
3-(CH.sub.3--SO.sub.2--NH)- F phenyl CH.sub.2CH.sub.3 Cl
3-(CH.sub.3--SO.sub.2--NH)- F phenyl CH.sub.2CH.sub.3 F phenyl F
CH.sub.2CH.sub.3 Cl phenyl F CH.sub.2CH.sub.3 CH.sub.3 phenyl F
3-pyridyl CH(CH.sub.3).sub.2 F 3-pyridyl F CH(CH.sub.3).sub.2 Cl
4-pyridyl F CH(CH.sub.3).sub.2 F pyrazolyl F CH(CH.sub.3).sub.2 Cl
pyrazolyl F CH(CH.sub.3).sub.2 F 4-pyridyl F CH(CH.sub.3).sub.2 Cl
4-pyridyl F CH(CH.sub.3).sub.2 F 2-(CH.sub.3--SO.sub.2--NH)- F
phenyl CH(CH.sub.3).sub.2 Cl 3-(CH.sub.3--SO.sub.2--NH)- F phenyl
CH(CH.sub.3).sub.2 F 3-(CH.sub.3--SO.sub.2--NH)- F phenyl
CH(CH.sub.3).sub.2 Cl 3-(CH.sub.3--SO.sub.2--NH)- F phenyl
CH(CH.sub.3).sub.2 CH.sub.3 phenyl F CH(CH.sub.3).sub.2 Cl phenyl F
CH(CH.sub.3).sub.2 Fl phenyl F CH(CH.sub.3).sub.2 Cl 3-pyridyl F
3-pyridyl CH(CH.sub.3).sub.2 F 4-pyridyl F CH(CH.sub.3).sub.2 Cl
pyrazolyl F CH(CH.sub.3).sub.2 CH.sub.3 pyrazolyl F
CH(CH.sub.3).sub.2 CH.sub.3 4-pyridyl F CH(CH.sub.3).sub.2 CH.sub.3
4-pyridyl F CH(CH.sub.3).sub.2 CH.sub.3 2-(CH.sub.3--SO.sub.2--NH)-
F phenyl CH(CH.sub.3).sub.2 F 3-(CH.sub.3--SO.sub.2--NH)- F phenyl
CH(CH.sub.3).sub.2 Cl 3-(CH.sub.3--SO.sub.2--NH)- F phenyl
3-(CH.sub.3--SO.sub.2--NH)- phenyl n-butyl F phenyl F n-butyl Cl
phenyl F n-butyl F phenyl F n-butyl Cl 3-pyridyl F n-butyl F
3-pyridyl F n-butyl Cl 4-pyridyl F n-butyl F pyrazolyl F n-butyl Cl
pyrazolyl F n-butyl CH.sub.3 4-pyridyl F n-butyl Cl 4-pyridyl F
n-butyl F 2-(CH.sub.3--SO.sub.2--NH)- F phenyl n-butyl CH.sub.3
3-(CH.sub.3--SO.sub.2--NH)- F phenyl n-butyl F
3-(CH.sub.3--SO.sub.2--NH)- F phenyl 3-(CH.sub.3--SO.sub.2--NH)-
phenyl n-butyl F phenyl F n-butyl Cl phenyl F phenyl sec-butyl F
3-pyridyl F sec-butyl Cl 3-pyrldyl F sec-butyl F 4-pyridyl F
sec-butyl Cl pyrazolyl F sec-butyl F pyrazolyl F sec-butyl Cl
4-pyridyl F sec-butyl F 4-pyridyl F sec-butyl Cl CF.sub.3 F
CH.sub.2CF.sub.3 F phenyl F CH.sub.2CF.sub.3 Cl phenyl F
CH.sub.2CF.sub.3 F phenyl F CH.sub.2CF.sub.3 Cl 3-pyridyl F
CH.sub.2CF.sub.3 F 3-pyridyl F CH.sub.2CF.sub.3 Cl 4-pyridyl F
CH.sub.2CF.sub.3 F pyrazolyl F CH.sub.2CF.sub.3 Cl pyrazolyl F
4-pyridyl CH.sub.2CCl.sub.3 F 4-pyridyl F CH.sub.2CCl.sub.3 Cl
2-(CH.sub.3--SO.sub.2--NH)- F phenyl CH.sub.2CCl.sub.3 F
3-(CH.sub.3--SO.sub.2--NH)- F phenyl CH.sub.2CCl.sub.3 Cl
3-(CH.sub.3--SO.sub.2--NH)- F phenyl CH.sub.2CCl.sub.3 F
3-(CH.sub.3--SO.sub.2--NH)- F phenyl CH.sub.2CCl.sub.3 Cl phenyl F
CH.sub.2CCl.sub.3 F phenyl F CH.sub.2CCl.sub.3 Cl phenyl F
3-pyridyl ##STR00196## F 3-pyridyl F ##STR00197## Cl 4-pyridyl F
##STR00198## F pyrazolyl F ##STR00199## Cl pyrazolyl F ##STR00200##
F 4-pyridyl F ##STR00201## Cl 4-pyridyl F ##STR00202## F
2-(CH.sub.3--SO.sub.2--NH)- phenyl F ##STR00203## Cl
3-(CH.sub.3--SO.sub.2--NH)- phenyl F 3-(CH.sub.3--SO.sub.2--NH)-
phenyl CH.sub.2CH.sub.2F F 3-(CH.sub.3--SO.sub.2--NH)- F phenyl
CH.sub.2CH.sub.2F Cl phenyl F CH.sub.2CH.sub.2F F phenyl F
CH.sub.2CH.sub.2F Cl phenyl F CH.sub.2CH.sub.2F F 3-pyridyl F
CH.sub.2CH.sub.2F Cl 3-pyridyl F CH.sub.2CH.sub.2F F 4-pyridyl F
CH.sub.2CH.sub.2F Cl pyrazolyl F pyrazolyl CH.sub.2CH.sub.2Cl F
4-pyridyl F CH.sub.2CH.sub.2Cl Cl 4-pyridyl F CH.sub.2CH.sub.2Cl F
2-(CH.sub.3--SO.sub.2--NH)- F phenyl CH.sub.2CH.sub.2Cl Cl
3-(CH.sub.3--SO.sub.2--NH)- F phenyl CH.sub.2CH.sub.2Cl F
3-(CH.sub.3--SO.sub.2--NH)- F phenyl CH.sub.2CH.sub.2Cl Cl
3-(CH.sub.3--SO.sub.2--NH)- F phenyl CH.sub.2CH.sub.2Cl F phenyl F
CH.sub.2CH.sub.2Cl Cl phenyl F phenyl CH.sub.2CH.sub.2CH.sub.2Cl F
3-pyridyl F CH.sub.2CH.sub.2CH.sub.2Cl Cl 3-pyridyl F
CH.sub.2CH.sub.2CH.sub.2Cl F 4-pyridyl F CH.sub.2CH.sub.2CH.sub.2Cl
Cl pyrazolyl F CH.sub.2CH.sub.2CH.sub.2Cl F pyrazolyl F
CH.sub.2CH.sub.2CH.sub.2Cl Cl 4-pyridyl F
CH.sub.2CH.sub.2CH.sub.2Cl F 4-pyridyl F CH.sub.2CH.sub.2CH.sub.2Cl
Cl 2-(CH.sub.3--SO.sub.2--NH)- F phenyl 3-(CH.sub.3--SO.sub.2--NH)-
phenyl CH.sub.2CH.sub.2OH F 3-(CH.sub.3--SO.sub.2--NH)- F phenyl
CH.sub.2CH.sub.2OH Cl 3-(CH.sub.3--SO.sub.2--NH)- F phenyl
CH.sub.2CH.sub.2OH F phenyl F CH.sub.2CH.sub.2OH Cl phenyl F
CH.sub.2CH.sub.2OH F phenyl F CH.sub.2CH.sub.2OH Cl 3-pyridyl F
CH.sub.2CH.sub.2OH F 3-pyridyl F CH.sub.2CH.sub.2OH Cl 4-pyridyl F
pyrazolyl CH.sub.2CH.sub.2CH.sub.2OH F pyrazolyl F
CH.sub.2CH.sub.2CH.sub.2OH Cl 4-pyridyl F
CH.sub.2CH.sub.2CH.sub.2OH F 4-pyridyl F CH.sub.2CH.sub.2CH.sub.2OH
Cl 2-(CH.sub.3--SO.sub.2--NH)- F phenyl CH.sub.2CH.sub.2CH.sub.2OH
F 3-(CH.sub.3--SO.sub.2--NH)- F phenyl CH.sub.2CH.sub.2CH.sub.2OH
Cl 3-(CH.sub.3--SO.sub.2--NH)- F phenyl CH.sub.2CH.sub.2CH.sub.2OH
F 3-(CH.sub.3--SO.sub.2--NH)- F phenyl CH.sub.2CH.sub.2CH.sub.2OH
Cl phenyl F phenyl (CH.sub.2).sub.4OH F phenyl F (CH.sub.2).sub.4OH
Cl 3-pyridyl F (CH.sub.2).sub.4OH F 3-pyridyl F (CH.sub.2).sub.4OH
Cl 4-pyridyl F (CH.sub.2).sub.4OH F pyrazolyl F (CH.sub.2).sub.4OH
Cl pyrazolyl F (CH.sub.2).sub.4OH F 4-pyridyl F (CH.sub.2).sub.4OH
Cl 4-pyridyl F 2-(CH.sub.3--SO.sub.2--NH)- phenyl
CH.sub.2CH.sub.2OCH.sub.3 F 3-(CH.sub.3--SO.sub.2--NH)- F
phenyl CH.sub.2CH.sub.2OCH.sub.3 Cl 3-(CH.sub.3--SO.sub.2--NH)- F
phenyl CH.sub.2CH.sub.2OCH.sub.3 F 3-(CH.sub.3--SO.sub.2--NH)- F
phenyl CH.sub.2CH.sub.2OCH.sub.3 Cl phenyl F
CH.sub.2CH.sub.2OCH.sub.3 F phenyl F CH.sub.2CH.sub.2OCH.sub.3 Cl
phenyl F CH.sub.2CH.sub.2OCH.sub.3 F 3-pyridyl F
CH.sub.2CH.sub.2OCH.sub.3 Cl 3-pyridyl F 4-pyridyl
(CH.sub.2).sub.3OCH.sub.3 F pyrazolyl F (CH.sub.2).sub.3OCH.sub.3
Cl pyrazolyl F (CH.sub.2).sub.3OCH.sub.3 F 4-pyridyl F
(CH.sub.2).sub.3OCH.sub.3 Cl 4-pyridyl F (CH.sub.2).sub.3OCH.sub.3
F 2-(CH.sub.3--SO.sub.2--NH)- F phenyl (CH.sub.2).sub.3OCH.sub.3 Cl
3-(CH.sub.3--SO.sub.2--NH)- F phenyl (CH.sub.2).sub.3OCH.sub.3 F
3-(CH.sub.3--SO.sub.2--NH)- F phenyl (CH.sub.2).sub.3OCH.sub.3 Cl
3-(CH.sub.3--SO.sub.2--NH)- F phenyl phenyl CH.sub.2CH.sub.2OEt F
phenyl F CH.sub.2CH.sub.2OEt Cl phenyl F CH.sub.2CH.sub.2OEt F
3-pyridyl F CH.sub.2CH.sub.2OEt Cl 3-pyridyl F CH.sub.2CH.sub.2OEt
F 4-pyridyl F CH.sub.2CH.sub.2OEt Cl pyrazolyl F
CH.sub.2CH.sub.2OEt F pyrazolyl F CH.sub.2CH.sub.2OEt Cl 4-pyridyl
F
[0255] Tables 4a and 4b show embodiments of this invention which
are compounds of formula I, where G=R.sub.1d, Z is F, X is F and
R.sub.1d and R.sup.0 are defined in the table. Each line in the
table corresponds to five species which differ only at position
Y.
TABLE-US-00004 TABLE 4a ##STR00204## CMPD # A, A' B R.sup.0 1(a-d)
H, H H OCH.sub.3 2(a-d) H, H H NHCH.sub.3 3(a-d) H, H H
CH.sub.2CH.sub.3 4(a-d) H, H H CH.sub.2CH.dbd.CH.sub.2 5(a-d) H, H
H CN 6(a-d) H, H H CF.sub.3 7(a-d) H, H H F 8(a-d) H, H H
C.sub.6H.sub.6 9(a-d) H, H --CH.sub.2CH(OH)CH.sub.2OH OCH.sub.3
10(a-d) H, H --CH.sub.2CH(OH)CH.sub.2OH NHCH.sub.3 11(a-d) H, H
--CH.sub.2CH(OH)CH.sub.2OH CH.sub.2CH.sub.3 12(a-d)
--(CH.sub.2).sub.2-- --CH.sub.2(C.sub.3H.sub.5) OCH.sub.3 13(a-d)
--(CH.sub.2).sub.2-- --CH.sub.2(C.sub.3H.sub.5) NHCH.sub.3 14(a-d)
--(CH.sub.2).sub.2-- --CH.sub.2(C.sub.3H.sub.5) CH.sub.2CH.sub.3
15(a-d) --(CH.sub.2).sub.2-- CH.sub.3 F 16(a-d)
--(CH.sub.2).sub.2-- --CH.sub.2CH.sub.2OH F 17(a-d)
--(CH.sub.2).sub.2-- --(CH.sub.2).sub.2CH(OH)CH.sub.2OH F 18(a-d)
CH.sub.3, H --(CH.sub.2).sub.2CH(OH)CH.sub.2OH F 19(a-d)
--(CH.sub.2).sub.2-- CH.sub.3 OCH.sub.3 20(a-d)
--(CH.sub.2).sub.2-- --CH.sub.2CH.sub.2OH OCH.sub.3 21(a-d)
--(CH.sub.2).sub.2-- --(CH.sub.2).sub.2CH(OH)CH.sub.2OH OCH.sub.3
22(a-d) CH.sub.3, H --(CH.sub.2).sub.2CH(OH)CH.sub.2OH OCH.sub.3
23(a-d) --(CH.sub.2).sub.2-- CH.sub.3 H 24(a-d)
--(CH.sub.2).sub.2-- --CH.sub.2CH.sub.2OH H 25(a-d)
--(CH.sub.2).sub.2-- --(CH.sub.2).sub.2CH(OH)CH.sub.2OH H 26(a-d)
CH.sub.3, H --(CH.sub.2).sub.2CH(OH)CH.sub.2OH H 27(a-d) H, H H
OCH.sub.3 28(a-d) H, H H NHCH.sub.3 29(a-d) H, H H CH.sub.2CH.sub.3
30(a-d) H, H H CH.sub.2CH.dbd.CH.sub.2 31(a-d) H, H H CN 32(a-d) H,
H H CF.sub.3 33(a-d) H, H H F 34(a-d) H, H H C.sub.6H.sub.6 35(a-d)
H, H --CH.sub.2CH(OH)CH.sub.2OH OCH.sub.3 36(a-d) H, H
--CH.sub.2CH(OH)CH.sub.2OH NHCH.sub.3 37(a-d) H, H
--CH.sub.2CH(OH)CH.sub.2OH CH.sub.2CH.sub.3 38(a-d)
--(CH.sub.2).sub.2-- --CH.sub.2(C.sub.3H.sub.5) OCH.sub.3 39(a-d)
--(CH.sub.2).sub.2-- --CH.sub.2(C.sub.3H.sub.5) NHCH.sub.3 40(a-d)
--(CH.sub.2).sub.2-- --CH.sub.2(C.sub.3H.sub.5) CH.sub.2CH.sub.3
41(a-d) --(CH.sub.2).sub.2-- CH.sub.3 F 42(a-d)
--(CH.sub.2).sub.2-- --CH.sub.2CH.sub.2OH F 43(a-d)
--(CH.sub.2).sub.2-- --(CH.sub.2).sub.2CH(OH)CH.sub.2OH F 44(a-d)
CH.sub.3, H --(CH.sub.2).sub.2CH(OH)CH.sub.2OH F 45(a-d)
--(CH.sub.2).sub.2-- CH.sub.3 OCH.sub.3 46(a-d)
--(CH.sub.2).sub.2-- --CH.sub.2CH.sub.2OH OCH.sub.3 47(a-d)
--(CH.sub.2).sub.2-- --(CH.sub.2).sub.2CH(OH)CH.sub.2OH OCH.sub.3
48(a-d) CH.sub.3, H --(CH.sub.2).sub.2CH(OH)CH.sub.2OH OCH.sub.3
49(a-d) --(CH.sub.2).sub.2-- CH.sub.3 H 50(a-d)
--(CH.sub.2).sub.2-- --CH.sub.2CH.sub.2OH H 51(a-d)
--(CH.sub.2).sub.2-- --(CH.sub.2).sub.2CH(OH)CH.sub.2OH H 52(a-d)
CH.sub.3, H --(CH.sub.2).sub.2CH(OH)CH.sub.2OH H Y.sub.a =
CH.sub.3; Y.sub.b = Br; Y.sub.c = I; Y.sub.d = Cl;
TABLE-US-00005 TABLE 4b CMPD # A, A' B R.sup.0 1(a-d) H, H H
2-furanyl 2(a-d) H, H H 1,2,3 triazolyl-4-yl 3(a-d) H, H H
4-imidazolyl 4(a-d) H, H H 2-furanyl 5(a-d) H, H H 1,2,3
triazolyl-4-yl 6(a-d) H, H H 4-imidazolyl 7(a-d) H, H
--(CH.sub.2).sub.2CH(OH)CH.sub.2OH 2-furanyl 8(a-d) H, H
--(CH.sub.2).sub.2CH(OH)CH.sub.2OH 1,2,3 triazolyl-4-yl 9(a-d) H, H
--(CH.sub.2).sub.2CH(OH)CH.sub.2OH 4-imidazolyl 10(a-d)
--(CH.sub.2).sub.2-- --CH.sub.2(C.sub.3H.sub.5) 2-furanyl 11(a-d)
--(CH.sub.2).sub.2-- --CH.sub.2(C.sub.3H.sub.5) 1,2,3
triazolyl-4-yl 12(a-d) --(CH.sub.2).sub.2--
--CH.sub.2(C.sub.3H.sub.5) 4-imidazolyl 13(a-d)
--(CH.sub.2).sub.2-- CH.sub.3 4-thiazolyl 14(a-d)
--(CH.sub.2).sub.2-- --CH.sub.2CH.sub.2OH 4-thiazolyl 15(a-d)
--(CH.sub.2).sub.2-- --(CH.sub.2).sub.2CH(OH)CH.sub.2OH 4-thiazolyl
16(a-d) CH.sub.3, H --(CH.sub.2).sub.2CH(OH)CH.sub.2OH 4-thiazolyl
17(a-d) --(CH.sub.2).sub.2-- CH.sub.3 2-oxazolyl 18(a-d)
--(CH.sub.2).sub.2-- --CH.sub.2CH.sub.2OH 2-oxazolyl 19(a-d)
--(CH.sub.2).sub.2-- --(CH.sub.2).sub.2CH(OH)CH.sub.2OH 2-oxazolyl
20(a-d) CH.sub.3, H --(CH.sub.2).sub.2CH(OH)CH.sub.2OH 2-oxazolyl
21(a-d) H, H H 2-furanyl 22(a-d) H, H H 1,2,3 triazolyl-4-yl
23(a-d) H, H H 4-imidazolyl 24(a-d) H, H H 2-furanyl 25(a-d) H, H H
1,2,3 triazolyl-4-yl 26(a-d) H, H H 4-imidazolyl 27(a-d) H, H
--CH.sub.2CH(OH)CH.sub.2OH 2-furanyl 28(a-d) H, H
--CH.sub.2CH(OH)CH.sub.2OH 1,2,3 triazolyl-4-yl 29(a-d) H, H
--CH.sub.2CH(OH)CH.sub.2OH 4-imidazolyl 30(a-d)
--(CH.sub.2).sub.2-- --CH.sub.2(C.sub.3H.sub.5) 2-furanyl 31(a-d)
--(CH.sub.2).sub.2-- --CH.sub.2(C.sub.3H.sub.5) 1,2,3
triazolyl-4-yl 32(a-d) --(CH.sub.2).sub.2--
--CH.sub.2(C.sub.3H.sub.5) 4-imidazolyl 33(a-d)
--(CH.sub.2).sub.2-- CH.sub.3 4-thiazolyl 34(a-d)
--(CH.sub.2).sub.2-- --CH.sub.2CH.sub.2OH 4-thiazolyl 35(a-d)
--(CH.sub.2).sub.2-- --(CH.sub.2).sub.2CH(OH)CH.sub.2OH 4-thiazolyl
36(a-d) CH.sub.3, H --(CH.sub.2).sub.2CH(OH)CH.sub.2OH 4-thiazolyl
37(a-d) --(CH.sub.2).sub.2-- CH.sub.3 2-oxazolyl 38(a-d)
--(CH.sub.2).sub.2-- --CH.sub.2CH.sub.2OH 2-oxazolyl 39(a-d)
--(CH.sub.2).sub.2-- --(CH.sub.2).sub.2CH(OH)CH.sub.2OH 2-oxazolyl
40(a-d) CH.sub.3, H --(CH.sub.2).sub.2CH(OH)CH.sub.2OH
2-oxazolyl
[0256] Table 5a shows embodiments of this invention which are
compounds of formula I, where G is Ar.sub.1, Ar.sub.2 or R.sub.1d,
and where R.sup.0 is H, Z is F and G and X are defined in the
table. Each line in the table corresponds to five species (Y.sub.a,
Y.sub.b, Y.sub.c, Y.sub.d and Y.sub.e) which differ only at
position Y, where Y.sub.a=SCH.sub.3; Y.sub.b=Br; Y.sub.c=I;
Y.sub.dY=Cl; Y.sub.e.dbd.CH.sub.3.
TABLE-US-00006 TABLE 5a ##STR00205## Compound # G = R.sub.1d,
Ar.sub.1, or Ar.sub.2 X 1 (a-e) phenyl Cl 2 (a-e) phenyl F 3 (a-e)
2-F-phenyl Cl 4 (a-e) 2-F-phenyl F 5 (a-e) 3-F-phenyl Cl 6 (a-e)
3-F-phenyl F 7 (a-e) 4-F-phenyl Cl 8 (a-e) 4-F-phenyl F 9 (a-e)
2,4-di-F-phenyl Cl 10 (a-e) 2,4-di-F-phenyl F 11 (a-e)
2,5-di-F-phenyl Cl 12 (a-e) 2,5-di-F-phenyl F 13 (a-e)
2,6-di-F-phenyl Cl 14 (a-e) 2,6-di-F-phenyl F 15 (a-e)
3,4-di-F-phenyl Cl 16 (a-e) 3,4-di-F-phenyl F 17 (a-e)
3,5-di-F-phenyl Cl 18 (a-e) 3,5-di-F-phenyl F 19 (a-e)
2,6-di-F-phenyl Cl 20 (a-e) 2,6-di-F-phenyl F 21 (a-e)
2,3,4-tri-F-phenyl Cl 22 (a-e) 2,3,4-tri-F-phenyl F 23 (a-e)
3,4,5-tri-F-phenyl Cl 24 (a-e) 3,4,5-tri-F-phenyl F 25 (a-e)
penta-F-phenyl Cl 26 (a-e) penta-F-phenyl F 27 (a-e)
3-Cl-4-F-phenyl Cl 28 (a-e) 3-Cl-4-F-phenyl F 29 (a-e)
2-Cl-4-F-phenyl Cl 30 (a-e) 2-Cl-4-F-phenyl F 31 (a-e)
2-F-3-Cl-phenyl Cl 32 (a-e) 2-F-3-Cl-phenyl F 33 (a-e)
2-F-4-Cl-phenyl Cl 34 (a-e) 2-F-4-Cl-phenyl F 35 (a-e)
2-F-5-Cl-phenyl Cl 36 (a-e) 2-F-5-Cl-phenyl F 37 (a-e)
3-cyano-4-F-phenyl Cl 38 (a-e) 3-cyano-4-F-phenyl F 39 (a-e)
2-Cl-phenyl Cl 40 (a-e) 2-Cl-phenyl F 41 (a-e) 3-Cl-phenyl Cl 42
(a-e) 3-Cl-phenyl F 43 (a-e) 4-Cl-phenyl Cl 44 (a-e) 4-Cl-phenyl F
45 (a-e) 2,3-di-Cl-phenyl Cl 46 (a-e) 2,3-di-Cl-phenyl F 47 (a-e)
2,5-di-Cl-phenyl Cl 48 (a-e) 2,5-di-Cl-phenyl F 49 (a-e)
2,6-di-Cl-phenyl Cl 50 (a-e) 2,6-di-Cl-phenyl F 51 (a-e)
3,5-di-Cl-phenyl Cl 52 (a-e) 3,5-di-Cl-phenyl F 53 (a-e)
2,4-di-Cl-phenyl Cl 54 (a-e) 2,4-di-Cl-phenyl F 55 (a-e)
3,4-di-Cl-phenyl Cl 56 (a-e) 3,4-di-Cl-phenyl F 57 (a-e)
2,4,6-tri-Cl-phenyl Cl 58 (a-e) 2,4,6-tri-Cl-phenyl F 59 (a-e)
2-Cl-4-CF.sub.3-phenyl Cl 60 (a-e) 2-Cl-4-CF.sub.3-phenyl F 61
(a-e) 2-CF.sub.3-phenyl Cl 62 (a-e) 2-CF.sub.3-phenyl F 63 (a-e)
3-CF.sub.3-phenyl Cl 64 (a-e) 3-CF.sub.3-phenyl F 65 (a-e)
4-CF.sub.3-phenyl Cl 66 (a-e) 4-CF.sub.3-phenyl F 67 (a-e)
2-CF.sub.3O phenyl Cl 68 (a-e) 2-CF.sub.3O phenyl F 69 (a-e)
3-CF.sub.3O phenyl Cl 70 (a-e) 3-CF.sub.3O phenyl F 71 (a-e)
4-CF.sub.3O phenyl Cl 72 (a-e) 4-CF.sub.3O phenyl F 73 (a-e)
2-CHF.sub.2O phenyl Cl 74 (a-e) 2-CHF.sub.2O phenyl F 75 (a-e)
2-methyl-5-nitro-phenyl Cl 76 (a-e) 2-methyl-5-nitro-phenyl F 77
(a-e) 2-cyano-phenyl Cl 78 (a-e) 2-cyano-phenyl F 79 (a-e)
3-cyano-phenyl Cl 80 (a-e) 3-cyano-phenyl F 81 (a-e) 4-cyano-phenyl
Cl 82 (a-e) 4-cyano-phenyl F 83 (a-e) 4-methoxy-phenyl Cl 84 (a-e)
4-methoxy-phenyl F 85 (a-e) 3,4-dimethoxy-phenyl Cl 86 (a-e)
3,4-dimethoxy-phenyl F 87 (a-e) 3-carbamyl-phenyl Cl 88 (a-e)
3-carbamyl-phenyl F 89 (a-e) 3-carboxyl-phenyl Cl 90 (a-e)
3-carboxyl-phenyl F 91 (a-e) 3-(N,N-dimethylcarbamoyl)phenyl Cl 92
(a-e) 3-(N,N-dimethylcarbamoyl)phenyl F 93 (a-e)
4-methylsulfonyl-phenyl Cl 94 (a-e) 4-methylsulfonyl-phenyl F 95
(a-e) 3-(1,3,4 oxadiazol-2-yl)phenyl Cl 96 (a-e) 3-(1,3,4
oxadiazol-2-yl)phenyl F 97 (a-e) 3-(1,3,4 thiadiazol-2-yl)phenyl Cl
98 (a-e) 3-(1,3,4 thiadiazol-2-yl)phenyl F 99 (a-e)
3-(5-methyl-1-1,3,4-oxadiazol)phenyl Cl 100 (a-e)
3-(5-methyl-1-1,3,4-oxadiazol)phenyl F 101 (a-e)
3-(5-methyl-1-1,3,4-thiadiazol)phenyl Cl 102 (a-e)
3-(5-methyl-1-1,3,4-thiadiazol)phenyl F 103 (a-e) 3-amidinyl-phenyl
Cl 104 (a-e) 3-amidinyl-phenyl F 105 (a-e) 3-(1H-tetrazolyl)phenyl
Cl 106 (a-e) 3-(1H-tetrazolyl)phenyl F 107 (a-e) 4-acetamido-phenyl
Cl 108 (a-e) 4-acetamido-phenyl F 109 (a-e)
3-Cl-4-[(N-morpholinylcarbonyl)amino]phenyl Cl 110 (a-e)
3-Cl-4-[(N-morpholinylcarbonyl)amino]phenyl F 111 (a-e)
3-Cl-4-[(N-pyrrolidinylcarbonyl)amino]phenyl Cl 112 (a-e)
3-Cl-4-[(N-pyrrolidinylcarbonyl)amino]phenyl F 113 (a-e)
3,5-dimethylisoxazolyl Cl 114 (a-e) 3,5-dimethylisoxazolyl F 115
(a-e) 4-(N-morpholinylsulfonyl)phenyl Cl 116 (a-e)
4-(N-morpholinylsulfonyl)phenyl F 117 (a-e) 3-F-benzyl Cl 118 (a-e)
3-F-benzyl F 119 (a-e) 4-F-benzyl Cl 120 (a-e) 4-F-benzyl F 121
(a-e) 3-F-phenyl-ethyl Cl 122 (a-e) 3-F-phenyl-ethyl F 123 (a-e)
4-F-phenyl-ethyl Cl 124 (a-e) 4-F-phenyl-ethyl F 125 (a-e)
8-quinolinyl Cl 126 (a-e) 8-quinolinyl F 127 (a-e) 2-thienyl Cl 128
(a-e) 2-thienyl F 129 (a-e) 2,3-di-Cl-thien-5-yl Cl 130 (a-e)
2,3-di-Cl-thien-5-yl F 131 (a-e) 1,3,5 trimethyl-1H-pyrazolyl Cl
132 (a-e) 1,3,5 trimethyl-1H-pyrazolyl F 133 (a-e)
1,3-dimethyl-5-Cl-1H-pyrazolyl Cl 134 (a-e)
1,3-dimethyl-5-Cl-1H-pyrazolyl F 135 (a-e)
1-methyl-3CF.sub.3-1H-pyrazol-4-yl Cl 136 (a-e)
1-methyl-3CF.sub.3-1H-pyrazol-4-yl F 137 (a-e)
2-acetamido-4-methyl-thiazol-5-yl Cl 138 (a-e)
2-acetamido-4-methyl-thiazol-5-yl F 139 (a-e)
2,4-dimethyl-thiazol-5-yl Cl 140 (a-e) 2,4-dimethyl-thiazol-5-yl F
141 (a-e) 1,2-dimethyl-1H-imidazol-4-yl Cl 142 (a-e)
1,2-dimethyl-1H-imidazol-4-yl F Y.sub.a = SCH.sub.3; Y.sub.b = Br;
Y.sub.c = I; Y.sub.d = Cl; Y.sub.e = CH.sub.3
[0257] Table 5b shows embodiments of this invention which are
compounds of formula I, where G is Ar.sub.1, Ar.sub.2 or R.sub.1d,
and where R.sup.0 is H, Z is F and G and X are defined in the
table. Each line in the table corresponds to five species (Y.sub.a,
Y.sub.b, Y.sub.c, Y.sub.d and Y.sub.e) which differ only at
position Y, where Y.sub.a=phenyl; Y.sub.b=3-substituted phenyl;
Y.sub.c=3-pyridyl; Y.sub.d=4-pyridyl; Y.sub.e=3-pyrazolyl.
