Spiropiperidine urea-derived compounds as soluble epoxide hydrolase inhibitors

Abstract

The invention provides new heterocyclic compounds having the general formula (I) wherein X, Y, A, B, C, and R1 are as described herein, compositions including the compounds, processes of manufacturing the compounds and methods of using the compounds as soluble epoxide hydrolase inhibitors.

Description

[0001] F. Hoffmann-La Roche AG, CH-4070 Basel, Switzerland Case: 38983 SPIROPIPERIDINE UREA-DERIVED COMPOUNDS AS SOLUBLE EPOXIDE HYDROLASE INHIBITORS Field of the Invention The present invention relates to organic compounds useful for therapy or prophylaxis in a human, in particular to selected spiropiperidine urea-derived compounds as inhibitors of soluble epoxide hydrolase (sEH) for the treatment or prophylaxis of diseases and disorders that are associated with sEH, such as diabetic retinopathy, pain and neurodegenerative diseases. Background of the Invention Diabetic retinopathy is a common and serious complication of diabetes mellitus, affecting the blood vessels in the retina of the eye. It is a leading cause of blindness in adults. The pathogenesis of diabetic retinopathy is complex and involves various molecular and cellular mechanisms. One enzyme that has gained attention in the context of diabetic retinopathy is soluble epoxide hydrolase (sEH). Soluble epoxide hydrolase plays a crucial role in the metabolism of epoxyeicosatrienoic acids (EETs), which are lipid mediators derived from arachidonic acid. EETs have been shown to possess anti-inflammatory, vasodilatory, and angiogenic properties, making them important regulators of vascular function. In the context of diabetic retinopathy, alterations in the EET pathway and increased activity of sEH have been observed in the development and progression of the disease. Several studies have demonstrated that diabetic conditions lead to an upregulation of sEH in the retina. The increased activity of sEH results in the degradation of EETs, leading to a reduction in their beneficial effects. This imbalance in the EET pathway contributes to the vascular dysfunction, inflammation, and oxidative stress observed in diabetic retinopathy. The role of sEH in diabetic retinopathy extends beyond its impact on EET metabolism. sEH has been linked to the regulation of endothelial cell function, vascular permeability, and CNE / 05.11.2024 inflammation, all of which are critical factors in the development of diabetic retinopathy. Inhibition of sEH has shown promising results in preclinical studies, suggesting that targeting this enzyme could be a potential therapeutic strategy for diabetic retinopathy. Moreover, the interactions between sEH and other molecular pathways implicated in diabetic retinopathy, such as the vascular endothelial growth factor (VEGF) pathway, highlight the complexity of the disease and the potential for targeted interventions. Combining sEH inhibition with existing anti-VEGF therapies may offer a synergistic approach to address multiple aspects of diabetic retinopathy pathogenesis. Epoxidation of arachidonic acid by cytochrome P450 enzymes during inflammation and injury yields epoxyeicosatrienoic acids (EETs). The EETs have a variety of biological effects including modulation of inflammation, endothelial function and neuronal cell survival. EETs levels are regulated by soluble epoxide hydrolase (sEH), the major enzyme responsible for their degradation and conversion to inactive dihydroxyeicosatrienoic acids (DHETs). sEH, thereby, limits many of the biological actions of EETs. EETs produce important biological effects, particularly in the vascular and nervous systems. Inhibiting sEH increases the half-life of EETs, which in turn translates into beneficial therapeutic effects. sEH inhibitors may have utility in treatment of diabetic retinopathy [M.-H. Wang, A. S. Ibrahim, G. Hsiao, A. Tawfik, M. Al-Shabrawey, Prostaglandins Other Lipid Mediat. 2020, 148, 106449; J. Hu, S. Dziumbla, J. Lin,S.-I. Bibli, S. Zukunft, J. de Mos, K. Awwad, T. Frömel, A. Jungmann, K. Devraj, Z. Cheng, L. Wang, S. Fauser, C. G. Eberhart, A. Sodhi, B. D. Hammock, S. Liebner, O. J. Müller, C.Glaubitz, H.-P. Hammes, R. Popp, I. Fleming, Nature 2017, 552, 248–252], neuropathic andinflammatory pain [P. Sivaram, K. Ish, Inflamm. Allergy-drug Targets 2012, 11, 143–158; W.M. Karen, G. Aldrin, M. B. Cindy, H. D. Bruce, Neurotherapeutics 2020, 17, 900–916; C.Brenneis, M. Sisignano, O. Coste, K. Altenrath, M. J. Fischer, C. Angioni, I. Fleming, R. P.Brandes, P. W. Reeh, C. J. Woolf, G. Geisslinger, K. Scholich, Mol Pain 2011, 7, 78; P.Sivaram, K. Ish, Drug Discov. Today 2015, 20, 1382–1390; B. Inceoglu, S. L. Jinks, A. Ulu, C.M. Hegedus, K. Georgi, K. R. Schmelzer, K. Wagner, P. D. Jones, C. Morisseau, B. D.Hammock, Proc. National Acad. Sci. 2008, 105, 18901–18906; K. M. Wagner, C. B.McReynolds, W. K. Schmidt, B. D. Hammock, Pharmacol. Ther. 2017, 180, 62–76; K.Hiesinger, K. M. Wagner, B. D. Hammock, E. Proschak, S. H. Hwang, Prostaglandins OtherLipid Mediat. 2019, 140, 31–39; S. D. Kodani, C. Morisseau, Biochimie 2019, 159, 59–65; K.Wagner, B. Inceoglu, B. D. Hammock, Prostaglandins Other Lipid Mediat. 2011, 96, 76–83],neurodegenerative diseases [Z. Sydney, T. P. Julian, C. Sydney, S. Samantha, R. Mira, G. Anna,I. Diego, H. D. Bruce, B. V. Cesar, Prog. Neurobiol. 2019, 172, 23–39; R. Qian, M. Min, Y.Jun, N. Risa, Y. Akihiro, I. Kei-ichi, K. Kenta, M. Shigeo, H. Hee Sung, S. Shinji, A. Wado, H.Nobutaka, H. D. Bruce, H. Kenji, Proc. National Acad. Sci. 2018, 115, E5815; M. Pallàs, S.Vázquez, C. Sanfeliu, C. Galdeano, C. Griñán-Ferré, Biomolecules 2020, 10, 703; J. Atone, K.Wagner, K. Hashimoto, B. D. Hammock, Prostaglandins Other Lipid Mediat. 2020, 147,106385; C. Griñán-Ferré, S. Codony, E. Pujol, J. Yang, R. Leiva, C. Escolano, D. Puigoriol- Illamola, J. Companys-Alemany, R. Corpas, C. Sanfeliu, B. Pérez, M. I. Loza, J. Brea, C.Morisseau, B. D. Hammock, S. Vázquez, M. Pallàs, C. Galdeano, Neurotherapeutics 2020, 17,1825–1835], acute respiratory distress syndrome (ARDS) [W. Tao, G. Xu, Y. Luo, P.-S. Li,Inflammopharmacology 2022, 30, 2027–2033], cardiovascular diseases [L. Aurelien, G.Dominique, J. Robinson, B. Jeremy, Cardiovasc. Hematological Agents Medicinal Chem 2012,10, 212–222; I. D. John, H. D. Bruce, Nature Rev. Drug Discov. 2009, 8, 794–805]; rheumatoidarthritis (RA) [L. Qinglin, H. Shaoqi, H. Lichuang, Z. Jida, C. Gang, Front. Pharmacol. 2021,12, 648137], inflammatory bowel disease (IBD) and Crohn's disease [Y. Guang-Yu, Proc.National Acad. Sci. 2018, 115, 5827–5828; Z. Wanying, Y. L. Allison, L. Jie, L. Haonan, D.Hua, C. Tae Yeon, B. Han, M. A. Kristina, H. D. Bruce, Y. Guang-Yu, Digest. Dis. Sci. 2012,57, 2580–2591]. In conclusion, suppressing the action and / or the activation of sEH is a promising new therapeutic strategy for the treatment or prevention of various diseases and disorders, and there continues to be a high unmet medical need for new sEH inhibitors. Summary of the Invention In a first aspect, the present invention provides a compound of formula (I) wherein A, B, C, X, Y, and R1are as described herein. In further aspects, the present invention provides processes for manufacturing the compounds of formula (I), pharmaceutical compositions comprising the compounds of formula (I), as well as methods of using the compounds of formula (I) in the treatment or prophylaxis of diseases and disorders that are associated with sEH. Detailed Description of the Invention Definitions Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein, unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed. The term “alkyl” refers to a mono- or multivalent, e.g., a mono- or bivalent, linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms (“C1-C6-alkyl”), e.g., 1, 2, 3, 4, 5, or 6 carbon atoms. In some embodiments, the alkyl group contains 1 to 3 carbon atoms, e.g., 1, 2 or 3 carbon atoms. Some non-limiting examples of alkyl include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl. Particularly preferred, yet non-limiting examples of alkyl include methyl and isopropyl. The term “alkoxy” refers to an alkyl group, as previously defined, attached to the parent molecular moiety via an oxygen atom. Unless otherwise specified, the alkoxy group contains 1 to 6 carbon atoms (“C1-C6-alkoxy”). In some preferred embodiments, the alkoxy group contains contains 1 to 4 carbon atoms. In still other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. A particularly preferred, yet non-limiting example of alkoxy is methoxy. The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of 6 to 10 ring members (“C6-C10-aryl”), wherein at least one ring in the system is aromatic. Some non-limiting examples of aryl include phenyl and 9H-fluorenyl (e.g.9H-fluoren-9-yl). A particularly preferred, yet non-limiting example of aryl is phenyl. The term "heteroaryl" refers to a mono- or multivalent, mono- or bicyclic ring system having a total of 5 to 10 ring members, wherein at least one ring in the ring system is aromatic and contains one or more heteroatoms. Preferably, the heteroaryl comprises 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. More preferably, the heteroaryl is a 5- to 6-membered monocyclic heteroaryl or a 9- to 10-membered fused bicyclic heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. More preferably, the heteroaryl is a 5- to 6-membered monocyclic heteroaryl or a 9- to 10-membered fused bicyclic heteroaryl comprising 1 to 2 nitrogen atoms. Some preferred, yet non-limiting examples of heteroaryl include thiazolyl (e.g. thiazol-2-yl); oxazolyl (e.g. oxazol-2-yl); oxadiazolyl; 1,2,4-oxadiazol-5-yl; pyridyl (e.g.2- pyridyl); pyrazolyl (e.g. pyrazol-1-yl); triazolyl; tetrazolyl; pyrazinyl; imidazolyl (e.g. imidazole-1-yl); and 1H-indazolyl. A particularly preferred, yet non-limiting example of heteroaryl includes 1H-indazolyl. The term “cycloalkyl” as used herein refers to a saturated monocyclic hydrocarbon group of 3 to 6 ring carbon atoms (“C3-6-cycloalkyl”). Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Preferred, yet non-limiting examples of cycloalkyl include cyclopropyl and cyclobutyl. The term "pharmaceutically acceptable salt" refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, N-acetylcystein and the like. In addition, these salts may be prepared by addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like. Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins and the like. Particular pharmaceutically acceptable salts of compounds of formula (I) are hydrochloride salts. The compounds of formula (I) can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereioisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates. According to the Cahn-Ingold-Prelog Convention, the asymmetric carbon atom can be of the "R" or "S" configuration. The abbreviation “sEH” refers to soluble epoxide hydrolases. The abbreviation “hsEH” refers to human soluble epoxide hydrolases. The abbreviation “19,20-EpDPA” refers to (±)19,20-epoxy-4Z,7Z,10Z,13Z,16Z- docosapentaenoic acid. The abbreviation “19,20-DiHDPA” refers to (±)19,20-dihydroxy-4Z,7Z,10Z,13Z,16Z- docosapentaenoic acid. The term “treatment” as used herein includes: (1) inhibiting the state, disorder or condition (e.g. arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical symptom thereof); and / or (2) relieving the condition (i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms). The benefit to a patient to be treated is either statistically significant or at least perceptible to the patient or to the physician. However, it will be appreciated that when a medicament is administered to a patient to treat a disease, the outcome may not always be effective treatment. The term “prophylaxis” as used herein includes: preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition. The term “neurodegenerative diseases” relates to diseases that are related to the progressive loss of structure or function of neurons, including death of neurons. Examples of neurodegenerative diseases include, but are not limited to, multiple sclerosis, Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. The term “pain” relates to an unpleasant sensory and emotional experience associated with actual or potential tissue damage. Examples of pain include, but are not limited to, nociceptive pain, chronic pain (including idiopathic pain), neuropathic pain including chemotherapy induced neuropathy, phantom pain and phsychogenic pain. A particular example of pain is neuropathic pain, which is caused by damage or disease affecting any part of the nervous system involved in bodily feelings (i.e., the somatosensory system). In one embodiment, “pain” is neuropathic pain, e.g. neuropathic pain resulting from amputation or thoracotomy. In one embodiment, “pain” is chemotherapy induced neuropathy. The term “diabetic retinopathy” as used herein refers to a medical condition characterized by damage to the blood vessels in the retina of the eye, primarily resulting from complications associated with diabetes mellitus. Compounds of the Invention In a first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: X is CH2or O; Y is C=O or CR2R3; A is selected from C6-C10-aryl and 5- to 10-membered heteroaryl; B is C3-C6-cycloalkyl; the group heteroaromatic group selected from: R1, R2, R4, and R5are each independently selected from hydrogen and C1-C6-alkyl; and R3is selected from hydroxy and C1-C6-alkoxy. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X is CH2or O; and Y is C=O; or (ii) X is O; and Y is CR2R3; wherein R2and R3are as defined herein. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X is CH2; Y is C=O; and (ii) X is CH2 or O; Y is C=O; and (iii) X is O; heteroaromatic group selected from: wherein R2, R3, R4, and R5are as defined herein. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: X is CH2or O; and Y is C=O. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: X is O; and Y is CR2R3; wherein R2and R3are as defined herein. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is selected from phenyl, 5- to 6- membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, and 9- to 10- membered fused bicyclic heteroaryl comprising 1-4 heteroatoms selected from N, O, and S. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is selected from phenyl and a 9-membered fused bicyclic heteroaryl comprising 1-2 nitrogen atoms. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is selected from phenyl and 1H-indazolyl. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is phenyl. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is 1H-indazolyl. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from cyclopropyl and cyclobutyl. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is cyclopropyl. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is cyclobutyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the group wherein R4and R5are as defined herein. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the group ; wherein R4and R5are as defined herein. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the group ; wherein R4and R5are as defined herein. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the group ; wherein R4and R5are as defined herein. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R1is selected from hydrogen and C1-C3-alkyl. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R1is selected from hydrogen and methyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is selected from phenyl, 5- to 6-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, and 9- to 10-membered fused bicyclic heteroaryl comprising 1-4 heteroatoms selected from N, O, and S; and R1is selected from hydrogen and C1-C3-alkyl. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is selected from phenyl and a 9-membered fused bicyclic heteroaryl comprising 1-2 nitrogen atoms; and R1is selected from hydrogen and C1-C3-alkyl. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is selected from phenyl and 1H-indazolyl; and R1is selected from hydrogen and methyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R2is selected from hydrogen and C1-C3-alkyl; and R3is selected from hydroxy and C1-C3-alkoxy. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R2is selected from hydrogen and methyl; and R3is selected from hydroxy and methoxy. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R4is selected from hydrogen and C1-C3-alkyl. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R4is selected from hydrogen, methyl and isopropyl. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R4is methyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R5is selected from hydrogen and C1-C3-alkyl. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R5is selected from hydrogen and methyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R4and R5are each independently selected from hydrogen and C1-C3-alkyl. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R4is selected from hydrogen, methyl and isopropyl; and R5is selected from hydrogen and methyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: X is CH2or O; Y is C=O or CR2R3; A is selected from phenyl, 5- to 6-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, and 9- to 10-membered fused bicyclic heteroaryl comprising 1-4 heteroatoms selected from N, O, and S; B is C3-C6-cycloalkyl;;R1, R2, R4, and R5are each independently selected from hydrogen and C1-C3-alkyl; and R3is selected from hydroxy and C1-C3-alkoxy. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: X is CH2or O; Y is C=O or CR2R3; A is selected from phenyl and a 9-membered fused bicyclic heteroaryl comprising 1-2 nitrogen atoms; B is cyclopropyl and cyclobutyl; R1, R2, and R5are each independently selected from hydrogen and methyl; R3is selected from hydroxy and methoxy; and R4is selected from hydrogen, methyl and isopropyl. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: X is CH2or O; Y is C=O or CR2R3; A is selected from phenyl and 1H-indazolyl; B is cyclopropyl and cyclobutyl; R1, R2, and R5are each independently selected from hydrogen and methyl; R3is selected from hydroxy and methoxy; and R4is selected from hydrogen, methyl and isopropyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is selected from the group consisting of: 2-Isopropyl-7-oxo-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6H-pyrano[3,2-c]pyrazole-5,4'- piperidine]-1'-carboxamide; 2-Methyl-7-oxo-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6H-pyrano[3,2-c]pyrazole-5,4'- piperidine]-1'-carboxamide; 1-Methyl-7-oxo-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6H-pyrano[3,2-c]pyrazole-5,4'- piperidine]-1'-carboxamide; trans-2-Methyl-7-oxo-N-(3-phenylcyclobutyl)spiro[6H-pyrano[3,2-c]pyrazole-5,4'-piperidine]- 1'-carboxamide; trans-1-Methyl-7-oxo-N-(3-phenylcyclobutyl)spiro[6H-pyrano[3,2-c]pyrazole-5,4'-piperidine]- 1'-carboxamide; trans-1-Methyl-7-oxo-N-(3-phenylcyclobutyl)spiro[4,6-dihydroindazole-5,4'-piperidine]-1'- carboxamide; trans-2-Methyl-7-oxo-N-(3-phenylcyclobutyl)spiro[4,6-dihydroindazole-5,4'-piperidine]-1'- carboxamide; 2-Isopropyl-7-oxo-N-[(1R,2S)-2-phenylcyclopropyl]spiro[4,6-dihydropyrazolo[1,5-a]pyridine- 5,4'-piperidine]-1'-carboxamide; (7S)-7-Hydroxy-1-methyl-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6,7-dihydropyrano[3,2- c]pyrazole-5,4'-piperidine]-1'-carboxamide; (7R)-7-Hydroxy-1-methyl-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6,7-dihydropyrano[3,2- c]pyrazole-5,4'-piperidine]-1'-carboxamide; (7S)-7-hydroxy-1-methyl-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6,7-dihydropyrano[3,2- c]pyrazole-5,4'-piperidine]-1'-carboxamide; (7R)-7-hydroxy-1-methyl-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6,7-dihydropyrano[3,2- c]pyrazole-5,4'-piperidine]-1'-carboxamide; (7S)-7-Methoxy-1-methyl-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6,7-dihydropyrano[3,2- c]pyrazole-5,4'-piperidine]-1'-carboxamide; (7R)-7-Methoxy-1-methyl-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6,7-dihydropyrano[3,2- c]pyrazole-5,4'-piperidine]-1'-carboxamide; (7S)-7-methoxy-1-methyl-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6,7-dihydropyrano[3,2- c]pyrazole-5,4'-piperidine]-1'-carboxamide; (7R)-7-methoxy-1-methyl-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6,7-dihydropyrano[3,2- c]pyrazole-5,4'-piperidine]-1'-carboxamide; (7S)-7-Hydroxy-1,7-dimethyl-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6H-pyrano[3,2- c]pyrazole-5,4'-piperidine]-1'-carboxamide; (7R)-7-Hydroxy-1,7-dimethyl-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6H-pyrano[3,2- c]pyrazole-5,4'-piperidine]-1'-carboxamide; (7S)-7-hydroxy-1,7-dimethyl-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6H-pyrano[3,2-c]pyrazole- 5,4'-piperidine]-1'-carboxamide; (7R)-7-hydroxy-1,7-dimethyl-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6H-pyrano[3,2-c]pyrazole- 5,4'-piperidine]-1'-carboxamide; 1,3-Dimethyl-7-oxo-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6H-pyrano[3,2-c]pyrazole-5,4'- piperidine]-1'-carboxamide; trans-1,3-Dimethyl-7-oxo-N-(3-phenylcyclobutyl)spiro[6H-pyrano[3,2-c]pyrazole-5,4'- piperidine]-1'-carboxamide; trans-1-Methyl-N-[3-(1-methylindazol-4-yl)cyclobutyl]-7-oxo-spiro[6H-pyrano[3,2-c]pyrazole- 5,4'-piperidine]-1'-carboxamide; cis-1-methyl-N-[3-(1-methylindazol-4-yl)cyclobutyl]-7-oxo-spiro[6H-pyrano[3,2-c]pyrazole- 5,4'-piperidine]-1'-carboxamide; trans-7-Oxo-N-(3-phenylcyclobutyl)spiro[4,6-dihydropyrazolo[1,5-a]pyridine-5,4'-piperidine]- 1'-carboxamide; trans-2-Methyl-7-oxo-N-(3-phenylcyclobutyl)spiro[4,6-dihydropyrazolo[1,5-a]pyridine-5,4'- piperidine]-1'-carboxamide; trans-3-Methyl-7-oxo-N-(3-phenylcyclobutyl)spiro[4,6-dihydropyrazolo[1,5-a]pyridine-5,4'- piperidine]-1'-carboxamide; 8-Oxo-N-[(1R,2S)-2-phenylcyclopropyl]spiro[7H-pyrano[3,2-d]pyrimidine-6,4'-piperidine]-1'- carboxamide; 1-Isopropyl-7-oxo-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6H-pyrano[3,2-c]pyrazole-5,4'- piperidine]-1'-carboxamide; and 7-Oxo-N-[(1R,2S)-2-phenylcyclopropyl]spiro[1,6-dihydropyrano[3,2-c]pyrazole-5,4'- piperidine]-1'-carboxamide. In a particular embodiment, the present invention provides pharmaceutically acceptable salts of the compounds according to formula (I) as described herein, especially hydrochloride salts. In a further particular embodiment, the present invention provides compounds according to formula (I) as described herein. In some embodiments, the compounds of formula (I) are isotopically-labeled by having one or more atoms therein replaced by an atom having a different atomic mass or mass number. Such isotopically-labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of this disclosure. Examples of isotopes that can be incorporated into the compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur,fluorine, chlorine, and iodine, such as, but not limited to, 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O,17O, 18O, 31P, 32P, 35S, 18F, 36Cl, 123I, and 125I, respectively. Certain isotopically-labeledcompounds of formula (I), for example, those incorporating a radioactive isotope, are useful indrug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, andcarbon-14, i.e., 14C, are particularly useful for this purpose in view of their ease of incorporationand ready means of detection. For example, a compound of formula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeuticadvantages resulting from greater metabolic stability, for example, increased in vivo half-life orreduced dosage requirements. Thus, the present invention encompasses compounds of formula (I) wherein one or more hydrogen atoms have been replaced by deuterium.Substitution with positron emitting isotopes, such as 11C, 18F, 15O and 13N, can be useful inPositron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non- labeled reagent previously employed. Processes of Manufacturing The preparation of compounds of formula (I) of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the invention are shown in the following general schemes. The skills required for carrying out the reaction and purification of the resulting products are known to those persons skilled in the art. The substituents and indices used in the following description of the processes have the significance given herein, unless indicated to the contrary. If one of the starting materials, intermediates or compounds of formula (I) contain one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protective groups (as described e.g., in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wutts, 5th Ed., 2014, John Wiley & Sons, N.Y.) can be introduced before the critical step applying methods well known in the art. Such protective groups can be removed at a later stage of the synthesis using standard methods described in the literature. If starting materials or intermediates contain stereogenic centers, compounds of formula (I) can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art e.g., chiral HPLC, chiral SFC or chiral crystallization. Racemic compounds can e.g., be separated into their antipodes via diastereomeric salts by crystallization with optically pure acids or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent. It is equally possible to separate starting materials and intermediates containing stereogenic centers to afford diastereomerically / enantiomerically enriched starting materials and intermediates. Using such diastereomerically / enantiomerically enriched starting materials and intermediates in the synthesis of compounds of formula (I) will typically lead to the respective diastereomerically / enantiomerically enriched compounds of formula (I). A person skilled in the art will acknowledge that in the synthesis of compounds of formula (I) - insofar not desired otherwise - an “orthogonal protection group strategy” will be applied, allowing the cleavage of several protective groups one at a time each without affecting other protective groups in the molecule. The principle of orthogonal protection is well known in theart and has also been described in literature (e.g. Barany and R. B. Merrifield, J. Am. Chem. Soc.1977, 99, 7363; H. Waldmann et al., Angew. Chem. Int. Ed. Engl. 1996, 35, 2056).A person skilled in the art will acknowledge that the sequence of reactions may be varied depending on reactivity and nature of the intermediates. In more detail, the compounds of formula (I) can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. Also, for reaction conditions described in literature affecting the described reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY.1999). It was found convenient to carry out the reactions in the presence or absence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. The described reactions can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the described reactions in a temperature range between -78 °C to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 hours to several days will usually suffice to yield the described intermediates and compounds. The reaction sequence is not limited to the one displayed in the schemes, however, depending on the starting materials and their respective reactivity, the sequence of reaction steps can be freely altered. If starting materials or intermediates are not commercially available or their synthesis not described in literature, they can be prepared in analogy to existing procedures for close analogues or as outlined in the experimental section. In general, the compounds of formula (I) according to the invention, wherein Y is C=O and the remaining variables are as defined herein, can be synthesized as shown in Scheme 1. Thus, a compound of formula (II), wherein A, B, and R1are as defined herein, can be reacted with a compound of formula (III), wherein Y is C=O and X and C are as defined herein, under conditions used generally for the formation of ureas, known in the art, or mentioned, forexample, in A. K. Ghosh, M. Brindisi, J. Med. Chem. 2020, 63, 2751–2788. Scheme 1 As an example, a compound of formula (II) can be reacted with a stoichiometric amount of a compound of formula (III) in the presence of a stoichiometric amount of an appropriate phosgene equivalent, e.g. carbonyldiimidazole (CDI), further in the presence of an over- stoichiometric amount of an appropriate non-nucleophlic base, e.g. triethylamine or diisopropyl ethylamine, in an aprotic solvent, such as dichloromethane. The obtained reaction mixtures may be purified by methods known in art, e.g. by column chromatography, reversed phase HPLC, normal phase HPLC, or supercritical fluid chromatography (SFC), using achiral or chiral solid phases. Compounds of formula (II) are either commercially available or can be synthesized using methods known in the art. As an example, compounds of formula (II) can be accessed by a sequence depicted in Scheme 2. Scheme 2 Thus, compounds of formula (IV), wherein A, and R1are as defined herein, and Y is an appropriate reactive group, selected from halide, boronic ester, boronic acid, trisalkyltin, preferably bromide, or chloride, can be reacted with a compound of formula (V), wherein B is as defined herein, PG is an appropriate base stabile protecting group, such as a carbamate, e.g. tert- butoxycarbonyl-, or benzyloxycarbonyl- carbamate, and X is halide, preferably iodide, or bromide, in the presence of a stoichiometric amount of an appropriate inert base, e.g. alkali carbonate, such as sodium carbonate as well as in the presence of a catalytic or stoichiometric amount of one or more transition metal complexes, such as Palladium- and / or Iridium- and / or Nickel complexes, preferably [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis[3,5- difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]Iridium(III) hexafluorophosphate (Ir[dF(CF3)ppy]2(dtbpy)(PF6), CAS [870987-63-6]), and [4,4′-bis(1,1-dimethylethyl)-2,2′- bipyridine] nickel (II) dichloride (NiCl2.dtbbpy, CAS [1034901-50-2]), further optionally in the presence of a stoichiometric amount of an appropriate reducing agent, e.g. tris(trimethylsilyl)silane (TTMSS, CAS [1873-77-4]), optionally under irradiation of visible or ultraviolet light, preferably LED light with a wavelength of 455 nm, in a polar aprotic solvent, such as dioxane or dimethoxyethane, under an inert atmosphere. The resulting compounds of formula (VI) can then be deprotected to obtain compounds of formula (II), depending on the protecting group PG, by methods known in the art, e.g. as described in the book “Greene's Protective Groups in Organic Synthesis”, written by Peter G. M. Wuts, Theodora W. Greene (2006). In the case of PG being tert-butoxycarbonyl (Boc), cleavage of the protection group PG can be achieved e.g. by stirring with an excess of an appropriate organic or inorganic acid, such as trifluoroacetic acid or hydrochloric acid, either neat or in an appropriate organic solvent, such as dichloromethane, or 1,4-dioxane. In some cases, depending on the method of isolation, the compound of formula (II) is isolated as a salt of the potential acid used for the deprotection, or the purification. Likewise, the compound of formula (II) can be isolated e.g. as trifluoroacetate, hydrochloride, hydrobromide, or formate salt. The other building block, compound of formula (III), wherein X is O, Y is C=O and the group R4and R5are as defined herein, can be prepared as depicted in Scheme 3.

