US2004106794A1PendingUtilityA1
3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands
Est. expiryApr 16, 2021(expired)· nominal 20-yr term from priority
Inventors:Arthur G. TaverasCynthia AkiRichard BondJianping ChaoMichael P. DwyerJohan FerreiraJianhua ChaoYounong YuJohn J. BaldwinBernd KaiserGe LiJ. MerrittPurakkattle BijuKingsley NelsonLaura Rokosz
A61P 37/06A61P 9/00A61P 37/02A61P 7/02A61P 9/12A61P 9/10A61P 35/00A61P 27/16A61P 25/28A61P 33/06A61P 31/14A61P 31/18A61P 31/12A61P 27/02A61P 25/00A61P 29/00A61P 31/04A61P 31/00A61P 11/06C07D 207/335A61P 17/02A61P 1/16C07C 225/20A61P 1/04C07D 307/52A61P 17/00C07D 317/46C07D 307/82C07D 217/24C07D 307/38C07D 409/14C07C 2601/04C07D 307/68A61P 19/02C07D 307/83C07D 413/14C07C 2601/14C07D 409/12A61P 1/18C07D 333/36A61P 13/12C07D 307/81C07C 2602/08C07C 255/59C07D 405/12A61P 1/02C07D 319/18C07D 213/74A61P 19/06C07D 413/12C07C 237/44C07D 295/26A61P 19/10C07D 333/20C07C 237/36C07C 311/39A61P 11/00A61P 11/14A61P 17/10A61P 17/06C07C 237/30C07D 333/42
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Claims
Abstract
There are disclosed compounds of the formula or a pharmaceutically acceptable salt or solvate thereof which are useful for the treatment of chemokine-mediated diseases such as acute and chronic inflammatory disorders and cancer.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of the formula:
and the pharmaceutically acceptable salts and solvates thereof, wherein:
A is selected from the group consisting of:
wherein the above rings of said A groups are substituted with 1 to 6 substituents each independently selected from the group consisting of: R 9 groups;
wherein one or both of the above rings of said A groups are substituted with 1 to 6 substituents each independently selected from the group consisting of: R 9 groups;
wherein the above phenyl rings of said A groups are substituted with 1 to 3 substituents each independently selected from the group consisting of: R 9 groups; and
B is selected from the group consisting of:
provided that R 3 for this group is selected from the group consisting of: —C(O)NR 13 R 14 ,
n is 0 to 6;
p is 1 to 5;
X is O, NH, or S;
Z is 1 to 3;
R 2 is selected from the group consisting of: hydrogen, OH, —C(O)OH, —SH, —SO 2 NR 13 R 14 , —NHC(O)R 13 , —NHSO 2 NR 13 R 14 , —NHSO 2 R 1 , —NR 13 R 14 , —C(O)NR 13 R 14 , —C(O)NHOR 13 , —C(O)NR 13 OH, —S(O 2 )OH, —OC(O)R 13 , an unsubstituted heterocyclic acidic functional group, and a substituted heterocyclic acidic functional-group; wherein there are 1 to 6 substituents on said substituted heterocyclic acidic functional group each substituent being independently selected from the group consisting of: R 9 groups;
each R 3 and R 4 is independently selected from the group consisting of: hydrogen, cyano, halogen, alkyl, alkoxy, —OH, —CF 3 , —OCF 3 , —NO 2 , —C(O)R 13 , —C(O)OR 13 , —C(O)NHR 17 , —C(O)NR 13 R 14 , —SO (t) NR 13 R 14 , —SO (t) R 13 , —C(O)NR 13 OR 14 , unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl,
wherein there are 1 to 6 substituents on said substituted aryl group and each substituent is independently selected from the group consisting of: R 9 groups; and wherein there are 1 to 6 substituents on said substituted heteroaryl group and each substituent is independently selected from the group consisting of: R 9 groups;
each R 5 and R 6 are the same or different and are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, —CF 3 , —OCF 3 , —NO 2 , —C(O)R 13 , —C(O)OR 13 , —C(O)NR 13 R 14 , —SO (t) NR 13 R 14 , —C(O)NR 13 OR 14 , cyano, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl group; wherein there are 1 to 6 substituents on said substituted aryl group and each substituent is independently selected from the group consisting of: R 9 groups; and wherein there are 1 to 6 substituents on said substituted heteroaryl group and each substituent is independently selected from the group consisting of: R 9 groups;
each R 7 and R 8 is independently selected from the group consisting of: H, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, —CO 2 R 13 , —CONR 13 R 14 , alkynyl, alkenyl, and cycloalkenyl; and wherein there are one or more substituents on said substituted R 7 and R 8 groups, wherein each substituent is independently selected from the group consisting of:
a) halogen,
b) —CF 3 ,
c) —COR 13 ,
d) —OR 13 ,
e) —NR 13 R 14 ,
f) —NO 2 ,
g) —CN,
h) —SO 2 OR 13 ,
i) —Si(alkyl) 3 , wherein each alkyl is independently selected,
j) —Si(aryl) 3 , wherein each alkyl is independently selected,
k) —(R 13 ) 2 R 14 Si, wherein each R 13 is independently selected,
l) —CO 2 R 13 ,
m) —C(O)NR 13 R 14 ,
n) —SO 2 NR 13 R 14 ,
o) —SO 2 R 13 ,
p) —OC(O)R 13 ,
q) —OC(O)NR 13 R 14 ,
r) —NR 13 C(O)R 14 , and
s) —NR 13 CO 2 R 14 ;
R 8a is selected from the group consisting of: hydrogen, alkyl, cycloalkyl and cycloalkylalkyl;
each R 9 is independently selected from the group consisting of:
a) —R 13 ,
b) halogen,
c) —CF 3 ,
d) —COR 13 ,
e) —OR 13 ,
f) —NR 13 R 14 ,
g) —NO 2 ,
h) —CN,
i) —SO 2 R 3 ,
j) —SO 2 NR 13 R 14 ,
k) —NR 13 COR 14 ,
l) —CONR 13 R 14 ,
m) —NR 13 CO 2 R 14 ,
n) —CO 2 R 13 ,
p) alkyl substituted with one or more —OH groups,
q) alkyl substituted with one or more —NR 13 R 14 group, and
r) —N(R 13 )SO 2 R 14 ;
each R 10 and R 11 is independently selected from the group consisting of R 13 , hydrogen, alkyl (e.g., C 1 to C 6 , such as methyl), halogen, —CF 3 , —OCF 3 , —NR 13 R 14 —NR 13 C(O)NR 13 R 14 , —OH, —C(O)OR 13 , —SH, —SO (t) NR 13 R 14 , —SO 2 R 13 , —NHC(O)R 13 , —NHSO 2 NR 13 R 14 —NHSO 2 R 13 , C(O)NR 13 R 14 , —C(O)NR 13 OR 14 , —OC(O)R 13 and cyano;
R 12 is selected from the group consisting of: hydrogen, —C(O)OR 13 , unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkylalkyl, and unsubstituted or substituted heteroarylalkyl group; wherein there are 1 to 6 substituents on the substituted R 12 groups and each substituent is independently selected from the group consisting of: R 9 groups;
each R 13 and R 14 is independently selected from the group consisting of: H, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted fluoroalkyl, and unsubstituted or substituted heterocycloalkylalkyl (wherein “heterocyloalkyl” means heterocyclic); wherein there are 1 to 6 substituents on said substituted R 13 and R 14 groups and each substituent is independently selected from the group consisting of: alkyl, —CF 3 , —OH, alkoxy, aryl, arylalkyl, fluroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, —N(R 40 ) 2 , —C(O)OR 15 , —C(O)NR 15 R 16 , —S(O) t NR 15 R 16 , —C(O)R 15 , —SO 2 R 15 provided that R 15 is not H, halogen, and —NHC(O)NR 15 R 16 ; or
