BRPI0608934A2 - diarylamine-containing compounds and compositions, and their use as modulators of nuclear steroid hormone receptors - Google Patents

Abstract

COMPOUNDS AND COMPOSITIONS CONTAINING DIARYLAMINE, AND THEIR USE AS MODULATORS OF NUCLEAR STEROID HORMONE RECEPTORS. Described herein in this patent application are compounds which include a structural characteristic of diarylamine. Also described herein in this patent application are methods for making such compounds, methods for using said compounds to modulate steroid hormone nuclear receptor activity, and pharmaceutical compositions and medicaments comprising said compounds. Also described herein in this patent application are methods for using said compounds, pharmaceutical compositions and medicaments for treating and / or preventing diseases or conditions associated with the activity of nuclear steroid hormone receptors.

Description

Patent Descriptive Report for "COMPOUNDS AND COMPOSITIONS CONTAINING D1ARYLAMINE, AND ITS USE AS NUCLEAR STEROID HORMONE RECEPTOR MODULATORS".

FIELD OF INVENTION

Compounds, methods for making said compounds, pharmaceutical compositions and medicaments comprising said compounds, and methods for using said compounds to treat or prevent diseases or conditions associated with steroid hormone nuclear receptor activity are disclosed. BACKGROUND OF THE INVENTION

Nuclear steroid hormone receptors represent a subset of the nuclear hormone receptor superfamily. Named after the cognate ligand which forms complex with the receptor in its native state, nuclear steroid hormone receptors include the glucocorticoid receptor (GR), the androgen receptor (AR), the mineralocorticoid receptor (MR), estrogen receptor (ER), and progesterone receptor (PR). The mineralocorticoid receptor is expressed in epithelial tissues, heart, kidneys, brain, vascular tissues and bones. Aldosterone is the endogenous ligand of mineralocorticoid receptors and is essentially synthesized in the adrenal glands, heart, brain and blood vessels. Several harmful effects are attributable to aldosterone, for example: sodium / water retention, renal fibrosis, vascular inflammation, vascular fibrosis, endothelial dysfunction, coronary inflammation, reduction in coronary blood flow, ventricular arrhythmias, myocardial fibrosis, hypertrophy. ventricular and direct injury to cardiovascular systems, essentially the heart, vasculature and kidneys. The action of aldosterone on all target organs is through activation of the mineralocorticoid receptor. The glucocorticoid receptor is expressed in almost all tissues and organ systems and is crucial for the integrity of central nervous system function and the maintenance of cardiovascular, metabolic, and immune homeostasis. SUMMARY OF THE INVENTION In one aspect they are compounds comprising a diarylamine structure. In one embodiment, said diarylamine compounds are diheteroarylamine compounds. In additional or alternate embodiments, one of the heteroaryl groups of such diheteroarylamine compounds comprises a phthalazine structure. In additional or alternative embodiments, one of the heteroaryl groups of similar dimethylarylamine compounds comprises a five membered ring comprising a CN group.

In another aspect is the use of similar compounds comprising a diarylamine structure for modulating a nuclear receptor. In one embodiment, said diarylamine compounds are diheteroarylamine compounds. In additional or alternative embodiments, one of the heteroaryl groups of such diheteroarylamino compounds comprises a phthalazine structure. In additional or alternate embodiments, one of the heteroaryl groups of such dihydroarylamine compounds comprises a five membered ring comprising a CN group.

In another aspect is the use of such compounds comprising a diarylamine structure in the treatment of a disease or

condition, or to produce a medicament for treating a disease or condition, wherein modulating at least one nuclear receptor activity may prevent, inhibit or ameliorate the pathology and / or symptoms of the disease or condition. In one embodiment, said diarylamino compounds are diheteroarylamine compounds. In additional modalities

or alternatively, one of the heteroaryl groups of such dihydroarylamine compounds comprises a phthalazine structure. In additional or alternative embodiments, one of the heteroaryl groups of similar diheteroarylamine compounds comprises a five membered ring comprising a CN group. In one embodiment, nuclear receptors

They are nuclear receptors of steroid hormones.

In another aspect are pharmaceutical compositions comprising a similar compound comprising a diarylamine structure. In one embodiment, the diarylamine compounds are dihydroarylamine compounds. In additional or alternative embodiments, one of the heteroaryl groups of such diheteroarylamine compounds comprises a phthalazine structure; in additional or alternative embodiments, one of the heteroaryl groups of such diheteroarylamine compounds comprises a five membered ring comprising a CN group.

In another aspect are methods for manufacturing said compounds comprising a diarylamine structure. In one embodiment, said diarylamine compounds are diheteroarylamine compounds.

In additional or alternative embodiments, one of the unlike heteroaryl groups composed of diheteroarylamine comprises a deftalazine structure; in additional or alternative embodiments, one of the heteroaryl groups of such diheteroarylamine compounds comprises a five membered ring comprising a CN group.

In another aspect they are compounds having the structure of Formula wherein: (a) A is CR3 = CR4, N = CR4, CR3 = N, or CR3R3-; Q is CR5 = CR6, N = CR6, CR5 = N, or C ReRes L is CR9 or N; Z is CR8 or N; (b) R1 is selected from the group consisting of H, OH, NH2, SH, NO2, CN, and an optionally substituted moiety selected from -L | -alkyl, -L-cycloalkyl, -L | -heteroalkyl, Lrhaloalkyl, -1H-aryl, -Lheterocycloalkyl, and -Lrheteroaryl, wherein U is selected from a bond, O, NH, S, -C (O) -, -C (S) -, -C (0) 0- -C (O) NH-, -S (O) -, -S (O) 2, and -S (O) NH-; wherein said optional substituents are selected from halogen, OH, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl and halo-C1-6 alkoxy; (c) R2 is selected from the group consisting of H and an optionally substituted moiety selected from -L2-alkyl, -L2-cycloalkyl, -L2-heteroalkyl, -L2-haloalkyl, -L2-aryl, -L2-heterocycloalkyl, and -L 2 -heteroaryl, wherein L 2 is selected from a bond. -C (O) -, -C (S) -, -C (O) 0-, -C (O) NH-, -S (O) - -S (O) 2, and -S (O) NH-, wherein said optional substituents are selected from halogen, OH, Gi-e alkyl, C1-6 alkoxy, halo-C1-6 alkyl, halo alkoxy, aryl, haloaryl, and heteroaryl; R3, R3-, R4, R5, Re, Re-, Rs and R9 are independently selected from H, halogen, OH, NH2, SH, NO2, CN, and an optionally substituted moiety selected from -U-alkyl, -U-cycloalkyl, -U-heterdalkyl, -U-haloalkyl, -U-aryl, -L3-heterocycloalkyl, and -U-heteroaryl, wherein U is selected from a bond, O, NH, S, -C (O ) -, -C (S) -, -C (O) 0-, -C (O) NH-, -S (O) -, -S (O) 2, and -S (O) NH-; wherein said optional substituents are selected from halogen, OH, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl and halo-C1-6 alkoxy, or R2 and R3 taken together form a 4-8 membered ring optionally substituted; wherein the ring is heterocyclic, cycloalkyl, or aryl; (d) R7 is selected from the group consisting of H, halogen, and an optionally substituted moiety selected from -UH, -U-alkyl, -U-cycloalkyl, -L4-heteroalkyl, -U-haloalkyl, -U-aryl, -U-heterocycloalkyl, and -U-heteroaryl, wherein U is selected from a bond, O, NH, OCH 2, NHCH 2, S, C 1 -C 6 alkylene, -C (O) -, -C (S) -, -C (O ) O-, -C (O) NH-, -S (O) -, -S (O) 2, and -S (O) NH-; wherein said optional substituents are selected from H, halogen, cyano, OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, alkoxy, haloC 1 and alkoxy, C 1 -C 4 thioalkyl, C 1 -C 4 thioalkoxy aryl, aryl, halo aryl, (e) R10 and Rn are independently selected from d-Cealkyl and C1 -C6 haloalkyl, or R10 and Rn together form an optionally substituted 3 to 8 membered heterocyclic ring; (f) X is (G) Y is O, Nou S, provided that when L is N and Z is C, each of R 1, R 2, R 3, R 4, R 5, Re, R 7, R 1a and R 6 are not. are H; and a pharmaceutically acceptable salt, N-oxide pharmaceutically acceptable, pharmaceutically acceptable metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof.

In one embodiment of the above-mentioned aspect L is N. In an additional or alternative embodiment of this aspect Z is N. In an additional or alternative embodiment of this aspect X is S. In an additional or alternative embodiment of this aspect L is N and X is S. In an additional or alternative mode of this aspect 2 is N and X is S. In an additional or alternative mode of this aspect A is CR3 = CR4 and Q is CR5 = CR6. In an additional or alternative embodiment of this aspect A is CR3 = CR4 and Q is N = CR6. In an additional or alternative embodiment of this aspect A is CR3 = N and Q is CR5 = CR6.

In an additional embodiment, the compound has one of the following

following structures:

<formula> formula see original document page 6 </formula>

In an additional embodiment of any of the six structures mentioned above, R 1 is alkyl. In an additional embodiment, Ri is

selected from the group: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, 2-hexyl, and 3-hexyl. In an additional or alternative embodiment, R 2 is selected from the group H, alkyl, and -C (O) alkyl. In an additional or alternative embodiment, R3 is H. In an additional or alternative embodiment, R4 is H. In

an additional or alternative embodiment, R 5 is H. In an additional or alternative embodiment, R 6 is H. In an additional or alternative embodiment, R 7 is an optionally substituted group selected from U-aryl, -U-heterocycloalkyl, and -L 4 -heteroaryl. In an additional or alternative embodiment, L4 is selected from a bond, O, NH, OCH2, NHCH2, S, CrC6.

alkylene, -C (O) -, -C (O) 0-, and -C (O) NH-.

In an additional or alternative embodiment of this composite aspect having the structure of Formula (1) is selected from <formula> formula see original document page 7 </formula> In an additional or alternative embodiment of this composite aspect having the structure of Formula (1) is selected from

<formula> formula see original document page 7 </formula> <formula> formula see original document page 8 </formula>

In another aspect are methods for modulating the activity of naming a nuclear steroid hormone receptor comprising contacting at least one nuclear steroid hormone receptor with a compound having the structure of Formula (1),

<formula> formula see original document page 8 </formula> where (a) A is CR3 = CR4, N = CR4, CR3 = N, or CR3R3-; Q is CR5 = CR6, N = CR6, CR5 = N, or C ReRe-; L is CR9 or N; Z is CR8 or N; (b) R: is selected from the group consisting of H, OH, Nhfe, SH, NO 2, CN, and an optionally substituted moiety selected from -Lralkyl, -Li-cycloalkyl, -Lrheteroalkyl, -Lrhaloalkyl, -U-aryl , -Heterocycloalkyl, and -1'heteroaryl, wherein Li is selected from a bond, O, NH, S, -C (O) -, -C (S) -, -C (0) 0-, -C (0) NH-, -S (O) -, -S (O) 2, and -S (O) NH-; wherein said optional substituents are selected from halogen, OH, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl and halo-C1-6 alkoxy; (c) R2 is selected from the group consisting of H and an optionally substituted moiety selected from -L2-alkyl, -L2-cycloalkyl, -L2-heteroalkyl, -L2-haloalkyl, -L2-aryl, -L2-heterocycloalkyl, and -L 2 -heteroaryl, wherein L 2 is selected from a bond, -C (O) -, -C (S) -, -C (O) 0-, -C (O) NH-, -S (O) - -S (O) 2, and -S (O) NH- wherein said optional substituents are selected from halogen, OH, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl, halo alkoxy, aryl, haloaryl, and heteroaryl; R3, R3-, R4, R5. Re. Re-, Rs and R9 are independently selected from H, halogen, OH, NH2, SH, NO2, CN, and an optionally substituted moiety selected from -L3-alkyl, -L3-cycloalkyl, -L3-heteroalkyl, L3-haloalkyl, -L3-aryl, -U-heterocycloalkyl, and -U-heteroaryl, wherein L3 is selected from a bond, O, NH, S, -C (O) -, -C (S) -, - C (O) O-, -C (O) NH-, -S (O) -, -S (O) 2, and -S (O) NH-; wherein said optional substituents are selected from halogen, OH, d- and alkyl, C1-6 alkoxy, halo-C1-6 alkyl and halo-C1-6 alkoxy; or R2 and R3 when taken together form an optionally substituted 4- to 8-membered ring; wherein the ring is heterocyclic, cycloalkyl, or aryl; (d) R 7 is selected from the group consisting of H, halogen, and an optionally substituted moiety selected from -UH, -U-alkyl, -U-cycloalkyl, -U-heteroalkyl, -U-haloalkyl, -U-aryl , -U-heterocycloalkyl, and -U-heteroaryl, wherein U is selected from a bond, O, NH, OCH 2, NHCH 2, S, C 1 -C 6 alkylene, -C (O) -, -C (S) -, -C ( O) O-, -C (O) NH-, -S (O) -, -S (O) 2, and -S (O) NH-; wherein said optional substituents are selected from H, halogen, cyano, OH, C1 -C6 alkyl, C1 -C6 haloalkyl, C1-4 alkoxy, halo alkoxy, C1 -C4 thioalkyl, C1 -C4 thioalkoxy aryl, aryl, halo aryl, heteroaryl, halo heteroaryl and NR10 R11; (e) R10 and Rn are independently selected from d-C6 alkyl and C1-C6 haloalkyl, or R10 and Rn together form an optionally substituted 3 to 8 membered heterocyclic ring; (f) X is O, N or S; (g) Y is O, N or S; or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically acceptable metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof.

In an additional or alternative embodiment of this compound aspect of Formula (1), it directly contacts at least one nu-clear steroid hormone receptor. In an additional or alternate embodiment, contact occurs in vitro. In an additional mode or

Alternatively, contact occurs in vivo.

In an additional or alternative embodiment of this aspect L is N. In an additional or alternative embodiment of this aspect Z is N. In an additional or alternative embodiment of this aspect X is S. In an additional or alternative embodiment of this aspect LéNeXéS. In one moment

Additional or alternative embodiment of this aspect Z is N and X is S. In an additional or alternative embodiment of this aspect A is CR3 = CR4 and Q is CR5 = CR6. In an additional or alternative embodiment of this aspect A is CR 3 = CR 4 and Q is N = CR 6. In an additional or alternative embodiment of this aspect A is CR3 = N and Q is CR5 = CR6.

In an additional embodiment, the compound has one of the following

following structures:

In an additional embodiment of any of the six structures mentioned above, R 1 is alkyl. In an additional embodiment, R 1 is selected from the group: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, 2-hexyl, and 3-hexyl. In an additional or alternative embodiment, R 2 is selected from the group H, alkyl, and -C (O) alkyl. In an additional or alternative embodiment, R3 is H. In an additional or alternative embodiment, R4 is H. In an additional or alternative embodiment, R5 is H. In an additional or alternative embodiment, R6 is H. In an additional or alternative embodiment R7 is an optionally substituted group selected from U-aryl, -U-heterocycloalkyl, and -U-heteroaryl. In an additional or alternative embodiment, U is selected from a bond, O, NH, OCH 2, NHCH 2, S, d-C 6 alkylene, -C (O) -, -C (0) 0-, and -C (0 ) NH-.

In an additional or alternative embodiment of this aspect the compound having the structure of Formula (1) is selected from

<formula> formula see original document page 11 </formula>

In an additional or alternative embodiment of this aspect the compound having the structure of Formula (1) is selected from

<formula> formula see original document page 11 </formula> <formula> formula see original document page 12 </formula> <formula> formula see original document page 13 </formula>

Another aspect is a pharmaceutical composition comprising at least one compound having the structure of Formula (1),

wherein (a) A is CR3 = CR4, N = CR4, CR3 = N, or CR3R3 '; Q is CR 5 = CR 6, N = CR 6, CR 5 = N, or C R 6 R e '; L is CR9 or N; Z is CR8 or N; (b) R1 is selected from the group consisting of H, OH, NH2, SH, NO2, CN, and an optionally substituted moiety selected from -Lalkyl, -Lcycloalkyl, -Lrheteroalkyl, -Li-haloalkyl, -Larila, -l_i -heterocycloalkyl, and -Lrheteroaryl, wherein Li is selected from a bond, O, NH, S, -C (O) -, -C (S) -, -C (0) 0-, -C (0) NH -, -S (O) -, -S (O) 2, and -S (O) NH-; wherein said optional substituents are selected from halogen, OH, d 6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl and halo-C1-6 alkoxy; (c) R2 is selected from the group consisting of H and an optionally substituted moiety selected from -L2-alkyl, -L2-cycloalkyl, -L2-heteroalkyl, -L2-haloalkyl, -L2-aryl, -L2-heterocycloalkyl, and -L 2 -heteroaryl, wherein L 2 is selected from a bond, -C (O) -, -C (S) -, -C (O) 0-, -C (O) NH-, -S (O) - -S (O) 2, and -S (O) NH- wherein said optional substituents are selected from halogen, OH, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl, halo -C 1-6 alkoxy, aryl, haloaryl, and heteroaryl; R3, R3-, R4, R5, R6, Re, Re and R9 are independently selected from H, halogen, OH, NH2, SH, NO2, CN, and an optionally substituted moiety selected from -L3-alkyl, - U-cycloalkyl, -L3-heteroalkyl, -L3-haloalkyl, -U-aryl, -U-heterocycloalkyl, and -L3-heteroaryl, wherein L3 is selected from a bond, O, NH, S, -C (O) -, -C (S) -, -C (O) 0-, -C (O) NH-, -S (O) -, -S (O) 2, and -S (O) NH-; wherein said optional substituents are selected from halogen, OH, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl and halo-C1-6 alkoxy; or R2 and R3 when taken together form an optionally substituted 4- to 8-membered ring; wherein the ring is heterocyclic, cycloalkyl, or aryl; (d) R7 is selected from the group consisting of H, halogen, and an optionally substituted moiety selected from -L4-H, -U-alkyl, -U-cycloalkyl, -U-heteroalkyl, -U-haloalkyl, -U -aryl, -L4-heterocycloalkyl, and -U-heteroaryl, wherein U is selected from a bond, O, NH, OCH2, NHCH2, S, C1 -C6 alkylene, -C (O) -, -C (S) -, -C (0) O-, -C (O) NH-, -S (O) -, -S (O) 2, and -S (O) NH-; â € ƒâ € ƒâ € ƒwherein said optional substituents are selected from H, halogen, cyano, OH, C1 -C6 alkyl, C1 -C6 haloalkyl, C1-6 alkoxy, halo-d-e alkoxy, C1 -C4 thioalkyl, C1 -C4 thioalkoxy aryl, aryl, halo aryl, heteroaryl, halo heteroaryl; (e) R 10 and R 11 are independently selected from C 1 -C 6 alkyl and C 1 -C 6 haloalkyl, or R 10 and R 11 together form an optionally substituted 3 to 8 membered heterocyclic ring; (f) X is O, N or S; (g) Y is O, N or S; or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically acceptable metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in admixture with one or more suitable excipients.

In an additional or alternative embodiment of this aspect one or more excipients are suitable for parenteral administration. In an additional or alternative embodiment of this aspect one or more excipients are suitable for oral administration. In an additional or alternative embodiment of this aspect one or more excipients are suitable for ophthalmic administration.

