SARM1 inhibitors

Abstract

The invention provides compounds having the general formula (I) wherein A, L, X, Y, Z, V, W, and R1 to R4 are as described herein, compositions including the compounds, processes of manufacturing the compounds and methods of using the5 compounds in the treatment or prevention of diseases that are associated with SARM1.

Description

[0001] F. Hoffmann-La Roche AG, CH-4070 Basel, Switzerland

[0002] Case: P39448

[0003] SARM1 INHIBITORS

[0004] Field of the Invention

[0005] 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.

[0006]

[0007] of the Invention

[0008] 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.

[0009] of the Invention

[0010] In a first aspect, the present invention provides compounds of formula (I)

[0011] CNE / 24.09.2025

[0012]

[0013] wherein A, L, X, Y, Z, V, W, and R1to R4are as defined herein.

[0014] 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).

[0015] Detailed Description of the Invention

[0016] Definitions

[0017] 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.

[0018] 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 (“Ci-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 nonlimiting 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 (“Cs-io-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[4.2.0.02’5.03’8.04’7]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 nonlimiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cubanyl, l-bicyclo[l.l.l]pentanyl, norbornanyl, and l-bicyclo[2.2.2]octanyl. A particularly preferred, yet non-limiting example of cycloalkyl is cyclopropyl.

[0019] 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 (“Ci-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 nonlimiting example of alkoxy is methoxy.

[0020] 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-l -methylethoxy, and 3-fluoro-2-fluoro-propoxy. A particularly preferred, yet non-limiting example of haloalkoxy is trifluoromethoxy.

[0021] The term “halogen” or “halo” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0022] Preferably, the term “halogen” or “halo” refers to fluoro (F), chloro (Cl) or bromo (Br).

[0023] 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.

[0024] The term “hydroxy” refers to an -OH group.

[0025] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of 6 to 10 ring members (“Ce-Cio-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.

[0026] 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, l,3-benzoxazol-2-yl, benzothiophenyl, imidazo[l,2-a]pyridin-6-yl, l,3-benzoxazol-4-yl, 2,3-dihydrobenzofurane, l,3-benzoxazol-5-yl, l,3-benzoxazol-6-yl, l,3-benzoxazol-7-yl, 1H-indazol-3-yl, lH-indazol-4-yl, oxadiazolyl, pyrazolyl, triazolyl, isothiazolyl, thienyl, and tetrazolyl. A particularly preferred, yet non-limiting example of heteroaryl is pyridyl.

[0027] The term "heteroaryl oxy" refers to a heteroaryl group, as defined herein, bound to the parent moiety through an oxygen atom. A preferred, yet non-limiting example of heteroaryl oxy is pyridyl oxy.

[0028] 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.

[0029] 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 azeti din-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-l-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), imidazolinone, and morpholinyl.

[0030] 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 tri fluoromethyl.

[0031] 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.

[0032] 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.

[0033] The abbreviation “SARM1” refers to Sterile Alpha and TIR Motif Containing 1.

[0034] The term “treatment” or “treating” 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.

[0035] The term “prophylaxis” or “preventing” 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.

[0036] SARM1

[0037] 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 NATH, 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, el000300). 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).

[0038] 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.

[0039] 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 SARMl activity to ameliorate various neurological disorders associated with axonal loss.

[0040]

[0041] of the Invention

[0042] In a first aspect, the present invention provides a compound of formula (I)

[0043]

[0044] or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:

[0045] A is selected from the group consisting of Ce-Cio-aryl, Cs-Cio-cycloalkyl, 5- to 14- membered heteroaryl comprising 1 to 4 heteroatoms independently selected from N, O, and S, and 3- to 14-membered heterocyclyl comprising 1 to 4 heteroatoms independently selected from N, O, and S;

[0046] L is -(CH2)m- or -(CH2)n-X1-X2-(CH2)P-*; wherein the asterisk indicates the point of attachment of L to the pyrazole ring or to the 6-membered heteroaryl ring; m is 1, 2, or 3;

[0047] n is 0, 1, or 2;

[0048] p is 1 or 2;

[0049] V is selected from the group consisting of CHR5, NR6, O, and S;

[0050] W is CHR7or NR8; provided that when V is NR6, O or S, W is CHR7;

[0051] X, Y, and Z are each independently selected from CH and N, provided that at most two of X, Y, and Z are N;

[0052] (i) X1is selected from the group consisting of NRX1, O, SO2, and CRxlaRxlb; and X2is selected from the group consisting of NRX1, O, and CH2; or

[0053] (ii) X1is C=O and X2is NRX2; or

[0054] (iii) X1and X2, taken together, form an imine of formula -N=CRX2-; or

[0055] (iv) X1is CHRX1Cand X2is CHRX2a;

[0056] RX1is hydrogen or Ci-Ce-alkyl; Rxlais selected from the group consisting of hydroxy, halogen, Ci-Ce-alkyl, halo-Ci-Ce- alkyl, and 5- to 6-membered heteroaryloxy comprising 1 to 4 heteroatoms independently selected from N, O, and S; and Rxlbis hydrogen or halogen; or Rxlaand Rxlb, taken together with the carbon atom to which they are attached, form a C3- Cio-cycloalkyl or a 3- to 6-membered heterocyclyl comprising 1 to 4 heteroatoms independently selected from N, O, and S;

[0057] RX2is hydrogen or Ci-Ce-alkyl;

[0058] Rxlcand RX2a, taken together with the carbon atoms to which they are attached, form a C3- Cio-cycloalkyl;

[0059] R1is selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce-alkyl, halo- Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkoxy, and Cs-Cio-cycloalkyl;

[0060] R2and R3are each independently selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce-alkyl, halo-Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkoxy, and C3-C10- cycloalkyl; and

[0061] (i) R4, R5, R6, R7, and R8are each independently selected from the group consisting of hydrogen and Ci-Ce-alkyl; or

[0062] (ii) R4and R5or R6, taken together with the atoms to which they are attached, form a 5- to 6 membered heterocycle; and

[0063] R7and R8are selected from the group consisting of hydrogen and Ci-Ce-alkyl; or (iii) R4and R7or R8, taken together with the atoms to which they are attached, form a 5- to 6 membered heterocycle; and

[0064] R5and R6are selected from the group consisting of hydrogen and Ci-Ce-alkyl; or (iv) R4is selected from the group consisting of hydrogen and Ci-Ce-alkyl; and

[0065] R5or R6, and R7or R8, taken together with the atoms to which they are attached, form a 3- to 6-membered heterocycle.

[0066] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:

[0067] A is selected from the group consisting of Ce-Cio-aryl, Cs-Cio-cycloalkyl, 5- to 14- membered heteroaryl comprising 1 to 4 heteroatoms independently selected from N, O, and S, and 3- to 14-membered heterocyclyl comprising 1 to 4 heteroatoms independently selected from N, O, and S;

[0068] L is -(CH2)m- or -(CH2)n-X1-X2-(CH2)P-*; wherein the asterisk indicates the point of attachment of L to the pyrazole ring or to the 6-membered heteroaryl ring; m is 1, 2, or 3;

[0069] n is 0, 1, or 2;

[0070] p is 1 or 2;

[0071] V is selected from the group consisting of CHR5, NR6, O, and S;

[0072] W is CHR7or NR8; provided that when V is NR6, O or S, W is CHR7;

[0073] X, Y, and Z are each independently selected from CH and N, provided that at most two of X, Y, and Z are N;

[0074] (i) X1is selected from the group consisting of NRX1, SO2, and CRxlaRxlb; and X2is selected from the group consisting of NRX1, O, and CH2; or

[0075] (ii) X1is C=O and X2is NRX2; or

[0076] (iii) X1and X2, taken together, form an imine of formula -N=CRX2-; or

[0077] (iv) X1is CHRX1Cand X2is CHRX2a;

[0078] RX1is hydrogen or Ci-Ce-alkyl;

[0079] Rxlais selected from the group consisting of hydroxy, halogen, Ci-Ce-alkyl, halo-Ci-Ce- alkyl, and 5- to 6-membered heteroaryloxy comprising 1 to 4 heteroatoms independently selected from N, O, and S; and Rxlbis hydrogen or halogen; or Rxlaand Rxlb, taken together with the carbon atom to which they are attached, form a C3- Cio-cycloalkyl or a 3- to 6-membered heterocyclyl comprising 1 to 4 heteroatoms independently selected from N, O, and S;

[0080] RX2is hydrogen or Ci-Ce-alkyl;

[0081] Rxlcand RX2a, taken together with the carbon atoms to which they are attached, form a C3- Cio-cycloalkyl;

[0082] R1is selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce-alkyl, halo- Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkoxy, and Cs-Cio-cycloalkyl;

[0083] R2and R3are each independently selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce-alkyl, halo-Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkoxy, and C3-C10- cycloalkyl; and

[0084] (i) R4, R5, R6, R7, and R8are each independently selected from the group consisting of hydrogen and Ci-Ce-alkyl; or

[0085] (ii) R4and R5or R6, taken together with the atoms to which they are attached, form a 5- to 6 membered heterocycle; and

[0086] R7and R8are selected from the group consisting of hydrogen and Ci-Ce-alkyl; or (iii) R4and R7or R8, taken together with the atoms to which they are attached, form a 5- to 6 membered heterocycle; and R5and R6are selected from the group consisting of hydrogen and Ci-Ce-alkyl; or (iv) R4is selected from the group consisting of hydrogen and Ci-Ce-alkyl; and

[0087] R5or R6, and R7or R8, taken together with the atoms to which they are attached, form a 3- to 6-membered heterocycle.

[0088] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:

[0089] L is -(CH2)m- or -(CH2)n-X1-X2-(CH2)P-*; wherein the asterisk indicates the point of attachment of L to the pyrazole ring;

[0090] m is 2 or 3;

[0091] n is 0;

[0092] p is O or l;

[0093] (i) X1is NRX1or O; and X2is CH2; or

[0094] (ii) X1is C=O and X2is NRX2; or

[0095] (iii) X1and X2, taken together, form an imine of formula -N=CRX2-;

[0096] RX1is hydrogen; and

[0097] RX2is hydrogen or Ci-Ce-alkyl.

[0098] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:

[0099] L is -(CH2)m- or -(CH2)n-X1-X2-(CH2)P-*; wherein the asterisk indicates the point of attachment of L to the pyrazole ring;

[0100] m is 2 or 3;

[0101] n is 0;

[0102] P is 1;

[0103] (i) X1is NRX1; and X2is CH2; or

[0104] (ii) X1is C=O and X2is NRX2; or

[0105] (iii) X1and X2, taken together, form an imine of formula -N=CRX2-;

[0106] RX1is hydrogen; and

[0107] RX2is hydrogen or Ci-Ce-alkyl.

[0108] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:

[0109] L is -(CH2)m- or -(CH2)n-X1-X2-(CH2)P-*; wherein the asterisk indicates the point of attachment of L to the pyrazole ring; m is 2 or 3;

[0110] n is 0;

[0111] p is O or l;

[0112] (i) X1is NRX1or O; and X2is CH2; or

[0113] (ii) X1is C=O and X2is NRX2; or

[0114] (iii) X1and X2, taken together, form an imine of formula -N=CRX2-;

[0115] RX1is hydrogen; and

[0116] RX2is hydrogen or methyl.

[0117] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:

[0118] L is -(CH2)m- or -(CH2)n-X1-X2-(CH2)P-*; wherein the asterisk indicates the point of attachment of L to the pyrazole ring;

[0119] m is 2 or 3;

[0120] n is 0;

[0121] P is 1;

[0122] (i) X1is NRX1; and X2is CH2; or

[0123] (ii) X1is C=O and X2is NRX2; or

[0124] (iii) X1and X2, taken together, form an imine of formula -N=CRX2-;

[0125] RX1is hydrogen; and

[0126] RX2is hydrogen or methyl

[0127] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:

[0128] L is -(CH2)m- or -(CH2)n-X1-X2-(CH2)P-*; wherein the asterisk indicates the point of attachment of L to the pyrazole ring;

[0129] m is 2 or 3;

[0130] n is 0;

[0131] p is O or l;

[0132] (i) X1is NRX1or O; and X2is CH2; or

[0133] (ii) X1and X2, taken together, form an imine of formula -N=CRX2-;

[0134] RX1is hydrogen.

