US2003225269A1PendingUtilityA1
Inhibitors of interleukin-1beta converting enzyme
Est. expiryDec 20, 2015(expired)· nominal 20-yr term from priority
Inventors:Mark James BatchelorDavid BebbingtonGuy BemisWolf Herman FridmanRoger John GillespieJulian GolecDavid J. LaufferDavid J. LivingstonSaroop Singh MatharuMichael D. MullicanMark A. MurckoRobert MurdochRobert E. Zelle
A61P 7/04A61P 9/00A61P 5/14A61P 7/06A61P 9/10A61P 3/10A61P 37/00A61P 37/08A61P 7/00A61P 43/00A61P 37/06A61P 35/04A61P 35/00A61P 35/02A61P 25/16A61P 3/00A61P 29/00A61P 25/28A61P 31/04A61P 25/00A61P 31/00A61P 31/18A61P 1/00A61P 1/18A61P 13/12A61P 19/00A61P 17/14A61P 1/16A61P 1/04A61P 17/02A61P 19/08A61P 17/06A61P 11/00A61P 17/00A61P 11/06A61P 17/04A61P 19/10A61P 21/04A61P 21/00A61P 19/02C07D 471/04C07K 5/0821C07D 401/06C07D 409/12C07D 405/12C07D 401/12C07D 405/14C07K 5/06139A61K 38/00C07D 243/12C07D 417/12C07D 487/04C07D 413/12C07D 403/12C07K 5/0202C07K 5/02A61K 31/55C07D 498/04
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Claims
Abstract
The present invention relates to novel classes of compounds which are inhibitors of interleukin-1β converting enzyme. The ICE inhibitors of this invention are characterized by specific structural and physicochemical features. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting ICE activity and consequently, may be advantageously used as agents against IL-1-, apoptosis-, IGIF-, and IFN-γ-mediated diseases, inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, infectious diseases, degenerative diseases, and necrotic diseases. This invention also relates to methods for inhibiting ICE activity, for treating interleukin- 1 -, apoptosis-, IGIF- and IFN-γ-mediated diseases and decreasing IGIF and IFN-γ production using the compounds and compositions of this invention. This invention also relates to methods for preparing N-acylamino compounds.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A compound represented by the formula:
wherein:
X 1 is —CH;
g is 0 or 1;
each J is independently selected from the group consisting of —H, —OH, and —F, provided that when a first and second J are bound to a C and said first J is —OH, said second J is —H;
m is 0, 1, or 2;
T is —OH, —CO—CO 2 H, —CO 2 H, or any bioisosteric replacement for —CO 2 H;
R 1 is selected from the group consisting of the following formulae, in which any ring may optionally be singly or multiply substituted at any carbon by Q 1 , at any nitrogen by R 5 , or at any atom by ═O, —OH, —CO 2 H, or halogen; and any saturated ring may optionally be unsaturated at one or two bonds;
wherein each ring C is independently chosen from the group consisting of benzo, pyrido, thieno, pyrrolo, furano, thiazolo, isothiazolo, oxazolo, isoxazolo, pyrimido, imidazolo, cyclopentyl, and cyclohexyl;
R 3 is:
—CN,
—CH═CH—R 9 ,
—CH═N—O—R 9 ,
—(CH 2 ) 1-3 —T 1 —R 9 ,
—CJ 2 —R 9 ,
—CO—R 13 , or
each R 4 is independently selected from the group consisting of:
—H,
—Ar 1 ,
—R 9 ,
—T 1 —R 9 , and
—(CH 2 ) 1,2,3 —T 1 —R 9 ;
each T 1 is independently selected from the group consisting of:
CH═CH—,
—O—,
—S—,
—SO—,
—SO 2 —,
—NR 10 —,
—NR 10 —CO—,
—CO—,
—O—CO—,
—CO—O—,
—CO—NR 10 —,
—O—CO—NR 10 —,
—NR 10 —CO—O—,
—NR 10 —CO—NR 10 —,
—SO 2 —NR 10 —,
—NR 10 —SO 2 —, and
—NR 10 —SO 2 —NR 10 —;
each R 5 is independently selected from the group consisting of:
—H,
—Ar 1 ,
—CO—Ar 1 ,
—SO 2 —Ar 1 ,
—CO—NH 2 ,
—SO 2 —NH 2 ,
—R 9 ,
—CO—R 9 ,
—CO—O—R 9 ,
—SO 2 —R 9 ,
and
R 6 is:
—H
—Ar 1 ,
—R 9 ,
—(CH 2 ) 1,2,3 —T 1 —R 9 , or
an α-amino acid side chain residue;
each R 9 is a C 1-6 straight or branched alkyl group optionally singly or multiply substituted with —OH, —F, or ═O and optionally substituted with one or two Ar 1 groups;
each R 10 is independently selected from the group consisting of —H or a C 1-6 straight or branched alkyl group;
each R 13 is independently selected from the group consisting of —Ar 2 , —R 4 and
each Ar 1 is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings, a cycloalkyl group which contains between 3 and 15 carbon atoms and between 1 and 3 rings, said cycloalkyl group being optionally benzofused, and a heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocycle group containing at least one heteroatom group selected from —O—, —S—, —SO—, —SO 2 —, ═N—, and —NH—, said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted with —NH 2 , —CO 2 H,
—Cl, —F, —Br, —I, —NO 2 , —CN, ═O, —OH, -perfluoro C 1-3 alkyl,
or —Q 1 ;
each Ar 2 is independently selected from the following group, in which any ring may optionally be singly or multiply substituted by —Q 1 and —Q 2 :
each Q 1 is independently selected from the group consisting of:
—Ar 1
—O—Ar 1
—R 9 ,
—T 1 —R 9 , and
—(CH 2 ) 1,2,3 —T 1 —R 9 ;
each Q 2 is independently selected from the group consisting of —OH, —NH 2 , —CO 2 H, —Cl, —F, —Br, —I,
—NO 2 , —CN, —CF 3 , and
provided that when —Ar 1 is substituted with a Q 1 group which comprises one or more additional —Ar 1 groups, said additional —Ar 1 groups are not substituted with Q 1 ;
each X is independently selected from the group consisting of ═N—, and ═CH—;
each X 2 is independently selected from the group consisting of —O—, —CH 2 —, —NH—, —S—, —SO—, and —SO 2 —;
each Y is independently selected from the group consisting of —O—, —S—, and —NH;
provided that when
g is 0,
J is —H,
m is 1,
T is —CO 2 H,
X 2 is O,
R 5 is benzyloxycarbonyl, and
ring C is benzo,
then R 3 cannot be —CO—R 13 when:
R 13 is —CH 2 —O—Ar 1 and
Ar 1 is 1-phenyl-3-triflucromethylpyrazole-5-yl wherein the phenyl is optionally substituted with a chlorine atom;
or when
R 13 is —CH 2 —O—CO—Ar 1 , wherein
Ar 1 is 2,6-dichlorophenyl.
2 . The compound according to claim 1 , wherein:
X 1 is —CH; g is 0; J is —H; m is 0 or 1 and T is —CO—CO 2 H, or any bioisosteric replacement for —CO 2 H, or m is 1 and T is —CO 2 H; ring C is benzo optionally substituted with —C 1-3 alkyl, —O—C 1-13 alkyl, —Cl, —F or —CF 3 ; R 5 is:
—CO—Ar 1
—SO 2 —Ar 1 ,
—CO—NH 2 ,
—CO—NH—Ar 1
—CO—R 9 ,
—CO—O—R 9
—SO 2 —R 9 , or
—CO—NH—R 9 ,
R 7 is —H and R 6 is: —H,
—R 9 , or
—Ar 1 ;
R 9 is a C 1-6 straight or branched alkyl group optionally substituted with ═O and optionally substituted with —Ar 1 ; R 10 is H or a —C 1-3 straight or branched alkyl group; Ar 1 is phenyl, naphthyl, pyridyl, benzothiazolyl, thienyl, benzothienyl, benzoxazolyl, 2-indanyl, or indolyl optionally substituted with —O—C 1-3 alkyl,
—NH—C 1-3 alkyl, —N—(C 1-3 alkyl) 2 , —Cl, —F, —CF 3 ,
—C 1-3 alkyl, or
Q 1 is R 9 or —(CH 2 ) 0,1,2 —T 1 —(CH 2 ) 0,1,2 —Ar 1 , wherein T 1 is —O— or —S—; each X is independently selected from the group consisting of ═N—, and ═CH—; each X 2 is independently selected from the group consisting of —O—, —CH 2 —, —NH—, —S—, —SO—, and —SO 2 —.
3 . The compound according to claim 1 or 2 , wherein the R 1 group is:
wherein
X 2 is:
—O—,
—S—,
—SO 2 —, or
—NH—;
optionally substituted with R 5 or Q 1 at X 2 when X 2 is —NH—; and
ring C is benzo substituted with —C 1-3 alkyl, —O—C 1-3 alkyl, —Cl, —F or —CF 3 .
4 . A compound represented by the formula:
wherein:
R 1 is selected from the group consisting of the following formulae:
ring C is chosen from the group consisting of benzo, pyrido, thieno, pyrrolo, furano, thiazolo, isothiazolo, oxazolo, isoxazolo, pyrimido, imidazolo, cyclopentyl, and cyclohexyl;
R 2 is:
m is 1 or 2;
R 5 is selected from the group consisting of:
—C(O)—R 10 ,
—C(O)O—R 9 ,
—S(O) 2 —R 9 ,
—C(O)—CH 2 —O—R 9 ,
—C(O)C(O)—R 10 ,
—R 9 ,
—H, and
—C(O)C(O)—OR 10 ;
Y 2 is H 2 or O;
X 7 is —N(R 8 )— or —O—;
R 6 is selected from the group consisting of —H and —CH 3 ;
R 8 is selected from the group consisting of:
—C(O)—R 10 ,
—C(O)O—R 9 ,
—C(O)—N(H)—R 10 ,
—S(O) 2 —R 9 ,
—S(O) 2 —NH—R 10 ,
—C(O)—CH 2 —OR 10 ,
—C(O)C(O)—R 10 ;
—C(O)—CH 2 N(R 10 )(R 10 ),
—C(O)—CH 2 C(O)—O—R 9 ,
—C(O)—CH 2 C(O)—R 9 ,
—H, and
—C(O)—C(O)—OR 10 ;
each R 9 is independently selected from the group consisting of —Ar 3 and a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein the —C 1-6 alkyl group is optionally unsaturated;
each R 10 is independently selected from the group consisting of —H, —Ar 3 , a —C 3-6 cycloalkyl group, and a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein the —C 1-6 alkyl group is optionally unsaturated;
R 13 is selected from the group consisting of H, Ar 3 , and a C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , —CONH 2 , —OR 5 , —OH,
—OR 9 , or —CO 2 H;
each R 51 is independently selected from the group consisting of R 9 , —C(O)—R 9 , —C(O)—N(H)—R 9 , or each R 51 taken together forms a saturated 4-8 member carbocyclic ring or heterocyclic ring containing —O—, —S—, or —NH—;
each R 21 is independently selected from the group consisting of —H or a —C 1-6 straight or branched alkyl group;
each Ar 3 is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings and an aromatic heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocyclic group containing at least one heteroatom group selected from —O—, —S—, —SO—, SO 2 , ═N—, and —NH—, said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by —Q 1 ;
each Q 1 is independently selected from the group consisting of —NH 2 , —CO 2 H, —Cl, —F, —Br, —I, —NO 2 , —CN, ═O, —OH, -perfluoro C 1-3 alkyl, R 5 , —OR 5 , —NHR 5 , —OR 9 ,
—NHR 9 , —R 9 , —C(O)—R 10 , and
provided that when —Ar 3 is substituted with a Q 1 group which comprises one or more additional —Ar 3 groups, said additional —Ar 3 groups are not substituted with another —Ar 3 .
5 . The compound according to claim 4 , wherein R 5 is selected from the group consisting of:
—C(O)—R 10 , —C(O)O—R 9 , and —C(O)—NH—R 10 .
6 . The compound according to claim 4 , wherein R 5 is selected from the group consisting of:
—S(O) 2 —R 9 , —S(O) 2 —NH—R 10 , —C(O)—C(O)—R 10 , —R 9 , and —C(O)—C(O)—OR 10 .