In an additional or alternative embodiment of this aspect L is N. In an additional or alternative embodiment of this aspect Z is N. In an additional or alternative embodiment of this aspect X is S. In an additional or alternative embodiment of this aspect L is N and X is S. In an additional or alternative embodiment of this aspect aspect Z is N and X is S. In an additional or alternative embodiment of this aspect A is CR3 = CR4 and Q is CR5 = CR6. In an additional or alternative embodiment of this aspect A is CR3 = CR4 and Q is N = CR6- In an additional or alternative embodiment of this aspect A is CR3 = N and Q is CR5 = CR6. In an additional embodiment, the compound has one of the following: following structures:

<formula> formula see original document page 15 </formula>

In an additional embodiment of any of the six

mentioned above, R 1 is alkyl. In an additional embodiment, R 1 is selected from the group: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, 2-hexyl, and 3-hexyl. In an additional or alternative embodiment, R 2 is selected from the group H, alkyl, and -C (O) alkyl. In an additional or alternative embodiment, R3 is H. In an additional or alternative embodiment, R4 is H. In an additional or alternative embodiment, R5 is H. In an additional or alternative embodiment, R6 is H. In an additional or alternative embodiment R7 is an optionally substituted group selected from U-aryl, -L4-heterocycloalkyl, and -U-heteroaryl. In an additional or alternative embodiment, U is selected from a bond, O, NH, OCH 2, NHCH 2, S, C 1 -C 6 alkylene, -C (O) -, -C (0) 0-, and -C (0 ) NH-.

In an additional or alternative embodiment of this aspect the compound having the structure of Formula (1) is selected from

<formula> formula see original document page 15 </formula>

In an additional or alternative embodiment of this aspect the compound having the structure of Formula (1) is selected. In another aspect are methods for treating a disease in an animal in which modulation of steroidal hormone nuclear receptor activities may prevent, inhibit or ameliorate. disease pathology and / or symptomatology, the method of which comprises administering to the animal a therapeutically effective amount of a compound having the structure of Formula (1),

wherein (a) A is CR3 = CR4) N = CR4, CR3 = N, or CR3R3s Q is CR5 = CR6, N = CR6, CR5 = N, or C R6R6 '; L is CR9 or N; Z is CR8 or N; (b) Ri is selected from the group consisting of H, OH, NH2) SH, NO2, CN, and an optionally substituted moiety selected from -Lralkyl, -Lrcycloalkyl, -Lrheteroalkyl, -U-aryl, -Lrheterocycloalkyl , and -Lrheteroaryl, wherein U is selected from a bond, O, NH, S, -C (O) -, -C (S) -, -C (O) 0-, -C (O) NH-, -S (O) -, -S (O) 2, and -S (O) NH-; wherein said optional substituents are selected from halogen, OH, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl and halo-C1-6 alkoxy; (c) R2 is selected from the group consisting of H and an optionally substituted moiety selected from -L2-alkyl, -L2-cycloalkyl, -L2-heteroalkyl, -L2-haloalkyl, -L2-aryl, -L2-heterocycloalkyl, and -L 2 -heteroaryl, wherein L 2 is selected from a bond. -C (O) -, -C (S) -, -C (O) 0-, -C (O) NH-, -S (O) - -S (O) 2, and -S (O) NH- wherein said optional substituents are selected from halogen, OH, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl, halo -C 1-6 alkoxy, aryl, haloaryl, and heteroaryl; R3, R3 ', R4, R5, Re, Re', Rs and Rg are independently selected from H, halogen, OH, NH2, SH, NO2, CN, and an optionally substituted moiety selected from -L3-alkyl, -L3-cycloalkyl, -L3-heteroalkyl, -L3-haloalkyl, -L3-aryl, -L3-heterocycloalkyl, and -U-heteroaryl, wherein L3 is selected from a bond, O, NH, S, -C (O ) -, -C (S) -, -C (O) 0-, -C (O) NH-, -S (O) -, -S (O) 2, and -S (O) NH-; wherein said optional substituents are selected from halogen, OH, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl and halo-C1-6 alkoxy; or when R 2 and R 3 taken together form an optionally substituted 4 to 8 membered ring; wherein the ring is heterocyclic, cycloalkyl, or aryl; (d) R7 is selected from the group consisting of H, halogen, and an optionally substituted moiety selected from -L4-H, -U-alkyl, -U-cycloalkyl, -U-heteroalkyl, -U-haloalkyl, -U-aryl, -L4-heterocycloalkyl, and -U-heteroaryl, wherein U is selected from a bond, O, NH, OCH2, NHCH2, S, C1 -C6 alkylene, -C (O) -, -C (S) -, -0 (O) O-, -C (O) NH-, -S (O) -, -S (O) 2, and -S (O) NH-; wherein said optional substituents are selected from H, halogen, cyano, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo C 1 -C 6 alkoxy, C 1 -C 4 thioalkyl, C 1 -C 4 thioalkoxy aryl, aryl, halo aryl heteroaryl, halo heteroaryl, and NR 10 R 11; (e) R 10 and R 11 are independently selected from C 1 -C 6 alkyl and C 1 -C 6 haloalkyl, or R 10 and R 11 together form an optionally substituted 3 to 8 membered heterocyclic ring; (f) X is O, N or S; (g) Y is O, Nou S; or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically acceptable metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof.

In an additional embodiment, the compound has one of the following structures:

In an additional embodiment of any of the six structures mentioned above, R 1 is alkyl. In an additional embodiment, R 1 is selected from the group: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, 2-oilyl, and 3-hexyl. In an additional or alternative embodiment, R 2 is selected from the group H, alkyl, and -C (O) alkyl. In an additional or alternative embodiment, R3 is H. In an additional or alternative embodiment, R4 is H. In an additional or alternative embodiment, R5 is H. In an additional or alternative embodiment, R6 is H. In an additional or alternative embodiment R7 is an optionally substituted group selected from L4-aryl, -L4-heterocycloalkyl, and -U-heteroaryl. In an additional or alternative embodiment, U is selected from a bond, O, NH, OCH 2, NHCH 2, S, C 1 -C 6 alkylene, -C (O) -, -C (0) 0-, and -C (0) NH-.

In an additional or alternative embodiment, the nuclear steroid hormone receptor is selected from the group consisting of a glucocorticoid receptor, a mineralocorticoid receptor, an androgen receptor, an estrogen receptor, and a progesterone receptor.

In a further or alternative embodiment, the method further comprises administering a therapeutically effective amount of a second Substance, wherein the second Substance is used to treat a disease or condition selected from the group consisting of hypokalemia, hypertension, heart failure. congestive disease, renal failure, in particular chronic renal failure, restenosis, atherosclerosis, syndromes X, obesity, nephropathy, post-myocardial infarction, coronary heart disease, increased collagen formation, fibrosis and remodeling after hypertension and endothelial dysfunction.

The substance is selected from the group consisting of an anti-obesity agent, an antihypertensive agent, an inotropic agent, a hypolipidemic agent, an angiotensin converting enzyme (ACE) inhibitor, a membrane pump Na-K-ATPase inhibitor. , a neutral endopeptidase (NEP) inhibitor, an ACE / NEP inhibitor, an angiotensin II antagonist, a 3-adrenergic receptor blocker, an inotropic agent, a calcium channel blocker, and a 3 hydroxy-3-methylglutaryl coenzyme Aredutase (HMG-CoA). In an additional or alternative embodiment, the compound of Formula (1) is administered prior to the second substance. In an additional or alternative embodiment, the compound of Formula (1) is administered with the second substance. In an additional or alternative embodiment, the compound of Formula (1) is administered after the second substance. In an additional or alternative embodiment, the compound of Formula (1) and the second substance are administered in the same pharmaceutical composition.

Another aspect is the use of a compound having the structure of

Formula (1)

in the manufacture of a medicament for treating a disease in an animal in which the activity of nuclear steroid hormone receptors contributes to the pathology and / or symptomatology of the disease or condition, and wherein, (a) A is CR3 = CR4, N = CR4 ) CR3 = N, or CR3R3 '; Q is CR5 = CR6, N = CR6, CR5 = N, orC ReRes L is CR9 or N; Z is CR8 or N; (b) Rr is selected from the group consisting of H, OH, NH2, SH, NO2, CN, and an optionally substituted moiety selected from -L4 alkyl, -Lcycloalkyl, -Lrheteroalkyl, -Li-haloalkyl, -L_i-aryl, - L-heterocycloalkyl, and -Lrheteroaryl, wherein Li is selected from a bond, O, NH, S, -C (O) -, -C (S) -, -C (0) 0-, -C (0) NH-,

In an additional or alternative embodiment, the second subs - S (O) -, -S (0) 2, and -S (0) NH-; wherein said optional substituents are selected from halogen, OH, C1-6 alkyl, d -6 alkoxy, halo-C1-6 alkyl and halo-C1-6 alkoxy; (c) R2 is selected from the group consisting of H and an optionally substituted moiety selected from -L2-alkyl, -L2-cycloalkyl, -L2-heteroalkyl, -L2-haloalkyl, -L2-aryl, -L2-heterocycloalkyl, and - L 2 -heteroaryl, wherein L 2 is selected from a bond, -C (O) -, -C (S) -, -C (O) 0-, -C (O) NH-, -S (O) -, -S (O) 2, and -S (O) NH-; wherein said optional substituents are selected from halogen, OH, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl, halo-d- and alkoxy, aryl, halo aryl, and heteroaryl; R3, R3 ', R4, R5, Re, Re'. Rs and Rg are independently selected from H, halogen, OH, NH2, SH, NO2, CN, and an optionally substituted moiety selected from -13-alkyl, -L3-cycloalkyl, -L3-heteroalkyl, - U-haloalkyl, -L3-aryl, -L3-heterocycloalkyl, and -U-heteroaryl, wherein U is selected from a bond, O, NH, S, -C (O) -, -C (S) -, -C (0) O-, -C (O) NH-, -S (O) -, -S (O) 2, and -S (O) NH-; wherein said optional substituents are selected from halogen, OH, d- and alkyl, d- and alkoxy, halo-C1-6 alkyl and halo-C1-6 alkoxy; or taken together R2 and R3 form an optionally substituted 4- to 8-membered ring; wherein the ring is heterocyclic, cycloalkyl, or aryl; (d) R7 is selected from the group consisting of H, halogen, an optionally substituted moiety selected from -UH, -U-alkyl, -U-cycloalkyl, -U-heteroalkyl, -U-haloalkyl, -U-aryl, U-heterocycloalkyl, and -U-heteroaryl, wherein U is selected from a bond, O, NH, OCH 2, NHCH 2, S, d-C 6 alkylene, -C (O) -, -C (S) -, - C (O) O-, -C (O) NH-, -S (O) -, -S (O) 2, and -S (O) NH-; wherein said optional substituents are selected from H, halogen, cyano, OH, C1 -C6 alkyl, C1 -C6 alkoxy, C1-6 alkoxy, halo C1 -C6 alkoxy, dd thioalkyl, C1 -C4 thioalkoxy aryl, aryl, halo aryl, heteroaryl, halo heteroaryl, and NR10 R11; (e) R 10 and R 11 are independently selected from C 1 -C 6 alkyl and C 1 -C 6 haloalkyl, or R 10 and R 11 together form an optionally substituted 3 to 8 membered heterocyclic ring; (f) X is O, N or S; (g) Y is O, N or S; or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically acceptable metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof.

In an additional embodiment, the compound has one of the following structures:

<formula> formula see original document page 22 </formula>

In an additional embodiment of any of the six

mentioned above, R 1 is alkyl. In an additional embodiment, R 1 is selected from the group: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, 2-hexyl, and 3-hexyl. In an additional or alternative embodiment, R 2 is selected from the group H, alkyl, and -C (O) alkyl. In an additional or alternative embodiment, R3 is H. In an additional or alternative embodiment, R4 is H. In an additional or alternative embodiment, R5 is H. In an additional or alternative embodiment, R6 is H. In an additional or alternative embodiment R7 is an optionally substituted group selected from U-aryl, -U-heterocycloalkyl, and -L4-heteroaryl. In an additional or alternative embodiment, U is selected from a bond, O, NH, OCH 2, NHCH 2, S, d-C 6 alkylene, -C (O) -, -C (0) 0-, and -C (0 ) NH-.

In an additional or alternative embodiment of this nuclear steroid hormone receptor aspect it is selected from the group consisting of a glucocorticoid receptor, a mineralocorticoid receptor, an androgen receptor, an estrogen receptor, and a deprogesterone receptor.

In another aspect are methods for preparing a compound having the structure of Formula (1), comprising admixing a compound of Formula (D): with a compound having the structure: H, under conditions such as: -

appropriate reaction reactions.

In another aspect are methods for preparing a compound having the structure of Formula (1), comprising mixing a compound of

Formula (E): <formula> formula see original document page 23 </formula>

with a bromination agent under suitable reaction conditions, followed by mixing the resulting compound with a cyanination agent under suitable reaction conditions.

In another aspect are methods for preparing a compound having the structure of Formula (E), comprising mixing a compound of Formula (D):

<formula> formula see original document page 23 </formula>

(D) with a compound having the structure: H, under conditions

appropriate reaction reactions.

For convenience, all aspects and embodiments described in this section and elsewhere herein in this patent application use a single formula, such as "Formula (1)," by way of example. However, all aspects and embodiments described herein in this patent application apply equally well to all formulas set forth herein in this patent application that fall within the scope of Formula (1). For example, all aspects and embodiments described herein in this patent application may be applied to compounds having the structure of Formula (2), Formula (3), Formula (4), Formula (5), Formula (6), Formula (7), Formula (8), Formula (9), Formula (10), Formula (11), Formula (12), Formula (13), Formula (14), Formula (15), Formula (16), Formula (17), Formula (18), Formula (19), Formula (20), Formula (21), Formula (22), Formula (23), Formula (24), Formula (25), Formula (A) ), Formula (B), as well as all specific compounds falling within the scope of this generic formula.

Other objects, features and advantages of the methods and compositions described herein in this patent application will become apparent from the following detailed description. It should be understood, however, that the detailed description and specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art. in the art from this detailed description.

These and other aspects of the present invention will become apparent upon reference to the following detailed description. In addition, all patents and other references cited herein, in this patent application, which describe in more detail some procedures or compositions, and are incorporated by reference in their entirety. DETAILED DESCRIPTION OF THE INVENTION Some Chemical Terminology

Unless otherwise indicated, the following terms used in this application, including the specification and claims, have the definitions given below. It should be noted that, as used in the specification and the appended claims, the singular forms "one," "one", and "the", "a" include plural referents unless the context clearly orientates otherwise. The definition of routine chemistry terms can be found in reference works, including Carey and Sundberg "Ad-vanced Organic Chemistry 4 ™ Ed." Vol. A (2000) and B (2001), PlenumPress, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are employed within the skill of the art.

The term "alkenyl group" as used herein in this patent application refers to a hydrocarbon chain having one or more double bonds therein. The double bond of one alkenyl group may be unconjugated or conjugated to another unsaturated group. Suitable alkynyl groups include, but are not limited to, (C 2 -C 8) alkenyl groups such as vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl 4- (2-methyl-3-butene) pentenyl. The alkenyl moiety may be straight chain, branched, or cyclic (in which case it would also be known as a "cycloalkenyl" group), and may be unsubstituted or substituted.

The term "alkoxy" as used herein in this patent application includes -O- (alkyl) where alkyl is as defined herein in this patent application. By way of example only, C1-6 alkoxy includes, but is not limited to, methoxy, ethoxy, and the like. An alkoxy group may be unsubstituted or substituted.

The term "alkyl," as used herein, in this dependent application, refers to a hydrocarbon group having from 1 to 10 carbon atoms and may include straight, branched, cyclic, saturated and unsaturated characteristics. Whenever appearing herein, in this patent application, a numeric range such as "1 to 10" refers to each integer within the given range; for example, "1 to 10 carbon atoms" or "Cmo" or "(C1 -C10)" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to and including 10. carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated. The alkyl moiety may be a "saturated alkyl" group, which means that it does not contain any alkyl or alkyl moieties. Typical saturated alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3- methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2- methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl, and longer alkyl groups such as heptyl, and octyl. The alkyl moiety may also be an "unsaturated alkyl" moiety which means that it contains at least one alkyl or alkyl moiety. An "alkene" moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond, and an "alkene" portion refers to a group consisting of at least two carbon atoms and at least one carbon atom. a carbon-carbon triple bond. Typical unsaturated alkyl groups include, but are not limited to, ethenyl, propenyl, butenyl, and the like. An alkyl group may be unsubstituted or substituted. Substituted alkyl groups include, but are not limited to, halogen substituted alkyl groups, such as, by way of example only, trifluoromethyl, pentafluoroethyl, and the like.

The term "alkylamine," as used herein, in this patent application, refers to the group -N (alkyl) xHy, where x and y are selected from the group x = 1, y = 1 and x = 2, y = 0. When x = 2, the alkyl groups taken together may optionally form a cyclic ring system and additionally when x = 2 the alkyl groups may be the same or different. An alkylamine group may be unsubstituted or substituted.

The term "alkynyl" group, as used herein, in this patent application, refers to a hydrocarbon chain having one or more triple bonds therein. Triple bonding of an alkynyl group may be unconjugated or conjugated to another unsaturated group. Suitable alkynyl groups include, but are not limited to, (C 2 -C 6) alkynyl groups, such as ethinyl, propynyl, butynyl, pentinyl, hexinyl, methylpropinyl, 4-methyl-1-butynyl, 4-propyl-2-pentinyl, and 4-butyl-2-hexinyl. The alkynyl moiety may be straight or branched, and may be unsubstituted or substituted.

The term "amide," as used herein, in this dependent application, refers to a chemical moiety of the formula -C (O) NHR or -NHC (O) R, where R is selected from the group consisting of alkyl, cycloalkyl , aryl, and heterocyclic (linked through a ring carbon). Both can be formed from any amine or carboxy side chain on the compounds described herein in this patent application. Specific procedures and groups for preparing said amides are well known to those skilled in the art and may readily be found from reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated herein into this patent application by reference in its entirety. An amide group may be unsubstituted or substituted.

The term "aromatic" or "aryl" as used herein in this patent application refers to a closed ring structure which has at least one ring having a conjugated pi electron system and includes both carbocyclic aryl and heterocyclic aryl groups. (or "heteroaryl" or "heteroaromatic"). The carbocyclic or aromatic heterocyclic group may contain from 5 to 20 ring atoms. The term includes fused ring monocyclic or polycyclic groups (that is, rings which share adjacent pairs of carbon atoms). An aromatic group may be unsubstituted or substituted.

The term "aryloxy" as used herein in this patent application includes -O-aryl group, wherein aryl is as defined herein in this patent application. An aryloxy group may be unsubstituted or substituted.

The term "bond" or "single bond," as used herein, in this

patent application, refers to a covalent bond between two

l

any of which may be part of a larger portion.

The terms "carbocyclic" or "cycloalkyl," as used herein in this patent application, refer to a compound which contains one or more covalently closed ring structures, and that atoms forming the backbone of the ring are all carbon atoms. A similar group may have from 3 to 20 ring carbon atoms and may be unsaturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic fused, spirocyclic, bridged polycyclic or polycyclic comprising carbon and hydrogen atoms. Carbocyclic alkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. A carbocyclic aromatic group includes, but is not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl and naphthyl, as well as benzo-fused carbocyclic moieties such as dibenzosuberenone and dibenzosuberone only. A carbocyclic group may be unsubstituted or substituted.

The term "ester," as used herein, in this dependent application, refers to a chemical moiety of formula -COOR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, and heterocyclic (bonded through a ring carbon). Any hydroxy or carboxyl lateral chain on the compounds described herein in this patent application may be esterified. The procedures and specific groups for preparing said esters are known to those skilled in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999 , which is incorporated herein by patent application by reference in its entirety. An ester group may be unsubstituted or substituted.

The terms "heteroalkyl", "heteroalkenyl" and "heteroalkynyl" as used herein in this patent application include optionally substituted alkyl, alkenyl and alkynyl moieties having one or more backbone chain atoms selected from a different atom carbon, eg oxygen, nitrogen, sulfur, phosphorus or combinations thereof. A "heteroalkyl", "heteroalkenyl" and "heteroalkynyl" group may be unsubstituted or substituted.