[0135] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein: L is -(CH2)m- or -(CH2)n-X1-X2-(CH2)P-*; wherein the asterisk indicates the point of attachment of L to the pyrazole ring;

[0136] m is 2 or 3;

[0137] n is 0;

[0138] p is O or l;

[0139] (i) X1is NRX1or O; and X2is CH2; or

[0140] (ii) X1and X2, taken together, form an imine of formula -N=CRX2-;

[0141] RX1is hydrogen.

[0142] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:

[0143] L is -(CH2)m- or -(CH2)n-X1-X2-(CH2)P-*; wherein the asterisk indicates the point of attachment of L to the pyrazole ring;

[0144] m is 2 or 3;

[0145] n is 0;

[0146] P is 1;

[0147] X1isNRxl;

[0148] X2is CH2; and

[0149] RX1is hydrogen.

[0150] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein L is selected from the group consisting of-(CH2)2- -(CH2)3-, and -NH(CH2)2-*; wherein the asterisk indicates the point of attachment of L to the pyrazole ring.

[0151] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:

[0152] (i) X, Y and Z are all CH; or

[0153] (ii) X is N; and Y and Z are both CH; or

[0154] (iii) Y is N; and X and Z are both CH.

[0155] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein X is N; and Y and Z are both CH. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein Y is N; and X and Z are both CH.

[0156] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein X, Y and Z are all CH.

[0157] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:

[0158] (i) V is CHR5;

[0159] W is CHR7;

[0160] R4is hydrogen;

[0161] R5is hydrogen; and

[0162] R7is hydrogen; or

[0163] (ii) V is CHR5;

[0164] W is NR8;

[0165] R4and R8, taken together with the atoms to which they are attached, form a 5- to 6- membered heterocycle; and

[0166] R5is hydrogen; or

[0167] (iii) V is CHR5;

[0168] W is CHR7;

[0169] R4and R7, taken together with the atoms to which they are attached, form a 5- to 6- membered heterocycle; and

[0170] R5is hydrogen.

[0171] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:

[0172] (i) V is CHR5;

[0173] W is CHR7;

[0174] R4is hydrogen;

[0175] R5is hydrogen; and

[0176] R7is hydrogen; or

[0177] (ii) V is CHR5;

[0178] W is NR8; R4and R8, taken together with the atoms to which they are attached, form an imidazolinone; and

[0179] R5is hydrogen; or

[0180] (iii) V is CHR5;

[0181] W is CHR7;

[0182] R4and R7, taken together with the atoms to which they are attached, form a pyrrolidinone; and

[0183] R5is hydrogen.

[0184] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:

[0185] (i) V is CHR5;

[0186] W is CHR7;

[0187] R4is hydrogen;

[0188] R5is hydrogen; and

[0189] R7is hydrogen; or

[0190] (ii) V is CHR5;

[0191] W is NR8;

[0192] R4and R8, taken together with the atoms to which they are attached, form a 5- to 6- membered heterocycle; and

[0193] R5is hydrogen.

[0194] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:

[0195] (i) V is CHR5;

[0196] W is CHR7;

[0197] R4is hydrogen;

[0198] R5is hydrogen; and

[0199] R7is hydrogen; or

[0200] (ii) V is CHR5;

[0201] W is NR8;

[0202] R4and R8, taken together with the atoms to which they are attached, form an imidazolinone; and

[0203] R5is hydrogen. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:

[0204] V is CHR5;

[0205] W is CHR7;

[0206] R4is hydrogen;

[0207] R5is hydrogen; and

[0208] R7is hydrogen.

[0209] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:

[0210] V is CHR5;

[0211] W is NR8;

[0212] R4and R8, taken together with the atoms to which they are attached, form an imidazolinone; and R5is hydrogen.

[0213] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:

[0214] V is CHR5;

[0215] W is CHR7;

[0216] R4is hydrogen;

[0217] R5is hydrogen; and

[0218] R7is hydrogen.

[0219] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein R1is hydrogen.

[0220] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:

[0221] A is Ce-Cio-aryl or 5- to 14-membered heteroaryl comprising 1 to 4 heteroatoms independently selected from N, O, and S;

[0222] R2is halogen or cyano; and

[0223] R3is hydrogen or halogen.

[0224] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein: A is phenyl or pyridyl;

[0225] R2is selected from the group consisting of fluoro, chloro, and cyano; and

[0226] R3is hydrogen or fluoro.

[0227] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:

[0228] A is Ce-Cio-aryl;

[0229] R2is halogen; and

[0230] R3is hydrogen or halogen.

[0231] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:

[0232] A is phenyl;

[0233] R2is fluoro or chloro; and

[0234] R3is hydrogen or fluoro.

[0235] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:

[0236] A is Ce-Cio-aryl or 5- to 14-membered heteroaryl comprising 1 to 4 heteroatoms independently selected from N, O, and S;

[0237] L is -(CH2)m- or -(CH2)n-X1-X2-(CH2)P-*; wherein the asterisk indicates the point of attachment of L to the pyrazole ring;

[0238] (i) X1is NRX1or O; and X2is CH2; or

[0239] (ii) X1is C=O and X2is NRX2; or

[0240] (iii) X1and X2, taken together, form an imine of formula -N=CRX2-;

[0241] RX1is hydrogen;

[0242] RX2is hydrogen or Ci-Ce-alkyl;

[0243] m is 2 or 3;

[0244] n is 0;

[0245] p is O or l;

[0246] (i) V is CHR5;

[0247] W is CHR7;

[0248] R4is hydrogen;

[0249] R5is hydrogen; and

[0250] R7is hydrogen; or (ii) V is CHR5;

[0251] W is NR8;

[0252] R4and R8, taken together with the atoms to which they are attached, form a 5- to 6- membered heterocycle; and

[0253] R5is hydrogen;

[0254] (i) X, Y and Z are all CH; or

[0255] (ii) X is N; and Y and Z are both CH; or

[0256] (iii) Y is N; and X and Z are both CH;

[0257] R1is hydrogen;

[0258] R2is halogen or cyano; and

[0259] R3is hydrogen or halogen.

[0260] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:

[0261] A is phenyl or pyridyl;

[0262] L is -(CH2)m- or -(CH2)n-X1-X2-(CH2)P-*; wherein the asterisk indicates the point of attachment of L to the pyrazole ring;

[0263] (i) X1is NRX1or O; and X2is CH2; or

[0264] (ii) X1is C=O and X2is NRX2; or

[0265] (iii) X1and X2, taken together, form an imine of formula -N=CRX2-;

[0266] RX1is hydrogen;

[0267] RX2is hydrogen or methyl;

[0268] m is 2 or 3;

[0269] n is 0;

[0270] p is O or l;

[0271] (i) V is CHR5;

[0272] W is CHR7;

[0273] R4is hydrogen;

[0274] R5is hydrogen; and

[0275] R7is hydrogen; or

[0276] (ii) V is CHR5;

[0277] W is NR8;

[0278] R4and R8, taken together with the atoms to which they are attached, form imidazolinone; and R5is hydrogen;

[0279] (i) X, Y and Z are all CH; or

[0280] (ii) X is N; and Y and Z are both CH; or

[0281] (iii) Y is N; and X and Z are both CH;

[0282] R1is hydrogen;

[0283] R2is selected from the group consisting of fluoro, chloro, and cyano; and

[0284] R3is hydrogen or fluoro.

[0285] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:

[0286] A is Ce-Cio-aryl;

[0287] L is -(CH2)m- or -(CH2)n-X1-X2-(CH2)P-*; wherein the asterisk indicates the point of attachment of L to the pyrazole ring;

[0288] X1isNRxl;

[0289] X2is CH2;

[0290] RX1is hydrogen;

[0291] m is 2 or 3;

[0292] n is 0;

[0293] P is 1;

[0294] V is CHR5;

[0295] W is CHR7;

[0296] X, Y and Z are all CH;

[0297] R1is hydrogen;

[0298] R2is halogen;

[0299] R3is hydrogen or halogen;

[0300] R4is hydrogen;

[0301] R5is hydrogen; and

[0302] R7is hydrogen.

[0303] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:

[0304] A is phenyl;

[0305] L is -(CH2)m- or -(CH2)n-X1-X2-(CH2)P-*; wherein the asterisk indicates the point of attachment of L to the pyrazole ring;

[0306] X1isNRxl; X2is CH2;

[0307] RX1is hydrogen;

[0308] m is 2 or 3;

[0309] n is 0;

[0310] P is 1;

[0311] V is CHR5;

[0312] W is CHR7;

[0313] X, Y and Z are all CH;

[0314] R1is hydrogen;

[0315] R2is fluoro or chloro;

[0316] R3is hydrogen or fluoro;

[0317] R4is hydrogen;

[0318] R5is hydrogen; and

[0319] R7is hydrogen.

[0320] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:

[0321] A is Ce-Cio-aryl or 5- to 14-membered heteroaryl comprising 1 to 4 heteroatoms independently selected from N, O, and S;

[0322] L is — (CH2)m— or -(CH2)n-X1-X2-(CH2)P-*; wherein the asterisk indicates the point of attachment of L to the pyrazole ring;

[0323] (i) X1is NRX1; and X2is CH2; or

[0324] (ii) X1is C=O and X2is NRX2; or

[0325] (iii) X1and X2, taken together, form an imine of formula -N=CRX2-;

[0326] RX1is hydrogen;

[0327] RX2is hydrogen or Ci-Ce-alkyl;

[0328] m is 2 or 3;

[0329] n is 0;

[0330] P is 1;

[0331] (i) V is CHR5;

[0332] W is CHR7;

[0333] R4is hydrogen;

[0334] R5is hydrogen; and

[0335] R7is hydrogen; or (ii) V is CHR5;

[0336] W is NR8;

[0337] R4and R8, taken together with the atoms to which they are attached, form a 5- to 6- membered heterocycle;

[0338] R5is hydrogen; or

[0339] (iii) V is CHR5;

[0340] W is CHR7;

[0341] R4and R7, taken together with the atoms to which they are attached, form a 5- to 6- membered heterocycle; and

[0342] R5is hydrogen;

[0343] (i) X, Y and Z are all CH; or

[0344] (ii) X is N; and Y and Z are both CH; or

[0345] (iii) Y is N; and X and Z are both CH;

[0346] R1is hydrogen;

[0347] R2is halogen or cyano; and

[0348] R3is hydrogen or halogen.

[0349] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:

[0350] A is phenyl or pyridyl;

[0351] L is -(CH2)m- or -(CH2)n-X1-X2-(CH2)P-*; wherein the asterisk indicates the point of attachment of L to the pyrazole ring;

[0352] (i) X1is NRX1; and X2is CH2; or

[0353] (ii) X1is C=O and X2is NRX2; or

[0354] (iii) X1and X2, taken together, form an imine of formula -N=CRX2-;

[0355] RX1is hydrogen;

[0356] RX2is hydrogen or methyl;

[0357] m is 2 or 3;

[0358] n is 0;

[0359] P is 1;

[0360] (i) V is CHR5;

[0361] W is CHR7;

[0362] R4is hydrogen;

[0363] R5is hydrogen; and R7is hydrogen; or

[0364] (ii) V is CHR5;

[0365] W is NR8;

[0366] R4and R8, taken together with the atoms to which they are attached, form imidazolinone; and

[0367] R5is hydrogen; or

[0368] (iii) V is CHR5;

[0369] W is CHR7;

[0370] R4and R7, taken together with the atoms to which they are attached, form a pyrrolidinone; and

[0371] R5is hydrogen;

[0372] (i) X, Y and Z are all CH; or

[0373] (ii) X is N; and Y and Z are both CH; or

[0374] (iii) Y is N; and X and Z are both CH;

[0375] R1is hydrogen;

[0376] R2is selected from the group consisting of fluoro, chloro, and cyano; and

[0377] R3is hydrogen or fluoro.

