WO2025045746A1

WO2025045746A1 - Pyrazole derivatives as sarm1 inhibitors useful for the treatment of neurodegenerative disorders

Info

Publication number: WO2025045746A1
Application number: PCT/EP2024/073625
Authority: WO
Inventors: Nina AREGGER; Joerg Benz; Paola CARAMENTI; Claire Julie GASSER; Maude GIROUD; Uwe Grether; Wolfgang Haap; Bernd Kuhn; Emmanuel Pinard; Kostiantyn PRYSTUPA; Martin Ritter; Didier Rombach; Philipp Claudio SCHMID; Nora Denise Hélène SECHET; Sandra Steiner; Claudio ZAMBALDO
Original assignee: F Hoffmann La Roche AG; Hoffmann La Roche Inc
Current assignee: F Hoffmann La Roche AG; Hoffmann La Roche Inc
Priority date: 2023-08-25
Filing date: 2024-08-23
Publication date: 2025-03-06
Anticipated expiration: 2026-02-25

Abstract

The invention provides compounds having the general formula (I) wherein X, Y, Z, and R1 to R8a are as described herein, compositions including the compounds, processes of manufacturing the compounds and methods of using the compounds in the treatment or prevention of diseases that are associated with SARM1.

Description

F. Hoffmann-La Roche AG, CH-4070 Basel, Switzerland Case: P38603 SARM1 INHIBITORS Field of the Invention The present invention relates to organic compounds useful for therapy or prophylaxis in a mammal, and in particular to Sterile Alpha And TIR Motif Containing 1 (SARM1) inhibitors for the treatment or prevention of amyotrophic lateral sclerosis, spinal muscular atrophy, chemotherapy induced peripheral neuropathy, diabetes induced peripheral neuropathy, multiple sclerosis, Parkinson's disease, glaucoma, stroke, traumatic brain injury, and Charcot-Marie- Tooth disease. Background of the Invention Axonal degeneration is a central driver of disability and disease progression in neurodegenerative and neurological disorders including multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), frontotemporal dementia, Parkinson’s disease, Alzheimer’s disease and peripheral neuropathies. Due to their high energy demands in order to propagate action potentials and ensure protein transport over sometimes meter-long distances, axons are particularly sensitive to metabolic stress following for example mitochondrial disruption or microtubule disassembly. Instead of being a passive dying process however, the resulting axonal degeneration is now understood to involve key molecular components and steps. Programmed axonal degeneration, also known as Wallerian degeneration, is a key molecular mechanism driving axonal loss. As an early pathological feature of numerous neurological conditions associated with an increasing societal and economic burden, therapeutic approaches to target the prevention of axonal degeneration therefore hold significant treatment potential. Summary of the Invention In a first aspect, the present invention provides compounds of formula (I) CNE/26.07.2024 wherein X, Y, Z, and R¹ to R^8a are as defined herein. In further aspects, the invention provides compositions including the compounds of formula (I), processes of manufacturing the compounds of formula (I) and methods of using the compounds of formula (I). 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 (“C1-6-alkyl”), e.g., 1, 2, 3, 4, 5, or 6 carbon atoms. In some embodiments, the alkyl group contains 1 to 4 carbon atoms, e.g., 1, 2, 3, or 4 carbon atoms. In other embodiments, the alkoxy group contains 1 to 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. A particularly preferred, yet non-limiting example of alkyl is methyl. The term “cycloalkyl” as used herein refers to a saturated monocyclic, bicyclic, tricyclic, tetracyclic or pentacyclic hydrocarbon group of 3 to 10 ring carbon atoms (“C_3-10-cycloalkyl”). In some preferred embodiments, the cycloalkyl group is a monocyclic or bicyclic hydrocarbon group of 3 to 8 ring carbon atoms. In some particularly preferred embodiments, the cycloalkyl group is a monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. “Bicyclic cycloalkyl” refers to cycloalkyl moieties consisting of two saturated carbocycles having two carbon atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and to spirocyclic moieties, i.e., the two rings are connected via one common ring atom. A preferred, yet non-limiting example of a pentacyclic cycloalkyl is cubanyl (pentacyclo[4.2.0.0^2,5.0^3,8.0^4,7]octane). Preferably, the cycloalkyl group is a monocyclic hydrocarbon group of 3 to 6 ring carbon atoms, e.g., of 3, 4, 5 or 6 carbon atoms. Some non- limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cubanyl, 1-bicyclo[1.1.1]pentanyl, norbornanyl, and 1-bicyclo[2.2.2]octanyl. A particularly preferred, yet non-limiting example of cycloalkyl is cyclopropyl. The term “cycloalkenyl” as used herein refers to a partly unsaturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms (“C_3-10-cycloalkyl”). In some preferred embodiments, the cycloalkenyl group is a monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. “Bicyclic cycloalkenyl” refers to cycloalkenyl moieties consisting of two carbocycles having two carbon atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and to spirocyclic moieties, i.e., the two rings are connected via one common ring atom, wherein at least one of the two rings is partly unsaturated. Preferably, the cycloalkenyl group is a monocyclic hydrocarbon group of 3 to 6 ring carbon atoms, e.g., of 3, 4, 5 or 6 carbon atoms. Some non-limiting examples of cycloalkenyl include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl. A particularly preferred, yet non-limiting example of cycloalkenyl is cyclopentenyl. 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 (“C1-6-alkoxy”). In some embodiments, the alkoxy group contains 1 to 4 carbon atoms, e.g., 1, 2, 3, or 4 carbon atoms. In 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 “haloalkoxy” refers to an alkoxy group, wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by a halogen atom, preferably fluoro. Preferably, “haloalkoxy” refers to an alkoxy group wherein 1, 2 or 3 hydrogen atoms of the alkoxy group have been replaced by a halogen atom, most preferably fluoro. Preferred, yet non-limiting examples of haloalkoxy are trifluoromethoxy, 3,3,3-trifluoropropoxy, 2,2,2-trifluoro-1-methyl- ethoxy, and 3-fluoro-2-fluoro-propoxy. A particularly preferred, yet non-limiting example of haloalkoxy is trifluoromethoxy. The term “halocycloalkyl” refers to a cycloalkyl group, wherein at least one of the hydrogen atoms of the cycloalkyl group has been replaced by a halogen atom, preferably fluoro. Preferably, “halocycloalkyl” refers to a cycloalkyl group wherein 1, 2 or 3 hydrogen atoms of the cycloalkyl group have been replaced by a halogen atom, most preferably fluoro. A preferred, yet non-limiting example of halocycloalkyl is difluorocyclopropyl (e.g., 1,1-difluorocyclopropyl or 2,2-difluorocyclopropyl). The term “halogen” or “halo” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I). Preferably, the term “halogen” or “halo” refers to fluoro (F), chloro (Cl) or bromo (Br). Particularly preferred, yet non-limiting examples of “halogen” or “halo” are fluoro (F) and chloro (Cl). The term “cyano” refers to a –CN (nitrile) group. The term “hydroxy” refers to an –OH group. 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, indanyl, 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, monocyclic, bicyclic or tricyclic, preferably monocyclic or bicyclic ring system having a total of 5 to 14 ring members, preferably, 5 to 12 ring members, for example 5 to 11, 5 to 10, 5 to 9, 5 to 8, 5 to 7 or 5 to 6 ring members, wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms. Preferably, “heteroaryl” refers to a 5-9 membered monocyclic or bicyclic heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. Some non-limiting examples of heteroaryl include pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, 1,3-benzoxazol-2-yl, benzothiophenyl, imidazo[1,2-a]pyridin-6-yl, 1,3-benzoxazol-4- yl, 2,3-dihydrobenzofurane, 1,3-benzoxazol-5-yl, 1,3-benzoxazol-6-yl, 1,3-benzoxazol-7-yl, 1H- indazol-3-yl, 1H-indazol-4-yl, oxadiazolyl, pyrazolyl, triazolyl, isothiazolyl, thienyl, and tetrazolyl. The term “heterocyclyl” as used herein refers to a saturated or partly unsaturated mono- or bicyclic, preferably monocyclic ring system of 3 to 14 ring atoms, e.g.3 to 13, 3 to 12, 3 to 11, 3 to 10, 3 to 9, 3 to 8, 3 to 7, 3 to 6 or 3 to 5 ring atoms, preferably 3 to 10 ring atoms, more preferably 3 to 10 ring atoms, most preferably 3 to 8 ring atoms, wherein 1, 2, or 3 of said ring atoms are heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Preferably, 1 to 2 of said ring atoms are selected from N and O, the remaining ring atoms being carbon. “Bicyclic heterocyclyl” refers to heterocyclic moieties consisting of two cycles having two ring atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and to spirocyclic moieties, i.e., the two rings are connected via one common ring atom. Some non-limiting examples of monocyclic heterocyclyl groups include azetidin-3-yl, azetidin-2-yl, 2-azaspiro[3.3]heptan-2-yl, 2,6-diazaspiro[3.3]heptan-2-yl, 2- azaspiro[3.4]octan-2-yl, 5-oxa-2-azaspiro[3.4]octan-2-yl, pyrrolidinyl (e.g. pyrrolidin-1-yl), thiomorpholinyl, oxetan-3-yl, oxetan-2-yl, tetrahydrofuranyl (e.g. tetrahydrofuran-2-yl), tetrahydropyranyl (e.g. tetrahydropyran-2-yl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4- piperidinyl, piperazinyl (e.g. piperazin-1-yl), and morpholinyl. The term “haloalkyl” refers to an alkyl group as defined herein, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a halogen atom, preferably fluoro. Preferably, “haloalkyl” refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms of the alkyl group have been replaced by a halogen atom, most preferably fluoro. Preferred, yet non-limiting examples of haloalkyl are trifluoromethyl, difluoromethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl. A particularly preferred, yet non-limiting example of haloalkyl is trifluoromethyl. The term “hydroxyalkyl” refers to an alkyl group, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a hydroxy group. Preferably, “hydroxyalkyl” refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms, most preferably 1 hydrogen atom of the alkyl group have been replaced by a hydroxy group. Preferred, yet non-limiting examples of hydroxyalkyl are 2-hydroxy-1,1-dimethylethyl, 2-hydroxy-2-methyl-propyl, hydroxymethyl and hydroxyethyl (e.g.2-hydroxyethyl or 1-hydroxyethyl). 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. 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. The compounds of formula (I) can be present in the form of tautomers, for example at the central pyrazole ring. The compound structures are written in one tautomeric form only, but the invention is to be understood to encompass all tautomeric forms. The abbreviation “SARM1” refers to Sterile Alpha and TIR Motif Containing 1. 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 mammal and especially 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. SARM1 Axonal breakdown distal to the site of an injury is a key feature of programmed axonal degeneration or Wallerian degeneration and is characterized by mitochondrial disruption, loss of nicotinamide adenine dinucleotide (NAD+), increased intracellular calcium levels and axonal fragmentation (Conforti, L., et al., Nat. Rev. Neurosci., 2014, 15, 394–409). The central component of the programmed axonal degeneration mechanism is Sterile Alpha And TIR Motif Containing 1 (SARM1) (Osterloh, J.M., et al., Science, 2012, 337, 481-484). SARM1 is an NAD+ hydrolase that depletes levels of NAD+ by cleaving it into the metabolites: nicotinamide (NAM) and adenosine diphosphate ribose (ADPR) or cyclic ADPR. The resulting loss of NAD+, an essential metabolite involved in energy metabolism and axonal homeostasis (Hopkins, E.L., et al., 2021, Front. Mol. Biosci., 8:703532), and increase in cADPR, a modulator of intra-axonal calcium levels (Li, Y., et al., 2022, J. Cell Biol., 221, e202106080), contributes to the subsequent axonal degeneration process. Other molecular components of the Wallerian axonal degeneration pathway have been identified including axonal survival factors like nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2). Under normal conditions, axonal survival factors such as NMNAT2 are continuously turned over and replenished by anterograde transport along the axon from the cell body (Gilley, J. & Coleman, M.P., 2010, PLoS Biol., 8, e1000300). NMNAT2 maintains axonal energetics by catalyzing the formation of NAD+ from nicotinamide mononucleotide (NMN) and adenosine tri-phosphate (ATP). However during injury or disease, disruption of microtubule assembly or mitochondrial depolarization in axons leads to loss of NMNAT2 transport followed by NMNAT2 depletion. SARM1 is activated in turn by reduced NMNAT2 levels as a result of loss of NAD+, a negative SARM1 ligand, and accumulation of NMN, a positive SARM1 ligand (Figley, M.D., et al., 2021, Neuron, 109, 1118-1136). SARM1 is a multidomain protein consisting of an autoinhibitory ARM domain, tandem oligomerization SAM domains and a catalytic TIR domain. While originally thought to exist as a monomer in solution, recent high-resolution cryo-EM structures have revealed that SARM1 exists as an octamer with the ARM domains locking the TIR domains in an inactive conformation (Bratkowski, M., et al., 2020, Cell Rep., 32, 107999). This was followed by identification of an allosteric site in which both NMN and NAD+ can bind (Jiang, Y., et al., 2020, Nature, 588, 658-663; Figley, M.D., et al., 2021, Neuron, 109, 1118-1136). The increase in NMN/NAD+ during axonal injury and the higher affinity of NMN for SARM1 results in replacement of NAD+ in the allosteric pocket, releasing the ARM domains and allowing for TIR domain catalytic activity. Both in vitro and in vivo studies of SARM1 loss-of-function have highlighted the central role of SARM1 in programmed axonal degeneration. SARM1 genetic knockout has been shown to protect axons in both human and rodent neuronal cultures following physical (axotomy) or chemical injury, for example due to chemotherapeutic drugs such as vincristine (Osterloh, J.M., et al., Science, 2012, 337, 481-484; Chen, Y., et al., 2021, Exp. Neurol., 339, 113636). In vivo, deletion of SARM1 prevents nerve fiber loss and restores normal pain sensitivity in models of chemotherapy-induced peripheral neuropathy (Geisler, S., et al., 2016, Brain, 139, 3092-3108) and diabetic peripheral neuropathy (Cheng, Y., et al., 2019, Diabetes, 68, 2120-2130). SARM1 deletion also attenuates axonal degeneration in pre-clinical models of ALS (White, M.A., et al., Acta Neuropathol. Commun., 7, 166) and MS (Viar, K., et al., 2020, PLoS One, 15, e0235110). In models of eye disorders, SARM1 deficiency has been found to block loss of axons of retinal ganglion cells in glaucoma models (Finnegan, L.K., et al., 2022, Int. J. Mol. Sci., 23, 1606) and of photoreceptors in retinitis pigmentosa models (Ozaki, E., et al., 2020, Life Sci. Alliance., 3, e201900618). These combined studies underscore the therapeutic potential of blocking SARM1 activity to ameliorate various neurological disorders associated with axonal loss. Compounds of the Invention In a first aspect, the present invention provides a compound of Formula (I)

or a pharmaceutically acceptable salt, or a tautomer thereof, wherein: X, Y and Z are each selected from CH and N, provided that at most two of X, Y and Z are N; R¹ is selected from hydrogen, halogen, hydroxy, cyano, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C3-C10-cycloalkyl, and NR^9aR^9b; R² is selected from hydrogen, halogen, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy, C₃-C₁₀-cycloalkyl, and 3-14 membered heterocycloalkyl; R^3a and R^3b are each independently selected from hydrogen and C1-C6-alkyl; or R^3a and R^3b, taken together with the carbon atom to which they are attached, form a C3- C₁₀-cycloalkyl; or R^3a and R^4a, taken together with the carbon atoms to which they are attached, form a C3- C10-cycloalkyl; R^3b is selected from hydrogen and C1-C6-alkyl; and R^4b is selected from hydrogen, halogen, cyano, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy, and hydroxy- C1-C6-alkyl; or R^4a and R^4b are each independently selected from hydrogen, halogen, cyano, hydroxy, C1- C₆-alkyl, C₁-C₆-alkoxy, and hydroxy-C₁-C₆-alkyl; or R^4a and R^4b, taken together with the carbon atom to which they are attached, form a C₃- C10-cycloalkyl; or R^4a and R⁵, taken together with the carbon atom to which they are attached, form a C3-C10- cycloalkyl; and R^4b is selected from hydrogen, halogen, cyano, hydroxy, C₁-C₆-alkyl, C1-C6-alkoxy, and hydroxy-C1-C6-alkyl; or R⁵ is selected from hydrogen, halogen, and C1-C6-alkyl; or R⁵ and R⁷, taken together with the carbon atoms to which they are attached, form a C₃-C₁₀- cycloalkenyl; R^6a and R^6b are each independently selected from hydrogen and C1-C6-alkyl; or R^6a and R^6b, taken together with the carbon atom to which they are attached, form a C₃- C10-cycloalkyl; or R^6a and R⁵, taken together with the carbon atom to which they are attached, form a C3-C10- cycloalkyl; and R^6b is selected from hydrogen and C1-C6-alkyl; R⁷ is selected from hydrogen, halogen, cyano, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆- alkoxy, halo-C1-C6-alkoxy, C3-C10-cycloalkyl, C1-C6-alkyl-SO2-, C1-C6-alkyl-NH- SO2, and C1-C6-alkyl-N(C1-C6-alkyl)-SO2-; R⁸ and R^8a are each independently selected from hydrogen and halogen; R^9a and R^9b are each independently selected from hydrogen, C1-C6-alkyl, C3-C10- cycloalkyl, halo-C1-C6-alkyl, and halo-C3-C10-cycloalkyl; A is selected from C3-C10-cycloalkyl, C6-C10-aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocyclyl. In one embodiment, the present invention provides a compound of Formula (I) as described herein, wherein the compound of formula (I) is a compound of formula (Ib),

or a pharmaceutically acceptable salt, or a tautomer thereof, wherein: X, Y and Z are each selected from CH and N, provided that at most two of X, Y and Z are N; R¹ is selected from hydrogen, halogen, hydroxy, cyano, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C3-C10-cycloalkyl, and NR^9aR^9b; R² is selected from hydrogen, halogen, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C₁-C₆-alkoxy, C₃-C₁₀-cycloalkyl, and 3-14 membered heterocycloalkyl; R^3a and R^3b are each independently selected from hydrogen and C1-C6-alkyl; or R^3a and R^3b, taken together with the carbon atom to which they are attached, form a C₃- C₁₀-cycloalkyl; or R^3a and R^4a, taken together with the carbon atoms to which they are attached, form a C3- C10-cycloalkyl; R^3b is selected from hydrogen and C1-C6-alkyl; and R^4b is selected from hydrogen, halogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy, and hydroxy-C₁-C₆- alkyl; or R^4a and R^4b are each independently selected from hydrogen, halogen, hydroxy, C1-C6- alkyl, C₁-C₆-alkoxy, and hydroxy-C₁-C₆-alkyl; or R^4a and R^4b, taken together with the carbon atom to which they are attached, form a C3- C10-cycloalkyl; or R^4a and R⁵, taken together with the carbon atom to which they are attached, form a C3-C10- cycloalkyl; and R^4b is selected from hydrogen, halogen, hydroxy, C₁-C₆-alkyl, C₁-C₆- alkoxy, and hydroxy-C1-C6-alkyl; or R⁵ is selected from hydrogen, halogen, and C1-C6-alkyl; or R⁵ and R⁷, taken together with the carbon atoms to which they are attached, form a C3-C10- cycloalkenyl; R^6a and R^6b are each independently selected from hydrogen and C₁-C₆-alkyl; or R^6a and R^6b, taken together with the carbon atom to which they are attached, form a C3- C₁₀-cycloalkyl; or R^6a and R⁵, taken together with the carbon atom to which they are attached, form a C₃-C₁₀- cycloalkyl; and R^6b is selected from hydrogen and C1-C6-alkyl; R⁷ is selected from hydrogen, halogen, cyano, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6- alkoxy, halo-C₁-C₆-alkoxy, C₃-C₁₀-cycloalkyl, C₁-C₆-alkyl-SO₂-, C₁-C₆-alkyl-NH- SO2, and C1-C6-alkyl-N(C1-C6-alkyl)-SO2-; R⁸ is selected from hydrogen and halogen; R^9a and R^9b are each independently selected from hydrogen, C₁-C₆-alkyl, C₃-C₁₀- cycloalkyl, halo-C1-C6-alkyl, and halo-C3-C10-cycloalkyl; A is selected from C3-C10-cycloalkyl, C6-C10-aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocyclyl. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein the compound of formula (I) is not (3,3-dimethyl-4-phenylpyrrolidin-1-yl)-(3-pyridin-4-yl-1H-pyrazol-5-yl)methanone (i)

In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein: (i) X, Y and Z are CH; or (ii) X and Z are CH and Y is N; and R¹ is hydrogen. In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein X and Z are CH; Y is N; and R¹ is hydrogen. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein R² is selected from hydrogen and C₁-C₆-alkyl. In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein R² is hydrogen. The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein: (i) R^3a and R^3b are each independently selected from hydrogen and C1-C6-alkyl; R^4a is selected from hydrogen, halogen, hydroxy, cyano, C₁-C₆-alkyl and hydroxy-C₁-C₆- alkyl; and R^4b is hydrogen; or (ii) R^3a and R^4a, taken together with the carbon atoms to which they are attached, form a C₃-C₆-cycloalkyl; and R^3b and R^4b are both hydrogen. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein R^3a and R^3b are each independently selected from hydrogen and C₁-C₆-alkyl. In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein R^3a and R^3b are both hydrogen. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein: R^4a is selected from hydrogen and hydroxy; and R^4b is hydrogen. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein: R^4a is selected from hydrogen, halogen, hydroxy, cyano, C₁-C₆-alkyl and hydroxy-C₁-C₆- alkyl; and R^4b is hydrogen. In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein: R^4a is selected from hydrogen, hydroxy, cyano, C1-C6-alkyl and hydroxy-C1-C6-alkyl; and R^4b is hydrogen. In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein R^4a and R^4b are both hydrogen. In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein: R^4a is selected from hydrogen, hydroxy, cyano, methyl, and hydroxymethyl; and R^4b is hydrogen. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein A is selected from C₆-C₁₀- aryl and 5- to 14-membered heteroaryl. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein A is selected from phenyl and 5- to 9-membered heteroaryl. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein A is selected from phenyl, pyridyl, and thienyl. In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein A is selected from phenyl and thienyl. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein A is phenyl. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein A is thienyl. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein A is selected from: (i) phenyl; (ii) indanyl; (iii) a 5-membered heteroaryl selected from:

wherein a wavy line indicates the point of attachment of A to the remainder of formula (I); (iv) a 6-membered heteroaryl

; wherein U, V and W are each independently selected from CH and N, provided that at least one of U, V and W is N; and the wavy line indicates the point of attachment of A to the remainder of formula (I); (v) a 9-membered heteroaryl selected from:

wherein a wavy line indicates the point of attachment of A to the remainder of formula (I); (vi) bicyclo[1.1.1]pentanyl; and (vii) cubanyl. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein: (i) R⁵ is selected from hydrogen and halogen; and R⁷ is selected from hydrogen, halogen, cyano, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆- alkoxy, halo-C₁-C₆-alkoxy, and C₃-C₁₀-cycloalkyl; or (ii) R⁵ and R⁷, taken together with the carbon atoms to which they are attached, form a C₃-C₁₀-cycloalkenyl; and R⁸ and R^8a are each independently selected from hydrogen and halogen; and A is selected from C6-C10-aryl and 5- to 14-membered heteroaryl. In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein: R⁵ is hydrogen; R⁷ is halogen; R⁸ is selected from hydrogen and halogen; and R^8a is hydrogen; and A is selected from C6-C10-aryl and 5- to 14-membered heteroaryl. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein: R⁵ is hydrogen; R⁷ is selected from chloro and fluoro; R⁸ is selected from hydrogen and fluoro; R^8a is hydrogen; and A is selected from phenyl and thienyl. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein the compound of formula (I) is a compound of formula (Ib) and wherein: (i) R⁵ is selected from hydrogen and halogen; and R⁷ is selected from hydrogen, halogen, cyano, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6- alkoxy, halo-C1-C6-alkoxy, and C3-C10-cycloalkyl; or (ii) R⁵ and R⁷, taken together with the carbon atoms to which they are attached, form a C₃-C₁₀-cycloalkenyl; and R⁸ is selected from hydrogen and halogen; and A is selected from C6-C10-aryl and 5- to 14-membered heteroaryl. In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein the compound of formula (I) is a compound of formula (Ib) and wherein: R⁵ is hydrogen; R⁷ is halogen; R⁸ is selected from hydrogen and halogen; and A is selected from C6-C10-aryl and 5- to 14-membered heteroaryl. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein the compound of formula (I) is a compound of formula (Ib) and wherein: R⁵ is hydrogen; R⁷ is selected from chloro and fluoro; R⁸ is selected from hydrogen and fluoro; and A is selected from phenyl and thienyl. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein the compound of formula (I) is a compound of formula (Ib) and wherein: (i) R⁵ is selected from hydrogen and halogen; and R⁷ is selected from hydrogen, halogen, cyano, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆- alkoxy, halo-C1-C6-alkoxy, and C3-C10-cycloalkyl; or (ii) R⁵ and R⁷, taken together with the carbon atoms to which they are attached, form a C₃-C₁₀-cycloalkenyl; and R⁸ is selected from hydrogen and halogen. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein: (i) R⁵ is selected from hydrogen and halogen; and R⁷ is selected from hydrogen, halogen, cyano, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6- alkoxy, halo-C1-C6-alkoxy, and C3-C10-cycloalkyl; or (ii) R⁵ and R⁷, taken together with the carbon atoms to which they are attached, form a C3-C10-cycloalkenyl; and R⁸ and R^8a are each independently selected from hydrogen and halogen. In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein the compound of formula (I) is a compound of formula (Ib) and wherein: R⁵ is hydrogen; R⁷ is halogen; and R⁸ is selected from hydrogen and halogen. In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein: R⁵ is hydrogen; R⁷ is halogen; R⁸ is selected from hydrogen and halogen; and R^8a is hydrogen. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein the compound of formula (I) is a compound of formula (Ib) and wherein: R⁵ is hydrogen; R⁷ is selected from chloro and fluoro; and R⁸ is selected from hydrogen and fluoro. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein: R⁵ is hydrogen; R⁷ is selected from chloro and fluoro; R⁸ is selected from hydrogen and fluoro; and R^8a is hydrogen. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein: R^6a is selected from hydrogen and C1-C6-alkyl; and R^6b is hydrogen. In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein R^6a and R^6b are both hydrogen. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein: R^3a and R^3b are each independently selected from hydrogen and C₁-C₆-alkyl; or R^3a and R^4a, taken together with the carbon atoms to which they are attached, form a C3-C10- cycloalkyl; R^3b is selected from hydrogen and C₁-C₆-alkyl; and R^4b is selected from hydrogen, halogen, cyano, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy, and hydroxy-C₁-C₆- alkyl; or R^4a and R^4b are each independently selected from hydrogen, halogen, cyano, hydroxy, C1- C₆-alkyl, C₁-C₆-alkoxy, and hydroxy-C₁-C₆-alkyl; R^6a and R^6b are each independently selected from hydrogen and C1-C6-alkyl; or R^6a and R⁵, taken together with the carbon atom to which they are attached, form a C3-C10- cycloalkyl; and R^6b is selected from hydrogen and C₁-C₆-alkyl. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein: (i) X, Y and Z are CH; or (ii) X and Z are CH and Y is N; R¹ is hydrogen; R² is selected from hydrogen and C1-C6-alkyl; R^3a and R^3b are each independently selected from hydrogen and C₁-C₆-alkyl; R^4a is selected from hydrogen and hydroxy; R^4b is hydrogen; (i) R⁵ is selected from hydrogen and halogen; and R⁷ is selected from hydrogen, halogen, cyano, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆- alkoxy, halo-C1-C6-alkoxy, and C3-C10-cycloalkyl; or (ii) R⁵ and R⁷, taken together with the carbon atoms to which they are attached, form a C3-C10-cycloalkenyl; R^6a is selected from hydrogen and C1-C6-alkyl; R^6b is hydrogen; R⁸ is selected from hydrogen and halogen; and A is selected from C6-C10-aryl and 5- to 14-membered heteroaryl. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein: (i) X, Y and Z are CH; or (ii) X and Z are CH and Y is N; R¹ is hydrogen; R² is selected from hydrogen and C₁-C₆-alkyl; (i) R^3a and R^3b are each independently selected from hydrogen and C1-C6-alkyl; R^4a is selected from hydrogen, halogen, hydroxy, cyano, C₁-C₆-alkyl and hydroxy-C₁-C₆- alkyl; and R^4b is hydrogen; or (ii) R^3a and R^4a, taken together with the carbon atoms to which they are attached, form a C3-C6-cycloalkyl; and R^3b and R^4b are both hydrogen; (i) R⁵ is selected from hydrogen and halogen; and R⁷ is selected from hydrogen, halogen, cyano, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6- alkoxy, halo-C1-C6-alkoxy, and C3-C10-cycloalkyl; or (ii) R⁵ and R⁷, taken together with the carbon atoms to which they are attached, form a C3-C10-cycloalkenyl; R^6a is selected from hydrogen and C1-C6-alkyl; R^6b is hydrogen; R⁸ and R^8a are each independently selected from hydrogen and halogen; and A is selected from C6-C10-aryl and 5- to 14-membered heteroaryl. In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein: X and Z are CH; Y is N; R¹ is hydrogen; R² is hydrogen; R^3a and R^3b are both hydrogen; R^4a and R^4b are both hydrogen; R⁵ is hydrogen; R^6a and R^6b are both hydrogen; R⁷ is halogen; R⁸ is selected from hydrogen and halogen; and A is selected from C6-C10-aryl and 5- to 14-membered heteroaryl. In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein: X and Z are CH; Y is N; R¹ is hydrogen; R² is hydrogen; R^3a and R^3b are both hydrogen; R^4a is selected from hydrogen, hydroxy, cyano, C₁-C₆-alkyl and hydroxy-C₁-C₆-alkyl; R^4b is hydrogen; R⁵ is hydrogen; R^6a and R^6b are both hydrogen; R⁷ is halogen; R⁸ is selected from hydrogen and halogen; R^8a is hydrogen; and A is selected from C₆-C₁₀-aryl and 5- to 14-membered heteroaryl. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein: X and Z are CH; Y is N; R¹ is hydrogen; R² is hydrogen; R^3a and R^3b are both hydrogen; R^4a and R^4b are both hydrogen; R⁵ is hydrogen; R^6a and R^6b are both hydrogen; R⁷ is selected from chloro and fluoro; R⁸ is selected from hydrogen and fluoro; and A is selected from phenyl and thienyl. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein: X and Z are CH; Y is N; R¹ is hydrogen; R² is hydrogen; R^3a and R^3b are both hydrogen; R^4a is selected from hydrogen, hydroxy, cyano, methyl, and hydroxymethyl; R^4b hydrogen; R⁵ is hydrogen; R^6a and R^6b are both hydrogen; R⁷ is selected from chloro and fluoro; R⁸ is selected from hydrogen and fluoro; R^8a is hydrogen; and A is selected from phenyl and thienyl. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein said compound of formula (I) is selected from: [3-(4-chlorophenyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [3-phenylpyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [5-bromospiro[indane-1,3'-pyrrolidine]-1'-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [3-(4-chlorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [3-(4-chlorophenyl)pyrrolidin-1-yl]-(4-methyl-3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(2-chlorophenyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [3-(3-chlorophenyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [3-(2-chloro-4-fluoro-phenyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [3-(5-chloro-2-thienyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [3-(5-chloro-2-thienyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [2,2-dimethyl-4-phenyl-pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [3-(2-ethylphenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [(3R,4S)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5- yl]methanone and [(3S,4R)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-[3-(4- pyridyl)-1H-pyrazol-5-yl]methanone; [3-(p-tolyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [3-(3,5-difluorophenyl)-3-fluoro-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; 4-[1-(3-pyridazin-4-yl-1H-pyrazole-5-carbonyl)pyrrolidin-3-yl]benzonitrile; [3-(3,4-difluorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; (3-pyridazin-4-yl-1H-pyrazol-5-yl)-[3-[3-(trifluoromethoxy)phenyl]pyrrolidin-1- yl]methanone; [3-(6-chloro-3-pyridyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [3-(5-chloro-2-pyridyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [(3R,4S)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone and [(3S,4R)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3- pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [(3R,4R)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone and [(3S,4S)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3- pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [3-(3,4-difluorophenyl)-3-fluoro-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [2,5-dimethyl-3-phenyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [(2R,4R)-4-(4-fluorophenyl)-2-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone and [(2S,4R)-4-(4-fluorophenyl)-2-methyl-pyrrolidin-1-yl]-(3-pyridazin- 4-yl-1H-pyrazol-5-yl)methanone; [(3R)-3-(4-chlorophenyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone ; [(3S)-3-(4-chlorophenyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [(3R)-3-(6-chloro-3-pyridyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [(3S)-3-(6-chloro-3-pyridyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [(3R,4S)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3S,4R)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; (3-cyclobutylpyrrolidin-1-yl)-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; (3-cyclopropylpyrrolidin-1-yl)-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; 5-[1-(3-pyridazin-4-yl-1H-pyrazole-5-carbonyl)pyrrolidin-3-yl]thiophene-2-carbonitrile; [3-(benzothiophen-2-yl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; (3-imidazo[1,2-a]pyridin-6-ylpyrrolidin-1-yl)-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(2,2-difluoroindan-5-yl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1}-pyrazol-5-yl)methanone; [3-(2,3-dihydrobenzofuran-6-yl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(benzothiophen-6-yl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [3-(1,3-benzoxazol-5-yl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [3-(3-chloroisothiazol-5-yl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [3-(4-chloro-2-thienyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [3-(4-chlorophenyl)pyrrolidin-1-yl]-[4-(difluoromethoxy)-3-pyridazin-4-yl-1H-pyrazol-5- yl]methanone; [3-(4-chlorophenyl)pyrrolidin-1-yl]-(4-methoxy-3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(4-chlorophenyl)pyrrolidin-1-yl]-(4-cyclopropyl-3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; (3-pyridazin-4-yl-1H-pyrazol-5-yl)-[3-[2-(trifluoromethyl)thiazol-5-yl]pyrrolidin-1- yl]methanone; [3-(2-chlorothiazol-5-yl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [3-(2-methylthiazol-5-yl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [5-(4-chlorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl]-[3-(4-pyridyl)-1H-pyrazol-5- yl]methanone; [3-(4-chlorophenyl)-2,3,3a,4,5,6,7,7a-octahydroindol-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5- yl]methanone; [3-(3,4-difluoro-5-methoxy-phenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3R,4R)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3S,4S)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(4-chlorophenyl)pyrrolidin-1-yl]-(4-methoxy-3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(4-chlorophenyl)pyrrolidin-1-yl]-[3-(3-fluoro-4-pyridyl)-1H-pyrazol-5-yl]methanone; [3-(2-chlorothiazol-5-yl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [3-(5-chlorothiazol-2-yl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [3-(4-chloro-3-fluoro-phenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; 5-[1-(3-pyridazin-4-yl-1H-pyrazole-5-carbonyl)pyrrolidin-3-yl]thiophene-2-carbonitrile; [(3S)-3-(3,4-difluorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3R)-3-(3,4-difluorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3R)-3-(3,4-difluorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3S)-3-(3,4-difluorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [4-(4-chlorophenyl)-2-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(5-bromo-2-thienyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [3-(5-methyl-2-thienyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [3-(4-bromophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; (4-chloro-3-pyridazin-4-yl-1H-pyrazol-5-yl)-[3-(3,4-difluorophenyl)pyrrolidin-1- yl]methanone; [3-(4-methyl-2-thienyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; (4-chloro-3-pyridazin-4-yl-1H-pyrazol-5-yl)-[(3S)-3-(3,4-difluorophenyl)pyrrolidin-1- yl]methanone; (4-chloro-3-pyridazin-4-yl-1H-pyrazol-5-yl)-[(3R)-3-(3,4-difluorophenyl)pyrrolidin-1- yl]methanone; (4-chloro-3-pyridazin-4-yl-1H-pyrazol-5-yl)-[(3R)-3-(3,4-difluorophenyl)pyrrolidin-1- yl]methanone; (4-chloro-3-pyridazin-4-yl-1H-pyrazol-5-yl)-[(3S)-3-(3,4-difluorophenyl)pyrrolidin-1- yl]methanone; [3-(4-bromophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [(3R,4S)-3-(4-bromophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3S,4R)-3-(4-bromophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3S,4R)-3-(4-bromophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3R,4S)-3-(4-bromophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(benzothiophen-2-yl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [3-(4-bromo-5-methyl-2-thienyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3S)-3-(4-chlorophenyl)pyrrolidin-1-yl]-[3-(3-methyl-4-pyridyl)-1H-pyrazol-5- yl]methanone; [(3R)-3-(4-chlorophenyl)pyrrolidin-1-yl]-[3-(3-methyl-4-pyridyl)-1H-pyrazol-5- yl]methanone; [(3R)-3-(4-chlorophenyl)pyrrolidin-1-yl]-[3-(3-methyl-4-pyridyl)-1H-pyrazol-5- yl]methanone; [(3S)-3-(4-chlorophenyl)pyrrolidin-1-yl]-[3-(3-methyl-4-pyridyl)-1H-pyrazol-5- yl]methanone; (4-bromo-3-pyridazin-4-yl-1H-pyrazol-5-yl)-[(3S)-3-(4-chlorophenyl)pyrrolidin-1- yl]methanone; (4-bromo-3-pyridazin-4-yl-1H-pyrazol-5-yl)-[(3R)-3-(4-chlorophenyl)pyrrolidin-1- yl]methanone; (4-bromo-3-pyridazin-4-yl-1H-pyrazol-5-yl)-[(3R)-3-(4-chlorophenyl)pyrrolidin-1- yl]methanone; (4-bromo-3-pyridazin-4-yl-1H-pyrazol-5-yl)-[(3S)-3-(4-chlorophenyl)pyrrolidin-1- yl]methanone; [(3R,4S)-3-(4-chlorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(3S,4R)-3-(4-chlorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(3S,4R)-3-(4-chlorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(3R,4S)-3-(4-chlorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [3-[3-(difluoromethyl)-4-fluoro-phenyl]pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3S)-3-(4-chlorophenyl)pyrrolidin-1-yl]-(4-fluoro-3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3R)-3-(4-chlorophenyl)pyrrolidin-1-yl]-(4-fluoro-3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3R)-3-(4-chlorophenyl)pyrrolidin-1-yl]-(4-fluoro-3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3S)-3-(4-chlorophenyl)pyrrolidin-1-yl]-(4-fluoro-3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3R,4S)-3-(4-chlorophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3S,4R)-3-(4-chlorophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(4-chlorophenyl)pyrrolidin-1-yl]-(4-cyclopropyl-3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3R,4S)-3-(4-chlorophenyl)-4-[(1S)-1-hydroxyethyl]pyrrolidin-1-yl]-(3-pyridazin-4-yl- 1H-pyrazol-5-yl)methanone; [(3R,4S)-3-(4-chlorophenyl)-4-[(1R)-1-hydroxyethyl]pyrrolidin-1-yl]-(3-pyridazin-4-yl- 1H-pyrazol-5-yl)methanone; [(3R,4S)-3-(4-chlorophenyl)-4-[(1R)-1-hydroxyethyl]pyrrolidin-1-yl]-(3-pyridazin-4-yl- 1H-pyrazol-5-yl)methanone; [(3R,4S)-3-(4-chlorophenyl)-4-[(1S)-1-hydroxyethyl]pyrrolidin-1-yl]-(3-pyridazin-4-yl- 1H-pyrazol-5-yl)methanone; [(3R)-3-(4-chloro-2-thienyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3S)-3-(4-chloro-2-thienyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [(3S)-3-(4-chloro-2-thienyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [(3R)-3-(4-chloro-2-thienyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3R,4S)-3-(3,4-difluorophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol- 5-yl)methanone; [(3S,4R)-3-(3,4-difluorophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol- 5-yl)methanone; (3S,4R)-4-(4-chlorophenyl)-1-(3-pyridazin-4-yl-1H-pyrazole-5-carbonyl)pyrrolidine-3- carbonitrile; (3R,4S)-4-(4-chlorophenyl)-1-(3-pyridazin-4-yl-1H-pyrazole-5-carbonyl)pyrrolidine-3- carbonitrile; (3R,4S)-4-(4-chlorophenyl)-1-(3-pyridazin-4-yl-1H-pyrazole-5-carbonyl)pyrrolidine-3- carbonitrile; (3S,4R)-4-(4-chlorophenyl)-1-(3-pyridazin-4-yl-1H-pyrazole-5-carbonyl)pyrrolidine-3- carbonitrile; [(3S,4R)-3-(3,4-difluorophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol- 5-yl)methanone; [(3R,4S)-3-(3,4-difluorophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol- 5-yl)methanone; [(3R,4S)-3-(4-chlorophenyl)-4-fluoro-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3S,4R)-3-(4-chlorophenyl)-4-fluoro-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3S,4R)-3-(4-chlorophenyl)-4-fluoro-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3R,4S)-3-(4-chlorophenyl)-4-fluoro-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3R,4S)-3-(3,4-difluorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(3S,4R)-3-(3,4-difluorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(3S,4R)-3-(3,4-difluorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(3R,4S)-3-(3,4-difluorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; and [3-(4-chlorophenyl)pyrrolidin-1-yl]-[3-(3-methoxy-4-pyridyl)-1H-pyrazol-5-yl]methanone. In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein said compound of formula (I) is selected from: [3-(4-chlorophenyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [3-phenylpyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [5-bromospiro[indane-1,3'-pyrrolidine]-1'-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [3-(4-chlorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [3-(4-chlorophenyl)pyrrolidin-1-yl]-(4-methyl-3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(2-chlorophenyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [3-(3-chlorophenyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [3-(2-chloro-4-fluoro-phenyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [3-(5-chloro-2-thienyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [3-(5-chloro-2-thienyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [2,2-dimethyl-4-phenyl-pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [3-(2-ethylphenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [(3R,4S)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5- yl]methanone and [(3S,4R)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-[3-(4- pyridyl)-1H-pyrazol-5-yl]methanone; [3-(p-tolyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [3-(3,5-difluorophenyl)-3-fluoro-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; 4-[1-(3-pyridazin-4-yl-1H-pyrazole-5-carbonyl)pyrrolidin-3-yl]benzonitrile; [3-(3,4-difluorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; (3-pyridazin-4-yl-1H-pyrazol-5-yl)-[3-[3-(trifluoromethoxy)phenyl]pyrrolidin-1- yl]methanone; [3-(6-chloro-3-pyridyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [3-(5-chloro-2-pyridyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [(3R,4S)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone and [(3S,4R)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3- pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [(3R,4R)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone and [(3S,4S)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3- pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [3-(3,4-difluorophenyl)-3-fluoro-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [2,5-dimethyl-3-phenyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [(2R,4R)-4-(4-fluorophenyl)-2-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone and [(2S,4R)-4-(4-fluorophenyl)-2-methyl-pyrrolidin-1-yl]-(3-pyridazin- 4-yl-1H-pyrazol-5-yl)methanone; [(3R)-3-(4-chlorophenyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [(3S)-3-(4-chlorophenyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [(3R)-3-(6-chloro-3-pyridyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [(3S)-3-(6-chloro-3-pyridyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [(3R,4S)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3S,4R)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; . In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein said compound of formula (I) is selected from: [3-(4-chlorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [3-(5-chloro-2-thienyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [3-(3,4-difluorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; and [(3R,4S)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein said compound of formula (I) is selected from: [3-(4-chlorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [3-(5-chloro-2-thienyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [3-(3,4-difluorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; and [(3R,4S)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3S)-3-(3,4-difluorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone or [(3R)-3-(3,4-difluorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3R,4S)-3-(4-chlorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone or [(3S,4R)-3-(4-chlorophenyl)-4-(hydroxymethyl)pyrrolidin- 1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [(3R,4S)-3-(4-chlorophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone or [(3S,4R)-3-(4-chlorophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4- yl-1H-pyrazol-5-yl)methanone; (3R,4S)-4-(4-chlorophenyl)-1-(3-pyridazin-4-yl-1H-pyrazole-5-carbonyl)pyrrolidine-3- carbonitrile or (3S,4R)-4-(4-chlorophenyl)-1-(3-pyridazin-4-yl-1H-pyrazole-5- carbonyl)pyrrolidine-3-carbonitrile; [(3S,4R)-3-(3,4-difluorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone or [(3R,4S)-3-(3,4-difluorophenyl)-4- (hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein said compound of formula (I) is [3-(4-chlorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein said compound of formula (I) is [3-(5-chloro-2-thienyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein said compound of formula (I) is [3-(3,4-difluorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein said compound of formula (I) is [(3R,4S)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3- pyridazin-4-yl-1H-pyrazol-5-yl)methanone. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein said compound of formula (I) is selected from [(3S)-3-(3,4-difluorophenyl)pyrrolidin-1-yl]-(3- pyridazin-4-yl-1H-pyrazol-5-yl)methanone and [(3R)-3-(3,4-difluorophenyl)pyrrolidin-1-yl]-(3- pyridazin-4-yl-1H-pyrazol-5-yl)methanone. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein said compound of formula (I) is selected from [(3R,4S)-3-(4-chlorophenyl)-4- (hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone and [(3S,4R)-3- (4-chlorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein said compound of formula (I) is selected from [(3R,4S)-3-(4-chlorophenyl)-4-methyl-pyrrolidin-1- yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone and [(3S,4R)-3-(4-chlorophenyl)-4-methyl- pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein said compound of formula (I) is selected from (3R,4S)-4-(4-chlorophenyl)-1-(3-pyridazin-4-yl-1H- pyrazole-5-carbonyl)pyrrolidine-3-carbonitrile and (3S,4R)-4-(4-chlorophenyl)-1-(3-pyridazin-4- yl-1H-pyrazole-5-carbonyl)pyrrolidine-3-carbonitrile. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein said compound of formula (I) is selected from [(3S,4R)-3-(3,4-difluorophenyl)-4- (hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone and [(3R,4S)-3- (3,4-difluorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone. In a particular embodiment, the present invention provides pharmaceutically acceptable salts of the compounds according to formula (I) as described herein. In a further particular embodiment, the present invention provides compounds according to formula (I) as described herein as free bases. In a particular embodiment, the present invention provides a tautomer of the compound of formula (I) described herein, wherein said tautomer is of formula (Ia):

wherein the variables are as defined herein. In a particular embodiment, the present invention provides a tautomer of the compound of formula (I) described herein, wherein said tautomer is of formula (Ic): wherein the variables are as defined 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-labeled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.³H, and carbon-14, i.e., ¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and 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 therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be useful in Positron 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 the art 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. A person skilled in the art will recognize that the compounds of the present invention can be drawn in two tautomeric forms at the central pyrazole. Only one tautomeric form is shown in the following schemes in order to ease representation. The following abbreviations are used in the present text: AcOH = acetic acid; AIBN = Azobisisobutyronitrile; Ar = Argon; BH3·SMe2 = borane dimethylsulfide; Boc = tert-butyloxycarbonyl; Bu3SnH = tributyltin hydride; CataCXium A Pd G3 = mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2′-amino-1,1′-biphenyl)]palladium(II); Cbz = benzyloxycarbonyl; CH3CN = acetonitrile; DAST = N,N-diethyl-S,S,S-trifluoro-λ⁴-sulfanamine; 1,2-DCE = 1,2-dichloroethane; DCM = dichloromethane; DEA = diethylamine; DIPEA = N,N- Diisopropylethylamine; DMA = N,N-dimethylacetamide; DMF = N,N-dimethylformamide; dtbbpy = 4,4′-Di-tert-butyl-2,2′-dipyridyl; (4,4’-dtbbpy)NiCl₂ = [4,4′-bis(1,1-dimethylethyl)-2,2′- bipyridine] nickel (II) dichloride; ESI = electrospray ionization; EtOAc = ethyl acetate; EtOH = ethanol; FC = flash chromatography; h = hour(s); H2 = hydrogen; H2O = water; H2O2 = hydrogen peroxide; HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3- oxide hexafluorophosphate; HCl = hydrochloric acid; HCOOH = formic acid; HPLC = high performance liquid chromatography; IPA = isopropyl alcohol; ⁱPr2O = diisopropylether; KOH = potassium hydroxide; KO^tBu = potassium tert-butoxide; KOTMS = Potassium trimethylsilanolate; K₃PO₄ = potassium phosphate; LiAlH₄ = lithium aluminium hydride; LiCl = lithium chloride; LiHMDS = Lithium bis(trimethylsilyl)amide; LiOH = lithium hydroxide; mCPBA = 3- chlorobenzene-1-carboperoxoic acid; MeOH = methanol; 2-Me-THF = 2-methyltetrahydrofuran; mg = milligram(s); min = minute(s); MgSO₄ = magnesium sulfate; mL = milliliter(s); mm = millimeter(s); MS = mass spectrum; MTBE = 2-methoxy-2-methylpropane; m/z = mass-to-charge ratio; N2 = nitrogen; NaBH4 = sodium borohydride; NaH = sodium hydride; NaHCO3 = sodium bicarbonate; NaOH = sodium hydroxide; NaO^tBu = sodium tert-butoxide; Na₂SO₄ = sodium sulfate; Na₂S₂O₃ = sodium thiosulfate; n-BuLi = n-Buthyllithium; NBS = N-bromosuccinimide; NH4Cl = ammonium chloride; NH4OAc = ammonium acetate; NIS = N-iodosuccinimide; nm = nanometer(s); NO2CH3 = nitromethane; Pd = palladium; Pd(dppf)Cl2·CH2Cl2 = [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane; Pd(PPh3)2Cl2 = bis(triphenylphosphine)palladium chloride; PE = petroleum ether; PG = protecting group; psi = pounds per square inch(es); PtO2 = Platinum(IV) oxide; SFC = supercritical fluid chromatography; SEM = trimethylsilylethoxymethyl; SiO₂ = silicon dioxide; THP = tetrahydropyrane; TMS = trimethylsilyl; T₃P^® = propylphosphonic anhydride; TEA = triethylamine; TFA = trifluoroacetic acid; tR = retention time; µL = microliter(s); µm = micrometer(s). The present compounds of general formula (I) wherein X, Y, Z, R¹, R², R^3a, R^3b, R^4a, R^4b, R⁵, R^6a, R^6b, A, R⁷, R⁸ and R^8a are as described herein and can be prepared starting from intermediate carboxylic acid of formula 1 as shown in Scheme 1. Carboxylic acid 1 can be coupled to amine 2 using a coupling agent such as T₃P^® or HATU (but not restricted to) in the presence of a base (e.g. TEA or DIPEA) in a solvent such as DMF or EtOAc to generate compounds of general formula (I). Carboxylic acids of general formula 1 and amines of general formula 2 can be either commercially available or prepared via methods described in the Schemes below. Additionally, if the corresponding protected amine was commercially available, deprotection could be performed using standard methods to generate the desired amine 2.

Scheme 1 Alternatively, the present compounds of general formula (I) wherein X, Y, Z, R¹, R², R^3a, R^3b, R^4a, R^4b, R⁵, R^6a, R^6b, A, R⁷, R⁸ and R^8a are as described herein and can be prepared starting from an intermediate of formula 3 as shown in Scheme 2. Hydrolysis of the ester group in intermediate 3 (R⁹ = e.g. but not limited to Me, Et, tert-butyl) and deprotection of the pyrazole nitrogen protecting group (PG) can be performed applying methods known to a person skilled in the art (e.g., an ethyl ester group using HCl in water at 100 °C and as described for example in “Protective Groups in Organic Chemistry” by T.W. Greene and P.G.M. Wuts, 4th Ed., 2006, Wiley N.Y.), to furnish intermediates of general formula 1 in situ. In some instances and as shown in Scheme 2, hydrolysis of the ester of compound 3 occurs concomitantly with the removal of the protecting group PG, but deprotection of the pyrazole could also happen prior to or following ester hydrolysis. Intermediate 1 can be activated in-situ with a coupling agent such as T₃P^® or HATU in the presence of a base (e.g. DIPEA or TEA) in a solvent such as DMF or EtOAc to generate compounds of general formula (I) upon treatment with amine 2. Compounds of general formula (I) can also be further functionalized, e.g. via a chlorination step. A final deprotection step may also be necessary to afford compounds of general formula (I). Scheme 2 The building blocks of general formula 1 are either commercially available or can be prepared as depicted for example in Scheme 3 via methods known to the person skilled of the art.

