Glucocorticoid receptor modulators to treat cervical cancer

Abstract

To provide Glucocorticoid receptor modulators to treat cervical cancer.SOLUTION: Methods for treating a subject having a cancerous tumor are disclosed. The methods comprise administering to the subject an effective amount of a non-steroidal selective glucocorticoid receptor modulator (SGRM) and an effective amount of a chemotherapeutic agent. The tumor may be cervical cancer. The SGRM may be a fused azadecalin. In embodiments, the SGRM may be a heteroaryl ketone fused azadecalin or an octahydro fused azadecalin.SELECTED DRAWING: None

Description

[Background technology]

[0001] background Cancer is the number one cause of death in the U.S. For example, cervical cancer often has a poor prognosis (even when diagnosed early), and signs and symptoms may not appear until the cancer is quite advanced, and complete surgical removal is not possible.

[0002] Conventional treatment options for cancers such as cervical cancer include surgery, radiation therapy, and chemotherapy. Not all cancers, and not all cervical cancers, are resectable at the time of diagnosis. Tumors such as cervical cancer tumors at advanced stages often require radiation therapy or chemotherapy treatment.

[0003] Radiation therapy requires maximized exposure of diseased tissues while sparing the surrounding normal tissues. Interstitial therapy, where needles containing a radioactive source are implanted into the tumor, has become a valuable new approach. In this way, a large dose of radiation can be delivered locally while sparing the surrounding normal structures. Intraoperative radiation therapy, where the beam is placed directly on the tumor during surgery while the normal structures are safely away from the beam, is another specialized radiation technique. Again, this achieves effective irradiation of the tumor while limiting exposure to the surrounding structures. Despite the clear advantages of the approach in its presumed local control of irradiation, patient survival rates are still very low.

[0004] Chemotherapy relies on generalized damage to DNA and destabilization of chromosome structure, which eventually leads to the destruction of cancer cells.However, the non-selective nature of these treatments often results in severe and debilitating side effects.The systemic use of these drugs can cause damage to normal, healthy organs and tissues, compromising the long-term health of the patient. The effect of glucocorticoid receptor ("GR")-mediated signaling pathway on cancer cells is generally controversial. On the one hand, activation of the GR signaling pathway is thought to favorably induce apoptosis in malignant lymphoid cancers. See Schlossmacher, J. Endocrino. (2011) 211, 17-25. On the other hand, it has been reported that drugs that block the GR signaling pathway can enhance chemotherapy in killing breast cancer cells. See U.S. Patent No. 9,149,485. Mifepristone, a steroidal nonselective drug that blocks the GR signaling pathway and other steroidal signaling pathways, including the progesterone-receptor signaling pathway, has been suggested for the treatment of cervical cancer (U.S. Patent Publication No. 2004 / 0102422). However, GR signaling is thought to have the opposite effect in some other cancers. For example, the conventional wisdom regarding pancreatic cancer is that glucocorticoids (e.g., dexamethasone) can reduce the side effects of the chemotherapy agents and should be co-administered with the chemotherapy agents in treating pancreatic cancer. Zhang et al., BMC Cancer, March 15, 2006 6: 61. Additionally, dexamethasone (a glucocorticoid receptor agonist) has been reported to inhibit pancreatic cancer cell growth. See Normal et al., J. Surg. Res. 1994 Jul; 57(1): 33-8. Thus, reports in the literature are often conflicting, and it remains unclear whether glucocorticoid signaling has an effect on cancer, and whether such effects may be positive or negative. Thus, in light of the lack of good treatment options for many cancer patients, improved treatments for cancerous tumors, including cervical cancer, are desirable. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] U.S. Patent No. 9,149,485 [Patent Document 2] US Patent Application Publication No. 2004 / 0102422 [Non-patent literature]

[0006] [Non-Patent Document 1] Schlossmacher, J. Endocrino. (2011) 211, 17-25 [Non-Patent Document 2] Zhang et al., BMC Cancer, 2006 March 15 6: 61 [Non-Patent Document 2] Normal et al., J. Surg. Res. 1994 Jul; 57(1): 33-8 Summary of the Invention [Means for solving the problem]

[0007] Abstract Disclosed herein are methods for treating a subject hosting a cancerous tumor (e.g., a cervical cancer tumor or other cancerous tumor (e.g., breast cancer, ovarian cancer, prostate cancer)). The present application provides a novel and surprising combination therapy for treating patients suffering from cancer, including patients suffering from cervical cancer and other cancers, using a nonsteroidal compound that inhibits GR signaling. The method includes administering to the subject an effective amount of a chemotherapeutic agent and an effective amount of a nonsteroidal selective glucocorticoid receptor modulator (SGRM) to reduce the tumor burden of a cancerous tumor in the subject. In some cases, the cancerous tumor is a cervical cancer tumor.

[0008] In some cases, the chemotherapeutic agent is selected from the group consisting of anti-microtubule agents, alkylating agents, topoisomerase inhibitors, endoplasmic reticulum stress inducers, antimetabolites, mitotic inhibitors, and combinations thereof. In some cases, the chemotherapeutic agent is a taxane. In some cases, the chemotherapeutic agent is selected from the group consisting of nab-paclitaxel, 5-fluorouracil (5-FU), gemcitabine, cisplatin, and capecitabine.

[0009] In some cases, the glucocorticoid receptor modulator is administered orally. In some cases, the glucocorticoid receptor modulator is administered by transdermal application, by nebulized suspension, or by aerosol spray.

[0010] In some cases, the effective amount of the SGRM is a daily dose between 1-100 mg / kg / day, where the SGRM is administered with at least one chemotherapeutic agent. In some embodiments, the daily dose of the SGRM is 1 mg / kg / day, 2 mg / kg / day, 4 mg / kg / day, 6 mg / kg / day, 8 mg / kg / day, 10 mg / kg / day, 12 mg / kg / day, 14 mg / kg / day, 16 mg / kg / day, 18 mg / kg / day, 20 mg / kg / day, 30 mg / kg / day, 40 mg / kg / day, 50 mg / kg / day, 60 mg / kg / day, 70 mg / kg / day, 80 mg / kg / day, 90 mg / kg / day, or 100 mg / kg / day. In some cases, the glucocorticoid receptor modulator is administered for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 25 weeks, 30 weeks, 35 weeks, 40 weeks, 45 weeks, 50 weeks, 55 weeks, 60 weeks, 65 weeks, 70 weeks, 75 weeks, or 80 weeks. In some cases, the glucocorticoid receptor modulator scaffold is a fused azadecalin. In some cases, the fused azadecalin has the following formula: [ka] or salts and isomers thereof, L in the ceremony 1 and L 2 is a member independently selected from a bond and unsubstituted alkylene; R 1 is an unsubstituted alkyl, an unsubstituted heteroalkyl, an unsubstituted heterocycloalkyl, -OR 1A , N.R. 1C R 1D , -C(O)NR 1C R 1D , and -C(O)OR 1A wherein R is a member selected from 1A is a member selected from hydrogen, unsubstituted alkyl, and unsubstituted heteroalkyl; R 1C and R 1D is a member independently selected from unsubstituted alkyl and unsubstituted heteroalkyl, where R 1C and R 1D are optionally joined to form an unsubstituted ring together with the nitrogen to which they are attached, said ring optionally including an additional ring nitrogen; R 2 is the expression: [ka] wherein R 2G is a member selected from hydrogen, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, -CN, and -CF; J is phenyl; t is an integer from 0 to 5; X is -S(O)-; and R 5 1 to 5 R as needed 5A phenyl substituted with a group, where R5A is hydrogen, halogen, -OR 5A1 , S(O2)NR 5A2 R 5A3 , -CN, and unsubstituted alkyl, 5A1 is a member selected from hydrogen and unsubstituted alkyl, and R 5A2 and R 5A3 is a member independently selected from hydrogen and unsubstituted alkyl. In some cases, the fused azadecalin is [ka] It is.

[0011] In some cases, the glucocorticoid receptor modulator scaffold is a heteroaryl ketone fused azadecalin or an octahydro fused azadecalin. In some cases, the heteroaryl ketone fused azadecalin has the formula: [ka] or salts and isomers thereof, wherein R 1 has 5 to 6 ring members and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S, and optionally each R 1a and each R is a heteroaryl ring substituted with 1 to 4 groups independently selected from 1a is 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 3-8ring J is selected from the group consisting of a cycloalkyl ring, a heterocycloalkyl ring, an aryl ring, and a heteroaryl ring, wherein said heterocycloalkyl ring and heteroaryl ring have 5 to 6 ring members and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S; each R 2 is 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 , S.R. 2a , S(O)R 2a , S(O)2R 2a , C 3-8 Cycloalkyl, and C 3-8 heterocycloalkyl, wherein the heterocycloalkyl group optionally comprises 1 to 4 R 2c or two R 2 The groups combine to form an oxo group (=O); or two R 2 The groups combine to form a heterocycloalkyl ring having 5-6 ring members and 1-3 heteroatoms each independently selected from the group consisting of N, O and S, wherein the heterocycloalkyl ring optionally contains 1-3 R 2d R 2a and R 2b are hydrogen and C, respectively. 1-6 alkyl; each R 2c is hydrogen, halogen, hydroxy, C 1-6 Alkoxy, C 1-6 Haloalkoxy, CN, and NR 2a R 2b each R 2dis hydrogen and C 1-6 alkyl, or two R attached to the same ring atom 2d The groups combine to form (=O); R 3 Each of them can be set to 1 to 4 R as necessary. 3a R is selected from the group consisting of phenyl and pyridyl, each substituted with a phenyl group; 3a is hydrogen, halogens, and C 1-6 haloalkyl; and the subscript n is an integer from 0 to 3.

[0012] In some cases, the heteroaryl ketone-fused azadecalin is [ka] It is.

[0013] In some cases, the octahydro-fused azadecalin has the formula: [ka] or salts and isomers thereof, R in the formula 1 has 5 to 6 ring members and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S, and optionally each R 1a and each R is a heteroaryl ring substituted with 1 to 4 groups independently selected from 1a is hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, N-oxide, and C 3-8 ring J is selected from the group consisting of aryl rings and heteroaryl rings having 5-6 ring members and 1-4 heteroatoms each independently selected from the group consisting of N, O and S; each R 2 is hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6Alkoxy, 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 , S.R. 2a , S(O)R 2a , S(O)2R 2a , C 3-8 Cycloalkyl and C having 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S. 3-8 heterocycloalkyl; or two R on adjacent ring atoms are independently selected from the group consisting of 2 The groups combine to form a heterocycloalkyl ring having 5-6 ring members and 1-3 heteroatoms each independently selected from the group consisting of N, O and S, wherein the heterocycloalkyl ring optionally contains 1-3 R 2c R 2a , R 2b and R 2c are hydrogen and C, respectively. 1-6 alkyl; each R 3a are independently halogen; and the subscript n is an integer from 0 to 3.

[0014] In some cases, the SGRM is CORT125134, i.e., (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, which has the following structure: [ka] has.

[0015] In some cases, the SGRM is CORT125281, i.e., ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, which has the following structure: [ka] has. [Brief description of the drawings]

[0016] [Figure 1] FIG. 1 shows tumor growth data from five groups of mice treated with: 1) intravenous (iv) vehicle; 2) 7.5 mg / kg iv paclitaxel; 3) CORT125134 (30 mg / kg) and paclitaxel (7.5 mg / kg); 4) 15 mg / kg iv paclitaxel; and 5) CORT125134 (30 mg / kg) and paclitaxel (15 mg / kg).

[0017] [Diagram 2] Figure 2 shows the effect of CORT125134 in combination with paclitaxel in a triple-negative breast cancer (TNBC) mouse xenograft model. Ten mice per group were administered CORT125134 orally daily and intravenous paclitaxel every 4 days. Data represent the mean + SEM.

[0018] [Diagram 3] Figure 3 shows the effect of CORT125134 in combination with gemcitabine / carboplatin in an ovarian cancer mouse xenograft model. Ten mice per group were administered CORT125134 intraperitoneally (ip) on days 43, 44, 50, and 51, and gemcitabine / carboplatin ip on days 44 and 51. Data represent mean values.

[0019] [Figure 4] Figure 4 shows the effect of CORT125134 in combination with castration in a prostate cancer (CRPC) mouse xenograft model. 10 mice per group were orally administered CORT125134 daily for 21 days. Data represent the mean + SEM. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] Detailed Description A. Introduction Using this method disclosed herein, an effective amount of SGRM can be administered in combination with an effective amount of chemotherapy to treat a patient with cancerous tumor by reducing the cancerous tumor burden.In an embodiment, the cancer is cervical cancer.Applicant has found that treatment with SGRM in combination with chemotherapy is more effective than treatment with the therapeutic agent alone.