[0378] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:

[0379] A is Ce-Cio-aryl;

[0380] L is -(CH2)m- or -(CH2)n-X1-X2-(CH2)P-*; wherein the asterisk indicates the point of attachment of L to the pyrazole ring;

[0381] X1isNRxl;

[0382] X2is CH2;

[0383] RX1is hydrogen;

[0384] m is 2 or 3;

[0385] n is 0;

[0386] P is 1;

[0387] V is CHR5;

[0388] W is CHR7;

[0389] X, Y and Z are all CH;

[0390] R1is hydrogen;

[0391] R2is halogen; R3is hydrogen or halogen;

[0392] R4is hydrogen;

[0393] R5is hydrogen; and

[0394] R7is hydrogen.

[0395] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:

[0396] A is phenyl;

[0397] L is -(CH2)m- or -(CH2)n-X1-X2-(CH2)P-*; wherein the asterisk indicates the point of attachment of L to the pyrazole ring;

[0398] X1isNRxl;

[0399] X2is CH2;

[0400] RX1is hydrogen;

[0401] m is 2 or 3;

[0402] n is 0;

[0403] P is 1;

[0404] V is CHR5;

[0405] W is CHR7;

[0406] X, Y and Z are all CH;

[0407] R1is hydrogen;

[0408] R2is fluoro or chloro;

[0409] R3is hydrogen or fluoro;

[0410] R4is hydrogen;

[0411] R5is hydrogen; and

[0412] R7is hydrogen.

[0413] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, selected from:

[0414] 3-(4-Fluorophenyl)-N-(8-methyl-9-oxo-3,4,8,12-tetrazatricyclo[8.4.0.02,6]tetradeca- 1(10), 2, 5, 11, 13 -pentaen-5 -yl)propanamide;

[0415] 3-(4-Chlorophenyl)-N-(3,4,12-triazatricyclo[8.4.0.02,6]tetradeca-l(10),2,5,l l,13-pentaen-5- yl)propanamide;

[0416] 3-(4-Fluorophenyl)-N-(9-oxa-3,4,12-triazatricyclo[8.4.0.02,6]tetradeca-l(10),2,5,l 1,13-pentaen- 5-yl)propanamide;

[0417] 3-(4-Chlorophenyl)-N-(4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-3-yl)propanamide; 3-(6-Chloro-3-pyridyl)-N-(4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-3-yl)propanamide;

[0418] 3-(4-Chloro-3-fluoro-phenyl)-N-(4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-3-yl)propanamide; 3-(4-Chlorophenyl)-N-(4,5-dihydro-2H-pyrazolo[4,3-c][l,7]naphthyridin-3-yl)propanamide; 3-(4-Chlorophenyl)-N-(2H-pyrazolo[4,3-c][l,7]naphthyridin-3-yl)propanamide;

[0419] 3-(4-Cyanophenyl)-N-(3,4,9,12-tetrazatricyclo[8.4.0.02,6]tetradeca-l(10),2,5,ll,13-pentaen-5- yl)propanamide;

[0420] 3-(6-Chloro-3-pyridyl)-N-(3,4,9,12-tetrazatricyclo[8.4.0.02,6]tetradeca-l(10),2,5,ll,13-pentaen- 5-yl)propanamide;

[0421] 3-(4-Chlorophenyl)-N-(3,4,9,12-tetrazatricyclo[8.4.0.02,6]tetradeca-l(10),2,5,l l,13-pentaen-5- yl)propanamide;

[0422] rac-(3RS)-3-[(4-Chlorophenyl)methyl]-l-(4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-3- yl)pyrrolidin-2-one;2,2,2-trifluoroacetate;

[0423] l-[(4-Chlorophenyl)methyl]-3-(4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-3-yl)imidazolidin-2- one;2,2,2-trifluoroacetic acid;

[0424] 3-(4-Chlorophenyl)-N-(3,4,l l,12-tetrazatricyclo[8.4.0.02,6]tetradeca-l(10),2,5,l l,13-pentaen-5- yl)propanamide;

[0425] 3-(4-Chlorophenyl)-N-(4,5-dihydro-2H-pyrazolo[3,4-f]phthalazin-3-yl)propanamide; and 3-(6-Chloro-3-pyridyl)-N-(4,5-dihydro-2H-pyrazolo[3,4-f]phthalazin-3-yl)propanamide.

[0426] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, or a tautomer thereof, selected from: 3-(4-Chlorophenyl)-N-(3,4,12-triazatricyclo[8.4.0.02,6]tetradeca-l(10),2,5,l l,13-pentaen-5- yl)propanamide;

[0427] 3-(4-Chloro-3-fluoro-phenyl)-N-(4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-3-yl)propanamide; and

[0428] 3-(4-Chlorophenyl)-N-(3,4,9,12-tetrazatricyclo[8.4.0.02,6]tetradeca-l(10),2,5,l l,13-pentaen-5- yl)propanamide.

[0429] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, which is 3-(4-Chlorophenyl)-N-(3,4,12-triazatricyclo[8.4.0.02,6]tetradeca-l(10),2,5,ll,13-pentaen-5-yl)propanamide.

[0430] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, which is 3-(4-Chloro-3-fluoro-phenyl)-N-(4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-3-yl)propanamide. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, which is 3-(4-Chlorophenyl)-N-(3,4,9,12-tetrazatricyclo[8.4.0.02,6]tetradeca-l(10),2,5,ll,13-pentaen-5-yl)propanamide.

[0431] 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.

[0432] 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,nC,13C,14C,13N,15N,15O,17O,18O,31P,32P,35S,18F,36C1,123I, and125I, 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.

[0433] 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.

[0434] Substitution with positron emitting isotopes, such asnC,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0435] 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 nonlabeled reagent previously employed. Processes of Manufacturing

[0436] 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.

[0437] 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.

[0438] 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).

[0439] 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.

[0440] 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.

[0441] 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:

[0442] 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.

[0443] 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.

[0444] 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.

[0445] The following abbreviations are used in the present text:

[0446] °C = degree(s) Celsius; ACN = acetonitrile; AcOH = acetic acid; Ar = Argon; aq. = aqeous; Boc = tert-butyl oxy carbonyl;lBuOI< = potassium tert-butoxide; CO2 = carbon dioxide; DCM = dichloromethane; DEA = diethylamine; DIPEA = A,A-diisopropylethylamine; DMF = N,N-dimethylformamide; equiv. = equivalent(s); ESI = electrospray ionization; EtOAc = ethyl acetate; EtOH = ethanol; FA = formic acid; FC = flash chromatography; g = gram(s); h = hour(s); HATU = l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate; HC1 = hydrogen chloride; HPLC = high performance liquid chromatography; K2CO3 = potassium carbonate; LiHMDS = Lithium bis(trimethylsilyl)amide; M = molar(s); MeOH = methanol; 2-Me-THF = 2-methyltetrahydrofuran; mg = milligram(s); min = minute(s); MgSCU = magnesium sulfate; mL = milliliter(s); mm = millimeter(s); MS = mass spectrum; MW = microwave oven; m / z = mass-to-charge ratio; mmol = millimole(s); N2 = nitrogen; NaH = sodium hydride; NaHCCE = sodium bicarbonate; ISfeSCU = sodium sulfate; NH3 = ammonia; NH4CI = ammonium chloride; NIS = N-iodosuccinimide; nm = nanometer(s); NMP = A-methylpyrrolidone; Pd(OAc)2 = Palladium(II) acetate; PG = protecting group; prep-TLC = preparative thin layer chromatography; SFC = supercritical fluid chromatography; SiCh = silicon dioxide; SPhos = dicyclohexyl(2',6'-dimethoxy[l,l'-biphenyl]-2-yl)phosphane; SPhos Pd G3 = (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl) [2-(2'-amino-l, 1 '-biphenyl)]palladium(II) methanesulfonate; T3P® = propylphosphonic anhydride; TEA = triethylamine; TFA = trifluoroacetic acid; THF = tetrahydrofuran; tR = retention time; TsOH = 4-methylbenzene-l-sulfonic acid; wt% = weight percent; pL = microliter(s); pm = micrometer(s).

[0447] Compounds of general formula (I) can be prepared from amines of general formula 1 and carboxylic acids of general formula 2, in an amide coupling using a coupling agent such as but not limited to T3P® in the presence of a base (e.g. DIPEA) and a polar solvent such as DMF (Scheme 1). When not commercially available, building blocks 1 and 2 can be prepared as described in the schemes below. In some instances, compounds of general formula (I) bearing a protecting group were deprotected to still give a compound of general formula (I), using a suitable deprotection method known to a person skilled in the art.

[0448]

[0449] Scheme 1

[0450] Alternatively, compounds of general formula (I) can be prepared from halides 3 (X = Br, I) and amides 4 in an Ullmann-type coupling, using a base such as CS2CO3, a ligand (e.g. phenanthroline), a copper source (e.g. [Bu4NCul2]2) in 1,4-di oxane, at elevated temperatures (Scheme 2). When not commercially available, building blocks 3 and 4 can be prepared as described in the schemes below. In some instances, compounds of general formula (I) bearing a protecting group were deprotected to still give a compound of general formula (I), using a suitable deprotection method known to a person skilled in the art.

[0451]

[0452] Scheme 2

[0453] Amines of general formula 1 where L = -(CH2)n-X1-X2-(CH2)P-*, in which n = 0, X1= C=O, X2= NMe and p = 1, depicted in Scheme 3 as amines 5, can be prepared from carboxylic acids 6 and methylamine 7 via an amide coupling, using e.g. but not limited to DIPEA and HATU in a solvent such as DCM, giving amides 8. Upon treatment with a base such as tBuOK, amides 8 undergoes a cyclization, to give intermediates 9. Intermediates 9 gives amines of formula 5 upon treatment with hydrazine hydrate at elevated temperatures, in a solvent such as NMP.

[0454]

[0455] Scheme 3

[0456] Alternatively, amines of general formula 1 where L = -(CH2)m-, in which m = 3, depicted in Scheme 4 as amine 10, can be prepared from bromoaryl 11. A Negishi cross-coupling between bromoaryls 11 and zincate 12 using e.g. SPhos and Pd(OAc)2 or SPhos Pd G3 in THF, at 80 °C in the microwave, yields intermediates 13. Cyclization of 13 upon treatment with a base such as LiHMDS in THF or in THF / ethylbenzene at -78 °C gives a-cyano-ketones 14. Upon treatment of a-cyano-ketones 14 with hydrazine hydrate in EtOH at elevated temperatures, aminopyrazoles 10 can be obtained.

[0457]

[0458] Scheme 4

[0459] Alternatively, amines of general formula 1 where L = -(CH2)n-X1-X2-(CH2)P-* where n = 0, X1= O, X2= CH2, and p = 1, depicted in Scheme 5 as amines 15, can be prepared from hydroxyls 16 and alkyl bromide 17 in an alkylation reaction, using a base such as K2CO3 in a solvent such as ACN, to give (9-alkylation products 18. Cyclization of 18 using a base such as LiHMDS in THF affords a-cyano-ketones 19. Upon treatment of a-cyano-ketones 19 with hydrazine hydrate in THF at elevated temperatures, aminopyrazoles 15 can be obtained.

[0460]

[0461] Scheme 5

[0462] Alternatively, amines of general formula 1 where L = -(CH2)m-, in which m = 2, depicted in Scheme 6 as amines 20, can be prepared starting from commercially available ketones 21. Ketones 21 can be converted to a-cyano-ketones 22 upon treatment with a base such as LiHMDS in THF followed by addition of tosylformonitrile. Upon treatment of a-cyano-ketones 22 with hydrazine hydrate in EtOH at elevated temperatures, aminopyrazoles 20 can be obtained.

[0463]

[0464] Scheme 6

[0465] Alternatively, amines of general formula 1 where L = -(CH2)n-X1-X2-(CH2)P-*, in which n = 0, X1= N-PG, X2= CH2, p = 0, depicted in Scheme 7 as amines 23, can be prepared starting from commercially available ketones 25. Ketones 25 can be converted to a-cyano-ketones 24 upon treatment with a base such as NaH in DMF followed by addition of acrylonitrile. Upon treatment of a-cyano-ketones 24 with hydrazine hydrate in 1-BuOH at elevated temperatures, aminopyrazoles 23 can be obtained.

