Octahydro fused azadecalin glucocorticoid receptor modulators

Abstract

To provide new compositions and new methods for modulating GR receptors.SOLUTION: The present invention provides octahydro fused azadecalin compounds and methods of using the compounds as glucocorticoid receptor modulators. In some embodiments, the present invention provides a pharmaceutical composition including a compound of the present invention and a pharmaceutically acceptable excipient. In some embodiments, the present invention provides a method of modulating a glucocorticoid receptor, the method including contacting a glucocorticoid receptor with a compound of the present invention, thereby modulating the glucocorticoid receptor.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 61 / 985,035, filed April 28, 2014, and U.S. Provisional Patent Application No. 61 / 908,313, filed November 25, 2013, each of which is incorporated herein by reference in its entirety for all purposes. [Background technology]

[0002] 2. Background of the Invention In most species, including humans, the physiological glucocorticoid is cortisol (hydrocortisone). Glucocorticoids are secreted in response to ACTH (corticotropin), which shows both circadian rhythmic fluctuations and elevations in response to stress and food. Cortisol levels respond within minutes to many physical and psychological stresses, including trauma, surgery, exercise, anxiety, and depression. Cortisol is a steroid that acts by binding to the glucocorticoid receptor (GR) within cells. In humans, glucocorticoid receptors exist in two forms: the ligand-binding GR-alpha of 777 amino acids; and the GR-beta isoform, which lacks the 50 carboxy-terminal residues. Because these contain the ligand-binding domain, GR-beta cannot bind natural ligands and is constitutively localized in the nucleus. GR is also known as the GR-II receptor. The biological actions of cortisol, including those caused by hypercortisolism, can be modulated at the GR level using receptor modulators, such as agonists, partial agonists and antagonists. Several different classes of agents can block the physiological effects of GR-agonist binding. These antagonists include compositions that block the ability of agonists to efficiently bind and / or activate GR by binding to GR. One such known GR antagonist, mifepristone, has been found to be an effective antiglucocorticoid agent in humans (Bertagna (1984) J. Clin. Endocrinol. Metab. 59:25). Mifepristone has been shown to be effective in treating 10 -9 Dissociation constant of M (K d ) to GR (Cadepond (1997) Annu. Rev. Med. 48:129). What is needed in the art are new compositions and methods for modulating the GR receptor. Surprisingly, the present invention fulfills these and other needs. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Bertagna(1984)J.Clin.Endocrinol.Metab.59:25 [Non-Patent Document 2] Cadepond(1997)Annu.Rev.Med.48:129 Summary of the Invention [Means for solving the problem]

[0004] Brief Summary of the Invention The present invention provides a number of fused azadecalin compounds. In some embodiments, the present invention provides a compound having the following formula: [ka] wherein R of formula I is 1 is a heteroaryl ring having 5-6 ring members and 1-4 heteroatoms which may each independently be N, O or S, and each independently R 1a Each R in formula I is a heteroaryl ring optionally substituted with 1 to 4 groups which may be 1a are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, N-oxide or C 3-8 Ring J of formula I can be an aryl ring or a heteroaryl ring having 5-6 ring members and 1-4 heteroatoms, each of which can be independently N, O, or S. Each R of formula I can be an aryl ring or a heteroaryl ring having 5-6 ring members and 1-4 heteroatoms, each of which can be independently N, O, or S. 2 are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkyl-C 1-6 Alkoxy, -CN, -OH, -NR 2a R 2b , -C(O)R 2a , -C(O)OR 2a , -C(O)NR 2a R 2b , -SR 2a , -S(O)R 2a , -S(O)2R 2a , C 3-8 cycloalkyl or C with 1-3 heteroatoms, each of which may be independently N, O, or S 3-8 Alternatively, two R on adjacent ring atoms may be heterocycloalkyl. 2 The groups taken together form a heterocycloalkyl ring having 5-6 ring members and 1-3 heteroatoms (each of which may independently be N, O or S), where the heterocycloalkyl ring is comprised of 1-3 R 2c R of formula I is optionally substituted with a group. 2a , R2b and R 2c are each independently hydrogen or C 1-6 Each R in formula I can be alkyl. 3a may be independently halogen. The subscript n in formula I may be an integer from 0 to 3. The compounds of formula I may also be salts and isomers thereof.

[0005] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharma- ceutically acceptable excipient.

[0006] In some embodiments, the present invention provides a method of modulating a glucocorticoid receptor, the method comprising contacting the glucocorticoid receptor with a compound of the present invention, thereby modulating the glucocorticoid receptor. In one embodiment, for example, the following items are provided: (Item 1) formula: [ka] or salts and isomers thereof, wherein R 1 are each independently selected from the group consisting of 5 to 6 ring members, N, O and S. A heteroaryl ring having 1 to 4 heteroatoms, 1a is a heteroaryl ring optionally substituted with 1 to 4 groups each independently selected from Each R 1a are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, N-oxide and C 3-8 cycloalkyl; Ring J is selected from the group consisting of aryl rings and heteroaryl rings having 5-6 ring members and 1-4 heteroatoms each independently selected from the group consisting of N, O and S; Each R 2 are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkyl-C 1-6 Alkoxy, -CN, -OH, -NR 2a R 2b , -C(O)R 2a , -C(O)OR 2a , -C(O)NR 2a R 2b , -SR 2a , -S(O)R 2a , -S(O)2R 2a , C 3-8 Cycloalkyl and C having 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S 3-8 heterocycloalkyl; Alternatively, two R on adjacent ring atoms 2 The groups taken together form a heterocycloalkyl ring having 5-6 ring members and 1-3 heteroatoms each independently selected from the group consisting of N, O and S, wherein the heterocycloalkyl ring is selected from 1-3 R 2c optionally substituted with a group; R 2a , R 2b and R 2C each independently represents hydrogen and C 1-6 selected from the group consisting of alkyl; Each R 3a are independently halogen; The subscript n is an integer from 0 to 3. The compound or its salts and isomers. (Item 2) R 1 is a heteroaryl ring having 5-6 ring members and 1-4 heteroatoms each independently selected from the group consisting of N, O and S; 1a is a heteroaryl ring optionally substituted with 1 to 3 groups each independently selected from Each R1a are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 3-8 cycloalkyl; Ring J is selected from the group consisting of aryl rings and heteroaryl rings having 5-6 ring members and 1-3 heteroatoms each independently selected from the group consisting of N, O and S; Each R 2 are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, CN, -NR 2a R 2b , C 3-8 Cycloalkyl and C having 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S 3-8 heterocycloalkyl; Alternatively, two R on adjacent ring atoms 2 The groups taken together form a heterocycloalkyl ring having 5-6 ring members and 1-3 heteroatoms each independently selected from the group consisting of N, O and S, wherein the heterocycloalkyl ring is selected from 1-3 R 2c optionally substituted with a group; R 2a , R 2b and R 2C each independently represents hydrogen and C 1-6 selected from the group consisting of alkyl; Each R 3a are independently halogen; The subscript n is an integer from 0 to 3; The compound according to item 1. (Item 3) R 1 is a heteroaryl ring having 5-6 ring members and 1-3 heteroatoms each independently selected from the group consisting of N, O and S; 1ais a heteroaryl ring optionally substituted with 1 to 2 groups each independently selected from Each R 1a are independently hydrogen, C 1-6 Alkyl, halogen and C 1-6 haloalkyl; Ring J is selected from the group consisting of aryl rings and heteroaryl rings having 5-6 ring members and 1-3 heteroatoms each independently selected from the group consisting of N and S; Each R 2 are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 selected from the group consisting of haloalkyl and -CN; R 3a But F; The subscript n is an integer from 0 to 1. The compound according to any one of items 1 to 2. (Item 4) R 1 is a heteroaryl ring having 5-6 ring members and 1-2 heteroatoms each independently selected from the group consisting of N and S; 1a is a heteroaryl ring optionally substituted with 1 to 2 groups each independently selected from Each R 1a are independently hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl; Ring J is selected from the group consisting of phenyl, pyridine, pyrazole, and triazole; 2 are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 selected from the group consisting of haloalkyl and -CN; R 3a But F. The compound according to any one of items 1 to 3. (Item 5) R 1 is selected from the group consisting of pyridine and thiazole; Ring J is selected from the group consisting of phenyl, pyridine, pyrazole, and triazole; 2 are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 selected from the group consisting of haloalkyl and -CN; R 3a But F. The compound according to any one of items 1 to 4. (Item 6) R 1 is selected from the group consisting of 2-thiazole, 4-thiazole, 5-thiazole, 2-pyridine, 3-pyridine and 4-pyridine. (Item 7) R 1 is selected from the group consisting of 2-thiazole, 4-thiazole and 2-pyridine. (Item 8) R 1 is pyridyl. (Item 9) R 1 is thiazole. (Item 10) R 1a are independently hydrogen, C 1-6 Alkyl and C 1-6 The compound according to any one of items 1 to 9, selected from the group consisting of haloalkyl. (Item 11) R 1a is independently selected from the group consisting of hydrogen, methyl and trifluoromethyl. (Item 12) 12. The compound according to any one of items 1 to 11, wherein ring J is selected from the group consisting of phenyl, pyridine, pyrazole and triazole. (Item 13) Ring J is phenyl, 2-pyridine, 3-pyridine, 4-pyridine, 1-pyrazole, 3- 13. The compound according to any one of items 1 to 12, selected from the group consisting of pyrazole, 4-pyrazole, 5-pyrazole, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl and 1,2,4-triazol-5-yl. (Item 14) R 2 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, F, Cl, -CF3 and -CN. (Item 15) The structure: [ka] 14. The compound according to any one of items 1 to 13, having the formula: (Item 16) The compound is ((4aR,8aS)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, ((4aR,8aS)-6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, ((4aR,8aS)-6-((3,4-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-propyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((1-propyl-1H- pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((3-fluorophenyl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-5-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, ((4aR,8aS)-6-((1-ethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, ((4aR,8aS)-6-((1-ethyl-1H-pyrazol-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, ((4aR,8aS)-6-((2-ethyl-2H-1,2,3-triazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((6-(trifluoromethyl)pyridin-2-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-propyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone, 3-(((4aR,8aS)-1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8,8a,9-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)benzonitrile, ((4aR,8aS)-6-((3-fluoro-4-(trifluoromethyl)phenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((1-propyl-1H-1,2,3-triazol-5-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((1-methyl-1H-1,2,3-triazol-5-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((1-isopropyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, ((4aR,8aS)-6-((2-ethyl-2H-1,2,3-triazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl) 4-(trifluoromethyl)pyridin-2-yl)methanone, ((4aR,8aS)-6-((2H-1,2,3-triazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((1-isopropyl-1H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((6-(trifluoromethyl)pyridin-2-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((6-(trifluoromethyl)pyridin-2-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone, and ((4aR,8aS)-6-((2-ethyl-2H-1,2,3-triazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone The compound according to item 1, selected from the group consisting of: (Item 17) A pharmaceutical composition comprising a compound according to any one of items 1 to 16 and a pharma- ceutically acceptable excipient. (Item 18) A method of modulating a glucocorticoid receptor, the method comprising the step of contacting the glucocorticoid receptor with a compound according to any one of items 1 to 16, thereby modulating the glucocorticoid receptor. (Item 19) A method for treating a disorder through antagonizing a glucocorticoid receptor, the method comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of items 1 to 16, thereby treating the disorder. [Brief description of the drawings]

[0007] [Figure 1] FIG. 1 shows various synthetic schemes for producing compounds of the present invention. [Diagram 2] FIG. 2 shows various synthetic schemes for producing compounds of the invention. [Diagram 3] FIG. 3 shows various synthetic schemes for producing compounds of the invention. [Figure 4] FIG. 4 shows various synthetic schemes for producing compounds of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] Detailed Description of the Invention I. Overview The present invention provides compounds that can modulate glucocorticoid receptor (GR) and thereby provide beneficial therapeutic effects. These compounds include octahydro-fused azadecalins. The present invention also provides a method for treating diseases and disorders by modulating GR receptor with the compounds of the present invention.

[0009] II. Definition The abbreviations used herein have their conventional meaning within the chemical and biological arts.

[0010] Where substituents are specified by their conventional chemical formula written from left to right, they equally encompass chemically identical substituents which may be derived by writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0011] "Alkyl" refers to a straight or branched chain saturated aliphatic radical having the indicated number of carbon atoms. Alkyl can be any number of carbons (e.g., C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 1-7 , C 1-8 , C 1-9 , C 1-10 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 ) For example, C 1-6 Alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and the like.

[0012] "Alkoxy" refers to an alkyl group having an oxygen atom connecting the alkyl group to the point of attachment: alkyl-O-. Like alkyl groups, alkoxy groups can be C 1-6 Alkoxy groups can have any suitable number of carbon atoms, such as, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, and the like.

[0013] "Halogen" refers to fluorine, chlorine, bromine and iodine.

[0014] "Haloalkyl" refers to an alkyl, as defined above, in which some or all of the hydrogen atoms have been replaced with halogen atoms. Similar to alkyl groups, haloalkyl groups include C 1-6 For example, haloalkyl includes trifluoromethyl, fluoromethyl, etc. In some cases, the term "perfluoro" can be used to define a compound or radical in which all hydrogens are replaced with fluorine. For example, perfluoromethane includes 1,1,1-trifluoromethyl.

[0015] "Haloalkoxy" refers to an alkoxy group in which some or all of the hydrogen atoms are replaced with halogen atoms. Similar to alkyl groups, haloalkoxy groups can be C 1-6 Alkoxy groups can have any suitable number of carbon atoms, such as 1, 2, 3, or more. Alkoxy groups can be substituted with one, two, three, or more halogens. When all hydrogens are replaced with halogens, such as fluorine, the compound is per-substituted, such as perfluorinated. Haloalkoxy includes, but is not limited to, trifluoromethoxy, 2,2,2,-trifluoroethoxy, perfluoroethoxy, and the like.

[0016] "Cycloalkyl" means a saturated or partially unsaturated monocyclic, fused bicyclic or bridged polycyclic ring assembly containing three to twelve ring atoms, or the number of atoms indicated. Cycloalkyl refers to an alkyl group consisting of any number of carbons (e.g., C 3-6 , C 4-6 , C 5-6 , C 3-8 , C 4-8 , C 5-8 , C 6-8 , C 3-9 , C 3-10 , C 3-11 and C 3-12). Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2]bicyclooctane, decahydronaphthalene, and adamantane. The cycloalkyl group can also be partially unsaturated, having one or more double or triple bonds within the ring. Representative cycloalkyl groups that are partially unsaturated include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4-, and 1,5-isomers), norbornene, and norbornadiene. When the cycloalkyl is a saturated monocyclic C 3-8 When cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 3-6 When it is cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0017] "Heterocycloalkyl" refers to a saturated ring system having 3-12 ring members and 1-4 heteroatoms of N, O, and S. Additional heteroatoms may also be useful, including but not limited to B, Al, Si, and P. The heteroatoms may also be oxidized, such as but not limited to -S(O)- and -S(O)2-. Heterocycloalkyl groups may contain any number of ring atoms (e.g., 3-6, 4-6, 5-6, 3-8, 4-8, 5-8, 6-8, 3-9, 3-10, 3-11, or 3-12 ring members). Any suitable number of heteroatoms (e.g., 1, 2, 3, or 4, or 1-2, 1-3, 1-4, 2-3, 2-4, or 3-4) may be included in the heterocycloalkyl group. The heterocycloalkyl groups may include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxalidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. Heterocycloalkyl groups may also be fused with aromatic or non-aromatic ring systems to form members including, but not limited to, indoline.

[0018] When a heterocycloalkyl contains 3 to 8 ring members and 1 to 3 heteroatoms, representative members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, oxane, tetrahydrothiophene, thiane, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, morpholine, thiomorpholine, dioxane, and dithiane. Heterocycloalkyls can also form rings with 5 to 6 ring members and 1 to 2 heteroatoms, representative members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, and morpholine.

[0019] "Aryl" refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. An aryl group can contain any suitable number of ring atoms (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 ring atoms) and 6 to 10, 6 to 12, or 6 to 14 ring members. Aryl groups can be monocyclic, fused to form bicyclic or tricyclic groups, or linked by bonds to form biaryl groups. Representative aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl, which has a methylene linking group. Some aryl groups have 6 to 12 ring members (e.g., phenyl, naphthyl, or biphenyl). Other aryl groups have 6 to 10 ring members (e.g., phenyl or naphthyl). Some other aryl groups have 6 ring members (e.g., phenyl). Aryl groups can be substituted or unsubstituted.

[0020] "Heteroaryl" refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, where 1 to 5 of the ring atoms are heteroatoms such as N, O, or S. Additional heteroatoms may also be useful, including but not limited to B, Al, Si, and P. The heteroatoms may also be oxidized, such as but not limited to N-oxide, -S(O)-, and -S(O)2-. Heteroaryl groups may contain any number of ring atoms, such as 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms, such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5, may be included in the heteroaryl group. Heteroaryl groups can have 5 to 8 ring members and 1 to 4 heteroatoms, or 5 to 8 ring members and 1 to 3 heteroatoms, or 5 to 6 ring members and 1 to 4 heteroatoms, or 5 to 6 ring members and 1 to 3 heteroatoms. Heteroaryl groups can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole and isoxazole. Heteroaryl groups may also be fused to an aromatic ring system, such as a phenyl ring, to form members including, but not limited to, benzopyrroles (e.g., indole and isoindole), benzopyridines (e.g., quinoline and isoquinoline), benzopyrazines (quinoxalines), benzopyrimidines (quinazolines), benzopyridazines (e.g., phthalazine and cinnoline), benzothiophenes, and benzofurans. Other heteroaryl groups include heteroaryl rings linked by bonds, such as bipyridines. Heteroaryl groups may be substituted or unsubstituted.