TABLE-US-00007 TABLE 5b ##STR00206## Compound # G = R.sub.1d,
Ar.sub.1, or Ar.sub.2 X 1 (a-e) phenyl Cl 2 (a-e) phenyl F 3 (a-e)
2-F-phenyl Cl 4 (a-e) 2-F-phenyl F 5 (a-e) 3-F-phenyl Cl 6 (a-e)
3-F-phenyl F 7 (a-e) 4-F-phenyl Cl 8 (a-e) 4-F-phenyl F 9 (a-e)
2,4-di-F-phenyl Cl 10 (a-e) 2,4-di-F-phenyl F 11 (a-e)
2,5-di-F-phenyl Cl 12 (a-e) 2,5-di-F-phenyl F 13 (a-e)
2,6-di-F-phenyl Cl 14 (a-e) 2,6-di-F-phenyl F 15 (a-e)
3,4-di-F-phenyl Cl 16 (a-e) 3,4-di-F-phenyl F 17 (a-e)
3,5-di-F-phenyl Cl 18 (a-e) 3,5-di-F-phenyl F 19 (a-e)
2,6-di-F-phenyl Cl 20 (a-e) 2,6-di-F-phenyl F 21 (a-e)
2,3,4-tri-F-phenyl Cl 22 (a-e) 2,3,4-tri-F-phenyl F 23 (a-e)
3,4,5-tri-F-phenyl Cl 24 (a-e) 3,4,5-tri-F-phenyl F 25 (a-e)
penta-F-phenyl Cl 26 (a-e) penta-F-phenyl F 27 (a-e)
3-Cl-4-F-phenyl Cl 28 (a-e) 3-Cl-4-F-phenyl F 29 (a-e)
2-Cl-4-F-phenyl Cl 30 (a-e) 2-Cl-4-F-phenyl F 31 (a-e)
2-F-3-Cl-phenyl Cl 32 (a-e) 2-F-3-Cl-phenyl F 33 (a-e)
2-F-4-Cl-phenyl Cl 34 (a-e) 2-F-4-Cl-phenyl F 35 (a-e)
2-F-5-Cl-phenyl Cl 36 (a-e) 2-F-5-Cl-phenyl F 37 (a-e)
3-cyano-4-F-phenyl Cl 38 (a-e) 3-cyano-4-F-phenyl F 39 (a-e)
2-Cl-phenyl Cl 40 (a-e) 2-Cl-phenyl F 41 (a-e) 3-Cl-phenyl Cl 42
(a-e) 3-Cl-phenyl F 43 (a-e) 4-Cl-phenyl Cl 44 (a-e) 4-Cl-phenyl F
45 (a-e) 2,3-di-Cl-phenyl Cl 46 (a-e) 2,3-di-Cl-phenyl F 47 (a-e)
2,5-di-Cl-phenyl Cl 48 (a-e) 2,5-di-Cl-phenyl F 49 (a-e)
2,6-di-Cl-phenyl Cl 50 (a-e) 2,6-di-Cl-phenyl F 51 (a-e)
3,5-di-Cl-phenyl Cl 52 (a-e) 3,5-di-Cl-phenyl F 53 (a-e)
2,4-di-Cl-phenyl Cl 54 (a-e) 2,4-di-Cl-phenyl F 55 (a-e)
3,4-di-Cl-phenyl Cl 56 (a-e) 3,4-di-Cl-phenyl F 57 (a-e)
2,4,6-tri-Cl-phenyl Cl 58 (a-e) 2,4,6-tri-Cl-phenyl F 59 (a-e)
2-Cl-4-CF.sub.3-phenyl Cl 60 (a-e) 2-Cl-4-CF.sub.3-phenyl F 61
(a-e) 2-CF.sub.3-phenyl Cl 62 (a-e) 2-CF.sub.3-phenyl F 63 (a-e)
3-CF.sub.3-phenyl Cl 64 (a-e) 3-CF.sub.3-phenyl F 65 (a-e)
4-CF.sub.3-phenyl Cl 66 (a-e) 4-CF.sub.3-phenyl F 67 (a-e)
2-CF.sub.3O phenyl Cl 68 (a-e) 2-CF.sub.3O phenyl F 69 (a-e)
3-CF.sub.3O phenyl Cl 70 (a-e) 3-CF.sub.3O phenyl F 71 (a-e)
4-CF.sub.3O phenyl Cl 72 (a-e) 4-CF.sub.3O phenyl F 73 (a-e)
4-CHF.sub.2O-phenyl Cl 74 (a-e) 4-CHF.sub.2O-phenyl F 75 (a-e)
2-methyl-5-nitro-phenyl Cl 76 (a-e) 2-methyl-5-nitro-phenyl F 77
(a-e) 2-cyano-phenyl Cl 78 (a-e) 2-cyano-phenyl F 79 (a-e)
3-cyano-phenyl Cl 80 (a-e) 3-cyano-phenyl F 81 (a-e) 4-cyano-phenyl
Cl 82 (a-e) 4-cyano-phenyl F 83 (a-e) 4-methoxy-phenyl Cl 84 (a-e)
4-methoxy-phenyl F 85 (a-e) 3,4-dimethoxy-phenyl Cl 86 (a-e)
3,4-dimethoxy-phenyl F 87 (a-e) 3-carbamyl-phenyl Cl 88 (a-e)
3-carbamyl-phenyl F 89 (a-e) 3-carboxyl-phenyl Cl 90 (a-e)
3-carboxyl-phenyl F 91 (a-e) 3-(N,N-dimethylcarbamoyl)phenyl Cl 92
(a-e) 3-(N,N-dimethylcarbamoyl)phenyl F 93 (a-e)
4-methylsulfonyl-phenyl Cl 94 (a-e) 4-methylsulfonyl-phenyl F 95
(a-e) 3-(1,3,4 oxadiazol-2-yl)phenyl Cl 96 (a-e) 3-(1,3,4
oxadiazol-2-yl)phenyl F 97 (a-e) 3-(1,3,4 thiadiazol-2-yl)phenyl Cl
98 (a-e) 3-(1,3,4 thiadiazol-2-yl)phenyl F 99 (a-e)
3-(5-methyl-1,3,4-oxadiazol)phenyl Cl 100 (a-e)
3-(5-methyl-1,3,4-oxadiazol)phenyl F 101 (a-e)
3-(5-methyl-1,3,4-thiadiazol)phenyl Cl 102 (a-e)
3-(5-methyl-1,3,4-thiadiazol)phenyl F 103 (a-e) 3-amidinyl-phenyl
Cl 104 (a-e) 3-amidinyl-phenyl F 105 (a-e) 3-(1H-tetrazolyl)phenyl
Cl 106 (a-e) 3-(1H-tetrazolyl)phenyl F 107 (a-e) 4-acetamido-phenyl
Cl 108 (a-e) 4-acetamido-phenyl F 109 (a-e)
3-Cl-4-[(N-morpholinylcarbonyl) Cl amino]phenyl 110 (a-e)
3-Cl-4-[(N-morpholinylcarbonyl) F amino]phenyl 111 (a-e)
3-Cl-4-[(N-pyrrolidinylcarbonyl) Cl amino]phenyl 112 (a-e)
3-Cl-4-[(N-pyrrolidinylcarbonyl) F amino]phenyl 113 (a-e)
3,5-dimethylisoxazolyl Cl 114 (a-e) 3,5-dimethylisoxazolyl F 115
(a-e) 4-(N-morpholinylsulfonyl)phenyl Cl 116 (a-e)
4-(N-morpholinylsulfonyl)phenyl F 117 (a-e) 3-F-benzyl Cl 118 (a-e)
3-F-benzyl F 119 (a-e) 4-F-benzyl Cl 120 (a-e) 4-F-benzyl F 121
(a-e) 3-F-phenyl-ethyl Cl 122 (a-e) 3-F-phenyl-ethyl F 123 (a-e)
4-F-phenyl-ethyl Cl 124 (a-e) 4-F-phenyl-ethyl F 125 (a-e)
8-quinolinyl Cl 126 (a-e) 8-quinolinyl F 127 (a-e) 2-thienyl Cl 128
(a-e) 2-thienyl F 129 (a-e) 2,3-di-Cl-thien-5-yl Cl 130 (a-e)
2,3-di-Cl-thien-5-yl F 131 (a-e) 1,3,5 trimethyl-1H-pyrazolyl Cl
132 (a-e) 1,3,5 trimethyl-1H-pyrazolyl F 133 (a-e)
1,3-dimethyl-5-Cl-1H-pyrazolyl Cl 134 (a-e)
1,3-dimethyl-5-Cl-1H-pyrazolyl F 135 (a-e)
1-methyl-3-CF.sub.3-1H-pyrazol-4-yl Cl 136 (a-e)
1-methyl-3-CF.sub.3-1H-pyrazol-4-yl F 137 (a-e)
2-acetamido-4-methyl-thiazol-5-yl Cl 138 (a-e)
2-acetamido-4-methyl-thiazol-5-yl F 139 (a-e)
2,4-dimethyl-thiazol-5-yl Cl 140 (a-e) 2,4-dimethyl-thiazol-5-yl F
141 (a-e) 1,2-dimethyl-1H-imidazol-4-yl Cl 142 (a-e)
1,2-dimethyl-1H-imidazol-4-yl F 143 (a-e) 1-(2-hydroxyethyl)
cyclopropyl F 144 (a-e) 1-(3-hydroxypropyl) cyclopropyl F 145 (a-e)
1-(2,3-dihydroxypropyl) cyclopropyl F 146 (a-e)
1-(3,4-dihydroxybutyl) cyclopropyl F 147 (a-e)
1-(2,3-dihydroxypropyl) cyclobutyl F Y.sub.a = phenyl; Y.sub.b =
3-substituted phenol; Y.sub.c = 3-pyridyl; Y.sub.d = 4-pyridyl;
Y.sub.e = 3-pyrazolyl
Synthetic Procedures
[0258] In another aspect, methods for synthesizing the compounds
described herein are provided. In some embodiments, the compounds
described herein can be prepared by the methods described below.
The procedures and examples below are intended to illustrate those
methods. Neither the procedures nor the examples should be
construed as limiting the invention in any way. Compounds described
herein may also be synthesized using standard synthetic techniques
known to those of skill in the art or using methods known in the
art in combination with methods described herein. In additions,
solvents, temperatures and other reaction conditions presented
herein may vary according to the practice and knowledge of those of
skill in the art.
[0259] The starting materials used for the synthesis of the
compounds as described herein can be obtained from commercial
sources, such as Aldrich Chemical Co. (Milwaukee, Wis.), Sigma
Chemical Co. (St. Louis, Mo.), or the starting materials can be
synthesized. The compounds described herein, and other related
compounds having different substituents can be synthesized using
techniques and materials known to those of skill in the art, such
as described, for example, in March, ADVANCED ORGANIC CHEMISTRY
4.sup.th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC
CHEMISTRY 4.sup.th Ed., Vols. A and B (Plenum 2000, 2001), and
Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3.sup.rd
Ed., (Wiley 1999) (all of which are incorporated by reference in
their entirety). General methods for the preparation of compound as
disclosed herein may be derived from known reactions in the field,
and the reactions may be modified by the use of appropriate
reagents and conditions, as would be recognized by the skilled
person, for the introduction of the various moieties found in the
formulae as provided herein. As a guide the following synthetic
methods may be utilized.
Formation of Covalent Linkages by Reaction of an Electrophile with
a Nucleophile
[0260] The compounds described herein can be modified using various
electrophiles or nucleophiles to form new functional groups or
substituents. The table below entitled "Examples of Covalent
Linkages and Precursors Thereof" lists selected examples of
covalent linkages and precursor functional groups which yield and
can be used as guidance toward the variety of electrophiles and
nucleophiles combinations available. Precursor functional groups
are shown as electrophilic groups and nucleophilic groups.
TABLE-US-00008 Covalent Linkage Product Electrophile Nucleophile
Carboxamides Activated esters Amines/anilines Carboxamides Acyl
azides Amines/anilines Carboxamides Acyl halides Amines/anilines
Esters Acyl halides Alcohols/phenols Esters Acyl nitriles
Alcohols/phenols Carboxamides Acyl nitriles Amines/anilines Imines
Aldehydes Amines/anilines Hydrazones Aldehydes or ketones
Hydrazines Oximes Aldehydes or ketones Hydroxylamines Alkyl amines
Alkyl halides Amines/anilines Esters Alkyl halides Carboxylic acids
Thioethers Alkyl halides Thiols Ethers Alkyl halides
Alcohols/phenols Thioethers Alkyl sulfonates Thiols Esters Alkyl
sulfonates Carboxylic acids Ethers Alkyl sulfonates
Alcohols/phenols Esters Anhydrides Alcohols/phenols Carboxamides
Anhydrides Amines/anilines Thiophenols Aryl halides Thiols Aryl
amines Aryl halides Amines Thioethers Aziridines Thiols Boronate
esters Boronates Glycols Carboxamides Carboxylic acids
Amines/anilines Esters Carboxylic acids Alcohols Hydrazines
Hydrazides Carboxylic acids N-acylureas or Anhydrides Carbodiimides
Carboxylic acids Esters Diazoalkanes Carboxylic acids Thioethers
Epoxides Thiols Thioethers Haloacetamides Thiols Ammotriazines
Halotriazines Amines/anilines Triazinyl ethers Halotriazines
Alcohols/phenols Amidines Imido esters Amines/anilines Ureas
Isocyanates Amines/anilines Urethanes Isocyanates Alcohols/phenols
Thioureas Isothiocyanates Amines/anilines Thioethers Maleimides
Thiols Phosphite esters Phosphoramidites Alcohols Silyl ethers
Silyl halides Alcohols Alkyl amines Sulfonate esters
Amines/anilines Thioethers Sulfonate esters Thiols Esters Sulfonate
esters Carboxylic acids Ethers Sulfonate esters Alcohols
Sulfonamides Sulfonyl halides Amines/anilines Sulfonate esters
Sulfonyl halides Phenols/alcohols
Examples of Covalent Linkages and Precursors Thereof
Use of Protecting Groups
[0261] In the reactions described, it may be necessary to protect
reactive functional groups, for example hydroxy, amino, imino, thio
or carboxy groups, where these are desired in the final product, to
avoid their unwanted participation in the reactions. Protecting
groups are used to block some or all reactive moieties and prevent
such groups from participating in chemical reactions until the
protective group is removed. It is preferred that each protective
group be removable by a different means. Protective groups that are
cleaved under totally disparate reaction conditions fulfill the
requirement of differential removal. Protective groups can be
removed by acid, base, and hydrogenolysis. Groups such as trityl,
dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile
and may be used to protect carboxy and hydroxy reactive moieties in
the presence of amino groups protected with Cbz groups, which are
removable by hydrogenolysis, and Fmoc groups, which are base
labile. Carboxylic acid and hydroxy reactive moieties may be
blocked with base labile groups such as, but not limited to,
methyl, ethyl, and acetyl in the presence of amines blocked with
acid labile groups such as t-butyl carbamate or with carbamates
that are both acid and base stable but hydrolytically
removable.
[0262] Carboxylic acid and hydroxy reactive moieties may also be
blocked with hydrolytically removable protective groups such as the
benzyl group, while amine groups capable of hydrogen bonding with
acids may be blocked with base labile groups such as Fmoc.
Carboxylic acid reactive moieties may be protected by conversion to
simple ester compounds as exemplified herein, or they may be
blocked with oxidatively-removable protective groups such as
2,4-dimethoxybenzyl, while co-existing amino groups may be blocked
with fluoride labile silyl carbamates.
[0263] Allyl blocking groups are useful in then presence of acid-
and base-protecting groups since the former are stable and can be
subsequently removed by metal or pi-acid catalysts. For example, an
allyl-blocked carboxylic acid can be deprotected with a
Pd-catalyzed reaction in the presence of acid labile t-butyl
carbamate or base-labile acetate amine protecting groups. Yet
another form of protecting group is a resin to which a compound or
intermediate may be attached. As long as the residue is attached to
the resin, that functional group is blocked and cannot react. Once
released from the resin, the functional group is available to
react.
[0264] Protecting or blocking groups may be selected from:
##STR00207##
[0265] Other protecting groups, plus a detailed description of
techniques applicable to the creation of protecting groups and
their removal are described in Greene and Wuts, Protective Groups
in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York,
N.Y., 1999, and Kocienski, Protective Groups, Thieme Verlag, New
York, N.Y., 1994, which are incorporated herein by reference in
their entirety.
Preparing Compounds of Formula I
[0266] Compounds of this invention can be prepared by a variety of
methods. The procedures below are intended to illustrate those
methods, and the examples given are intended to illustrate the
scope of this invention. Neither the methods not the examples
should be construed as limiting the invention in any way.
[0267] I. The Preparation of Compound of Formula VI is Outlined
Below
##STR00208##
[0268] Scheme I above illustrates the preparation of sulfonamide
derivatives of formula VI. 1,2 Diamine derivative (formula IV) can
be easily prepared in two steps from the desired nitro derivatives
(formula I). Compounds of formula IV can be reacted with the
sulfonyl chloride derivatives (formula V, see next scheme) to form
the desired sulfonamide. Alternatively, the 1,2 diamine derivatives
IV can be protected to for an imidazolidone (formula VII), before
being reacted with the corresponding sulfonyl chloride.
Deprotection of the 1,2 diamine VIII under basic conditions
provided the desired material VI.
[0269] II. The General Route to Synthesis Compound of General
Formula V is Outlined Below
##STR00209##
[0270] Scheme II above shows one example of the preparation of
complex sulfonyl chloride. Compound XX can be synthesized from IX,
alkylated, and converted to the potassium salt XII. Treatment of
the salt with SOCl.sub.2 or POCl.sub.3 affords the desired
compounds. Other more specific procedures to prepare unique
sulfonyl chloride derivatives are reported in the experimental
section.
[0271] III. The General Route to Synthesis Compound of General
Formula XIII is Outlines Scheme 3.
##STR00210##
Scheme III above illustrates the preparation of sulfonamide
derivatives of general formula XII. For example, these compounds
can be easily obtained by reacting the compound VI with a boronic
acid using a palladium catalyst under Suzuki conditions.
[0272] IV. The General Route to Synthesis Compound of General
Formula XIII is Outlines Scheme 4.
##STR00211##
Scheme IV above illustrates the preparation of sulfonamide
derivatives of general formula XV. The vinyl sulfonamide (XIV) is
reacted with amines to form derivatives of general formulas XV.
Further Forms of Compounds of Formula I
Isomers of Compounds of Formula I
[0273] The compounds described herein may exist as geometric
isomers. The compounds described herein may possess one or more
double bonds. The compounds presented herein include all cis,
trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as
the corresponding mixtures thereof. In some situations, compounds
may exist as tautomers. The compounds described herein include all
possible tautomers within the formulas described herein. The
compounds described herein may possess one or more chiral centers
and each center may exist in the R or S configuration. The
compounds described herein include all diastereomeric,
enantiomeric, and epimeric forms as well as the corresponding
mixtures thereof. In additional embodiments of the compounds and
methods provided herein, mixtures of enantiomers and/or
diastereoisomers, resulting from a single preparative step,
combination, or interconversion may also be useful for the
applications described herein. The compounds described herein can
be prepared as their individual stereoisomers by reacting a racemic
mixture of the compound with an optically active resolving agent to
form a pair of diastereoisomeric compounds, separating the
diastereomers and recovering the optically pure enantiomers. While
resolution of enantiomers can be carried out using covalent
diastereomeric derivatives of the compounds described herein,
dissociable complexes are preferred (e.g., crystalline
diastereomeric salts). Diastereomers have distinct physical
properties (e.g., melting points, boiling points, solubilities,
reactivity, etc.) and can be readily separated by taking advantage
of these dissimilarities. The diastereomers can be separated by
chiral chromatography, or preferably, by separation/resolution
techniques based upon differences in solubility. The optically pure
enantiomer is then recovered, along with the resolving agent, by
any practical means that would not result in racemization. A more
detailed description of the techniques applicable to the resolution
of stereoisomers of compounds from their racemic mixture can be
found in Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers,
Racemates and Resolutions," John Wiley And Sons, Inc., 1981, herein
incorporated by reference in its entirety.
Labeled Compounds of Formula I
[0274] Also described herein are isotopically-labeled compounds of
formula I and methods of treating disorders. For example, the
invention provides for methods of treating diseases, by
administering isotopically-labeled compounds of formula I. The
isotopically-labeled compounds of formula I can be administered as
pharmaceutical compositions. Thus, compounds of formula I also
include isotopically-labeled compounds, which are identical to
those recited herein, but for the fact that one or more atoms are
replaced by an atom having an atomic mass or mass number different
from the atomic mass or mass number usually found in nature.
Examples of isotopes that can be incorporated into compounds of the
invention include isotopes of hydrogen, carbon, nitrogen, oxygen,
phosphorous, sulfur, fluorine and chloride, such as .sup.2H,
.sup.3H, .sup.13C, .sup.14C, .sup.15N, .sup.180, .sup.17O,
.sup.31P, .sup.32P, .sup.35S, .sup.18F, and .sup.36Cl,
respectively. Compounds described herein, pharmaceutically
acceptable salts, esters, prodrugs, solvate, hydrates or
derivatives thereof which contain the aforementioned isotopes
and/or other isotopes of other atoms are within the scope of this
invention. Certain isotopically-labeled compounds of formula I, for
example those into which radioactive isotopes such as .sup.3H and
.sup.14C are incorporated, are useful in drug and/or substrate
tissue distribution assays. Tritiated, i. e., .sup.3H and
carbon-14, i. e., .sup.14C, isotopes are particularly preferred for
their ease of preparation and detectability. Further, substitution
with heavier isotopes such as deuterium, i. e., .sup.2H, can afford
certain therapeutic advantages resulting from greater metabolic
stability, for example increased in vivo half-life or reduced
dosage requirements and, hence, may be preferred in some
circumstances. Isotopically labeled compounds, pharmaceutically
acceptable salt, ester, prodrug, solvate, hydrate or derivative
thereof can generally be prepared by carrying out procedures
described herein, by substituting a readily available isotopically
labeled reagent for a non-isotopically labeled reagent.
[0275] The compounds described herein may be labeled by other
means, including, but not limited to, the use of chromophores or
fluorescent moieties, bioluminescent labels, or chemiluminescent
labels.
Pharmaceutically Acceptable Salts of Compounds of Formula I
[0276] Also described herein are pharmaceutically acceptable salts
of compounds of formula I and methods of treating disorders. For
example, the invention provides for methods of treating diseases,
by administering pharmaceutically acceptable salts of compounds of
formula I. The pharmaceutically acceptable salts of compounds of
formula I can be administered as pharmaceutical compositions.
[0277] Thus, the compounds described herein can be prepared as
pharmaceutically acceptable salts formed when an acidic proton
present in the parent compound either is replaced by a metal ion,
for example an alkali metal ion, an alkaline earth ion, or an
aluminum ion; or coordinates with an organic base. Base addition
salts can also be prepared by reacting the free acid form of the
compounds described herein with a pharmaceutically acceptable
inorganic or organic base, including, but not limited to organic
bases such as ethanolamine, diethanolamine, triethanolamine,
tromethamine, N-methylglucamine, and the like and inorganic bases
such as aluminum hydroxide, calcium hydroxide, potassium hydroxide,
sodium carbonate, sodium hydroxide, and the like. In addition, the
salt forms of the disclosed compounds can be prepared using salts
of the starting materials or intermediates.
[0278] Further, the compounds described herein can be prepared as
pharmaceutically acceptable salts formed by reacting the free base
form of the compound with a pharmaceutically acceptable inorganic
or organic acid, including, but not limited to, inorganic acids
such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
acid, phosphoric acid metaphosphoric acid, and the like; and
organic acids such as acetic acid, propionic acid, hexanoic acid,
cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic
acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric
acid, Q-toluenesulfonic acid, tartaric acid, trifluoroacetic acid,
citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid,
cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic
acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,
2-hydroxyethanesulfonic acid, benzenesulfonic acid,
2-naphthalenesulfonic acid,
4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic
acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid),
3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic
acid, lauryl sulfuric acid, gluconic acid, glutamic acid,
hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic
acid.
Solvates of Compounds of Formula I
[0279] Also described herein are solvates of compounds of formula I
and methods of treating disorders. For example, the invention
provides for methods of treating diseases, by administering
solvates of compounds of formula I. The solvates of compounds of
formula I can be administered as pharmaceutical compositions.
[0280] Solvates contain either stoichiometric or non-stoichiometric
amounts of a solvent, and may be formed during the process of
crystallization with pharmaceutically acceptable solvents such as
water, ethanol, and the like. Hydrates are formed when the solvent
is water, or alcoholates are formed when the solvent is alcohol.
Solvates of the compounds described herein can be conveniently
prepared or formed during the processes described herein. By way of
example only, hydrates of the compounds described herein can be
conveniently prepared by recrystallization from an aqueous/organic
solvent mixture, using organic solvents including, but not limited
to, dioxane, tetrahydrofuran or methanol. In addition, the
compounds provided herein can exist in unsolvated as well as
solvated forms. In general, the solvated forms are considered
equivalent to the unsolvated forms for the purposes of the
compounds and methods provided herein.
Polymorphs of Compounds of Formula I
[0281] Also described herein are polymorphs of compounds of formula
I and methods of treating disorders. For example, the invention
provides for methods of treating diseases, by administering
polymorphs of compounds of formula I. The polymorphs of compounds
of formula I can be administered as pharmaceutical
compositions.
[0282] Thus, the compounds described herein include all their
crystalline forms, known as polymorphs. Polymorphs include the
different crystal packing arrangements of the same elemental
composition of a compound. Polymorphs may have different X-ray
diffraction patterns, infrared spectra, melting points, density,
hardness, crystal shape, optical and electrical properties,
stability, and solubility. Various factors such as the
recrystallization solvent, rate of crystallization, and storage
temperature may cause a single crystal form to dominate.
Prodrugs of Compounds of Formula I
[0283] Also described herein are prodrugs of compounds of formula I
and methods of treating disorders. For example, the invention
provides for methods of treating diseases, by administering
prodrugs of compounds of formula I. The prodrugs of compounds of
formula I can be administered as pharmaceutical compositions.
[0284] Prodrugs are generally drug precursors that, following
administration to a subject and subsequent absorption, are
converted to an active, or a more active species via some process,
such as conversion by a metabolic pathway. Some prodrugs have a
chemical group present on the prodrug that renders it less active
and/or confers solubility or some other property to the drug. Once
the chemical group has been cleaved and/or modified from the
prodrug the active drug is generated. Prodrugs are often useful
because, in some situations, they may be easier to administer than
the parent drug. They may, for instance, be bioavailable by oral
administration whereas the parent is not. The prodrug may also have
improved solubility in pharmaceutical compositions over the parent
drug. An example, without limitation, of a prodrug would be a
compound as described herein which is administered as an ester (the
"prodrug") to facilitate transmittal across a cell membrane where
water solubility is detrimental to mobility but which then is
metabolically hydrolyzed to the carboxylic acid, the active entity,
once inside the cell where water-solubility is beneficial. A
further example of a prodrug might be a short peptide (polyamino
acid) bonded to an acid group where the peptide is metabolized to
reveal the active moiety.
[0285] Prodrugs may be designed as reversible drug derivatives, for
use as modifiers to enhance drug transport to site-specific
tissues. The design of prodrugs to date has been to increase the
effective water solubility of the therapeutic compound for
targeting to regions where water is the principal solvent. See,
e.g., Fedorak et al., Am. J. Physiol., 269:G.sub.210-218 (1995);
McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al.,
Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int.
J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J.
Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci.,
64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel
Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; and
Edward B. Roche, Bioreversible Carriers in Drug Design, American
Pharmaceutical Association and Pergamon Press, 1987, all
incorporated herein in their entirety.
[0286] Additionally, prodrug derivatives of compounds described
herein can be prepared by methods known to those of ordinary skill
in the art (e.g., for further details see Saulnier et al., (1994),
Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985). By
way of example only, appropriate prodrugs can be prepared by
reacting a non-derivatized compound of formula I with a suitable
carbamylating agent, such as, but not limited to,
1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or
the like. Prodrug forms of the herein described compounds, wherein
the prodrug is metabolized in vivo to produce a derivative as set
forth herein are included within the scope of the claims. Indeed,
some of the herein-described compounds may be a prodrug for another
derivative or active compound.
[0287] In some embodiments, prodrugs include compounds wherein an
amino acid residue, or a polypeptide chain of two or more (e. g.,
two, three or four) amino acid residues is covalently joined
through an amide or ester bond to a free amino, hydroxy or
carboxylic acid group of compounds of the present invention. The
amino acid residues include but are not limited to the 20 naturally
occurring amino acids commonly designated by three letter symbols
and also includes 4-hydroxyproline, hydroxylysine, demosine,
isodemosine, 3-methylhistidine, norvaline, beta-alanine,
gamma-aminobutyric acid, cirtulline, homocysteine, homoserine,
ornithine and methionine sulfone. Additional types of prodrugs are
also encompassed.
[0288] Compounds of formula I having free amino, amido, hydroxy or
carboxylic groups can be converted into prodrugs. For instance,
free carboxyl groups can be derivatized as amides or alkyl esters.
Free hydroxy groups may be derivatized using groups including but
not limited to hemisuccinates, phosphate esters,
dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as
outlined in Advanced Drug Delivery Reviews 1996, 19, 115. Carbamate
prodrugs of hydroxy and amino groups are also included, as are
carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy
groups.
[0289] Derivatization of hydroxy groups as (acyloxy) methyl and
(acyloxy) ethyl ethers wherein the acyl group may be an alkyl
ester, optionally substituted with groups including but not limited
to ether, amine and carboxylic acid functionalities, or where the
acyl group is an amino acid ester as described above, are also
encompassed. Prodrugs of this type are described in J. Med. Chem.
1996, 39, 10. Free amines can also be derivatized as amides,
sulfonamides or phosphonamides. All of these prodrug moieties may
incorporate groups including but not limited to ether, amine and
carboxylic acid functionalities.
[0290] Sites on the aromatic ring portions of compounds of formula
I may be susceptible to various metabolic reactions, therefore
incorporation of appropriate substituents on the aromatic ring
structures, can reduce, minimize or eliminate this metabolic
pathway.
Pharmaceutical Compositions
[0291] Described herein are pharmaceutical compositions. In some
embodiments, the pharmaceutical compositions comprise an effective
amount of a compound formula I, or a pharmaceutically acceptable
salt, ester, prodrug, solvate, hydrate or derivative thereof. In
some embodiments, the pharmaceutical compositions comprise an
effective amount of a compound formula I, or a pharmaceutically
acceptable salt, ester, prodrug, solvate, hydrate or derivative
thereof and at least one pharmaceutically acceptable carrier. In
some embodiments the pharmaceutical compositions are for the
treatment of disorders. In some embodiments the pharmaceutical
compositions are for the treatment of disorders in a mammal. In
some embodiments the pharmaceutical compositions are for the
treatment of disorders in a human.
MEK Modulation
[0292] Also described herein are methods of modulating MEK activity
by contacting MEK with an amount of a compound of formula I
sufficient to modulate the activity of MEK. Modulate can be
inhibiting or activating MEK activity. In some embodiments, the
invention provides methods of inhibiting MEK activity by contacting
MEK with an amount of a compound of formula I sufficient to inhibit
the activity of MEK. In some embodiments, the invention provides
methods of inhibiting MEK activity in a solution by contacting said
solution with an amount of a compound of formula I sufficient to
inhibit the activity of MEK in said solution. In some embodiments,
the invention provides methods of inhibiting MEK activity in a cell
by contacting said cell with an amount of a compound described
herein sufficient to inhibit the activity of MEK in said cell. In
some embodiments, the invention provides methods of inhibiting MEK
activity in a tissue by contacting said tissue with an amount of a
compound described herein sufficient to inhibit the activity of MEK
in said tissue. In some embodiments, the invention provides methods
of inhibiting MEK activity in an organism by contacting said
organism with an amount of a compound described herein sufficient
to inhibit the activity of MEK in said organism. In some
embodiments, the invention provides methods of inhibiting MEK
activity in an animal by contacting said animal with an amount of a
compound described herein sufficient to inhibit the activity of MEK
in said animal. In some embodiments, the invention provides methods
of inhibiting MEK activity in a mammal by contacting said mammal
with an amount of a compound described herein sufficient to inhibit
the activity of MEK in said mammal. In some embodiments, the
invention provides methods of inhibiting MEK activity in a human by
contacting said human with an amount of a compound described herein
sufficient to inhibit the activity of MEK in said human.