[0021] B. Definition As used herein, the terms "tumor" and "cancer" are used interchangeably and both refer to the abnormal growth of tissue resulting from excessive cell division. A tumor that can invade surrounding tissues and / or metastasize is said to be "malignant." A tumor that does not metastasize is said to be "benign."

[0022] As used herein, the term "subject" or "patient" refers to a human or non-human organism. Thus, the methods and compositions described herein are applicable to both human and veterinary diseases. In certain embodiments, the subject is a "patient", i.e., a living human undergoing medical care for a disease or condition. This includes people with undefined illnesses who are being investigated for signs of pathology. Preferred are subjects with an existing diagnosis of cervical cancer, which is targeted by the compositions and methods of the present invention. In some cases, the subject may be simultaneously afflicted with one or more types of cancer, at least one of which is cervical cancer, which is targeted by the compositions and methods of the present invention.

[0023] As used herein, the term "cancerous tumor" refers to any solid or semi-solid malignant neoplastic growth.

[0024] As used herein, the term "cervical cancer" refers to any tumor in or originating from the cervix of a patient.

[0025] As used herein, the term "tumor load" or "tumor burden" generally refers to the number of cancer cells, the size of a tumor, or the amount of cancer in a subject's body at any given time. Tumor burden can be detected, for example, by measuring the expression of tumor-specific gene markers and measuring tumor size by a number of well-known biochemical or imaging methods disclosed herein (below).

[0026] As used herein, the term "effective amount" or "therapeutic amount" refers to an amount of a pharmacological agent effective to treat, eliminate, or alleviate at least one symptom of the disease being treated. In some cases, "therapeutically effective amount" or "effective amount" may refer to an amount of a functional agent or pharmaceutical composition useful for exhibiting a detectable therapeutic or inhibitory effect. The effect may be detected by any assay method known in the art. The effective amount may be an amount effective to induce an anti-tumor response; for purposes of this disclosure, an effective amount of an SGRM or an effective amount of a chemotherapeutic agent is an amount that reduces tumor burden or produces other desirable beneficial clinical outcomes related to cancer improvement when used in combination with a chemotherapeutic agent or SGRM, respectively.

[0027] As used herein, the terms "administer," "administering," "administered," or "administration" refer to providing a compound or composition (e.g., those described herein) to a subject or patient.

[0028] As used herein, the term "combination therapy" refers to the administration of at least two pharmaceutical agents to a subject to treat a disease. The two agents are , simultaneously, or sequentially in any order during all or part of the treatment period. The at least two agents can be administered according to the same or different dosing regimens. In some cases, one agent is administered according to a scheduled regimen while the other agent is administered intermittently. In some cases, both agents are administered intermittently. In some embodiments, one agent (e.g., an SGRM) is administered daily and the other agent (e.g., a chemotherapeutic agent) is administered every 2, 3, or 4 days.

[0029] As used herein, the term "compound" is used to indicate a molecular moiety of a unique, identifiable chemical structure. A molecular moiety ("compound") may exist in the form of a free species, where the molecular moiety is not associated with other molecules. A compound may also exist as part of a larger aggregate, where the compound is associated with other molecule(s) but nevertheless retains its chemical identity. A solvate (wherein the molecular moiety ("compound") of the chemical structure defined herein is associated with a molecule(s) of a solvent) is an example of such an associated form. A hydrate is a solvate in which the associated solvent is water. The description "compound" refers to the molecular moiety (of the described structure) itself, regardless of whether the compound exists in a free or associated form.

[0030] As used herein, the term "pharmaceutical acceptable carrier" is intended to include any and all solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc., that are compatible with pharmaceutical administration.The use of such media and agents for pharmaceutical active substances is well known in the art.Except insofar as any conventional media or agent is incompatible with the active compound, its use in the composition is contemplated.Auxiliary active compounds can also be incorporated into the composition.

[0031] The term "glucocorticosteroids" ("GC") or "glucocorticoids" refers to steroid holomones that bind to the glucocorticoid receptor. Glucocorticosteroids are typically characterized by having 21 carbon atoms, an α,β-unsaturated ketone in ring A, and an α-ketol group attached to ring D. They vary in the degree of oxygenation or hydroxylation at C-11, C-17, and C-19; see Rawn, "Biosynthesis and Transport of Membrane Lipids and Formation of Cholesterol Derivatives", in Biochemistry, Daisy et al. (eds.), 1989, pg. 567.

[0032] As used herein, the term "glucocorticoid receptor ("GR") refers to a family of intracellular receptors that specifically bind cortisol and / or cortisol analogs. The glucocorticoid receptor is also referred to as the cortisol receptor. The term includes isoforms of GR, recombinant GR and mutant GR. "Glucocorticoid receptor ("GR") refers to type II GR that specifically binds cortisol and / or cortisol analogs (e.g., dexamethasone) (see, e.g., Turner & Muller, J. Mol. Endocrinol. October 1, 2005 35 283-292).

[0033] "Glucocorticoid receptor modulator" refers to any compound that inhibits any biological response associated with the binding of GR to an agonist. For example, a GR agonist (e.g., dexamethasone) inhibits the binding of GR to HepG2 cells (a human hepatocellular carcinoma cell line; ECACC, Dexamethasone increases the activity of tyrosine aminotransferase (TAT) in the GR1 receptor agonist, GR2 receptor agonist, and GR3 receptor agonist (GR4 receptor agonist). Thus, GR modulators of the present invention can be identified by measuring the ability of the compound to inhibit the effect of dexamethasone. TAT activity can be measured as outlined in A. Ali et al. (J. Med. Chem., 2004, 47, 2441-2452). Modulators have an IC of less than 10 micromolar. 50 (half maximal inhibition concentration). See Example 1 (below).

[0034] As used herein, the term "selective glucocorticoid receptor modulator" refers to any composition or compound that inhibits any biological response associated with the binding of GR to an agonist. By "selective," it is meant that the drug preferentially binds to GR rather than other nuclear receptors, such as the progesterone receptor (PR), mineralocorticoid receptor (MR), or androgen receptor (AR). The selective glucocorticoid receptor modulator binds to MR, AR, or PR, to both MR and PR, to both MR and AR, to both AR and PR, or to MR, AR, and PR with an affinity (its K d In a more preferred embodiment, the selective glucocorticoid receptor modulator binds GR with an affinity (its K) that is 100-fold higher than its affinity for MR, AR, or PR, for both MR and PR, for both MR and AR, for both AR and PR, or for MR, AR, and PR. d In another embodiment, the selective glucocorticoid receptor modulator binds GR with an affinity (its K) that is 1000-fold greater than its affinity for MR, AR, or PR, for both MR and PR, for both MR and AR, for both AR and PR, or for MR, AR, and PR. d Combine GR with the 1 / 1000th of the value.

[0035] As used herein, the term "composition" is intended to include products that contain specific components, such as the above compounds, their tautomeric forms, their derivatives, their analogs, their stereoisomers, their polymorphs, their deuterated species, their pharma- ceutically acceptable salts, esters, ethers, metabolites, mixtures of isomers, their pharma- ceutically acceptable solvates, and pharma- ceutical compositions in specified amounts, as well as any products that result, directly or indirectly, from the combination of the specified components in the specified amounts. Such terms related to pharmaceutical compositions are intended to include products that contain the active component(s) and the inactive component(s) that constitute the carrier, as well as any products that result, directly or indirectly, from the combination of any two or more of the components, from the complexation or aggregation, or from the dissociation of one or more of the components, or from other types of reactions or interactions of one or more of the components. Thus, the pharmaceutical compositions of the present invention are meant to include any compositions made by mixing the compounds of the present invention and their pharma- ceutical acceptable carriers.

[0036] In some embodiments, the term "consisting essentially of" refers to a composition in a formulation in which the only active ingredient is the indicated active ingredient, although other compounds to stabilize, preserve, etc. the formulation may be included but are not directly involved in the therapeutic effect of the indicated active ingredient. In some embodiments, the term "consisting essentially of" refers to a composition that includes the active ingredient and a component that facilitates the release of the active ingredient. For example, the composition may include one or more components that provide an extended release of the active ingredient to the subject over time. In some embodiments, the term "consisting of" refers to a composition that includes the active ingredient and a pharma- ceutically acceptable carrier or excipient.

[0037] As used herein, the phrase "non-steroidal backbone" in the context of SGRMs refers to SGRMs that share no structural homology to cortisol with its steroid backbone, which contains 17 carbon atoms bonded in four fused rings, and are not modifications of cortisol. Such compounds include synthetic mimetics and analogs of proteins, including partially peptidic, pseudopeptidic, and non-peptidic molecular entities.

[0038] Non-steroidal SGRM compounds include SGRMs with fused azadecalin skeleton, heteroaryl ketone fused azadecalin skeleton, and octahydro fused azadecalin skeleton.Exemplary glucocorticoid receptor modulators with fused azadecalin skeleton include those described in U.S. Patent No. 7,928,237 and U.S. Patent No. 8,461,172.Exemplary glucocorticoid receptor modulators with heteroaryl ketone fused azadecalin skeleton include those described in U.S. Patent No. 8,859,774 (titled Heteroaryl-Ketone Fused Azadecalin Glucocorticoid Receptor Modulators). Exemplary glucocorticoid receptor modulators having an octahydro fused azadecalin scaffold include those described in U.S. Patent Application Publication No. 2015-0148341 A1 (entitled Octahydro Fused Azadecalin Glucocorticoid Receptor Modulators, filed November 21, 2014).

[0039] Where substituents are specified by their conventional, left-to-right written chemical formula, they equally encompass the chemically identical substituents resulting from writing the structure from right-to-left. For example, -CH2O- is equivalent to -OCH2-.

[0040] "Alkyl" refers to a linear or branched, saturated aliphatic radical having the number of carbon atoms indicated. Alkyl can contain any number of carbon atoms (e.g., C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 1-7 , C 1-8 , C 1-9 , C 1-10 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 , and C 5-6 ). For example, C 1-6 Alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, and hexyl.

[0041] "Alkoxy" refers to an alkyl group having an oxygen atom connecting the alkyl group to the point of attachment: alkyl-O-. With respect to the alkyl group, the alkoxy group can have any suitable number of carbon atoms (e.g., C 1-6 Alkoxy groups include, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, and the like.

[0042] "Halogen" refers to fluorine, chlorine, bromine, and iodine.

[0043] "Haloalkyl" refers to an alkyl (as defined above) in which some or all of the hydrogen atoms have been replaced with halogen atoms. With respect to the alkyl group, the haloalkyl group may have any suitable number of carbon atoms (e.g., C 1-6 ), including trifluoromethyl, fluoromethyl, and the like.

[0044] The term "perfluoro" can be used to define a compound or radical in which all hydrogens have been replaced with fluorines. For example, perfluoromethane includes 1,1,1-trifluoromethyl.

[0045] "Haloalkoxy" refers to an alkoxy group in which some or all of the hydrogen atoms are replaced with halogen atoms. With respect to its alkyl group, the haloalkoxy group can have any suitable number of carbon atoms (e.g., C 1-6 ). The alkoxy group can be substituted with one, two, three, or more halogens. If all hydrogens are replaced with halogens (e.g., by fluorine), the compound is per substituted (e.g., perfluorinated). Haloalkoxy includes, but is not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and perfluoroethoxy.

[0046] "Cycloalkyl" refers to a saturated or partially unsaturated, monocyclic, fused bicyclic, or bridged polycyclic ring assembly containing 3 to 12 ring atoms, or the number of atoms indicated. Cycloalkyl can contain any number of carbon atoms (e.g., C 3-6 , C 4-6 , C 5-6 , C 3-8 , C 4-8 , C 5-8 , C 6-8 , C 3-9 , C 3-10 , C 3-11 , and C 3-12). Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2]bicyclooctane, decahydronaphthalene, and adamantane. Cycloalkyl groups can also be partially unsaturated, having one or more double or triple bonds in the ring. Representative cycloalkyl groups that are partially unsaturated include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4-, and 1,5-isomers), norbornene, and norbornadiene. When cycloalkyl is a saturated monocyclic C 3-8 When cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 3-6 When it is cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0047] "Heterocycloalkyl" refers to a saturated ring system having 3-12 ring members and 1-4 heteroatoms of N, O, and S. Additional heteroatoms may also be useful (including, but not limited to, B, Al, Si, and P). The heteroatoms may also be oxidized (e.g., including, but not limited to, -S(O)- and -S(O)2-). Heterocycloalkyl groups may contain any number of ring atoms (e.g., 3-6, 4-6, 5-6, 3-8, 4-8, 5-8, 6-8, 3-9, 3-10, 3-11, or 3-12 ring members). Any suitable number of heteroatoms may be included in the heterocycloalkyl group (e.g., 1, 2, 3, or 4, or 1-2, 1-3, 1-4, 2-3, 2-4, or 3-4). The heterocycloalkyl groups may include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. The heterocycloalkyl groups may also be fused to aromatic or non-aromatic ring systems to form members including, but not limited to, indoline.