[0021] The heteroaryl group may be linked through any position on the ring. For example, pyrrole includes 1-, 2-, and 3-pyrrole, pyridine includes 2-, 3-, and 4-pyridine, imidazole includes 1-, 2-, 4-, and 5-imidazole, pyrazole includes 1-, 3-, 4-, and 5-pyrazole, triazole includes 1-, 4-, and 5-triazole, tetrazole includes 1- and 5-tetrazole, pyrimidine includes 2-, 4-, 5-, and 6-pyrimidine, pyridazine includes 3- and 4-pyridazine, 1,2,3-triazine includes 4- and 5-triazine, 1 ,2,4-triazines include 3-, 5- and 6-triazines, 1,3,5-triazines include 2-triazines, thiophenes include 2- and 3-thiophenes, furans include 2- and 3-furans, thiazoles include 2-, 4- and 5-thiazoles, isothiazoles include 3-, 4- and 5-isothiazoles, oxazoles include 2-, 4- and 5-oxazoles, isoxazoles include 3-, 4- and 5-isoxazoles, indoles include 1-, 2- and 3-indoles, and isoindoles include includes 1- and 2-isoindole, quinoline includes 2-, 3-, and 4-quinoline, isoquinoline includes 1-, 3-, and 4-isoquinoline, quinazoline includes 2- and 4-quinoazoline, cinnoline includes 3- and 4-cinnoline, benzothiophene includes 2- and 3-benzothiophene, and benzofuran includes 2- and 3-benzofuran.

[0022] Some heteroaryl groups include heteroaryl groups having 5 to 10 ring members and 1 to 3 ring atoms containing N, O, or S (e.g., pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, and benzofuran). Other heteroaryl groups include heteroaryl groups having 5 to 8 ring members and 1 to 3 heteroatoms (e.g., pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole and isoxazole).Some other heteroaryl groups include heteroaryl groups having 9 to 12 ring members and 1 to 3 heteroatoms (e.g., indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, benzofuran and bipyridine). Still other heteroaryl groups include heteroaryl groups having 5 to 6 ring members and 1 to 2 ring heteroatoms including N, O or S (e.g., pyrrole, pyridine, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan, thiazole, isothiazole, oxazole and isoxazole).

[0023] Some heteroaryl groups contain 5-10 ring members and only nitrogen heteroatoms (e.g., pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine and cinnoline). Other heteroaryl groups contain 5-10 ring members and only oxygen heteroatoms (e.g., furan and benzofuran). Some other heteroaryl groups contain 5-10 ring members and only sulfur heteroatoms (e.g., thiophene and benzothiophene). Still other heteroaryl groups contain 5 to 10 ring members and at least two heteroatoms (e.g., imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiazole, isothiazole, oxazole, isoxazole, quinoxaline, quinazoline, phthalazine, and cinnoline).

[0024] "Heteroatom" refers to O, S or N.

[0025] "Salt" refers to the acid salt or base salt of the compound used in the method of the present invention. Illustrative examples of pharmaceutically acceptable salts are salts of mineral acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), salts of organic acids (such as acetic acid, propionic acid, glutamic acid, citric acid, etc.), and salts of quaternary ammonium (such as methyl iodide, ethyl iodide, etc.). It is understood that pharmaceutically acceptable salts are non-toxic. Further information regarding suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985 (incorporated herein by reference).

[0026] "Isomers" refers to compounds that have the same chemical formula but are structurally distinguishable.

[0027] "Tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one form to another.

[0028] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to substances that aid in the administration and absorption of active agents by a subject, and can be included in the compositions of the present invention without causing significant adverse toxicological effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solution, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavors and colors, etc. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0029] "Modulating the glucocorticoid receptor" refers to a method for modulating the response of the glucocorticoid receptor to glucocorticoids, glucocorticoid antagonists, agonists and partial agonists, which comprises contacting the glucocorticoid receptor with an effective amount of the antagonist, agonist or partial agonist, and detecting a change in the activity of the GR.

[0030] "GR modulators" refers to compounds that agonize and / or antagonize the glucocorticoid receptor and are defined as compounds of Formula I below.

[0031] "Glucocorticoid receptor" ("GR") refers to a family of intracellular receptors that specifically bind cortisol and / or cortisol analogs (e.g., dexamethasone). Glucocorticoid receptors are also referred to as cortisol receptors. The term includes isoforms of GR, recombinant GR, and mutant GR.

[0032] "Glucocorticoid receptor antagonist" refers to any composition or compound that partially or completely inhibits (antagonizes) the binding of a GR agonist (e.g., cortisol or a synthetic or natural cortisol analog) to the glucocorticoid receptor (GR). "Specific glucocorticoid receptor antagonist" refers to any composition or compound that inhibits any biological response associated with the binding of GR to an agonist. "Specific" refers to a drug that preferentially binds to GR rather than other nuclear receptors (e.g., mineralocorticoid receptor (MR) or progesterone receptor (PR)).

[0033] "Contacting" refers to the process of bringing at least two different chemical species into contact so that they can react with each other or interact such that one has an effect on the other.

[0034] "Treat," "treating," and "treatment" refer to any indicia of success in treating or ameliorating an injury, condition, or symptom, including any objective or subjective parameter (e.g., alleviation; remission; reducing symptoms or making the injury, condition, or symptom tolerable to the patient; slowing the rate of degeneration or decline; making the end point of degeneration less debilitating; improving the physical or mental well-being of the patient). Treating or ameliorating symptoms may be based on objective or subjective parameters, including the results of a physical examination, a neuropsychiatric examination, and / or a psychiatric evaluation.

[0035] A "patient" or a "subject in need thereof" refers to a pharmaceutical agent as provided herein. A therapeutic agent refers to a living organism suffering from or susceptible to a condition that can be treated by administration of a therapeutic composition. Non-limiting examples include humans, other mammals, and other non-mammals.

[0036] "Disorder" or "condition" refers to a state or condition of a patient or subject that can be treated with a glucocorticoid receptor modulator of the present invention. Examples of disorders or conditions include, but are not limited to, obesity, hypertension, depression, anxiety, and Cushing's syndrome.

[0037] "Antagonize" refers to blocking the binding of an agonist at a receptor molecule or inhibiting the signal generated by a receptor-agonist. Receptor antagonists block or attenuate the response mediated by an agonist.

[0038] A "therapeutically effective amount" refers to an amount of a conjugated functional agent or pharmaceutical composition useful for treating or ameliorating a specified disease or condition, or for exhibiting a detectable therapeutic or inhibitory effect, which can be detected by any assay method known in the art.

[0039] The description of the compound of the present invention is limited by the principle of chemical bonding known to those skilled in the art.Therefore, when a group can be substituted by one or more of several substituents, such substitution is selected to be compatible with the principle of chemical bonding and to bring about a compound that is not inherently unstable and / or may be known to those skilled in the art to be unstable under ambient conditions (e.g., aqueous, neutral or physiological conditions).

[0040] III.Compound The present invention provides a number of fused azadecalin compounds. In some embodiments, the present invention provides a compound having the following formula: [ka] wherein R of formula I is 1 is a heteroaryl ring having 5-6 ring members and 1-4 heteroatoms which may each independently be N, O or S, and each independently R 1aEach R in formula I is a heteroaryl ring optionally substituted with 1 to 4 groups which may be 1a are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, N-oxide or C 3-8 Ring J of formula I can be an aryl ring or a heteroaryl ring having 5-6 ring members and 1-4 heteroatoms, each of which can be independently N, O, or S. Each R of formula I can be an aryl ring or a heteroaryl ring having 5-6 ring members and 1-4 heteroatoms, each of which can be independently N, O, or S. 2 are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkyl-C 1-6 Alkoxy, -CN, -OH, -NR 2a R 2b , -C(O)R 2a , -C(O)OR 2a , -C(O)NR 2a R 2b , -SR 2a , -S(O)R 2a , -S(O)2R 2a , C 3-8 cycloalkyl, or C with 1-3 heteroatoms, each of which may be independently N, O, or S 3-8 Alternatively, the adjacent rings may be heterocycloalkyl. Two R on an atom 2 The groups taken together form a heterocycloalkyl ring having 5-6 ring members and 1-3 heteroatoms (each of which may be independently N, O or S), where the heterocycloalkyl ring is comprised of 1-3 R 2c R of formula I is optionally substituted with a group. 2a , R 2b and R 2c are each independently hydrogen or C 1-6 Each R in formula I can be alkyl. 3amay be independently halogen. The subscript n in formula I may be an integer from 0 to 3. The compounds of formula I may also be salts and isomers thereof.

[0041] In some embodiments, R of formula I 1 is a heteroaryl ring having 5-6 ring members and 1-4 heteroatoms which may each independently be N, O or S, and each independently R 1a Each R in formula I may be a heteroaryl ring optionally substituted with 1 to 3 groups selected from 1a is hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 3-8 Ring J of formula I can be an aryl ring or a heteroaryl ring having 5-6 ring members and 1-3 heteroatoms, each of which can be independently N, O, or S. Each R of formula I can be an aryl ring or a heteroaryl ring having 5-6 ring members and 1-3 heteroatoms, each of which can be independently N, O, or S. 2 are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, CN, -NR 2a R 2b , C 3-8 Cycloalkyl or C having 1-3 heteroatoms which may each independently be N, O or S. 3-8 Heterocycloalkyl may be N, O or S, and the heterocycloalkyl ring may optionally be 1-3 R 2c R in formula I is substituted with a group. 2a , R 2b and R 2c are each independently hydrogen or C 1-6 Each R can be alkyl. 3a may be independently halogen. The subscript n in formula I may be an integer from 0 to 3. The compounds of formula I may also be salts and isomers thereof.

[0042] In some embodiments, R 1is a heteroaryl ring having 5-6 ring members and 1-3 heteroatoms which may each independently be N, O or S, and each independently R 1a Each R may be a heteroaryl ring optionally substituted with 1 to 2 groups, each of which may be 1a are independently hydrogen, C 1-6 Alkyl, halogen or C 1-6 Ring J can be an aryl ring or a heteroaryl ring having 5-6 ring members and 1-3 heteroatoms which can independently be N or S. Each R in formula I 2 are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 R can be haloalkyl or -CN. 3a may be F. The subscript n may be an integer from 0 to 1.

[0043] In some embodiments, R 1 is a heteroaryl ring having 5-6 ring members and 1-3 heteroatoms which may each independently be N or S, each independently being R 1a Each R may be a heteroaryl ring optionally substituted with 1 to 2 groups, each of which may be 1a are independently hydrogen, C 1-6 Alkyl or C 1-6 Ring J can be phenyl, pyridine, pyrazole, or triazole. Each R 2 are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 R can be haloalkyl or -CN. 3a can be F.

[0044] In some embodiments, R 1 can be pyridine or thiazole. Ring J can be phenyl, pyridine, pyrazole or triazole. Each R 2 are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 R can be haloalkyl or -CN. 3amay be F. In some embodiments, R 1 can be 2-thiazole, 4-thiazole, 5-thiazole, 2-pyridine, 3-pyridine, or 4-pyridine. 1 can be 2-pyridine; 2-thiazole or 4-thiazole. In some embodiments, R 1 can be pyridine. In some embodiments, R 1 may be a triazole. In some embodiments, R 1a are independently hydrogen, C 1-6 Alkyl or C 1-6 In some embodiments, R 1a may be independently hydrogen, methyl or trifluoromethyl.

[0045] In some embodiments, ring J can be phenyl, pyridine, pyrazole, or triazole. In some embodiments, ring J can be phenyl, 2-pyridine, 3-pyridine, 4-pyridine, 1-pyrazole, 3-pyrazole, 4-pyrazole, 5-pyrazole, 1,2,3-triazol-4-yl, 1,2,3,-triazol-5-yl, 1,2,4-triazol-3-yl, or 1,2,4-triazol-5-yl. In some embodiments, R 2 may be independently hydrogen, methyl, ethyl, propyl, isopropyl, F, Cl, or -CF3.

[0046] The compounds of the present invention contain at least one stereogenic center at the bridgehead carbon. Thus, the compounds may contain mixtures of isomers, including enantiomers, in racemic mixtures or enantiomerically pure mixtures that are substantially R- or S-isomers. The compounds may also adopt a cis or trans conformation across the bridgehead carbons (carbons 4a and 8a) of the 4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinoline portion of the compounds. In some embodiments, the compounds of formula I have the following structure: [ka] may have:

[0047] Any suitable heteroaryl can be used as R in the compounds of the present invention as defined in the definitions above. 1 In some embodiments, R 1 The heteroaryl of R can have 5 to 6 ring members and 1 to 4 heteroatoms, each of which can be independently N, O, or S, and each of which can be independently R 1a In some embodiments, R 1 The heteroaryl of R can have 5 to 6 ring members and 1 to 3 heteroatoms, each of which can be independently N, O, or S, and each of which can be independently R 1a In some embodiments, R 1 The heteroaryl of R may have 5-6 ring members and 1-2 heteroatoms, each of which may be independently N, O, or S, and each of which may be independently R 1a In some embodiments, R 1 The heteroaryl of R may have 5-6 ring members and 1-2 heteroatoms, each of which may independently be N or S, 1a It can be optionally substituted with 1 to 4 groups which can be:

[0048] In some embodiments, R 1 The heteroaryl of can be pyrrole, pyrazole, imidazole, triazole, tetrazole, furan, oxazole, isoxazole, oxadiazole, thiophene, thiazole, isothiazole, thiadiazole, pyridine, pyrazine, pyrimidine, or pyridazine. 1Heteroaryl in the formula (I) is 2-pyrrole, 3-pyrrole, 1-pyrazole, 3-pyrazole, 4-pyrazole, 5-pyrazole, 2-imidazole, 4-imidazole, 5-imidazole, 1,2,3-triazol-4-yl, 1,2,3,-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,3,4-tetrazol-1-yl, 1,2,3,4,tetrazol-5-yl, 2-furan, 3-furan, 2-oxazole, 4-oxazole, 5-oxazole, 3-isopropyl ether ...3,4-tetrazol-1-yl, 1,2,3,4,tetrazol-5-yl, 1,2,3,4,tetrazol-5-yl, 1,2,3,4,tetrazol-5-yl, 1,2,3,4,tetrazol-1-yl, 1,2,3,4,tetrazol-5-yl, 1,2,3,4,tetrazol-5-yl, 1,2,3,4,tetrazol-1-yl, 1,2 Oxazole, 4-isoxazole, 5-isoxazole, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 2-thiophene, 3-thiophene, 2-thiazole, 4-thiazole, 5-thiazole, 3-isothiazole, 4-isothiazole, 5-isothiazole, 1,2,3-thiadiazole-4- In some embodiments, R may be 1,2,3-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1,3,4-thiadiazol-2-yl, 2-pyridine, 3-pyridine, 4-pyridine, pyrazine, 2-pyrimidine, 4-pyrimidine, 5-pyrimidine, 6-pyrimidine, 3-pyridazine, 4-pyridazine, 5-pyridazine, or 6-pyridazine. 1 The heteroaryl of R can be pyrazole, imidazole, triazole, furan, oxazole, oxadiazole, thiophene, thiazole, pyridine, pyrazine, or pyrimidine. 1 The heteroaryl of R can be imidazole, furan, oxazole, oxadiazole, thiophene, thiazole, or pyridine. 1Heteroaryl in the formula (I) is selected from the group consisting of 1-pyrazole, 3-pyrazole, 4-pyrazole, 5-pyrazole, 2-imidazole, 4-imidazole, 5-imidazole, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 2-furan, 3-furan, 2-oxazole, 4-oxazole, 5-oxazole, 1, It can be 2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 2-thiophene, 3-thiophene, 2-thiazole, 4-thiazole, 5-thiazole, 2-pyridine, 3-pyridine, 4-pyridine, pyrazine, 2-pyrimidine, 4-pyrimidine, 5-pyrimidine or 6-pyrimidine. 1 The heteroaryl in can be 3-pyrazole, 4-pyrazole, 2-imidazole, 1,2,4-triazol-5-yl, 2-furan, 2-oxazole, 4-oxazole, 1,3,4-oxadiazol-2-yl, 2-thiophene, 2-thiazole, 4-thiazole, 5-thiazole, 2-pyridine, 3-pyridine, 4-pyridine, pyrazine, or 2-pyrimidine. 1 The heteroaryl in can be 2-imidazole, 4-imidazole, 5-imidazole, 2-furan, 3-furan, 2-oxazole, 4-oxazole, 5-oxazole, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 2-thiophene, 3-thiophene, 2-thiazole, 4-thiazole, 5-thiazole, 2-pyridine, 3-pyridine or 4-pyridine.

[0049] In some embodiments, R 1 The heteroaryl in R can be pyridine or thiazole. 1The heteroaryl of R can be 2-thiazole, 4-thiazole, 5-thiazole, 2-pyridine, 3-pyridine, or 4-pyridine. 1 The heteroaryl in R can be 2-thiazole, 4-thiazole, or 2-pyridine. 1 The heteroaryl of R can be pyridine. 1 The heteroaryl in can be thiazole.

[0050] In some embodiments, R 1 Each heteroaryl in 1a In some embodiments, each R 1a are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -CN, N-oxide, C 3-8 Cycloalkyl or C 3-8 In some embodiments, each R 1a are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy also is C 3-8 In some embodiments, each R 1a are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 In some embodiments, each R 1a are independently hydrogen, C 1-6 Alkyl or C 1-6 In some embodiments, each R 1a are independently hydrogen or C 1-6 R can be alkyl. 1aThe alkyl of can be any suitable alkyl group (e.g., methyl, ethyl, propyl, butyl, pentyl, and hexyl, among others). In some embodiments, each R 1a may be independently hydrogen, methyl, ethyl, trifluoromethyl, methoxy, or pyrrolidinyl. 1a may independently be hydrogen, methyl, or trifluoromethyl. In some embodiments, each R 1a may be independently hydrogen or methyl.

[0051] In some embodiments, R 1 The heteroaryl in can be 3-pyrazole, 4-pyrazole, 2-imidazole, 1,2,4-triazol-5-yl, 2-furan, 2-oxazole, 4-oxazole, 1,3,4-oxadiazol-2-yl, 2-thiophene, 2-thiazole, 4-thiazole, 5-thiazole, 2-pyridine, 3-pyridine, 4-pyridine, pyrazine or 2-pyrimidine, and ring J can be 2-pyridine, 3-pyridine, 4-pyridine, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl or isoxazol-4-yl.