Abnormal Cell Growth
[0293] Also described herein are compounds, pharmaceutical
compositions and methods for inhibiting abnormal cell growth. In
some embodiments, the abnormal cell growth occurs in a mammal.
Methods for inhibiting abnormal cell growth comprise administering
an effective amount of a compound of formula I, or a
pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate
or derivative thereof, wherein abnormal cell growth is inhibited
Methods for inhibiting abnormal cell growth in a mammal comprise
administering to the mammal an amount of a compound of formula I,
or a pharmaceutically acceptable salt, ester, prodrug, solvate,
hydrate or derivative thereof, wherein the amounts of the compound,
salt, ester, prodrug, solvate, hydrate or derivative, is effective
in inhibiting abnormal cell growth in the mammal.
[0294] In some embodiments, the methods comprise administering an
effective amount of a compound of formula I, or a pharmaceutically
acceptable salt, ester, prodrug, solvate, hydrate or derivative
thereof, in combination with an amount of a chemotherapeutic,
wherein the amounts of the compound, salt, ester, prodrug, solvate,
hydrate or derivative, and of the chemotherapeutic are together
effective in inhibiting abnormal cell growth. Many
chemotherapeutics are presently known in the art and can be used in
combination with the compounds of the invention. In some
embodiments, the chemotherapeutic is selected from the group
consisting of mitotic inhibitors, alkylating agents,
anti-metabolites, intercalating antibiotics, growth factor
inhibitors, cell cycle inhibitors, enzymes, topoisomerase
inhibitors, biological response modifiers, anti-hormones,
angiogenesis inhibitors, and anti-androgens.
[0295] Also described are methods for inhibiting abnormal cell
growth in a mammal comprising administering to the mammal an amount
of a compound of formula I, or a pharmaceutically acceptable salt,
ester, prodrug, solvate, hydrate or derivative thereof, in
combination with radiation therapy, wherein the amounts of the
compound, salt, ester, prodrug, solvate, hydrate or derivative, is
in combination with the radiation therapy effective in inhibiting
abnormal cell growth or treating the hyperproliferative disorder in
the mammal. Techniques for administering radiation therapy are
known in the art, and these techniques can be used in the
combination therapy described herein. The administration of the
compound of formula I in this combination therapy can be determined
as described herein.
[0296] The invention also relates to a method of and to a
pharmaceutical composition of inhibiting abnormal cell growth in a
mammal which comprises an amount of a compound of formula I, or a
pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate
or derivative thereof, or an isotopically-labeled derivative
thereof, and an amount of one or more substances selected from
anti-angiogenesis agents, signal transduction inhibitors, and
antiproliferative agents.
[0297] Anti-angiogenesis agents, such as MMP-2
(matrix-metalloprotienase 2) inhibitors, MMP-9
(matrix-metalloprotienase 9) inhibitors, and COX-11 (cyclooxygenase
11) inhibitors, can be used in conjunction with a compound of the
present invention and pharmaceutical compositions described herein.
Examples of useful COX-II inhibitors include CELEBREX.TM.
(alecoxib), valdecoxib, and rofecoxib. Examples of useful matrix
metalloproteinase inhibitors are described in WO 96/33172
(published Oct. 24, 1996), WO 96/27583 (published Mar. 7, 1996),
European Patent Application No. 97304971.1 (filed Jul. 8, 1997),
European Patent Application No. 99308617.2 (filed Oct. 29, 1999),
WO 98/07697 (published Feb. 26, 1998), WO 98/03516 (published Jan.
29, 1998), WO 98/34918 (published Aug. 13, 1998), WO 98/34915
(published Aug. 13, 1998), WO 98/33768 (published Aug. 6, 1998), WO
98/30566 (published Jul. 16, 1998), European Patent Publication
606,046 (published Jul. 13, 1994), European Patent Publication 931,
788 (published Jul. 28, 1999), WO 90/05719 (published May 31,
1990), WO 99/52910 (published Oct. 21, 1999), WO 99/52889
(published Oct. 21, 1999), WO 99/29667 (published Jun. 17, 1999),
PCT International Application No. PCT/IB98/01113 (filed Jul. 21,
1998), European Patent Application No. 99302232.1 (filed Mar. 25,
1999), Great Britain Patent Application No. 9912961.1 (filed Jun.
3, 1999), U.S. Provisional Application No. 60/148,464 (filed Aug.
12, 1999), U.S. Pat. No. 5,863,949 (issued Jan. 26, 1999), U.S.
Pat. No. 5,861,510 (issued Jan. 19, 1999), and European Patent
Publication 780,386 (published Jun. 25, 1997), all of which are
incorporated herein in their entireties by reference. Preferred
MMP-2 and MMP-9 inhibitors are those that have little or no
activity inhibiting MMP-1. More preferred, are those that
selectively inhibit MMP-2 and/or AMP-9 relative to the other
matrix-metalloproteinases (i. e., MAP-1, MMP-3, MMP-4, MMP-5,
MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some
specific examples of MMP inhibitors useful in the present invention
are AG-3340, RO 32-3555, and RS 13-0830.
Modes of Administration
[0298] Described herein are compounds of formula I or a
pharmaceutically acceptable salt, solvate, polymorph, ester,
tautomer or prodrug thereof. Also described, are pharmaceutical
compositions comprising a compound of formula I or a
pharmaceutically acceptable salt, solvate, polymorph, ester,
tautomer or prodrug thereof. The compounds and compositions
described herein may be administered either alone or in combination
with pharmaceutically acceptable carriers, excipients or diluents,
in a pharmaceutical composition, according to standard
pharmaceutical practice.
[0299] Administration of the compounds and compositions described
herein can be effected by any method that enables delivery of the
compounds to the site of action. These methods include oral routes,
intraduodenal routes, parenteral injection (including intravenous,
subcutaneous, intraperitoneal, intramuscular, intravascular or
infusion), topical, and rectal administration. For example,
compounds described herein can be administered locally to the area
in need of treatment. This may be achieved by, for example, but not
limited to, local infusion during surgery, topical application,
e.g., cream, ointment, injection, catheter, or implant, said
implant made, e.g., out of a porous, non-porous, or gelatinous
material, including membranes, such as sialastic membranes, or
fibers. The administration can also be by direct injection at the
site (or former site) of a tumor or neoplastic or pre-neoplastic
tissue. Those of ordinary skill in the art are familiar with
formulation and administration techniques that can be employed with
the compounds and methods of the invention, e.g., as discussed in
Goodman and Gilman, The Pharmacological Basis of Therapeutics,
current ed.; Pergamon; and Remington's, Pharmaceutical Sciences
(current edition), Mack Publishing Co., Easton, Pa.
[0300] The formulations include those suitable for oral, parenteral
(including subcutaneous, intradermal, intramuscular, intravenous,
intraarticular, and intramedullary), intraperitoneal, transmucosal,
transdermal, rectal and topical (including dermal, buccal,
sublingual and intraocular) administration although the most
suitable route may depend upon for example the condition and
disorder of the recipient. The formulations may conveniently be
presented in unit dosage form and may be prepared by any of the
methods well known in the art of pharmacy. All methods include the
step of bringing into association a compound of the subject
invention or a pharmaceutically acceptable salt, ester, prodrug or
solvate thereof ("active ingredient") with the carrier which
constitutes one or more accessory ingredients. In general, the
formulations are prepared by uniformly and intimately bringing into
association the active ingredient with liquid carriers or finely
divided solid carriers or both and then; if necessary, shaping the
product into the desired formulation.
[0301] Formulations suitable for oral administration may be
presented as discrete units such as capsules, cachets or tablets
each containing a predetermined amount of the active ingredient; as
a powder or granules; as a solution or a suspension in an aqueous
liquid or a non-aqueous liquid; or as an oil-in-water liquid
emulsion or a water-in-oil liquid emulsion. The active ingredient
may also be presented as a bolus, electuary or paste.
[0302] Pharmaceutical preparations which can be used orally include
tablets, push-fit capsules made of gelatin, as well as soft, sealed
capsules made of gelatin and a plasticizer, such as glycerol or
sorbitol. Tablets may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared by compressing in a suitable machine the active ingredient
in a free-flowing form such as a powder or granules, optionally
mixed with binders, inert diluents, or lubricating, surface active
or dispersing agents. Molded tablets may be made by molding in a
suitable machine a mixture of the powdered compound moistened with
an inert liquid diluent. The tablets may optionally be coated or
scored and may be formulated so as to provide slow or controlled
release of the active ingredient therein. All formulations for oral
administration should be in dosages suitable for such
administration. 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. In
addition, stabilizers may be added. Dragee cores are provided with
suitable coatings. For this purpose, concentrated sugar solutions
may be used, which may optionally contain gum arabic, talc,
polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or
titanium dioxide, lacquer solutions, and suitable organic solvents
or solvent mixtures. Dyestuffs or pigments may be added to the
tablets or Dragee coatings for identification or to characterize
different combinations of active compound doses.
[0303] Pharmaceutical preparations may be formulated for parenteral
administration by injection, e.g., by bolus injection or continuous
infusion. Formulations for injection may be presented in unit
dosage form, e.g., in ampoules or in multi-dose containers, with an
added preservative. The compositions may take such forms as
suspensions, solutions or emulsions in oily or aqueous vehicles,
and may contain formulatory agents such as suspending, stabilizing
and/or dispersing agents. The formulations may be presented in
unit-dose or multi-dose containers, for example sealed ampoules and
vials, and may be stored in powder form or in a freeze-dried
(lyophilized) condition requiring only the addition of the sterile
liquid carrier, for example, saline or sterile pyrogen-free water,
immediately prior to use. Extemporaneous injection solutions and
suspensions may be prepared from sterile powders, granules and
tablets of the kind previously described.
[0304] Formulations for parenteral administration include aqueous
and non-aqueous (oily) sterile injection solutions of the active
compounds which may contain antioxidants, buffers, bacteriostats
and solutes which render the formulation isotonic with the blood of
the intended recipient; and aqueous and non-aqueous sterile
suspensions which may include suspending agents and thickening
agents. Suitable lipophilic solvents or vehicles include fatty oils
such as sesame oil, or synthetic fatty acid esters, such as ethyl
oleate or triglycerides, or liposomes. Aqueous injection
suspensions may contain substances which increase the viscosity of
the suspension, such as sodium carboxymethyl cellulose, sorbitol,
or dextran. Optionally, the suspension may also contain suitable
stabilizers or agents which increase the solubility of the
compounds to allow for the preparation of highly concentrated
solutions.
[0305] Pharmaceutical preparations may also be formulated as a
depot preparation. Such long acting formulations may be
administered by implantation (for example subcutaneously or
intramuscularly) or by intramuscular injection. Thus, for example,
the compounds may be formulated with suitable polymeric or
hydrophobic materials (for example as an emulsion in an acceptable
oil) or ion exchange resins, or as sparingly soluble derivatives,
for example, as a sparingly soluble salt.
[0306] For buccal or sublingual administration, the compositions
may take the form of tablets, lozenges, pastilles, or gels
formulated in conventional manner. Such compositions may comprise
the active ingredient in a flavored basis such as sucrose and
acacia or tragacanth.
[0307] Pharmaceutical preparations may also be formulated in rectal
compositions such as suppositories or retention enemas, e.g.,
containing conventional suppository bases such as cocoa butter,
polyethylene glycol, or other glycerides.
[0308] Pharmaceutical preparations may be administered topically,
that is by non-systemic administration. This includes the
application of a compound of the present invention externally to
the epidermis or the buccal cavity and the instillation of such a
compound into the ear, eye and nose, such that the compound does
not significantly enter the blood stream. In contrast, systemic
administration refers to oral, intravenous, intraperitoneal and
intramuscular administration.
[0309] Pharmaceutical preparations suitable for topical
administration include liquid or semi-liquid preparations suitable
for penetration through the skin to the site of inflammation such
as gels, liniments, lotions, creams, ointments or pastes, and drops
suitable for administration to the eye, ear or nose. The active
ingredient may comprise, for topical administration, from 0.001% to
10% w/w, for instance from 1% to 2% by weight of the formulation.
It may however comprise as much as 10% w/w but preferably will
comprise less than 5% w/w, more preferably from 0.1% to 1% w/w of
the formulation.
[0310] Pharmaceutical preparations for administration by inhalation
are conveniently delivered from an insufflator, nebulizer
pressurized packs or other convenient means of delivering an
aerosol spray. Pressurized packs may comprise a suitable propellant
such as dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In
the case of a pressurized aerosol, the dosage unit may be
determined by providing a valve to deliver a metered amount.
Alternatively, for administration by inhalation or insufflation,
pharmaceutical preparations may take the form of a dry powder
composition, for example a powder mix of the compound and a
suitable powder base such as lactose or starch. The powder
composition may be presented in unit dosage form, in for example,
capsules, cartridges, gelatin or blister packs from which the
powder may be administered with the aid of an inhalator or
insufflator.
[0311] It should be understood that in addition to the ingredients
particularly mentioned above, the compounds and compositions
described herein may include other agents conventional in the art
having regard to the type of formulation in question, for example
those suitable for oral administration may include flavoring
agents.
Formulations
[0312] The compounds or compositions described herein can be
delivered in a vesicle, e.g., a liposome (see, for example, Langer,
Science 1990, 249, 1527-1533; Treat et al., Liposomes in the
Therapy of Infectious Disease and Cancer, Lopez-Bernstein and
Fidler, Ed., Liss, N.Y., pp. 353-365, 1989). The compounds and
pharmaceutical compositions described herein can also be delivered
in a controlled release system. In one embodiment, a pump may be
used (see, Sefton, 1987; CRC Crit. Ref Biomed. Eng. 14:201;
Buchwald et al. Surgery, 1980 88, 507; Saudek et al. N. Engl. Med.
1989, 321, (574). Additionally, a controlled release system can be
placed in proximity of the therapeutic target. (See, Goodson,
Medical Applications of Controlled Release, 1984, Vol. 2, pp.
115-138). The pharmaceutical compositions described herein can also
contain the active ingredient in a form suitable for oral use, for
example, as tablets, troches, lozenges, aqueous or oily
suspensions, dispersible powders or granules, emulsions, hard or
soft capsules, or syrups or elixirs. Compositions intended for oral
use may be prepared according to any method known to the art for
the manufacture of pharmaceutical compositions, and such
compositions may contain one or more agents selected from the group
consisting of sweetening agents, flavoring agents, coloring agents
and preserving agents in order to provide pharmaceutically elegant
and palatable preparations. Tablets contain the active ingredient
in admixture with non-toxic pharmaceutically acceptable excipients
which are suitable for the manufacture of tablets. These excipients
may be, for example, inert diluents, such as calcium carbonate,
sodium carbonate, lactose, calcium phosphate or sodium phosphate;
granulating and disintegrating agents, such as microcrystalline
cellulose, sodium crosscarmellose, corn starch, or alginic acid;
binding agents, for example starch, gelatin, polyvinyl-pyrrolidone
or acacia, and lubricating agents, for example, magnesium stearate,
stearic acid or talc. The tablets may be un-coated or coated by
known techniques to mask the taste of the drug or delay
disintegration and absorption in the gastrointestinal tract and
thereby provide a sustained action over a longer period. For
example, a water soluble taste masking material such as
hydroxypropylmethyl-cellulose or hydroxypropylcellulose, or a time
delay material such as ethyl cellulose, or cellulose acetate
butyrate may be employed as appropriate. Formulations for oral use
may also be presented as hard gelatin capsules wherein the active
ingredient is mixed with an inert solid diluent, for example,
calcium carbonate, calcium phosphate or kaolin, or as soft gelatin
capsules wherein the active ingredient is mixed with water soluble
carrier such as polyethyleneglycol or an oil medium, for example
peanut oil, liquid paraffin, or olive oil.
[0313] Aqueous suspensions contain the active material in admixture
with excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example
sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethyl-cellulose, sodium alginate,
polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or
wetting agents may be a naturally-occurring phosphatide, for
example lecithin, or condensation products of an alkylene oxide
with fatty acids, for example polyoxyethylene stearate, or
condensation products of ethylene oxide with long chain aliphatic
alcohols, for example heptadecaethylene-oxycetanol, or condensation
products of ethylene oxide with partial esters derived from fatty
acids and a hexitol such as polyoxyethylene sorbitol monooleate, or
condensation products of ethylene oxide with partial esters derived
from fatty acids and hexitol anhydrides, for example polyethylene
sorbitan monooleate. The aqueous suspensions may also contain one
or more preservatives, for example ethyl, or n-propyl
p-hydroxybenzoate, one or more coloring agents, one or more
flavoring agents, and one or more sweetening agents, such as
sucrose, saccharin or aspartame.
[0314] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil, for example arachis oil, olive oil,
sesame oil or coconut oil, or in mineral oil such as liquid
paraffin. The oily suspensions may contain a thickening agent, for
example beeswax, hard paraffin or cetyl alcohol. Sweetening agents
such as those set forth above, and flavoring agents may be added to
provide a palatable oral preparation. These compositions may be
preserved by the addition of an anti-oxidant such as butylated
hydroxyanisol or alpha-tocopherol.
[0315] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
ingredient in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above. Additional excipients, for example
sweetening, flavoring and coloring agents, may also be present.
These compositions may be preserved by the addition of an
anti-oxidant such as ascorbic acid.
[0316] Pharmaceutical compositions may also be in the form of an
oil-in-water emulsions. The oily phase may be a vegetable oil, for
example olive oil or arachis oil, or a mineral oil, for example
liquid paraffin or mixtures of these. Suitable emulsifying agents
may be naturally-occurring phosphatides, for example soy bean
lecithin, and esters or partial esters derived from fatty acids and
hexitol anhydrides, for example sorbitan monooleate, and
condensation products of the said partial esters with ethylene
oxide, for example polyoxyethylene sorbitan monooleate. The
emulsions may also contain sweetening agents, flavoring agents,
preservatives and antioxidants.
[0317] Syrups and elixirs may be formulated with sweetening agents,
for example glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, a preservative,
flavoring and coloring agents and antioxidant.
[0318] Pharmaceutical compositions may be in the form of a sterile
injectable aqueous solution. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution and
isotonic sodium chloride solution. The sterile injectable
preparation may also be a sterile injectable oil-in-water
microemulsion where the active ingredient is dissolved in the oily
phase. For example, the active ingredient may be first dissolved in
a mixture of soybean oil and lecithin. The oil solution then
introduced into a water and glycerol mixture and processed to form
a microemulsion. The injectable solutions or microemulsions may be
introduced into a patient's blood-stream by local bolus injection.
Alternatively, it may be advantageous to administer the solution or
microemulsion in such a way as to maintain a constant circulating
concentration of the instant compound. In order to maintain such a
constant concentration, a continuous intravenous delivery device
may be utilized. An example of such a device is the Deltec
CADD-PLUS.TM. model 5400 intravenous pump. The pharmaceutical
compositions may be in the form of a sterile injectable aqueous or
oleagenous suspension for intramuscular and subcutaneous
administration. This suspension may be formulated according to the
known art using those suitable dispersing or wetting agents and
suspending agents which have been mentioned above. The sterile
injectable preparation may also be a sterile injectable solution or
suspension in a non-toxic parenterally-acceptable diluent or
solvent, for example as a solution in 1,3-butane diol. In addition,
sterile, fixed oils are conventionally employed as a solvent or
suspending medium. For this purpose any bland fixed oil may be
employed including synthetic mono- or diglycerides. In addition,
fatty acids such as oleic acid find use in the preparation of
injectables.
[0319] Pharmaceutical compositions may also be administered in the
form of suppositories for rectal administration of the drug. These
compositions can be prepared by mixing the inhibitors with a
suitable non-irritating excipient which is solid at ordinary
temperatures but liquid at the rectal temperature and will
therefore melt in the rectum to release the drug. Such materials
include cocoa butter, glycerinated gelatin, hydrogenated vegetable
oils, mixtures of polyethylene glycols of various molecular weights
and fatty acid esters of polyethylene glycol.
[0320] For topical use, creams, ointments, jellies, solutions or
suspensions, etc., containing a compound or composition of the
invention can be used. As used herein, topical application can
include mouth washes and gargles.
[0321] Pharmaceutical compositions may be administered in
intranasal form via topical use of suitable intranasal vehicles and
delivery devices, or via transdermal routes, using those forms of
transdermal skin patches well known to those of ordinary skill in
the art. To be administered in the form of a transdermal delivery
system, the dosage administration will, of course, be continuous
rather than intermittent throughout the dosage regimen.
Doses
[0322] The amount of pharmaceutical compositions administered will
firstly be dependent on the mammal being treated. In the instances
where pharmaceutical compositions are administered to a human
subject, the daily dosage will normally be determined by the
prescribing physician with the dosage generally varying according
to the age, sex, diet, weight, general health and response of the
individual patient, the severity of the patient's symptoms, the
precise indication or condition being treated, the severity of the
indication or condition being treated, time of administration,
route of administration, the disposition of the composition, rate
of excretion, drug combination, and the discretion of the
prescribing physician. Also, the route of administration may vary
depending on the condition and its severity. Preferably, the
pharmaceutical composition is in unit dosage form. In such form,
the preparation is subdivided into unit doses containing
appropriate quantities of the active component, e.g., an effective
amount to achieve the desired purpose. Determination of the proper
dosage for a particular situation is within the skill of the art.
Generally, treatment is initiated with smaller dosages which are
less than the optimum dose of the compound. Thereafter, the dosage
is increased by small amounts until the optimum effect under the
circumstances is reached. For convenience, the total daily dosage
may be divided and administered in portions during the day if
desired. The amount and frequency of administration of the
compounds described herein, and if applicable other therapeutic
agents and/or therapies, will be regulated according to the
judgment of the attending clinician (physician) considering such
factors as described above. Thus the amount of pharmaceutical
composition to be administered may vary widely. Administration may
occur in an amount of between about 0.001 mg/kg of body weight to
about 100 mg/kg of body weight per day (administered in single or
divided doses), more preferably at least about 0.1 mg/kg of body
weight per day. A particular therapeutic dosage can include, e.g.,
from about 0.01 mg to about 7000 mg of compound, and preferably
includes, e.g., from about 0.05 mg to about 2500 mg. The quantity
of active compound in a unit dose of preparation may be varied or
adjusted from about 0.1 mg to 1000 mg, preferably from about 1 mg
to 300 mg, more preferably 10 mg to 200 mg, according to the
particular application. In some instances; dosage levels below the
lower limit of the aforesaid range may be more than adequate, while
in other cases still larger doses may be employed without causing
any harmful side effect, e.g. by dividing such larger doses into
several small doses for administration throughout the day. The
amount administered will vary depending on the particular IC.sub.50
value of the compound used. In combinational applications in which
the compound is not the sole therapy, it may be possible to
administer lesser amounts of compound and still have therapeutic or
prophylactic effect.
Dosage Forms
[0323] The pharmaceutical composition may, for example, be in a
form suitable for oral administration as a tablet, capsule, pill,
powder, sustained release formulations, solution, suspension, for
parenteral injection as a sterile solution, suspension or emulsion,
for topical administration as an ointment or cream or for rectal
administration as a suppository. The pharmaceutical composition may
be in unit dosage forms suitable for single administration of
precise dosages. The pharmaceutical composition will include a
conventional pharmaceutical carrier or excipient and a compound
according to the invention as an active ingredient. In addition, it
may include other medicinal or pharmaceutical agents, carriers,
adjuvants, etc.
[0324] Exemplary parenteral administration forms include solutions
or suspensions of active compounds in sterile aqueous solutions,
for example, aqueous propylene glycol or dextrose solutions. Such
dosage forms can be suitably buffered, if desired.
[0325] Suitable pharmaceutical carriers include inert diluents or
fillers, water and various organic solvents. The pharmaceutical
compositions may, if desired, contain additional ingredients such
as flavorings, binders, excipients and the like. Thus for oral
administration, tablets containing various excipients, such as
citric acid may be employed together with various disintegrants
such as starch, alginic acid and certain complex silicates and with
binding agents such as sucrose, gelatin and acacia. Additionally,
lubricating agents such as magnesium stearate, sodium lauryl
sulfate and talc are often useful for tableting purposes. Solid
compositions of a similar type may also be employed in soft and
hard filled gelatin capsules. Preferred materials, therefore,
include lactose or milk sugar and high molecular weight
polyethylene glycols. When aqueous suspensions or elixirs are
desired for oral administration the active compound therein may be
combined with various sweetening or flavoring agents, coloring
matters or dyes and, if desired, emulsifying agents or suspending
agents, together with diluents such as water, ethanol, propylene
glycol, glycerin, or combinations thereof.
[0326] Methods of preparing various pharmaceutical compositions
with a specific amount of active compound are known, or will be
apparent, to those skilled in this art. For examples, see
Remington's Pharmaceutical Sciences, Mack Publishing Company,
Ester, Pa., 18th Edition (1990).
Combination Therapies
[0327] The compounds described herein or a pharmaceutically
acceptable salt, solvate, polymorph, ester, tautomer or prodrug
thereof may be administered as a sole therapy. The compounds
described herein or a pharmaceutically acceptable salt, solvate,
polymorph, ester, tautomer or prodrug thereof may also be
administered in combination with another therapy or therapies.
[0328] By way of example only, if one of the side effects
experienced by a patient upon receiving one of the compounds
described herein is hypertension, then it may be appropriate to
administer an anti-hypertensive agent in combination with the
compound. Or, by way of example only, the therapeutic effectiveness
of one of the compounds described herein may be enhanced by
administration of an adjuvant (i.e., by itself the adjuvant may
only have minimal therapeutic benefit, but in combination with
another therapeutic agent, the overall therapeutic benefit to the
patient is enhanced). Or, by way of example only, the benefit
experienced by a patient may be increased by administering one of
the compounds described herein with another therapeutic agent
(which also includes a therapeutic regimen) that also has
therapeutic benefit. By way of example only, in a treatment for
diabetes involving administration of one of the compounds described
herein, increased therapeutic benefit may result by also providing
the patient with another therapeutic agent for diabetes. In any
case, regardless of the disease, disorder or condition being
treated, the overall benefit experienced by the patient may simply
be additive of the two therapeutic agents or the patient may
experience a synergistic benefit.
[0329] Other therapies include, but are not limited to
administration of other therapeutic agents, radiation therapy or
both. In the instances where the compounds described herein are
administered with other therapeutic agents, the compounds described
herein need not be administered in the same pharmaceutical
composition as other therapeutic agents, and may, because of
different physical and chemical characteristics, be administered by
a different route. For example, the compounds/compositions may be
administered orally to generate and maintain good blood levels
thereof, while the other therapeutic agent may be administered
intravenously. The determination of the mode of administration and
the advisability of administration, where possible, in the same
pharmaceutical composition, is well within the knowledge of the
skilled clinician. The initial administration can be made according
to established protocols known in the art, and then, based upon the
observed effects, the dosage, modes of administration and times of
administration can be modified by the skilled clinician. The
particular choice of compound (and where appropriate, other
therapeutic agent and/or radiation) will depend upon the diagnosis
of the attending physicians and their judgment of the condition of
the patient and the appropriate treatment protocol. Other
therapeutic agents may include chemotherapeutic agents, such as
anti-tumor substances, for example those selected from, mitotic
inhibitors, for example vinblastine; alkylating agents, for example
cis-platin, carboplatin and cyclophosphamide; anti-metabolites, for
example 5-fluorouracil, cytosine arabinside and hydroxyurea, or,
for example, one of the preferred anti-metabolites disclosed in
European Patent Application No. 239362 such as N-(5-[N-(3,
4-dihydro-2-methyl-4-oxoquinazolin-6-yhnethyl)-N-methylamino]-2-thenoyl)--
L-glutamic acid; growth factor inhibitors; cell cycle inhibitors;
intercalating antibiotics, for example adriamycin and bleomycin;
enzymes, for example, interferon; and anti-hormones, for example
anti-estrogens such as Nolvadex.TM. (tamoxifen) or, for example
anti-androgens such as Casodex.TM.
(4'-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3'-(trifluoromet-
hyl) propionanilide). Such conjoint treatment may be achieved by
way of the simultaneous, sequential or separate dosing of the
individual components of treatment.
[0330] The compounds and compositions described herein (and where
appropriate chemotherapeutic agent and/or radiation) may be
administered concurrently (e.g., simultaneously, essentially
simultaneously or within the same treatment protocol) or
sequentially, depending upon the nature of the disease, the
condition of the patient, and the actual choice of chemotherapeutic
agent and/or radiation to be administered in conjunction (i.e.,
within a single treatment protocol) with the
compound/composition.
[0331] In combinational applications and uses, the
compound/composition and the chemotherapeutic agent and/or
radiation need not be administered simultaneously or essentially
simultaneously, and the initial order of administration of the
compound/composition, and the chemotherapeutic agent and/or
radiation, may not be important. Thus, the compounds/compositions
of the invention may be administered first followed by the
administration of the chemotherapeutic agent and/or radiation; or
the chemotherapeutic agent and/or radiation may be administered
first followed by the administration of the compounds/compositions
of the invention. This alternate administration may be repeated
during a single treatment protocol. The determination of the order
of administration, and the number of repetitions of administration
of each therapeutic agent during a treatment protocol, is well
within the knowledge of the skilled physician after evaluation of
the disease being treated and the condition of the patient. For
example, the chemotherapeutic agent and/or radiation may be
administered first, especially if it is a cytotoxic agent, and then
the treatment continued with the administration of the
compounds/compositions of the invention followed, where determined
advantageous, by the administration of the chemotherapeutic agent
and/or radiation, and so on until the treatment protocol is
complete. Thus, in accordance with experience and knowledge, the
practicing physician can modify each protocol for the
administration of a compound/composition for treatment according to
the individual patient's needs, as the treatment proceeds. The
attending clinician, in judging whether treatment is effective at
the dosage administered, will consider the general well-being of
the patient as well as more definite signs such as relief of
disease-related symptoms, inhibition of tumor growth, actual
shrinkage of the tumor, or inhibition of metastasis. Size of the
tumor can be measured by standard methods such as radiological
studies, e.g., CAT or MRI scan, and successive measurements can be
used to judge whether or not growth of the tumor has been retarded
or even reversed. Relief of disease-related symptoms such as pain,
and improvement in overall condition can also be used to help judge
effectiveness of treatment.
[0332] Specific, non-limiting examples of possible combination
therapies include use of the compounds of the invention with agents
found in the following pharmacotherapeutic classifications as
indicated below. These lists should not be construed to be closed,
but should instead serve as illustrative examples common to the
relevant therapeutic area at present. Moreover, combination
regimens may include a variety of routes of administration and
should include oral, intravenous, intraocular, subcutaneous,
dermal, and inhaled topical.