R 13 and R 14 taken together with the nitrogen they are attached to in the groups —C(O)NR 13 R 14 and —SO 2 NR 13 R 14 form an unsubstituted or substituted saturated heterocyclic ring, said ring optionally containing one additional heteroatom selected from the group consisting of: O, S and NR 18 ; wherein there are 1 to 3 substituents on the substituted cyclized R 13 and R 14 groups and each substituent is independently selected from the group consisting of: alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, —C(O)OR 15 , —C(O)NR 15 R 16 , —SO t NR 15 R 16 , —C(O)R 15 , —SO 2 R 15 provided that R 15 is not H, —NHC(O)NR 15 R 16 , —NHC(O)OR 15 , halogen, and a heterocycloalkenyl group;
each R 15 and R 16 is independently selected from the group consisting of: H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl;
R 17 is selected from the group consisting of: —SO 2 alkyl, —SO 2 aryl, —SO 2 cycloalkyl, and —SO 2 heteroaryl;
R 18 is selected from the group consisting of: H, alkyl, aryl, heteroaryl, —C(O)R 19 , —SO 2 R 19 and —C(O)NR 19 R 20 ;
each R 19 and R 20 is independently selected from the group consisting of: alkyl, aryl and heteroaryl;
R 30 is selected from the group consisting of: alkyl, cycloalkyl, —CN, —NO 2 , or —SO 2 R 15 provided that R 15 is not H;
each R 31 is independently selected from the group consisting of: unsubstituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl and unsubstituted or substituted cycloalkyl; wherein there are 1 to 6 substituents on said substituted R 31 groups and each substituent is independently selected from the group consisting of: alkyl, halogen and —CF 3 ;
each R 40 is independently selected from the group consisting of: H, alkyl and cycloalkyl; and
t is 0, 1 or 2.
2 . The compound of claim 1 wherein B is selected from the group consisting of:
provided that R 3 for this group is selected from the group consisting of: —C(O)NR 13 R 14 ,
3 . The compound of claim 1 wherein B is:
wherein R 3 is selected from the group consisting of: —C(O)NR 13 R 14 ,
4 . The compound of claim 1 wherein B is:
5 . The compound of claim 1 wherein B is:
R 2 is —OH, and R 13 and R 14 are each the same or different alkyl group.
6 . The compound of claim 1 wherein B is
R 3 is selected from the group consisting of:
7 . The compound of claim 1 wherein B is:
and R 2 is —OH.
8 . The compound of claim 1 wherein B is
R 13 and R 14 are each the same or different alkyl group.
9 . The compound of claim 1 wherein B is
and R 3 is selected from the group consisting of:
10 . The compound of claim 1 wherein B is
11 . The compound of claim 10 wherein R 2 is —OH.
12 . The compound of claim 10 wherein R 13 and R 14 are the same or different alkyl group.
13 . The compound of claim 12 wherein the R 2 substituent is —OH.
14 . The compound of claim 12 wherein R 13 and R 14 methyl.
15 . The compound of claim 14 wherein the R 2 substituent is —OH.
16 . The compound of claim 1 wherein B is selected from the group consisting of:
17 . The compound of claim 1 wherein B is
18 . The compound of claim 17 wherein R 11 is H.
19 . The compound of claim 17 wherein R 2 is —OH.
20 . The compound of claim 17 wherein R 3 is —C(O)NR 13 R 14 .
21 . The compound of claim 17 wherein R 2 is —OH and R 3 is —C(O)NR 13 R 14 .
22 . The compound of claim 17 wherein R 2 is —OH, R 3 is —C(O)NR 13 R 14 , and R 11 is H.
23 . The compound of claim 22 wherein R 13 and R 14 are each independently selected from the group consisting of: alkyl, unsubstituted heteroaryl and substituted heteroaryl.
24 . The compound of claim 17 wherein R 3 is —S(O) t NR 13 R 14 .
25 . The compound of claim 24 wherein R 2 is —OH.
26 . The compound of claim 25 wherein the R 13 and R 14 substituents are the same or different and are selected from the group consisting of: H and alkyl.
27 . The compound of claim 26 wherein each R 13 and R 14 are independently selected from the group consisting of: H, methyl, ethyl, isopropyl and t-butyl.
28 . The compound of claim 27 wherein R 13 and R 14 are ethyl.
29 . The compound of claim 1 wherein B is
30 . The compound of claim 1 wherein B is
31 . The compound of claim 1 wherein A is
wherein the furan ring is unsubstituted or substituted.
32 . The compound of claim 1 wherein A is
wherein the furan ring is substituted.
33 . The compound of claim 1 wherein A is
wherein the furan ring is substituted with at least one alkyl group.
34 . The compound of claim 31 wherein R 7 and R 8 are independently selected from the group consisting of: H and alkyl.
35 . The compound of claim 34 wherein R 7 is H, and R 8 is alkyl.
36 . The compound of claim 33 wherein R 7 and R 5 are independently selected from the group consisting of: H and alkyl.
37 . The compound of claim 36 wherein R 7 is H, and R 8 is alkyl.
38 . The compound of claim 1 wherein A is selected from the group consisting of:
wherein the above rings are unsubstituted, or the above rings are substituted with 1 to 3 substituents independently selected from the group consisting of: H, F, Cl, Br, alkyl, cycloalkyl, and —CF 3 ; R 7 is selected from the group consisting of: H, —CF 3 , —CF 2 CH 3 , methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R 8 is H; and
wherein R 7 is selected from the group consisting of: H, —CF 3 , —CF 2 CH 3 , methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R 8 is H; and R 8a is as defined for formula IA.
39 . The compound of claim 4 wherein A is
wherein the furan ring is unsubstituted or substituted.
40 . The compound of claim 4 wherein A is
wherein the furan ring is substituted with at least one alkyl group.
41 . The compound of claim 40 wherein R 7 and R 8 are independently selected from the group consisting of: H and alkyl.
42 . The compound of claim 41 wherein R 7 is H and R 8 is alkyl.
43 . The compound of claim 5 wherein A is
wherein the furan ring is unsubstituted or substituted.
44 . The compound of claim 4 wherein A is
wherein the furan ring is substituted with at least one alkyl group.
45 . The compound of claim 44 wherein R 7 and R 8 are independently selected from the group consisting of: H and alkyl.
46 . The compound of claim 45 wherein R 7 is H and R 8 is alkyl.
47 . The compound of claim 10 wherein A is
wherein the furan ring is unsubstituted or substituted.
48 . The compound of claim 10 wherein A is
wherein the furan ring is substituted with at least one alkyl group.