[0052] Ring J of formula I can be any suitable ring. In some embodiments, ring J of formula I can be a cycloalkyl ring, a heterocycloalkyl ring, an aryl ring, or a heteroaryl ring, where the heterocycloalkyl ring and the heteroaryl ring can have 5-6 ring members and 1-4 heteroatoms, each of which can be independently N, O, or S. In some embodiments, ring J can be a heterocycloalkyl, an aryl, or a heteroaryl. Suitable heterocycloalkyl groups include those defined in the definitions above. In some embodiments, the heterocycloalkyl can be tetrahydrofuran. Suitable aryl groups for ring J include those defined in the definitions above. Representative aryl groups include phenyl and naphthyl. In some embodiments, the aryl group of ring J can be phenyl. Suitable heteroaryl groups for ring J include those defined in the definitions above. Representative heteroaryl groups include pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole and isoxazole. In some embodiments, heteroaryl can be pyridyl or thiophene. In some embodiments, ring J can be aryl or heteroaryl. In some embodiments, ring J can be phenyl, pyridine, imidazole, pyrazole, triazole, tetrazole, thiadiazole, isothiazole or isoxazole. In some embodiments, ring J can be phenyl, pyridine, pyrazole or triazole. In some embodiments, ring J can be phenyl, 2-pyridine, 3-pyridine, 4-pyridine, 1-pyrazole, 3-pyrazole, 4-pyrazole, 5-pyrazole, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl, and 1,2,4-triazol-5-yl. In some embodiments, ring J can be phenyl.In some embodiments, ring J can be pyridine. In some embodiments, ring J can be pyrazole. In some embodiments, ring J can be triazole.

[0053] Ring J of formula I can be any suitable number of R 2 Each R of formula I may be substituted with a group. 2 are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkyl-C 1-6 Alkoxy, -CN, -OH, -NR 2a R 2b , -C(O)R 2a , -C(O)OR 2a , -C(O)NR 2a R 2b , -SR 2a , -S(O)R 2a , -S(O)2R 2a , C 3-8 Cycloalkyl or C 3-8 heterocycloalkyl, where the heterocycloalkyl group is selected from 1 to 4 R 2c In some embodiments, each R of formula I is optionally substituted with a substituted aryl group. 2 are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkyl-C 1-6 Alkoxy, -CN, -NR 2a R 2b , -C(O)OR 2a , -S(O)2R 2a , C 3-8 Cycloalkyl or C 3-8 In some embodiments, each R of formula I can be a heterocycloalkyl, where the heterocycloalkyl group has 5 to 6 ring members and 1 to 2 heteroatoms. 2 are independently hydrogen, C 1-6Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkyl-C 1-6 Alkoxy, -CN, -NR 2a R 2b , -S(O)2R 2a , C 3-8 Cycloalkyl or C 3-8 Each R in formula I can be a heterocycloalkyl, where the heterocycloalkyl group has 5 to 6 ring members and 1 to 2 heteroatoms. 2 are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -CN, -NR 2a R 2b , C 3-8 Cycloalkyl or C 3-8 heterocycloalkyl, where the heterocycloalkyl group is selected from 1 to 4 R 2c In some embodiments, each R 2 are independently hydrogen, halogen, C 1-6 It can be haloalkyl, -CN, or heterocycloalkyl having 5-6 ring members and 1-2 heteroatoms, where at least one heteroatom is N. Heterocycloalkyl groups having 5-6 ring members and 1-2 heteroatoms, where at least one is nitrogen, include, but are not limited to, pyrrolidine, piperidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3-, and 1,4-isomers), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, morpholine, or thiomorpholine. In some embodiments, each R 2 may be independently hydrogen, methyl, ethyl, propyl, isopropyl, F, Cl, -CF, CHOMe, OMe, OCHF, -CN, -NMe, -C(O)OH, -C(O)NMe, -S(O)Me, pyrrolidine, piperidine, or morpholine.2 may be independently hydrogen, methyl, ethyl, F, Cl, -CF, OMe, OCHF, -CN, -NMe, -S(O)Me, pyrrolidine, piperidine, or morpholine. 2 may be independently hydrogen, methyl, ethyl, n-propyl, isopropyl, F, Cl, and -CF. In some embodiments, R 2 Ring J can be -CF3. Ring J can be 1, 2, 3 or 4 R 2 In some embodiments, ring J can be substituted with one R 2 The group is substituted.

[0054] Alternatively, two R on adjacent atoms of ring J 2 The groups may together form a heterocycloalkyl ring having 5-6 ring members and 1-3 heteroatoms (each of which may be N, O or S), where the heterocycloalkyl ring is comprised of 1-3 R 2c Optionally substituted with two R 2 When the groups are taken together, any suitable heterocycloalkyl group can be formed. In some embodiments, two R 2 The heterocycloalkyl formed by the combination of groups can have 6 ring members and 1 to 2 heteroatoms, each of which can be N, O, or S. In some embodiments, two R 2 The heterocycloalkyl formed by the combination of groups can have 6 ring members and 1 to 2 heteroatoms, each of which can be N or O. In some embodiments, two R 2 The heterocycloalkyl formed by the combination of the groups can have 6 ring members and two heteroatoms, each of which can be N or O. In some embodiments, two R 2 Base The heterocycloalkyl formed by the combination can be morpholine. When ring J is pyridine and the heterocycloalkyl is two R 2When formed by a combination of groups, the combination can be any suitable pyridooxazine, such as 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl. 2 When the groups taken together form a heterocycloalkyl, the heterocycloalkyl may be one to three R 2c It may be substituted with a group.

[0055] Some R 2 The group is R 2a and R 2b R 2a and R 2b are each independently hydrogen or C 1-6 It may be alkyl.

[0056] Each R 3a can be any halogen. In some embodiments, each R 3a The groups may independently be F, I, Cl, or Br. In some embodiments, R 3a can be F. R 3a The groups may be present at any position on the phenyl ring to form a 2-, 3-, or 4-substituted ring. In some embodiments, the phenyl ring is substituted at the 4 position.

[0057] The subscript n in formula I can be an integer from 0 to 3. In some embodiments, the subscript n can be 0, 1, 2, or 3. In some embodiments, the subscript n can be 0 or 1. In some embodiments, the subscript n can be 0. In some embodiments, the subscript n can be 1.

[0058] R in Formula I 3a When is 4-fluoro, the compounds of the present invention have the following structure: [ka] may have:

[0059] In some embodiments, the compound of formula I is: ((4aR,8aS)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, ((4aR,8aS)-6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, ((4aR,8aS)-6-((3,4-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-propyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octaphenyl Doro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((3-fluorophenyl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-5-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, ((4aR,8aS)-6-((1-ethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, ((4aR,8aS)-6-((1-ethyl-1H-pyrazol-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, ((4aR,8aS)-6-((2-ethyl-2H-1,2,3-triazole-4-yl) (4-(trifluoromethyl)pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((6-(trifluoromethyl)pyridin-2-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-propyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone, 3-(((4aR,8aS)-1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8,8a,9-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)benzonitrile, ((4aR,8aS)-6-((3-fluoro-4-(trifluoromethyl)phenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((1-propyl-1H-1,2,3-triazol-5-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((1-methyl-1H-1,2,3-triazol-5-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((1-isopropyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, ((4aR,8aS)-6-((2-ethyl-2H-1,2,3-triazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, ((4aR,8aS)-6-((2H-1,2,3-triazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((1-isopropyl-1H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((6-(trifluoromethyl)pyridin-2-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((6-(trifluoromethyl)pyridin-2-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone, ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone, or It can be ((4aR,8aS)-6-((2-ethyl-2H-1,2,3-triazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone.

[0060] The compounds of the present invention may also be in the form of their salts and isomers. In some embodiments, the compounds of the present invention include the salt forms thereof. Examples of applicable salt forms include hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate (e.g., (+)-tartrate, (-)-tartrate, or mixtures thereof, including racemic mixtures), succinate, benzoate, and salts with amino acids such as glutamic acid. These salts can be prepared by methods known to those skilled in the art. When the compounds of the present invention contain a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of applicable acid addition salts include hydrochloride, hydrobromide, These include salts obtained from inorganic acids such as nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphorous acid, as well as salts obtained from organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Also included are salts of amino acids such as alginates, and salts of organic acids such as glucuronic acid or galactunoric acids (see, for example, Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds of the present invention contain functional groups that allow the compounds to be converted into base addition salts. Further information regarding suitable pharma- ceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, incorporated herein by reference.

[0061] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0062] Certain compounds of the present invention can exist in non-solvated form as well as solvated form, including hydrated form.Normally, solvated form is equivalent to non-solvated form and is included within the scope of the present invention.Certain compounds of the present invention can exist in multiple crystalline or amorphous forms.Normally, all physical forms are equivalent for the use contemplated by the present invention and are intended to be within the scope of the present invention.

[0063] Certain compounds of the invention possess asymmetric carbon atoms (optical centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomers (which may be defined in terms of absolute stereochemistry as (R)- or (S)-, or in the case of amino acids, (D)- or (L)-) and individual isomers are encompassed within the scope of the invention. The compounds of the invention do not include compounds known in the art to be too unstable to synthesize and / or to be isolated. The invention is intended to include compounds in racemic and optically pure form. Optically active (R)- and (S)-isomers or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0064] Isomers include compounds that have the same number and kinds of atoms, and therefore the same molecular weight, but differ in the structural arrangement or configuration of the atoms.

[0065] It will be apparent to one of ordinary skill in the art that certain compounds of the invention may exist in tautomeric forms, all of which are within the scope of the invention. A tautomer is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0066] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Thus, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.

[0067] Unless otherwise stated, the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds of the present invention may contain radioactive isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125(125 I), Carbon-13( 13 C) or carbon-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0068] In addition to salt forms, the present invention provides compounds in the form of prodrugs. Prodrugs of the compounds described herein are compounds that undergo easy chemical changes under physiological conditions to provide the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0069] The compounds of the invention can be prepared as shown in Figure 1. The starting materials can be obtained from commercial sources, by using known synthetic methods, and by using the methods described in U.S. Patent No. 7,928,237, which is incorporated herein by reference. The ester I is converted to the ketone IV by reaction with a suitable organometallic reagent (e.g., a Grignard, organolithium, organoboron, organocerium or organozinc reagent) in a solvent (e.g., ether or tetrahydrofuran or a similar aprotic solvent). Preferably, the reaction is carried out using an aryllithium reagent in a solvent (e.g., ether or tetrahydrofuran). It may be advantageous to carry out the reaction at low temperatures. The ketone of formula IV can also be prepared by reacting an aldehyde of formula II with a suitable organometallic reagent, followed by oxidation of the resulting alcohol of formula III with a suitable oxidizing agent, such as a Dess-Martin periodinane reagent, in an inert solvent such as dichloromethane. If necessary, the tert-butoxycarbonyl protecting group is removed from IV by treatment with an acid (e.g., HCl, HBr, trifluoroacetic acid, p-toluenesulfonic acid or methanesulfonic acid, preferably HCl or trifluoroacetic acid) in a solvent (e.g., dioxane, dichloromethane, ethanol or tetrahydrofuran) under anhydrous or aqueous conditions. Preferably, the reaction is carried out using either HCl in dioxane or trifluoroacetic acid in dichloromethane. Amine V is converted to a compound of formula (1) by treatment with a suitable substituted sulfonyl halide (e.g., sulfonyl chloride VI) in an inert solvent (e.g., dichloromethane, toluene or tetrahydrofuran, preferably dichloromethane) in the presence of a base (e.g., N,N-di-isopropylethylamine or triethylamine). It may be convenient to carry out the sulfonylation reaction in situ without isolating amine V. Compounds of formula (1) may also be prepared from amines of formula V in a two-step sequence starting from the reaction of amine V with a halo-substituted sulfonyl chloride VII to give halo-substituted sulfonamide derivatives exemplified by VIII (wherein X represents a halogen).The halogen substituent X can be converted to the substituent R by any standard method known to those skilled in the art. 2 It can be converted in the following way.

[0070] Alternatively, compounds of formula (1) are prepared as shown in Figure 2. If necessary, the tert-butoxycarbonyl protecting group is removed from I by treatment with an acid (e.g., HCl, HBr, trifluoroacetic acid, p-toluenesulfonic acid or methanesulfonic acid, preferably HCl or trifluoroacetic acid) in a solvent (e.g., dioxane, dichloromethane, ethanol or tetrahydrofuran) under anhydrous or aqueous conditions. Preferably, the reaction is carried out using either HCl in dioxane or trifluoroacetic acid in dichloromethane. Amine IX is converted to sulfonamide of formula X as described for the conversion of amine of formula V to sulfonamide of formula (1). The ester group in compound of formula X is removed by condensation in an inert solvent (e.g., dichloromethane, tetrahydrofuran, The aldehyde of formula XI is converted to an aldehyde of formula XI by using a reducing agent (e.g., DIBAL-H, LiAlH4 or RED-AL, preferably DIBAL-H) ​​in benzene or toluene, preferably dichloromethane. It may be convenient to convert X to XI using a two-step process involving reduction of the ester to an alcohol and subsequent oxidation of the alcohol to an aldehyde of formula XI. The oxidation may be carried out using any suitable procedure such as the Swern reaction or an oxidation reagent such as the Dess-Martin periodinane reagent in a suitable solvent such as dichloromethane. The aldehyde of formula XI is converted to an alcohol of formula XII using a suitable organometallic reagent (e.g., a Grignard reagent, an organolithium reagent, an organoboron reagent, an organocerium reagent or an organozinc reagent). The alcohol of formula XII is converted to a ketone of formula (1) by oxidation. Suitable oxidation conditions include the Swern reaction and the use of the Dess-Martin periodinane reagent. Alternatively, esters of formula X are directly converted to ketones of formula (1) using a suitable organometallic reagent, preferably an aryllithium reagent, in a suitable solvent such as ether or tetrahydrofuran.

[0071] J represents triazole, R 2Compounds of formula I, where alk represents an alkyl, require the synthesis of a suitable triazole sulfonyl chloride. The triazole sulfonyl chlorides used in the present invention may be prepared by any suitable method known to those skilled in the art, such as the method shown in FIG. 3. In FIG. 3, alk represents an alkyl group. Commercially available triazole thiol XIII is converted to a suitable protected thiol, such as benzylthiotriazole XIV, using any suitable conditions known to those skilled in the art. Preferably, thiol XIII is treated with benzyl bromide in a suitable solvent, such as ethanol. Alkylation of a protected thiol, such as benzylthiol XIV, gives a mixture of three regioisomers, alkylpyrazoles XVa, XVb and XVc. The exact ratio of products depends on the conditions used for the alkylation reaction. For example, the use of a suitable alkyl iodide in N,N-dimethylformamide in the presence of potassium carbonate gives triazole XVa as the major product. The regiochemistry of the alkylated triazole is determined using any suitable method known to those skilled in the art. For example, regiochemistry can be assigned by comparison with information in the scientific literature, by performing NOE experiments, by chemical manipulations that yield compounds of known structure, or by comparison with samples made by alternative, obvious synthetic routes. For example, the synthetic route shown in Figure 4 specifically yields triazole sulfides of formula XVc. In Figure 4, alk represents an alkyl group.

[0072] The triazoles of formula XV can be converted to sulfonyl chlorides of formula XVI by any suitable method known to those skilled in the art. For example, oxidative cleavage of the thiobenzyl group can be utilized using a suitable oxidizing agent. The sulfonyl chlorides of formula XVI can be obtained by using N-chlorosuccinimide or chlorine gas in a suitable solvent such as acetic acid.

[0073] IV. Pharmaceutical Compositions In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharma- ceutically acceptable excipient.

[0074] A. Formulation The compositions of the present invention may be prepared in a wide variety of oral, parenteral and topical dosage forms. Oral preparations include tablets, pills, powders, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, and the like, suitable for oral ingestion by the patient. The compositions of the present invention may also be administered by injection, i.e., intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally, or intraperitoneally. The compositions described herein may also be administered by inhalation, for example, intranasally. Additionally, the compositions of the present invention may be administered transdermally. The compositions of the present invention may also be administered by intraocular, intravaginal and intrarectal routes (including suppositories), intravenously, intragastrically, intraperitoneally, ...peritoneally, intraperitoneally, intraperitoneally, intraperitoneally, intraperitoneally, intraperitoneally, intraperitoneally, intraperitoneally, intraperitoneally, intraperitoneally, intraperitoneally, intraperitoneally, intraperitoneally, intraperitoneally, intraperitoneally, intraperitoneally They may also be administered by injection, powder and aerosol formulations (e.g., for steroid inhalants, see Rohatagi, J. Clin. Pharmacol. 35:1187-1193, 1995; Tjwa, Ann. Allergy Asthma Immunol. 75:107-111, 1995). Thus, the present invention also provides pharmaceutical compositions comprising a pharma- ceutically acceptable carrier or excipient and a compound of the present invention.

[0075] For preparing pharmaceutical compositions from the compounds of the present invention, pharma- ceutically acceptable carriers can be solid or liquid.Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories and dispersible granules.Solid carriers can be one or more substances that can act as diluents, flavorings, binders, preservatives, tablet disintegrating agents or encapsulating materials.Details regarding the techniques for formulation and administration are fully described in the scientific and patent literature, for example, see the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton PA ("Remington's").

[0076] In powders, the carrier is a finely divided solid that is in a mixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in a suitable ratio and compressed into the desired shape and size. The powders and tablets preferably contain 5% or 10% to 70% of the compound of the present invention.

[0077] Suitable solid excipients include, but are not limited to, magnesium carbonate; magnesium stearate; talc; pectin; dextrin; starch; tragacanth; low melting wax; cocoa butter; carbohydrates; sugars (including but not limited to lactose, sucrose, mannitol or sorbitol, starches from corn, wheat, rice, potato or other plants); celluloses (e.g., methylcellulose, hydroxypropylmethyl-cellulose or sodium carboxymethylcellulose); and gums (including acacia and tragacanth); and proteins (including but not limited to gelatin and collagen). If desired, disintegrating or solubilizing agents (e.g., cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof (e.g., sodium alginate)) may be added.