The terms "heteroaryl" or, alternatively, "heteroaromatic," as used herein, in this patent application, refer to a grouparyaryl that includes one or more ring heteroatoms selected from nitrogen, oxygen, sulfur. By way of example, an "heteroaromatic" or "heteroaryl" moiety containing N refers to an aromatic group in which at least one of the ring backbone atoms is a nitrogen atom. A polycyclic heteroaryl group may be fused or unfused. A heteroaryl group may be unsubstituted or substituted.

The term "heterocyclic," as used herein, in this patent application, refers to ring structures in which the ring backbone contains at least one atom selected from nitrogen, oxygen, and sulfur. Examples of heterocyclic aromatic groups include, but are not limited to, acridinyl, benzo [1,3] dioxol, benzimidazolyl, benzindazolyl, benzoisooxazolyl, benzoquisazolyl, benzofuranyl, benzofurazanyl, benzo-pyranyl, benzothiazolyl, benzo [b] thienyl, benzothiophenyl benzothiopyranyl, benzotriazolyl, benzoxazolyl, carbazolyl, carbolinyl, cinolinyl, furanyl, furaza-nila, furopyridinyl, furyl, imidazolyl, indazolyl, indolyl, indolidinyl, indolizinyl, isobenzofuranyl, isoindolyl, isoxolinylila, isoxolinylila, oxadiazolyl, oxazolyl, phenoxazinyl, phenothiazinyl, phenazinyl, fenoxatrinyl, thiantrenyl, fenatridinyl, fenatrolinyl, phthalazinyl, pteridinyl, purinyl, puteridinyl, pyrazyl, pyrazolyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl , quinolinyl, quinoxalinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, (1,2,3) - and (1,2,4) -triazolyl and seme lhan-tes. In addition, a heterocyclic group may be unsubstituted or substituted. Examples of non-aromatic heterocyclic groups include, but are not limited to, azepinyl, azepan-2-onyl, azetidinyl, diazepinyl, dihydrofuranyl, dihydropyranyl, dihydrothienyl, dioxanyl, dioxolanyl, 1,4-dioxa-8-aza-spiro [4.5] dec-8-yl, dithianyl, dithiolanil, homopiperidinyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl, morpholinyl, oxazepinyl, oxepanyl, oxetanyl, oxylanil, piperidine, piperidinonyl, pyrerinyl pyrrolidinyl, pyridazinyl pyrrolidinonyl, pyrrolinyl, quinolizinyl, thietanyl, tetrahydrofuranyl, tetrahydroquinolyl, tetrahydroothienyl, tetrahydropyranyl, tetraii-dropyridinyl, tetrahydropyranyl, thiazepinyl, tiepanyl, thiomorpholinyl, thioranyl, thioranyl, thioranyl, thioranyl. The heterocyclic group may be fused or unfused. Terms referring to groups also encompass all possible autonomers.

The term "halogen," as used herein, in this patent application means fluorine, chlorine, bromine or iodine. Preferred halogen groups are fluorine, chlorine and bromine.

The terms "haloalkyl," "haloalkenyl," "haloalkyl" and "haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy structures that are substituted by one or more halogen groups or combinations thereof.

The term "member ring" as used herein in this patent application may encompass any cyclic structure. The term "members" is intended to denote the number of atoms of the ring skeleton. Therefore, for example, cyclohexyl, pyridine, pyran and thiopyran are 6-membered rings and cyclopentyl, pyrrol, furan, and thiophene are 5-membered rings.

The term "portion," as used herein, in this dependent application, refers to a specific segment or functional group of a molecule. Chemical portions are often recognized chemical entities embedded in or attached to a molecule.

The term "protecting group," as used herein, in this patent application, refers to a chemical moiety which blocks some or all reactive moieties and prevents said groups from participating in chemical reactions until the protecting moiety is removed.

The term "reagent," as used herein, in this patent application, refers to a nucleophile or electrophile used to create covalent bonds.

The term "sulfonyl" refers to the presence of a sulfur atom, which is optionally chained to another moiety such as an alkyl group, an aryl group, or a heterocyclic group. Aryl or alkylsulfonyl moieties have the formula -SO 2 R ', wherein R' is alkyl or aryl as defined herein in this patent application, and include, but are not limited to, methylsulfonyl, ethylsulfonyl and phenylsulfonyl groups. A sulfonyl group may be unsubstituted or substituted. A phenylsulfonyl is optionally substituted with 1 to 3 substituents independently selected from halogen, alkyl, and alkoxy.

Unless otherwise indicated, when a substituent is considered to be "optionally substituted", it is indicated that the substituent is a group which may be substituted with one or more groups individually and independently selected from, for example. alkenyl, alkyl, alkoxy, alkylamine, alkylthio, alkynyl, amide, amino, including mono- and disubstituted amino groups, aryl, aryloxy, arylthio, carbonyl, carbocyclic, cyano, cycloalkyl, halogen, heteroalkyl, heteroalkenyl , heteroaryl, heteroaryl, heterocyclyl, hydroxy, isocyanate, isothiocyanate, mer-capto, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-starch, N-starch, S-sulfonamide, N sulfonamido, C-carboxy, O-carboxy, perhaloalkyl, perfluoroalkyl, silyl, sulfonyl, thiocarbonyl, thiocyanate, trihalo-methanesulfonyl, and protected compounds thereof. Protecting groups which may form the compounds protected from the above substituents are known to those skilled in the art and can be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Koienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein into this patent application by reference in their entirety. Some Pharmaceutical Terminology

The term "acceptable" with respect to a formulation, composition or ingredient as used herein in this patent application means having no persistent detrimental effect on the overall health of the subject being treated.

The term "agonist," as used herein, in this dependent application, refers to a molecule such as a compound, drug, enzyme activator or hormonal modulator which enhances the activity of another molecule or the activity of a receptor site.

The term "antagonist," as used herein, in this patent application, refers to a molecule such as a compound, a drug, an enzyme inhibitor or a hormone modulator, which diminishes or predicts the action of another molecule or activity of a receptor site.

The term "carrier" as used herein in this patent application refers to relatively non-toxic chemical compounds or agents which facilitate incorporation of a compound into cells or tissues.

The terms "co-administration" or the like as used herein in this patent application are intended to encompass the administration of selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered via or via different routes of administration or administration. at the same time or at different times.

The terms "effective amount" or "therapeutically effective amount" as used herein in this patent application refer to a sufficient amount of an agent or compound being administered which will to some extent alleviate one or more of the symptoms of the disease or condition. being treated. The result may be reduction and / or relief of signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of the composition comprising a compound as described herein, in this patent application, required to provide a clinically significant reduction in a disease. An "effective" amount appropriate in any individual case may be determined using techniques such as a dose escalation study.

The terms "reinforcing" or "reinforcing," as used herein, in this patent application, means increasing or prolonging either the potency or duration of a desired effect. Therefore, with respect to enhancing the effect of therapeutic agents, the term "enhancing" refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An "effective enhancing amount," as used herein, in this patent application, refers to an amount suitable for enhancing the effect of another therapeutic agent on a desired system.

The terms "kit" and "article of manufacture" are used as synonyms.

The term "metabolite," as used herein, in this patent application, refers to a derivative of a compound which is formed when the compound is metabolized.

The term "active metabolite," as used herein, in this patent application, refers to a biologically active derivative of a compound that is formed when the compound is metabolized.

The term "metabolized," as used herein, in this patent application, refers to the sum of processes (including, but not limited to, hydrolysis reactions and enzyme catalyzed reactions) by which a particular substance is altered by an organism. Thus, enzymes may produce structural changes specific to a compound. For example, cytochrome P450 catalyzes a variety of oxidative and reductive reactions whereas uridine diphosphate glucuronyltransferences catalyze the transfer of an activated glycuronic acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and group sulphydryl. Additional information on metabolism can be obtained from The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996).

The term "modular," as used herein, in this dependent application means interacting with a target either directly or indirectly in order to alter the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target. target activity, limit target activity, or prolong target activity.

The term "modulator," as used herein, in this patent application, refers to a molecule that interacts with a target either directly or indirectly. Interactions include, but are not limited to, the interactions of an agonist and an antagonist.

By "pharmaceutically acceptable," as used herein, in this patent application, refers to a material, such as a diluent carrier, which does not negate the biological activity or properties of the compound, and is relatively non-toxic, that is, The material may be administered to an individual without causing undesirable biological effects or interacting in a detrimental manner with any of the components of the composition in which it is contained.

The term "pharmaceutically acceptable salt" of a compound as used herein in this patent application refers to a pharmaceutically acceptable salt.

The term "pharmaceutical combination" as used herein in this patent application means a product which results from the mixing or combination of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, for example a compound of Formula (1) and a co-agent, are both administered to a patient simultaneously as a single entity or dosage. The term "non-fixed combination" means that the active ingredients, for example a compound of Formula (1) and a co-agent, are administered to a patient as single entities either concurrently, concurrently or sequentially without drug limit. specific intervening times, wherein said administration provides effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, for example the administration of three or more active ingredients.

The term "pharmaceutical composition" as used herein in this patent application refers to a mixture of an active compound with other chemical components such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or ex. -customers.

A "prodrug," as used herein, in this patent application refers to a drug or compound in which metabolic processes within the body convert the drug or compound into an active pharmacological form.

The term "subject" or "patient" encompasses mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, nonhuman primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs, and the like. Non-mammalian examples include, but are not limited to, birds, fish and the like. In one embodiment of the methods and compositions provided herein, in this patent application, the mammal is a human being.

The terms "treating", "treating" or "treatment" as used herein in this patent application include alleviating, alleviating or ameliorating symptoms of a disease or condition, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of the symptoms, inhibit the disease or condition, for example, stop the development of the disease or condition, alleviate the disease or condition, cause regression of the disease or condition, alleviate a condition caused by the disease or condition, or stop symptoms of the disease or condition.Illustrative Biological ActivityReceptor mineralocorticoid (MR)

Mineralocorticoids are so named for their role in the metabolism of minerals, sodium, and potassium. The traditional role for these steroids has been in regulating the balance of epithelial tissue and fluid electrolytes responsive to their effects, such as kidney and distal colon. Mineralocorticoid-producing receptors and enzymes have been identified in non-epithelial tissues such as the heart and the vasculature, as well as the favorable effects of blocking this pathway under various conditions such as heart failure and hypertension.

In visceral tissues, such as the kidney and intestines, mineralocorticoid receptors regulate sodium retention, potassium excretion, and water balance in response to aldosterone. Elevations in aldosterone levels, or over-stimulation of mineralocorticoid receptors, are linked to various pathological conditions or disease states including Conn's syndrome, primary and secondary hyperaldosteronism, increased sodium retention, increased excretion. magnesium and potassium (diuresis), increased water retention, hypertension (combined systolic and systolic / diastolic), arrhythmias, myocardial fibrosis, myocardial infarction, Barter syndrome, congestive heart failure (FCC), and conditions associated with levels in catecholamine excess. In addition, the expression of mineralocorticoid receptors in the brain appears to play a role in controlling neuronal excitability, regulating the negative hypothalamic-pituitary-adrenal axis, and cognitive aspects of behavioral performance. In particular, mineralocorticoid receptors, and modulation of mineralocorticoid receptor activity, are involved in anxiety and major depression. Finally, mineralocorticoid receptor expression may be related to differentiation of breast carcinomas.

Compounds which selectively modulate mino-locorticoid receptors would be of clinical importance in the treatment or prevention of a variety of diseases and conditions, including, but not limited to, cancer, Conn's syndrome, secondary secondary hyperaldosteronism, increased retention of sodium, increased magnesium and potassium excretion (diuresis), increased water retention, hypertension (combined isolated systolic and diastolic), arrhythmias, myocardial fibrosis, myocardial infarction, Barter's Syndrome, congestive heart failure (FCC), conditions associated with excess catecholamine levels, cognitive dysfunctions, psychoses, cognitive conditions, memory disorders, mood conditions, depression, bipolar condition, anxiety conditions, and personality conditions. glucocorticoids (GR),

Glucocorticoids, a class of corticosteroids, are endogenous hormones with profound effects on the immune system and multiple organ systems. They suppress a variety of immune and inflammatory functions by inhibiting inflammatory cytokines such as ILA-1, ILA-2, ILA-6, eTNF, inhibition of arachidonic acid metabolites including prostaglandins and leukotrienes, T lymphocyte depletion, and reducing expression of adhesion molecules on endothelial cells. In addition to these effects, glucocorticoids stimulate liver glucose production and protein catabolism, play a role in hydroelectrolytic balance, reduce calcium absorption, and inhibit osteoblast function.

Glucocorticoid receptors are expressed in all tissues and organ systems and are crucial for the integrity of central nervous system function and the maintenance of cardiovascular, metabolic, and immune homeostasis. Glucocorticoids (eg, cortisol, corticosterone, and cortisone), and glucocorticoid receptors, have been implicated in the etiology of a variety of pathological conditions or disease states. For example, cortisol high secretion is implicated in the pathogenesis of diseases resulting in muscle weakness, increased skin melanin pigmentation, weight loss, hypotension, and hypoglycemia. On the other hand, excessive or prolonged glucocorticoid secretion has been correlated with Cushing's syndrome and may also result in obesity, hypertension, glucose intolerance, hyperglycemia, diabetes mellitus, osteoporosis, polyuria, and polydipsia.

Compounds which selectively modulate glucocorticoid receptors would be of clinical importance in the treatment or prevention of a variety of diseases and conditions, including, but not limited to, inflammation, tissue rejection, autoimmunity, malignancies such as leukemia and lymphoma, Cushing's syndrome. , acute adrenal insufficiency, congenital adrenal hyperplasia, rheumatic fever, polyarteritis nodosa, granulomatous polyarteritis, inhibition of myeloid cell lines, immune-proliferation / apoptosis, HPA axis suppression and regulation, hypercortisolemia, Thl / Th2 cytokine balance modulation , chronic kidney disease, stroke, spinal cord injury, hypocalcemia, hyperglycemia, adrenal insufficiency

acute, chronic primary adrenal insufficiency, secondary adrenal insufficiency

i

congenital adrenal hyperplasia, cerebral edema, thrombocytopenia, Little's syndrome, inflammatory bowel disease, systemic lupus erythematosus, polyartitis nodosa, Wegener's granulomatosis, giant cell arthritis, arthritis, osteoarthritis, hay fever, allergic rhinitis, urticaria, angi-anurotic edema, chronic obstructive pulmonary disease, asthma, tendonitis, bursitis, Crohn's disease, ulceratin colitis, chronic autoimmune active hepatitis, organ transplantation, hepatitis, and cirrhosis; detached wound healing and restoration, inflammatory scalp alopecia, panniculitis, psoriasis, discoid lupuseritis, inflamed cysts, atopic dermatitis, pyoderma gangrenous, pemphigus vulgaris, systemic lupus erythematosus, dermatomyositis, polycillitis, fasciitis, vasculitis Inflammatory, sarcoidosis, Sweet's disease, Type 1 reactive leprosy, Capillary hemangiomas, Contact dermatitis, Atopic dermatitis, Lichen planus, Dermatitis and exfoliative, Erythema nodosum, Acne, Hirsutism, Epidermal necrolysis, Erythema multiforme, Skin T-cell lymphoma, Emphysema , neuroinflammatory conditions, multiple sclerosis and Alzheimer's disease. Androgen receptor (RA)

Androgens bind to a specific receptor, the anadrogenic receptor (AR), within target tissue cells. The androgen receptor is expressed in numerous body tissues and is the receptor through which the physiological effects as well as the pathophysiological effects of endogenous anhydrogenic ligands such as testosterone (T) and dihydrotestosterone (DHT) are expressed. Structurally, the androgen receptor is composed of three major functional domains: the ligand binding domain (LBD), the DNA binding domain, and the amino terminal domain. A compound that binds the androgen receptor and simulates the effects of an endogenous androgen receptor is referred to as an androgen receptor agonist, whereas a compound that inhibits the effects of an endogenous androgen receptor ligand is termed an antagonist. androgen receptor receptor. Androgen binding to the receptor activates and causes the receptor to bind DNA binding sites adjacent to the target genes. Hence this interacts with coactive activators and basic transcription factors to regulate gene expression. Thus, through their receptor, androgens cause changes in gene expression in cells. These changes essentially have consequences on metabolic production, differentiation or cell proliferation that are visible in target tissue physiology.

Compounds which selectively modulate androgen receptors would be of clinical importance in the treatment or prevention of a variety of diseases and conditions, including, but not limited to, prostate cancer, benign prostatic hyperplasia, hirsutism in women, alopecia, anorexia nervosa, cancer. breast cancer, acne, musculoskeletal conditions such as bone disease, hematopoietic conditions, musculoskeletal disease, rheumatologic disease, debilitating disease, cancer, AIDS, cachexia, for hormone replacement therapy (HRT), employed in male contraception, to male performance enhancement for male reproductive conditions, and primary or secondary male hypogonadism.

Stromal receptor (ER)

Estrogens play important roles in the development and homeostasis of both male and female reproductive, central nervous, skeletal, and cardiovascular systems. The estrogen receptor (ER) is expressed in a variety of tissues including prostate, bladder, ovary, testis, lung, small intestine, vascular endothelium, and various parts of the brain.

Compounds which selectively modulate estrogen receptors would be of clinical importance in the treatment or prevention of a variety of diseases and conditions, including, but not limited to, prostate cancer, testicular cancer, ovarian cancer, lung cancer, cardiovascular disease, neurodegenerative conditions, urinary incontinence, central nervous system conditions, multiple sclerosis, gastrointestinal tract conditions, osteoporosis, bone loss, bone fractures, osteopoise, Paget's disease, abnormally increased bone movement, periodontal disease, tooth loss, rheumatoid arthritis, osteoarthritis, peri-prosthetic osteolysis, osteogenesis imperfecta, metastatic bone disease, malignancy hypercalcemia, and multiple myeloma, cartilage degeneration, endometriosis, uterine fibroid disease, breast cancer, uterine cancer, hot flushes, deterioration of function cognitive impairment, brain degenerative conditions, restoration, gine coma, proliferation of vascular smooth muscle cells, obesity and incontinence. Procesterone receptor (PR).

Progesterone is a steroid hormone known primarily for its role in the development and maintenance of the reproductive system. Progesterone is the natural ligand for progesterone receptors and when bound forms a receptor / ligand complex. This complex binds to specific genetic promoters present in cell DNA and emulates the production of mRNA and protein encoded by this gene. Synthetic ligands for progesterone receptors may be agonists, which mimic the action of the natural hormone, or they may be antagonists, which inhibit the effect of the hormone.

Progesterone has been implicated in a wide range of biological processes outside the reproductive tract. In the peripheral nervous system aprogesterone stimulates the myelination of regenerating nerves. Progesterone is synthesized by Sçhwann cells (the myelin-producing cell type), and progesterone receptors were detected in primary rat Schwann cell cultures, suggesting the presence of an autocrine loop. Aprogesterone appears to promote the formation of myelin by binding to progesterone receptors and to stimulate transcription of the transcription factor Krox-20, which in turn stimulates the transcription of various proteinmyelin genes. Therefore, both local and systemic progesterone production may contribute to neurofibroma growth. Therefore, compounds which selectively modulate progesterone receptors would be of clinical importance in the treatment or prevention of a variety of diseases and conditions, including, but not limited to, hormone-dependent breast cancers, uterine and ovarian cancers, and non-malignant chronic conditions and conditions. such as fibroids, hormone dependent prostate cancer, and hormone replacement therapy.

Compounds of Formula (1), pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically acceptable metabolites, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable solvates thereof, modulate the activity of steroidal hormone receptors and as such are useful for treating diseases or conditions in which the aberrant activity of steroid hormone nuclear receptors contributes to the pathology and / or symptoms of a disease or condition.