7 . The compound according to claim 5 or 6 , wherein:
m is 1;
R 13 is H or a C 1-4 straight or branched alkyl group optionally substituted with —Ar 3 , —OH, —OR 9 , —CO 2 H, wherein the R 9 is a C 1-4 branched or straight chain alkyl group; wherein Ar 3 is morpholinyl or phenyl, wherein the phenyl is optionally substituted with Q 1 ;
R 21 is —H or —CH 3 ;
R 51 is a C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein Ar 3 is phenyl, optionally substituted by —Q 1 ;
each Ar 3 cyclic group is independently selected from the set consisting of phenyl, naphthyl, thienyl, quinolinyl, isoquinolinyl, pyrazolyl, thiazolyl, isoxazolyl, benzotriazolyl, benzimidazolyl, thienothienyl, imidazolyl, thiadiazolyl, benzo[b]thiophenyl, pyridyl, benzofuranyl, and indolyl, and said cyclic group optionally being singly or multiply substituted by —Q 1 ;
each Q 1 is independently selected from the group consisting of —NH 2 , —Cl, —F, —Br, —OH, —R 9 , —NH—R 5 wherein R 5 is —C(O)—R 10 or —S(O) 2 —R 9 , —OR 5 wherein R 5 is —C(O)—R 10 , —OR 9 , —NHR 9 , and
wherein each R 9 and R 10 are independently a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 wherein Ar 3 is phenyl;
provided that when —Ar 3 is substituted with a Q 1 group which comprises one or more additional —Ar 3 groups, said additional —Ar 3 groups are not substituted with another —Ar 3 .
8 . A compound represented by the formula:
wherein:
m is 1 or 2;
R 1 is selected from the group consisting of the following formulae:
ring C is chosen from the group consisting of benzo, pyrido, thieno, pyrrolo, furano, thiazolo, isothiazolo, oxazolo, isoxazolo, pyrimido, imidazolo, cyclopentyl, and cyclohexyl;
R 3 is selected from the group consisting of:
—CN,
—C(O)—H,
—C(O)—CH 2 —T 1 —R 11 ,
—C(O)—CH 2 —F,
—C═N—O—R 9 , and
—CO—Ar 2 ;
R 5 is selected from the group consisting of:
—C(O)—R 10 ,
—C(O)O—R 9 ,
—S(O) 2 —R 9 ,
—C(O)—CH 2 —O—R 9 ,
—C(O)C(O)—R 10 ,
—R 9 ,
—H, and
—C(O)C(O)—OR 10 ,
Y 2 is H 2 or O;
X 7 is —N(R 8 )— or —O—;
each T 1 is independently selected from the group consisting of —O—, —S—, —S(O)—, and —S(O) 2 —;
R 6 is selected from the group consisting of —H and —CH 3 ;
R 8 is selected from the group consisting of:
—C(O)—R 10 ,
—C(O)O—R 9 ,
—C(O)—NH—R 10 ,
—S(O) 2 —R 9 ,
—S(O) 2 —NH—R 10 ,
—C(O)—CH 2 —OR 10 ,
—C(O)C(O)—R 10 ,
—C(O)—CH 2 —N(R 10 )(R 10 ),
—C(O)—CH 2 C(O)—O—R 9 ,
—C(O)—CH 2 C(O)—R 9 ,
—H, and
—C(O)—C(O)—OR 10 ;
each R 9 is independently selected from the group consisting of —Ar 3 and a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein the —C 1-6 alkyl group is optionally unsaturated;
each R 10 is independently selected from the group consisting of —H, —Ar 3 , a —C 3-6 cycloalkyl group, and a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein the —C 1-6 alkyl group is optionally unsaturated;
each R 11 is independently selected from the group consisting of:
—Ar 4 ,
—(CH 2 ) 1-3 —Ar 4 ,
—H, and
—C(O)—Ar 4 ;
R 13 is selected from the group consisting of H,
Ar 3 , and a C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , —CONH 2 , —OR 5 , —OH, —OR 9 , or —CO 2 H;
OR 13 is optionally —N(H)—OH;
each R 21 is independently selected from the group consisting of —H or a —C 1-6 straight or branched alkyl group;
Ar 2 is independently selected from the following group, in which any ring may optionally be singly or multiply substituted by —Q 1 or phenyl, optionally substituted by Q 1 :
wherein each Y is independently selected from the group consisting of O and S;
each Ar 3 is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings and an aromatic heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocyclic group containing at least one heteroatom group selected from —O—, —S—, —SO—, SO 2 , ═N—, and —NH—, —N(R 5 )—, and —N(R 9 )— said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by —Q 1 ;
each Ar 4 is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings, and a heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocyclic group containing at least one heteroatom group selected from —O—, —S—, —SO—, SO 2 , ═N—, —NH—, —N(R 5 )—, and —N(R 9 )— said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by —Q 1 ;
each Q 1 is independently selected from the group consisting of —NH 2 , —CO 2 H, —Cl, —F, —Br, —I, —NO 2 , —CN, ═O, —OH, -perfluoro C 1-3 alkyl, R 5 , —OR 5 , —NHR 5 , —OR 9 , —NHR 9 , —R 9 , —C(O)—R 10 , and
provided that when —Ar 3 is substituted with a Q 1 group which comprises one or more additional —Ar 3 groups, said additional —Ar 3 groups are not substituted with another —Ar 3 .
9 . The compound according to claim 8 , wherein R 1 is (e11).
10 . The compound according to claim 8 , wherein R 1 is (e12).
11 . The compound according to claim 8 , wherein R 1 is (y1).
12 . The compound according to claim 8 , wherein R 1 is (y2).
13 . The compound according to claim 8 , wherein and R 1 is (z).
14 . The compound according to claim 8 , wherein R 1 is (w2).
15 . The compound according to claim 14 , wherein:
m is 1; ring C is benzo, pyrido, or thieno; R 3 is selected from the group consisting of —C(O)—H, —C(O)—Ar 2 , and —C(O)CH 2 —T 1 —R 11 ; R 5 is selected from the group consisting of:
—C(O)—R 10 , wherein R 10 is —Ar 3 ;
—C(O)O—R 9 , wherein R 9 is —CH 2 —Ar 3 ;
—C(O)C(O)—R 10 , wherein R 10 is —Ar 3 ;
—R 9 , wherein R 9 is a C 1-2 alkyl group substituted with —Ar 3 ; and
—C(O)C(O)—OR 10 , wherein R 10 is —CH 2 Ar 3 ;
T 1 is O or S; R 6 is H; R 8 is selected from the group consisting —C(O)—R 10 , —C(O)—CH 2 —OR 10 , and —C(O)CH 2 —N(R 10 )(R 10 ), wherein R 10 is H, CH 3 , or —CH 2 CH 3 ; R 11 is selected from the group consisting of —Ar 4 , —(CH 2 ) 1-3 —Ar 4 , and —C(O)—Ar 4 ; R 13 is H or a C 1-4 straight or branched alkyl group optionally substituted with —Ar 3 , —OH, —OR 9 , —CO 2 H, wherein the R 9 is a C 1-4 branched or straight chain alkyl group; wherein Ar 3 is morpholinyl or phenyl, wherein the phenyl is optionally substituted with Q 1 ; Ar 2 is (hh); Y is O; each Ar 3 cyclic group is independently selected from the set consisting of phenyl, naphthyl, thienyl, quinolinyl, isoquinolinyl, thiazolyl, benzimidazolyl, thienothienyl, thiadiazolyl, benzotriazolyl, benzo[b]thiophenyl, benzofuranyl, and indolyl, and said cyclic group optionally being singly or multiply substituted by —Q 1 ; each Ar 4 cyclic group is independently selected from the set consisting of phenyl, tetrazolyl, naphthyl, pyridinyl, oxazolyl, pyrimidinyl, and indolyl, and said cyclic group optionally being singly or multiply substituted by —Q 1 ; each Q 1 is independently selected from the group consisting of —NH 2 , —Cl, —F, —Br, —OH, —R 9 , —NH—R 5 wherein R 5 is —C(O)—R 10 or —S(O) 2 —R 9 , —OR 5 wherein R 5 is —C(O)—R 10 , —OR 9 , —NHR 9 , and wherein each R 9 and R 10 are independently a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 wherein Ar 3 is phenyl;
provided that when —Ar 3 is substituted with a Q 1 group which comprises one or more additional —Ar 3 groups, said additional —Ar 3 groups are not substituted with another —Ar 3 .
16 . The compound according to claim 8 , wherein R 1 is (e10) and X 5 is N.
17 . The compound according to claim 16 , wherein R 3 is CO—Ar 2 .
18 . The compound according to claim 16 , wherein R 3 is —C(O)—CH 2 —T 1 —R 11 and R 11 is —(CH 2 ) 1-3 —Ar 4 .
19 . The compound according to claim 16 , wherein:
R 3 is —C(O)—CH 2 —T 1 —R 11 ; T 1 is O; and R 11 is —C(O)—Ar 4 .
20 . The compound according to claim 16 , wherein R 3 is —C(O)—H.
21 . The compound according to claim 16 , wherein R 3 is —CO—CH 2 —T 1 —R 11 and R 11 is —Ar 4 .
22 . The compound according to any one of claims 19 - 21 , wherein R 5 is selected from the group consisting of:
—C(O)—R 0 o, —C(O)O—R 9 , and —C(O)—NH—R 10 .
23 . The compound according to claim 22 , wherein:
m is 1; T 1 is O or S,
provided that when R 3 is —C(O)—CH 2 —T 1 —R 11 , T 1 is O;
R 13 is H or a C 1-4 straight or branched alkyl group optionally substituted with —Ar 3 , —OH, —OR 9 , —CO 2 H, wherein the R 9 is a C 1-4 branched or straight chain alkyl group; wherein Ar 3 is morpholinyl or phenyl, wherein the phenyl is optionally substituted with Q 1 ; R 21 is —H or —CH 3 ; Ar 2 is (hh); Y is O; each Ar 3 cyclic group is independently selected from the set consisting of phenyl, naphthyl, thienyl, quinolinyl, isoquinolinyl, pyrazolyl, thiazolyl, isoxazolyl, benzotriazolyl, benzimidazolyl, thienothienyl, imidazolyl, thiadiazolyl, benzo[b]thiophenyl, pyridyl, benzofuranyl, and indolyl, and said cyclic group optionally being singly or multiply substituted by —Q 1 ; each Ar 4 cyclic group is independently selected from the set consisting of phenyl, tetrazolyl, pyridinyl, oxazolyl, naphthyl, pyrimidinyl, and thienyl, and said cyclic group optionally being singly or multiply substituted by —Q 1 ; each Q 1 is independently selected from the group consisting of —NH 2 , —Cl, —F, —Br, —OH, —R 9 , —NH—R 5 wherein R 5 is —C(O)—R 10 or —S(O) 2 —R 9 , —OR 5 wherein R 5 is —C(O)—R 10 , —OR 9 , —NHR 9 , and wherein each R 9 and R 10 are independently a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 wherein Ar 3 is phenyl;
provided that when —Ar 3 is substituted with a Q 1 group which comprises one or more additional —Ar 3 groups, said additional —Ar 3 groups are not substituted with another —Ar 3 .
24 . The compound according to any one of claims 19 - 21 , wherein R 5 is selected from the group consisting of:
—S(O) 2 —R 9 , —S(O) 2 —NH—R 10 , —C(O)—C(O)—R 10 , —R 9 , and —C(O)—C(O)—OR 10 .
