U.S. patent application number 12/275152 was filed with the patent office on 2009-05-28 for biaryl pde4 inhibitors for treating pulmonary and cardiovascular disorders.
This patent application is currently assigned to DECODE GENETICS EHF. Invention is credited to Alex Burgin, Mark E. Gurney, Timothy Hagen, Alexander Kiselyov, Munagala Rao, Jasbir Singh.
Application Number | 20090136473 12/275152 |
Document ID | / |
Family ID | 40376234 |
Filed Date | 2009-05-28 |
United States Patent
Application |
20090136473 |
Kind Code |
A1 |
Singh; Jasbir ; et
al. |
May 28, 2009 |
BIARYL PDE4 INHIBITORS FOR TREATING PULMONARY AND CARDIOVASCULAR
DISORDERS
Abstract
The present invention relates to a genus of biaryl compounds
containing at least one further ring. The compounds are PDE4
inhibitors useful for the treatment and prevention of stroke,
myocardial infarct and cardiovascular inflammatory diseases and
disorders. The compounds have general formula Ia, Ib, Ic or Id:
##STR00001## A particular embodiment is ##STR00002##
Inventors: |
Singh; Jasbir; (Naperville,
IL) ; Gurney; Mark E.; (Grand Rapids, MI) ;
Burgin; Alex; (Kingston, WA) ; Kiselyov;
Alexander; (San Diego, CA) ; Rao; Munagala;
(Westmont, IL) ; Hagen; Timothy; (Lisle,
IL) |
Correspondence
Address: |
HESLIN ROTHENBERG FARLEY & MESITI PC
5 COLUMBIA CIRCLE
ALBANY
NY
12203
US
|
Assignee: |
DECODE GENETICS EHF
Reykjavik
IS
|
Family ID: |
40376234 |
Appl. No.: |
12/275152 |
Filed: |
November 20, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60989551 |
Nov 21, 2007 |
|
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|
Current U.S.
Class: |
424/94.1 ;
514/210.18; 514/275; 514/297; 514/300; 514/318; 514/319; 514/343;
514/350; 514/354; 514/357; 514/363; 514/406; 544/297; 546/121;
546/194; 546/279.1; 546/290; 546/306; 546/326; 548/138; 548/376.1;
560/43 |
Current CPC
Class: |
A61K 45/06 20130101;
C07D 213/74 20130101; A61P 35/00 20180101; C07C 307/10 20130101;
A61K 31/4427 20130101; C07D 257/04 20130101; C07D 401/06 20130101;
C07C 217/84 20130101; C07D 213/73 20130101; C07D 473/40 20130101;
C07D 471/04 20130101; A61K 31/426 20130101; A61P 25/00 20180101;
C07D 277/42 20130101; A61P 19/00 20180101; A61P 19/10 20180101;
A61P 25/28 20180101; C07D 207/16 20130101; A61K 31/5377 20130101;
A61P 9/00 20180101; C07B 2200/05 20130101; C07D 275/06 20130101;
C07D 473/18 20130101; C07D 213/89 20130101; A61P 1/00 20180101;
A61P 9/10 20180101; A61P 19/08 20180101; A61P 43/00 20180101; C07D
285/135 20130101; C07D 213/40 20130101; C07D 401/04 20130101; C07C
69/94 20130101; C07C 275/32 20130101; C07C 275/62 20130101; C07D
239/42 20130101; C07D 231/12 20130101; A61P 25/24 20180101; C07D
213/38 20130101; C07D 213/81 20130101; C07D 403/04 20130101; C07D
213/76 20130101; A61K 31/437 20130101; A61P 13/10 20180101; C07D
213/79 20130101; C07D 233/90 20130101; A61K 31/397 20130101; C07C
65/40 20130101; C07D 213/75 20130101; C07D 213/65 20130101; C07D
213/84 20130101; A61K 31/44 20130101; C07D 285/12 20130101; C07D
205/04 20130101; C07D 213/64 20130101; A61P 29/00 20180101; A61P
11/00 20180101; A61P 11/06 20180101; C07C 305/24 20130101; A61K
31/41 20130101; A61P 25/22 20180101; A61K 31/136 20130101; A61P
25/14 20180101; A61K 31/4418 20130101 |
Class at
Publication: |
424/94.1 ;
548/376.1; 546/290; 544/297; 546/326; 560/43; 548/138; 546/194;
546/279.1; 546/121; 546/306; 514/406; 514/350; 514/275; 514/354;
514/363; 514/318; 514/343; 514/300; 514/357; 514/210.18; 514/297;
514/319 |
International
Class: |
A61K 31/44 20060101
A61K031/44; C07D 231/12 20060101 C07D231/12; C07D 213/64 20060101
C07D213/64; C07D 239/42 20060101 C07D239/42; C07D 213/79 20060101
C07D213/79; C07C 275/28 20060101 C07C275/28; C07D 285/135 20060101
C07D285/135; A61K 31/433 20060101 A61K031/433; A61K 31/4439
20060101 A61K031/4439; A61P 1/00 20060101 A61P001/00; A61P 11/00
20060101 A61P011/00; A61P 35/00 20060101 A61P035/00; A61P 9/00
20060101 A61P009/00; A61K 31/122 20060101 A61K031/122; A61K 31/4353
20060101 A61K031/4353; A61K 31/435 20060101 A61K031/435; A61K
31/4427 20060101 A61K031/4427; A61K 31/437 20060101 A61K031/437;
A61K 31/4545 20060101 A61K031/4545; C07D 401/06 20060101
C07D401/06; C07D 471/04 20060101 C07D471/04; C07D 213/72 20060101
C07D213/72; A61K 31/415 20060101 A61K031/415; A61K 31/4412 20060101
A61K031/4412; A61K 31/495 20060101 A61K031/495 |
Claims
1. A compound of formula Ia, Ib, Ic or Id: ##STR00101## or salt
thereof wherein R.sup.1 is an optionally substituted carbocycle or
optionally substituted heterocycle of three or fewer rings;
R.sup.1a is chosen from (a) a residue chosen from ##STR00102##
wherein R.sup.40 is chosen from H, halogen, OH, NH.sub.2 and
CH.sub.3; (b) a substituted heterocycle of three or fewer rings or
substituted carbocycle of three or fewer rings; and (c) a
heterocycle that is itself substituted with a heterocycle carrying
a further substituent; wherein substituents on the heterocycle or
carbocycle are chosen from hydroxy, carboxy, alkoxycarbonyl,
carboxyalkylcarbonylamino, carboxyalkyl, carboxyalkoxy,
carboxyalkylthio, carboxyalkylaminocarbonylamino, guanidino, the
residue of an amino acid and the residue of an N-methylated amino
acid; R.sup.2 is an optionally substituted carbocycle or optionally
substituted heterocycle of two or fewer rings; R.sup.3 is chosen
from H, --C(.dbd.O)NH.sub.2, --(C.sub.1-C.sub.6)alkyl,
halo(C.sub.1-C.sub.6)alkyl, --(C.sub.1-C.sub.6)alkyl-R.sup.30,
--(C.sub.2-C.sub.6)alkyl-R.sup.31, and saturated 4- or 5-membered
heterocycle optionally substituted with methyl; R.sup.30 is chosen
from --C(.dbd.O)NH.sub.2 and 4- or 5-membered heterocycle
optionally substituted with methyl; R.sup.31 is chosen from
(C.sub.1-C.sub.4)alkoxy, amino, hydroxy,
(C.sub.1-C.sub.6)alkylamino and di(C.sub.1-C.sub.6)alkylamino;
R.sup.4 is chosen from H and F; R.sup.6 is chosen from H,
(C.sub.1-C.sub.6)alkyl and halogen; X is N, N.fwdarw.O, or
C--R.sup.5; R.sup.5 is chosen from H, halogen, OH,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, CF.sub.3, CN,
NH.sub.2, CH.sub.2OH, CH.sub.2NH.sub.2 and C.ident.CH; and M is
chosen from direct bond, --C(R.sup.20)(R.sup.21)--, --O--,
--NR.sup.22--, --S(O).sub.n--, --C(.dbd.O)--,
--C(R.sup.20)(R.sup.21)C(R.sup.20)(R.sup.21)--,
--C(R.sup.20).dbd.C(R.sup.21)--, --C(R.sup.20)(R.sup.21)--O--,
--C(R.sup.20)(R.sup.21)--NR.sup.22--,
--C(R.sup.20)(R.sup.21)--S(O).sub.n--,
--C(R.sup.20)(R.sup.21)--C(.dbd.O)--, --O--C(R.sup.20)(R.sup.2)--,
--NR.sup.22--C(R.sup.20)(R.sup.21)--,
--S(O).sub.n--C(R.sup.20)(R.sup.21)--,
--C(.dbd.O)--C(R.sup.20)(R.sup.21)-- and ##STR00103## is a five or
six-membered ring optionally substituted with methyl; n is zero,
one or two; and R.sup.20, R.sup.21 and R.sup.22 are selected
independently in each occurrence from H and
(C.sub.1-C.sub.4)alkyl.
2. A compound or salt of formula Ia or Ic according to claim 1
wherein X is N or N.fwdarw.O.
3. A compound or salt of formula Ia or Ic according to claim 1
wherein X is CR.sup.5.
4. A compound or salt according to any of claims 1, 2 or 3 wherein
M is chosen from direct bond, --CH.sub.2--, --CH(OH)--,
--C[(CH.sub.3)(OH)]--, --C[(CH.sub.3)(NH.sub.2)]--, --C(.dbd.O)--,
--O--, --NH--, --N(CH.sub.3)--, --S(O).sub.n--, --CH.sub.2NH--,
--CH.sub.2CH.sub.2--, --CH.dbd.CH--, --CH.sub.2S(O).sub.n--,
--CH.sub.2O-- and ##STR00104##
5. A compound or salt according to claim 1 wherein R.sup.1 or
R.sup.1a is a substituted phenyl.
6. A compound or salt according to claim 1 wherein R.sup.1 or
R.sup.1a is an optionally substituted heterocycle chosen from
pyrazole, pyrrole, indole, quinoline, isoquinoline,
tetrahydroisoquinoline, benzofuran, benzodioxan, benzodioxole,
morpholine, thiazole, pyridine, pyridine N-oxide, pyrimidine,
thiene, furan, oxazole, oxazoline, oxazolidine, isoxazolidine,
isoxazole, dioxane, azetidine, piperazine, piperidine, pyrrolidine,
pyridazine, azepine, pyrazolidine, imidazole, imidazoline,
imidazolidine, purine, imidazolopyridine, pyrazine, thiazolidine,
isothiazole, 1,2-thiazine-1,1-dioxide,
2,6,7-trioxabicyclo[2.2.2]octane, quinuclidine, isothiazolidine,
benzimidazole, thiadiazole, benzopyran, benzothiazole,
benzotriazole, benzoxazole, benzoxadiazole, tetrahydrofuran,
tetrahydropyran, benzothiene, thiamorpholine, thiamorpholine
sulfoxide, thiamorpholine sulfone, oxadiazole, triazole, tetrazole,
isoindole, pyrrolopyridine, triazolopyridine and the dihydro and
tetrahydro congeners thereof.
7. A compound or salt according to claim 6 wherein R.sup.1 or
R.sup.1a is an optionally substituted heterocycle chosen from
pyrazole, benzodioxole, morpholine, thiazole, pyridine, pyridine
N-oxide, pyrimidine, thiene, oxazolidine, isoxazole, azetidine,
piperazine, pyrrolidine, imidazole, imidazolidine,
imidazolopyridine, pyrazine, 1,2-thiazine-1,1-dioxide,
benzimidazole, thiadiazole, benzotriazole, benzoxazole, oxadiazole,
triazole, tetrazole, isoindole, pyrrolopyridine, triazolopyridine
and the dihydro and tetrahydro congeners thereof.
8. A compound or salt according to claim 5 wherein R.sup.1 is
phenyl substituted with a substituent chosen from halogen,
haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxyalkyl, carbonyl,
phenyl, heteroaryl, benzenesulfonyl, hydroxy, alkoxy, haloalkoxy,
oxaalkyl, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl,
alkoxycarbonylamino, carboxyalkyl, carboxyalkoxy, carboxyalkylthio,
alkoxycarbonylaminoalkyl, carboxyalkylcarbonylamino, carboxamido,
aminocarbonyloxy, alkylaminocarbonyl, dialkylaminocarbonyl,
aminocarbonylalkyl, cyano, acetoxy, nitro, amino, alkylamino,
dialkylamino, aminoalkyl, (alkyl)(aryl)aminoalkyl, alkylaminoalkyl,
dialkylaminoalkyl, dialkylaminoalkoxy, alkyl(hydroxyalkyl)amino,
heterocyclylalkoxy, mercapto, alkylthio, alkylsulfonyl,
alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, arylthio,
arylsulfonyl, arylsulfonylamino, arylsulfinyl, arylsulfonyl,
acylaminoalkyl, acylaminoalkoxy, acylamino, amidino, aryl, benzyl,
heterocyclyl, heterocyclylalkyl, phenoxy, benzyloxy, heteroaryloxy,
heterocyclylamino, hydroxyimino, alkoxyimino, oxaalkyl,
aminosulfonyl, trityl, amidino, guanidino, ureido,
--NHC(.dbd.O)NHalkyl, --NHC(.dbd.O)NH-heterocyclyl,
-alkyl-NHC(.dbd.O)N(alkyl).sub.2, heterocyclylalkylcarbonylamino,
benzyloxyphenyl, benzyloxy, the residues of amino acids, amino acid
amides, protected residues of aminoacids, protected residues of
amino acid amides, N-methylated amino acids and N-methylated amino
acid amides.
9. A compound or salt according to claim 5 wherein R.sup.1 is
phenyl substituted with a substituent chosen from --CH.sub.3,
--CH.sub.2CF.sub.3, --CF.sub.3, --CHO, --COOH, --CN, halogen, --OH,
--OEt, --C(.dbd.O)NH.sub.2, --C(.dbd.O)NHEt,
--C(.dbd.O)NMe.sub.2-COOCH.sub.3, --COOEt,
--CH.sub.2NHC(.dbd.O)NH.sub.2, --CH(CH.sub.3)NHC(.dbd.O)NH.sub.2,
--CH.sub.2NHC(.dbd.O)H, --CH.sub.2NHC(.dbd.O)CH.sub.3,
--CH.sub.2C(.dbd.O)NH.sub.2, --CH.sub.2COOH, --CH.sub.2COOEt,
--CH.sub.2NHC(.dbd.O)OEt, --CH.sub.2NHC(.dbd.O)O--C.sub.6H.sub.5,
--CH.sub.2NHC(.dbd.O)C(.dbd.O)NH.sub.2, --CH.sub.2NHC(.dbd.O)NHEt,
--C(CH.sub.3).sub.2OH, --CH.sub.2NHC(.dbd.O)N(CH.sub.3).sub.2,
--CH.sub.2NHC(.dbd.O)NHCH.sub.3, --CH.sub.2NH.sub.2,
--CH(CH.sub.3)NH.sub.2, --C(CH.sub.3).sub.2NH.sub.2, --CH.sub.2OH,
--CH.sub.2CH.sub.2OH, --CH.sub.2NHSO.sub.2CH.sub.3,
--CH.sub.2C(.dbd.O)NHEt, --OCH.sub.3, --OC(.dbd.O)NH.sub.2,
--OCH.sub.2CH.sub.2N(CH.sub.3).sub.2, --OCH.sub.2CH.sub.2OCH.sub.3,
--OCH(CH.sub.3)COOH, --SCH.sub.2COOH, --NHC(.dbd.O)NH.sub.2,
--NHC(.dbd.O)NHEt, --NHCH.sub.3, --NHEt, --NH(tBoc),
--NHCH.sub.2COOH, --N(CH.sub.3)CH.sub.2COOH,
--NHC(.dbd.O)NHCH.sub.2CH.sub.2Cl, --NHSO.sub.2NH.sub.2, --NHEt,
--N(CH.sub.3).sub.2, --NH.sub.2, --NH(CH.sub.3)C(.dbd.O)NH.sub.2,
--NHSO.sub.2CH.sub.3, --N(SO.sub.2CH.sub.3).sub.2,
--NHC(.dbd.O)OCH.sub.3, --NHC(.dbd.O)OtBu, --NHC(.dbd.O)CH.sub.3,
--SO.sub.2NH.sub.2, --NHC(.dbd.O)CH.sub.2CH.sub.2COOH,
--NHC(.dbd.O)NHCH.sub.2COOH, --CH.sub.2NHCHO,
--NHC(.dbd.O)NHCH.sub.2COOEt, --NHC(.dbd.O)NH(CH.sub.2).sub.3COOEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.2COOEt,
--N(CH.sub.3)CH.sub.2CH.sub.2OH, --NHC(.dbd.O)OEt,
--N(Et)C(.dbd.O)OEt, --NHC(.dbd.O)NH(CH.sub.2).sub.2COOH,
--NHC(.dbd.O)CH.sub.2N(CH.sub.3).sub.2,
--NHC(.dbd.O)NH(CH.sub.2).sub.3COOH, --NHC(.dbd.O)CH.sub.2NH.sub.2,
--NHC(.dbd.O)CH.sub.2CH.sub.2NH.sub.2,
--NHC(.dbd.O)CH.sub.2NH(tBoc), ##STR00105##
10. A compound or salt according to claim 6 wherein R.sup.1 is a
heterocycle substituted with a substituent chosen from halogen,
haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxyalkyl, carbonyl,
phenyl, heteroaryl, benzenesulfonyl, hydroxy, alkoxy, haloalkoxy,
oxaalkyl, carboxy, alkoxycarbonyl, alkoxycarbonylamino,
alkoxycarbonylaminoalkyl, carboxyalkyl, carboxyalkoxy,
carboxyalkylthio, carboxyalkylcarbonylamino, carboxamido,
aminocarbonyloxy, alkylaminocarbonyl, dialkylaminocarbonyl,
aminocarbonylalkyl, cyano, acetoxy, nitro, amino, alkylamino,
dialkylamino, aminoalkyl, (alkyl)(aryl)aminoalkyl, alkylaminoalkyl,
dialkylaminoalkyl, dialkylaminoalkoxy, alkyl(hydroxyalkyl)amino,
heterocyclylalkoxy, mercapto, alkylthio, alkylsulfonyl,
alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, arylthio,
arylsulfonyl, arylsulfonylamino, arylsulfinyl, arylsulfonyl,
acylaminoalkyl, acylaminoalkoxy, acylamino, amidino, aryl, benzyl,
heterocyclyl, heterocyclylalkyl, phenoxy, benzyloxy, heteroaryloxy,
heterocyclylamino, hydroxyimino, alkoxyimino, oxaalkyl,
aminosulfonyl, trityl, amidino, guanidino, ureido,
--NHC(.dbd.O)NHalkyl, --NHC(.dbd.O)NH-heterocyclyl,
-alkyl-NHC(.dbd.O)N(alkyl).sub.2, heterocyclylalkylcarbonylamino,
benzyloxyphenyl, benzyloxy, the residues of amino acids, amino acid
amides, protected residues of aminoacids, protected residues of
amino acid amides, N-methylated amino acids and N-methylated amino
acid amides.
11. A compound or salt according to claim 6 wherein R.sup.1 is a
heterocycle substituted with a substituent chosen from --CH.sub.3,
--CH.sub.2CF.sub.3, --CF.sub.3, --CHO, --COOH, --CN, halogen, --OH,
--OEt, --C(.dbd.O)NH.sub.2, --C(.dbd.O)NHEt,
--C(.dbd.O)NMe.sub.2-COOCH.sub.3, --COOEt,
--CH.sub.2NHC(.dbd.O)NH.sub.2, --CH(CH.sub.3)NHC(.dbd.O)NH.sub.2,
--CH.sub.2NHC(.dbd.O)H, --CH.sub.2NHC(.dbd.O)CH.sub.3,
--CH.sub.2C(.dbd.O)NH.sub.2, --CH.sub.2COOH, --CH.sub.2COOEt,
--CH.sub.2NHC(.dbd.O)OEt, --CH.sub.2NHC(.dbd.O)O--C.sub.6H.sub.5,
--CH.sub.2NHC(.dbd.O)C(.dbd.O)NH.sub.2, --CH.sub.2NHC(.dbd.O)NHEt,
--C(CH.sub.3).sub.2OH, --CH.sub.2NHC(.dbd.O)N(CH.sub.3).sub.2,
--CH.sub.2NHC(.dbd.O)NHCH.sub.3, --CH.sub.2NH.sub.2,
--CH(CH.sub.3)NH.sub.2, --C(CH.sub.3).sub.2NH.sub.2, --CH.sub.2OH,
--CH.sub.2CH.sub.2OH, --CH.sub.2NHSO.sub.2CH.sub.3,
--CH.sub.2C(.dbd.O)NHEt, --OCH.sub.3, --OC(.dbd.O)NH.sub.2,
--OCH.sub.2CH.sub.2N(CH.sub.3).sub.2, --OCH.sub.2CH.sub.2OCH.sub.3,
--OCH(CH.sub.3)COOH, --SCH.sub.2COOH, --NHC(.dbd.O)NH.sub.2,
--NHC(.dbd.O)NHEt, --NHCH.sub.3, --NHEt, --NH(tBoc),
--NHCH.sub.2COOH, --N(CH.sub.3)CH.sub.2COOH,
--NHC(.dbd.O)NHCH.sub.2CH.sub.2Cl, --NHSO.sub.2NH.sub.2, --NHEt,
--N(CH.sub.3).sub.2, --NH.sub.2, --NH(CH.sub.3)C(.dbd.O)NH.sub.2,
--NHSO.sub.2CH.sub.3, --N(SO.sub.2CH.sub.3).sub.2,
--NHC(.dbd.O)OCH.sub.3, --NHC(.dbd.O)OtBu, --NHC(.dbd.O)CH.sub.3,
--SO.sub.2NH.sub.2, --NHC(.dbd.O)CH.sub.2CH.sub.2COOH,
--NHC(.dbd.O)NHCH.sub.2COOH, --CH.sub.2NHCHO,
--NHC(.dbd.O)NHCH.sub.2COOEt, --NHC(.dbd.O)NH(CH.sub.2).sub.3COOEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.2COOEt,
--N(CH.sub.3)CH.sub.2CH.sub.2OH, --NHC(.dbd.O)OEt,
--N(Et)C(.dbd.O)OEt, --NHC(.dbd.O)NH(CH.sub.2).sub.2COOH,
--NHC(.dbd.O)CH.sub.2N(CH.sub.3).sub.2,
--NHC(.dbd.O)NH(CH.sub.2).sub.3COOH, --NHC(.dbd.O)CH.sub.2NH.sub.2,
--NHC(.dbd.O)CH.sub.2CH.sub.2NH.sub.2,
--NHC(.dbd.O)CH.sub.2NH(tBoc), ##STR00106##
12. A compound or salt of formula Ia according to claim 1 wherein
R.sup.1a is chosen from a substituted heterocycle of three or fewer
rings; a monocyclic heterocycle attached to a substituted
monocyclic heterocycle; and a substituted carbocycle of three or
fewer rings wherein substituents on the heterocycle or carbocycle
are chosen from --COOH, --OH, --COOCH.sub.3, --COOEt,
--CH.sub.2COOH, --CH.sub.2COOEt, --CH.sub.2NHC(.dbd.O)OEt,
--CH.sub.2NHC(.dbd.O)C(.dbd.O)NH.sub.2, --OCH(CH.sub.3)COOH,
--SCH.sub.2COOH, --NHCH.sub.2COOH, --N(CH.sub.3)CH.sub.2COOH,
--NHSO.sub.2NH.sub.2, --NHC(.dbd.O)CH.sub.2CH.sub.2COOH,
--NHC(.dbd.O)NHCH.sub.2COOH, --NHC(.dbd.O)NHCH.sub.2COOEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.3COOEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.2COOEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.2COOH,
--NHC(.dbd.O)NH(CH.sub.2).sub.3COOH and 5-tetrazolyl.
13. A compound or salt according to claim 1 wherein R.sup.2 is
chosen from optionally substituted phenyl, optionally substituted
monocyclic unsaturated heterocycle, unsubstituted bicyclic
unsaturated heterocycle and fluoro-substituted bicyclic unsaturated
heterocycle.
14. A compound or salt according to claim 13 wherein R.sup.2 is
chosen from optionally substituted phenyl, indole, benzodioxole,
benzoxadiazole, benzodioxan, benzimidazole, oxadiazole, pyrazole,
pyridine and pyridine N-oxide.
15. A compound or salt according to claim 14 wherein R.sup.2 is
chosen from meta-substituted phenyl, indole, benzodioxole,
2,2-difluorobenzodioxole, benzooxadiazole, benzimidazole,
5-(pyridin-4-yl)[1,2,4]oxadiazole,
5-(pyridin-4-yl)[1,3,4]oxadiazole, benzodioxan, 4-chloropyrazole,
4-(pyridin-4-yl)pyrazole, 6-chloropyridine,
3-(trifluoromethyl)pyrazole, and pyridine N-oxide.
16. A compound or salt according to claim 14 wherein R.sup.2 is
substituted phenyl: ##STR00107## wherein R.sup.7 is chosen from
hydrogen, halogen, nitro, cyano, halo(C.sub.1-C.sub.6)alkyl,
hydroxy, (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)oxaalkyl,
carboxy, (C.sub.1-C.sub.6)alkoxycarbonyl, aminocarbonyl
(--CONH.sub.2), (C.sub.1-C.sub.6)alkylaminocarbonyl, acyl,
hydroxy(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy,
amino(C.sub.1-C.sub.6)alkyl, amino, (C.sub.1-C.sub.6)alkylamino,
di[(C.sub.1-C.sub.6)alkyl]amino, mercapto,
(C.sub.1-C.sub.6)alkylthio, (C.sub.1-C.sub.6)alkylsulfinyl,
(C.sub.1-C.sub.6)alkylsulfonyl, (C.sub.1-C.sub.6)alkylsulfonamido,
acylamino, amidino, phenyl, benzyl, heterocyclyl, phenoxy,
benzyloxy, and heteroaryloxy; and R.sup.8 and R.sup.13 are chosen
independently from H and F.
17. A compound or salt according to claim 16, wherein R.sup.8 and
R.sup.13 are H and R.sup.7 is chosen from hydrogen, fluoro, chloro,
bromo, nitro, cyano, acetyl, trifluoromethyl, methoxy,
trifluoromethoxy, oxadiazolyl, tetrazolyl, methylthio,
methanesulfinyl, methanesulfonyl, methansulfonamido, amino,
methoxymethyl, hydroxyethyl, and morpholinyl.
18. A compound or salt of formula Ib, Ic or Id according to claim
1, wherein R.sup.1 is chosen from optionally substituted phenyls;
optionally substituted five membered heteroaryls selected from
thiazoles, thiadiazoles, pyrazoles, oxadiazole, isoxazoles,
triazoles, imidazoles, thiophenes, tetrazoles and oxazoles;
optionally substituted six membered hereroaryls selected from
pyridines, pyrimidines, pyridazinones, pyrimidinone, pyridinone,
pyrazines and diazines; optionally substituted 5- and 6-membered
non-aryl heterocyclics selected from tetrahydrothiophenes,
piperazine, oxazolidinones, imidazolidinones, morpholines,
piperidines, pyrrolidinones, pyrrolidinediones, pyrrolidines,
piperidinones, piperidinediones and trioxa-bicyclo[2.2.2]octanes;
and optionally substituted fused bicycles selected from
benzoxazolones, indoles, isoindolinediones,
2H-pyrrolopyridinediones, purines, indolinediones,
triazolopyridinones, benzimidazoles, benzoxadiazoles, quinolines
and quinolones; wherein the substituents are chosen independently
from hydrogen, halogen, halo(C.sub.1-C.sub.6)alkyl, hydroxyl,
(C.sub.1-C.sub.6)alkoxy, carboxy, (C.sub.1-C.sub.6)alkoxycarbonyl,
aminocarbonyl (--CONH.sub.2), (C.sub.1-C.sub.6)alkylaminocarbonyl,
cyano, carbonyl(oxo), acyl, hydroxy(C.sub.1-C.sub.6)alkyl,
halo(C.sub.1-C.sub.6)alkoxy, amino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, nitro, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
mercapto, (C.sub.1-C.sub.6)alkylthio, sulfoxide, sulfone,
sulfonate, sulfonimide, acylamino, amidino, phenyl, benzyl,
heteroaryl, phenoxy, benzyloxy, heteroaryloxy,
aminocarbonyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkyl,
carboxy(C.sub.1-C.sub.6)alkyl, formylamino(C.sub.1-C.sub.6)alkyl,
carboxy(C.sub.1-C.sub.6)alkylamino,
--(CH.sub.2).sub.p--NR.sup.12CO--(CH.sub.2).sub.q--NR.sup.9R.sup.10,
--NHSO.sub.2R.sup.11,
--OCH.sub.2CH.sub.2NR.sup.9R.sup.10--NHSO.sub.2NR.sup.9R.sup.10,
--SO.sub.2NR.sup.9R.sup.10, --(CH.sub.2)p-NHCOR.sup.9,
OCONR.sup.9R.sup.10 and NR.sup.12COOR.sup.11; R.sup.3 is chosen
from --CH.sub.3, --CH.sub.2CH.sub.3, --CF.sub.3, --CHF.sub.2 and
--CH.sub.2F; R.sup.5 is chosen from H, --F, --OH, --CH.sub.3,
--OCH.sub.3, --CF.sub.3, --CN, --NH.sub.2 and --C.ident.CH; R.sup.2
is (a) phenyl and R.sup.7 is chosen from H, halogen, nitro, acetyl,
hydroxyethyl, --NH.sub.2, --SCH.sub.3, methoxycarbonyl,
--SOCH.sub.3, --SO.sub.2CH.sub.3, --OCH.sub.3, --OCF.sub.3, --CN,
--CF.sub.3, --CH.sub.2OCH.sub.3; or (b) benzoxadiazole,
benzodioxole, 2,2-difluorobenzodioxole, benzoxadiazole,
benzodioxan, benzimidazole, oxadiazole, pyrazole, pyridine and
pyridine N-oxide; R.sup.9 is chosen from H, (C.sub.1-C.sub.6)alkyl,
halo(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxycarbonyl,
carboxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarboxy(C.sub.1-C.sub.6)alkyl; R.sup.10 is
H, (C.sub.1-C.sub.6)alkyl, or taken together, or R.sup.9 and
R.sup.10 together form a heterocycle optionally substituted with
(C.sub.1-C.sub.6)alkyl; p is 0 or 1, q is 0, 1 or 2, R.sup.11 is
linear (C.sub.1-C.sub.6)alkyl, R.sup.12 is H or
(C.sub.1-C.sub.6)alkyl; or two adjacent substituents together form
an optionally substituted fused heterocyclic ring.
19. A compound or salt of formula Ia according to claim 1, wherein
R.sup.1a is chosen from substituted phenyl; substituted five
membered heteroaryls selected from thiazoles, thiadiazoles,
pyrazoles, oxadiazole, isoxazoles, triazoles, imidazoles,
thiophenes, tetrazoles and oxazoles; substituted six membered
heteroaryls selected from pyridines, pyrimidines, pyridazinones,
pyrimidinone, pyridinone, pyrazines and diazines; substituted 5-
and 6-membered non-aryl heterocyclics selected from
tetrahydrothiophenes, piperazine, oxazolidinones, imidazolidinones,
morpholines, piperidines, pyrrolidinones, pyrrolidinediones,
pyrrolidines, piperidinones, piperidinediones and
trioxa-bicyclo[2.2.2]octanes; substituted fused bicycles selected
from benzoxazolones, indoles, isoindolinediones,
2H-pyrrolopyridinediones, purines, indolinediones,
triazolopyridinones, benzimidazoles, benzoxadiazoles, quinolines
and quinolones and substituted heterocyclylheterocycles selected
from azetidinylpyrimidines, pyrrolidinylpyrimidines,
piperidinylpyrimidines, azetidinylpyridines, pyrrolidinylpyridines
and piperidinylpyridines; wherein the substituents are chosen
independently from --COOH, --OH, --COOCH.sub.3, --COOEt,
--CH.sub.2COOH, --CH.sub.2COOEt, --CH.sub.2NHC(.dbd.O)OEt,
--CH.sub.2NHC(.dbd.O)C(.dbd.O)NH.sub.2, --OCH(CH.sub.3)COOH,
--SCH.sub.2COOH, --NHCH.sub.2COOH, --N(CH.sub.3)CH.sub.2COOH,
--NHSO.sub.2NH.sub.2, --NHC(.dbd.O)CH.sub.2CH.sub.2COOH,
--NHC(.dbd.O)NHCH.sub.2COOH, --NHC(.dbd.O)NHCH.sub.2COOEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.3COOEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.2COOEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.2COOH,
--NHC(.dbd.O)NH(CH.sub.2).sub.3COOH and 5-tetrazolyl; R.sup.3 is
chosen from --CH.sub.3, --CH.sub.2CH.sub.3, --CF.sub.3, --CHF.sub.2
and --CH.sub.2F; R.sup.5 is chosen from H, --F, --OH, --CH.sub.3,
--OCH.sub.3, --CF.sub.3, --CN, --NH.sub.2 and --C.ident.CH; R.sup.2
is (a) phenyl and R.sup.7 is chosen from H, halogen, nitro, acetyl,
hydroxyethyl, --NH.sub.2, --SCH.sub.3, methoxycarbonyl,
--SOCH.sub.3, --SO.sub.2CH.sub.3, --OCH.sub.3, --OCF.sub.3, --CN,
--CF.sub.3, --CH.sub.2OCH.sub.3; or (b) benzoxadiazole,
benzodioxole, 2,2-difluorobenzodioxole, benzoxadiazole,
benzodioxan, benzimidazole, oxadiazole, pyrazole, pyridine and
pyridine N-oxide; R.sup.9 is chosen from H, (C.sub.1-C.sub.6)alkyl,
halo(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxycarbonyl,
carboxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarboxy(C.sub.1-C.sub.6)alkyl; R.sup.10 is
H, (C.sub.1-C.sub.6)alkyl, or taken together, or R.sup.9 and
R.sup.10 together form a heterocycle optionally substituted with
(C.sub.1-C.sub.6)alkyl; p is 0 or 1, q is 0, 1 or 2, R.sup.11 is
linear (C.sub.1-C.sub.6)alkyl, R.sup.12 is H or
(C.sub.1-C.sub.6)alkyl; or two adjacent substituents together form
an optionally substituted fused heterocyclic ring.
20. A compound or salt according to claim 1 of formula ##STR00108##
wherein R.sup.1b is phenyl, five-membered heteroaryl, six-membered
heteroaryl, 4-7 membered non-aryl heterocycle or fused bicycle;
R.sup.14 is chosen from --COOH, --OH, --COOCH.sub.3, --COOEt,
--CH.sub.2COOH, --CH.sub.2COOEt, --CH.sub.2NHC(.dbd.O)OEt,
--CH.sub.2NHC(.dbd.O)C(.dbd.O)NH.sub.2, --OCH(CH.sub.3)COOH,
--SCH.sub.2COOH, --NHCH.sub.2COOH, --N(CH.sub.3)CH.sub.2COOH,
--NHSO.sub.2NH.sub.2, --NHC(.dbd.O)CH.sub.2CH.sub.2COOH,
--NHC(.dbd.O)NHCH.sub.2COOH, --NHC(.dbd.O)NHCH.sub.2COOEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.3COOEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.2COOEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.2COOH,
--NHC(.dbd.O)NH(CH.sub.2).sub.3COOH, 5-tetrazolyl and monocyclic
heterocycle substituted with any of the foregoing; R.sup.27 is
chosen from hydrogen, halogen, nitro, cyano,
halo(C.sub.1-C.sub.6)alkyl, hydroxy, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)oxaalkyl, carboxy,
(C.sub.1-C.sub.6)alkoxycarbonyl, aminocarbonyl (--CONH.sub.2),
(C.sub.1-C.sub.6)alkylaminocarbonyl, acyl,
hydroxy(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy,
amino(C.sub.1-C.sub.6)alkyl, amino, (C.sub.1-C.sub.6)alkylamino,
di[(C.sub.1-C.sub.6)alkyl]amino, mercapto,
(C.sub.1-C.sub.6)alkylthio, (C.sub.1-C.sub.6)alkylsulfinyl,
(C.sub.1-C.sub.6)alkylsulfonyl, (C.sub.1-C.sub.6)alkylsulfonamido,
acylamino, amidino, phenyl, benzyl, heterocyclyl, phenoxy,
benzyloxy, and heteroaryloxy; R.sup.28 is chosen from H and F, or
R.sup.27 together with R.sup.28 forms a five-membered ring.
21. A compound or salt according to claim 1 of formula ##STR00109##
wherein R.sup.1c is phenyl, five-membered heteroaryl, six-membered
heteroaryl, 4-7 membered non-aryl heterocycle or fused bicycle;
R.sup.14 is chosen from H, --CH.sub.2NHC(.dbd.O)NH.sub.2,
--NHC(.dbd.O)NH.sub.2, --NHC(.dbd.O)NHEt, --CH.sub.3,
--CH.sub.2CF.sub.3, --CH.sub.2NHC(.dbd.O)CH.sub.3, --NHCH.sub.3,
--NHEt, --NH(tBoc), --CHO, --NHC(.dbd.O)NHCH.sub.2CH.sub.2Cl,
--NHSO.sub.2NH.sub.2, --NHEt, --N(CH.sub.3).sub.2, --NH.sub.2,
--COOH, --C(.dbd.O)NH.sub.2, --CH.sub.2C(.dbd.O)NH.sub.2,
--CH.sub.2COOH, --CH.sub.2COOEt, --CN, --OCH.sub.3,
--OC(.dbd.O)NH.sub.2, --NH(CH.sub.3)C(.dbd.O)NH.sub.2, halogen,
--CH.sub.2NHC(.dbd.O)OEt, --NHSO.sub.2CH.sub.3,
--N(SO.sub.2CH.sub.3).sub.2, --NHC(.dbd.O)OCH.sub.3, --OH,
--CH.sub.2NHC(.dbd.O)N(CH.sub.3).sub.2, --CH.sub.2NH.sub.2,
--CH.sub.2OH, --CH.sub.2CH.sub.2OH, --SO.sub.2NH.sub.2,
--NHC(.dbd.O)NHCH.sub.2COOH, --CH.sub.2NHCHO,
--NHC(.dbd.O)NHCH.sub.2COOEt, --COOCH.sub.3, --COOEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.3COOEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.2COOEt, --OCH(CH.sub.3)COOH,
--SCH.sub.2COOH, --NH(Et)C(.dbd.O)OEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.2COOH, --CH.sub.2NHSO.sub.2CH.sub.3,
--OEt, --NHC(.dbd.O)CH.sub.2N(CH.sub.3).sub.2,
--NHC(.dbd.O)NH(CH.sub.2).sub.3COOH, --NHC(.dbd.O)CH.sub.2NH.sub.2,
--NHC(.dbd.O)CH.sub.2CH.sub.2NH.sub.2,
--NHC(.dbd.O)CH.sub.2NH(tBoc),
--OCH.sub.2CH.sub.2N(CH.sub.3).sub.2, --OCH.sub.2CH.sub.2OCH.sub.3,
3'-nitro-6-methoxybiphenyl-3-ylmethyl,
tetrahydroimidazol-2-on-1-yl,
3-methyltetrahydroimidazol-2-one-1-yl, pyrazol-1-yl, ##STR00110##
R.sup.15 is chosen from H, NO.sub.2, OH, NH.sub.2, and
--NHSO.sub.2NH.sub.2; or R.sup.15 together with R.sup.14 forms
methylene dioxy; R.sup.27 is chosen from hydrogen, halogen, nitro,
cyano, halo(C.sub.1-C.sub.6)alkyl, hydroxy,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)oxaalkyl, carboxy,
(C.sub.1-C.sub.6)alkoxycarbonyl, aminocarbonyl (--CONH.sub.2),
(C.sub.1-C.sub.6)alkylaminocarbonyl, acyl,
hydroxy(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy,
amino(C.sub.1-C.sub.6)alkyl, amino, (C.sub.1-C.sub.6)alkylamino,
di[(C.sub.1-C.sub.6)alkyl]amino, mercapto,
(C.sub.1-C.sub.6)alkylthio, (C.sub.1-C.sub.6)alkylsulfinyl,
(C.sub.1-C.sub.6)alkylsulfonyl, (C.sub.1-C.sub.6)alkylsulfonamido,
acylamino, amidino, phenyl, benzyl, heterocyclyl, phenoxy,
benzyloxy, and heteroaryloxy; R.sup.28 is chosen from H and F, or
R.sup.27 together with R.sup.28 forms a five-membered ring.