[0466]

[0467] Scheme 7

[0468] Alternatively, amines of general formula 1 where L = -(CH2)n-X1-X2-(CH2)P-*, in which n = 0, X1= N-PG, X2= CH2, p = 1, depicted in Scheme 8 as amines 26, can be prepared starting from commercially available protected amines 27. A-Alkylation of alkyl bromide 17 by amines 27 affords A-alkylation products 28, using a base such as NaH in a solvent such as THF. Cyclization of 28 using a base such as LiHMDS in THF affords a-cyano-ketones 29. Upon treatment of a-cyano-ketones 29 with hydrazine hydrate in THF at elevated temperatures, aminopyrazoles 26 can be obtained.

[0469]

[0470] Scheme 8

[0471] Compounds of general formula 3, where L = -(CH2)m- in which m = 2, depicted in Scheme 9 as compound 30, can be prepared from commercially available a a,P-unsaturated ketones 31.

[0472] Treatment of compounds 31 with hydrazine hydrate in 1,4-di oxane at elevated temperature affords the corresponding pyrazoles 32. Iodination of pyrazoles 32 with NIS in DCM at elevated temperature in the MW (pressure build-up should be monitored with care) affords the iodinated pyrazoles 33. A protection step, e.g. with 3,4-dihydropyran in THF in the presence of an acid such as TsOH affords the corresponding protected pyrazoles 30. It should be noted that other suitable protecting groups can be introduced using methods known to a person skilled in the art.

[0473]

[0474] Scheme 9

[0475] Compounds of general formula (I), where L = -(CH2)n-X1-X2-(CH2)P-*, in which n and p = 0, X1and X2, taken together, form an imine of formula -N=CRX2-, and RX2= hydrogen, depicted in Scheme 10 as imine 34, can be isolated as a by-product of a deprotection step of protected amines 35, upon treatment with an acid such as TFA.

[0476]

[0477] Scheme 10

[0478] 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, wherein the process is as described in any one of Schemes 1 to 10 above, or a combination thereof.

[0479] 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.

[0480] SARM1 Inhibitory Activity

[0481] 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.

[0482] 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.

[0483] 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.

[0484] 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.

[0485] Enzymatic reactions were ran in a 10 pL volume consisting of 8nM human SARM1 (aa28-724), 100 pM Nicotinamide (NMN) and 30 pM Nicotinamide Adenine Dinculeotide (NAD). Assay reagents were prepared in 25 mM HEPES pH 7.2, 50 mM NaCl, 1 mM EDTA and 0.0025% Tween20. To determine compound ICso’s, reactions were incubated for 60minutes at room temperature in the presence of a 12-point concentration response curve of compound (starting concentration lOOp M; 1 in 3 dilution between each point; 2% DMSO) and then quenched with 40 pL 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.

[0486] 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.

[0487] Table 1

[0488]

[0489]

[0490] the Compounds of the Invention

[0491] 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.

[0492] 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.

[0493] 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.

[0494] 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.

[0495] 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.

[0496] 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.

[0497] In one embodiment, said condition affecting the nervous system is neurodegenerative disorder.

[0498] 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.

[0499] In a particularly preferred embodiment, said condition associated with SARM1 is amyotrophic lateral sclerosis.

[0500] In a particularly preferred embodiment, said condition associated with SARM1 is spinal muscular atrophy.

[0501] In a particularly preferred embodiment, said condition associated with SARM1 is chemotherapy induced peripheral neuropathy.

[0502] In a particularly preferred embodiment, said condition associated with SARM1 is diabetes induced peripheral neuropathy.

[0503] In a particularly preferred embodiment, said condition associated with SARM1 is multiple sclerosis.

[0504] Pharmaceutical Compositions and Administration

[0505] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier.

[0506] In one embodiment, there is provided a pharmaceutical composition according to Example 17 or 18.

[0507] 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, dragees, 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).

[0508] 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, dragees 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, dragees and hard gelatin capsules.

[0509] Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid substances and liquid polyols, etc.

[0510] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.

[0511] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

[0512] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semisolid or liquid polyols, etc.

[0513] Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, viscosityincreasing 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.

[0514] 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.

[0515] 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.

[0516] 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.

[0517] 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 tetrahydrofuran ring can be either cis or trans and was assigned arbitrarily.

[0518] All reaction examples and intermediates were prepared under an argon atmosphere if not specified otherwise.

[0519] 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.

[0520] Example 1

[0521] 3-(4-Fluorophenyl)-N-(8-methyl-9-oxo-3,4,8,12-tetrazatricyclo[8.4.0.02,6Jtetradeca- 1 (10),2,5,ll,13-pentaen-5-yl)propananude

[0522]

[0523] Step a): Methyl 3-[2-cyanoethyl(methyl)carbamoyl]pyridine-4-carboxylate

[0524] To a solution of 4-(methoxycarbonyl)nicotinic acid (CAS RN: 24202-74-2, 2.00 g, 11.04 mmol, 1.00 equiv.) inDCM (30 mL) was added 3-(methylamino)propanenitrile (CAS RN: 693-05-0, 1.02 g, 12.14mmol, 1.10 equiv.), DIPEA (3.85 mL, 22.08 mmol, 2.00 equiv.) and HATU (6.30 g, 16.56 mmol, 1.50 equiv.). The mixture was stirred at 20 °C for 2 h before being poured into water and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated. The residue was purified by FC (SiCh; petroleum ether / EtOAc) to give the title compound (1.20 g, 44% yield) as a colorless oil. MS (ESI): m / z = 248.1 [M+H]+.

[0525] Step b): rac-(6RS)-8-Methyl-5,9-dioxo-6, 7-dihydropyrido[3,4-c]azepine-6-carbonitrile

[0526] To a solution of methyl 3-[2-cyanoethyl(methyl)carbamoyl]pyridine-4-carboxylate (1.20 g, 4.85 mmol, 1.00 equiv.) in THF (12 mL) was added t-BuOK (1 M in THF) (7.3 mL, 7.28 mmol, 1.50 equiv.) at 0 °C. The mixture was stirred at 0 °C for 1 h before being evaporated. Purification by prep-HPLC (Phenomenex Luna Cl 8, 10 pm, 150 x 25 mm; ACN / water (FA)) gave the title compound (200 mg, 19% yield) as a dark red solid. MS (ESI): m / z = 216.1 [M+H]+.

[0527] Step c) : 5-Amino-8-methyl-3, 4, 8, 12-tetrazatricyclo[ 8.4.0.02, 6] tetradeca- 1( 10),2,5,ll, 13-pentaen-9-one

[0528] To a solution of ?LC,-(6^S>)-8-methyl-5,9-dioxo-6,7-dihydropyrido[ 3,4-c]azepine-6-carbonitrile (150 mg, 0.70 mmol, 1.00 equiv.) in NMP (6.0 mL) was added hydrazine hydrate (279 mg, 5.58 mmol, 8.00 equiv.) at 25 °C. The mixture was stirred at 110 °C for 4 h before being purified by prep-HPLC (Waters Xbridge, 5 pm, 150 x 25 mm; ACN / water (ammonia hydroxide v / v)), to give the title compound (135 mg, 33% yield) as a yellow oil. MS (ESI): m / z = 230.2 [M+H]+.

[0529] Step d): 3-( 4-Fluorophenyl)-N-(8-methyl-9-oxo-3, 4, 8, 12-tetrazatricyclo[ 8.4.0.02, 6]tetradeca- 1 (10), 2, 5, 11, 13-pentaen-5-yl)propanamide

[0530]

[0531] To a solution of 3-(4-fluorophenyl)propanoic acid (CAS RN: 459-31-4, 119 mg, 0.71 mmol, 1.20 equiv.), 5-amino-8-methyl-3,4,8,12-tetrazatricyclo[8.4.0.02’6]tetradeca-l(10),2,5,l 1,13-pentaen-9-one (135 mg, 0.59 mmol, 1.00 equiv.), and DIPEA (0.31 mL, 1.77 mmol, 3.00 equiv.) in DMF (3 mL) was added T3P® (50 wt% in EtOAc) (562 mg, 0.88 mmol, 1.50 equiv.). The mixture was stirred at 25 °C for 1 h before being purified by prep-HPLC (Phenomenex Luna Cl 8, 10 pm, 150 x 25 mm; ACN / water (FA)), to give the title compound (1.5 mg, 1% yield) as a white solid. MS (ESI): m / z = 380.1 [M+H]+.

[0532] Example 2

[0533] 3-(4-Chlorophenyl)-N-(3,4,12-triazatricyclo[8.4.0.02,6]tetradeca-l (10),2,5,ll,13-pentaen-5-yl)propanamide

[0534]

[0535] Step a): Ethyl 3-(4-cyanobutyl)pyridine-4-carboxylate

[0536] To a solution of 3-bromoisonicotinic acid ethyl ester (CAS RN: 13959-01-8, 300 mg, 1.30 mmol, 1.00 equiv.) in THF (2.6 mL) was added palladium (II) acetate (20 mg, 0.09 mmol, 0.07 equiv.) and SPhos (CAS RN: 657408-07-6, 54 mg, 0.13 mmol, 0.10 equiv.) in a microwave vial. Three vacuum / argon cycles were performed before bromo(4-cyanobutyl)zinc (0.5 M in THF) (CAS RN: 226570-68-9, 3.9 mL, 1.96 mmol, 1.50 equiv.) was added. The vial was sealed and the mixture was heated to 80 °C and stirred for 2 h at this temperature. The mixture was quenched with saturated aq. NH4CI- solution and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and evaporated. Purification by FC (SiCh; DCM / MeOH) gave the title compound (230 mg, 65% yield) as a yellow oil. MS (ESI): m / z = 233.2 [M+H]+.

[0537] Step b): rac-(6RS)-5-Oxo-6, 7,8,9-tetrahydrocyclohepta[c]pyridine-6-carbonitrile

[0538] To a solution of ethyl 3-(4-cyanobutyl)pyridine-4-carboxylate (223 mg, 0.83 mmol, 1.00 equiv.) in THF (8.3 mL) was added dropwise LiHMDS (1 M in THF / ethylbenzene) (1.2 mL, 1.24 mmol, 1.50 equiv.) at -78 °C. The mixture was stirred at -78 °C for 1 h before being slowly warmed up to 23 °C, quenched with saturated aq. NH4Cl-solution and evaporated. Purification by FC (SiCL; DCM / MeOH) gave the title compound (129 mg, 82% yield) as a yellow solid. MS (ESI): m / z = 187.1 [M+H]+.

[0539] Step c): 3, 4, 12-Triazatricyclo [8.4.0.02,6]tetradeca-l(l 0), 2, 5,11, 13-pentaen-5-amine

[0540] To a solution of rac-(6RS)-5-oxo-6,7,8,9-tetrahydrocyclohepta[c]pyridine-6-carbonitrile (124 mg, 0.67 mmol, 1.00 equiv.) in EtOH (3.3 mL) was added hydrazine (35 wt% in water) (0.299 mL, 3.33 mmol, 5.00 equiv.) at room temperature. The resulting mixture was heated to 80 °C and stirred for 30 h at this temperature. After cooling down to 23 °C, the solvent was evaporated and the residue was dissolved in THF before saturated aq. TMLCl-solution was added. The resulting biphasic solution was evaporated. Purification by FC (SiCh; DCM / MeOH) gave the title compound (86 mg, 64% yield) as a yellow oil. MS (ESI): m / z = 201.2 [M+H]+. Step d): 3-(4-Chlorophenyl)-N-(3, 4, 12-triazatricyclo[8.4.0.02,6]tetradeca- 1(10), 2,5,11, 13-pentaen-5-yl)propanamide

[0541]

[0542] To a solution of 3-(4-chlorophenyl)propanoic acid (CAS RN: 2019-34-3, 29 mg, 0.15 mmol, 1.00 equiv.) inDMF (0.52 mL) was added T3P® (50 wt% inEtOAc) (0.138 mL, 0.23 mmol, 1.50 equiv.) followed by 3,4,12-triazatricyclo[8.4.0.02’6]tetradeca-l(10),2,5,ll,13-pentaen-5-amine (31 mg, 0.15 mmol, 1.00 equiv.) and DIPEA (0.054 mL, 0.31 mmol, 2.00 equiv.). The mixture was stirred at 23 °C for 1 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 (SiCh; DCM / MeOH) gave the title compound (19 mg, 34% yield) as a white solid. MS (ESI): m / z = 367.2 [M+H]+.

