US2009062358A1PendingUtilityA1
Peroxisome proliferator activated receptor alpha agonists
Est. expiryNov 10, 2020(expired)· nominal 20-yr term from priority
Inventors:Ivan Collado CanoSamuel James DominianniGarret Jay EtgenCristina Garcia-ParedesRichard Duane JohnstonMichael E. LetourneauNathan B. MantloMichael John MartinelliDaniel Ray MayhughAshraf SaeedRichard ThompsonXiaodong WangDavid Scott CoffeyChristopher Randall SchmidJeffrey T. VicenziYanping Xu
A61P 9/12A61P 9/00A61P 43/00A61P 3/06A61P 9/10A61P 3/10A61P 3/04A61P 3/00C07C 281/04C07D 409/06C07D 417/12C07C 281/06C07D 409/12C07D 249/12C07D 413/06C07D 401/06C07D 405/06C07C 257/22
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Claims
Abstract
The present invention is directed to compounds represented by the following structural formula, and pharmaceutically acceptable salts, solvates and hydrates thereof, R1 is a substituted or unsubstituted group selected from C 1 -C 8 alkyl, aryl-C 0-2 -alkyl, heteroaryl-C 0-2 -alkyl, C3-C6 cycloalkylaryl-C 0-2 -alkyl or phenyl. W is O or S. R2 is H or a substituted or unsubstituted group selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and heteroaryl. X is a C 2 -C 5 alkylene linker wherein one carbon atom of the linker may be replaced with O, NH or S. Y is C, O, S, NH or a single bond. Furthermore, E is (CH 2 ) n COOH, wherein n is 0, 1, 2 or 3, or C(R3)(R4)A, wherein A is an acidic functional group such as carboxyl, carboxamide substituted or unsubstituted sulfonamide, or substituted or unsubstituted tetrazole. R3 is H, saturated or unsaturated C 1 -C 5 alkyl, C 1 -C 5 alkoxy. Additionally, R4 is H, halo, a substituted or unsubstituted group selected from C 1 -C 5 alkyl, C 1 -C 5 alkoxy, C 3 -C 6 cycloalkyl, arylC 0 -C 4 alkyl and phenyl, or R3 and R4 are combined to form a C 3 -C 4 cycloalkyl.
Claims
exact text as granted — not AI-modified1 . A compound represented by the following structural
Formula I:
and pharmaceutically acceptable salts, solvates and
hydrates thereof, wherein:
(a) R1 is selected from the group consisting of hydrogen, substituted or unsubstituted group selected from C 1 -C 8 alkyl, aryl-C 0-4 -alkyl, heteroaryl-C 0-4 -alkyl, C 3 -C 6 cycloalkylaryl-C 0-2 -alkyl, and —CH 2 —C(O)—R17-R18, wherein R17 is O or NH and R18 is optionally substituted benzyl;
(b) W is O or S;
(c) R2 is H or a substituted or unsubstituted group
selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 allyl, aryl-C 0-4 -alkyl, heteroaryl-C 0-4 -alkyl, sulfonamide, amide, OR10 and C 3 -C 6 cycloalkyl;
(d) X is an optionally substituted C 1 -C 5 alkylene linker wherein one carbon atom of the linker may be replaced with O, NH or S;
(e) Y is C, O, S, NH or a single bond; and
(f) E is selected from the group consisting of hydrogen, C(R3)(R4)A, A, substituted or unsubstituted selected from the group consisting of (CH 2 ) n COOR19, C 1 -C 6 alkyl, C 1 -C 6 allyl, aryl-C 0-4 -alkyl, thio-C 1-4 -alkyl, thioaryl, C 1-4 alkoxyaryl, C 1-4 alkoxy C 1-4 alkyl, aminoaryl, and aminoC 1-4 alkyl, and wherein
(i) n is 0, 1, 2 or 3,
(ii) A is an functional group selected from the group consisting of carboxyl, C 1 -C 3 alkylnitrile, carboxamide, substituted or unsubstituted sulfonamide, substituted or unsubstituted acylsulfonamide and substituted or unsubstituted tetrazole;
(iii) R3 is H, saturated or unsaturated C 1 -C 5
alkyl, C 1 -C 5 alkoxy, and
(iv) R4 is H, halo, a substituted or
unsubstituted group selected from C 1 -C 5
alkyl, C 1 -C 5 alkoxy, C 3 -C 6 cycloalkyl, aryl C 0 -C 4 alkyl and phenyl, or R3 and R4 are combined to form a C 3 -C 4 cycloalkyl;
(v) R19 is selected from the group consisting of hydrogen, optionally substituted arylmethyl and optionally substituted C 1 -C 4 alkyl;
(g) R8 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkylenyl, and halo;
(h) R9 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkylenyl, halo, substituted or unsubstituted aryl, substituted or unsubstituted aryl-C 1 -C 4 alkyl, substituted or unsubstituted heteroaryl, C 1 -C 6 allyl, and OR10; and
(i) R10 is independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl.