[0078] Dragee cores are provided with suitable coatings (e.g. concentrated sugar solutions) which may also include gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or dragee coatings for product identification or to characterize the amount of active compound (i.e. dosage). The pharmaceuticals of the present invention may also be used orally, for example, using push-fit capsules made of gelatin, as well as sealed soft capsules made of gelatin and a coating agent (e.g. glycerol or sorbitol). Push-fit capsules may contain the compound of the present invention mixed with a filler or binder (e.g. lactose or starch), a lubricant (e.g. talc or magnesium stearate) and, if necessary, a stabilizer. In soft capsules, the compound of the present invention may be dissolved or suspended in a suitable liquid (e.g. fatty oils, liquid paraffin or liquid polyethylene glycol) with or without stabilizers.

[0079] For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter is first melted and the compound of the present invention is dispersed homogeneously therein by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.

[0080] Liquid form preparations include solutions, suspensions and emulsions, for example, water or water / propylene glycol solutions.For parenteral injection, liquid preparations can be formulated in solutions in aqueous polyethylene glycol solution.

[0081] Aqueous solutions suitable for oral use can be prepared by dissolving the compounds of the present invention in water and adding suitable colorants, flavorings, stabilizers and thickening agents, as desired. Aqueous suspensions suitable for oral use are prepared by dissolving the finely divided active ingredient in water and dispersing or wetting agents, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic, and dispersing or wetting agents, such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with fatty acids and heptadecaethyleneoxycetanol, ... The aqueous suspension may be prepared by dispersing in water with a condensation product of ethylene oxide with a partial ester derived from a xylitol (e.g., polyoxyethylene sorbitol mono-oleate) or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate). The aqueous suspension may also contain one or more preservatives (e.g., ethyl p-hydroxybenzoate or n-propyl p-hydroxybenzoate), one or more coloring agents, one or more flavoring agents, and one or more sweetening agents (e.g., sucrose, aspartame, or saccharin). The formulation may be adjusted for osmolality.

[0082] Also includes the preparation of solid form that is intended to be converted into the preparation of liquid form for oral administration immediately before use.Such liquid form includes solution, suspension and emulsion.These preparations can contain coloring agent, flavoring agent, stabilizer, buffer, artificial and natural sweetener, dispersant, thickener, solubilizer, etc. in addition to active ingredient.

[0083] Oily suspensions can be formulated by suspending the compounds of the present invention in a vegetable oil (e.g., peanut oil, olive oil, sesame oil or coconut oil) or mineral oil (e.g., liquid paraffin); or mixtures thereof. The oily suspensions can contain a thickening agent (e.g., beeswax, hard paraffin or cetyl alcohol). Sweeteners (e.g., glycerol, sorbitol or sucrose) can be added to provide a palatable oral preparation. These preparations can be preserved by adding an antioxidant such as ascorbic acid. For an example of an injectable oily vehicle, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. The pharmaceutical preparations of the present invention can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil, or mixtures thereof, as described above. Suitable emulsifying agents include naturally occurring gums (e.g., gum arabic and gum tragacanth), naturally occurring phosphatides (e.g., soybean lecithin), esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan mono-oleate) and condensation products of these partial esters with ethylene oxide (e.g., polyoxyethylene sorbitan mono-oleate). Emulsions may also contain sweetening and flavoring agents, as in the formulation of syrups and elixirs. Such formulations may also contain a demulcent, preservative or coloring agent.

[0084] The compositions of the invention can also be delivered as microspheres for slow release in the body. For example, the microspheres can be formulated for administration via intradermal injection of drug-containing microspheres that slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995); as biodegradable injectable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863, 1995); or as microspheres for oral administration (see, e.g., Eyles, J. (See Pharm. Pharmacol. 49:669-674, 1997.) Both the transdermal and intradermal routes provide constant delivery over periods of weeks or months.

[0085] In another embodiment, the composition of the present invention can be formulated for parenteral administration (e.g., intravenous (IV) administration or administration into a body cavity or lumen of an organ). The preparation for administration usually comprises a solution of the composition of the present invention dissolved in a pharmaceutically acceptable carrier. Acceptable vehicles and solvents that can be used are water and Ringer's solution, isotonic sodium chloride. In addition, sterile fixed oils can be conventionally used as a solvent or suspending medium. For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables as well. These solutions are sterile and usually free of undesirable substances. These preparations can be sterilized by conventional well-known sterilization techniques. They can contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions (e.g., pH adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc.). The concentration of the composition of the present invention in these preparations can vary widely and can be selected mainly based on the volume of fluid, viscosity, body weight, etc., according to the specific mode of administration selected and the needs of the patient. For IV administration, the preparation can be a sterile injectable preparation (e.g., a sterile injectable aqueous or oily suspension). This suspension can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent (e.g., a solution of 1,3-butanediol).

[0086] In another embodiment, the formulation of the composition of the present invention can be delivered by using liposomes, which fuse with cell membrane or are endocytosed, i.e., by using ligands attached to the liposomes or directly attached to oligonucleotides that bind to cell surface membrane protein receptors, resulting in endocytosis.In particular, liposomes can be used to focus the delivery of the composition of the present invention to target cells in vivo, when the liposome surface has ligands specific to target cells or is otherwise preferentially directed to specific organs (see, for example, Al-Muhammed, J.Microencapsul.13:293-306,1996; Chonn, Curr.Opin.Biotechnol.6:698-708,1995; Ostro, Am.J.Hosp.Pharm.46:1576-1587,1989).

[0087] Lipid-based drug delivery systems include lipid solutions, lipid emulsions, lipid dispersions, self-emulsifying drug delivery systems (SEDDS) and self-microemulsifying drug delivery systems (SMEDDS). In particular, SEDDS and SMEDDS are isotropic mixtures of lipids, surfactants and co-surfactants that can spontaneously disperse in aqueous media and form fine emulsions (SEDDS) or microemulsions (SMEDDS). The lipids useful in the formulation of the present invention include any natural or synthetic lipids, including but not limited to sesame seed oil, olive oil, castor oil, peanut oil, fatty acid esters, glycerol esters, Labrafil®, Labrasol®, Cremophor®, Solutol®, Tween®, Capryol®, Capmul®, Captex® and Peceol®.

[0088] B. Administration The compounds and compositions of the present invention can be delivered by any suitable means, including oral, parenteral and topical methods. The compositions may be formulated as liquids, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders and aerosols.

[0089] Pharmaceuticals are preferably present in unit dosage form.In such form, preparation is subdivided into unit doses containing appropriate amounts of the compounds and compositions of the present invention.The unit dosage form can be a packaged preparation, the package containing discrete amounts of preparation (for example, packaged tablets, capsules, and powders in vials or ampoules).Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or the appropriate number of any of these in packaged form.

[0090] The compounds and compositions of the present invention can be co-administered with other agents. Co-administration includes administration of the compounds or compositions of the present invention within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20 or 24 hours of the other agents. Co-administration also includes administration at the same time, near the same time (e.g., within about 1, 5, 10, 15, 20 or 30 minutes of each other), or sequentially in any order. Furthermore, the compounds and compositions of the present invention can each be administered once a day, or two, three or more times a day to provide a preferred daily dosage level.

[0091] In some embodiments, coadministration can be achieved by coformulation, i.e., preparing a single pharmaceutical composition that contains the compounds and compositions of the invention and any other agents. Alternatively, the various components can be formulated separately.

[0092] The compounds and compositions of the present invention, as well as any other optional agents, may be present in any suitable amount and may depend on a variety of factors, including, but not limited to, the weight and age of the subject, the state of the disease, etc. Suitable dosage ranges include about 0.1 mg to about 10,000 mg, or about 1 mg to about 1000 mg, or about 10 mg to about 750 mg, or about 25 mg to about 500 mg, or about 50 mg to about 250 mg. Suitable dosages also include about 1 mg, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 mg.

[0093] The compositions may also include other compatible therapeutic agents. The compounds described herein may be used in combination with each other, with other active agents known to be useful in modulating the glucocorticoid receptor, or with adjuvants that may not be effective alone but may contribute to the effectiveness of the active agent.

[0094] V. Methods for Modulating Glucocorticoid Receptors and Treating Disorders In some embodiments, the present invention provides a method of modulating a glucocorticoid receptor, the method comprising contacting the glucocorticoid receptor with a compound of the present invention, thereby modulating the glucocorticoid receptor.

[0095] In some embodiments, the present invention provides a method of treating a disorder through antagonizing a glucocorticoid receptor, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention, thereby treating the disorder.

[0096] In some other embodiments, the present invention provides methods of treating a disorder through antagonizing the glucocorticoid receptor, comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention, thereby treating the disorder.

[0097] In an exemplary embodiment, the GR modulator is an antagonist of GR activity (also referred to herein as a "glucocorticoid receptor antagonist"). A glucocorticoid receptor antagonist, as used herein, refers to any composition or compound that inhibits any biological response associated with the binding of a GR to a glucocorticoid receptor (GR) by partially or completely inhibiting (antagonizing) the binding of the GR agonist (e.g., cortisol and synthetic or natural cortisol analogs) to the agonist.

[0098] In a related embodiment, the GR modulator is a specific glucocorticoid receptor antagonist. As used herein, a specific glucocorticoid receptor antagonist refers to a composition or compound that inhibits any biological response associated with the binding of GR to an agonist by preferentially binding to GR rather than another nuclear receptor (NR). In some embodiments, a specific glucocorticoid receptor antagonist preferentially binds to GR rather than to mineralocorticoid receptor (MR) or progesterone receptor (PR). In an exemplary embodiment, a specific glucocorticoid receptor antagonist preferentially binds to GR rather than to mineralocorticoid receptor (MR). In another exemplary embodiment, a specific glucocorticoid receptor antagonist preferentially binds to GR rather than to progesterone receptor (PR).

[0099] In a related embodiment, the specific glucocorticoid receptor antagonist is a K receptor antagonist for other nuclear receptors. d A binding constant (K d In another embodiment, the specific glucocorticoid receptor antagonist binds to GR at the K d A binding constant (K dIn another embodiment, the specific glucocorticoid receptor antagonist binds to GR at the K d A binding constant (K d ) binds to GR.

[0100] Examples of disorders or conditions suitable for use with the present invention include obesity, diabetes, cardiovascular disease, hypertension, Syndrome X, depression, anxiety, glaucoma, human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS), neurodegeneration, Alzheimer's disease, Parkinson's disease, Huntington's disease, cognitive enhancement, Cushing's syndrome, Addison's disease, osteoporosis, frailty, muscle weakness, inflammatory diseases, osteoarthritis, rheumatoid arthritis, asthma and rhinitis, diseases related to adrenal function, viral infections, immune deficiencies, immune regulation, autoimmune diseases, allergies, wound healing, obsessive-compulsive behavior, multidrug resistance, addiction, psychosis, anorexia, cachexia, post-traumatic stress disorder, post-operative fractures, medical catabolism, and the like. The disorders or symptoms include, but are not limited to, major depression, mild cognitive impairment, psychosis, dementia, hyperglycemia, central serous retinopathy, alcoholism, stress disorder, antipsychotic-induced weight gain, delirium, cognitive impairment in depressed patients, cognitive decline in individuals with Down's syndrome, psychosis associated with interferon-alpha treatment, chronic pain, pain associated with gastroesophageal reflux disease, postpartum psychosis, postpartum depression, neurological disorders in premature infants, migraine headaches, and cancer (e.g., ovarian, breast, and prostate cancer). In some embodiments, the disorder or symptom may be major depression, stress disorder, or antipsychotic-induced weight gain. In other embodiments, the disorder or symptom may be Cushing's syndrome.

[0101] A. Binding Assays The GR modulators of the invention can be tested for binding activity in a variety of assays, for example, by screening for the ability to compete with a GR ligand, such as dexamethasone, for binding to the glucocorticoid receptor. Those of skill in the art will recognize that there are a number of ways to perform such competitive binding assays. In some embodiments, In this method, GR is preincubated with a labeled GR ligand and then contacted with the test compound. This type of competitive binding assay is referred to herein as binding displacement. These assays are sometimes referred to as direct binding assays (DBAs). A change (e.g., a decrease) in the amount of ligand bound to GR suggests that the molecule is a potential GR modulator. Alternatively, binding of a test compound to GR can be measured directly using a labeled test compound. This latter type of assay is called a direct binding assay.

[0102] Both direct and competitive binding assays can be used in a variety of different formats, which may be similar to those used in immunoassays and receptor binding assays. For a description of various formats for binding assays, including competitive and direct binding assays, see Basic and Clinical Immunology 7th Edition (D. Stites and A. Terr, 1999). ed.) 1991; Enzyme Immunoassay, E.T. Maggio, ed., CRC Press, Boca Raton, Florida (1980); and "Practice and Theory of Enzyme Immunoassays", P. Tijssen, Laboratory Techniques in Biochemistry and Molecular Biology, Elsevier Science Publishers BV Amsterdam (1985), each of which is incorporated herein by reference.

[0103] In a solid-phase competitive binding assay, for example, a sample compound can compete with a labeled analyte for a specific binding site on a binding agent bound to a solid surface. In this type of format, the labeled analyte can be a GR ligand, and the binding agent can be a GR bound to a solid phase. Alternatively, the labeled analyte can be a labeled GR, and the binding agent can be a solid phase GR ligand. The concentration of the labeled analyte bound to the capture agent is inversely proportional to the ability of the test compound to compete in the binding assay.

[0104] Alternatively, competitive binding assays can be performed in liquid phase, and bound labeled protein can be separated from unbound labeled protein by using any of a variety of techniques known in the art. For example, several procedures have been developed to distinguish between bound and excess bound ligand or bound and excess unbound test compound. These include identification of bound complexes by sedimentation in sucrose gradients, gel electrophoresis or gel isoelectric focusing; precipitation of receptor-ligand complexes with protamine sulfate or adsorption onto hydroxylapatite; and removal of unbound compounds or ligands by adsorption onto dextran-coated charcoal (DCC) or binding to immobilized antibodies. After separation, the amount of bound ligand or test compound is measured.

[0105] Alternatively, homogeneous binding assays can be performed that do not require a separation step. For example, the label on GR can be altered by the binding of GR to its ligand or test compound. This alteration in the labeled GR results in a decrease or increase in the signal emitted by the label, so that the measurement of the label at the end of the binding assay allows detection or quantification of the bound GR. A wide variety of labels can be used. The components can be labeled by any one of several methods. Useful radioactive labels include: 3 H, 125 I, 35 S, 14 C or 32Useful non-radioactive labels include those that incorporate P. Useful non-radioactive labels include those that incorporate fluorophores, chemiluminescent substances, phosphorescent substances, electrochemiluminescent substances, and the like. Fluorescent substances are particularly useful in analytical techniques used to detect shifts in protein structure (e.g., fluorescence anisotropy and / or fluorescence polarization). The choice of label depends on the sensitivity required, ease of conjugation with the compound, stability requirements, and available instrumentation. Various labeling or signal generation systems that may be used include those that incorporate fluorophores, chemiluminescent substances, phosphorescent substances, electrochemiluminescent substances, and the like. For a review of stems, see U.S. Patent No. 4,391,904, which is incorporated herein by reference in its entirety for all purposes. The labels can be attached directly or indirectly to the desired component of the assay according to methods well known in the art.

[0106] By using high-throughput screening methods, a large number of potential modulator compounds can be assayed. Such "compound libraries" are then screened in one or more assays as described herein to identify library members (particular chemical species or subclasses) that exhibit desired characteristic activities. Preparation and screening of chemical libraries are well known to those skilled in the art. Devices for preparing chemical libraries are commercially available (see, for example, 357MPS, 390MPS, Advanced Chem Tech, Louisville KY, Symphony, Rainin, Woburn, MA, 433A Applied Biosystems, Foster City, CA, 9050 Plus, Millipore, Bedford, MA).

[0107] B. Cell-Based Assays Cell-based assays require whole cells or cell fractions containing GR to assay for binding or modulation of GR activity by the compounds of the present invention.Exemplary cell types that can be used according to the methods of the present invention include, for example, any mammalian cell (including white blood cells, such as neutrophils, monocytes, macrophages, eosinophils, basophils, mast cells and lymphocytes, such as T cells and B cells, leukemia, Burkitt's lymphoma, tumor cells (including mouse mammary tumor virus cells), endothelial cells, fibroblasts, cardiac cells, muscle cells, breast tumor cells, ovarian carcinomas, cervical carcinomas, glioblastomas, liver cells, kidney cells and neuronal cells) and fungal cells, including yeast.Cells can be primary cells or tumor cells or other types of immortal cell lines.Of course, GR can be expressed in cells that do not express an endogenous version of GR.

[0108] In some cases, fragments of GR as well as protein fusions can be used for screening. When molecules that compete with GR ligands for binding are desired, the GR fragments used are those that can bind to those ligands (e.g., dexamethasone). Alternatively, any fragment of GR can be used as a target to identify molecules that bind to GR. GR fragments can include, for example, any fragment of at least 20, 30, 40, 50 amino acids, up to a protein that contains all but one amino acid of GR.

[0109] In some embodiments, signal transduction triggered by GR activation is used to identify GR regulators. GR signal transduction activity can be measured in many ways. For example, downstream molecular events can be monitored to measure signal transduction activity. Downstream events include those activities or manifestations that occur as a result of GR receptor stimulation. Exemplary downstream events useful in functional evaluation of transcription activation and antagonism in unaltered cells include the upregulation of several glucocorticoid response element (GRE)-dependent genes (PEPCK, tyrosine aminotransferase, aromatase). In addition, certain cell types that are sensitive to GR activation can be used (e.g., osteocalcin expression in osteoblasts, which is downregulated by glucocorticoids; primary hepatocytes that show glucocorticoid-mediated upregulation of PEPCK and glucose-6-phosphate (G-6-Pase)). GRE-mediated gene expression has also been demonstrated in transfected cell lines using well-known sequences controlled by GREs, such as the mouse mammary tumor virus promoter (MMTV) transfected upstream of a reporter gene construct. Examples of useful reporter gene constructs include luciferase (luc), alkaloid (ALK), and mitogen-activated receptor (MCR) promoters. These include lysine phosphatase (ALP) and chloramphenicol acetyltransferase (CAT). Functional evaluation of transcriptional repression can be performed in cell lines such as monocytes or human skin fibroblasts. Useful functional assays include IL-1 beta stimulated expression of IL-6; downregulation of collagenase, cyclooxygenase-2 and various chemokines (MCP-1, RANTES); LPS stimulated release of cytokines, such as TNFα; or assays measuring the expression of genes controlled by NFkB or AP-1 transcription factors in transfected cell lines.