49 . The compound of claim 48 wherein R 7 and R 8 are independently selected from the group consisting of: H and alkyl.
50 . The compound of claim 49 wherein R 7 is H and R 8 is alkyl.
51 . The compound of claim 11 wherein A is
wherein the furan ring is unsubstituted or substituted.
52 . The compound of claim 11 wherein A is
wherein the furan ring is substituted with at least one alkyl group.
53 . The compound of claim 52 wherein R 7 and R 8 are independently selected from the group consisting of: H and alkyl.
54 . The compound of claim 53 wherein R 7 is H and R 8 is alkyl.
55 . The compound of claim 13 wherein A is
wherein the furan ring is unsubstituted or substituted.
56 . The compound of claim 13 wherein A is
wherein the furan ring is substituted with at least one alkyl group.
57 . The compound of claim 56 wherein R 7 and R 8 are independently selected from the group consisting of: H and alkyl.
58 . The compound of claim 57 wherein R 7 is H and R 8 is alkyl.
59 . The compound of claim 1 wherein:
(1) A is selected from the group consisting of:
wherein the above rings are unsubstituted, or the above rings are substituted with 1 to 3 substituents independently selected from the group consisting of: F, Cl, Br, alkyl, cycloalkyl, and —CF 3 ; R 7 is selected from the group consisting of: H, —CF 3 , —CF 2 CH 3 , methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R 8 is H; and
wherein R 7 is selected from the group consisting of: H, —CF 3 , —CF 2 CH 3 , methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R 8 is H; and R 8a is as defined for formula IA;
(2) B is:
and
wherein:
R 2 is selected from the group consisting of: H, OH, —NHC(O)R 13 and —NHSO 2 R 13 ;
R 4 is selected from the group consisting of: H, —NO 2 , cyano, —CH 3 or —CF 3 ;
R 5 is selected from the group consisting of: H, —CF 3 , —NO 2 , halogen and cyano; and
R 6 is selected from the group consisting of: H, alkyl and —CF 3 ; and
each R 13 and R 14 is independently selected from the group consisting of: methyl and ethyl.
60 . The compound of claim 1 wherein:
(1) A is selected from the group consisting of:
wherein the above rings are unsubstituted, or the above rings are substituted with 1 to 3 substituents independently selected from the group consisting of: F, Cl, Br, alkyl, cycloalkyl, and —CF 3 ; R 7 is selected from the group consisting of: H, —CF 3 , —CF 2 CH 3 , methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R 8 is H; and
wherein R 7 is selected from the group consisting of: H, —CF 3 , —CF 2 CH 3 , methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R 8 is H; and Raa is as defined for formula IA;
(2) B is selected:
wherein:
R 2 is selected from the group consisting of: H, OH, —NHC(O)R 13 and —NHSO 2 R 13 ;
R 3 is selected from the group consisting of: —C(O)NR 13 R 14 —SO 2 NR 13 R 14 , —NO 2 , cyano, and —SO 2 R 13 ;
R 11 is selected from the group consisting of: H, halogen and alkyl; and
each R 13 and R 14 is independently selected from the group consisting of: H, methyl, ethyl, isopropyl, and t-butyl.
61 . The compound of claim 1 wherein:
(1) A is selected from the group consisting of:
wherein the above rings are unsubstituted, or the above rings are substituted with 1 to 3 substituents independently selected from the group consisting of: F, Cl, Br, alkyl, cycloalkyl, and —CF 3 ; R 7 is selected from the group consisting of: H, —CF 3 , —CF 2 CH 3 , methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R 8 is H; and
wherein R 7 is selected from the group consisting of: H, —CF 3 , —CF 2 CH 3 , methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R 8 is H; and R 8a is as defined for formula IA;
(2) B is selected:
wherein:
R 2 is selected from the group consisting of: H, OH, —NHC(O)R 13 and —NHSO 2 R 13 ;
R 3 is —SO 2 NR 13 R 14 ;
R 11 is selected from the group consisting of: H, halogen and alkyl; and
each R 13 and R 14 is independently selected from the group consisting of: H, methyl, ethyl, isopropyl, and t-butyl.
62 . The compound of claim 1 wherein:
(1) A is selected from the group consisting of:
wherein the above rings are unsubstituted, or the above rings are substituted with 1 to 3 substituents independently selected from the group consisting of: F, Cl, Br, alkyl, cycloalkyl, and —CF 3 ; R 7 is selected from the group consisting of: H, —CF 3 , —CF 2 CH 3 , methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R 8 is H; and
wherein R 7 is selected from the group consisting of: H, —CF 3 , —CF 2 CH 3 , methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R 8 is H; and R 8a is as defined for formula IA;
(2) B is selected:
wherein:
R 2 is selected from the group consisting of: H, OH, —NHC(O)R 13 and —NHSO 2 R 13 ;
R 3 is —SO 2 NR 13 R 14 ;
R 11 is selected from the group consisting of: H, halogen and alkyl; and
each R 13 and R 14 is ethyl.
63 . The compound of claim 1 wherein
(1) A is selected from the group consisting of:
(2) B is:
wherein:
R 2 is —OH;
R 4 is selected form the group consisting of: H, —CH 3 and —CF 3 ;
R 5 is selected from the group consisting of: H and cyano;
R 6 is selected from the group consisting of: H, —CH 3 and —CF 3 ;
R 13 and R 14 are methyl.
64 . The compound of claim 1 wherein
(1) A is selected from the group consisting of:
(2) B is:
wherein:
R 2 is —OH;
R 3 is selected from the group consisting of: —SO 2 NR 13 R 14 and —CONR 13 R 14 ;
R 11 is H; and
each R 13 and R 14 are independently selected from the group consisting of: H, methyl, ethyl, isopropyl and t-butyl.
65 . The compound of claim 1 wherein
(1) A is selected from the group consisting of:
(2) B is:
wherein:
R 2 is —OH;
R 3 is —SO 2 NR 13 R 14 ;
R 11 is H; and
each R 13 and R 14 are independently selected from the group consisting of: H, methyl, ethyl, isopropyl and t-butyl.
66 . The compound of claim 1 wherein
(1) A is selected from the group consisting of:
(2) B is:
wherein:
R 2 is —OH;
R 3 is —SO 2 NR 13 R 14 ;
R 11 is H; and
R 13 and R 14 are ethyl.
67 . The compound of claim 1 wherein said compound is a calcium salt.
68 . The compound of claim 1 wherein said compound is a sodium salt.
69 . The compound of claim 1 wherein said compound is selected from the group consisting of:
70 . The compound of claim 1 selected from the group consisting of:
71 . The compound of claim 1 selected from the group consisting of:
72 . The compound of claim 1 selected from the group consisting of:
73 . The compound of claim 72 wherein said compound is a calcium or sodium salt.
74 . The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
75 . The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
76 . The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
77 . The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
78 . The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
79 . The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
80 . The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
81 . The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
82 . The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
83 . The compound of claim 1 wherein said compound is;
or a pharmaceutically acceptable salt or solvate thereof.
84 . The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
85 . The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
86 . The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
87 . The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
88 . The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
89 . The compound of claim 84 wherein said compound is a calcium or sodium salt.