22. A compound or salt according to claim 20 wherein R.sup.27 and
R.sup.28 represent a fused heterocycle at 3- and 4-positions so
that the residue formed from R.sup.27 and R.sup.28 together with
the phenyl to which they are attached is chosen from:
##STR00111##
23. A compound or salt according to claim 20 wherein R.sup.27 is
chosen from halogen, nitro, acetyl, hydroxyethyl, amino,
methylthio, trifluoromethyl, methoxymethyl, methoxycarbonyl,
trifluoromethoxy, cyano and 1,3,4-thiadiazol-2-yl, or taken
together R.sup.7 and R.sup.8 are methylenedioxy or
difluoromethylenedioxy.
24. A compound or salt according to claim 23 wherein R.sup.1b or
R.sup.1c is chosen from a benzene ring, a triazole, a pyridine or
pyridine-N-oxide, a pyrazole, a tetrahydrothiophene, an imidazole,
a pyrimidine, a thiadiazole, and an imidazopyridine.
25. A compound or salt according to claim 1 wherein R.sup.5 is
fluoro, H, CN or OH.
26. A compound or salt according to claim 1 wherein R.sup.3 is
methyl or fluoromethyl.
27. A compound or salt according to claim 1 of formula:
##STR00112## wherein R.sup.3a is methyl, fluorinated methyl or
HSO.sub.3; Y is CH, CF or N.fwdarw.O; R.sup.27a is chosen from
halogen, cyano, acetyl, methylthio, nitro and trifluoromethyl; and
R.sup.16 is chosen from --NR.sup.17C(.dbd.O)NR.sup.18R.sup.19 and
##STR00113## wherein ##STR00114## is a 4-7 membered ring
heterocycle attached through its nitrogen; R.sup.17, and R.sup.18
are independently chosen from H, (C.sub.1-C.sub.6)alkyl and
halo(C.sub.1-C.sub.6)alkyl; R.sup.19 is chosen from H,
(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl,
--[(C.sub.1-C.sub.6)alkyl]COOH, and
--[(C.sub.1-C.sub.6)alkyl]COO(C.sub.1-C.sub.6)alkyl; and R.sup.20
is chosen from a carboxylic acid, a carboxamide, a carboxylic
ester, a primary, secondary or tertiary alcohol and a primary,
secondary or tertiary amine.
28. A salt of a compound of claim 1 wherein the salt is a
pharmaceutically acceptable salt.
29. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and a compound or pharmaceutically acceptable
salt according to claim 1.
30. A pharmaceutical composition comprising (a) a pharmaceutically
acceptable carrier; (b) a compound or pharmaceutically acceptable
salt according to claim 1; and (c) a second agent chosen from
cholinesterase inhibitors, NMDA antagonists, calpain inhibitors and
antioxidants.
31. A pharmaceutical composition according to claim 30 wherein said
second agent is chosen from tacrine, huperzine, donepezil,
lanicemine, remacemide, neramexane, memantine, vitamin E and
coenzyme Q10.
32. A method for the treatment or prophylaxis of a disease or
condition mediated by peripheral phosphodiesterase-4 comprising
administering to a mammal a therapeutically effective amount of a
compound according to claim 1.
33. A method according to claim 32 wherein said disease or
condition is chosen from stroke, myocardial infarct, and
cardiovascular inflammatory conditions.
34. A method according to claim 32 wherein said disease or
condition is cancer.
35. A method according to claim 32 wherein said disease or
condition is chosen from asthma and COPD.
36. A method for treating or preventing bone loss comprising
administering to a mammal a therapeutically effective amount of a
compound according to claim 1.
37. A method for treating bladder inflammation, bladder
overactivity and pain arising from bladder inflammation comprising
administering to a mammal a therapeutically effective amount of a
compound according to claim 1.
38. A compound or salt according to claim 21 wherein R.sup.27 and
R.sup.28 represent a fused heterocycle at 3- and 4-positions so
that the residue formed from R.sup.27 and R.sup.28 together with
the phenyl to which they are attached is chosen from:
##STR00115##
39. A compound or salt according to claim 21 wherein R.sup.27 is
chosen from halogen, nitro, acetyl, hydroxyethyl, amino,
methylthio, trifluoromethyl, methoxymethyl, methoxycarbonyl,
trifluoromethoxy, cyano and 1,3,4-thiadiazol-2-yl, or taken
together R.sup.7 and R.sup.8 are methylenedioxy or
difluoromethylenedioxy.
40. A compound or salt according to claim 39 wherein R.sup.1b or
R.sup.1c is chosen from a benzene ring, a triazole, a pyridine or
pyridine-N-oxide, a pyrazole, a tetrahydrothiophene, an imidazole,
a pyrimidine, a thiadiazole, and an imidazopyridine.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority from U.S. provisional
application 60/989,551, filed Nov. 21, 2007, the entire disclosure
of which is incorporated herein by reference. The application is
related to, but does not claim priority from, four other US
non-provisional applications filed of even date herewith and having
Jasbir Singh as a common inventor. The applications are titled
"BIARYL PDE4 INHIBITORS FOR TREATING INFLAMMATORY, CARDIOVASCULAR
AND CNS DISORDERS", "SUBSTITUTED BENZOAZOLE PDE4 INHIBITORS FOR
TREATING INFLAMMATORY, CARDIOVASCULAR AND CNS DISORDERS",
"SUBSTITUTED BENZOAZOLE PDE4 INHIBITORS FOR TREATING PULMONARY AND
CARDIOVASCULAR DISORDERS" and "4- (OR5-) SUBSTITUTED CATECHOL
DERIVATIVES". Their disclosures are incorporated herein by
reference.
FIELD OF THE INVENTION
[0002] The present invention relates to a chemical genus of biaryl
inhibitors of phosphodiesterase-4 (PDE4) useful for the treatment
and prevention of stroke, myocardial infarct and cardiovascular
inflammatory diseases and disorders.
BACKGROUND OF THE INVENTION
[0003] PDE4 is the major cAMP-metabolizing enzyme found in
inflammatory and immune cells. PDE4 inhibitors have proven
potential as anti-inflammatory drugs, especially in inflammatory
pulmonary diseases such as asthma, COPD and rhinitis. They suppress
the release of cytokines and other inflammatory signals and inhibit
the production of reactive oxygen species. A large number of PDE4
inhibitors have been developed for a variety of clinical
indications (Torphy and Page. 2000. TIPS 21, 157-159; Burnouf and
Pruniaux. 2002. Curr. Pharm. Design 8, 1255-1296; Lipworth. 2005.
Lancet 365, 167-175). To quote from a recent article in the British
Journal of Pharmacology, "PDE4 inhibitors have been in development
as a novel anti-inflammatory therapy since the 1980s with asthma
and chronic obstructive pulmonary disease (COPD) being primary
indications. Despite initial optimism, none have yet reached the
market. In most cases, the development of PDE4 inhibitors of
various structural classes, including cilomilast, filaminast,
lirimilast, piclamilast, tofimilast . . . has been discontinued due
to lack of efficacy. A primary problem is the low therapeutic ratio
of these compounds, which severely limits the dose that can be
given. Indeed, for many of these compounds it is likely that the
maximum tolerated dose is either sub-therapeutic or at the very
bottom of the efficacy dose-response curve. Therefore, the
challenge is to overcome this limitation." [Giembycz, Brit. J.
Pharmacol. 155, 288-290 (2008)]. Many of the PDE4 inhibitors of the
prior art have not reached the market because of the adverse side
effect of emesis (Giembycz 2005. Curr. Opin. Pharm. 5, 238-244).
Analysis of all known PDE4 inhibitors suggests that they are
competitive with cAMP and bind within the active site (Houslay et
al. 2005. DDT 10, 1503-1519); this may explain their narrow
therapeutic ratio. The compounds of the present invention are
non-competitive inhibitors of cAMP while being gene-specific
inhibitors (PDE4D), and, based on the target rationale and in vitro
potency, a person of skill in the art would expect the compounds to
be useful as anti-inflammatory agents for the treatment,
amelioration or prevention of inflammatory diseases and of
complications arising therefrom.
SUMMARY OF THE INVENTION
[0004] The present invention relates to compounds exhibiting PDE4
enzyme inhibition, having the general formula Ia, Ib, Ic or Id:
##STR00003##
[0005] In these compounds,
R.sup.1 is an optionally substituted carbocycle or optionally
substituted heterocycle of three or fewer rings; R.sup.1a is chosen
from
[0006] (a) a residue chosen from
##STR00004##
wherein R.sup.40 is chosen from H, halogen, OH, NH.sub.2 and
CH.sub.3;
[0007] (b) a substituted heterocycle of three or fewer rings or
substituted carbocycle of three or fewer rings; and
[0008] (c) a heterocycle that is itself substituted with a
heterocycle carrying a further substituent;
wherein substituents on the heterocycle or carbocycle are chosen
from hydroxy, carboxy, alkoxycarbonyl, carboxyalkylcarbonylamino,
carboxyalkylaminocarbonylamino, guanidino, 5-tetrazolyl, the
residue of an amino acid and the residue of an N-methylated amino
acid; R.sup.2 is an optionally substituted carbocycle or optionally
substituted heterocycle of two or fewer rings; R.sup.3 is chosen
from H, --C(.dbd.O)NH.sub.2, --(C.sub.1-C.sub.6)alkyl,
halo(C.sub.1-C.sub.6)alkyl, --(C.sub.1-C.sub.6)alkyl-R.sup.30,
--(C.sub.2-C.sub.6)alkyl-R.sup.31, and saturated 4- or 5-membered
heterocycle optionally substituted with methyl; R.sup.30 is chosen
from --C(.dbd.O)NH.sub.2 and 4- or 5-membered heterocycle
optionally substituted with methyl; R.sup.31 is chosen from
(C.sub.1-C.sub.4)alkoxy, amino, hydroxy,
(C.sub.1-C.sub.6)alkylamino and di(C.sub.1-C.sub.6)alkylamino;
R.sup.4 is chosen from H and F; R.sup.6 is chosen from H,
(C.sub.1-C.sub.6)alkyl and halogen;
X is N, N.fwdarw.O, or C--R.sup.5;
[0009] R.sup.5 is chosen from H, halogen, OH,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, CF.sub.3, CN,
NH.sub.2, CH.sub.2OH, CH.sub.2NH.sub.2 and C.ident.CH; and M is
chosen from direct bond, --C(R.sup.20)(R.sup.21)--, --O--,
--NR.sup.22--, --S(O).sub.n--, --C(.dbd.O)--,
--C(R.sup.20)(R.sup.21)C(R.sup.20)(R.sup.21)--,
--C(R.sup.20).dbd.C(R.sup.21)--, --C(R.sup.20)(R.sup.21)--O--,
--C(R.sup.20)(R.sup.21)--NR.sup.22--,
--C(R.sup.20)(R.sup.21)--S(O).sub.n--,
--C(R.sup.20)(R.sup.21)--C(.dbd.O)--, --O--C(R.sup.20)(R.sup.21)--,
--NR.sup.22--C(R.sup.20)(R.sup.21)--,
--S(O).sub.n--C(R.sup.20)(R.sup.21)--,
--C(.dbd.O)--C(R.sup.20)(R.sup.21)-- and
##STR00005##
is a five or six-membered ring optionally substituted with methyl;
n is zero, one or two; and R.sup.20, R.sup.21 and R.sup.22 are
selected independently in each occurrence from H and
(C.sub.1-C.sub.4)alkyl.
[0010] The present invention also relates to pharmaceutical
compositions comprising a pharmaceutically acceptable carrier and a
therapeutically effective amount of at least one compound of the
general formula I (i.e. Ia, Ib, Ic or Id) described above. When the
compound is present as a salt, the salt should be a
pharmaceutically acceptable salt.
[0011] In a third aspect, the invention relates to methods for the
treatment or prophylaxis of a disease or condition mediated by
peripheral (i.e. outside the CNS) phosphodiesterase-4. The methods
comprise administering to a mammal a therapeutically effective
amount of a compound having the general formula I. The compounds of
the invention do not appear to penetrate the blood-brain barrier
and are therefore of particular utility in treating peripherally
PDE4 mediated diseases without the liability of central side
effects, such as emesis. The disease or condition may be related to
allergic, acute or chronic inflammation. The disease may be, for
example, atherosclerosis, thrombosis, stroke, acute coronary
syndrome, stable angina, peripheral vascular disease, critical leg
ischemia, intermittent claudication, abdominal aortic aneurysm or
myocardial infarction.
[0012] Selective PDE4 inhibitors of the invention are also useful
for treating asthma and Chronic Obstructive Pulmonary Disease
(COPD). Compounds of the invention, which inhibit tumor growth and
metastases, also find utility in the treatment and prevention of
cancer, including esophageal cancer, brain cancer, pancreatic
cancer, and colon cancer. Compounds of the invention may also find
utility in the treatment and prevention of bone loss, bladder
inflammation, bladder overactivity or pain arising from bladder
inflammation.
[0013] These and other embodiments of the present invention will
become apparent in conjunction with the description and claims that
follow.
DETAILED DESCRIPTION OF THE INVENTION
[0014] Throughout this specification the substituents are defined
when introduced and retain their definitions.
[0015] Unless otherwise specified, alkyl is intended to include
linear, branched, or cyclic hydrocarbon structures and combinations
thereof. A combination would be, for example, cyclopropylmethyl.
Lower alkyl refers to alkyl groups of from 1 to 6 carbon atoms.
Examples of lower alkyl groups include methyl, ethyl, propyl,
isopropyl, butyl, s- and t-butyl and the like. Preferred alkyl
groups are those of C.sub.20 or below; C.sub.1 to C.sub.8 are more
preferred. Cycloalkyl is a subset of alkyl and includes cyclic
hydrocarbon groups of from 3 to 8 carbon atoms. Examples of
cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl
and the like.
[0016] C.sub.1 to C.sub.20 hydrocarbon includes alkyl, cycloalkyl,
polycycloalkyl, alkenyl, alkynyl, aryl and combinations thereof.
Examples include benzyl, phenethyl, cyclohexylmethyl, camphoryl and
naphthylethyl. Hydrocarbon refers to any substituent comprised of
hydrogen and carbon as the only elemental constituents.
[0017] Unless otherwise specified, the term "carbocycle" is
intended to include ring systems in which the ring atoms are all
carbon but of any oxidation state. Thus
(C.sub.3-C.sub.10)carbocycle refers to both non-aromatic and
aromatic systems, including such systems as cyclopropane, benzene,
cyclopentene and cyclohexene; (C.sub.8-C.sub.12)carbopolycycle
refers to such systems as norbornane, decalin, indane and
naphthalene. Carbocycle, if not otherwise limited, refers to
monocycles, bicycles and polycycles.
[0018] Alkoxy or alkoxyl refers to groups of from 1 to 8 carbon
atoms of a straight, branched or cyclic configuration and
combinations thereof attached to the parent structure through an
oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy,
cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to
groups containing one to four carbons. For the purpose of this
application, alkoxy and lower alkoxy include methylenedioxy and
ethylenedioxy. Alkoxyalkyl refers to ether groups of from 3 to 8
atoms of a straight, branched, cyclic configuration and
combinations thereof attached to the parent structure through an
alkyl. Examples include methoxymethyl, methoxyethyl, ethoxypropyl,
and the like. Alkoxyaryl refers to alkoxy substituents attached to
an aryl, wherein the aryl is attached to the parent structure.
Arylalkoxy refers to aryl substituents attached to an oxygen,
wherein the oxygen is attached to the parent structure. Substituted
arylalkoxy refers to a substituted aryl substituent attached to an
oxygen, wherein the oxygen is attached to the parent structure.
[0019] Oxaalkyl refers to alkyl residues in which one or more
carbons (and their associated hydrogens) have been replaced by
oxygen. Examples include methoxypropoxy; 3,6,9-trioxadecyl;
2,6,7-trioxabicyclo[2.2.2]octane and the like. The term oxaalkyl is
intended as it is understood in the art [see Naming and Indexing of
Chemical Substances for Chemical Abstracts, published by the
American Chemical Society, 196, but without the restriction of
127(a)], i.e. it refers to compounds in which the oxygen is bonded
via a single bond to its adjacent atoms (forming ether bonds); it
does not refer to doubly bonded oxygen, as would be found in
carbonyl groups. Similarly, thiaalkyl and azaalkyl refer to alkyl
residues in which one or more carbons has been replaced by sulfur
or nitrogen, respectively. Examples include ethylaminoethyl and
methylthiopropyl.
[0020] Unless otherwise specified, acyl refers to formyl and to
groups of 1, 2, 3, 4, 5, 6, 7 and 8 carbon atoms of a straight,
branched, cyclic configuration, saturated, unsaturated and aromatic
and combinations thereof, attached to the parent structure through
a carbonyl functionality. One or more carbons in the acyl residue
may be replaced by nitrogen, oxygen or sulfur as long as the point
of attachment to the parent remains at the carbonyl. Examples
include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl,
benzyloxycarbonyl and the like. Lower-acyl refers to groups
containing one to four carbons. The double bonded oxygen, when
referred to as a substituent itself is called "oxo".
[0021] Aryl and heteroaryl mean (i) a phenyl group (or benzene) or
a monocyclic 5- or 6-membered heteroaromatic ring containing 1-4
heteroatoms selected from O, N, or S; (ii) a bicyclic 9- or
10-membered aromatic or heteroaromatic ring system containing 0-4
heteroatoms selected from O, N, or S; or (iii) a tricyclic 13- or
14-membered aromatic or heteroaromatic ring system containing 0-5
heteroatoms selected from O, N, or S. Aryl, as understood herein,
includes residues in which one or more rings are aromatic, but not
all need be. Thus aromatic 6- to 14-membered carbocyclic rings
include, e.g., benzene, naphthalene, indane, tetralin, and fluorene
and the 5- to 10-membered aromatic heterocyclic rings include,
e.g., imidazole, pyridine, indole, thiophene, benzopyranone,
thiazole, furan, benzimidazole, quinoline, isoquinoline,
quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.
[0022] Arylalkyl refers to a substituent in which an aryl residue
is attached to the parent structure through alkyl. Examples are
benzyl, phenethyl and the like. Heteroarylalkyl refers to a
substituent in which a heteroaryl residue is attached to the parent
structure through alkyl. In one embodiment, the alkyl group of an
arylalkyl or a heteroarylalkyl is an alkyl group of from 1 to 6
carbons. Examples include, e.g., pyridinylmethyl, pyrimidinylethyl
and the like.
[0023] Heterocycle means a cycloalkyl or aryl carbocycle residue in
which from one to three carbons is replaced by a heteroatom
selected from the group consisting of N, O and S. The nitrogen and
sulfur heteroatoms may optionally be oxidized, and the nitrogen
heteroatom may optionally be quaternized. Unless otherwise
specified, a heterocycle may be non-aromatic or aromatic. It is to
be noted that heteroaryl is a subset of heterocycle in which the
heterocycle is aromatic. Examples of heterocyclic residues that
fall within the scope of the invention include pyrazole, pyrrole,
indole, quinoline, isoquinoline, tetrahydroisoquinoline,
benzofuran, benzodioxan, benzodioxole (commonly referred to as
methylenedioxyphenyl, when occurring as a substituent), morpholine,
thiazole, pyridine (including 2-oxopyridine), pyridine N-oxide,
pyrimidine, thiophene (i.e. thiene), furan, oxazole, oxazoline,
oxazolidine, isoxazolidine, isoxazole, dioxane, azetidine,
piperazine, piperidine, pyrrolidine, pyridazine, azepine,
pyrazolidine, imidazole, imidazoline, imidazolidine,
imidazolopyridine, pyrazine, thiazolidine, isothiazole,
1,2-thiazine-1,1-dioxide, quinuclidine, isothiazolidine,
benzimidazole, thiadiazole, benzopyran, benzothiazole,
benzotriazole, benzoxazole, tetrahydrofuran, tetrahydropyran,
benzothiene, thiamorpholine, thiamorpholine sulfoxide,
thiamorpholine sulfone, oxadiazole, triazole, tetrazole, isatin
(dioxoindole), phthalimide (dioxoisoindole), pyrrolopyridine,
triazolopyridine and the dihydro and tetrahydro congeners of the
fully unsaturated ring systems among the foregoing.
[0024] An oxygen heterocycle is a heterocycle containing at least
one oxygen in the ring; it may contain additional oxygens, as well
as other heteroatoms. Oxygen heterocycles found in the examples of
the invention include tetrahydrofuran, benzodioxole, morpholine,
isoxazole and 2,6,7-trioxabicyclo[2.2.2]octane. A sulphur
heterocycle is a heterocycle containing at least one sulphur in the
ring; it may contain additional sulphurs, as well as other
heteroatoms. A nitrogen heterocycle is a heterocycle containing at
least one nitrogen in the ring; it may contain additional
nitrogens, as well as other heteroatoms.
[0025] As used herein, the term "optionally substituted" may be
used interchangeably with "unsubstituted or substituted". The term
"substituted" refers to the replacement of one or more hydrogen
atoms in a specified group with a specified radical. For example,
substituted alkyl, aryl, cycloalkyl, heterocyclyl etc. refer to
alkyl, aryl, cycloalkyl, or heterocyclyl wherein up to three H
atoms in each residue are replaced with halogen, haloalkyl, alkyl,
acyl, alkoxyalkyl, hydroxyalkyl, carbonyl (i.e. oxo), phenyl,
heteroaryl, benzenesulfonyl, hydroxy, alkoxy, haloalkoxy, oxaalkyl,
carboxy, carboxyalkyl, carboxyalkoxy, carboxyalkylthio,
alkoxycarbonyl [--C(.dbd.O)O-alkyl], alkoxycarbonylamino
[--NHC(.dbd.O)O-alkyl], alkoxycarbonylaminoalkyl
[-alkyl-NHC(.dbd.O)O-alkyl], carboxyalkylcarbonylamino
[--NHC(.dbd.O)-alkyl-COOH], carboxamido [--C(.dbd.O)NH.sub.2],
aminocarbonyloxy [--OC(.dbd.O)NH.sub.2], alkylaminocarbonyl
[--C(.dbd.O)NH-alkyl], dialkylaminocarbonyl
[--C(.dbd.O)N(alkyl).sub.2], aminocarbonylalkyl
[-alkyl-C(.dbd.O)NH.sub.2], cyano, acetoxy, nitro, amino,
alkylamino, dialkylamino, aminoalkyl, (alkyl)(aryl)aminoalkyl,
alkylaminoalkyl (including cycloalkylaminoalkyl),
dialkylaminoalkyl, dialkylaminoalkoxy, alkyl(hydroxyalkyl)amino,
heterocyclylalkoxy, mercapto, alkylthio, alkylsulfonyl,
alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, arylthio,
arylsulfonyl, arylsulfonylamino, arylsulfinyl, arylsulfonyl,
acylaminoalkyl, acylaminoalkoxy, acylamino, amidino, aryl, benzyl,
heterocyclyl, heterocyclylalkyl, phenoxy, benzyloxy, heteroaryloxy,
heterocyclylamino, hydroxyimino, alkoxyimino, oxaalkyl,
aminosulfonyl, trityl, amidino, guanidino, ureido,
--NHC(.dbd.O)NHalkyl, --NHC(.dbd.O)NH-heterocyclyl,
-alkyl-NHC(.dbd.O)N(alkyl).sub.2, heterocyclylalkylcarbonylamino,
benzyloxyphenyl, and benzyloxy. Although oxo is included among the
substituents referred to in "optionally substituted", it will be
appreciated by persons of skill in the art that, because oxo is a
divalent radical, there are circumstances in which it will not be
appropriate as a substituent (e.g. on phenyl). Additional
substituents that are considered within the scope of the term,
particularly for R.sup.1, are the are the residues of amino acids,
amino acid amides, protected residues of aminoacids and their
amides, and N-methylated (mono- or di-, as appropriate) amino acids
and amino acid amides.
[0026] For the purpose of R.sup.1, the substituents alkyl, acyl,
alkoxyalkyl, hydroxyloweralkyl, phenyl, heteroaryl,
benzenesulfonyl, loweralkoxy, haloalkoxy, oxaalkyl, alkoxycarbonyl,
alkoxycarbonylamino, carboxamido, alkylaminocarbonyl, amino,
alkylamino, (alkyl)(aryl)aminoalkyl, alkylaminoalkyl,
heterocyclylalkoxy, alkylthio, sulfonylamino, alkylsulfinyl,
alkylsulfonyl, acylaminoalkyl, acylaminoalkoxy, acylamino, amidino,
aryl, benzyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkoxy,
phenoxy, benzyloxy, heteroaryloxy, heterocyclylamino, oxaalkyl,
aminosulfonyl, amidino, guanidino, ureido, benzyloxyphenyl, and
benzyloxy may be further substituted with one or two substituents
from the list of substituents above. Substituents that are
considered within the scope of the term, particularly for R.sup.1,
are the are the residues of amino acids, amino acid amides and
protected residues of aminoacids and their amides, as well as the
following specific residues: --CH.sub.3, --CH.sub.2CF.sub.3,
--CF.sub.3, --CHO, --COOH, --CN, halogen, --OH, --OEt,
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NHEt,
--C(.dbd.O)NMe.sub.2-COOCH.sub.3, --COOEt,
--CH.sub.2NHC(.dbd.O)NH.sub.2, --CH(CH.sub.3)NHC(.dbd.O)NH.sub.2,
--CH.sub.2NHC(.dbd.O)H, --CH.sub.2NHC(.dbd.O)CH.sub.3,
--CH.sub.2C(.dbd.O)NH.sub.2, --CH.sub.2COOH, --CH.sub.2COOEt,
--CH.sub.2NHC(.dbd.O)OEt, --CH.sub.2NHC(.dbd.O)O--C.sub.6H.sub.5,
--CH.sub.2NHC(.dbd.O)C(.dbd.O)NH.sub.2, --CH.sub.2NHC(.dbd.O)NHEt,
--C(CH.sub.3).sub.2OH, --CH.sub.2NHC(.dbd.O)N(CH.sub.3).sub.2,
--CH.sub.2NHC(.dbd.O)NHCH.sub.3, --CH.sub.2NH.sub.2,
--CH(CH.sub.3)NH.sub.2, --C(CH.sub.3).sub.2NH.sub.2, --CH.sub.2OH,
--CH.sub.2CH.sub.2OH, --CH.sub.2NHSO.sub.2CH.sub.3,
--CH.sub.2C(.dbd.O)NHEt, --OCH(CH.sub.3)COOH, --SCH.sub.2COOH,
--OCH.sub.3, --OC(.dbd.O)NH.sub.2,
--OCH.sub.2CH.sub.2N(CH.sub.3).sub.2, --OCH.sub.2CH.sub.2OCH.sub.3,
--NHC(.dbd.O)NH.sub.2, --NHC(.dbd.O)NHEt, --NHCH.sub.3, --NHEt,
--NH(tBoc), --NHCH.sub.2COOH ("residue of glycine"),
--N(CH.sub.3)CH.sub.2COOH ("residue of N-methylglycine"),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2Cl, --NHSO.sub.2NH.sub.2, --NHEt,
--N(CH.sub.3).sub.2, --NH.sub.2, --NH(CH.sub.3)C(.dbd.O)NH.sub.2,
--NHSO.sub.2CH.sub.3, --N(SO.sub.2CH.sub.3).sub.2,
--NHC(.dbd.O)OCH.sub.3, --NHC(.dbd.O)OtBu, --NHC(.dbd.O)CH.sub.3,
--SO.sub.2NH.sub.2, --NHC(.dbd.O)CH.sub.2CH.sub.2COOH,
--NHC(.dbd.O)NHCH.sub.2COOH, --CH.sub.2NHCHO,
--NHC(.dbd.O)NHCH.sub.2COOEt, --NHC(.dbd.O)NH(CH.sub.2).sub.3COOEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.2COOEt,
--N(CH.sub.3)CH.sub.2CH.sub.2OH, --NHC(.dbd.O)OEt,
--N(Et)C(.dbd.O)OEt, --NHC(.dbd.O)NH(CH.sub.2).sub.2COOH,
--NHC(.dbd.O)CH.sub.2N(CH.sub.3).sub.2,
--NHC(.dbd.O)NH(CH.sub.2).sub.3COOH, --NHC(.dbd.O)CH.sub.2NH.sub.2,
--NHC(.dbd.O)CH.sub.2CH.sub.2NH.sub.2,
--NHC(.dbd.O)CH.sub.2NH(tBoc),
##STR00006##
The term "a residue of an amino acid, amino acid amide", etc.
refers to an amino acid etc. minus the functional groups that are
considered part of the bond to the parent structure. For example,
in the molecule illustrated below:
##STR00007##
after one subtracts the hydrogen that connects N-methyl alanine to
the phenyl ring, the structure of A that remains is:
##STR00008##
This is not sensu stricto an N-methyl amino acid, since it lacks
the hydrogen on the amino terminus. This and similar structures
that lack atoms at the points of attachment (e.g. the H of
NH.sub.2) are referred to herein as "residues" of their respective
parents.
[0027] The terms "haloalkyl" and "haloalkoxy" mean alkyl or alkoxy,
respectively, substituted with one or more halogen atoms. The terms
"alkylcarbonyl" and "alkoxycarbonyl" mean --C(.dbd.O)alkyl or
--C(O)alkoxy, respectively.
[0028] The term "halogen" means fluorine, chlorine, bromine or
iodine. In one embodiment, halogen may be fluorine or chlorine.
[0029] Substituents R.sup.n are generally defined when introduced
and retain that definition throughout the specification and in all
independent claims.
[0030] In the characterization of some of the substituents, it is
recited that certain substituents may combine to form rings. Unless
stated otherwise, it is intended that such rings may exhibit
various degrees of unsaturation (from fully saturated to fully
unsaturated), may include heteroatoms and may be substituted with
lower alkyl or alkoxy.
[0031] It will be recognized that the compounds of this invention
can exist in radiolabeled form, i.e., the compounds may contain one
or more atoms containing an atomic mass or mass number different
from the atomic mass or mass number usually found in nature.
Radioisotopes of hydrogen, carbon, phosphorous, fluorine, and
chlorine include .sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N,
.sup.35S, .sup.18F, and .sup.36Cl, respectively. Compounds that
contain those radioisotopes and/or other radioisotopes of other
atoms are within the scope of this invention. Tritiated, i.e.
.sup.3H, and carbon-14, i.e., .sup.14C, radioisotopes are
particularly preferred for their ease in preparation and
detectability. Compounds that contain isotopes .sup.11C, .sup.13N,
.sup.15O and .sup.18F are well suited for positron emission
tomography. Radiolabeled compounds of formula I of this invention
and prodrugs thereof can generally be prepared by methods well
known to those skilled in the art. Conveniently, such radiolabeled
compounds can be prepared by carrying out the procedures disclosed
in the Examples and Schemes by substituting a readily available
radiolabeled reagent for a non-radiolabeled reagent.
[0032] As used herein (particularly in the claims), and as would be
understood by the person of skill in the art, the recitation of "a
compound" is intended to include salts, solvates, co-crystals and
inclusion complexes of that compound as well as any stereoisomeric
form, or a mixture of any such forms of that compound in any ratio.
Thus, in accordance with some embodiments of the invention, a
compound as described herein, including in the contexts of
pharmaceutical compositions, methods of treatment, and compounds
per se, is provided as the salt form. Thus, for example, the
recitation "a compound of formula I" as depicted above, in which
R.sup.1 is imidazolyl, would include imidazolium salts. In a
particular embodiment, the term "compound of formula I" refers to
the compound or a pharmaceutically acceptable salt thereof.
[0033] The compounds described herein may contain asymmetric
centers and may thus give rise to enantiomers, diastereomers, and
other stereoisomeric forms. Each chiral center may be defined, in
terms of absolute stereochemistry, as (R)- or (S)-. The present
invention is meant to include all such possible isomers, in any
ratio from racemic to optically pure forms. Optically active (R)-
and (S)-isomers may be prepared using chiral synthons or chiral
reagents, or resolved using conventional techniques. The prefix
"rac" refers to a racemate. When the compounds described herein
contain olefinic double bonds or other centers of geometric
asymmetry, and unless specified otherwise, it is intended that the
compounds include both E and Z geometric isomers. The
representation of the configuration of any carbon-carbon double
bond appearing herein is selected for convenience only, and unless
explicitly stated, is not intended to designate a particular
configuration. Thus a carbon-carbon double bond depicted
arbitrarily as E may be Z, E, or a mixture of the two in any
proportion. Likewise, all tautomeric forms are also intended to be
included.
[0034] The term "solvate" refers to a compound of Formula I in the
solid state, wherein molecules of a suitable solvent are
incorporated in the crystal lattice. A suitable solvent for
therapeutic administration is physiologically tolerable at the
dosage administered. Examples of suitable solvents for therapeutic
administration are ethanol and water. When water is the solvent,
the solvate is referred to as a hydrate. In general, solvates are
formed by dissolving the compound in the appropriate solvent and
isolating the solvate by cooling or using an antisolvent. The
solvate is typically dried or azeotroped under ambient conditions.
Inclusion complexes are described in Remington: The Science and
Practice of Pharmacy 19.sup.th Ed. (1995) volume 1, page 176-177,
which is incorporated herein by reference. The most commonly
employed inclusion complexes are those with cyclodextrins, and all
cyclodextrin complexes, natural and synthetic, are specifically
encompassed within the claims.
[0035] The term "pharmaceutically acceptable salt" refers to salts
prepared from pharmaceutically acceptable non-toxic acids or bases
including inorganic acids and bases and organic acids and bases.
When the compounds of the present invention are basic, salts may be
prepared from pharmaceutically acceptable non-toxic acids including
inorganic and organic acids. Suitable pharmaceutically acceptable
anions for the compounds of the present invention include acetate,
benzenesulfonate (besylate), benzoate, bicarbonate, bisulfate,
carbonate, camphorsulfonate, citrate, ethanesulfonate, fumarate,
gluconate, glutamate, glycolate, bromide, chloride, isethionate,
lactate, maleate, malate, mandelate, methanesulfonate, mucate,
nitrate, pamoate, pantothenate, phosphate, succinate, sulfate,
tartrate, trifluoroacetate, p-toluenesulfonate, acetamidobenzoate,
adipate, alginate, aminosalicylate, anhydromethylenecitrate,
ascorbate, aspartate, calcium edetate, camphorate, camsylate,
caprate, caproate, caprylate, cinnamate, cyclamate,
dichloroacetate, edetate (EDTA), edisylate, embonate, estolate,
esylate, fluoride, formate, gentisate, gluceptate, glucuronate,
glycerophosphate, glycolate, glycollylarsanilate, hexylresorcinate,
hippurate, hydroxynaphthoate, iodide, lactobionate, malonate,
mesylate, napadisylate, napsylate, nicotinate, oleate, orotate,
oxalate, oxoglutarate, palmitate, pectinate, pectinate polymer,
phenylethylbarbiturate, picrate, pidolate, propionate, rhodanide,
salicylate, sebacate, stearate, tannate, theoclate, tosylate and
the like. The desired salt may be obtained by ion exchange of
whatever counter ion is obtained in the synthesis of the quat.
These methods are well known to persons of skill. Although
pharmaceutically acceptable counter ions will be preferred for
preparing pharmaceutical formulations, other anions are quite
acceptable as synthetic intermediates. When the compounds contain
an acidic side chain, suitable pharmaceutically acceptable base
addition salts for the compounds of the present invention include
metallic salts made from aluminum, calcium, lithium, magnesium,
potassium, sodium and zinc or organic salts made from lysine,
N,N'-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and
procaine.
[0036] The graphic representations of racemic, ambiscalemic and
scalemic or enantiomerically pure compounds used herein are taken
from Maehr J. Chem. Ed. 62, 114-120 (1985): solid and broken wedges
are used to denote the absolute configuration of a chiral element;
wavy lines and single thin lines indicate disavowal of any
stereochemical implication which the bond it represents could
generate; solid and broken bold lines are geometric descriptors
indicating the relative configuration shown but denoting racemic
character; and wedge outlines and dotted or broken lines denote
enantiomerically pure compounds of indeterminate absolute
configuration.
[0037] Terminology related to "protecting", "deprotecting" and
"protected" functionalities occurs throughout this application.
Such terminology is well understood by persons of skill in the art
and is used in the context of processes that involve sequential
treatment with a series of reagents. In that context, a protecting
group refers to a group, which is used to mask a functionality
during a process step in which it would otherwise react, but in
which reaction is undesirable. The protecting group prevents
reaction at that step, but may be subsequently removed to expose
the original functionality. The removal or "deprotection" occurs
after the completion of the reaction or reactions in which the
functionality would interfere. Thus, when a sequence of reagents is
specified, as it is in the processes of the invention, the person
of ordinary skill can readily envision those groups that would be
suitable as "protecting groups". Suitable groups for that purpose
are discussed in standard textbooks in the field of chemistry, such
as Protective Groups in Organic Synthesis by T. W. Greene [John
Wiley & Sons, New York, 1991], which is incorporated herein by
reference.
[0038] A comprehensive list of abbreviations utilized by organic
chemists appears in the first issue of each volume of the Journal
of Organic Chemistry. The list, which is typically presented in a
table entitled "Standard List of Abbreviations", is incorporated
herein by reference.
[0039] In general, the compounds of the present invention may be
prepared by the methods illustrated in the general reaction schemes
as, for example, described below, or by modifications thereof,
using readily available starting materials, reagents and
conventional synthesis procedures. In these reactions, it is also
possible to make use of variants that are in themselves known, but
are not mentioned here. The starting materials, are either
commercially available, synthesized as described in the examples or
may be obtained by the methods well known to persons of skill in
the art.
[0040] PDE4 inhibitors have been shown to be effective therapeutic
agents in clinical studies. For example, administration of
cilomilast and roflumilast (PDE4 inhibitors) to patients suffering
from asthma and COPD showed initially excellent results, although
the effect of cilomilast disappeared on long-term trial [Lipworth,
Lancet 365, 167-175 (2005)]. Genetic studies have clearly
demonstrated an association between PDE4D and ischemic stroke
(Gretarsdottir et al. 2003. Nature Genetics. 35, 1-8). Selective
PDE4 inhibitors (e.g. rolipram) are also useful for treating bone
loss [Yao et al., J. Musculoskelet. Neuronal Interact. 7, 119-130
(2007)].