[0543] Example 3

[0544] 3-(4-Fluorophenyl)-N-(9-oxa-3,4,12-triazatricyclo[8.4.0.02’6]tetradeca-l (10), 2, 5, 11,13-pentaen-5-yl)propanainide

[0545]

[0546] Step a): Methyl 3-(3-cyanopropoxy)pyridine-4-carboxylate

[0547] To a solution of methyl 3-hydroxyisonicotinate (CAS RN: 10128-72-0, 1.00 g, 6.53 mmol, 1.00 equiv.) in ACN (20 mL) was added K2CO3 (1.35 g, 9.79 mmol, 1.50 equiv.) followed by 4-bromo butyronitrile (CAS RN: 5332-06-9, 1.16 g, 7.84 mmol, 1.20 equiv.). The mixture was stirred at 65 °C for 12 h, before being evaporated. Purification by FC (SiCh; petroleum ether / EtOAc) gave the title compound (800 mg, 56% yield) as a yellow oil. MS (ESI): m / z = 221.0 [M+H]+.

[0548] Step b): rac-( 4RS) -5-Oxo-3, 4-dihydro-2H-oxepino[ 2, 3-c ]pyridine-4-carbonitrile To a solution of methyl 3 -(3 -cyanopropoxy )pyridine-4-carboxylate (1.40 g, 6.36 mmol, 1.00 equiv.) in THF (42 mL) was added dropwise LiHMDS (1 M in THF) (13 mL, 12.71 mmol, 2.00 equiv.) under N2. The mixture was stirred at 25 °C for 1 h. The mixture was quenched by addition of NH4CI before being poured into water and extracted three times with EtOAc. The aqueous layer was purified by prep-HPLC and lyophilized to give the title compound (800 mg, 67% yield) as a yellow solid. MS (ESI): m / z = 189.5 [M+H]+.

[0549] Step c): 9-Oxa-3,4, 12-triazatricyclo[8.4. O.Q2’6]tetradeca-l(10),2,5, 11, 13-pentaen-5-amine

[0550] To a solution of rac-(4RS)-5-oxo-3,4-dihydro-2H-oxepino[2,3-c]pyridine-4-carbonitrile (700 mg, 3.72 mmol, 1.00 equiv.) in THF (35 mL) was added hydrazine hydrate (372 mg, 7.44 mmol, 2.00 equiv.) at 25 °C .The mixture was stirred at 70 °C for 12 h. The mixture was poured into water and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and evaporated. Purification by FC (SiO2; DCM / MeOH) gave the title compound (550 mg, 73% yield) as a yellow oil. MS (ESI): m / z = 203.0 [M+H]+.

[0551] Step d) : 3-(4-Fluorophenyl)-N-( 9-oxa-3, 4, 12-triazatricyclo[ 8.4.0.02' ] tetradeca- 1 (10), 2, 5,11,13-pentaen-5-yl)propanamide

[0552]

[0553] The title compound was prepared in analogy to Example 1, step d) starting from 9-oxa-3,4,12-triazatricyclo[8.4.0.02’6]tetradeca-l(10),2,5,l l,13-pentaen-5-amine and 3-(4-fluorophenyl)propanoic acid (CAS RN: 459-31-4) as a white solid. MS (ESI): m / z = 353.1 [M+H]+.

[0554] Example 4

[0555] 3-(4-Chlorophenyl)-N-(4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-3-yl)propananude

[0556]

[0557] Step a): rac-(6RS)-5-Oxo-7,8-dihydro-6H-isoquinoline-6-carbonitrile

[0558] To a solution of 7,8-dihydro-6H-isoquinolin-5-one (CAS RN: 21917-86-2, 3.61 g, 24.29 mmol, 1.00 equiv.) in THF (65 mL) was added LiHMDS (1 M in THF / ethylbenzene) (49 mL, 48.59 mmol, 2.00 equiv.) at -78 °C. The resulting solution was stirred at -40 °C for 1 h, following by the addition of tosylformonitrile (CAS RN: 19158-51-1, 8.8 g, 48.59 mmol, 2.00 equiv.) in THF (30 mL). The mixture was stirred at -40 °C for 1 h before being quenched with saturated aq. NH4CI-solution and evaporated. The resulting residue was purified by FC (SiCL; DCM / MeOH) to give the title compound (2.47 g, 58% yield) as a yellow powder. MS (ESI): m / z = 173.1 [M+H]+.

[0559] Step b): 4,5-Dihydro-2H-pyrazolo[3,4-f]isoquinolin-3-amine

[0560] To a solution of rac-(6RS)-5-oxo-7,8-dihydro-6H-isoquinoline-6-carbonitrile (2.47 g, 14.2 mmol, I.00 equiv.) in EtOH (140 mL) was added hydrazine (35 wt% in water) (15 mL, 167.2 mmol, I I.78 equiv.) at 23 °C. The resulting mixture was heated to 80 °C and stirred at this temperature for 32 h. Additional hydrazine (35 wt% in water) (10 mL, 111.5 mmol, 7.85 equiv.) was added and the solution was heated to 80 °C and stirred at this temperature for 2 days. The mixture was quenched with 2 M aq. HCl-solution and evaporated. Purification by FC (SiCh; DCM / MeOH) gave the title compound (1.40 g, 50% yield) as a yellow oil. MS (ESI): m / z = 187.1 [M+H]+.

[0561] Step c) : 3-(4-Chlorophenyl)-N-( 4, 5-dihydro-2H-pyrazolo[ 3, 4-f]isoquinolin-3-yl)propanamide

[0562]

[0563] To a solution 3-(4-chlorophenyl)propanoic acid (CAS RN: 2019-34-3,51.56 mg, 0.28 mmol, 1.30 equiv.) inDMF (1.0 mL) was added DIPEA (0.112 mL, 0.64 mmol, 3.00 equiv.) followed by T3P® (50 wt% in EtOAc) (0.166 mL, 0.28 mmol, 1.30 equiv.). The mixture was stirred at 23 °C for 5 min before being treated with 4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-3-amine (40 mg, 0.21 mmol, 1.00 equiv.). The mixture was stirred at 23 °C for 18 h before being purified by prep-HPLC (Gemini NX, 5 pm, 100 x 30 mm; ACN / water + 0.1% TEA) to give the title compound (9 mg, 12% yield) as an off-white solid. MS (ESI): m / z = 353.1 [M+H]+.

[0564] Example 5

[0565] 3-(6-Chloro-3-pyridyl)-N-(4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-3-yl)propanamide

[0566]

[0567] The title compound was prepared in analogy to Example 4, step c) starting from 4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-3-amine and 3-(6-chloro-3-pyridyl)propanoic acid (CAS RN: 117528-23-1), and isolated as a light yellow powder. MS (ESI): m / z = 354.2 [M+H]+.

[0568] Example 6

[0569] 3-(4-Chloro-3-fluoro-phenyl)-N-(4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-3-yl)propananude

[0570]

[0571] The title compound was prepared in analogy to Example 4, step c) starting from 4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-3 -amine and 3-(4-chloro-3-fluoro-phenyl)propanoic acid (CAS RN: 881189-65-7) and isolated as an off-white solid. MS (ESI): m / z = 371.1 [M+H]+.

[0572] Example 7

[0573] 3-(4-Chlorophenyl)-N-(4,5-dihydro-2H-pyrazolo[4,3-c][l,7]naphthyridin-3-yl)propananude

[0574]

[0575] Step a): tert-Butyl rac-(3RS)-3-cyano-4-oxo-2,3-dihydro-l, 7 -naphthyridine-1 -carboxylate To a solution of methyl 3-( / c / 7-butoxycarbonylamino)pyridine-4-carboxylate (CAS RN: 854381-91-2, 1.50 g, 5.95 mmol, 1.00 equiv.) in DMF (54 mL) was added NaH (60% dispersion in mineral oil) (250 mg, 6.24 mmol, 1.05 equiv.) at 0 °C. The mixture was stirred at 0 °C for 30 min before being treated with acrylonitrile (CAS RN: 107-13-1, 0.411 mL, 6.24 mmol, 1.05 equiv.). The mixture was stirred at 0 °C for 30 min and at 23 °C for 18 h. The mixture was quenched with saturated aq. NH4CI- solution and volatiles were evaporated. Purification by FC (SiCL; DCM / MeOH) followed by SFC (column achiral 2-EP, 5 pm, 250 x 20 mm; 24% MeOH) gave the title compound (217 mg, 13% yield) as a yellow powder. MS (ESI): m / z = 274.3 [M+H]+.

[0576] Step b): tert-Butyl 3-amino-2,4-dihydropyrazolo[4,3-c][l,7]naphthyridine-5-carboxylate

[0577] To a solution of tert-butyl rac-(3RS)-3-cyano-4-oxo-2,3-dihydro-l, 7 -naphthyridine-1 -carboxylate (215 mg, 0.77 mmol, 1.00 equiv.) in 1-butanol (2 mL) was added hydrazine (35 wt% in water) (1.04 mL, 11.56 mmol, 15.00 equiv.). The reaction vial was sealed and the mixture was stirred at 100 °C for 18 h. Volatiles were evaporated. Purification by prep-HPLC (Gemini NX, 5 pm, 100 x 30 mm; ACN / water + 0.1% FA) gave the title compound (36 mg, 14% yield, 85% purity) as a yellow solid. MS (ESI): m / z = 288.3 [M+H]+.

[0578] Step c): tert-Butyl 3-[3-(4-chlorophenyl)propanoylamino]-2,4-dihydropyrazolo[4,3-c][l,7 ]naphthyridine-5-carboxylate

[0579] To a solution of 3-(4-chlorophenyl)propanoic acid (CAS RN: 2019-34-3, 39 mg, 0.21 mmol, 1.20 equiv.) in DMF (1 mL) was added DIPEA (0.046 mL, 0.26 mmol, 1.50 equiv.) followed by T3P® (50 wt% in EtOAc) (133 mg, 0.21 mmol, 1.20 equiv.). The mixture was stirred at 23 °C for 15 min before being treated with tert-butyl 3-amino-2,4-dihydropyrazolo[4,3-c][l,7]naphthyridine-5-carboxylate (50 mg, 0.174 mmol, 1.00 equiv.). The mixture was stirred at 23 °C for 18 h before being poured into DCM and washed with saturated aq. NH4CI- solution. The aqueous layer was back-extracted with DCM. The combined organic layers were dried over Na2SC>4 and evaporated. Purification by FC (SiCh; DCM / MeOH) gave the title compound (26 mg, 31% yield) as a light yellow gum. MS (ESI): m / z = 454.4 [M+H]+.

[0580] Step d): 3-(4-Chlorophenyl)-N-(4,5-dihydro-2H-pyrazolo[4,3-c] [l,7]naphthyridin-3-yl)propanamide

[0581]

[0582] To a solution of tert-butyl 3-[3-(4-chlorophenyl)propanoylamino]-2,4-dihydropyrazolo[4,3-c][l,7]naphthyridine-5-carboxylate (26 mg, 0.06 mmol, 1.00 equiv.) in DCM (0.50 mL) was added TFA (0.044 mL, 0.57 mmol, 10.00 equiv.) and the mixture was stirred at 23 °C for 18 h, before being evaporated. The crude product was purified by prep-HPLC (Gemini NX, 5 pm, 100 x 30 mm; ACN / water + 0.1% TEA). The isolated product was repurified by SFC (column chiral Torus2pic, 5 pm, 250 x 20 mm; 33% MeOH + 0.2% DEA) to give the title compound (7 mg, 32% yield, 90% purity) as a white solid. MS (ESI): m / z = 354.3 [M+H]+.

