Fused Ring Azadecalin Glucocorticoid Receptor Modulators
The present invention provides a novel class of fused ring azadecalin compounds and methods of using the compounds as glucocorticoid receptor modulators.
1 . A compound having the formula:
wherein,
L 1 and L 2 are members independently selected from a bond, —O—, —S—, S(O)—, —S(O 2 )—, —C(O)—, —C(O)O—, —C(O)NH—, substituted or unsubstituted alkylene, and substituted or unsubstituted heteroalkylene;
the dashed line b is optionally a bond;
the ring A is a member selected from substituted or unsubstituted 5 to 6 membered heterocycloalkyl, and substituted or unsubstituted heteroaryl;
R 1 is a member selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR 1A , —NR 1C R 1D , —C(O)NR 1C R 1D , —C(O)OR 1A , wherein
R 1A is a member selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
R 1C and R 1D are members independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl,
wherein R 1C and R 1D are optionally joined to form a substituted or unsubstituted ring with the nitrogen to which they are attached, wherein said ring optionally comprises an additional ring nitrogen, and
R 2 is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —S(O 2 )R 2A , —S(O 2 )NR 2B R 2C , and ═NOR 2D , wherein
R 2A , R 2B , R 2C , and R 2D are members independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
2 . The compound of claim 1 , wherein A is a member selected from:
unsubstituted 5 to 6 membered heterocycloalkyl comprising at least one heteroatom selected from N, O and S;
substituted 5 to 6 membered heterocycloalkyl comprising 1 to 3 substituents and at least one ring heteroatom selected from N, O and S;
unsubstituted aryl comprising at least one heteroatom selected from N, O and S; and
substituted aryl comprising 1 to 3 substituents and at least one ring heteroatom selected from N, O and S.
3 . The compound of claim 1 , wherein A is a member selected from substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted furanyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thienyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, and substituted or unsubstituted pyrazinyl.
4 . The compound of claim 1 , wherein A is a substituted or unsubstituted pyrazolyl.
5 . The compound of claim 1 , wherein A is substituted with a member selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, —NR 3A R 3B , and —OR 3C , wherein
R 3A and R 3B are members independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, and substituted or unsubstituted heteroaryl, wherein
R 3A and R 3B are optionally joined to form a substituted or unsubstituted ring with the nitrogen to which they are attached, wherein said ring optionally comprises an additional ring heteroatom, and
R 3C is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
6 . The compound of claim 5 , wherein A is substituted with a member selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
7 . The compound of claim 1 having the formula
wherein,
the dashed ring represents unsaturated, partially saturated, or fully saturated bonds within ring E;
Z 1 is a member selected from —NR 5 —, ═N—, —O—, and —S—, wherein
R 5 is a member selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted aryl;
Z 2 is a member selected from —CR 6A R 6B —, ═CR 6A —, —C(O)—, —NR 6C —, ═N—, —O—, —CR 6A R 6B —NR 6C —, ═CR 6A —NR 6C —, —CR 6A R 6B —N═, and ═CR 6A —N═, wherein
R 6C is a member selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl,
R 6A and R 6B are members independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, —NR 6A1 R 6A2 , and —OR 6A3 , wherein
R 6A1 and R 6A2 are members independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein
R 6A1 and R 6A2 are optionally joined to form a substituted or unsubstituted ring with the nitrogen to which they are attached, wherein said ring optionally comprises an additional ring heteroatom, and
R 6A3 is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl,
wherein R 6A and R 6C are optionally joined together to form a substituted or unsubstituted ring, wherein said ring optionally comprises an additional ring heteroatom;
Z 3 is a member selected from —CR 7A R 7B —, ═CR 7A —, —C(O)—, —NR 7C —, ═N—, —O—, and —S—, wherein
R 7C is a member selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted aryl,
R 7A and R 7B are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, —NR 7A1 R 7A2 , and —OR 7A3 , wherein
R 7A1 and R 7A2 are members independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein
R 7A1 and R 7A2 are optionally joined to form a substituted or unsubstituted ring with the nitrogen to which they are attached, wherein said ring optionally comprises an additional ring heteroatom, and
R 7A3 is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
wherein R 5 is optionally joined with R 6A or R 6C to form a substituted or unsubstituted ring, wherein said ring optionally comprises an additional ring heteroatom;
wherein R 7A is optionally joined with R 6A or R 6C to form a substituted or unsubstituted ring, wherein said ring optionally comprises an additional ring heteroatom; and
wherein R 7C is optionally joined with R 6A or R 6C to form a substituted or unsubstituted ring, wherein said ring optionally comprises an additional ring heteroatom.