25 . The compound according to claim 24 , wherein:
m is 1; T 1 is O or S,
provided that when R 3 is —C(O)—CH 2 —T 1 —R 11 , T 1 is O;
R 13 is H or a C 1-4 straight or branched alkyl group optionally substituted with —Ar 3 , —OH, —OR 9 , —CO 2 H, wherein the R 9 is a C 1-4 branched or straight chain alkyl group; wherein Ar 3 is morpholinyl or phenyl, wherein the phenyl is optionally substituted with Q 1 ; R 21 is —H or —CH 3 ; Ar 2 is (hh); Y is O; each Ar 3 cyclic group is independently selected from the set consisting of phenyl, naphthyl, thienyl, quinolinyl, isoquinolinyl, pyrazolyl, thiazolyl, isoxazolyl, benzotriazolyl, benzimidazolyl, thienothienyl, imidazolyl, thiadiazolyl, benzo[b]thiophenyl, pyridyl, benzofuranyl, and indolyl, and said cyclic group optionally being singly or multiply substituted by —Q 1 ; each Ar 4 cyclic group is independently selected from the set consisting of phenyl, tetrazolyl, pyridinyl, oxazolyl, naphthyl, pyrimidinyl, and thienyl, and said cyclic group optionally being singly or multiply substituted by —Q 1 ; each Q 1 is independently selected from the group consisting of —NH 2 , —Cl, —F, —Br, —OH, —R 9 , —NH—R 5 wherein R 5 is —C(O)—R 10 or —S(O) 2 —R 9 , —OR 5 wherein R 5 is —C(O)—R 10 , —OR 9 , —NHR 9 , and wherein each R 9 and R 10 are independently a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 wherein Ar 3 is phenyl;
provided that when —Ar 3 is substituted with a Q 1 group which comprises one or more additional —Ar 3 groups, said additional —Ar 3 groups are not substituted with another —Ar 3 .
26 . A compound represented by the formula:
wherein:
m is 1 or 2;
R 1 is:
R 3 is —CO—Ar 2 ;
R 5 is selected from the group consisting of:
—C(O)—R 10 ,
—C(O)O—R 9 ,
—S(O) 2 —R 9 ,
—C(O)—CH 2 —O—R 9 ,
—C(O)C(O)—R 10 ,
—R 9 ,
—H, and
—C(O)C(O)—OR 10 ,
X 5 is CH;
Y 2 is H 2 or O;
each R 9 is independently selected from the group consisting of —Ar 3 and a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein the —C 1-6 alkyl group is optionally unsaturated;
each R 10 is independently selected from the group consisting of —H, —Ar 3 , a —C 3-6 cycloalkyl group, and a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein the —C 1-6 alkyl group is optionally unsaturated;
R 13 is selected from the group consisting of H,
Ar 3 , and a C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , —CONH 2 , —OR 5 , —OH,
—OR 9 , or —CO 2 H;
OR 13 is optionally —N(H)—OH;
each R 21 is independently selected from the group consisting of —H or a —C 1-6 straight or branched alkyl group;
Ar 2 is independently selected from the following group, in which any ring may optionally be singly or multiply substituted by —Q 1 or phenyl, optionally substituted by Q 1 :
wherein each Y is independently selected from the group consisting of O and S;
each Ar 3 is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings and an aromatic heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocyclic group containing at least one heteroatom group selected from —O—, —S—, —SO—, SO 2 , ═N—, and —NH—, —N(R 5 )—, and —N(R 9 )— said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by —Q 1 ;
each Ar 4 is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings, and a heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocyclic group containing at least one heteroatom group selected from —O—, —S—, —SO—, SO 2 , ═N—, —NH—, —N(R 5 )—, and —N(R 9 )— said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by —Q 1 ; each Q 1 is independently selected from the group consisting of —NH 2 , —CO 2 H, —Cl, —F, —Br, —T, —NO 2 , —CN, ═O, —OH, -perfluoro C 1-3 alkyl, R 5 , —OR 5 , —NHR 5 , —OR 9 , —NHR 9 , —R 9 , —C(O)—R 10 , and
provided that when —Ar 3 is substituted with a Q 1 group which comprises one or more additional —Ar 3 groups, said additional —Ar 3 groups are not substituted with another —Ar 3 .
27 . A compound represented by the formula:
wherein:
m is 1 or 2;
R 1 is:
R 3 is —C(O)—CH 2 —T 1 —R 11 and R 11 is —(CH 2 ) 1-3 —Ar 4 ;
R 5 is selected from the group consisting of:
—C(O)—R 10 ,
—C(O)O—R 9 ,
—S(O) 2 —R 9 ,
—C(O)—CH 2 —O—R 9 ,
—C(O)C(O)—R 10 ,
—R 9 ,
—H, and
—C(O)C(O)—OR 10 ,
X 5 is CH;
Y 2 is H 2 or O;
each T 1 is independently selected from the group consisting of —O—, —S—, —S(O)—, and —S(O) 2 —;
each R 9 is independently selected from the group consisting of —Ar 3 and a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein the —C 1-6 alkyl group is optionally unsaturated;
each R 10 is independently selected from the group consisting of —H, —Ar 3 , a —C 3-6 cycloalkyl group, and a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein the —C 1-6 alkyl group is optionally unsaturated;
R 13 is selected from the group consisting of H,
Ar 3 , and a C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , —CONH 2 , —OR 5 , —OH, —OR 9 , or —CO 2 H;
OR 13 is optionally —N(H)—OH;
each R 21 is independently selected from the group consisting of —H or a —C 1-6 straight or branched alkyl group;
each Ar 3 is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings and an aromatic heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocyclic group containing at least one heteroatom group selected from —O—, —S—, —SO—, SO 2 , ═N—, and —NH—, —N(R 5 )—, and —N(R 9 )— said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by —Q 1 ;
each Ar 4 is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings, and a heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocyclic group containing at least one heteroatom group selected from —O—, —S—, —SO—, SO 2 , ═N—, —NH—, —N(R 5 )—, and —N(R 9 )— said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by —Q 1 ;
each Q 1 is independently selected from the group consisting of —NH 2 , —CO 2 H, —Cl, —F, —Br, —I, —NO 2 , —CN, ═O, —OH, -perfluoro C 1-3 alkyl, —R 5 , —OR 5 , —NHR 5 , —OR 9 , —NHR 9 , —R 9 , —C(O)—R 10 , and
provided that when —Ar 3 is substituted with a Q 1 group which comprises one or more additional —Ar 3 groups, said additional —Ar 3 groups are not substituted with another —Ar 3 .
28 . The compound according to claim 26 or 27 , wherein R 5 is selected from the group consisting of:
—C(O)—R 10 ,
—C(O)O—R 9 , and
—C(O)—NH—R 10 .
29 . The compound according to claim 28 , wherein:
m is 1; T 1 is O or S; R 13 is H or a C 1-4 straight or branched alkyl group optionally substituted with —Ar 3 , —OH, —OR 9 , —CO 2 H, wherein the R 9 is a C 1-4 branched or straight chain alkyl group; wherein Ar 3 is morpholinyl or phenyl, wherein the phenyl is optionally substituted with Q 1 ; R 21 is —H or —CH 3 ; Ar 2 is (hh); Y is O; each Ar 3 cyclic group is independently selected from the set consisting of phenyl, naphthyl, thienyl, quinolinyl, isoquinolinyl, pyrazolyl, thiazolyl, isoxazolyl, benzotriazolyl, benzimidazolyl, thienothienyl, imidazolyl, thiadiazolyl, benzo[b]thiophenyl, pyridyl, benzofuranyl, and indolyl, and said cyclic group optionally being singly or multiply substituted by —Q 1 ; each Ar 4 cyclic group is independently selected from the set consisting of phenyl, tetrazolyl, pyridinyl, oxazolyl, naphthyl, pyrimidinyl, and thienyl, and said cyclic group optionally being singly or multiply substituted by —Q 1 ; each Q 1 is independently selected from the group consisting of —NH 2 , —Cl, —F, —Br, —OH, —R 9 , —NH—R 5 wherein R 5 is —C(O)—R 10 or —S(O) 2 —R 9 , —OR 5 wherein R 5 is —C(O)—R 10 , —OR 9 , —NHR 9 , and wherein each R 9 and R 10 are independently a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 wherein Ar 3 is phenyl;
provided that when —Ar 3 is substituted with a Q 1 group which comprises one or more additional —Ar 3 groups, said additional —Ar 3 groups are not substituted with another —Ar 3 .
30 . The compound according to claim 26 or 27 , wherein R 5 is selected from the group consisting of:
—S(O) 2 —R 9 ,
—S(O) 2 —NH—R 10 ,
—C(O)—C(O)—R 10 ,
—R 9 , and
—C(O)—C(O)—OR 10 .
31 . The compound according to claim 30 , wherein:
m is 1; T 1 is O or S; R 13 is H or a C 1-4 straight or branched alkyl group optionally substituted with —Ar 3 , —OH, —OR 9 , —CO 2 H, wherein the R 9 is a C 1-4 branched or straight chain alkyl group; wherein Ar 3 is morpholinyl or phenyl, wherein the phenyl is optionally substituted with Q 1 ; R 21 is —H or —CH 3 ; Ar 2 is (hh); Y is O; each Ar 3 cyclic group is independently selected from the set consisting of phenyl, naphthyl, thienyl, quinolinyl, isoquinolinyl, pyrazolyl, thiazolyl, isoxazolyl, benzotriazolyl, benzimidazolyl, thienothienyl, imidazolyl, thiadiazolyl, benzo[b]thiophenyl, pyridyl, benzofuranyl, and indolyl, and said cyclic group optionally being singly or multiply substituted by —Q 1 ; each Ar 4 cyclic group is independently selected from the set consisting of phenyl, tetrazolyl, pyridinyl, oxazolyl, naphthyl, pyrimidinyl, and thienyl, and said cyclic group optionally being singly or multiply substituted by —Q 1 ; each Q 1 is independently selected from the group consisting of —NH 2 , —Cl, —F, —Br, —OH, —R 9 , —NH—R 5 wherein R 5 is —C(O)—R 10 or —S(O) 2 —R 9 , —OR 5 wherein R 5 is —C(O)—R 10 , —OR 9 , —NHR 9 , and wherein each R 9 and R 10 are independently a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 wherein Ar 3 is phenyl;
provided that when —Ar 3 is substituted with a group which comprises one or more additional —Ar 3 groups, said additional —Ar 3 groups are not substituted with another —Ar 3 .
32 . A compound represented by the formula:
wherein:
m is 1 or 2;
R 1 is:
R 3 is —C(O)—CH 2 —T 1 —R 11 ; T 1 is O; and R 11 is —C(O)—Ar 4 ;
R 5 is selected from the group consisting of:
—S(O) 2 —R 9 ,
—S(O) 2 —NH—R 10 ,
—C(O)—C(O)—R 10 ,
—R 9 , and
—C(O)—C(O)—OR 10 ;
X 5 is CH;
Y 2 is H 2 or O;
each R 9 is independently selected from the group consisting of —Ar 3 and a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein the —C 1-6 alkyl group is optionally unsaturated;
each R 10 is independently selected from the group consisting of —H, —Ar 3 , a —C 3-6 cycloalkyl group, and a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein the —C 1-6 alkyl group is optionally unsaturated;
R 13 is selected from the group consisting of H, Ar 3 , and a C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , —CONH 2 , —OR 5 , —OH,
—OR 9 , or —CO 2 H;
OR 13 is optionally —N(H)—OH;
each R 21 is independently selected from the group consisting of —H or a —C 1-6 straight or branched alkyl group;
each Ar 3 is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings and an aromatic heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocyclic group containing at least one heteroatom group selected from —O—, —S—, —SO—, SO 2 , ═N—, and —NH—, —N(R 5 )—, and —N(R 9 )— said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by —Q 1 ;
each Ar 4 is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings, and a heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocyclic group containing at least one heteroatom group selected from —O—, —S—, —SO 2 , ═N—, —NH—, —N(R 5 )—, and —N(R 9 )— said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by —Q 1 ;
each Q 1 is independently selected from the group consisting of —NH 2 , —CO 2 H, —Cl, —F, —Br, —I, —NO 2 , —CN, ═O, —OH, -perfluoro C 1-3 alkyl, R 5 , —OR 5 , —NHR 5 , —OR 9 , —NHR 9 , —R 9 , —C(O)—R 10 , and
provided that when —Ar 3 is substituted with a Q 1 group which comprises one or more additional —Ar 3 groups, said additional —Ar 3 groups are not substituted with another —Ar 3 .