90 . The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
91 . The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
92 . The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
93 . The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
94 . The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
95 . The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
96 . A method of treating a chemokine-mediated disease, in a patient in need of such treatment, wherein the chemokine binds to a CXCR2 and/or CXCR1 receptor in said patient, comprising administering to said patient an effective amount of at least one compound of claim 1 .
97 . A method of treating a chemokine-mediated disease, in a patient in need of such treatment, wherein the chemokine binds to a CXC receptor in said patient, comprising administering to said patient an effective amount of at least one compound of claim 1 .
98 . The method of claim 96 wherein the chemokine mediated disease is selected from the group consisting of: psoriasis, atopic dermatitis, asthma, COPD, adult respiratory disease, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, stroke, cardiac and renal reperfusion injury, glomerulonephritis, thrombosis, Alzheimer's disease, graft vs. host reaction, allograft rejections, malaria, acute respiratory distress syndrome, delayed type hypersensitivity reaction, atherosclerosis, cerebral and cardiac ischemia, osteoarthritis, multiple sclerosis, restinosis, angiogenesis, osteoporosis, gingivitis, respiratory viruses, herpes viruses, hepatitis viruses, HIV, Kaposi's sarcoma associated virus, meningitis, cystic fibrosis, pre-term labor, cough, pruritis, multi-organ dysfunction, trauma, strains, sprains, contusions, psoriatic arthritis, herpes, encephalitis, CNS vasculitis, traumatic brain injury, CNS tumors, subarachnoid hemorrhage, post surgical trauma, interstitial pneumonitis, hypersensitivity, crystal induced arthritis, acute and chronic pancreatitis, acute alcoholic hepatitis, necrotizing enterocolitis, chronic sinusitis, angiogenic ocular disease, ocular inflammation, retinopathy of prematurity, diabetic retinopathy, macular degeneration with the wet type preferred and corneal neovascularization, polymyositis, vasculitis, acne, gastric and duodenal ulcers, celiac disease, esophagitis, glossitis, airflow obstruction, airway hyperresponsiveness, bronchiectasis, bronchiolitis, bronchiolitis obliterans, chronic bronchitis, cor pulmonae, cough, dyspnea, emphysema, hypercapnea, hyperinflation, hypoxemia, hyperoxia-induced inflammations, hypoxia, surgical lung volume reduction, pulmonary fibrosis, pulmonary hypertension, right ventricular hypertrophy, peritonitis associated with continuous ambulatory peritoneal dialysis (CAPD), granulocytic ehrlichiosis, sarcoidosis, small airway disease, ventilation-perfusion mismatching, wheeze, colds, gout, alcoholic liver disease, lupus, burn therapy, periodontitis, transplant reperfusion injury and early transplantation.
99 . A method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of at least one compound of claim 1 .
100 . A method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of at least one compound of claim 1 in combination with the administration of at least one anticancer agent.
101 . The method of claim 100 wherein said anticancer agent is selected from the group consisting of: alkylating agents, antimetabolites, natural products and their derivatives, hormones, anti-hormones, anti-angiogenic agents and steroids, and synthetics.
102 . A method of inhibiting angiogenesis in a patient in need of such treatment comprising administering to said patient an effective amount of at least one compound of claim 1 .
103 . A method of inhibiting angiogenesis in a patient in need of such treatment comprising administering to said patient an effective amount of at least one compound of claim 1 in combination with the administration an effective amount of at least one anti-angiogenesis compound.
104 . A method of treating a disease selected from the group consisting of: gingivitis, respiratory viruses, herpes viruses, hepatitis viruses, HIV, kaposi's sarcoma associated virus and atherosclerosis, in a patient in need of such treatment, comprising administering to said patient an effective amount of at least one compound of claim 1 .
105 . The method of claim 96 wherein the chemokine mediated disease is an angiogenic ocular disease.
106 . The method of claim 105 wherein said angiogenic ocular disease is selected from the group consisting of: ocular inflammation, retinopathy of prematurity, diabetic retinopathy, macular degeneration with the wet type preferred and corneal neovascularization.
107 . The method of claim 99 wherein the cancer treated is melanoma, gastric carcinoma, or non-small cell lung carcinoma.
108 . The method of claim 100 wherein the cancer treated is melanoma, gastric carcinoma, or non-small cell lung carcinoma.
109 . The method of claim 101 , wherein the cancer treated is melanoma, gastric carcinoma, or non-small cell lung carcinoma.
110 . A pharmaceutical composition comprising an effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable carrier.
111 . The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
112 . A method of treating a chemokine-mediated disease, in a patient in need of such treatment, wherein the chemokine binds to a CXCR2 and/or CXCR1 receptor in said patient, comprising administering to said patient an effective amount of at least one compound of formula IA:
and the pharmaceutically acceptable salts and solvates thereof, wherein:
A is selected from the group consisting of:
wherein the above rings of said A groups are substituted with 1 to 6 substituents each independently selected from the group consisting of: R 9 groups;
wherein one or both of the above rings of said A groups are substituted with 1 to 6 substituents each independently selected from the group consisting of: R 9 groups;
wherein the above phenyl rings of said A groups are substituted with 1 to 3 substituents each independently selected from the group consisting of: R 9 groups; and
B is:
n is 0 to 6; p is 1 to 5; X is O, NH, or S; Z is 1 to 3; R 2 is selected from the group consisting of: hydrogen, OH, —C(O)OH, —SH, —SO 2 NR 13 R 14 , —NHC(O)R 13 , —NHSO 2 NR 13 R 14 , —NHSO 2 R 13 , —NR 13 R 14 —C(O)NR 13 R 14 , —C(O)NHOR 13 , —C(O)NR 13 OH, —S(O 2 )OH, —OC(O)R 13 , an unsubstituted heterocyclic acidic functional group, and a substituted heterocyclic acidic functional group; wherein there are 1 to 6 substituents on said substituted heterocyclic acidic functional group each substituent being independently selected from the group consisting of: R 9 groups; each R 3 and R 4 is independently selected from the group consisting of: hydrogen, cyano, halogen, alkyl, alkoxy, —OH, —CF 3 , —OCF 3 , —NO 2 , —C(O)R 13 , —C(O)OR 13 , —C(O)NHR 17 , —SO (t) NR 13 R 14 , —SO (t) R 13 , —C(O)NR 13 OR 14 , unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl; wherein there are 1 to 6 substituents on said substituted aryl group and each substituent is independently selected from the group consisting of: R 9 groups; and wherein there are 1 to 6 substituents on said substituted heteroaryl group and each substituent is independently selected from the group consisting of: R 9 groups; each R 5 and R 6 are the same or different and are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, —CF 3 , —OCF 3 , —NO 2 , —C(O)R 3 , —C(O)OR 13 , —C(O)NR 13 R 14 , —SO (t) NR 13 R 14 , —C(O)NR 13 OR 14 , cyano, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl group; wherein there are 1 to 6 substituents on said substituted aryl group and each substituent is independently selected from the group consisting of: R 9 groups; and wherein there are 1 to 6 substituents on said substituted heteroaryl group and each substituent is independently selected from the group consisting of: R 9 groups; each R 7 and R 8 is independently selected from the group consisting of: H, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, —CO 2 R 13 , —CONR 13 R 14 , alkynyl, alkenyl, and cycloalkenyl; and wherein there are one or more substituents on said substituted R 7 and R 8 groups, wherein each substituent is independently selected from the group consisting of:
a) halogen,
b) —CF 3 ,
c) —COR 13 ,
d) —OR 13 ,
e) —NR 13 R 14 ,
f) —NO 2 ,
g) —CN,
h) —SO 2 OR 13 ,
i) —Si(alkyl) 3 , wherein each alkyl is independently selected,
j) —Si(aryl) 3 , wherein each alkyl is independently selected,
k) —(R 13 ) 2 R 14 Si, wherein each R 13 is independently selected,
l) —CO 2 R 13 ,
m) —C(O)NR 13 R 14 ,
n) —SO 2 NR 13 R 14 ,
o) —SO 2 R 13 ,
p) —OC(O)R 13 ,
q) —OC(O)NR 13 R 14 ,
r) —NR 13 C(O)R 14 , and
s) —NR 13 CO 2 R 14 ;
R 8a is selected from the group consisting of: hydrogen, alkyl, cycloalkyl and cycloalkylalkyl; each R 9 is independently selected from the group consisting of:
a) —R 13 ,
b) halogen,
c) —CF 3 ,
d) —COR 13 ,
e) —OR 13 ,
f) —NR 13 R 14 ,
g) —NO 2 ,
h) —CN,
i) —SO 2 R 13 ,
j) —SO 2 NR 13 R 14 ,
k) —NR 13 COR 14 ,
l) —CONR 13 R 14 ,
m) —NR 3 CO 2 R 14 ,
n) —CO 2 R 13 ,
p) alkyl substituted with one or more —OH groups,
q) alkyl substituted with one or more —NR 13 R 14 group, and
r) —N(R 13 )SO 2 R 14 ;
R 12 is selected from the group consisting of: hydrogen, —C(O)OR 13 , unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkylalkyl, and unsubstituted or substituted heteroarylalkyl group; wherein there are 1 to 6 substituents on the substituted R 12 groups and each substituent is independently selected from the group consisting of: R 9 groups; each R 13 and R 14 is independently selected from the group consisting of: H, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted fluoroalkyl, and unsubstituted or substituted heterocycloalkylalkyl; wherein there are 1 to 6 substituents on said substituted R 13 and R 14 groups and each substituent is independently selected from the group consisting of: alkyl, —CF 3 , —OH, alkoxy, aryl, arylalkyl, fluroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, —N(R 40 ) 2 , —C(O)OR 15 , —C(O)NR 15 R 16 , —S(O) t NR 15 R 16 , —C(O)R 15 , —SO 2 R 15 provided that R 15 is not H, halogen, and —NHC(O)NR 15 R 16 ; or R 13 and R 14 taken together with the nitrogen they are attached to in the groups —NR 13 R 14 , —C(O)NR 13 R 14 , —SO 2 NR 13 R 14 , —OC(O)NR 13 R 14 , —CONR 13 R 14 —NR 13 C(O)NR 13 R 14 , —SO t NR 13 R 14 , —NHSO 2 NR 13 R 14 form an unsubstituted or substituted saturated heterocyclic ring, said ring optionally containing one additional heteroatom selected from the group consisting of: O, S and NR 18 ; wherein there are 1 to 3 substituents on the substituted cyclized R 13 and R 14 groups and each substituent is independently selected from the group consisting of: alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, —C(O)OR 15 , —C(O)NR 15 R 16 , —SO t NR 15 R 16 , —C(O)R 15 , —SO 2 R 15 provided that R 15 is not H, —NHC(O)NR 15 R 16 , —NHC(O)OR 15 , halogen, and a heterocycloalkenyl group; each R 15 and R 16 is independently selected from the group consisting of: H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl; R 17 is selected from the group consisting of: —SO 2 alkyl, —SO 2 aryl, —SO 2 cycloalkyl, and —SO 2 heteroaryl; R 18 is selected from the group consisting of: H, alkyl, aryl, heteroaryl, —C(O)R 19 , —SO 2 R 19 and —C(O)NR 19 R 20 ; each R 19 and R 20 is independently selected from the group consisting of: alkyl, aryl and heteroaryl; each R 40 is independently selected from the group consisting of: H, alkyl and cycloalkyl; and t is 0, 1 or 2.
113 . The method of claim 112 wherein the chemokine mediated disease is selected from the group consisting of: psoriasis, atopic dermatitis, asthma, COPD, adult respiratory disease, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, stroke, cardiac and renal reperfusion injury, glomerulonephritis, thrombosis, Alzheimer's disease, graft vs. host reaction, allograft rejections, malaria, acute respiratory distress syndrome, delayed type hypersensitivity reaction, atherosclerosis, cerebral and cardiac ischemia, osteoarthritis, multiple sclerosis, restinosis, angiogenesis, osteoporosis, gingivitis, respiratory viruses, herpes viruses, hepatitis viruses, HIV, Kaposi's sarcoma associated virus, meningitis, cystic fibrosis, pre-term labor, cough, pruritis, multi-organ dysfunction, trauma, strains, sprains, contusions, psoriatic arthritis, herpes, encephalitis, CNS vasculitis, traumatic brain injury, CNS tumors, subarachnoid hemorrhage, post surgical trauma, interstitial pneumonitis, hypersensitivity, crystal induced arthritis, acute and chronic pancreatitis, acute alcoholic hepatitis, necrotizing enterocolitis, chronic sinusitis, angiogenic ocular disease, ocular inflammation, retinopathy of prematurity, diabetic retinopathy, macular degeneration with the wet type preferred and corneal neovascularization, polymyositis, vasculitis, acne, gastric and duodenal ulcers, celiac disease, esophagitis, glossitis, airflow obstruction, airway hyperresponsiveness, bronchiectasis, bronchiolitis, bronchiolitis obliterans, chronic bronchitis, cor pulmonae, cough, dyspnea, emphysema, hypercapnea, hyperinflation, hypoxemia, hyperoxia-induced inflammations, hypoxia, surgical lung volume reduction, pulmonary fibrosis, pulmonary hypertension, right ventricular hypertrophy, peritonitis associated with continuous ambulatory peritoneal dialysis (CAPD), granulocytic ehrlichiosis, sarcoidosis, small airway disease, ventilation-perfusion mismatching, wheeze, colds, gout, alcoholic liver disease, lupus, burn therapy, periodontitis, transplant reperfusion injury and early transplantation.