8 . The compound of claim 7 , wherein
Z 1 is —NR 5 —;
Z 2 is ═N—; and
Z 3 is ═CR 7A —.
9 . The compound of claim 8 , wherein
R 7A is hydrogen; and
R 5 is a member selected from hydrogensubstituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl and substituted or unsubstituted heteroarylalkyl.
10 . The compound of claim 7 , wherein R 5 has the formula:
wherein,
R 5A is a member selected from hydrogen, halogen, —OR 5A1 , —NR 5A2 R 5A3 , —S(O 2 )NR 5A2 R 5A3 , —CN, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein
R 5A1 is a member selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, and
R 5A2 and R 5A3 are members independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
m is an integer from 0 to 10; and
n is an integer from 1 to 5.
11 . The compound of claim 10 , wherein
n is 1;
m is 0 or 1; and
R 5A1 , R 5A2 and R 5A3 are hydrogen.
12 . The compound of claim 7 , wherein
Z 1 is —NR 5 —;
Z 2 is ═CR 6A —; and
Z 3 is ═N—.
13 . The compound of claim 12 , wherein R 5 is a member selected from hydrogen and substituted or unsubstituted aryl.
14 . The compound of claim 8 , wherein R 5 and R 7A are hydrogen and b is a bond.
15 . The compound of claim 1 , wherein R 1 is a member selected from substituted or unsubstituted (C 1 -C 10 ) alkyl, substituted or unsubstituted 2-10 membered heteroalkyl, substituted or unsubstituted (C 3 -C 7 ) cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
16 . The compound of claim 1 , wherein R 1 has the formula:
wherein,
q is an integer selected from 1 to 5;
R 1B is a member selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —NR 1B1 R 1B2 , —OR 1B3 , and —C(O)NR 1B4 R 1B5 wherein
R 1B1 and R 1B2 are members independently selected from hydrogen, substituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, and substituted or unsubstituted heteroaryl, wherein R 1B1 and R 1B2 are optionally joined to form a substituted or unsubstituted ring with the nitrogen to which they are attached, wherein said ring optionally comprises an additional ring heteroatom, and
R 1B3 is a member selected from
hydrogen,
substituted or unsubstituted heteroalkyl comprising a nitrogen,
substituted or unsubstituted heterocycloalkyl comprising a ring nitrogen,
substituted or unsubstituted heteroaryl comprising a ring nitrogen, and
alkyl substituted with a substituted or unsubstituted heteroalkyl comprising a nitrogen, substituted or unsubstituted heterocycloalkyl comprising a ring nitrogen, and substituted or unsubstituted heteroaryl comprising a ring nitrogen; and
R 1B4 and R 1B5 are members independently selected from
hydrogen,
substituted or unsubstituted heteroalkyl comprising a nitrogen,
substituted or unsubstituted heterocycloalkyl comprising a ring nitrogen,
substituted or unsubstituted heteroaryl comprising a ring nitrogen, and
alkyl substituted with a substituted or unsubstituted heteroalkyl comprising a nitrogen, substituted or unsubstituted heterocycloalkyl comprising a ring nitrogen, and substituted or unsubstituted heteroaryl comprising a ring nitrogen, wherein
R 1B4 and R 1B5 are optionally joined to form a substituted or unsubstituted ring with the nitrogen to which they are attached, wherein said ring optionally comprises a heteroatom.
17 . The compound of claim 16 , wherein
q is an integer selected from 1 to 3;
R 1B is a member selected from hydrogen, substituted alkyl, substituted or unsubstituted heteroalkyl, substituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted aryl, and substituted or unsubstituted heteroaryl.