[0048] When the heterocycloalkyl contains 3 to 8 ring members and 1 to 3 heteroatoms, representative members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, oxane, tetrahydrothiophene, thiane, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, morpholine, thiomorpholine, dioxane, and dithiane. Heterocycloalkyl can also form rings with 5 to 6 ring members and 1 to 2 heteroatoms, representative members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, and morpholine.

[0049] "Aryl" refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. Aryl groups can contain any suitable number of ring atoms (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 ring atoms) and 6 to 10, 6 to 12, or 6 to 14 ring members. Aryl groups can be monocyclic, fused to form bicyclic or tricyclic groups, or linked by bonds to form biaryl groups. Representative aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl with methylene linking groups. Some aryl groups have 6 to 12 ring members (e.g., phenyl, naphthyl, or biphenyl). Other aryl groups have 6 to 10 ring members (e.g., phenyl or naphthyl). Some other aryl groups have 6 ring members (e.g., phenyl). The aryl group can be substituted or unsubstituted.

[0050] "Heteroaryl" refers to a monocyclic, fused bicyclic, or tricyclic aromatic ring assembly containing 5-16 ring atoms, where 1-5 of the ring atoms are heteroatoms (e.g., N, O, or S). Additional heteroatoms can also be useful (including, but not limited to, B, Al, Si, and P). The heteroatoms can also be oxidized (e.g., including, but not limited to, N-oxide, -S(O)-, and -S(O)2-). Heteroaryl groups can contain any number of ring atoms (e.g., 3-6, 4-6, 5-6, 3-8, 4-8, 5-8, 6-8, 3-9, 3-10, 3-11, or 3-12 ring members). Any suitable number of heteroatoms can be included in the heteroaryl group (e.g., 1, 2, 3, 4, or 5; or 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, or 3-5). The heteroaryl group can have 5-8 ring members and 1-4 heteroatoms, or 5-8 ring members and 1-3 heteroatoms, or 5-6 ring members and 1-4 heteroatoms, or 5-6 ring members and 1-3 heteroatoms. The heteroaryl group can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. The heteroaryl group may also be fused to an aromatic ring system (e.g., a phenyl ring) to form members including, but not limited to, benzopyrroles (e.g., indole and isoindole), benzopyridines (e.g., quinoline and isoquinoline), benzopyrazines (quinoxalines), benzopyrimidines (quinazolines), benzopyridazines (e.g., phthalazine and cinnoline), benzothiophenes, and benzofurans. Other heteroaryl groups include heteroaryl rings linked by bonds (e.g., bipyridines). Heteroaryl groups may be substituted or unsubstituted.

[0051] The heteroaryl group may be linked through any position on the ring. For example, pyrrole includes 1-, 2-, and 3-pyrrole; pyridine includes 2-, 3-, and 4-pyridine; imidazole includes 1-, 2-, 4-, and 5-imidazole; pyrazole includes 1-, 3-, 4-, and 5-pyrazole; triazole includes 1-, 4-, and 5-triazole; tetrazole includes 1- and 5-tetrazole; pyrimidine includes 2-, 4-, 5-, and 6-pyrimidine; pyridazine includes 3- and 4-pyridazine; 1,2,3-triazine includes 4- and 5-triazine; 1,2,4-triazine includes 3-, 5-, and 6-triazine; 1,3,5-triazine includes 2-triazine; thiophene includes 2- and 3-thiophene; furan includes 2- and 3-thiophene; and 3-furan; thiazoles include 2-, 4-, and 5-thiazoles; isothiazoles include 3-, 4-, and 5-isothiazoles; oxazoles include 2-, 4-, and 5-oxazoles; isoxazoles include 3-, 4-, and 5-isoxazoles; indoles include 1-, 2-, and 3-indoles; isoindoles include 1- and 2-isoindole; quinolines include 2-, 3-, and 4-quinolines; isoquinolines include 1-, 3-, and 4-isoquinolines; quinazolines include 2- and 4-quinazolines; cinnolines include 3- and 4-cinnolines; benzothiophenes include 2- and 3-benzothiophenes; and benzofurans include 2- and 3-benzofurans.

[0052] Some heteroaryl groups include those having 5 to 10 ring members and 1 to 3 ring atoms (including N, O, or S): for example, pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, and benzofuran). Other heteroaryl groups include those having 5 to 8 ring members and 1 to 3 heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Some other heteroaryl groups include those having 9 to 12 ring members and 1 to 3 heteroatoms, such as indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, benzofuran, and bipyridine. Still other heteroaryl groups include those having 5 to 6 ring members and 1 to 2 ring heteroatoms (including N, O, or S): for example, pyrrole, pyridine, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.

[0053] Some heteroaryl groups contain 5-10 ring members and only nitrogen heteroatoms (e.g., pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, and cinnoline). Other heteroaryl groups contain 5-10 ring members and only oxygen heteroatoms (e.g., furan and benzofuran). Some other heteroaryl groups contain 5-10 ring members and only sulfur heteroatoms (e.g., thiophene and benzothiophene). Still other heteroaryl groups contain 5 to 10 ring members and at least two heteroatoms (e.g., imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiazole, isothiazole, oxazole, isoxazole, quinoxaline, quinazoline, phthalazine, and cinnoline).

[0054] "Heteroatom" refers to O, S, or N.

[0055] "Salt" refers to an acid or base salt of a compound used in the method of the present invention. Illustrative examples of pharmaceutically acceptable salts are salts of inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), salts of organic acids (such as acetic acid, propionic acid, glutamic acid, citric acid, etc.), and salts of quaternary ammonium (such as methyl iodide, ethyl iodide, etc.). It is understood that the pharmaceutically acceptable salts are non-toxic. Further information regarding suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0056] "Isomers" refer to compounds that have the same chemical formula but are structurally distinguishable.

[0057] "Tautomer" refers to two or more structural isomers that exist in equilibrium and are readily converted from one form to another.

[0058] The description of the compounds of the present invention is limited by the principles of chemical bonding known to those skilled in the art. Thus, when a group can be substituted with one or more of many substituents, such substituents are selected to conform to the principles of chemical bonding and to produce compounds that are not inherently unstable and / or known to those skilled in the art to be potentially unstable under ambient conditions (e.g., aqueous, neutral, or physiological conditions).

[0059] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to substances that aid in the administration of an active agent to a subject and the absorption of the active agent by the subject, and that may be included in the compositions of the present invention without causing adverse toxic effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavors and colors, etc. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0060] C. Cervical tumor Cervical cancer is a malignant tumor within or originating from the cervix. It is the fourth most common cause of death in women worldwide. In the United States, well over 10,000 new cases are identified each year. Patients with cervical cancer may not experience symptoms during the early stages of the disease. Risk factors for cervical cancer in women include a history of human papillomavirus (HPV) infection, smoking, and other factors. However, not all patients within the currently recognized risk categories will develop cervical cancer.

[0061] Symptoms of cervical cancer include abnormal vaginal bleeding and pain in the pelvic region. Cervical cancer can be, for example, squamous cell carcinoma, and adenocarcinoma, adenosquamous carcinoma, small cell carcinoma, neuroendocrine tumor, or other cancer types. Visual screening of the cervix is ​​commonly performed during routine patient visits, often using a visual contrast agent (e.g., acetic acid), but the results are inconclusive. A "Pap smear" test is used to screen for cervical cancer, but the negative results of that screening test are often inaccurate. A biopsy of cervical tissue can be used to identify or diagnose cervical cancer. One or more of imaging-based methods (e.g., magnetic resonance imaging (MRI), computed tomography (CT), X-ray, and positron emission tomography (PET) scans, or ultrasound (US)) are often performed on subjects suspected of having cervical cancer, for example, based on the presentation of relevant clinical symptoms. The results of these biopsies or imaging tests, often in combination with the patient's medical history, physical examination, and lab tests, provide information regarding the precise diagnosis and the origin of the tumor.

[0062] The presence, type and stage of cervical cancer may be confirmed by histological analysis of the tumor performed by a pathologist. Histology defines many aspects of the clinical treatment, management, and prognosis of cervical cancer.

[0063] D. Cancerous tumors The methods disclosed herein are applicable to treating cancerous tumors. After a diagnosis of cervical cancer, the tumor can be evaluated to determine the stage and other tumor characteristics.

[0064] E. Glucocorticoid receptor modulators (GRMs) Generally, the treatment of cancerous tumors can be provided by administering an effective amount of chemotherapy in combination with an effective amount of SGRM of any chemical structure or mechanism of action.Provided herein are exemplary GRM classes and specific members of such classes.However, those skilled in the art can easily recognize other related or unrelated SGRMs that can be used in the treatment methods described herein.

[0065] Nonsteroidal anti-glucocorticoid receptor modulators Provided herein are exemplary classes of nonsteroidal glucocorticoid receptor modulators (GRMs) and specific members of such classes that can be used for the methods disclosed herein. However, those skilled in the art will readily recognize other related or unrelated glucocorticoid receptor modulators that can be used in the treatment methods described herein. These include synthetic mimetics and protein analogs, including partially peptidic, pseudopeptidic, and nonpeptidic molecular entities. For example, oligomeric peptidomimetics useful in the present invention include (α-β-unsaturated) peptide sulfonamides, N-substituted glycine derivatives, oligocarbamates, oligourea peptidomimetics, hydrazino peptides, oligosulfones, etc. (see, for example, Amour, Int. J. Pept. Protein Res. 43:297-304, 1994; de Bont, Bioorganic & Medicinal Chem. 4:667-672, 1996).

[0066] Examples of nonsteroidal GR modulators include the GR antagonist compounds disclosed in U.S. Pat. Nos. 5,696,127; 6,570,020; and 6,051,573; the GR antagonist compounds disclosed in U.S. Patent Application 20020077356, the glucocorticoid receptor antagonists disclosed in Bradley et al., J. Med. Chem. 45, 2417-2424 (2002), such as 4α(S)-benzyl-2(R)-chloroethynyl-1,2,3,4,4α,9,10,10α(R)-octahydro-phenanthrene-2,7-diol ("CP 394531") and 4α(S)-benzyl-2(R)-prop-1-ynyl-1,2,3,4,4α,9,10,10α(R)-octahydro-phenanthrene-2,7-diol ("CP 409069"); as well as compounds disclosed in PCT International Application No. WO 96 / 19458, which describes non-steroidal compounds (e.g., 6-substituted-1,2-dihydro-N-protected-quinolines) that are high affinity, highly selective antagonists of steroid receptors.

[0067] For additional compounds that may be utilized in the methods of the present invention, as well as methods for identifying and making such compounds, see U.S. Pat. Nos. 4,296,206 (see above); 4,386,085 (see above); 4,447,424; 4,477,445; 4,519,946; 4,540,686; 4,547,493; 4,634,695; 4,634,696; 4,753,932; 4,774,236; 4,808,710; 4,814,327; 4,829,060; 4,861,763; 4,912,097; 4,921,638; No. 4,943,566; No. 4,954,490; No. 4,978,657; No. 5,006,518; No. 5,043,332; No. 5,064 , No. 5,073,548; No. 5,089,488; No. 5,089,635; No. 5,093,507; No. 5,095,010; No. 5 ,095,129; 5,132,299; 5,166,146; 5,166,199; 5,173,405; 5,276,023; 5,380,839; 5,348,729; 5,426,102; 5,439,913; and 5,616,458; as well as WO 96 / 19458 (which describes non-steroidal compounds (e.g., 6-substituted-1,2-dihydro N-1 protected quinolines) that are high affinity, highly selective modulators (antagonists) of steroid receptors).

[0068] In some embodiments, the combination therapy for treating cancer includes a GRM having a fused azadecalin backbone, a heteroaryl ketone fused azadecalin backbone, or an octahydro fused azadecalin backbone.