[0002] Scheme 3 Thus, a compound of formula (VII), wherein PG is a suitable base stabile protecting group, e.g. benzyl (Bn), benzyloxycarbonyl (Cbz), or tert-butoxycarbonyl (Boc), can be reacted with a compound of formula (VIII), wherein the group ; R4and R5are as defined herein, in the presence of a stoichiometric or substoichiometric amount of a suitable base, such as pyrrolidine, or piperidine, in a suitable polar protic or aprotic solvent, for example methanol, at elevated temperatures, preferably 20°C – 100°C, more preferably 40°C – 80°C. The resulting compounds of formula (IX) can be deprotected to obtain compounds of formula (III) by methods known in art, e.g. as described in the book “Greene's Protective Groups in Organic Synthesis”, written by Peter G. M. Wuts, Theodora W. Greene (2006). As examples, in case of PG being Bn, the deprotection can be achieved using hydrogenation conditions, e.g. by stirring a solution of a compound of formula (IX) in an alcohol, e.g. methanol, under an atmosphere of hydrogen in the presence of a catalytic or stoichiometric amount of Palladium, or, alternatively, by reacting it with a stoichiometric amount or an excess of 1-chloroethyl carbonochloridate in a suitable aprotic solvent, e.g.1,2-dichloroethane, at elevated temperatures, e.g.40°C – 100°C. In case of PG = Cbz, the deprotection can be achieved by reacting the compound of formula (IX) with a suitable acid, such as hydrogen bromide, in a suitable protic or aprotic solvent, e.g. methanol. In case of PG = Boc, the deprotection can be achieved by reacting the compound of formula (IX) with a suitable acid, such as hydrogen chloride, or 2,2,2- trifluoroacetic acid, in a suitable protic or aprotic solvent, e.g. dichloromethane, tetrahydrofuran, 1,4-dioxane, or methanol. In some cases, depending on the method of isolation, the compound of formula (III) is isolated as a salt of the potential acid used for the deprotection, or the purification. Likewise, the compound of formula (III) can be isolated e.g. as trifluoroacetate, hydrochloride, hydrobromide, or formate salt. Alternatively, compounds of formula (III), wherein X is O, Y is C=O, the group R4and R5are as defined herein can be prepared as shown in Scheme 4. Scheme 4 Thus, a compound of formula (VII), wherein PG1 is a suitable base stabile protecting group, e.g. benzyl (Bn), can be reacted with a compound of formulae (Xa) or (Xb), or a mixture thereof, wherein R5is as defined herein, and PG2 is a suitable base stabile protecting group, that is ideally orthogonal to PG1, e.g.4-methoxybenzyl (PMB), in the presence of a stoichiometric or substoichiometric amount of a suitable base, such as pyrrolidine, or piperidine, in a suitable polar protic or aprotic solvent, for example methanol, at elevated temperatures, preferably 20°C – 100°C, more preferably 40°C – 80°C. The resulting compounds of formula (XIa) or (XIb), respectively, or a mixture thereof, can be deprotected to obtain compounds of formula (XII) by methods known in art, e.g. as described in the book “Greene's Protective Groups in Organic Synthesis”, written by Peter G. M. Wuts, Theodora W. Greene (2006). As example, in case of PG2 being PMB, the deprotection can be achieved by reacting the compound of formula (XIa) or (XIb), or a mixture thereof, with a suitable acid, such as 2,2,2-trifluoroacetic acid, in a suitable protic or aprotic solvent, e.g.1,2-dichloroethane, at elevated temperatures of 40 – 100°C. The compounds of formula (XII) have to be understood as inseparable mixture of tautomers, the hydrogen is localized at either nitrogen of the pyrazole ring, both tautomers are in a rapid equilibrium. For clarity, only one tautomer is shown. The compounds of formula (XII) can be alkylated at the pyrazole ring by reaction with a suitable alkylating agent R4-LG, wherein R4is as defined above, and LG is an appropriate leaving group, such as halide, preferably bromide or iodide, or sulfonate, e.g. tosylate, mesylate, or triflate, in the presence of a suitable base, e.g. alkali carbonate, such as cesium carbonate, or sodium hydride, in a polar aprotic solvent, such as dimethylformamide, acetonitrile, or acetone. In most cases, a mixture of regioisomeric products of formulae (XIII) and (XIV) is formed, which can be separated by methods known in the art, e.g. by column chromatography, reversed phase HPLC, normal phase HPLC, or supercritical fluid chromatography (SFC), using achiral or chiral solid phases. The resulting separated compounds of formulae (XIII) and (XIV) can be deprotected to obtain compounds of formula (III), as specified above, respectively, by methods known in art, e.g. as described in the book “Greene's Protective Groups in Organic Synthesis”, written by Peter G. M. Wuts, Theodora W. Greene (2006). As example, in case of PG1 being Bn, the deprotection can be achieved using hydrogenation conditions, e.g. by stirring a solution of a compound of formula (IX) in an alcohol, e.g. methanol, under an atmosphere of hydrogen in the presence of a catalytic or stoichiometric amount of Palladium, or, alternatively, by reacting it with a stoichiometric amount or an excess of 1-chloroethyl carbonochloridate in a suitable aprotic solvent, e.g.1,2- dichloroethane, at elevated temperatures, e.g.40°C – 100°C. In some cases, depending on the method of isolation, the compound of formula (III) is isolated as a salt of the potential acid used for the deprotection, or the purification. Likewise, the compound of formula (III) can be isolated e.g. as trifluoroacetate, hydrochloride, hydrobromide, or formate salt. Compounds of formula (III), wherein X is CH2, Y is C=O, the group ;R4is as defined above, and R5is hydrogen, can be prepared as shown in Scheme 5. Scheme 5 Thus, a compound of formula (XIV), wherein X is CH2, Y is C=O, R5is hydrogen, and PG is a suitable base stabile protecting group, e.g. benzyloxycarbonyl (Cbz), can be alkylated at the pyrazole ring by reaction with a suitable alkylating agent R4-LG, wherein R4is as defined herein, and LG is an appropriate leaving group, such as halide, preferably bromide or iodide, or sulfonate, e.g. tosylate, mesylate, or triflate, in the presence of a suitable base, e.g. alkali carbonate, such as cesium carbonate, or sodium hydride, in a polar aprotic solvent, such as dimethylformamide, acetonitrile, or acetone. In most cases, a mixture of regioisomeric products of formulae (XV) and (XVI) is formed, which can be separated by methods known in the art, e.g. by column chromatography, reversed phase HPLC, normal phase HPLC, or supercritical fluid chromatography (SFC), using achiral or chiral solid phases. The resulting separated compounds of formulae (XV) and (XVI) can be deprotected to obtain compounds of formula (III), as specified above, respectively, by methods known in art, e.g. as described in the book “Greene's Protective Groups in Organic Synthesis”, written by Peter G. M. Wuts, Theodora W. Greene (2006). As example, in case of PG being Cbz, the deprotection can be achieved by reaction with strong acids, such as hydrogen bromide, in a suitable solvent, e.g. dichloromethane, or acetic acid, or a mixture thereof. The synthesis of starting compounds of formula (XIV) as specified above, and wherein PG is Cbz, is detailed in the intermediates section of this patent (Int-22). Alternatively, compounds of formula (III), wherein X is O or CH2, Y is C=O, the group are as defined herein can be prepared asoutlined in Scheme 6. Thus, a compound of formula (XVII), which is a special case of compounds of formula (III), wherein X is O or CH2, Y is C=O, the group , R4 is as definedherein, and R5is hydrogen, that can be synthesized as described in Scheme 3 (X = O), Scheme 4 (X = O), or Scheme 5 (X = CH2), can be protected with a suitable protecting group PG to form a compound of formula (XVI) using methods known in art, e.g. as described in the book “Greene's Protective Groups in Organic Synthesis”, written by Peter G. M. Wuts, Theodora W. Greene (2006). A suitable protecting group should be stable against basic and oxidative conditions, such as tert-butoxycarbonyl (Boc). In order to achieve the protection, compounds of formula (XVII), can be reacted, for example in the case of PG = Boc, with a stoichiometric or excess amount of di-t-butyldicarbonate, in the presence of a stoichiometric or excess amount of a suitable base, e.g. triethylamine, in an appropriate protic or aprotic solvent, such as methanol. In the next step, a compound of formula (XVIII) can be oxidized to form a compound of formula (XIX), wherein Z is halogen, preferably bromine or iodine, by reaction with a stoichiometric amount of a suitable halogenating agent, such as bromine or N-bromosuccinimide (NBS) in the case Z = Br, or iodine or N-iodosuccinimide (NIS) in the case Z = I, in a suitable inert solvent, e.g. dichloromethane. Compounds of formula (XIX) can be reacted with compounds of formula R5- W, wherein R5is as defined above and W is an appropriate reactive group, selected from halogen, boronic ester, boronic acid, trisalkyltin, preferably boronic acid, boronic ester, bromine, or iodine, in the presence of a stoichiometric amount of an appropriate inert base, e.g. alkali carbonate, such as potassium carbonate or sodium carbonate as well as in the presence of a catalytic or stoichiometric amount of one or more transition metal complexes, such as Palladium- and / or Iridium- and / or Nickel complexes, preferably tetrakis(triphenylphosphine) palladium(0), further optionally in the presence of a stoichiometric amount of an appropriate reducing agent, e.g. tris(trimethylsilyl)silane (TTMSS, CAS [1873-77-4]), optionally under irradiation of visible or ultraviolet light, preferably LED light with a wavelength of 455 nm, in a polar solvent, such as dioxane, water or dimethoxyethane, or mixtures thereof, under an inert atmosphere. The resulting compounds of formula (XIII) can then be deprotected to obtain compounds of formula (III), as specified above, depending on the protecting group PG, by methods known in the art, e.g. as described in the book “Greene's Protective Groups in Organic Synthesis”, written by Peter G. M. Wuts, Theodora W. Greene (2006). In the case of PG being tert-butoxycarbonyl (Boc), cleavage of the protection group PG can be achieved e.g. by stirring with an excess of an appropriate organic or inorganic acid, such as trifluoroacetic acid or hydrochloric acid, either neat or in an appropriate organic solvent, such as dichloromethane, or 1,4-dioxane. In some cases, depending on the method of isolation, the compound of formula (III) specified above is isolated as a salt of the potential acid used for the deprotection, or the purification. Likewise, the compound of formula (III) specified above can be isolated e.g. as trifluoroacetate, hydrochloride, hydrobromide, or formate salt. Compounds of formula (I), wherein X is CH2 or O, Y is CR2R3, A and B are as defined herein, the group heteroaromatic group selected from: R2, R3, R4, and R5are as defined herein, can be synthesized as shown in Scheme 7. Scheme 7 Thus, a compound of formula (XXI), wherein A, B, C, and R1are as specified herein, can be reacted with a stoichiometric amount of an appropriate reagent to introduce R3and prepare the reduced compound of formula (XXII). In case of R3= hydrogen, the transformation can be achieved by reaction with a stoichiometric amount of an appropriate reducing agent, e.g. sodium borohydride, or lithium borohydride, in a polar solvent, such as methanol. In case of R3= C1-C6- alkyl, the transformation can be achieved by reaction with an appropriate organometallic reagent, e.g. alkyllithium lithium bromide complex, in an aprotic, polar solvent, such as tetrahydrofuran. The compounds of formula (XXII) can be separated into the two formed epimers by methods known in art, e.g. by column chromatography, reversed phase HPLC, normal phase HPLC, or supercritical fluid chromatography (SFC), using achiral or chiral solid phases. The formed hydroxyl group can be alkylated to form compounds of formula (XXIII) by reaction with stoichiometric amounts of an appropriate alkylating agent R-LG, wherein R is C1- C6-alkyl, and LG is a suitable leaving group, such as halogen, preferably iodine or bromine, or sulfonate, e.g. tosylate, mesylate, or triflate, in the presence of an appropriate base, such as sodium hydride, or cesium carbonate, in a suitable aprotic, polar solvent, such as tetrahydrofuran, acetonitrile, or acetone. The compounds of formula (XXIII) can be separated into the two formed epimers by methods known in art, e.g. by column chromatography, reversed phase HPLC, normal phase HPLC, or supercritical fluid chromatography (SFC), using achiral or chiral solid phases. In some cases, depending on the method of isolation, the compounds of formulae (XXII) or (XXIII) specified above are isolated as a salt of the potential acid used for the purification. Likewise, the compound of formula (III) specified above can be isolated e.g. as trifluoroacetate, hydrochloride, or formate salt. Compounds of formula (III), wherein X is CH2, Y is C=O, the group , and R4, and R5are as defined herein can be synthesized as shown in Scheme 8. Scheme 8 Thus, a compound of formula (XXIV), wherein R4and R5are as defined herein, and PG is a suitable protecting group that is stable against basic and oxidative conditions, such as benzyloxycarbonyl (Cbz), can be deprotected by methods known in art, e.g. as described in the book “Greene's Protective Groups in Organic Synthesis”, written by Peter G. M. Wuts, Theodora W. Greene (2006). As example, in case of PG being Cbz, the deprotection can be achieved by reaction with strong acids, such as hydrogen bromide, in a suitable solvent, e.g. dichloromethane, or acetic acid, or a mixture thereof. Compounds of formula (XXIV) in turn can be prepared as depicted in Scheme 9. Scheme 9 Thus, a compound of formula (XXVI), wherein PG is a suitable protecting group that is stable against basic and oxidative conditions, such as benzyloxycarbonyl (Cbz), or tert-butoxycarbonyl (Boc), and that can be synthesized by methods known in the art or, for R = Cbz, as detailed in the experimental section of this patent (Int-41), can be reacted with a stoichiometric amount of a compound of formula (XXVII), wherein R is trimethylsilyl or C1-C6-alkyl, in the presence of a stoichiometric amount of a suitable strong, non-nucleophilic base, such as lithium diisopropylamide, further in the presence of a substoichiometric amount of a suitable copper salt, e.g. copper(I)iodide, in an aprotic polar solvent, such as tetrahydrofuran, at low temperatures of - 80°C – -40°C. The resulting compound of formula (XXVIII) can be reacted with an excess of hydrazine hydrate in an appropriate polar solvent, e.g. dimethylformamide, to form a compound of formula (XXIX), wherein R4corresponds to R in compounds of the formula (XXVII) in case of R = C1-C6-alkyl, and wherein R4= hydrogen in case of R = trimethylsilyl. The compound of formula (XXIX) can be cyclized by stirring under elevated temperatures of 80°C – 150°C in a suitable polar solvent, such as dimethylformamide to afford a compound of formula (XXX). In the next step, a compound of formula (XXX) can be oxidized to form a compound of formula (XXXI), wherein Z is halogen, preferably bromine or iodine, by reaction with a stoichiometric amount of a suitable halogenating agent, such as bromine or N-bromosuccinimide (NBS) in the case Z = Br, or iodine or N-iodosuccinimide (NIS) in the case Z = I, in a suitable inert solvent, e.g. dichloromethane. Lastly, compounds of formula (XXXI) can be reacted with compounds of formula R5-W, wherein R5is as defined above and W is an appropriate reactive group, selected from halogen, boronic ester, boronic acid, trisalkyltin, preferably bromine, or iodine, in the presence of a stoichiometric amount of an appropriate inert base, e.g. alkali carbonate, such as sodium carbonate as well as in the presence of a catalytic or stoichiometric amount of one or more transition metal complexes, such as Palladium- and / or Iridium- and / or Nickel complexes, preferably [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis[3,5-difluoro-2-[5- (trifluoromethyl)-2-pyridinyl-N]phenyl-C]Iridium(III) hexafluorophosphate (Ir[dF(CF3)ppy]2(dtbpy)(PF6), CAS [870987-63-6]), and [4,4′-bis(1,1-dimethylethyl)-2,2′- bipyridine] nickel (II) dichloride (NiCl2.dtbbpy, CAS [1034901-50-2]), further optionally in the presence of a stoichiometric amount of an appropriate reducing agent, e.g. tris(trimethylsilyl)silane (TTMSS, CAS [1873-77-4]), optionally under irradiation of visible or ultraviolet light, preferably LED light with a wavelength of 455 nm, in a polar aprotic solvent, such as dioxane or dimethoxyethane, under an inert atmosphere. Alternatively, compounds of formula (XXIV) can be prepared as depicted in Scheme 10. Scheme 10 A compound of formula (XXXII), wherein PG is a suitable protecting group that is stable against basic conditions, such as benzyloxycarbonyl (Cbz), or benzyl (Bn), and that can be synthesized by methods known in the art or, for R = Bn, as detailed in the experimental section of this patent (Int-27), can be reacted with a stoichiometric amount of a compound of formula HC≡C-R4, wherein R4is C1-C6-alkyl, in the presence of a stoichiometric amount of a suitable strong base, such as n-butyl lithium, in an aprotic polar solvent, such as tetrahydrofuran, at low temperatures of -90°C – -60°C. The resulting compound of formula (XXVIII) can be reacted with an excess of hydrazine hydrate in an appropriate polar solvent, e.g. dimethylformamide, to form a compound of formula (XXXIV). The