Novel modulators of sigma-2 receptors and methods of use thereof

Abstract

To provide new modulators of sigma-2 receptors and methods of their use.SOLUTION: Pharmaceutical compositions of the invention include functionalised lactone derivatives having a disease-modifying action in the treatment of diseases associated with dysregulation of sigma- 2 receptor activity. The invention includes novel sigma-2 receptor binding substances, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof. The invention further relates to compositions containing an effective amount of one or more compounds according to the invention and an excipient. Methods of treating or preventing diseases involving dysregulation of sigma-2 receptor activity include administering to a subject an effective amount of a compound or composition according to the invention.SELECTED DRAWING: None

Description

[Technical Field]

[0001] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under Grant No. HHSN-271-2008-00025-C awarded by the National Institute of Mental Health and Grant No. 1R41AG052249-01 awarded by the National Institute on Aging. The government has certain rights in this invention.

[0002] Embodiments of the present invention are directed to novel compounds useful as sigma-2 receptor binding agents and methods of use thereof. Embodiments are further directed to novel chemical species useful in the treatment of diseases associated with dysregulated activity of the sigma-2 receptor.

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 474,277, filed March 21, 2017, which is incorporated herein by reference in its entirety. [Background technology]

[0004] Sigma-1 and sigma-2 receptors were first identified in the mid-1970s based on interactions with radioligands. In 1976, studies of the physiological properties of (±)-SKF-10,047 (N-allylnormetazocine) and its structurally related benzomorphan analogs, morphine and ketazocine, in a chronic spinal canine model identified three receptor subtypes: μ-opioid receptors, κ-opioid receptors, and σ-opioid receptors (Martin, WR; Eades, CG; Thompson, JA; Huppler, RE; Gilbert, PE. The effects of morphine- and nalorphine-like drugs in the nondependent and morphine-dependent chronic spinal dog. J. Pharmacol. Exp. Ther. 1976, 197, 517-532). Subsequently, it was discovered that (-)-SKF-10,047 binds to both μ and κ opioid receptors, while (+)-SKF-10,047 selectively binds to σ receptors (sigma receptors). However, the true function of σ receptors remained unknown (Matsumoto, RR Sigma Receptors: Historical Perspective and Background. In Sigma Receptors: Chemistry, Cell Biology and Clinical Implications; Matsumoto, RR, Bowen, WD, Su, T.-P., Eds.; Springer Science: New York, NY, 2007; pp 1-23. Collier, TL; Waterhouse, RN; Kassiou, M. Imaging sigma receptors: applications in drug development. Curr. Pharm. Des. 2007, 13, 51-72.). Do's [ 3The availability of [H]o-ditolylguanidine (DTG) facilitated more detailed binding studies of ligands to sigma receptors, ultimately leading to the identification of two distinct subtypes, sigma receptors and sigma receptors (Hellewell, S.B.; Bowen, W.D. A sigma-like binding site in rat pheochromocytoma (PC12) cells: decreased affinity for (+)-benzomorphans and lower molecular weight suggest a different sigma receptor form from that of guinea pig brain. Brain Res. 1990, 527, 244-253.). However, the exact structure of the σ2 receptor remains unknown, and recent photoaffinity labeling experiments suggest that the σ2 receptor is synonymous with progesterone receptor membrane component-1 (PGRMC1) (Xu, J. et al. Identification of the PGRMC1 protein complex as the putative sigma-2 receptor binding site. Nat. Commun. 2, 380 (2011)).

[0005] The therapeutic utility of compounds that can bind to σ2 receptor or regulate the activity of σ2 receptor is also being explored.Recently, for example, it has been discovered that compounds that can bind to σ2 receptor can inhibit the binding of beta-amyloid protein (Aβ) oligomers to neurons, thereby preventing downstream synaptic toxicity.This aspect of σ2 receptor binding substances provides the opportunity for the application of σ2 receptor binding substances as therapeutic agents for Alzheimer's disease, mild cognitive impairment, and memory impairment.Furthermore, it has been shown that compounds that can bind to σ2 receptor can remove beta-amyloid protein (Aβ) oligomers from neurons, thereby preventing downstream synaptic toxicity. This aspect of σ2 receptor binding agents further provides opportunities for the application of σ2 receptor binding agents as therapeutic agents for Alzheimer's disease, mild cognitive impairment, and memory impairment (Izzo, NJ et al. Alzheimer's therapeutics targeting amyloid Beta 1-42 oligomers I: abeta 42 oligomer binding to specific neuronal receptors is displaced by drug candidates that improve cognitive deficits. PLoS One 9, e111898 (2014). Izzo, NJ et al. Alzheimer's Therapeutics Targeting Amyloid Beta 1-42 Oligomers II: Sigma-2 / PGRMC1 Receptors Mediate Abeta 42 Oligomer Binding and Synaptotoxicity. PLoS One 9, e111899 (2014)).

[0006] In addition, it has been shown that the expression of σ2 receptor is elevated in tumor cells compared with normal cells.The cancer cells in which σ2 receptor overexpression occurs include, but are not limited to, pancreatic cancer, lung cancer, breast cancer, malignant melanoma, prostate cancer and ovarian cancer.In addition, it has been found that compounds that can bind to σ2 receptor can regulate its activity and induce the death of cancer cells.Therefore, σ2 receptor is a promising target for identifying anti-cancer drugs, and compounds that can bind to σ2 receptor provide opportunities for the development of new anti-cancer drugs. Dysregulation of sigma-2 receptor activity also affects many neuropsychiatric disorders, including, but not limited to, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, post-traumatic stress disorder, depression, bipolar disorder, anorexia nervosa, bulimia nervosa, substance use disorders, and schizophrenia. (Guo, L.; Zhen, X. Sigma-2 Receptor ligands: Neurobiological effects. Current Medicinal Chemistry, 2015, 22, 8, 989-1003. Skuza, G. Pharmacology of sigma (σ) receptor ligands from a behavioral perspective. Current Pharmaceutical Design, 2012, 18, 7, 863-874.) Therefore, σ2 receptor is a promising target for the treatment of neuropsychiatric disorders, including but not limited to generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, post-traumatic stress disorder, depression, bipolar disorder, anorexia nervosa, bulimia nervosa, substance use disorder, and schizophrenia. Compounds that can regulate σ2 receptor and bind to σ2 receptor provide the opportunity to identify new treatments for many neuropsychiatric disorders, including but not limited to generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, post-traumatic stress disorder, depression, bipolar disorder, anorexia nervosa, bulimia nervosa, substance use disorder, and schizophrenia. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Martin, WR; Eades, CG; Thompson, JA; Huppler, RE; Gilbert, PE The effects of morphine- and nalorphine-like drugs in the nondependent and morphine-dependent spinal chronic dog. J. Pharmacol. Exp. Ther. 1976, 197, 517-532 [Non-patent document 2] Matsumoto, RR Sigma Receptors: Historical Perspective and Background. In Sigma Receptors: Chemistry, Cell Biology and Clinical Implications; Matsumoto, RR, Bowen, WD, Su, T.-P., Eds.; Springer Science: New York, NY, 2007; pp 1-23. Collier, TL; Waterhouse, RN; Kassiou, M. Imaging sigma receptors: applications in drug development. Curr. Pharm. Des. 2007, 13, 51-72 [Non-patent document 3] Hellewell, S. B.; Bowen, W. D. A sigma-like binding site in rat pheochromocytoma (PC12) cells: decreased affinity for (+)-benzomorphans and lower molecular weight suggest a different sigma receptor form from that of guinea pig brain. Brain Res. 1990, 527, 244-253 [Non-Patent Document 4] Xu, J. et al. Identification of the PGRMC1 protein complex as the putative sigma-2 receptor binding site. Nat. Commun. 2, 380 (2011) [Non-Patent Document 5] Izzo, N. J. et al. Alzheimer’s therapeutics targeting amyloid Beta 1-42 oligomers I: abeta 42 oligomer binding to specific neuronal receptors is displaced by drug candidates that improve cognitive deficits. PLoS One 9, e111898 (2014) [Non-Patent Document 6] Izzo, N. J. et al. Alzheimer’s Therapeutics Targeting Amyloid Beta 1-42 Oligomers II: Sigma-2 / PGRMC1 Receptors Mediate Abeta 42 Oligomer Binding and Synaptotoxicity. PLoS One 9, e111899 (2014) [Non-Patent Document 7] Guo, L.; Zhen, X. Simga-2 Receptor ligands: Neurobiological effects. Current Medicincal Chemistry, 2015, 22, 8, 989-1003. Skuza, G. Pharmacology of sigma (σ) receptor ligands from a behavioral perspective. Current Pharmaceutical Design, 2012, 18, 7, 863-874 Summary of the Invention

[0008] The present invention is directed to novel sigma-2 receptor binding agents, namely compounds of formula (I): It is something that [ka] including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein: A is, [ka] and [ka] selected from the group consisting of: n is 1, 2, or 3; R 1a and R 1b are each independently selected from the group consisting of hydrogen, C1-6 straight chain alkyl and C1-6 branched alkyl, or R 1a and R 1b may, together with the atom to which they are attached, form a ring having 3 to 7 ring atoms; R 2 is 0 to 3 non-hydrogen R 4 Benzene ring optionally substituted with a group, 0-2 non-hydrogen R 5 A 4-pyridine ring optionally substituted with a group, and 0 to 2 non-hydrogen R 5A 3-pyridine ring optionally substituted with a group, and 0 to 2 non-hydrogen R 5 a 2-pyridine ring optionally substituted with a group; R 3 is 0 to 3 non-hydrogen R 4 Benzene ring optionally substituted with a group, 0-2 non-hydrogen R 5 A 4-pyridine ring optionally substituted with a group, and 0 to 2 non-hydrogen R 5 A 3-pyridine ring optionally substituted with a group, and 0 to 2 non-hydrogen R 5 a 2-pyridine ring optionally substituted with a group; R 4 represents hydrogen, OH, NO2, halogen, CN, C1-6 linear alkyl, C3-7 branched alkyl at each occurrence. Alkyl, C3-7 cycloalkyl, C1-6 linear alkoxy, C3-7 branched alkoxy, C3-7 Cycloalkoxy, C1-6 straight-chain haloalkyl, C3-7 branched haloalkyl, C1-6 straight-chain haloalkoxy, heterocyclyl, -S(C1-6 straight-chain alkyl), S(C3-7 branched alkyl) , -S(C3-7 cycloalkyl), -SO2(C1-6 linear alkyl), SO2(C3-7 branched alkyl), -SO2(C3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 , and N.R. 9a SO2NR 12a R 12b independently selected from the group consisting of: R 4a , R 4b , R 4c , R 4d , and R 4e The term refers to each R on the benzene ring. 4 Specify the group may be used for; R 5 At each occurrence position, hydrogen, OH, NO2, halogen, CN, C 1-6 Linear alkyl, C 3-7 Branched Alkyl, C 3-7 Cycloalkyl, C 1-6 Linear alkoxy, C 3-7 Branched alkoxy, C 3-7 Cycloalkoxy, C 1-6 Linear haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Straight-chain haloalkoxy, heterocyclyl, -S(C 1-6 Straight-chain alkyl), S(C 3-7 Branched alkyl), -S(C 3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 , and N.R. 9a SO2NR 12a R 12b independently selected from the group consisting of: R 5a , R 5b , R 5c and R 5d The term refers to each R on the pyridine ring. 5 may be used to designate a group; R 6 At each occurrence, hydrogen, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; R 7 At each occurrence, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7independently selected from the group consisting of cycloalkyl; R 8a At each occurrence position, H, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; R 8b At each occurrence position, H, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; R 9a At each occurrence position, H, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; R 9b At each occurrence position, H, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; R 9a and R 9b may together with the atom to which they are attached form a ring having 3 to 7 ring atoms optionally containing oxygen; R 10 At each occurrence position, H, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; R 11 At each occurrence, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 Cycloa independently selected from the group consisting of: R 12a At each occurrence, hydrogen, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; and R12b At each occurrence, hydrogen, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 cycloalkyl.

[0009] The present invention further comprises: The present invention relates to compositions containing an effective amount of one or more compounds according to the present invention and an excipient.

[0010] The present invention also provides a method for treating a variety of conditions, including, for example, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, post-traumatic stress disorder, depression, bipolar disorder, anorexia nervosa, and dyslipidemia. The present invention relates to a method for treating or preventing diseases involving dysregulated activity of sigma-2 receptors, such as neuropsychiatric disorders such as eating disorders, substance use disorders, schizophrenia, Alzheimer's disease, mild cognitive impairment, and memory disorders, and cancers such as pancreatic cancer, lung cancer, breast cancer, malignant melanoma, prostate cancer, and ovarian cancer, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.

[0011] The present invention further relates to a method for treating or preventing diseases involving dysregulated activity of sigma-2 receptors, such as neuropsychiatric disorders, e.g., generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, post-traumatic stress disorder, depression, bipolar disorder, anorexia nervosa, bulimia nervosa, substance use disorders, schizophrenia, Alzheimer's disease, mild cognitive impairment, and memory disorders, and cancers, e.g., pancreatic cancer, lung cancer, breast cancer, malignant melanoma, prostate cancer, and ovarian cancer, said method comprising administering to a subject a composition containing an effective amount of one or more compounds according to the invention and an excipient.

[0012] The present invention further relates to a method for treating or preventing a disease involving overexpression of sigma-2 receptors, such as pancreatic cancer, lung cancer, breast cancer, malignant melanoma, prostate cancer and ovarian cancer, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.

[0013] The present invention further relates to a method for treating or preventing diseases involving overexpression of sigma-2 receptors, such as pancreatic cancer, lung cancer, breast cancer, malignant melanoma, prostate cancer and ovarian cancer, said method comprising administering to a subject a composition containing an effective amount of one or more compounds according to the invention and an excipient.

[0014] The present invention also relates to a method for treating or preventing a disease or condition associated with dysregulated activity of the sigma-2 receptor, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.

[0015] The present invention further relates to a method for treating or preventing a disease or condition associated with dysregulated activity of the sigma-2 receptor, said method comprising administering to a subject a composition comprising an effective amount of one or more compounds according to the invention and an excipient.

[0016] The present invention further relates to processes for preparing the binding agent modulators of the sigma-2 receptor of the present invention.

[0017] These and other objects, features, and advantages will become apparent to those skilled in the art upon reading the following detailed description and the appended claims. All percentages, ratios, and proportions herein are by weight unless otherwise specified. All temperatures are in degrees Celsius (°C) unless otherwise specified. All cited documents are, in relevant part, incorporated herein by reference, but the citation of any document should not be construed as an admission that it is prior art with respect to the present invention. In certain embodiments, for example, the following are provided: (Item 1) A compound having the following formula (I): [ka] including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein: A is, [ka] and [ka] selected from the group consisting of: n is 1, 2, or 3; R 1a and R 1b are independently hydrogen, C 1-6 Linear alkyl and C 1-6 branched alkyl, or R 1a and R 1b may, together with the atom to which they are attached, form a ring having 3 to 7 ring atoms; R 2 is 0 to 3 non-hydrogen R 4 Benzene ring optionally substituted with a group, 0-2 non-hydrogen R 5 A 4-pyridine ring optionally substituted with a group, and 0 to 2 non-hydrogen R 5 A 3-pyridine ring optionally substituted with a group, and 0 to 2 non-hydrogen R 5 a 2-pyridine ring optionally substituted with a group; R 3 is 0 to 3 non-hydrogen R 4 Benzene ring optionally substituted with a group, 0-2 non-hydrogen R 5 A 4-pyridine ring optionally substituted with a group, and 0 to 2 non-hydrogen R 5 A 3-pyridine ring optionally substituted with a group, and 0 to 2 non-hydrogen R 5 a 2-pyridine ring optionally substituted with a group; R 4 At each occurrence position, hydrogen, OH, NO2, halogen, CN, C 1-6 Linear alkyl, C 3-7 Branch cyclic alkyl, C3-7 cycloalkyl, C 1-6 Linear alkoxy, C 3-7 Branched alkoxy, C 3-7 Cycloalkoxy, C 1-6 Linear haloalkyl, C3-7 Branched haloalkyl, C 1-6 Straight-chain haloalkoxy, heterocyclyl, -S(C 1-6 Straight-chain alkyl), S(C3-7 branched alkyl), -S(C 3-7 cycloalkyl), -SO2(C 1-6 Linear alkyl), SO2(C 3-7 Branched alkyl), -S O2(C 3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 , and N.R. 9a SO2NR 12a R 12b independently selected from the group consisting of: R 4a , R 4b , R 4c , R 4d , and R 4e The term refers to each R on the benzene ring. 4 Specify the group may be used to R 5 At each occurrence position, hydrogen, OH, NO2, halogen, CN, C 1-6 Linear alkyl, C 3-7 Branch C alkyl 3-7 Cycloalkyl, C 1-6 Linear alkoxy, C 3-7 Branched alkoxy, C 3-7 Cycloalkoxy, C 1-6 Linear haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Straight-chain haloalkoxy, heterocyclyl, -S(C 1-6 Straight-chain alkyl), S(C 3-7 Branched alkyl), -S(C 3-7 cycloalkyl), COR6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 , and N.R. 9a SO2NR 12a R 12b independently selected from the group consisting of: R 5a , R 5b , R 5c and R 5d The term refers to each R on the pyridine ring. 5 may be used to designate a group; R 6 At each occurrence, hydrogen, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; R 7 At each occurrence, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; R 8a At each occurrence position, H, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; R 8b At each occurrence position, H, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; R 9a At each occurrence position, H, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; R 9b At each occurrence position, H, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; R 9a and R 9b may together with the atom to which they are attached form a ring having 3 to 7 ring atoms optionally containing oxygen; R 10 At each occurrence position, H, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; R 11 At each occurrence, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 Cyclo independently selected from the group consisting of alkyl; R 12a At each occurrence, hydrogen, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; and R 12b At each occurrence, hydrogen, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 A compound independently selected from the group consisting of cycloalkyl. (Item 2) The compound having formula (I) is a compound having formula (II) below: [ka] Item 1. The compound according to item 1, including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes thereof. (Item 3) The compound having formula (I) is a compound having formula (IIa): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 4a , R 4b , R 4c , R 4d and R 4e At least two of the groups in R are hydrogen, 4a , R 4b , R 4c , R 4d and R 4e 0 to 3 of the groups are independently OH, NO2, halogen, CN, C 1-6 Linear alkyl, C 3-7 Branched alkyl, C3-7 cycloalkyl, C 1-6 Linear alkoxy, C 3-7 Branched alkoxy, C 3-7 Cycloalkoxy, C1-6 linear haloalkyl, C3-7 branched haloalkyl, C 1-6 Linear haloalkoxy, -S(C 1-6 Straight-chain alkyl), S(C 3-7 Branched alkyl), heterocyclyl, -S(C 3-7 cycloalkyl), -SO2(C 1-6 Linear alkyl), SO2(C3-7 Branched alkyl), -SO2(C3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 , and N.R. 9a SO2NR 12a R 12b selected from the group consisting of The compound according to item 1. (Item 4) The compound having formula (I) is a compound having the following formula (IIb): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 5a , R 5b , R 5c , and R 5d At least two of the groups in R are hydrogen, 5a , R 5b , R 5c , and R 5d 0 to 2 of the groups are independently OH, NO2, halogen, CN, C 1-6 Linear alkyl, C 3-7 Branched alkyl, C 3-7 Cycloalkyl, C 1-6 Linear alkoxy, C 3-7 Branched alkoxy, C 3-7 Cycloalkoxy, C 1-6 Linear haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Straight-chain haloalkoxy, heterocyclyl, -S(C 1-6 Straight-chain alkyl), S(C 3-7 Branched alkyl), -S(C 3-7 cycloalkyl), -SO2(C 1-6 Linear alkyl), SO2(C 3-7 branched alkyl), -SO2(C 3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 and N.R. 9a SO2NR 12a R 12b The compound according to item 1, selected from the group consisting of: (Item 5) The compound having formula (I) is a compound having the following formula (IIc): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 5a , R 5b , R 5c , and R 5d At least two of the groups in R are hydrogen, 5a , R 5b , R 5c , and R 5d 0 to 2 of the groups are independently OH, NO2, halogen, CN, C 1-6 Linear alkyl, C 3-7 Branched alkyl, C 3-7 Cycloalkyl, C 1-6 Linear alkoxy, C 3-7 Branched alkoxy, C 3-7 Cycloalkoxy, C 1-6 Linear haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Straight-chain haloalkoxy, heterocyclyl, -S(C 1-6 Straight-chain alkyl), S(C 3-7 Branched alkyl), -S(C 3-7 cycloalkyl), -SO2(C 1-6 Linear alkyl), SO2(C 3-7 branched alkyl), -SO2(C 3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 and N.R. 9a SO2NR 12a R 12b The compound according to item 1, selected from the group consisting of: (Item 6) The compound having formula (I) is a compound having formula (IId): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 5a , R 5b , R 5c , and R 5d At least two of the groups in R are hydrogen, 5a , R 5b , R 5c , and R 5d 0 to 2 of the groups are independently OH, NO2, halogen, CN, C 1-6 Linear alkyl, C 3-7 Branched alkyl, C 3-7 Cycloalkyl, C 1-6 Linear alkoxy, C 3-7 Branched alkoxy, C 3-7 Cycloalkoxy, C 1-6 Linear haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Straight-chain haloalkoxy, heterocyclyl, -S(C 1-6 Straight-chain alkyl), S(C 3-7 Branched alkyl), -S(C 3-7 cycloalkyl), -SO2(C 1-6 Linear alkyl), SO2(C 3-7 branched alkyl), -SO2(C 3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 and N.R. 9a SO2NR 12a R12b The compound according to item 1, selected from the group consisting of: (Item 7) The compound having formula (I) is a compound having formula (VI): [ka] Item 1. The compound according to item 1, including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes thereof. (Item 8) The compound having formula (I) is a compound having formula (VIa): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 4a , R 4b , R 4c , R 4d and R 4e At least two of the groups in R are hydrogen, 4a , R 4b , R 4c , R 4d and R 4e 0 to 3 of the groups are independently OH, NO2, halogen, CN, C 1-6 Linear alkyl, C 3-7 Branched alkyl, C 3-7 Cycloalkyl, C 1-6 Linear alkoxy, C 3-7 Branched alkoxy, C 3-7 Cycloalkoxy, C 1-6 Linear haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Straight-chain haloalkoxy, heterocyclyl, -S(C 1-6 Straight-chain alkyl), S(C 3-7 Branched alkyl), -S(C 3-7 cycloalkyl), -SO2(C 1-6 Linear alkyl), SO2(C 3-7 Branched alkyl), -SO2(C3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 , and N.R. 9a SO2NR 12a R 12b selected from the group consisting of The compound according to item 1. (Item 9) The compound having formula (I) is a compound having formula (VIb): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 5a , R 5b , R 5c , and R 5d At least two of the groups in R are hydrogen, 5a , R 5b , R 5c , and R 5d 0 to 2 of the groups are independently OH, NO2, halogen, CN, C 1-6 Linear alkyl, C 3-7 Branched alkyl, C 3-7 Cycloalkyl, C 1-6 Linear alkoxy, C 3-7 Branched alkoxy, C 3-7 Cycloalkoxy, C 1-6 Linear haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Straight-chain haloalkoxy, heterocyclyl, -S(C 1-6 Straight-chain alkyl), S(C 3-7 Branched alkyl), -S(C 3-7 cycloalkyl), -SO2(C 1-6Linear alkyl), SO2(C 3-7 branched alkyl), -SO2(C 3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 and N.R. 9a SO2NR 12a R 12b The compound according to item 1, selected from the group consisting of: (Item 10) The compound having formula (I) is a compound having formula (VIc): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 5a , R 5b , R 5c , and R 5d At least two of the groups in R are hydrogen, 5a , R 5b , R 5c , and R 5d 0 to 2 of the groups are independently OH, NO2, halogen, CN, C 1-6 Linear alkyl, C 3-7 Branched alkyl, C 3-7 Cycloalkyl, C 1-6 Linear alkoxy, C 3-7 Branched alkoxy, C 3-7 Cycloalkoxy, C 1-6 Linear haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Straight-chain haloalkoxy, heterocyclyl, -S(C 1-6 Straight-chain alkyl), S(C 3-7 Branched alkyl), -S(C3-7 cycloalkyl), -SO2(C 1-6 Linear alkyl), SO2(C 3-7 branched alkyl), -SO2(C 3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 and N.R. 9a SO2NR 12a R 12b The compound according to item 1, selected from the group consisting of: (Item 11) The compound having formula (I) is a compound having formula (VId): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 5a , R 5b , R 5c , and R 5d At least two of the groups in R are hydrogen, 5a , R 5b , R 5c , and R 5d 0 to 2 of the groups are independently OH, NO2, halogen, CN, C 1-6 Linear alkyl, C 3-7 Branched alkyl, C 3-7 Cycloalkyl, C 1-6 Linear alkoxy, C 3-7 Branched alkoxy, C 3-7 Cycloalkoxy, C 1-6 Linear haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Straight-chain haloalkoxy, heterocyclyl, -S(C 1-6Straight-chain alkyl), S(C 3-7 Branched alkyl), -S(C 3-7 cycloalkyl), -SO2(C 1-6 Linear alkyl), SO2(C 3-7 branched alkyl), -SO2(C 3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 and N.R. 9a SO2NR 12a R 12b The compound according to item 1, selected from the group consisting of: (Item 12) The compound having formula (I) is selected from the group consisting of: (R)-3-(2-(6-(pyridin-4-yl)-2,6-diazospiro[3.3]heptan-2-yl)ethyl)-2- Oxaspiro[4.5]decan-1-one: (S)-3-(2-(6-(pyridin-4-yl)-2,6-diazospiro[3.3]heptan-2-yl)ethyl)-2- Oxaspiro[4.5]decan-1-one: (R)-3,3-diethyl-5-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (S)-3-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (R)-3,3-diethyl-5-(2-(5-(2-isopropylphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-(2-isopropylphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3-(2-(5-(3-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)- yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (S)-3-(2-(5-(3-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)- yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (R)-3-(2-(5-(2-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)- yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (S)-3-(2-(5-(2-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)- yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (R)-3-(2-(5-(2,6-dimethylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (S)-3-(2-(5-(2,6-dimethylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (R)-3-(2-(6-(3-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethoxylate ethyl)-2-oxaspiro[4.5]decan-1-one; (S)-3-(2-(6-(3-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethoxylate ethyl)-2-oxaspiro[4.5]decan-1-one; (R)-3-(2-(6-(2-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethoxylate ethyl)-2-oxaspiro[4.5]decan-1-one; (S)-3-(2-(6-(2-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethoxylate ethyl)-2-oxaspiro[4.5]decan-1-one; (R)-3-(2-(6-(2,6-dimethylpyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (S)-3-(2-(6-(2,6-dimethylpyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (R)-3,3-Diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl) (ethyl)dihydrofuran-2(3H)-one; (S)-3,3-Diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-isopropyl) (ethyl)dihydrofuran-2(3H)-one; (R)-3,3-Diethyl-5-(2-(5-(m-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl) (ethyl)dihydrofuran-2(3H)-one; (S)-3,3-Diethyl-5-(2-(5-(m-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-isopropyl) (ethyl)dihydrofuran-2(3H)-one; (R)-3,3-Diethyl-5-(2-(5-(p-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl) (ethyl)dihydrofuran-2(3H)-one; (S)-3,3-Diethyl-5-(2-(5-(p-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-isopropyl) (ethyl)dihydrofuran-2(3H)-one; (R)-2-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydride (pyrrolo[3,4-c]pyrrole-2(1H)-yl)benzonitrile; (S)-2-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydride (pyrrolo[3,4-c]pyrrole-2(1H)-yl)benzonitrile; (R)-3-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydride (pyrrolo[3,4-c]pyrrole-2(1H)-yl)benzonitrile; (S)-3-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydride (pyrrolo[3,4-c]pyrrole-2(1H)-yl)benzonitrile; (R)-4-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydride (pyrrolo[3,4-c]pyrrole-2(1H)-yl)benzonitrile; (S)-4-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydride (pyrrolo[3,4-c]pyrrole-2(1H)-yl)benzonitrile; (R)-3,3-diethyl-5-(2-(5-(2-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-(2-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-diethyl-5-(2-(5-(3-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-(3-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-diethyl-5-(2-(5-(4-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-(4-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-diethyl-5-(2-(5-(2-morpholinophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-Diethyl-5-(2-(5-(2-morpholinophenyl)hexahydropyrrolo[3,4-c]pyrrole) (2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-diethyl-5-(2-(5-(2-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-(2-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-diethyl-5-(2-(5-(3-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one: (S)-3,3-diethyl-5-(2-(5-(3-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-diethyl-5-(2-(5-(4-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; and (S)-3,3-diethyl-5-(2-(5-(4-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-diethyl-5-(2-(5-phenylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-phenylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; or a pharmaceutically acceptable salt thereof. (Item 13) A composition comprising an effective amount of at least one compound according to item 1. (Item 14) 14. The composition according to item 13, further comprising at least one excipient. (Item 15) the at least one compound is (R)-3-(2-(6-(pyridin-4-yl)-2,6-diazospiro[3.3]heptan-2-yl)ethyl)-2- Oxaspiro[4.5]decan-1-one: (S)-3-(2-(6-(pyridin-4-yl)-2,6-diazospiro[3.3]heptan-2-yl)ethyl)-2- Oxaspiro[4.5]decan-1-one: (R)-3,3-diethyl-5-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (S)-3-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (R)-3,3-diethyl-5-(2-(5-(2-isopropylphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-(2-isopropylphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3-(2-(5-(3-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)- yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (S)-3-(2-(5-(3-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)- yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (R)-3-(2-(5-(2-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)- yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (S)-3-(2-(5-(2-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)- yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (R)-3-(2-(5-(2,6-dimethylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (S)-3-(2-(5-(2,6-dimethylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (R)-3-(2-(6-(3-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethoxylate ethyl)-2-oxaspiro[4.5]decan-1-one; (S)-3-(2-(6-(3-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethoxylate ethyl)-2-oxaspiro[4.5]decan-1-one; (R)-3-(2-(6-(2-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethoxylate ethyl)-2-oxaspiro[4.5]decan-1-one; (S)-3-(2-(6-(2-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethoxylate ethyl)-2-oxaspiro[4.5]decan-1-one; (R)-3-(2-(6-(2,6-dimethylpyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (S)-3-(2-(6-(2,6-dimethylpyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (R)-3,3-Diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl) (ethyl)dihydrofuran-2(3H)-one; (S)-3,3-Diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-isopropyl) (ethyl)dihydrofuran-2(3H)-one; (R)-3,3-Diethyl-5-(2-(5-(m-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl) (ethyl)dihydrofuran-2(3H)-one; (S)-3,3-Diethyl-5-(2-(5-(m-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-isopropyl) (ethyl)dihydrofuran-2(3H)-one; (R)-3,3-Diethyl-5-(2-(5-(p-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl) (ethyl)dihydrofuran-2(3H)-one; (S)-3,3-Diethyl-5-(2-(5-(p-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-isopropyl) (ethyl)dihydrofuran-2(3H)-one; (R)-2-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydride (pyrrolo[3,4-c]pyrrole-2(1H)-yl)benzonitrile; (S)-2-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydride (pyrrolo[3,4-c]pyrrole-2(1H)-yl)benzonitrile; (R)-3-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydride (pyrrolo[3,4-c]pyrrole-2(1H)-yl)benzonitrile; (S)-3-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydride (pyrrolo[3,4-c]pyrrole-2(1H)-yl)benzonitrile; (R)-4-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydride (pyrrolo[3,4-c]pyrrole-2(1H)-yl)benzonitrile; (S)-4-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydride (pyrrolo[3,4-c]pyrrole-2(1H)-yl)benzonitrile; (R)-3,3-diethyl-5-(2-(5-(2-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-(2-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-diethyl-5-(2-(5-(3-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-(3-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-diethyl-5-(2-(5-(4-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-(4-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-diethyl-5-(2-(5-(2-morpholinophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-(2-morpholinophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-diethyl-5-(2-(5-(2-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-(2-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-diethyl-5-(2-(5-(3-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one: (S)-3,3-diethyl-5-(2-(5-(3-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-diethyl-5-(2-(5-(4-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; and (S)-3,3-diethyl-5-(2-(5-(4-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-diethyl-5-(2-(5-phenylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-phenylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; 15. The composition according to item 14, which is at least one of the above pharmaceutically acceptable forms. (Item 16) 1. A method for treating a disease involving dysregulation of sigma-2 receptor activity, said method comprising administering to a subject an effective amount of at least one compound according to item 1 to treat said disease. A method, comprising: (Item 17) 17. The method of claim 16, wherein the at least one compound is administered in a composition further comprising at least one excipient. (Item 18) the at least one compound is (R)-3-(2-(6-(pyridin-4-yl)-2,6-diazospiro[3.3]heptan-2-yl)ethyl)-2- Oxaspiro[4.5]decan-1-one: (S)-3-(2-(6-(pyridin-4-yl)-2,6-diazospiro[3.3]heptan-2-yl)ethyl)-2- Oxaspiro[4.5]decan-1-one: (R)-3,3-diethyl-5-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (S)-3-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (R)-3,3-diethyl-5-(2-(5-(2-isopropylphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-(2-isopropylphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3-(2-(5-(3-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)- yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (S)-3-(2-(5-(3-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)- yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (R)-3-(2-(5-(2-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)- yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (S)-3-(2-(5-(2-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)- yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (R)-3-(2-(5-(2,6-dimethylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (S)-3-(2-(5-(2,6-dimethylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (R)-3-(2-(6-(3-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethoxylate ethyl)-2-oxaspiro[4.5]decan-1-one; (S)-3-(2-(6-(3-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethoxylate ethyl)-2-oxaspiro[4.5]decan-1-one; (R)-3-(2-(6-(2-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethoxylate ethyl)-2-oxaspiro[4.5]decan-1-one; (S)-3-(2-(6-(2-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethoxylate ethyl)-2-oxaspiro[4.5]decan-1-one; (R)-3-(2-(6-(2,6-dimethylpyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (S)-3-(2-(6-(2,6-dimethylpyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (R)-3,3-Diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl) (ethyl)dihydrofuran-2(3H)-one; (S)-3,3-Diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-isopropyl) (ethyl)dihydrofuran-2(3H)-one; (R)-3,3-Diethyl-5-(2-(5-(m-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl) (ethyl)dihydrofuran-2(3H)-one; (S)-3,3-Diethyl-5-(2-(5-(m-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-isopropyl) (ethyl)dihydrofuran-2(3H)-one; (R)-3,3-Diethyl-5-(2-(5-(p-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl) (ethyl)dihydrofuran-2(3H)-one; (S)-3,3-Diethyl-5-(2-(5-(p-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-isopropyl) (ethyl)dihydrofuran-2(3H)-one; (R)-2-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydride (pyrrolo[3,4-c]pyrrole-2(1H)-yl)benzonitrile; (S)-2-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydride (pyrrolo[3,4-c]pyrrole-2(1H)-yl)benzonitrile; (R)-3-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydride (pyrrolo[3,4-c]pyrrole-2(1H)-yl)benzonitrile; (S)-3-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydride (pyrrolo[3,4-c]pyrrole-2(1H)-yl)benzonitrile; (R)-4-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydride (pyrrolo[3,4-c]pyrrole-2(1H)-yl)benzonitrile; (S)-4-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydride (pyrrolo[3,4-c]pyrrole-2(1H)-yl)benzonitrile; (R)-3,3-diethyl-5-(2-(5-(2-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-(2-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-Diethyl-5-(2-(5-(3-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrole -2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-(3-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-diethyl-5-(2-(5-(4-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-(4-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-diethyl-5-(2-(5-(2-morpholinophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-(2-morpholinophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-diethyl-5-(2-(5-(2-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-(2-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-diethyl-5-(2-(5-(3-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one: (S)-3,3-diethyl-5-(2-(5-(3-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-diethyl-5-(2-(5-(4-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-(4-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-diethyl-5-(2-(5-phenylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-phenylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; Item 18. The method according to item 17, wherein the compound is at least one of the compounds comprising the compound of formula (I) and the compound of formula (II), or a pharmaceutically acceptable form thereof. (Item 19) 17. The method of item 16, wherein the disease involving dysregulation of sigma-2 receptor activity is selected from the group consisting of generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, post-traumatic stress disorder, depression, bipolar disorder, anorexia nervosa, bulimia nervosa, substance use disorder, schizophrenia, Alzheimer's disease, mild cognitive impairment, memory disorder, and cancer. (Item 20) 20. The method of claim 19, wherein the cancer is selected from the group consisting of pancreatic cancer, lung cancer, breast cancer, malignant melanoma, prostate cancer, and ovarian cancer. DETAILED DESCRIPTION OF THE INVENTION

[0018] There is evidence that sigma-2 receptor plays a role in many pathological conditions, including but not limited to neuropsychiatric disorders such as generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, post-traumatic stress disorder, depression, bipolar disorder, anorexia nervosa, bulimia nervosa, substance use disorder, and schizophrenia, cancers such as pancreatic cancer, lung cancer, breast cancer, malignant melanoma, prostate cancer, and ovarian cancer, as well as Alzheimer's disease, mild cognitive impairment, and memory impairment.It is believed that the activity modulator of sigma-2 receptor has beneficial effects on patients suffering from these diseases and disorders.There are disorders that are affected by the dysregulation of sigma-2 receptor, and the modulation of the activity of sigma-2 receptor by therapeutic agents can be a promising therapeutic alleviation method. Such disorders include, but are not limited to, neuropsychiatric disorders such as generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, post-traumatic stress disorder, depression, bipolar disorder, anorexia nervosa, bulimia nervosa, substance use disorders, and schizophrenia; cancers such as pancreatic cancer, lung cancer, breast cancer, malignant melanoma, prostate cancer, and ovarian cancer; and Alzheimer's disease, mild cognitive impairment, and memory disorders.