[0069] Exemplary GRMs having a fused azadecalin backbone include those described in U.S. Patent Nos. 7,928,237; 8,461,172; and 8,557,839, and can be prepared as disclosed therein. These patents are incorporated herein by reference in their entirety. In some cases, the GRM having a fused azadecalin backbone has the following structure: [ka] or salts and isomers thereof, L 1 and L 2 is a member independently selected from a bond and unsubstituted alkylene; R 1 is an unsubstituted alkyl, an unsubstituted heteroalkyl, an unsubstituted heterocycloalkyl, -OR 1A , -NR 1C R 1D , -C(O)NR 1C R 1D , and -C(O)OR 1A is a member selected from R 1A is a member selected from hydrogen, unsubstituted alkyl, and unsubstituted heteroalkyl; R 1C and R 1D is a member independently selected from unsubstituted alkyl and unsubstituted heteroalkyl; Here, R 1C and R 1D optionally combine to form unsaturation together with the nitrogen to which they are attached, wherein the ring optionally includes an additional ring nitrogen; R 2 is the expression: [ka] wherein R 2Gis a member selected from hydrogen, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, -CN, and -CF3; J is phenyl; t is an integer from 0 to 5; X is -S(O2)-; and R 5 1 to 5 R as needed 5A phenyl substituted with a group, R 5A is hydrogen, halogen, -OR 5A1 , -S(O2)NR 5A2 R 5A3 , -CN, and unsubstituted alkyl, R 5A1 is a member selected from hydrogen and unsubstituted alkyl, and R 5A2 and R 5A3 is a member independently selected from hydrogen and unsubstituted alkyl.

[0070] Exemplary GRMs having a heteroaryl ketone-fused azadecalin backbone include those described in US 2014 / 0038926, which may be prepared as disclosed therein and are incorporated herein by reference in their entirety. In some cases, the GRM having a heteroaryl ketone-fused azadecalin backbone has the following structure: [ka] or salts and isomers thereof, R 1 has 5 to 6 ring members and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S, and optionally each R 1a is a heteroaryl ring substituted with 1 to 4 groups independently selected from Each R 1a is hydrogen, C 1-6 Alkyl, halogen, C1-6 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 said heterocycloalkyl and heteroaryl rings have 5 to 6 ring members and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S; Each R 2 is 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)2R 2a , C 3-8 Cycloalkyl, and C 3-8 heterocycloalkyl, wherein the heterocycloalkyl group optionally comprises 1 to 4 R 2c Is substituted with a group; Alternatively, two R linked to the same carbon 2 Do groups combine to form an oxo group (=O); Or, two R 2 The groups combine to form a heterocycloalkyl ring having 5-6 ring members and 1-3 heteroatoms each independently selected from the group consisting of N, O and S, wherein the heterocycloalkyl ring optionally contains 1-3 R 2d substituted with a group; R 2a and R 2bare hydrogen and C, respectively. 1-6 independently selected from the group consisting of alkyl; Each R 2c is hydrogen, halogen, hydroxy, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -CN, and -NR 2a R 2b independently selected from the group consisting of: Each R 2d is hydrogen and C 1-6 alkyl, or two R attached to the same ring atom 2d The groups combine to form (=O); R 3 Each of them can be set to 1 to 4 R as necessary. 3a substituted with phenyl and pyridyl; Each R 3a is hydrogen, halogens, and C 1-6 haloalkyl; and The subscript n is an integer from 0 to 3.

[0071] Exemplary GRMs having an octahydro-fused azadecalin backbone include those described in U.S. Patent Publication No. 20150148341 (filed November 21, 2014) and may be prepared as described therein. The disclosure of U.S. Patent Publication No. 20150148341 is incorporated herein by reference in its entirety. In some cases, the GRM having an octahydro-fused azadecalin backbone may have the following structure: [ka] or salts and isomers thereof, R 1 has 5 to 6 ring members and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S, and optionally each R 1a is a heteroaryl ring substituted with 1 to 4 groups independently selected from Each R 1a is hydrogen, C 1-6 Alkyl, halogen, C1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, N-oxide, and C 3-8 independently selected from the group consisting of cycloalkyl; Ring J is selected from the group consisting of aryl rings and heteroaryl rings having 5-6 ring members and 1-4 heteroatoms each independently selected from the group consisting of N, O and S; Each R 2 is 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)2R 2a , C 3-8 Cycloalkyl and C having 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S. 3-8 heterocycloalkyl; Alternatively, two R on adjacent ring atoms 2 groups combine to form a heterocycloalkyl ring having 5-6 ring members and 1-3 heteroatoms each independently selected from the group consisting of N, O and S, wherein the heterocycloalkyl ring optionally further comprises 1-3 R 2c substituted with a group; R 2a , R 2b and R 2c are hydrogen and C, respectively. 1-6 independently selected from the group consisting of alkyl; Each R 3a are independently halogen; and The subscript n is an integer from 0 to 3.

[0072] F. Identification of Selective Glucocorticoid Receptor Modulators (SGRMs) To determine whether a test compound is an SGRM, the compound is first subjected to an assay to measure its ability to bind to GR and inhibit GR-mediated activity, which determines whether the compound is a glucocorticoid receptor modulator. If the compound is identified as a glucocorticoid receptor modulator, it is then subjected to a selectivity test to determine whether the compound can specifically bind to GR compared to non-GR proteins (e.g., estrogen receptor, progesterone receptor, androgen receptor, or mineralocorticoid receptor). In one embodiment, the SGRM binds to GR with substantially higher affinity, e.g., at least 10-fold higher affinity, than to non-GR proteins. The SGRM may exhibit 100-fold, 1000-fold, or greater selectivity for binding to GR compared to binding to non-GR proteins.

[0073] i. Join The ability of a test compound to bind to the glucocorticoid receptor can be measured using a variety of assays, for example, by screening the ability of the test compound to compete with a glucocorticoid receptor ligand (e.g., dexamethasone) for binding to the glucocorticoid receptor. Those skilled in the art will recognize that there are many ways to perform such competitive binding assays. In some embodiments, the glucocorticoid receptor is pre-incubated with a labeled glucocorticoid receptor ligand and then contacted with a test compound. This type of competitive binding assay may also be referred to herein as a binding displacement assay. A decrease in the amount of labeled ligand bound to the glucocorticoid receptor indicates that the test compound binds to the glucocorticoid receptor. In some cases, the labeled ligand is a fluorescently labeled compound (e.g., a fluorescently labeled steroid or steroid analog). Alternatively, the binding of the test compound to the glucocorticoid receptor can be measured directly with a labeled test compound. This latter type of assay is referred to as a direct binding assay.

[0074] Both direct and competitive binding assays can be used in a variety of different formats. The formats can be similar to those used in immunoassays and receptor binding assays. For a description of different formats for binding assays, including competitive and direct binding assays, see Basic and Clinical Immunology, 7th Edition (D. Stites and A. Terr, eds.) 1991; Enzyme Immunoassay, ET Maggio, ed., CRC Press, Boca Raton, Florida (1980); and "Practice and Theory of Enzyme Immunoassays", P. Tijssen, Laboratory Techniques in Biochemistry and Molecular Biology, Elsevier Science Publishers BV Amsterdam (1985), each of which is incorporated herein by reference.

[0075] In a solid-phase competitive binding assay, for example, the sample compound can compete with a labeled analyte for specific binding sites on a binding agent bound to a solid surface. In this type of format, the labeled analyte can be a glucocorticoid receptor ligand and the binding agent can be a glucocorticoid receptor bound to a solid phase. Alternatively, the labeled analyte can be a labeled glucocorticoid receptor and the binding agent can be a solid phase glucocorticoid receptor ligand. The concentration of labeled analyte bound to the capture agent is inversely proportional to the ability of the test compound to compete in the binding assay.

[0076] Alternatively, the competitive binding assay can be carried out in liquid phase, and any of a variety of techniques known in the art can be used to separate the bound labeled protein from the unbound labeled protein. For example, several procedures have been developed to distinguish between bound and excess bound ligand or between bound and excess unbound test compound. These include identification of bound complexes by sedimentation in sucrose gradients, gel electrophoresis, or gel isoelectric focusing; precipitation of the receptor-ligand complex with protamine sulfate or adsorption onto hydroxyapatite; and removal of unbound compound or ligand by adsorption onto dextran-coated activated charcoal (DCC) or binding to immobilized antibody. After separation, the amount of bound ligand or test compound is determined.

[0077] Alternatively, homogenous binding assays can be performed in which no separation step is required. For example, the label on the glucocorticoid receptor can be altered by binding of the glucocorticoid receptor to its ligand or test compound. This alteration in the labeled glucocorticoid receptor results in a decrease or increase in the signal emitted by the label, such that measurement of the label at the end of the binding assay allows detection or quantification of the glucocorticoid receptor in the bound state. A wide variety of labels can be used. The components can be labeled by one of several methods. Useful radioactive labels include: 3 H, 125 I, 35 S, 14 C, or 32P. Useful non-radioactive labels include those incorporating fluorophores, chemiluminescent agents, phosphorescent agents, electrochemiluminescent agents, and the like. Fluorescent agents are particularly useful in analytical techniques used to detect shifts in protein structure (e.g., fluorescence anisotropy and / or fluorescence polarization). The choice of label depends on the sensitivity required, ease of conjugation with the compound, stability requirements, and available instrumentation. For a review of various labeling or signal producing systems that may be used, see U.S. Pat. No. 4,391,904, which is incorporated by reference in its entirety for all purposes. The label may be directly or indirectly attached to the desired component of the assay according to methods well known in the art. In some cases, the test compound is contacted with GR in the presence of a fluorescently labeled ligand (e.g., a steroid or steroid analog) with known affinity for the GR, and the amount of bound and free labeled ligand is estimated by measuring the fluorescence polarization of the labeled ligand.

[0078] ii.Activity 1) HepG2 tyrosine aminotransferase (TAT) assay Compounds that exhibit the desired binding affinity to GR are tested for their activity in inhibiting GR-mediated activity. The compounds are typically subjected to a tyrosine aminotransferase assay (TAT assay), which evaluates the ability of the test compound to inhibit the induction of tyrosine aminotransferase activity by dexamethasone. See Example 1. GR modulators suitable for the methods disclosed herein have an IC of less than 10 micromolar. 50 (50% inhibitory concentration). Other assays, including but not limited to those described below, can also be developed to confirm the GR modulating activity of the compounds.

[0079] 2) Cell-based assays Cell-based assays involving whole cells or cell fractions containing glucocorticoid receptors can also be used to assay the binding of test compounds or the modulation of glucocorticoid receptor activity. Exemplary cell types that can be used according to the methods of the present invention include, for example, any mammalian cell, including leukocytes such as neutrophils, monocytes, macrophages, eosinophils, basophils, mast cells, and lymphocytes (e.g., T cells and B cells), leukemia cells, Burkitt's lymphoma cells, tumor cells (including mouse mammary tumor virus cells), endothelial cells, fibroblasts, cardiac cells, muscle cells, breast tumor cells, ovarian cancer carcinoma, cervical cancer, glioblastoma, liver cells, kidney cells, and neuronal cells, as well as fungal cells (including yeast). Cells can be primary cells or other types of tumor cells or immortalized cell lines. Of course, the glucocorticoid receptor can be expressed in cells that do not express an endogenous version of the glucocorticoid receptor.

[0080] In some cases, fragments of the glucocorticoid receptor, as well as protein fusions, can be used for screening. If a molecule that competes with the glucocorticoid receptor ligand for binding is desired, the GR fragment used is one that can bind to the ligand (e.g., dexamethasone). Alternatively, any fragment of GR can be used as a target to identify molecules that bind to the glucocorticoid receptor. Glucocorticoid receptor fragments can include any fragment of, for example, at least 20, 30, 40, 50 amino acids, up to a protein that contains all but one amino acid of the glucocorticoid receptor.

[0081] In some embodiments, the reduction of glucocorticoid receptor activation-triggered signal transduction is used to identify glucocorticoid receptor modulators. The glucocorticoid receptor signal transduction activity can be determined in many ways. For example, downstream molecular events can be monitored to determine signal transduction activity. Downstream events include those activities or expressions that occur as a result of glucocorticoid receptor stimulation. Exemplary downstream events that are useful in functional evaluation of transcription activation and antagonism in unaltered cells include the upregulation of many glucocorticoid response element (GRE)-dependent genes (PEPCK, tyrosine aminotransferase, aromatase). In addition, specific cell types that are susceptible to GR activation can be used (e.g., osteocalcin expression in osteoblasts is downregulated by glucocorticoids; primary hepatocytes show glucocorticoid-mediated upregulation of PEPCK and glucose-6-phosphate (G-6-Pase). GRE-mediated gene expression has also been demonstrated in transfected cell lines using well-known GRE regulatory sequences (e.g., mouse mammary tumor virus promoter (MMTV) transfected upstream of a reporter gene construct). Examples of useful reporter gene constructs include luciferase (luc), alkaline phosphatase (ALP) and chloramphenicol acetyltransferase (CAT). Functional evaluation of transcriptional repression can be performed in cell lines such as monocytes or human dermal fibroblasts. Useful functional assays include those that measure IL-1β-stimulated IL-6 expression; downregulation of collagenase, cyclooxygenase-2 and various chemokines (MCP-1, RANTES); LPS-stimulated cytokine release (e.g., TNFα); or expression of genes regulated by NFkB or AP-1 transcription factors in transfected cell lines.