compound of formula (XXXIV) can be cyclized by stirring under conditions usually used for the formation of amides, known in the art. For example, a compound of formula (XXXIV) can be stirred with a stoichiometric amount of an appropriate activating reagent, such as hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU), in the presence of an excess of a suitable base, e.g. diisopropylamine, or triethylamine, in a suitable polar solvent, such as dimethylformamide to afford a compound of formula (XXX). In the next step, a compound of formula (XXX) can be oxidized to form a compound of formula (XXXI), wherein Z is halogen, preferably bromine or iodine, by reaction with a stoichiometric amount of a suitable halogenating agent, such as bromine or N- bromosuccinimide (NBS) in the case Z = Br, or iodine or N-iodosuccinimide (NIS) in the case Z = I, in a suitable inert solvent, e.g. dichloromethane. Lastly, compounds of formula (XXXI) can be reacted with compounds of formula R5-W, wherein R5is as defined above and W is an appropriate reactive group, selected from halogen, boronic ester, boronic acid, trisalkyltin, preferably bromine, or iodine, in the presence of a stoichiometric amount of an appropriate inert base, e.g. alkali carbonate, such as sodium carbonate as well as in the presence of a catalytic or stoichiometric amount of one or more transition metal complexes, such as Palladium- and / or Iridium- and / or Nickel complexes, preferably [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine- N1,N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]Iridium(III) hexafluorophosphate (Ir[dF(CF3)ppy]2(dtbpy)(PF6), CAS [870987-63-6]), and [4,4′-bis(1,1- dimethylethyl)-2,2′-bipyridine] nickel (II) dichloride (NiCl2.dtbbpy, CAS [1034901-50-2]), further optionally in the presence of a stoichiometric amount of an appropriate reducing agent, e.g. tris(trimethylsilyl)silane (TTMSS, CAS [1873-77-4]), optionally under irradiation of visible or ultraviolet light, preferably LED light with a wavelength of 455 nm, in a polar aprotic solvent, such as dioxane or dimethoxyethane, under an inert atmosphere. In one aspect, the present invention provides a process of manufacturing a comopound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said process is as described in any one of schemes 1 to 10, or a combination thereof. In a further aspect, the present invention provides a compound of formula (I) as described herein, when manufactured according to any one of the processes described herein. sEH Inhibitory Activity Compounds of the present invention are sEH inhibitors. Thus, in one aspect, the present invention provides the use of compounds of formula (I) as described herein for inhibiting sEH in a human. In a further aspect, the present invention provides compounds of formula (I) as described herein for use in a method of inhibiting sEH in a human. In a further aspect, the present invention provides the use of compounds of formula (I) as described herein for the preparation of a medicament for inhibiting sEH in a human. In a further aspect, the present invention provides a method for inhibiting sEH in a human, which method comprises administering an effective amount of a compound of formula (I) as described herein to the human. Determination of hsEH enzymatic inhibitory IC50 values reported herein were perfomed using a RapidFire Mass Sepctrometry (RFMS) based assay, with purified recombinant human soluble epoxide hydrolases proteins (hsEH). Enzyme concentrations were set to 0.5 nM. The enzyme was incubated at room temperature for 15min with compounds (top concentration: 10µM; semi- log dilution, 11 doses) in 50mM TRIS pH 8.0 buffer, containing also 1mM EDTA, 0.01% Tween20, 0.05% BSA and 2% DMSO. The substrate (19,20-EpDPA) was then added ([Substrate]= 4µM), and enzymatic reactions (final volume 20µL) were stopped after 1 hour of incubation at room temperature by addition of 40µL of 50:50 H2O:CH3CN stop solution. Those final mixtures were injected on RFMS platform (Agilent RapidFire 300 coupled with Thermo Scientific TSQ Quantiva mass spectrometer) to accurately quantify substrate (19,20-EpDPA, S) and product (19,20-DiHDPA, P) of the reaction. All measurements were done in triplicate, and P / (P+S) ratio was calculated for each sample. Compound activity was then determined by using Genedata analysis software. Results in the hsEH activity enzymatic assay are provided for compounds of formula (I) in Table 1. Table 1. Results in hsEH inhibitory activity Example No. IC50 (hsEH, nM) Example No. IC50 (hsEH, nM)1 2.0 13 17.22 2.8 14 9.13 1.4 15 1.24 3.8 16 1.65 1.4 17 1.16 3.4 18 26.67 7.0 19 33.38 6.6 20 17.89 18.6 21 6.010 2.4 22 6.911 6.8 23 0.512 1.6 24 1.7In one aspect, the present invention provides compounds of formula (I) and their pharmaceutically acceptable salts or esters as described herein, wherein said compounds of formula (I) and their pharmaceutically acceptable salts or esters have IC50’s for hsEH inhibition below 25 µM, preferably below 10 µM, more preferably below 5 µM as measured in the hsEH inhibitory assay described herein. In one embodiment, compounds of formula (I) and their pharmaceutically acceptable salts or esters as described herein have IC50(hsEH inhibition) values <25 µM, particular compounds have IC50values <1 µM, further particular compounds have IC50values <100 nM, as measured in the hsEH assay described herein. Using the Compounds of the Invention In one aspect, the present invention provides a compound of formula (I) as described herein for use as therapeutically active substance. In a further aspect, the present invention provides a compound of formula (I) as described herein for use in the treatment or prophylaxis of diseases and disorders that are associated with sEH. In a further aspect, the present invention provides a method for the treatment or prophylaxis of diseases and disorders that are associated with sEH in a human, which method comprises administering an effective amount of a compound of formula (I) as described herein to the human. In a further aspect, the present invention provides the use of a compound of formula (I) as described herein for the treatment or prophylaxis of diseases and disorders that are associated with sEH. In a further aspect, the present invention provides the use of a compound of formula (I) as described herein in the preparation of a medicament for the treatment or prophylaxis of diseases and disorders that are associated with sEH. In one embodiment, said diseases and disorders that are associated with sEH are selected from diabetic retinopathy, pain and neurodegenerative diseases. In one embodiment, said diseases and disorders that are associated with sEH are selected from diabetic retinopathy, neuropathic pain and neurodegenerative diseases. In a preferred embodiment, said diseases and disorders that are associated with sEH are diabetic retinopathy. In one embodiment, said diseases and disorders that are associated with sEH are neuropathic pain. In one embodiment, said diseases and disorders that are associated with sEH are neurodegenerative diseases. Pharmaceutical Compositions and Administration In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier. The compounds of formula (I) and their pharmaceutically acceptable salts and esters can be used as medicaments (e.g. in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories). However, the administration can also be effected parentally, such as intramuscularly or intravenously (e.g. in the form of injection solutions). The compounds of formula (I) and their pharmaceutically acceptable salts and esters can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragées and hard gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragées and hard gelatin capsules. Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi- solid substances and liquid polyols, etc. Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc. Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc. Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi- solid or liquid polyols, etc. Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, viscosity- increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances. The dosage can vary in wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g. about 300 mg per person), divided into preferably 1-3 individual doses, which can consist, for example, of the same amounts, should be appropriate. It will, however, be clear that the upper limit given herein can be exceeded when this is shown to be indicated. Tablet Formulation (Wet Granulation)Item Ingredients mg / tablet1. Compound of formula (I) 5 25 100 5002. Lactose Anhydrous DTG 125 105 30 1503. Sta-Rx 1500 6 6 6 304. Microcrystalline Cellulose 30 30 30 1505. Magnesium Stearate 1 1 1 1Total 167 167 167 831Manufacturing Procedure 1. Mix items 1, 2, 3 and 4 and granulate with purified water. 2. Dry the granules at 50°C. 3. Pass the granules through suitable milling equipment. 4. Add item 5 and mix for three minutes; compress on a suitable press. Capsule FormulationItem Ingredients mg / capsule1. Compound of formula (I) 5 25 100 5002. Hydrous Lactose 159 123 148 ---3. Corn Starch 25 35 40 704. Talc 10 15 10 255. Magnesium Stearate 1 2 2 5Total 200 200 300 600Manufacturing Procedure 1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes. 2. Add items 4 and 5 and mix for 3 minutes. 3. Fill into a suitable capsule. Examples The invention will be more fully understood by reference to the following examples. The claims should not, however, be construed as limited to the scope of the examples. In case the preparative examples are obtained as a mixture of enantiomers, the pure enantiomers can be separated by methods described herein or by methods known to the man skilled in the art, such as e.g., chiral chromatography (e.g., chiral SFC) or crystallization. All reaction examples and intermediates were prepared under an argon atmosphere if not specified otherwise. The compounds disclosed and described herein have been named using the IUPAC naming function of Biovia Draw 22.1. If there is a discrepancy between a depicted structure and a name given to that structure, then the depicted structure controls. The following abbreviations are used in the experimental part: THF = tetrahydrofuran; MTBE = methyl-tert-butylether; DMF = dimethylformamide; rt = room temperature, 20-25°C: Boc = t-butyloxycarbonyl:HPLC = High Performance Liquid Chromatography;HBTU = Hexafluorophosphate Benzotriazole Tetramethyl Uronium;HATU = Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium; SFC = Supercritical Liquid Chromatography. Starting materials Basic chemicals and solvents were purchased and used as is without further purification. Intermediates Int-1, Int-2, Int-4, Int-6, Int-13, Int-13, Int-14, Int-25, Int-35, Int-36, Int-39, Int-40, Int-51 are commercially available, or they can be synthesized using methods known in the art. INTERMEDIATES Intermediate 8: 1'-Benzylspiro[2,6-dihydropyrano[3,2-c]pyrazole-5,4'-piperidine]-7-one (Int-8) Int-7 Int-8Step 1: 1-[(4-Methoxyphenyl)methylhydrazono]propan-2-one (Int-3) (4-Methoxyphenyl)methylhydrazine hydrochloride (Int-1, 30.0 g, 159 mmol) was dissolved in water (300 mL) and a solution of pyruvic aldehyde (Int-2, 12.7 g, 53.0 mmol) in water (150 mL) was added dropwise at 25°C within 10 min. The mixture was stirred at 25°C for 50 min. Then, the reaction mixture was extracted with ethyl acetate (3 x 100 mL), the combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a dark brown oil (11.0 g, 53.3 mmol, 95% yield). MS m / z (ESI): 207.0 [M+H]+. Step 2: 1-[4-Hydroxy-1-[(4-methoxyphenyl)methyl]pyrazol-3-yl]ethanone (Int-5) Glyoxal (Int-4, 34.8 g, 240 mmol) was dissolved in methanol (30 mL), and 1-[(4- methoxyphenyl)methylhydrazono]propan-2-one (Int-3, 11.0 g, 48.0 mmol) and water (300 mL) were added. The mixture was stirred at 100°C for 5 h. After cooling, the reaction mixture was extracted with ethyl acetate (3 x 200 mL), the combined organic layers were washed with brine (200 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified via reversed phase chromatography (330 g, Flash Column Welch Ultimate XB_C1820-40 μm, flow rate 100 ml / min, acetonitrile / water, isocratic 40:60 (v / v)), the product containing fractions were lyophilized to yield the title compound as a brown solid (8.6 g, 35 mmol, 73% yield). MS m / z (ESI): 245.0 [M-H]-. Step 3: 1'-Benzyl-2-[(4-methoxyphenyl)methyl]spiro[6H-pyrano[3,2-c]pyrazole-5,4'-piperidine]- 7-one (Int-7) 1-[4-Hydroxy-1-[(4-methoxyphenyl)methyl]pyrazol-3-yl]ethanone (Int-5, 14.5 g, 58.9 mmol) was dissolved in methanol (300 mL), and 1-benzyl-4-piperidone (Int-6, 10.9 mL, 58.9 mmol) and pyrrolidine (1.48 mL, 17.3 mmol) were added subsequently. The mixture was then heated at 60 °C for 20 h. After that, the reaction mixture was extracted with ethyl acetate (3 x 100 mL), the combined organic layers were washed with brine (100 mL), dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, 330 g, petroleum ether / ethyl acetate, gradient 10:90 to 20:80 (v / v)). The product containing fractions were combined and concentrated in vacuo to give the title compound as a yellow solid (10.3 g, 24.7 mmol, 42% yield). MS m / z (ESI): 416.4 [M-H]-. Step 4: 1'-Benzylspiro[2,6-dihydropyrano[3,2-c]pyrazole-5,4'-piperidine]-7-one (Int-8) 1'-Benzyl-2-[(4-methoxyphenyl)methyl]spiro[6H-pyrano[3,2-c]pyrazole-5,4'-piperidine]-7-one (Int-7, 2.50 g, 5.09 mmol) was dissolved in 1,2-dichloroethane (120 mL), and 2,2,2- trifluoroacetic acid (50.0 mL, 649 mmol) was added. The mixture was stirred at 80°C for 20 h. After cooling, the mixture was concentrated in vacuo, the residue was purified by column chromatography (silica gel, 100 g, petroleum ether / ethyl acetate, gradient 25:75 to 50:50). The product containing fractions were combined and concentrated in vacuo to give the title compound as a dark brown solid (2.33 g, 7.85 mmol, 92% yield). MS m / z (ESI): 296.3 [M-H]-. Intermediate 10: 1'-Benzyl-2-isopropyl-spiro[6H-pyrano[3,2-c]pyrazole-5,4'-piperidine]-7- one (Int-9) and 1'-benzyl-1-isopropyl-spiro[6H-pyrano[3,2-c]pyrazole-5,4'-piperidine]-7- one (Int-10) 1'-Benzylspiro[2,6-dihydropyrano[3,2-c]pyrazole-5,4'-piperidine]-7-one (Int-8, 700 mg, 1.41 mmol) was dissolved in DMF (10 mL), 2-iodopropane (264 mg, 1.55 mmol) and cesium carbonate (552 mg, 1.69 mmol) were added and the mixture was stirred at 35°C for 24 h. After that, the reaction mixture was filtered and the filtrate was purified directly via prep-HPLC (Waters Xbridge 150 x 25mm x 5um, flow 25 mL / min, water (+0.1% ammonia) / acetonitrile, gradient 53:47 to 23:77) to obtain 1'-benzyl-2-isopropyl-spiro[6H-pyrano[3,2-c]pyrazole-5,4'- piperidine]-7-one (Int-9, 170 mg, 34% yield) as first eluting regioisomer and as a white solid.MS m / z (ESI): 340.2 [M+H]+. 1H NMR (400 MHz, CDCl3): δ ppm 7.22 – 7.26 (m, 3H), 7.18 –7.20 (m, 2H), 7.03 (s, 1H), 4.42 (hept, J = 6.7 Hz, 1H), 3.47 (br s, 2H), 2.59 (s, 2H), 2.51 – 2.59(m, 2H), 2.29 – 2.40 (m, 2H), 1.96 – 2.03 (m, 2H), 1.62 – 1.75 (m, 2H), 1.45 (d, J = 6.7 Hz, 6H).Further, 1'-benzyl-1-isopropyl-spiro[6H-pyrano[3,2-c]pyrazole-5,4'-piperidine]-7-one (Int-10, 154 mg, 32% yield) was obtained as second eluting regioisomer and as a white solid. MS m / z(ESI): 340.1 [M+H]+. 1H NMR (400 MHz, CDCl3): δ ppm 7.23 – 7.25 (m, 3H), 7.18 – 7.20 (m,2H), 7.13 (s, 1H), 5.09 (hept, J = 6.6 Hz, 1H), 3.49 (br s, 2H), 2.52 – 2.60 (m, 2H), 2.52 (s, 2H),2.31 – 2.41 (m, 2H), 1.97 – 2.04 (m, 2H), 1.61 – 1.72 (m, 2H), 1.38 (d, J = 6.6 Hz, 6H).Intermediate 12: 1'-Benzyl-2-methyl-spiro[6H-pyrano[3,2-c]pyrazole-5,4'-piperidine]-7- one (Int-11) and 1'-benzyl-1-methyl-spiro[6H-pyrano[3,2-c]pyrazole-5,4'-piperidine]-7-one (Int-12) 1'-Benzylspiro[2,6-dihydropyrano[3,2-c]pyrazole-5,4'-piperidine]-7-one (Int-8, 2000 mg, 6.73 mmol) was dissolved in DMF (20 mL), iodomethane (1.05 g, 7.4 mmol) and cesium carbonate (2.63 g, 8.07 mmol) were added and the mixture was stirred at 25°C for 30 min. After that, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified directly via prep-HPLC (Kromasil Eternity XT 250 x 80 mm x 10 um, flow 140 mL / min, water (+0.1% ammonia) / acetonitrile, gradient 69:31 to 39:61) to obtain 1'-benzyl-2-methyl-spiro[6H- pyrano[3,2-c]pyrazole-5,4'-piperidine]-7-one (Int-11, 130 mg, 6% yield) as first elutingregioisomer and as a white solid. MS m / z (ESI): 312.1 [M+H]+. 1H NMR (400 MHz, CDCl3): δ ppm 7.30 – 7.34 (m, 3H), 7.26 – 7.28 (m, 2H), 7.07 (s, 1H), 3.93 (s, 3H), 3.53 (s, 2H), 2.66 (s, 2H), 2.57 – 2.64 (m, 2H), 2.36 – 2.45 (m, 2H), 2.02 – 2.10 (m, 2H), 1.69 – 1.79 (m, 2H). Further, 1'-benzyl-1-methyl-spiro[6H-pyrano[3,2-c]pyrazole-5,4'-piperidine]-7-one (Int-12, 180 mg, 9% yield) was obtained as second eluting regioisomer and as a white solid. MS m / z (ESI):312.1 [M+H]+. 1H NMR (400 MHz, CDCl3): δ ppm 7.20 – 7.31 (m, 5H), 7.12 (s, 1H), 4.00 (s,3H), 3.48 (s, 2H), 2.54 (s, 2H), 2.53 – 2.62 (m, 2H), 2.33 – 2.43 (m, 2H), 1.99 – 2.08 (m, 2H), 1.62 – 1.74 (m, 2H). Intermediate 24: Benzyl 1-methyl-7-oxo-spiro[4,6-dihydroindazole-5,4'-piperidine]-1'- carboxylate (Int-23) and benzyl 2-methyl-7-oxo-spiro[4,6-dihydroindazole-5,4'-piperidine]- 1'-carboxylate (Int-24) Step 1: Benzyl 9-oxo-3-azaspiro[5.5]undec-10-ene-3-carboxylate (Int-15) In a 2 L 3 neck round bottom flask fitted with a Dean−Stark trap, 4-formyl-N-Cbz-piperidine (Int-13, 20.0 g, 80.9 mmol) was dissolved in toluene (160 mL) and p-toluenesulfonic acid (1.39 g, 8.09 mmol) was added. The mixture was heated to 70 °C. Methyl vinyl ketone (Int-14, 13.7 mL, 166 mmol) was then added and the reaction mixture was heated at reflux for 16 h collecting expelled water in the trap. After cooling to 25 °C, the mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate (100 mL). The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated concentrated in vacuo. The resulting dark-brown oil was purified by flash chromatography (silica gel, 220 g, petroleum ether / ethyl acetate, gradient 90:10 to 20:80 (v / v)) to afford the title compound as a dark brown oil (13.2 g, 44.2 mmol, 55% yield). TLC (petroleum ether / ethyl acetate 1:1 (v / v)): Rf = 0.75(potassium permanganate stain). 