18 . The compound of claim 16 , wherein R 1 has the formula:
wherein,
R 1B is a member selected from hydrogen, —NR 1B1 R 1B2 , —OR 1B3 , substituted or unsubstituted (C 1 -C 10 ) alkyl, substituted or unsubstituted 2-10 membered heteroalkyl, substituted or unsubstituted (C 3 -C 7 )cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
19 . The compound of claim 16 , wherein R 1B is a member selected from —C(O)NR 1B4 R 1B5 and substituted or unsubstituted heteroaryl comprising a ring nitrogen, wherein
R 1B4 and R 1B5 are members independently selected from
hydrogen,
substituted or unsubstituted heteroalkyl comprising a nitrogen,
substituted or unsubstituted heterocycloalkyl comprising a ring nitrogen,
substituted or unsubstituted heteroaryl comprising a ring nitrogen, and
alkyl substituted with a substituted or unsubstituted heteroalkyl comprising a nitrogen, substituted or unsubstituted heterocycloalkyl comprising a ring nitrogen, and substituted or unsubstituted heteroaryl comprising a ring nitrogen, wherein
R 1B4 and R 1B5 are optionally joined to form a substituted or unsubstituted ring with the nitrogen to which they are attached, wherein said ring optionally comprises a heteroatom.
20 . The compound of claim 19 , wherein R 1B1 , R 1B2 , R 1B3 , R 1B4 and R 1B5 are members independently selected from hydrogen and a substituted or unsubstituted ring, wherein said ring optionally comprises a nitrogen atom and at least one additional ring heteroatom.
21 . The compound of claim 1 , wherein R 2 is a member selected from substituted or unsubstituted (C 1 -C 10 ) alkyl, substituted or unsubstituted 2-10 membered heteroalkyl, substituted or unsubstituted (C 3 -C 7 ) cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
22 . The compound of claim 1 , R 2A , R 2B , R 2C , and R 2D are members independently selected from substituted or unsubstituted (C 1 -C 10 ) alkyl, substituted or unsubstituted 2-10 membered heteroalkyl, substituted or unsubstituted (C 3 -C 7 ) cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
23 . The compound of claim 1 , R 2 has the formula:
wherein,
R 2G is a member selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
J is a substituted or unsubstituted ring selected from substituted or unsubstituted (C 3 -C 7 ) cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
t is an integer from 0 to 5; and
X is a member selected from a bond, —S(O 2 )—, and —S(O 2 )N 2I —, wherein
R 2I is a member selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted heteroalkyl.
24 . The compound of claim 23 , wherein
R 2G is a member selected from hydrogen, substituted or unsubstituted (C 1 -C 10 ) alkyl, substituted or unsubstituted 2-10 membered heteroalkyl, substituted or unsubstituted (C 3 -C 7 )cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
J is a substituted or unsubstituted ring selected from substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
t is 1; and
R 2I is hydrogen.
25 . The compound of claim 23 , wherein R 2G is a branched or unbranched (C 1 -C 10 )alkyl.
26 . The compound of claim 23 , wherein X is —S(O 2 )—.
27 . The compound of claim 1 , wherein L 1 and L 2 are members independently selected from a bond and unsubstituted (C 1 -C 6 ) alkylene.
28 . The compound of claim 1 , wherein
the dashed line b is a bond;
R 1 is substituted or unsubstituted benzyl; and
R 2 has the formula:
wherein,
R 2G is a member selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl,
J is a substituted or unsubstituted ring selected from substituted or unsubstituted (C 3 -C 7 ) cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl,
t is an integer fro 0 to 5, and
X is —S(O 2 )—;
L 1 is a bond; and
L 2 is a bond.
29 . A method of treating a disorder or condition through modulating a glucocorticoid receptor, the method comprising administering to a subject in need of such treatment, an effective amount of the compound of one of claims 1 - 28 .
30 . A method of treating a disorder or condition through antagonizing a glucocorticoid receptor, the method comprising administering to a subject in need of such treatment, an effective amount of the compound of one of claims 1 - 28 .
31 . A method of modulating a glucocorticoid receptor including the steps of contacting a glucocorticoid receptor with an effective amount of the compound of one of claims 1 - 28 and detecting a change in the activity of the glucocorticoid receptor.
32 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound of one of claims 1 - 28 .