[0110] Typically, the compound tested in the whole cell assay is also tested in a cytotoxicity assay. The cytotoxicity assay is used to measure the extent to which the detected regulatory effect is due to the effect of cells that bind to non-GR. In an exemplary embodiment, the cytotoxicity assay comprises contacting constitutively active cells with the test compound. Any reduction in cell activity indicates a cytotoxic effect.

[0111] C. Specificity The compounds of the present invention may be subjected to specificity assays (also referred to herein as selectivity assays). Typically, specificity assays involve testing compounds that bind to GR in vitro or in cell-based assays for the extent to which they bind to non-GR proteins. Selectivity assays may be performed in vitro or in cell-based systems as described above. Binding may be tested against any suitable non-GR protein, including antibodies, receptors, enzymes, and the like. In an exemplary embodiment, the non-GR binding protein is a cell surface receptor or a nuclear receptor. In another exemplary embodiment, the non-GR protein is a steroid receptor (e.g., estrogen receptor, progesterone receptor, androgen receptor, or mineralocorticoid receptor).

[0112] The terms and expressions used herein are used as descriptive and not limiting terms, and the use of such terms and expressions to exclude the equivalents of the properties shown and described or parts thereof is not intended, and it is recognized that various modifications may be within the scope of the invention as claimed. Furthermore, any one or more properties of any embodiment of the invention may be combined with any one or more other properties of any other embodiment of the invention without departing from the scope of the invention. For example, the properties of the GR modulator compounds apply equally to the methods of treating disease conditions and / or pharmaceutical compositions described herein. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes. EXAMPLES

[0113] VI. Working Examples Structures are named according to standard IUPAC nomenclature using the CambridgeSoft ChemDraw naming package.

[0114] at ambient temperature using a Bruker Avance III spectrometer (400 MHz) 1 1 H NMR spectra were recorded.

[0115] Mass spectrometry (LCMS) experiments measuring retention times and associated mass ions were performed as follows: Agilent Infinity 1260 LC6120 with positive and negative ion electrospray and ELS / UV@254 nm detection using an Agilent Zorbax Extend C18, Rapid Resolution HT 1.8 micron C18 30×4.6 mm column and a flow rate of 2.5 mL / min. The experiment was carried out using a quadrupole mass spectrometer. The initial solvent system was 95% water with 0.1% formic acid (solvent A) and 5% acetonitrile with 0.1% formic acid (solvent B), which was then gradient to 5% solvent A and 95% solvent B over the next 3.0 minutes, then the flow rate was increased to 4.5 mL / min and held at 95% B for 0.5 minutes. Over 0.1 minutes, the gradient returned to 95% A and 5% B and 3.5 mL / min, and held at these conditions for 0.3 minutes; for the final 0.1 minutes, the gradient returned to the original starting conditions of 95% A 5% B at 2.5 mL / min. Intermediate 1A. (4aR,8aS)-Methyl 1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate [ka]

[0116] A solution of (4aR,8aS)-6-tert-butyl 4a-methyl 1-(4-fluorophenyl)-4a,5,7,8,8a,9-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate (WO 2005087769; 0.35 g, 0.815 mmol) in HCl (4M solution in dioxane) (4.07 ml, 16.30 mmol) was stirred at room temperature for 1 hour, after which the solvent was evaporated to give a white solid. This material was dissolved in dichloromethane (10 ml) and Hunig's base (0.712 ml, 4.07 mmol) was added followed by 4-(trifluoromethyl)benzene-1-sulfonyl chloride (0.239 g, 0.978 mmol). The reaction mixture was stirred at room temperature for 4 days, then the solvent was evaporated and the crude product was purified by column chromatography on silica gel (gradient: 20-40% ethyl acetate in isohexane) to give (4aR,8aS)-methyl 1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate as a colourless gum (0.38 g). LCMS: RT 2.66 min, m+H=538.0.

[0117] The following intermediates were similarly prepared from the appropriate starting materials: Intermediate 1B. (4aR,8aS)-Methyl 6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate [ka]

[0118] LCMS: RT3.12min, m+H=538.1 / 540.1 Intermediate 1C. (4aR,8aS)-Methyl 6-((3,4-difluorophenyl)sulfonyl) (phenyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate [ka]

[0119] LCMS:RT2.80min,m+H=506.0. Intermediate 2A. (4aR,8aS)-tert-Butyl 1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8,8a,9-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate [ka]

[0120] 2-Bromopyridine (0.690 ml, 7.10 mmol) in dry tetrahydrofuran (5 ml) was added to butyllithium (2.5 M in hexane) (2.91 ml, 7.28 mmol) in dry tetrahydrofuran (3 ml) at -78°C. The reaction mixture was stirred at -78°C for 45 minutes. A solution of (4aR,8aS)-6-tert-butyl 4a-methyl 1-(4-fluorophenyl)-4a,5,7,8,8a,9-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate (1.0 g, 2.328 mmol) in dry tetrahydrofuran (8 ml) was added dropwise and the reaction mixture was stirred at -78°C for 45 minutes. Water (10 ml) was added and the reaction mixture was stirred at room temperature for 10 minutes. The aqueous phase was extracted with ethyl acetate (2 x 10 ml). The combined organic phases were washed with brine (10 ml), dried (magnesium sulfate) and the solvent removed to give a brown oil. The crude product was purified by column chromatography on silica gel (gradient: 10-70% ethyl acetate in isohexane) to give (4aR,8aS)-tert-butyl 1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8,8a,9-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (766 mg) as a pale yellow solid. LCMS: RT 2.70 min, m+H=477.

[0121] The following intermediates were similarly prepared from the appropriate starting materials: Intermediate 2B. (4aR,8aS)-tert-Butyl 1-(4-fluorophenyl)-4a-(4-(trifluoromethyl)picolinoyl)-4a,5,7,8,8a,9-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate [ka]

[0122] LCMS: RT2.88 min, m+H=545.3. Intermediate 2C. (4aR,8aS)-tert-butyl 1-(4-fluorophenyl)-4a-(thiazole-2-carbonyl)-4a,5,7,8,8a,9-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate [ka]

[0123] Instead of tetrahydrofuran, diethyl ether is used as the solvent. LCMS: RT 2.67 min, m+H=482.9. Intermediate 2D. (R)-tert-Butyl 1-(4-fluorophenyl)-4a-(4-methylpicolinoyl)-4a,5,7,8,8a,9-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate [ka]

[0124] LCMS: RT2.77 min, m+H=491.3. Intermediate 2E. (R)-tert-Butyl 1-(4-fluorophenyl)-4a-(thiazole-5-carbonyl)-4a,5,7,8,8a,9-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate [ka]

[0125] Instead of tetrahydrofuran, diethyl ether is used as the solvent. LCMS: RT 2.51 min, m+H=483.2. Intermediate 3A. 4-(benzylthio)-1H-1,2,3-triazole [ka]

[0126] Benzyl bromide (11.79 ml, 99 mmol) was added dropwise to a solution of sodium 1H-1,2,3-triazole-4-thiolate (12.2 g, 99 mmol) in ethanol (100 ml) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 20 min. The reaction mixture was diluted with ethyl acetate (100 ml), washed with water (100 ml), brine (100 ml) and dried (sodium sulfate). Removal of the solvent gave 4-(benzylthio)-1H-1,2,3-triazole (16.9 g) as a white solid. LCMS: RT 1.66 min, m+H=191; 1H NMR (400 MHz, CDCl3): δ 9.72 (1H, v br s), 7.47 (1H, s), 7.30-7.21 (5H, m), 4.12 (2H, s). Intermediate 3B. 2-(Benzylthio)-6-(trifluoromethyl)pyridine [ka]

[0127] To a suspension of sodium hydride (0.170 g, 4.24 mmol) in tetrahydrofuran (10 ml) was added dropwise benzylthiol (0.338 ml, 2.88 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 15 min and then 2-fluoro-6-(trifluoromethyl)pyridine (0.365 ml, 3.03 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min. Methanol (1 ml) was carefully added and the reaction mixture was stirred at 0° C. for a further 10 min and then water (5 ml) and dichloromethane (10 ml) were added. The organic layer was collected using a phase separation cartridge and then concentrated in vacuo to give 2-(benzylthio)-6-(trifluoromethyl)pyridine (538 mg) as a colourless oil. LCMS: 2.80 min at RT, m+H=270.1. Intermediate 4A. 4-(benzylthio)-2-methyl-2H-1,2,3-triazole [ka]

[0128] Iodomethane (2.409 ml, 38.7 mmol) was added dropwise to a mixture of 4-(benzylthio)-1H-1,2,3-triazole (3.7 g, 19.35 mmol) and potassium carbonate (5.88 g, 42.6 mmol) in N,N-dimethylformamide (40 ml) at 0° C. The reaction mixture was then allowed to warm to room temperature and stirred for 1 h. Water (40 ml) and ethyl acetate (40 ml) were added and the phases were separated. The organic phase was washed with water (2×40 ml), brine (40 ml), dried (sodium sulfate) and the solvent removed to give a yellow oil. The crude product was purified by column chromatography on silica gel (gradient: 0-100% ethyl acetate in isohexane) to give 4-(benzylthio)-2-methyl-2H-1,2,3-triazole (1.61 g) as the major first-eluting regioisomeric product as a colorless oil. LCMS: RT 2.05 min, m+H=206; 1H NMR (400 MHz, DMSO-d6): δ 7.68 (1H, s), 7.35 - 7.19 (5H, m), 4.18 (2H, s), 4.11 (3H, s). Intermediate 4B. 4-(benzylthio)-1-methyl-1H-1,2,3-triazole [ka]

[0129] Obtained as a pale yellow oil (883 mg) as the third eluting regioisomeric product from the above reaction. LCMS: RT 1.68 min, m+H=206; 1H NMR (400 MHz, DMSO-d6): δ 8.02 (1H, s), 7.34 - 7.19 (5H, m), 4.12 (2H, s), 4.00 (3H, s).

[0130] The following intermediates were similarly prepared from the appropriate starting materials: Intermediate 4C. 4-(Benzylthio)-2-propyl-2H-1,2,3-triazole [ka]

[0131] Obtained as the major first eluting regioisomeric product. LCMS: RT 2.36 min, m+H=234.2; 1H NMR (400 MHz, DMSO-d6): δ 7.69 (1H, s), 7.28-7.27 (4H, m), 7.25-7.20 (1H, m), 4.32 (2H, t, J = 7.0 Hz), 4.18 (2H, s), 1.83 (2H, sext, J = 7.0 Hz), 0.78 (3H, t, J = 7.0 Hz). Intermediate 4D. 4-(Benzylthio)-2-isopropyl-2H-1,2,3-triazole [ka]

[0132] Obtained as the major first eluting regioisomeric product. LCMS: RT 2.41 min, m+H=234; 1H NMR (400 MHz, DMSO-d6): δ 7.67 (1H, s), 7.31-7.21 (5H, m), 4.76 (1H, sept, J = 6.7 Hz), 4.17 (2H, s), 1.44 (6H, d, J = 6.7 Hz). Intermediate 4E. 4-(Benzylthio)-2-ethyl-2H-1,2,3-triazole [ka]

[0133] Obtained as the major first eluting regioisomeric product. LCMS: RT 2.24 min, m+H=220; 1H NMR (400 MHz, DMSO-d6): δ 7.69 (1H, s), 7.32 - 7.21 (5H, m), 4.39 (2H, q, J = 7.3 Hz), 4.18 (2H, s), 1.40 (3H, t, J = 7.3 Hz). Intermediate 4F. 4-(Benzylthio)-1-methyl-1H-1,2,3-triazole [ka]

[0134] Obtained as the minor second eluting regioisomeric product. LCMS: RT 1.79 min, m+H=206; 1H NMR (400 MHz, DMSO-d6): δ 7.71 (1H, s), 7.36 - 7.23 (3H, m), 7.22 - 7.14 (2H, m), 4.09 (2H, s), 3.73 (3H, s). Intermediate 4G. 1-Propyl-1H-1,2,3-triazole-5-sulfonyl chloride [ka]

[0135] Obtained as a minor second eluting regioisomeric product. LCMS: RT2.08 min, m+H=234.2;1H NMR (400 MHz, DMSO-d6): δ 7.74 (1H, s), 7.38-7.12 (5H, m), 4.13 (2H, s), 4.06 (2H, t, J = 7.0 Hz), 1.66 (2H, sext, J = 7.0 Hz), 0.74 (3H, t, J = 7.0 Hz). Intermediate 4H. 4-(Benzylthio)-1-isopropyl-1H-1,2,3-triazole [ka]

[0136] Obtained as a minor third eluting regioisomeric product. LCMS: RT 1.99 min, m+H=234; 1H NMR (400 MHz, DMSO-d6): δ 8.10 (1H, s), 7.30-7.18 (5H, m), 4.76 (1H, sept, J = 6.7 Hz), 4.10 (2H, s), 1.43 (6H, d , J = 6.7 Hz). Intermediate 5A. 2-Methyl-2H-1,2,3-triazole-4-sulfonyl chloride [ka]

[0137] N-Chlorosuccinimide (3.38 g, 25.3 mmol) was added to a solution of 4-(benzylthio)-2-methyl-2H-1,2,3-triazole (1.3 g, 6.33 mmol) in acetic acid (32 ml) and water (16 ml) and the mixture was stirred at room temperature for 1 hour. Water (40 ml) was added and the mixture was extracted with ethyl acetate (40 ml). The organic phase was washed with saturated aqueous sodium bicarbonate (40 ml), brine (40 ml), dried (magnesium sulfate) and the solvent removed to give 2-methyl-2H-1,2,3-triazole-4-sulfonyl chloride (1.35 g) as a pale yellow oil. LCMS (quenched in morpholine): RT 1.09 min, m+H+morpholine-Cl=233.1; 1H NMR (400 MHz, CDCl3): δ 8.11 (1H, s), 4.36 (3H, s).

[0138] The following intermediates were similarly prepared from the appropriate starting materials: Intermediate 5B. 1-Methyl-1H-1,2,3-triazole-4-sulfonyl chloride [ka]

[0139] LCMS (quenched in morpholine): RT 0.86 min, m+H+morpholine-Cl=233.1; 1H NMR (400 MHz, CDCl3): δ 8.22 (1H, s), 4.25 (3H, s). Intermediate 5C. 2-Propyl-2H-1,2,3-triazole-4-sulfonyl chloride [ka]

[0140] LCMS (quenched in morpholine): RT 1.62 min, m+H+morpholine-Cl=261.2; 1H NMR (400 MHz, CDCl3): δ 8.11 (1H, s), 4.53 (2H, t, J = 7.1 Hz), 2.08 (2H, sext, J = 7.1 Hz), 0.98 (3H, t, J = 7.1 Hz). Intermediate 5D. 2-Isopropyl-2H-1,2,3-triazole-4-sulfonyl chloride [ka]

[0141] LCMS (quenched in morpholine): R 1.64 min, m+H+morpholine-Cl=261; 1H NMR (400 MHz, CDCl3): δ 7.62 (1H, s), 4.76 (1H, sept., J = 6.7 Hz), 1.46 (6H, d, J = 6.7 Hz). Intermediate 5E. 2-Ethyl-2H-1,2,3-triazole-4-sulfonyl chloride [ka]

[0142] LCMS (quenched in morpholine): RT 1.37 min, m+H+morpholine-Cl=247; 1H NMR (400 MHz, CDCl3): δ 8.11 (1H, s), 4.62 (2H, q, J = 7.4 Hz), 1.66 (3H, t, J = 7.4 Hz). Intermediate 5F. 6-(Trifluoromethyl)pyridine-2-sulfonyl chloride [ka]

[0143] LCMS (quenched into morpholine): RT 1.84 min, m+H+morpholine-Cl=297.1. Intermediate 5G. 1-Methyl-1H-1,2,3-triazole-5-sulfonyl chloride [ka]

[0144] Chlorine gas was bubbled through a solution of 4-(benzylthio)-1-methyl-1H-1,2,3-triazole (200 mg, 0.974 mmol) in dichloromethane (15 ml) and water (3 ml) at 0° C. for 2 min, then the reaction mixture was stirred at 0° C. for a further 5 min. Water (10 ml) was added and the mixture was extracted with dichloromethane (10 ml). The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to give 1-methyl-1H-1,2,3-triazole-5-sulfonyl chloride (317 mg) as a colourless oil. LCMS (quenched into morpholine): RT 1.17 min, m+H+morpholine-Cl=233.1; 1H NMR (400 MHz, CDCl3): δ 8.27 (1H, s), 4.40 (3H, s).

