Granted Patent B2

US 12,370,175 · App. 18/124,959 · Granted Jul 29, 2025

Inventors: Hazel Hunt (Storrington, GB); Thaddeus S. Block (Menlo Park, CA)

Assignee: Corcept Therapeutics, Inc.

A61K31/416A61K31/03A61K31/18A61K31/337A61K31/4192A61K31/44A61K31/473A61K31/513A61K31/7068A61K33/243A61K45/06

Abstract

Claims (103)

1. A method of treating a subject hosting a non-ACTH-secreting pancreatic tumor, the method comprising administering to the subject an effective amount of an antimicrotubule agent selected from a vinca alkaloid and a taxane, and administering between about 20 milligrams per day (mg/day) and about 1000 mg/day of a nonsteroidal selective glucocorticoid receptor modulator (SGRM), wherein the SGRM comprises a fused azadecalin structure having the formula:

wherein

L 1 and L 2 are members independently selected from a bond and unsubstituted alkylene;

R 1 is a member selected from unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted heterocycloalkyl, —OR 1A , NR 1C R 1D , —C(O) NR 1C R 1D , and —C(O) OR 1A , wherein

R 1A is a member selected from hydrogen, unsubstituted alkyl and unsubstituted heteroalkyl,

R 1C and R 1D are members independently selected from unsubstituted alkyl and unsubstituted heteroalkyl,

wherein R 1C and R 1D are optionally joined to form an unsubstituted ring with the nitrogen to which they are attached, wherein said ring optionally comprises an additional ring nitrogen;

R 2 has the formula:

wherein

R 2G is a member selected from hydrogen, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, —CN, and —CF 3 ;

J is phenyl;

t is an integer from 0 to 5;

X is —S(O 2 )—; and

R 5 is phenyl optionally substituted with 1-5 R 5A groups, wherein

R 5A is a member selected from hydrogen, halogen, —OR 5A1 , S(O 2 )NR 5A2 R 5A3 , —CN, and unsubstituted alkyl, wherein

R 5A1 is a member selected from hydrogen and unsubstituted alkyl, and

R 5A2 and R 5A3 are members independently selected from hydrogen and unsubstituted alkyl,

and salts thereof; or

a heteroaryl-ketone fused azadecalin structure having the formula:

wherein

R 1 is a heteroaryl ring having from 5 to 6 ring members and from 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S, optionally substituted with 1-4 groups each independently selected from R 1a ;

each R 1a is independently selected from the group consisting of hydrogen, C 1-6 alkyl, halogen, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, CN, N-oxide, C 3-8 cycloalkyl, and C 3-8 heterocycloalkyl;

ring J is selected from the group consisting of a cycloalkyl ring, a heterocycloalkyl ring, an aryl ring and a heteroaryl ring, wherein the heterocycloalkyl and heteroaryl rings have from 5 to 6 ring members and from 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S;

each R 2 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, halogen, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl-C 1-6 alkoxy, CN, OH, NR 2a R 2b , C(O)R 2a , C(O)OR 2a , C(O)NR 2a R 2b , SR 2a , S(O)R 2a , S(O) 2 R 2a , C 3-8 cycloalkyl, and C 3-8 heterocycloalkyl, wherein the heterocycloalkyl groups are optionally substituted with 1-4 R 2c groups;

alternatively, two R 2 groups linked to the same carbon are combined to form an oxo group (═O);

alternatively, two R 2 groups are combined to form a heterocycloalkyl ring having from 5 to 6 ring members and from 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S, wherein the heterocycloalkyl ring is optionally substituted with from 1 to 3 R 2d groups;

R 2a and R 2b are each independently selected from the group consisting of hydrogen and C 1-6 alkyl;

each R 2c is independently selected from the group consisting of hydrogen, halogen, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, CN, and NR 2a R 2b ;

each R 2d is independently selected from the group consisting of hydrogen and C 1-6 alkyl, or two R 2d groups attached to the same ring atom are combined to form (═O);