33 . A compound represented by the formula:
wherein:
m is 1 or 2;
R 1 is:
R 3 is —C(O)—H;
R 5 is selected from the group consisting of:
—S(O) 2 —R 9 ,
—S(O) 2 —NH—R 10 ,
—C(O)—C(O)—R 10 ,
—R 9 , and
—C(O)—C(O)—OR 10 ;
X 5 is CH;
Y 2 is H 2 or O;
each R 9 is independently selected from the group consisting of —Ar 3 and a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein the —C 1-6 alkyl group is optionally unsaturated;
each R 10 is independently selected from the group consisting of —H, —Ar 3 , a —C 3-6 cycloalkyl group, and a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein the —C 1-6 alkyl group is optionally unsaturated;
R 13 is selected from the group consisting of H,
Ar 3 , and a C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , —CONH 2 , —OR 5 , —OH,
—OR 9 , or —CO 2 H;
OR 13 is optionally —N(H)—OH;
each R 21 is independently selected from the group consisting of —H or a —C 1-6 straight or branched alkyl group;
each Ar 3 is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings and an aromatic heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocyclic group containing at least one heteroatom group selected from —O—, —S—, —SO—, SO 2 , ═N—, and —NH—, —N(R 5 )—, and —N(R 9 )— said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by —Q 1 ;
each Q 1 is independently selected from the group consisting of —NH 2 , —CO 2 H, —Cl, —F, —Br, —I, —NO 2 , —CN, ═O, —OH, -perfluoro C 1-3 alkyl, R 5 , —OR 5 , —NHR 5 , —OR 9 , —NHR 9 , —R 9 , —C(O)—R 10 , and
provided that when —Ar 3 is substituted with a Q 1 group which comprises one or more additional —Ar 3 groups, said additional —Ar 3 groups are not substituted with another —Ar 3 .
34 . The compound according to claim 32 or 33 , wherein:
m is 1;
R 13 is H or a C 1-4 straight or branched alkyl group optionally substituted with —Ar 3 , —OH, —OR 9 , —CO 2 H, wherein the R 9 is a C 1-4 branched or straight chain alkyl group; wherein Ar 3 is morpholinyl or phenyl, wherein the phenyl is optionally substituted with Q 1 ;
R 21 is —H or —CH 3 ;
each Ar 3 cyclic group is independently selected from the set consisting of phenyl, naphthyl, thienyl, quinolinyl, isoquinolinyl, pyrazolyl, thiazolyl, isoxazolyl, benzotriazolyl, benzimidazolyl, thienothienyl, imidazolyl, thiadiazolyl, benzo[b]thiophenyl, pyridyl, benzofuranyl, and indolyl, and said cyclic group optionally being singly or multiply substituted by —Q 1 ;
each Ar 4 cyclic group is independently selected from the set consisting of phenyl, tetrazolyl, pyridinyl, oxazolyl, naphthyl, pyrimidinyl, and thienyl, and said cyclic group optionally being singly or multiply substituted by —Q 1 ;
each Q 1 is independently selected from the group consisting of —NH 2 , —Cl, —F, —Br, —OH, —R 9 , —NH—R 5 wherein R 5 is —C(O)—R 10 or —S(O) 2 —R 9 , —OR 5 wherein R 5 is —C(O)—R 10 , —OR 9 , —NHR 9 , and
wherein each R 9 and R 10 are independently a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 wherein Ar 3 is phenyl;
provided that when —Ar 3 is substituted with a Q 1 group which comprises one or more additional —Ar 3 groups, said additional —Ar 3 groups are not substituted with another —Ar 3 .
35 . A compound represented by the formula:
wherein:
m is 1;
R 1 is:
R 3 is —CO—CH 2 —T 1 —R 11 and R 11 is —Ar 4 ;
R 5 is selected from the group consisting of:
—C(O)—R 10 ,
—C(O)O—R 9 , and
—C(O)—NH—R 10 ;
X 5 is CH;
Y 2 is O;
T 1 is O or S;
each R 9 is independently selected from the group consisting of —Ar 3 and a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein is the —C 1-6 alkyl group is optionally unsaturated;
each R 10 is independently selected from the group consisting of —H, —Ar 3 , a —C 3-6 cycloalkyl group, and a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein the —C 1-6 alkyl group is optionally unsaturated;
R 13 is H or a C 1-4 straight or branched alkyl group optionally substituted with —Ar 3 , —OH, —OR 9 , —CO 2 H, wherein the R 9 is a C 1-4 branched or straight chain alkyl group; wherein Ar 3 is morpholinyl or phenyl, wherein the phenyl is optionally substituted with Q 1 ;
R 21 is —H or —CH 3 ;
each Ar 3 cyclic group is independently selected from the set consisting of phenyl, naphthyl, thienyl, quinolinyl, isoquinolinyl, pyrazolyl, thiazolyl, isoxazolyl, benzotriazolyl, benzimidazolyl, thienothienyl, imidazolyl, thiadiazolyl, benzo[b]thiophenyl, pyridyl, benzofuranyl, and indolyl, and said cyclic group optionally being singly or multiply substituted by —Q 1 ;
each Ar 4 cyclic group is independently selected from the set consisting of phenyl, tetrazolyl, pyridinyl, oxazolyl, naphthyl, pyrimidinyl, and thienyl, and said cyclic group optionally being singly or multiply substituted by —Q 1 ;
each Q 1 is independently selected from the group consisting of —NH 2 , —Cl, —F, —Br, —OH, —R 9 , —NH—R 5 wherein R 5 is —C(O)—R 10 or —S(O) 2 —R 9 , —OR 5 wherein R 5 is —C(O)—R 10 , —OR 9 , —NHR 9 , and
wherein each R 9 and R 10 are independently a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 wherein Ar 3 is phenyl;
provided that when —Ar 3 is substituted with a Q 1 group which comprises one or more additional —Ar 3 groups, said additional —Ar 3 groups are not substituted with another —Ar 3 .
36 . A compound represented by the formula:
wherein:
m is 1;
R 1 is:
R 3 is —CO—CH 2 —T 1 —R 11 and R 11 is —Ar 4 ;
R 5 is selected from the group consisting of:
—S(O) 2 —R 9 ,
—S(O) 2 —NH—R 10 ,
—(O)—C(O)—R 10 ,
—R 9 , and
—C(O)—C(O)—OR 10 ;
X 5 is CH;
Y 2 is O;
T 1 is O or S;
each R 9 is independently selected from the group consisting of —Ar 3 and a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein the —C 1-6 alkyl group is optionally unsaturated;
each R 10 is independently selected from the group consisting of —H, —Ar 3 , a —C 3-6 cycloalkyl group, and a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein the —C 1-6 alkyl group is optionally unsaturated;
R 13 is H or a C 1-4 straight or branched alkyl group optionally substituted with —Ar 3 , —OH, —OR 9 , —CO 2 H, wherein the R 9 is a C 1-4 branched or straight chain alkyl group; wherein Ar 3 is morpholinyl or phenyl, wherein the phenyl is optionally substituted with Q 1 ;
R 21 is —H or —CH 3 ;
each Ar 3 cyclic group is independently selected from the set consisting of phenyl, naphthyl, thienyl, quinolinyl, isoquinolinyl, pyrazolyl, thiazolyl, isoxazolyl, benzotriazolyl, benzimidazolyl, thienothienyl, imidazolyl, thiadiazolyl, benzo[b]thiophenyl, pyridyl, benzofuranyl, and indolyl, and said cyclic group optionally being singly or multiply substituted by —Q 1 ;
each Ar 4 cyclic group is independently selected from the set consisting of phenyl, tetrazolyl, pyridinyl, oxazolyl, naphthyl, pyrimidinyl, and thienyl, and said cyclic group optionally being singly or multiply substituted by —Q 1 ;
each Q 1 is independently selected from the group consisting of —NH 2 , —Cl, —F, —Br, —OH, —R 9 , —NH—R 5 wherein R 5 is —C(O)—R 10 or —S(O) 2 —R 9 , —OR 5 wherein R 5 is —C(O)—R 10 , —OR 9 , —NHR 9 , and
wherein each R 9 and R 10 are independently a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 wherein Ar 3 is phenyl;
provided that when —Ar 3 is substituted with a Q 1 group which comprises one or more additional —Ar 3 groups, said additional —Ar 3 groups are not substituted with another —Ar 3 .
37 . The compound according to claim 7 selected from the group consisting of:
38 . The compound according to claim 8 or 68 , selected from the group consisting of:
39 . The compound according to claim 15 selected from the group consisting of:
40 . The compound according to claim 8 or 68 , selected from the group consisting of:
41 . The compound according to claim 33 selected from the group consisting of:
42 . A pharmaceutical composition comprising an ICE inhibitor according to any one of claims 1 - 41 and 57 - 135 in an amount effective for treating or preventing an IL-1-mediated disease and a pharmaceutically acceptable carrier.
43 . A pharmaceutical composition comprising an ICE inhibitor according to any one of claims 1 - 41 and 57 - 135 in an amount effective for treating or preventing an apoptosis-mediated disease and a pharmaceutically acceptable carrier.
44 . The pharmaceutical composition according to claim 42 , wherein the IL-1-mediated disease is an inflammatory disease selected from the group consisting of osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma, and adult respiratory distress syndrome.
45 . The pharmaceutical composition according to claim 44 , wherein the inflammatory disease is osteoarthritis or acute pancreatitis.
46 . The pharmaceutical composition according to claim 42 , wherein the IL-1-mediated disease is an autoimmune disease selected from the group consisting of glomeralonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Grave's disease, autoimmune gastritis, insulin-dependent diabetes mellitus (Type I), autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, inflammatory bowel disease, Crohn's disease, psoriasis, and graft vs host disease.
47 . The pharmaceutical composition according to claim 46 , wherein the autoimmune disease is rheumatoid arthritis, inflammatory bowel disease, or Crohn's disease, or psoriasis.
48 . The pharmaceutical composition according to claim 42 , wherein the IL-1-mediated disease is a destructive bone disorder selected from the group consisting of osteoporosis or multiple myeloma-related bone disorder.
49 . The pharmaceutical composition according to claim 42 , wherein the IL-1-mediated disease is a proliferative disorder selected from the group consisting of acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, and multiple myeloma.
50 . The pharmaceutical composition according to claim 42 , wherein the IL-1-mediated disease is an infectious disease, selected from the group consisting of sepsis, septic shock, and Shigellosis.
51 . The pharmaceutical composition according to claim 42 , wherein the IL-1-mediated disease is a degenerative or necrotic disease, selected from the group consisting of Alzheimer's disease, Parkinson's disease, cerebral ischemia, and myocardial ischemia.
52 . The pharmaceutical composition according to claim 51 , wherein the degenerative disease is Alzheimer's disease.
53 . The pharmaceutical composition according to claim 43 , wherein the apoptosis-mediated disease is a degenerative disease, selected from the group consisting of Alzheimer's disease, Parkinson's disease, cerebral ischemia, myocardial ischemia, spinal muscular atrophy, multiple sclerosis, AIDS-related encephalitis, HIV-related encephalitis, aging, alopecia, and neurological damage due to stroke.
54 . A pharmaceutical composition for inhibiting an ICE-mediated function comprising an ICE inhibitor according to any one of claims 1 - 41 and 57 -135 and a pharmaceutically acceptable carrier.
55 . A method for treating or preventing a disease selected from the group consisting of an IL-1 mediated disease, an apoptosis mediated disease, an inflammatory disease, an autoimmune disease, a destructive bone disorder, a proliferative disorder, an infectious disease, a degenerative disease, a necrotic disease, osteoarthritis, pancreatitis, asthma, adult respiratory distress syndrome, glomeralonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Grave's disease, autoimmune gastritis, insulin-dependent diabetes mellitus (Type I), autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, inflammatory bowel disease, Crohn's disease, psoriasis, graft vs host disease, osteoporosis, multiple myeloma-related bone disorder, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, Shigellosis, Alzheimer's disease, Parkinson's disease, cerebral ischemia, myocardial ischemia, spinal muscular atrophy, multiple sclerosis, AIDS-related encephalitis, HIV-related encephalitis, aging, alopecia, and neurological damage due to stroke in a patient comprising the step of administering to said patient a pharmaceutical composition according to any one of claims 42 to 54 .
56 . The method according to claim 55 , wherein the disease is selected from the group consisting of osteoarthritis, acute pancreatitis, rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, psoriasis, and Alzeheimer's disease.