2 . (canceled)
3 . A compound as claimed by any one of claims 1 or 2 wherein W is O.
4 . A compound as claimed by any one of claims 1 , 2 or 3 wherein E is A.
5 . A compound as claimed by any one of claims 1 , 2 , 3 or 4 wherein A is COOH.
6 . A compound as claimed by any one of claims 1 , 2 , 3 , 4 or 5 wherein Y is O.
7 . A compound as claimed by any one of claims 1 , 2 , 3 , 4 or 5 wherein Y is C.
8 . A compound of claim 7 wherein E is selected from the group consisting of aryl-C 0-4 -alkyl, thio-C 1-4 -alkyl, thioaryl, C 1-4 alkoxyaryl, C 1-4 alkoxyalkyl, aminoaryl, and aminoC 1-4 alkyl.
9 . A compound as claimed by any one of claims 1 , 2 , 3 , 6 , or 7 wherein E is a group of the formula:
wherein R14 is selected from the group consisting of CF 3 , substituted or unsubstituted phenyl, substituted or unsubstituted aryl-C 0-4 -alkyl, and C 1-6 -alkyl.
10 . A compound as claimed by any one of claims 1 , 2 , 3 , 6 , or 7 wherein E is a group of the formula:
wherein R14 is selected from the group consisting of CF 3 , substituted or unsubstituted phenyl, substituted or unsubstituted aryl-C 0-4 -alkyl, and C 1-6 -alkyl.
11 . A compound as claimed by any one of claims 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , or 10 wherein X is optionally substituted C 2 -C 5 alkylene.
12 . A compound as claimed by any one of claims 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , or 11 wherein X is propylene.
13 . A compound of claim 1 which is Propanoic Acid, 2-[4-[3-[2,5-dihydro-1-[(4-methylphenyl)methyl]-5-oxo-1H-1,2,4-triazol-3-yl]propyl]phenoxy]-2-methyl-.
14 . A compound of claim 13 which is Crystalline Propanoic Acid, 2-[4-[3-[2,5-dihydro-1-[(4-methylphenyl)methyl]-5-oxo-1H-1,2,4-triazol-3-yl]propyl]phenoxy]-2-methyl- having an X-ray diffraction pattern which comprises at least one of the following peaks: 13.2+/−0.2, 15.9+/−0.2, 20.7+/−0.2, and 24.1+/−0.2 in 20 when obtained from a copper radiation source.
15 . A compound as claimed by any one of claims 1 , 2 , 5 , 11 or 12 that is represented by the following structural
formula:
and pharmaceutically acceptable salts, solvates and
hydrates thereof, wherein:
(a) R1 is selected from the group consisting of hydrogen, substituted or unsubstituted group selected from C 1 -C 8 alkyl, aryl-C 0-4 -alkyl, heteroaryl-C 0 -4-alkyl, C 3 -C 6 cycloalkylaryl-C 0-2 -alkyl, and —CH 2 —C(O)—R17-R18, wherein R17 is O or NH and R18 is optionally substituted benzyl;
(b) R2 is H or a substituted or unsubstituted group
selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and
heteroaryl;
(c) X is a C 2 -C 5 alkylene linker wherein one carbon
atom of the linker may be replaced with O, NH or
S;
(d) Q is C, O or S;
(e) A is a functional group selected from the group consisting of carboxyl, C 1 -C 3 alkylnitrile, carboxamide, substituted or unsubstituted sulfonamide, substituted or unsubstituted acylsulfonamide and substituted or unsubstituted tetrazole;
(f) R3 is H, saturated or unsaturated C 1 -C 5 alkyl,
C 1 -C 5 alkoxy; and
(g) R4 is H, halo, a substituted or unsubstituted
group selected from C 1 -C 5 alkyl, C 1 -C 5 alkoxy,
C 3 -C 6 cycloalkyl and phenyl, or R3 and R4 are
combined to form a C 3 -C 4 cycloalkyl.