[0583] Example 8

[0584] 3-(4-Chlorophenyl)-N-(2H-pyrazolo[4,3-c][l,7]naphthyridin-3-yl)propananude

[0585]

[0586] To a solution of tert-butyl 3-[3-(4-chlorophenyl)propanoylamino]-2,4-dihydropyrazolo[4,3-c][l,7]naphthyridine-5-carboxylate (26 mg, 0.06 mmol, 1.00 equiv.) in DCM (0.50 mL) was added TFA (0.044 mL, 0.57 mmol, 10.00 equiv.) and the mixture was stirred at 23 °C for 18 h, before being evaporated. The crude product was purified by prep-HPLC (Gemini NX, 5 pm, 100 x 30 mm; ACN / water + 0.1% TEA). The isolated product was repurified by SFC (column chiral Torus2pic, 5 pm, 250 x 20 mm; 33% MeOH + 0.2% DEA) to give the title compound (2 mg, 10% yield, 95% purity) as a colorless gum. MS (ESI): m / z = 352.2 [M+H]+.

[0587] Example 9

[0588] 3-(4-Cyanophenyl)-N-(3,4,9,12-tetrazatricyclo[8.4.0.02,6]tetradeca-l (10),2,5,ll,13-pentaen-5-yl)propanamide

[0589]

[0590] Step a): Methyl 3-[tert-butoxycarbonyl(3-cyanopropyl)amino]pyridine-4-carboxylate

[0591] To a solution of methyl 3-(tert-butoxycarbonylamino)pyridine-4-carboxylate (CAS RN: 854381-91-2, 280 mg, 1.11 mmol, 1.00 equiv.)inTHF (5 mL) was added NaH (60% dispersion in mineral oil) (47 mg, 1.17 mmol, 1.05 equiv.) at 0 °C. The mixture was stirred at 0 °C for 30 min before being treated with 4-bromobutyronitrile (CAS RN: 5332-06-9,172 mg, 1.17 mmol, 1.05 equiv.). The mixture was warmed up to 23 °C and stirred for 18 h at this temperature. DMF (1 mL) was added and the mixture was stirred at 23 °C for 1 h and at 50 °C for 18 h. NaH (60% dispersion in mineral oil) (11 mg, 0.28 mmol, 0.25 equiv.) and 4-bromobutyronitrile (172 mg, 1.17 mmol, 1.05 equiv.) were added. The mixture was stirred at 60 °C for 18 h before being quenched with saturated aq. NT Cl-solution and extracted with EtOAc. The aqueous layer was back-extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and evaporated. Purification by SFC (column achiral PBT, 5 pm, 250 x 30 mm; 5% MeOH) gave the title compound (105 mg, 28% yield) as a colorless gum. MS (ESI): m / z = 320.3 [M+H]+.

[0592] Step b): tert-Butyl rac-(4RS)-4-cyano-5-oxo-3,4-dihydro-2H-pyrido[3,4-b]azepine-l-carboxylate

[0593] To a solution of methyl 3-[tert-butoxycarbonyl(3-cyanopropyl)amino]pyridine-4-carboxylate (1.20 g, 3.76 mmol, 1.00 equiv.) in THF (37 mL) was added dropwise LiHMDS (1.5 M in THF) (3.8 mL, 5.64 mmol, 1.50 equiv.) at -78 °C. The mixture was stirred at -78 °C for 1 h before being quenched with saturated aq. NH4CI- solution at -78 °C and allowed to slowly warm up to 23 °C. Volatiles were removed in vacuo. Purification by FC (SiCL; DCM / MeOH) gave the title compound (805 mg, 67% yield, 90% purity) as a yellow gum. MS (ESI): m / z = 288.2 [M+H]+.

[0594] Step c): tert-Butyl 5-amino-3,4,9,12-tetrazatricyclo[8.4.0.026]tetradeca-l(10),2,5,l 1,13-pentaene-9-carboxylate

[0595] To a solution of tert-butyl rac-(4RS)-4-cyano-5-oxo-3,4-dihydro-2H-pyrido[3,4-b]azepine-l- carboxylate (800 mg, 2.78 mmol, 1.00 equiv.) in ethanol (6.5 mL) was added hydrazine (35 wt% in water) (3.75 mL, 41.77 mmol, 15.00 equiv.). The reaction vial was sealed and the mixture was stirred at 70 °C for 78 h. Volatiles were removed in vacuo. Purification by FC (SiCL; DCM / MeOH) gave the title compound (657 mg, 74% yield) as a light yellow solid. MS (ESI): m / z = 302.3 [M+H]+.

[0596] Step d): tert-Butyl 5-[3-(4-cyanophenyl)propanoylamino]-3,4,9,12- tetr azatricyclo [ 8.4.0.02, 6]tetradeca-l(l 0), 2, 5, 11, 13-pentaene-9-carboxylate

[0597] The title compound was prepared in analogy to Example 7, step c) starting from tert-butyl 5-amino- 3,4,9,12-tetrazatricyclo[8.4.0.02’6]tetradeca-l(10),2,5,ll,13-pentaene-9-carboxylate and 3-(4- cyanophenyl)propanoic acid (CAS RN: 42287-94-5) as a white gum. MS (ESI): m / z = 459.4 [M+H]+. Step e ) : 3-(4-Cyanophenyl)-N-( 3, 4, 9, 12-tetrazatricyclo[ 8.4.0.02, 6]tetradeca-l (10), 2, 5,11,13-pentaen-5-yl)propanamide

[0598]

[0599] The title compound was prepared in analogy to Example 7, step d) starting from tert-butyl 5-[3- (4-cyanophenyl)propanoylamino]-3,4,9,12-tetrazatricyclo[8.4.0.02’6]tetradeca-l(10),2,5,ll,13-pentaene-9-carboxylate and TFA as a colorless gum. MS (ESI): m / z = 359.3 [M+H]+.

[0600] Example 10

[0601] 3-(6-Chloro-3-pyridyl)-N-(3, 4, 9, 12-tetrazatricyclo[8.4.0.026]tetradeca-l (10),2, 5, 11,13-pentaen- 5-yl)propanamide

[0602]

[0603] Step a): tert-Butyl 5-[3-(6-chloro-3-pyridyl)propanoylamino]-3,4,9,12- tetr azatricyclo [ 8.4.0.02, 6]tetradeca-l(l 0), 2, 5, 11, 13-pentaene-9-carboxylate

[0604] The title compound was prepared in analogy to Example 7, step c) starting from tert-butyl 5-amino- 3,4,9,12-tetrazatricyclo[8.4.0.02’6]tetradeca-l(10),2,5,ll,13-pentaene-9-carboxylate and 3-(6- chi oro-3 -pyridyl)propanoic acid (CAS RN: 117528-23-1) as an off-white solid. MS (ESI): m / z = 469.4 [M+H]+.

[0605] Step b): 3-( 6-Chloro-3-pyridyl)-N-( 3, 4, 9, 12-tetrazatricyclo[8.4.0.02,6]tetradeca-l(l 0), 2, 5,11, 13-pentaen-5-yl)propanamide (ELN045439-375)

[0606]

[0607] The title compound was prepared in analogy to Example 7, step d) starting from tert-butyl 5-[3- (6-chloro-3-pyridyl)propanoylamino]-3,4,9,12-tetrazatricyclo[8.4.0.02’6]tetradeca- l(10),2,5,ll,13-pentaene-9-carboxylate and TFA as a colorless gum. MS (ESI): m / z = 369.3 [M+H]+.

[0608] Example 11

[0609] 3-(4-Chlorophenyl)-N-(3,4,9,12-tetrazatricyclo[8.4.0.02’6]tetradeca-l (10),2,5,ll,13-pentaen-5-yl)propanamide

[0610]

[0611] Step a): tert-Butyl 5-[3-(4-chlorophenyl)propanoylamino]-3,4,9,12- tetr azatricyclo [ 8.4.0.02, 6]tetradeca-l(l 0), 2, 5, 11, 13-pentaene-9-carboxylate

[0612] The title compound was prepared in analogy to Example 7, step c) starting from tert-butyl 5-amino- 3,4,9,12-tetrazatricyclo[8.4.0.02’6]tetradeca-l(10),2,5,ll,13-pentaene-9-carboxylate and 3-(4- chlorophenyl)propanoic acid (CAS RN: 2019-34-3) as an off-white solid. MS (ESI): m / z = 468.4 [M+H]+.

[0613] Step b): 3-(4-Chlorophenyl)-N-(3, 4,9, 12-tetr azatricyclo [8.4.0.02,6]tetradeca-l(10),2,5, 11,13-pentaen-5-yl)propanamide

[0614]

[0615] The title compound was prepared in analogy to Example 7, step d) starting from tert-butyl 5-[3-(4-chlorophenyl)propanoylamino]-3,4,9,12-tetrazatricyclo[8.4.0.02’6]tetradeca-l(10),2,5,l 1,13-pentaene-9-carboxylate and TFA as a colorless gum. MS (ESI): m / z = 368.3 [M+H]+.

[0616] Example 12

[0617] rac-(3RS)-3-[(4-Chlorophenyl)methyl]-l-(4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-3-yl)pyrrolidin-2-one;2,2,2-trifluoroacetate

[0618]

[0619] Step a): 4, 5-Dihydr o-2H-pyrazolo[ 3, 4-j] isoquinoline

[0620] To a solution of (6E)-6-(dimethylaminomethylene)-7,8-dihydroisoquinolin-5-one (CAS RN: 209741-61-7, 4.00 g, 19.78 mmol, 1.00 equiv.) in 1,4-dioxane (40 mL) was added hydrazine hydrate (1.98 g, 39.56 mmol, 2.00 equiv.). The mixture was stirred at 80 °C for 4 h. The reaction was quenched with 12 mL of NH4CI -solution, poured into water and extracted with EtOAc. The combined extracts were washed with brine, dried over ISfeSCU, filtered and evaporated to give the title compound (3.00 g, 17.52 mmol, 89% yield) as a brown oil that was used as such in the next reaction without any further purification. MS (ESI): m / z = 172.1 [M+H]+.

[0621] Step b): 3-Iodo-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline

[0622] To a solution of 4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline (2.50 g, 14.6 mmol, 1.00 equiv.) in DCM (45 mL) was added NIS (3.60 g, 16.06 mmol, 1.10 equiv.). The mixture was stirred at 130 °C for 30 min under microwave irradiation before being concentrated under reduced pressure. Purification by FC (SiCh; petroleum ether / EtOAc) gave the title compound (1.60 g, 5.39 mmol, 37% yield) as a yellow solid. MS (ESI): m / z = 297.9 [M+H]+.

[0623] Step c) : rac-3-Iodo-2-[ ( 2RS)-tetrahydropyran-2-yl ]-4, 5-dihydropyrazolo [ 3, 4-j] isoquinoline To a solution of 3-iodo-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline (500 mg, 1.68 mmol, 1.00 equiv.) and dihydropyrane (CAS RN: 110-87-2 , 1.36 mL, 14.86 mmol, 8.83 equiv.) in THF (7 mL) was added TsOH (190 mg, 1.10 mmol, 0.66 equiv.). The mixture was stirred at 80 °C for 12 h, before being evaporated. Purification by FC (SiO?; petroleum ether / EtOAc) gave the title compound (400 mg, 62% yield) as a yellow solid. MS (ESI): m / z = 382.1 [M+H]+.