[0082] Compounds tested in whole cell assays can also be tested in cytotoxicity assays. Cytotoxicity assays are used to determine the extent to which observed effects are due to non-glucocorticoid receptor binding cellular effects. In an exemplary embodiment, the cytotoxicity assay involves contacting constitutively active cells with the test compound. Any reduction in cellular activity indicates a cytotoxic effect.

[0083] 3) Further Assays Further illustrative of the many assays that can be used to identify compositions to be utilized in the methods of the present invention are assays based on glucocorticoid activity in vivo. For example, an assay that evaluates the ability of a putative GR modulator to inhibit the incorporation of 3H-thymidine into DNA in cells stimulated by glucocorticoids can be used. Alternatively, the putative GR modulator can compete with 3H-dexamethasone for binding to hepatocellular carcinoma tissue culture GR (see, e.g., Choi et al., Steroids 57:313-318, 1992). As another example, the ability of a putative GR modulator to block nuclear binding of the 3H-dexamethasone-GR complex can be used (Alexandrova et al., J. Steroid Biochem. Mol. Biol. 41:723-725, 1992). To further identify putative GR modulators, kinetic assays that can distinguish between glucocorticoid agonists and modulators by receptor binding kinetics can also be used (as described in Jones, Biochem J. 204:721-729, 1982).

[0084] In another illustrative example, the assay described by Daune, Molec. Pharm. 13:948-955, 1977; and U.S. Patent No. 4,386,085 can be used to identify anti-glucocorticoid activity. Briefly, thymocytes from adrenalectomized rats are incubated with various concentrations of a test compound (putative GR modulator) in a nutrient medium containing dexamethasone. 3H-uridine is added to the cell cultures, which are further incubated, and the extent of incorporation of the radiolabel into the polynucleotides is measured. 3 GR modulators decrease the amount of H-uridine, thus counteracting this effect.

[0085] iii.Selectivity The GR modulators selected above are then subjected to a selectivity assay to determine whether they are SGRMs. Typically, the selectivity assay involves testing compounds that bind glucocorticoid receptors in vitro for the degree to which they bind to non-glucocorticoid receptor proteins. The selectivity assay can be performed in vitro or in a cell-based system (as described above). Binding can be tested against any suitable non-glucocorticoid receptor protein, including antibodies, receptors, enzymes, and the like. In an exemplary embodiment, the non-glucocorticoid receptor binding protein is a cell surface receptor or a nuclear receptor. In another exemplary embodiment, the non-glucocorticoid receptor protein is a steroid receptor (e.g., an estrogen receptor, a progesterone receptor, an androgen receptor, or a mineralocorticoid receptor).

[0086] The selectivity of an antagonist of GR compared to its MR can be measured using various assays known to those skilled in the art. For example, a specific antagonist can be identified by measuring the ability of the antagonist to bind to GR compared to MR (see, for example, U.S. Patent Nos. 5,606,021; 5,696,127; 5,215,916; and 5,071,773). Such analysis can be performed either using a direct binding assay or by evaluating competitive binding to purified GR or MR in the presence of a known ligand. In an exemplary assay, cells that stably express high levels of glucocorticoid receptor or mineralocorticoid receptor (see, for example, U.S. Patent No. 5,606,021) are used as a source of purified receptor. The affinity of the ligand to its receptor is then measured directly. Those GR modulators that exhibit at least a 10-fold, 100-fold, and often 1000-fold greater affinity for the GR compared to the MR are then selected for use in the methods of the invention.

[0087] The selectivity assay may also include assaying the ability to inhibit GR-mediated activity but not MR-mediated activity. One way to identify such GR-specific modulators is to use transfection assay to evaluate the ability of antagonists to prevent the activation of reporter constructs (see, for example, Bocquel et al., J. Steroid Biochem Molec. Biol. 45:205-215, 1993; U.S. Pat. Nos. 5,606,021 and 5,929,058). In an exemplary transfection assay, an expression plasmid encoding a receptor and a reporter plasmid containing a reporter gene linked to a receptor-specific regulatory element are co-transfected into a suitable receptor-negative host cell. The transfected host cell is then cultured in the presence and absence of a hormone (e.g., cortisol or its analogs) that can activate the hormone-responsive promoter / enhancer element of the reporter plasmid. The transfected and cultured host cells are then monitored for induction (i.e., presence) of the product of the reporter gene sequence. Finally, the expression and / or steroid binding capacity of the hormone receptor protein (encoded by the receptor DNA sequence on the expression plasmid and produced in the transfected and cultured host cells) is measured by determining the activity of the reporter gene in the presence and absence of antagonist. The antagonist activity of a compound can be determined in comparison with known antagonists of the GR and MR receptors (see, for example, U.S. Pat. No. 5,696,127). Efficacy is then reported as the percent maximal response observed for each compound compared to a reference antagonist compound. GR modulators that show at least 100-fold, often 1000-fold, or greater activity against GR compared to MR, PR, or AR are then selected for use in the methods disclosed herein.

[0088] An exemplary SGRM that can be used in the methods disclosed herein is CORT 108297, i.e., (R)-(4a-ethoxymethyl-1-(4-fluorophenyl)-6-(4-trifluoromethyl-benzenesulfonyl)-4,4a,5,6,7,8-hexahydro-1H,1,2,6-triaza-cyclopenta[b]naphthalene, which has the following structure: [ka]

[0089] An exemplary SGRM that can be used in the methods disclosed herein is CORT 125134, i.e., (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, which has the following structure: [ka]

[0090] Another exemplary SGRM that can be used in the methods disclosed herein is CORT125281, i.e., ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, which has the following structure: [ka]

[0091] G. Pharmaceutical Compositions and Administration In some embodiments, the invention provides a pharmaceutical composition comprising a pharma- ceutically acceptable excipient and an SGRM.

[0092] SGRMs can be prepared and administered in a wide variety of oral, parenteral, and topical dosage forms. Oral preparations include tablets, pills, powders, dragees, capsules, liquids, lozenges, gels, syrups, slurries, suspensions, and the like, suitable for ingestion by a patient. SGRMs can also be administered by injection, i.e., intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally, or intraperitoneally. SGRMs can also be administered by inhalation, e.g., intranasally. Additionally, SGRMs can be administered transdermally. Thus, the present invention also provides pharmaceutical compositions comprising a pharma- ceutically acceptable carrier or excipient and an SGRM.

[0093] For preparing pharmaceutical compositions from SGRM, pharma- ceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials. Formulation and Administration Technical details regarding administration are fully described in the scientific and patent literature (see, e.g., the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton Pa. ("Remington's").

[0094] In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient, the SGRM. In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

[0095] The powders and tablets preferably contain 5% or 10% to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with an encapsulating material as a carrier to provide a capsule in which the active ingredient, with or without other carriers, is surrounded by a carrier, which is thus in association with the ingredient. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0096] Suitable solid excipients are carbohydrate or protein fillers, including, but not limited to, sugars (including lactose, sucrose, mannitol, or sorbitol); starches derived from corn, wheat, rice, potato, or other plants; celluloses (such as methylcellulose, hydroxypropylmethylcellulose, or sodium carboxymethylcellulose); and gums (including gum arabic and gum tragacanth); and proteins (such as gelatin and collagen). If desired, disintegrants or solubilizers can be added (e.g., cross-linked polyvinylpyrrolidone, agar, alginic acid, or a salt thereof (e.g., sodium alginate)).

[0097] Dragee cores are provided with suitable coating agents such as concentrated sugar solutions (which may also contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer liquid, and suitable organic solvents or solvent mixtures). Dyes or pigments may be added to the tablet or dragee coating for product identification or to characterize the amount of active compound (i.e., dosage). The pharmaceutical preparations of the present invention may also be used orally using push-fit capsules made of, for example, gelatin, and soft-sealed capsules made of gelatin and a coating agent (e.g., glycerol or sorbitol). Push-fit capsules may contain the GR modulator mixed with a filler or binder (e.g., lactose or starch), a lubricant (e.g., talc or magnesium stearate), and, if necessary, a stabilizer. In soft capsules, the GR modulator compound may be dissolved or suspended in a suitable liquid (e.g., fatty oils, liquid paraffin, or liquid polyethylene glycol) with or without stabilizers.

[0098] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions.For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

[0099] Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents (as desired). Aqueous suspensions suitable for oral use may be made by dispersing the finely divided active component in water with viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with fatty acids and partial esters derived from hexitols (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with fatty acids and partial esters derived from hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin. The preparations may be adjusted for osmolality.

[0100] Also included are solid form preparations that are intended to be converted into liquid form preparations for oral administration immediately before use.Such liquid forms include solutions, suspensions and emulsions.These preparations can contain, in addition to their active ingredients, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0101] Oil suspensions can be formulated by suspending the SGRM in a vegetable oil (e.g., peanut oil, olive oil, sesame oil, or coconut oil) or in a mineral oil (e.g., liquid paraffin); or in a mixture thereof. The oil suspensions can contain a thickening agent (e.g., beeswax, hard paraffin, or cetyl alcohol). Sweeteners can be added to provide a palatable oral preparation (e.g., glycerol, sorbitol, or sucrose). These preparations can be preserved by adding an antioxidant (e.g., ascorbic acid). For examples of injectable oil vehicles, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. The pharmaceutical preparations of the present invention can also be in the form of oil-in-water emulsions. The oil phase can be a vegetable oil or a mineral oil (as above), or a mixture thereof. Suitable emulsifying agents include naturally occurring gums (e.g., acacia and tragacanth), naturally occurring phosphatides (e.g., soybean lecithin), esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate), and the condensation products of these partial esters with ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). The emulsions may also contain sweetening and flavoring agents, as in the formulation of syrups and elixirs. Such formulations may also contain a demulcent, preservative, or coloring agent.

[0102] SGRMs can be delivered transdermally by the topical route and can be formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, dusts, and aerosols.

[0103] SGRMs can also be delivered as microspheres for slow release in the body. For example, microspheres can be delivered via intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995); as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863, 1995); or as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). Both the transdermal and intradermal routes provide constant delivery over weeks or months.

[0104] The pharmaceutical formulations of the present invention may be provided as salts and may be formed with many acids, including but not limited to hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, and the like. Salts tend to be more soluble in aqueous or other protic solvents than their corresponding free base forms. In other cases, the preparations may be lyophilized powders in 1 mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol, pH range 4.5-5.5, which are combined with a buffer prior to use.

[0105] In another embodiment, the formulations of the present invention can be delivered by the use of liposomes that fuse with the cell membrane or are endocytosed, i.e., by using a ligand attached to the liposome or directly to the oligonucleotide that binds to a surface membrane protein receptor of the cell that undergoes endocytosis. By using liposomes, delivery of the GR modulator to the target cell in vivo can be focused, especially if the liposome surface has a ligand specific for the target cell or is otherwise directed preferentially to a specific organ (see, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989).

[0106] The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate amounts of the active component, GRM. The unit dosage form can be a packaged preparation, a package containing discrete quantities of the preparation (e.g., packeted tablets, capsules, and powders in vials or ampoules). Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or the appropriate number of any of these in packaged form.

[0107] The amount of active ingredient in a unit dose preparation may vary or be adjusted from 0.1 mg to 10,000 mg, more typically from 1.0 mg to 6,000 mg, and most typically from 50 mg to 500 mg. Suitable dosages also include about 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, or 2000 mg, according to the particular application and the potency of the active ingredient. The composition may also contain other compatible therapeutic agents, if desired.

[0108] Single or multiple administrations of the formulation may be administered depending on the dosage and frequency as required and tolerated by the patient. The formulation should provide a sufficient amount of the active agent to effectively treat the disease state. Thus, in one embodiment, the pharmaceutical formulation for oral administration of GRM is in a daily amount between about 0.01 and about 150 mg per kg of body weight per day (mg / kg / day). In some embodiments, the daily amount is about 1.0-100 mg / kg / day, 5-50 mg / kg / day, 10-30 mg / kg / day, and 10-20 mg / kg / day. Lower dosages may be used, particularly when the drug is administered to an anatomically isolated site (e.g., the cerebrospinal fluid (CSF) space) into the bloodstream, into a body cavity, or into the lumen of an organ, as opposed to oral administration. With local administration, substantially higher dosages may be used. Actual methods for preparing formulations for parenteral administration will be known or apparent to those of skill in the art and are described in more detail in publications such as Remington's, supra. See also Nieman, In "Receptor Mediated Antisteroid Action", Agarwal, et al., eds., De Gruyter, New York (1987).