[0019] There has long been a need for novel sigma-2 receptor binding agents and sigma-2 receptor activity modulators that provide therapeutic relief to patients suffering from diseases associated with dysregulation of sigma-2 receptors. The present invention addresses the need to identify novel sigma-2 receptor binding agents and sigma-2 receptor activity modulators that can treat diseases associated with dysregulation of sigma-2 receptor activity. The present invention addresses the need to develop novel therapeutic agents for the treatment and prevention of neuropsychiatric disorders such as generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, post-traumatic stress disorder, depression, bipolar disorder, anorexia nervosa, bulimia nervosa, substance use disorders, and schizophrenia; cancers such as pancreatic cancer, lung cancer, breast cancer, malignant melanoma, prostate cancer, and ovarian cancer; and Alzheimer's disease, mild cognitive impairment, and memory impairment.

[0020] The sigma-2 receptor binding substances and sigma-2 receptor activity modulators of the present invention can treat and prevent neuropsychiatric disorders such as generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, post-traumatic stress disorder, depression, bipolar disorder, anorexia nervosa, bulimia nervosa, substance use disorders, and schizophrenia, cancers such as pancreatic cancer, lung cancer, breast cancer, malignant melanoma, prostate cancer, and ovarian cancer, as well as diseases associated with sigma-2 receptor dysregulation, such as Alzheimer's disease, mild cognitive impairment, and memory disorders. Without wishing to be bound by theory, it is believed that the sigma-2 receptor binding substances and sigma-2 receptor activity modulators of the present invention can alleviate, ameliorate, or control diseases and disorders associated with sigma-2 receptor dysregulation. Diseases and disorders include, but are not limited to, neuropsychiatric disorders such as generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, post-traumatic stress disorder, depression, bipolar disorder, anorexia nervosa, bulimia nervosa, substance use disorders, and schizophrenia; cancers such as pancreatic cancer, lung cancer, breast cancer, malignant melanoma, prostate cancer, and ovarian cancer; and Alzheimer's disease, mild cognitive impairment, and memory disorders.

[0021] The sigma-2 receptor binding substances and sigma-2 receptor activity modulators of the present invention can also treat and prevent neuropsychiatric disorders such as generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, post-traumatic stress disorder, depression, bipolar disorder, anorexia nervosa, bulimia nervosa, substance use disorders, and schizophrenia, cancers such as pancreatic cancer, lung cancer, breast cancer, malignant melanoma, prostate cancer, and ovarian cancer, as well as diseases associated with overexpression of sigma-2 receptors, such as Alzheimer's disease, mild cognitive impairment, and memory disorders. Without wishing to be bound by theory, it is believed that the sigma-2 receptor binding substances and sigma-2 receptor activity modulators of the present invention can alleviate, ameliorate, or control diseases and disorders associated with overexpression of sigma-2 receptors. Diseases and disorders include, but are not limited to, neuropsychiatric disorders such as generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, post-traumatic stress disorder, depression, bipolar disorder, anorexia nervosa, bulimia nervosa, substance use disorders, and schizophrenia; cancers such as pancreatic cancer, lung cancer, breast cancer, malignant melanoma, prostate cancer, and ovarian cancer; and Alzheimer's disease, mild cognitive impairment, and memory disorders.

[0022] Throughout this specification, when a composition is described as having, comprising, or including a particular ingredient, or when a process is described as having, comprising, or including a particular process step, Where listed, it is contemplated that compositions of the present teachings consist essentially of or consist of the recited components, and processes of the present teachings consist essentially of or consist of the recited process steps.

[0023] Whenever an element or component is described herein as being included in and / or selected from a recited list of elements or components, it should be understood that the element or component may be any one of the recited elements or components, or may be selected from a group consisting of two or more of the recited elements or components.

[0024] As used herein, the use of the singular includes the plural (and vice versa) unless otherwise specified. Furthermore, when the term "about" is used before a quantitative value, the present teachings also include the particular quantitative value itself, unless otherwise specified.

[0025] It should be understood that the order of steps or order for performing certain actions is immaterial so long as the present teachings remain operable. Moreover, two or more steps or actions may be conducted simultaneously.

[0026] As used herein, the term "halogen" means chlorine, bromine, fluorine, and iodine.

[0027] As used herein, unless otherwise stated, "alkyl" and / or "aliphatic" whether used alone or as part of a substituent group, refers to an alkyl group having 1 to 20 carbon atoms. represents straight and branched carbon chains having a specified number of carbon atoms (e.g., C 1-6 ) independently refer to the number of carbon atoms in the alkyl moiety or to the alkyl portion of a larger alkyl-containing substituent. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, and the like. The alkyl group can be optionally substituted. Non-limiting examples of substituted alkyl groups include hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, 1-chloroethyl, 2-hydroxyethyl, 1,2-difluoroethyl, 3-carboxypropyl, and the like. (C 1-6 In the case of a substituent having multiple alkyl groups, such as alkylamino, the alkyl groups The alkyl groups may be the same or different.

[0028] As used herein, the terms "alkenyl" and "alkynyl" groups, whether used alone or as part of a substituent group, refer to groups having two or more carbon atoms, preferably means a straight or branched carbon chain having 2 to 20 carbon atoms, and an alkenyl chain means a chain having It has at least one double bond, and the alkynyl chain has at least one triple bond in the chain. The alkenyl group and the alkynyl group can be optionally substituted. Non-limiting examples of alkenyl groups include ethenyl, 3-propenyl, 1-propenyl (also known as 2-methylethenyl), isopropenyl (also known as 2-methylethen-2-yl), buten-4-yl, etc. Non-limiting examples of substituted alkenyl groups include 2-chloroethenyl (also known as 2-chlorovinyl), 4-hydroxybuten-1-yl, 7-hydroxy-7-methyloct-4-en-2-yl, 7-hydroxy-7-methyloct-4-en-2-yl, etc. Non-limiting examples of alkynyl groups include ethynyl, prop-2-ynyl (also known as propargyl), propyn-1-yl, and 2-methyl-hex-4-yn-1-yl. Non-limiting examples of substituted alkynyl groups include 5-hydroxybenzoyl, ... 6-hydroxy-6-methylhept-3-yn-2-yl, 5- hydroxy-5-ethylhept-3-ynyl and the like.

[0029] As used herein, "cycloalkyl," whether used alone or as part of another group, refers to a group having, for example, 3 to 14 ring carbon atoms, preferably 3 to 7 or 3 to 14 ring carbon atoms. Cyclized alkyl and alkenyl groups with 6 ring carbon atoms or 3 to 4 ring carbon atoms and cyclized alkynyl groups, and optionally represent a non-aromatic carbon-containing ring containing one or more (e.g., 1, 2, or 3) double or triple bonds. The group may be monocyclic (e.g., cyclohexyl) or polycyclic (e.g., containing fused, bridged, and / or spiro ring structures), with the carbon atoms located inside or outside the ring structure. Any suitable ring position of the cycloalkyl group can be covalently linked to the defined chemical structure. The cycloalkyl ring can be optionally substituted. Non-limiting examples of cycloalkyl groups include cyclopropyl, 2-methyl-cyclopropyl, cyclopropenyl, cyclopentyl, cyclohex ... butyl, 2,3-dihydroxycyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl, decalinyl, 2,5-dimethylcyclopentyl, 3,5-dichlorocyclohexyl, 4-hydroxycyclohexyl, 3,3,5-trimethylcyclohex-1-yl, octanyl Examples of cycloalkyl include hydropentalenyl, octahydro-1H-indenyl, 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl, decahydroazulenyl, bicyclo[6.2.0]decanyl, decahydronaphthalenyl, and dodecahydro-1H-fluorenyl. The term "cycloalkyl" also includes carbocyclic rings that are bicyclic hydrocarbon rings, non-limiting examples of which include bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, 1,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl.

[0030] "Haloalkyl" refers to an alkyl group having the specified number of carbon atoms substituted with one or more halogens. It is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups. Haloalkyl groups include perhalo groups in which all hydrogens on the alkyl group have been replaced with halogens (e.g., -CF3, -CF2CF3). The haloalkyl group may optionally be substituted with one or more substituents in addition to halogen. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl groups.

[0031] The term "alkoxy" refers to the group -O-alkyl, where the alkyl group is as defined above. As defined above. The alkoxy group may be optionally substituted. The term C3-C6 cyclic alkoxy refers to a group containing 3 to 6 carbon atoms and at least one oxygen atom. C3-C6 cyclic alkyl rings (e.g., tetrahydrofuran, tetrahydro-2H-pyran). A alkoxy group may be optionally substituted.

[0032] The term "haloalkoxy" refers to the group -O-haloalkyl, where haloalkoxy is An alkyl group is as defined above. Examples of haloalkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and pentafluoroethoxyl.

[0033] The term "aryl" used alone or as part of another group refers to a 6-carbon Aryl groups are defined herein as unsaturated aromatic monocyclic rings or unsaturated aromatic polycyclic rings of 10 to 14 carbons. Aryl rings can be, for example, phenyl or naphthyl rings, each optionally substituted with one or more moieties capable of replacing one or more hydrogen atoms. Non-limiting examples of aryl groups include phenyl, naphthylene-1-yl, naphthylene-2-yl, 4-fluorophenyl, 2-hydroxyphenyl, 3-methylphenyl, 2-amino-4-fluoro ... 2-(N,N-diethylamino)phenyl, 2-cyanophenyl, 2,6-di-tert-butylphenyl, 3-methoxyphenyl, 8-hydroxynaphthylene-2-yl 4,5-dimethoxynaphthyl Aryl groups include, for example, naphthylene-1-yl, and 6-cyano-naphthylene-1-yl. For example, one or more saturated or partially saturated carbocyclic rings (e.g., bicyclo[4.2.0]octa-1,3,5-to) which may be substituted at one or more carbon atoms of an aromatic ring and / or a saturated or partially saturated ring. It also includes a phenyl or naphthyl ring fused to a phenyl ring or naphthyl ring (indanyl, iodophenyl, indanyl).

[0034] The term "arylalkyl" or "aralkyl" refers to the group -alkyl-aryl, where the alkyl and aryl groups are as defined herein. The aralkyl groups of the present invention are optionally substituted. Examples of arylalkyl groups include, for example, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, fluorenylmethyl, and the like.

[0035] The terms "heterocyclic" and / or "heterocycle" and / or "heterocyclyl", whether used alone or as part of another group, refer to heterocyclic rings having 3 to 20 atoms. One or more rings, at least one atom of at least one ring being nitrogen (N), Heterocyclic groups are defined as rings in which the heteroatom is selected from oxygen (O), sulfur (S), and the ring containing the heteroatom is non-aromatic. In heterocyclic groups containing two or more fused rings, the non-heteroatom is The heteroatom-containing ring may be aryl (e.g., indolinyl, tetrahydroquinolinyl, chromanyl). Exemplary heterocyclic groups have 3 to 14 ring atoms, 1 to 5 of which are nitrogen atoms. Heterocycles are heteroatoms independently selected from N, oxygen (O), or sulfur (S). One or more N or S atoms in the group can be oxidized. A heterocyclic group can be optionally substituted.

[0036] Non-limiting examples of heterocyclic units having a single ring include diazirinyl, aziridinyl, urazolyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl, isothiazolyl, isothiazolinyl, oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl (valerolactam), 2,3,4,5-tetrahydrofuranyl, and the like. 1H-azepinyl, 2,3-dihydro-1H-indole, and 1,2,3,4-tetrahydro-quinoline Non-limiting examples of heterocyclic units having two or more rings include hexahydrogen. 1H-pyrrolidinyl, 3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro-1H-indolyl, 1,2,3,4-tetrahydroquinolinyl, chromanyl, Examples include isochromanyl, indolinyl, isoindolinyl, and decahydro-1H-cycloocta[b]pyrrolyl.

[0037] The term "heteroaryl," whether used alone or as part of another group, is defined herein as one or more rings having from 5 to 20 atoms; In this case, at least one atom of at least one ring is a heteroatom selected from nitrogen (N), oxygen (O), or sulfur (S), and in this case further At least one of the rings containing a heteroatom is aromatic. In heteroaryl groups, the non-heteroatom-containing ring may be carbocyclic (e.g., 6,7-dihydro-5H-cyclopentapyrimidine) or aryl (e.g., benzofuranyl, benzothiophenyl, indolyl). Exemplary heteroaryl groups have 5 to 14 ring atoms. 1 to 5 ring heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S); One or more N or S atoms in a heteroaryl group can be oxidized. Heteroaryl groups can also be substituted. Non-limiting examples of heteroaryl rings containing a single ring include 1,2,3,4-tetrazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1H-imidazolyl, oxazolyl, furanyl, thiopheneyl, and the like. Heteroaryl rings containing two or more fused rings include aryl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl. Non-limiting examples include benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl, 9H-purinyl, 6-amino-9H-purinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, and the like. quinolyl, 7H-pyrrolo[2,3-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, 2-phenylbenzo[d]thiazolyl, 1H-indolyl, 4,5,6,7-tetrahydro-1-H-indolyl, quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl, 8-hydroxyquinolinyl, 1H-benzo-[d]imidazol-2(3H)-onyl, 1H-benzo[d]imidazolyl, and isoquinolyl Nil is an example.

[0038] One non-limiting example of the above-mentioned heteroaryl group is C1-C5 heteroaryl, which has 1 to 5 carbon ring atoms and at least one additional ring atom that is a heteroatom independently selected from nitrogen (N), oxygen (O), or sulfur (S) (preferably 1 to 4 additional ring atoms that are heteroatoms). Examples of C1-C5 heteroaryl include, but are not limited to: Triazinyl, thiazol-2-yl, thiazol-4-yl, imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, isoxazolin-5-yl, furan-2-yl, Included are furan-3-yl, thiophen-2-yl, thiophen-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl.

[0039] Unless otherwise specified, two substituents taken together form a ring having a specified number of ring atoms (e.g., R 2 and R 3 Together with the nitrogen (N) attached to them, they have 3 to 7 ring members. When a ring is formed, the ring is composed of carbon atoms and, optionally, one or more (e.g., 1 to 3) additional hetero atoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). The ring may have atoms. The ring may be saturated or partially saturated and may be optionally substituted.

[0040] For the purposes of the present invention, fused ring units as well as spirocyclic rings, bicyclic rings, and the like, containing a single heteroatom are considered to belong to the ring family corresponding to heteroatom-containing rings. For example, 1,2,3,4-tetrahydroquinoline, having the formula: [ka] In the present invention, 6,7-dihydro-5H-cyclopentapyrimidine having the formula: [ka] In the present invention, it is considered a heteroaryl unit. When a fused ring unit contains heteroatoms in both the saturated ring and the aryl ring, the aryl ring is dominant and determines the classification of the ring species. For example, 1,2,3,4-tetrahydro-[1,8]naphthyridine having the following formula: [ka] In the present invention, it is considered a heteroaryl unit.

[0041] When a term or any of its prefix roots appears in the name of a substituent, the name should be interpreted to include the limitations provided herein. For example, when the term "alkyl" or "aryl" or any of its prefix roots appears in the name of a substituent (e.g., arylaryl), alkyl, alkylamino), the name should be construed to include the limitations given above for "alkyl" and "aryl."

[0042] The term "substituted" is used throughout this specification. The term "substituted" is defined herein as a moiety, whether acyclic or cyclic, having one or more hydrogen atoms replaced with substituents (e.g., 1 to 10) as defined herein below. Substituents can replace one or two hydrogen atoms of a single moiety at a time. Furthermore, these substituents can replace two hydrogen atoms attached to two adjacent carbons to form the substituent, i.e., a new moiety or unit. For example, substitution units where a single hydrogen atom is replaced include halogen, hydroxyl, etc. Substitutions of two hydrogen atoms include carbonyl, oximino, etc. Substitutions of two hydrogen atoms on adjacent carbon atoms include epoxy, etc. The term "substituted" is used throughout this specification to indicate that a moiety can have one or more hydrogen atoms replaced by a substituent. When a moiety is described as "substituted," any number of hydrogen atoms may be substituted. For example, difluoromethyl is a substituted C1 alkyl, trifluoromethyl is a substituted C1 alkyl, 4-hydroxyphenyl is a substituted aromatic ring, and (N,N-dimethyl) is a substituted C1 alkyl. (5-amino)octanyl is a substituted C8 alkyl, 3-guanidinopropyl is a substituted C3 alkyl, and 2-carboxypyridinyl is a substituted heteroaryl.

[0043] Variable groups defined herein, for example, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, aryloxy, aryl, heterocyclic, and heteroaryl groups defined herein, whether used alone or as part of another group, can be optionally substituted. Optionally substituted groups are similarly designated.

[0044] Non-limiting examples of substituents that can be substituted for hydrogen atoms on a moiety are: halogen (chlorine (Cl), bromine (Br), fluorine (F), and iodine (I)), -CN, -NO2, oxo (=O). , -OR 13 , -SR 13 , -N(R 13 )2, -NR 13 C(O)R 13 , -SO2R 13 , -SO2OR 13 , -SO2N(R 13 )2, -C(O)R 13 , -C(O)OR 13 , -C(O)N(R 13 )2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-14 cycloalkyl, aryl, heterocycle, or heteroaryl, wherein each of the alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocycle, and heteroaryl groups is optionally selected from halogen, —CN, —NO2, oxo, and —OR 13 1 to 10 (e.g., 1 to 6 or 1 to 4) independently selected from substituted with groups; R 13 independently at each occurrence, hydrogen, -OR 14 , -SR 14 , -C(O)R 14 , -C(O)OR 14 , -C(O)N(R 14 )2, -SO2R 14 , -S(O)2OR 14 , -N(R 14)2, -NR 14 C(O)R 14 , C 1-6 Alkyl , C 1-6 Haloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, cycloalkyl (e.g., C 3-6 cycloalkyl), aryl, heterocycle, or heteroaryl, or two R 13 unit together with the atom to which they are attached form an optionally substituted carbocyclic or heterocyclic ring, wherein said carbocyclic or heterocyclic ring has 3 to 7 ring atoms; R 14 is independently generated at each occurrence position, Basic, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, cycloalkyl (e.g., C 3-6 cycloalkyl), aryl, heterocycle or heteroaryl, or or two R's 14 The units, together with the atoms to which they are attached, may be optionally substituted carbocyclic or polycyclic rings. The carbocyclic or heterocyclic rings each have from 3 to 7 ring atoms.

[0045] In some embodiments, the substituent is i) -OR 15 ;for example, -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3; ii) -C(O)R 15 ;for example, -COCH3, -COCH2CH3, -COCH2CH2CH3; iii) -C(O)OR 15 ;for example, -CO2CH3, -CO2CH2CH3, -CO2CH2CH2CH3; iv) -C(O)N(R 15 )2; e.g., -CONH2, -CONHCH3, -CON(CH3)2; v) -N(R 15 )2; for example, -NH2, -NHCH3, -N(CH3)2, -NH(CH2CH3); vi) halogens: -F, -Cl, -Br, and -I; vii) -CH e X g where X is a halogen, m is 0-2, and e+g=3; for example, —CH2F, —CHF2, —CF3, —CCl3, or —CBr3; viii) -SO2R 15 ;For example, -SO2H;-SO2CH3;-SO2C6H5: ix) C1-C6 linear alkyl, branched alkyl, or cyclic; x) Cyano xi) nitro, xii) N(R 15 )C(O)R 15 ; xiii) oxo(=O); xiv) heterocycles, and xv) heteroaryl. In the formula, each R 15 are independently hydrogen, optionally substituted C1-C6 straight chain alkyl or branched alkyl (e.g., optionally substituted C1-C4 straight chain alkyl or branched alkyl), or optionally substituted C3-C6 cycloalkyl (e.g., optionally substituted or two R 15 The units can be joined together to form a ring containing 3 to 7 ring atoms. In certain embodiments, each R 15 are independently hydrogen or any It is a C1-C6 straight chain or branched alkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkyl optionally substituted with halogen.

[0046] At various places in the present specification, substituents of compounds are disclosed in groups or in ranges. It is specifically intended that the description also include individual subsets of such group members and ranges. For example, "C 1-6The term "alkyl" includes C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl C1-C3 alkyl, C1-C2 alkyl, C2-C6 alkyl, C2-C5 alkyl, C2-C4 alkyl, C2-C3 alkyl, C3-C6 alkyl, C3-C5 alkyl, C3-C4 alkyl, C4-C6 alkyl, C4-C5 Alkyl, and C5-C6 alkyl are specifically intended to be disclosed individually.

[0047] In the present invention, the terms "compound," "analog," and "composition of matter" equally adequately refer to the sigma-2 receptor activity modulators and sigma-2 receptor binding substances described herein, including all enantiomeric forms, diastereomeric forms, salts, etc., and these terms "compound," "analog," and "composition of matter" are used interchangeably throughout the present specification.

[0048] The compounds described herein may contain asymmetric atoms (also called chiral centers), and some compounds may contain one or more asymmetric atoms or centers, which can give rise to optical isomers (enantiomers) and diastereomers. The teachings and compounds disclosed herein include such enantiomers and diastereomers, as well as racemic separations of enantiomerically pure R and S stereoisomers and other mixtures of R and S stereoisomers with pharmaceutically acceptable salts. Optical isomers can be obtained in pure form by standard procedures known to those skilled in the art, including, but not limited to, diastereomeric salt formation, kinetic resolution, and asymmetric synthesis. The present teachings also encompass cis and trans isomers of compounds containing alkenyl moieties (e.g., alkenes and imines). It is also understood that the present teachings encompass all possible positional isomers, and mixtures thereof, which can be obtained in pure form by standard separation procedures known to those skilled in the art, including, but not limited to, column chromatography, thin layer chromatography, and high performance liquid chromatography.

[0049] Pharmaceutically acceptable salts of the compounds of the present teachings can have acidic moieties and can be formed using organic and inorganic bases. Depending on the number of acidic hydrogens available for deprotonation, both monoanionic and polyanionic salts are contemplated. Suitable salts formed with bases Examples of inorganic bases include metal salts such as alkali metal or alkaline earth metal salts, for example, sodium, potassium, or magnesium salts; ammonia salts and organic amine salts, such as salts formed with morpholine, thiomorpholine, piperidine, pyrrolidine, mono-, di-, or tri-lower alkylamines (e.g., ethyl-tert-butylamine, diethylamine, diisopropylamine, triethylamine, or dimethylpropylamine), or mono-, di-, or trihydroxy-lower alkylamines (e.g., monoethanolamine, diethanolamine, or triethanolamine). Specific non-limiting examples of inorganic bases include NaHCO3, Na2CO3, KHCO3, K2CO3, Cs2CO3, LiOH, NaOH, KOH , NaH2PO4, Na2HPO4, and Na3PO4. Inner salts can also be formed. Similarly, when the compounds disclosed herein contain a basic moiety, salts can be formed using organic and inorganic acids. For example, salts can be formed with the following acids: acetic acid, propionic acid, lactic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, tartaric acid, succinic acid, dichloroacetic acid, ethenesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalenesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phosphoric acid, phthalic acid, propionic acid, succinic acid, sulfuric acid, tartaric acid, toluenesulfonic acid, and camphorsulfonic acid, as well as other known pharmaceutically acceptable acids.

[0050] When any variable occurs more than one time in any component or in any formula, its definition in each occurrence is independent of its definition at every other occurrence (e.g., N(R 9 )2, each R 9 (the groups may be the same or different). Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0051] As used herein, the terms "treat" and "treating" and "treatment" mean to partially or completely alleviate, inhibit, improve, and / or relieve a condition from which a patient may suffer.

[0052] As used herein, "therapeutically effective" and "effective dose" refer to a substance or amount that elicits a desired biological activity or effect.

[0053] Unless otherwise noted, the terms "subject" or "patient" are used interchangeably and refer to mammals, such as human patients and non-human primates, as well as laboratory and other animals, such as rabbits, rats, and mice. Thus, as used herein, the term "subject" or "patient" refers to any mammalian patient or subject to which a compound of the present invention can be administered. In exemplary embodiments of the present invention, to identify a patient for treatment with the methods of the present invention, validated screening methods are used to measure risk factors associated with the targeted or suspected disease or condition, or to measure the subject's existing disease or condition status. These screening methods include, for example, conventional workups to measure risk factors that may be associated with the targeted or suspected disease or condition. These and other routine methods allow clinicians to select patients in need of treatment using the methods and compounds of the present invention.

[0054] Sigma-2 receptor binding substances and sigma-2 receptor activity modulators

[0055] The sigma-2 receptor binding substances and sigma-2 receptor activity modulators of the present invention include all enantiomeric and diastereomeric forms having the following formulae:

[0056] The present invention is directed to novel sigma-2 receptor binding agents, namely compounds of formula (I): It is something that [ka] including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein: A is, [ka] and [ka] selected from the group consisting of: n is 1, 2, or 3; R 1a and R 1b are each independently selected from the group consisting of hydrogen, C1-6 straight chain alkyl and C1-6 branched alkyl, or R 1a and R 1b may, together with the atom to which they are attached, form a ring having 3 to 7 ring atoms; R 2 is 0 to 3 non-hydrogen R 4 Benzene ring optionally substituted with a group, 0-2 non-hydrogen R 5 A 4-pyridine ring optionally substituted with a group, and 0 to 2 non-hydrogen R 5 A 3-pyridine ring optionally substituted with a group, and 0 to 2 non-hydrogen R 5 a 2-pyridine ring optionally substituted with a group; R 3 is 0 to 3 non-hydrogen R 4 Benzene ring optionally substituted with a group, 0-2 non-hydrogen R 5 A 4-pyridine ring optionally substituted with a group, and 0 to 2 non-hydrogen R 5 A 3-pyridine ring optionally substituted with a group, and 0 to 2 non-hydrogen R 5 a 2-pyridine ring optionally substituted with a group; R 4 represents hydrogen, OH, NO2, halogen, CN, C1-6 linear alkyl, C3-7 branched alkyl at each occurrence. Alkyl, C3-7 cycloalkyl, C1-6 linear alkoxy, C3-7 branched alkoxy, C3-7 Cycloalkoxy, C1-6 straight-chain haloalkyl, C3-7 branched haloalkyl, C1-6 straight-chain haloalkoxy, heterocyclyl, -S(C1-6 straight-chain alkyl), S(C3-7 branched alkyl) , -S(C3-7 cycloalkyl), -SO2(C1-6 linear alkyl), SO2(C3-7 branched alkyl), -SO2(C3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 , and N.R. 9a SO2NR 12a R 12b independently selected from the group consisting of: R 4a , R 4b , R 4c , R 4d , and R 4e The term refers to each R on the benzene ring. 4 Specify the group may be used for; R 5 At each occurrence position, hydrogen, OH, NO2, halogen, CN, C 1-6 Linear alkyl, C 3-7 Branched Alkyl, C 3-7 Cycloalkyl, C 1-6 Linear alkoxy, C 3-7 Branched alkoxy, C 3-7 Cycloalkoxy, C 1-6 Linear haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Straight-chain haloalkoxy, heterocyclyl, -S(C 1-6 Straight-chain alkyl), S(C 3-7 Branched alkyl), -S(C 3-7cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 , and N.R. 9a SO2NR 12a R 12b independently selected from the group consisting of: R 5a , R 5b , R 5c and R 5d The term refers to each R on the pyridine ring. 5 may be used to designate a group; R 6 At each occurrence, hydrogen, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; R 7 At each occurrence, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; R 8a At each occurrence position, H, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; R 8b At each occurrence position, H, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; R 9a At each occurrence position, H, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7independently selected from the group consisting of cycloalkyl; R 9b At each occurrence position, H, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; R 9a and R 9b may together with the atom to which they are attached form a ring having 3 to 7 ring atoms optionally containing oxygen; R 10 At each occurrence position, H, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; R 11 At each occurrence, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 Cycloa independently selected from the group consisting of: R 12a At each occurrence, hydrogen, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; and R 12b At each occurrence, hydrogen, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 cycloalkyl.

[0057] In one embodiment, the present invention includes a compound having the following formula (II): [ka] This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes thereof.

[0058] In one embodiment, the present invention includes a compound having the following formula (IIa): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 4a , R 4b , R 4c , R 4d and R 4e At least two of the groups in R are hydrogen, 4a , R 4b , R 4c , R 4d and R 4e groups are independently selected from OH, NO2, halogen, CN, C1-6 straight chain alkyl, C3-7 branched alkyl, C3-7 cycloalkyl, C1-6 straight chain alkoxy, C3-7 branched alkoxy, C3-7 cycloalkoxy, C1-6 straight chain haloalkyl, C3-7 branched haloalkyl, C1-6 straight chain haloalkoxy, -S(C1-6 straight chain alkyl), S(C3-7 branched alkyl), heterocyclyl, -S(C3-7 cycloalkyl), -SO2(C1-6 straight chain alkyl), SO2(C3-7 branched alkyl), Branched alkyl), -SO2(C3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 , and N.R. 9a SO2NR 12a R 12b is selected from the group consisting of:

[0059] In one embodiment, the present invention includes a compound having the following formula (IIb): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 5a , R 5b , R 5c , and R 5d At least two of the groups in R are hydrogen, 5a , R 5b , R 5c , and R 5d groups are independently selected from 0 to 2 of OH, NO2, halogen, CN, C1-6 straight chain alkyl, C3-7 branched alkyl, C3-7 cycloalkyl, C1-6 straight chain alkoxy, C3-7 branched alkoxy, C3-7 cycloalkoxy, C1-6 straight chain haloalkyl, C3-7 branched haloalkyl, C1-6 straight chain haloalkoxy, heterocyclyl, -S(C1-6 straight chain alkyl), S(C3-7 branched alkyl), -S(C3-7 cycloalkyl), -SO2(C1-6 straight chain alkyl), SO2(C3-7 branched alkoxy), -SO2(C3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 and N.R. 9a SO2NR 12a R 12b is selected from the group consisting of:

[0060] In one embodiment, the present invention includes a compound having the following formula (IIc): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 5a , R 5b , R 5c , and R5d At least two of the groups in R are hydrogen, 5a , R 5b , R 5c , and R 5d groups are independently selected from 0 to 2 of OH, NO2, halogen, CN, C1-6 straight chain alkyl, C3-7 branched alkyl, C3-7 cycloalkyl, C1-6 straight chain alkoxy, C3-7 branched alkoxy, C3-7 cycloalkoxy, C1-6 straight chain haloalkyl, C3-7 branched haloalkyl, C1-6 straight chain haloalkoxy, heterocyclyl, -S(C1-6 straight chain alkyl), S(C3-7 branched alkyl), -S(C3-7 cycloalkyl), -SO2(C1-6 straight chain alkyl), SO2(C3-7 branched alkoxy), -SO2(C3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 and N.R. 9a SO2NR 12a R 12b is selected from the group consisting of:

[0061] In one embodiment, the present invention includes a compound having the following formula (IId): [ka] Hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and and complexes, wherein: R 5a , R 5b , R 5c , and R 5d At least two of the groups in R are hydrogen, 5a , R 5b , R 5c , and R 5dgroups are independently selected from 0 to 2 of OH, NO2, halogen, CN, C1-6 straight chain alkyl, C3-7 branched alkyl, C3-7 cycloalkyl, C1-6 straight chain alkoxy, C3-7 branched alkoxy, C3-7 cycloalkoxy, C1-6 straight chain haloalkyl, C3-7 branched haloalkyl, C1-6 straight chain haloalkoxy, heterocyclyl, -S(C1-6 straight chain alkyl), S(C3-7 branched alkyl), -S(C3-7 cycloalkyl), -SO2(C1-6 straight chain alkyl), SO2(C3-7 branched alkoxy), -SO2(C3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 and N.R. 9a SO2NR 12a R 12b is selected from the group consisting of:

[0062] In one embodiment, the present invention includes a compound having the following formula (III): [ka] This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes thereof.