1H NMR (400 MHz, CDCl3): δ ppm 7.23 – 7.31 (m, 5H), 6.71(d, J = 10.3 Hz, 1H), 5.87 (d, J = 10.3 Hz, 1H), 5.05 (s, 2H), 3.37 – 3.59 (m, 4H), 2.37 (t, J = 6.8 Hz, 2H), 1.88 (t, J = 6.8 Hz, 2H), 1.44 – 1.62 (m, 4H). Step 2: Benzyl 8-(dimethylaminomethylene)-9-oxo-3-azaspiro[5.5]undec-10-ene-3-carboxylate (Int-16) Benzyl 9-oxo-3-azaspiro[5.5]undec-10-ene-3-carboxylate (Int-15, 3.76 g, 12.5 mmol) was dissolved in toluene (70 mL) and N,N,N',N',N",N"-hexamethylmethanetriamine (2.61 mL, 15.1 mmol) was added. The reaction was stirred at 110 °C for 3 h. After cooling to 25 °C, the reaction solution was concentrated in vacuo to provide the title compound as a dark brown solid, which was used in the next step without further purification (40.0 g, 11.3 mmol, 90% yield). MS m / z (ESI): 355.3 [M+H]+. Step 3: Benzyl spiro[1,4-dihydroindazole-5,4'-piperidine]-1'-carboxylate (Int-17) Benzyl (8E)-8-(dimethylaminomethylene)-9-oxo-3-azaspiro[5.5]undec-10-ene-3-carboxylate (Int-16, 4.40 g, 12.4 mmol) was dissolved in ethanol (75 mL) and hydrazine hydrate (932 mg, 18.6 mmol) was added. The mixture was stirred at 80 °C for 2 h. After cooling to 25 °C, it was concentrated under reduced pressure to give the title compound as crude product as a dark brownsolid (3.90 g, 12.1 mmol, 97% yield). MS m / z (ESI): 324.3 [M+H]+. 1H NMR (400 MHz, d6-DMSO): δ ppm 7.27 – 7.43 (m, 6H), 6.46 (d, J = 9.9 Hz, 1H), 5.91 (d, J = 9.9 Hz, 1H), 5.07 (s, 2H), 3.35 – 3.53 (m, 4H), 2.58 (s, 2H), 1.34 – 1.55 (m, 4H). Step 4: Benzyl 1-tetrahydropyran-2-ylspiro[4H-indazole-5,4'-piperidine]-1'-carboxylate (Int-18) Benzyl spiro[1,4-dihydroindazole-5,4'-piperidine]-1'-carboxylate (Int-17, crude from preceeding step, 3.43 g, 10.6 mmol) was dissolved in 1,2-dichloroethane (35 mL), and dihydropyran (3.87 mL, 42.4 mmol) as well as p-toluenesulfonic acid (364 mg, 2.12 mmol) were added. The mixture was stirred at 45 °C for 5 h. After cooling to 25 °C, it was washed with water (30 mL). The layers were separated, the aqueous phase was extracted with dichloromethane (3 x 100 mL), the combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate, gradient 2:1 to 1:1 (v / v)) to yield the title compound as a lightbrown oil (1.98 g, 4.86 mmol, 46% yield). MS m / z (ESI): 408.3 [M+H]+. 1H NMR (400 MHz,CDCl3): δ ppm 7.17 – 7.30 (m, 6H), 6.48 (d, J = 9.9 Hz, 1H), 5.85 (d, J = 10.0 Hz, 1H), 5.17 – 5.22 (m, 1H), 5.05 (s, 2H), 3.93 – 4.02 (m, 1H), 3.56 – 3.64 (m, 1H), 3.35 – 3.52 (m, 4H), 2.52 (s, 2H), 1.92 – 2.08 (m, 4H), 1.37 – 1.67 (m, 6H). Step 5: Benzyl 6-bromo-7-hydroxy-1-tetrahydropyran-2-yl-spiro[6,7-dihydro-4H-indazole-5,4'- piperidine]-1'-carboxylate (Int-19) Benzyl 1-tetrahydropyran-2-ylspiro[1,4-dihydroisoindole-5,4'-piperidine]-1'-carboxylate (Int-18, 1.98 g, 4.86 mmol) was dissolved in tetrahydrofuran (30 mL) and water (10 mL), and N- bromosuccinimide (867 mg, 4.87 mmol) was added. The reaction was stirred for 30 min at 25 °C. Then, it was diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium thiosulfate solution (30 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a dark brown oil (2.32 g, 4.60 mmol, 95% yield), that was used in the next step without further purification. MS m / z (ESI): 504.2, 506.2 [M+H]+, Br isotopes. Step 6: Benzyl 6-bromo-7-oxo-1-tetrahydropyran-2-yl-spiro[4,6-dihydroindazole-5,4'- piperidine]-1'-carboxylate (Int-20) Benzyl 6-bromo-7-hydroxy-1-tetrahydropyran-2-yl-spiro[6,7-dihydro-4H-indazole-5,4'- piperidine]-1'-carboxylate (Int-19, 776 mg, 1.54 mmol) was dissolved in dichloromethane (20 mL), and (1,1,1-triacetoxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (783 mg, 1.85 mmol) was added. The mixture was stirred vigorously at 20 °C for 0.5 h. Then, the reaction was stopped by addition of saturated aqueous sodium sulphite solution (12 mL) and saturated aqueous sodium hydrogencarbonate solution (15 mL). The mixture was stirred at 20 °C for 20 min. After that, it was extracted with dichloromethane (3 x 80 mL), the combined extracts were washed with brine (2 x 30 mL) and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 20 g, petroleum ether / ethyl acetate, gradient 75:25 to 0:100) to afford the title compound as an orange oil (502 mg, 1.00 mmol, 65% yield). MS m / z (ESI): 418.0, 420.0 [M+H-THP]+, Br isotopes. Step 7: Benzyl 7-oxo-1-tetrahydropyran-2-yl-spiro[4,6-dihydroindazole-5,4'-piperidine]-1'- carboxylate (Int-21) Benzyl 6-bromo-7-oxo-1-tetrahydropyran-2-yl-spiro[4,6-dihydroindazole-5,4'-piperidine]-1'- carboxylate (Int-20, 1.21 g, 2.4 mmol) was dissolved in tetrahydrofuran (24 mL) and saturated aqueous ammonium chloride solution (24 mL) and zinc powder (461 mg, 7.2 mmol) was added. The mixture was stirred vigorously at 20 °C for 0.5 h. Then, it was diluted with water (50 mL) and ethyl acetate (100 mL) and the layers were separated. The organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude title compound as a light brown solid (800 mg, 1.89 mmol, 64% yield), that was used in the nextstep without further purification. MS m / z (ESI): 424.3 [M+H]+. 1H NMR (400 MHz, CDCl3): δppm 7.52 (s, 1H), 7.29 – 7.38 (m, 5H), 5.46 (dd, J = 2.9, 9.0 Hz, 1H), 5.12 (s, 2H), 4.02 – 4.09 (m, 1H), 3.66 – 3.74 (m, 1H), 3.43 – 3.55 (m, 4H), 2.75 (s, 2H), 2.59 (s, 2H), 1.96 – 2.18 (m, 4H), 1.52 – 1.73 (m, 6H). Step 8: Benzyl 7-oxospiro[4,6-dihydro-1H-indazole-5,4'-piperidine]-1'-carboxylate hydrochloride (Int-22) Benzyl 7-oxo-1-tetrahydropyran-2-yl-spiro[4,6-dihydroindazole-5,4'-piperidine]-1'-carboxylate (Int-21, crude from preceeding step, 550 mg, 1.3 mmol) was dissolved in ethyl acetate (6 mL) and a solution of hydrogen chloride in dioxane (4M, 0.6 mL, 2.4 mmol) was added. The mixture was stirred at 20 °C for 3 h. After that, it was diluted with petroleum ether (20 mL) and the precipitate was filtered off, washed with petroleum ether (20 mL) and dried in high vacuum to yield the title compound as a white solid (336 mg, 0.99 mmol, 76% yield). MS m / z (ESI): 340.2[M+H]+. 1H NMR (400 MHz, CDCl3): δ ppm 8.96 (br s, 2H), 7.93 (s, 1H), 7.30 – 7.40 (m, 5H),5.14 (s, 2H), 3.49 – 3.56 (m, 4H), 2.87 (s, 2H), 2.70 (s, 2H), 1.54 – 1.62 (m, 4H). Step 9: Benzyl 1-methyl-7-oxo-spiro[4,6-dihydroindazole-5,4'-piperidine]-1'-carboxylate (Int- 23) and benzyl 2-methyl-7-oxo-spiro[4,6-dihydroindazole-5,4'-piperidine]-1'-carboxylate (Int-24)Benzyl 7-oxospiro[4,6-dihydro-1H-indazole-5,4'-piperidine]-1'-carboxylate hydrochloride (Int- 22, 336 mg, 0.89 mmol) was dissolved in in DMF (5 mL) and cesium carbonate (583 mg, 1.79 mmol) was added. The suspension was stirred for 15 min and iodomethane (140 mg, 0.99 mmol) was added. The mixture was stirred at 20 °C for 3.25 h. After that, it was filtered and the filtrate was purified directly by prep HPLC (Phenomenex luna C18150 x 25 mm x 10 um, flow 25 mL / min, water (+0.1% TFA) / acetonitrile, gradient 70:30 to 30:70) to yield benzyl 2-methyl-7- oxo-spiro[4,6-dihydroindazole-5,4'-piperidine]-1'-carboxylate (Int-24, 55 mg, 0.16 mmol, 17% yield) as a black solid, and benzyl 1-methyl-7-oxo-spiro[4,6-dihydroindazole-5,4'-piperidine]-1'- carboxylate (Int-23, 155 mg, 0.44 mmol, 49% yield) as a black solid. Characterisation Int-24(minor regioisomer): MS m / z (ESI): 354.1 [M+H]+. 1H NMR (400 MHz, d6-DMSO): δ ppm7.62 (s, 1H), 7.29 – 7.39 (m, 5H), 5.06 (s, 2H), 3.89 (s, 3H), 3.26 – 3.51 (m, 4H), 2.73 (s, 2H),2.51 (s, 2H), 1.38 – 1.46 (m, 4H); Int-23 (major regioisomer): MS m / z (ESI): 354.1 [M+H]+. 1H NMR (400 MHz, d6-DMSO): δ ppm 7.41 (s, 1H), 7.28 – 7.39 (m, 5H), 5.06 (s, 2H), 4.01 (s, 3H), 3.33 – 3.49 (m, 4H), 2.74 (s, 2H), 2.56 (s, 2H), 1.39 – 1.49 (m, 4H). The structures of theregioisomers were assigned based on analysis of 1H-13C 2D NMR spectra.Intermediate 30: 1'-Benzyl-2-isopropyl-spiro[4,6-dihydropyrazolo[1,5-a]pyridine-5,4'- piperidine]-7-one (Int-30) Int-28 Int-29 Int-30Step 1: 2-[1-Benzyl-4-(carboxymethyl)-4-piperidyl]acetic acid (Int-26) 9-Benzyl-2,4-dioxo-3,9-diazaspiro[5.5]undecane-1,5-dicarbonitrile (Int-25, 3.00 g, 9.31 mmol) was dissolved in concentrated sulfuric acid (20 mL) and the mixture was stirred at 100°C for 8 h and at 150°C for 8 h. After cooling, the pH of the mixture was adjusted to 3 by addition of sodium hydroxide, and the mixture was purified via reversed phase chromatography (water (+0.1% TFA) / acetonitrile, gradient 90:10 to 10:90). The product containing fractions were combined and lyophilized to yield the title compound as a white solid (2.00 g, 6.86 mmol, 74% yield). MS m / z (ESI): 292.4 [M+H]+. Step 2: 9-Benzyl-3-oxa-9-azaspiro[5.5]undecane-2,4-dione hydrochloride (Int-27) 2-[1-Benzyl-4-(carboxymethyl)-4-piperidyl]acetic acid (Int-26, 800 mg, 2.75 mmol) was dissolved in acetic anhydride (10 mL) and the mixture was stirred at 110°C for 16 h. After cooling to 25°C, ethyl acetate (20 mL) was added, followed by dropwise addition of a solution of hydrogen chloride in dioxane (4M, 20 mL, 80 mmol). The mixture was stirred at 25°C for 10 min, the precipitate was filtered off and dried in high vacuum to afford the title compound as a white solid (750 mg, 2.42 mmol, 88% yield). MS m / z (ESI): 274.1 [M+H]+. Step 3: 2-[1-Benzyl-4-(5-methyl-2-oxo-hex-3-ynyl)-4-piperidyl]acetic acid (Int-28) 3-Methyl-1-butyne (214 mg, 3.15 mmol) was dissolved in tetrahydrofuran (3 mL) and the solution was cooled to -78°C (acetone / dry ice). A solution of n-butyl lithium in n-hexane (2.5 M, 1.17 mL, 2.94 mmol) was added and the mixture was stirred at -78°C for 0.5 h. Then, 9- benzyl-3-oxa-9-azaspiro[5.5]undecane-2,4-dione hydrochloride (Int-27, 650 mg, 2.1 mmol) was added and the mixture was stirred at -78°C for an additional 0.5 h. After that, the reaction mixture was poured into an aqueous solution of ammonium chloride (1M, 50 mL), extracted with ethyl acetate (3 x 100 mL), the combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reversed phase chromatography (water (+0.1% ammonia) / acetonitrile, gradient 90:10 to 10:90). The product containing fractions were combined and lyophilized to yield the title compound as a white solid (100 mg, 0.29 mmol, 14% yield). MS m / z (ESI): 342.2 [M+H]+.1H NMR (400 MHz, CDCl3): δ ppm 7.29 – 7.36 (m, 5H), 3.77 (s, 2H), 2.70 (hept, J = 7.0 Hz, 1H), 2.66 (s, 2H), 2.46 (s, 2H), 2.35 – 2.57 (m, 4H), 2.18 – 2.35 (m, 2H), 1.65 – 1.74 (m, 2H), 1.21 (d, J = 6.9 Hz, 6H). Step 4: 2-[1-Benzyl-4-[(3-isopropyl-1H-pyrazol-5-yl)methyl]-4-piperidyl]acetic acid (Int-29) 2-[1-Benzyl-4-(5-methyl-2-oxo-hex-3-ynyl)-4-piperidyl]acetic acid (Int-28, 50 mg, 0.15 mmol) was dissolved in DMF (3 mL) and hydrazine hydrate (12.5 mg, 0.24 mmol) was added dropwise at 0°C. The mixture was stirred at 25°C for 1 h. After that, it was purified directly by reversed phase chromatography (water (+0.1% ammonia) / acetonitrile, gradient 90:10 to 10:90). The product containing fractions were combined and lyophilized to give the title compound as a white solid (50 mg, 0.14 mmol, 96% yield). MS m / z (ESI): 356.2 [M+H]+. Step 5: 1'-Benzyl-2-isopropyl-spiro[4,6-dihydropyrazolo[1,5-a]pyridine-5,4'-piperidine]-7-one (Int-30) 2-[1-Benzyl-4-[(3-isopropyl-1H-pyrazol-5-yl)methyl]-4-piperidyl]acetic acid (Int-29, 45 mg, 0.13 mmol) was dissolved in DMF (15 mL), and HATU (72 mg, 0.19 mmol) and diisopropylethylamine (49 mg, 0.38 mmol) were added at 25°C. The mixture was stirred at 25°C for 1 h. After that, it was purified by reversed phase chromatography (water (+0.1% ammonia) / acetonitrile, gradient 90:10 to 10:90). The product containing fractions were combined and lyophilized to give the title compound as a white solid (40 mg, 0.12 mmol, 94% yield). MS m / z(ESI): 338.2 [M+H]+. 1H NMR (400 MHz, d4-MeOH): δ ppm 7.31 – 7.35 (m, 5H), 6.23 (s, 1H),3.59 (s, 2H), 2.92 – 3.00 (m, 3H), 2.76 (s, 2H), 2.48 – 2.57 (m, 4H), 1.55 – 1.61 (m, 4H), 1.25 (d, J = 7.0 Hz, 6H). Intermediate 34: 1,3-Dimethylspiro[6H-pyrano[3,2-c]pyrazole-5,4'-piperidine]-7-one hydrochloride (Int-34) Int-33 Int-34 Step 1: tert-Butyl 1-methyl-7-oxo-spiro[6H-pyrano[3,2-c]pyrazole-5,4'-piperidine]-1'- carboxylate (Int-31) 1-Methylspiro[6H-pyrano[3,2-c]pyrazole-5,4'-piperidine]-7-one hydrochloride (Int-59, 60 mg, 0.23 mmol) was dissolved in methanol (1 mL) and triethylamine (60 uL, 0.47 mmol) was added. After stirring for 15 min, di-t-butyldicarbonate (61 mg, 0.28 mmol) was added and the mixture was stirred for 0.5 h at 25 °C. After that, it was concentrated in vacuo and purified by preparative tlc (petroleum ether / ethyl acetate 3:1 (v / v)) to yield the title compound as a colorless gum (60 mg, 0.19 mmol, 80% yield). as a colorless gum. MS m / z (ESI): 322.2 [M+H]+.Step 2: tert-Butyl 3-bromo-1-methyl-7-oxo-spiro[6H-pyrano[3,2-c]pyrazole-5,4'-piperidine]-1'-carboxylate (Int-32) tert-Butyl 1-methyl-7-oxo-spiro[6H-pyrano[2,3-c]pyrazole-5,4'-piperidine]-1'-carboxylate (Int- 31, 80 mg, 0.25 mmol) was dissolved in dichloromethane (3 mL), and bromine (48 mg, 0.3 mmol) was added at 25 °C. The mixture became cloudy and was stirred at 35 °C for 3 h. Then, an additional portion of bromine (60 mg, 0.38 mmol) was added and the mixture was stirred at 35 °C for further 3 h. After cooling, triethylamine (0.10 mL, 0.73 mmol) was added, the mixture was stirred for 10 min, di-tert-butyl dicarbonate (100 mg, 0.46 mmol) was added and the mixture was stirred for 1 h at 25 °C. After that, the mixture was concentrated in vacuo and purified by preparative tlc (silica, petroleum ether / ethyl acetate 3:1 (v / v), 254 nm, Rf = 0.5). The title compound was isolated as a light yellow solid (50 mg, 0.12 mmol, 50% yield), along with 30 mg of starting material. MS m / z (ESI): 400.1, 402.1 [M+H, Br isotopes]+.Step 3: tert-Butyl 1,3-dimethyl-7-oxo-spiro[6H-pyrano[3,2-c]pyrazole-5,4'-piperidine]-1'-carboxylate (Int-33) tert-Butyl 3-bromo-1-methyl-7-oxo-spiro[6H-pyrano[2,3-d]pyrazole-5,4'-piperidine]-1'- carboxylate (Int-32, 50 mg, 0.12 mmol) was dissolved in dioxane (2 mL) and water (0.5 mL) and methylboronic acid (30 mg, 0.5 mmol) as well as potassium carbonate (37 mg, 0.27 mmol) were added. The mixture was degassed by bubbling through nitrogen for 10 min, tetrakis(triphenylphosphine) palladium(0) (14.4 mg, 0.01 mmol) was added and mixture was degassed with nitrogen (3 x). Then, the mixture was stirred at 120 °C for 1 h. After cooling to 25 °C, it was diluted with ethyl acetate (15 mL) and water (10 mL). Phases were separated, the aqueous phase was extracted with ethyl acetate (2 x 30 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative tlc (petroleum ether / ethyl acetate 3:1 (v / v), 254 nm, Rf = 0.4) to obtain the title compound as a light yellow oil (18 mg, 0.05 mmol, 43% yield). MS m / z (ESI): 336.2 [M+H]+. Step 4: 1,3-Dimethylspiro[6H-pyrano[3,2-c]pyrazole-5,4'-piperidine]-7-one hydrochloride (Int- 34) tert-Butyl 1,3-dimethyl-7-oxo-spiro[6H-pyrano[2,3-d]pyrazole-5,4'-piperidine]-1'-carboxylate (Int-33, 18 mg, 0.05 mmol) was dissolved in 1,4-dioxane (1 mL) and a solution of hydrogen chloride in dioxane (1.6 M, 0.03 mL, 0.05 mmol) was added. The mixture was stirred at 25°C for 3 h. After that, it was concentrated in vacuo to yield the title compound as a light grey solid (15 mg, 0.06 mmol). MS m / z (ESI): 236.1 [M+H]+. Intermediate 38: 3-(1-Methylindazol-4-yl)cyclobutanamine 2,2,2-trifluoroacetate salt (Int- 38) Step 1: tert-Butyl N-[3-(1-methylindazol-4-yl)cyclobutyl]carbamate (Int-37)4-Bromo-1-methyl-indazole (Int-35, 150 mg, 0.71 mmol) was dissolved in degassed dimethoxyethane (4 mL), tert-butyl N-(3-iodocyclobutyl)carbamate (Int-36, 275 mg, 0.92 mmol), [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis[3,5-difluoro-2-[5- (trifluoromethyl)-2-pyridinyl-N]phenyl-C]Iridium(III) hexafluorophosphate (Ir[dF(CF3)ppy]2(dtbpy)(PF6), CAS [870987-63-6], 8.0 mg, 0.01 mmol), [4,4′-bis(1,1- dimethylethyl)-2,2′-bipyridine] nickel (II) dichloride (NiCl2.dtbbpy, CAS [1034901-50-2], 1.4 mg, 0.01 mmol), tris(trimethylsilyl)silane (TTMSS, CAS [1873-77-4], 177 mg, 0.71 mmol) and sodium carbonate (151 mg, 1.42 mmol) were added. The mixture was again degassed and stirred at 25°C for 16 h under irradiation with a 455 nm blue LED. After that, the mixture was diluted with ethyl acetate (10 mL), and water (20 mL). Phases were separated, the aqueous phase was extracted with ethyl acetate (2 x 30 mL). The combined extracts were washed with brine (60 mL) and a saturated aqueous solution of calcium chloride (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative tlc (petroleum ether / ethyl acetate 5:1 (v / v), 254 nm, Rf = 0.25), followed by preparative HPLC (Phenomenex luna C18150 x 25 mm x 10 um, flow 25 mL / min, water (+0.1% formic acid) / acetonitrile, gradient 55:45 to 25:75). The product containing fractions were lyophilized to yield the title compound as a white solid (160 mg, 0.53 mmol, 75% yield). MS m / z (ESI): 302.2 [M+H]+. Step 2: 3-(1-Methylindazol-4-yl)cyclobutanamine 2,2,2-trifluoroacetate salt (Int-38)tert-Butyl N-[3-(1-methylindazol-4-yl)cyclobutyl]carbamate (Int-37, 36 mg, 0.12 mmol) wasdissolved in dichloromethane (0.5 mL) and a solution of 2,2,2-trifluoroacetic acid in dichloromethane (1:5 (v / v), 2 mL) was added. The mixture was stirred at 25°C for 2 h. After that, it was concentrated in vacuo to yield the title compound as a light brown oil (36 mg, 0.11 mmol, 92% yield) as a light brown oil. MS m / z (ESI): 202.1 [M+H]+. Intermediate 45: Spiro[4,6-dihydropyrazolo[1,5-a]pyridine-5,4'-piperidine]-7-one hydrobromide (Int-45) Step 1: Benzyl 4-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)piperidine-1-carboxylate (Int- 41) Benzyl 4-oxopiperidine-1-carboxylate (Int-39, 8.5 mL, 42.9 mmol) was dissolved in pyridine (4.2 mL) and 2,2-dimethyl-1,3-dioxane-4,6-dione (Int-40, 6.18 g, 42.9 mmol) as well as piperidine (36.5 mg, 0.43 mmol) were added. The mixture was stirred at 45 °C for 1 h. After that, it solidified and was let standing for 11 h. Methanol (10 mL) was added and the resulting mixture was stirred for 30 min, the suspension was filtered off, the precipitate was washed with methanol (10 mL), and dried in vacuo to afford the title compound as a colorless solid (12.0 g,33.4 mmol, 78% yield). 