[0333] For the treatment of oncologic diseases, proliferative
disorders, and cancers, compounds according to the present
invention may be administered with an agent selected from the group
comprising: aromatase inhibitors, antiestrogen, anti-androgen,
corticosteroids, gonadorelin agonists, topoisomerase 1 and 2
inhibitors, microtubule active agents, alkylating agents,
nitrosoureas, antineoplastic antimetabolites, platinum containing
compounds, lipid or protein kinase targeting agents, IMiDs, protein
or lipid phosphatase targeting agents, anti-angiogenic agents, Akt
inhibitors, IGF-I inhibitors, FGF3 modulators, mTOR inhibitors,
Smac mimetics, HDAC inhibitors, agents that induce cell
differentiation, bradykinin I receptor antagonists, angiotensin II
antagonists, cyclooxygenase inhibitors, heparanase inhibitors,
lymphokine inhibitors, cytokine inhibitors, IKK inhibitors, P38MAPK
inhibitors, HSP90 inhibitors, multlikinase inhibitors,
bisphosphanates, rapamycin derivatives, anti-apoptotic pathway
inhibitors, apoptotic pathway agonists, PPAR agonists, inhibitors
of Ras isoforms, telomerase inhibitors, protease inhibitors,
metalloproteinase inhibitors, and aminopeptidase inhibitors.
[0334] For the treatment of oncologic diseases, proliferative
disorders, and cancers, compounds according to the present
invention may be administered with an agent selected from the group
comprising: dacarbazine (DTIC), actinomycins C.sub.2, C.sub.3, D,
and F.sub.1, cyclophosphamide, melphalan, estramustine,
maytansinol, rifamycin, streptovaricin, doxorubicin, daunorubicin,
epirubicin, idarubicin, detorubicin, carminomycin, idarubicin,
epirubicin, esorubicin, mitoxantrone, bleomycins A, A.sub.2, and B,
camptothecin, Irinotecan.RTM., Topotecan.RTM., 9-aminocamptothecin,
10,11-methylenedioxycamptothecin, 9-nitrocamptothecin, bortezomib,
temozolomide, TAS103, NP10052, combretastatin, combretastatin A-2,
combretastatin A-4, calicheamicins, neocarcinostatins, epothilones
A B, C, and semi-synthetic variants, Herceptin.RTM., Rituxan.RTM.,
CD40 antibodies, asparaginase, interleukins, interferons,
leuprolide, and pegaspargase, 5-fluorouracil, fluorodeoxyuridine,
ptorafur, 5'-deoxyfluorouridine, UFT, MITC, S-1 capecitabine,
diethylstilbestrol, tamoxifen, toremefine, tolmudex, thymitaq,
flutamide, fluoxymesterone, bicalutamide, finasteride, estradiol,
trioxifene, dexamethasone, leuproelin acetate, estramustine,
droloxifene, medroxyprogesterone, megesterol acetate,
aminoglutethimide, testolactone, testosterone, diethylstilbestrol,
hydroxyprogesterone, mitomycins A, B and C, porfiromycin,
cisplatin, carboplatin, oxaliplatin, tetraplatin, platinum-DACH,
ormaplatin, thalidomide, lenalidomide, CI-973, telomestatin,
CHIR258, Rad 001, SAHA, Tubacin, 17-AAG, sorafenib, JM-216,
podophyllotoxin, epipodophyllotoxin, etoposide, teniposide,
Tarceva.RTM., Iressa.RTM., Imatinib.RTM., Miltefosine.RTM.,
Perifosine.RTM., aminopterin, methotrexate, methopterin,
dichloro-methotrexate, 6-mercaptopurine, thioguanine, azattuoprine,
allopurinol, cladribine, fludarabine, pentostatin,
2-chloroadenosine, deoxycytidine, cytosine arabinoside, cytarabine,
azacitidine, 5-azacytosine, gencitabine, 5-azacytosine-arabinoside,
vincristine, vinblastine, vinorelbine, leurosine, leurosidine and
vindesine, paclitaxel, taxotere and docetaxel.
[0335] For the treatment of inflammatory diseases and pain,
compounds according to the present invention may be administered
with an agent selected from the group comprising: corticosteroids,
non-steroidal anti-inflammatories, muscle relaxants and
combinations thereof with other agents, anaesthetics and
combinations thereof with other agents, expectorants and
combinations thereof with other agents, antidepressants,
anticonvulsants and combinations thereof; antihypertensives,
opioids, topical cannabinoids, and other agents, such as
capsaicin.
[0336] For the treatment of inflammatory diseases and pain,
compounds according to the present invention may be administered
with an agent selected from the group comprising: betamethasone
dipropionate (augmented and nonaugemnted), betamethasone valerate,
clobetasol propionate, prednisone, methyl prednisolone, diflorasone
diacetate, halobetasol propionate, amcinonide, dexamethasone,
dexosimethasone, fluocinolone acetononide, fluocinonide,
halocinonide, clocortalone pivalate, dexosimetasone,
flurandrenalide, salicylates, ibuprofen, ketoprofen, etodolac,
diclofenac, meclofenamate sodium, naproxen, piroxicam, celecoxib,
cyclobenzaprine, baclofen, cyclobenzaprinellidocaine,
baclofen/cyclobenzaprine, cyclobenzaprine/lidocaine/ketoprofen,
lidocaine, lidocaine/deoxy-D-glucose, prilocaine, EMLA Cream
(Eutectic Mixture of Local Anesthetics (lidocaine 2.5% and
prilocaine 2.5%), guaifenesin,
guaifenesinlketoprofen/cyclobenzaprine, amitryptiline, doxepin,
desipramine, imipramine, amoxapine, clomipramine, nortriptyline,
protriptyline, duloxetine, mirtazepine, nisoxetine, maprotiline,
reboxetine, fluoxetine, fluvoxamine, carbamazepine, felbamate,
lamotrigine, topiramate, tiagabine, oxcarbazepine, carbamezipine,
zonisamide, mexiletine, gabapentin/clonidine,
gabapentin/carbamazepine, carbamazepine/cyclobenzaprine,
antihypertensives including clonidine, codeine, loperamide,
tramadol, morphine, fentanyl, oxycodone, hydrocodone, levorphanol,
butorphanol, menthol, oil of wintergreen, camphor, eucalyptus oil,
turpentine oil; CB1/CB2 ligands, acetaminophen, infliximab; n)
nitric oxide synthase inhibitors, particularly inhibitors of
inducible nitric oxide synthase; and other agents, such as
capsaicin.
[0337] For the treatment of ophthalmologic disorders and diseases
of the eye, compounds according to the present invention may be
administered with an agent selected from the group comprising:
beta-blockers, carbonic anhydrase inhibitors, .alpha.- and
.beta.-adrenergic antagonists including al-adrenergic antagonists,
.alpha.2 agonists, miotics, prostaglandin analogs, corticosteroids,
and immunosuppressant agents.
[0338] For the treatment of ophthalmologic disorders and diseases
of the eye, compounds according to the present invention may be
administered with an agent selected from the group comprising:
timolol, betaxolol, levobetaxolol, carteolol, levobunolol,
propranolol, brinzolamide, dorzolamide, nipradilol, iopidine,
brimonidine, pilocarpine, epinephrine, latanoprost, travoprost,
bimatoprost, unoprostone, dexamethasone, prednisone,
methylprednisolone, azathioprine, cyclosporine, and
immunoglobulins.
[0339] For the treatment of autoimmune disorders, compounds
according to the present invention may be administered with an
agent selected from the group comprising: corticosteroids,
immunosuppressants, prostaglandin analogs and antimetabolites.
[0340] For the treatment of autoimmune disorders, compounds
according to the present invention may be administered with an
agent selected from the group comprising: dexamethasome,
prednisone, methylprednisolone, azathioprine, cyclosporine,
immunoglobulins, latanoprost, travoprost, bimatoprost, unoprostone,
infliximab, rutuximab and methotrexate.
[0341] For the treatment of metabolic disorders, compounds
according to the present invention may be administered with an
agent selected from the group comprising: insulin, insulin
derivatives and mimetics, insulin secretagogues, insulin
sensitizers, biguanide agents, alpha-glucosidase inhibitors,
insulinotropic sulfonylurea receptor ligands, protein tyrosine
phosphatase-IB (PTP-IB) inhibitors, GSK3 (glycogen synthase
kinase-3) inhibitors, GLP-1 (glucagon like peptide-1), GLP-1
analogs, DPPIV (dipeptidyl peptidase IV) inhibitors, RXR ligands
sodium-dependent glucose co-transporter inhibitors, glycogen
phosphorylase A inhibitors, an AGE breaker, PPAR modulators, and
non-glitazone type PPARS agonist.
[0342] For the treatment of metabolic disorders, compounds
according to the present invention may be administered with an
agent selected from the group comprising: insulin, metformin,
Glipizide, glyburide, Amaryl, meglitinides, nateglinide,
repaglinide, PT-112, SB-517955, SB4195052, SB-216763, NN-57-05441,
NN-57-05445, GW-0791, AGN-.sup. 194.sup.204, T-1095, BAY R3401,
acarbose Exendin-4, DPP728, LAF237, vildagliptin, MK-0431,
saxagliptin, GSK23A, pioglitazone, rosiglitazone,
(R)-1-{4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benze-
-nesulfonyl}2,3-dihydro-1H-indole-2-carboxylic acid described in
the patent application WO 03/043985, as compound 19 of Example 4,
and GI-262570.
Diseases
[0343] Described herein are methods of treating a disease in an
individual suffering from said disease comprising administering to
said individual an effective amount of a composition comprising a
compound of formula I or a pharmaceutically acceptable salt,
solvate, polymorph, ester, tautomer or prodrug thereof.
[0344] The invention also extends to the prophylaxis or treatment
of any disease or disorder in which MEK kinase plays a role
including, without limitation: oncologic, hematologic,
inflammatory, ophthalmologic, neurological, immunologic,
cardiovascular, and dermatologic diseases as well as diseases
caused by excessive or unregulated pro-inflammatory cytokine
production including for example excessive or unregulated TNF,
IL-1, IL-6 and IL-8 production in a human, or other mammal. The
invention extends to such a use and to the use of the compounds for
the manufacture of a medicament for treating such cytokine-mediated
diseases or disorders. Further, the invention extends to the
administration to a human an effective amount of a MEK inhibitor
for treating any such disease or disorder.
[0345] Diseases or disorders in which MEK kinase plays a role,
either directly or via pro-inflammatory cytokines including the
cytokines TNF, IL-1, IL-6 and IL-8, include, without limitation:
dry eye, glaucoma, autoimmune diseases, inflammatory diseases,
destructive-bone disorders, proliferative disorders,
neurodegenerative disorders, viral diseases, allergies, infectious
diseases, heart attacks, angiogenic disorders, reperfusion/ischemia
in stroke, vascular hyperplasia, organ hypoxia, cardiac
hypertrophy, thrombin-induced platelet aggregation, and conditions
associated with prostaglandin endoperoxidase synthetase-2
(COX-2).
[0346] In certain aspects of the invention, the disease is a
hyperproliferative condition of the human or animal body,
including, but not limited to cancer, hyperplasias, restenosis,
inflammation, immune disorders, cardiac hypertrophy,
atherosclerosis, pain, migraine, angiogenesis-related conditions or
disorders, proliferation induced after medical conditions,
including but not limited to surgery, angioplasty, or other
conditions.
[0347] In further embodiments, said hyperproliferative condition is
selected from the group consisting of hematologic and
nonhematologic cancers. In yet further embodiments, said
hematologic cancer is selected from the group consisting of
multiple myeloma; leukemias, and lymphomas. In yet further
embodiments, said leukemia is selected from the group consisting of
acute and chronic leukemias. In yet further embodiments, said acute
leukemia is selected from the group consisting of acute lymphocytic
leukemia (ALL) and acute nonlymphocytic leukemia (ANLL). In yet
further embodiments, said chronic leukemia is selected from the
group consisting of chronic lymphocytic leukemia (CLL) and chronic
myelogenous leukemia (CML). In further embodiments, said lymphoma
is selected from the group consisting of Hodgkin's lymphoma and
non-Hodgkin's lymphoma. In further embodiments, said hematologic
cancer is multiple myeloma. In other embodiments, said hematologic
cancer is of low, intermediate, or high grade. In other
embodiments, said nonhematologic cancer is selected from the group
consisting of: brain cancer, cancers of the head and neck, lung
cancer, breast cancer, cancers of the reproductive system, cancers
of the digestive system, pancreatic cancer, and cancers of the
urinary system. In further embodiments, said cancer of the
digestive system is a cancer of the upper digestive tract or
colorectal cancer. In further embodiments, said cancer of the
urinary system is bladder cancer or renal cell carcinoma. In
further embodiments, said cancer of the reproductive system is
prostate cancer.
[0348] Additional types of cancers which may be treated using the
compounds and methods described herein include: cancers of oral
cavity and pharynx, cancers of the respiratory system, cancers of
bones and joints, cancers of soft tissue, skin cancers, cancers of
the genital system, cancers of the eye and orbit, cancers of the
nervous system, cancers of the lymphatic system, and cancers of the
endocrine system. In certain embodiments, these cancer s may be
selected from the group consisting of: cancer of the tongue, mouth,
pharynx, or other oral cavity; esophageal cancer, stomach cancer,
or cancer of the small intestine; colon cancer or rectal, anal, or
anorectal cancer; cancer of the liver, intrahepatic bile duct,
gallbladder, pancreas, or other biliary or digestive organs;
laryngeal, bronchial, and other cancers of the respiratory organs;
heart cancer, melanoma, basal cell carcinoma, squamous cell
carcinoma, other non-epithelial skin cancer; uterine or cervical
cancer; uterine corpus cancer; ovarian, vulvar, vaginal, or other
female genital cancer; prostate, testicular, penile or other male
genital cancer; urinary bladder cancer; cancer of the kidney;
renal, pelvic, or urethral cancer or other cancer of the
genito-urinary organs; thyroid cancer or other endocrine cancer;
chronic lymphocytic leukemia; and cutaneous T-cell lymphoma, both
granulocytic and monocytic.
[0349] Yet other types of cancers which may be treated using the
compounds and methods described herein include: adenocarcinoma,
angiosarcoma, astrocytoma, acoustic neuroma, anaplastic
astrocytoma, basal cell carcinoma, blastoglioma, chondrosarcoma,
choriocarcinoma, chordoma, craniopharyngioma, cutaneous melanoma,
cystadenocarcinoma, endotheliosarcoma, embryonal carcinoma,
ependymoma, Ewing's tumor, epithelial carcinoma, fibrosarcoma,
gastric cancer, genitourinary tract cancers, glioblastoma
multiforme, hemangioblastoma, hepatocellular carcinoma, hepatoma,
Kaposi's sarcoma, large cell carcinoma, leiomyosarcoma,
liposarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma,
medullary thyroid carcinoma, medulloblastoma, meningioma
mesothelioma, myelomas, myxosarcoma neuroblastoma,
neurofibrosarcoma, oligodendroglioma, osteogenic sarcoma,
epithelial ovarian cancer, papillary carcinoma, papillary
adenocarcinomas, parathyroid tumors, pheochromocytoma, pinealoma,
plasmacytomas, retinoblastoma, rhabdomyosarcoma, sebaceous gland
carcinoma, seminoma, skin cancers, melanoma, small cell lung
carcinoma, squamous cell carcinoma, sweat gland carcinoma,
synovioma, thyroid cancer, uveal melanoma, and Wilm's tumor.
[0350] Also described are methods for the treatment of a
hyperproliferative disorder in a mammal that comprise administering
to said mammal a therapeutically effective amount of a compound of
formula I, or a pharmaceutically acceptable salt, ester, prodrug,
solvate, hydrate or derivative thereof, in combination with an
anti-tumor agent. In some embodiments, the anti-tumor agent is
selected from the group consisting of mitotic inhibitors,
alkylating agents, anti-metabolites, intercalating antibiotics,
growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors,
topoisomerase inhibitors, biological response modifiers,
anti-hormones, angiogenesis inhibitors, and anti-androgens.
[0351] The disease to be treated using the compounds, compositions
and methods described herein may be a hematologic disorder. In
certain embodiments, said hematologic disorder is selected from the
group consisting of sickle cell anemia, myelodysplastic disorders
(MDS), and myeloproliferative disorders. In further embodiments,
said myeloproliferative disorder is selected from the group
consisting of polycythemia vera, myelofibrosis and essential
thrombocythemia.
[0352] The compounds, compositions and methods described herein may
be useful as anti-inflammatory agents with the additional benefit
of having significantly less harmful side effects. The compounds,
compositions and methods described herein are useful to treat
arthritis, including but not limited to rheumatoid arthritis,
spondyloarthropathies, gouty arthritis, osteoarthritis, systemic
lupus erythematosus, juvenile arthritis, acute rheumatic arthritis,
enteropathic arthritis, neuropathic arthritis, psoriatic arthritis,
and pyogenic arthritis. The compounds, compositions and methods
described herein are also useful in treating osteoporosis and other
related bone disorders. These compounds, compositions and methods
described herein can also be used to treat gastrointestinal
conditions such as reflux esophagitis, diarrhea, inflammatory bowel
disease, Crohn's disease, gastritis, irritable bowel syndrome and
ulcerative colitis. The compounds, compositions and methods
described herein may also be used in the treatment of pulmonary
inflammation, such as that associated with viral infections and
cystic fibrosis. In addition, the compounds, compositions and
methods described herein are also useful in organ transplant
patients either alone or in combination with conventional
immunomodulators. Yet further, the compounds, compositions and
methods described herein are useful in the treatment of pruritis
and vitaligo. In particular, compounds, compositions and methods
described herein are useful in treating the particular inflammatory
disease rheumatoid arthritis.
[0353] Further inflammatory diseases which may be prevented or
treated include, without limitation: asthma, allergies, respiratory
distress syndrome or acute or chronic pancreatitis. Furthermore,
respiratory system diseases may be prevented or treated including
but not limited to chronic obstructive pulmonary disease, and
pulmonary fibrosis. In addition, MEK kinase inhibitors described
herein are also associated with prostaglandin endoperoxidase
synthetase-2 (COX-2) production. Pro-inflammatory mediators of the
cyclooxygenase pathway derived from arachidonic acid, such as
prostaglandins, are produced by inducible COX-2 enzyme. Regulation
of COX-2 would regulate these pro-inflammatory mediators, which
affect a wide variety of cells and are important and critical
inflammatory mediators of a wide variety of disease states and
conditions. In particular, these inflammatory mediators have been
implicated in pain, such as in the sensitization of pain receptors,
and edema. Accordingly, additional MEK kinase-mediated conditions
which may be prevented or treated include edema, analgesia, fever
and pain such as neuromuscular pain, headache, dental pain,
arthritis pain and pain caused by cancer.
[0354] Further, the disease to be treated by the compounds,
compositions and methods described herein may be an ophthalmologic
disorder. Ophthalmologic diseases and other diseases in which
angiogenesis plays a role in pathogenesis, may be treated or
prevented and include, without limitation, dry eye (including
Sjogren's syndrome), macular degeneration, closed and wide angle
glaucoma, retinal ganglion degeneration, occular ischemia,
retinitis, retinopathies, uveitis, ocular photophobia, and of
inflammation and pain associated with acute injury to the eye
tissue. The compounds, compositions and methods described herein
can be used to treat glaucomatous retinopathy and/or diabetic
retinopathy. The compounds, compositions and methods described
herein can also be used to treat post-operative inflammation or
pain as from ophthalmic surgery such as cataract surgery and
refractive surgery. In further embodiments, said ophthalmologic
disorder is selected from the group consisting of dry eye, closed
angle glaucoma and wide angle glaucoma.
[0355] Further, the disease to be treated by the compounds,
compositions and methods described herein may be an autoimmune
disease. Autoimmune diseases which may be prevented or treated
include, but are not limited to: rheumatoid arthritis, inflammatory
bowel disease, inflammatory pain, ulcerative colitis, Crohn's
disease, periodontal disease, temporomandibular joint disease,
multiple sclerosis, diabetes, glomerulonephritis, systemic lupus
erythematosus, scleroderma, chronic thyroiditis, Grave's disease,
hemolytic anemia, autoimmune gastritis, autoimmune neutropenia,
thrombocytopenia, chronic active hepatitis, myasthenia gravis,
atopic dermatitis, graft vs. host disease, and psoriasis.
Inflammatory diseases which may be prevented or treated include,
but are not limited to: asthma, allergies, respiratory distress
syndrome or acute or chronic pancreatitis. In particular,
compounds, compositions and methods described herein are useful in
treating the particular autoimmune diseases rheumatoid arthritis
and multiple sclerosis.
[0356] Further, the disease to be treated by the compounds,
compositions and methods described herein may be a dermatologic
disorder. In certain embodiments, said dermatologic disorder is
selected from the group including, without limitation, melanoma,
base1 cell carcinoma, squamous cell carcinoma, and other
non-epithelial skin cancer as well as psoriasis and persistent
itch, and other diseases related to skin and skin structure, may be
treated or prevented with MEK kinase inhibitors of this
invention.
[0357] Metabolic diseases which may be treated or prevented
include, without limitation, metabolic syndrome, insulin
resistance, and Type 1 and Type 2 diabetes. In addition, the
compositions described herein can be used to treat insulin
resistance and other metabolic disorders such as atherosclerosis
that are typically associated with an exaggerated inflammatory
signaling.
[0358] The compounds, compositions and methods described herein are
also useful in treating tissue damage in such diseases as vascular
diseases, migraine headaches, periarteritis nodosa, thyroiditis,
aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever,
type I diabetes, neuromuscular junction disease including
myasthenia gravis, white matter disease including multiple
sclerosis, sarcoidosis, nephritis, nephrotic syndrome, Behcet's
syndrome, polymyositis, gingivitis, periodontis, hypersensitivity,
swelling occurring after injury, ischemias including myocardial
ischemia, cardiovascular ischemia, and ischemia secondary to
cardiac arrest, and the like. The compounds, compositions and
methods described herein can also be used to treat allergic
rhinitis, respiratory distress syndrome, endotoxin shock syndrome,
and atherosclerosis.
[0359] Further, the disease to be treated by the compounds,
compositions and methods described herein may be a cardiovascular
condition. In certain embodiments, said cardiovascular condition is
selected from the group consisting of atherosclerosis, cardiac
hypertrophy, idiopathic cardiomyopathies, heart failure,
angiogenesis-related conditions or disorders, and proliferation
induced after medical conditions, including, but not limited to
restenosis resulting from surgery and angioplasty.
[0360] Further, the disease to be treated by the compounds,
compositions and methods described herein may be a neurological
disorder. In certain embodiments, said neurologic disorder is
selected from the group consisting of Parkinson's disease,
Alzheimer's disease, Alzheimer's dementia, and central nervous
system damage resulting from stroke, ischemia and trauma. In other
embodiments, said neurological disorder is selected from the group
consisting of epilepsy, neuropathic pain, depression and bipolar
disorders.
[0361] Further, the disease to be treated by the compounds,
compositions and methods described herein may cancer such as acute
myeloid leukemia, thymus, brain, lung, squamous cell, skin, eye,
retinoblastoma, intraocular melanoma, oral cavity and
oropharyngeal, bladder, gastric, stomach, pancreatic, bladder,
breast, cervical, head, neck, renal, kidney, liver, ovarian,
prostate, colorectal, esophageal, testicular, gynecological,
thyroid, CNS, PNS, AIDS related AIDS-Related (e.g. Lymphoma and
Kaposi's Sarcoma) or Viral-Induced cancer. In some embodiments, the
compounds and compositions are for the treatment of a non-cancerous
hyperproliferative disorder such as benign hyperplasia of the skin
(e. g., psoriasis), restenosis, or prostate (e. g., benign
prostatic hypertrophy (BPH)).
[0362] Further, the disease to be treated by the compounds,
compositions and methods described herein may pancreatitis, kidney
disease (including proliferative glomerulonephritis and
diabetes-induced renal disease), pain, a disease related to
vasculogenesis or angiogenesis, tumor angiogenesis, chronic
inflammatory disease such as rheumatoid arthritis, inflammatory
bowel disease, atherosclerosis, skin diseases such as psoriasis,
eczema, and scleroderma, diabetes, diabetic retinopathy,
retinopathy of prematurity, age-related macular degeneration,
hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast,
lung, pancreatic, prostate, colon and epidermoid cancer in a
mammal.
[0363] Further, the disease to be treated by the compounds,
compositions and methods described herein may the prevention of
blastocyte implantation in a mammal.
[0364] Patients that can be treated with the compounds described
herein, or a pharmaceutically acceptable salt, ester, prodrug,
solvate, hydrate or derivative of said compounds, according to the
methods of this invention include, for example, patients that have
been diagnosed as having psoriasis; restenosis; atherosclerosis;
BPH; breast cancer such as a ductal carcinoma in duct tissue in a
mammary gland, medullary carcinomas, colloid carcinomas, tubular
carcinomas, and inflammatory breast cancer; ovarian cancer,
including epithelial ovarian tumors such as adenocarcinoma in the
ovary and an adenocarcinoma that has migrated from the ovary into
the abdominal cavity; uterine cancer; cervical cancer such as
adenocarcinoma in the cervix epithelial including squamous cell
carcinoma and adenocarcinomas; prostate cancer, such as a prostate
cancer selected from the following: an adenocarcinoma or an
adenocarinoma that has migrated to the bone; pancreatic cancer such
as epitheliod carcinoma in the pancreatic duct tissue and an
adenocarcinoma in a pancreatic duct; bladder cancer such as a
transitional cell carcinoma in urinary bladder, urothelial
carcinomas (transitional cell carcinomas), tumors in the urothelial
cells that line the bladder, squamous cell carcinomas,
adenocarcinomas, and small cell cancers; leukemia such as acute
myeloid leukemia (AML), acute lymphocytic leukemia, chronic
lymphocytic leukemia, chronic myeloid leukemia, hairy cell
leukemia, myelodysplasia, and myeloproliferative disorders; bone
cancer; lung cancer such as non-small cell lung cancer (NSCLC),
which is divided into squamous cell carcinomas, adenocarcinomas,
and large cell undifferentiated carcinomas, and small cell lung
cancer; skin cancer such as basal cell carcinoma, melanoma,
squamous cell carcinoma and actinic keratosis, which is a skin
condition that sometimes develops into squamous cell carcinoma; eye
retinoblastoma; cutaneous or intraocular (eye) melanoma; primary
liver cancer (cancer that begins in the liver); kidney cancer;
thyroid cancer such as papillary, follicular, medullary and
anaplastic; AIDS-related lymphoma such as diffuse large B-cell
lymphoma, B-cell immunoblastic lymphoma and small non-cleaved cell
lymphoma; Kaposi's Sarcoma; viral-induced cancers including
hepatitis B virus (HBV), hepatitis C virus (HCV), and
hepatocellular carcinoma; human lymphotropic virus-type 1 (HTLV-1)
and adult T-cell leukemia/lymphoma; and human papilloma virus (HPV)
and cervical cancer; central nervous system cancers (CNS) such as
primary brain tumor, which includes gliomas (astrocytoma,
anaplastic astrocytoma, or glioblastoma multiforme),
Oligodendroglioma, Ependymoma, Meningioma, Lymphoma, Schwannoma,
and Medulloblastoma; peripheral nervous system (PNS) cancers such
as acoustic neuromas and malignant peripheral nerve sheath tumor
(MPNST) including neurofibromas and schwannomas, malignant fibrous
cytoma, malignant fibrous histiocytoma, malignant meningioma,
malignant mesothelioma, and malignant mixed Mullerian tumor; oral
cavity and oropharyngeal cancer such as, hypopharyngeal cancer,
laryngeal cancer, nasopharyngeal cancer, and oropharyngeal cancer;
stomach cancer such as lymphomas, gastric stromal tumors, and
carcinoid tumors; testicular cancer such as germ cell tumors
(GCTs), which include seminomas and nonseminomas, and gonadal
stromal tumors, which include Leydig cell tumors and Sertoli cell
tumors; thymus cancer such as to thymomas, thymic carcinomas,
Hodgkin disease, non-Hodgkin lymphomas carcinoids or carcinoid
tumors; rectal cancer; and colon cancer.
Kits
[0365] The compounds, compositions and methods described herein
provide kits for the treatment of disorders, such as the ones
described herein. These kits comprise a compound, compounds or
compositions described herein in a container and, optionally,
instructions teaching the use of the kit according to the various
methods and approaches described herein. Such kits may also include
information, such as scientific literature references, package
insert materials, clinical trial results, and/or summaries of these
and the like, which indicate or establish the activities and/or
advantages of the composition, and/or which describe dosing,
administration, side effects, drug interactions, or other
information useful to the health care provider. Such information
may be based on the results of various studies, for example,
studies using experimental animals involving in vivo models and
studies based on human clinical trials. Kits described herein can
be provided, marketed and/or promoted to health providers,
including physicians, nurses, pharmacists, formulary officials, and
the like. Kits may also, in some embodiments, be marketed directly
to the consumer.
[0366] The compounds described herein can be utilized for
diagnostics and as research reagents. For example, the compounds
described herein, either alone or in combination with other
compounds, can be used as tools in differential and/or
combinatorial analyses to elucidate expression patterns of genes
expressed within cells and tissues. As one non-limiting example,
expression patterns within cells or tissues treated with one or
more compounds are compared to control cells or tissues not treated
with compounds and the patterns produced are analyzed for
differential levels of gene expression as they pertain, for
example, to disease association, signaling pathway, cellular
localization, expression level, size, structure or function of the
genes examined. These analyses can be performed on stimulated or
unstimulated cells and in the presence or absence of other
compounds which affect expression patterns.
[0367] Besides being useful for human treatment, the compounds and
formulations of the present invention are also useful for
veterinary treatment of companion animals, exotic animals and farm
animals, including mammals, rodents, and the like. More preferred
animals include horses, dogs, and cats.
[0368] The examples and preparations provided below further
illustrate and exemplify the compounds of the present invention and
methods of preparing such compounds. It is to be understood that
the scope of the present invention is not limited in any way by the
scope of the following examples and preparations. In the following
examples molecules with a single chiral center, unless otherwise
noted, exist as a racemic mixture. Those molecules with two or more
chiral centers, unless otherwise noted, exist as a racemic mixture
of diastereomers. Single enantiomers/diastereomers may be obtained
by methods known to those skilled in the art.
EXAMPLES
[0369] General Procedures for the Synthesis of Sulfonamides
Procedure A
[0370] To a solution of the amine (1 eq) in anhydrous
dichloromethane (3 mL/mmole) was added anhydrous triethylamine (5
eq). To this solution was added the sulfonyl chloride (1 eq) and
the solution was stirred at room temperature for 16 h. The solvent
was evaporated and the residue was purified by flash column
chromatography on silica.
Procedure B
[0371] To a stirred solution of the amine (1 eq) in anhydrous
pyridine (5 mL/mmole) was added the sulfonyl chloride (1-5 eq). The
reaction mixture was stirred at 40.degree. C. for 48 hours. The
reaction mixture was partitioned with water and EtOAc. The organic
layer was washed with brine, dried (MGSO.sub.4) and concentrated
under reduced pressure. The residue was purified by flash column
chromatography on silica.
Procedure C: Substitution of the Iodo-Atom
[0372] A suspension containing 1 eq. aryl iodide, 1.5 equiv. of the
boronic acid or boronic ester, 0.25 eq. PdCl.sub.2(dppf).times.DCM
and 10 eq. anhydrous K.sub.2CO.sub.3 powder in a deoxygenated
mixture of dioxane and water (3:1) was heated in a microwave
reactor for 60 min at 115.degree. C. It was extracted using aq.
NH.sub.4Cl/THF, and the organic fraction was dried using
Na.sub.2SO.sub.4. The crude reaction products were purified using
flash-column chromatography (Si, EtOAc/Hexanes, or
CHCl.sub.3/MeOH). Yields: 20-40%.