[0063] In one embodiment, the present invention includes a compound having the following formula (IIIa): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 4a , R 4b , R 4c , R 4d and R 4eAt least two of the groups in R are hydrogen, 4a , R 4b , R 4c , R 4d and R 4e groups are independently selected from OH, NO2, halogen, CN, C1-6 straight chain alkyl, C3-7 branched alkyl, C3-7 cycloalkyl, C1-6 straight chain alkoxy, C3-7 branched alkoxy, C3-7 cycloalkoxy, C1-6 straight chain haloalkyl, C3-7 branched haloalkyl, C1-6 straight chain haloalkoxy, heterocyclyl, -S(C1-6 straight chain alkyl), S(C3-7 branched alkyl), -S(C3-7 cycloalkyl), -SO2(C1-6 straight chain alkyl), SO2(C3-7 branched Branched alkyl), -SO2(C3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 , and N.R. 9a SO2NR 12a R 12b is selected from the group consisting of:

[0064] In one embodiment, the present invention includes a compound having the following formula (IIIb): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 5a , R 5b , R 5c , and R 5d At least two of the groups in R are hydrogen, 5a , R 5b , R 5c , and R 5dgroups are independently selected from 0 to 2 of OH, NO2, halogen, CN, C1-6 straight chain alkyl, C3-7 branched alkyl, C3-7 cycloalkyl, C1-6 straight chain alkoxy, C3-7 branched alkoxy, C3-7 cycloalkoxy, C1-6 straight chain haloalkyl, C3-7 branched haloalkyl, C1-6 straight chain haloalkoxy, heterocyclyl, -S(C1-6 straight chain alkyl), S(C3-7 branched alkyl), -S(C3-7 cycloalkyl), -SO2(C1-6 straight chain alkyl), SO2(C3-7 branched alkoxy), -SO2(C3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 and N.R. 9a SO2NR 12a R 12b is selected from the group consisting of:

[0065] In one embodiment, the present invention includes a compound having the following formula (IIIc): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 5a , R 5b , R 5c , and R 5d At least two of the groups in R are hydrogen, 5a , R 5b , R 5c , and R 5dgroups are independently selected from 0 to 2 of OH, NO2, halogen, CN, C1-6 straight chain alkyl, C3-7 branched alkyl, C3-7 cycloalkyl, C1-6 straight chain alkoxy, C3-7 branched alkoxy, C3-7 cycloalkoxy, C1-6 straight chain haloalkyl, C3-7 branched haloalkyl, C1-6 straight chain haloalkoxy, heterocyclyl, -S(C1-6 straight chain alkyl), S(C3-7 branched alkyl), -S(C3-7 cycloalkyl), -SO2(C1-6 straight chain alkyl), SO2(C3-7 branched alkoxy), -SO2(C3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 and N.R. 9a SO2NR 12a R 12b is selected from the group consisting of:

[0066] In one embodiment, the present invention includes a compound having the following formula (IId): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 5a , R 5b , R 5c , and R 5d At least two of the groups in R are hydrogen, 5a , R 5b , R 5c , and R 5dgroups are independently selected from 0 to 2 of OH, NO2, halogen, CN, C1-6 straight chain alkyl, C3-7 branched alkyl, C3-7 cycloalkyl, C1-6 straight chain alkoxy, C3-7 branched alkoxy, C3-7 cycloalkoxy, C1-6 straight chain haloalkyl, C3-7 branched haloalkyl, C1-6 straight chain haloalkoxy, heterocyclyl, -S(C1-6 straight chain alkyl), S(C3-7 branched alkyl), -S(C3-7 cycloalkyl), -SO2(C1-6 straight chain alkyl), SO2(C3-7 branched alkoxy), -SO2(C3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 and N.R. 9a SO2NR 12a R 12b is selected from the group consisting of:

[0067] In one embodiment, the present invention includes a compound having the following formula (IV): [ka] This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes thereof.

[0068] In one embodiment, the present invention includes a compound having the following formula (IVa): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 4a , R 4b , R 4c , R 4d and R 4eAt least two of the groups in R are hydrogen, 4a , R 4b , R 4c , R 4d and R 4e groups are independently selected from OH, NO2, halogen, CN, C1-6 straight chain alkyl, C3-7 branched alkyl, C3-7 cycloalkyl, C1-6 straight chain alkoxy, C3-7 branched alkoxy, C3-7 cycloalkoxy, C1-6 straight chain haloalkyl, C3-7 branched haloalkyl, C1-6 straight chain haloalkoxy, heterocyclyl, -S(C1-6 straight chain alkyl), S(C3-7 branched alkyl), -S(C3-7 cycloalkyl), -SO2(C1-6 straight chain alkyl), SO2(C3-7 branched Branched alkyl), -SO2(C3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 , and N.R. 9a SO2NR 12a R 12b is selected from the group consisting of:

[0069] In one embodiment, the present invention includes a compound having the following formula (IVb): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 5a , R 5b , R 5c , and R 5d At least two of the groups in R are hydrogen, 5a , R 5b , R 5c , and R 5dgroups are independently selected from 0 to 2 of OH, NO2, halogen, CN, C1-6 straight chain alkyl, C3-7 branched alkyl, C3-7 cycloalkyl, C1-6 straight chain alkoxy, C3-7 branched alkoxy, C3-7 cycloalkoxy, C1-6 straight chain haloalkyl, C3-7 branched haloalkyl, C1-6 straight chain haloalkoxy, heterocyclyl, -S(C1-6 straight chain alkyl), S(C3-7 branched alkyl), -S(C3-7 cycloalkyl), -SO2(C1-6 straight chain alkyl), SO2(C3-7 branched alkoxy), -SO2(C3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 and N.R. 9a SO2NR 12a R 12b is selected from the group consisting of:

[0070] In one embodiment, the present invention includes a compound having the following formula (IVc): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 5a , R 5b , R 5c , and R 5d At least two of the groups in R are hydrogen, 5a , R 5b , R 5c , and R 5dgroups are independently selected from 0 to 2 of OH, NO2, halogen, CN, C1-6 straight chain alkyl, C3-7 branched alkyl, C3-7 cycloalkyl, C1-6 straight chain alkoxy, C3-7 branched alkoxy, C3-7 cycloalkoxy, C1-6 straight chain haloalkyl, C3-7 branched haloalkyl, C1-6 straight chain haloalkoxy, heterocyclyl, -S(C1-6 straight chain alkyl), S(C3-7 branched alkyl), -S(C3-7 cycloalkyl), -SO2(C1-6 straight chain alkyl), SO2(C3-7 branched alkoxy), -SO2(C3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 and N.R. 9a SO2NR 12a R 12b is selected from the group consisting of:

[0071] In one embodiment, the present invention includes a compound having the following formula (IVd): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 5a , R 5b , R 5c , and R 5d At least two of the groups in R are hydrogen, 5a , R 5b , R 5c , and R 5dgroups are independently selected from 0 to 2 of OH, NO2, halogen, CN, C1-6 straight chain alkyl, C3-7 branched alkyl, C3-7 cycloalkyl, C1-6 straight chain alkoxy, C3-7 branched alkoxy, C3-7 cycloalkoxy, C1-6 straight chain haloalkyl, C3-7 branched haloalkyl, C1-6 straight chain haloalkoxy, heterocyclyl, -S(C1-6 straight chain alkyl), S(C3-7 branched alkyl), -S(C3-7 cycloalkyl), -SO2(C1-6 straight chain alkyl), SO2(C3-7 branched alkoxy), -SO2(C3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 and N.R. 9a SO2NR 12a R 12b is selected from the group consisting of:

[0072] In one embodiment, the present invention includes a compound having the following formula (V): [ka] This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes thereof.

[0073] In one embodiment, the present invention includes a compound having the following formula (Va): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 4a , R 4b , R 4c , R 4d and R 4eAt least two of the groups in R are hydrogen, 4a , R 4b , R 4c , R 4d and R 4e groups are independently selected from OH, NO2, halogen, CN, C1-6 straight chain alkyl, C3-7 branched alkyl, C3-7 cycloalkyl, C1-6 straight chain alkoxy, C3-7 branched alkoxy, C3-7 cycloalkoxy, C1-6 straight chain haloalkyl, C3-7 branched haloalkyl, C1-6 straight chain haloalkoxy, heterocyclyl, -S(C1-6 straight chain alkyl), S(C3-7 branched alkyl), -S(C3-7 cycloalkyl), -SO2(C1-6 straight chain alkyl), SO2(C3-7 branched Branched alkyl), -SO2(C3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 , and N.R. 9a SO2NR 12a R 12b is selected from the group consisting of:

[0074] In one embodiment, the present invention includes a compound having the following formula (Vb): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 5a , R 5b , R 5c , and R 5d At least two of the groups in R are hydrogen, 5a , R 5b , R 5c , and R 5dgroups are independently selected from 0 to 2 of OH, NO2, halogen, CN, C1-6 straight chain alkyl, C3-7 branched alkyl, C3-7 cycloalkyl, C1-6 straight chain alkoxy, C3-7 branched alkoxy, C3-7 cycloalkoxy, C1-6 straight chain haloalkyl, C3-7 branched haloalkyl, C1-6 straight chain haloalkoxy, heterocyclyl, -S(C1-6 straight chain alkyl), S(C3-7 branched alkyl), -S(C3-7 cycloalkyl), -SO2(C1-6 straight chain alkyl), SO2(C3-7 branched alkoxy), -SO2(C3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 and N.R. 9a SO2NR 12a R 12b is selected from the group consisting of:

[0075] In one embodiment, the present invention includes a compound having the following formula (Vc): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 5a , R 5b , R 5c , and R 5d At least two of the groups in R are hydrogen, 5a , R 5b , R 5c , and R 5dgroups are independently selected from 0 to 2 of OH, NO2, halogen, CN, C1-6 straight chain alkyl, C3-7 branched alkyl, C3-7 cycloalkyl, C1-6 straight chain alkoxy, C3-7 branched alkoxy, C3-7 cycloalkoxy, C1-6 straight chain haloalkyl, C3-7 branched haloalkyl, C1-6 straight chain haloalkoxy, heterocyclyl, -S(C1-6 straight chain alkyl), S(C3-7 branched alkyl), -S(C3-7 cycloalkyl), -SO2(C1-6 straight chain alkyl), SO2(C3-7 branched alkoxy), -SO2(C3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 and N.R. 9a SO2NR 12a R 12b is selected from the group consisting of:

[0076] In one embodiment, the present invention includes a compound having the following formula (Vd): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 5a , R 5b , R 5c , and R 5d At least two of the groups in R are hydrogen, 5a , R 5b , R 5c , and R 5dgroups are independently selected from 0 to 2 of OH, NO2, halogen, CN, C1-6 straight chain alkyl, C3-7 branched alkyl, C3-7 cycloalkyl, C1-6 straight chain alkoxy, C3-7 branched alkoxy, C3-7 cycloalkoxy, C1-6 straight chain haloalkyl, C3-7 branched haloalkyl, C1-6 straight chain haloalkoxy, heterocyclyl, -S(C1-6 straight chain alkyl), S(C3-7 branched alkyl), -S(C3-7 cycloalkyl), -SO2(C1-6 straight chain alkyl), SO2(C3-7 branched alkoxy), -SO2(C3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 and N.R. 9a SO2NR 12a R 12b is selected from the group consisting of:

[0077] In one embodiment, the present invention includes a compound having the following formula (VI): [ka] This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes thereof.

[0078] In one embodiment, the present invention includes a compound having the following formula (VIa): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 4a , R 4b , R 4c , R 4d and R 4eAt least two of the groups in R are hydrogen, 4a , R 4b , R 4c , R 4d and R 4e groups are independently selected from OH, NO2, halogen, CN, C1-6 straight chain alkyl, C3-7 branched alkyl, C3-7 cycloalkyl, C1-6 straight chain alkoxy, C3-7 branched alkoxy, C3-7 cycloalkoxy, C1-6 straight chain haloalkyl, C3-7 branched haloalkyl, C1-6 straight chain haloalkoxy, heterocyclyl, -S(C1-6 straight chain alkyl), S(C3-7 branched alkyl), -S(C3-7 cycloalkyl), -SO2(C1-6 straight chain alkyl), SO2(C3-7 branched Branched alkyl), -SO2(C3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 , and N.R. 9a SO2NR 12a R 12b is selected from the group consisting of:

[0079] In one embodiment, the present invention includes a compound having the following formula (VIb): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 5a , R 5b , R 5c , and R 5d At least two of the groups in R are hydrogen, 5a , R 5b , R 5c , and R 5dgroups are independently selected from 0 to 2 of OH, NO2, halogen, CN, C1-6 straight chain alkyl, C3-7 branched alkyl, C3-7 cycloalkyl, C1-6 straight chain alkoxy, C3-7 branched alkoxy, C3-7 cycloalkoxy, C1-6 straight chain haloalkyl, C3-7 branched haloalkyl, C1-6 straight chain haloalkoxy, heterocyclyl, -S(C1-6 straight chain alkyl), S(C3-7 branched alkyl), -S(C3-7 cycloalkyl), -SO2(C1-6 straight chain alkyl), SO2(C3-7 branched alkoxy), -SO2(C3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 and N.R. 9a SO2NR 12a R 12b is selected from the group consisting of:

[0080] In one embodiment, the present invention includes a compound having the following formula (VIc): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 5a , R 5b , R 5c , and R 5d At least two of the groups in R are hydrogen, 5a , R 5b , R 5c , and R 5dgroups are independently selected from 0 to 2 of OH, NO2, halogen, CN, C1-6 straight chain alkyl, C3-7 branched alkyl, C3-7 cycloalkyl, C1-6 straight chain alkoxy, C3-7 branched alkoxy, C3-7 cycloalkoxy, C1-6 straight chain haloalkyl, C3-7 branched haloalkyl, C1-6 straight chain haloalkoxy, heterocyclyl, -S(C1-6 straight chain alkyl), S(C3-7 branched alkyl), -S(C3-7 cycloalkyl), -SO2(C1-6 straight chain alkyl), SO2(C3-7 branched alkoxy), -SO2(C3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 and N.R. 9a SO2NR 12a R 12b is selected from the group consisting of:

[0081] In one embodiment, the present invention includes a compound having the following formula (VId): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 5a , R 5b , R 5c , and R 5d At least two of the groups in R are hydrogen, 5a , R 5b , R 5c , and R 5dgroups are independently selected from 0 to 2 of OH, NO2, halogen, CN, C1-6 straight chain alkyl, C3-7 branched alkyl, C3-7 cycloalkyl, C1-6 straight chain alkoxy, C3-7 branched alkoxy, C3-7 cycloalkoxy, C1-6 straight chain haloalkyl, C3-7 branched haloalkyl, C1-6 straight chain haloalkoxy, heterocyclyl, -S(C1-6 straight chain alkyl), S(C3-7 branched alkyl), -S(C3-7 cycloalkyl), -SO2(C1-6 straight chain alkyl), SO2(C3-7 branched alkoxy), -SO2(C3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 and N.R. 9a SO2NR 12a R 12b is selected from the group consisting of:

[0082] In one embodiment, the present invention includes a compound having the following formula (VII): [ka] This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes thereof.

[0083] In one embodiment, the present invention includes a compound having the following formula (VIIa): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 4a , R 4b , R 4c , R 4d and R 4eAt least two of the groups in R are hydrogen, 4a , R 4b , R 4c , R 4d and R 4e groups are independently selected from OH, NO2, halogen, CN, C1-6 straight chain alkyl, C3-7 branched alkyl, C3-7 cycloalkyl, C1-6 straight chain alkoxy, C3-7 branched alkoxy, C3-7 cycloalkoxy, C1-6 straight chain haloalkyl, C3-7 branched haloalkyl, C1-6 straight chain haloalkoxy, heterocyclyl, -S(C1-6 straight chain alkyl), S(C3-7 branched alkyl), -S(C3-7 cycloalkyl), -SO2(C1-6 straight chain alkyl), SO2(C3-7 branched Branched alkyl), -SO2(C3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 , and N.R. 9a SO2NR 12a R 12b is selected from the group consisting of:

[0084] In one embodiment, the present invention includes a compound having the following formula (VIIb): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 5a , R 5b , R 5c , and R 5d At least two of the groups in R are hydrogen, 5a , R 5b , R 5c , and R 5dgroups are independently selected from 0 to 2 of OH, NO2, halogen, CN, C1-6 straight chain alkyl, C3-7 branched alkyl, C3-7 cycloalkyl, C1-6 straight chain alkoxy, C3-7 branched alkoxy, C3-7 cycloalkoxy, C1-6 straight chain haloalkyl, C3-7 branched haloalkyl, C1-6 straight chain haloalkoxy, heterocyclyl, -S(C1-6 straight chain alkyl), S(C3-7 branched alkyl), -S(C3-7 cycloalkyl), -SO2(C1-6 straight chain alkyl), SO2(C3-7 branched alkoxy), -SO2(C3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 and N.R. 9a SO2NR 12a R 12b is selected from the group consisting of:

[0085] In one embodiment, the present invention includes a compound having the following formula (VIIc): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 5a , R 5b , R 5c , and R 5d At least two of the groups in R are hydrogen, 5a , R 5b , R 5c , and R 5dgroups are independently selected from 0 to 2 of OH, NO2, halogen, CN, C1-6 straight chain alkyl, C3-7 branched alkyl, C3-7 cycloalkyl, C1-6 straight chain alkoxy, C3-7 branched alkoxy, C3-7 cycloalkoxy, C1-6 straight chain haloalkyl, C3-7 branched haloalkyl, C1-6 straight chain haloalkoxy, heterocyclyl, -S(C1-6 straight chain alkyl), S(C3-7 branched alkyl), -S(C3-7 cycloalkyl), -SO2(C1-6 straight chain alkyl), SO2(C3-7 branched alkoxy), -SO2(C3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 and N.R. 9a SO2NR 12a R 12b is selected from the group consisting of:

[0086] In one embodiment, the present invention includes a compound having the following formula (VIId): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 5a , R 5b , R 5c , and R 5d At least two of the groups in R are hydrogen, 5a , R 5b , R 5c , and R 5d 0 to 2 of the groups are independently selected from OH, NO2, halogen, CN, C1-6 linear alkyl, C3-7 branched alkyl, C3-7 cycloalkyl, C1-6 linear alkoxy, C3-7 branched alkyl, koxy, C3-7 cycloalkoxy, C1-6 straight-chain haloalkyl, C3-7 branched haloalkyl, C1-6 straight-chain haloalkoxy, heterocyclyl, -S(C1-6 straight-chain alkyl), S(C3-7 branched alkyl), -S(C3-7 cycloalkyl), -SO2(C1-6 straight-chain alkyl), SO2(C3-7 branched alkyl) -SO2(C3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 and N.R. 9a SO2NR 12a R 12b is selected from the group consisting of:

[0087] In one embodiment, the present invention includes a compound having the following formula (VIII): [ka] This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes thereof.

[0088] In one embodiment, the present invention includes a compound having the following formula (VIIIa): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 4a , R 4b , R 4c , R 4d and R 4e At least two of the groups in R are hydrogen, 4a , R 4b , R 4c , R 4d and R4e groups are independently selected from OH, NO2, halogen, CN, C1-6 straight chain alkyl, C3-7 branched alkyl, C3-7 cycloalkyl, C1-6 straight chain alkoxy, C3-7 branched alkoxy, C3-7 cycloalkoxy, C1-6 straight chain haloalkyl, C3-7 branched haloalkyl, C1-6 straight chain haloalkoxy, heterocyclyl, -S(C1-6 straight chain alkyl), S(C3-7 branched alkyl), -S(C3-7 cycloalkyl), -SO2(C1-6 straight chain alkyl), SO2(C3-7 branched Branched alkyl), -SO2(C3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 , and N.R. 9a SO2NR 12a R 12b is selected from the group consisting of:

[0089] In one embodiment, the present invention includes a compound having the following formula (VIIIb): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 5a , R 5b , R 5c , and R 5d At least two of the groups in R are hydrogen, 5a , R 5b , R 5c , and R 5dgroups are independently selected from OH, NO2, halogen, CN, C1-6 straight chain alkyl, C3-7 branched alkyl, C3-7 cycloalkyl, C1-6 straight chain alkoxy, C3-7 branched alkoxy, C3-7 cycloalkoxy, C1-6 straight chain haloalkyl, C3-7 branched haloalkyl C1-6 straight-chain haloalkoxy, heterocyclyl, -S(C1-6 straight-chain alkyl), S(C3-7 branched alkyl), -S(C3-7 cycloalkyl), -SO2(C1-6 straight-chain alkyl), SO2(C3-7 branched alkyl) -SO2(C3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 and N.R. 9a SO2NR 12a R 12b is selected from the group consisting of:

[0090] In one embodiment, the present invention includes a compound having the following formula (VIIIc): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 5a , R 5b , R 5c , and R 5d At least two of the groups in R are hydrogen, 5a , R 5b , R 5c , and R 5dgroups are independently selected from 0 to 2 of OH, NO2, halogen, CN, C1-6 straight chain alkyl, C3-7 branched alkyl, C3-7 cycloalkyl, C1-6 straight chain alkoxy, C3-7 branched alkoxy, C3-7 cycloalkoxy, C1-6 straight chain haloalkyl, C3-7 branched haloalkyl, C1-6 straight chain haloalkoxy, heterocyclyl, -S(C1-6 straight chain alkyl), S(C3-7 branched alkyl), -S(C3-7 cycloalkyl), -SO2(C1-6 straight chain alkyl), SO2(C3-7 branched alkoxy), -SO2(C3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 and N.R. 9a SO2NR 12a R 12b is selected from the group consisting of:

[0091] In one embodiment, the present invention includes a compound having the following formula (VIIId): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 5a , R 5b , R 5c , and R 5d At least two of the groups in R are hydrogen, 5a , R 5b , R 5c , and R 5dgroups are independently selected from 0 to 2 of OH, NO2, halogen, CN, C1-6 straight chain alkyl, C3-7 branched alkyl, C3-7 cycloalkyl, C1-6 straight chain alkoxy, C3-7 branched alkoxy, C3-7 cycloalkoxy, C1-6 straight chain haloalkyl, C3-7 branched haloalkyl, C1-6 straight chain haloalkoxy, heterocyclyl, -S(C1-6 straight chain alkyl), S(C3-7 branched alkyl), -S(C3-7 cycloalkyl), -SO2(C1-6 straight chain alkyl), SO2(C3-7 branched alkoxy), -SO2(C3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 and N.R. 9a SO2NR 12a R 12b is selected from the group consisting of:

[0092] In one embodiment, the present invention includes a compound having the following formula (IX): [ka] This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes thereof.

[0093] In one embodiment, the present invention includes a compound having the following formula (IXa): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 4a , R 4b , R 4c , R 4d and R 4eAt least two of the groups in R are hydrogen, 4a , R 4b , R 4c , R 4d and R 4e groups are independently selected from OH, NO2, halogen, CN, C1-6 straight chain alkyl, C3-7 branched alkyl, C3-7 cycloalkyl, C1-6 straight chain alkoxy, C3-7 branched alkoxy, C3-7 cycloalkoxy, C1-6 straight chain haloalkyl, C3-7 branched haloalkyl, C1-6 straight chain haloalkoxy, heterocyclyl, -S(C1-6 straight chain alkyl), S(C3-7 branched alkyl), -S(C3-7 cycloalkyl), -SO2(C1-6 straight chain alkyl), SO2(C3-7 branched Branched alkyl), -SO2(C3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 , and N.R. 9a SO2NR 12a R 12b is selected from the group consisting of:

[0094] In one embodiment, the present invention includes a compound having the following formula (IXb): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 5a , R 5b , R 5c , and R 5d At least two of the groups in R are hydrogen, 5a , R 5b , R 5c , and R 5dgroups are independently selected from 0 to 2 of OH, NO2, halogen, CN, C1-6 straight chain alkyl, C3-7 branched alkyl, C3-7 cycloalkyl, C1-6 straight chain alkoxy, C3-7 branched alkoxy, C3-7 cycloalkoxy, C1-6 straight chain haloalkyl, C3-7 branched haloalkyl, C1-6 straight chain haloalkoxy, heterocyclyl, -S(C1-6 straight chain alkyl), S(C3-7 branched alkyl), -S(C3-7 cycloalkyl), -SO2(C1-6 straight chain alkyl), SO2(C3-7 branched alkoxy), -SO2(C3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 and N.R. 9a SO2NR 12a R 12b is selected from the group consisting of:

[0095] In one embodiment, the present invention includes a compound having the following formula (IXc): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 5a , R 5b , R 5c , and R 5d At least two of the groups in R are hydrogen, 5a , R 5b , R 5c , and R 5dgroups are independently selected from 0 to 2 of OH, NO2, halogen, CN, C1-6 straight chain alkyl, C3-7 branched alkyl, C3-7 cycloalkyl, C1-6 straight chain alkoxy, C3-7 branched alkoxy, C3-7 cycloalkoxy, C1-6 straight chain haloalkyl, C3-7 branched haloalkyl, C1-6 straight chain haloalkoxy, heterocyclyl, -S(C1-6 straight chain alkyl), S(C3-7 branched alkyl), -S(C3-7 cycloalkyl), -SO2(C1-6 straight chain alkyl), SO2(C3-7 branched alkoxy), -SO2(C3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 and N.R. 9a SO2NR 12a R 12b is selected from the group consisting of:

[0096] In one embodiment, the present invention includes a compound having the following formula (IXd): [ka] including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof, wherein: R 5a , R 5b , R 5c , and R 5d At least two of the groups in R are hydrogen, 5a , R 5b , R 5c , and R 5dgroups are independently selected from 0 to 2 of OH, NO2, halogen, CN, C1-6 straight chain alkyl, C3-7 branched alkyl, C3-7 cycloalkyl, C1-6 straight chain alkoxy, C3-7 branched alkoxy, C3-7 cycloalkoxy, C1-6 straight chain haloalkyl, C3-7 branched haloalkyl, C1-6 straight chain haloalkoxy, heterocyclyl, -S(C1-6 straight chain alkyl), S(C3-7 branched alkyl), -S(C3-7 cycloalkyl), -SO2(C1-6 straight chain alkyl), SO2(C3-7 branched alkoxy), -SO2(C3-7 cycloalkyl), COR 6 , CO2R 7 ,CONR 8a R 8b , SO2NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO2R 11 and N.R. 9a SO2NR 12a R 12b is selected from the group consisting of:

[0097] In some embodiments, A is [ka] is.

[0098] In some embodiments, A is [ka] is.

[0099] In some embodiments, n is 1.

[0100] In some embodiments, n is 2.

[0101] In some embodiments, n is 3.

[0102] In some embodiments, R1a is hydrogen.

[0103] In some embodiments, R 1a is C 1-6 It is a straight chain alkyl.

[0104] In some embodiments, R 1a is a C1-6 branched alkyl.

[0105] In some embodiments, R 1b is hydrogen.

[0106] In some embodiments, R 1b is a C1-6 straight chain alkyl.

[0107] In some embodiments, R 1b is a C1-6 branched alkyl.

[0108] In some embodiments, R 1a and R 1b has three ring atoms along with the atoms to which they are attached Forms a ring.

[0109] In some embodiments, R 1a and R 1b have four ring atoms along with the atoms to which they are attached Forms a ring.

[0110] In some embodiments, R 1a and R 1b have five ring atoms along with the atoms to which they are attached Forms a ring.

[0111] In some embodiments, R 1a and R 1b have 6 ring atoms along with the atoms to which they are attached Forms a ring.

[0112] In some embodiments, R 1a and R 1bhas 7 ring atoms along with the atoms to which they are attached Forms a ring.

[0113] In some embodiments, R 2 is 0 to 3 R that are not hydrogen 4 is a benzene ring optionally substituted with a group.

[0114] In some embodiments, R 2 is 0 to 2 R that are not hydrogen 5 is a 4-pyridine ring optionally substituted with a group.

[0115] In some embodiments, R 2 is 0 to 2 R that are not hydrogen 5 is a 3-pyridine ring optionally substituted with a group.

[0116] In some embodiments, R 2 is 0 to 2 R that are not hydrogen 5 is a 2-pyridine ring optionally substituted with a group.

[0117] In some embodiments, R 3 is 0 to 3 R that are not hydrogen 4 is a benzene ring optionally substituted with a group.

[0118] In some embodiments, R 3 is 0 to 2 R that are not hydrogen 5 is a 4-pyridine ring optionally substituted with a group.

[0119] In some embodiments, R 3 is 0 to 2 R that are not hydrogen 5 is a 3-pyridine ring optionally substituted with a group.

[0120] In some embodiments, R 3 is 0 to 2 R that are not hydrogen 5 is a 2-pyridine ring optionally substituted with a group.

[0121] In some embodiments, R 4 is hydrogen.

[0122] In some embodiments, R 4 is OH.

[0123] In some embodiments, R 4 is NO2.

[0124] In some embodiments, R 4 is a halogen.

[0125] In some embodiments, R 4 is CN.

[0126] In some embodiments, R 4 is a C1-6 straight chain alkyl.

[0127] In some embodiments, R 4 is a C3-7 branched alkyl.

[0128] In some embodiments, R 4 is C3-7 cycloalkyl.

[0129] In some embodiments, R 4 is C1-6 straight chain alkoxy.

[0130] In some embodiments, R 4 is a C3-7 branched alkoxy.

[0131] In some embodiments, R 4 is C3-7 cycloalkoxy.

[0132] In some embodiments, R 4 is a C1-6 straight chain haloalkyl.

[0133] In some embodiments, R 4 is a C3-7 branched haloalkyl.

[0134] In some embodiments, R 4is a C1-6 straight chain haloalkoxy.

[0135] In some embodiments, R 4 is heterocyclyl.

[0136] In some embodiments, R 4 is -S(C1-6 straight chain alkyl).

[0137] In some embodiments, R 4 is -S(C3-7 branched alkyl).

[0138] In some embodiments, R 4 is —S(C3-7 cycloalkyl).

[0139] In some embodiments, R 4 is -SO2(C1-6 linear alkyl).

[0140] In some embodiments, R 4 is -SO2(C3-7 branched alkyl).

[0141] In some embodiments, R 4 is -SO2(C3-7cycloalkyl).

[0142] In some embodiments, R 4 is COR 6 is.

[0143] In some embodiments, R 4 is CO2R 7 is.

[0144] In some embodiments, R 4 CONR 8a R 8b is.

[0145] In some embodiments, R 4 is SO2NR 8a R 8b is.

[0146] In some embodiments, R 4 is NR 9a R 9b is.

[0147] In some embodiments, R 4 is NR 9a COR 10 is.

[0148] In some embodiments, R 4 is NR 9a SO2R 11 is.

[0149] In some embodiments, R 4 is NR 9a SO2NR 12a R 12b is.

[0150] In some embodiments, R 4a is hydrogen.

[0151] In some embodiments, R 4a is OH.

[0152] In some embodiments, R 4a is NO2.

[0153] In some embodiments, R 4a is a halogen.

[0154] In some embodiments, R 4a is CN.

[0155] In some embodiments, R 4a is C 1-6 It is a straight chain alkyl.

[0156] In some embodiments, R 4a is a C3-7 branched alkyl.

[0157] In some embodiments, R 4a is C3-7 cycloalkyl.

[0158] In some embodiments, R 4a is C1-6 straight chain alkoxy.

[0159] In some embodiments, R 4a is a C3-7 branched alkoxy.

[0160] In some embodiments, R 4a is C3-7 cycloalkoxy.

[0161] In some embodiments, R 4a is a C1-6 straight chain haloalkyl.

[0162] In some embodiments, R 4a is a C3-7 branched haloalkyl.

[0163] In some embodiments, R 4a is a C1-6 straight chain haloalkoxy.

[0164] In some embodiments, R 4a is heterocyclyl.

[0165] In some embodiments, R 4a is -S(C1-6 straight chain alkyl).

[0166] In some embodiments, R 4a is -S(C3-7 branched alkyl).

[0167] In some embodiments, R 4a is —S(C3-7 cycloalkyl).

[0168] In some embodiments, R 4a is -SO2(C1-6 linear alkyl).

[0169] In some embodiments, R 4a is -SO2(C3-7 branched alkyl).

[0170] In some embodiments, R 4a is -SO2(C3-7cycloalkyl).

[0171] In some embodiments, R 4a is COR 6 is.

[0172] In some embodiments, R 4a is CO2R 7 is.

[0173] In some embodiments, R 4a CONR 8a R 8b is.

[0174] In some embodiments, R 4a is SO2NR 8a R 8b is.

[0175] In some embodiments, R 4a is NR 9a R 9b is.

[0176] In some embodiments, R 4a is NR 9a COR 10 is.

[0177] In some embodiments, R 4a is NR 9a SO2R 11 is.

[0178] In some embodiments, R 4a is NR 9a SO2NR 12a R 12b is.

[0179] In some embodiments, R 4b is hydrogen.

[0180] In some embodiments, R 4b is OH.

[0181] In some embodiments, R 4b is NO2.

[0182] In some embodiments, R 4b is a halogen.

[0183] In some embodiments, R 4b is CN.

[0184] In some embodiments, R 4b is a C1-6 straight chain alkyl.

[0185] In some embodiments, R 4b is a C3-7 branched alkyl.

[0186] In some embodiments, R 4b is C3-7 cycloalkyl.

[0187] In some embodiments, R 4b is C1-6 straight chain alkoxy.

[0188] In some embodiments, R 4b is a C3-7 branched alkoxy.

[0189] In some embodiments, R 4b is C3-7 cycloalkoxy.

[0190] In some embodiments, R 4b is a C1-6 straight chain haloalkyl.

[0191] In some embodiments, R 4b is a C3-7 branched haloalkyl.

[0192] In some embodiments, R 4b is a C1-6 straight chain haloalkoxy.

[0193] In some embodiments, R b is heterocyclyl.

[0194] In some embodiments, R 4b is -S(C1-6 straight chain alkyl).

[0195] In some embodiments, R 4b is -S(C3-7 branched alkyl).