1H NMR (400 MHz, CDCl3): δ ppm 7.32 - 7.40 (m, 5H), 5.17 (s, 2H),3.70 (t, J = 5.9 Hz, 4H), 3.19 (t, J = 5.4 Hz, 4H), 1.75 (s, 6H).Step 2: Benzyl 4-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-4-(2-oxo-4-trimethylsilyl-but-3- ynyl)piperidine-1-carboxylate (Int-42) A solution of lithium diisopropylamide in tetrahydrofuran (2 M, 1.8 mL, 3.6 mmol) was diluted with tetrahydrofuran (10 mL) and cooled to -60 °C under nitrogen atmosphere. Then, 4- trimethylsilylbut-3-yn-2-one (507 mg, 3.6 mmol) was added. After 30 min stirring at -60 °C, copper(l) iodide (264 mg, 1.39 mmol) was added, and stirring was continued for 10 min. Then, a solution of benzyl 4-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)piperidine-1-carboxylate (Int-41, 1.00 g, 2.78 mmol) in THF (5 mL) was added dropwise at -60 °C. The mixture was stirred at -60 °C for 2 h. Then, it was warmed to -20 °C, and the reaction was stopped by addition of a saturated aqueous solution of ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (3 x 30 mL), the combined organic extracts washed with brine (30 mL) and concentrated in vacuo. The residue was purified by reversed phase chromatography (water (+0.1% formic acid) / acetonitrile, isocratic 25:75 (v / v)). The product containing fractions were combined and lyophilized to afford the title compound as a yellow oil (400 mg, 0.8 mmol, 29% yield). MS m / z (ESI): 500.3 [M+H]+. Step 3: Benzyl 4-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-4-(1H-pyrazol-5- ylmethyl)piperidine-1-carboxylate (Int-43) Benzyl 4-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-4-(2-oxo-4-trimethylsilyl-but-3- ynyl)piperidine-1-carboxylate (Int-42, 400 mg, 0.8 mmol) was dissolved in dimethylformamide (10 mL), and the solution was cooled to 0 – 4 °C (ice bath). Hydrazine hydrate (102 mg, 2.0 mmol) was added and the mixture was stirred at 20 °C for 12 h. After that, the mixture was purified directly by reversed phase chromatography (water (+0.1% formic acid) / acetonitrile, gradient 50:50 to 40:60 (v / v)). The product containing fractions were combined and lyophilized to yield the title compound as a yellow oil (300 mg, 0.68 mmol, 85% yield). MS m / z (ESI): 441.2 [M+H]+. Step 4: Benzyl 7-oxospiro[4,6-dihydropyrazolo[1,5-a]pyridine-5,4'-piperidine]-1'-carboxylate (Int-44) Benzyl 4-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-4-(1H-pyrazol-5-ylmethyl)piperidine-1- carboxylate (Int-43, 300 mg, 0.68 mmol) was dissolved in dimethylformamide (10 mL) and water (1 mL). The solution was stirred at 100 °C for 5 h. After that, the mixture was purified directly by reversed phase chromatography (water (+0.1% formic acid) / acetonitrile, gradient 50:50 to 40:60 (v / v)). The product containing fractions were combined and lyophilized to obtain the title compound as a yellow solid (20 mg, 0.06 mmol, 9% yield). MS m / z (ESI): 340.3 [M+H]+.1H NMR (400 MHz, CDCl3): δ ppm 7.75 (s, 1H), 7.30 - 7.40 (m, 5H), 6.21 (s, 1H), 5.13 (s, 2H), 3.45 – 3.60 (m, 4H), 2.94 (s, 2H), 2.79 (s, 2H), 1.50 – 1.60 (m, 4H). Step 5: Spiro[4,6-dihydropyrazolo[1,5-a]pyridine-5,4'-piperidine]-7-one hydrobromide (Int-45) Benzyl 7-oxospiro[4,6-dihydropyrazolo[1,5-a]pyridine-5,4'-piperidine]-1'-carboxylate (Int-44, 15 mg, 0.04 mmol) was dissolved in dichloromethane (2 mL) and a solution of hydrogen bromide in acetic acid (33% (m / m), 0.5 mL) was added at 0 °C. The mixture was stirred at 0 °C for 1 h. After that, it was concentrated in vacuo to afford the title compound as a brown oil, that was used in the next step without further purification (ca.15 mg, quant. yield). MS m / z (ESI): 206.1 [M+H]+. Intermediate 48: 2-Methylspiro[4,6-dihydropyrazolo[1,5-a]pyridine-5,4'-piperidine]-7-one hydrobromide (Int-48) Int-48 Step 1: Benzyl 4-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-4-(2-oxopent-3-ynyl)piperidine-1- carboxylate (Int-46) A solution of lithium diisopropylamide in tetrahydrofuran (2 M, 0.9 mL, 1.8 mmol) was diluted with tetrahydrofuran (4 mL) and cooled to -60 °C under nitrogen atmosphere. Then, pent-3-yn- 2-one (148 mg, 1.8 mmol) was added. After 30 min stirring at -60 °C, copper(l) iodide (132 mg, 0.7 mmol) was added, and stirring was continued for 10 min. Then, a solution of benzyl 4-(2,2- dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)piperidine-1-carboxylate (Int-41, 500 mg, 1.39 mmol) in THF (5 mL) was added dropwise at -60 °C. The mixture was stirred at -60 °C for 2 h. Then, it was warmed to -20 °C, and the reaction was stopped by addition of a saturated aqueous solution of ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (3 x 30 mL), the combined organic extracts washed with brine (30 mL) and concentrated in vacuo to yield the crude title compound as a yellow oil, that was used in the next step without further purification (300 mg, 0.68 mmol, 49% yield). MS m / z (ESI): 442.3 [M+H]+. Step 2: Benzyl 2-methyl-7-oxo-spiro[4,6-dihydropyrazolo[1,5-a]pyridine-5,4'-piperidine]-1'- carboxylate (Int-47) Benzyl 4-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-4-(2-oxopent-3-ynyl)piperidine-1- carboxylate (Int-46, 300 mg, 0.68 mmol, crude from preceeding step) was dissolved in dimethylformamide (5 mL) and hydrazine hydrate (69 mg, 1.36 mmol) was added. The mixture was stirred at 20 °C for 1 h. After that, the mixture was purified directly by reversed phase chromatography (water (+0.1% formic acid) / acetonitrile, gradient 50:50 to 40:60 (v / v)). The product containing fractions were combined and lyophilized to yield the title compound as a yellow oil (70 mg, 0.2 mmol, 29% yield). MS m / z (ESI): 354.4 [M+H]+.1H NMR (400 MHz, CDCl3): δ ppm 7.30 – 7.41 (m, 5H), 6.03 (s, 1H), 5.13 (s, 2H), 3.43 – 3.60 (m, 4H), 2.88 (s, 2H), 2.73 (s, 2H), 2.32 (s, 3H), 2.03 – 2.51 (m, 4H). Step 3: 2-Methylspiro[4,6-dihydropyrazolo[1,5-a]pyridine-5,4'-piperidine]-7-one hydrobromide (Int-48) Benzyl 2-methyl-7-oxo-spiro[4,6-dihydropyrazolo[1,5-a]pyridine-5,4'-piperidine]-1'-carboxylate (Int-47, 70 mg, 0.2 mmol) was dissolved in dichloromethane (1 mL) and a solution of hydrogen bromide in acetic acid (33% (m / m), 0.1 mL) was added at 0 °C. The mixture was stirred at 0 °C for 1 h. After that, it was concentrated in vacuo to afford the title compound as a yellow oil, that was used in the next step without further purification (50 mg, 0.17 mmol, 84% yield). MS m / z (ESI): 220.3 [M+H]+. Intermediate 50: Benzyl 3-methyl-7-oxo-spiro[4,6-dihydropyrazolo[1,5-a]pyridine-5,4'- piperidine]-1'-carboxylate (Int-50) Step 1: Benzyl 3-bromo-7-oxo-spiro[4,6-dihydropyrazolo[1,5-a]pyridine-5,4'-piperidine]-1'- carboxylate (Int-49) Benzyl 7-oxospiro[4,6-dihydropyrazolo[1,5-a]pyridine-5,4'-piperidine]-1'-carboxylate (Int-44, 430 mg, 1.27 mmol) was dissolved in dichloromethane (3 mL) and bromine (243 mg, 1.52 mmol) was added at 25°C. The mixture became cloudy and was stirred at 35 °C for 1 h. A second portion of bromine (243 mg, 1.52 mmol) was added at 25°C and the mixture was stirred at 35 °C for additional 2 h. After cooling, it was concentrated in vacuo, the residue was purified by column chromatography (silica gel, 4 g, petroleum ether / ethyl acetate, gradient 3:1 to 1:1 (v / v)) to afford the title compound as a light yellow solid (200 mg, 0.48 mmol, 29% yield). MSm / z (ESI): 420.2 [M+H]+. 1H NMR (400 MHz, CDCl3): δ ppm 7.75 (s, 1H), 7.30 – 7.40 (m, 5H),5.14 (s, 2H), 3.56 – 3.64 (m, 2H), 3.45 – 3.53 (m, 2H), 2.87 (s, 2H), 2.80 (s, 2H), 1.80 – 2.34 (m, 4H). Step 2: Benzyl 3-methyl-7-oxo-spiro[4,6-dihydropyrazolo[1,5-a]pyridine-5,4'-piperidine]-1'- carboxylate (Int-50) Benzyl 3-bromo-7-oxo-spiro[4,6-dihydropyrazolo[1,5-a]pyridine-5,4'-piperidine]-1'-carboxylate (Int-49, 40 mg, 0.10 mmol) was dissolved in degassed dimethoxyethane (3 mL), methyl iodide (136 mg, 0.96 mmol), [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis[3,5-difluoro-2-[5- (trifluoromethyl)-2-pyridinyl-N]phenyl-C]Iridium(III) hexafluorophosphate (Ir[dF(CF3)ppy]2(dtbpy)(PF6), CAS [870987-63-6], 1.1 mg, 1.0 umol), [4,4′-bis(1,1- dimethylethyl)-2,2′-bipyridine] nickel (II) dichloride (NiCl2.dtbbpy, CAS [1034901-50-2], 0.2 mg, 1.0 umol), tris(trimethylsilyl)silane (TTMSS, CAS [1873-77-4], 23.8 mg, 0.10 mmol) and sodium carbonate (20.3 mg, 0.19 mmol) were added. The mixture was again degassed and stirred at 25°C for 16 h under irradiation with a 455 nm blue LED. After that, the mixture was diluted with ethyl acetate (15 mL), and water (10 mL). Phases were separated, the aqueous phase was extracted with ethyl acetate (2 x 30 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative tlc (petroleum ether / ethyl acetate 3:1 (v / v), 254 nm, Rf = 0.4) to obtain the title compound as a light yellow solid (28 mg, 0.08 mmol, 82% yield). MS m / z (ESI): 354.1 [M+H]+. Intermediate 56: Benzyl 8-oxospiro[7H-pyrano[3,2-d]pyrimidine-6,4'-piperidine]-1'- carboxylate (Int-56) Step 1: 5-Benzyloxy-2-chloro-4-(1-ethoxyvinyl)pyrimidine (Int-52) 5-Benzyloxy-2,4-dichloro-pyrimidine (Int-51, 2.00 g, 7.84 mmol) and potassium fluoride (1.82 g, 31.4 mmol) were dissolved in DMF (30 mL), and bis-triphenylphosphine-palladium(II) chloride (550 mg, 0.78 mmol) and tributyl(1-ethoxyvinyl)tin (2.84 g, 7.86 mmol) were added under nitrogen atmosphere. The mixture was stirred at 75 °C for 3 h. After cooling to 25°C, the mixture was diluted with ethyl acetate (40 mL) and water (25 mL). Phases were separated, the aqueous phase was extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine (60 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 20 g, petroleum ether / ethyl acetate, gradient 10:1 to 3:1 (v / v)) to yield the title compound as a light brown solid (1.80 g, 6.19 mmol,79% yield). MS m / z (ESI): 291.1 [M+H]+. 1H NMR (400 MHz, CDCl3): δ ppm 8.29 (s, 1H),7.34 – 7.47 (m, 5H), 5.20 (s, 2H), 5.11 (d, J = 2.8 Hz, 1H), 4.70 (d, J = 2.8 Hz, 1H), 3.95 (q, J =7.0 Hz, 2H), 1.40 (t, J = 7.0 Hz, 3H).Step 2: 1-(5-Benzyloxy-2-chloro-pyrimidin-4-yl)ethanone (Int-53) 5-Benzyloxy-2-chloro-4-(1-ethoxyvinyl)pyrimidine (Int-52, 1.77 g, 6.09 mmol) was dissolved in 1,4-dioxane (50 mL) and aqueous hydrochloric acid (1M, 5.0 mL, 5.0 mmol) was added at 20°C. The mixture was stirred at 50°C for 0.5 h. After cooling, the mixture was concentrated in vacuo to afford the title compound as a white solid, that was used in the next step without further purification (1.50 g, 5.71 mmol, 94% yield). MS m / z (ESI): 263.1 [M+H]+. Step 3: 1-(5-Hydroxy-2,5-dihydropyrimidin-4-yl)ethanone (Int-54) 1-(5-Benzyloxy-6-chloro-pyrimidin-4-yl)ethanone (Int-53, 1.50 g, 5.71 mmol) was dissolved in ethanol (20 mL) and ethyl acetate (2.0 mL). Triethylamine (1.0 mL, 7.35 mmol) followed by palladium (10% on charcoal, 100 mg) were added under nitrogen atmosphere at 25°C in one portion. The mixture was degassed by subsequent atmosphere evacuation under vacuum – refill with hydrogen cycles (3 x). After that, it was stirred at 25°C for 8 h under a hydrogen atmosphere (balloon). It was filtered, washed with ethanol (15 mL), and the filtrate was concentrated in vacuo to obtain the title compound as a crude mixture (light brown oil, 1.50 g), that was used in the next step without further purification. Step 4: 1-(5-Hydroxypyrimidin-4-yl)ethanone (Int-55) 1-(5-Hydroxy-2,5-dihydropyrimidin-4-yl)ethanone (Int-54, 1.50 g, 5.71 mmol, crude from preceeding step) was dissolved in dichloroethane (50 mL), and manganese dioxide (4.65 g, 53.5 mmol) was added. The mixture was stirred at 50°C for 1 h. After cooling, it was filtered and the filtrate was concentrated in vacuo. The residue was purified by reversed phase chromatography (water (+0.1% ammonia) / acetonitrile, isocratic, 50:50 (v / v)). The product containing fractions were combined and lyophilized to yield the title compound as a light yellow oil (300 mg, 2.17 mmol, 38% yield over 2 steps). MS m / z (ESI): 139.1 [M+H]+. Step 5: Benzyl 8-oxospiro[7H-pyrano[3,2-d]pyrimidine-6,4'-piperidine]-1'-carboxylate (Int-56) 1-(5-Hydroxypyrimidin-4-yl)ethanone (Int-55, 110 mg, 0.8 mmol) was dissolved in methanol (5 mL), N-benzyloxycarbonyl-4-piperidone (204 mg, 0.88 mmol) followed by pyrrolidine (0.100 mL, 1.19 mmol) were added at 20 °C. The mixture was stirred at 20 °C for 3h, and became brown during that time. After that, it was concentrated in vacuo and the residue was purified by reversed phase chromatography (water (+0.1% formic acid) / acetonitrile, isocratic 60:40 (v / v)). The product containing fractions were combined and lyophilized to obtain the title compound asa yellow oil (80 mg, 0.23 mmol, 28% yield). MS m / z (ESI): 354.3 [M+H]+. 1H NMR (400 MHz,CDCl3): δ ppm 9.06 (s, 1H), 8.79 (s, 1H), 7.31 – 7.40 (m, 5H), 5.15 (s, 2H), 3.94 – 4.11 (m, 2H), 3.25 – 3.37 (m, 2H), 2.95 (s, 2H), 2.03 – 2.12 (m, 2H), 1.66 – 1.78 (m, 2H). Intermediate 69: Spiro[1,6-dihydropyrano[3,2-c]pyrazole-5,4'-piperidine]-7-one 2,2,2- trifluoroacetic acid salt (Int-69)Step 1: tert-Butyl 1-[(4-methoxyphenyl)methyl]-7-oxo-spiro[6H-pyrano[3,2-c]pyrazole-5,4'-piperidine]-1'-carboxylate (Int-68) 1-[4-Hydroxy-1-[(4-methoxyphenyl)methyl]pyrazol-3-yl]ethanone (Int-5, 3.0 g, 10.4 mmol) wasdissolved in methanol (60 mL), and tert-butyl 4-oxopiperidine-1-carboxylate (2.27 g, 11.4mmol) and pyrrolidine (0.26 mL, 3.11 mmol) were added subsequently. The mixture was heated at 60 °C for 20 h. After cooling, the reaction mixture was extracted with ethyl acetate (3 x 200 mL), the combined organic layers were washed with brine (200 mL), dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, 100 g, petroleum ether / ethyl acetate, gradient 10:90 to 20:80 (v / v)). The product containing fractions were combined and concentrated in vacuo to give the title compound as a brown oil (1.12 g, 2.62 mmol, 25% yield). MS m / z (ESI): 426.2 [M-H]-. Step 2: Spiro[1,6-dihydropyrano[3,2-c]pyrazole-5,4'-piperidine]-7-one 2,2,2-trifluoroacetic acid salt (Int-69) tert-Butyl 1-[(4-methoxyphenyl)methyl]-7-oxo-spiro[6H-pyrano[3,2-c]pyrazole-5,4'-piperidine]- 1'-carboxylate (Int-68, 480 mg, 1.12 mmol) was dissolved in 1,2-dichloroethane (24 mL) and 2,2,2-trifluoroacetic acid (11.5 mL, 150 mmol) was added. The mixture was stirred at 80°C for 20 h. After cooling, the mixture was concentrated in vacuo to provide the title compound as a brown solid, that was used in the next step without further purification (351 mg, 1.09 mmol, 68% yield). MS m / z (ESI): 208.1 [M+H]+. EXAMPLES Example 1 2-Isopropyl-7-oxo-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6H-pyrano[3,2-c]pyrazole-5,4'- piperidine]-1'-carboxamide Step 1: 2-Isopropylspiro[6H-pyrano[3,2-c]pyrazole-5,4'-piperidine]-7-one (Int-57) 1'-Benzyl-2-isopropyl-spiro[6H-pyrano[3,2-c]pyrazole-5,4'-piperidine]-7-one (Int-9, 170 mg, 0.50 mmol) was dissolved in 1,2-dichloroethane (20 mL) and 1-chloroethyl carbonochloridate (283 mg, 2.0 mmol) was added. The mixture was stirred at 80°C for 2 h. After cooling, the mixture was concentrated in vacuo, methanol (20 mL) was added and the mixture was stirred at 70°C for 1 h. Then, methanol was removed in vacuo again to give the crude title compound (92 mg, 0.37 mmol, 74% yield) as a dark brown gum, that was used in the next step without further purification. MS m / z (ESI): 250.4 [M+H]+. Step 2: 2-Isopropyl-7-oxo-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6H-pyrano[3,2-c]pyrazole- 5,4'-piperidine]-1'-carboxamide (1) (1R,2S)-2-Phenylcyclopropanamine (44 mg, 0.33 mmol) was dissolved in dichloromethane (5 mL), carbonyldiimidazole (CDI, 60 mg, 0.37 mmol) and triethylamine (0.15 mL, 1.11 mmol) were added and the mixture was stirred at 25 °C for 10 min. Then, 2-isopropylspiro[6H- pyrano[3,2-c]pyrazole-5,4'-piperidine]-7-one (Int-57, 92 mg, crude from preceeding step, 0.37 mmol) was added. The mixture was stirred at 25 °C for 50 min. After that, it was concentrated in vacuo and the residue purified by prep-HPLC (Phenomenex luna C18150 x 25 mm x 10 um, flow 25 mL / min, water (+0.1% formic acid) / acetonitrile, gradient 67:33 to 37:63). The product containing fractions were lyophilized to yield the title compound as a white solid (45 mg, 0.11mmol, 22% yield over 2 steps). MS m / z (ESI): 409.3 [M+H]+. 