Selective spirocyclic glucocorticoid receptor modulators
The present invention encompasses compounds of Formula (I) and Formula (II) or pharmaceutically acceptable salts or hydrates thereof, which are useful as selective glucocorticoid receptor ligands for treating a variety of autoimmune and inflammatory diseases or conditions. Pharmaceutical compositions and methods of use are also included.
1. A compound of Formula II
wherein
m is 0, 1 or 2;
n is 0 or 1;
X and Y are each independently selected from CH 2 , S and O;
R 1 is phenyl or pyridyl said phenyl or pyridyl optionally mono or di- substituted with a substituent independently selected from the group consisting of:
(a) halo,
(b) OCH 3 ,
(c) CH 3 , and
(d) CN;
R 2 and R 3 are each individually hydrogen or methyl; and
each R 4 is independently selected from the group consisting of
(1) —OH,
(2) —C 1-6 alkyl optionally substituted with 1, 2 or 3 substituents selected independently from hydroxy, oxo, —COOH, amino, methylamino, di-methylamino, =S, and halo,
(3) C 2-6 alkenyl optionally substituted with 1, 2 or 3 substituents selected independently from hydroxy, halo and —C(O)—O—C 1-2 alkyl,
(4) C 2-6 alkynyl optionally substituted with 1, 2 or 3 substituents selected independently from hydroxy and halo,
(5) phenyl optionally substituted with 1, 2 or 3 substituents selected independently from hydroxy, C 1-2 alkyl, —COOH, —C(O)—O—CH 3 and halo,
(6) —C 1-2 alkyl-phenyl optionally substituted with 1, 2 or 3 substituents independently selected from hydroxy, C 1-2 alkyl and halo,
(7) —CO 2 H,
(8) —CO 2 C 1-3 alkyl,
(9) —OC 1-3 alkyl,
(10) —SO 2 —C 1-3 alkyl,
(11) —SO 2 -phenyl optionally substituted with 1, 2 or 3 substituents independently selected from hydroxy, C 1-2 alkyl and halo
(12) —C 1-2 alkyl-O—C 1-2 alkyl,
(13) —C 1-2 alkyl-O—C 2-4 alkenyl,
(14) —C 1-2 alkyl-O-phenyl optionally substituted with with 1, 2 or 3 substituents independently selected from hydroxy, C 1-2 alkyl and halo,
(15) —C 1-2 alkyl-C(O)O—C 1-2 alkyl,
(16) 2-(1,3-dioxan)ethyl,
(17) —C 1-2 alkyl-C(O)—NH-phenyl and
(18) —C 1-2 alkyl-C(O)—NHN.
2. A compound according to claim 1 wherein each R 4 is independently selected from the group consisting of —C 1-6 alkyl or hydrogen.
3. A compound according to claim 1 wherein X and Y are both O or are both S or X is O and Y is CH 2 ; and
R 1 is phenyl optionally mono or di-substituted with halo.
4. A compound selected from the group consisting of the following groups:
ii)
k
R
1
Vinyl
1
Phenyl
1
4-fluorophenyl
2
Benzyl
2
Vinyl
2
Ethyl
iii)
k
D
A
C
Ra
Rb
1
O
CH 2
CH 2
propyl
Propyl
1
O
CH 2
CHOH
propyl
Propyl
1
O
CH 2
CH 2
allyl
Allyl
1
O
CH 2
CHOH
allyl
Allyl
1
O
CH 2
CH 2
methyl
Methyl
1
O
CH 2
CHOH
methyl
Methyl
1
O
CH 2
C(O)
methyl
Methyl
1
O
CH 2
CH 2
H
H
1
O
CH 2
CHOH
H
H
2
CH 2
O
CH 2
ethyl
H
2
CH 2
O
CH 2
H
Ethyl
2
CH 2
O
CH 2
H
Phenyl
2
O
CH 2
CH(allyl)
allyl
Allyl
2
O
CH 2
CH 2
methyl
Methyl
2
O
CH 2
CH 2
benzyl
Benzyl
2
O
CH 2
CH 2
allyl
Allyl
2
O
CH 2
CHOH
methyl
Methyl
2
O
CH 2
CHOH
allyl
Allyl
2
O
CH 2
CH(allyl)
H
H
2
O
CH 2
C(O)
methyl
Methyl
2
O
CH 2
C(O)
allyl
Allyl
v)
k
R
1
Phenyl
2
Ethyl
2
Phenyl
v)
Ra
Methyl
Allyl
Isopropyl
2-methoxyethyl
CH 2 CO 2 Et
2-(1,3-dioxan)ethyl
vii)
C 1
D 1
A 1
B 1
C(O)
NCH 3
C(O)
NH
NCH 2 Ph
C(O)
NCH 3
C(O)
NCH 3
C(O)
NCH 3
C(O)
NCH 2 CH═CH 2
C(O)
NCH 3
C(O)
C(O)
NCH 3
C(O)
NCH 2 Ph
C(O)
NCH 3
C(O)
NCH 3
C(O)
NCH 3
C(O)
NCH 2 CH═CH 2
C(O)
NCH 3
C(O)
NH
N(CH 2 ) 2 CO 2 H
C(O)
NCH 2 Ph
C(O)
NH
C(O)
N(CH 2 ) 2 CO 2 H
C(O)
NH
C(O)
C(O)
C(O)
NCH 3
C(O)
N(CH 2 ) 2 CO 2 H
C(O)
NCH 3
C(O)
NCH 2 CH═CH 2
C(O)
NCH 2 CH═CH 2
C(O)
•NCH 2 Ph
C(O)
NCH 2 Ph
C(O)
NH
C(S)
NCH 2 Ph
C(O)
NH
C(S)
NH
C(O)
NH
C(S)
NCH 2 CH═CH 2
C(O)
NH
C(S)
NCH 3
C(O)
NH
CH 2
NCH 2 Ph
C(O)
NH
CH 2
NH
C(O)
C(O)
NCH 3
CH 2
NCH 3
NH
CH 2
NCH 3
C(O)
and
or a pharmaceutically acceptable salt of any of the foregoing compounds.
5. A pharmaceutical composition comprising acompound according to claim 1 in combination with a pharmaceutically acceptable carrier.