[0196] In some embodiments, R 4b is —S(C3-7 cycloalkyl).

[0197] In some embodiments, R 4b is -SO2(C1-6 linear alkyl).

[0198] In some embodiments, R 4b is -SO2(C3-7 branched alkyl).

[0199] In some embodiments, R 4b is -SO2(C3-7cycloalkyl).

[0200] In some embodiments, R 4b is COR 6 is.

[0201] In some embodiments, R 4b is CO2R 7 is.

[0202] In some embodiments, R 4b CONR 8a R 8b is.

[0203] In some embodiments, R 4b is SO2NR 8a R 8b is.

[0204] In some embodiments, R 4b is NR 9a R 9b is.

[0205] In some embodiments, R 4b is NR 9a COR 10 is.

[0206] In some embodiments, R 4b is NR 9a SO2R 11 is.

[0207] In some embodiments, R 4b is NR 9a SO2NR 12a R 12b is.

[0208] In some embodiments, R 4c is hydrogen.

[0209] In some embodiments, R 4c is OH.

[0210] In some embodiments, R 4c is NO2.

[0211] In some embodiments, R 4c is a halogen.

[0212] In some embodiments, R 4c is CN.

[0213] In some embodiments, R 4c is a C1-6 straight chain alkyl.

[0214] In some embodiments, R 4c is a C3-7 branched alkyl.

[0215] In some embodiments, R 4c is C3-7 cycloalkyl.

[0216] In some embodiments, R 4c is C1-6 straight chain alkoxy.

[0217] In some embodiments, R4c is a C3-7 branched alkoxy.

[0218] In some embodiments, R 4c is C3-7 cycloalkoxy.

[0219] In some embodiments, R 4c is a C1-6 straight chain haloalkyl.

[0220] In some embodiments, R 4c is a C3-7 branched haloalkyl.

[0221] In some embodiments, R 4c is a C1-6 straight chain haloalkoxy.

[0222] In some embodiments, R 4c is heterocyclyl.

[0223] In some embodiments, R 4c is -S(C1-6 straight chain alkyl).

[0224] In some embodiments, R 4c is -S(C3-7 branched alkyl).

[0225] In some embodiments, R 4c is —S(C3-7 cycloalkyl).

[0226] In some embodiments, R 4c is -SO2(C1-6 linear alkyl).

[0227] In some embodiments, R 4c is -SO2(C3-7 branched alkyl).

[0228] In some embodiments, R 4c is -SO2(C3-7cycloalkyl).

[0229] In some embodiments, R 4c is COR6 is.

[0230] In some embodiments, R 4c is CO2R 7 is.

[0231] In some embodiments, R 4c CONR 8a R 8b is.

[0232] In some embodiments, R 4c is SO2NR 8a R 8b is.

[0233] In some embodiments, R 4c is NR 9a R 9b is.

[0234] In some embodiments, R 4c is NR 9a COR 10 is.

[0235] In some embodiments, R 4c is NR 9a SO2R 11 is.

[0236] In some embodiments, R 4c is NR 9a SO2NR 12a R 12b is.

[0237] In some embodiments, R 4d is hydrogen.

[0238] In some embodiments, R 4d is OH.

[0239] In some embodiments, R 4d is NO2.

[0240] In some embodiments, R 4d is a halogen.

[0241] In some embodiments, R 4d is CN.

[0242] In some embodiments, R 4d is a C1-6 straight chain alkyl.

[0243] In some embodiments, R 4d is a C3-7 branched alkyl.

[0244] In some embodiments, R 4d is C3-7 cycloalkyl.

[0245] In some embodiments, R 4d is C1-6 straight chain alkoxy.

[0246] In some embodiments, R 4d is a C3-7 branched alkoxy.

[0247] In some embodiments, R 4d is C3-7 cycloalkoxy.

[0248] In some embodiments, R 4d is a C1-6 straight chain haloalkyl.

[0249] In some embodiments, R 4d is a C3-7 branched haloalkyl.

[0250] In some embodiments, R 4d is a C1-6 straight chain haloalkoxy.

[0251] In some embodiments, R 4d is heterocyclyl.

[0252] In some embodiments, R 4d is -S(C1-6 straight chain alkyl).

[0253] In some embodiments, R4d is -S(C3-7 branched alkyl).

[0254] In some embodiments, R 4d is —S(C3-7 cycloalkyl).

[0255] In some embodiments, R 4d is -SO2(C1-6 linear alkyl).

[0256] In some embodiments, R 4d is -SO2(C3-7 branched alkyl).

[0257] In some embodiments, R 4d is -SO2(C3-7cycloalkyl).

[0258] In some embodiments, R 4d is COR 6 is.

[0259] In some embodiments, R 4d is CO2R 7 is.

[0260] In some embodiments, R 4d CONR 8a R 8b is.

[0261] In some embodiments, R 4d is SO2NR 8a R 8b is.

[0262] In some embodiments, R 4d is NR 9a R 9b is.

[0263] In some embodiments, R 4d is NR 9a COR 10 is.

[0264] In some embodiments, R 4d is NR9a SO2R 11 is.

[0265] In some embodiments, R 4d is NR 9a SO2NR 12a R 12b is.

[0266] In some embodiments, R 4e is hydrogen.

[0267] In some embodiments, R 4e is OH.

[0268] In some embodiments, R 4e is NO2.

[0269] In some embodiments, R 4e is a halogen.

[0270] In some embodiments, R 4e is CN.

[0271] In some embodiments, R 4e is a C1-6 straight chain alkyl.

[0272] In some embodiments, R 4e is a C3-7 branched alkyl.

[0273] In some embodiments, R 4e is C3-7 cycloalkyl.

[0274] In some embodiments, R 4e is C1-6 straight chain alkoxy.

[0275] In some embodiments, R 4e is a C3-7 branched alkoxy.

[0276] In some embodiments, R 4e is C3-7 cycloalkoxy.

[0277] In some embodiments, R 4e is a C1-6 straight chain haloalkyl.

[0278] In some embodiments, R 4e is a C3-7 branched haloalkyl.

[0279] In some embodiments, R 4e is a C1-6 straight chain haloalkoxy.

[0280] In some embodiments, R 4e is heterocyclyl.

[0281] In some embodiments, R 4e is -S(C1-6 straight chain alkyl).

[0282] In some embodiments, R 4e is -S(C3-7 branched alkyl).

[0283] In some embodiments, R 4e is —S(C3-7 cycloalkyl).

[0284] In some embodiments, R 4e is -SO2(C1-6 linear alkyl).

[0285] In some embodiments, R 4e is -SO2(C3-7 branched alkyl).

[0286] In some embodiments, R 4e is -SO2(C3-7cycloalkyl).

[0287] In some embodiments, R 4e is COR 6 is.

[0288] In some embodiments, R 4e is CO2R 7 is.

[0289] In some embodiments, R 4e CONR 8a R 8b is.

[0290] In some embodiments, R 4e is SO2NR 8a R 8b is.

[0291] In some embodiments, R 4a is NR 9a R 9b is.

[0292] In some embodiments, R 4e is NR 9a COR 10 is.

[0293] In some embodiments, R 4e is NR 9a SO2R 11 is.

[0294] In some embodiments, R 4e is NR 9a SO2NR 12a R 12b is.

[0295] In some embodiments, R 5 is hydrogen.

[0296] In some embodiments, R 5 is OH.

[0297] In some embodiments, R 5 is NO2.

[0298] In some embodiments, R 5 is a halogen.

[0299] In some embodiments, R 5 is CN.

[0300] In some embodiments, R 5is a C1-6 straight chain alkyl.

[0301] In some embodiments, R 5 is a C3-7 branched alkyl.

[0302] In some embodiments, R 5 is C3-7 cycloalkyl.

[0303] In some embodiments, R 5 is C1-6 straight chain alkoxy.

[0304] In some embodiments, R 5 is a C3-7 branched alkoxy.

[0305] In some embodiments, R 5 is C3-7 cycloalkoxy.

[0306] In some embodiments, R 5 is a C1-6 straight chain haloalkyl.

[0307] In some embodiments, R 5 is a C3-7 branched haloalkyl.

[0308] In some embodiments, R 5 is a C1-6 straight chain haloalkoxy.

[0309] In some embodiments, R 5 is -S(C1-6 straight chain alkyl).

[0310] In some embodiments, R 5 is -S(C3-7 branched alkyl).

[0311] In some embodiments, R 5 is —S(C3-7 cycloalkyl).

[0312] In some embodiments, R 5 is -SO2(C1-6 linear alkyl).

[0313] In some embodiments, R 5 is -SO2(C3-7 branched alkyl).

[0314] In some embodiments, R 5 is -SO2(C3-7cycloalkyl).

[0315] In some embodiments, R 5 is COR 6 is.

[0316] In some embodiments, R 5 is CO2R 7 is.

[0317] In some embodiments, R 5 CONR 8a R 8b is.

[0318] In some embodiments, R 5 is SO2NR 8a R 8b is.

[0319] In some embodiments, R 5 is NR 9a R 9b is.

[0320] In some embodiments, R 5 is NR 9a COR 10 is.

[0321] In some embodiments, R 5 is NR 9a SO2R 11 is.

[0322] In some embodiments, R 5 is NR 9a SO2NR 12a R 12b is.

[0323] In some embodiments, R5a is hydrogen.

[0324] In some embodiments, R 5a is OH.

[0325] In some embodiments, R 5a is NO2.

[0326] In some embodiments, R 5a is a halogen.

[0327] In some embodiments, R 5a is CN.

[0328] In some embodiments, R 5a is C 1-6 It is a straight chain alkyl.

[0329] In some embodiments, R 5a is a C3-7 branched alkyl.

[0330] In some embodiments, R 5a is C3-7 cycloalkyl.

[0331] In some embodiments, R 5a is C1-6 straight chain alkoxy.

[0332] In some embodiments, R 5a is a C3-7 branched alkoxy.

[0333] In some embodiments, R 5a is C3-7 cycloalkoxy.

[0334] In some embodiments, R 5a is a C1-6 straight chain haloalkyl.

[0335] In some embodiments, R 5a is a C3-7 branched haloalkyl.

[0336] In some embodiments, R5a is a C1-6 straight chain haloalkoxy.

[0337] In some embodiments, R 5a is -S(C1-6 straight chain alkyl).

[0338] In some embodiments, R 5a is -S(C3-7 branched alkyl).

[0339] In some embodiments, R 5a is —S(C3-7 cycloalkyl).

[0340] In some embodiments, R 5a is -SO2(C1-6 linear alkyl).

[0341] In some embodiments, R 5a is -SO2(C3-7 branched alkyl).

[0342] In some embodiments, R 5a is -SO2(C3-7cycloalkyl).

[0343] In some embodiments, R 5a is COR 6 is.

[0344] In some embodiments, R 5a is CO2R 7 is.

[0345] In some embodiments, R 5a CONR 8a R 8b is.

[0346] In some embodiments, R 5a is SO2NR 8a R 8b is.

[0347] In some embodiments, R 5a is NR 9a R 9b is.

[0348] In some embodiments, R 5a is NR 9a COR 10 is.

[0349] In some embodiments, R 5a is NR 9a SO2R 11 is.

[0350] In some embodiments, R 5a is NR 9a SO2NR 12a R 12b is.

[0351] In some embodiments, R 5b is hydrogen.

[0352] In some embodiments, R 5b is OH.

[0353] In some embodiments, R 5b is NO2.

[0354] In some embodiments, R 5b is a halogen.

[0355] In some embodiments, R 5b is CN.

[0356] In some embodiments, R 5b is a C1-6 straight chain alkyl.

[0357] In some embodiments, R 5b is a C3-7 branched alkyl.

[0358] In some embodiments, R 5b is C3-7 cycloalkyl.

[0359] In some embodiments, R 5b is C1-6 straight chain alkoxy.

[0360] In some embodiments, R 5b is a C3-7 branched alkoxy.

[0361] In some embodiments, R 5b is C3-7 cycloalkoxy.

[0362] In some embodiments, R 5b is a C1-6 straight chain haloalkyl.

[0363] In some embodiments, R 5b is a C3-7 branched haloalkyl.

[0364] In some embodiments, R 5b is a C1-6 straight chain haloalkoxy.

[0365] In some embodiments, R 5b is -S(C1-6 straight chain alkyl).

[0366] In some embodiments, R 5b is -S(C3-7 branched alkyl).

[0367] In some embodiments, R 5b is —S(C3-7 cycloalkyl).

[0368] In some embodiments, R 5b is -SO2(C1-6 linear alkyl).

[0369] In some embodiments, R 5b is -SO2(C3-7 branched alkyl).

[0370] In some embodiments, R 5b is -SO2(C3-7cycloalkyl).

[0371] In some embodiments, R 5b is COR 6 is.

[0372] In some embodiments, R 5b is CO2R 7 is.

[0373] In some embodiments, R 5b CONR 8a R 8b is.

[0374] In some embodiments, R 5b is SO2NR 8a R 8b is.

[0375] In some embodiments, R 5b is NR 9a R 9b is.

[0376] In some embodiments, R 5b is NR 9a COR 10 is.

[0377] In some embodiments, R 5b is NR 9a SO2R 11 is.

[0378] In some embodiments, R 5b is NR 9a SO2NR 12a R 12b is.

[0379] In some embodiments, R 5c is hydrogen.

[0380] In some embodiments, R 5c is OH.

[0381] In some embodiments, R 5c is NO2.

[0382] In some embodiments, R 5c is a halogen.

[0383] In some embodiments, R 5c is CN.

[0384] In some embodiments, R 5c is a C1-6 straight chain alkyl.

[0385] In some embodiments, R 5c is a C3-7 branched alkyl.

[0386] In some embodiments, R 5c is C3-7 cycloalkyl.

[0387] In some embodiments, R 5c is C1-6 straight chain alkoxy.

[0388] In some embodiments, R 5c is a C3-7 branched alkoxy.

[0389] In some embodiments, R 5c is C3-7 cycloalkoxy.

[0390] In some embodiments, R 5c is a C1-6 straight chain haloalkyl.

[0391] In some embodiments, R 5c is a C3-7 branched haloalkyl.

[0392] In some embodiments, R 5c is a C1-6 straight chain haloalkoxy.

[0393] In some embodiments, R 5c is -S(C1-6 straight chain alkyl).

[0394] In some embodiments, R 5c is -S(C3-7 branched alkyl).

[0395] In some embodiments, R 5c is —S(C3-7 cycloalkyl).

[0396] In some embodiments, R 5c is -SO2(C1-6 linear alkyl).

[0397] In some embodiments, R 5c is -SO2(C3-7 branched alkyl).

[0398] In some embodiments, R 5c is -SO2(C3-7cycloalkyl).

[0399] In some embodiments, R 5c is COR 6 is.

[0400] In some embodiments, R 5c is CO2R 7 is.

[0401] In some embodiments, R 5c CONR 8a R 8b is.

[0402] In some embodiments, R 5c is SO2NR 8a R 8b is.

[0403] In some embodiments, R 5c is NR 9a R 9b is.

[0404] In some embodiments, R 5c is NR 9a COR 10 is.

[0405] In some embodiments, R 5c is NR 9a SO2R 11 is.

[0406] In some embodiments, R 5c is NR 9a SO2NR12a R 12b is.

[0407] In some embodiments, R 5d is hydrogen.

[0408] In some embodiments, R 5d is OH.

[0409] In some embodiments, R 5d is NO2.

[0410] In some embodiments, R 5d is a halogen.

[0411] In some embodiments, R 5d is CN.

[0412] In some embodiments, R 5d is a C1-6 straight chain alkyl.

[0413] In some embodiments, R 5d is a C3-7 branched alkyl.

[0414] In some embodiments, R 5d is C3-7 cycloalkyl.

[0415] In some embodiments, R 5d is C1-6 straight chain alkoxy.

[0416] In some embodiments, R 5d is a C3-7 branched alkoxy.

[0417] In some embodiments, R 5d is C3-7 cycloalkoxy.

[0418] In some embodiments, R 5d is a C1-6 straight chain haloalkyl.

[0419] In some embodiments, R 5dis a C3-7 branched haloalkyl.

[0420] In some embodiments, R 5d is a C1-6 straight chain haloalkoxy.

[0421] In some embodiments, R 5d is -S(C1-6 straight chain alkyl).

[0422] In some embodiments, R 5d is -S(C3-7 branched alkyl).

[0423] In some embodiments, R 5d is —S(C3-7 cycloalkyl).

[0424] In some embodiments, R 5d is -SO2(C1-6 linear alkyl).

[0425] In some embodiments, R 5d is -SO2(C3-7 branched alkyl).

[0426] In some embodiments, R 5d is -SO2(C3-7cycloalkyl).

[0427] In some embodiments, R 5d is COR 6 is.

[0428] In some embodiments, R 5d is CO2R 7 is.

[0429] In some embodiments, R 5d CONR 8a R 8b is.

[0430] In some embodiments, R 5d is SO2NR 8a R 8b is.

[0431] In some embodiments, R 5d is NR 9a R 9b is.

[0432] In some embodiments, R 5d is NR 9a COR 10 is.

[0433] In some embodiments, R 5d is NR 9a SO2R 11 is.

[0434] In some embodiments, R 5d is NR 9a SO2NR 12a R 12b is.

[0435] In some embodiments, R 6 is hydrogen.

[0436] In some embodiments, R 6 is a C1-6 straight chain alkyl.

[0437] In some embodiments, R 6 is a C3-7 branched alkyl.

[0438] In some embodiments, R 6 is C3-7 cycloalkyl.

[0439] In some embodiments, R 7 is a C1-6 straight chain alkyl.

[0440] In some embodiments, R 7 is a C3-7 branched alkyl.

[0441] In some embodiments, R 7 is C3-7 cycloalkyl.

[0442] In some embodiments, R 8a is hydrogen.

[0443] In some embodiments, R 8a is a C1-6 straight chain alkyl.

[0444] In some embodiments, R 8a is a C3-7 branched alkyl.

[0445] In some embodiments, R 8a is C3-7 cycloalkyl.

[0446] In some embodiments, R 8b is hydrogen.

[0447] In some embodiments, R 8b is a C1-6 straight chain alkyl.

[0448] In some embodiments, R 8b is a C3-7 branched alkyl.

[0449] In some embodiments, R 8b is C3-7 cycloalkyl.

[0450] In some embodiments, R 9a is hydrogen.

[0451] In some embodiments, R 9a is a C1-6 straight chain alkyl.

[0452] In some embodiments, R 9a is a C3-7 branched alkyl.

[0453] In some embodiments, R 9a is C3-7 cycloalkyl.

[0454] In some embodiments, R 9b is hydrogen.

[0455] In some embodiments, R 9b is a C1-6 straight chain alkyl.

[0456] In some embodiments, R 9b is a C3-7 branched alkyl.

[0457] In some embodiments, R 9b is C3-7 cycloalkyl.

[0458] In some embodiments, R 9a and R 9b has three ring atoms along with the atoms to which they are attached Forms a ring.

[0459] In some embodiments, R 9a and R 9b have four ring atoms along with the atoms to which they are attached Forms a ring.

[0460] In some embodiments, R 9a and R 9b have five ring atoms along with the atoms to which they are attached Forms a ring.

[0461] In some embodiments, R 9a and R 9b together with the atoms to which they are attached form a ring having six ring atoms which optionally contains oxygen.

[0462] In some embodiments, R 9a and R 9b together with the atoms to which they are attached form a ring having seven ring atoms, optionally containing oxygen.

[0463] In some embodiments, R 10 is hydrogen.

[0464] In some embodiments, R 10 is a C1-6 straight chain alkyl.

[0465] In some embodiments, R 10 is a C3-7 branched alkyl.

[0466] In some embodiments, R 10 is C3-7 cycloalkyl.

[0467] In some embodiments, R 11 is hydrogen.

[0468] In some embodiments, R 11 is a C1-6 straight chain alkyl.

[0469] In some embodiments, R 11 is a C3-7 branched alkyl.

[0470] In some embodiments, R 11 is C3-7 cycloalkyl.

[0471] In some embodiments, R 12a is hydrogen.

[0472] In some embodiments, R 12a is a C1-6 straight chain alkyl.

[0473] In some embodiments, R 12a is a C3-7 branched alkyl.

[0474] In some embodiments, R 12a is C3-7 cycloalkyl.

[0475] In some embodiments, R 12b is hydrogen.

[0476] In some embodiments, R 12b is a C1-6 straight chain alkyl.

[0477] In some embodiments, R 12b is a C3-7 branched alkyl.

[0478] In some embodiments, R 12b is C3-7 cycloalkyl.

[0479] Examples of compounds of the present invention include, but are not limited to, the following compounds or pharmaceutically acceptable forms thereof: (R)-3-(2-(6-(pyridin-4-yl)-2,6-diazospiro[3.3]heptan-2-yl)ethyl)-2-o Xaspiro[4.5]decane-1-one: (S)-3-(2-(6-(pyridin-4-yl)-2,6-diazospiro[3.3]heptan-2-yl)ethyl)-2-o Xaspiro[4.5]decane-1-one: (R)-3,3-diethyl-5-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (S)-3-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (R)-3,3-diethyl-5-(2-(5-(2-isopropylphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-(2-isopropylphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3-(2-(5-(3-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl) (ethyl)-2-oxaspiro[4.5]decan-1-one; (S)-3-(2-(5-(3-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl) (ethyl)-2-oxaspiro[4.5]decan-1-one; (R)-3-(2-(5-(2-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl) (ethyl)-2-oxaspiro[4.5]decan-1-one; (S)-3-(2-(5-(2-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl) (ethyl)-2-oxaspiro[4.5]decan-1-one; (R)-3-(2-(5-(2,6-dimethylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (S)-3-(2-(5-(2,6-dimethylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (R)-3-(2-(6-(3-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl yl)-2-oxaspiro[4.5]decan-1-one; (S)-3-(2-(6-(3-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl yl)-2-oxaspiro[4.5]decan-1-one; (R)-3-(2-(6-(2-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl yl)-2-oxaspiro[4.5]decan-1-one; (S)-3-(2-(6-(2-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl yl)-2-oxaspiro[4.5]decan-1-one; (R)-3-(2-(6-(2,6-dimethylpyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl) Ethyl)-2-oxaspiro[4.5]decan-1-one; (S)-3-(2-(6-(2,6-dimethylpyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl) Ethyl)-2-oxaspiro[4.5]decan-1-one; (R)-3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-diethyl-5-(2-(5-(m-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-(m-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-diethyl-5-(2-(5-(p-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-(p-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-2-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydro Pyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile; (S)-2-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydro Pyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile; (R)-3-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydro Pyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile; (S)-3-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydro Pyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile; (R)-4-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydro Pyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile; (S)-4-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydro Pyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile; (R)-3,3-diethyl-5-(2-(5-(2-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-(2-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-diethyl-5-(2-(5-(3-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-(3-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-diethyl-5-(2-(5-(4-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-(4-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-diethyl-5-(2-(5-(2-morpholinophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-(2-morpholinophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-diethyl-5-(2-(5-(2-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-(2-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-diethyl-5-(2-(5-(3-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one: (S)-3,3-diethyl-5-(2-(5-(3-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-diethyl-5-(2-(5-(4-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-(4-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-diethyl-5-(2-(5-phenylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-Diethyl-5-(2-(5-phenylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one.

[0480] Exemplary embodiments include compounds having the following formula (II): [ka] In the formula, R 1a , R 1b , R 2 and non-limiting examples of n are defined herein in Table 1 below. Table 1 [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

[0481] Exemplary embodiments include a compound having the following formula (X): Possible salt forms include: [ka] In the formula, R 2 and non-limiting examples of n are defined herein in Table 2 below. Table 2 [Table 2-1] [Table 2-2] [Table 2-3]

[0482] Exemplary embodiments include compounds having the following formula (XI) or a pharmaceutically acceptable salt form thereof: [ka] In the formula, R 2 and non-limiting examples of n are defined herein in Table 3 below. Table 3 [Table 3-1] [Table 3-2] [Table 3-3]

[0483] Exemplary embodiments include compounds having the following formula (XII): Possible salt forms include: [ka] In the formula, R 2 and non-limiting examples of n are defined herein in Table 4 below. Table 4 [Table 4-1] [Table 4-2]

[0484] Exemplary embodiments include compounds having the following formula (XIII) or a pharmaceutically acceptable salt form thereof: [ka] In the formula, R 2 and non-limiting examples of n are defined herein in Table 5 below. Table 5 [Table 5-1] [Table 5-2]

[0485] Exemplary embodiments include compounds having the following formula (VI): [ka] In the formula, R 1a , R 1b , R 3 and non-limiting examples of n are defined herein in Table 6 below. Table 6 [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7]

[0486] Exemplary embodiments include a compound having the following formula (XIV) or a pharmaceutically acceptable salt thereof: Possible salt forms include: [ka] In the formula, R 3 and non-limiting examples of n are defined herein in Table 7 below. Table 7 [Table 7-1] [Table 7-2]

[0487] Exemplary embodiments include compounds having the following formula (XV): [ka] In the formula, R 3 and non-limiting examples of n are defined herein in Table 8 below. Table 8 [Table 8-1] [Table 8-2]

[0488] Exemplary embodiments include compounds having the following formula (XVI): Possible salt forms include: [ka] In the formula, R 3 and non-limiting examples of n are defined herein in Table 9 below. Table 9 [Table 9-1] [Table 9-2] [Table 9-3]

[0489] Exemplary embodiments include compounds having the following formula (XVII) or a pharmaceutically acceptable salt form thereof: [ka] In the formula, R 3 and non-limiting examples of n are defined herein in Table 10 below. Table 10 [Table 10-1] [Table 10-2]

[0490] Exemplary embodiments include a compound having the following formula (II): Possible salt forms include: [ka] In the formula, R 1a , R 1b , R 2 and n are defined herein in Table 11 below. can be. Table 11 [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4] [Table 11-5] [Table 11-6] [Table 11-7]

[0491] Exemplary embodiments include a compound having the following formula (X): Possible salt forms include: [ka] In the formula, R 2 and non-limiting examples of n are defined herein in Table 12 below. Table 12 [Table 12-1] [Table 12-2]

[0492] Exemplary embodiments include compounds having the following formula (XI) or a pharmaceutically acceptable salt form thereof: [ka] In the formula, R 2 and non-limiting examples of n are defined herein in Table 13 below. Table 13 [Table 13-1] [Table 13-2]

[0493] Exemplary embodiments include compounds having the following formula (XII): Possible salt forms include: [ka] In the formula, R 2 and non-limiting examples of n are defined herein in Table 14 below. Table 14 [Table 14-1] [Table 14-2]

[0494] Exemplary embodiments include compounds having the following formula (XIII) or a pharmaceutically acceptable salt form thereof: [ka] In the formula, R 2 and non-limiting examples of n are defined herein in Table 15 below. Table 15 [Table 15-1] [Table 15-2] [Table 15-3]

[0495] Exemplary embodiments include compounds having the following formula (VI): [ka] In the formula, R 1a , R 1b , R 3 and n are defined herein in Table 16 below. can be. Table 16 [Table 16-1] [Table 16-2] [Table 16-3] [Table 16-4] [Table 16-5] [Table 16-6] [Table 16-7]

[0496] Exemplary embodiments include a compound having the following formula (XIV) or a pharmaceutically acceptable salt thereof: Possible salt forms include: [ka] In the formula, R 3 and non-limiting examples of n are defined herein in Table 17 below. Table 17 [Table 17-1] [Table 17-2] [Table 17-3]

[0497] Exemplary embodiments include compounds having the following formula (XV): [ka] In the formula, R 3and non-limiting examples of n are defined herein in Table 18 below. Table 18 [Table 18-1] [Table 18-2] [Table 18-3]

[0498] Exemplary embodiments include compounds having the following formula (XVI): Possible salt forms include: [ka] In the formula, R 3 and non-limiting examples of n are defined herein in Table 19 below. Table 19 [Table 19-1] [Table 19-2] [Table 19-3]

[0499] Exemplary embodiments include compounds having the following formula (XVII) or a pharmaceutically acceptable salt form thereof: [ka] In the formula, R 3 and non-limiting examples of n are defined herein in Table 20 below. Table 20 [Table 20-1] [Table 20-2]

[0500] For purposes of illustrating the manner in which compounds of the present invention are named and referred to herein, compounds having the formula: [ka] has the chemical name 3-(2-(5-(pyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one.

[0501] For purposes of illustrating the manner in which compounds of the present invention are named and referred to herein, compounds having the formula: [ka] is 3-(2-(6-(pyridin-4-yl)-2,6-diazospiro[3.3]heptan-2-yl)ethyl)-2-o It has the chemical name xaspiro[4.5]decan-1-one.

[0502] For purposes of the present invention, for example, a compound represented by the racemic formula: [ka] The following formula: [ka] or two enantiomers having the formula: [ka] or mixtures thereof, or, if a second chiral center is present, all diastereomers, are equally fully represented.

[0503] In all of the embodiments provided herein, examples of suitable optional substituents are not intended to limit the scope of the claims. Compounds of the invention can include any of the substituents or combinations of substituents provided herein. process

[0504] The present invention further relates to processes for preparing the sigma-2 receptor binding substances and sigma-2 receptor activity modulators of the present invention.

[0505] Compounds of the present teachings can be prepared from commercially available starting materials, compounds known in the literature, or readily prepared compounds according to the procedures outlined herein using standard synthetic methods and procedures known to those skilled in the art. The compounds can be prepared from intermediates that are suitable for use in the synthesis of organic molecules. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be readily obtained from the relevant scientific literature or from standard textbooks in the field. It will be understood that where typical or preferred process conditions (i.e., reaction temperature, time, molar ratios of reactants, solvent, pressure, etc.) are given, other process conditions can also be used unless otherwise specified. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art using routine optimization procedures. Those skilled in the art of organic synthesis will recognize that the nature and order of the synthetic steps presented can be varied in order to optimize the formation of the compounds described herein.

[0506] The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) spectroscopic methods such as infrared spectroscopy, spectrophotometry (e.g., UV-visible), and mass spectrometry The reaction may be monitored by HPLC or by chromatography, such as high pressure liquid chromatography (HPLC), gas chromatography (GC), gel permeation chromatography (GPC), or thin layer chromatography (TLC).

[0507] Preparation of compounds may involve the protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups can be easily determined by those skilled in the art. The chemical properties of protecting groups are described, for example, in Greene et al., Protective Groups in Organic Synthesis, 2d. Ed. (Wiley & Sons, 1991), the entire disclosure of which is incorporated herein by reference for all purposes.

[0508] The reactions or processes described herein can be carried out in a suitable solvent, which can be easily selected by one skilled in the art of organic synthesis. A suitable solvent typically does not substantially react with the reactants, intermediates, and / or products at the temperature at which the reaction is carried out, i.e., at temperatures ranging from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in one solvent or in a mixture of two or more solvents. Depending on the particular reaction step, a suitable solvent for the particular reaction step can be selected.

[0509] The compounds of these teachings can be prepared by methods known in the art of organic chemistry. The reagents used to prepare the compounds of these teachings can be commercially obtained or can be prepared by standard procedures described in the literature. For example, the compounds of the present invention can be prepared according to the methods illustrated in the general synthetic schemes: General synthetic scheme for the preparation of compounds

[0510] The reagents used in the preparation of the compounds of this invention are either commercially available or can be prepared by standard procedures described in the literature. According to the present invention, this class of compounds can be produced by one of the following reaction schemes.