16 . A compound as claimed by claim 15 wherein A is COOH.
17 . A compound as claimed by any one of claims 15 , or 16 wherein R3 is methyl.
18 . A compound as claimed by any one of claims 15 , 16 or 17 wherein R4 is methyl.
19 . A compound as claimed by any one of claims 1 , 2 , 11 or 12 that is represented by the following structural
formula:
and pharmaceutically acceptable salts, solvates and
hydrates thereof, wherein:
(a) R1 is selected from the group consisting of hydrogen, substituted or unsubstituted group selected from C 1 -C 8 alkyl, aryl-C 0-4 -alkyl, heteroaryl-C 0-4 -alkyl, C 3 -C 6 cycloalkylaryl-C 0-2 -alkyl, and —CH 2 —C(O)—R17-R18, wherein R17 is O or NH and R18 is optionally substituted benzyl;
(b) R2 is H or a substituted or unsubstituted group
selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and
heteroaryl;
(c) X is an optionally substituted C 1 -C 5 alkylene linker wherein one carbon atom of the linker may be replaced with O, NH or
S;
(d) Q is C, O or S;
(e) R3 is H, saturated or unsaturated C 1 -C 5 alkyl,
C 1 -C 5 alkoxy; and
(f) R4 is H, halo, a substituted or unsubstituted
group selected from C 1 -C 5 alkyl, C 1 -C 5 alkoxy,
C 3 -C 6 cycloalkyl and phenyl, or R3 and R4 are
combined to form a C 3 -C 4 cycloalkyl.
20 . A compound as claimed by any one of claims 1 - 12 , 15 , 16 , 17 , 18 , or 19 wherein R1 selected from the group consisting of a substituted or unsubstituted C 1 -C 8 alkyl, aryl-C 0-4 -alkyl, heteroaryl-C 0-4 -alkyl, and C 3 -C 6 cycloalkylaryl-C 0-2 -alkyl.
21 . A compound as claimed by any one of claims 1 - 12 , 15 , 16 , 17 , 18 , 19 or 20 wherein R1 is substituted aryl.
22 . A compound as claimed by any one of claims 1 , 2 , 11 , or 12 that is represented by the following structural
formula:
and pharmaceutically acceptable salts, solvates and
hydrates thereof, wherein:
(a) R2 is H or a substituted or unsubstituted group
selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and
heteroaryl;
(b) X is an optionally substituted C 1 -C 5 alkylene linker wherein one carbon atom of the linker may be replaced with O, NH or S;
(c) R3 is H, saturated or unsaturated C 1 -C 5 alkyl,
C 1 -C 5 alkoxy;
(d) R4 is H, halo, a substituted or unsubstituted
group selected from C 1 -C 5 alkyl, C 1 -C 5 alkoxy,
C 3 -C 6 cycloalkyl and phenyl, or R3 and R4 are
combined to form a C 3 -C 4 cycloalkyl;
(e) V is a bond or a unsubstituted or substituted
C 1 -C 3 alkylene group; and
(f) R5 is substituted or unsubstituted group selected
from aryl, heteroaryl and cycloalkyl groups.