Scheme 3 Heterocyclic-alkyl-ketone derivatives 4 in which R¹ and R² are as described herein, can be acylated for example with oxalate intermediates 5 (R⁹ = e.g. but not limited to Me, Et, tert-butyl) using a suitable base such as LiHMDS or KOtBu in an appropriate solvent such as THF or Toluene to provide intermediate 6 (Step a). Intermediates 6 are either commercially available or can be prepared according to literature methods. Intermediates 6 can be cyclized to intermediates 7 using methods well known in the art, for example by treatment of 6 with hydrazine in AcOH (step b) at temperatures between 0 °C and 100 °C. Hydrolysis of the ester group in intermediates 7, applying methods known in the art (e.g., an ethyl ester group using LiOH in water at temperatures between 23 °C and 40 °C and as described for example in “Protective Groups in Organic Chemistry” by T.W. Greene and P.G.M. Wuts, 4th Ed., 2006, Wiley N.Y.), furnishes intermediates 1 (step c). Alternatively, carboxylic acids of general formula 1 can be generated from intermediate 8 (Scheme 3). Intermediates 8 (R⁹ = e.g. but not limited to Me, Et, tert-butyl) are commercially available or can be prepared according to literature methods. Intermediates 8 can be protected on one of the two nitrogens by a suitable protecting group (PG), that signifies a protective group such as SEM, THP, Boc or Cbz by using a suitable base such as DIPEA or TEA in an appropriate solvent such as DCM to provide intermediate 9 (step d). Reactions of this type and the use of these reagents are widely described in literature (“Protective Groups in Organic Chemistry” by T.W. Greene and P.G.M. Wuts, 4th Ed., 2006, Wiley N.Y.) Intermediates 9 can be reacted with aryl or heteroaryl boronic acids or boronic esters 10, B(OR¹⁰)2 = e.g. boronic acid or 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane (pinacol) ester, either commercially available or prepared using literature procedures using a suitable catalyst (e.g. dichloro[1,1’-bis(diphenylphosphino)-ferrocene]palladium(II) dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0), methanesulfonato(diadamantyl-n-butylphosphino)-2'- amino-1,1'-biphenyl-2-yl)palladium(ii) or palladium(II)acetate with triphenylphosphine) in an appropriate solvent (e.g. dioxane, dimethoxyethane, water, toluene, DMF or mixtures thereof), a suitable base (e.g. K3PO4, NaHCO3, K2CO3, KOTMS, or TEA), and in some cases with the addition of trimethylborate at temperatures between room temperature and the boiling point of the solvent or solvent mixture, to yield compounds 3 (step e). Suzuki reactions of this type are broadly described in literature (e.g. A. Suzuki, Pure Appl. Chem. 1991, 63, 419-422; A. Suzuki, N. Miyaura, Chem. Rev.1995, 95, 2457-2483) and are well known to those skilled in the art. Hydrolysis of the ester group and removal of the protecting group PG in intermediates 3, can be done by applying methods known to the person skilled in the art (e.g., an ethyl ester group using HCl in water at 100 °C and as described for example in “Protective Groups in Organic Chemistry” by T.W. Greene and P.G.M. Wuts, 4th Ed., 2006, Wiley N.Y.), and furnishes intermediates of general formula 1 (step f). It should be understood that the hydrolysis and the deprotection can be performed in one step, or, in some instances, the deprotection could occur prior to saponification, or the saponification could be performed prior to the deprotection. When R² is a halide (e.g. Cl, Br, I), building blocks 3 and 7 can be further functionalized via for example but not limited to Ullmann couplings or other etherification methods known to a person skilled in the art, or a variety of cross-couplings (e.g. but not limited to Suzuki-Miyaura) for C-C bond formation. Alternatively, compounds of general formula 2 where R^4b = OH or F can be prepared starting from commercially available intermediates of formula 11 or 12 as shown in Scheme 4. Scheme 4 Epoxides of general formula 11, in which PG signifies a suitable protective group such as Boc, can be subjected to a ring-opening reaction using in-situ generated organocuprate species generated by intermediates 13, in which the W signifies a magnesiate organometallic species, and a suitable additive such as CuI in an appropriate solvent as 2-Me-THF in a temperature range between 0 °C and 23 °C, giving the corresponding alcohol of general formula 14 (step g) (described e.g. in J. Med. Chem.2002, 45, 10, 2101–2111). Alcohols of general formula 14 can be transformed into the corresponding fluoro-containing pyrrolidine using a fluorinating agent such as e.g. DAST, giving intermediate 14a (step k). Subsequent deprotection using suitable reaction conditions affords amines of general formula 2 (step j). Intermediates 15 may be prepared by carboboration from intermediates 12 using halogenated building block 13, in which the W signifies a suitable halogen group, and by using for example bis(pinacolato)diboron as boron source, a suitable base such as NaOtBu and NiCl2∙DME as catalyst in an appropriate solvent such as DMA (step h). Reactions of this type and the use of these reagents are well described in literature (J. Am. Chem. Soc. 2018, 140, 159−162). Oxidation of intermediate 15 (in which B(OR¹⁰)2 = e.g. boronic acid or 4,4,5,5-tetramethyl-2-phenyl-1,3,2- dioxaborolane (pinacol) ester) applying methods known in the art (e.g., by treatment with a peroxide reagent such as H₂O₂ and a suitable base such as NaOH) can deliver intermediates 14 (step i). Removal of the protective group in intermediates 14, applying methods known in the art (e.g., for a Boc group using TFA or HCl in DCM in neat conditions or in a suitable solvent such as DCM or mixtures thereof and as described for example in “Protective Groups in Organic Chemistry” by T.W. Greene and P.G.M. Wuts, 4th Ed., 2006, Wiley N.Y.), furnishes intermediates of general formula 2 (step j). Intermediates of general formula 2 can be obtained as mixtures of diastereomers and enantiomers, respectively, or as single stereoisomers depending on whether racemic mixtures or enantiomerically pure forms of intermediates 11 and 12 are employed in the synthesis. Amines of general formula 2 where A is (hetero)aryl can be prepared from intermediates 16 and 17 (Scheme 5). When R¹¹ = Br, I and R¹² = Br, I, intermediates 16 and 17 can be coupled in a photochemical reaction using Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆, NiCl₂∙DME, dtbbpy and (TMS)₃SiH, to obtain protected amine 18. Alternatively, when R¹¹ = Br, the cross-coupling can be carried out under Negishi conditions with a zincate transiently generated from 16 (R¹¹ = I) and a halide 17 (R¹² = Br, I). Deprotection of intermediate 18 under standard reaction conditions (as described for example in “Protective Groups in Organic Chemistry” by T.W. Greene and P.G.M. Wuts, 4th Ed., 2006, Wiley N.Y.) could afford the corresponding amine of general formula 2. Alternatively, C- linked heteroaryl rings A may be installed using standard heterocyclic ring syntheses, typically starting from acid or cyano derivatives of 16.

Scheme 5 Alternatively, amines of general formula 2 where A is (hetero)aryl can be prepared from ketone 19 and intermediate 17, where R¹² = Br, I (Scheme 6). Generation of the corresponding lithiated species or Grignard reagent of intermediate 17 using e.g. n-BuLi in THF for the former or isopropylmagnesium chloride lithium chloride complex (Turbo-Grignard) in THF for the latter. Removal of the hydroxy group in intermediate 20 using e.g. trimethylsilane and TFA followed by deprotection could deliver intermediates of general formula 2. Scheme 6 Alternatively, amines of general formula 2 where A is (hetero)aryl can be prepared from ketone 19 (Scheme 7). Intermediate 19 can be treated with tosylhydrazine to generate the corresponding tosylhydrazone, which can be treated with a boronic acid of formula 21 in the presence of a base such as potassium carbonate, to generate intermediate 2 following a deprotection step (as described e.g. in Angew. Chem. Int. Ed.2011, 50, 7486 – 7500).

1. generation of the tosylhydrazone

2. 3. deprotection

19

Scheme 7 Alternatively, amines of general formula 2 where R^4a and R⁵, taken together with the carbon atom to which they are attached, form a C3-cycloalkyl, can be prepared from boronic ester 22 and (hetero)aryl 17 where R¹² = Cl, Br, I in a Pd-catalyzed cross-couplings using e.g. Pd(dppf)Cl₂ in the presence of a base such as potassium carbonate in a solvent such as 1,4-dioxane and water at 80 °C, to give alkenes of general formula 23 (Scheme 8). Cyclopropanation using KOH, benzyltriethylammonium chloride and CHBr₃ in dichloromethane can generate cyclopropane 24. Radical dehalogenation using e.g. AIBN and Bu3SnH followed by deprotection generates intermediates of general formula 2. A person skilled in the art will recognize that amines of general formula 2 can also be prepared following hydrogenation of alkene 23 and deprotection. Scheme 8 Alternatively, acids of general formula 1 can be prepared starting from commercially available acids 25 (Scheme 9). Iodination of acid 25 using e.g. but not limited to NIS in DMF affords iodopyridazine 26. Iodopyrazine 26 can be protected on one of the two nitrogens by a suitable protecting group (PG), that signifies a protective group such as SEM, THP, Boc or Cbz by using a suitable base such as DIPEA or TEA in an appropriate solvent such as DCM to provide intermediate 27 (step d). Depending on the protecting group, in particular when PG = SEM, the carboxylic acid also gets protected. Reactions of this type and the use of these reagents are widely described in literature (“Protective Groups in Organic Chemistry” by T.W. Greene and P.G.M. Wuts, 4th Ed., 2006, Wiley N.Y.). Intermediates 27 can be reacted with aryl or heteroaryl boronic acids or boronic esters 10, B(OR¹⁰)₂ = e.g. boronic acid or 4,4,5,5-tetramethyl-2-phenyl-1,3,2- dioxaborolane (pinacol) ester, either commercially available or prepared using literature procedures using a suitable catalyst (e.g. dichloro[1,1`-bis(diphenylphosphino)- ferrocene]palladium(II) dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0) or palladium(II)acetate with triphenylphosphine) in an appropriate solvent (e.g. dioxane, dimethoxyethane, water, toluene, DMF or mixtures thereof) and a suitable base (e.g. K3PO4, NaHCO₃, K₂CO₃ or TEA) at temperatures between room temperature and the boiling point of the solvent or solvent mixture, to yield compounds 1, after a deprotection step. Suzuki reactions of this type are broadly described in literature (e.g. A. Suzuki, Pure Appl. Chem.1991, 63, 419-422; A. Suzuki, N. Miyaura, Chem. Rev.1995, 95, 2457-2483) and are well known to those skilled in the art. Scheme 9 Alternatively, amines of general formula 2 where R^4a = hydroxyl-C1-C6-alkyl or cyano and R^3a = R^3b = R^4b = R⁵ = R^6a = R^6b = H can be prepared from intermediates 28 and 29, affording pyrrolidine 30 (Scheme 10). Reduction of pyrrolidine 30 with e.g. LiAlH₄ in THF, followed by a deprotection step, affords amine of general formula 31. Deprotection of pyrrolidine 30 affords amine 32.

Scheme 10 Alternatively, building blocks of general formula 2 where R^3a and R^4a, taken together with the carbon atoms to which they are attached, form a C3-C10-cycloalkyl (amine 33), can be prepared starting from nitroalkene 34 and commercially enamine 35, affording compound 36 (Scheme 11). Compound 36 can by cyclized to the corresponding hexahydro-2H-indole 37 upon treatment with LiAlH4. Reduction of 37 with acetic acid and NaBH4 in EtOH affords the amines 33. Scheme 11 Alternatively, amines of general formula 2 where R^4a = Me (shown as amine 38 in Scheme 12), can be prepared via an organocatalyzed (catalyst here: 39) Michael addition of aldehydes 40 to nitroalkenes 34, to afford compound 41. Subsequent cyclization of 41 under reducing conditions, e.g. Zn and AcOH, affords amines 38.

Scheme 12 Alternatively, amines of general formula 2 where R^4a = hydroxyl-C₁-C₆-alkyl (here amine 42) can be prepared starting from commercially available pyrrolidines 43 (Scheme 13). If not commercially available, the corresponding unprotected pyrrolidine can be simply protected to give 43. Saponification of 43 affords carboxylic acid 44. Reduction of the carboxylic acid 44 using e.g. but not limited to BH₃·SMe₂, followed by deprotection, gives pyrrolidines 42. Some extra protecting group manipulation may be needed prior to the second step.

Scheme 13 In one aspect, the present invention provides a process of manufacturing a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, comprising: reacting a carboxylic acid 1, wherein X, Y, Z, R¹ and R² are as defined in claim 1,

1 with an amine 2, wherein R^3a, R^3b, R^4a, R^4b, R⁵, R^6a, R^6b, R⁷, R⁸, and A are as defined in claim 1,

in the presence of a coupling reagent and a base, to form said compound of formula (I). In one embodiment, said base is selected from TEA and DIPEA. In one embodiment, said coupling reagent is selected from T₃P^® and HATU. In one embodiment, said process is performed in a solvent selected from DMF and EtOAc. In one aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, when manufactured according to any one of the processes described herein. SARM1 Inhibitory Activity Compounds of the present invention are SARM1 inhibitors. Thus, in one aspect, the present invention provides the use of compounds of formula (I) as described herein for inhibiting the function of human SARM1 in a subject in need thereof. In a further aspect, the present invention provides compounds of formula (I) as described herein for use in a method of inhibiting the function of human SARM1 in a subject in need thereof. 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 the function of human SARM1 in a subject in need thereof. In a further aspect, the present invention provides a method for inhibiting the function of human SARM1 in a subject in need thereof, which method comprises administering an effective amount of a compound of formula (I) as described herein to the subject. SARM1 inhibitory potency of the compounds of formula (I) according to the invention was measured using the following assay. Enzymatic reactions were ran in a 10µL volume consisting of 8nM human SARM1 (aa28-724), 100µM Nicotinamide (NMN) and 30µM Nicotinamide Adenine Dinculeotide (NAD). Assay reagents were prepared in 25mM HEPES pH 7.2, 50mM NaCl, 1mM EDTA and 0.0025% Tween20. To determine compound IC50’s, reactions were incubated for 60minutes at room temperature in the presence of a 12-point concentration response curve of compound (starting concentration 100µM; 1 in 3 dilution between each point; 2% DMSO) and then quenched with 40µL of 0.125% Formic Acid. The peak area of NAD and linear ADPR were measured by a RapidFire High Throughput Mass Spectrometry System (Agilent Technologies, Santa Clara, CA) using an API5000 triple quadrupole mass spectrometer (AB Sciex Framingham, MA). The ratio of linear ADPR to NAD peak area was then plotted against compound concentration to obtain an IC50 as fitted via non-linear regression. SARM1 inhibitory potencies of the compounds of formula (I) according to the invention as measured in the assay described above are presented in Table 1. Table 1 Example IC50 (hSARM1) Example IC50 (hSARM1) [µM] [µM] 1 0.387 21 0.351 2 4.507 22 9.221 3 3.189 23 2.267 4 0.191 24 9.479 5 0.427 25 9.535 6 3.036 26 0.194 7 1.285 27 0.625 8 0.458 28 0.682 9 0.194 29 2.830 10 0.098 30 0.172 11 7.39 31 0.761 12 3.887 32 0.521 13 0.624 33 2.125 14 2.911 34 5.923 15 3.740 35 0.698 16 2.170 36 1.217 17 0.105 37 1.785 18 6.184 38 8.296 19 0.469 39 0.073 20 9.664 40 0.746 Example IC50 (hSARM1) Example IC50 (hSARM1) [µM] [µM] 41 0.057 61 1.237 42 0.183 62 3.059 43 8.692 63 0.095 44 0.114 64 0.492 45 1.536 65 0.051 46 0.188 66 3.023 47 0.142 67 0.217 48 7.406 68 0.196 49 0.379 69 0.749 50 0.068 70 0.214 51 0.461 71 3.336 52 1.360 72 0.563 53 0.084 73 0.030 54 8.131 74 0.072 55 2.167 75 0.506 56 0.500 76 4.504 57 2.209 77 1.316 58 0.340 78 0.093 59 1.778 79 3.050 60 0.072 Using the Compounds of the Invention In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, or a tautomer thereof, as described herein for use as a therapeutically active substance. In a further aspect, the present invention provides a method of treating or preventing a condition associated with SARM1 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, or a pharmaceutical composition described herein. In a further aspect, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, or a pharmaceutical composition described herein, for use in a method of treating or preventing a condition associated with SARM1 in a subject in need thereof. In a further aspect, the present invention provides the use of a compound of formula (I) described herein, or of a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition described herein, in a method of treating or preventing a condition associated with SARM1 in a subject in need thereof. In a further aspect, the present invention provides the use of a compound of formula (I) described herein, or of a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in a method of treating or preventing a condition associated with SARM1 in a subject in need thereof. In one embodiment, said condition associated with SARM1 is a condition affecting the nervous system, including the central nervous system and the peripheral nervous system. In one embodiment, said condition affecting the nervous system is neurodegenerative disorder. In one embodiment, said condition associated with SARM1 is selected from amyotrophic lateral sclerosis, spinal muscular atrophy, chemotherapy induced peripheral neuropathy, diabetes induced peripheral neuropathy, multiple sclerosis, Parkinson's disease, glaucoma, stroke, traumatic brain injury, and Charcot-Marie-Tooth disease. In a preferred embodiment, said condition associated with SARM1 is selected from amyotrophic lateral sclerosis, spinal muscular atrophy, chemotherapy induced peripheral neuropathy, diabetes induced peripheral neuropathy, and multiple sclerosis. In a particularly preferred embodiment, said condition associated with SARM1 is amyotrophic lateral sclerosis. In a particularly preferred embodiment, said condition associated with SARM1 is spinal muscular atrophy. In a particularly preferred embodiment, said condition associated with SARM1 is chemotherapy induced peripheral neuropathy. In a particularly preferred embodiment, said condition associated with SARM1 is diabetes induced peripheral neuropathy. In a particularly preferred embodiment, said condition associated with SARM1 is multiple sclerosis. 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. In one embodiment, there is provided a pharmaceutical composition according to Example 80 or 81. The compounds of formula (I) and their pharmaceutically acceptable salts 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 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. 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. 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 diastereoisomers or mixtures of diastereoisomers. According to the Cahn-Ingold- Prelog Convention the asymmetric carbon atom can be of the "R" or "S" configuration. For the compounds described in the patent the absolute stereochemistry was arbitrarily assigned. The relative configuration at the pyrrolidine ring can be either cis or trans and was assigned arbitrarily. All reaction examples and intermediates were prepared under an argon or a nitrogen atmosphere if not specified otherwise. The compounds disclosed and described herein have been named using the IUPAC naming function of Biovia Draw 22.1. Where more than one name is associated with a Formula (I) compound or intermediate, the chemical structure shall define the compound. Example 1 [3-(4-Chlorophenyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone

To a solution of 3-(4-pyridyl)-1H-pyrazole-5-carboxylic acid (A1; 60 mg, 317.18 µmol) in DMF (298.02 µL) were added DIPEA (77 µL, 441.27 µmol) and T3P^® (195 µL, 330.95 µmol). The mixture was treated with 3-(4-chlorophenyl)pyrrolidine (CAS RN: 120418-62-4; 58 mg, 317.18 µmol) and stirred at 23 °C for 18 h before being poured into 2-Me-THF and washed with water and brine.The organic layer was dried over Na2SO4 and evaporated. Purification by FC (SiO2; DCM/MeOH) gave the title compound as a racemic mixture (13 mg, 16%) and as a light yellow powder. MS (ESI): m/z = 353.2 [M+H]⁺ In analogy to Example 1, Examples in the following table were generated, using the respective building blocks A1 to A10 and B1 to B2 and C1 to C14 or the indicated commercially available ones. Depending from the quality and form of starting materials, different equivalents of DIPEA and coupling agent T3P^® were adopted. In some cases (marked with *) the reaction was carried out within a different amount of time [h] or with a different temperature [°C]. In some cases, reverse phase, HPLC or SFC were used as purification methods instead of FC. MS Building Ex. Structure Systematic Name (ESI): Blocks m/z [3- A1 and 3- 319.1 phenylpyrrolidin- phenylpyrroli [M+H]⁺ 1-yl]-[3-(4- dine CAS pyridyl)-1H- RN:936-44-7 pyrazol-5- *reaction time: 16 h, purified by yl]methanone trituration (CH₃CN) [5- A1 and 5- 425.0 bromospiro[indane bromo-2,3- [M+H]⁺ -1,3'-pyrrolidine]- dihydrospiro[i 1'-yl]-[3-(4- ndene-1,3'- pyridyl)-1H- pyrrolidine] *reaction time: 16 h pyrazol-5- hydrochloride yl]methanone CAS RN: 2551116-78-8 [3-(4- A2 and 3-(4- 354.1 chlorophenyl)pyrro chlorophenyl) [M+H]⁺ lidin-1-yl]-(3- pyrrolidine pyridazin-4-yl-1H- CAS RN: pyrazol-5- 120418-62-4 *reaction time: 2 h. Purification by yl)methanone RP-HPLC. Aqueous HCl 4 M at 100 °C was used to activate A2 in-situ as additive prior to the coupling. [3-(4- A3 and 3-(4- 368.1 chlorophenyl)pyrro chlorophenyl) [M+H]⁺ lidin-1-yl]-(4- pyrrolidine methyl-3- CAS RN: pyridazin-4-yl-1H- 120418-62-4 *HATU (45.03 mg, 118.43 µmol) pyrazol-5- added as additive. Purification by yl)methanone RP-HPLC [3-(2- A1 and 3-(2- 353.1 chlorophenyl)pyrro Chlorophenyl [M+H]⁺ lidin-1-yl]-[3-(4- )pyrrolidine pyridyl)-1H- CAS RN: pyrazol-5- 885277-67-8 *reaction time: 16 h. Purification by yl]methanone RP-HPLC [3-(3- A1 and 3-(3- 353.2 chlorophenyl)pyrro Chlorophenyl [M+H]⁺ lidin-1-yl]-[3-(4- )pyrrolidine pyridyl)-1H- CAS RN: pyrazol-5- 914299-59-5 *reaction time: 16 h. Purification by yl]methanone RP-HPLC [3-(2-chloro-4- A1 and 3-(2- 371.1 fluoro- chloro-4- [M+H]⁺ phenyl)pyrrolidin- fluorophenyl) 1-yl]-[3-(4- pyrrolidine pyridyl)-1H- CAS RN: *reaction time: 16 h. pyrazol-5- 1260821-92-8 yl]methanone [3-(5-chloro-2- A1 and 3-(5- 359.0 thienyl)pyrrolidin- chlorothiophe [M+H]⁺ 1-yl]-[3-(4- n-2- pyridyl)-1H- yl)pyrrolidine pyrazol-5- CAS RN: yl]methanone 1260868-91-4 *reaction time: 16 h. [3-(5-chloro-2- A4 and 3-(5- 360.0 thienyl)pyrrolidin- chlorothiophe [M+H]⁺ 1-yl]-(3-pyridazin- n-2- 4-yl-1H-pyrazol-5- yl)pyrrolidine yl)methanone CAS RN: 1260868-91-4 *reaction time: 16 h. Purification by RP-HPLC [2,2-dimethyl-4- A1 and 2,2- 347.2 phenyl-pyrrolidin- dimethyl-4- [M+H]⁺ 1-yl]-[3-(4- phenylpyrroli pyridyl)-1H- dine pyrazol-5- hydrochloride *reaction time: 2 h. yl]methanone CAS RN: 2126161-12-2 [3-(2- A4 and 3-(2- 348.3 ethylphenyl)pyrroli ethylphenyl)p [M+H]⁺ din-1-yl]-(3- yrrolidine pyridazin-4-yl-1H- CAS RN: pyrazol-5- 1247925-28-5 *reaction time: 2 h. Purification by yl)methanone RP-HPLC [(3R,4S)-3-(4- A1 and C1 369.1 chlorophenyl)-4- [M+H]⁺ and hydroxy- pyrrolidin-1-yl]-[3- (4-pyridyl)-1H- pyrazol-5- yl]methanone and [(3S,4R)-3-(4- *HATU (708.78 mg, 1.86 mmol) chlorophenyl)-4- added as additive instead. hydroxy- Purification by RP-HPLC pyrrolidin-1-yl]-[3- (4-pyridyl)-1H- pyrazol-5- yl]methanone [3-(p- A4 and 3-(4- 334.2 tolyl)pyrrolidin-1- methylphenyl [M+H]⁺ yl]-(3-pyridazin-4- )pyrrolidine yl-1H-pyrazol-5- CAS RN: yl)methanone 899425-95-7 *reaction time: 2 h. Purification by RP-HPLC [3-(3,5- A4 and 3- 374.2 difluorophenyl)-3- (3,5- [M+H]⁺ fluoro-pyrrolidin- difluoropheny 1-yl]-(3-pyridazin- l)-3- 4-yl-1H-pyrazol-5- fluoropyrrolid yl)methanone ine *reaction time: 2 h. Purification by hydrochloride RP-HPLC CAS RN 1803583-15-4 4-[1-(3-pyridazin- A4 and 4- 345.2 4-yl-1H-pyrazole- (pyrrolidin-3- [M+H]⁺ 5- yl)benzonitril carbonyl)pyrrolidi e n-3-yl]benzonitrile hydrochloride *reaction time: 2 h. Purification by CAS RN: RP-HPLC 1203684-95-0 [3-(3,4- A4 and 3- 356.2 difluorophenyl)pyr (3,4- [M+H]⁺ rolidin-1-yl]-(3- difluoropheny pyridazin-4-yl-1H- l)pyrrolidine pyrazol-5- CAS RN: yl)methanone 848822-98-0 *reaction time: 16 h, purified by FC (C18, CH₃CN/H₂O) (3-pyridazin-4-yl- A4 and 3-[3- 404.2 1H-pyrazol-5-yl)- (trifluorometh [M+H]⁺ [3-[3- oxy)phenyl]p (trifluoromethoxy) yrrolidine;hyd * reaction time: 2.3 h, purified by phenyl]pyrrolidin- rochloride FC (C18, CH₃CN/H₂O) 1-yl]methanone CAS RN: 2703779-38-6 [3-(6-chloro-3- A4 and B1 355.2 pyridyl)pyrrolidin- [M+H]⁺ 1-yl]-(3-pyridazin- 4-yl-1H-pyrazol-5- yl)methanone *reaction time: 1 h at 70 °C, purified by RP-HPLC [3-(5-chloro-2- A4 and B2 355.2 pyridyl)pyrrolidin- [M+H]⁺ 1-yl]-(3-pyridazin- 4-yl-1H-pyrazol-5- yl)methanone *reaction time: 1 h at 70 °C, purified by RP-HPLC [(3R,4S)-3-(4- A4 and rac- 370.2 chlorophenyl)-4- (3S,4R)-4-(4- [M+H]⁺ hydroxy- chlorophenyl) and pyrrolidin-1-yl]-(3- pyrrolidin-3- pyridazin-4-yl-1H- ol CAS RN: pyrazol-5- 1883426-04-7 yl)methanone and [(3S,4R)-3-(4- chlorophenyl)-4- *reaction time: 1 h at 50 °C, purified hydroxy- by RP-HPLC pyrrolidin-1-yl]-(3- pyridazin-4-yl-1H- pyrazol-5- yl)methanone [(3R,4R)-3-(4- A4 and C2 370.2 chlorophenyl)-4- [M+H]⁺ hydroxy- and pyrrolidin-1-yl]-(3- pyridazin-4-yl-1H- pyrazol-5- yl)methanone and [(3S,4S)-3-(4- chlorophenyl)-4- *reaction time: 1 h at 23 °C, purified hydroxy- by RP-HPLC. C2 protected in-situ pyrrolidin-1-yl]-(3- using 5.0 equiv. of DIPEA and 1.1 pyridazin-4-yl-1H- equiv. of TMSCl used as additive. pyrazol-5- yl)methanone [3-(3,4- A4 and 3- 356.3 difluorophenyl)-3- fluoro-3-(4- [M+H]⁺ fluoro-pyrrolidin- fluorophenyl) 1-yl]-(3-pyridazin- pyrrolidine 4-yl-1H-pyrazol-5- hydrochloride *reaction time: 12 h. Purification by yl)methanone CAS RN: RP-HPLC 1803589-76-5 [2,5-dimethyl-3- A4 and 2,5- 348.4 phenyl-pyrrolidin- dimethyl-3- [M+H]⁺ 1-yl]-(3-pyridazin- phenylpyrroli 4-yl-1H-pyrazol-5- dine CAS yl)methanone RN: 87774- 50-3 *reaction time: 12 h. Purification by RP-HPLC [(2R,4R)-4-(4- A4 and 4-(4- 352.2 fluorophenyl)-2- fluorophenyl) [M+H]⁺ methyl-pyrrolidin- -2- and 1-yl]-(3-pyridazin- methylpyrroli 4-yl-1H-pyrazol-5- dine, Mixture yl)methanone and of [(2S,4R)-4-(4- diastereomers fluorophenyl)-2- CAS RN: methyl-pyrrolidin- 1334148-23-0 1-yl]-(3-pyridazin- 4-yl-1H-pyrazol-5- yl)methanone [(3R)-3-(4- A1 and 3-(4- 353.1 chlorophenyl)pyrro chlorophenyl) [M+H]⁺ lidin-1-yl]-[3-(4- pyrrolidine pyridyl)-1H- (CAS RN: pyrazol-5- 120418-62-4 *reaction time: 70 h. Purification by yl]methanone SFC (Chiral column AD-H, 5 µm, 250 x 30 mm, 90% MeOH). tR = 2.663 min) [(3S)-3-(4- A1 and 3-(4- 353.1 chlorophenyl)pyrro chlorophenyl) [M+H]⁺ lidin-1-yl]-[3-(4- pyrrolidine pyridyl)-1H- (CAS RN: pyrazol-5- 120418-62-4 *reaction time: 70 h. Purification by yl]methanone SFC (Chiral column AD-H, 5 µm, 250 x 30 mm, 90% MeOH). t_R = 4.166 min) [(3R)-3-(6-chloro- A1 and B1 354.2 3- [M+H]⁺ pyridyl)pyrrolidin- 1-yl]-[3-(4- pyridyl)-1H- *Chiral column IK, 5 µm, 250 x 20 pyrazol-5- mm, 50% MeOH yl]methanone [(3S)-3-(6-chloro- A1 and B1 354.2 3- [M+H]⁺ pyridyl)pyrrolidin- 1-yl]-[3-(4- pyridyl)-1H- *Chiral column IK, 5 µm, 250 x 20 pyrazol-5- mm, 50% MeOH yl]methanone [(3R,4S)-3-(4- A4 and C1 370.2 chlorophenyl)-4- [M+H]⁺ hydroxy- pyrrolidin-1-yl]-(3- pyridazin-4-yl-1H- *Chiral column IA, 5 µm, 250 x 20 pyrazol-5- mm, 55% MeOH yl)methanone [(3R,4S)-3-(4- A4 and C1 370.2 chlorophenyl)-4- [M+H]⁺ hydroxy- pyrrolidin-1-yl]-(3- pyridazin-4-yl-1H- *Chiral column IA, 5 µm, 250 x 20 pyrazol-5- mm, 55% MeOH yl)methanone [3-(4- A1 and C3 407.1 chlorophenyl)- [M+H]⁺ 2,3,3a,4,5,6,7,7a- octahydroindol-1- yl]-[3-(4-pyridyl)- 1H-pyrazol-5- yl]methanone [3-(3,4-difluoro-5- A4 and 3- 386.1 methoxy- (3,4-difluoro- [M+H]⁺ phenyl)pyrrolidin- 5-methoxy- 1-yl]-(3-pyridazin- phenyl)pyrrol 4-yl-1H-pyrazol-5- idine;hydroch loride(CAS yl)methanone RN: 1909316- 70-6) [3-(2- A4 and 2- 361.2 chlorothiazol-5- chloro-5- [M+H]⁺ yl)pyrrolidin-1-yl]- pyrrolidin-3- (3-pyridazin-4-yl- yl- 1H-pyrazol-5- thiazole;dihyd rochloride yl)methanone (CAS RN: 2995291-13- 7) [3-(5- _{A4 and C12} ^361.2 chlorothiazol-2- [M+H]⁺ yl)pyrrolidin-1-yl]- (3-pyridazin-4-yl- 1H-pyrazol-5- yl)methanone [3-(4-chloro-3- A4 and 3-(4- 372.2 fluoro- chloro-3- [M+H]⁺ phenyl)pyrrolidin- fluoro- 1-yl]-(3-pyridazin- phenyl)pyrrol 4-yl-1H-pyrazol-5- idine; hydrochloride yl)methanone (CAS RN: 2995292-31- 2) 5-[1-(3-pyridazin- A4 and 5- 351.2 4-yl-1H-pyrazole- pyrrolidin-3- [M+H]⁺ 5- ylthiophene- carbonyl)pyrrolidi 2- n-3-yl]thiophene- carbonitrile;2, 2,2- 2-carbonitrile trifluoroacetic acid (CAS RN: 2995275- 84-6) [4-(4- A4 and 4-(4- 368.2 chlorophenyl)-2- chlorophenyl) [M+H]⁺ methyl-pyrrolidin- -2-methyl- 1-yl]-(3-pyridazin- pyrrolidine 4-yl-1H-pyrazol-5- (CAS RN: 1340185-89- yl)methanone 8) [3-(5-bromo-2- A4 and 3-(5- 406.2 thienyl)pyrrolidin- bromo-2- [M+H]⁺ 1-yl]-(3-pyridazin- thienyl)pyrrol 4-yl-1H-pyrazol-5- idine (CAS yl)methanone RN: 1159816- 35-9) [3-(5-methyl-2- A4 and 3-(5- 340.3 thienyl)pyrrolidin- methyl-2- [M+H]⁺ 1-yl]-(3-pyridazin- thienyl)pyrrol 4-yl-1H-pyrazol-5- idine;hydroch yl)methanone loride (CAS RN: 2995286- 87-6) [3-(4- A4 and 3-(4- 412.3 bromophenyl)-4- bromophenyl) [M+H]⁺ methyl-pyrrolidin- -4-methyl- 1-yl]-(3-pyridazin- pyrrolidine 4-yl-1H-pyrazol-5- (CAS RN: 1538187-17- yl)methanone 5) H N _N [3-(4-methyl-2- A4 and 3-(4- 340.3 N N thienyl)pyrrolidin- [M+H]⁺ N _S methyl-2- O 1-yl]-(3-pyridazin- thienyl)pyrrol 4-yl-1H-pyrazol-5- idine (CAS yl)methanone RN: 1337131- 76-6) [3-(4- A4 and 3-(4- 398.2 bromophenyl)pyrr bromophenyl) [M+H]⁺ olidin-1-yl]-(3- pyrrolidine;hy pyridazin-4-yl-1H- drochloride *solvent: MeCH3 / DMF pyrazol-5- (CAS RN: 1187931-39- yl)methanone 0) [3-(benzothiophen- _{A4 and C13} ^376.2 2-yl)pyrrolidin-1- [M+H]⁺ yl]-(3-pyridazin-4- yl-1H-pyrazol-5- *solvent: MeCH₃ / DMF yl)methanone [3-(4-bromo-5- A4 and 3-(4- 420.1 methyl-2- bromo-5- [M+H]⁺ thienyl)pyrrolidin- methyl-2- 1-yl]-(3-pyridazin- thienyl)pyrrol 4-yl-1H-pyrazol-5- idine;hydroch loride (CAS yl)methanone RN: 3017265- 83-4) [(3S)-3-(4- A5 and 3-(4- 367.1 chlorophenyl)pyrro chlorophenyl) [M+H]⁺ or lidin-1-yl]-[3-(3- pyrrolidine methylpyridin-4- CAS RN: yl)-1H-pyrazol-5- 120418-62-4 yl]methanone or [(3R)-3-(4- chlorophenyl)pyrro *reaction time: 12 h. The coupling lidin-1-yl]-[3-(3- was followed by SEM deprotection methylpyridin-4- using TFA (1.0 eq) in DCM (362 yl)-1H-pyrazol-5- mM) at 25 °C for 1 h. Purification yl]methanone by SFC (Chiralpak AY-3, 12 nm, 5 µm, 50x4.6 mm, CO2/IPA+0.05% DEA). tR = 1.940 min. [(3R)-3-(4- A5 and 3-(4- 367.1 chlorophenyl)pyrro chlorophenyl) [M+H]⁺ or lidin-1-yl]-[3-(3- pyrrolidine methylpyridin-4- CAS RN: yl)-1H-pyrazol-5- 120418-62-4 yl]methanone or [(3S)-3-(4- chlorophenyl)pyrro *reaction time: 12 h. The coupling lidin-1-yl]-[3-(3- was followed by SEM deprotection methylpyridin-4- using TFA (1.0 eq) in DCM (362 yl)-1H-pyrazol-5- mM) at 25 °C for 1 h. Purification yl]methanone by SFC (Chiralpak AY-3, 12 nm, 5 µm, 50x4.6 mm, CO2/IPA+0.05% DEA). tR = 2.798 min. (4-bromo-3- A6 and 3-(4- 434.1 pyridazin-4-yl-1H- chlorophenyl) [M+H]⁺ or pyrazol-5-yl)- pyrrolidine [(3R)-3-(4- CAS RN: chlorophenyl)pyrro 120418-62-4 lidin-1- yl]methanone or (4-bromo-3- *reaction time: 1 h. Purification by pyridazin-4-yl-1H- SFC (Chiralpak AD-3, 12 nm, 5 µm, pyrazol-5-yl)- 50x4.6 mm, CO₂/MeOH+0.05% [(3S)-3-(4- DEA). tR = 1.999 min. chlorophenyl)pyrro lidin-1- yl]methanone (4-bromo-3- A6 and 3-(4- 434.1 pyridazin-4-yl-1H- chlorophenyl) [M+H]⁺ or pyrazol-5-yl)- pyrrolidine [(3S)-3-(4- CAS RN: chlorophenyl)pyrro 120418-62-4 lidin-1- yl]methanone or (4-bromo-3- *reaction time: 1 h. Purification by pyridazin-4-yl-1H- SFC (Chiralpak AD-3, 12 nm, 5 µm, pyrazol-5-yl)- 50x4.6 mm, CO₂/MeOH+0.05% [(3R)-3-(4- DEA). tR = 2.249 min. chlorophenyl)pyrro lidin-1- yl]methanone [3-[3- _{A4 and C14} ^388.3 (difluoromethyl)- [M+H]⁺ 4-fluoro- phenyl]pyrrolidin- 1-yl]-(3-pyridazin- 4-yl-1H-pyrazol-5- yl)methanone [(3R,4S)-3-(4- A4 and 3-(4- 368.1 chlorophenyl)-4- chlorophenyl) [M+H]⁺ methyl-pyrrolidin- -4- or 1-yl]-(3-pyridazin- methylpyrroli 4-yl-1H-pyrazol-5- dine (CAS RN: 1534601- yl)methanone or 97-2) [(3S,4R)-3-(4- chlorophenyl)-4- methyl-pyrrolidin- 1-yl]-(3-pyridazin- * separation by RP-HPLC 4-yl-1H-pyrazol-5- yl)methanone [(3R,4S)-3-(4- _{A4 and C11} ^398.6 chlorophenyl)-4- [M+H]⁺ [(1S)-1- hydroxyethyl]pyrr or olidin-1-yl]-(3- pyridazin-4-yl-1H- pyrazol-5- yl)methanone or [(3R,4S)-3-(4- chlorophenyl)-4- [(1R)-1- *reaction time: 12 h. The coupling hydroxyethyl]pyrr was preceded by Boc deprotection olidin-1-yl]-(3- using aqueous HCl (0.1 mL, 0.79 pyridazin-4-yl-1H- mmol) in HFIP (1.5 mL) at 25 °C pyrazol-5- for 1 h. Purification by RP-HPLC; t_R yl)methanone = 1.993 min HO Cl [(3R,4S)-3-(4- _{A4 and C11} ^398.2 H chlorophenyl)-4- [M+H]⁺ H N ^N N [(1R)-1- N O hydroxyethyl]pyrr or N olidin-1-yl]-(3- HO Cl pyridazin-4-yl-1H- H pyrazol-5- H yl)methanone or N ^N N [(3R,4S)-3-(4- N O N chlorophenyl)-4- [(1S)-1- *reaction time: 12 h. The coupling hydroxyethyl]pyrr was preceded by Boc deprotection olidin-1-yl]-(3- using aqueous HCl (0.1 mL, 0.79 pyridazin-4-yl-1H- mmol) in HFIP (1.5 mL) at 25 °C pyrazol-5- for 1h. Purification by RP-HPLCtR yl)methanone = 2.027 min [(3R)-3-(4-chloro- _{A4 and C6} ^360.1 2- [M+H]⁺ thienyl)pyrrolidin- 1-yl]-(3-pyridazin- or 4-yl-1H-pyrazol-5- yl)methanone or [(3S)-3-(4-chloro- 2- thienyl)pyrrolidin- 1-yl]-(3-pyridazin- 4-yl-1H-pyrazol-5- *reaction’s time: 20 h. Purification yl)methanone by SFC (Chiral Whelk(r,r), 5 µm, 250 x 20 mm, 45% MeOH). tR = 2.867 min [(3S)-3-(4-chloro- _{A4 and C6} ^360.1 2- [M+H]⁺ thienyl)pyrrolidin- 1-yl]-(3-pyridazin- or 4-yl-1H-pyrazol-5- yl)methanone or [(3R)-3-(4-chloro- 2- thienyl)pyrrolidin- 1-yl]-(3-pyridazin- *reaction’s time: 20 h. Purification 4-yl-1H-pyrazol-5- by SFC (Chiral Whelk(r,r), 5 µm, yl)methanone 250 x 20 mm, 45% MeOH). t_R = 3.114 min F [(3S,4R)-3-(3,4- _{A4 and C7} ^370.2 F difluorophenyl)-4- [M+H]⁺ H N N ^N methyl-pyrrolidin- N O 1-yl]-(3-pyridazin- N or 4-yl-1H-pyrazol-5- F yl)methanone or F [(3R,4S)-3-(3,4- H N ^N N difluorophenyl)-4- N O methyl-pyrrolidin- N 1-yl]-(3-pyridazin- *reaction’s time: 14 h. Purification 4-yl-1H-pyrazol-5- by RP-HPLC yl)methanone (3S,4R)-4-(4- _{A4 and C8} ^379.2 chlorophenyl)-1- [M+H]⁺ (3-pyridazin-4-yl- 1H-pyrazole-5- or carbonyl)pyrrolidi ne-3-carbonitrile or (3R,4S)-4-(4- chlorophenyl)-1- (3-pyridazin-4-yl- 1H-pyrazole-5- *reaction’s time: 20 h. carbonyl)pyrrolidi ne-3-carbonitrile (3R,4S)-4-(4- _{A4 and C9} ^379.2 chlorophenyl)-1- [M+H]⁺ (3-pyridazin-4-yl- 1H-pyrazole-5- or carbonyl)pyrrolidi ne-3-carbonitrile or (3S,4R)-4-(4- chlorophenyl)-1- (3-pyridazin-4-yl- 1H-pyrazole-5- *reaction’s time: 20 h. carbonyl)pyrrolidi ne-3-carbonitrile

[(3R,4S)-3-(3,4- _{A4 and C7} ^370.2 difluorophenyl)-4- [M+H]⁺ methyl-pyrrolidin- 1-yl]-(3-pyridazin- or 4-yl-1H-pyrazol-5- yl)methanone or [(3S,4R)-3-(3,4- difluorophenyl)-4- methyl-pyrrolidin- 1-yl]-(3-pyridazin- *reaction’s time: 14 h. Purification 4-yl-1H-pyrazol-5- by RP-HPLC yl)methanone [(3R,4S)-3-(4- _{A4 and C10} ^372.1 chlorophenyl)-4- [M+H]⁺ fluoro-pyrrolidin- or 1-yl]-(3-pyridazin- 4-yl-1H-pyrazol-5- yl)methanone or [(3S,4R)-3-(4- chlorophenyl)-4- fluoro-pyrrolidin- *reaction's time: 3.5 h. Purification 1-yl]-(3-pyridazin- by SFC (Column chiral OD-H, 5 4-yl-1H-pyrazol-5- µm, 250 x 20 mm, 27% MeOH). t_R yl)methanone = 3.253 min. 76 [(3S,4R)-3-(4- _{A4 and C10} ^372.1 chlorophenyl)-4- [M+H]⁺ fluoro-pyrrolidin- or 1-yl]-(3-pyridazin- 4-yl-1H-pyrazol-5- yl)methanone or [(3R,4S)-3-(4- chlorophenyl)-4- fluoro-pyrrolidin- *reaction's time: 3.5 h. Purification 1-yl]-(3-pyridazin- by SFC (Column chiral OD-H, 5 4-yl-1H-pyrazol-5- µm, 250 x 20 mm, 27% MeOH). tR yl)methanone = 3.577 min. 79 [3-(4- A10 and 3-(4- 383.2 chlorophenyl)pyrro chlorophenyl) [M+H]⁺ lidin-1-yl]-[3-(3- pyrrolidine methoxy-4- CAS RN: pyri 120418-62-4 *reaction time: 20 h. The coupling dyl)-1H- was followed by SEM deprotection pyrazol-5- using TFA (20.3 eq) in DCM (118 yl]methanone mM) at 25 °C for 20 h. Example 34 [(3R,4R)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone or [(3S,4S)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3-pyridazin-4-yl- 1H-pyrazol-5-yl)methanone

[(3R,4R)-3-(4-Chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone and [(3S,4S)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone (Example 22; 23 mg, 0.06 mmol) was separated by chiral SFC (chiral column IH, 5 µm, 250 x 20 mm, 40% MeOH), to give the title compound (10 mg, 42%) as a light brown solid. MS (ESI): m/z = 370.3 [M + H]⁺. t_R = 1.64 min. Example 35 [3-(4-chlorophenyl)pyrrolidin-1-yl]-(4-methoxy-3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone

A solution of potassium 4-methoxy-5-pyridazin-4-yl-2-(2-trimethylsilylethoxymethyl)pyrazole-3- carboxylate (10.4 mg, 24.09 µmol) in 4 M HCl aq (120.45 µL, 481.8 µmol) was stirred at 50 °C for 1 h, before being evaporated. The residue was treated with DMF (300 µL), 3-(4- chlorophenyl)pyrrolidine;hydrochloride (CAS RN: 1095545-18-8; 5.78 mg, 26.5 µmol), DIPEA (18.93 µL, 108.41 µmol) and HATU (10.08 mg, 26.5 µmol), and stirred for 18 h at 23 °C. Purification by RP-HPLC gave the title compound (4 mg, 39%) as a white solid. MS (ESI): m/z = 384.2 [M+H]⁺ Step a): 3-iodo-4-methoxy-1H-pyrazole-5-carboxylic acid;hydrochloride To a suspension of 4-methoxy-1H-pyrazole-5-carboxylic acid;hydrochloride (CAS RN: 2375273- 71-3; 50 mg, 280 µmol) in DMF (3 mL) was added NIS (125.99 mg, 560 µmol). The mixture was stirred for 18 h at 23 °C, and was used directly in the next step as a DMF solution. MS (ESI): m/z = 269.0 [M+H]⁺ Step b): 3-iodo-4-methoxy-1-(2-trimethylsilylethoxymethyl)pyrazole-5-carboxylic acid 2- trimethylsilylethoxymethyl ester To a solution of 3-iodo-4-methoxy-1H-pyrazole-5-carboxylic acid;hydrochloride (82 mg, 242.39 µmol) in DMF (3 mL) at 0 °C were added DIPEA (296.33 µL, 1.7 mmol) and SEMCl (128.97 µL, 727.17 µmol). The mixture was stirred for 18 h at 23 °C, before being poured into EtOAc and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and evaporated. Purification by FC (SiO2; heptane/EtOAc) gave the title compound (98 mg, 73% as a light yellow viscous oil and as a mixture of regioisomers. MS (ESI): m/z = 529.3 [M+H]⁺. Step c): potassium 4-methoxy-5-pyridazin-4-yl-2-(2-trimethylsilylethoxymethyl)pyrazole-3- carboxylate To a mixture of 3-iodo-4-methoxy-1-(2-trimethylsilylethoxymethyl)pyrazole-5-carboxylic acid 2- trimethylsilylethoxymethyl ester (96 mg, 172.55 µmol) and 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridazine (CAS RN: 863422-41-7; 42.67 mg, 207.06 µmol) in 1,4-dioxane (1 mL) and water (100 µL) was added tripotassium phosphate (109.88 mg, 517.66 µmol) at 23 °C under Ar. The mixture was degassed for 5 min by bubbling Ar through and 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (7.13 mg, 8.63 µmol) was added. The resulting mixture was stirred for 3 h at 100 °C under Ar atmosphere, before being filtered and evaporated. Purification by FC (SiO₂; DCM/MeOH) gave the title compound (10 mg, 12%) as a light yellow solid and as a mixture of regioisomers. MS (ESI): m/z = 351.3 [M+H]⁺ Example 36 [3-(4-chlorophenyl)pyrrolidin-1-yl]-[3-(3-fluoro-4-pyridyl)-1H-pyrazol-5-yl]methanone

To a solution of [3-(4-chlorophenyl)pyrrolidino]-[5-(3-fluoro-4-pyridyl)-2-(2- trimethylsilylethoxymethyl)pyrazol-3-yl]methanone (8 mg, 15.97 µmol) in DCM (159.66 µL) was added TFA (24.6 µL, 319.32 µmol). The mixture was stirred for 17 h at 23 °C, before being evaporated. The residue was dissolved in EtOH, and to the solution was added sodium acetate (6.55 mg, 79.83 µmol). The mixture was stirred for 1 h at 23 °C, before being treated with a saturated solution of NH₄Cl and evaporated. Purification by FC (SiO₂; DCM/MeOH) gave the title compound (4 mg, 69%) as a colorless oil. MS (ESI): m/z = 371.2 [M+H]⁺ Step a): 3-bromo-1-(2-trimethylsilylethoxymethyl)pyrazole-5-carboxylic acid ethyl ester To a solution of 3-bromo-1H-pyrazole-5-carboxylic acid ethyl ester (CAS RN: 1886994-07-5; 50 mg, 228.27 µmol) in THF (500 µL) was added NaH (13.7 mg, 342.4 µmol) followed by SEMCl (45 µL, 251.1 µmol), at 23 °C. The mixture was stirred for 16 h at 23 °C, before being treated with a saturated solution of NH4Cl. The biphasic solution was evaporated. Purification by FC (SiO2; heptane/EtOAc) gave the title compound (52 mg, 66%) as a colorless oil. MS(ESI): m/z = 349.1/351.1 [M+H]⁺ (bromine isotopes). Step b): 5-(3-fluoro-4-pyridyl)-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylic acid ethyl ester To an Ar degassed solution of 3-bromo-1-(2-trimethylsilylethoxymethyl)pyrazole-5-carboxylic acid ethyl ester (43 mg, 123.1 µmol) and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine (CAS RN: 458532-88-2; 30.2 mg, 135.41 µmol) in DME (1.23 mL) was added methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(ii) (CAS RN: 1651823-59-4; 8.97 mg, 12.31 µmol). The solution was evacuated and backfilled with Ar three times before trimethyl borate (42 µL, 369.31 µmol) was added followed by KOTMS (CAS RN: 10519-96-7; 37.9 mg, 295.45 µmol) in DME (0.6 mL). The mixture was evacuated and backfilled with Ar three times before being stirred at 100 °C for 16 h. The mixture was quenched with brine and the bisphasic resulting solution was evaporated. Purification by FC (SiO2; heptane/EtOAc) gave the title compound (11 mg, 22%) as a colorless oil. MS (ESI): m/z = 366.3 [M+H]⁺ Step c): 5-(3-fluoro-4-pyridyl)-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylic acid To a solution of 5-(3-fluoro-4-pyridyl)-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylic acid ethyl ester (10 mg, 27.36 µmol) in MeOH (273.62 µL) was added 4 M NaOH (54.72 µL, 218.9 µmol) at 23 °C. The reaction mixture was stirred at 23 °C for 15 h before being evaporated. The residue was diluted in DCM and water before being acidified with a 3 M hydrogen chloride solution. The aqueous layer was extracted with DCM and the combined organic layers were evaporated, to give the title compound (9 mg, 96%) as a white solid that was used without further purification in the next step. MS(ESI): m/z = 338.2 [M+H]⁺ Step d): [3-(4-chlorophenyl)pyrrolidino]-[5-(3-fluoro-4-pyridyl)-2-(2- trimethylsilylethoxymethyl)pyrazol-3-yl]methanone To a solution of 5-(3-fluoro-4-pyridyl)-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylic acid (8.9 mg, 26.38 µmol) in DMF (264 µL) was added T3P^® (24 µL, 39.56 µmol) before being treated with 3-(4-chlorophenyl)pyrrolidine (CAS RN: 120418-62-4; 4.79 mg, 26.38 µmol) and DIPEA (9.21 µL, 52.75 µmol). The mixture was stirred at 23 °C for 115 h before being evaporated. Purification by FC (SiO₂; DCM/MeOH) gave the title compound (8 mg, 59%) as a colorless oil. MS (ESI): m/z = 501.4 [M+H]⁺ Example 41 [(3S)-3-(3,4-difluorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone or [(3R)-3-(3,4-difluorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone

[3-(3,4-Difluorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone (Example 17; 62 mg, 174.5 µmol) was separated by chiral SFC (Column chiral AD-H, 5 µm, 250 x 20 mm, 50% MeOH) to give the title compound (29 mg, 47%) as a white solid. MS (ESI): m/z = 356.3 [M+H]⁺; tR = 3.02 min. Example 42 [(3R)-3-(3,4-difluorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone or [(3S)-3-(3,4-difluorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone

[3-(3,4-Difluorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone (Example 17; 62 mg, 174.5 µmol) was separated by chiral SFC (Column chiral AD-H, 5 µm, 250 x 20 mm, 50% MeOH) to give the title compound (30 mg, 48%) as a white solid. MS (ESI): m/z = 356.3 [M+H]⁺; t_R = 3.87 min. Example 47 (4-chloro-3-pyridazin-4-yl-1H-pyrazol-5-yl)-[3-(3,4-difluorophenyl)pyrrolidin-1- yl]methanone

To a suspension of 3-pyridazin-4-yl-1H-pyrazole-5-carboxylic acid (A4; 36 mg, 179.85 µmol) in DMF (300 µL) was added NCS (26.42 mg, 197.83 µmol). The mixture was stirred at 80 °C for 3 h, before being cooled down to 23 °C. The mixture was treated with 3-(3,4- difluorophenyl)pyrrolidine (CAS RN: 848822-98-0; 39.54 mg, 215.82 µmol), DIPEA (125.64 µL, 719.39 µmol) and T3P^® (171.67 mg, 269.77 µmol) and stirred for 15 h at 23 °C. Purification by RP-HPLC gave the title compound (25 mg, 34%) as a white solid. MS (ESI): m/z = 390.2 [M+H]⁺ Example 49 (4-chloro-3-pyridazin-4-yl-1H-pyrazol-5-yl)-[(3S)-3-(3,4-difluorophenyl)pyrrolidin-1- yl]methanone or (4-chloro-3-pyridazin-4-yl-1H-pyrazol-5-yl)-[(3R)-3-(3,4- difluorophenyl)pyrrolidin-1-yl]methanone

(4-Chloro-3-pyridazin-4-yl-1H-pyrazol-5-yl)-[3-(3,4-difluorophenyl)pyrrolidin-1-yl]methanone (Example 47; 24 mg, 58.5 µmol) was separated by chiral SFC (Column chiral OD-H, 5 µm, 250 x 20 mm, 33% MeOH) to give the title compound (11 mg, 48%) as a white solid. MS (ESI): m/z = 390.2 [M+H]⁺; t_R = 3.02 min. Example 50 (4-chloro-3-pyridazin-4-yl-1H-pyrazol-5-yl)-[(3R)-3-(3,4-difluorophenyl)pyrrolidin-1- yl]methanone or (4-chloro-3-pyridazin-4-yl-1H-pyrazol-5-yl)-[(3S)-3-(3,4- difluorophenyl)pyrrolidin-1-yl]methanone

(4-Chloro-3-pyridazin-4-yl-1H-pyrazol-5-yl)-[3-(3,4-difluorophenyl)pyrrolidin-1-yl]methanone (Example 47; 24 mg, 58.5 µmol) was separated by chiral SFC (Column chiral OD-H, 5 µm, 250 x 20 mm, 33% MeOH) to give the title compound (10 mg, 43%) as a white solid. MS (ESI): m/z = 390.2 [M+H]⁺; tR = 3.55 min. Example 52 [(3R,4S)-3-(4-bromophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone or [(3S,4R)-3-(4-bromophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl- 1H-pyrazol-5-yl)methanone

[3-(4-Bromophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone (Example 46; 12 mg, 28.8 µmol) was separated by chiral SFC (Column chiral SZ, 5 µm, 250 x 20 mm, 45% MeOH) to give the title compound (2 mg, 14%) as a lyophilized powder. MS (ESI): m/z = 412.2 [M+H]⁺; tR = 2.76 min. Example 53 [(3S,4R)-3-(4-bromophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone or [(3R,4S)-3-(4-bromophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl- 1H-pyrazol-5-yl)methanone [3-(4-Bromophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone (Example 46; 12 mg, 28.8 µmol) was separated via chiral SFC (Column chiral SZ, 5 µm, 250 x 20 mm, 45% MeOH) to give the title compound (2 mg, 15%) as a lyophilized powder. MS (ESI): m/z = 412.2 [M+H]⁺; tR = 3.08 min. Example 56 [(3S)-3-(4-chlorophenyl)pyrrolidin-1-yl]-[3-(3-methylpyridin-4-yl)-1H-pyrazol-5- yl]methanone or [(3R)-3-(4-chlorophenyl)pyrrolidin-1-yl]-[3-(3-methylpyridin-4-yl)-1H- pyrazol-5-yl]methanone

Example 60 [(3R,4S)-3-(4-chlorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone

A solution of (3R,4S)-3-(4-chlorophenyl)-4-methylol-pyrrolidine-1-carboxylic acid tert-butyl ester (C4; 49 mg, 157 µmol) in hexafluoroisopropanol (3 mL) was treated with 25% aqueous HCl (150 µL), at 23 °C. The mixture was stirred for 2 h at 23 °C, before being evaporated. The residue was taken into 4 mL of MeCH3/water 1:1, flash frozen, and lyophilized, to afford a white powder, which was directly engaged in the next step: To a solution of 3-pyridazin-4-yl-1H-pyrazole-5- carboxylic acid;hydrochloride (A4; 39 mg, 172.87 µmol) in acetonitrile (1 mL) was added DIPEA (160 µL, 918.58 µmol) and T3P^® (139 µL, 235.73 µmol). The dark solution was treated with the above-deprotected pyrrolidine suspended in 0.5 mL anhydrous DMF, and stirred for 2 h at 23 °C. Purification by RP-HPLC gave the title compound (19 mg, 30%) as a white powder. MS (ESI): 384.2 [M+H]⁺ Example 61 [(3S,4R)-3-(4-chlorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone

A solution of (3S,4R)-3-(4-chlorophenyl)-4-methylol-pyrrolidine-1-carboxylic acid tert-butyl ester (C5; 51 mg, 163.57 µmol) in hexafluoroisopropanol (3 mL) was treated with 25% aqueous HCl (150 µL), at 23 °C. The mixture was stirred for 2 h at 23 °C, before being evaporated. The residue was taken into 4 mL of MeCH₃/water 1:1, flash frozen, and lyophilized, to afford a white powder, which was directly engaged in the next step: To a solution of 3-pyridazin-4-yl-1H- pyrazole-5-carboxylic acid;hydrochloride (A4; 41 mg, 179.92 µmol) in acetonitrile (1.04 mL) was added DIPEA (160 µL, 918.58 µmol) and T3P^® (145 µL, 245.35 µmol). The dark solution was treated with the above-deprotected pyrrolidine suspended in 0.5 mL anhydrous DMF, and stirred at for 2 h at 23 °C, before being evaporated. Purification by RP-HPLC gave the title compound (12 mg, 19%) as a white powder. MS (ESI): 384.2 [M+H]⁺ Example 63 [(3R)-3-(4-chlorophenyl)pyrrolidin-1-yl]-(4-fluoro-3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone or [(3S)-3-(4-chlorophenyl)pyrrolidin-1-yl]-(4-fluoro-3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone [3-(4-Chlorophenyl)pyrrolidin-1-yl]-(4-fluoro-3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone;2,2,2-trifluoroacetic acid (A7; 100 mg, 210 µmol) was separated by chiral SFC (DAICEL Chiralpak IG, 10 µm, 250 x 30 mm, CH3CN/IPA + 0.1% NH3OH) to give the title compound (27 mg, 35%) as a white solid. MS (ESI): m/z = 372.1 [M+H]⁺; tR = 1.580 min. Example 64 [(3S)-3-(4-chlorophenyl)pyrrolidin-1-yl]-(4-fluoro-3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone or [(3R)-3-(4-chlorophenyl)pyrrolidin-1-yl]-(4-fluoro-3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone

[3-(4-Chlorophenyl)pyrrolidin-1-yl]-(4-fluoro-3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone;2,2,2-trifluoroacetic acid (A7; 100 mg, 210 µmol) was separated by chiral SFC (DAICEL Chiralpak IG, 10 µm, 250 x 30 mm, CH₃CN/IPA + 0.1% NH₃OH) to give the title compound (35 mg, 46%) as a white solid. MS (ESI): m/z = 372.2 [M+H]⁺; tR = 2.084 min. Example 66 [3-(4-chlorophenyl)pyrrolidin-1-yl]-(4-cyclopropyl-3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone;2,2,2-trifluoroacetic acid

A solution of [3-(4-chlorophenyl)pyrrolidin-1-yl]-[4-cyclopropyl-5-pyridazin-4-yl-2-(2- trimethylsilylethoxymethyl)pyrazol-3-yl]methanone (330.0 mg, 0.63 mmol) in TFA (2.0 mL) and DCM (2 mL) was stirred for 1 h at 25 °C, before being evaporated. Purification by RP-HPLC gave the title compound (181 mg, 57%) as an off-white solid. MS (ESI): m/z = 394.1 [M+H]⁺ Step a): methyl 3-bromo-1-(2-trimethylsilylethoxymethyl)pyrazole-5-carboxylate To a solution of methyl 3-bromo-1H-pyrazole-5-carboxylate (CAS RN: 1328893-17-9; 10.0 g, 48.78 mmol) in DMF (70 mL) was added NaH (3902.25 mg, 97.56 mmol), at 0 °C under N2. The mixture was stirred for 30 min at this temperature, before being treated with SEMCl (17.27 mL, 97.56 mmol). The mixture was stirred for 30 min at 25 °C, before being poured into saturated NH4Cl aqueous solution (100 mL) and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. Purification by FC (SiO₂; PE/EtOAc) gave the title compound (12.0 g, 73%) as a colorless oil. MS (ESI): m/z = 357.1 [M+Na+H]⁺ Step b): methyl 5-pyridazin-4-yl-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate To a solution of methyl 3-bromo-1-(2-trimethylsilylethoxymethyl)pyrazole-5-carboxylate (13.0 g, 38.77 mmol) in 1,4-dioxane (130 mL) was added 4-(tributylstannyl)pyridazine (CAS RN: 194865- 89-9; 15.0 g, 40.71 mmol), Pd(Ph3P)2Cl2 (2.7 g, 3.88 mmol), at 25 °C under N2. The mixture was stirred for 12 h at 100 °C, before being poured into water (100 mL) and then extracted with EtOAc. The combined organic layers were dried over Na₂SO₄, filtered and evaporated. Purification by FC (SiO2; PE/EtOAc) gave the title compound (10.6 g, 82%) as a yellow solid. MS (ESI): m/z = 335.1 [M+H]⁺ Step c): methyl 4-bromo-3-pyridazin-4-yl-1H-pyrazole-5-carboxylate To a solution of methyl 5-pyridazin-4-yl-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (10.6 g, 31.69 mmol) in acetic acid (1903.28 mg, 31.69 mmol) was added NBS (11.8 g, 66.56 mmol) at 25 °C. The mixture was stirred for 12 h at 100 °C, before being slowly treated with solid NaHCO3 until pH 8. The resulting precipitate was collected by filtration. The filtrate was poured into water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and evaporated. Purification by RP-HPLC gave the title compound (2.0 g, 22%) as a dark green powder. MS (ESI): m/z = 283.0 [M+H]⁺ Step d): methyl 4-bromo-5-pyridazin-4-yl-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate To a solution of methyl 4-bromo-3-pyridazin-4-yl-1H-pyrazole-5-carboxylate (1.9 g, 6.71 mmol) in THF (20 mL) was added NaH (537 mg, 13.42 mmol), at 0 °C under N₂. The mixture was stirred for 30 min at this temperature, before being treated with SEMCl (2.38 mL, 13.42 mmol). The mixture was stirred for 30 min at 25 °C, before being poured into saturated aqueous NH4Cl solution (20 mL). The aqueous solution was extracted with EtOAc, and the combined organic layers were dried over Na₂SO₄, filtered, and evaporated. Purification by FC (SiO₂; PE/EtOAc) gave the title compound (1.1 g, 38%) as a a brown solid. MS (ESI): m/z = 415.0 [M+H]⁺ Step e): methyl 4-cyclopropyl-5-pyridazin-4-yl-2-(2-trimethylsilylethoxymethyl)pyrazole-3- carboxylate To a solution of methyl 4-bromo-5-pyridazin-4-yl-2-(2-trimethylsilylethoxymethyl)pyrazole-3- carboxylate (1.0 g, 2.42 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added cyclopropylboronic acid (CAS RN: 411235-57-9; 623 mg, 7.26 mmol), K₂CO₃ (1003 mg, 7.26 mmol), and Pd(dppf)Cl₂·CH₂Cl₂ (197 mg, 0.24 mmol), at 25 °C under N₂. The mixture was stirred for 12 h at 80 °C, before being cooled down and evaporated. Purification by FC (SiO2; PE/EtOAc) gave the title compound (800 mg, 88%) as a yellow oil. MS (ESI): m/z = 375.2 [M+H]⁺ Step f): 4-cyclopropyl-5-pyridazin-4-yl-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylic acid To a solution of methyl 4-cyclopropyl-5-pyridazin-4-yl-2-(2-trimethylsilyl- ethoxymethyl)pyrazole-3-carboxylate (400.0 mg, 1.07 mmol) in 1:1:1 THF/EtOH/water (3 mL) was added LiOH (224.29 mg, 5.34 mmol), at 25 °C. The mixture was stirred for 12 h at 25 °C, before being evaporated. Purification by RP-HPLC gave the title compound (250 mg, 65%) as a brown solid. MS (ESI): m/z = 361.2 [M+H]⁺ Step g): [3-(4-chlorophenyl)pyrrolidin-1-yl]-[4-cyclopropyl-5-pyridazin-4-yl-2-(2- trimethylsilylethoxymethyl)pyrazol-3-yl]methanone To a solution of 4-cyclopropyl-5-pyridazin-4-yl-2-(2-trimethylsilylethoxymethyl)pyrazole-3- carboxylic acid (200 mg, 0.55 mmol) in DMF (5 mL) was added DIPEA (0.46 mL, 2.77 mmol) and HATU (316 mg, 0.83 mmol). The mixture was stirred at 25 °C for 10 min, before being treated with 3-(4-chlorophenyl)pyrrolidine (CAS RN: 120418-62-4; 111 mg, 0.61 mmol). The mixture was stirred for 1 h at 25 °C, and poured into water (20 mL). The aqueous solution was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated. Purification by FC (SiO2; PE/EtOAc) gave the title compound (340 mg, 94%) as a brown oil. MS (ESI): m/z = 524.3 [M+H]⁺ Example 77 [(3R,4S)-3-(3,4-difluorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone or [ -3-(3,4-difluorophenyl)-4-(hydroxymethyl)pyrrolidin-1-

yl]-(3- 4-yl-1H-pyrazol-5-yl)methanone

To a solution of [(3R,4S)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-(3,4- difluorophenyl)pyrrolidino]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone or [(3S,4R)-3-[[tert- butyl(dimethyl)silyl]oxymethyl]-4-(3,4-difluorophenyl)pyrrolidino]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone A8 (84.6 mg, 0.168 mmol) in DCM (1 mL) was added TFA (65 µL, 838.16 µmol). The reaction was stirred at 23 °C over 4 h, then concentrated under vacuo. Purification by FC (SiO₂; DCM/MeOH) delivered the title compound (33 mg, 48%) as a white powder. MS (ESI): m/z = 386.2 [M+H]⁺ Example 78 [(3S,4R)-3-(3,4-difluorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone or [ -3-(3,4-difluorophenyl)-4-(hydroxymethyl)pyrrolidin-1-

yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone

To a solution of [(3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-(3,4- difluorophenyl)pyrrolidino]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone or [(3R,4S)-3-[[tert- butyl(dimethyl)silyl]oxymethyl]-4-(3,4-difluorophenyl)pyrrolidino]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone A9 (96 mg, 0.183 mmol) in DCM (1 mL) was added TFA (70 µL, 838.16 µmol). The reaction was stirred at 23 °C over 4 h and evaporated. Purification by FC (SiO₂; DCM/MeOH) delivered the title compound (19 mg, 27%) as a white powder. MS (ESI): m/z = 386.2 [M+H]⁺ Building blocks Example A1: 3-(4-pyridyl)-1H-pyrazole-5-carboxylic acid

To a solution of ethyl 3-(4-pyridyl)-1H-pyrazole-5-carboxylate (160 mg, 0.74 mmol) in THF (1 mL), EtOH (1 mL) and H2O (1 mL) was added LiOH∙H2O (155 mg, 3.68 mmol) at 20 °C and the resulting mixture was stirred at 40 °C for 2 h to give a yellow suspension. The reaction mixture was concentrated under reduced pressure to remove THF and EtOH. Purification by RP-HPLC gave the title compound (100 mg, 72%) as a yellow solid. MS (ESI): m/z= 190.1 [M+H]⁺ Step a): ethyl 2,4-dioxo-4-(4-pyridyl)butanoate Into a 100-mL round-bottom flask, 4-acetylpyridine (CAS RN: 1122-54-9; 2 g, 16.51 mmol) was dissolved in toluene (30 mL). KOtBu (3698.2 mg, 33.02 mmol) and diethyl oxalate (2.24 mL, 16.51 mmol) were added at 0 °C. The resulting solution was stirred for 2 h at 23 °C, before being evaporated. Purification by RP-HPLC gave the title compound (1.0 g, 26%) as a yellow solid. MS (ESI): m/z = 222.1 [M+H]⁺ Step b): ethyl 3-(4-pyridyl)-1H-pyrazole-5-carboxylate Into a solution of ethyl 2,4-dioxo-4-(4-pyridyl)butanoate (1.5 g, 6.78 mmol) in AcOH (15 mL), was added hydrazine (13.56 mL, 13.56 mmol). The solution was stirred at 70 °C for 1 h. The resulting mixture was concentrated in vacuo. The mixture was acidified to pH = 7-8 with aqueous NaHCO3. The resulting solution was extracted with 3 x 50 mL of EtOAc and washed with 50 mL of brine. The organic layer was dried over anhydrous Na₂SO_4, filtered and evaporated to give the title compound (700 mg, 41%) as a yellow solid. MS (ESI): m/z = 218 [M+H]⁺ Example A2: methyl 5-pyridazin-4-yl-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate and methyl 5-pyridazin-4-yl-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate

To a mixture of 5-bromo-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylic acid methyl ester (160 mg, 477.23 µmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine (98 mg, 477.23 µmol) in 1,4-dioxane (1 mL) and water (100 µL) were added K₃PO₄ (203 mg, 954.45 µmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (20 mg, 23.86 µmol) at 23 °C under Ar atmosphere. The resulting mixture was stirred for 18 h at 100 °C under Ar atmosphere. Purification by FC (SiO₂; heptane/EtOAc) delivered the title compound as a mixture of regioisomer (27 mg, 16%) and as a light yellow oil. MS (ESI): m/z = 335.1 [M+H]⁺ Step a): methyl 5-bromo-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate and methyl 5- bromo-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate

To a solution of 3-bromo-1H-pyrazole-5-carboxylic acid methyl ester (CAS RN: 1328893-17-9; 100 mg, 487.78 µmol) in DCM (1 mL) at 0 °C were added DIPEA (170 µL, 975.56 µmol) and 2- (trimethylsilyl)ethoxymethyl chloride (173 µL, 975.56 µmol). The mixture was stirred at 23 °C for 2 h before being poured into EtOAc and washed with water and brine. The organic layer was dried over Na2SO4 and evaporated. Purification by FC (SiO2; heptane/EtOAc) delivered the title compound as a mixture of regioisomers (160 mg, 93%) and as a colorless oil. MS (ESI): m/z = 335.0 [M+H]⁺. Note: the mixture of regioisomers was used as such in the next step. Example A3: 4-methyl-3-pyridazin-4-yl-1H-pyrazole-5-carboxylic acid;hydrochloride

The solution of the regioisomer mixture composed by 4-methyl-5-pyridazin-4-yl-2-(2- trimethylsilylethoxymethyl)pyrazole-3-carboxylic acid ethyl ester and ethyl 4-methyl-5- pyridazin-4-yl-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (89 mg, 0.233 mmol) in 4 M aqueous HCl (583.1 µL, 2.33 mmol) was stirred at 100 °C for 3 h. The mixture was evaporated to give the title compound (45 mg, 76%) as a light brown solid. The crude was used as such in the next reaction without any further purification. MS (ESI): m/z= 205.1 [M+H]⁺ Step a): 5-bromo-4-methyl-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylic acid ethyl ester and ethyl 5-bromo-4-methyl-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate To a solution of 3-bromo-4-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (CAS RN: 1257861-04-3; 115 mg, 493.44 µmol) in DCM (1 mL) at 0 °C were added DIPEA (172 µL, 986.87 µmol) and 2-(trimethylsilyl)ethoxymethyl chloride (175 µL, 986.87 µmol). The mixture was stirred at 23 °C for 2 h, before being poured into EtOAc and washed with water and brine. The organic layer was dried over Na₂SO₄, filtered, and evaporated. Purification by FC (SiO₂; heptane/EtOAc) gave the title compound as a mixture of regioisomers (170 mg, 90%) and as a colorless viscous oil that was used as such in the next reaction without any further purification. MS (ESI): m/z= 365.0 [M+H]⁺ Step b): 4-methyl-5-pyridazin-4-yl-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylic acid ethyl ester and ethyl 4-methyl-5-pyridazin-4-yl-1-(2-trimethylsilylethoxymethyl)pyrazole-3- carboxylate To a mixture of 5-bromo-4-methyl-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylic acid ethyl ester and ethyl 5-bromo-4-methyl-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (170 mg, 444.51 µmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine (CAS RN: 863422-41-7; 110 mg, 533.41 µmol) in 1,4-dioxane (1 mL) and water (100 µL) were added K3PO4 (189 mg, 889.02 µmol) at 23 °C under Ar. The resulting mixture was degassed for 5 min with Ar and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (18 mg, 22.23 µmol) was added. The resulting mixture was stirred for 3 h at 100 °C. To the mixture were added further equivalents of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridazine (CAS RN: 863422-41-7; 46 mg, 222.26 µmol) and 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (9 mg, 11.11 µmol). The resulting mixture was stirred for further 1 h at 100 °C. The suspension was filtered and the solvent was evaporated. Purification by FC (SiO2; MeOH/DCM) gave the title compound as a mixture of regioisomers (89 mg, 52%) and as a pink viscous oil. MS (ESI): m/z= 363.2 [M+H]⁺ Example A4: 3-pyridazin-4-yl-1H-pyrazole-5-carboxylic acid

To a solution of ethyl 3-pyridazin-4-yl-1H-pyrazole-5-carboxylate (20 mg, 0.09 mmol) in THF (0.100 mL), EtOH (0.100 mL) and H₂O (0.100 mL) was added LiOH∙H₂O (19 mg, 0.46 mmol) at 25 °C. The resulting solution was stirred for 2 h at 23 °C. The solvent was evaporated. Purification by RP-HPLC gave the title compound (6 mg, 34%) as a white solid. MS (ESI): m/z= 191.1 [M+H]⁺ Step a): ethyl 2,4-dioxo-4-pyridazin-4-yl-butanoate To a solution of 1-pyridazin-4-ylethanone (CAS RN: 50901-46-7; 3.6 g, 29.48 mmol) in THF (36 mL) was added LiHMDS (38.32 mL, 38.32 mmol) dropwise, at -78 °C for 1 h. Then diethyl oxalate (6.01 mL, 44.22 mmol) in THF (0.5 mL) was added dropwise at -78 °C .The mixture was stirred at 25 °C for 12 h .The reaction was poured into MTBE (100 mL) at 25 ℃ and stirred for 30 min. The resulting suspension was evaporated to give the title compound (3.1 g, 42%) as a yellow solid. MS (ESI): m/z= 223.1 [M+H]⁺ Step b): ethyl 3-pyridazin-4-yl-1H-pyrazole-5-carboxylate To a solution of ethyl 2,4-dioxo-4-pyridazin-4-yl-butanoate (6.3 g, 28.35 mmol) in AcOH (32 mL) was added hydrazine hydrate (7.21 mL, 85.06 mmol) at 0 ℃. The mixture was stirred at 25 °C for 12 h.The reaction was evaporated to give the title compound (6.0 g, 83%) as a yellow solid. The crude was used as such in the next reaction without any further purification. MS (ESI): m/z= 219.2 [M+H]⁺ Example A5: 5-(3-methyl-4-pyridyl)-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylic acid

To a solution of methyl 5-(3-methyl-4-pyridyl)-2-(2-trimethylsilylethoxymethyl)pyrazole-3- carboxylate (160.0 mg, 0.46 mmol) in THF (0.500 mL), EtOH (0.500 mL) and H₂O (0.500 mL) was added LiOH∙H₂O (96.69 mg, 2.3 mmol) at 25 °C. The resulting solution was stirred for 1 h at 25 °C. The solvent was evaporated. Purification by RP-HPLC gave the title compound (100 mg, 65%) as a white powder. MS (ESI): m/z= 334.1 [M+H]⁺ Step a): methyl 3-bromo-1-(2-trimethylsilylethoxymethyl)pyrazole-5-carboxylate To a solution of methyl 3-bromo-1H-pyrazole-5-carboxylate (CAS RN: 1328893-17-9; 5.0 g, 24.4 mmol) in DMF (73 mL) was added NaH (1.95 g, 48.78 mmol), at 0 °C under N2. The mixture was stirred for 30 min at this temperature, before being treated with SEMCl (8.63 mL, 48.78 mmol). The mixture was stirred for 30 min at 25 °C, before being poured into saturated NH₄Cl aqueous solution (100 mL) and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and evaporated. Purification by FC (SiO₂; PE/EtOAc) gave the title compound (4.2 g, 51%) as a colorless oil. MS (ESI): m/z = 357.0 [M+Na+H]⁺ Step b): methyl 5-(3-methyl-4-pyridyl)-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate To a solution of methyl 3-bromo-1-(2-trimethylsilylethoxymethyl)pyrazole-5-carboxylate (500 mg, 1.49 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added 3-methylpyridine-4-boronic acid (CAS RN: 894808-72-1; 245 mg, 1.79 mmol), K2CO3 (411 mg, 2.98 mmol), and Pd(dppf)Cl2·CH2Cl2 (121.7 mg, 0.15 mmol), at 25 °C under N2. The mixture was stirred for 12 h at 100 °C, before being filtered and evaporated. Purification by FC (SiO₂; PE/EtOAc) gave the title compound (160 mg, 31%) as a yellow oil. Compound characterized by ¹H NMR (400 MHz, CDCl3) δ = 8.52 (s, 1H), 8.49 (d, J = 5.1 Hz, 1H), 7.53 (d, J = 5.1 Hz, 1H), 7.19 (s, 1H), 5.93 (s, 2H), 3.95 (s, 3H), 3.72 - 3.62 (m, 2H), 2.53 (s, 3H), 1.01 - 0.86 (m, 2H), -0.03 (s, 9H) Example A6: 4-bromo-3-pyridazin-4-yl-1H-pyrazole-5-carboxylic acid