[0511] Compounds of the present disclosure may be prepared according to any of the processes outlined in Schemes 1-8 below. [ka]

[0512] Therefore, appropriately substituted compound (1) is a known compound or can be prepared by known methods. The compound of formula (2) is a compound that is known or prepared by a known method, and is a compound that is prepared by a known method, for example, palladium acetate, palladium bis(triphenylphosphine) Dichloride, Palladium tetrakis(triphenylphosphine), Bis(acetonitrile)dichloropalladium[1,1'-bis(diphenylphosphino)ferrocene]dichloropara Palladium catalysts such as tris(dibenzylideneacetone)dipalladium(0) In the presence of a base such as potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, optionally in the presence of an organic base such as triethylamine, diisopropylethylamine, pyridine, optionally in the presence of a base such as 2,2'-bis(2,3'-dihydroxybenzoyl)-2,3'-dihydroxybenzoyl (Diphenylphosphino)-1,1'-dinaphthalene, 2,2'-bis(di-p-tolylphosphino)-1,1'-dinaphthyl, 1,1'-dinaphthalene-2,2'-diyl)bis[bis(3,5-dimethylphenyl )phosphine], 5,5'-bis[di(3,5-xylyl)phosphino]-4,4'-bi-1,3-benzodioxole, 5,5'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4,4'-bi-1,3-benzodioxole, etc. The compound of formula (3) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, or sulfuric acid, optionally in the presence of an organic solvent such as methylene chloride, dichloroethane, 1,4-dioxane, tetrahydrofuran, methanol, or ethanol, to give a compound of formula (4). obtain. [ka]

[0513] The appropriately substituted compound (5) is a known compound or a compound prepared by known methods. The compound of formula (6) is a known compound or a compound prepared by a known method. and compounds such as palladium acetate, palladium bis(triphenylphosphine) dichloride, palladium tetrakis(triphenylphosphine), bis(acetonitrile)dichloropalladium [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, trichloropalladium In the presence of a palladium catalyst such as bis(dibenzylideneacetone)dipalladium(0), e.g. In the presence of a base such as potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, optionally in the presence of an organic base such as triethylamine, diisopropylethylamine, pyridine, optionally in the presence of an organic base such as 2,2'-bis(diphenyl 2,2'-bis(di-p-tolylphosphino)-1,1'-dinaphthyl, 1,1'-dinaphthalene-2,2'-diyl)bis[bis(3,5-dimethylphenyl)phosphine ], 5,5'-bis[di(3,5-xylyl)phosphino]-4,4'-bi-1,3-benzodioxole, 5,5'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4,4'-bi-1,3- In the presence of a bis(diphenylphosphino)-derived compound such as benzodioxole, for example, in a solvent such as toluene, benzene, xylene, 1,4-dioxane, tetrahydrofuran, methylene chloride, 1,2-dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, optionally with heating and optionally with microwave irradiation, a compound of formula (7) is obtained. The compound of formula (7) can be prepared by reacting it with an acid such as trifluoroacetic acid, hydrochloric acid, or sulfuric acid, or optionally with the acid. in the presence of an organic solvent such as methylene chloride, dichloroethane, 1,4-dioxane, tetrahydrofuran, methanol, or ethanol to obtain a compound of formula (8). [ka]

[0514] The appropriately substituted compound (9) is a known compound or a compound prepared by known methods. The compound of formula (10) is a known compound or a compound prepared by a known method, and is reacted with, for example, palladium acetate, palladium bis(triphenylphosphine) dichloride, palladium tetrakis(triphenylphosphine), bis(acetonitrile)dichloropalladium [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, trichloropalladium, In the presence of a palladium catalyst such as bis(dibenzylideneacetone)dipalladium(0), e.g. In the presence of a base such as potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, optionally in the presence of an organic base such as triethylamine, diisopropylethylamine, pyridine, optionally in the presence of an organic base such as 2,2'-bis(diphenyl 2,2'-bis(di-p-tolylphosphino)-1,1'-dinaphthyl, 1,1'-dinaphthalene-2,2'-diyl)bis[bis(3,5-dimethylphenyl)phosphine ], 5,5'-bis[di(3,5-xylyl)phosphino]-4,4'-bi-1,3-benzodioxole, 5,5'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4,4'-bi-1,3- Reaction of the compound of formula (11) with hydrogen in the presence of a bis(diphenylphosphino)-derived compound, such as benzodioxole, in a solvent such as toluene, benzene, xylene, 1,4-dioxane, tetrahydrofuran, methylene chloride, 1,2-dichloroethane, N,N-dimethylformamide, or N,N-dimethylacetamide, optionally with heating and optionally with microwave irradiation, provides a compound of formula (11). Reaction of the compound of formula (11) with hydrogen in the presence of a palladium catalyst, such as palladium on carbon, palladium on Celite, palladium on barium sulfate, palladium acetate, palladium bis(triphenylphosphine)dichloride, or palladium tetrakis(triphenylphosphine), in a solvent such as methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, or 1,4-dioxane, provides a compound of formula (12). [ka]

[0515] The appropriately substituted compound (13) is a known compound or a compound prepared by known methods, and can be prepared by reacting a compound of formula (14) with, for example, palladium acetate, palladium bis(triphenylphosphine) dichloride, palladium tetrakis(triphenylphosphine), bis(acetonitrile)dichloropalladium [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, trichloropalladium, In the presence of a palladium catalyst such as bis(dibenzylideneacetone)dipalladium(0), e.g. in the presence of a base such as potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, optionally with, for example, triethylamine, diisopropyl 2,2'-bis(diphenyl)-2,2'-diisopropyl-2,2'-diphenyl ... 2,2'-bis(di-p-tolylphosphino)-1,1'-dinaphthyl, 1,1'-dinaphthalene-2,2'-diyl)bis[bis(3,5-dimethylphenyl)phosphine ], 5,5'-bis[di(3,5-xylyl)phosphino]-4,4'-bi-1,3-benzodioxole, 5,5'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4,4'-bi-1,3- Reaction of the compound of formula (15) with hydrogen in the presence of a bis(diphenylphosphino)-derived compound, such as benzodioxole, in a solvent such as toluene, benzene, xylene, 1,4-dioxane, tetrahydrofuran, methylene chloride, 1,2-dichloroethane, N,N-dimethylformamide, or N,N-dimethylacetamide, optionally with heating and optionally with microwave irradiation, provides a compound of formula (15). Reaction of the compound of formula (15) with hydrogen in the presence of a palladium catalyst, such as palladium on carbon, palladium on Celite, palladium on barium sulfate, palladium acetate, palladium bis(triphenylphosphine)dichloride, or palladium tetrakis(triphenylphosphine), in a solvent such as methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, or 1,4-dioxane, provides a compound of formula (16). [ka]

[0516] Appropriately substituted compounds of formula (17) are known compounds or compounds prepared by known methods, where X is, for example, chlorine, bromine, iodine, mesylate, tosylate, etc. The compound of formula (18), which is a leaving group, is reacted with a base such as lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, or sodium hydride in an organic solvent such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide, or dimethylacetamide to obtain a compound of formula (19). The compound of formula (19) is then treated with paraformaldehyde in the presence of an acid such as sulfuric acid or hydrochloric acid, or in the presence of acetic acid, optionally with heating and optionally with microwave irradiation in an organic solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide, or dimethylacetamide to obtain a compound of formula (20). Compounds of formula (20) are then treated with a base, such as sodium hydroxide, potassium hydroxide, or lithium hydroxide, in a solvent such as water, methanol, ethanol, or isopropanol, optionally with heating, followed by treatment with an acid, such as sulfuric acid or hydrochloric acid, in a solvent such as water, methanol, ethanol, or isopropanol, to provide compounds of formula (21). Compounds of formula (21) are then converted to compounds of formula (22) using methods known to those skilled in the art, where LG is a leaving group, such as mesylate, tosylate, nosylate, or bromine. Therefore, the compound of formula (21) can be reacted with methanesulfonyl chloride, toluenesulfonyl chloride, p-nitrophenyl ether, etc. in the presence of a base such as triethylamine, diisopropylamine, pyridine, or 2,6-lutidine in an organic solvent such as methylene chloride, dichloromethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran, or 1,4-dioxane to give the desired product. Alternatively, compound (21) may be treated with a sulfonyl chloride, such as methylsulfonyl chloride, to give a compound of formula (22). Alternatively, compound (21) may be treated with carbon tetrabromide in the presence of triphenylphosphine, for example, in a solvent such as methylene chloride, dichloroethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran, or 1,4-dioxane, optionally with heating and optionally with microwave irradiation, to give a compound of formula (22). Compound (22) may be treated with a sulfonyl chloride, such as methylsulfonyl chloride, to give a compound of formula (23). Alternatively, compound (21) may be treated with carbon tetrabromide in the presence of triphenylphosphine, for example, in a solvent such as methylene chloride, dichloroethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran, or 1,4-dioxane, optionally with heating and optionally with microwave irradiation, to give a compound of formula (22). Alternatively, compound (22) may be treated with a sulfonyl chloride, such as methylsulfonyl chloride, to give a compound of formula (24). with a compound of formula (23), which is a known compound or a compound prepared by known methods, optionally with heating, to give a compound of formula (24). [ka]

[0517] Appropriately substituted compounds of formula (25) are known compounds or compounds prepared by known methods, where X is, for example, chlorine, bromine, iodine, mesylate, tosylate, etc. The compound of formula (26) which is a leaving group and, for example, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium hydride, n-butyllithium, sec-butyllithium, tert-butyllithium The compound of formula (27) is reacted with paraformaldehyde in the presence of an acid such as sulfuric acid or hydrochloric acid in the presence of acetic acid, optionally with heating and optionally with microwave irradiation, in an organic solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide, or dimethylacetamide to obtain a compound of formula (28). The compound of formula (28) is then treated with a base such as sodium hydroxide, potassium hydroxide, or lithium hydroxide in a solvent such as water, methanol, ethanol, or isopropanol, optionally with heating, followed by treatment with an acid such as sulfuric acid or hydrochloric acid in a solvent such as water, methanol, ethanol, or isopropanol, optionally with heating, to obtain a compound of formula (29). Compounds of formula (29) are then converted to compounds of formula (30) using methods known to those skilled in the art. LG is a leaving group, such as mesylate, tosylate, nosylate, or bromine. Thus, compounds of formula (29) can be treated with a sulfonyl chloride, such as methanesulfonyl chloride, toluenesulfonyl chloride, or p-nitrophenylsulfonyl chloride, in the presence of a base, such as triethylamine, diisopropylamine, pyridine, or 2,6-lutidine, in an organic solvent, such as methylene chloride, dichloromethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran, or 1,4-dioxane, to give compounds of formula (30). Alternatively, compounds of formula (29) can be treated with a sulfonyl chloride, such as methanesulfonyl chloride, toluenesulfonyl chloride, or p-nitrophenylsulfonyl chloride, in the presence of triphenylphosphine, in an organic solvent, such as methylene chloride, dichloroethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, or Treatment with carbon tetrabromide in a solvent such as tetrahydrofuran or 1,4-dioxane, optionally with heating and optionally with microwave irradiation, provides a compound of formula (30). Compounds of formula (30) can be optionally methylated in an organic solvent such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide, or dimethylacetamide, optionally in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, or 2,6-lutidine. Reaction with a compound of formula (31), a known compound or a compound prepared by known methods, using microwave irradiation and optionally heating, provides a compound of formula (32).

[0518] Compounds of formula (37) can be prepared according to the process outlined in Scheme 7. [ka]

[0519] The compound of formula (33) is reacted with a base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, or lithium carbonate in the presence of a solvent such as methanol, ethanol, isopropanol, or water, optionally with heating and optionally with microwave irradiation, to obtain a compound of formula (34). The compound of formula (34) is then reacted with iodine in the presence of a base such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium carbonate, potassium carbonate, lithium bicarbonate, sodium hydroxide, potassium hydroxide, or lithium hydroxide in the presence of a solvent such as tetrahydrofuran, ethyl ether, or 1,4-dioxane to obtain a compound of formula (35). The compound of formula (35) is optionally reacted with iodine in an organic solvent such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide, or dimethylacetamide, optionally in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, or 2,6-lutidine, optionally with microwave irradiation. Selectively reacting with a compound of formula (36), a known compound or a compound prepared by known methods, with heating to give a compound of formula (37).

[0520] Compounds of formula (46) can be prepared according to the process outlined in Scheme 8. [ka]

[0521] The compound of formula (38) is reacted with ruthenium chloride in the presence of sodium periodate in a solvent such as acetonitrile, methanol, ethanol, or isopropanol to obtain a compound of formula (39). The compound of formula (39) is reacted with a compound of formula (40), which is a known compound or a compound prepared by a known method, in the presence of a solvent such as ethyl ether, tetrahydrofuran, or 1,4-dioxane to obtain a compound of formula (41). The compound of formula (41) is reacted with ruthenium chloride in the presence of sodium periodate in a solvent such as acetonitrile, methanol, or ethanol to obtain a compound of formula (39). The compound of formula (43) is reacted with ruthenium chloride in a solvent such as methanol, ethanol, isopropanol, or the like to provide a compound of formula (42). The compound of formula (42) is reacted with a reducing agent such as lithium borohydride, sodium borohydride, or sodium cyanoborohydride in a solvent such as methanol, ethanol, isopropanol, or acetonitrile to provide a compound of formula (42). The compound of formula (43) is then converted to a compound of formula (44) using methods known to those skilled in the art, where LG is a leaving group such as mesylate, tosylate, nosylate, or bromine. Thus, treatment of compound of formula (43) with a sulfonyl chloride, such as methanesulfonyl chloride, toluenesulfonyl chloride, or p-nitrophenylsulfonyl chloride, in the presence of a base, such as triethylamine, diisopropylamine, pyridine, or 2,6-lutidine, in an organic solvent, such as methylene chloride, dichloromethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran, or 1,4-dioxane, provides compound of formula (44). Alternatively, treatment of compound of formula (43) with carbon tetrabromide in the presence of triphenylphosphine, in a solvent, such as methylene chloride, dichloroethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran, or 1,4-dioxane, optionally with heating and optionally with microwave irradiation, provides compound of formula (44). Compounds of formula (44) can be reacted in an organic solvent such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide, dimethylacetamide, and the like, optionally with a base such as triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, and the like. with a compound of formula (45), i.e., a known compound or a compound prepared by known methods, in the presence of, optionally with microwave irradiation and optionally with heating, to provide a compound of formula (46).

[0522] The examples provided below provide representative methods for preparing exemplary compounds of the invention. One of ordinary skill in the art would know how to substitute the appropriate reagents, starting materials, and purification methods known to those skilled in the art to prepare compounds of the invention. [Example]

[0523] The practice of the present invention is illustrated by the following non-limiting examples. The examples provided below provide representative methods for preparing exemplary compounds of the present invention. One of ordinary skill in the art would know how to substitute the appropriate reagents, starting materials, and purification methods known to those skilled in the art to prepare compounds of the present invention.

[0524] In the following examples: 1 H-NMR spectra were obtained on a Varian Mercury 300-MHz NMR. Purity (%) and mass spectrometric analysis were performed using a Waters Alliance 2695 HPLC / MS (Waters Symmetry C18, 4.6 × 75 mm, 3.5 μm) equipped with a 2996 diode array detector from 210 nm to 400 nm. Spectral data was measured. [ka]

[0525] Example 1: Preparation of methyl 2,2-dimethylpent-4-enoate: The reaction was carried out under a nitrogen atmosphere. The reaction was carried out in oven-dried glassware. To a stirred solution of freshly prepared lithium diisopropylamide (1 M, 1.10 equiv.) in 35 ml of anhydrous tetrahydrofuran, isobutyric acid methyl ester (3.32 g, 32.6 mmol, 1.0 equiv.) was added dropwise at -78 °C for 0.5 h. The mixture was allowed to stir at this temperature for 30 min, and then allyl bromide (5.35 g, 44.0 mmol) and hexamethyl Phosphoramide (HMPA) (2.91 g, 16.3 mmol) was added dropwise over 0.5 hours. The mixture was stirred overnight at room temperature and then diluted with 10% HCl (while cooling in an ice bath) until acidic (pH = 2). The reaction mixture was quenched. The organic layer was separated, and the aqueous layer was extracted with hexane (3×100 mL). The extract was washed with 10% NaHCO (200 mL) and brine (200 mL). The solution was then dried over MgSO, concentrated in vacuo, and distilled to give the pure product. 1 H NMR (400 MHz, CDCl3) δ 5.73 (dd, J = 9.4, 17.7, 1H), 5.04 (dd, J = 1.9, 13.5, 2H), 4.12 (q, J = 7.1, 2H), 2.28 (d, J = 7.4, 2H), 1.25 (t, J = 7.1, 3H), 1.17 (s, 6H); 13 C NMR (101 MHz, CDCl3) δ 177.42, 134.42, 117.88, 77.68, 77.36, 77.04, 60.35, 44.91, 42.25, 24.92, 14.35

[0526] The following compound can be prepared by the methyl 2,2-dimethylpent-4-enoate procedure: One of ordinary skill in the art would know how to substitute the appropriate reagents, starting materials, and purification methods known to those skilled in the art to prepare the compounds presented herein. [ka]

[0527] Example 2: Preparation of methyl 2,2-diethylpent-4-enoate: The title compound was synthesized from 2-ethyl-butyric acid It was prepared according to the procedure for methyl 2,2-dimethylpent-4-enoate, except that the ethyl ester was replaced with methyl isobutyrate. 1 H NMR (300 MHz, CDCl3) δ 5.68 (dd, J = 9.9, 17.2, 1H), 5.16 - 4.97 (m, 2H), 4.14 (q, J = 7.1, 2H), 2.33 (d, J = 7.4, 2H), 1.59 (dt, J = 6.5, 7.5, 5H), 1.26 (t, J = 7.1, 3H), 0.80 (t, J = 7.5, 6H) [ka]

[0528] Example 3: Preparation of 1-allylcyclobutanecarboxylic acid: The reaction was carried out under nitrogen atmosphere. The reaction was carried out in a dry glassware. To a well-stirred solution of lithium diisopropylamide (1 M, 10.76 mmol, 2.30 equiv.) To this solution, cyclobutanecarboxylic acid (4.68 g, 46.8 mmol, 1.0 equiv) was added dropwise at 0 °C over 0.5 h. The mixture was heated to 50 °C for 6 h, then cooled to 0 °C. NaI (0.697 g, 4.68 mmol, 0.1 equiv) was added in one portion, followed by a mixture of allyl bromide (7.58 g, 63.2 mmol, 1.35 equiv) and HMPA (4.18 g, 23.4 mmol, 0.5 equiv) added dropwise over 0.5 h. The reaction mixture was stirred overnight at room temperature and quenched with 10% HCl (with cooling in an ice bath) until acidic (pH = 2). The organic layer was separated, and the aqueous layer was extracted with ether (3 × 250 mL). The organic layers were combined and washed with brine. The solution was then dried over MgSO4 and concentrated in vacuo to give a crude oil, which was then purified by filtration. Purification via rush chromatography (silica; ethyl acetate / hexane, 1%–10%) did. 1 H NMR (400 MHz, CDCl3) δ 5.77 (ddt, J = 7.1, 10.2, 17.2, 1H), 5.17 - 4.99 (m, 2H), 2.59 - 2.38 (m, 4H), 2.07 - 1.84 (m, 4H). 13 C NMR (101 MHz, CDCl) δ 184.04, 133.90, 118.19, 47.20, 41.74, 29.57, 15.65; Rf, 0.43 (hexane:ethyl acetate 10:1); HRMS (CI): [M+H] , C8H 13 Calculated O2 141.0916; measured 141.0911.

[0529] The following compounds can be prepared by the 1-allylcyclobutanecarboxylic acid procedure. Those skilled in the art will know how to substitute the appropriate reagents, starting materials, and purification methods known to those skilled in the art to prepare the compounds presented herein. It would be. [ka]

[0530] Example 4: Preparation of 1-allylcyclopentanecarboxylic acid: Cyclopentanecarboxylic acid and cyclopentanecarboxylic acid The title compound was prepared following the procedure for 1-allylcyclobutanecarboxylic acid, except substituting cyclobutanecarboxylic acid. 1 H NMR (400 MHz, CDCl3) δ 5.77 (ddt, J = 7.2, 10.2, 17.4, 1H), 5.17 - 4.94 (m, 2H), 2.38 (d, J = 7.2, 2H), 2.20 - 2.02 (m, 2H), 1.79 - 1.47 (m, 6H). 13 C NMR (101 MHz, CDCl3) δ 184.94, 134.96, 118.02, 53.75, 42.96, 35.89, 25.47. Rf, 0.50 (hexane:ethyl acetate 10:1); HRMS (CI): [M+H], CH 15Calculated O2 155.1072; measured 155.1068. [ka]

[0531] Example 5: Preparation of 1-allylcyclohexanecarboxylic acid: Cyclohexanecarboxylic acid and cyclohexanecarboxylic acid The title compound was prepared following the procedure for 1-allylcyclobutanecarboxylic acid, except substituting cyclobutanecarboxylic acid. 1 H NMR (400 MHz, CDCl3) δ 12.13 (bro 1H), 5.83 - 5.63 (m, 1H), 5.12 - 5.00 (m, 2H), 2.27 (m, 2H), 2.04 (m, 2H), 1.66 - 1.50 (m, 3H), 1.49 - 1.33 (m, 2H), 1.33 - 1.17 (m, 3H). [ka]

[0532] Example 6: Preparation of 5-(2-hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one: A mixture of glacial acetic acid (28.6 g, 477 mmol, 53.6 equiv.), paraformaldehyde (0.80 g, 26.7 mmol, 3.0 equiv.) and H2SO4 (0.5 g, 4.45 mmol, 0.57 equiv.) was stirred at 70 °C for 30 min, and then 2,2- Methyl dimethylpent-4-enoate (1.26 g, 8.9 mmol, 1.0 equiv.) was added dropwise over 10 min. The reaction mixture was then maintained at 70-80 °C and allowed to stir overnight. The acetic acid was removed under reduced pressure, and the reaction was quenched with 10% NaHCO3 solution. The mixture was then extracted with ethyl acetate (3 × 50 mL), and the combined organic phases were concentrated in vacuo to give a crude oil. The crude oil was used in the next step without further purification.

[0533] The crude oil (200 mg, 1.0 mmol, 1 equiv.) was dissolved in 30% NaOH (800 mg NaOH, 20 mmol, 20 equiv.) in water. The mixture was refluxed for 2 hours. The mixture was cooled in an ice bath and acidified (pH < 2) with excess 30% H2SO4. The resulting mixture was extracted with ethyl acetate (3x25 mL), and the combined organic layers were washed with 10% NaHCO3 (50 mL), brine (50 mL), dried over MgSO4, and concentrated in vacuo to give the crude product, which was further purified by column chromatography (ethyl acetate / hexane, 10%-60%). 1 H NMR (400 MHz, CDCl3) δ 4.70-4.60 (m, 1H), 3.90-3.78 (m, 2H), 2.22 (dd, J = 5.9, 12.7, 1H), 1.98 - 1.87 (m, 2H), 1.80 (dd, J = 5.9, 12.7, 1H), 1.28 (d, J = 4.8, 6H). 13 C NMR (101 MHz, CDCl3) δ 182.26, 75.01, 59.58, 43.93, 40.62, 38.69, 25.31, 24.61; Rf, 0.34 (hexane:ethyl acetate 1:1); analytical. C8H 14 Calculated O3: C, 60.74; H, 8.92; Measured values: C, 60.47; H, 8.86.

[0534] The following compound is 5-(2-hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one Those skilled in the art will know how to substitute the appropriate reagents, starting materials, and purification methods known to those skilled in the art to prepare the compounds presented herein. [ka]

[0535] Example 7: Preparation of 3,3-diethyl-5-(2-hydroxyethyl)dihydrofuran-2(3H)-one: Replacing ethyl 2,2-diethylpent-4-enoate with methyl 2,2-dimethylpent-4-enoate Except for the above, the natural order of 5-(2-hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one The title compound was prepared accordingly: 1 H NMR (400 MHz, CDCl3) δ 4.62 (dtd, J = 5.3, 7.3, 9.5, 1H), 3.78 (t, J = 6.1, 2H), 3.20 (s, 1H), 2.19 (dd, J = 6.8, 13.1, 1H), 1.97 - 1.81 (m, 3H), 1.70 - 1.56 (m, 4H), 0.93 (dt, J = 7.5, 20.7, 6H); 13 C NMR (101 MHz, CDCl3) δ 181.46, 75.10, 58.91, 48.77, 39.13, 37.76, 29.21, 28.30, 8.83, 8.73; Rf, 0.36 (hexane:ethyl acetate 5:2); analytical. C 10 H 18 Calculated O3 values: C, 64.49; H, 9.74; Found: C, 64.20; H, 9.57. [ka]

[0536] Example 8: Preparation of 7-(2-hydroxyethyl)-6-oxaspiro[3.4]octan-5-one: Substituting 1-allylcyclobutanecarboxylic acid for methyl 2,2-dimethylpent-4-enoate. Except for 5-(2-hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one, the table is The title compound was prepared: 1H NMR (400 MHz, CDCl3) δ 4.60 - 4.50 (m, 1H), 3.82 (t, J = 5.9, 2H), 2.61 - 2.40 (m, 3H), 2.19 - 1.96 (m, 5H). 1.92-185 (m, 2H); 13 C NMR (101 MHz, CDCl3) δ 181.25, 75.46, 59.66, 44.62, 42.42, 38.47, 31.95, 29.64, 16.79; Rf, 0.40 (hexane:ethyl acetate) Chill 1:2);C9H 15 Calculated O3 value 171.1021; measured value 171.1016. [ka]

[0537] Example 9: Preparation of 3-(2-hydroxyethyl)-2-oxaspiro[4.4]nonan-1-one: Substituting 1-allylcyclopentanecarboxylic acid for methyl 2,2-dimethylpent-4-enoate. Except for 5-(2-hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one, the table is The title compound was prepared: 1 H NMR (400 MHz, CDCl3) δ 4.65 - 4.56 (m, 1H), 3.84 - 3.76 (m, 2H), 2.74 (s, 1H), 2.28 (dd, J = 5.8, 12.6, 1H), 2.20 - 2.10 (m, 1H), 2.00 - 1.56 (m, 10H); 13 C NMR (101 MHz, CDCl) δ 183.02, 75.77, 59.20, 50.35, 43.41, 38.41, 37.49, 36.93, 25.67, 25.58; Rf, 0.46 (hexane:ethyl acetate 1:2); HRMS (CI): [M+H], C 10 H 17 O3 Calculated value 185.1178; measured value 185.1171. [ka]

[0538] Example 10: Preparation of 3-(2-hydroxyethyl)-2-oxaspiro[4.5]decan-1-one: 1-A The substitution of methyl 2,2-dimethylpent-4-enoate for methyl cyclohexanecarboxylic acid Except for the following, 5-(2-hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one was prepared according to the natural procedure. The title compound was prepared: 1 H NMR (400 MHz, CDCl3) δ 4.62 (m, 1H), 3.82 (t, J = 5.9, 2H), 2.43 (dd, J = 6.2, 12.9, 1H), 2.22 (s, 1H), 2.00 - 1.17 (m, 13H). 13 C NMR (101 MHz, CDCl3) δ 181.96, 75.37, 59.55, 45.13, 39.88, 38.91, 34.54, 31.71, 25.57, 22.42, 22.36; Rf, 0.46 (hexane:ethyl acetate 1:2); analytical. C 11 H 18 Calculated O3 values: C, 66.64; H, 9.15; Found: C, 66.48; H, 9.17. [ka]

[0539] Example 11: Preparation of 2-(4,4-dimethyl-5-oxotetrahydrofuran-2-yl)ethyl 4-methylbenzenesulfonate: 5-(2-hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-ol To a stirred solution of methylamine (0.316 g, 2 mmol, 1.0 equiv.) and triethylamine (0.152 g, 1.5 mmol, 1.5 equiv.) in anhydrous dichloromethane was added dropwise a solution of p-TosCl (0.475 g, 2.5 mmol, 1.25 equiv.) in dichloromethane at 0 °C. The resulting mixture was stirred at 0 °C for 1 h and then at room temperature overnight. The reaction mixture was then diluted with dichloromethane (50 mL), washed with 10% HCl, brine, dried over MgSO4, and concentrated in vacuo to give a yellowish oil. The crude product was then purified by flash chromatography (silica gel; ethyl acetate / hexanes, 0% to 40%). Preparation gave the desired tosylate. 1 H NMR (300 MHz, CDCl3) δ 7.72 (m, 2H), 7.29 (m, 2H), 4.39 (m, 1H), 4.10 (m, 2H), 2.38 (s, 3H), 2.09 (m, 1H), 1.93 (m, 2H), 1.65 (m, 1H), 1.16 (d, J = 4.8, 6H); 13 C NMR (101 MHz, CDCl3) 13 C NMR (101 MHz, CDCl3) δ 181.26, 145.16, 132.53, 130.03, 127.84, 77.68, 77.36, 77.04, 72.93, 66.83, 42.99, 40.23, 34.97, 24.82, 24.12, 21.57; HRMS (CI): [M+H] 313.1;Analytical. C 15 H 20 Calculated values ​​for O5S: C, 57.67; H, 6.45; Found values: C, 57.85; H, 6.63.

[0540] The following compounds can be prepared by the procedure of 2-(4,4-dimethyl-5-oxotetrahydrofuran-2-yl)ethyl 4-methylbenzenesulfonate. One of ordinary skill in the art would know how to substitute the appropriate reagents, starting materials, and purification methods known to those skilled in the art to prepare the compounds presented herein. [ka]

[0541] Example 12: Preparation of 2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl 4-methylbenzenesulfonate: The title compound was synthesized from 3,3-diethyl-5-(2-hydroxyethyl)dihydrobenzenesulfonate. Prepared following the procedure for 2-(4,4-dimethyl-5-oxotetrahydrofuran-2-yl)ethyl 4-methylbenzenesulfonate, except substituting furan-2(3H)-one for 5-(2-hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one. 1 H NMR (300 MHz, CDCl3) δ 7.79 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 4.55 - 4 .33 (m, 1H), 4.14 (dd, J = 6.5, 13.3 Hz, 3H), 2.46 (s, 3H), 2.21 - 1.84 (m, 3H), 1.83 - 1.68 (m, 1H), 1.58 (t, J = 7.4 Hz, 4H), 0.89 (dt, J = 7.5, 18.0 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ 180.33, 145.30, 132.72, 130.15, 128.03, 77.68, 77.36, 77.04, 73.18, 66.95, 48.67, 37.53, 35.82, 29.14, 28.23, 21.76, 8.81, 8.74. Analytical. C 17 H 24 O5S Calculated: C, 59.98; H, 7.11; Found: C, 60.27; H, 7.25. [ka]

[0542] Example 13: Preparation of 2-(5-oxo-6-oxaspiro[3.4]octan-7-yl)ethyl 4-methylbenzenesulfonate: The title compound was prepared from 7-(2-hydroxyethyl)-6-oxaspiro[3.4]octan-7-yl Prepared following the procedure for 2-(4,4-dimethyl-5-oxotetrahydrofuran-2-yl)ethyl 4-methylbenzenesulfonate, except substituting 5-(2-hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one for tan-5-one. 1 H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 4.37 (tdd, J = 8.8, 6.0, 4.3 Hz, 1H), 4.21 - 4.05 (m, 2H), 2.57 - 2.32 (m, 6H), 2.19 - 1.82 (m, 7H); 13 C NMR (101 MHz, CDCl3) δ 180.41, 145.24, 132.68, 130.10, 128.02, 73.38, 66.76, 44.33, 41.79, 35.10, 31.72, 29.28, 21.76, 16.51. [ka]

[0543] Example 14: Preparation of 2-(1-oxo-2-oxaspiro[4.4]nonan-3-yl)ethyl 4-methylbenzenesulfonate: The title compound was prepared by replacing 3-(2-hydroxyethyl)-2-oxaspiro[4.4]nonan-1-one with 5-(2-hydroxyethyl)-3,3-dimethyl-dihydro-furan-2-one Prepared following the procedure for 2-(4,4-dimethyl-5-oxotetrahydrofuran-2-yl)ethyl 4-methylbenzenesulfonate with the following exceptions: 1 H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 4.51 - 4.35 (m, 1H), 4.25 - 4.06 (m, 2H), 2.45 (s, 3H), 2.28 - 2.08 (m, 2H), 2.08 - 1.91 (m, 2H), 1.87 - 1.52 (m, 9H); 13 C NMR (101 MHz, CDCl3) δ 181.90, 145.26, 132.76, 130.12, 128.07, 73.71, 66.85, 50.19, 43.07, 37.44, 36.81, 35.19, 25.61, 25.50, 21.79. [ka]

[0544] Example 15: Preparation of 2-(1-oxo-2-oxaspiro[4.5]decan-3-yl)ethyl 4-methylbenzenesulfonate: The title compound was prepared by replacing 3-(2-hydroxyethyl)-2-oxaspiro[4.5]decan-1-one with 5-(2-hydroxyethyl)-3,3-dimethyl-dihydro-furan-2-one Prepared following the procedure for 2-(4,4-dimethyl-5-oxotetrahydrofuran-2-yl)ethyl 4-methylbenzenesulfonate with the following exceptions: 1 H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 4.51 - 4.38 (m, 1H), 4.26 - 4.12 (m, 2H), 2.45 (s, 3H), 2.36 (dd, J = 12.9, 6.2 Hz, 1H), 2.12 - 1.87 (m, 2H), 1.85 - 1.68 (m, 3H), 1.65 - 1.50 (m, 5H), 1.43 - 1.14 (m, 3H); 13 C NMR (101 MHz, CDCl3) δ 180.97, 145.2 7, 132.76, 130.12, 128.07, 73.28, 66.85, 44.96, 39.48, 35.58, 34.35, 31.52, 25.37, 22.23, 22.16, 21.80. [ka]

[0545] Example 16: Preparation of 5-(2-bromoethyl)-3,3-diethyldihydrofuran-2(3H)-one: To a solution of 3,3-diethyl-5-(2-hydroxyethyl)dihydrofuran-2(3H)-one (8.03 g, 43.0 mmol, 1 equiv.) in tetrahydrofuran (143 mL) was added triphenylphosphine (16.94 g, 64.6 mmol, 1.5 equiv.). The resulting solution was cooled to 0° C., and carbon tetrabromide (21.44 g, 64.6 mmol, 1.5 equiv.) was added in one portion. The reaction was allowed to stir at 22° C. overnight. The reaction mixture was diluted with ether, filtered, concentrated in vacuo onto Celite, and further purified by column chromatography (ethyl acetate / hexanes, 0% to 30%, solid load). 1 H NMR (400 MHz, CDCl3) δ4.60 (m, 1H), 3.53 (dd, J= 5.5, 7.6 Hz, 2H), 2.27-2.07 (m, 3H), 1.82 (dd, J= 9.3, 13.0 Hz, 1H), 1.69-1.57 (m, 4H), 0.93 (dt, J= 7.5, 25.7 Hz, 6H). [ka]

[0546] Example 17: Preparation of 3-(2-bromoethyl)-2-oxaspiro[4.5]decan-1-one: 3-(2-hydroxyethyl)-2-oxaspiro[4.5]decan-1-one was prepared by the same procedure as in Example 1, except that 3,3-diethyl-5-(2-hydroxyethyl)dihydrofuran-2(3H)-one was substituted for 5-(2-bromoethyl)-3,3-dihydrofuran-2(3H)-one. The title compound was prepared following the procedure for ethyldihydrofuran-2(3H)-one. 1 H NMR (400 MHz, CDCl3) δ4.61 (m, 1H), 3.53 (dd, J= 5.5, 7.6 Hz, 2H), 2.44 (dd, J= 6.4, 12.9 Hz, 1H), 2.29-2.07 (m, 2H), 1.88-1.70 (m, 3H), 1.69-1.54 (m, 4H), 1.53-1.44 (m, 1H), 1.44-1.18 (m, 3H). [ka]

[0547] Example 18: Preparation of 2,2-diethylpent-4-enoic acid: 2,2-diethylpent-4-enoic acid ethyl The solution (0.2 g, 0.28 mmol) was dissolved in NaOH (0.4 g, 10 mmol), MeOH (2.5 mL), and HO (2.5 mL) to prepare a microfluidic solution. The mixture was mixed in a microwave vial. The mixture was then heated at 160°C in a microwave reactor for 2 hours. The mixture was then acidified with 10% HCl and washed with ether (3x30ml). The combined organic phases were dried over MgSO4 and concentrated in vacuo to give the crude product which was further purified in the next step. Used without purification. [ka]

[0548] Example 19: Preparation of 3,3-diethyl-5-(iodomethyl)dihydrofuran-2(3H)-one: 2,2-di Ethyl pent-4-enoate (1.77 g, 11.67 mmol) was stirred in tetrahydrofuran (34 mL), ether (12 mL), and saturated NaHCO3 solution (57 mL). The mixture was protected from light. I2 was added to 12 mL of tetrahydrofuran. The mixture was stirred at room temperature overnight. The reaction was quenched by adding sodium thiosulfate to the mixture. The mixture was extracted with ethyl acetate (3x50 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to give a crude oil. was obtained, which was purified by flash chromatography (silica gel; ethyl acetate / hexane, 0% to 25%). 1 H NMR (400 MHz, CDCl3) δ 4.42 (dtd, J = 9.0, 7.3, 4.6 Hz, 1H), 3.41 (dd, J = 10.2, 4.6 Hz, 1H), 3.23 (dd, J = 10.2, 7.5 Hz, 1H), 2.25 (dd, J = 13.3, 6.9 Hz, 1H), 1.86 (dd, J = 13.3, 9.1 Hz, 1H), 1.63 (m, 4H), 0.94 (dt, J = 10.4, 7.5 Hz, 6H). MS (LC / MS, M+H + ): 283.0

[0549] The following compounds can be prepared by the procedure of 3,3-diethyl-5-(iodomethyl)dihydrofuran-2(3H)-one. One of ordinary skill in the art would know how to substitute the appropriate reagents, starting materials, and purification methods known to those skilled in the art to prepare the compounds presented herein. [ka]

[0550] Example 20: Preparation of 3-(iodomethyl)-2-oxaspiro[4.4]nonan-1-one: Title Compound replaced 1-allylcyclopentanecarboxylic acid with 2,2-diethylpent-4-enoic acid. Prepared following the procedure for 3,3-diethyl-5-(iodomethyl)dihydrofuran-2(3H)-one with the following exceptions: 1H NMR (400 MHz, CDCl3) δ 4.48 - 4.34 (m, 1H), 3.39 (dd, J = 10.2, 4.9 Hz, 1H), 3.23 (dd, J = 10.2, 7.5 Hz, 1H), 2.35 (dd, J = 12.9, 6.1 Hz, 1H), 2.20 - 2.04 (m, 1H), 1.93 - 1.54 (m, 8H); 13 C NMR (101 MHz, CDCl3) δ 181.57, 75.96, 50.71, 43.44, 37.84, 36.89, 25.45, 25.36, 7.02; + ): 281.0 [ka]

[0551] Example 21: Preparation of 3-(iodomethyl)-2-oxaspiro[4.5]decan-1-one: Title Compound replaced 1-allylcyclohexanecarboxylic acid with 2,2-diethylpenta-4-enoic acid. Prepared following the procedure for 3,3-diethyl-5-(iodomethyl)dihydrofuran-2(3H)-one with the following exceptions: 1 H NMR (400 MHz, CDCl3) δ 4.42 (dtd, J = 9.2, 6.9, 4.6 Hz, 1H), 3.41 (dd, J = 10.3, 4.6 Hz, 1H), 3.26 (dd, J = 10.2, 7.3 Hz, 1H), 2.50 (dd, J = 13.1, 6.5 Hz, 1H), 1.85 - 1.49 (m, 8H), 1.44 - 1.20 (m, 3H); MS (LC / MS, M+H [ka]

[0552] Example 22: Preparation of 3-hydroxy-2-oxaspiro[4.4]nonan-1-one: 1-allylcyclo Pentanecarboxylic acid (10.93 g, 71 mmol, 1 equiv.), a stock solution of RuCl (0.514 g, 0.035 M water To a stirred solution of NaIO (30.8 g, 142 mmol, 2.04 equiv.) and CHCN (500 mL) was added NaIO (30.8 g, 142 mmol, 2.04 equiv.). was added in several portions over 30 minutes at room temperature. The suspension was stirred for an additional 30 minutes at room temperature. The reaction was quenched with saturated aqueous Na2S2O3 and the two layers were separated. The aqueous layer was diluted with ethyl acetate. The residue was purified by flash column chromatography (silica gel; ethyl acetate / hexane, 10% to 50%) to give the desired product. 1 H NMR (400 MHz, CDCl3) δ 5.87 (s, 1H), 5.28 (s, 1H), 2.06 (dd, J = 35.1, 28.9 Hz, 4H), 1.90 - 1.44 (m, 6H); 13 C NMR (101 MHz, CDCl3) δ 183.20, 49.58, 43.94, 38.28, 25.42.