23 . A compound as claimed by any one of claims 1 , 2 , 11 or 12 that is represented by the following structural
formula:
and pharmaceutically acceptable salts, solvates and
hydrates thereof, wherein:
(a) R2 is H or a substituted or unsubstituted group
selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and
heteroaryl (delete heteroaryl);
(b) X is an optionally substituted C 1 -C 5 alkylene linker wherein one carbon atom of the linker may be replaced with O, NH or S;
(c) R3 is H, saturated or unsaturated C 1 -C 5 alkyl,
C 1 -C 5 alkoxy;
(d) R4 is H, halo, a substituted or unsubstituted
group selected from C 1 -C 5 alkyl, C 1 -C 5 alkoxy,
C 3 -C 6 cycloalkyl and phenyl, or R3 and R4 are
combined to form a C 3 -C 4 cycloalkyl;
(e) V is a bond or a unsubstituted or substituted
C 1 -C 3 alkylene group; and
(f) R6 is H, OH, C 1 -C 5 alkyl, alkoxy, halo, haloalkyl,
haloalkoxy, nitro, phenyl, aryloxy, SO 2 R7, SR7,
cyano, benzyloxy, phenoxy, alkylcarboxamido or
COOH wherein R7 is an alkyl or a haloalkyl.
24 . A compound of claim 23 wherein V is methylene.
25 . A compound as claimed by any one of claims 23 or 24 wherein X is propylene.
26 . A compound as claimed by any one of claims 23 , 24 or 25 wherein R3 is methyl.
27 . A compound as claimed by any one of claims 23 , 24 , 25 or 26 wherein R4 is methyl.
28 . A compound as claimed by any one of claims 1 or 2 that is represented by the following structural
formula:
and pharmaceutically acceptable salts, solvates and
hydrates thereof, wherein:
(a) R2 is H or a substituted or unsubstituted group
selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and
heteroaryl (delete heteroaryl);
(b) R3 is H, saturated or unsaturated C 1 -C 5 alkyl,
C 1 -C 5 alkoxy;
(c) R4 is H, halo, a substituted or unsubstituted
group selected from C 1 -C 5 alkyl, C 1 -C 5 alkoxy,
C 3 -C 6 cycloalkyl and phenyl, or R3 and R4 are
combined to form a C 3 -C 4 cycloalkyl; and
(d) R6 is independently selected from the group consisting of H, OH, C1-C5 alkyl, alkoxy, halo, haloalkyl, haloalkoxy, nitro, phenyl, aryloxy, SO2R7, SR7, cyano, benzyloxy, phenoxy, alkylcarboxamido or COOH wherein R7 is an alkyl or a haloalkyl.
29 . A compound as claimed by any one of claims 1 , 2 , or 4 - 28 , that is represented by the following structure:
wherein R6 is independently selected from the group consisting of H, OH, C 1 -C 5 alkyl, alkoxy, halo, haloalkyl, haloalkoxy, nitro, phenyl, aryloxy, SO2R7, SR7, cyano, benzyloxy, phenoxy, alkylcarboxamido or COOH wherein R7 is an alkyl or a haloalkyl.
30 . A compound as claimed by any one of claims 1 , 2 , or 4 - 29 wherein there are two R6 substituents independently selected from the group consisting of hydrogen, C 1 -C 5 alkyl, Cl, F, OCH 3 , CF 3 , and SCF 3 .
31 . A compound as claimed by any one of claims 1 , 2 , or 4 - 30 wherein EY is
32 . A compound represented by the following structural
formula:
and pharmaceutically acceptable salts, solvates and
hydrates thereof, wherein:
(a) R1 is selected from the group consisting of hydrogen, substituted or unsubstituted group selected from C 1 -C 8 alkyl, aryl-C 0-4 -alkyl, heteroaryl-C 0-4 -alkyl, C 3 -C 6 cycloalkylaryl-C 0-2 -alkyl, and —CH 2 —C(O)—R17-R18, wherein R17 is O or NH and R18 is optionally substituted benzyl;
(b) W is O or S;
(c) R2 is H or a substituted or unsubstituted group
selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkyl, aryl-C 0-4 -alkyl, heteroaryl-C 0-4 -alkyl, sulfonamide, amide, OR10 and C 3 -C 6 cycloalkyl;
(d) X is an optionally substituted C 1 -C 5 alkylene linker wherein one carbon atom of the linker may be replaced with O, NH or S;
(e) Y is C, O, S, NH or a single bond; and
(f) E is selected from the group consisting of hydrogen, C(R3)(R4)A, A, substituted or unsubstituted selected from the group consisting of (CH 2 ) n COOR19, C 1 -C 6 alkyl, C 1 -C 6 allyl, aryl-C 0-4 -alkyl, thio-C 1-4 -alkyl, thioaryl, C 1-4 alkoxyaryl, C 1-4 alkoxy C 1-4 alkyl, aminoaryl, and aminoC 1-4 alkyl, and wherein