Procedure D: Synthesis of
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-2-(alkylamino)ethan-
esulfonamide
[0373] 2-Chloro-ethanesulfonyl chloride (0.1 ml, 1 mmol) was added
to a solution of
5,6-difluoro-N.sup.1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine
(0.364 g, 1 mmol) and triethylamine (0.28 ml, 2 mmol) in
CH.sub.2Cl.sub.2 (5 ml) and the reaction mixture was stirred at
room temperature for 16 h. Then it's treated with an excess amine
(10 eq) either in solution or as a neat liquid. The reaction
mixture stirred at room temperature for additional 6 h. The
reaction mixture diluted with CH.sub.2Cl.sub.2 (10 ml) and water
(10 ml). The organic layer was sequentially washed with dil. HCl
(2.times.20 ml, 2N) and saturated NaHCO.sub.3 (2.times.10 ml)
solution. Then the CH.sub.2Cl.sub.2 layer dried (MgSO.sub.4) and
evaporated to obtain the crude product. The impure product was
purified under preparative HPLC conditions to obtain the pure
products in 50-60% yield.
Example 1
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)methanesulfonamide
Step A: 2,3-Difluoro-N-(2-fluoro-4-iodophenyl)-6-nitroaniline
##STR00212##
[0375] To a solution of 2-fluoro-4-iodoaniline (11.40 g, 47 mmol)
in 100 ml anhydrous THF at 0.degree. C., 47 ml of a 1M solution of
LHMDS in THF (47 mmol) was added dropwise. The color of the
solution turned dark purple. The solution was transferred via
cannula to a dropping funnel, and the solution (containing the
amine free base) was added in small portions to a solution of
2,3,4-trifluoronitrobenzene (8.321 g, 47.0 mmol) in anhydrous THF
(50 ml) at 0.degree. C. After completion of addition the mixture
was stirred under argon at room temperature for 15 hours. The
volume of the solvent was reduced, followed by extraction using
ethyl acetate and brine. The organic layer was dried over sodium
sulfate, the solvent was removed, and the obtained dark oil was
purified by flash chromatography (EtOAc/hexane 1:5, R.sub.f=0.58)
yielding the crude product, which became a brown solid upon drying
in vacuo (yield: 6.23 g, 33.6%): m/z=393 [M-1].sup.-.
Step B:
5,6-Difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine
##STR00213##
[0377] To a solution of nitro-diarylamine (6.23 g, 15.8 mmol) in
300 ml ethanol was added iron powder (13.74 g, 246 mmol) and
ammonium chloride (13.59 g, 254 mmol) and the mixture was heated
with stirring at 100.degree. C. oil bath temperature for 14 hours.
It was filtered and the residue washed two times with ethanol. The
ethanol was removed in vacuo, and the residue was extracted using
ethyl acetate/1M NaOH solution. During the extraction, more
precipitate was formed which was filtered and discarded. The
combined organic layers were washed with brine and dried over
sodium sulfate. The solvent was removed, and the crude product was
recrystallized from CHCl.sub.3/hexane (1:50). The product was
obtained as brown needles (2.094 g, 66%,), R.sub.f=0.44 (EtOAc/Hex
1:3), 1H-NMR (500 MHz, CDCl.sub.3), .delta.=7.40-7.38 (dd, 1H,
J=11.3 Hz, J=1.5 Hz), 7.25-7.23 (d, 1H, J=8.5 Hz), 6.97-6.92 (q,
1H, J=9 Hz), 6.51-6.48 (m, 1H), 6.24-6.21 (t, 1H, J=9 Hz), 5.3 (s,
1H, NH, br), 3.80 (s, 2H, NH.sub.2, br), LRMS (ESI): m/z=365
[M+H].sup.-.
Step C:
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)methanesulfon-
amide
##STR00214##
[0379] According to the general procedure A,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was
reacted with methanesulfonyl chloride to obtain the desired
product. .sup.1H NMR: (500 MHz, CDCl.sub.3): .delta.=7.38-7.37 (d,
1H), 7.35-7.34 (m, 1H), 7.27-7.26 (m, 1H), 7.20-7.0 (q, 1H), 6.68
(s, 1H, br), 6.15-6.12 (q, 1H), 5.65 (s, 1H, br), 2.95 (s, 3H);
m/z=441 [M-1].sup.-.
Example 2
2
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)cyclopropanesulfona-
mide
##STR00215##
[0381] According to the general procedure A,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was
reacted with cyclopropanesulfonyl chloride to obtain the desired
product. .sup.1H NMR: (500 MHz, CDCl.sub.3): .delta.=7.38-7.37 (d,
1H), 7.35-7.34 (m, 1H), 121-1 Id (m, 1H), 7.20-7.0 (q, 1H), 6.68
(s, 1H, br), 6.15-6.12 (q, 1H), 5.65 (s, 1H, br), 3.25-3.20 (m,
1H), 2.4-2.3 (m, 2H), 2.0-1.8 (m, 2H); m/z=467 [M-1].sup.-.
Example 3
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)propane-2-sulfonamide
##STR00216##
[0383] According to the general procedure A,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was
reacted with isopropylsulfonyl chloride to obtain the desired
product. Yield: 39%. .sup.1H-NMR (500 MHz, CDCl.sub.3):
.delta.=7.50-7.43 (m, 1H), 7.35-7.34 (m, 1H), 7.27-7.26 (m, 1H),
7.15-7.09 (q, 1H, J=1.6 Hz), 6.62 (s, 1H, br), 6.22-6.18 (q, 1H,
J=1.5 Hz), 5.65 (s, 1H, br), 3.30-3.28 (m, 1H), 1.38-1.37 (d, 6H,
J=1.2 Hz); m/z=469 [M-1].sup.-.
Example 4
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)butane-1-sulfonamide
##STR00217##
[0385] According to the general procedure A,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was
reacted with n-butylsulfonyl chloride to obtain the desired
product. Yield: 55%. .sup.1H-NMR (500 MHz, CDCl.sub.3):
.delta.=7.50-7.43 (m, 1H), 7.35-7.34 (m, 1H), 7.27-7.26 (m, 1H),
7.15-7.09 (q, 1H, J=1.6 Hz), 6.62 (s, 1H, br), 6.22-6.18 (q, 1H,
J=1.5 Hz).sub.5 5.65 (s, 1H, br), 3.06-3.031 (t, 2H, J=1.4 Hz),
1.75-1.71 (m, 2H), 1.38-1.36 (m, 2H), 0.87-0.86 (t, 3H, J=1.3 Hz);
m/z=483 [M-1].sup.-.
Example 5
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-2,2,2-trifluoro
ethane sulfonamide
##STR00218##
[0387] According to the general procedure A,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was
reacted with 1,1,1-trifluoroethylsulfonyl chloride to obtain the
desired product. Yield: 28%. m/z=509 [M-1].sup.-.
Example 6
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)butane-2-sulfonaniide
##STR00219##
[0389] According to the general procedure A,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was
reacted with sec-butylsulfonyl chloride to obtain the desired
product. Yield: 22%. .sup.1H-NMR (500 MHz, MeOH[d4]):
.delta.=7.60-7.40 (m, 3H), 7.18-7.00 (q, 1H), 6.55-6.45 (m, 1H),
3.55-3.50 (nm, 1H), 2.20-2.00 (m, 1H), 1.80-1.60 (m, 1H), 1.43-1.40
(d, 3H), 1.06-1.04 (t, 3H); m/z=483 [M-1].sup.-.
Example 7
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-N-methyl
cyclopropane sulfonamide
##STR00220##
[0391] To a solution of
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)cyclopropane-sulfona-
mide (see Example 2) (283.9 mg, 0.61 mmol) in 3 ml anhydrous THF
was added at -78.degree. C. a IM solution of LHMDS (0.6 ml, 0.6
mol) and the solution was stirred for 10 min at this temperature.
Then, methyl iodide (0.8 ml, 1.824 g, 12.9 mmol) was added and the
mixture was warmed to room temperature and stirred for 7 h. The
solvent was removed and the residue extracted using EtOAc and
brine. The organic fractions were dried using Na.sub.2SO.sub.4 and
the solvent was removed. The obtained crude product was purified
using flash-column chromatography (Si, EtOAc/Hexanes 1:2,
R.sub.f=0.45). Yield: 205 mg, 70%). .sup.1H-NMR (500 MHz,
CDCl.sub.3): .delta.=7.41-7.39 (d, 1H, J=10 Hz), 7.30-7.29 (d, 1H,
J=8.0 Hz), 7.23-7.20 (m, 1H), 6.98-6.93 (q, 1H, J=8.5 Hz), 6.60 (s,
1H, br), 6.51-6.47 (m, 1H), 3.23 (s, 3H), 2.46-2.42 (m, 1H),
1.19-1.16 (m, 2H), 1.04-1.02 (m, 2H); m/z=481 [M-1].sup.-.
Example 8
1-Chloro-N-(3,4-difluoro-2-(2-fluoro-2-(2-fluoro-4-iodophenylamino)phenyl)
methane sulfonamide
##STR00221##
[0393] According to the general procedure A,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was
reacted with chloromethanesulfonyl chloride to obtain the desired
product, m/z=475 [M-1].sup.-.
Example 9
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-2-methylpropane-2-su-
lfonamide
##STR00222##
[0395] According to the general procedure B,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was
reacted with 2-methylpropane-2-sulfonyl chloride (synthesized
according to the literature procedure) to obtain the desired
product. .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.50 (m, 1H),
7.43 (dd, J=1.8 & 10.5 Hz, 1H), 7.28 (br s, 1H), 7.10 (dd,
J=9.0 & 17.7 Hz, 1H), 6.48 (br s, D.sub.2O exchangeable, 1H),
6.19 (t, J=7.8 & 9.6 Hz, 1H), 5.58 (br s, D.sub.2O
exchangeable, 1H), 1.39 (s, 9H); m/z=383 [M-1].sup.-.
Example 10
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)cyclopentanesulfonami-
de
##STR00223##
[0397] According to the general procedure B,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was
reacted with cyclopentanesulfonyl chloride to obtain the desired
product .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.42 (dd, J=2.1
& 10.5 Hz, 1H), 7.36 (ddd, J=2.4, 4.8, & 9.3 Hz, 1H), 7.25
(m, 2H), 7.10 (dd, J=9.6 & 17.7 Hz, 1H), 6.67 (br s, D.sub.2O
exchangeable, 1H), 6.20 (dt, J=1.5, 8.4 & 17.4 Hz, 1H), 3.53
(p, 1H), 1.80 (m, 8H); m/z=495 [M-1].sup.-.
Example 11
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)cyclohexanesulfonamid-
e
##STR00224##
[0399] According to the general procedure B,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was
reacted with cyclohexanesulfonyl chloride to obtain the desired
product. .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.43 (dd, J=1.5
& 10.2 Hz, 1H), 7.37 (ddd, J-=2.4, 4.8 & 9.6 Hz, 1H), 7.27
(m, 1H), 7.11 (dd, J=9.3 & 18.0 Hz, 1H), 6.64 (br s, 1H), 6.18
(dt, J=1.5, 9.0 & 17.4 Hz, 1H), 5.63 (br s, 1H), 2.95 (triplet
of triplet, 2.10-1.16 (m, 10H); m/z=509 [M-1].sup.-.
Example 12
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-1-methylcyclopropane-
-1-sulfonamide
Step A: n-Butyl 3-chloro-1-propanesulfonate
##STR00225##
[0401] Triethylamine (28 ml, 200 mmol) in CH.sub.2Cl.sub.2 (50 ml)
was slowly added to an ice-cooled solution of
3-chloro-1-propanesulfonyl chloride (36.6 g, 200 mmol) and
1-butanol (18.4 g, 240 in mol) in CH.sub.2Cl.sub.2 (250 ml) and
stirring was continued for 16 h. The mixture was diluted with
CH.sub.2Cl.sub.2 (200 ml), washed (aqueous HCl) and dried
(MgSO.sub.4) and the solvent was evaporated to obtain the titled
product 1 (40.85 g, 95%) in crude form as slightly yellow oil which
was used for the next reaction without further purification.
.sup.1H NMR (CDCl.sub.3) .delta. 0.94 (t, J=7.5 Hz, 3H), 1.44
(sextet, 2H), 1.72 (quintet, 2H), 2.31 (quintet, 2H), 3.27 (t,
J=6.9 Hz, 2H), 3.68 (t, J=6.3 Hz), 4.23 (t, J=6.6 Hz, 2H).
Step B: 1-Butyl cyclopropanesulfonate
##STR00226##
[0403] Solutions of 1-butyl 3-chloro-1-propanesulfonate (4.6 g,
21.39 mmol in 25 ml THF) and of butyllithium (14.7 ml, 23.53 mmol,
1.6M, THF) were simultaneously added to THF (150 ml) at -78.degree.
C. under nitrogen atmosphere. The solution was allowed to warm to
0.degree. C. and then quenched with water (2 ml). The volatiles
evaporated under reduced pressure and the residue extracted with
CH.sub.2Cl.sub.2 (150 ml). The extract was washed with water and
dried (MgSO.sub.4) and evaporated to give crude desired product
(3.23 g, 78.22%) in almost pure form as pale yellow oil which was
used for next step without further purification. .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 0.94 (t, J=7.5 Hz, 3H), 1.07 (m, 2H), 1.25
(m, 2H), 1.45 (sextet, 2H), 1.74 (quintet, 2H), 2.45 (heptet, 1H),
4.23 (t, J=6.6 Hz, 2H).
Step C: Butyl-Methyl-cyclopropanesulfonate
##STR00227##
[0405] To a solution of 1-Butyl cyclopropanesulfonate (1 g, 5.58
mmol) in THF (15 ml) butyllithium solution (3.84 ml, 6.14 mmol,
1.6M, THF) was slowly added at -78.degree. C. under nitrogen
atmosphere. After 15 minutes MeI (0.72 ml, 11.16 mmol) was added
and the solution was allowed to warm to 0.degree. C. and quenched
with water (1 ml). The volatiles evaporated under reduced pressure
and the residue extracted with CH.sub.2Cl.sub.2 (100 ml). The
extract was washed with water, dried (MgSO.sub.4) and evaporated.
The residue was purified over silica gel chromatography (eluants:
hexane/CH.sub.2Cl.sub.2) to obtain the titled product (0.59 g,
55.0%) as a colorless oil. .sup.1H NMR (300 MHz, CDCl.sub.3)) &
0.84 (m, 2H), 0.95 (t, J=7.2 Hz, 3H), 1.43 (m, 4H), 1.53 (s, 3H),
1.74 (m, 2H), 4.21 ((t, J=6.6 Hz, 2H).
Step D: 1-Potassium 1-Methyl-cyclopropanesulfonate
##STR00228##
[0407] A mixture of 1-Butyl 1-Methyl-cyclopropanesulfonate (0.386
g, 2 mmol) and potassium thiocyanate (0.194 g, 2 mmol) in DME (5
ml) and water (5 ml) was refluxed for 16 h. The volatiles were
evaporated to obtain the crude sulfonate (0.348 g, quantitative)
which was dried under vacuum at 50.degree. C. for 16 h. The crude
product was used in the next reaction without further purification.
.sup.1H NMR (300 MHz, D.sub.2O) .delta. 0.56 (t, J=6.3 Hz, 2H),
0.96 (t, J=6.3 Hz, 2H), 1.26 (s, 3H).
Step E: 1-Methyl-cyclopropanesulfonylchloride
##STR00229##
[0409] A solution of 1-potassium 1-methyl-cyclopropanesulfonate
(0.348 g, 2 mmol), thionyl chloride (5 ml) and DMF (5 drops) was
refluxed at 60.degree. C. for 16 h. The volatiles evaporated under
reduced pressure and the residue extracted with CH.sub.2Cl.sub.2
(50 ml). The extract was washed with water, dried (MgSO.sub.4) and
evaporated to obtain the crude product as yellow gummy oil which
was used in the next reaction without further purification.
Step F:
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-1-methylcycl-
opropane-1-sulfonamide
##STR00230##
[0411] According to the general procedure B,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was
reacted with 1-methyl-cyclopropanesulfonylchloride to obtain the
desired product. .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.42
(dd, J=1.8 & 10.5 Hz, 1H), 7.36 (ddd, J=2.4, 4.5 & 9.0 Hz,
1H), 7.27 (d, J=6.0 Hz, 1H), 7.07 (dd, J=9.3 & 17.7 Hz, 1H),
6.24 (dt, J=2.1, 8.7 & 17.4 Hz, 1H), 5.86 (br s, 1H), 1.43 (s,
3H), 1.33 (t, J=5.4 Hz, 2H), 0.75 (dd, J=5.1 & 6.3 Hz, 2$H);
m/z=481 [M-1].sup.-.
Example 13
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-1-(2,3-dihydroxyprop-
yl) cyclopropane-1-sulfonamide
Step A: Butyl cyclopropanesulfonate
##STR00231##
[0413] Cyclopropanesulfonyl chloride (5 g, 35 mmol, 1 eq) was
dissolved in an excess BuOH (20 ml), the reaction mixture was
cooled at -10.degree. C. and pyridine (5.8 mL, 70 mmol, 2 eq) was
slowly added dropwise. The mixture was slowly warmed at room
temperature and stirred overnight. The solvent was removed under
reduced pressure and the resulting white solid was dissolved in
CHCl.sub.3. The organic phase was washed with water, brine and
dried (MgSO.sub.4) and concentrated to give an oil (4.8 g, 24.9
mmol, 71%). .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 4.25 (t,
2H), 2.46 (m, 1H), 1.74 (m, 2H), 1.45 (m, 2H), 1.25 (dd, 2H), 1.09
(dd, 2H), 0.93 (t, 3H).
Step B: Butyl 1-allylcyclopropane-1-sulfonate
##STR00232##
[0415] To a solution of 1-butyl cyclopropanesulfonate (4.8 g, 24.9
mmol) in THF at -78.degree. C. was added simultaneously
butyllithium solution (15.6 ml, 24.9 mmol, 1.6M, THF) and allyl
iodide (24.9 mmol) under nitrogen atmosphere. The reaction mixture
was stirred 2 hours at -78.degree. C. and 3 hours at room
temperature. The volatiles were evaporated under reduced pressure
and the residue extracted with CH.sub.2Cl.sub.2 (100 ml). The
extract was washed with water, dried (MgSO.sub.4) and evaporated.
The residue was purified over silica gel chromatography (eluants:
hexane/CH.sub.2Cl.sub.2) to obtain the titled product (3.75 g,
69.0%) as a colorless oil, .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta. 5.6 (m, 1H), 5.13-5.08 (t, 2H), 4.21 (t, 2H), 2.65 (d, 2H),
1.7 (m, 2H), 1.4 (m, 4H), 0.93 (m, 5H).
Step C: Potassium 1-allylcyclopropane-1-sulfonate
##STR00233##
[0417] A mixture of 1-butyl 1-methyl-cyclopropanesulfonate (3.75 g,
17.2 mmol) and potassium thiocyanate (1.7 g, 17.2 mmol) in DME (20
ml) and water (20 ml) was refluxed for 16 h. The volatiles were
evaporated to obtain the crude sulfonate (3.44 g, quantitative)
which was dried under vacuum at 50.degree. C. for 16 h. The crude
product was used in the next reaction without further purification.
.sup.1H NMR (CDCl.sub.3): .delta. 5.6 (m, 1H), 4.91-4.85 (dd, 2H),
2.471-2.397 (d, 2H), 0.756 (m, 2H), 0.322 (m, 2H).
Step D: 1-allylcyclopropane-1-sulfonyl chloride
##STR00234##
[0419] A solution of potassium 1-allylcyclopropane-1-sulfonate
(3.44 g, 17.2 mmol), thionyl chloride (10 ml) and DMF (5 drops) was
refluxed at 60.degree. C. for 16 h. The volatiles evaporated under
reduced pressure and the residue extracted with CH.sub.2Cl.sub.2
(50 ml). The extract was washed with water, dried (MgSO.sub.4) and
evaporated to obtain the crude product as yellow gummy oil which
was washed with hexane and used in the next reaction without
further purification (2.7 g, 15 mmol, 87%). .sup.1HNMR (300 MHz,
CDCl.sub.3): .delta. 5.728 (m, 1H), 5.191 (t, 2H), 2.9 (d, 2H),
0.756 (m, 2H), 0.322 (m, 2H).
Step E:
1-allyl-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)cyclo-
propane-1-sulfonamide
##STR00235##
[0421] According to the general procedure B,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was
reacted with 1-allylcyclopropane-1-sulfonyl chloride to obtain the
desired product. m/z=507 [M-1].sup.-.
Step F:
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-1-(2,3-dihyd-
roxypropyl)cyclopropane-1-sulfonamide
##STR00236##
[0423]
1-Allyl-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)cyclop-
ropane-1-sulfonamide (0.77 g, 1.52 mmol) and 4-methylmorpholine
N-oxide (0.18 g, 1.52 mmol) were dissolved in THF (50 mL). Osmium
tetroxide was added at room temperature (0.152 mmol, 0.965 mL, 4%
in H.sub.2O) and the reaction mixture was stirred at room
temperature for 16 hours. EtOAc was added, the organic phase was
washed with water, dried (MgSO.sub.4) and concentrated under
reduced pressure. The residue was purified over silica gel
chromatography (eluants: EtOAc/MeOH) to obtain the titled product
(0.65 g, 79%). .sup.1H NMR (300 MHz, CDCl.sub.3+D.sub.2O): .delta.
7.38 (dd, J=1.8 & 10.5 Hz, 1H), 7.36 (ddd, J=2.4, 5.1 & 9.3
Hz, 1H), 7.25 (d, J=8.7 Hz, 1H), 7.02 (dd, J=9.0 & 17.7 Hz,
1H), 6.27 (dt, J=3.0, 8.7 & 17.4 Hz, 1H), 3.92 (m, 1H), 3.54
(dd, J=3.9 & 11.1 Hz, 1H), 3.39 (dd, J=6.6 & 11.1 Hz, 1H),
2.16 (dd, J=9.6 & 15.9 Hz, 1H), 1.59 (d, J=14.1 Hz, 1H), 1.41
(m, 1H), 1.26 (m, 1H), 0.83 (m, 2H); m/z=542 [M-1].sup.-.
Example 14
(S)--N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-1-(2,3-dihydrox-
ypropyl)cyclopropane-1-sulfonamide
##STR00237##
[0425] The pure S isomer was obtained by chiral HPLC separation of
the racemic mixture (example 13). .sup.1H NMR (300 MHz,
CDCl.sub.3+D.sub.2O): .delta. 7.38 (dd, J=1.8 & 10.5 Hz, 1H),
7.36 (ddd, J=2.4, 5.1 & 9.3 Hz, 1H), 7.25 (d, J=8.7 Hz, 1H),
7.02 (dd, J=9.0 & 17.7 Hz, 1H), 6.27 (dt, J=3.0, 8.7 & 17.4
Hz, 1H), 3.92 (m, 1H), 3.54 (dd, J=3.9 & 11.1 Hz, 1H), 3.39
(dd, J=6.6 & 11.1 Hz, 1H), 2.16 (dd, J=9.6 & 15.9 Hz, 1H),
1.59 (d, J=14.1 Hz, 1H), 1.41 (m, 1H), 1.26 (m, 1H), 0.83 (m, 2H);
m/z=542 [M-1].sup.-.
Example 15
(R)--N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-1-(2,3-dihydrox-
ypropyl)cyclopropane-1-sulfonamide
##STR00238##
[0427] The pure R isomer was obtained by chiral HPLC separation of
the racemic mixture (example 13). .sup.1H NMR (300 MHz,
CDCl.sub.3+D.sub.2O): .delta. 7.38 (dd, J=1.8 & 10.5 Hz, 1H),
7.36 (ddd, J=2.4, 5.1 & 9.3 Hz, 1H), 7.25 (d, J=8.7 Hz, 1H),
7.02 (dd, J=9.0 & 17.7 Hz, 1H), 6.27 (dt, J=3.0, 8.7 & 17.4
Hz, 1H), 3.92 (m, 1H), 3.54 (dd, J=3.9 & 11.1 Hz, 1H), 3.39
(dd, J=6.6 & 11.1 Hz, 1H), 2.16 (dd, J=9.6 & 15.9 Hz, 1H),
1.59 (d, J=14.1 Hz, 1H), 1.41 (m, 1H), 1.26 (m, 1H), 0.83 (m, 2H);
m/z=542 [M-1].sup.-.
Example 16
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-1-(2-hydroxyethyl)cy-
clopropane-1-sulfonamide
Step A: 2-d-bromocyclopropyl)ethanol
##STR00239##
[0429] To a solution of neat diethyl zinc (3.3 ml, 3.977 g, 30
mmol) in 100 ml anhydrous DCM was added very slowly trifluoroacetic
acid (2.31 ml, 3.4188 g, 30 mmol) dropwise at 0.degree. C.
(Caution: Violent gas evolution, exothermic!). After completed
addition of the TFA, the suspension was stirred for 20 min at the
same temperature, followed by the addition of diiodo methane (2.45
ml, 8.134 g, 30.4 mmol). It was further stirred at 0.degree. C. for
20 min, and then a solution of 3-bromobut-3-en-1-ol (1 ml, 1.523 g,
10.1 mmol) in 10 ml DCM was added at the same temperature. After
complete addition, the mixture was warmed to room temperature and
stirred for 4 hours. The mixture was quenched with 100 ml MeOH and
40 ml brine, and it was further stirred for 30 min. The solvents
were reduced, and the residue extracted using CHCl.sub.3/aq.
NH.sub.4Cl. The organic layers were collected, washed with brine
and water, and the solvent was removed to give
2-(1-bromocyclopropyl)-ethanol in sufficient purity (1.6564 g,
100%). .sup.1H-NMR (500 MHz, CDCl.sub.3): 3=3.90-3.83 (t, 2H),
1.91-1.87 (t, 2H), 1.71 (s, 1H, br), 1.14-1.09 (m, 2H), 0.83-0.79
(m, 2H).
Step B: TBS protected 2-(1-bromocyclopropyl)ethanol
##STR00240##
[0431] To a solution of the cyclopropyl alcohol (Step A) (1.303 g,
7.95 mmol) in 30 ml anhydrous DCM was added anhydrous pyridine (1.2
ml, 1,1736 g, 14.8 mmol) and TBSOTf (2.7 ml, 3.1077 g, 11.76 mol)
and the solution was stirred at room temperature for 16 h. It was
extracted with CHCl.sub.3/brine and the organic fraction was dried
with MgSO.sub.4. The solvent was reduced and the crude product
purified using flash-column chromatography (Si, CHCl.sub.3/hexanes
1:10, R.sub.f=0.4). Yield 0.796 g, 36%. .sup.1H-NMR (500 MHz,
CDCl.sub.3): .delta.=3.95-3.75 (t, 2H), 1.95-1.85 (t, 2H),
1.15-1.05 (m, 2H), 0.95-0.80 (m, HH), 0.15-0.05 (s, 6H).
Step C: TBS protected 2-(1-chlorosulfonylcyclopropyl)ethanol
##STR00241##
[0433] To a solution of the cyclopropyl bromide prepared in step B
(1.1227 g, 4.04 mmol) in 15 ml anhydrous diethyl ether was added a
1.7 M solution of t-BuLi in pentane (4.8 ml, 8.16 mmol) at
-78.degree. C. The solution was stirred for 30 min at this
temperature, and was then transferred via a transfer canola into a
solution of freshly distilled sulfuryl chloride (0.65 ml, 1.029 g,
8.1 mmol) in 8 ml diethyl ether at -78.degree. C. The yellow
suspension was warmed to room temperature. The solvent was removed,
and the residue was dried in vacuo to remove excessive sulfuryl
chloride. Then, the residue was extracted two times with hexane,
and after filtration the solvent was evaporated in vacuo to give
the sulfonyl chloride in sufficient purity as a colorless oil.
Yield: 870 mg (72%). .sup.1H-NMR (300 MHz, CDCl.sub.3):
.delta.=3.95-3.85 (t, 2H), 2.35-2.25 (t, 2H), 1.80-1.70 (m, 211),
1.45-1.38 (m, 2H), 0.90 (s, 9H), 0.10 (s, 6H).
Step D: TBS-protected
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-1-(2-hydroxyethyl)c-
yclopropane-1-sulfonamide
##STR00242##
[0435] According to the general procedure B,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was
reacted with the cyclpropylsulfonyl chloride prepared in step C to
obtain the desired product. .sup.1H-NMR (300 MHz, CDCl.sub.3):
.delta.=7.44-7.39 (dd, 1H), 7.32-7.24 (m, 2H), 7.1-6.98 (q, 1H),
6.34-6.24 (m, 1H), 6.16 (s, 1H, br), 3.85-3.75 (t, 2H), 2.15-2.00
(t, 2H), 1.35-1.20 (m, 2H), 0.95-0.75 (m, 1H), 0.10 (s, 6H);
m/z=625 [M-1].sup.-.
Step E:
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-1-(2-hydroxy-
ethyl)cyclopropane-1-sulfonamide
##STR00243##
[0437] To a solution of the TBS-protected sulfonamide prepared in
step D (21 mg, 0.033 mmol) in 1 ml THF was added 0.1 ml aq. 0.2N
HCl solution at 0.degree. C. and the solution was stirred for 2 h.
The solvents were reduced and the residue was extracted using aq.
NaHCO.sub.3 solution and EtOAc. The organic fractions were dried
with MgSO.sub.4 and the volatiles were removed. The crude product
was purified using flash-column chromatography (Si, CHCl.sub.3/MeOH
10:1, R.sub.f=0.45) to give the pure product. Yield: 16.9 mg
(100%). .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=7.44-7.39 (dd,
1H), 7.32-7.24 (m, 2H), 7.1-6.98 (q, 1H), 6.34-6.24 (m, 1H), 6.16
(s, 1H, br), 3.85-3.75 (t, 2H), 2.15-2.00 (t, 2H), 1.35-1.20 (m,
2H), 0.95-0.85 (m, 2H); m/z=511 [M-1].sup.-.
Example 17
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-3-hydroxypropane-1-s-
ulfonamide
##STR00244##
[0439] To a solution of
3-chloro-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-propane-1--
sulfonamide (69.4 mg, 0.138 mmol) in a mixture of 8 ml 1,4-dioxane
and 2 ml H.sub.2O was added KOH powder (0.674 g, 12.0 mmol) and the
mixture was heated to the reflux temperature for 3 days. It was
extracted using EtOAc/brine, the organic fraction was dried with
Na.sub.2SO.sub.4 and the volatiles were removed. The residue was
purified using flash-column chromatography (Si, DCM/MeOH 5:1,
R.sub.f=0.3). Yield: 41 mg (62%). .sup.1H-NMR (500 MHz, MeOH [d4]):
.delta.=7.38-7.21 (d, 1H), 7.23-7.21 (d, 1H), 7.06-7.00 (q, 1H),
6.52-6.50 (m, 1H), 6.17-6.13 (t, 1H), 3.30-3.27 (t, 2H), 2.86-2.83
(t, 2H), 2.05-2.00 (m, 2H); m/z=485 [M-1].sup.-.
Example 18
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-2-methyl-5-(trifluor-
omethyl)furan-3-sulfonamide
##STR00245##
[0441] According to the general procedure B,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine (0.182
mmol) was reacted with 2-methyl-5-(trifluoromethyl)furan-3-sulfonyl
chloride (0.5 mmol) to form
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-2-methyl-5-(trifluo-
romethyl)furan-3-sulfonamide. .sup.1H NMR (CDCl.sub.3) .delta. 2.2
(s, 3H), 5.3 (s, 1H), 6.0 (dt, 1H), 6.8 (s, 1H), 6.95 (s, 1H),
7.0-7.3 (m, 3H), 7.4 (dd, 1H).