[0041] Additionally, a PDE4 inhibitor, YM976, was shown to
ameliorate the effects of experimentally-induced interstitial
cystitis in rats, resulting in a decrease in the frequency of
urination and an increase in the volume of urine at each time of
urination [Kitta et al., BJU Int. 102, 1472-1476 (2008)]. Another
PDE4 inhibitor, IC485, was shown to be equally efficacious as
tolteradine tartrate, a marketed drug for treating overactive
bladder, in a rodent model of obstructive bladder [Kaiho et al. BJU
Int. 101, 615-20 (2008)]. These findings suggest that PDE4
inhibitors will be useful in treating symptoms of bladder
overactivity, inflammation and pain.
[0042] Furthermore, the compounds, compositions and methods of the
present invention may be useful in treating cancer.
Phosphodiesterase activity has been shown to be associated with
hematological malignancies [Lerner et al., Biochem. J. 393, 21-41
(2006); Ogawa et al., Blood 99, 3390-3397 (2002)].
[0043] Furthermore, the compounds, compositions and methods of the
present invention, particularly when radiolabeled as described
above or labeled by methods well-known in the art with florescent
and spin labels, may be employed as imaging agents and in other
ways for diagnosis and/or treatment. Moreover, immobilization of
compounds of the invention on solid support could be of utility for
affinity purification and modification of compounds of the
invention with chemically active groups may be used for protein
labeling.
[0044] For many of the utilities outlined above, it may be
advantageous to administer compounds of the general formula I
together with cholinesterase inhibitors (e.g. tacrine, huperzine,
donepezil); NMDA antagonists (e.g. lanicemine, remacemide,
neramexane, memantine); calpain inhibitors (e.g. CEP-3122);
antioxidants (e.g. vitamin E, coenzyme Q10) and agents that have
shown clinical efficacy but whose mechanism is unclear (e.g.
dimebon).
[0045] The terms "methods of treating or preventing" mean
amelioration, prevention or relief from the symptoms and/or effects
associated with disorders. The term "preventing" as used herein
refers to administering a medicament beforehand to forestall or
obtund an acute episode. The person of ordinary skill in the
medical art (to which the present method claims are directed)
recognizes that the term "prevent" is not an absolute term. In the
medical art it is understood to refer to the prophylactic
administration of a drug to substantially diminish the likelihood
or seriousness of a condition, and this is the sense intended in
applicants' claims. As used herein, reference to "treatment" of a
patient is intended to include prophylaxis.
[0046] The term "mammal" is used in its dictionary sense. Humans
are included in the group of mammals, and humans would be the
preferred subjects of the methods.
[0047] While it may be possible for compounds of formula I to be
administered as the raw chemical, it will often be preferable to
present them as part of a pharmaceutical composition. In accordance
with an embodiment of the present invention there is provided a
pharmaceutical composition comprising a compound of formula I or a
pharmaceutically acceptable salt thereof, together with one or more
pharmaceutically carriers thereof and optionally one or more other
therapeutic ingredients. The carrier(s) must be "acceptable" in the
sense of being compatible with the other ingredients of the
formulation and not deleterious to the recipient thereof.
Furthermore, when reference is made in an independent claim to a
compound or a pharmaceutically acceptable salt thereof, it will be
understood that claims which depend from that independent claim
which refer to such a compound also include pharmaceutically
acceptable salts of the compound, even if explicit reference is not
made to the salts in the dependent claim.
[0048] The formulations include those suitable for oral, parenteral
(including subcutaneous, intradermal, intramuscular, intravenous
and intraarticular), rectal and topical (including dermal, buccal,
sublingual and intraocular) administration. The most suitable route
may depend upon 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. Such methods include the step of bringing into
association a compound of formula I or a pharmaceutically
acceptable salt 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.
[0049] 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.
[0050] A tablet 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 a binder, lubricant, inert diluent, lubricating, surface
active or dispersing agent. 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 sustained, delayed
or controlled release of the active ingredient therein. The
pharmaceutical compositions may include a "pharmaceutically
acceptable inert carrier", and this expression is intended to
include one or more inert excipients, which include starches,
polyols, granulating agents, microcrystalline cellulose, diluents,
lubricants, binders, disintegrating agents, and the like. If
desired, tablet dosages of the disclosed compositions may be coated
by standard aqueous or nonaqueous techniques, "Pharmaceutically
acceptable carrier" also encompasses controlled release means.
[0051] Pharmaceutical compositions may also optionally include
other therapeutic ingredients, anti-caking agents, preservatives,
sweetening agents, colorants, flavors, desiccants, plasticizers,
dyes, and the like. Any such optional ingredient must be compatible
with the compound of formula I to insure the stability of the
formulation. The composition may contain other additives as needed,
including for example lactose, glucose, fructose, galactose,
trehalose, sucrose, maltose, raffinose, maltitol, melezitose,
stachyose, lactitol, palatinite, starch, xylitol, mannitol,
myoinositol, and the like, and hydrates thereof, and amino acids,
for example alanine, glycine and betaine, and peptides and
proteins, for example albumen.
[0052] Examples of excipients for use as the pharmaceutically
acceptable carriers and the pharmaceutically acceptable inert
carriers and the aforementioned additional ingredients include, but
are not limited to binders, fillers, disintegrants, lubricants,
anti-microbial agents, and coating agents.
[0053] The dose range for adult humans is generally from 0.005 mg
to 10 g/day orally. Tablets or other forms of presentation provided
in discrete units may conveniently contain an amount of compound of
formula I which is effective at such dosage or as a multiple of the
same, for instance, units containing 5 mg to 500 mg, usually around
10 mg to 200 mg. The precise amount of compound administered to a
patient will be the responsibility of the attendant physician.
However, the dose employed will depend on a number of factors,
including the age and sex of the patient, the precise disorder
being treated, and its severity.
[0054] A dosage unit (e.g. an oral dosage unit) can include from,
for example, 1 to 30 mg, 1 to 40 mg, 1 to 100 mg, 1 to 300 mg, 1 to
500 mg, 2 to 500 mg, 3 to 100 mg, 5 to 20 mg, 5 to 100 mg (e.g. 1
mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg,
12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 25
mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg,
75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 150 mg, 200 mg, 250 mg,
300 mg, 350 mg, 400 mg, 450 mg, 500 mg) of a compound described
herein.
[0055] For additional information about pharmaceutical compositions
and their formulation, see, for example, Remington: The Science and
Practice of Pharmacy, 20.sup.th Edition, 2000. The agents can be
administered, e.g., by intravenous injection, intramuscular
injection, subcutaneous injection, intraperitoneal injection,
topical, sublingual, intraarticular (in the joints), intradermal,
buccal, ophthalmic (including intraocular), intranasally (including
using a cannula), or by other routes. The agents can be
administered orally, e.g., as a tablet or cachet containing a
predetermined amount of the active ingredient, gel, pellet, paste,
syrup, bolus, electuary, slurry, capsule, powder, granules, as a
solution or a suspension in an aqueous liquid or a non-aqueous
liquid, as an oil-in-water liquid emulsion or a water-in-oil liquid
emulsion, via a micellar formulation (see, e.g. WO 97/11682) via a
liposomal formulation (see, e.g., EP 736299, WO 99/59550 and WO
97/13500), via formulations described in WO 03/094886 or in some
other form. The agents can also be administered transdermally (i.e.
via reservoir-type or matrix-type patches, microneedles, thermal
poration, hypodermic needles, iontophoresis, electroporation,
ultrasound or other forms of sonophoresis, jet injection, or a
combination of any of the preceding methods (Prausnitz et al. 2004,
Nature Reviews Drug Discovery 3:115)). The agents can be
administered locally, for example, at the site of injury to an
injured blood vessel. The agents can be coated on a stent. The
agents can be administered using high-velocity transdermal particle
injection techniques using the hydrogel particle formulation
described in U.S. 20020061336. Additional particle formulations are
described in WO 00/45792, WO 00/53160, and WO 02/19989. An example
of a transdermal formulation containing plaster and the absorption
promoter dimethylisosorbide can be found in WO 89/04179. WO
96/11705 provides formulations suitable for transdermal
administration. The agents can be administered in the form a
suppository or by other vaginal or rectal means. The agents can be
administered in a transmembrane formulation as described in WO
90/07923. The agents can be administered non-invasively via the
dehydrated particles described in U.S. Pat. No. 6,485,706. The
agent can be administered in an enteric-coated drug formulation as
described in WO 02/49621. The agents can be administered
intranasally using the formulation described in U.S. Pat. No.
5,179,079. Formulations suitable for parenteral injection are
described in WO 00/62759. The agents can be administered using the
casein formulation described in U.S. 20030206939 and WO 00/06108.
The agents can be administered using the particulate formulations
described in U.S. 20020034536.
[0056] The agents, alone or in combination with other suitable
components, can be administered by pulmonary route utilizing
several techniques including but not limited to intratracheal
instillation (delivery of solution into the lungs by syringe),
intratracheal delivery of liposomes, insufflation (administration
of powder formulation by syringe or any other similar device into
the lungs) and aerosol inhalation. Aerosols (e.g., jet or
ultrasonic nebulizers, metered-dose inhalers (MDIs), and dry-Powder
inhalers (DPIs)) can also be used in intranasal applications.
Aerosol formulations are stable dispersions or suspensions of solid
material and liquid droplets in a gaseous medium and can be placed
into pressurized acceptable propellants, such as hydrofluoroalkanes
(HFAs, i.e. HFA-134a and HFA-227, or a mixture thereof),
dichlorodifluoromethane (or other chlorofluorocarbon propellants
such as a mixture of Propellants 11, 12, and/or 114), propane,
nitrogen, and the like. Pulmonary formulations may include
permeation enhancers such as fatty acids, and saccharides,
chelating agents, enzyme inhibitors (e.g., protease inhibitors),
adjuvants (e.g., glycocholate, surfactin, span 85, and nafamostat),
preservatives (e.g., benzalkonium chloride or chlorobutanol), and
ethanol (normally up to 5% but possibly up to 20%, by weight).
Ethanol is commonly included in aerosol compositions as it can
improve the function of the metering valve and in some cases also
improve the stability of the dispersion. Pulmonary formulations may
also include surfactants which include but are not limited to bile
salts and those described in U.S. Pat. No. 6,524,557 and references
therein. The surfactants described in U.S. Pat. No. 6,524,557,
e.g., a C.sub.8-C.sub.16 fatty acid salt, a bile salt, a
phospholipid, or alkyl saccharide are advantageous in that some of
them also reportedly enhance absorption of the compound in the
formulation. Also suitable in the invention are dry powder
formulations comprising a therapeutically effective amount of
active compound blended with an appropriate carrier and adapted for
use in connection with a dry-Powder inhaler. Absorption enhancers
which can be added to dry powder formulations of the present
invention include those described in U.S. Pat. No. 6,632,456. WO
02/080884 describes new methods for the surface modification of
powders. Aerosol formulations may include U.S. Pat. No. 5,230,884,
U.S. Pat. No. 5,292,499, WO 017/8694, WO 01/78696, U.S. 2003019437,
U.S. 20030165436, and WO 96/40089 (which includes vegetable oil).
Sustained release formulations suitable for inhalation are
described in U.S. 20010036481A1, 20030232019A1, and U.S.
20040018243A1 as well as in WO 01/13891, WO 02/067902, WO
03/072080, and WO 03/079885. Pulmonary formulations containing
microparticles are described in WO 03/015750, U.S. 20030008013, and
WO 00/00176. Pulmonary formulations containing stable glassy state
powder are described in U.S. 20020141945 and U.S. Pat. No.
6,309,671. Other aerosol formulations are described in EP 1338272A1
WO 90/09781, U.S. Pat. No. 5,348,730, U.S. Pat. No. 6,436,367, WO
91/04011, and U.S. Pat. No. 6,294,153 and U.S. Pat. No. 6,290,987
describes a liposomal based formulation that can be administered
via aerosol or other means. Powder formulations for inhalation are
described in U.S. 20030053960 and WO 01/60341. The agents can be
administered intranasally as described in U.S. 20010038824.
[0057] Solutions of medicament in buffered saline and similar
vehicles are commonly employed to generate an aerosol in a
nebulizer. Simple nebulizers operate on Bernoulli's principle and
employ a stream of air or oxygen to generate the spray particles.
More complex nebulizers employ ultrasound to create the spray
particles. Both types are well known in the art and are described
in standard textbooks of pharmacy such as Sprowls' American
Pharmacy and Remington's The Science and Practice of Pharmacy.
Other devices for generating aerosols employ compressed gases,
usually hydrofluorocarbons and chlorofluorocarbons, which are mixed
with the medicament and any necessary excipients in a pressurized
container, these devices are likewise described in standard
textbooks such as Sprowls and Remington.
[0058] The agent can be incorporated into a liposome to improve
half-life. The agent can also be conjugated to polyethylene glycol
(PEG) chains. Methods for pegylation and additional formulations
containing PEG-conjugates (i.e. PEG-based hydrogels, PEG modified
liposomes) can be found in Harris and Chess, Nature Reviews Drug
Discovery 2:214-221 and the references therein. The agent can be
administered via a nanocochleate or cochleate delivery vehicle
(BioDelivery Sciences International). The agents can be delivered
transmucosally (i.e. across a mucosal surface such as the vagina,
eye or nose) using formulations such as that described in U.S. Pat.
No. 5,204,108. The agents can be formulated in microcapsules as
described in WO 88/01165. The agent can be administered
intra-orally using the formulations described in U.S. 20020055496,
WO 00/47203, and U.S. Pat. No. 6,495,120. The agent can be
delivered using nanoemulsion formulations described in WO
01/91728A2.
[0059] In general, compounds of formula I may be prepared by the
methods illustrated in the general reaction schemes as, for
example, described below, or by modifications thereof, using
readily available starting materials, reagents and conventional
synthesis procedures. In these reactions, it is also possible to
make use of variants that are in themselves known, but are not
mentioned here.
[0060] The present invention relates to compounds exhibiting PDE4
enzyme inhibition, having the general formula Ia, Ib, Ic or Id:
##STR00009##
In some embodiments of Ia or Ic, X is N or N.fwdarw.O; in others, X
is CR.sup.5. In another embodiment, M is chosen from direct bond,
--CH.sub.2--, --CH(OH)--, --C[(CH.sub.3)(OH)]--,
--C[(CH.sub.3)(NH.sub.2)]--, --C(.dbd.O)--, --O--, --NH--,
--N(CH.sub.3)--, --S(O).sub.n--, --CH.sub.2NH--,
--CH.sub.2CH.sub.2--, --CH.dbd.CH--, --CH.sub.2S(O).sub.n--,
--CH.sub.2O-- and
##STR00010##
[0061] In one embodiment, R.sup.1 or R.sup.1a is a substituted
phenyl. In another embodiment, R.sup.1 is an unsubstituted
heterocycle. In another embodiment, R.sup.1 or R.sup.1a is a
substituted heterocycle. In both heterocycle embodiments, the
heterocycle may be chosen from pyrazole, pyrrole, indole,
quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran,
benzodioxan, benzodioxole, morpholine, thiazole, pyridine, pyridine
N-oxide, pyrimidine, thiene, furan, oxazole, oxazoline,
oxazolidine, isoxazolidine, isoxazole, dioxane, azetidine,
piperazine, piperidine, pyrrolidine, pyridazine, azepine,
pyrazolidine, imidazole, imidazoline, imidazolidine, purine,
imidazolopyridine, pyrazine, thiazolidine, isothiazole,
1,2-thiazine-1,1-dioxide, 2,6,7-trioxabicyclo[2.2.2]octane,
quinuclidine, isothiazolidine, benzimidazole, thiadiazole,
benzopyran, benzothiazole, benzotriazole, benzoxazole,
benzoxadiazole, tetrahydrofuran, tetrahydropyran, benzothiene,
thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone,
oxadiazole, triazole, tetrazole, isoindole, pyrrolopyridine,
triazolopyridine and the dihydro and tetrahydro congeners thereof,
whether specifically named or not. For example, a dihydro congener
of indole would be indoline or dihydroindole; a tetrahydro congener
of pyridine would be piperidine. In a further embodiment, R.sup.1
is an optionally substituted heterocycle chosen from pyrazole,
benzodioxole, morpholine, thiazole, pyridine, pyridine N-oxide,
pyrimidine, thiene, oxazolidine, isoxazole, azetidine, piperazine,
pyrrolidine, imidazole, imidazolidine, imidazolopyridine, pyrazine,
1,2-thiazine-1,1-dioxide, benzimidazole, thiadiazole,
benzotriazole, benzoxazole, oxadiazole, triazole, tetrazole,
isoindole, pyrrolopyridine, triazolopyridine and their dihydro and
tetrahydro congeners.
[0062] In an embodiment, the substituted phenyl or substituted
heterocycle is substituted with a substituent chosen from halogen,
haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxyalkyl, carbonyl,
phenyl, heteroaryl, benzenesulfonyl, hydroxy, alkoxy, haloalkoxy,
oxaalkyl, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl,
alkoxycarbonylamino, carboxyalkyl, carboxyalkoxy, carboxyalkylthio,
alkoxycarbonylaminoalkyl, carboxyalkylcarbonylamino, carboxamido,
aminocarbonyloxy, alkylaminocarbonyl, dialkylaminocarbonyl,
aminocarbonylalkyl, cyano, acetoxy, nitro, amino, alkylamino,
dialkylamino, aminoalkyl, (alkyl)(aryl)aminoalkyl, alkylaminoalkyl,
dialkylaminoalkyl, dialkylaminoalkoxy, alkyl(hydroxyalkyl)amino,
heterocyclylalkoxy, mercapto, alkylthio, alkylsulfonyl,
alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, arylthio,
arylsulfonyl, arylsulfonylamino, arylsulfinyl, arylsulfonyl,
acylaminoalkyl, acylaminoalkoxy, acylamino, amidino, aryl, benzyl,
heterocyclyl, heterocyclylalkyl, phenoxy, benzyloxy, heteroaryloxy,
heterocyclylamino, hydroxyimino, alkoxyimino, oxaalkyl,
aminosulfonyl, trityl, amidino, guanidino, ureido,
--NHC(.dbd.O)NHalkyl, --NHC(.dbd.O)NH-heterocyclyl,
-alkyl-NHC(.dbd.O)N(alkyl).sub.2, heterocyclylalkylcarbonylamino,
benzyloxyphenyl, benzyloxy, the residues of amino acids, amino acid
amides, protected residues of aminoacids, protected residues of
amino acid amides, N-methylated amino acids and N-methylated amino
acid amides. Exemplary amino acids are glycine, alanine and
proline. Exemplary carboxyalkoxy and carboxyalkylthio are lactic
acid and thioglycollic acid respectively.
[0063] In another embodiment, the substituted phenyl or substituted
heterocycle is substituted with a substituent chosen from
--CH.sub.3, --CH.sub.2CF.sub.3, --CF.sub.3, --CHO, --COOH, --CN,
halogen, --OH, --OEt, --C(.dbd.O)NH.sub.2, --C(.dbd.O)NHEt,
--C(.dbd.O)NMe.sub.2-COOCH.sub.3, --COOEt,
--CH.sub.2NHC(.dbd.O)NH.sub.2, --CH(CH.sub.3)NHC(.dbd.O)NH.sub.2,
--CH.sub.2NHC(.dbd.O)H, --CH.sub.2NHC(.dbd.O)CH.sub.3,
--CH.sub.2C(.dbd.O)NH.sub.2, --CH.sub.2COOH, --CH.sub.2COOEt,
--CH.sub.2NHC(.dbd.O)OEt, --CH.sub.2NHC(.dbd.O)O--C.sub.6H.sub.5,
--CH.sub.2NHC(.dbd.O)C(.dbd.O)NH.sub.2, --CH.sub.2NHC(.dbd.O)NHEt,
--C(CH.sub.3).sub.2OH, --CH.sub.2NHC(.dbd.O)N(CH.sub.3).sub.2,
--CH.sub.2NHC(.dbd.O)NHCH.sub.3, --CH.sub.2NH.sub.2,
--CH(CH.sub.3)NH.sub.2, --C(CH.sub.3).sub.2NH.sub.2, --CH.sub.2OH,
--CH.sub.2CH.sub.2OH, --CH.sub.2NHSO.sub.2CH.sub.3,
--CH.sub.2C(.dbd.O)NHEt, --OCH.sub.3, --OC(.dbd.O)NH.sub.2,
--OCH.sub.2CH.sub.2N(CH.sub.3).sub.2, --OCH.sub.2CH.sub.2OCH.sub.3,
--OCH(CH.sub.3)COOH, --SCH.sub.2COOH, --NHC(.dbd.O)NH.sub.2,
--NHC(.dbd.O)NHEt, --NHCH.sub.3, --NHEt, --NH(tBoc),
--NHCH.sub.2COOH, --N(CH.sub.3)CH.sub.2COOH,
--NHC(.dbd.O)NHCH.sub.2CH.sub.2Cl, --NHSO.sub.2NH.sub.2, --NHEt,
--N(CH.sub.3).sub.2, --NH.sub.2, --NH(CH.sub.3)C(.dbd.O)NH.sub.2,
--NHSO.sub.2CH.sub.3, --N(SO.sub.2CH.sub.3).sub.2,
--NHC(.dbd.O)OCH.sub.3, --NHC(.dbd.O)OtBu, --NHC(.dbd.O)CH.sub.3,
--SO.sub.2NH.sub.2, --NHC(.dbd.O)CH.sub.2CH.sub.2COOH,
--NHC(.dbd.O)NHCH.sub.2COOH, --CH.sub.2NHCHO,
--NHC(.dbd.O)NHCH.sub.2COOEt, --NHC(.dbd.O)NH(CH.sub.2).sub.3COOEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.2COOEt,
--N(CH.sub.3)CH.sub.2CH.sub.2OH, --NHC(.dbd.O)OEt,
--N(Et)C(.dbd.O)OEt, --NHC(.dbd.O)NH(CH.sub.2).sub.2COOH,
--NHC(.dbd.O)CH.sub.2N(CH.sub.3).sub.2,
--NHC(.dbd.O)NH(CH.sub.2).sub.3COOH, --NHC(.dbd.O)CH.sub.2NH.sub.2,
--NHC(.dbd.O)CH.sub.2CH.sub.2NH.sub.2,
--NHC(.dbd.O)CH.sub.2NH(tBoc),
##STR00011##
[0064] In embodiments of formula Ia, R.sup.1a may be (1) a
substituted heterocycle of three or fewer rings; (2) a monocyclic
heterocycle attached to a substituted monocyclic heterocycle; or
(3) a substituted carbocycle of three or fewer rings. The
substituents on the heterocycle or carbocycle may be chosen from
--COOH, --OH, --COOCH.sub.3, --COOEt, --CH.sub.2COOH,
--CH.sub.2COOEt, --CH.sub.2NHC(.dbd.O)OEt,
--CH.sub.2NHC(.dbd.O)C(.dbd.O)NH.sub.2, --OCH(CH.sub.3)COOH,
--SCH.sub.2COOH, --NHCH.sub.2COOH, --N(CH.sub.3)CH.sub.2COOH,
--NHSO.sub.2NH.sub.2, --NHC(.dbd.O)CH.sub.2CH.sub.2COOH,
--NHC(.dbd.O)NHCH.sub.2COOH, --NHC(.dbd.O)NHCH.sub.2COOEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.3COOEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.2COOEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.2COOH,
--NHC(.dbd.O)NH(CH.sub.2).sub.3COOH and 5-tetrazolyl. An example of
the second class of embodiments, a monocyclic heterocycle attached
to a monocyclic heterocycle substituted with a carboxylic acid is
the R.sup.1a residue found in example A053 below:
##STR00012##
[0065] In an embodiment, R.sup.2 is chosen from optionally
substituted phenyl, optionally substituted monocyclic unsaturated
heterocycle, unsubstituted bicyclic unsaturated heterocycle and
fluoro-substituted bicyclic unsaturated heterocycle. In a further
embodiment, R.sup.2 is chosen from optionally substituted phenyl,
indole, benzodioxole, benzoxadiazole, benzodioxan, benzimidazole,
oxadiazole, pyrazole, pyridine and pyridine N-oxide. In a further
embodiment, R.sup.2 is chosen from meta-substituted phenyl, indole,
benzodioxole, 2,2-difluorobenzodioxole, benzooxadiazole,
benzimidazole, 5-(pyridin-4-yl)[1,2,4]oxadiazole,
5-(pyridin-4-yl)[1,3,4]oxadiazole, benzodioxan, 4-chloropyrazole,
4-(pyridin-4-yl)pyrazole, 6-chloropyridine,
3-(trifluoromethyl)pyrazole, and pyridine N-oxide.
[0066] In another embodiment, R.sup.2 is substituted phenyl:
##STR00013##
wherein R.sup.7 is chosen from hydrogen, halogen, nitro, cyano,
halo(C.sub.1-C.sub.6)alkyl, hydroxy, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)oxaalkyl, carboxy,
(C.sub.1-C.sub.6)alkoxycarbonyl, aminocarbonyl (--CONH.sub.2),
(C.sub.1-C.sub.6)alkylaminocarbonyl, acyl,
hydroxy(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy,
amino(C.sub.1-C.sub.6)alkyl, amino, (C.sub.1-C.sub.6)alkylamino,
di[(C.sub.1-C.sub.6)alkyl]amino, mercapto,
(C.sub.1-C.sub.6)alkylthio, (C.sub.1-C.sub.6)alkylsulfinyl,
(C.sub.1-C.sub.6)alkylsulfonyl, (C.sub.1-C.sub.6)alkylsulfonamido,
acylamino, amidino, phenyl, benzyl, heterocyclyl, phenoxy,
benzyloxy, and heteroaryloxy; and R.sup.8 and R.sup.13 are chosen
independently from H and F. In a further embodiment, R.sup.8 and
R.sup.13 are H and R.sup.7 is chosen from hydrogen, fluoro, chloro,
bromo, nitro, cyano, acetyl, trifluoromethyl, methoxy,
trifluoromethoxy, oxadiazolyl, tetrazolyl, methylthio,
methanesulfinyl, methanesulfonyl, methansulfonamido, amino,
methoxymethyl, hydroxyethyl, and morpholinyl.
[0067] In embodiments of formulae Ib and Ic, R.sup.1 may be chosen
from optionally substituted phenyl, optionally substituted five
membered heteroaryl, optionally substituted six-membered
heteroaryl, optionally substituted 4-7 membered non-aryl
heterocycle, and optionally substituted fused bicycle. For example,
R.sup.1 may be chosen from optionally substituted phenyls;
optionally substituted five membered heteroaryls selected from
thiazoles, thiadiazoles, pyrazoles, oxadiazole, isoxazoles,
triazoles, imidazoles, thiophenes, tetrazoles and oxazoles;
optionally substituted six membered hereroaryls selected from
pyridines, pyrimidines, pyridazinones, pyrimidinone, pyridinone,
pyrazines and diazines; optionally substituted 5- and 6-membered
non-aryl heterocyclics selected from tetrahydrothiophenes,
piperazine, oxazolidinones, imidazolidinones, morpholines,
piperidines, pyrrolidinones, pyrrolidinediones, pyrrolidines,
piperidinones, piperidinediones and trioxa-bicyclo[2.2.2]octanes;
and optionally substituted fused bicycles selected from
benzoxazolones, indoles, isoindolinediones,
2H-pyrrolopyridinediones, purines, indolinediones,
triazolopyridinones, benzimidazoles, benzoxadiazoles, quinolines
and quinolones; wherein the substituents are chosen independently
from hydrogen, halogen, halo(C.sub.1-C.sub.6)alkyl, hydroxyl,
(C.sub.1-C.sub.6)alkoxy, carboxy, (C.sub.1-C.sub.6)alkoxycarbonyl,
aminocarbonyl (--CONH.sub.2), (C.sub.1-C.sub.6)alkylaminocarbonyl,
cyano, carbonyl(oxo), acyl, hydroxy(C.sub.1-C.sub.6)alkyl,
halo(C.sub.1-C.sub.6)alkoxy, amino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, nitro, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
mercapto, (C.sub.1-C.sub.6)alkylthio, sulfoxide, sulfone,
sulfonate, sulfonimide, acylamino, amidino, phenyl, benzyl,
heteroaryl, phenoxy, benzyloxy, heteroaryloxy,
aminocarbonyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkyl,
carboxy(C.sub.1-C.sub.6)alkyl, formylamino(C.sub.1-C.sub.6)alkyl,
carboxy(C.sub.1-C.sub.6)alkylamino,
--(CH.sub.2).sub.p--NR.sup.12CO--(CH.sub.2).sub.q--NR.sup.9R.sup.10,
--NHSO.sub.2R.sup.11,
--OCH.sub.2CH.sub.2NR.sup.9R.sup.10--NHSO.sub.2NR.sup.9R.sup.10,
--SO.sub.2NR.sup.9R.sup.10, --(CH.sub.2)p--NHCOR.sup.9,
OCONR.sup.9R.sup.10 and NR.sup.12COOR.sup.11;
R.sup.3 is chosen from --CH.sub.3, --CH.sub.2CH.sub.3, --CF.sub.3,
--CHF.sub.2 and --CH.sub.2F; R.sup.5 is chosen from H, --F, --OH,
--CH.sub.3, --OCH.sub.3, --CF.sub.3, --CN, --NH.sub.2 and
--C.ident.CH;
R.sup.2 is
[0068] (a) phenyl and R.sup.7 is chosen from H, halogen, nitro,
acetyl, hydroxyethyl, --NH.sub.2, --SCH.sub.3, methoxycarbonyl,
--SOCH.sub.3, --SO.sub.2CH.sub.3, --OCH.sub.3, --OCF.sub.3, --CN,
--CF.sub.3, --CH.sub.2OCH.sub.3; or
[0069] (b) benzoxadiazole, benzodioxole, 2,2-difluorobenzodioxole,
benzoxadiazole, benzodioxan, benzimidazole, oxadiazole, pyrazole,
pyridine and pyridine N-oxide; [0070] R.sup.9 is chosen from H,
(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonyl, carboxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarboxy(C.sub.1-C.sub.6)alkyl; R.sup.10 is
H, (C.sub.1-C.sub.6)alkyl, or taken together, or R.sup.9 and
R.sup.10 together form a heterocycle optionally substituted with
(C.sub.1-C.sub.6)alkyl; p is 0 or 1, q is 0, 1 or 2, R.sup.11 is
linear (C.sub.1-C.sub.6)alkyl, R.sup.12 is H or
(C.sub.1-C.sub.6)alkyl; or two adjacent substituents together form
an optionally substituted fused heterocyclic ring.
[0071] In embodiments of formulae Ib and Ic, R.sup.1a may be chosen
from substituted phenyl; substituted five membered heteroaryls
selected from thiazoles, thiadiazoles, pyrazoles, oxadiazole,
isoxazoles, triazoles, imidazoles, thiophenes, tetrazoles and
oxazoles; substituted six membered heteroaryls selected from
pyridines, pyrimidines, pyridazinones, pyrimidinone, pyridinone,
pyrazines and diazines; substituted 5- and 6-membered non-aryl
heterocyclics selected from tetrahydrothiophenes, piperazine,
oxazolidinones, imidazolidinones, morpholines, piperidines,
pyrrolidinones, pyrrolidinediones, pyrrolidines, piperidinones,
piperidinediones and trioxa-bicyclo[2.2.2]octanes; and substituted
fused bicycles selected from benzoxazolones, indoles,
isoindolinediones, 2H-pyrrolopyridinediones, purines,
indolinediones, triazolopyridinones, benzimidazoles,
benzoxadiazoles, quinolines and quinolones. In these cases the
substituents are chosen independently from --COOH, --OH,
--COOCH.sub.3, --COOEt, --CH.sub.2COOH, --CH.sub.2COOEt,
--CH.sub.2NHC(.dbd.O)OEt, --CH.sub.2NHC(.dbd.O)C(.dbd.O)NH.sub.2,
--OCH(CH.sub.3)COOH, --SCH.sub.2COOH, --NHCH.sub.2COOH,
--N(CH.sub.3)CH.sub.2COOH, --NHSO.sub.2NH.sub.2,
--NHC(.dbd.O)CH.sub.2CH.sub.2COOH, --NHC(.dbd.O)NHCH.sub.2COOH,
--NHC(.dbd.O)NHCH.sub.2COOEt, --NHC(.dbd.O)NH(CH.sub.2).sub.3COOEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.2COOEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.2COOH,
--NHC(.dbd.O)NH(CH.sub.2).sub.3COOH and 5-tetrazolyl;
R.sup.3 is chosen from --CH.sub.3, --CH.sub.2CH.sub.3, --CF.sub.3,
--CHF.sub.2 and --CH.sub.2F; R.sup.5 is chosen from H, --F, --OH,
--CH.sub.3, --OCH.sub.3, --CF.sub.3, --CN, --NH.sub.2 and
--C.ident.CH;
R.sup.2 is
[0072] (a) phenyl and R.sup.7 is chosen from H, halogen, nitro,
acetyl, hydroxyethyl, --NH.sub.2, --SCH.sub.3, methoxycarbonyl,
--SOCH.sub.3, --SO.sub.2CH.sub.3, --OCH.sub.3, --OCF.sub.3, --CN,
--CF.sub.3, --CH.sub.2OCH.sub.3; or
[0073] (b) benzoxadiazole, benzodioxole, 2,2-difluorobenzodioxole,
benzoxadiazole, benzodioxan, benzimidazole, oxadiazole, pyrazole,
pyridine and pyridine N-oxide; [0074] R.sup.9 is chosen from H,
(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonyl, carboxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarboxy(C.sub.1-C.sub.6)alkyl; R.sup.10 is
H, (C.sub.1-C.sub.6)alkyl, or taken together, or R.sup.9 and
R.sup.10 together form a heterocycle optionally substituted with
(C.sub.1-C.sub.6)alkyl; p is 0 or 1, q is 0, 1 or 2, R.sup.11 is
linear (C.sub.1-C.sub.6)alkyl, [0075] R.sup.12 is H or
(C.sub.1-C.sub.6)alkyl; or two adjacent substituents together form
an optionally substituted fused heterocyclic ring.
[0076] One embodiment of compounds of the general class of Ia has
the formula
##STR00014##
wherein [0077] R.sup.1b is phenyl, five-membered heteroaryl,
six-membered heteroaryl, 4-7 membered non-aryl heterocycle or fused
bicycle; [0078] R.sup.14 is chosen from --COOH, --OH,
--COOCH.sub.3, --COOEt, --CH.sub.2COOH, --CH.sub.2COOEt,
--CH.sub.2NHC(.dbd.O)OEt, --CH.sub.2NHC(.dbd.O)C(.dbd.O)NH.sub.2,
--OCH(CH.sub.3)COOH, --SCH.sub.2COOH, --NHCH.sub.2COOH,
--N(CH.sub.3)CH.sub.2COOH, --NHSO.sub.2NH.sub.2,
--NHC(.dbd.O)CH.sub.2CH.sub.2COOH, --NHC(.dbd.O)NHCH.sub.2COOH,
--NHC(.dbd.O)NHCH.sub.2COOEt, --NHC(.dbd.O)NH(CH.sub.2).sub.3COOEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.2COOEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.2COOH,
--NHC(.dbd.O)NH(CH.sub.2).sub.3COOH, 5-tetrazolyl and monocyclic
heterocycle substituted with any of the foregoing; [0079] R.sup.27
is chosen from hydrogen, halogen, nitro, cyano,
halo(C.sub.1-C.sub.6)alkyl, hydroxy, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)oxaalkyl, carboxy,
(C.sub.1-C.sub.6)alkoxycarbonyl, aminocarbonyl (--CONH.sub.2),
(C.sub.1-C.sub.6)alkylaminocarbonyl, acyl,
hydroxy(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy,
amino(C.sub.1-C.sub.6)alkyl, amino, (C.sub.1-C.sub.6)alkylamino,
di[(C.sub.1-C.sub.6)alkyl]amino, mercapto,
(C.sub.1-C.sub.6)alkylthio, (C.sub.1-C.sub.6)alkylsulfinyl,
(C.sub.1-C.sub.6)alkylsulfonyl, (C.sub.1-C.sub.6)alkylsulfonamido,
acylamino, amidino, phenyl, benzyl, heterocyclyl, phenoxy,
benzyloxy, and heteroaryloxy; R.sup.28 is chosen from H and F, or
R.sup.27 together with R.sup.28 forms a five-membered ring. An
example of an R.sup.14 that is "a monocyclic heterocycle
substituted with any of the foregoing" is example A063 below in
which R.sup.14 is
##STR00015##
[0080] Embodiments of the general class of Ib and Ic have the
formulae:
##STR00016##
wherein [0081] R.sup.1c is phenyl, five-membered heteroaryl,
six-membered heteroaryl, 4-7 membered non-aryl heterocycle or fused
bicycle; [0082] R.sup.14 is chosen from H,
--CH.sub.2NHC(.dbd.O)NH.sub.2, --NHC(.dbd.O)NH.sub.2,
--NHC(.dbd.O)NHEt, --CH.sub.3, --CH.sub.2CF.sub.3,
--CH.sub.2NHC(.dbd.O)CH.sub.3, --NHCH.sub.3, --NHEt, --NH(tBoc),
--CHO, --NHC(.dbd.O)NHCH.sub.2CH.sub.2Cl, --NHSO.sub.2NH.sub.2,
--NHEt, --N(CH.sub.3).sub.2, --NH.sub.2, --COOH,
--OCH(CH.sub.3)COOH, --SCH.sub.2COOH, --C(.dbd.O)NH.sub.2,
--CH.sub.2C(.dbd.O)NH.sub.2, --CH.sub.2COOH, --CH.sub.2COOEt, --CN,
--OCH.sub.3, --OC(.dbd.O)NH.sub.2, --NH(CH.sub.3)C(.dbd.O)NH.sub.2,
halogen, --CH.sub.2NHC(.dbd.O)OEt, --NHSO.sub.2CH.sub.3,
--N(SO.sub.2CH.sub.3).sub.2, --NHC(.dbd.O)OCH.sub.3, --OH,
--CH.sub.2NHC(.dbd.O)N(CH.sub.3).sub.2, --CH.sub.2NH.sub.2,
--CH.sub.2OH, --CH.sub.2CH.sub.2OH, --SO.sub.2NH.sub.2,
--NHC(.dbd.O)NHCH.sub.2COOH, --CH.sub.2NHCHO,
--NHC(.dbd.O)NHCH.sub.2COOEt, --COOCH.sub.3, --COOEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.3COOEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.2COOEt, --NH(Et)C(.dbd.O)OEt,
--NHC(.dbd.O)NH(CH.sub.2).sub.2COOH, --CH.sub.2NHSO.sub.2CH.sub.3,
--OEt, --NHC(.dbd.O)CH.sub.2N(CH.sub.3).sub.2,
--NHC(.dbd.O)NH(CH.sub.2).sub.3COOH, --NHC(.dbd.O)CH.sub.2NH.sub.2,
--NHC(.dbd.O)CH.sub.2CH.sub.2NH.sub.2,
--NHC(.dbd.O)CH.sub.2NH(tBoc),
--OCH.sub.2CH.sub.2N(CH.sub.3).sub.2, --OCH.sub.2CH.sub.2OCH.sub.3,
3'-nitro-6-methoxybiphenyl-3-ylmethyl,
tetrahydroimidazol-2-on-1-yl,
3-methyltetrahydroimidazol-2-one-1-yl, pyrazol-1-yl,
##STR00017##
[0082] R.sup.15 is chosen from H, NO.sub.2, OH, NH.sub.2, and
--NHSO.sub.2NH.sub.2; or R.sup.15 together with R.sup.14 forms
methylene dioxy; [0083] R.sup.27 is chosen from hydrogen, halogen,
nitro, cyano, halo(C.sub.1-C.sub.6)alkyl, hydroxy,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)oxaalkyl, carboxy,
(C.sub.1-C.sub.6)alkoxycarbonyl, aminocarbonyl (--CONH.sub.2),
(C.sub.1-C.sub.6)alkylaminocarbonyl, acyl,
hydroxy(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy,
amino(C.sub.1-C.sub.6)alkyl, amino, (C.sub.1-C.sub.6)alkylamino,
di[(C.sub.1-C.sub.6)alkyl]amino, mercapto,
(C.sub.1-C.sub.6)alkylthio, (C.sub.1-C.sub.6)alkylsulfinyl,
(C.sub.1-C.sub.6)alkylsulfonyl, (C.sub.1-C.sub.6)alkylsulfonamido,
acylamino, amidino, phenyl, benzyl, heterocyclyl, phenoxy,
benzyloxy, and heteroaryloxy; R.sup.28 is chosen from H and F, or
R.sup.27 together with R.sup.28 forms a five-membered ring.