O, N or S; and Y is O, N or S. In addition, A is selected from CR3 = CR4, N = CR4, CR3 = N, and CR3R3-, whereas Q is selected from CR5 = CR6, N = CR6, CR5 = N , and CR6Re '. The substituents R3> R3 ', R4, R5, Re, Re1, Rs, and R9 are independently selected from H, halogen, OH, NH2, SH, NO2, CN, and an optionally substituted moiety selected from -L3- alkyl, -U-cycloalkyl, -L3-heteroalkyl, -U-haloalkyl, -L3-aryl, -L3-heterocycloalkyl, and -U-heteroaryl, wherein L3 is selected from a bond, O, NH, S, -C (O) -, -C (S) -, -C (0) 0- (any orientation), -C (0) NH- (any orientation), -S (O) -, -S (0) 2, and -S (0) NH- (any orientation); wherein the optional substituents are selected from halogen, OH, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl and halo-C1-6 alkoxy. The substituents R7, Re, and Rg are independently selected from the group consisting of H, halogen, and an optionally substituted moiety selected from -UH, -U-alkyl, -U-cycloalkyl, -U-heteroalkyl, -U- haloalkyl, -U-aryl, -U-heterocycloalkyl, and -U-heteroaryl, wherein U is selected from a bond, O, NH, OCH 2) NHCH 2, S, C 1 -C 6 alkylene, -G (0) -, -C (S) -, -C (0) 0- (any orientation), -C (0) NH- (any orientation), -S (O) -, -S (0) 2, and -S (0) NH- (any orientation); wherein said optional substituents are selected from H, halogen, cyano, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-6alkoxy, halo-C1-6 alkoxy, C1 -C4 thioalkyl, C1-C4 thioalkoxy aryl, aryl , halo aryl, heteroaryl or halo heteroaryl, NR10 R11, wherein R10 and Rn are independently H, C1 -C6 alkyl, C1 -C6 haloalkyl, or when taken together form an optionally substituted 3 to 8 membered heterocyclic ring. Formula (1) R 1 is selected from the group consisting of H, OH, NH 2, SH, NO 2, CN, and an optionally substituted moiety selected from -U-alkyl, -U-cycloalkyl, -U-

r2 k (1)

In compounds of Formula (1), L is CRg or N; Z is CRs or N; X is heteroalkyl, -Lrhaloalkyl, -Larryl, -Li-heterocycloalkyl, and -Lrheteroaryl, where l is selected from a bond, O, NH, S, -C (0) -, -C (S) -, -C ( 0) 0- (any orientation), -C (0) NH- (any orientation), -S (O) -, -S (0) 2, and -S (0) NH- (any orientation); wherein said optional substituents are selected from halogen, OH, C1-6 alkyl, C1-6 alkoxy, halo-d- and alkyl and halo C1-6 alkoxy; while R2 is selected from the group consisting of H, and an optionally substituted moiety selected from -L2-alkyl, -L2-cycloalkyl, -L2-heteroalkyl, -L2-haloalkyl, -L2-aryl, L2-heterocycloalkyl, and -L2-heteroaryl, wherein L2 is selected from a bond, -C (O) -, -C (S) -, -C (0) 0- (any orientation), - C (0) NH - (any orientation), -S (O) -, -S (0) 2, and -S (0) NH- (any orientation); wherein said optional substituents are selected from H, halogen, OH, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl, halo-C1- and alkoxy, aryl, halo aryl, and heteroaryl. Alternatively, substituents R 2 and R 3 taken together may form an optionally substituted 4 to 8 membered ring; wherein the ring is heterocyclic, cycloalkyl, or aryl.

Some embodiments of Formula (1) are shown below as Formula (2), Formula (3), Formula (4), Formula (5), Formula (6), Formula (7), Formula (8), Formula ( 9), Formula (10), Formula (11), Formula (12), Formula (13), Formula (14), Formula (15), Formula (16), Formula (17), Formula (18), Formula (19), Formula (20), Formula (21), Formula (22), Formula (23), Formula (24), and Formula (25). <formula> formula see original document page 42 </formula> <formula > formula see original document page 43 </formula> (24), and

(25).

STEROIDS

Compounds of Formula (A), pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically acceptable metabolites, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable solvates thereof are considered modulators of nuclear hormone receptor activity. steroids and, as such, are useful for treating diseases or conditions in which the aberrant activity of nuclear steroid hormone receptors contributes to the pathology and / or symptoms of a disease or condition.

compounds of Formula (1), with the addition that Ra is selected from the group consisting of H, halogen, CN, OH, NO2, N3, NH2, SH, and an optionally substituted moiety selected from -L3-alkyl, - U-cycloalkyl, -U-heteroalkyl, -L3-haloalkyl, -L3-aryl, -L3-heterocycloalkyl, and -U-heteroaryl, wherein L3 is selected from a bond, O, NH, S, -C (O) -, - C (S) -, -C (0) 0- (any orientation), -C (0) NH- (any orientation), - S (O) -, -S (0) 2, and -S (0) NH- (any orientation); wherein the optional substituents are selected from halogen, OH, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl and halo-C1-6 alkoxy.

Pharmaceutically acceptable N-oxides, pharmaceutically acceptable metabolites, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable solvates thereof, are considered modulators of steroid hormone nuclear receptor activity and as such are useful for treating diseases or conditions under which the aberrant activity of

The substituents for compounds of Formula (A) are as with

Compounds of Formula (B), pharmaceutically acceptable salts, nuclear steroid hormone receptors contribute to the pathology and / or symptoms of a disease or condition.

In compounds of Formula (B), ring structure J is a heterocycle. In some embodiments the ring structure J contains at least two heteroatoms, and in additional embodiments the heteroatoms of the ring structure J are selected from N, O or S. The substituents for compounds of Formula (B) are as with compounds. of Formula (1) and Formula (A).

Compound Synthesis

Compounds of Formula (1) and compounds having the structures described in the previous section may be synthesized using routine synthetic techniques known to those skilled in the art or using methods known in the art in combination with methods described herein in this patent application. . In addition, solvents, temperatures and other reaction conditions set forth herein in this patent application may vary according to the practice and knowledge of those skilled in the art.

The starting material used for the synthesis of Formula 1a (1) compounds compounds having the structures described in the previous section as described herein, in this patent application, can be obtained from commercial sources, such as Aldrich Chemical Co. . (Milwaukee, Wis.), SigmaChemical Co. (St. Louis, Mo.), or the raw materials can be synthesized. The compounds described herein, in this patent application, and other related compounds having different substituents may be synthesized using techniques and materials known to those of ordinary skill, as described, for example, in March, Advanced Organic Chemistry 4m Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4 Ed., Vol. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference in their entirety). General methods for preparing the compound as described herein in this patent application may be derived from field-known reactions, and the reactions may be modified by the use of appropriate reagents and conditions, as would be recognized by the skilled person, to the introduction of the various portions found in the formulas as provided herein in this patent application. As a guideline the following synthetic methods can be used.

Covalent Bonding by Reaction of an Electrophile with a Nucleleph

The compounds described herein in this patent application may be modified using various electrophiles or nucleophiles to form new functional groups or substituents. Table 1 entitled "Examples of Covalent Bonds and Precursor Of The Same" lists selected examples of covalent bonds and precursor functional groups which produce and can be used as a guide for the variety of available electrophile and nucleophile combinations. Precursor functional groups are shown as electrophilic groups and nucleophilic groups.

Table 1: Examples of Covalent Bonds and Precursors of Same

<table> table see original document page 46 </column> </row> <table> <table> table see original document page 47 </column> </row> <table> where these are desired in the final product to avoid your unwanted participation in the reactions. Protecting groups are used to block parts of all reactive moieties and prevent said groups from participating in chemical reactions until the protecting group is removed. It is preferred that each protective group be removable by a different means. Protecting groups that are cleaved under totally different reaction conditions satisfy the differential removal requirement. Protecting groups may be removed by acid, base, and hydrogenolysis. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid unstable and may be used to protect reactive carboxy and hydroxy moieties in the presence of Cbz-protected amino groups which are removable by hydrogenolysis and Fmoc groups which are unstable. in base. Reactive moieties with carboxylic acid and hydroxy can be blocked with base unstable groups such as, but not limited to, methyl, ethyl, and acetyl in the presence of amines blocked with acid unstable groups such as t-butyl carbamate or carbamates that are either They are stable in acid as in base but are hydrolytically removable.

Carboxylic acid and hydroxy reactive moieties may also be blocked with hydrolytically removable protecting groups such as the benzyl group, whereas amino groups capable of hydrogen bonding with acids may be blocked with base unstable groups such as Fmoc. Carboxylic acid reactive moieties may be protected by conversion to single ester compounds as exemplified herein in this patent application, or may be blocked with oxidatively removable protecting groups such as 2,4-dimethoxybenzyl, whereas co-existing amino groups may be blocked with silyl fluoride-unstable carbamates.

Atyl blocking groups are useful in the presence of acid and base protecting groups since the foregoing are stable and may then be removed by metal catalysts or β-acids. For example, an allyl blocked carboxylic acid may be deprotected with a Pd0 catalyzed reaction in the presence of acid-labile or base-unstable acid-t-butyl carbamate protecting groups. Still another form of protecting group is a resin to which a compound or intermediate may be attached. While the residue is attached to the resin, the functional group is blocked and cannot react. Once released from the resin, the functional group is available to react.

Typically lockout / protection groups can be selected from:

<formula> formula see original document page 49 </formula>

Other protecting groups, plus a detailed description of techniques applicable to creating and removing protecting groups are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski. Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference in their entirety.

Synthetic schemes for obtaining compounds of Formula (1) may depend on the identity of L and Z. By way of example, compounds of Formula (2), wherein L is N and Z is N, may be synthesized according to Schemes. typical reaction reactions 1a, 1b, 2a and 2b; compounds of Formula (3) wherein L is N and Z is C may be synthesized according to typical reaction Scheme 4a and 4b; compounds of Formula (4) wherein L is C and Z is N may be synthesized according to typical reaction Scheme 6a and 6b; and compounds of Formula (5) wherein L is N and Z is N may be synthesized according to typical reaction Scheme 6a and 6b.

Compounds of Formula (2) may be synthesized according to reaction scheme 1a, wherein anhydride (A) compounds are alkylated or acuted to give compounds of Formula (B). Treatment of compounds of Formula (B) with hydrazine yields intermediate compounds of Formula (C), which are transformed into chlorine compounds (D) by a chlorination step. Amination of chlorine compounds (D) yields amino compounds (E), which are brominated, and damaged to provide compounds of Formula (2). Scheme 1a

Alkylation or acylation <formula> formula see original document page 50 </formula> (B)

Hydrazine

<formula> formula see original document page 50 </formula>

where r7 is - r>

Amination

<formula> formula see original document page 50 </formula>

1) Bromination

2) Cyanation

r- (2)

Alternatively, compounds of Formula (2) may be synthesized according to reaction scheme 1b, wherein anhydride compounds (A) are alkylated or acidified to give compounds of Formula (B). Treatment of compounds of Formula (B) with hydrazine yields intermediate compounds of Formula (C), which are transformed into chlorine compounds (D) by a chlorination step. Amination of the chlorine compounds (D) with cyano substituted amino compounds yields compounds of Formula (2). Scheme 1b

,? Alkylation

Q \\% or acylationFY "Vw Hydrazinaf Y" "" * "

<formula> formula see original document page 50 </formula> In addition, compounds of Formula (2) may be synthesized according to reaction scheme 2a or reaction scheme 2b, wherein a phosphonium salt (F) is successively acylated or alkylated, treated with hydrazine, and then chlorinated to provide chloro-phthalazine compounds (D). Amination of (D) followed by bromination and cyanation (scheme 2a) gives compounds of Formula (2), or alternatively amination of chloro-phthalazine compounds (D) with cyano substituted amino compounds (scheme 2b) also yields compounds of Formula (2). Scheme 2a

<formula> formula see original document page 51 </formula>

Alternatively, the compounds of Formula (2) may be synthesized according to Reaction Scheme 3, wherein the initial Suzuki binding of dichloro compounds of Formula (G) to a vinylic boronic acid gives compounds of Formula (H), which are amino to the amino compounds of Formula (I). Oxidative cleavage of the styrene substituent on the amino compounds of Formula (I) provides the amino compounds with an acidic substituent (Formula (J)) which may be used for further transformations such as, by way of example only, olefinization, grignard additions, and aldol chemistry as a method for altering the R7 substituent. <formula> formula see original document page 52 </formula>

The compounds of Formula (2) may also be synthesized according to Reaction Scheme 4, wherein the dichloro compound (G) is subjected to a nucleophilic substitution with an alcohol or an amine to obtain compounds of Formula (K). which is followed by an amination reaction to provide compounds of Formula (L). The X-R 'substituent on compounds of Formula (L) may be modified to alter the group R7 on compounds of Formula (2). Scheme 4

<formula> formula see original document page 52 </formula>

Alternatively, the compounds of Formula (2) may also be synthesized according to Reaction Scheme 5, in which the sequence sequences in Scheme 4 have been reversed, wherein the dichloro compound (G) is subjected to amination to provide compounds of formula (2). Formula (M) which is followed by a nucleophilic substitution with an alcohol or an amine to obtain compounds of Formula (L). The X-R 'substituent on compounds of Formula (L) may be modified to change the R7 group on compounds of Formula (2). <formula> formula see original document page 53 </formula>

Compounds of Formula (2) may also be synthesized according to Reaction Scheme 6 and 7, wherein one unsubstituted amino group is substituted with several R2 groups. Scheme 6

<formula> formula see original document page 53 </formula>

In particular, the synthesis of phthalazine compounds of Formula (22) is shown, by way of example only, in Reaction Scheme 8, wherein an aryl substrate is condensed onto an italic anhydride compound to provide an indene-1-compound. one. Treatment of the indene-1-one compound with hydrazine, followed by chlorination with POCl 3 or other chlorination reagents yields the chlorphthalazine compound. Amination of the chloro-phthalazine compound yields the corresponding amino compound, wherein bromination of this amino compound followed by cyanation (e.g. using Zn (CN) 2 and Pd (PPh3) 4 under microwave irradiation) provides the phthalazine compounds of Formula ( 22). In addition, the synthesis of phthalazine compounds of Formula (22) is shown, by way of example only, in Reaction Scheme 9, where dichlorophthalazine is subjected to a bond. of Suzuki with a vinylic boronic acid and the resulting styrene substituted chlorophthalazine is mixed, thereby creating the styrene substituted aminophthalazine. Oxidative styrene cleavage provides an aldehyde which can be used for further transformations such as, by way of example only, olefination, Grignard additions, and aldol chemistry, as a method for altering the R7 substituent and obtaining various phthalazine compounds of Formula (22). <formula> formula see original document page 54 </formula>

Phthalazine compounds of Formula (22) may also be synthesized as shown, by way of example only, in Reaction Scheme 10, wherein dichlorophthalazine compounds are subjected to a nucleophilic substitution with an alcohol or an amine to obtain chlorophthalazine compounds. which are aminated to provide substituted amino phthalazine compounds. The X-R 'substituent on aminophthalazine compounds may be modified to alter the R7 group in compounds of Formula (22). Figure 10

Alternatively, the phthalazine compounds of Formula (22) may also be synthesized as shown, by way of example only, in Reaction Scheme 11, wherein the steps in Scheme 8 have been reversed. Dichlorophthalazine compounds are initially aminated to provide substituted aminophthalazine compounds which are then subjected to a nucleophilic substitution with an alcohol or an amine to obtain substituted aminophthalazine compounds. The X-R 'substituent on aminophthalazine compounds may be modified to alter the R7 group in compounds of Formula (22). Scheme 11

<formula> formula see original document page 55 </formula> Alternatively, the phthalazine compounds of Formula (22) can also be synthesized as shown, by way of example only, in Reaction Scheme 12, wherein amino group substitution produces compounds of Formula (22). Scheme 12 <formula> formula see original document page 56 </formula>

Y Acetyl chloride 1 '

where R2 is CH

Compounds of Formula (3) occur when L is N and Z is C. Said compounds may be synthesized according to Reaction Scheme 13a, wherein chlorine compounds (O) are obtained by chlorination of compounds of Formula (N). . Chlorine compounds are then aminated to produce compounds of Formula (P), which are brominated and then cyanated to provide compounds of Formula (3). Figure 13a <formula> formula see original document page 56 </formula> (P)

(3)

Similarly, compounds of Formula (3) may be synthesized according to Reaction Scheme 13b, wherein the chlorination of compounds of Formula (N), followed by amination with an amine compound comprising a cyano substituent yields compounds of Formula (N). 3). Figure 13b

<formula> formula see original document page 56 </formula> The synthesis of isoquinoline compounds of Formula (23) is shown by way of example only in Reaction Scheme 14, wherein an isoquinoline-1-one compound is chlorinated with POCl 3 or other chlorination reagents to provide the corresponding chloro-isoquinoline compound. Amination of the chloro-isoquinoline compound yields the corresponding amino compound, wherein bromination followed by cyanation (e.g. using Zn (CN) 2 and Pd (PPh3) and under microwave irradiation) provides the isoquinoline compounds of Formula ( 23). Scheme 14

<formula> formula see original document page 57 </formula>

Compounds of Formula (4) occur when L is C and Z is N. Said compounds may be synthesized according to Reaction Scheme 15a, wherein chlorine (R) compounds are obtained by chlorination of compounds of Formula (Q) . Chlorine compounds are then aminated to produce compounds of Formula (S), which are brominated and then damaged to provide compounds of Formula (4). Figure 15a

<formula> formula see original document page 57 </formula>

Similarly, compounds of Formula (4) may be synthesized according to Reaction Scheme 15b, wherein chlorination of compounds of Formula (Q), followed by amination with an amine compound comprising a cyano substituent yields compounds of Formula (4). ). Figure 15b

<formula> formula see original document page 57 </formula>

The synthesis of isoquinoline compounds of Formula (24) is shown, by way of example only, in Reaction Scheme 16, wherein an isoquinolinol compound is chlorinated with POCl 3 or other chlorination reagents to provide the chlorine compound. corresponding isoquinoline. Amination of the chloro-isoquinoline compounds yields the corresponding amino compound, wherein bromination followed by cyanation (e.g. using Zn (CN) 2 and Pd (PPh3) 4 under microwave irradiation) provides the isoquinoline compounds of Formula (24). . Scheme 16

x-

YN Pd binding L jl Kl 2) Cyanation X. X, N

"yvv

0UCU k \

(24)

Starting isoquinoline compounds used in the synthesis of compounds of Formula (23) and Formula (24) as shown in Reaction Scheme 14 and Reaction Scheme 16 may be synthesized by known methods including, but not limited to, Gabri-el-Colman reorganization, Bischler-Napieralski reaction, Pictet-Gams isoquinoline synthesis, and Pictet-Spengler isoquinoline synthesis. A non-limiting example of the synthesis of an isoquinoline is shown in Reaction Scheme 17 (the substituent R 'may be either in useful or trans orientation). <formula> formula see original document page 58 </formula> Compounds of Formula (5) occur when L is C and Z is C. The said compounds may be synthesized according to Reaction Scheme 18a, where compounds of Chlorine (U) are obtained by chlorination of compounds of Formula (T). Chlorine compounds are then aminated to produce compounds of Formula (V), which are brominated and then cyanated to provide compounds of Formula (5). <formula> formula see original document page 59 </formula>

Similarly, compounds of Formula (5) may be synthesized according to Reaction Scheme 18b, wherein chlorination of compounds of Formula (T), followed by amination with an amine compound comprising a cyano substituent yields compounds of Formula (5). ). Scheme 18b

<formula> formula see original document page 59 </formula>

The synthesis of naphthalene compounds of Formula (25) is shown, by way of example only, in Reaction Scheme 19, wherein a naphthalene compound is chlorinated to provide the corresponding chloro-naphthalene compound. Amination of the chloro-naphthalene compound yields the corresponding amino compound, wherein bromination followed by cyanation (e.g. using Zn (CN) 2 and Pd (PPh3) 4 under microwave irradiation) provides the naphthalene compounds of Formula (25). .