Example 19
N-(5-(N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)sulfamoyl)-meth-
ylthiazol-2-yl)acetamide
##STR00246##
[0443] According to the general procedure B,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine (0.182
mmol) was reacted with 2-acetamido-4-methylthiazole-5-sulfonyl
chloride (0.5 mmol) to obtain
N-(5-(N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)sulfamoyl)-4-m-
ethylthiazol-2-yl)acetamide. .sup.1H NMR (CDCl.sub.3)) .delta. 2.1
(s, 3H), 2.2 (s, 3H), 5.9 (dt, 1H), 6.05 (s, 1H), 7.0-7.6 (m, 3H),
7.4 (dd, 1H), 8.0 (s, 1H).
Example 20
5-(5-Chloro-1,2,4-thiadiazol-3-yl)-N-(3,4-difluoro-2-(2-fluoro-4-iodopheny-
lamino)phenyl)thiophene-2-sulfonamide
##STR00247##
[0445] According to the general procedure B,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine (0.182
mmol) was reacted with
5-(5-chloro-1,2,4-thiadiazol-3-yl)thiophene-2-sulfonyl chloride
(0.5 mmol) to obtain
5-(5-chloro-1,2,4-thiadiazol-3-yl)-N-(3,4-difluoro-2-(2-fluoro-4-iodophen-
ylamino)phenyl)thiophene-2-sulfonamide. .sup.1H NMR (300 MHz,
CDCl.sub.3)) .delta. 5.8 (dt, 1H), 5.95 (s, 1H), 6.95 (d, 1H), 7.4
(m, 2H), 7.6 (d, 1H), 7.8 (s, 1H).
Example 21
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-3,5-dimethylisoxazol-
e-4-sulfonamide
##STR00248##
[0447] According to the general procedure B,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamine (0.182
mmol) was reacted with 3,5-dimethylisoxazole-4-sulfonyl chloride
(0.5 mmol) to obtain N-(3,4-difluoro-2-(2-fluoro-4-iodophenyl
amino)phenyl)-3,5-dimethylisoxazole-4-sulfonamide. .sup.1H NMR (300
MHz, CDCl.sub.3)) .delta. 2.2 (s, 3H), 2.4 (s, 3H), 5.8 (s, 1H),
6.0 (dt, 1H), 5.95 (s, 1H), 6.9 (s, 1H), 7.0 (q, 1H), 7.2 (m, 31H),
7.4 (dd, 1H).
Example 22
5-Chloro-N-(3,4-difluoro-2-(2-fluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-
-1,3-dimethyl-1H-pyrazole-4-sulfonamide
##STR00249##
[0449] According to the general procedure B,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine (0.182
mmol) was reacted with 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl
chloride (0.5 mmol) to obtain
5-chloro-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)
phenyl)-1,3-dimethyl-1H-pyrazole-4-sulfonamide. .sup.1H NMR (300
MHz, CDCl.sub.3)) .delta. 2.1 (s, 3H), 3.6 (s, 3H), 5.8 (s, 1H),
5.95 (dt, 1H), 7.0 (q, 1H), 7.2 (d, 1H), 7.3 (m, 2H), 7.4 (dd,
1H).
Example 23
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-2,5-dimethylfuran-3--
sulfonamide
##STR00250##
[0451] According to the general procedure B,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamine (0.182
mmol) was reacted with 2,5-dimethylfuran-3-sulfonyl chloride (0.5
mmol) to obtain N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)
phenyl)-2,5-dimethylfuran-3-sulfonamide. .sup.1H NMR (300 MHz,
CDCl.sub.3)) .delta. 2.2 (s, 3H), 2.3 (s, 3H), 5.8 (s, 1H), 6.0
(dt, 1H), 6.8 (s, 1H), 7.0 (q, 1H), 7.2 (d, 1H), 7.3 (m, 21), 7.4
(dd, 1H).
Example 24
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-1-methyl-3-(trifluor-
omethyl)-1H-pyrazole-4-sulfonamide
##STR00251##
[0453] According to the general procedure B,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamine (0.182
mmol) was reacted with
1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-sulfonyl chloride (0.5
mmol) to obtain
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-1-methyl-3-(triflur-
omethyl)-H-pyrazole-4-sulfonamide. .sup.1H NMR (300 MHz,
CDCl.sub.3)) 3.8 (s, 3H), 5.7 (s, 1H), 6.0 (dt, 1H), 7.0 (q, 1H),
7.2 (m, 2H), 7.4 (dd, 1H), 7.8 (s, 1H).
Example 25
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-2,4-dimethylthiazole-
-5-sulfonamide
##STR00252##
[0455] According to the general procedure B,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamine (0.182
mmol) was reacted with 2,4-dimethylthiazole-5-sulfonyl chloride
(0.5 mmol) to obtain
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-2,4-dimethyl-
thiazole-5-sulfonamide. .sup.1H NMR (300 MHz, CDCl.sub.3)) .delta.
2.3 (s, 3H), 2.6 (s, 3H), 5.7 (s, 1H), 5.9 (dt, 1H), 7.1 (q, 1H),
7.2 (d, 1H), 7.3 (m, 1H), 7.4 (d, 1H), 7.4 (s, 1H).
Example 26
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-1,2-dimethyl-H-imida-
zole-4-sulfonamide
##STR00253##
[0457] According to the general procedure B,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was
reacted with 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride to
obtain the title compound. .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta. 7.95 (br s, 1H), 7.37 (dd, J=1.8 & 10.8 Hz, 1H),
7.32-7.14 (m, 3H), 6.98 (dd, J=9.6 & 17.7 Hz, 1H), 5.87 (dt,
J=4.2, 9.0 & 17.4 Hz, 1H), 5.55 (br s, 1H), 3.49 (s, 3H), 2.31
(s, 3H).
Example 27
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)thiophene-3-sulfonami-
de
##STR00254##
[0459] According to the general procedure B,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was
reacted with thiophene-3-sulfonyl chloride to obtain the title
compound. .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 8.00 (dd,
J=1.2 & 3.3 Hz, 1H), 7.45 (dd, J=0.9 & 5.1 Hz, 1H), 7.35
(m, 2H), 7.27 (m, 2H), 6.91 (dd, J=9.3 & 17.1 Hz, 1H), 6.64
(ddd, J=2.1, 4.8 & 8.7 Hz, 1H), 6.34 (dt, J=5.4, 8.7 & 14.1
Hz, 1H), 5.98 (br d, J=2.1 Hz, D.sub.2O exchangeable, 1H).
Example 28
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)furan-2-sulfonamide
##STR00255##
[0461] According to the general procedure B,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was
reacted with furan-2-sulfonyl chloride to obtain the title
compound. .sup.1H NMR (300 MHz, CDCl.sub.3): t 7.53 (br s, D.sub.2O
exchangeable, 1H), 7.38 (dd, J=1.8 & 10.5 Hz, 1H), 7.30 (d,
J=8.4 Hz, 1H), 7.21 (d, J=3.0 Hz, 1H), 6.96 (dd, J=8.7 & 16.5
Hz, 1H), 6.87 (ddd, J=1.8, 5.1 & 9.0 Hz, 1H), 6.53 (dd, J=1.8
& 3.6 Hz, 1H), 6.44 (dt, J=5.1, 8.7 & 13.8 Hz, 1H), 6.22
(br s, D.sub.2O exchangeable, 1H).
Example 29
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-5-methylthiophene-2--
sulfonamide
##STR00256##
[0463] According to the general procedure B,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was
reacted with 5-methylthiophene-2-sulfonyl chloride to obtain the
title compound. .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.34
(dd, J=0.9 & 10.2 Hz, 1H), 7.30 (ddd, J=2.1, 4.8 & 9.0 Hz,
1H), 7.25 (d, J=3.9 Hz, 1), 7.07 (m, 2H), 6.65 (dd, J=1.2 & 3.9
Hz, 1H), 5.89 (dt, J=2.4, 8.7 & 17.4 Hz, 1H), 5.54 (br s,
D.sub.2O exchangeable, 1H), 2.46 (s, 3H).
Example 30
5-Chloro-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)thiophene-2--
sulfonamide
##STR00257##
[0465] According to the general procedure B,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene1,2-diamine was
reacted with 5-chlorothiophene-2-sulfonyl chloride to obtain the
title compound. .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.38
(dd, J=1.5 & 10.2 Hz, 1H), 7.32 (ddd, J=2.1, 5.1 & 9.3 Hz,
1H), 7.25 (d, J=3.9 Hz, 1H), 7.10 (dd, J=9.0 & 18.6 Hz, 3H),
6.84 (d, J=4.2 Hz, 1H), 5.86 (dt, J=1.8, 8.7 & 17.4 Hz, 1H),
5.49 (br s, D.sub.2O exchangeable, 1H).
Example 31
5-Bromo-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)thiophene-2-s-
ulfonamide
##STR00258##
[0467] According to the general procedure B,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene1,2-diamine was
reacted with 5-bromothiophene-2-sulfonyl chloride to obtain the
title compound. .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.
7.39-7.29 (m, 2H), 7.20-7.05 (m, 3H), 6.96 (d, J=3.6 Hz, 1H), 5.85
(dt, J=2.1, 9.0 & 17.4 Hz, 1H), 5.54 (br s, 1H).
Example 32
4-Bromo-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)thiophene-3-s-
ulfonamide
##STR00259##
[0469] According to the general procedure B,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene1,2-diamine was
reacted with 4-bromothiophene-3-sulfonyl chloride to obtain the
title compound. .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.48 (br
m, 2H), 7.39 (dd, J=1.8 & 10.5 Hz, 1H), 7.28 (ddd, J=2.4, 4.8
& 9.0 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 7.02 (m, 1H), 6.02 (dt,
J=2.4, 8.7 & 17.4 Hz, 1H), 5.68 (br s, 1H).
Example 33
4-Bromo-5-chloro-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)thio-
phene-2-sulfonamide
##STR00260##
[0471] According to the general procedure B,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene1,2-diamine was
reacted with 4-bromo-5-chlorothiophene-2-sulfonyl chloride to
obtain the title compound. .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta. 7.42-7.34 (m, 2H), 7.25 (br m, 3H), 7.13 (dd, J=9.0 &
17.1 Hz, 1H), 6.02 (dt, J=2.4, 6.6 & 17.4 Hz, 1H), 5.52 (br s,
1H).
Example 34
3-Bromo-5-chloro-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamine)
phenyl)thiophene-2-sulfonamide
##STR00261##
[0473] According to the general procedure B,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene1,2-diamine was
reacted with 3-bromo-5-chlorothiophene-2-sulfonyl chloride to
obtain the title compound. .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta. 7.41 (dd, J=2.1 & 10.5 Hz, 1H), 7.35 (br m, 2H), 7.31
(dd, J=2.1 & 4.2 Hz, 1H), 7.19 (d, J=8.7 Hz, 1H), 7.08 (dd,
J=9.0 & 17.4 Hz, 1H), 6.02 (dt, J=2.1, 8.4 & 17.1 Hz, 1H),
5.59 (br s, 1H).
Example 35
N-(3,4-fluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-2,5-dimethylthiophene--
3-sulfonamide
##STR00262##
[0475] According to the general procedure B,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene1,2-diamine was
reacted with 2,5-dimethylthiophene-3-sulfonyl chloride to obtain
the title compound. .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.39
(dd, J=1.8 & 10.2 Hz, 1H), 7.24-7.16 (br m, 2H), 7.13 (dd J=9.0
& 17.4 Hz, 1H), 6.77 (d, J=9.6 Hz, 1H), 5.98 (dt, J=2.4, 8.7
& 17.4 Hz, 1H), 5.55 (br s, 1H), 2.33 (s, 6H).
Example 36
2,5-Dichloro-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)thiophen-
e-3-sulfonamide
##STR00263##
[0477] According to the general procedure B,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene1,2-diamine was
reacted with 2,5-dichlorothiophene-3-sulfonyl chloride to obtain
the title compound. .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.41
(dd, J=1.5 & 10.5 Hz, 1H), 7.28-7.20 (m, 2H), 7.08 (dd, J=9.0
& 17.4 Hz, 21), 6.99 (s, 1H), 6.03 (dt, J=2.1, 8.7 & 17.4
Hz, 1H), 5.56 (br s, 1H).
Example 37
Methyl 3-(N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)
sulfamoyl)thiophene-2-carboxylate
##STR00264##
[0479] According to the general procedure B,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl) benzene 1,2-diamine was
reacted with methyl 3-(chlorosulfonyl)thiophene-2-carboxylate to
obtain the title compound. .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta. 8.58 (s, 1H), 7.43 (dd, J=5.1 & 10.8 Hz, 2H), 7.35 (dd,
J=1.8 & 10.2 Hz, 1H), 7.31 (ddd, J=2.1, 4.2 & 9.3 Hz, 1H),
7.04 (m, 2H), 5.88 (dt, J=2.7, 8.7 & 17.4 Hz, 1H), 5.65 (br s,
1H), 3.85 (s, 3H).
Example 38
Methyl
5-(N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)sulfamoyl)--
1-methyl-1H-pyrrole-2-carboxylate
##STR00265##
[0481] According to the general procedure B,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene1,2-diamine was
reacted with methyl
5-(chlorosulfonyl)-1-methyl-1H-pyrrole-2-carboxylate to obtain the
title compound. .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.37
(dd, J=1.8 & 10.5 Hz, 1H), 7.29 (m, 2H), 7.12-6.94 (m, 4H),
5.87 (dt, J=1.8, 8.4 & 17.4 Hz, 1H), 5.56 (br s, 1H), 3.65 (s,
3H), 3.75 (s, 3H).
Example 39
##STR00266##
[0483] According to the general procedure A,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene1,2-diamine was
reacted with the corresponding sulfonyl chloride to obtain the
title compound. Yield: 22%. m/z=508 [M-1].sup.-.
Example 40
3-Chloro-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)propane-1-su-
lfonamide
##STR00267##
[0485] According to the general procedure A,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was
reacted with 3-chloropropane-1-sulfonyl chloride to obtain the
desired product. .sup.1H NMR (500 MHz, CDCl.sub.3):
.delta.=7.39-7.38 (d, 1H), 7.35-7.34 (m, 1H), 7.27-7.26 (m, 1H),
7.10-7.0 (q, 1H), 6.63 (s, 1H, br), 6.15-6.11 (q, 1H), 5.60 (s, 1H,
br), 3.60-3.56 (t, 2H), 3.22-3.20 (m, 2H), 2.22-2.16 (m, 2H).
Example 41
N-(2-(4-chloro-2-fluorophenylamino)-3,4-difluorophenyl)
cyclopropanesulfonamide
##STR00268##
[0487] See example 1. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
0.85-0.95 (m, 2H), 1.05-1.15 (m, 2H), 2.2-2.4 (m, 1H), 5.8 (s, 1H),
6.3 (t, 1H), 6.6-7.4 (m, 511); m/z=375 [M-1].sup.-.
Example 42
N-(3,4-difluoro-2-(4-iodo-2-methylphenylamino)phenyl)cyclopropanesulfonami-
de
##STR00269##
[0489] See example 1. .sup.1H NMR (CDCl.sub.3) .delta. 0.80-1.0 (m,
2H), 1.05-1.20 (m, 2H), 1.55 (s, 3H), 2.4-2.5 (m, 1H), 5.6 (s, 1H),
6.2 (dd, 1H), 6.4 (s, 1H), 7.1 (q, 1H), 7.3-7.4 (m, 2H), 7.5 (s,
1H); m/z=463 [M-1].sup.-.
Example 43
N-(2-(4-tert-butyl-2-chlorophenylamino)-3,4-difluorophenyl)
cyclopropanesulfonamide
##STR00270##
[0491] See example 1. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
0.9-1.0 (m, 2H), 1.05-1.20 (m, 2H), 1.3 (s, 9H), 2.4-2.5 (m, 1H),
5.8 (s, 1H), 6.3 (dd, 1H), 6.6 (s, 1H), 7.0-7.2 (m, 2H), 7.3-7.4
(m, 2H); m/z=413 [M-1].sup.-.
Example 44
N-(2-(2,4-dichlorophenylamino)-3,4-difluorophenyl)cyclopropanesulfonamide
##STR00271##
[0493] See example 1. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
0.9-1.0 (m, 2H), 1.05-1.20 (m, 2H), 2.4-2.5 (m, 1H), 6.0 (s, 1H),
6.3 (dd, 1H), 6.6 (s, 1H), 7.0-72 (m, 2H), 7.3-7.4 (m, 2H); m/z=392
[M-1].sup.-.
Example 45
3-Chloro-N-(3,4-difluoro-2-(2-fluoro-4-trifluormethyl)
phenylamino)phenyl)propane-1-sulfonamide
##STR00272##
[0495] See example 1. .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.
7.39-7.26 (m, 2H), 7.25 (m, 1H), 7.18 (dd, J=9.0 & 17.7 Hz,
1H), 6.78 (br s, D.sub.2O exchangeable, 1H), 6.50 (t, J=8.1 Hz,
1H), 6.00 (br d, D.sub.2O exchangeable, J=1.5 Hz, 1H), 3.63 (t,
J=6.0 & 6.3 Hz, 2H), 3.29 (t, J=7.2 & 7.8 Hz, 2H), 2.26
(quintet, 2H); m/z=445 [M-1].sup.-.
Example 46
N-(3,4-difluoro-2-(2-chloro-4-trifluoromethyl)phenylamino)methanesulfonami-
de
##STR00273##
[0497] See example 1. .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.
7.65 (d, J=7.8 Hz, 1H), 7.33 (m, 2H), 7.19 (dd, J=9.3 & 17.4
Hz, 1H), 6.90 (br s, D.sub.2O exchangeable, 1H), 6.45 (dd, J=1.5
& 8.4 Hz, 1H), 6.39 (br s, D.sub.2O exchangeable, 1H), 3.02 (s,
3H); m/z=399 [M-1].sup.-.
Example 47
3-Chloro-N-(3,4-difluoro-2-(2-chloro-4-trifluoromethyl)
phenylamino)phenyl)propane-1-sulfonamide
##STR00274##
[0499] See example 1. .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.
7.66 (d, J=1.5 Hz, 1H), 7.36 (m, 2H), 7.19 (dd, J=9.0 & 17.4
Hz, 1H), 6.91 (br s, D.sub.2O exchangeable, 1H), 6.50 (dd, J=8.4
& 1.5 Hz, 1H), 6.37 (s, D.sub.2O exchangeable, 1H), 3.62 (t,
J=6.0 Hz, 2H), 3.29 (t, J=7.5 & 7.8 Hz, 2H), 2.27 (quintet,
2H); m/z=462 [M-1].sup.-.
Example 48
3-Chloro-N-(3,4-difluoro-2-(2-bromo-4-trifluoromethyl)
phenylamino)phenyl)propane-1-sulfonamide
##STR00275##
[0501] See example 1. .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.
7.82 (s, 1H), 7.38 (m, 2H), 7.20 (dd, J=9.0 & 17.7 Hz, 1H),
6.62 (br s, D.sub.2O exchangeable, 1H), 6.43 (d, J=8.4 Hz, 1H),
6.23 (s, D.sub.2O exchangeable, 1H), 3.65 (t, J=6.0 Hz, 2H), 3.30
(t, J=7.5 Hz, 21), 2.28 (quintet, 2H); m/z=506 [M-1].sup.-.
Example 49
Cyclopropanesulfonic acid
(3,4,6-trifluoro-2-(2-fluoro-4-iodo-phenylamino)-phenyl)-amide
Step A:
(2-Fluoro-4-iodo-phenyl)-(2,3,5-trifluoro-6-nitro-phenyl)-amine
##STR00276##
[0503] A stirred solution of 2-fluoro-4-iodoaniline (3.64 gm, 15.37
mmol) in dry THF (100 ml) under nitrogen was cooled to -78.degree.
C. and a solution of 1.0 M lithium hexa methyl disilazide
(LiN(SiMe.sub.3).sub.2) "LHMDS" (15.37 ml, 15.37 mmol) was added
slowly. This reaction mixture was kept stirring at -78.degree. C.
for another hour and then 2,3,4,6-tetrafluoronitrobenzene was
added. The reaction mixture was allowed to warm to room temperature
and stirring continued for another 16 hours. Ethyl acetate (200 ml)
was added to the reaction mixture and was washed with water.
Organic layer was dried over sodium sulfate and further purified by
column chromatography to provide yellow solid (3.75 gm, yield:
59.24%). M-H.sup.+: 410.9. .sup.1H NMR (DMSO, 300 MHz): 6.85 (t,
1H); 7.38 (d, 1H); 7.62 (m, 2H); 8.78 (s, 1H).
Step B:
3,4,6-Trifluoro-N.sup.2-(2-Fluoro-4-iodo-phenyl)-benzene-1,2-diami-
ne
##STR00277##
[0505] To the stirred solution of
(2-fluoro-4-iodo-phenyl)-(2,3,5-trifluoro-6-nitro-phenyl)-amine 3
(5.2 gm, 12.62 mmol) in EtOH (200 ml), ammonium chloride (10.12 gm,
189.3 mmol) and iron powder (10.57 gm, 189.3 mmol) was added. This
reaction mixture was kept stirring at reflux for 16 hours. Reaction
mixture was allowed to cool and was filtered over celite and
concentrated to dryness. The residue obtained was taken into EtOAc
and was washed with water. The EtOAc layer was dried over sodium
sulfate and further purified by crystallization from EtOH to
provide off-white solid (3.2 gm, yield 66.39%). M-H.sup.+: 381.1.
.sup.1H NMR (DMSO, 300 MHz): 5.0 (s, 2H); 6.2 (t, 1H); 7.2-7.3 (m,
2H); 7.45 (s, 1H); 7.5 (d, 1H).
Step C:
4,6,7-Trifluoro-1-(2-Fluoro-4-iodo-phenyl)-1,3-dihydrobenzoimidazo-
le-2-one
##STR00278##
[0507] To the stirred solution of
3,4,6-trifluoro-N2-(2-Fluoro-4-iodo-phenyl)-benzene-1,2-diamine 3
(0.285 gm, 0.74 mmol) in CH.sub.2Cl.sub.2 (2 ml),
1,1'-carbonyldiimidazole (0.125 gm, 0.75 mmol) was added. This
reaction mixture was kept stirring at room temperature for 16 hours
when product precipitated out. The white solid was filtered and
used further without any purification. (0.2 gm, yield: 65.85%):
m/z=407 [M-1].sup.-.
Step DIE: Cyclopropanesulfonic acid
(3,4,6-trifluoro-2-(2-fluoro-4-iodo-phenylamino)-phenyl)-amide
##STR00279##
[0509] A stirred solution of
4,6,7-trifluoro-1-(2-fluoro-4-iodo-phenyl)-1,3,-dihydrobenzimidazol-2-one
(0.2 gm, 0.41 mmol) in dry THF (4 ml) under nitrogen was cooled to
-78.degree. C. and a solution of 1.0 M LiHMDS (0.41 ml, 0.41 mmol)
was added slowly. (2 ml) followed by addition of
cyclopropanesulfonyl chloride (0.050 ml, 0.49 mmol). This reaction
mixture was kept stirring at room temperature for 16 hours,
concentrated to dryness and was taken into EtOAc. The EtOAc was
washed with water, dried over sodium sulfate and concentrated to
dryness. The residue obtained
1-cyclopropanesulfonyl-4,5,7-trifluoro-3-(2-fluoro-4-iodo-phenyl)-1,3-dih-
ydro-benzimidazol-2-one 5 was taken into dioxane (2 ml) and to this
1.0 N NaOH (0.5 ml) was added and kept stirring at room 50.degree.
C. for 16 hours. TLC indicated incomplete reaction, the product was
purified by HPLC to provide off-white solid (4.4 mg) M+H.sup.+:
484.7, M-H.sup.+: 486.7. .sup.1H NMR (CDCl.sub.3, 300 MHZ): 0.9-1.1
(m, 2H); 1.1-1.2 (m, 2H); 2.45-2.55 (m, 1H); 6.05 (s, 1H);
6.44-6.54 (m, 1H); 7.1 (s, 1H); 7.4-7.7 (d, 1H); 7.38- 7.44 (dd,
1H); m/z=485 [M-1].sup.-.
Example 50
N-(3,4-difluoro-2-(4-fluoro-2-iodophenylamino)-6-ethoxyphenyl)
cyclopropane sulfonamide
Step A:
(2J-Difluoro-5-methoxy-6-nitro-phenyl)-(2-fluoro-4-iodo-phenyl)-am-
ine
##STR00280##
[0511] A stirred solution of
(2-fluoro-4-iodo-phenyl)-(2,3,5-trifluoro-6-nitro-phenyl)amine
(1.23 gm, 3 mmol) in dry THF (25 ml) under nitrogen was cooled to
-78.degree. C. and a solution of 25% NaOMe (0.68 ml, 0.3 mmol) was
added slowly. Reaction mixture was allowed to warm to room
temperature and stirring continued for another 16 hours. TLC
indicated incomplete reaction. Ethyl acetate (100 ml) was added to
the reaction mixture and was washed with water. Organic layer was
dried over sodium sulfate and further purified by column
chromatography to provide yellow solid (0.6 gm, yield: 47.6%).
m/z=424 [M=H].sup.+.
Step B:
5,6-Difluoro-N1-(4-fluoro-2-iodophenyl)-3-methoxybenzene-1,2-diami-
ne
##STR00281##
[0513] To the stirred solution of
(2,3-difluoro-5-methoxy-6-nitro-phenyl)-(2-fluoro-4-iodo-phenyl)-amine
(0.57 gm, 1.34 mmol) in EtOH (20 ml), ammonium chloride (1.18 gm,
20.16 mmol) and iron powder (1.15 gm, 21.44 mmol) was added. This
reaction mixture was kept stirring at reflux for 16 hours. Reaction
mixture was allowed to cool and was filtered over celite and
concentrated to dryness. The residue obtained was taken into EtOAc
and was washed with water. The EtOAc layer was dried over sodium
sulfate and further purified by crystallization from EtOH to
provide off-white solid (0.47 gm, yield: 90.3%). M-H.sup.+: 393.2.
.sup.1H NMR (DMSO, 300 MHz): 3.76 (s, 3H); 6.1 (t, 1H); 6.8-7.0 (m,
1H); 7.2 (d, 1H); 7.35 (s, 1H); 7.42 (d, 1H).
Step C:
6,7-Difluoro-1-(4-fluoro-2-iodophenyl)-4-methoxy-1H-benzo[d]imidaz-
ol-2(3H)-one
##STR00282##
[0515] To the stirred solution of
5,6-difluoro-N1-(4-fluoro-2-iodophenyl)-3-methoxybenzene-1,2-diamine
(0.17 gm, 0.43 mmol) in CH.sub.2Cl.sub.2 (2 ml),
1,1'-Carbonyldiimidazole (0.085 gm, 0.53 mmol) was added. This
reaction mixture was kept stirring at room temperature for 16 hours
when product precipitated out. The white solid was filtered and
used further without any purification. (0.089 gm); m/z=419
[M-1].sup.-.
Step D/F:
N-(3,4-difluoro-2-(4-fluoro-2-iodophenylamino)-6-methoxyphenyl)c-
yclopropanesulfonamide
##STR00283##
[0517] A stirred solution of
1-(cyclopropylsulfonyl)-4,5-difluoro-3-(2-fluoro-4-iodophenyl)-7-methoxy--
1H-benzo[d]imidazol-2(3H)-one (0.89 gm, 0.17 mmol) in dry THF (4
ml) under nitrogen was cooled to -78.degree. C. and a solution of
1.0 M LiHMDS (0.17 ml, 0.17 mmol) was added slowly. (2 ml) followed
by addition of cyclopropanesulfonyl chloride (0.021 ml, 0.21 mmol).
This reaction mixture was kept stirring at room temperature for 16
hours, concentrated to dryness and was taken into EtOAc. The EtOAc
was washed with water, dried over sodium sulfate and concentrated
to dryness. The resulting
1-(cyclopropylsulfonyl)-4,5-difluoro-3-(2-fluoro-4-iodophenyl)-7-methoxy--
1-benzo[d]imidazol-2(3H)-one was taken into dioxane (2 ml) and to
this 1.0 N NaOH (0.5 ml) was added and kept stirring at room
50.degree. C. for 16 hours. TLC indicated incomplete reaction, the
product was purified by HPLC to provide off-white solid (2.5 mg)
M+H: 484.7, M-H.sup.+: 497.3. .sup.1H NMR (CDCl.sub.3, 300 MHz):
0.85-0.95 (m, 2H); 1.05-1.15 (m, 2H); 2.4-2.5 (m, 1H); 3.9 (s, 3H);
6.1 (s, 1H); 6.4-6.6 (m, 2H); 7.3 (m, 1H); 7.35-7.4 (dd, 1H);
m/z=497 [M-1].sup.-.
Example 51
Methylsulfonic acid
(3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-6-methoxy-phenyl)-amide
##STR00284##
[0519] A stirred solution of
5,6-difluoro-N-(4-fluoro-2-iodophenyl)-3-methoxybenzene-1,2-diamine
(0.150 gm, 0.38 mmol) in dry CH.sub.2Cl.sub.2 (4 ml), TEA (0.264
ml, 1.9 mmol) and methanesulfonyl chloride was added slowly. This
reaction mixture was kept stirring at room temperature for 16
hours, TLC indicated incomplete reaction along with starting
material two products were observed. The reaction mixture was
washed with water, organic layer was dried over sodium sulfate and
concentrated to dryness, the product was purified by column
chromatography. The minor product was found to be the expected
compound (6.4 mg). M-H.sup.+: 471.5. .sup.1H NMR (CDCl.sub.3, 300
MHz): 3.9 (s, 3H); 6.05 (s, 1H); 6.4-6.5 (m, 1H); 6.5-6.6 (m, 1H);
7.2 (s, 1H); 7.28 (d, 1H); 7.35-7.4 (d, 1H); m/z=471
[M-1].sup.-.
Example 52
1-(2,3-Dihydroxy-propyl)-cyclopropanesulfonic acid
[3,4,6-trifluoro-2-(4-fluoro-2-iodo-phenylamino)-phenyl]-amide
Step A: 1-Allyl-cyclopropanesulfonic acid
[3,4,6-trifluoro-2-(2-fluoro-4-iodophenylamino)phenyl]-amide
##STR00285##
[0521] According to the general procedure B,
1-allyl-cyclopropanesulfonyl chloride was reacted with
3,5,6-trifluoro-N-(2-fluoro-4-iodophenyl)benzene-1,2-diamine to
obtain the title product. .sup.1H NMR (CDCl.sub.3, 300 MHz):
.delta. 7.41 (dd, 1H), 7.38 (dd, 1H), 7.09 (s, 1H), 6.78 (m, 1H),
6.49 (m, 1H), 5.96 (s, 1H), 5.86 (m, 1H), 5.18 (d, 2H), 2.76 (d,
2H), 1.23 (m, 2H), 0.872 (m, 2H).
Step B:
1-(2,3-Dihydroxypropyl)-N-(3,4,6-trifluoro-2-(2-fluoro-4-iodopheny-
lamino)phenyl)cyclopropane-1-sulfonamide
##STR00286##
[0523] 1-Allyl-cyclopropanesulfonic acid
[3,4,6-trifluoro-2-(2-fluoro-4-iodo-phenyl amino)-phenyl]-amide
(110 mg, 0.21 mmol) and 4-methylmorpholine N-oxide (24.6 mg, 0.21
mmol) was dissolved in THF (8 mL). Osmium tetroxide was added at
room temperature (0.021 mmol, 0.153 mL, 4% in H.sub.2O) and the
reaction mixture was stirred at room temperature for 16 hours.