[0084] In further embodiments R.sup.27 and R.sup.28 represent a
fused heterocycle at 3- and 4-positions so that the residue formed
from R.sup.27 and R.sup.28 together with the phenyl to which they
are attached is chosen from:
##STR00018##
[0085] In other embodiments, R.sup.27 is chosen from halogen,
nitro, acetyl, hydroxyethyl, amino, methylthio, trifluoromethyl,
methoxymethyl, methoxycarbonyl, trifluoromethoxy, cyano and
1,3,4-thiadiazol-2-yl, or taken together R.sup.7 and R.sup.8 are
methylenedioxy or difluoromethylenedioxy. In the foregoing
embodiments, R.sup.1a may be chosen from a benzene ring, a
triazole, a pyridine or pyridine-N-oxide, a pyrazole, a
tetrahydrothiophene, an imidazole, a pyrimidine, a thiadiazole, and
an imidazopyridine.
[0086] In an embodiment of the invention, R.sup.5 is fluoro, H, CN
or OH. In other embodiments, R.sup.3 is methyl or fluoromethyl.
[0087] Another embodiment of compounds of the invention have the
formula
##STR00019##
In these compounds R.sup.3a is methyl, fluorinated methyl or
HSO.sub.3; Y is CH or N.fwdarw.O; R.sup.27a is chosen from halogen,
cyano, acetyl, methylthio, nitro and trifluoromethyl; and R.sup.16
is chosen from --NR.sup.17C(.dbd.O)NR.sup.18R.sup.19 and
##STR00020##
[0088] wherein
##STR00021##
is a 4-7 membered ring heterocycle attached through its nitrogen;
R.sup.17, and R.sup.18 are independently chosen from H,
(C.sub.1-C.sub.6)alkyl and halo(C.sub.1-C.sub.6)alkyl; R.sup.19 is
chosen from H, (C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl,
--[(C.sub.1-C.sub.6)alkyl]COOH, and
--[(C.sub.1-C.sub.6)alkyl]COO(C.sub.1-C.sub.6)alkyl; and R.sup.20
is chosen from a carboxylic acid, a carboxamide, a carboxylic
ester, a primary, secondary or tertiary alcohol and a primary,
secondary or tertiary amine. Examples of a carboxylic acid, a
carboxamide, a carboxylic ester, a primary, secondary or tertiary
alcohol and a primary, secondary or tertiary amine include --COOH,
--CONH.sub.2, --CONHCH.sub.3, --CON(CH.sub.3).sub.2, --COOCH.sub.3,
--CH.sub.2OH, --CH(CH.sub.3)OH, --C(CH.sub.3).sub.2OH,
--CH.sub.2NH.sub.2, --CH(CH.sub.3)NH.sub.2 and
--C(CH.sub.3).sub.2NH.sub.2.
[0089] All of the compounds falling within the foregoing parent
genera Ia, Ib and Ic are useful as peripheral PDE4 inhibitors. It
may be found upon examination that species and genera not presently
excluded are not patentable to the inventors in this application
because they have been disclosed. In this case, the exclusion of
species and genera in applicants' claims are to be considered
artifacts of patent prosecution and not reflective of the
inventors' concept or description of their invention. The
invention, in a composition aspect, is all active compounds of
formulae Ia, Ib and Ic except those that are in the public's
possession.
[0090] In general, the compounds of the present invention may be
prepared by the methods illustrated in the general reaction schemes
as, for example, described below, or by modifications thereof,
using readily available starting materials, reagents and
conventional synthesis procedures.
[0091] Generally compounds of the Formula I, where R.sup.2 is a
substituted aryl/heteroaryl and the two biaryl groups are linked by
a C--C bond, may be prepared from appropriately functionalized
alkoxy-aryl ether derivatives containing desirable functionalities
W, where W may for example be CH, N, COH, CF, etc (Route A, Scheme
A1). The biaryl portion can be constructed first, typically via
Suzuki or Stille coupling (G1->G2). In such case either
Y=halogen or OSO2R (OTf, ONf) and the other reagent would be
R2-B(OR)2 or R2-SnR3' or vise versa, where R2-halogen is coupled
with G1 containing boronate/boronic acid or trialkyltin as Y. When
A is a carbon derived substituent, e.g. CH3, CH2OH, CO2R'', CN etc.
these groups are converted to provide intermediate G3 where D is
either a halogen or OTf, ONf, or OCOOR'' (carbonate) such that
substituent (R1) is introduced by employing a transition-metal
catalyzed coupling reactions such as Suzuki, Stille or Negishi
reaction. An alternative route to compounds of type G4 involves
essentially reversing the order of incorporation of R1 and R2
fragments. The route B, as highlighted in Scheme A1, allows
formation of G6, where the R2 fragment is introduced at later stage
in the sequence, analogous to chemistries employed for G1-G2, for
examples Suzuki, Stille coupling.
##STR00022##
[0092] One may attach R1, which may be aryl, heterocyclic, acyclic,
aliphatic, or any other desirable variety of functionality, to the
central aromatic ring (Ar) by a wide rage of tether groups M. The
central aromatic ring (Ar) may be a biaryl ring system with a R2
group already attached, or the R2 group may be attached subsequent
to that of R1. The linker group M may be a linear chain of one or
more atoms consisting of C, N, O, or S. The linker group M may also
consist of functionalities including, but not limited to amide,
sulfonamide, sulfone, or ketone. It is evident to one skilled in
the art that many of these exemplified functional groups may be
attached in more than one way, for example, Ar--CH2-O--R1 or
Ar--O--CH2-R1. Considering those compounds with M groups such as S
or O, the heteroatom may originally be in the Ar or the R1 group.
Some examples of how the two groups can then be joined are
nucleophilic aromatic substitution, metal-promoted coupling, and
nucleophilic displacement (Scheme A2). Chemical reactivity of the
Ar and R1 groups should of course be considered when determining
which partner contains the linker heteroatom, and which shall serve
as the reaction partner. For example, it is well understood that in
aromatic ring systems an electron-withdrawing group para- or ortho-
to a leaving group (e.g. halogen) allows susceptibility of the
aromatic halogen for nucleophilic displacement. Thus, Ar1 group
containing NO2, CO2R, ketone, CN etc. would allow formation of
aryl-M-aryl(heteroaryl) intermediates. The linker group M may also
be subject to further elaboration. For example, sulfides may be
oxidized to sulfoxides and sulfones and amines may be subjected to
alkylation or reductive amination. Well known synthetic
transformations can be used to create tether groups M such as ether
amide, sulfonamide, and the like. The functional group location in
the precursor Ar and R1 groups can be used to dictate the nature
and type of the linkage (e.g. alternative ethers), as mentioned
above.
##STR00023##
[0093] The key fragments Ar and R1 could also be joined using non
transition-metal catalyzed C--C bond forming coupling reactions.
When A=H, Fridele-Crafts acylation or alkylation can be employed to
combine the Ar and R1 groups. Given the chemical reactivity of the
aromatic para-methoxy group in the Ar ring, Friedel-Crafts
acylation would typically involve a suitably elaborated R1-COCl
(acid chloride) group to form compound G10. In this case J=CO,
which can be reduced to the secondary alcohol (typically with
hydride-based reducing agents). If a R'MgX or other such
organometallic agent is used, the J=CO group can be transformed
into the tertiary alcohol with simultaneous addition of an R'
group. In another variation, the J=CO group can be converted into
the imine or oxime using standard procedures and addition of an
R'MgX-type reagent results in the tertiary amine derivative. If
desired, the J=CO group can be reduced, using a number of well
established methods, to the CH2 group (M). In another variation,
when A=H, an aldehyde group can be introduced using either
Vilsmeier reaction or using Lewis acid (TiCl4, BF3.OEt2 etc.)
mediated reaction with dichloromethylmethyl. The aldehyde
functionality can subsequently be transformed into a suitable
transition-metal catalyzed coupling reaction partner. Alternatively
the aldehye could be used for Wittig reaction forming olefin or
CH2CH2 linkage to incorporate R1. In yet another variation,
substituent "A" can be various types of carbonyl (aldehyde or
ketone) or imine groups. In one example, addition of a suitably
elaborated organometallic R1 group (e.g. R1-MgX) to aldehyde G9
(A=CHO) would result in G10 with J=C(H)OH. Reduction of this
alcohol gives rise to G11 with M=CH.sub.2. Similar types of
transformations could be employed by one skilled in the art if G9
contained A=ketone or imine.
##STR00024##
[0094] Alternatively, the C--C bond forming reaction between the Ar
and R1 groups could be accomplished by displacement of a leaving
group on the R1 by a nucleophile present in the tether region M
(Scheme G4) of G12. The activating group could be either removed to
provide Z=H (Z=CO2R-decarboxylation of or Z=CN, decyanation) or
these could be further transformed to other functional groups e.g.
Z=CH2)H or CH2NH2. When M-Z is CH2-halide or CH2-O-sulfonate, R1
fragment can be introduced via formation of ether linkage. This
allows attachment of R1 to the central aromatic ring by spacers (M)
of varying lengths and compositions. (Scheme A4)
##STR00025##
[0095] The R1 group could also be assembled form an acyclic
intermediate to form a heterocylic or heteroaromatic ring. Examples
of these chemistries include formation of 5-membered heteroaryls
such as oxadiazole, thiadiazole, triazole (G17) form acyl hydrazide
(G16); thiazole from 2-halo-ketone or dipolar cycloaddition
reactions from olefin or acetylic group to form 5-membered
heterocycles or 5-membered heteroaryls (G18) [Scheme A5].
Alternatively the 6-membered heteroaryl or heterocyclic rings could
be formed using Diels-Alder or hetero-Diels-Alder chemistries using
appropriately substituted alkyl aryl ether bearing either a
dienophile or a diene functionalities. The necessary acyclic
precursors could be synthesized by standard methods according to
previously described intermediates (e.g. aldehyde, alkyl halide)
schemes.
##STR00026##
[0096] When the R2 group is linked to the Ar group thru a
heteroatom (N), these biaryl systems could be prepared by
organometallic mediated aza-coupling reactions or other
nucleophilic aromatic substitution-based procedures (Scheme G6).
The Ar--(N)R2 biaryl may be formed from intermediate G6 where R1
group is already in place. Alternatively, the (N)R2 ring can be
added to the central Ar ring first, R1 can be attached through a
variety of means using approaches described in previous schemes.
Examples of (HN)R2 heteroaryl or heterocyclic rings include, but
not limited to, imidazole, pyrrole, pyrazole, pyrrolidine, or
triazole. The R2 functional group can be fully elaborated prior to
addition of the (N)R2 to the Ar, or suitably elaborated after
formation of the key C--N bond.
##STR00027##
[0097] The diverse selection of substituents present in R1 and R2
could be formed by standard functional group transformations that
are well know in the art. Some of these include formation of amide,
sulfonamide, ureas, imidazolone, oxazolones, carbamates from the
R2, R3, or Ar ring fragments bearing appropriate amine, carboxylic
acid, alcohol, or phenol groups. A particularly useful aromatic
ring functionalization technique, in which either the R2 or R1
rings can be employed, is the nucleophilic displacement of
ortho-halo N-containing aromatic rings (G20, scheme A7). Examples
of ring substrates useful in this type of transformation include
2-halo-pyridine, 2-halo-pyrimidine and 2-halo-imidazole.
Additionally, other leaving groups besides halogens (X) may be used
such as sulfonate esters (OTf, ONf). These displacement reactions
can be carried out using alkali or tertiary amine bases, or could
be mediated through the use of an organometallic reagent such as
palladium or aluminum reagents. Examples of nucleophiles (R'')
useful in this type of transformation include amines (primary,
secondary, acyclic, or cyclic), alcohols, phenols, NH-containing
heterocycle groups (imidazole, or pyrrazole) groups capable of
performing nucleophilic displacement.
##STR00028##
[0098] When R1 group contains additional functional groups, such as
amine, ester/acid/alcohols many of which may have be masked or
protected during the previous chemistries, these could be used for
further functional group manipulations. A wide variety of
modifications of R1 functionalities may be achieved using well
established synthetic procedures including, but not limited to,
alkylation, reductive amination, nucleophilic displacement,
cyclization, saponification, and oxidation/reduction. Additionally,
like these functional group manipulations, Ar1 mono-cyclic may be
further transformed to a bi-cyclic ring. Examples of such ring
transformations may be represented by elaboration of pyridine
derivatives to imidazo[1,2-a]pyridine and imidazo[1,5-a]pyridine.
These functional group manipulations and bicyclic ring elaborations
may be accomplished at any chemically suitable point in the
synthesis prior to or post incorporation of R2 or other synthetic
transformations.
[0099] These above transformations could be carried out from
alkylated phenols containing or lacking fluoro substituents in the
central Ar ring. Several of these approaches are also applicable to
3-alkoxy pyridines as the Ar ring starting materials. The
non-limiting specific examples described in later schemes are meant
to serve as examples of the broad scope of possible reactions.
Similarly, analogs where W.dbd.CH2OH, COOH, CN, CONH2 etc. (or
suitably protected precursors) could be derived by following
similar chemistries (schemes A1-A7) and these functional groups
could be derived form an ester or amide derived starting
material.
[0100] The following examples of compounds were prepared.
TABLE-US-00001 TABLE 1 ##STR00029## ExNo X R3 M Rb Ra A-001 C--H
CH3 CH2 3-NO2 7-(Saccharine) A-008 C--F CH3 CH2 3-Cl 4-(NHSO2NH2)
phenyl A-011 C--F CH3 CH2 3-Cl (3-OH, 4-NHSO2NH2) phenyl A-016 C--F
CH3 CH2 3-COCH3 4-(NHSO2NH2) phenyl A-018 C--F CH3 CH2 3-COCH3
4-(COOCH3) phenyl A-019 C--F CH3 CH2 3-COCH3 4-(COOH) phenyl A-022
C--F CH3 CH2 3-Br 4-(NHCONHCH2COOH) phenyl A-023 C--F CH3 CH2 3-Br
4-(NHCONHCH2CH2COOH) phenyl A-039 C--F CH3 CH2 3-Cl
6-{imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester} A-043 C--F
CH3 CH2 3-Cl 6-{imidazo[1,2-a]pyridine-2-carboxylic acid} A-051
C--F CH3 CH2 3-Cl 6-{imidazo[1,5-a]pyridine-2-carboxylic acid}
A-062 SO3--Na+ CH3 CH2 CH2 4-(NHCONH2) phenyl A-064 C--H CH3 CO
3-Cl 4-(NHCONHCONH2) phenyl A-065 C--H CH3 CD(OH) 3-Cl
4-(NHCONHCONH2) phenyl B-080 N--O CH3 CH2 3-NO2 4-F-phenyl B-084 CH
CH3 CH2 * 4-F-phenyl * Rb-phenyl is replaced by 3-pyridyl
N-oxide
TABLE-US-00002 TABLE 2 ##STR00030## ExNo X R3 M Rb P Q U V W Ra
A-010 C--F CH3 CH2 3-Cl CH CH N CH C (W)--NHSO2NH2 A-012 C--F CH3
CH2 3-Cl CH CH N N C (W)--NHSO2NH2 A-013 C--F CH3 CH2 3-COCH3 CH CH
N CH C (W)--NHSO2NH2 A-014 C--F CH3 CH2 3-Cl CH CH CH N--O C
(W)--NHCONH2 A-015 C--F CH3 CH2 3-Cl CH CH N N--O C (W)--NHCONH2
A-017 C--F CH3 CH2 3-COCH3 CH CH N N C (W)--NHSO2NH2 A-020 C--F CH3
CH2 3-COCH3 CH CH N CH C (W)--CO2CH3 A-021 C--F CH3 CH2 3-COCH3 CH
CH N CH C (W)--CO2H A-028 C--F CH3 CH2 3-Cl CH CH N CH C
(W)--NHCONHCH2CO2H A-029 C--F CH3 CH2 3-Cl CH CH N CH C
(W)--NHCONHCH2CH2CO2Et A-032 C--F CH3 CH2 3-Cl CH CH N CH C
(W)--NHCONHCH2CH2CO2H A-033 C--F CH3 CH2 3-Cl CH CH N CH C
(W)--CO--N(Piperidine-4-CO2Et) A-034 C--F CH3 CH2 3-Cl CH CH N CH C
(W)--CO--N(Piperidine-4-COOH) A-035 C--F CH3 CH2 3-Cl CH CH N CH C
(W)--NHCH2CO2H A-036 C--F CH3 CH2 3-Cl CH CH N CH C (W)--OH A-037
C--F CH3 CH2 3-Cl CH CH N CH C (W)--N(COCH3)CH2CO2H A-038 C--F CH3
CH2 3-Cl CH CH N CH C (W)--CO-1N-pyrrolidine-3-CO2H) A-040 C--F CH3
CH2 3-Cl CH CH N N C (W)-1N-(S)-Proline A-041 C--F CH3 CH2 3-Cl CH
CH N N C (W)-1N-(piperidine-3-CO2H) A-042 C--F CH3 CH2 3-Cl CH CH N
CH C (W)-1H-5-tetrazolyl A-044 C--F CH3 CH2 3-Cl CH CH N N C
(W)-1N-(pyrrolidine-3-CO2H) A-045 C--F CH3 CH2 3-Cl CH CH N N C
(W)-1N-(pyrrolidine-3-CO2Me A-047 C--F CH3 CH2 3-Cl CH CH N N C
(W)-sarcosine A-048 C--F CH3 CH2 3-Cl CH CH CH N C
(W)--CH2NHCOCO2Et A-049 C--F CH3 CH2 3-Cl CH CH N N C
(W)--N(azetidine-(W)--COOH) A-050 C--F CH3 CH2 3-Cl CH CH CH N C
(W)--CONHSO2CH3 A-053 C--F CH3 CH2 3-Cl CH CH N N C
(W)--N(azetidine-4-COOH) A-054 C--F CH3 CH2 3-Cl CH CH CH N C
(W)--N(azetidine-2-COOH) A-056 C--F CH3 CH2 3-Cl CH CH CH N C
(W)--N(CH2--COOH)--CONHEt A-057 C--F CH3 CH2 3-Cl CH CH CH N C
(W)--N(CH2--COOH)--CONH2 A-061 C--F CH3 CH2 3-Cl CH CH CH N C
(W)--N(azetidine-(S)-2-COOH) A-063 C--F CH3 CH2 3-Cl CH CH CH N C
(W)--N(R)-Proline A-066 C--F CH3 CH2 3-Cl CH CH CH N C
(W)--N(azetidine-(R)-2-COOH) A-067 C--H CH3 CH2 3-Cl CH CH CH N C
(W)--N(azetidine-2-COOH) A-068 C--H CH3 CH2 3-Cl CH CH CH N C
(W)--N(R)-Proline A-069 C--F CH3 CH2 3-Cl CH CH CH N C
(W)--N(R)-Proline methyl ester A-070 C--F CH3 CH2 3-Cl CH CH CH N C
(W)--N(3-pipecolic acid) A-071 C--H CH3 CH2 3-Cl CH CH CH N C
(W)--COOH A-072 C--F CH3 CH2 3-Cl CH CH CH N C (W)--N(S)-Proline
A-073 C--H CH3 CH2 3-Cl CH CH CH N C (W)--COOCH3 A-074 C--F CH3 CH2
3-Cl CH CH CH N C (W)--N(CH3)--CH2COOH A-075 C--H CF2H CH2 3-Cl CH
CH CH N C (W)--COOCH3 A-076 C--H CF2H CH2 3-Cl CH CH CH N C
(W)-Tetrazole A-077 C--H CH3 CH2 3-Cl CH CH CH N C
(W)--N(CH3)--CH2COOH A-078 C--H CF2H CH2 3-Cl CH CH CH N C
(W)--N(CH3)--CH2COOH A-079 C--H CF2H CH2 3-Cl CH CH CH N C
(W)--N(CH3)--[S]CH(CH3)--COOH B-081 CF CH3 CH2 3-Cl CH CH N--O CH C
(W)--NHCONHEt B-082 CF CH3 CH2 3-Cl CH CH N--O CH C
(W)--CH2--NHCONHEt B-083 CF CH3 CH2 3-Cl CH CH N--O CH C
(W)--CH2-(1-imidazolidin-2-one)
TABLE-US-00003 TABLE 3 ##STR00031## ExNo Core R3 M Rb P Q U V Ra
A-006 C--H CH3 CH2 3-NO2 C(CH3) C(CH3) N N (U)-CH2COOH A-024 C--F
CH3 CH2 3-Cl S N C N (U)--NHCONHCH2COOCH2CH3 A-025 C--F CH3 CH2
3-Cl S N C N (U)--NHCONHCH2CH2COOCH2CH3 A-026 C--F CH3 CH2 3-Cl S N
C N (U)--NHCONHCH2COOH A-027 C--F CH3 CH2 3-Cl S N C N
(U)--NHCONHCH2CH2COOH A-030 C--F CH3 CH2 3-Cl S N C N
(U)--NHCONH(CH2)3COOCH2CH3 A-031 C--F CH3 CH2 3-Cl S N C N
(U)--NHCONH(CH2)3COOH A-058 C--F CH3 CH2 3-Cl N NH N N --
TABLE-US-00004 TABLE 4 ##STR00032## ExNo X M Rb N(Rc) A-002 C--H
CH2 3-NO2 N-Saccharin A-003 C--H CH2 3-NO2
9N-2-Amino-6-chloropurine A-004 C--H CH2 3-NO2 9N-Guanine A-005
C--H CH2 3-NO2 N-L-4-Hydroxyproline methyl ester A-007 C--H CH2
3-NO2 1N-Pyridin-2-one-4-carboxylic acid A-059 C--F CH2 3-Cl
1N-Imidazole-4-carboxylic acid A-060 C--F CH2 3-Cl
1N-Imidazole-5-carboxylic acid
[0101] In-vitro assay for PDE4 enzymes. The in-vitro activity of
PDE4 enzymes and the in-vitro potency of therapeutic agents
described in the present invention was measured using a real-time,
enzyme-coupled spectrophotometric assay. By using three different
coupling enzymes, the product of the PDE4 reaction is coupled to
the oxidation of the reduced form .beta.-nicotinamide adenine
dinucleotide (NADH), which dissipation can be monitored
spectrophotmetrically at 340 nM.
[0102] Assay description. Buffer A containing 50 mM Tris, pH 8.0,
16 mM MgCl.sub.2 and 80 mM KCl is prepared and stored at room
temperature. Buffer B containing 50 mM Tris, pH 8.0 is prepared and
stored at room temperature. Stock solutions of the following
reagents are prepared in Buffer B and stored at -20.degree. C.:
Adenosine-5'-triphosphate (ATP), cyclic adenosine-5'-monophosphate
(cAMP), phosphoenolpyruvate (PEP) and NADH. An assay mix is
prepared by mixing Buffer A, trichloroethylphosphine (TCEP), ATP,
PEP, NADH, myokinase (MK), pyruvate kinase (PK), lactate
dehydroganese (LDH) and PDE4 to a final volume of 20 mL, which is
enough for a single 96-well assay plate. Assay mix (180 .mu.L) and
test article (10 .mu.L) in 1:1 DMSO/H.sub.2O mixture is
pre-incubated at room temperature for 10 min. The enzymatic
reaction is initiated by addition of cAMP (10 .mu.L). Final
concentration of all components in the assay (200 .mu.L/well) are
as follows: 10 mM MgCl.sub.2, 50 mM KCl, 5 mM TCEP, 2.5% DMSO, 0.4
mM NADH, 1 mM PEP, 0.04 mM ATP, 5 units MK, 1 unit PK, 1 unit LDH
and appropriate amount of PDE4. Reaction progress curves are
monitored in a plate reader capable of measuring light absorbance
at 340 nM. A decrease in light absorbance at 340 nm is due to
oxidation of NADH. Positive controls containing no test article and
negative controls containing no test article and no cAMP are
included on every assay plate. Reaction rates are determined from
the slopes of the linear portions of the progress curves. All data
is percent normalized with respect to controls and presented as
percent inhibition.
[0103] The results of testing of representative species are shown
below in Tables A and B. The activities are designated A=<5
.mu.M, B=5-20 .mu.M, C=20-40 .mu.M.
TABLE-US-00005 TABLE A Cmpd No hPDE4D A-001 A A-002 B A-003 A A-004
B A-005 C A-006 A A-007 B A-008 A A-010 A A-011 A A-012 A A-013 A
A-014 A A-015 A A-016 A A-017 A A-018 A A-019 A A-020 A A-021 B
A-022 A A-023 A A-024 A A-025 A A-026 A A-027 A A-028 A A-029 A
A-030 A A-031 A A-032 A A-033 A A-034 A A-035 A A-036 A A-037 A
A-038 A A-039 A A-040 A A-041 A A-042 A A-043 A A-044 A A-045 A
A-047 A A-048 A A-049 A A-050 A A-051 A A-053 A A-054 A A-056 A
A-057 A A-058 B A-059 A A-060 A A-061 A A-062 A A-063 A A-064 B
A-065 A A-066 A A-067 A A-068 A A-069 A A-070 A A-071 A A-072 A
A-073 A A-074 A A-075 A A-076 A A-077 A A-078 A A-079 A B-080 A
B-081 A B-082 A B-083 A B-084 B
TABLE-US-00006 TABLE B Cmpd No. hPDE4B A-001 C A-003 B A-004 C
A-006 B A-007 B A-008 A A-010 A A-011 B A-012 A A-013 A A-014 B
A-015 A A-016 A A-017 A A-018 C A-019 B A-020 A A-021 B A-027 C
A-028 A A-030 B A-031 B A-032 B A-034 C A-035 A A-036 A A-037 A
A-038 A A-040 A A-041 B A-042 A A-043 B A-044 C A-047 A A-048 A
A-049 A A-050 A A-051 A A-052 A A-053 B A-054 A A-055 A A-057 A
A-058 C A-059 B A-060 B A-061 B A-063 A A-064 B A-065 B A-066 A
A-067 B A-068 A A-070 B A-073 A A-074 A A-075 A A-076 A B-080 A
B-081 A B-082 A B-083 A
[0104] The activity of PDE4 inhibitors described in the present
invention was also measured using in an ex-vivo assay measuring
leukotriene E4 (LTE4) in human whole blood after Sephadex
stimulation. The anti-inflammatory activity of therapeutic agents
of the present invention is demonstrated by the inhibition of
eosinophil activation as measured by sephadex bead stimulated LTE4
production in whole human blood. For each sample, 356 .mu.l of
heparinized human whole blood (Vacutainer tube #6480) is added to
wells of a 96 well plate. Then, 4 .mu.l of a series of compound
dilutions (in DMSO) are added in triplicates, suspension mixed and
allowed to incubate at 37.degree. C. for 15 min with gentle
shaking. After that, blood samples are stimulated by adding 40
.mu.L of Sephadex G-15 beads (Sigma-Aldrich, Sweden). The beads are
predissolved in PBS (0.16 g/mL PBS). After mixing, the suspension
is incubated at 37.degree. C. for 90 min. Then, 8 .mu.L of 15%
EDTA/PBS is added to each sample, mixed and plate centrifuged for 5
min at 115.times.g at 21.degree. C. and supernatants taken. In each
plate, 10 positive controls and 10 negative controls are used,
containing DMSO instead of compound solution. The positive controls
are stimulated with Sephadex as described for the samples, and in
the negative controls (unstimulated), Sephadex solution is replaced
by PBS. LTE.sub.4 levels in the resulting plasma samples are
determined using a commercial enzyme-linked immunoassay (Cayman
Chemical Company, Ann Arbor, Mich.) according to the manufacturer's
instructions. Examples A-008, A-016, A-035, A-037, A-054 and A-066
showed IC50<1 .mu.M in this ex-vivo assay, whereas A-028 and
A-055 gave IC50>1 .mu.M. Persons of skill in the art accept that
positive results in PDE4 models are predictive of therapeutic
utility as discussed above.
[0105] Syntheses of examples of the invention are shown below:
##STR00033##
2-Methoxy-5-methyl-3'-nitro-biphenyl
INT-1
[0106] A reaction mixture of 2-methoxy-5-methylphenyl boronic acid
(5 g, 30.3 mmol), 3-nitro-iodobenzen (7.5 g, 30.3 mmol),
K.sub.2CO.sub.3 (8.36 g, 60.6 mmol), Pd(OAc).sub.2 (339 mg, 1.52
mmol) in methanol (150 ml) and water (30 ml) was stirred at room
temperature for 20 hours. The reaction mixture was diluted with
ethyl acetate (600 ml) washed with diluted NaHSO.sub.3 aq., water,
brine and dried over Na.sub.2SO.sub.4. After removal of solvent,
6.7 g of crude product INT-1 was obtained. Yield: 91%.
5-Bromomethyl-2-methoxy-3'-nitro-biphenyl
INT-2
[0107] To a mixture of compound INT-1 (6.95 g, 28.5 mmol) in carbon
tetrachloride (350 ml), Bromine (1.54 ml, 29.9 mmol) was added at
room temperature. The reaction mixture was stirred at 80.degree. C.
under sun lamp for 2 hours with the protection of N.sub.2. After
removal of solvent, the residue was purified by 150 g silica gel
column chromatography with ethyl acetate/Hexane as eluent to give
5.6 g of product INT-2. Yield: 61%.
##STR00034##
[0108] A-003. Synthesis of
6-Chloro-9-(6-methoxy-3'-nitro-biphenyl-3-ylmethyl)-9H-purin-2-ylamine.
A suspension of INT-2 (322 mg, 1.00 mmol), 2-amino-6-chloropurine
(169 mg, 1.00 mmol), and solid potassium carbonate (276 mg, 2.00
mmol) in dimethyl formamide (10 mL) was stirred at room temperature
for 18 h. The reaction mixture was poured over water (100 mL),
stirred for 10 min, and the resulting precipitate collected. The
crude material was dissolved in ethyl acetate (30 mL), dried over
sodium sulfate, filtered, the solvent removed under vacuum. The
crude residue was purified by trituration in hexanes/ethyl acetate
(100 mL: 30 mL) several times to obtain A-003 (58.5 mg, 14% yield)
as a yellow solid.
[0109] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 3.78 (s, 3H) 5.27 (s,
2H) 6.93 (s, 2H) 7.15 (d, J=8.45 Hz, 1H) 7.29-7.43 (m, 1H) 7.47 (d,
J=2.15 Hz, 1H) 7.62-7.83 (m, 1H) 7.92 (d, J=7.65 Hz, 1H) 8.13-8.41
(m, 3H)
[0110] A-004. Synthesis of
2-Amino-9-(6-methoxy-3'-nitro-biphenyl-3-ylmethyl)-1,9-dihydro-purin-6-on-
e. A solution of A-003 (60 mg, 0.15 mmol) and anhydrous sodium
hydroxide (1.2 g, 30 mmol) in water (6 mL) and dimethyl formamide
(6 mL) was stirred at room temperature for 5 min. The yellow
solution was quenched with the addition of water (50 mL). The
resulting precipitate was collected by filtration, dissolved in
ethyl acetate (10 mL), dried over sodium sulfate, filtered, and the
solvent removed under vacuum to obtain A-004 (29.9 mg, 51% yield)
as a yellow solid.
[0111] 1H NMR (400 MHz, DMSO-d6) .delta. 3.77 (s, 3H) 5.19 (s, 2H)
5.82 (s, 2H) 6.91 (br. s., 1H) 7.14 (d, J=8.59 Hz, 1H) 7.30 (dd,
J=8.45, 2.01 Hz, 1H) 7.42 (d, J=2.01 Hz, 1H) 7.71 (t, J=7.98 Hz,
1H) 7.83 (s, 1H) 7.91 (d, J=7.78 Hz, 1H) 8.16-8.23 (m, 1H) 8.27 (d,
J=1.61 Hz, 1H)
[0112] A-005
##STR00035##
(2R,4S)-4-Hydroxy-1-(6-methoxy-3'-nitro-biphenyl-3-ylmethyl)-pyrrolidine--
2-carboxylic acid methyl ester
[0113] Into a 20 mL vial with stir bar added Int-2 (0.30 g, 0.93
mmol), (2R,4S)-4-Hydroxy-pyrrolidine-2-carboxylic acid methyl ester
hydrochloride (0.62 mmol), Cs.sub.2CO.sub.3 (0.20 g, 0.62 mmol),
and DMF (2 mL). The reaction was stirred for 4 days at room
temperature and then 10 mL water was added. The product was
extracted with ethyl acetate (3.times.10 mL) and the organics were
combined and concentrated. The residue was purified by flash column
chromatography using 0-5% methanol/dichloromethane to obtain 36 mg
(8%) of A-005. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
2.03-2.15 (m, 1H) 2.27 (dt, J=13.8, 7.1 Hz, 1H) 2.51 (dd, J=10.2,
3.6 Hz, 1H) 3.37 (dd, J=10.1, 5.6 Hz, 1H) 3.57-3.73 (m, 5H) 3.83
(s, 3H) 3.90 (d, J=12.9 Hz, 1H) 4.48 (br. s., 1H) 6.96 (d, J=8.3
Hz, 1H) 7.29 (d, J=2.0 Hz, 1H) 7.33 (dd, J=8.3, 2.0 Hz, 1H) 7.56
(t, J=8.0 Hz, 1H) 7.86 (d, J=7.7 Hz, 1H) 8.17 (dd, J=8.2, 1.3 Hz,
1H) 8.37-8.44 (m, 1H). LC/MS=93.7%, 387.1, (APCI+)
[0114] A-006A
##STR00036##
Int-3
[0115] Synthesis of
3-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-pentane-2,4-dione. To a
solution of 2,4-pentadione in dimethoxyethane (5 mL) was added NaH
(80 mg, 1.2 mmol). After 30 minutes at room temperature, Int-2 (322
mg, 1.0 mmol) was added and the reaction was stirred at room
temperature overnight. To the reaction was added 30 mL of water and
the product was extracted with 2.times.30 mL EtOAc, washed with
brine, dried over Na.sub.2SO.sub.4, and concentrated. The residue
was purified by flash column chromatography eluting with 2:1
Hexanes:EtOAc to afford the title compound (106 mg, 31%).
[0116] Synthesis of
[4-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-3,5-dimethyl-pyrazol-1-yl]-ac-
etic acid ethyl ester. To a solution of INT-3 (102 mg, 0.300 mmol)
in 1,2-dimethoxyethane (5 mL), were added ethyl hydrazinoacetate
hydrochloride (93 mg, 0.60 mmol) and 4 Angstrom molecular sieves
(200 mg), and the reaction was stirred at reflux for 3 h. The hot
suspension was filtered and the solvent removed under vacuum. The
residue was dissolved in dichloromethane (10 mL) and washed with
water (30 mL). The aqueous wash was extracted with dichloromethane
(2.times.30 mL), and the extracts combined. The organic solution
was washed with brine, dried over sodium sulfate, filtered, and the
solvent removed under vacuum. The crude material was purified by
silica gel column chromatography (2:1 hexanes:ethyl acetate) to
give A-006A (97.1 mg, 76% yield).
[0117] 1H NMR (CHLOROFORM-d) d: 8.38 (t, J=1.9 Hz, 1H), 8.15 (dd,
J=8.2, 2.3 Hz, 1H), 7.79-7.82 (m, 1H), 7.53-7.56 (m, 1H), 7.07-7.10
(m, 2H), 6.90 (d, J=9.1 Hz, 1H), 4.79 (s, 2H), 4.21 (q, J=7.1 Hz,
2H), 3.80 (s, 3H), 3.74 (s, 2H), 2.13 (s, 3H), 2.13 (s, 3H), 1.26
(t, J=7.1 Hz, 3H). LCMS: 98.7% purity.
[0118] A-006.
[0119] Synthesis of
[4-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-3,5-dimethyl-pyrazol-1-yl]-ac-
etic acid. To a solution of A-006A (105 mg, 0.25 mmol) in ethanol
(1 mL) was added 2 M aqueous sodium hydroxide solution (0.625 mL,
1.25 mmol) and the reaction was stirred at 50.degree. C. for 3 h.
The reaction was acidified to pH 6 with 10% aqueous hydrogen
chloride solution. The suspension was extracted with diethyl ether
(5 mL), dried over sodium sulfate, and concentrated en vacuo. The
crude was purified by silica gel column chromatography (10%
methanol in dichloromethane) to give A-006 (33.1 mg, 34% yield) as
a white powder. 1H NMR (CHLOROFORM-d) d: 8.32-8.39 (m, 1H),
8.11-8.19 (m, 1H), 7.80 (d, J=7.7 Hz, 1H), 7.49-7.58 (m, 1H),
7.02-7.10 (m, 1H), 6.90 (d, J=9.1 Hz, 1H), 4.77 (s, 2H), 3.80 (s,
3H), 3.73 (s, 2H), 2.16 (s, 3H), 2.15 (s, 3H). LCMS=97.6%
purity.
##STR00037##
Int-3
[0120]
1-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-2-oxo-1,2-dihydro-pyridi-
ne-4-carbonitrile
[0121] Into a 100 mL RBF with stir bar was added Int-2 (2.76 g,
8.55 mmol), 2-Hydroxy-isonicotinonitrile (934 mg, 7.78 mmol),
K.sub.2CO.sub.3 (2.36 g, 17.11 mmol), and DME (30 mL). The
suspension was stirred for 18 hours at 80.degree. C. and then RT
for 2 days. The reaction was filtered, the filtrate was
concentrated and the resulting solid was triturated with ether to
give 2.12 g (75%) of Int-3 as a yellow solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.=8.29 (s, 1H), 8.20 (dd, J=1.3, 8.3 Hz, 1H),
8.12 (d, J=7.1 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.73 (t, J=8.0 Hz,
1H), 7.49 (d, J=2.0 Hz, 1H), 7.43 (dd, J=1.9, 8.5 Hz, 1H), 7.16 (d,
J=8.6 Hz, 1H), 7.04 (d, J=1.3 Hz, 1H), 6.56 (dd, J=1.7, 7.0 Hz,
1H), 5.12 (s, 2H), 3.79 (s, 3H). LC/MS=96.1%, 361.0 (APCI-).
##STR00038##
[0122] A-007
1-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-2-oxo-1,2-dihydro-pyridine-4-ca-
rboxylic acid
[0123] Into a 20 mL vial with stir bar was added Int-3 (480 mg,
1.33 mmol), 3 mL of ethanol, and 3 mL of 1N NaOH (aq). The solution
was stirred at 80.degree. C. for 1 hour then cooled to room
temperature. About half the volume of solvent was evaporated and
the solution was washed twice with DCM. The remaining aqueous
portion was added to a 6N HCl solution and stirred for 1 hour,
after which time the solids were filtered and washed with water.