(i) n is 0, 1, 2 or 3,
(ii) A is a functional group selected from the group consisting of carboxyl, C 1 -C 3 alkylnitrile, carboxamide, substituted or unsubstituted sulfonamide, substituted or unsubstituted acylsulfonamide and substituted or unsubstituted tetrazole;
(iii) R3 is H, saturated or unsaturated C 1 -C 5
alkyl, C 1 -C 5 alkoxy, and
(iv) R4 is H, halo, a substituted or
unsubstituted group selected from C 1 -C 5
alkyl, C 1 -C 5 alkoxy, C 3 -C 6 cycloalkyl, aryl C 0 -C 4 alkyl and phenyl, or R3 and R4 are combined to form a C 3 -C 4 cycloalkyl;
(v) R19 is selected from the group consisting of hydrogen, optionally substituted arylmethyl and optionally substituted C 1 -C 4 alkyl;
(g) R8 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkylenyl, and halo;
(h) R9 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkylenyl, halo, substituted or unsubstituted aryl, substituted or unsubstituted aryl-C 1 -C 4 alkyl, substituted or unsubstituted heteroaryl, C 1 -C 6 allyl, and OR10;
(i) R10 is independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl;
(j) Z is C 0 -C 3 alkylene, O, S, N, O—(C 0 -C 2 alkylene), S—(C 0 -C 2 alkylene), and N—(C 0 -C 2 alkylene); and
(k) — is an optional bond to form a double bond.
33 . A compound of claim 32 having the formula:
34 . A compound of 33 represented by the structural formula:
35 . A compound of claim 32 represented by the structural formula:
36 . A compound of claim 32 represented by the following structure:
37 . A compound of claim 32 represented by the following structure:
38 . A compound as claimed by 32 wherein A is COOH.
39 . A compound as claimed by claim 32 wherein W is O.
40 . A compound as claimed by claim 39 wherein R2 is C 1 -C 4 alkyl.
41 . A compound as claimed by claim 40 , wherein X is C 2 -C 3 alkylene.
42 . A compound as claimed by claim 41 wherein R1 is optionally substituted phenyl or benzyl.
43 . A compound as claimed by claim 32 , wherein R1 is a substituted or unsubstituted group selected from the group consisting of C 1 -C 8 alkyl, aryl-C 0-4 -alkyl, heteroaryl-C 0-4 -alkyl, C 3 -C 6 cycloalkylaryl-C 0-2 -alkyl and phenyl.
44 . A compound as claimed by claim 32 wherein said compound is radiolabeled.
45 . A compound as claimed by claim 44 wherein said compound is tritiated.
46 . A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and at least one compound as claimed by any one of claim 42 , or a pharmaceutically acceptable salt, solvate or hydrate thereof.
47 . A method of modulating a peroxisome proliferator
activated receptor, comprising the step of contacting the receptor with at least one compound as claimed by any one of claims 1 - 43 , or a pharmaceutically acceptable salt, solvate or hydrate thereof.
48 . The method of claim 47 , wherein the peroxisome
proliferator activated receptor is an α receptor.
49 . A method of treating diabetes mellitus in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of at least one compound of claims 1 - 43 , or a pharmaceutically acceptable salt, solvate or hydrate thereof.
50 . A method of preventing diabetes mellitus in a mammal, comprising the step of administering to the mammal an
effective amount of at least one compound of claims 1 - 43 , or a pharmaceutically acceptable salt, solvate or hydrate thereof.
51 . The method of any one of claims 49 or 50 wherein the compound lowers blood glucose levels.
52 . A method of treating cardiovascular disease in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of at least one compound of claims 1 - 43 , or a pharmaceutically acceptable salt, solvate or hydrate thereof.
53 . A method of preventing cardiovascular disease in a mammal, comprising the step of administering to the mammal an effective amount of at least one compound of claims 1 - 43 , or a pharmaceutically acceptable salt, solvate or hydrate thereof.
54 . The method of any one of claims 52 or 53 wherein the compound lowers triglycerides in the mammal.