R 3 is selected from the group consisting of phenyl and pyridyl, each optionally substituted with 1-4 R 3a groups;

each R 3a is independently selected from the group consisting of hydrogen, halogen, and C 1-6 haloalkyl; and

subscript n is an integer from 0 to 3;

and salts thereof; or

an octahydro fused azadecalin structure having the formula:

wherein

R 1 is a heteroaryl ring having from 5 to 6 ring members and from 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S, optionally substituted with 1-4 groups each independently selected from R 1a ;

each R 1a is independently selected from the group consisting of hydrogen, C 1-6 alkyl, halogen, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, N-oxide, and C 3-8 cycloalkyl;

ring J is selected from the group consisting of an aryl ring and a heteroaryl ring having from 5 to 6 ring members and from 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S;

each R 2 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, halogen, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl-C 1-6 alkoxy, CN, OH, NR 2a R 2b , C(O)R 2a , C(O)OR 2a , C(O)NR 2a R 2b , SR 2a , S(O)R 2a , S(O) 2 R 2a , C 3-8 cycloalkyl, and C 3-8 heterocycloalkyl having from 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S;

alternatively, two R 2 groups on adjacent ring atoms are combined to form a heterocycloalkyl ring having from 5 to 6 ring members and from 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S, wherein the heterocycloalkyl ring is optionally substituted with from 1 to 3 R 2c groups;

R 2a , R 2b and R 2c are each independently selected from the group consisting of hydrogen and C 1-6 alkyl;

each R 3a is independently halogen; and

subscript n is an integer from 0 to 3,

and salts thereof,

to reduce the tumor load of the pancreatic tumor.

2. The method of claim 1 , wherein the non-ACTH-secreting pancreatic tumor is an exocrine pancreatic tumor.

3. The method of claim 1 , wherein the antimicrotubule agent is a vinca alkaloid selected from the group consisting of vinorelbine, vincristine, vindesine, vinblastine, vincaleukoblastine, and combinations thereof.

4. The method of claim 1 , wherein the antimicrotubule agent is a taxane selected from the group consisting of docetaxel, paclitaxel, nanoparticle albumin-bound paclitaxel (nab-paclitaxel), docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel), polyglutamate bound-paclitaxel (PG-paclitaxel), ANG105 (Angiopep-2 bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxel bound to the erbB2-recognizing peptide EC-1), glucose-conjugated paclitaxel, and combinations thereof.

5. The method of claim 1 , wherein the antimicrotubule agent is selected from the group consisting of nab-paclitaxel, paclitaxel, docetaxel, vinorelbine, vincristine, and vinblastine.

6. The method of claim 1 , wherein the antimicrotubule agent is a taxane selected from docetaxel, paclitaxel, and nab-paclitaxel.

7. The method of claim 1 , wherein the nonsteroidal selective glucocorticoid receptor modulator is a compound comprising a fused azadecalin structure having the following formula:

wherein

L 1 and L 2 are members independently selected from a bond and unsubstituted alkylene;

R 1 is a member selected from unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted heterocycloalkyl, —OR 1A , NR 1C R 1D , —C(O) NR 1C R 1D , and —C(O) OR 1A , wherein

R 1A is a member selected from hydrogen, unsubstituted alkyl and unsubstituted heteroalkyl,

R 1C and R 1D are members independently selected from unsubstituted alkyl and unsubstituted heteroalkyl,

wherein R 1C and R 1D are optionally joined to form an unsubstituted ring with the nitrogen to which they are attached, wherein said ring optionally comprises an additional ring nitrogen;

R 2 has the formula:

wherein

R 2G is a member selected from hydrogen, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, —CN, and —CF 3 ;

J is phenyl;

t is an integer from 0 to 5;

X is —S(O 2 )—; and

R 5 is phenyl optionally substituted with 1-5 R 5A groups, wherein

R 5A is a member selected from hydrogen, halogen, —OR 5A1 , S(O 2 )NR 5A2 R 5A3 , —CN, and unsubstituted alkyl, wherein

R 5A1 is a member selected from hydrogen and unsubstituted alkyl, and

R 5A2 and R 5A3 are members independently selected from hydrogen and unsubstituted alkyl,

and salts thereof.