1H NMR (400 MHz, CDCl3): δppm 7.26 – 7.28 (m, 2H), 7.18 – 7.20 (m, 3H), 7.12 (s, 1H), 4.83 (br s, 1H), 4.51 (hept, J = 6.7Hz, 1H), 3.68 – 3.76 (m, 2H), 3.19 – 3.28 (m, 2H), 2.82 – 2.87 (m, 1H), 2.67 (s, 2H), 2.07 – 2.14(m, 2H), 2.00 – 2.06 (m, 1H), 1.61 – 1.70 (m, 2H), 1.54 (d, J = 6.7 Hz, 6H), 1.19 – 1.25 (m, 1H),1.11 – 1.17 (m, 1H). Example 2 2-Methyl-7-oxo-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6H-pyrano[3,2-c]pyrazole-5,4'- piperidine]-1'-carboxamide Step 1: 2-Methyl-spiro[6H-pyrano[3,2-c]pyrazole-5,4'-piperidine]-7-one (Int-58) 1'-Benzyl-2-methyl-spiro[6H-pyrano[3,2-c]pyrazole-5,4'-piperidine]-7-one (Int-11, 110 mg, 0.35 mmol) was dissolved in 1,2-dichloroethane (20 mL) and 1-chloroethyl carbonochloridate (283 mg, 2.0 mmol) was added. The mixture was stirred at 80°C for 2 h. After cooling, the mixture was concentrated in vacuo, methanol (20 mL) was added and the mixture was stirred at 70°C for 1 h. Then, methanol was removed in vacuo again to give the crude title compound (80 mg, 0.35 mmol, quant. yield) as a dark brown oil, that was used in the next step without further purification. MS m / z (ESI): 222.1 [M+H]+. Step 2: 2-Methyl-7-oxo-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6H-pyrano[3,2-c]pyrazole-5,4'- piperidine]-1'-carboxamide (2) (1R,2S)-2-Phenylcyclopropanamine (43 mg, 0.33 mmol) was dissolved in dichloromethane (5 mL), carbonyldiimidazole (CDI, 59 mg, 0.36 mmol) and triethylamine (0.15 mL, 1.11 mmol) were added and the mixture was stirred at 25 °C for 10 min. Then, 2-methyl-spiro[6H- pyrano[3,2-c]pyrazole-5,4'-piperidine]-7-one (Int-58, 80 mg, crude from preceeding step, 0.35 mmol) was added. The mixture was stirred at 25 °C for 50 min. After that, it was concentrated in vacuo and the residue purified by prep-HPLC (Phenomenex luna C18150 x 25 mm x 10 um, flow 25 mL / min, water (+0.1% formic acid) / acetonitrile, gradient 72:28 to 42:58). The product containing fractions were lyophilized to yield the title compound as a colorless gum (35 mg,0.09 mmol, 25% yield over 2 steps). MS m / z (ESI): 381.1 [M+H]+. 1H NMR (400 MHz,CDCl3): δ ppm 7.24 – 7.29 (m, 2H), 7.16 – 7.20 (m, 3H), 7.08 (s, 1H), 4.83 (s, 1H), 3.95 (s, 3H), 3.68 – 3.75 (m, 2H), 3.18 – 3.27 (m, 2H), 2.82 – 2.87 (m, 1H), 2.68 (s, 2H), 2.07 – 2.14 (m, 2H), 2.01 – 2.06 (m, 1H), 1.61 – 1.70 (m, 2H), 1.19 – 1.25 (m, 1H), 1.11 – 1.17 (m, 1H). Example 3 1-Methyl-7-oxo-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6H-pyrano[3,2-c]pyrazole-5,4'- piperidine]-1'-carboxamide Step 1: 1-Methyl-spiro[6H-pyrano[3,2-c]pyrazole-5,4'-piperidine]-7-one (Int-59) 1'-Benzyl-1-methyl-spiro[6H-pyrano[3,2-c]pyrazole-5,4'-piperidine]-7-one (Int-12, 248 mg, 0.80 mmol) was dissolved in 1,2-dichloroethane (20 mL) and 1-chloroethyl carbonochloridate (283 mg, 2.0 mmol) was added. The mixture was stirred at 80°C for 6 h. After cooling, the mixture was concentrated in vacuo, methanol (20 mL) was added and the mixture was stirred at 70°C for 1 h. Then, methanol was removed in vacuo again to give the crude title compound (250 mg, quant. yield) as a dark brown gum, that was used in the next step without further purification. MS m / z (ESI): 222.1 [M+H]+. Step 2: 1-Methyl-7-oxo-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6H-pyrano[3,2-c]pyrazole-5,4'- piperidine]-1'-carboxamide (3) (1R,2S)-2-Phenylcyclopropanamine (530 mg, 3.98 mmol) was dissolved in dichloromethane (6 mL), carbonyldiimidazole (CDI, 645 mg, 3.98 mmol) and triethylamine (1.85 mL, 13.3 mmol) were added and the mixture was stirred at 25 °C for 5 min. Then, 1-methyl-spiro[6H- pyrano[3,2-c]pyrazole-5,4'-piperidine]-7-one (Int-59, 587 mg, crude from preceeding step, 2.65 mmol) was added. The mixture was stirred at 25 °C for 55 min. After that, it was concentrated in vacuo and the residue purified by prep-HPLC (Phenomenex luna C18150 x 25 mm x 10 um, flow 25 mL / min, water (+0.1% formic acid) / acetonitrile, gradient 72:28 to 42:58). The product containing fractions were lyophilized to yield the title compound as a white solid (479 mg, 1.26mmol, 47% yield). MS m / z (ESI): 381.2 [M+H]+. 1H NMR (400 MHz, CDCl3): δ ppm 7.24 –7.30 (m, 2H), 7.16 – 7.21 (m, 4H), 4.85 (s, 1H), 4.07 (s, 3H), 3.70 – 3.77 (m, 2H), 3.20 – 3.29 (m, 2H), 2.82 – 2.87 (m, 1H), 2.68 (s, 2H), 2.07 – 2.14 (m, 2H), 2.01 – 2.06 (m, 1H), 1.61 – 1.70 (m, 2H), 1.19 – 1.25 (m, 1H), 1.11 – 1.17 (m, 1H). Example 4 trans-2-Methyl-7-oxo-N-(3-phenylcyclobutyl)spiro[6H-pyrano[3,2-c]pyrazole-5,4'- piperidine]-1'-carboxamide trans-3-Phenylcyclobutanamine (100 mg, 0.68 mmol) was dissolved in dichloromethane (1 mL), carbonyl diimidazole (CDI, 110 mg, 0.68 mmol) and triethylamine (0.31 mL, 2.26 mmol) were added and the mixture was stirred at 25 °C for 5 min. Then, 2-methyl-spiro[6H-pyrano[3,2- c]pyrazole-5,4'-piperidine]-7-one (Int-58, 100 mg, crude from preceeding step, 0.45 mmol) was added. The mixture was stirred at 25 °C for 55 min. After that, it was concentrated in vacuo and the residue purified by prep-HPLC (Phenomenex luna C18150 x 25 mm x 10 um, flow 25 mL / min, water (+0.1% formic acid) / acetonitrile, gradient 66:34 to 36:64). The product containing fractions were lyophilized to afford the title compound as a white solid (7.9 mg, 0.02mmol, 4% yield). MS m / z (ESI): 395.2 [M+H]+. 1H NMR (400 MHz, CDCl3): δ ppm 7.28 – 7.38(m, 5H), 7.18 – 7.24 (m, 1H), 7.09 (s, 1H), 4.70 – 4.78 (m, 1H), 4.39 – 4.48 (m, 1H), 3.95 (s, 3H), 3.70 – 3.78 (m, 2H), 3.53 – 3.62 (m, 1H), 3.20 – 3.29 (m, 2H), 2.69 (s, 2H), 2.55 – 2.64 (m, 2H), 2.31 – 2.40 (m, 2H), 2.08 – 2.16 (m, 2H), 1.62 – 1.73 (m, 2H). Example 5 trans-1-Methyl-7-oxo-N-(3-phenylcyclobutyl)spiro[6H-pyrano[3,2-c]pyrazole-5,4'- piperidine]-1'-carboxamide trans-3-Phenylcyclobutanamine (50 mg, 0.34 mmol) was dissolved in dichloromethane (1 mL), carbonyldiimidazole (CDI, 55 mg, 0.34 mmol) and triethylamine (0.16 mL, 1.13 mmol) were added and the mixture was stirred at 25 °C for 5 min. Then, 1-methyl-spiro[6H-pyrano[3,2- c]pyrazole-5,4'-piperidine]-7-one (Int-59, 50 mg, crude from preceeding step, 0.22 mmol) was added. The mixture was stirred at 25 °C for 55 min. After that, it was concentrated in vacuo and the residue purified by prep-HPLC (Phenomenex luna C18150 x 25 mm x 10 um, flow 25 mL / min, water (+0.1% formic acid) / acetonitrile, gradient 57:43 to 37:63). The product containing fractions were lyophilized to give the title compound as a white solid (8.8 mg, 0.02mmol, 10% yield). MS m / z (ESI): 395.2 [M+H]+. 1H NMR (400 MHz, CDCl3): δ ppm 7.27 –7.36 (m, 5H), 7.20 – 7.23 (m, 1H), 7.19 (s, 1H), 4.72 – 4.81 (m, 1H), 4.39 – 4.49 (m, 1H), 4.08 (s, 3H), 3.71 – 3.79 (m, 2H), 3.53 – 3.63 (m, 1H), 3.22 – 3.31 (m, 2H), 2.63 (s, 2H), 2.56 – 2.63 (m, 2H), 2.32 – 2.40 (m, 2H), 2.11 – 2.17 (m, 2H), 1.62 – 1.72 (m, 2H). Example 6 trans-1-Methyl-7-oxo-N-(3-phenylcyclobutyl)spiro[4,6-dihydroindazole-5,4'-piperidine]-1'- carboxamide Step 1: 1-Methylspiro[4,6-dihydroindazole-5,4'-piperidine]-7-one hydrobromide (Int-60) Benzyl 1-methyl-7-oxo-spiro[4,6-dihydroindazole-5,4'-piperidine]-1'-carboxylate (Int-23, 70 mg, 0.2 mmol) was dissolved in dichloromethane (1 mL) and a solution of hydrogen bromide in acetic acid (1.0 M, 0.1 mL, 0.1 mmol) was added. The reaction was stirred at 20 °C for 0.5 h. After that, it was concentrated in vacuo to give the crude product (65 mg), which was used in the next step without further purification. MS m / z (ESI): 220.2 [M+H]+.Step 2: trans-1-Methyl-7-oxo-N-(3-phenylcyclobutyl)spiro[4,6-dihydroindazole-5,4'-piperidine]-1'-carboxamide (6) N.N'-Carbonyldiimidazole (42 mg, 0.26 mmol) was dissolved in dichloromethane (0.5 mL) and a solution of trans-3-phenylcyclobutanamine (38 mg, 0.26 mmol) in dichloromethane (0.5 mL) as well as triethylamine (0.15 mL, 1.08 mmol) were added. The resulting mixture was stirred at 20°C for 10 min. Then, 1-methylspiro[4,6-dihydroindazole-5,4'-piperidine]-7-one hydrobromide (Int-60, crude from preceeding step, 65 mg, ca. 0.2 mmol) was added. The mixture was stirred at 20 °C for additional 50 min. After that, the mixture was concentrated in vacuo and the residue was purified by prep-HPLC (Phenomenex luna C18150 x 25 mm x 10 um, flow 25 mL / min, water (+0.1% formic acid) / acetonitrile, gradient 62:38 to 32:68). The product containing fractions were lyophilized to yield the title compound as a white solid (21 mg, 55 umol, 28% yield over two steps). MS m / z (ESI): 393.3 [M+H]+.1H NMR (400 MHz, CDCl3): δ ppm 7.28 – 7.37 (m, 5H), 7.18 – 7.23 (m, 1H), 4.77 – 4.88 (m, 1H), 4.38 – 4.48 (m, 1H), 4.15 (s, 3H), 3.53 – 3.62 (m, 1H), 3.34 – 3.46 (m, 4H), 2.78 (s, 2H), 2.57 (s, 2H), 2.55 – 2.63 (m, 2H), 2.31 – 2.40 (m, 2H), 1.54 – 1.68 (m, 4H). Example 7 trans-2-Methyl-7-oxo-N-(3-phenylcyclobutyl)spiro[4,6-dihydroindazole-5,4'-piperidine]-1'- carboxamide Step 1: 2-Methylspiro[4,6-dihydroindazole-5,4'-piperidine]-7-one hydrobromide (Int-61) Benzyl 2-methyl-7-oxo-spiro[4,6-dihydroindazole-5,4'-piperidine]-1'-carboxylate (Int-24, 55 mg, 0.16 mmol) was dissolved in dichloromethane (1 mL) and a solution of hydrogen bromide in acetic acid (1.0 M, 0.1 mL, 0.1 mmol) was added. The reaction was stirred at 20 °C for 0.5 h. After that, it was concentrated in vacuo to give the crude product (50 mg), which was used in the next step without further purification. MS m / z (ESI): 220.2 [M+H]+.Step 2: trans-2-Methyl-7-oxo-N-(3-phenylcyclobutyl)spiro[4,6-dihydroindazole-5,4'-piperidine]-1'-carboxamide (7) N.N'-Carbonyldiimidazole (32 mg, 0.20 mmol) was dissolved in dichloromethane (0.5 mL) anda solution of trans-3-phenylcyclobutanamine (29 mg, 0.20 mmol) in dichloromethane (0.5 mL)as well as triethylamine (0.12 mL, 0.83 mmol) were added. The resulting mixture was stirred at 20°C for 10 min. Then, 2-methylspiro[4,6-dihydroindazole-5,4'-piperidine]-7-one hydrobromide (Int-61, crude from preceeding step, 50 mg, ca. 0.16 mmol) was added. The mixture was stirred at 20 °C for additional 50 min. After that, the mixture was concentrated in vacuo and the residue was purified by prep-HPLC (Phenomenex luna C18250 x 50 mm x 15 um, flow 25 mL / min, water (+0.1% formic acid) / acetonitrile, gradient 68:32 to 38:62). The product containing fractions were lyophilized to obtain the title compound as a white solid (32 mg, 80 umol, 50% yield over two steps). MS m / z (ESI): 393.3 [M+H]+.1H NMR (400 MHz, CDCl3): δ ppm 7.25 – 7.35 (m, 5H), 7.17 – 7.23 (m, 1H), 4.68 – 4.75 (m, 1H), 4.39 – 4.48 (m, 1H), 3.99 (s, 3H), 3.55 – 3.62 (m, 1H), 3.36 – 3.42 (m, 4H), 2.75 (s, 2H), 2.61 (s, 2H), 2.54 – 2.62 (m, 2H), 2.31 – 2.39 (m, 2H), 1.55 – 1.67 (m, 4H). Example 8 2-Isopropyl-7-oxo-N-[(1R,2S)-2-phenylcyclopropyl]spiro[4,6-dihydropyrazolo[1,5- a]pyridine-5,4'-piperidine]-1'-carboxamide Step 1: 2-Isopropylspiro[4,6-dihydropyrazolo[1,5-a]pyridine-5,4'-piperidine]-7-one (Int-62) 1'-Benzyl-2-isopropyl-spiro[4,6-dihydropyrazolo[1,5-a]pyridine-5,4'-piperidine]-7-one (Int-30, 30 mg, 0.09 mmol) was dissolved in 1,2-dichloroethane (1 mL) and 1-chloroethyl carbonochloridate (38 mg, 0.27 mmol) was added dropwise at 25°C. The mixture was stirred at 80°C for 1 h. After cooling to 25°C, it was concentrated in vacuo, the residue was dissolved in methanol (10 mL) and the mixture was stirred at 70°C for 0.5 h. After cooling again to 25°C, it was concentrated in vacuo to afford the crude title compound as a white solid (30 mg), which was used in the next step without further purification. MS m / z (ESI): 248.2 [M+H]+. Step 2: 2-Isopropyl-7-oxo-N-[(1R,2S)-2-phenylcyclopropyl]spiro[4,6-dihydropyrazolo[1,5- a]pyridine-5,4'-piperidine]-1'-carboxamide (8) (1R,2S)-2-Phenylcyclopropanamine (19.4 mg, 0.15 mmol) was dissolved in dichloromethane (2 mL) and carbonyldiimidazole (CDI, 25.6 mg, 0.16 mmol) as well as triethylamine (37 mg, 0.36 mmol) were added at 25°C. The mixture was stirred at 25°C for 5 min, 2-isopropylspiro[4,6- dihydropyrazolo[1,5-a]pyridine-5,4'-piperidine]-7-one (Int-62, crude from preceeding step, 30 mg, ca.0.09 mmol) was added and the mixture was stirred at 25°C for 10 min. After that, it was concentrated in vacuo, the residue was purified by preparative HPLC (Phenomenex luna C18 150 x 25 mm x 10 um, flow 25 mL / min, water (+0.1% formic acid) / acetonitrile, gradient 60:40 to 40:60). The product containing fractions were lyophilized to yield the title compound as awhite solid (6.2 mg, 0.02 mmol, 22% yield). MS m / z (ESI): 407.4 [M+H]+. 1H NMR (400 MHz,CDCl3): δ ppm 7.23 – 7.29 (m, 2H), 7.15 – 7.20 (m, 3H), 6.09 (s, 1H), 4.83 (br s, 1H), 3.36 – 3.42 (m, 4H), 3.05 (hept, J = 6.9 Hz, 1H), 2.89 (s, 2H), 2.81 – 2.87 (m, 1H), 2.75 (s, 2H), 1.99 – 2.06 (m, 1H), 1.53 – 1.61 (m, 4H), 1.28 (d, J = 7.0 Hz, 6H), 1.09 – 1.26 (m, 2H). Example 9 and example 10(7S or 7R)-7-Hydroxy-1-methyl-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6,7-dihydropyrano[3,2-c]pyrazole-5,4'-piperidine]-1'-carboxamide (example 9) and (7R or 7S)- 7-hydroxy-1-methyl-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6,7-dihydropyrano[3,2- c]pyrazole-5,4'-piperidine]-1'-carboxamide (example 10) 1-Methyl-7-oxo-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6H-pyrano[3,2-c]pyrazole-5,4'- piperidine]-1'-carboxamide (3, 20.0 mg, 52.6 umol) was dissolved in methanol (530 uL) and sodium borohydride (2.0 mg, 53 umol) was added under inert atmosphere at 0oC. The reaction was stirred for 45 min at 0°C. Then, a saturated aqueous solution of sodium hydrogen carbonate (20 mL) was added, and the mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was then purified via flash chromatography (silica gel, 12 g, dichloromethane / methanol, gradient 10:0 to 9:1 (v / v)) to obtain the racemic title compound as a white powder. This material was separated by chiral SFC (Daicel Chiralpac OZ-H, 5 um, 250 x 20 mm, supercritical carbondioxide / methanol, isocratic 70:30 (v / v)) into the two diastereomeric title compounds. After lyophilization of the product containing fractions, the first eluting diastereomer 9 was isolated as a white powder (4.7 mg, 22% yield). MS m / z (ESI): 383.2 [M+H]+.1H NMR (300 MHz, CDCl3): δ ppm 7.23 - 7.30 (m, 2H), 7.14 - 7.21 (m, 3H), 7.10 (s, 1H), 4.93 (dd, J = 5.0, 5.2 Hz, 1H), 4.87 (s, 1H), 3.86 (s, 3H), 3.58 - 3.79 (m, 2H), 3.13 - 3.31 (m, 2H), 2.81 – 2.88 (m, 1H), 1.99 – 2.18 (m, 3H), 1.77 - 1.96 (m, 2H), 1.55 - 1.69 (m, 2H), 1.09 - 1.28 (m, 2H). The second eluting diastereoisomer 10 was isolated as a white powder (4.0 mg,19% yield). MS m / z (ESI): 383.2 [M+H]+. 1H NMR (300 MHz, CDCl3): δ ppm 7.23 - 7.30 (m,2H), 7.14 - 7.21 (m, 3H), 7.10 (s, 1H), 4.93 (dd, J = 4.9, 4.9 Hz, 1H), 4.87 (s, 1H), 3.86 (s, 3H), 3.58 - 3.78 (m, 2H), 3.14 - 3.31 (m, 2H), 2.80 – 2.87 (m, 1H), 1.99 – 2.18 (m, 3H), 1.77 - 1.96 (m, 2H), 1.55 - 1.69 (m, 2H), 1.09 - 1.26 (m, 2H). Example 11 and example 12(7S or 7R)-7-Methoxy-1-methyl-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6,7-dihydropyrano[3,2-c]pyrazole-5,4'-piperidine]-1'-carboxamide (example 11) and (7R or 7S)-7-methoxy-1-methyl-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6,7-dihydropyrano[3,2- c]pyrazole-5,4'-piperidine]-1'-carboxamide (example 12) Step 1: 7-Hydroxy-1-methyl-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6,7-dihydropyrano[3,2- c]pyrazole-5,4'-piperidine]-1'-carboxamide (Int-63) 1-Methyl-7-oxo-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6H-pyrano[3,2-c]pyrazole-5,4'- piperidine]-1'-carboxamide (3, 66 mg, 173 umol) was dissolved in methanol (2 mL) and sodium borohydride (6.6 mg, 173 umol) was added under inert atmosphere at 0oC. After 10 min stirring at 0°C, the reaction was stopped by addition of saturated aqueous ammonium chloride solution (10 mL) and diluted with tert-butyl methyl ether (20 mL). After phase separation, the aqueous phase was extracted with tert-butyl methyl ether (2 x 20 mL), the combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 25 g, dichloromethane / methanol, gradient 10:0 to 9:1 (v / v)) to obtain the title compound as a white powder (39 mg, 56% yield). MS m / z (ESI): 383.2 [M+H]+.Step 2: (7S or 7R)-7-Methoxy-1-methyl-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6,7-dihydropyrano[3,2-c]pyrazole-5,4'-piperidine]-1'-carboxamide (11) and (7R or 7S)-7-methoxy-1- methyl-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6,7-dihydropyrano[3,2-c]pyrazole-5,4'- piperidine]-1'-carboxamide (12) 7-Hydroxy-1-methyl-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6,7-dihydropyrano[2,3-d]pyrazole- 5,4'-piperidine]-1'-carboxamide (Int-63, 25 mg, 65 umol) was dissolved in tetrahydrofuran (654 uL) and sodium hydride (2.0 mg, 84 umol) was added under inert atmosphere at 0oC. After 10 min, methyl iodide (4.5 uL, 10.2 mg, 71.9 umol) was added and the mixture was stirred for 14 h at 0°C, and was allowed to warm to room temperature during that time. Then, additional methyl iodide (4.1 uL, 9.3 mg, 65 umol) was added and the mixture stirred for additional 2 h at room temperature. Then, it was diluted with ethyl acetate (10 mL) and saturated aqueous sodium hydrogencarbonate solution (10 mL). After phase separation, the aqueous layer was extracted with ethyl acetate (3 x 10 mL), the combined organic layers were washed with saturated aqueous sodium hydrogencarbonate solution (2 x 10 mL) and brine (2 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 12 g, dichloromethane / methanol, gradient 10:0 to 9:1 (v / v)) to obtain the racemic title compound as a white powder. This material was separated by chiral SFC (Daicel Chiralpac IH, 5 um, 250 x 20 mm, supercritical carbondioxide / methanol, isocratic 80:20 (v / v)) into the two diastereomeric title compounds. After lyophilization of the product containing fractions, the first eluting diastereomer 11 was isolated as a white powder (2.3 mg, 8% yield). MS m / z (ESI): 397.3 [M+H]+.1H NMR (300 MHz, CDCl3): δ ppm 7.23 - 7.31 (m, 2H), 7.15 - 7.21 (m, 3H), 7.11 (s, 1H), 4.83 (s, 1H), 4.45 (dd, J = 3.8, 4.8 Hz, 1H), 3.81 (s, 3H), 3.75 – 3.84 (m, 1H), 3.52 - 3.61 (m, 1H), 3.44 (s, 3H), 3.12 - 3.35 (m, 2H), 2.82 - 2.88 (m, 1H), 2.16 – 2.25 (m, 1H), 2.00 - 2.13 (m, 2H), 1.78 - 1.93 (m, 2H), 1.48 - 1.74 (m, 2H), 1.09 - 1.24 (m, 2H). The second eluting diastereoisomer 12 was isolated as awhite powder (2.3 mg, 8% yield). MS m / z (ESI): 397.4 [M+H]+. 