114 . A method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of at least one compound of formula IA:
and the pharmaceutically acceptable salts and solvates thereof, wherein:
A is selected from the group consisting of:
wherein the above rings of said A groups are substituted with 1 to 6 substituents each independently selected from the group consisting of: R 9 groups;
wherein one or both of the above rings of said A groups are substituted with 1 to 6 substituents each independently selected from the group consisting of: R 9 groups;
wherein the above phenyl rings of said A groups are substituted with 1 to 3 substituents each independently selected from the group consisting of: R 9 groups; and
B is:
n is 0 to 6; p is 1 to 5; X is O, NH, or S; Z is 1 to 3; R 2 is selected from the group consisting of: hydrogen, OH, —C(O)OH, —SH, —SO 2 NR 13 R 14 , —NHC(O)R 13 , —NHSO 2 NR 13 R 14 , —NHSO 2 R 13 , —NR 13 R 14 , —C(O)NR 13 R 14 —C(O)NHOR 13 , —C(O)NR 13 OH, —S(O 2 )OH, —OC(O)R 13 , an unsubstituted heterocyclic acidic functional group, and a substituted heterocyclic acidic functional group; wherein there are 1 to 6 substituents on said substituted heterocyclic acidic functional group each substituent being independently selected from the group consisting of: R 9 groups; each R 3 and R 4 is independently selected from the group consisting of: hydrogen, cyano, halogen, alkyl, alkoxy, —OH, —CF 3 , —OCF 3 , —NO 2 , —C(O)R 13 , —C(O)OR 13 , —C(O)NHR 17 , —SO (t) NR 13 R 14 , —SO (t) R 13 , —C(O)NR 3 OR 14 , unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl; wherein there are 1 to 6 substituents on said substituted aryl group and each substituent is independently selected from the group consisting of: R 9 groups; and wherein there are 1 to 6 substituents on said substituted heteroaryl group and each substituent is independently selected from the group consisting of: R 9 groups; each R 5 and R 6 are the same or different and are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, —CF 3 , —OCF 3 , —NO 2 , —C(O)R 13 —C(O)OR 13 , —C(O)NR 13 R 14 , —SO (t) NR 13 R 14 , —C(O)NR 13 OR 14 , cyano, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl group; wherein there are 1 to 6 substituents on said substituted aryl group and each substituent is independently selected from the group consisting of: R 9 groups; and wherein there are 1 to 6 substituents on said substituted heteroaryl group and each substituent is independently selected from the group consisting of: R 9 groups; each R 7 and R 8 is independently selected from the group consisting of: H, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, —CO 2 R 13 , —CONR 13 R 14 , alkynyl, alkenyl, and cycloalkenyl; and wherein there are one or more substituents on said substituted R 7 and R 8 groups, wherein each substituent is independently selected from the group consisting of:
a) halogen,
b) —CF 3 ,
c) —COR 13 ,
d) —OR 13 ,
e) —NR 13 R 14 ,
f) —NO 2 ,
g) —CN,
h) —SO 2 OR 13 ,
i) —Si(alkyl) 3 , wherein each alkyl is independently selected,
j) —Si(aryl) 3 , wherein each alkyl is independently selected,
k) —(R 13 ) 2 R 14 Si, wherein each R 13 is independently selected,
l) —CO 2 R 13 ,
m) —C(O)NR 13 R 14 ,
n) —SO 2 NR 13 R 14 ,
o) —SO 2 R 13 ,
p) —OC(O)R 13 ,
q) —OC(O)NR 13 R 14 ,
r) —NR 13 C(O)R 14 , and
s) —NR 13 CO 2 R 14 ;
R 8a is selected from the group consisting of: hydrogen, alkyl, cycloalkyl and cycloalkylalkyl; each R 9 is independently selected from the group consisting of:
a) —R 13 ,
b) halogen,
c) —CF 3 ,
d) —COR 13 ,
e) —OR 13 ,
f) —NR 13 R 14 ,
g) —NO 2 ,
h) —CN,
i) —SO 2 R 13 ,
j) —SO 2 NR 13 R 14 ,
k) —NR 13 COR 14 ,
l) —CONR 13 R 14 ,
m) —NR 13 CO 2 R 14 ,
n) —CO 2 R 13 ,
p) alkyl substituted with one or more —OH groups,
q) alkyl substituted with one or more —NR 13 R 14 group, and
r) —N(R 13 )SO 2 R 14 ;
R 12 is selected from the group consisting of: hydrogen, —C(O)OR 13 , unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkylalkyl, and unsubstituted or substituted heteroarylalkyl group; wherein there are 1 to 6 substituents on the substituted R 12 groups and each substituent is independently selected from the group consisting of: R 9 groups; each R 13 and R 14 is independently selected from the group consisting of: H, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted fluoroalkyl, and unsubstituted or substituted heterocycloalkylalkyl; wherein there are 1 to 6 substituents on said substituted R 13 and R 14 groups and each substituent is independently selected from the group consisting of: alkyl, —CF 3 , —OH, alkoxy, aryl, arylalkyl, fluroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, —N(R 40 ) 2 , —C(O)OR 15 , —C(O)NR 15 R 16 , —S(O) t NR 15 R 16 , —C(O)R 15 , —SO 2 R 15 provided that R 15 is not H, halogen, and —NHC(O)NR 15 R 16 ; or R 13 and R 14 taken together with the nitrogen they are attached to in the groups —NR 13 R 14 , —C(O)NR 13 R 14 , —SO 2 NR 13 R 14 , —OC(O)NR 13 R 14 , —CONR 13 R 14 —NR 13 C(O)NR 13 R 14 , —SO t NR 13 R 14 , —NHSO 2 NR 13 R 14 form an unsubstituted or substituted saturated heterocyclic ring, said ring optionally containing one additional heteroatom selected from the group consisting of: O, S and NR 18 ; wherein there are 1 to 3 substituents on the substituted cyclized R 13 and R 14 groups and each substituent is independently selected from the group consisting of: alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, —C(O)OR 15 , —C(O)NR 15 R 16 , —SO t NR 15 R 16 , —C(O)R 15 , —SO 2 R 15 provided that R 15 is not H, —NHC(O)NR 15 R 16 , —NHC(O)OR 15 , halogen, and a heterocycloalkenyl group; each R 15 and R 16 is independently selected from the group consisting of: H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl; R 17 is selected from the group consisting of: —SO 2 alkyl, —SO 2 aryl, —SO 2 cycloalkyl, and —SO 2 heteroaryl; R 18 is selected from the group consisting of: H, alkyl, aryl, heteroaryl, —C(O)R 19 , —SO 2 R 19 and —C(O)NR 19 R 20 ; each R 19 and R 20 is independently selected from the group consisting of: alkyl, aryl and heteroaryl; each R 40 is independently selected from the group consisting of: H, alkyl and cycloalkyl; and t is 0, 1 or 2.
115 . The method of claim 114 wherein said compound of formula IA is administered in combination with the administration of at least one anticancer agent.
116 . The method of claim 115 wherein said anticancer agent is selected from the group consisting of: alkylating agents, antimetabolites, natural products and their derivatives, hormones, anti-hormones, anti-angiogenic agents and steroids, and synthetics.