The solid was dried in a vacuum dessicator for 3 days to yield 366
mg (72%) of A-007 as a light-yellow solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.=8.28 (d, J=1.6 Hz, 1H), 8.20 (dd, J=1.5, 8.1
Hz, 1H), 7.99 (d, J=7.0 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.72 (t,
J=7.9 Hz, 1H), 7.48 (d, J=2.0 Hz, 1H), 7.42 (dd, J=2.0, 8.5 Hz,
1H), 7.16 (d, J=8.5 Hz, 1H), 6.87 (d, J=1.6 Hz, 1H), 6.57 (dd,
J=1.7, 7.0 Hz, 1H), 5.13 (s, 2H), 3.79 (s, 3H). LC/MS=95.9%,
[0124] Synthesis of A-016
##STR00039## ##STR00040##
Int-4
Synthesis of 3-Bromo-2-fluoro-4-methoxy-benzaldehyde
[0125] In a 3-neck 250 mL round bottomed flask equipped with
nitrogen lines and a stir bar was placed
2-bromo-1-fluoro-3-methoxy-benzene (2.0 g, 9.75 mmol) and
dichloromethane (48 mL). The solution was cooled in an ice water
bath for 15 minutes and then titanium tetrachloride (5.02 mL, 45.8
mmol) and dichloromethyl methyl ether (1.32 mL, 14.6 mmol) were
added and the reaction mixture was allowed to warm to room
temperature and react for 2 hours. The reaction mixture was slowly
added to ice water (250 mL) and extracted with dichloromethane
(2.times.100 mL). The organic portions were combined, washed with a
saturated sodium bicarbonate solution (75 mL), water (75 mL) and
brine (75 mL), dried (MgSO.sub.4) and concentrated. The crude
material was triturated with hexanes (15 mL) to produce 1.67 g of
Int-4 as an off-white solid in 74% yield. MS (ESI+): 233.2 (M+)
Int-5
Synthesis of (3-Bromo-2-fluoro-4-methoxy-phenyl)-methanol
[0126] In a 100 mL round bottomed flask equipped with a stir bar
was placed Int-4 (1.67 g, 7.17 mmol), methanol (12 mL),
dichloromethane (12 mL) and sodium borohydride. The reaction
mixture was allowed to stir at room temperature for 17 hours,
quenched with water (10 mL) and 1M HCl (5 mL) and extracted with
dichloromethane (2.times.30 mL). The organic portions were
combined, washed with brine (30 mL), dried (MgSO.sub.4) and
concentrated. The crude material was triturated with hexanes (15
mL) to produce 955 mg of Int-5 as a white solid in 57% yield.
Int-6
Synthesis of
1-(2'-Fluoro-3'-hydroxymethyl-6'-methoxy-biphenyl-3-yl)-ethanone
[0127] In a 40 mL vial equipped with a stir bar was placed Int-5
(950 mg, 4.04 mmol), 3-acetylylphenylboronic acid (729 mg, 4.44
mmol), potassium carbonate (1.68 g, 12.1 mmol), triphenylphosphine
(318 mg, 1.21 mmol), 1,4-dioxane (8 mL), 50% aqueous ethanol (8 mL)
followed by palladium (II) acetate (90.7 mg, 0.404 mmol). The
mixture was heated to 68.degree. C. for 72 hours and then cooled to
room temperature. The palladium catalyst was removed via filtration
through Celite. To the filtrate was added 1M HCl (30 mL) and water
(30 mL). The aqueous portion was extracted with ethyl acetate
(2.times.30 mL), the organic portions were combined, washed with
brine (30 mL), dried (MgSO.sub.4) and concentrated. The crude
material was purified by column chromatography utilizing 50%
EtOAc/hexanes as the eluent to produce 614 mg of Int-6 as an
off-white solid in 55% yield.
Int-7
Synthesis of Carbonic acid
3'-acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl ester methyl
ester
[0128] In an 18 mL vial equipped with a stir bar was placed Int-6
(400 mg, 1.46 mmol), anhydrous tetrahydrofuran (4.9 mL) and
pyridine (154 .mu.L, 1.90 mmol). The resulting clear solution was
cooled in an ice water bath for 10 minutes and then methyl
chloroformate (124 .mu.L, 1.61 mmol) was added and reaction mixture
was slowly warmed to room temperature and reacted for 17 hours.
Additional pyridine (154 .mu.L, 1.90 mmol) and methyl chloroformate
(124 .mu.L, 1.61 mmol) were introduced and the reaction mixture
stirred for another 17 hours at room temperature. The reaction was
acidified to pH 1 with 1M HCl, water (30 mL) was added followed by
an extraction with dichlormethane (2.times.30 mL). The organic
portions were combined, washed with brine (30 mL), dried
(MgSO.sub.4) and concentrated. The crude material was purified by
column chromatography utilizing 40% EtOAc/hexanes as the eluent to
produce 346 mg of Int-7 as a colorless viscous oil in 71%
yield.
Int-8
Synthesis of
[4-(3'-Acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-carbamic
acid tert-butyl ester
[0129] In an 8 mL vial equipped with a stir bar was placed Int-7
(295 mg, 0.888 mmol), 4-[(tert-butoxycarbonyl)amino]-phenylboronic
acid (232 mg, 0.977 mmol), potassium carbonate (270 mg, 1.95 mmol),
1,5-bis(diphenylphosphino)pentane (39.1 mg, 0.0888 mmol),
allylpalladium(II) chloride dimer (16.2 mg, 0.0444 mmol) and
dimethylformamide (1.5 mL). The reaction mixture was heated to
80.degree. C. for 17 hours. In order to consume residual Int-7,
additional allylpalladium(II) chloride dimer (32.5 mg, 0.0888 mmol)
and 1,5-bis(diphenylphosphino)pentane (78.2 mg, 0.178 mmol) were
added and the reaction mixture was allowed to stir at 80.degree. C.
for 17 hours. The reaction mixture was filtered through Celite and
to the filtrate was added water (40 mL) and a saturated ammonium
chloride solution (40 mL). After an extraction with ethyl acetate
(2.times.50 mL), the organic portions were combined, washed with
brine (50 mL), dried (MgSO.sub.4) and concentrated. The crude
material was purified by column chromatography utilizing 30%
EtOAc/hexanes as the eluent to produce 365 mg of Int-8 as a pale
yellow solid in 91% yield.
Int-9
Synthesis of
1-[3'-(4-Amino-benzyl)-2'-fluoro-6'-methoxy-biphenyl-3-yl]-ethanone;
hydrochloride
[0130] In an 8 mL vial equipped with a stir bar was placed Int-8
(265 mg, 0.590 mmol), dichloromethane (2.0 ml) and trifluoroacetic
acid (438 .mu.L, 5.90 mmol). The reaction mixture was stirred at
room temperature for 4 hours and then quenched to pH 7 with a
saturated sodium bicarbonate solution. After the addition of water
(30 mL) and extraction with dichloromethane (2.times.30 mL), the
organic portions were combined, washed with brine (30 mL), dried
(MgSO.sub.4) and concentrated. The crude material was treated with
diethyl ether (3 mL) and 2.0 M HCl in diethyl ether (1 mL) and
allowed to stir at room temperature for 2 hours. The solid was
collected an washed with diethyl ether (3.times.2 mL) to produce
139 mg of Int-9 as a pale orange powder in 61% yield.
[0131] A-016
Sulfamoylation of
1-[3'-(4-Amino-benzyl)-2'-fluoro-6'-methoxy-biphenyl-3-yl]-ethanone;
hydrochloride
[0132] In an 8 mL vial equipped with a stir bar was placed
dichloromethane (400 .mu.L) and chlorosulfonyl isocyanate (13.5
.mu.L, 0.155 mmol). The solution was cooled in an ice water bath
for 5 minutes and then tert-butanol (15.9 .mu.L, 0.167 mmol) was
added and the reaction mixture was warmed to room temperature for
25 minutes. Then a solution of Int-9 (46 mg, 0.119 mmol), pyridine
(106 .mu.L, 0.131 mmol) and dichloromethane (300 .mu.L) was added
and the reaction mixture was stirred at room temperature for 17
hours. The reaction was quenched with water (30 mL) and extracted
with dichloromethane (2.times.30 mL). The organic portions were
combined, washed with 1M HCl (30 mL) and brine (30 mL), dried
(MgSO.sub.4) and concentrated. To this Boc protected intermediate
was added 1,4-dioxane (600 .mu.L) and 4.0 M HCl in 1,4-dioxane (400
.mu.L). The mixture was stirred at room temperature for 17 hours
and then quenched with water (30 mL) and extracted with
dichlormethane (2.times.30 mL). The organic portions were combined,
washed with a saturated sodium bicarbonate solution (30 mL) and
brine (30 mL), dried (MgSO.sub.4) and concentrated to produce 12 mg
of A-016 as an orange viscous oil in 24% yield.
[0133] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.62 (s, 3H), 3.76
(s, 3H), 3.95 (s, 2H), 4.63 (bs, 2H), 6.34 (bs, 1H), 6.73 (d, J=8
Hz, 1H), 7.10-7.24 (m, 5H), 7.52 (t, J=8 Hz, 1H), 7.60 (d, J=6 Hz,
1H), 7.94 (d, J=8 Hz, 1H), 7.99 (bs, 1H).
[0134] Synthesis of A-017
##STR00041##
Int-10
Synthesis of
1-[3'-(2-Amino-pyrimidin-5-ylmethyl)-2'-fluoro-6'-methoxy-biphenyl-3-yl]--
ethanone hydrochloride
[0135] In an 18 mL vial equipped with a stir bar was placed Int-7
(704 mg, 2.12 mmol),
5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine
(515 mg, 2.33 mmol), potassium carbonate (879 mg, 6.36 mmol),
1,5-bis(diphenylphosphino)pentane (280 mg, 0.636 mmol),
allylpalladium(II) chloride dimer (116 mg, 0.318 mmol) and
dimethylformamide (4.2 mL). The reaction mixture was heated to
70.degree. C. for 65 hours. The reaction mixture was filtered
through Celite and to the filtrate were added water (40 mL) and a
saturated ammonium chloride solution (40 mL). After an extraction
with ethyl acetate (2.times.50 mL), the organic portions were
combined, washed with brine (50 mL), dried (MgSO.sub.4) and
concentrated. The crude material was purified by column
chromatography utilizing 20% acetone/DCM (gradient elution
increased to 30%, then 40% acetone/DCM) as the eluent to produce
341 mg of Int-10 (free base) an off-white solid in 46% yield. Then
Int-10 (free base) (20 mg, 0.0569 mmol) was treated with
1,4-dioxane (1 mL) and the mixture was heated to form a solution.
To this solution was added 4.0M HCl in 1,4-dioxane (1 mL) and the
mixture was stirred at room temperature for 3 hours. The solvent
was removed via nitrogen stream and the resulting solid was
triturated with diethyl ether (1 mL), collected via suction
filtration and washed with diethyl ether (3.times.1 mL) to produce
12 mg of Int-10 as a pale yellow solid in 55% yield.
A-017 Sulfamoylation of
1-[3'-(2-Amino-pyrimidin-5-ylmethyl)-2'-fluoro-6'-methoxy-biphenyl-3-yl]--
ethanone
[0136] In an 8 mL vial equipped with a stir bar was placed
dichloromethane (500 .mu.L) and chlorosulfonyl isocyanate (32.2
.mu.L, 0.371 mmol). The solution was cooled in an ice water bath
for 5 minutes and then tert-butanol (38.2 .mu.L, 0.399 mmol) was
added and the reaction mixture was warmed to room temperature for
25 minutes. Then a solution of Int-10 (free base) (100 mg, 0.285
mmol), pyridine (254 .mu.L, 3.14 mmol) and dichloromethane (500
.mu.L) was added and the reaction mixture was stirred at room
temperature for 3 hours. The reaction was quenched with water (30
mL) and extracted with dichloromethane (2.times.30 mL). The organic
portions were combined, washed with 1M HCl (30 mL) and brine (30
mL), dried (MgSO.sub.4) and concentrated. To this Boc protected
intermediate was added 1,4-dioxane (1.5 mL) and 4.0 M HCl in
1,4-dioxane (1.0 mL). The mixture was stirred at 50.degree. C. for
2 hours and then quenched with water (30 mL) and extracted with
dichloromethane (2.times.30 mL). The organic portions were
combined, washed with a saturated sodium bicarbonate solution (30
mL) and brine (30 mL), dried (MgSO.sub.4) and concentrated. The
crude material was triturated with 20% acetone/DCM to produce 9.5
mg of A-017 as a white solid in 8% yield.
[0137] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 2.59 (s, 3H),
3.73 (s, 3H), 3.91 (bs, 2H), 6.97 (d, J=8 Hz, 1H), 7.08 (bs, 2H),
7.36 (t, J=9 Hz, 1H), 7.57-7.58 (m, 2H), 7.87 (s, 1H), 7.94-7.96
(m, 1H), 8.46 (s, 2H), 10.96 (bs, 1H). MS (APCI+): 431.1 (M+1),
LC-MS: 97%.
A-018 Synthesis of
4-(3'-Acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-benzoic acid
methyl ester
##STR00042##
[0139] A suspension of Int-7 (300 mg, 0.928 mmol),
4-methoxycarbonylbenzylboronic acid (184 mg, 1.02 mmol), and
potassium carbonate (385 mg, 2.78 mmol) in dimethylformamide (2 mL)
was purged with nitrogen and allylpalladiumchloride dimmer (50.9
mg, 0.139 mmol) and bis(diphenylphosphino)pentane (123 mg, 0.278
mmol) were added. The reaction was heated to 65.degree. C.
overnight. To this reaction was added ethyl acetate (5 mL) and
water (5 mL), the layers were filtered through celite, the celite
washed with ethyl acetate (15 mL) and water (15 mL), and the layers
separated. The aqueous layer was extracted with ethyl acetate
(2.times.50 mL), and the organic extracts combined and washed with
brine (100 mL). The organic solution was dried over magnesium
sulfate, filtered, and the solvent removed under vacuum to give
crude product. The product was purified by flash silica gel column
chromatography (25% ethyl acetate in hexanes), then on a
preparatory silica gel TLC plate (eluting with 25% ethyl acetate in
hexanes) and triturated in diethyl ether (5 mL) to give A-018 (72.4
mg, 20% yield) as a white powder.
[0140] 1H NMR (400 MHz CDCl3) d: 7.991-7.939 (m, 4H), 7.586-7.583
(m, 1H), 7.517 (t, J=7.80 Hz, 1H), 7.299 (d, J=8.80 Hz, 2H), 7.107
(t, J=8.60 Hz, 1H), 6.742-6.720 (m, 1H), 4.027 (s, 2H), 3.899 (s,
3H), 3.758 (s, 3H), 2.619 (s, 3H).
[0141] LCMS=96.6% purity. MS (APCI+)=394.1 (M+2).
A-020 Synthesis of
5-(3'-Acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridine-2-carboxyli-
c acid methyl ester
##STR00043##
[0143] A suspension of Int-7 (500 mg, 1.50 mmol),
2-methylcarboxypyridine-5-boronic acid pinocol ester (435 mg, 1.65
mmol), and potassium carbonate (624 mg, 4.51 mmol) in
dimethylformamide (3.5 mL) was degassed under a nitrogen stream for
15 min. To this solution was added bis(diphenylphosphino)pentate
(199 mg, 0.451 mmol) and allylpalladiumchloride dimer (82.7 mg,
0.226 mmol). The reaction was heated to 65.degree. C. for 50 h. The
reaction was diluted with ethyl acetate (50 mL) and filtered
through celite. To the filtrate was added water (50 mL), and the
layers separated. The aqueous wash was extracted with ethyl acetate
(2.times.50 mL), and all three organic extracts combined and washed
with brine (100 mL). The organic solution was dried over magnesium
sulfate, filtered, and the solvent removed under vacuum. The
residue was purified by flash silica gel column chromatography (5%
acetone in dichloromethane) and triturated in diethyl ether (15
mL), filtered, and washed with diethyl ether (5 mL) to give A-020
(190.6 mg, 32% yield) as a white powder. 1H NMR (400 MHz CDCl3) d:
8.656 (d, J=2.00 Hz, 1H), 8.062 (d, J=8.00 Hz, 1H), 7.973-7.940 (m,
2H), 7.665 (dd, J=8.20 Hz, 2.20 Hz, 1H), 7.574 (dd, J=7.60 Hz, 1.60
Hz, H), 7.518 (t, J=7.60 Hz, 1H), 7.125 (t, J=8.60 Hz, 1H), 6.747
(d, J=8.80 Hz, 1H), 4.053 (s, 2H), 3.996 (s, 3H), 3.765 (s, 3H),
2.618 (s, 3H). LCMS=100.0% purity. MS (APCI+)=394.1 (M+1).
[0144] Synthesis of A-019 and A-021
##STR00044##
A-019 Synthesis of
4-(3'-Acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-benzoic
acid
[0145] A solution of A-018 (65.0 mg, 0.166 mmol) in methanol (750
uL), water (750 uL), and 1 N aqueous sodium hydroxide (231 uL,
0.231 mmol) was stirred at room temperature overnight. The
resultant white suspension was dissolved with tetrahydrofuran (1
mL), and stirred at room temperature for 2 h. Reaction showed
completion by silica TLC (Rf=0.07 in 50% ethyl acetate in hexanes).
The tetrahydrofuran and methanol were removed under vacuum, and 1 N
aqueous hydrochloric acid (2 mL) was added. The aqueous suspension
was extracted with ethyl acetate (2.times.25 mL), the organic
extracts combined, and washed with brine (10 mL) that had been
acidified with 1 N aqueous hydrochloric acid (3 mL), dried over
sodium sulfate, filtered, and the solvent removed under vacuum to
give A-019 (42.6 mg, 68% yield) as a white powder.
[0146] 1H NMR (400 MHz d6-DMSO) d: 12.81 (s, 1H), 7.962-7.935 (m,
1H), 7.880-7.860 (m, 3H), 7.577 (d, J=5.20 Hz, 2H), 7.366-7.322 (m,
3H), 6.965 (d, J=8.80 Hz, 1H), 4.030 (s, 2H), 3.729 (s, 3H), 2.600
(s, 3H). LCMS=100.0% purity. MS (APCI-)=377.0 (M-1).
A-021 Synthesis of
5-(3'-Acetyl-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridine-2-carboxyli-
c acid
[0147] A solution of A-020 (150 mg, 0.381 mmol) in tetrahydrofuran
(1 mL), methanol (1 mL), water (1 mL) and 1 N aqueous sodium
hydroxide (0.763 mL) was stirred at room temperature for 18 h.
Approximately one half of the solvent was removed under vacuum. The
remaining solution was adjusted to pH 3 by addition of glacial
acetic acid. The suspension was extracted with dichloromethane (10
mL), water (5 mL) was added to the wash, and the aqueous wash was
extracted with additional dichloromethane (2.times.10 mL). All
three organic extracts were combined, dried over magnesium sulfate,
filtered, and the solvent removed under vacuum, and the residue was
dried under high vacuum for 24 h. The resultant beige syrup was
impure with ethyl acetate and acetic acid, so the residue was
crystallized in diethyl ether (5 mL), stirred for 30 min, filtered,
and washed with hexanes (2.times.2 mL) to give A-021 (90.6 mg, 63%
yield) as a white powder.
[0148] 1H NMR (400 MHz d6-DMSO) d: 8.622 (d, J=2.00 Hz, 1H),
7.989-7.936 (m, 2H), 7.869 (s, 1H), 7.779 (dd, J=7.80 Hz, 2.20 Hz,
1H), 7.576 (d, J=5.20 Hz, 2H), 7.387 (t, J=8.80 Hz, 1H), 6.982 (d,
J=8.40 Hz, 1H), 4.081 (s, 2H), 3.732 (s, 3H), 2.588 (s, 3H).
[0149] LCMS=100.0% purity (APCI+). MS (APCI+)=380.0 (M+1)
[0150] Synthesis of A-022
##STR00045##
Int-11
Synthesis of 3'-Bromo-6-fluoro-2-methoxy-biphenyl
[0151] To a mixture of 2-fluoro-5-methoxyphenyl boronic acid (1 g,
5.9 mmol, 1 eq.), Pd(PPh.sub.3).sub.4 (340 mg, 0.3 mmol, 0.05 eq.)
was added toluene (48 ml) and EtOH (12 ml) followed by the
1-bromo-3-iodo benzene (2 g, 7.1 mmol, 1.2 eq) and 2N
Na.sub.2CO.sub.3 aq. (6 ml, 2 eq.). The mixture was stirred at 90 C
for 3 hr. After cooling to room temperature, the aqueous layer was
separated and the organic layer was dried over MgSO.sub.4. Removal
of solvent under reduced pressure gave a residue, which was
purified by chromatography on silica gel using hexane followed by
hexane/EtOAc (20:1) as eluent to give 1.37 g of desired product
Int-11 as colorless oil in 83% yield.
Int-12
Synthesis of
N-[4-(3'-Bromo-2-fluoro-6-methoxy-biphenyl-3-carbonyl)-phenyl]-acetamide
[0152] To AlCl.sub.3 (400 mg, 3.3 mmol, 3 eq.) was added
nitrobenzene (2 ml) at rt. The mixture was stirred at rt for 1 hr.
Then 4-Acetylamino-benzoyl chloride (200 mg, 1 mmol, 1 eq.) was
added in one portion followed by a solution of Int-11 in DCM (2
ml). The resulting mixture was stirred at rt until the acid
chloride was consumed in 3 hr. The mixture was added water and then
extracted with ethyl acetate. The organic layer was separated and
dried. Evaporation of solvent gave a residue, which was purified by
chromatography on silica gel using EtOAc/hexane (1:1 then 2:1) as
eluent to give 221 mg off desired product Int-12 in 50% yield.
Int-13
Synthesis of
N-[4-(3'-Bromo-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-acetamide
[0153] To a solution of Int-12 (170 mg, 0.38 mmol, 1 eq.) in
trifluoroacetic acid (1 ml) was added triethylsilane (0.5 ml). The
mixture was stirred at rt for 4 hr. and then volatile material was
removed under reduced pressure to give a residue, which was
triturated with DCM/hexane (1:2). The solid was filtered and washed
with hexane. After drying, 190 mg of Int-13 was obtained in
quantitative yield.
Int-14
Synthesis of
4-(3'-Bromo-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenylamine
[0154] In a 40 ml vial was charged with Int-13 (230 mg, 0.54 mmol,
1 eq.), conc. HCl (8 ml) and EtOH (8 ml). The mixture was stirred
at 85 C for 5 hr. After cooling to room temperature, water was
added followed by addition of NaHCO.sub.3 aq. The mixture was
extracted with EtOAc. The organic layer was separated and dried.
Removal of solvent gave 176 mg of desired product Int-14 without
further purification (85% yield).
Int-15
Synthesis of
{3-[4-(3'-Bromo-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-ureido}-a-
cetic acid ethyl ester
[0155] To an 8 mL vial containing Int-14 (108 mg, 0.280 mmol) was
added a magnetic stir bar and pyridine (0.5 mL). To this stirring
solution was added ethyl isocyanatoacetate (62 uL, 72 mg, 0.56
mmol) dropwise over 15 s. The solution was allowed to stir at room
temperature overnight. The reaction mixture was diluted with water
(5 mL) and rapidly stirred at room temperature for 2 h. The
resulting solid was filtered, rinsed with water (2.times.3 mL) and
dried to yield 120 mg (83%) of Int-15 as a solid. 1H NMR (400 MHz,
DMSO-d6) 1.19 (t, J=7.2 Hz, 3H), 3.71 (s, 3H), 3.84 (m, 4H), 4.10
(q, J=7.2 Hz, 2H), 6.38 (t, J=5.6 Hz, 1H), 6.91 (d, J=8.0 Hz, 1H)
7.08 (m, 2H), 7.26, t, J=8.8 Hz, 1H), 7.30 (m, 3H), 7.38 (dd,
apparent triplet, J=8.0, 7.6 Hz, 1H), 7.49 (s, 1H), 7.55 (m,
1H).
A-022 Synthesis of
{3-[4-(3'-Bromo-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-ureido}-a-
cetic acid
##STR00046##
[0157] To an 8 mL vial containing Int-15 (70 mg, 0.136 mmol) and a
magnetic stir bar was added anhydrous tetrahydrofuran (2 mL)
followed by 1M aqueous lithium hydroxide (408 uL, 0.408 mmol).
After 1 h, the reaction mixture was concentrated under a stream of
nitrogen gas to a final volume of .about.0.4 mL and then diluted
with water to a total volume of 3 mL. With stirring, 2 N aqueous
HCl (250 uL, 0.5 mmol) was added dropwise over .about.1 min
affording a clumpy solid. The mixture was stirred for 30 min at
room temperature affording a free-flowing solid which was filtered
and dried to give 50 mg (76%) yield of A-022.
[0158] 1H NMR (400 MHz, DMSO-d6) 3.71 (s, 3H), 3.77 (d, J=5.6 Hz,
2H), 3.84 (s, 2H) 6.30 (t, H=5.6 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H),
7.25 (dd, apparent triplet, J=9.2, 8.4 Hz, 1H), 7.30 (m, 3H), 7.38
(dd, apparent triplet, J=8.0, 7.6 Hz, 1H), 7.49 (m, 1H), 7.55 (m,
1H), 8.68 (s, 1H), 12.53 (br s, 1H). MS (APCI+): 487.0 (M.sup.+),
489 (M.sup.++2); LC-MS: 98.0%.
A-023 Synthesis of
3-{3-[4-(3'-Bromo-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-ureido}-
-propionic acid
##STR00047##
[0159] Synthesis of
3-{3-[4-(3'-Bromo-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-ureido}-
-propionic acid ethyl ester
[0160] Compound Int-16 was synthesized in a manner analogous to
those described for the synthesis of compound Int-15, using Int-14
(101 mg, 0.26 mmol) and ethyl isocyanatopropionate in place of
ethyl isocyanatoacetate to give 117 mg (85%) of Int-16 as an
off-white solid.
[0161] 1H NMR (400 MHz, DMSO-d6) 1.19 (t, J=7.6 Hz, 3H), 2.47 (t,
J=6.4 Hz, 2H), 3.29 (dd, J=6.4, 5.6 Hz, 2H), 3.72 (s, 3H), 3.84 (s,
2H), 4.07 (q, J=7.6 Hz, 2H), 6.17 (t, H=5.6 Hz, 1H), 6.91 (d, J=8.8
Hz, 1H), 7.06 (m, 2H), 7.25 (dd, apparent triplet, J=8.4 Hz, 1H),
7.30 (m, 3H), 7.38 (dd, apparent triplet, J=8.0, 7.6 Hz, 1H), 7.49
(m, 1H), 7.55 (m, 1H).
[0162] Compound A-023 was synthesized in a manner analogous to
those described for the synthesis of compound A-022 using compound
Int-16 (73 mg, 0.26 mmol) to give 46 mg (67%) of A-023 as a
solid.
[0163] 1H NMR (400 MHz, DMSO-d6) .delta. 2.40 (t, J=6.4 Hz, 2H),
3.26 (dd, J=6.4, 5.6 Hz, 2H), 3.71 (s, 3H), 3.83 (s, 2H), 6.16 (t,
H=5.6 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 7.06 (m, 2H), 7.27 (m, 3H),
7.32 (m, 1H), 7.38 (dd, apparent triplet, J=8.0, 7.6 Hz, 1H), 7.49
(m, 1H), 7.55 (m, 1H), 8.47 (s, 1H), 12.25 (br s, 1H). MS (APCI+):
501.0 (M.sup.+), 503 (M.sup.++2); LC-MS: 97.8%.
[0164] Synthesis of A-024, A-025, A-026, A-027:
##STR00048##
Int-17
Synthesis of 3-Bromo-2-fluoro-4-methoxy-benzaldehyde using
titanium(IV)chloride
[0165] A solution of 2-bromo-3-fluoroanisol (5.00 g, 24.3 mmol) in
dichloromethane (120 mL) was cooled to 0.degree. C. in a salt-ice
bath and purged with nitrogen. The reaction was allowed to stir 15
min under nitrogen. To the reaction was added titanium(IV)chloride
(23.1 g, 122 mmol), followed by a,a-dichloromethyl-methylether
(4.21 g, 36.6 mmol) at 0.degree. C. under nitrogen. The reaction
was allowed to warm to room temperature and stirred for 22 h. The
red solution was poured into ice water (600 mL), and extracted into
dichloromethane (3.times.200 mL). The organic extracts were
combined, washed with saturated aqueous sodium bicarbonate
(2.times.400 mL), water (2.times.400 mL), and brine (400 mL), dried
over sodium sulfate, filtered, and the solvent removed under vacuum
to give wet product. The product was dried in a vacuum oven at
80.degree. C. overnight to give Int-17 (5.75 g, quantitative
yield).
[0166] 1H NMR (400 MHz CDCl3) .delta. 10.22 (s, 1H), 7.86 (dd,
J=8.8 Hz, 7.6 Hz, 1H), 6.82 (d, J=8.4 Hz, 1H), 4.01 (s, 3H).
Int-18
Synthesis of
3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-carbaldehyde
[0167] A mixture of Int-17 (2.0 g, 7.98 mmol), 3-chlorophenyl
boronic acid (1.4 g, 8.76 mmol) and cesium carbonate (5.2 g, 15.9
mmol) in dimethylformamide (20 mL) was degassed with a nitrogen
stream for 4 min. To the reaction was added palladium(II) acetate
(89 mg, 0.398 mmol) and the reaction was stirred at 50.degree. C.
for 2 h and at room temperature for 16 h. Additional palladium(II)
acetate (89 mg, 0.398 mmol) was added and the reaction stirred at
50.degree. C. for 2 h. The reaction was cooled, filtered through
celite, and washed with ethyl acetate. The reaction was partitioned
with ethyl acetate (100 mL) and water (100 mL), and brine was added
(20 mL). The aqueous layer was extracted with ethyl acetate
(2.times.75 mL) and the combined extracts washed with aqueous 5%
lithium chloride (50 mL), aqueous 0.5 N hydrochloric acid (50 mL),
water (2.times.50 mL), and brine (50 mL). The solution was dried
over magnesium sulfate, filtered, and the solvent removed under
vacuum to give crude Int-18 (2.2 g, 98% yield) which was used in
the next step without further purification.
Int-19
Synthesis of
(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-methanol
[0168] A solution of Int-18 (2.00 g, 6.8 mmol) in tetrahydrofuran
(18 mL) and water (6 mL) was cooled to 0.degree. C. in an ice water
bath. To the solution was added sodium borohydride (388 mg, 10
mmol). The reaction was stirred for 10 minutes, and upon completion
was diluted with water (10 mL) and aqueous saturated ammonium
chloride (40 mL). The reaction was extracted with ethyl acetate (50
mL, 100 mL), and the combined extracts washed with water
(2.times.50 mL) and brine (50 mL). The organic extract was dried
over magnesium sulfate, filtered, and the solvent removed under
vacuum to give Int-19 (2.1 g) which was used in the next step
without further purification.
Int-20
Synthesis of
3-Bromomethyl-3'-chloro-2-fluoro-6-methoxy-biphenyl
[0169] A solution of Int-19 (5.44 mmol; 1.0 eq.) and
triphenylphosphine (5.98 mmol; 1.1 eq.) was cooled to 0-5.degree.
C., and N-bromosuccinimide (5.98 mmol; 1.1 eq.) was added. The
mixture was allowed to stir, and warm to room temperature for h
hours. Additional N-bromosuccinmide (0.54 mmol; 0.1 eq.) and
triphenylphosphine (0.54 mmol; 0.1 eq.) were added, and the
reaction was stirred for an additional 1 hour. The reaction was
then diluted with water, and the layers separated. The organic
portion was washed with successive portions of water and brine,
dried over magnesium sulfate, and filtered through a short pad of
silica gel. The filtrate was concentrated, and the residue purified
via silica gel plug filtration, using 1% acetone/hexanes as eluent
to afford the title compound as white needles in 78% yield. .sup.1H
NMR, CDCl.sub.3; 400 MHz): .delta. 3.79 (s, 3H), 4.55 (s, 2H), 6.76
(dd, J=8.8, 1.2 Hz, 1H), 7.28 (m, 1H), 7.34-7.38 (M, 3H), 7.39 (m,
1H).
Int-21
Synthesis of Carbonic acid
3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl ester methyl
ester
[0170] A solution of
(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-methanol (Int-19)
(3.00 g, 11.3 mmol) in pyridine (2.31 g, 29.3 mmol) and
tetrahydrofuran (40 mL) was cooled to 0.degree. C. in an ice water
bath. The reaction vessel was purged with nitrogen and methyl
chloroformate (2.34 g, 24.8 mmol) was added. The ice bath was
removed and the reaction was stirred at room temperature overnight.
The white suspension was adjusted to pH 2 by addition of 1 N
aqueous hydrochloric acid (.about.25 mL) and the yellow biphasic
solution was diluted with dichloromethane (200 mL) and water (150
mL). The layers were separated, and the aqueous layer was extracted
with dichloromethane (2.times.100 mL). The dichloromethane extracts
were combined, washed with water (2.times.200 mL) and brine (200
mL), dried over sodium sulfate, filtered, and the solvent removed
under vacuum to give Int-21 (3.84 g, quantitative yield). 1H NMR
(400 MHz CDCl3) d: 7.41-7.32 (m, 4H), 7.29-7.27 (m, 1H), 6.77 (dd,
J=8.4 Hz, 0.8 Hz, 1H), 5.20 (s, 2H), 3.80 (s, 3H), 3.80 (s, 3H).
LCMS=98.2% purity. MS (APCI+)=249.0 (M-78), MS (APCI-)=249.0
(M-78).
##STR00049##
Int-22
Synthesis of
(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-acetonitrile
[0171] A suspension of Int-20 (15.2 mmol; 1.0 eq.) and sodium
cyanide (22.8 mmol; 1.5 eq.) in aqueous isopropyl alcohol was
refluxed for 1 hour. The reaction was cooled to room temperature,
and concentrated to remove the isopropyl alcohol. The resultant
aqueous layer was extracted with 2 portions of ethyl acetate, and
the organics washed successively with water and brine, and dried
over magnesium sulfate. The residue was purified via flash
chromatography on silica gel, using 10% acetone/hexanes as eluent
to afford the title compound (Int-22) as a white solid in 57%
yield. (.sup.1H NMR, CDCl.sub.3; 400 MHz): .delta. 3.80 (s, 3H),
3.93 (s, 2H), 6.80 (dd, J=8.8, 1.6 Hz, 1H), 7.26 (m, 1H), 7.35-7.41
(M, 4H).
[0172] Synthesis of Int-23:
##STR00050##
Int-23]
Synthesis of
5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-[1,3,4]thiadiazol-2--
ylamine
[0173] A mixture of Int-22 (0.91 mmol; 1.0 eq.) and
thiosemicarbazide (1.03 mmol; 1.1 eq.) in trifluoroacetic acid was
heated to 60.degree. C. for 6 hours, and allowed to cool to room
temperature. The mixture was added to ice water, stirred for 1
hour, and filtered. The filter cake was washed with water, and the
solid dried at 45-50.degree. C. under vacuum for 5 hours to afford
the title compound in 99% yield.
A-024 Synthesis of
{3-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-[1,3,4]thiadiazo-
l-2-yl]-ureido}-acetic acid ethyl ester
##STR00051##
[0175] To a solution of Int-23 in pyridine at room temperature was
added the isocyanate. The resultant mixture was stirred at room
temperature for 3 days, and added to water. The resultant
suspension was stirred for 1 hour, filtered, and washed with water.
The solid was dried in vacuo over ethyl acetate vapors to afford
the desired product as a white solid in 67% yield.
[0176] (.sup.1H NMR, DMSO-d.sub.6; 400 MHz): .delta. 1.17 (t, J=7.2
Hz, 3H), 3.34 (d, J=6.4 Hz, 2H), 3.75 (s, 3H), 4.06 (q, J=7.2 Hz,
2H), 4.27 (s, 2H), 6.69 (bs 1H), 6.99 (d, J=8.8 Hz, 1H), 7.29 (d,
J=6.8 Hz, 1H), 7.37 (s, 1H), 7.40-7.48 (M, 4H), 10.79 (s, 1H).
[0177] LC/MS (90.7%) APCI.sup.+ found: 479.0; calc'd: 478.9 m/z
A-025 Synthesis of
3-{3-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-[1,3,4]thiadia-
zol-2-yl]-ureido}-propionic acid ethyl ester:
[0178] This compound was prepared analogous to A-024 in 51%
yield.
[0179] (.sup.1H NMR, DMSO-d.sub.6; 400 MHz): 1.19 (t, J=7.2 Hz,
3H), 3.75 (s, 3H), 3.90 (d, J=6.0 Hz, 2H), 4.05-4.13 (M, 2H), 4.27
(s, 2H), 6.51 (dd, J=6.0 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 7.29 (d,
J=6.8 Hz, 1H), 7.37 (s, 1H), 7.40-7.48 (M, 4H), 11.11 (s, 1H).
A-026 Synthesis of
{3-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-[1,3,4]thiadiazo-
l-2-yl]-ureido}-acetic acid
[0180] To a solution of starting ester in THF was added excess 1M
aqueous lithium hydroxide. The biphasic mixture was stirred at room
temperature until TLC indicated complete consumption of starting
material. The THF was removed with a stream of nitrogen, and the
resultant aq. solution was acidified with 3 N hydrochloric acid to
pH 1-2. The resultant solids were filtered, washed with water, and
dried in vacuo over ethyl acetate vapors to afford the desired
product as a white solid in 70% yield.
[0181] (.sup.1H NMR, DMSO-d.sub.6; 400 MHz): .delta. 3.75 (s, 3H),
3.83 (d, J=5.6 Hz, 2H), 4.27 (s, 2H), 6.83 (m, 1H), 6.99 (d, J=8.4
Hz, 1H), 7.29 (d, J=7.2 Hz, 1H), 7.38 (s, 1H), 7.40-7.48 (M, 4H),
11.06 s, 1H), 12.70 (s, 1H). LC/MS (91.7%) APCI.sup.- found: 449.0
(M-1); calc'd: 450.9 m/z.
[0182] A-027 Synthesis of
3-{3-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-[1,3,4]thiadia-
zol-2-yl]-ureido}-propionic acid: This compound was prepared
analogous to A-026 in 68% yield.
[0183] (.sup.1H NMR, DMSO-d.sub.6; 400 MHz): .delta. 2.42 (t, J=6.4
Hz, 2H), 3.32 (t, J=6.4 Hz, 2H), 3.75 (s, 3H), 4.26 (s, 2H), 6.71
(m, 1H), 6.99 (d, J=8.4 Hz, 1H), 7.29 (d, J=6.8 Hz, 1H), 7.38 (s,
1H), 7.40-7.46 (M, 4H), 10.80 (s, 1H), 12.32 (s, 1H).
[0184] LC/MS (91.7%) APCI.sup.- found: 463.0 (M-1); calc'd: 464.9
m/z
[0185] Synthesis of A-033 and A-034
##STR00052##
Int-22 Synthesis of
5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridine-2-carboxyli-
c acid methyl ester.
[0186] Int-22 was synthesized from Int-21 (516 mg, 1.59 mmol) and
2-methylcarboxypyridine-5-boronic acid pinocol ester (460 mg, 1.75
mmol) using the same procedure as A-020. The crude material was
purified by flash silica gel column chromatography (0-5% acetone in
dichloromethane) to give Int-22 (381.4 mg, 62% yield) as an orange
syrup.