57 . A compound represented by the formula:
wherein:
R 1 is selected from the group consisting of the following formulae:
ring C is chosen from the group consisting of benzo, pyrido, thieno, pyrrolo, furano, thiazolo, isothiazolo, oxazolo, isoxazolo, pyrimido, imidazolo, cyclopentyl, and cyclohexyl;
R 2 is:
m is 1 or 2; each R 5 is independently selected from the group consisting of:
—C(O)—R 10 ,
—C(O)O—R 9 ,
—C(O)—N(R 10 )(R 10 )
—S(O) 2 —R 9 ,
—S(O) 2 —NH—R 10 ,
—C(O)—CH 2 —O—R 9 ,
—C(O)C(O)—R 10 ,
—R 9 ,
—H,
—C(O)C(O)—OR 10 , and
—C(O)C(O)—N(R 9 )(R 10 );
X 5 is CH or N;
Y 2 is H 2 or O;
X 7 is —N(R 8 )— or —O—;
R 6 is selected from the group consisting of —H and —CH 3 ;
R 8 is selected from the group consisting of:
—C(O)—R 10 ,
—C(O)O—R 9 ,
—C(O)—N(H)—R 10 ,
—S(O) 2 —R 9 ,
—S(O) 2 —NH—R 10 ,
—C(O)—CH 2 —OR 10 ,
—C(O)C(O)—R 10 ;
—C(O)—CH 2 N(R 10 )(R 10 ),
—C(O)—CH 2 C(O)—O—R 9 ,
—C(O)—CH 2 C(O)—R 9 ,
—H, and
—C(O)—C(O)—OR 10 ;
each R 9 is independently selected from the group consisting of —Ar 3 and a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein the —C 1-6 alkyl group is optionally unsaturated;
each R 10 is independently selected from the group consisting of —H, —Ar 3 , a —C 3-6 cycloalkyl group, and a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein the —C 1-6 alkyl group is optionally unsaturated;
R 13 is selected from the group consisting of H,
Ar 3 , and a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , —CONH 2 , —OR 5 , —OH,
—OR 9 , or —CO 2 H;
each R 51 is independently selected from the group consisting of R 9 , —C(O)—R 9 , —C(O)—N(H)—R 9 , or each R 51 taken together forms a saturated 4-8 member carbocyclic ring or heterocyclic ring containing —O—, —S—, or —NH—;
each R 21 is independently selected from the group consisting of —H or a —C 1-6 straight or branched alkyl group;
each Ar 3 is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings and an aromatic heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocyclic group containing at least one heteroatom group selected from —O—, —S—, —SO—, SO 2 , ═N—, and —NH—, said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by —Q 1 ;
each Q 1 is independently selected from the group consisting of —NH 2 , —CO 2 H, —Cl, —F, —Br, —I, —NO 2 , —CN, ═O, —OH, -perfluoro C 1-3 alkyl, R 5 , —OR 5 , —NHR 5 , —OR 9 , —N(R 9 )(R 10 ), —R 9 , —C(O)—R 10 , and
provided that when —Ar 3 is substituted with a Q 1 group which comprises one or more additional —Ar 3 groups, said additional —Ar 3 groups are not substituted with another —Ar 3 .
58 . The compound according to claim 57 , wherein R 1 is (w2).
59 . The compound according to claim 57 , wherein R 1 is (e10) and X 5 is CH.
60 . The compound according to claim 57 , wherein R 1 is (e10) and X 5 is N.
61 . The compound according to claim 57 , selected from the group consisting of:
62 . A compound represented by the formula:
wherein:
m is 1 or 2;
R 1 is selected from the group consisting of the following formulae:
ring C is chosen from the group consisting of benzo, pyrido, thieno, pyrrolo, furano, thiazolo, isothiazolo, oxazolo, isoxazolo, pyrimido, imidazolo, cyclopentyl, and cyclohexyl;
R 3 is selected from the group consisting of:
—CN,
—C(O)—H,
—C(O)—CH 2 —T 1 —R 11 ,
—C(O)—CH 2 —F,
—C═N—O—R 9 , and
—CO—Ar 2 ;
each R 5 is independently selected from the group consisting of:
—C(O)—R 10 ,
—C(O)O—R 9 ,
—C(O)—N(R 10 )(R 10 )
—S(O) 2 —R 9 ,
—S(O) 2 —NH—R 10 ,
—C(O)—CH 2 —O—R 9 ,
—C(O)C(O)—R 10 ,
—R 9 ,
—H,
—C(O)C(O)—OR 10 , and
—C(O)C(O)—N(R 9 )(R 10 );
Y 2 is H 2 or O;
X 7 is —N(R 8 )— or —O—;
each T 1 is independently selected from the group consisting of —O—, —S—, —S(O)—, and —S(O) 2 —;
R 6 is selected from the group consisting of —H and —CH 3 ;
R 8 is selected from the group consisting of:
—C(O)—R 10 ,
—C(O)O—R 9 ,
—C(O)—NH—R 10 ,
—S(O) 2 —R 9 ,
—S(O) 2 —NH—R 10 ,
—C(O)—CH 2 —OR 10 ,
—C(O)C(O)—R 10 ,
—C(O)—CH 2 —N(R 10 )(R 10 ),
—C(O)—CH 2 C(O)—O—R 9 ,
—C(O)—CH 2 C(O)—R 9 ,
—H, and
—C(O)—C(O)—OR 10 ;
each R 9 is independently selected from the group consisting of —Ar 3 and a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein the —C 1-6 alkyl group is optionally unsaturated;
each R 10 is independently selected from the group consisting of —H, —Ar 3 , a —C 3-6 cycloalkyl group, and a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein the —C 1-6 alkyl group is optionally unsaturated;
each R 11 is independently selected from the group consisting of:
—Ar 4 ,
—(CH 2 ) 1-3 —Ar 4 ,
—H, and
—C(O)—Ar 4 ;
R 15 is selected from the group consisting of —OH, —OAr 3 , —N(H)—OH, and —OC 1-6 , wherein C 16 is a straight or branched alkyl group optionally substituted with —Ar 3 , —CONH 2 , —OR 5 , —OH, —OR 9 , or —CO 2 H;
each R 21 is independently selected from the group consisting of —H or a —C 1-6 straight or branched alkyl group;
Ar 2 is independently selected from the following group, in which any ring may optionally be singly or multiply substituted by —Q 1 or phenyl, optionally substituted by Q 1 :
wherein each Y is independently selected from the group consisting of O and S;
each Ar 3 is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings and an aromatic heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocyclic group containing at least one heteroatom group selected from —O—, —S—, —SO—, SO 2 , N—, and —NH—, —N(R 5 )—, and —N(R 9 )— said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by —Q 1 ;
each Ar 4 is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings, and a heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocyclic group containing at least one heteroatom group selected from —O—, —S—, —SO—, SO 2 , ═N—, —NH—, —N(R 5 )—, and —N(R 9 )— said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by —Q 1 ;
each Q 1 is independently selected from the group consisting of —NH 2 , —CO 2 H, —Cl, —F, —Br, —I, —NO 2 , —CN, ═O, —OH, -perfluoro C 1-3 alkyl, R 5 , —OR 5 , —NHR 5 , —OR 9 , —N(R 9 )(R 10 ), —R 9 , —C(O)—R 10 , and
provided that when —Ar 3 is substituted with a Q 1 group which comprises one or more additional —Ar 3 groups, said additional —Ar 3 groups are not substituted with another —Ar 3 .
63 . The compound according to claim 62 , wherein R 1 is (w2).
64 . The compound according to claim 62 , wherein R 1 is (e10-A).
65 . A compound represented by the formula:
wherein:
m is 1 or 2;
R 1 is:
R 3 is selected from the group consisting of:
—CN,
—C(O)—H,
—C(O)—CH 2 —T 1 —R 11 ,
—C(O)—CH 2 —F,
—C═N—O—R 9 , and
—CO—Ar 2 ;
each R 5 is independently selected from the group consisting of:
—C(O)—R 10 ,
—C(O)O—R 9 ,
—C(O)—N(R 10 )(R 10 )
—S(O) 2 —R 9 ,
—S(O) 2 —NH—R 10 ,
—C(O)—CH 2 —O—R 9 ,
—C(O)C(O)—R 10 ,
—R 9 ,
—H,
—C(O)C(O)—OR 1 , and
—C(O)C(O)—N(R 9 )(R 10 );
Y 2 is H 2 or O;
each T 1 is independently selected from the group consisting of —O—, —S—, —S(O)—, and —S(O) 2 —;
each R 9 is independently selected from the group consisting of —Ar 3 and a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein the —C 1-6 alkyl group is optionally unsaturated;
each R 10 is independently selected from the group consisting of —H, —Ar 3 , a —C 3-6 cycloalkyl group, and a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein the —C 1-6 alkyl group is optionally unsaturated;
each R 11 is independently selected from the group consisting of:
—Ar 4 ,
—(CH 2 ) 1-3 —Ar 4 ,
—H, and
—C(O)—Ar 4 ;
R 15 is selected from the group consisting of —OH,
—OAr 3 , —N(H)—OH, and —OC 116 , wherein C 16 is a straight or branched alkyl group optionally substituted with —Ar 3 , —CONH 2 , —OR 5 , —OH, —OR 9 , or —CO 2 H;
R 21 is —CH 3 ;
Ar 2 is independently selected from the following group, in which any ring may optionally be singly or multiply substituted by —Q 1 or phenyl, optionally substituted by Q 1 :
wherein each Y is independently selected from the group consisting of O and S;
each Ar 3 is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings and an aromatic heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocyclic group containing at least one heteroatom group selected from —O—, —S—, —SO—, SO 2 , ═N—, and —NH—, —N(R 5 )—, and —N(R 9 )— said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by —Q 1 ;
each Ar 4 is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings, and a heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocyclic group containing at least one heteroatom group selected from —O—, —S—, —SO—, SO 2 , ═N—, —NH—, —N(R 5 )—, and —N(R 9 )— said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by —Q 1 ;
each Q 1 is independently selected from the group consisting of —NH 2 , —CO 2 H, —Cl, —F, —Br, —I, —NO 2 , —CN, ═O, —OH, -perfluoro C 1-3 alkyl, R 5 , —OR 5 , —NHR 5 , —OR 9 , —N(R 9 )(R 10 ), —R 9 , —C(O)—R 10 , and
provided that when —Ar 3 is substituted with a Q 1 group which comprises one or more additional —Ar 3 groups, said additional —Ar 3 groups are not substituted with another —Ar 3 .
66 . A compound represented by the formula:
wherein:
m is 1 or 2;
R 3 is selected from the group consisting of:
—CN,
—C(O)—H,
—C(O)—CH 2 —T 1 —R 11 ,
—C(O)—CH 2 —F,
—C═N—O—R 9 , and
—CO—Ar 2 ;
each R 5 is —C(O)C(O)—OR 10 ;
Y 2 is H 2 or O;
each T 1 is independently selected from the group consisting of —O—, —S—, —S(O)—, and —S(O) 2 —;
each R 9 is independently selected from the group consisting of —Ar 3 and a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein the —C 1-6 alkyl group is optionally unsaturated;
each R 10 is independently selected from the group consisting of —H, —Ar 3 , a —C 3-6 cycloalkyl group, and a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein the —C 1-6 alkyl group is optionally unsaturated;
each R 1 P is independently selected from the group consisting of:
—Ar 4 ,
—(CH 2 ) 1-3 —Ar 4 ,
—H, and
—C(O)—Ar 4 ;
R 15 is selected from the group consisting of —OH,
—OAr 3 , —N(H)—OH, and —OC 116 , wherein C 16 is a straight or branched alkyl group optionally substituted with —Ar 3 , —CONH 2 , —OR 5 , —OH, —OR 9 , or —CO 2 H;
each R 21 is independently selected from the group consisting of —H or a —C 1-6 straight or branched alkyl group;
Ar 2 is independently selected from the following group, in which any ring may optionally be singly or multiply substituted by —Q 1 or phenyl, optionally substituted by Q 1 :
wherein each Y is independently selected from the group consisting of O and S;
each Ar 3 is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings and an aromatic heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocyclic group containing at least one heteroatom group selected from —O—, —S—, —SO—, SO 2 , ═N—, and —NH—, —N(R 5 )—, and —N(R 9 )— said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by —Q 1 ;
each Ar 4 is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings, and a heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocyclic group containing at least one heteroatom group selected from —O—, —S—, —SO—, SO 2 , ═N—, —NH—, —N(R 5 )—, and —N(R 9 )— said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by —Q 1 ;
each Q 1 is independently selected from the group consisting of —NH 2 , —CO 2 H, —Cl, —F, —Br, —I, —NO 2 , —CN, O, —OH, -perfluoro C 1-3 alkyl, R 5 , —OR 5 , —NHR 5 , —OR 9 , —N(R 9 )(R 10 ), —R 9 , —C(O)—R 10 , and
provided that when —Ar 3 is substituted with a Q 1 group which comprises one or more additional —Ar 3 groups, said additional —Ar 3 groups are not substituted with another —Ar 3 .