55 . The method of any one of claims 52 , 53 , or 54 wherein the compound lowers low density lipoproteins in the mammal.
56 . The method of claims 52 , 53 or 54 wherein the compound increases high density lipoproteins in a mammal.
57 . A method of treating Syndrome X in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of at least one compound of claims 1 - 43 , or a pharmaceutically acceptable salt, solvate or hydrate thereof.
58 . A method of preventing Syndrome X in a mammal, comprising the step of administering to the mammal an effective amount of at least one compound of claims 1 - 43 , or a pharmaceutically acceptable salt, solvate or hydrate thereof.
59 . The method of claim 58 wherein the compound lowers blood glucose levels.
60 . The method of any one of claims 58 or 59 wherein the compound lowers serum concentration of triglycerides in the mammal.
61 . The method of any one of claims 58 , 59 or 60 wherein the compound lowers serum concentration of low density lipoproteins in the mammal.
62 . The method of any one of claims 58 , 59 , 60 or 61 wherein the compound increases serum concentration of high density lipoproteins in a mammal.
63 . A method of treating obesity in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of at least one compound of claims 1 - 43 , or a pharmaceutically acceptable salt, solvate or hydrate thereof.
64 . A method of preventing obesity in a mammal, comprising the step of administering to the mammal an effective amount of at least one compound of claims 1 - 43 , or a pharmaceutically acceptable salt, solvate or hydrate thereof.
65 . The method of any one of claims 47 - 64 wherein the mammal is a human.
66 . A compound for use in therapy for a disorder modulated by a peroxisome proliferator activated receptor, wherein the compound, or pharmaceutically acceptable salt, solvate or hydrate thereof, is a compound of claims 1 - 43 .
67 . Use of a compound for the manufacture of a medicament for the treatment of a condition modulated by a peroxisome proliferator activated receptor, wherein the compound, or pharmaceutically acceptable salt, solvate or hydrate thereof, is a compound of claims 1 - 43 .
68 . (canceled)
69 . A process for preparing a triazolone from an acyl semicarbazide comprising contacting said acyl semicarbazide with an acid.
70 . A process as claimed by claim 69 wherein the acid is a sulfonic acid.
71 . A process as claimed by claim 69 wherein the acid is pyridinium hydrochloride.
72 . A process as claimed by any one of claims 69 , 70 , or 71 wherein the triazalone is represented by Formula I.
73 . A compound of the formula:
wherein
(a) R1 is hydrogen or is selected from the group consisting of a substituted or unsubstituted group selected from C 1 -C 8 alkyl, aryl-C 0-4 -alkyl, heteroaryl-C 0-4 -alkyl, and C 3 -C 6 cycloalkylaryl-C 0-2 -alkyl;
(b) R2 is H or a substituted or unsubstituted group
selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 allyl, aryl-C 0-4 -alkyl, heteroaryl-C 0-4 -alkyl, sulfonamide, amide, OR10 and C 3 -C 6 cycloalkyl;
(c) X is an optionally substituted C 1 -C 5 alkylene linker wherein one carbon atom of the linker may be replaced with O, NH or S;
(d) Y is C, O, S, NH or a single bond; and
(e) E is selected from the group consisting of hydrogen, (CH 2 ) n COOR19, C(R3)(R4)A, substituted or unsubstituted selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 allyl, aryl-C 0-4 -alkyl, thio-C 1-4 -alkyl, thioaryl, C 1-4 alkoxyaryl, C 1-4 alkoxy C 1-4 alkyl, aminoaryl, and aminoC 1-4 alkyl, and wherein
(i) n is 0, 1, 2 or 3,
(ii) A is a functional group selected from the group consisting of carboxyl, C 1 -C 3 alkylnitrile, carboxamide, substituted or unsubstituted sulfonamide, substituted or unsubstituted acylsulfonamide and substituted or unsubstituted tetrazole;
(iii) R3 is H, saturated or unsaturated C 1 -C 5
alkyl, C 1 -C 5 alkoxy, and
(iv) R4 is H, halo, a substituted or
unsubstituted group selected from C 1 -C 5
alkyl, C 1 -C 5 alkoxy, C 3 -C 6 cycloalkyl, aryl C 0 -C 4 alkyl and phenyl, or R3 and R4 are combined to form a C 3 -C 4 cycloalkyl;
(v) R19 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl and optionally substituted arylmethyl;
(f) R8 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkylenyl, and halo;
(g) R9 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkylenyl, halo, substituted or unsubstituted aryl, substituted or unsubstituted aryl-C 1 -C 4 alkyl, substituted or unsubstituted heteroaryl, C 1 -C 6 allyl, and OR10; and
(h) R10 is independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl; and
(i) R15 is selected from the group consisting of hydrogen and an optionally substituted substituent selected from the group consisting of C 1 -C 4 alkyl, aryl, and benzyl.