[0109] The duration of treatment with an SGRM to reduce the tumor burden of a cancerous tumor or otherwise ameliorate symptoms of that tumor can vary according to the severity of the subject's condition and the subject's response to the SGRM. In some embodiments, the SGRM can be administered for a period of about 1 week to 104 weeks (2 years), more typically about 6 weeks to 80 weeks, and most typically about 9 to 60 weeks. Suitable administration periods also include 5 to 9 weeks, 5 to 16 weeks, 9 to 16 weeks, 16 to 24 weeks, 16 to 32 weeks, 24 to 32 weeks, 24 to 48 weeks, 32 to 48 weeks, 32 to 52 weeks, 48 ​​to 52 weeks, 48 ​​to 64 weeks, 52 to 64 weeks, 52 to 72 weeks, 64 to 72 weeks, 64 to 80 weeks, 72 to 80 weeks, 72 to 88 weeks, 80 to 88 weeks, 80 to 96 weeks, 88 to 96 weeks, and 96 to 104 weeks. Suitable administration periods also include 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 24 weeks, 25 weeks, 30 weeks, 32 weeks, 35 weeks, 40 weeks, 45 weeks, 48 ​​weeks, 50 weeks, 52 weeks, 55 weeks, 60 weeks, 64 weeks, 65 weeks, 68 weeks, 70 weeks, 72 weeks, 75 weeks, 80 weeks, 85 weeks, 88 weeks, 90 weeks, 95 weeks, 96 weeks, 100 weeks, and 104 weeks.Generally, administration of SGRM should be continued until clinically significant reduction or improvement is observed.Treatment with SGRM according to the present invention can last for about 2 years or even longer.

[0110] In some embodiments, administration of the SGRM may be stopped, non-consecutively, for one or more periods followed by one or more periods during which administration is resumed. Suitable periods for administration to cease include 5-9 weeks, 5-16 weeks, 9-16 weeks, 16-24 weeks, 16-32 weeks, 24-32 weeks, 24-48 weeks, 32-48 weeks, 32-52 weeks, 48-52 weeks, 48-64 weeks, 52-64 weeks, 52-72 weeks, 64-72 weeks, 64-80 weeks, 72-80 weeks, 72-88 weeks, 80-88 weeks, 80-96 weeks, 88-96 weeks, and 96-100 weeks. Suitable periods for administration to cease also include 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 24 weeks, 25 weeks, 30 weeks, 32 weeks, 35 weeks, 40 weeks, 45 weeks, 48 ​​weeks, 50 weeks, 52 weeks, 55 weeks, 60 weeks, 64 weeks, 65 weeks, 68 weeks, 70 weeks, 72 weeks, 75 weeks, 80 weeks, 85 weeks, 88 weeks, 90 weeks, 95 weeks, 96 weeks, and 100 weeks.

[0111] The dosage regimen also takes into account pharmacokinetic parameters well known in the art, i.e., rate of absorption, bioavailability, metabolism, clearance, etc. (see, e.g., Hidalgo-Aragones (1996) J. Steroid Biochem. Mol. Biol. 58:611-617; Groning (1996) Pharmazie 51:337-341; Fotherby (1996) Contraception 54:59-69; Johnson (1995) J. Pharm. Sci. 84:1144-1146; Rohatagi (1995) Pharmazie 50:610-613; Brophy (1983) Eur. J. Clin. Pharmacol. 24:103-108; see latest edition of Remington's, supra). The state of the art allows the clinician to determine the dosage regimen for each individual patient, GR modulator and disease or condition to be treated.

[0112] SGRMs may be used in combination with other active agents known to be useful in modulating the glucocorticoid receptor, or with adjunct agents that may not be effective alone, but may contribute to the effectiveness of the active agent.

[0113] In some embodiments, co-administration includes administering one active agent, the SGRM, within 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 20 hours, or 24 hours of the second active agent. Co-administration includes administering two active agents simultaneously, at about the same time (e.g., within about 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be achieved by co-formulation, i.e., preparing a single pharmaceutical composition that includes both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active agents and / or auxiliary agents can be linked or conjugated to each other.

[0114] After a pharmaceutical composition containing a GR modulator of the invention is formulated in an acceptable carrier, the composition is placed in an appropriate container and labeled for treatment of an indicated condition. For administration of an SGRM, such labeling would include, for example, instructions regarding the amount, frequency and method of administration.

[0115] The pharmaceutical compositions of the present invention may be provided as salts and may be formed with many acids, including but not limited to hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, and the like. Salts tend to be more soluble in aqueous or other protic solvents than their corresponding free base forms. In other cases, the preparations may be lyophilized powders in 1 mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol, pH range 4.5-5.5, which are combined with a buffer prior to use.

[0116] In another embodiment, the compositions of the present invention are useful for parenteral administration (e.g., intravenous (IV) administration or administration into a cavity or lumen of a body or organ). The formulation for administration generally comprises a solution of the compositions of the present invention dissolved in a pharmaceutically acceptable carrier. Among the acceptable vehicles and solvents that can be used are water and Ringer's solution, isotonic sodium chloride. In addition, sterile, fixed oils can be conventionally used as a solvent or suspending medium. For this purpose, any bland, fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids (e.g., oleic acid) can be used in the preparation of injectables as well. These solutions are sterile and generally free of undesirable substances. These formulations can be sterilized by conventional, well-known sterilization techniques. The formulations can contain pharmaceutically acceptable auxiliary substances, such as pH adjusting and buffering agents, tonicity adjusting agents (e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc.), as necessary to approximate physiological conditions. The concentration of the composition of the present invention in these preparations can vary widely and is selected mainly based on fluid volume, viscosity, body weight, etc., according to the specific mode of administration selected and the needs of the patient. For IV administration, the preparation can be a sterile injectable preparation (e.g., a sterile injectable aqueous or oily suspension). The suspension can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent (e.g., a solution of 1,3-butanediol).

[0117] H. Chemotherapeutic Agents Chemotherapeutic agents suitable for use in combination with the SGRMs of the present invention include agents that have the property of killing cancer cells or inhibiting cancer cell growth (e.g., those disclosed in U.S. Patent Publication No. 20150218274, and also at http: / / chemocare.com / chemotherapy / what-is-chemotherapy / types-of-chemotherapy.aspx). These agents include, but are not limited to, anti-microtubule agents (e.g., taxanes and vinca alkaloids), topoisomerase inhibitors and antimetabolites (e.g., nucleoside analogs (e.g., that act like gemcitabine)), mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, mitotic inhibitors, anthracyclines, intercalating agents, agents that can interfere with signal transduction pathways, agents that promote apoptosis, proteasome inhibitors, and the like.

[0118] Alkylating agents are most active in the stationary phase of cells. These types of drugs are cell cycle non-specific. Exemplary alkylating agents that may be used in combination with the SGRMs of the present invention include, but are not limited to, the following: nitrogen mustards, ethylenimine derivatives, alkylsulfonates, nitrosoureas, and triazenes: uracil mustard (Aminouracil Mustard®, Chlorethaminacil®, Demethyldopan®, Desmethyldopan®, Haemanthamine®, Nordopan®, Uracil nitrogen mustard, ethylenimine derivatives, alkylsulfonates, nitrosoureas, and triazenes). Mustard®, Uracillost®, Uracilmostaza®, Uramustin®, Uramustine®), chlormethine (Mustargen®), cyclophosphamide (Cytoxan®, Neosar®, Clafen®, Endoxan®, Procytox®, Revimmune.TM.), ifosfamide (Mitoxana®), melphalan (Alkeran®), chlorambucil (Leukeran®), pipobromobromide (Pentan-2000®), brodalumab (Bordeaux ... mandel (Amedel®, Vercyte®), triethylenemelamine (Hemel®, Hexalen®, Hexastat®), triethylenethiophosphoramine, thiotepa (Thioplex®), busulfan (Busilvex®, Myleran®), carmustine (BiCNU®), lomustine (CeeNU®), streptozocin (Zanosar®), and dacarbazine (DTIC-Dome®).Further exemplary alkylating agents include, but are not limited to, oxaliplatin (Eloxatin®); temozolomide (Temodar® and Temodal®); dactinomycin (also known as actinomycin-D, Cosmegen®); melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, Alkeran®); altretamine (also known as hexamethylmelamine (HMM), Hexalen®); carmustine (BiCNU®); bendamustine (Treanda®); busulfan (Busulfex® and Myleran®); carboplatin (Paraplatin®); lomustine (CC NU, also known as CeeNU®); cisplatin (CDDP, also known as Platinol® and Platinol®-AQ); chlorambucil (Leukeran®); cyclophosphamide (Cytoxan® and Neosar®); dacarbazine (DTIC, also known as DIC and imidazole carboxamide, DTIC-Dome®); altretamine (hexamethylmelamine (HMM), also known as Hexalen®); ifosfamide (Ifex®); prednumustine; procarbazine (Matulane®); mechlorethamine (nitrogen mustard, mustine and mechlorethamine hydrochloride. hydrochloride), and is known as Mustargen®; streptozocin (Zanosar®); thiotepa (thiophosphoamide, and is also known as TESPA and TSPA, and is Thioplex®); cyclophosphamide (Endoxan®, Cytoxan®, Neosar®, Procytox®, Revimmune®); and bendamustine HCl (Treanda®).

[0119] Antitumor antibiotics are chemo agents derived from natural products produced by species of the soil fungus Streptomyces. These drugs act during multiple phases of the cell cycle and are considered to be cell cycle specific. There are several types of antitumor antibiotics, including, but not limited to, anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, mitoxantrone, and idarubicin), chromomycins (e.g., dactinomycin and plicamycin), mitomycins, and bleomycins.

[0120] Antimetabolites are a type of chemotherapy treatment that is cell cycle specific. If the cells incorporate these antimetabolite substances into the cell metabolism, they cannot divide. These classes of chemotherapy agents include folate antagonists (e.g., methotrexate); pyrimidine antagonists (e.g., 5-fluorouracil, foxuridine, cytarabine, capecitabine, and gemcitabine); purine antagonists (e.g., 6-mercaptopurine and 6-thioguanine); adenosine deaminase inhibitors (e.g., cladribine, fludarabine, nelarabine, and pentostatin).

[0121] Exemplary anthracyclines that may be used in combination with the SGRMs of the invention include, for example, doxorubicin (Adriamycin® and Rubex®); bleomycin (Lenoxane®); daunorubicin (daunorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride, Cerubidine®); daunorubicin liposome (daunorubicin citrate liposome, DaunoXome®); mitoxantrone (DHAD, Novantrone®); epirubicin (Ellence); idarubicin (Idamycin®, Idamycin PFS®); mitomycin C (Mutamycin®); geldanamycin; herbimycin; ravidomycin; and desacetylravidomycin.

[0122] Anti-microtubule agents include vinca alkaloids and taxanes. Exemplary vinca alkaloids that may be used in combination with the SGRMs of the invention include, but are not limited to, vinorelbine tartrate (Navelbine®), vincristine (Oncovin®), and vindesine (Eldisine®); vinblastine (vinblastine sulfate, also known as vincaleukoblastine and VLB, Alkaban-AQ® and Velban®); and vinorelbine (Navelbine®). Exemplary taxanes that may be used in combination with the SGRMs of the invention include, but are not limited to, paclitaxel and docetaxel. Non-limiting examples of paclitaxel agents include nanoparticle albumin-bound paclitaxel ("nab-paclitaxel" marketed as ABRAXANE by Abraxis Bioscience), docosahexaenoic acid-bound paclitaxel (DHA-paclitaxel, Taxoprexin marketed by Protarga), polyglutamic acid-bound paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX marketed by Cell Therapeutic), tumor-activated prodrug (TAP), ANG105 (Angiopep-2 bound to a triad of paclitaxel, marketed by ImmunoGen), paclitaxel-EC-1 (paclitaxel bound to the erbB2 recognition peptide EC-1; Li et al., Biopolymers (2007) 87:225-230), and glucose-conjugated paclitaxel (e.g., 2'-paclitaxel methyl 2-glucopyranosyl succinate, see Liu et al., Bioorganic & Medicinal Chemistry Letters (2007) 17:617-620).