67 . The compound according to claim 66 , wherein R 21 is —CH 3 .
68 . A compound represented by the formula:
wherein:
m is 1 or 2;
R 1 is:
R 3 is selected from the group consisting of:
—CN,
—C(O)—H,
—C(O)—CH 2 —T 1 —R 11 ,
—C(O)—CH 2 —F,
—C═N—O—R 9 , and
—CO—Ar 2 ;
each R 5 is independently selected from the group consisting of:
—C(O)—R 10 ,
—C(O)O—R 9 ,
—C(O)—N(R 10 )(R 10 )
—S(O) 2 —R 9 ,
—S(O) 2 —NH—R 10 ,
—C(O)—CH 2 —O—R 9 ,
—C(O)C(O)—R 10 ,
—R 9 ,
—H,
—C(O)C(O)—OR 10 , and
—C(O)C(O)—N(R 9 )(R 10 );
Y 2 is H 2 or O;
each T 1 is independently selected from the group consisting of —O—, —S—, —S(O)—, and —S(O) 2 —;
each R 9 is independently selected from the group consisting of —Ar 3 and a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein the —C 1-6 alkyl group is optionally unsaturated;
each R 10 is independently selected from the group consisting of —H, —Ar 3 , a —C 3-6 cycloalkyl group, and a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein the —C 1-6 alkyl group is optionally unsaturated;
each R 11 is independently selected from the group consisting of:
—Ar 4 ,
—(CH 2 ) 1-3 —Ar 4 ,
—H, and
—C(O)—Ar 4 ;
R 15 is selected from the group consisting of —OH, —OAr 3 , —N(H)—OH, and —OC 1-6 , wherein C 1-6 is a straight or branched alkyl group optionally substituted with —Ar 3 , —CONH 2 , —OR 5 , —OH, —OR 9 , or —CO 2 H;
each R 21 is independently selected from the group consisting of —H or a —C 1-6 straight or branched alkyl group;
Ar 2 is independently selected from the following group, in which any ring may optionally be singly or multiply substituted by —Q 1 or phenyl, optionally substituted by Q 1 :
wherein each Y is independently selected from the group consisting of O and S;
each Ar 3 is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings and an aromatic heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocyclic group containing at least one heteroatom group selected from —O—, —S—, —SO—, SO 2 , ═N—, and —NH—, —N(R 5 )—, and —N(R 9 )— said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by —Q 1 ;
each Ar 4 is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings, and a heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocyclic group containing at least one heteroatom group selected from —O—, —S—, —SO—, SO 2 , ═N—, —NH—, —N(R 5 )—, and —N(R 9 )— said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by —Q 1 ;
each Q 1 is independently selected from the group consisting of —NH 2 , —CO 2 H, —Cl, —F, —Br, —I, —NO 2 , —CN, ═O, —OH, -perfluoro C 1-3 alkyl, R 5 , —OR 5 , —NHR 5 , —OR 9 , —N(R 9 )(R 10 ), —R 9 , —C(O)—R 10 , and
provided that when —Ar 3 is substituted with a Q 1 group which comprises one or more additional —Ar 3 groups, said additional —Ar 3 groups are not substituted with another —Ar 3 ;
provided that when:
m is 1;
R 15 is —OH;
R 21 is —H; and
Y 2 is O and R 3 is —C(O)—H, then R 5 cannot be:
—C(O)—R 10 , wherein R 10 is —Ar 3 and the Ar 3 cyclic group is phenyl, unsubstituted by —Q 1 , 4-(carboxymethoxy)phenyl, 2-fluorophenyl, 2-pyridyl, N-(4-methylpiperazino)methylphenyl, or
—C(O)—OR 9 , wherein R 9 is —CH 2 —Ar 3 , and the Ar 3 cyclic group is phenyl, unsubstituted by —Q 1 ; and when
Y 2 is O, R 3 is —C(O)—CH 2 —T 1 —R 11 , T 1 is O, and R 11 is Ar 4 , wherein the Ar 4 cyclic group is 5-(1-(4-chlorophenyl)-3-trifluoromethyl)pyrazolyl), then R 5 cannot be:
—H;
—C(O)—R 10 , wherein R 10 is —Ar 3 and the Ar 3 cyclic group is 4-(dimethylaminomethyl)phenyl, phenyl, 4-(carboxymethylthio)phenyl, 4-(carboxyethylthio)phenyl, 4-(carboxyethyl)phenyl, 4-(carboxypropyl)phenyl, 2-fluorophenyl, 2-pyridyl, N-(4-methylpiperazino)methylphenyl, or
—C(O)—OR 9 , wherein R 9 is isobutyl or —CH 2 —Ar 3 and the Ar 3 cyclic group is phenyl;
and when R 11 is Ar 4 , wherein the Ar 4 cyclic group is 5-(1-phenyl-3-trifluoromethyl)pyrazolyl or 5-(1-(4-chloro-2-pyridinyl)-3-trifluoromethyl)pyrazolyl, then R 5 cannot be:
—C(O)—OR 9 , wherein R 9 is —CH 2 —Ar 3 , and the Ar 3 cyclic group is phenyl;
and when R 11 is Ar 4 , wherein the Ar 4 cyclic group is 5-(1-(2-pyridyl)-3-trifluoromethyl)pyrazolyl), then R 5 cannot be:
—C(O)—R 10 , wherein R 10 is —Ar 3 and the Ar 3 cyclic group is 4-(dimethylaminomethyl)phenyl, or
—C(O)—OR 9 , wherein R 9 is —CH 2 —Ar 3 , and the Ar 3 cyclic group is phenyl, unsubstituted by —Q 1 ; and when
Y 2 is O, R 3 is —C(O)—CH 2 —T 1 —R 11 , T 1 is O, and R 1 P is —C(O)—Ar 4 , wherein the Ar 4 cyclic group is 2,5-dichlorophenyl, then R 5 cannot be:
—C(O)—R 10 , wherein R 10 is —Ar 3 and the Ar 3 cyclic group is 4-(dimethylaminomethyl)phenyl, 4-(N-morpholinomethyl)phenyl, 4-(N-methylpiperazino)methyl)phenyl, 4-(N-(2-methyl)imidazolylmethyl)phenyl, 5-benzimidazolyl, 5-benztriazolyl, N-carboethoxy-5-benztriazolyl, N-carboethoxy-5-benzimidazolyl, or
—C(O)—OR 9 , wherein R 9 is —CH 2 —Ar 3 , and the Ar 3 cyclic group is phenyl, unsubstituted by —Q 1 ,; and when
Y 2 is H 2 , R 3 is —C(O)—CH 2 —T 1 —R 11 , T 1 is O, and R 11 is —C(O)—Ar 4 , wherein the Ar 4 cyclic group is 2,5-dichlorophenyl, then R 5 cannot be:
—C(O).—OR 9 , wherein R 9 is —CH 2 —Ar 3 and the Ar 3 cyclic group is phenyl.
69 . The compound according to claim 68 , wherein R 21 is —CH 3 .
70 . The compound according to claim 68 , wherein R 5 is —C(O)—C(O)—OR 10 .
71 . The compound according to claim 68 , wherein R 5 is —C(O)—C(O)—OR 10 and R 21 is —CH 3 .
72 . The compound according to any one of claims 66 , 67 , 70 and 71 , wherein R 3 is —C(O)—H.
73 . The compound according to any one of claims 65 , 68 and 69 , wherein R 3 is —C(O)—H.
74 . The compound according to claim 68 , wherein:
R 3 is —C(O)—H, and R 5 is —C(O)—R 10 , wherein: R 10 is Ar 3 , wherein the Ar 3 cyclic group is phenyl optionally being singly or multiply substituted by:
—F,
—Cl,
—N(H)—R 5 , wherein —R 5 is —H or —C(O)—R 10 , wherein R 10 is a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein Ar 3 is phenyl,
—N(R 9 )(R 10 ), wherein R 9 and R 10 are independently a —C 1-4 straight or branched alkyl group, or
—O—R 5 , wherein R 5 is H or a —C 1-4 straight or branched alkyl group.
75 . The compound according to claim 74 , wherein Ar 3 is phenyl being optionally singly or multiply substituted at the 3- or 5-position by —Cl or at the 4-position by —NH—R 5 , —N(R 9 )(R 10 ), or —O—R 5 .
76 . The compound according to claim 68 , wherein:
R 3 is —C(O)—H; R 5 is —C(O)—R 10 , wherein R 10 is Ar 3 and the Ar 3 cyclic group is selected from the group consisting of is indolyl, benzimidazolyl, thienyl, and benzo[b]thiophenyl, and said cyclic group optionally being singly or multiply substituted by —Q 1 .
77 . The compound according to claim 68 , wherein:
R 3 is —C(O)—H; and R 5 is —C(O)—R 10 , wherein R 10 is Ar 3 and the Ar 3 cyclic group is selected from quinolyl and isoquinolyl, and said cyclic group optionally being singly or multiply substituted by —Q 1 .
78 . The compound according to claim 68 , wherein:
R 3 is —C(O)—H; and R 5 is —C(O)—R 10 , wherein R 10 is Ar 3 and the Ar 3 cyclic group is phenyl, substituted by
79 . The compound according to claim 68 , selected from the group consisting of:
80 . A compound represented by the formula:
C is a ring chosen from the set consisting of benzo, pyrido, thieno, pyrrolo, furano, thiazolo, isothiazolo, oxazolo, isoxazolo, pyrimido, imidazolo, cyclopentyl, and cyclohexyl; the ring optionally being singly or multiply substituted by —Q 1 ;
each R 5 is independently selected from the group consisting of:
—C(O)—R 10 ,
—C(O)O—R 9 ,
—C(O)—N(R 10 )(R 10 )
—S(O) 2 —R 9 ,
—S(O) 2 —NH—R 10 ,
—C(O)—CH 2 —O—R 9 ,
—C(O)C(O)—R 10 ,
—R 9 ,
—H,
—C(O)C(O)—OR 10 , and
—C(O)C(O)—N(R 9 )(R 10 );
X 5 is CH or N;
Y 2 is H 2 or O;
R 6 is selected from the group consisting of —H and —CH 3 ;
R 8 is selected from the group consisting of:
—C(O)—R 10 ,
—C(O)O—R 9 ,
—C(O)—N(H)—R 10 ,
—S(O) 2 —R 9 ,
—S(O) 2 —NH—R 10 ,
—C(O)—CH 2 —OR 10 ,
—C(O)C(O)—R 10 ;
—C(O)—CH 2 N(R 10 )(R 10 ),
—C(O)—CH 2 C(O)—O—R 9 ,
—C(O)—CH 2 C(O)—R 9 ,
—H, and
—C(O)—C(O)—OR 10 ;
each R 9 is independently selected from the group consisting of —Ar 3 and a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein the —C 1-6 alkyl group is optionally unsaturated;
each R 10 is independently selected from the group consisting of —H, —Ar 3 , a —C 3-6 cycloalkyl group, and a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein the —C 1-6 alkyl group is optionally unsaturated;
R 13 is selected from the group consisting of H, Ar 3 , and a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , —CONH 2 , —OR 5 , —OH,
—OR 9 , or —CO 2 H;
each R 51 is independently selected from the group consisting of R 9 , —C(O)—R 9 , —C(O)—N(H)—R 9 , or each R 51 taken together forms a saturated 4-8 member carbocyclic ring or heterocyclic ring containing —O—, —S—, or —NH—;
each R 21 is independently selected from the group consisting of —H or a —C 1-6 straight or branched alkyl group;
each Ar 3 is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings and an aromatic heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocyclic group containing at least one heteroatom group selected from —O—, —S—, —SO—, SO 2 , ═N—, and —NH—, said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by —Q 1 ;
each Q 1 is independently selected from the group consisting of —NH 2 , —CO 2 H, —Cl, —F, —Br, —I, —NO 2 , —CN, ═O, —OH, -perfluoro C 1-3 alkyl, R 5 , —OR 5 , —NHR 5 , —OR 9 ,
—N (R 9 )(R 10 ), —R 9 , —C(O)—R 10 , and
provided that when —Ar 3 is substituted with a Q 1 group which comprises one or more additional —Ar 3 groups, said additional —Ar 3 groups are not substituted with another —Ar 3 .