Scheme 19 <formula> formula see original document page 59 </formula>

Additional Compound Shapes

For convenience, the form and other characteristics of the compounds described in this section and elsewhere herein in this patent application use a single formula, such as "Formula (1)," by way of example. However, the form and other characteristics of the compounds described herein in this patent application apply equally well to all of the formulas set forth herein in this patent application that fall within the scope of Formula (1). For example, the form and other characteristics of the compounds described herein in this patent application may be applied to compounds having the structure of Formula (2), Formula (3), Formula (4), Formula (5), Formula (6). ), Formula (7), Formula (8), Formula (9), Formula (10), Formula (11), Formula (12), Formula (13), Formula (14), Formula (15), Formula (16) ), Formula (17), Formula (18), Formula (19), Formula (20), Formula (21), Formula (22), Formula (23), Formula (24), Formula (25), Formula (A) ), Formula (B), as well as all specific compounds within the scope of this generic formula.

Compounds of Formula (1) may be prepared as some pharmaceutically acceptable salts formed when an acidic proton present in the parent compound or is substituted by a metal ion, for example an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinated with an organic base. In addition, salt forms of the described compounds may be prepared using salts of the raw materials or intermediates.

Compounds of Formula (1) may be prepared as a pharmaceutically acceptable acid addition salt (which is a type of a pharmaceutically acceptable salt) by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to. not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanopropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, Q-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo [2.2.2] oct-2-eno-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis- (3-hydroxy-2-eno-1) -carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid eharic, and muconic acid.

Alternatively, compounds of Formula (1) may be prepared as some pharmaceutically acceptable base addition salts (which is a type of a pharmaceutically acceptable salt) by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base, including but not limited to organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like and inorganic bases such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. .

It should be understood that a reference to a pharmaceutically acceptable salt includes solvent addition forms or crystal forms thereof, particularly solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the crystallization process with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds of Formula (1) may be prepared or formed conveniently during the processes described herein in this patent application. By way of example only, hydrates of compounds of Formula (1) may conveniently be prepared by recrystallization from a mixture of aqueous / organic solvents using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol. . In addition, the compounds provided herein in this patent application may exist in unsolvated as well as unsolvated forms. In general, unsolvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein in this patent application. Compounds of Formula (1) include crystalline forms, also known as polymorphs. Polymorphs include the different crystalline conditioning arrangements of the same elemental composition of a compound. Polymorphs generally have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystalline form, optical and electrical properties, stability, and solubility. Several factors such as recrystallization solvent, crystallization index, and storage temperature can cause a single crystalline form to dominate.

Compounds of Formula (1) in non-oxidized form may be prepared from N-oxides of compounds of Formula (1) by treating with a reducing agent such as, but not limited to, sulfur, sulfur dioxide, triphenyl phosphine, boride. of lithium, sodium borohydride, phosphorus trichloride, tribromide, or the like in a suitable inert organic solvent, such as, but not limited to, acetonitrile, ethanol, aqueous dioxane, or the like at 0 to 80 ° C.

Compounds of Formula (1) may be prepared as prodrugs. Prodrugs are generally drug precursors which, upon administration to a subject and subsequent absorption, are converted into an active species, or a more active species through some process, such as conversion by a metabolic pathway. Some prodrugs have a chemical group present in the prodrug that makes it less active and / or confers solubility or some other property to the drug. Once the chemical group has been cleaved and / or modified from the prodrug the active drug is produced. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. For example, they may be bioavailable by oral administration whereas the parent may not. The prodrug may also have greater solubility in pharmaceutical compositions compared to the parent drug. An example, without limitation, of a prodrug would be a compound of Formula (1) which is administered as an ester (the "prodrug") to facilitate transmission across a cell membrane where water solubility is detrimental to water. Mobility but which is then metabolically hydrolyzed to carboxylic acid, the active entity, once inside the cell where water solubility is beneficial. A further example of a prodrug may be a short peptide (polyamino acid) attached to an acidic group where the peptide is metabolized to reveal the active moiety.

Prodrugs may be designated as reversible drug derivatives for use as modifiers to enhance drug transport to site-specific tissues. The design of prodrugs so far has been to increase the effective water solubility of the therapeutic compound to target regions where water is the major solvent. See, for example, Fedorak et al., Am. J. Physiol., 269: G210-218 (1995); McLoed et al., Gastroenterol, 106: 405-413 (1994); Hochhaus et al., Biomed. Chrom., 6: 283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64: 181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all incorporated herein into this patent application in its entirety.

Additionally, prodrug derivatives of compounds of Formula (1) may be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters , Vol. 4, p. 1985). By way of example only, suitable prodrugs may be prepared by reacting a non-derivative compound of Formula (1) with a suitable carbamylating agent, such as, but not limited to, 1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like. . Prodrug forms of the compounds described herein, in this patent application, wherein the prodrug is metabolized in vivo to produce a derivative as determined herein, in this patent application, are included within the scope of the claims. Indeed, some of the compounds described herein in this patent application may be a prodrug for another derivative or active compound.

Sites on the aromatic ring portion of compounds of Formula (1) may be susceptible to various metabolic reactions, therefore incorporation of appropriate substituents on aromatic ring structures, such as, by way of example only, halogens may reduce, minimize or eliminate this metabolic pathway.

The compounds described herein, in this patent application, may be isotopically labeled (for example, with a radioisotope) or by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or labels. chemiluminescent. The compounds of Formula (1) may have one or more chiral centers and each center may exist in the R or S configuration. The compounds disclosed herein in this patent application include all diastereomeric, enantiomeric, and epimeric forms as well as appropriate mixtures. the same. Compounds of Formula (1) may be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. Although resolution of enantiomers can be accomplished using covalent diastereomeric derivatives of the compounds described herein, in this patent application dissociable complexes (e.g. crystalline diastereomeric salts) are preferred. Diastereomers have distinct physical properties (eg, melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated for these dissimilarities. Diastereomers may be separated by chiral chromatography, or preferably by separation / resolution techniques based on differences in solubility. The optically pure enantiomer is then recovered, together with the resolving agent, by any practical means that would not result in racemization. A more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques, André Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions," John Wiley And Sons, Inc., 1981, incorporated herein into this patent application by reference in its entirety.

Additionally, the compounds and methods provided herein, in this patent application, may exist as geometric isomers. The compounds and methods provided herein in this patent application include all useful isomers, trans, syn, anti, entgegen (E), and zu-sammen (Z) as well as the appropriate mixtures thereof. In some situations, compounds may exist as tautomers. All tautomers are included within the formulas described herein, in this patent application, are provided by compounds and methods herein, in this patent application. Additional embodiments of the compounds and methods provided herein, in this patent application, mixtures of enantiomers and / or diastereoisomers resulting from a single preparative step, combination, or interconversion may also be useful for the applications described herein in this patent application. Pharmaceutical Composition / Formulation / Administration

For convenience, the form and other characteristics of the compounds described in this section and elsewhere herein in this patent application use a single formula, such as "Formula (1)," by way of example. However, the form and other characteristics of the compounds described herein in this patent application apply equally well to all of the formulas set forth herein in this patent application that fall within the scope of Formula (1). For example, the pharmaceutical compositions and formulations described herein, in this patent application, may be applied to compounds having the structure of Formula (2), Formula (3), Formula (4), Formula (5), Formula (6), Formula (7), Formula (8), Formula (9), Formula (10), Formula (11), Formula (12), Formula (13), Formula (14), Formula (15), Formula (16), Formula (17), Formula (18), Formula (19), Formula (20), Formula (21), Formula (22), Formula (23), Formula (24), Formula (25), Formula (A), Formula (B), as well as all specific compounds within the scope of this generic formula. A pharmaceutical composition as used herein in this patent application refers to a mixture of a compound of Formula (1) with other components. chemicals, such as vehicles, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. Pharmaceutical composition containing compounds of Formula (1) may be administered in therapeutically effective amounts as pharmaceutical compositions by any conventional form and route known in the art including, but not limited to: intravenous, oral, rectal, aerosol, parenteral, ophthalmic, pulmonary administration. , transdermal, vaginal, optic, nasal, and topical.

Compound can be administered in a local rather than systemic manner, for example by injecting the compound directly into an organ, often in a gradual release or depot formulation. In addition, a pharmaceutical composition containing compounds of Formula (1) may be administered in a drug delivery system oriented, for example, on an organ-specific antibody-coated liposome. The liposomes will be oriented towards and selectively absorbed by the organ. In addition, the pharmaceutical composition containing compounds of Formula (1) may be provided as a quick release formulation, as a prolonged release formulation, or as an intermediate release formulation.

For oral administration, compounds of Formula (1) may be readily formulated by combining the active compounds with pharmaceutically acceptable carriers or excipients known in the art. Said carriers allow the compounds described herein in this patent application to be formulated as tablets, powders, pills, pills, capsules, liquids, gels, syrups, elixirs, semifluid pastes, suspensions and the like for oral ingestion by a patient. to be treated.

Pharmaceutical preparations for oral use may be obtained by mixing one or more solid excipients with one or more of the compounds described herein, in this patent application, optionally comminuting the resulting mixture, and processing the granule mixture, after adding suitable auxiliaries, if desired, to get pill or pill cores. Suitable excipients are in particular fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate may be added.

Dragon cores are provided with suitable coatings. For this purpose concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablet or dragee coatings for identification or to characterize different combinations of active compound doses.

Pharmaceutical preparations which may be used orally include push-fit capsules made of gelatin as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules may contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and / or lubricants such as talc or optionally stabilizing magnesium stearate. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.

For buccal or sublingual administration, the compositions may take the form of conventionally formulated tablets, lozenges, or gels. Parental injections may involve bolus injection or continuous infusion. The pharmaceutical composition of Formula (1) may be in a form suitable for parenteral injection as some sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as suspensions for appropriate oily injections. Suitable lipophilic solvents or carriers include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain stabilizers or suitable agents which increase the solubility of the compounds to enable the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, for example sterile pyrogen-free water, prior to use.

The compounds of Formula (1) may be administered topically and may be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated stems, balms, creams or ointments. Said pharmaceutical compounds may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

Formulations suitable for transdermal administration of compounds having the structure of Formula (1) may employ transdermal delivery devices and transdermal delivery patches and may be lipophilic emulsions or buffered aqueous solutions dissolved and / or dispersed in a polymer or an adhesive. Said plasters may be constructed for continuous release, pulsatile, or on demand pharmaceutical agents. Still further, the transdermal release of the compounds of Formula (1) may be accomplished by iontophoretic patches and the like. Additionally, transdermal patches may provide controlled release of the compounds of Formula (1). The absorption index may be retarded by using index control membranes or by capturing the compound within a polymer matrix or gel. Instead, absorption boosters may be used to increase absorption. An absorption enhancer or carrier may include pharmaceutically acceptable solvents absorbable to aid passage through the skin. For example, transdermal devices are in the form of a bandage comprising a support member, a reservoir containing the compound optionally with vehicles, optionally an index control barrier for releasing the compound into the host skin at a predetermined controlled rate for a given period. extended period of time, and means for securing the device to the skin.

For administration by inhalation, the compounds of Formula (1) may be in the form of an aerosol, mist or powder. Pharmaceutical compositions of Formula (1) are conveniently delivered as an aerosol spray presentation from pressurized packs or a nebulizer, using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges such as, by way of example only, gelatin for use in an inhaler or insufflator may be formulated containing a powder mixture of the compound and a suitable powder base such as lactose or starch.

The compounds of Formula (1) may also be formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas containing conventional suppository bases such as cocoa butter. or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. In the suppository forms of the compositions, a low melting wax is first melted such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter.

In practicing the methods of treatment or use provided herein, in this patent application, therapeutically effective amounts of compounds of Formula (1) provided herein, in this patent application, are administered in a pharmaceutical composition to a mammal having a disease or condition to be treated. Preferably, the mammal is a human being. A therapeutically effective amount may vary widely depending upon the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. The compounds may be used alone or in combination with one or more therapeutic agents as components of mixtures.

Pharmaceutical compositions may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate the processing of active compounds into preparations which may be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the known techniques, vehicles, and excipients may be used as appropriate and as understood in the art. Pharmaceutical compositions comprising a compound of Formula (1) may be manufactured in a conventional manner, such as, by way of example only, by conventional mixing, dissolving, granulating, dredging, levigating, emulsifying processes. , encapsulation, capture or compression.

Pharmaceutical compositions will include at least one pharmaceutically acceptable carrier, diluent or excipient and a compound of Formula (1) described herein, in this patent application, as an active ingredient in free acid or free base form, or in a pharmaceutically salt form. acceptable. In addition, the methods and pharmaceutical compositions described herein, in this patent application, include the use of N-oxides, crystalline forms (also known as polymorphs), as well as active methometabolites of these compounds having the same type of activity. In some situations, the compounds may exist as tautomers. All tautomers are included within the scope of the compounds disclosed herein in this patent application. Additionally, the compounds described herein in this patent application may exist in unsolvated forms as well as solvated with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds disclosed herein in this patent application are also considered to be described herein in this patent application. In addition, the pharmaceutical compositions may include other medicinal or pharmaceutical agents, carriers, adjuvants such as preservatives, stabilizers, humectants or emulsifiers, solution stimulators, salts to regulate osmotic pressure, and / or buffers. In addition, the pharmaceutical compositions may also contain other therapeutically valuable substances.

Methods for preparing compositions comprising the compounds described herein in this patent application include formulating the compounds with one or more inert pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, capsules, and suppositories. Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as described herein, in this patent application. Semi-solid compositions include, but are not limited to, gels, suspensions and creams. The compositions may be in the form of liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions may also contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so on.

A summary of the pharmaceutical compositions described herein in this patent application can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa .: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Mareei Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999), herein, to this patent application, incorporated by reference in its entirety.

Administration Methods and Treatment Methods

For convenience, the form and other characteristics of the compounds described in this section and elsewhere herein in this patent application use a single formula, such as "Formula (1)," by way of example. However, the compositions, uses and methods described herein, in this patent application, apply equally well to all formulas presented herein, in this patent application, which fall within the scope of Formula (1), including compounds having the following formula. structure of Formula (2), Formula (3), Formula (4), Formula (5), Formula (6), Formula (7), Formula (8), Formula (9), Formula (10), Formula (11) ), Formula (12), Formula (13), Formula (14), Formula (15), Formula (16), Formula (17), Formula (18), Formula (19), Formula (20), Formula (21) ), Formula (22), Formula (23), Formula (24), Formula (25), Formula (A), Formula (B), as well as any specific compounds falling within the scope of this generic formula.

The compounds of Formula (1) may be used in the preparation of medicaments for the treatment of diseases or conditions in which the activity of nuclear steroid hormone receptors contributes to disease pathology and / or symptomatology. In addition, a method for treating any of the diseases or conditions described herein, in this patent application, in a subject in need of such treatment, involves administering pharmaceutical compositions containing at least one compound of Formula (1), or a pharmaceutically salt. pharmaceutically acceptable N-oxide, pharmaceutically acceptable metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts for said subject.

Compositions containing the one or more compounds described herein, in this patent application, may be administered for propulatic and / or therapeutic treatments. In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially stop the symptoms of the disease or condition. Effective amounts for this use will depend on the severity and course of the disease or condition, prior therapy, the patient's health condition, weight, and drug response, and the discretion of the treating physician. It is well within the skill of the art for a person to determine the therapeutically effective amounts referred to by routine experimentation (including, but not limited to, a clinical trial of scaling data).

Compositions containing the one or more compounds described herein, in this patent application, may be used to treat a disease state or condition selected from: arteriosclerosis, neurological diseases, cancer, Conn's syndrome, primary and secondary hyperaldosteronism. , increased sodium retention, increased magnesium and potassium excretion (diuresis), increased water retention, hypertension (combined systolic and systolic / diastolic), arrhythmias, myocardial fibrosis, myocardial infarction, Barter syndrome, congestive heart failure (CHF), conditions associated with catecholamine excess levels, cognitive dysfunctions, psychoses, cognitive conditions, memory disorders, mood conditions, depression, bipolar condition, anxiety conditions, and personality conditions, inflammation, tissue rejection , autoimmunity, malignancies such as leukemias and lymphomas, Cu-shing syndrome, adrenal insufficiency l acute, congenital adrenal hyperplasia, rheumatic fever, polyarteritis nodosa, granulomatous polyarteritis, inhibition of myeloid cell lines, immune proliferation / apoptosis, suppression and regulation of HPA axis, hypercortisolemia, Th1 / Th2 cytokine balance modulation, stroke and spinal cord injury, hypocalcemia, hyperglycemia, chronic primary adrenal insufficiency, secondary adrenal insufficiency, cerebral edema, thrombocytopenia, Little's syndrome, inflammatory bowel disease, systemic lupus erythematosus, polyartitis nodosa, Wegener's granulomatosis , giant cell arthritis, rheumatoid arthritis, osteoarthritis, hay fever, allergic rhinitis, urticaria, angioneurotic edema, chronic obstructive pulmonary disease, asthma, tendonitis, bursitis, Crohn's disease, colitisulceratin, autoimmune chronic active hepatitis, organ transplantation hepatitis, cirrhosis; wound healing and tissue restoration, inflammatory scalp alopecia, panniculitis, psoriasis, discoid lupus, inflamed cysts, atopic dermatitis, pyoderma gangrenosum, pemphigus vulgaris, eosinophilic fasciitis, recurrent sarcoidosis, recurrent vasculitis, Sweet's disease, type 1 reactive leprosy, capillary hemangiomas, contact dermatitis, lichen planus, exfoliative dermatitis, erythemanous, acne, hirsutism, toxic epidermal necrolysis, erythema multiforme, emphysema, neuroinflammatory conditions, multiple sclerosis, Al-zheimer disease, prostate, benign prostatic hyperplasia, alopecia, anorexia nervosa, breast cancer, musculoskeletal conditions, such as bone disease, hematopoietic conditions, neuromuscular disease, rheumatic disease, debilitating disease, AIDS, cachexia, for hormone replacement therapy (HRT) employed in male contraception to male performance, for male reproductive conditions, primary or secondary male hypogonadism, testicular cancer, cancer of the lung, cardiovascular disease, neurodegenerative conditions, central nervous system conditions, gastrointestinal tract conditions, osteoporosis, bone loss, bone fractures, Paget's disease, abnormally enlarged bone turnover, periodontal disease, toe loss, periprosthetic osteolysis, osteogenesis imperfecta, metastatic bone disease, malignancy hypercalcemia, and multiple myeloma, decartilage degeneration, endometriosis, uterine fibroid disease, uterine cancer , hot flushes, degenerative brain conditions, restenosis, gynecomastia, proliferation of vascular smooth muscle cells, obesity, incontinence, and nonmalignant chronic conditions such as fibroids, in a patient in need of such treatment, the method comprising administering to the patient a single condition. An effective entity of a compound described herein, in this patent application, or a tautomer, prodrug, solvate, or salt thereof.

In the event that the patient's condition does not improve, the physician's discretion in administering the compounds may be administered chronically, that is, for an extended period of time, including throughout the patient's life span to improve or otherwise control or limit the symptoms of the patient's disease or condition. In the event that the patient's condition improves, at the discretion of the physician the administration of the compounds may be administered continuously or temporarily withheld for a certain length of time (ie, a "drug slack").