1H NMR (300 MHz, CDCl3): δppm 7.23 - 7.31 (m, 2H), 7.12 - 7.21 (m, 3H), 7.11 (s, 1H), 4.82 (s, 1H), 4.45 (dd, J = 3.8, 4.9 Hz, 1H), 3.81 (s, 3H), 3.75 – 3.81 (m, 1H), 3.52 - 3.61 (m, 1H), 3.44 (s, 3H), 3.11 - 3.35 (m, 2H), 2.82 - 2.88 (m, 1H), 2.16 – 2.25 (m, 1H), 2.00 - 2.13 (m, 2H), 1.78 - 1.92 (m, 2H), 1.47 - 1.74 (m, 2H), 1.10 - 1.24 (m, 2H). Example 13 and example 14(7S or 7R)-7-Hydroxy-1,7-dimethyl-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6H-pyrano[3,2-c]pyrazole-5,4'-piperidine]-1'-carboxamide (example 13) and (7R or 7S)-7-hydroxy-1,7- dimethyl-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6H-pyrano[3,2-c]pyrazole-5,4'-piperidine]- 1'-carboxamide (example 14) 1-Methyl-7-oxo-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6H-pyrano[3,2-c]pyrazole-5,4'- piperidine]-1'-carboxamide (3, 83.8 mg, 220 umol) was dissolved in tetrahydrofuran (1.5 mL) under inert atmosphere and the solution was cooled to 0 – 4 °C (ice bath). Then, a solution of methyllithium lithium bromide complex in tetrahydrofuran (1.5 M, 161 uL, 242 umol) was added. The reaction was stirred for 10 min at 0°C. Then, a saturated aqueous solution of ammonium chloride (10 mL) was added, and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate (3 x 20 mL), and brine (3 x 20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was then purified via flash chromatography (silica gel, 24 g, dichloromethane / methanol, gradient 10:0 to 9:1 (v / v)) to yield the racemic title compound as a white powder. This material was separated by chiral SFC (Daicel Chiralpac OD-H, 5 um, 250 x 20 mm, supercritical carbondioxide / (methanol + 0.2% diethyl amine), gradient 80:20 to 60:40 (v / v)) into the two diastereomeric title compounds. After lyophilization of the product containing fractions, the first eluting diastereomer 13 was isolated as a white powder (7.2 mg, 8% yield). MS m / z (ESI): 397.3 [M+H]+.1H NMR (300 MHz, CDCl3): δ ppm 7.23 - 7.30 (m, 2H), 7.13 - 7.20 (m, 3H), 7.08 (s, 1H), 4.94 (br s, 1H), 3.93 (s, 3H), 3.68 – 3.77 (m, 1H), 3.55 – 3.64 (m, 1H), 3.22 – 3.33 (m, 1H), 3.05 – 3.16 (m, 1H), 2.80 – 2.87 (m, 1H), 2.08 – 2.17 (m, 1H), 1.96 – 2.06 (m, 3H), 1.77 – 1.86 (m, 1H), 1.65 (s, 3H), 1.49 – 1.69 (m, 1H), 1.09 – 1.32 (m, 4H). The second eluting diastereoisomer 14 was isolated as a white powder (10.1 mg, 11%yield). MS m / z (ESI): 397.3 [M+H]+. 1H NMR (300 MHz, CDCl3): δ ppm 7.23 - 7.30 (m, 2H),7.13 - 7.20 (m, 3H), 7.08 (s, 1H), 4.90 (br s, 1H), 3.94 (s, 3H), 3.69 – 3.79 (m, 1H), 3.55 – 3.65 (m, 1H), 3.22 – 3.34 (m, 1H), 3.05 – 3.17 (m, 1H), 2.79 – 2.87 (m, 1H), 2.09 – 2.20 (m, 1H), 1.96 – 2.07 (m, 3H), 1.78 – 1.87 (m, 1H), 1.65 (s, 3H), 1.49 – 1.70 (m, 1H), 1.09 – 1.34 (m, 4H). Example 15 1,3-Dimethyl-7-oxo-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6H-pyrano[3,2-c]pyrazole-5,4'- piperidine]-1'-carboxamide (1R,2S)-2-Phenylcyclopropanamine (5.7 mg, 0.04 mmol) was dissolved in dichloromethane (1 mL), and carbonyldiimidazole (6.9 mg, 0.04 mmol) and triethylamine (0.02 mL, 0.15 mmol) were added The mixture was stirred at 25°C for 10 min. Then, a solution of 1,3- dimethylspiro[6H-pyrano[3,2-c]pyrazole-5,4'-piperidine]-7-one hydrochloride (Int-34, 10.5 mg, 0.04 mmol) in dichloromethane (1 mL) was added dropwise. The pH should be >7. The reaction mixture was stirred at 25 °C for 20 min. After that, it was concentrated in vacuo and the residue was purified by preparative HPLC (Phenomenex luna C18150 x 25 mm x 10 um, flow 25 mL / min, water (+0.1% formic acid) / acetonitrile, gradient 59:41 to 39:61). The product containing fractions were lyophilized to obtain the title compound as a light yellow oil (2.2 mg,0.01 mmol, 14% yield). MS m / z (ESI): 359.3 [M+H]+. 1H NMR (400 MHz, CDCl3): δ ppm 7.24- 7.30 (m, 2H), 7.16 - 7.20 (m, 3H), 4.85 (s, 1H), 4.00 (s, 3H), 3.70 – 3.77 (m, 2H), 3.19 – 3.28 (m, 2H), 2.82 – 2.87 (m, 1H), 2.59 (s, 2H), 2.20 (s, 3H), 2.09 – 2.15 (m, 2H), 2.01 – 2.07 (m, 1H), 1.57 – 1.68 (m, 2H), 1.19 – 1.27 (m, 1H), 1.11 – 1.17 (m, 1H). Example 16 trans-1,3-Dimethyl-7-oxo-N-(3-phenylcyclobutyl)spiro[6H-pyrano[3,2-c]pyrazole-5,4'- piperidine]-1'-carboxamide trans-3-Phenylcyclobutanamine (3.8 mg, 0.03 mmol) was dissolved in dichloromethane (1 mL), and carbonyldiimidazole (5.0 mg, 0.03 mmol) and triethylamine (0.02 mL, 0.12 mmol) were added The mixture was stirred at 25°C for 10 min. Then, a solution of 1,3-dimethylspiro[6H- pyrano[3,2-c]pyrazole-5,4'-piperidine]-7-one hydrochloride (Int-34, 6.3 mg, 0.02 mmol) in dichloromethane (1 mL) was added dropwise. The pH should be >7. The reaction mixture was stirred at 25 °C for 20 min. After that, it was concentrated in vacuo and the residue was purified by preparative HPLC (Phenomenex luna C18150 x 25 mm x 10 um, flow 25 mL / min, water (+0.1% formic acid) / acetonitrile, gradient 57:43 to 37:63). The product containing fractions were lyophilized to obtain the title compound as a white solid (4.4 mg, 0.01 mmol, 46% yield).MS m / z (ESI): 409.3 [M+H]+. 1H NMR (400 MHz, CDCl3): δ ppm 7.26 - 7.36 (m, 4H), 7.18 -7.23 (m, 1H), 4.72 (d, J = 6.1 Hz, 1H), 4.39 – 4.49 (m, 1H), 4.01 (s, 3H), 3.72 – 3.80 (m, 2H),3.54 – 3.63 (m, 1H), 3.20 – 3.29 (m, 2H), 2.60 (s, 2H), 2.55 – 2.64 (m, 2H), 2.32 – 2.40 (m, 2H), 2.21 (s, 3H), 2.10 – 2.16 (m, 2H), 1.59 – 1.70 (m, 2H). Example 17 and example 18 trans-1-Methyl-N-[3-(1-methylindazol-4-yl)cyclobutyl]-7-oxo-spiro[6H-pyrano[3,2-c]pyrazole-5,4'-piperidine]-1'-carboxamide (example 17) and cis-1-methyl-N-[3-(1-methylindazol-4-yl)cyclobutyl]-7-oxo-spiro[6H-pyrano[3,2-c]pyrazole-5,4'-piperidine]-1'- carboxamide (example 18) Step 1: 1-Methyl-N-[3-(1-methylindazol-4-yl)cyclobutyl]-7-oxo-spiro[6H-pyrano[3,2- c]pyrazole-5,4'-piperidine]-1'-carboxamide (Int-64) 3-(1-Methylindazol-4-yl)cyclobutanamine 2,2,2-trifluoroacetate salt (Int-38, 34 mg, 0.11 mmol) was dissolved in dichloromethane (1 mL) and carbonyl diimidazole (17 mg, 0.11 mmol, 1.32 eq) as well as triethylamine (0.06 mL, 0.41 mmol) were added dropwise at 25 °C. The mixture was stirred at 25°C for 10 min. Then, a solution of 1-methylspiro[6H-pyrano[2,3-d]pyrazole-5,4'- piperidine]-7-one hydrochloride (Int-59, 28 mg, 0.08 mmol) in dichloromethane (1 mL) was added dropwise to maintain the pH > 7. The reaction mixture was stirred at 25 °C for 20 min. After that, it was concentrated in vacuo, the residue was purified by preparative HPLC (Phenomenex luna C18150 x 25 mm x 10 um, flow 25 mL / min, water (+0.1% formic acid) / acetonitrile, gradient 68:32 to 38:62). The product containing fractions were lyophilized to obtain the title compound as a white solid (20 mg, 0.04 mmol, 55% yield). MS m / z (ESI): 449.2 [M+H]+.Step 2: trans-1-Methyl-N-[3-(1-methylindazol-4-yl)cyclobutyl]-7-oxo-spiro[6H-pyrano[3,2-c]pyrazole-5,4'-piperidine]-1'-carboxamide (17) and cis-1-methyl-N-[3-(1-methylindazol-4-yl)cyclobutyl]-7-oxo-spiro[6H-pyrano[3,2-c]pyrazole-5,4'-piperidine]-1'-carboxamide (18) 1-Methyl-N-[3-(1-methylindazol-4-yl)cyclobutyl]-7-oxo-spiro[6H-pyrano[3,2-c]pyrazole-5,4'- piperidine]-1'-carboxamide (Int-64, 20 mg, 0.04 mmol) was separated by preparative SFC (Daicel Chiralcel OX, 250 x 30 mm x 10 um, flow 75 mL / min, sc carbon dioxide / (0.1% ammonia in 2-propanol), isocratic 55:45) into the two stereoisomeric title compounds. After lyophilization of the product containing fractions, the first eluting stereoisomer 17 was isolated as a light yellow oil (6.7 mg, 32% yield). MS m / z (ESI): 449.2 [M+H]+.1H NMR (400 MHz,CDCl3): δ ppm 7.92 (s, 1H), 7.34 – 7.40 (m, 1H), 7.24 – 7.28 (m, 1H), 7.19 (s, 1H), 7.10 (d, J =7.0 Hz, 1H), 4.77 (d, J = 6.0 Hz, 1H), 4.39 – 4.51 (m, 1H), 4.08 (s, 3H), 4.08 (s, 3H), 3.94 – 4.03(m, 1H), 3.73 – 3.82 (m, 2H), 3.22 – 3.33 (m, 2H), 2.71 – 2.80 (m, 2H), 2.63 (s, 2H), 2.42 – 2.52 (m, 2H), 2.11 – 2.19 (m, 2H), 1.61 – 1.74 (m, 2H). The second eluting stereoisomer 18 wasisolated as a light blue oil (3.5 mg, 16% yield). MS m / z (ESI): 449.2 [M+H]+. 1H NMR (400MHz, CDCl3): δ ppm 7.96 (s, 1H), 7.31 – 7.36 (m, 1H), 7.22 – 7.27 (m, 1H), 7.18 (s, 1H), 6.92(d, J = 7.0 Hz, 1H), 4.56 – 4.62 (m, 1H), 4.38 – 4.48 (m, 1H), 4.08 (s, 3H), 4.06 (s, 3H), 3.67 –3.77 (m, 2H), 3.54 – 3.65 (m, 1H), 3.18 – 3.28 (m, 2H), 2.96 – 3.06 (m, 2H), 2.61 (s, 2H), 2.05 – 2.16 (m, 4H), 1.56 – 1.70 (m, 2H). The assignment of the configurations cis- and trans- wasbased on analysis of 2D 1H and 13C nmr spectra.Example 19 trans-7-Oxo-N-(3-phenylcyclobutyl)spiro[4,6-dihydropyrazolo[1,5-a]pyridine-5,4'- piperidine]-1'-carboxamide trans-3-Phenylcyclobutanamine (13.0 mg, 0.09 mmol) was dissolved in dichloromethane (1 mL) and carbonyldiimidazole (CDI, 14.3 mg, 0.09 mmol) as well as triethylamine (0.04 mL, 0.26 mmol) were added at 25°C. The mixture was stirred at 25°C for 10 min, spiro[4,6- dihydropyrazolo[1,5-a]pyridine-5,4'-piperidine]-7-one hydrobromide (Int-45, crude from preceeding step, 15 mg, ca.0.04 mmol) was added and the mixture was stirred at 25°C for 20 min. After that, it was concentrated in vacuo, the residue was purified by preparative HPLC (Phenomenex luna C18150 x 25 mm x 10 um, flow 25 mL / min, water (+0.1% formic acid) / acetonitrile, gradient 68:32 to 38:62). The product containing fractions were lyophilized to obtain the title compound as a white solid (5.0 mg, 0.01 mmol, 25% yield). MS m / z (ESI): 379.2[M+H]+. 1H NMR (400 MHz, CDCl3): δ ppm 7.76 (s, 1H), 7.25 – 7.34 (m, 4H), 7.18 – 7.22 (m,1H), 6.22 (s, 1H), 4.68 (d, J = 6.3 Hz, 1H), 4.37 – 4.47 (m, 1H), 3.53 – 3.63 (m, 1H), 3.38 –3.43 (m, 4H), 2.93 (s, 2H), 2.79 (s, 2H), 2.54 – 2.61 (m, 2H), 2.30 – 2.38 (m, 2H), 1.52 – 1.62 (m, 4H). Example 20 trans-2-Methyl-7-oxo-N-(3-phenylcyclobutyl)spiro[4,6-dihydropyrazolo[1,5-a]pyridine- 5,4'-piperidine]-1'-carboxamide trans-3-Phenylcyclobutanamine (29.4 mg, 0.2 mmol) was dissolved in dichloromethane (1 mL) and carbonyldiimidazole (CDI, 32.4 mg, 0.2 mmol) as well as triethylamine (0.12 mL, 0.83 mmol) were added dropwise at 25°C. The mixture was stirred at 25°C for 10 min, a solution of 2-methylspiro[4,6-dihydropyrazolo[1,5-a]pyridine-5,4'-piperidine]-7-one hydrobromide (Int-48, crude from preceeding step, 50 mg, 0.17 mmol) in dichloromethane (1 mL) was added and the mixture was stirred at 25°C for 20 min. After that, it was concentrated in vacuo, the residue was purified by preparative HPLC (Phenomenex luna C18150 x 25 mm x 10 um, flow 25 mL / min, water (+0.1% formic acid) / acetonitrile, gradient 72:28 to 42:58). The product containing fractions were lyophilized to afford the title compound as a white solid (16 mg, 0.04 mmol, 23%yield). MS m / z (ESI): 393.2 [M+H]+. 1H NMR (400 MHz, CDCl3): δ ppm 7.26 – 7.35 (m, 4H),7.18 – 7.23 (m, 1H), 6.04 (s, 1H), 4.69 (d, J = 6.4 Hz, 1H), 4.38 – 4.48 (m, 1H), 3.53 – 3.62 (m,1H), 3.38 – 3.44 (m, 4H), 2.89 (s, 2H), 2.78 (s, 2H), 2.55 – 2.62 (m, 2H), 2.33 (s, 3H), 2.31 – 2.39 (m, 2H), 1.56 – 1.61 (m, 4H). Example 21 trans-3-Methyl-7-oxo-N-(3-phenylcyclobutyl)spiro[4,6-dihydropyrazolo[1,5-a]pyridine- 5,4'-piperidine]-1'-carboxamide Step 1: 3-Methylspiro[4,6-dihydropyrazolo[1,5-a]pyridine-5,4'-piperidine]-7-one hydrobromide (Int-65) Benzyl 3-methyl-7-oxo-spiro[4,6-dihydropyrazolo[1,5-a]pyridine-5,4'-piperidine]-1'-carboxylate(Int-50, 28 mg, 0.08 mmol) was dissolved in dichloromethane (1 mL) and a solution of hydrogen bromide in acetic acid (33% (m / m), 0.1 mL) was added at 0 °C. The mixture was stirred at 0 °C for 1 h. After that, it was concentrated in vacuo to afford the title compound as a brown solid, that was used in the next step without further purification (25.5 mg, quant.).Step 2: trans-3-Methyl-7-oxo-N-(3-phenylcyclobutyl)spiro[4,6-dihydropyrazolo[1,5-a]pyridine-5,4'-piperidine]-1'-carboxamide (21) trans-3-Phenylcyclobutanamine (16 mg, 0.11 mmol) was dissolved in dichloromethane (1 mL), and carbonyl diimidazole (CDI, 17 mg, 0.11 mmol) followed by triethylamine (50 uL, 0.36 mmol) were added. The mixture was stirred at 25°C for 10 min. Then, a solution of 3- methylspiro[4,6-dihydropyrazolo[1,5-a]pyridine-5,4'-piperidine]-7-one hydrobromide (Int-65, 25.5 mg, 0.28 mmol, crude from preceeding step) in dichloromethane (1 mL) was added dropwise to ensure the pH stayed >7. The reaction mixture was stirred at 25 °C for 20 min. After that, it was concentrated in vacuo, the residue was purified by preparative HPLC (Phenomenex luna C18150 x 25 mm x 10 um, flow 25 mL / min, water (+0.1% formic acid) / acetonitrile, gradient 71:29 to 41:59). The product containing fractions were lyophilized to yield the title compound as a light green gum (9.0 mg, 0.02 mmol, 26% yield). MS m / z (ESI): 393.3 [M+H]+.1H NMR (400 MHz, CDCl3): δ ppm 7.64 (s, 1H), 7.18 – 7.36 (m, 5H), 4.67 – 4.72 (m, 1H), 4.39 – 4.47 (m, 1H), 3.53 – 3.62 (m, 1H), 3.38 – 3.44 (m, 4H), 2.80 (s, 2H), 2.78 (s, 2H), 2.54 – 2.63 (m, 2H), 2.31 – 2.40 (m, 2H), 2.03 (s, 3H), 1.55 – 1.62 (m, 4H). Example 22 8-Oxo-N-[(1R,2S)-2-phenylcyclopropyl]spiro[7H-pyrano[3,2-d]pyrimidine-6,4'-piperidine]- 1'-carboxamide Step 1: Spiro[7H-pyrano[3,2-d]pyrimidine-6,4'-piperidine]-8-one hydrobromide (Int-66) Benzyl 8-oxospiro[7H-pyrano[3,2-d]pyrimidine-6,4'-piperidine]-1'-carboxylate (Int-56, 100 mg, 0.28 mmol) was dissolved in dichloromethane (2 mL) and a solution of hydrogen bromide in acetic acid (33% (m / m), 0.5 mL) was added at 0 °C. The mixture was stirred at 0 °C for 1 h. After that, it was concentrated in vacuo to afford the title compound as a brown oil, that was used in the next step without further purification (85 mg, quant.). MS m / z (ESI): 220.1 [M+H]+. Step 2: 8-Oxo-N-[(1R,2S)-2-phenylcyclopropyl]spiro[7H-pyrano[3,2-d]pyrimidine-6,4'- piperidine]-1'-carboxamide (22) (1R,2S)-2-Phenylcyclopropanamine (45 mg, 0.34 mmol) was dissolved in dichloromethane (2 mL), and carbonyl diimidazole (CDI, 55 mg, 0.34 mmol) followed by triethylamine (0.16 mL, 1.13 mmol) were added. The mixture was stirred at 25°C for 10 min. Then, a solution of spiro[7H-pyrano[3,2-d]pyrimidine-6,4'-piperidine]-8-one hydrobromide (Int-66, 85 mg, 0.28 mmol, crude from preceeding step) in dichloromethane (1 mL) was added dropwise to ensure the pH stayed >7. The reaction mixture was stirred at 25 °C for 20 min. After that, it was concentrated in vacuo, the residue was purified by preparative HPLC (Phenomenex luna C18 150 x 25 mm x 10 um, flow 25 mL / min, water (+0.1% formic acid) / acetonitrile, gradient 75:25 to 45:55). The product containing fractions were lyophilized to yield the title compound as alight red solid (37 mg, 0.10 mmol, 36% yield). MS m / z (ESI): 379.2 [M+H]+. 1H NMR (400MHz, CDCl3): δ ppm 9.07 (s, 1H), 8.79 (s, 1H), 7.24 – 7.30 (m, 2H), 7.15 – 7.21 (m, 3H), 4.89 (s, 1H), 3.74 – 3.81 (m, 2H), 3.24 – 3.33 (m, 2H), 2.96 (s, 2H), 2.82 – 2.88 (m, 1H), 2.01 – 2.13 (m, 3H), 1.71 – 1.80 (m, 2H), 1.20 – 1.27 (m, 1H), 1.11 – 1.17 (m, 1H). Example 23 1-Isopropyl-7-oxo-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6H-pyrano[3,2-c]pyrazole-5,4'- piperidine]-1'-carboxamide Step 1: 1-Isopropylspiro[6H-pyrano[3,2-c]pyrazole-5,4'-piperidine]-7-one (Int-67) 1'-Benzyl-1-isopropyl-spiro[6H-pyrano[3,2-c]pyrazole-5,4'-piperidine]-7-one (Int-10, 150 mg, 0.44 mmol) was dissolved in 1,2-dichloroethane (20 mL) and 1-chloroethyl carbonochloridate (283 mg, 2.0 mmol) was added. The mixture was stirred at 80°C for 2 h. After cooling, the mixture was concentrated in vacuo, methanol (20 mL) was added and the mixture was stirred at 70°C for 1 h. Then, methanol was removed in vacuo again to give the crude title compound (101 mg, 0.41 mmol, 92% yield) as a green solid, that was used in the next step without further purification. MS m / z (ESI): 250.4 [M+H]+. Step 2: 1-Isopropyl-7-oxo-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6H-pyrano[3,2-c]pyrazole- 5,4'-piperidine]-1'-carboxamide (23) (1R,2S)-2-Phenylcyclopropanamine (34 mg, 0.25 mmol) was dissolved in dichloromethane (1 mL), carbonyldiimidazole (CDI, 45 mg, 0.28 mmol) and triethylamine (0.12 mL, 0.84 mmol) were added and the mixture was stirred at 25 °C for 10 min. Then, 1-isopropylspiro[6H- pyrano[3,2-c]pyrazole-5,4'-piperidine]-7-one (Int-67, 70 mg, crude from preceeding step, 0.28 mmol) was added. The mixture was stirred at 25 °C for 50 min. After that, it was concentrated in vacuo and the residue purified by prep-HPLC (Phenomenex luna C18150 x 25 mm x 10 um, flow 25 mL / min, water (+0.1% formic acid) / acetonitrile, gradient 58:42 to 28:72). The product containing fractions were lyophilized to obtain the title compound as a white solid (64 mg, 0.16mmol, 55% yield). MS m / z (ESI): 409.2 [M+H]+. 1H NMR (400 MHz, CDCl3): δ ppm 7.15 –7.33 (m, 5H), 7.10 – 7.13 (m, 1H), 5.17 (hept, J = 6.7 Hz, 1H), 4.83 (br s, 1H), 3.69 – 3.77 (m,2H), 3.21 – 3.30 (m, 2H), 2.82 – 2.88 (m, 1H), 2.62 (s, 2H), 2.08 – 2.15 (m, 2H), 2.01 – 2.07 (m,1H), 1.59 – 1.70 (m, 2H), 1.47 (d, J = 6.7 Hz, 6H), 1.19 – 1.32 (m, 1H), 1.11 – 1.17 (m, 1H).Example 24 7-Oxo-N-[(1R,2S)-2-phenylcyclopropyl]spiro[1,6-dihydropyrano[3,2-c]pyrazole-5,4'- piperidine]-1'-carboxamide (1R,2S)-2-Phenylcyclopropanamine (78 mg, 0.59 mmol) was dissolved in dichloromethane (4 mL), carbonyldiimidazole (CDI, 106 mg, 0.65 mmol) and triethylamine (0.46 mL, 3.27 mmol) were added and the mixture was stirred at 25 °C for 10 min. Then, spiro[1,6- dihydropyrano[3,2-c]pyrazole-5,4'-piperidine]-7-one 2,2,2-trifluoroacetic acid salt (Int-69, 210 mg, crude from preceeding step, 0.65 mmol) was added. The mixture was stirred at 25 °C for 50 min. After that, it was concentrated in vacuo and the residue purified by prep-HPLC (Waters Xbridge 150 x 25 mm x 5 um, flow 25 mL / min, water (+0.1% ammonia) / acetonitrile, gradient 78:22 to 48:52). The product containing fractions were lyophilized to obtain the titlecompound as a white solid (39 mg, 0.11 mmol, 16% yield). MS m / z (ESI): 367.1 [M+H]+. 1HNMR (400 MHz, DMSO-d6): δ ppm 7.46 (s, 1H), 7.21 – 7.27 (m, 2H), 7.06 – 7.16 (m, 3H), 6.82(d, J = 3.0 Hz, 1H), 3.64 – 3.72 (m, 2H), 2.98 – 3.09 (m, 2H), 2.71 (s, 2H), 2.65 – 2.73 (m, 1H),1.83 – 1.93 (m, 3H), 1.54 – 1.65 (m, 2H), 1.11 – 1.19 (m, 1H), 1.02 – 1.09 (m, 1H).

