Glucocorticoid receptor modulators to treat pancreatic cancer

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 a taxane chemotherapeutic agent and an effective amount of a nonsteroidal selective glucocorticoid receptor modulator (SGRM) to reduce the tumor load of the pancreatic tumor, wherein the SGRM is a compound comprising 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,

or salts and isomers thereof.

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

3. The method of claim 1 , comprising administering a further chemotherapeutic agent, wherein said further chemotherapeutic agent is selected from the group consisting of alkylating agents, topoisomerase inhibitors, endoplasmic reticulum stress inducing agents, antimetabolites, mitotic inhibitors and combinations thereof.

4. The method of claim 1 , wherein said taxane chemotherapeutic agent is selected from paclitaxel, docetaxel, nab-paclitaxel, docosahexaenoic-bound paclitaxel, polyglutamate-bound paclitaxel, TAP, ANG-105, paclitaxel-EC-1, and glucose-conjugated paclitaxel.

5. The method of claim 3 , wherein the further chemotherapeutic agent is selected from the group consisting of 5-fluorouracil (5-FU), gemcitabine, cisplatin and capecitabine.

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

7. A method of treating a subject hosting a non-ACTH-secreting pancreatic tumor, the method comprising administering to the subject an effective amount of a taxane chemotherapeutic agent and an effective amount of a nonsteroidal selective glucocorticoid receptor modulator (SGRM) to reduce the tumor load of the pancreatic tumor, wherein the SGRM 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 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;

or salts and isomers thereof.

8. The method of claim 7 , wherein the nonsteroidal selective glucocorticoid receptor modulator is the compound comprising a heteroaryl ketone fused azadecalin having the formula:

9. A method of treating a subject hosting a non-ACTH-secreting pancreatic tumor, the method comprising administering to the subject an effective amount of a taxane chemotherapeutic agent and an effective amount of a nonsteroidal selective glucocorticoid receptor modulator (SGRM) to reduce the tumor load of the pancreatic tumor, wherein the SGRM 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)OR 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,

or salts and isomers thereof.

10. The method of claim 9 , wherein the nonsteroidal selective glucocorticoid receptor modulator is the compound comprising an octahydro fused azadecalin which has the following structure:

11. The method of claim 7 , wherein the non-ACTH-secreting pancreatic tumor is an exocrine pancreatic tumor.

12. The method of claim 7 , comprising administering a further chemotherapeutic agent, wherein said further chemotherapeutic agent is selected from the group consisting of alkylating agents, topoisomerase inhibitors, endoplasmic reticulum stress inducing agents, antimetabolites, mitotic inhibitors and combinations thereof.

13. The method of claim 7 , wherein said taxane chemotherapeutic agent is selected from paclitaxel, docetaxel, nab-paclitaxel, docosahexaenoic-bound paclitaxel, polyglutamate-bound paclitaxel, TAP, ANG-105, paclitaxel-EC-1, and glucose-conjugated paclitaxel.

14. The method of claim 12 , wherein the further chemotherapeutic agent is selected from the group consisting of 5-fluorouracil (5-FU), gemcitabine, cisplatin and capecitabine.

15. The method of claim 9 , wherein the non-ACTH-secreting pancreatic tumor is an exocrine pancreatic tumor.

16. The method of claim 9 , comprising administering a further chemotherapeutic agent, wherein said further chemotherapeutic agent is selected from the group consisting of alkylating agents, topoisomerase inhibitors, endoplasmic reticulum stress inducing agents, antimetabolites, mitotic inhibitors and combinations thereof.

17. The method of claim 9 , wherein said taxane chemotherapeutic agent is selected from paclitaxel, docetaxel, nab-paclitaxel, docosahexaenoic-bound paclitaxel, polyglutamate-bound paclitaxel, TAP, ANG-105, paclitaxel-EC-1, and glucose-conjugated paclitaxel.

18. The method of claim 16 , wherein the further chemotherapeutic agent is selected from the group consisting of 5-fluorouracil (5-FU), gemcitabine, cisplatin and capecitabine.