Once the patient's condition has improved, a maintenance dose is administered if necessary. Thereafter, dosing or frequency of administration, or both, may be reduced, depending on the symptoms, to a level at which the improved disease or condition is conserved. However, patients may require intermittent treatment on a long term basis in any recurrent symptoms.

In some cases, it may be appropriate to administer therapeutically effective amounts of at least one of the compounds described herein in this patent application (or some pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically acceptable metabolites, pharmaceutically acceptable prodrugs, and solvates). pharmaceutically acceptable compounds thereof) in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a patient receiving one of the compounds herein in this patent application is inflammation, then it may be appropriate to administer an anti-inflammatory agent in combination with the initial therapeutic agent. By way of example only, the therapeutic efficacy of one of the compounds described herein in this patent application may be enhanced by the administration of an adjuvant (i.e. the adjuvant alone may have only minimal therapeutic benefit, but in combination with another therapeutic agent, the total therapeutic benefit to the patient is enhanced). Or, by way of example only, the benefit experienced by a patient may be increased by administering one of the compounds described herein in this patent application with another therapeutic agent (which also includes therapeutic regimen) which also has therapeutic benefit. In any case, regardless of the disease or condition being treated, the patient's overall benefit may simply be additive to both therapeutic agents or the patient may experience a synergistic benefit. For example, synergistic effects may occur with compounds of Formula (1) and other substances used in the treatment of hypokalemia, hypertension, congestive heart failure, renal failure, in particular chronic renal failure, restenosis, atherosclerosis, syndrome X, obesity, nephropathy, post-myocardial infarction, coronary heart disease, increased collagen formation, fibrosis and remodeling after hypertension and endothelial dysfunction. Examples of said compounds include anti-obesity agents, such as orlistat, antihypertensive agents, inotropic agents, and polypidemic agents including, but not limited to, loop diuretics such as ethacrinic acid, furosemide and torsemide; angiotensin converting enzyme (ACE) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perinodopril, quinapril, ramipril and trandolepril; membrane pump Na-K-ATPase inhibitors such as digoxin; neutral dendopeptidase (NEP) inhibitors; ACE / NEP inhibitors such as omapatrilat, sampatrilat, and fasidotril; angiotensin II antagonists such as candesar-tan, eprosartan, irbesartan, iosartan, telmisartan and valsartan, in particularvalsartan; β-adrenergic receptor blockers such as acebutolol, betaxolol, bisoprolol, metoprolol, nadolol, propanolol, sotalol and timolol; inotropic agents such as digoxin, dobutamine and milrinone; dechannel calcium blockers such as amlodipine, bepridil, diltiazem, felodipine, nicardipine, nimodipine, nifedipine, nisoldipine and verapamil; and 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMG-CoA) inhibitors such as lovas-tatine, pitavastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin, dalvastatin, atorvastatin, rosuvastatin and rivastati . Where the compounds described herein, in this patent application, are administered in combination with other therapies, the dosages of the co-administered compounds will vary depending upon the type of co-drug employed, the specific drug employed, the disease or condition being administered. treated and so on. Further, when co-administered with one or more biologically active agents, the compound provided herein in this patent application may be administered simultaneously with one or more biologically active agents, or subsequently. If administered sequentially, the attending physician will decide upon the appropriate protein administration sequence in combination with one or more biologically active agents.

In any case, the multiple therapeutic agents (one of which is one of the compounds described herein, in this patent application) may be administered in any order or simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single form. unified, or in multiple forms (the example title only, either as a single pill or as two separate pills). One of the therapeutic agents may be administered in multiple doses, or both may be administered as multiple doses. If not simultaneous, the timing between multiple doses may range from another ten weeks to less than four weeks. In addition, combination methods, compositions and formulations should not be limited to the use of only two agents; we aim to use multiple therapeutic combinations.

In addition, the compounds of Formula (1) may also be used in combination with procedures that may provide additional or synergistic benefit to the patient. By way of example only, patients are expected to find therapeutic and / or prophylactic benefit by the methods described herein, in this patent application, wherein the pharmaceutical composition of Formula (1) and / or combinations with other therapies are combined. with genetic experimentation to determine if the individual is a vehicle of a mutant gene known to be correlated with some diseases or conditions.

The compounds of Formula (1) and combination therapies may be administered before, during or after the occurrence of a disease or condition, and the timing of administration of the compound-containing composition may vary. Thus, for example, the compounds may be used as a prophylactic and may be administered continuously to subjects with a propensity for conditions or diseases to prevent the occurrence of the disease or condition. The compounds and compositions may be administered to a subject during or as soon as possible after the onset of symptoms. Administration of the compounds may be initiated within the first 48 hours of symptom onset, preferably within the first 48 hours of symptom onset, more preferably within the first 6 hours of symptom onset, and even more preferably within 3 hours. onset of symptoms. Initial administration may be by any practical route, such as, for example, an intravenous injection, a bolus injection, a 5 minute to about 5 hour infusion, a pill, a capsule, a transdermal patch, a buccal release, and the like, or a combination. the same. A compound is preferably administered as soon as practicable after the onset of a disease or condition is detected or suspected, and for a duration necessary for treating the disease, such as, for example, from about 1 ° C. month to about 3 months. Duration of treatment may vary for each subject, and duration may be determined using known criteria. For example, the compound or a formulation containing the compound may be administered for at least 2 weeks, preferably from about 1 month to about 5 years, and more preferably from about 1 month to about 3 years.

The pharmaceutical composition described herein, in this patent application, may be in unit dosage form suitable for single administration of accurate dosages. In unit dosage form, the formulation is divided into dosage units containing appropriate amounts of one or more compounds. The dosage unit may be in the form of a pack containing different amounts of the formulation. Non-limiting examples are packaged tablets or capsules, powdered in vials or ampoules. Aqueous suspension compositions may be packaged in non-resealable single dose containers. Alternatively, multi-dose resealable containers may be used, in which case it is typical to include a preservative in the composition. By way of example only, parenteral injection formulations may be presented in unit dosage form which include, but are not limited to, ampoules or multi-dose containers with a preservative added.

Suitable daily dosages for the compounds of Formula (1) described herein, in this patent application, are from about 0.03 to 2.5mg / kg by body weight. An indicated daily dosage in the largest mammal, including, but not limited to, humans, is within the range of about 0.5 mg to about 100 mg, conveniently administered in divided doses including, but not limited to, up to four times a week. day or in delayed form. Dosage unit forms suitable for oral administration comprise from about 1 to 50 mg of active ingredient. The foregoing ranges are simply suggestive, since the number of variables regarding an individual treatment regimen is large, and considerable deviations from these recommended values are not uncommon. The dosages reported may be altered depending upon a variety of variables, not limited to the activity of the compound used, the disease or condition being treated, the mode of administration, the needs of the individual subject, the severity of the disease or condition being treated, and the clinical criteria. .

The toxicity and therapeutic efficacy of such therapeutic regimens may be determined by standard pharmaceutical procedures in experimental cell or animal cultures, including, but not limited to, determining LD50 (the lethal dose for 50% of the population) and ED50 (therapeutically adose). effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio between LD50 and ED50. Compounds with high therapeutic indices are preferred. Data from cell culture evidence and animal studies can be used to formulate a dosage range for use in humans. The dosage of said compounds is preferably within a range of circulating concentrations that includes the ED50 with minimal toxicity. The dosage may vary within this range depending on the dosage form employed and the route of administration used.

For use in the therapeutic applications described herein, in this patent application, kits and articles of manufacture are also described herein in this patent application. Said kits may comprise a vehicle, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container (s) comprising one of the separate elements to be used. in a method described herein, in this patent application. Suitable containers include, for example, bottles, vials, syringes, test tubes. Containers may be formed of a variety of materials such as glass or plastic.

For example, the container (s) may comprise one or more compounds described herein in this patent application, optionally in a composition or in combination with another agent as described herein in this patent application. The container (s) optionally have a sterile access port (for example, the container may be an intravenous solution pouch or a vial having a stopper perforated by a hypodermic injection needle). Said kits optionally comprising a compound with a description or identification label or instructions relating to its use in the methods described herein in this patent application. A kit may typically comprise one or more additional containers, each with one or more of several materials ( such as reagents, optionally in concentrated form, and / or devices) desirable from a commercial and user point of view for use of a compound described herein in this patent application. Non-limiting examples of similar materials include, but are not limited to, buffers, diluents, filters, needles, syringes; vehicle, packaging, container, labels listing the contents of the vials and / or tubes and / or instructions for use, and packaging supplements with instructions for use. Typically a series of instructions will also be included.

A label may be on or associated with the container. A label may be on a container when letters, numbers, or other characters forming the label are affixed, molded, or caused within the container itself; A label may be associated with a container when it is present within a receptacle or vehicle which also holds the container, for example as a supplement to the package. A label may be used to indicate that the content should be used for a specific therapeutic application. The label may also indicate instructions for use of the content, as in the methods described herein, in this patent application. ILLUSTRATIVE EXAMPLES

The following examples provide illustrative methods for fabricating and testing the efficacy and safety of the compounds of Formula (1). These examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein in this patent application. All methods described and claimed herein, in this patent application, may be performed and performed without undue experimentation in light of the present disclosure. It will be apparent to those skilled in the art that variations may be applied to the methods and stages or sequence of steps of the method described herein in this dependent application without departing from the concept, spirit and scope of the claims. All such similar substitutes and apparent modifications to those of skill in the art are considered to be within the spirit, scope and concept of the appended claims. Example 1: Synthesis of lndene-1-one compounds

Example 1a: Synthesis of 3-Hydroxy-2- (pyridin-4-yl) inden-1-one

<formula> formula see original document page 82 </formula>

3-Hydroxy-2- (pyridin-4-yl) inden-1-one can be synthesized by the following procedure. A mixture of italic anhydride (6 g, 40.5 mmol) and 4-picoline (4.0 mL, 40.6 mmol) is heated at 170 ° C for 24 hours. The resulting materials are stirred in boiling ethanol, filtered, and washed with ethanol and diethyl ether, yielding 4.85 g of the title compound. 1H NMR (DMSO-c / 6) 8.72 (d, 2H), 8.18 (d, 2H), 7.50 (m, 4H). Example 1b: Synthesis of 3-Hydroxy-2- (pyridine) 3-yl) inden-1-one

OH

3-Hydroxy-2- (pyridin-3-yl) inden-1-one can be synthesized by the following procedure. Sodium methanolate (24.3 g, 0.45 mol) is slowly added to an ice-cold solution of phthalide (20 g, 0.15 mol), 3-pyridinecarboxaldehyde (14.1 ml, 0.15 mol), and ethyl propionate (75 mL) in methanol (150 mL). The reaction mixture warms to room temperature and after 15 minutes at room temperature the reaction mixture is heated to 65 ° C for 2.5 hours, and then cooled back to room temperature. The resulting mixture is concentrated under reduced pressure and diluted with water (700 ml) yielding a dark red solution which is extracted with diethyl ether. The aqueous layer is acidified with acetic acid (35mL) while stirring, resulting in a reddish suspension. This suspension is filtered and washed with water, ethyl acetate and finally diethyl ether to give 19.1 g of 3-Hydroxy-2- (pyridin-3-yl) inden-1-one: 1H NMR (DMSO-c / 6) 9.75 (s, 1H), 9.45 (d, 1H), 8.23 (d, 1H), 7.80 (dd, 1H), 7.38 (m, 2H), 7.32 (m, 2H) .Example 2: Synthesis of Phthalazine-1-one CompoundsExample 2a: Synthesis of 4- (pyridin-4-yl) methyl-2H-phthalazin-1-one. <formula> formula see original document page 83 </formula>

4- (pyridin-4-yl) methyl-2H-phthalazin-1-one can be synthesized by

following procedure. A suspension of 3-Hydroxy-2- (pyridin-4-yl) inden-1-one (4.85g, 21.8mmols) in hydrazine monohydrate (25ml) is heated to 110 ° C for 8 hours during which new white precipitate forms. Cooling the reaction mixture to 0 ° C, followed by filtration, washing with ethanol and diethyl ether affords 4.1 g of 4- (pyridin-4-yl) methyl-2H-phthalazin-1-one. 1H NMR (DMSO-cfe) 8.48 (d, 2H), 8.27 (d, 2H), 7.88 (m, 3H), 7.32 (d, 2H), 4.35 (s, 2H) ) .Example 3: Synthesis of Chloro-Phthalazine CompoundsExample 3a: Synthesis of 1-Chloro-4- (4-pyridylmethyl) phthalazine. <formula> formula see original document page 83 </formula> following procedure. 4- (Pyridin-4-yl) methyl-2H-phthalazin-1-one (2.73g, 11.5mmols) in acetonitrile (42ml) and HCl / dioxane (4N, 5.74ml, 23mmol) is Phosphoryl chloride (2.64 ml, 28.9 mmol) is added. The reaction mixture is stirred at 55 ° C for 30 hours, after which a solution of NaHCO3 (11.20 g) in water (137 ml) is added to the ice-cold white suspension. Stirring and filtration of this suspension yields 2.7g of 1-Chloro-4- (4-pyridylmethyl) phthalazine. 1H NMR (DMSO-d6) 8.46 (d, 2H), 8.35 (m, 2H), 8.14 (m, 2H), 7.33 (d, 2H), 4.77 (s, 2H) ) .Example 4: Synthesis of Phthalazin-1-amine CompoundsExample 4a: Synthesis of / V- (4-tert-buf / 7thiazol-2-yl) -4 - ((pyridin-4yl) methyl) phthalazin-1-amine .

N - (4-tert-yl] -thiazol-2-yl) -4 - ((pyridin-4yl) methyl) phthalazin-1-amine may be synthesized by the following procedure. A mixture of 1-Chloro-4-

<formula> formula see original document page 83 </formula>

1-Chloro-4- (4-pyridylmethyl) phthalazine can be synthesized by se- (4-pyridylmethyl) phthalazine, (100 mg, 0.39 mmol), 4-tert-bi / f / 7thiazole-2-amine (91mg , 59 mmols) and K 2 CO 3 (161 mg, 1.17 mmol) is suspended in 1 ml DMF in a microwave reaction tube, and irradiated to 170 ° C for 30 minutes. The reaction mixture is then dissolved in ethyl acetate, and washed with water and brine. Chromatography of the sample preparation using ethyl acetate / hexanes (1: 1) affords 15 mg of N - (4-tert-Î ± 7thiazol-2-yl) -4 - ((pyridin-4-yl) methyl) phthalazin-1-amine. 1H NMR (CDCl3 -dj) 8.68 (d, 1H), 8.48 (s, 2H), 7.62 (m, 2H), 7.50 (d, 1H), 7.26 (s, 2H) ), 6.44 (s, 1H), 4.25 (s, 2H), 1.32 (s, 9H).

Example 5: Synthesis of Phthalazin-1-amine-bromo Compounds

Example 5a: Synthesis of A / - (4-teA-c-bL / Wa-5-bromotiazol-2-yl) -4 - ((pyridine-2-yl)

4yl) methyl) phthalazin-1-amine.

4yl) methyl) phthalazin-1-amine may be synthesized by the following procedure. Tetrabutylammonium tribromide (116 mg, 0.24 mmol) is added to a solution of / V- (4-e / -c-uf / ftiazole). -2-yl) -4 - ((pyridin-4yl) methyl) phthalazin-1-amine (90mg, 0.24 mmol) in 5 mL of CHCl3 and the reaction mixture is stirred at room temperature for 2 hours. Chromatography of the resulting product sample preparation affords 101 mg of β- (4-tert-6i / f / 7a-5-bromothiazol-2-yl) -4 - ((pyridin-4yl) methyl) phthalazin-1-amine. 1H NMR (CDCb-d6) 8.58 (d, 1H), 8.41 (s, 2H), 7.65 (m, 2H), 7.46 (d, 1H), 7.26 (s, 2H), 4.22 (s, 2H), 1.41 (s, 9H).

Example 6: Synthesis of Phthazaz-1-amine Compounds

Example 6a: Synthesis of 2- (1- (9-pyridin-4-yl) methyl) phthalazin-4-ylamino) -4-tert

butylthiazole-5-carbonitrile.

V / PHT-1 Synthesis of 2- (1- (9-pyridin-4-yl) methyl) phthalazin-4-ylamino) -4-tert-butylthiazol-5-carbonitrile (PHT-1) can be synthesized by the following procedure:

Synthesis of A / - (4-tert-Î ± uf / 7a-5-bromotiazol-2-yl) -4 - ((pyridine. A suspension of A / - (4-tert-Î »L / 1 / 7a-5-bromotiazol-2-yl) -4 - ((pyridin-4yl) methyl) phthalazin-1-amine (20 mg, 44 mmols), Zn (CN) 2 (large excess) ePd (PPh3) 4 (3 mg, 2.5 mmols) in 1 ml DMF is irradiated under normal conditions (180 ° C for 30 min.) The resulting solution is diluted with ethyl acetate and washed with water and brine. totuene / acetone (9: 1) provides 8 mg of PHT-1. 1H NMR (DMSO-cfe) 8.90 (d, 1H), 8.49 (d, 2H), 8.27 (d, 1H), 8.07 (d, 2H), 7.33 (d, 2H), 4.71 (s, 2H), 4.51 (s, 1H), 1.49 (s, 9H). Example 6b: Synthesis of 2- (1- (9-Pyridin-3-yl) methyl) phthalazin-4-ylamino) -4-tert-butylthiazol-5-carbonitrile

<formula> formula see original document page 85 </formula> Synthesis of 2- (1- (9-Pyridin-3-yl) methyl) phthalazin-4-ylamino) -4-tert-butylthiazol-5-carbonitrile (PHT- 2) can be synthesized by the following procedure according to Scheme 2b. A mixture of 80-mg (0.44 mmol) of 2-amino-4-tert-butyl-thiazol-5-carbonitrile, 94 mg (0.36 mmol) of 1-chloro-4- (3-pyridin-3-ylmethyl) ) -phthalazine, Cul 40 mg (0.026 mmol), 53 mL (0.052 mmol, 12% / substrate) and 112 mg (0.88 mmol) of K2 CO3 in 4 mL DMF is heated to 80 ° C under irradiation. microwave for 30 minutes. After cooling, water is added and the solution extracted with ethyl acetate (E-tOAc). The organic layers are combined, washed with water and brine, and then dried over MgSO4. Evaporation of solvents followed by LC-MS purification affords 29 mg (0.104 mmol) of 2- (1- (9-Pyridin-3-yl) methyl) phthalazin-4-ylamino) -4-tert-butylthiazole-5-carbonitrile ( PHT-2) and 18.2 mg (0.044 mmol) of 4-tert-Butyl-2- [4- (pyridin-3-carbonyl) -phthalazin-1-ylamino] -thiazol-5-carbonitrile (PHT-5) as a byproduct.Example 6c: Synthesis of 2- (1- (9-Pyridin-2-yl) methyl) phthalazin-4-ylamino) -4-tert-butylthiazol-5-carbonitrile

PHT-3

Synthesis of 2- (1- (9-Pyridin-2-yl) methyl) phthalazin-4-ylamino) -4-tert-butylthiazol-5-carbonitrile (PHT-3) can be synthesized by the following procedure according to Scheme 2b as described for the synthesis of PHT-2.