[0624] Step d) : 3-[(4-Chlorophenyl)methyl ]-l-(2-tetrahydropyran-2-yl-4, 5-dihydropyrazolo [ 3, 4-j]isoquinolin-3-yl)pyrrolidin-2-one

[0625] To a solution of rac-3-iodo-2-[(2RS)-tetrahydropyran-2-yl]-4,5-dihydropyrazolo[3,4-j] isoquinoline (218 mg, 0.57 mmol, 1.50 equiv.) and 3-[(4-chlorophenyl)methyl]pyrrolidin-2-one (CAS RN: 356558-20-8, 80 mg, 0.38 mmol, 1.00 equiv.), CS2CO3 (248 mg, 0.76 mmol, 2.00 equiv.), phenanthroline (18 mg, 0.10 mmol, 0.27 equiv.) in 1,4-dioxane (2.0 mL) was added [Bu4NCuI2]2 (56.88 mg, 0.05 mmol, 0.13 equiv.). The mixture was stirred at 120 °C for 12 h before being evaporated. Purification by prep-TLC (SiCh; petroleum ether / EtOAc) gave the title compound (150 mg, 68% yield, 80% purity) as a yellow oil. MS (ESI): m / z = 463.1 [M+H]+. Step e): rac-(3RS)-3-[(4-Chlorophenyl)methyl]-l-(4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-3-yl)pyrrolidin-2-one;2, 2, 2-trifhioroacetate

[0626]

[0627] To a solution of 3-[(4-chlorophenyl)methyl]-l-(2-tetrahydropyran-2-yl-4,5-dihydropyrazolo[3,4- f]isoquinolin-3-yl)pyrrolidin-2-one (150 mg, 0.32 mmol, 1.00 equiv.) inDCM (4.0 mL) was added TFA (0.8 mL, 0.61 mmol, 1.88 equiv.). The mixture was stirred at 25 °C for 1 h before being evaporated. Purification by prep-HPLC (Phenomenex Luna C 18, 10 pm, 150x25 mm; ACN / water (TFA)) gave the title compound (18 mg, 14% yield) as a yellow solid. MS (ESI): m / z = 379.1 [M+H]+. Example 13

[0628] 1 -[(4- Chlorophenyl) methyl]-3-(4, 5-dihydro-2H-pyrazolo[3, 4-f]isoquinolin-3-yl) inudazolidin-2-one;2,2,2-trifluoroacetic acid

[0629]

[0630] Step a) : rac-l-[ ( 4-Chloropheny I) methyl ]-3-[ 2-[ ( 2RS)-tetrahydropyran-2-yl ]-4, 5-dihydropyrazolo[ 3, 4-f]isoquinolin-3-yl ]imidazolidin-2-one

[0631] To a solution of l-[(4-chlorophenyl)methyl]imidazolidin-2-one (CAS RN: 60927-95-9, 62 mg, 0.30 mmol, 1.50 equiv.) and rac-3-iodo-2-[(2RS)-tetrahydropyran-2-yl]-4,5-dihydropyrazolo [ 3, 4-f] isoquinoline (75 mg, 0.20 mmol, 1.00 equiv.), phenanthroline (14 mg, 0.08 mmol, 0.40 equiv.), CS2CO3 (192 mg, 0.59 mmol, 3.00 equiv.) in 1,4-dioxane (3.0 mL) was added [BU4NCUI2]2 (44 mg, 0.04 mmol, 0.20 equiv.). The mixture was stirred under nitrogen atmosphere at 120 °C for 12 h before being evaporated. Purification by prep-TLC (SiO2; petroleum ether / EtOAc) gave the title compound (80 mg, 88% yield) as a yellow oil. MS (ESI): m / z = 464.3 [M+H]+.

[0632] Step b): l-[ ( 4-Chlorophenyl)methyl -3-( 4, 5-dihydro-2H-pyrazolo[ 3, 4-f]isoquinolin-3-yl)imidazolidin-2-one;2, 2, 2 -trifluoroacetic acid

[0633]

[0634] To a solution of rac-l-[(4-chlorophenyl)methyl]-3-[2-[(2RS)-tetrahydropyran-2-yl]-4,5-dihydropyrazolo[3,4-f]isoquinolin-3-yl]imidazolidin-2-one (80 mg, 0.17 mmol, 1.00 equiv.) in DCM (2.0 mL) was added TFA (0.4 mL, 0.17 mmol, 1.00 equiv.). The mixture was stirred at 25 °C for 1 h before being evaporated. Purification by prep-HPLC (Phenom enex Luna Cl 8, 10 pm, 150 x 25 mm; ACN / water (FA)) gave the title compound (24 mg, 37% yield) as a yellow solid. MS (ESI): m / z = 380.1 [M+H]+.

[0635] Example 14

[0636] 3-(4-Chlorophenyl)-N-(3,4,ll,12-tetrazatricyclo[8.4.0.02,6Jtetradeca-1 (10),2,5,ll,13-pentaen-5-yl)propanamide

[0637]

[0638] Step a): Ethyl 3-(4-cyanobutyl)pyridazine-4-carboxylate

[0639] A vial was charged with ethyl 3-chloropyridazine-4-carboxylate (CAS RN: 1445-54-1, 2.50 g, 13.4 mmol, 1.00 equiv.) and SPhos Pd G3 (261 mg, 0.33 mmol, 0.03 equiv.). Three vacuum / argon cycles were performed before THF (25 mL) was added followed by bromo(4-cyanobutyl)zinc (0.5 M solution in THF) (CAS RN: 226570-68-9, 34.8 mL, 17.4 mmol, 1.30 equiv.). The mixture was stirred at 60 °C for 4 h before being poured onto saturated aq. TMLCl-solutionZEtOAc and extracted three times with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and evaporated. Purification by FC (SiCL; heptane / (EtOAc:EtOH 3:1)) gave the title compound (2.28 g, 71% yield) as an orange viscous oil. MS (ESI): m / z = 234.2 [M+H]+.

[0640] Step b): rac-(6RS)-5-Oxo-6, 7,8,9-tetrahydrocyclohepta[c]pyridazine-6-carbonitrile

[0641] To a solution of ethyl 3-(4-cyanobutyl)pyridazine-4-carboxylate (2.25 g, 9.65 mmol, 1.00 equiv.) in THF (68 mL) was added dropwise LiHMDS (1 M solution in THF) (12.5 mL, 12.5 mmol, 1.30 equiv.) at -78 °C. The mixture was stirred at -78 °C for 1 h before being quenched with saturated aq. NH4Cl-solution and then allowed to slowly warm up to 23 °C. Volatiles were removed in vacuo. Purification by FC (SiCL; DCM / MeOH) gave the title compound (2.40 g, 99% yield, 75% purity) as an orange gum, which was used without further purification. MS (ESI): m / z = 188.1 [M+H]+.

[0642] Step c): 3, 4, 11, 12-tetrazatricyclo[ 8.4.0.02, 6] tetradeca- 1 (10), 2, 5, 11, 13-pentaen-5-amine

[0643] To a solution of rac-(6RS)-5-oxo-6,7,8,9-tetrahydrocyclohepta[c]pyridazine-6-carbonitrile (2.39 g, 9.58 mmol, 1.00 equiv., 75% purity) in EtOH (30 mL) was added hydrazine (35 wt% in water) (6.9 mL, 76.6 mmol, 8.00 equiv.) and acetic acid (0.82 mL, 14.4 mmol, 1.50 equiv.). The mixture was stirred at 75 °C for 18 h, before being evaporated. Purification by FC (SiCh; (DCM / MeOH (25% aq. NH3)) gave the title compound (1.23 g, 60% yield) as a yellow solid. MS (ESI): m / z = 202.2 [M+H]+.

[0644] Step d): 3-(4-Chlorophenyl)-N-(3,4, 11, 12-tetr azatricyclo [8.4.0.02,6tetradeca-1 (10), 2, 5, 11,13-pentaen-5-yl)propanamide

[0645]

[0646] The title compound was prepared in analogy to Example 7, step c) starting from 3,4,11,12-tetrazatricyclo[8.4.0.02’6]tetradeca-l(10),2,5,l l,13-pentaen-5-amine and 3-(4- chlorophenyl)propanoic acid (CAS RN: 2019-34-3) as a white solid. MS (ESI): m / z = 368.3 [M+H]+.

[0647] Example 15

[0648] 3-(4-Chlorophenyl)-N-(4,5-dihydro-2H-pyrazolo[3,4-f]phthalazin-3-yl)propananude

[0649]

[0650] Step a): rac-( 6RS) -5 -Oxo- 7, 8-dihydro-6H -phthalazine-6-carbonitrile

[0651] To a solution of 7,8-dihydro-6H-phthalazin-5-one (CAS RN: 1823337-10-5, 1.00 g, 6.75 mmol, 1.00 equiv.) in THF (12 mL) was added dropwise LiHMDS (IM solution in THF) (15.5 mL, 15.5 mmol, 2.30 equiv.) at -78 °C. The mixture was stirred at -78 °C for 1 h before a solution of p-tolylsulfonylformonitrile (CAS RN: 19158-51-1,1.59 g, 8.77 mmol, 1.30 equiv.) in THF (6.0 mL) was added. The mixture was stirred at -78 °C for 3 h before being quenched with water. The reaction volume was reduced in vacuo. Purification by FC (SiCh; DCM / MeOH) followed by further purification by SFC (Achiral Taurus 2PIC, CO2 / MeOH) gave the title compound (306 mg, 22% yield, 85% purity) as an orange solid. MS (ESI): m / z = 174.1 [M+H]+. Step b): 4,5-Dihydro-2H-pyrazolo[3,4-f]phthalazin-3-amine

[0652] To a solution of rac-(6RS)-5-oxo-7,8-dihydro-6H-phthalazine-6-carbonitrile (300 mg, 1.47 mmol, 1.00 equiv., 85% purity) in EtOH (8.0 mL) was added hydrazine (35 wt% in water) (1.06 mL, 11.8 mmol, 8.00 equiv.). The mixture was stirred at 70 °C for 18 h before acetic acid (0.084 mL, 1.47 mmol, 1.00 equiv.) was added. The mixture was stirred at 70 °C for 21 h before being evaporated. The crude product was dissolved in methanol followed by addition of triethylamine (0.308 mL, 2.21 mmol, 1.50 equiv.), adsorbed on SiCL and dried in vacuo. Purification by FC (SiCL; (DCM / MeOH (25% aq. NH3)) gave the title compound (139 mg, 48% yield) as a yellow solid. MS (ESI): m / z = 188.1 [M+H]+.

[0653] Step c) : 3-(4-Chlorophenyl)-N-( 4, 5-dihydro-2H-pyrazolo[ 3, 4-f]phthalazin-3-yl)propanamide

[0654]

[0655] The title compound was prepared in analogy to Example 7, step c) starting from 4,5-dihydro-2H-pyrazolo[3,4-f]phthalazin-3 -amine and 3-(4-chlorophenyl)propanoic acid (CAS RN: 2019-34-3) as a white solid. MS (ESI): m / z = 368.3 [M+H]+.

[0656] Example 16

[0657] 3-(6-Chloro-3-pyridyl)-N-(4,5-dihydro-2H-pyrazolo[3,4-f]phthalazin-3-yl)propananude

[0658]

[0659] The title compound was prepared in analogy to Example 7, step c) starting from 4,5-dihydro-2H-pyrazolo[3,4-f]phthalazin-3 -amine and 3-(6-chloro-3-pyridyl)propanoic acid (CAS RN: 117528-23-1) as an off-white solid. MS (ESI): m / z = 355.2 [M+H]+.