8. The method of claim 7 , wherein the nonsteroidal selective glucocorticoid receptor modulator comprising a fused azadecalin structure is:

9. The method of claim 1 , wherein the nonsteroidal selective glucocorticoid receptor modulator is a compound comprising a heteroaryl ketone fused azadecalin structure having the formula:

wherein

R 1 is a heteroaryl ring having from 5 to 6 ring members and from 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S, optionally substituted with 1-4 groups each independently selected from R 1a ;

each R 1a is independently selected from the group consisting of hydrogen, C 1-6 alkyl, halogen, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, CN, N-oxide, C 3-8 cycloalkyl, and C 3-8 heterocycloalkyl;

ring J is selected from the group consisting of a cycloalkyl ring, a heterocycloalkyl ring, an aryl ring and a heteroaryl ring, wherein the heterocycloalkyl and heteroaryl rings have from 5 to 6 ring members and from 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S;

each R 2 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, halogen, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl-C 1-6 alkoxy, CN, OH, NR 2a R 2b , C(O)R 2a , C(O)OR 2a , C(O)NR 2a R 2b , SR 2a , S(O)R 2a , S(O) 2 R 2a , C 3-8 cycloalkyl, and C 3-8 heterocycloalkyl, wherein the heterocycloalkyl groups are optionally substituted with 1-4 R 2c groups;

alternatively, two R 2 groups linked to the same carbon are combined to form an oxo group (═O);

alternatively, two R 2 groups are combined to form a heterocycloalkyl ring having from 5 to 6 ring members and from 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S, wherein the heterocycloalkyl ring is optionally substituted with from 1 to 3 R 2d groups;

R 2a and R 2b are each independently selected from the group consisting of hydrogen and C 1-6 alkyl;

each R 2c is independently selected from the group consisting of hydrogen, halogen, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, CN, and NR 2a R 2b ,

each R 2d is independently selected from the group consisting of hydrogen and C 1-6 alkyl, or two R 2d groups attached to the same ring atom are combined to form (═O);

R 3 is selected from the group consisting of phenyl and pyridyl, each optionally substituted with 1-4 R 3a groups;

each R 3a is independently selected from the group consisting of hydrogen, halogen, and C 1-6 haloalkyl; and

subscript n is an integer from 0 to 3;

and salts thereof.

10. The method of claim 1 , wherein the nonsteroidal selective glucocorticoid receptor modulator is a compound comprising a heteroaryl ketone fused azadecalin having the formula:

11. The method of claim 1 , wherein the nonsteroidal selective glucocorticoid receptor modulator compound is a compound comprising an octahydro fused azadecalin structure having the formula:

wherein

R 1 is a heteroaryl ring having from 5 to 6 ring members and from 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S, optionally substituted with 1-4 groups each independently selected from R 1a ;

each R 1a is independently selected from the group consisting of hydrogen, C 1-6 alkyl, halogen, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, N-oxide, and C 3-8 cycloalkyl;

ring J is selected from the group consisting of an aryl ring and a heteroaryl ring having from 5 to 6 ring members and from 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S;

each R 2 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, halogen, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl-C 1-6 alkoxy, CN, OH, NR 2a R 2b , C(O)R 2a , C(O)OR 2a , C(O)NR 2a R 2b , SR 2a , S(O)R 2a , S(O) 2 R 2a , C 3-8 cycloalkyl, and C 3-8 heterocycloalkyl having from 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S;

alternatively, two R 2 groups on adjacent ring atoms are combined to form a heterocycloalkyl ring having from 5 to 6 ring members and from 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S, wherein the heterocycloalkyl ring is optionally substituted with from 1 to 3 R 2c groups;

R 2a , R 2b and R 2c are each independently selected from the group consisting of hydrogen and C 1-6 alkyl;

each R 3a is independently halogen; and

subscript n is an integer from 0 to 3,

and salts thereof.

12. The method of claim 1 , wherein the nonsteroidal selective glucocorticoid receptor modulator is a compound comprising an octahydro fused azadecalin which has the following structure:

13. The method of claim 1 , wherein the SGRM is administered intermittently.

14. The method of claim 7 , wherein the SGRM is administered intermittently.

15. The method of claim 8 , wherein the SGRM is administered intermittently.

16. The method of claim 9 , wherein the SGRM is administered intermittently.

17. The method of claim 11 , wherein the SGRM is administered intermittently.

18. The method of claim 12 , wherein the SGRM is administered intermittently.

Assignments (1)

Continuity (9)

References Cited (71)