To a solution of methyl 4-bromo-3-pyridazin-4-yl-1H-pyrazole-5-carboxylate (250 mg, 0.88 mmol) in THF (0.500 mL), EtOH (0.500 mL) and H2O (0.500 mL) was added LiOH∙H2O (185 mg, 4.42 mmol) at 25 °C. The resulting solution was stirred for 12 h at 25 °C. The solvent was evaporated. Purification by RP-HPLC gave the title compound (100 mg, 65%) as a white powder. MS (ESI): m/z= 268.9 [M+H]⁺ Step a): methyl 3-bromo-1-(2-trimethylsilylethoxymethyl)pyrazole-5-carboxylate To a solution of methyl 3-bromo-1H-pyrazole-5-carboxylate (CAS RN: 1328893-17-9; 5.0 g, 24.4 mmol) in DMF (35 mL) was added NaH (1.95 g, 19.51 mmol), at 0 °C under N2. The mixture was stirred for 30 min at this temperature, before being treated with SEMCl (8.63 mL, 48.78 mmol). The mixture was stirred for 30 min at 25 °C, before being poured into saturated NH₄Cl aqueous solution (100 mL) and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. Purification by FC (SiO2; PE/EtOAc) gave the title compound (4.2 g, 51%) as a colorless oil. MS (ESI): m/z = 357.0 [M+Na+H]⁺ Step b): methyl 5-pyridazin-4-yl-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate To a solution of methyl 3-bromo-1-(2-trimethylsilylethoxymethyl)pyrazole-5-carboxylate (2.0 g, 38.77 mmol) in 1,4-dioxane (88 mL) was added 4-(tributylstannyl)pyridazine (CAS RN: 194865- 89-9; 2.4 g, 6.56 mmol) and Pd(Ph₃P)₂Cl₂ (417 mg, 0.6 mmol), at 25 °C under N₂. The mixture was stirred for 12 h at 100 °C, before being poured into water (100 mL) and then extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and evaporated. FC (SiO2; PE/EtOAc) gave the title compound (1.5 g, over quant.) as a yellow solid. MS (ESI): m/z = 335.1 [M+H]⁺ Step c): methyl 4-bromo-3-pyridazin-4-yl-1H-pyrazole-5-carboxylate To a solution of methyl 5-pyridazin-4-yl-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (100 mg, 0.3 mmol) in AcOH (1.0 mL, 0.3 mmol) was added NBS (112 mg, 0.63 mmol) at 25 °C. The mixture was heated at 100 °C for 12 h. Purification by RP-HPLC gave the title compound (25 mg, 30%) as a yellow solid. MS (ESI): m/z= 283.0 [M+H]⁺ Example A7: [3-(4-chlorophenyl)pyrrolidin-1-yl]-(4-fluoro-3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone;2,2,2-trifluoroacetic acid

To a solution of [3-(4-chlorophenyl)pyrrolidin-1-yl]-[4-fluoro-5-pyridazin-4-yl-2-(2- trimethylsilylethoxymethyl)pyrazol-3-yl]methanone (150 mg, 0.3 mmol) in DCM (1 mL) was added TFA (1.0 mL, 0.3 mmol). The reation was stirred at 25 °C for 1 h. The solvent was removed in vacuo. Purification by RP-HPLC delivered the title compound (100 mg, 69%) as a white solid. MS (ESI): m/z 372.1 [M+H]⁺ Step a): 4-fluoro-3,5-diiodo-1H-pyrazole In a flask under Ar, to a solution of 4-fluoro-1H-pyrazole (CAS RN: 35277-02-2; 4.0 g, 46.47 mmol) in CHCl3 (80 mL), was added NIS (10.46 g, 46.5 mmol). The solution was stirred at 80 °C for 2 h. Purification by FC (SiO₂, Heptane/EtOAc) delivered the title compound (600 mg, 4%) as a white solid. MS (ESI): m/z 338.8 [M+H]⁺ Step b): 2-[(4-fluoro-3,5-diiodo-pyrazol-1-yl)methoxy]ethyl-trimethyl-silane In a flask under Ar, to a solution of 4-fluoro-3,5-diiodo-1H-pyrazole (400.0 mg, 1.18 mmol) in THF (8 mL),was added NaH (94.71 mg, 2.37 mmol ) at 0°C. The reaction was stirred at 0 °C for 30 min, then SEMCl (0.42 mL, 2.37 mmol) was added dropwise at 0°C under N2. The solution was stirred at 25 °C for 30 min. The reaction mixture was poured into saturated aqueous NH₄Cl solution (20 mL), and the mixture was extracted with EtOAc (3 x 20 mL). The combined organic layes were washed with brine, dried over Na2SO4, filtered and evaporated. Purification by RP- HPLC delivered the title compound (250 mg, 45%) as a white solid. MS (ESI): m/z = 468.9 [M+H]⁺ Step c): 2-[(4-fluoro-5-iodo-3-pyridazin-4-yl-pyrazol-1-yl)methoxy]ethyl-trimethyl-silane To a solution of 2-[(4-fluoro-3,5-diiodo-pyrazol-1-yl)methoxy]ethyl-trimethyl-silane (350 mg, 38.77 mmol) in 1,4-dioxane (10 mL) was added 4-(tributylstannyl)pyridazine (CAS RN: 194865- 89-9; 221 mg, 0.6 mmol) and Pd(Ph3P)2Cl2 (52 mg, 0.07 mmol), at 25 °C under N2. The mixture was stirred for 12 h at 100 °C, before being poured into water (100 mL) and then extracted with EtOAc. The combined organic layers were dried over Na₂SO₄, filtered and evaporated. FC (SiO₂; PE/EtOAc) gave the title compound (100 mg, 32%) as a yellow solid. MS (ESI): m/z = 421.0 [M+H]⁺ Step d): methyl 4-fluoro-5-pyridazin-4-yl-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate To a solution of 2-[(4-fluoro-5-iodo-3-pyridazin-4-yl-pyrazol-1-yl)methoxy]ethyl-trimethyl- silane (50 mg, 0.12 mmol) in MeOH (1 mL) was added Pd(dppf)Cl2·CH2Cl2 (10 mg, 0.01 mmol) and TEA (0.02 mL, 0.18 mmol). The mixture was degassed with Ar and then backfilled with CO (50 psi). The mixture was stirred at 80 °C for 24 h. The reaction was stopped and the extra CO appropriately removed under a flow of Ar. Purification by RP-HPLC delivered the title compound (15 mg, 36%) as a colorless oil. MS (ESI): m/z = 353.1 [M+H]⁺ Step e): 4-fluoro-5-pyridazin-4-yl-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylic acid To a solution of methyl 4-fluoro-5-pyridazin-4-yl-2-(2-trimethylsilylethoxymethyl)pyrazole-3- carboxylate (270 mg, 0.77 mmol) in THF (1 mL), EtOH (1 mL) and water (1 mL), was added LiOH (161 mg, 3.83 mmol). The reation was stirred at 25 °C for 1 h, and evaporated. Purification by RP-HPLC delivered the title compound (174 mg, 67%) as a white solid. MS (ESI): m/z = 339.1 [M+H]⁺ Step f): [3-(4-chlorophenyl)pyrrolidin-1-yl]-[4-fluoro-5-pyridazin-4-yl-2-(2- trimethylsilylethoxymethyl)pyrazol-3-yl]methanone To a solution of 4-fluoro-5-pyridazin-4-yl-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylic acid (170 mg, 0.5 mmol) in DMF (2 mL) were added DIPEA (0.26 mL, 1.51 mmol) and HATU (229 mg, 0.6 mmol). The mixture was stirred at 25 °C for 10 min. Then 3-(4- chlorophenyl)pyrrolidine (CAS RN: 120418-62-4; 110 mg, 0.6 mmol) was added and the mixture stirred at 25 °C for 1 h. Purification by RP-HPLC gave the title compound (150 mg, 59%) as a yellow oil. MS (ESI): m/z = 502.2 [M+H]⁺ Examples A8 and A9: [(3R,4S)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-(3,4- difluorophenyl)pyrrolidino]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone or [(3S,4R)-3-[[tert- butyl(dimethyl)silyl]oxymethyl]-4-(3,4-difluorophenyl)pyrrolidino]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone A8 and [(3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-(3,4- difluorophenyl)pyrrolidino]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone or [(3R,4S)-3-[[tert- butyl(dimethyl)silyl]oxymethyl]-4-(3,4-difluorophenyl)pyrrolidino]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone A9

To a solution of rac trans-[3-(3,4-difluorophenyl)-4-methylol-pyrrolidino]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone (388 mg, 995.5 µmol) in DCM (8 mL) was added imidazole (CAS RN: 288-32-4; 81.33 mg, 1.19 mmol). The reaction mixture was stirred at 23 °C for 30 min. TBDMS- Cl (158 mg, 1.05 mmol) was then added at 0 °C. The reaction was stirred at 23 °C over 15 h. The reaction was diluted with water and extracted with DCM. The combined organic phases were washed with brine, dried over Na₂SO₄, filtered and evaporated. Purification by FC (SiO₂; DCM/MeOH) and by SFC (chiral Wrr, 5μm, 250 x 20mm, 42% MeOH) delivered the title compounds as single enantiomers A8 (85 mg, 17%, tR = 4.116 min) as a white powder. MS (ESI): m/z = 386.2 [M+H]⁺; and A9 (96 mg, 35%, t_R = 4.642 min) as a white powder. MS (ESI): m/z = 386.2 [M+H]⁺ Step a): 1-benzyl-4-(3,4-difluorophenyl)pyrrolidine-3-carboxylic acid methyl ester To a solution of (E)-3-(3,4-difluorophenyl)acrylic acid methyl ester (CAS RN: 218430-47-8; 1.99 g, 9.03 mmol) in DCM (15 mL) was added N-(methoxymethyl)-N- (trimethylsilylmethyl)benzylamine (CAS RN: 93102-05-7; 3.22 g, 13.6 mmol) at 0 °C. The reaction mixture was stirred at 23 °C over 16 h, before being evaporated. Purification by FC (SiO₂; DCM/MeOH) delivered the title compound (1.89 g, 53%) as a colorless liquid. MS (ESI): m/z = 332.2 [M+H]⁺ Step b): [1-benzyl-4-(3,4-difluorophenyl)pyrrolidin-3-yl]methanol To a solution of 1-benzyl-4-(3,4-difluorophenyl)pyrrolidine-3-carboxylic acid methyl ester (900 mg, 2.31 mmol) in THF (12 mL) was added dropwise LiAlH41 M in THF (2.54 mL, 2.54 mmol) at 0 °C. The reaction was stirred at 23 °C over 2.5 h. The mixture was quenched with 1 M aqueous NaOH and diluted with EtOAc and water. The mixture was then neutralized with 1 M aqueous HCl. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated, to give the title compound (604 mg, 78%) as a white waxy solid. MS (ESI): m/z = 304.2 [M+H]⁺ Step c): [4-(3,4-difluorophenyl)pyrrolidin-3-yl]methanol A solution of [1-benzyl-4-(3,4-difluorophenyl)pyrrolidin-3-yl]methanol (604 mg, 1.79 mmol) in MeOH (20 mL) and Pd/C (191 mg, 179.2 µmol) was degassed with Ar at 23 °C. The mixture was then filled with H₂ and stirred at 23 °C over 4 h. The resulting suspension was then filtered, washed with MeOH and evaporated to deliver the title compound (366 mg, 91%) as a light brown oil. MS (ESI): m/z = 214.1 [M+H]⁺ Step d): rac trans-[3-(3,4-difluorophenyl)-4-methylol-pyrrolidino]-(3-pyridazin-4-yl-1H-pyrazol- 5-yl)methanone To a solution of 3-pyridazin-4-yl-1H-pyrazole-5-carboxylic acid (A4; 380 mg, 1.96 mmol) and [4- (3,4-difluorophenyl)pyrrolidin-3-yl]methanol (366 mg, 1.63 mmol) in DMF (8 mL) were added DIPEA (854 µL, 4.89 mmol) and T₃P^® (720 µL, 2.44 mmol) at 23 °C. The reaction was stirred at 23 °C for 16 h. The reaction was quenched with water, diluted with Me-THF. The aqueous layer was extracted three times with 2-Me-THF. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and evaporated. Purification by FC (SiO₂; DCM/MeOH) delivered the title compound (438 mg, 69%) as a light yellow powder. MS (ESI): m/z = 386.2 [M+H]⁺ Example A10: 5-(3-methoxy-4-pyridyl)-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylic acid

To solution of 5-(2-methoxy-3-pyridyl)-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylic acid ethyl ester (32 mg, 0.081 mmol) in THF (410 µL) was added 2 M KOH (162 µL, 324 µmol). The mixture was stirred at 23 °C for 14 h. HCl (1 M aqueous solution) was added until pH = 5. The mixture was extracted with EtOAc (3x20 mL) and the combined organic phases washed with brine (20 mL), dried over Na2SO4, filtered and evaporated, to give the title compound (55 mg, over quant.) as a white solid. MS (ESI): m/z = 350.3 [M+H]⁺ Step a): 3-bromo-1-(2-trimethylsilylethoxymethyl)pyrazole-5-carboxylic acid ethyl ester A solution of 3-bromo-1H-pyrazole-5-carboxylic acid ethyl ester (CAS RN: 1886994-07-5; 1.0 g, 4.57 mmol) in THF, extra dry (24 mL) was cooled to 0 °C and treated with NaH (182 mg, 6.83 mmol). The mixture was stirred at 23 °C for 45 min. SEMCl (892 µL, 5.03 mmol) was then added dropwise at 0 °C. The reaction mixture was stirred at 23 °C for 2 h. The reaction was quenched by the addition of water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and evaporated. Purification by FC (SiO₂; heptane/EtOAc) delivered the title compound (1.195 g, 71%) as a colorless oil. MS (ESI): m/z = 351.1 [M+H]⁺ Step b): 5-(2-methoxy-3-pyridyl)-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylic acid ethyl ester A solution of 3-bromo-1-(2-trimethylsilylethoxymethyl)pyrazole-5-carboxylic acid ethyl ester (100 mg, 286.29 µmol), 3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (CAS RN: 1243312-43-7; 100 mg, 425.37 µmol), cataCXium A Pd G3 (CAS RN: 1651823-59-4; 19 mg, 26.1 µmol), trimethyl borate (66 µL, 590.7 µmol) and KOTMS (86 mg, 670.36 µmol) in DME, extra dry (2.56 mL) was degassed under Ar. The reaction mixture stirred at 80 °C for 14 h, before being evaporated. Purification by FC (SiO2; heptane/EtOAc) delivered the title compound (32.2 mg, 28%) as a colorless oil. MS (ESI): m/z = 378.2 [M+H]⁺ Example B1: 2-chloro-5-[rac(3RS)-pyrrolidin-3-yl]-pyridine;4-methylbenzenesulfonic acid

To a solution of 3-(6-chloro-3-pyridyl)pyrrolidine-1-carboxylic acid tert-butyl ester (CAS RN: 174789-94-7; 421 mg, 1.37 mmol) in EtOAc (3.75 mL) were added p-toluenesulfonic acid monohydrate (573.21 mg, 3.01 mmol) and the mixture was stirred at 80 °C for 5 h. The mixture was cooled down to 23° C overnight. To the suspension was added 0.5 mL of MeOH. Filtration over sintered funnel delivered the title compound (314 mg, 61%) as a colorless solid. MS (ESI): m/z= 183.1 [M+H]⁺. In analogy to Example B1, Examples in the following table were generated, using the respective commercially available blocks. MS, Building Ex. Structure Systematic Name ESI: Blocks m/z B^{2 N} _Cl 5-chloro-2-[rac- tert-butyl 3-(5- 183.0 O (3SR)-pyrrolidin-3- chloropyridin- [M+H]⁺ N S H ^{H O} _O yl]pyridine;4- 2- methylbenzenesulfo yl)pyrrolidine- nic acid 1-carboxylate CAS RN: 1211591-19-3 Example C1: (3S,4R)-4-(4-chlorophenyl)pyrrolidin-3-ol;2,2,2-trifluoroacetic acid and (3R,4S)-4-(4-chlorophenyl)pyrrolidin-3-ol;2,2,2-trifluoroacetic acid To a solution of rac-(3R,4S)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert- butyl ester (200 mg, 671.64 µmol) in DCM (2.24 mL) was added TFA (517.43 µL, 6.72 mmol) the mixture was stirred for 2 h at 23 °C. The solvent was evaporated and the crude was used as such in the coupling reaction (0.581 g, quant., 18% purity) as a dark red oil. MS (ESI): m/z = 198.0 [M+H]⁺ Step a): rac-(3R,4S)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester To CuI (33.93 mg, 178.17 µmol) in an Ar-filled flask was added 1 M of 4- chlorophenylmagnesium bromide in THF (CAS RN: 873-77-8; 4.05 mL, 4.05 mmol). To the light yellow suspension, a solution of 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert- butyl ester (CAS RN: 114214-49-2; 500 mg, 2.7 mmol) in 2-Me-THF (2.83 mL) was added dropwise over 10 minutes. The mixture was stirred at 23 °C for 3 h before being poured onto NH4Cl, extracted with EtOAc and washed with water and brine.The organic layer was dried over Na₂SO₄ and evaporated. Purification by FC (SiO₂; heptane/EtOAc) delivered the title compound (0.564 g; 32%, 50% purity) as a colorless oil. The product was used without further purification in the next step. MS (ESI): m/z = 242.1 [M-C₄H₈+H]⁺ Example C2: rac-(3R,4R)-4-(4-chlorophenyl)pyrrolidin-3-ol

To a solution of rac-(3R,4R)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert- butyl ester (288 mg, 0.967 mmol) in DCM (2 mL) was added TFA (1745.1 µL, 9.67 mmol) and the mixture was stirred at 23 °C for 45 min. The solvent was evaporated. Purification by FC (SiO₂-NH₂; MeOH/CH₃CN) delivered the title compound (0.208 g, 90%) as a light brown oil. MS (ESI): m/z = 198.1 [M+H]⁺ Step a): rac-(3R,4R)-3-(4-chlorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrrolidine-1-carboxylic acid tert-butyl ester To an Ar flushed two-neck flask were added 1-bromo-4-chloro-benzene (CAS RN: 106-39-8; 2.41 g, 12.6 mmol) and 3-pyrroline-1-carboxylic acid tert-butyl ester (CAS RN: 73286-70-1; 711 mg, 4.2 mmol) and THF (9 mL). To the solution were added bis(pinacolato)diboron (CAS RN: 73183-34-3; 2.13 g, 8.4 mmol) followed by NaOtBu (606 mg, 6.3 mmol) and a blue, turbid solution of NiCl₂∙DME (46 mg, 210.08 µmol) in DMA (1 mL). The suspension was stirred at 23 °C for 18 h. The reaction mixture was diluted with water and EtOAc and the mixture was filtered over Dicalite^®. The filtrate layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed once with water, dried over MgSO4, filtered, treated with Isolute and evaporated. The product was purified by FC (SiO₂; heptane/EtOAc) to deliver the title compound (1.04 g; 61%) as a colorless oil. MS (ESI): m/z = 352.2 [M-C4H8+H]⁺ Step b): rac-(3R,4R)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester To an ice-cold solution of rac-(3R,4R)-3-(4-chlorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 1.23 mmol) in THF (5.5 mL) were added 2 M aqueous NaOH (5.52 mL, 11.04 mmol) and H2O235% in water (5.58 mL, 63.77 mmol) and the mixture was vigourously stirred in an ice-bath for 1 h. The mixture was added dropwise to an ice-cold aqueous saturated Na2S2O3 solution (9 mL) until no peroxides were detected. The aqueous layer was extracted 2x with EtOAc. The organic layers were washed with brine, dried over MgSO4, filtered and evaporated. Purification by FC (SiO2; heptane/EtOAc) delivered the title compound (288 mg, 79%) as a colorless oil. MS (ESI): m/z = 242.1 [M-C4H8+H]⁺. Example C3: 3-(4-chlorophenyl)-2,3,3a,4,5,6,7,7a-octahydro-1H-indole;hydrochloride

A solution of 3-(4-chlorophenyl)-3,3a,4,5,6,7-hexahydro-2H-indole (500 mg, 2.1 mmol) in EtOH (5 mL) was treated with NaBH4 (180 mg, 4.7 mmol) and 1 M AcOH (10 mL), at 0 °C. The mixture was stirred for 4 h at 23 °C, before being evaporated. Water was added and the mixture was extracted with Et2O. The water phase was basified with NaOH and the water phase was back- extracted with Et₂O. The organic layer was washed with water and dried over K₂CO₃, to give the title compound (360 mg, 73%) as a colorless crystal. Step a): 4-[6-[1-(4-chlorophenyl)-2-nitro-ethyl]cyclohexen-1-yl]morpholine In an oven-dried vial under nitrogen atmosphere, 1-morpholinocyclohexene (CAS RN: 670-80-4; 64.16 g, 38 mmol) was dissolved in DCM (160 mL) and the resulting solution cooled to 0 °C under vigorous stirring. After 70 min, a solution of 1-nitro-2-(4-chlorophenyl)ethylene (CAS RN: 101671-01-6; 58.75 g, 32 mmol) in DCM (320 mL) was added over 17 min. The mixture was stirred at 0 °C for 1.5 h. The solvent was evaporated at 40 °C and the residue washed with 180 mL of ⁱPr₂O to deliver the title compound (103.2 g, 92%) as a white crystalline solid. Mp: 125-125 °C. Step b): 3-(4-chlorophenyl)-3,3a,4,5,6,7-hexahydro-2H-indole A solution of LiAlH₄ (3.15 g, 83 mmol) in THF (133 mL) was placed under nitrogen flow and within 30 min 4-[6-[1-(4-chlorophenyl)-2-nitro-ethyl]cyclohexen-1-yl]morpholine (11.3 g, 32 mmol) was added and the resulting mixture was stirred at reflux overnight. The mixture was cooled to 0 °C and EtOH (30 mL) was added, followed by H₂O-THF mixture. The solid was filtered off and the solvent removed under reduced pressure. The crude was then dissolved in Et₂O and 3x50 mL of ice cold HCl were added to the mixture. The water phase was back-extracted with Et2O and then basified with 3 N NaOH. Back extraction with Et₂O was used, dried over K₂CO₃ and the solvent removed in vacuo. Purification by FC (SiO2; Et2O) gave the title compound (5.0 g, 67 %) as a crude yellow oil. Example C4: tert-butyl (3R,4S)-3-(4-chlorophenyl)-4-(hydroxymethyl)pyrrolidine-1- carboxylate

The apparatus was heat-dried and cooled under Ar flow. (3S,4R)-1-tert-butoxycarbonyl-4-(4- chlorophenyl)pyrrolidine-3-carboxylic acid (0.5 g, 1.53 mmol) was dissolved in THF (7.5 mL). BH3·SMe2 complex (1.54 mL, 3.07 mmol) was added dropwise at 0 °C. The mixture was stirred for 15 min before the ice bath was removed and stirred at 23 °C for 2 h. The reaction was cooled to 0 °C and quenched with MeOH, before being evaporated. Purification by FC (SiO₂; heptane/EtOAc) delivered the title compound (410 mg, 86%) as a waxy white solid. MS (ESI): m/z = 311.9 [M+H]⁺ Step a): (3S,4R)-1-tert-butoxycarbonyl-4-(4-chlorophenyl)pyrrolidine-3-carboxylic acid O1-tert-Butyl O3-methyl (3S,4R)-4-(4-chlorophenyl)pyrrolidine-1,3-dicarboxylate D1 (3.3 g, 9.7 mmol) was dissolved in 1,4-dioxane (50 mL) and 2 M aqueous NaOH (50 mL) was added dropwise. The reaction was stirred at 23 °C overnight. To the reaction were added iced water (50 g) and the resulting slurry was gently neutralized with aqueous HCl 25% N until pH = 1. The water phase was extracted with EtOAc. The combined organic layers were dried over Na₂SO₄, filtered and evaporated, to give the title compound (2.8g, 88%) as a white solid. MS (ESI): m/z = 324.3 [M-H]- Example C5: tert-butyl (3S,4R)-3-(4-chlorophenyl)-4-(hydroxymethyl)pyrrolidine-1- carboxylate

The apparatus was heat-dried and cooled under Ar flow. (3R,4S)-1-tert-butoxycarbonyl-4-(4- chlorophenyl)pyrrolidine-3-carboxylic acid (0.5 g, 1.53 mmol) was dissolved in THF (7.5 mL). BH₃·SMe₂ complex (1.54 mL, 3.07 mmol) was added dropwise at 0 °C. The reaction mixture was stirred for 15 min before the ice bath was removed and stirred at 23 °C for 2 h. The reaction was cooled to 0 °C and quenched with MeOH, before being evaporated. Purification by FC (SiO2; heptane/EtOAc) delivered the title compound (410 mg, 86%) as a waxy white solid.¹H NMR (300 MHz, CDCl₃): δ = 7.35 - 7.29 (m, 2H), 7.24 - 7.17 (m, 2H), 4.02 - 3.80 (m, 2H), 3.61 (br d, J = 6.8 Hz, 2H), 3.50 - 3.31 (m, 1H), 3.26 - 3.10 (m, 1H), 1.48 ppm (s, 9H). Step a): (3R,4S)-1-tert-butoxycarbonyl-4-(4-chlorophenyl)pyrrolidine-3-carboxylic acid O1-tert-Butyl O3-methyl (3R,4S)-4-(4-chlorophenyl)pyrrolidine-1,3-dicarboxylate D2 (3.2 g, 9.7 mmol) was dissolved in 1,4-dioxane (50 mL) and 2 M aqueous NaOH (50 mL) was added dropwise. The reaction was stirred at 23 °C overnight. To the reaction were added iced water (50 g) and the resulting slurry was gently neutralized with aqueous HCl 25% N until pH = 1. The water phase was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and evaporated, to give the title compound (2.7g, 88%) as a white solid. MS (ESI): m/z = 324.3 [M-H]⁺ Example C6: 3-(4-chloro-2-thienyl)pyrrolidine; 1:1 hydrogen chloride