117 . A method of inhibiting angiogenesis, in a patient in need of such treatment, comprising administering to said patient an effective amount of at least one compound of formula IA:
and the pharmaceutically acceptable salts and solvates thereof, wherein:
A is selected from the group consisting of:
wherein the above rings of said A groups are substituted with 1 to 6 substituents each independently selected from the group consisting of: R 9 groups;
wherein one or both of the above rings of said A groups are substituted with 1 to 6 substituents each independently selected from the group consisting of: R 9 groups;
wherein the above phenyl rings of said A groups are substituted with 1 to 3 substituents each independently selected from the group consisting of: R 9 groups; and
B is:
n is 0 to 6; p is 1 to 5; X is O, NH, or S; Z is 1 to 3; R 2 is selected from the group consisting of: hydrogen, OH, —C(O)OH, —SH, —SO 2 NR 13 R 14 , —NHC(O)R 13 , —NHSO 2 N R 13 R 14 , —NHS O 2 R 13 , —NR 13 R 14 , —C(O)NR 13 R 14 , —C(O)NH O R 13 , —C(O)NR 13 OH, —S(O 2 )OH, —OC(O)R 13 , an unsubstituted heterocyclic acidic functional group, and a substituted heterocyclic acidic functional group; wherein there are 1 to 6 substituents on said substituted heterocyclic acidic functional group each substituent being independently selected from the group consisting of: R 9 groups; each R 3 and R 4 is independently selected from the group consisting of: hydrogen, cyano, halogen, alkyl, alkoxy, —OH, —CF 3 , —OCF 3 , —NO 2 , —C(O)R 13 , —C(O)OR 13 , —C(O)NHR 17 , —SO (t) NR 13 R 14 , —SO (t) R 3 , —C(O)NR 13 OR 14 , unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl; wherein there are 1 to 6 substituents on said substituted aryl group and each substituent is independently selected from the group consisting of: R 9 groups; and wherein there are 1 to 6 substituents on said substituted heteroaryl group and each substituent is independently selected from the group consisting of: R 9 groups; each R 5 and R 6 are the same or different and are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, —CF 3 , —OCF 3 , —NO 2 , —C(O)R 13 —C(O)OR 13 , —C(O)NR 13 R 14 , —SO (t) NR 13 R 14 , —C(O)NR 13 OR 14 , cyano, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl group; wherein there are 1 to 6 substituents on said substituted aryl group and each substituent is independently selected from the group consisting of: R 9 groups; and wherein there are 1 to 6 substituents on said substituted heteroaryl group and each substituent is independently selected from the group consisting of: R 9 groups; each R 7 and R 8 is independently selected from the group consisting of: H, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, —CO 2 R 13 , —CONR 13 R 14 , alkynyl, alkenyl, and cycloalkenyl; and wherein there are one or more substituents on said substituted R 7 and R 8 groups, wherein each substituent is independently selected from the group consisting of:
a) halogen,
b) —CF 3 ,
c) —COR 13 ,
d) —OR 13 ,
e) —NR 13 R 14 ,
f) —NO 2 ,
g) —CN,
h) —SO 2 OR 13 ,
i) —Si(alkyl) 3 , wherein each alkyl is independently selected,
j) —Si(aryl) 3 , wherein each alkyl is independently selected,
k) —(R 13 ) 2 R 14 Si, wherein each R 13 is independently selected,
l) —CO 2 R 13 ,
m) —C(O)NR 13 R 14 ,
n) —SO 2 NR 13 R 14 ,
o) —SO 2 R 13 ,
p) —OC(O)R 13 ,
q) —OC(O)NR 13 R 14 ,
r) —NR 3 C(O)R 14 , and
s) —NR 13 CO 2 R 14 ;
R 8a is selected from the group consisting of: hydrogen, alkyl, cycloalkyl and cycloalkylalkyl; each R 9 is independently selected from the group consisting of:
a) —R 13 ,
b) halogen,
c) —CF 3 ,
d) —COR 13 ,
e) —OR 13 ,
f) —NR 13 R 14 ,
g) —NO 2 ,
h) —CN,
i) —SO 2 R 13 ,
j) —SO 2 NR 13 R 14 ,
k) —NR 13 COR 14 ,
l) —CONR 13 R 14 ,
m) —NR 3 CO 2 R 14 ,
n) —CO 2 R 13 ,
p) alkyl substituted with one or more —OH groups,
q) alkyl substituted with one or more —NR 13 R 14 group, and
r) —N(R 13 )SO 2 R 14 ;
R 12 is selected from the group consisting of: hydrogen, —C(O)OR 13 , unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkylalkyl, and unsubstituted or substituted heteroarylalkyl group; wherein there are 1 to 6 substituents on the substituted R 12 groups and each substituent is independently selected from the group consisting of: R 9 groups; each R 13 and R 14 is independently selected from the group consisting of: H, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted fluoroalkyl, and unsubstituted or substituted heterocycloalkylalkyl; wherein there are 1 to 6 substituents on said substituted R 13 and R 14 groups and each substituent is independently selected from the group consisting of: alkyl, —CF 3 , —OH, alkoxy, aryl, arylalkyl, fluroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, —N(R 40 ) 2 , —C(O)OR 15 , —C(O)NR 15 R 16 , —S(O) t NR 15 R 16 , —C(O)R 15 , —SO 2 R 15 provided that R 15 is not H, halogen, and —NHC(O)NR 15 R 16 ; or R 13 and R 14 taken together with the nitrogen they are attached to in the groups —NR 13 R 14 , —C(O)NR 13 R 14 , —SO 2 NR 13 R 14 , —OC(O)NR 13 R 14 , —CONR 13 R 14 —NR 13 C(O)NR 13 R 14 , —SO t NR 13 R 14 , —NHSO 2 NR 13 R 14 form an unsubstituted or substituted saturated heterocyclic ring, said ring optionally containing one additional heteroatom selected from the group consisting of: O, S and NR 18 ; wherein there are 1 to 3 substituents on the substituted cyclized R 13 and R 14 groups and each substituent is independently selected from the group consisting of: alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, —C(O)OR 15 , —C(O)NR 15 R 16 , —SO t NR 15 R 16 , —C(O)R 15 , —SO 2 R 15 provided that R 5 is not H, —NHC(O)NR 15 R 16 , —NHC(O)OR 15 , halogen, and a heterocycloalkenyl group; each R 15 and R 16 is independently selected from the group consisting of: H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl; R 17 is selected from the group consisting of: —SO 2 alkyl, —SO 2 aryl, —SO 2 cycloalkyl, and —SO 2 heteroaryl; R 18 is selected from the group consisting of: H, alkyl, aryl, heteroaryl, —C(O)R 19 , —SO 2 R 19 and —C(O)NR 19 R 20 ; each R 19 and R 20 is independently selected from the group consisting of: alkyl, aryl and heteroaryl; each R 40 is independently selected from the group consisting of: H, alkyl and cycloalkyl; and t is 0, 1 or 2.
118 . The method of claim 117 wherein said compound of formula IA is administered in combination with the administration an effective amount of at least one anti-angiogenesis compound.