[0187] 1H NMR (400 MHz CDCl3) .delta. 8.65 (d, J=2.4 Hz, 1H), 8.06
(d, J=8.0 Hz, 1H), 7.66 (dd, J=8.0 Hz, 2.0 Hz, 1H), 7.37-7.39 (m,
3H), 7.26-7.24 (m, 1H), 7.11 (t, J=8.6 Hz, 1H), 6.78 (dd, J=8.6 Hz,
1.0 Hz, 1H), 4.04 (s, 2H), 4.00 (s, 3H), 3.77 (s, 3H). LCMS=96.8%
purity. MS (APCI+)=386.0 (M+1).
Int-23
Synthesis of
5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridine-2-carboxyli-
c acid
[0188] To a solution of Int-22 (317 mg, 0.822 mmol) in
tetrahydrofuran (2.2 mL), methanol (2.2 mL), and water (2.2 mL) was
added 1 N aqueous sodium hydroxide (1.64 mL, 1.64 mmol). The
resultant solution was stirred at room temperature for 23 h. The pH
was adjusted with glacial acetic acid to pH 4. Approximately 3/4 of
the solvent was removed under vacuum and the remaining suspension
was diluted with water (10 mL). The suspension was extracted with
dichloromethane (3.times.10 mL), and the combined extracts were
dried over magnesium sulfate, filtered, and the solvent removed
under vacuum to give crude Int-23 (250.8 mg, 82% yield) as a beige
solid.
[0189] 1H NMR (400 MHz CDCl3) .delta. 8.50 (m, 1H), 8.13 (d, J=7.6
Hz, 1H), 7.76-7.71 (m, 1H), 7.37-7.32 (m, 3H), 7.26-7.24 (m, 1H),
7.13 (t, J=8.6 Hz, 1H), 6.74 (d, J=8.8 Hz, 1H), 4.05 (s, 2H), 3.77
(s, 3H).
A-033 Synthesis of
1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridine-2-carbon-
yl]-piperidine-4-carboxylic acid ethyl ester
[0190] A solution of Int-23 (75.0 mg, 0.202 mmol),
piperidine-4-carboxylic acid ethyl ester (34.9 mg, 0.222 mmol),
EDCI (42.6 mg, 0.222 mol), and HOBt (30.0 mg, 0.222 mmol) in
tetrahydrofuran (2 mL) was stirred at room temperature for 16 h.
The solvent was removed under vacuum and the residue was suspended
in ethyl acetate (20 mL). The organic suspension was washed with
1:1 saturated aqueous sodium bicarbonate and water (20 mL), and the
wash was extracted with ethyl acetate (20 mL). The organic extracts
were combined, washed with water (20 mL), brine (20 mL), dried over
sodium sulfate, filtered and the solvent removed under vacuum to
give crude product as a yellow grease. The product was purified by
silica gel preparatory thin layer chromatography (10% methanol in
dichloromethane) to give A-033 (88.3 mg, 86% yield).
[0191] 1H NMR (400 mHz CDCl3) .delta.: 8.47 (s, 1H), 7.63-7.54 (m,
3H), 7.39-7.28 (m, 3H), 7.12 (t, J=8.6 Hz, 1H), 6.73 (d, J=8.4 Hz,
1H), 4.55-4.52 (m, 1H), 4.15 (q, J=14.0 Hz, 2H), 3.95 (m, 1H), 3.77
(s, 3H), 3.21-3.01 (m, 2H), 2.61-2.55 (m, 1H), 2.51-2.02 (m, 1H),
1.86-1.80 (m, 3H), 1.26 (t, J=7.0 Hz, 3H). LCMS=97.4%. MS
(APCI+)=511.0 (M+1).
[0192] A-034
Synthesis of
1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridine-2-carbon-
yl]-piperidine-4-carboxylic acid
[0193] A solution of A-033 (60.0 mg, 0.117 mmol) in tetrahydrofuran
(2 mL), water (2 mL), and 1 N aqueous sodium hydroxide (0.176 mL,
0.176 mmol) was stirred at room temperature for 3 h. The
tetrahydrofuran was removed under vacuum, and glacial acetic acid
was added (0.5 mL). The aqueous suspension was extracted with
dichloromethane (5 mL), then diluted with water (10 mL), and
extracted with dichloromethane (10 mL). The organic extracts were
combined, washed with brine (15 mL), dried over magnesium sulfate,
filtered, and the solvent removed under vacuum to give product as a
gummy material. The gummy solid was dried under high vacuum at room
temperature for 1 h, to give A-034 (43.7 mg, 77% yield).
[0194] 1H NMR (400 MHz CDCl3) .delta.: 8.55 (d, J=2.0 Hz, 1H), 7.65
(dd, J=8.0 Hz, 2.0 Hz, 1H), 7.56-7.46 (m, 2H), 7.39-7.27 (m, 3H),
7.13 (t, J=8.6 Hz, 1H), 6.73 (d, J=7.6 Hz, 1H), 4.56-4.53 (m, 1H),
4.01 (s, 1H), 3.88-3.85 (m, 1H), 3.77 (s, 3H), 3.16-3.02 (m, 2H),
2.65-2.60 (m, 1H), 2.06 (brs 1H), 1.89 (brs, 3H). LCMS=98.1%
purity. MS (APCI-)=481.1 (M-1).
[0195] Synthesis of A-038
##STR00053##
Int-24
Synthesis of
1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridine-2-carbon-
yl]-pyrrolidine-3-carboxylic acid methyl ester
[0196] To a solution of Int-23 (100 mg, 0.269 mmol) and
pyrrolidine-3-carboxylic acid methyl ester (49.0 mg, 0.296 mmol) in
tetrahydrofuran (3 mL), was added HOBt (40.0 mg, 0.296 mmol) and
EDCI (56.7 mg, 0.296 mmol). Dimethylformamide (1 mL) was added and
the reaction stirred at room temperature overnight. Additional
pyrrolidine-3-carboxylic acid methyl ester (25.0 mg) was added, and
the reaction stirred at room temperature overnight. The solvent was
removed under vacuum and dichloromethane (10 mL) and water (10 mL)
were added. The layers were separated, and the water extracted with
dichloromethane (10 mL). The organic extracts were combined, washed
with water (20 mL), saturated aqueous sodium bicarbonate (20 mL),
and brine (20 mL), dried over magnesium sulfate, filtered, and the
solvent removed under vacuum to give crude product. The crude
material was purified by silica gel preparatory thin layer
chromatography (eluting with 10% acetone in dichloromethane) to
give Int-24 (28.4 mg, 22% yield) as a clear oil.
A-038 Synthesis of
1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridine-2-carbon-
yl]-pyrrolidine-3-carboxylic acid
[0197] A solution of Int-24 (25.0 mg, 0.0518 mmol) and 1 N aqueous
sodium hydroxide (77.7 uL, 0.0777 mmol) in tetrahydrofuran (1 mL)
and water (1 mL) was stirred at room temperature for 3 h. The
solvent was removed under vacuum and the residue was neutralized
with 10 drops of glacial acetic acid. The crude material was
dissolved in water (5 mL) and dichloromethane (5 mL) and the two
layers separated. The aqueous solution was extracted with
dichloromethane (5 mL) and the combined dichloromethane layers were
washed with water (5 mL) and brine (5 mL), dried over magnesium
sulfate, filtered, and the solvent removed under a nitrogen stream
to give crude product as a beige powder. The product was purified
by silica gel preparatory thin layer chromatography (eluted with
25% acetone in dichloromethane with 3 developments) to give A-038
(11.6 mg, 48% yield).
[0198] 1H NMR (400 MHz d6-DMSO) .delta.: 8.51 (d, J=7.6 Hz, 1H),
7.74-7.66 (m, 2H), 7.45-7.28 (m, 5H), 6.96 (d, J=8.4 Hz, 1H), 4.03
(s, 2H), 3.76-3.64 (m, 7H), 2.95 (s, 1H), 2.02 (m, 2H). LCMS=98.1%
purity. MS (APCI-)=467.1 (M-1).
##STR00054##
Int-25
[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl-
amine
[0199] Into a 250 mL round bottom flask was added Int-21 (8.04 g,
24.76 mmol),
5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine
(4.09 g, 18.57 mmol), K.sub.2CO.sub.3 (10.27 g, 74.27 mmol), and
DMF (100 mL). After degassing for 20 minutes with N.sub.2,
Allylpalladium(II) chloride dimer (1.36 g, 3.71 mmol) and
1,5-bis(diphenylphosphano)pentane (3.27 g, 7.43 mmol) were added
and the reaction stirred for 18 hours at 80.degree. C. and room
temperature for 2 days. Water was added and the product was
extracted with EtOAc. The organics were concentrated and then the
residue purified by flash column chromatography (0-5% MeOH/DCM) to
provide Int-25 (4.1 g, 48%) as a red oil. The compound was used as
is in the next reaction.
[0200] A-039
##STR00055##
6-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-imidazo[1,2-a]pyridi-
ne-2-carboxylic acid ethyl ester
[0201] Into an 18 mL vial were added Int-25 (565 mg, 1.65 mmol),
3-Bromo-2-oxo-propionic acid ethyl ester (0.52 mL, 4.12 mmol), and
dimethoxyethane (DME, 5 mL). The reaction was stirred at room
temperature for 18 hours. Saturated NaHCO.sub.3 (aq) was added and
the product was extracted with EtOAc. The organics were
concentrated and purified by flash column chromatography (5%
Acetone/DCM) to give a tan solid. The solid was triturated with
ether to obtain A-039 (198 mg, 26%) as an off-white solid.
.sup.1H-NMR (400 MHz, CDCl3): 8.51 (s, 1H), 8.39 (s, 1H), 7.56 (d,
J=9.4 Hz, 1H), 7.49-7.35 (m, 4H), 7.30 (d, J=6.7 Hz, 1H), 7.25 (dd,
J=1.3, 9.4 Hz, 1H), 6.97 (d, J=8.6 Hz, 1H), 4.29 (q, J=7.1 Hz, 2H),
3.96 (s, 2H), 3.74 (s, 3H), 1.31 (t, J=7.0 Hz, 3H).
[0202] A-043
##STR00056##
6-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-imidazo[1,2-a]pyridi-
ne-2-carboxylic acid
[0203] Into an 8 mL vial was added A-039 (39 mg, 0.089 mmol), 1N
NaOH (1 mL), and 1 mL EtOH. The reaction was stirred at room
temperature for 18 hours and then 60.degree. C. for 1 hour. The pH
was adjusted to about 5 with 1N HCl and a light-colored precipitate
formed. The solid was filtered, washed with water, and dried under
high vacuum to obtain A-043 (22.2 mg, 61%) as an off-white solid.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): 8.36 (s, 1H), 8.14 (s, 1H),
7.39 (m, 6H), 7.14 (dd, 1H, J=9.2, 2.0 Hz), 6.96 (d, 1H, J=8.4 Hz),
3.93 (s, 2H), 3.73 (s, 3H). LC/MS=94.6%, 411.0 (APCI+).
##STR00057##
Int-26
5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carbonitrile
[0204] Into a 250 mL RBF was added 3.0 g
5-Bromo-pyridine-2-carbonitrile (3.0 g, 16.39 mmol),
Bis(pinacolato)diboron (4.58 g, 18.03 mmol), KOAc (5.47 g, 55.74
mmol), and DMSO (100 mL). After degassing for 20 minutes,
PdCl.sub.2dppf-CH.sub.2Cl.sub.2 (1.39 g, 1.64 mmol) was added and
the solution was stirred for 24 hours at 80.degree. C., and then
room temperature for 3 days. 50 mL water was added and the product
was extracted with ethyl acetate. The combined organics were washed
with brine, dried over Na.sub.2SO.sub.4 and concentrated. The
dark-colored residue was purified by FCC eluting with 20%
acetone/hexanes to give a red solid. The solid was triturated with
hexane to give 1.72 g (46%) Int-26 as a light-pink solid.
Int-27
[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylmethyl]--
carbamic acid tert-butyl ester
[0205] Into a 20 mL vial was added Int-26 (401 mg, 1.22 mmol),
Int-20 (336 mg, 1.46 mmol), K.sub.2CO.sub.3 (504 mg, 3.65 mmol),
DME (5 mL), water (0.5 mL), ethanol (0.5 mL), and the suspension
was degasses for 15 minutes. Pd(PPh.sub.3).sub.4 (141 mg, 0.12
mmol) was added and the reaction stirred at 80.degree. C. for 16
hours. The reaction was diluted with water and extracted with ethyl
acetate. The organics were concentrated and purified by FCC eluting
with 15-20% ethyl acetate/hexanes to afford Int-27 (64 mg, 15%) as
a light-yellow oil. .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta.=8.62 (br. s., 1H), 7.68-7.56 (m, 2H), 7.40-7.30 (m, 3H),
7.26-7.21 (m, 1H), 7.13 (t, J=8.4 Hz, 1H), 6.75 (d, J=8.3 Hz, 1H),
4.03 (br. s., 2H), 3.78 (s, 3H). LC/MS=98.5%, 353.0 (APCI+).
A-042 Ex-428
5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-(1H-tetrazol-5-yl)--
pyridine
[0206] Into a 20 mL vial was added Int-27 (129 mg, 0.37 mmol),
NH.sub.4Cl (137 mg, 2.56 mmol), NaN.sub.3 (119 mg, 1.83 mmol), and
DMF (3 mL). The reaction was stirred for 18 hours at 80.degree. C.,
then filtered and concentrated. The residue was purified by FCC
eluting with 25-75% acetone/DCM, then 10% methanol/DCM to afford a
colorless oil. The oil was treated with ether to afford A-042 (13
mg, 9%) as a tan solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.=8.49 (br. s., 1H), 7.95 (br. s., 1H), 7.66 (br. s., 1H),
7.49-7.33 (m, 4H), 7.32-7.25 (m, 1H), 6.96 (d, J=8.6 Hz, 1H), 4.00
(br. s., 2H), 3.73 (s, 3H). LC/MS=100.0%, 396.0 (APCI+).
[0207] Synthesis of A-047
##STR00058##
Int-28
Synthesis of 2-chloro-pyrimidine-5-boronic acid
[0208] A 200 mL round bottom was charged under nitrogen with
5-bromo-2-chloro pyrimidine (30 mmol, 5.79 g), toluene (48 mL), THF
(12 mL) and triisopropyl borate (36 mmol, 8.4 mL). The mixture was
stirred at -70.degree. C. and n-butyl lithium (2.5M in hexane, 36
mmol, 14.4 mL) was added slowly (1.5 h period). After 2 h of
stirring at -70.degree. C., the reaction was warmed to -20.degree.
C. before 2N HCl (30 mL) was added. Upon the HCl addition the
reaction mixture turned from a pale homogeneous solution to a white
bi-phasic solution. When the mixture reached rt, it was transferred
to a reparatory funnel and the layers were separated. The aqueous
layer was neutralized to PH=7 with 1N NaOH followed by extractions
with THF (3.times.150 mL). The combined organic layers were dried
over NA2SO4 and concentrated. The crude was dissolved in THF (5 mL)
and ether (100 mL) was added. A yellow solid precipitated out. The
solid was collected and dried to give Int-28 (3.79 g) as a pale
yellow solid.
Int-29
Synthesis of
3'-Chloro-2-fluoro-3-(4-iodo-benzyl)-6-methoxy-biphenyl
[0209] Int-20 (2.5 mmol, 824 mg) and Int-28 (2.5 mmol, 400 mg) were
dissolved in toluene (10 mL) and ethanol (2.5 mL). Pd
(PPh.sub.3).sub.4 (144 mg, 0.125 mmol) was added followed by
Na.sub.2CO.sub.3 in water (2M, 5 mL, 2.5 mmol). The reaction
mixture was heated overnight at 85.degree. C. The resultant mixture
was diluted with EtOAc (25 mL), washed with water and brine, and
then dried over Na.sub.2SO.sub.4. The organic solution was filtered
and concentrated under reduced pressure. The crude was purified by
silica gel (40 g) column (1/2 inch diameter) chromatography, eluted
with Hexane/EtOAc (9:1) gave the title compound (297.4 mg) as a
pale yellow solid.
A-047 Synthesis of
{[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyrimidin-2-yl]-me-
thyl-amino}-acetic acid
[0210] In an 8 mL vial equipped with a stir bar was placed Int-29
(120 mg, 0.330 mmol), N-methylglycine (44.1 mg, 0.495 mmol),
isopropanol (1.5 mL) and diisopropylethylamine (172 .mu.L, 0.990
mmol). The reaction mixture was heated to 80.degree. C. for 18
hours. This material was combined with the reaction mixture of an
identical reaction run on a 20 mg scale. The mixture was treated
with saturated sodium bicarbonate solution (60 mL), water (30 mL),
(pH 8) and extracted with ethyl acetate (2.times.50 mL) to remove
organic impurities. The organic portions were combined, washed with
saturated sodium bicarbonate solution (75 mL) and all of the
aqueous portions were then combined and acidified to pH 1 with 3M
hydrochloric acid. The aqueous portion was extracted with ethyl
acetate (3.times.75 mL) and the organic portions were combined,
washed with brine (100 mL), dried (magnesium sulfate) and
concentrated to produce 44 mg of A-047 as a white powder in 27%
yield.
[0211] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 3.11 (s, 3H),
3.72 (s, 3H), 3.77 (s, 2H), 4.24 (s, 2H), 6.93 (d, J=9 Hz, 1H),
7.284-7.328 (m, 2H), 7.38 (s, 1H), 7.43-7.46 (m, 2H), 8.25 (bs,
2H).
##STR00059##
[0212] Int-30
C-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-meth-
ylamine
[0213] Into a 100 mL RBF was added Int-27 (0.55 g, 1.56 mmol),
methanol (20 mL), concentrated HCl (0.65 mL, 7.79 mmol), and 10%
Pd/C (100 mg). The suspension was stirred under a H.sub.2 balloon
for 18 hours, and then filtered through Celite. The filtrate was
concentrated. To the solid was added 1N NaOH and the product was
extracted with DCM. The DCM was concentrated and purified by FCC
eluting with 5-10% methanol/DCM to give Int-30 (89 mg, 16%) as a
colorless oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.=8.55 (d,
J=1.2 Hz, 1H), 8.32 (br. s., 3H), 7.71 (dd, J=1.9, 7.9 Hz, 1H),
7.50-7.37 (m, 3H), 7.36 (d, J=5.4 Hz, 2H), 7.27 (d, J=6.6 Hz, 1H),
6.96 (d, J=8.6 Hz, 1H), 4.75 (br. s., 2H), 4.14 (q, J=5.8 Hz, 2H),
4.01 (s, 2H), 3.73 (s, 3H). LC/MS=95.1%, 357.1 (APCI+).
[0214] A-048
##STR00060##
N-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylmethy-
l]-oxalamic acid ethyl ester
[0215] Into an 18 mL vial was added Int-30 (152 mg, 0.43 mmol), TEA
(0.11 mL, 0.85 mmol), and DCM (4 mL). The solution was cooled to
0.degree. C. and Ethyl chlorooxoacetate (71 uL, 0.64 mmoL) was
added. After 20 minutes at room temperature the reaction was washed
with brine and the organics were concentrated. The semi-solid was
triturated with 1:1 ether:EtOAc, filtered, and washed with EtOAc to
provide the title compound (69 mg, 35%) as a gray-blue solid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.=9.38 (t, J=6.0 Hz, 1H),
8.41 (s, 1H), 7.59 (dd, J=4.0, 8.0 Hz, 2H), 7.48-7.25 (m, 8H), 7.22
(d, J=8.1 Hz, 2H), 6.94 (d, J=8.6 Hz, 2H), 4.39 (d, J=6.0 Hz, 2H),
4.32-4.18 (m, 2H), 3.94 (s, 2H), 3.72 (s, 3H), 1.27 (t, J=7.1 Hz,
3H). LC/MS=97.9%, 457.0 (APCI+).
[0216] A-050
##STR00061##
N-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridine-2-carbon-
yl]-methanesulfonamide
[0217] Into an 8 mL vial was added Int-23 (85 mg, 0.23 mmol),
Methanesulfonamide (26 mg, 0.27 mmoL), EDCI (88 mg, 0.46 mmol),
DMAP (56 mg, 0.46 mmol), DCM (2 mL), and 0.5 mL of DMSO. After
stirring for 3 days at room temperature 2 mL of water was added and
the layers were separated. The organic layer was washed with
2.times.2 mL NH.sub.4Cl (sat) and then concentrated. The residue
was purified by flash column chromatography eluting with 50%
Acetone/DCM. This material was triturated with ether to afford the
title compound (27.2 mg, 26%) as a white solid. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta.=8.66 (br. s., 1H), 7.98 (d, J=7.9 Hz,
1H), 7.72 (d, J=7.5 Hz, 1H), 7.50-7.32 (m, 4H), 7.28 (d, J=6.4 Hz,
1H), 6.96 (d, J=8.6 Hz, 1H), 4.05 (s, 2H), 3.73 (s, 3H), 2.95 (s,
3H). LC/MS=100.0%, 449.0 (APCI+).
##STR00062##
Int-31
6-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-imidazo[1,5-a]pyridin-
e-3-carboxylic acid ethyl ester
[0218] Into a 4 mL vial was added A-048 (44 mg, 0.096 mmol), DCM (1
mL), pyridine (31 uL, 0.48 mmol), and POCl.sub.3 (13 uL, 0.14
mmol). The reaction was stirred at room temperature for 18 hours
after which 2 mL of water was added. The layers were separated and
the product was extracted with 2 mL of DCM. The organics were
combined, concentrated, and purified by flash column chromatography
eluting with 20% Acetone/Hexanes to afford a light-yellow
semi-solid. Trituration of the residue with hexanes provided a
solid which was filtered, washed with hexanes, and dried. The title
compound was obtained as a tan solid (8.2 mg, 19%).
[0219] A-051
##STR00063##
6-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-imidazo[1,5-a]pyridi-
ne-3-carboxylic acid hydrochloride
[0220] Into an 8 mL vial was added Int-31 (42 mg, 0.14 mmol), EtOH
(1 mL), and 1N NaOH (1 mL). The reaction was stirred at 60.degree.
C. for 1 hour. After cooling to room temperature some insoluble
matter was removed by filtration through a nylon filter. The EtOH
was evaporated and the pH of the remaining aqueous phase was
adjusted to pH=1 with 1N HCl. The solids which formed were
filtered, washed with water, and dried under vacuum to afford the
title compound (A-051) (14.2 mg, 23%) as a yellow solid. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta.=9.15 (s, 1H), 7.79 (d, J=9.3
Hz, 1H), 7.65 (s, 1H), 7.51-7.34 (m, 4H), 7.33-7.25 (m, 1H), 7.10
(s, 1H), 6.97 (d, J=8.6 Hz, 1H), 4.02 (s, 2H), 3.74 (s, 3H).
[0221] Synthesis of A-052
##STR00064##
A-052
5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-(1H-tetrazol-5-yl)--
pyridine
[0222] Into a 20 mL vial was added Int-27 (129 mg, 0.37 mmol),
NH.sub.4Cl (137 mg, 2.56 mmol), NaN.sub.3 (119 mg, 1.83 mmol), and
DMF (3 mL). The reaction was stirred for 18 hours at 80.degree. C.,
then filtered and concentrated. The residue was purified by FCC
eluting with 25-75% acetone/DCM, then 10% methanol/DCM to afford a
colorless oil. The oil was treated with ether to afford A-052 (13
mg, 9%) as a tan solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.=8.49 (br. s., 1H), 7.95 (br. s., 1H), 7.66 (br. s., 1H),
7.49-7.33 (m, 4H), 7.32-7.25 (m, 1H), 6.96 (d, J=8.6 Hz, 1H), 4.00
(br. s., 2H), 3.73 (s, 3H). LC/MS=100.0%, 396.0 (APCI+).
[0223] Synthesis of A-055
##STR00065##
Int-32 Synthesis of
5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine
[0224] A suspension of Int-20 (824 mg, 2.50 mmol),
2-fluoropyridin-5-boronic acid (352 mg, 2.50 mmol), 2 M aqueous
sodium carbonate (2.5 mL, 5.00 mmol), and
palladium(0)tetrakis(triphenylphosphine) (144 mg, 0.125 mmol) in
toluene (10 mL) and ethanol (2.5 mL) was stirred at 80.degree. C.
overnight under a high pressure nitrogen atmosphere. The reaction
was cooled to room temperature, diluted with water (10 mL), and
extracted with ethyl acetate (2.times.20 mL). The combined extracts
were dried over sodium sulfate, filtered, and concentrated under
vacuum. The residue was purified by silica gel column
chromatography (4:1 hexanes/ethyl acetate) to give Int-32 (694.7
mg, 78% yield) as a white solid.
A-055 Synthesis of
1-[5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-aze-
tidine-2-carboxylic acid
[0225] To
5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-py-
ridine (Int-32) (0.2 g, 0.58 mmol) and azetidine-2-carboxylic acid
(2) (0.18 g, 1.74 mmol) was added
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.44 g, 2.89 mmol). The
reaction mixture was stirred and heated at 160.degree. C. for 20
min. Cooled to room temperature, diluted with dichloromethane (8
mL), washed with 0.5 N HCl (2.times.4 mL), dried with
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by silica gel column chromatography using 3% methanol in
dichloromethane to afford 0.19 g (77%) of A-055 as off-white solid.
1H NMR (DMSO-d6, 400 MHz): 7.87 (d, J=2.0 Hz, 1H), 7.4-7.47 (m,
2H), 7.37 (s, 1H), 7.2-7.3 (m, 3H), 6.91 (d, J=8.4 Hz, 1H), 6.55
(d, J=8.8 Hz, 1H), 4.08 (dd, J=9.0, 6.8 Hz, 1H), 3.62-3.74 (m, 2H),
3.74 (s, 2H), 3.71 (s, 3H), 2.18-2.3 (m, 2H); MS (APCI+): 427.1
(M+1), LC-MS: 97.1%; HPLC 95.2%
[0226] Synthesis of A-062
##STR00066##
Int-33
Synthesis of [4-(3-Bromo-4-methoxy-benzyl)-phenyl]-urea Int-33
[0227] To a 40 mL vial equipped with a teflon screw cap and a
magnetic stir bar was added 2-bromo-4-bromomethyl-1-methoxybenzene
(649 mg, 2.32 mmol),
[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea (577
mg, 2.20 mmol) and potassium phosphate 933 mg, 4.40 mmol). To the
vial was then added dimethoxyethane (15 mL), ethanol (3.7 mL) and
water (3.7 mL). To this stirring solution was added
tetrakis(triphenylphosphine) palladium (127 mg, 0.11 mmol) and the
solution was degassed by bubbling N2 gas through the solution for
20 min. The vial was capped and placed in an oil bath with stirring
at 65.degree. C. for 12.5 h. The cooled reaction mixture was
concentrated under a stream of N2 gas to a total volume of .about.5
mL and then diluted with ethyl acetate (20 mL) and water (10 mL).
Upon shaking a white solid precipitates. The solid is filtered and
dried to afford 272 mg (34%) of compound Int-33 as a white
solid.
[0228] 1H NMR (400 MHz, DMSO-d6) 3.78 (s, 2H), 3.80 (s, 3H), 5.77
(br s, 2H), 7.01 (d, J=8.4 Hz, 1H), 7.05 (m, 2H), 7.17 (dd, J=8.4,
2.0 Hz, 1H), 7.29 (m, 2H), 7.37 (d, J=2.0 Hz, 1H), 8.43 (br s, 1H).
MS (APCI+): 335.0 (M.sup.+); 337.0 (M.sup.++2), LC-MS: 99.3%
Int-34
Synthesis of
[4-(3'-Chloro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-urea
[0229] To a 20 mL vial equipped with a magnetic stir bar and a
screw cap was added compound Int-33 (250 mg, 0.746 mmol),
dimethoxyethane (5 mL), ethanol (1 mL) and water (1 mL). To this
mixture was added 3-chlorophenylboronic acid (140 mg, 0.895 mmol),
potassium phosphate (316 mg, 1.49 mmol) and
tetrakis(triphenylphosphine) palladium (30 mg, 0.0254 mmol). The
stirring reaction mixture was degassed by bubbling N.sub.2 gas
through the solution for 10 min. The vial was capped and placed in
an oil bath with stirring at 80.degree. C. for 16 h. The cooled
reaction mixture was concentrated to dryness, then diluted with
water (5 mL) and ethyl acetate (15 mL). The aqueous layer was
extracted with ethyl acetate (2.times.5 mL) and the combined
organic extracts were dried (Na.sub.2SO.sub.4), filtered and
concentrated under a stream of N2 gas. The residue was purified by
flash chromatography on silica gel (35 g) utilizing 9:1
dichloromethane/acetone as eluent. Fractions pure by TLC were
combined and concentrated to give 139 mg (51%) of Int-34 as an
off-white solid. 1H NMR (400 MHz, DMSO-d6) 3.74 (s, 3H), 3.83 (s,
2H), 5.75 (br s, 2H), 7.03 (d, J=8.4 Hz, 1H), 7.08 (m, 2H), 7.15
(d, J=2.4 Hz, 1H), 7.18 (dd, J=8.4, 2.4 Hz, 1H), 7.28 (m, 2H),
7.36-7.41 (m, 3H), 7.48 (m, 1H), 8.40 (br s, 1H). MS (APCI+): 367.0
(M.sup.++1); LC-MS: 95.9%.
Int-35
[0230] To a suspension of Int-34 (2.2 mmol, 1.0 eq.) in
dichloromethane at -70.degree. C. was added a 1.0 M solution of
boron tribromide in dichloromethane (6.6 mmol, 3 eq) over 5
minutes. The resultant mixture was allowed to stir and warm to
ambient temperature, and stirred for 20 minutes. The reaction was
poured into ice water (100 mL), stirred for 30 minutes, filtered,
and the cake washed with successive portions of water and hexanes.
The solids were dried in vacuo over ethyl acetate vapors for 4
hours to afford the title compound, which was taken into further
reactions as is. A portion of the title compound was further
purified via chromatography on silica gel using acetone in
dichloromethane as eluent, followed by trituration with
dichloromethane to afford the title compound as a white solid.
(.sup.1H NMR, DMSO-d.sub.6; 400 MHz): 3.78 (s, 2H), 5.75 (s, 2H),
6.86 (d, J=8.0 Hz, 1H), 7.00 (dd, J=8.4, 2.4 Hz, 1H), 7.07 (d,
J=8.4 Hz, 2H), 7.12 (d, J=2.4 Hz, 1H), 7.28 (d, J=8.4 Hz, 2H), 7.4
(m, 1H), 7.41 (dd, J=8.0, 7.6 Hz, 1H), 4.47 (m, 1H), 7.56 (m, 1H),
8.40 (s, 1H), 9.50 (s, 1H). LC/MS (100%) APCI.sup.+ found: 353.0,
calc'd: 352.8 m/z
A-062 Synthesis of Sodium sulfate of
[4-(3'-Chloro-6-hydroxy-biphenyl-3-ylmethyl)-phenyl]-urea
[0231] In an 18 mL vial equipped with a stir bar and atmosphere of
nitrogen was placed Int-35 (250 mg, 0.709 mmol), pyridine (2.5 mL)
and sulfur trioxide-pyridine complex (226 mg, 1.42 mmol). The
mixture was stirred at room temperature for 18 hours. Additional
sulfur trioxide-pyridine complex (100 mg) was added and the
reaction mixture was heated to 70.degree. C. for 4 hours. The
reaction mixture was concentrated with a stream of nitrogen,
methanol (2.5 mL) was added and then 1M NaOH was added to attain pH
8. A white solid formed which was removed via suction filtration.
The filtrate was concentrated and diethyl ether (3 mL) was added
which resulted in a yellowish semi-solid. The solid was collected,
and dried in a high vacuum oven at 35.degree. C. for 5 hours
resulting in an off-white powder. The material was purified by
dissolving the crude material in water (4 mL, made basic by
addition of a few drops of concentrated ammonium hydroxide) and
washing with ethyl acetate (3.times.4 mL). The aqueous portion was
lyophilized overnight to produce 56 mg of A-062 as a fluffy white
solid in 17% yield.
[0232] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 3.83 (s, 2H),
5.88 (s, 2H), 6.95 (d, J=6 Hz, 1H), 7.08-7.13 (m, 3H), 7.31 (d, J=9
Hz, 2H), 7.34-7.36 (m, 1H), 7.40 (t, J=8 Hz, 1H), 7.48-7.50 (m,
1H), 7.56 (d, J=8 Hz, 1H), 7.64 (t, J=2 Hz, 1H), 8.74 (bs, 1H).
[0233] LC-MS: 98%
[0234] Synthesis of A-064 and A-065
##STR00067##
Int-37 Synthesis of
(4-amino-phenyl)-(3'-chloro-6-methoxy-biphenyl-3-yl)-methanone
[0235] To a 25 mL vial which contained
(3'-chloro-6-methoxy-biphenyl-3-yl)-(4-nitro-phenyl)-methanone
(Int-36 (prepared in a similar manner as Int-12), 500 mg, 1.3
mmole) in EtOH--H2O (1:1, 15 mL) was added NH4Cl (200 mg, 4 mmole)
and then Fe (150 mg, 3 mmole) at rt. The reaction mixture was
allowed to stir at rt for 72 h. The mixture was poured onto 50 mL
water, extracted with ethyl acetate (3.times.30 mL), washed with
water (20 mL), brine (30 mL) and dried over Na2SO4. The solvent was
removed under vacuum to yield 420 mg
(4-amino-phenyl)-(3'-chloro-6-methoxy-biphenyl-3-yl)-methanone
(Int-37) in 85% yield 1H NMR (DMSO-d6, 400 MHz): .delta.=7.70 (dd,
J=8.4, 2.4 Hz, 1H), 7.40-7.57 (m, 7H), 7.25 (d, J=8.8 Hz, 1H), 6.61
(d, J=8.8 Hz, 2H), 6.09 (s, 2H), 3.88 (s, 3H)
A-064 Synthesis of 1-acetic
amido-3-[4-(3'-chloro-6-methoxy-biphenyl-3-carbonyl)-phenyl]-urea
[0236] To a 25 mL vial which contained
(4-amino-phenyl)-(3'-chloro-6-methoxy-biphenyl-3-yl)-methanone
(Int-37, 420 mg, 1.3 mmol) in pyridine (2 mL) and THF (8 mL) was
added TMS-isocyanate (1.7 mL, excess) at rt. The mixture was
allowed to stir at rt for 100 h. The mixture was poured onto 25 mL
ice-water solution, 5 mL of sat. NaHCO3 was added and the mixture
which formed was allowed to stir at rt for 2 h. The mixture was
extracted with ethyl acetate (3.times.30 mL), washed with water (20
mL), brine (30 mL) and dried over Na2SO4. The solvent was removed
to provide the crude which was separated by silica gel column
chromatography with ethyl acetate-hexane as eluent to yield 250 mg
of 1-acetic
amido-3-[4-(3'-chloro-6-methoxy-biphenyl-3-carbonyl)-phenyl]-urea
(A-064) in 48.4% yield. 1H NMR (DMSO-d6, 400 MHz): .delta.=10.6
(br, s, 1H), 9.37 (br. s., 1H), 7.40-7.81 (m., 7H), 7.30 (d, J=8.4
Hz, 1H), 6.84-7.10 (m, 2H), 3.90 (s, 3H). LC/MS Calc. 423.86;
APCI+(M+1): 424.1, 95%
A-065 Synthesis of 1-acetic
amido-3-{4-[(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-hydroxy-deutero--
methyl]-phenyl}-urea
[0237] To a 50 mL flask which contained 1-acetic
amido-3-[4-(3'-chloro-6-methoxy-biphenyl-3-carbonyl)-phenyl]-urea
(A-064, 100 mg, 0.3 mmole) in THF (7 mL) and D2O (3 mL) was added
NaBD4 (130 mg, 0.7 mmole) at 0.degree. C. The reaction mixture was
allowed to warm to rt and stir at rt for 24 h. The reaction mixture
was poured onto 40 mL ice-water, neutralized with NH4Cl (sat. 4
mL), extracted with ethyl acetate (3.times.30 mL), washed with
water (20 mL), brine (20 mL) and dried over Na2SO4. After removal
of solvent, the residue was separated by silica gel column
chromatography with ethyl acetate-hexane as eluent to give 70 mg of
1-acetic
amido-3-{4-[(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-hydroxy-deutero--
methyl]-phenyl}-urea in 26% yield. 1H NMR (DMSO-d6, 400 MHz):
.delta.=9.89 (s, 1H), 8.80 (s, 1H), 7.47 (br, s, 1H), 7.42 (d,
J=6.8 Hz, 1H), 7.28-7.39 (m, 7H), 7.05 (d, J=7.2 Hz, 1H), 5.75 (s,
1H), 3.74 (s, 3H). LC/MS Calc. 426.87; APCI.sup.+ (M-OH): 309.1,
98%
[0238] Synthesis of A-035, A-056, A-037, and A-057
##STR00068##
[0239] (Int-38) Synthesis of
5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylamine
A mixture of Int-20 (0.3 g, 0.91 mmol) and
2-aminopyridine-5-boronic acid pinacol (0.24 g, 1.1 mmol) in
DME/EtOH/H.sub.2O (4/1/1, 12 ml) was added potassium phosphate
(0.39 g, 1.82 mmol) and tetrakis(triphenylphosphine)palladium (0)
(53 mg, 0.046 mmol) under nitrogen. The reaction mixture was heated
to 80 C for 2 h. The reaction was diluted with water, extracted
with ethyl acetate, washed with water and brine, and dried over
Na2SO4. After it was concentrated in vacuo, the residue was
purified by a chromatography on silica gel to yield the desire
product, which was converted to its HCl salt Int-38 (0.165 g,
50%).
Int-39
Synthesis of
N-[5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-ace-
tamide
[0240] To a 20 mL vial which contained the mixture of
5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylamine
(Int-38, 420 mg, 1.2 mmol) in pyridine (2 mL) was added Ac.sub.2O
(2 mL, excess) at 0 C. The mixture was allowed to warm to rt and
stir at rt for 16 h and then was poured onto 50 mL ice-water
solution. The solid which formed was filtered out, washed with
water (3.times.15 mL), dried over air to yield 360 mg (85% yield)
of the title product (Int-39).
Int-40
Synthesis of
{acetyl-[5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-y-
l]-amino}-acetic acid methyl ester
[0241] To a 25 mL vial which contained NaH (40% in mineral oil, 40
mg, 1 mmol) in DMF (2 mL) was added
N-[5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-ace-
tamide (Int-39, 77 mg, 0.2 mmol) at 0.degree. C. The reaction
mixture was allowed to warm to rt and stir at rt for 1 h, cooled to
0.degree. C., bromo-acetic acid methyl ester (153 mg, 1.0 mmol) was
added. The mixture was allowed to warm to rt and stir at rt for 16
h and then was poured onto 25 mL ice-water solution which was
extracted with ethyl acetate (3.times.20 mL), washed with water
(3.times.20 mL), brine (20 mL) and dried over Na2SO4. After removal
of solvent, the residue was purified by silica gel column
chromatography with ethyl acetate-hexane as eluent to give 68 mg of
the title compound in 74% yield.
A-035
Synthesis of
[5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylamino]--
acetic acid
[0242] To a 20 mL vial which contained Int-40 (37 mg, 0.08 mmol) in
MeOH (2 mL) was added LiOH (1 N in water, 2 mL, 2 mmol) at rt. The
reaction mixture was allowed to stir at rt for 48 h. The mixture
was poured onto 25 mL ice-water solution, acidified with the
addition of 2N HCl to pH=1-2 and then was extracted with ethyl
acetate (3.times.20 mL), washed with water (3.times.20 mL), brine
(20 mL) and dried over Na2SO4. After removal of solvent, the crude
was purified by dissolving in acetone, adding 30 mL 1:9 ethyl
acetate-hexane and then removal the acetone slowly to yield the
semi-solid which was separated from the aq. layer and dried under
vacuum to give 20 mg of A-035 in 60% yield.