74 . A compound of claim 73 having the formula:
75 . A compound as claimed by any one of claims 73 and 74 wherein X is C 2 -C 5 alkylene.
76 . A compound as claimed by any one of claims 73 , 74 , or 75 wherein A is selected from the group consisting of COOH, and C 1 -C 3 alkylnitrile.
77 . A compound as claimed by any one of claims 73 , 74 , 75 , or 76 wherein R2 is C 1 -C 4 alkyl.
78 . A compound as claimed by any one of claims 73 , 74 , 75 , 76 or 77 , wherein X is C 2 -C 3 alkylene.
79 . A compound as claimed by any one of claims 73 , 74 , 75 , 76 , 77 , or 78 wherein R1 is optionally substituted phenyl or benzyl.
80 . A compound as claimed by any one of claims 73 , 74 , 75 , 76 , 77 , 78 , or 79 wherein R1 is a substituted or unsubstituted group selected from the group consisting of C 1 -C 8 alkyl, aryl-C 0-4 -alkyl, heteroaryl-C 0-4 -alkyl, C 3 -C 6 cycloalkylaryl-C 0-2 -alkyl and phenyl.
81 . A compound of the formula:
wherein
(a) R1 is hydrogen or is selected from the group consisting of a substituted or unsubstituted group selected from C 1 -C 8 alkyl, aryl-C 0-4 -alkyl, heteroaryl-C 0-4 -alkyl, and C 3 -C 6 cycloalkylaryl-C 0-2 -alkyl;
(b) R2 is H or a substituted or unsubstituted group
selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 allyl, aryl-C 0-4 -alkyl, heteroaryl-C 0-4 -alkyl, sulfonamide, amide, OR10 and C 3 -C 6 cycloalkyl;
(c) X is an optionally substituted C 1 -C 5 alkylene linker wherein one carbon atom of the linker may be replaced with O, NH or S;
(d) Y is C, O, S, NH or a single bond; and
(e) E is selected from the group consisting of hydrogen, substituted or unsubstituted selected from the group consisting of (CH 2 ) n COOR19, C(R3)(R4)A, C 1 -C 6 alkyl, C 1 -C 6 allyl, aryl-C 0-4 -alkyl, thio-C 1-4 -alkyl, thioaryl, C 1-4 alkoxyaryl, C 1-4 alkoxy C 1-4 alkyl, aminoaryl, and aminoC 1-4 alkyl, and wherein
(i) n is 0, 1, 2 or 3,
(ii) A is an acidic functional group selected from the group consisting of carboxyl, C 1 -C 3 alkylnitrile, carboxamide, substituted or unsubstituted sulfonamide, substituted or unsubstituted acylsulfonamide and substituted or unsubstituted tetrazole;
(iii) R3 is H, saturated or unsaturated C 1 -C 5 alkyl, C 1 -C 5 alkoxy, and
(iv) R4 is H, halo, a substituted or
unsubstituted group selected from C 1 -C 5
alkyl, C 1 -C 5 alkoxy, C 3 -C 6 cycloalkyl, aryl C 0 -C 4 alkyl and phenyl, or R3 and R4 are combined to form a C 3 -C 4 cycloalkyl;
(v) R19 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl and optionally substituted arylmethyl;
(f) R8 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkylenyl, and halo;
(g) R9 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkylenyl, halo, substituted or unsubstituted aryl, substituted or unsubstituted aryl-C 1 -C 4 alkyl, substituted or unsubstituted heteroaryl, C 1 -C 6 allyl, and OR10; and
(h) R10 is independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl.
82 . A compound as claimed by claim 81 wherein X is C 2 -C 5 alkylene.