[0553] The following compounds were prepared by the procedure for 3-hydroxy-2-oxaspiro[4.4]nonan-1-one: Those of ordinary skill in the art will know how to substitute the appropriate reagents, starting materials, and purification methods known to those skilled in the art to prepare the compounds presented herein. [ka]

[0554] Example 23: Preparation of 3-hydroxy-2-oxaspiro[4.5]decan-1-one: 1-allylcyclo The title compound was prepared following the procedure for 3-hydroxy-2-oxaspiro[4.4]nonan-1-one, except replacing hexanecarboxylic acid with 1-allylcyclopentanecarboxylic acid: 1 H NMR (400 MHz, CDCl3) δ 5.86 (t, J = 4.5 Hz, 1H), 4.47 (bro 1H), 2.18 (m, 2H), 1.83 - 1.43 (m, 7H), 1.32 (d, J = 5.8 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 181.91, 96.88, 44.52, 40.54, 34.06, 25.28, 22.23. [ka]

[0555] Example 24: Preparation of 3-(but-3-en-1-yl)-2-oxaspiro[4.4]nonan-1-one: The reaction was carried out in oven-dried glassware under a nitrogen atmosphere. To a stirred solution of freshly prepared but-1-enemagnesium bromide Grignard reagent (96 mmol, 1 M, 3 equiv.) in anhydrous ether was added 3-hydroxy-2-oxaspiro[4.4]nonan-1-one (5.0 g, 32.0 mmol, 1.0 equiv.) for 0.5 min. The reaction mixture was stirred at room temperature overnight and quenched with 10% HCl (while cooling in an ice bath) until acidic (pH = 2). The organic layer was separated and the aqueous layer was diluted with ethyl acetate. The extract was diluted with 10% NaHCO3 (100 mL) and brine (200 mL). The solution was then dried over MgSO4, concentrated in vacuo, and purified by flash column chromatography. The product was purified by chromatography (silica gel; ethyl acetate / hexane, 0% to 25%). The desired product was obtained. 1H NMR (400 MHz, CDCl3) δ 5.79 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 5.15 - 4.88 (m, 2H), 4.36 (ddt, J = 9.7, 7.9, 5 .5 Hz, 1H), 2.18 (m, 4H), 1.93 - 1.46 (m, 10H); 13 C NMR (101 MHz, CDCl3) δ 182.55, 137.26, 115.62, 77.19, 50.28, 43.24, 37.51, 36.91, 34.83, 29.70, 25.56, 25.47.

[0556] The following compound was synthesized by the procedure 3-(but-3-en-1-yl)-2-oxaspiro[4.4]nonan-1-one Those of ordinary skill in the art will know how to substitute the appropriate reagents, starting materials, and purification methods known to those skilled in the art to prepare the compounds presented herein. [ka]

[0557] Example 25: Preparation of 3-(but-3-en-1-yl)-2-oxaspiro[4.5]decan-1-one: The compound is identical to 3-(but-3-en-1-yl)-2-oxaspiro[4.5]decan-1-one except that 3-hydroxy-2-oxaspiro[4.4]nonan-1-one is replaced by 3-hydroxy-2-oxaspiro[4.5]decan-1-one. Prepared according to the procedure for pyro[4.4]nonan-1-one. 1 H NMR (400 MHz, CDCl3) δ 5.80 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.17 - 4.89 (m, 2H), 4.48 - 4.31 (m, 1H), 2.36 (dd, J = 12.9, 6.3 Hz, 1H), 2.30 - 2.08 (m, 2H), 1.87 - 1.17 (m, 13H); 13 C NMR (101 MHz, CDCl3) δ 181.68, 137.31, 115.67, 76.77, 45.04, 39.55, 35.31, 34.43, 31.70, 29.75, 25.42, 22.29, 22.22 [ka]

[0558] Example 26: Preparation of 3-(1-oxo-2-oxaspiro[4.4]nonan-3-yl)propyl 4-methylbenzenesulfonate: To a stirred solution of 3-(but-3-en-1-yl)-2-oxaspiro[4.4]nonan-1-one (0.194 g, 1 mmol, 1 equiv.), RuCl stock solution (7.2 mg, 0.035 M in water, 0.035 equiv.), and CHCN (6 mL) was added NaIO (434 mg, 2.04 mmol, 2.04 equiv.) in several portions over 5 minutes at room temperature. The suspension was allowed to stir for an additional 30 minutes at room temperature. The reaction was quenched with saturated aqueous NaSO. The mixture was quenched and the two layers were separated. The aqueous layer was extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. The crude aldehyde The product was used in the next step without further purification.

[0559] The reaction was carried out in oven-dried glassware under a nitrogen atmosphere. To a stirred solution of the crude aldehyde (0.196 g, 1 mmol, 1 equiv.) in anhydrous methanol was added NaBH4 (74 mg, 2.0 mmol, 2 equiv.). was added in one portion to the mixture at 0° C. The reaction mixture was stirred at room temperature for an additional hour and quenched with brine (while cooling in an ice bath). The organic layer was separated and the aqueous layer was washed with ethyl acetate (3×20 mL). The combined organic layers were then dried over MgSO4 and concentrated in vacuo. The alcohol was used in the next step without further purification.

[0560] To a stirred solution of crude alcohol (0.396 g, 2 mmol, 1.0 equiv) and EtN (0.303 g, 3 mmol, 1.5 equiv) in anhydrous dichloromethane was added dropwise a solution of p-TosCl (0.475 g, 2.5 mmol, 1.25 equiv) in dichloromethane at 0° C. The resulting mixture was stirred at 0° C. for 1 h and allowed to stir at room temperature overnight. The reaction mixture was then diluted with dichloromethane (50 mL), washed with 10% HCl, brine, dried over MgSO4, and concentrated in vacuo to give a yellowish oil. This crude product was then purified by flash chromatography (silica gel; ethyl acetate / hexanes, 0% to 40%). Purification gave the desired tosylate. 1 H NMR (400 MHz, CDCl3) δ 7.82 - 7. 71 (m, 2H), 7.35 (m, 2H), 4.37 - 4.23 (m, 1H), 4.06 (qdd, J = 10.0, 6.7, 5.2 Hz, 2H), 2.45 (s, 3H), 2.15 (m, 2H), 1.92 - 1.50 (m, 12H); 13 C NMR (101 MHz, CDCl3) δ 182.29, 145.03, 133.05, 130.04, 128.00, 76.90, 69.91, 50.24, 43.20, 37.53, 36.92, 31.74, 25.59, 25.49, 25.37, 21.76.

[0561] The following compound is 4-methylbenzenesulfonic acid 3-(1-oxo-2-oxaspiro[4.4]nona) The compounds can be prepared by the procedure of (3-methyl-3-phenyl-propyl). Those skilled in the art would know how to substitute the appropriate reagents, starting materials, and purification methods known to those skilled in the art to prepare the compounds presented herein. [ka]

[0562] Example 27 Preparation of 3-(1-oxo-2-oxaspiro[4.5]decan-3-yl)propyl 4-methylbenzenesulfonate: 4-methylbenzenesulfonate was prepared by the same procedure as in Example 27 except that 3-(but-3-en-1-yl)-2-oxaspiro[4.5]decan-1-one was replaced with 3-(but-3-en-1-yl)-2-oxaspiro[4.4]nonan-1-one. 3-(1-oxo-2-oxaspiro[4.4]nonan-3-yl)propyl methylbenzenesulfonate The title compound was prepared according to the procedure described above. 1 H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 4.39 - 4.26 (m, 1H), 4.16 - 3.97 (m, 2H), 2.44 (s, 3H), 2.32 (dt, J = 15.8, 7.9 Hz, 1H), 1.98 - 1.13 (m, 16H); 13 C NMR (101 MHz, CDCl3) δ 181.36, 145.03, 133.05, 130.03, 127.99, 76.46, 69.91, 44.97, 39.54, 34.40, 32.15, 31.68, 25.37, 25.36, 22.25, 22.18, 21.76 [ka]

[0563] Example 28: Preparation of 5-(2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one: 5-(2-bromoethyl)-3,3-diethyldihydrofuran-2(3H)-one Hydrofuran-2(3H)-one (0.400 g, 1.53 mmol, 1 equiv.), acetonitrile (8 mL), 2-benzo[a]pyrrolidone (2H)-one (0.400 g, 1.53 mmol, 1 equiv.), Octahydropyrrolo[3,4-c]pyrrole (0.340 g, 1.68 mmol, 1.1 equiv.) and KCO (1.05 g , 7.65 mmol, 5 equiv) was heated and stirred at 80° C. for 24 h. The resulting mixture was then filtered and concentrated in vacuo to give a crude residue, which was further purified by column chromatography (methanol / dichloromethane, 0% to 10%). 1 H NMR (400 MHz, CDCl3) δ7.25-7.14 (m, 4H), 7.14-7.06 (m, 1H), 4.38 (m, 1H), 3.46 (s, 2H), 2.64-2.48 (m, 6H), 2.48-2.38 (m, 2H), 2.28-2.13 (m, 4H), 2.02 (dd, J= 6.8, 13.0 Hz, 1H), 1.87-1.59 (m, 3H), 1.58-1.44 (m, 4H), 0.83 (dt, J= 7.3, 21.4 Hz, 6H); MS (LC / MS, M+H + ): m / z 371.2 [ka]

[0564] Example 29: Preparation of 3-(2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one: 3-(2-bromoethyl)-2-oxaspiro[4.5] Decan-1-one and 5-(2-bromoethyl)-3,3-diethyldihydrofuran-2(3H)-one were placed 5-(2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)- The title compound was prepared following the procedure in (ethyl)-3,3-diethyldihydrofuran-2(3H)-one. 1 H NMR (400 MHz, CDCl3) δ7.26-7.17 (m, 4H), 7.17-7.10 (m, 1H), 4.40 (m, 1H), 3.50 (s, 2H), 2.69-2.52 (m, 6H), 2.49 (t, J= 7.4 Hz, 2H), 2.30 (dd, J= 6.3, 12.8 Hz, 1H), 2.27-2.16 (m, 4H), 1.88-1.61 (m, 5H), 1.61-1.45 (m, 4H), 1.44-1.37 (m, 1H), 1.36-1.07 (m, 3H); MS (LC / MS, M+H + ): m / z 383.2 [ka]

[0565] Example 30: Preparation of 3,3-diethyl-5-(2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one: 5-(2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one rol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one (540 mg, 1.46 mmol A mixture of 1,2-dimethyl-3-(2-(2H-pyridinyl)-2-propanol)-4-(4-(2H-pyridinyl)-2-propanol)-4-(2H-pyridinyl)-2-propanol (1 equiv., 1 equiv.), Pd / C (108 mg, 20 wt%), and MeOH (5.0 mL) was stirred for 3 days under 1 atm of H (balloon filled) at 22° C. The mixture was filtered through a plug of Celite, washed with MeOH (50 mL), and concentrated in vacuo to give the crude product, which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ4.42 (m, 1H), 2.83 (b, 1H), 2.69 (m, 2H), 2.55-2.39 (m, 4H), 2.33 (m, 2H), 2.26 (t, J= 7.0 Hz, 2H), 2.14 (dd, J= 1.7, 9.0 Hz, 2H), 1.91 (dd, J= 6.7, 13.0 Hz, 1H), 1.71-1.47 (m, 3H), 1.45-1.32 (m, 4H), 0.69 (dt, J= 7.4, 19.2 Hz, 6H); MS (LC / MS, M+H + ): m / z 281.2 [ka]

[0566] Example 31: 3-(2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxa Preparation of spiro[4.5]decan-1-one: 3-(2-(5-benzylhexahydropyrrolo[3,4-c]pyrrole) The title compound was prepared by following the procedure for 3,3-diethyl-5-(2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one, except replacing 5-(2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one with 5-(2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one. 1 H NMR (400 MHz, CDCl3) δ4.55 (m, 1H), 2.94 (m, 2H), 2.82-2.63 (m, 5H), 2.63-2.46 (m, 3H), 2.42 (m, 2H), 1.97-1.60 (m, 8H), 1.59-1.43 (m, 3H), 1.43-1.22 (m, 4H); ): m / z 293.2 [ka]

[0567] Example 32: 3,3-diethyl-5-(2-(5-(pyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrolidone) Preparation of 3,3-diethyl-5-(2-(hexyl-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one A solution of dihydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one (0.180 g, 0.642 mmol, 1 equiv.), 1-butanol (6.4 mL), 4-bromopyridine hydrochloride (0.249 g, 1.28 mmol, 2.0 equiv.), and triethylamine (0.325 g, 3.21 mmol, 5 equiv.) was heated and stirred at 120° C. for 24 hours. The resulting solution was concentrated in vacuo to give a crude residue, which was further purified by HPLC. Column chromatography (methanol / dichloromethane, 0%–10%, w / 0.1% NH4OH) ) and purified. 1 H NMR (400 MHz, CDCl3) δ8.13 (dd, J= 1.4, 3.5 Hz, 2H), 6.32 (dd, J= 1.5, 3.5 Hz, 2H), 4.37 (m, 1H), 3.45 (dd, J= 8.3, 9.2 Hz, 2H), 3.12 (dt, J= 3.4, 9.9 Hz, 2H), 2.90 (m, 2H), 2.62 (m, 2H), 2.50 (t, J= 7.4 Hz, 2H), 2.46 (m, 2H), 2.02 (dd, J= 6.8, 13.0 Hz, 1H), 1.85-1.61 (m, 3H), 1.52 (q, J= 7.5 Hz, 4H), 0.82 (dt, J= 5.7, 13.2 Hz, 6H); MS (LC / MS, M+H + ): m / z 358.2 [ka]

[0568] Example 33: 3-(2-(5-(pyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl) Preparation of 3-(2-(hexahydroxyethyl)ethyl)-2-oxaspiro[4.5]decan-1-one: The title compound was prepared by the procedure Dropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one and , 3,3-diethyl-5-(2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydr Except for replacing 2-(5-pyridin-4-yl)-3,3-diethyl-5-(2-(5-pyridin-4-yl)-2(H)-one, Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one It was prepared according to the procedure. 1 H NMR (400 MHz, CDCl3) δ8.13 (d, J= 5.6 Hz, 2H), 6.33 (d, J= 6.2 Hz, 2H), 4.38 (m, 1H), 3.46 (m, 2H), 3.13 (dt, J= 3.7, 10.0 Hz, 2H), 2.91 (m, 2H), 2.68-2.57 (m, 2H), 2.55-2.41 (m, 4H), 2.28 (dd, J= 6.2, 12.8 Hz, 1H), 1.95-1.43 (m, 9H), 1.43-1.33 (m, 1H), 1.32-1.04 (m, 3H); MS (LC / MS, M+H + ): m / z 370.2. [ka]

[0569] Example 34: Preparation of 1-(benzyloxy)-2-bromobenzene: To a solution of 2-bromophenol (1.0 g, 5.78 mmol, 1.01 equiv) in acetonitrile (14 mL) was added benzyl bromide (0.975 g, 5.7 mmol, , 1.0 equiv) and K2CO3 (1.09 g, 7.87 mmol, 1.38 equiv) were added. The mixture was allowed to stir at 22 °C overnight. The reaction was filtered and concentrated in vacuo to give a crude residue which was further purified by column chromatography (hexane / ethyl acetate, 0% to 10%). 1 H NMR (400 MHz, CDCl3) δ7.60 (dd, J= 1.6, 7.8 Hz, 1H), 7.51 (m, 2H), 7.42 (t, J= 7.6 Hz, 2H), 7.35 (m, 1H), 7.29-7.22 (m, 1H), 6.97 (dd, J= 1.2 8.3 Hz, 1H), 6.88 (td, J= 1.3, 7.6 Hz, 1H), 5.19 (s, 2H). [ka]

[0570] Example 35: Preparation of 1-(benzyloxy)-3-bromobenzene: 3-Bromophenol and 2-bromophenol The procedure for 1-(benzyloxy)-2-bromobenzene was repeated except that 2-bromophenol was substituted. The title compound was prepared accordingly: 1 H NMR (400 MHz, CDCl3) δ7.50-7.34 (m, 5H), 7.23-7.10 (m, 3H), 6.95 (m, 1H), 5.08 (s, 2H). [ka]

[0571] Example 36: Preparation of 1-(benzyloxy)-4-bromobenzene: 4-Bromophenol and 2-bromophenol The procedure for 1-(benzyloxy)-2-bromobenzene was repeated except that 2-bromophenol was substituted. The title compound was prepared accordingly: 1H NMR (400 MHz, CDCl3) δ7.51-7.33 (m, 7H), 6.91 (d, J= 9.1 Hz, 2H), 5.08 (s, 2H). [ka]

[0572] Example 37: Preparation of 4-(2-bromophenyl)morpholine: The reaction was carried out in oven-dried glassware under a nitrogen atmosphere. 1,2-Dibromobenzene (1.0 g, 4.24 mmol, 1.0 equiv.) and morpholine (0.370 g, 4.24 mmol, 1.0 equiv.) in anhydrous toluene (10.6 mL), The following were added in this order: Pd2(dba)3 (0.097 g, 5 mol%), BINAP (0.197 g, 7.5 mol%), and NaOtBu (0.448 g, 5.08 mmol, 1.2 equiv). The resulting mixture was stirred at 80 °C under a N2 sweep overnight. The reaction mixture was cooled to 22 °C and then filtered through a Celite plug. The filtrate was collected and concentrated in vacuo to give the crude residue, which was further purified by column chromatography (hexane / ethyl acetate, 0% to 20%). 1 H NMR (400 MHz, CDCl3) δ7.55 (dd, J= 1.5, 7.9 Hz, 1H), 7.25 (td, J= 1.4, 7.8 Hz, 1H), 7.00 (dd, J= 1.4, 8.0 Hz, 1H), 6.89 (td, J= 1.4, 7.7 ): m / z 241.9, 243.8 [ka]

[0573] Example 38: Preparation of tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate: The reaction was carried out in oven-dried glassware under a nitrogen atmosphere. 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester hemioxylate (0.300 g, 1.23 m To a solution of Pd(dba) (0.030 g, 2.5 mol%), BINAP (0.0450 g, 1.0 eq.), and bromobenzene (0.176 g, 1.12 mmol, 1.0 eq.) in anhydrous toluene (14 mL) was added the following in the following order: Pd(dba) (0.030 g, 2.5 mol%), BINAP (0.0450 g, 1.0 eq.), and bromobenzene (0.176 g, 1.12 mmol, 1.0 eq.). , 1.5 / Pd), triethylamine (0.125 g, 1.23 mmol, 1.1 equiv.), and NaOtBu (0.355 g, 3.69 mmol, 3.3 equiv.). The resulting mixture was stirred at 110 °C under a N sweep overnight. The reaction mixture was cooled to 22 °C and then filtered through a plug of Celite. The filtrate was collected and concentrated in vacuo to give a crude residue, which was further purified by column chromatography (hexane / ethyl acetate, 0% to 30%). 1 H NMR (400 MHz, CDCl3) δ7.21 (m, 2H), 6.93 (m, 1H), 6.74 (d, J= 8.3 Hz, 2H), 4.23 (s, 4H), 4.19 (s, 4H), 1.38 (s, 9H); MS (LC / MS, M+H) + ): m / z 275.2 [ka]

[0574] Example 39: 6-(pyridin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert- Preparation of butyl: 4-Bromopyridine hydrochloride and 2 equivalents of triethylenediamine, replacing bromobenzene. 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carbohydrate was used, except that ethylamine was used. The title compound was prepared following the procedure for tert-butyl phosphate.1 H NMR (400 MHz, CDCl3) δ8.09 (d, J= 6.5 Hz, 2H), 6.28 (d, J= 6.7 Hz, 2H), 4.12 (s, 4H), 4.06 (s, 4H), 1.37 (s, 9H); MS (LC / MS, M+H + ): m / z 276.2 [ka]

[0575] Example 40: Preparation of tert-butyl 6-(3-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate: 4-Bromo-3-methylpyridine hydrochloride was prepared by the same procedure as in Example 1 except that 4-bromo-3-methylpyridine hydrochloride and 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate were used, replacing bromobenzene and using 2 equivalents of triethylamine. The title compound was prepared following the procedure for tert-butyl butane-2-carboxylate. 1 H NMR (400 MHz, CDCl3) δ8.05 (d, J= 5.5 Hz, 1H), 7.94 (s, 1H), 6.12 (d, J= 5.4 Hz, 1H), 4.08 (s, 4H), 4.02 (s, 4H), 2.10 (s, 3H) 1.37 (s, 9H); MS (LC / MS, M+H + ): m / z 290.2 [ka]

[0576] Example 41 Preparation of tert-butyl 6-(2-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate: The title compound was prepared by following the procedure for tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except replacing 4-bromo-2-methylpyridine with bromobenzene. 1H NMR (400 MHz, CDCl3) δ8.05 (d, J= 5.5 Hz, 1H), 6.07-6.00 (m, 2H), 4.02 (s, 4H), 3.95 (s, 4H), 2.35 (s, 3H), 1.37 (s, 9H); MS (LC / MS, M+H + ): m / z 290.2 [ka]

[0577] Example 42 Preparation of tert-butyl 6-(2,6-dimethylpyridin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate: The title compound was prepared by following the procedure for tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except replacing 4-bromo-2,6-dimethylpyridine with bromobenzene. 1 H NMR (400 MHz, CDCl3) δ 5.90 (s, 2H), 4.01 (s, 4H), 3.92 (s, 4H), 2.32 (s, 6H), 1.37 (s, 9H); ): m / z 304.2 [ka]

[0578] Example 43: 5-(3-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)- Preparation of tert-butyl carboxylate: tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate. The title compound was prepared following the procedure for tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except that hemioxylate was substituted, 4-bromo-3-methylpyridine hydrochloride was substituted for bromobenzene, and 2 equivalents of triethylamine were used. . 1 H NMR (400 MHz, CDCl3) δ8.03 (d, J= 5.8 Hz, 1H), 7.97 (s, 1H), 6.37 (d, J= 5.8 Hz, 1H), 3.64-3.44 (m, 4H), 3.33-3.10 (m, 4H), 2.86 (b, 2H), 2.24 (s, 3H), 1.38 (s, 9H); MS (LC / MS, M+H + ): m / z 304.2 [ka]

[0579] Example 44: 5-(2-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)- Preparation of tert-butyl carboxylate: tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate. 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carbohydrate, except for replacing hemioxylate and 4-bromo-2-methylpyridine with bromobenzene. The title compound was prepared following the procedure for tert-butyl phosphate. 1H NMR (400 MHz, CDCl3) δ7.99 (d, J= 5.9 Hz, 1H), 6.13 (d, J= 2.2 Hz, 1H), 6.09 (dd, J= 2.4, 5.8 Hz, 1H), 3.54 (dd, J= 7.2, 11.2 Hz, 2H), 3.42 (b, 2H), 3.21 (m, 1H), 3.17-2.99 (m, 3H), 2.88 (b, 2H), 2.32 (s, 3H), 1.36 (s, 9H); MS (LC / MS, M+H + ): m / z 304.2 [ka]

[0580] Example 45 Preparation of tert-butyl 5-(2,6-dimethylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: Preparation of tert-butyl 5-(2,6-dimethylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate by the same procedure as in Example 45, except replacing tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate with 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester hemioxylate and 4-bromo-2,6-dimethylpyridine with bromobenzene. The title compound was prepared following the procedure for tert-butyl carboxylate. 1 H NMR (400 MHz, CDCl3) δ5.98 (s, 2H), 3.52 (m, 2H), 3.41 (m, 2H), 3.21 (m, 1H), 3.16-2.99 (m, 3H), 2.86 (b, 2H), 2.29 (s, 6H), 1.34 (s, 9H); MS (LC / MS, M+H + ): m / z 318.2. [ka]

[0581] Example 46: 5-(o-Tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert- Preparation of butyl: The title compound was prepared by following the procedure for tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except substituting tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate for 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester hemioxylate and 1-bromo-2-methylbenzene for bromobenzene. 1 H NMR (400 MHz, CDCl3) δ7.18-7.10 (m, 2H), 6.96-6.89 (m, 2H), 3.69 (b, 2H), 3.36 (b, 2H), 3.18 (b, 2H), 3.05 (b, 2H), 2.91 (b, 2H), 2.33 (s, 3H), 1.52 (s, 9H); MS (LC / MS, M+H + ): m / z 303.2 [ka]

[0582] Example 47: 5-(m-Tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert- Preparation of butyl: The title compound was prepared by following the procedure for tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except substituting tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate for 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester hemioxylate and 1-bromo-3-methylbenzene for bromobenzene. 1H NMR (400 MHz, CDCl3) δ7.17 (t, J= 7.8 Hz, 1H), 6.59 (d, J= 7.5 Hz, 1H), 6.46-6.37 (m, 2H), 3.68 (b, 2H), 3.52 (b, 2H), 3.42 (m, 1H), 3.29 (m, 1H), 3.23 (m, 2H), 2.97 (b, 2H), 2.38 (s, 3H), 1.54 (s, 9H); MS (LC / MS, M+H + ): m / z 303.2 [ka]

[0583] Example 48: 5-(p-Tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert- Preparation of butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except that tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate was replaced with tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate, and tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate was prepared by substituting tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate for tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate, and 1-bromo-4-methylbenzene for bromobenzene. The title compound was prepared according to the procedure. 1 H NMR (400 MHz, CDCl3) δ7.09 (d, J= 8.1 Hz, 2H), 6.52 (d, J= 8.5 Hz, 2H), 3.68 (m, 2H), 3.57 (b, 2H), 3.42 (m, 1H), 3.28 (m, 1H), 3.21 (m, 2H), 3.00 (b, 2H), 2.30 (s, 3H), 1.51 (s, 9H); MS (LC / MS, M+H + ): m / z 303.2. [ka]

[0584] Example 49: Preparation of tert-butyl 5-(2-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate and 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester hemioxide. The title compound was prepared following the procedure for tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except substituting the hemioxylate and substituting 1-bromo-2-methoxybenzene for bromobenzene. 1 H NMR (400 MHz, CDCl3) δ6.91-6.78 (m, 3H), 6.76-6.67 (m, 1H), 3.80 (s, 3H), 3.61 (b, 2H), 3.45 (b, 2H), 3.40-3.22 (m, 2H), 3.14 (b, 2H), 2.90 (b, 2H), 1.46 (s, 9H); MS (LC / MS, M+H + ): m / z 319.2. [ka]

[0585] Example 50: Preparation of tert-butyl 5-(3-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate and 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester hemioxide. The title compound was prepared following the procedure for tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except substituting the hemioxylate and substituting 1-bromo-3-methoxybenzene for bromobenzene. 1H NMR (400 MHz, CDCl3) δ7.13 (t, J= 8.1 Hz, 1H), 6.29 (dd, J= 2.2, 8.1 Hz, 1H), 6.18 (dd, J= 1.8, 8.1 Hz, 1H), 6.10 (t, J= 2.2 Hz, 1H), 3.79 (s, 3H), 3.63 (m, 2H), 3.50 (m, 2H), 3.37 (m, 1H), 3.30-3.11 (m, 3H), 2.95 (b, 2H), 1.48 (s, 9H); MS (LC / MS, M+H + ): m / z 319.2 [ka]

[0586] Example 51: Preparation of tert-butyl 5-(4-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate and 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester hemioxide. The title compound was prepared following the procedure for tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except substituting the hemioxylate and substituting 1-bromo-4-methoxybenzene for bromobenzene. 1 H NMR (400 MHz, CDCl3) δ6.83 (d, J= 9.0 Hz, 2H), 6.50 (d, J= 9.0 Hz, 2H), 3.73 (s, 3H), 3.62 (m, 2H), 3.48-3.29 (m, 3H), 3.23 (m, 1H), 3.12 (dd, J= 3.5, 9.3 Hz, 2H), 2.93 (b, 2H), 1.46 (s, 9H); MS (LC / MS, M+H + ): m / z 319.2. [ka]

[0587] Example 52: Preparation of tert-butyl 5-(2-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate and 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester hemioxy Hemioxylate and 2-bromobenzonitrile and bromobenzene The title compound was prepared following the procedure for tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except where replaced. 1 H NMR (400 MHz, CDCl3) δ7.39 (dd, J= 1.6, 7.8 Hz, 1H), 7.30 (m, 1H), 6.66 (t, J= 7.5 Hz, 1H), 6.59 (d, J= 8.5 Hz, 1H), 3.80 (m, 2H), 3.61 (m, 2H), 3.52 (m, 1H), 3.44 (m, 1H), 3.28 (m, 2H), 2.95 (b, 2H), 1.42 (s, 9H); MS (LC / MS, M+H + ): m / z 314.2. [ka]

[0588] Example 53: Preparation of tert-butyl 5-(3-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate and 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester hemioxy Hemioxylate and 3-bromobenzonitrile and bromobenzene The title compound was prepared following the procedure for tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except where replaced. 1 H NMR (400 MHz, CDCl3) δ7.22 (m, 1H), 6.88 (d, J= 7.5 Hz, 1H), 6.71-6.64 (m, 2H), 3.62 (m, 2H), 3.49 (m, 2H), 3.31 (m, 1H), 3.23 (m, 1H), 3.16 (dd, J= 3.9, 9.7 Hz, 2H), 2.99 (b, 2H), 1.42 (s, 9H); MS (LC / MS, M+H + ): m / z 314.2 [ka]

[0589] Example 54: Preparation of tert-butyl 5-(4-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate and 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester hemioxy Hemioxylate and 4-bromobenzonitrile and bromobenzene The title compound was prepared following the procedure for tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except where replaced. 1 H NMR (400 MHz, CDCl3) δ7.35 (d, J= 8.9 Hz, 2H), 6.41 (d, J= 8.9 Hz, 2H), 3.57 (m, 2H), 3.50 (m, 2H), 3.26 (m, 1H), 3.21-3.06 (m, 3H), 2.95 (b, 2H), 1.37 (s, 9H); MS (LC / MS, M+H + ): m / z 314.2. [ka]

[0590] Example 55: Preparation of tert-butyl 5-(2-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: Hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carbo The title compound was prepared by following the procedure for tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except substituting tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate for 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester hemioxylate and substituting 1-(benzyloxy)-2-bromobenzene for bromobenzene. 1 H NMR (400 MHz, CDCl3) δ7.36-7.23 (m, 4H), 7.20 (m, 1H), 6.79 (m, 2H), 6.72 (m, 1H), 6.65 (m, 1H), 4.94 (s, 2H), 3.50 (b, 2H), 3.33 (m, 2H), 3.27-3.02 (m, 3H), 2.76 (b, 2H), 1.35 (s, 9H); MS (LC / MS, M+H + ): m / z 395.2. [ka]

[0591] Example 56: Preparation of tert-butyl 5-(3-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: Hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carbo The title compound was prepared by following the procedure for tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except substituting tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate for 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester hemioxylate and substituting 1-(benzyloxy)-3-bromobenzene for bromobenzene. 1 H NMR (400 MHz, CDCl3) δ7.47 (m, 2H), 7.41 (t, J= 7.6 Hz, 2H), 7.34 (m, 1H), 7.17 (t, J= 8.2 Hz, 1H), 6.39 (dd, J= 1.7, 8.0 Hz, 1H), 6.23 (m, 2H), 5.08 (s, 2H), 3.66 (m, 2H), 3.53 (m, 2H), 3.40 (m, 1H), 3.33-3.14 (m, 3H), 2.99 (b, 2H), 1.49 (s, 9H); MS (LC / MS, M+H) + ): m / z 395.2. [ka]