[0145] The following intermediates were similarly prepared from the appropriate starting materials: Intermediate 5H. 1-Propyl-1H-1,2,3-triazole-5-sulfonyl chloride [ka]

[0146] LCMS (quenched in morpholine): RT 1.58 min, m+H+morpholine-Cl=261.1;1H NMR (400 MHz, CDCl3): δ 8.27 (1H, s), 4.68-4.64 (2H, m), 2.12 (2H, sext, J = 7.1 Hz), 1.05 (3H, t, J = 7.1 Hz). Intermediate 5I. 3-Fluoro-4-(trifluoromethyl)benzene-1-sulfonyl chloride [ka]

[0147] 3-Fluoro-4-(trifluoromethyl)aniline (5 g, 27.9 mmol) was dissolved in acetonitrile (10 ml), cooled to 0° C., and treated with tetrafluoroboric acid (48% in water, 6.49 ml, 41.9 mmol) and tert-butyl nitrite (4.98 ml, 41.9 mmol). The reaction mixture was maintained at 0° C. for 1 h. During this time, sulfur dioxide gas was bubbled through a suspension of copper(I) chloride (4.15 g, 41.9 mmol) in acetonitrile (40 ml) at 0° C. with vigorous stirring for 30 min, until the suspension was saturated with the gas. When the diazotization reaction was complete after 1 h, this solution was added dropwise to the suspension of copper(I) chloride, allowing vigorous evolution of gas. The reaction mixture was then allowed to warm to room temperature and stirred for 1 h, after which it was poured onto 100 ml of ice / water slurry. Diethyl ether (150 ml) was added to form a precipitate which was removed by filtration. The filtrate was washed with water (100 ml) and brine (100 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to give 3-fluoro-4-(trifluoromethyl)benzene-1-sulfonyl chloride (6.62 g) as an orange oil. LCMS (quenched into morpholine): RT 2.25 min, m+H+morpholine-Cl=314.1. Intermediate 5J. 1-Isopropyl-1H-1,2,3-triazole-4-sulfonyl chloride [ka]

[0148] N-Chlorosuccinimide (0.458 g, 3.43 mmol) was added to a solution of 4-(benzylthio)-1-isopropyl-1H-1,2,3-triazole (0.20 g, 0.857 mmol) in acetic acid (6 ml) and water (3 ml) and the resulting mixture was stirred at room temperature for 1 h. Water (8 ml) was added and the mixture was extracted with ethyl acetate (8 ml). The organic phase was washed with saturated aqueous sodium bicarbonate (8 ml), brine (8 ml) and dried. Removal of the solvent over magnesium sulfate gave 1-isopropyl-1H-1,2,3-triazole-4-sulfonyl chloride (311 mg) as a colorless oil. LCMS (quenched into morpholine): R 1.47 min, m+H+morpholine-Cl=261; 1H NMR (400 MHz, CDCl3): δ 8.26 (1H, s), 4.95 (1H, sept., J = 6.7 Hz), 1.68 (6H, d, J = 6.7 Hz).

[0149] The following intermediates were similarly prepared from the appropriate starting materials: Intermediate 5K. 2H-1,2,3-triazole-4-sulfonyl chloride [ka]

[0150] LCMS (quenched in morpholine): RT 1.64 min, m+H+morpholine-Cl=219.1; 1H NMR (400 MHz, CDCl3): δ 9.06 (1H, br s), 8.31 (1H, s). Intermediate 6A. (R)-tert-Butyl 1-(4-fluorophenyl)-4a-(thiazole-4-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate [ka]

[0151] A solution of 4-bromo-2-(trimethylsilyl)thiazole (3.00 g, 12.70 mmol) in dry ether (3 mL) was added to a solution of isopropylmagnesium chloride (2M in tetrahydrofuran) (6.35 ml, 12.70 mmol) in dry ether (16 mL) at 0° C. The resulting suspension was stirred at 0° C. for 50 min. A solution of (R)-6-tert-butyl 4a-methyl 1-(4-fluorophenyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate (1.81 g, 4.23 mmol) in dry ether:tetrahydrofuran (4:1; total volume 15 mL) at 0° C. was added dropwise to the suspension and the reaction mixture was stirred at room temperature for 3.5 h. Water (50 mL) was added and the reaction mixture was stirred at room temperature for 10 min. The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give an orange oil. The crude orange oil was diluted with acetonitrile (30 mL) and 1 M HCl (4.2 mL) and stirred at room temperature for 45 min. The reaction was diluted with ethyl acetate (100 mL) and washed sequentially with brine (50 mL), saturated aqueous sodium bicarbonate (50 mL), and then brine (50 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo to give an orange oil. The crude product was purified by column chromatography on silica gel (gradient: 0-45% ethyl acetate in isohexane) to give (R)-tert-butyl 1-(4-fluorophenyl)-4a-(thiazole-4-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (932 mg) as a pale yellow foamy solid. LCMS (Method F, ES-API): RT 2.55 min, m+H=481.0. Intermediate 7A. (4aR,8aS)-tert-butyl 1-(4-fluorophenyl)-4a-(thiazole-4-carbonyl)-4a,5,7,8,8a,9-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate [ka]

[0152] A solution of (R)-tert-butyl 1-(4-fluorophenyl)-4a-(thiazole-4-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (420 mg, 0.874 mmol) in methanol (40 mL) was hydrogenated on an H-Cube (10% palladium / carbon, 30×4 mm, full hydrogen, 55° C., 1 mL / min). Removal of the solvent gave (4aR,8aS)-tert-butyl 1-(4-fluorophenyl)-4a-(thiazole-4-carbonyl)-4a,5,7,8,8a,9-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (385 mg) as an orange solid. LCMS (Method F, ES-API): RT2.51 min, m+H=483.2. Example 1A. ((4aR,8aS)-1-(4-Fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone [ka]

[0153] A solution of 2-bromopyridine (0.109 ml, 1.116 mmol) in dry tetrahydrofuran (2 ml) was added to a solution of butyllithium (2.5 M in hexane) (0.417 ml, 1.042 mmol) in dry tetrahydrofuran (1.2 ml) and the reaction mixture was stirred under nitrogen at −78° C. for 45 minutes. A solution of (4aR,8aS)-methyl 1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate (0.2 g, 0.372 mmol) in dry tetrahydrofuran (2 ml) was then added dropwise. The reaction mixture was stirred at -78°C for 45 minutes then quenched by the addition of 10:1 methanol:acetic acid (5ml) and stirred at room temperature for a further 10 minutes. The mixture was diluted with ethyl acetate (200ml), washed with saturated aqueous ammonium chloride (2x50ml) and brine (50ml), dried (magnesium sulfate), filtered and evaporated to give a colourless gum. The crude product was Purification by column chromatography on silica gel (gradient: 10% ethyl acetate in dichloromethane) gave ((4aR,8aS)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone (0.06 g) as a white solid. LCMS:RT2.76min,m+H=585.0;1H NMR (400 MHz, CDCl3):δ 8.60-8.56 (1H, m), 7.81-7.76 (4H, m), 7.70-7.65 (2H, m), 7.48-7.39 (3H, m), 7.29 (1H, s), 7.16-7.10 (2H, m), 5.62 (1H, dd, J = 12.3, 2.0 Hz), 4.27 (1H, d, J = 16.2 Hz), 3.99-3.94 (1H, m), 3.40 (1H, dd, J = 16.7, 11.2 Hz), 2.69 (1H, dd, J = 16.4, 5.9 Hz), 2.56-2.40 (4H, m), 1.79-1.68 (2H, m).

[0154] The following examples were similarly prepared from the appropriate intermediates: Example 1B. ((4aR,8aS)-6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone [ka]

[0155] LCMS: RT3.34 min, m+H=584.8 / 586.8; 1H NMR (400 MHz, CDCl3): δ 8.56 (1H, dt, J = 4.8, 1.3 Hz), 7.79-7.78 (2H, m), 7.72 (1H, d, J = 1.9 Hz), 7.50-7.41 (5H, m), 7.29 (1H, s), 7.17-7.11 (2H, m), 5.56 (1H, dd, J = 12.3, 1.9 Hz), 4.26 (1H, d, J = 16.9 Hz), 3.98-3.94 (1H, m), 3.39 (1H, dd, J = 16.0, 11.8 Hz), 2.69 (1H, dd, J = 16.1, 6.0 Hz), 2.58-2.40 (4H, m), 1.81-1.70 (2H, m). Example 1C. ((4aR,8aS)-6-((3,4-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone [ka]

[0156] LCMS: RT2.63 min, m+H=553.0;1H NMR (400 MHz, CDCl3):δ 8.60-8.59 (1H, m), 7.83-7.77 (2H, m), 7.50-7.40 (5H, m), 7.30 (1H, s), 7.25-7.18 (1H, m), 7.17-7.11 (2H, m), 5.57 (1H, dd, J = 12.3, 2.0 Hz), 4.29 (1H, d, J = 16.9 Hz), 3.95-3.92 (1H, m), 3.40 (1H, dd, J = 16.0, 11.8 Hz), 2.69 (1H, dd, J = 16.3, 6.0 Hz), 2.56-2.40 (4H, m), 1.80-1.68 (2H, m). Example 2A. ((4aR,8aS)-1-(4-Fluorophenyl)-6-((2-propyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone [ka]

[0157] A solution of (4aR,8aS)-tert-butyl 1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8,8a,9-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (200 mg, 0.420 mmol) in 4M HCl / dioxane (2098 μl, 8.39 mmol) was stirred at room temperature for 45 min. The solvent was removed to give a pale yellow solid. This was dissolved in dichloromethane (8 mL) and diisopropylamine (367 μl, 2.098 mmol) and then 2-propyl-2H-1,2,3-triazole-4-sulfonyl chloride (117 mg, 0.420 mmol) was added. The reaction mixture was stirred at room temperature for 15 min and the solvent was removed to give a brown oil. The crude product was purified by column chromatography on silica gel (gradient: 0-70% ethyl acetate in cyclohexane) to give ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-propyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone (156 mg) as a white solid. LCMS:RT2.60min,m+H=550.0;1H NMR (400 MHz, CDCl3):δ 8.66 (1H, ddd, J = 4.7, 1.7, 0.9 Hz), 7.85 - 7.76 (3H, m), 7.51 - 7.45 (2H, m), 7.43 (1H, ddd, J = 7.1, 4.7, 1.7 Hz), 7.33 (1H, s), 7.19 - 7.09 (2H, m), 5.68 (1H, dd, J = 12.4, 2.1 Hz), 4.43 (2H, t, J = 7.1 Hz), 4.37 (1H, d, J = 16.2 Hz), 4.00 - 3.93 (1H, m), 3.46 (1H, dd, J = 16.2, 11.1 Hz), 2.70 (1H, dd, J = 16.2, 6.0 Hz), 2.64 - 2.36 (4H, m), 2.02 (2H, sextet, J = 7.3 Hz), 1.79 - 1.71 (2H, m), 0.94 (3H, t, J = 7.3 Hz).

[0158] The following examples were similarly prepared from the appropriate intermediates: Example 2B. ((4aR,8aS)-1-(4-Fluorophenyl)-6-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone [ka]

[0159] LCMS:RT2.45min,m+H=549.1;1H NMR (400 MHz, CDCl3):δ 8.64 (1H, ddd, J = 4.7, 1.7, 0.9 Hz), 7.85-7.82 (1H, m), 7.79 (1H, td, J = 7.3, 1.7 Hz), 7.70-7.64 (2H, m), 7.52-7.45 (2H, m), 7.43 (1H, ddd, J = 7.3, 4.8, 1.5 Hz), 7.33 (1H, s), 7.19-7.08 (2H, m), 5.52 (1H, dd, J = 11.9, 2.1 Hz), 4.35 (1H, d, J = 16.2 Hz), 4.15-4.02 (2H, m), 3.88-3.81 (1H, m), 3.45 (1H, dd, J = 15.5, 11.1 Hz), 2.69 (1H, dd, J = 16.2, 6.0 Hz), 2.56 (1H, d, J = 16.2 Hz), 2.48-2.33 (2H, m), 2.26 (1H, d, J = 11.9 Hz), 1.90 (2H, sextet, J = 7.3 Hz), 1.82-1.65 (2H, m), 0.91 (3H, t, J = 7.3 Hz). Example 2C. ((4aR,8aS)-1-(4-Fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone [ka]

[0160] LCMS:RT2.61min,m+H=590.0;1H NMR (400 MHz, CDCl3):δ 8.86 (1H, d, J = 5.0 Hz), 8.10 (1H, s), 7.81 (1H, s), 7.70-7.62 (1H, m), 7.52-7.44 (2H, m), 7.33 (1H, s), 7.20-7.11 (2H, m), 5.64 (1H, dd, J = 12.5, 2.0 Hz), 4.26 (3H, s), 4.25 (1H, d, J = 16.2 Hz), 4.02-3.90 (1H, m), 3.44 (1H, dd, J = 16.2, 10.8 Hz), 2.73 (1H, dd, J = 16.2, 5.9 Hz), 2.67-2.53 (3H, m), 2.43 (1H, qd, J = 13.2, 5.0 Hz), 1.88-1.75 (2H, m). Example 2D. ((4aR,8aS)-1-(4-Fluorophenyl)-6-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone [ka]

[0161] LCMS:RT2.72min,m+H=617.0;1H NMR (400 MHz, CDCl3):δ 8.86 (1H, d, J = 5.0 Hz), 8.13-8.08 (1H, m), 7.70-7.62 (3H, m), 7.51-7.42 (2H, m), 7.33 (1H, s), 7.20-7.10 (2H, m), 5.49 (1H, dd, J = 12.0, 2.0 Hz), 4.23 (1H, d, J = 16.1 Hz), 4.09 (2H, t, J = 7.2 Hz), 3.88-3.78 (1H, m), 3.43 (1H, dd, J = 16.1, 11.0 Hz), 2.71 (1H, dd, J = 16.3, 6.0 Hz), 2.60 (1H, d, J = 16.3 Hz), 2.49-2.32 (2H, m), 2.27 (1H, d, J = 12.1 Hz), 1.90 (2H, sextet, J = 7.2 Hz), 1.83-1.68 (2H, m), 0.91 (3H, t, J = 7.2 Hz). Example 2E. ((4aR,8aS)-1-(4-Fluorophenyl)-6-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone [ka]

[0162] LCMS:RT2.45min,m+H=554.9;1H NMR (400 MHz, CDCl3):δ 8.04 (1H, d, J = 3.1 Hz), 7.74 (1H, s), 7.69 (1H, d, J = 0.5 Hz), 7.65 (1H, d, J = 3.1 Hz), 7.53-7.46 (2H, m), 7.40 (1H, s), 7.21-7.13 (2H, m), 5.47 (1H, dd, J = 12.0, 2.1 Hz), 4.23 (1H, d, J = 16.2 Hz), 4.12 (2H, t, J = 7.2 Hz), 3.94-3.85 (1H, m), 3.44 (1H, dd, J = 16.2, 11.1 Hz), 2.72 (1H, dd, J = 16.2, 6.0 Hz), 2.62 (1H, d, J = 16.2 Hz), 2.54-2.41 (2H, m), 2.36 (1H, d, J = 12.1 Hz), 1.95 (2H, sextet, J = 7.3 Hz), 1.87-1.75 (2H, m), 0.95 (3H, t, J = 7.3 Hz). Example 2F. ((4aR,8aS)-1-(4-fluorophenyl)-6-((3-fluorophenyl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone [ka]

[0163] LCMS:RT2.65min,m+H=534.9;1H NMR (400 MHz, CDCl3):δ 8.66 (1H, ddd, J = 4.7, 1.7, 1.0 Hz), 7.88-7.77 (2H, m), 7.53-7.43 (5H, m), 7.41-7.35 (1H, m), 7.35 (1H, s), 7.29-7.22 (1H, m), 7.22-7.12 (2H, m), 5.62 (1H, dd, J = 12.2, 2.1 Hz), 4.35 (1H, d, J = 16.2 Hz), 3.98-3.86 (1H, m), 3.44 (1H, dd, J = 16.2, 11.1 Hz), 2.70 (1H, dd, J = 16.2, 5.9 Hz), 2.56 (1H, d, J = 16.2 Hz), 2.51-2.41 (2H, m), 2.39 (1H, d, J = 12.2 Hz), 1.83-1.65 (2H, m). Example 2G. ((4aR,8aS)-1-(4-Fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone [ka]

[0164] LCMS:RT2.79min,m+H=584.9;1H NMR (400 MHz, CDCl3):δ 8.66-8.61 (1H, m), 7.94 (1H, s), 7.88 (1H, br. d, J = 7.9 Hz), 7.84-7.77 (3H, m), 7.61 (1H, t, J = 7.8 Hz), 7.53-7.41 (3H, m), 7.33 (1H, s), 7.21-7.11 (2H, m), 5.66 (1H, dd, J = 12.2, 2.1 Hz), 4.31 (1H, d, J = 16.2 Hz), 4.03-3.91 (1H, m), 3.43 (1H, dd, J = 16.2, 11.2 Hz), 2.71 (1H, dd, J = 16.2, 5.9 Hz), 2.62-2.35 (4H, m), 1.85 - 1.68 (2H, m). Example 2H. ((4aR,8aS)-1-(4-Fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone [ka]

[0165] Instead of HCl / dioxane, trifluoroacetic acid / dichloromethane is used. LCMS: RT 2.44 min, m+H=589.2; 1H NMR (400 MHz, CDCl3): δ 8.84 (1H, d, J = 5.0 Hz), 8.10 (1H, m), 7.66-7.65 (3H, m), 7.50-7.45 (2H, m), 7.33 (1H, s), 7.18-7.12 (2H, m), 5.47 (1H, dd, J = 11.8, 2.0 Hz), 4.22 (1H, d, J = 16.2 Hz), 3.92 (3H, s), 3.85-3.83 (1H, m), 3.42 (1H, dd, J = 16.5, 11.4 Hz), 2.71 (1H, dd, J = 16.5, 5.8 Hz), 2.60 (1H, d, J = 16.2 Hz), 2.46-2.34 (2H, m), 2.29 (1H, d, J = 12.0 Hz), 1.84-1.70 (2H, m). Example 2I. ((4aR,8aS)-1-(4-Fluorophenyl)-6-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone [ka]

[0166] Instead of HCl / dioxane, trifluoroacetic acid / dichloromethane is used. LCMS: RT 2.49 min, m+H=589.2; 1H NMR (400 MHz, CDCl3): δ 8.85 (1H, d, J=5.0 Hz), 8.10-8.09 (1H, m), 7.65-7.63 (1H, m), 7.50-7.45 (2H, m), 7.38 (1H, d, J = 2.5 Hz), 7.34 (1H, s), 7.18-7.12 (2H, m), 6.55 (1H, d, J = 2.5 Hz), 5.57 (1H, dd, J = 11.8, 2.0 Hz), 4.27 (1H, d, J = 16.2 Hz), 3.97 (3H, s), 3.93-3.89 (1H, m), 3.44 (1H, dd, J = 16.2, 10.9 Hz), 2.71 (1H, dd, J = 16.4, 6.0 Hz), 2.63-2.55 (2H, m), 2.54 (1H, d, J = 12.2 Hz), 2.45-2.34 (1H, m), 1.82-1.74 (2H, m). Example 2J. ((4aR,8aS)-1-(4-Fluorophenyl)-6-((1-methyl-1H-pyrazol-5-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone [ka]