[0243] 1H NMR (DMSO-d6, 400 MHz): .delta.=7.85 (br, s, 1H),
7.68-7.80 (m, 2H), 7.28-7.46 (m, 5H), 7.07-7.10 (m, 1H), 6.96 (d,
J=8.8 Hz, 1H), 4.18 (s, 2H), 3.88 (s, 2H), 3.73 (s, 3H). Calc.
400.8; APCI.sup.+ (M+1): 401.0
A-056 Synthesis of
{1-[5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-3--
ethyl-ureido}-acetic acid
[0244] To a 20 mL vial which contained A-035 (18 mg, 0.05 mmol) in
pyridine (2 mL) was added ethylisocyanate (0.2 mL, excess) at rt.
The mixture was allowed to stir at rt for 48 h. The mixture was
poured onto 20 mL ice-water solution and the solid which formed was
filtered out, washed with water (20 mL) and dissolved in
dioxane-H2O (1:1, 10 mL). 250 mg KOH was added to the solution at
rt. The mixture was allowed to stir at rt for 16 h and then the
solution was adjusted to pH=1 with the addition of 2 N HCl,
extracted with ethyl acetate (3.times.20 mL), washed with water (20
mL), brine (20 mL) and dried over Na2SO4. After removal of solvent,
crude was separated by a chromatography on silica gel with ethyl
acetate-hexane as eluent to give 17 mg of A-056 in 50% yield.
[0245] 1H NMR (CHLOROFORM-d, 400 MHz): .delta.=8.20 (br, s, 1H),
8.15 (d, J=8.8 Hz, 1H), 7.57 (dd, J=8.8, 2.4 Hz, 1H), 7.25-7.39 (m,
4H), 7.09 (t, J=8.4 Hz, 1H), 6.71 (d, J=8.4 Hz, 1H), 4.50 (s, 2H),
3.93 (s, 2H), 3.74 (s, 3H), 3.66 (q, J=7.6 Hz, 2H), 1.27 (t, J=7.6
Hz, 3H)). LC/MS Calc. 471.9; APCI.sup.+ (M-OH): 454.1, 100%
A-057 Synthesis of
{1-[5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-ur-
eido}-acetic acid
[0246] To a 20 mL vial which A-035 (80 mg, 0.2 mmol) in pyridine (5
mL) was added TMS-isocyanate (0.5 mL, excess) at rt. The mixture
was allowed to stir at rt for 48 h. The mixture was poured onto 20
mL ice-water solution and the solid which formed was filtered out,
washed with water (20 mL) and dissolved in dioxane-5%/NaHCO3 (1:1,
10 mL). The mixture was allowed to stir at rt for 24 h. After the
solution was adjusted to pH=1 with the addition of 2H HCl, the
solid which formed was filtered out, washed with water (20 mL),
dried through air to yield 20 mg of desired A-057 in 22% yield.
[0247] 1H NMR (DMSO-d6, 400 MHz): .delta.=11.26 (s, 1H), 8.24 (d,
J=2.0 Hz, 1H), 8.05 (d, J=8.4 Hz, 1H), 7.67 (dd, J=8.8, 2.4 Hz,
1H), 7.25-7.49 (m, 5H), 6.93 (d, J=8.8 Hz, 1H), 4.43 (s, 2H), 3.92
(s, 2H), 3.72 (s, 3H), 3.57 (s, 3H). LC/MS Calc. 443.9; APCI.sup.+
(M-OH): 426.1, 100%
A-037 Synthesis of
{acetyl-[5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-y-
l]-amino}-acetic acid
[0248] To a 20 mL vial which contained Int-40 (150 mg, 0.34 mmol)
in MeOH (2 mL) was added KOH (1 N in water, 2 mL, 2 mmol) at
0.degree. C. The reaction mixture was allowed to warm to rt and
stir at rt for 24 h. The mixture was cooled to 0.degree. C.,
acidified with the addition of 2N HCl to pH=1-2 and then 20 mL
water was added. The mixture was extracted with CH2Cl2-MeOH (20:1,
5.times.20 mL). The combined organic layers washed with brine (20
mL) and dried over Na2SO4. Removal of solvent under vacuum to
afford 120 mg of the title compound (A-037) in 77% yield. 1H NMR
(DMSO-d6, 400 MHz): .delta.=8.33 (s, 1H), 7.85 (br, s, 1H),
7.78-7.80 (m, 2H), 7.28-7.46 (m, 4H), 6.95 (d, J=8.0 Hz, 1H), 4.44
(s, 2H), 3.97 (s, 2H), 3.73 (s, 3H), 2.07 (s, 3H).
[0249] Synthesis of A-061
##STR00069##
A-061 Synthesis of
(R)-1-[5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-
-azetidine-2-carboxylic acid
[0250] To
5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-py-
ridine (Int-32) (0.2 g, 0.58 mmol) and D-azetidine-2-carboxylic
acid (2) (0.18 g, 1.74 mmol) was added
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.44 g, 2.89 mmol). The
reaction mixture was stirred and heated at 160.degree. C. for 20
min. Cooled to room temperature, diluted with dichloromethane (8
mL), washed with 0.5 N HCl (2.times.4 mL), dried with
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by silica gel column chromatography using 3% methanol in
dichloromethane to afford 0.1 g (40%) of A-061 as an off-white
solid. 1H NMR (DMSO-d6, 400 MHz): 7.98 (d, J=2.0 Hz, 1H), 7.4-7.47
(m, 3H), 7.37 (s, 1H), 7.24-7.3 (m, 2H), 6.92 (d, J=8.4 Hz, 1H),
6.41 (d, J=8.8 Hz, 1H), 4.08 (dd, J=8.8, 7.2 Hz, 1H), 3.7-3.792 (m,
2H), 3.8 (s, 2H), 3.72 (s, 3H), 2.3-2.56 (m, 2H); MS (APCI+): 427.1
(M+1), LC-MS: 90.1%.
[0251] Synthesis of A-063
##STR00070##
A-063 Synthesis of
(S)-1-[5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-
-pyrrolidine-2-carboxylic acid
[0252] To
5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-py-
ridine (Int-32) (0.15 g, 0.43 mmol) and
(S)-pyrrolidine-2-carboxylic acid (2) (0.15 g, 1.3 mmol) was added
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.33 g, 2.17 mmol). The
reaction mixture was stirred and heated at 160.degree. C. for 20
min. Cooled to room temperature, diluted with dichloromethane (8
mL), washed with 0.5 N HCl (2.times.4 mL), dried with
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by silica gel column chromatography using 5% methanol in
dichloromethane to afford 0.04 g (21%) of A-063 as an off-white
solid. 1H NMR (DMSO-d6, 400 MHz): 7.93 (d, J=2.4 Hz, 1H), 7.4-7.65
(m, 2H), 7.34-7.38 (m, 2H), 7.23-7.3 (m, 2H), 6.92 (d, J=8.4 Hz,
1H), 6.4 (d, J=8.4 Hz, 1H), 4.6-4.68 (m, 1H), 3.77 (s, 2H), 3.71
(s, 3H), 3.26-3.48 (m, 2H), 2.16-2.25 (m, 1H), 1.9-2.03 (m, 3H); MS
(APCI+): 441.1 (M+1), LC-MS: 97.8%.
[0253] Synthesis of A-066
##STR00071##
A-066 Synthesis of
(S)-1-[5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-
-azetidine-2-carboxylic acid
[0254] To
5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-py-
ridine (Int-32) (0.2 g, 0.58 mmol) and L-azetidine-2-carboxylic
acid (2) (0.18 g, 1.74 mmol) was added
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.44 g, 2.89 mmol). The
reaction mixture was stirred and heated at 160.degree. C. for 20
min. Cooled to room temperature, diluted with dichloromethane (8
mL), washed with 0.5 N HCl (2.times.4 mL), dried with
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by silica gel column chromatography using 5% methanol in
dichloromethane to afford 0.042 g (17%) of A-066 as an off-white
solid. 1H NMR (DMSO-d6, 400 MHz): 7.98 (d, J=2.0 Hz, 1H), 7.39-7.48
(m, 3H), 7.37 (s, 1H), 7.24-7.3 (m, 2H), 6.92 (d, J=8.4 Hz, 1H),
6.4 (d, J=8.4 Hz, 1H), 4.58 (dd, J=9.2, 6.4 Hz, 1H), 3.7-3.9 (m,
2H), 3.8 (s, 2H), 3.72 (s, 3H), 2.3-2.55 (m, 2H); MS (APCI+): 427.1
(M+1), LC-MS: 100%.
[0255] Synthesis of A-067
##STR00072##
A-067 Synthesis of
1-[5-(3'-chloro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-azetidine-2--
carboxylic acid acetate salt
[0256] To
5-(3'-chloro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine
(Int-41, prepared in a similar manner as Int-32) (0.27 g, 0.82
mmol) and azetidine-2-carboxylic acid (0.12 g, 1.24 mmol) was added
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.63 g, 4.12 mmol). The
reaction mixture was stirred and heated at 160.degree. C. for 30
min. Cooled to room temperature, diluted with dichloromethane (8
mL), washed with 0.5 N HCl (2.times.4 mL), dried with
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by silica gel column chromatography using 5% methanol in
dichloromethane to afford 0.1 g off-white solid. The solid was
dissolved in acetic acid (5 mL), lyophilized to afford 0.102 g
(30%) of A-067 as an off-white solid. 1H NMR (DMSO-d6, 400 MHz):
8.02 (d, J=2.0 Hz, 1H), 7.36-7.5 (m, 5H), 7.14-7.22 (m, 2H), 7.04
(d, J=8.4 Hz, 1H), 6.38 (d, J=8.4 Hz, 1H), 4.58 (dd, J=8.8, 6.8 Hz,
1H), 3.7-3.9 (m, 2H), 3.79 (s, 2H), 3.73 (s, 3H), 2.3-2.55 (m, 2H),
1.91 (s, 3H); MS (APCI+): 409.1 (M+1), LC-MS: 100%.
[0257] Synthesis of A-068
##STR00073##
A-068 Synthesis of
(S)-1-[5-(3'-chloro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-pyrrolid-
ine-2-carboxylic acid
[0258] To
5-(3'-chloro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine
(Int-41) (0.15 g, 0.46 mmol) and (S)-pyrrolidine-2-carboxylic acid
(0.11 g, 0.92 mmol) was added 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) (0.35 g, 2.29 mmol). The reaction mixture was stirred and
heated at 160.degree. C. for 20 min. Cooled to room temperature,
diluted with dichloromethane (8 mL), washed with 0.5 N HCl
(2.times.4 mL), dried with Na.sub.2SO.sub.4, filtered, and
concentrated to afford 0.19 g (98%) of A-068 as light yellow solid.
1H NMR (DMSO-d6, 400 MHz): 7.96 (d, J=1.2 Hz, 1H), 7.78 (br s, 1H),
7.36-7.54 (m, 4H), 7.24-7.27 (m, 2H), 7.06 (d, J=8.8 Hz, 1H), 6.84
(br s, 1H), 4.65-4.7 (m, 1H), 3.86 (s, 2H), 3.76 (s, 3H), 3.45-3.65
(m, 2H), 1.85-2.3 (m, 4H); MS (APCI+): 423.2 (M+1), LC-MS:
95.8%.
[0259] Synthesis of A-069
##STR00074##
A-069 Synthesis of
(S)-1-[5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-
-pyrrolidine-2-carboxylic acid methyl ester
[0260] To A-063 (0.1 g, 0.22 mmol) in methanol (2.5 mL) was added
con. sulfuric acid (0.1 mL). The reaction mixture was stirred and
heated at 60.degree. C. for 2 h. Cooled to room temperature,
concentrated. Water (5 mL) was added and the product was extracted
with dichloromethane (2.times.6 mL), washed with brine (4 mL),
dried with Na.sub.2SO.sub.4, filtered, and concentrated to afford
0.088 g (90%) of A-069 as white solid. 1H NMR (DMSO-d6, 400 MHz):
7.91 (d, J=2.0 Hz, 1H), 7.75 (br s, 1H), 7.41-7.48 (m, 2H),
7.26-7.38 (m, 3H), 6.95 (d, J=8.8 Hz, 1H), 6.9 (br s, 1H), 4.7-4.8
(m, 1H), 3.89 (s, 2H), 3.73 (s, 3H), 3.66 (s, 3H), 3.45-3.65 (m,
2H), 1.85-2.35 (m, 4H); MS (APCI+): 455.1 (M+1), LC-MS: 94.1%.
[0261] Synthesis of A-072
##STR00075##
A-072 Synthesis of
(R)-1-[5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-
-pyrrolidine-2-carboxylic acid
[0262] To
5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-py-
ridine (Int-32) (0.15 g, 0.43 mmol) and
(R)-pyrrolidine-2-carboxylic acid (2) (0.1 g, 0.87 mmol) was added
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.33 g, 2.17 mmol). The
reaction mixture was stirred and heated at 160.degree. C. for 20
min. Cooled to room temperature, diluted with dichloromethane (8
mL), washed with 0.5 N HCl (2.times.4 mL), dried with
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by silica gel column chromatography using 5% methanol in
dichloromethane to afford 0.14 g (73%) of A-072 as white solid. 1H
NMR (DMSO-d6, 400 MHz): 7.93 (d, J=2.4 Hz, 1H), 7.34-7.46 (m, 4H),
7.26-7.3 (m, 2H), 6.91 (d, J=8.4 Hz, 1H), 6.4 (d, J=8.8 Hz, 1H),
4.35 (dd, J=9.2, 2.8 Hz, 1H), 3.77 (s, 2H), 3.72 (s, 3H), 3.3-3.48
(m, 2H), 2.15-2.25 (m, 1H), 1.9-2.06 (m, 3H); MS (APCI+): 441.1
(M+1), LC-MS: 98.0%.
[0263] Synthesis of A-074
##STR00076##
A-074 Synthesis of
{[5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-meth-
yl-amino}-acetic acid
[0264] To
5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-py-
ridine (Int-32) (0.15 g, 0.43 mmol) and sarcosine (2) (0.08 g, 0.87
mmol) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.33 g,
2.17 mmol). The reaction mixture was stirred and heated at
160.degree. C. for 35 min. Cooled to room temperature, diluted with
dichloromethane (8 mL), washed with 0.5 N HCl (2.times.4 mL), dried
with Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by silica gel column chromatography using 5-10% methanol
in dichloromethane to afford 0.09 g (50%) of A-074 as an off-white
solid. 1H NMR (DMSO-d6, 400 MHz): 7.94 (d, J=2.4 Hz, 1H), 7.24-7.48
(m, 6H), 6.91 (d, J=8.8 Hz, 1H), 6.56 (d, J=8.4 Hz, 1H), 4.16 (s,
2H), 3.77 (s, 2H), 3.71 (s, 3H), 2.99 (s, 3H); MS (APCI+): 416.6
(M+1), LC-MS: 100%.
[0265] Synthesis of A-077
##STR00077##
A-077 Synthesis of
{[5-(3'-chloro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-methyl-amino}-
-acetic acid
[0266] To
5-(3'-chloro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine
(Int-41) (0.12 g, 0.37 mmol) and sarcosine (2) (0.07 g, 0.73 mmol)
was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.283 g, 1.8
mmol). The reaction mixture was stirred and heated at 150.degree.
C. for 40 min. Cooled to room temperature, diluted with
dichloromethane (8 mL), washed with 0.5 N HCl (2.times.4 mL), dried
with Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by silica gel column chromatography using 5-10% methanol
in dichloromethane to afford 0.11 g (74%) of A-077 as light green
solid. 1H NMR (DMSO-d6, 400 MHz): 7.9 (d, J=2.0 Hz, 1H), 7.36-7.5
(m, 5H), 7.18-7.22 (m 2H), 7.03 (d, J=8.4 Hz, 1H), 6.56 (d, J=8.8
Hz, 1H), 4.2 (s, 2H), 3.77 (s, 2H), 3.73 (s, 3H), 2.99 (s, 3H); MS
(APCI+): 397.1 (M+1), LC-MS: 100%.
[0267] Synthesis of A-070
##STR00078##
A-070 Synthesis of
5'-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-3,4,5,6-tetrahydro--
2H-[1,2']bipyridinyl-3-carboxylic acid
[0268] In an 8 mL vial equipped with a stir bar was placed Int-32
(200 mg, 0.578 mmol), piperidine-3-carboxylic acid (224 mg, 1.73
mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (407 uL, 2.89 mmol).
The mixture was heated to 160.degree. C. for 1 hour and then cooled
to room temperature. The reaction mixture was treated with water (4
mL) and 1M HCl (6 mL). The aqueous portion was extracted with
dichloromethane (2.times.30 mL), the organic portions were
combined, washed with brine (15 mL), dried (MgSO.sub.4) and
concentrated. The crude material was purified by silica gel column
chromatography utilizing 10% isopropanol/DCM as the eluent to
provide 100 mg of A-070 as a pale yellow viscous oil in 38% yield.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 1.04 (d, J=6 Hz, 2H),
1.58-1.67 (m, 1H), 1.91-1.95 (m, 1H), 2.35-2.42 (m, 1H), 2.87-2.98
(m, 2H), 3.72 (s, 3H), 3.78 (s, 2H), 3.95 (bd, J=12 Hz, 1H), 4.26
(dd, J=13, 4 Hz, 1H), 6.78 (d, J=9 Hz, 1H), 6.92 (d, J=8 Hz, 1H),
7.26-7.30 (m, 2H), 7.35 (d, J=3 Hz, 1H), 7.37 (s, 1H), 7.41-7.47
(m, 2H), 8.00 (d, J=2 Hz, 1H), 12.27 (bs, 1H). MS (APCI+): 455.2
(M+1), LC-MS: 97%
[0269] Synthesis of A-075
##STR00079##
(Int-42) 3-Bromo-4-difluoromethoxy-benzaldehyde
[0270] Into a 5 L round bottom flask equipped with a mechanical
stirrer and a heating mantle was added 3-bromo-4-hydroxy
benzaldehyde (100.5 g, 0.50 mol), Cs.sub.2CO.sub.3 (244.4 g, 0.75
mol), Sodium chlorodifluoroacetate (190.6 g, 1.25 mol), and DMF (1
L). The reaction was stirred at 65.degree. C. for 1 hour and then
cooled to .about.35.degree. C. The reaction mixture was added by a
separatory funnel over 10 minutes to 12 L of ice water. The mixture
was stirred for 1 hour and then the solids were filtered through a
glass frit. The filter cake was washed with 2.times.500 mL water
and then dried in a 40.degree. C. vacuum for 18 hours followed by a
vacuum dessicator for 5 days. The title product (65.7 g, 52%) was
obtained as a tan solid.
[0271] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.=9.96 (s, 1H),
8.26 (d, J=1.7 Hz, 1H), 8.00 (dd, J=1.9, 8.5 Hz, 1H), 7.54 (d,
J=8.5 Hz, 1H), 7.49 (t, J=72.6 Hz, 1H)
(Int-43) 3'-Chloro-6-difluoromethoxy-biphenyl-3-carbaldehyde
[0272] Into a 5 L 3-neck round bottom flask was added Int-42 (58.4
g, 232.6 mmol), 3-chlorophenylboronic acid (40.0 g, 255.9 mmol),
DMF (1.17 L), and 2M aqueous Cs.sub.2CO.sub.3 (233 mL, 464.2 mmol).
The suspension was degassed with bubbling N.sub.2 for 30 minutes
and then Pd(OAc).sub.2 (5.3 g, 23.3 mmol) was added. The mixture
was slowly warmed to 50.degree. C. over 1 hour, cooled to room
temperature, and then filtered through Celite, washing with DMF. 2
L of water was added to the filtrate and the product was extracted
with 4.times.750 mL EtOAc. The combined organics were washed with 1
L brine, dried over Na.sub.2SO.sub.4, and then concentrated. The
residue was passed through a 200 g SiO.sub.2 plug eluting with 15%
Acetone/Hexane and then concentrated to afford the title compound
as a red oil which was used as is.
(Int-44) (3'-Chloro-6-difluoromethoxy-biphenyl-3-yl)-methanol
[0273] Into a 3 L round bottom flask equipped with magnetic
stirring was added Int-43 (78.1 g, 276.5 mmol), THF (500 mL) and
water (500 mL). The cloudy solution was cooled to 0.degree. C. and
then NaBH.sub.4 (15.7 g, 414.8 mmol) was added in 4 portions over
15 minutes. After stirring for an additional 15 minutes, the layers
were separated. The aqueous layer was extracted with 2.times.500 mL
EtOAc. The organics were combined, washed with brine, and
concentrated. The residue was purified by flash column
chromatography eluting with 5-20% Acetone/Hexane to provide the
title compound (43.3 g, 65% 2 steps) as a near colorless oil
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.=7.56-7.38 (m, 6H), 7.27
(d, J=9.0 Hz, 1H), 7.14 (t, J=73.9 Hz, 1H), 5.28 (t, J=5.8 Hz, 1H),
4.54 (d, J=5.6 Hz, 2H)
Int-45
Synthesis of carbonic acid
3'-chloro-6-difluoromethoxy-biphenyl-3-ylmethyl ester methyl
ester-
[0274] The same procedure as described for Int-21 was followed.
Isolated 1.55 g of Int-45 as a white solid in 75% yield.
A-075 Synthesis of
5-(3'-Chloro-6-difluoromethoxy-biphenyl-3-ylmethyl)-pyridine-2-carboxylic
acid methyl ester
[0275] In a 40 mL vial equipped with a stir bar was placed Int-45
(700 mg, 2.04 mmol),
5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic
acid methyl ester (590 mg, 2.24 mmol), potassium carbonate (846 mg,
6.12 mmol), 1,5-bis(diphenylphosphino)pentane (270 mg, 0.612 mmol)
and DMF (10 mL). The reaction mixture was degassed for 15 minutes
by bubbling nitrogen and then allylpalladium(II) chloride dimer
(112 mg, 0.306 mmol) was added. The reaction mixture was heated to
85.degree. C. for 4 hours. To the reaction mixture was added water
(40 mL) and ethyl acetate (40 mL) and the mixture was filtered
through Celite. The layers of the filtrate were separated and the
aqueous portion was extracted with ethyl acetate (40 mL). The
organic portions were combined, washed with brine (40 mL), dried
(MgSO.sub.4) and concentrated. The crude material was purified by a
50 gram silica gel SNAP cartridge (Biotage SP4 Flash Chromatography
instrument) utilizing gradient elution of 12-100% ethyl
acetate/hexanes to produce 458 mg A-075 as a viscous yellow solid
in 56% yield.
[0276] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 3.86 (s, 3H),
4.12 (s, 2H), 7.13 (t, J=74 Hz, 1H), 7.25 (d, J=8 Hz, 1H), 7.37
(dd, J=8, 2 Hz, 1H), 7.57 (dt, J=7, 2 Hz, 1H), 7.44-7.52 (m, 4H),
7.88 (dd, J=8, 2 Hz, 1H), 7.99 (d, J=8 Hz, 1H), 8.71 (s, 1H).
[0277] MS (APCI+): 404.5 (M+1) LC/MS: 98%
[0278] Synthesis of A-076
##STR00080##
(Int-46) 5-Bromomethyl-3'-chloro-2-difluoromethoxy-biphenyl
[0279] Into a 2 L round bottom flask equipped with magnetic
stirring were added Int-44 (39.6 g, 139.1 mmol), DCM (500 mL), and
the solution was cooled to 0.degree. C. PPh.sub.3 (73.0 g, 278.2
mmol) and NBS (49.5 g, 278.2 mmol) were added and the solution was
stirred for 30 minutes. The solution was washed with 2.times.500 mL
water, 500 mL brine, dried over Na.sub.2SO.sub.4, and concentrated.
Purification by flash column chromatography (15% Acetone/Hexane)
provided the title compound (43.5 g, 90%) as colorless oil. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta.=7.62-7.38 (m, 5H), 7.37 (s,
1H), 7.31 (d, J=8.3 Hz, 1H), 7.21 (t, J=73.7 Hz, 1H), 4.77 (s,
2H)
Int-47
Synthesis of
5-(3'-Chloro-6-difluoromethoxy-biphenyl-3-ylmethyl)-pyridine-2-carbonitri-
le
[0280] In a 40 mL vial equipped with a stir bar was placed Int-46
(1.0 g, 2.88 mmol),
5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carbonitrile
(729 mg, 3.17 mmol), tetrakis(triphenylphosphine)palladium (166 mg,
0.144 mmol), ethanol (4.4 mL) and toluene (17.6 mL). After stirring
for 5 minutes, a 2M aqueous solution of sodium carbonate (2.88 mL)
was added and the reaction mixture was degassed by bubbling
nitrogen through the mixture. After heating at 80.degree. C. for
2.5 hours, the reaction was filtered through Celite and the
filtrate was diluted with water (40 mL) and extracted with ethyl
acetate (2.times.60 mL). The organic portions were combined, dried
(MgSO.sub.4), concentrated and purified by silica gel column
chromatography utilizing 40% ethyl acetate/hexanes as the eluent to
produce 859 mg of Int-47 as a yellow viscous oil in 80% yield.
A-076 Synthesis of
5-(3'-Chloro-6-difluoromethoxy-biphenyl-3-ylmethyl)-2-(1H-tetrazol-5-yl)--
pyridine hydrochloride salt
[0281] In an 8 mL vial equipped with a stir bar was placed Int-47
(150 mg, 0405 mmol), sodium azide (29.0 mg, 0.466 mmol), ammonium
chloride (23.9 mg, 0.466 mmol) and dimethylformamide (700 uL). The
solution was heated to 100.degree. C. for 5 hours and then the
inorganic salts were filtered off. After concentrating the reaction
mixture, water (3 mL) and 1M HCl (3 mL) were added. The semi-solid
was collected and dried to produce 167 mg of A-076 (free base) as
an off-white solid in quantitative yield. To A-076 (free base) (140
mg, 0.341 mmol) was added diethyl ether (3 mL) and 2M HCl in
diethyl ether (800 uL). The mixture was allowed to stir at room
temperature for 10 minutes, concentrated and dried to produce 131
mg of A-076 as a white solid in 86% yield.
[0282] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 4.15 (s, 2H),
7.13 (t, J=74 Hz, 1H), 7.27 (d, J=8 Hz, 1H), 7.40-7.53 (m, 6H),
7.98 (dd, J=8, 2 Hz, 1H), 8.16 (d, J=8 Hz, 1H), 8.81 (D, J=2 Hz,
1H).
[0283] Synthesis of A-078 and A-079
##STR00081##
Int-48
Synthesis of
5-(3'-Chloro-6-difluoromethoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine
[0284] Prepared in a similar manner as A-075. Isolated 372 mg of
Int-48 as a viscous oil with slight dark yellow tinge in 70%
yield.
A-078 Synthesis of
{[5-(3'-Chloro-6-difluoromethoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-methy-
l-amino}-acetic acid
[0285] In an 8 mL vial equipped with a stir bar was placed Int-48
(190 mg, 0.522 mmol), N-methylglycine (140 mg, 1.57 mmol) and
1,8-diazabicyclo[5.4.0]undec-7-ene (368 uL, 2.61 mmol). The mixture
was heated to 160.degree. C. for 35 minutes and then diluted with
DCM (15 mL). The organic portion was washed with 0.5M HCl
(3.times.10 mL) and the aqueous washes were combined and extracted
with DCM (15 mL). The organic portions were combined, dried
(MgSO.sub.4) and concentrated. The crude material was purified by
silica gel column chromatography utilizing 10% isopropanol/DCM
(with 1% AcOH) as the eluent to produce 17 mg of A-078 as a light
green solid in 8% yield.
[0286] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 2.99 (s, 3H),
3.83 (s, 2H), 4.20 (s, 2H), 6.58 (d, J=8 Hz, 1H), 7.10 (t, J=74 Hz,
1H), 7.21 (d, J=8 Hz, 1H), 7.30 (dd, J=9, 2 Hz, 1H), 7.37 (d, J=2
Hz, 1H), 7.40-7.51 (m, 5H), 8.01 (d, J=2 Hz, 1H), 12.37 (s,
1H).
[0287] MS (ESI+): 435.0 (M+2), LC/MS: 97%
A-079 Synthesis of
(R)-2-{[5-(3'-Chloro-6-difluoromethoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-
-methyl-amino}-propionic acid
[0288] In an 8 mL vial equipped with a stir bar was placed Int-48
(173 mg, 0.476 mmol), N-.alpha.-methyl-D-alanine HCl (199 mg, 1.43
mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (403 uL, 2.86 mmol).
The mixture was heated to 160.degree. C. for 35 minutes and then
diluted with DCM (15 mL). The organic portion was washed with 0.5M
HCl (3.times.10 mL) and the aqueous washes were combined and
extracted with DCM (15 mL). The organic portions were combined,
dried (MgSO.sub.4) and concentrated. The crude material was
purified by silica gel column chromatography utilizing 10%
isopropanol/DCM (with 1% AcOH) as the eluent to produce 56 mg of a
yellow solid which still contained impurities. The impure material
was purified by preparative TLC (20.times.20 cm, 1500 microns)
using 10% isopropanol/DCM as the eluent to produce 18 mg of A-079
as a yellow solid in 4% yield.
[0289] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 1.35 (t, J=8 Hz,
3H), 2.84 (s, 3H), 3.84 (s, 2H), 3.94 (q, J=7 Hz, 1H), 6.59 (d, J=9
Hz, 1H), 7.10 (t, J=74 Hz, 1H), 7.21 (d, J=8 Hz, 1H), 7.29-7.32 (m,
2H), 7.37 (d, J=2 Hz, 1H), 7.40-7.51 (m, 4H), 8.01 (d, J=2 Hz, 1H),
12.37 (bs, 1H). MS (APCI+): 447.1 (M+1)
[0290] Synthesis of A-073
##STR00082##
A-073 Synthesis of
5-(3'-chloro-6-methoxy-biphenyl-3-ylmethyl)-pyridine-2-carboxylic
methyl ester
[0291] To a 250 mL flask which contained the mixture of carbonic
acid 3'-chloro-6-methoxy-biphenyl-3-ylmethyl ester methyl ester
(Int-49, Prepared in a similar manner as Int-021, 2.0 g, 6.6 mmol)
and
5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic
acid methyl ester (1.6 g, 6 mmol) in DME (30 mL) was added K2CO3
(2.5 g, 18 mmol), [Pd(y.sup.3C.sub.3H.sub.5Cl)].sub.2 (300 mg, 0.8
mmol) and DPPPent (800 mg, 1.9 mmol) at rt under nitrogen. The
reaction mixture was heated to 85.degree. C. and stirred at
85.degree. C. for 16 h. The reaction mixture was cooled to rt,
poured onto ice-water (200 mL), The semi-solid which formed was
separated from the aq. layer to provide the crude which was
purified by a chromatography on silica gel with
dichloromethane-acetone as eluent to yield the title compound (1200
mg, 50%) 1H NMR (CHLOROFORM-d, 400 MHz): .delta.=8.64 (s, 1H), 8.05
(d, J=8.0 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.47 (s, 1H), 7.29-7.36
(m, 2H), 7.11 (d, J=8.0 Hz, 1H), 7.09 (d, J=2.0 Hz, 1H), 6.93 (d,
J=8.4 Hz, 1H), 4.04 (s, 2H), 3.99 (s, 3H), 3.80 (s, 3H). LC/MS:
Calc. 367.84; APCI+(M+1): 368.1, 99%
[0292] Synthesis of A-058
##STR00083##
Int-50 Synthesis of
(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-acetonitrile
[0293] A suspension of Int-20 (15.2 mmol; 1.0 eq.) and sodium
cyanide (22.8 mmol; 1.5 eq.) in aqueous isopropyl alcohol was
refluxed for 1 hour. The reaction was cooled to room temperature,
and concentrated to remove the isopropyl alcohol. The resultant
aqueous layer was extracted with 2 portions of ethyl acetate, and
the organics washed successively with water and brine, and dried
over magnesium sulfate. The residue was purified via flash
chromatography on silica gel, using 10% acetone/hexanes as eluent
to afford the title compound as a white solid in 57% yield.
[0294] (.sup.1H NMR, CDCl.sub.3; 400 MHz): 3.80 (s, 3H), 3.93 (s,
2H), 6.80 (dd, J=8.8, 1.6 Hz, 1H), 7.26 (m, 1H), 7.35-7.41 (M,
4H)
A-058
5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-1H-tetrazole
[0295] Into an 18 mL vial was added Int-50 (138 mg, 0.50 mmol),
NH.sub.4Cl (187 mg, 3.50 mmol), NaN.sub.3 (65 mg, 1.00 mmol), and
DMF (4 mL). The reaction was stirred at 80.degree. C. for 4 hours
and then 100.degree. C. for 18 hours. The suspension was filtered
through a glass frit and a SiO.sub.2 plug and then concentrated.
The residue was purified by flash column chromatography eluting
with 25%-50% Acetone/Hexanes. The solid was dried on a 50.degree.
C. vacuum oven for 8 hours, the room temperature for 18 hours. The
title compound (25 mg, 16%) was obtained as a tan solid. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta.=16.19 (br. s., 1H), 7.50-7.40
(m, 2H), 7.40-7.33 (m, 2H), 7.29 (d, J=6.6 Hz, 1H), 6.99 (d, J=8.6
Hz, 1H), 4.27 (s, 2H), 3.75 (s, 3H). LC/MS=98.7%, 317.0
(APCI+).
[0296] Synthesis of A-071
##STR00084##
Int-52
5-(3'-Chloro-6-methoxy-biphenyl-3-ylmethyl)-pyridine-2-carboxylic
acid methyl ester
[0297] Into a 250 mL round bottom flask was added
5-Bromomethyl-3'-chloro-2-methoxy-biphenyl (Int-51, prepared in a
similar manner as Int-20, 4.89 g, 15.69 mmol),
5-(1,5-Dimethyl-2,4-dioxa-3-bora-bicyclo[3.1.0]hex-3-yl)-pyridine-2-carbo-
xylic acid methyl ester (4.52 g, 17.26 mmol), toluene (120 mL),
EtOH (20 mL), water (20 mL), and K.sub.3PO.sub.4 (6.66 g, 31.38
mmol). The suspension was degassed with N.sub.2 for 15 minutes and
then Pd(PPh.sub.3).sub.4 (1.81 g, 1.57 mmol) was added and the
reaction was stirred at 80.degree. C. for 1 hour. The layers were
separated and the aqueous was extracted with 50 mL EtOAc. The
organics were combined and washed with 50 mL brine, dried over
Na.sub.2SO.sub.4, and concentrated. The residue was purified by
flash column chromatography eluting with 10% Acetone/Hexanes to
afford the title compound (0.89 g, 15%) as a light-yellow oil.
A-071
5-(3'-Chloro-6-methoxy-biphenyl-3-ylmethyl)-pyridine-2-carboxylic
acid
[0298] Into an 18 mL vial was added Int-52 (185 mg, 0.50 mmol),
EtOH (4 mL), and 1N NaOH (4 mL). After stirring at room temperature
for 1 hour the EtOH was evaporated. The pH was adjusted to about 4
with conc. HCl and the resulting solids were filtered and dried in
a 50.degree. C. vacuum oven for 4 hours. The title compound (99 mg,
56%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.=8.66 (d, J=1.6 Hz, 1H), 7.96 (d, J=7.9 Hz, 1H), 7.82 (dd,
J=1.9, 7.9 Hz, 1H), 7.50 (s, 1H), 7.46-7.34 (m, 3H), 7.31-7.22 (m,
2H), 7.12-7.03 (m, 1H), 4.05 (s, 2H), 3.75 (s, 3H)
[0299] Synthesis of A-059 and A-060
##STR00085##
[0300] Int-53 and Int-54
Int-53
1-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-1H-imidazole-4-carbox-
ylic acid methyl ester
Int-54
1-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-1H-imidazole-2-carbox-
ylic acid methyl ester
[0301] Into an 18 mL vial was added Methyl 4-imidazolecarboxylate
(113 mg, 0.90 mmol), DMF (3 mL), and NaH (43 mg, 1.08 mmol). After
20 minutes at room temperature Int-20 (295 mg, 0.90 mmol) was
added. The reaction was stirred for 2 hours at room temperature and
then water was added. The product was extracted with EtOAc and the
organics were concentrated. The residue was purified by flash
column chromatography eluting with 6%-10% Acetone/DCM to separate
the regioisomers. The 4-substituted ester (Int-53, 67 mg, 20%) and
the 2-substituted ester (Int-54, 79 mg, 23%) were obtained as
colorless oils.
##STR00086##
A-059
1-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-1H-imidazole-4-carbox-
ylic acid
[0302] Into an 8 mL vial was added Int-53 (31 mg, 0.08 mmol), EtOH
(1 mL), and 2 N NaOH (1 mL). After stirring for 2 hours at room
temperature the EtOH was evaporated. The pH was adjusted to about 5
with concentrated HCl which produced w white precipitate. The solid
was filtered and dried in a 50.degree. C. vacuum oven for 2 hours
to provide the title compound (6 mg, 20%) as a white solid. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta.=7.80 (s, 2H), 7.50-7.36 (m,
4H), 7.29 (d, J=6.2 Hz, 1H), 7.02 (d, J=8.7 Hz, 1H), 5.26 (s, 2H),
3.75 (s, 3H). MS=361.1 (APCI+).
##STR00087##
A-060
3-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-3H-imidazole-4-carbox-
ylic acid
[0303] Into an 8 mL vial was added Int-54 (38 mg, 0.10 mmol), EtOH
(1 mL), and 2 N NaOH (1 mL). After stirring for 2 hours at room
temperature the EtOH was evaporated. The pH was adjusted to about 5
with concentrated HCl which produced w white precipitate. The solid
was filtered and dried in a 50.degree. C. vacuum oven for 2 hours
to provide the title compound (17 mg, 47%) as a white solid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.=12.87 (br. s., 1H),
7.97 (s, 1H), 7.61 (s, 1H), 7.50-7.42 (m, 2H), 7.39 (s, 1H), 7.30
(d, J=6.4 Hz, 1H), 7.08-6.99 (m, 1H), 6.98-6.91 (m, 1H), 5.55 (s,
2H), 3.73 (s, 3H). LC/MS=361.1 (APCI+).
[0304] Synthesis of A-030 and A-031
##STR00088##
Int-55 Synthesis of
5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-[1,3,4]thiadiazol-2--
ylamine
[0305] A mixture of Int-50 (0.998 mmol, 1.0 eq.) and
thiosemicarbazide (2.99 mmol; 3 eq.) in excess phosphorous
oxychloride was heated to 120.degree. C. for 45 minutes, and
allowed to cool to room temperature. The resultant mixture was
added to water, and extracted with 2 portions of ethyl acetate. The
organics were washed with brine, and dried over magnesium sulfate.
The residue was purified via flash chromatography on silica gel
using 5% (1N NH.sub.3 in MeOH) in dichloromethane as eluent to
afford the title compound in 39% yield.