81 . The compound according to claim 80 , wherein:
m is 1; C is a ring chosen from the set consisting of benzo, pyrido, or thieno the ring optionally being singly or multiply substituted by halogen, —NH 2 , —NH—R 5 , —NH—R 9 , —OR 10 , or —R 9 , wherein R 9 is a straight or branched C 1-4 alkyl group, and R 10 is H or a straight or branched C 1-4 alkyl group; R 6 is H; R 13 is H or a C 1-4 straight or branched alkyl group optionally substituted with —Ar 3 , —OH, —OR 9 , —CO 2 H, wherein the R 9 is a C 1-4 branched or straight chain alkyl group; wherein Ar 3 is morpholinyl or phenyl, wherein the phenyl is optionally substituted by —Q 1 ; R 21 is —H or —CH 3 ; R 51 is a C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein Ar 3 is phenyl, optionally substituted by —Q 1 ; each Ar 3 cyclic group is independently selected from the set consisting of phenyl, naphthyl, thienyl, quinolinyl, isoquinolinyl, pyrazolyl, thiazolyl, isoxazolyl, benzotriazolyl, benzimidazolyl, thienothienyl, imidazolyl, thiadiazolyl, benzo[b]thiophenyl, pyridyl, benzofuranyl, and indolyl, and said cyclic group optionally being singly or multiply substituted by —Q 1 ; each Q 1 is independently selected from the group consisting of —NH 2 , —Cl, —F, —Br, —OH, —R 9 , —NH—R 5 wherein R 5 is —C(O)—R 10 or —S(O) 2 —R 9 , —OR 5 wherein R 5 is —C(O)—R 10 , —OR 9 , —NHR 9 , and wherein each R 9 and R 10 are independently a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 wherein Ar 3 is phenyl;
provided that when —Ar 3 is substituted with a Q 1 group which comprises one or more additional —Ar 3 groups, said additional —Ar 3 groups are not substituted with another —Ar 3 .
82 . The compound according to claim 81 , wherein R 1 is (w2).
83 . The compound according to claim 82 , selected from the group consisting of:
84 . The compound according to claim 82 , wherein R 8 is selected from the group consisting of:
—C(O)—R 10 , —C(O)O—R 9 , —C(O)—CH 2 —OR 10 , and —C(O)—CH 2 C(O)—R 9 .
85 . The compound according to claim 84 , wherein R 8 is —C(O)—CH 2 —OR 10 and R 10 is —H or —CH 3 .
86 . The compound according to claim 81 , wherein R 1 is (e10) and X 5 is CH.
87 . The compound according to claim 81 , wherein R 1 is (e10) and X 5 is N.
88 . The compound according to any one of claims 80 - 87 wherein R 5 is —C(O)—R 10 or —C(O)—C(O)—R 10 .
89 . The compound according to claim 88 , wherein R 10 is Ar 3 .
90 . The compound according to claim 89 , wherein:
R 5 is —C(O)—R 10 and R 10 is Ar 3 , wherein the Ar 3 cyclic group is phenyl optionally being singly or multiply substituted by:
—R 9 , wherein R 9 is a C 1-4 straight or branched alkyl group;
—F,
—Cl,
—N(H)—R 5 , wherein —R 5 is —H or —C(O)—R 10 , wherein R 10 is a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein Ar 3 is phenyl,
—N(R 9 )(R 10 ), wherein R 9 and R 10 are independently a —C 1-4 straight or branched alkyl group, or
—O—R 5 , wherein R 5 is H or a —C 1-4 straight or branched alkyl group.
91 . The compound according to claim 90 , selected from the group consisting of:
92 . The compound according to claim 90 , wherein Ar 3 is phenyl being singly or multiply substituted at the 3- or 5-position by —Cl or at the 4-position by —NH—R 5 , —N(R 9 )(R 10 ), or —O—R 5 .
93 . The compound according to claim 92 , selected from the group consisting of:
94 . The compound according to claim 92 , selected from the group consisting of:
95 . The compound according to claim 90 , wherein Ar 3 is phenyl being singly or multiply substituted at the 3- or 5-position by —R 9 , wherein R 9 is a C 1-4 straight or branched alkyl group; and at the 4-position by —O—R 5 .
96 . The compound according to claim 95 , selected from the group consisting of:
97 . The compound according to claim 95 , selected from the group consisting of:
98 . The compound according to claim 89 , wherein:
R 5 is —C(O)—R 10 , wherein R 10 is Ar 3 and the Ar 3 cyclic group is selected from the group consisting of is indolyl, benzimidazolyl, thienyl, quinolyl, isoquinolyl and benzo[b]thiophenyl, and said cyclic group optionally being singly or multiply substituted by —Q 1 .
99 . The compound according to claim 98 , wherein the Ar 3 cyclic group is isoquinolyl, and said cyclic group optionally being singly or multiply substituted by —Q 1 .
100 . The compound according to claim 99 selected from the group consisting of:
101 . The compound according to claim 99 , selected from the group consisting of:
102 . The compound according to claim 89 , wherein R 5 is —C(O)—R 10 , wherein R 10 is Ar 3 and the Ar 3 cyclic group is phenyl, substituted by
103 . The compound according to claim 102 , selected from the group consisting of:
104 . A compound represented by the formula:
wherein:
m is 1 or 2;
R 1 is selected from the group consisting of the following formulae:
C is a ring chosen from the set consisting of benzo, pyrido, thieno, pyrrolo, furano, thiazolo, isothiazolo, oxazolo, isoxazolo, pyrimido, imidazolo, cyclopentyl, and cyclohexyl, the ring optionally being singly or multiply substituted by —Q 1 ,;
R 3 is selected from the group consisting of:
—CN,
—C(O)—H,
—C(O)—CH 2 —T 1 —R 11 ,
—C(O)—CH 2 —F,
—C═N—O—R 9 , and
—CO—Ar 2 ;
each R 5 is independently selected from the group consisting of:
—C(O)—R 10 ,
—C(O)O—R 9 ,
—C(O)—N(R 10 )(R 10 )
—S(O) 2 —R 9 ,
—S(O) 2 —NH—R 10 ,
—C(O)—CH 2 —O—R 9 ,
—C(O)C(O)—R 10 ,
—R 9 ,
—H,
—C(O)C(O)—OR 10 , and
—C(O)C(O)—N (R 9 )(R 10 );
each T 1 is independently selected from the group consisting of —O—, —S—, —S(O)—, and —S(O) 2 —;
R 6 is selected from the group consisting of —H and —CH 3 ;
R 8 is selected from the group consisting of:
—C(O)—R 10 ,
—C(O)O—R 9 ,
—C(O)—NH—R 10 ,
—S(O) 2 —R 9 ,
—S(O) 2 —NH—R 10 ,
—C(O)—CH 2 —OR 10 ,
—C(O)C(O)—R 10 ,
—C(O)—CH 2 —N(R 10 )(R 10 ),
—C(O)—CH 2 C(O)—O—R 9 ,
—C(O)—CH 2 C(O)—R 9 ,
—H, and
—C(O)—C(O)—OR 10 ;
each R 9 is independently selected from the group consisting of —Ar 3 and a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein the —C 1-6 alkyl group is optionally unsaturated;
each R 10 is independently selected from the group consisting of —H, —Ar 3 , a —C 3-6 cycloalkyl group, and a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein the —C 1-6 alkyl group is optionally unsaturated;
each R 11 is independently selected from the group consisting of:
—Ar 4 ,
—(CH 2 ) 1-3 —Ar 4 ,
—H, and
—C(O)—Ar 4 ;
R 15 is selected from the group consisting of —OH,
—OAr 3 , —N(H)—OH, and —OC 116 , wherein C 16 is a straight or branched alkyl group optionally substituted with —Ar 3 , —CONH 2 , —OR 5 , —OH, —OR 9 , or —CO 2 H;
Ar 2 is independently selected from the following group, in which any ring may optionally be singly or multiply substituted by —Q 1 or phenyl, optionally substituted by Q 1 :
wherein each Y is independently selected from the group consisting of O and S;
each Ar 3 is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings and an aromatic heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocyclic group containing at least one heteroatom group selected from —O—, —S—, —SO—, SO 2 , ═N—, and —NH—, —N(R 5 )—, and —N(R 9 )— said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by —Q 1 ;
each Ar 4 is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings, and a heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocyclic group containing at least one heteroatom group selected from —O—, —S—, —SO—, SO 2 , ═N—, —NH—, —N(R 5 )—, and —N(R 9 )— said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by —Q 1 ;
each Q 1 is independently selected from the group consisting of —NH 2 , —CO 2 H, —Cl, —F, —Br, —I, —NO 2 , —CN, ═O, —OH, -perfluoro C 1-3 alkyl, R 5 , —OR 5 , —NHR 5 , —OR 9 , —N(R 9 )(R 10 ), —R 9 , —C(O)—R 10 , and
provided that when —Ar 3 is substituted with a Q 1 group which comprises one or more additional —Ar 3 groups, said additional —Ar 3 groups are not substituted with another —Ar 3 .
105 . The compound according to claim 104 , wherein:
m is 1; C is a ring chosen from the set consisting of benzo, pyrido, and thieno, the ring optionally being singly or multiply substituted by halogen, —NH 2 , —NH—R 5 , or —NH—R 9 , —OR 10 , or —R 9 , wherein R 9 is a straight or branched C 1-4 alkyl group, and R 10 is H or a straight or branched C 1-4 alkyl group; T 1 is O or S; R 6 is H; R 11 is selected from the group consisting of —Ar 4 , —(CH 2 ) 1-3 —Ar 4 , and —C(O)—Ar 4 ; Ar 2 is (hh); Y is O; each Ar 3 cyclic group is independently selected from the set consisting of phenyl, naphthyl, thienyl, quinolinyl, isoquinolinyl, thiazolyl, benzimidazolyl, thienothienyl, thiadiazolyl, benzotriazolyl, benzo[b]thiophenyl, benzofuranyl, and indolyl, and said cyclic group optionally being singly or multiply substituted by —Q 1 ; each Ar 4 cyclic group is independently selected from the set consisting of phenyl, tetrazolyl, naphthyl, pyridinyl, oxazolyl, pyrimidinyl, or indolyl, and said cyclic group optionally being singly or multiply substituted by —Q 1 ; each Q 1 is independently selected from the group consisting of —NH 2 , —Cl, —F, —Br, —OH, —R 9 , —NH—R 5 wherein R 5 is —C(O)—R 10 or —S(O) 2 —R 9 , —OR 5 wherein R 5 is —C(O)—R 10 , —OR 9 , —NHR 9 , and wherein each R 9 and R 10 are independently a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 wherein Ar 3 is phenyl;
provided that when —Ar 3 is substituted with a Q 1 group which comprises one or more additional —Ar 3 groups, said additional —Ar 3 groups are not substituted with another —Ar 3 .
106 . The compound according to claim 105 , wherein R 8 is selected from the group consisting of:
—C(O)—R 10 , —C(O)O—R 9 , —C(O)—CH 2 —OR 10 , and —C(O)—CH 2 C(O)—R 9 .
107 . The compound according to claim 106 , wherein R 8 is —C(O)—CH 2 —OR 10 and R 10 is —H or —CH 3 .