[0167] Instead of HCl / dioxane, trifluoroacetic acid / dichloromethane is used. LCMS: RT 2.60 min, m+H=589.2; 1H NMR (400 MHz, CDCl3): δ 8.77 (1H, d, J = 4.9 Hz), 8.07-8.06 (1H, m), 7.66-7.64 (1H, m), 7.49-7.44 (2H, m), 7.30 (1H, d, J = 2.0 Hz), 7.29 (1H, s), 7.18-7.12 (2H, m), 6.60 (1H, d, J = 2.0 Hz), 5.55 (1H, dd, J = 12.6, 2.2 Hz), 4.18 (1H, d, J = 16.2 Hz), 4.01-3.97 (1H, m), 3.91 (3H, s), 3.37 (1H, dd, J = 16.4, 11.1 Hz), 2.76-2.69 (2H, m), 2.68 (1H, d, J = 12.6 Hz), 2.61 (1H, d, J = 16.2 Hz), 2.52-2.40 (1H, m), 1.89-1.80 (2H, m). Example 2K. ((4aR,8aS)-6-((1-ethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone [ka]

[0168] Instead of HCl / dioxane, trifluoroacetic acid / dichloromethane is used. LCMS: RT 2.54 min, m+H=603.2; 1H NMR (400 MHz, CDCl3): δ 8.85 (1H, d, J=5.1 Hz), 8.10 (1H, m), 7.70 (1H, s), 7.66-7.65 (2H, m), 7.50-7.45 (2H, m), 7.33 (1H, s), 7.18-7.12 (2H, m), 6.60 (1H, d, J = 2.0 Hz), 5.48 (1H, dd, J = 12.1, 2.0 Hz), 4.23 (1H, d, J = 16.4 Hz), 4.18 (2H, q, J = 7.2 Hz), 3.85-3.83 (1H, m), 3.42 (1H, dd, J = 16.4, 11.1 Hz), 2.71 (1H, dd, J = 16.2, 6.0 Hz), 2.60 (1H, d, J = 16.2 Hz), 2.46-2.34 (1H, m), 2.29 (1H, d, J = 12.1 Hz), 1.82-1.71 (2H, m), 1.51 (3H, t, J = 7.2 Hz). Example 2L. ((4aR,8aS)-6-((1-ethyl-1H-pyrazol-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone [ka]

[0169] Instead of HCl / dioxane, trifluoroacetic acid / dichloromethane is used. LCMS:RT2.70min,m+H=603.3;1H NMR (400 MHz, CDCl3):δ 8.78 (1H, d, J = 5.0 Hz), 8.07 (1H, m), 7.66-7.64 (1H, m), 7.49-7.44 (2H, m), 7.36 (1H, d, J = 2.0 Hz), 7.29 (1H, s), 7.18-7.12 (2H, m), 6.58 (1H, d, J = 2.0 Hz), 5.57 (1H, dd, J = 12.5, 2.0 Hz), 4.32 (3H, m), 3.98-3.94 (1H, m), 3.38 (1H, dd, J = 16.2, 10.8 Hz), 2.76-2.69 (2H, m), 2.66 (1H, d, J = 12.6 Hz), 2.61 (1H, d, J = 16.2 Hz), 2.51-2.40 (1H, m), 1.89-1.80 (2H, m), 1.39 (3H, t, J = 7.2 Hz). Example 2M. ((4aR,8aS)-1-(4-Fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone [ka]

[0170] LCMS: RT2.79 min, m+H=590.7;1H NMR (400 MHz, CDCl3):δ 7.94 (1H, d, J = 3.1 Hz), 7.82 (2H, d, J = 8.2 Hz), 7.71 (2H, d, J = 8.2 Hz), 7.59 (1H, d, J = 3.1 Hz), 7.48 - 7.42 (2H, m), 7.34 (1H, s), 7.17 - 7.10 (2H, m), 5.43 (1H, dd, J = 12.3, 2.1 Hz), 4.16 (1H, d, J = 16.0 Hz), 4.05 - 3.96 (1H, m), 3.37 (1H, dd, J = 16.0, 10.6 Hz), 2.69 (1H, dd, J = 16.4, 5.7 Hz), 2.59 - 2.42 (4H, m), 1.84 - 1.77 (2H, m). Example 2N. ((4aR,8aS)-1-(4-Fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone [ka]

[0171] LCMS:RT2.61min,m+H=549.9;1H NMR (400 MHz, CDCl3):δ 8.68 (1H, ddd, J = 4.8, 1.7, 1.0 Hz), 7.88 - 7.78 (3H, m), 7.54 - 7.42 (3H, m), 7.37 (1H, s), 7.21 - 7.12 (2H, m), 5.70 (1H, dd, J = 12.4, 2.1 Hz), 4.90 (1H, sept, J = 6.7 Hz), 4.40 (1H, d, J = 16.3 Hz), 4.02 - 3.96 (1H, m), 3.48 (1H, dd, J = 16.3, 10.9 Hz), 2.72 (1H, dd, J = 16.3, 5.9 Hz), 2.66 - 2.58 (2H, m), 2.55 (1H, d, J = 12.4 Hz), 2.46 (1H, qd, J = 13.8, 5.0 Hz), 1.83 - 1.75 (2H, m), 1.62 (6H, d, J = 6.7 Hz). Example 2O. ((4aR,8aS)-6-((2-ethyl-2H-1,2,3-triazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone [ka]

[0172] LCMS:RT2.68min,m+H=604.3;1H NMR (400 MHz, CDCl3):δ 8.86 (1H, d, J = 5.0 Hz), 8.10 (1H, m), 7.81 (1H, s), 7.67-7.66 (1H, m), 7.50-7.45 (1H, m), 7.33 (1H, s), 7.18-7.12 (2H, m), 5.64 (1H, dd, J = 12.4, 2.0 Hz), 4.52 (2H, q, J = 7.3 Hz), 4.25 (1H, d, J = 16.4 Hz), 3.98-3.93 (1H, m), 3.43 (1H, dd, J = 16.4, 11.1 Hz), 2.72 (1H, dd, J = 16.2, 5.9 Hz), 2.60 (1H, d, J = 16.2 Hz), 2.64-2.58 (2H, m), 2.56 (1H, d, J = 12.6 Hz), 2.48-2.36 (1H, m), 1.84-1.76 (2H, m), 1.60 (3H, t, J = 7.3 Hz). Example 2 P. ((4aR,8aS)-1-(4-Fluorophenyl)-6-((1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone [ka]

[0173] LCMS:RT2.45min,m+H=590.2;1H NMR (400 MHz, CDCl3):δ 8.85 (1H, d, J = 5.0 Hz), 8.11-8.10 (1H, m), 7.88 (1H, s), 7.66-7.65 (1H, m), 7.50-7.45 (2H, m), 7.34 (1H, s), 7.18-7.12 (2H, m), 5.68 (1H, dd, J = 12.6, 2.0 Hz), 4.26 (1H, d, J = 16.4 Hz), 4.15 (3H, s), 3.97-3.92 (1H, m), 3.43 (1H, dd, J = 16.4, 11.1 Hz), 2.78-2.70 (3H, m), 2.63 (1H, d, J = 16.2 Hz), 2.47-2.36 (1H, m), 1.87-1.78 (2H, m). Example 2Q. ((4aR,8aS)-1-(4-Fluorophenyl)-6-((6-(trifluoromethyl)pyridin-2-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone [ka]

[0174] LCMS: RT2.68 min, m+H=585.6;1H NMR (400 MHz, CDCl3):δ 8.61-8.53 (1H, m), 7.96 (1H, t, J = 7.7 Hz), 7.86 (1H, d, J = 7.7 Hz), 7.78-7.68 (3H, m), 7.46-7.39 (2H, m), 7.37 (1H, ddd, J = 6.9, 4.8, 2.0 Hz), 7.31 (1H, s), 7.14-7.01 (2H, m), 5.68 (1H, dd, J = 12.9, 2.1 Hz), 4.32 (1H, d, J = 16.3 Hz), 4.05-3.94 (1H, m), 3.46-3.33 (1H, m), 2.93 (1H, td, J = 12.6, 3.1 Hz), 2.91 (1H, d, J = 12.9 Hz), 2.65 (1H, dd, J = 16.3, 6.0 Hz), 2.54 (1H, d, J = 16.3 Hz), 2.37 (1H, qd, J = 12.9, 5.1 Hz), 1.87-1.76 (1H, m), 1.76-1.64 (1H, m). Example 2R. ((4aR,8aS)-1-(4-Fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone [ka]

[0175] LCMS:RT2.44min,m+H=536.3;1H NMR (400 MHz, CDCl3):δ:8.49 (1H, d, J = 5.0 Hz), 7.80 (1H, s), 7.66-7.65 (1H, m), 7.50-7.45 (2H, m), 7.32 (1H, s), 7.24-7.23 (1H, m), 7.17-7.11 (2H, m), 5.73 (1H, dd, J = 12.5, 2.2 Hz), 4.36 (1H, d, J = 16.1 Hz), 4.25 (3H, s), 3.98-3.94 (1H, m), 3.44 (1H, dd, J = 16.4, 11.3 Hz), 2.69 (1H, dd, J = 16.1, 5.9 Hz), 2.64-2.42 (4H, m), 2.37 (3H, s), 1.79-1.70 (2H, m). Example 2S. ((4aR,8aS)-1-(4-Fluorophenyl)-6-((2-propyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone [ka]

[0176] LCMS:RT2.50min,m+H=556.2;1H NMR (400 MHz, CDCl3):δ:8.85 (1H, d, J = 2.2 Hz), 8.18 (1H, d, J = 2.2 Hz), 7.83 (1H, s), 7.50-7.44 (2H, m), 7.35 (1H, s), 7.17-7.11 (2H, m), 5.54 (1H, dd, J = 12.6, 2.0 Hz), 4.44 (2H, dd, J = 7.2 Hz), 4.19 (1H, d, J = 16.3 Hz), 3.99-3.95 (1H, m), 3.46 (1H, dd, J = 16.4, 11.1 Hz), 2.68 (1H, dd, J = 16.4, 5.9 Hz), 2.62-2.48 (4H, m), 2.02 (2H, sext, J = 7.2 Hz), 1.83-1.75 (2H, m), 0.94 (3H, t, J = 7.2 Hz). Example 2T. 3-(((4aR,8aS)-1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8,8a,9-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)benzonitrile [ka]

[0177] LCMS:RT2.46min,m+H=542.2;1H NMR (400 MHz, CDCl3):δ:8.63 (1H, ddd, J = 4.7, 1.3 Hz), 7.92-7.88 (2H, m), 7.81-7.79 (2H, m), 7.77 (1H, ddd, J = 7.7, 1.3 Hz), 7.58 (1H, dt, J = 7.7, 0.6 Hz), 7.48-7.42 (3H, m), 7.30 (1H, s), 7.17-7.11 (2H, m), 5.66 (1H, dd, J = 12.3, 2.1 Hz), 4.27 (1H, d, J = 16.1 Hz), 3.98-3.95 (1H, m), 3.39 (1H, dd, J = 16.1, 11.2 Hz), 2.68 (1H, dd, J = 16.3, 6.1 Hz), 2.55-2.39 (4H, m), 1.80-1.69 (2H, m). Example 2U. ((4aR,8aS)-6-((3-fluoro-4-(trifluoromethyl)phenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone [ka]

[0178] LCMS:RT2.79min,m+H=603.3;1H NMR (400 MHz, CDCl3):δ 8.63 (1H, ddd, J = 4.7, 1.3 Hz), 7.79-7.78 (2H, m), 7.66 (1H, dd, J = 7.7 Hz), 7.54 (1H, d, J = 8.0 Hz), 7.49-7.42 (4H, m), 7.30 (1H, s), 7.17-7.11 (2H, m), 5.64 (1H, dd, J = 12.4, 2.0 Hz), 4.26 (1H, d, J = 16.1 Hz), 4.00-3.96 (1H, m), 3.39 (1H, dd, J = 16.4, 11.2 Hz), 2.69 (1H, dd, J = 16.2, 6.0 Hz), 2.60-2.41 (4H, m), 1.80-1.71 (2H, m). Example 2V. ((4aR,8aS)-1-(4-fluorophenyl)-6-((4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone [ka]

[0179] LCMS:RT2.39min,m+H=589.3;1H NMR (400 MHz, CDCl3):δ 8.61 (1H, ddd, J = 4.7, 1.6, 0.9 Hz), 8.05 (1H, d, J = 2.0 Hz), 7.83-7.81 (1H, m), 7.77 (1H, dd, J = 7.4, 1.6 Hz), 7.49-7.44 (2H, m), 7.40 (1H, ddd, J = 7.3, 4.7, 1.6 Hz), 7.32 (1H, s), 7.16-7.10 (2H, m), 7.04 (1H, d, J = 2.0 Hz), 5.51 (1H, dd, J = 12.1, 2.0 Hz), 4.31 (1H, d, J = 16.2 Hz), 4.23-4.21 (2H, m), 3.87-3.84 (1H, m), 3.55-3.53 (2H, m), 3.43 (1H, dd, J = 16.4, 11.1 Hz), 3.22 (3H, s), 2.67 (1H, dd, J = 16.3, 6.1 Hz), 2.54 (1H, d, J = 16.2 Hz), 2.47-2.36 (2H, m), 2.32 (1H, J = 12.0 Hz), 1.76-1.66 (2H, m). Example 2W. ((4aR,8aS)-1-(4-Fluorophenyl)-6-((1-propyl-1H-1,2,3-triazol-5-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone [ka]

[0180] LCMS:RT2.48min,m+H=556.2;1H NMR (400 MHz, CDCl3):δ 7.94 (1H, d, J = 3.1 Hz), 7.87 (1H, s), 7.62 (1H, d, J = 3.1 Hz), 7.48-7.42 (2H, m), 7.32 (1H, s), 7.17-7.11 (2H, m), 5.45 (1H, dd, J = 12.7, 2.1 Hz), 4.38-4.27 (2H, m), 4.14 (1H, d, J = 16.1 Hz), 4.06-4.01 (1H, m), 3.37 (1H, dd, J = 16.1, 11.1 Hz), 2.86 - 2.70 (3H, m), 2.61 (1H, d, J = 16.1 Hz), 2.53-2.42 (1H, m), 1.97-1.82 (4H, m), 0.94 (3H, t, J = 7.3 Hz). Example 2X. ((4aR,8aS)-1-(4-fluorophenyl)-6-((1-methyl-1H-1,2,3-triazol-5-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone [ka]

[0181] LCMS:RT2.56min,m+H=590.3;1H NMR (400 MHz, CDCl3):δ 8.77 (1H, d, J = 5.0 Hz), 8.04 (1H, m), 7.89 (1H, s), 7.69-7.67 (1H, m), 7.48-7.43 (2H, m), 7.28 (1H, s), 7.18-7.12 (2H, m), 5.59 (1H, dd, J = 12.6, 2.0 Hz), 4.12 (1H, d, J = 16.3 Hz), 4.06 (3H, s), 4.06-4.01 (1H, m), 3.35 (1H, dd, J = 16.4, 11.2 Hz), 2.82-2.72 (3H, m), 2.61 (1H, d, J = 16.2 Hz), 2.47-2.36 (1H, qd, J = 13.0,5.2 Hz), 1.91-1.82 (2H, m). Example 2Y. ((4aR,8aS)-1-(4-Fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone [ka]

[0182] LCMS:RT2.30min,m+H=528.2;1H NMR (400 MHz, CDCl3):δ 8.02 (1H, d, J = 3.1 Hz), 7.82 (1H, s), 7.61 (1H, d, J = 3.1 Hz), 7.49-7.44 (2H, m), 7.35 (1H, s), 7.17-7.10 (2H, m), 5.58 (1H, dd, J = 12.6, 2.1 Hz), 4.26 (3H, s), 4.22 (1H, d, J = 16.4 Hz), 4.04-3.96 (1H, m), 3.41 (1H, dd, J = 16.4, 11.4 Hz), 2.73-2.58 (4H, m), 2.54-2.43 (1H, m), 1.88-1.77 (2H, m). Example 2Z. ((4aR,8aS)-1-(4-Fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone [ka]

[0183] LCMS:RT2.53min,m+H=556.2;1H NMR (400 MHz, CDCl3):δ 8.03 (1H, d, J = 3.1 Hz), 7.80 (1H, s), 7.61 (1H, d, J = 3.1 Hz), 7.49-7.44 (2H, m), 7.35 (1H, s), 7.17-7.11 (2H, m), 5.60 (1H, dd, J = 12.6, 2.1 Hz), 4.88 (1H, sept, J = 6.7 Hz), 4.23 (1H, d, J = 16.4 Hz), 4.02-3.98 (1H, m), 3.41 (1H, dd, J = 16.1, 11.2 Hz), 2.73-2.58 (4H, m), 2.49 (1H, dq, J = 12.5, 5.0 Hz), 1.88-1.74 (2H, m), 1.61 (6H, d, J = 6.7 Hz). Example 2AA. ((4aR,8aS)-1-(4-Fluorophenyl)-6-((1-isopropyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone [ka]