[0306] (.sup.1H NMR, DMSO-d.sub.6; 400 MHz): 3.75 (s, 3H), 4.17 (s,
2H), 6.98 (d, J=8.0 Hz, 1H), 7.29 (d, J=6.4 Hz, 1H), 7.37-7.41 (M,
2H), 7.43-7.49 (M, 2H), 7.58-7.76 (bs, 2H)
A-030
4-{3-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-[1,3,4]thiadiaz-
ol-2-yl]-ureido}-butyric acid ethyl ester
[0307] To a solution of Int-55 (125 mg, 0.36 mmol) in pyridine (0.5
mL) at room temperature was added 4-Isocyanato-butyric acid ethyl
ester (136 uL, 0.89 mmol). The resultant solution was stirred at
room temperature for 18 hours and then at 50.degree. C. for 24
hours. To the solution was added 10 mL of water and the product was
extracted with 3.times.15 mL EtOAc and the combined organics were
dried over Na.sub.2SO.sub.4, and concentrated. 5 mL of ether was
added to the yellow oil and the solution was allowed to stand at
room temperature for 18 hours. The resulting solid was filtered,
washed with ether, and dried to afford the title compound (66 mg,
36%) as a white solid. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
10.72 (s, 1H), 7.48-7.37 (m, 4H), 7.30-7.28 (m, 1H), 6.99 (d, J=8.4
Hz, 1H), 6.91 (bs, 1H), 4.26 (s, 2H), 4.03 (q, J=7.1 Hz, 2H), 3.75
(s, 3H), 3.12 (q, J=6.0 Hz, 2H), 2.28 (t, J=7.6 Hz, 2H), 1.66
(quin, J=7.6 Hz, 2H), 1.15 (t, J=7.0 Hz, 3H). LC/MS=91.1%, 507.0
(APCI+).
A-031
4-{3-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-[1,3,4]thiadiaz-
ol-2-yl]-ureido}-butyric acid
[0308] To a solution of A-030 (35 mg, 0.069 mmol) in THF (0.5 mL)
was added 1M aqueous lithium hydroxide (345 uL, 0.35 mmol). The
reaction was stirred at room temperature for 1 hour. The THF was
removed with a stream of nitrogen, and the resultant aq. solution
was acidified with 6N HCl to pH 1-2. After stirring for 30 minutes
at room temperature, the resultant solids were filtered, washed
with water, and dried in a 50.degree. C. vacuum oven for 4 hours.
The title compound (19.8 mg, 60%) was obtained as a tan solid.
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 10.78 (bs, 1H),
7.48-7.38 (m, 3H), 7.30-7.28 (m, 1H), 6.99 (d, J=8.0 Hz, 1H), 6.94
(bs, 1H), 4.26 (s, 2H), 3.75 (s, 3H), 3.12 (q, J=6.7 Hz, 2H), 2.21
(t, J=7.4 Hz, 2H), 1.65 (t, quin=7.0 Hz, 2H).
[0309] Synthesis of A-002
##STR00089##
A-002 Synthesis of
2-(6-Methoxy-3'-nitro-biphenyl-3-ylmethyl)-1,1-dioxo-1,2-dihydro-1lambda*-
6*-benzo[d]isothiazol-3-one
[0310] To a solution of Int-02 (161 mg, 0.500 mmol) and saccharin
(183 mg, 1.00 mmol) in dimethyl formamide (1.5 mL) was added sodium
hydride (60% weight dispersion, 40 mg, 1.00 mmol) at -78.degree. C.
After hydrogen gas evolution ceased the reaction was stirred at
120.degree. C. overnight. The reaction mixture was filtered, and
the filtrate concentrated under reduced pressure. The residue was
diluted with ethyl acetate (15 mL), washed with water, brine, dried
over sodium sulfate, filtered, and the solvent removed under
vacuum. The product was purified by trituration with hexanes (50
mL) and ethyl acetate (5 mL) to give A-002 (190 mg, 90% yield). 1H
NMR (400 MHz, CHLOROFORM-d) .delta. 3.83 (s, 3H) 4.92 (s, 2H) 6.99
(d, J=8.45 Hz, 1H) 7.46-7.61 (m, 3H) 7.78-7.98 (m, 4H) 8.06 (d,
J=7.11 Hz, 1H) 8.17 (dd, J=8.25, 1.41 Hz, 1H) 8.42 (t, J=1.74 Hz,
1H)
[0311] LCMS=94% purity.
[0312] Synthesis of A-040
##STR00090##
A-040 Synthesis of
1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyrimidin-2-yl]-p-
yrrolidine-2-carboxylic acid
[0313] A solution of Int-29 (100 mg, 0.28 mmol),
pyrrolidine-2-carboxylic acid tert-butyl ester (72 mg, 0.42 mmol),
and diisopropylethylamine (0.15 mL, 0.84 mmol) in
2-methyl-1-propanol (1 mL) was stirred at 80.degree. C. for 4 days.
The reaction was cooled to room temperature and concentrated under
vacuum. To the crude material was added tetrahydrofuran (5 mL) and
1 M aqueous lithium hydroxide (0.56 mL, 0.56 mmol) and the solution
heated to 80.degree. C. overnight. The reaction was cooled to room
temperature, and acidified to pH 3 with 2 N aqueous hydrochloric
acid. To the reaction was added trifluoroacetic acid (0.84 mmol)
and the reaction heated to 80.degree. C. overnight. The reaction
was cooled to room temperature and concentrated en vacuo, and the
residue was purified by silica gel column chromatography (2:1
hexanes/ethyl acetate) to give A-040 (49.1 mg, 35% yield) as a
white solid. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.=8.32 (br.
s., 2H), 7.40-7.30 (m, 3H), 7.14 (t, J=8.6 Hz, 1H), 6.74 (d, J=8.5
Hz, 1H), 4.59-4.51 (m, 1H), 3.83 (s, 2H), 3.77 (s, 3H), 3.75-3.66
(m, 1H), 3.65-3.55 (m, 1H), 2.13-2.02 (m, 4H). LC/MS=95%, 442.0
(APCI+).
[0314] Synthesis of A-044
##STR00091##
A-041. Synthesis of
1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyrimidin-2-yl]-p-
iperidine-2-carboxylic acid
[0315] A solution of Int-29 (100 mg, 0.28 mmol), nipecotic acid (54
mg, 0.42 mmol), and diisopropylethylamine (0.15 mL, 0.84 mmol) in
2-methyl-1-propanol (1 mL) was stirred at 80.degree. C. overnight.
The reaction was cooled to room temperature and concentrated en
vacuo. The crude was purified by silica gel column chromatography
(20:1 dichloromethane/methanol), triturated in
dichloromethane/hexanes to give A-041 (36.5 mg, 29% yield) as a
cream colored solid.
[0316] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.56 (br. s., 1H)
1.71-1.87 (m, 2H) 2.17 (s, 2H) 2.50-2.68 (m, 1H) 3.05-3.15 (m, 1H)
3.26 (dd, J=13.28, 10.06 Hz, 1H) 3.71-3.80 (m, 5H) 4.45 (d, J=13.15
Hz, 1H) 4.69 (dd, J=13.35, 3.56 Hz, 1H) 6.70 (d, J=8.45 Hz, 1H)
7.10 (t, J=8.52 Hz, 1H) 7.29-7.41 (m, 3H) 8.22 (s, 2H).
LCMS=97%.
[0317] Synthesis of A-044
##STR00092##
A-045 Synthesis of
1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyrimidin-2-yl]-p-
yrrolidine-3-carboxylic acid methyl ester
[0318] A mixture of Int-29 (100 mg, 0.28 mmol),
pyrrolidine-2-carboxylic acid methyl ester (70 mg, 0.42 mmol), and
diisopropylethylamine (0.15 mL, 0.84 mmol) in 2-methyl-1-propanol
(1 mL) was stirred at 80.degree. C. overnight. The reaction was
cooled, and the solvent removed under vacuum. The crude was
purified twice by silica gel column chromatography (4:1
hexanes/ethyl acetate, 2:1 hexanes/ethyl acetate) to give A-045
(44.7 mg, 35% yield). .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta.=8.21 (s, 2H), 7.40-7.29 (m, 3H), 7.08 (t, J=8.6 Hz, 1H),
6.69 (d, J=8.5 Hz, 1H), 3.88-3.74 (m, 3H), 3.76 (s, 2H), 3.75 (s,
3H), 3.72 (s, 3H), 3.63-3.53 (m, 1H), 3.19 (quin, J=7.4 Hz, 1H),
2.33-2.22 (m, 2H). LC/MS=94.7%, 456.1 (APCI+).
A-044 Synthesis of
1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyrimidin-2-yl]-p-
yrrolidine-3-carboxylic acid
[0319] A mixture of Int-29 (35 mg, 0.075 mmol) and trifluoroacetic
acid (85 mg, 0.75 mmol) in water (0.5 mL) and dichloromethane (2
mL) was stirred at room temperature overnight. The reaction was
heated to 80.degree. C. for 3 days. The reaction was diluted with
dichloromethane (2 mL) and water (1 mL), separated, and the aqueous
portion extracted with dichloromethane (2.times.2 mL). The combined
organic extracts were dried over sodium sulfate, filtered, and
concentrated. The residue was purified by silica gel column
chromatography (40:1 dichloromethane/methanol) to give A-044 (30.7
mg, 93% yield).
[0320] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.=8.26 (s, 2H),
7.48-7.40 (m, 2H), 7.37 (s, 1H), 7.33-7.25 (m, 2H), 6.93 (d, J=8.6
Hz, 1H), 3.77 (s, 2H), 3.72 (s, 3H), 3.67-3.60 (m, 2H), 3.55-3.43
(m, 2H), 3.15 (quin, J=7.0 Hz, 1H), 2.23-2.04 (m, 2H). LC/MS=93.6%,
442.0 (APCI+).
[0321] Synthesis of A-053
##STR00093##
A-053 Synthesis of
1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyrimidin-2-yl]-a-
zetidine-3-carboxylic acid
[0322] A mixture of Int-29 (100 mg, 0.28 mmol),
azetidine-3-carboxylic acid (42 mg, 0.42 mmol), and
diisopropylethylamine (0.15 mL, 0.84 mmol) in 2-methyl-1-propanol
(1 mL) was stirred at 80.degree. C. overnight. The reaction was
cooled, and the solvent removed under vacuum. The crude was
purified twice by silica gel column chromatography (18:
hexanes/ethyl acetate), triturated with diethyl
ether/dichloromethane, and purified by silica gel preparatory thin
layer chromatography (9:1 dichloromethane/methanol) to give A-053
(11.5 mg, 9.6% yield).
[0323] 1H NMR (400 MHz, DMSO-d6) .delta. 2.03-2.24 (m, 2H) 3.15 (t,
J=6.98 Hz, 1H) 3.25 (s, 1H) 3.44-3.55 (m, 1H) 3.64 (t, J=6.91 Hz,
1H) 3.72 (s, 2H) 3.77 (s, 2H) 6.93 (d, J=8.59 Hz, 1H) 7.25-7.34 (m,
2H) 7.37 (s, 1H) 7.40-7.47 (m, 2H) 8.19-8.28 (m, 2H)
[0324] Synthesis of A-049
##STR00094##
A-049. Synthesis of
1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyrimidin-2-yl]-a-
zetidine-2-carboxylic acid
[0325] A mixture of azetidine-2-carboxylic acid (56 mg, 0.56 mmol)
and sodium hydride (60% weight dispersion, 33 mg, 0.84 mmol) in
dimethylformamide (1 mL) was stirred under gas evolution ceased.
After 2 min of stirring Int-29 (102 mg, 0.28 mmol) was added, and
the reaction heated at 120.degree. C. overnight. The reaction was
cooled to room temperature, diluted with water (15 mL), and
extracted with ethyl acetate (3.times.5 mL). The combined extracts
were dried over sodium sulfate, filtered, and the solvent removed
under vacuum. The residue was purified by silica gel column
chromatography (9:1 dichloromethane/methanol) to give A-049 (65.3
mg, 58% yield) as a cream solid.
[0326] 1H NMR (400 MHz, DMSO-d6) .delta. 2.17-2.28 (m, 1H)
2.55-2.67 (m, 1H) 3.72 (s, 3H) 3.78 (s, 2H) 3.87-4.05 (m, 2H) 4.63
(dd, J=9.12, 5.77 Hz, 1H) 6.93 (d, J=8.59 Hz, 1H) 7.25-7.36 (m, 2H)
7.38 (s, 1H) 7.41-7.47 (m, 2H) 8.25 (s, 2H) 12.64 (br. s., 1H).
LCMS=95.0%
[0327] Preparation of B-080
##STR00095## ##STR00096##
[0328] Synthesis of 2-iodo-3-methoxy-6-methyl-pyridine (I-95). To
2-iodo-6-methyl-pyridin-3-ol (1.0 g, 4.25 mmol) and K.sub.2CO.sub.3
(1.18 g, 8.51 mmol) in acetone (20 mL) was added MeI (0.91 g, 6.38
mmol). The reaction was stirred at 45.degree. C. under N.sub.2 for
20 h. The reaction was cooled to room temperature and concentrated.
The residue was purified by silica gel column chromatography using
dichloromethane to afford 1.04 g (98%) of I-95 as light yellow
solid.
[0329] Synthesis of 3-methoxy-6-methyl-2-(3-nitro-phenyl)-pyridine
(I-113). To I-95 (0.5 g, 2.0 mmol), 3-nitrophenylboronic acid (0.5
g, 3.06 mmol), triphenylphosphine (0.11 g, 0.4 mmol),
K.sub.2CO.sub.3 (0.83 g, 6.0 mmol) and palladium(II) acetate (0.045
g, 0.2 mmol) was added DME (16 mL), and EtOH--H.sub.2O (1:1, 4 mL).
Argon gas was bubbled through the stirred reaction for 5 min. The
reaction was stirred at 60.degree. C. under argon for 18 h. The
reaction was cooled to room temperature, concentrated, and H.sub.2O
and dichloromethane (40 mL each) were added. The organic layer was
separated and the aqueous layer was extracted with dichloromethane
(2.times.25 mL). The combined organic extracts were dried with
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by silica gel column chromatography using 1:1
dichloromethane-hexanes then dichloromethane to afford 0.22 g (44%)
of I-113 as a light yellow solid.
[0330] Synthesis of
6-bromomethyl-3-methoxy-2-(3-nitro-phenyl)-pyridine (I-114). To
I-113 (0.21 g, 0.86 mmol) and NBS (0.17 g, 0.95 mmol) in CCl.sub.4
(10 mL) was added benzoylperoxide (0.02 g, 0.08 mmol). The reaction
was stirred at 60.degree. C. under N.sub.2 for 18 h. The reaction
was cooled to room temperature and concentrated. The residue was
dissolved in a mixture of dichloromethane and hexanes (1:1, 8 mL)
and purified by silica gel column chromatography using 1:1
dichloromethane:hexanes then dichloromethane to afford 0.15 g (55%)
of I-114 as a light brown solid.
[0331] Synthesis of
6-(4-fluoro-benzyl)-3-methoxy-2-(3-nitro-phenyl)-pyridine (P-023).
To I-114 (0.05 g, 0.15 mmol), 4-fluorophenylboronic acid (1) (0.032
g, 0.23 mmol), triphenylphosphine (0.004 g, 0.015 mmol),
K.sub.3PO.sub.4 (0.066 g, 0.31 mmol), and palladium(II)acetate
(0.002 g, 0.008 mmol) was added DME (1.8 mL), and EtOH--H.sub.2O
(1:1, 0.6 mL). The reaction was stirred at 160.degree. C. for 5 min
using Biotage-60 Microwave Synthesizer. The reaction was cooled to
room temperature and concentrated. The residue was purified by
silica gel column chromatography using 1:1 dichloromethane-hexanes
then dichloromethane to afford 0.024 g (46%) of P-023 as a light
brown viscous liquid. 1H NMR (CDCl.sub.3, 400 MHz): 8.89 (dd,
J=2.0, 1.6 Hz, 1H), 8.32-8.36 (m, 1H), 8.2-8.24 (m, 1H), 7.59 (t,
J=8.4 Hz, 1H), 7.22-7.3 (m, 3H), 7.07 (d, J=8.4 Hz, 1H), 6.96-7.04
(m, 2H), 4.14 (s, 2H), 3.88 (s, 3H); MS (APCI+): 339.1 (M+1),
LC-MS: 100%.
[0332] 6-(4-Fluoro-benzyl)-3-methoxy-2-(3-nitro-phenyl)-pyridine
1-oxide (B-080). A reaction mixture of compound P-023 (100 mg, 0.3
mmole) and 3-chloroperoxybenzoic acid (101 mg, 0.45 mmole) in DCM
(10 ml) was stirred at r.t. over night. The reaction mixture washed
with saturated NaHCO3 (3.times.6 ml), water (2.times.8 ml), dried
over Na2SO4. After removal of solvent, the residue was washed with
ether (5 ml)/Hexane (5 ml) to give 66 mg of product B-080. Yield:
62%; .sup.1H-NMR (400 MHz, DMSO-d.sub.6); MS (APCI+): 355.1 (M+1);
LC-MS: 97%. 1H NMR (CDCl3, 400 MHz): d=3.79 (3H, s), 4.19 (2H, s),
6.90 (1H, d, J=9.2 Hz), 6.98 (1H, d, J=8.8 Hz), 7.04 (2H, m), 7.27
(2H, m), 7.64 (1H, dd, J=8 and 8 Hz), 7.89 (1H, m), 8.28 (1H, m),
8.39 (1H, m).
[0333] Synthesis of B-081
##STR00097##
[0334] Synthesis of
1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-1-oxy-pyridin-2-y-
l]-3-ethyl-urea (P-397). A solution of P-356 (82.7 mg, 0.200 mmol)
in diethyl ether (5 mL) was stirred at room temperature with
peracetic acid (32% wt., 0.06 mL, 0.300 mmol) for 3 h. The mixture
was concentrated and the residue purified by silica gel column
chromatography (19:1 dichloromethane/methanol) to give P-397 (27.6
mg, 32% yield). .sup.1H NMR (400 MHz, CDCl3): 1.12 (t, 3H)
3.17-3.35 (m, 2H), 3.72-3.80 (m, 3H), 3.87 (s, 2H), 6.64-6.78 (m,
1H), 6.86 (br s, 1H), 7.02-7.17 (m, 1H), 7.22 (s, 1H), 7.29-7.43
(m, 3H), 7.93 (s, 1H), 8.36 (d, J=8.9 Hz, 1H), 9.73 (s, 1H) ppm.
LCMS=100% purity. APCI (-)=428.1 (M-2).
[0335] Synthesis of B-082
##STR00098##
[0336] Synthesis of 3-bromo-2-fluoro-4-methoxy-benzaldehyde (I-30).
In a 3-necked 250 mL round-bottomed flask equipped with nitrogen
lines and a stir bar was placed 2-bromo-1-fluoro-3-methoxy-benzene
(I-29, 2.0 g, 9.75 mmol) and dichloromethane (48 mL). The solution
was cooled in an ice water bath for 15 minutes and then titanium
tetrachloride (5.02 mL, 45.8 mmol) and dichloromethyl methyl ether
(1.32 mL, 14.6 mmol) were added and the reaction mixture was
allowed to warm to room temperature and react for 2 hours. The
reaction mixture was slowly added to ice water (250 mL) and
extracted with dichloromethane (2.times.100 mL). The organic
portions were combined, washed with a saturated sodium bicarbonate
solution (75 mL), water (75 mL) and brine (75 mL), dried
(MgSO.sub.4) and concentrated. The crude material was triturated
with hexanes (15 mL) to produce 1.67 g of
3-bromo-2-fluoro-4-methoxy-benzaldehyde (I-30) as an off-white
solid in 74% yield. MS (ESI+): 233.2 (M+).
[0337] Synthesis of (3-bromo-2-fluoro-4-methoxy-phenyl)-methanol
(I-31). In a 100 mL round bottomed flask equipped with a stir bar
was placed 3-bromo-2-fluoro-4-methoxy-benzaldehyde (I-30, 1.67 g,
7.17 mmol), methanol (12 mL), dichloromethane (12 mL) and sodium
borohydride. The reaction mixture was allowed to stir at room
temperature for 17 hours, quenched with water (10 mL) and 1M HCl (5
mL) and extracted with dichloromethane (2.times.30 mL). The organic
portions were combined, washed with brine (30 mL), dried
(MgSO.sub.4) and concentrated. The crude material was triturated
with hexanes (15 mL) to produce 955 mg (57%) of
(3-bromo-2-fluoro-4-methoxy-phenyl)-methanol (I-31) as a white
solid.
[0338] Synthesis of
(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-methanol (I-32). Into
a 100 mL round bottom flask was added
(3-bromo-2-fluoro-4-methoxy-phenyl)-methanol (I-31, 1.04 g, 4.0
mmol), 3-chlorophenylboronic acid (0.76 g, 4.8 mmol),
Pd(PPh.sub.3).sub.4 (0.45 g, 0.41 mmol), Na.sub.2CO.sub.3 (6 mL, 2M
aq), toluene, (32 mL), and EtOH (11 mL). The reaction was degassed
with N.sub.2, then stirred at 80.degree. C. for 24 hours. Water was
added and the product was extracted with ethyl acetate. The
combined organics were concentrated and filtered through a
SiO.sub.2 plug eluting with 50% ethyl acetate/hexanes. The solid
was triturated with ether and filtered. The filtrate was
concentrated and triturated with ether and filtered. The filter
cakes were combined and purified by flash column chromatography
eluting with 20% acetone/hexanes to give
(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-methanol (I-32, 0.79
g, 67%) as a white solid.
[0339] Synthesis of
3-bromomethyl-3'-chloro-2-fluoro-6-methoxy-biphenyl (I-33). Into a
250 mL round bottom flask was added
(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-methanol synthesized
above (1.21 g, 4.54 mmol), dichloromethane (20 mL), PPh.sub.3 (1.19
g, 4.54 mmol), and the solution was cooled to 0.degree. C. NBS
(0.81 g, 4.54 mmol) was added and the reaction stirred for 2 hours
at 0.degree. C. The organics were washed with H.sub.2O and
concentrated. The residue was purified by flash column
chromatography eluting with 8% ethyl acetate/hexanes to give
3-bromomethyl-3'-chloro-2-fluoro-6-methoxy-biphenyl (I-33, 956 mg,
64%) as an off-white solid.
[0340] Synthesis of
5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carbonitrile
(I-238). Into a 250 mL round-bottomed flask was added 3.0 g of
5-bromo-pyridine-2-carbonitrile (3.0 g, 16.39 mmol),
bis(piniacolato)diboron (4.58 g, 18.03 mmol), KOAc (5.47 g, 55.74
mmol), and DMSO (100 mL). After degassing for 20 minutes,
PdCl.sub.2dppf-CH.sub.2Cl.sub.2 (1.39 g, 1.64 mmol) was added and
the solution was stirred for 24 hours at 80.degree. C., and then at
room temperature for 3 days. 50 mL water was added and the product
was extracted with ethyl acetate. The combined organics were washed
with brine, dried over Na.sub.2SO.sub.4 and concentrated. The
dark-colored residue was purified by flash column chromatography
eluting with 20% acetone/hexanes to give a red solid. The solid was
triturated with hexane to give 1.72 g (46%) of I-238 as a
light-pink solid.
[0341] Synthesis of
[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylmethyl]-
-carbamic acid tert-butyl ester (P-355). Into a 20 mL vial was
added I-33 (401 mg, 1.22 mmol), I-238 (336 mg, 1.46 mmol),
K.sub.2CO.sub.3 (504 mg, 3.65 mmol), DME (5 mL), water (0.5 mL),
ethanol (0.5 mL), and the suspension was degasses for 15 minutes.
Tetrakis(triphenylphosphine) palladium(0) (141 mg, 0.12 mmol) was
added and the reaction stirred at 80.degree. C. for 16 hours. The
reaction was diluted with water and extracted with ethyl acetate.
The organics were concentrated and purified by flash column
chromatography eluting with 15-20% ethyl acetate/hexanes to afford
P-355 (64 mg, 15%) as a light-yellow oil. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.62 (br s, 1H), 7.68-7.56 (m, 2H), 7.40-7.30
(m, 3H), 7.26-7.21 (m, 1H), 7.13 (t, J=8.4 Hz, 1H), 6.75 (d, J=8.3
Hz, 1H), 4.03 (br s, 2H), 3.78 (s, 3H) ppm. LC/MS=98.5%, 353.0
(APCI+).
[0342] Synthesis of
C-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-met-
hylamine (P-344). Into a 100 mL round bottom flask was added P-355
(0.55 g, 1.56 mmol), methanol (20 mL), concentrated HCl (0.65 mL,
7.79 mmol), and 10% Pd/C (100 mg). The suspension was stirred under
a H.sub.2 balloon for 18 hours, then filtered through Celite. The
filtrate was concentrated. To the solid was added 1N aqueous NaOH
and the product was extracted with dichloromethane. The
dichloromethane was concentrated and purified by flash column
chromatography eluting with 5-10% methanol/dichloromethane to give
P-344 (89 mg, 16%) as a colorless oil. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) 8.55 (d, J=1.2 Hz, 1H), 8.32 (br s, 3H), 7.71 (dd,
J=1.9, 7.9 Hz, 1H), 7.50-7.37 (m, 3H), 7.36 (d, J=5.4 Hz, 2H), 7.27
(d, J=6.6 Hz, 1H), 6.96 (d, J=8.6 Hz, 1H), 4.75 (br s, 2H), 4.14
(q, J=5.8 Hz, 2H), 4.01 (s, 2H), 3.73 (s, 3H) ppm. LC/MS=95.1%,
357.1 (APCI+).
[0343] Synthesis of
C-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-met-
hylamine (P-344). Into a 100 mL round bottom flask was added P-355
(0.55 g, 1.56 mmol), methanol (20 mL), concentrated HCl (0.65 mL,
7.79 mmol), and 10% Pd/C (100 mg). The suspension was stirred under
a H.sub.2 balloon for 18 hours, then filtered through Celite. The
filtrate was concentrated. To the solid was added 1N aqueous NaOH
and the product was extracted with dichloromethane. The
dichloromethane was concentrated and purified by flash column
chromatography eluting with 5-10% methanol/dichloromethane to give
P-344 (89 mg, 16%) as a colorless oil. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) 8.55 (d, J=1.2 Hz, 1H), 8.32 (br s, 3H), 7.71 (dd,
J=1.9, 7.9 Hz, 1H), 7.50-7.37 (m, 3H), 7.36 (d, J=5.4 Hz, 2H), 7.27
(d, J=6.6 Hz, 1H), 6.96 (d, J=8.6 Hz, 1H), 4.75 (br s, 2H), 4.14
(q, J=5.8 Hz, 2H), 4.01 (s, 2H), 3.73 (s, 3H) ppm. LC/MS=95.1%,
357.1 (APCI+).
[0344] Synthesis of
1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylmethy-
l]-3-ethyl-urea (P-372). Into an 8 mL vial was added P-344 (23 mg,
0.064 mmol), dichloromethane (1.5 mL), and the solution was cooled
to room temperature. Ethyl isocyanate (8 uL, 0.097 mmol) was added
and the reaction was stirred for 18 hours at room temperature and
then concentrated. To the resulting solid was added 4.0 M HCl
dioxane and the solution was stirred for 18 hours at room
temperature and then concentrated. The oil which was obtained was
treated with ether to form a solid, which was filtered to afford
P-372 (15.1 mg, 50%) as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) 8.63 (s, 1H), 8.14 (d, J=8.3 Hz, 1H), 7.63 (d, J=8.2
Hz, 1H), 7.51-7.33 (m, 4H), 7.28 (d, J=6.3 Hz, 1H), 6.98 (d, J=8.6
Hz, 1H), 6.62 (br s, 1H), 6.31 (br s, 1H), 4.42 (s, 2H), 4.10 (s,
2H), 3.74 (s, 3H), 3.01 (q, J=7.1 Hz, 2H), 0.99 (t, J=7.1 Hz, 3H)
ppm. MS: 428.1 (APCI+).
[0345]
1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-1-oxy-pyrid-
in-2-ylmethyl]-3-ethyl-urea (B-082). Into an 18 mL vial was added
P-372 (66 mg, 0.15 mmol), dichloromethane (4 mL), and the solution
was cooled to 0.degree. C. mCPBA (69 mg, 0.31 mmol) was added and
the reaction was stirred at room temperature for 1 hour after which
5 mL of saturated aqueous NaHCO.sub.3 was added. The layers were
separated and the organic layer was washed sequentially with 5 mL
each of saturated aqueous NaHCO.sub.3, H.sub.2O, and brine. The
residue was then washed with 1N NaOH (2.times.5 mL), water (5 mL),
and brine (5 mL). The product was dried over Na.sub.2SO.sub.4,
filtered and concentrated to obtain B-082 (14.8 mg, 22%) as a white
solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.19 (s, 1H), 7.53-7.34
(m, 4H), 7.29 (d, J=6.6 Hz, 1H), 7.25-7.16 (m, 2H), 6.96 (d, J=8.6
Hz, 1H), 6.38 (t, J=6.0 Hz, 1H), 6.17 (t, J=5.4 Hz, 1H), 4.22 (d,
J=6.2 Hz, 2H), 3.91 (s, 2H), 3.73 (s, 3H), 3.09-2.91 (m, 2H), 0.97
(t, J=7.2 Hz, 3H) ppm. LC/MS=100.0%, 444.1 (APCI+).
[0346] Synthesis of B-083
##STR00099##
[0347] Synthesis of
1-(2-Chloro-ethyl)-3-[5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl-
)-pyridin-2-ylmethyl]-urea (I-239). Into an 8 mL vial was added
P-344 (63 mg, 0.177 mmol), dichloromethane (2 mL), and the reaction
was cooled to 0.degree. C. Chloroethyl isocyanate (19 mg, 0.177
mmol) was added and the reaction was stirred at room temperature
for 1 hour and then concentrated to yield I-239 which was used as
is.
[0348] Synthesis of
1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylmethy-
l]-imidazolidin-2-one (P-374). Into an 8 mL vial was added I-239
(82 mg, 0.177 mmol), THF (2 mL), and the suspension was cooled to
0.degree. C. Sodium hydride (8 mg, 0.212 mmol) was added and the
reaction was stirred at room temperature for 3 days. An additional
4 mg of sodium hydride was added and the reaction was stirred at
50.degree. C. for 1 hour. Water was added and the product was
extracted with ethyl acetate. The organics were concentrated and
purified by flash column chromatography eluting with 25-50%
acetone/dichloromethane to give P-374 (35 mg, 47%, 2 steps) as a
white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.42 (d, J=1.5 Hz,
1H), 7.60 (dd, J=1.9, 7.9 Hz, 1H), 7.49-7.39 (m, 2H), 7.37 (s, 1H),
7.34 (t, J=8.7 Hz, 1H), 7.28 (d, J=6.7 Hz, 1H), 7.19 (d, J=7.9 Hz,
1H), 6.94 (d, J=8.6 Hz, 1H), 6.41 (s, 1H), 4.28 (s, 2H), 3.95 (s,
2H), 3.72 (s, 3H), 3.31-3.19 (m, 4H) ppm. LC/MS=100.0%, 426.1
(APCI+).
[0349]
1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-1-oxy-pyrid-
in-2-ylmethyl]-imidazolidin-2-one (B-083). Into an 18 mL vial was
added P-374 (62 mg, 0.15 mmol), dichloromethane (4 mL), and the
solution was cooled to 0.degree. C. mCPBA (82 mg, 0.36 mmol) was
added and the reaction was stirred at room temperature for 1 hour
after which 5 mL of aqueous 1N NaOH was added. The layers were
separated and the aqueous layer was extracted with dichloromethane
(2.times.3 mL). The organics were combined and washed with water (5
mL) and brine (5 mL) and then concentrated. The residue was taken
up in 5 mL of EtOAc and it was washed with 5 mL of brine, dried
over Na.sub.2SO.sub.4, and concentrated to a solid. The residue was
triturated with ether to afford B-083 (23.5 mg, 35%) as a white
solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.23 (s, 1H), 7.49-7.34
(m, 4H), 7.32-7.16 (m, 3H), 6.96 (d, J=8.6 Hz, 1H), 6.56 (s, 1H),
4.31 (s, 2H), 3.93 (s, 2H), 3.73 (s, 3H), 3.45-3.36 (m, 2H),
3.32-3.25 (m, 2H) ppm. LC/MS=93.4%, 442.0 (APCI+).
[0350] Synthesis of B-084
##STR00100##
[0351] Synthesis of
3-[5-(4-Fluoro-benzyl)-2-methoxy-phenyl]-pyridine (P-474). A
suspension of I-168 (158 mg, 0.53 mmol), 3-pyridineboronic acid
(61.5 mg, 0.50 mmol), palladium(0)bis(dibenzylideneacetone) (14.4
mg, 0.025 mmol), and triphenylphosphine (13.1 mg, 0.050 mmol) in
dimethylformamide (5 mL) and 1 M aqueous sodium carbonate (1.5 mL,
1.5 mmol) was heated to 85.degree. C. with stirring overnight. The
solvent was removed under vacuum and the residue suspended in ethyl
acetate (15 mL). The organic suspension was washed with water
(3.times.15 mL) and brine, dried over sodium sulfate and the
solvent removed under vacuum to give crude material. The residue
was purified by silica gel preparatory thin layer chromatography to
afford 69.1 mg (47%) of P-474
[0352] Synthesis of
3-[5-(4-Fluoro-benzyl)-2-methoxy-phenyl]-pyridine 1-oxide (B-084).
A vial was charged with P-474 (60 mg, 0.20 mmol), methyl ruthenium
oxide (2.5 mg, 0.010 mmol), 30% aqueous hydrogen peroxide (0.5 mL),
and dichloromethane (1.0 mL). The reaction was allowed to stir at
room temperature for 3 days. The biphasic mixture was treated with
catalytic amount of manganese dioxide (1.7 mg, 0.02 mmol) and
carefully stirred until the oxygen evolution ceased (1 h). The
phases were separated, the aqueous layer extracted into
dichloromethane (2.times.1 mL), the organic layers combined, dried
over sodium sulfate, and the solvent removed under vacuum to afford
20.9 mg of B-084 in 34% yield. .sup.1H NMR (400 MHz, CDCl.sub.3)
3.82 (s, 3H) 3.94 (s, 2H) 6.89-7.24 (m, 8H) 7.41 (d, J=8.1 Hz, 1H)
8.16 (d, J=6.3 Hz, 1H) 8.44 (s, 1H) ppm. LCMS=92.0% purity.
[0353] The following compounds were prepared by methods analogous
to those described above.
TABLE-US-00007 PCTUS Ex No 1H NMR data LCMS A-001 1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 3.85 (s, 3H) 4.55 (s, 2H) 6.98 (d, J =
8.45 Hz, 1H) 7.31 (d, J = 7.78 Hz, 1H) 7.38 (d, J = 2.28 Hz, 1H)
7.43 (dd, J = 8.45, 2.28 Hz, 1H) 7.48-7.68 (m, 3H) 7.77 (s, 1H)
7.85 (d, J = 7.65 Hz, 1H) 8.19 (dd, J = 8.18, 1.34 Hz, 1H) 8.40 (t,
J = 1.81 Hz, 1H) A-008 1H NMR (CHLOROFORM-d, 400 MHz): .delta. =
7.29-7.41 (m, 7H), 7.19-7.29 (m, 12H), 7.07-7.18 (m, 7H), 6.71 (s,
2H), 6.38 (br. s., 2H), 4.64 (br. s., 4H), 3.94 (s, 5H), 3.75 (s,
7H), 2.14 (s, 1H), 1.26 (s, 3H), 0.89 ppm (s, 1H) A-010 1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm 7.94 (br. s., 1H) 7.65 (dd, J = 9.1,
1.9 Hz, 1H) 7.30-7.40 (m, 3H) 7.23-7.29 (m, 2H) 7.12 (t, J = 8.5
Hz, 1H) 6.73 (d, J = 8.6 Hz, 1H) 3.87 (s, 2H) 3.77 (s, 3H) A-011 1H
NMR (400 MHz, DMSO, d-6)3.72 (3H, s), 3.82 (2H, s), 6.64-6.68 (2H,
m) 6.91-6.94 (3H, m), 7.20 (1H, d, J = 8 Hz), 7.26-7.31 (2H, m),
7.37 (1H, br), 7.41-7.48 (2H, m), 7.70 (1H, s). A-012 1H NMR (400
MHz, DMSO-d6) .delta. ppm 10.95 (s, 1H) 8.45 (s, 2H) 7.19-7.54 (m,
5H) 7.07 (s, 2H) 6.96 (d, J = 8.6 Hz, 1H) 3.89 (s, 2H) 3.74 (s, 3H)
A-013 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.89-8.04 (m, 2H)
7.54-7.63 (m, 1H) 7.53 (d, J = 7.6 Hz, 1H) 7.25-7.34 (m, 7H) 7.09
(t, J = 8.6 Hz, 1H) 6.71 (d, J = 8.5 Hz, 1H) 6.46 (d, J = 8.5 Hz,
1H) 3.83 (s, 3H) 3.75 (s, 3H) 2.62 (s, 3H) A-014 1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 7.98 (s, 1H) 7.26-7.46 (m, 5H) 7.05-7.17
(m, 3H) 7.00 (s, 1H) 6.70 (s, 1H) 5.47 (br. s., 1H) 3.81 (br. s.,
2H) 3.76 (s, 3H) A-015 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
7.98 (s, 1H) 7.29-7.44 (m, 3H) 7.06-7.15 (m, 2H) 7.00 (s, 1H) 6.70
(s, 1H) 5.47 (br. s., 1H) 3.81 (br. s., 2H) 3.76 (s, 3H) A-028
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. = 8.09 (s, 1H), 7.63
(br. s., 1H), 7.48-7.40 (m, 3H), 7.37 (s, 1H), 7.32-7.25 (m, 4H),
6.94 (d, J = 8.6 Hz, 1H), 3.89 (s, 2H), 3.87 (s, 2H), 3.73 (s, 3H)
A-029 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.24 (t, 3H) 2.63
(t, J = 6.37 Hz, 2H) 3.64 (q, J = 6.31 Hz, 2H)3.76 (s, 3H) 3.87 (s,
2H) 4.15 (q, J = 7.20 Hz, 2H) 6.57 (d, J = 8.45 Hz, 1H) 6.71 (d, J
= 8.45 Hz, 1H) 6.92 (s, 1H) 7.09 (t, J = 8.52 Hz, 1H) 7.29-7.40 (m,
3H) 7.44 (dd, J = 8.32, 2.15 Hz, 1H) 8.07 (d, J = 1.74 Hz, 1H) 9.52
(br. s., 1H) A-032 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. =
9.37 (br. s., 1H), 8.15 (br. s., 1H), 8.04 (s, 1H), 7.59 (d, J =
7.6 Hz, 1H), 7.49-7.23 (m, 6H), 6.94 (d, J = 8.6 Hz, 1H), 3.87 (s,
2H), 3.73 (s, 3H), 2.57-2.53 (m, 2H), 2.47-2.41 (m, 2H) A-036 1H
NMR (CHLOROFORM-d, 400 MHz): .delta. = 8.06 (s, 1H), 7.25-7.39 (m,
5H), Calc.343.8; 7.07 (t, J = 8.6 Hz, 1H), 6.67 (d, J = 8.5 Hz,
1H), 6.47 (d, J = 8.7 Hz, 1H), 3.80 (s, APCI.sup.+(M + 2H), 3.74
(s, 3H). CHO): 371.1, 97.6% A-054 1H NMR (400 MHz, DMSO-d6) .delta.
ppm 3.72 (s, 3H) 3.75-3.94 (m, 3H) 4.56 (br. s., 1H) 6.40 (d, J =
8.45 Hz, 1H) 6.92 (d, J = 8.59 Hz, 1H) 7.21-7.47 (m, 5H) 7.97 (s,
1H)
* * * * *