Under Ar, to a solution of 3-(4-chloro-2-thienyl)pyrrolidine-1-carboxylic acid tert-butyl ester (61 mg, 0.194 mmol) in DCM, extra dry (400 µL) was added 4 M HCl in 1,4-dioxane (243 µL, 971.59 µmol) and the mixture was stirred at 23 °C for 1 h before being evaporated to give the title compound (44 mg, 81%) as a light brown oil. MS (ESI): m/z = 188.0 [M+H]⁺

To a vial under Ar were added N-Boc-3-bromopyrrolidine (CAs RN: 939793-16-5; 181 mg, 724.12 µmol), 2-bromo-4-chlorothiophene (CAS RN: 32431-92-8; 71 µL, 658.29 µmol), tris(trimethylsilyl)silane (203 µL, 658.29 µmol) and Na₂CO₃ (105 mg, 987.44 µmol). Degassed DME, extra dry (3 mL) was added. The vial was evacuated and backfilled with Ar. (4,4'- Dtbbpy)NiCl2 (3 mg, 6.58 µmol) and [Ir(dF(CF3)ppy)2(dtbbpy)](PF6) (7 mg, 6.58 µmol) were added. The reaction was degassed with Ar for 15 min and then irradiated at 450 nm at 23 °C for 19 h. The mixture was filtered and evaporated. Purification by FC (SiO2; heptane/EtOAc) gave the title compound (60.79 mg, 30%) as a colorless oil. MS (ESI): m/z = 232.0 [M+H-tBu]⁺ Example C7: rac-(3R,4S)-3-(3,4-difluorophenyl)-4-methyl-pyrrolidine

To a solution of 3-(3,4-difluorophenyl)-2-methyl-4-nitro-butyraldehyde (1.01 g, 3.33 mmol) in water (12 mL) and AcOH (12 mL) was added Zinc (5.22 g, 79.84 mmol) at 0 °C. The reaction was stirred at 23 °C over 2 h, then quenched with a solution of NaHCO₃ and diluted with water and EtOAc. The zinc was filtered. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. Purification by FC (SiO2; DCM/MeOH) delivered the title compound (278 mg, 38%) as an orange waxy solid. MS (ESI): m/z = 198.2 [M+H]⁺ Step a): (E)-1,2-difluoro-4-(2-nitrovinyl)benzene 3,4-difluorobenzaldehyde (CAS RN: 34036-07-2; 711 mg, 5 mmol) was dropped into a solution of NH₄OAc (848 mg, 11 mmol) in dry NO₂CH₃ (9.37 mL, 175 mmol) and AcOH (20.04 mL, 350 mmol) at 90 °C under vigorous stirring. The mixture was refluxed for 3 h, then poured into water and extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and evaporated. Purification by FC (SiO₂; heptane/EtOAc) delivered the title compound (560 mg, 57%) as a light yellow solid. MS (ESI): m/z = 185.9 [M+H]⁺ Step b): 3-(3,4-difluorophenyl)-2-methyl-4-nitro-butyraldehyde To a solution of (E)-1,2-difluoro-4-(2-nitrovinyl)benzene (1.46 g, 6.29 mmol) in DCM (12.6 mL) were added rac-tert-butyl-[diphenyl(pyrrolidin-2-yl)methoxy]-dimethyl-silane (CAS RN: 1802157-92-1; 231 mg, 629.48 µmol) and 4-nitrophenol (CAS RN: 100-02-07; 262.7 mg, 1.89 mmol), following by the addition of propionaldehyde (CAS RN: 123-38-6; 994 µL, 18.88 mmol). The reaction was stirred at 23 °C over 18 h, before being evaporated. Purification by FC (SiO2; heptane/EtOAc) delivered the title compound as a mixture of syn-diasteromers (1.01 g, 53%) as a yellow liquid. ¹H NMR (300 MHz, DMSO-d₆) δ = 9.67 (d, J = 1.2 Hz, 1H), 9.50 (d, J = 1.8 Hz, 1H), 7.59 - 7.47 (m, 1H), 7.45 - 7.27 (m, 1H), 7.18 (dtd, J = 2.1, 4.1, 8.3 Hz, 1H), 5.11 - 4.98 (m, 2H), 3.97 - 3.81 (m, 1H), 2.90 - 2.78 (m, 1H), 1.05 (d, J = 7.3 Hz, 1H), 0.91 - 0.70 ppm (m, 3H) Examples C8 and C9: rel-(3S,4R)-4-(4-chlorophenyl)pyrrolidine-3-carbonitrile C8 and rel- (3R,4S)-4-(4-chlorophenyl)pyrrolidine-3-carbonitrile C9

To a solution of trans-1-benzyl-4-(4-chlorophenyl)pyrrolidine-3-carbonitrile (596 mg, 1.81 mmol) in CH₃CN (19 mL) was added 2,2,2-trichloroethyl chloroformate (CAS RN: 17341-93-4; 366 µL, 2.71 mmol). The reaction mixture was stirred at 23 °C for 16 h, then evaporated. The residue was dissolved in AcOH (19 mL) and Zn (354 mg, 5.42 mmol) was added. The reaction was stirred at 23 °C for 3 h, then filtered and evaporated. The residue was dissolved in EtOAc, quenched with NaHCO3 saturated solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. Purification by FC (SiO2; DCM/MeOH) and SFC (Chiral column AD-H, 5 µm, 250 x 30 mm, IPA/EtOH/MeOH) delivered the title compounds C8(78 mg, 20%, t_R = 1.427 min) as a white powder (MS (ESI): m/z = 207.1 [M+H]⁺) and C9(75 mg, 18%, t_R = 2.157 min) as a white powder (MS (ESI): m/z = 207.1 [M+H]⁺) Step a): trans-1-benzyl-4-(4-chlorophenyl)pyrrolidine-3-carbonitrile To a solution of (E)-3-(4-chlorophenyl)acrylonitrile (CAS RN: 14378-04-2; 1.04 g, 6.29 mmol) in DCM (10 mL) was added N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (CAS RN: 93102-05-7; 2.24 g, 9.44 mmol). TFA was then added (121 µL, 1.57 mmol) at 0 °C. The reaction mixture was stirred at 23 °C for 16 h before being evaporated. Purification by FC (SiO₂; heptane/EtOAc) delivered the title compound (1.095 g, 53%) as a colorless liquid. MS (ESI): m/z = 297.1 [M+H]⁺ Example C10: rac-(3R,4S)-3-(4-chlorophenyl)-4-fluoro-pyrrolidine; 1:12,2,2-trifluoroacetic acid

To a solution of rac-(3R,4S)-3-(4-chlorophenyl)-4-fluoro-pyrrolidine-1-carboxylic acid benzyl ester (73 mg, 196.84 µmol), TFA (304 µL, 3.94 mmol) and water (15 µL) in DCM (1 mL) was added Pd/C 10% (8 mg) and the suspension was stirred under H2 for 3 days. The mixture was filtered and evaporated. The residue was azeotroped with toluene and the solvent removed in vacuo to deliver the title compound (89 mg, 86%) as a brown oil. MS (ESI): m/z = 200.1 [M+H]⁺ Step a): 1-carboxybenzyl-3-pyrrolidine 3-Pyrrolidine (CAS RN: 109-96-6; 2.5 g, 36.2 mmol) and TEA (6.05 mL, 82.6 mmol) were dissolved in toluene (120 mL). A solution of benzyl chloroformate (5.4 mL, 26.4 mmol) in toluene (10 mL) was added over a period of 10 min at 0° C. A white suspension resulted. The reaction mixture was quenched with NH4Cl saturated aqueous solution and extracted with MTBE. The combined organic layers were washed with water and brine, dried over Na₂SO₄, filtered and evaporated to give the title compound (7.05 g, 96%). MS (ESI): m/z = 204.2 [M+H]⁺ Step b): rac-(3R,4S)-benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate To a solution of 1-carboxybenzyl-3-pyrrolidine (3.0 g, 14.8 mmol) in 1,2-DCE (30 mL) was added mCPBA (6.55 g, 26.6 mmol) and the reaction was stirred at 23 °C for 20 h. The reaction mixture was diluted with DCM, washed with saturated NaOH aqueous solution (0.5 M), water and brine, dried over Na2SO4, filtered and evaporated, to give the title compound (2.7g, 83%) as a colorless oil. MS (ESI): m/z = 220.2 [M+H]⁺ Step c): rac-(3R,4S)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidine-1-carboxylic acid benzyl ester To a slurry of CuI (25 mg; 0.131 mmol) in THF (2mL) cooled to 0 °C, 4-chloro-pheпylmagпesium bromide (CAS RN: 100-58-3; 1.305 ml; 1.305 mmol) was added dropwise. The resulting mixture was stirred for 10 min before a solution of rac-(3R,4S)-benzyl 6-oxa-3-azabicyclo[3.1.0]hexane- 3-carboxylate (191 mg; 0.870 mmol) in THF ( 1 mL) was added dropwise. The reaction was stirred at 23 °C for 4 h. Extra 4-chloro-pheпylmagпesium bromide (870 µL; 0.870 mmol) was added dropwise. The reaction was stirred at 23 °C for 4 h. The mixture was quenched by the addition of water and extracted with MTBE. The reunited organic layers were washed with brine (5 mL), dried over Na2SO4 and the solvent evporated. Purification by FC (SiO2; heptane/EtOAc) delivered the title compound (175 mg, 61%) as a light brown solid. MS (ESI): m/z = 332.1 [M+H]⁺ Step d): rac-(3R,4S)-3-(4-chlorophenyl)-4-fluoro-pyrrolidine-1-carboxylic acid benzyl ester To a solution of rac-(3R,4S)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidine-1-carboxylic acid benzyl ester (100 mg, 301.4 µmol) in DCM (3 mL) at – 78 °C was added DAST (CAS RN: 38078-09-0; 59.73 µL, 452.09 µmol) and the mixture was stirred at – 78°C for 1.75 h. The mixture was poured intoNaHCO3 saturated aqueous solution and extracted with DCM. The combined organic layers were dried over MgSO4, filtered, and evaporated. Purification by FC (SiO2; heptane/EtOAc) delivered the title compound (73 mg; 43%) as a light brown solid. MS (ESI): m/z = 334.1 [M+H]⁺ Example C11: tert-butyl (3R,4S)-3-(4-chlorophenyl)-4-(1-hydroxyethyl)pyrrolidine-1- carboxylate

Under Ar atmosphere, tert-butyl (3R,4S)-3-(4-chlorophenyl)-4-(hydroxymethyl)pyrrolidine-1- carboxylate (C4; 101 mg, 0.32 mmol), was dissolved in DCM, extra dry (3 mL). The solution was cooled to 0 °C, then Dess-Martin periodinane (233 mg, 0.55 mmol) was added and the resulting suspension stirred for 5 h at 0 °C. The mixture was diluted with DCM and 10 mL NaHCO3 saturated aqueous solution and stirred for 30 min. The resulting mixture was extracted with DCM and the combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and evaporated. The crude was re-dissolved in 2 mL anhydrous THF, cooled to 0 °C and treated with methylmagnesium bromide 3.4 M in THF (CAS RN: 75-16-1; 600 µL, 2.0 mmol). The reaction was stirred at 23 °C for 18 h. The mixture was quenched with MeOH, diluted with EtOAc and washed with water. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated. Purification by FC (SiO2; DCM/MeOH) gave the title compound (50 mg, 43%) as a colorless oil. MS (ESI): m/z = 270.1 [M+H-Buten]⁺ Example C12: 5-chloro-2-pyrrolidin-3-yl-thiazole;2,2,2-trifluoroacetic acid

To a solution of tert-butyl 3-(5-chlorothiazol-2-yl)pyrrolidine-1-carboxylate (300 mg, 1.04 mmol) in DCM (4 mL) was added TFA (0.8 mL, 1.25 mmol). The mixture was stirred for 30 min at 23 °C, before being evaporated. Purification by RP-HPLC gave the title compound (200 mg, 64%) as a white solid. MS (ESI): m/z = 189.0 [M+H]⁺ Step a): tert-butyl 3-(5-chlorothiazol-2-yl)-2,5-dihydropyrrole-1-carboxylate To a solution of tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H- pyrrole-1-carboxylate (CAS RN: 212127-83-8; 1.49 g, 5.04 mmol) and 2-bromo-5-chlorothiazole (CAS RN: 16629-15-5; 2.0 g, 10.08 mmol), K₂CO₃ (2.78 g, 20.15 mmol) in 1,4-dioxane (40 mL) and water (10 mL) was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (822 mg, 1.01 mmol), under N₂. The mixture was stirred for 12 h at 100 °C, before being cooled down and evaporated, to give the crude title compound (900 mg, 31%) as a yellow solid. MS (ESI): m/z = 230.9 [M-C4H8+H]⁺ Step b): tert-butyl 3-(5-chlorothiazol-2-yl)pyrrolidine-1-carboxylate To a solution of tert-butyl 3-(5-chlorothiazol-2-yl)-2,5-dihydropyrrole-1-carboxylate (400 mg, 1.39 mmol) in MeOH (10 mL) was added PtO₂ (141 mg, 0.62 mmol) at 25 °C under N₂. The mixture was stirred at 25 °C under H2 atmosphere (balloon) for 12 h, before being filtered off in a N₂ atmosphere. The filtrate was evaporated. Purification by FC (SiO₂; PE/EtOAc) gave the title compound (280 mg, 70%) as a yellow oil. MS (ESI): m/z = 233.0 [M-C₄H₈+H]⁺ Example C13: 3-(benzothiophen-2-yl)pyrrolidine;hydrochloride

A solution of tert-butyl 3-(benzothiophen-2-yl)pyrrolidine-1-carboxylate (200 mg, 0.66 mmol) in 2 M HCl in 1,4-dioxane (10.0 mL, 20.0 mmol) was stirred for 2 h at 25 °C, before being diluted with 1,4-dioxane (5 mL) and filtered. The cake was dried under vacuum, to give the title compound (102 mg, 64%) as a pink solid. MS (ESI): m/z = 204.0 [M+H]⁺ Step a): tert-butyl 3-(benzothiophen-2-yl)-2,5-dihydropyrrole-1-carboxylate To a solution of 2-bromobenzothiophene (CAS RN: 5394-13-8; 1.0 g, 4.69 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 2,5-dihydro-1H-pyrrole-1-carboxylate (CAS RN: 212127-83-8; 1385 mg, 4.69 mmol), K₂CO₃ (1946 mg, 14.08 mmol) and Pd(dppf)Cl2·CH2Cl2 (383 mg, 0.47 mmol) at 25 °C under N2. The solution was stirred at 100 °C for 2 h, before being cooled down and evaporated. Purification by FC (SiO₂; PE/EtOAc) gave the title compound (900 mg, 64%) as a white solid. MS (ESI): m/z = 246.0 [M-C₄H₈+H]⁺ Step b): tert-butyl 3-(benzothiophen-2-yl)pyrrolidine-1-carboxylate To a solution of tert-butyl 3-(benzothiophen-2-yl)-2,5-dihydropyrrole-1-carboxylate (600 mg, 1.99 mmol) in MeOH (20 mL) was added Pd/C 10% (300 mg, 0.28 mmol), under N₂. The mixture was stirred at 25 °C for 1.5 h under hydrogen balloon (at 15 psi), before being filtered and evaporated. Purification by FC (SiO2; PE/EtOAc) gave the title compound (500 mg, 83%) as a yellow solid. MS (ESI): m/z = 248 [M-C₄H₈+H]⁺ Example C14: 3-[3-(difluoromethyl)-4-fluoro-phenyl]pyrrolidine;hydrochloride To a solution of 3-[3-(difluoromethyl)-4-fluoro-phenyl]pyrrolidine-1-carboxylic acid tert-butyl ester (116 mg, 0.264 mmol) in DCM (500 µL) was added 4 M HCl in 1,4-dioxane (330 µL, 1.32 mmol). The mixture was stirred for 1.5 h at 23 °C, before being treated with Et₂O. The resulting precipitate was filtered off and washed with Et₂O, to give the title compound (66 mg, 86%) as a white solid. MS (ESI): m/z = 216.1 [M+H]⁺ Step a): 3-[3-(difluoromethyl)-4-fluoro-phenyl]pyrrolidine-1-carboxylic acid tert-butyl ester To a vial were added N-Boc-3-bromopyrrolidine (CAS RN: 939793-16-5; 171.19 mg, 684.41 µmol), 4-bromo-2-difluoromethyl-1-fluorobenzene (CAS RN: 445303-69-5; 86 µL, 622.19 µmol), tris(trimethylsilyl)silane (192 µL, 622.19 µmol) and sodium carbonate (98.92 mg, 933.29 µmol). The vial was evacuated and backfilled with Ar three times. Degassed DME, extra dry (3 mL) was added at 23 °C. The vial was once again evacuated and backfilled with Ar three times. (4,4'-Dtbbpy)NiCl2 (2.48 mg, 6.22 µmol) and (4,4'-di-t-butyl-2,2'-bipyridine)bis[3,5-difluoro-2- [5-trifluoromethyl-2-pyridinyl-kappan)phenyl-kappac]iridium(iii) hexafluorophosphate (6.98 mg, 6.22 µmol) were added. The mixture was sparged with Ar for 10 min and then irradiated at 450 nm at 23 °C for 24 h, before being filtered (Dicalite^®) and evaporated. Purification by FC (SiO2; heptane/EtOAc) gave the title compound (116 mg, 42%) as a light yellow oil. MS (ESI): m/z = 260.1 [M+H-tBu]⁺ Examples D1 and D2: O1-tert-butyl O3-methyl (3S,4R)-4-(4-chlorophenyl)pyrrolidine-1,3- dicarboxylate D1 and O1-tert-butyl O3-methyl (3R,4S)-4-(4-chlorophenyl)pyrrolidine-1,3- dicarboxylate D2

O1-tert-butyl O3-methyl rac-(3S,4R)-4-(4-chlorophenyl)pyrrolidine-1,3-dicarboxylate (7.0 g, 20.6 mmol) was separated by chiral HPLC (Chiarcel AD, Heptane:iPrOH 95:5, 220 nm) to give the title compounds D1 (3.3 g, 47%, (-)-enantiomer) as a colorless oil and title compound D2 (3.2 g, 46%, (+)-enantiomer) as a colorless oil. ¹H NMR (300 MHz, CDCl3) δ = 7.40 - 7.17 (m, 4H), 4.14 - 3.77 (m, 2H), 3.75 - 3.49 (m, 5H), 3.47 - 3.30 (m, 1H), 3.25 - 3.07 (m, 1H), 1.66 - 1.38 ppm (m, 9H). Step a): methyl rac-(3S,4R)-1-benzyl-4-(4-chlorophenyl)pyrrolidine-3-carboxylate Under Ar atmosphere, methyl 3-(4-chlorophenyl)propenoate (CAS RN: 20754-21-6; 9.0g 45.7 mmol) was dissolved in DCM (180 mL). N-(Methoxymethyl)-N- (trimethylsilylmethyl)benzylamine (CAS RN: 93102-005-7; 14.02 mL, 54.9 mmol) was added dropwise and the reaction cooled to 0 °C. TFA (350 mL) was added dropwise over 5 min and the reaction stirred at 23 °C for 1.5 h. The reaction was carefully quenched with saturated aqueous Na₂CO₃ solution and extracted with DCM. The organic phases were combined, dried over Na₂SO₄, filtered, and evaporated. Purification by FC (SiO2; heptane/EtOAc) delivered the title compound (10.2 g, 68%) as a colorless oil. Step b): O1-tert-butyl O3-methyl rac-(3S,4R)-4-(4-chlorophenyl)pyrrolidine-1,3-dicarboxylate Under Ar atmosphere, methyl rac-(3S,4R)-1-benzyl-4-(4-chlorophenyl)pyrrolidine-3-carboxylate (10.2 g, 30 mmol) was dissolved in 1,2-DCE (100 mL). 1-Chloroethyl chloroformiate (4.05 mL, 37.1 mmol) was added dropwise and the reaction was heated to 50 °C and stirred overnight. The reaction was diluted with MeOH (100 mL) and stirred under reflux for 1 h, before being evaporated. The resulting white solid residue was suspended in THF (100 mL) and the reaction mixture cooled to 0 °C. TEA (4.3 mL, 30 mmol) and Boc₂O (8.09 g, 37.1 mmol) were dissolved in THF (10 mL) and added dropwise. The reaction was stirred at 23 °C for 1 h. The mixture was then diluted with MTBE and H2O. The mixture was acidified with conc. HCl until pH = 1. and extracted twice with MTBE. The organic phases were combined, dried over Na₂SO₄, filtered, and evaporated. Purification by FC (SiO₂; heptane/EtOAc) gave the title compound (6.5g, 62%) as a white solid.¹H NMR (300 MHz, CDCl3) δ = 7.36 - 7.28 (m, 2H), 7.23 - 7.16 (m, 2H), 4.00 - 3.79 (m, 2H), 3.69 - 3.51 (m, 5H), 3.46 - 3.28 (m, 1H), 3.22 - 3.07 (m, 1H), 1.48 ppm (br s, 9H) Example 80 A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of tablets of the following composition: Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg Example 81 A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of capsules of the following composition: Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg

Claims

Claims 1. A compound of formula (I)

or a pharmaceutically acceptable salt, or a tautomer thereof, wherein: X, Y and Z are each selected from CH and N, provided that at most two of X, Y and Z are N; R¹ is selected from hydrogen, halogen, hydroxy, cyano, C₁-C₆-alkyl, halo-C₁-C₆- alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy, C₃-C₁₀-cycloalkyl, and NR^9aR^9b; R² is selected from hydrogen, halogen, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6- alkoxy, halo-C1-C6-alkoxy, C3-C10-cycloalkyl, and 3-14 membered heterocycloalkyl; R^3a and R^3b are each independently selected from hydrogen and C1-C6-alkyl; or R^3a and R^3b, taken together with the carbon atom to which they are attached, form a C₃-C₁₀-cycloalkyl; or R^3a and R^4a, taken together with the carbon atoms to which they are attached, form a C3-C10-cycloalkyl; R^3b is selected from hydrogen and C1-C6-alkyl; and R^4b is selected from hydrogen, halogen, cyano, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy, and hydroxy-C₁-C₆-alkyl; or R^4a and R^4b are each independently selected from hydrogen, halogen, cyano, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy, and hydroxy-C₁-C₆-alkyl; or R^4a and R^4b, taken together with the carbon atom to which they are attached, form a C3-C10-cycloalkyl; or R^4a and R⁵, taken together with the carbon atom to which they are attached, form a C₃-C₁₀-cycloalkyl; and R^4b is selected from hydrogen, halogen, cyano, hydroxy, C1-C6-alkyl, C1-C6-alkoxy, and hydroxy-C1-C6-alkyl; or R⁵ is selected from hydrogen, halogen, and C1-C6-alkyl; or R⁵ and R⁷, taken together with the carbon atoms to which they are attached, form a C₃-C₁₀-cycloalkenyl; R^6a and R^6b are each independently selected from hydrogen and C₁-C₆-alkyl; or R^6a and R^6b, taken together with the carbon atom to which they are attached, form a C₃-C₁₀-cycloalkyl; or R^6a and R⁵, taken together with the carbon atom to which they are attached, form a C3-C10-cycloalkyl; and R^6b is selected from hydrogen and C1-C6-alkyl; R⁷ is selected from hydrogen, halogen, cyano, C1-C6-alkyl, halo-C1-C6-alkyl, C1- C₆-alkoxy, halo-C₁-C₆-alkoxy, C₃-C₁₀-cycloalkyl, C₁-C₆-alkyl-SO₂-, C₁-C₆- alkyl-NH-SO2, and C1-C6-alkyl-N(C1-C6-alkyl)-SO2-; R⁸ and R^8a are each independently selected from hydrogen and halogen; R^9a and R^9b are each independently selected from hydrogen, C₁-C₆-alkyl, C₃-C₁₀- cycloalkyl, halo-C1-C6-alkyl, and halo-C3-C10-cycloalkyl; A is selected from C3-C10-cycloalkyl, C6-C10-aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocyclyl.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein: (i) X, Y and Z are CH; or (ii) X and Z are CH and Y is N; and R¹ is hydrogen.

3. The compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein X and Z are CH; Y is N; and R¹ is hydrogen.

4. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein R² is selected from hydrogen and C1-C6-alkyl.

5. The compound of formula (I) according to claim 4, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein R² is hydrogen.

6. The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein: (i) R^3a and R^3b are each independently selected from hydrogen and C₁-C₆-alkyl; R^4a is selected from hydrogen, halogen, hydroxy, cyano, C1-C6-alkyl and hydroxy-C₁-C₆-alkyl; and R^4b is hydrogen; or (ii) R^3a and R^4a, taken together with the carbon atoms to which they are attached, form a C3-C6-cycloalkyl; and R^3b and R^4b are both hydrogen.

7. The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein R^3a and R^3b are both hydrogen.

8. The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein: R^4a is selected from hydrogen, hydroxy, cyano, C1-C6-alkyl and hydroxy-C1-C6- alkyl; and R^4b is hydrogen.

9. The compound of formula (I) according to claim 8, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein: R^4a is selected from hydrogen, hydroxy, cyano, methyl, and hydroxymethyl; and R^4b is hydrogen.

10. The compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein: (i) R⁵ is selected from hydrogen and halogen; and R⁷ is selected from hydrogen, halogen, cyano, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, and C3-C10-cycloalkyl; or (ii) R⁵ and R⁷, taken together with the carbon atoms to which they are attached, form a C3-C10-cycloalkenyl; and R⁸ and R^8a are each independently selected from hydrogen and halogen.

11. The compound of formula (I) according to claim 10, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein: R⁵ is hydrogen; R⁷ is halogen; R⁸ is selected from hydrogen and halogen; and R^8a is hydrogen.

12. The compound of formula (I) according to claim 11, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein: R⁵ is hydrogen; R⁷ is selected from chloro and fluoro; R⁸ is selected from hydrogen and fluoro; and R^8a is hydrogen.

13. The compound of formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein: R^6a is selected from hydrogen and C1-C6-alkyl; and R^6b is hydrogen.

14. The compound of formula (I) according to claim 13, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein R^6a and R^6b are both hydrogen.