[0592] Example 57: Preparation of tert-butyl 5-(4-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: Hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carbo The title compound was prepared by following the procedure for tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except substituting tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate for 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester hemioxylate and substituting 1-(benzyloxy)-4-bromobenzene for bromobenzene. 1 H NMR (400 MHz, CDCl3) δ7.46 (m, 2H), 7.40 (t, J= 7.8 Hz, 2H), 7.34 (m, 1H), 6.95 (d, J= 9.0 Hz, 2H), 6.54 (d, J= 8.8 Hz, 2H), 5.03 (s, 2H), 3.67 (b, 2H), 3.47 (b, 2H), 3.40 (m, 1H), 3.28 (m, 1H), 3.18 (dd, J= 3.4, 9.3Hz, 2H), 2.99 (b, 2H), 1.50 (s, 9H); ): m / z 395.2. [ka]

[0593] Example 58: Preparation of tert-butyl 5-(2-morpholinophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: Reaction of tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate with tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester hemiester Hemioxylate replacement and 4-(2-bromophenyl)morpholine 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except for replacing the bromobenzene. The title compound was prepared following the procedure for tert-butyl carboxylate. 1 H NMR (400 MHz, CDCl3) δ7.04-6.89 (m, 3H), 6.85 (d, J= 7.8 Hz, 1H), 3.85 (t, J= 4.5 Hz, 4H), 3.62 (b, 2H), 3.48-3.21 (m, 6H), 3.04 (t, J= 4.5 Hz, 4H), 2.92 (b, 2H), 1.48 (s, 9H); MS (LC / MS, M+H + ): m / z 374.2. [ka]

[0594] Example 59: Preparation of 2-benzyl-5-(2-isopropylphenyl)octahydropyrrolo[3,4-c]pyrrole: Replacing 2-benzyloctahydropyrrolo[3,4-c]pyrrole with 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester hemioxylate The procedure for tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate was followed, except that 1-bromo-2-isopropylbenzene was replaced with bromobenzene. The compound was prepared. The product was purified by column chromatography (dichloromethane / MeOH, 0% to 5%). 1 H NMR (400 MHz, CDCl3) δ7.54-7.33 (m, 6H), 7.32-7.11 (m, 3H), 3.77 (s, 2H), 3.65 (sept, J= 6.9 Hz, 1H), 3.15 (m, 2H), 3.09-2.99 (m, 4H), 2.96 (m, 2H), 2.47 (dd, J= 4.9, 8.8 Hz, 2H), 1.39 (d, J= 6.9 Hz, 9H); MS (LC / MS, M+H + ): m / z 321.2. [ka]

[0595] Example 60 Preparation of 2-phenyl-2,6-diazaspiro[3.3]heptane trifluoroacetate: To a solution of tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate (0.054 g, 0.196 mmol, 1 equiv) in dichloromethane (1 mL) at 0° C. was added trifluoroacetic acid (1 mL). The reaction was stirred at 22° C. for 30 min, then diluted with MeOH and concentrated in vacuo to give the product as the TFA salt. MS (LC / MS, M+H + ): m / z 175.2. [ka]

[0596] Example 61: 2-(pyridin-4-yl)-2,6-diazaspiro[3.3]heptane ditrifluoroacetate Preparation of the acid salt: 6-(pyridin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert- The title compound was prepared by following the procedure for 2-phenyl-2,6-diazaspiro[3.3]heptane trifluoroacetate, except replacing butyl with tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate. MS (LC / MS, M+H + ): m / z 176.2. [ka]

[0597] Example 62: 2-(3-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptane dithionite Preparation of tert-butyl 6-(3-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate: Prepare 2-phenyl-2,6-diazaspiro[3.3]heptane triflate except that tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate was replaced with tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate. The title compound was prepared according to the procedure for the difluoroacetate salt. MS (LC / MS, M+H + ): m / z 190.2. [ka]

[0598] Example 63: 2-(2-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptane dithionite Preparation of tert-butyl 6-(2-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate: Prepare 2-phenyl-2,6-diazaspiro[3.3]heptane triflate except that tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate was replaced with tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate. The title compound was prepared according to the procedure for the difluoroacetate salt. MS (LC / MS, M+H + ): m / z 190.2. [ka]

[0599] Example 64: Preparation of 2-(2,6-dimethylpyridin-4-yl)-2,6-diazaspiro[3.3]heptane tert-butyl 6-(2,6-dimethylpyridin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate and tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate The title compound was prepared following the procedure for 2-phenyl-2,6-diazaspiro[3.3]heptane trifluoroacetate, except for the substitution. MS (LC / MS, M+H + ): m / z 204.2. [ka]

[0600] Example 65: Preparation of 2-(3-methylpyridin-4-yl)octahydropyrrolo[3,4-c]pyrrole ditrifluoroacetate: Reaction of tert-butyl 5-(3-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate with 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate 2-phenyl-2,6-diazaspiro[3.3]hepta, except that tert-butyl carboxylate was replaced The title compound was prepared according to the procedure for the trifluoroacetate salt of benzophenone. MS (LC / MS, M+H +): m / z 204.2. [ka]

[0601] Example 66: Preparation of 2-(2-methylpyridin-4-yl)octahydropyrrolo[3,4-c]pyrrole ditrifluoroacetate: Reaction of tert-butyl 5-(2-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate with 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate 2-phenyl-2,6-diazaspiro[3.3]hepta, except that tert-butyl carboxylate was replaced The title compound was prepared according to the procedure for the trifluoroacetate salt of benzophenone. MS (LC / MS, M+H + ): m / z 204.2. [ka]

[0602] Example 67: Preparation of 2-(2,6-dimethylpyridin-4-yl)octahydropyrrolo[3,4-c]pyrrole: 5-(2,6-dimethylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carbohydrate tert-Butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert- The title compound was prepared following the procedure for 2-phenyl-2,6-diazaspiro[3.3]heptane trifluoroacetate, except for replacing butyl. MS (LC / MS, M+H + ): m / z 218.2. [ka]

[0603] Example 68: Preparation of 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole: 5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole tert-Butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (0.490 g, 1.62 mmol, 1 To a solution of 100 equivalents of 1,2-dichloromethane (4 mL) was added trifluoroacetic acid (2 mL) at 0° C. The reaction was stirred at 22° C. for 30 minutes, then diluted with MeOH and concentrated in vacuo to give the product as the TFA salt. The salt was then suspended in saturated NaHCO3 solution and the free product was extracted with methylene chloride (3 x 15 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The product was obtained as the free base: MS (LC / MS, M+H + ): m / z 203.2. [ka]

[0604] Example 69: Preparation of 2-(m-tolyl)octahydropyrrolo[3,4-c]pyrrole: 5-(m-tolyl)hexahydropyrrolo[3,4-c]pyrrole tert-Butyl 2-hydroxypyrrolo[3,4-c]pyrrole-2(1H)-carboxylate and 5-(m-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate The title compound was prepared following the procedure for 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole, except for substituting tert-butyl octahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate. MS (LC / MS, M+H + ): m / z 203.2. [ka]

[0605] Example 70: Preparation of 2-(p-tolyl)octahydropyrrolo[3,4-c]pyrrole: 5-(p-tolyl)hexahydropyrrolo[3,4-c]pyrrole The title compound was prepared following the procedure for 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole, except for replacing hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate with tert-butyl 5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate. MS (LC / MS, M+H + ): m / z 203.2 [ka]

[0606] Example 71: Preparation of 2-(2-methoxyphenyl)octahydropyrrolo[3,4-c]pyrrole: Replacing tert-butyl 5-(2-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate with tert-butyl 5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate Follow the procedure for 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole except for the substitution The compound was prepared. MS (LC / MS, M+H + ): m / z 219.2. [ka]

[0607] Example 72: Preparation of 2-(4-methoxyphenyl)octahydropyrrolo[3,4-c]pyrrole: Replacing tert-butyl 5-(4-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate with tert-butyl 5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate Follow the procedure for 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole except for the substitution The compound was prepared. MS (LC / MS, M+H + ): m / z 219.2. [ka]

[0608] Example 73: Preparation of 3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile: 5-(3-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl 5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl The procedure for 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole was followed except for replacing The title compound was prepared. MS (LC / MS, M+H + ): m / z 214.2 [ka]

[0609] Example 74: Preparation of 4-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile: 5-(4-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl 5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl The procedure for 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole was followed except for replacing The title compound was prepared. MS (LC / MS, M+H + ): m / z 214.2. [ka]

[0610] Example 75 Preparation of 2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile hydrochloride: To a solution of tert-butyl 5-(2-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (0.408 g, 1.30 mmol, 1 equiv) in MeOH (1 mL) at 0° C. was added 1 M methanolic HCl (3 mL). The reaction was stirred at 22° C. overnight, then diluted with MeOH and concentrated in vacuo to give The product was obtained as the HCl salt. MS (LC / MS, M+H + ): m / z 214.2. [ka]

[0611] Example 76: Preparation of 2-(3-methoxyphenyl)octahydropyrrolo[3,4-c]pyrrole hydrochloride 5-(3-Methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert- The title compound was prepared following the procedure for 2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile hydrochloride, except butyl was replaced with tert-butyl 5-(2-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate. MS (LC / MS, M+H + ): m / z 219.2. [ka]

[0612] Example 77: 2-(2-(benzyloxy)phenyl)octahydropyrrolo[3,4-c]pyrrole salt Preparation of the acid salt: The title compound was prepared by following the procedure for 2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile hydrochloride, except replacing tert-butyl 5-(2-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate with tert-butyl 5-(2-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate. MS (LC / MS, M+H + ): m / z 295.2. [ka]

[0613] Example 78: 2-(3-(benzyloxy)phenyl)octahydropyrrolo[3,4-c]pyrrole salt Preparation of the acid salt: The title compound was prepared by following the procedure for 2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile hydrochloride, except replacing tert-butyl 5-(3-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate with tert-butyl 5-(2-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate. MS (LC / MS, M+H + ): m / z 295.2. [ka]

[0614] Example 79: 2-(4-(benzyloxy)phenyl)octahydropyrrolo[3,4-c]pyrrole salt Preparation of the acid salt: The title compound was prepared by following the procedure for 2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile hydrochloride, except replacing tert-butyl 5-(4-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate with tert-butyl 5-(2-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate. MS (LC / MS, M+H+ ): m / z 295.2. [ka]

[0615] Example 80 Preparation of 4-(2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)morpholine hydrochloride: The title compound was prepared by following the procedure for 2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile hydrochloride, except replacing tert-butyl 5-(2-morpholinophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate with tert-butyl 5-(2-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate. MS (LC / MS, M+H + ): m / z 274.2. [ka]

[0616] Example 81: Preparation of 2-(2-isopropylphenyl)octahydropyrrolo[3,4-c]pyrrole: To a dry round-bottom flask was added 0.04 g of 10% Pd / C (20 wt%), wetted with a small amount of ethyl acetate. A solution of 2-benzyl-5-(2-isopropylphenyl)octahydropyrrolo[3,4-c]pyrrole (0.20 g, 0.624 mmol, 1 equiv.) in MeOH (2.1 mL) was then slowly added to the round-bottom flask containing the Pd / C. The system was then flushed three times with H2 using a balloon filled with H2. The reaction mixture was stirred at room temperature for 5 days under 1 atm of H2. The Pd / C was filtered through a plug of Celite. The filtrate was concentrated in vacuo to give a crude oil of 2-(2-isopropylphenyl)octahydropyrrolo[3,4-c]pyrrole, which was carried on to the next step without further purification. MS (LC / MS, M+H + ): m / z 231.2. [ka]

[0617] Example 82: 3-(2-(6-(pyridin-4-yl)-2,6-diazospiro[3.3]heptan-2-yl)ethyl Preparation of 3-(2-bromoethyl)-2-oxaspiro[4.5]decan-1-one trifluoroacetate. A mixture of 3-(2-bromoethyl)-2-oxaspiro[4.5]decan-1-one (0.057 g, 0.221 mmol, 1 equiv.), acetonitrile (2 mL), 2-(pyridin-4-yl)-2,6-diazaspiro[3.3]heptane ditrifluoroacetate (0.098 g, 0.266 mmol, 1.2 equiv.), and K2CO3 (0.153 g, 1.11 mmol, 5 equiv.) was refluxed and stirred for 3 days. The resulting mixture was then filtered and concentrated in vacuo to give a crude residue, which was first purified by column chromatography (methanol / dichloromethane, 0%-10% w / 0.1% NH4OH). The resulting fraction was purified by column chromatography on a C18 column. The mixture was further purified by acetonitrile / H2O, 0% to 100%, w / 0.1% TFA. 1 H NMR (400 MHz, MeOD) δ8.11 (d, J= 7.4 Hz, 2H), 6.67 (d, J= 7.1 Hz, 2H), 4.70-4.17 (b, 9H), 3.44 (m, 2H), 2.54 (dd, J= 6.2, 12.9 Hz, 1H), 2.10-1.99 (m, 1H), 1.98-1.86 (m, 1H), 1.83-1.61 (m, 6H), 1.60-1.44 (m, 3H), 1.43-1.21 (m, 2H); MS (LC / MS, M+H + ): =356.2. [ka]

[0618] Example 83: 3,3-diethyl-5-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl) Preparation of 5-(2-bromoethyl)-3,3-diethyldihydrofuran-2(3H)-one A mixture of furan-2(3H)-one (0.080 g, 0.324 mmol, 1 equiv.), acetonitrile (2 mL), 2-phenyl-2,6-diazaspiro[3.3]heptane trifluoroacetate (0.288 g, 0.389 mmol, 1.2 equiv.), and K2CO3 (0.224 g, 1.62 mmol, 5 equiv.) was refluxed and stirred for 3 days. The resulting mixture was filtered and concentrated in vacuo to give a crude residue, which was first purified by column chromatography (methanol / dichloromethane, 0% to 10%). 1 H NMR (400 MHz, CDCl2H), 2.04 (dd, J= 6.7, 13.0 Hz, 1H), 1.71 (dd, J= 9.4, 13.1 Hz, 1H), 1.67-1.43 (m, 6H), 1.83-1.61 (m, 6H), 0.85 (dt, J= 7.5, 21.9 Hz, 6H); MS (LC / MS, M+H + ): 343.2. [ka]

[0619] Example 84: Preparation of 3-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-2-oxaspiro[4.5]decan-1-one by replacing 3-(2-bromoethyl)-2-oxaspiro[4.5]decan-1-one with 5-(2-bromoethyl)-3,3-diethyldihydrofuran-2(3H)-one Except for 3,3-diethyl-5-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)ethyl) The title compound was prepared following the procedure for (I)dihydrofuran-2(3H)-one. 1H NMR (400 MHz, CDCl3) δ7.13 (m, 2H), 6.67 (t, J= 7.4 Hz, 1H), 6.37 (d, J= 8.5 Hz, 2H), 4.38 (m, 1H), 3.86 (s, 4H), 3.29 (s, 4H), 2.50 (t, J= 7.9 Hz, 2H), 2.30 (dd, J= 6.2, 12.9 Hz, 1H), 1.81-1.45 (m, 9H), 1.45-1.37 (m, 1H), 1.37-1.08 (m, 3H);): m / z 355.2. [ka]

[0620] Example 85: Preparation of 3,3-diethyl-5-(2-(5-(2-isopropylphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one: 2-(2-isopropyl The procedure for 3,3-diethyl-5-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)dihydrofuran-2(3H)-one was followed, except that 2-phenyl-2,6-diazaspiro[3.3]heptane trifluoroacetate was substituted for 3,3-diethyl-5-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)dihydrofuran-2(3H)-one. The title compound was prepared: 1 H NMR (400 MHz, CDCl3) δ7.18 (dd, J= 1.5, 7.4 Hz, 1H), 7.10-6.90 (m, 3H), 4.43 (m, 1H), 3.38 (sept, J= 6.9 Hz, 1H), 3.01-2.84 (m, 4H), 2.83-2.66 (m, 4H), 2.52 (t, J= 6.8 Hz, 2H), 2.19 (m, 2H), 2.06 (dd, J= 6.8, 13.1 Hz, 1H), 1.91-1.67 (m, 3H), 1.63-1.44 (m, 4H), 1.15 (d, J= 6.9 Hz, 6H), 0.86 (dt, J= 7.3, 19.3 Hz, 6H); MS (LC / MS, M+H+ ): m / z 399.2. [ka]

[0621] Example 86: Preparation of 3-(2-(5-(2-isopropylphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one: By replacing 3-(2-bromoethyl)-2-oxaspiro[4.5]decan-1-one with 5-(2-bromoethyl)-3,3-diethyldihydrofuran-2(3H)-one, and 2-(2-isopropylphenyl)octahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl, 3,3-diethyl-5-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)ethoxylate) except that 2-phenyl-2,6-diazaspiro[3.3]heptane trifluoroacetate was replaced with 3,3-diethyl-5-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)ethoxylate). The title compound was prepared according to the procedure for (ethyl)dihydrofuran-2(3H)-one: 1 H NMR (400 MHz, CDCl3) δ7.18 (dd, J= 1.5, 7.0 Hz, 1H), 7.09-6.94 (m, 3H), 4.44 (m, 1H), 3.37 (sept, J= 6.8 Hz, 1H), 2.99-2.83 (m, 4H), 2.82-2.66 (m, 4H), 2.52 (t, J= 7.2 Hz, 2H), 2.32 (dd, J= 6.3, 12.7 Hz, 1H), 2.24-2.12 (m, 2H), 1.93-1.81 (m, 1H), 1.80-1.46 (m, 8H), 1.46-1.37 (m, 1H), 1.37-1.04 (m, 9H) MS (LC / MS, M+H + ): m / z 411.2. [ka]

[0622] Example 87: 3-(2-(5-(3-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2 Preparation of (1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one: 3-(2-bromoethyl)-2- Oxaspiro[4.5]decan-1-one (0.100 g, 0.383 mmol, 1 equiv.), acetonitrile (4 mL), 2-(3-methylpyridin-4-yl)octahydropyrrolo[3,4-c]pyrrole ditrifluoroacetic acid A mixture of salt (0.299 g, 0.766 mmol, 2 equiv.) and K2CO3 (0.264 g, 1.91 mmol, 5 equiv.) was refluxed and stirred for 3 days. The resulting mixture was then filtered and concentrated in vacuo to give the crude residue. The obtained fraction was purified by column chromatography on a C18 column (acetonitrile / H2O, 0% to 100% w / 0.1% NH4OH). The residue was further purified by filtration (methanol / dichloromethane, 0% to 10% w / 0.1% NH4OH). 1 H NMR (400 MHz, CDCl3) δ8.06 (d, J= 18.7 Hz, 2H), 6.49 (d, J= 4.7 Hz, 1H), 4.38 (m, 1H), 3.20 (m, 2H), 3.04 (m, 2H), 2.83-2.66 (m, 4H), 2.47 (m, 2H), 2.35-2.21 (m, 3H), 2.17 (s, 3H), 1.85-1.74 (m, 1H), 1.74-1.40 (m, 8H), 1.40-1.32 (m, 1H), 1.31-1.02 (m, 3H); MS (LC / MS, M+H + ): m / z 384.2. [ka]

[0623] Example 88: Preparation of 3-(2-(5-(2-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one: 2-(2-methylpyridin-4-yl)octahydropyrrolo[3,4-c]pyrrole ditrifluoroacetate and 2-(3-methylpyridin-4-yl)octahydropyrrolo[3,4-c]pyrrole ditrifluoroacetate Diazin-4-yl)octahydropyrrolo[3,4-c]pyrrole ditrifluoroacetate substituted The title compound was prepared following the procedure for 3-(2-(5-(3-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one, with the following exception: 1 H NMR (400 MHz, CDCl3) δ7.99 (d, J= 5.4 Hz, 1H), 6.23-6.07 (m, 2H), 4.35 (m, 1H), 3.40 (t, J= 8.5 Hz, 2H), 3.08 (dt, J= 3.3, 9.9 Hz, 2H), 2.85 (b, 2H), 2.65-2.53 (m, 2H), 2.52-2.36 (m, 4H), 2.32 (s, 3H), 2.25 (dd, J= 6.3, 12.8 Hz, 1H), 1.84-1.39 (m, 9H), 1.39-1.29 (m, 1H), 1.28-1.01 (m, 3H); MS (LC / MS, M+H + ): m / z 384.2 [ka]

[0624] Example 89: Preparation of 3-(2-(5-(2,6-dimethylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one: 2-(2,6-dimethylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl 2-(3-methylpyridin-4-yl)octahydropyrrolo[3,4-c]pyrrole ditrifluoroacetate and 2-(3-methylpyridin-4-yl)octahydropyrrolo[3,4-c]pyrrole ditrifluoroacetate The title compound was prepared following the procedure for 3-(2-(5-(3-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one, except for the substitution: 1 H NMR (400 MHz, CDCl3) δ6.02 (s, 2H), 4.35 (m, 1H), 3.38 (m, 2H), 3.08 (dt, J= 3.1, 9.9 Hz, 2H), 2.84 (b, 2H), 2.68-2.53 (m, 2H), 2.53-2.36 (m, 4H), 2.36-2.17 (m, 7H), 1.84-1.39 (m, 9H), 1.3 8-1.30 (m, 1H), 1.28-0.97 (m, 3H); MS (LC / MS, M+H + ): m / z 398.2. [ka]

[0625] Example 90: Preparation of 3-(2-(6-(3-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-2-oxaspiro[4.5]decan-1-one: The title compound was prepared according to the procedure for 3-(2-(5-(3-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one, except replacing 2-(3-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptane ditrifluoroacetate with 2-(3-methylpyridin-4-yl)octahydropyrrolo[3,4-c]pyrrole ditrifluoroacetate. 1 H NMR (400 MHz, CDCl3) δ8.02 (d, J= 5.2 Hz, 1H), 7.90 (s, 1H), 6.11 (d, J= 5.6 Hz, 1H), 4.38 (m, 1H), 4.06 (s, 4H), 3.29 (s, 4H), 2.49 (t, J= 7.8 Hz, 2H), 2.30 (dd, J= 6.2, 12.9 Hz, 1H), 2.11 (s, 3H), 1.83-1.45 (m, 9H), 1.45-1.37 (m, 1H), 1.37-1.08 (m, 3H); MS (LC / MS, M+H + ): m / z 370.2. [ka]

[0626] Example 91: Preparation of 3-(2-(6-(2-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-2-oxaspiro[4.5]decan-1-one: The title compound was prepared according to the procedure for 3-(2-(5-(3-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one, except replacing 2-(2-methylpyridin-4-yl)-2,6-diazaspiro[3.3]heptane ditrifluoroacetate with 2-(3-methylpyridin-4-yl)octahydropyrrolo[3,4-c]pyrrole ditrifluoroacetate. 1 H NMR (400 MHz, CDCl3) δ8.03 (d, J= 5.4 Hz, 1H), 6.07-5.97 (m, 2H), 4.38 (m, 1H), 3.91 (s, 4H), 3.28 (s, 4H), 2.55-2.41 (m, 2H), 2.34 (s, 3H), 2.30 (dd, J= 6.2, 12.8 Hz, 1H), 1.82-1.45 (m, 9H), 1.45-1.37 (m, 1H), 1.37-1.07 (m, 3H); MS (LC / MS, M+H+ ): m / z 370.2. [ka]

[0627] Example 92: Preparation of 3-(2-(6-(2,6-dimethylpyridin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-2-oxaspiro[4.5]decan-1-one ... by the reaction of 2-(2,6-dimethylpyridin-4-yl)-2,6-diazaspiro[3.3]heptane ditrifluoroacetate with 2-(3-methylpyridin-4-yl)-2-oxaspiro[4.5]decan-1-one. (4-yl)octahydropyrrolo[3,4-c]pyrrole ditrifluoroacetate replacement The title compound was prepared following the procedure for 3-(2-(5-(3-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one, except that a third purification via column chromatography on a C18 column (acetonitrile / water, 0% to 100%, w / 0.1% HCOOH) was required: 1 H NMR (400 MHz, CDCl3) δ5.97 (s, 2H), 4.45 (m, 1H), 4.21 (s, 4H), 3.55 (s, 4H), 2.70 (m, 2H), 2.57 (s, 6H), 2.40 (dd, J= 6.2, 12.7 Hz, 1H), 1.91-1.54 (m, 9H), 1.54-1.45 (m, 1H), 1.45-1.13 (m, 3H); MS (LC / MS, M+H + ): m / z 384.2. [ka]

[0628] Example 93: Preparation of 3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one: 5-(2-bromoethyl)-3,3-diethyl Dihydrofuran-2(3H)-one (0.075 g, 0.301 mmol, 1 equiv.), acetonitrile (3 mL), 2-(o- A mixture of (tolyl)octahydropyrrolo[3,4-c]pyrrole (0.073 g, 0.361 mmol, 1.2 equiv) and N,N-diisopropylethylamine (0.116 g, 0.903 mmol, 3 equiv) was microwaved at 120 °C for 4 h. The resulting solution was concentrated in vacuo to give a crude residue, which was first purified by column chromatography (methanol / dichloromethane, 0% to 10%). 1 H NMR (400 MHz, CDCl3) δ7.15 (m, 2H), 6.96 (m, 2H), 4.50 (m, 1H), 3.08-2.92 (m, 6H), 2.86 (b, 2H), 2.60 (t, J= 6.9 Hz, 2H), 2.37-2.24 (m, ): m / z 371.2. [ka]

[0629] Example 94 Preparation of 3,3-diethyl-5-(2-(5-(m-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one: The title compound was prepared by following the procedure for 3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one, except replacing 2-(m-tolyl)octahydropyrrolo[3,4-c]pyrrole with 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole. 1 H NMR (400 MHz, CDCl3) δ7.13 (t, J= 8.0 Hz, 1H), 6.58 (d, J= 7.4 Hz, 1H), 6.53-6.45 (m, 2H), 4.47 (m, 1H), 3.37 (m, 2H), 3.18 (dt, J= 2.8, 9.4 Hz, 2H), 2.95 (b, 2H), 2.86 (m, 2H), 2.59 (t, J= 7.0 Hz, 2H), 2.41 (dd, J= 4.0, 8.9 Hz, 2H), 2.33 (s, 3H), 2.12 (dd, J= 6.6, 13.0 Hz, 1H), 1.97-1.73 (m, 3H), 1.62 (q, J= 7.5 Hz, 4H), 0.92 (dt, J= 7.5, 14.8 Hz, 6H); MS (LC / MS, M+H m / z 371.2. [ka]

[0630] Example 95 Preparation of 3,3-diethyl-5-(2-(5-(p-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one: The title compound was prepared by following the procedure for 3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one, except replacing 2-(p-tolyl)octahydropyrrolo[3,4-c]pyrrole with 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole. 1 H NMR (400 MHz, CDCl3) δ6.89 (d, J= 8.4 Hz, 2H), 6.45 (d, J= 8.4 Hz, 2H), 4.32 (m, 1H), 3.17 (m, 2H), 2.99 (dt, J= 3.0, 9.2 Hz, 2H), 2.78 (b, 2H), 2.70 (m, 2H), 2.42 (t, J= 6.9 Hz, 2H), 2.42 (dd, J= 4.0, 8.8 Hz, 2H), 2.11 (s, 3H), 2.97 (dd, J= 6.8, 13.0 Hz, 1H), 1.81-1.57 (m, 3H), 1.45 (q, J= 7.2 Hz, 4H), 0.76 (dt, J= 7.5, 14.7 Hz, 6H); MS (LC / MS, M+H + ): m / z 371.2. [ka]

[0631] Example 96: 2-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexyl Preparation of 2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile: 2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile hydrochloride and 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile The procedure for 3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one was repeated, except that pyrrolo[3,4-c]pyrrole was replaced. The title compound was prepared accordingly. 1 H NMR (400 MHz, CDCl3) δ7.45 (dd, J= 1.5, 7.6 Hz, 1H), 7.36 (m, 1H), 6.81-6.68 (m, 2H), 4.45 (m, 1H), 3.62 (m, 2H), 3.45 (td, J= 2.0, 8.6 Hz, 2H), 2.92 (b, 2H), 2.74 (m, 2H), 2.63-2.53 (m, 2H), 2.52-2.46 (m, 2H), 2.11 (dd, J= 6.8, 13.0 Hz, 1H), 1.94-1.70 (m, 3H), 1.58 (qd, J= 2.6, 7.4 Hz, 4H), 0.88 (dt, J= 7.3, 14.8 Hz, 6H); MS (LC / MS, M+H. [ka]

[0632] Example 97: 3-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexyl Preparation of 3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile: 3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)benzonitrile was prepared by the reaction of 3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile with 3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole) but replacing 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole. Pyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one was prepared according to the procedure shown in Table 1. The title compound was prepared. 1 H NMR (400 MHz, CDCl3) δ7.26 (m, 1H), 6.95 (d, J= 7.5 Hz, 1H), 6.82-6.75 (m, 2H), 4.44 (m, 1H), 3.44 (t, J= 8.7 Hz, 2H), 3.15 (dt, J= 3.8, 9.4 Hz, 2H), 2.98 (b, 2H), 2.73 (m, 2H), 2.57 (t, J= 7.0 Hz, 2H), 2.50 (dd, J= 3.1, 9.1 Hz, 2H), 2.10 (dd, J= 6.8, 12.9 Hz, 1H), 1.94-1.70 (m, 3H), 1.59 (q, J= 7.3 Hz, 4H), 0.89 (dt, J= 5.4, 14.9 Hz, 6H); MS (LC / MS, M+H) + ): m / z 382.2. [ka]

[0633] Example 98: 4-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexyl Preparation of 4-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile: 4-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile was prepared by the reaction of 3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole) with 5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole)-2-(hexahydropyrrolo[3,4-c]pyrrole). Pyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one was prepared according to the procedure shown in Table 1. The title compound was prepared. 1 H NMR (400 MHz, CDCl3) δ7.44 (d, J= 8.9 Hz, 2H), 6.54 (d, J= 8.7 Hz, 2H), 4.44 (m, 1H), 3.55 (t, J= 9.0 Hz, 2H), 3.23 (dt, J= 3.6, 9.9 Hz, 2H), 3.00 (b, 2H), 2.72 (m, 2H), 2.64-2.50 (m, 4H), 2.10 (dd, J= 6.7, 13.1 Hz, 1H), 1.94-1.71 (m, 3H), 1.59 (q, J= 7.5 Hz, 4H), 0.89 (dt, J= 5.1, 14.9 Hz, 6H); MS (LC / MS, M+H + ): m / z 382.2. [ka]

[0634] Example 99 Preparation of 3,3-diethyl-5-(2-(5-(2-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one: The title compound was prepared by following the procedure for 3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one, except replacing 2-(2-methoxyphenyl)octahydropyrrolo[3,4-c]pyrrole with 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole. 1H NMR (400 MHz, CDCl3) δ6.83-6.61 (m, 4H), 4.34 (m, 1H), 3.71 (s, 3H), 3.23 (q, J= 7.5 Hz, 2H), 2.86 (m, 2H), 2.72 (b, 2H), 2.58 (b, 2H), 2.44 (m, 2H), 2.31 (dt, J= 3.2, 8.8 Hz, 2H), 1.98 (dd, J= 6.8, 13.1 Hz, 1H), 1.84-1.73 (m, 1H), 1.73-1.58 (m, 2H), 1.47 (qd, J= 1.5, 7.5 Hz, 4H), 0.77 (dt, J= 7.3, 15.8 Hz, 6H); MS (LC / MS, M+H + ): m / z 387.2. [ka]

[0635] Example 100: 3,3-diethyl-5-(2-(5-(3-methoxyphenyl)hexahydropyrrolo[3,4-c] Preparation of pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one: 2-(3-methoxyphenyl) 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole and 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole The title compound was prepared following the procedure for 3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one, except for replacing the methyl group. 1 H NMR (400 MHz, CDCl3) δ7.14 (t, J= 8.2 Hz, 1H), 6.30 (m, 2H), 6.20 (t, J= 2.2 Hz, 1H), 4.46 (m, 1H), 3.79 (s, 3H), 3.38 (t, J= 8.2 Hz, 2H), 3.17 (dt, J= 3.0, 9.5 Hz, 2H), 2.94 (b, 2H), 2.86-2.77 (m, 2H), 2.57 (t, J= 7.1 Hz, 2H), 2.42 (dd, J= 3.9, 9.0 MS (LC / MS, M+H + ): m / z 387.2. [ka]

[0636] Example 101: 3,3-diethyl-5-(2-(5-(4-methoxyphenyl)hexahydropyrrolo[3,4-c] Preparation of pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one: 2-(4-methoxyphenyl) 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole and 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole The title compound was prepared following the procedure for 3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one, except for replacing the methyl group. 1 H NMR (400 MHz, CDCl3) δ6.83 (d, J= 9.0 Hz, 2H), 6.65 (d, J= 9.0 Hz, 2H), 4.46 (m, 1H), 3.76 (s, 3H), 3.28 (m, 2H), 3.10 (dt, J= 3.2, 9.1 Hz, 2H), 2.92 (b, 2H), 2.84 (b, 2H), 2.63-2.51 (m, 2H), 2.39 (dd, J= 4.0, 8.7 Hz, 2H), 2.11 (dd, J= 6.8, 13.0 Hz, 1H), 1.97-1.71 (m, 3H), 1.61 (qd, J= 1.3, 7.4 Hz, 4H), 0.91 (dt, J= 7.3, 14.8 Hz, 6H); MS (LC / MS, M+H + ): m / z 387.2. [ka]

[0637] Example 102: Preparation of 3,3-diethyl-5-(2-(5-(2-morpholinophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one pyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)morpholine hydrochloride and 3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one, except that 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole is replaced The title compound was prepared according to the procedure. 1 H NMR (400 MHz, CDCl3) δ7.05-6.94 (m, 3H), 6.91-6.83 (m, 1H), 4.49 (m, 1H) 3.85 (t, J= 4.7 Hz, 4H), 3.68-3.42 (m, 4H), 3.22-2.84 (m, 10H), 2.61 (b, 2H), 2.30 (b, 1H), 2.19 (dd, J= 6.7, 13.2 Hz, 1H), 2.05-1.90 (m, 1H), 1.84 (dd, J= 9.3, 1 3.2 Hz, 1H), 1.67-1.56 (m, 4H), 0.91 (dt, J= 7.3, 16.5 Hz, 6H); MS (LC / MS, M+H + ): m / z 442.2. [ka]