108 . The compound according to claim 105 , wherein R 3 is —C(O)—Ar 2 ,
109 . The compound according to claim 105 , wherein R 3 is —C(O)CH 2 —T 1 —R 11 ;
110 . The compound according to claim 105 , wherein R 3 is —C(O)—H.
111 . The compound according to claim 110 , wherein R 8 is selected from the group consisting of:
—C(O)—R 10 , —C(O)O—R 9 , —C(O)—CH 2 —OR 10 , and —C(O)—CH 2 C(O)—R 9 .
112 . The compound according to claim 111 , selected from the group consisting of:
113 . The compound according to claim 111 , wherein R 8 is —C(O)—CH 2 —OR 10 and R 10 is —H or —CH 3 .
114 . The compound according to claim 68 , wherein:
m is 1; T 1 is O or S; R 21 is —H or —CH 3 ; Ar 2 is (hh); Y is O; each Ar 3 cyclic group is independently selected from the set consisting of phenyl, naphthyl, thienyl, quinolinyl, isoquinolinyl, pyrazolyl, thiazolyl, isoxazolyl, benzotriazolyl, benzimidazolyl, thienothienyl, imidazolyl, thiadiazolyl, benzo[b]thiophenyl, pyridyl, benzofuranyl, and indolyl and said cyclic group being singly or multiply substituted by —Q 1 ; each Ar 4 cyclic group is independently selected from the set consisting of phenyl, tetrazolyl, pyridinyl, oxazolyl, naphthyl, pyrimidinyl, and thienyl and said cyclic group being singly or multiply substituted by —Q 1 ; each Q 1 is independently selected from the group consisting of —NH 2 , —Cl, —F, —Br, —OH, —R 9 , —NH—R 5 wherein R 5 is —C(O)—R 10 or —S(O) 2 —R 9 , —OR 5 wherein R 5 is —C(O)—R 10 , —OR 9 , —NHR 9 , and wherein each R 9 and R 10 are independently a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 wherein Ar 3 is phenyl;
provided that when —Ar 3 is substituted with a Q 1 group which comprises one or more additional —Ar 3 groups, said additional —Ar 3 groups are not substituted with another —Ar 3 .
115 . The compound according to claim 114 , wherein R 3 is —C(O)—Ar 2 .
116 . The compound according to claim 114 , wherein R 3 is —C(O)CH 2 —T 1 —R 11 ;
117 . The compound according to claim 114 , wherein R 3 is —C(O)—H.
118 . The compound according to any one of claims 104 - 117 , wherein R 5 is —C(O)—R 10 or —C(O)C(O)—R 10 .
119 . The compound according to claim 118 , wherein R 10 is Ar 3 .
120 . The compound according to claim 119 , wherein:
R 5 is —C(O)—R 10 and R 10 is Ar 3 , wherein the Ar 3 cyclic group is phenyl optionally being singly or multiply substituted by: —R 9 , wherein R 9 is a C 1-4 straight or branched alkyl group; —F, —Cl, —N(H)—R 5 , wherein —R 5 is —H or —C(O)—R 10 , wherein R 10 is a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein Ar 3 is phenyl, —N(R 9 )(R 10 ), wherein R 9 and R 10 are independently a —C 1-4 straight or branched alkyl group, or —O—R 5 , wherein R 5 is H or a —C 1-4 straight or branched alkyl group.
121 . The compound according to claim 120 , selected from the group consisting of:
122 . The compound according to claim 120 , wherein Ar 3 is phenyl being singly or multiply substituted at the 3- or 5-position by —Cl or at the 4-position by —NH—R 5 , —N(R 9 )(R 10 ), or —O—R 5 .
123 . The compound according to claim 122 , selected from the group consisting of:
124 . The compound according to claim 122 , selected from the group consisting of:
125 . The compound according to claim 120 , wherein Ar 3 is phenyl being singly or multiply substituted at the 3- or 5-position by —R 9 , wherein R 9 is a C 1-4 straight or branched alkyl group; and at the 4-position by —O—R 5 .
126 . The compound according to claim 125 , selected from the group consisting of:
127 . The compound according to claim 125 , wherein the compound is:
128 . The compound according to claim 119 , wherein:
R 5 is —C(O)—R 10 , wherein R 10 is Ar 3 and the Ar 3 cyclic group is selected from the group consisting of is indolyl, benzimidazolyl, thienyl, quinolyl, isoquinolyl and benzo[b]thiophenyl, and said cyclic group optionally being singly or multiply substituted by —Q 1 .
129 . The compound according to claim 128 , selected from the group consisting of:
130 . The compound according to claim 128 , wherein the Ar 3 cyclic group is isoquinolyl, and said cyclic group optionally being singly or multiply substituted by —Q 1 .
131 . The compound according to claim 130 , wherein the compound is:
132 . The compound according to claim 130 , wherein the compound is:
133 . The compound according to claim 119 ,
wherein R 5 is —C(O)—R 10 , wherein R 10 is Ar 3 and the Ar 3 cyclic group is phenyl, substituted by
134 . The compound according to claim 133 , wherein the compound is:
135 . The compound according to claim 133 , wherein the compound is:
136 . A pharmaceutical composition, comprising a compound according to any one of claims 1 - 41 and 57 -135 in an amount effective for decreasing IGIF production and a pharmaceutically acceptable carrier.
137 . A pharmaceutical composition comprising a compound according to any one of claims 1 - 41 and 57 -135 in an amount effective for decreasing IFN-γ production and a pharmaceutically acceptable carrier.
138 . A method for treating or preventing a disease selected from an IGIF mediated disease, an IFN-γ mediated disease, an inflammatory disease, an autoimmune disease, an infectious disease, a proliferative disease, a neurodegenerative disease, a necrotic disease, osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma, rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, ulcerative collitis, cerebral ischemia, myocardial ischemia, adult respiratory distress syndrome, infectious hepatitis, sepsis, septic shock, Shigeilosis, glomerulonephritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, insulin-dependent diabetes mellitus (Type I), juvenile diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, myasthenia gravis, multiple sclerosis, psoriasis, lichenplanus, graft vs. host disease, acute dermatomyositis, eczema, primary cirrhosis, hepatitis, uveitis, Behcet's disease, acute dermatomyositis, atopic skin disease, pure red cell aplasia, aplastic anemia, amyotrophic lateral sclerosis and nephrotic syndrome comprising the step of administering to said patient a pharmaceutical composition according to claims 136 or 137.
139 . The method according to claim 138 , wherein the disease is selected from an inflammatory disease, an autoimmune disease, an infectious disease, rheumatoid arthritis, ulcerative collitis, Crohn's disease, hepatitis, adult respiratory distress syndrome, glomerulonephritis, insulin-dependent diabetes mellitus (Type I), juvenile diabetes, psoriasis, graft vs. host disease, and hepatitis.
140 . A process for preparing an N-acylamino compound, comprising the steps of:
a) mixing a carboxylic acid with an N-alloc-protected amine in the presence of an inert solvent, triphenylphoshine, a nucleophilic scavenger, and tetrakis-triphenyl phosphine palladium(0) at ambient temperature under an inert atmosphere; and b) adding to the step a) mixture, HOBT and EDC; and optionally comprising the further step of: c) hydrolyzing the step b) mixture in the presence of a solution comprising an acid and H 2 O, wherein the step b) mixture is optionally concentrated.
141 . The process according to claim 140 , wherein the inert solvent is CH 2 Cl 2 , DMF, or a mixture of CH 2 Cl 2 and DMF.
142 . The process according to claim 140 , wherein the nucleophilic scavenger is dimedone, morpholine, trimethylsilyl dimethylamine or dimethyl barbituric acid.
143 . The process according to claim 142 , wherein the nucleophilic scavenger is trimethylsilyl dimethylamine or dimethyl barbituric acid.
144 . The process according to claim 142 , wherein the inert solvent is CH 2 Cl 2 , DMF, or a mixture of CH 2 Cl 2 and DMF.
145 . The process according to claim 144 , wherein the nucleophilic scavenger is dimethyl barbituric acid.
146 . The process according to claim 145 , wherein the solution comprises trifluoroacetic acid in about 1-90% by weight.
147 . The process according to claim 146 , wherein the solution comprises trifluoroacetic acid in about 20-50% by weight.
148 . The process according to claim 145 , wherein the solution comprises hydrochloric acid in about 0.1-30% by weight.
149 . The process according to claim 148 , wherein the solution comprises hydrochloric acid in about 5-15% by weight.
150 . The process according to any one of claims 140 - 149 , wherein the N-acylamino compound is represented by formula (VIII):
wherein:
R 1 is selected from the group consisting of the following formulae:
and
C is a ring chosen from the set consisting of benzo, pyrido, thieno, pyrrolo, furano, thiazolo, isothiazolo, oxazolo, isoxazolo, pyrimido, imidazolo, cyclopentyl, and cyclohexyl, the ring optionally being singly or multiply substituted by halogen, —NH 2 , or —NH—R 9 ,;
R 2 is:
m is 1 or 2;
each R 5 is independently selected from the group consisting of:
—C(O)—R 10 ,
—C(O)O—R 9 ,
—C(O)—N(R 10 )(R 10 )
—S(O) 2 —R 9 ,
—S(O) 2 —NH—R 10 ,
—C(O)—CH 2 —O—R 9 ,
—C(O)C(O)—R 10 ,
—R 9 ,
—H,
—C(O)C(O—OR 10 , and
—C(O)C(O)—N(R 9 )(R 10 );
X 5 is CH or N;
Y 2 is H 2 or O;
X 7 is —N(R 8 )— or —O—;
R 6 is selected from the group consisting of —H and —CH 3 ;
R 8 is selected from the group consisting of:
—C(O)—R 10 ,
—C(O)O—R 9 ,
—C(O)—N(H)—R 10 ,
—S(O) 2 —R 9 ,
—S(O) 2 —NH—R 10 ,
—C(O)—CH 2 —OR 10 ,
—C(O)C(O)—R 10 ;
—C(O)—CH 2 N(R 10 )(R 10 ),
—C(O)—CH 2 C(O)—O—R 9 ,
—C(O)—CH 2 C(O)—R 9 ,
—H, and
—C(O)—C(O)—OR 10 ;
each R 9 is independently selected from the group consisting of —Ar 3 and a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein the —C 1-6 alkyl group is optionally unsaturated;
each R 10 is independently selected from the group consisting of —H, —Ar 3 , a —C 3-6 cycloalkyl group, and a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , wherein the —C 1-6 alkyl group is optionally unsaturated;
R 13 is selected from the group consisting of H, Ar 3 , and a —C 1-6 straight or branched alkyl group optionally substituted with —Ar 3 , —CONH 2 , —OR 5 , —OH,
—OR 9 , or —CO 2 H;
each R 51 is independently selected from the group consisting of R 9 , —C(O)—R 9 , —C(O)—N(H)—R 9 , or each R 51 taken together forms a saturated 4-8 member carbocyclic ring or heterocyclic ring containing —O—, —S—, or —NH—;
each R 21 is independently selected from the group consisting of —H or a —C 1-6 straight or branched alkyl group;
each Ar 3 is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings and an aromatic heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocyclic group containing at least one heteroatom group selected from —O—, —S—, —SO—, SO 2 , ═N—, and —NH—, said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by —Q 1 ;
each Q 1 is independently selected from the group consisting of —NH 2 , —CO 2 H, —Cl, —F, —Br, —I, —NO 2 , —CN, ═O, —OH, -perfluoro C 1-3 alkyl, R 5 , —OR 5 , —NHR 5 , —OR 9 , —N(R 9 )(R 10 ), —R 9 , —C(O)—R 10 , and
provided that when —Ar 3 is substituted with a Q 1 group which comprises one or more additional —Ar 3 groups, said additional —Ar 3 groups are not substituted with another —Ar 3 ;
151 . The process according to any one of claims 140 - 149 wherein the N-alloc protected amine is:
R 51 is independently selected from the group consisting of R 9 , —C(O)—R 9 , —C(O)—N(H)—R 9 , or each R 51 taken together forms a saturated 4-8 member carbocyclic ring or heterocyclic ring containing —O—, —S—, or —NH—;
152 . The process according to any one of claims 140 - 149 , wherein R 1 is:
153 . The process according to any one of claims 140 - 149 , wherein R 1 is:Join the waitlist — get patent alerts
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