83 . A compound as claimed by any one of claims 81 or 82 wherein A is selected from the group consisting of COOH, and C 1 -C 3 alkylnitrile.
84 . A compound as claimed by any one of claims 81 , 82 , or 83 wherein R2 is C 1 -C 4 alkyl.
85 . A compound as claimed by any one of claims 81 , 82 , 83 , or 84 , wherein X is C 2 -C 3 alkylene.
86 . A compound as claimed by any one of claims 81 , 82 , 83 , 84 , or 85 wherein R1 is optionally substituted phenyl or benzyl.
87 . A compound of the formula:
wherein
(a) R1 is hydrogen or is selected from the group consisting of a substituted or unsubstituted group selected from C 1 -C 8 alkyl, aryl-C 0-4 -alkyl, heteroaryl-C 0-4 -alkyl, and C 3 -C 6 cycloalkylaryl-C 0-2 -alkyl;
(b) R2 is H or a substituted or unsubstituted group
selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 allyl, aryl-C 0-4 -alkyl, heteroaryl-C 0-4 -alkyl, sulfonamide, amide, OR10 and C 3 -C 6 cycloalkyl;
(c) X is an optionally substituted C 1 -C 5 alkylene linker wherein one carbon atom of the linker may be replaced with O, NH or S;
(d) Y is C, O, S, NH or a single bond; and
(e) E is selected from the group consisting of hydrogen, substituted or unsubstituted selected from the group consisting of (CH 2 ) n COOR19, C(R3)(R4)A, C 1 -C 6 alkyl, C 1 -C 6 allyl, aryl-C 0-4 -alkyl, thio-C 1-4 -alkyl, thioaryl, C 1-4 alkoxyaryl, C 1-4 alkoxy C 1-4 alkyl, aminoaryl, and aminoC 1-4 alkyl, and wherein
(i) n is 0, 1, 2 or 3,
(ii) A is an acidic functional group selected from the group consisting of carboxyl, C 1 -C 3 alkylnitrile, carboxamide, substituted or unsubstituted sulfonamide, substituted or unsubstituted acylsulfonamide and substituted or unsubstituted tetrazole;
(iii) R3 is H, saturated or unsaturated C 1 -C 5
alkyl, C 1 -C 5 alkoxy, and
(iv) R4 is H, halo, a substituted or
unsubstituted group selected from C 1 -C 5
alkyl, C 1 -C 5 alkoxy, C 3 -C 6 cycloalkyl, aryl C 0 -C 4 alkyl and phenyl, or R3 and R4 are combined to form a C 3 -C 4 cycloalkyl;
(v) R19 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl and optionally substituted arylmethyl;
(f) R8 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkylenyl, and halo;
(g) R9 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkylenyl, halo, substituted or unsubstituted aryl, substituted or unsubstituted aryl-C 1 -C 4 alkyl, substituted or unsubstituted heteroaryl, C 1 -C 6 allyl, and OR10; and
(h) R10 is independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl.
88 . A compound as claimed by claim 87 wherein X is C 2 -C 5 alkylene.
89 . A compound as claimed by any one of claims 87 or 88 wherein A is selected from the group consisting of COOH, and C 1 -C 3 alkylnitrile.
90 . A compound as claimed by any one of claims 87 , 88 , or 89 wherein R2 is C 1 -C 4 alkyl.
91 . A compound as claimed by any one of claims 87 , 88 , 89 , or 90 , wherein X is C 2 -C 3 alkylene.
92 . A compound as claimed by any one of claims 87 , 88 , 89 , 90 , or 91 wherein R1 is optionally substituted phenyl or benzyl.
93 . A compound as claimed by claim 32 wherein E is selected from the group consisting of hydrogen, C(R3)(R4)A, substituted or unsubstituted selected from the group consisting of (CH 2 ) n COOH, C 1 -C 6 alkyl, C 1 -C 6 allyl, aryl-C 0-4 -alkyl, thio-C 1-4 -alkyl, thioaryl, C 1-14 alkoxyaryl, C 1-4 alkoxy C 1-4 alkyl, aminoaryl, and aminoC 1-4 -alkyl.
94 . (canceled)Join the waitlist — get patent alerts
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