[0184] LCMS: RT2.41 min, m+H=549.3;1H NMR (400 MHz, CDCl3):8.63 (1H, ddd, J = 4.7, 1.6, 0.8 Hz), 7.82 (1H, ddd, J = 7.8, 1.3, 0.8 Hz), 7.77 (1H, dd, J = 7.4, 1.6 Hz), 7.72 (1H, s), 7.64 (1H, d, J = 0.8 Hz), 7.49-7.44 (2H, m), 7.41 (1H, ddd, J = 7.3, 4.8, 1.6 Hz), 7.31 (1H, s), 7.15-7.09 (2H, m), 5.51 (1H, dd, J = 12.0, 2.0 Hz), 4.47 (1H, sept, J = 6.7 Hz), 4.34 (1H, d, J = 16.1 Hz), 3.85-3.78 (1H, m), 3.43 (1H, dd, J = 16.4, 11.2 Hz), 2.68 (1H, dd, J = 16.2, 6.0 Hz), 2.56 (1H, d, J = 16.2 Hz), 2.46-2.32 (2H, m), 2.26 (1H, d, J = 12.0 Hz), 1.82-1.64 (2H, m), 1.49 (6H, dd, J = 6.7, 1.1 Hz). Example 2AB. ((4aR,8aS)-6-((2-ethyl-2H-1,2,3-triazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone [ka]

[0185] LCMS: RT2.43 min, m+H=536.2;1H NMR (400 MHz, CDCl3):8.63 (1H, ddd, J = 4.7, 1.6, 0.9 Hz), 7.84-7.77 (3H, m), 7.50-7.45 (2H, m), 7.43 (1H, ddd, J = 7.0, 4.7, 1.6 Hz), 7.33 (1H, s), 7.17-7.11 (2H, m), 5.68 (1H, dd, J = 12.4, 1.9 Hz), 4.51 (2H, q, J = 7.3 Hz), 4.36 (1H, d, J = 16.2 Hz), 3.99-3.92 (1H, m), 3.45 (1H, dd, J = 16.2, 11.3 Hz), 2.69 (1H, dd, J = 16.2, 6.0 Hz), 2.63-2.55 (2H, m), 2.52 (1H, d, J = 12.3 Hz), 2.43 (1H, dq, J = 13.4, 4.8 Hz), 1.80-1.71 (2H, m), 1.59 (3H, t, J = 7.3 Hz). Example 2AC. ((4aR,8aS)-1-(4-Fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone [ka]

[0186] LCMS:RT2.31min,m+H=522.2;1H NMR (400 MHz, CDCl3):δ 8.65 (1H, ddd, J = 4.7, 1.6, 0.9 Hz), 7.84-7.77 (3H, m), 7.50-7.46 (2H, m), 7.43 (1H, ddd, J = 7.1, 4.7, 1.6 Hz), 7.33 (1H, s), 7.17-7.11 (2H, m), 5.68 (1H, dd, J = 12.4, 2.0 Hz), 4.36 (1H, d, J = 16.2 Hz), 3.99-3.91 (1H, m), 4.25 (3H, s), 3.45 (1H, dd, J = 16.2, 11.3 Hz), 2.70 (1H, dd, J = 16.2, 6.0 Hz), 2.64-2.55 (2H, m), 2.53 (1H, d, J = 12.4 Hz), 2.43 (1H, dq, J = 13.4, 4.7 Hz), 1.80-1.71 (2H, m). Example 2AD. ((4aR,8aS)-1-(4-Fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone [ka]

[0187] LCMS:RT2.79min,m+H=618.3;1H NMR (400 MHz, CDCl3):δ 8.87 (1H, d, J = 5.0 Hz), 8.10-8.09 (1H, m), 7.80 (1H, s), 7.66 (1H, dd, J = 5.0, 1.0 Hz), 7.50-7.44 (2H, m), 7.32 (1H, s), 7.17-7.11 (2H, m), 5.64 (1H, dd, J = 12.5, 2.0 Hz), 4.88 (1H, sept, J = 6.6 Hz), 4.25 (1H, d, J = 16.2 Hz), 3.99-3.91 (1H, m), 3.43 (1H, dd, J = 16.2, 10.9 Hz), 2.71 (1H, dd, J = 16.4, 6.0 Hz), 2.63-2.56 (2H, m), 2.54 (1H, d, J = 12.4 Hz), 2.42 (1H, dq, J = 13.4, 4.8 Hz), 1.86-1.75 (2H, m), 1.60 (6H, d, J = 6.6 Hz). Example 2AE. ((4aR,8aS)-6-((2H-1,2,3-triazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone [ka]

[0188] LCMS:RT2.39min,m+H=576.2;1H NMR (400 MHz, CDCl3):δ 8.87 (1H, d, J = 5.0 Hz), 8.11-8.10 (1H, m), 7.93 (1H, s), 7.66 (1H, dd, J = 5.0, 1.0 Hz), 7.50-7.45 (2H, m), 7.39 (1H, s), 7.19-7.13 (2H, m), 5.64 (1H, dd, J = 12.5, 1.9 Hz), 4.27 (1H, d, J = 16.2 Hz), 3.98-3.91 (1H, m), 3.42 (1H, dd, J = 16.2, 11.3 Hz), 2.71 (1H, dd, J = 16.6, 6.1 Hz), 2.66-2.59 (3H, m), 2.40 (1H, dq, J = 13.5, 4.7 Hz), 1.85-1.74 (2H, m). Example 2AF. ((4aR,8aS)-1-(4-Fluorophenyl)-6-((1-isopropyl-1H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone [ka]

[0189] LCMS: RT2.37 min, m+H=550.2;1H NMR (400 MHz, CDCl3):8.65 (1H, ddd, J = 4.7, 1.6, 0.9 Hz), 7.90 (1H, s), 7.84 (1H, ddd, J = 8.0, 1.3, 0.9 Hz), 7.79 (1H, dt, J = 7.3, 1.6 Hz), 7.51-7.46 (2H, m), 7.42 (1H, ddd, J = 7.3, 4.7, 1.6 Hz), 7.34 (1H, s), 7.17-7.11 (2H, m), 5.70 (1H, dd, J = 12.4, 2.0 Hz), 4.85 (1H, sept, J = 6.7 Hz), 4.38 (1H, d, J = 16.2 Hz), 4.01-3.92 (1H, m), 3.45 (1H, dd, J = 16.4, 11.0 Hz), 2.81-2.68 (3H, m), 2.59 (1H, d, J = 15.9 Hz), 2.43 (1H, dq, J = 13.9, 5.0 Hz), 1.84-1.73 (2H, m), 1.59 (6H, dd, J = 6.7, 2.0 Hz). Example 2AG. ((4aR,8aS)-1-(4-Fluorophenyl)-6-((6-(trifluoromethyl)pyridin-2-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone [ka]

[0190] LCMS: RT2.58 min, m+H=592.2; 1H NMR (400 MHz, CDCl3): 1H NMR (400 MHz, CDCl3) δ 8.07-8.01 (2H, m), 7.95 (1H, d, J = 7.8 Hz), 7.83 (1H, d, J = 7.8 Hz), 7.60 (1H, d, J = 3.1 Hz), 7.48-7.45 (2H, m), 7.34 (1H, s), 7.16-7.12 (2H, m), 5.62 (1H, dd, J = 12.9, 1.6 Hz), 4.24 (1H, d, J = 16.1 Hz), 4.13-4.09 (1H, m), 3.42 (1H, dd, J = 16.1, 11.6 Hz), 3.07-3.00 (2H, m), 2.72 (1H, dd, J = 16.4, 6.1 Hz), 2.63 (1H, d, J = 16.2 Hz), 2.50 (1H, dq, J = 12.9, 5.0 Hz), 1.99-1.90 (1H, m), 1.81-1.78 (1H, m). Example 2AH. ((4aR,8aS)-1-(4-Fluorophenyl)-6-((6-(trifluoromethyl)pyridin-2-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone [ka]

[0191] LCMS:RT2.53min,m+H=592.2;1H NMR (400 MHz, CDCl3):1H NMR (400 MHz, CDCl3) δ 8.83 (1H, d, J = 2.1 Hz), 8.15 (1H, d, J = 2.1 Hz), 8.07-8.03 (1H, m), 7.96 (1H, d, J = 7.6 Hz), 7.82 (1H, dd, J = 7.6, 0.9 Hz), 7.50 - 7.45 (2H, m), 7.33 (1H, s), 7.17 - 7.11 (2H, m), 5.58 (1H, dd, J = 12.9, 2.0 Hz), 4.18 (1H, d, J = 16.4 Hz), 4.10 - 4.06 (1H, m), 3.47 (1H, dd, J = 16.2, 11.3 Hz), 3.04 - 2.97 (1H, m), 2.95 (1H, d, J = 13.1 Hz), 2.70 (1H, dd, J = 16.2, 6.1 Hz), 2.59 - 2.45 (2H, m), 1.95 - 1.97 (1H, m), 1.82 - 1.73 (1H, m). Example 2AI. ((4aR,8aS)-1-(4-Fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone [ka]

[0192] LCMS:RT2.21min,m+H=528.2;1H NMR (400 MHz, CDCl3):1H NMR (400 MHz, CDCl3) δ 8.85 (1H, d, J = 2.0 Hz), 8.17 (1H, d, J = 2.0 Hz), 7.82 (1H, s), 7.50-7.45 (2H, m), 7.34 (1H, s), 7.17-7.11 (2H, m), 5.53 (1H, dd, J = 12.6, 2.1 Hz), 4.26 (3H, s), 4.19 (1H, d, J = 16.4 Hz), 4.00-3.96 (1H, m), 3.46 (1H, dd, J = 15.7, 10.9 Hz), 2.72-2.43 (5H, m), 1.84-1.73 (2H, m). Example 2AJ. ((4aR,8aS)-1-(4-Fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone [ka]

[0193] LCMS:RT2.46min,m+H=556.2;1H NMR (400 MHz, CDCl3):1H NMR (400 MHz, CDCl3) δ 8.86 (1H, d, J = 2.1 Hz), 8.17 (1H, d, J = 2.1 Hz), 7.80 (1H, s), 7.50-7.45 (2H, m), 7.35 (1H, s), 7.17-7.11 (2H, m), 5.54 (1H, dd, J = 12.6, 2.1 Hz), 4.89 (1H, sept, J = 6.8 Hz), 4.19 (1H, d, J = 16.4 Hz), 4.02-3.94 (1H, m), 3.46 (1H, dd, J = 16.4, 12.0 Hz), 2.71-2.43 (5H, m), 1.84-1.72 (2H, m), 1.61 (6H, d, J = 6.8 Hz). Example 2AK. ((4aR,8aS)-6-((2-ethyl-2H-1,2,3-triazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone [ka]

[0194] LCMS:RT2.33min,m+H=542.2;1H NMR (400 MHz, CDCl3):1H NMR (400 MHz, CDCl3) δ 8.87 (1H, d, J = 2.0 Hz), 8.19 (1H, d, J = 2.0 Hz), 7.83 (1H, s), 7.52-7.46 (2H, m), 7.36 (1H, s), 7.19-7.13 (2H, m), 5.55 (1H, dd, J = 12.6, 2.2 Hz), 4.54 (2H, q, J = 7.2 Hz), 4.20 (1H, d, J = 16.4 Hz), 4.01-3.97 (1H, m), 3.48 (1H, dd, J = 15.8, 11.0 Hz), 2.73-2.46 (5H, m), 1.87-1.77 (2H, m), 1.62 (3H, t, J = 7.2 Hz).

[0195] Example 3. Human glucocorticoid receptor (GR) fluorescence polarization (FP) binding assay Below is a description of the FP assay for measuring compound inhibition of labeled glucocorticoid binding to human recombinant GR.

[0196] The binding affinity of the test compounds was measured using an FP binding assay using human recombinant GR (PanVera P2812) and a fluorescently labeled glucocorticoid ligand (Fluorome GS Red) (PanVera P2894). The presence of an inhibitor prevents the formation of the GS Red / GR complex, resulting in a decrease in the measured polarization value. The change in the polarization value in the presence of the test compound was used to calculate the binding affinity of the compound for GR. is used to.

[0197] The assay was performed in a final volume of 20 μl in 384-well black round-bottom polypropylene microtiter plates. The assay contained 5 μl of 1 nM GR (final concentration), 5 μl of 0.5 nM Fluorome GS Red (final concentration) in the presence of 10 μl of test compound. Positive control wells (high polarization) received 10 μl of 2% (v:v) DMSO vehicle (1% (v / v) final concentration) + 5 μl of 1 nM GR and 5 μl of 0.5 nM Fluorome GS Red. Negative control wells (low polarization) received 10 μl of 2 μM dexamethasone (1 μM final concentration) + 5 μl of 1 nM GR and 5 μl of 0.5 nM Fluorome GS Red. Assay blank background wells (used for normalization) received 15 μl of 1×GS screening buffer + 5 μl of GR.

[0198] I C 50 For the determination of (the concentration of compound that displaces 50% of bound GS Red), compounds were tested in duplicate at eight different concentrations in two independent experiments. Compounds were prepared as solubilized solids at 10 mM in DMSO. On the day of the assay, eight-point half-log serial dilutions (55 μl DMSO+25 μl compound solution) were prepared. A 1:50 dilution (1 μl compound solution+49 μl 1×GR screening buffer) was prepared for each compound. The compounds were prepared at 2× the final assay concentration.

[0199] The above reagents were added to a 384-well microtiter plate in the following order: 10 μl test compound / vehicle / 1 μM dexamethasone, 5 μl Fluorome GS Red, and 5 μl GR. The plate was mixed and incubated at room temperature for 4 hours. FP was measured using an Envision Excite plate reader with 535 nm excitation and 590 nm emission interference filters.

[0200] The millipolarization (mP) values ​​were calculated using the following equation: mP = 1000 * (SG * P) / (S + G * P) where S and P are assay blank background subtracted fluorescence units and G=G factor (1.07).

[0201] The IC value of the compound was calculated by plotting [compound] versus % inhibition curves and fitting the data to a 4-parameter logistic fit equation. 50 Values ​​were calculated using the ligand depletion correction equation (see below), assuming that the antagonists are competitive inhibitors with respect to dexamethasone, as IC 50 From the experimental values, compound K i The equilibrium dissociation constant (ECL) value was determined (Pharmacologic Analysis of Drug Receptor Interactions, 2 nd Ed., p385-410, 1993, Raven Press, New York).

number

[0202] 10x GR screening buffer (100 mM potassium phosphate pH 7.4, 200 mM Na2MoO4, 1 mM EDTA, 20% (v / v) DMSO). To prepare 1x GR screening buffer, mix 1 ml 10x GR screening buffer (PanVera P2814) + 1 ml stabilizing peptide (PanVera P2815) + 7.95 ml MQ water at 4°C. Add 50 μl 1M DTT, vortex and keep on ice until use.

[0203] Example 4. HepG2 tyrosine aminotransferase (TAT) assay Glucocorticoid-mediated activation of TAT occurs through transactivation of a glucocorticoid response element in the TAT promoter by glucocorticoid receptor-agonist complexes. The following protocol describes an assay for measuring induction of TAT by dexamethasone in HepG2 cells (human hepatocellular carcinoma cell line; ECACC, UK).

[0204] TAT activity was measured as outlined in A. Ali et al., J. Med. Chem., 2004, 47, 2441-2452. Dexamethasone had a mean EC 50 The production of TAT was induced at a concentration of 0.01 mg / mL (half maximal effect).

[0205] HepG2 cells were cultured at 37°C in 5% / 95% (v / v) CO2 / air using MEME medium supplemented with 10% (v / v) fetal bovine serum; 2 mM L-glutamine and 1% (v / v) NEAA. The HepG2 cells were counted and cultured at 0.125 × 10 in phenol red-free RPMI 1640, 10% (v / v) charcoal stripped FBS, 2 mM L-glutamine. 6The density of cells / ml was adjusted and seeded at 25,000 cells / well in 200 μl into 96-well sterile tissue culture microtiter plates and incubated at 37° C., 5% CO 2 for 24 hours.

[0206] Remove the growth medium and add assay medium {phenol red-free RPMI 1640, 2 mM L-glutamine + 10 μM forskolin}. Test compounds were screened against a challenge of 100 nM dexamethasone. Compounds were diluted in half-log serial dilutions from 10 mM stocks into 100% (v / v) dimethyl sulfoxide. An 8-point half-log dilution curve was then generated, followed by a 1:100 dilution into assay medium to obtain 10× final assay [compound]: this gave a range of final assay [compound] from 10 to 0.003 μM in 0.1% (v / v) dimethyl sulfoxide.

[0207] Test compounds were pre-incubated with cells in microtiter plates at 37° C., 5 / 95 (v / v) CO2 / air for 30 min, followed by addition of 100 nM dexamethasone, followed by a 20-h time course, resulting in optimal TAT induction.

[0208] HepG2 cells were then lysed with 30 μl of cell lysis buffer containing a protease inhibitor cocktail for 15 min at 4° C. Then, 155 μl of substrate mixture containing 5.4 mM tyrosine sodium salt, 10.8 mM alpha-ketoglutarate and 0.06 mM pyridoxal 5′-phosphate in 0.1 M potassium phosphate buffer (pH 7.4) was added. After 2 h of incubation at 37° C., the reaction was terminated by adding 15 μl of 10 M aqueous potassium hydroxide solution, and the plate was incubated for another 30 min at 37° C. The product of TAT activity was measured by absorbance at λ 340 nm.

[0209] % Inhibition for [compound] (normalized to 100 nM dexamethasone TAT stimulation) The IC was calculated by plotting the mean and mean logistic regression line (p < 0.05) and fitting the data to a four-parameter logistic equation. 50 The IC values ​​were calculated using the Cheng and Prusoff equation, assuming that the antagonist is a competitive inhibitor with respect to dexamethasone. 50 Values ​​were converted to Ki (equilibrium dissociation constant). [Table 1-1] [Table 1-2] In Table 1, K less than 0.5 nM i GR binding compounds with a K value of 0.5 nM to less than 1.0 nM are indicated by +++. i Compounds with a K value of at least 1.0 nM are indicated by ++; i Compounds with a K value less than 20 nM are indicated by +. i TAT activity with a K value of 20 nM to less than 100 nM is indicated by +++. i Compounds with a K value of at least 100 nM are indicated by ++; i Compounds with a value are indicated by +.

[0210] Although the foregoing invention has been described in some detail by way of illustrations and examples for purposes of clarity of understanding, those skilled in the art will recognize that certain changes and modifications may be practiced within the scope of the appended claims.Furthermore, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference.In the event of any conflict between this application and the references provided herein, this application shall control.

Claims

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

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