Claims

CLAIMS1. A compound of formula (I)or a pharmaceutically acceptable salt thereof, wherein: X is CH2 or O; Y is C=O or CR2R3; A is selected from C6-C10-aryl and 5- to 10-membered heteroaryl; B is C3-C6-cycloalkyl;(iv) ;R1, R2, R4, and R5are each independently selected from hydrogen and C1-C6-alkyl; and R3is selected from hydroxy and C1-C6-alkoxy.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable saltthereof, wherein A is selected from phenyl, 5- to 6-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, and 9- to 10-membered fused bicyclic heteroaryl comprising 1-4 heteroatoms selected from N, O, and S.

3. The compound of formula (I) according to claim 2, or a pharmaceutically acceptable saltthereof, wherein A is selected from phenyl and a 9-membered fused bicyclic heteroaryl comprising 1-2 nitrogen atoms.

4. The compound of formula (I) according to claim 3, or a pharmaceutically acceptable saltthereof, wherein A is selected from phenyl and 1H-indazolyl.

5. The compound of formula (I) according to any one of claims 1 to 4, or a pharmaceuticallyacceptable salt thereof, wherein B is selected from cyclopropyl and cyclobutyl.

6. The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceuticallyacceptable salt thereof, wherein R1is selected from hydrogen and C1-C3-alkyl.

7. The compound of formula (I) according to claim 6, or a pharmaceutically acceptable saltthereof, wherein R1is selected from hydrogen and methyl.

8. The compound of formula (I) according to any one of claims 1 to 7, or a pharmaceuticallyacceptable salt thereof, wherein: R2is selected from hydrogen and C1-C3-alkyl; and R3is selected from hydroxy and C1-C3-alkoxy.

9. The compound of formula (I) according to claim 8, or a pharmaceutically acceptable saltthereof, wherein: R2is selected from hydrogen and methyl; andR3is selected from hydroxy and methoxy.

10. The compound of formula (I) according to any one of claims 1 to 9, or a pharmaceuticallyacceptable salt thereof, wherein R4is selected from hydrogen and C1-C3-alkyl.

11. The compound of formula (I) according to claim 10, or a pharmaceutically acceptable saltthereof, wherein R4is selected from hydrogen, methyl and isopropyl.

12. The compound of formula (I) according to claim 11, or a pharmaceutically acceptable saltthereof, wherein R4is methyl.

13. The compound of formula (I) according to any one of claims 1 to 12, or apharmaceutically acceptable salt thereof, wherein R5is selected from hydrogen and C1-C3- alkyl.

14. The compound of formula (I) according to claim 13, or a pharmaceutically acceptable saltthereof, wherein R5is selected from hydrogen and methyl.

15. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable saltthereof, wherein: X is CH2or O; Y is C=O or CR2R3; A is selected from phenyl, 5- to 6-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, and 9- to 10-membered fused bicyclic heteroaryl comprising 1-4 heteroatoms selected from N, O, and S; B is C3-C6-cycloalkyl; the groupheteroaromatic group selected from: (i)R1, R2, R4, and R5are each independently selected from hydrogen and C1-C3-alkyl; and R3is selected from hydroxy and C1-C3-alkoxy.

16. The compound of formula (I) according to claim 15, or a pharmaceutically acceptable saltthereof, wherein: X is CH2 or O; Y is C=O or CR2R3; A is selected from phenyl and a 9-membered fused bicyclic heteroaryl comprising 1-2 nitrogen atoms; B is cyclopropyl and cyclobutyl; the groupheteroaromatic group selected from: (i);R1, R2, and R5are each independently selected from hydrogen and methyl; R3is selected from hydroxy and methoxy; and R4is selected from hydrogen, methyl and isopropyl.

17. The compound of formula (I) according to claim 16, or a pharmaceutically acceptable saltthereof, wherein: X is CH2 or O; Y is C=O or CR2R3; A is selected from phenyl and 1H-indazolyl; B is cyclopropyl and cyclobutyl; the groupheteroaromatic group selected from: (i)R1, R2, and R5are each independently selected from hydrogen and methyl; R3is selected from hydroxy and methoxy; and R4is selected from hydrogen, methyl and isopropyl.

18. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable saltthereof, wherein said compound of formula (I) is selected from the group consisting of: 2-Isopropyl-7-oxo-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6H-pyrano[3,2-c]pyrazole-5,4'- piperidine]-1'-carboxamide; 2-Methyl-7-oxo-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6H-pyrano[3,2-c]pyrazole-5,4'- piperidine]-1'-carboxamide; 1-Methyl-7-oxo-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6H-pyrano[3,2-c]pyrazole-5,4'- piperidine]-1'-carboxamide; trans-2-Methyl-7-oxo-N-(3-phenylcyclobutyl)spiro[6H-pyrano[3,2-c]pyrazole-5,4'- piperidine]-1'-carboxamide; trans-1-Methyl-7-oxo-N-(3-phenylcyclobutyl)spiro[6H-pyrano[3,2-c]pyrazole-5,4'- piperidine]-1'-carboxamide; trans-1-Methyl-7-oxo-N-(3-phenylcyclobutyl)spiro[4,6-dihydroindazole-5,4'-piperidine]- 1'-carboxamide; trans-2-Methyl-7-oxo-N-(3-phenylcyclobutyl)spiro[4,6-dihydroindazole-5,4'-piperidine]- 1'-carboxamide;2-Isopropyl-7-oxo-N-[(1R,2S)-2-phenylcyclopropyl]spiro[4,6-dihydropyrazolo[1,5- a]pyridine-5,4'-piperidine]-1'-carboxamide; (7S)-7-Hydroxy-1-methyl-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6,7-dihydropyrano[3,2- c]pyrazole-5,4'-piperidine]-1'-carboxamide; (7R)-7-Hydroxy-1-methyl-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6,7-dihydropyrano[3,2- c]pyrazole-5,4'-piperidine]-1'-carboxamide; (7S)-7-hydroxy-1-methyl-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6,7-dihydropyrano[3,2- c]pyrazole-5,4'-piperidine]-1'-carboxamide; (7R)-7-hydroxy-1-methyl-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6,7-dihydropyrano[3,2- c]pyrazole-5,4'-piperidine]-1'-carboxamide; (7S)-7-Methoxy-1-methyl-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6,7-dihydropyrano[3,2- c]pyrazole-5,4'-piperidine]-1'-carboxamide; (7R)-7-Methoxy-1-methyl-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6,7-dihydropyrano[3,2- c]pyrazole-5,4'-piperidine]-1'-carboxamide; (7S)-7-methoxy-1-methyl-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6,7-dihydropyrano[3,2- c]pyrazole-5,4'-piperidine]-1'-carboxamide; (7R)-7-methoxy-1-methyl-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6,7-dihydropyrano[3,2- c]pyrazole-5,4'-piperidine]-1'-carboxamide; (7S)-7-Hydroxy-1,7-dimethyl-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6H-pyrano[3,2- c]pyrazole-5,4'-piperidine]-1'-carboxamide; (7R)-7-Hydroxy-1,7-dimethyl-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6H-pyrano[3,2- c]pyrazole-5,4'-piperidine]-1'-carboxamide; (7S)-7-hydroxy-1,7-dimethyl-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6H-pyrano[3,2- c]pyrazole-5,4'-piperidine]-1'-carboxamide; (7R)-7-hydroxy-1,7-dimethyl-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6H-pyrano[3,2- c]pyrazole-5,4'-piperidine]-1'-carboxamide; 1,3-Dimethyl-7-oxo-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6H-pyrano[3,2-c]pyrazole- 5,4'-piperidine]-1'-carboxamide; trans-1,3-Dimethyl-7-oxo-N-(3-phenylcyclobutyl)spiro[6H-pyrano[3,2-c]pyrazole-5,4'- piperidine]-1'-carboxamide; trans-1-Methyl-N-[3-(1-methylindazol-4-yl)cyclobutyl]-7-oxo-spiro[6H-pyrano[3,2- c]pyrazole-5,4'-piperidine]-1'-carboxamide; cis-1-methyl-N-[3-(1-methylindazol-4-yl)cyclobutyl]-7-oxo-spiro[6H-pyrano[3,2- c]pyrazole-5,4'-piperidine]-1'-carboxamide;trans-7-Oxo-N-(3-phenylcyclobutyl)spiro[4,6-dihydropyrazolo[1,5-a]pyridine-5,4'- piperidine]-1'-carboxamide; trans-2-Methyl-7-oxo-N-(3-phenylcyclobutyl)spiro[4,6-dihydropyrazolo[1,5-a]pyridine- 5,4'-piperidine]-1'-carboxamide; trans-3-Methyl-7-oxo-N-(3-phenylcyclobutyl)spiro[4,6-dihydropyrazolo[1,5-a]pyridine- 5,4'-piperidine]-1'-carboxamide; 8-Oxo-N-[(1R,2S)-2-phenylcyclopropyl]spiro[7H-pyrano[3,2-d]pyrimidine-6,4'- piperidine]-1'-carboxamide; 1-Isopropyl-7-oxo-N-[(1R,2S)-2-phenylcyclopropyl]spiro[6H-pyrano[3,2-c]pyrazole-5,4'- piperidine]-1'-carboxamide; and 7-Oxo-N-[(1R,2S)-2-phenylcyclopropyl]spiro[1,6-dihydropyrano[3,2-c]pyrazole-5,4'- piperidine]-1'-carboxamide.

19. A compound of formula (I) according to any one of claims 1 to 18 for use astherapeutically active substance.

20. A pharmaceutical composition comprising a compound of formula (I) according to anyone of claims 1 to 18 and a therapeutically inert carrier.

21. Use of a compound of formula (I) according to any one of claims 1 to 18 for the treatmentor prophylaxis of diseases and disorders that are associated with sEH.

22. A compound of formula (I) according to any one of claims 1 to 18 for use in the treatmentor prophylaxis of diseases and disorders that are associated with sEH.

23. Use of a compound of formula (I) according to any one of claims 1 to 18 in the preparationof a medicament for the treatment or prophylaxis of diseases and disorders that are associated with sEH.

24. A method for the treatment or prophylaxis of diseases and disorders that are associatedwith sEH in a human, which method comprises administering an effective amount of a compound of formula (I) according to any one of claims 1 to 18 to the human.

25. The invention as described hereinbefore.

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