EtOAc was added, the organic phase was washed with water, dried
(MgSO.sub.4) and concentrated under reduced pressure. The residue
was purified over silica gel chromatography (eluants: EtOAc/MeOH)
to obtain the titled product (0.89 g, 75%). .sup.1H NMR
(CDCl.sub.3, 300 MHz): .delta. 7.39 (dd, J=1.5 & 10.6 Hz, 1H),
7.29 (d, J=8.8 Hz, 1H), 7.28 (s, 1H), 6.97 (s, 1H), 6.76 (m, 1H),
6.49 (m, 1H), 4.13 (m, 1H), 3.66 (dd, =3.7 & 11.4 Hz, 1H), 3.53
(dd. J=6.7 & 11.2 Hz, 1H), 2.50 (dd, J=10.0 & 16.1 Hz, 1H),
1.6 (m, 1H), 1.46 (m, 1H), 1.28 (m, 1H), 1.20 (r, 2H), 0.92 (m,
2H); m/z=559 [M-1].sup.-.
Example 53
(S)-1-(2,3-dihydroxypropyl)-N-(3,4,6-trifluoro-2-(2-fluoro-4-iodophenylami-
no)phenyl)cyclopropane-1-sulfonamide
##STR00287##
[0525] The pure S isomer was obtained by chiral HPLC separation of
the racemic mixture (example 52). .sup.1H NMR (CDCl.sub.3, 300
MHz): .delta. 7.39 (dd, J=1.5 & 10.6 Hz.sub.5 1H), 7.29 (d,
J=8.8 Hz, 1H), 7.28 (s, 1H), 6.97 (s, 1H), 6.76 (m, 1H), 6.49 (m,
1H), 4.13 (m, 1H), 3.66 (dd, J=3.7 & 11.4 Hz.sub.5 1H), 3.53
(dd, J=6.7 & 11.2 Hz, 1H), 2.50 (dd, J=10.0 & 16.1 Hz, 1H),
1.6 (m, 1H), 1.46 (m, 1H), 1.28 (m, 1H), 1.20 (m, 2H), 0.92 (m,
2H); m/z=559 [M-1].sup.-.
Example 54
(R)-1-(2,3-dihydroxypropyl)-N-(3,4,6-trifluoro-2-(2-fluoro-4-iodophenylami-
no)phenyl)cyclopropane-1-sulfonamide
##STR00288##
[0527] The pure R isomer was obtained by chiral HPLC separation of
the racemic mixture (example 52). .sup.1H NMR (CDCl.sub.3, 300
MHz): .delta. 7.39 (dd, J=1.5 & 10.6 Hz, 1H), 7.29 (d, J=8.8
Hz, 1H), 7.28 (s, 1H), 6.97 (s, 1H), 6.76 (r, 1H), 6.49 (m, 1H),
4.13 (m, 1H), 3.66 (dd, J=3.7 & 11.4 Hz, 1H), 3.53 (dd, J=6.7
& 11.2 Hz, 1H), 2.50 (dd, J=10.0 & 16.1 Hz, 1H), 1.6 (m,
1H), 1.46 (m, 1H), 1.28 (m, 1H), 1.20 (m, 2H), 0.92 (nm, 2H);
m/z=559 [M-1].sup.-.
Example 55
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-1-(2,3-dihydroxyprop-
yl)cyclopropane-1-sulfonamide
Step A:
1-Allyl-N-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphe-
nyl)cyclopropane-1-sulfonamide
##STR00289##
[0529] According to the general procedure B,
1-allyl-cyclopropanesulfonyl chloride was reacted with
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)-3-methoxybenzene-1,2-diamine
to obtain the title product. .sup.1H NMR (CDCl.sub.3, 300 MHz):
.delta. 7.417 (dd, 1H), 7.309 (s, 1H), 7.25 (m, 1H), 6.89 (m, 1H),
6.52 (m, 1H), 6.427 (m, 1H), 6.03 (s, 1H), 5.668 (m, 1H), 5.11 (t,
1H), 3.9 (s, 3H), 2.75 (d, 2H), 1.21 (m, 2H), 0.767 (m, 2H).
Step B:
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-1-(2,3-dihyd-
roxypropyl) cyclopropane-1-sulfonamide
##STR00290##
[0531]
1-Allyl-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphe-
nyl) cyclopropane-1-sulfonamide (97 mg, 0.18 mmol) and
4-methylmorpholine N-oxide (21 mg, 0.18 mmol) were dissolved in THF
(8 mL). Osmium tetroxide was added at room temperature (0.018 mmol,
0.13 mL, 4% in H.sub.2O) and the reaction mixture was stirred at
room temperature for 16 hours. EtOAc was added, the organic phase
was washed with water, dried (MgSO.sub.4) and concentrated under
reduced pressure. The residue was purified over silica gel
chromatography (eluants: EtOAc/MeOH) to obtain the titled product
(0.80 g, 78%). .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 7.38 (dd,
J=1.7 & 10.3 Hz, 1H), 7.26 (m, 1H), 7.14 (s, 1H), 6.87 (s, 1H),
6.53 (dd, J=6.8 & 11.4 Hz, 1H), 6.43 (m, 1H), 4.06 (m, 1H),
3.89 (s, 3H), 3.63 (dd, J=3.7 & 11.1 Hz, 1H), 3.49 (dd, J=6.4
& 11.1 Hz, 1H), 2.3 (dd, J=9.7 & 16.1 Hz, 1H), 1.77 (dd,
J=1.9 & 16.0 Hz, 1H), 1.37 (m, 1H), 1.25 (m, 1H), 1.21 (m, 2H),
0.86 (m, 2H); m/z=571 [M-1].sup.-.
Example 56
(S)--N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,-
3-dihydroxypropyl)cyclopropane-1-sulfonamide
##STR00291##
[0533] The pure S isomer was obtained by chiral HPLC separation of
the racemic mixture (example 55). .sup.1H NMR (CDCl.sub.3, 300
MHz): .delta. 7.38 (dd, J=1.7 & 10.3 Hz, 1H), 7.26 (m, 1H),
7.14 (s, 1H), 6.87 (s, 1H), 6.53 (dd, J=6.8 & 11.4 Hz, 1H),
6.43 (m, 1H), 4.06 (m, 1H), 3.89 (s, 3H), 3.63 (dd, J=3.7 &
11.1 Hz, 1H), 3.49 (dd, J=6.4 & 11.1 Hz, 1H), 2.3 (dd, J=9.7
& 16.1 Hz, 1H), 1.77 (dd, J=1.9 & 16.0 Hz, 1H), 1.37 (m,
1H), 1.25 (m, 1H), 1.21 (m, 2H), 0.86 (m, 2H); m/z=571
[M-1].sup.-.
Example 57
(R)--N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,-
3-dihydroxypropyl)cyclopropane-1-sulfonamide
##STR00292##
[0535] The pure R isomer was obtained by chiral HPLC separation of
the racemic mixture (example 55). .sup.1H NMR (CDCl.sub.3, 300
MHz): .delta. 7.38 (dd, J=1.7 & 10.3 Hz, 1H), 7.26 (m, 1H),
7.14 (s, 1H), 6.87 (s, 1H), 6.53 (dd, J=6.8 & 11.4 Hz, 1H),
6.43 (m, 1H), 4.06 (m, 1H), 3.89 (s, 3H), 3.63 (dd, J=3.7 &
11.1 Hz, 1H), 3.49 (dd, J=6.4 & 11.1 Hz, 1H), 2.3 (dd, J=9.7
& 16.1 Hz, 1H), 1.77 (dd, J=1.9 & 16.0 Hz, 1H), 1.37 (m,
1H), 1.25 (m, 1H), 1.21 (m, 2H), 0.86 (m, 2H); m/z=571
[M-1].sup.-.
Example 58
1-(2-hydroxyethyl)-N-(3,4,6-trifluoro-2-(2-fluoro-4-iodophenylamino)phenyl-
) cyclopropane-1-sulfonamide
Step A: TBS-protected
1-(2-hydroxyethyl)-N-(3,4,6-trifluoro-2-(2-fluoro-4-iodophenylamino)
phenyl) cyclopropane-1-sulfonamide
##STR00293##
[0537] According to the general procedure B, the sulfonyl chloride
prepared in step C of example 16 was reacted with
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)-3-fluorobenzene-1,2-diamine
to obtain the title product. Yield: 13%. .sup.1H-NMR (300 MHz,
CDCl.sub.3): .delta.=7.51 (s, 1H, br), 7.37-7.35 (d, 1H), 7.27-7.25
(d, 1H), 6.94 (s, 1H, br), 6.78-6.68 (m, 1H), 6.46-6.44 (m, 1H),
3.90-3.88 (t, 2H), 2.12-2.10 (t, 2H), 1.31-1.28 (m, 2H), 0.91-0.89
(m, 2H), 0.86 (s, 9H), 0.05 (s, 6H); m/z=643 [M-1].sup.-
Step B:
1-(2-hydroxyethyl)-N-(3,4,6-trifluoro-2-(2-fluoro-4-iodophenylamin-
o)-phenyl) cyclopropane-1-sulfonamide
##STR00294##
[0539] Same procedure as in step E, example 16. Yield: 100%.
.sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=7.51 (s, 1H, br),
7.37-7.35 (d, 1H); 7.27-7.25 (d, 1H), 6.94 (s, 1H, br), 6.78-6.68
(m, 1H), 6.46-6.44 (m, 1H), 3.90-3.88 (t, 2H), 2.12-2.10 (t, 2H),
1.31-1.28 (m, 2H), 0.91-0.89 (m, 2H); m/z=529 [M-1].sup.-.
Example 59
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2-hydro-
xyethyl)cyclopropane-1-sulfonamide
Step A: TBS-protected
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2-hydr-
oxyethyl)cyclopropane-1-sulfonamide
##STR00295##
[0541] According to the general procedure B, the sulfonyl chloride
prepared in step C of example 16 was reacted with
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)-3-methoxy-benzene-1,2-diamine
to obtain the title product. Yield: 37%. .sup.1H-NMR (300 MHz,
CDCl.sub.3): .delta.=7.40-7.34 (dd, 1H), 7.23-7.21 (m, 1H), 6.61
(s, 1H, br), 6.57-6.49 (dd, 1H), 6.48-6.39 (m, 1H), 3.9-3.7 (m,
5H), 2.15-2.05 (t, 2H), 1.30-1.20 (m, 2H), 0.95-0.80 (m, 1H), 0.05
(s, 6H); m/z=655 [M-1].sup.-.
Step B:
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1--
(2-hydroxyethyl)cyclopropane-1-sulfonamide
##STR00296##
[0543] Same procedure as in step E, example 16. Yield: 100%.
.sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=7.40-7.34 (dd, 1H),
7.23-7.21 (m, 1H), 6.61 (s, 1H, br), 6.57-6.49 (dd, 1H), 6.48-6.39
(m, 1H), 3.9-3.7 (m, 5H), 2.15-2.05 (t, 2H), 1.30-1.20 (m, 2H),
0.95-0.80 (m, 2H); m/z=541 [M-1].sup.-.
Example 60
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(3-hydro-
xy-2-(hydroxymethyl)propyl)cyclopropane-1-sulfonamide
Step A: Dimethyl 2-(2-bromoallyl)malonate
##STR00297##
[0545] To a suspension of sodium hydride (5.0 g, 125 mmol) in HMPA
(50 ml, distilled from calcium hydride) was added a solution of
dimethyl malonate (11.7 ml, 100 mmol) in HMPA (5 ml) at 0.degree.
C. under argon. The mixture was heated to 50.degree. C. and stirred
1 hour. Following this the solution was again cooled to 0.degree.
C., and a solution of 2,3-dibromopropene (12.2 ml, 100 mmol) in
HMPA (5 ml) was added to the reaction mixture. Next, the solution
was warmed to 40.degree. C. and stirred for 1 hour. The reaction
mixture was quenched with aq. HCl (10%, 88 ml) and extracted with
ether (3.times.45 ml). The organic fractions were collected, dried
over MgSO--.sub.4, and the solvent was removed in vacuo. The crude
oil was purified via silica gel chromatography (eluants:
chloroform/hexane) to obtain the titled product as a colorless oil
(16.3 g, 65%). .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 5.70 (d,
J=1.8 Hz, 1H), 5.48 (d, J=1.8 Hz, 1H), 3.63 (t, J=7.5 Hz, 1H), 3.76
(s, 6H), 3.04 (d, J=7.5 Hz, 2H).
Step B: 2-(2-Bromoallyl)propane-1,3-diol
##STR00298##
[0547] Lithium aluminum hydride (1.9 g, 7.65 mmol) was slurried in
anhydrous diethyl ether (50 ml) and cooled to -78.degree. C. in a
dry ice/acetone bath. A solution of the product from step A (0.639
g, 16.84 mmol) in dry ether (26 ml) was then added dropwise. After
the malonate was added, the solution was allowed warm to room
temperature and stirring was continued for 3 hours. The reaction
was quenched with brine (50 ml), extracted with ethyl acetate
(3.times.25 ml) and dried over MgSO.sub.4. The solvent was removed
in vacuo to give the desired product (1.3 g, 86%) which was used
for the next step without further purification. .sup.1H-NMR (300
MHz, CDCl.sub.3) .delta. 5.66 (d, J=1.2 Hz, 1H), 5.48 (d, J=1.5 Hz,
1H), 3.86 (m, 2H), 3.73 (m, 2H), 2.51 (d, J=7.5 Hz, 2H), 2.40 (br
s, 2H), 2.15 (m, 1H).
Step C: Di-tert-butyldimethylsilyl protected
2-(2-bromoallyl)propane-1,3-diol
##STR00299##
[0549] The product from step B (2.8 g, 14.20 mmol) was dissolved in
anhydrous THF (140 ml). Anhydrous pyridine (2.5 ml, 31.24 mmol) was
added, and the solution was cooled to 0.degree. C.
tert-Butyldimethylsilyltriflate (7.2 ml, 31.24 mmol) was added
dropwise, and upon completion, the reaction solution was heated to
35.degree. C. After stirring for 6 days, the reaction was quenched
with 100 ml brine, extracted with ethyl acetate (3.times.50 ml) and
dried over MgSO.sub.4. The combined organic phases were evaporated
to obtain the crude product (5.5 g, 91%) as a yellow oil which was
used in the next step without further purification. .sup.1H-NMR
(300 MHz, CDCl.sub.3) .delta. 5.54 (d, J=0.9 Hz, 1H), 5.40 (d,
J=1.2 Hz, 1H), 3.55 (d, J=5.4, 4 H), 2.40 (d, J=6.9 Hz, 2H), 1.97
(m, 1H), 0.85 (s, 18H), 0.02 (s, 9H).
Step D: Di-tert-butyldimethylsilyl protected
2-((1-bromocyclopropyl)methyl) propane-1,3-diol
##STR00300##
[0551] A reaction flask was charged with anhydrous CH.sub.2Cl.sub.2
(10 ml) and diethyl zinc (1.0 M in hexanes, 4.65 ml, 4.65 mmol) at
0.degree. C. Trifluoroacetic acid (0.358 ml, 4.65 mmol) was added
dropwise and the solution was allowed to stir for 20 minutes.
Diiodomethane (0.375 ml, 4.65 mmol) was then added and the solution
was stirred for another 20 minutes. Finally, the product from step
C (0.492 g, 1.16 mmol) was added and the solution was allowed to
warm to ambient temperature, stirring for 16 hours. The reaction
was quenched with saturated aqueous NH.sub.4Cl. The layers were
partitioned and the aqueous phase was extracted with chloroform
(3.times.5 ml). The combined organic phases were washed with brine
(10 ml), dried over MgSO.sub.4, and the volatiles were removed in
vacuo. The resulting crude was purified via silica gel
chromatography (eluants: chloroform/hexanes) to provide the product
as a clear oil (0.280 g, 64%). .sup.1H-NMR (300 MHz, CDCl.sub.3)
.delta. 3.66 (d, J=5.4, 4H), 2.08 (m, 1H), 1.64 (d, J=6.9, 2 H),
1.13 (m, 2H), 0.88 (s, 18H), 0.81 (m, 2H), 0.04 (s, 9H).
Step E: Di-tert-butyldimethylsilyl protected
1-(3-hydroxy-2-hydroxymethyl)propyl)cyclopropane-1-sulfonyl
chloride
##STR00301##
[0553] The product from step D (0.507 g, 1.16 mmol) was dissolved
in anhydrous ether (6 ml) and the reaction solution was cooled to
-78.degree. C. Following this, tert-butyllithium (1.7 M in pentane,
1.50 ml, 2.55 mmol) was added dropwise over 5 minutes. After
stirring for 0.5 hours, the lithiated product was transferred via
cannula to a stirred solution of sulfuryl chloride (0.206 ml, 2.55
mmol) in dry ether (6 ml) at -78.degree. C. Once the transfer is
complete, the solution was allowed to warm to room temperature, the
solvent was evaporated and the resulting white solid was slurried
in dry hexanes. This slurry was immediately filtered through
celite, and all volatiles were removed in vacuo. The resulting
crude product (0.376 g, 71%) was isolated as a yellow oil and was
used in the following step without further purification.
.sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 3.60 (m, 4H), 2.16 (m,
1H), 2.03 (d, 2H), 0.88 (s, 18H), 0.04 (s, 9H).
Step F: Di-tert-butyldimethylsilyl protected
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(3-hydr-
oxy-2-(hydroxymethyl)propyl) cyclopropane-1-sulfonamide
##STR00302##
[0555]
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)-3-methoxybenzene-1,2-diamin-
e (8.8 mg, 0.022 mmol) was dissolved in anhydrous pyridine (0.5 ml)
under an argon atmosphere. The product from step E (20.5 mg, 0.045
mmol), dissolved in dry pyridine (0.5 ml), was added to the
reaction flask and the mixture was heated at 80.degree. C. for 21
hours. The solvent was removed in vacuo and the resulting crude was
purified via silica gel chromatography (eluents: ethyl
acetate/hexanes) to provide the title compound (2.75 mg, 15%). m/z
813.5 (M-1).sup.-.
Step G:
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1--
(3-hydroxy-2-(hydroxymethyl)propyl)cyclopropane-1-sulfonamide
##STR00303##
[0557] The product from step F (27.9 mg, 0.0342 mmol) was dissolved
in THF (1 ml) and treated with aqueous HCl (1.2 N, 0.2 ml) at
0.degree. C. The resulting solution was stirred for 4 hours.
Following this, the reaction was quenched with saturated aqueous
NaHCO.sub.3, extracted with ethyl acetate, dried over MgSO.sub.4
and the volatiles were removed in vacuo. The resulting crude was
purified via silica gel chromatography (eluents:
methanol/chloroform) followed by LC-MS purification to provide the
title compound (11.8 mg, 59%). .sup.1H-NMR (300 MHz, CD.sub.3OD)
.delta. 7.32 (dd, 1H), 7.21 (d, 1H), 6.76 (dd, 1H), 6.33 (n, 1H),
3.82 (s, 3H), 3.52 (d, 4H), 2.01 (m, 1H), 1.88 (d, 2H), 1.07 (m,
2H), 0.75 (m, 2H), m/z 585.3 (M-1).sup.-.
Example 61
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)
cyclobutane sulfonamide
Step A: Cyclobutanesulfonyl chloride
##STR00304##
[0559] To a suspension of Mg turnings (0.790 g, 32.5 mmol) in 20 ml
anhydrous diethyl ether was added a solution of cyclobutylbromide
(1.8 nil, 2.5722 g, 19.1 mmol) in 20 ml diethyl ether in small
portions with strong stirring. After the initial exothermic
reaction had ceased, the mixture was further heated to the reflux
temperature for 30 min. The suspension was cooled down to room
temperature and the supernatant was added in small portions to an
ice-cold solution of sulfuryl chloride (4.6 ml, 7.728 g, 57.2 mmol)
in 30 ml anhydrous DCM. After complete addition, the suspension was
warmed to room temperature and the volatiles were removed in vacuo.
The residue was dried in oil-pump vacuo for 15 min, then it was
extracted with hexane (150 ml). The hexane suspension was filtered
and the hexane was removed in vacuo to give the crude product as
dark purple oil which was used for the next step without further
purification. There is still some unreacted cyclopropylbromide
present. Crude yield: 1.1 g (38%).
Step B:
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)cyc-
lobutanesulfonamide
##STR00305##
[0561] According to the general procedure B, the cyclobutylsulfonyl
chloride prepared in the step above was reacted with
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)-3-methoxy-benzene-1,2-diamine
to obtain the title product. Yield: 75%. .sup.1H-NMR (300 MHz,
CDCl.sub.3): .delta.=7.44 (s, 1H, br), 7.41-7.36 (dd, 1H),
7.24-7.23 (m, 1H), 6.54-6.38 (m, 2H), 5.90 (s, 1H, br), 3.85-3.75
(m, 5H), 2.60-2.40 (m, 2H), 2.25-2.15 (m, 1H), 2.15-1.95 (m, 2H);
m/z=511 [M-1].sup.-.
Example 62
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methylphenyl)-1-(2,3-dihy-
droxypropyl)cyclopropane-1-sulfonamide
Step A: (3,4,5-Trifluorophenyl)methanol
##STR00306##
[0563] To a cooled (-5.degree. C.) solution of
3,4,5-trifluorobenzaldehyde (7.0 g, 43.75 mmol) in a mixture (50
ml, 9:1) of THF and water NaBH.sub.4 (1.662 g, 43.75 mmol) was
slowly added in portions over a period of 30 min. The reaction
mixture was allowed to attain room temperature over a period of 2 h
and carefully poured into ice-cold dil HCl (200 ml, IN). The oily
layer was extracted into CH.sub.2Cl.sub.2 (250 ml) and the organic
layer washed with water (200 ml), dried (MgSO.sub.4) and
evaporated. The crude product (7.08 g, quantitative) obtained was
taken forward without further purification.
Step B: 5-(Bromomethyl)-1,2,3-trifluorobenzene
##STR00307##
[0565] To a solution of the (3,4,5-Trifluorophenyl)methanol (40
mmol) in CH.sub.2Cl.sub.2 (150 ml), a solution of thionyl bromide
(6.16 ml, 80 mmol) in CH.sub.2Cl.sub.2 (50 ml) was added slowly.
The reaction mixture stirred at room temperature for 16 h and
poured into ice-water (200 ml). The organic layer was separated and
washed with saturated NaHCO.sub.3 (2.times.200 ml), water (200 ml),
dried (MgSO.sub.4) and evaporated to obtain the corresponding bromo
compound as a pale yellow oil in quantitative yield. The crude
product was carried forward for the next reaction without further
purification.
Step C: 1,2,3-Trifluoro-5-methylbenzene
##STR00308##
[0567] The above bromo compound (40 mmol) was mixed with
triethylsilane (48 mmol) and the reaction mixture was treated with
solid PdCl.sub.2 (4 mmol) in small portions. After a few minutes a
vigorous exothermic reaction was ensued and care was taken to
reflux the contents of the flask by placing a reflux condenser. The
reaction mixture was stirred at room temperature for additional 6 h
and the contents were allowed to settle over 16 h. Then the crude
liquid product was decanted carefully and carried forward for the
next reaction without further purification. It was assumed tat the
reaction proceeds in quantitative yield.
Step D: 1,2,3-Trifluoro-5-methyl-4-nitrobenzene
##STR00309##
[0569] 1,2,3-Trifluoro-5-methylbenzene (40 mmol) was added to conc.
H.sub.2SO.sub.4 (50 ml) at 0-5.degree. C. Then the reaction mixture
was slowly treated with cone. HNO.sub.3 (3.39 ml, 48.44 mmol, 90%)
while maintaining the internal temperature below 20.degree. C. The
reaction mixture was stirred at room temperature for 16 h and
poured onto ice (300 g) and the oily layer was extracted with
CH.sub.2Cl.sub.2 (2.times.125 ml). The organic layer was washed
with water (2.times.200 ml), brine (200 ml) and dried (MgSO.sub.4)
and evaporated to obtain the crude product which was purified over
flash silica gel chromatography to obtain the title product (6.5 g,
85%). .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 6.96 (septet, 1H),
2.39 (s, 3H). .sup.1H-NMR (CDCl.sub.3): .delta. -128.18, -141.50,
-159.05.
Step E:
2,3-Difluoro-N-(2-fluoro-4-iodophenyl)-5-methyl-6-nitroaniline
##STR00310##
[0571] 2-Fluoro-4-iodoaniline and
1,2,3-trifluoro-5-methyl-4-nitrobenzene were reacted using the
condition described in Example 1 (Step A) to form the title
compound. M-H.sup.+: 407.9
Step F:
56-Difluoro-N1-(2-fluoro-4-iodophenyl)-3-methylbenzene-1,2-diamine
##STR00311##
[0573]
2,3-Difluoro-N-(2-fluoro-4-iodophenyl)-5-methyl-6-nitroaniline was
reduced using the condition described in Example 1 (step B) to form
the title compound. M-H.sup.+: 377.4
Step G:
1-Allyl-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methylphe-
nyl)cyclopropane-1-sulfonamide
##STR00312##
[0575] According to the general procedure B,
1-allyl-cyclopropanesulfonyl chloride (142 mg, 142 mg) was reacted
with
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)-3-methylbenzene-1,2-diamine
(150 mg, 0.4 mmol) to obtain the title product (100 mg, 47%);
m/z=521 [M-1].sup.-.
Step H:
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methylphenyl)-1-(-
2,3-dihydroxypropyl)cyclopropane-1-sulfonamide
##STR00313##
[0577]
1-Allyl-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methylphen-
yl) cyclopropane-1-sulfonamide (150 mg, 0.29 mmol) and
4-methylmorpholine N-oxide (33 mg, 0.29 mmol) was dissolved in THF
(5 mL) Osmium tetroxide was added at room temperature (0.029 mmol,
0.18 mL, 4% in H.sub.2O) and the reaction mixture was stirred at
room temperature for 16 hours. EtOAc was added, the organic phase
was washed with water, dried (MgSO.sub.4) and concentrated under
reduced pressure. The residue was purified over silica gel
chromatography (eluants: EtOAc/MeOH) to obtain the titled product
(0.110 g, 68%). .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 7.07 (m,
1H), 6.97 (br m, 2H), 6.84 (m, 2H), 6.60 (br m, 2H), 3.98 (br in,
1H), 3.58 (m, 1H), 3.43 (m, 1H), 3.20 (d, J=3.9 Hz, 1H), 2.42 (s,
3H), 2.31 (dd, J=9.9 & 15.6 Hz, 1H), 2.01 (br t, 1H), 2.31 (dd,
J=9.9 & 15.6 Hz, 1H), 1.66 (dd, J=2.1 & 15.9 Hz, 1H), 1.52
(m, 1H), 1.40 (m, 1H), 0.91 (m, 2H).
Example 63
1-(2,3-Dihydroxypropyl)-N-(6-ethyl-3,4-difluoro-2-(2-fluoro-4-iodophenylam-
ino) phenyl) cyclopropane-1-sulfonamide
Step A: 1-(3,4,5-Trifluorophenyl)ethanol
##STR00314##
[0579] An ethereal solution (17.41 ml, 52.24 mmol, 3M) of MeMgBr
was slowly added at -78.degree. C. to a solution of
3,4,5-trifluorobenzaldehyde (6.96 g, 43.53 mmol) in THF (125 ml).
The reaction mixture was stirred at room temperature for 16 h and
was cooled (0.degree. C.) and was quenched, sequentially, with
excess ethyl acetate (10 ml) and water (5 ml). Excess anhydrous
MgSO.sub.4 (5 g) was added and stirred for 30 minutes at room
temperature. The suspension was filtered over celite and the solids
were washed with ethyl acetate (2.times.25 ml). The combined
filtrate was evaporated to obtain the product in quantitative yield
(7.65 g).
Step B: 5-(1-Bromoethyl)-1,2,3-trifluorobenzene
##STR00315##
[0581] To a solution of the 1-(3,4,5-Trifluorophenyl)ethanol: (7.65
g, 43.5 mmol) in CH.sub.2Cl.sub.2 (250 ml), a solution of thionyl
bromide (18.1 g, 87 mmol) in CH.sub.2Cl.sub.2 (50 ml) was added
slowly. The reaction mixture stirred at room temperature for 16 h
and poured into ice-water (200 ml). The organic layer was separated
and washed with saturated NaHCO.sub.3 (2.times.200 ml), water (200
ml), dried (MgSO.sub.4) and evaporated to obtain the corresponding
bromo compound as a pale yellow oil in quantitative yield (10.4 g).
The crude product was carried forward for the next reaction without
further purification.
Step C: 5-Ethyl-1,2,3-trifluorobenzene
##STR00316##
[0583] The above bromo compound (9.65 g, 40.4 mmol) was mixed with
triethylsilane (41 mmol) and the reaction mixture was treated with
solid PdCl.sub.2 (177 mg, 4 mmol) in small portions. After a few
minutes a vigorous exothermic reaction was ensued and care was
taken to reflux the contents of the flask by placing a reflux
condenser. The reaction mixture was stirred at room temperature for
additional 6 h and the contents were allowed to settle over 16 h.
Then the crude liquid product was decanted carefully and carried
forward for the next reaction without further purification. It was
assumed tat the reaction proceeds in quantitative yield.
Step D: 1-Ethyl-3,4,5-trifluoro-2-nitrobenzene
##STR00317##
[0585] 1,2,3-Trifluoro-5-methylbenzene (6.46 g, 40.4 mmol) was
added to cone. H.sub.2SO.sub.4 (50 ml) at 0-5.degree. C. Then the
reaction mixture was slowly treated with cone. HNO.sub.3 (3.39 ml,
48.44 mmol, 90%) while maintaining the internal temperature below
20.degree. C. The reaction mixture was stirred at room temperature
for 16 h and poured onto ice (300 g) and the oily layer was
extracted with CH.sub.2Cl.sub.2 (2.times.125 ml). The organic layer
was washed with water (2.times.200 ml), brine (200 ml) and dried
(MgSO.sub.4) and evaporated to obtain the crude product which was
purified over flash silica gel chromatography to obtain the title
product (6.6 g, 79%). .sup.1H NMR (CDCl.sub.3): .delta. 6.98
(septet, 1H), 2.68 (q, 2H), 1.26 (t, J=7.8 & 7.2 Hz, 3H).
Step E: 3-Ethyl-5,6-difluoro-N-(2-fluoro-4-iodophenyl-2
nitroaniline
##STR00318##
[0587] 2-Fluoro-4-iodoaniline (2.05 g, 10 mmol) and
1-ethyl-3,4,5-trifluoro-2-nitrobenzene (2.37 g, 10 mmol) were
reacted using the condition described in example 1 (Step A) to form
the title compound (2.47 g, 60%); m/z=407 [M-1].sup.-.
Step F:
3-Ethyl-5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine
##STR00319##
[0589] 1,2,3-Trifluoro-5-methyl-4-nitrobenzene (2.47 g, 5.85 mmol)
was reduced using the condition described in example 1 (Step B) to
form the title compound. M-H.sup.+: 393
Step G:
1-Allyl-N-(6-ethyl-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phen-
yl)cyclopropane-1-sulfonamide
##STR00320##
[0591] According to the general procedure B,
1-allyl-cyclopropanesulfonyl chloride (230 mg, 1.27 mmol) was
reacted with
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)-3-methylbenzene-1,2-diamine
(100 mg, 0.255 mmol) to obtain the title product (72 mg, 53%);
m/z=535 [M-1].