Example 6d: Synthesis of 2- (1- (9-thien-3-yl) methyl) phthalazin-4-ylamino) -4-tert-butylthiazol-5-carbonitrile

<formula> formula see original document page 86 </formula> PHT-4Synthesis of 2- (1- (9-thien-3-yl) methyl) phthalazin-4-ylamino) -4-tert-butylthiazole-5-carbonitrile ( PHT-4) can be synthesized by the following procedure according to Scheme 2b as described for the synthesis of PHT-2. PHT-4 MS (ES +) 405, m / z (M + 1) 406, C21 H19 N5 S2 requires 405. Example 6e: Synthesis of 4-tert-Butyl-2-4- (pyridine-3-carbonyl) phthalazin-1 ylaminol-thiazol-5-carbonitrile

<formula> formula see original document page 86 </formula> PHT-5Synthesis of 4-tert-Butyl-2- [4- (pyridin-3-carbonyl) -phthalazin-1-ylamino] -thiazole-5-carbonitrile (PHT -5) may be synthesized by the following procedure according to Scheme 2b as described for the PHT-2 synthesis. PHT-5 MS (ES +) 414, m / z (M + 1) 415, C22H18N6OS requires 414. Example 6f: Synthesis of 4-tert-Butyl-2-4- (pyridine-4-carbonyl) -phthalazin-1- ylaminol-thiazol-5-carbonitrile

<formula> formula see original document page 86 </formula> PHT-6

Synthesis of 4-tert-Butyl-2- [4- (pyridin-4-carbonyl) -phthalazin-1-ylamino] -thiazol-5-carbonitrile (PHT-6) can be synthesized by the following procedure according to Scheme 2b as described for PHT-2 synthesis. PHT-6 MS (ES +) 414, m / z (M + 1) 415, C22 H18 N6 OS requires 414. Example 6a: Synthesis of 4-tert-Butyl-2-4- (5-fluoro-pyridin-3-ylmethyl) - phthalazin-1-ylaminol-thiazol-5-carbonitrile

<formula> formula see original document page 87 </formula>

Synthesis of 4-tert-Butyl-2- [4- (5-fluoro-pyridin-3-ylmethyl) -phthalazin-1-one

ylamino] thiazole-5-carbonitrile (PHT-7) can be synthesized by the following procedure according to Scheme 2b. A mixture of 2-amino-4-tert-butyl-thiazol-5-carbonitrile, 1-chloro-4- (5-fluoro-pyridin-3-ylmethyl) -phthalazine, Cul (0.1 mol equiv), K3PO4 ( 3 mol equiv) and N, N, N \ N'-tetramethyl-ethane-1,2-diamine (5 mol equiv) in dioxane is heated to 180 ° C under tri-microwave irradiation for 30 minutes. After cooling, water is added and the solution is extracted with ethyl acetate (EtOAc). The organic layers are combined, washed with water and brine, then dried over MgSO4. Evaporation of solvents followed by purification by LC-MS provides 4-tert-Butyl-2- [4- (5-fluoro-pyridin-3-ylmethyl) -phthalazin-1-ylamino] -thiazol-5-carbonitrile (PHT) -7). MS: (ES +) 419 m / z (M + 1) + C 22 H 20 FN 6 S requires 419. Example 6h: Synthesis of 4-tert-Butyl-2- (4-formyl-phthalazin-1-ylamino) -thiazol-5-carbonitrile.

Carbonitrile (PHT-8) can be synthesized by the following procedure according to Scheme 5. PHT-8 is prepared by a standard dichlorophthalazine and boronic E-styryl Su-zuki bond using Pd (PPh3) 4 eK3PO4 in refluxing dioxane to provide 1-chloro-4-styryl phthalazine. Chloride is then substituted with 2-amino-4-tert-butyl-thiazol-5-carbonitrile using the copper binding conditions described above in the synthesis of PHT-6 to provide 4-tert-butyl-2- (4). (styryl-phthalazin-1-ylamino) -thiazol-5-carbonitrile: MS: (ES +) 412 m / z (M + 1) + C24H22N5S requires 412. PHT-8 is obtained by 4-tert-butyl-2-ozonolysis (4-Styryl-phthalazin-1-ylamino) -thiazol-5-carbonitrile in dichloromethane / methanol (3/1) at -78 ° C, quenching with Me2S and purification by silica gel chromatography: MS: (ES +) 338

Synthesis of 4-tert-Butyl-2- (4-formyl-phthalazin-1-ylamino) -thiazol-5-m / z (M + 1) + C 17 H 16 N 5 OS requires 338.

Example 6i: Synthesis of 4-tert-Butyl-2-4- (cyano-phenyl-methyl) -phthalazin-1-ylaminol-thiazol-5-carbonitrile.

Carbonitrile (PHT-9) can be synthesized by the following procedure according to Scheme 8. Phenyl acetonitrile is mixed with tBuOK dichlorophthalazine and heated. The resulting compound (1-chloro-4- (cyano-phenyl-methyl) -phthalazine) is attached to 2-amino-4-tert-butyl-thiazole-5-carbonitrile using Cul (0.1 mol equiv), K3PO4 ( 3 mo equiv) and N, N, N \ N'-tetramethyl-ethane-1- (2-diamine (5 mo equiv) in dioxane at 180 ° C under microwave irradiation for 30 minutes. After cooling water is added and the solution is extracted with ethyl acetate (EtOAc) The organic layers are combined, washed with water and brine, then dried over MgSO4. E-evaporation of solvents followed by purification by LC-MS affords 4-tert-Butyl-2 - [4- (Cyano-phenyl-methyl) -phthalazin-1-ylamino] -thiazol-5-carbonitrile (PHT-9): MS: (ES +) 426 m / z (M + 1) + C 24 H 21 N 6 S requires 426. Example 6i: Synthesis of 4-tert-Butyl-2-4- (pyridin-3-ylmethoxy) phthalazin-1-ylaminol-thiazol-5-carbonitrile

thiazole-5-carbonitrile (PHT-10: MS: (ES +) 417 m / z (M + 1) + C 22 H 21 N 6 OS requires

417) is obtained as described for the synthesis of PHT-9.

Example 6k: Synthesis of 4-tert-Butyl-2- (4- (pyridin-3-ylmethyl) -amino1-phthalazin-1- <formula> formula see original document page 88 </formula> ylamino) -thiazole-5 -carbonitrile

Synthesis of 4-tert-Butyl-2- {4 - [(pyridin-3-ylmethyl) -amino] -phthalazin-1-ylamino} -thiazol-5-carbonitrile (PHT-11: MS: (ES +) 416 m / z (M + 1) + C 22 H 22 N 7 S

4-tert-Butyl-2- [4- (cyano-phenyl-methyl) -phthalazin-1-ylamino] -thiazol-5- <formula> formula see original document page 88 </formula> Synthesis of 4-tert-Butyl -2- [4- (pyridin-3-ylmethoxy) -phthalazin-1-ylamino] -require 416)) is obtained as described for the synthesis of pht-9. Example 61: Synthesis of 4-tert-Butyl-2 -4- (pyridin-2-ylmethoxy) -phthalazin-1-ylamino-1-thiazol-5-carbonitrile

<formula> formula see original document page 89 </formula> nc pht-12Synthesis of 4-tert-Butyl-2- [4- (pyridin-2-ylmethoxy) -phthalazin-1-ylamino] -thiazole-5- carbonitrile (pht-12: MS: (ES +) 417 m / z (M + 1) + C 22 h 21 N 6 OS requires 417)) is obtained as described for the synthesis of pht-9. Example 6m: Synthesis of 4-tert-Butyl-2 -4- (pyridin-4-ylmethoxy) -phthalazin-1-ylaminol-thiazol-5-carbonitrile

<formula> formula see original document page 89 </formula> Synthesis of 4-tert-Butyl-2- [4- (pyridin-4-ylmethoxy) -phthalazin-1-ylamino] -thiazol-5-carbonitrile (pht-13 : MS: (ES +) 417 m / z (M + 1) + C 22 H 21 N 6 OS requires 417)) is obtained as described for the synthesis of pht-9. Example 6n: Synthesis of 4-tert-Butyl-2-f4- (pyridin -4-ylmethoxy) -phthalazin-1-ylaminol-thiazol-5-carbonitrile

-KrY

, n ^, ch3

PHT-14

Synthesis of 4-tert-Butyl-2- [4- (pyridin-4-ylmethoxy) -phthalazin-1-ylamino] -thiazol-5-carbonitrile (PHT-14: MS: (ES +) 431 m / z (M + 1) + C 23 H 23 N 6 OS requires 431) is obtained as described for the synthesis of PHT-9. Example 6: Synthesis of 2- (1- (9-pyridin-4-yl) methyl) phthalazin-4-yl-A / -acetylamino ) -4-tert-Butylthiazole-5-carbonitrile

PHT-15

2- (1- (9-pyridin-4-yl) methyl) phthalazin-4-yl-N -acetylamino) -4-tert-butylthiazol-5-carbonitrile (PHT-15) may be synthesized according to Es 12. To a solution of 2- (1- (9-pyridin-4-yl) methyl) phthalazin-4-ylamino) -4-tert-butylthiazol-5-carbonitrile (10 mg, 0.025 mmol), and 11.5 µl (3.0eq.) of Et 3 N in 1 ml of dry CH 2 Cl 2 is added 5.8 ml (3.0 eq.) of acetyl chloride. The mixture is stirred for 12 hours at room temperature and solvents are then removed before purification of the crude product through LC-MS.

Example 7: Pharmaceutical CompositionsExample 7a: Parenteral Composition

To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100 mg of a water soluble salt of a compound of Formula (1) is dissolved in DMSO and then mixed with 10 mL of 0.9% sterile saline. The mixture is incorporated into a dosage unit form suitable for injection administration.Example 7b: Oral Composition

To prepare a pharmaceutical composition for oral release, 100 mg of a compound of Formula (1) is mixed with 750 mg of lactose. The mixture is incorporated into an oral dosage unit form, such as a hard gelatin capsule. which is suitable for oral administration.

Example 8: Mineralocorticoid Receptor Antagonism Functional Test

The antagonist activity of the mineralocorticoid receptors of the compounds is determined in a reporter system of two mammalian hybrids. The mineralocorticoid receptor N-terminus (MR-NT, amino acid coding sequence 1-597) is fused to the VP16 gene activation domain. The mineralocorticoid receptor ligand binding domain (MR-LBD,

sequence encoding amino acids 672-984) is fused to the binding domain

.i

DNA synthesis of the yeast gene Gal4. The mineralocorticoid receptor gene is cloned from a comPCR human kidney cDNA library.

The test is performed on 384-well slides. Briefly, 293T cells (ATCC) are transfected with expression vectors for Gal4-MR-LBD and VP16-MR NT, and a luciferase reporter vector containing Gal4 binding frequency (pG5-Luc). Cells are laminated to 384 well slides immediately after transfection (approximately 3X10 4 cells / well in 50 nJ of medium). The medium is supplemented with 3% charcoal dextran-treated fetal bovine serum (Hyclone). Twenty four hours after transfection, compounds prepared in DMSO are transferred to cells. Cells are then stimulated with 0.4 nM final aldosterone concentration (Acros) and incubated at 37 ° C for another 24 hours before luciferase activity is tested with 20 µl Bright-GIo (Promega) using a luminometer (CLIPR). Luciferase expression is used as an indicator of aldosterone-induced mineralo-corticoid receptor transactivation. Each compound is tested in duplicates with 12 concentration titration. IC50 values (defined as the concentration of test compound required to antagonize 50% of aldosterone-induced mineralocorticoid receptor activity) are determined from the dose response curve.

Example 9: Functional Test of Glycocorticoid Receptor Antagonism

The antagonist activity of glucocorticoid receptors in the compounds is determined in a two mammalian hybrid reporter system. The glucocorticoid receptor ligand binding domain (GR-LBD, amino acid coding sequence 541-778) is fused to the DNA deletion domain of the yeast gene Gal4. The glucocorticoid receptor gene is cloned from a PCR human pulmonary cDNA library.

The assay is performed on 384-well slides: COS-7 (ATCC) cells are transfected with expression vectors for Gal4-GR-LBD and a luciferase reporter vector containing Gal4 binding sequence (pG5-Luc). Cells are laminated to 384-well slides immediately after transfection (approximately 8000 cells / well in 50 µl medium). The medium is supplemented with 3% fetal bovine serum treated with charcoal dextran (Hyclone). Twenty-four hours after transfection, compounds prepared in DMSO are transferred to cells. Ascells are then stimulated with 10 nM final concentration of hexamethasone (Sigma) and incubated at 37 ° C for another 24 hours before luciferase activity is tested with 20 nl Bright-GIo (Promega) using a luminometer (CLIPR). Luciferase expression is used as an indicator of dexa-metasone-induced glucocorticoid receptor transactivation. Each compound is tested in duplicates with a titration of 12 concentrations. IC 50 values (defined as the concentration of test compound required to antagonize 50% of dexamethasone-induced glucocorticoid receptor activity) are determined from the dose response curve.

Example 10: Functional Test of Proqesterone Receptor Antagonism

The progesterone receptor antagonist activity of the compounds is determined by progesterone-induced alkaline phosphatase activity in the T-47D cell line (ATCC). In T-47D breast cancer cells, progesterone specifically induces de novo synthesis of membrane-associated alkaline phosphatase in a time and dose dependent manner (Di Lorenzo et al., Cancer Research, 51: 4470-4475 ( 1991)). The enzymatic activity of alkaline phosphatase can be measured with a chemiluminescent substrate, such as CSPD® (Applied Biosys-tems).

The test is performed on 384-well slides. Briefly, T-47D cells are laminated to 384 well slides at a density of approximately 2.5 X 10 4 cells / well in 50 µl medium supplemented with 10% fetal bovine serum. Twenty-four hours later, the hate is aspirated. New medium that is free of phenol red and serum is added to the cells. Compounds prepared in DMSO are transferred to ascells. Cells are then stimulated with 3 nM final progesterone concentration (Sigmaj and incubated at 37 ° C for another 24 hours before alkaline phosphatase is tested with 25 µl CSPD® (Applied Biosystems) using a luminometer (CLIPR). Alkaline phosphatase is used as an indicator of progesterone-induced progesterone receptor transactivation Each compound is tested in duplicates with a titration of 12 concentrations IC50 values (defined as the concentration of test compound required to antagonize 50% of progesterone-induced progesterone receptors) are determined from the dose response curve.

Example 11: Functional Test of Androgen Receptor Antagonism Compound androgen receptor antagonist activity is determined with the MDA-Kb2 cell line (ATCC), which stably expresses the reporter MMTV luciferase. The MMTV promoter is a mouse mammary tumor viral promoter that contains androgen receptor response elements. MDA-kb2 cells are derived from MDA-MB-453 cells, which have been shown to express high levels of functional endogenous androgen receptor (Wilson et al., Toxicological Sciences, 66: 69-81 (2002)). In stimulation with anhydrogenic receptor ligands such as dihydrotestosterone, the reporter MMTV luciferase may be activated.

The test is performed on 384-well slides. Briefly, MDA-kb2 cells are laminated to 384-well slides at a density of approximately 2.4 X 10 4 cells / well in 50 µl of medium. The medium is supplemented with 5% fetal bovine serum treated with charcoal-dextran (Hyclone). Twenty-four hours later, compounds prepared in DMSO are transferred to the cells. Cells are then stimulated with 0.3 nM final dihydrotestosterone (Sigma) concentration and incubated at 37 ° C for another 24 hours prior to luciferase activity assayed with 20 µl Bright-GIo (Promega) using a luminometer ( CLI-PR). Luciferase expression is used as an indicator of dihydrotestosterone-induced androgen receptor transaction. Each compound is tested in duplicates with a titration of 12 concentrations. IC50 values (defined as the concentration of test compound required to antagonize 50% of dihydrotestosterone-induced androgen receptor activity) are determined from the dose response curve.

Typical test compounds were evaluated using the functional tests described above for the different steroidal hormone nuclear receptors. The ability of typical test compounds to antagonize 50% of the specified steroid hormone nuclear receptors is shown in Table 2 as a range of IC50 values. Table 2: IC50 ranges for required test compounds. 50% of the specified steroid hormone nuclear receptors. A => 10

B = 1 -10C = 0.1 - 1D = <0.1 <table> table see original document page 94 </column> </row> <table>

It is understood that the examples and embodiments described herein,

For the purposes of the patent application, it is for illustrative purposes only and that various modifications or changes in the light of the same are suggested to persons skilled in the art and should be included within the spirit and scope of this application and the scope of the appended claims. All publications, patents, and patent applications cited herein, in this application

patent application, are hereby incorporated by reference for all purposes.

Claims (58)