[0123] Exemplary proteasome inhibitors that may be used in combination with the SGRMs of the invention include, but are not limited to, the following: bortezomib (Velcade.RTM.); carfilzomib (PX-171-007, (S)-4-methyl-N--((S)-1-(((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2 -morpholinoacetamido-o)-4-phenylbutanamido)-pentanamide); marizomib (NPI-0052); ixazomib citrate (MLN-9708); delanzomib (CEP-18770); and O-methyl-N-[(2-methyl-5-thiazolyl)carbonyl]-L-seryl-O-methyl-N-[(1S)-2-[(-2R)-2-methyl-2-oxiranyl]-2-oxo-1-(phenylmethyl)ethyl]-L-serinamide (ONX-0912).

[0124] In some embodiments, the chemotherapeutic agent is selected from the group consisting of: chlorambucil, cyclophosphamide, ifosfamide, melphalan, streptozocin, carmustine, lomustine, bendamustine, uramustine, estramustine, carmustine, nimustine, ranimustine, mannosulfan, busulfan, dacarbazine, temozolomide, thiotepa, altretamine, 5-fluorouracil (5-FU), 6-mercaptopurine ( 6-MP), capecitabine, cytarabine, floxuridine, fludarabine, gemcitabine, hydroxyurea, methotrexate, pemetrexed, daunorubicin, doxorubicin, epirubicin, idarubicin, SN-38, ARC, NPC, camptothecin, topotecan, 9-nitrocamptothecin, 9-aminocamptothecin, rubifen, gimatecan, diflomotecan, BN80927, DX- 895 If, MAG-CPT, amsacrine, etoposide, etoposide phosphate, teniposide, doxorubicin, paclitaxel, docetaxel, gemcitabine, accatin III, 10-deacetyltaxol, 7-xylosyl-10-deacetyltaxol, cephalomannine, 10-deacetyl-7-epitaxol, 7-epitaxol, 10-deacetylbaccatin III, 10-deacetylcephalomannine, gemcitabine, irinotecan, albumin-bound paclitaxel, oxaliplatin, capecitabine, cisplatin, docetaxel, irinotecan liposomal, and etoposide, and combinations thereof.

[0125] In certain embodiments, the chemotherapeutic agent is administered at a dose and schedule that may be guided by doses and schedules approved by the U.S. Food and Drug Administration (FDA) or other regulatory agencies, subject to empirical optimization. In some cases, the chemotherapeutic agent is administered at a dose of about 100-1000 mg, e.g., about 200 mg-800 mg, about 300 mg-700 mg, or about 400 mg-600 mg, e.g., about 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, or 700 mg. The administration schedule may vary, e.g., weekly, every 5 days, every 4 days, every other day, to daily, twice a day, or three times a day. In one embodiment, the chemotherapeutic agent is administered at a dose of about 100 mg-600 mg daily, e.g., daily, every other day, or three times a day, for all or part of the treatment period. is administered every 4 days at oral or intravenous doses of about 100 mg, 200 mg, 260 mg, 300 mg, 400 mg, or 600 mg. In some embodiments, the chemotherapeutic agent is a taxane, which may be used in accordance with the methods of the invention at any standard dose (e.g., those approved by the FDA). In various embodiments, the taxane is nab-paclitaxel, which is administered at a dose ranging from 80 mg to 125 mg per square meter of body surface area as an intravenous infusion over 30 minutes on days 1, 8, and 15 of every 28 day cycle.

[0126] In still further embodiments, more than one chemotherapeutic agent may be administered simultaneously or sequentially in any order during all or part of the treatment period. The two agents may be administered according to the same or different dosing regimens.

[0127] I. Combination Therapy Various combinations of SGRMs and chemotherapeutic agents (or combinations of such agents and compounds) can be used to reduce tumor burden in patients. "Combination therapy" or "in combination with" is not intended to mean that the therapeutic agents must be administered simultaneously and / or formulated for delivery together, although these delivery methods are within the scope described herein. The SGRM and chemotherapeutic agent can be administered according to the same or different dosing regimens. In some embodiments, the SGRM and chemotherapeutic agent are administered sequentially in any order during all or part of the treatment period. In some embodiments, the SGRM and anti-cancer agent are administered simultaneously or nearly simultaneously (e.g., within about 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, or 30 minutes of each other). Non-limiting examples of combination therapy are as follows, with administration of the SGRM and chemo agent, e.g., the SGRM is "A" and the anti-cancer agent, or compound given as part of the chemotherapeutic regimen, is "B":

[0128] A / B / AB / A / BB / B / AA / A / BA / B / BB / A / AA / B / B / BB / A / B / B

[0129] B / B / B / AB / B / A / BA / A / B / BA / B / A / BA / B / B / A B / B / A / A

[0130] B / A / B / AB / A / A / BA / A / A / BB / A / A / AA / B / A / A A / A / B / A

[0131] Administration of the therapeutic compound or agent to the patient follows general protocols for the administration of such compounds, taking into account the toxicity, if any, of the treatment. Surgical intervention may also be applied in combination with the described treatment. The present methods involved are directed to the use of other treatment modalities, e.g. For example, surgery, radiation therapy, targeted therapy, immunotherapy, growth factor inhibitors, or the use of anti-angiogenic factors.

[0132] J. Assessing improvements in reducing tumor burden The SGRM treatment disclosed herein can reduce tumor burden and provide patients with cancerous tumors with beneficial clinical outcomes.The methods for measuring these responses are well known to those skilled in the art of cancer treatment (e.g., as described in the Response Evaluation Criteria in Solid Tumors ("RECIST") guidelines available at ctep.cancer.gov / protocolDevelopment / docs / recist_guideline.pdf).

[0133] In one approach, the tumor burden is measured by assaying the expression of tumor-specific biomarkers. This approach is particularly useful for metastatic tumors. Tumor-specific biomarkers are proteins or other molecules that are specific to cancer cells or are much more abundant in them when compared to non-cancerous cells. Biomarkers that may be useful for identifying cervical cancer include, for example, alpha-actinin-4. Pyruvate kinase isozyme M1 / M2, etc. (see, for example, Van Raemdonck et al., PLoS One September 2014, http: / / dx.doi.org / 10.1371 / jounal.pone.0160488).

[0134] Methods for measuring the expression level of tumor-specific gene markers are well known. In some embodiments, the mRNA of gene markers is isolated from blood samples or tumor tissues, and real-time reverse transcriptase-polymerase chain reaction (RT-PCR) is performed to quantify the expression of the gene markers. In some embodiments, Western blot or immunohistochemistry analysis is performed to evaluate the protein expression of the tumor-specific gene markers. Typically, the level of the tumor-specific gene marker is measured in multiple samples taken over the course of the combination therapy of the present invention, and a decrease in the level correlates with a decrease in tumor burden.

[0135] In another approach, the reduction of tumor burden by the combination therapy disclosed herein is shown by the reduction of tumor size or the reduction of cancer volume in the body.The measurement of tumor size is typically achieved by imaging-based techniques.For example, computed tomography (CT) scan can provide accurate and reliable anatomical information not only of tumor shrinkage or tumor growth, but also of disease progression by identifying either growth in existing lesions or the occurrence of new lesions or tumor metastasis.

[0136] In yet another approach, reduction in tumor burden can be assessed by functional and metabolic imaging techniques. These techniques can provide earlier assessment of therapeutic response by observing changes in perfusion, oxygenation, and metabolism. For example, 18 F-FDG PET uses radiolabeled glucose analog molecules to assess tissue metabolism. Tumors typically have elevated uptake of glucose, and changes in values ​​corresponding to a decrease in tumor tissue metabolism indicate a reduction in tumor burden. A similar imaging technique is disclosed in Kang et al., Korean J. Radiol. (2012) 13(4) 371-390.

[0137] Patients receiving the treatments disclosed herein may show various degrees of tumor burden reduction. In some cases, patients may show a complete response (CR) (also referred to as "no evidence of disease (NED)"). CR means that all detectable tumors have disappeared as shown by examination, physical examination and scans. In some cases, patients receiving the combination therapy disclosed herein may experience a partial response (PR), which generally corresponds to at least 50% in total tumor volume, but there is also evidence that some residual disease still remains. In some cases, the residual disease in a deep partial response may actually be dead tumor or scar, so that some patients classified as having a PR may actually have a CR. Also, many patients who show shrinkage during treatment may show further shrinkage with continued treatment and achieve a CR. In some cases, patients receiving the combination therapy may experience a Minor Response (MR), which generally means a small amount of shrinkage, more than 25% of total tumor volume, but less than the 50% that would result in a PR. In some cases, patients receiving combination therapy may show stable disease (SD), meaning that their tumors generally remain the same size, but may contain either a small amount of growth (typically less than 20% or 25%) or a small amount of shrinkage (less than PR, unless a minor response occurs, in which case SD is typically defined as less than 25%).

[0138] Desirable beneficial or clinical outcomes from the combination therapy may also include, for example, reduced (i.e., slowed and / or stopped to some extent) cancer cell invasion into surrounding organs; inhibited (i.e., slowed and / or stopped to some extent) tumor metastasis; increased response rate (RR); increased duration of response; alleviation to some extent of one or more symptoms associated with the cancer; reduced doses of other medications required to treat the disease; delayed progression of the disease; and / or prolonged patient survival and / or improved quality of life. Methods for assessing these effects are well known and / or disclosed, for example, at cancerguide.org / endpoints.html and in the RECIST guidelines (supra).

[0139] All publications and patent applications cited in this specification are herein incorporated by reference in their entirety as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0140] Although the foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity of understanding, it will be readily apparent to those skilled in the art in light of the teachings of the invention that certain changes and modifications can be made thereto without departing from the spirit or scope of the appended claims. EXAMPLES

[0141] The following examples are offered by way of illustration only and not by way of limitation. Those of skill in the art will readily recognize a variety of non-critical parameters that could be changed or modified to yield essentially similar results.

[0142] Example 1. HepG2 Tyrosine Aminotransferase (TAT) Assay The following protocol describes an assay for measuring induction of TAT by dexamethasone in HepG2 cells (human hepatoma cell line; ECACC, UK). HepG2 cells are cultured at 37°C, 5% / 95% (v / v) CO2 / air using MEME medium supplemented with 10% (v / v) fetal bovine serum; 2 mM L-glutamine and 1% (v / v) NEAA. The HepG2 cells are then counted and cultured at 0.125 x 10 in RPMI 1640 without phenol red, 10% (v / v) charcoal stripped FBS, 2 mM L-glutamine. 6 The cells are adjusted to obtain a density of 10,000 cells / ml and seeded into 96-well sterile tissue culture microtiter plates at 25,000 cells / well in 200 μl and incubated at 37° C., 5% CO 2 for 24 hours.

[0143] Growth medium is then removed and replaced with assay medium {RPMI 1640 without phenol red, 2 mM L-glutamine + 10 μM forskolin}. Test compounds are then screened against a 100 nM dexamethasone challenge. Compounds are then serially half log diluted from a 10 mM stock in 100% (v / v) dimethyl sulfoxide. An 8-point half log dilution curve is then generated, followed by a 1:100 dilution into assay medium resulting in 10x the final assay compound concentration. This results in final assay compound concentrations ranging from 10 to 0.003 μM in 0.1% (v / v) dimethyl sulfoxide.

[0144] Test compounds are pre-incubated with cells in microtiter plates for 30 minutes at 37° C., 5 / 95 (v / v) CO2 / air before addition of 100 nM dexamethasone, then allowed for optimal TAT induction for a subsequent 20 hours.

[0145] HepG2 cells are then lysed with 30 μl of cell lysis buffer containing a protease inhibitor cocktail for 15 minutes at 4° C. Then 155 μl of substrate mixture containing 5.4 mM tyrosine sodium salt, 10.8 mM α-ketoglutarate and 0.06 mM pyridoxal 5′ phosphate in 0.1 M potassium phosphate buffer (pH 7.4) can be added. After 2 hours of incubation at 37° C., the reaction can be terminated by adding 15 μl of 10 M potassium hydroxide aqueous solution, and the plate can be incubated for an additional 30 minutes at 37° C. The TAT activity product can be measured by absorbance at λ340 nm.

[0146] I C 50 Values ​​may be calculated by plotting % inhibition (normalized to 100 nM dexamethasone TAT stimulation) versus compound concentration and fitting the data to a four parameter logistic equation. IC 50 Values ​​can be converted to Ki (equilibrium dissociation constant) using the Cheng and Prusoff equation, assuming that the antagonist is a competitive inhibitor with respect to dexamethasone.