Step H:
1-(2,3-Dihydroxypropyl-N-(6-ethyl-3,4-difluoro-2-(2-fluoro-4-iodop-
henylamino)phenyl)cyclopropane-1-sulfonamide
##STR00321##
[0593]
1-Allyl-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methylphen-
yl) cyclopropane-1-sulfonamide (70 mg, 0.13 mmol) and
4-methylmorpholine N-oxide (15 mg, 0.13 mmol) was dissolved in THF
(2 mL). Osmium tetroxide was added at room temperature (0.013 mmol)
0.075 mL, 4% in H.sub.2O) and the reaction mixture was stirred at
room temperature for 16 hours. EtOAc was added, the organic phase
was washed with water, dried (MgSO.sub.4) and concentrated under
reduced pressure. The residue was purified over silica gel
chromatography (eluants: EtOAc/MeOH) to obtain the titled product.
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.38 (dd, J=2.1 &
10.8 Hz, 1H), 7.27 (m, 2H), 7.12 (br s, 1H), 6.91 (dd, J=8.1 &
10.8 Hz, 1H), 6.69 (br s, 1H), 6.36 (dt, J=4.8, 8.7 & 13.5 Hz,
1H), 4.00 (m, 1H), 3.62 (dd, J=3.6 & 10.5 Hz, 1H), 3.47 (br m,
2H), 2.81 (q, 2H), 2.40 (dd, J=10.2 & 15.9 Hz, 1H), 1.73 (br m,
2H), 1.58 (m, 1H), 1.43 (m, 1H), 0.94 (m, 2H).
Example 64
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-(2-methoxyethoxy)phenyl)--
1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide
Step A: 1,2,3-Trifluoro-5-(2-methoxyethoxy)-4-nitrobenzene
##STR00322##
[0595] To a mixture of 3,4,5-trifluoro-2-nitrophenol (1.93, 10
mmol), Ph.sub.3P (3.93 g, 15 mmol), and 2-methoxy-ethanol (1.18 ml,
15 mmol) in anhydrous THF (25 ml) a solution of diisopropyl
azodicarboxylate (2.91 ml, 15 mmol) in THF (5 ml) was added at
0.degree. C. and the reaction mixture was stirred at room
temperature for 16 h. The volatiles were evaporated and the residue
was dissolved in CH.sub.2Cl.sub.2 (100 ml) and the organic layer
was washed with water (100 ml), brine (100 ml) dried (MgSO.sub.4)
and evaporated. The residue obtained was purified over flash silica
gel chromatography to obtain the titled product in 68% (1.70 g)
yield. .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 6.78 (ddd, J=2.4,
6.0, 11.7 Hz, 1H), 4.19 (t, J=4.5 Hz, 2H), 3.72 (t, J=4.5 Hz, 2H),
3.39 (s, 3H).
Step B:
2,3-Difluoro-N1-(2-fluoro-4-iodophenyl)-5-(2-methoxyethoxy)-6-nitr-
oaniline
##STR00323##
[0597] 2-Fluoro-4-iodoaniline (1.6 g, 6.8 mmol) and
1,2,3-trifluoro-5-(2-methoxyethoxy)-4-nitrobenzene (1.7 g, 6.8
mmol) were reacted using the condition described in Example 1 (Step
A) to form the title compound (1.02 g, 32%); m/z=467 [M-1].
Step C:
5,6-Difluoro-N1-(2-fluoro-4-iodophenyl)-3-(2-methoxyethoxy)benzene-
-1,2-diamine
##STR00324##
[0599]
2,3-Difluoro-N-(2-fluoro-4-iodophenyl)-5-(2-methoxyethoxy)-6-nitroa-
niline (1.017 g, 2.17 mmol) was reduced using the condition
described in Example 1 (Step B) to form the title compound; m/z=337
[M-1].
Step D:
1-Allyl-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-(2-methox-
yethoxy)phenyl)cyclopropane-1-sulfonamide
##STR00325##
[0601] According to the general procedure B,
1-allyl-cyclopropanesulfonyl chloride (450 rug, 2.5 mmol) was
reacted with
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)-3-(2-methoxyethoxy)benzene-1,2-di-
amine (219 mg, 2.5 mmol) to obtain the title product (230 mg, 78%);
m/z=581 [M-1].
Step E:
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-(2-methoxyethoxy)-
phenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide
##STR00326##
[0603]
1-allyl-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-(2-methoxy-
ethoxy)phenyl)cyclopropane-1-sulfonamide (230 rug, 0.395 mmol) and
4-methylmorpholine N-oxide (46 mg, 0.395 mmol) was dissolved in THF
(2 mL). Osmium tetroxide was added at room temperature (0.039 mmol,
0.25 mL, 4% in H.sub.2O) and the reaction mixture was stirred at
room temperature for 16 hours. EtOAc was added, the organic phase
was washed with water, dried (MgSO.sub.4) and concentrated under
reduced pressure. The residue was purified over silica gel
chromatography (eluants: EtOAc/MeOH) to obtain the titled product.
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.36 (dd, J=1.8 &
10.5 Hz, 1H), 7.27 (m, 2H), 6.56 (dd, J=6.9 & 11.4 Hz, 1H),
6.40 (dt, J=5.7, 7.5 & 12.9 Hz, 1H), 4.17 (m, 2H), 4.01 (m,
1H), 3.78 (m, 2H), 3.60 (dd, J=3.6 & 11.1 Hz, 1H), 3.47 (m,
1H), 3.45 (s, 3H), 2.36 (dd, J=9.6 & 15.9 Hz, 1H), 1.78 (dd,
J=2.4 & 15.6 Hz, 1H), 1.45-1.25 (m, 2H), 0.89 (m, 2H).
Example 65
2,4-dichloro-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)
benzene sulfonamide
##STR00327##
[0605] Synthesized by method A using the appropriate sulfonyl
chloride, m/z=571 [M-1].sup.-.
Example 66
2-chloro-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-4-(trifluor-
omethyl)benzenesulfonamide
##STR00328##
[0607] Synthesized by method A using the appropriate sulfonyl
chloride, m/z=605 [M-1].
Example 67
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-2-(trifluoromethoxy)
benzene sulfonamide
##STR00329##
[0609] Synthesized by method A using the appropriate sulfonyl
chloride, m/z=587 [M-1].
Example 68
4-(N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)sulfamoyl)benzoic
acid
##STR00330##
[0611] Synthesized by method A using the appropriate sulfonyl
chloride, m/z=584 [M-1].
Example 69
N-(3,4-difluoro-2-(2-fluoro-1-iodophenylamino)phenyl)benzenesulfonamide
##STR00331##
[0613] Synthesized by method A using the appropriate sulfonyl
chloride, m/z=503 [M-1].
Example 70
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-2-fluorobenzene
sulfonamide
##STR00332##
[0615] Synthesized by method A using the appropriate sulfonyl
chloride, m/z=521 [M-1].
[0616] General Procedure 1: Substitution of the Iodine Atom:
[0617] A suspension containing 1 eq. aryl iodide, 1.5 equiv. of the
boronic acid or boronic ester, 0.25 eq. PdCl.sub.2(dppf).times.DCM
and 10 eq. anhydrous K.sub.2CO.sub.3 powder in a deoxygenated
mixture of dioxane and water (3:1) was heated in a microwave
reactor for 60 min at 115.degree. C. It was extracted using aq.
NH.sub.4Cl/THF, and the organic fraction was dried using
Na.sub.2SO.sub.4. The crude reaction products were purified using
flash-column chromatography (Si, EtOAc/Hexanes, or
CHCl.sub.3/MeOH). Yields: 20-40%.
Example 71
N-(3,4-difluoro-2-(2-fluoro-4-methylphenylamino)phenyl)cyclopropanesulfona-
mide
##STR00333##
[0619] General procedure D: .sup.1H-NMR (500 MHz, CDCl.sub.3):
.delta.=7.38-7.36 (m, 1H), 7.06-7.03 (q, 1H), 6.92-6.90 (1H),
6.73-6.72 (d, 1H), 6.63 (s, 1H, br), 6.37-6.33 (t, 1H), 5.54 (s,
1H, br), 2.42-2.39 (m, 1H), 2.25 (s, 3H), 1.14-1.11 (m, 2H),
0.94-0.90 (m, 2H); m/z=355 [M-1].
[0620] Where racemic mixtures of chiral compounds have been
resolved into separate enantiomers, the phrase "substantially free"
of the epimer, as used herein, means an enantiomeric excess of at
least 90%.
Example 72
N-(3,4-difluoro-2-(2-fluoro-4-(1H-pyrazol-4-yl)phenylamino)phenyl)cyclopro-
pane sulfonamide
Step A: 2,3-Difluoro-N-(2-fluoro-4-iodophenyl)-6-nitroaniline
##STR00334##
[0622] To a solution of 2-fluoro-4-iodoaniline (11.40 g, 47 mmol)
in 100 ml anhydrous THF at 0.degree. C., 47 ml of a IM solution of
LHMDS in THF (47 mmol) was added dropwise. The color of the
solution turned dark purple. The solution was transferred via
cannula to a dropping funnel, and the solution (containing the
amine free base) was added in small portions to a solution of
2,3,4-trifluoronitrobenzene (8.321 g, 47.0 mmol) in anhydrous THF
(50 ml) at 0.degree. C. After completion of addition the mixture
was stirred under argon at room temperature for 15 hours. The
volume of the solvent was reduced, followed by extraction using
ethyl acetate and brine. The organic layer was dried over sodium
sulfate, the solvent was removed, and the obtained dark oil was
purified by flash chromatography (EtOAc/hexane 1:5, R.sub.f=0.58)
yielding the crude product, which became a brown solid upon drying
in vacuo (yield: 6.23 g, 33.6%). m/z=393 [M-1].sup.-.
Step B:
5,6-Difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine
##STR00335##
[0624] To a solution of nitro-diarylamine (6.23 g, 15.8 mmol) in
300 ml ethanol was added iron powder (13.74 g, 246 mmol) and
ammonium chloride (13.59 g, 254 mmol) and the mixture was heated
with stirring at 100.degree. C. oil bath temperature for 14 hours.
It was filtered and the residue washed two times with ethanol. The
ethanol was removed in vacuo, and the residue was extracted using
ethyl acetate/1M NaOH solution. During the extraction, more
precipitate was formed which was filtered and discarded. The
combined organic layers were washed with brine and dried over
sodium sulfate. The solvent was removed, and the crude product was
recrystallized from CHCl.sub.3/hexane (1:50). The product was
obtained as brown needles (2.094 g, 66%,). R.sub.f=0.44 (EtOAc/Hex
1:3). .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta.=7.40-7.38 (dd, 1H,
J=11.3 Hz, J=1.5 Hz). 7.25-7.23 (d, 1H, J=8.5 Hz), 6.97-6.92 (q,
1H, J=9 Hz), 6.51-6.48 (m, 1H), 6.24-6.21 (t, 1H, J=9 Hz), 5.3 (s,
1H, NH, br), 3.80 (s, 2H, NH.sub.2, br); LRMS (ESI): m/z=365
[M+H].sup.+.
Step C:
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)cyclopropane
sulfonamide
##STR00336##
[0626] According to the general procedure A,
5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was
reacted with cyclopropanesulfonyl chloride to obtain the desired
product. (500 MHz, CDCl.sub.3): .delta.=7.38-7.37 (d, 1H),
7.35-7.34 (m, 1H), 7.27-7.26 (m, 1H), 7.20-7.0 (q, 1H), 6.68 (s,
1H, br), 6.15-6.12 (q, 1H), 5.65 (s, 1H, br), 3.25-3.20 (m, 1H),
2.4-2.3 (m, 2H), 2.0-1.8 (m, 2H); m/z=467 [M-1].sup.-.
Step D:
N-(3,4-difluoro-2-(2-fluoro-4-(1H-pyrazol-4-yl)phenylamino)phenyl)
cyclopropanesulfonamide
##STR00337##
[0628] General procedure C: .sup.1H-NMR (500 MHz, CDCl.sub.3):
.delta.=8.00-7.90 (m, 2H), 7.30-7.20 (m, 2H), 7.15-7.10 (m, 1H),
7.05-7.00 (m, 1H), 6.70-6.60 (m, 1H), 2.40-2.35 (m, 1H), 1.05-1.0
(m, 2H), 0.95-0.85 (m, 2H); m/z=407 [M-1].sup.-.
Example 73
N-(3,4-difluoro-2-(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenylamino)phenyl-
) cyclopropanesulfonamide
##STR00338##
[0630] General procedure C: .sup.1H-NMR (500 MHz, CDCl.sub.3):
.delta.=7.95 (s, 1H), 7.75 (s, 1H), 7.30-7.20 (m, 2H), 7.15-7.10
(m, 1H), 7.05-7.00 (m, 1H), 6.70-6.60 (m, 1H), 3.95 (s, 3H),
2.40-2.35 (m, 1H), 1.05-1.0 (m, 2H), 0.95-0.85 (m, 2H); m/z=421
[M-1].sup.-
Example 74
N-(3,4-difluoro-2-(2-fluoro-4-(1H-pyrazol-3-yl)phenylamino)phenyl)
cyclopropanesulfonamide
##STR00339##
[0632] General procedure C: .sup.1H-NMR (500 MHz, CDCl.sub.3):
.delta.=7.90 (s, 1H), 7.80 (s, 1H), 7.30-7.20 (m, 2H), 7.15-7.10
(m, 1), 7.05-7.00 (m, 1H), 6.70-6.60 (m, 1H), 3.95 (s, 3H),
2.40-2.35 (m, 1H), 1.05-1.0 (m, 2H), 0.95-0.85 (m, 2H); m/z=407
[M-1].sup.-
Example 75
N-(3,4-difluoro-2-(2-fluoro-4-(pyridin-4-yl)phenylamino)phenyl)
cyclopropanesulfonamide
##STR00340##
[0634] General procedure C: .sup.1H-NMR (500 MHz, CDCl.sub.3):
.delta.=8.62-8.61 (d, 2H), 7.43-7.41 (m, 4H), 7.23-7.22 (m, 1H),
7.16-7.11 (q, 1H), 6.61-6.58 (t, 1H), 6.11 (s, 1H, br), 2.53-2.50
(m, 1H), 1.21-1.10 (m, 2H), 1.02-0.99 (m, 2H); ml/z 418
[M-1].sup.-.
Example 76
N-(3,4-difluoro-2-(2-fluoro-4-(pyridin-3-yl)phenylamino)phenyl)
cyclopropanesulfonamide
##STR00341##
[0636] General procedure C: .sup.1H-NMR (500 MHz, [D6]-DMSO):
.delta.=9.45 (s, 1H), 8.91 (s, 1H), 8.54 (s, 1H), 8.07-8.06 (d,
1H), 7.76-7.70 (m, 2H), 7.46-7.34 (m, 2H), 7.34-7.33 (d, 2H),
6.80-6.78 (m, 1H), 0.86-0.79 (m, 4H); m/z=418 [M-1].sup.-.
Example 77
N-(2-(4-cyano-2-fluorophenylamino)-3,4-difluorophenyl)cyclopropanesulfonam-
ide
##STR00342##
[0638] A suspension containing the aryl iodide (75.5 mg, 0.161
mmol), CuCN (46.6 mg, 0.520 mmol and Pd(OAc).sub.2 (0.47 mg) in 1
ml anhydrous DMF was heated to 130.degree. C. for 60 min. in a
microwave reactor. The mixture was extracted using brine/THF, and
the organic fractions were dried using Na.sub.2SO.sub.4. Subsequent
flash-column chromatography gave the product as a dark red
semi-solid (R=0.42 (EtOAc/Hexanes 1:1). Yield: 15%. m/z=366
[M-1].sup.-.
Example 78
N-(3,4-difluoro-2-(3-fluorobiphenyl-4-ylamino)phenyl)cyclopropanesulfonami-
de
##STR00343##
[0640] General procedure C: .sup.1H-NMR (500 MHz, CDCl.sub.3):
.delta.=7.55-7.53 (m, 2H), 7.45-7.3 (m, 5H), 7.20-7.15 (d, 1H),
7.13-7.10 (q, 1H), 6.70 (s, IN, br), 6.60-6.55 (t, 1H), 5.75 (s,
1H, br), 2.53-2.50 (m, 1H), 1.21-1.10 (m, 2H), 1.02-0.99 (m, 2H);
m/z=417 [M-1].sup.-.
Example 79
N-(2-(3'-acetyl-3-fluorobiphenyl-4-ylamino)-3,4-difluorophenyl)
cyclopropanesulfonamide
##STR00344##
[0642] General procedure C: .sup.1H-NMR (500 MHz, CDCl.sub.3):
.delta.=8.6 (s, 1H), 7.86-7.85 (d, 1H), 7.68-7.66 (d, 1H),
7.49-7.46 (t, 1H), 7.38-7.33 (m, 2H), 7.20-7.18 (d, 1H), 7.09-7.03
(q, 1H), 6.90 (s, 1H, br), 6.57-6.54 (t, 1H), 5.90 (s, 1H), br),
2.61 (s, 3H), 2.46-2.43 (m, 1H), 1.15-1.13 (m, 2H), 0.94-0.91 (m,
2H); m/z=459 [M-1].sup.-.
Example 80
N-(2-(4'-cyano-3-fluorobiphenyl-4-ylamino)-3,4-difluorophenyl)
cyclopropanesulfonamide
##STR00345##
[0644] General procedure C: .sup.1H-NMR (500 MHz, CDCl.sub.3):
.delta.=7.68-7.66 (m, 2H), 7.58-7.57 (m, 2H), 7.38-7.35 (m, 2H),
7.20-7.18 (d, 1), 7.18-7.02 (q, 1H), 6.67 (s, 1H, br), 6.58-6.54
(t, 1H), 5.99 (s, 1H, br), 2.47-2.44 (m, 1H), 1.15-1.13 (m, 2H),
0.94-0.91 (m, 2H); m/z=442 [M-1].sup.-.
Example 81
N-(2-(3,4'-difluorobiphenyl-4-ylamino)-3,4-difluorophenyl)cyclopropanesulf-
onamide
##STR00346##
[0646] General procedure C: .sup.1H-NMR (500 MHz, CDCl.sub.3):
.delta.=7.44-7.37 (m, 3H), 7.29-7.27 (d, 1H), 7.11-7.05 (m, 4H),
6.70 (s, 1H, br), 6.53-6.50 (t, 1H), 5.81 (s, 1H, br), 2.47-2.44
(m, 1H), 1.15-1.13 (m, 2H), 0.94-0.91 (m, 2H); m/z=435
[M-1].sup.-.
Example 82
N-(3,4-difluoro-2-(3-fluoro-4'-(methylsulfonamido)biphenyl-4-ylamino)pheny-
l) cyclopropanesulfonamide
##STR00347##
[0648] General procedure C: .sup.1H-NMR (500 MHz, [D6]-DMSO):
.delta.=9.39 (s, 1H, br), 7.63-7.60 (m, 3H), 7.53-7.50 (d, 1H),
7.30-7.23 (m, 4H), 7.74-7.65 (m, 1H), 2.99 (s, 3H), 0.80-0.73 (m,
4H); m/z=510 [M-1].sup.-.
Example 83
N-(3,4-difluoro-2-(2-fluoro-4-methylphenylamino)phenyl)cyclopropanesulfona-
mide
##STR00348##
[0650] General procedure C: .sup.1H-NMR (500 MHz, CDCl.sub.3):
.delta.=7.38-7.36 (m, 1H), 7.06-7.03 (q, 1H), 6.92-6.90 (1H),
6.73-6.72 (d, 1H), 6.63 (s, 1H, br), 6.37-6.33 (t, 1H), 5.54 (s,
1H, br), 2.42-2.39 (m, 1H), 2.25 (s, 3H), 1.14-1.11 (m, 2H),
0.94-0.90 (m, 2H); m/z=355 [M-1].sup.-.
Example 84
4'-(6-(cyclopropanesulfonamido)-2,3-difluorophenylamino)-3'-fluorobiphenyl-
-3-carboxylic acid
##STR00349##
[0652] General procedure C: .sup.1H-NMR (500 MHz, [D4]-MeOH):
.delta.=8.21 (s, 1H), 7.93-7.91 (d, 1H), 7.73-7.72 (d, 1H),
7.47-7.43 (m, 21), 7.33-7.31 (d, 2H), 7.15-7.12 (q, 1H), 6.71-6.68
(i, 1H), 2.51-2.46 (m, 1H), 0.94-0.93 (m, 2H), 0.88-0.87 (m, 2H);
m/z=499 [M-1].sup.-.
Example 85
N-(3,4-difluoro-2-(3-fluoro-3'-(methylsulfonamido)biphenyl-4-ylamino)pheny-
l) cyclopropanesulfonamide
##STR00350##
[0654] General procedure C: .sup.1H-NMR (500 MHz, [D4]-MeOH):
.delta.=7.92 (s, 1H), 7.46-7.34 (m, 5H), 7.34-7.31 (d, 1H),
7.29-7.22 (m, 1H), 7.16-7.15 (q, 1H), 6.74-6.71 (m, 1H), 2.80 (s,
3H), 2.54-2.51 (m, 1H), 0.94-0.92 (m, 2H), 0.91-0.90 (m, 2H);
m/z=510 [M-1].sup.-.
Example 86
N-(3,4-difluoro-2-(3-fluoro-2'-(methylsulfonamido)biphenyl-4-ylamino)pheny-
l) cyclopropanesulfonamide
##STR00351##
[0656] General procedure C: .sup.1H-NMR (500 MHz, [D4]-MeOH):
.delta.=7.50-7.49 (d, 1H), 7.40-7.32 (m, 4H), 7.29-7.28 (d, 1H),
7.26-7.10 (m, 2H), 6.73-6.71 (m, 1H), 2.80 (s, 3H), 2.51-2.49 (m,
1H), 0.94-0.92 (m, 2H), 0.91-0.90 (r, 2H); m/z=510 [M-1].sup.-.
Example 87
N-(3,4-difluoro-2-(3-fluoro-4'-(trifluoromethoxy)biphenyl-4-ylamino)phenyl-
) cyclopropanesulfonamide
##STR00352##
[0658] General procedure C: .sup.1H-NMR (500 MHz, [D4]-MeOH):
.delta.=7.69-7.67 (d, 2H), 7.46-7.43 (d, 1H), 7.36-7.33 (m, 4H),
7.30-7.29 (q, 1H), 6.73-6.72 (m, 1H), 2.51-2.49 (m, 1H), 0.94-0.92
(m, 2H), 0.91-0.90 (nm, 2H); m/z=501 [M-1].sup.-.
Example 88
N-(3,4-Difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-2-(methylamino)
ethanesulfonamide
##STR00353##
[0660] General procedure D. .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta. 9.01 (br s, D.sub.2O exchangeable, 1H), 7.36 (dd, J=2.1
& 10.5 Hz, 1H), 7.27 (r, 1H), 7.17 (m, 1H), 7.03 (dd, J=9.0
& 16.8 Hz, 1H), 6.48 (s, D.sub.2O exchangeable, 1H), 6.31 (dt,
J=3.0, 8.7 & 17.4 Hz, 1H), 3.45 (br t. 2H). 3.31 (br s, 2H),
2.65 (s. 3H). 1.80 (br s, D.sub.2O exchangeable, 1H).
Example 89
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-2-(2-(dimethylamino)-
ethylamino) ethanesulfonamide
##STR00354##
[0662] General procedure D. 1H NMR (300 MHz, CDCl.sub.3): .delta.
7.35 (m, 1H), 7.25 (m, 1H), 7.18 (d, J=8.7 Hz, 1H), 7.02 (dd, J=8.7
& 18.0 Hz, 1H), 6.38 (m, 1H), 6.18 (dd, J=8.7 & 17.1 Hz,
1H), 3.62 (t, J=5.7 & 6.3 Hz, 2H), 3.35 (m, 2H), 3.26 (m, 2H),
3.26 (t, J=5.7 & 6.6 Hz, 2H), 3.11 (t, J=5.1 & 6.0 Hz, 2H),
2.85 (s, 6H).
Example 90
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-2-(ethyl(methyl)amin-
o) ethanesulfonamide
##STR00355##
[0664] General procedure D. .sup.1H NMR (300 MHz,
(CDCl.sub.3+D.sub.2O)): .delta. 7.39 (dd, J=1.5 & 10.5 Hz, 1H),
7.31 (m, 21H), 7.07 (dd, J=9.0 & 17.4 Hz, 1H), 6.30 (dt, J=2.4,
9.0 & 17.4 Hz, 1H), 3.55 (t, J=6.9 & 7.8 Hz, 2H), 3.38 (br
t, J=6.0 & 8.7 Hz, 2H), 3.05 (q, 2H), 2.69 (s, 3H), 1.31 (t,
J=7.2 Hz, 311).
Example 91
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-2-(4-methylpiperazin-
-1-yl) ethanesulfonamide
##STR00356##
[0666] General procedure D. .sup.1H NMR (300 MHz, CD.sub.3OD):
.delta. 7.45 (dd, J=2.1 & 10.8 Hz, 1H), 7.30 (m, 2H), 7.16 (dd,
J=9.6 & 17.7 Hz, 1H), 6.39 (dt, J=3.3, 9.3 & 17.7 Hz, 1H),
3.26 (m, J=7.5 Hz, 2H), 3.10 (br m, 6H), 2.87 (s, 3H), 2.82 (t,
J=7.5 Hz, 2H), 2.48 (br m, 4H).
Biological Activity
[0667] Generation of IC50 Data
[0668] Materials and preparation of reagents: Human GST-MEK1 and
the constitutively active allele GST-MEK1.sup.CA (harboring the
mutations Ser218Asp and Ser222Asp) were subcloned into the yeast
expression vector pGEM4Z (Promega, Madison, Wis.) from the wild
type human MEK1 cDNA. GST-MEK1.sup.CA was expressed in Escherichia
coli and partially purified using Glutathione Sepharose 4B affinity
resin (Amersham Pharmacia Biotech, Piscataway, N.J.). The ERK2
allele was subcloned from MAPK2/Erk2 cDNA (wild type) in pUSEamp
(Upstate Biotechnology, Inc., Waltham, Mass.) into the vector
pET21a (Novagen, Madison, Wis.) resulting in an N-terminal
histidine-tagged mouse ERK2 allele. ERK2 was expressed and purified
to homogeneity [Zhang, 1993 #33]. Myelin basic protein (MBP) was
purchased from Gibco BRL (Rockville, Md.). EasyTides adenosine
5'-triphosphate (ATP) ([.gamma.-.sup.33P]) (NEN Perkin Elmer,
Wellesley, Mass.) was the source of radiolabel for all kinase
reactions. Activated Raf-1 (truncated) and activated MAPKinase
2/ERK2 were purchased from Upstate, Inc. (Lake Placid, N.Y.). 4-20%
Criterion Precast gels were purchased from Bio-Rad (Hercules,
Calif.).
[0669] Determination of enzymatic activity: Compounds were diluted
from dimethylsulfoxide (DMSO) stocks into 1.times.HMNDE (20 mM
HEPES pH 7.2, 1 mM MgCl.sub.2, 100 mM NaCl, 1.25 mM DTT, 0.2 mM
EDTA). A typical 25-microliter assay contained 0.002 nanomoles
MEK1.sup.CA, 0.02 nanomoles ERK2, 0.25 nanomoles MBP, 0.25
nanomoles unlabeled ATP, and 0.1 .mu.Ci [.gamma..sup.33P] ATP. The
screening assay essentially comprised four additions. Five .mu.l of
diluted compound were dispensed to 96-well assay plates. Ten .mu.l
of 2.5.times. enzyme cocktail (MEK1.sup.CA and ERK2 only) were then
added to each well followed by a pre-incubation for 30 minutes at
ambient temperature. Ten .mu.l of 2.5.times. substrate cocktail
(labeled and unlabeled ATP plus MBP) were then added, followed by
incubation for 60 minutes at ambient temperature. Finally, 100
.mu.l of 10% trichloroacetic acid (TCA) were added and incubated
for 30 minutes at room temperature to halt the reaction and
precipitate radiolabeled protein products. Reaction products were
harvested on glass fiber 96 well filter plates prewetted with water
and 1% pyrophosphate. The filter plate was then washed 5 times with
water. Water was displaced by absolute ethanol and the plate was
allowed to air dry for 30 minutes at room temperature. A back seal
was applied manually and 40 .mu.l of scintillation cocktail were
dispensed to each well. A top seal was applied and the plate was
counted in the TopCount for two seconds per well.
[0670] For certain experiments a truncated version of MEK that
requires activation by Raf kinase were used.
[0671] Generation of EC50 Data
[0672] Effects of compounds in the cell were determined by Western
blotting for phosphorylated ERK. MDA-MB-231 breast cancer cells
were plated in a 48 well plate at 20,000 cells per well and grown
in a 37.degree. humidified CO.sub.2 incubator. The following day,
the growth media (DMEM+10% fetal bovine serum) was removed and
replaced with starve media (DMEM+0.1% fetal bovine serum). Cells
were incubated in the starve media for sixteen hours and then
treated with a range of compound concentrations for thirty minutes.
After incubation with compound, cells were stimulated with 100
ng/ml EGF for five minutes. The cells were then lysed and analyzed
by Western blot using a monoclonal antibody raised to
phosphorylated ERK. The signal was amplified using a secondary
antibody conjugated to a near -IR dye and detected on a Licor
Odyssey scanner. The intensity of signal was quantitated and this
data was used to generate dose response curves and EC50
calculations.
TABLE-US-00009 Com- pound Acti- Num- vity ber Structure .mu.M 1000
##STR00357## A 1001 ##STR00358## A 1002 ##STR00359## B 1003
##STR00360## C 1004 ##STR00361## C 1005 ##STR00362## C 1006
##STR00363## C 1007 ##STR00364## C 1008 ##STR00365## C 1009
##STR00366## C 1010 ##STR00367## A 1011 ##STR00368## C 1012
##STR00369## B 1013 ##STR00370## B 1014 ##STR00371## C 1015
##STR00372## D 1016 ##STR00373## C 1017 ##STR00374## B 1018
(Racemic) ##STR00375## A 1019 (Racemic) ##STR00376## A 1020
(Racemic) ##STR00377## A 1021 (S isomer) ##STR00378## A 1022 (R
isomer) ##STR00379## B 1023 (R isomer) ##STR00380## B 1024 (S
isomer) ##STR00381## B 1025 ##STR00382## B 1026 ##STR00383## A 1027
##STR00384## A 1028 ##STR00385## A 1029 ##STR00386## C 1030
##STR00387## C 1031 ##STR00388## A Legend: A, EC.sub.50 = <2.0
nM; B, EC.sub.50 = 2.0-15 nM; C, EC.sub.50 = 15 nM-100 nM; D,
EC.sub.50 > 100 nM, IC.sub.50 < 20 .mu.M; F, EC.sub.50 >
100 nM, IC.sub.50 > 20 .mu.M
TABLE-US-00010 MDA pERK ELISA CPD # Structure EC.sub.50 0497618
##STR00389## E 0497620 ##STR00390## E 0497654 ##STR00391## D
0497688 ##STR00392## E 0497689 ##STR00393## E 0497692 ##STR00394##
E 0499266 ##STR00395## E 0499267 ##STR00396## ND 0499268
##STR00397## ND 0499271 ##STR00398## E 0530701 ##STR00399## D
0530716 ##STR00400## ND 0530717 ##STR00401## ND 0561599
##STR00402## C 0561608 ##STR00403## C 0620926 ##STR00404## E
0620927 ##STR00405## C 0621002 ##STR00406## C 0621016 ##STR00407##
C 0621026 ##STR00408## D 0621029 ##STR00409## D 0621030
##STR00410## ND Legend: A, EC.sub.50 = <2.0 nM; B, EC.sub.50 =
2.0-15 nM; C, EC.sub.50 = 15 nM-100 nM; D, EC.sub.50 = 100 nM-200
nM; E, EC.sub.50 > 200 nM; ND = not yet determined
* * * * *