[0638] Example 103: Preparation of 5-(2-(5-(2-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one: 2-(2-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl (phenyl)octahydropyrrolo[3,4-c]pyrrole hydrochloride and 2-(o-tolyl)octa 3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one, except that hexahydropyrrolo[3,4-c]pyrrole was replaced by The title compound was prepared according to the procedure. 1 H NMR (400 MHz, CDCl3) δ7.46-7.29 (m, 5H), 7.01-6.86 (m, 3H), 6.81 (dd, J= 1.4, 7.7 Hz, 1H), 5.03 (s, 2H), 4.43 (m, 1H), 3.61 (b, 2H), 3.36 (t, J= 10.6 Hz, 2H), 3.17-2.97 (m, 3H), 2.91 (td, J= 5.3, 12.2 Hz, 1H), 2.86-2.73 (m, 2H), 2.58-2.37 (m, 2H), 2.30 (m, 1H), 2.17 (dd, J= 6.7, 13.1 Hz, 1H), 1.92-1.73 (m, 2H), 1.61 (q, J= 7.4 Hz, 4H), 0.91 (dt, J= 7.0, 13.9 Hz, 6H); MS (LC / MS, M+H + ): m / z 463.2. [ka]

[0639] Example 104: Preparation of 5-(2-(5-(3-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one: 2-(3-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl (phenyl)octahydropyrrolo[3,4-c]pyrrole hydrochloride and 2-(o-tolyl)octa 3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one, except that hexahydropyrrolo[3,4-c]pyrrole was replaced by The title compound was prepared according to the procedure. 1 H NMR (400 MHz, CDCl3) δ7.39-7.33 (m, 2H), 7.33-7.26 (m, 2H), 7.26-7.20 (m, 1H), 7.05 (m, 1H), 6.29 (dd, J= 1.7, 8.1 Hz, 1H), 6.24-6.18 (m, 2H), 4.96 (s, 2H), 4.37 (m, 1H), 3.28 (m, 2H), 3.08 (dt, J= 2.9, 9.3 Hz, 2H), 2.93-2.81 (m, 2H), 2.81-2.69 (m, 2H), 2.50 (t, J= 7.2 Hz, 2H), 2.33 (dd, J 3.9, 8.9 MS (LC / MS, M+H + ): m / z 463.2. [ka]

[0640] Example 105: Preparation of 5-(2-(5-(4-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one: 2-(4-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl (phenyl)octahydropyrrolo[3,4-c]pyrrole hydrochloride and 2-(o-tolyl)octa 3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one, except that hexahydropyrrolo[3,4-c]pyrrole was replaced by The title compound was prepared according to the procedure. 1 H NMR (400 MHz, CDCl3) δ7.37-7.31 (m, 2H), 7.31-7.25 (m, 2H), 7.24-7.18 (m, 1H), 6.81 (d, J= 9.0 Hz, 2H), 6.55 (d, J= 9.0 Hz, 2H), 4.92 (s, 2H), 4.37 (m, 1H), 3.19 (m, 2H), 3.01 (dt, J= 3.1, 9.3 Hz, 2H), 2.89-2.80 (m, 2H), 2.80-2.70 (m, 2H), 2.48 (t, J= 6.9 Hz, 2H), 2.29 (dd, J 3.9, 8.6 Hz, 2H), 2.02 (dd, J= 6.7, 13.1 Hz, 1H), 1.87-1.62 (m, 3H), 1.52 (q, J= 7.3 Hz, 4H), 0.82 (dt, J= 7.5, 14.5 Hz, 6H); MS (LC / MS, M+H + ): m / z 463.2. [ka]

[0641] Example 106: Preparation of 3,3-diethyl-5-(2-(5-(2-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one: In a dry round-bottom flask To this was added 0.013 g of 10% Pd / C (20 wt%), wetted with a small amount of ethyl acetate. Next, a solution of 5-(2-(5-(2-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one (0.065 g, 0.140 mmol, 1 equiv.) in MeOH (1.5 mL) was slowly added to the round-bottom flask containing the Pd / C. The system was then flushed with H2 three times using a balloon filled with H2. The reaction was stirred at room temperature overnight under 1 atm of H2. The Pd / C was removed by filtration through a plug of Celite. The filtrate was concentrated in vacuo to give a crude residue, which was first purified by column chromatography (methanol / dichloromethane, 0% to 10%). 1 H NMR (400 MHz, CDCl3) δ7.13 (dd, J= 1.3, 7.8 Hz, 1H), 7.05 (td, J= 1.3, 7.7 Hz, 1H), 6.93 (dd, J= 1.3, 8.1 Hz, 1H), 6.85 (td, J= 1.4, 7.7 Hz, 1H), 4.52 (m, 1H), 3.12-3.00 (m, 2H), 2.98-2.74 (m, 6H), 2.65 (t, J= 7.3 Hz, 2H), 2.58-2.46 (m, 2H), 2.16 (dd, J= 6.7, 13.1 Hz, 1H), 2.00-1.76 (m, 3H), 1.64 (q, J= 7.5 Hz, 4H), 0.95 (dt, J= 7.4, 22.8 Hz, 6H); MS (LC / MS, M+H + ): m / z 373.2. [ka]

[0642] Example 107: Preparation of 3,3-diethyl-5-(2-(5-(3-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one: 5-(2-(5-(3-(benzoyl) (( ... 2-(5-(2-benzyloxy)phenyl)hexahydro-2(3H)-one 3,3-diethyl-5-(2-(5-(2-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one was replaced with 3,3-diethyl-5-(2-(5-(2-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one. Following the procedure of (3,4-c)pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one The compounds were prepared. 1 H NMR (400 MHz, CDCl3) δ6.85 (t, J= 8.1 Hz, 1H), 6.00 (td, J= 1.8, 7.6 Hz, 2H), 5.91 (t, J= 2.3 Hz, 1H), 4.24 (m, 1H), 3.18-3.05 (m, 2H), 2.97 (d, J= 9.2 Hz, 2H), 2.83-2.64 (m, 4H), 2.44 (t, J= 7.3 Hz, 2H), 2.25 (m, 2H), 1.91 (dd, J= 6.7, 13.1 Hz, 1H), 1.77-1.53 ​​(m, 3H), 1.40 (q, J= 7.4 Hz, 4H), 0.70 (dt, J= 7.4, 15.6 Hz, 6H); MS (LC / MS, M+H + ): m / z 373.2. [ka]

[0643] Example 108: Preparation of 3,3-diethyl-5-(2-(5-(4-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one trifluoroacetate: 5-(2-(5-(4-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3 3,3-diethyl-5-(2-(5-(2-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one, except that 5-(2-(5-(2-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one was substituted for 5-(2-(5-(2-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one and the reaction time was extended to 3 days. The title compound was prepared following the procedure for hydrofuran-2(3H)-one. Second purification via column chromatography on a C18 column (acetonitrile / water, 0% to 100%, w / 0.1% TFA). What was needed: 1 H NMR (400 MHz, MeOD) δ6.78-6.67 (m, 4H), 4.54 (m, 1H), 3.69 (b, 2H), 3.45 (dd, J= 7.2, 9.6 Hz, 2H), 3.40-3.09 (m, 6H), 2.98 (m, 2H), 2.28 (dd, J= 6.7, 13.2 Hz, 1H), 2.20-1.97 (m, 2H), 1.91 (dd, J= 9.4, 13.2 Hz, 1H), 1.74-1.52 (m, 4H), 0.94 (dt, J= 5.0, 14.9 Hz, 6H); MS (LC / MS, M+H + ): m / z 373.2. [ka]

[0644] Example 109: Preparation of 3,3-diethyl-5-(2-(5-phenylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one: The title compound was prepared by following the procedure for 3,3-diethyl-5-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)dihydrofuran-2(3H)-one, except substituting 2-phenyloctahydropyrrolo[3,4-c]pyrrole dihydrochloride for 2-phenyl-2,6-diazaspiro[3.3]heptane trifluoroacetate. Ta: 1 H NMR (400 MHz, CDCl3) δ7.14 (m, 2H), 6.64 (t, J= 7.2 Hz, 1H), 6.57 (d, J= 8.5 Hz, 2H), 4.37 (m, 1H), 3.29 (t, J= 8.1 Hz, 2H), 3.08 (dt, J= 2.7, 9.3 Hz, 2H), 2.92-2.79 (b, 2H), 2.78-2.65 (m, 2H), 2.47 (t, J= 6.9 Hz, 2H), 2.32 (dd, J= 4.0, 8.9 Hz, 2H), 2.02 (dd, J= 6.7, 13.1 Hz, 1H), 1.87-1.61 (m, 3H), 1.51 (q, J= 7.3 Hz, 4H), 0.81 (dt, J= 7.5, 13.9 Hz, 6H); MS (LC / MS, M+H + ): m / z 357.2 formulation

[0645] The present invention also relates to compositions or formulations containing the sigma-2 receptor binding substances and sigma-2 receptor activity modulators of the present invention. Generally, the compositions of the present invention comprise an effective amount of one or more compounds of the present disclosure and salts thereof of the present invention effective to provide modulation of sigma-2 receptor activity, and one or more excipients.

[0646] In the present invention, the terms "excipient" and "carrier" are used interchangeably throughout the description of the present invention and are defined herein as "ingredients used in the formulation of safe and effective pharmaceutical compositions."

[0647] Formulators understand that the use of excipients primarily aids in the delivery of safe, stable, and functional pharmaceutical agents, serving not only as part of the overall delivery vehicle but also as a means for the effective absorption of the active ingredient by the recipient. Excipients can serve a simple and straightforward role similar to that of an inert filler, or, as used herein, excipients may also serve as a partial pH stabilizing means or coating to ensure safe delivery of the ingredient to the stomach. Formulators can also take advantage of the fact that the compounds of the present invention have improved cellular efficacy, pharmacokinetic properties, and even improved oral bioavailability.

[0648] The present teachings also provide pharmaceutical compositions comprising at least one compound described herein and one or more pharmaceutically acceptable carriers, excipients, or diluents. Examples of such carriers are well known to those skilled in the art and may be prepared according to acceptable pharmaceutical procedures, such as those described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, PA (1985), the entire disclosure of which is incorporated herein by reference for all purposes. As used herein, "pharmaceutically acceptable" refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological standpoint and does not adversely affect the active ingredient. Thus, a pharmaceutically acceptable carrier is one that is compatible with other ingredients contained in the formulation and is biologically acceptable. Supplementary active ingredients may also be incorporated into the pharmaceutical composition.

[0649] The compounds of the present teachings can be administered orally or parenterally, either directly or in combination with conventional pharmaceutical carriers. Suitable solid carriers can include one or more substances that can also function as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or disintegrants, or encapsulating materials. The compounds can be formulated in conventional ways, for example, in a manner similar to that used for known sigma-2 receptor modulators. Oral formulations containing the compounds disclosed herein can include any conventionally used oral form, including tablets, capsules, buccal forms, troches, lozenges, and oral liquids, suspensions, or solutions. In the case of powders, the carrier can be a finely divided solid, or it can be mixed with the finely divided compound. In the case of tablets, the compounds disclosed herein can be mixed with a carrier having the necessary compression properties in appropriate proportions and compressed into the desired shape and size. Powders and tablets can contain up to 99% of the compound.

[0650] Capsules may contain a mixture of one or more compounds disclosed herein with an inert filler and / or diluent, such as pharmaceutically acceptable starch (e.g., corn, potato, or tapioca starch), sugars, artificial sweeteners, powdered cellulose (e.g., crystalline and microcrystalline cellulose), flour, gelatin, gums, and the like.

[0651] Useful tablet formulations can be made by conventional compression, wet granulation, or dry granulation methods and can be formulated with pharmaceutically acceptable diluents, binders, lubricants, disintegrants, surface modifiers (including surfactants), and the like. ), suspending agents or stabilizers may be used, examples of which include, but are not limited to, magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, microcrystalline cellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, polyvinylpyrrolidine, alginic acid, gum acacia, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low-melting waxes, and ion exchange resins. Surface modifiers include nonionic and anionic surface modifiers. Representative examples of surface modifiers include poloxamer 188, benzalkonium chloride, calcium stearate, cetostearyl alcohol, These include, but are not limited to, cetomacrogol emulsifying wax, sorbitan ester, colloidal silicon dioxide, phosphate, sodium dodecyl sulfate, magnesium aluminum silicate, and triethanolamine.The oral formulation herein can utilize standard delayed-release or sustained-release formulations to change the absorption of compound.Oral formulation can also be comprised of adding the compound disclosed herein to water or fruit juice, if necessary, containing suitable solubilizer or emulsifier.

[0652] Liquid carriers can be used to prepare solutions, suspensions, emulsions, syrups, elixirs, and can be used for inhalation delivery. The compounds of the present teachings can be dissolved or suspended in pharmaceutically acceptable liquid carriers, such as water, organic solvents, or a mixture of both, or pharmaceutically acceptable oils or fats. Liquid carriers can include other suitable pharmaceutical additives, such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavorings, suspending agents, thickeners, dyes, viscosity regulators, stabilizers, and osmolality regulators. Examples of liquid carriers for oral and parenteral administration include, but are not limited to, water (particularly including the additives described herein, e.g., cellulose derivatives such as sodium carboxymethylcellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols such as glycols) and their derivatives, and oils (e.g., fractionated coconut oil and peanut oil). For parenteral administration, the carrier can be an oily ester, such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. Liquid carriers for pressurized compositions can be halogenated hydrocarbons or other pharmaceutically acceptable propellants.

[0653] Liquid pharmaceutical compositions that are sterile solutions or suspensions can be utilized, for example, for intramuscular, intraperitoneal, or subcutaneous injection. Sterile solutions can also be administered intravenously. Compositions for oral administration can be in either liquid or solid form.

[0654] The pharmaceutical composition is preferably in unit dosage form, such as, for example, tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such dosage forms, the pharmaceutical composition may be subdivided into unit doses containing appropriate amounts of the compound. The unit dosage form may be a packaged composition, such as, for example, packeted powders, vials, ampoules, prefilled syringes, or sachets containing liquids. Alternatively, the unit dosage form may be a capsule or tablet itself, or an appropriate number of any composition in packaged form. Such unit dosage forms may contain from about 1 mg / kg to about 500 mg / kg of the compound and may be administered in a single dose or in two or more doses. Such doses may be administered by any method useful for introducing the compound into the recipient's bloodstream, for example, orally, via an implant, parenterally (including intravenous, intraperitoneal, and subcutaneous injections), rectally, vaginally, or transdermally.

[0655] When administered to treat or suppress a particular disease state or disorder, it will be understood that the effective dosage will vary depending on the particular compound employed, the mode of administration, and the severity of the condition being treated, as well as various physical factors associated with the individual being treated. A patient already suffering from a disease can be provided with a compound of the present teachings in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications. The dosage used in treating a particular individual must typically be subjectively determined by the attending physician. The variables involved include the specific condition and its state, as well as the size, age, and response pattern of the patient.

[0656] In some cases, it may be desirable to administer the compound directly to a patient's airways using devices such as, but not limited to, metered-dose inhalers, respiratory inhalers, multi-dose dry powder inhalers, pumps, squeeze sprayers, aerosol dispensers, and aerosol sprayers. For administration via intranasal or intrabronchial inhalation, the compounds of the present teachings can be formulated into liquid, solid, or aerosol compositions. Liquid compositions illustratively contain one or more compounds of the present teachings dissolved, partially dissolved, or suspended in one or more pharmaceutically acceptable solvents and can be administered, for example, using a pump or squeeze sprayer. The solvent can be, for example, isotonic saline or bacteriostatic water. Solid compositions illustratively include powder preparations containing one or more compounds of the present teachings, which are mixed with lactose or other inert powders that can be used intrabronchially. The compositions can also be administered, for example, by an aerosol dispenser or by a device that breaks or punctures a capsule enclosing the solid composition and delivers the solid composition via inhalation. Aerosol compositions can include, by way of example, one or more compounds of the present teachings, a propellant, a surfactant, and a cosolvent, and can be administered, for example, using a metered dose device. Propellant agents include chlorofluorocarbons (CFCs), hydrofluorocarbons (HFCs), and the like. The propellant may be a hydroxyalkane (HFA), or other physiologically and environmentally acceptable propellant. do.

[0657] The compounds described herein can be administered parenterally or intraperitoneally.These compounds or their pharmaceutically acceptable salts, hydrates, or esters can be prepared as aqueous solutions or suspensions by appropriately mixing with surfactants such as hydroxypropyl cellulose.Dispersions can also be prepared in glycerol, liquid polyethylene glycol, and their mixtures in oils.Under normal storage and use conditions, these preparations generally contain preservatives to prevent the growth of microorganisms.

[0658] Pharmaceutical forms suitable for injection can include sterile aqueous solution or dispersion, and sterile powder for extemporaneously preparing sterile injectable solution or dispersion.In some embodiments, said form can be sterilized, and its viscosity allows it to flow through syringe.Preferably, said form is stable under the conditions of manufacture and storage, and can be protected from the contaminating action of microorganisms such as bacteria and fungi.Carrier can be, for example, solvent or dispersion medium containing water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol), their suitable mixture, and vegetable oil.

[0659] The compounds described herein can be administered transdermally, i.e., across the surface of the body and inside the body passages, including epithelial and mucosal tissues. Such administration can be carried out using the compounds of the present teachings (including their pharmaceutically acceptable salts, hydrates, or esters) in lotions, creams, foams, patches, suspensions, solutions, and suppositories (such as rectal and vaginal).

[0660] Transdermal administration can be achieved by using a transdermal patch containing a compound, such as a compound disclosed herein, and a carrier that is inert to the compound, non-toxic to the skin, and capable of delivering the compound through the skin and allowing systemic absorption into the bloodstream. The carrier can take any number of forms, such as creams and ointments, pastes, gels, and occlusive devices. Creams and ointments are viscous liquid or semisolid emulsions, either oil-in-water or water-in-oil. It is possible. Pastes consisting of absorbent powders dispersed in petroleum or hydrophilic petroleum containing the compound may also be suitable. A variety of occlusive devices can be used to release the compound into the bloodstream, such as a semipermeable membrane covering a reservoir containing the compound, with or without a carrier, or a matrix containing the compound. Other occlusive devices are known in the literature.

[0661] The compound described herein can be administered rectally or vaginally in the form of conventional suppositories.Suppository preparations can be made from conventional materials, including cocoa butter, with or without the addition of glycerin, and wax that changes the melting point of suppository.Water-soluble suppository bases, such as polyethylene glycols of various molecular weights, can also be used.

[0662] Lipid formulations or nanocapsules can be used to deliver compounds of the present teachings to host cells in vitro or can be introduced in vivo. Lipid formulations and nanocapsules can be prepared by methods known in the art.

[0663] In order to enhance the effectiveness of the compounds of the present teachings, it may be desirable to combine the compounds with other drugs effective in treating the target disease. For example, other active compounds (i.e., other active ingredients or drugs) effective in treating the target disease can be administered together with the compounds of the present teachings. The other drugs can be administered at the same time or at different times as the compounds disclosed herein.

[0664] Compounds of the present teachings can be useful for treating or suppressing a pathological condition or disorder in a mammal, e.g., a human subject. Accordingly, the present teachings provide methods for treating or suppressing a pathological condition or disorder by administering to a mammal a compound of the present teachings (including pharmaceutically acceptable salts thereof) or a pharmaceutical composition comprising one or more compounds of the present teachings in combination or association with a pharmaceutically acceptable carrier. Compounds of the present teachings can be administered alone or in combination with other therapeutically effective compounds or therapeutic methods for treating or suppressing the pathological condition or disorder.

[0665] As a non-limiting example of a composition according to the present invention, about 0.001 mg to about 1000 mg of the present invention One or more compounds listed above and one or more excipients, about 0.01 mg to about 100 mg of the compound of the present disclosure according to the present invention One or more compounds and one or more excipients, about 0.1 mg to about 10 mg of one or more compounds of the present disclosure according to the present invention The compound may include one or more excipients. procedure

[0666] The following procedures may be utilized to evaluate and select compounds as sigma-2 receptor binding agents and modulators of sigma-2 receptor activity.

[0667] Radiolabeled binding assay for Sigma-2 receptors:

[0668] A solution of the compound of the present disclosure to be tested is dissolved in Assay Buffer or DMSO, depending on its solubility. A 1 mg / ml stock solution is prepared in Assay Buffer. A similar stock solution of the reference compound, haloperidol, is also prepared as a positive control. Eleven dilutions (5x assay concentration) of the compounds of the present disclosure and haloperidol are prepared in Assay Buffer by serial dilution to give concentrations ranging from 10 pM to 10 μM. A range of final equivalent assay concentrations is obtained.

[0669] 5nM 3 H-1,3-di-(2-tolyl)guanidine ( 3 The stock concentration of H-DTG was 50 mM Tris-HCl. The radioligand is prepared in 10 mM MgCl2, 1 mM EDTA, pH 7.4 (Assay Buffer). Aliquots (50 μl) of the radioligand are dispensed into wells of a 96-well plate containing 100 μl of Assay Buffer. Each stage of the test compound of the present disclosure and the haloperidol positive control reference compound is Make 50 μl aliquots of the serial dilutions.

[0670] A membrane fraction (50 μL) of cells expressing recombinant sigma-2 receptor is dispensed into each well. Membranes are prepared from stably transfected cell lines expressing the sigma-2 receptor, grown on 10 cm plates, by harvesting the monolayers, rinsing with PBS, resuspending and lysing in cold hypotonic 50 mM Tris-HCl (pH 7.4), centrifuging at 20,000 × g, and discarding the supernatant. This membrane preparation is diluted with 3 mL of chilled Assay Buffer and stored at -80°C. They are resuspended and homogenized by passage several times through a 26 gauge needle before use in the assay.

[0671] The 250 μl reaction was incubated at room temperature for 1.5 hours and then plated onto a 96-well Filtermate plate. On 0.3% polyethyleneimine-treated 96-well filter mats using Bestar The filter mat is harvested by rapid filtration. To reduce nonspecific binding, four rapid 500 μl washes are performed with chilled Assay Buffer. After drying the filter mat, The radioactivity remaining on the filter was measured by Microbeta scintillation. Count using a counter.

[0672] The raw data (dpm) representing total radioligand binding (i.e., specific + nonspecific binding) was calculated as The data are plotted as a function of the logarithm of the molar concentration of the competitor (i.e., test compound or reference compound). Nonlinear regression of the normalized (i.e., percentage of radioligand binding compared to binding observed in the absence of test compound or reference compound) raw data is performed using a built-in three-parameter logistic model that describes binding of the ligand competitor to the radioligand-labeled site. This is performed using Prism 4.0 (GraphPad Software): y=bottom+[(top-bottom) / (1+10x-logIC 50 )] where the bottom represents the residual radioligand binding (i.e., the residual radioligand binding) measured in the presence of 10 μM of the reference compound. The log IC is equal to the total radioligand binding observed in the absence of competitor (i.e., nonspecific binding), and the upper part is equal to the total radioligand binding observed in the absence of competitor. 50 (i.e., a ligand that reduces radioligand binding by 50%) The K (logarithm of the K) is estimated from the data and used to obtain K from the Cheng-Prusoff approximation: Ki=IC 50 / (1+[ligand] / KD) where [ligand] equals the assay radioligand concentration and KD equals the binding constant of the radioligand to the target receptor.

[0673] Compounds of the present disclosure were also screened at a single concentration of 10 μM using the same method described for testing radiolabeled binding to sigma-2 receptors. 3 H-DTG binding The percent inhibition is calculated.

[0674] Results for representative compounds according to the invention are listed in Table 21. Table 21: Sigma-2 receptor radiolabeled binding study results for exemplary compounds of the present disclosure [Table 21-1] [Table 21-2] [Table 21-3]

Claims

1. Formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein: A is, 【Chemistry 2】 and n is 1, 2, or 3; R 1a and R 1b are independently hydrogen, C 1-6 Linear alkyl and C 1-6 branched alkyl, or R 1a and R 1b may together with the atom to which they are attached form a ring having 3 to 7 ring atoms; R 2 is 0 to 2 non-hydrogen R 5 a 4-pyridine ring optionally substituted with a group; R 5 is hydrogen, OH, NO at each occurrence position. 2 , halogen, CN, C 1-6 Linear alkyl, C 3-7 Branched alkyl, C 3-7 Cycloalkyl, C 1-6 Linear alkoxy, C 3-7 Branched alkoxy, C 3-7 Cycloalkoxy, C 1-6 Linear haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Straight-chain haloalkoxy, heterocyclyl, -S(C 1-6 Straight-chain alkyl), S(C 3-7 Branched alkyl), -S(C 3-7 cycloalkyl), COR 6 , CO 2 R 7 ,CONR 8a R 8b , SO 2 NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO 2 R 11 , and N.R. 9a SO 2 NR 12a R 12b are independently selected from the group consisting of: R 5a , R 5b , R 5c and R 5d The term refers to each R on the pyridine ring. 5 may be used to designate a group; R 6 At each occurrence, hydrogen, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; R 7 At each occurrence, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; R 8a At each occurrence position, H, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; R 8b At each occurrence position, H, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; R 9a At each occurrence position, H, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; R 9b At each occurrence position, H, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; R 9a and R 9b may together with the atom to which they are attached form a ring having 3 to 7 ring atoms optionally containing oxygen; R 10 At each occurrence position, H, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; R 11 At each occurrence, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; R 12a At each occurrence, hydrogen, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; and R 12b At each occurrence, hydrogen, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 or a pharmaceutically acceptable salt thereof, wherein the compound is independently selected from the group consisting of: cycloalkyl;

2. 2. The compound of claim 1, wherein n is 1.

3. 2. The compound of claim 1, wherein n is 2.

4. 2. The compound of claim 1, wherein n is 3.

5. The 4-pyridine ring has one R that is not hydrogen. 5 The compound according to any one of claims 1 to 4, which is substituted with a group.

6. The 4-pyridine ring has two R 5 The compound according to any one of claims 1 to 4, which is substituted with a group.

7. The compound of any one of claims 1 to 4, wherein the 4-pyridine ring is unsubstituted.

8. The compound having formula (I) has the following formula (IId): 【Transformation 8】 or a pharmaceutically acceptable salt thereof, wherein: R 5a , R 5b , R 5c , and R 5d At least two of the groups in R are hydrogen, 5a , R 5b , R 5c , and R 5d 0 to 2 of these are independently OH, NO 2 , halogen, CN, C 1-6 Linear alkyl, C 3-7 Branched alkyl, C 3-7 Cycloalkyl, C 1-6 Linear alkoxy, C 3-7 Branched alkoxy, C 3-7 Cycloalkoxy, C 1-6 Linear haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Straight-chain haloalkoxy, heterocyclyl, -S(C 1-6 Straight-chain alkyl), S(C 3-7 Branched alkyl), -S(C 3-7 cycloalkyl), -SO 2 (C 1-6 Linear alkyl), SO 2 (C 3-7 Branched alkyl), -SO 2 (C 3-7 cycloalkyl), COR 6 , CO 2 R 7 ,CONR 8a R 8b , SO 2 NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO 2 R 11 and N.R. 9a SO 2 NR 12a R 12b 2. The compound of claim 1, selected from the group consisting of:

9. The compound having formula (I) is selected from the group consisting of: (R)-3-(2-(5-(3-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (S)-3-(2-(5-(3-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (R)-3-(2-(5-(2-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (S)-3-(2-(5-(2-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (R)-3-(2-(5-(2,6-dimethylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; or (S)-3-(2-(5-(2,6-dimethylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; or a pharmaceutically acceptable salt thereof.

10. A compound having the following formula (I) (including pharmaceutically acceptable salts thereof): 【Chemistry 1】 During the ceremony: A is, 【Chemistry 2】 selected from the group consisting of: n is 1, 2, or 3; R 1a and R 1b are independently hydrogen, C 1-6 Linear alkyl and C 1-6 branched alkyl, or R 1a and R 1b may, together with the atom to which they are attached, form a cycloalkyl ring having 3 to 7 ring atoms; R 2 is 0 to 2 non-hydrogen R 5 a 3-pyridine ring optionally substituted with a group, or 0-2 non-hydrogen R 5 a 2-pyridine ring optionally substituted with a group; R 5 is hydrogen, OH, NO at each occurrence position. 2 , halogen, CN, C 1-6 Linear alkyl, C 3-7 Branched alkyl, C 3-7 Cycloalkyl, C 1-6 Linear alkoxy, C 3-7 Branched alkoxy, C 3-7 Cycloalkoxy, C 1-6 Linear haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Straight-chain haloalkoxy, heterocyclyl, -S(C 1-6 Straight-chain alkyl), S(C 3-7 Branched alkyl), -S(C 3-7 cycloalkyl), COR 6 , CO 2 R 7 ,CONR 8a R 8b , SO 2 NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO 2 R 11 , and N.R. 9a SO 2 NR 12a R 12b are independently selected from the group consisting of: R 5a , R 5b , R 5c and R 5d The term refers to each R on the pyridine ring. 5 may be used to designate a group; R 6 At each occurrence, hydrogen, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; R 7 At each occurrence, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; R 8a At each occurrence position, H, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; R 8b At each occurrence position, H, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; R 9a At each occurrence position, H, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; R 9b At each occurrence position, H, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; R 9a and R 9b may together with the atom to which they are attached form a ring having 3 to 7 ring atoms optionally containing oxygen; R 10 At each occurrence position, H, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; R 11 At each occurrence, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; R 12a At each occurrence, hydrogen, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 independently selected from the group consisting of cycloalkyl; and R 12b At each occurrence, hydrogen, C 1-6 Linear alkyl, C 3-7 Branched alkyl, and C 3-7 A compound independently selected from the group consisting of cycloalkyl.

11. The compound having formula (I) is a compound having the following formula (IIb) (including pharmaceutically acceptable salts thereof): 【Transformation 6】 During the ceremony: R 5a , R 5b , R 5c , and R 5d At least two of the groups in R are hydrogen, 5a , R 5b , R 5c , and R 5d 0 to 2 of these are independently OH, NO 2 , halogen, CN, C 1-6 Linear alkyl, C 3-7 Branched alkyl, C 3-7 Cycloalkyl, C 1-6 Linear alkoxy, C 3-7 Branched alkoxy, C 3-7 Cycloalkoxy, C 1-6 Linear haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Straight-chain haloalkoxy, heterocyclyl, -S(C 1-6 Straight-chain alkyl), S(C 3-7 Branched alkyl), -S(C 3-7 cycloalkyl), -SO 2 (C 1-6 Linear alkyl), SO 2 (C 3-7 Branched alkyl), -SO 2 (C 3-7 cycloalkyl), COR 6 , CO 2 R 7 ,CONR 8a R 8b , SO 2 NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO 2 R 11 and N.R. 9a SO 2 NR 12a R 12b 11. The compound of claim 10, selected from the group consisting of:

12. The compound having formula (I) is a compound having the following formula (IIc) (including pharmaceutically acceptable salts thereof): 【Transformation 7】 During the ceremony: R 5a , R 5b , R 5c , and R 5d At least two of the groups in R are hydrogen, 5a , R 5b , R 5c , and R 5d 0 to 2 of these are independently OH, NO 2 , halogen, CN, C 1-6 Linear alkyl, C 3-7 Branched alkyl, C 3-7 Cycloalkyl, C 1-6 Linear alkoxy, C 3-7 Branched alkoxy, C 3-7 Cycloalkoxy, C 1-6 Linear haloalkyl, C 3-7 Branched haloalkyl, C 1-6 Straight-chain haloalkoxy, heterocyclyl, -S(C 1-6 Straight-chain alkyl), S(C 3-7 Branched alkyl), -S(C 3-7 cycloalkyl), -SO 2 (C 1-6 Linear alkyl), SO 2 (C 3-7 Branched alkyl), -SO 2 (C 3-7 cycloalkyl), COR 6 , CO 2 R 7 ,CONR 8a R 8b , SO 2 NR 8a R 8b , N.R. 9a R 9b , N.R. 9a COR 10 , N.R. 9a SO 2 R 11 and N.R. 9a SO 2 NR 12a R 12b 11. The compound of claim 10, selected from the group consisting of:

13. 11. The compound of claim 10, wherein n is 1.

14. 11. The compound of claim 10, wherein n is 2.

15. 11. The compound of claim 10, wherein n is 3.

16. The 3-pyridine ring or the 2-pyridine ring is 5 The compound according to any one of claims 10 to 15, which is substituted with a group.

17. The 3-pyridine ring or the 2-pyridine ring is a ring in which two R 5 The compound according to any one of claims 10 to 15, which is substituted with a group.

18. The compound according to any one of claims 10 to 15, wherein the 3-pyridine ring or the 2-pyridine ring is unsubstituted.

19. 11. A pharmaceutical composition comprising an effective amount of at least one compound of claim 1 or 10.

20. 20. The pharmaceutical composition of claim 19, further comprising at least one excipient.

21. the at least one compound is (R)-3-(2-(5-(3-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (S)-3-(2-(5-(3-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (R)-3-(2-(5-(2-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (S)-3-(2-(5-(2-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (R)-3-(2-(5-(2,6-dimethylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; or (S)-3-(2-(5-(2,6-dimethylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; 21. The pharmaceutical composition according to claim 20, which is at least one of:

22. A composition comprising an effective amount of at least one compound described in any one of claims 1 or 10 for treating a disease involving dysregulation of sigma-2 receptor activity, characterized in that the composition is administered to a subject.

23. 23. The composition of claim 22, wherein the composition further comprises at least one excipient.

24. the at least one compound is (R)-3-(2-(5-(3-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (S)-3-(2-(5-(3-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (R)-3-(2-(5-(2-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (S)-3-(2-(5-(2-methylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (R)-3-(2-(5-(2,6-dimethylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; or (S)-3-(2-(5-(2,6-dimethylpyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; or at least one of these pharmaceutically acceptable salts.

25. 23. The composition of claim 22, wherein the disease involving dysregulation of sigma-2 receptor activity is selected from the group consisting of generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, post-traumatic stress disorder, depression, bipolar disorder, anorexia nervosa, bulimia nervosa, substance use disorder, schizophrenia, Alzheimer's disease, mild cognitive impairment, memory disorder, and cancer.

26. 26. The composition of claim 25, wherein the cancer is selected from the group consisting of pancreatic cancer, lung cancer, breast cancer, malignant melanoma, prostate cancer, and ovarian cancer.

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