[0147] Example 2. Reduction of transplanted cervical cancer tumor growth in mice using combination therapy of CORT125134 and paclitaxel A suspension of human HeLa cervical cancer cells was injected subcutaneously (5 million cells / mouse) into the right flank of 5-6 week-old immunosuppressed female mice (Balb / c nude). Tumors were grown until they reached a volume of 100–200 mm. 3Mice were then divided into 5 groups (10 mice / group). Group 1 received paclitaxel vehicle (sterile saline) intravenously (iv) every 4 days and CORT125134 vehicle orally (po) (10% DMSO, 0.1% Tween 80 and 89.9% HPMC (0.5%), 10ml / kg) every 4 days. Group 2 received paclitaxel (7.5mg / kg) iv every 4 days. Group 3 received paclitaxel iv every 4 days and CORT125134 (30mg / kg) po the day before and the same day as paclitaxel administration. Group 4 received paclitaxel (15mg / kg) iv every 4 days. Group 5 received paclitaxel (15 mg / kg) iv every 4 days and CORT125134 (30 mg / kg) po the day before and the day of paclitaxel (15 mg / kg) iv administration.

[0148] The longest (L) and shortest (S) diameters of the tumors were measured three times a week with electronic calipers, and tumor volumes were calculated using the formula for an ellipsoid: S 2 The tumor growth data is shown in Figure 1, where the mean tumor volume for each group of mice is plotted against the number of days of tumor growth since the start of treatment. Table 1 provides a summary of the results. All treatments provide benefits compared to vehicle alone. The combination of paclitaxel and CORT125134 is more effective than paclitaxel alone for both doses of paclitaxel. [Table 1]

[0149] Example 2. Treatment of triple-negative breast cancer explants with CORT125134 in combination with paclitaxel MDA-MB-231 cells (10 million cells / mouse) were injected orthotopically into the right mammary fat pad in groups of female Balb / c nude mice. Tumors grew to a volume of 100–200 mm. 3Upon reaching 10 days of age, the mice were randomized into groups of 10 and treatment was initiated. Mice were treated as follows: Group 1 received vehicle daily, Group 2 received paclitaxel 5 mg / kg iv every 4 days, and Group 3 received paclitaxel 5 mg / kg iv every 4 days and CORT125134 30 mg / kg po daily. Tumor volumes were measured in two dimensions using calipers three times a week and the volumes were calculated in mm using the formula V=0.5a×b2, where a and b are the long and short diameters of the tumor, respectively. 3 The treatment was continued for 28 days, but the condition was not good or the condition was below 3000 mm 3 Any mice bearing tumors greater than 1 were terminated. For comparisons between two groups, an independent samples t-test was used; for comparisons between three or more groups, a one-way ANOVA was performed followed by multiple comparisons. A p-value <0.05 was considered statistically significant. The effect of CORT125134 in combination with paclitaxel in a triple-negative breast cancer (TNBC) mouse xenograft model is shown in Figure 2. Data represent the mean + SEM. Administration of paclitaxel at a dose of 5 mg / kg was not effective in this model, p was not significant compared to vehicle-treated mice. The combination of paclitaxel and CORT125134 achieved significant inhibition of tumor growth compared to vehicle-treated mice (p<0.05) or compared to the use of paclitaxel alone (p<0.05).

[0150] Example 3. Treatment of ovarian cancer explants with CORT125134 in combination with gemcitabine / carboplatin The effect of CORT125134 in combination with gemcitabine / carboplatin in an ovarian cancer mouse xenograft model is shown in Figure 3, which represents the results of groups of 10 mice per group. CORT125134 was administered intraperitoneally (ip) on days 43, 44, 50, and 51, and gemcitabine / carboplatin was administered ip on days 44 and 51. Data represent mean values. SK-OV-3 cells (5 million cells / mouse) were injected into the right flank of female Balb / c nude mice. Tumors reached a volume of 200 mm 3 When the mice reached 10 mg / kg, they were randomized into groups of 10 and treatment was initiated. Mice were treated as follows: Group 1 received vehicle on days 1, 2, 8, and 9 of dosing; Group 2 received gemcitabine (80 mg / kg) on ​​days 2 and 9 of dosing; Group 1 received gemcitabine / carboplatin (15 mg / kg ip) and carboplatin (15 mg / kg ip), and Group 2 received gemcitabine / carboplatin in the same regimen as Group 2, plus CORT125134 (20 mg / kg ip) administered on days 1, 2, 8, and 9. Tumor volumes were measured three times a week and tumor volumes were calculated as detailed above. 3 Any mice bearing tumors greater than 100 were terminated. The results were analyzed as shown in Example 2 above. Administration of gemcitabine / carboplatin at these doses was not effective in the SK-OV-3 model (p=NS vs. vehicle-treated mice). The combination of gemcitabine / carboplatin with CORT125134 achieved significant inhibition of tumor growth compared to vehicle (p<0.001) and compared to carboplatin / gemcitabine (p<0.01).

[0151] Example 4. Treatment of prostate cancer explants with cort125134 in castrated mice The effect of CORT125134 in combination with castration in a prostate cancer (CRPC) mouse xenograft model is shown in Figure 4. 22Rv1 cells (10 million cells / mouse) were injected into the right flank of male Balb / c nude mice. The tumors were 100-200 mm in volume.3 When the mice reached 300 mm 3 , they were randomized into groups of 10 and then 2 of the 3 groups were castrated. Treatment began the day after castration as follows: Group 1 (non-castrated) received vehicle, Group 2 (castrated) received vehicle, and Group 3 (castrated) received 30 mg / kg CORT125134 orally (po) daily for 21 days. Tumor volumes were measured 3 times a week as described above. 3 Any mice bearing tumors greater than 100 were terminated. The results were analyzed as shown in Example 2 above. Data represent the mean + SEM. Castrated mice showed reduced tumor growth compared to non-castrated mice (p<0.0001). Administration of CORT125134 to castrated mice also inhibited tumor growth compared to non-castrated mice (p<0.0001). The combination of castration and CORT125134 was more effective than castration alone (p<0.05).

[0152] Example 5. Treatment of Patients with Cervical Cancer with SGRM and Chemotherapeutic Agents A 68-year-old female patient complains of upper abdominal pain. She has experienced episodes of loss of appetite, nausea and vomiting, and significant weight loss. A CT scan shows a suspected tumor in the cervix. The suspected tumor is confirmed to be cancerous by tissue analysis. The patient is treated with CORT125134 at a dose of 200 mg once daily for 8 weeks in combination with intravenous infusion of nab-paclitaxel at a dose of 80 mg / m2 body surface area as an intravenous infusion over 30 minutes on days 1, 8, and 15 of every 28-day cycle. Tumor burden is monitored with enhanced MRI before, during, and after treatment. The imaging shows that the tumor size is decreasing and the reduction is greater than 50% at the end of the treatment period. The present invention provides, for example, the following items. (Item 1) 1. A method for treating a subject harboring a cancerous tumor, the method comprising administering to the subject an effective amount of a chemotherapeutic agent and an effective amount of a nonsteroidal selective glucocorticoid receptor modulator (SGRM) to reduce the tumor burden of the cancerous tumor. (Item 2) 2. The method according to item 1, wherein the cancerous tumor is a cervical cancer tumor. (Item 3) 2. The method of claim 1, wherein the chemotherapeutic agent is selected from the group consisting of taxanes, alkylating agents, topoisomerase inhibitors, endoplasmic reticulum stress inducers, antimetabolites, mitotic inhibitors, and combinations thereof. (Item 4) 4. The method of claim 3, wherein the chemotherapeutic agent is a taxane. (Item 5) 4. The method of claim 3, wherein the chemotherapeutic agent is selected from the group consisting of nab-paclitaxel, 5-fluorouracil (5-FU), gemcitabine, cisplatin and capecitabine. (Item 6) 2. The method of claim 1, wherein the glucocorticoid receptor modulator scaffold is a fused azadecalin. (Item 7) The fused azadecalin has the following formula: [ka] or salts and isomers thereof, wherein L 1 and L 2 is a member independently selected from a bond and unsubstituted alkylene; R 1 is an unsubstituted alkyl, an unsubstituted heteroalkyl, an unsubstituted heterocycloalkyl, -OR 1A , N.R. 1C R 1D , -C(O)NR 1C R 1D , and -C(O)OR 1A is a member selected from R 1A is a member selected from hydrogen, unsubstituted alkyl, and unsubstituted heteroalkyl; R 1C and R 1D is a member independently selected from unsubstituted alkyl and unsubstituted heteroalkyl; Here, R 1C and R 1D are optionally joined to form an unsubstituted ring together with the nitrogen to which they are attached, said ring optionally including an additional ring nitrogen; R 2 is the expression: [ka] wherein R 2G is a member selected from hydrogen, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, -CN, and -CF3; J is phenyl; t is an integer from 0 to 5; X is -S(O2)-; and R 5 is 1 to 5 R 5A phenyl optionally substituted with a group, R 5A is hydrogen, halogen, -OR 5A1 , S(O2)NR 5A2 R 5A3 , -CN, and unsubstituted alkyl, R 5A1 is a member selected from hydrogen and unsubstituted alkyl, and R 5A2 and R 5A3 is a member independently selected from hydrogen and unsubstituted alkyl; The method according to item 6. (Item 8) The condensed azadecalin is [ka] 7. The method according to item 6, wherein (Item 9) 7. The method of claim 6, wherein the glucocorticoid receptor modulator scaffold is a heteroaryl ketone fused azadecalin or an octahydro fused azadecalin. (Item 10) The heteroaryl ketone fused azadecalin has the formula: [ka] or salts and isomers thereof, R 1 has 5 to 6 ring members and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S, and optionally each R 1a is a heteroaryl ring substituted with 1 to 4 groups independently selected from Each R 1a is 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 ring and the heteroaryl ring have 5-6 ring members and 1-4 heteroatoms each independently selected from the group consisting of N, O, and S; Each R 2 is hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkyl-C1-6 Alkoxy, CN, OH, NR 2a R 2b , C(O)R 2a , C(O)OR 2a , C(O)NR 2a R 2b , S.R. 2a , S(O)R 2a , S(O)2R 2a , C 3-8 Cycloalkyl, and C 3-8 heterocycloalkyl, where the heterocycloalkyl group optionally comprises 1 to 4 R 2c Is substituted with a group; Alternatively, two R linked to the same carbon 2 Do groups combine to form an oxo group (=O); Or, two R 2 The groups combine to form a heterocycloalkyl ring having 5-6 ring members and 1-3 heteroatoms each independently selected from the group consisting of N, O and S, where the heterocycloalkyl ring optionally contains 1-3 R 2d substituted with a group; R 2a and R 2b are hydrogen and C, respectively. 1-6 independently selected from the group consisting of alkyl; Each R 2c is hydrogen, halogen, hydroxy, C 1-6 Alkoxy, C 1-6 Haloalkoxy, CN, and NR 2a R 2b independently selected from the group consisting of: Each R 2d is hydrogen and C 1-6 or two R attached to the same ring atom thereof, independently selected from the group consisting of alkyl, 2d The groups combine to form (=O); R 3 Each of them can be set to 1 to 4 R as necessary. 3a substituted with phenyl and pyridyl; Each R 3a is hydrogen, halogens, and C1-6 haloalkyl; and The subscript n is an integer from 0 to 3. Item 9. The method according to item 9. (Item 11) The heteroaryl ketone fused azadecalin is [ka] 10. The method according to item 9, wherein (Item 12) The octahydro-fused azadecalin has the formula: [ka] or salts and isomers thereof, R 1 has 5 to 6 ring members and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S, and optionally each R 1a is a heteroaryl ring substituted with 1 to 4 groups independently selected from Each R 1a is hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, N-oxide, and C 3-8 independently selected from the group consisting of cycloalkyl; Ring J is selected from the group consisting of aryl rings and heteroaryl rings having 5-6 ring members and 1-4 heteroatoms each independently selected from the group consisting of N, O and S; Each R 2 is 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 , S.R. 2a , S(O)R 2a , S(O)2R 2a , C 3-8 Cycloalkyl and C having 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S. 3-8 heterocycloalkyl; Alternatively, two R on adjacent ring atoms 2 The groups combine to form a heterocycloalkyl ring having 5-6 ring members and 1-3 heteroatoms each independently selected from the group consisting of N, O and S, where the heterocycloalkyl ring optionally contains 1-3 R 2c substituted with a group; R 2a , R 2b and R 2c are hydrogen and C, respectively. 1-6 independently selected from the group consisting of alkyl; Each R 3a are independently hydrogen; and The subscript n is an integer from 0 to 3. Item 9. The method according to item 9. (Item 13) The octahydro-fused azadecalin has the formula: [ka] 10. The method according to item 9, comprising the steps of:

Claims

[Claim 1] The invention as depicted in the drawings.

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