[0660] Example 17

[0661] 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:

[0662] Per tablet Active ingredient 200 mg

[0663] Microcrystalline cellulose 155 mg

[0664] Com starch 25 mg

[0665] Talc 25 mg

[0666] Hydroxypropylmethylcellulose 20 mg

[0667] 425 mg

[0668] Example 18

[0669] 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:

[0670] Per capsule

[0671] Active ingredient 100.0 mg

[0672] Com starch 20.0 mg

[0673] Lactose 95.0 mg

[0674] Talc 4.5 mg

[0675] Magnesium stearate 0.5 mg

[0676] 220.0 mg

Claims

Claims1. A compound of formula (I)or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:A is selected from the group consisting of Ce-Cio-aryl, Cs-Cio-cycloalkyl, 5- to 14- membered heteroaryl comprising 1 to 4 heteroatoms independently selected from N, O, and S, and 3- to 14-membered heterocyclyl comprising 1 to 4 heteroatoms independently selected from N, O, and S;L is -(CH2)m- or -(CH2)n-X1-X2-(CH2)P-*; wherein the asterisk indicates the point of attachment of L to the pyrazole ring or to the 6-membered heteroaryl ring; m is 1, 2, or 3;n is 0, 1, or 2;p is 1 or 2;V is selected from the group consisting of CHR5, NR6, O, and S;W is CHR7or NR8; provided that when V is NR6, O or S, W is CHR7;X, Y, and Z are each independently selected from CH and N, provided that at most two of X, Y, and Z are N;(i) X1is selected from the group consisting of NRX1, SO2, and CRxlaRxlb; and X2is selected from the group consisting of NRX1, O, and CH2; or(ii) X1is C=O and X2is NRX2; or(iii) X1and X2, taken together, form an imine of formula -N=CRX2-; or(iv) X1is CHRX1Cand X2is CHRX2a;RX1is hydrogen or Ci-Ce-alkyl;Rxlais selected from the group consisting of hydroxy, halogen, Ci-Ce-alkyl, halo-Ci- Ce-alkyl, and 5- to 6-membered heteroaryloxy comprising 1 to 4 heteroatoms independently selected from N, O, and S; and Rxlbis hydrogen or halogen; or Rxlaand Rxlb, taken together with the carbon atom to which they are attached, form a Cs-Cio-cycloalkyl or a 3- to 6-membered heterocyclyl comprising 1 to 4 heteroatoms independently selected from N, O, and S;RX2is hydrogen or Ci-Ce-alkyl;Rxlcand RX2a, taken together with the carbon atoms to which they are attached, form a Cs-Cio-cycloalkyl;R1is selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce-alkyl, halo-Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkoxy, and Cs-Cio-cycloalkyl; R2and R3are each independently selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce-alkyl, halo-Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce- alkoxy, and Cs-Cio-cycloalkyl; and(i) R4, R5, R6, R7, and R8are each independently selected from the group consisting of hydrogen and Ci-Ce-alkyl; or(ii) R4and R5or R6, taken together with the atoms to which they are attached, form a 5- to 6 membered heterocycle; andR7and R8are selected from the group consisting of hydrogen and Ci-Ce-alkyl; or(iii) R4and R7or R8, taken together with the atoms to which they are attached, form a 5- to 6 membered heterocycle; andR5and R6are selected from the group consisting of hydrogen and Ci-Ce-alkyl; or(iv) R4is selected from the group consisting of hydrogen and Ci-Ce-alkyl; and R5or R6, and R7or R8, taken together with the atoms to which they are attached, form a 3- to 6-membered heterocycle.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:L is -(CH2)m- or -(CH2)n-X1-X2-(CH2)P-*; wherein the asterisk indicates the point of attachment of L to the pyrazole ring;m is 2 or 3;n is 0;P is 1;(i) X1is NRX1; and X2is CH2; or(ii) X1is C=O and X2is NRX2; or(iii) X1and X2, taken together, form an imine of formula -N=CRX2-;RX1is hydrogen; andRX2is hydrogen or Ci-Ce-alkyl.

3. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:L is -(CH2)m- or -(CH2)n-X1-X2-(CH2)P-*; wherein the asterisk indicates the point of attachment of L to the pyrazole ring;m is 2 or 3;n is 0;P is 1;(i) X1is NRX1; and X2is CH2; or(ii) X1is C=O and X2is NRX2; or(iii) X1and X2, taken together, form an imine of formula -N=CRX2-;RX1is hydrogen; andRX2is hydrogen or methyl.

4. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:L is -(CH2)m- or -(CH2)n-X1-X2-(CH2)P-*; wherein the asterisk indicates the point of attachment of L to the pyrazole ring;m is 2 or 3;n is 0;P is 1;X1isNRxl;X2is CH2; andRX1is hydrogen.

5. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein L is selected from the group consisting of -(CH2)2-, -(CH2)3-, and -NH(CH2)2-*; wherein the asterisk indicates the point of attachment of L to the pyrazole ring.

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) X, Y and Z are all CH; or(ii) X is N; and Y and Z are both CH; or(iii) Y is N; and X and Z are both CH.

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 X, Y and Z are all CH.

8. The compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:(i) V is CHR5;W is CHR7;R4is hydrogen;R5is hydrogen; andR7is hydrogen; or(ii) V is CHR5;W is NR8;R4and R8, taken together with the atoms to which they are attached, form a 5- to 6-membered heterocycle; andR5is hydrogen; or(iii) V is CHR5;W is CHR7;R4and R7, taken together with the atoms to which they are attached, form a 5- to 6-membered heterocycle; andR5is hydrogen.

9. The compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:(i) V is CHR5;W is CHR7;R4is hydrogen;R5is hydrogen; andR7is hydrogen; or(ii) V is CHR5;W is NR8;R4and R8, taken together with the atoms to which they are attached, form an imidazolinone; andR5is hydrogen; or(iii) V is CHR5;W is CHR7;R4and R7, taken together with the atoms to which they are attached, form a pyrrolidinone; andR5is hydrogen.

10. The compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:V is CHR5;W is CHR7;R4is hydrogen;R5is hydrogen; andR7is hydrogen.

11. The compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein R1is hydrogen.

12. The compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:A is Ce-Cio-aryl or 5- to 14-membered heteroaryl comprising 1 to 4 heteroatoms independently selected from N, O, and S;R2is halogen or cyano; andR3is hydrogen or halogen.

13. The compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:A is phenyl or pyridyl;R2is selected from the group consisting of fluoro, chloro, and cyano; and R3is hydrogen or fluoro.

14. The compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:A is Ce-Cio-aryl;R2is halogen; andR3is hydrogen or halogen.

15. The compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:A is phenyl;R2is fluoro or chloro; andR3is hydrogen or fluoro.

16. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:A is Ce-Cio-aryl or 5- to 14-membered heteroaryl comprising 1 to 4 heteroatoms independently selected from N, O, and S;L is -(CH2)m- or -(CH2)n-X1-X2-(CH2)P-*; wherein the asterisk indicates the point of attachment of L to the pyrazole ring;(i) X1is NRX1; and X2is CH2; or(ii) X1is C=O and X2is NRX2; or(iii) X1and X2, taken together, form an imine of formula -N=CRX2-;RX1is hydrogen;RX2is hydrogen or Ci-Ce-alkyl;m is 2 or 3;n is 0;P is 1;(i) V is CHR5;W is CHR7;R4is hydrogen;R5is hydrogen; andR7is hydrogen; or(ii) V is CHR5;W is NR8;R4and R8, taken together with the atoms to which they are attached, form a 5- to 6-membered heterocycle;R5is hydrogen; or(iii) V is CHR5;W is CHR7;R4and R7, taken together with the atoms to which they are attached, form a 5- to 6-membered heterocycle; andR5is hydrogen;(i) X, Y and Z are all CH; or(ii) X is N; and Y and Z are both CH; or(iii) Y is N; and X and Z are both CH;R1is hydrogen;R2is halogen or cyano; andR3is hydrogen or halogen.

17. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:A is phenyl or pyridyl;L is -(CH2)m- or -(CH2)n-X1-X2-(CH2)P-*; wherein the asterisk indicates the point of attachment of L to the pyrazole ring;(i) X1is NRX1; and X2is CH2; or(ii) X1is C=O and X2is NRX2; or(iii) X1and X2, taken together, form an imine of formula -N=CRX2-;RX1is hydrogen;RX2is hydrogen or methyl;m is 2 or 3;n is 0;P is 1;(i) V is CHR5;W is CHR7;R4is hydrogen;R5is hydrogen; andR7is hydrogen; or(ii) V is CHR5;W is NR8;R4and R8, taken together with the atoms to which they are attached, form imidazolinone; andR5is hydrogen; or(iii) V is CHR5;W is CHR7;R4and R7, taken together with the atoms to which they are attached, form a pyrrolidinone; andR5is hydrogen;(i) X, Y and Z are all CH; or(ii) X is N; and Y and Z are both CH; or(iii) Y is N; and X and Z are both CH;R1is hydrogen;R2is selected from the group consisting of fluoro, chloro, and cyano; andR3is hydrogen or fluoro.

18. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:A is Ce-Cio-aryl;L is -(CH2)m- or -(CH2)n-X1-X2-(CH2)P-*; wherein the asterisk indicates the point of attachment of L to the pyrazole ring;X1isNRxl;X2is CH2;RX1is hydrogen;m is 2 or 3;n is 0;P is 1;V is CHR5;W is CHR7;X, Y and Z are all CH;R1is hydrogen;R2is halogen;R3is hydrogen or halogen;R4is hydrogen;R5is hydrogen; andR7is hydrogen.

19. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:A is phenyl;L is -(CH2)m- or -(CH2)n-X1-X2-(CH2)P-*; wherein the asterisk indicates the point of attachment of L to the pyrazole ring;X1isNRxl;X2is CH2;RX1is hydrogen;m is 2 or 3;n is 0;P is 1;V is CHR5;W is CHR7;X, Y and Z are all CH;R1is hydrogen;R2is fluoro or chloro;R3is hydrogen or fluoro;R4is hydrogen;R5is hydrogen; andR7is hydrogen.

20. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, or a tautomer thereof, selected from:3-(4-Fluorophenyl)-N-(8-methyl-9-oxo-3,4,8,12-tetrazatricyclo[8.4.0.02,6]tetradeca- 1(10), 2, 5, 11, 13 -pentaen-5 -yl)propanamide;3-(4-Chl orophenyl)-N-(3, 4, 12-tri azatri cyclo[8.4.0.02, 6]tetradeca- 1(10), 2,5,11,13- pentaen-5-yl)propanamide;3-(4-Fluorophenyl)-N-(9-oxa-3,4,12-triazatricyclo[8.4.0.02,6]tetradeca- 1(10), 2, 5, 11, 13 -pentaen-5 -yl)propanamide;3-(4-Chlorophenyl)-N-(4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-3-yl)propanamide; 3-(6-Chloro-3-pyridyl)-N-(4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-3- yl)propanamide;3-(4-Chloro-3-fluoro-phenyl)-N-(4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-3- yl)propanamide;3-(4-Chlorophenyl)-N-(4,5-dihydro-2H-pyrazolo[4,3-c][l,7]naphthyri din-3- yl)propanamide;3-(4-Chlorophenyl)-N-(2H-pyrazolo[4,3-c][l,7]naphthyridin-3-yl)propanamide;3-(4-Cyanophenyl)-N-(3,4,9,12-tetrazatricyclo[8.4.0.02,6]tetradeca-l(10),2,5,ll,13- pentaen-5-yl)propanamide;3-(6-Chloro-3-pyridyl)-N-(3,4,9,12-tetrazatricyclo[8.4.0.02,6]tetradeca- 1(10), 2, 5, 11, 13 -pentaen-5 -yl)propanamide;3-(4-Chlorophenyl)-N-(3,4,9,12-tetrazatricyclo[8.4.0.02,6]tetradeca-l(10),2,5,l 1,13- pentaen-5-yl)propanamide;rac-(3RS)-3-[(4-Chlorophenyl)methyl]-l-(4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin- 3-yl)pyrrolidin-2-one;2,2,2-trifluoroacetate;l-[(4-Chlorophenyl)methyl]-3-(4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-3- yl)imidazolidin-2-one;2,2,2-trifluoroacetic acid;3-(4-Chlorophenyl)-N-(3,4,l l,12-tetrazatricyclo[8.4.0.02,6]tetradeca-l(10),2,5,l 1,13- pentaen-5-yl)propanamide;3-(4-Chlorophenyl)-N-(4,5-dihydro-2H-pyrazolo[3,4-f]phthalazin-3-yl)propanamide; and3-(6-Chloro-3-pyridyl)-N-(4,5-dihydro-2H-pyrazolo[3,4-f]phthalazin-3- yl)propanamide.

21. The compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, or a tautomer thereof, for use as a therapeutically active substance.

22. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, or a tautomer thereof, and a therapeutically inert carrier.

23. 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 20, or a pharmaceutically acceptable salt, or a tautomer thereof, or the pharmaceutical composition according to claim 22.

24. The method according to claim 23, wherein said condition associated with SARM1 is a condition affecting the nervous system, including the central nervous system and the peripheral nervous system.

25. The method according to claim 24, wherein said condition affecting the nervous system is neurodegenerative disorder.

26. The method according to claim 23, 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.

27. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, or a tautomer thereof, or a pharmaceutical composition according to claim 22, for use in a method according to any one of claims 23 to 26.

28. Use of a compound according to any one of claims 1 to 20, or of a pharmaceutically acceptable salt thereof, or of a tautomer thereof, or of a pharmaceutical composition according to claim 22, in a method according to any one of claims 23 to 26.

29. Use of a compound according to any one of claims 1 to 20, or of a pharmaceutically acceptable salt thereof, or of a tautomer thereof, in the preparation of a medicament for use in a method according to any one of claims 23 to 26.

30. The invention as described hereinbefore.

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