119 . A method of treating a disease selected from the group consisting of: gingivitis, respiratory viruses, herpes viruses, hepatitis viruses, HIV, kaposi's sarcoma associated virus and atherosclerosis, in a patient in need of such treatment, comprising administering to said patient an effective amount of at least one compound of formula IA:
and the pharmaceutically acceptable salts and solvates thereof, wherein:
A is selected from the group consisting of:
wherein the above rings of said A groups are substituted with 1 to 6 substituents each independently selected from the group consisting of: R 9 groups;
wherein one or both of the above rings of said A groups are substituted with 1 to 6 substituents each independently selected from the group consisting of: R 9 groups;
wherein the above phenyl rings of said A groups are substituted with 1 to 3 substituents each independently selected from the group consisting of: R 9 groups; and
B is:
n is 0 to 6; p is 1 to 5; X is O, NH, or S; Z is 1 to 3; R 2 is selected from the group consisting of: hydrogen, OH, —C(O)OH, —SH, —SO 2 NR 13 R 14 , —NHC(O)R 13 , —NHSO 2 NR 13 R 14 , —NHSO 2 R 13 , —NR 13 R 14 —C(O)NR 13 R 14 , —C(O)NHOR 13 , —C(O)N R 13 OH, —S(O 2 )OH, —OC(O)R 13 , an unsubstituted heterocyclic acidic functional group, and a substituted heterocyclic acidic functional group; wherein there are 1 to 6 substituents on said substituted heterocyclic acidic functional group each substituent being independently selected from the group consisting of: R 9 groups; each R 3 and R 4 is independently selected from the group consisting of: hydrogen, cyano, halogen, alkyl, alkoxy, —OH, —CF 3 , —OCF 3 , —NO 2 , —C(O)R 13 , —C(O)OR 13 , —C(O)NHR 17 , —SO (t) NR 13 R 14 , —SO (t) R 13 , —C(O)NR 13 OR 14 , unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl; wherein there are 1 to 6 substituents on said substituted aryl group and each substituent is independently selected from the group consisting of: R 9 groups; and wherein there are 1 to 6 substituents on said substituted heteroaryl group and each substituent is independently selected from the group consisting of: R 9 groups; each R 5 and R 6 are the same or different and are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, —CF 3 , —OCF 3 , —NO 2 , —C(O)R 13 , —C(O)OR 13 , —C(O)NR 13 R 14 , —SO (t) NR 13 R 14 , —C(O)NR 13 OR 14 , cyano, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl group; wherein there are 1 to 6 substituents on said substituted aryl group and each substituent is independently selected from the group consisting of: R 9 groups; and wherein there are 1 to 6 substituents on said substituted heteroaryl group and each substituent is independently selected from the group consisting of: R 9 groups; each R 7 and R 8 is independently selected from the group consisting of: H, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, —CO 2 R 13 , —CONR 13 R 14 , alkynyl, alkenyl, and cycloalkenyl; and wherein there are one or more substituents on said substituted R 7 and R 8 groups, wherein each substituent is independently selected from the group consisting of:
a) halogen,
b) —CF 3 ,
c) —COR 13 ,
d) —OR 13 ,
e) —NR 13 R 14 ,
f) —NO 2 ,
g) —CN,
h) —SO 2 OR 13 ,
i) —Si(alkyl) 3 , wherein each alkyl is independently selected,
j) —Si(aryl) 3 , wherein each alkyl is independently selected,
k) —(R 13 ) 2 R 14 Si, wherein each R 13 is independently selected,
l) —CO 2 R 13 ,
m) —C(O)NR 13 R 14 ,
n) —SO 2 NR 13 R 14 ,
o) —SO 2 R 13 ,
p) —OC(O)R 13 ,
q) —OC(O)NR 13 R 14 ,
r) —NR 13 C(O)R 14 , and
s) —NR 13 CO 2 R 14 ;
R 8a is selected from the group consisting of: hydrogen, alkyl, cycloalkyl and cycloalkylalkyl; each R 9 is independently selected from the group consisting of:
a) —R 13 ,
b) halogen,
c) —CF 3 ,
d) —COR 13 ,
e) —OR 13 ,
f) —NR 13 R 14 ,
g) —NO 2 ,
h) —CN,
i) —SO 2 R 13 ,
j) —SO 2 NR 13 R 14 ,
k) —NR 13 COR 14 ,
l) —CONR 13 R 14 ,
m) —NR 13 CO 2 R 14 ,
n) —CO 2 R 13 ,
p) alkyl substituted with one or more —OH groups,
q) alkyl substituted with one or more —NR 13 R 14 group, and
r) —N(R 13 )SO 2 R 14 ;
R 12 is selected from the group consisting of: hydrogen, —C(O)OR 13 , unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkylalkyl, and unsubstituted or substituted heteroarylalkyl group; wherein there are 1 to 6 substituents on the substituted R 12 groups and each substituent is independently selected from the group consisting of: R 9 groups;
each R 13 and R 14 is independently selected from the group consisting of: H, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted fluoroalkyl, and unsubstituted or substituted heterocycloalkylalkyl; wherein there are 1 to 6 substituents on said substituted R 13 and R 14 groups and each substituent is independently selected from the group consisting of: alkyl, —CF 3 , —OH, alkoxy, aryl, arylalkyl, fluroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, —N(R 40 ) 2 , —C(O)OR 15 , —C(O)NR 15 R 16 , —S(O) t NR 15 R 16 , —C(O)R 15 , —SO 2 R 15 provided that R 15 is not H, halogen, and —NHC(O)NR 15 R 16 ; or
R 13 and R 14 taken together with the nitrogen they are attached to in the groups —NR 13 R 14 , —C(O)NR 13 R 14 , —SO 2 NR 13 R 14 , —OC(O)NR 13 R 14 —, NHSO 2 NR 13 R 14 , —NR 13 C(O)NR 13 R 14 , —SO t NR 13 R 14 , —NHSO 2 NR 13 R 14 form an unsubstituted or substituted saturated heterocyclic ring, said ring optionally containing one additional heteroatom selected from the group consisting of: O, S and NR 18 ; wherein there are 1 to 3 substituents on the substituted cyclized R 13 and R 14 groups and each substituent is independently selected from the group consisting of: alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, —C(O)OR 15 , —C(O)NR 15 R 16 , —SO t NR 15 R 16 , —C(O)R 15 , —SO 2 R 15 provided that R 15 is not H, —NHC(O)NR 15 R 16 , —NHC(O)OR 15 , halogen, and a heterocycloalkenyl group;
each R 15 and R 16 is independently selected from the group consisting of: H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl;
R 17 is selected from the group consisting of: —SO 2 alkyl, —SO 2 aryl, —SO 2 cycloalkyl, and —SO 2 heteroaryl;
R 18 is selected from the group consisting of: H, alkyl, aryl, heteroaryl, —C(O)R 19 , —SO 2 R 19 and —C(O)NR 19 R 20 ;
each R 19 and R 20 is independently selected from the group consisting of: alkyl, aryl and heteroaryl;
each R 40 is independently selected from the group consisting of: H, alkyl and cycloalkyl; and
t is 0, 1 or 2.
120 . The method of claim 112 wherein the chemokine mediated disease is an angiogenic ocular disease.
121 . The method of claim 120 wherein said angiogenic ocular disease is selected from the group consisting of: ocular inflammation, retinopathy of prematurity, diabetic retinopathy, macular degeneration with the wet type preferred and corneal neovascularization.
122 . The method of claim 114 wherein the cancer treated is melanoma, gastric carcinoma, or non-small cell lung carcinoma.
123 . The method of claim 115 wherein the cancer-treated is melanoma, gastric carcinoma, or non-small cell lung carcinoma.
124 . The method of claim 116 , wherein the cancer treated is melanoma, gastric carcinoma, or non-small cell lung carcinoma.
125 . The compound of claim 1 selected from the group consisting of the final compounds of Examples 1 to 1311.Cited by (0)
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