15. The compound of formula (I) according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein A is selected from: (i) phenyl; (ii) indanyl; (iii) a 5-membered heteroaryl selected from:

wherein a wavy line indicates the point of attachment of A to the remainder of formula (I); (iv) a 6-membered heteroaryl ; wherein U, V and W are each independently selected from CH and N, provided that at least one of U, V and W is N; and the wavy line indicates the point of attachment of A to the remainder of formula (I); (v) a 9-membered heteroaryl selected from:

wherein a wavy line indicates the point of attachment of A to the remainder of formula (I); (vi) bicyclo[1.1.1]pentanyl; and (vii) cubanyl.

16. The compound of formula (I) according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein A is selected from C₆-C₁₀-aryl and 5- to 14-membered heteroaryl.

17. The compound of formula (I) according to claim 16, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein A is selected from phenyl and thienyl.

18. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein: (i) X, Y and Z are CH; or (ii) X and Z are CH and Y is N; R¹ is hydrogen; R² is selected from hydrogen and C1-C6-alkyl; (i) R^3a and R^3b are each independently selected from hydrogen and C₁-C₆-alkyl; R^4a is selected from hydrogen, halogen, hydroxy, cyano, C₁-C₆-alkyl and hydroxy-C1-C6-alkyl; and R^4b is hydrogen; or (ii) R^3a and R^4a, taken together with the carbon atoms to which they are attached, form a C₃-C₆-cycloalkyl; and R^3b and R^4b are both hydrogen; (i) R⁵ is selected from hydrogen and halogen; and R⁷ is selected from hydrogen, halogen, cyano, C1-C6-alkyl, halo-C1-C6-alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy, and C₃-C₁₀-cycloalkyl; or (ii) R⁵ and R⁷, taken together with the carbon atoms to which they are attached, form a C3-C10-cycloalkenyl; R^6a is selected from hydrogen and C₁-C₆-alkyl; R^6b is hydrogen; R⁸ and R^8a are each independentlyselected from hydrogen and halogen; and A is selected from C₆-C₁₀-aryl and 5- to 14-membered heteroaryl.

19. The compound of formula (I) according to claim 18, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein: X and Z are CH; Y is N; R¹ is hydrogen; R² is hydrogen; R^3a and R^3b are both hydrogen; R^4a is selected from hydrogen, hydroxy, cyano, C₁-C₆-alkyl and hydroxy-C₁-C₆- alkyl; R^4b is hydrogen; R⁵ is hydrogen; R^6a and R^6b are both hydrogen; R⁷ is halogen; R⁸ is selected from hydrogen and halogen; R^8a is hydrogen; and A is selected from C6-C10-aryl and 5- to 14-membered heteroaryl.

20. The compound of formula (I) according to claim 19, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein: X and Z are CH; Y is N; R¹ is hydrogen; R² is hydrogen; R^3a and R^3b are both hydrogen; R^4a is selected from hydrogen, hydroxy, cyano, methyl, and hydroxymethyl; R^4b is hydrogen; R⁵ is hydrogen; R^6a and R^6b are both hydrogen; R⁷ is selected from chloro and fluoro; R⁸ is selected from hydrogen and fluoro; R^8a is hydrogen; and A is selected from phenyl and thienyl.

21. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein said compound of formula (I) is selected from: [3-(4-chlorophenyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [3-phenylpyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [5-bromospiro[indane-1,3'-pyrrolidine]-1'-yl]-[3-(4-pyridyl)-1H-pyrazol-5- yl]methanone; [3-(4-chlorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [3-(4-chlorophenyl)pyrrolidin-1-yl]-(4-methyl-3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(2-chlorophenyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [3-(3-chlorophenyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [3-(2-chloro-4-fluoro-phenyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5- yl]methanone; [3-(5-chloro-2-thienyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [3-(5-chloro-2-thienyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [2,2-dimethyl-4-phenyl-pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [3-(2-ethylphenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [(3R,4S)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol- 5-yl]methanone; [(3S,4R)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol- 5-yl]methanone; [3-(p-tolyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [3-(3,5-difluorophenyl)-3-fluoro-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; 4-[1-(3-pyridazin-4-yl-1H-pyrazole-5-carbonyl)pyrrolidin-3-yl]benzonitrile; [3-(3,4-difluorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; (3-pyridazin-4-yl-1H-pyrazol-5-yl)-[3-[3-(trifluoromethoxy)phenyl]pyrrolidin-1- yl]methanone; [3-(6-chloro-3-pyridyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(5-chloro-2-pyridyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3R,4S)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(3S,4R)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(3R,4R)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(3S,4S)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [3-(3,4-difluorophenyl)-3-fluoro-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [2,5-dimethyl-3-phenyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(2R,4R)-4-(4-fluorophenyl)-2-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(2S,4R)-4-(4-fluorophenyl)-2-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(3R)-3-(4-chlorophenyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [(3S)-3-(4-chlorophenyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [(3R)-3-(6-chloro-3-pyridyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5- yl]methanone; [(3S)-3-(6-chloro-3-pyridyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5- yl]methanone; [(3R,4S)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(3S,4R)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; (3-cyclobutylpyrrolidin-1-yl)-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; (3-cyclopropylpyrrolidin-1-yl)-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; 5-[1-(3-pyridazin-4-yl-1H-pyrazole-5-carbonyl)pyrrolidin-3-yl]thiophene-2- carbonitrile; [3-(benzothiophen-2-yl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; (3-imidazo[1,2-a]pyridin-6-ylpyrrolidin-1-yl)-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(2,2-difluoroindan-5-yl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1}-pyrazol-5- yl)methanone; [3-(2,3-dihydrobenzofuran-6-yl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(benzothiophen-6-yl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(1,3-benzoxazol-5-yl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(3-chloroisothiazol-5-yl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(4-chloro-2-thienyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(4-chlorophenyl)pyrrolidin-1-yl]-[4-(difluoromethoxy)-3-pyridazin-4-yl-1H- pyrazol-5-yl]methanone; [3-(4-chlorophenyl)pyrrolidin-1-yl]-(4-methoxy-3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(4-chlorophenyl)pyrrolidin-1-yl]-(4-cyclopropyl-3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; (3-pyridazin-4-yl-1H-pyrazol-5-yl)-[3-[2-(trifluoromethyl)thiazol-5-yl]pyrrolidin-1- yl]methanone; [3-(2-chlorothiazol-5-yl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(2-methylthiazol-5-yl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [5-(4-chlorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl]-[3-(4-pyridyl)-1H-pyrazol-5- yl]methanone; [3-(4-chlorophenyl)-2,3,3a,4,5,6,7,7a-octahydroindol-1-yl]-[3-(4-pyridyl)-1H- pyrazol-5-yl]methanone; [3-(3,4-difluoro-5-methoxy-phenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3R,4R)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(3S,4S)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [3-(4-chlorophenyl)pyrrolidin-1-yl]-(4-methoxy-3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(4-chlorophenyl)pyrrolidin-1-yl]-[3-(3-fluoro-4-pyridyl)-1H-pyrazol-5- yl]methanone; [3-(2-chlorothiazol-5-yl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(5-chlorothiazol-2-yl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(4-chloro-3-fluoro-phenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; 5-[1-(3-pyridazin-4-yl-1H-pyrazole-5-carbonyl)pyrrolidin-3-yl]thiophene-2- carbonitrile; [(3S)-3-(3,4-difluorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3R)-3-(3,4-difluorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3R)-3-(3,4-difluorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3S)-3-(3,4-difluorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [4-(4-chlorophenyl)-2-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(5-bromo-2-thienyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(5-methyl-2-thienyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(4-bromophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; (4-chloro-3-pyridazin-4-yl-1H-pyrazol-5-yl)-[3-(3,4-difluorophenyl)pyrrolidin-1- yl]methanone; [3-(4-methyl-2-thienyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; (4-chloro-3-pyridazin-4-yl-1H-pyrazol-5-yl)-[(3S)-3-(3,4-difluorophenyl)pyrrolidin- 1-yl]methanone; (4-chloro-3-pyridazin-4-yl-1H-pyrazol-5-yl)-[(3R)-3-(3,4-difluorophenyl)pyrrolidin- 1-yl]methanone; (4-chloro-3-pyridazin-4-yl-1H-pyrazol-5-yl)-[(3R)-3-(3,4-difluorophenyl)pyrrolidin- 1-yl]methanone; (4-chloro-3-pyridazin-4-yl-1H-pyrazol-5-yl)-[(3S)-3-(3,4-difluorophenyl)pyrrolidin- 1-yl]methanone; [3-(4-bromophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [(3R,4S)-3-(4-bromophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(3S,4R)-3-(4-bromophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(3S,4R)-3-(4-bromophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(3R,4S)-3-(4-bromophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [3-(benzothiophen-2-yl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(4-bromo-5-methyl-2-thienyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3S)-3-(4-chlorophenyl)pyrrolidin-1-yl]-[3-(3-methyl-4-pyridyl)-1H-pyrazol-5- yl]methanone; [(3R)-3-(4-chlorophenyl)pyrrolidin-1-yl]-[3-(3-methyl-4-pyridyl)-1H-pyrazol-5- yl]methanone; [(3R)-3-(4-chlorophenyl)pyrrolidin-1-yl]-[3-(3-methyl-4-pyridyl)-1H-pyrazol-5- yl]methanone; [(3S)-3-(4-chlorophenyl)pyrrolidin-1-yl]-[3-(3-methyl-4-pyridyl)-1H-pyrazol-5- yl]methanone; (4-bromo-3-pyridazin-4-yl-1H-pyrazol-5-yl)-[(3S)-3-(4-chlorophenyl)pyrrolidin-1- yl]methanone; (4-bromo-3-pyridazin-4-yl-1H-pyrazol-5-yl)-[(3R)-3-(4-chlorophenyl)pyrrolidin-1- yl]methanone; (4-bromo-3-pyridazin-4-yl-1H-pyrazol-5-yl)-[(3R)-3-(4-chlorophenyl)pyrrolidin-1- yl]methanone; (4-bromo-3-pyridazin-4-yl-1H-pyrazol-5-yl)-[(3S)-3-(4-chlorophenyl)pyrrolidin-1- yl]methanone; [(3R,4S)-3-(4-chlorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl- 1H-pyrazol-5-yl)methanone; [(3S,4R)-3-(4-chlorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl- 1H-pyrazol-5-yl)methanone; [(3S,4R)-3-(4-chlorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl- 1H-pyrazol-5-yl)methanone; [(3R,4S)-3-(4-chlorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl- 1H-pyrazol-5-yl)methanone; [3-[3-(difluoromethyl)-4-fluoro-phenyl]pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(3S)-3-(4-chlorophenyl)pyrrolidin-1-yl]-(4-fluoro-3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3R)-3-(4-chlorophenyl)pyrrolidin-1-yl]-(4-fluoro-3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3R)-3-(4-chlorophenyl)pyrrolidin-1-yl]-(4-fluoro-3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3S)-3-(4-chlorophenyl)pyrrolidin-1-yl]-(4-fluoro-3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3R,4S)-3-(4-chlorophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(3S,4R)-3-(4-chlorophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [3-(4-chlorophenyl)pyrrolidin-1-yl]-(4-cyclopropyl-3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3R,4S)-3-(4-chlorophenyl)-4-[(1S)-1-hydroxyethyl]pyrrolidin-1-yl]-(3-pyridazin- 4-yl-1H-pyrazol-5-yl)methanone; [(3R,4S)-3-(4-chlorophenyl)-4-[(1R)-1-hydroxyethyl]pyrrolidin-1-yl]-(3-pyridazin- 4-yl-1H-pyrazol-5-yl)methanone; [(3R,4S)-3-(4-chlorophenyl)-4-[(1R)-1-hydroxyethyl]pyrrolidin-1-yl]-(3-pyridazin- 4-yl-1H-pyrazol-5-yl)methanone; [(3R,4S)-3-(4-chlorophenyl)-4-[(1S)-1-hydroxyethyl]pyrrolidin-1-yl]-(3-pyridazin- 4-yl-1H-pyrazol-5-yl)methanone; [(3R)-3-(4-chloro-2-thienyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3S)-3-(4-chloro-2-thienyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3S)-3-(4-chloro-2-thienyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3R)-3-(4-chloro-2-thienyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3R,4S)-3-(3,4-difluorophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(3S,4R)-3-(3,4-difluorophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; (3S,4R)-4-(4-chlorophenyl)-1-(3-pyridazin-4-yl-1H-pyrazole-5- carbonyl)pyrrolidine-3-carbonitrile; (3R,4S)-4-(4-chlorophenyl)-1-(3-pyridazin-4-yl-1H-pyrazole-5- carbonyl)pyrrolidine-3-carbonitrile; (3R,4S)-4-(4-chlorophenyl)-1-(3-pyridazin-4-yl-1H-pyrazole-5- carbonyl)pyrrolidine-3-carbonitrile; (3S,4R)-4-(4-chlorophenyl)-1-(3-pyridazin-4-yl-1H-pyrazole-5- carbonyl)pyrrolidine-3-carbonitrile; [(3S,4R)-3-(3,4-difluorophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(3R,4S)-3-(3,4-difluorophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(3R,4S)-3-(4-chlorophenyl)-4-fluoro-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol- 5-yl)methanone; [(3S,4R)-3-(4-chlorophenyl)-4-fluoro-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol- 5-yl)methanone; [(3S,4R)-3-(4-chlorophenyl)-4-fluoro-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol- 5-yl)methanone; [(3R,4S)-3-(4-chlorophenyl)-4-fluoro-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol- 5-yl)methanone; [(3R,4S)-3-(3,4-difluorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4- yl-1H-pyrazol-5-yl)methanone; [(3S,4R)-3-(3,4-difluorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4- yl-1H-pyrazol-5-yl)methanone; [(3S,4R)-3-(3,4-difluorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4- yl-1H-pyrazol-5-yl)methanone; [(3R,4S)-3-(3,4-difluorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4- yl-1H-pyrazol-5-yl)methanone; and [3-(4-chlorophenyl)pyrrolidin-1-yl]-[3-(3-methoxy-4-pyridyl)-1H-pyrazol-5- yl]methanone.

22. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein said compound of formula (I) is selected from: [3-(4-chlorophenyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [3-phenylpyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [5-bromospiro[indane-1,3'-pyrrolidine]-1'-yl]-[3-(4-pyridyl)-1H-pyrazol-5- yl]methanone; [3-(4-chlorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [3-(4-chlorophenyl)pyrrolidin-1-yl]-(4-methyl-3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(2-chlorophenyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [3-(3-chlorophenyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [3-(2-chloro-4-fluoro-phenyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5- yl]methanone; [3-(5-chloro-2-thienyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [3-(5-chloro-2-thienyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [2,2-dimethyl-4-phenyl-pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [3-(2-ethylphenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [(3R,4S)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol- 5-yl]methanone; [(3S,4R)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol- 5-yl]methanone; [3-(p-tolyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [3-(3,5-difluorophenyl)-3-fluoro-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; 4-[1-(3-pyridazin-4-yl-1H-pyrazole-5-carbonyl)pyrrolidin-3-yl]benzonitrile; [3-(3,4-difluorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; (3-pyridazin-4-yl-1H-pyrazol-5-yl)-[3-[3-(trifluoromethoxy)phenyl]pyrrolidin-1- yl]methanone; [3-(6-chloro-3-pyridyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(5-chloro-2-pyridyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3R,4S)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(3S,4R)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(3R,4R)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(3S,4S)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [3-(3,4-difluorophenyl)-3-fluoro-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [2,5-dimethyl-3-phenyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(2R,4R)-4-(4-fluorophenyl)-2-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(2S,4R)-4-(4-fluorophenyl)-2-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(3R)-3-(4-chlorophenyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [(3S)-3-(4-chlorophenyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5-yl]methanone; [(3R)-3-(6-chloro-3-pyridyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5- yl]methanone; [(3S)-3-(6-chloro-3-pyridyl)pyrrolidin-1-yl]-[3-(4-pyridyl)-1H-pyrazol-5- yl]methanone; [(3R,4S)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(3S,4R)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [3-(4-chlorophenyl)-2,3,3a,4,5,6,7,7a-octahydroindol-1-yl]-[3-(4-pyridyl)-1H- pyrazol-5-yl]methanone; [3-(3,4-difluoro-5-methoxy-phenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3R,4R)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(3S,4S)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [3-(4-chlorophenyl)pyrrolidin-1-yl]-(4-methoxy-3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(4-chlorophenyl)pyrrolidin-1-yl]-[3-(3-fluoro-4-pyridyl)-1H-pyrazol-5- yl]methanone; [3-(2-chlorothiazol-5-yl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(5-chlorothiazol-2-yl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(4-chloro-3-fluoro-phenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; 5-[1-(3-pyridazin-4-yl-1H-pyrazole-5-carbonyl)pyrrolidin-3-yl]thiophene-2- carbonitrile; [(3S)-3-(3,4-difluorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3R)-3-(3,4-difluorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3R)-3-(3,4-difluorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3S)-3-(3,4-difluorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [4-(4-chlorophenyl)-2-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(5-bromo-2-thienyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(5-methyl-2-thienyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(4-bromophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; (4-chloro-3-pyridazin-4-yl-1H-pyrazol-5-yl)-[3-(3,4-difluorophenyl)pyrrolidin-1- yl]methanone; [3-(4-methyl-2-thienyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; (4-chloro-3-pyridazin-4-yl-1H-pyrazol-5-yl)-[(3S)-3-(3,4-difluorophenyl)pyrrolidin- 1-yl]methanone; (4-chloro-3-pyridazin-4-yl-1H-pyrazol-5-yl)-[(3R)-3-(3,4-difluorophenyl)pyrrolidin- 1-yl]methanone; (4-chloro-3-pyridazin-4-yl-1H-pyrazol-5-yl)-[(3R)-3-(3,4-difluorophenyl)pyrrolidin- 1-yl]methanone; (4-chloro-3-pyridazin-4-yl-1H-pyrazol-5-yl)-[(3S)-3-(3,4-difluorophenyl)pyrrolidin- 1-yl]methanone; [3-(4-bromophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [(3R,4S)-3-(4-bromophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(3S,4R)-3-(4-bromophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(3S,4R)-3-(4-bromophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(3R,4S)-3-(4-bromophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [3-(benzothiophen-2-yl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(4-bromo-5-methyl-2-thienyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3S)-3-(4-chlorophenyl)pyrrolidin-1-yl]-[3-(3-methyl-4-pyridyl)-1H-pyrazol-5- yl]methanone; [(3R)-3-(4-chlorophenyl)pyrrolidin-1-yl]-[3-(3-methyl-4-pyridyl)-1H-pyrazol-5- yl]methanone; [(3R)-3-(4-chlorophenyl)pyrrolidin-1-yl]-[3-(3-methyl-4-pyridyl)-1H-pyrazol-5- yl]methanone; [(3S)-3-(4-chlorophenyl)pyrrolidin-1-yl]-[3-(3-methyl-4-pyridyl)-1H-pyrazol-5- yl]methanone; (4-bromo-3-pyridazin-4-yl-1H-pyrazol-5-yl)-[(3S)-3-(4-chlorophenyl)pyrrolidin-1- yl]methanone; (4-bromo-3-pyridazin-4-yl-1H-pyrazol-5-yl)-[(3R)-3-(4-chlorophenyl)pyrrolidin-1- yl]methanone; (4-bromo-3-pyridazin-4-yl-1H-pyrazol-5-yl)-[(3R)-3-(4-chlorophenyl)pyrrolidin-1- yl]methanone; (4-bromo-3-pyridazin-4-yl-1H-pyrazol-5-yl)-[(3S)-3-(4-chlorophenyl)pyrrolidin-1- yl]methanone; [(3R,4S)-3-(4-chlorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl- 1H-pyrazol-5-yl)methanone; [(3S,4R)-3-(4-chlorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl- 1H-pyrazol-5-yl)methanone; [(3S,4R)-3-(4-chlorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl- 1H-pyrazol-5-yl)methanone; [(3R,4S)-3-(4-chlorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl- 1H-pyrazol-5-yl)methanone; [3-[3-(difluoromethyl)-4-fluoro-phenyl]pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(3S)-3-(4-chlorophenyl)pyrrolidin-1-yl]-(4-fluoro-3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3R)-3-(4-chlorophenyl)pyrrolidin-1-yl]-(4-fluoro-3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3R)-3-(4-chlorophenyl)pyrrolidin-1-yl]-(4-fluoro-3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3S)-3-(4-chlorophenyl)pyrrolidin-1-yl]-(4-fluoro-3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3R,4S)-3-(4-chlorophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(3S,4R)-3-(4-chlorophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [3-(4-chlorophenyl)pyrrolidin-1-yl]-(4-cyclopropyl-3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3R,4S)-3-(4-chlorophenyl)-4-[(1S)-1-hydroxyethyl]pyrrolidin-1-yl]-(3-pyridazin- 4-yl-1H-pyrazol-5-yl)methanone; [(3R,4S)-3-(4-chlorophenyl)-4-[(1R)-1-hydroxyethyl]pyrrolidin-1-yl]-(3-pyridazin- 4-yl-1H-pyrazol-5-yl)methanone; [(3R,4S)-3-(4-chlorophenyl)-4-[(1R)-1-hydroxyethyl]pyrrolidin-1-yl]-(3-pyridazin- 4-yl-1H-pyrazol-5-yl)methanone; [(3R,4S)-3-(4-chlorophenyl)-4-[(1S)-1-hydroxyethyl]pyrrolidin-1-yl]-(3-pyridazin- 4-yl-1H-pyrazol-5-yl)methanone; [(3R)-3-(4-chloro-2-thienyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3S)-3-(4-chloro-2-thienyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3S)-3-(4-chloro-2-thienyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3R)-3-(4-chloro-2-thienyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3R,4S)-3-(3,4-difluorophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(3S,4R)-3-(3,4-difluorophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; (3S,4R)-4-(4-chlorophenyl)-1-(3-pyridazin-4-yl-1H-pyrazole-5- carbonyl)pyrrolidine-3-carbonitrile; (3R,4S)-4-(4-chlorophenyl)-1-(3-pyridazin-4-yl-1H-pyrazole-5- carbonyl)pyrrolidine-3-carbonitrile; (3R,4S)-4-(4-chlorophenyl)-1-(3-pyridazin-4-yl-1H-pyrazole-5- carbonyl)pyrrolidine-3-carbonitrile; (3S,4R)-4-(4-chlorophenyl)-1-(3-pyridazin-4-yl-1H-pyrazole-5- carbonyl)pyrrolidine-3-carbonitrile; [(3S,4R)-3-(3,4-difluorophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(3R,4S)-3-(3,4-difluorophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(3R,4S)-3-(4-chlorophenyl)-4-fluoro-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol- 5-yl)methanone; [(3S,4R)-3-(4-chlorophenyl)-4-fluoro-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol- 5-yl)methanone; [(3S,4R)-3-(4-chlorophenyl)-4-fluoro-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol- 5-yl)methanone; [(3R,4S)-3-(4-chlorophenyl)-4-fluoro-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol- 5-yl)methanone; [(3R,4S)-3-(3,4-difluorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4- yl-1H-pyrazol-5-yl)methanone; [(3S,4R)-3-(3,4-difluorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4- yl-1H-pyrazol-5-yl)methanone; [(3S,4R)-3-(3,4-difluorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4- yl-1H-pyrazol-5-yl)methanone; [(3R,4S)-3-(3,4-difluorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4- yl-1H-pyrazol-5-yl)methanone; and [3-(4-chlorophenyl)pyrrolidin-1-yl]-[3-(3-methoxy-4-pyridyl)-1H-pyrazol-5- yl]methanone.

23. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein said compound of formula (I) is selected from: [3-(4-chlorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5-yl)methanone; [3-(5-chloro-2-thienyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [3-(3,4-difluorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; and [(3R,4S)-3-(4-chlorophenyl)-4-hydroxy-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(3S)-3-(3,4-difluorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3R)-3-(3,4-difluorophenyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H-pyrazol-5- yl)methanone; [(3R,4S)-3-(4-chlorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl- 1H-pyrazol-5-yl)methanone; [(3S,4R)-3-(4-chlorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4-yl- 1H-pyrazol-5-yl)methanone; [(3R,4S)-3-(4-chlorophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; [(3S,4R)-3-(4-chlorophenyl)-4-methyl-pyrrolidin-1-yl]-(3-pyridazin-4-yl-1H- pyrazol-5-yl)methanone; (3R,4S)-4-(4-chlorophenyl)-1-(3-pyridazin-4-yl-1H-pyrazole-5- carbonyl)pyrrolidine-3-carbonitrile; (3S,4R)-4-(4-chlorophenyl)-1-(3-pyridazin-4-yl-1H-pyrazole-5- carbonyl)pyrrolidine-3-carbonitrile; [(3S,4R)-3-(3,4-difluorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4- yl-1H-pyrazol-5-yl)methanone; [(3R,4S)-3-(3,4-difluorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-(3-pyridazin-4- yl-1H-pyrazol-5-yl)methanone.

24. The compound of formula (I) according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, or a tautomer thereof, for use as a therapeutically active substance.

25. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, or a tautomer thereof, and a therapeutically inert carrier.

26. A method of treating or preventing a condition associated with SARM1 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, or a tautomer thereof, or the pharmaceutical composition according to claim 25.

27. The method according to claim 26, wherein said condition associated with SARM1 is a condition affecting the nervous system, including the central nervous system and the peripheral nervous system.

28. The method according to claim 27, wherein said condition affecting the nervous system is neurodegenerative disorder.

29. The method according to claim 26, wherein said condition associated with SARM1 is selected from amyotrophic lateral sclerosis, spinal muscular atrophy, chemotherapy induced peripheral neuropathy, diabetes induced peripheral neuropathy, multiple sclerosis, Parkinson's disease, glaucoma, stroke, traumatic brain injury, and Charcot-Marie-Tooth disease.

30. A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, or a tautomer thereof, or a pharmaceutical composition according to claim 25, for use in a method according to any one of claims 26 to 29.

31. Use of a compound according to any one of claims 1 to 23, or of a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition according to claim 25, in a method according to any one of claims 26 to 29.

32. Use of a compound according to any one of claims 1 to 23, or of a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in a method according to any one of claims 26 to 29.

33. A process of manufacturing a compound of formula (I) according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, or a tautomer thereof, comprising: reacting a carboxylic acid 1, wherein X, Y, Z, R¹ and R² are as defined in claim 1,

with an amine 2, wherein R^3a, R^3b, R^4a, R^4b, R⁵, R^6a, R^6b, R⁷, R⁸, R^8a, and A are as defined in claim 1,

in the presence of a coupling reagent and a base, to form said compound of formula (I).

34. A compound of formula (I) according to any one of claims 1 to 23, when manufactured according to the process of claim 33.

35. The invention as described hereinbefore.