A compound having the structure of Formula (1) wherein: (a) A is CR3 = CR4, N = CR4, CR3 = N, or CR3R3; Q is CR 5 = CR 6, N = CR 6, CR 5 = N, or C R 6 R 6 '; L is CR9 or N; Z is CR8 or N (b) R1 is selected from the group consisting of H, OH, NH2, SH, NO2, CN, and an optionally substituted moiety selected from -Lralkyl, -Lrcycloalkyl, -Lrheteroalkyl, -Lrhaloalkyl, -Larryl , -Heterocycloalkyl, and -Lrheteroaryl, wherein Li is selected from a bond, O, NH, S, -C (O) -, -C (S) -, -C (O) 0-, -C ( O) NH-, -S (O) -, -S (O) 2, and -S (O) NH- wherein said optional substituents are selected from halogen, OH, C1-6 alkyl, Cvealcoxy, halo (C) R2 is selected from the group consisting of H and an optionally substituted moiety selected from -L2-alkyl, -L2-cycloalkyl, -L2-heteroalkyl, -L2-C1-6 alkyl and halo-d-alkoxy; haloalkyl, -L2-aryl, -L2-heterocycloalkyl, and -L2-heteroaryl, wherein L2 is selected from a bond, -C (0) -, -C (S) -, - C (0) 0-, - C (O) NH-, -S (O) -, -S (O) 2, and -S (O) NH-; wherein said optional substituents are selected from halogen, OH, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl, halo-C1-6 alkoxy, aryl, haloaryl, and heteroaryl; ', R4, R5, Re, Re-, Rs and R9 are independently selected from H, halogen, OH, NH2, SH, NO2, CN, and an optionally substituted moiety selected from -L3-alkyl, -L3-cycloalkyl, -L3-heteroalkyl, -U-haloalkyl, -L3-aryl, -L3-heterocycloalkyl, and -L3-heteroaryl, wherein L3 is selected from a bond, O, NH, S, -C (O ) -, -C (S) -, -C (O) 0-, -C (O) NH-, -S (O) -, -S (O) 2, and -S (O) NH-; wherein said optional substituents are selected from halogen, OH, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl and halo-d-alkoxy; R2 and R3 together form an optionally substituted 4 to 8 membered ring; wherein the ring is heterocyclic, cycloalkyl, or aryl: (d) R7 is selected from the group consisting of H, halogen, and an optionally substituted moiety selected from -UH, -U-alkyl, -U-cycloalkyl, -U- heteroalkyl, -U-haloalkyl, -U-aryl, -U-heterocycloalkyl, and -U-heteroaryl, wherein U is selected from a bond, O, NH, OCH 2) NHCH 2, S, d-C 6 alkylene, -C (O) -, -C (S) -, -C (O) 0-, -C (O) NH-, -S (O) -, -S (O) 2, and -S (O) NH- ; wherein said optional substituents are selected from H, halogen, cyano, OH, d-C6 alkyl, C1 -C6 haloalkyl, d-6 alkoxy, halo-d-6 alkoxy, dd thioalkyl, C1-C4 thioalkoxy aryl, aryl, halo aryl, heteroaryl, halo heteroaryl, and NR10 Rn; (e) R10 and Rn are independently selected from d-C6 alkyl and d-C6 haloalkyl, or R10 and Rn together form an optionally substituted 3 to 8 membered heterocyclic ring; (f) X is O, NR2 or S (g) Y is N; provided that when L is N and Z is C, each of R 1, R 2, R 3, R 4 R 10, Re, R 7, R 8 and R 9 is not H, or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, metabolite. pharmaceutically acceptable, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof. A compound according to claim 1, wherein L is N. A compound according to claim 1, wherein Z is N. A compound according to claim 1, having the structure: A compound according to claim 1, having the structure: A compound according to claim 1 having the structure: <formula> formula see original document page 97 </formula> A compound according to claim 1, having the structure: <formula> formula see original document page 97 </formula> A compound according to claim 7, having the structure: <formula> formula see original document page 97 </formula> A compound according to claim 8, having the structure: <formula> formula see original document page 97 </formula> A compound according to claim 1, wherein A is CR 3 = CR 4 and Q is N = CR 6. A compound according to claim 1, wherein A is CR 3 = N and Q is CR 5 = CR 6. A compound according to claim 1, wherein the compound having the structure of Formula (1) is selected from <formula> formula see original document page 97 </formula> A compound according to claim 1, wherein the compound having the structure of Formula (1) is selected from <formula> formula see original document page 98 </formula> A method for modulating the activity of at least one steroid hormone receptor comprising comprising contacting at least one steroid hormone nuclear receptor with a compound having the structure of Formula (1), <formula> formula see original document page 99 </ formula (a) A is CR3 = CR4, N = CR4) CR3 = N, or CR3R3-; Q is CR 5 = CR 6, N = CR 6, CR 5 = N, or C R 6 R 6 '; L is CR9 or N; Z is CR 8 or N (b) R 1 is selected from the group consisting of H, OH, NH 2, SH, NO 2, CN, and an optionally substituted moiety selected from -L 1-alkyl, -L-cycloalkyl, -L-heteroalkyl, Lrhaloalkyl, -l_raryl, -Lrheterocycloalkyl, and -Lrheteroaryl, wherein L is selected from a bond, O, NH, S, -C (O) -, -C (S) -, -C (0) 0 -, -C (O) NH-, -S (O) -, -S (O) 2, and -S (O) NH- wherein said optional substituents are selected from halogen, OH, d- (c) R2 is selected from the group consisting of H and an optionally substituted moiety selected from -L2-alkyl, -L2-cycloalkyl, - (C1-6 alkoxy, halo-C1-6 alkyl and halo-C1-6 alkoxy); L2-heteroalkyl, -L2-haloalkyl, -L2-aryl, -L2-heterocycloalkyl, and -L2-heteroaryl, wherein L2 is selected from a bond, -C (O) -, -C (S) -, - C (0) O-, -C (O) NH-, -S (O) -, -S (O) 2, and -S (O) NH-; wherein said optional substituents are selected from halogen, OH, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl, halo-C1-6 alkoxy, aryl, halo aryl, and heteroaryl; , R4, R5, Re, Re-, Rs and R9 are independently selected from H, halogen, OH, NH2, SH, NO2, CN, and an optionally substituted moiety selected from -L3-alkyl, - L3-cycloalkyl, -L3-heteroalkyl, -L3-haloalkyl, -L3-aryl, -L3-heterocycloalkyl, and -L3-heteroaryl, wherein L3 is selected from a bond, O, NH, S, -C (O) -, -C (S) -, -C (O) 0-, -C (O) NH-, -S (O) -, -S (O) 2, and -S (O) NH-; wherein said optional substituents are selected from halogen, OH, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl and halo-C1-6 alkoxy, R2 and R3 together form an optionally substituted 4-8 membered ring; wherein the ring is heterocyclic, cycloalkyl, or aryl: (d) R7 is selected from the group consisting of H, halogen, and an optionally substituted moiety selected from -UH, -U-alkyl, -U-cycloalkyl, -U- heteroalkyl, -U-haloalkyl, -U-aryl, -U-heterocycloalkyl, and -U-heteroaryl, wherein U is selected from a bond, O, NH, OCH2, NHCH2) S, C1 -C6 alkylene, -C (O ) -, -C (S) -, -C (O) 0-, -C (O) NH-, -S (O) -, -S (O) 2, and -S (O) NH-; wherein said optional substituents are selected from H, halogen, cyano, OH, C1-C6 alkyl, C1-C6haloalkyl, C1-6 alkoxy, halo-C1-6 alkoxy, C1 -C4 thioalkyl, C1 -C4 thioalkoxy aryl, aryl, halo aryl , heteroaryl, halo heteroaryl, and NR10 R11: (e) R10 and Rn are independently selected from d-C6 alkyl and d-C6 haloalkyl, or R10 and Rn together form an optionally substituted 3 to 8 membered heterocyclic ring; (f) X is O, N or S. (g) Y is O, N or S. or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically acceptable metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate of same. The method of claim 14, wherein the compound of Formula (1) directly contacts at least one nuclear steroid hormone receptor. The method of claim 15, wherein the contact occurs in vitro. The method of claim 15, wherein the contact occurs in vivo. The method of claim 14, wherein L is N. The method of claim 14, wherein Z is N. The method according to claim 14, wherein the compound has the structure: <formula> formula see original document page 101 </formula> A method according to claim 14, wherein the compound has the structure: <formula> formula see original document page 101 </formula> The method according to claim 14, wherein the compound has the structure: <formula> formula see original document page 101 </formula> The method of claim 14, wherein the compound has the structure: <formula> formula see original document page 102 </formula> A method according to claim 23, wherein the compound has the structure: <formula> formula see original document page 0 </formula> The method of claim 24, wherein the compound has the structure: CR3 = CR4 and Q is N = CR6. The method of claim 14, wherein A is The method of claim 14, wherein A is CR 3 = N and Q is CR 5 = CR 6. The method of claim 14, wherein the compound having the structure of Formula (1) is selected from Rs. The method according to claim 14, wherein the compound having the structure of Formula (1) is selected from <formula> formula see original document page 102 </formula> <formula> formula see original document page 103 < / formula> <formula> formula see original document page 104 </formula> A pharmaceutical composition comprising at least one compound having the structure of Formula (1), wherein, (a) A is CR3 = CR4, N = CR4, CR3 = N, or CR3R3 '; Q is CR 5 = CR 6) N = CR 6, CR 5 = N, or C R 6 R 6 '; L is CR9 or N; Z is CR8 or N; (b) Rt is selected from the group consisting of H, OH, NH2, SH, NO2, CN, and an optionally substituted moiety selected from -Lralquila, -Lrcycloalkyl, -Lrheteroalkyl, -Lrhaloalkyl, -Lrarila , -Heterocycloalkyl, and -Lrheteroaryl, wherein Li is selected from a bond, O, NH, S, -C (O) -, -C (S) -, -C (O) 0-, -C ( O) NH-, -S (O) -, -S (O) 2, and -S (O) NH- wherein said optional substituents are selected from halogen, OH, C1-6 alkyl, C1-6. (C) R2 is selected from the group consisting of H and an optionally substituted moiety selected from -L2-alkyl, -L2-cycloalkyl, -L2-heteroalkyl, (6) alkoxy, halo-C1-6 alkyl and halo-alkoxy; , -L2-haloalkyl, -L2-aryl, -L2-heterocycloalkyl, and -L2-heteroaryl, wherein L2 is selected from a bond, -C (O) -, -C (S) -, -C (O) O-, -C (O) NH-, -S (O) -, -S (O) 2, and -S (O) NH-; wherein said optional substituents are selected from halogen, OH, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl, halo-C1-6 alkoxy, aryl, halo aryl, and heteroaryl; Ffe, R3 ', R4, Rs, Re, R &, Re and R9 are independently selected from H, halogen, OH, NH2, SH, NO2, CN, and an optionally substituted moiety selected from -U-alkyl, - L3-cycloalkyl, -L3-heteroalkyl, -L3-haloalkyl, -U-aryl, -U-heterocycloalkyl, and -L3-heteroaryl, wherein U is selected from a bond, O, NH, S, -C (O) -, -C (S) -, -C (O) 0-, -C (O) NH-, -S (O) -, -S (O) 2, and -S (O) NH-; wherein said optional substituents are selected from halogen, OH, C1-6 alkyl, C1-6 alkoxy, halo-C1-4 alkyl and halo-C1-6 alkoxy; R2 and R3 together form an optionally substituted 4- to 8-membered ring; wherein the ring is heterocyclic, cycloalkyl, or aryl: (d) R 7 is selected from the group consisting of H, halogen, and an optionally substituted moiety selected from -UH, -U-alkyl, -1,4-cycloalkyl, -U- heteroalkyl, -L4-haloalkyl, -L4-aryl, -L4-heterocycloalkyl, and -U-heteroaryl, wherein L4 is selected from a bond, O, NH, OCH2, NHCH2, S, CrC6alkylene, -C (O ) -, -C (S) -, -C (O) 0-, -C (O) NH-, -S (O) -, -S (O) 2, and -S (O) NH-; wherein said optional substituents are selected from H, halogen, cyano, OH, C1 -C6 alkyl, C1 -C6 alkoxy, C1-6 alkoxy, halo C1-6 alkoxy, C1 -C4 thioalkyl, C1 -C4 thioalkoxy aryl, aryl, halo aryl, heteroaryl, halo heteroaryl, and NR10R11; (e) R10 and Rn are independently selected from d-C6 alkyl and d-C6 haloalkyl, or R10 and Rn together form a 3 to 8 membered heterocyclic ring optionally (f) X is O, N or S; (g) Y is O, N or S; or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically acceptable metabolite, pharmaceutically acceptable prodrug, or pharmaceutically solvate. acceptable in combination with one or more suitable excipients. The pharmaceutical composition of claim 30, wherein the one or more excipients are suitable for parenteral administration. The pharmaceutical composition of claim 30, wherein the one or more excipients are suitable for oral administration. The pharmaceutical composition of claim 30, wherein the one or more excipients are suitable for ophthalmic administration. The pharmaceutical composition of claim 30, wherein L is N. The pharmaceutical composition of claim 30, wherein Z is N. The pharmaceutical composition of claim 30, wherein the compound has the structure: <formula> formula see original document page 106 </formula> The pharmaceutical composition of claim 30, wherein the compound has the structure: <formula> formula see original document page 106 </formula> The pharmaceutical composition of claim 30, wherein the compound has the structure: <formula> formula see original document page 106 </formula> The pharmaceutical composition of claim 30, wherein the compound has the structure: The pharmaceutical composition of claim 39, wherein the compound has the structure: <formula> formula see original document page 107 </formula> The pharmaceutical composition of claim 40, wherein the compound has the structure: <formula> formula see original document page 107 </formula> The pharmaceutical composition of claim 30, wherein A is CR3 = CR4 and Q is N = CR6. The pharmaceutical composition of claim 30, wherein A is CR3 = N and Q is CR5 = CR6. The pharmaceutical composition of claim 30, wherein the compound having the structure of Formula (1) is selected from <formula> formula see original document page 107 </formula> The pharmaceutical composition of claim 30, wherein the compound having the structure of Formula (1) is selected from <formula> formula see original document page 107 </formula> (2), <formula> formula see original document page 107 </formula> (3), <formula> formula see original document page 108 </formula> <formula> formula see original document page 109 </formula> 46. A method of treating a disease in an animal in which the modulation of nuclear steroid hormone receptor activities can prevent, inhibit or ameliorate disease pathology and / or symptomatology, the method of which comprises administering to the animal a third amount. - peutically effective of a compound having the structure of Formula (1), wherein, (a) A is CR3 = CR4) N = CR4) CR3 = N, or CR3R3s Q is CR 5 = CR 6> N = CR 6, CR 5 = N, or C R 6 R 6 '; L is CR9 or N; (B) R1 is selected from the group consisting of H, OH, NH2, SH, NO2, CN, and an optionally substituted moiety selected from -1H-alkyl, -Lrdcloalkyl, -L1-heteroalkyl, Lrhaloalkyl, -Larryl, -Lrheterocycloalkyl, and -Lrheteroaryl, wherein U is selected from a bond, O, NH, S, -C (O) -, -C (S) -, -C (0) 0- -C (O) NH-, -S (O) -, -S (O) 2, and -S (O) NH-, wherein said optional substituents are selected from halogen, OH, C1-6. (C1-6 alkoxy, halo-C1-4 alkyl and halo-C1-6 alkoxy) (c) R2 is selected from the group consisting of H and an optionally substituted moiety selected from -L2-alkyl, -L2 -cycloalkyl, -L2-heteroalkyl, -L2-haloalkyl, -L2-aryl, -L2-heterocycloalkyl, and -L2-heteroaryl, wherein L2 is selected from a bond, -C (0) -, -C (S) -, -C (O) 0-, -C (O) NH-, -S (O) -, -S (O) 2, and -S (O) NH-; wherein said optional substituents are selected from halogen, OH, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, aryl, haloaryl, and heteroaryl; , R4, Rs, Re, Re ', Re and R9 are independently selected from H, halogen, OH, NH2, SH, NO2, CN, and an optionally substituted moiety selected from -U-alkyl, - 1-3-cycloalkyl, -L3-heteroalkyl, -L3-haloalkyl, -L3-aryl, -L3-heterocycloalkyl, and -L3-heteroaryl, wherein L3 is selected from a bond, O, NH, S, -C (O) -, - C (S) -, -C (O) 0-, -C (O) NH-, -S (O) -, -S (O) 2, and -S (O) NH-; wherein said optional substituents are selected from halogen, OH, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl and halo-C1-6 alkoxy; R2 and R3 together form an optionally substituted 4 to 8 membered ring; wherein the ring is heterocyclic, cycloalkyl, or aryl; (d) R 7 is selected from the group consisting of H, halogen, and an optionally substituted moiety selected from -UH, -U-alkyl, -U-cycloalkyl, -U-heteroalkyl , -L4-haloalkyl, -L4-aryl, -U-heterocycloalkyl, and -U-heteroaryl, wherein U is selected from a bond, O, NH, OGH2, NHCH2, S, C1 -C6 alkylene, -C (O) -, -C (S) -, -C (O) 0-, -C (O) NH-, -S (O) -, - S (O) 2, and -S (O) NH-; wherein said optional substituents are selected from H, halogen, cyano, OH, C1 -C6 alkyl, C1 -C6 haloalkyl, d-alkoxy, halo C1-6 alkoxy, C1 -C4 thioalkyl, C1 -C4 thioalkoxy aryl, aryl, halo aryl, heteroaryl, haloheteroaryl, and NR10 R11: (e) R10 and Rn are independently selected from C1 -C6 alkyl and C1-C6 haloalkyl, or R10 and Rn together form an optionally substituted 3 to 8 membered heterocyclic ring; (f) X is O, N or S. (g) Y is O, N or S. or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically acceptable metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate of same. The method of claim 46, wherein the steroid hormone nuclear receptor is selected from the group consisting of a glucocorticoid receptor, a mineralocorticoid receptor, an androgen receptor, an estrogen receptor, and a progesterone receptor. A method according to claim 47 further comprising administering a therapeutically effective amount of a second substance, wherein the second substance is used to treat a disease or condition selected from the group consisting of hypokalemia, hypertension, congestive heart failure, renal failure, in particular chronic renal failure, restenosis, atherosclerosis, syndrome X, obesity, nephropathy, post-myocardial infarction, coronary heart disease, increased collagen formation, fibrosis and remodeling after hypertension and endothelial dysfunction. A method according to claim 48, wherein the second substance is selected from the group consisting of an antiobesity agent, an antihypertensive agent, an inotropic agent, a polypidemic agent, an enzyme inhibitor. angiotensin converter (ACE), a membrane pump Na-K-ATPase inhibitor, a neutral endopeptidase (NEP) inhibitor, an ACE / NEP inhibitor, an angiotensin II antagonist, a D receptor blocker -adrenergics, an inotropic agent, a calcium channel blocker, and a 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA) inhibitor. The method of claim 47, wherein the compound of Formula (1) is administered before the second substance. A method according to claim 47, wherein the compound of Formula (1) is administered with the second substance. The method of claim 47, wherein the compound of Formula (1) is administered after the second substance. The method of claim 51, wherein the compound of Formula (1) and the second substance are administered in the same pharmaceutical composition. 54. Use of a compound having the structure of Formula (1) in the manufacture of a medicament for treating a disease in an animal in which the activity of nuclear steroid hormone receptors contributes to disease pathology and / or symptomatology, (a) A is CR3 = CR4, N = CR4, CR3 = N, or CR3R3 '; Q is CR5 = CR6) N = CR6, CR5 = N, or C R6R &; L is CR9 or N; (B) R1 is selected from the group consisting of H, OH, NH2, SH, NO2, CN, and an optionally substituted moiety selected from -U-alkyl, -Lcycloalkyl, -Lrheteroalkyl, -Lrhaloalkyl, -Li-aryl, -Lrheterocycloalkyl, and -Lrheteroaryl, wherein Li is selected from a bond, O, NH, S, -C (O) -, -C (S) -, -C (0) 0- -C (O) NH-, -S (O) -, -S (O) 2, and -S (O) NH- wherein said optional substituents are selected from halogen, OH, C1-6 alkyl (C1-6 alkoxy, halo-C1-6 alkyl and halo-C1-6 alkoxy) (c) R2 is selected from the group consisting of H and an optionally substituted moiety selected from -L2-alkyl, -L2-cycloalkyl, 1,2-heteroalkyl, -L2-haloalkyl, -L2-aryl, -L2-heterocycloalkyl, and -L2-heteroaryl, wherein L2 is selected from a bond. -C (O) -, -C (S) -, -C (0) O-, -C (O) NH-, -S (O) -, -S (O) 2, and -S (O) NH-; wherein said optional substituents are selected from halogen, OH, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl, halo-C1-6 alkoxy, aryl, halo aryl, and heteroaryl; , R3s R4, R5, Re, Res Rs and R9 are independently selected from H, halogen, OH, NH2, SH, NO2> CN, and an optionally substituted moiety selected from -L3-alkyl, -L3 -cycloalkyl, -L3-heteroalkyl, -L3-haloalkyl, -L3-aryl, -L3-heterocycloalkyl, and -L3-heteroaryl, wherein L3 is selected from a bond, O, NH, S, -C (O) - -C (S) -, -C (O) 0-, -C (O) NH-, -S (O) -, -S (O) 2, and -S (O) NH-; wherein said optional substituents are selected from halogen, OH, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl and halo-C1-6 alkoxy, R2 and R3 together form an optionally substituted 4-8 membered ring; wherein the ring is heterocyclic, cycloalkyl, or aryl, wherein: (d) R7 is selected from the group consisting of H, halogen, and an optionally substituted moiety selected from -UH, -U-alkyl, -U-cycloalkyl, -U-heteroalkyl, -U-haloalkyl, -U-aryl, -U-heterocycloalkyl, and -U-heteroaryl, wherein U is selected from a bond, O, NH, OCH 2> NHCH 2, S, C 1 -C 6 alkylene -C (O) -, -C (S) -, -C (O) 0-, -C (O) NH-, -S (O) -, -S (O) 2, and -S (O ) NH-; wherein said optional substituents are selected from H, halogen, cyano, OH, C1 -C6 alkyl, C1 -C6 haloalkyl, d-alkoxy, halo C1-6 alkoxy, C1 -C4 thioalkyl, C1 -C4 thioalkoxy aryl, aryl, halo aryl, heteroaryl, (e) R10 and Rn are independently selected from C1 -C6 alkyl and d-C6 haloalkyl, or R10 and Rn together form an optionally substituted 3 to 8 membered heterocyclic ring; (f) X is O (G) Y is O, N or S. or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof. Use according to claim 54, wherein the steroid hormone nuclear receptor is selected from the group consisting of a glucocorticoid receptor, a mineralocorticoid receptor, an androgen receptor, an estrogen receptor, and a progesterone receptor. A method of preparing the compound as defined in claim 1 having the structure of Formula (1), comprising mixing a compound of Formula (D): formula (D) ) with a compound having the structure: H under suitable reaction conditions. A method for preparing the compound as defined in claim 1 having the structure of Formula (1), comprising mixing a compound of Formula (E): bromination agent under suitable reaction conditions, followed by mixing the resulting compound with a cyanination agent under suitable reaction conditions. A method for preparing the compound according to claim 57 having the structure of Formula (E), comprising mixing a compound of Formula (D): a formula having a compound having the structure: H under appropriate reaction conditions.